Androgens are bronchoactive drugs that act by relaxing airway smooth muscle and preventing bronchospasm.

PubMed

Montaño, Luis M; Espinoza, Julia; Flores-Soto, Edgar; Chávez, Jaime; Perusquía, Mercedes

2014-07-01

Changes in the androgen levels in asthmatic men may be associated with the severity of asthma. Androgens induce a nongenomic relaxation in airway smooth muscle, but the underlying mechanisms remain unclear. The aim of this study was to investigate the potential bronchorelaxing action of testosterone (TES) and its metabolites (5α- and 5β-dihydrotestosterone (DHT). A preventive effect on ovalbumin (OVA)-induced bronchospasm was observed in sensitized guinea pigs for each androgen. Androgens were studied in response to bronchoconstrictors: carbachol (CCh) and KCl in isolated trachea rings with and without epithelium from non-sensitized and sensitized animals as well as on OVA-induced contraction. Androgens concentration-dependently abolished the contraction in response to CCh, KCl, and OVA. There were significant differences in the sensitivity to the relaxation induced by each androgen. 5β-DHT was more potent for relaxing KCl-induced contraction, while TES and 5α-DHT were more potent for CCh- and OVA-induced contraction. No differences were found in preparations with and without epithelium or in the presence of a nitric oxide (NO) synthase inhibitor or an inhibitor of K(+) channels. These data indicate the absence of involvement of the epithelium-, NO- and K(+) channels-dependent pathway in androgen-induced relaxation. However, in dissociated tracheal myocytes loaded with the calcium-binding fluorescent dye Fura -2, physiological concentrations of androgens decreased the KCl-induced [Ca(2+)]i increment. 5β-DHT was the most potent at decreasing KCl-induced [Ca(2+)]i increment and preventing bronchospasm. We suggest that androgen-induced brochorelaxation was mediated via decreased Ca(2+) influx through L-type Ca(2+)channels but additional Ca(2+) entry blockade may be involved. Molecular changes in androgen structure may determine its preferential site of action. © 2014 Society for Endocrinology.

Regulation of expression of Na+,K+-ATPase in androgen-dependent and androgen-independent prostate cancer

PubMed Central

Blok, L J; Chang, G T G; Steenbeek-Slotboom, M; Weerden, W M van; Swarts, H G P; Pont, J J H H M De; Steenbrugge, G J van; Brinkmann, A O

1999-01-01

The β1-subunit of Na+,K+-ATPase was isolated and identified as an androgen down-regulated gene. Expression was observed at high levels in androgen-independent as compared to androgen-dependent (responsive) human prostate cancer cell lines and xenografts when grown in the presence of androgens. Down-regulation of the β1-subunit was initiated at concentrations between 0.01 nM and 0.03 nM of the synthetic androgen R1881 after relatively long incubation times (> 24 h). Using polyclonal antibodies, the concentration of β1-subunit protein, but not of the α1-subunit protein, was markedly reduced in androgen-dependent human prostate cancer cells (LNCaP-FGC) cultured in the presence of androgens. In line with these observations it was found that the protein expression of total Na+,K+-ATPase in the membrane (measured by 3H-ouabain binding) was also markedly decreased. The main function of Na+,K+-ATPase is to maintain sodium and potassium homeostasis in animal cells. The resulting electrochemical gradient is facilitative for transport of several compounds over the cell membrane (for example cisplatin, a chemotherapeutic agent experimentally used in the treatment of hormone-refractory prostate cancer). Here we observed that a ouabain-induced decrease of Na+,K+-ATPase activity in LNCaP-FGC cells results in reduced sensitivity of these cells to cisplatin-treatment. Surprisingly, androgen-induced decrease of Na+,K+-ATPase expression, did not result in significant protection against the chemotherapeutic agent. © 1999 Cancer Research Campaign PMID:10487609

Interrelation of androgen receptor and miR-30a and miR-30a function in ER-, PR-, AR+ MDA-MB-453 breast cancer cells.

PubMed

Lyu, Shuhua; Liu, Han; Liu, Xia; Liu, Shan; Wang, Yahong; Yu, Qi; Niu, Yun

2017-10-01

The association between androgen-induced androgen receptor (AR) activating signal and microRNA (miR)-30a was investigated, as well as the function of miR-30a in estrogen receptor-negative (ER - ), progesterone receptor-negative (PR - ), and AR-positive (AR + ) MDA-MB-453 breast cancer cells. Androgen-induced AR activating signal upregulated the expression of AR, and downregulated the expression of miR-30a, b and c. Bioinformatics analysis indicated a putative miR-30a, b and c binding site in the 3'-untranslated region of AR mRNA. It was confirmed that the AR gene is a direct target of miR-30a, whereas AR does not target the miR-30a promoter, and AR activating signal may indirectly downregulate miR-30a through other cell signaling pathways. In this positive feedback mechanism AR is then upregulated through miR-30a. Overexpression of miR-30a inhibited cell proliferation, whereas inhibition of miR-30a expression by specific antisense oligonucleotides, increased cell growth. Previously, androgen-induced AR activating signal was demonstrated to inhibit cell proliferation in ER - , PR - and AR + MDA-MB-453 breast cancer cells, but AR activating signal downregulated the expression of miR-30a, relieving the inhibition of MDA-MB-453 cell growth. Therefore, in MDA-MB-453 breast cancer cells, miR-30a has two different functions regarding cell growth: Inhibition of cell proliferation through a positive feedback signaling pathway; and the relative promotion of cell proliferation through downregulation of miR-30a. Thus, the association between AR activating signal and microRNAs is complex, and microRNAs may possess different functions due to different signaling pathways. Although the results of the present study were obtained in one cell line, they contribute to subsequent studies on ER - , PR - and AR + breast cancer.

Small molecule screening reveals a transcription-independent pro-survival function of androgen receptor in castration-resistant prostate cancer

PubMed Central

Narizhneva, Natalia V.; Tararova, Natalia D.; Ryabokon, Petro; Shyshynova, Inna; Prokvolit, Anatoly; Komarov, Pavel G.; Purmal, Andrei A.; Gudkov, Andrei V.; Gurova, Katerina V.

2010-01-01

In prostate cancer (PCa) patients, initial responsiveness to androgen deprivation therapy is frequently followed by relapse due to development of treatment-resistant androgen-independent PCa. This is typically associated with acquisition of mutations in AR that allow activity as a transcription factor in the absence of ligand, indicating that androgen-independent PCa remains dependent on AR function. Our strategy to effectively target AR in androgen-independent PCa involved using a cell-based readout to isolate small molecules that inhibit AR transactivation function through mechanisms other than modulation of ligand binding. A number of the identified inhibitors were toxic to AR-expressing PCa cells regardless of their androgen dependence. Among these, some only suppressed PCa cell growth (ARTIS), while others induced cell death (ARTIK). ARTIK, but not ARTIS, compounds caused disappearance of AR protein from treated cells. siRNA against AR behaved like ARTIK compounds, while a dominant negative AR mutant that prevents AR-mediated transactivation but does not eliminate the protein showed only a growth suppressive effect. These observations reveal a transcription-independent function of AR that is essential for PCa cell viability and, therefore, is an ideal target for anti-PCa treatment. Indeed, several of the identified AR inhibitors demonstrated in vivo efficacy in mouse models of PCa and are candidates for pharmacologic optimization. PMID:19946220

Methoxychlor affects multiple hormone signaling pathways in the largemouth bass (Micropterus salmoides) liver

PubMed Central

Martyniuk, Christopher J.; Spade, Daniel J.; Blum, Jason L.; Kroll, Kevin J.; Denslow, Nancy D.

2011-01-01

Methoxychlor (MXC) is an organochlorine pesticide that has been shown to have estrogenic activity by activating estrogen receptors and inducing vitellogenin production in male fish. Previous studies report that exposure to MXC induces changes in mRNA abundance of reproductive genes in the liver and testes of largemouth bass (Micropterus salmoides). The objective of the present study was to better characterize the mode of action of MXC by measuring the global transcriptomic response in the male largemouth liver using an oligonucleotide microarray. Microarray analysis identified highly significant changes in the expression of 37 transcripts (p<0.001) (20 induced and 17 decreased) in the liver after MXC injection and a total of 900 expression changes (p<0.05) in transcripts with high homology to known genes. Largemouth bass estrogen receptor alpha (esr1) and androgen receptor (ar) were among the transcripts that were increased in the liver after MXC treatment. Functional enrichment analysis identified the molecular functions of steroid binding and androgen receptor activity as well as steroid hormone receptor activity as being significantly over-represented gene ontology terms. Pathway analysis identified c-fos signaling as being putatively affected through both estrogen and androgen signaling. This study provides evidence that MXC elicits transcriptional effects through the estrogen receptor as well as androgen receptor-mediated pathways in the liver. PMID:21276474

Food availability affects the maternal transfer of androgens and antibodies into eggs of a colonial seabird

USGS Publications Warehouse

Gasparini, J.; Boulinier, T.; Gill, V.A.; Gil, D.; Hatch, Shyla A.; Roulin, A.

2007-01-01

Mothers can improve the quality of their offspring by increasing the level of certain components in their eggs. To examine whether or not mothers increase deposition of such components in eggs as a function of food availability, we food-supplemented black-legged kittiwake females (Rissa tridactyla) before and during egg laying and compared deposition of androgens and antibodies into eggs of first and experimentally induced replacement clutches. Food-supplemented females transferred lower amounts of androgens and antibodies into eggs of induced replacement clutches than did non-food-supplemented mothers, whereas first clutches presented no differences between treatments. Our results suggest that when females are in lower condition, they transfer more androgens and antibodies into eggs to facilitate chick development despite potential long-term costs for juveniles. Females in prime condition may avoid these potential long-term costs because they can provide their chicks with more and higher quality resources. ?? 2007 The Authors.

SMILE upregulated by metformin inhibits the function of androgen receptor in prostate cancer cells.

PubMed

Lee, Seung-Yon; Song, Chin-Hee; Xie, Yuan-Bin; Jung, Chaeyong; Choi, Hueng-Sik; Lee, Keesook

2014-11-28

Metformin, a diabetes drug, has been reported to inhibit the growth of prostate cancer cells. In this study, we investigated the effect and action mechanism of metformin on the function of androgen receptor (AR), a key molecule in the proliferation of prostate cancer cells. Metformin was found to reduce androgen-dependent cell growth and the expression of AR target genes by inhibiting AR function in prostate cancer cells such as LNCaP and C4-2 cells. Interestingly, metformin upregulated the protein level of small heterodimer partner-interacting leucine zipper (SMILE), a coregulator of nuclear receptors, and knockdown of SMILE expression with shRNA abolished the inhibitory effect of metformin on AR function. Further studies revealed that SMILE protein itself suppressed the transactivation of AR, and its ectopic expression resulted in the repressed expression of endogenous AR target genes, PSA and NKX3.1, in LNCaP cells. In addition, SMILE protein physically interacted with AR and competed with the AR coactivator SRC-1 to modulate AR transactivation. As expected, SMILE repressed androgen-dependent growth of LNCaP and C4-2 cells. Taken together, these results suggest that SMILE, which is induced by metformin, functions as a novel AR corepressor and may mediate the inhibitory effect of metformin on androgen-dependent growth of prostate cancer cells. Copyright © 2014. Published by Elsevier Ireland Ltd.

Androgens and bone.

PubMed

De Oliveira, D H A; Fighera, T M; Bianchet, L C; Kulak, C A M; Kulak, J

2012-12-01

Testosterone is the major gonadal sex steroid produced by the testes in men. Androgens induce male sexual differentiation before birth and sexual maturation during puberty; in adult men, they maintain the function of the male genital system, including spermatogenesis. Testosterone is also produced in smaller amounts by the ovaries in women. The adrenal glands produce the weaker androgens dehydroepiandrosterone, dehydroepiandrosterone sulfate, and androstenedione. Because testosterone can be metabolized to estradiol by the aromatase enzyme, there has been controversy as to which gonadal sex steroid has the greater skeletal effect. In this respect, there is increasing evidence that at least part of the effects of androgens in men can be explained by their aromatization into estrogens. The current evidence suggests that estradiol plays a greater role in maintenance of skeletal health than testosterone, but that androgens also have direct beneficial effects on bone.

Regulation of protein kinase C-related kinase (PRK) signalling by the TPα and TPβ isoforms of the human thromboxane A2 receptor: Implications for thromboxane- and androgen- dependent neoplastic and epigenetic responses in prostate cancer.

PubMed

O'Sullivan, Aine G; Mulvaney, Eamon P; Kinsella, B Therese

2017-04-01

The prostanoid thromboxane (TX) A 2 and its T Prostanoid receptor (the TP) are increasingly implicated in prostate cancer (PCa). Mechanistically, we recently discovered that both TPα and TPβ form functional signalling complexes with members of the protein kinase C-related kinase (PRK) family, AGC- kinases essential for the epigenetic regulation of androgen receptor (AR)-dependent transcription and promising therapeutic targets for treatment of castrate-resistant prostate cancer (CRPC). Critically, similar to androgens, activation of the PRKs through the TXA 2 /TP signalling axis induces phosphorylation of histone H3 at Thr11 (H3Thr11), a marker of androgen-induced chromatin remodelling and transcriptional activation, raising the possibility that TXA 2 -TP signalling can mimic and/or enhance AR-induced cellular changes even in the absence of circulating androgens such as in CRPC. Hence the aim of the current study was to investigate whether TXA 2 /TP-induced PRK activation can mimic and/or enhance AR-mediated cellular responses in the model androgen-responsive prostate adenocarcinoma LNCaP cell line. We reveal that TXA 2 /TP signalling can act as a neoplastic- and epigenetic-regulator, promoting and enhancing both AR-associated chromatin remodelling (H3Thr11 phosphorylation, WDR5 recruitment and acetylation of histone H4 at lysine 16) and AR-mediated transcriptional activation (e.g of the KLK3/prostate-specific antigen and TMPRSS2 genes) through mechanisms involving TPα/TPβ mediated-PRK1 and PRK2, but not PRK3, signalling complexes. Overall, these data demonstrate that TPα/TPβ can act as neoplastic and epigenetic regulators by mimicking and/or enhancing the actions of androgens within the prostate and provides further mechanistic insights into the role of the TXA 2 /TP signalling axis in PCa, including potentially in CRPC. Copyright © 2017 Elsevier B.V. All rights reserved.

The androgen receptor controls expression of the cancer-associated sTn antigen and cell adhesion through induction of ST6GalNAc1 in prostate cancer

PubMed Central

Munkley, Jennifer; Oltean, Sebastian; Vodák, Daniel; Wilson, Brian T.; Livermore, Karen E.; Zhou, Yan; Star, Eleanor; Floros, Vasileios I.; Johannessen, Bjarne; Knight, Bridget; McCullagh, Paul; McGrath, John; Crundwell, Malcolm; Skotheim, Rolf I.; Robson, Craig N.; Leung, Hing Y.; Harries, Lorna W.; Rajan, Prabhakar; Mills, Ian G.; Elliott, David J.

2015-01-01

Patterns of glycosylation are important in cancer, but the molecular mechanisms that drive changes are often poorly understood. The androgen receptor drives prostate cancer (PCa) development and progression to lethal metastatic castration-resistant disease. Here we used RNA-Seq coupled with bioinformatic analyses of androgen-receptor (AR) binding sites and clinical PCa expression array data to identify ST6GalNAc1 as a direct and rapidly activated target gene of the AR in PCa cells. ST6GalNAc1 encodes a sialytransferase that catalyses formation of the cancer-associated sialyl-Tn antigen (sTn), which we find is also induced by androgen exposure. Androgens induce expression of a novel splice variant of the ST6GalNAc1 protein in PCa cells. This splice variant encodes a shorter protein isoform that is still fully functional as a sialyltransferase and able to induce expression of the sTn-antigen. Surprisingly, given its high expression in tumours, stable expression of ST6GalNAc1 in PCa cells reduced formation of stable tumours in mice, reduced cell adhesion and induced a switch towards a more mesenchymal-like cell phenotype in vitro. ST6GalNAc1 has a dynamic expression pattern in clinical datasets, being significantly up-regulated in primary prostate carcinoma but relatively down-regulated in established metastatic tissue. ST6GalNAc1 is frequently upregulated concurrently with another important glycosylation enzyme GCNT1 previously associated with prostate cancer progression and implicated in Sialyl Lewis X antigen synthesis. Together our data establishes an androgen-dependent mechanism for sTn antigen expression in PCa, and are consistent with a general role for the androgen receptor in driving important coordinate changes to the glycoproteome during PCa progression. PMID:26452038

Green tea polyphenol EGCG blunts androgen receptor function in prostate cancer

PubMed Central

Siddiqui, Imtiaz A.; Asim, Mohammad; Hafeez, Bilal B.; Adhami, Vaqar M.; Tarapore, Rohinton S.; Mukhtar, Hasan

2011-01-01

Androgen deprivation therapy is the major treatment for advanced prostate cancer (PCa). However, it is a temporary remission, and the patients almost inevitably develop hormone refractory prostate cancer (HRPC). HRPC is almost incurable, although most HRPC cells still express androgen receptor (AR) and depend on the AR for growth, making AR a prime drug target. Here, we provide evidence that epigallocatechin-3-gallate (EGCG), the major polyphenol in green tea, is a direct antagonist of androgen action. In silico modeling and FRET-based competition assay showed that EGCG physically interacts with the ligand-binding domain of AR by replacing a high-affinity labeled ligand (IC50 0.4 μM). The functional consequence of this interaction was a decrease in AR-mediated transcriptional activation, which was due to EGCG mediated inhibition of interdomain N-C termini interaction of AR. Treatment with EGCG also repressed the transcriptional activation by a hotspot mutant AR (T877A) expressed ectopically as well as the endogenous AR mutant. As the physiological consequence of AR antagonism, EGCG repressed R1881-induced PCa cell growth. In a xenograft model, EGCG was found to inhibit AR nuclear translocation and protein expression. We also observed a significant down-regulation of androgen-regulated miRNA-21 and up-regulation of a tumor suppressor, miRNA-330, in tumors of mice treated with EGCG. Taken together, we provide evidence that EGCG functionally antagonizes androgen action at multiple levels, resulting in inhibition of PCa growth.—Siddiqui, I. A., Asim, M., Hafeez, B. B., Adhami, V. M., Tarapore, R. S., Mukhtar, H. Green tea polyphenol EGCG blunts androgen receptor function in prostate cancer. PMID:21177307

Androgens and the male reproductive tract: an overview of classical roles and current perspectives.

PubMed

Patrão, Marilia T C C; Silva, Erick J R; Avellar, Maria Christina W

2009-11-01

Androgens are steroid hormones that play key roles in the development and maintenance of male phenotype and reproductive function. These hormones also affect the function of several non-reproductive organs, such as bone and skeletal muscle. Endogenous androgens exert most of their effects by genomic mechanisms, which involve hormone binding to the androgen receptor (AR), a ligand-activated transcription factor, resulting in the modulation of gene expression. AR-induced non-genomic mechanisms have also been reported. A large number of steroidal and non-steroidal AR-ligands have been developed for therapeutic use, including the treatment of male hypogonadism (AR agonists) and prostate diseases (AR antagonists), among other pathological conditions. Here, the AR gene and protein structure, mechanism of action and AR gene homologous regulation were reviewed. The AR expression pattern, its in vivo regulation and physiological relevance in the developing and adult testis and epididymis, which are sites of sperm production and maturation, respectively, were also presented.

Androgen receptor requires JunD as a coactivator to switch on an oxidative stress generation pathway in prostate cancer cells.

PubMed

Mehraein-Ghomi, Farideh; Basu, Hirak S; Church, Dawn R; Hoffmann, F Michael; Wilding, George

2010-06-01

Relatively high oxidative stress levels in the prostate are postulated to be a major factor for prostate carcinogenesis and prostate cancer (CaP) progression. We focused on elucidating metabolic pathways of oxidative stress generation in CaP cells. Previously, we showed that the transcription factor JunD is essential for androgen-induced reactive oxygen species (ROS) production in androgen-dependent human CaP cells. We also recently showed that androgen induces the first and regulatory enzyme spermidine/spermine N1-acetyltransferase (SSAT) in a polyamine catabolic pathway that produces copious amounts of metabolic ROS. Here, we present coimmunoprecipitation and Gaussia luciferase reconstitution assay data that show that JunD forms a complex with androgen-activated androgen receptor (AR) in situ. Our chromatin immunoprecipitation assay data show that JunD binds directly to a specific SSAT promoter sequence only in androgen-treated LNCaP cells. Using a vector containing a luciferase reporter gene connected to the SSAT promoter and a JunD-silenced LNCaP cell line, we show that JunD is essential for androgen-induced SSAT gene expression. The elucidation of JunD-AR complex inducing SSAT expression leading to polyamine oxidation establishes the mechanistic basis of androgen-induced ROS production in CaP cells and opens up a new prostate-specific target for CaP chemopreventive/chemotherapeutic drug development. Copyright 2010 AACR.

Seminal Plasma Proteins as Androgen Receptor Coregulators Promote Prostate Cancer Growth

DTIC Science & Technology

2014-10-01

structural proteins in human semen containing a high concentration of Zn2+, and their physiological functions have been well characterized...Specifically, semenogelins, upon binding to Zn2+, play an important role in gel-like formation of the semen [1]. After ejaculation, these proteins are degraded...determined whether SgI regulated the expression of PSA, an androgen- inducible AR target and also known to proteolyze SgI in semen [1,2], in prostate

Abhydrolase domain containing 2, an androgen target gene, promotes prostate cancer cell proliferation and migration.

PubMed

Obinata, Daisuke; Takada, Shogo; Takayama, Ken-ichi; Urano, Tomohiko; Ito, Akiko; Ashikari, Daisaku; Fujiwara, Kyoko; Yamada, Yuta; Murata, Taro; Kumagai, Jinpei; Fujimura, Tetsuya; Ikeda, Kazuhiro; Horie-Inoue, Kuniko; Homma, Yukio; Takahashi, Satoru; Inoue, Satoshi

2016-04-01

The androgen receptor (AR) plays a key role in the development of prostate cancer. AR signalling mediates the expression of androgen-responsive genes, which are involved in prostate cancer development and progression. Our previous chromatin immunoprecipitation study showed that the region of abhydrolase domain containing 2 (ABHD2) includes a functional androgen receptor binding site. In this study, we demonstrated that ABHD2 is a novel androgen-responsive gene that is overexpressed in human prostate cancer tissues. The expression levels of ABHD2 in androgen-sensitive cells were evaluated by quantitative reverse transcription polymerase chain reaction and western-blot analyses. LNCaP and VCaP cells with ABHD2 overexpression or short interfering RNA (siRNA) knockdown were used for functional analyses. ABHD2 expression was examined in clinical samples of prostate cancer by immunohistochemistry. We showed that ABHD2 expression is increased by androgen in LNCaP and VCaP cells. This androgen-induced ABHD2 expression was diminished by bicalutamide. While stable expression of ABHD2 affected the enhancement of LNCaP cell proliferation and migration, siRNA-mediated ABHD2 knockdown suppressed cell proliferation and migration. In addition, the siRNA treatment significantly repressed the tumour growth derived from LNCaP cells in athymic mice. Immunohistochemical analysis of ABHD2 expression in tumour specimens showed a positive correlation of ABHD2 immunoreactivity with high Gleason score and pathological N stage. Moreover, patients with high immunoreactivity of ABHD2 showed low cancer-specific survival rates and a resistance to docetaxel-based chemotherapy. ABHD2 is a novel androgen-regulated gene that can promote prostate cancer growth and resistance to chemotherapy, and is a novel target for diagnosis and treatment of prostate cancer. Copyright © 2016 Elsevier Ltd. All rights reserved.

Androgens and Hypertension in Men and Women: a Unifying View.

PubMed

Moretti, Costanzo; Lanzolla, Giulia; Moretti, Marta; Gnessi, Lucio; Carmina, Enrico

2017-05-01

This review was designed to revaluate the androgen role on the mechanisms of hypertension and cardiovascular risks in both men and women. Sex steroids are involved in the regulation of blood pressure, but pathophysiological mechanism is not well understood. Androgens have an important effect on metabolism, adipose and endothelial cell function, and cardiovascular risk in both men and women. A focal point in this contest is represented by the possible gender-specific regulation of different tissues and in particular of the adipose cell. Available data confirm that androgen deficiency is linked to increased prevalence of hypertension and cardiovascular diseases. Adipocyte dysfunction seems to be the main involved mechanism. Androgen replacement reduces inflammation state in man, protecting by metabolic syndrome progression. In women, androgen excess has been considered as promoting factor of cardiovascular risk. However, recent data suggest that excessive androgen production has little effect per se in inducing hypertension in young women of reproductive age. Also in postmenopausal women, data on relative androgen excess and hypertension are missing, while adrenal androgen deficiency has been associated to increased mortality. Molecular mechanisms linking androgen dysregulation to hypertension are almost Unknown, but they seem to be related to increased visceral fat, promoting a chronic inflammatory state through different mechanisms. One of these may involve the recruitment and over-activation of NF-kB, a ubiquitous transcription factor also expressed in adipose cells, where it may cause the production of cytokines and other immune factors. The NF-kB signalling pathway may also influence brown adipogenesis leading to the preferential enlargement of visceral adipocytes. Chronic inflammation and adipocyte dysfunction may alter endothelial function leading to hypertension. Both in men and in women, particularly in the post-menopausal period, hypoandrogenism seems to be a major determinant of the increased prevalence of hypertension. The relationship between androgen signalling and NF-kB might explain the pathophysiological mechanism leading to the development of endothelium dysfunction and hypertension.

Androgen-androgen receptor system improves chronic inflammatory conditions by suppressing monocyte chemoattractant protein-1 gene expression in adipocytes via transcriptional regulation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Morooka, Nobukatsu, E-mail: amorooka@gunma-u.ac.jp; Ueguri, Kei; Yee, Karen Kar Lye

Age-related decreases in sex hormones are closely related to chronic inflammation in obesity and metabolic diseases. Particularly, the molecular basis of androgen activity in regulating inflammation and controlling metabolism remains largely unknown. Obese adipocytes secrete monocyte chemoattractant protein-1 (MCP-1), a key chemokine that promotes the infiltration of monocytes/macrophages into adipose tissue, thereby leading to metabolic disorders. Here, we studied the role of androgen-androgen receptor (AR) action in regulating MCP-1 expression in adipose tissue. We observed the induction of Mcp-1 expression in 3T3-L1 adipocytes co-cultured with RAW264.7 macrophages. Additionally, Mcp-1 expression was upregulated by culturing in conditioned medium derived from inflammatorymore » macrophages (M1-Mφ) containing tumor necrosis factor-alpha (TNF-α). We found that sex hormones downregulated TNF-α-induced Mcp-1 and interleukin (Il)-6 expression in 3T3-L1 adipocytes. Furthermore, luciferase-reporter analysis indicated that MCP-1 promoter activity was predominantly suppressed by dihydrotestosterone (DHT)-AR interactions through functional canonical nuclear factor-kappa B (NF-κB) sites, whereas non-canonical NF-κB site containing important flanking sequences exhibited minor contributions to DHT-AR transcriptional repression. These findings suggested that androgen-AR suppressed obesity-induced chronic inflammation in adipose tissue. - Highlights: • DHT, non-aromatizable androgen suppresses Mcp-1 expression in adipocytes. • Mcp-1 transcription was negatively regulated by DHT-AR action. • DHT-AR selectively regulates Mcp-1 transcription through distinct NF-κB sites.« less

The physiological and pharmacological basis for the ergogenic effects of androgens in elite sports.

PubMed

Choong, Karen; Lakshman, Kishore M; Bhasin, Shalender

2008-05-01

Androgen doping in power sports is undeniably rampant worldwide. There is strong evidence that androgen administration in men increases skeletal muscle mass, maximal voluntary strength and muscle power. However, we do not have good experimental evidence to support the presumption that androgen administration improves physical function or athletic performance. Androgens do not increase specific force or whole body endurance measures. The anabolic effects of testosterone on the skeletal muscle are mediated through androgen receptor signaling. Testosterone promotes myogenic differentiation of multipotent mesenchymal stem cells and inhibits their differentiation into the adipogenic lineage. Testosterone binding to androgen receptor induces a conformational change in androgen receptor protein, causing it to associate with beta-catenin and TCF-4 and activate downstream Wnt target genes thus promoting myogenic differentiation. The adverse effects of androgens among athletes and recreational bodybuilders are under reported and include acne, deleterious changes in the cardiovascular risk factors, including a marked decrease in plasma high-density lipoproteins (HDL) cholesterol level, suppression of spermatogenesis resulting in infertility, increase in liver enzymes, hepatic neoplasms, mood and behavioral disturbances, and long term suppression of the endogenous hypothalamic-pituitary-gonadal axis. Androgens are often used in combination with other drugs which may have serious adverse events of their own. In spite of effective methods for detecting androgen doping, the policies for screening of athletes are highly variable in different countries and organizations and even existing policies are not uniformly enforced. 2008, Asian Journal of Andrology, SIMM and SJTU. All rights reserved.

Compounds from Cynomorium songaricum with Estrogenic and Androgenic Activities Suppress the Oestrogen/Androgen-Induced BPH Process.

PubMed

Wang, Xueni; Tao, Rui; Yang, Jing; Miao, Lin; Wang, Yu; Munyangaju, Jose Edouard; Wichai, Nuttapong; Wang, Hong; Zhu, Yan; Liu, Erwei; Chang, Yanxu; Gao, Xiumei

2017-01-01

To investigate the phytoestrogenic and phytoandrogenic activities of compounds isolated from CS and uncover the role of CS in prevention of oestrogen/androgen-induced BPH. Cells were treated with CS compounds, and immunofluorescence assay was performed to detect the nuclear translocation of ER α or AR in MCF-7 or LNCaP cells; luciferase reporter assay was performed to detect ERs or AR transcriptional activity in HeLa or AD293 cells; MTT assay was performed to detect the cell proliferation of MCF-7 or LNCaP cells. Oestrogen/androgen-induced BPH model was established in rat and the anti-BPH, anti-estrogenic, and anti-androgenic activities of CS in vivo were further investigated. The nuclear translocation of ER α was stimulated by nine CS compounds, three of which also stimulated AR translocation. The transcriptional activities of ER α and ER β were induced by five compounds, within which only ECG induced AR transcriptional activity as well. Besides, ECG stimulated the proliferation of both MCF-7 cells and LNCaP cells. CS extract suppressed oestrogen/androgen-induced BPH progress in vivo by downregulation of E2 and T level in serum and alteration of the expressions of ER α , ER β , and AR in the prostate. Our data demonstrates that compounds from CS exhibit phytoestrogenic and phytoandrogenic activities, which may contribute to inhibiting the oestrogen/androgen-induced BPH development.

Evolution of the androgen-induced male phenotype.

PubMed

Fuxjager, Matthew J; Miles, Meredith C; Schlinger, Barney A

2018-01-01

The masculine reproductive phenotype varies significantly across vertebrates. As a result, biologists have long recognized that many of the mechanisms that support these phenotypes-particularly the androgenic system-is evolutionarily labile, and thus susceptible to the effects of selection for different traits. However, exactly how androgenic signaling systems vary in a way which results in dramatically different functional outputs, remain largely unclear. We explore this topic here by outlining four key-but non-mutually exclusive-hypotheses that propose how the mechanisms of androgenic signaling might change over time to potentiate the emergence of phenotypical variation in masculine behavior and physiology. We anchor this framework in a review of our own studies of a tropical bird called the golden-collared manakin (Manacus vitellinus), which has evolved an exaggerated acrobatic courtship display that is heavily androgen-dependent. The result is an example of how the cellular basis of androgenic action can be modified to support a unique reproductive repertoire. We end this review by highlighting a broad pathway forward to further pursue the intricate ways by which the mechanisms of hormone action evolve to support processes of adaptation and animal design.

An Interdomain Interaction of the Androgen Receptor Is Required for Its Aggregation and Toxicity in Spinal and Bulbar Muscular Atrophy*

PubMed Central

Orr, Christopher R.; Montie, Heather L.; Liu, Yuhong; Bolzoni, Elena; Jenkins, Shannon C.; Wilson, Elizabeth M.; Joseph, James D.; McDonnell, Donald P.; Merry, Diane E.

2010-01-01

Polyglutamine expansion within the androgen receptor (AR) causes spinal and bulbar muscular atrophy (SBMA) and is associated with misfolded and aggregated species of the mutant AR. We showed previously that nuclear localization of the mutant AR was necessary but not sufficient for SBMA. Here we show that an interdomain interaction of the AR that is central to its function within the nucleus is required for AR aggregation and toxicity. Ligands that prevent the interaction between the amino-terminal FXXLF motif and carboxyl-terminal AF-2 domain (N/C interaction) prevented toxicity and AR aggregation in an SBMA cell model and rescued primary SBMA motor neurons from 5α-dihydrotestosterone-induced toxicity. Moreover, genetic mutation of the FXXLF motif prevented AR aggregation and 5α-dihydrotestosterone toxicity. Finally, selective androgen receptor modulators, which prevent the N/C interaction, ameliorated AR aggregation and toxicity while maintaining AR function, highlighting a novel therapeutic strategy to prevent the SBMA phenotype while retaining AR transcriptional function. PMID:20826791

Single amino acid substitutions at 2 of 14 positions in an ultra-conserved region of the androgen receptor yield an androgen-binding domain that is reversibly thermolabile

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vasiliou, M.; Lumbroso, R.; Alvarado, C.

1994-09-01

The stereochemistry of the androgen receptor (AR) that is responsible for androgen-specific binding and for its contribution to the transregulatory attributes of an androgen-receptor complex are unknown. Our objective is to define structure-function relations of the human AR by correlating germline missense mutations at its X-linked locus with its resultant misbehavior. Subjects with Arg773Cys have complete androgen insensitivity. We and several other laboratories have reported that their genital skin fibroblasts (GSF) have negligible androgen-binding activity at 37{degrees}. We have found that Phe763Leu also causes CAI, but with approximately 10 fmol/mg protein androgen-binding activity at 37{degrees} (R-deficient). Within COS-1 cells transfectedmore » with each mutant AR cDNA, Phe763Leu and Arg773Cys androgen-binding activities are reversibly thermolabile, by a factor of 2, at 37{degrees} versus 22{degrees}, only in the presence of androgen; in the absence of androgen they are thermostable at 37{degrees}. We have discovered that (for a reason yet unknown) the GSF from a third family with Arg773Cys (and no other coding sequence mutation) have 20-40 mol/mg protein of androgen-binding activity at 37{degrees} when measured with 3-6 nFM androgen. This activity reversibly doubles at 22{degrees}. The reversible thermolability of an AR with Arg773Cys (and probably with Phe763Leu) is demonstrable within GSF. Ligand-dependence of this thermolability implies that ligand induces these mutant AR to undergo a deviant conformational change in, or near, a 14-aa region that shares 90% identity/similarity with its closest receptor relatives.« less

Methyltestosterone-induced transient hyperthyroidism in a hypothyroid patient.

PubMed

Krysiak, R; Okopien, B

2013-01-01

In this paper we report different effects of methyltestosterone administration on thyroid function in two twin brothers, one of whom suffered from hypothyroidism, while the other was apparently healthy. Methyltestosterone, which is a non-aromatisable androgen, resulted in a marked reduction of thyroxine-binding globulin (TBG), irrespectively of the patient's hormonal status, while the impact on free thyroid hormones depended on baseline thyroid function. Our research shows that a possibility of the use of non-aromatisable androgens or other drugs affecting TBG levels should be taken into consideration in all hypothyroid patients receiving levothyroxine, in whom thyroid hormone status suddenly changes without any apparent reason.

Androgen-Induced Cell Migration: Role of Androgen Receptor/Filamin A Association

PubMed Central

Castoria, Gabriella; D'Amato, Loredana; Ciociola, Alessandra; Giovannelli, Pia; Giraldi, Tiziana; Sepe, Leandra; Paolella, Giovanni; Barone, Maria Vittoria; Migliaccio, Antimo; Auricchio, Ferdinando

2011-01-01

Background Androgen receptor (AR) controls male morphogenesis, gametogenesis and prostate growth as well as development of prostate cancer. These findings support a role for AR in cell migration and invasiveness. However, the molecular mechanism involved in AR-mediated cell migration still remains elusive. Methodology/Principal Findings Mouse embryo NIH3T3 fibroblasts and highly metastatic human fibrosarcoma HT1080 cells harbor low levels of transcriptionally incompetent AR. We now report that, through extra nuclear action, AR triggers migration of both cell types upon stimulation with physiological concentrations of the androgen R1881. We analyzed the initial events leading to androgen-induced cell migration and observed that challenging NIH3T3 cells with 10 nM R1881 rapidly induces interaction of AR with filamin A (FlnA) at cytoskeleton. AR/FlnA complex recruits integrin beta 1, thus activating its dependent cascade. Silencing of AR, FlnA and integrin beta 1 shows that this ternary complex controls focal adhesion kinase (FAK), paxillin and Rac, thereby driving cell migration. FAK-null fibroblasts migrate poorly and Rac inhibition by EHT impairs motility of androgen-treated NIH3T3 cells. Interestingly, FAK and Rac activation by androgens are independent of each other. Findings in human fibrosarcoma HT1080 cells strengthen the role of Rac in androgen signaling. The Rac inhibitor significantly impairs androgen-induced migration in these cells. A mutant AR, deleted of the sequence interacting with FlnA, fails to mediate FAK activation and paxillin tyrosine phosphorylation in androgen-stimulated cells, further reinforcing the role of AR/FlnA interaction in androgen-mediated motility. Conclusions/Significance The present report, for the first time, indicates that the extra nuclear AR/FlnA/integrin beta 1 complex is the key by which androgen activates signaling leading to cell migration. Assembly of this ternary complex may control organ development and prostate cancer metastasis. PMID:21359179

The neural androgen receptor: a therapeutic target for myelin repair in chronic demyelination

PubMed Central

Hussain, Rashad; Ghoumari, Abdel M.; Bielecki, Bartosz; Steibel, Jérôme; Boehm, Nelly; Liere, Philippe; Macklin, Wendy B.; Kumar, Narender; Habert, René; Mhaouty-Kodja, Sakina; Tronche, François; Sitruk-Ware, Regine

2013-01-01

Myelin regeneration is a major therapeutic goal in demyelinating diseases, and the failure to remyelinate rapidly has profound consequences for the health of axons and for brain function. However, there is no efficient treatment for stimulating myelin repair, and current therapies are limited to anti-inflammatory agents. Males are less likely to develop multiple sclerosis than females, but often have a more severe disease course and reach disability milestones at an earlier age than females, and these observations have spurred interest in the potential protective effects of androgens. Here, we demonstrate that testosterone treatment efficiently stimulates the formation of new myelin and reverses myelin damage in chronic demyelinated brain lesions, resulting from the long-term administration of cuprizone, which is toxic for oligodendrocytes. In addition to the strong effect of testosterone on myelin repair, the number of activated astrocytes and microglial cells returned to low control levels, indicating a reduction of neuroinflammatory responses. We also identify the neural androgen receptor as a novel therapeutic target for myelin recovery. After the acute demyelination of cerebellar slices in organotypic culture, the remyelinating actions of testosterone could be mimicked by 5α-dihydrotestosterone, a metabolite that is not converted to oestrogens, and blocked by the androgen receptor antagonist flutamide. Testosterone treatment also failed to promote remyelination after chronic cuprizone-induced demyelination in mice with a non-functional androgen receptor. Importantly, testosterone did not stimulate the formation of new myelin sheaths after specific knockout of the androgen receptor in neurons and macroglial cells. Thus, the neural brain androgen receptor is required for the remyelination effect of testosterone, whereas the presence of the receptor in microglia and in peripheral tissues is not sufficient to enhance remyelination. The potent synthetic testosterone analogue 7α-methyl-19-nortestosterone, which has been developed for long-term male contraception and androgen replacement therapy in hypogonadal males and does not stimulate prostate growth, also efficiently promoted myelin repair. These data establish the efficacy of androgens as remyelinating agents and qualify the brain androgen receptor as a promising drug target for remyelination therapy, thus providing the preclinical rationale for a novel therapeutic use of androgens in males with multiple sclerosis. PMID:23365095

ERG signaling in prostate cancer is driven through PRMT5-dependent methylation of the Androgen Receptor.

PubMed

Mounir, Zineb; Korn, Joshua M; Westerling, Thomas; Lin, Fallon; Kirby, Christina A; Schirle, Markus; McAllister, Gregg; Hoffman, Greg; Ramadan, Nadire; Hartung, Anke; Feng, Yan; Kipp, David Randal; Quinn, Christopher; Fodor, Michelle; Baird, Jason; Schoumacher, Marie; Meyer, Ronald; Deeds, James; Buchwalter, Gilles; Stams, Travis; Keen, Nicholas; Sellers, William R; Brown, Myles; Pagliarini, Raymond A

2016-05-16

The TMPRSS2:ERG gene fusion is common in androgen receptor (AR) positive prostate cancers, yet its function remains poorly understood. From a screen for functionally relevant ERG interactors, we identify the arginine methyltransferase PRMT5. ERG recruits PRMT5 to AR-target genes, where PRMT5 methylates AR on arginine 761. This attenuates AR recruitment and transcription of genes expressed in differentiated prostate epithelium. The AR-inhibitory function of PRMT5 is restricted to TMPRSS2:ERG-positive prostate cancer cells. Mutation of this methylation site on AR results in a transcriptionally hyperactive AR, suggesting that the proliferative effects of ERG and PRMT5 are mediated through attenuating AR's ability to induce genes normally involved in lineage differentiation. This provides a rationale for targeting PRMT5 in TMPRSS2:ERG positive prostate cancers. Moreover, methylation of AR at arginine 761 highlights a mechanism for how the ERG oncogene may coax AR towards inducing proliferation versus differentiation.

Androgens in pregnancy: roles in parturition

PubMed Central

Makieva, Sofia; Saunders, Philippa T.K.; Norman, Jane E.

2014-01-01

BACKGROUND Understanding the physiology of pregnancy enables effective management of pregnancy complications that could otherwise be life threatening for both mother and fetus. A functional uterus (i) retains the fetus in utero during pregnancy without initiating stretch-induced contractions and (ii) is able to dilate the cervix and contract the myometrium at term to deliver the fetus. The onset of labour is associated with successful cervical remodelling and contraction of myometrium, arising from concomitant activation of uterine immune and endocrine systems. A large body of evidence suggests that actions of local steroid hormones may drive changes occurring in the uterine microenvironment at term. Although there have been a number of studies considering the potential role(s) played by progesterone and estrogen at the time of parturition, the bio-availability and effects of androgens during pregnancy have received less scrutiny. The aim of this review is to highlight potential roles of androgens in the biology of pregnancy and parturition. METHODS A review of published literature was performed to address (i) androgen concentrations, including biosynthesis and clearance, in maternal and fetal compartments throughout gestation, (ii) associations of androgen concentrations with adverse pregnancy outcomes, (iii) the role of androgens in the physiology of cervical remodelling and finally (iv) the role of androgens in the physiology of myometrial function including any impact on contractility. RESULTS Some, but not all, androgens increase throughout gestation in maternal circulation. The effects of this increase are not fully understood; however, evidence suggests that increased androgens might regulate key processes during pregnancy and parturition. For example, androgens are believed to be critical for cervical remodelling at term, in particular cervical ripening, via regulation of cervical collagen fibril organization. Additionally, a number of studies highlight potential roles for androgens in myometrial relaxation via non-genomic, AR-independent pathways critical for the pregnancy reaching term. Understanding of the molecular events leading to myometrial relaxation is an important step towards development of novel targeted tocolytic drugs. CONCLUSIONS The increase in androgen levels throughout gestation is likely to be important for establishment and maintenance of pregnancy and initiation of parturition. Further investigation of the underlying mechanisms of androgen action on cervical remodelling and myometrial contractility is needed. The insights gained may facilitate the development of new therapeutic approaches to manage pregnancy complications such as preterm birth. PMID:24643344

Androgens in pregnancy: roles in parturition.

PubMed

Makieva, Sofia; Saunders, Philippa T K; Norman, Jane E

2014-01-01

Understanding the physiology of pregnancy enables effective management of pregnancy complications that could otherwise be life threatening for both mother and fetus. A functional uterus (i) retains the fetus in utero during pregnancy without initiating stretch-induced contractions and (ii) is able to dilate the cervix and contract the myometrium at term to deliver the fetus. The onset of labour is associated with successful cervical remodelling and contraction of myometrium, arising from concomitant activation of uterine immune and endocrine systems. A large body of evidence suggests that actions of local steroid hormones may drive changes occurring in the uterine microenvironment at term. Although there have been a number of studies considering the potential role(s) played by progesterone and estrogen at the time of parturition, the bio-availability and effects of androgens during pregnancy have received less scrutiny. The aim of this review is to highlight potential roles of androgens in the biology of pregnancy and parturition. A review of published literature was performed to address (i) androgen concentrations, including biosynthesis and clearance, in maternal and fetal compartments throughout gestation, (ii) associations of androgen concentrations with adverse pregnancy outcomes, (iii) the role of androgens in the physiology of cervical remodelling and finally (iv) the role of androgens in the physiology of myometrial function including any impact on contractility. Some, but not all, androgens increase throughout gestation in maternal circulation. The effects of this increase are not fully understood; however, evidence suggests that increased androgens might regulate key processes during pregnancy and parturition. For example, androgens are believed to be critical for cervical remodelling at term, in particular cervical ripening, via regulation of cervical collagen fibril organization. Additionally, a number of studies highlight potential roles for androgens in myometrial relaxation via non-genomic, AR-independent pathways critical for the pregnancy reaching term. Understanding of the molecular events leading to myometrial relaxation is an important step towards development of novel targeted tocolytic drugs. The increase in androgen levels throughout gestation is likely to be important for establishment and maintenance of pregnancy and initiation of parturition. Further investigation of the underlying mechanisms of androgen action on cervical remodelling and myometrial contractility is needed. The insights gained may facilitate the development of new therapeutic approaches to manage pregnancy complications such as preterm birth. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.

SOCS3 Modulates the Response to Enzalutamide and Is Regulated by Androgen Receptor Signaling and CpG Methylation in Prostate Cancer Cells.

PubMed

Handle, Florian; Erb, Holger H H; Luef, Birgit; Hoefer, Julia; Dietrich, Dimo; Parson, Walther; Kristiansen, Glen; Santer, Frédéric R; Culig, Zoran

2016-06-01

The proinflammatory cytokine IL6 is associated with bad prognosis in prostate cancer and implicated in progression to castration resistance. Suppressor of cytokine signaling 3 (SOCS3) is an IL6-induced negative feedback regulator of the IL6/Janus kinase (JAK)/STAT3 pathway. This study reveals that the SOCS3 promoter is hypermethylated in cancerous regions compared with adjacent benign tissue in prostate cancer using methylation-specific qPCR. A series of in vitro experiments was performed to assess the functional impact of low SOCS3 expression during anti-androgen treatment. Using lentivirus-mediated knockdown, it was demonstrated for the first time that SOCS3 regulates IL6/JAK/STAT3 signaling in androgen receptor-positive LNCaP cells. In addition, SOCS3 mRNA is upregulated by the anti-androgens bicalutamide and enzalutamide. This effect is caused by androgen receptor-mediated suppression of IL6ST and JAK1 expression, which leads to altered STAT3 signaling. Functionally, knockdown of SOCS3 led to enhanced androgen receptor activity after 3 weeks of enzalutamide treatment in an inflammatory setting. Furthermore, the stemness/self-renewal associated genes SOX2 and NANOG were strongly upregulated by the long-term treatment, and modulation of SOCS3 expression was sufficient to counteract this effect. These findings prove that SOCS3 plays an important role during anti-androgen treatment in an inflammatory environment. SOCS3 is frequently inactivated by promoter hypermethylation in prostate cancer, which disrupts the feedback regulation of IL6 signaling and leads to reduced efficacy of enzalutamide in the presence of inflammatory cytokines. Mol Cancer Res; 14(6); 574-85. ©2016 AACR. ©2016 American Association for Cancer Research.

Steroidal androgens and nonsteroidal, tissue-selective androgen receptor modulator, S-22, regulate androgen receptor function through distinct genomic and nongenomic signaling pathways.

PubMed

Narayanan, Ramesh; Coss, Christopher C; Yepuru, Muralimohan; Kearbey, Jeffrey D; Miller, Duane D; Dalton, James T

2008-11-01

Androgen receptor (AR) ligands are important for the development and function of several tissues and organs. However, the poor oral bioavailability, pharmacokinetic properties, and receptor cross-reactivity of testosterone, coupled with side effects, place limits on its clinical use. Selective AR modulators (SARMs) elicit anabolic effects in muscle and bone, sparing reproductive organs like the prostate. However, molecular mechanisms underlying the tissue selectivity remain ambiguous. We performed a variety of in vitro studies to compare and define the molecular mechanisms of an aryl propionamide SARM, S-22, as compared with dihydrotestosterone (DHT). Studies indicated that S-22 increased levator ani muscle weight but decreased the size of prostate in rats. Analysis of the upstream intracellular signaling events indicated that S-22 and DHT mediated their actions through distinct pathways. Modulation of these pathways altered the recruitment of AR and its cofactors to the PSA enhancer in a ligand-dependent fashion. In addition, S-22 induced Xenopus laevis oocyte maturation and rapid phosphorylation of several kinases, through pathways distinct from steroids. These studies reveal novel differences in the molecular mechanisms by which S-22, a nonsteroidal SARM, and DHT mediate their pharmacological effects.

Circulating androgens in women: exercise-induced changes.

PubMed

Enea, Carina; Boisseau, Nathalie; Fargeas-Gluck, Marie Agnès; Diaz, Véronique; Dugué, Benoit

2011-01-01

Physical exercise is known to strongly stimulate the endocrine system in both sexes. Among these hormones, androgens (e.g. testosterone, androstenedione, dehydroepiandrosterone) play key roles in the reproductive system, muscle growth and the prevention of bone loss. In female athletes, excessive physical exercise may lead to disorders, including delay in the onset of puberty, amenorrhoea and premature osteoporosis. The free and total fractions of circulating androgens vary in response to acute and chronic exercise/training (depending on the type), but the physiological role of these changes is not completely understood. Although it is commonly accepted that only the free fraction of steroids has a biological action, this hypothesis has recently been challenged. Indeed, a change in the total fraction of androgen concentration may have a significant impact on cells (inducing genomic or non-genomic signalling). The purpose of this review, therefore, is to visit the exercise-induced changes in androgen concentrations and emphasize their potential effects on female physiology. Despite some discrepancies in the published studies (generally due to differences in the types and intensities of the exercises studied, in the hormonal status of the group of women investigated and in the methods for androgen determination), exercise is globally able to induce an increase in circulating androgens. This can be observed after both resistance and endurance acute exercises. For chronic exercise/training, the picture is definitely less clear and there are even circumstances where exercise leads to a decrease of circulating androgens. We suggest that those changes have significant impact on female physiology and physical performance.

A Small Molecule Polyamine Oxidase Inhibitor Blocks Androgen-Induced Oxidative Stress and Delays Prostate Cancer Progression in the TRAMP Mouse Model

PubMed Central

Basu, Hirak S.; Thompson, Todd A.; Church, Dawn R.; Clower, Cynthia C.; Mehraein-Ghomi, Farideh; Amlong, Corey A.; Martin, Christopher T.; Woster, Patrick M.; Lindstrom, Mary J.; Wilding, George

2009-01-01

High levels of reactive oxygen species (ROS) present in human prostate epithelia are an important etiological factor in prostate cancer (CaP) occurrence, recurrence and progression. Androgen induces ROS production in the prostate by a yet unknown mechanism. Here, to the best of our knowledge, we report for the first time that androgen induces an overexpression of spermidine/spermine N1-acetyltransferase (SSAT), the rate-limiting enzyme in the polyamine oxidation pathway. As prostatic epithelia produce a large excess of polyamines, the androgen-induced polyamine oxidation that produces H2O2 could be a major reason for the high ROS levels in the prostate epithelia. A small molecule polyamine oxidase inhibitor N,N'-butanedienyl butanediamine (MDL 72,527 or CPC-200) effectively blocks androgen-induced ROS production in human CaP cells as well as significantly delays CaP progression and death in animals developing spontaneous CaP. These data demonstrate that polyamine oxidation is not only a major pathway for ROS production in prostate, but inhibiting this pathway also successfully delays prostate cancer progression. PMID:19773450

Effect of Cuscuta reflexa Roxb on androgen-induced alopecia.

PubMed

Pandit, Shweta; Chauhan, Nagendra Singh; Dixit, V K

2008-09-01

Alopecia is a psychologically distressing condition. Androgenetic alopecia, which affects millions of men and women, is an androgen-driven disorder. Here, Cuscuta reflexa Roxb is evaluated for hair growth activity in androgen-induced alopecia. Petroleum ether extract of C. reflexa was studied for its hair growth-promoting activity. Alopecia was induced in albino mice by testosterone administration for 20 days. Its inhibition by simultaneous administration of extract was evaluated using follicular density, anagen/telogen ratio, and microscopic observation of skin sections. To investigate the mechanism of observed activity, in vitro experiments were performed to study the effect of extract and its major component on activity of 5alpha-reductase enzyme. Petroleum ether extract of C. reflexa exhibited promising hair growth-promoting activity as reflected from follicular density, anagen/telogen ratio, and skin sections. Inhibition of 5alpha-reductase activity by extract and isolate suggest that the extract reversed androgen-induced alopecia by inhibiting conversion of testosterone to dihydrotestosterone. The petroleum ether extract of C. reflexa and its isolate is useful in treatment of androgen-induced alopecia by inhibiting the enzyme 5alpha-reductase.

Testosterone and 17β-estradiol have opposite effects on podocyte apoptosis that precedes glomerulosclerosis in female estrogen receptor knockout mice

PubMed Central

Doublier, Sophie; Lupia, Enrico; Catanuto, Paola; Periera-Simon, Simone; Xia, Xiaomei; Korach, Ken; Berho, Mariana; Elliot, Sharon J.; Karl, Michael

2016-01-01

Podocyte damage and apoptosis are thought to be important if not essential in the development of glomerulosclerosis. Female estrogen receptor knockout mice develop glomerulosclerosis at 9 months of age due to excessive ovarian testosterone production and secretion. Here, we studied the pathogenesis of glomerulosclerosis in this mouse model to determine whether testosterone and/or 17β-estradiol directly affect the function and survival of podocytes. Glomerulosclerosis in these mice was associated with the expression of desmin and the loss of nephrin, markers of podocyte damage and apoptosis. Ovariectomy preserved the function and survival of podocytes by eliminating the source of endogenous testosterone production. In contrast, testosterone supplementation induced podocyte apoptosis in ovariectomized wild-type mice. Importantly, podocytes express functional androgen and estrogen receptors, which, upon stimulation by their respective ligands, have opposing effects. Testosterone induced podocyte apoptosis in vitro by androgen receptor activation, but independent of the TGF-β1 signaling pathway. Pretreatment with 17β-estradiol prevented testosterone-induced podocyte apoptosis, an estrogen receptor-dependent effect mediated by activation of the ERK signaling pathway, and protected podocytes from TGF-β1- or TNF-α-induced apoptosis. Thus, podocytes are target cells for testosterone and 17β-estradiol. These hormones modulate podocyte damage and apoptosis. PMID:20962747

Testosterone and 17β-estradiol have opposite effects on podocyte apoptosis that precedes glomerulosclerosis in female estrogen receptor knockout mice.

PubMed

Doublier, Sophie; Lupia, Enrico; Catanuto, Paola; Periera-Simon, Simone; Xia, Xiaomei; Korach, Ken; Berho, Mariana; Elliot, Sharon J; Karl, Michael

2011-02-01

Podocyte damage and apoptosis are thought to be important if not essential in the development of glomerulosclerosis. Female estrogen receptor knockout mice develop glomerulosclerosis at 9 months of age due to excessive ovarian testosterone production and secretion. Here, we studied the pathogenesis of glomerulosclerosis in this mouse model to determine whether testosterone and/or 17β-estradiol directly affect the function and survival of podocytes. Glomerulosclerosis in these mice was associated with the expression of desmin and the loss of nephrin, markers of podocyte damage and apoptosis. Ovariectomy preserved the function and survival of podocytes by eliminating the source of endogenous testosterone production. In contrast, testosterone supplementation induced podocyte apoptosis in ovariectomized wild-type mice. Importantly, podocytes express functional androgen and estrogen receptors, which, upon stimulation by their respective ligands, have opposing effects. Testosterone induced podocyte apoptosis in vitro by androgen receptor activation, but independent of the TGF-β1 signaling pathway. Pretreatment with 17β-estradiol prevented testosterone-induced podocyte apoptosis, an estrogen receptor-dependent effect mediated by activation of the ERK signaling pathway, and protected podocytes from TGF-β1- or TNF-α-induced apoptosis. Thus, podocytes are target cells for testosterone and 17β-estradiol. These hormones modulate podocyte damage and apoptosis.

The role of androgens in follicle maturation and ovulation induction: friend or foe of infertility treatment?

PubMed Central

2011-01-01

Background Effects of androgens on follicle maturation have been controversial for some time. Here, we review the potential of their applications in improving human ovulation induction, based on human and animal data, reported in the literature. Methods We reviewed the published literature for the years 2005-2011, using relevant key words, in PubMed, Medline and Cochrane reviews, and then performed secondary reviews of referenced articles, which previously had not been known or preceded the searched time period. A total of 217 publications were reviewed. Results Contrary to widely held opinion, recent data, mostly developed in the mouse, convincingly demonstrate essential contribution of androgens to normal follicle maturation and, therefore, female fertility. Androgens appear most engaged at preantral and antral stages, primarily affect granulosa cells, and exert effects via androgen receptors (AR) through transcriptional regulation but also in non-genomic ways, with ligand-activated AR modulating follicle stimulating hormone (FSH) activity in granulosa cells. While some androgens, like testosterone (T) and dehydroepiandrosterone (DHEA), appear effective in improving functional ovarian reserve (FOR) in women with diminished ovarian reserve (DOR), others may even exert opposite effects. Such differences in androgens may, at least partially, reflect different levels of agonism to AR. Discussion Selective androgens appear capable of improving early stages of folliculogenesis. They, therefore, may represent forerunners of a completely new class of ovulation-inducing medications, which, in contrast to gonadotropins, affect follicle maturation at much earlier stages. PMID:21849061

Male gender identity in complete androgen insensitivity syndrome.

PubMed

T'Sjoen, Guy; De Cuypere, Griet; Monstrey, Stan; Hoebeke, Piet; Freedman, F Kenneth; Appari, Mahesh; Holterhus, Paul-Martin; Van Borsel, John; Cools, Martine

2011-06-01

Women and girls with complete androgen insensitivity syndrome (CAIS) invariably have a female typical core gender identity. In this case report, we describe the first case of male gender identity in a CAIS individual raised female leading to complete sex reassignment involving both androgen treatment and phalloplasty. CAIS was diagnosed at age 17, based on an unambiguously female phenotype, a 46,XY karyotype, and a 2660delT androgen receptor (AR) gene mutation, leading to a premature stop in codon 807. Bilateral gonadectomy was performed but a short period of estrogen treatment induced a negative emotional reaction and treatment was stopped. Since the age of 3, childhood-onset cross gender behavior had been noticed. After a period of psychotherapy, persisting male gender identity was confirmed. There was no psychiatric co-morbidity and there was an excellent real life experience. Testosterone substitution was started, however without inducing any of the desired secondary male characteristics. A subcutaneous mastectomy was performed and the patient received phalloplasty by left forearm free flap and scrotoplasty. Testosterone treatment was continued, without inducing virilization, and bone density remained normal. The patient qualifies as female-to-male transsexual and was treated according to the Standards of Care by the World Professional Association for Transgender Health with good outcome. However, we do not believe that female sex of rearing as a standard procedure should be questioned in CAIS. Our case challenges the role of a functional AR pathway in the development of male gender identity.

Adrenal hyperandrogenism is induced by fetal androgen excess in a rhesus monkey model of polycystic ovary syndrome.

PubMed

Zhou, Rao; Bird, Ian M; Dumesic, Daniel A; Abbott, David H

2005-12-01

Adrenal androgen excess is found in approximately 25-60% of women with polycystic ovary syndrome (PCOS), but the mechanisms underlying PCOS-related adrenal androgen excess are unclear. The objective of this study was to determine whether adrenal androgen excess is manifest in a nonhuman primate model for PCOS. Six prenatally androgenized (PA) and six control female rhesus monkeys of similar age, body weight, and body mass index were studied during d 2-6 of two menstrual cycles or anovulatory 30-d periods. Predexamethasone adrenal steroid levels were assessed in the first cycle (cycle 1). In a subsequent cycle (cycle 2), occurring one to three cycles after cycle 1, adrenal steroids were determined 14.5-16.0 h after an i.m. injection of 0.5 mg/kg dexamethasone (postdexamethasone levels) and after an i.v. injection of 50 microg ACTH-(1-39). Both before and after dexamethasone, serum levels of dehydroepiandrosterone (DHEA) in PA females exceeded those in controls. After ACTH injection, PA females exhibited higher circulating levels of DHEA, androstenedione, and corticosterone but comparable levels of 17alpha-hydroxyprogesterone, cortisol, the sulfoconjugate of DHEA, and testosterone compared with controls. Enhanced basal and ACTH-stimulated adrenal androgen levels in PA female monkeys may reflect up-regulation of 17,20 lyase activity in the adrenal zona reticularis, causing adrenal androgen excess comparable with that found in PCOS women with adrenal androgen excess. These findings open the possibility that PCOS adrenal hyperandrogenism may have its origins in fetal androgen excess reprogramming of adrenocortical function.

Atrazine activates multiple signaling pathways enhancing the rapid hCG-induced androgenesis in rat Leydig cells.

PubMed

Pogrmic-Majkic, Kristina; Fa, Svetlana; Samardzija, Dragana; Hrubik, Jelena; Kaisarevic, Sonja; Andric, Nebojsa

2016-08-10

Atrazine (ATR) is an endocrine disruptor that affects steroidogenic process, resulting in disruption of reproductive function of the male and female gonads. In this study, we used the primary culture of peripubertal Leydig cells to investigate the effect of ATR on the rapid androgen production stimulated by human chorionic gonadotropin (hCG). We demonstrated that ATR activated multiple signaling pathways enhancing the rapid hCG-stimulated androgen biosynthesis in Leydig cells. Low hCG concentration (0.25ng/mL) caused cAMP-independent, but ERK1/2-dependent increase in androgen production after 60min of incubation. Co-treatment with ATR for 60min enhanced the cAMP production in hCG-stimulated cells. Accumulation of androgens was prevented by addition of U0126, N-acetyl-l-cysteine and AG1478. Co-treatment with hCG and ATR for 60min did not alter steroidogenic acute regulatory protein (Star) mRNA level in Leydig cells. After 120min, hCG further increased androgenesis in Leydig cells that was sensitive to inhibition of the cAMP/PKA, ERK1/2 and ROS signaling pathways. Co-treatment with ATR for 120min further enhanced the hCG-induced androgen production, which was prevented by inhibition of the calcium, PKC and EGFR signaling cascades. After 120min, ATR enhanced the expression of Star mRNA in hCG-stimulated Leydig cells through activation of the PKA and PKC pathway. Collectively, these data suggest that exposure to ATR caused perturbations in multiple signaling pathways, thus enhancing the rapid hCG-dependent androgen biosynthesis in peripubertal Leydig cells. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Different profiles of neuroendocrine cell differentiation evolve in the PC-310 human prostate cancer model during long-term androgen deprivation.

PubMed

Jongsma, Johan; Oomen, Monique H; Noordzij, Marinus A; Van Weerden, Wytske M; Martens, Gerard J M; van der Kwast, Theodorus H; Schröder, Fritz H; van Steenbrugge, Gert J

2002-03-01

Neuroendocrine (NE) cells are androgen-independent cells and secrete growth-modulating peptide hormones via a regulated secretory pathway (RSP). We studied NE differentiation after long-term androgen withdrawal in the androgen-dependent human prostate cancer xenograft PC-310. Tumor-bearing nude mice were killed at 0, 2, 5, 7, 14, 21, 47, 84, and 154 days after castration. The half-life of the PC-310 tumor was 10 days, with a stable residual tumor volume of 30--40% after 21 days and longer periods of androgen deprivation. Proliferative activity and prostate-specific antigen serum levels decreased to zero after castration, whereas cell-cycle arrest was manifested by increased p27(kip1) expression. A temporary downregulation of androgen receptor (AR) expression was noted after androgen deprivation. The expression of chromogranin A, secretogranin III, and secretogranin V (7B2) increased 5 days after castration and later. Subsequently, pro-hormone convertase 1 and peptidyl alpha--amidating monooxygenase as well as vascular endothelial growth factor were expressed from 7 days after castration on. Finally, such growth factors as gastrin-releasing peptide and serotonin were expressed in a small part of the NE cells 21 days after castration, but strong expression was induced late during androgen deprivation, that is, 84 and 154 days after castration, respectively. Androgen deprivation of the NE-differentiated PC-310 model induced the formation of NE-differentiated AR(minus sign) and non-NE AR(+) tumor residues. The NE-differentiated cells actively produced growth factors via an RSP that may lead to hormone-refractory disease. The dormant non-NE AR(+) tumor cells were shown to remain androgen sensitive even after long-term androgen deprivation. In the PC-310 xenograft, time-dependent NE differentiation and subsequent maturation were induced after androgen depletion. The androgen-dependent PC-310 xenograft model constitutes an excellent model for studying the role of NE cells in the progression of clinical prostate cancer. Copyright 2002 Wiley-Liss, Inc.

The effect of androgen excess on maternal metabolism, placental function and fetal growth in obese dams.

PubMed

Fornes, Romina; Maliqueo, Manuel; Hu, Min; Hadi, Laila; Jimenez-Andrade, Juan M; Ebefors, Kerstin; Nyström, Jenny; Labrie, Fernand; Jansson, Thomas; Benrick, Anna; Stener-Victorin, Elisabet

2017-08-14

Pregnant women with polycystic ovary syndrome (PCOS) are often overweight or obese. To study the effects of maternal androgen excess in obese dams on metabolism, placental function and fetal growth, female C57Bl6J mice were fed a control (CD) or a high fat/high sucrose (HF/HS) diet for 4-10 weeks, and then mated. On gestational day (GD) 15.5-17.5, dams were injected with dihydrotestosterone (CD-DHT, HF/HS-DHT) or a vehicle (CD-Veh, HF/HS-Veh). HF/HS dams had higher fat content, both before mating and on GD18.5, with no difference in glucose homeostasis, whereas the insulin sensitivity was higher in DHT-exposed dams. Compared to the CD groups, the livers from HF/HS dams weighed more on GD18.5, the triglyceride content was higher, and there was a dysregulation of liver enzymes related to lipogenesis and higher mRNA expression of Fitm1. Fetuses from HF/HS-Veh dams had lower liver triglyceride content and mRNA expression of Srebf1c. Maternal DHT exposure, regardless of diet, decreased fetal liver Pparg mRNA expression and increased placental androgen receptor protein expression. Maternal diet-induced obesity, together with androgen excess, affects maternal and fetal liver function as demonstrated by increased triglyceride content and dysfunctional expression of enzymes and transcription factors involved in de novo lipogenesis and fat storage.

SIGNIFICANCE OF EXPERIMENTAL STUDIES FOR ASSESSING ADVERSE EFFECTS OF ENDOCRINE-DISRUPTING CHEMICALS

EPA Science Inventory

The U.S. Environmental Protection Agency (US EPA) is developing an endocrine disruptor screening and testing program to detect chemicals that alter hypothalamic-pituitary-gonadal (HPG) function, estrogen, androgen, and thyroid (EAT) hormone synthesis or metabolism and induce andr...

Androgen actions on endothelium functions and cardiovascular diseases

PubMed Central

Cai, Jing-Jing; Wen, Juan; Jiang, Wei-Hong; Lin, Jian; Hong, Yuan; Zhu, Yuan-Shan

2016-01-01

The roles of androgens on cardiovascular physiology and pathophysiology are controversial as both beneficial and detrimental effects have been reported. Although the reasons for this discrepancy are unclear, multiple factors such as genetic and epigenetic variation, sex-specificity, hormone interactions, drug preparation and route of administration may contribute. Recently, growing evidence suggests that androgens exhibit beneficial effects on cardiovascular function though the mechanism remains to be elucidated. Endothelial cells (ECs) which line the interior surface of blood vessels are distributed throughout the circulatory system, and play a crucial role in cardiovascular function. Endothelial progenitor cells (EPCs) are considered an indispensable element for the reconstitution and maintenance of an intact endothelial layer. Endothelial dysfunction is regarded as an initiating step in development of atherosclerosis and cardiovascular diseases. The modulation of endothelial functions by androgens through either genomic or nongenomic signal pathways is one possible mechanism by which androgens act on the cardiovascular system. Obtaining insight into the mechanisms by which androgens affect EC and EPC functions will allow us to determine whether androgens possess beneficial effects on the cardiovascular system. This in turn may be critical in the prevention and therapy of cardiovascular diseases. This article seeks to review recent progress in androgen regulation of endothelial function, the sex-specificity of androgen actions, and its clinical applications in the cardiovascular system. PMID:27168746

Enzalutamide inhibits androgen receptor-positive bladder cancer cell growth.

PubMed

Kawahara, Takashi; Ide, Hiroki; Kashiwagi, Eiji; El-Shishtawy, Kareem A; Li, Yi; Reis, Leonardo O; Zheng, Yichun; Miyamoto, Hiroshi

2016-10-01

Emerging preclinical evidence suggests that androgen-mediated androgen receptor (AR) signals promote bladder cancer progression. However, little is known about the efficacy of an AR signaling inhibitor, enzalutamide, in the growth of bladder cancer cells. In this study, we compared the effects of enzalutamide and 2 other classic antiandrogens, flutamide and bicalutamide, on androgen-induced bladder cancer cell proliferation, migration, and invasion as well as tumor growth in vivo. Thiazolyl blue cell viability assay, flow cytometry, scratch wound-healing assay, transwell invasion assay, real-time polymerase chain reaction, and reporter gene assay were performed in AR-positive (e.g., UMUC3, TCCSUP, and 647V-AR) and AR-negative (e.g., UMUC3-AR-short hairpin RNA [shRNA], TCCSUP-AR-shRNA, 647V) bladder cancer lines treated with dihydrotestosterone and each AR antagonist. We also used a mouse xenograft model for bladder cancer. Dihydrotestosterone increased bladder cancer cell proliferation, migration, and invasion indicating that endogenous or exogenous AR was functional. Enzalutamide, hydroxyflutamide, and bicalutamide showed similar inhibitory effects, without significant agonist activity, on androgen-mediated cell viability/apoptosis, cell migration, and cell invasion in AR-positive lines. No significant effects of dihydrotestosterone as well as AR antagonists on the growth of AR-negative cells were seen. Correspondingly, in UMUC3 cells, these AR antagonists down-regulated androgen-induced expression of AR, matrix metalloproteinase-2, and interleukin-6. Androgen-enhanced AR-mediated transcriptional activity was also blocked by each AR antagonist exhibiting insignificant agonist activity. In UMUC3 xenograft-bearing mice, oral gavage treatment with each antiandrogen retarded tumor growth, and only enzalutamide demonstrated a statistically significant suppression compared with mock treatment. Our current data support recent observations indicating the involvement of the AR pathway in bladder cancer growth and further suggest that AR antagonists, including enzalutamide, are of therapeutic benefit in AR-positive bladder cancer. Copyright © 2016 Elsevier Inc. All rights reserved.

Sex steroid receptors in male human bladder: expression and biological function.

PubMed

Chavalmane, Aravinda K; Comeglio, Paolo; Morelli, Annamaria; Filippi, Sandra; Fibbi, Benedetta; Vignozzi, Linda; Sarchielli, Erica; Marchetta, Matilde; Failli, Paola; Sandner, Peter; Saad, Farid; Gacci, Mauro; Vannelli, Gabriella B; Maggi, Mario

2010-08-01

In male, lower urinary tract symptoms (LUTS) have been associated, beside benign prostatic hyperplasia, to some unexpected comorbidities (hypogonadism, obesity, metabolic syndrome), which are essentially characterized by an unbalance between circulating androgens/estrogens. Within the bladder, LUTS are linked to RhoA/Rho-kinase (ROCK) pathway overactivity. To investigate the effects of changing sex steroids on bladder smooth muscle. ER α, ER β, GPR30/GPER1 and aromatase mRNA expression was analyzed in male genitourinary tract tissues, and cells isolated from bladder, prostate, and urethra. Estrogen and G1 effect on RhoA/ROCK signaling output like cell migration, gene expression, and cytoskeletal remodeling, and [Ca(2+) ](i) was also studied in hB cells. Contractile studies on bladder strips from castrated male rats supplemented with estradiol and testosterone was also performed. The effects of classical (ER α, ER β) and nonclassical (GPR30/GPER1) estrogen receptor ligands (17 β-estradiol and G1, respectively) and androgens on RhoA/ROCK-.mediated cell functions were studied in hB cells. Contractility studies were also performed in bladder strips from castrated male rats supplemented with testosterone or estradiol. Aromatase and sex steroid receptors, including GPR30, were expressed in human bladder and mediates several biological functions. Both 17 β-estradiol and G1 activated calcium transients and induced RhoA/ROCK signaling (cell migration, cytoskeleton remodeling and smooth muscle gene expression). RhoA/ROCK inhibitors blunted these effects. Estrogen-, but not androgen-supplementation to castrated rats increased sensitivity to the ROCK inhibitor, Y-27632 in isolated bladder strips. In hB cells, testosterone elicited effects similar to estrogen, which were abrogated by blocking its aromatization through letrozole. Our data indicate for the first time that estrogen-more than androgen-receptors up-regulate RhoA/ROCK signaling. Since an altered estrogen/androgen ratio characterizes conditions, such as aging, obesity and metabolic syndrome, often associated to LUTS, we speculate that a relative hyperestrogenism may induce bladder overactivity through the up-regulation of RhoA/ROCK pathway. © 2010 International Society for Sexual Medicine.

AR-v7 protein expression is regulated by protein kinase and phosphatase

PubMed Central

Li, Yinan; Xie, Ning; Gleave, Martin E.; Rennie, Paul S.; Dong, Xuesen

2015-01-01

Failure of androgen-targeted therapy and progression of castration-resistant prostate cancer (CRPC) are often attributed to sustained expression of the androgen receptor (AR) and its major splice variant, AR-v7. Although the new generation of anti-androgens such as enzalutamide effectively inhibits AR activity, accumulating pre-clinical and clinical evidence indicates that AR-v7 remains constitutively active in driving CRPC progression. However, molecular mechanisms which control AR-v7 protein expression remain unclear. We apply multiple prostate cancer cell models to demonstrate that enzalutamide induces differential activation of protein phosphatase-1 (PP-1) and Akt kinase depending on the gene context of cancer cells. The balance between PP-1 and Akt activation governs AR phosphorylation status and activation of the Mdm2 ubiquitin ligase. Mdm2 recognizes phosphorylated serine 213 of AR-v7, and induces AR-v7 ubiquitination and protein degradation. These findings highlight the decisive roles of PP-1 and Akt for AR-v7 protein expression and activities when AR is functionally blocked. PMID:26378044

A small molecule polyamine oxidase inhibitor blocks androgen-induced oxidative stress and delays prostate cancer progression in the transgenic adenocarcinoma of the mouse prostate model.

PubMed

Basu, Hirak S; Thompson, Todd A; Church, Dawn R; Clower, Cynthia C; Mehraein-Ghomi, Farideh; Amlong, Corey A; Martin, Christopher T; Woster, Patrick M; Lindstrom, Mary J; Wilding, George

2009-10-01

High levels of reactive oxygen species (ROS) present in human prostate epithelia are an important etiologic factor in prostate cancer (CaP) occurrence, recurrence, and progression. Androgen induces ROS production in the prostate by a yet unknown mechanism. Here, to the best of our knowledge, we report for the first time that androgen induces an overexpression of spermidine/spermine N1-acetyltransferase, the rate-limiting enzyme in the polyamine oxidation pathway. As prostatic epithelia produce a large excess of polyamines, the androgen-induced polyamine oxidation that produces H2O2 could be a major reason for the high ROS levels in the prostate epithelia. A small molecule polyamine oxidase inhibitor N,N'-butanedienyl butanediamine (MDL 72,527 or CPC-200) effectively blocks androgen-induced ROS production in human CaP cells, as well as significantly delays CaP progression and death in animals developing spontaneous CaP. These data show that polyamine oxidation is not only a major pathway for ROS production in prostate, but inhibiting this pathway also successfully delays CaP progression.

The AhR Ligand, TCDD, Regulates Androgen Receptor Activity Differently in Androgen-Sensitive versus Castration-Resistant Human Prostate Cancer Cells.

PubMed

Ghotbaddini, Maryam; Powell, Joann B

2015-07-06

The reported biological effects of TCDD include induction of drug metabolizing enzymes, wasting syndrome and tumor promotion. TCDD elicits most of its effects through binding the aryl hydrocarbon receptor (AhR). TCDD induced degradation of AhR has been widely reported and requires ubiquitination of the protein. The rapid depletion of AhR following TCDD activation serves as a mechanism to modulate AhR mediated gene induction. In addition to inducing AhR degradation, TCDD has been reported to induce degradation of hormone receptors. The studies reported here, evaluate the effect of TCDD exposure on androgen receptor (AR) expression and activity in androgen-sensitive LNCaP and castration-resistant C4-2 prostate cancer cells. Our results show that TCDD exposure does not induce AhR or AR degradation in C4-2 cells. However, both AhR and AR are degraded in LNCaP cells following TCDD exposure. In addition, TCDD enhances AR phosphorylation and induces expression of AR responsive genes in LNCaP cells. Our data reveals that TCDD effect on AR expression and activity differs in androgen-sensitive and castration-resistant prostate cancer cell models.

Selective Androgen Receptor Downregulators (SARDs): A New Prostate Cancer Therapy

DTIC Science & Technology

2006-10-01

of the androgen receptor messenger RNA and functional inhibition of androgen receptor activity by a hammerhead ribozyme . Mol Endocrinol, 12: 1558...cleavage of the androgen receptor messenger RNA and functional inhibition of androgen receptor activity by a hammerhead ribozyme . Mol Endocrinol...used to down-regulate the AR include antisense oligonucleotides (9, 10), ribozyme treatments (11, 12), AR dominant negatives (13) and small

Huntingtin interacting protein 1 modulates the transcriptional activity of nuclear hormone receptors.

PubMed

Mills, Ian G; Gaughan, Luke; Robson, Craig; Ross, Theodora; McCracken, Stuart; Kelly, John; Neal, David E

2005-07-18

Internalization of activated receptors regulates signaling, and endocytic adaptor proteins are well-characterized in clathrin-mediated uptake. One of these adaptor proteins, huntingtin interacting protein 1 (HIP1), induces cellular transformation and is overexpressed in some prostate cancers. We have discovered that HIP1 associates with the androgen receptor through a central coiled coil domain and is recruited to DNA response elements upon androgen stimulation. HIP1 is a novel androgen receptor regulator, significantly repressing transcription when knocked down using a silencing RNA approach and activating transcription when overexpressed. We have also identified a functional nuclear localization signal at the COOH terminus of HIP1, which contributes to the nuclear translocation of the protein. In conclusion, we have discovered that HIP1 is a nucleocytoplasmic protein capable of associating with membranes and DNA response elements and regulating transcription.

Potent antiandrogen and androgen receptor activities of an Angelica gigas-containing herbal formulation: identification of decursin as a novel and active compound with implications for prevention and treatment of prostate cancer.

PubMed

Jiang, Cheng; Lee, Hyo-Jeong; Li, Guang-xun; Guo, Junming; Malewicz, Barbara; Zhao, Yan; Lee, Eun-Ok; Lee, Hyo-Jung; Lee, Jae-Ho; Kim, Min-Seok; Kim, Sung-Hoon; Lu, Junxuan

2006-01-01

Androgen and androgen receptor (AR)-mediated signaling are crucial for the development of prostate cancer. Identification of novel and naturally occurring phytochemicals that target androgen and AR signaling from Oriental medicinal herbs holds exciting promises for the chemoprevention of this disease. In this article, we report the discovery of strong and long-lasting antiandrogen and AR activities of the ethanol extract of a herbal formula (termed KMKKT) containing Korean Angelica gigas Nakai (AGN) root and nine other Oriental herbs in the androgen-dependent LNCaP human prostate cancer cell model. The functional biomarkers evaluated included a suppression of the expression of prostate-specific antigen (PSA) mRNA and protein (IC50, approximately 7 microg/mL, 48-hour exposure) and an inhibition of androgen-induced cell proliferation through G1 arrest and of the ability of androgen to suppress neuroendocrine differentiation at exposure concentrations that did not cause apoptosis. Through activity-guided fractionation, we identified decursin from AGN as a novel antiandrogen and AR compound with an IC50 of approximately 0.4 microg/mL (1.3 micromol/L, 48-hour exposure) for suppressing PSA expression. Decursin also recapitulated the neuroendocrine differentiation induction and G1 arrest actions of the AGN and KMKKT extracts. Mechanistically, decursin in its neat form or as a component of AGN or KMKKT extracts inhibited androgen-stimulated AR translocation to the nucleus and down-regulated AR protein abundance without affecting the AR mRNA level. The novel antiandrogen and AR activities of decursin and decursin-containing herbal extracts have significant implications for the chemoprevention and treatment of prostate cancer and other androgen-dependent diseases.

Early embryonic androgen exposure induces transgenerational epigenetic and metabolic changes.

PubMed

Xu, Ning; Chua, Angela K; Jiang, Hong; Liu, Ning-Ai; Goodarzi, Mark O

2014-08-01

Androgen excess is a central feature of polycystic ovary syndrome (PCOS), which affects 6% to 10% of young women. Mammals exposed to elevated androgens in utero develop PCOS-like phenotypes in adulthood, suggesting fetal origins of PCOS. We hypothesize that excess androgen exposure during early embryonic development may disturb the epigenome and disrupt metabolism in exposed and unexposed subsequent generations. Zebrafish were used to study the underlying mechanism of fetal origins. Embryos were exposed to androgens (testosterone and dihydrotestosterone) early at 26 to 56 hours post fertilization or late at 21 to 28 days post fertilization. Exposed zebrafish (F0) were grown to adults and crossed to generate unexposed offspring (F1). For both generations, global DNA methylation levels were examined in ovaries using a luminometric methylation assay, and fasting and postprandial blood glucose levels were measured. We found that early but not late androgen exposure induced changes in global methylation and glucose homeostasis in both generations. In general, F0 adult zebrafish exhibited altered global methylation levels in the ovary; F1 zebrafish had global hypomethylation. Fasting blood glucose levels were decreased in F0 but increased in F1; postprandial glucose levels were elevated in both F0 and F1. This androgenized zebrafish study suggests that transient excess androgen exposure during early development can result in transgenerational alterations in the ovarian epigenome and glucose homeostasis. Current data cannot establish a causal relationship between epigenetic changes and altered glucose homeostasis. Whether transgenerational epigenetic alteration induced by prenatal androgen exposure plays a role in the development of PCOS in humans deserves study.

Early Embryonic Androgen Exposure Induces Transgenerational Epigenetic and Metabolic Changes

PubMed Central

Xu, Ning; Chua, Angela K.; Jiang, Hong; Liu, Ning-Ai

2014-01-01

Androgen excess is a central feature of polycystic ovary syndrome (PCOS), which affects 6% to 10% of young women. Mammals exposed to elevated androgens in utero develop PCOS-like phenotypes in adulthood, suggesting fetal origins of PCOS. We hypothesize that excess androgen exposure during early embryonic development may disturb the epigenome and disrupt metabolism in exposed and unexposed subsequent generations. Zebrafish were used to study the underlying mechanism of fetal origins. Embryos were exposed to androgens (testosterone and dihydrotestosterone) early at 26 to 56 hours post fertilization or late at 21 to 28 days post fertilization. Exposed zebrafish (F0) were grown to adults and crossed to generate unexposed offspring (F1). For both generations, global DNA methylation levels were examined in ovaries using a luminometric methylation assay, and fasting and postprandial blood glucose levels were measured. We found that early but not late androgen exposure induced changes in global methylation and glucose homeostasis in both generations. In general, F0 adult zebrafish exhibited altered global methylation levels in the ovary; F1 zebrafish had global hypomethylation. Fasting blood glucose levels were decreased in F0 but increased in F1; postprandial glucose levels were elevated in both F0 and F1. This androgenized zebrafish study suggests that transient excess androgen exposure during early development can result in transgenerational alterations in the ovarian epigenome and glucose homeostasis. Current data cannot establish a causal relationship between epigenetic changes and altered glucose homeostasis. Whether transgenerational epigenetic alteration induced by prenatal androgen exposure plays a role in the development of PCOS in humans deserves study. PMID:24992182

Specific and non-overlapping functions of testosterone and 11-ketotestosterone in the regulation of professional phagocyte responses in the teleost fish gilthead seabream.

PubMed

Aguila, S; Castillo-Briceño, P; Sánchez, M; Cabas, I; García-Alcázar, A; Meseguer, J; Mulero, V; García-Ayala, A

2013-03-01

Sex hormones, both estrogens and androgens, have a strong impact on immunity in mammals. In fish, the role of androgens in immunity has received little attention and contradictory conclusions have been obtained. However, it is well known that sex steroids are involved in fish growth, osmoregulation and gonad remodelation. In this study, we examine the in vitro effects of testosterone and 11-ketotestosterone, the two main fish androgens, on the professional phagocytes of the teleost fish gilthead seabream (Sparus aurata L.). Although both testosterone and 11-ketotestosterone failed to modulate the respiratory burst of seabream phagocytes, testosterone but not 11-ketotestosterone was able to increase the phagocytic ability of non-activated phagocytes. Curiously, 11-ketotestosterone was more powerful than testosterone at inducing the expression of its own receptor, namely androgen receptor b (ARb), in acidophilic granulocytes (AGs), but none of them affected the basal ARb expression levels in macrophages (MØ). Furthermore, although physiological concentrations of testosterone exerted a pro-inflammatory effect on both AGs and MØs, 11-ketotestosterone showed an anti-inflammatory effect in AGs and a strong pro-inflammatory effect in MØs. Interestingly, both androgens modulated the expression of toll-like receptors in these two immune cell types, suggesting that androgens might regulate the sensitivity of phagocytes to pathogens and damage signals. Testosterone and 11-ketotestosterone have a competitive effect, at least, on the modulation of the expression of some genes. Therefore, our results show for the first time a non-overlapping role for testosterone and 11-ketotestosterone in the regulation of professional phagocyte functions in fish. Copyright © 2012 Elsevier Ltd. All rights reserved.

Bmp7 and Lef1 are the downstream effectors of androgen signaling in androgen-induced sex characteristics development in medaka.

PubMed

Ogino, Yukiko; Hirakawa, Ikumi; Inohaya, Keiji; Sumiya, Eri; Miyagawa, Shinichi; Denslow, Nancy; Yamada, Gen; Tatarazako, Norihisa; Iguchi, Taisen

2014-02-01

Androgens play key roles in the morphological specification of male type sex attractive and reproductive organs, whereas little is known about the developmental mechanisms of such secondary sex characters. Medaka offers a clue about sexual differentiation. They show a prominent masculine sexual character for appendage development, the formation of papillary processes in the anal fin, which has been induced in females by exogenous androgen exposure. This current study shows that the development of papillary processes is promoted by androgen-dependent augmentation of bone morphogenic protein 7 (Bmp7) and lymphoid enhancer-binding factor-1 (Lef1). Androgen receptor (AR) subtypes, ARα and ARβ, are expressed in the distal region of outgrowing bone nodules of developing papillary processes. Development of papillary processes concomitant with the induction of Bmp7 and Lef1 in the distal bone nodules by exposure to methyltestosterone was significantly suppressed by an antiandrogen, flutamide, in female medaka. When Bmp signaling was inhibited in methyltestosterone-exposed females by its inhibitor, dorsomorphin, Lef1 expression was suppressed accompanied by reduced proliferation in the distal bone nodules and retarded bone deposition. These observations indicate that androgen-dependent expressions of Bmp7 and Lef1 are required for the bone nodule outgrowth leading to the formation of these secondary sex characteristics in medaka. The formation of androgen-induced papillary processes may provide insights into the mechanisms regulating the specification of sexual features in vertebrates.

Androgen-induced Long Noncoding RNA (lncRNA) SOCS2-AS1 Promotes Cell Growth and Inhibits Apoptosis in Prostate Cancer Cells*

PubMed Central

Misawa, Aya; Takayama, Ken-ichi; Urano, Tomohiko; Inoue, Satoshi

2016-01-01

Long noncoding RNAs (lncRNA) have been associated with the development of cancer. However, the interplay between lncRNAs and androgen receptor (AR) signaling in prostate cancer is still unclear. Here, we identified lncRNAs induced by androgen in AR-positive prostate cancer cells, where induction was abolished by AR knockdown as well as an anti-androgen, bicalutamide. By combining these data, we identified an androgen-regulated lncRNA, suppressor of cytokine signaling 2-antisense transcript 1 (SOCS2-AS1), the expression of which was higher in castration-resistant prostate cancer model cells, i.e. long-term androgen-deprived (LTAD) cells, than in parental androgen-dependent LNCaP cells. SOCS2-AS1 promoted castration-resistant and androgen-dependent cell growth. We found that SOCS2-AS1 knockdown up-regulated genes related to the apoptosis pathway, including tumor necrosis factor superfamily 10 (TNFSF10), and sensitized prostate cancer cells to docetaxel treatment. Moreover, we also demonstrated that SOCS2-AS1 promotes androgen signaling by modulating the epigenetic control for AR target genes including TNFSF10. These findings suggest that SOCS2-AS1 plays an important role in the development of castration-resistant prostate cancer by repressing apoptosis. PMID:27342777

GH improves spatial memory and reverses certain anabolic androgenic steroid-induced effects in intact rats.

PubMed

Grönbladh, Alfhild; Johansson, Jenny; Nöstl, Anatole; Nyberg, Fred; Hallberg, Mathias

2013-01-01

GH has previously been shown to promote cognitive functions in GH-deficient rodents. In this study we report the effects of GH on learning and memory in intact rats pretreated with the anabolic androgenic steroid nandrolone. Male Wistar rats received nandrolone decanoate (15 mg/kg) or peanut oil every third day for 3 weeks and were subsequently treated with recombinant human GH (1.0 IU/kg) or saline for 10 consecutive days. During the GH/saline treatment spatial learning and memory were tested in the Morris water maze (MWM). Also, plasma levels of IGF1 were assessed and the gene expression of the GH receptors (Ghr), Igf1 and Igf2, in hippocampus and frontal cortex was analyzed. The results demonstrated a significant positive effect of GH on memory functions and increased gene expression of Igf1 in the hippocampus was found in the animals treated with GH. In addition, GH was demonstrated to increase the body weight gain and was able to attenuate the reduced body weight seen in nandrolone-treated animals. In general, the rats treated with nandrolone alone did not exhibit any pronounced alteration in memory compared with controls in the MWM, and in many cases GH did not induce any alteration. Regarding target zone crossings, considered to be associated with spatial memory, the difference between GH- and steroid-treated animals was significant and administration of GH improved this parameter in the latter group. In conclusion, GH improves spatial memory in intact rats and can reverse certain effects induced by anabolic androgenic steroid.

Androgens and Female Sexual Function and Dysfunction--Findings From the Fourth International Consultation of Sexual Medicine.

PubMed

Davis, Susan R; Worsley, Roisin; Miller, Karen K; Parish, Sharon J; Santoro, Nanette

2016-02-01

Androgens have been implicated as important for female sexual function and dysfunction. To review the role of androgens in the physiology and pathophysiology of female sexual functioning and the evidence for efficacy of androgen therapy for female sexual dysfunction (FSD). We searched the literature using online databases for studies pertaining to androgens and female sexual function. Major reviews were included and their findings were summarized to avoid replicating their content. Quality of data published in the literature and recommendations were based on the GRADES system. The literature supports an important role for androgens in female sexual function. There is no blood androgen level below which women can be classified as having androgen deficiency. Clinical trials have consistently demonstrated that transdermal testosterone (T) therapy improves sexual function and sexual satisfaction in women who have been assessed as having hypoactive sexual desire disorder. The use of T therapy is limited by the lack of approved formulations for women and long-term safety data. Most studies do not support the use of systemic dehydroepiandrosterone therapy for the treatment of FSD in women with normally functioning adrenals or adrenal insufficiency. Studies evaluating the efficacy and safety of vaginal testosterone and dehydroepiandrosterone for the treatment of vulvovaginal atrophy are ongoing. Available data support an important role of androgens in female sexual function and dysfunction and efficacy of transdermal T therapy for the treatment of some women with FSD. Approved T formulations for women are generally unavailable. In consequence, the prescribing of T mostly involves off-label use of T products formulated for men and individually compounded T formulations. Long-term studies to determine the safety of T therapy for women and possible benefits beyond that of sexual function are greatly needed. Copyright © 2016. Published by Elsevier Inc.

Selective androgen receptor modulators as function promoting therapies.

PubMed

Bhasin, Shalender; Jasuja, Ravi

2009-05-01

The past decade has witnessed an unprecedented discovery effort to develop selective androgen receptor modulators (SARMs) that improve physical function and bone health without adversely affecting the prostate and cardiovascular outcomes. This review describes the historical evolution, the rationale for SARM development, and the mechanisms of testosterone action and SARM selectivity. Although steroidal SARMs have been around since the 1940s, a number of nonsteroidal SARMs that do not serve as substrates for CYP19 aromatase or 5alpha-reductase, act as full agonists in muscle and bone and as partial agonists in prostate are in development. The differing interactions of steroidal and nonsteroidal compounds with androgen receptor (AR) contribute to their unique pharmacologic actions. Ligand binding induces specific conformational changes in the ligand-binding domain, which could modulate surface topology and protein-protein interactions between AR and coregulators, resulting in tissue-specific gene regulation. Preclinical studies have demonstrated the ability of SARMs to increase muscle and bone mass in preclinical rodent models with varying degree of prostate sparing. Phase I trials of SARMs in humans have reported modest increments in fat-free mass. SARMs hold promise as a new class of function promoting anabolic therapies for a number of clinical indications, including functional limitations associated with aging and chronic disease, frailty, cancer cachexia, and osteoporosis.

Prenatal Androgen Exposure Causes Hypertension and Gut Microbiota Dysbiosis.

PubMed

Sherman, Shermel; Sarsour, Nadeen; Salehi, Marziyeh; Schroering, Allen; Mell, Blair; Joe, Bina; Hill, Jennifer W

2018-02-22

Conditions of excess androgen in women, such as polycystic ovary syndrome (PCOS), often exhibit intergenerational transmission. One way in which the risk for PCOS may be increased in daughters of affected women is through exposure to elevated androgens in utero. Hyperandrogenemic conditions have serious health consequences, including increased risk for hypertension and cardiovascular disease. Recently, gut dysbiosis has been found to induce hypertension in rats, such that blood pressure can be normalized through fecal microbial transplant. Therefore, we hypothesized that the hypertension seen in PCOS has early origins in gut dysbiosis caused by in utero exposure to excess androgen. We investigated this hypothesis with a model of prenatal androgen (PNA) exposure and maternal hyperandrogenemia by single-injection of testosterone cypionate or sesame oil vehicle (VEH) to pregnant dams in late gestation. We then completed a gut microbiota and cardiometabolic profile of the adult female offspring. The metabolic assessment revealed that adult PNA rats had increased body weight and increased mRNA expression of adipokines: adipocyte binding protein 2, adiponectin, and leptin in inguinal white adipose tissue. Radiotelemetry analysis revealed hypertension with decreased heart rate in PNA animals. The fecal microbiota profile of PNA animals contained higher relative abundance of bacteria associated with steroid hormone synthesis, Nocardiaceae and Clostridiaceae, and lower abundance of Akkermansia, Bacteroides, Lactobacillus, Clostridium. The PNA animals also had an increased relative abundance of bacteria associated with biosynthesis and elongation of unsaturated short chain fatty acids (SCFAs). We found that prenatal exposure to excess androgen negatively impacted cardiovascular function by increasing systolic and diastolic blood pressure and decreasing heart rate. Prenatal androgen was also associated with gut microbial dysbiosis and altered abundance of bacteria involved in metabolite production of short chain fatty acids. These results suggest that early-life exposure to hyperandrogenemia in daughters of women with PCOS may lead to long-term alterations in gut microbiota and cardiometabolic function.

Androgen excess and metabolic disorders in women with PCOS: beyond the body mass index.

PubMed

Condorelli, R A; Calogero, A E; Di Mauro, M; Mongioi', L M; Cannarella, R; Rosta, G; La Vignera, S

2018-04-01

Insulin resistance is a common feature among women with polycystic ovary syndrome (PCOS), especially in those patients with hyperandrogenism and chronic anovulation. PCOS women are at risk for developing metabolic syndrome, impaired glucose tolerance and type II diabetes mellitus (DM II). The aim of this review is to explore the existing knowledge of the interplay between androgen excess, pancreatic β-cell function, non-alcoholic fatty liver disease (NAFLD), intra-abdominal and subcutaneous (SC) abdominal adipocytes in PCOS, providing a better comprehension of the molecular mechanisms of diabetologic interest. A comprehensive MEDLINE ® search was performed using relevant key terms for PCOS and DM II. Insulin-induced hyperandrogenism could impair pancreatic β-cell function, the SC abdominal adipocytes' lipid storage capacity, leading to intra-abdominal adipocyte hypertrophy and lipotoxicity, which in turn promotes insulin resistance, and could enhance NAFLD. Fetal hyperandrogenism exposure prompts to metabolic disorders. Treatment with flutamide showed to partially reverse insulin resistance. Metabolic impairment seems not to be dependent only on the total fat mass content and body weight in women with PCOS and might be ascribed to the androgen excess.

Orphan nuclear receptor TLX contributes to androgen insensitivity in castration-resistant prostate cancer via its repression of androgen receptor transcription.

PubMed

Jia, Lin; Wu, Dinglan; Wang, Yuliang; You, Wenxing; Wang, Zhu; Xiao, Lijia; Cai, Ganhui; Xu, Zhenyu; Zou, Chang; Wang, Fei; Teoh, Jeremy Yuen-Chun; Ng, Chi-Fai; Yu, Shan; Chan, Franky L

2018-03-20

The metastatic castration-resistant prostate cancer (CRPC) is a lethal form of prostate cancer, in which the expression of androgen receptor (AR) is highly heterogeneous. Indeed, lower AR expression and attenuated AR signature activity is shown in CRPC tissues, especially in the subset of neuroendocrine prostate cancer (NEPC) and prostate cancer stem-like cells (PCSCs). However, the significance of AR downregulation in androgen insensitivity and de-differentiation of tumor cells in CRPC is poorly understood and much neglected. Our previous study shows that the orphan nuclear receptor TLX (NR2E1), which is upregulated in prostate cancer, plays an oncogenic role in prostate carcinogenesis by suppressing oncogene-induced senescence. In the present study, we further established that TLX exhibited an increased expression in metastatic CRPC. Further analyses showed that overexpression of TLX could confer resistance to androgen deprivation and anti-androgen in androgen-dependent prostate cancer cells in vitro and in vivo, whereas knockdown of endogenous TLX could potentiate the sensitivity to androgen deprivation and anti-androgen in prostate cancer cells. Our study revealed that the TLX-induced resistance to androgen deprivation and anti-androgen was mediated through its direct suppression of AR gene transcription and signaling in both androgen-stimulated and -unstimulated prostate cancer cells. We also characterized that TLX could bind directly to AR promoter and repress AR transcription by recruitment of histone modifiers, including HDAC1, HDAC3, and LSD1. Together, our present study shows, for the first time, that TLX can contribute to androgen insensitivity in CRPC via repression of AR gene transcription and signaling, and also implicates that targeting the druggable TLX may have a potential therapeutic significance in CRPC management, particularly in NEPC and PCSCs.

Chemoprevention of rat prostate carcinogenesis by dietary 16alpha-fluoro-5-androsten-17-one (fluasterone), a minimally androgenic analog of dehydroepiandrosterone.

PubMed

McCormick, David L; Johnson, William D; Kozub, Nicole M; Rao, K V N; Lubet, Ronald A; Steele, Vernon E; Bosland, Maarten C

2007-02-01

Dehydroepiandrosterone (DHEA) is a potent inhibitor of prostate carcinogenesis in rats. However, concerns related to the possible androgenicity of DHEA may preclude its use for chemoprevention of human prostate cancer. Studies were performed to compare the androgenicity of DHEA and a fluorinated DHEA analog, 16alpha-fluoro-5-androsten-17-one (fluasterone), and to determine the chemopreventive activity of fluasterone in the rat prostate. Comparisons of accessory sex gland weight and histology in gonadectomized male rats demonstrated that fluasterone is less androgenic than is DHEA. Fluasterone conferred significant protection against prostate carcinogenesis induced in Wistar-Unilever rats by a sequential regimen of N-methyl-N-nitrosourea+testosterone. Chronic administration of fluasterone at levels of 2000 and 1000 mg/kg diet reduced the incidence of adenocarcinoma in the dorsolateral/anterior prostate from 64% in dietary controls to 28 and 31%, respectively. Other than a dose-related suppression of body weight gain, chronic exposure to fluasterone induced no clinical evidence of toxicity; suppression of body weight gain may be either a pharmacological effect or a minimally toxic effect of the compound. These data demonstrate that a minimally androgenic analog of DHEA protects against prostate carcinogenesis induced in rats by a chemical carcinogen + androgen. The reduced androgenicity of fluasterone may obviate toxicities associated with the androgenicity of the parent compound. On this basis, fluasterone merits consideration for evaluation in clinical trials for prostate cancer prevention. The chemopreventive activity of a non-androgenic DHEA analog suggests that at least a portion of the chemopreventive activity of DHEA in the rat prostate is unrelated to hormonal effects.

Huntingtin interacting protein 1 modulates the transcriptional activity of nuclear hormone receptors

PubMed Central

Mills, Ian G.; Gaughan, Luke; Robson, Craig; Ross, Theodora; McCracken, Stuart; Kelly, John; Neal, David E.

2005-01-01

Internalization of activated receptors regulates signaling, and endocytic adaptor proteins are well-characterized in clathrin-mediated uptake. One of these adaptor proteins, huntingtin interacting protein 1 (HIP1), induces cellular transformation and is overexpressed in some prostate cancers. We have discovered that HIP1 associates with the androgen receptor through a central coiled coil domain and is recruited to DNA response elements upon androgen stimulation. HIP1 is a novel androgen receptor regulator, significantly repressing transcription when knocked down using a silencing RNA approach and activating transcription when overexpressed. We have also identified a functional nuclear localization signal at the COOH terminus of HIP1, which contributes to the nuclear translocation of the protein. In conclusion, we have discovered that HIP1 is a nucleocytoplasmic protein capable of associating with membranes and DNA response elements and regulating transcription. PMID:16027218

Artemisinin disrupts androgen responsiveness of human prostate cancer cells by stimulating the 26S proteasome-mediated degradation of the androgen receptor protein.

PubMed

Steely, Andrea M; Willoughby, Jamin A; Sundar, Shyam N; Aivaliotis, Vasiliki I; Firestone, Gary L

2017-10-01

Androgen receptor (AR) expression and activity is highly linked to the development and progression of prostate cancer and is a target of therapeutic strategies for this disease. We investigated whether the antimalarial drug artemisinin, which is a sesquiterpene lactone isolated from the sweet wormwood plant Artemisia annua, could alter AR expression and responsiveness in cultured human prostate cancer cell lines. Artemisinin treatment induced the 26S proteasome-mediated degradation of the receptor protein, without altering AR transcript levels, in androgen-responsive LNCaP prostate cancer cells or PC-3 prostate cancer cells expressing exogenous wild-type AR. Furthermore, artemisinin stimulated AR ubiquitination and AR receptor interactions with the E3 ubiquitin ligase MDM2 in LNCaP cells. The artemisinin-induced loss of AR protein prevented androgen-responsive cell proliferation and ablated total AR transcriptional activity. The serine/threonine protein kinase AKT-1 was shown to be highly associated with artemisinin-induced proteasome-mediated degradation of AR protein. Artemisinin treatment activated AKT-1 enzymatic activity, enhanced receptor association with AKT-1, and induced AR serine phosphorylation. Treatment of LNCaP cells with the PI3-kinase inhibitor LY294002, which inhibits the PI3-kinase-dependent activation of AKT-1, prevented the artemisinin-induced AR degradation. Furthermore, in transfected receptor-negative PC-3 cells, artemisinin failed to stimulate the degradation of an altered receptor protein (S215A/S792A) with mutations in its two consensus AKT-1 serine phosphorylation sites. Taken together, our results indicate that artemisinin induces the degradation of AR protein and disrupts androgen responsiveness of human prostate cancer cells, suggesting that this natural compound represents a new potential therapeutic molecule that selectively targets AR levels.

The influence of androgens, anti-androgens, and castration on cell proliferation in the jejunal and colonic crypt epithelia, and in dimethylhydrazine-induced adenocarcinoma of rat colon.

PubMed

Tutton, P J; Barkla, D H

1982-01-01

Androgenic hormones have previously been shown to promote cell proliferation in the small intestine of rat and androgen receptors have been demonstrated in carcinomata of the large intestine of rat. In this study the influence of testosterone and of castration on epithelial cell proliferation in the small intestine, the large intestine and in dimethylhydrazine-induced colonic tumours is compared. Cell proliferation in the small intestine and in colonic tumours was accelerated by testosterone treatment, and cell proliferation in colonic tumours, but not in the small intestine, was retarded following castration. Cell proliferation in colonic tumours was also inhibited by the anti-androgenic drug, Flutamide. Testosterone and castration each failed to influence cell proliferation in the colonic crypt epithelium of both normal and carcinogen-treated animals.

Sexual dimorphism and the effects of the X-linked Tfm locus on hexobarbitone metabolism and action in mice.

PubMed

King, D K; Shapiro, B H

1981-09-01

1 Normal males of the testicular feminized strain of mice (Tfm) had longer hexobarbitone-induced sleeping times than females, and hepatic hexobarbitone hydroxylase activity different in that the Km was higher and the Vmax lower in the male. 2 Castration and androgen replacement studies indicated that testicular androgens were responsible for the sexual differences in drug metabolism found in this mouse strain. 3 Hepatic hexobarbitone metabolism and action were feminized in the intact, androgen-insensitive, genetically male Tfm mouse. Furthermore, hexobarbitone hydroxylase activities were less responsive to large doses of testosterone in Tfm mice than in normal males. 4 The Tfm mouse with a deficiency in androgen receptors responded to the enzyme-inductive effects of phenobarbitone and softwood bedding, indicating that these inducers do not act through the androgen receptors.

Resveratrol, piceatannol and analogs inhibit activation of both wild-type and T877A mutant androgen receptor.

PubMed

Lundqvist, Johan; Tringali, Corrado; Oskarsson, Agneta

2017-11-01

Prostate cancer growth and progression are mainly dependent on androgens and many current prostate cancer treatment options target the synthesis or function of androgens. We have previously reported that resveratrol and synthetic analogs of resveratrol with a higher bioavailability inhibit the synthesis of androgens in human adrenocortical H295R cells. Now we have studied the antiandrogenic properties of resveratrol, piceatannol and analogs in two different prostate cell lines; LNCaP and RWPE. LNCaP carry a T877A mutation in the androgen receptor while RWPE has a wild-type androgen receptor. We found that resveratrol, piceatannol and all studied analogs were able to inhibit a dihydrotestosterone-induced activation of the androgen receptor, showing that they act as antiandrogens. In LNCaP cells, all studied compounds were able to statistically significantly decrease the androgenic signaling in concentrations ≥1μM and the synthetic analogs trimethylresveratrol (RSVTM) and tetramethylpiceatannol (PICTM) were the most potent compounds. RWPE cells were not as responsive to the studied compounds as the LNCaP cells. A statistically significant decrease in the androgenic signaling was observed at concentrations ≤5μM for most compounds and RSVTM was found to be the most potent compound. Further, we studied the effects of resveratrol, piceatannol and analogs on the levels of prostate-specific antigen (PSA) in LNCaP cells and found that all studied compounds decreased the level of PSA and that the synthetic analogs diacetylresveratrol (RSVDA), triacetylresveratrol (RSVTA) and RSVTM were the most potent compounds, decreasing the PSA level by approx. 50% at concentrations ≥10μM. In a cell-free receptor binding assay we were unable to show binding of resveratrol or analogs to the ligand binding domain of the androgen receptor, indicating that the observed effects are mediated via other mechanisms than direct ligand competition. We conclude that the resveratrol, piceatannol and analogs are highly interesting for chemoprevention of prostate cancer, since they have a high potency both as inhibitors of androgen synthesis and androgen receptor activation. Copyright © 2017 Elsevier Ltd. All rights reserved.

TBT-induced imposex in marine neogastropods is mediated by an increasing androgen level

NASA Astrophysics Data System (ADS)

Bettin, C.; Oehlmann, J.; Stroben, E.

1996-09-01

Tributyltin (TBT) exposure at different concentrations (5, 60, and 100 ng TBT as Sn/l) induces a concentration- and time-dependent imposex (=pseudohermaphroditism) development in female Nucella lapillus and Hinia reticulata. In both species the average imposex stage, termed as vas deferens sequence (VDS) index, and the average female penis length increases with increasing TBT concentration and duration of TBT exposure. Testosterone added at a concentration of 500 ng/l induces a faster and more intensive imposex development compared to that induced by the TBT concentrations used in the present experiments. Radioimmunological determination of endogenous steroid content reveals increasing testosterone titres in female gastropods exposed to TBT which correlate with the TBT concentration used and the duration of the experiment. The most marked and highest increase of the endogenous testosterone level is exhibited by females, of both species exposed to testosterone. Simulataneous exposure to TBT and to the antiandrogen cyproterone acetate which suppresses imposex development completely in N. lapillus and reduces imposex development strongly in H. reticulata proves that the imposex-inducing effects of TBT are mediated by an increasing androgen level and are not caused directly by the organotin compound itself. Further-more, TBT-induced imposex development can be suppressed in both snails by adding estrogens to the aqueous medium. These observations suggest that TBT causes an inhibition of the cytochrome P-450 dependent aromatase system which catalyses the aromatization of androgens to estrogens. The increase of the androgen content or the shift of the androgen-estrogen balance in favour of androgens induces the development of pseudohermaphroditism in marine prosobranchs. Artificial inhibition of the cytochrome P-450 dependent aromatase system using SH 489 (1-methyl-1,4-androstadiene-3,17-dione) as a steroidal aromatase inhibitor and flavone as a nonsteroidal aromatase inhibitor induces imposex development in N. lapillus as well as in H. reticulata.

Androgen effects on skeletal muscle: implications for the development and management of frailty

PubMed Central

O’Connell, Matthew DL; Wu, Frederick CW

2014-01-01

Androgens have potent anabolic effects on skeletal muscle and decline with age in parallel to losses in muscle mass and strength. This loss of muscle mass and function, known as sarcopenia, is the central event in development of frailty, the vulnerable health status that presages adverse outcomes and rapid functional decline in older adults. The potential role of falling androgen levels in the development of frailty and their utility as function promoting therapies in older men has therefore attracted considerable attention. This review summarizes current concepts and definitions in muscle ageing, sarcopenia and frailty, and evaluates recent developments in the study of androgens and frailty. Current evidence from observational and interventional studies strongly supports an effect of androgens on muscle mass in ageing men, but effects on muscle strength and particularly physical function have been less clear. Androgen treatment has been generally well–tolerated in studies of older men, but concerns remain over higher dose treatments and use in populations with high cardiovascular risk. The first trials of selective androgen receptor modulators (SARMs) suggest similar effects on muscle mass and function to traditional androgen therapies in older adults. Important future directions include the use of these agents in combination with exercise training to promote functional ability across different populations of older adults, as well as more focus on the relationships between concurrent changes in hormone levels, body composition and physical function in observational studies. PMID:24457838

Androgen deprivation therapy sensitizes prostate cancer cells to T-cell killing through androgen receptor dependent modulation of the apoptotic pathway

PubMed Central

Ardiani, Andressa; Gameiro, Sofia R.; Kwilas, Anna R.; Donahue, Renee N.; Hodge, James W.

2014-01-01

Despite recent advances in diagnosis and management, prostrate cancer remains the second most common cause of death from cancer in American men, after lung cancer. Failure of chemotherapies and hormone-deprivation therapies is the major cause of death in patients with castration-resistant prostate cancer (CRPC). Currently, the androgen inhibitors enzalutamide and abiraterone are approved for treatment of metastatic CRPC. Here we show for the first time that both enzalutamide and abiraterone render prostate tumor cells more sensitive to T cell-mediated lysis through immunogenic modulation, and that these immunomodulatory activities are androgen receptor (AR)-dependent. In studies reported here, the NAIP gene was significantly down-regulated in human prostate tumor cells treated in vitro and in vivo with enzalutamide. Functional analysis revealed that NAIP played a critical role in inducing CTL sensitivity. Amplification of AR is a major mechanism of resistance to androgen-deprivation therapy (ADT). Here, we show that enzalutamide enhances sensitivity to immune-mediated killing of prostate tumor cells that overexpress AR. The immunomodulatory properties of enzalutamide and abiraterone provide a rationale for their use in combination with immunotherapeutic agents in CRPC, especially for patients with minimal response to enzalutamide or abiraterone alone, or for patients who have developed resistance to ADT. PMID:25344864

Androgen Deficiency During Mid- and Late Pregnancy Alters Progesterone Production and Metabolism in the Porcine Corpus Luteum

PubMed Central

Knapczyk-Stwora, Katarzyna; Ciereszko, Renata E.; Golas, Aniela; Wieciech, Iwona; Slomczynska, Maria

2014-01-01

We determined whether androgen deficiency induced by flutamide treatment during mid- and late pregnancy affects the functions of the porcine corpus luteum (CL). Pregnant gilts were injected with flutamide between days 43 and 49 (gestation day [GD] 50F), days 83 and 89 (GD90F), or days 101 and 107 (GD108F) of gestation. Antiandrogen treatment increased the luteal progesterone concentration in the GD50F group and decreased progesterone content in the GD90F and GD108F groups. Luteal levels of side-chain cleavage cytochrome P450 (CYP11A1) mRNA and protein were significantly downregulated in the GD90F and GD108F groups as compared with the respective controls. The 3β-hydroxysteroid dehydrogenase/Δ5-Δ4 isomerase (HSD3B) mRNA and protein expression were significantly reduced only in the GD108F group as compared with the control. Decreased luteal 20α-hydroxysteroid dehydrogenase (AKR1C1) mRNA and protein levels were observed in the GD50F group. Thus, androgen deficiency during pregnancy in pigs led to CL dysfunction that is marked by decreased progesterone production. Furthermore, exposure to flutamide during late pregnancy downregulated steroidogenic enzymes (CYP11A1 and HSD3B) in pigs. We conclude that androgens are important regulators of CL function during pregnancy. PMID:24429677

Androgen deficiency during mid- and late pregnancy alters progesterone production and metabolism in the porcine corpus luteum.

PubMed

Grzesiak, Malgorzata; Knapczyk-Stwora, Katarzyna; Ciereszko, Renata E; Golas, Aniela; Wieciech, Iwona; Slomczynska, Maria

2014-06-01

We determined whether androgen deficiency induced by flutamide treatment during mid- and late pregnancy affects the functions of the porcine corpus luteum (CL). Pregnant gilts were injected with flutamide between days 43 and 49 (gestation day [GD] 50F), days 83 and 89 (GD90F), or days 101 and 107 (GD108F) of gestation. Antiandrogen treatment increased the luteal progesterone concentration in the GD50F group and decreased progesterone content in the GD90F and GD108F groups. Luteal levels of side-chain cleavage cytochrome P450 (CYP11A1) mRNA and protein were significantly downregulated in the GD90F and GD108F groups as compared with the respective controls. The 3β-hydroxysteroid dehydrogenase/Δ5-Δ4 isomerase (HSD3B) mRNA and protein expression were significantly reduced only in the GD108F group as compared with the control. Decreased luteal 20α-hydroxysteroid dehydrogenase (AKR1C1) mRNA and protein levels were observed in the GD50F group. Thus, androgen deficiency during pregnancy in pigs led to CL dysfunction that is marked by decreased progesterone production. Furthermore, exposure to flutamide during late pregnancy downregulated steroidogenic enzymes (CYP11A1 and HSD3B) in pigs. We conclude that androgens are important regulators of CL function during pregnancy.

Neonatal Handling Produces Sex Hormone-Dependent Resilience to Stress-Induced Muscle Hyperalgesia in Rats.

PubMed

Alvarez, Pedro; Green, Paul G; Levine, Jon D

2018-06-01

Neonatal handling (NH) of male rat pups strongly attenuates stress response and stress-induced persistent muscle hyperalgesia in adults. Because female sex is a well established risk factor for stress-induced chronic muscle pain, we explored whether NH provides resilience to stress-induced hyperalgesia in adult female rats. Rat pups underwent NH, or standard (control) care. Muscle mechanical nociceptive threshold was assessed before and after water avoidance (WA) stress, when they were adults. In contrast to male rats, NH produced only a modest protection against WA stress-induced muscle hyperalgesia in female rats. Gonadectomy completely abolished NH-induced resilience in male rats but produced only a small increase in this protective effect in female rats. The administration of the antiestrogen drug fulvestrant, in addition to gonadectomy, did not enhance the protective effect of NH in female rats. Finally, knockdown of the androgen receptor by intrathecal antisense treatment attenuated the protective effect of NH in intact male rats. Together, these data indicate that androgens play a key role in NH-induced resilience to WA stress-induced muscle hyperalgesia. NH induces androgen-dependent resilience to stress-induced muscle pain. Therefore, androgens may contribute to sex differences observed in chronic musculoskeletal pain and its enhancement by stress. Copyright © 2018 The American Pain Society. Published by Elsevier Inc. All rights reserved.

TBECH, 1,2-dibromo-4-(1,2 dibromoethyl) cyclohexane, alters androgen receptor regulation in response to mutations associated with prostate cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kharlyngdoh, Joubert Banjop; Asnake, Solomon; Prad

Point mutations in the AR ligand-binding domain (LBD) can result in altered AR structures leading to changes of ligand specificity and functions. AR mutations associated to prostate cancer (PCa) have been shown to result in receptor activation by non-androgenic substances and anti-androgenic drugs. Two AR mutations known to alter the function of anti-androgens are the AR{sub T877A} mutation, which is frequently detected mutation in PCa tumors and the AR{sub W741C} that is rare and has been derived in vitro following exposure of cells to the anti-androgen bicalutamide. AR activation by non-androgenic environmental substances has been suggested to affect PCa progression.more » In the present study we investigated the effect of AR mutations (AR{sub W741C} and AR{sub T877A}) on the transcriptional activation following exposure of cells to an androgenic brominated flame retardant, 1,2-dibromo-4-(1,2 dibromoethyl) cyclohexane (TBECH, also named DBE-DBCH). The AR mutations resulted in higher interaction energies and increased transcriptional activation in response to TBECH diastereomer exposures. The AR{sub T877A} mutation rendered AR highly responsive to low levels of DHT and TBECH and led to increased AR nuclear translocation. Gene expression analysis showed a stronger induction of AR target genes in LNCaP cells (AR{sub T877A}) compared to T-47D cells (AR{sub WT}) following TBECH exposure. Furthermore, AR knockdown experiments confirmed the AR dependency of these responses. The higher sensitivity of AR{sub T877A} and AR{sub W741C} to low levels of TBECH suggests that cells with these AR mutations are more susceptible to androgenic endocrine disrupters. - Highlights: • TBECH, is an endocrine disrupting compound that differ in activity depending on AR structure and sequence. • TBECH interaction with the human AR-LBD containing the mutations W741C and T877A is increased compared to the wild type receptor • The mutations, W741C and T877A, are more potent than the wild type receptor at inducing AR nuclear translocation and transcriptional activation following TBECH exposure. • TBECH mediates action on androgen response genes via AR signaling.« less

Androgen receptor: structure, role in prostate cancer and drug discovery

PubMed Central

Tan, MH Eileen; Li, Jun; Xu, H Eric; Melcher, Karsten; Yong, Eu-leong

2015-01-01

Androgens and androgen receptors (AR) play a pivotal role in expression of the male phenotype. Several diseases, such as androgen insensitivity syndrome (AIS) and prostate cancer, are associated with alterations in AR functions. Indeed, androgen blockade by drugs that prevent the production of androgens and/or block the action of the AR inhibits prostate cancer growth. However, resistance to these drugs often occurs after 2–3 years as the patients develop castration-resistant prostate cancer (CRPC). In CRPC, a functional AR remains a key regulator. Early studies focused on the functional domains of the AR and its crucial role in the pathology. The elucidation of the structures of the AR DNA binding domain (DBD) and ligand binding domain (LBD) provides a new framework for understanding the functions of this receptor and leads to the development of rational drug design for the treatment of prostate cancer. An overview of androgen receptor structure and activity, its actions in prostate cancer, and how structural information and high-throughput screening have been or can be used for drug discovery are provided herein. PMID:24909511

MECHANISMS IN ENDOCRINOLOGY: The sexually dimorphic role of androgens in human metabolic disease.

PubMed

Schiffer, Lina; Kempegowda, Punith; Arlt, Wiebke; O'Reilly, Michael W

2017-09-01

Female androgen excess and male androgen deficiency manifest with an overlapping adverse metabolic phenotype, including abdominal obesity, insulin resistance, type 2 diabetes mellitus, non-alcoholic fatty liver disease and an increased risk of cardiovascular disease. Here, we review the impact of androgens on metabolic target tissues in an attempt to unravel the complex mechanistic links with metabolic dysfunction; we also evaluate clinical studies examining the associations between metabolic disease and disorders of androgen metabolism in men and women. We conceptualise that an equilibrium between androgen effects on adipose tissue and skeletal muscle underpins the metabolic phenotype observed in female androgen excess and male androgen deficiency. Androgens induce adipose tissue dysfunction, with effects on lipid metabolism, insulin resistance and fat mass expansion, while anabolic effects on skeletal muscle may confer metabolic benefits. We hypothesise that serum androgen concentrations observed in female androgen excess and male hypogonadism are metabolically disadvantageous, promoting adipose and liver lipid accumulation, central fat mass expansion and insulin resistance. © 2017 The authors.

MECHANISMS IN ENDOCRINOLOGY: The sexually dimorphic role of androgens in human metabolic disease

PubMed Central

Schiffer, Lina; Kempegowda, Punith; Arlt, Wiebke

2017-01-01

Female androgen excess and male androgen deficiency manifest with an overlapping adverse metabolic phenotype, including abdominal obesity, insulin resistance, type 2 diabetes mellitus, non-alcoholic fatty liver disease and an increased risk of cardiovascular disease. Here, we review the impact of androgens on metabolic target tissues in an attempt to unravel the complex mechanistic links with metabolic dysfunction; we also evaluate clinical studies examining the associations between metabolic disease and disorders of androgen metabolism in men and women. We conceptualise that an equilibrium between androgen effects on adipose tissue and skeletal muscle underpins the metabolic phenotype observed in female androgen excess and male androgen deficiency. Androgens induce adipose tissue dysfunction, with effects on lipid metabolism, insulin resistance and fat mass expansion, while anabolic effects on skeletal muscle may confer metabolic benefits. We hypothesise that serum androgen concentrations observed in female androgen excess and male hypogonadism are metabolically disadvantageous, promoting adipose and liver lipid accumulation, central fat mass expansion and insulin resistance. PMID:28566439

Comparison of steroid receptors from the androgen responsive DDT1 cell line and the nonresponsive HVP cell line.

PubMed

Norris, J S; Kohler, P O

1978-01-01

Two hamster cell lines have been isolated from androgen target tissue. The DDT1 cells derived from ductus deferens tissue exhibit a growth response to androgens, while the HVP cells derived from ventral prostate are androgen unresponsive. Both cell lines contain androgen receptors, that are similar when compared by kinetic methods, sedimentation velocity, chromatographic procedures or nuclear translocation ability. The forms of the high salt extracted nuclear receptors are indistinguishable chromatographically. Therefore, we postulate that the lesion preventing androgen induced growth in the HVP cell line is subseqent to nuclear translocation of the steroid receptor complex.

Androgen Triggers the Pro-Migratory CXCL12/CXCR4 Axis in AR-Positive Breast Cancer Cell Lines: Underlying Mechanism and Possible Implications for the Use of Aromatase Inhibitors in Breast Cancer.

PubMed

Azariadis, Kalliopi; Kiagiadaki, Fotini; Pelekanou, Vasiliki; Bempi, Vasiliki; Alexakis, Kostas; Kampa, Marilena; Tsapis, Andreas; Castanas, Elias; Notas, George

2017-01-01

Reports regarding the role of androgen in breast cancer (BC) are conflicting. Some studies suggest that androgen could lead to undesirable responses in the presence of certain BC tumor characteristics. We have shown that androgen induces C-X-C motif chemokine 12 (CXCL12) in BC cell lines. Our aim was to identify the mechanisms regulating the phenotypic effects of androgen-induced CXCL12 on Androgen Receptor (AR) positive BC cell lines. We analyzed the expression of CXCL12 and its receptors with qPCR and ELISA and the role of Nuclear Receptor Coactivator 1 (NCOA1) in this effect. AR effects on the CXCL12 promoter was studied via Chromatin-immunoprecipitation. We also analyzed publically available data from The Cancer Genome Atlas to verify AR-CXCL12 interactions and to identify the effect or Aromatase Inhibitors (AI) therapy on CXCL12 expression and disease progression in AR positive cases. CXCL12 induction occurs only in AR-positive BC cell lines, possibly via an Androgen Response Element, upstream of the CXCL12 promoter. The steroid receptor co-regulator NCOA1 is critical for this effect. Androgen only induced the motility of p53-mutant BC cells T47D cells via upregulation of CXCR4 expression while they had no effect on wild-type p53 MCF-7 cells. Loss of CXCR4 expression and depletion of CXCL12 abolished the effect of androgen in T47D cells while inhibition of p53 expression in MCF-7 cells made them responsive to androgen and increased their motility in the presence to androgen. Patients with estrogen receptor positive (ER+)/AR+ BC treated with AIs were at increased risk of disease progression compared to ER+/AR+ non-AI treated and ER+/AR- AI treated cases. AIs may lead to unfavorable responses in some ER/AR positive BC cases, especially in patients with AR+, p53 mutant tumors. © 2017 The Author(s). Published by S. Karger AG, Basel.

MODE OF ACTION: INHIBITION OF ANDROGEN RECEPTOR FUNCTION--VINCLOZOLIN-INDUCED MALFORMATIONS IN REPRODUCTIVE DEVELOPMENT

EPA Science Inventory

Vinclozolin is a fungicide that has been shown to cause Leydig cell tumors and atrophy of the accessory sex glands in adult rodents. In addition, exposure of rats during pregnancy causes a pattern of malformations in the male urogenital tract. A wealth of standard toxicological s...

Androgen receptor-related diseases: what do we know?

PubMed

Shukla, G C; Plaga, A R; Shankar, E; Gupta, S

2016-05-01

The androgen receptor (AR) and the androgen-AR signaling pathway play a significant role in male sexual differentiation and the development and function of male reproductive and non-reproductive organs. Because of AR's widely varied and important roles, its abnormalities have been identified in various diseases such as androgen insensitivity syndrome, spinal bulbar muscular atrophy, benign prostatic hyperplasia, and prostate cancer. This review provides an overview of the function of androgens and androgen-AR mediated diseases. In addition, the diseases delineated above are discussed with respect to their association with mutations and other post-transcriptional modifications in the AR. Finally, we present an introduction to the potential therapeutic application of most recent pharmaceuticals including miRNAs in prostate cancer that specifically target the transactivation function of the AR at post-transcriptional stages. © 2016 American Society of Andrology and European Academy of Andrology.

No effect of sex steroids on compensatory muscle hypertrophy

NASA Technical Reports Server (NTRS)

Max, S. R.; Rance, N. E.

1984-01-01

The effects of orchiectomy and/or subcutaneously implanted testosterone propionate (TP) on the hypertrophic response of rat plantaris muscles to functional overload (induced by bilateral removal of gastrocnemius and soleus muscles) are investigated experimentally. Muscle wet weight, metabolic substrate oxidation, and cytosolic androgen-receptor binding are measured, and the results are presented in tables. Eight weeks after surgery, the plantaris muscle weight as a percentage of body weight is found to be about twice that in rats without muscle overload, regardless of the sex-hormone status. Overloading causes decreased ability to oxidize glucose and pyruvate, decreased succinate dehydrogenase specific activity, and no change in the ability to oxidize beta-hydroxybutyrate or in androgen-receptor binding. The oxidative response is unaffected by orchiectomy or TP or both. It is argued that the actions of sex hormones and functional overload are not synergistic.

Male-typical courtship, spawning behavior, and olfactory sensitivity are induced to different extents by androgens in the goldfish suggesting they are controlled by different neuroendocrine mechanisms.

PubMed

Ghosal, Ratna; Sorensen, Peter W

2016-06-01

Male-typical reproductive behaviors vary greatly between different species of fishes with androgens playing a variety of roles that appear especially important in the gonochorist cypriniform fishes. The goldfish is an important model for the cypriniformes and while it is clear that male goldfish are fully feminized by prostaglandin F2α(PGF2α), it is not clear whether females will exhibit normal levels of male-typical reproductive behaviors as well as olfactory function when treated with androgens. To answer this question, we exposed sexually-regressed adult female goldfish to several types of androgen and monitored their tendencies to court (inspect females) and mate (spawn, or attempt to release gametes) while monitoring their olfactory sensitivity until changes in these attributes were maximized. Untreated adult males (intact) were included to determine the extent of masculinization. Treatments included the natural androgens, 11-ketotestosterone and testosterone (KT and T), administered via capsules (KT+T-implanted fish); the artificial androgen, methyltestosterone (MT), administered via capsules (MT-C); and MT administered in the fishes' water (MT-B). Male-typical olfactory sensitivity to a pheromone (15keto-PGF2α) increased in all androgen-treated groups and by week 6 was fully equivalent to that of males. Male-typical courtship behavior increased in all androgen-treated groups although slowly, and only MT-B females came to exhibit levels equivalent to those of males after 18weeks. In contrast, male-typical mating activity increased only slightly, with MT-B females reaching levels one-third that of males after 30weeks. We conclude that while androgens fully masculinize olfactory sensitivity and courtship behavior in goldfish, mating behavior is controlled by a different neuroendocrine mechanism(s) that has yet to be fully elucidated. Copyright © 2016 Elsevier Inc. All rights reserved.

Public health impact of androgens.

PubMed

Kanayama, Gen; Kaufman, Marc J; Pope, Harrison G

2018-06-01

To summarize recent findings regarding the public health impact of androgen abuse. Abuse of androgens (also called 'anabolic-androgenic steroids') has grown into a major worldwide substance abuse problem involving tens of millions of individuals, of whom about 98% are men. Most androgen abusers are still under age 50 today, and thus, the long-term effects of these drugs are only beginning to be understood. Recent studies confirm that long-term supraphysiologic androgen exposure produces cardiovascular toxicity, characterized especially by cardiomyopathy and atherosclerotic disease. Withdrawal from androgens after long-term use may produce prolonged and sometimes irreversible hypogonadism in men. Supraphysiologic androgen levels may sometimes cause irritability, aggressiveness, and violence, whereas androgen withdrawal may cause depression. However, these psychiatric effects are idiosyncratic, affecting only a minority of users. Emerging evidence now also suggests that long-term androgen exposure may cause neurotoxicity, raising the possibility that aging androgen abusers may be at increased risk for dementia. Several recent studies have also described androgen-induced hepatotoxicity, nephrotoxicity, and adverse musculoskeletal effects. Recent studies have demonstrated marked adverse effects of long-term androgen abuse. As increasing numbers of androgen abusers reach middle age, these effects will likely represent an emerging public health problem.

Androgens Exert a Cysticidal Effect upon Taenia crassiceps by Disrupting Flame Cell Morphology and Function

PubMed Central

Ambrosio, Javier R.; Valverde-Islas, Laura; Nava-Castro, Karen E.; Palacios- Arreola, M. Isabel; Ostoa-Saloma, Pedro; Reynoso-Ducoing, Olivia; Escobedo, Galileo; Ruíz-Rosado, Azucena; Dominguez-Ramírez, Lenin; Morales-Montor, Jorge

2015-01-01

The effects of testosterone (T4) and dihydrotestosterone (DHT) on the survival of the helminth cestode parasite Taenia crassiceps, as well as their effects on actin, tubulin and myosin expression and their assembly into the excretory system of flame cells are described in this paper. In vitro evaluations on parasite viability, flow cytometry, confocal microscopy, video-microscopy of live flame cells, and docking experiments of androgens interacting with actin, tubulin, and myosin were conducted. Our results show that T4 and DHT reduce T. crassiceps viability in a dose- and time-dependent fashion, reaching 90% of mortality at the highest dose used (40 ng/ml) and time exposed (10 days) in culture. Androgen treatment does not induce differences in the specific expression pattern of actin, tubulin, and myosin isoforms as compared with control parasites. Confocal microscopy demonstrated a strong disruption of the parasite tegument, with reduced assembly, shape, and motion of flame cells. Docking experiments show that androgens are capable of affecting parasite survival and flame cell morphology by directly interacting with actin, tubulin and myosin without altering their protein expression pattern. We show that both T4 and DHT are able to bind actin, tubulin, and myosin affecting their assembly and causing parasite intoxication due to impairment of flame cell function. Live flame cell video microscopy showing a reduced motion as well changes in the shape of flame cells are also shown. In summary, T4 and DHT directly act on T. crassiceps cysticerci through altering parasite survival as well as the assembly and function of flame cells. PMID:26076446

The Hsp90 Inhibitor, 17-AAG, Prevents the Ligand-Independent Nuclear Localization of Androgen Receptor in Refractory Prostate Cancer Cells

PubMed Central

Saporita, Anthony J.; Ai, Junkui; Wang, Zhou

2010-01-01

BACKGROUND Androgen receptor (AR) is the key molecule in androgen-refractory prostate cancer. Despite androgen ablative conditions, AR remains active and is necessary for the growth of androgen-refractory prostate cancer cells. Nuclear localization of AR is a prerequisite for its transcriptional activation. We examined AR localization in androgen-dependent and androgen-refractory prostate cancer cells. METHODS AND RESULTS We demonstrate increased nuclear localization of a GFP-tagged AR in the absence of hormone in androgen-refractory C4-2 cells compared to parental androgen-sensitive human prostate cancer LNCaP cells. Analysis of AR mutants impaired in ligand-binding indicates that the nuclear localization of AR in C4-2 cells is truly androgen-independent. The hsp90 inhibitor, 17-allylamino-17-demethoxygeldanamycin (17-AAG), inhibits basal PSA expression and disrupts the ligand-independent nuclear localization of AR at doses much lower than required to inhibit androgen-induced nuclear import. CONCLUSIONS Hsp90 is a key regulator of ligand-independent nuclear localization and activation of AR in androgen-refractory prostate cancer cells. PMID:17221841

Mitochondrial Respiratory Function Induces Endogenous Hypoxia

PubMed Central

Prior, Sara; Kim, Ara; Yoshihara, Toshitada; Tobita, Seiji; Takeuchi, Toshiyuki; Higuchi, Masahiro

2014-01-01

Hypoxia influences many key biological functions. In cancer, it is generally believed that hypoxic condition is generated deep inside the tumor because of the lack of oxygen supply. However, consumption of oxygen by cancer should be one of the key means of regulating oxygen concentration to induce hypoxia but has not been well studied. Here, we provide direct evidence of the mitochondrial role in the induction of intracellular hypoxia. We used Acetylacetonatobis [2-(2′-benzothienyl) pyridinato-kN, kC3’] iridium (III) (BTP), a novel oxygen sensor, to detect intracellular hypoxia in living cells via microscopy. The well-differentiated cancer cell lines, LNCaP and MCF-7, showed intracellular hypoxia without exogenous hypoxia in an open environment. This may be caused by high oxygen consumption, low oxygen diffusion in water, and low oxygen incorporation to the cells. In contrast, the poorly-differentiated cancer cell lines: PC-3 and MDAMB231 exhibited intracellular normoxia by low oxygen consumption. The specific complex I inhibitor, rotenone, and the reduction of mitochondrial DNA (mtDNA) content reduced intracellular hypoxia, indicating that intracellular oxygen concentration is regulated by the consumption of oxygen by mitochondria. HIF-1α was activated in endogenously hypoxic LNCaP and the activation was dependent on mitochondrial respiratory function. Intracellular hypoxic status is regulated by glucose by parabolic dose response. The low concentration of glucose (0.045 mg/ml) induced strongest intracellular hypoxia possibly because of the Crabtree effect. Addition of FCS to the media induced intracellular hypoxia in LNCaP, and this effect was partially mimicked by an androgen analog, R1881, and inhibited by the anti-androgen, flutamide. These results indicate that mitochondrial respiratory function determines intracellular hypoxic status and may regulate oxygen-dependent biological functions. PMID:24586439

Relaxin receptor antagonist AT-001 synergizes with docetaxel in androgen-independent prostate xenografts.

PubMed

Neschadim, Anton; Pritzker, Laura B; Pritzker, Kenneth P H; Branch, Donald R; Summerlee, Alastair J S; Trachtenberg, John; Silvertown, Joshua D

2014-06-01

Androgen hormones and the androgen receptor (AR) pathway are the main targets of anti-hormonal therapies for prostate cancer. However, resistance inevitably develops to treatments aimed at the AR pathway resulting in androgen-independent or hormone-refractory prostate cancer (HRPC). Therefore, there is a significant unmet need for new, non-androgen anti-hormonal strategies for the management of prostate cancer. We demonstrate that a relaxin hormone receptor antagonist, AT-001, an analog of human H2 relaxin, represents a first-in-class anti-hormonal candidate treatment designed to significantly curtail the growth of androgen-independent human prostate tumor xenografts. Chemically synthesized AT-001, administered subcutaneously, suppressed PC3 xenograft growth by up to 60%. AT-001 also synergized with docetaxel, standard first-line chemotherapy for HRPC, to suppress tumor growth by more than 98% in PC3 xenografts via a mechanism involving the downregulation of hypoxia-inducible factor 1 alpha and the hypoxia-induced response. Our data support developing AT-001 for clinical use as an anti-relaxin hormonal therapy for advanced prostate cancer.

Non-neural androgen receptors affect sexual differentiation of brain and behaviour.

PubMed

Monks, D A; Swift-Gallant, A

2018-02-01

Although gonadal testosterone is the principal endocrine factor that promotes masculine traits in mammals, the development of a male phenotype requires local production of both androgenic and oestrogenic signals within target tissues. Much of our knowledge concerning androgenic components of testosterone signalling in sexual differentiation comes from studies of androgen receptor (Ar) loss of function mutants. Here, we review these studies of loss of Ar function and of AR overexpression either globally or selectively in the nervous system of mice. Global and neural mutations affect socio-sexual behaviour and the neuroanatomy of these mice in a sexually differentiated manner. Some masculine traits are affected by both global and neural mutation, indicative of neural mediation, whereas other masculine traits are affected only by global mutation, indicative of an obligatory non-neural androgen target. These results support a model in which multiple sites of androgen action coordinate to produce masculine phenotypes. Furthermore, AR overexpression does not always have a phenotype opposite to that of loss of Ar function mutants, indicative of a nonlinear relationship between androgen dose and masculine phenotype in some cases. Potential mechanisms of Ar gene function in non-neural targets in producing masculine phenotypes are discussed. © 2017 British Society for Neuroendocrinology.

Multivalent Peptidomimetic Conjugates as Inhibitors of Androgen Receptor Function in Therapy Resistant Prostate Cancer

DTIC Science & Technology

2016-10-01

hormones that play a critical role in stimulating prostate cancer growth . Androgens activate a protein called the androgen receptor (AR), which...5-15 3 1. INTRODUCTION: Androgens are hormones that play a critical role in stimulating prostate cancer growth . Androgens...regulates genes involved in cell growth . Although powerful anti-androgen drugs can be administered to block AR action and have been used successfully to

Anabolic androgenic steroids, an easily forgotten cause of polycythaemia and cerebral infarction.

PubMed

Low, M S Y; Vilcassim, S; Fedele, P; Grigoriadis, G

2016-04-01

Excessive anabolic androgenic steroids (both exogenous and endogenous) are known causes of polycythaemia and ischaemic cardiovascular events. Despite this, they are commonly forgotten in the workup of patients. We report a case of exogenous anabolic androgenic steroid-induced polycythaemia and stroke and explore possible pitfalls for clinicians. © 2016 Royal Australasian College of Physicians.

Prevalence of functional disorders of androgen excess in unselected premenopausal women: a study in blood donors.

PubMed

Sanchón, Raúl; Gambineri, Alessandra; Alpañés, Macarena; Martínez-García, M Ángeles; Pasquali, Renato; Escobar-Morreale, Héctor F

2012-04-01

The polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women. On the contrary, the prevalences of other disorders of androgen excess such as idiopathic hyperandrogenism and idiopathic hirsutism remain unknown. We aimed to obtain an unbiased estimate of the prevalence in premenopausal women of (i) signs of androgen excess and (ii) PCOS, idiopathic hyperandrogenism and idiopathic hirsutism. A multicenter prevalence survey included 592 consecutive premenopausal women (393 from Madrid, Spain and 199 from Bologna, Italy) reporting spontaneously for blood donation. Immediately before donation, we conducted clinical and biochemical phenotyping for androgen excess disorders. We determined the prevalence of (i) hirsutism, acne and alopecia as clinical signs of androgen excess and (ii) functional disorders of androgen excess, including PCOS, defined by the National Institute of Child Health and Human Development/National Institute of Health criteria, idiopathic hyperandrogenism and idiopathic hirsutism. Regarding clinical signs of hyperandrogenism, hirsutism and acne were equally frequent [12.2% prevalence; 95% confidence interval (CI): 9.5-14.8%], whereas alopecia was uncommon (1.7% prevalence, 95% CI: 0.7-2.7%). Regarding functional disorders of androgen excess, PCOS and idiopathic hirsutism were equally frequent (5.4% prevalence, 95% CI: 3.6-7.2) followed by idiopathic hyperandrogenism (3.9% prevalence, 95% CI: 2.3-5.4). Clinical signs of hyperandrogenism and functional disorders of androgen excess show a high prevalence in premenopausal women. The prevalences of idiopathic hyperandrogenism and idiopathic hirsutism are similar to that of PCOS, highlighting the need for further research on the pathophysiology, consequences for health and clinical implications of these functional forms of androgen excess.

Androgen receptor-negative human prostate cancer cells induce osteogenesis in mice through FGF9-mediated mechanisms.

PubMed

Li, Zhi Gang; Mathew, Paul; Yang, Jun; Starbuck, Michael W; Zurita, Amado J; Liu, Jie; Sikes, Charles; Multani, Asha S; Efstathiou, Eleni; Lopez, Adriana; Wang, Jing; Fanning, Tina V; Prieto, Victor G; Kundra, Vikas; Vazquez, Elba S; Troncoso, Patricia; Raymond, Austin K; Logothetis, Christopher J; Lin, Sue-Hwa; Maity, Sankar; Navone, Nora M

2008-08-01

In prostate cancer, androgen blockade strategies are commonly used to treat osteoblastic bone metastases. However, responses to these therapies are typically brief, and the mechanism underlying androgen-independent progression is not clear. Here, we established what we believe to be the first human androgen receptor-negative prostate cancer xenografts whose cells induced an osteoblastic reaction in bone and in the subcutis of immunodeficient mice. Accordingly, these cells grew in castrated as well as intact male mice. We identified FGF9 as being overexpressed in the xenografts relative to other bone-derived prostate cancer cells and discovered that FGF9 induced osteoblast proliferation and new bone formation in a bone organ assay. Mice treated with FGF9-neutralizing antibody developed smaller bone tumors and reduced bone formation. Finally, we found positive FGF9 immunostaining in prostate cancer cells in 24 of 56 primary tumors derived from human organ-confined prostate cancer and in 25 of 25 bone metastasis cases studied. Collectively, these results suggest that FGF9 contributes to prostate cancer-induced new bone formation and may participate in the osteoblastic progression of prostate cancer in bone. Androgen receptor-null cells may contribute to the castration-resistant osteoblastic progression of prostate cancer cells in bone and provide a preclinical model for studying therapies that target these cells.

Androgen receptor–negative human prostate cancer cells induce osteogenesis in mice through FGF9-mediated mechanisms

PubMed Central

Li, Zhi Gang; Mathew, Paul; Yang, Jun; Starbuck, Michael W.; Zurita, Amado J.; Liu, Jie; Sikes, Charles; Multani, Asha S.; Efstathiou, Eleni; Lopez, Adriana; Wang, Jing; Fanning, Tina V.; Prieto, Victor G.; Kundra, Vikas; Vazquez, Elba S.; Troncoso, Patricia; Raymond, Austin K.; Logothetis, Christopher J.; Lin, Sue-Hwa; Maity, Sankar; Navone, Nora M.

2008-01-01

In prostate cancer, androgen blockade strategies are commonly used to treat osteoblastic bone metastases. However, responses to these therapies are typically brief, and the mechanism underlying androgen-independent progression is not clear. Here, we established what we believe to be the first human androgen receptor–negative prostate cancer xenografts whose cells induced an osteoblastic reaction in bone and in the subcutis of immunodeficient mice. Accordingly, these cells grew in castrated as well as intact male mice. We identified FGF9 as being overexpressed in the xenografts relative to other bone-derived prostate cancer cells and discovered that FGF9 induced osteoblast proliferation and new bone formation in a bone organ assay. Mice treated with FGF9-neutralizing antibody developed smaller bone tumors and reduced bone formation. Finally, we found positive FGF9 immunostaining in prostate cancer cells in 24 of 56 primary tumors derived from human organ-confined prostate cancer and in 25 of 25 bone metastasis cases studied. Collectively, these results suggest that FGF9 contributes to prostate cancer–induced new bone formation and may participate in the osteoblastic progression of prostate cancer in bone. Androgen receptor–null cells may contribute to the castration-resistant osteoblastic progression of prostate cancer cells in bone and provide a preclinical model for studying therapies that target these cells. PMID:18618013

Development of Protein Degradation Inducers of Androgen Receptor by Conjugation of Androgen Receptor Ligands and Inhibitor of Apoptosis Protein Ligands.

PubMed

Shibata, Norihito; Nagai, Katsunori; Morita, Yoko; Ujikawa, Osamu; Ohoka, Nobumichi; Hattori, Takayuki; Koyama, Ryokichi; Sano, Osamu; Imaeda, Yasuhiro; Nara, Hiroshi; Cho, Nobuo; Naito, Mikihiko

2018-01-25

Targeted protein degradation using small molecules is a novel strategy for drug development. We have developed hybrid molecules named specific and nongenetic inhibitor of apoptosis protein [IAP]-dependent protein erasers (SNIPERs) that recruit IAP ubiquitin ligases to degrade target proteins. Here, we show novel SNIPERs capable of inducing proteasomal degradation of the androgen receptor (AR). Through derivatization of the SNIPER(AR) molecule at the AR ligand and IAP ligand and linker, we developed 42a (SNIPER(AR)-51), which shows effective protein knockdown activity against AR. Consistent with the degradation of the AR protein, 42a inhibits AR-mediated gene expression and proliferation of androgen-dependent prostate cancer cells. In addition, 42a efficiently induces caspase activation and apoptosis in prostate cancer cells, which was not observed in the cells treated with AR antagonists. These results suggest that SNIPER(AR)s could be leads for an anticancer drug against prostate cancers that exhibit AR-dependent proliferation.

Anabolic androgenic steroid-induced Takotsubo cardiomyopathy

PubMed Central

Sella, Gianluigi; Bellanti, Giancarlo; Margheri, Massimo

2015-01-01

Anabolic steroid abuse, aimed at increasing muscle mass, has been growing in recent years. We describe a case of a 25-year-old bodybuilder who, after taking nandrolone and stanozolol, presented with Takotsubo syndrome. The angiography showed a normal coronary anatomy with the absence of stenosis. The left ventricular function was completely normalised after 1 week. PMID:25804946

Sphingosine Kinase-1 Is Central to Androgen-Regulated Prostate Cancer Growth and Survival

PubMed Central

Dayon, Audrey; Brizuela, Leyre; Martin, Claire; Mazerolles, Catherine; Pirot, Nelly; Doumerc, Nicolas; Nogueira, Leonor; Golzio, Muriel; Teissié, Justin; Serre, Guy; Rischmann, Pascal; Malavaud, Bernard; Cuvillier, Olivier

2009-01-01

Background Sphingosine kinase-1 (SphK1) is an oncogenic lipid kinase notably involved in response to anticancer therapies in prostate cancer. Androgens regulate prostate cancer cell proliferation, and androgen deprivation therapy is the standard of care in the management of patients with advanced disease. Here, we explored the role of SphK1 in the regulation of androgen-dependent prostate cancer cell growth and survival. Methodology/Principal Findings Short-term androgen removal induced a rapid and transient SphK1 inhibition associated with a reduced cell growth in vitro and in vivo, an event that was not observed in the hormono-insensitive PC-3 cells. Supporting the critical role of SphK1 inhibition in the rapid effect of androgen depletion, its overexpression could impair the cell growth decrease. Similarly, the addition of dihydrotestosterone (DHT) to androgen-deprived LNCaP cells re-established cell proliferation, through an androgen receptor/PI3K/Akt dependent stimulation of SphK1, and inhibition of SphK1 could markedly impede the effects of DHT. Conversely, long-term removal of androgen support in LNCaP and C4-2B cells resulted in a progressive increase in SphK1 expression and activity throughout the progression to androgen-independence state, which was characterized by the acquisition of a neuroendocrine (NE)-like cell phenotype. Importantly, inhibition of the PI3K/Akt pathway—by negatively impacting SphK1 activity—could prevent NE differentiation in both cell models, an event that could be mimicked by SphK1 inhibitors. Fascinatingly, the reversability of the NE phenotype by exposure to normal medium was linked with a pronounced inhibition of SphK1 activity. Conclusions/Significance We report the first evidence that androgen deprivation induces a differential effect on SphK1 activity in hormone-sensitive prostate cancer cell models. These results also suggest that SphK1 activation upon chronic androgen deprivation may serve as a compensatory mechanism allowing prostate cancer cells to survive in androgen-depleted environment, giving support to its inhibition as a potential therapeutic strategy to delay/prevent the transition to androgen-independent prostate cancer. PMID:19956567

Multivalent Peptidomimetic Conjugates as Inhibitors of Androgen Receptor Function in Therapy-Resistant Prostate Cancer

DTIC Science & Technology

2017-10-01

Requirements ........................ 5 9. Appendices ......................................................... none 1. INTRODUCTION: Androgens are ...hormones that play a critical role in stimulating prostate cancer growth. Androgens activate a protein called the androgen receptor ( AR ), which...regulates genes involved in cell growth. Although powerful anti-androgen drugs can be administered to block AR action and have been used successfully to

Androgens inhibit adipogenesis during human adipose stem cell commitment to predipocyte formation

PubMed Central

Chazenbalk, Gregorio; Singh, Prapti; Irge, Dana; Shah, Amy; Abbott, David H; Dumesic, Daniel A

2013-01-01

Androgens play a pivotal role in the regulation of body fat distribution. Adipogenesis is a process whereby multipotent adipose stem cells (ASCs) initially become preadipocytes (ASC commitment to preadipocytes) before differentiating into adipocytes. Androgens inhibit human (h) subcutaneous (SC) abdominal preadipocyte differentiation in both sexes, but their effects on hASC commitment to preadipocyte formation is unknown. We therefore examined whether androgen exposure to human (h) ASCs, isolated from SC abdominal adipose of nonobese women, impairs their commitment to preadipocyte formation and/or subsequent differentiation into adipocytes. For this, isolated hASCs from SC abdominal lipoaspirate were cultured in adipogenesis-inducing medium for 0.5–14 days in the presence of testosterone (T, 0–100 nM) or dihydrotestosterone (DHT, 0–50 nM). Adipogenesis was determined by immunofluorescence microscopy and by quantification of adipogenically relevant transcriptional factors, PPARγ, C/EBPα and C/EBPβ. We found that a 3-day exposure of hASCs to T (50 nM) or DHT (5 nM) in adipogenesis-inducing medium impaired lipid acquisition and decreased PPARγ, C/EBPα and C/EBPβ gene expression. The inhibitory effects of T and DHT at this early-stage of adipocyte differentiation, were partially and completely reversed by flutamide (F, 100 nM), respectively. The effect of androgens on hASC commitment to a preadipocyte phenotype was examined via activation of BMP4 signaling. T (50 nM) and DHT (5nM) significantly inhibited the stimulatory effect of BMP4-induced ASC commitment to the preadipocyte phenotype, as regards PPARγ and C/EBPα gene expression. Our findings indicate that androgens, in part through androgen receptor action, impair BMP4-induced commitment of SC hASCs to preadipocytes and also reduce early-stage adipocyte differentiation, perhaps limiting adipocyte numbers and fat storage in SC abdominal adipose. PMID:23707571

Dissecting the roles of the androgen receptor in prostate cancer from molecular perspectives.

PubMed

Hu, Jieping; Wang, Gongxian; Sun, Ting

2017-05-01

Androgen receptor plays a pivotal role in prostate cancer progression, and androgen deprivation therapy to intercept androgen receptor signal pathway is an indispensable treatment for most advanced prostate cancer patients to delay cancer progression. However, the emerging of castration-resistant prostate cancer reminds us the alteration of androgen receptor, which includes androgen receptor mutation, the formation of androgen receptor variants, and androgen receptor distribution in cancer cells. In this review, we introduce the process of androgen receptor and also its variants' formation, translocation, and function alteration by protein modification or interaction with other pathways. We dissect the roles of androgen receptor in prostate cancer from molecular perspective to provide clues for battling prostate cancer, especially castration-resistant prostate cancer.

In vitro steroid-induced meiosis in Rhinella arenarum oocytes: role of pre-MPF activation.

PubMed

Arias Torres, Ana Josefina; Bühler, Marta Inés; Zelarayán, Liliana Isabel

2016-04-01

In this work we showed the relationship between seasonal periods and the response of R. arenarum follicles and oocytes to different steroids. Using in vitro germinal vesicle breakdown (GVBD) assays, we demonstrated that P4 is the main steroid capable of inducing maturation in R. arenarum oocytes and follicles. In the second part of this work we showed that androgens can activate pre-maturation promoting factors (pre-MPFs) such as P4, by cytoplasm microinjection experiments. The results indicated that the steroids assayed induced oocyte and follicle maturation in a dose- and time-dependent manner. In oocytes, P4 was the most efficient steroid as a maturation inducer (EC50 of the reproductive period, 6 nM, EC50 of the non-reproductive period ≅ 30 nM). Androgens (DHEA, dehydroepiandrosterone; T, testosterone; and AD, androstenedione) were less efficient maturation inducers than P4 (EC50 reproductive period ≅ 50, 120 and 600 nM respectively). Similar results were obtained with intact follicles in both seasonal periods. Although the response of follicles to the different androgens was variable, in no case was it above the above the response induced by P4. Independently of the season, oocytes and follicles incubated in P4, P5 and T underwent GVBD after 6-10 h while oocytes and follicles incubated in DHEA and AD matured more slowly. Furthermore, we demonstrated that microinjection of mature cytoplasm from androgen-treated oocytes is sufficient to promote GVBD in immature recipient oocytes (DHEA, 57 ± 12%; AD, 60 ± 8%; T, 56 ± 13%). Thus, androgens such as DHEA, T and AD are as competent as P4 to activate pre-MPF.

The anabolic steroid nandrolone alters cannabinoid self-administration and brain CB1 receptor density and function.

PubMed

Struik, Dicky; Fadda, Paola; Zara, Tamara; Zamberletti, Erica; Rubino, Tiziana; Parolaro, Daniela; Fratta, Walter; Fattore, Liana

2017-01-01

Clinical and pre-clinical observations indicate that anabolic-androgenic steroids can induce neurobiological changes that alter the rewarding effects of drugs of abuse. In this study, we investigated the effect of the anabolic steroid nandrolone on the rewarding properties of the cannabinoid CB 1 receptor agonist WIN55,212-2 (WIN) in rats. Lister Hooded male rats were treated intramuscularly with nandrolone (15mg/kg) or vehicle for 14 consecutive days, and then allowed to self-administer WIN (12.5μg/kg/infusion) intravenously. After reaching stable drug intake, self-administration behavior was extinguished to examine drug- and cue-induced reinstatement of cannabinoid-seeking behavior. Other behavioral parameters presumed to influence drug-taking and drug-seeking behaviors were examined to gain more insight into the behavioral specificity of nandrolone treatment. Finally, animals were sacrificed for analysis of CB 1 receptor density and function in selected brain areas. We found that nandrolone-treated rats self-administered up to 2 times more cannabinoid than vehicle-treated rats, but behaved similarly to control rats when tested for drug- and cue-induced reinstatement of cannabinoid-seeking behavior. Enhanced cannabinoid intake by nandrolone-treated rats was not accompanied by changes in locomotor activity, sensorimotor gating, or memory function. However, our molecular data show that after chronic WIN self-administration nandrolone-treated rats display altered CB 1 receptor density and function in selected brain areas. We hypothesize that increased cannabinoid self-administration in nandrolone-treated rats results from a nandrolone-induced decrease in reward function, which rats seem to compensate by voluntarily increasing their cannabinoid intake. Altogether, our findings corroborate the hypothesis that chronic exposure to anabolic-androgenic steroids induces dysfunction of the reward pathway in rats and might represent a potential risk factor for abuse of cannabis and other drugs in humans. Copyright © 2016 Elsevier Ltd. All rights reserved.

Opposing effects of estradiol- and testosterone-membrane binding sites on T47D breast cancer cell apoptosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kampa, Marilena; Nifli, Artemissia-Phoebe; Charalampopoulos, Ioannis

Classical steroid mode of action involves binding to intracellular receptors, the later acting as ligand-activated nuclear transcription factors. Recently, membrane sites for different steroids have been also identified, mediating rapid, non-genomic, steroid actions. Membrane sites for estrogen and androgen have been found in a number of different cell types, bearing or not classical intracellular receptors. In the present study, with the use of radioligand binding, flow cytometry and confocal laser microscopy, we report that T47D human breast cancer cells express specific and saturable membrane receptors for both estrogen (K {sub D} 4.06 {+-} 3.31 nM) and androgen (K {sub D}more » 7.64 {+-} 3.15 nM). Upon activation with BSA-conjugated, non-permeable ligands (E{sub 2}-BSA and testosterone-BSA), membrane estrogen receptors protect cells from serum-deprivation-induced apoptosis, while androgen receptors induce apoptosis in serum-supplemented T47D cells. In addition, co-incubation of cells with a fixed concentration of one steroid and varying concentrations of the other reversed the abovementioned effect (apoptosis for androgen, and anti-apoptosis for E{sub 2}), suggesting that the fate of the cell depends on the relative concentration of either steroid in the culture medium. We also report the identification of membrane receptors for E{sub 2} and androgen in biopsy slides from breast cancer patients. Both sites are expressed, with the staining for membrane E{sub 2} being strongly present in ER-negative, less differentiated, more aggressive tumors. These findings suggest that aromatase inhibitors may exert their beneficial effects on breast cancer by also propagating the metabolism of local steroids towards androgen, inducing thus cell apoptosis through membrane androgen receptor activation.« less

Prenatal Androgen Excess Negatively Impacts Body Fat Distribution in a Nonhuman Primate Model of Polycystic Ovary Syndrome (PCOS)

PubMed Central

Bruns, Cristin M; Baum, Scott T; Colman, Ricki J; Dumesic, Daniel A; Eisner, Joel R; Jensen, Michael D; Whigham, Leah D; Abbott, David H

2008-01-01

Introduction Prenatally androgenized (PA) female rhesus monkeys share metabolic abnormalities in common with PCOS women. Early gestation exposure (E) results in insulin resistance, impaired pancreatic beta-cell function and type 2 diabetes, while late gestation exposure (L) results in supranormal insulin sensitivity that declines with increasing body mass index (BMI). Objective To determine whether PA females have altered body fat distribution. Design Five EPA, 5 LPA, and 5 control adult female monkeys underwent somatometrics, dual x-ray absorptiometry (DXA) and abdominal computed tomography (CT). Five control and 5 EPA females underwent an intravenous glucose tolerance test to assess the relationship between body composition and glucoregulation. Results There were no differences in age, weight, BMI, or somatometrics. LPA females had ∼20% greater DXA-determined total fat and percent body fat, as well as total and percent abdominal fat than EPA or control females (p≤0.05). LPA females also had ∼40% more CT-determined non-visceral abdominal fat than EPA or control females (p≤0.05). The volume of visceral fat was similar among the 3 groups. EPA (R2=0.94, p≤0.01) and LPA (R2=0.53, p=0.16) females had a positive relationship between visceral fat and BMI, although not significant for LPA females. Conversely, control females had a positive relationship between non-visceral fat and BMI (R2=0.98, p≤0.001). There was a positive relationship between basal insulin and total body (R2=0.95, p≤0.007), total abdominal (R2=0.81, p≤0.04), and visceral (R2=0.82, p≤0.03) fat quantities in EPA, but not control females. Conclusions Prenatal androgenization in female rhesus monkeys induces adiposity-dependent visceral fat accumulation, and late gestation androgenization causes increased total body and non-visceral fat mass. Early gestation androgenization induces visceral fat-dependent hyperinsulinemia. The relationship between the timing of prenatal androgen exposure and body composition phenotypes in this nonhuman primate model for PCOS may provide insight into the heterogeneity of metabolic defects found in PCOS women. PMID:17471299

Prenatal androgen excess negatively impacts body fat distribution in a nonhuman primate model of polycystic ovary syndrome.

PubMed

Bruns, C M; Baum, S T; Colman, R J; Dumesic, D A; Eisner, J R; Jensen, M D; Whigham, L D; Abbott, D H

2007-10-01

Prenatally androgenized (PA) female rhesus monkeys share metabolic abnormalities in common with polycystic ovary syndrome (PCOS) women. Early gestation exposure (E) results in insulin resistance, impaired pancreatic beta-cell function and type 2 diabetes, while late gestation exposure (L) results in supranormal insulin sensitivity that declines with increasing body mass index (BMI). To determine whether PA females have altered body fat distribution. Five early-treated PA (EPA), five late-treated PA (LPA) and five control adult female monkeys underwent somatometrics, dual-X-ray absorptiometry (DXA) and abdominal computed tomography (CT). Five control and five EPA females underwent an intravenous glucose tolerance test to assess the relationship between body composition and glucoregulation. There were no differences in age, weight, BMI or somatometrics. LPA females had approximately 20% greater DXA-determined total fat and percent body fat, as well as total and percent abdominal fat than EPA or control females (P< or =0.05). LPA females also had approximately 40% more CT-determined non-visceral abdominal fat than EPA or control females (P< or =0.05). The volume of visceral fat was similar among the three groups. EPA (R (2)=0.94, P< or =0.01) and LPA (R (2)=0.53, P=0.16) females had a positive relationship between visceral fat and BMI, although not significant for LPA females. Conversely, control females had a positive relationship between non-visceral fat and BMI (R (2)=0.98, P< or =0.001). There was a positive relationship between basal insulin and total body (R (2)=0.95, P< or =0.007), total abdominal (R (2)=0.81, P< or =0.04) and visceral (R (2)=0.82, P< or =0.03) fat quantities in EPA, but not control females. Prenatal androgenization in female rhesus monkeys induces adiposity-dependent visceral fat accumulation, and late gestation androgenization causes increased total body and non-visceral fat mass. Early gestation androgenization induces visceral fat-dependent hyperinsulinemia. The relationship between the timing of prenatal androgen exposure and body composition phenotypes in this nonhuman primate model for PCOS may provide insight into the heterogeneity of metabolic defects found in PCOS women.

Androgen Control of Cell Proliferation and Cytoskeletal Reorganization in Human Fibrosarcoma Cells

PubMed Central

Chauhan, Sanjay; Kunz, Susan; Davis, Kelli; Roberts, Jordan; Martin, Greg; Demetriou, Manolis C.; Sroka, Thomas C.; Cress, Anne E.; Miesfeld, Roger L.

2009-01-01

We recently generated an HT-1080-derived cell line called HT-AR1 that responds to dihydrotestosterone (DHT) treatment by undergoing cell growth arrest in association with cytoskeletal reorganization and induction of neuroendocrine-like cell differentiation. In this report, we show that DHT induces a dose-dependent increase in G0/G1 growth-arrested cells using physiological levels of hormone. The arrested cells increase in cell size and contain a dramatic redistribution of desmoplakin, keratin 5, and chromogranin A proteins. DHT-induced cytoskeletal changes were also apparent from time lapse video microscopy that showed that androgen treatment resulted in the rapid appearance of neuronal-like membrane extensions. Expression profiling analysis using RNA isolated from DHT-treated HT-AR1 cells revealed that androgen receptor activation leads to the coordinate expression of numerous cell signaling genes including RhoB, PTGF-β, caveolin-2, Egr-1, myosin 1B, and EHM2. Because RhoB has been shown to have a role in tumor suppression and neuronal differentiation in other cell types, we investigated RhoB signaling functions in the HT-AR1 steroid response. We found that steroid induction of RhoB was DHT-specific and that newly synthesized RhoB protein was post-translationally modified and localized to endocytic vesicles. Moreover, treatment with a farnesyl transferase inhibitor reduced DHT-dependent growth arrest, suggesting that prenylated RhoB might function to inhibit HT-AR1 cell proliferation. This was directly shown by transfecting HT-AR1 cells with RhoB coding sequences containing activating or dominant negative mutations. PMID:14576147

Hormonal changes during menopause.

PubMed

Al-Azzawi, Farook; Palacios, Santiago

2009-06-20

Ovarian senescence occurs gradually during the fourth and fifth decades of life, leading to menopause at an average age of about 51 years. This senescence results in a changing hormonal milieu, with decreases in the levels of estrogens and androgens. Similar changes may be induced by surgical menopause (bilateral oophorectomy) or ovarian failure resulting from cancer treatment. The declining levels of estrogens and androgens affect many tissues of the body and can produce a variety of signs and symptoms, including vasomotor symptoms, decreased bone density, changes in mood and energy, loss of pubic hair and changes in the genital tissues, and effects on sexual function. Accurate measurement of testosterone levels in postmenopausal women requires methods that are validated in the lower ranges of testosterone level observed in this population.

Hypoxia-Independent Downregulation of Hypoxia-Inducible Factor 1 Targets by Androgen Deprivation Therapy in Prostate Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ragnum, Harald Bull; Røe, Kathrine; Division of Medicine, Department of Oncology, Akershus University Hospital, Lørenskog

2013-11-15

Purpose: We explored changes in hypoxia-inducible factor 1 (HIF1) signaling during androgen deprivation therapy (ADT) of androgen-sensitive prostate cancer xenografts under conditions in which no significant change in immunostaining of the hypoxia marker pimonidazole had occurred. Methods and Materials: Gene expression profiles of volume-matched androgen-exposed and androgen-deprived CWR22 xenografts, with similar pimonidazole-positive fractions, were compared. Direct targets of androgen receptor (AR) and HIF1 transcription factors were identified among the differentially expressed genes by using published lists. Biological processes affected by ADT were determined by gene ontology analysis. HIF1α protein expression in xenografts and biopsy samples from 35 patients receiving neoadjuvantmore » ADT was assessed by immunohistochemistry. Results: A total of 1344 genes showed more than 2-fold change in expression by ADT, including 35 downregulated and 5 upregulated HIF1 targets. Six genes were shared HIF1 and AR targets, and their downregulation was confirmed with quantitative RT-PCR. Significant suppression of the biological processes proliferation, metabolism, and stress response in androgen-deprived xenografts was found, consistent with tumor regression. Nineteen downregulated HIF1 targets were involved in those significant biological processes, most of them in metabolism. Four of these were shared AR and HIF1 targets, including genes encoding the regulatory glycolytic proteins HK2, PFKFB3, and SLC2A1. Most of the downregulated HIF1 targets were induced by hypoxia in androgen-responsive prostate cancer cell lines, confirming their role as hypoxia-responsive HIF1 targets in prostate cancer. Downregulation of HIF1 targets was consistent with the absence of HIF1α protein in xenografts and downregulation in patients by ADT (P<.001). Conclusions: AR repression by ADT may lead to downregulation of HIF1 signaling independently of hypoxic fraction, and this may contribute to tumor regression. HIF1α expression is probably not a useful hypoxia biomarker during ADT in prostate cancer.« less

Follicular expression of pro-inflammatory cytokines tumour necrosis factor-α (TNFα), interleukin 6 (IL6) and their receptors in cattle: TNFα, IL6 and macrophages suppress thecal androgen production in vitro.

PubMed

Samir, Moafaq; Glister, Claire; Mattar, Dareen; Laird, Mhairi; Knight, Phil G

2017-07-01

Pro-inflammatory cytokines secreted by macrophages and other cell types are implicated as intraovarian factors affecting different aspects of ovarian function including follicle and corpus luteum 'turnover', steroidogenesis and angiogenesis. Here, we compared granulosal (GC) and thecal (TC) expression of TNF, IL6 and their receptors (TNFRSF1A, TNFRSF1B and IL6R) during bovine antral follicle development; all five mRNA transcripts were detected in both GC and TC and statistically significant cell-type and follicle stage-related differences were evident. Since few studies have examined cytokine actions on TC steroidogenesis, we cultured TC under conditions that retain a non-luteinized 'follicular' phenotype and treated them with TNFα and IL6 under basal and LH-stimulated conditions. Both TNFα and IL6 suppressed androgen secretion concomitantly with CYP17A1 and LHCGR mRNA expression. In addition, TNFα reduced INSL3, HSD3B1 and NOS3 expression but increased NOS2 expression. IL6 also reduced LHCGR and STAR expression but did not affect HSD3B1, INSL3, NOS2 or NOS3 expression. As macrophages are a prominent source of these cytokines in vivo , we next co-cultured TC with macrophages and observed an abolition of LH-induced androgen production accompanied by a reduction in CYP17A1, INSL3, LHCGR, STAR, CYP11A1 and HSD3B1 expression. Exposure of TC to bacterial lipopolysaccharide also blocked LH-induced androgen secretion, an effect reduced by a toll-like receptor blocker (TAK242). Collectively, the results support an inhibitory action of macrophages on thecal androgen production, likely mediated by their secretion of pro-inflammatory cytokines that downregulate the expression of LHCGR, CYP17A1 and INSL3. Bovine theca interna cells can also detect and respond directly to lipopolysaccharide. © 2017 Society for Reproduction and Fertility.

Androgens Up-regulate Transcription of the Notch Inhibitor Numb in C2C12 Myoblasts via Wnt/β-Catenin Signaling to T Cell Factor Elements in the Numb Promoter*

PubMed Central

Liu, Xin-Hua; Wu, Yong; Yao, Shen; Levine, Alice C.; Kirschenbaum, Alexander; Collier, Lauren; Bauman, William A.; Cardozo, Christopher P.

2013-01-01

Androgen signaling via the androgen receptor is a key pathway that contributes to development, cell fate decisions, and differentiation, including that of myogenic progenitors. Androgens and synthetic steroids have well established anabolic actions on skeletal muscle. Wnt and Notch signaling pathways are also essential to myogenic cell fate decisions during development and tissue repair. However, the interactions among these pathways are largely unknown. Androgenic regulation of Wnt signaling has been reported. Nandrolone, an anabolic steroid, has been shown to inhibit Notch signaling and up-regulate Numb, a Notch inhibitor. To elucidate the mechanisms of interaction between nandrolone and Wnt/Notch signaling, we investigated the effects of nandrolone on Numb expression and Wnt signaling and determined the roles of Wnt signaling in nandrolone-induced Numb expression in C2C12 myoblasts. Nandrolone increased Numb mRNA and protein levels and T cell factor (Tcf) transcriptional activity via inhibition of glycogen synthase kinase 3β. Up-regulation of Numb expression by nandrolone was blocked by the Wnt inhibitors, sFRP1 and DKK1, whereas Wnt3a increased Numb mRNA and protein expression. In addition, we observed that the proximal promoter of the Numb gene had functional Tcf binding elements to which β-catenin was recruited in a manner enhanced by both nandrolone and Wnt3a. Moreover, site-directed mutagenesis indicated that the Tcf binding sites in the Numb promoter are required for the nandrolone-induced Numb transcriptional activation in this cell line. These results reveal a novel molecular mechanism underlying up-regulation of Numb transcription with a critical role for increased canonical Wnt signaling. In addition, the data identify Numb as a novel target gene of the Wnt signaling pathway by which Wnts would be able to inhibit Notch signaling. PMID:23649620

Mitochondrial redox signaling by p66Shc is involved in regulating androgenic growth stimulation of human prostate cancer cells

PubMed Central

Veeramani, S; Yuan, T-C; Lin, F-F; Lin, M-F

2009-01-01

p66Shc is shown to negatively regulate the life span in mice through reactive oxygen species (ROS) production. Recent reports, however, revealed that p66Shc protein level is significantly elevated in several human cancer tissues and growth-stimulated carcinoma cells, suggesting a mitogenic and carcinogenic role for p66Shc. In this communication, we demonstrate for the first time that p66Shc mediates androgenic growth signals in androgen-sensitive human prostate cancer cells through mitochondrial ROS production. Growth stimulation of prostate cancer cells with 5α-dihydrotestosterone (DHT) is accompanied by increased p66Shc level and ROS production, which is abolished by antioxidant treatments. However, antioxidant treatments do not affect the transcriptional activity of androgen receptor (AR) as observed by its inability to block DHT-induced prostate-specific antigen expression, an AR-dependent correlate of prostate cancer progression. Elevated expression of p66Shc by cDNA transfection increases the basal cell proliferation and, thus, reduces additional DHT-induced cell proliferation. Furthermore, DHT increases the translocation of p66Shc into mitochondria and its interaction with cytochrome c. Conversely, both redox-negative p66Shc mutant (W134F), which is deficient in cytochrome c interaction, and p66Shc small interfering RNA decrease DHT-induced cell proliferation. These results collectively reveal a novel role for p66Shc–ROS pathway in androgen-induced prostate cancer cell proliferation and, thus, may play a role in early prostate carcinogenesis. PMID:18504439

Trichosanthes kirilowii Exerts Androgenic Activity via Regulation of PSA and KLK2 in 22Rv1 Prostate Cancer Cells.

PubMed

Jeong, Soo-Jin; Choi, Ji-Yoon; Dong, Mi-Sook; Seo, Chang-Seob; Shin, Hyeun-Kyoo

2017-01-01

The androgen comprises a group of hormones that play roles in male reproductive activity as well as personal characteristics. We investigated the androgenic activity of various herbal medicines in human prostate cancer 22Rv1 cells. Herbal extracts of Trichosanthes kirilowii (TK), Asarum sieboldii (AS), Sanguisorba officinalis (SO), and Xanthium strumarium (XS) were selected to have androgenic effects based on a preliminary in vitro screening system. TK, AS, SO, and XS enhanced the proliferation of 22Rv1 cells without having cytotoxic effects. All tested herbal extracts increased androgen receptor (AR)-induced transcriptional activity in the absence or presence of dihydrotestosterone (DHT). In an AR-binding assay, TK, but not AS, SO, or XS, produced a significant inhibition of AR binding activity, indicating it has androgenic activity. Additionally, TK treatment positively regulated mRNA expression of the AR-related molecular targets prostate-specific antigen (PSA) and kallikrein 2 (KLK2) compared with untreated control. Taken together, TK-enhanced AR-mediated transcriptional activity might be an attractive candidate drug for treating androgen-related diseases. Trichosantheskirilowii (TK), Asarumsieboldii (AS), Sanguisorbaofficinalis (SO), and Xanthium strumarium (XS) enhanced the proliferation of 22Rv1 cells without having cytotoxic effects.TK, AS, SO, and XS increased androgen receptor (AR)-induced transcriptional activity.TK, but not AS, SO, or XS, produced a significant inhibition against AR-binding activity.TK treatment positively regulated mRNA expression of the AR-related molecular targets prostate-specific antigen and kallikrein 2. Abbreviations used: BPH: benign prostatic hyperplasia; AR: androgen receptor; DHT: dihydrotestosterone; PSA: prostate-specific antigen; TK: Trichosanthes kirilowii; AS: Asarum sieboldii; SO: Sanguisorba officinalis; XS: Xanthium strumarium; ATCC: American Type Culture Collection; FBS: fetal bovine serum; PBS: phosphate-buffered saline; SD: standard deviation; ARE: androgenresponsive element; KLK: kallikrein.

Experimentally induced gestational androgen excess disrupts glucoregulation in rhesus monkey dams and their female offspring.

PubMed

Abbott, David H; Bruns, Cristin R; Barnett, Deborah K; Dunaif, Andrea; Goodfriend, Theodore L; Dumesic, Daniel A; Tarantal, Alice F

2010-11-01

Discrete fetal androgen excess during early gestation in rhesus monkeys (Macaca mulatta) promotes endocrine antecedents of adult polycystic ovary syndrome (PCOS)-like traits in female offspring. Because developmental changes promoting such PCOS-like metabolic dysfunction remain unclear, the present study examined time-mated, gravid rhesus monkeys with female fetuses, of which nine gravid females received 15 mg of testosterone propionate (TP) subcutaneously daily from 40 to 80 days (first to second trimesters) of gestation [term, mean (range): 165 (155-175) days], whereas an additional six such females received oil vehicle injections over the same time interval. During gestation, ultrasonography quantified fetal growth measures and was used as an adjunct for fetal blood collections. At term, all fetuses were delivered by cesarean section for postnatal studies. Blood samples were collected from dams and infants for glucose, insulin, and total free fatty acid (FFA) determinations. TP injections transiently accelerated maternal weight gain in dams, very modestly increased head diameter of prenatally androgenized (PA) fetuses, and modestly increased weight gain in infancy compared with concurrent controls. Mild to moderate glucose intolerance, with increased area-under-the-curve circulating insulin values, occurred in TP-injected dams during an intravenous glucose tolerance test in the early second trimester. Moreover, reduced circulating FFA levels occurred in PA fetuses during a third trimester intravenous glucagon-tolbutamide challenge (140 days gestation), whereas excessive insulin sensitivity and increased insulin secretion relative to insulin sensitivity occurred in PA infants during an intravenous glucose-tolbutamide test at ∼1.5 mo postnatal age. Data from these studies suggest that experimentally induced fetal androgen excess may result in transient hyperglycemic episodes in the intrauterine environment that are sufficient to induce relative increases in pancreatic function in PA infants, suggesting in this nonhuman primate model that differential programming of insulin action and secretion may precede adult metabolic dysfunction.

Experimentally induced gestational androgen excess disrupts glucoregulation in rhesus monkey dams and their female offspring

PubMed Central

Bruns, Cristin R.; Barnett, Deborah K.; Dunaif, Andrea; Goodfriend, Theodore L.; Dumesic, Daniel A.; Tarantal, Alice F.

2010-01-01

Discrete fetal androgen excess during early gestation in rhesus monkeys (Macaca mulatta) promotes endocrine antecedents of adult polycystic ovary syndrome (PCOS)-like traits in female offspring. Because developmental changes promoting such PCOS-like metabolic dysfunction remain unclear, the present study examined time-mated, gravid rhesus monkeys with female fetuses, of which nine gravid females received 15 mg of testosterone propionate (TP) subcutaneously daily from 40 to 80 days (first to second trimesters) of gestation [term, mean (range): 165 (155–175) days], whereas an additional six such females received oil vehicle injections over the same time interval. During gestation, ultrasonography quantified fetal growth measures and was used as an adjunct for fetal blood collections. At term, all fetuses were delivered by cesarean section for postnatal studies. Blood samples were collected from dams and infants for glucose, insulin, and total free fatty acid (FFA) determinations. TP injections transiently accelerated maternal weight gain in dams, very modestly increased head diameter of prenatally androgenized (PA) fetuses, and modestly increased weight gain in infancy compared with concurrent controls. Mild to moderate glucose intolerance, with increased area-under-the-curve circulating insulin values, occurred in TP-injected dams during an intravenous glucose tolerance test in the early second trimester. Moreover, reduced circulating FFA levels occurred in PA fetuses during a third trimester intravenous glucagon-tolbutamide challenge (140 days gestation), whereas excessive insulin sensitivity and increased insulin secretion relative to insulin sensitivity occurred in PA infants during an intravenous glucose-tolbutamide test at ∼1.5 mo postnatal age. Data from these studies suggest that experimentally induced fetal androgen excess may result in transient hyperglycemic episodes in the intrauterine environment that are sufficient to induce relative increases in pancreatic function in PA infants, suggesting in this nonhuman primate model that differential programming of insulin action and secretion may precede adult metabolic dysfunction. PMID:20682841

Induction of autophagy in the porcine corpus luteum of pregnancy following anti-androgen treatment.

PubMed

Grzesiak, M; Knapczyk-Stwora, K; Slomczynska, M

2016-12-01

Experimentally induced androgen deficiency during late pregnancy leads to decreased progesterone synthesis in the porcine corpus luteum (CL), which suggested an onset of functional luteolysis. It was shown that luteal regression in mammals involves not only apoptosis but also autophagy. Therefore, this study aimed to examine whether anti-androgen flutamide treatment during late pregnancy in pigs induces apoptosis and/or autophagy within luteal cells. Flutamide (50 mg/kg b.w.) was administered into pregnant gilts between 83 - 89 (GD90F) or 101 - 107 (GD108F) gestational days (GD). CLs were retrieved on day 90 or 108 of pregnancy (n = 3/each group). Detection of apoptosis was performed by TUNEL assay and assessment of cleaved caspase 3 level. Both assays revealed that luteal rate of apoptosis was unaffected by flutamide treatment either in the GD90F or GD108F groups. Moreover, pro-apoptotic protein Bax was downregulated on GD108. The autophagy was examined by expression of two markers, LC3-II and Lamp1. Flutamide led to greater expression of LC3-II protein form in the GD90F and GD108F groups. Likewise, the mRNA and protein levels of Lamp1 were elevated in both flutamide-treated groups. The activation of autophagy is regulated by Beclin 1 and the increased Beclin 1 mRNA and protein expression was found in the GD90F and GD108F groups. Beclin 1 is a Bcl-2-binding protein, thus Beclin1/Bcl-2 interactions were examined using immunoprecipitation. Beclin 1/Bcl-2 complexes were less abundant following flutamide treatment in both flutamide-exposed groups. In summary, we concluded that androgen deficiency induced autophagy by disrupting Beclin 1/Bcl-2 interplay in the porcine CL during pregnancy. The role of autophagy in luteal regression in pigs requires further evaluation.

Therapeutic potential of the SARMs: revisiting the androgen receptor for drug discovery.

PubMed

Segal, Scott; Narayanan, Ramesh; Dalton, James T

2006-04-01

Selective androgen receptor modulators (SARMS) bind to the androgen receptor and demonstrate anabolic activity in a variety of tissues; however, unlike testosterone and other anabolic steroids, these nonsteroidal agents are able to induce bone and muscle growth, as well as shrinking the prostate. The potential of SARMS is to maximise the positive attributes of steroidal androgens as well as minimising negative effects, thus providing therapeutic opportunities in a variety of diseases, including muscle wasting associated with burns, cancer, end-stage renal disease, osteoporosis, frailty and hypogonadism. This review summarises androgen physiology, the current status of the R&D of SARMS and potential therapeutic indications for this emerging class of drugs.

Estrogen induces androgen-repressed SOX4 expression to promote progression of prostate cancer cells.

PubMed

Yang, Muyi; Wang, Jing; Wang, Lin; Shen, Chengwu; Su, Bo; Qi, Mei; Hu, Jing; Gao, Wei; Tan, Weiwei; Han, Bo

2015-09-01

The sex determing region Y-box 4 (SOX4) gene is a critical developmental transcriptional factor that is overexpressed in prostate cancer (PCa). While we and others have investigated the role of SOX4 overexpression in PCa, the molecular mechanism underlying its aberrant expression remains unclear. Immunohistochemistry were utilized to detect SOX4 expression and the correlation between estrogen receptor β (ERβ), androgen receptor (AR) and SOX4 in a cohort of 94 clinical specimens. Real-time quantitative PCR and Western blotting were used to study the transcript and protein expression levels. Immunofluorescence staining and co-immunoprecipitation were performed to assess the interaction and subcellular location of ERβ and AR. Chromatin immunoprecipitation (ChIP) assays and Luciferase reporter assays were performed to explore the binding and transcriptional activities of ERβ and AR to the SOX4 promoter. Cellular function was evaluated by MTS, invasion and wound healing assays. SOX4 expression is up-regulated in Castration-Resistant Prostate Cancer (CRPC) tumors compared to hormone-dependent PCa (HDPC) cases. Increased expression was also observed in PCa cells after long-term androgen-deprivation treatment (ADT). In vitro data indicated that SOX4 is an AR transcriptional target and down-regulated by dihydrotestosterone (DHT) via AR. 17β-estradiol (E2) up-regulates SOX4 expression in the absence of androgen through the formation of a protein complex between ERβ and AR. Knockdown of AR or ERβ blocks the E2-induced SOX4 expression. ChIP assays confirmed that both ERβ and AR bind to the SOX4 promoter in response to E2. Functionally, silencing SOX4 significantly attenuates the proliferative effect, as well as the capacity of migration and invasion of E2 on PCa cells. Clinically, overexpression of SOX4 is significantly associated with ERβ expression in PCa. In addition, this association is still retained in CRPC patients with poor prognosis. These findings suggest that SOX4 is a novel DHT-repressed AR-target gene. E2 could promote proliferation of PCa cells through the up-regulation of SOX4 under androgen-depleted environment. Our data provides a possible molecular basis for the overexpression of SOX4 in CRPC and may facilitate the detection and prevention of the emergence of CRPC. © 2015 Wiley Periodicals, Inc.

Hypochlorite Oxidation of Select Androgenic Steroids

EPA Science Inventory

Steroid hormones are vital for regulation of various biological functions including sexual development. Elevated concentrations of natural and synthetic androgenic steroids have been shown to adversely affect normal development in indigenous aqueous species. Androgens and their s...

Inhibition of 5α-Reductase in Rat Prostate Reveals Differential Regulation of Androgen-Response Gene Expression by Testosterone and Dihydrotestosterone

PubMed Central

Dadras, Soheil S.; Cai, Xiaoyan; Abasolo, Ibane; Wang, Zhou

2001-01-01

The growth and development of some of the male sex accessory organs such as the prostate requires the conversion of testosterone to dihydrotestosterone (DHT) by 5α-reductase. To provide insights into the role of testosterone versus DHT in the prostate, we studied the impact of finasteride, a potent and specific inhibitor of 5α-reductase, on the expression of prostatic androgen-response genes in testis-intact rats and in 7-day castrated rats. Finasteride inhibition of the conversion of testosterone to DHT was confirmed by measuring serum and intraprostatic androgens. As expected, finasteride treatment caused a reduction in the wet weight of the prostate in the testis-intact rats and inhibited the testosterone-stimulated prostatic regrowth in the 7-day castrated rats. Although finasteride treatment had little or no effect on the expression of the surveyed androgen-response genes in testis-intact rats, its administration enhanced the expression of many androgen-response genes during the testosterone-stimulated regrowth of the regressed prostate in castrated rats. These observations suggest that testosterone is more potent than DHT in stimulating the expression of many androgen-response genes in the regressed prostate. The expression of androgen-response genes is mainly prostate specific and thus is likely to be associated with androgen-dependent prostatic differentiation. Therefore, testosterone is more potent than DHT in inducing differentiation and weaker in stimulating proliferation during prostate regrowth. The fact that testosterone is a strong inducer of prostatic differentiation has potential clinical implications. PMID:11444528

Identification of a new plant extract for androgenic alopecia treatment using a non-radioactive human hair dermal papilla cell-based assay.

PubMed

Jain, Ruchy; Monthakantirat, Orawan; Tengamnuay, Parkpoom; De-Eknamkul, Wanchai

2016-01-21

Androgenic alopecia (AGA) is a major type of human scalp hair loss, which is caused by two androgens: testosterone (T) and 5α-dihydrotestosterone (5α-DHT). Both androgens bind to the androgen receptor (AR) and induce androgen-sensitive genes within the human hair dermal papilla cells (HHDPCs), but 5α-DHT exhibits much higher binding affinity and potency than T does in inducing the involved androgen-sensitive genes. Changes in the induction of androgen-sensitive genes during AGA are caused by the over-production of 5α-DHT by the 5α-reductase (5α-R) enzyme; therefore, one possible method to treat AGA is to inhibit this enzymatic reaction. RT-PCR was used to identify the presence of the 5α-R and AR within HHDPCs. A newly developed AGA-relevant HHDPC-based assay combined with non-radioactive thin layer chromatography (TLC) detection was used for screening crude plant extracts for the identification of new 5α-R inhibitors. HHDPCs expressed both 5α-R type 1 isoform of the enzyme (5α-R1) and AR in all of the passages used in this study. Among the thirty tested extracts, Avicennia marina (AM) displayed the highest inhibitory activity at the final concentration of 10 μg/ml, as the production of 5α-DHT decreased by 52% (IC50 = 9.21 ± 0.38 μg/ml). Avicennia marina (AM) was identified as a potential candidate for the treatment of AGA based on its 5α-R1-inhibitory activity.

Multivalent Peptidomimetic Conjugates as Inhibitors of Androgen Receptor Function in Therapy-Resistant Prostate Cancer

DTIC Science & Technology

2016-10-01

STATEMENT: Approved for Public Release; Distribution Unlimited The views, opinions and/or findings contained in this report are those of the author...Androgens are hormones that play a critical role in stimulating prostate cancer growth. Androgens activate a protein called the androgen receptor ( AR ), which...regulates genes involved in cell growth. Although powerful anti-androgen drugs can be administered to block AR action and have been used

Sertoli cell androgen receptor expression regulates temporal fetal and adult Leydig cell differentiation, function, and population size.

PubMed

Hazra, Rasmani; Jimenez, Mark; Desai, Reena; Handelsman, David J; Allan, Charles M

2013-09-01

We recently created a mouse model displaying precocious Sertoli cell (SC) and spermatogenic development induced by SC-specific transgenic androgen receptor expression (TgSCAR). Here we reveal that TgSCAR regulates the development, function, and absolute number of Leydig cells (LCs). Total fetal and adult type LC numbers were reduced in postnatal and adult TgSCAR vs control testes, despite normal circulating LH levels. Normal LC to SC ratios found in TgSCAR testes indicate that SC androgen receptor (SCAR)-mediated activity confers a quorum-dependent relationship between total SC and LC numbers. TgSCAR enhanced LC differentiation, shown by elevated ratios of advanced to immature LC types, and reduced LC proliferation in postnatal TgSCAR vs control testes. Postnatal TgSCAR testes displayed up-regulated expression of coupled ligand-receptor transcripts (Amh-Amhr2, Dhh-Ptch1, Pdgfa-Pdgfra) for potential SCAR-stimulated paracrine pathways, which may coordinate LC differentiation. Neonatal TgSCAR testes displayed normal T and dihydrotestosterone levels despite differential changes to steroidogenic gene expression, with down-regulated Star, Cyp11a1, and Cyp17a1 expression contrasting with up-regulated Hsd3b1, Hsd17b3, and Srd5a1 expression. TgSCAR males also displayed elevated postnatal and normal adult serum testosterone levels, despite reduced LC numbers. Enhanced adult-type LC steroidogenic output was revealed by increased pubertal testicular T, dihydrotestosterone, 3α-diol and 3β-diol levels per LC and up-regulated steroidogenic gene (Nr5a1, Lhr, Cyp11a1, Cyp17a1, Hsd3b6, Srd5a1) expression in pubertal or adult TgSCAR vs control males, suggesting regulatory mechanisms maintain androgen levels independently of absolute LC numbers. Our unique gain-of-function TgSCAR model has revealed that SCAR activity controls temporal LC differentiation, steroidogenic function, and population size.

Excessive training induces molecular signs of pathologic cardiac hypertrophy.

PubMed

da Rocha, Alisson L; Teixeira, Giovana R; Pinto, Ana P; de Morais, Gustavo P; Oliveira, Luciana da C; de Vicente, Larissa Gaioto; da Silva, Lilian E C M; Pauli, José R; Cintra, Dennys E; Ropelle, Eduardo R; de Moura, Leandro P; Mekary, Rania A; de Freitas, Ellen C; da Silva, Adelino S R

2018-05-24

Chronic exercise induces cardiac remodeling that promotes left ventricular hypertrophy and cardiac functional improvement, which are mediated by the mammalian or the mechanistic target of rapamycin (mTOR) as well as by the androgen and glucocorticoid receptors (GRs). However, pathological conditions (i.e., chronic heart failure, hypertension, and aortic stenosis, etc.) also induce cardiac hypertrophy, but with detrimental function, high levels of proinflammatory cytokines and myostatin, elevated fibrosis, reduced adenosine monophosphate-activated protein kinase (AMPK) activation, and fetal gene reactivation. Furthermore, recent studies have evidenced that excessive training induced an inflammatory status in the serum, muscle, hypothalamus, and liver, suggesting a pathological condition that could also be detrimental to cardiac tissue. Here, we verified the effects of three running overtraining (OT) models on the molecular parameters related to physiological and pathological cardiac hypertrophy. C57BL/6 mice performed three different OT protocols and were evaluated for molecular parameters related to physiological and pathological cardiac hypertrophy, including immunoblotting, reverse transcription polymerase chain reaction, histology, and immunohistochemistry analyses. In summary, the three OT protocols induced left ventricle (LV) hypertrophy with signs of cardiac fibrosis and negative morphological adaptations. These maladaptations were accompanied by reductions in AMPKalpha (Thr172) phosphorylation, androgen receptor, and GR expressions, as well as by an increase in interleukin-6 expression. Specifically, the downhill running-based OT model reduced the content of some proteins related to the mTOR signaling pathway and upregulated the β-isoform of myosin heavy-chain gene expression, presenting signs of LV pathological hypertrophy development. © 2018 Wiley Periodicals, Inc.

Endocrine antecedents of polycystic ovary syndrome (PCOS) in fetal and infant prenatally androgenized female rhesus monkeys

PubMed Central

Abbott, David H; Barnett, Deborah K; Levine, Jon E; Padmanabhan, Vasantha; Dumesic, Daniel A; Jacoris, Steve; Tarantal, Alice F

2008-01-01

Experimentally induced fetal androgen excess induces polycystic ovary syndrome (PCOS)-like traits in adult female rhesus monkeys. Developmental changes leading to this endocrinopathy are not known. We therefore studied 15 time-mated, gravid female rhesus monkeys with known female fetuses. Nine dams received daily subcutaneous injections of 15 mg testosterone propionate (TP) and six received injections of oil vehicle (controls) from 40 through 80 days of gestation (term 165 [range: ±10] days), and all fetuses were delivered by Cesarean-section using established methods at term. Ultrasound-guided fetal blood sample collection and peripheral venous sample collection of dams and subsequent infants enabled determination of circulating levels of steroid hormones, LH and FSH. TP injections elevated serum testosterone and androstenedione levels in the dams and prenatally androgenized (PA) fetuses. After cessation of TP injections, testosterone levels mostly normalized, while serum androstenedione levels in PA infants were elevated. TP injections did not increase estrogen levels in the dams, PA fetuses and infants, yet conjugated estrogen levels were elevated in the TP-injected dams. Serum levels of LH and FSH were elevated in late gestation PA fetuses, and LH levels were elevated in PA infants. These studies suggest that experimentally-induced fetal androgen excess increases gonadotropin secretion in PA female fetuses and infants, and elevates endogenous androgen levels in PA infants. Thus, in this nonhuman primate model, differential programming of the fetal hypothalamo-pituitary unit with concomitant hyperandrogenism provides evidence to suggest developmental origins of LH and androgen excess in adulthood. PMID:18385445

Preventable effect of L-threonate, an ascorbate metabolite, on androgen-driven balding via repression of dihydrotestosterone-induced dickkopf-1 expression in human hair dermal papilla cells.

PubMed

Kwack, Mi Hee; Ahn, Ji Sup; Kim, Moon Kyu; Kim, Jung Chul; Sung, Young Kwan

2010-10-01

In a previous study, we recently claimed that dihydrotestosterone (DHT)-inducible dickkopf-1 (DKK-1) expression is one of the key factors involved in androgen-potentiated balding. We also demonstrated that L-ascorbic acid 2-phosphate (Asc 2-P) represses DHT-induced DKK-1 expression in cultured dermal papilla cells (DPCs). Here, we investigated whether or not L-threonate could attenuate DHT-induced DKK-1 expression. We observed via RT-PCR analysis and enzyme-linked immunosorbent assay that DHT-induced DKK-1 expression was attenuated in the presence of L-threonate. We also found that DHT-induced activation of DKK-1 promoter activity was significantly repressed by L-threonate. Moreover, a co-culture system featuring outer root sheath (ORS) keratinocytes and DPCs showed that DHT inhibited the growth of ORS cells, which was then significantly reversed by L-threonate. Collectively, these results indicate that L-threonate inhibited DKK-1 expression in DPCs and therefore is a good treatment for the prevention of androgen-driven balding.

Impact of Androgen Deprivation Therapy on Self-Reported Cognitive Function in Men with Prostate Cancer.

PubMed

Marzouk, Shireen; Naglie, Gary; Tomlinson, George; Duff Canning, Sarah; Breunis, Henriette; Timilshina, Narhari; Alibhai, Shabbir M H

2018-03-01

Although androgen deprivation therapy is widely used to treat prostate cancer, its effects on cognitive function are unclear. To our knowledge no prior report has examined the impact of androgen deprivation therapy on self-reported cognitive function. Three groups of men 50 years old or older who were matched on age and education were enrolled in the study, including 81 with prostate cancer starting on continuous androgen deprivation therapy, 84 controls with prostate cancer not receiving androgen deprivation therapy and 85 healthy controls. Two scales from the FACT-Cog (Functional Assessment of Cancer Therapy-Cognitive subscale) version 3 were used to assess self-reported cognitive function. Changes in cognitive scores with time were analyzed by 2 approaches, including 1) multivariable regression and 2) calculation of the proportion of subjects per group with a decrease of 1 SD or more. Multivariable regression was applied to assess predictors of a decline in self-reported cognitive function. We also examined relationships between the FACT-Cog and a neuropsychological battery of 15 tests. Mean participant age was 69 years (range 50 to 87). The mean educational level was 15 years (range 8 to 24). FACT-Cog scores were similar at baseline across the cohorts. Neither analytical approach revealed that androgen deprivation therapy was associated with changes in self-reported cognitive function on either FACT-Cog scale. Mood and fatigue correlated with changes in self-reported cognitive function. The relationship between self-reported and objective cognitive measures was weak (maximum Spearman correlation coefficient 0.14) and only 2 of 30 correlations were statistically significant. A total of 12 months of androgen deprivation therapy were not associated with self-reported cognitive function changes in older men with nonmetastatic prostate cancer. Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Expression and potential role of the peptide orexin-A in prostate cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Valiante, Salvatore; Liguori, Giovanna; Tafuri, Simona

The peptides orexin-A and orexin-B and their G protein-coupled OX1 and OX2 receptors are involved in multiple physiological processes in the central nervous system and peripheral organs. Altered expression or signaling dysregulation of orexins and their receptors have been associated with a wide range of human diseases including narcolepsy, obesity, drug addiction, and cancer. Although orexin-A, its precursor molecule prepro-orexin and OX1 receptor have been detected in the human normal and hyperplastic prostate tissues, their expression and function in the prostate cancer (PCa) remains to be addressed. Here, we demonstrate for the first time the immunohistochemical localization of orexin-A inmore » human PCa specimens, and the expression of prepro-orexin and OX1 receptor at both protein and mRNA levels in these tissues. Orexin-A administration to the human androgen-dependent prostate carcinoma cells LNCaP up-regulates OX1 receptor expression resulting in a decrease of cell survival. Noteworthy, nanomolar concentrations of the peptide counteract the testosterone-induced nuclear translocation of the androgen receptor in the cells: the orexin-A action is prevented by the addition of the OX1 receptor antagonist SB-408124 to the test system. These findings indicate that orexin-A/OX1 receptor interaction interferes with the activity of the androgen receptor which regulates PCa onset and progression, thus suggesting that orexin-A and its receptor might represent novel therapeutic targets to challenge this aggressive cancer. - Highlights: • Orexin-A and OX1 receptor are present in human cancer prostate tissues. • Orexin-A up-regulates OX1 receptor expression in LNCaP cells. • Orexin-A inhibits testosterone-induced nuclear translocation of androgen receptor.« less

Tetragonia tetragonioides (Pall.) Kuntze Regulates Androgen Production in a Letrozole-Induced Polycystic Ovary Syndrome Model.

PubMed

Pyun, Bo-Jeong; Yang, Hyun; Sohn, Eunjin; Yu, Song Yi; Lee, Dongoh; Jung, Dong Ho; Ko, Byoung Seob; Lee, Hye Won

2018-05-14

Tetragonia tetragonioides (Pall.) Kuntze (TTK) is a medicinal plant traditionally used to treat various diseases such as diabetic, inflammatory, and female-related disorders. Polycystic ovary syndrome (PCOS) is a common endocrinological disorder in women of reproductive age, and hyperandrogenism is a prominent feature of PCOS resulting in anovulation and infertility. In this study, we investigated the effects of a TTK extract on androgen generation and regulation of steroidogenic enzymes in vitro and in vivo. Human adrenocortical NCI-H295R cells were used to assess the effects of TTK extract on production of dehydroepiandrosterone and testosterone, as well as the protein expression of steroidogenic enzymes. Further, a letrozole-induced PCOS rat model was used in vivo to assess whether dietary administration of TTK extract restores normal hormones and reduces PCOS symptoms. TTK extract significantly inhibited forskolin (FOR)-induced androgen production in NCI-H295R cells and serum luteinizing hormone, testosterone, and follicular cysts, but not estradiol, were reduced in letrozole-induced PCOS rats orally administered the TTK extract. In addition, TTK extract inhibits androgen biosynthesis through the ERK-CREB signaling pathway, which regulates CYP17A1 or HSD3B2 expression. TTK extract could be utilized for the prevention and treatment of hyperandrogenism and other types of PCOS.

Androgens: basic biology and clinical implication.

PubMed

Orwoll, E S

2001-10-01

Although androgens have been considered essential modulators of bone biology in men, recent studies have indicated that estrogen may have an important, if not dominant, role. Nevertheless, there is strong evidence that androgens have independent skeletal actions. Nonaromatizable androgens influence a variety of aspects of bone cell biology and are capable of modulating bone remodeling and bone mass. It appears that androgens are particularly important in the control of periosteal bone formation, an effect that might underlie the gender difference in bone size. Alterations in androgen receptor function affect bone metabolism, and new information suggests that androgens modulate receptor homeostasis. The clinical implications of androgen effects, and how they interact with those of estrogens, are somewhat unclear. It is likely that overall bone homeostasis and gender differences depend on a combination of androgenic and estrogenic actions. Androgens may well provide advantages in the prevention and therapy of metabolic bone disorders in both men and women.

PROVIDING A BETTER UNDERSTANDING OF THE SCIENCE UNDERLYING THE EFFECTS, EXPOSURE, ASSESSMENT, AND MANAGEMENT OF EDCS: DOES MILD HYPOTHYROIDISM INDUCED BY ENVIRONMENTAL CONTAMINANTS IRREVERSIBLY ALTER CNS FUNCTION IN THE JUVENILE AND ADULT ANIMAL?

EPA Science Inventory

SUMMARY: The NTD research project on Endocrine-Disrupting Chemicals (EDC) is focused on the effects of thyroid hormone (TH) deficiencies on the developing brain and is one component of a larger NHEERL research program evaluating androgen, estrogen, and thyroid-disrupting chemical...

Bicalutamide-induced hepatotoxicity: A rare adverse effect.

PubMed

Hussain, Salwa; Haidar, Abdallah; Bloom, Robert E; Zayouna, Nafea; Piper, Michael H; Jafri, Syed-Mohammed R

2014-01-01

Male, 81 FINAL DIAGNOSIS: Prostate cancer Symptoms: Anorexia • dark urine • joundice • letargy Casodex Clinical Procedure: - Specialty: Oncology. Adverse events of drug therapy. Bicalutamide is a nonsteroidal anti-androgen used extensively during the initiation of androgen deprivation therapy with a luteinizing hormone-releasing hormone (LHRH) agonist to reduce the symptoms of tumor flare in patients with metastatic prostate neoplasm. It can cause gynecomastia, hot flashes, fatigue, and decreased libido through competitive androgen receptor blockade. Although not as common, acute drug-induced liver injury is also possible with bicalutamide therapy. Typically, this results in transient derangement of liver function and patients remain asymptomatic. We share our experience with a case of symptomatic acute hepatotoxicity secondary to the use of bicalutamide and use this opportunity to present a brief review of existing literature. An 81-year-old African American male with metastatic prostate neoplasm presented with nonspecific symptoms along with jaundice of 1-day duration. He was started on a trial of bicalutamide 3 weeks prior to presentation. On physical examination, scleral icterus was noted. Workup revealed acutely elevated liver transaminases (>5 times the upper limit of normal), alkaline phosphatase, conjugated hyperbilirubinemia, and coagulopathy. Other etiologies, including viruses, common toxins, drugs, autoimmune, and copper-induced hepatitis, were considered. Bicalutamide was discontinued and the patient was managed with supportive care. He showed improvement of clinical and laboratory abnormalities within days. While rare, clinically significant and potentially life-threatening liver injury can result from use of bicalutamide. Prompt recognition and discontinuation of bicalutamide is necessary to avoid serious complications from this adverse reaction.

Effect of propofol on androgen receptor activity in prostate cancer cells.

PubMed

Tatsumi, Kenichiro; Hirotsu, Akiko; Daijo, Hiroki; Matsuyama, Tomonori; Terada, Naoki; Tanaka, Tomoharu

2017-08-15

Androgen receptor is a nuclear receptor and transcription factor activated by androgenic hormones. Androgen receptor activity plays a pivotal role in the development and progression of prostate cancer. Although accumulating evidence suggests that general anesthetics, including opioids, affect cancer cell growth and impact patient prognosis, the effect of those drugs on androgen receptor in prostate cancer is not clear. The purpose of this study was to investigate the effect of the general anesthetic propofol on androgen receptor activity in prostate cancer cells. An androgen-dependent human prostate cancer cell line (LNCaP) was stimulated with dihydrotestosterone (DHT) and exposed to propofol. The induction of androgen receptor target genes was investigated using real-time reverse transcription polymerase chain reaction, and androgen receptor protein levels and localization patterns were analyzed using immunoblotting and immunofluorescence assays. The effect of propofol on the proliferation of LNCaP cells was analyzed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Propofol significantly inhibited DHT-induced expression of androgen receptor target genes in a dose- and time-dependent manner, and immunoblotting and immunofluorescence assays indicated that propofol suppressed nuclear levels of androgen receptor proteins. Exposure to propofol for 24h suppressed the proliferation of LNCaP cells, whereas 4h of exposure did not exert significant effects. Together, our results indicate that propofol suppresses nuclear androgen receptor protein levels, and inhibits androgen receptor transcriptional activity and proliferation in LNCaP cells. Copyright © 2017 Elsevier B.V. All rights reserved.

USP22 regulates oncogenic signaling pathways to drive lethal cancer progression.

PubMed

Schrecengost, Randy S; Dean, Jeffry L; Goodwin, Jonathan F; Schiewer, Matthew J; Urban, Mark W; Stanek, Timothy J; Sussman, Robyn T; Hicks, Jessica L; Birbe, Ruth C; Draganova-Tacheva, Rossitza A; Visakorpi, Tapio; DeMarzo, Angelo M; McMahon, Steven B; Knudsen, Karen E

2014-01-01

Increasing evidence links deregulation of the ubiquitin-specific proteases 22 (USP22) deubitiquitylase to cancer development and progression in a select group of tumor types, but its specificity and underlying mechanisms of action are not well defined. Here we show that USP22 is a critical promoter of lethal tumor phenotypes that acts by modulating nuclear receptor and oncogenic signaling. In multiple xenograft models of human cancer, modeling of tumor-associated USP22 deregulation demonstrated that USP22 controls androgen receptor accumulation and signaling, and that it enhances expression of critical target genes coregulated by androgen receptor and MYC. USP22 not only reprogrammed androgen receptor function, but was sufficient to induce the transition to therapeutic resistance. Notably, in vivo depletion experiments revealed that USP22 is critical to maintain phenotypes associated with end-stage disease. This was a significant finding given clinical evidence that USP22 is highly deregulated in tumors, which have achieved therapeutic resistance. Taken together, our findings define USP22 as a critical effector of tumor progression, which drives lethal phenotypes, rationalizing this enzyme as an appealing therapeutic target to treat advanced disease.

New Strategy for Prostate Cancer Prevention Based on Selenium Suppression of Androgen Receptor Signaling

DTIC Science & Technology

2007-10-01

regulates androgen receptor, and finasteride , a 5α-reductase inhibitor, has a synerigistic effect in inhibiting the growth of prostate cancer cells...impact of the selenium and finasteride combination on androgen signaling; 2) Identifying the pro-apoptotic target genes of FOXO1 that are induced by...selenium; 3) studying the potential AR antagonistic effect of finasteride . The last was not proposed in the original application. But we strongly

Postmenopausal virilization after spousal use of topical androgens.

PubMed

Merhi, Zaher O; Santoro, Nanette

2007-04-01

To increase awareness of the potential to cause virilization in postmenopausal woman secondary to a spouse's use of topical androgen. Case report. University-affiliated teaching hospital. A 63-year-old postmenopausal woman with virilization. Removal of the source of androgen exposure. Regression of the biochemical and physical signs of androgen excess in a woman after cessation of T gel use by her partner, and reinitiation of use with precautions against potential methods of transfer. This case highlights the unintentional transdermal absorption of testosterone sufficient to induce virilization in a couple who were aware of this potential problem. The apparent source of androgen absorption was a washcloth that the couple shared. The diagnosis can be established with a detailed history and a few blood tests (total and free T, and DHEAS) to exclude other sources of androgens. This report reinforces the need to consider exogenous androgen exposure in the differential diagnosis of virilization in adults when the more common causes have been excluded.

Roles for the Stem Cell–Associated Intermediate Filament Nestin in Prostate Cancer Migration and Metastasis

PubMed Central

Kleeberger, Wolfram; Bova, G. Steven; Nielsen, Matthew E.; Herawi, Mehsati; Chuang, Ai-Ying; Epstein, Jonathan I.; Berman, David M.

2011-01-01

The intermediate filament protein Nestin identifies stem/progenitor cells in adult tissues, but the function of Nestin is poorly understood. We investigated Nestin expression and function in common lethal cancers. Nestin mRNA was detected in cell lines from small cell lung, and breast cancers, and particularly elevated in cell lines derived from prostate cancer metastases. Whereas the androgen-independent lines PC3, 22RV1, and DU145 all expressed Nestin transcripts under standard culture conditions, the androgen-dependent line LnCaP expressed Nestin only on androgen withdrawal. We confirmed associations of Nestin expression, androgen withdrawal, and metastatic potential by immunohistochemical analysis of samples from 254 prostate cancer patients. Cytoplasmic Nestin protein was readily identifiable in prostate cancer cells from 75% of patients with lethal androgen-independent disease, even in cancer sampled from the prostate itself. However, Nestin expression was undetectable in localized androgen-deprived tumors and in metastases without prior androgen deprivation. To address its function, we reduced Nestin levels with short hairpin RNAs, markedly inhibiting in vitro migration and invasion in prostate cancer cells but leaving cell growth intact. Nestin knockdown also diminished metastases 5-fold compared with controls despite uncompromised tumorigenicity at the site of inoculation. These results specify a function for Nestin in cell motility and identify a novel pathway for prostate cancer metastasis. Activity of this pathway may be selected by the extraprostatic environment or, as supported by our data, may originate within the prostate after androgen deprivation. Further dissection of this novel Nestin migration pathway may lead to strategies to prevent and neutralize metastatic spread. PMID:17909025

Androgen Receptor Signaling in Bladder Cancer

PubMed Central

Li, Peng; Chen, Jinbo; Miyamoto, Hiroshi

2017-01-01

Emerging preclinical findings have indicated that steroid hormone receptor signaling plays an important role in bladder cancer outgrowth. In particular, androgen-mediated androgen receptor signals have been shown to correlate with the promotion of tumor development and progression, which may clearly explain some sex-specific differences in bladder cancer. This review summarizes and discusses the available data, suggesting the involvement of androgens and/or the androgen receptor pathways in urothelial carcinogenesis as well as tumor growth. While the precise mechanisms of the functions of the androgen receptor in urothelial cells remain far from being fully understood, current evidence may offer chemopreventive or therapeutic options, using androgen deprivation therapy, in patients with bladder cancer. PMID:28241422

A novel class of pyranocoumarin anti-androgen receptor signaling compounds.

PubMed

Guo, Junming; Jiang, Cheng; Wang, Zhe; Lee, Hyo-Jeong; Hu, Hongbo; Malewicz, Barbara; Lee, Hyo-Jung; Lee, Jae-Ho; Baek, Nam-In; Jeong, Jin-Hyun; Kim, Dae-Keun; Kang, Kyung-Sun; Kim, Sung-Hoon; Lu, Junxuan

2007-03-01

Androgen and the androgen receptor (AR)-mediated signaling are crucial for prostate cancer development. Novel agents that can inhibit AR signaling in ligand-dependent and ligand-independent manners are desirable for the chemoprevention of prostate carcinogenesis and for the treatment of advanced prostate cancer. We have shown recently that the pyranocoumarin compound decursin from the herb Angelica gigas possesses potent anti-AR activities distinct from the anti-androgen bicalutamide. Here, we compared the anti-AR activities and the cell cycle arrest and apoptotic effects of decursin and two natural analogues in the androgen-dependent LNCaP human prostate cancer cell culture model to identify structure-activity relationships and mechanisms. Decursin and its isomer decursinol angelate decreased prostate-specific antigen expression with IC(50) of approximately 1 mumol/L. Both inhibited the androgen-stimulated AR nuclear translocation and transactivation, decreased AR protein abundance through proteasomal degradation, and induced G(0/1) arrest and morphologic differentiation. They also induced caspase-mediated apoptosis and reactive oxygen species at higher concentrations. Furthermore, they lacked the agonist activity of bicalutamide in the absence of androgen and were more potent than bicalutamide for suppressing androgen-stimulated cell growth. Decursinol, which does not contain a side chain, lacked the reactive oxygen species induction and apoptotic activities and exerted paradoxically an inhibitory and a stimulatory effect on AR signaling and cell growth. In conclusion, decursin and decursinol angelate are members of a novel class of nonsteroidal compounds that exert a long-lasting inhibition of both ligand-dependent and ligand-independent AR signaling. The side chain is critical for sustaining the anti-AR activities and the growth arrest and apoptotic effects.

Testofen, a specialised Trigonella foenum-graecum seed extract reduces age-related symptoms of androgen decrease, increases testosterone levels and improves sexual function in healthy aging males in a double-blind randomised clinical study.

PubMed

Rao, Amanda; Steels, Elizabeth; Inder, Warrick J; Abraham, Suzanne; Vitetta, Luis

2016-06-01

This study examined the effect of Testofen, a specialised Trigonella foenum-graecum seed extract on the symptoms of possible androgen deficiency, sexual function and serum androgen concentrations in healthy aging males. This was a double-blind, randomised, placebo-controlled trial involving 120 healthy men aged between 43 and 70 years of age. The active treatment was standardised Trigonella foenum-graecum seed extract at a dose of 600 mg/day for 12 weeks. The primary outcome measure was the change in the Aging Male Symptom questionnaire (AMS), a measure of possible androgen deficiency symptoms; secondary outcome measures were sexual function and serum testosterone. There was a significant decrease in AMS score over time and between the active and placebo groups. Sexual function improved, including number of morning erections and frequency of sexual activity. Both total serum testosterone and free testosterone increased compared to placebo after 12 weeks of active treatment. Trigonella foenum-graecum seed extract is a safe and effective treatment for reducing symptoms of possible androgen deficiency, improves sexual function and increases serum testosterone in healthy middle-aged and older men.

Male sex steroids and hormonal control of male courtship behavior in the yellow-bellied slider turtle, Trachemys scripta

USGS Publications Warehouse

Garstka, W.R.; Cooper, W.E.; Wasmund, K.W.; Lovich, J.E.

1991-01-01

Survey of androgens and estrogens in serum, liver and testes of male yellow-bellied slider turtles, Trachemys (= Pseudemys) scripta, a species exhibiting dissociated gametogenesis age-dependent melanism, revealed the presence of numerous androgen precursors, androgens, androgen metabolites, and estrogens in quantities varying with season, tissue, and male coloration.The most commonly found and abundant androgens in all males were dehydroepiandrosterone (DHEA) and androstenedione, which were present at significantly higher levels in testes than in serum or liver.Epitestosterone was found in the serum and liver of only melanistic males; testosterone was only rarely recovered.Behavioral testing of castrated male turtles implanted with various androgens, as well as intact and sham-operated controls, revealed that melanistic males courted more frequently than nonmelanistic males, and that exogenous testosterone was most effective in inducing courtship behavior in castrated males.

An androgen receptor negatively induced long non-coding RNA ARNILA binding to miR-204 promotes the invasion and metastasis of triple-negative breast cancer.

PubMed

Yang, Fang; Shen, Yan; Zhang, Wenwen; Jin, Juan; Huang, Doudou; Fang, Hehui; Ji, Wenfei; Shi, Yaqin; Tang, Lin; Chen, Weiwei; Zhou, Guohua; Guan, Xiaoxiang

2018-05-29

Androgen receptor (AR) is emerging as a novel prognostic biomarker in triple-negative breast cancer (TNBC), but the underlying mechanisms remain unknown. As accumulating evidence has shown that long non-coding RNAs (lncRNAs) regulate important cancer hallmarks, we hypothesised that AR-regulated lncRNAs might play roles in TNBC progression. Here, we performed experiments with or without DHT treatment in three TNBC cell lines, and we identified an AR negatively induced lncRNA (ARNILA), which correlated with poor progression-free survival (PFS) in TNBC patients and promoted epithelial-mesenchymal transition (EMT), invasion and metastasis in vitro and in vivo. Subsequently, we demonstrated that ARNILA functioned as a competing endogenous RNA (ceRNA) for miR-204 to facilitate expression of its target gene Sox4, which is known to induce EMT and contribute to breast cancer progression, thereby promoting EMT, invasion and metastasis of TNBC. Our findings not only provide new insights into the mechanisms of lncRNA in regulating AR but also suggest ARNILA as an alternative therapeutic target to suppress metastasis of TNBC patients.

Altered ovarian function affects skeletal homeostasis independent of the action of follicle-stimulating hormone.

PubMed

Gao, Jianjun; Tiwari-Pandey, Rashmi; Samadfam, Rana; Yang, Yinzhi; Miao, Dengshun; Karaplis, Andrew C; Sairam, M Ram; Goltzman, David

2007-06-01

Osteoporosis is a leading public health problem. Although a major cause in women is thought to be a decline in estrogen, it has recently been proposed that FSH or follitropin is required for osteoporotic bone loss. We examined the FSH receptor null mouse (FORKO mouse) to determine whether altered ovarian function could induce bone loss independent of FSH action. By 3 months of age, FORKO mice developed age-dependent declines in bone mineral density and trabecular bone volume of the lumbar spine and femur, which could be partly reversed by ovarian transplantation. Bilateral ovariectomy reduced elevated circulating testosterone levels in FORKO mice and decreased bone mass to levels indistinguishable from those in ovariectomized wild-type controls. Androgen receptor blockade and especially aromatase inhibition each produced bone volume reductions in the FORKO mouse. The results indicate that ovarian secretory products, notably estrogen, and peripheral conversion of ovarian androgen to estrogen can alter bone homeostasis independent of any bone resorptive action of FSH.

Multivalent Peptidomimetic Conjugates as Inhibitors of Androgen Receptor Function in Therapy-Resistant Prostate Cancer

DTIC Science & Technology

2017-10-01

STATEMENT: Approved for Public Release; Distribution Unlimited The views, opinions and/or findings contained in this report are those of the author...S) 12. DISTRIBUTION / AVAILABILITY STATEMENT Approved for Public Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Androgens are ...hormones that play a critical role in stimulating prostate cancer growth. Androgens activate a protein called the androgen receptor ( AR ), which

AZD1152-HQPA induces growth arrest and apoptosis in androgen-dependent prostate cancer cell line (LNCaP) via producing aneugenic micronuclei and polyploidy.

PubMed

Zekri, Ali; Ghaffari, Seyed H; Ghanizadeh-Vesali, Samad; Yaghmaie, Marjan; Salmaninejad, Arash; Alimoghaddam, Kamran; Modarressi, Mohammad H; Ghavamzadeh, Ardeshir

2015-02-01

Prostate cancer is the frequent non-cutaneous tumor with high mortality in men. Prostate tumors contain cells with different status of androgen receptor. Androgen receptor plays important roles in progression and treatment of prostate cancer. Aurora B kinase, with oncogenic potential, is involved in chromosome segregation and cytokinesis, and its inhibition is a promising anti-cancer therapy. In the present study, we aimed to investigate the effects of Aurora B inhibitor, AZD1152-HQPA, on survival and proliferation of androgen receptor (AR)-positive prostate cancer cells. LNCaP was used as androgen-dependent prostate cancer cell line. We explored the effects of AZD1152-HQPA on cell viability, DNA content, micronuclei formation, and expression of genes involved in apoptosis and cell cycle. Moreover, the expression of Aurora B and AR were investigated in 23 benign prostatic hyperplasia and 38 prostate cancer specimens. AZD1152-HQPA treatment induced defective cell survival, polyploidy, and cell death in LNCaP cell line. Centromeric labeling with fluorescence in situ hybridization (FISH) showed that the loss of whole chromosomes is the origin of micronuclei, indicating on aneugenic action of AZD1152-HQPA. Treatment of AZD1152-HQPA decreased expression of AR. Moreover, we found weak positive correlations between the expression of Aurora B and AR in both benign prostatic hyperplasia and prostate cancer specimens (r = 0.25, r = 0.41). This is the first time to show that AZD1152-HQPA can be a useful therapeutic strategy for the treatment of androgen-dependent prostate cancer cell line. AZD1152-HQPA induces aneugenic mechanism of micronuclei production. Taken together, this study provides new insight into the direction to overcome the therapeutic impediments against prostate cancer.

Androgen receptor and chemokine receptors 4 and 7 form a signaling axis to regulate CXCL12-dependent cellular motility.

PubMed

Hsiao, Jordy J; Ng, Brandon H; Smits, Melinda M; Wang, Jiahui; Jasavala, Rohini J; Martinez, Harryl D; Lee, Jinhee; Alston, Jhullian J; Misonou, Hiroaki; Trimmer, James S; Wright, Michael E

2015-03-31

Identifying cellular signaling pathways that become corrupted in the presence of androgens that increase the metastatic potential of organ-confined tumor cells is critical to devising strategies capable of attenuating the metastatic progression of hormone-naïve, organ-confined tumors. In localized prostate cancers, gene fusions that place ETS-family transcription factors under the control of androgens drive gene expression programs that increase the invasiveness of organ-confined tumor cells. C-X-C chemokine receptor type 4 (CXCR4) is a downstream target of ERG, whose upregulation in prostate-tumor cells contributes to their migration from the prostate gland. Recent evidence suggests that CXCR4-mediated proliferation and metastasis of tumor cells is regulated by CXCR7 through its scavenging of chemokine CXCL12. However, the role of androgens in regulating CXCR4-mediated motility with respect to CXCR7 function in prostate-cancer cells remains unclear. Immunocytochemistry, western blot, and affinity-purification analyses were used to study how androgens influenced the expression, subcellular localization, and function of CXCR7, CXCR4, and androgen receptor (AR) in LNCaP prostate-tumor cells. Moreover, luciferase assays and quantitative polymerase chain reaction (qPCR) were used to study how chemokines CXCL11 and CXCL12 regulate androgen-regulated genes (ARGs) in LNCaP prostate-tumor cells. Lastly, cell motility assays were carried out to determine how androgens influenced CXCR4-dependent motility through CXCL12. Here we show that, in the LNCaP prostate-tumor cell line, androgens coordinate the expression of CXCR4 and CXCR7, thereby promoting CXCL12/CXCR4-mediated cell motility. RNA interference experiments revealed functional interactions between AR and CXCR7 in these cells. Co-localization and affinity-purification experiments support a physical interaction between AR and CXCR7 in LNCaP cells. Unexpectedly, CXCR7 resided in the nuclear compartment and modulated AR-mediated transcription. Moreover, androgen-mediated cell motility correlated positively with the co-localization of CXCR4 and CXCR7 receptors, suggesting that cell migration may be linked to functional CXCR4/CXCR7 heterodimers. Lastly, CXCL12-mediated cell motility was CXCR7-dependent, with CXCR7 expression required for optimal expression of CXCR4 protein. Overall, our results suggest that inhibition of CXCR7 function might decrease the metastatic potential of organ-confined prostate cancers.

Targeting a Novel Androgen Receptor-Repressed Pathway in Prostate Cancer Therapy

DTIC Science & Technology

2017-09-01

AURKA and CENPE. [ Study is on - going] Major Task 3: Test the hypothesis that androgen deprivation-induced PKD1 expression. Major Task 4: Test the...Subtask 3: Conduct detail analysis of the pathway identified in Subtask 2 and assessing its impact on PKD1 expression. This study is on -going. We...enzalutamide, in androgen-sensitivity PrCa cells. We have completed this subtask. In this study , although PKD2 overexpression had little impact on LNCaP

Neuroendocrine androgen action is a key extraovarian mediator in the development of polycystic ovary syndrome.

PubMed

Caldwell, Aimee S L; Edwards, Melissa C; Desai, Reena; Jimenez, Mark; Gilchrist, Robert B; Handelsman, David J; Walters, Kirsty A

2017-04-18

Polycystic ovary syndrome (PCOS) is a complex hormonal disorder characterized by reproductive, endocrine, and metabolic abnormalities. As the origins of PCOS remain unknown, mechanism-based treatments are not feasible and current management relies on treatment of symptoms. Hyperandrogenism is the most consistent PCOS characteristic; however, it is unclear whether androgen excess, which is treatable, is a cause or a consequence of PCOS. As androgens mediate their actions via the androgen receptor (AR), we combined a mouse model of dihydrotestosterone (DHT)-induced PCOS with global and cell-specific AR-resistant (ARKO) mice to investigate the locus of androgen actions that mediate the development of the PCOS phenotype. Global loss of the AR reveals that AR signaling is required for all DHT-induced features of PCOS. Neuron-specific AR signaling was required for the development of dysfunctional ovulation, classic polycystic ovaries, reduced large antral follicle health, and several metabolic traits including obesity and dyslipidemia. In addition, ovariectomized ARKO hosts with wild-type ovary transplants displayed normal estrous cycles and corpora lutea, despite DHT treatment, implying extraovarian and not intraovarian AR actions are key loci of androgen action in generating the PCOS phenotype. These findings provide strong evidence that neuroendocrine genomic AR signaling is an important extraovarian mediator in the development of PCOS traits. Thus, targeting AR-driven mechanisms that initiate PCOS is a promising strategy for the development of novel treatments for PCOS.

Male sexual behavior does not require elevated testosterone in a lizard (Coleonyx elegans, Eublepharidae).

PubMed

Golinski, Alison; John-Alder, Henry; Kratochvíl, Lukáš

2011-01-01

Male sexual behavior depends on gonadal androgens in species of all major vertebrate lineages, including reptiles. However, male sexual behavior includes distinct appetitive and consummatory phases, typically denoted as courtship and mounting, with potentially different hormonal control. Different proximate controls of courtship versus mounting could enable disconnected evolutionary losses and gains of various aspects of male sexual behavior. Male courtship display, which is activated by testosterone (T) in many species, is an ancestral trait in the lizard family Eublepharidae. However, Coleonyx elegans (Yucatan Banded Gecko) lost the courtship display, while retaining a highly simplified male sexual behavior that involves only mounting for copulation. We performed surgical manipulations (castration with and without T replacement in adult males; implantation of adult females with exogenous T) to investigate hormonal mechanisms involved in this evolutionary novelty. Our results indicate that the expression of simplified sexual behavior in C. elegans does not require elevated circulating levels of T, a finding that is previously unreported in lizards. In females, however, exogenous T induced male-like mounting. Thus, the mounting phase of sexual behavior is not activated by T in the traditional sense of this term but probably requires post-natal, maturational organization (if not periodic reorganization) by androgens. We conclude that the simplification of male sexual behavior and its independence from elevated levels of circulating androgens in C. elegans evolved via 1) evolutionary loss of the androgen-activated courtship display and 2) retention of the mounting phase, which has a longer "functional memory" for the effects of androgenic steroids. Copyright © 2010 Elsevier Inc. All rights reserved.

Trichosanthes kirilowii Exerts Androgenic Activity via Regulation of PSA and KLK2 in 22Rv1 Prostate Cancer Cells

PubMed Central

Jeong, Soo-Jin; Choi, Ji-Yoon; Dong, Mi-Sook; Seo, Chang-Seob; Shin, Hyeun-Kyoo

2017-01-01

Background: The androgen comprises a group of hormones that play roles in male reproductive activity as well as personal characteristics. Objective: We investigated the androgenic activity of various herbal medicines in human prostate cancer 22Rv1 cells. Materials and Methods: Herbal extracts of Trichosanthes kirilowii (TK), Asarum sieboldii (AS), Sanguisorba officinalis (SO), and Xanthium strumarium (XS) were selected to have androgenic effects based on a preliminary in vitro screening system. Results: TK, AS, SO, and XS enhanced the proliferation of 22Rv1 cells without having cytotoxic effects. All tested herbal extracts increased androgen receptor (AR)-induced transcriptional activity in the absence or presence of dihydrotestosterone (DHT). In an AR-binding assay, TK, but not AS, SO, or XS, produced a significant inhibition of AR binding activity, indicating it has androgenic activity. Additionally, TK treatment positively regulated mRNA expression of the AR-related molecular targets prostate-specific antigen (PSA) and kallikrein 2 (KLK2) compared with untreated control. Conclusion: Taken together, TK-enhanced AR-mediated transcriptional activity might be an attractive candidate drug for treating androgen-related diseases. SUMMARY Trichosantheskirilowii (TK), Asarumsieboldii (AS), Sanguisorbaofficinalis (SO), and Xanthium strumarium (XS) enhanced the proliferation of 22Rv1 cells without having cytotoxic effects.TK, AS, SO, and XS increased androgen receptor (AR)-induced transcriptional activity.TK, but not AS, SO, or XS, produced a significant inhibition against AR-binding activity.TK treatment positively regulated mRNA expression of the AR-related molecular targets prostate-specific antigen and kallikrein 2. Abbreviations used: BPH: benign prostatic hyperplasia; AR: androgen receptor; DHT: dihydrotestosterone; PSA: prostate-specific antigen; TK: Trichosanthes kirilowii; AS: Asarum sieboldii; SO: Sanguisorba officinalis; XS: Xanthium strumarium; ATCC: American Type Culture Collection; FBS: fetal bovine serum; PBS: phosphate-buffered saline; SD: standard deviation; ARE: androgenresponsive element; KLK: kallikrein PMID:28216900

Androgen receptor and immune inflammation in benign prostatic hyperplasia and prostate cancer

PubMed Central

Izumi, Kouji; Li, Lei; Chang, Chawnshang

2014-01-01

Both benign prostatic hyperplasia (BPH) and prostate cancer (PCa) are frequent diseases in middle-aged to elderly men worldwide. While both diseases are linked to abnormal growth of the prostate, the epidemiological and pathological features of these two prostate diseases are different. BPH nodules typically arise from the transitional zone, and, in contrast, PCa arises from the peripheral zone. Androgen deprivation therapy alone may not be sufficient to cure these two prostatic diseases due to its undesirable side effects. The alteration of androgen receptor-mediated inflammatory signals from infiltrating immune cells and prostate stromal/epithelial cells may play key roles in those unwanted events. Herein, this review will focus on the roles of androgen/androgen receptor signals in the inflammation-induced progression of BPH and PCa. PMID:26594314

Transcripts of genes encoding reproductive neuroendocrine hormones and androgen receptor in the brain and testis of goldfish exposed to vinclozolin, flutamide, testosterone, and their combinations.

PubMed

Golshan, Mahdi; Habibi, Hamid R; Alavi, Sayyed Mohammad Hadi

2016-08-01

Vinclozolin (VZ) is a pesticide that acts as an anti-androgen to impair reproduction in mammals. However, VZ-induced disruption of reproduction is largely unknown in fish. In the present study, we have established a combination exposure in which adult goldfish were exposed to VZ (30 and 100 μg/L), anti-androgen flutamide (Flu, 300 μg/L), and androgen testosterone (T, 1 μg/L) to better understand effects of VZ on reproductive endocrine system. mRNA levels of kisspeptin (kiss-1 and kiss-2) and its receptor (gpr54), salmon gonadotropin-releasing hormone (gnrh3) and androgen receptor (ar) in the mid-brain, and luteinizing hormone receptor (lhr) in the testis were analyzed and compared with those of control following 10 days of exposure. kiss-1 mRNA level was increased in goldfish exposed to 100 µg/L VZ and to Flu, while kiss-2 mRNA level was increased following exposure to Flu and to combinations of 30 µg/L VZ with Flu, 100 µg/L VZ with T, and Flu with T. gpr54 mRNA level was increased in goldfish exposed to Flu and to combination of 30 µg/L VZ with Flu and 100 µg/L VZ with T. gnrh3 mRNA level was increased in goldfish exposed to 100 µg/L VZ, to Flu, and to combinations of 30 µg/L VZ with Flu, 100 µg/L VZ with T, and Flu with T. The mid-brain ar mRNA level was increased in goldfish exposed to Flu and to combinations of 30 µg/L VZ with Flu, 100 µg/L VZ with T, and Flu with T. Testicular lhr mRNA level was increased in goldfish exposed to Flu and to combination of 30 µg/L VZ with Flu. These results suggest that VZ and Flu are capable of interfering with kisspeptin and GnRH systems to alter pituitary and testicular horonal functions in adult goldfish and the brain ar mediates VZ-induced disruption of androgen production.

Smooth muscle cell-specific knockout of androgen receptor: a new model for prostatic disease.

PubMed

Welsh, Michelle; Moffat, Lindsey; McNeilly, Alan; Brownstein, David; Saunders, Philippa T K; Sharpe, Richard M; Smith, Lee B

2011-09-01

Androgen-driven stromal-epithelial interactions play a key role in normal prostate development and function as well as in the progression of common prostatic diseases such as benign prostatic hyperplasia and prostate cancer. However, exactly how, and via which cell type, androgens mediate their effects in the adult prostate remains unclear. This study investigated the role for smooth muscle (SM) androgen signaling in normal adult prostate homeostasis and function using mice in which androgen receptor was selectively ablated from prostatic SM cells. In adulthood the knockout (KO) mice displayed a 44% reduction in prostate weight and exhibited histological abnormalities such as hyperplasia, inflammation, fibrosis, and reduced expression of epithelial, SM, and stem cell identify markers (e.g. p63 reduced by 27% and Pten by 31%). These changes emerged beyond puberty and were not explained by changes in serum hormones. Furthermore, in response to exogenous estradiol, adult KO mice displayed an 8.5-fold greater increase in prostate weight than controls and developed urinary retention. KO mice also demonstrated a reduced response to castration compared with controls. Together these results demonstrate that prostate SM cells are vital in mediating androgen-driven stromal-epithelial interactions in adult mouse prostates, determining cell identity and function and limiting hormone-dependent epithelial cell proliferation. This novel mouse model provides new insight into the possible role for SM androgen action in prostate disease.

Effects of androgens on insulin action in women: is androgen excess a component of female metabolic syndrome?

PubMed

Corbould, A

2008-10-01

Hyperinsulinemia as a consequence of insulin resistance causes hyperandrogenemia in women. The objective was to review evidence for the converse situation, i.e. whether androgens adversely influence insulin action. Androgen excess could potentially contribute to the pathogenesis of insulin resistance in women with polycystic ovary syndrome (PCOS), metabolic syndrome/type 2 diabetes, and in obese peripubertal girls. An Entrez-PubMed search was conducted to identify studies addressing the relationship of androgens with metabolic syndrome/type 2 diabetes in women. Studies reporting outcomes of androgen administration, interventions to reduce androgen effects in hyperandrogenemic women, and basic studies investigating androgen effects on insulin target tissues were reviewed. Multiple studies showed associations between serum testosterone and insulin resistance or metabolic syndrome/type 2 diabetes risk in women, but their cross-sectional nature did not allow conclusions about causality. Androgen administration to healthy women was associated with development of insulin resistance. Intervention studies in women with hyperandrogenism were limited by small subject numbers and use of indirect methods for assessing insulin sensitivity. However, in three of the seven studies using euglycemic hyperinsulinemic clamps, reduction of androgen levels or blockade of androgen action improved insulin sensitivity. Testosterone administration to female rats caused skeletal muscle insulin resistance. Testosterone induced insulin resistance in adipocytes of women in vitro. In conclusion, the metabolic consequences of androgen excess in women have been under-researched. Studies of long-term interventions that lower androgen levels or block androgen effects in young women with hyperandrogenism are needed to determine whether these might protect against metabolic syndrome/type 2 diabetes in later life. Copyright (c) 2008 John Wiley & Sons, Ltd.

Expression of a hyperactive androgen receptor leads to androgen-independent growth of prostate cancer cells.

PubMed

Hsieh, Chen-Lin; Cai, Changmeng; Giwa, Ahmed; Bivins, Aaronica; Chen, Shao-Yong; Sabry, Dina; Govardhan, Kumara; Shemshedini, Lirim

2008-07-01

Cellular changes that affect the androgen receptor (AR) can cause prostate cancer to transition from androgen dependent to androgen independent, which is usually lethal. One common change in prostate tumors is overexpression of the AR, which has been shown to lead to androgen-independent growth of prostate cancer cells. This led us to hypothesize that expression of a hyperactive AR would be sufficient for androgen-independent growth of prostate cancer cells. To test this hypothesis, stable lune cancer prostate (LNCaP) cell lines were generated, which express a virion phosphoprotein (VP)16-AR hybrid protein that contains full-length AR fused to the strong viral transcriptional activation domain VP16. This fusion protein elicited as much as a 20-fold stronger transcriptional activity than the natural AR. Stable expression of VP16-AR in LNCaP cells yielded androgen-independent cell proliferation, while under the same growth conditions the parental LNCaP cells exhibited only androgen-dependent growth. These results show that expression of a hyperactive AR is sufficient for androgen-independent growth of prostate cancer cells. To study the molecular basis of this enhanced growth, we measured the expression of soluble guanylyl cyclase-alpha1 (sGCalpha1), a subunit of the sGC, an androgen-regulated gene that has been shown to be involved in prostate cancer cell growth. Interestingly, the expression of sGCalpha1 is androgen independent in VP16-AR-expressing cells, in contrast to its androgen-induced expression in control LNCaP cells. RNA(I)-dependent inhibition of sGCalpha1 expression resulted in significantly reduced proliferation of VP16-AR cells, implicating an important role for sGCalpha1 in the androgen-independent growth of these cells.

Multivalent Peptidomimetic Conjugates as Inhibitors of Androgen Receptor Function in Therapy-Resistant Prostate Cancer

DTIC Science & Technology

2017-10-01

STATEMENT: Approved for Public Release; Distribution Unlimited The views, opinions and/or findings contained in this report are those of the author(s) and...S) 12. DISTRIBUTION / AVAILABILITY STATEMENT Approved for Public Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Androgens are ...hormones that play a critical role in stimulating prostate cancer growth. Androgens activate a protein called the androgen receptor ( AR ), which

Multivalent Peptidomimetic Conjugates as Inhibitors of Androgen Receptor Function in Therapy-Resistant Prostate Cancer

DTIC Science & Technology

2016-10-01

STATEMENT: Approved for Public Release; Distribution Unlimited The views, opinions and/or findings contained in this report are those of the author(s) and...AVAILABILITY STATEMENT Approved for Public Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Androgens are hormones that play a critical...role in stimulating prostate cancer growth. Androgens activate a protein called the androgen receptor ( AR ), which regulates genes involved in cell

Androgens in health and disease: An overview

PubMed Central

Jordan, Cynthia L.; DonCarlos, Lydia

2009-01-01

This special issue of Hormones and Behavior, “Androgens in health and disease: new insights into roles and mechanisms of action,” is prompted by a number of relatively recent findings that androgens affect brain morphology and function in ways not previously or widely appreciated. Moreover, recent results also make it clear that androgens utilize a variety of signaling molecules to exert their effects on the brain, which may or may not depend on the classic nuclear androgen receptor (AR). The papers in this issue underscore these two points. This overview is not intended as a comprehensive review of androgen action on the nervous system, since the papers in this issue serve that purpose, but rather to frame the basic issues and themes that tie these papers together. The sum effect of the stories told in this issue encourages us to broaden and refocus our view of androgen action on brain and behavior—to recognize that androgens affect many aspects of brain structure and function throughout the lifespan, from shaping its sexual phenotype to influencing its propensity for disease and repair, and that at least some of these actions are exerted via non-classical modes of action that in many cases were first identified in non-neural tissue or cells. PMID:18407273

Characterization of Atrazine-Induced Gonadal Malformations in African Clawed Frogs (Xenopus laevis) and Comparisons with Effects of an Androgen Antagonist (Cyproterone Acetate) and Exogenous Estrogen (17β-Estradiol): Support for the Demasculinization/Feminization Hypothesis

PubMed Central

Hayes, Tyrone B.; Stuart, A. Ali; Mendoza, Magdalena; Collins, Atif; Noriega, Nigel; Vonk, Aaron; Johnston, Gwynne; Liu, Roger; Kpodzo, Dzifa

2006-01-01

Atrazine is a potent endocrine disruptor that both chemically castrates and feminizes male amphibians. It depletes androgens in adult frogs and reduces androgen-dependent growth of the larynx in developing male larvae. It also disrupts normal gonadal development and feminizes the gonads of developing males. Gonadal malformations induced by atrazine include hermaphrodites and males with multiple testes [single sex polygonadism (SSP)], and effects occur at concentrations as low as 0.1 ppb (μg/L). Here, we describe the frequencies at which these malformations occur and compare them with morphologies induced by the estrogen, 17β-estradiol (E2), and the antiandrogen cyproterone acetate, as a first step in testing the hypothesis that the effects of atrazine are a combination of demasculinization and feminization. The various forms of hermaphroditism did not occur in controls. Nonpigmented ovaries, which occurred at relatively high frequencies in atrazine-treated larvae, were found in four individuals out of more than 400 controls examined (1%). Further, we show that several types of gonadal malformations (SSP and three forms of hermaphroditism) are produced by E2 exposure during gonadal differentiation, whereas a final morphology (nonpigmented ovaries) appears to be the result of chemical castration (disruption of androgen synthesis and/or activity) by atrazine. These experimental findings suggest that atrazine-induced gonadal malformations result from the depletion of androgens and production of estrogens, perhaps subsequent to the induction of aromatase by atrazine, a mechanism established in fish, amphibians, reptiles, and mammals (rodents and humans). PMID:16818259

A hypothetical pathogenesis model for androgenic alopecia: clarifying the dihydrotestosterone paradox and rate-limiting recovery factors.

PubMed

English, Robert S

2018-02-01

Androgenic alopecia, also known as pattern hair loss, is a chronic progressive condition that affects 80% of men and 50% of women throughout a lifetime. But despite its prevalence and extensive study, a coherent pathology model describing androgenic alopecia's precursors, biological step-processes, and physiological responses does not yet exist. While consensus is that androgenic alopecia is genetic and androgen-mediated by dihydrotestosterone, questions remain regarding dihydrotestosterone's exact role in androgenic alopecia onset. What causes dihydrotestosterone to increase in androgenic alopecia-prone tissues? By which mechanisms does dihydrotestosterone miniaturize androgenic alopecia-prone hair follicles? Why is dihydrotestosterone also associated with hair growth in secondary body and facial hair? Why does castration (which decreases androgen production by 95%) stop pattern hair loss, but not fully reverse it? Is there a relationship between dihydrotestosterone and tissue remodeling observed alongside androgenic alopecia onset? We review evidence supporting and challenging dihydrotestosterone's causal relationship with androgenic alopecia, then propose an evidence-based pathogenesis model that attempts to answer the above questions, account for additionally-suspected androgenic alopecia mediators, identify rate-limiting recovery factors, and elucidate better treatment targets. The hypothesis argues that: (1) chronic scalp tension transmitted from the galea aponeurotica induces an inflammatory response in androgenic alopecia-prone tissues; (2) dihydrotestosterone increases in androgenic alopecia-prone tissues as part of this inflammatory response; and (3) dihydrotestosterone does not directly miniaturize hair follicles. Rather, dihydrotestosterone is a co-mediator of tissue dermal sheath thickening, perifollicular fibrosis, and calcification - three chronic, progressive conditions concomitant with androgenic alopecia progression. These conditions remodel androgenic alopecia-prone tissues - restricting follicle growth space, oxygen, and nutrient supply - leading to the slow, persistent hair follicle miniaturization characterized in androgenic alopecia. If true, this hypothetical model explains the mechanisms by which dihydrotestosterone miniaturizes androgenic alopecia-prone hair follicles, describes a rationale for androgenic alopecia progression and patterning, makes sense of dihydrotestosterone's paradoxical role in hair loss and hair growth, and identifies targets to further improve androgenic alopecia recovery rates: fibrosis, calcification, and chronic scalp tension. Copyright © 2017 The Author. Published by Elsevier Ltd.. All rights reserved.

Antiandrogenic properties of parabens and other phenolic containing small molecules in personal care products

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen Jiangang; Ahn, Ki Chang; Gee, Nancy A.

2007-06-15

To identify the androgenic potency of commonly used antimicrobials, an in vitro androgen receptor-mediated transcriptional activity assay was employed to evaluate the androgenic/antiandrogenic activity of parabens and selected other antimicrobials containing a phenolic moiety. This cell-based assay utilizes a stably transfected cell line that lacks critical steroid metabolizing enzymes and is formatted in a 96-well format. At a concentration of 10 {mu}M, methyl-, propyl- and butyl-4-hydroxybenzoate (parabens) inhibited testosterone (T)-induced transcriptional activity by 40%, 33% and 19%, respectively (P < 0.05), while 4-hydroxybenzoic acid, the major metabolite of parabens, had no effect on T-induced transcriptional activity. Triclosan inhibited transcriptional activitymore » induced by T by more than 92% at a concentration of 10 {mu}M, and 38.8% at a concentration of 1.0 {mu}M (P < 0.05). Thirty-four percent of T-induced transcriptional activity was inhibited by thymol at 10 {mu}M (P < 0.05). Cell proliferation and/or cytotoxicity were not observed in any of the treatments. None of the compounds appeared to be androgenic when tested individually without T. The data presented in this report demonstrate that some widely used antimicrobial compounds have antiandrogenic properties and warrant further investigation to fully understand their potential impact on human reproductive health.« less

Epididymal phospholipidosis is a possible mechanism for spermatotoxicity induced by the organophosphorus insecticide fenitrothion in rats.

PubMed

Miyake, Mio; Ito, Yuki; Suzuki, Himiko; Tomizawa, Motohiro; Sato, Hirotaka; Liu, Ming; Okamura, Ai; Nakajima, Tamie; Ohtani, Katsumi; Takino, Hisashi; Inagaki, Hiroshi; Kamijima, Michihiro

2018-03-15

Fenitrothion (FNT) is used worldwide in agricultural and public health settings. Spermatogenesis is a toxicological target of FNT under high-dose exposure. Although anti-androgenic action is postulated to be the mechanism associated with this toxicity, few studies have examined histopathology of androgen-dependent male accessory sex organs. The present study aimed to reveal the effects of FNT on the accessory organs of rats exhibiting spermatotoxicity in the absence of testicular histopathological changes. Furthermore, a possible novel molecular target was clarified. Male Wistar rats were orally administered 5 or 10 mg/kg FNT or its major metabolite 3-methyl-4-nitrophenol (MNP), or vehicle only, 4 days per week for 9 weeks. Then the epididymis, prostate, and seminal vesicles were collected. FNT and MNP did not show anti-androgenic effects but FNT induced cytoplasmic vacuolation in the epithelial cells of epididymal ducts and hyperplasia of mucosal folds/epithelial papillomatosis in seminal vesicles. FNT and MNP induced epididymal phospholipidosis, which was presumably caused by inhibition of epididymal secreted phospholipase A2 (sPLA2). Percentages of morphologically normal sperm and immature sperm were significantly predicted from both epididymal sPLA2 and phospholipid levels and from epididymal sPLA2, respectively. These results suggest that epididymal phospholipidosis plays an important role in FNT-induced spermatotoxicity. Anti-androgenic actions were not observed. Copyright © 2017 Elsevier B.V. All rights reserved.

Androgen Ablation Augments Prostate Cancer Vaccine Immunogenicity Only When Applied After Immunization

PubMed Central

Koh, Yi T.; Gray, Andrew; Higgins, Sean A.; Hubby, Bolyn; Kast, W. Martin

2009-01-01

Background Androgen ablation (AA) causes apoptosis of normal and neoplastic prostate cells. It is a standard treatment for advanced prostate cancer. Androgen ablation-mediated immunological effects include bone marrow hyperplasia, thymic regeneration, T and B cell lymphopoeisis and restoration of age-related peripheral T cell dysfunction. Androgens also regulate the transcription of several cytokines. Dendritic cells (DC) are the most potent antigen presenting cells that can activate antigen-specific naïve T cells. Despite myriad clinical trials involving DC-based prostate cancer immunotherapies, the effects of AA on DC function remain largely uncharacterized. Therefore, we investigated the effects of AA on DC and whether it could improve the efficacy of prostate cancer immunotherapy. Methods Cytokine expression changes due to AA were quantified by multiplex ELISA. Flow cytometry was used to assess AA-mediated effects on DC maturation and expression of costimulatory markers. Mixed leukocyte reactions and cell-mediated lysis assays elucidated the role of androgens in DC function. The effect of AA on the efficacy of vaccination against a prostate tumor-associated antigen was tested using Elispot assays. Results Androgen ablation increased dendritic cell maturation and costimulatory marker expression, but had no effect on DC costimulatory function. However, DC isolated from castrated mice increased the expression of key cytokines by antigen-experienced T cells while decreasing their expression in naïve cells. Finally, androgen ablation improved immune responses to vaccination only when applied after immunization. Conclusion Androgen ablation causes differential effects of DC on primary and secondary T cell responses, thus augmenting vaccine immunogenicity only when applied after immunization. PMID:19143030

Ontogeny and reversal of brain circuit abnormalities in a preclinical model of PCOS.

PubMed

Silva, Mauro Sb; Prescott, Melanie; Campbell, Rebecca E

2018-04-05

Androgen excess is a hallmark of polycystic ovary syndrome (PCOS), a prevalent yet poorly understood endocrine disorder. Evidence from women and preclinical animal models suggests that elevated perinatal androgens can elicit PCOS onset in adulthood, implying androgen actions in both PCOS ontogeny and adult pathophysiology. Prenatally androgenized (PNA) mice exhibit a robust increase of progesterone-sensitive GABAergic inputs to gonadotropin-releasing hormone (GnRH) neurons implicated in the pathogenesis of PCOS. It is unclear when altered GABAergic wiring develops in the brain, and whether these central abnormalities are dependent upon adult androgen excess. Using GnRH-GFP-transgenic mice, we determined that increased GABA input to GnRH neurons occurs prior to androgen excess and the manifestation of reproductive impairments in PNA mice. These data suggest that brain circuit abnormalities precede the postpubertal development of PCOS traits. Despite the apparent developmental programming of circuit abnormalities, long-term blockade of androgen receptor signaling from early adulthood rescued normal GABAergic wiring onto GnRH neurons, improved ovarian morphology, and restored reproductive cycles in PNA mice. Therefore, androgen excess maintains changes in female brain wiring linked to PCOS features and the blockade of androgen receptor signaling reverses both the central and peripheral PNA-induced PCOS phenotype.

Ontogeny and reversal of brain circuit abnormalities in a preclinical model of PCOS

PubMed Central

Silva, Mauro S.B.; Prescott, Melanie; Campbell, Rebecca E.

2018-01-01

Androgen excess is a hallmark of polycystic ovary syndrome (PCOS), a prevalent yet poorly understood endocrine disorder. Evidence from women and preclinical animal models suggests that elevated perinatal androgens can elicit PCOS onset in adulthood, implying androgen actions in both PCOS ontogeny and adult pathophysiology. Prenatally androgenized (PNA) mice exhibit a robust increase of progesterone-sensitive GABAergic inputs to gonadotropin-releasing hormone (GnRH) neurons implicated in the pathogenesis of PCOS. It is unclear when altered GABAergic wiring develops in the brain, and whether these central abnormalities are dependent upon adult androgen excess. Using GnRH-GFP–transgenic mice, we determined that increased GABA input to GnRH neurons occurs prior to androgen excess and the manifestation of reproductive impairments in PNA mice. These data suggest that brain circuit abnormalities precede the postpubertal development of PCOS traits. Despite the apparent developmental programming of circuit abnormalities, long-term blockade of androgen receptor signaling from early adulthood rescued normal GABAergic wiring onto GnRH neurons, improved ovarian morphology, and restored reproductive cycles in PNA mice. Therefore, androgen excess maintains changes in female brain wiring linked to PCOS features and the blockade of androgen receptor signaling reverses both the central and peripheral PNA-induced PCOS phenotype. PMID:29618656

Androgens affect muscle, motor neuron, and survival in a mouse model of SOD1-related amyotrophic lateral sclerosis.

PubMed

Aggarwal, Tanya; Polanco, Maria J; Scaramuzzino, Chiara; Rocchi, Anna; Milioto, Carmelo; Emionite, Laura; Ognio, Emanuela; Sambataro, Fabio; Galbiati, Mariarita; Poletti, Angelo; Pennuto, Maria

2014-08-01

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by selective loss of upper and lower motor neurons and skeletal muscle atrophy. Epidemiologic and experimental evidence suggest the involvement of androgens in ALS pathogenesis, but the mechanism through which androgens modify the ALS phenotype is unknown. Here, we show that androgen ablation by surgical castration extends survival and disease duration of a transgenic mouse model of ALS expressing mutant human SOD1 (hSOD1-G93A). Furthermore, long-term treatment of orchiectomized hSOD1-G93A mice with nandrolone decanoate (ND), an anabolic androgenic steroid, worsened disease manifestations. ND treatment induced muscle fiber hypertrophy but caused motor neuron death. ND negatively affected survival, thereby dissociating skeletal muscle pathology from life span in this ALS mouse model. Interestingly, orchiectomy decreased androgen receptor levels in the spinal cord and muscle, whereas ND treatment had the opposite effect. Notably, stimulation with ND promoted the recruitment of endogenous androgen receptor into biochemical complexes that were insoluble in sodium dodecyl sulfate, a finding consistent with protein aggregation. Overall, our results shed light on the role of androgens as modifiers of ALS pathogenesis via dysregulation of androgen receptor homeostasis. Copyright © 2014 Elsevier Inc. All rights reserved.

[Elucidating the molecular mechanism of prostate cancer progression under chronic hypoxia and development of the novel therapeutic approach].

PubMed

Nomura, Takeo; Yamasaki, Mutsushi; Mimata, Hiromitsu

2014-12-01

Cancer cells encounter a hypoxic microenvironment during tumor growth and progression. In addition, androgen-deprivation therapy against prostate cancer can develop secondary to a hypoxic condition caused by drastic blood supply reduction because androgen drives angiogenic inducers including vascular endothelial growth factor (VEGF) and inhibits angiogenesis inhibitor prostatic pigment epithelium-derived factor (PEDF). Extreme hypoxic conditions are not suitable for cancer survival, however, cancer cells soon adapt to a hypoxic environment and survive. We established a prostate cancer cell line cultured under chronic hypoxia and analyzed a castration-resistant phenotype. Here, the Vav3 was identified as a key oncogenic molecule associated with castration-resistance under chronic hypoxia. We analyzed the functions of Vav3 and Vav3-mediated signaling to establish a novel therapeutic target for castration-resistant prostate cancer.

PROSTATE REGULATION: MODELING ENDOGENOUS ...

EPA Pesticide Factsheets

Prostate function is an important indicator of androgen status in toxicological studies making predictive modeling of the relevant pharmacokinetics and pharmacodynamics desirable. Prostate function is an important indicator of androgen status in toxicological studies making predictive modeling of the relevant pharmacokinetics and pharmacodynamics desirable.

ELEVATION OF C-FLIP IN CASTRATE-RESISTANT PROSTATE CANCER ANTAGONIZES THERAPEUTIC RESPONSE TO ANDROGEN-RECEPTOR TARGETED THERAPY

PubMed Central

McCourt, Clare; Maxwell, Pamela; Mazzucchelli, Roberta; Montironi, Rodolfo; Scarpelli, Marina; Salto-Tellez, Manuel; O’Sullivan, Joe M.; Longley, Daniel B.; Waugh, David J.J.

2012-01-01

Purpose To characterize the importance of cellular Fas-associated death domain (FADD)-like interleukin 1β-converting enzyme (FLICE) inhibitory protein (c-FLIP), a key regulator of caspase 8 (FLICE)-promoted apoptosis, in modulating the response of prostate cancer (CaP) cells to androgen receptor (AR)-targeted therapy. Experimental Design c-FLIP expression was characterized by immunohistochemical analysis of prostatectomy tissue. The functional importance of c-FLIP to survival and modulating response to bicalutamide was studied by molecular and pharmacological interventions. Results c-FLIP expression was increased in high-grade prostatic intra-epithelial neoplasia (HGPIN) and CaP tissue relative to normal prostate epithelium (P<0.001). Maximal c-FLIP expression was detected in castrate-resistant CaP (CRPC) (P<0.001). In vitro, silencing of c-FLIP induced spontaneous apoptosis and increased 22Rv1 and LNCaP cell sensitivity to bicalutamide, determined by flow cytometry, PARP cleavage and caspase activity assays. The histone deacetylase inhibitors (HDACi), droxinostat and SAHA, also down-regulated c-FLIP expression, induced caspase-8 and caspase-3/7 mediated apoptosis and increased apoptosis in bicalutamide-treated cells. Conversely, the elevated expression of c-FLIP detected in the CRPC cell line VCaP underpinned their insensitivity to bicalutamide and SAHA in vitro. However, knockdown of c-FLIP induced spontaneous apoptosis in VCaP cells, indicating its relevance to cell survival and therapeutic resistance. Conclusion c-FLIP reduces the efficacy of AR-targeted therapy and maintains the viability of CaP cells. A combination of HDACi with androgen-deprivation therapy (ADT) may be effective in early-stage disease, using c-FLIP expression as a predictive biomarker of sensitivity. Direct targeting of c-FLIP however may be relevant to enhance the response of existing and novel therapeutics in CRPC. PMID:22623731

DIFFERENTIAL DISPLAY OF TRENBOLONE AND DEHP INDUCED GENE TRANSCRIPT PATTERNS IN FATHEAD MINNOW LIVER

EPA Science Inventory

The endocrine disruptor risk assessment process is being delayed without more robust data on the estrogenic and androgenic activity of chemicals found in the environment such as trenbolone and di(2-ethylhexyl) phthalate (DEHP). Trenbolone is an androgenic compound known to reduc...

Bidirectional sex change induced by sex steroid implantation in the hermaphrodite fish, Pseudolabrus sieboldi.

PubMed

Ohta, Kohei; Sakai, Mami; Sundaray, Jittendra Kumar; Kitano, Takeshi; Takeda, Tatsusuke; Yamaguchi, Akihiko; Matsuyama, Michiya

2012-11-01

Sex steroids have been suggested to be involved in gonadal sex change in hermaphrodite fish. Aromatase, the enzyme that catalyzes the conversion of androgens into estrogens, is a principal enzyme regulating gonadal sex. However, the detailed functions of each steroid hormone remain to be evaluated. Recent studies have demonstrated that estradiol-17β (E2) is synthesized via estrone (E1) in some hermaphrodite species. On the other hand, 11-ketotestosterone (11KT) is produced in the testis via testosterone (T). In this study, we hypothesized that E1 and T are also involved in the sex change as precursors for E2 and 11KT, respectively. We implanted females of the wrasse, Pseudolabrus sieboldi, with T and 11KT, and males with E1 and E2, by use of sustained-release capsules. In females, testicular tissues and body color change were observed after androgen administration, in which 11KT was more effective than T. In contrast, after estrogen administration, the gonads of males contained oocytes. In females, the administration of T and 11KT resulted in reduced serum E2 levels. Conversely, serum 11KT levels decreased in the E1- and E2-treated males. Thus, we successfully induced bidirectional sex change in the gonad by estrogen and androgen administration in vivo. Moreover, this study raises the possibility that E1 and T are involved in the sex change as precursors for E2 and 11KT, respectively. Copyright © 2012 Wiley Periodicals, Inc.

Androgen dependent mechanisms of pro-angiogenic networks in placental and tumor development.

PubMed

Metzler, Veronika M; de Brot, Simone; Robinson, Robert S; Jeyapalan, Jennie N; Rakha, Emad; Walton, Thomas; Gardner, David S; Lund, Emma F; Whitchurch, Jonathan; Haigh, Daisy; Lochray, Jack M; Robinson, Brian D; Allegrucci, Cinzia; Fray, Rupert G; Persson, Jenny L; Ødum, Niels; Miftakhova, Regina R; Rizvanov, Albert A; Hughes, Ieuan A; Tadokoro-Cuccaro, Rieko; Heery, David M; Rutland, Catrin S; Mongan, Nigel P

2017-08-01

The placenta and tumors share important characteristics, including a requirement to establish effective angiogenesis. In the case of the placenta, optimal angiogenesis is required to sustain the blood flow required to maintain a successful pregnancy, whereas in tumors establishing new blood supplies is considered a key step in supporting metastases. Therefore the development of novel angiogenesis inhibitors has been an area of active research in oncology. A subset of the molecular processes regulating angiogenesis are well understood in the context of both early placentation and tumorigenesis. In this review we focus on the well-established role of androgen regulation of angiogenesis in cancer and relate these mechanisms to placental angiogenesis. The physiological actions of androgens are mediated by the androgen receptor (AR), a ligand dependent transcription factor. Androgens and the AR are essential for normal male embryonic development, puberty and lifelong health. Defects in androgen signalling are associated with a diverse range of clinical disorders in men and women including disorders of sex development (DSD), polycystic ovary syndrome in women and many cancers. We summarize the diverse molecular mechanisms of androgen regulation of angiogenesis and infer the potential significance of these pathways to normal and pathogenic placental function. Finally, we offer potential research applications of androgen-targeting molecules developed to treat cancer as investigative tools to help further delineate the role of androgen signalling in placental function and maternal and offspring health in animal models. Copyright © 2017 Elsevier Ltd. All rights reserved.

Neuroendocrine androgen action is a key extraovarian mediator in the development of polycystic ovary syndrome

PubMed Central

Caldwell, Aimee S. L.; Edwards, Melissa C.; Desai, Reena; Jimenez, Mark; Gilchrist, Robert B.; Walters, Kirsty A.

2017-01-01

Polycystic ovary syndrome (PCOS) is a complex hormonal disorder characterized by reproductive, endocrine, and metabolic abnormalities. As the origins of PCOS remain unknown, mechanism-based treatments are not feasible and current management relies on treatment of symptoms. Hyperandrogenism is the most consistent PCOS characteristic; however, it is unclear whether androgen excess, which is treatable, is a cause or a consequence of PCOS. As androgens mediate their actions via the androgen receptor (AR), we combined a mouse model of dihydrotestosterone (DHT)-induced PCOS with global and cell-specific AR-resistant (ARKO) mice to investigate the locus of androgen actions that mediate the development of the PCOS phenotype. Global loss of the AR reveals that AR signaling is required for all DHT-induced features of PCOS. Neuron-specific AR signaling was required for the development of dysfunctional ovulation, classic polycystic ovaries, reduced large antral follicle health, and several metabolic traits including obesity and dyslipidemia. In addition, ovariectomized ARKO hosts with wild-type ovary transplants displayed normal estrous cycles and corpora lutea, despite DHT treatment, implying extraovarian and not intraovarian AR actions are key loci of androgen action in generating the PCOS phenotype. These findings provide strong evidence that neuroendocrine genomic AR signaling is an important extraovarian mediator in the development of PCOS traits. Thus, targeting AR-driven mechanisms that initiate PCOS is a promising strategy for the development of novel treatments for PCOS. PMID:28320971

Androgen receptor agonists increase lean mass, improve cardiopulmonary functions and extend survival in preclinical models of Duchenne muscular dystrophy.

PubMed

Ponnusamy, Suriyan; Sullivan, Ryan D; You, Dahui; Zafar, Nadeem; He Yang, Chuan; Thiyagarajan, Thirumagal; Johnson, Daniel L; Barrett, Maron L; Koehler, Nikki J; Star, Mayra; Stephenson, Erin J; Bridges, Dave; Cormier, Stephania A; Pfeffer, Lawrence M; Narayanan, Ramesh

2017-07-01

Duchenne muscular dystrophy (DMD) is a neuromuscular disease that predominantly affects boys as a result of mutation(s) in the dystrophin gene. DMD is characterized by musculoskeletal and cardiopulmonary complications, resulting in shorter life-span. Boys afflicted by DMD typically exhibit symptoms within 3-5 years of age and declining physical functions before attaining puberty. We hypothesized that rapidly deteriorating health of pre-pubertal boys with DMD could be due to diminished anabolic actions of androgens in muscle, and that intervention with an androgen receptor (AR) agonist will reverse musculoskeletal complications and extend survival. While castration of dystrophin and utrophin double mutant (mdx-dm) mice to mimic pre-pubertal nadir androgen condition resulted in premature death, maintenance of androgen levels extended the survival. Non-steroidal selective-AR modulator, GTx-026, which selectively builds muscle and bone was tested in X-linked muscular dystrophy mice (mdx). GTx-026 significantly increased body weight, lean mass and grip strength by 60-80% over vehicle-treated mdx mice. While vehicle-treated castrated mdx mice exhibited cardiopulmonary impairment and fibrosis of heart and lungs, GTx-026 returned cardiopulmonary function and intensity of fibrosis to healthy control levels. GTx-026 elicits its musculoskeletal effects through pathways that are distinct from dystrophin-regulated pathways, making AR agonists ideal candidates for combination approaches. While castration of mdx-dm mice resulted in weaker muscle and shorter survival, GTx-026 treatment increased the muscle mass, function and survival, indicating that androgens are important for extended survival. These preclinical results support the importance of androgens and the need for intervention with AR agonists to treat DMD-affected boys. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Annatto Tocotrienol Induces a Cytotoxic Effect on Human Prostate Cancer PC3 Cells via the Simultaneous Inhibition of Src and Stat3.

PubMed

Sugahara, Ryosuke; Sato, Ayami; Uchida, Asuka; Shiozawa, Shinya; Sato, Chiaki; Virgona, Nantiga; Yano, Tomohiro

2015-01-01

Prostate cancer is one of the most frequently occurring cancers and often acquires the potential of androgen-independent growth as a malignant phenotype. Androgen-independent prostate cancer has severe chemoresistance towards conventional chemotherapeutic agents, so a new treatment approach is required for curing such prostate cancer. In this context, the present study was undertaken to check if annatto tocotrienol (main component δ-tocotrienol) could suppress cell growth in human prostate cancer (PC3, androgen-independent type) cells via the inhibition of Src and Stat3. The tocotrienol showed cytotoxic effects on PC3 cells in a dose-dependent manner, and the effect depended on G1 arrest in the cell cycle and subsequent induction of apoptosis. In a cytotoxic dose, the tocotrienol suppressed cellular growth via the simultaneous inhibition of Src and Stat3. Similarly, the treatment combination of both Src and Stat3 inhibitors induced cytotoxic effects in PC3 cells in an additive manner compared to each by itself. With respect to cell cycle regulation and the induction of apoptosis, the combination treatment showed a similar effect to that of the tocotrienol treatment. These results suggest that annatto tocotrienol effectively induces cytotoxicity in androgen-independent prostate cancer cells via the suppression of Src and Stat3.

Inappropriate activation of the androgen receptor by nonsteroids: involvement of the Src kinase pathway and its therapeutic implications.

PubMed

Desai, Sonal J; Ma, Ai-Hong; Tepper, Clifford G; Chen, Hong-Wu; Kung, Hsing-Jien

2006-11-01

The inappropriate activation of androgen receptor (AR) by nonsteroids is considered a potential mechanism in the emergence of hormone-refractory prostate tumors, but little is known about the properties of these "pseudoactivated" AR. Here, we present the first comprehensive analysis closely examining the properties of AR activated by the neuropeptide bombesin that distinguish it from androgen-activated AR. We show that bombesin-activated AR (a) is required for bombesin-induced growth of LNCaP cells, (b) has a transcriptional profile overlapping with, but not identical to, androgen-activated AR, (c) activates prostate-specific antigen by preferentially binding to its proximal promoter, and (d) assembles a distinct coactivator complex. Significantly, we found that Src kinase is critical for bombesin-induced AR-mediated activity and is required for translocation and transactivation of AR. Additionally, we identify c-Myc, a Src target gene, to be activated by bombesin and a potential coactivator of AR-mediated activity specific to bombesin-induced signaling. Because Src kinase is often activated by other nonsteroids, such as other neuropeptides, growth factors, chemokines, and cytokines, our findings have general applicability and provide rationale for investigating the efficacy of the Src kinase pathway as a target for the prevention of relapsed prostate cancers.

Synthesis of magnetic molecularly imprinted polymers with excellent biocompatibility for the selective separation and inhibition of testosterone in prostate cancer cells.

PubMed

Tang, Xiaoshuang; Li, Feng; Jia, Jing; Yang, Chao; Liu, Wei; Jin, Ben; Wang, Xinyang; Gao, Ruixia; He, Dalin; Guo, Peng

2017-01-01

Androgen plays an important role in the progression of prostate cancer. In the present study, novel magnetic molecularly imprinted polymers (MMIPs) with good biocompatibility were produced for the selective separation and inhibition of testosterone in prostate cancer cells. MMIPs were prepared by using magnetic nanospheres, gelatin, and testosterone as the supporting materials, functional monomer, and the template molecule, respectively. The characterization of the resultant products was investigated by transmission electron microscopy, X-ray diffraction, and vibrating sample magnetometry. To test whether MMIPs can remove testosterone in biologic samples, human LNCaP (androgen-dependent) and C4-2 (androgen-independent) prostate cancer cells were selected as cell models. The translocation of androgen receptor (AR) was detected by immunofluorescence assay, and the expression of PSA mRNA was detected by real-time quantitative polymerase chain reaction analysis. Cell flow cytometry analysis was performed to detect cell cycle arrest. The synthesized nanomaterials (MMIPs) possessed high crystallinity, satisfactory superparamagnetic properties, and uniform imprinted shell, and exhibited high adsorption capacity, fast kinetics, and high selectivity for testosterone. Moreover, the obtained imprinted nanomaterials could selectively enrich and detect testosterone in the LNCaP cell samples as a solid-phase extractant coupled with high-performance liquid chromatography. In addition, the MMIPs could freely enter prostate cancer cells and suppress the translocation of AR into the cell nucleus. We further found that MMIPs inhibited upregulation of AR downstream target genes in LNCaP and C4-2 cells; also, MMIPs inhibited cell growth and induced obvious cell cycle arrest in androgen-dependent LNCaP cells, but had no obvious effect on androgen-independent C4-2 cells. Our results indicate that the obtained imprinted nanomaterials can specifically and effectively bind testosterone and recover it from prostate cancer cells. Moreover, the MMIPs can freely enter prostate cancer cells and block the activation of testosterone-AR pathway. Thus, the MMIPs may be a new option for antiandrogen therapy in prostate cancer.

Combined Exposure to Anti-Androgens Exacerbates Disruption of Sexual Differentiation in the Rat

PubMed Central

Hass, Ulla; Scholze, Martin; Christiansen, Sofie; Dalgaard, Majken; Vinggaard, Anne Marie; Axelstad, Marta; Metzdorff, Stine Broeng; Kortenkamp, Andreas

2007-01-01

Objective The aim of this study was to assess whether the joint effects of three androgen receptor antagonists (vinclozolin, flutamide, procymidone) on male sexual differentiation after in utero and postnatal exposures can be predicted based on dose–response data of the individual chemicals. Methods Test chemicals and mixtures were administered by gavage to time-mated nulliparous, young adult Wistar rats from gestational day 7 to the day before expected birth, and from postnatal days 1–16. Changes in anogenital distance (AGD) and nipple retention (NR) in male offspring rats were chosen as end points for extensive dose–response studies. Vinclozolin, flutamide, and procymidone were combined at a mixture ratio proportional to their individual potencies for causing retention of six nipples in male offspring. Results With AGD as the end point, the joint effects of the three anti-androgens were essentially dose additive. The observed responses for NR were slightly higher than those expected on the basis of dose addition. A combination of doses of each chemical, which on its own did not produce statistically significant AGD alterations, induced half-maximal mixture effects. At individual doses associated with only modest effects on NR, the mixture induced NR approaching female values in the males. Conclusions Effects of a mixture of similarly acting anti-androgens can be predicted fairly accurately on the basis of the potency of the individual mixture components by using the dose addition concept. Exposure to anti-androgens, which individually appears to exert only small effects, may induce marked responses in concert with, possibly unrecognized, similarly acting chemicals. PMID:18174960

Maternal androgen excess and obesity induce sexually dimorphic anxiety-like behavior in the offspring.

PubMed

Manti, Maria; Fornes, Romina; Qi, Xiaojuan; Folmerz, Elin; Lindén Hirschberg, Angelica; de Castro Barbosa, Thais; Maliqueo, Manuel; Benrick, Anna; Stener-Victorin, Elisabet

2018-03-22

Maternal polycystic ovary syndrome (PCOS), a condition associated with hyperandrogenism, is suggested to increase anxiety-like behavior in the offspring. Because PCOS is closely linked to obesity, we investigated the impact of an adverse hormonal or metabolic maternal environment and offspring obesity on anxiety in the offspring. The obese PCOS phenotype was induced by chronic high-fat-high-sucrose (HFHS) consumption together with prenatal dihydrotestosterone exposure in mouse dams. Anxiety-like behavior was assessed in adult offspring with the elevated-plus maze and open-field tests. The influence of maternal androgens and maternal and offspring diet on genes implicated in anxiety were analyzed in the amygdala and hypothalamus with real-time PCR ( n = 47). Independent of diet, female offspring exposed to maternal androgens were more anxious and displayed up-regulation of adrenoceptor α 1B in the amygdala and up-regulation of hypothalamic corticotropin-releasing hormone ( Crh). By contrast, male offspring exposed to a HFHS maternal diet had increased anxiety-like behavior and showed up-regulation of epigenetic markers in the amygdala and up-regulation of hypothalamic Crh. Overall, there were substantial sex differences in gene expression in the brain. These findings provide novel insight into how maternal androgens and obesity exert sex-specific effects on behavior and gene expression in the offspring of a PCOS mouse model.-Manti, M., Fornes, R., Qi, X., Folmerz, E., Lindén Hirschberg, A., de Castro Barbosa, T., Maliqueo, M., Benrick, A., Stener-Victorin, E. Maternal androgen excess and obesity induce sexually dimorphic anxiety-like behavior in the offspring.

Human Prostatic Acid Phosphatase: Structure, Function and Regulation

PubMed Central

Muniyan, Sakthivel; Chaturvedi, Nagendra K.; Dwyer, Jennifer G.; LaGrange, Chad A.; Chaney, William G.; Lin, Ming-Fong

2013-01-01

Human prostatic acid phosphatase (PAcP) is a 100 kDa glycoprotein composed of two subunits. Recent advances demonstrate that cellular PAcP (cPAcP) functions as a protein tyrosine phosphatase by dephosphorylating ErbB-2/Neu/HER-2 at the phosphotyrosine residues in prostate cancer (PCa) cells, which results in reduced tumorigenicity. Further, the interaction of cPAcP and ErbB-2 regulates androgen sensitivity of PCa cells. Knockdown of cPAcP expression allows androgen-sensitive PCa cells to develop the castration-resistant phenotype, where cells proliferate under an androgen-reduced condition. Thus, cPAcP has a significant influence on PCa cell growth. Interestingly, promoter analysis suggests that PAcP expression can be regulated by NF-κB, via a novel binding sequence in an androgen-independent manner. Further understanding of PAcP function and regulation of expression will have a significant impact on understanding PCa progression and therapy. PMID:23698773

Identification and Characterization of ART-27, a Novel Coactivator for the Androgen Receptor N Terminus

PubMed Central

Markus, Steven M.; Taneja, Samir S.; Logan, Susan K.; Li, Wenhui; Ha, Susan; Hittelman, Adam B.; Rogatsky, Inez; Garabedian, Michael J.

2002-01-01

The androgen receptor (AR) is a ligand-regulated transcription factor that stimulates cell growth and differentiation in androgen-responsive tissues. The AR N terminus contains two activation functions (AF-1a and AF-1b) that are necessary for maximal transcriptional enhancement by the receptor; however, the mechanisms and components regulating AR transcriptional activation are not fully understood. We sought to identify novel factors that interact with the AR N terminus from an androgen-stimulated human prostate cancer cell library using a yeast two-hybrid approach designed to identify proteins that interact with transcriptional activation domains. A 157-amino acid protein termed ART-27 was cloned and shown to interact predominantly with the AR153–336, containing AF-1a and a part of AF-1b, localize to the nucleus and increase the transcriptional activity of AR when overexpressed in cultured mammalian cells. ART-27 also enhanced the transcriptional activation by AR153–336 fused to the LexA DNA-binding domain but not other AR N-terminal subdomains, suggesting that ART-27 exerts its effect via an interaction with a defined region of the AR N terminus. ART-27 interacts with AR in nuclear extracts from LNCaP cells in a ligand-independent manner. Interestingly, velocity gradient sedimentation of HeLa nuclear extracts suggests that native ART-27 is part of a multiprotein complex. ART-27 is expressed in a variety of human tissues, including sites of androgen action such as prostate and skeletal muscle, and is conserved throughout evolution. Thus, ART-27 is a novel cofactor that interacts with the AR N terminus and plays a role in facilitating receptor-induced transcriptional activation. PMID:11854421

SREBF1 Activity is Regulated by an AR/mTOR Nuclear Axis in Prostate Cancer.

PubMed

Audet-Walsh, Etienne; Vernier, Mathieu; Yee, Tracey; Laflamme, Chloe E; Li, Susan; Chen, Yonghong; Giguere, Vincent

2018-05-21

Reprogramming of cellular metabolism is an important feature of prostate cancer (PCa), including altered lipid metabolism. Recently, it was observed that the nuclear fraction of mTOR is essential for the androgen-mediated metabolic reprogramming of PCa cells. Herein, it is demonstrated that the androgen receptor (AR) and mTOR bind to regulatory regions of sterol regulatory element binding transcription factor 1 (SREBF1) to control its expression, while dual activation of these signaling pathways also promotes SREBF1 cleavage and its translocation to the nucleus. Consequently, SREBF1 recruitment to regulatory regions of its target genes is induced upon treatment with the synthetic androgen R1881, an effect abrogated upon inhibition of the mTOR signaling pathway. In turn, pharmacological and genetic inhibition of SREBF1 activity impairs the androgen-mediated induction of the key lipogenic genes fatty acid synthase (FASN) and stearoyl-CoA desaturase (SCD1). Consistent with these observations, the expression of SREBF1, FASN and SCD1 is significantly correlated in human PCa tumor clinical specimens. Functionally, blockade of SREBF1 activity reduces the androgen-driven lipid accumulation. Interestingly, decreased triglyceride accumulation observed upon SREBF1 inhibition is paralleled by an increase in mitochondrial respiration, indicating a potential rewiring of citrate metabolism in PCa cells. Altogether, these data define an AR/mTOR nuclear axis, in the context of PCa, as a novel pathway regulating SREBF1 activity and citrate metabolism. The finding that an AR/mTOR complex promotes SREBP expression and activity enhances our understanding of the metabolic adaptation necessary for prostate cancer cell growth and suggests novel therapeutic approaches to target metabolic vulnerabilities in tumors. Copyright ©2018, American Association for Cancer Research.

Identification and characterization of ART-27, a novel coactivator for the androgen receptor N terminus.

PubMed

Markus, Steven M; Taneja, Samir S; Logan, Susan K; Li, Wenhui; Ha, Susan; Hittelman, Adam B; Rogatsky, Inez; Garabedian, Michael J

2002-02-01

The androgen receptor (AR) is a ligand-regulated transcription factor that stimulates cell growth and differentiation in androgen-responsive tissues. The AR N terminus contains two activation functions (AF-1a and AF-1b) that are necessary for maximal transcriptional enhancement by the receptor; however, the mechanisms and components regulating AR transcriptional activation are not fully understood. We sought to identify novel factors that interact with the AR N terminus from an androgen-stimulated human prostate cancer cell library using a yeast two-hybrid approach designed to identify proteins that interact with transcriptional activation domains. A 157-amino acid protein termed ART-27 was cloned and shown to interact predominantly with the AR(153-336), containing AF-1a and a part of AF-1b, localize to the nucleus and increase the transcriptional activity of AR when overexpressed in cultured mammalian cells. ART-27 also enhanced the transcriptional activation by AR(153-336) fused to the LexA DNA-binding domain but not other AR N-terminal subdomains, suggesting that ART-27 exerts its effect via an interaction with a defined region of the AR N terminus. ART-27 interacts with AR in nuclear extracts from LNCaP cells in a ligand-independent manner. Interestingly, velocity gradient sedimentation of HeLa nuclear extracts suggests that native ART-27 is part of a multiprotein complex. ART-27 is expressed in a variety of human tissues, including sites of androgen action such as prostate and skeletal muscle, and is conserved throughout evolution. Thus, ART-27 is a novel cofactor that interacts with the AR N terminus and plays a role in facilitating receptor-induced transcriptional activation.

Activation of AMP-Activated Protein Kinase by 3,3′-Diindolylmethane (DIM) Is Associated with Human Prostate Cancer Cell Death In Vitro and In Vivo

PubMed Central

Chen, Di; Banerjee, Sanjeev; Cui, Qiuzhi C.; Kong, Dejuan; Sarkar, Fazlul H.; Dou, Q. Ping

2012-01-01

There is a large body of scientific evidence suggesting that 3,3′-Diindolylmethane (DIM), a compound derived from the digestion of indole-3-carbinol, which is abundant in cruciferous vegetables, harbors anti-tumor activity in vitro and in vivo. Accumulating evidence suggests that AMP-activated protein kinase (AMPK) plays an essential role in cellular energy homeostasis and tumor development and that targeting AMPK may be a promising therapeutic option for cancer treatment in the clinic. We previously reported that a formulated DIM (BR-DIM; hereafter referred as B-DIM) with higher bioavailability was able to induce apoptosis and inhibit cell growth, angiogenesis, and invasion of prostate cancer cells. However, the precise molecular mechanism(s) for the anti-cancer effects of B-DIM have not been fully elucidated. In the present study, we investigated whether AMP-activated protein kinase (AMPK) is a molecular target of B-DIM in human prostate cancer cells. Our results showed, for the first time, that B-DIM could activate the AMPK signaling pathway, associated with suppression of the mammalian target of rapamycin (mTOR), down-regulation of androgen receptor (AR) expression, and induction of apoptosis in both androgen-sensitive LNCaP and androgen-insensitive C4-2B prostate cancer cells. B-DIM also activates AMPK and down-regulates AR in androgen-independent C4-2B prostate tumor xenografts in SCID mice. These results suggest that B-DIM could be used as a potential anti-cancer agent in the clinic for prevention and/or treatment of prostate cancer regardless of androgen responsiveness, although functional AR may be required. PMID:23056607

Dopamine D2 Receptors Act Upstream of AVP in the Latero-Anterior Hypothalamus to Modulate Adolescent Anabolic/Androgenic Steroid-Induced Aggression in Syrian Hamsters

PubMed Central

Morrison, Thomas R.; Ricci, Lesley A.; Melloni, Richard H.

2015-01-01

In pubertal male Syrian hamsters, exposure to anabolic/androgenic steroids (AAS) during adolescence facilitates a high level of offensive aggression modulated by the enhanced development and activity of the vasopressin (AVP) and dopamine (DA) neural systems within the latero-anterior hypothalamus (LAH), i.e., a brain region implicated in the control of aggression. The present studies provide a detailed report of the pharmacologic interactions between AVP and DA D2 receptor signaling within the LAH in the control of adolescent AAS-induced offensive aggression. Male Syrian hamsters were treated with AAS throughout adolescence and tested for aggression after local infusion of the DA D2 receptor antagonist eticlopride (ETIC) alone, or in combination with AVP in the LAH in an effort to determine the influence of DA D2 receptors relative to AVP-receptor mediated aggression mechanisms. As previously shown, ETIC infusion into the LAH suppressed adolescent AAS-induced aggressive responding; however, the AAS-induced aggressive phenotype was rescued by the co-infusion of AVP into the LAH. These behavioral data indicate that interactions between AVP and DA neural systems within the LAH modulate the control of aggression following adolescent exposure to AAS and that DA D2 receptor signaling functions upstream of AVP in the LAH to control this behavioral response. PMID:25798632

The Role of Stromally Produced Cathepsin D in Promoting Prostate Tumorigenesis

DTIC Science & Technology

2012-09-01

combination with androgen in the NBL rat model produced a 100% incidence of PCa. Treatment with androgen alone induced PCa with a 40% incidence (30...prostate, Eur. Urol. 30, 243–248 (1996). 30. M. C. Bosland, H. Ford, L. Horton, Induction at high incidence of ductal prostate adenocarcinomas in NBL / Cr

The Role of Stromally Produced Cathepsin D in Promoting Prostate Tumorigenesis

DTIC Science & Technology

2013-09-01

estrogens in combination with androgen in the NBL rat model produced a 100% incidence of PCa. Treatment with androgen alone induced PCa with a 40% incidence...1996). 30. Bosland, M. C., Ford, H. & Horton, L. Induction at high incidence of ductal prostate adenocarcinomas in NBL /Cr and Sprague-Dawley Hsd:SD

Characteristics of Men Who Report Persistent Sexual Symptoms After Finasteride Use for Hair Loss.

PubMed

Basaria, Shehzad; Jasuja, Ravi; Huang, Grace; Wharton, Whitney; Pan, Hong; Pencina, Karol; Li, Zhuoying; Travison, Thomas G; Bhawan, Jag; Gonthier, Renaud; Labrie, Fernand; Dury, Alain Y; Serra, Carlo; Papazian, Allen; O'Leary, Michael; Amr, Sami; Storer, Thomas W; Stern, Emily; Bhasin, Shalender

2016-12-01

Some men who use finasteride for hair loss report persistent sexual and other symptoms after discontinuing finasteride therapy. To determine whether these persistent symptoms after discontinuation of finasteride use are due to androgen deficiency, decreased peripheral androgen action, or persistent inhibition of steroid 5α-reductase (SRD5A) enzymes. Finasteride users, who reported persistent sexual symptoms after discontinuing finasteride (group 1); age-matched finasteride users who did not report sexual symptoms (group 2); and healthy men who had never used finasteride (group 3). Sexual function, mood, affect, cognition, hormone levels, body composition, functional magnetic resonance imaging (fMRI) response to sexually and affectively valenced stimuli, nucleotide sequences of androgen receptor (AR), SRD5A1, and SRD5A2; expression levels of androgen-dependent genes in skin. Academic medical center. Symptomatic finasteride users were similar in body composition, strength, and nucleotide sequences of AR, SRD5A1, and SRD5A2 genes to asymptomatic finasteride users and nonusers. Symptomatic finasteride users had impaired sexual function, higher depression scores, a more negative affectivity balance, and more cognitive complaints than men in groups 2 and 3 but had normal objectively assessed cognitive function. Testosterone, dihydrotestosterone, 5α-androstane-3α,17β-diol-glucuronide, testosterone to dihydrotestosterone and androsterone glucuronide to etiocholanolone glucuronide ratios, and markers of peripheral androgen action and expression levels of AR-dependent genes in skin did not differ among groups. fMRI blood oxygen level-dependent responses to erotic and nonerotic stimuli revealed abnormal function in brain circuitry linked to sexual arousal and major depression. We found no evidence of androgen deficiency, decreased peripheral androgen action, or persistent peripheral inhibition of SRD5A in men with persistent sexual symptoms after finasteride use. Symptomatic finasteride users revealed depressed mood and fMRI findings consistent with those observed in depression.

Characteristics of Men Who Report Persistent Sexual Symptoms After Finasteride Use for Hair Loss

PubMed Central

Basaria, Shehzad; Jasuja, Ravi; Huang, Grace; Wharton, Whitney; Pan, Hong; Pencina, Karol; Li, Zhuoying; Travison, Thomas G.; Bhawan, Jag; Gonthier, Renaud; Labrie, Fernand; Dury, Alain Y.; Serra, Carlo; Papazian, Allen; O'Leary, Michael; Amr, Sami; Storer, Thomas W.; Stern, Emily

2016-01-01

Context: Some men who use finasteride for hair loss report persistent sexual and other symptoms after discontinuing finasteride therapy. Objective: To determine whether these persistent symptoms after discontinuation of finasteride use are due to androgen deficiency, decreased peripheral androgen action, or persistent inhibition of steroid 5α-reductase (SRD5A) enzymes. Participants: Finasteride users, who reported persistent sexual symptoms after discontinuing finasteride (group 1); age-matched finasteride users who did not report sexual symptoms (group 2); and healthy men who had never used finasteride (group 3). Outcomes: Sexual function, mood, affect, cognition, hormone levels, body composition, functional magnetic resonance imaging (fMRI) response to sexually and affectively valenced stimuli, nucleotide sequences of androgen receptor (AR), SRD5A1, and SRD5A2; expression levels of androgen-dependent genes in skin. Setting: Academic medical center. Results: Symptomatic finasteride users were similar in body composition, strength, and nucleotide sequences of AR, SRD5A1, and SRD5A2 genes to asymptomatic finasteride users and nonusers. Symptomatic finasteride users had impaired sexual function, higher depression scores, a more negative affectivity balance, and more cognitive complaints than men in groups 2 and 3 but had normal objectively assessed cognitive function. Testosterone, dihydrotestosterone, 5α-androstane-3α,17β-diol-glucuronide, testosterone to dihydrotestosterone and androsterone glucuronide to etiocholanolone glucuronide ratios, and markers of peripheral androgen action and expression levels of AR-dependent genes in skin did not differ among groups. fMRI blood oxygen level-dependent responses to erotic and nonerotic stimuli revealed abnormal function in brain circuitry linked to sexual arousal and major depression. Conclusions: We found no evidence of androgen deficiency, decreased peripheral androgen action, or persistent peripheral inhibition of SRD5A in men with persistent sexual symptoms after finasteride use. Symptomatic finasteride users revealed depressed mood and fMRI findings consistent with those observed in depression. PMID:27662439

Anti-Androgenic Activity of Nardostachys jatamansi DC and Tribulus terrestris L. and Their Beneficial Effects on Polycystic Ovary Syndrome-Induced Rat Models.

PubMed

Sandeep, Palakkil Mavilavalappil; Bovee, Toine F H; Sreejith, Krishnan

2015-08-01

Polycystic ovary syndrome (PCOS) is a major hyperandrogenic disorder. Many drugs prescribed specifically to treat PCOS have side effects; however, previous studies suggest that natural therapeutics including botanicals may be less invasive and equally effective for the management of PCOS. In the present study, plants were screened for antiandrogenic activity using the RIKILT yeast Androgen bioAssay (RAA). Selected positive plants were subsequently tested for their efficacy against PCOS induced by estradiol valerate (EV) in rat models. RAA revealed the antiandrogenic property of Nardostachys jatamansi DC (NJ), Tribulus terrestris L. (TT), and Embelia tsjeriam-cottam DC (EJ), whereas Whithania somnifera Dunal (WS), Symplocos racemosa Roxb. (SR), and Helicteres isora L. (HI) exhibited androgenic properties. EJ also exhibited mild androgenic activity and therefore was excluded from further study. EV administration reduced the weight gain and disrupted cyclicity in all rats. NJ and TT extract treatment normalized estrous cyclicity and steroidal hormonal levels and regularized ovarian follicular growth. The in vitro antiandrogenic activity of plant extracts and their positive effects on different parameters of PCOS were proved in vivo.

Early Hormonal Influences on Cognitive Functioning in Congenital Adrenal Hyperplasia.

ERIC Educational Resources Information Center

Resnick, Susan M.; And Others

1986-01-01

Reports the results of cognitive test performance and early childhood activities in individuals with congenital adrenal hyperplasia, an autosomal recessive disorder associated with elevated prenatal adrenal androgen levels, demonstrating the effects of early exposure to excess androgenizing hormones on sexually dimorphic cognitive functioning.…

Influence of androgen receptor CAG polymorphism on sexual function recovery after testosterone therapy in late-onset hypogonadism.

PubMed

Tirabassi, Giacomo; Corona, Giovanni; Biagioli, Andrea; Buldreghini, Eddi; delli Muti, Nicola; Maggi, Mario; Balercia, Giancarlo

2015-02-01

Androgen receptor (AR) CAG polymorphism has been found to influence sexual function. However, no study has evaluated its potential to condition sexual function recovery after testosterone replacement therapy (TRT) in a large cohort of hypogonadic subjects. To evaluate the role of this polymorphism in sexual function improvement after TRT in late-onset hypogonadism (LOH). Seventy-three men affected by LOH were retrospectively considered. Evaluations were performed before TRT started (time 0) and before the sixth undecanoate testosterone injection. International Index of Erectile Function (IIEF) questionnaire (erectile function [EF], orgasmic function [OF], sexual desire [SD], intercourse satisfaction [IS], overall satisfaction [OS], and total IIEF-15 score); total and free testosterone and estradiol; AR gene CAG repeat number. TRT induced a significant increase in total and free testosterone and estradiol. All IIEF domains significantly improved after TRT. AR CAG repeats negatively and significantly correlated with all the variations (Δ-) of sexual function domains, except for Δ-OS. Conversely, Δ-total testosterone was found to be positively and significantly correlated with sexual function domain variations, except for Δ-IS and Δ-OS. Δ-estradiol did not correlate significantly with any of the variations of sexual function domains. After inclusion in generalized linear models, the number of AR gene CAG triplets was found to be independently and negatively associated with Δ-EF, Δ-SD, Δ-IS, and Δ-Total IIEF-15 score, whereas Δ-total testosterone was independently and positively associated with Δ-EF, Δ-OF, Δ-SD, and Δ-Total IIEF-15 score. However, after including time 0 total testosterone in the model, AR gene CAG triplets remained independently and negatively associated only with Δ-EF and Δ-Total IIEF-15 score, whereas Δ-total testosterone was independently and positively associated only with Δ-EF. Longer length of AR gene CAG repeat tract seems to lower TRT-induced improvement of sexual function in LOH. © 2014 International Society for Sexual Medicine.

Transcriptional up-regulation of the human androgen receptor by androgen in bone cells.

PubMed

Wiren, K M; Zhang, X; Chang, C; Keenan, E; Orwoll, E S

1997-06-01

Androgen regulation of androgen receptor (AR) expression has been observed in a variety of tissues, generally as inhibition, and is thought to attenuate cellular responses to androgen. AR is expressed in osteoblasts, the bone-forming cell, suggesting direct actions of androgens on bone. Here we characterized the effect of androgen exposure on AR gene expression in human osteoblastic SaOS-2 and U-2 OS cells. Treatment of osteoblastic cells with the nonaromatizable androgen 5alpha-dihydrotestosterone increased AR steady state messenger RNA levels in a time- and dose-dependent fashion. Reporter assays with 2.3 kilobases of the proximal 5'-flanking region of the human AR promoter linked to the chloramphenicol acetyltransferase gene in transfected cultures showed that up-regulation of AR promoter activity by androgen was time and dose dependent. Treatment with other steroid hormones, including progesterone, 17beta-estradiol, and dexamethasone, was without effect. The antiandrogen hydroxyflutamide completely antagonized androgen up-regulation. Thus, in contrast to many other androgen target tissues, androgen exposure increases steady state AR messenger RNA levels in osteoblasts. This regulation occurs at least partially at the level of transcription, is mediated by the 5'-promoter region of the AR gene, and is dependent on functional AR. These results suggest that physiological concentrations of androgens have significant effects on AR expression in skeletal tissue.

Synaptic long-term potentiation and depression in the rat medial vestibular nuclei depend on neural activation of estrogenic and androgenic signals.

PubMed

Scarduzio, Mariangela; Panichi, Roberto; Pettorossi, Vito Enrico; Grassi, Silvarosa

2013-01-01

Estrogenic and androgenic steroids can be synthesised in the brain and rapidly modulate synaptic transmission and plasticity through direct interaction with membrane receptors for estrogens (ERs) and androgens (ARs). We used whole cell patch clamp recordings in brainstem slices of male rats to explore the influence of ER and AR activation and local synthesis of 17β-estradiol (E2) and 5α-dihydrotestosterone (DHT) on the long-term synaptic changes induced in the neurons of the medial vestibular nucleus (MVN). Long-term depression (LTD) and long-term potentiation (LTP) caused by different patterns of high frequency stimulation (HFS) of the primary vestibular afferents were assayed under the blockade of ARs and ERs or in the presence of inhibitors for enzymes synthesizing DHT (5α-reductase) and E2 (P450-aromatase) from testosterone (T). We found that LTD is mediated by interaction of locally produced androgens with ARs and LTP by interaction of locally synthesized E2 with ERs. In fact, the AR block with flutamide prevented LTD while did not affect LTP, and the blockade of ERs with ICI 182,780 abolished LTP without influencing LTD. Moreover, the block of P450-aromatase with letrozole not only prevented the LTP induction, but inverted LTP into LTD. This LTD is likely due to the local activation of androgens, since it was abolished under blockade of ARs. Conversely, LTD was still induced in the presence of finasteride the inhibitor of 5α-reductase demonstrating that T is able to activate ARs and induce LTD even when DHT is not synthesized. This study demonstrates a key and opposite role of sex neurosteroids in the long-term synaptic changes of the MVN with a specific role of T-DHT for LTD and of E2 for LTP. Moreover, it suggests that different stimulation patterns can lead to LTD or LTP by specifically activating the enzymes involved in the synthesis of androgenic or estrogenic neurosteroids.

Anabolic steroid induced hypogonadism in young men.

PubMed

Coward, Robert M; Rajanahally, Saneal; Kovac, Jason R; Smith, Ryan P; Pastuszak, Alexander W; Lipshultz, Larry I

2013-12-01

The use of anabolic androgenic steroids has not been traditionally discussed in mainstream medicine. With the increased diagnosis of hypogonadism a heterogeneous population of men is now being evaluated. In this larger patient population the existence of anabolic steroid induced hypogonadism, whether transient or permanent, should now be considered. We performed an initial retrospective database analysis of all 6,033 patients who sought treatment for hypogonadism from 2005 to 2010. An anonymous survey was subsequently distributed in 2012 to established patients undergoing testosterone replacement therapy. Profound hypogonadism, defined as testosterone 50 ng/dl or less, was identified in 97 men (1.6%) in the large retrospective cohort initially reviewed. The most common etiology was prior anabolic androgenic steroid exposure, which was identified in 42 men (43%). Because of this surprising data, we performed an anonymous followup survey of our current hypogonadal population of 382 men with a mean±SD age of 49.2±13.0 years. This identified 80 patients (20.9%) with a mean age of 40.4±8.4 years who had prior anabolic androgenic steroid exposure. Hypogonadal men younger than 50 years were greater than 10 times more likely to have prior anabolic androgenic steroid exposure than men older than 50 years (OR 10.16, 95% CI 4.90-21.08). Prior anabolic androgenic steroid use significantly correlated negatively with education level (ρ=-0.160, p=0.002) and number of children (ρ=-0.281, p<0.0001). Prior anabolic androgenic steroid use is common in young men who seek treatment for symptomatic hypogonadism and anabolic steroid induced hypogonadism is the most common etiology of profound hypogonadism. These findings suggest that it is necessary to refocus the approach to evaluation and treatment paradigms in young hypogonadal men. Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

EVALUATION OF THE MODEL ANTI-ANDROGEN FLUTAMIDE FOR ASSESSING THE MECHANISTIC BASIS OF RESPONSES TO AN ANDROGEN IN THE FATHEAD MINNOW (JOURNAL ARTICLE)

EPA Science Inventory

In this study we characterized the effects of flutamide, a model mammalian androgen receptor (AR) antagonist, on endocrine function in the fathead minnow (Pimephales promelas), a small fish species which is widely used for testing endocrine-disrupting chemicals (EDCs). Binding a...

Androgen-independent proliferation of LNCaP prostate cancer cells infected by xenotropic murine leukemia virus-related virus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kakoki, Katsura; Department of AIDS Research, Institute of Tropical Medicine, G-COE, Nagasaki University, Nagasaki 852-8523; Department of Urology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523

Highlights: • XMRV infection induces androgen-independent growth in LNCaP cells. • XMRV infection reduces expression of androgen receptor. • XMRV promotes appearance of androgen blocker-resistant prostate cancer cells. - Abstract: Xenotropic murine leukemia virus-related virus (XMRV) is a novel gammaretrovirus that was originally isolated from human prostate cancer. It is now believed that XMRV is not the etiologic agent of prostate cancer. An analysis of murine leukemia virus (MLV) infection in various human cell lines revealed that prostate cancer cell lines are preferentially infected by XMRV, and this suggested that XMRV infection may confer some sort of growth advantage tomore » prostate cancer cell lines. To examine this hypothesis, androgen-dependent LNCaP cells were infected with XMRV and tested for changes in certain cell growth properties. We found that XMRV-infected LNCaP cells can proliferate in the absence of the androgen dihydrotestosterone. Moreover, androgen receptor expression is significantly reduced in XMRV-infected LNCaP cells. Such alterations were not observed in uninfected and amphotropic MLV-infected LNCaP cells. This finding explains why prostate cancer cell lines are preferentially infected with XMRV.« less

Brain responses to sexual images in 46,XY women with complete androgen insensitivity syndrome are female-typical.

PubMed

Hamann, Stephan; Stevens, Jennifer; Vick, Janice Hassett; Bryk, Kristina; Quigley, Charmian A; Berenbaum, Sheri A; Wallen, Kim

2014-11-01

Androgens, estrogens, and sex chromosomes are the major influences guiding sex differences in brain development, yet their relative roles and importance remain unclear. Individuals with complete androgen insensitivity syndrome (CAIS) offer a unique opportunity to address these issues. Although women with CAIS have a Y chromosome, testes, and produce male-typical levels of androgens, they lack functional androgen receptors preventing responding to their androgens. Thus, they develop a female physical phenotype, are reared as girls, and develop into women. Because sexually differentiated brain development in primates is determined primarily by androgens, but may be affected by sex chromosome complement, it is currently unknown whether brain structure and function in women with CAIS is more like that of women or men. In the first functional neuroimaging study of (46,XY) women with CAIS, typical (46,XX) women, and typical (46, XY) men, we found that men showed greater amygdala activation to sexual images than did either typical women or women with CAIS. Typical women and women with CAIS had highly similar patterns of brain activation, indicating that a Y chromosome is insufficient for male-typical human brain responses. Because women with CAIS produce male-typical or elevated levels of testosterone which is aromatized to estradiol these results rule out aromatization of testosterone to estradiol as a determinate of sex differences in patterns of brain activation to sexual images. We cannot, however, rule out an effect of social experience on the brain responses of women with CAIS as all were raised as girls. Copyright © 2014 Elsevier Inc. All rights reserved.

Androgen receptor signaling and mutations in prostate cancer

PubMed Central

Koochekpour, Shahriar

2010-01-01

Normal and neoplastic growth of the prostate gland are dependent on androgen receptor (AR) expression and function. Androgenic activation of the AR, in association with its coregulatory factors, is the classical pathway that leads to transcriptional activity of AR target genes. Alternatively, cytoplasmic signaling crosstalk of AR by growth factors, neurotrophic peptides, cytokines or nonandrogenic hormones may have important roles in prostate carcinogenesis and in metastatic or androgen-independent (AI) progression of the disease. In addition, cross-modulation by various nuclear transcription factors acting through basal transcriptional machinery could positively or negatively affect the AR or AR target genes expression and activity. Androgen ablation leads to an initial favorable response in a significant number of patients; however, almost invariably patients relapse with an aggressive form of the disease known as castration-resistant or hormone-refractory prostate cancer (PCa). Understanding critical molecular events that lead PCa cells to resist androgen-deprivation therapy is essential in developing successful treatments for hormone-refractory disease. In a significant number of hormone-refractory patients, the AR is overexpressed, mutated or genomically amplified. These genetic alterations maintain an active presence for a highly sensitive AR, which is responsive to androgens, antiandrogens or nonandrogenic hormones and collectively confer a selective growth advantage to PCa cells. This review provides a brief synopsis of the AR structure, AR coregulators, posttranslational modifications of AR, duality of AR function in prostate epithelial and stromal cells, AR-dependent signaling, genetic changes in the form of somatic and germline mutations and their known functional significance in PCa cells and tissues. PMID:20711217

Low Testosterone Alters the Activity of Mouse Prostate Stem Cells.

PubMed

Zhou, Ye; Copeland, Ben; Otto-Duessel, Maya; He, Miaoling; Markel, Susan; Synold, Tim W; Jones, Jeremy O

2017-04-01

Low serum testosterone (low T) has been repeatedly linked to worse outcomes in men with newly diagnosed prostate cancer (PC). How low T contributes to these outcomes is unknown. Here we demonstrate that exposure to low T causes significant changes in the mouse prostate and prostate stem cells. Mice were castrated and implanted with capsules to achieve castrate, normal, or sub-physiological levels of T. After 6 weeks of treatment, LC-MS/MS was used to quantify the levels of T and dihydrotestosterone (DHT) in serum and prostate tissue. FACS was used to quantify the percentages of purported prostate stem and transit amplifying (TA) cells in mouse prostates. Prostate tissues were also stained for the presence of CD68+ cells and RNA was extracted from prostate tissue or specific cell populations to measure changes in transcript levels with low T treatment. Despite having significantly different levels of T and DHT in the serum, T and DHT concentrations in prostate tissue from different T treatment groups were similar. Low T treatment resulted in significant alterations in the expression of androgen biosynthesis genes, which may be related to maintaining prostate androgen levels. Furthermore, the expression of androgen-regulated genes in the prostate was similar among all T treatment groups, demonstrating that the mouse prostate can maintain functional levels of androgens despite low serum T levels. Low T increased the frequency of prostate stem and TA cells in adult prostate tissue and caused major transcriptional changes in those cells. Gene ontology analysis suggested that low T caused inflammatory responses and immunofluorescent staining indicated that low T treatment led to the increased presence of CD68+ macrophages in prostate tissue. Low T alters the AR signaling axis which likely leads to maintenance of functional levels of prostate androgens. Low T also induces quantitative and qualitative changes in prostate stem cells which appear to lead to inflammatory macrophage infiltration. These changes are proposed to lead to an aggressive phenotype once cancers develop and may contribute to the poor outcomes in men with low T. Prostate 77:530-541, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Doping with anabolic androgenic steroids (AAS): Adverse effects on non-reproductive organs and functions.

PubMed

Nieschlag, Eberhard; Vorona, Elena

2015-09-01

Since the 1970s anabolic androgenic steroids (AAS) have been abused at ever increasing rates in competitive athletics, in recreational sports and in bodybuilding. Exceedingly high doses are often consumed over long periods, in particular by bodybuilders, causing acute or chronic adverse side effects frequently complicated by additional polypharmacy. This review summarizes side effects on non-reproductive organs and functions; effects on male and female reproduction have been recently reviewed in a parallel paper. Among the most striking AAS side effects are increases in haematocrit and coagulation causing thromboembolism, intracardiac thrombosis and stroke as well as other cardiac disturbances including arrhythmias, cardiomyopathies and possibly sudden death. 17α-alkylated AAS are liver toxic leading to cholestasis, peliosis, adenomas and carcinomas. Hyperbilirubinaemia can cause cholemic nephrosis and kidney failure. AAS abuse may induce exaggerated self-confidence, reckless behavior, aggressiveness and psychotic symptoms. AAS withdrawal may be accompanied by depression and suicidal intentions. Since AAS abuse is not or only reluctantly admitted physicians should be aware of the multitude of serious side effects when confronted with unclear symptoms.

Selective Androgen Receptor Modulators (SARMs) as Function Promoting Therapies

PubMed Central

Bhasin, Shalender; Jasuja, Ravi

2010-01-01

Purpose of review The last decade has witnessed unprecedented discovery effort to develop selective androgen receptor modulators (SARMs) that improve physical function and bone health without adversely affecting the prostate and cardiovascular outcomes. This review describes the historical evolution, the rationale for SARM development, and the mechanisms of testosterone action and SARM selectivity. Recent Findings While steroidal SARMs have been around since the 1940s, a number of nonsteroidal SARMs that do not serve as substrates for CYP19 aromatase or 5α-reductase, act as full agonists in muscle and bone and as partial agonists in prostate are in development. The differing interactions of steroidal and nonsteroidal compounds with AR contribute to their unique pharmacologic actions. Ligand binding induces specific conformational changes in the ligand binding domain, which could modulate surface topology and protein-protein interactions between AR and coregulators, resulting in tissue-specific gene regulation. Preclinical studies have demonstrated the ability of SARMs to increase muscle and bone mass in preclinical rodent models with varying degree of prostate sparing. Phase I trials of SARMs in humans have reported modest increments in fat-free mass. Summary SARMs hold promise as a new class of function promoting anabolic therapies for a number of clinical indications, including functional limitations associated with aging and chronic disease, frailty, cancer cachexia, and osteoporosis. PMID:19357508

Effects of male sex hormones on gender identity, sexual behavior, and cognitive function.

PubMed

Zhu, Yuan-shan; Cai, Li-qun

2006-04-01

Androgens, the male sex hormones, play an essential role in male sexual differentiation and development. However, the influence of these sex hormones extends beyond their roles in sexual differentiation and development. In many animal species, sex hormones have been shown to be essential for sexual differentiation of the brain during development and for maintaining sexually dimorphic behavior throughout life. The principals of sex determination in humans have been demonstrated to be similar to other mammals. However, the hormonal influence on sexual dimorphic differences in the nervous system in humans, sex differences in behaviors, and its correlations with those of other mammals is still an emerging field. In this review, the roles of androgens in gender and cognitive function are discussed with the emphasis on subjects with androgen action defects including complete androgen insensitivity due to androgen receptor mutations and 5alpha-reductase-2 deficiency syndromes due to 5alpha-reductase-2 gene mutations. The issue of the complex interaction of nature versus nurture is addressed.

Activation of p300 histone acetyltransferase activity and acetylation of the androgen receptor by bombesin in prostate cancer cells.

PubMed

Gong, J; Zhu, J; Goodman, O B; Pestell, R G; Schlegel, P N; Nanus, D M; Shen, R

2006-03-30

Androgen receptor signaling in prostate cancer cells is augmented by the androgen receptor (AR) coactivator p300, which transactivates and acetylates the AR in the presence of dihydrotestosterone (DHT). As prostate cancer (PC) cells progress to androgen independence, AR signaling remains intact, indicating that other factors stimulate AR activities in the absence of androgen. We previously reported that neuropeptide growth factors could transactivate the AR in the presence of very low concentrations of DHT. Here, we examine the involvement of p300 in neuropeptide activation of AR signaling. Transfection of increasing concentrations of p300 in the presence of bombesin into PC-3 cells resulted in a linear increase in AR transactivation, suggesting that p300 acts as a coactivator in neuropeptide-mediated AR transactivation. P300 is endowed with histone acetyltransferase (HAT) activity. Therefore, we examine the effect of bombesin on p300 HAT activity. At 4 h after the addition of bombesin, p300 HAT activity increased 2.0-fold (P<0.01). Incubation with neutral endopeptidase, which degrades bombesin, or bombesin receptor antagonists blocked bombesin-induced p300 HAT activity. To explore the potential signaling pathways involved in bombesin-induced p300 HAT activity, we examined Src and PKCdelta pathways that mediate bombesin signaling. Inhibitors of Src kinase activity or Src kinase siRNA blocked bombesin-induced p300 HAT activity, whereas PKCdelta inhibitors or PKCdelta siRNA significantly increased bombesin-induced p300 HAT activity suggesting that Src kinase and PKCdelta kinase are involved in the regulation of p300 HAT activity. As AR is acetylated in the presence of 100 nM DHT, we next examined whether bombesin-induced p300 HAT activity would result in enhanced AR acetylation. Bombesin-induced AR acetylation at the same motif KLKK observed in DHT-induced acetylation. Elimination of p300 using p300 siRNA reduced AR acetylation, demonstrating that AR acetylation was mediated by p300. AR acetylation results in AR transactivation and the expression of the AR-regulated gene prostate-specific antigen (PSA). Therefore, we examined bombesin-induced AR transactivation and PSA expression in the presence and absence of p300 siRNA and found inhibition of p300 expression reduced bombesin-induced AR transactivation and PSA expression. Together these results demonstrate that bombesin, via Src and PKCdelta signaling pathways, activates p300 HAT activity which leads to enhanced acetylation of AR resulting in increased expression of AR-regulated genes.

Androgen and AR contribute to breast cancer development and metastasis: an insight of mechanisms.

PubMed

Feng, J; Li, L; Zhang, N; Liu, J; Zhang, L; Gao, H; Wang, G; Li, Y; Zhang, Y; Li, X; Liu, D; Lu, J; Huang, B

2017-05-18

The role of androgen and androgen receptor (AR) in breast carcinogenesis has long been a disputed issue. This report provides a mechanistic insight into how androgen and AR contributes to invasion and metastasis of breast cancer. We find that dihydrotestosterone (DHT) is able to induce the epithelial-to-mesenchymal transition in breast cancer cells in an AR-dependent/estrogen receptor-independent manner. This process is dependent on the demethylation activity of lysine-specific demethylase 1A (LSD1) by epigenetically regulating the target genes E-cadherin and vimentin. In vivo, DHT promotes metastasis in a nude mouse model, and AR and LSD1 are indispensable in this process. We establish that higher expression of nucleus AR to cytoplasm AR associated with worse prognostic outcomes in breast cancer patient samples. This study maps an 'androgen-AR/LSD1-target genes' pathway in breast carcinogenesis, implicating the importance of hormonal balance in women, and the potential clinical significance of serum androgen and AR in prediction of breast cancer and selection of breast cancer therapy.

Review: fetal programming of polycystic ovary syndrome by androgen excess: evidence from experimental, clinical, and genetic association studies.

PubMed

Xita, Nectaria; Tsatsoulis, Agathocles

2006-05-01

Polycystic ovary syndrome (PCOS) is a common endocrine disorder of premenopausal women, characterized by hyperandrogenism, polycystic ovaries, and chronic anovulation along with insulin resistance and abdominal obesity as frequent metabolic traits. Although PCOS manifests clinically during adolescence, emerging data suggest that the natural history of PCOS may originate in intrauterine life. Evidence from experimental, clinical, and genetic research supporting the hypothesis for the fetal origins of PCOS has been analyzed. Female primates, exposed in utero to androgen excess, exhibit the phenotypic features of PCOS during adult life. Clinical observations also support a potential fetal origin of PCOS. Women with fetal androgen excess disorders, including congenital 21-hydroxylase deficiency and congenital adrenal virilizing tumors, develop features characteristic of PCOS during adulthood despite the normalization of androgen excess after birth. The potential mechanisms of fetal androgen excess leading to a PCOS phenotype in humans are not clearly understood. However, maternal and/or fetal hyperandrogenism can provide a plausible mechanism for fetal programing of PCOS, and this, in part, may be genetically determined. Thus, genetic association studies have indicated that common polymorphic variants of genes determining androgen activity or genes that influence the availability of androgens to target tissues are associated with PCOS and increased androgen levels. These genomic variants may provide the genetic link to prenatal androgenization in human PCOS. Prenatal androgenization of the female fetus induced by genetic and environmental factors, or the interaction of both, may program differentiating target tissues toward the development of PCOS phenotype in adult life.

Structure-based Virtual Screening and Identification of a Novel Androgen Receptor Antagonist*

PubMed Central

Song, Chin-Hee; Yang, Su Hui; Park, Eunsook; Cho, Suk Hee; Gong, Eun-Yeung; Khadka, Daulat Bikram; Cho, Won-Jea; Lee, Keesook

2012-01-01

Hormonal therapies, mainly combinations of anti-androgens and androgen deprivation, have been the mainstay treatment for advanced prostate cancer because the androgen-androgen receptor (AR) system plays a pivotal role in the development and progression of prostate cancers. However, the emergence of androgen resistance, largely due to inefficient anti-hormone action, limits the therapeutic usefulness of these therapies. Here, we report that 6-(3,4-dihydro-1H-isoquinolin-2-yl)-N-(6-methylpyridin-2-yl)nicotinamide (DIMN) acts as a novel anti-androgenic compound that may be effective in the treatment of both androgen-dependent and androgen-independent prostate cancers. Through AR structure-based virtual screening using the FlexX docking model, fifty-four compounds were selected and further screened for AR antagonism via cell-based tests. One compound, DIMN, showed an antagonistic effect specific to AR with comparable potency to that of the classical AR antagonists, hydroxyflutamide and bicalutamide. Consistent with their anti-androgenic activity, DIMN inhibited the growth of androgen-dependent LNCaP prostate cancer cells. Interestingly, the compound also suppressed the growth of androgen-independent C4–2 and CWR22rv prostate cancer cells, which express a functional AR, but did not suppress the growth of the AR-negative prostate cancer cells PPC-1, DU145, and R3327-AT3.1. Taken together, the results suggest that the synthetic compound DIMN is a novel anti-androgen and strong candidate for useful therapeutic agent against early stage to advanced prostate cancer. PMID:22798067

Cyproterone acetate enhances TRAIL-induced androgen-independent prostate cancer cell apoptosis via up-regulation of death receptor 5.

PubMed

Chen, Linjie; Wolff, Dennis W; Xie, Yan; Lin, Ming-Fong; Tu, Yaping

2017-03-07

Virtually all prostate cancer deaths occur due to obtaining the castration-resistant phenotype after prostate cancer cells escaped from apoptosis and/or growth suppression initially induced by androgen receptor blockade. TNF-related apoptosis-inducing ligand (TRAIL) was an attractive cancer therapeutic agent due to its minimal toxicity to normal cells and remarkable apoptotic activity in tumor cells. However, most localized cancers including prostate cancer are resistant to TRAIL-induced apoptosis, thereby creating a therapeutic challenge of inducing TRAIL sensitivity in cancer cells. Herein the effects of cyproterone acetate, an antiandrogen steroid, on the TRAIL-induced apoptosis of androgen receptor-negative prostate cancer cells are reported. Cell apoptosis was assessed by both annexin V/propidium iodide labeling and poly (ADP-ribose) polymerase cleavage assays. Gene and protein expression changes were determined by quantitative real-time PCR and western blot assays. The effect of cyproterone acetate on gene promoter activity was determined by luciferase reporter assay. Cyproterone acetate but not AR antagonist bicalutamide dramatically increased the susceptibility of androgen receptor-negative human prostate cancer PC-3 and DU145 cells to TRAIL-induced apoptosis but no effects on immortalized human prostate stromal PS30 cells and human embryonic kidney HEK293 cells. Further investigation of the TRAIL-induced apoptosis pathway revealed that cyproterone acetate exerted its effect by selectively increasing death receptor 5 (DR5) mRNA and protein expression. Cyproterone acetate treatment also increased DR5 gene promoter activity, which could be abolished by mutation of a consensus binding domain of transcription factor CCAAT-enhancer-binding protein homologous protein (CHOP) in the DR5 gene promoter. Cyproterone acetate increases CHOP expression in a concentration and time-dependent manner and endoplasmic reticulum stress reducer 4-phenylbutyrate could block cyproterone acetate-induced CHOP and DR5 up-regulation. More importantly, siRNA silencing of CHOP significantly reduced cyproterone acetate-induced DR5 up-regulation and TRAIL sensitivity in prostate cancer cells. Our study shows a novel effect of cyproterone acetate on apoptosis pathways in prostate cancer cells and raises the possibility that a combination of TRAIL with cyproterone acetate could be a promising strategy for treating castration-resistant prostate cancer.

TGFβ1 alters androgenic metabolites and hydroxysteroid dehydrogenase enzyme expression in human prostate reactive stromal primary cells: Is steroid metabolism altered by prostate reactive stromal microenvironment?

PubMed Central

Piao, Yun-shang; Wiesenfeld, Paddy; Sprando, Robert; Arnold, Julia T.

2013-01-01

The inflammatory tissue microenvironment can be an active promoter in preneoplastic cancer lesions. Altered steroid hormone metabolism as induced by the inflammatory microenvironment may contribute to epithelial cancer progression. Dehydroepiandrosterone sulfate (DHEAS) is the most abundant endogenous steroid hormone present in human serum and can be metabolized to DHEA, androgens and/or estrogens in peripheral tissues. We have previously reported that TGFβ1-induced reactive prostate stromal cells increase DHEA metabolism to active androgens and alter prostate cancer cell gene expression. While much of the focus on mechanisms of prostate cancer and steroid metabolism is in the epithelial cancer cells, this study focuses on TGFβ1-induced effects on DHEA metabolic pathways and enzymes in human prostate stromal cells. In DHEA-treated primary prostate stromal cells, TGFβ1 produced time- and dose-dependent increases in metabolism of DHEA to androstenedione and testosterone. Also TGFβ1-treated prostate stromal cells exhibited changes in the gene expression of enzymes involved in steroid metabolism including up-regulation of 3β hydroxysteroid dehydrogenase (HSD), and down-regulation of 17βHSD5, and 17βHSD2. These studies suggest that reactive prostate stroma and the inflammatory microenvironment may contribute to altered steroid metabolism and increased intratumoral androgens. PMID:23770322

TGFβ1 alters androgenic metabolites and hydroxysteroid dehydrogenase enzyme expression in human prostate reactive stromal primary cells: Is steroid metabolism altered by prostate reactive stromal microenvironment?

PubMed

Piao, Yun-shang; Wiesenfeld, Paddy; Sprando, Robert; Arnold, Julia T

2013-11-01

The inflammatory tissue microenvironment can be an active promoter in preneoplastic cancer lesions. Altered steroid hormone metabolism as induced by the inflammatory microenvironment may contribute to epithelial cancer progression. Dehydroepiandrosterone sulfate (DHEAS) is the most abundant endogenous steroid hormone present in human serum and can be metabolized to DHEA, androgens and/or estrogens in peripheral tissues. We have previously reported that TGFβ1-induced reactive prostate stromal cells increase DHEA metabolism to active androgens and alter prostate cancer cell gene expression. While much of the focus on mechanisms of prostate cancer and steroid metabolism is in the epithelial cancer cells, this study focuses on TGFβ1-induced effects on DHEA metabolic pathways and enzymes in human prostate stromal cells. In DHEA-treated primary prostate stromal cells, TGFβ1 produced time- and dose-dependent increases in metabolism of DHEA to androstenedione and testosterone. Also TGFβ1-treated prostate stromal cells exhibited changes in the gene expression of enzymes involved in steroid metabolism including up-regulation of 3β hydroxysteroid dehydrogenase (HSD), and down-regulation of 17βHSD5, and 17βHSD2. These studies suggest that reactive prostate stroma and the inflammatory microenvironment may contribute to altered steroid metabolism and increased intratumoral androgens. Published by Elsevier Ltd.

Why do winners keep winning? Androgen mediation of winner but not loser effects in cichlid fish

PubMed Central

Oliveira, Rui F.; Silva, Ana; Canário, Adelino V.M.

2009-01-01

Animal conflicts are influenced by social experience such that a previous winning experience increases the probability of winning the next agonistic interaction, whereas a previous losing experience has the opposite effect. Since androgens respond to social interactions, increasing in winners and decreasing in losers, we hypothesized that socially induced transient changes in androgen levels could be a causal mediator of winner/loser effects. To test this hypothesis, we staged fights between dyads of size-matched males of the Mozambique tilapia (Oreochromis mossambicus). After the first contest, winners were treated with the anti-androgen cyproterone acetate and losers were supplemented with 11-ketotestosterone. Two hours after the end of the first fight, two contests were staged simultaneously between the winner of the first fight and a naive male and between the loser of first fight and another naive male. The majority (88%) of control winners also won the second interaction, whereas the majority of control losers (87%) lost their second fight, thus confirming the presence of winner/loser effects in this species. As predicted, the success of anti-androgen-treated winners in the second fight decreased significantly to chance levels (44%), but the success of androgenized losers (19%) did not show a significant increase. In summary, the treatment with anti-androgen blocks the winner effect, whereas androgen administration fails to reverse the loser effect, suggesting an involvement of androgens on the winner but not on the loser effect. PMID:19324741

Androgen induces gonadal soma-derived factor, Gsdf, in XX gonads correlated to sex-reversal but not Dmrt1 directly, in the teleost fish, northern medaka (Oryzias sakaizumii).

PubMed

Horie, Yoshifumi; Myosho, Taijun; Sato, Tadashi; Sakaizumi, Mitsuru; Hamaguchi, Satoshi; Kobayashi, Tohru

2016-11-15

In the inbred HNI-II strain of Oryzias sakaizumii, Dmy and Gsdf are expressed in XY gonads from Stages 35 and 36, respectively, similarly to the inbred Hd-rR strain of Oryzias latipes. However, Dmrt1 respectively becomes detectable at Stage 36 and 5 days post hatching (dph) in the two strains. In XX HNI-II embryos, 17α-methyltestosterone (MT) induces Gsdf mRNA from Stage 36, accompanied by complete sex-reversal in all treated individuals (MT, 10 ng/mL), while Dmrt1 mRNA was first detectable at 5 dph. In XX d-rR, MT induced Gsdf mRNA expression and sex-reversal in only some of the treated individuals. Together, these results suggest the testis differentiation cascade in XY individuals differs between the HNI-II and Hd-rR strains. In addition, it is suggested that androgen-induced XX sex-reversal proceeds via an androgen-Gsdf-Dmrt1 cascade and that Gsdf plays an important role in sex-reversal in medaka. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Increased phospho-AKT is associated with loss of the androgen receptor during the progression of N-methyl-N-nitrosourea-induced prostate carcinogenesis in rats.

PubMed

Liao, Zhiming; Wang, Shihua; Boileau, Thomas W-M; Erdman, John W; Clinton, Steven K

2005-07-01

Characterization of molecular events during N-methyl-N-nitrosourea (MNU)-induced rat prostate carcinogenesis enhances the utility of this model for the preclinical assessment of preventive strategies. Androgen independence is typical of advanced human prostate cancer and may occur through multiple mechanisms including the loss of androgen receptor (AR) expression and the activation of alternative signaling pathways. We examined the interrelationships between AR and p-AKT expression by immunohistochemical staining during MNU-androgen-induced prostate carcinogenesis in male Wistar-Unilever rats. Histone nuclear staining and image analysis was employed to assess parallel changes in chromatin and nuclear structure. The percentage of AR positive nuclei decreased (P < 0.01) as carcinogenesis progressed: hyperplasia (92%), atypical hyperplasia (92%), well-differentiated adenocarcinoma (57%), moderately-differentiated adenocarcinoma (19%), and poorly-differentiated adenocarcinoma (10%). Conversely, p-AKT staining increased significantly during carcinogenesis. Sparse staining was observed in normal tissues (0.2% of epithelial area) and hyperplastic lesions (0.1%), while expression increased significantly (P < 0.001) in atypical hyperplasia (7.6%), well-differentiated adenocarcinoma (16.7%), moderately-differentiated adenocarcinoma (19.6%), and poorly-differentiated adenocarcinoma (17.4%). In parallel, nuclear morphometry revealed increased nuclear size, greater irregularity, and lower DNA compactness as cancers became more poorly differentiated. In the MNU model, the progressive evolution of dominant tumor cell populations showing an increase in p-AKT in parallel with a decline in AR staining suggests that activation of AKT signaling may be one of several mechanisms contributing to androgen insensitivity during prostate cancer progression. Our observations mimic findings suggested by human studies and support the relevance of the MNU model in preclinical studies of preventive strategies. (c) 2005 Wiley-Liss, Inc.

Androgen deprivation results in time-dependent hypoxia in LNCaP prostate tumours: informed scheduling of the bioreductive drug AQ4N improves treatment response.

PubMed

Ming, Louise; Byrne, Niall M; Camac, Sarah Nicole; Mitchell, Christopher A; Ward, Claire; Waugh, David J; McKeown, Stephanie R; Worthington, Jenny

2013-03-15

Androgen withdrawal induces hypoxia in androgen-sensitive tissue; this is important as in the tumour microenvironment, hypoxia is known to drive malignant progression. Our study examined the time-dependent effect of androgen deprivation therapy (ADT) on tumour oxygenation and investigated the role of ADT-induced hypoxia on malignant progression in prostate tumours. LNCaP xenografted tumours were treated with anti-androgens and tumour oxygenation measured. Dorsal skin fold (DSF) chambers were used to image tumour vasculature in vivo. Quantitative PCR (QPCR) identified differential gene expression following treatment with bicalutamide. Bicalutamide-treated and vehicle-only-treated tumours were re-established in vitro, and invasion and sensitivity to docetaxel were measured. Tumour growth delay was calculated following treatment with bicalutamide combined with the bioreductive drug AQ4N. Tumour oxygenation measurements showed a precipitate decrease following initiation of ADT. A clinically relevant dose of bicalutamide (2 mg/kg/day) decreased tumour oxygenation by 45% within 24 hr, reaching a nadir of 0.09% oxygen (0.67 ± 0.06 mmHg) by Day 7; this persisted until Day 14 when it increased up to Day 28. Using DSF chambers, LNCaP tumours treated with bicalutamide showed loss of small vessels at Days 7 and 14 with revascularisation occurring by Day 21. QPCR showed changes in gene expression consistent with the vascular changes and malignant progression. Cells from bicalutamide-treated tumours were more malignant than vehicle-treated controls. Combining bicalutamide with AQ4N (50 mg/kg, single dose) caused greater tumour growth delay than bicalutamide alone. Our study shows that bicalutamide-induced hypoxia selects for cells that show malignant progression; targeting hypoxic cells may provide greater clinical benefit. Copyright © 2012 UICC.

Identifying Environmental Chemicals as Agonists of the Androgen Receptor by Applying a Quantitative High-throughput Screening Platform

EPA Science Inventory

Background: The androgen receptor (AR, NR3C4) is a nuclear receptor whose main function is acting as a transcription factor regulating gene expression for male sexual development and maintaining accessory sexual organ function. It is also a necessary component of female fertility...

Developmental programming by androgen affects the circadian timing system in female mice.

PubMed

Mereness, Amanda L; Murphy, Zachary C; Sellix, Michael T

2015-04-01

Circadian clocks play essential roles in the timing of events in the mammalian hypothalamo-pituitary-ovarian (HPO) axis. The molecular oscillator driving these rhythms has been localized to tissues of the HPO axis. It has been suggested that synchrony among these oscillators is a feature of normal reproductive function. The impact of fertility disorders on clock function and the role of the clock in the etiology of endocrine pathology remain unknown. Polycystic ovarian syndrome (PCOS) is a particularly devastating fertility disorder, affecting 5%-10% of women at childbearing age with features including a polycystic ovary, anovulation, and elevated serum androgen. Approximately 40% of these women have metabolic syndrome, marked by hyperinsulinemia, dyslipidemia, and insulin resistance. It has been suggested that developmental exposure to excess androgen contributes to the etiology of fertility disorders, including PCOS. To better define the role of the timing system in these disorders, we determined the effects of androgen-dependent developmental programming on clock gene expression in tissues of the metabolic and HPO axes. Female PERIOD2::luciferase (PER2::LUC) mice were exposed to androgen (dihydrotestosterone [DHT]) in utero (Days 16-18 of gestation) or for 9-10 wk (DHT pellet) beginning at weaning (pubertal androgen excess [PAE]). As expected, both groups of androgen-treated mice had disrupted estrous cycles. Analysis of PER2::LUC expression in tissue explants revealed that excess androgen produced circadian misalignment via tissue-dependent effects on phase distribution. In vitro treatment with DHT differentially affected the period of PER2::LUC expression in tissue explants and granulosa cells, indicating that androgen has direct and tissue-specific effects on clock gene expression that may account for the effects of developmental programming on the timing system. © 2015 by the Society for the Study of Reproduction, Inc.

Modulation of Androgen Receptor Signaling in Hormonal Therapy-Resistant Prostate Cancer Cell Lines

PubMed Central

Marques, Rute B.; Dits, Natasja F.; Erkens-Schulze, Sigrun; van IJcken, Wilfred F. J.; van Weerden, Wytske M.; Jenster, Guido

2011-01-01

Background Prostate epithelial cells depend on androgens for survival and function. In (early) prostate cancer (PCa) androgens also regulate tumor growth, which is exploited by hormonal therapies in metastatic disease. The aim of the present study was to characterize the androgen receptor (AR) response in hormonal therapy-resistant PC346 cells and identify potential disease markers. Methodology/Principal Findings Human 19K oligoarrays were used to establish the androgen-regulated expression profile of androgen-responsive PC346C cells and its derivative therapy-resistant sublines: PC346DCC (vestigial AR levels), PC346Flu1 (AR overexpression) and PC346Flu2 (T877A AR mutation). In total, 107 transcripts were differentially-expressed in PC346C and derivatives after R1881 or hydroxyflutamide stimulations. The AR-regulated expression profiles reflected the AR modifications of respective therapy-resistant sublines: AR overexpression resulted in stronger and broader transcriptional response to R1881 stimulation, AR down-regulation correlated with deficient response of AR-target genes and the T877A mutation resulted in transcriptional response to both R1881 and hydroxyflutamide. This AR-target signature was linked to multiple publicly available cell line and tumor derived PCa databases, revealing that distinct functional clusters were differentially modulated during PCa progression. Differentiation and secretory functions were up-regulated in primary PCa but repressed in metastasis, whereas proliferation, cytoskeletal remodeling and adhesion were overexpressed in metastasis. Finally, the androgen-regulated genes ENDOD1, MCCC2 and ACSL3 were selected as potential disease markers for RT-PCR quantification in a distinct set of human prostate specimens. ENDOD1 and ACSL3 showed down-regulation in high-grade and metastatic PCa, while MCCC2 was overexpressed in low-grade PCa. Conclusions/Significance AR modifications altered the transcriptional response to (anti)androgens in therapy-resistant cells. Furthermore, selective down-regulation of genes involved in differentiation and up-regulation of genes promoting proliferation and invasion suggest a disturbed balance between the growth and differentiation functions of the AR pathway during PCa progression. These findings may have implications in the current treatment and development of novel therapeutical approaches for metastatic PCa. PMID:21829708

Neuroendocrine mechanisms of development of experimental hyperandrogen-induced anovulation.

PubMed

Reznikov, A G; Sinitsyn, P V; Tarasenko, L V; Polyakova, L I

2003-10-01

An experimental model of hyperandrogen-induced anovulatory infertility (s.c. implantation of Silastic capsules containing testosterone into adult female rats) was used to study morphological, hormonal, and biochemical measures characterizing the state of the hypothalamo-hypophyseal-ovarian system. Impairments in functional androgen metabolism in the hypothalamus were seen, with decreases in the Luliberin sensitivity of the hypophysis, changes in the structure of estral cycles, and morphological changes in the ovaries; these findings are evidence for neuroendocrine disturbances in the control of ovulation. Flutamide, an experimental antiandrogen, led to partial normalization of the hormonal, biochemical, and morphological characteristics, as well as to recovery of fertility in females with anovulatory infertility.

Dual action of high estradiol doses on MNU-induced prostate neoplasms in a rodent model with high serum testosterone: Protective effect and emergence of unstable epithelial microenvironment.

PubMed

Gonçalves, Bianca F; de Campos, Silvana G P; Góes, Rejane M; Scarano, Wellerson R; Taboga, Sebastião R; Vilamaior, Patricia S L

2017-06-01

Estrogens are critical players in prostate growth and disease. Estrogen therapy has been the standard treatment for advanced prostate cancer for several decades; however, it has currently been replaced by alternative anti-androgenic therapies. Additionally, studies of its action on prostate biology, resulting from an association between carcinogens and estrogen, at different stages of life are scarce or inconclusive about its protective and beneficial role on induced-carcinogenesis. Thus, the aim of this study was to determine whether estradiol exerts a protective and/or stimulatory role on N-methyl-N-nitrosurea-induced prostate neoplasms. We adopted a rodent model that has been used to study induced-prostate carcinogenesis: the Mongolian gerbil. We investigated the occurrence of neoplasms, karyometric patterns, androgen and estrogen receptors, basal cells, and global methylation status in ventral and dorsolateral prostate tissues. Histopathological analysis showed that estrogen was able to slow tumor growth in both lobes after prolonged treatment. However, a true neoplastic regression was observed only in the dorsolateral prostate. In addition to the protective effects against neoplastic progression, estrogen treatment resulted in an epithelium that exhibited features distinctive from a normal prostate, including increased androgen-insensitive basal cells, high androgens and estrogen receptor positivity, and changes in DNA methylation patterns. Estrogen was able to slow tumor growth, but the epithelium exhibited features distinct from a normal prostatic epithelium, and this unstable microenvironment could trigger lesion recurrence over time. © 2017 Wiley Periodicals, Inc.

Negative Impact of Testosterone Deficiency and 5α-Reductase Inhibitors Therapy on Metabolic and Sexual Function in Men.

PubMed

Traish, Abdulmaged M

2017-01-01

Androgens are steroid hormones with pleotropic and diverse biochemical and physiological functions, and androgen deficiency exerts a negative impact on human health. Testosterone (T) either directly or via its transformation into the more potent metabolite 5α-dihydrotestosterone (5α-DHT) or via aromatization into estradiol (E 2 ) modulates important biochemical signaling pathways of human physiology and plays a critical role in the growth and/or maintenance of functions in a host of tissues and organs. T and 5α-DHT play an important role in regulating physiology of the muscle, adipose tissue, liver, bone, and central nervous system, as well as reproductive and sexual functions. Thus, androgen deficiency (also referred to as hypogonadism) is a well-recognized medical condition and if remained untreated will have a negative impact on human health and quality of life.In this chapter, we have summarized the negative impact of T deficiency (TD) on a host of physiological functions including reduced lean body mass (LBM), increased fat mass (FM), increased insulin resistance (IR), metabolic syndrome (MetS) and adiposity, reduced bone mineral density (BMD), anemia, sexual dysfunction, and reduced quality of life and increased mortality. In addition, we discuss another critical aspect of unrecognized form of androgen deficiency resulting from inhibition of 5α-reductases with drugs, such as finasteride and dutasteride, to block transformation of T into 5α-DHT in the course of treatment of benign prostatic hyperplasia (BPH) and male pattern hair loss, also known as androgenetic alopecia (AGA). The negative impact of drugs that inhibit transformation of T to 5α-DHT by 5α-reductases on metabolic function is manifested in fat accumulation in the liver, which may predispose to nonalcoholic fatty liver disease (NAFLD). Also, inhibition of 5α-DHT formation increases glucose synthesis and reduces glucose disposal potentially contributing to hyperglycemia, IR, and elevated activities of liver function enzymes concomitant with reduction in circulating T levels, worsening erectile dysfunction (ED), and reduced quality of life.Although we have attempted to summarize the current literature pertaining to this critical topic "androgen deficiency" and its impact on men's health and quality of life, there remain many gaps in the knowledge regarding the biochemical pathways that are involved in the pathophysiology of androgen deficiency. We wish to clearly state that there are areas of controversies, including whether age-related androgen deficiency (functional hypogonadism) merits treatment and whether T therapy provided real proven benefits. Finally, considerable debate exists with respect to the potential and purported cardiovascular (CV) risks of treating TD with exogenous T. For brevity sake, we will not discuss in detail the benefits of T therapy in men with TD since this topic is comprehensively covered by Dr. F. Saad's chapter in this book, entitled "Testosterone Therapy and Glucose Homeostasis in Men with Testosterone Deficiency (Hypogonadism)."We have made a concerted effort to address the controversy of T therapy in men with TD in the discussion. However, we wish to acknowledge that these issues will remain a matter of debate for some time to come. Only with advances in fundamental basic science and clinical research, some of these controversial issues may be laid to rest. Nevertheless, we believe that there is considerable body of credible evidence to suggest that T therapy of men with TD is safe and effective and provides a host of health benefits and therefore merits considerations in men with TD, irrespective of the underlying cause or etiology. An additional aspect of androgen deficiency is the drug-induced reduction in 5α-DHT levels by the use of 5α-reductase inhibitors. We also believe that physicians prescribing 5α-reductase inhibitors (i.e., finasteride or dutasteride) for relief of BPH symptoms or treatment of hair loss should engage their patients in a productive discussion regarding the potential adverse side effects of these medications on their overall health and quality of life.

Splicing Factor Prp8 Interacts With NES(AR) and Regulates Androgen Receptor in Prostate Cancer Cells.

PubMed

Wang, Dan; Nguyen, Minh M; Masoodi, Khalid Z; Singh, Prabhpreet; Jing, Yifeng; O'Malley, Katherine; Dar, Javid A; Dhir, Rajiv; Wang, Zhou

2015-12-01

Androgen receptor (AR) plays a pivotal role in the development of primary as well as advanced castration-resistant prostate cancer. Previous work in our lab identified a novel nuclear export signal (NES) (NES(AR)) in AR ligand-binding domain essential for AR nucleocytoplasmic trafficking. By characterizing the localization of green fluorescence protein (GFP)-tagged NES(AR), we designed and executed a yeast mutagenesis screen and isolated 7 yeast mutants that failed to display the NES(AR) export function. One of those mutants was identified as the splicing factor pre-mRNA processing factor 8 (Prp8). We further showed that Prp8 could regulate NES(AR) function using short hairpin RNA knockdown of Prp8 coupled with a rapamycin export assay in mammalian cells and knockdown of Prp8 could induce nuclear accumulation of GFP-tagged AR in PC3 cells. Prp8 expression was decreased in castration-resistant LuCaP35 xenograft tumors as compared with androgen-sensitive xenografts. Laser capture microdissection and quantitative PCR showed Prp8 mRNA levels were decreased in human prostate cancer specimens with high Gleason scores. In prostate cancer cells, coimmunoprecipitation and deletion mutagenesis revealed a physical interaction between Prp8 and AR mainly mediated by NES(AR). Luciferase assay with prostate specific antigen promoter-driven reporter demonstrated that Prp8 regulated AR transcription activity in prostate cancer cells. Interestingly, Prp8 knockdown also increased polyubiquitination of endogenous AR. This may be 1 possible mechanism by which it modulates AR activity. These results show that Prp8 is a novel AR cofactor that interacts with NES(AR) and regulates AR function in prostate cancer cells.

The Bcl-2-Beclin 1 interaction in (-)-gossypol-induced autophagy versus apoptosis in prostate cancer cells.

PubMed

Lian, Jiqin; Karnak, David; Xu, Liang

2010-11-01

Bcl-2 is a key dual regulator of autophagy and apoptosis, but how the level of Bcl-2 influences the cellular decision between autophagy and apoptosis is unclear. The natural BH3-mimetic (-)-gossypol preferentially induces autophagy in androgen-independent (AI) prostate cancer cells that have high levels of Bcl-2 and are resistant to apoptosis, whereas apoptosis is preferentially induced in androgen-dependent or -independent cells with low Bcl-2. (-)-Gossypol induces autophagy via blocking Bcl-2-Beclin 1 interaction at the endoplasmic reticulum (ER), together with downregulating Bcl-2, upregulating Beclin 1 and activating the autophagic pathway. Furthermore, (-)-gossypol-induced autophagy is Beclin 1- and Atg5-dependent. These results provide new insights into the mode of cell death induced by Bcl-2 inhibitors, which could facilitate the rational design of clinical trials by selecting patients who are most likely to benefit from the Bcl-2-targeted molecular therapy.

Aberrant AR Signaling as a Function of Declining Androgen

DTIC Science & Technology

2006-08-01

Prescott J, Henderson M, Tilley WD, Coetzee GA. GRIP1 mediates the interaction between the amino- and carboxyl-termini of the androgen receptor. Biol...involve AR occupancy of the PSA locus. Can. Res. 65:8003-8008, 2005. Prescott , J. Coetzee, GA: Molecular Chaperones throughout the life cycle of...for Microbiology . All Rights Reserved. Locus-Wide Chromatin Remodeling and Enhanced Androgen Receptor-Mediated Transcription in Recurrent Prostate

Comparative anti-androgenic actions of vinclozolin and flutamide on transgenerational adult onset disease and spermatogenesis.

PubMed

Anway, Matthew D; Rekow, Stephen S; Skinner, Michael K

2008-10-01

Exposure of gestating female rats to the anti-androgenic endocrine disruptor vinclozolin has been shown to induce transgenerational adult onset disease phenotypes. The current study, was designed to compare the actions of vinclozolin to the known anti-androgenic compound flutamide. The gestating female rats were exposed to intraperitoneal injections during embryonic day 8-14 (E8-E14) to 100mg/kg/day vinclozolin or flutamide at either 5mg or 20mg/kg/day. As previously observed, vinclozolin induced a transgenerational testis phenotype of increased spermatogenic cell apoptosis and decreased epididymal sperm number. In contrast, the flutamide exposures resulted in a testis phenotype of increased spermatogenic cell apoptosis and decreased epididymal sperm numbers in the F1 generation only, and not the F2 and F3 generation adult males. Interestingly, some of the low dose (5mg/kg) flutamide F2 generation offspring developed spinal agenesis and supernummery development (polymelia) of limbs. Although the actions of vinclozolin and flutamide appear similar in the F1 generation males, the transgenerational effects of vinclozolin do not appear to be acting through the same anti-androgenic mechanism as flutamide.

Comparative anti-androgenic actions of vinclozolin and flutamide on transgenerational adult onset disease and spermatogenesis

PubMed Central

Anway, Matthew D.; Rekow, Stephen S.; Skinner, Michael K.

2017-01-01

Exposure of gestating female rats to the anti-androgenic endocrine disruptor vinclozolin has been shown to induce transgenerational adult onset disease phenotypes. The current study, was designed to compare the actions of vinclozolin to the known anti-androgenic compound flutamide. The gestating female rats were exposed to intraperitoneal injections during embryonic day 8–14 (E8–E14) to 100 mg/kg/day vinclozolin or flutamide at either 5mg or 20 mg/kg/day. As previously observed, vinclozolin induced a transgenerational testis phenotype of increased spermatogenic cell apoptosis and decreased epididymal sperm number. In contrast, the flutamide exposures resulted in a testis phenotype of increased spermatogenic cell apoptosis and decreasedepididymal spermnumbers in the F1 generation only, and not the F2 and F3 generation adult males. Interestingly, some of the lowdose (5 mg/kg) flutamide F2 generation offspring developed spinal agenesis and supernummery development (polymelia) of limbs. Although the actions of vinclozolin and flutamide appear similar in the F1 generation males, the transgenerational effects of vinclozolin do not appear to be acting through the same anti-androgenic mechanism as flutamide. PMID:18762243

Effects of HO-/MeO-PBDEs on androgen receptor: in vitro investigation and helix 12-involved MD simulation.

PubMed

Wang, Xiaoxiang; Yang, Huaiyu; Hu, Xinxin; Zhang, Xiaowei; Zhang, Qiansen; Jiang, Hualiang; Shi, Wei; Yu, Hongxia

2013-10-15

Hydroxylated and methoxylated polybrominated diphenyl ethers (HO-/MeO-PBDEs) have received increasing attention for their potential endocrine disrupting activities and widely environmental distribution. However, little information is available for the anti-androgenic activities, and the molecular mechanism of interactions with androgen receptor (AR) is not fully understood. In the present study, cell line assay and computational simulation were integrated to systematically explore the molecular mechanism of interactions between chemicals and AR. The metabolites with similar molecular structures exhibited different anti-androgenic activity while none of them showed androgenic activity. According to the multisystem molecular dynamics simulation, minute differences in the structure of ligands induced dramatic different conformational transition of AR-ligand binding domain (LBD). The Helix12 (H12) component of active ligands occupied AR-LBD could become stable, but this component continued to fluctuate in inactive ligands occupied AR-LBD. Settling time and reposition of H12 obtained in dynamics process are important factors governing anti-androgenic activities. The related settling times were characteristic of anti-androgenic potencies of the tested chemicals. Overall, in our study, the stable reposition of H12 is characterized as a computational mark for identifying AR antagonists from PBDE metabolites, or even other various environmental pollutants.

Artificial masculinization in tilapia involves androgen receptor activation.

PubMed

Golan, Matan; Levavi-Sivan, Berta

2014-10-01

Estrogens have a pivotal role in natural female sexual differentiation of tilapia while lack of steroids results in testicular development. Despite the fact that androgens do not participate in natural sex differentiation, synthetic androgens, mainly 17-α-methyltestosterone (MT) are effective in the production of all-male fish in aquaculture. The sex inversion potency of synthetic androgens may arise from their androgenic activity or else as inhibitors of aromatase activity. The current study is an attempt to differentiate between the two alleged activities in order to evaluate their contribution to the sex inversion process and aid the search for novel sex inversion agents. In the present study, MT inhibited aromatase activity, when applied in vitro as did the non-aromatizable androgen dihydrotestosterone (DHT). In comparison, exposure to fadrozole, a specific aromatase inhibitor, was considerably more effective. Androgenic activity of MT was evaluated by exposure of Sciaenochromis fryeri fry to the substance and testing for the appearance of blue color. Flutamide, an androgen antagonist, administered concomitantly with MT, reduced the appearance of the blue color and the sex inversion potency of MT in a dose-dependent manner. In tilapia, administration of MT, fadrozole or DHT resulted in efficient sex inversion while flutamide reduced the sex inversion potency of all three compounds. In the case of MT and DHT the decrease in sex inversion efficiency caused by flutamide is most likely due to the direct blocking of the androgen binding to its cognate receptor. The negative effect of flutamide on the efficiency of the fadrozole treatment may indicate that the masculinizing activity of fadrozole may be attributed to excess, un-aromatized, androgens accumulated in the differentiating gonad. The present study shows that when androgen receptors are blocked, there is a reduction in the efficiency of sex inversion treatments. Our results suggest that in contrast to natural sex differentiation, during sex inversion treatments, androgens, either endogenous or exogenous, participate in inducing testicular differentiation. Copyright © 2014 Elsevier Inc. All rights reserved.

The Role of Retinal Determination Gene Network (RDGN) in Hormone Signaling Transduction and Prostate Tumorigenesis

DTIC Science & Technology

2012-10-01

support with our hypothesis, expressions of AR co-repressors (48-50), HDAC1, HDAC3 or SirT1 inhibit the ligand-induced AR activation at different...signaling and androgen-dependent growth. We hypothesis that DACH1/Six1/Eya pathway is an endogenous regulator of AR trans- activation and contributes to...mechanism. Inhibitory function of Eya1 on AR transactivation required a phosphates activity and could be enhanced by ectopic expression of co-repressors

Change to either a nonandrogenic or androgenic progestin-containing oral contraceptive preparation is associated with improved sexual function in women with oral contraceptive-associated sexual dysfunction.

PubMed

Davis, Susan R; Bitzer, Johannes; Giraldi, Annamaria; Palacios, Santiago; Parke, Susanne; Serrani, Marco; Mellinger, Uwe; Nappi, Rossella E

2013-12-01

It is a commonly held belief that combined oral contraceptive (COC) pills containing an androgenic progestin may be less likely to impair sexual function than COCs containing an anti-androgenic progestin. The study aims to compare the effects of a COC containing a progestin with an anti-androgenic profile (estradiol valerate [E2 V]/dienogest [DNG]) to that of one with an androgenic progestin (ethinyl estradiol [EE]/levonorgestrel [LNG]) on sexual function in women with COC-associated sexual dysfunction. In this multicenter, randomized, double-blind, noninferiority study, women with COC-associated female sexual dysfunction (FSD) were randomized to E2 V/DNG or EE/LNG for six cycles. The primary outcome was the change in the sum of Female Sexual Function Index (FSFI) desire and arousal component scores between baseline and cycle 6. Secondary outcome measures included changes to the FSFI domains, the Female Sexual Distress Scale (FSDS-R), Vaginal Health Assessment, the Atrophy Symptom Questionnaire, and the Psychological General Well Being Index over six treatment cycles. The main outcome is the change in the sum of FSFI desire and arousal component scores between baseline and cycle 6. Of 276 women screened, 213 received treatment and 191 completed the study. The mean increase in the sum of FSFI desire and arousal component scores was 5.90 (standard deviation [SD] 5.45) for E2 V/DNG and 5.79 (SD 6.17) for EE/LNG (change from baseline P < 0.0001, both groups). Both treatments showed equal efficacy and were associated with improvements in all domains of the FSFI, with no between-group differences. Both COCs reduced the distress associated with FSD, as indicated by reduced FSDS-R scores. In women with COC-associated FSD, switching to either E2 V/DNG or EE/LNG was associated with equivalent improvements in symptoms, challenging the perception that COCs containing anti-androgenic progestins have a detrimental effect on sexual function relative to those containing androgenic progestins. © 2013 International Society for Sexual Medicine.

Interplay Between Cytoplasmic and Nuclear Androgen Receptor Splice Variants Mediate Castration Resistance

PubMed Central

Zhan, Yang; Zhang, Guanyi; Wang, Xiaojie; Qi, Yanfeng; Bai, Shanshan; Li, Dongying; Ma, Tianfang; Sartor, Oliver; Flemington, Erik K.; Zhang, Haitao; Lee, Peng; Dong, Yan

2016-01-01

Androgen receptor splice variants (AR-Vs) are implicated in resistance of prostate cancer to androgen-directed therapies. When expressed alone in cells, some AR-Vs (e.g., AR-V7) localize primarily to the nucleus, whereas others (e.g., AR-V1, AR-V4, and AR-V6) localize mainly to the cytoplasm. Significantly, the latter are often co-expressed with the nucleus-predominant AR-Vs and the full-length AR (AR-FL). An important question to be addressed is whether the cytoplasmic-localized AR-Vs play a role in castration-resistant prostate cancer (CRPC) through interaction with the nucleus-predominant AR-Vs and AR-FL. Here, it is demonstrated that AR-V1, -V4, and -V6 can dimerize with both AR-V7 and AR-FL. Consequently, AR-V7 and androgen-bound AR-FL induced nuclear localization of AR-V1, -V4, and -V6, and these variants, in turn, mitigated the ability of the anti-androgen enzalutamide to inhibit androgen-induced AR-FL nuclear localization. Interestingly, the impact of nuclear localization of AR-V4 and -V6 on AR transactivation differs from that of AR-V1. Nuclear localization leads to an increased ability of AR-V4 and -V6 to transactivate both canonical AR targets and AR-V-specific targets and to confer castration-resistant cell growth. However, while AR-V1, which lacks inherent transcriptional activity, appears to activate AR-FL in an androgen-independent manner, it significantly antagonizes AR-V7 transactivation. Together, these data demonstrate that the complex interactions among different AR-Vs and AR-FL play a significant role in castration resistant disease. Implications This study suggests important consequences for clinical castration resistance due to simultaneous expression of AR-FL and AR-Vs in patient tumors and suggests that dissecting these interactions should help develop effective strategies to disrupt AR-V signaling. PMID:27671337

A study of the prostate, androgens and sexual activity of male rats

PubMed Central

Hernandez, Maria Elena; Soto-Cid, Abraham; Aranda-Abreu, Gonzalo E; Díaz, Rosaura; Rojas, Fausto; Garcia, Luis I; Toledo, Rebeca; Manzo, Jorge

2007-01-01

Background The prostate is a sexual gland that produces important substances for the potency of sperm to fertilize eggs within the female reproductive tract, and is under complex endocrine control. Taking advantage of the peculiar behavioral pattern of copulating male rats, we developed experimental paradigms to determine the influence of sexual behavior on the level of serum testosterone, prostate androgen receptors, and mRNA for androgen receptors in male rats displaying up to four consecutive ejaculations. Methods The effect of four consecutive ejaculations was investigated by determining levels of (i) testosterone in serum by solid phase RIA, (ii) androgen receptors at the ventral prostate with Western Blots, and (iii) androgen receptors-mRNA with RT-PCR. Data were analyzed with a one-way ANOVA followed by a post hoc application of Dunnett's test if required. Results The constant execution of sexual behavior did not produce any change in the weight of the ventral prostate. Serum testosterone increased after the second ejaculation, and remained elevated even after four ejaculations. The androgen receptor at the ventral prostate was higher after the first to third ejaculations, but returned suddenly to baseline levels after the fourth ejaculation. The level of mRNA increased after the first ejaculation, continued to increase after the second, and reached the highest peak after the third ejaculation; however, it returned suddenly to baseline levels after the fourth ejaculation. Conclusion Four consecutive ejaculations by sexually experienced male rats had important effects on the physiological responses of the ventral prostate. Fast responses were induced as a result of sexual behavior that involved an increase and decrease in androgen receptors after one and four ejaculations, respectively. However, a progressive response was observed in the elevation of mRNA for androgen receptors, which also showed a fast decrease after four ejaculations. All of these changes with the prostate gland occurred in the presence of a sustained elevation of testosterone in the serum that started after two ejaculations. A consideration of these fast-induced changes suggests that the nerve supply plays a key role in prostate physiology during the sexual behavior of male rats. PMID:17367532

SPECIES DIFFERENCES IN ANDROGEN AND ESTROGEN RECEPTOR STRUCTURE AND FUNCTION AMONG VERTEBRATES AND INVERTEBRATES: INTERSPECIES EXTRAPOLATIONS REGARDING ENDOCRINE DISRUPTING CHEMICALS

EPA Science Inventory

Species Differences in Androgen and Estrogen Receptor Structure and Function Among Vertebrates and Invertebrates: Interspecies Extrapolations regarding Endocrine Disrupting Chemicals
VS Wilson1, GT Ankley2, M Gooding 1,3, PD Reynolds 1,4, NC Noriega 1, M Cardon 1, P Hartig1,...

Impaired helix 12 dynamics due to proline 892 substitutions in the androgen receptor are associated with complete androgen insensitivity.

PubMed

Elhaji, Youssef A; Stoica, Ileana; Dennis, Sheldon; Purisima, Enrico O; Lumbroso, Rose; Beitel, Lenore K; Trifiro, Mark A

2006-03-15

Structural studies of the ligand-binding domain (LBD) of several steroid receptors have revealed that the dynamic properties of the C-terminal helix 12 (H12) are the major determinant of the activation mode of these receptors. H12 exhibits high mobility and different conformations in the absence of ligand. Upon ligand binding, H12 is stabilized in a precise position to seal the ligand-binding pocket and finalize the assembly of the activation function (AF-2) domain. In this study, we investigated the role of the conserved proline 892 of the androgen receptor (AR) in directing the dynamic location and orientation of the AR-H12. We used a combined approach including kinetic and biochemical assays with molecular dynamic simulations to analyze two substitutions (P892A and P892L) identified in individuals with complete androgen insensitivity syndrome. Our analyses revealed distinct mechanisms by which these substitutions impair H12 function resulting in severely defective receptors. The AR-P892A receptor exhibited reduced ligand binding and transactivational potential because of an increased flexibility in H12. The AR-P892L substitution renders the receptor inactive due to a distorted, unstructured and misplaced H12. To confirm the mutants' inability to stabilize H12 in an active position, we have developed a novel in vivo assay to evaluate the accessibility of the H12-docking site on the AR-LBD surface. An extrinsic AR-H12 peptide was able to interact with wild-type and mutant LBDs in the absence of ligand. Ligand-induced proper positioning of the intrinsic H12 of wild-type AR prevented these interactions, whereas the misplacement of the mutants' H12 did not. Proline at this position may be critical for H12 dynamics not only in the AR, but also in other nuclear receptors where this proline is conserved.

Adolescent Anabolic/Androgenic Steroids: Aggression and Anxiety During Exposure Predict Behavioral Responding During Withdrawal in Syrian Hamsters (Mesocricetus auratus)

PubMed Central

Ricci, Lesley A.; Morrison, Thomas R.; Melloni, Richard H.

2014-01-01

In the U.S. and worldwide anabolic/androgenic steroid use remains high in the adolescent population. This is concerning given that anabolic/androgenic steroid use is associated with a higher incidence of aggressive behavior during exposure and anxiety during withdrawal. This study uses pubertal Syrian hamsters (Mesocricetus auratus) to investigate the hypothesis that an inverse behavioral relationship exists between anabolic/androgenic steroid-induced aggression and anxiety across adolescent exposure and withdrawal. In the first experiment, we examined aggression and anxiety during adolescent anabolic/androgenic steroid exposure and withdrawal. Adolescent anabolic/androgenic steroid administration produced significant increases in aggression and decreases in anxiety during the exposure period followed by significant decreases in aggression and increases in anxiety during anabolic/androgenic steroid withdrawal. In a second experiment, anabolic/androgenic steroid exposed animals were separated into groups based on their aggressive response during the exposure period and then tested for anxiety during exposure and then for both aggression and anxiety during withdrawal. Data were analyzed using a within subjects repeated measures predictive analysis. Linear regression analysis revealed that the difference in aggressive responding between the anabolic/androgenic steroid exposure and withdrawal periods was a significant predictor of differences in anxiety for both days of testing. Moreover, the combined data suggest that the decrease in aggressive behavior from exposure to withdrawal predicts an increase in anxiety-like responding within these same animals during this time span. Together these findings indicate that early anabolic/androgenic steroid exposure has potent aggression- and anxiety- eliciting effects and that these behavioral changes occur alongside a predictive relationship that exists between these two behaviors over time. PMID:24126136

Androgenic effect of honeybee drone milk in castrated rats: roles of methyl palmitate and methyl oleate.

PubMed

Seres, A B; Ducza, E; Báthori, M; Hunyadi, A; Béni, Z; Dékány, M; Hajagos-Tóth, J; Verli, J; Gáspár, Róbert

2014-04-28

Numerous honeybee (Apis mellifera) products have been used in traditional medicine to treat infertility and to increase vitality in both men and women. Drone milk (DM) is a relatively little-known honeybee product with a putative sexual hormone effect. The oestrogenic effect of a fraction of DM has recently been reported in rats. However, no information is available on the androgenic effects of DM. The purpose of the present study was to determine the androgen-like effect of DM in male rats and to identify effective compounds. A modified Hershberger assay was used to investigate the androgenic effect of crude DM, and the plasma level of testosterone was measured. The prostatic mRNA and protein expression of Spot14-like androgen-inducible protein (SLAP) were also examined with real-time PCR and Western blot techniques. GC-MS and NMR spectroscopic investigations were performed to identify the active components gained by bioactivity-guided fractionation. The crude DM increased the relative weights of the androgen-dependent organs and the plasma testosterone level in castrated rats and these actions were flutamide-sensitive. DM increased the tissue mRNA and protein level of SLAP, providing further evidence of its androgen-like character. After bioactivity-guided fractionation, two fatty acid esters, methyl palmitate (MP) and methyl oleate (MO), were identified as active compounds. MP alone showed an androgenic effect, whereas MO increased the weight of androgen-sensitive tissues and the plasma testosterone level only in combination. The experimental data of DM and its active compounds (MO and MP) show androgenic activity confirming the traditional usage of DM. DM or MP or/and MO treatments may project a natural mode for the therapy of male infertility. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Primary Xenografts of Human Prostate Tissue as a Model to Study Angiogenesis Induced by Reactive Stroma

PubMed Central

Montecinos, Viviana P.; Godoy, Alejandro; Hinklin, Jennifer; Vethanayagam, R. Robert; Smith, Gary J.

2012-01-01

Characterization of the mechanism(s) of androgen-driven human angiogenesis could have significant implications for modeling new forms of anti-angiogenic therapies for CaP and for developing targeted adjuvant therapies to improve efficacy of androgen-deprivation therapy. However, models of angiogenesis by human endothelial cells localized within an intact human prostate tissue architecture are until now extremely limited. This report characterizes the burst of angiogenesis by endogenous human blood vessels in primary xenografts of fresh surgical specimens of benign prostate or prostate cancer (CaP) tissue that occurs between Days 6–14 after transplantation into SCID mice pre-implanted with testosterone pellets. The wave of human angiogenesis was preceded by androgen-mediated up-regulation of VEGF-A expression in the stromal compartment. The neo-vessel network anastomosed to the host mouse vascular system between Days 6–10 post-transplantation, the angiogenic response ceased by Day 15, and by Day 30 the vasculature had matured and stabilized, as indicated by a lack of leakage of serum components into the interstitial tissue space and by association of nascent endothelial cells with mural cells/pericytes. The angiogenic wave was concurrent with the appearance of a reactive stroma phenotype, as determined by staining for α-SMA, Vimentin, Tenascin, Calponin, Desmin and Masson's trichrome, but the reactive stroma phenotype appeared to be largely independent of androgen availability. Transplantation-induced angiogenesis by endogenous human endothelial cells present in primary xenografts of benign and malignant human prostate tissue was preceded by induction of androgen-driven expression of VEGF by the prostate stroma, and was concurrent with and the appearance of a reactive stroma phenotype. Androgen-modulated expression of VEGF-A appeared to be a causal regulator of angiogenesis, and possibly of stromal activation, in human prostate xenografts. PMID:22303438

Resveratrol Reduces Steroidogenesis in Rat Ovarian Theca-Interstitial Cells: The Role of Inhibition of Akt/PKB Signaling Pathway

PubMed Central

Ortega, Israel; Villanueva, Jesus A.; Wong, Donna H.; Cress, Amanda B.; Sokalska, Anna; Stanley, Scott D.

2012-01-01

Polycystic ovary syndrome is characterized by theca-interstitial hyperplasia and increased expression of steroidogenic genes, leading to excessive androgen production. Resveratrol, a natural polyphenol, promotes apoptosis and reduces rat theca-interstitial cell growth, in part by inhibiting the mevalonate pathway and decreasing the availability of substrates of isoprenylation [farnesyl-pyrophosphate (FPP) and geranylgeranyl-pyrophosphate (GGPP)]. This study evaluated the effect of resveratrol on rat theca-interstitial cell steroidogenesis. Because resveratrol may activate sirtuins, this study also investigated whether steroidogenesis was affected by sirtuin inhibitors (nicotinamide, sirtinol). Theca-interstitial cells were cultured with or without resveratrol (1–10 μm), GGPP (30 μm), FPP (30 μm), nicotinamide (1 mm), and/or sirtinol (10 μm). Resveratrol did not affect progesterone levels but reduced androgen production in a concentration-dependent fashion (androstenedione by up to 78% and androsterone by up to 76%). This inhibitory effect correlated with a decrease in mRNA expression of genes regulating androgen production, especially Cyp17a1 (by up to 73%). GGPP and FPP had no effect on androgen levels and Cyp17a1 mRNA levels and did not alter the effects induced by resveratrol. Similarly, sirtuin inhibitors did not reverse resveratrol-induced inhibition of steroidogenesis. However, resveratrol decreased activity of serine-threonine kinase/protein kinase B pathway, a cell-signaling pathway involved in ovarian steroidogenesis. The present findings indicate that resveratrol reduces androgen production primarily by inhibiting Cyp17a1 mRNA expression, and this inhibition may be mediated, in part, by blocking the activity of the serine-threonine kinase/protein kinase B pathway. These findings may be of clinical relevance to conditions associated with excessive production of androgens by theca cells, such as polycystic ovary syndrome. PMID:22719052

Synergistic activation of the androgen receptor by bombesin and low-dose androgen.

PubMed

Dai, Jie; Shen, Ruoqian; Sumitomo, Makoto; Stahl, Rosalyn; Navarro, Daniel; Gershengorn, Marvin C; Nanus, David M

2002-07-01

Neuropeptide growth factors such as bombesinare implicated in progression to androgen-independent prostate cancer (PC). We examined the impact of bombesin on androgen receptor (AR)-mediated gene expression. The AR together with the AR-responsive probasin ARR(3)tk-luc or PSA-pPUE-ELB-luc promoter was cotransfected into Swiss 3T3 and PC-3 cells, both of which express high-affinity bombesin receptors; the cells were incubated with bombesin (0-50 nM) and dihydrotestosterone (DHT; 0-10 nM), and luciferase activities were measured. DHT increased transcription approximately 40-fold at doses of 1 and 10 nM but had no effect at 10 pM. Bombesin alone, or with 1 or 10 nM DHT, did not further increase transcription. However, 5 nM bombesin and 10 pM DHT, doses that by themselves had no effect, resulted in a approximately 20 fold increase in transcription (P < 0.005). This synergistic effect was blocked by bombesin receptor antagonists and recombinant neutral endopeptidase, which hydrolyzes bombesin. Bombesin and DHT together also increased binding of nuclear extracts from PC-3 cells transfected with AR to a consensus androgen response element in mobility shift assays and increased the level of secreted prostate-specific antigen in LNCaP cell supernatant compared with DHT or bombesin alone. Immunoprecipitation of AR from (32)P-labeled LNCaP cells revealed that 5 nM bombesin + 10 pM DHT induced AR phosphorylation comparable with 1 nM DHT, whereas bombesin or 10 pM DHT alone did not. These data indicate that bombesin can synergize with low (castrate) levels of DHT to induce AR-mediated transcription and suggest that neuropeptides promote AR-mediated signaling in androgen-independent prostate cancer.

A child with pituitary gigantism and precocious adrenarche: does GH and/or PRL advance the onset of adrenarche?

PubMed

Iwatani, N; Kodama, M; Seto, H

1992-06-01

We describe a female child with pituitary gigantism and precocious adrenarche. From two years of age she showed unusual overgrowth, and at 5 years old she was 133.5 cm (+ 5.5 SD) tall and weighed 40.5 kg. Her precocious manifestations were public hair, acne vulgaris, hirsutism, and advanced bone age. Endocrinological examination revealed markedly increased serum growth hormone (GH) and prolactin (PRL), which responded paradoxically to a TRH test. In addition, the concentrations of serum dehydroepiandrosterone (DHA) and its sulfate (DHAS) were increased to adult levels, moving in accordance with changes in ACTH, which suggested that these androgens were secreted from the adrenal glands functionally. These androgens seemed to be responsible for her partial precocity. Prior reports have suggested that GH and/or PRL overproduction might have played a role in the induction of adrenarche. Also, in previous reports of 9 gigantism patients under 10 years old, the manifestation of precocious adrenarche was suggested in 8. Further investigation of the influence of GH and PRL on adrenal androgen production in children with pituitary gigantism is required. On the other hand, in short children with normal GH secretion, attention should be paid to whether or not the GH therapy in early childhood induces precocious adrenarche.

Androgen receptor (AR) suppresses miRNA-145 to promote renal cell carcinoma (RCC) progression independent of VHL status

PubMed Central

Chen, Yuan; Sun, Yin; Rao, Qun; Xu, Hua; Li, Lei; Chang, Chawnshang

2015-01-01

Mutational inactivation of the VHL tumor suppressor plays key roles in the development of renal cell carcinoma (RCC), and mutated VHL-mediated VEGF induction has become the main target for the current RCC therapy. Here we identified a signal pathway of VEGF induction by androgen receptor (AR)/miRNA-145 as a new target to suppress RCC progression. Mechanism dissection revealed that AR might function through binding to the androgen receptor element (ARE) located on the promoter region of miRNA-145 to suppress p53's ability to induce expression of miRNA-145 that normally suppresses expression of HIF2α/VEGF/MMP9/CCND1. Suppressing AR with AR-shRNA or introducing exogenous miRNA-145 mimic can attenuate RCC progression independent of VHL status. MiR-145 mimic in preclinical RCC orthotopic xenograft mouse model revealed its efficacy in suppression of RCC progression. These results together identified signals by AR-suppressed miRNA-145 as a key player in the RCC progression via regulating HIF2α/VEGF/MMP9/CCND1 expression levels. Blockade of the newly identified signal by AR inhibition or miRNA-145 mimics has promising therapeutic benefit to suppress RCC progression. PMID:26304926

Androgens and menopause.

PubMed

Shulman, L P

2009-12-01

The cessation of ovarian sex steroidigenesis, either as result as surgical extirpation, certain medical therapies or the gradual cessation of ovarian function, leads to menopause with all its associated physiological, physical and lifestyle changes. The changing hormonal milieu of menopause is most commonly associated with declining levels of estrogens. However, ovarian senescence also results in declining levels of androgens. Indeed, it is the loss of physiological levels of estrogens and androgens that result in the varied signs and symptoms of menopause including vasomotor symptoms, bone mineral density loss, reduced interest in sex, alterations in mood and energy and hair loss, among others. This paper will provide a review of the role of androgens in the menopause and assess the potential of androgen therapies in the management of the menopause.

Selective Androgen Receptor Down-Regulators (SARDs): A New Prostate Cancer Therapy

DTIC Science & Technology

2007-10-01

PCa (9). Thus far, the techniques that have been used to down-regulate the AR include antisense oligonucleotides (10, 11), ribozyme treatments (12...Our findings suggest that ICI may present a useful treatment option for patients with AR-dependent PCa. Unlike the ribozyme , antisense, siRNA, or...Catalytic cleavage of the androgen receptor messenger RNA and functional inhibition of androgen receptor activity by a hammerhead ribozyme . Mol Endocrinol

The HSP90 inhibitor 17-PAG effectively inhibits the proliferation and migration of androgen-independent prostate cancer cells

PubMed Central

Peng, Ruixian; Li, Zhenyu; Lin, Zhiyuan; Wang, Yang; Wang, Wei; Hu, Bo; Wang, Xilong; Zhang, Jun; Wang, Yangyun; Zhou, Renyuan; Lu, Chunhua; Shen, Yuemao; Wang, Jifeng; Shi, Guowei

2015-01-01

Castration-resistant prostate cancer (CRPC) ultimately occurs after a period of treatment with androgen deprivation therapy. Furthermore, CRPC patients can only derive limited survival benefits from traditional cytotoxic drugs. HSP90, which is a molecular chaperone, plays a vital role in client protein processing and maintaining the function of cells. HSP90 is usually overexpressed in prostate cancer tissues, which makes it a potential target for managing prostate cancer. Geldanamycin (GA), which was recognized as the first natural HSP90 inhibitor, has demonstrated potent anti-tumor efficacy in large-scale pre-clinical studies, but its application in the clinic is not permitted due to its liver toxicity and unstable physical properties. In this study, we report a new GA derivative, 17-PAG (17-(propynylamino)-17-demethoxygeldanamycin), which demonstrates highly effective anti-tumor activity against androgen-independent prostate cancer cells. Treating cells with 17-PAG dose-dependently suppressed proliferation, reduced colony formation and induced apoptosis of DU-145/C4-2B cells. Moreover, 17-PAG suppressed the migration and invasion of DU-145/C4-2B cells by regulating epithelial mesenchymal transition (EMT). 17-PAG also downregulated the HSP90 client proteins, including Her2, EGFR, C-Raf, AKT, p-AKT, and CDK4. Animal assays confirmed that 17-PAG shows strong anti-tumor effects with no obvious organ toxicity in DU-145 cell xenografted nude mice. These results provide us with a potential target for treating androgen-independent prostate cancer in a safe and effective manner. PMID:26693070

Key Learnings from the Endocrine Disruptor Screening Program (EDSP) Tier 1 Rodent Uterotrophic and Hershberger Assays

PubMed Central

Marty, M Sue; O'Connor, John C

2014-01-01

In 2009, companies began screening compounds using the US Environmental Protection Agency's Endocrine Disruptor Screening Program (EDSP). EDSP has two tiers: Tier 1 includes 11 assays to identify compounds with potential endocrine activity. This article describes two laboratories' experiences conducting Tier 1 uterotrophic and Hershberger assays. The uterotrophic assay detects estrogen receptor agonists through increases in uterine weight. The advantages of the uterotrophic rat models (immature vs. adult ovariectomized) and exposure routes are discussed. Across 29 studies, relative differences in uterine weights in the vehicle control group and 17α-ethynylestradiol–positive control group were reasonably reproducible. The Hershberger assay detects androgen receptor (AR) agonists, antagonists, and 5α-reductase inhibitors through changes in accessory sex tissue (AST) weights. Across 23 studies, AST weights were relatively reproducible for the vehicle groups (baseline), testosterone propionate (TP) groups (androgenic response), and flutamide + TP groups (antiandrogenic response). In one laboratory, one and four compounds were positive in the androgenic and antiandrogenic portions of the assay, respectively. Each compound was also positive for AR binding. In the other laboratory, three compounds showed potential antiandrogenic activity, but each compound was negative for AR binding and did not fit the profile for 5α-reductase inhibition. These compounds induced hepatic enzymes that enhanced testosterone metabolism/clearance, resulting in lower testosterone and decreased capacity to maintain AST weights. The Hershberger androgenic and antiandrogenic performance criteria were generally attainable. Overall, the uterotrophic and Hershberger assays were easily adopted and function as described for EDSP screening, although the mode of action for positive results may not be easily determined. PMID:24515841

Effects of fenoterol on the skeletal system depend on the androgen level.

PubMed

Śliwiński, Leszek; Cegieła, Urszula; Pytlik, Maria; Folwarczna, Joanna; Janas, Aleksandra; Zbrojkiewicz, Małgorzata

2017-04-01

The role of sympathetic nervous system in the osseous tissue remodeling is not clear enough. The effects of fenoterol, a selective β 2 -adrenomimetic drug, on the skeletal system of normal and androgen deficient (orchidectomized) rats were studied in vivo. Osteoclastogenesis and mRNA expression in osteoblasts were investigated in vitro in mouse cell cultures. Fenoterol administered to animals with physiological androgen level unfavorably affected the skeletal system, damaging the bone microarchitecture. Androgen deficiency induced osteoporotic changes, and fenoterol protected the osseous tissue from consequences of androgen deficiency. The results of in vitro studies correlated with the in vivo observations. A significantly increased number of osteoclasts in bone marrow cell cultures to which testosterone and fenoterol were added simultaneously was demonstrated. In cultures without the addition of testosterone, fenoterol significantly inhibited osteoclastogenesis in comparison with control cultures. The results indicate the favorable action of fenoterol in conditions of testosterone deficiency, and its destructive influence upon the skeleton in the presence of androgens. The results confirm the key role of sympathetic nervous system in the regulation of bone remodeling. Copyright © 2016. Published by Elsevier Urban & Partner Sp. z o.o.

Computational Modeling and Simulation of Genital Tubercle Development

EPA Pesticide Factsheets

Hypospadias is a developmental defect of urethral tube closure that has a complex etiology involving genetic and environmental factors, including anti-androgenic and estrogenic disrupting chemicals; however, little is known about the morphoregulatory consequences of androgen/estrogen balance during genital tubercle (GT) development. Computer models that predictively model sexual dimorphism of the GT may provide a useful resource to translate chemical-target bipartite networks and their developmental consequences across the human-relevant chemical universe. Here, we describe a multicellular agent-based model of genital tubercle (GT) development that simulates urethrogenesis from the sexually-indifferent urethral plate stage to urethral tube closure. The prototype model, constructed in CompuCell3D, recapitulates key aspects of GT morphogenesis controlled by SHH, FGF10, and androgen pathways through modulation of stochastic cell behaviors, including differential adhesion, motility, proliferation, and apoptosis. Proper urethral tube closure in the model was shown to depend quantitatively on SHH- and FGF10-induced effects on mesenchymal proliferation and epithelial apoptosis??both ultimately linked to androgen signaling. In the absence of androgen, GT development was feminized and with partial androgen deficiency, the model resolved with incomplete urethral tube closure, thereby providing an in silico platform for probabilistic prediction of hypospadias risk across c

Critical appraisal of androgen use in hereditary angioedema: a systematic review.

PubMed

Riedl, Marc A

2015-04-01

To provide an objective basis for evaluating the risk-benefit ratio of long-term androgen use in patients with hereditary angioedema (HAE). PubMed was searched with no time limitations using the keywords hereditary angioedema or angio-oedema combined with danazol, stanozolol, and androgen. Qualifying articles were English-language reports of androgen use in patients with HAE, with relevant safety and/or efficacy information. Reports were categorized according to level of evidence (LOE). The search process identified 153 citations, 63 of which contained relevant information; 2 additional publications were identified while other citations were being reviewed. Fifteen LOE 2 studies and multiple LOE 4 reports provided efficacy data, confirming a high level of prophylactic efficacy for androgen therapy in HAE, with occasional reports of poor prophylactic response. Common adverse events include weight gain, menstrual irregularities, virilization, headaches, myalgias or cramps, mood changes, and elevations in creatine phosphokinase level, liver function test results, and serum lipid level. The risk of adverse events is often correlated with dose and/or treatment duration. Rare cases of hepatic adenomas and hepatocellular carcinoma associated with long-term androgen use often had no preceding changes in liver function test results. Androgen therapy may be effective for most patients with HAE; however, potential risks and adverse effects must be carefully considered and discussed with patients when considering options for long-term HAE prophylaxis. Copyright © 2015 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

EFFECTS OF ENVIRONMENTAL ANTIANDROGENS IN EXPERIMENTAL ANIMALS

EPA Science Inventory

In mammals, the androgens testosterone (T) and dihydrotestosterone (DHT) are critical for normal male reproductive development and function. In humans, drugs that act as androgen receptor (AR) agonists and antagonists or inhibit fetal steroidogenesis can cause pseudohermaphrodi...

Gonadectomy reduces the density of androgen receptor-immunoreactive neurons in male rat's hippocampus: testosterone replacement compensates it.

PubMed

Moghadami, Sajjad; Jahanshahi, Mehrdad; Sepehri, Hamid; Amini, Hossein

2016-01-28

In the present study, the role of gonadectomy on memory impairment and the density of androgen receptor-immunoreactive neurons in rats' hippocampus as well as the ability of testosterone to compensate of memory and the density of androgen receptors in the hippocampus was evaluated. Adult male rats (except intact-no testosterone group) were bilaterally castrated, and behavioral tests performed 2 weeks later. Animals bilaterally cannulated into lateral ventricles and then received testosterone (10, 40 and 120 µg/0.5 µl DMSO) or vehicle (DMSO; 0.5 µl) for gonadectomized-vehicle group, 30 min before training in water maze test. The androgen receptor-immunoreactive neurons were detected by immunohistochemical technique in the hippocampal areas. In the gonadectomized male rats, a memory deficit was found in Morris water maze test on test day (5th day) after DMSO administration. Gonadectomy decreased density of androgen receptor-immunoreactive neurons in the rats' hippocampus. The treatment with testosterone daily for 5 days attenuated memory deficits induced by gonadectomy. Testosterone also significantly increased the density of androgen receptor-immunoreactive neurons in the hippocampal areas. The intermediate dose of this hormone (40 µg) appeared to have a significant effect on spatial memory and the density of androgen receptor-immunoreactive neurons in gonadectomized rats' hippocampus. The present study suggests that testosterone can compensate memory failure in gonadectomized rats. Also testosterone replacement can compensate the reduction of androgen receptor-immunoreactive neurons density in the rats' hippocampus after gonadectomy.

Epigenetic repression of regulator of G-protein signaling 2 promotes androgen-independent prostate cancer cell growth.

PubMed

Wolff, Dennis W; Xie, Yan; Deng, Caishu; Gatalica, Zoran; Yang, Mingjie; Wang, Bo; Wang, Jincheng; Lin, Ming-Fong; Abel, Peter W; Tu, Yaping

2012-04-01

G-protein-coupled receptor (GPCR)-stimulated androgen-independent activation of androgen receptor (AR) contributes to acquisition of a hormone-refractory phenotype by prostate cancer. We previously reported that regulator of G-protein signaling (RGS) 2, an inhibitor of GPCRs, inhibits androgen-independent AR activation (Cao et al., Oncogene 2006;25:3719-34). Here, we show reduced RGS2 protein expression in human prostate cancer specimens compared to adjacent normal or hyperplastic tissue. Methylation-specific PCR analysis and bisulfite sequencing indicated that methylation of the CpG island in the RGS2 gene promoter correlated with RGS2 downregulation in prostate cancer. In vitro methylation of this promoter suppressed reporter gene expression in transient transfection studies, whereas reversal of this promoter methylation with 5-aza-2'-deoxycytidine (5-Aza-dC) induced RGS2 reexpression in androgen-independent prostate cancer cells and inhibited their growth under androgen-deficient conditions. Interestingly, the inhibitory effect of 5-Aza-dC was significantly reduced by an RGS2-targeted short hairpin RNA, indicating that reexpressed RGS2 contributed to this growth inhibition. Restoration of RGS2 levels by ectopic expression in androgen-independent prostate cancer cells suppressed growth of xenografts in castrated mice. Thus, RGS2 promoter hypermethylation represses its expression and unmasks a latent pathway for AR transactivation in prostate cancer cells. Targeting this reversible process may provide a new strategy for suppressing prostate cancer progression by reestablishing its androgen sensitivity. Copyright © 2011 UICC.

Synaptic Long-Term Potentiation and Depression in the Rat Medial Vestibular Nuclei Depend on Neural Activation of Estrogenic and Androgenic Signals

PubMed Central

Scarduzio, Mariangela; Panichi, Roberto; Pettorossi, Vito Enrico; Grassi, Silvarosa

2013-01-01

Estrogenic and androgenic steroids can be synthesised in the brain and rapidly modulate synaptic transmission and plasticity through direct interaction with membrane receptors for estrogens (ERs) and androgens (ARs). We used whole cell patch clamp recordings in brainstem slices of male rats to explore the influence of ER and AR activation and local synthesis of 17β-estradiol (E2) and 5α-dihydrotestosterone (DHT) on the long-term synaptic changes induced in the neurons of the medial vestibular nucleus (MVN). Long-term depression (LTD) and long-term potentiation (LTP) caused by different patterns of high frequency stimulation (HFS) of the primary vestibular afferents were assayed under the blockade of ARs and ERs or in the presence of inhibitors for enzymes synthesizing DHT (5α-reductase) and E2 (P450-aromatase) from testosterone (T). We found that LTD is mediated by interaction of locally produced androgens with ARs and LTP by interaction of locally synthesized E2 with ERs. In fact, the AR block with flutamide prevented LTD while did not affect LTP, and the blockade of ERs with ICI 182,780 abolished LTP without influencing LTD. Moreover, the block of P450-aromatase with letrozole not only prevented the LTP induction, but inverted LTP into LTD. This LTD is likely due to the local activation of androgens, since it was abolished under blockade of ARs. Conversely, LTD was still induced in the presence of finasteride the inhibitor of 5α-reductase demonstrating that T is able to activate ARs and induce LTD even when DHT is not synthesized. This study demonstrates a key and opposite role of sex neurosteroids in the long-term synaptic changes of the MVN with a specific role of T-DHT for LTD and of E2 for LTP. Moreover, it suggests that different stimulation patterns can lead to LTD or LTP by specifically activating the enzymes involved in the synthesis of androgenic or estrogenic neurosteroids. PMID:24265837

Relative importance of prenatal and postnatal androgen action in determining growth of the penis and anogenital distance in the rat before, during and after puberty.

PubMed

van den Driesche, S; Scott, H M; MacLeod, D J; Fisken, M; Walker, M; Sharpe, R M

2011-12-01

Experimental animal studies show that measurement of anogenital distance (AGD) and/or penis length may provide lifelong 'read-outs' of foetal androgen exposure during the masculinization programming window (MPW). However, variation in postnatal androgen exposure may complicate interpretation of such measurements. This is important to clarify if such measurements are to be applied to humans. The present aim was to evaluate effects of prenatal and/or postnatal manipulation of androgen production/action on growth of AGD and the penis in rats. Pregnant rats were treated daily before (e13.5-e21.5) and after birth (postnatal days 1-15) with either vehicle, 500 mg/kg di(n-butyl) phthalate (DBP) or 100 mg/kg flutamide (postnatal only) in prenatal + postnatal treatment combinations (N = 6 treatment combinations); DBP impairs androgen production whereas flutamide impairs androgen action. Male offspring were killed on postnatal day 8 (prepuberty), 25 (early puberty) or 90 (adulthood) when AGD was measured, the penis dissected out and its weight and length measured; plasma testosterone and ventral prostate weight were measured at day 90 to assess endogenous androgen exposure. In controls, penis length, girth and AGD increased 2.2-, 5.3-and 5.9-fold respectively from day 8 to day 90. Significant inhibition of penis growth and final length and girth was induced by treatments that inhibited postnatal androgen action. Conversely, growth and ultimate (adult) AGD was inhibited by prenatal inhibition of androgen production whereas postnatal androgen inhibition had negligible effect. Nevertheless, AGD and penis length were highly correlated at every age (R(2) > 0.33; p < 0.0001). However, altered endogenous androgen exposure may confound interpretation of changes in adults exposed prenatally/postnatally to DBP/flutamide. We conclude that AGD provides a lifelong guide to prenatal androgen exposure (in the MPW) whereas penis size reflects both prenatal + postnatal androgen exposure. At the group treatment level, prepubertal measurement of either AGD or penis size accurately predicts their size in adulthood. © 2011 The Authors. International Journal of Andrology © 2011 European Academy of Andrology.

Defining a Role for the Oncogene Beta-Catenin in Prostate Epithelial Growth and Invasion

DTIC Science & Technology

2011-07-01

receptor function. To determine in increased or decreased Wnt signaling can affect androgen receptor function, we harvested E15.5 UGSs from Esr1 -Cre x...beta-cateninfl/fl and Esr1 -Cre APCfl/fl embryos and treated them with 2 uM tamoxifen and zero, low, normal, or high androgen to determine if high

Saw Palmetto induces growth arrest and apoptosis of androgen-dependent prostate cancer LNCaP cells via inactivation of STAT 3 and androgen receptor signaling.

PubMed

Yang, Yang; Ikezoe, Takayuki; Zheng, Zhixing; Taguchi, Hirokuni; Koeffler, H Phillip; Zhu, Wei-Guo

2007-09-01

PC-SPES is an eight-herb mixture that has an activity against prostate cancer. Recently, we purified Saw Palmetto (Serenoa repens) from PC-SPES and found that Saw Palmetto induced growth arrest of prostate cancer LNCaP, DU145, and PC3 cells with ED50s of approximately 2.0, 2.6, and 3.3 microl/ml, respectively, as measured by mitochondrial-dependent conversion of the the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Saw Palmetto induced apoptosis of LNCaP cells in a time- and dose-dependent manner as measured by TUNEL assays. Also, Saw Palmetto increased the expression of p21waf1 and p53 protein in LNCaP cells. In addition, we found that Saw Palmetto down-regulated DHT- or IL-6-induced expression of prostate specific antigen in conjunction with down-regulation of the level of androgen receptor in the nucleus as measured by Western blot analysis. Moreover, Saw Palmetto down-regulated the IL-6-induced level of the phosphorylated form of STAT 3 in LNCaP cells. Furthermore, Saw Palmetto inhibited the growth of LNCaP cells present as tumor xenografts in BALB/c nude mice without adverse effect. These results indicate that Saw Palmetto might be useful for the treatment of individuals with prostate cancer.

Effects of a monophasic combined oral contraceptive containing nomegestrol acetate and 17β-oestradiol in comparison to one containing levonorgestrel and ethinylestradiol on markers of endocrine function.

PubMed

Ågren, Ulla M; Anttila, Marjatta; Mäenpää-Liukko, Kristiina; Rantala, Maija-Liisa; Rautiainen, Hilkka; Sommer, Werner F; Mommers, Ellen

2011-12-01

To compare the effects of two monophasic combined oral contraceptives, containing either nomegestrol acetate/17β-oestradiol (NOMAC/E2) or levonorgestrel/ ethinylestradiol (LNG/EE) on endocrine function, androgens, and sex hormone-binding globulin (SHBG). Randomised, open-label, multi-centre trial involving 121 healthy women, aged 18-50 years old. Participants received NOMAC/E2 (2.5 mg/1.5 mg) in a 24/4-day regimen (n=60) or LNG/EE (150 μg/30 μg) in a 21/7-day regimen (n=61) for six cycles. The primary outcome was the change from baseline to cycle 6 in markers of adrenal and thyroid function, androgens, and SHBG. Total cortisol, corticosteroid-binding globulin (CBG), and thyroxine-binding globulin (TBG) increased from baseline in both groups, with significantly greater increases in the LNG/EE group. No relevant changes from baseline or differences between the groups were observed for thyroid-stimulating hormone (TSH) and free thyroxine (T4). Androgens and androgen precursors decreased from baseline in both groups, with significantly greater decreases in the LNG/EE group (except for free testosterone). A greater increase in SHBG was observed with NOMAC/E2 than with LNG/EE. NOMAC/E2 has significantly less influence on markers of adrenal and thyroid function and androgens than LNG/EE. The clinical relevance of these findings requires further study.

Effects of a monophasic combined oral contraceptive containing nomegestrol acetate and 17β-oestradiol in comparison to one containing levonorgestrel and ethinylestradiol on markers of endocrine function

PubMed Central

Ågren, Ulla M; Anttilat, Marjatta; Mäenpää-Liukko, Kristiina; Rantala, Maija-Liisa; Rautiainen, Hilkka; Sommer, Werner F; Mommers, Ellen

2011-01-01

Objectives To compare the effects of two monophasic combined oral contraceptives, containing either nomegestrol acetate/17β-oestradiol (NOMAC/E2) or levonorgestrel/ ethinylestradiol (LNG/EE) on endocrine function, androgens, and sex hormone-binding globulin (SHBG). Methods Randomised, open-label, multi-centre trial involving 121 healthy women, aged 18-50 years old. Participants received NOMAC/E2 (2.5 mg/1.5 mg) in a 24/4-day regimen (n = 60) or LNG/EE (150 μg/30 μg) in a 21/7-day regimen (n = 61) for six cycles. The primary outcome was the change from baseline to cycle 6 in markers of adrenal and thyroid function, androgens, and SHBG. Results Total cortisol, corticosteroid-binding globulin (CBG), and thyroxine-binding globulin (TBG) increased from baseline in both groups, with significantly greater increases in the LNG/EE group. No relevant changes from baseline or differences between the groups were observed for thyroid-stimulating hormone (TSH) and free thyroxine (T4). Androgens and androgen precursors decreased from baseline in both groups, with significantly greater decreases in the LNG/EE group (except for free testosterone). A greater increase in SHBG was observed with NOMAC/E2 than with LNG/EE. Conclusions NOMAC/E2 has significantly less influence on markers of adrenal and thyroid function and androgens than LNG/EE. The clinical relevance of these findings requires further study. PMID:21942708

Restoration of the cellular secretory milieu overrides androgen dependence of in vivo generated castration resistant prostate cancer cells overexpressing the androgen receptor.

PubMed

Patki, Mugdha; Huang, Yanfang; Ratnam, Manohar

2016-07-22

It is believed that growth of castration resistant prostate cancer (CRPC) cells is enabled by sensitization to minimal residual post-castrate androgen due to overexpression of the androgen receptor (AR). Evidence is derived from androgen-induced colony formation in the absence of cell-secreted factors or from studies involving forced AR overexpression in hormone-dependent cells. On the other hand, standard cell line models established from CRPC patient tumors (e.g., LNCaP and VCaP) are hormone-dependent and require selection pressure in castrated mice to re-emerge as CRPC cells and the resulting tumors then tend to be insensitive to the androgen antagonist enzalutamide. Therefore, we examined established CRPC model cells produced by castration of mice bearing hormone-dependent cell line xenografts including CRPC cells overexpressing full-length AR (C4-2) or co-expressing wtAR and splice-variant AR-V7 that is incapable of ligand binding (22Rv1). In standard colony formation assays, C4-2 cells were shown to be androgen-dependent and sensitive to enzalutamide whereas 22Rv1 cells were incapable of colony formation under identical conditions. However, both C4-2 and 22Rv1 cells formed colonies in conditioned media derived from the same cells or from HEK293 fibroblasts that were proven to lack androgenic activity. This effect was (i) not enhanced by androgen, (ii) insensitive to enzalutamide, (iii) dependent on AR (in C4-2) and on AR-V7 and wtAR (in 22Rv1) and (iv) sensitive to inhibitors of several signaling pathways, similar to androgen-stimulation. Therefore, during progression to CRPC in vivo, coordinate cellular changes accompanying overexpression of AR may enable cooperation between hormone-independent activity of AR and actions of cellular secretory factors to completely override androgen-dependence and sensitivity to drugs targeting hormonal factors. Copyright © 2016 Elsevier Inc. All rights reserved.

Differential display RT PCR of total RNA from human foreskin fibroblasts for investigation of androgen-dependent gene expression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nitsche, E.M.; Moquin, A.; Adams, P.S.

1996-05-03

Male sexual differentiation is a process that involves androgen action via the androgen receptor. Defects in the androgen receptor, many resulting from point mutations in the androgen receptor gene, lead to varying degrees of impaired masculinization in chromosomally male individuals. To date no specific androgen regulated morphogens involved in this process have been identified and no marker genes are known that would help to predict further virilization in infants with partial androgen insensitivity. In the present study we first show data on androgen regulated gene expression investigated by differential display reverse transcription PCR (dd RT PCR) on total RNA frommore » human neonatal genital skin fibroblasts cultured in the presence or absence of 100 nM testosterone. Using three different primer combinations, 54 cDNAs appeared to be regulated by androgens. Most of these sequences show the characteristics of expressed mRNAs but showed no homology to sequences in the database. However 15 clones with significant homology to previously cloned sequences were identified. Seven cDNAs appear to be induced by androgen withdrawal. Of these, five are similar to ETS (expression tagged sequences) from unknown genes; the other two show significant homology to the cDNAs of ubiquitin and human guanylate binding protein 2 (GBP-2). In addition, we have identified 8 cDNA clones which show homologies to other sequences in the database and appear to be upregulated in the presence of testosterone. Three differential expressed sequences show significant homology to the cDNAs of L-plastin and one to the cDNA of testican. This latter gene codes for a proteoglycan involved in cell social behavior and therefore of special interest in this context. The results of this study are of interest in further investigation of normal and disturbed androgen-dependent gene expression. 49 refs., 2 figs., 5 tabs.« less

PTEN loss promotes intratumoral androgen synthesis and tumor microenvironment remodeling via aberrant activation of RUNX2 in castration-resistant prostate cancer

PubMed Central

Yang, Yinhui; Bai, Yang; He, Yundong; Zhao, Yu; Chen, Jiaxiang; Ma, Linlin; Pan, Yunqian; Hinten, Michael; Zhang, Jun; Karnes, R. Jeffrey; Kohli, Manish; Westendorf, Jennifer J.; Li, Benyi; Zhu, Runzhi; Huang, Haojie; Xu, Wanhai

2018-01-01

Purpose Intratumoral androgen synthesis (IAS) is a key mechanism promoting androgen receptor (AR)reactivation and anti-androgen resistance in castration-resistant prostate cancer (CRPC). However, signaling pathways driving aberrant IAS remain poorly understood. Experimental Design The effect of components of the AKT-RUNX2-osteocalcin (OCN)-GPRC6A-CREB signaling axis on expression of steroidogenesis genes CYP11A1 and CYP17A1 and testosterone level were examined in PTEN-null human PCa cell lines. Pten knockout mice were employed to examine the effect of Runx2 heterozygous deletion or abiraterone acetate (ABA), a prodrug of the CYP17A1 inhibitor abiraterone on Cyp11a1 and Cyp17a1 expression, testosterone level and tumor microenvironment (TME) remodeling in vivo. Results We uncovered that activation of the AKT-RUNX2-OCN-GPRC6A-CREB signaling axis induced expression of CYP11A1 and CYP17A1 and testosterone production in PTEN-null PCa cell lines in culture. Deletion of Runx2 in Pten homozygous knockout prostate tumors decreased Cyp11a1 and Cyp17a1 expression, testosterone level and tumor growth in castrated mice. ABA treatment also inhibited testosterone synthesis and alleviated Pten loss-induced tumorigenesis in vivo. Pten deletion induced TME remodeling, but Runx2 heterozygous deletion or ABA treatment reversed the effect of Pten loss by decreasing expression of the collagenase Mmp9. Conclusions Abnormal RUNX2 activation plays a pivotal role in PTEN loss-induced IAS and TME remodeling, suggesting that the identified signaling cascade represents a viable target for effective treatment of PTEN-null PCa including CRPC. PMID:29167276

Cognitive Impacts of Estrogen Treatment in Androgen-Deprived Males: What Needs to be Resolved.

PubMed

Wibowo, Erik

2017-01-01

Many prostate cancer (PCa) patients are on androgen deprivation therapy (ADT) as part of their cancer treatments but ADT may lead to cognitive impairments. ADT depletes men of both androgen and estrogen. Whether estradiol supplementation can improve cognitive impairments in patients on ADT is understudied. To summarize data on the effects of estradiol treatment on cognitive function of androgen-deprived genetic male populations (PCa patients and male-to-female transsexuals) and castrated male animals. Publications were identified by a literature search on PubMed and Google Scholar. While some studies showed that estradiol improves cognitive function (most notably, spatial ability) for castrated rats, what remains uninvestigated are: 1) whether estradiol can improve cognition after long-term androgen deprivation, 2) how estradiol affects memory retention, and 3) how early vs. delayed estradiol treatment after castration influences cognition. For androgendeprived genetic males, estradiol treatment may improve some cognitive functions (e.g., verbal and visual memory), but the findings are not consistent due to large variability in the study design between studies. Future studies are required to determine the best estradiol treatment protocol to maximize cognitive benefits for androgen-deprived genetic males. Tests that assess comparable cognitive domains in human and rodents are needed. What particularly under-investigated is how the effects of estradiol on cognitive ability intersect with other parameters; sleep, depression and physical fatigue. Such studies have clinical implications to improve the quality of life for both PCa patients on ADT as well as for male-to-female transsexuals. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Androgen responsiveness of the new human endometrial cancer cell line MFE-296.

PubMed

Hackenberg, R; Beck, S; Filmer, A; Hushmand Nia, A; Kunzmann, R; Koch, M; Slater, E P; Schulz, K D

1994-04-01

MFE-296 endometrial cancer cells express androgen receptors in vitro. These cells, which are tumorigenic in nude mice, are derived from a moderately differentiated human endometrial adenocarcinoma. They express vimentin and the cytokeratins 7, 8, 18, and 19. Karyotyping revealed near-tetraploidy for most of the cells. No marker chromosomes were observed. DNA analyses confirmed the genetic identity of the cell line and the patient from whom the cell line was derived. Proliferation of MFE-296 cells was inhibited by the progestin R5020 and the androgen dihydrotestosterone (DHT). The inhibition of proliferation by DHT was antagonized by the antiandrogen Casodex, demonstrating the involvement of the androgen receptor. Androgen binding was determined at 22,000 binding sites per cell using a whole-cell assay (KD = 0.05 nM) and 30 fmol/mg protein with the dextran charcoal method; 7 fmol/mg protein of progesterone receptors were found, whereas estrogen receptors were below 5 fmol/mg protein. The androgen receptor was functionally intact, as demonstrated by transfection experiments with a reporter-gene construct, containing an androgen-responsive element. In MFE-296 cells the content of the androgen receptor was up-regulated by its own ligand.

EFFECTS OF ENVIRONMENTAL ANTIANDROGENS ON REPRODUCTIVE DEVELOPMENT IN EXPERIMENTAL ANIMALS

EPA Science Inventory

In mammals, the androgens testosterone (T) and dihydrotestosterone (DHT) are critical for normal male reproductive development and function. In humans, drugs that act as androgen receptor (AR) agonists and antagonists or inhibit fetal steroidogenesis can cause pseudohermaphrodi...

Bisphenol A affects androgen receptor function via multiple mechanisms.

PubMed

Teng, Christina; Goodwin, Bonnie; Shockley, Keith; Xia, Menghang; Huang, Ruili; Norris, John; Merrick, B Alex; Jetten, Anton M; Austin, Christopher P; Tice, Raymond R

2013-05-25

Bisphenol A (BPA), is a well-known endocrine disruptor compound (EDC) that affects the normal development and function of the female and male reproductive system, however the mechanisms of action remain unclear. To investigate the molecular mechanisms of how BPA may affect ten different nuclear receptors, stable cell lines containing individual nuclear receptor ligand binding domain (LBD)-linked to the β-Gal reporter were examined by a quantitative high throughput screening (qHTS) format in the Tox21 Screening Program of the NIH. The results showed that two receptors, estrogen receptor alpha (ERα) and androgen receptor (AR), are affected by BPA in opposite direction. To confirm the observed effects of BPA on ERα and AR, we performed transient transfection experiments with full-length receptors and their corresponding response elements linked to luciferase reporters. We also included in this study two BPA analogs, bisphenol AF (BPAF) and bisphenol S (BPS). As seen in African green monkey kidney CV1 cells, the present study confirmed that BPA and BPAF act as ERα agonists (half maximal effective concentration EC50 of 10-100 nM) and as AR antagonists (half maximal inhibitory concentration IC50 of 1-2 μM). Both BPA and BPAF antagonized AR function via competitive inhibition of the action of synthetic androgen R1881. BPS with lower estrogenic activity (EC50 of 2.2 μM), did not compete with R1881 for AR binding, when tested at 30 μM. Finally, the effects of BPA were also evaluated in a nuclear translocation assays using EGPF-tagged receptors. Similar to 17β-estradiol (E2) which was used as control, BPA was able to enhance ERα nuclear foci formation but at a 100-fold higher concentration. Although BPA was able to bind AR, the nuclear translocation was reduced. Furthermore, BPA was unable to induce functional foci in the nuclei and is consistent with the transient transfection study that BPA is unable to activate AR. Published by Elsevier Ireland Ltd.

Hsa-miR-146a-5p modulates androgen-independent prostate cancer cells apoptosis by targeting ROCK1.

PubMed

Xu, Bin; Huang, Yeqing; Niu, Xiaobing; Tao, Tao; Jiang, Liang; Tong, Na; Chen, Shuqiu; Liu, Ning; Zhu, Weidong; Chen, Ming

2015-12-01

MicroRNAs (miRNAs) have been demonstrated playing important roles in the procession of prostate cancer cells transformation from androgen-dependence to androgen-independence. We conducted the miRNA microarray and realtime PCR analyses in both androgen-dependent (ADPC) and androgen-independent prostate cancer (AIPC) tissues. We also explored the role of hsa-miR-146a-5p (miR-146a) in MSKCC prostate cancer clinical database. Moreover, the impact of miR-146a on prostate cancer cells apoptosis were detected by Hoechst staining and fluorescence-activated cell sorter (FACS). Its target is predicted by DIANA LAB online database and the result was assumed by western blotting and luciferase assay. We demonstrated that miR-146a was down-regulated in AIPC tissues and cell lines compared to that in the ADPC tissues. In MSKCC data re-analyses, we found that miR-146a was underexpressed in metastatic prostate cancer tissues and those with Gleason score >8, moreover, low level of miR-146a represented a high biochemical relapse rate after radical prostatectomy. In the functional analyses, we transfected miR-146a mimics into CPRC cell lines and found miR-146a induced cells apoptosis. In mechanic analyses, we found that miR-146a inhibited the basal level of Rho-associated, coiled-coil containing protein kinase 1 (ROCK1) expression by targeting its 3'UTR and an inverse correlation of expression between miR-146a and ROCK1 was observed. Moreover, caspase 3 activity was stimulated by miR-146a overexpression. miR-146a has a critical role in the process of AIPC prostate cancer cells apoptosis through regulation of ROCK/Caspase 3 pathway. Targeting this pathway may be a promising therapeutic strategy for future personalized anti-cancer treatment. © 2015 Wiley Periodicals, Inc.

Developing Laryngeal Muscle of Xenopus laevis as a Model System: Androgen-Driven Myogenesis Controls Fiber Type Transformation

PubMed Central

Nasipak, Brian; Kelley, Darcy B.

2014-01-01

The developmental programs that contribute to myogenic stem cell proliferation and muscle fiber differentiation control fiber numbers and twitch type. In this study, we describe the use of an experimental model system—androgen-regulated laryngeal muscle of juvenile clawed frogs, Xenopus laevis—to examine the contribution of proliferation by specific populations of myogenic stem cells to expression of the larynx-specific myosin heavy chain isoform, LM. Androgen treatment of juveniles (Stage PM0) resulted in up-regulation of an early (Myf-5) and a late (myogenin) myogenic regulatory factor; the time course of LM up-regulation tracked that of myogenin. Myogenic stem cells stimulated to proliferate by androgen include a population that expresses Pax-7, a marker for the satellite cell myogenic stem cell population. Since androgen can switch muscle fiber types from fast to slow even in denervated larynges, we developed an ex vivo culture system to explore the relation between proliferation and LM expression. Cultured whole larynges maintain sensitivity to androgen, increasing in size and LM expression. Blockade of cell proliferation with cis-platin prevents the switch from slow to fast twitch muscle fibers as assayed by ATPase activity. Blockade of cell proliferation in vivo also resulted in inhibition of LM expression. Thus, both in vivo and ex vivo, inhibition of myogenic stem cell proliferation blocks androgen-induced LM expression and fiber type switching in juveniles. PMID:21954146

Vasopressin differentially modulates aggression and anxiety in adolescent hamsters administered anabolic steroids.

PubMed

Morrison, Thomas R; Ricci, Lesley A; Melloni, Richard H

2016-11-01

Adolescent Syrian hamsters (Mesocricetus auratus) treated with anabolic/androgenic steroids display increased offensive aggression and decreased anxiety correlated with an increase in vasopressin afferent development, synthesis, and neural signaling within the anterior hypothalamus. Upon withdrawal from anabolic/androgenic steroids, this neurobehavioral relationship shifts as hamsters display decreased offensive aggression and increased anxiety correlated with a decrease in anterior hypothalamic vasopressin. This study investigated the hypothesis that alterations in anterior hypothalamic vasopressin neural signaling modulate behavioral shifting between adolescent anabolic/androgenic steroid-induced offensive aggression and anxiety. To test this, adolescent male hamsters were administered anabolic/androgenic steroids and tested for offensive aggression or anxiety following direct pharmacological manipulation of vasopressin V1A receptor signaling within the anterior hypothalamus. Blockade of anterior hypothalamic vasopressin V1A receptor signaling suppressed offensive aggression and enhanced general and social anxiety in hamsters administered anabolic/androgenic steroids during adolescence, effectively reversing the pattern of behavioral response pattern normally observed during the adolescent exposure period. Conversely, activation of anterior hypothalamic vasopressin V1A receptor signaling enhanced offensive aggression in hamsters exposed to anabolic/androgenic steroids during adolescence. Together, these findings suggest that the state of vasopressin neural development and signaling in the anterior hypothalamus plays an important role in behavioral shifting between aggression and anxiety following adolescent exposure to anabolic/androgenic steroids. Copyright © 2016 Elsevier Inc. All rights reserved.

Oriental herbs as a source of novel anti-androgen and prostate cancer chemopreventive agents.

PubMed

Lu, Junxuan; Kim, Sung-Hoon; Jiang, Cheng; Lee, HyoJeong; Guo, Junming

2007-09-01

Androgen and androgen receptor (AR) signaling are crucial for the genesis of prostate cancer (PCa), which can often develop into androgen-ligand-independent diseases that are lethal to the patients. Recent studies show that even these hormone-refractory PCa require ligand-independent AR signaling for survival. As current chemotherapy is largely ineffective for PCa and has serious toxic sideeffects, we have initiated a collaborative effort to identify and develop novel, safe and naturally occurring agents that target AR signaling from Oriental medicinal herbs for the chemoprevention and treatment of PCa. We highlight our discovery of decursin from an Oriental formula containing Korean Angelica gigas Nakai (Dang Gui) root as a novel anti-androgen/AR agent. We have identified the following mechanisms to account for the specific anti-AR actions: rapid block of AR nuclear translocation, inhibition of binding of 5alpha-dihydrotestesterone to AR and increased proteasomal degradation of AR protein. Furthermore, decursin lacks the agonist activity of the "pure" anti-androgen bicalutamide and is more potent than bicalutamide in inducing PCa apoptosis. Structure-activity analyses reveal a critical requirement of the side-chain on decursin or its structural isomer decursinol angelate for anti-AR, cell cycle arrest and proapoptotic activities. This work demonstrates the feasibility of using activity-guided fractionation in cell culture assays combined with mechanistic studies to identify novel anti-androgen/ AR agents from complex herbal mixtures.

Vasopressin Differentially Modulates Aggression and Anxiety in Adolescent Hamsters Administered Anabolic Steroids

PubMed Central

Morrison, Thomas R.; Ricci, Lesley A.; Melloni, Richard H.

2016-01-01

Adolescent Syrian hamsters (Mesocricetus auratus) treated with anabolic/androgenic steroids display increased offensive aggression and decreased anxiety correlated with an increase in vasopressin afferent development, synthesis, and neural signaling within the anterior hypothalamus. Upon withdrawal from anabolic/androgenic steroids, this neurobehavioral relationship shifts as hamsters display decreased offensive aggression and increased anxiety correlated with a decrease in anterior hypothalamic vasopressin. This study investigated the hypothesis that alterations in anterior hypothalamic vasopressin neural signaling modulate behavioral shifting between adolescent anabolic/androgenic steroid-induced offensive aggression and anxiety. To test this, adolescent male hamsters were administered anabolic/androgenic steroids and tested for offensive aggression or anxiety following direct pharmacological manipulation of vasopressin V1A receptor signaling within the anterior hypothalamus. Blockade of anterior hypothalamic vasopressin V1A receptor signaling suppressed offensive aggression and enhanced general and social anxiety in hamsters administered anabolic/androgenic steroids during adolescence, effectively reversing the pattern of behavioral response pattern normally observed during the adolescent exposure period. Conversely, activation of anterior hypothalamic vasopressin V1A receptor signaling enhanced offensive aggression in hamsters exposed to anabolic/androgenic steroids during adolescence. Together, these findings suggest that the state of vasopressin neural development and signaling in the anterior hypothalamus plays an important role in behavioral shifting between aggression and anxiety following adolescent exposure to anabolic/androgenic steroids. PMID:27149949

Mass spectrometry of selective androgen receptor modulators.

PubMed

Thevis, Mario; Schänzer, Wilhelm

2008-07-01

Nonsteroidal selective androgen receptor modulators (SARMs) are an emerging class of drugs for treatment of various diseases including osteoporosis and muscle wasting as well as the correction of age-related functional decline such as muscle strength and power. Several SARMs, which have advanced to preclinical and clinical trials, are composed of diverse chemical structures including arylpropionamide-, bicyclic hydantoin-, quinoline-, and tetrahydroquinoline-derived nuclei. Since January 2008, SARMs have been categorized as anabolic agents and prohibited by the World Anti-Doping Agency (WADA). Suitable detection methods for these low-molecular weight drugs were based on mass spectrometric approaches, which necessitated the elucidation of dissociation pathways in order to characterize and identify the target analytes in doping control samples as well as potential metabolic products and synthetic analogs. Fragmentation patterns of representatives of each category of SARMs after electrospray ionization (ESI) and collision-induced dissociation (CID) as well as electron ionization (EI) are summarized. The complexity and structural heterogeneity of these drugs is a daunting challenge for detection methods. Copyright 2008 John Wiley & Sons, Ltd.

Registered report: the androgen receptor induces a distinct transcriptional program in castration-resistant prostate cancer in man

PubMed Central

Chronscinski, Denise; Cherukeri, Srujana; Tan, Fraser; Lomax, Joelle; Iorns, Elizabeth

2015-01-01

The Prostate Cancer Foundation-Movember Foundation Reproducibility Initiative (PCFMFRI) seeks to address growing concerns about reproducibility in scientific research by conducting replications of recent papers in the field of prostate cancer. This Registered Report describes the proposed replication plan of key experiments from “The Androgen Receptor Induces a Distinct Transcriptional Program in Castration-Resistant Prostate Cancer in Man” by Sharma and colleagues (2013), published in Cancer Cell in 2013. Of thousands of targets for the androgen receptor (AR), the authors elucidated a subset of 16 core genes that were consistently downregulated with castration and re-emerged with castration resistance. These 16 AR binding sites were distinct from those observed in cells in culture. The authors suggested that cellular context can have dramatic effects on downstream transcriptional regulation of AR binding sites. The present study will attempt to replicate Fig. 7C by comparing gene expression of the 16 core genes identified by Sharma and colleagues in xenograft tumor tissue compared to androgen treated LNCaP cells in vitro. The Prostate Cancer Foundation-Movember Foundation Reproducibility Initiative is a collaboration between the Prostate Cancer Foundation, the Movember Initiative, and Science Exchange, and the results of the replications will be published by PeerJ. PMID:26401447

FTY720 and (S)-FTY720 vinylphosphonate inhibit sphingosine kinase 1 and promote its proteasomal degradation in human pulmonary artery smooth muscle, breast cancer and androgen-independent prostate cancer cells

PubMed Central

Tonelli, Francesca; Lim, Keng Gat; Loveridge, Carolyn; Long, Jaclyn; Pitson, Stuart M.; Tigyi, Gabor; Bittman, Robert; Pyne, Susan; Pyne, Nigel J.

2010-01-01

Sphingosine kinase 1 (SK1) is an enzyme that catalyses the phosphorylation of sphingosine to produce the bioactive lipid sphingosine 1-phosphate (S1P). We demonstrate here that FTY720 (Fingolimod™) and (S)-FTY720 vinylphosphonate are novel inhibitors of SK1 catalytic activity and induce the proteasomal degradation of this enzyme in human pulmonary artery smooth muscle cells, MCF-7 breast cancer cells and androgen-independent LNCaP-AI prostate cancer cells. Proteasomal degradation of SK1 in response to FTY720 and (S)-FTY720 vinylphosphonate is associated with the down-regulation of the androgen receptor in LNCaP-AI cells. (S)-FTY720 vinylphosphonate also induces the apoptosis of these cells. These findings indicate that SK1 is involved in protecting LNCaP-AI from apoptosis. This protection might be mediated by so-called ‘inside-out’ signalling by S1P, as LNCaP-AI cells exhibit increased expression of S1P2/3 receptors and reduced lipid phosphate phosphatase expression (compared with androgen-sensitive LNCaP cells) thereby potentially increasing the bioavailability of S1P at S1P2/3 receptors. PMID:20570726

Membrane androgen receptor characteristics of human ZIP9 (SLC39A) zinc transporter in prostate cancer cells: Androgen-specific activation and involvement of an inhibitory G protein in zinc and MAP kinase signaling.

PubMed

Thomas, Peter; Pang, Yefei; Dong, Jing

2017-05-15

Characteristics of novel human membrane androgen receptor (mAR), ZIP9 (SLC39A9), were investigated in ZIP9-transfected PC-3 cells (PC3-ZIP9). Ligand blot analysis showed plasma membrane [ 3 H]-T binding corresponds to the position of ZIP9 on Western blots which suggests ZIP9 can bind [ 3 H]-T alone, without a protein partner. Progesterone antagonized testosterone actions, blocking increases in zinc, Erk phosphorylation and apoptosis, further evidence that ZIP9 is specifically activated by androgens. Pre-treatment with GTPγS and pertussis toxin decreased plasma membrane [ 3 H]-T binding and blocked testosterone-induced increases in Erk phosphorylation and intracellular zinc, indicating ZIP9 is coupled to an inhibitory G protein (Gi) that mediates both MAP kinase and zinc signaling. Testosterone treatment of nuclei and mitochondria which express ZIP9 decreased their zinc contents, suggesting ZIP9 also regulates free zinc through releasing it from these intracellular organelles. The results show ZIP9 is a specific Gi coupled-mAR mediating testosterone-induced MAP kinase and zinc signaling in PC3-ZIP9 cells. Copyright © 2017 Elsevier B.V. All rights reserved.

INTERACTION OF ORGANOPHOSPHATE PESTICIDES AND RELATED COMPOUNDS WITH THE ANDROGEN RECEPTOR

EPA Science Inventory

Identification of several environmental chemicals capable of binding to the androgen receptor (AR) and interfering with its normal function has heightened concern for adverse effects across a broad spectrum of environmental chemicals. We previously demonstrated AR antagonist act...

[Antiandrogen gynecomastia: an inescapable harm? Radiotherapy: a simple and efficient solution!].

PubMed

Couke, Philippe A; Jichliski, Patrice; Matzinger, Oscar; Ozsahin, Mahmut; Bulling, Shelley M; Zouhair, Abderrahim

2004-01-01

Anti-androgen induced gynecomastia, resulting from a treatment induced imbalance between oestrogens and androgens, is a frequently encountered side effect in the hormonal treatment of patients with prostatic cancer. One might expect to face an increase in the overall incidence of this side effect in the next-coming years as randomized trials clearly point to the evidence of the therapeutic benefit of anti-androgenic treatment for this prostatic cancer. Gynecomastia is often accompanied by mastodynia and does hamper quality of life. Surgery should be considered for established irreversible gynecomastia characterized by hyalinization and extensive fibrosis. However, radiotherapy is the treatment of choice for gynecomastia at it's early stage, or could eventually be considered as a prophylactic treatment in high risk patients. It is a safe and extremely well tolerated treatment resulting in a high degree of therapeutic success with a demonstrated effect on quality of life as reported in randomized trials. To date no medical treatment is proven effective nor devoid from deleterious effects and licenced for this indication.

Perinatal androgens and adult behavior vary with nestling social system in siblicidal boobies.

PubMed

Müller, Martina S; Brennecke, Julius F; Porter, Elaine T; Ottinger, Mary Ann; Anderson, David J

2008-06-18

Exposure to androgens early in development, while activating adaptive aggressive behavior, may also exert long-lasting effects on non-target components of phenotype. Here we compare these organizational effects of perinatal androgens in closely related Nazca (Sula granti) and blue-footed (S. nebouxii) boobies that differ in neonatal social system. The older of two Nazca booby hatchlings unconditionally attacks and ejects the younger from the nest within days of hatching, while blue-footed booby neonates lack lethal aggression. Both Nazca booby chicks facultatively upregulate testosterone (T) during fights, motivating the prediction that baseline androgen levels differ between obligately siblicidal and other species. We show that obligately siblicidal Nazca boobies hatch with higher circulating androgen levels than do facultatively siblicidal blue-footed boobies, providing comparative evidence of the role of androgens in sociality. Although androgens confer a short-term benefit of increased aggression to Nazca booby neonates, exposure to elevated androgen levels during this sensitive period in development can also induce long-term organizational effects on behavior or morphology. Adult Nazca boobies show evidence of organizational effects of early androgen exposure in aberrant adult behavior: they visit unattended non-familial chicks in the colony and direct mixtures of aggression, affiliative, and sexual behavior toward them. In a longitudinal analysis, we found that the most active Non-parental Adult Visitors (NAVs) were those with a history of siblicidal behavior as a neonate, suggesting that the tendency to show social interest in chicks is programmed, in part, by the high perinatal androgens associated with obligate siblicide. Data from closely related blue-footed boobies provide comparative support for this interpretation. Lacking obligate siblicide, they hatch with a corresponding low androgen level, and blue-footed booby adults show a much lower frequency of NAV behavior and a lower probability of behaving aggressively during NAV interactions. This species difference in adult social behavior appears to have roots in both pleiotropic and experiential effects of nestling social system. Our results indicate that Nazca boobies experience life-long consequences of androgenic preparation for an early battle to the death.

Androgen Receptor (AR) Suppresses Normal Human Prostate Epithelial Cell Proliferation via AR/β-catenin/TCF-4 Complex Inhibition of c-MYC Transcription

PubMed Central

Antony, Lizamma; van der Schoor, Freek; Dalrymple, Susan L.; Isaacs, John T.

2016-01-01

INTRODUCTION Physiologic testosterone continuously stimulates prostate stromal cell secretion of paracrine growth factors (PGFs), which if unopposed would induce hyperplastic overgrowth of normal prostate epithelial cells (PrECs). METHODS Lentiviral shRNA stable knock down of c-MYC, β-catenin, or TCF-4 completely inhibits normal (i.e., non-transformed) human PrECs growth. c-MYC enhancer driven reporter expression and growth is inhibited by two chemically distinct molecules, which prevent β-catenin signaling either by blocking TCF-4 binding (i.e., toxoflavin) or by stimulating degradation (i.e., AVX939). Recombinant DKK1 protein at a dose, which inhibits activation of canonical Wnt signaling does not inhibit PrEC growth. Nuclear β-catenin translocation and PrEC growth is prevented by both lack of PGFs or Akt inhibitor-I. Growth inhibition induced by lack of PGFs, toxoflavin, or Akt inhibitor-I is overcome by constitutive c-MYC transcription. RESULTS In the presence of continuous PGF signaling, PrEC hyperplasia is prevented by androgen binding to AR suppressing c-MYC transcription, resulting in G0 arrest/terminal differentiation independent of Rb, p21, p27, FoxP3, or down regulation of growth factors receptors and instead involves androgen-induced formation of AR/β-catenin/TCF-4 complexes, which suppress c-MYC transcription. Such suppression does not occur when AR is mutated in its zinc-finger binding domain. DISCUSSION Proliferation of non-transformed human PrECs is dependent upon c-MYC transcription via formation/binding of β-catenin/TCF-4 complexes at both 5′ and 3′ c-MYC enhancers stimulated by Wnt-independent, PGF induced Akt signaling. In the presence of continuous PGF signaling, PrEC hyperplasia is prevented by androgen-induced formation of AR/β-catenin/TCF-4 complexes, which retains binding to 3′ c-MYC enhancer, but now suppresses c-MYC transcription. PMID:24913829

Impact of androgen and dietary advanced glycation end products on female rat liver.

PubMed

Palioura, Eleni; Palimeri, Sotiria; Piperi, Christina; Sakellariou, Stratigoula; Kandaraki, Eleni; Sergentanis, Theodoros; Levidou, Georgia; Agrogiannis, George; Papalois, Apostolos; Korkolopoulou, Penelope; Diamanti-Kandarakis, Evanthia; Papavassiliou, Athanasios G

2015-01-01

Advanced glycation end products (AGEs) have been related to a wide range of liver disorders including hyperandrogenic states such as the Polycystic Ovary Syndrome (PCOS). The aim of the present study is to evaluate the potential impact of dietary glycotoxins exposure and androgen excess on hepatic histology and biochemistry in an androgenized female rat model. The study population consisted of 80 female Wistar rats, divided in 3 groups, a group of prepubertal (Group A, n=30) and adult rats (Group B, n=20) that were androgenized via subcutaneous implantation of dihydrotestosterone-containing pellets as well as a group of adult non-androgenized rodents (Group C, n=30). All groups were randomly assigned either to a high-AGE or low-AGE diet for 3 months. Rats fed with a high-AGE diet exhibited significantly elevated levels of gamma-glutamyl transferase (x03B3;GT) (p≤0.0002) and indices of AGE immunostaining in liver tissue (p<0.01) when compared to the respective low-AGE group, while aspartate aminotransferase (AST) levels were affected only in non-androgenized animals (p=0.0002). Androgenization per se constitutes an aggravating factor as demonstrated by the elevated x03B3;GT levels in adult androgenized animals compared to non-androgenized, independent of diet content (p=0.0002) and by the elevated AST and alanine aminotransferase (ALT) levels in low-AGE subgroups (adult androgenized vs. non-androgenized, p=0.0002) followed by increased immunohistochemical AGE deposition in hepatocytes of the latter categories (p=0.0007). The present study suggests that androgens and glycotoxins may contribute synergistically to distort hepatic physiology and function as observed in hyperandrogenic conditions. © 2015 The Author(s) Published by S. Karger AG, Basel.

Visualising Androgen Receptor Activity in Male and Female Mice

PubMed Central

Dart, D. Alwyn; Waxman, Jonathan; Aboagye, Eric O.; Bevan, Charlotte L.

2013-01-01

Androgens, required for normal development and fertility of males and females, have vital roles in the reproductive tract, brain, cardiovascular system, smooth muscle and bone. Androgens function via the androgen receptor (AR), a ligand-dependent transcription factor. To assay and localise AR activity in vivo we generated the transgenic “ARE-Luc” mouse, expressing a luciferase reporter gene under the control of activated endogenous AR. In vivo imaging of androgen-mediated luciferase activity revealed several strongly expressing tissues in the male mouse as expected and also in certain female tissues. In males the testes, prostate, seminal vesicles and bone marrow all showed high AR activity. In females, strong activity was seen in the ovaries, uterus, omentum tissue and mammary glands. In both sexes AR expression and activity was also found in salivary glands, the eye (and associated glands), adipose tissue, spleen and, notably, regions of the brain. Luciferase protein expression was found in the same cell layers as androgen receptor expression. Additionally, mouse AR expression and activity correlated well with AR expression in human tissues. The anti-androgen bicalutamide reduced luciferase signal in all tissues. Our model demonstrates that androgens can act in these tissues directly via AR, rather than exclusively via androgen aromatisation to estrogens and activation of the estrogen receptor. Additionally, it visually demonstrates the fundamental importance of AR signalling outside the normal role in the reproductive organs. This model represents an important tool for physiological and developmental analysis of androgen signalling, and for characterization of known and novel androgenic or antiandrogenic compounds. PMID:23940781

Vinclozolin--no transgenerational inheritance of anti-androgenic effects after maternal exposure during organogenesis via the intraperitoneal route.

PubMed

Schneider, Steffen; Marxfeld, Heike; Gröters, Sibylle; Buesen, Roland; van Ravenzwaay, Bennard

2013-06-01

The goal of this study was to examine the potential transgenerational inheritance of anti-androgenic effects induced by Vinclozolin administered intraperitoneally to pregnant Wistar rats (Crl:WI[Han]). Dams were dosed with Vinclozolin at 0, 4 or 100mg/kg bw/d on gestation days 6-15. Male offspring of F1-F3 generations were bred with untreated females to yield F2-F4 offspring. No evident anti-androgenic effects were observed at 4mg/kg bw/d, but a case of hypospadias as well as delayed sexual maturation in F1 male offspring was observed as a sign of anti-androgenicity at 100mg/kg bw/d. However, F1-F3 males developed normally to sexual maturity and were able to mate and to generate healthy progeny. Sperm count, morphology and motility were not affected in F1-F4 generation male offspring. In conclusion, transgenerational inheritance of Vinclozolin's anti-androgenic effects was not evident in outbred Wistar rats. Copyright © 2013 Elsevier Inc. All rights reserved.

Androgen-dependent and independent process of bone formation in the distal segment of Os penis in the rat.

PubMed

Murakami, R; Izumi, K; Yamaoka, I

1995-11-01

The distal segment of the os penis of the rat develops as a fibrocartilage which is replaced with non-lamellar bone by endochondral ossification after puberty. Development of the fibrocartilage and its calcification have been shown to be induced by androgens, but androgen-dependency of the endochondral ossification has not been studied in detail. In the present study, immature male rats of various ages were castrated and the ossification of the fibrocartilage of os penis was examined. In rats castrated at 6 weeks, when the fibrocartilage was scarcely calcified, ossification did not occur even at 24 weeks. When the castrated rats were treated with testosterone, ossification started before 12 weeks of age. In rats castrated at 8 weeks, when the fibrocartilage was heavily calcified, endochondral ossification was observed in some of the animals (5/7) at 24 weeks of age. The results of this study indicate that once the fibrocartilage is calcified, the endochondral ossification can take place without androgen, although the androgen can promote the process of ossification.

SLCO2B1 and SLCO1B3 May Determine Time to Progression for Patients Receiving Androgen Deprivation Therapy for Prostate Cancer

PubMed Central

Yang, Ming; Xie, Wanling; Mostaghel, Elahe; Nakabayashi, Mari; Werner, Lillian; Sun, Tong; Pomerantz, Mark; Freedman, Matthew; Ross, Robert; Regan, Meredith; Sharifi, Nima; Figg, William Douglas; Balk, Steven; Brown, Myles; Taplin, Mary-Ellen; Oh, William K.; Lee, Gwo-Shu Mary; Kantoff, Philip W.

2011-01-01

Purpose Androgen deprivation therapy (ADT), an important treatment for advanced prostate cancer, is highly variable in its effectiveness. We hypothesized that genetic variants of androgen transporter genes, SLCO2B1 and SLCO1B3, may determine time to progression on ADT. Patients and Methods A cohort of 538 patients with prostate cancer treated with ADT was genotyped for SLCO2B1 and SLCO1B3 single nucleotide polymorphisms (SNP). The biologic function of a SLCO2B1 coding SNP in transporting androgen was examined through biochemical assays. Results Three SNPs in SLCO2B1 were associated with time to progression (TTP) on ADT (P < .05). The differences in median TTP for each of these polymorphisms were about 10 months. The SLCO2B1 genotype, which allows more efficient import of androgen, enhances cell growth and is associated with a shorter TTP on ADT. Patients carrying both SLCO2B1 and SLCO1B3 genotypes, which import androgens more efficiently, exhibited a median 2-year shorter TTP on ADT, demonstrating a gene-gene interaction (Pinteraction = .041). Conclusion Genetic variants of SLCO2B1 and SLCO1B3 may function as pharmacogenomic determinants of resistance to ADT in prostate cancer. PMID:21606417

17β-trenbolone, an anabolic–androgenic steroid as well as an environmental hormone, contributes to neurodegeneration

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ma, Fucui, E-mail: mafucui@hotmail.com; Key Laboratory of Animal Resistance, College of Life Science, Shandong Normal University, 88 East Wenhua Road, Jinan 250014; Liu, Daicheng, E-mail: liudch@sdnu.edu.cn

Both genetic and environmental factors contribute to neurodegenerative disorders. In a large number of neurodegenerative diseases (for example, Alzheimer's disease (AD)), patients do not carry the mutant genes. Other risk factors, for example the environmental factors, should be evaluated. 17β-trenbolone is a kind of environmental hormone as well as an anabolic–androgenic steroid. 17β-trenbolone is used as a growth promoter for livestock in the USA. Also, a large portion of recreational exercisers inject 17β-trenbolone in large doses and for very long time to increase muscle and strength. 17β-trenbolone is stable in the environment after being excreted. In the present study, 17β-trenbolonemore » was administered to adult and pregnant rats and the primary hippocampal neurons. 17β-trenbolone's distribution and its effects on serum hormone levels and Aβ42 accumulation in vivo and its effects on AD related parameters in vitro were assessed. 17β-trenbolone accumulated in adult rat brain, especially in the hippocampus, and in the fetus brain. It altered Aβ42 accumulation. 17β-trenbolone induced apoptosis of primary hippocampal neurons in vitro and resisted neuroprotective function of testosterone. Presenilin-1 protein expression was down-regulated while β-amyloid peptide 42 (Aβ42) production and caspase-3 activities were increased. Both androgen and estrogen receptors mediated the processes. 17β-trenbolone played critical roles in neurodegeneration. Exercisers who inject large doses of trenbolone and common people who are exposed to 17β-trenbolone by various ways are all influenced chronically and continually. Identification of such environmental risk factors will help us take early prevention measure to slow down the onset of neurodegenerative disorders. - Highlights: • The widely used anabolic–androgenic steroid 17β-trenbolone has neurotoxicity. • 17β-trenbolone crosses the blood brain barrier and placental barrier. • Rat has high level of 17β-trenbolone in hippocampus after intramuscular injection. • 17β-trenbolone induces apoptosis of primary hippocampal neurons. • 17β-trenbolone affects Alzheimer's disease-related proteins Aβ42 and presenilin-1.« less

A selective androgen receptor modulator that reduces prostate tumor size and prevents orchidectomy-induced bone loss in rats.

PubMed

Allan, George; Lai, Muh-Tsann; Sbriscia, Tifanie; Linton, Olivia; Haynes-Johnson, Donna; Bhattacharjee, Sheela; Dodds, Robert; Fiordeliso, James; Lanter, James; Sui, Zhihua; Lundeen, Scott

2007-01-01

The pharmacological activity of JNJ-26146900 is described. JNJ-26146900 is a nonsteroidal androgen receptor (AR) ligand with tissue-selective activity in rats. The compound was evaluated in in vitro and in vivo models of AR activity. It binds to the rat AR with a K(i) of 400nM and acts as a pure androgen antagonist in an in vitro cell-based assay. Its in vitro profile is similar to the androgen antagonist bicalutamide (Casodex). In intact rats, JNJ-26146900 reduces ventral prostate weight with an oral potency (ED(50)) of 20-30mg/kg, again comparable to that of bicalutamide. JNJ-26146900 prevented prostate tumor growth in the Dunning rat model, maximally inhibiting growth at a dose of 10mg/kg. It slowed tumor growth significantly in a CWR22-LD1 mouse xenograft model of human prostate cancer. It was tested in aged male rats for its ability to prevent bone loss and loss of lean body mass following orchidectomy. After 6 weeks of dosing, bone volume decreased by 33% in orchidectomized versus intact vehicle-treated rats with a probability (P) of less than 0.05, as measured by micro-computerized tomography analysis. At a dose of 30mg/kg, JNJ-26146900 significantly reduced castration-induced tibial bone loss as indicated by the following parameters: bone volume, trabecular connectivity, trabecular number and spacing between trabeculae. Bone mineral density decreased from 229+/-34mg/cm(3) of hydroxyapatite to 166+/-26mg/cm(3) following orchidectomy, and was maintained at 194+/-20mg/cm(3) with JNJ-26146900 treatment (P<0.05 relative to orchidectomy alone). Using magnetic resonance imaging, the compound was found to partially prevent orchidectomy-induced loss of lean body mass. Our data show that selective androgen receptor modulators (SARMs) have the potential for anabolic effects on bone and muscle while maintaining therapeutic efficacy in prostate cancer.

Androgen-induced alterations in endometrial proteins crucial in recurrent miscarriages.

PubMed

Rahman, Tanzil Ur; Ullah, Kamran; Guo, Meng-Xi; Pan, Hai-Tao; Liu, Juan; Ren, Jun; Jin, Lu-Yang; Zhou, Yu-Zhong; Cheng, Yi; Sheng, Jian-Zhong; Huang, He-Feng

2018-05-15

High androgen level impairs endometrial receptivity in women experiences the recurrent miscarriage. The mechanism of androgen actions on endometrium is still uncertain. We hypothesized that androgen has a direct effect on the endometrium in women with recurrent miscarriage. In the present study, we assess the impact of androgen (A 2 ) at high concentration (10 -7 M) on Ishikawa cells compared with the physiological concentration of androgen (10 -9 M). To go into deeper analysis, we use global stable isotopes labeled profiling tactic using iTRAQ reagents, followed by 2D LC-MS/MS. We determine 175 non-redundant proteins, and 18 of these were quantified. The analysis of differentially expressed proteins (DEPs) identified 8 up-regulated proteins and 10 down-regulated in the high androgen group. These DEPs were examined by ingenuity pathway (IPA) analysis and established that these proteins might play vital roles in recurrent miscarriage and endometrium receptivity. In addition, proteins cyclin-dependent kinase inhibitor 2a (CDKN2a), endothelial protein C receptor (EPCR), armadillo repeat for velocardiofacial (ARVCF) were independently confirmed using western blot. Knockdown of CDKN2a significantly decreased the expression level of CDKN2a protein in ishikawa cells, and decreased migration ( p < 0.01), invasion ( p < 0.05), proliferation ( p < 0.05), and the rate of Jar spheroid attachment ( p < 0.05) to Ishikawa cell monolayer. The present results suggest that androgen at high concentration could alter the expression levels of proteins related to endometrium development and embryo implantation, which might be a cause of the impaired endometrial receptivity and miscarriage.

Flutamide-mediated androgen blockade evokes osteopenia in the female rat.

PubMed

Goulding, A; Gold, E

1993-06-01

Androgens are believed to play a role in building and maintaining bone in the female, as well as in the male. The antiandrogen drug flutamide inhibits responses to androgens from both the gonads and the adrenals. Antiandrogens prevent androgens stimulating bone cell proliferation and differentiation in vitro, but effects of androgen blockade on bone metabolism in vivo have not been tested. The present study was undertaken to determine whether androgen blockade with flutamide (15 mg/kg body weight orally daily) would influence bone turnover or bone composition (1) in female rats with intact ovaries and (2) in rats made estrogen-deficient with the luteinizing hormone releasing hormone (LHRH) agonist, buserelin (25 micrograms/kg body weight per day SC). Four groups of rats with 45Ca-labeled skeletons were studied for 4 weeks: group A, placebo; group B, buserelin; group C, flutamide; group D, flutamide+buserelin. Total-body calcium values (mean +/- SD) were (mg) 2007 +/- 109, 1779 +/- 138 (P < 0.01 versus group A), 1818 +/- 140 (P < 0.01 versus group A), and 1690 +/- 75 (P < 0.01 versus group A) in groups A-D, respectively. Thus both buserelin and flutamide induced osteopenia. Skeletal 45Ca changes suggested buserelin-mediated estrogen deficiency bone loss was due to increased bone resorption, but flutamide-mediated androgen deficiency bone thinning was caused principally by reduced bone formation. These findings support the view that androgens play an important role in preserving bone mass in the female rat. Importantly, adequate estrogen status did not compensate for flutamide-mediated osteopenia.(ABSTRACT TRUNCATED AT 250 WORDS)

Selective Androgen Receptor Modulator RAD140 Is Neuroprotective in Cultured Neurons and Kainate-Lesioned Male Rats

PubMed Central

Jayaraman, Anusha; Christensen, Amy; Moser, V. Alexandra; Vest, Rebekah S.; Miller, Chris P.; Hattersley, Gary

2014-01-01

The decline in testosterone levels in men during normal aging increases risks of dysfunction and disease in androgen-responsive tissues, including brain. The use of testosterone therapy has the potential to increase the risks for developing prostate cancer and or accelerating its progression. To overcome this limitation, novel compounds termed “selective androgen receptor modulators” (SARMs) have been developed that lack significant androgen action in prostate but exert agonist effects in select androgen-responsive tissues. The efficacy of SARMs in brain is largely unknown. In this study, we investigate the SARM RAD140 in cultured rat neurons and male rat brain for its ability to provide neuroprotection, an important neural action of endogenous androgens that is relevant to neural health and resilience to neurodegenerative diseases. In cultured hippocampal neurons, RAD140 was as effective as testosterone in reducing cell death induced by apoptotic insults. Mechanistically, RAD140 neuroprotection was dependent upon MAPK signaling, as evidenced by elevation of ERK phosphorylation and inhibition of protection by the MAPK kinase inhibitor U0126. Importantly, RAD140 was also neuroprotective in vivo using the rat kainate lesion model. In experiments with gonadectomized, adult male rats, RAD140 was shown to exhibit peripheral tissue-specific androgen action that largely spared prostate, neural efficacy as demonstrated by activation of androgenic gene regulation effects, and neuroprotection of hippocampal neurons against cell death caused by systemic administration of the excitotoxin kainate. These novel findings demonstrate initial preclinical efficacy of a SARM in neuroprotective actions relevant to Alzheimer's disease and related neurodegenerative diseases. PMID:24428527

Promising alternative clinical uses of prostaglandin F2α analogs: beyond the eyelashes.

PubMed

Choi, Young M; Diehl, Joseph; Levins, Paul C

2015-04-01

Prostaglandin F2α analogs, commonly prescribed for glaucoma treatment, have been shown to induce side effects such as cutaneous hypertrichosis and hyperpigmentation. Therefore, these medications have theoretic applications in the treatment of alopecia and disorders of hypopigmentation. We reviewed the literature to find original studies assessing the use of prostaglandin F2α analogs in these settings. Studies and reports were analyzed in regards to androgenic alopecia, alopecia areata, chemotherapy-induced alopecia, vitiligo, and hypopigmented scarring. Based on the results of these studies, and consideration of pathophysiologic mechanism, the most promising applications for prostaglandin F2α analogs include androgenic alopecia, chemotherapy-induced alopecia, and alopecia areata concurrently treated with corticosteroids. Copyright © 2014 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

Prenatal androgen exposure alters girls' responses to information indicating gender-appropriate behaviour

PubMed Central

Hines, Melissa; Pasterski, Vickie; Spencer, Debra; Neufeld, Sharon; Patalay, Praveetha; Hindmarsh, Peter C.; Hughes, Ieuan A.; Acerini, Carlo L.

2016-01-01

Individual variability in human gender-related behaviour is influenced by many factors, including androgen exposure prenatally, as well as self-socialization and socialization by others postnatally. Many studies have looked at these types of influences in isolation, but little is known about how they work together. Here, we report that girls exposed to high concentrations of androgens prenatally, because they have the genetic condition congenital adrenal hyperplasia, show changes in processes related to self-socialization of gender-related behaviour. Specifically, they are less responsive than other girls to information that particular objects are for girls and they show reduced imitation of female models choosing particular objects. These findings suggest that prenatal androgen exposure may influence subsequent gender-related behaviours, including object (toy) choices, in part by changing processes involved in the self-socialization of gendered behaviour, rather than only by inducing permanent changes in the brain during early development. In addition, the findings suggest that some of the behavioural effects of prenatal androgen exposure might be subject to alteration by postnatal socialization processes. The findings also suggest a previously unknown influence of early androgen exposure on later processes involved in self-socialization of gender-related behaviour, and thus expand understanding of the developmental systems regulating human gender development. PMID:26833843

Prenatal androgen exposure alters girls' responses to information indicating gender-appropriate behaviour.

PubMed

Hines, Melissa; Pasterski, Vickie; Spencer, Debra; Neufeld, Sharon; Patalay, Praveetha; Hindmarsh, Peter C; Hughes, Ieuan A; Acerini, Carlo L

2016-02-19

Individual variability in human gender-related behaviour is influenced by many factors, including androgen exposure prenatally, as well as self-socialization and socialization by others postnatally. Many studies have looked at these types of influences in isolation, but little is known about how they work together. Here, we report that girls exposed to high concentrations of androgens prenatally, because they have the genetic condition congenital adrenal hyperplasia, show changes in processes related to self-socialization of gender-related behaviour. Specifically, they are less responsive than other girls to information that particular objects are for girls and they show reduced imitation of female models choosing particular objects. These findings suggest that prenatal androgen exposure may influence subsequent gender-related behaviours, including object (toy) choices, in part by changing processes involved in the self-socialization of gendered behaviour, rather than only by inducing permanent changes in the brain during early development. In addition, the findings suggest that some of the behavioural effects of prenatal androgen exposure might be subject to alteration by postnatal socialization processes. The findings also suggest a previously unknown influence of early androgen exposure on later processes involved in self-socialization of gender-related behaviour, and thus expand understanding of the developmental systems regulating human gender development. © 2016 The Author(s).

ID4 promotes AR expression and blocks tumorigenicity of PC3 prostate cancer cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Komaragiri, Shravan Kumar; Bostanthirige, Dhanushka H.; Morton, Derrick J.

Deregulation of tumor suppressor genes is associated with tumorigenesis and the development of cancer. In prostate cancer, ID4 is epigenetically silenced and acts as a tumor suppressor. In normal prostate epithelial cells, ID4 collaborates with androgen receptor (AR) and p53 to exert its tumor suppressor activity. Previous studies have shown that ID4 promotes tumor suppressive function of AR whereas loss of ID4 results in tumor promoter activity of AR. Previous study from our lab showed that ectopic ID4 expression in DU145 attenuates proliferation and promotes AR expression suggesting that ID4 dependent AR activity is tumor suppressive. In this study, wemore » examined the effect of ectopic expression of ID4 on highly malignant prostate cancer cell, PC3. Here we show that stable overexpression of ID4 in PC3 cells leads to increased apoptosis and decreased cell proliferation and migration. In addition, in vivo studies showed a decrease in tumor size and volume of ID4 overexpressing PC3 cells, in nude mice. At the molecular level, these changes were associated with increased androgen receptor (AR), p21, and AR dependent FKBP51 expression. At the mechanistic level, ID4 may regulate the expression or function of AR through specific but yet unknown AR co-regulators that may determine the final outcome of AR function. - Highlights: • ID4 expression induces AR expression in PC3 cells, which generally lack AR. • ID4 expression increased apoptosis and decreased cell proliferation and invasion. • Overexpression of ID4 reduces tumor growth of subcutaneous xenografts in vivo. • ID4 induces p21 and FKBP51 expression- co-factors of AR tumor suppressor activity.« less

Functional potentiation of leptin-signal transducer and activator of transcription 3 signaling by the androgen receptor.

PubMed

Fan, WuQiang; Yanase, Toshihiko; Nishi, Yoshihiro; Chiba, Seiichi; Okabe, Taijiro; Nomura, Masatoshi; Yoshimatsu, Hironobu; Kato, Shigeaki; Takayanagi, Ryoichi; Nawata, Hajime

2008-12-01

Hypogonadism is associated with increased fat mass and dysregulation of metabolic homeostasis in men. Our previous study revealed that androgen receptor (AR)-null male mice (ARL-/Y) develop late-onset obesity and are leptin-resistant. The present study evaluated how hypothalamic AR contributes to central leptin-signal transducer and activator of transcription 3 (STAT3) signaling. We evaluated leptin action in wild-type and ARL-/Y mice, the anatomic co-relationship between AR and leptin signaling in the hypothalamus, and the effects of AR on leptin-mediated STAT3 transactivation and nuclear translocation. AR deletion in male mice results in a weaker leptin-induced suppression of food intake and body weight drop even before the onset of overt obesity. In wild-type male but not female mice, AR was highly expressed in various hypothalamic nuclei that also expressed the long-form leptin receptor (OBRB) and co-resided with OBRB directly in the arcuate neurons. In vitro, AR significantly enhanced STAT3-mediated transcription of leptin target genes including POMC and SOCS3. This effect relied on the AR N-terminal activation function-1 (AF-1) domain and was specific to AR in that none of the other sex steroid hormone receptors tested showed similar effects. AR enhanced the low concentrations of leptin-induced STAT3 nuclear translocation in vitro, and ARL-/Y mice receiving leptin had impaired STAT3 nuclear localization in the arcuate neurons. These findings indicate that AR in the hypothalamus functions as a regulator of central leptin-OBRB-STAT3 signaling and has a physiological role in energy homeostasis and metabolic regulation in male mice.

N-Butanol and Aqueous Fractions of Red Maca Methanolic Extract Exerts Opposite Effects on Androgen and Oestrogens Receptors (Alpha and Beta) in Rats with Testosterone-Induced Benign Prostatic Hyperplasia.

PubMed

Fano, Diego; Vásquez-Velásquez, Cinthya; Gonzales-Castañeda, Cynthia; Guajardo-Correa, Emanuel; Orihuela, Pedro A; Gonzales, Gustavo F

2017-01-01

Benign Prostatic Hyperplasia (BPH) affects, worldwide, 50% of 60-year-old men. The Peruvian plant red maca (Lepidium meyenii) inhibits BPH in rodents. This study aimed to determine the effects of methanolic red maca extract and its n-butanol and aqueous fractions on expression of androgen and oestrogen receptors in rats with testosterone enanthate-induced BPH. Thirty-six rats in six groups were studied. Control group received 2 mL of vehicle orally and 0.1 mL of propylene glycol intramuscularly. The second group received vehicle orally and testosterone enanthate (TE) (25 mg/0.1 mL) intramuscularly in days 1 and 7. The other four groups were BPH-induced with TE and received, during 21 days, 3.78 mg/mL of finasteride, 18.3 mg/mL methanol extract of red maca, 2 mg/mL of n-butanol fraction, or 16.3 mg/mL of aqueous fraction from red maca. Treatments with red maca extract and its n-butanol but not aqueous fraction reduced prostate weight similar to finasteride. All maca treated groups restored the expression of ER β , but only the aqueous fraction increased androgen receptors and ER α . In conclusion, butanol fraction of red maca reduced prostate size in BPH by restoring expression of ER β without affecting androgen receptors and ER α . This effect was not observed with aqueous fraction of methanolic extract of red maca.

N-Butanol and Aqueous Fractions of Red Maca Methanolic Extract Exerts Opposite Effects on Androgen and Oestrogens Receptors (Alpha and Beta) in Rats with Testosterone-Induced Benign Prostatic Hyperplasia

PubMed Central

Vásquez-Velásquez, Cinthya

2017-01-01

Benign Prostatic Hyperplasia (BPH) affects, worldwide, 50% of 60-year-old men. The Peruvian plant red maca (Lepidium meyenii) inhibits BPH in rodents. This study aimed to determine the effects of methanolic red maca extract and its n-butanol and aqueous fractions on expression of androgen and oestrogen receptors in rats with testosterone enanthate-induced BPH. Thirty-six rats in six groups were studied. Control group received 2 mL of vehicle orally and 0.1 mL of propylene glycol intramuscularly. The second group received vehicle orally and testosterone enanthate (TE) (25 mg/0.1 mL) intramuscularly in days 1 and 7. The other four groups were BPH-induced with TE and received, during 21 days, 3.78 mg/mL of finasteride, 18.3 mg/mL methanol extract of red maca, 2 mg/mL of n-butanol fraction, or 16.3 mg/mL of aqueous fraction from red maca. Treatments with red maca extract and its n-butanol but not aqueous fraction reduced prostate weight similar to finasteride. All maca treated groups restored the expression of ERβ, but only the aqueous fraction increased androgen receptors and ERα. In conclusion, butanol fraction of red maca reduced prostate size in BPH by restoring expression of ERβ without affecting androgen receptors and ERα. This effect was not observed with aqueous fraction of methanolic extract of red maca. PMID:29375645

TGFβ Superfamily Members Mediate Androgen Deprivation Therapy-Induced Obese Frailty in Male Mice

PubMed Central

Pan, Chunliu; Singh, Shalini; Sahasrabudhe, Deepak M.; Chakkalakal, Joe V.; Krolewski, John J.

2016-01-01

First line treatment for recurrent and metastatic prostate cancer is androgen deprivation therapy (ADT). Use of ADT has been increasing in frequency and duration, such that side effects increasingly impact patient quality of life. One of the most significant side effects of ADT is sarcopenia, which leads to a loss of skeletal muscle mass and function, resulting in a clinical disability syndrome known as obese frailty. Using aged mice, we developed a mouse model of ADT-induced sarcopenia that closely resembles the phenotype seen in patients, including loss of skeletal muscle strength, reduced lean muscle mass, and increased adipose tissue. Sarcopenia onset occurred about 6 weeks after castration and was blocked by a soluble receptor (ActRIIB-Fc) that binds multiple TGFβ superfamily members, including myostatin, growth differentiation factor 11, activin A, activin B, and activin AB. Analysis of ligand expression in both gastrocnemius and triceps brachii muscles demonstrates that each of these proteins is induced in response to ADT, in 1 of 3 temporal patterns. Specifically, activin A and activin AB levels increase and decline before onset of strength loss at 6 weeks after castration, and myostatin levels increase coincident with the onset of strength loss and then decline. In contrast, activin B and growth differentiation factor 11 levels increase after the onset of strength loss, 8–10 weeks after castration. The observed patterns of ligand induction may represent differential contributions to the development and/or maintenance of sarcopenia. We hypothesize that some or all of these ligands are targets for therapy to ameliorate ADT-induced sarcopenia in prostate cancer patients. PMID:27611336

Growth Inhibition by Testosterone in an Androgen Receptor Splice Variant-Driven Prostate Cancer Model.

PubMed

Nakata, Daisuke; Nakayama, Kazuhide; Masaki, Tsuneo; Tanaka, Akira; Kusaka, Masami; Watanabe, Tatsuya

2016-12-01

Castration resistance creates a significant problem in the treatment of prostate cancer. Constitutively active splice variants of androgen receptor (AR) have emerged as drivers for resistance to androgen deprivation therapy, including the next-generation androgen-AR axis inhibitors abiraterone and enzalutamide. In this study, we describe the characteristics of a novel castration-resistant prostate cancer (CRPC) model, designated JDCaP-hr (hormone refractory). JDCaP-hr was established from an androgen-dependent JDCaP xenograft model after surgical castration. The expression of AR and its splice variants in JDCaP-hr was evaluated by immunoblotting and quantitative reverse transcription-polymerase chain reaction. The effects of AR antagonists and testosterone on JDCaP-hr were evaluated in vivo and in vitro. The roles of full-length AR (AR-FL) and AR-V7 in JDCaP-hr cell growth were evaluated using RNA interference. JDCaP-hr acquired a C-terminally truncated AR protein during progression from the parental JDCaP. The expression of AR-FL and AR-V7 mRNA was upregulated by 10-fold in JDCaP-hr compared with that in JDCaP, indicating that the JDCaP and JDCaP-hr models simulate castration resistance with some clinical features, such as overexpression of AR and its splice variants. The AR antagonist bicalutamide did not affect JDCaP-hr xenograft growth, and importantly, testosterone induced tumor regression. In vitro analysis demonstrated that androgen-independent prostate-specific antigen secretion and cell proliferation of JDCaP-hr were predominantly mediated by AR-V7. JDCaP-hr cell growth displayed a bell-shaped dependence on testosterone, and it was suppressed by physiological concentrations of testosterone. Testosterone induced rapid downregulation of both AR-FL and AR-V7 expression at physiological concentrations and suppressed expression of the AR target gene KLK3. Our findings support the clinical value of testosterone therapy, including bipolar androgen therapy, in the treatment of AR-overexpressed CRPC driven by AR splice variants that are not clinically actionable at present. Prostate 76:1536-1545, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Amino acid substitutions in the hormone-binding domain of the human androgen receptor alter the stability of the hormone receptor complex.

PubMed Central

Marcelli, M; Zoppi, S; Wilson, C M; Griffin, J E; McPhaul, M J

1994-01-01

We have investigated the basis of androgen resistance in seven unrelated individuals with complete testicular feminization or Reifenstein syndrome caused by single amino acid substitutions in the hormone-binding domain of the androgen receptor. Monolayer-binding assays of cultured genital skin fibroblasts demonstrated absent ligand binding, qualitative abnormalities of androgen binding, or a decreased amount of qualitatively normal receptor. The consequences of these mutations were examined by introducing the mutations by site-directed mutagenesis into the androgen receptor cDNA sequence and expressing the mutant cDNAs in mammalian cells. The effects of the amino acid substitutions on the binding of different androgens and on the capacity of the ligand-bound receptors to activate a reporter gene were investigated. Substantial differences were found in the responses of the mutant androgen receptors to incubation with testosterone, 5 alpha-dihydrotestosterone, and mibolerone. In several instances, increased doses of hormone or increased frequency of hormone addition to the incubation medium resulted in normal or near normal activation of a reporter gene by cells expressing the mutant androgen receptors. These studies suggest that the stability of the hormone receptor complex is a major determinant of receptor function in vivo. Images PMID:7929841

Effects of androgen replacement therapy on cornea and tear function in men with idiopathic hypogonadotropic hypogonadism.

PubMed

Gokce, Gokcen; Hurmeric, Volkan; Mumcuoglu, Tarkan; Ozge, Gokhan; Basaran, Yalcin; Unal, Hilmi Umut; Bolu, Erol; Mutlu, Fatih Mehmet

2015-05-01

Idiopathic hypogonadotropic hypogonadism (IHH) is an endocrine disorder defined with the presence of typical clinical signs and symptoms plus laboratory confirmation of serum testosterone (T) levels lower than 300 ng/dl. Androgen replacement therapy (ART) is the first-step treatment of male IHH. To date, no clinical trial, which investigates the changes on corneal structure and tear function, of systemic ART in men have been published. The objective of this study was to investigate the effects of ART on cornea and tear function in patients with IHH. This prospective, interventional study was conducted at the Gulhane Military Medical Academy, Ankara, Turkey, a tertiary referral military hospital. Thirty-four eyes of 17 men with IHH patients were evaluated with Schirmer I test, ultrasound pachymeter, applanation tonometer and confocal microscopy. A Testosterone compound (Sustanon® 250 mg) was administered by intramuscular injection in the course of a 3-week period to induce puberty, and human chorionic gonadotropin (Pregnyl® 5000 IU) was administered twice weekly for 3 months to induce fertility. The patients were re-evaluated at the third month of the treatment. Main Outcome Measures were Schirmer score, central corneal thickness (CCT), intraocular pressure (IOP), endothelial cell density, coefficient of variation and cell shape. Schirmer scores showed similar results after the treatment compared to pre-treatment levels (p = 0.14). There was no statistically significant difference in CCT and IOP compared to baseline data (p = 0.96, p = 0.73, respectively), and no significant differences were found in corneal endothelial cell density, percentage of cell size variability or hexagonality (p = 0.83, p = 0.58, p = 0.64, respectively). This is the first study that investigates the effects of ART on corneal structure and tear function in men. ART seems to have no short-term effects on corneal structure and tear function. Further publications of larger, long-term and controlled studies are needed.

Overexpression of HepaCAM inhibits cell viability and motility through suppressing nucleus translocation of androgen receptor and ERK signaling in prostate cancer.

PubMed

Song, Xuedong; Wang, Yin; Du, Hongfei; Fan, Yanru; Yang, Xue; Wang, Xiaorong; Wu, Xiaohou; Luo, Chunli

2014-07-01

HepaCAM is suppressed in a variety of human cancers, and involved in cell adhesion, growth, migration, invasion, and survival. However, the expression and function of HepaCAM in prostate cancer are still unknown. HepaCAM expression has been detected by RT-PCR, Western blotting and immunohistochemistry staining in prostate cell lines RWPE-1, LNCap, DU145, PC3, and in 75 human prostate tissue specimens, respectively. Meanwhile, the cell proliferation ability was detected by WST-8 assay. The role of HepaCAM in prostate cancer cell migration and invasion was examined by wound healing and transwell assay. And flow cytometry was used to observe the apoptosis of prostate cancer cells. Then we detected changes of Androgen Receptor translocation and ERK signaling using immunofluorescence staining and western blot after overexpression of HepaCAM. The HepaCAM expression was significantly down-regulated in prostate cancer tissues and undetected in prostate cancer cells. However, the low HepaCAM expression was not statistically associated with clinicopathological characteristics of prostate cancer. Overexpression of HepaCAM in prostate cancer cells decreased the cell proliferation, migration and invasion, and induced the cell apoptosis. Meanwhile, HepaCAM prevented the androgen receptor translocation from the cytoplasm to the nucleus and down-regulated the MAPK/ERK signaling. Our results suggested that HepaCAM acted as a tumor suppressor in prostate cancer. HepaCAM inhibited cell viability and motility which might be through suppressing the nuclear translocation of Androgen Receptor and down-regulating the ERK signaling. Therefore, it was indicated that HepaCAM may be a potential therapeutic target for prostate cancer. © 2014 Wiley Periodicals, Inc.

Ropren® treatment reverses anxiety-like behavior and monoamines levels in gonadectomized rat model of Alzheimer's disease.

PubMed

Fedotova, Julia; Soultanov, Vagif; Nikitina, Tamara; Roschin, Victor; Ordyan, Natalia; Hritcu, Lucian

2016-10-01

Previous studies indicated that reduced androgen levels may contribute to both physical and cognitive disorders in men, including Alzheimer's disease. New drug candidates for Alzheimer's disease in patients with androgen deficiency should ideally be able to act not only on multiple brain targets but also to correct impaired endocrine functions in hypogonadal men with Alzheimer's disease. Ropren ® is one such candidate for the treatment of Alzheimer's disease in men with an imbalance of androgens. Accordingly, the aim of the current study was to examine the effects of long-term Ropren ® administration (8.6mg/kg, orally, once daily, for 28 days) on the anxiety-like behavior and monoamines levels in the rat hippocampus using a β-amyloid (25-35) rat model of Alzheimer's disease following gonadectomy. Ropren ® was administered to the gonadectomized (GDX) rats and GDX rats treated with testosterone propionate (TP, 0.5mg/kg, subcutaneous, once daily, for 28 days). Anxiety-like behavior was assessed in the elevated plus maze (EPM) and the light-dark test (LDT), locomotor and grooming activities were assessed in the open field test (OFT). Ropren ® alone or in combination with TP-induced anxiolytic effects as evidenced in the EPM and in the LDT and increased locomotor activity in the OFT. Additionally, it was observed that dopamine (DA) and serotonin (5-HT) levels increased while 5-hydroxyindoleacetic acid (5-HIAA)/5-HT ratio in the hippocampus decreased. Our results indicate that Ropren ® has a marked anxiolytic-like action due to an increase in the monoamines levels in the experimental rat model of Alzheimer's disease with altered levels of androgens. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Sorafenib Action in Hepatitis B Virus X-Activated Oncogenic Androgen Pathway in Liver through SHP-1.

PubMed

Wang, Sheng-Han; Yeh, Shiou-Hwei; Shiau, Chung-Wai; Chen, Kuen-Feng; Lin, Wei-Hsiang; Tsai, Ting-Fen; Teng, Yuan-Chi; Chen, Ding-Shinn; Chen, Pei-Jer

2015-10-01

Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) shows a higher incidence in men, mainly because of hepatitis B X (HBx)-mediated enhancement of androgen receptor (AR) activity. We aimed to examine this pathway in hepatocarcinogenesis and to identify drug(s) specifically blocking this carcinogenic event in the liver. HBx transgenic mice that spontaneously develop HCC (n = 28-34 per group) were used, either by knockout of hepatic AR or by castration. Efficacy of several HCC-targeted drugs in suppressing HBx-induced AR activity was evaluated, and cellular factors mediating suppression were investigated in cultured cells. Tissue specificity of the candidate drug was validated using mouse tissues. Data were analyzed with Chi-square and Student's t tests. All statistical tests were two-sided. The androgen pathway was shown to be important in early stage hepatocarcinogenesis of HBx transgenic mice. The tumor incidence was decreased from 80% to 32% by AR knockout (P < .001) and from 90% to 25% by early castration (P < .001). Sorafenib markedly inhibited the HBx-enhanced AR activity through activating the SHP-1 phosphatase, which antagonized the activation of Akt/GSK3β and c-Src by HBx. Moreover, SHP-1 protein level was much higher in the liver than in testis, which enabled sorafenib to inhibit aberrant AR activity in the HBx-expressing liver, while not affecting the physiological AR function in normal liver or testis. The androgen pathway may be a druggable target for the chemoprevention of HBV-related HCC, and sorafenib might be used as a tissue- and disease-specific regimen for the chemoprevention of HBV-related HCC. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Key learnings from the Endocrine Disruptor Screening Program (EDSP) Tier 1 rodent uterotrophic and Hershberger assays.

PubMed

Marty, M Sue; O'Connor, John C

2014-02-01

In 2009, companies began screening compounds using the US Environmental Protection Agency's Endocrine Disruptor Screening Program (EDSP). EDSP has two tiers: Tier 1 includes 11 assays to identify compounds with potential endocrine activity. This article describes two laboratories' experiences conducting Tier 1 uterotrophic and Hershberger assays. The uterotrophic assay detects estrogen receptor agonists through increases in uterine weight. The advantages of the uterotrophic rat models (immature vs. adult ovariectomized) and exposure routes are discussed. Across 29 studies, relative differences in uterine weights in the vehicle control group and 17α-ethynylestradiol-positive control group were reasonably reproducible. The Hershberger assay detects androgen receptor (AR) agonists, antagonists, and 5α-reductase inhibitors through changes in accessory sex tissue (AST) weights. Across 23 studies, AST weights were relatively reproducible for the vehicle groups (baseline), testosterone propionate (TP) groups (androgenic response), and flutamide + TP groups (antiandrogenic response). In one laboratory, one and four compounds were positive in the androgenic and antiandrogenic portions of the assay, respectively. Each compound was also positive for AR binding. In the other laboratory, three compounds showed potential antiandrogenic activity, but each compound was negative for AR binding and did not fit the profile for 5α-reductase inhibition. These compounds induced hepatic enzymes that enhanced testosterone metabolism/clearance, resulting in lower testosterone and decreased capacity to maintain AST weights. The Hershberger androgenic and antiandrogenic performance criteria were generally attainable. Overall, the uterotrophic and Hershberger assays were easily adopted and function as described for EDSP screening, although the mode of action for positive results may not be easily determined. © 2014 Wiley Periodicals, Inc.

Role of IKKalpha and STAT3 in the Emergence of Castration-Resistant Prostate Cancer

DTIC Science & Technology

2013-06-01

non-infectious, attenuated , live Salmonella typhimurium vector (Loeffler et al., 2006). This vaccine strategy was shown to induce a strong cytotoxic...androgen-deprived tumor stroma we orally administered a DNA vaccine encoding FAP that is specifically delivered to secondary lymphoid tissues by a...expressing cells using this vaccine also resulted in the disappearance of myofibroblasts that are positive for CXCL13 in the stroma of androgen

STRATEGIES TO REDUCE OR REPLACE THE USE OF ANIMALS IN THE ENDOCRINE SCREENING AND TESTING PROGRAM.

EPA Science Inventory

Abstract: The US Environmental Protection Agency (EPA) is developing a screening and testing program for endocrine disrupting chemicals (EDCs) to detect alterations of hypothalamic-pituitary-gonadal (HPG) function, estrogen, androgen and thyroid hormone synthesis and androgen (AR...

Investigation of the In Vitro and In Vivo efficiency of RM-532-105, a 17β-hydroxysteroid dehydrogenase type 3 inhibitor, in LAPC-4 prostate cancer cell and tumor models

PubMed Central

Kenmogne, Lucie Carolle; Roy, Jenny; Maltais, René; Rouleau, Mélanie; Neveu, Bertrand; Pouliot, Frédéric; Poirier, Donald

2017-01-01

In the fight against androgen-sensitive prostate cancer, the enzyme 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) is an attractive therapeutic target considering its key role in the formation of androgenic steroids. In this study, we attempted to assess the in vivo efficacy of the compound RM-532-105, an androsterone derivative developed as an inhibitor of 17β-HSD3, in the prostate cancer model of androgen-sensitive LAPC-4 cells xenografted in nude mice. RM-532-105 did not inhibit the tumor growth induced by 4-androstene-3,17-dione (4-dione); rather, the levels of the androgens testosterone (T) and dihydrotestosterone (DHT) increased within the tumors. In plasma, however, DHT levels increased but T levels did not. In troubleshooting experiments, the non-androgenic potential of RM-532-105 was confirmed by two different assays (LAPC-4 proliferation and androgen receptor transcriptional activity assays). The enzyme 5α-reductase was also revealed to be the predominant enzyme metabolizing 4-dione in LAPC-4 cells, yielding 5α-androstane-3,17-dione and not T. Other 17β-HSDs than 17β-HSD3 seem responsible in the androgen synthesis. From experiments with LAPC-4 cells, we fortuitously came across the interesting finding that 17β-HSD3 inhibitor RM-532-105 is concentrated inside tumors. PMID:28182747

Modeling Truncated AR Expression in a Natural Androgen Responsive Environment and Identification of RHOB as a Direct Transcriptional Target

PubMed Central

Tsai, Hui-Chi; Boucher, David L.; Martinez, Anthony; Tepper, Clifford G.; Kung, Hsing-Jien

2012-01-01

Recent studies identifying putative truncated androgen receptor isoforms with ligand-independent activity have shed new light on the acquisition of androgen depletion independent (ADI) growth of prostate cancer. In this study, we present a model system in which a C-terminally truncated variant of androgen receptor (TC-AR) is inducibly expressed in LNCaP, an androgen-dependent cell line, which expresses little truncated receptor. We observed that when TC-AR is overexpressed, the endogenous full length receptor (FL-AR) is transcriptionally downmodulated. This in essence allows us to “replace” FL-AR with TC-AR and compare their individual properties in exactly the same genetic and cellular background, which has not been performed before. We show that the TC-AR translocates to the nucleus, activates transcription of AR target genes in the absence of DHT and is sufficient to confer ADI growth to the normally androgen dependent LNCaP line. We also show that while there is significant overlap in the genes regulated by FL- and TC-AR there are also differences in the respective suites of target genes with each AR form regulating genes that the other does not. Among the genes uniquely activated by TC-AR is RHOB which is shown to be involved in the increased migration and morphological changes observed in LN/TC-AR, suggesting a role of RHOB in the regulation of androgen-independent behavior of prostate cancer cells. PMID:23209612

Withaferin A Induces Cell Death Selectively in Androgen-Independent Prostate Cancer Cells but Not in Normal Fibroblast Cells

PubMed Central

Nishikawa, Yukihiro; Okuzaki, Daisuke; Fukushima, Kohshiro; Mukai, Satomi; Ohno, Shouichi; Ozaki, Yuki; Yabuta, Norikazu; Nojima, Hiroshi

2015-01-01

Withaferin A (WA), a major bioactive component of the Indian herb Withania somnifera, induces cell death (apoptosis/necrosis) in multiple types of tumor cells, but the molecular mechanism underlying this cytotoxicity remains elusive. We report here that 2 μM WA induced cell death selectively in androgen-insensitive PC-3 and DU-145 prostate adenocarcinoma cells, whereas its toxicity was less severe in androgen-sensitive LNCaP prostate adenocarcinoma cells and normal human fibroblasts (TIG-1 and KD). WA also killed PC-3 cells in spheroid-forming medium. DNA microarray analysis revealed that WA significantly increased mRNA levels of c-Fos and 11 heat-shock proteins (HSPs) in PC-3 and DU-145, but not in LNCaP and TIG-1. Western analysis revealed increased expression of c-Fos and reduced expression of the anti-apoptotic protein c-FLIP(L). Expression of HSPs such as HSPA6 and Hsp70 was conspicuously elevated; however, because siRNA-mediated depletion of HSF-1, an HSP-inducing transcription factor, reduced PC-3 cell viability, it is likely that these heat-shock genes were involved in protecting against cell death. Moreover, WA induced generation of reactive oxygen species (ROS) in PC-3 and DU-145, but not in normal fibroblasts. Immunocytochemistry and immuno-electron microscopy revealed that WA disrupted the vimentin cytoskeleton, possibly inducing the ROS generation, c-Fos expression and c-FLIP(L) suppression. These observations suggest that multiple events followed by disruption of the vimentin cytoskeleton play pivotal roles in WA-mediated cell death. PMID:26230090

Inhibition of Rat 5α-Reductase Activity and Testosterone-Induced Sebum Synthesis in Hamster Sebocytes by an Extract of Quercus acutissima Cortex

PubMed Central

Koseki, Junichi; Matsumoto, Takashi; Matsubara, Yosuke; Tsuchiya, Kazuaki; Mizuhara, Yasuharu; Sekiguchi, Kyoji; Nishimura, Hiroaki; Watanabe, Junko; Kaneko, Atsushi; Hattori, Tomohisa; Maemura, Kazuya; Kase, Yoshio

2015-01-01

Objective. Bokusoku (BK) is an extract from the Quercus cortex used in folk medicine for treatment of skin disorders and convergence, and is present in jumihaidokuto, a traditional Japanese medicine that is prescribed for purulent skin diseases like acne vulgaris. The excess of sebum production induced by androgen is involved in the development of acne. Our aim is to examine whether BK and its constituents inhibit testosterone metabolism and testosterone-induced sebum synthesis. Methods. Measurements of 5α-reductase activity and lipogenesis were performed using rat liver microsomes and hamster sebocytes, respectively. Results. BK dose-dependently reduced the conversion of testosterone to a more active androgen, dihydrotestosterone in a 5α-reductase enzymatic reaction. Twenty polyphenols in BK categorized as gallotannin, ellagitannin, and flavonoid were identified by LC-MS/MS. Nine polyphenols with gallate group, tetragalloyl glucose, pentagalloyl glucose, eugeniin, 1-desgalloyl eugeniin, casuarinin, castalagin, stenophyllanin C, (−)-epicatechin gallate, and (−)-epigallocatechin gallate, inhibited testosterone metabolism. In particular, pentagalloyl glucose showed the strongest activity. BK and pentagalloyl glucose suppressed testosterone-induced lipogenesis, whereas they weakly inhibited the lipogenic action of insulin. Conclusions. BK inhibited androgen-related pathogenesis of acne, testosterone conversion, and sebum synthesis, partially through 5α-reductase inhibition, and has potential to be a useful agent in the therapeutic strategy of acne. PMID:25709710

Androgen Receptor-Mediated Growth Suppression of HPr-1AR and PC3-Lenti-AR Prostate Epithelial Cells

PubMed Central

Bolton, Eric C.

2015-01-01

The androgen receptor (AR) mediates the developmental, physiologic, and pathologic effects of androgens including 5α-dihydrotestosterone (DHT). However, the mechanisms whereby AR regulates growth suppression and differentiation of luminal epithelial cells in the prostate gland and proliferation of malignant versions of these cells are not well understood, though they are central to prostate development, homeostasis, and neoplasia. Here, we identify androgen-responsive genes that restrain cell cycle progression and proliferation of human prostate epithelial cell lines (HPr-1AR and PC3-Lenti-AR), and we investigate the mechanisms through which AR regulates their expression. DHT inhibited proliferation of HPr-1AR and PC3-Lenti-AR, and cell cycle analysis revealed a prolonged G1 interval. In the cell cycle, the G1/S-phase transition is initiated by the activity of cyclin D and cyclin-dependent kinase (CDK) complexes, which relieve growth suppression. In HPr-1AR, cyclin D1/2 and CDK4/6 mRNAs were androgen-repressed, whereas CDK inhibitor, CDKN1A, mRNA was androgen-induced. The regulation of these transcripts was AR-dependent, and involved multiple mechanisms. Similar AR-mediated down-regulation of CDK4/6 mRNAs and up-regulation of CDKN1A mRNA occurred in PC3-Lenti-AR. Further, CDK4/6 overexpression suppressed DHT-inhibited cell cycle progression and proliferation of HPr-1AR and PC3-Lenti-AR, whereas CDKN1A overexpression induced cell cycle arrest. We therefore propose that AR-mediated growth suppression of HPr-1AR involves cyclin D1 mRNA decay, transcriptional repression of cyclin D2 and CDK4/6, and transcriptional activation of CDKN1A, which serve to decrease CDK4/6 activity. AR-mediated inhibition of PC3-Lenti-AR proliferation occurs through a similar mechanism, albeit without down-regulation of cyclin D. Our findings provide insight into AR-mediated regulation of prostate epithelial cell proliferation. PMID:26372468

[Neuroendocrine differentiation in prostate adenocarcinoma].

PubMed

Ramírez-Balderrama, Lázaro; López-Briones, Sergio; Daza-Benítez, Leonel; Macías, Maciste H; López-Gaytán, Teresa; Pérez-Vázquez, Victoriano

2013-01-01

The human prostate is a gland composed of many types of cells and extracellular components with specific functions. The stromal compartment includes nerve tissue, fibroblasts, lymphocytes, macrophages, endothelial cells, and smooth muscular cells. The epithelial compartment is composed of luminal epithelial cells, basal cells, and a lesser number of neuroendocrine cells, which are transcendental in growth regulation, differentiation, and secretory function. In prostate cancer, neuroendocrine cells replicate especially in high grade and advanced stage, and hormonally treated tumoral cells adopt characteristics that make them resistant to hormonal deprivation. Androgen receptors have a crucial role in tumorigenesis of prostate adenocarcinoma. Deprivation hormone therapy blocks the expression of androgen receptors in the prostatic epithelial cells. Neuroendocrine cells lack androgen receptors; their growth is hormonally independent and that is why deprivation hormonal therapy does not eliminate the neoplasic neuroendocrine cells. In contrast, these types of cells proliferate after therapy and make a paracrine network, stimulating the proliferation of androgen-independent neoplastic cells, which finally lead to tumoral recurrence. In this work we describe the neuroendocrine function in normal tissue and in prostatic adenocarcinoma, including neoplasic proliferation stimulation, invasion, apoptosis resistance, and angiogenesis, and describe some molecular pathways involved in this neuroendocrine differentiation.

Developmental Programming: Postnatal Estradiol Modulation of Prenatally Organized Reproductive Neuroendocrine Function in Sheep

PubMed Central

Puttabyatappa, Muraly; Cardoso, Rodolfo C.; Herkimer, Carol; Veiga-Lopez, Almudena; Padmanabhan, Vasantha

2016-01-01

Gestational testosterone (T) excess, acting via both the androgenic and estrogenic pathways, advances puberty and disrupts the neuroendocrine estradiol (E) feedback and periovulatory hormonal dynamics in female sheep. These prenatally programmed defects may be subject to postnatal modifications by continued organizational and/or activational effects of steroids. The present study investigated 1) the organizational contribution of prenatal estrogen excess and 2) the impact of postnatal exposure to E in modulating the effects of prenatal androgen excess (T and dihydrotestosterone [DHT]) on puberty, neuroendocrine feedback mechanisms, and periovulatory hormonal dynamics in sheep. Pregnant Suffolk sheep were treated with T, DHT, E, or E plus DHT (ED) from days 30 to 90 of gestation. A subset of the control (C), T, and DHT female offspring received a constant-release E implant postnatally. Findings revealed that 1) prenatal E-treatment failed to reproduce the neuroendocrine disruptions predicted to be programmed by the estrogenic pathway and 2) prenatal ED-treatment did not adequately replicate the reproductive neuroendocrine defects induced by prenatal T excess. More importantly, continuous postnatal E-treatment, while delaying the onset of puberty and reducing the inhibitory effects of E on tonic luteinizing hormone (LH) release, failed to amplify the E positive feedback and periovulatory defects induced by prenatal T-treatment. Our results indicate that disruptions in E positive feedback mechanisms and periovulatory gonadotropin secretion induced by prenatal T-treatment are programmed predominantly during the prenatal life with postnatal exposure to E excess not contributing further to these disruptions. PMID:27222598

Androgens and endometrium: New insights and new targets.

PubMed

Simitsidellis, Ioannis; Saunders, Philippa T K; Gibson, Douglas A

2018-04-15

Androgens are synthesised in both the ovary and adrenals in women and play an important role in the regulation of female fertility, as well as in the aetiology of disorders such as polycystic ovarian syndrome, endometriosis and endometrial cancer. The endometrium is an androgen target tissue and the impact of AR-mediated effects has been studied using human endometrial tissue samples and rodent models. In this review we highlight recent evidence that endometrial androgen biosynthesis and intracrine action is important in preparation of a tissue microenvironment that can support implantation and establishment of pregnancy. The impact of androgens on endometrial cell proliferation, in repair of the endometrial wound at the time of menstruation and in endometrial disorders is discussed. Future directions for research focused on AR function as a therapeutic target are considered. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

Testosterone and Erectile Function: From Basic Research to a New Clinical Paradigm for Managing Men with Androgen Insufficiency and Erectile Dysfunction

PubMed Central

Traish, Abdulmaged M.; Goldstein, Irwin; Kim, Noel N.

2007-01-01

Objectives Androgens are essential for the development and growth of the penis, and they regulate erectile physiology by multiple mechanisms. Our goal is to provide a concise overview of the basic research and how this knowledge can be translated into a new clinical paradigm for patient management. In addition, this new paradigm may serve as a basis for stimulating constructive debate regarding the use of testosterone in men, and to promote new, innovative basic and clinical research to further understand the underlying mechanisms of androgen action in restoring erectile physiology. Methods A literature review was performed utilizing the US National Library of Medicine's PubMed database. Results On the basis of evidence derived from laboratory animal studies and clinical data, we postulate that androgen insufficiency disrupts cellular-signaling pathways and produces pathologic alterations in penile tissues, leading to erectile dysfunction. In this review, we discuss androgen-dependent cellular, molecular, and physiologic mechanisms modulating erectile function in the animal model, and the implication of this knowledge in testosterone use in the clinical setting to treat erectile dysfunction. The new clinical paradigm incorporates many of the consensed points of view discussed in traditional consensed algorithms exclusively designed for men with androgen insufficiency. There are, however, novel and innovative differences with this new clinical paradigm. This paradigm represents a fresh effort to provide mandatory and optional management strategies for men with both androgen insufficiency and erectile dysfunction. Conclusions The new clinical paradigm is evidence-based and represents one of the first attempts to address a logical management plan for men with concomitant hormonal and sexual health concerns. PMID:17329016

Androgen and androgen metabolite levels in serum and urine of East African chimpanzees (Pan troglodytes schweinfurthii): comparison of EIA and LC-MS analyses.

PubMed

Preis, Anna; Mugisha, Lawrence; Hauser, Barbara; Weltring, Anja; Deschner, Tobias

2011-12-01

The primary male androgen testosterone (T) is often used as an endocrinological marker to investigate androgen-behaviour interactions in males. In chimpanzees and bonobos, studies investigating the relationship between T levels and dominance rank or aggressive behaviour have revealed contradictory results. The immunoassays used in these studies were originally developed for the measurement of steroids in serum. Their application to non-invasively collected samples, however, can lead to methodological problems due to cross-reacting metabolites, which might occur in urine or faeces but not in blood. The overall aim of this study, therefore, is to clarify whether a T enzyme immunoassay (EIA) is an applicable method to monitor testicular function in adult male chimpanzees. To estimate the impact of cross-reacting androgens on the used T EIA, we compared the results of an EIA measurement with a set of androgen metabolite levels measured by LC-MS. In urine from male chimpanzees, cross-reactivities appear to exist mainly with T and its exclusive metabolites, 5α-dihydrotestosterone (5α-DHT) and 5α-androstanediol (androstanediol). Both urinary and serum T levels of male chimpanzees were significantly higher than female T levels when measured with the T EIA, indicating a reliable measurement of testicular androgens and their exclusive metabolites with the used EIA. In urine from female chimpanzees, the comparison between LC-MS and T EIA results indicated a higher impact of cross-reactions with adrenal androgen metabolites. Therefore, the investigation of urinary T levels in female chimpanzees with a T EIA seems to be problematic. Overall our results show that a T EIA can be a reliable method to monitor testicular function in male chimpanzee urine and that LC-MS is a valuable tool for the validation of immunoassays. Copyright © 2011 Elsevier Inc. All rights reserved.

Expression profiles and functional associations of endogenous androgen receptor and caveolin-1 in prostate cancer cell lines.

PubMed

Bennett, Nigel C; Hooper, John D; Johnson, David W; Gobe, Glenda C

2014-05-01

In prostate cancer (PCa) patients, the protein target for androgen deprivation and blockade therapies is androgen receptor (AR). AR interacts with many proteins that function to either co-activate or co-repress its activity. Caveolin-1 (Cav-1) is not found in normal prostatic epithelium, but is found in PCa, and may be an AR co-regulator protein. We investigated cell line-specific signatures and associations of endogenous AR and Cav-1 in six PCa cell lines of known androgen sensitivity: LNCaP (androgen sensitive); 22Rv1 (androgen responsive); PC3, DU145, and ALVA41 (androgen non-reliant); and RWPE1 (non-malignant). Protein and mRNA expression profiles were compared and electron microscopy used to identify cells with caveolar structures. For cell lines expressing both AR and Cav-1, knockdown techniques using small interfering RNA against AR or Cav-1 were used to test whether diminished expression of one affected the other. Co-sedimentation of AR and Cav-1 was used to test their association. A reporter assay for AR genomic activity was utilized following Cav-1 knockdown. AR-expressing LNCaP and 22Rv1 cells had low endogenous Cav-1 mRNA and protein. Cell lines that expressed little or no AR (DU145, PC3, ALVA41, and RWPE1) expressed high endogenous levels of Cav-1. AR knockdown in LNCaP cells had little effect on Cav-1, but Cav-1 knockdown inhibited AR expression and genomic activity. These data show endogenous AR and Cav-1 mRNA and protein expression is inversely related in PCa cells, with Cav-1 acting on the androgen/AR signaling axis possibly as an AR co-activator, demonstrated by diminished AR genomic activity following Cav-1 knockdown. © 2013 Wiley Periodicals, Inc.

PAPSS2 Deficiency Causes Androgen Excess via Impaired DHEA Sulfation—In Vitro and in Vivo Studies in a Family Harboring Two Novel PAPSS2 Mutations

PubMed Central

Oostdijk, Wilma; Idkowiak, Jan; Mueller, Jonathan W.; House, Philip J.; Taylor, Angela E.; O'Reilly, Michael W.; Hughes, Beverly A.; de Vries, Martine C.; Kant, Sarina G.; Santen, Gijs W. E.; Verkerk, Annemieke J. M. H.; Uitterlinden, André G.; Wit, Jan M.; Losekoot, Monique

2015-01-01

Context: PAPSS2 (PAPS synthase 2) provides the universal sulfate donor PAPS (3′-phospho-adenosine-5′-phosphosulfate) to all human sulfotransferases, including SULT2A1, responsible for sulfation of the crucial androgen precursor dehydroepiandrosterone (DHEA). Impaired DHEA sulfation is thought to increase the conversion of DHEA toward active androgens, a proposition supported by the previous report of a girl with inactivating PAPSS2 mutations who presented with low serum DHEA sulfate and androgen excess, clinically manifesting with premature pubarche and early-onset polycystic ovary syndrome. Patients and Methods: We investigated a family harboring two novel PAPSS2 mutations, including two compound heterozygous brothers presenting with disproportionate short stature, low serum DHEA sulfate, but normal serum androgens. Patients and parents underwent a DHEA challenge test comprising frequent blood sampling and urine collection before and after 100 mg DHEA orally, with subsequent analysis of DHEA sulfation and androgen metabolism by mass spectrometry. The functional impact of the mutations was investigated in silico and in vitro. Results: We identified a novel PAPSS2 frameshift mutation, c.1371del, p.W462Cfs*3, resulting in complete disruption, and a novel missense mutation, c.809G>A, p.G270D, causing partial disruption of DHEA sulfation. Both patients and their mother, who was heterozygous for p.W462Cfs*3, showed increased 5α-reductase activity at baseline and significantly increased production of active androgens after DHEA intake. The mother had a history of oligomenorrhea and chronic anovulation that required clomiphene for ovulation induction. Conclusions: We provide direct in vivo evidence for the significant functional impact of mutant PAPSS2 on DHEA sulfation and androgen activation. Heterozygosity for PAPSS2 mutations can be associated with a phenotype resembling polycystic ovary syndrome. PMID:25594860

Developmental Programming: Prenatal and Postnatal Androgen Antagonist and Insulin Sensitizer Interventions Prevent Advancement of Puberty and Improve LH Surge Dynamics in Prenatal Testosterone-Treated Sheep

PubMed Central

Veiga-Lopez, Almudena; Herkimer, Carol; Abi Salloum, Bachir; Moeller, Jacob; Beckett, Evan; Sreedharan, Rohit

2015-01-01

Prenatal T excess induces maternal hyperinsulinemia, early puberty, and reproductive/metabolic defects in the female similar to those seen in women with polycystic ovary syndrome. This study addressed the organizational/activational role of androgens and insulin in programming pubertal advancement and periovulatory LH surge defects. Treatment groups included the following: 1) control; 2) prenatal T; 3) prenatal T plus prenatal androgen antagonist, flutamide; 4) prenatal T plus prenatal insulin sensitizer, rosiglitazone; 5) prenatal T and postnatal flutamide; 6) prenatal T and postnatal rosiglitazone; and 7) prenatal T and postnatal metformin. Prenatal treatments spanned 30–90 days of gestation and postnatal treatments began at approximately 8 weeks of age and continued throughout. Blood samples were taken twice weekly, beginning at approximately 12 weeks of age to time puberty. Two-hour samples after the synchronization with prostaglandin F2α were taken for 120 hours to characterize LH surge dynamics at 7 and 19 months of age. Prenatal T females entered puberty earlier than controls, and all interventions prevented this advancement. Prenatal T reduced the percentage of animals having LH surge, and females that presented LH surge exhibited delayed timing and dampened amplitude of the LH surge. Prenatal androgen antagonist, but not other interventions, restored LH surges without normalizing the timing of the surge. Normalization of pubertal timing with prenatal/postnatal androgen antagonist and insulin sensitizer interventions suggests that pubertal advancement is programmed by androgenic actions of T involving insulin as a mediary. Restoration of LH surges by cotreatment with androgen antagonist supports androgenic programming at the organizational level. PMID:25919188

Developmental Programming: Prenatal and Postnatal Androgen Antagonist and Insulin Sensitizer Interventions Prevent Advancement of Puberty and Improve LH Surge Dynamics in Prenatal Testosterone-Treated Sheep.

PubMed

Padmanabhan, Vasantha; Veiga-Lopez, Almudena; Herkimer, Carol; Abi Salloum, Bachir; Moeller, Jacob; Beckett, Evan; Sreedharan, Rohit

2015-07-01

Prenatal T excess induces maternal hyperinsulinemia, early puberty, and reproductive/metabolic defects in the female similar to those seen in women with polycystic ovary syndrome. This study addressed the organizational/activational role of androgens and insulin in programming pubertal advancement and periovulatory LH surge defects. Treatment groups included the following: 1) control; 2) prenatal T; 3) prenatal T plus prenatal androgen antagonist, flutamide; 4) prenatal T plus prenatal insulin sensitizer, rosiglitazone; 5) prenatal T and postnatal flutamide; 6) prenatal T and postnatal rosiglitazone; and 7) prenatal T and postnatal metformin. Prenatal treatments spanned 30-90 days of gestation and postnatal treatments began at approximately 8 weeks of age and continued throughout. Blood samples were taken twice weekly, beginning at approximately 12 weeks of age to time puberty. Two-hour samples after the synchronization with prostaglandin F2α were taken for 120 hours to characterize LH surge dynamics at 7 and 19 months of age. Prenatal T females entered puberty earlier than controls, and all interventions prevented this advancement. Prenatal T reduced the percentage of animals having LH surge, and females that presented LH surge exhibited delayed timing and dampened amplitude of the LH surge. Prenatal androgen antagonist, but not other interventions, restored LH surges without normalizing the timing of the surge. Normalization of pubertal timing with prenatal/postnatal androgen antagonist and insulin sensitizer interventions suggests that pubertal advancement is programmed by androgenic actions of T involving insulin as a mediary. Restoration of LH surges by cotreatment with androgen antagonist supports androgenic programming at the organizational level.

Molecular Targeting of Prostate Cancer During Androgen Ablation: Inhibition of CHES1/FOXN3

DTIC Science & Technology

2010-05-10

target of rapamycin ( mTOR ) and hypoxia-inducible factor-1α (HIF-1α) target genes (12). Additionally, transcriptional activation of Bcl-2 by NF-κB...in resistance to hormone therapy (19). Elevated expression of genes encoding PI3K/Akt/ mTOR pathway components has also been implicated in androgen... mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat Med, 10

The Role of the Caspase-8 Inhibitor FLIP in Androgen-Withdrawal Induced Death of Prostate Epithelium

DTIC Science & Technology

2007-01-01

cells. Cancer Res 2000;60:2384-9. 20. Voelkel-Johnson C, King DL, Norris JS. Resistance of prostate cancer cells to soluble TNF-related apoptosis...Mukhopadhyay A, Bueso-Ramos C, Chatterjee D, Pantazis P, Aggarwal BB. Curcumin downregulates cell survival mechanisms in human prostate cancer cell...ethanol. LY294002 (Cayman) was dissolved in Androgens and FOXO3a regulate FLIP page 7 dimethylsulfoxide (DMSO). Soluble recombinant human TRAIL (Biomol

Histological and transcriptomic effects of 17α-methyltestosterone on zebrafish gonad development.

PubMed

Lee, Stephanie Ling Jie; Horsfield, Julia A; Black, Michael A; Rutherford, Kim; Fisher, Amanda; Gemmell, Neil J

2017-07-24

Sex hormones play important roles in teleost ovarian and testicular development. In zebrafish, ovarian differentiation appears to be dictated by an oocyte-derived signal via Cyp19a1a aromatase-mediated estrogen production. Androgens and aromatase inhibitors can induce female-to-male sex reversal, however, the mechanisms underlying gonadal masculinisation are poorly understood. We used histological analyses together with RNA sequencing to characterise zebrafish gonadal transcriptomes and investigate the effects of 17α-methyltestosterone on gonadal differentiation. At a morphological level, 17α-methyltestosterone (MT) masculinised gonads and accelerated spermatogenesis, and these changes were paralleled in masculinisation and de-feminisation of gonadal transcriptomes. MT treatment upregulated expression of genes involved in male sex determination and differentiation (amh, dmrt1, gsdf and wt1a) and those involved in 11-oxygenated androgen production (cyp11c1 and hsd11b2). It also repressed expression of ovarian development and folliculogenesis genes (bmp15, gdf9, figla, zp2.1 and zp3b). Furthermore, MT treatment altered epigenetic modification of histones in zebrafish gonads. Contrary to expectations, higher levels of cyp19a1a or foxl2 expression in control ovaries compared to MT-treated testes and control testes were not statistically significant during early gonad development (40 dpf). Our study suggests that both androgen production and aromatase inhibition are important for androgen-induced gonadal masculinisation and natural testicular differentiation in zebrafish.

Cardiac Nitric Oxide Synthases and Na⁺/K⁺-ATPase in the Rat Model of Polycystic Ovary Syndrome Induced by Dihydrotestosterone.

PubMed

Tepavčević, S; Milutinović, D V; Macut, D; Stanišić, J; Nikolić, M; Božić-Antić, I; Rodaljević, S; Bjekić-Macut, J; Matić, G; Korićanac, G

2015-05-01

Nitric oxide synthases (NOSs) and Na(+)/K(+)-ATPase are enzymes essential for regular functioning of the heart. Since both enzymes are under insulin and androgen regulation and since insulin action and androgen level were disturbed in polycystic ovary syndrome (PCOS), we hypothesized that cardiac nitric oxide (NO) production and sodium/potassium transport would be deteriorated in PCOS. To test our hypothesis we introduced animal model of PCOS based on dihydrotestosterone (DHT) treatment of female Wistar rats and analyzed protein expression, phosphorylation or subcellular localization of endothelial NOS (eNOS), inducible NOS (iNOS) and alpha subunits of Na(+)/K(+)-ATPase in the heart. Obtained results indicate that DHT treatment significantly decreased cardiac eNOS protein level and activating phosphorylation at serine 1,177, while inhibitory phosphorylation at threonine 495 was increased. In contrast to expression of eNOS, iNOS protein level in the heart of DHT-treated rats was significantly elevated. Furthermore, cardiac protein level of alpha 1 subunit of the ATPase, as well as its plasma membrane content, were decreased in rats with PCOS. In line with this, alpha 2 subunit protein level in fraction of plasma membranes was also significantly below control level. In conclusion, DHT treatment impaired effectiveness of NOSs and Na(+)/K(+)-ATPase in the female rat heart. Regarding the importance of NO production and sodium/potassium transport in the cardiac contraction and blood flow regulation, it implicates strong consequences of PCOS for heart functioning. © Georg Thieme Verlag KG Stuttgart · New York.

Species comparisons in molecular and functional attributes of the androgen and estrogen receptor

EPA Science Inventory

While endocrine disrupting compounds (EDCs) have the potential to act via several mechanisms of action, one of the most widely studied is the ability of environmental chemicals to interact directly with either the estrogen (ER) or androgen receptor (AR). In vitro screening assay...

Identification of Androgen Receptor Antagonists in Fish Using a Simple Bioassay with the Fathead Minnow Pimephales promelas .

EPA Science Inventory

Considerable effort has been expended on the development of bioassays to detect chemicals that affect endocrine function controlled by the vertebrate hypothalamic-pituitary-gonadal (HPG) axis via different mechanisms/modes of action (MOA). Antagonism of the androgen receptor (AR)...

Antihypertensive effects of androgens in conscious, spontaneously hypertensive rats.

PubMed

Perusquía, Mercedes; Herrera, Nieves; Ferrer, Mercedes; Stallone, John N

2017-03-01

Androgens are vasoactive steroids that induce acute vasodilation in a number of isolated vascular beds from different species, but the effects of these hormones on systemic blood pressure (BP) have been studied little. Although it has been reported that androgens exert systemic hypotensive effects through peripheral vasodilation in normotensive rats, there have not been any reports of systemic hypotensive effects of androgens in animals with hypertension. This study was designed to evaluate the acute effects of testosterone (TES) and its 5-reduced metabolites on systemic BP in hypertensive rats and to test the hypothesis that hypotestosteronemia may be involved in the pathogenesis of hypertension. Chronic, indwelling catheters were implanted in carotid artery and jugular vein of 18-21-week-old male spontaneously hypertensive rats (SHR) and normotensive-control Wistar-Kyoto (WKY) rats, for BP recording and drug administration, respectively. Bolus injections of TES, 5α- or 5β-dihydrotestosterone (5α- and 5β-DHT), were administrated cumulatively to conscious rats at doses of 0.1-100μmolkg -1 min -1 . 5β-DHT was also administrated during the pressor effect of Bay K 8644, an L-type voltage-operated Ca 2+ channel (L-VOCC) agonist. In separate experiments, BP of orchidectomized normotensive male WKY and Wistar rats, with or without androgen-replacement therapy, was evaluated weekly for 10 weeks by tail-cuff plethysmography. TES and its metabolites reduced BP in a dose-dependent manner, while heart rate was reduced with some androgens at the highest doses. The hypotensive effects of androgens were markedly greater in SHR, with a rank order potency of: 5β-DHT>TES>5α-DHT. 5β-DHT, the most potent antihypertensive androgen, abolished the pressor response to Bay K 8644 in SHR. TES deprivation by orchidectomy increased BP in normotensive WKY and Wistar rats, but this hypertension was prevented by TES replacement therapy. BP responses to androgens are androgen structure-dependent. These data indicate that: 1) androgens play a significant role in the control of BP and may contribute to the pathogenesis of hypertension; 2) blockade of L-VOCC is involved in the antihypertensive effects of androgens, which are non-genomically mediated; and 3) hypotestosteronemia may be a risk factor for hypertension. Copyright © 2016 Elsevier Ltd. All rights reserved.

Development and exploitation of a novel mutant androgen receptor modelling strategy to identify new targets for advanced prostate cancer therapy

PubMed Central

O'Neill, Daniel; Jones, Dominic; Wade, Mark; Grey, James; Nakjang, Sirintra; Guo, Wenrui; Cork, David; Davies, Barry R.; Wedge, Steve R.; Robson, Craig N.; Gaughan, Luke

2015-01-01

The persistence of androgen receptor (AR) signalling in castrate-resistant prostate cancer (CRPC) highlights the unmet clinical need for the development of more effective AR targeting therapies. A key mechanism of therapy-resistance is by selection of AR mutations that convert anti-androgens to agonists enabling the retention of androgenic signalling in CRPC. To improve our understanding of these receptors in advanced disease we developed a physiologically-relevant model to analyse the global functionality of AR mutants in CRPC. Using the bicalutamide-activated ARW741L/C mutation as proof of concept, we demonstrate that this mutant confers an androgenic-like signalling programme and growth promoting phenotype in the presence of bicalutamide. Transcriptomic profiling of ARW741L highlighted key genes markedly up-regulated by the mutant receptor, including TIPARP, RASD1 and SGK1. Importantly, SGK1 expression was found to be highly expressed in the KUCaP xenograft model and a CRPC patient biopsy sample both of which express the bicalutamide-activated receptor mutant. Using an SGK1 inhibitor, ARW741L transcriptional and growth promoting activity was reduced indicating that exploiting functional distinctions between receptor isoforms in our model may provide new and effective therapies for CRPC patients. PMID:26267320

An alternate pathway for androgen regulation of brain function: Activation of estrogen receptor beta by the metabolite of dihydrotestosterone, 5α-androstane 3β, 17β diol

PubMed Central

Handa, Robert J.; Pak, Toni R.; Kudwa, Andrea E.; Lund, Trent D.; Hinds, Laura

2008-01-01

The complexity of gonadal steroid hormone actions is reflected in their broad and diverse effects on a host of integrated systems including reproductive physiology, sexual behavior, stress responses, immune function, cognition, and neural protection. Understanding the specific contributions of androgens and estrogens in neurons that mediate these important biological processes is central to the study of neuroendocrinology. Of particular interest in recent years has been the biological role of androgen metabolites. The goal of this review is to highlight recent data delineating the specific brain targets for the dihydrotestosterone metabolite, 5α-androstane, 3β, 17β-diol (3β-Diol). Studies using both in vitro and in vivo approaches provide compelling evidence that 3β-Diol is an important modulator of the stress response mediated by the hypothalmo-pituitary-adrenal axis. Further, the actions of 3β-Diol are mediated by estrogen receptors, and not androgen receptors, often through a canonical estrogen response element in the promoter of a given target gene. These novel findings compel us to re-evaluate the interpretation of past studies and the design of future experiments aimed at elucidating the specific effects of androgen receptor signaling pathways. PMID:18067894

Allosteric alterations in the androgen receptor and activity in prostate cancer.

PubMed

Uo, Takuma; Plymate, Stephen R; Sprenger, Cynthia C

2017-09-01

Organisms have evolved to generate biological complexity in their proteome and transcriptome from a limited number of genes. This concept holds true for the androgen receptor, which displays a diversity of inclusion/exclusion events in its structural motifs as a mechanism of resistance to the most forefront anti-androgen therapies. More than 20 androgen receptor variants that lack various portions of ligand-binding domain have been identified in human prostate cancer (PCa) samples. Most of the variants are inactive on their own, with a few exceptions displaying constitutive activity. The full-length receptor and one or more variants can be co-expressed in the same cell under many circumstances, which raises the question of how these variants physically and functionally interact with the full-length receptor or one another in the course of PCa progression. To address this issue, in this review, we will characterize and discuss androgen receptor variants, including the novel variants discovered in the last couple of years (i) individually, (ii) with respect to their physical and functional interaction with one another and (iii) in clinical relevance. Here, we also introduce the very recent understanding of AR-Vs obtained through successful development of some AR-V-specific antibodies as well as identification of novel AR-Vs by data mining approaches. © 2017 Society for Endocrinology.

Modulatory role of androgenic and estrogenic neurosteroids in determining the direction of synaptic plasticity in the CA1 hippocampal region of male rats

PubMed Central

Pettorossi, Vito Enrico; Di Mauro, Michela; Scarduzio, Mariangela; Panichi, Roberto; Tozzi, Alessandro; Calabresi, Paolo; Grassi, Silvarosa

2013-01-01

Abstract Estrogenic and androgenic neurosteroids can rapidly modulate synaptic plasticity in the brain through interaction with membrane receptors for estrogens (ERs) and androgens (ARs). We used electrophysiological recordings in slices of young and adolescent male rats to explore the influence of sex neurosteroids on synaptic plasticity in the CA1 hippocampal region, by blocking ARs or ERs during induction of long‐term depression (LTD) and depotentiation (DP) by low‐frequency stimulation (LFS) and long‐term potentiation (LTP) by high‐frequency stimulation (HFS). We found that LTD and DP depend on ARs, while LTP on ERs in both age groups. Accordingly, the AR blocker flutamide affected induction of LTD reverting it into LTP, and prevented DP, while having no effect on HFS‐dependent LTP. Conversely, ER blockade with ICI 182,780 (ICI) markedly reduced LTP, but did not influence LTD and DP. However, the receptor blockade did not affect the maintenance of either LTD or LTP. Moreover, we found that similar to LTP and LTD induced in control condition, the LTP unveiled by flutamide during LFS and residual LTP induced by HFS under ICI depended on N‐methyl‐d aspartate receptor (NMDAR) activation. Furthermore, as the synaptic paired‐pulse facilitation (PPF) was not affected by either AR or ER blockade, we suggest that sex neurosteroids act primarily at a postsynaptic level. This study demonstrates for the first time the crucial role of estrogenic and androgenic neurosteroids in determining the sign of hippocampal synaptic plasticity in male rat and the activity‐dependent recruitment of androgenic and estrogenic pathways leading to LTD and LTP, respectively. PMID:24744863

Modulatory role of androgenic and estrogenic neurosteroids in determining the direction of synaptic plasticity in the CA1 hippocampal region of male rats.

PubMed

Pettorossi, Vito Enrico; Di Mauro, Michela; Scarduzio, Mariangela; Panichi, Roberto; Tozzi, Alessandro; Calabresi, Paolo; Grassi, Silvarosa

2013-12-01

Estrogenic and androgenic neurosteroids can rapidly modulate synaptic plasticity in the brain through interaction with membrane receptors for estrogens (ERs) and androgens (ARs). We used electrophysiological recordings in slices of young and adolescent male rats to explore the influence of sex neurosteroids on synaptic plasticity in the CA1 hippocampal region, by blocking ARs or ERs during induction of long-term depression (LTD) and depotentiation (DP) by low-frequency stimulation (LFS) and long-term potentiation (LTP) by high-frequency stimulation (HFS). We found that LTD and DP depend on ARs, while LTP on ERs in both age groups. Accordingly, the AR blocker flutamide affected induction of LTD reverting it into LTP, and prevented DP, while having no effect on HFS-dependent LTP. Conversely, ER blockade with ICI 182,780 (ICI) markedly reduced LTP, but did not influence LTD and DP. However, the receptor blockade did not affect the maintenance of either LTD or LTP. Moreover, we found that similar to LTP and LTD induced in control condition, the LTP unveiled by flutamide during LFS and residual LTP induced by HFS under ICI depended on N-methyl-d aspartate receptor (NMDAR) activation. Furthermore, as the synaptic paired-pulse facilitation (PPF) was not affected by either AR or ER blockade, we suggest that sex neurosteroids act primarily at a postsynaptic level. This study demonstrates for the first time the crucial role of estrogenic and androgenic neurosteroids in determining the sign of hippocampal synaptic plasticity in male rat and the activity-dependent recruitment of androgenic and estrogenic pathways leading to LTD and LTP, respectively.

Androgen Deprivation Accelerates the Prostatic Urethra Wound Healing After Thulium Laser Resection of the Prostate by Promoting Re-Epithelialization and Regulating the Macrophage Polarization.

PubMed

Wang, Xing-Jie; Zhuo, Jian; Luo, Guang-Heng; Zhu, Yi-Ping; Yu, Dian-Jun; Zhao, Rui-Zhe; Jiang, Chen-Yi; Shi, Yun-Feng; Li, Hao; Chen, Lei; Hao, Kui-Yuan; Han, Xia; Zhao, Sheng; Bei, Xiao-Yu; Jing, Yi-Feng; Xia, Shu-Jie

2017-05-01

Complications after a thulium laser resection of the prostate (TmLRP) are related to re-epithelialization of the prostatic urethra. Since prostate growth and development are induced by androgen, the aim of this study was to determine the role and explore the mechanism of androgen in wound healing of the prostatic urethra. Beagles that received TmLRPs were randomly distributed into a castration group, a testosterone undecanoate (TU) group, and a control group. The prostate wound was assessed once a week using a cystoscope. Histological analysis was then carried out to study the re-epithelialization of the prostatic urethra in each group. The inflammatory response in the wound tissue and urine was also investigated. The healing of the prostatic urethra after a TmLRP was more rapid in the castration group and slower in the TU group than that in the control group. Castration accelerated re-epithelialization by promoting basal cell proliferation in the wound surface and beneath the wound and by accelerating the differentiation of basal cells into urothelial cells. Castration reduced the duration of the inflammatory phase and induced the conversion of M1 macrophages to M2 macrophages, thus accelerating the maturation of the wound. By contrast, androgen supplementation enhanced the inflammatory response and prolonged the inflammatory phase. Moreover, the anti-inflammatory phase was delayed and weakened. Androgen deprivation promotes re-epithelialization of the wound, regulates the inflammatory response, and accelerates wound healing of the prostatic urethra after a TmLRP. Prostate 77:708-717, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Methyltestosterone-induced changes in electro-olfactogram responses and courtship behaviors of cyprinids.

PubMed

Belanger, Rachelle M; Pachkowski, Melanie D; Stacey, Norm E

2010-01-01

In the tinfoil barb (Barbonymus schwanenfeldii; family Cyprinidae), we previously found that increased olfactory sensitivity to a female prostaglandin pheromone could induce sexual behavior display in juvenile fish treated with androgens. Here, we determined if this phenomenon is widespread among cyprinid fishes by adding 17alpha-methyltestosterone (MT) to aquaria containing juveniles of 4 cyprinid species (tinfoil barbs; redtail sharkminnows, Epalzeorhynchos bicolor; goldfish, Carassius auratus; zebrafish, Danio rerio) and then using electro-olfactogram (EOG) recordings and behavioral assays to determine if androgen treatment enhances pheromone detection and male sex behaviors. In all 4 cyprinids, MT treatment increased the magnitudes and sensitivities of EOG response to prostaglandins and, consistent with our initial study on tinfoil barbs, did not affect EOG responses to the free and conjugated steroid to which each species is most sensitive. In zebrafish, EOG responses to prostaglandins were similar in MT-treated juveniles and adult males, whereas responses of control (ethanol exposed) fish were similar to those of adult females. Finally, as previously observed in tinfoil barbs, MT treatment of juvenile redtail sharkminnows increased courtship behaviors (nuzzling and quivering) with a stimulus fish. We conclude that androgen-induced increase in olfactory responsiveness to pheromonal prostaglandins is common among the family Cyprinidae. This phenomenon will help us unravel the development of sexually dimorphic olfactory-mediated behavior.

Androgen Receptor Roles in Insulin Resistance and Obesity in Males: The Linkage of Androgen-Deprivation Therapy to Metabolic Syndrome

PubMed Central

Yu, I-Chen; Lin, Hung-Yun; Sparks, Janet D.; Yeh, Shuyuan

2014-01-01

Prostate cancer (PCa) is one of the most frequently diagnosed malignancies in men. Androgen-deprivation therapy (ADT) is the first-line treatment and fundamental management for men with advanced PCa to suppress functions of androgen/androgen receptor (AR) signaling. ADT is effective at improving cancer symptoms and prolonging survival. However, epidemiological and clinical studies support the notion that testosterone deficiency in men leads to the development of metabolic syndrome that increases cardiovascular disease risk. The underlying mechanisms by which androgen/AR signaling regulates metabolic homeostasis in men are complex, and in this review, we discuss molecular mechanisms mediated by AR signaling that link ADT to metabolic syndrome. Results derived from various AR knockout mouse models reveal tissue-specific AR signaling that is involved in regulation of metabolism. These data suggest that steps be taken early to manage metabolic complications associated with PCa patients receiving ADT, which could be accomplished using tissue-selective modulation of AR signaling and by treatment with insulin-sensitizing agents. PMID:25249645

Impact of Early Postnatal Androgen Exposure on Voice Development

PubMed Central

Grisa, Leila; Leonel, Maria L.; Gonçalves, Maria I. R.; Pletsch, Francisco; Sade, Elis R.; Custódio, Gislaine; Zagonel, Ivete P. S.; Longui, Carlos A.; Figueiredo, Bonald C.

2012-01-01

Background The impact of early postnatal androgen exposure on female laryngeal tissue may depend on certain characteristics of this exposure. We assessed the impact of the dose, duration, and timing of early androgen exposure on the vocal development of female subjects who had been treated for adrenocortical tumor (ACT) in childhood. Methods The long-term effects of androgen exposure on the fundamental vocal frequency (F0), vocal pitch, and final height and the presence of virilizing signs were examined in 9 adult (age, 18.4 to 33.5 years) and 10 adolescent (13.6 to 17.8 years) female ACT patients. We also compared the current values with values obtained 0.9 years to 7.4 years after these subjects had undergone ACT surgery, a period during which they had shown normal androgen levels. Results Of the 19 subjects, 17 (89%) had been diagnosed with ACT before 4 years of age, 1 (5%) at 8.16 years, and 1 (5%) at 10.75 years. Androgen exposure (2 to 30 months) was sufficiently strong to cause pubic hair growth in all subjects and clitoromegaly in 74% (14/19) of the subjects, but did not reduce their height from the target value. Although androgen exposure induced a remarkable reduction in F0 (132 Hz) and moderate pitch virilization in 1 subject and partial F0 virilization, resulting in F0 of 165 and 169 Hz, in 2 subjects, the majority had normal F0 ranging from 189 to 245 Hz. Conclusions Female laryngeal tissue is less sensitive to androgen exposure between birth and adrenarche than during other periods. Differential larynx sensitivity to androgen exposure in childhood and F0 irreversibility in adulthood are age-, concentration-, duration-, and timing-dependent events that may also be affected by exposure to inhibitory or stimulatory hormones. Further studies are required to better characterize each of these factors. PMID:23284635

14-3-3η Amplifies Androgen Receptor Actions in Prostate Cancer

PubMed Central

Titus, Mark A.; Tan, Jiann-an; Gregory, Christopher W.; Ford, O. Harris; Subramanian, Romesh R.; Fu, Haian; Wilson, Elizabeth M.; Mohler, James L.; French, Frank S.

2009-01-01

Purpose Androgen receptor (AR) abundance and AR-regulated gene expression in castration-recurrent prostate cancer (CaP) are indicative of AR activation in the absence of testicular androgen. AR transactivation of target genes in castration-recurrent CaP occurs in part through mitogen signaling that amplifies the actions of AR and its coregulators. Herein we report on the role of 14-3-3η in AR action. Experimental Design and Results AR and 14-3-3η co-localized in COS cell nuclei with and without androgen and 14-3-3η promoted AR nuclear localization in the absence of androgen. 14-3-3η interacted with AR in cell-free binding and coimmunoprecipitation assays. In the recurrent human CaP cell line, CWR-R1, native endogenous AR transcriptional activation was stimulated by 14-3-3η at low DHT concentrations and was increased by EGF. Moreover, the DHT and EGF dependent increase in AR transactivation was inhibited by a dominant negative 14-3-3η. In the CWR22 CaP xenograft model, 14-3-3η expression was increased by androgen, suggesting a feed-forward mechanism that potentiates both 14-3-3η and AR actions. 14-3-3η mRNA and protein decreased following castration of tumor bearing mice and increased in tumors of castrate mice after treatment with testosterone. CWR22 tumors that recurred 5 months after castration contained 14-3-3η levels similar to the androgen-stimulated tumors removed before castration. In a human prostate tissue microarray of clinical specimens, 14-3-3η localized with AR in nuclei and the similar amounts expressed in castration-recurrent CaP, androgen-stimulated CaP and benign prostatic hyperplasia were consistent with AR activation in recurrent CaP. Conclusion 14-3-3η enhances androgen and mitogen induced AR transcriptional activity in castration-recurrent CaP. PMID:19996220

Oral contraception vs insulin sensitization for 18 months in nonobese adolescents with androgen excess: posttreatment differences in C-reactive protein, intima-media thickness, visceral adiposity, insulin sensitivity, and menstrual regularity.

PubMed

Ibáñez, Lourdes; Díaz, Marta; Sebastiani, Giorgia; Marcos, María Victoria; López-Bermejo, Abel; de Zegher, Francis

2013-05-01

An oral estro-progestagen is the standard medication given to adolescent girls with androgen excess, even when those girls are not at risk of pregnancy. The aim of this study was to compare on-treatment and post-treatment effects of intervention with an oral contraceptive vs an insulin-sensitizing treatment for androgen excess in nonobese adolescents. This was a randomized, open-label trial. Subjects were nonobese adolescent girls with hyperinsulinemic androgen excess and without risk of pregnancy (mean age, 16 years; body mass index, 23 kg/m²; n = 34). The effects of treatment with ethinylestradiol-cyproteroneacetate (EE-CA) vs a low-dose combination of pioglitazone (7.5 mg/d), flutamide (62.5 mg/d), and metformin (850 mg/d) (PioFluMet) for 18 months were studied. Posttreatment follow-up was for 6 months. Androgen excess (hirsutism and acne scores and serum testosterone), glucose-stimulated insulinemia, circulating C-reactive protein, carotid intima media thickness, body composition (absorptiometry), abdominal fat partitioning (magnetic resonance imaging), and menstrual regularity were measured. EE-CA and PioFluMet attenuated androgen excess similarly but had divergent, and even opposing, effects on other outcomes. Six months posttreatment, the PioFluMet-treated girls had a lower glucose-induced insulinemia, a lower C-reactive protein level, and a thinner intima media than the EE-CA-treated girls, and they were viscerally less adipose, had a higher lean mass, and were more likely to have regular cycles. The on-treatment and post-treatment effects of PioFluMet compared favorably with those of oral contraception in nonobese adolescents with androgen excess. The intervention whereby androgen excess is reduced in adolescence influences the post-treatment phenotype. PioFluMet-like interventions in adolescence may thus hold the potential to prevent part of the androgen-excess phenotype in adulthood, including adiposity and subfertility.

Manipulation of pre and postnatal androgen environments and anogenital distance in rats.

PubMed

Kita, Diogo H; Meyer, Katlyn B; Venturelli, Amanda C; Adams, Rafaella; Machado, Daria L B; Morais, Rosana N; Swan, Shanna H; Gennings, Chris; Martino-Andrade, Anderson J

2016-08-10

We examined the anogenital distance (AGD) plasticity in rats through the manipulation of the androgen environment in utero and during puberty. Dams were treated from gestation days 13-20 with vehicle, flutamide (20mg/kg/day), di-(2-ethylhexyl) phthalate (DEHP, 750mg/kg/day), or testosterone (1.0mg/kg/day). After weaning, male pups were randomly assigned to one of four postnatal groups, which received the same treatments given prenatally. Sixteen treatment groups were established based on the combination of pre- and postnatal exposures. The postnatal treatments were conducted from postnatal days 23-53. In utero flutamide and DEHP exposure significantly shortened male AGD, although this effect was more pronounced in flutamide-exposed rats. Postnatal flutamide, DEHP, and testosterone induced slight but significant reductions in male AGD. Our study indicates that AGD is a stable anatomical landmark that reflects the androgen action in utero, although it can also be slightly responsive to changes in the androgen environment following pubertal exposure. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Androgen-induced cerebral venous sinus thrombosis in a young body builder: case report

PubMed Central

Sahraian, Mohammad Ali; Mottamedi, Mahmood; Azimi, Amir Reza; Moghimi, Babak

2004-01-01

Background Cerebral venous sinus thrombosis is an infrequent disease with a variety of causes. Pregnancy, puerperium, contraceptive pills and intracranial infections are the most common causes. The patient may present with headache, focal neurological deficits and seizures. The clinical outcome is highly variable and treatment with heparin is advised. Case presentation The patient is a 22 year old male who presented with headache, repeated vomiting and papilledema. He was a bodybuilder doing exercise since 5 years ago, who had used nandrolone decaonoate 25 milligrams intramuscularly during the previous 5 months. Brain MRI and MRV showed superior sagital and transverse sinus thrombosis and extensive investigations did not reveal any known cause. Conclusions We suggested that androgen was the predisposing factor in our patient. Androgens may increase coagulation factors or platelet activity and cause arterial or venous thrombosis. As athletes may hide using androgens it should be considered as a predisposing factor for thrombotic events in such patients. PMID:15579201

TOFA (5-tetradecyl-oxy-2-furoic acid) reduces fatty acid synthesis, inhibits expression of AR, neuropilin-1 and Mcl-1 and kills prostate cancer cells independent of p53 status.

PubMed

Guseva, Natalya V; Rokhlin, Oskar W; Glover, Rebecca A; Cohen, Michael B

2011-07-01

A key player in prostate cancer development and progression is the androgen receptor (AR). Tumor-associated lipogenesis can protect cancer cells from carcinogenic- and therapeutic-associated treatments. Increased synthesis of fatty acids and cholesterol is regulated by androgens through induction of several genes in androgen-responsive cancer cells. Acetyl-CoA-carboxylase-α (ACCA) is a key enzyme in the regulation of fatty acids synthesis. Here we show that AR binds in vivo to intron regions of human ACCA gene. We also show that the level of ACCA protein in LNCaP depends on AR expression and that DHT treatment increases ACCA expression and fatty acid synthesis. Inhibition of ACCA by TOFA (5-tetradecyl-oxy-2-furoic acid) decreases fatty acid synthesis and induces caspase activation and cell death in most PCa cell lines. Our data suggest that TOFA can kill cells via the mitochondrial pathway since we found cytochrome c release after TOFA treatment in androgen sensitive cell lines. The results also imply that the pro-apoptotic effect of TOFA may be mediated via a decrease of neuropilin-1(NRP1) and Mcl-1expression. We have previously reported that Mcl-1 is under AR regulation and plays an important role in resistance to drug-induced apoptosis in prostate cancer cells, and NRP1 is known to regulate Mcl-1 expression. Here, we show for the first time that NRP1 expression is under AR control. Taken together, our data suggest that TOFA is a potent cell death inducing agent in prostate cancer cells.

External Genital Development, Urethra Formation, and Hypospadias Induction in Guinea Pig: A Double Zipper Model for Human Urethral Development.

PubMed

Wang, Shanshan; Shi, Mingxin; Zhu, Dongqing; Mathews, Ranjiv; Zheng, Zhengui

2018-03-01

To determine whether the guinea pig phallus would be an appropriate model of human penile development, we characterized the embryology and sexual differentiation of guinea pig external genitalia and attended to induce hypospadias in males and tubular urethra formation in females pharmacologically. The external genitalia of guinea pig were collected from genital swelling initiation to newborn stages, and scanning electronic microscopy and histology were performed to visualize the morphology and structure. Immunohistochemistry was used to determine the androgen receptor localization. Bicalutamide and methyltestosterone were given to pregnant dams to reveal the role and timing of androgen in guinea pig penile masculinization. Canalization and dorsal-to-ventral movement of the urethral canal develops the urethral groove in both sexes, and then the males perform distal-opening-proximal-closing to form tubular urethra. More nuclear-localized androgen receptor is found in proximal genital tubercles of males than in females at (E) 29. Antiandrogen treatment at E26-E30 can cause hypospadias, and methyltestosterone administration at E27-E31 can induce tubular urethra formation in females. Fetal development of the guinea pig phallus is homologous to that of humans. Although guinea pig has structures similar to mouse, the urethral groove and the tubular urethra formation are more similar to humans. Antiandrogen treatment causes hypospadias in males and additional androgen induces tubular urethra formation in females. Thus, guinea pig is an appropriate model for further study of cellular and molecular mechanisms involved in distal-opening-proximal-closing in tubular urethra formation and the evaluation of the pathophysiological processes of hypospadias. Published by Elsevier Inc.

ERG Expression Levels in Prostate Tumors Reflect Functional Status of the Androgen Receptor (AR) as a Consequence of Fusion of ERG with AR Regulated Gene Promoters

DTIC Science & Technology

2010-01-01

mathematically defined in the following formulas. ARGI = Σ (I PMEPA1 + IPSA +INKX3.1+IODC1+IAMD1) ARFI=CI=ARGI+IERG Detection of TMPRSS2-ERG Fusion Junctions...ERG expression into the Androgen Receptor Function Index, ARFI. ARGI = Σ (I PMEPA1 + IPSA +INKX3.1+IODC1+IAMD1) ARFI=CI=ARGI+IERG In the high ERG

Immunotoxicity of trenbolone acetate in Japanese quail

USGS Publications Warehouse

Quinn, M.J.; McKernan, M.; Lavoie, E.T.; Ottinger, M.A.

2007-01-01

Trenbolone acetate is a synthetic androgen that is currently used as a growth promoter in many meat-exporting countries. Despite industry laboratories classifying trenbolone as nonteratogenic, data showed that embryonic exposure to this androgenic chemical altered development of the immune system in Japanese quail. Trenbolone is lipophilic, persistent, and released into the environment in manure used as soil fertilizer. This is the first study to date to assess this chemical's immunotoxic effects in an avian species. A one-time injection of trenbolone into yolks was administered to mimic maternal deposition, and subsequent effects on the development and function of the immune system were determined in chicks and adults. Development of the bursa of Fabricius, an organ responsible for development of the humoral arm of the immune system, was disrupted, as indicated by lower masse, and smaller and fewer follicles at day 1 of hatch. Morphological differences in the bursas persisted in adults, although no differences in either two measures of immune function were observed. Total numbers of circulating leukocytes were reduced and heterophil-lymphocyte ratios were elevated in chicks but not adults. This study shows that trenbolone acetate is teratogenic and immunotoxic in Japanese quail, and provides evidence that the quail immune system may be fairly resilient to embryonic endocrine-disrupting chemical-induced alterations following no further exposure posthatch.

Cotargeting of Androgen Synthesis and Androgen Receptor Expression as a Novel Treatment for Castration Resistant Prostate Cancer

DTIC Science & Technology

2017-08-01

expression of both AR and AR-V7 in CRPC cells, and that knockdown or inhibition of PRMT5 suppresses growth of CRPC cells. These results support our...correlates with the expression of AR [9]. Preliminary data strongly suggest that PRMT5 regulates prostate cancer cell growth through epigenetic...findings as follow. 3B-1. Inhibition of PRMT5 suppresses cell growth and the expression of AR and AR-V7 in CRPC cells. We established inducible

Survival Signaling in Prostate Cancer: Role of Androgen Receptor and Integrins in Regulating Survival

DTIC Science & Technology

2010-01-01

basal cells with the monoamine oxidase A inhibitor clorgyline, 1,25-dihydroxyvitamin D3, all-trans retinoic acid and TGF-1 induced AR expression and...41, 85-97. Zhao, H., Nolley, R., Chen, Z., Reese, S. W. and Peehl, D. M. (2008). Inhibition of monoamine oxidase A promotes secretory differentiation...Confluent primary human prostate epithelial cell cultures were treated with KGF and androgen (DHT). After two weeks, a suprabasal cell layer formed in

Implication of multiple mechanisms in apoptosis induced by the synthetic retinoid CD437 in human prostate carcinoma cells.

PubMed

Sun, S Y; Yue, P; Lotan, R

2000-09-14

The synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) induces apoptosis in several types of cancer cell. CD437 inhibited the growth of both androgen-dependent and -independent human prostate carcinoma (HPC) cells in a concentration-dependent manner by rapid induction of apoptosis. CD437 was more effective in killing androgen-independent HPC cells such as DU145 and PC-3 than the androgen-dependent LNCaP cells. The caspase inhibitors Z-VAD-FMK and Z-DEVD-FMK blocked apoptosis induced by CD437 in DU145 and LNCaP cells, in which increased caspase-3 activity and PARP cleavage were observed, but not in PC-3 cells, in which CD437 did not induce caspase-3 activation and PARP cleavage. Thus, CD437 can induce either caspase-dependent or caspase-independent apoptosis in HPC cells. CD437 increased the expression of c-Myc, c-Jun, c-Fos, and death receptors DR4, DR5 and Fas. CD437's potency in apoptosis induction in the different cell lines was correlated with its effects on the expression of oncogenes and death receptors, thus implicating these genes in CD437-induced apoptosis in HPC cells. However, the importance and contribution of each of these genes in different HPC cell lines may vary. Because CD437 induced the expression of DR4, DR5 and Fas, we examined the effects of combining CD437 and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and Fas ligand, respectively, in HPC cells. We found synergistic induction of apoptosis, highlighting the importance of the modulation of these death receptors in CD437-induced apoptosis in HPC cells. This result also suggests a potential strategy of using CD437 with TRAIL for treatment of HPC. Oncogene (2000) 19, 4513 - 4522.

Integrated multi-omics analyses reveal the biochemical mechanisms and phylogenetic relevance of anaerobic androgen biodegradation in the environment

PubMed Central

Yang, Fu-Chun; Chen, Yi-Lung; Tang, Sen-Lin; Yu, Chang-Ping; Wang, Po-Hsiang; Ismail, Wael; Wang, Chia-Hsiang; Ding, Jiun-Yan; Yang, Cheng-Yu; Yang, Chia-Ying; Chiang, Yin-Ru

2016-01-01

Steroid hormones, such as androgens, are common surface-water contaminants. However, literature on the ecophysiological relevance of steroid-degrading organisms in the environment, particularly in anoxic ecosystems, is extremely limited. We previously reported that Steroidobacter denitrificans anaerobically degrades androgens through the 2,3-seco pathway. In this study, the genome of Sdo. denitrificans was completely sequenced. Transcriptomic data revealed gene clusters that were distinctly expressed during anaerobic growth on testosterone. We isolated and characterized the bifunctional 1-testosterone hydratase/dehydrogenase, which is essential for anaerobic degradation of steroid A-ring. Because of apparent substrate preference of this molybdoenzyme, corresponding genes, along with the signature metabolites of the 2,3-seco pathway, were used as biomarkers to investigate androgen biodegradation in the largest sewage treatment plant in Taipei, Taiwan. Androgen metabolite analysis indicated that denitrifying bacteria in anoxic sewage use the 2,3-seco pathway to degrade androgens. Metagenomic analysis and PCR-based functional assays showed androgen degradation in anoxic sewage by Thauera spp. through the action of 1-testosterone hydratase/dehydrogenase. Our integrative ‘omics' approach can be used for culture-independent investigations of the microbial degradation of structurally complex compounds where isotope-labeled substrates are not easily available. PMID:26872041

SYSTEMS MODELING OF PROSTATE REGULATION AND ...

EPA Pesticide Factsheets

The prostate is an androgen-dependent tissue that is an important site of disease in human males as well as an important indicator of androgen status in animals. The rat prostate is used for studying antiandrogenic drugs as well as for evaluation of endocrine disruption (e.g., Hershberger Assay). Pubertal changes in the prostate have been observed to be as sensitive to environmental antiandrogens as in utero effects. The goal of this research is to model the biology of prostate androgen function on a systems level to determine the factors responsible for the dose-response observable with androgens and antiandrogens in the male rat. This includes investigation of the roles of positive and negative feedback loops in prostatic response following castration and dosing with testosterone and/or antiandrogens. A biologically-based, systems-level model will be developed describing the regulation of the prostate by androgens. The model will extend an existing model for the male rat central axis, which describes feedback between luteinizing hormone and testosterone production in the testes, to include the prostate and conversion of testosterone to dihydrotestosterone (DHT). The prostate model will describe binding of androgens to the androgen receptor, 5α-reductase catalyzed production of DHT, and gene regulation affecting cell proliferation, apoptosis, and prostatic fluid production. The model will combine pharmacokinetic models for endogenous hormones (i.e., testost

SPECIES DIFFERENCES IN ANDROGEN AND ESTROGEN RECEPTOR STRUCTURE AND FUNCTION AMONG VERTEBRATES AND INVERTEBRATES FOR INTERSPECIES EXTRAPOLATION OF ENDOCRINE DISRUPTING CHEMICALS

EPA Science Inventory

In vitro screening assays designed to identify hormone minics or antagonists, including the EDSTAC Tier 1 Screening (TIS) Battery, typically use only mammalian estrogen (ER) and androgen receptors (AR). However, there is uncertainty concerning species differences in binding affin...

EFFECT OF THE ANTI-ANDROGENIC ENDOCRINE DISRUPTOR VINCLOZOLIN ON EMBRYONIC TESTIS CORD FORMATION AND POSTNATAL TESTIS DEVELOPMENT AND FUNCTION. (R827405)

EPA Science Inventory

Vinclozolin is a systemic dicarboximide fungicide that is used on fruits, vegetables, ornamental plants, and turf grass. Vinclozolin and its metabolites are known to be endocrine disruptors and act as androgen receptor antagonists. The hypothesis tested in the current study is...

Identification of a new androgen receptor (AR) co-regulator BUD31 and related peptides to suppress wild-type and mutated AR-mediated prostate cancer growth via peptide screening and X-ray structure analysis.

PubMed

Hsu, Cheng-Lung; Liu, Jai-Shin; Wu, Po-Long; Guan, Hong-Hsiang; Chen, Yuh-Ling; Lin, An-Chi; Ting, Huei-Ju; Pang, See-Tong; Yeh, Shauh-Der; Ma, Wen-Lung; Chen, Chung-Jung; Wu, Wen-Guey; Chang, Chawnshang

2014-12-01

Treatment with individual anti-androgens is associated with the development of hot-spot mutations in the androgen receptor (AR). Here, we found that anti-androgens-mt-ARs have similar binary structure to the 5α-dihydrotestosterone-wt-AR. Phage display revealed that these ARs bound to similar peptides, including BUD31, containing an Fxx(F/H/L/W/Y)Y motif cluster with Tyr in the +5 position. Structural analyses of the AR-LBD-BUD31 complex revealed formation of an extra hydrogen bond between the Tyr+5 residue of the peptide and the AR. Functional studies showed that BUD31-related peptides suppressed AR transactivation, interrupted AR N-C interaction, and suppressed AR-mediated cell growth. Combination of peptide screening and X-ray structure analysis may serve as a new strategy for developing anti-ARs that simultaneously suppress both wt and mutated AR function. Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Functional behavior and reproduction in androgenic sex reversed zebrafish (Danio rerio).

PubMed

Larsen, Mia G; Baatrup, Erik

2010-08-01

Endocrine-disrupting chemicals released into natural watercourses may cause biased sex ratios by sex reversal in fish populations. The present study investigated the androgenic sex reversal of zebrafish (Danio rerio) exposed to the androgenic compound 17beta-trenbolone (TB) and whether sex-changed females would revert to the female phenotype after cessation of TB exposure. 17beta-Trenbolone is a metabolite of trenbolone acetate, an anabolic steroid used as a growth promoter in beef cattle. 17beta-Trenbolone in runoff from cattle feedlots may reach concentrations that affect fish sexual development. Zebrafish were exposed to a concentration of 20 ng/L TB in a flow-through system for five months from egg until sexual maturity. This resulted in an all-male population. It was further found that all these phenotypic males displayed normal male courtship behavior and were able to reproduce successfully, implying that the sex reversal was complete and functional. None of the phenotypic males developed into females after six months in clean water, demonstrating that androgenic sex reversal of zebrafish is irreversible. Copyright 2010 SETAC

Progesterone receptor in the prostate: A potential suppressor for benign prostatic hyperplasia and prostate cancer.

PubMed

Chen, RuiQi; Yu, Yue; Dong, Xuesen

2017-02-01

Advanced prostate cancer undergoing androgen receptor pathway inhibition (ARPI) eventually progresses to castrate-resistant prostate cancer (CRPC), suggesting that (i) androgen receptor (AR) blockage is incomplete, and (ii) there are other critical molecular pathways contributing to prostate cancer (PCa) progression. Although most PCa occurs in the epithelium, prostate stroma is increasingly believed to play a crucial role in promoting tumorigenesis and facilitating tumor progression. In the stroma, sex steroid hormone receptors such as AR and estrogen receptor-α are implicated to have important functions, whereas the progesterone receptor (PR) remains largely under-investigated despite the high sequence and structural similarities between PR and AR. Stromal progesterone/PR signaling may play a critical role in PCa development and progression because not only progesterone is a critical precursor for de novo androgen steroidogenesis and an activator of mutant androgen receptors, but also PR functions in a ligand-independent manner in various important pathways. In fact, recent progress in our understanding of stromal PR function suggests that this receptor may exert an inhibitory effect on benign prostatic hyperplasia (BPH), reactive stroma development, and PCa progression. These early findings of stromal PR warrant further investigations as this receptor could be a potential biomarker and therapeutic target in PCa management. Copyright © 2016 Elsevier Ltd. All rights reserved.

Androgen-induced programs for prostate epithelial growth and invasion arise in embryogenesis and are reactivated in cancer

PubMed Central

Schaeffer, EM; Marchionni, L; Huang, Z; Simons, B; Blackman, A; Yu, W; Parmigiani, G; Berman, DM

2008-01-01

Cancer cells differentiate along specific lineages that largely determine their clinical and biologic behavior. Distinct cancer phenotypes from different cells and organs likely result from unique gene expression repertoires established in the embryo and maintained after malignant transformation. We used comprehensive gene expression analysis to examine this concept in the prostate, an organ with a tractable developmental program and a high propensity for cancer. We focused on gene expression in the murine prostate rudiment at three time points during the first 48 h of exposure to androgen, which initiates proliferation and invasion of prostate epithelial buds into surrounding urogenital sinus mesenchyme. Here, we show that androgen exposure regulates genes previously implicated in prostate carcinogenesis comprising pathways for the phosphatase and tensin homolog (PTEN), fibroblast growth factor (FGF)/mitogen-activated protein kinase (MAPK), and Wnt signaling along with cellular programs regulating such ‘hallmarks’ of cancer as angiogenesis, apoptosis, migration and proliferation. We found statistically significant evidence for novel androgeninduced gene regulation events that establish and/or maintain prostate cell fate. These include modulation of gene expression through microRNAs, expression of specific transcription factors, and regulation of their predicted targets. By querying public gene expression databases from other tissues, we found that rather than generally characterizing androgen exposure or epithelial budding, the early prostate development program more closely resembles the program for human prostate cancer. Most importantly, early androgen-regulated genes and functional themes associated with prostate development were highly enriched in contrasts between increasingly lethal forms of prostate cancer, confirming a ‘reactivation’ of embryonic pathways for proliferation and invasion in prostate cancer progression. Among the genes with the most significant links to the development and cancer, we highlight coordinate induction of the transcription factor Sox9 and suppression of the proapoptotic phospholipid-binding protein Annexin A1 that link early prostate development to early prostate carcinogenesis. These results credential early prostate development as a reliable and valid model system for the investigation of genes and pathways that drive prostate cancer. PMID:18794802

Overview of a workshop on screening methods for detecting potential (anti-) estrogenic/androgenic chemicals in wildlife

USGS Publications Warehouse

Ankley, Gerald T.; Mihaich, Ellen; Stahl, Ralph G.; Tillitt, Donald E.; Colborn, Theo; McMaster, Suzzanne; Miller, Ron; Bantle, John; Campbell, Pamela; Denslow, Nancy; Dickerson, Richard L.; Folmar, Leroy C.; Fry, Michael; Giesy, John P.; Gray, L. Earl; Guiney, Patrick; Hutchinson, Thomas; Kennedy, Sean W.; Kramer, Vincent; LeBlanc, Gerald A.; Mayes, Monte; Nimrod, Alison; Patino, Reynaldo; Peterson, Richard; Purdy, Richard; Ringer, Robert; Thomas, Peter C.; Touart, Les; Van Der Kraak, Glen; Zacharewski, Tim

1998-01-01

The U.S. Congress has passed legislation requiring the U.S. Environmental Protection Agency (U.S. EPA) to develop, validate, and implement screening tests for identifying potential endocrine-disrupting chemicals within 3 years. To aid in the identification of methods suitable for this purpose, the U.S. EPA, the Chemical Manufacturers Association, and the World Wildlife Fund sponsored several workshops, including the present one, which dealt with wildlife species. This workshop was convened with 30 international scientists representing multiple disciplines in March 1997 in Kansas City, Missouri, USA. Participants at the meeting identified methods in terms of their ability to indicate (anti-) estrogenic/androgenic effects, particularly in the context of developmental and reproductive processes. Data derived from structure-activity relationship models and in vitro test systems, although useful in certain contexts, cannot at present replace in vivo tests as the sole basis for screening. A consensus was reached that existing mammalian test methods (e.g., with rats or mice) generally are suitable as screens for assessing potential (anti-) estrogenic/ androgenic effects in mammalian wildlife. However, due to factors such as among-class variation in receptor structure and endocrine function, it is uncertain if these mammalian assays would be of broad utility as screens for other classes of vertebrate wildlife. Existing full and partial life-cycle tests with some avian and fish species could successfully identify chemicals causing endocrine disruption; however, these long-term tests are not suitable for routine screening. However, a number of short-term tests with species from these two classes exist that could serve as effective screening tools for chemicals inducing (anti-) estrogenic/androgenic effects. Existing methods suitable for identifying chemicals with these mechanisms of action in reptiles and amphibians are limited, but in the future, tests with species from these classes may prove highly effective as screens. In the case of invertebrate species, too little is known at present about the biological role of estrogens and androgens in reproduction and development to recommend specific assays.

Early-life exposure to Tris(1,3-dichloroisopropyl) phosphate induces dose-dependent suppression of sexual behavior in male rats.

PubMed

Kamishima, Manami; Hattori, Tatsuya; Suzuki, Go; Matsukami, Hidenori; Komine, Chiaki; Horii, Yasuyuki; Watanabe, Gen; Oti, Takumi; Sakamoto, Hirotaka; Soga, Tomoko; Parhar, Ishwar S; Kondo, Yasuhiko; Takigami, Hidetaka; Kawaguchi, Maiko

2018-05-01

Exposure to endocrine-disrupting chemicals may adversely affect animals, particularly during development. Tris(1,3-dichloroisopropyl) phosphate (TDCIPP) is an organophosphate with anti-androgen function in vitro that is present in indoor dust at relatively high concentrations. In male rats, androgens are necessary for the development of reproductive organs, as well as the endocrine and central nervous systems. However, we currently do not know the exact effects of TDCIPP exposure through suckling on subsequent reproductive behavior in males. Here, we show that TDCIPP exposure (25-250 mg kg -1 via oral administration over 28 consecutive days post-birth) suppressed male sexual behavior and reduced testes size. These changes were dose-dependent and appeared first in adults rather than in juveniles. These results demonstrate that TDCIPP exposure led to normal body growth and appearance in juveniles, but disrupted the endocrine system and physiology in adults. Therefore, assays should be performed using adult animals to ensure accuracy, and to confirm the influence of chemical substances given during early mammalian life. Copyright © 2017 John Wiley & Sons, Ltd.

Sexual function in infertile women with polycystic ovary syndrome and unexplained infertility.

PubMed

Diamond, Michael P; Legro, Richard S; Coutifaris, Christos; Alvero, Ruben; Robinson, Randal D; Casson, Peter A; Christman, Gregory M; Huang, Hao; Hansen, Karl R; Baker, Valerie; Usadi, Rebecca; Seungdamrong, Aimee; Bates, G Wright; Rosen, R Mitchell; Schlaff, William; Haisenleder, Daniel; Krawetz, Stephen A; Barnhart, Kurt; Trussell, J C; Santoro, Nanette; Eisenberg, Esther; Zhang, Heping

2017-08-01

While female sexual dysfunction is a frequent occurrence, characteristics in infertile women are not well delineated. Furthermore, the impact of infertility etiology on the characteristics in women with differing androgen levels observed in women with polycystic ovary syndrome and unexplained infertility has not been assessed. The objective of the study was to determine the characteristics of sexual dysfunction in women with polycystic ovary syndrome and unexplained infertility. A secondary data analysis was performed on 2 of Eunice Kennedy Shriver National Institute of Child Health and Human Development Cooperative Reproductive Medicine Networks clinical trials: Pregnancy in Polycystic Ovary Syndrome Study II and Assessment of Multiple Intrauterine Gestations From Ovarian Stimulation. Both protocols assessed female sexual function using the Female Sexual Function Inventory and the Female Sexual Distress Scale. Women with polycystic ovary syndrome had higher weight and body mass index than women with unexplained infertility (each P < .001), greater phenotypic (Ferriman-Gallwey hirsutism score, sebum score, and acne score; each P < .001), and hormonal (testosterone, free testosterone, and dehydroepiandrosterone; each P < .001) evidence of androgen excess. Sexual function scores, as assessed by the Female Sexual Function Inventory, were nearly identical. The Female Sexual Distress Scale total score was higher in women with polycystic ovary syndrome. The mean Female Sexual Function Inventory total score increased slightly as the free androgen index increased, mainly as a result of the desire subscore. This association was more pronounced in the women with unexplained infertility. Reproductive-age women with infertility associated with polycystic ovary syndrome and unexplained infertility, despite phenotypic and biochemical differences in androgenic manifestations, do not manifest clinically significant differences in sexual function. Copyright © 2017 Elsevier Inc. All rights reserved.

Bypass Mechanisms of the Androgen Receptor Pathway in Therapy-Resistant Prostate Cancer Cell Models

PubMed Central

Marques, Rute B.; Dits, Natasja F.; Erkens-Schulze, Sigrun; van Weerden, Wytske M.; Jenster, Guido

2010-01-01

Background Prostate cancer is initially dependent on androgens for survival and growth, making hormonal therapy the cornerstone treatment for late-stage tumors. However, despite initial remission, the cancer will inevitably recur. The present study was designed to investigate how androgen-dependent prostate cancer cells eventually survive and resume growth under androgen-deprived and antiandrogen supplemented conditions. As model system, we used the androgen-responsive PC346C cell line and its therapy-resistant sublines: PC346DCC, PC346Flu1 and PC346Flu2. Methodology/Principal Findings Microarray technology was used to analyze differences in gene expression between the androgen-responsive and therapy-resistant PC346 cell lines. Microarray analysis revealed 487 transcripts differentially-expressed between the androgen-responsive and the therapy-resistant cell lines. Most of these genes were common to all three therapy-resistant sublines and only a minority (∼5%) was androgen-regulated. Pathway analysis revealed enrichment in functions involving cellular movement, cell growth and cell death, as well as association with cancer and reproductive system disease. PC346DCC expressed residual levels of androgen receptor (AR) and showed significant down-regulation of androgen-regulated genes (p-value = 10−7). Up-regulation of VAV3 and TWIST1 oncogenes and repression of the DKK3 tumor-suppressor was observed in PC346DCC, suggesting a potential AR bypass mechanism. Subsequent validation of these three genes in patient samples confirmed that expression was deregulated during prostate cancer progression. Conclusions/Significance Therapy-resistant growth may result from adaptations in the AR pathway, but androgen-independence may also be achieved by alternative survival mechanisms. Here we identified TWIST1, VAV3 and DKK3 as potential players in the bypassing of the AR pathway, making them good candidates as biomarkers and novel therapeutical targets. PMID:20976069

Opposing Effects of Cyclooxygenase-2 (COX-2) on Estrogen Receptor β (ERβ) Response to 5α-Reductase Inhibition in Prostate Epithelial Cells*

PubMed Central

Liu, Teresa T.; Grubisha, Melanie J.; Frahm, Krystle A.; Wendell, Stacy G.; Liu, Jiayan; Ricke, William A.; Auchus, Richard J.; DeFranco, Donald B.

2016-01-01

Current pharmacotherapies for symptomatic benign prostatic hyperplasia (BPH), an androgen receptor-driven, inflammatory disorder affecting elderly men, include 5α-reductase (5AR) inhibitors (i.e. dutasteride and finasteride) to block the conversion of testosterone to the more potent androgen receptor ligand dihydrotestosterone. Because dihydrotestosterone is the precursor for estrogen receptor β (ERβ) ligands, 5AR inhibitors could potentially limit ERβ activation, which maintains prostate tissue homeostasis. We have uncovered signaling pathways in BPH-derived prostate epithelial cells (BPH-1) that are impacted by 5AR inhibition. The induction of apoptosis and repression of the cell adhesion protein E-cadherin by the 5AR inhibitor dutasteride requires both ERβ and TGFβ. Dutasteride also induces cyclooxygenase type 2 (COX-2), which functions in a negative feedback loop in TGFβ and ERβ signaling pathways as evidenced by the potentiation of apoptosis induced by dutasteride or finasteride upon pharmacological inhibition or shRNA-mediated ablation of COX-2. Concurrently, COX-2 positively impacts ERβ action through its effect on the expression of a number of steroidogenic enzymes in the ERβ ligand metabolic pathway. Therefore, effective combination pharmacotherapies, which have included non-steroidal anti-inflammatory drugs, must take into account biochemical pathways affected by 5AR inhibition and opposing effects of COX-2 on the tissue-protective action of ERβ. PMID:27226548

Anoctamin 1 (TMEM16A) is essential for testosterone-induced prostate hyperplasia.

PubMed

Cha, Joo Young; Wee, Jungwon; Jung, Jooyoung; Jang, Yongwoo; Lee, Byeongjun; Hong, Gyu-Sang; Chang, Beom Chul; Choi, Yoon-La; Shin, Young Kee; Min, Hye-Young; Lee, Ho-Young; Na, Tae-Young; Lee, Mi-Ock; Oh, Uhtaek

2015-08-04

Benign prostatic hyperplasia (BPH) is characterized by an enlargement of the prostate, causing lower urinary tract symptoms in elderly men worldwide. However, the molecular mechanism underlying the pathogenesis of BPH is unclear. Anoctamin1 (ANO1) encodes a Ca(2+)-activated chloride channel (CaCC) that mediates various physiological functions. Here, we demonstrate that it is essential for testosterone-induced BPH. ANO1 was highly amplified in dihydrotestosterone (DHT)-treated prostate epithelial cells, whereas the selective knockdown of ANO1 inhibited DHT-induced cell proliferation. Three androgen-response elements were found in the ANO1 promoter region, which is relevant for the DHT-dependent induction of ANO1. Administration of the ANO1 blocker or Ano1 small interfering RNA, inhibited prostate enlargement and reduced histological abnormalities in vivo. We therefore concluded that ANO1 is essential for the development of prostate hyperplasia and is a potential target for the treatment of BPH.

Anoctamin 1 (TMEM16A) is essential for testosterone-induced prostate hyperplasia

PubMed Central

Cha, Joo Young; Wee, Jungwon; Jung, Jooyoung; Jang, Yongwoo; Lee, Byeongjun; Hong, Gyu-Sang; Chang, Beom Chul; Choi, Yoon-La; Shin, Young Kee; Min, Hye-Young; Lee, Ho-Young; Na, Tae-Young; Lee, Mi-Ock; Oh, Uhtaek

2015-01-01

Benign prostatic hyperplasia (BPH) is characterized by an enlargement of the prostate, causing lower urinary tract symptoms in elderly men worldwide. However, the molecular mechanism underlying the pathogenesis of BPH is unclear. Anoctamin1 (ANO1) encodes a Ca2+-activated chloride channel (CaCC) that mediates various physiological functions. Here, we demonstrate that it is essential for testosterone-induced BPH. ANO1 was highly amplified in dihydrotestosterone (DHT)-treated prostate epithelial cells, whereas the selective knockdown of ANO1 inhibited DHT-induced cell proliferation. Three androgen-response elements were found in the ANO1 promoter region, which is relevant for the DHT-dependent induction of ANO1. Administration of the ANO1 blocker or Ano1 small interfering RNA, inhibited prostate enlargement and reduced histological abnormalities in vivo. We therefore concluded that ANO1 is essential for the development of prostate hyperplasia and is a potential target for the treatment of BPH. PMID:26153424

A novel prostate cancer therapeutic strategy using icaritin-activated arylhydrocarbon-receptor to co-target androgen receptor and its splice variants

PubMed Central

Sun, Feng; Indran, Inthrani R.; Zhang, Zhi Wei; Tan, M.H.Eileen; Li, Yu; Lim, Z.L.Ryan; Hua, Rui; Yang, Chong; Soon, Fen-Fen; Li, Jun; Xu, H.Eric; Cheung, Edwin; Yong, Eu-Leong

2015-01-01

Persistent androgen receptor (AR) signaling is the key driving force behind progression and development of castration-resistant prostate cancer (CRPC). In many patients, AR COOH-terminal truncated splice variants (ARvs) play a critical role in contributing to the resistance against androgen depletion therapy. Unfortunately, clinically used antiandrogens like bicalutamide (BIC) and enzalutamide (MDV), which target the ligand binding domain, have failed to suppress these AR variants. Here, we report for the first time that a natural prenylflavonoid, icaritin (ICT), can co-target both persistent AR and ARvs. ICT was found to inhibit transcription of key AR-regulated genes, such as KLK3 [prostate-specific antigen (PSA)] and ARvs-regulated genes, such as UBE2C and induce apoptosis in AR-positive prostate cancer (PC) cells. Mechanistically, ICT promoted the degradation of both AR and ARvs by binding to arylhydrocarbon-receptor (AhR) to mediate ubiquitin-proteasomal degradation. Therefore, ICT impaired AR transactivation in PC cells. Knockdown of AhR gene restored AR stability and partially prevented ICT-induced growth suppression. In clinically relevant murine models orthotopically implanted with androgen-sensitive and CRPC cells, ICT was able to target AR and ARvs, to inhibit AR signaling and tumor growth with no apparent toxicity. Our results provide a mechanistic framework for the development of ICT, as a novel lead compound for AR-positive PC therapeutics, especially for those bearing AR splice variants. PMID:25908644

Novel Inhibitors of Protein-Protein Interaction for Prostate Cancer Therapy

DTIC Science & Technology

2011-04-01

medical need. 7 REFERENCES 1. Babbar N, Hacker A, Huang Y, Casero RA Jr. Tumor necrosis factor alpha induces spermidine /spermine N-acetyl...PCa development and progression. We have published that activated androgen receptor (AR)-JunD complex induces spermidine /spermine N1-acetyl transferase

Developmental programming: postnatal estradiol amplifies ovarian follicular defects induced by fetal exposure to excess testosterone and dihydrotestosterone in sheep.

PubMed

Veiga-Lopez, A; Wurst, A K; Steckler, T L; Ye, W; Padmanabhan, V

2014-04-01

Excess of prenatal testosterone (T) induces reproductive defects including follicular persistence. Comparative studies with T and dihydrotestosterone (DHT) have suggested that follicular persistence is programmed via estrogenic actions of T. This study addresses the androgenic and estrogenic contributions in programming follicular persistence. Because humans are exposed to estrogenic environmental steroids from various sources throughout their life span and postnatal insults may also induce organizational and/or activational changes, we tested whether continuous postnatal exposure to estradiol (E) will amplify effects of prenatal steroids on ovarian function. Pregnant sheep were treated with T, DHT, E, or ED (E and DHT) from days 30 to 90 of gestation. Postnatally, a subset of the vehicle (C), T, and DHT females received an E implant. Transrectal ultrasonography was performed in the first breeding season during a synchronized cycle to monitor ovarian follicular dynamics. As expected, number of ≥8 mm follicles was higher in the T versus C group. Postnatal E reduced the number of 4 to 8 mm follicles in the DHT group. Percentage of females bearing luteinized follicles and the number of luteinized follicles differed among prenatal groups. Postnatal E increased the incidence of subluteal cycles in the prenatal T-treated females. Findings from this study confirm previous findings of divergences in programming effects of prenatal androgens and estrogens. They also indicate that some aspects of follicular dynamics are subject to postnatal modulation as well as support the existence of an extended organizational period or the need for a second insult to uncover the previously programmed event.

Developmental programming: postnatal estradiol modulation of prenatally organized reproductive neuroendocrine function in sheep.

PubMed

Puttabyatappa, Muraly; Cardoso, Rodolfo C; Herkimer, Carol; Veiga-Lopez, Almudena; Padmanabhan, Vasantha

2016-08-01

Gestational testosterone (TS) excess, acting via both the androgenic and estrogenic pathways, advances puberty and disrupts the neuroendocrine estradiol (E2) feedback and periovulatory hormonal dynamics in female sheep. These prenatally programmed defects may be subject to postnatal modifications by continued organizational and/or activational effects of steroids. This study investigated (1) the organizational contribution of prenatal estrogen excess and (2) the impact of postnatal exposure to E2 in modulating the effects of prenatal androgen excess (TS and dihydrotestosterone (DHT)) on puberty, neuroendocrine feedback mechanisms, and periovulatory hormonal dynamics in sheep. Pregnant Suffolk sheep were treated with TS, DHT, E2, or E2 plus DHT (ED) from days 30 to 90 of gestation. A subset of the control (C), TS, and DHT female offspring received a constant-release E2 implant postnatally. Findings revealed that (1) prenatal E2-treatment failed to reproduce the neuroendocrine disruptions predicted to be programmed by the estrogenic pathway and (2) prenatal E2D-treatment did not adequately replicate the reproductive neuroendocrine defects induced by prenatal TS excess. More importantly, continuous postnatal E2-treatment, while delaying the onset of puberty and reducing the inhibitory effects of E2 on tonic luteinizing hormone (LH) release, failed to amplify the E2-positive feedback and periovulatory defects induced by prenatal TS-treatment. Our results indicate that disruptions in E2-positive feedback mechanisms and periovulatory gonadotropin secretion induced by prenatal TS-treatment are programmed predominantly during the prenatal life with postnatal exposure to E2 excess not contributing further to these disruptions. © 2016 Society for Reproduction and Fertility.

Influence of testosterone on synaptic transmission in the rat medial vestibular nuclei: estrogenic and androgenic effects.

PubMed

Grassi, S; Frondaroli, A; Di Mauro, M; Pettorossi, V E

2010-12-15

In brainstem slices of young male rat, we investigated the influence of the neuroactive steroid testosterone (T) on the synaptic responses by analyzing the field potential evoked in the medial vestibular nucleus (MVN) by vestibular afferent stimulation. T induced three distinct and independent long-term synaptic changes: fast long-lasting potentiation (fLP), slow long-lasting potentiation (sLP) and long-lasting depression (LD). The fLP was mediated by 17β-estradiol (E(2)) since it was abolished by blocking the estrogen receptors (ERs) or the enzyme converting T to E(2). Conversely, sLP and LD were mediated by 5α-dihydrotestosterone (DHT) since they were prevented by blocking the androgen receptors (ARs) or the enzyme converting T to DHT. Therefore, the synaptic effects of T were mediated by its androgenic or estrogenic metabolites. The pathways leading to estrogenic and androgenic conversion of T might be co-localized since, the occurrence of fLP under block of androgenic pathway, and that of sLP and LD under estrogenic block, were higher than those observed without blocks. In case of co-localization, the effect on synaptic transmission should depend on the prevailing enzymatic activity. We conclude that circulating and neuronal T can remarkably influence synaptic responses of the vestibular neurons in different and opposite ways, depending on its conversion to estrogenic or androgenic metabolites. Copyright © 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

Anabolic steroids abuse-induced cardiomyopathy and ischaemic stroke in a young male patient.

PubMed

Shamloul, Reham Mohammed; Aborayah, Ahmed Fathy; Hashad, Assem; Abd-Allah, Foad

2014-02-26

We report a case of a 37-year-old man presented with acute stroke and hepatorenal impairment which were associated with anabolic-androgenic steroids (AAS) abuse over 2 years. Despite the absence of apparent symptoms and signs of congestive heart failure at presentation, an AAS-induced dilated cardiomyopathy with multiple thrombi in the left ventricle was attributed to be the underlying cause of his condition. Awareness of the complications of AAS led to the prompt treatment of the initially unrecognised dilated cardiomyopathy, and improved the liver and kidney functions. However, the patient was exposed to a second severe ischaemic event, which led to his death. This unique and complex presentation of AAS complications opens for better recognition and treatment of their potentially fatal effects.

Comparison between testosterone oenanthate-induced azoospermia and oligozoospermia in a male contraceptive study. IV. Suppression of endogenous testicular and adrenal androgens.

PubMed

Anderson, R A; Wallace, A M; Kicman, A T; Wu, F C

1997-08-01

Administration of supraphysiological doses of testosterone to normal men causes inhibition of spermatogenesis, but while most become azoospermic, 30-55% maintain a low rate of spermatogenesis. We have investigated whether there are differences in endogenous androgen production, of testicular and adrenal origin, which may be related to the degree of suppression of spermatogenesis. Thirty-three healthy Caucasian men were given weekly i.m. injections of 200 mg testosterone oenanthate (TE), 18 became azoospermic, while 15 remained oligozoospermic. Urinary excretion of epitestosterone, a specific testicular product, was reduced to <10% of pretreatment values, with no differences between the groups. Similar results were obtained for other markers of testicular steroidogenesis. Urinary and plasma adrenal androgens were also reduced during TE treatment: a statistically significant decrease in both (P < 0.001 and P < 0.05 respectively) was seen in the azoospermic but not oligozoospermic responders. These results suggest that testicular steroidogenesis is decreased to <10% by the administration of supraphysiological doses of exogenous testosterone. Differences in the degree of ongoing steroidogenesis in the testis do not appear to account for incomplete suppression of spermatogenesis, thus differences in androgen metabolism may underlie this heterogeneous response. A small but significant reduction in secretion of adrenal androgens was also detectable, the relevance of which is unclear.

Quality of life, self-esteem, fatigue, and sexual function in young men after cancer: a controlled cross-sectional study.

PubMed

Greenfield, Diana M; Walters, Stephen J; Coleman, Robert E; Hancock, Barry W; Snowden, John A; Shalet, Stephen M; DeRogatis, Leonard R; Ross, Richard J M

2010-03-15

Androgen deficiency is increasingly recognized in young male cancer survivors; however, its impact on quality of life (QOL) is not established. The authors investigated the relationship between androgen levels, QOL, self-esteem, fatigue, and sexual function in young male cancer survivors compared with control subjects. A cross-sectional, observational study of 176 male cancer survivors and 213 male controls aged 25 to 45 years was performed. Subjects completed 3 QOL scales (Medical Outcomes Study 36-Item Short-Form Health Survey version 2, the 12-item General Health Questionnaire [GHQ-12], and Aging Male Scale), and measures of self-esteem (Rosenberg Self-Esteem Scale), fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue), and sexual function (Derogatis Interview for Sexual Functioning-II Self-Report-Male). Cancer survivors had lower scores for all components of the Short-Form Health Survey, Aging Male Scale, and Functional Assessment of Chronic Illness Therapy-Fatigue, and for 4 of 5 subsections of the Derogatis Interview for Sexual Functioning than controls. The majority of these differences remained after adjusting by linear regression analysis. Levels of psychiatric disorder or self-esteem did not differ between the 2 groups. In cancer survivors, those with androgen deficiency (serum testosterone < or = 10 nmol/L) had lower scores than those without for all components of the Short-Form Health Survey, the General Health Questionnaire, Functional Assessment of Chronic Illness Therapy-Fatigue, and the Derogatis Interview for Sexual Functioning. Serum testosterone only weakly correlated with health measures. Young male cancer survivors self-report a marked impairment in QOL, energy levels, and quality of sexual functioning, and this was exacerbated in those with androgen deficiency. However, psychological distress was not elevated, self-esteem was normal, and sexual relationships were not impaired. The relationship with testosterone is complex, and appears dependent on a threshold level rather than direct correlation. Interventional trials are needed to determine whether testosterone replacement would improve QOL in young male cancer survivors.

Methylation of the PMEPA1 gene, a negative regulator of the androgen receptor in prostate cancer.

PubMed

Sharad, Shashwat; Ravindranath, Lakshmi; Haffner, Michael C; Li, Hua; Yan, Wusheng; Sesterhenn, Isabell A; Chen, Yongmei; Ali, Amina; Srinivasan, Alagarsamy; McLeod, David G; Yegnasubramanian, Srinivasan; Srivastava, Shiv; Dobi, Albert; Petrovics, Gyorgy

2014-06-01

The prostate transmembrane protein androgen induced 1 (PMEPA1) gene is highly expressed in prostate epithelial cells and is a direct transcriptional target for the androgen receptor (AR). AR protein levels are controlled by the AR-PMEPA1 negative feedback loop through NEDD4-E3 ligase. Reduced expression of PMEPA1 observed in prostate tumors, suggests that loss of PMEPA1 may play critical roles in prostate tumorigenesis. This study focuses on epigenetic mechanisms of reduced PMEPA1 expression in the cancer of the prostate (CaP). Benign (n = 77) and matched malignant (n = 77) prostate epithelial cells were laser capture micro-dissected from optimum cutting temperature embedded frozen prostate sections from 42 Caucasian American (CA) and 35 African American (AA) cases. Purified DNA specimens were analyzed for CpG methylation of the PMEPA1 gene. PMEPA1 mRNA expression levels were evaluated by qRT-PCR. Analysis of PMEPA1 methylation and mRNA expression in the same tumor cell populations indicated a significant inverse correlation between mRNA expression and methylation in CaP (P = 0.0115). We noted higher frequency of CpG methylation within the evaluated first intronic region of the PMEPA1 gene in prostate tumors of CA men as compared with AA. In CaP cell lines, PMEPA1 expression was induced and AR protein levels were diminished in response to treatment with the DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine (decitabine). Cell culture-based studies demonstrated that decitabine restores PMEPA1 expression in AR-positive CaP cell lines. This report reveals the potential role of PMEPA1 gene methylation in the regulation of AR stability. Thus, downregulation of PMEPA1 may result in increased AR protein levels and function in CaP cells, contributing to prostate tumorigenesis.

Methylation of the PMEPA1 gene, a negative regulator of the androgen receptor in prostate cancer

PubMed Central

Sharad, Shashwat; Ravindranath, Lakshmi; Haffner, Michael C; Li, Hua; Yan, Wusheng; Sesterhenn, Isabell A; Chen, Yongmei; Ali, Amina; Srinivasan, Alagarsamy; McLeod, David G; Yegnasubramanian, Srinivasan; Srivastava, Shiv; Dobi, Albert; Petrovics, Gyorgy

2014-01-01

The prostate transmembrane protein androgen induced 1 (PMEPA1) gene is highly expressed in prostate epithelial cells and is a direct transcriptional target for the androgen receptor (AR). AR protein levels are controlled by the AR-PMEPA1 negative feedback loop through NEDD4-E3 ligase. Reduced expression of PMEPA1 observed in prostate tumors, suggests that loss of PMEPA1 may play critical roles in prostate tumorigenesis. This study focuses on epigenetic mechanisms of reduced PMEPA1 expression in the cancer of the prostate (CaP). Benign (n = 77) and matched malignant (n = 77) prostate epithelial cells were laser capture micro-dissected from optimum cutting temperature embedded frozen prostate sections from 42 Caucasian American (CA) and 35 African American (AA) cases. Purified DNA specimens were analyzed for CpG methylation of the PMEPA1 gene. PMEPA1 mRNA expression levels were evaluated by qRT-PCR. Analysis of PMEPA1 methylation and mRNA expression in the same tumor cell populations indicated a significant inverse correlation between mRNA expression and methylation in CaP (P = 0.0115). We noted higher frequency of CpG methylation within the evaluated first intronic region of the PMEPA1 gene in prostate tumors of CA men as compared with AA. In CaP cell lines, PMEPA1 expression was induced and AR protein levels were diminished in response to treatment with the DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine (decitabine). Cell culture-based studies demonstrated that decitabine restores PMEPA1 expression in AR-positive CaP cell lines. This report reveals the potential role of PMEPA1 gene methylation in the regulation of AR stability. Thus, downregulation of PMEPA1 may result in increased AR protein levels and function in CaP cells, contributing to prostate tumorigenesis. PMID:24694733

Aging up-regulates ARA55 in stromal cells, inducing androgen-mediated prostate cancer cell proliferation and migration.

PubMed

Zou, Qingsong; Cui, Di; Liang, Shengjie; Xia, Shujie; Jing, Yifeng; Han, Bangmin

2016-06-01

Stromal cells in the peripheral zone (PZ) of the prostate from older males (PZ-old) could significantly promote Prostate cancer (PCa) growth compared with stromal cells from young males (PZ-young). But the mechanism is still unknown. In the co-culture system with PZ-old cells, Pc3/Du145 cells showed advanced proliferation and migration after Dihydrotestosterone (DHT) incubation, but DHT didn't show the similar effect in PZ-young co-culture system. Also, higher androgen/AR signal pathway activity and AR-related cytokines secretion (FGF-2, KGF, IGF-1) were found in PZ-old cells. As AR exprssison was equivalent in PZ-old and PZ-young cells, we focused on Androgen receptor associated protein-55(ARA55), a stromal-specific androgen receptor (AR) coactivator. ARA55 expression was higher in PZ-old cells compared with PZ-young cells in vitro. After knocking down ARA55 expression in PZ-old cells, the PCa growth- promoting effect from the PZ-old cells was diminished, which may be explained by the decreased the progressive cytokines secretion (FGF-2, KGF, IGF-1) from PZ-old stromal cells. In vivo, the consistent results were also found: PZ-old cells promoted prostate cancer cells growth, but this effect receded when knocking down ARA55 expression in PZ-old cells. From our study, we found PZ stromal cells presented age-related effects in proliferation and migration of prostate cancer cells in the androgen/AR dependent manner. As aging increased, more ARA55 were expressed in PZ stromal cells, leading to more sensitive androgen/androgen receptor (AR) signal pathway, then constituting a more feasible environment to cancer cells.

Cumulative and antagonistic effects of a mixture of the antiandrogens vinclozolin and iprodione in the pubertal male rat.

PubMed

Blystone, Chad R; Lambright, Christy S; Cardon, Mary C; Furr, Johnathan; Rider, Cynthia V; Hartig, Phillip C; Wilson, Vickie S; Gray, Leon E

2009-09-01

Vinclozolin and iprodione are dicarboximide fungicides that display antiandrogenic effects in the male rat, which suggests that a mixture would lead to cumulative effects on androgen-sensitive end points. Iprodione is a steroid synthesis inhibitor, but androgen receptor antagonist activity, which is displayed by vinclozolin, has not been fully evaluated. Here, we demonstrate that iprodione binds to the human androgen receptor (IC(50) = 86.0 microM), reduces androgen-dependent gene expression, and reduces androgen-sensitive tissue weights in castrated male rats (Hershberger assay). Since vinclozolin and iprodione affect common targets in the pubertal male rat, we tested the hypothesis that a mixture would have cumulative antiandrogenic effects. An iprodione dose, that does not significantly affect androgen-dependent morphological end points, was combined with vinclozolin doses (2 x 5 factorial design). Sprague-Dawley rats were dosed by gavage with vinclozolin at 0, 10, 30, 60, and 100 mg/kg/day with and without 50 mg iprodione/kg/day from postnatal day (PND) 23 to 55-57 (n = 8 per group). The age at puberty (preputial separation [PPS]), organ weights, serum hormones, and ex vivo testis steroid hormone production were measured. Vinclozolin delayed PPS, reduced androgen-sensitive organ weights, and increased serum testosterone. The addition of iprodione enhanced the vinclozolin inhibition of PPS (PND 47.5 vs.49.1; two-way ANOVA: iprodione main effect p = 0.0002). The dose response for several reproductive and nonreproductive organ weights was affected in a cumulative manner. In contrast, iprodione antagonized the vinclozolin-induced increase in serum testosterone. These results demonstrate that these fungicides interact on common targets in a tissue-specific manner when coadministered to the pubertal male rat.

Baicalein suppresses the androgen receptor (AR)-mediated prostate cancer progression via inhibiting the AR N-C dimerization and AR-coactivators interaction.

PubMed

Xu, Defeng; Chen, Qiulu; Liu, Yalin; Wen, Xingqiao

2017-12-01

Androgen receptor (AR) plays a critical role in prostate cancer (PCa) development and progression. Androgen deprivation therapy with antiandrogens to reduce androgen biosynthesis or prevent androgens from binding to AR are widely used to suppress AR-mediated PCa growth. However, most of ADT may eventually fail with development of the castration resistance after 12-24 months. Here we found that a natural product baicalein can effectively suppress the PCa progression via targeting the androgen-induced AR transactivation with little effect to AR protein expression. PCa cells including LNCaP, CWR22Rv1, C4-2, PC-3, and DU145, were treated with baicalein and luciferase assay was used to evaluate their effect on the AR transactivation. Cell growth and IC 50 were determined by MTT assay after 48 hrs treatment. RT-PCR was used to evaluate the mRNA levels of AR target genes including PSA, TMPRSS2, and TMEPA1. Western blot was used to determine AR and PSA protein expression. The natural product of baicalein can selectively inhibit AR transactivation with little effect on the other nuclear receptors, including ERα, and GR. At a low concentration, 2.5 μM of baicalein effectively suppresses the growth of AR-positive PCa cells, and has little effect on AR-negative PCa cells. Mechanism dissection suggest that baicalein can suppress AR target genes (PSA, TMPRSS2, and TMEPA1) expression in both androgen responsive LNCaP cells and castration resistant CWR22Rv1 cells, that may involve the inhibiting the AR N/C dimerization and AR-coactivators interaction. Baicalein may be developed as an effective anti-AR therapy via its ability to inhibit AR transactivation and AR-mediated PCa cell growth.

Ethinyl estradiol-cyproterone acetate versus low-dose pioglitazone-flutamide-metformin for adolescent girls with androgen excess: divergent effects on CD163, TWEAK receptor, ANGPTL4, and LEPTIN expression in subcutaneous adipose tissue.

PubMed

Díaz, Marta; Chacón, Matilde R; López-Bermejo, Abel; Maymó-Masip, Elsa; Salvador, Cristina; Vendrell, Joan; de Zegher, Francis; Ibáñez, Lourdes

2012-10-01

The aim was to compare the effects of a traditional therapy (an oral estroprogestagen) to those of a novel treatment (a low-dose combination of generics) in adolescent girls with androgen excess. In an open-label trial over 1 yr, 34 adolescents (age, 16 yr; body mass index, 23 kg/m2) with hyperinsulinemic androgen excess and without pregnancy risk were randomized to receive daily ethinyl estradiol-cyproterone acetate (EE-CA; Diane 35 Diario) or a low-dose combination of pioglitazone 7.5 mg/d, flutamide 62.5 mg/d, and metformin 850 mg/d (PioFluMet). Markers of androgen excess, C-reactive protein, high molecular weight adiponectin, lipids, carotid intima media thickness, body composition (absorptiometry), abdominal fat partitioning (magnetic resonance imaging), and gene expression in longitudinal biopsies of sc adipose tissue at the abdominal level (RT-PCR) were assessed at baseline and after 1 yr. EE-CA and low-dose PioFluMet reduced androgen excess comparably, but had divergent effects on C-reactive protein, high molecular weight adiponectin, lipids, carotid intima media thickness, lean mass, abdominal and visceral fat, and on the expression of CD163, leptin, TNF-like weak inducer of apoptosis receptor, and angiopoietin-like protein 4, respectively, related to macrophage activation, fat accretion, inflammation, and lipoprotein metabolism in adipose tissue. All these divergences pointed to a healthier condition on low-dose PioFluMet. EE-CA and PioFluMet are similarly effective in reversing androgen excess over 1 yr, but low-dose PioFluMet is superior in reversing inflammatory, metabolic, and cardiovascular anomalies that are often associated with androgen excess.

Currently used pesticides and their mixtures affect the function of sex hormone receptors and aromatase enzyme activity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kjeldsen, Lisbeth Stigaard; Ghisari, Mandana; Bonefeld-Jørgensen, Eva Cecilie, E-mail: ebj@mil.au.dk

The endocrine-disrupting potential of pesticides is of health concern, since they are found ubiquitously in the environment and in food items. We investigated in vitro effects on estrogen receptor (ER) and androgen receptor (AR) transactivity, and aromatase enzyme activity, of the following pesticides: 2-methyl-4-chlorophenoxyacetic acid (MCPA), terbuthylazine, iodosulfuron-methyl-sodium, mesosulfuron-methyl, metsulfuron-methyl, chlormequat chloride, bitertanol, propiconazole, prothioconazole, mancozeb, cypermethrin, tau fluvalinate, malathion and the metabolite ethylene thiourea (ETU). The pesticides were analyzed alone and in selected mixtures. Effects of the pesticides on ER and AR function were assessed in human breast carcinoma MVLN cells and hamster ovary CHO-K1 cells, respectively, using luciferasemore » reporter gene assays. Effects on aromatase enzyme activity were analyzed in human choriocarcinoma JEG-3 cells, employing the classical [{sup 3}H]{sub 2}O method. Five pesticides (terbuthylazine, propiconazole, prothioconazole, cypermethrin and malathion) weakly induced the ER transactivity, and three pesticides (bitertanol, propiconazole and mancozeb) antagonized the AR activity in a concentration-dependent manner. Three pesticides (terbuthylazine, propiconazole and prothioconazole) weakly induced the aromatase activity. In addition, two mixtures, consisting of three pesticides (bitertanol, propiconazole, cypermethrin) and five pesticides (terbuthylazine, bitertanol, propiconazole, cypermethrin, malathion), respectively, induced the ER transactivity and aromatase activity, and additively antagonized the AR transactivity. In conclusion, our data suggest that currently used pesticides possess endocrine-disrupting potential in vitro which can be mediated via ER, AR and aromatase activities. The observed mixture effects emphasize the importance of considering the combined action of pesticides in order to assure proper estimations of related health effect risks. - Highlights: • Currently used pesticides possess endocrine-disrupting (ED) potential in vitro. • ED effects can be mediated via sex hormone receptors and/or the aromatase enzyme. • Additive mixture effects on androgen receptor transactivity were observed.« less

Relationships between yolk androgens and nest density, laying date, and laying order in Western Burrowing Owls (Athene cunicularia hypugaea)

USGS Publications Warehouse

Welty, J.L.; Belthoff, J.R.; Egbert, J.; Schwabl, H.

2012-01-01

Increases in yolk androgens within and among avian clutches have been correlated with decreased incubation time, increased aggression within a nest, increased begging behaviour, decreased immune response, and decreased life span. Although the mechanisms that lead to variability in yolk androgens within and between clutches are not completely known, yolk androgens can be a function of both social and environmental conditions. We were interested in if and how nesting density, laying date, and laying order influenced yolk androgens in Western Burrowing Owls (Athene cunicularia hypugaea (Bonaparte, 1825)) in which nest density varies considerably. In 2006 and 2007, we used radioimmunoassay to quantify the concentrations of testosterone, 5a-dihydrotestosterone, and androstenedione in the egg yolks from one early and one latelaid egg in 47 nests of Burrowing Owls located in the Morley Nelson Snake River Birds of Prey National Conservation Area in southern Idaho. Nesting density had no detectable effect on yolk androgens. Yolk androgens varied temporally and peaked in the middle of the laying season while being low before and after this time period. Within nests, late-laid eggs had higher testosterone and dihydrotestosterone than early-laid eggs; adrostendione exhibited a similar pattern in one but not both years of our study. It is possible that the seasonal pattern in yolk androgens that we observed is related to aspects of mate quality for females or declining chances of fledging success for later nesting females, whereas rises in egg androgens between early and late eggs within clutches could reflect a mechanism to assist nestlings from late-laid eggs that hatch one to several days after their siblings to better compete for resources within the nest or promote survival in the presence of larger siblings.

Development of cell-penetrating bispecific antibodies targeting the N-terminal domain of androgen receptor for prostate cancer therapy.

PubMed

Goicochea, Nancy L; Garnovskaya, Maria; Blanton, Mary G; Chan, Grace; Weisbart, Richard; Lilly, Michael B

2017-12-01

Castration-resistant prostate cancer cells exhibit continued androgen receptor signaling in spite of low levels of ligand. Current therapies to block androgen receptor signaling act by inhibiting ligand production or binding. We developed bispecific antibodies capable of penetrating cells and binding androgen receptor outside of the ligand-binding domain. Half of the bispecific antibody molecule consists of a single-chain variable fragment of 3E10, an anti-DNA antibody that enters cells. The other half is a single-chain variable fragment version of AR441, an anti-AR antibody. The resulting 3E10-AR441 bispecific antibody enters human LNCaP prostate cells and accumulates in the nucleus. The antibody binds to wild-type, mutant and splice variant androgen receptor. Binding affinity of 3E10-AR441 to androgen receptor (284 nM) was lower than that of the parental AR441 mAb (4.6 nM), but could be improved (45 nM) through alternative placement of the affinity tags, and ordering of the VH and VK domains. The 3E10-AR441 bispecific antibody blocked genomic signaling by wild-type or splice variant androgen receptor in LNCaP cells. It also blocked non-genomic signaling by the wild-type receptor. Furthermore, bispecific antibody inhibited the growth of C4-2 prostate cancer cells under androgen-stimulated conditions. The 3E10-AR441 biAb can enter prostate cancer cells and inhibits androgen receptor function in a ligand-independent manner. It may be an attractive prototype agent for prostate cancer therapy. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Androgen regulation of the human hair follicle: the type I hair keratin hHa7 is a direct target gene in trichocytes.

PubMed

Jave-Suarez, Luis F; Langbein, Lutz; Winter, Hermelita; Praetzel, Silke; Rogers, Michael A; Schweizer, Juergen

2004-03-01

Previous work had shown that most members of the complex human hair keratin family were expressed in terminal scalp hairs. An exception to this rule was the type I hair keratin hHa7, which was only detected in some but not all vellus hairs of the human scalp (Langbein et al, 1999). Here we show that hHa7 exhibits constitutive expression in medullary cells of all types of male and female sexual hairs. Medullated beard, axillary, and pubic hairs arise during puberty from small, unmedullated vellus hairs under the influence of circulating androgens. This suggested an androgen-controlled expression of the hHa7 gene. Further evidence for this assumption was provided by the demonstration of androgen receptor (AR) expression in the nuclei of medullary cells of beard hairs. Moreover, homology search for the semipalindromic androgen receptor-binding element (ARE) consensus sequence GG(A)/(T)ACAnnnTGTTCT in the proximal hHa7 promoter revealed three putative ARE motifs. Electrophoretic mobility shift assays demonstrated the specific binding of AR to all three hHa7 AREs. Their function as AR-responsive elements, either individually or in concert within the hHa7 promoter, could be further confirmed by transfection studies with or without an AR expression vector in PtK2 and prostate PC3-Arwt cells, respectively in the presence or absence of a synthetic androgen. Our study detected hHa7 as the first gene in hair follicle trichocytes whose expression appears to be directly regulated by androgens. As such, hHa7 represents a marker for androgen action on hair follicles and might be a suitable tool for investigations of androgen-dependent hair disorders.

Neutral endopeptidase promotes phorbol ester-induced apoptosis in prostate cancer cells by inhibiting neuropeptide-induced protein kinase C delta degradation.

PubMed

Sumitomo, M; Shen, R; Goldberg, J S; Dai, J; Navarro, D; Nanus, D M

2000-12-01

Phorbol esters induce apoptosis in androgen-sensitive LNCaP cells, which express neutral endopeptidase (NEP), but not in androgen-independent prostate cancer (PC) cells, which lack NEP expression. We investigated the role of NEP in PC cell susceptibility to 12-O-tetradecanoylphorbol-13-acetate (TPA). Western analysis showed that expression of NEP and protein kinase Cdelta (PKCdelta) correlated with PC cell sensitivity to TPA-induced growth arrest and apoptosis in LNCaP cells and in TSU-Prl cells expressing an inducible wild-type NEP protein. Inhibition of NEP enzyme activity using the specific NEP inhibitor CGS24592, or inhibition of PKCdelta using Rottlerin at concentrations that inhibit PKCdelta but not PKCalpha, significantly inhibited TPA-induced growth inhibition and cell death. Furthermore, pulse-chase experiments showed PKCdelta is stabilized in LNCaP cells and in TSU-Pr1 cells overexpressing wild-type NEP compared with PC cells lacking NEP expression. This results from NEP inactivation of its neuropeptide substrates (bombesin and endothelin-1), which in the absence of NEP stimulate cSrc kinase activity and induce rapid degradation of PKCdelta protein. These results indicate that expression of enzymatically active NEP by PC cells is necessary for TPA-induced apoptosis, and that NEP inhibits neuropeptide-induced, cSrc-mediated PKCdelta degradation.

The Response of Prostate Smooth Muscle Cells to Testosterone Is Determined by the Subcellular Distribution of the Androgen Receptor.

PubMed

Peinetti, Nahuel; Scalerandi, María Victoria; Cuello Rubio, Mariana Micaela; Leimgruber, Carolina; Nicola, Juan Pablo; Torres, Alicia Ines; Quintar, Amado Alfredo; Maldonado, Cristina Alicia

2018-02-01

Androgen signaling in prostate smooth muscle cells (pSMCs) is critical for the maintenance of prostate homeostasis, the alterations of which are a central aspect in the development of pathological conditions. Testosterone can act through the classic androgen receptor (AR) in the cytoplasm, eliciting genomic signaling, or through different types of receptors located at the plasma membrane for nongenomic signaling. We aimed to find evidence of nongenomic testosterone-signaling mechanisms in pSMCs and their participation in cell proliferation, differentiation, and the modulation of the response to lipopolysaccharide. We demonstrated that pSMCs can respond to testosterone by a rapid activation of ERK1/2 and Akt. Furthermore, a pool of ARs localized at the cell surface of pSMCs is responsible for a nongenomic testosterone-induced increase in cell proliferation. Through membrane receptor stimulation, testosterone favors a muscle phenotype, indicated by an increase in smooth muscle markers. We also showed that the anti-inflammatory effects of testosterone, capable of attenuating lipopolysaccharide-induced proinflammatory actions, are promoted only by receptors located inside the cell. We postulate that testosterone might perform prohomeostatic effects through intracellular-initiated mechanisms by modulating cell proliferation and inflammation, whereas some pathological, hyperproliferative actions would be induced by membrane-initiated nongenomic signaling in pSMCs. Copyright © 2018 Endocrine Society.

Suspected ontogeny of a recently described hypo-androgenic PCOS-like phenotype with advancing age.

PubMed

Gleicher, Norbert; Kushnir, Vitaly A; Darmon, Sarah K; Wang, Qi; Zhang, Lin; Albertini, David F; Barad, David H

2018-03-01

A recent report described a new PCOS-like phenotype in lean older infertile women, and was characterized by high age-specific anti-Müllerian hormone (AMH) but hypo- rather than the expected hyper-androgenism. The hypo-androgenism was, furthermore, characterized of, likely, adrenal origin and autoimmune etiology. We extracted data on 708 consecutive infertility patients, and separated them into three age-strata, <35, 36-42, and >42 years. In each stratum, we investigated how levels of anti-Müllerian hormone (AMH) and testosterone (T) interrelate between high-AMH (AMH ≥ 75th quantile) and normal AMH (25th-75th quantile) and low-T (total testosterone ≤19.0 ng/dL), normal-T (19.0-29.0 ng/dL) and high-T (>29.0 ng/dL). High-AMH cycles were presumed to reflect PCOS-like patients. Routine in vitro fertilization (IVF) cycle outcomes and clinical phenotypes of patients were then compared between groups with AMH and T as statistical variables. This hypo-androgenic PCOS-like phenotype already exists in age stratum <35 years. It appears to arise from a lean, at very young ages hyper-androgenic PCOS phenotype that develops in comparison to controls (likely autoimmune-induced) insufficiency of the adrenal zona reticularis (low-T and low-DHEAS) and zona fasciculata (low-C), and is characterized by frequent evidence of autoimmunity. A degree of adrenal insufficiency, thus, concomitantly appears to affect adrenal androgen and, to lesser degrees, glucocorticoid production (mineralocorticoids were not investigated). Here investigated new PCOS-like phenotype demonstrates features compatible with what under Rotterdam criteria has been referred to as PCOS phenotype-D. If confirmed, the observation that the ontogeny of this phenotype already at young ages is, likely, driven by adrenal autoimmunity, supports the position of the androgen excess and PCOS society that the etiology of phenotype-D differs from that of classical hyper-androgenic PCOS of mostly ovarian etiology.

Androgens have antiresorptive effects on trabecular disuse osteopenia independent from muscle atrophy.

PubMed

Laurent, Michaël R; Jardí, Ferran; Dubois, Vanessa; Schollaert, Dieter; Khalil, Rougin; Gielen, Evelien; Carmeliet, Geert; Claessens, Frank; Vanderschueren, Dirk

2016-12-01

Aging hypogonadal men are at increased risk of osteoporosis and sarcopenia. Testosterone is a potentially appealing strategy to prevent simultaneous bone and muscle loss. The androgen receptor (AR) mediates antiresorptive effects on trabecular bone via osteoblast-lineage cells, as well as muscle-anabolic actions. Sex steroids also modify the skeletal response to mechanical loading. However, it is unclear whether the effects of androgens on bone remain effective independent of mechanical stimulation or rather require indirect androgen effects via muscle. This study aims to characterize the effects and underlying mechanisms of androgens on disuse osteosarcopenia. Adult male mice received a unilateral botulinum toxin (BTx) injection, and underwent sham surgery or orchidectomy (ORX) without or with testosterone (ORX+T) or dihydrotestosterone (ORX+DHT) replacement. Compared to the contralateral internal control hindlimb, acute trabecular number and bone volume loss was increased by ORX and partially prevented DHT. T was more efficient and increased BV/TV in both hindlimbs over sham values, although it did not reduce the detrimental effect of BTx. Both androgens and BTx regulated trabecular osteoclast surface as well as tartrate-resistant acid phosphatase expression. Androgens also prevented BTx-induced body weight loss but did not significantly influence paralysis or muscle atrophy. BTx and ORX both reduced cortical thickness via endosteal expansion, which was prevented by T but not DHT. In long-term follow-up, the residual trabecular bone volume deficit in sham-BTx hindlimbs was prevented by DHT but T restored it more efficiently to pre-treatment levels. Conditional AR deletion in late osteoblasts and osteocytes or in the satellite cell lineage increased age-related trabecular bone loss in both hindlimbs without influencing the effect of BTx on trabecular osteopenia. We conclude that androgens have antiresorptive effects on trabecular disuse osteopenia which do not require AR actions on bone via muscle or via osteocytes. Copyright © 2016 Elsevier Inc. All rights reserved.

Effects of model aromatizable (17α-methyltestosterone) and non-aromatizable (5α-dihydrotestosterone) androgens on the adult mummichog (Fundulus heteroclitus) in a short-term reproductive endocrine bioassay.

PubMed

Rutherford, Robert; Lister, Andrea; Hewitt, L Mark; MacLatchy, Deborah

2015-04-01

Androgens originating from pulp mill processing, sewage treatment facilities and agricultural activities have the potential for discharge into aquatic receiving environments. To assess androgen effects on reproductive endocrine status in fish in estuarine environments, male and female adult northern mummichog (Fundulus heteroclitus macrolepidotus) were exposed to an aromatizable androgen (17α-methyltestosterone; MT) and a non-aromatizable androgen (5α-dihydrotestosterone; DHT) in a short-term reproductive endocrine bioassay. Fish were nominally exposed to 10 μg/L or 100 μg/L DHT, or 0.1 μg/L or 1 μg/L MT for 14 days during gonadal recrudescence. Actual concentrations of androgens, as measured by enzyme immunoassay (EIA), were 10-49% of nominal MT 0.1, 3-6% of nominal MT 1, 5-10% of nominal DHT 10 and 3-25% of nominal DHT 100. Female mummichog were impacted to a greater degree by androgen exposure, with increased plasma testosterone (T) at 100 μg/L DHT, depressed plasma 17β-estradiol (E2) at both DHT concentrations and at 1 μg/L MT, as well as depressed in vitro E2 at both MT concentrations and 100 μg/L DHT. Males had depressed plasma T in the 10 μg/L DHT treatment and depressed in vitro 11-ketotestosterone production for both MT concentrations and 10 μg/L DHT. Ovarian aromatase gene expression was induced in females exposed to 1 μg/L MT. DHT at 100 μg/L increased hepatic vitellogenin-1 (VTG1) expression in males and depressed VTG1 expression in females. The range of responses between sexes and among species provides evidence for modes of actions and potential impacts of androgens in aquatic receiving environments. Copyright © 2015 Elsevier Inc. All rights reserved.

Adipose-derived stromal cells inhibit prostate cancer cell proliferation inducing apoptosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Takahara, Kiyoshi; Ii, Masaaki, E-mail: masaii@art.osaka-med.ac.jp; Inamoto, Teruo

2014-04-18

Highlights: • AdSC transplantation exhibits inhibitory effect on tumor progressions of PCa cells. • AdSC-induced PCa cell apoptosis may occur via the TGF-β signaling pathway. • High expression of the TGF-β1 gene in AdSCs. - Abstract: Mesenchymal stem cells (MSCs) have generated a great deal of interest in the field of regenerative medicine. Adipose-derived stromal cells (AdSCs) are known to exhibit extensive proliferation potential and can undergo multilineage differentiation, sharing similar characteristics to bone marrow-derived MSCs. However, as the effect of AdSCs on tumor growth has not been studied sufficiently, we assessed the degree to which AdSCs affect the proliferationmore » of prostate cancer (PCa) cell. Human AdSCs exerted an inhibitory effect on the proliferation of androgen-responsive (LNCaP) and androgen-nonresponsive (PC3) human PCa cells, while normal human dermal fibroblasts (NHDFs) did not, and in fact promoted PCa cell proliferation to a degree. Moreover, AdSCs induced apoptosis of LNCaP cells and PC3 cells, activating the caspase3/7 signaling pathway. cDNA microarray analysis suggested that AdSC-induced apoptosis in both LNCaP and PC3 cells was related to the TGF-β signaling pathway. Consistent with our in vitro observations, local transplantation of AdSCs delayed the growth of tumors derived from both LNCaP- and PC3-xenografts in immunodeficient mice. This is the first preclinical study to have directly demonstrated that AdSC-induced PCa cell apoptosis may occur via the TGF-β signaling pathway, irrespective of androgen-responsiveness. Since autologous AdSCs can be easily isolated from adipose tissue without any ethical concerns, we suggest that therapy with these cells could be a novel approach for patients with PCa.« less

Stromal Androgen Receptor in Prostate Cancer Development and Progression

PubMed Central

Leach, Damien A.; Buchanan, Grant

2017-01-01

Prostate cancer development and progression is the result of complex interactions between epithelia cells and fibroblasts/myofibroblasts, in a series of dynamic process amenable to regulation by hormones. Whilst androgen action through the androgen receptor (AR) is a well-established component of prostate cancer biology, it has been becoming increasingly apparent that changes in AR signalling in the surrounding stroma can dramatically influence tumour cell behavior. This is reflected in the consistent finding of a strong association between stromal AR expression and patient outcomes. In this review, we explore the relationship between AR signalling in fibroblasts/myofibroblasts and prostate cancer cells in the primary site, and detail the known functions, actions, and mechanisms of fibroblast AR signaling. We conclude with an evidence-based summary of how androgen action in stroma dramatically influences disease progression. PMID:28117763

Androgen deficiency in male patients diagnosed with ANCA-associated vasculitis: a cause of fatigue and reduced health-related quality of life?

PubMed

Tuin, Janneke; Sanders, Jan-Stephan F; Buhl, Birgit M; van Beek, André P; Stegeman, Coen A

2013-01-01

Low testosterone levels in men are associated with fatigue, limited physical performance and reduced health-related quality of life (HRQOL); however, this relationship has never been assessed in patients with anti-neutrophil cytoplasmic antibodies (ANCA) -associated vasculitides (AAV). The aim of this study was to assess the prevalence of androgen deficiency and to investigate the role of testosterone in fatigue, limited physical condition and reduced HRQOL in men with AAV. Male patients with AAV in remission were included in this study. Fatigue and HRQOL were assessed by the multi-dimensional fatigue inventory (MFI)-20 and RAND-36 questionnaires. Seventy male patients with a mean age of 59 years (SD 12) were included. Scores of almost all subscales of both questionnaires were significantly worse in patients compared to controls. Mean total testosterone and free testosterone levels were 13.8 nmol/L (SD 5.6) and 256 pmol/L (SD 102), respectively. Androgen deficiency (defined according to Endocrine Society Clinical Practice Guidelines) was present in 47% of patients. Scores in the subscales of general health perception, physical functioning and reduced activity were significantly worse in patients with androgen deficiency compared to patients with normal androgen levels. Testosterone and age were predictors for the RAND-36 physical component summary in multiple linear regression analysis. Testosterone, age, vasculitis damage index (VDI) and C-reactive protein (CRP) were associated with the MFI-20 subscale of general fatigue. This study showed that androgen deficiency was present in a substantial number of patients with AAV. Testosterone was one of the predictors for physical functioning and fatigue. Testosterone may play a role in fatigue, reduced physical performance and HRQOL in male patients with AAV.

ASC-J9(®) suppresses castration resistant prostate cancer progression via degrading the enzalutamide-induced androgen receptor mutant AR-F876L.

PubMed

Wang, Ronghao; Lin, Wanying; Lin, Changyi; Li, Lei; Sun, Yin; Chang, Chawnshang

2016-08-28

Androgen deprivation therapy (ADT) with the newly developed powerful anti-androgen enzalutamide (Enz, also known as MDV3100) has promising therapeutic effects to suppress castration resistant prostate cancer (CRPC) and extending patients' lives an extra 4.8 months. However, most Enz therapy eventually fails with the development of Enz resistance. The detailed mechanisms how CRPC develops Enz resistance remain unclear and may involve multiple mechanisms. Among them, the induction of the androgen receptor (AR) mutant AR-F876L in some CRPC patients may represent one driving force that confers Enz resistance. Here, we demonstrate that the AR degradation enhancer, ASC-J9(®), not only degrades wild-type AR, but also has the ability to target AR-F876L. The consequence of suppressing AR-F876L may then abrogate AR-F876L mediated CRPC cell proliferation and metastasis. Thus, developing ASC-J9(®) as a new therapeutic approach may represent a novel therapy to better suppress CRPC that has already developed Enz resistance. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

The Cell Cycle Inhibitor p27KIP1: A Key Mediator of G1 Arrest by Androgen Ablation an dby Vitamin D3 Analog

DTIC Science & Technology

2000-02-01

al., 1996; Tyers, 1996). gland . Higher doses of androgen cause growth arrest by p27 increases during differentiation in many cell inducing...innocuous hormones in human prostate cancer patients. These vitamin D3 analogs can inhibit prostate cancer growth and yet they do not cause the negative side...Vitamin D3 and a physiologic does of DHT could cause a synergistic growth arrest in prostate cancer cells (22). The vitamin D3 analogue EB 1089 has the

Association of Androgen Metabolism Gene Polymorphisms with Prostate Cancer Risk and Androgen Concentrations: Results from the Prostate Cancer Prevention Trial

PubMed Central

Price, Douglas K.; Chau, Cindy H.; Till, Cathee; Goodman, Phyllis J.; Leach, Robin J.; Johnson-Pais, Teresa L.; Hsing, Ann W.; Hoque, Ashraful; Parnes, Howard L.; Schenk, Jeannette M.; Tangen, Catherine M.; Thompson, Ian M.; Reichardt, Juergen K.V.; Figg, William D.

2016-01-01

Background Prostate cancer is highly influenced by androgens and genes. We investigated whether genetic polymorphisms along the androgen biosynthesis and metabolism pathways are associated with androgen concentrations or risk of prostate cancer or high-grade disease from finasteride treatment. Methods A nested case-control study from the Prostate Cancer Prevention Trial using cases drawn from men with biopsy-proven prostate cancer and biopsy-negative, frequency-matched controls was conducted to investigate the association of 51 single nucleotide polymorphisms (SNPs) in 12 genes of the androgen pathway with total, low-grade, and high-grade prostate cancer incidence and serum hormone concentrations. Results There were significant associations of genetic polymorphisms in SRD5A1 (rs3736316, rs3822430, rs1560149, rs248797, and rs472402) and SRD5A2 (rs2300700) with risk of high-grade prostate cancer in the placebo arm of the PCPT; two SNPs were significantly associated with increased risk (SRD5A1 rs472402 [OR, 1.70; 95% CI, 1.05-2.75, Ptrend=0.03]; SRD5A2 rs2300700 [OR, 1.94; 95% CI, 1.19-3.18, Ptrend=0.01]). Eleven SNPs in SRD5A1, SRD5A2, CYP1B1, and CYP3A4 were found to be associated with modifying mean serum androgen and sex hormone-binding globulin concentrations; two SNPs (SRD5A1 rs824811 and CYP1B1 rs10012, Ptrend<0.05) consistently and significantly altered all androgen concentrations. Several SNPs (rs3822430, rs2300700; CYP3A43 rs800672; CYP19 rs700519; Ptrend<0.05) were significantly associated with both circulating hormone levels and prostate cancer risk. Conclusion Germline genetic variations of androgen-related pathway genes are associated with serum androgen concentrations and risk of prostate cancer. Further studies to examine the functional consequence of novel causal variants are warranted. PMID:27164191

Determination of the source of androgen excess in functionally atypical polycystic ovary syndrome by a short dexamethasone androgen-suppression test and a low-dose ACTH test.

PubMed

Rosenfield, Robert L; Mortensen, Monica; Wroblewski, Kristen; Littlejohn, Elizabeth; Ehrmann, David A

2011-11-01

Polycystic ovary syndrome (PCOS) patients typically have 17-hydroxyprogesterone (17OHP) hyperresponsiveness to GnRH agonist (GnRHa) (PCOS-T). The objective of this study was to determine the source of androgen excess in the one-third of PCOS patients who atypically lack this type of ovarian dysfunction (PCOS-A). Aged-matched PCOS-T (n= 40), PCOS-A (n= 20) and controls (n= 39) were studied prospectively in a General Clinical Research Center. Short (4 h) and long (4-7 day) dexamethasone androgen-suppression tests (SDAST and LDAST, respectively) were compared in subsets of subjects. Responses to SDAST and low-dose adrenocorticotropic hormone (ACTH) were then evaluated in all. Testosterone post-SDAST correlated significantly with testosterone post-LDAST and 17OHP post-GnRHa (r = 0.671-0.672), indicating that all detect related aspects of ovarian dysfunction. An elevated dehydroepiandrosterone peak in response to ACTH, which defined functional adrenal hyperandrogenism, was similarly prevalent in PCOS-T (27.5%) and PCOS-A (30%) and correlated significantly with baseline dehydroepiandrosterone sulfate (DHEAS) (r = 0.708). Functional ovarian hyperandrogenism was detected by subnormal testosterone suppression by SDAST in most (92.5%) PCOS-T, but significantly fewer PCOS-A (60%, P< 0.01). Glucose intolerance was absent in PCOS-A, but present in 30% of PCOS-T (P < 0.001). Most of the PCOS-A cases with normal testosterone suppression in response to SDAST (5/8) lacked evidence of adrenal hyperandrogenism and were obese. Functional ovarian hyperandrogenism was not demonstrable by SDAST in 40% of PCOS-A. Most of these cases had no evidence of adrenal hyperandrogenism. Obesity may account for most hyperandrogenemic anovulation that lacks a glandular source of excess androgen, and the SDAST seems useful in making this distinction.

Determination of the source of androgen excess in functionally atypical polycystic ovary syndrome by a short dexamethasone androgen-suppression test and a low-dose ACTH test

PubMed Central

Rosenfield, Robert L.; Mortensen, Monica; Wroblewski, Kristen; Littlejohn, Elizabeth; Ehrmann, David A.

2011-01-01

BACKGROUND Polycystic ovary syndrome (PCOS) patients typically have 17-hydroxyprogesterone (17OHP) hyperresponsiveness to GnRH agonist (GnRHa) (PCOS-T). The objective of this study was to determine the source of androgen excess in the one-third of PCOS patients who atypically lack this type of ovarian dysfunction (PCOS-A). METHODS Aged-matched PCOS-T (n= 40), PCOS-A (n= 20) and controls (n= 39) were studied prospectively in a General Clinical Research Center. Short (4 h) and long (4–7 day) dexamethasone androgen-suppression tests (SDAST and LDAST, respectively) were compared in subsets of subjects. Responses to SDAST and low-dose adrenocorticotropic hormone (ACTH) were then evaluated in all. RESULTS Testosterone post-SDAST correlated significantly with testosterone post-LDAST and 17OHP post-GnRHa (r = 0.671–0.672), indicating that all detect related aspects of ovarian dysfunction. An elevated dehydroepiandrosterone peak in response to ACTH, which defined functional adrenal hyperandrogenism, was similarly prevalent in PCOS-T (27.5%) and PCOS-A (30%) and correlated significantly with baseline dehydroepiandrosterone sulfate (DHEAS) (r = 0.708). Functional ovarian hyperandrogenism was detected by subnormal testosterone suppression by SDAST in most (92.5%) PCOS-T, but significantly fewer PCOS-A (60%, P< 0.01). Glucose intolerance was absent in PCOS-A, but present in 30% of PCOS-T (P < 0.001). Most of the PCOS-A cases with normal testosterone suppression in response to SDAST (5/8) lacked evidence of adrenal hyperandrogenism and were obese. CONCLUSIONS Functional ovarian hyperandrogenism was not demonstrable by SDAST in 40% of PCOS-A. Most of these cases had no evidence of adrenal hyperandrogenism. Obesity may account for most hyperandrogenemic anovulation that lacks a glandular source of excess androgen, and the SDAST seems useful in making this distinction. PMID:21908468

Minoxidil may suppress androgen receptor-related functions.

PubMed

Hsu, Cheng-Lung; Liu, Jai-Shin; Lin, An-Chi; Yang, Chih-Hsun; Chung, Wen-Hung; Wu, Wen-Guey

2014-04-30

Although minoxidil has been used for more than two decades to treat androgenetic alopecia (AGA), an androgen-androgen receptor (AR) pathway-dominant disease, its precise mechanism of action remains elusive. We hypothesized that minoxidil may influence the AR or its downstream signaling. These tests revealed that minoxidil suppressed AR-related functions, decreasing AR transcriptional activity in reporter assays, reducing expression of AR targets at the protein level, and suppressing AR-positive LNCaP cell growth. Dissecting the underlying mechanisms, we found that minoxidil interfered with AR-peptide, AR-coregulator, and AR N/C-terminal interactions, as well as AR protein stability. Furthermore, a crystallographic analysis using the AR ligand-binding domain (LBD) revealed direct binding of minoxidil to the AR in a minoxidil-AR-LBD co-crystal model, and surface plasmon resonance assays demonstrated that minoxidil directly bound the AR with a K(d) value of 2.6 µM. Minoxidil also suppressed AR-responsive reporter activity and decreased AR protein stability in human hair dermal papilla cells. The current findings provide evidence that minoxidil could be used to treat both cancer and age-related disease, and open a new avenue for applications of minoxidil in treating androgen-AR pathway-related diseases.

Minoxidil may suppress androgen receptor-related functions

PubMed Central

Hsu, Cheng-Lung; Liu, Jai-Shin; Lin, An-Chi; Yang, Chih-Hsun; Chung, Wen-Hung; Wu, Wen-Guey

2014-01-01

Although minoxidil has been used for more than two decades to treat androgenetic alopecia (AGA), an androgen-androgen receptor (AR) pathway-dominant disease, its precise mechanism of action remains elusive. We hypothesized that minoxidil may influence the AR or its downstream signaling. These tests revealed that minoxidil suppressed AR-related functions, decreasing AR transcriptional activity in reporter assays, reducing expression of AR targets at the protein level, and suppressing AR-positive LNCaP cell growth. Dissecting the underlying mechanisms, we found that minoxidil interfered with AR-peptide, AR-coregulator, and AR N/C-terminal interactions, as well as AR protein stability. Furthermore, a crystallographic analysis using the AR ligand-binding domain (LBD) revealed direct binding of minoxidil to the AR in a minoxidil-AR-LBD co-crystal model, and surface plasmon resonance assays demonstrated that minoxidil directly bound the AR with a Kd value of 2.6 μM. Minoxidil also suppressed AR-responsive reporter activity and decreased AR protein stability in human hair dermal papilla cells. The current findings provide evidence that minoxidil could be used to treat both cancer and age-related disease, and open a new avenue for applications of minoxidil in treating androgen-AR pathway-related diseases. PMID:24742982

Sexual Fate Reprogramming in the Steroid-Induced Bi-Directional Sex Change in the Protogynous Orange-Spotted Grouper, Epinephelus coioides.

PubMed

Wu, Guan-Chung; Tey, Wei-Guan; Li, Hau-Wen; Chang, Ching-Fong

2015-01-01

Androgen administration has been widely used for masculinization in fish. The mechanism of the sex change in sexual fate regulation is not clear. Oral administration or pellet implantation was applied. We orally applied an aromatase inhibitor (AI, to decrease estrogen levels) and 17α-methyltestosterone (MT, to increase androgen levels) to induce masculinization to clarify the mechanism of the sex change in the protogynous orange-spotted grouper. After 3 mo of AI/MT administration, male characteristics were observed in the female-to-male sex change fish. These male characteristics included increased plasma 11-ketotestosterone (11-KT), decreased estradiol (E2) levels, increased male-related gene (dmrt1, sox9, and cyp11b2) expression, and decreased female-related gene (figla, foxl2, and cyp19a1a) expression. However, the reduced male characteristics and male-to-female sex change occurred after AI/MT-termination in the AI- and MT-induced maleness. Furthermore, the MT-induced oocyte-depleted follicle cells (from MT-implantation) had increased proliferating activity, and the sexual fate in a portion of female gonadal soma cells was altered to male function during the female-to-male sex change. In contrast, the gonadal soma cells were not proliferative during the early process of the male-to-female sex change. Additionally, the male gonadal soma cells did not alter to female function during the male-to-female sex change in the AI/MT-terminated fish. After MT termination in the male-to-female sex-changed fish, the differentiated male germ cells showed increased proliferating activities together with dormancy and did not show characteristics of both sexes in the early germ cells. In conclusion, these findings indicate for the first time in a single species that the mechanism involved in the replacement of soma cells is different between the female-to-male and male-to-female sex change processes in grouper. These results also demonstrate that sexual fate determination (secondary sex determination) is regulated by endogenous sex steroid levels.

Sexual Fate Reprogramming in the Steroid-Induced Bi-Directional Sex Change in the Protogynous Orange-Spotted Grouper, Epinephelus coioides

PubMed Central

Wu, Guan-Chung; Tey, Wei-Guan; Li, Hau-Wen; Chang, Ching-Fong

2015-01-01

Androgen administration has been widely used for masculinization in fish. The mechanism of the sex change in sexual fate regulation is not clear. Oral administration or pellet implantation was applied. We orally applied an aromatase inhibitor (AI, to decrease estrogen levels) and 17α-methyltestosterone (MT, to increase androgen levels) to induce masculinization to clarify the mechanism of the sex change in the protogynous orange-spotted grouper. After 3 mo of AI/MT administration, male characteristics were observed in the female-to-male sex change fish. These male characteristics included increased plasma 11-ketotestosterone (11-KT), decreased estradiol (E2) levels, increased male-related gene (dmrt1, sox9, and cyp11b2) expression, and decreased female-related gene (figla, foxl2, and cyp19a1a) expression. However, the reduced male characteristics and male-to-female sex change occurred after AI/MT-termination in the AI- and MT-induced maleness. Furthermore, the MT-induced oocyte-depleted follicle cells (from MT-implantation) had increased proliferating activity, and the sexual fate in a portion of female gonadal soma cells was altered to male function during the female-to-male sex change. In contrast, the gonadal soma cells were not proliferative during the early process of the male-to-female sex change. Additionally, the male gonadal soma cells did not alter to female function during the male-to-female sex change in the AI/MT-terminated fish. After MT termination in the male-to-female sex-changed fish, the differentiated male germ cells showed increased proliferating activities together with dormancy and did not show characteristics of both sexes in the early germ cells. In conclusion, these findings indicate for the first time in a single species that the mechanism involved in the replacement of soma cells is different between the female-to-male and male-to-female sex change processes in grouper. These results also demonstrate that sexual fate determination (secondary sex determination) is regulated by endogenous sex steroid levels. PMID:26714271

Endocrine correlates of musth in free-ranging Asian elephants (Elephas maximus) determined by non-invasive faecal steroid hormone metabolite measurements.

PubMed

Ghosal, Ratna; Ganswindt, André; Seshagiri, Polani B; Sukumar, Raman

2013-01-01

The occurrence of musth, a period of elevated levels of androgens and heightened sexual activity, has been well documented for the male Asian elephant (Elephas maximus). However, the relationship between androgen-dependent musth and adrenocortical function in this species is unclear. The current study is the first assessment of testicular and adrenocortical function in free-ranging male Asian elephants by measuring levels of testosterone (androgen) and cortisol (glucocorticoid--a physiological indicator of stress) metabolites in faeces. During musth, males expectedly showed significant elevation in faecal testosterone metabolite levels. Interestingly, glucocorticoid metabolite concentrations remained unchanged between musth and non-musth periods. This observation is contrary to that observed with wild and captive African elephant bulls and captive Asian bull elephants. Our results show that musth may not necessarily represent a stressful condition in free-ranging male Asian elephants.

Androgenic and estrogenic effects of the synthetic androgen 17alpha-methyltestosterone on sexual development and reproductive performance in the fathead minnow (Pimephales promelas) determined using the gonadal recrudescence assay.

PubMed

Pawlowski, S; Sauer, A; Shears, J A; Tyler, C R; Braunbeck, T

2004-06-24

The effects of the androgen, 17alpha-methyltestosterone were assessed on sexual development and reproductive performance in the fathead minnow (Pimephales promelas) using a gonadal recrudescence assay. In this assay, mature male and female fathead minnow, previously kept under simulated winter conditions (15 degrees C; 8:16 h light:dark regime) were transferred to simulated summer conditions (25 degrees C water temperature; 16:8 h light:dark regime) to induce gonadal recrudescence. To assess sexual development fish were exposed to nominal concentrations of 0, 0.1, 1, 5 and 50 microg/L 17alpha-methyltestosterone. After 3 weeks of chemical exposure, effects on condition (condition factor, CF), plasma vitellogenin (VTG), secondary sex characteristics, gonad growth (gonadosomatic index; GSI) and gonad histology were investigated. Reproductive performance, including reproductive output (egg production), spawning behaviour, and fertilisation rate were measured over a subsequent 3-week-period in breeding adults maintained in clean water. 17alpha-Methyltestosterone had no effects on the condition of fish at any of the doses tested. 17alpha-Methyltestosterone induced both androgenic and estrogenic effects with females generally more affected by 17alpha-methyltestosterone than males: atretic follicles and male-specific sex characteristics (androgenic effect) were induced in females at > or = 0.1 and > or = 1 microg/L 17alpha-methyltestosterone, respectively. An inhibitory effect on ovary growth occurred at an exposure concentration of 50 microg/L 17alpha-methyltestosterone. In males 1 microg/L 17alpha-methyltestosterone induced a concentration-response induction of plasma vitellogenin (estrogenic effect) likely due to its conversion into 17alpha-methylestradiol, rather to the competition with endogenous steroids and their cross reactivity with the estrogen receptor. In the fish breeding studies, concentration-dependent reductions in egg number, fertilisation rate and increases in abnormal sexual behaviour in females were observed. All of these effects occurred at exposure concentrations of > or = 5 microg/L 17alpha-methyltestosterone. Thus, it could be assumed that the observed estrogenic effects in male fathead minnow were likely to the conversion of 17alpha-methyltestosterone into the estrogen 17alpha-methylestradiol, rather to the acting of 17alpha-methyltestosterone itself. In conclusion to this, showing hormonally activity of 17alpha-methyltestosterone in fish down to 100 ng/L, indicates that its potency was close to the range of several naturally occurring estrogens.

p,p'-Dichlorodiphenyltrichloroethane (p,p'-DDT) and p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) repress prostate specific antigen levels in human prostate cancer cell lines.

PubMed

Wong, Lilian I L; Labrecque, Mark P; Ibuki, Naokazu; Cox, Michael E; Elliott, John E; Beischlag, Timothy V

2015-03-25

Despite stringent restrictions on their use by many countries since the 1970s, the endocrine disrupting chemicals, DDT and DDE are still ubiquitous in the environment. However, little attention has been directed to p,p'-DDT and the anti-androgen, p,p'-DDE on androgen receptor (AR) target gene transcription in human cells. Inhibitors of androgenic activity may have a deleterious clinical outcome in prostate cancer screens and progression, therefore we determined whether environmentally relevant concentrations of p,p'-DDT and p,p'-DDE negatively impact AR-regulated expression of prostate-specific antigen (PSA), and other AR target genes in human LNCaP and VCaP prostate cancer cells. Quantitative real-time PCR and immuno-blotting techniques were used to measure intracellular PSA, PSMA and AR mRNA and protein levels. We have shown for the first time that p,p'-DDT and p,p'-DDE repressed R1881-inducible PSA mRNA and protein levels in a dose-dependent manner. Additionally, we used the fully automated COBAS PSA detection system to determine that extracellular PSA levels were also significantly repressed. These chemicals achieve this by blocking the recruitment of AR to the PSA promoter region at 10 μM, as demonstrated by the chromatin immunoprecipitation (ChIP) in LNCaP cells. Both p,p'-DDT and p,p'-DDE repressed R1881-inducible AR protein accumulation at 10 μM. Thus, we conclude that men who have been exposed to either DDT or DDE may produce a false-negative PSA test when screening for prostate cancer, resulting in an inaccurate clinical diagnosis. More importantly, prolonged exposure to these anti-androgens may mimic androgen ablation therapy in individuals with prostate cancer, thus exacerbating the condition by inadvertently forcing adaptation to this stress early in the disease. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Expression of the androgen receptor in the testes and the concentrations of gonadotropins and sex steroid hormones in male turkeys (Meleagris gallopavo) during growth and development.

PubMed

Kiezun, J; Leska, A; Kaminska, B; Jankowski, J; Dusza, L

2015-04-01

Androgens, including testosterone (T) and androstenedione (A4), are essential for puberty, fertility and sexual functions. The biological activity of those hormones is mediated via the androgen receptor (AR). The regulation of androgen action in birds is poorly understood. Therefore, the present study analysed mRNA and protein expression of AR in the testes, plasma concentrations of the luteinizing hormone (LH), follicle-stimulating hormone (FSH), T, A4 and oestradiol (E2), as well as the levels of T, A4 and E2 in testicular homogenates of male turkeys (Meleagris gallopavo) at the age of 4, 8, 12, 16, 20, 24 and 28weeks. Plasma concentrations of LH and FSH, as well as plasma and testicular levels of T and A4 began to increase at 20weeks of age. The lowest plasma levels of E2 were noted at 20weeks relative to other growth stages. The 20th week of life seems to be the key phase in the development of the reproductive system of turkeys. The AR protein was found in the nuclei of testicular cells in all examined growth stages. Higher expression of AR protein in the testes beginning at 20weeks of age was accompanied by high plasma concentrations of LH and high plasma and testicular levels of androgens. This relationship seems to be necessary to regulate male sexual function. Copyright © 2014 Elsevier Inc. All rights reserved.

Critical role of androgen receptor in the postnatal period in male sexual behavior in rats.

PubMed

Yamada, Shunji; Ohoya, Miku; Takanami, Keiko; Matsuda, Ken Ichi; Kawata, Mitsuhiro

2015-11-16

Gonadal hormones have a developmental role in organization of the nervous system that regulates sexually dimorphic behavior. It is well known that androgen secreted from testes in the perinatal period is converted to estrogen by aromatase in rodent brain, and that estrogen and its receptor play a pivotal role in masculinization of brain structure and function. Treatment with flutamide, an androgen receptor (AR) antagonist, during the perinatal period inhibits development of malespecific brain structure and function, suggesting that androgen signaling via AR also influences brain masculinization. In this study, we investigated which stage during the postnatal period is critical for androgen signaling in brain masculinization. The postnatal period was designated as postnatal days (PD) 0-22, and divided into stages I (PD 0-7), II (PD 8-14), and III (PD 15-22). Newborn male rats were given flutamide subcutaneously in each stage. After adulthood, the effects of postnatal flutamide treatment on brain masculinization were evaluated byanalysis of male sexual behavior. Continuous inhibition of AR throughout stages I and II caused a robust reduction of the intromission ratio and ejaculation frequency compared with other groups. AR inhibition in stage I, II, or III did not cause any change. AR inhibition had no effect onmount behavior. These results show that stage-specific AR activation in the first two postnatal weeks may contribute to brain masculinization mediating male sexual behavior in adulthood. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Vascular responses to radiotherapy and androgen-deprivation therapy in experimental prostate cancer

PubMed Central

2012-01-01

Background Radiotherapy (RT) and androgen-deprivation therapy (ADT) are standard treatments for advanced prostate cancer (PC). Tumor vascularization is recognized as an important physiological feature likely to impact on both RT and ADT response, and this study therefore aimed to characterize the vascular responses to RT and ADT in experimental PC. Methods Using mice implanted with CWR22 PC xenografts, vascular responses to RT and ADT by castration were visualized in vivo by DCE MRI, before contrast-enhancement curves were analyzed both semi-quantitatively and by pharmacokinetic modeling. Extracted image parameters were correlated to the results from ex vivo quantitative fluorescent immunohistochemical analysis (qIHC) of tumor vascularization (9 F1), perfusion (Hoechst 33342), and hypoxia (pimonidazole), performed on tissue sections made from tumors excised directly after DCE MRI. Results Compared to untreated (Ctrl) tumors, an improved and highly functional vascularization was detected in androgen-deprived (AD) tumors, reflected by increases in DCE MRI parameters and by increased number of vessels (VN), vessel density ( VD), and vessel area fraction ( VF) from qIHC. Although total hypoxic fractions ( HF) did not change, estimated acute hypoxia scores ( AHS) – the proportion of hypoxia staining within 50 μm from perfusion staining – were increased in AD tumors compared to in Ctrl tumors. Five to six months after ADT renewed castration-resistant (CR) tumor growth appeared with an even further enhanced tumor vascularization. Compared to the large vascular changes induced by ADT, RT induced minor vascular changes. Correlating DCE MRI and qIHC parameters unveiled the semi-quantitative parameters area under curve ( AUC) from initial time-points to strongly correlate with VD and VF, whereas estimation of vessel size ( VS) by DCE MRI required pharmacokinetic modeling. HF was not correlated to any DCE MRI parameter, however, AHS may be estimated after pharmacokinetic modeling. Interestingly, such modeling also detected tumor necrosis very strongly. Conclusions DCE MRI reliably allows non-invasive assessment of tumors’ vascular function. The findings of increased tumor vascularization after ADT encourage further studies into whether these changes are beneficial for combined RT, or if treatment with anti-angiogenic therapy may be a strategy to improve the therapeutic efficacy of ADT in advanced PC. PMID:22621752

A Recurrent Germline Mutation in the 5'UTR of the Androgen Receptor Causes Complete Androgen Insensitivity by Activating Aberrant uORF Translation.

PubMed

Hornig, Nadine C; de Beaufort, Carine; Denzer, Friederike; Cools, Martine; Wabitsch, Martin; Ukat, Martin; Kulle, Alexandra E; Schweikert, Hans-Udo; Werner, Ralf; Hiort, Olaf; Audi, Laura; Siebert, Reiner; Ammerpohl, Ole; Holterhus, Paul-Martin

2016-01-01

A subset of patients with monogenic disorders lacks disease causing mutations in the protein coding region of the corresponding gene. Here we describe a recurrent germline mutation found in two unrelated patients with complete androgen insensitivity syndrome (CAIS) generating an upstream open reading frame (uORF) in the 5' untranslated region (5'-UTR) of the androgen receptor (AR) gene. We show in patient derived primary genital skin fibroblasts as well as in cell-based reporter assays that this mutation severely impacts AR function by reducing AR protein levels without affecting AR mRNA levels. Importantly, the newly generated uORF translates into a polypeptide and the expression level of this polypeptide inversely correlates with protein translation from the primary ORF of the AR thereby providing a model for AR-5'UTR mediated translational repression. Our findings not only add a hitherto unrecognized genetic cause to complete androgen insensitivity but also underline the importance of 5'UTR mutations affecting uORFs for the pathogenesis of monogenic disorders in general.

A Recurrent Germline Mutation in the 5’UTR of the Androgen Receptor Causes Complete Androgen Insensitivity by Activating Aberrant uORF Translation

PubMed Central

Hornig, Nadine C.; de Beaufort, Carine; Denzer, Friederike; Cools, Martine; Wabitsch, Martin; Ukat, Martin; Kulle, Alexandra E.; Schweikert, Hans-Udo; Werner, Ralf; Hiort, Olaf; Audi, Laura; Siebert, Reiner; Ammerpohl, Ole; Holterhus, Paul-Martin

2016-01-01

A subset of patients with monogenic disorders lacks disease causing mutations in the protein coding region of the corresponding gene. Here we describe a recurrent germline mutation found in two unrelated patients with complete androgen insensitivity syndrome (CAIS) generating an upstream open reading frame (uORF) in the 5’ untranslated region (5’-UTR) of the androgen receptor (AR) gene. We show in patient derived primary genital skin fibroblasts as well as in cell-based reporter assays that this mutation severely impacts AR function by reducing AR protein levels without affecting AR mRNA levels. Importantly, the newly generated uORF translates into a polypeptide and the expression level of this polypeptide inversely correlates with protein translation from the primary ORF of the AR thereby providing a model for AR-5′UTR mediated translational repression. Our findings not only add a hitherto unrecognized genetic cause to complete androgen insensitivity but also underline the importance of 5′UTR mutations affecting uORFs for the pathogenesis of monogenic disorders in general. PMID:27110943

Androgen responsiveness of Renilla luciferase reporter vectors is promoter, transgene, and cell line dependent.

PubMed

Mulholland, David J; Cox, Michael; Read, Jason; Rennie, Paul; Nelson, Colleen

2004-05-01

Renilla based reporters are frequently used as transfection controls for luciferase transcriptional reporter assays. However, recent evidence suggests that a commonly used reporter (HSV-thymidine kinase driven Renilla) is responsive to androgen receptor (AR) and glucocorticoid receptors in the presence of the cognate ligands, dihydrotestosterone (DHT) and dexamethasone (DEX), respectively [1]. We further validate this important technical difficulty by illustrating that in LNCaP prostate cancer cells, spurious Renilla luciferase activity is a function of (a) the promoter driving Renilla expression, (b) the presence of co-transfected transgenes, and (c) the androgen responsiveness of the cell line used. Using inhibitors of transcription and translation we showed that transcript interference or translational modulation is not a major means by which androgens affect Renilla luciferase activity. As luciferase reporter assays are a frequent means of studying transcriptional co-regulation in the highly androgen dependent LNCaP cell line, our data serves as a cautionary note that alternative normalization techniques should be employed to avoid misinterpretation of data. Copyright 2004 Wiley-Liss, Inc.

Androgenic correlates of genetic variation in the gene encoding 5alpha-reductase type 1.

PubMed

Ellis, Justine A; Panagiotopoulos, Sianna; Akdeniz, Aysel; Jerums, George; Harrap, Stephen B

2005-01-01

Androgens determine male secondary sexual characteristics and influence a variety of metabolic pathways. Circulating levels of androgens are highly heritable; however, the genes involved are largely unknown. The 5alpha-reductase enzymes types 1 and 2 responsible for converting testosterone to the more potent androgen dihydrotestosterone are encoded by the SRD5A1 and SRD5A2 genes, respectively. We performed indirect genetic association studies of SRD5A1 and SRD5A2 and the dihydrotestosterone/testosterone ratio that reflects the activity of 5alpha-reductase in 57 males with type 2 diabetes. We found evidence of significant association between a single nucleotide polymorphism in SRD5A1 and the dihydrotestosterone/testosterone ratio (median 0.10, interquartile range 0.08 vs. median 0.06, interquartile range 0.04, P = 0.009). The polymorphism was not associated with any diabetic phenotypes. These results suggest that functional genetic variants might exist in or around SRD5A1 that affect the activity of the 5alpha-reductase enzyme type 1 and influence androgen levels.

Androgen Regulation of 5α-Reductase Isoenzymes in Prostate Cancer: Implications for Prostate Cancer Prevention

PubMed Central

Li, Jin; Ding, Zhiyong; Wang, Zhengxin; Lu, Jing-Fang; Maity, Sankar N.; Navone, Nora M.; Logothetis, Christopher J.; Mills, Gordon B.; Kim, Jeri

2011-01-01

The enzyme 5α-reductase, which converts testosterone to dihydrotestosterone (DHT), performs key functions in the androgen receptor (AR) signaling pathway. The three isoenzymes of 5α-reductase identified to date are encoded by different genes: SRD5A1, SRD5A2, and SRD5A3. In this study, we investigated mechanisms underlying androgen regulation of 5α-reductase isoenzyme expression in human prostate cells. We found that androgen regulates the mRNA level of 5α-reductase isoenzymes in a cell type–specific manner, that such regulation occurs at the transcriptional level, and that AR is necessary for this regulation. In addition, our results suggest that AR is recruited to a negative androgen response element (nARE) on the promoter of SRD5A3 in vivo and directly binds to the nARE in vitro. The different expression levels of 5α-reductase isoenzymes may confer response or resistance to 5α-reductase inhibitors and thus may have importance in prostate cancer prevention. PMID:22194926

The role of fructose‑1,6‑bisphosphatase 1 in abnormal development of ovarian follicles caused by high testosterone concentration.

PubMed

Liu, Tao; Zhao, Han; Wang, Jianfeng; Shu, Xin; Gao, Yuan; Mu, Xiaoli; Gao, Fei; Liu, Hongbin

2017-11-01

The present study aimed to identify the molecular mechanisms underlying the effects of the fructose‑1,6‑bisphosphatase 1 (FBP1) signaling pathway within normal follicle development and in hyperandrogenism‑induced abnormal follicle growth. To achieve this, murine primary follicles, granulosa cells (GCs) and theca‑interstitial cells (TICs) were isolated, cultured in vitro and treated with a high concentration of androgens. A concentration of 1x10‑5 mol/l testosterone was considerable to induce hyperandrogenism by MTT assay. All cells were divided into four groups, as follows: Control group, testosterone group, androgen receptor antagonist‑flutamide group and flutamide + testosterone group. Flutamide was used in the present study as it blocks the effects of the androgen receptor. The mRNA expression levels of FBP1 were detected using reverse transcription‑quantitative polymerase chain reaction. The expression levels and localization of FBP1 were analyzed by western blot analysis and immunofluorescence staining. The experimental results demonstrated that androgen presence stimulated follicle development, whereas excessive testosterone inhibited development. FBP1 was identified as being mainly expressed in follicles; FBP1 protein was significantly expressed in GCs of the 14‑day‑cultured follicle, as well as in the cytoplasm and nuclei of GCs and TICs in vitro. Testosterone increased FBP1 expression during a specific range of testosterone concentrations. Testosterone increased the expression of FBP1 within GCs. Furthermore, FBP1 and phosphoenolpyruvate carboxykinase 1 (PCK1) mRNA expression was increased in GCs treated with testosterone, whereas forkhead box protein O1 (FOXO1) and peroxisome proliferator‑activated receptor γ coactivator‑1α mRNA expression was significantly decreased in the testosterone group. In TICs, testosterone and flutamide inhibited the mRNA expression levels of FOXO1 and glucose‑6‑phosphatase enzyme, and promoted the expression of PCK1. These results suggested that the FBP1 signaling pathway may serve an important role in normal follicle growth and hyperandrogenism‑induced abnormal development, which may be associated with abnormal glucose metabolism induced by high concentrations of testosterone.

The renal effects of prenatal testosterone in rats.

PubMed

Bábíčková, Janka; Borbélyová, Veronika; Tóthová, L'ubomíra; Kubišová, Katarína; Janega, Pavol; Hodosy, Július; Celec, Peter

2015-05-01

Previous studies have shown that prenatal testosterone affects the development of not only reproductive organs but also the brain and even glucose metabolism. Whether prenatal testosterone influences the kidney development is largely unknown. We analyzed whether testosterone modulation during prenatal development would affect renal function and the number of nephrons in adult offspring. Pregnant rats were treated with olive oil, testosterone (2 mg/kg), the androgen receptor blocker flutamide (5 mg/kg) or testosterone plus flutamide via daily intramuscular injections from gestation day 14 until delivery. Renal histology and functional parameters were assessed in male and female adult offspring. Macerated kidneys were used for nephron counting. Prenatal testosterone administration increased proteinuria in male rats by 256%. A similar 134% effect in female rats was not statistically significant. This effect was prevented when flutamide was co-administered. In male rats prenatal testosterone increased blood urea nitrogen. In female rats flutamide increased creatinine clearance. In male rats prenatal testosterone and flutamide led to higher and lower, respectively, interstitial collagen deposition in adulthood. Prenatal testosterone induces proteinuria in adulthood. This effect is mediated via androgen receptor. Additional effects seem to be sex specific. Further studies should focus on the timing and dosing of testosterone as well as the applicability to human development. Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Songbird chemical signals reflect uropygial gland androgen sensitivity and predict aggression: implications for the role of the periphery in chemosignaling.

PubMed

Whittaker, Danielle J; Rosvall, Kimberly A; Slowinski, Samuel P; Soini, Helena A; Novotny, Milos V; Ketterson, Ellen D

2018-01-01

Chemical signals can provide useful information to potential mates and rivals. The production mechanisms of these signals are poorly understood in birds, despite emerging evidence that volatile compounds from preen oil may serve as chemosignals. Steroid hormones, including testosterone (T), may influence the production of these signals, yet variation in circulating T only partly accounts for this variation. We hypothesized that odor is a T-mediated signal of an individual's phenotype, regulated in part by androgen sensitivity in the uropygial gland. We quantified natural variation in chemosignals, T, uropygial gland androgen sensitivity, and aggressive behavior in dark-eyed juncos (Junco hyemalis). The interaction between circulating T and androgen receptor transcript abundance significantly correlated with volatile concentrations in male, but not female, preen oil. In both sexes, odorant variables correlated with aggressive response to an intruder. Our results suggest that preen oil volatiles could function as signals of aggressive intent, and, at least in males, may be regulated by local androgen receptor signaling in the uropygial gland. Because these behavioral and chemical traits have been linked with reproductive success, local regulation of androgen sensitivity in the periphery has the potential to be a target of selection in the evolution of avian olfactory signaling.

Maternal testosterone exposure increases anxiety-like behavior and impacts the limbic system in the offspring.

PubMed

Hu, Min; Richard, Jennifer Elise; Maliqueo, Manuel; Kokosar, Milana; Fornes, Romina; Benrick, Anna; Jansson, Thomas; Ohlsson, Claes; Wu, Xiaoke; Skibicka, Karolina Patrycja; Stener-Victorin, Elisabet

2015-11-17

During pregnancy, women with polycystic ovary syndrome (PCOS) display high circulating androgen levels that may affect the fetus and increase the risk of mood disorders in offspring. This study investigated whether maternal androgen excess causes anxiety-like behavior in offspring mimicking anxiety disorders in PCOS. The PCOS phenotype was induced in rats following prenatal androgen (PNA) exposure. PNA offspring displayed anxiety-like behavior in the elevated plus maze, which was reversed by flutamide [androgen receptor (AR) blocker] and tamoxifen [selective estrogen receptor (ER) modulator]. Circulating sex steroids did not differ between groups at adult age. The expression of serotonergic and GABAergic genes associated with emotional regulation in the amygdala was consistent with anxiety-like behavior in female, and partly in male PNA offspring. Furthermore, AR expression in amygdala was reduced in female PNA offspring and also in females exposed to testosterone in adult age. To determine whether AR activation in amygdala affects anxiety-like behavior, female rats were given testosterone microinjections into amygdala, which resulted in anxiety-like behavior. Together, these data describe the anxiety-like behavior in PNA offspring and adult females with androgen excess, an impact that seems to occur during fetal life, and is mediated via AR in amygdala, together with changes in ERα, serotonergic, and GABAergic genes in amygdala and hippocampus. The anxiety-like behavior following testosterone microinjections into amygdala demonstrates a key role for AR activation in this brain area. These results suggest that maternal androgen excess may underpin the risk of developing anxiety disorders in daughters and sons of PCOS mothers.

A nonlinear competitive model of the prostate tumor growth under intermittent androgen suppression.

PubMed

Yang, Jing; Zhao, Tong-Jun; Yuan, Chang-Qing; Xie, Jing-Hui; Hao, Fang-Fang

2016-09-07

Hormone suppression has been the primary modality of treatment for prostate cancer. However long-term androgen deprivation may induce androgen-independent (AI) recurrence. Intermittent androgen suppression (IAS) is a potential way to delay or avoid the AI relapse. Mathematical models of tumor growth and treatment are simple while they are capable of capturing the essence of complicated interactions. Game theory models have analyzed that tumor cells can enhance their fitness by adopting genetically determined survival strategies. In this paper, we consider the survival strategies as the competitive advantage of tumor cells and propose a new model to mimic the prostate tumor growth in IAS therapy. Then we investigate the competition effect in tumor development by numerical simulations. The results indicate that successfully IAS-controlled states can be achieved even though the net growth rate of AI cells is positive for any androgen level. There is crucial difference between the previous models and the new one in the phase diagram of successful and unsuccessful tumor control by IAS administration, which means that the suggestions from the models for medication can be different. Furthermore we introduce quadratic logistic terms to the competition model to simulate the tumor growth in the environment with a finite carrying capacity considering the nutrients or inhibitors. The simulations show that the tumor growth can reach an equilibrium state or an oscillatory state with the net growth rate of AI cells being androgen independent. Our results suggest that the competition and the restraint of a limited environment can enhance the possibility of relapse prevention. Copyright © 2016 Elsevier Ltd. All rights reserved.

KDM1A triggers androgen-induced miRNA transcription via H3K4me2 demethylation and DNA oxidation.

PubMed

Yang, Shu; Zhang, Jiyuan; Zhang, Yalong; Wan, Xuechao; Zhang, Congzhe; Huang, Xiaohui; Huang, Wenhua; Pu, Honglei; Pei, Chaohan; Wu, Hai; Huang, Yan; Huang, Shengdong; Li, Yao

2015-06-15

Androgen receptor (AR) is a ligand dependent transcription factor that regulates the transcription of target genes. AR activity is closely involved in the maintenance and progression of prostate cancer. After the binding with androgen, AR moves into nucleus and binds to DNA sequence containing androgen response elements (ARE). Flavin-dependent monoamine oxidase KDM1A is necessary for AR driven transcription while the mechanism remains unclear. The association between androgen-dependent transcription and oxidation was tested through pharmaceutical inhibitions and siRNA knockdown of DNA oxidation repair components in prostate cancer cells. The recruitment of involved proteins and the histone methylation dynamics on ARE region was explored by chromatin immunoprecipitation (ChIP). Oxidation inhibition reduced AR dependent expression of KLK3, TMPRSS2, hsa-miR-125b2, and hsa-miR-133b. And such reduction could be restored by H2 O2 treatment. KDM1A recruitment and H3K4me2 demethylation on ARE regions, which produce H2 O2 , are associated with AR targets transcription. AR targets transcription and coupled oxidation recruit 8-oxoguanine-DNA glycosylase (OGG1) and the nuclease APEX1 to ARE regions. Such recruitment depends on KDM1A, and is necessary for AR targets transcription. Our work underlined the importance of histone demethylation and DNA oxidation/repairing machinery in androgen-dependent transcription. The present finds have implications for research into new druggable targets for prostate cancer relying on the cascade of AR activity regulation. © 2015 Wiley Periodicals, Inc.

Maternal testosterone exposure increases anxiety-like behavior and impacts the limbic system in the offspring

PubMed Central

Hu, Min; Richard, Jennifer Elise; Maliqueo, Manuel; Kokosar, Milana; Fornes, Romina; Benrick, Anna; Jansson, Thomas; Ohlsson, Claes; Wu, Xiaoke; Skibicka, Karolina Patrycja; Stener-Victorin, Elisabet

2015-01-01

During pregnancy, women with polycystic ovary syndrome (PCOS) display high circulating androgen levels that may affect the fetus and increase the risk of mood disorders in offspring. This study investigated whether maternal androgen excess causes anxiety-like behavior in offspring mimicking anxiety disorders in PCOS. The PCOS phenotype was induced in rats following prenatal androgen (PNA) exposure. PNA offspring displayed anxiety-like behavior in the elevated plus maze, which was reversed by flutamide [androgen receptor (AR) blocker] and tamoxifen [selective estrogen receptor (ER) modulator]. Circulating sex steroids did not differ between groups at adult age. The expression of serotonergic and GABAergic genes associated with emotional regulation in the amygdala was consistent with anxiety-like behavior in female, and partly in male PNA offspring. Furthermore, AR expression in amygdala was reduced in female PNA offspring and also in females exposed to testosterone in adult age. To determine whether AR activation in amygdala affects anxiety-like behavior, female rats were given testosterone microinjections into amygdala, which resulted in anxiety-like behavior. Together, these data describe the anxiety-like behavior in PNA offspring and adult females with androgen excess, an impact that seems to occur during fetal life, and is mediated via AR in amygdala, together with changes in ERα, serotonergic, and GABAergic genes in amygdala and hippocampus. The anxiety-like behavior following testosterone microinjections into amygdala demonstrates a key role for AR activation in this brain area. These results suggest that maternal androgen excess may underpin the risk of developing anxiety disorders in daughters and sons of PCOS mothers. PMID:26578781

Menstrual cycle-related changes in circulating androgens in healthy women with self-reported normal sexual function.

PubMed

Salonia, Andrea; Pontillo, Marina; Nappi, Rossella E; Zanni, Giuseppe; Fabbri, Fabio; Scavini, Marina; Daverio, Rita; Gallina, Andrea; Rigatti, Patrizio; Bosi, Emanuele; Bonini, Pier Angelo; Montorsi, Francesco

2008-04-01

There is currently neither a clinically useful, reliable and inexpensive assay to measure circulating levels of free testosterone (T) in the range observed in women, nor is there agreement on the serum free T threshold defining hypoandrogenism that is associated with female-impaired sexual function. Following the Clinical and Laboratory Standards Institute guidelines, we generated clinically applicable ranges for circulating androgens during specific phases of the menstrual cycle in a convenience sample of 120 reproductive-aged, regularly cycling healthy European Caucasian women with self-reported normal sexual function. All participants were asked to complete a semistructured interview and fill out a set of validated questionnaires, including the Female Sexual Function Index, the Female Sexual Distress Scale, and the 21-item Beck's Inventory for Depression. Between 8 am and 10 am, a venous blood sample was drawn from each participant during the midfollicular (day 5 to 8), the ovulatory (day 13 to 15), and the midluteal phase (day 19 to 22) of the same menstrual cycle. Serum levels of total and free testosterone, Delta(4)-androstenedione, dehydroepiandrosterone sulphate and sex hormone-binding globulin during the midfollicular, ovulatory and midluteal phase of the same menstrual cycle. Total and free T levels showed significant fluctuations, peaking during the ovulatory phase. No significant variation during the menstrual cycle were observed for Delta(4)-androstenedione and dehydroepiandrosterone sulphate. Despite the careful selection of participants that yielded an homogeneous group of women without sexual disorders, we observed a wide range of distribution for each of the circulating androgens measured in this study. This report provides clinically applicable ranges for androgens throughout the menstrual cycle in reproductive-aged, regularly cycling, young healthy Caucasian European women with self-reported normal sexual function.

Changes in amount and intracellular distribution of androgen receptor in human foreskin as a function of age.

PubMed Central

Roehrborn, C G; Lange, J L; George, F W; Wilson, J D

1987-01-01

To provide insight into the factors that control growth of the penis we measured the amount and intracellular distribution of specific high affinity androgen receptor in foreskins obtained at circumcision from 49 males varying in age from newborn to 59 yr. Total (cytosolic plus nuclear extract) androgen receptor decreased from approximately 40 fmol/g tissue weight in newborn foreskins to approximately 25 fmol/g by 1 yr of age. The amount of receptor rose in childhood to approximately 180 fmol/g in the late teenage years and fell thereafter to approximately 20-40 fmol/g in men older than 40 yr. The amount of receptor in the nuclear fraction increased at the time of puberty and subsequently decreased in parallel with the decline in total receptor level. These changes in androgen-receptor amount are similar when expressed per milligram DNA or per milligram protein. Images PMID:3491838

Endocrine Disrupting Chemicals Mediated through Binding Androgen Receptor Are Associated with Diabetes Mellitus

PubMed Central

Sakkiah, Sugunadevi; Wang, Tony; Zou, Wen; Wang, Yuping; Pan, Bohu; Tong, Weida; Hong, Huixiao

2017-01-01

Endocrine disrupting chemicals (EDCs) can mimic natural hormone to interact with receptors in the endocrine system and thus disrupt the functions of the endocrine system, raising concerns on the public health. In addition to disruption of the endocrine system, some EDCs have been found associated with many diseases such as breast cancer, prostate cancer, infertility, asthma, stroke, Alzheimer’s disease, obesity, and diabetes mellitus. EDCs that binding androgen receptor have been reported associated with diabetes mellitus in in vitro, animal, and clinical studies. In this review, we summarize the structural basis and interactions between androgen receptor and EDCs as well as the associations of various types of diabetes mellitus with the EDCs mediated through androgen receptor binding. We also discuss the perspective research for further understanding the impact and mechanisms of EDCs on the risk of diabetes mellitus. PMID:29295509

Short poly-glutamine repeat in the androgen receptor in New World monkeys.

PubMed

Hiramatsu, Chihiro; Paukner, Annika; Kuroshima, Hika; Fujita, Kazuo; Suomi, Stephen J; Inoue-Murayama, Miho

2017-12-01

The androgen receptor mediates various physiological and developmental functions and is highly conserved in mammals. Although great intraspecific length polymorphisms in poly glutamine (poly-Q) and poly glycine (poly-G) regions of the androgen receptor in humans, apes and several Old World monkeys have been reported, little is known about the characteristics of these regions in New World monkeys. In this study, we surveyed 17 species of New World monkeys and found length polymorphisms in these regions in three species (common squirrel monkeys, tufted capuchin monkeys and owl monkeys). We found that the poly-Q region in New World monkeys is relatively shorter than that in catarrhines (humans, apes and Old World monkeys). In addition, we observed that codon usage for poly-G region in New World monkeys is unique among primates. These results suggest that the length of polymorphic regions in androgen receptor genes have evolved uniquely in New World monkeys.

Dihydrotestosterone inhibits hair growth in mice by inhibiting insulin-like growth factor-I production in dermal papillae.

PubMed

Zhao, Juan; Harada, Naoaki; Okajima, Kenji

2011-10-01

We demonstrated that insulin-like growth factor-I (IGF-I) production in dermal papillae was increased and hair growth was promoted after sensory neuron stimulation in mice. Although the androgen metabolite dihydrotestosterone (DHT) inhibits hair growth by negatively modulating growth-regulatory effects of dermal papillae, relationship between androgen metabolism and IGF-I production in dermal papillae is not fully understood. We examined whether DHT inhibits IGF-I production by inhibiting sensory neuron stimulation, thereby preventing hair growth in mice. Effect of DHT on sensory neuron stimulation was examined using cultured dorsal root ganglion (DRG) neurons isolated from mice. DHT inhibits calcitonin gene-related peptide (CGRP) release from cultured DRG neurons. The non-steroidal androgen-receptor antagonist flutamide reversed DHT-induced inhibition of CGRP release. Dermal levels of IGF-I and IGF-I mRNA, and the number of IGF-I-positive fibroblasts around hair follicles were increased at 6h after CGRP administration. DHT administration for 3weeks decreased dermal levels of CGRP, IGF-I, and IGF-I mRNA in mice. Immunohistochemical expression of IGF-I and the number of proliferating cells in hair follicles were decreased and hair re-growth was inhibited in animals administered DHT. Co-administration of flutamide and CGRP reversed these changes induced by DHT administration. These observations suggest that DHT may decrease IGF-I production in dermal papillae by inhibiting sensory neuron stimulation through interaction with the androgen receptor, thereby inhibiting hair growth in mice. Copyright © 2011 Elsevier Ltd. All rights reserved.

The Role of the Capase-8 Inhibitor FLIP in Androgen-Withdrawal Induced Death of Prostate Epithelium

DTIC Science & Technology

2006-01-01

DL, Norris JS. Resistance of prostate cancer cells to soluble TNF- related apoptosis- inducing ligand (TRAIL/Apo2L) can be overcome by doxorubicin or...Bueso-Ramos C, Chatterjee D, Pantazis P, Aggarwal BB. Curcumin downregulates cell survival mechanisms in human prostate cancer cell lines. Oncogene

The Role of the Caspase-8 Inhibitor FLIP in Androgen-Withdrawal Induced Death of Prostate Epithelium

DTIC Science & Technology

2006-01-01

DL, Norris JS. Resistance of prostate cancer cells to soluble TNF- related apoptosis- inducing ligand (TRAIL/Apo2L) can be overcome by doxorubicin or...Bueso-Ramos C, Chatterjee D, Pantazis P, Aggarwal BB. Curcumin downregulates cell survival mechanisms in human prostate cancer cell lines. Oncogene

Molecular identification of an androgen receptor and its changes in mRNA levels during 17α-methyltestosterone-induced sex reversal in the orange-spotted grouper Epinephelus coioides.

PubMed

Shi, Yu; Liu, Xiaochun; Zhang, Haifa; Zhang, Yong; Lu, Danqi; Lin, Haoran

2012-09-01

Androgens play a crucial role in sex differentiation, sexual maturation, and spermatogenesis in vertebrates. The action of androgens is mediated via androgen receptors (ARs). The present study reports the cloning of the cDNA sequence of the ar in the orange-spotted grouper, with high expression in testis and relatively low in subdivision of brain areas. The cDNA sequence of ar was 2358 bp, encoding a protein of 759 amino acids (aa). Phylogenetic analysis showed that the ar cDNA sequence was closely related to that of threespot wrasse (Halichoeres trimaculatus) and medaka (Oryzias latipes) arβ. As deduced from the phylogenetic tree and the high amino acid identity with the ARβ subtype of other teleosts, grouper ar seems to be more closely related to the beta than the alpha subtype cloned to date. In the first week after 17α-methyltestosterone (MT) implantation, the transcript levels of ar in the hypothalamus declined significantly, and consistently stayed at low level expression to the second week, but increased back to the control levels in the third and fourth week. In the gonad, the mRNA expression of ar was not changed in the first week compared with the control, but increased significantly in the second week, consistently reached the highest level in the third week, dropped slightly but still higher than that of the control in the fourth week. The expression pattern of ar in hypothalamus and gonad during MT-induced sex reversal suggests the involvement of ar in regulating this process in the orange-spotted grouper. The present study provides the data of the changes in the mRNA levels of ar during MT-induced sex reversal in detail to help understand the complicated signals under sex reversal. Copyright © 2012 Elsevier Inc. All rights reserved.

Inhibition of telomerase potentiates enzalutamide efficiency of androgen-sensitive human prostate cancer cells.

PubMed

Gecgel, Karaca Kaan; Muduroglu, Mustafa; Erdogan, Suat

2017-01-01

Androgen deprivation therapy (ADT) is one of the main strategies to treat prostate cancer (PCa) at various stages of its development. Androgen receptor (AR) antagonists such as enzalutamide are mainstay treatments for castration-sensitive prostate cancer. Though, a majority of patients initially respond to ADT, most will eventually progress to castrate-resistant, due to the development of different mutations on the AR. PCa cells express high telomerase activity, and there is a correlation between the total activity of telomerase and the Gleason score. Therefore, we hypothesized that the combination of enzalutamide plus a telomerase inhibitor could be more effective than enzalutamide alone in decreasing cell survival. In this study MTT test, RT-qPCR and imagebased cytometry were used to investigate cell viability, apoptosis and cell cycle progression of androgen-responsive human prostate cancer LNCaP cells. The cells were treated with 5 μM enzalutamide and 40 μM telomerase inhibitor BIBR 1532, or with their combinations for 72 hrs. Enzalutamide and BIBR 1532 alone inhibited cell proliferation in a dose-dependent manner. The combinations of the two agents could synergistically induce apoptotic and necrotic cell death. Either inhibition of telomerase by BIBR 1532 or AR blockages by enzalutamide decreased prostate-specific antigen (PSA) and the catalytic component of telomerase, hTERT, expression. These results suggest that telomerase inhibition therapy may contribute to the efficacy of enzalutamide in the androgen-sensitive PCa model.

A Novel Dietary Flavonoid Fisetin Inhibits Androgen Receptor Signaling and Tumor Growth in Athymic Nude Mice

PubMed Central

Khan, Naghma; Asim, Mohammad; Afaq, Farrukh; Zaid, Mohammad Abu; Mukhtar, Hasan

2010-01-01

Androgen receptor (AR)–mediated signaling plays an important role in the development and progression of prostate cancer (PCa). Hormonal therapies, mainly with combinations of antiandrogens and androgen deprivation, are the mainstay treatment for advanced disease. However, emergence of androgen resistance largely due to inefficient antihormone action limits their therapeutic usefulness. Here, we report that fisetin, a novel dietary flavonoid, acts as a novel AR ligand by competing with the high-affinity androgen to interact with the ligand binding domain of AR. We show that this physical interaction results in substantial decrease in AR stability and decrease in amino-terminal/carboxyl-terminal (N-C) interaction of AR. This results in blunting of AR-mediated transactivation of target genes including prostate-specific antigen (PSA). In addition, treatment of LNCaP cells with fisetin decreased AR protein levels, in part, by decreasing its promoter activity and by accelerating its degradation. Fisetin also synergized with Casodex in inducing apoptosis in LNCaP cells. Treatment with fisetin in athymic nude mice implanted with AR-positive CWR22Rυ1 human PCa cells resulted in inhibition of tumor growth and reduction in serum PSA levels. These data identify fisetin as an inhibitor of AR signaling axis and suggest that it could be a useful chemopreventive and chemotherapeutic agent to delay progression of PCa. PMID:18922931

Co-induction of the heat shock response ameliorates disease progression in a mouse model of human spinal and bulbar muscular atrophy: implications for therapy

PubMed Central

Malik, Bilal; Nirmalananthan, Niranjanan; Gray, Anna L.; La Spada, Albert R.; Hanna, Michael G.

2013-01-01

Spinal and bulbar muscular atrophy, also known as Kennedy’s disease, is an adult-onset hereditary neurodegenerative disorder caused by an expansion of the polyglutamine repeat in the first exon in the androgen receptor gene. Pathologically, the disease is defined by selective loss of spinal and bulbar motor neurons causing bulbar, facial and limb weakness. Although the precise disease pathophysiology is largely unknown, it appears to be related to abnormal accumulation of the pathogenic androgen receptor protein within the nucleus, leading to disruption of cellular processes. Using a mouse model of spinal and bulbar muscular atrophy that exhibits many of the characteristic features of the human disease, in vivo physiological assessment of muscle function revealed that mice with the pathogenic expansion of the androgen receptor develop a motor deficit characterized by a reduction in muscle force, abnormal muscle contractile characteristics, loss of functional motor units and motor neuron degeneration. We have previously shown that treatment with arimoclomol, a co-inducer of the heat shock stress response, delays disease progression in the mutant superoxide dismutase 1 mouse model of amyotrophic lateral sclerosis, a fatal motor neuron disease. We therefore evaluated the therapeutic potential of arimoclomol in mice with spinal and bulbar muscular atrophy. Arimoclomol was administered orally, in drinking water, from symptom onset and the effects established at 18 months of age, a late stage of disease. Arimoclomol significantly improved hindlimb muscle force and contractile characteristics, rescued motor units and, importantly, improved motor neuron survival and upregulated the expression of the vascular endothelial growth factor which possess neurotrophic activity. These results provide evidence that upregulation of the heat shock response by treatment with arimoclomol may have therapeutic potential in the treatment of spinal and bulbar muscular atrophy and may also be a possible approach for the treatment of other neurodegenerative diseases. PMID:23393146

Enrichment of putative prostate cancer stem cells after androgen deprivation: upregulation of pluripotency transactivators concurs with resistance to androgen deprivation in LNCaP cell lines.

PubMed

Seiler, Daniel; Zheng, Junying; Liu, Gentao; Wang, Shunyou; Yamashiro, Joyce; Reiter, Robert E; Huang, Jiaoti; Zeng, Gang

2013-09-01

Prostate cancer stem cells (PCSC) offer theoretical explanations to many clinical and biological behaviors of the disease in human. In contrast to approaches of using side populations and cell-surface markers to isolate and characterize the putative PCSC, we hypothesize that androgen deprivation leads to functional enrichment of putative PCSC. Human prostate cancer lines LNCaP, LAPC4 and LAPC9 were depleted of androgen in cell cultures and in castrated SCID mice. The resultant androgen deprivation-resistant or castration-resistant populations, in particular in LNCaP and its derivative cell lines, displayed increased expression of pluripotency transactivators and significantly higher tumorigenicity. Individual tumor cell clones were isolated from castration-resistant bulk cultures of LNCaP (CR-LNCaP) and tested for tumorigenicity in male SCID mice under limiting dilution conditions. As few as 200 cells were able to form spheres in vitro, and generate tumors with similar growth kinetics as 10(6) LNCaP or 10(4) CR-LNCaP cells in vivo. These putative PCSC were CD44(+) /CD24(-) and lack the expression of prostate lineage proteins. When transplanted into the prostate of an intact male SCID mouse, these putative PCSC seemed to show limited differentiation into Ck5(+) , Ck8(+) , Ck5(+) /Ck8(+) , and AR(+) cells. On the other hand, stable transduction of LNCaP with retrovirus encoding Sox2 led to androgen-deprivation resistant growth and down-regulation of major prostate lineage gene products in vitro. Concurrence of overexpression of pluripotency transactivators and resistance to androgen deprivation supported the role of putative PCSC in the emergence of prostate cancer resistant to androgen deprivation. © 2013 Wiley Periodicals, Inc.

Effect of ovarian aging on androgen biosynthesis in a cynomolgus macaque model

PubMed Central

Ethun, K. F.; Wood, C. E.; Parker, C. R.; Kaplan, J. R.; Chen, H.; Appt, S. E.

2013-01-01

Objective The role of androgens in chronic disease pathogenesis, cognitive function and libido during menopause is of increasing interest. The aim of this study was to characterize the distribution and expression of androgenic proteins in the macaque ovary and to investigate the relationship between serum androgen concentrations, follicle number, and the persistence of androgenesis in the aging macaque ovary. Methods The subjects were 26 adult female cynomolgus macaques. Ovaries were immunostained for cytochrome P450 17α-hydroxylase/17–20 lyase (P450c17), 3β-hydroxysteroid dehydrogenase (3βHSD), and cytochrome b5 (cytb5). Based on primordial follicle counts, animals were divided into tertiles (low (≤200), intermediate (226–1232), and high (2372–4356)) to evaluate differences in androgen staining and changes in serum androgen concentrations following ovariectomy. Results Positive immunostaining for P450c17 and cytb5 within the theca interna layer of growing follicles persisted in advanced atretic follicles and secondary interstitial cells (residual stromal cells). Ovaries with low follicle numbers had less staining for all androgenic proteins compared to ovaries with higher numbers of growing follicles. Immunostaining for cytb5 was the most reliable marker for persistent androgenesis in ovaries with minimal primordial follicle numbers (<100) and residual stromal cells. Following ovariectomy, a significant decrease in testosterone (−27.7%, −30.8%, −27.5%; p < 0.01) and androstenedione (−33.4%, −35.7%, −46.0%; p < 0.01) was observed in monkeys with low, intermediate, and high primordial follicle counts, respectively. Conclusions Despite low follicle numbers, the aging macaque ovary retains the necessary proteins for androgenesis within residual stromal cells and contributes to peripheral androgen concentrations. PMID:21864136

Diethylstilbesterol revisited: androgen deprivation, osteoporosis and prostate cancer.

PubMed

Scherr, Douglas; Pitts, W Reid; Vaughn, E Darracott

2002-02-01

It is well described in the urological literature that androgen deprivation can result in accelerated bone breakdown and osteoporosis. Therefore, we evaluate the degree of bone breakdown in patients on conventional androgen deprivation with those on diethylstilbesterol alone or in conjunction with luteinizing hormone releasing hormone agonists or orchiectomy. During an 18-month period a total of 54 patients with clinically localized prostate cancer and 24 with benign prostatic hyperplasia were evaluated. All patients with prostate cancer were either treated with external beam radiotherapy without androgen deprivation or were started on androgen deprivation therapy. All patients were prospectively followed and evaluated for serum testosterone and estradiol along with urinary collagen type I cross-linked N-telopeptides. Three separate morning urine samples on 3 separate months were collected on each patient and analyzed for N-telopeptides. To correct for different levels of renal function, all N-telopeptides were measured as a ratio of urinary N-telopeptides/urine creatinine. All patients with any bone or skeletal abnormalities were excluded from study as were those with osseous metastatic disease. There was a statistically significant (p < 0.05) higher level of urinary N-telopeptides/creatinine in patients on androgen deprivation therapy who were not treated with diethylstilbesterol. The estrogenic effect of diethylstilbesterol protects one from bone resorption. Patients on diethylstilbesterol did not have any higher levels of bone breakdown than patients with benign prostatic hyperplasia or those who never received any androgen deprivation. Rapid bone turnover and resorption can be prevented with 1 mg. diethylstilbesterol alone or in conjunction with other modes of androgen deprivation. Therefore, diethylstilbesterol should be considered as monotherpy in men who require long-term antiandrogen therapy.

Implication of androgen receptor in urinary bladder cancer: a critical mini review.

PubMed

Rahmani, Arshad H; Alzohairy, Mohammad; Babiker, Ali Yousif Y; Khan, Amjad A; Aly, Salah M; Rizvi, Moshahid A

2013-01-01

Cancer is probably the most dreaded disease of mankind and the bladder cancer is the fifth most common type of cancer worldwide. It is a major cause of cancer morbidity and mortality. From amongst the bladder cancer, the Transitional Cell Carcinoma (TCC) is the most prevalent cancer of the bladder and accounts for 90% of all bladder cancer cases. Despite such a high prevalence, the molecular mechanism involved in the induction of bladder carcinoma and its progression are poorly understood. Tumorigenesis and tumor progression of bladder carcinomas are thought to result from the accumulation of multiple genetic alterations. The Androgen Receptor (AR) gene is located on the q arm of X chromosome (q11-12) and considered as a ligand-inducible transcription factor that regulates target gene expression. The Androgen plays a vital role in the development and maintenance of the normal urinary bladder. The AR is also involved in the development and progression of urinary bladder carcinoma, which is the most common type of carcinoma. Mutation in AR alters the ligand binding ability that may cause the progression and development of bladder cancer. Tumorigenesis and tumor progression are thought to result from changes in the function of hormonal receptor gene. The accumulation of the changes in AR expressions, determines the tumor's phenotype and ultimately the patient's clinical outcome. The early detection of which may help in management and prediction, how will it behave and respond to the therapeutic regimen. The present review aimed to study the mechanism and alteration of AR gene that play a vital role in the tumorIgenesis of bladder carcinoma.

Effects of exogenous testosterone on the ventral striatal BOLD response during reward anticipation in healthy women.

PubMed

Hermans, Erno J; Bos, Peter A; Ossewaarde, Lindsey; Ramsey, Nick F; Fernández, Guillén; van Honk, Jack

2010-08-01

Correlational evidence in humans shows that levels of the androgen hormone testosterone are positively related to reinforcement sensitivity and competitive drive. Structurally similar anabolic-androgenic steroids (AAS) are moreover widely abused, and animal studies show that rodents self-administer testosterone. These observations suggest that testosterone exerts activational effects on mesolimbic dopaminergic pathways involved in incentive processing and reinforcement regulation. However, there are no data on humans supporting this hypothesis. We used functional magnetic resonance imaging (fMRI) to investigate the effects of testosterone administration on neural activity in terminal regions of the mesolimbic pathway. In a placebo-controlled double-blind crossover design, 12 healthy women received a single sublingual administration of .5 mg of testosterone. During MRI scanning, participants performed a monetary incentive delay task, which is known to elicit robust activation of the ventral striatum during reward anticipation. Results show a positive main effect of testosterone on the differential response in the ventral striatum to cues signaling potential reward versus nonreward. Notably, this effect interacted with levels self-reported intrinsic appetitive motivation: individuals with low intrinsic appetitive motivation exhibited larger testosterone-induced increases but had smaller differential responses after placebo. Thus, the present study lends support to the hypothesis that testosterone affects activity in terminal regions of the mesolimbic dopamine system but suggests that such effects may be specific to individuals with low intrinsic appetitive motivation. By showing a potential mechanism underlying central reinforcement of androgen use, the present findings may moreover have implications for our understanding of the pathophysiology of AAS dependency. Copyright 2010 Elsevier Inc. All rights reserved.

Characterization of karyopherins in androgen receptor intracellular trafficking in the yeast model

PubMed Central

Nguyen, Minh M; Harmon, Robert M; Wang, Zhou

2014-01-01

Background: Mechanisms regulating androgen receptor (AR) subcellular localization represent an essential component of AR signaling. Karyopherins are a family of nucleocytoplasmic trafficking factors. In this paper, we used the yeast model to study the effects of karyopherins on the subcellular localization of the AR. Methods: Yeast mutants deficient in different nuclear transport factors were transformed with various AR based, GFP tagged constructs and their localization was monitored using microscopy. Results: We showed that yeast can mediate androgen-induced AR nuclear localization and that in addition to the import factor, Importinα/β, this process required the import karyopherin Sxm1. We also showed that a previously identified nuclear export sequence (NESAR) in the ligand binding domain of AR does not appear to rely on karyopherins for cytoplasmic localization. Conclusions: These results suggest that while AR nuclear import relies on karyopherin activity, AR nuclear export and/or cytoplasmic localization may require other undefined mechanisms. PMID:25031696

Developmental programming: impact of prenatal testosterone excess on pre- and postnatal gonadotropin regulation in sheep.

PubMed

Manikkam, Mohan; Thompson, Robert C; Herkimer, Carol; Welch, Kathleen B; Flak, Jonathan; Karsch, Fred J; Padmanabhan, Vasantha

2008-04-01

The goal of this study was to explore mechanisms that mediate hypersecretion of LH and progressive loss of cyclicity in female sheep exposed during fetal life to excess testosterone. Our working hypothesis was that prenatal testosterone excess, by its androgenic action, amplifies GnRH-induced LH (but not FSH) secretion and, thus, hypersecretion of LH in adulthood, and that this results from altered developmental gene expression of GnRH and estradiol (E2) receptors, gonadotropin subunits, and paracrine factors that differentially regulate LH and FSH synthesis. We observed that, relative to controls, females exposed during fetal life to excess testosterone, as well as the nor-aromatizable androgen dihydrotestosterone, exhibited enhanced LH but not FSH responses to intermittent delivery of GnRH boluses under conditions in which endogenous LH (GnRH) pulses were suppressed. Luteinizing hormone hypersecretion was more evident in adults than in prepubertal females, and it was associated with development of acyclicity. Measurement of pituitary mRNA concentrations revealed that prenatal testosterone excess induced developmental changes in gene expression of pituitary GnRH and E2 receptors and paracrine modulators of LH and FSH synthesis in a manner consistent with subsequent amplification of LH release. Together, this series of studies suggests that prenatal testosterone excess, by its androgenic action, amplifies GnRH-induced LH response, leading to LH hypersecretion and acyclicity in adulthood, and that this programming involves developmental changes in expression of pituitary genes involved in LH and FSH release.

MED1 mediates androgen receptor splice variant induced gene expression in the absence of ligand

PubMed Central

Liu, Gang; Sprenger, Cynthia; Wu, Pin-Jou; Sun, Shihua; Uo, Takuma; Haugk, Kathleen; Epilepsia, Kathryn Soriano; Plymate, Stephen

2015-01-01

The appearance of constitutively active androgen receptor splice variants (AR-Vs) has been proposed as one of the causes of castration-resistant prostate cancer (CRPC). However, the underlying mechanism of AR-Vs in CRPC transcriptional regulation has not been defined. A distinct transcriptome enriched with cell cycle genes, e.g. UBE2C, has been associated with AR-Vs, which indicates the possibility of an altered transcriptional mechanism when compared to full-length wild-type AR (ARfl). Importantly, a recent study reported the critical role of p-MED1 in enhancing UBE2C expression through a locus looping pattern, which only occurs in CRPC but not in androgen-dependent prostate cancer (ADPC). To investigate the potential correlation between AR-V and MED1, in the present study we performed protein co-immunoprecipitation, chromatin immunoprecipitation, and cell proliferation assays and found that MED1 is necessary for ARv567es induced UBE2C up-regulation and subsequent prostate cancer cell growth. Furthermore, p-MED1 is bound to ARv567es independent of full-length AR; p-MED1 has higher recruitment to UBE2C promoter and enhancer regions in the presence of ARv567es. Our data indicate that p-MED1 serves as a key mediator in ARv567es induced gene expression and suggests a mechanism by which AR-Vs promote the development and progression of CRPC. PMID:25481872

Developmental Programming

PubMed Central

Veiga-Lopez, A.; Wurst, A. K.; Steckler, T. L.; Ye, W.

2014-01-01

Excess of prenatal testosterone (T) induces reproductive defects including follicular persistence. Comparative studies with T and dihydrotestosterone (DHT) have suggested that follicular persistence is programmed via estrogenic actions of T. This study addresses the androgenic and estrogenic contributions in programming follicular persistence. Because humans are exposed to estrogenic environmental steroids from various sources throughout their life span and postnatal insults may also induce organizational and/or activational changes, we tested whether continuous postnatal exposure to estradiol (E) will amplify effects of prenatal steroids on ovarian function. Pregnant sheep were treated with T, DHT, E, or ED (E and DHT) from days 30 to 90 of gestation. Postnatally, a subset of the vehicle (C), T, and DHT females received an E implant. Transrectal ultrasonography was performed in the first breeding season during a synchronized cycle to monitor ovarian follicular dynamics. As expected, number of ≥8 mm follicles was higher in the T versus C group. Postnatal E reduced the number of 4 to 8 mm follicles in the DHT group. Percentage of females bearing luteinized follicles and the number of luteinized follicles differed among prenatal groups. Postnatal E increased the incidence of subluteal cycles in the prenatal T-treated females. Findings from this study confirm previous findings of divergences in programming effects of prenatal androgens and estrogens. They also indicate that some aspects of follicular dynamics are subject to postnatal modulation as well as support the existence of an extended organizational period or the need for a second insult to uncover the previously programmed event. PMID:24077439

3-Bromopyruvate induces rapid human prostate cancer cell death by affecting cell energy metabolism, GSH pool and the glyoxalase system.

PubMed

Valenti, Daniela; Vacca, Rosa A; de Bari, Lidia

2015-12-01

3-bromopyruvate (3-BP) is an anti-tumour drug effective on hepatocellular carcinoma and other tumour cell types, which affects both glycolytic and mitochondrial targets, depleting cellular ATP pool. Here we tested 3-BP on human prostate cancer cells showing, differently from other tumour types, efficient ATP production and functional mitochondrial metabolism. We found that 3-BP rapidly induced cultured androgen-insensitive (PC-3) and androgen-responsive (LNCaP) prostate cancer cell death at low concentrations (IC(50) values of 50 and 70 μM, respectively) with a multimodal mechanism of action. In particular, 3-BP-treated PC-3 cells showed a selective, strong reduction of glyceraldeide 3-phosphate dehydrogenase activity, due to the direct interaction of the drug with the enzyme. Moreover, 3-BP strongly impaired both glutamate/malate- and succinate-dependent mitochondrial respiration, membrane potential generation and ATP synthesis, concomitant with the inhibition of respiratory chain complex I, II and ATP synthase activities. The drastic reduction of cellular ATP levels and depletion of GSH pool, associated with significant increase in cell oxidative stress, were found after 3-BP treatment of PC-3 cells. Interestingly, the activity of both glyoxalase I and II, devoted to the elimination of the cytotoxic methylglyoxal, was strongly inhibited by 3-BP. Both N-acetylcysteine and aminoguanidine, GSH precursor and methylglyoxal scavenger, respectively, prevented 3-BP-induced PC-3 cell death, showing that impaired cell antioxidant and detoxifying capacities are crucial events leading to cell death. The provided information on the multi-target cytotoxic action of 3-BP, finally leading to PC-3 cell necrosis, might be useful for future development of 3-BP as a therapeutic option for prostate cancer treatment.

The inhibitory effects of capillarisin on cell proliferation and invasion of prostate carcinoma cells.

PubMed

Tsui, Ke-Hung; Chang, Ying-Ling; Yang, Pei-Shan; Hou, Chen-Pang; Lin, Yu-Hsiang; Lin, Bing-Wei; Feng, Tsui-Hsia; Juang, Horng-Heng

2018-04-01

Capillarisin (Cap), an active component of Artemisia capillaris root extracts, is characterized by its anti-inflammatory, anti-oxidant and anti-cancer properties. Nevertheless, the functions of Cap in prostate cancer have not been fully explored. We evaluated the potential actions of Cap on the cell proliferation, migration and invasion of prostate carcinoma cells. Cell proliferation and cell cycle distribution were measured by water-soluble tetrazolium-1 and flow cytometry assays. The expression of cyclins, p21, p27, survivin, matrix metallopeptidase (MMP2 and MMP9) were assessed by immunoblotting assays. Effects of Cap on invasion and migration were determined by wound closure and matrigel transmigration assays. The constitutive and interlukin-6 (IL-6)-inducible STAT3 activation of prostate carcinoma cells were determined by immunoblotting and reporter assays. Capillarisin inhibited androgen-independent DU145 and androgen-dependent LNCaP cell growth through the induction of cell cycle arrest at the G0/G1 phase by upregulating p21 and p27 while downregulating expression of cyclin D1, cyclin A and cyclin B. Cap decreased protein expression of survivin, MMP-2, and MMP-9 and therefore blocked the migration and invasion of DU145 cells. Cap suppressed constitutive and IL-6-inducible STAT3 activation in DU145 and LNCaP cells. Our data indicate that Cap blocked cell growth by modulation of p21, p27 and cyclins. The inhibitory effects of Cap on survivin, MMP-2, MMP-9 and STAT3 activation may account for the suppression of invasion in prostate carcinoma cells. Our data suggest that Cap might be a therapeutic agent in treating advanced prostate cancer with constitutive STAT3 or IL-6-inducible STAT3 activation. © 2017 John Wiley & Sons Ltd.

Chronic Exposure to Androgenic-Anabolic Steroids Exacerbates Axonal Injury and Microgliosis in the CHIMERA Mouse Model of Repetitive Concussion.

PubMed

Namjoshi, Dhananjay R; Cheng, Wai Hang; Carr, Michael; Martens, Kris M; Zareyan, Shahab; Wilkinson, Anna; McInnes, Kurt A; Cripton, Peter A; Wellington, Cheryl L

2016-01-01

Concussion is a serious health concern. Concussion in athletes is of particular interest with respect to the relationship of concussion exposure to risk of chronic traumatic encephalopathy (CTE), a neurodegenerative condition associated with altered cognitive and psychiatric functions and profound tauopathy. However, much remains to be learned about factors other than cumulative exposure that could influence concussion pathogenesis. Approximately 20% of CTE cases report a history of substance use including androgenic-anabolic steroids (AAS). How acute, chronic, or historical AAS use may affect the vulnerability of the brain to concussion is unknown. We therefore tested whether antecedent AAS exposure in young, male C57Bl/6 mice affects acute behavioral and neuropathological responses to mild traumatic brain injury (TBI) induced with the CHIMERA (Closed Head Impact Model of Engineered Rotational Acceleration) platform. Male C57Bl/6 mice received either vehicle or a cocktail of three AAS (testosterone, nandrolone and 17α-methyltestosterone) from 8-16 weeks of age. At the end of the 7th week of treatment, mice underwent two closed-head TBI or sham procedures spaced 24 h apart using CHIMERA. Post-repetitive TBI (rTBI) behavior was assessed for 7 d followed by tissue collection. AAS treatment induced the expected physiological changes including increased body weight, testicular atrophy, aggression and downregulation of brain 5-HT1B receptor expression. rTBI induced behavioral deficits, widespread axonal injury and white matter microgliosis. While AAS treatment did not worsen post-rTBI behavioral changes, AAS-treated mice exhibited significantly exacerbated axonal injury and microgliosis, indicating that AAS exposure can alter neuronal and innate immune responses to concussive TBI.

Chronic Exposure to Androgenic-Anabolic Steroids Exacerbates Axonal Injury and Microgliosis in the CHIMERA Mouse Model of Repetitive Concussion

PubMed Central

Namjoshi, Dhananjay R.; Cheng, Wai Hang; Carr, Michael; Martens, Kris M.; Zareyan, Shahab; Wilkinson, Anna; McInnes, Kurt A.; Cripton, Peter A.; Wellington, Cheryl L.

2016-01-01

Concussion is a serious health concern. Concussion in athletes is of particular interest with respect to the relationship of concussion exposure to risk of chronic traumatic encephalopathy (CTE), a neurodegenerative condition associated with altered cognitive and psychiatric functions and profound tauopathy. However, much remains to be learned about factors other than cumulative exposure that could influence concussion pathogenesis. Approximately 20% of CTE cases report a history of substance use including androgenic-anabolic steroids (AAS). How acute, chronic, or historical AAS use may affect the vulnerability of the brain to concussion is unknown. We therefore tested whether antecedent AAS exposure in young, male C57Bl/6 mice affects acute behavioral and neuropathological responses to mild traumatic brain injury (TBI) induced with the CHIMERA (Closed Head Impact Model of Engineered Rotational Acceleration) platform. Male C57Bl/6 mice received either vehicle or a cocktail of three AAS (testosterone, nandrolone and 17α-methyltestosterone) from 8–16 weeks of age. At the end of the 7th week of treatment, mice underwent two closed-head TBI or sham procedures spaced 24 h apart using CHIMERA. Post-repetitive TBI (rTBI) behavior was assessed for 7 d followed by tissue collection. AAS treatment induced the expected physiological changes including increased body weight, testicular atrophy, aggression and downregulation of brain 5-HT1B receptor expression. rTBI induced behavioral deficits, widespread axonal injury and white matter microgliosis. While AAS treatment did not worsen post-rTBI behavioral changes, AAS-treated mice exhibited significantly exacerbated axonal injury and microgliosis, indicating that AAS exposure can alter neuronal and innate immune responses to concussive TBI. PMID:26784694

Effect of gender and sex hormones on immune responses following shock.

PubMed

Angele, M K; Schwacha, M G; Ayala, A; Chaudry, I H

2000-08-01

Several clinical and experimental studies show a gender dimorphism of the immune and organ responsiveness in the susceptibility to and morbidity from shock, trauma, and sepsis. In this respect, cell-mediated immune responses are depressed in males after trauma-hemorrhage, whereas they are unchanged or enhanced in females. Sex hormones contribute to this gender-specific immune response after adverse circulatory conditions. Specifically, studies indicate that androgens are responsible for the immunodepression after trauma-hemorrhage in males. In contrast, female sex steroids seem to exhibit immunoprotective properties after trauma and severe blood loss, because administration of estrogen prevents the androgen-induced immunodepression in castrated male mice. Nonetheless, the precise underlying mechanisms for these immunomodulatory effects of sex steroids after shock remain unknown. Although testosterone depletion, testosterone receptor antagonism, or estrogen treatment has been shown to prevent the depression of immune functions after trauma-hemorrhage, it remains to be established whether differences in the testosterone-estradiol ratio are responsible for the immune dysfunction. Furthermore, sex hormone receptors have been identified on various immune cells, suggesting direct effects. Thus, the immunomodulatory properties of sex hormones after trauma-hemorrhage might represent novel therapeutic strategies for the treatment of immunodepression in trauma patients.

Double helix: reciprocity between juvenile play and brain development.

PubMed

Cooke, Bradley M; Shukla, Deep

2011-10-01

This review summarizes what is presently known about the function, sexual differentiation, and neural circuitry of juvenile rough-and-tumble play. Juvenile rough-and-tumble play is a unique motivated behavior that is widespread throughout the mammalian order and usually occurs more often in males. Immediate early gene studies indicate that cortical and subcortical circuits, many of which are sensitive to sex steroid hormones, mediate juvenile play. Sex differences in rough-and-tumble play are controlled in part by neonatal exposure to androgens or their estrogenic metabolites. Studies indicate that testicular androgens during play are also necessary to stimulate male-like levels of play initiation. The resemblance of rough-and-tumble play to aggression and sexual behavior has led some to question whether male-typical adult behavior is contingent upon the experience of play. Attempts to control the amount of play through social isolation show that social experience during adolescence is critical for male-typical adult behaviors to be expressed. This well-established finding, together with evidence that play induces neural plasticity, supports the hypothesis that juvenile play contributes to male-typical brain development that ultimately enables the expression of adult social and reproductive behavior. Copyright © 2011 Elsevier Ltd. All rights reserved.

High-throughput sensing and noninvasive imaging of protein nuclear transport by using reconstitution of split Renilla luciferase.

PubMed

Kim, Sung Bae; Ozawa, Takeaki; Watanabe, Shigeaki; Umezawa, Yoshio

2004-08-10

Nucleocytoplasmic trafficking of functional proteins plays a key role in regulating gene expressions in response to extracellular signals. We developed a genetically encoded bioluminescent indicator for monitoring the nuclear trafficking of target proteins in vitro and in vivo. The principle is based on reconstitution of split fragments of Renilla reniformis (Rluc) by protein splicing with a DnaE intein (a catalytic subunit of DNA polymerase III). A target cytosolic protein fused to the N-terminal half of Rluc is expressed in mammalian cells. If the protein translocates into the nucleus, the Rluc moiety meets the C-terminal half of Rluc, and full-length Rluc is reconstituted by protein splicing. We demonstrated quantitative cell-based in vitro sensing of ligand-induced translocation of androgen receptor, which allowed high-throughput screening of exo- and endogenous agonists and antagonists. Furthermore, the indicator enabled noninvasive in vivo imaging of the androgen receptor translocation in the brains of living mice with a charge-coupled device imaging system. These rapid and quantitative analyses in vitro and in vivo provide a wide variety of applications for screening pharmacological or toxicological compounds and testing them in living animals.

Characterization of an ICII82, 780-Induced, Estrogen Receptor (ER)-beta Mediated Apoptotic Pathway in Prostate Cancer Cells and Establishment of (ER)-beta-Regulated Electrophile-Processing Phase II Enzyme Downregulation as a Promotional Factor in Human Prostatic Carcinogenesis

DTIC Science & Technology

2001-05-01

absent in higher-grade cancers. ERP3 expression reappeared in metastatic prostatic carcinomas . The results were also compared to ERMo and androgen...metastatic prostatic carcinomas in bone and lymph nodes. The results were compared to ERax and androgen receptor expressions in those samples. Taken... carcinomas of the peripheral zone were in contrast strongly positive for the 13 receptor whereas its expression in grade 415 cancers was negligible to

Key structural features of nonsteroidal ligands for binding and activation of the androgen receptor.

PubMed

Yin, Donghua; He, Yali; Perera, Minoli A; Hong, Seoung Soo; Marhefka, Craig; Stourman, Nina; Kirkovsky, Leonid; Miller, Duane D; Dalton, James T

2003-01-01

The purposes of the present studies were to examine the androgen receptor (AR) binding ability and in vitro functional activity of multiple series of nonsteroidal compounds derived from known antiandrogen pharmacophores and to investigate the structure-activity relationships (SARs) of these nonsteroidal compounds. The AR binding properties of sixty-five nonsteroidal compounds were assessed by a radioligand competitive binding assay with the use of cytosolic AR prepared from rat prostates. The AR agonist and antagonist activities of high-affinity ligands were determined by the ability of the ligand to regulate AR-mediated transcriptional activation in cultured CV-1 cells, using a cotransfection assay. Nonsteroidal compounds with diverse structural features demonstrated a wide range of binding affinity for the AR. Ten compounds, mainly from the bicalutamide-related series, showed a binding affinity superior to the structural pharmacophore from which they were derived. Several SARs regarding nonsteroidal AR binding were revealed from the binding data, including stereoisomeric conformation, steric effect, and electronic effect. The functional activity of high-affinity ligands ranged from antagonist to full agonist for the AR. Several structural features were found to be determinative of agonist and antagonist activities. The nonsteroidal AR agonists identified from the present studies provided a pool of candidates for further development of selective androgen receptor modulators (SARMs) for androgen therapy. Also, these studies uncovered or confirmed numerous important SARs governing AR binding and functional properties by nonsteroidal molecules, which would be valuable in the future structural optimization of SARMs.

Computational Modeling and Simulation of Genital Tubercle ...

EPA Pesticide Factsheets

Hypospadias is a developmental defect of urethral tube closure that has a complex etiology. Here, we describe a multicellular agent-based model of genital tubercle development that simulates urethrogenesis from the urethral plate stage to urethral tube closure in differentiating male embryos. The model, constructed in CompuCell3D, implemented spatially dynamic signals from SHH, FGF10, and androgen signaling pathways. These signals modulated stochastic cell behaviors, such as differential adhesion, cell motility, proliferation, and apoptosis. Urethral tube closure was an emergent property of the model that was quantitatively dependent on SHH and FGF10 induced effects on mesenchymal proliferation and endodermal apoptosis, ultimately linked to androgen signaling. In the absence of androgenization, simulated genital tubercle development defaulted to the female condition. Intermediate phenotypes associated with partial androgen deficiency resulted in incomplete closure. Using this computer model, complex relationships between urethral tube closure defects and disruption of underlying signaling pathways could be probed theoretically in multiplex disturbance scenarios and modeled into probabilistic predictions for individual risk for hypospadias and potentially other developmental defects of the male genital tubercle. We identify the minimal molecular network that determines the outcome of male genital tubercle development in mice.

Negative regulation of parathyroid hormone-related protein expression by steroid hormones

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kajitani, Takashi; Tamamori-Adachi, Mimi; Okinaga, Hiroko

Highlights: {yields} Steroid hormones repress expression of PTHrP in the cell lines where the corresponding nuclear receptors are expressed. {yields} Nuclear receptors are required for suppression of PTHrP expression by steroid hormones, except for androgen receptor. {yields} Androgen-induced suppression of PTHrP expression appears to be mediated by estrogen receptor. -- Abstract: Elevated parathyroid hormone-related protein (PTHrP) is responsible for humoral hypercalcemia of malignancy (HHM), which is of clinical significance in treatment of terminal patients with malignancies. Steroid hormones were known to cause suppression of PTHrP expression. However, detailed studies linking multiple steroid hormones to PTHrP expression are lacking. Here wemore » studied PTHrP expression in response to steroid hormones in four cell lines with excessive PTHrP production. Our study established that steroid hormones negatively regulate PTHrP expression. Vitamin D receptor, estrogen receptor {alpha}, glucocorticoid receptor, and progesterone receptor, were required for repression of PTHrP expression by the cognate ligands. A notable exception was the androgen receptor, which was dispensable for suppression of PTHrP expression in androgen-treated cells. We propose a pathway(s) involving nuclear receptors to suppress PTHrP expression.« less

Biotransformation of 17α-methyltestosterone in sediment under different electron acceptor conditions.

PubMed

Homklin, Supreeda; Ong, Say Kee; Limpiyakorn, Tawan

2011-03-01

17α-Methyltestosterone (MT), an anabolic androgenic steroid, is used widely in inducing an all male population in aquaculture farming of fish, such as Nile tilapia (Oreochromis niloticus). Current understanding of the occurrence and fate of MT in the sediments and the surrounding areas of the aquaculture ponds are very limited. Bioassay tests showed that MT was biotransformed under aerobic and sulfate-reducing conditions with a half-life of 3.8d and 5.3d, respectively, with complete disappearance of androgenic activity. However, under methanogenic condition, MT was found to biotransform but the androgenic activity continued to persist even after 45 d of incubation. In contrast, MT was found to transform slowly under iron(III)-reducing condition and was hardly transformed under nitrate-reducing condition. A possible reason for the lack of transformation of MT under nitrate-reducing condition is the presence of the methyl group at the C-17 position. The results of this study suggest that MT and its degradation products with androgenic activity may potentially accumulate in the sediments of fish farming ponds under iron(III)-reducing, nitrate-reducing and methanogenic conditions. Copyright © 2010 Elsevier Ltd. All rights reserved.

Red ginseng extract promotes the hair growth in cultured human hair follicles.

PubMed

Park, Gyeong-Hun; Park, Ki-young; Cho, Hong-il; Lee, Sang-Min; Han, Ji Su; Won, Chong Hyun; Chang, Sung Eun; Lee, Mi Woo; Choi, Jee Ho; Moon, Kee Chan; Shin, Hyoseung; Kang, Yong Jung; Lee, Dong Hun

2015-03-01

Ginseng has been shown to promote hair growth in several recent studies. However, its effects on human hair follicles and its mechanisms of action have not been sufficiently elucidated. This study aimed to investigate the hair growth-promoting effects of red ginseng extract (RGE) and its ginsenosides. The proliferative activities of cultured human hair follicles treated with RGE and ginsenoside-Rb1 were assessed using Ki-67 immunostaining. Their effects on isolated human dermal papilla cells (hDPCs) were evaluated using cytotoxicity assays, immunoblot analysis of signaling proteins, and the determination of associated growth factors. We examined the ability of RGE and ginsenosides to protect hair matrix keratinocyte proliferation against dihydrotestosterone (DHT)-induced suppression and their effects on the expression of androgen receptor. The in vivo hair growth-promoting effect of RGE was also investigated in C57BL/6 mice. Both RGE and ginsenoside-Rb1 enhanced the proliferation of hair matrix keratinocytes. hDPCs treated with RGE or ginsenoside-Rb1 exhibited substantial cell proliferation and the associated phosphorylation of ERK and AKT. Moreover, RGE, ginsenoside-Rb1, and ginsenoside-Rg3 abrogated the DHT-induced suppression of hair matrix keratinocyte proliferation and the DHT-induced upregulation of the mRNA expression of androgen receptor in hDPCs. Murine experiments revealed that the subcutaneous injection of 3% RGE resulted in more rapid hair growth than the negative control. In conclusion, RGE and its ginsenosides may enhance hDPC proliferation, activate ERK and AKT signaling pathways in hDPCs, upregulate hair matrix keratinocyte proliferation, and inhibit the DHT-induced androgen receptor transcription. These results suggest that red ginseng may promote hair growth in humans.

Red Ginseng Extract Promotes the Hair Growth in Cultured Human Hair Follicles

PubMed Central

Park, Gyeong-Hun; Park, Ki-young; Cho, Hong-il; Lee, Sang-Min; Han, Ji Su; Chang, Sung Eun; Lee, Mi Woo; Choi, Jee Ho; Moon, Kee Chan; Shin, Hyoseung; Kang, Yong Jung; Lee, Dong Hun

2015-01-01

Abstract Ginseng has been shown to promote hair growth in several recent studies. However, its effects on human hair follicles and its mechanisms of action have not been sufficiently elucidated. This study aimed to investigate the hair growth-promoting effects of red ginseng extract (RGE) and its ginsenosides. The proliferative activities of cultured human hair follicles treated with RGE and ginsenoside-Rb1 were assessed using Ki-67 immunostaining. Their effects on isolated human dermal papilla cells (hDPCs) were evaluated using cytotoxicity assays, immunoblot analysis of signaling proteins, and the determination of associated growth factors. We examined the ability of RGE and ginsenosides to protect hair matrix keratinocyte proliferation against dihydrotestosterone (DHT)-induced suppression and their effects on the expression of androgen receptor. The in vivo hair growth-promoting effect of RGE was also investigated in C57BL/6 mice. Both RGE and ginsenoside-Rb1 enhanced the proliferation of hair matrix keratinocytes. hDPCs treated with RGE or ginsenoside-Rb1 exhibited substantial cell proliferation and the associated phosphorylation of ERK and AKT. Moreover, RGE, ginsenoside-Rb1, and ginsenoside-Rg3 abrogated the DHT-induced suppression of hair matrix keratinocyte proliferation and the DHT-induced upregulation of the mRNA expression of androgen receptor in hDPCs. Murine experiments revealed that the subcutaneous injection of 3% RGE resulted in more rapid hair growth than the negative control. In conclusion, RGE and its ginsenosides may enhance hDPC proliferation, activate ERK and AKT signaling pathways in hDPCs, upregulate hair matrix keratinocyte proliferation, and inhibit the DHT-induced androgen receptor transcription. These results suggest that red ginseng may promote hair growth in humans. PMID:25396716

Regulators of Androgen Action Resource: a one-stop shop for the comprehensive study of androgen receptor action.

PubMed

DePriest, Adam D; Fiandalo, Michael V; Schlanger, Simon; Heemers, Frederike; Mohler, James L; Liu, Song; Heemers, Hannelore V

2016-01-01

Androgen receptor (AR) is a ligand-activated transcription factor that is the main target for treatment of non-organ-confined prostate cancer (CaP). Failure of life-prolonging AR-targeting androgen deprivation therapy is due to flexibility in steroidogenic pathways that control intracrine androgen levels and variability in the AR transcriptional output. Androgen biosynthesis enzymes, androgen transporters and AR-associated coregulators are attractive novel CaP treatment targets. These proteins, however, are characterized by multiple transcript variants and isoforms, are subject to genomic alterations, and are differentially expressed among CaPs. Determining their therapeutic potential requires evaluation of extensive, diverse datasets that are dispersed over multiple databases, websites and literature reports. Mining and integrating these datasets are cumbersome, time-consuming tasks and provide only snapshots of relevant information. To overcome this impediment to effective, efficient study of AR and potential drug targets, we developed the Regulators of Androgen Action Resource (RAAR), a non-redundant, curated and user-friendly searchable web interface. RAAR centralizes information on gene function, clinical relevance, and resources for 55 genes that encode proteins involved in biosynthesis, metabolism and transport of androgens and for 274 AR-associated coregulator genes. Data in RAAR are organized in two levels: (i) Information pertaining to production of androgens is contained in a 'pre-receptor level' database, and coregulator gene information is provided in a 'post-receptor level' database, and (ii) an 'other resources' database contains links to additional databases that are complementary to and useful to pursue further the information provided in RAAR. For each of its 329 entries, RAAR provides access to more than 20 well-curated publicly available databases, and thus, access to thousands of data points. Hyperlinks provide direct access to gene-specific entries in the respective database(s). RAAR is a novel, freely available resource that provides fast, reliable and easy access to integrated information that is needed to develop alternative CaP therapies. Database URL: http://www.lerner.ccf.org/cancerbio/heemers/RAAR/search/. © The Author(s) 2016. Published by Oxford University Press.

Androgen Receptor-Mediated Escape Mechanisms from Androgen Ablation Therapy

DTIC Science & Technology

2005-10-01

intestinal polyps, the precursor of invasive carcinoma and colon cancer. Also, fain-of-function, truncated forms of 3-catenin occurring in metastatic prostate...STATEMENT: Approved for Public Release; Distribution Unlimited The views, opinions and/or findings contained in this report are those of the author(s) and...should not be construed as an official Department of the Army position, policy or decision unless so designated by other documentation. 20060503040

Relating Androgen Receptor Conformation to Function in Prostate Cancer Cells

DTIC Science & Technology

2005-01-01

line development , but have made progress towards resolving these issues and in development of alternate strategies. Task 1. Development of AR and...conformation. Task 2. Development of LNCaP Cells to Express Human AR mutants. We experienced unexpected difficulties in Task 2. We transfected the TET...Coactivators in AR Transactivation Summary Androgens drive sex differentiation, bone and muscle development , and promote growth of hormone dependent cancers

Transcriptional regulation of core autophagy and lysosomal genes by the androgen receptor promotes prostate cancer progression

PubMed Central

Blessing, Alicia M.; Rajapakshe, Kimal; Reddy Bollu, Lakshmi; Shi, Yan; White, Mark A.; Pham, Alexander H.; Lin, Chenchu; Jonsson, Philip; Cortes, Constanza J.; Cheung, Edwin; La Spada, Albert R.; Bast, Robert C.; Merchant, Fatima A.; Coarfa, Cristian; Frigo, Daniel E.

2017-01-01

ABSTRACT AR (androgen receptor) signaling is crucial for the development and maintenance of the prostate as well as the initiation and progression of prostate cancer. Despite the AR's central role in prostate cancer progression, it is still unclear which AR-mediated processes drive the disease. Here, we identified 4 core autophagy genes: ATG4B, ATG4D, ULK1, and ULK2, in addition to the transcription factor TFEB, a master regulator of lysosomal biogenesis and function, as transcriptional targets of AR in prostate cancer. These findings were significant in light of our recent observation that androgens promoted prostate cancer cell growth in part through the induction of autophagy. Expression of these 5 genes was essential for maximal androgen-mediated autophagy and cell proliferation. In addition, expression of each of these 5 genes alone or in combination was sufficient to increase prostate cancer cell growth independent of AR activity. Further, bioinformatic analysis demonstrated that the expression of these genes correlated with disease progression in 3 separate clinical cohorts. Collectively, these findings demonstrate a functional role for increased autophagy in prostate cancer progression, provide a mechanism for how autophagy is augmented, and highlight the potential of targeting this process for the treatment of advanced prostate cancer. PMID:27977328

Association of Androgen Excess with Glucose Intolerance in Women with Polycystic Ovary Syndrome.

PubMed

Zhang, Bingjie; Wang, Jing; Shen, Shanmei; Liu, Jiayi; Sun, Jie; Gu, Tianwei; Ye, Xiao; Zhu, Dalong; Bi, Yan

2018-01-01

Women with polycystic ovary syndrome (PCOS) show high prevalence of glucose intolerance. This study aimed to investigate the association of androgen excess with glucose intolerance in PCOS. A total of 378 women with PCOS participated in the study. Free androgen index (FAI) was selected as indicator of hyperandrogenism. Insulin sensitivity was assessed by 1/homeostasis model assessment of insulin resistance (1/HOMA-IR) and Matsuda insulin sensitivity index (ISI M ); β -cell function was assessed by disposition index (DI). We found that women with glucose intolerance had higher FAI levels compared to women with normal glucose tolerance (NGT) (prediabetes 6.2, T2DM 7.9 versus NGT 5.0, resp.; p < 0.001). Furthermore, there was a direct association between FAI levels and frequency of glucose intolerance (OR = 2.480, 95% CI 1.387-4.434), even after adjusting for age, BMI, waist circumference, hypertension, fasting insulin, testosterone, SHBG, and family history of diabetes. In addition, with FAI increase, glycosylated hemoglobin (HbA1c), plasma glucose concentrations, and serum insulin levels increased, while insulin sensitivity and β -cell function decreased. Our results suggested that androgen excess indicated by high FAI levels might serve as indicator of glucose intolerance, as it might promote insulin resistance and β -cell dysfunction in women with PCOS.

A dual yet opposite growth-regulating function of miR-204 and its target XRN1 in prostate adenocarcinoma cells and neuroendocrine-like prostate cancer cells

PubMed Central

Ding, Miao; Lin, Biaoyang; Li, Tao; Liu, Yuanyuan; Li, Yuhua; Zhou, Xiaoyu; Miao, Maohua; Gu, Jinfa; Pan, Hongjie; Yang, Fen; Li, Tianqi; Liu, Xin Yuan; Li, Runsheng

2015-01-01

Androgen deprivation therapy in prostate cancer (PCa) causes neuroendocrine differentiation (NED) of prostatic adenocarcinomas (PAC) cells, leading to recurrence of PCa. Androgen-responsive genes involved in PCa progression including NED remain largely unknown. Here we demonstrated the importance of androgen receptor (AR)-microRNA-204 (miR-204)-XRN1 axis in PCa cell lines and the rat ventral prostate. Androgens downregulate miR-204, resulting in induction of XRN1 (5′-3′ exoribonuclease 1), which we identified as a miR-204 target. miR-204 acts as a tumor suppressor in two PAC cell lines (LNCaP and 22Rv1) and as an oncomiR in two neuroendocrine-like prostate cancer (NEPC) cell lines (PC-3 and CL1). Importantly, overexpression of miR-204 and knockdown of XRN1 inhibited AR expression in PCa cells. Repression of miR-34a, a known AR-targeting miRNA, contributes AR expression by XRN1. Thus we revealed the AR-miR-204-XRN1-miR-34a positive feedback loop and a dual function of miR-204/XRN1 axis in prostate cancer. PMID:25797256

Transcriptional regulation of core autophagy and lysosomal genes by the androgen receptor promotes prostate cancer progression.

PubMed

Blessing, Alicia M; Rajapakshe, Kimal; Reddy Bollu, Lakshmi; Shi, Yan; White, Mark A; Pham, Alexander H; Lin, Chenchu; Jonsson, Philip; Cortes, Constanza J; Cheung, Edwin; La Spada, Albert R; Bast, Robert C; Merchant, Fatima A; Coarfa, Cristian; Frigo, Daniel E

2017-03-04

AR (androgen receptor) signaling is crucial for the development and maintenance of the prostate as well as the initiation and progression of prostate cancer. Despite the AR's central role in prostate cancer progression, it is still unclear which AR-mediated processes drive the disease. Here, we identified 4 core autophagy genes: ATG4B, ATG4D, ULK1, and ULK2, in addition to the transcription factor TFEB, a master regulator of lysosomal biogenesis and function, as transcriptional targets of AR in prostate cancer. These findings were significant in light of our recent observation that androgens promoted prostate cancer cell growth in part through the induction of autophagy. Expression of these 5 genes was essential for maximal androgen-mediated autophagy and cell proliferation. In addition, expression of each of these 5 genes alone or in combination was sufficient to increase prostate cancer cell growth independent of AR activity. Further, bioinformatic analysis demonstrated that the expression of these genes correlated with disease progression in 3 separate clinical cohorts. Collectively, these findings demonstrate a functional role for increased autophagy in prostate cancer progression, provide a mechanism for how autophagy is augmented, and highlight the potential of targeting this process for the treatment of advanced prostate cancer.

Critical androgen-sensitive periods of rat penis and clitoris development.

PubMed

Welsh, Michelle; MacLeod, David J; Walker, Marion; Smith, Lee B; Sharpe, Richard M

2010-02-01

Androgen control of penis development/growth is unclear. In rats, androgen action in a foetal 'masculinisation programming window' (MPW; e15.5-e18.5)' predetermines penile length and hypospadias occurrence. This has implications for humans (e.g. micropenis). Our studies aimed to establish in rats when androgen action/administration affects development/growth of the penis and if deficits in MPW androgen action were rescuable postnatally. Thus, pregnant rats were treated with flutamide during the MPW +/- postnatal testosterone propionate (TP) treatment. To assess penile growth responsiveness, rats were treated with TP in various time windows (late foetal, neonatal through early puberty, puberty onset, or combinations thereof). Phallus length, weight, and morphology, hypospadias and anogenital distance (AGD) were measured in mid-puberty (d25) or adulthood (d90) in males and females, plus serum testosterone in adult males. MPW flutamide exposure reduced adult penile length and induced hypospadias dose-dependently; this was not rescued by postnatal TP treatment. In normal rats, foetal (e14.5-e21.5) TP exposure did not affect male penis size but increased female clitoral size. In males, TP exposure from postnatal d1-24 or at puberty (d15-24), increased penile length at d25, but not ultimately in adulthood. Foetal + postnatal TP (e14-postnatal d24) increased penile size at d25 but reduced it at d90 (due to reduced endogenous testosterone). In females, this treatment caused the biggest increase in adult clitoral size but, unlike in males, phallus size was unaffected by TP during puberty (d15-24). Postnatal TP treatment advanced penile histology at d25 to more resemble adult histology. AGD strongly correlated with final penis length. It is concluded that adult penile size depends critically on androgen action during the MPW but subsequent growth depends on later androgen exposure. Foetal and/or postnatal TP exposure does not increase adult penile size above its 'predetermined' length though its growth towards this maximum is advanced by peripubertal TP treatment.

Coagulation factor VII is regulated by androgen receptor in breast cancer.

PubMed

Naderi, Ali

2015-02-01

Androgen receptor (AR) is widely expressed in breast cancer; however, there is limited information on the key molecular functions and gene targets of AR in this disease. In this study, gene expression data from a cohort of 52 breast cancer cell lines was analyzed to identify a network of AR co-expressed genes. A total of 300 genes, which were significantly enriched for cell cycle and metabolic functions, showed absolute correlation coefficients (|CC|) of more than 0.5 with AR expression across the dataset. In this network, a subset of 35 "AR-signature" genes were highly co-expressed with AR (|CC|>0.6) that included transcriptional regulators PATZ1, NFATC4, and SPDEF. Furthermore, gene encoding coagulation factor VII (F7) demonstrated the closest expression pattern with AR (CC=0.716) in the dataset and factor VII protein expression was significantly associated to that of AR in a cohort of 209 breast tumors. Moreover, functional studies demonstrated that AR activation results in the induction of factor VII expression at both transcript and protein levels and AR directly binds to a proximal region of F7 promoter in breast cancer cells. Importantly, AR activation in breast cancer cells induced endogenous factor VII activity to convert factor X to Xa in conjunction with tissue factor. In summary, F7 is a novel AR target gene and AR activation regulates the ectopic expression and activity of factor VII in breast cancer cells. These findings have functional implications in the pathobiology of thromboembolic events and regulation of factor VII/tissue factor signaling in breast cancer. Copyright © 2014 Elsevier Inc. All rights reserved.

Developmental programming of polycystic ovary syndrome (PCOS): prenatal androgens establish pancreatic islet α/β cell ratio and subsequent insulin secretion.

PubMed

Ramaswamy, S; Grace, C; Mattei, A A; Siemienowicz, K; Brownlee, W; MacCallum, J; McNeilly, A S; Duncan, W C; Rae, M T

2016-06-06

Exogenous androgenic steroids applied to pregnant sheep programmes a PCOS-like phenotype in female offspring. Via ultrasound guidance we applied steroids directly to ovine fetuses at d62 and d82 of gestation, and examined fetal (day 90 gestation) and postnatal (11 months old) pancreatic structure and function. Of three classes of steroid agonists applied (androgen - Testosterone propionate (TP), estrogen - Diethystilbesterol (DES) and glucocorticoid - Dexamethasone (DEX)), only androgens (TP) caused altered pancreatic development. Beta cell numbers were significantly elevated in prenatally androgenised female fetuses (P = 0.03) (to approximately the higher numbers found in male fetuses), whereas alpha cell counts were unaffected, precipitating decreased alpha:beta cell ratios in the developing fetal pancreas (P = 0.001), sustained into adolescence (P = 0.0004). In adolescence basal insulin secretion was significantly higher in female offspring from androgen-excess pregnancies (P = 0.045), and an exaggerated, hyperinsulinaemic response to glucose challenge (P = 0.0007) observed, whereas prenatal DES or DEX treatment had no effects upon insulin secretion. Postnatal insulin secretion correlated with beta cell numbers (P = 0.03). We conclude that the pancreas is a primary locus of androgenic stimulation during development, giving rise to postnatal offspring whose pancreas secreted excess insulin due to excess beta cells in the presence of a normal number of alpha cells.

Developmental programming of polycystic ovary syndrome (PCOS): prenatal androgens establish pancreatic islet α/β cell ratio and subsequent insulin secretion

PubMed Central

Ramaswamy, S.; Grace, C.; Mattei, A. A.; Siemienowicz, K.; Brownlee, W.; MacCallum, J.; McNeilly, A. S.; Duncan, W. C.; Rae, M. T.

2016-01-01

Exogenous androgenic steroids applied to pregnant sheep programmes a PCOS-like phenotype in female offspring. Via ultrasound guidance we applied steroids directly to ovine fetuses at d62 and d82 of gestation, and examined fetal (day 90 gestation) and postnatal (11 months old) pancreatic structure and function. Of three classes of steroid agonists applied (androgen - Testosterone propionate (TP), estrogen - Diethystilbesterol (DES) and glucocorticoid - Dexamethasone (DEX)), only androgens (TP) caused altered pancreatic development. Beta cell numbers were significantly elevated in prenatally androgenised female fetuses (P = 0.03) (to approximately the higher numbers found in male fetuses), whereas alpha cell counts were unaffected, precipitating decreased alpha:beta cell ratios in the developing fetal pancreas (P = 0.001), sustained into adolescence (P = 0.0004). In adolescence basal insulin secretion was significantly higher in female offspring from androgen-excess pregnancies (P = 0.045), and an exaggerated, hyperinsulinaemic response to glucose challenge (P = 0.0007) observed, whereas prenatal DES or DEX treatment had no effects upon insulin secretion. Postnatal insulin secretion correlated with beta cell numbers (P = 0.03). We conclude that the pancreas is a primary locus of androgenic stimulation during development, giving rise to postnatal offspring whose pancreas secreted excess insulin due to excess beta cells in the presence of a normal number of alpha cells. PMID:27265420

Membrane receptor-independent inhibitory effect of melatonin on androgen production in porcine theca cells.

PubMed

Wang, Heng; Pu, Yong; Luo, Lei; Li, Yunsheng; Zhang, Yunhai; Cao, Zubing

2018-06-01

Excessive secretion of androgens including androstenedione and testosterone in theca cells frequently causes female infertility in mammals. Melatonin is a potent inhibitor of androgen production in gonadal cells of several species in a membrane receptor-dependent manner. However, the function of melatonin in steroidogenesis of porcine theca cells remains unclear. Here we report that melatonin inhibits androgen biosynthesis independently of its membrane receptors in pigs. Using flow cytometry, immunofluorescence and RT-PCR we showed that the vast majority of cells isolated from the theca layer of antral follicles are indeed theca cells. Furthermore, we demonstrated that of the two of melatonin membrane receptors encoded in the porcine genome, theca cells exclusively express melatonin receptor 1B. Cell counting analysis indicated that different concentrations of melatonin did not alter the normal viability and proliferation of theca cells. Additionally, hormone radioimmunoassay and qPCR respectively showed that a high concentration of melatonin significantly repressed both androgen production and expression of steroidogenic genes involving StAR, CYP11A1, HSD3β and SET (P < 0.05), but did not impair progesterone production. Interestingly, these effects were not reversed by N-acetyl-2-benzyltryptamin, a melatonin membrane receptor antagonist. Overall, these results demonstrate that melatonin inhibits androgen production in porcine theca cells independently of its membrane receptor. Copyright © 2018 Elsevier Inc. All rights reserved.

Antivascular Effects of Neoadjuvant Androgen Deprivation for Prostate Cancer: An In Vivo Human Study Using Susceptibility and Relaxivity Dynamic MRI

DOE Office of Scientific and Technical Information (OSTI.GOV)

Alonzi, Roberto, E-mail: robertoalonzi@btinternet.com; Padhani, Anwar R.; Taylor, N. Jane

2011-07-01

Purpose: The antivascular effects of androgen deprivation have been investigated in animal models; however, there has been minimal investigation in human prostate cancer. This study tested the hypothesis that androgen deprivation causes significant reductions in human prostate tumor blood flow and the induction of hypoxia at a magnitude and in a time scale relevant to the neoadjuvant setting before radiotherapy. Methods and Materials: Twenty patients were examined, each with five multi-parameter magnetic resonance imaging scans: two scans before the commencement of androgen suppression, one scan after 1 month of hormone treatment, and two further scans after 3 months of therapy.more » Quantitative parametric maps of the prostate informing on relative blood flow (rBF), relative blood volume (rBV), vascular permeability (transfer constant [K{sup trans}]), leakage space (v{sub e}) and blood oxygenation (intrinsic relaxivity [R{sub 2}*]) were calculated. Results: Tumor blood volume and blood flow decreased by 83% and 79%, respectively, in the first month (p < 0.0001), with 74% of patients showing significant changes. The proportion of individual patients who achieved significant changes in T1 kinetic parameter values after 3 months of androgen deprivation for tumor measurements was 68% for K{sup trans} and 53% for v{sub e} By 3 months, significant increases in R{sub 2}* had occurred in prostate tumor, with a rise of 41.1% (p < 0.0001). Conclusions: Androgen deprivation induces profound vascular collapse within 1 month of starting treatment. Increased R{sub 2}* in regions of prostate cancer and a decrease in blood volume suggest a reduction in tumor oxygenation.« less

Comparison of 7α-methyl-19-nortestosterone effectiveness alone or combined with progestins on androgen receptor mediated-transactivation.

PubMed

García-Becerra, Rocío; Ordaz-Rosado, David; Noé, Gabriela; Chávez, Bertha; Cooney, Austin J; Larrea, Fernando

2012-02-01

7α-methyl-19-nortestosterone (MENT) is an androgen with potent gonadotropin inhibitory activity and prostate-sparing effects. These attributes give MENT advantages over testosterone as a male contraceptive, but, as in the case of testosterone, a partial dose-dependent suppression of spermatogenesis has been observed. Combination of testosterone or MENT with synthetic progestins improves the rate of azoospermia; however, it is unknown whether these combinations affect hormone androgenicity or exert synergistic effects via progestational or androgenic interaction. Herein, using transactivation assays, we examined the ability of MENT alone or combined with several 19-nor-derived synthetic progestins to activate androgen receptor (AR)-dependent gene transcription. In addition, the capability of 7α-methyl-estradiol (7α-methyl-E(2)), an aromatized metabolite of MENT, to transactivate gene transcription via estrogen receptor α (ERα; ESR1) or ERβ (ESR2) was also investigated. As expected, MENT induced gene transactivation through either the progesterone receptor (PGR) or the AR. MENT was as efficient as progesterone in activating PGR-mediated reporter gene expression, but it was ten times more potent than testosterone and dihydrotestoterone in activating of AR-driven gene expression. The addition of increasing concentrations of other 19-nortestosterone derivatives (norethisterone or levonorgestrel) did not affect, in a significant manner, the ability of MENT to activate AR-dependent reporter gene transcription. The same results were obtained with different cell lines. 7α-Methyl-E(2) resulted in potent estrogen activity via both ER subtypes with efficiency similar to natural E(2). These results suggest that the addition of 19-nortestosterone-derived progestins, as a hormonal adjuvant in male fertility strategies for effective spermatogenic suppression, does not display any detrimental effect that would interfere with MENT androgenic transcriptional activity.

Novel Nine-Exon AR Transcripts (Exon 1/Exon 1b/Exons 2-8) in Normal and Cancerous Breast and Prostate Cells.

PubMed

Hu, Dong Gui; McKinnon, Ross A; Hulin, Julie-Ann; Mackenzie, Peter I; Meech, Robyn

2016-12-27

Nearly 20 different transcripts of the human androgen receptor (AR) are reported with two currently listed as Refseq isoforms in the NCBI database. Isoform 1 encodes wild-type AR (type 1 AR) and isoform 2 encodes the variant AR45 (type 2 AR). Both variants contain eight exons: they share common exons 2-8 but differ in exon 1 with the canonical exon 1 in isoform 1 and the variant exon 1b in isoform 2. Splicing of exon 1 or exon 1b is reported to be mutually exclusive. In this study, we identified a novel exon 1b (1b/TAG) that contains an additional TAG trinucleotide upstream of exon 1b. Moreover, we identified AR transcripts in both normal and cancerous breast and prostate cells that contained either exon 1b or 1b/TAG spliced between the canonical exon 1 and exon 2, generating nine-exon AR transcripts that we have named isoforms 3a and 3b. The proteins encoded by these new AR variants could regulate androgen-responsive reporters in breast and prostate cancer cells under androgen-depleted conditions. Analysis of type 3 AR-GFP fusion proteins showed partial nuclear localization in PC3 cells under androgen-depleted conditions, supporting androgen-independent activation of the AR. Type 3 AR proteins inhibited androgen-induced growth of LNCaP cells. Microarray analysis identified a small set of type 3a AR target genes in LNCaP cells, including genes known to modulate growth and proliferation of prostate cancer ( PCGEM1 , PEG3 , EPHA3 , and EFNB2 ) or other types of human cancers ( TOX3 , ST8SIA4 , and SLITRK3 ), and genes that are diagnostic/prognostic biomarkers of prostate cancer ( GRINA3 , and BCHE ).

Nonsteroidal selective androgen receptor modulators enhance female sexual motivation.

PubMed

Jones, Amanda; Hwang, Dong Jin; Duke, Charles B; He, Yali; Siddam, Anjaiah; Miller, Duane D; Dalton, James T

2010-08-01

Women experience a decline in estrogen and androgen levels after natural or surgically induced menopause, effects that are associated with a loss of sexual desire and bone mineral density. Studies in our laboratories have shown the beneficial effects of selective androgen receptor modulators (SARMs) in the treatment of osteoporosis and muscle wasting in animal models. A series of S-3-(phenoxy)-2-hydroxy-2-methyl-N-(4-cyano-3-trifluoromethyl-phenyl)-propionamide analogs was synthesized to evaluate the effects of B-ring substitutions on in vitro and in vivo pharmacologic activity, especially female sexual motivation. The androgen receptor (AR) relative binding affinities ranged from 0.1 to 26.5% (relative to dihydrotestosterone) and demonstrated a range of agonist activity at 100 nM. In vivo pharmacologic activity was first assessed by using male rats. Structural modifications to the B-ring significantly affected the selectivity of the SARMs, demonstrating that single-atom substitutions can dramatically and unexpectedly influence activity in androgenic (i.e., prostate) and anabolic (i.e., muscle) tissues. (S)-N-(4-cyano-3-trifluoromethyl-phenyl)-3-(3-fluoro,4-chlorophenoxy)-2-hydroxy-2-methyl-propanamide (S-23) displayed full agonist activity in androgenic and anabolic tissues; however, the remaining SARMs were more prostate-sparing, selectively maintaining the size of the levator ani muscle in castrated rats. The partner-preference paradigm was used to evaluate the effects of SARMs on female sexual motivation. With the exception of two four-halo substituted analogs, the SARMs increased sexual motivation in ovariectomized rats, with potency and efficacy comparable with testosterone propionate. These results indicate that the AR is important in regulating female libido given the nonaromatizable nature of SARMs and it could be a superior alternative to steroidal testosterone preparations in the treatment of hypoactive sexual desire disorder.

Nonsteroidal Selective Androgen Receptor Modulators Enhance Female Sexual Motivation

PubMed Central

Jones, Amanda; Hwang, Dong Jin; Duke, Charles B.; He, Yali; Siddam, Anjaiah; Miller, Duane D.

2010-01-01

Women experience a decline in estrogen and androgen levels after natural or surgically induced menopause, effects that are associated with a loss of sexual desire and bone mineral density. Studies in our laboratories have shown the beneficial effects of selective androgen receptor modulators (SARMs) in the treatment of osteoporosis and muscle wasting in animal models. A series of S-3-(phenoxy)-2-hydroxy-2-methyl-N-(4-cyano-3-trifluoromethyl-phenyl)-propionamide analogs was synthesized to evaluate the effects of B-ring substitutions on in vitro and in vivo pharmacologic activity, especially female sexual motivation. The androgen receptor (AR) relative binding affinities ranged from 0.1 to 26.5% (relative to dihydrotestosterone) and demonstrated a range of agonist activity at 100 nM. In vivo pharmacologic activity was first assessed by using male rats. Structural modifications to the B-ring significantly affected the selectivity of the SARMs, demonstrating that single-atom substitutions can dramatically and unexpectedly influence activity in androgenic (i.e., prostate) and anabolic (i.e., muscle) tissues. (S)-N-(4-cyano-3-trifluoromethyl-phenyl)-3-(3-fluoro,4-chlorophenoxy)-2-hydroxy-2-methyl-propanamide (S-23) displayed full agonist activity in androgenic and anabolic tissues; however, the remaining SARMs were more prostate-sparing, selectively maintaining the size of the levator ani muscle in castrated rats. The partner-preference paradigm was used to evaluate the effects of SARMs on female sexual motivation. With the exception of two four-halo substituted analogs, the SARMs increased sexual motivation in ovariectomized rats, with potency and efficacy comparable with testosterone propionate. These results indicate that the AR is important in regulating female libido given the nonaromatizable nature of SARMs and it could be a superior alternative to steroidal testosterone preparations in the treatment of hypoactive sexual desire disorder. PMID:20444881

PCA3 noncoding RNA is involved in the control of prostate-cancer cell survival and modulates androgen receptor signaling

PubMed Central

2012-01-01

Background PCA3 is a non-coding RNA (ncRNA) that is highly expressed in prostate cancer (PCa) cells, but its functional role is unknown. To investigate its putative function in PCa biology, we used gene expression knockdown by small interference RNA, and also analyzed its involvement in androgen receptor (AR) signaling. Methods LNCaP and PC3 cells were used as in vitro models for these functional assays, and three different siRNA sequences were specifically designed to target PCA3 exon 4. Transfected cells were analyzed by real-time qRT-PCR and cell growth, viability, and apoptosis assays. Associations between PCA3 and the androgen-receptor (AR) signaling pathway were investigated by treating LNCaP cells with 100 nM dihydrotestosterone (DHT) and with its antagonist (flutamide), and analyzing the expression of some AR-modulated genes (TMPRSS2, NDRG1, GREB1, PSA, AR, FGF8, CdK1, CdK2 and PMEPA1). PCA3 expression levels were investigated in different cell compartments by using differential centrifugation and qRT-PCR. Results LNCaP siPCA3-transfected cells significantly inhibited cell growth and viability, and increased the proportion of cells in the sub G0/G1 phase of the cell cycle and the percentage of pyknotic nuclei, compared to those transfected with scramble siRNA (siSCr)-transfected cells. DHT-treated LNCaP cells induced a significant upregulation of PCA3 expression, which was reversed by flutamide. In siPCA3/LNCaP-transfected cells, the expression of AR target genes was downregulated compared to siSCr-transfected cells. The siPCA3 transfection also counteracted DHT stimulatory effects on the AR signaling cascade, significantly downregulating expression of the AR target gene. Analysis of PCA3 expression in different cell compartments provided evidence that the main functional roles of PCA3 occur in the nuclei and microsomal cell fractions. Conclusions Our findings suggest that the ncRNA PCA3 is involved in the control of PCa cell survival, in part through modulating AR signaling, which may raise new possibilities of using PCA3 knockdown as an additional therapeutic strategy for PCa control. PMID:23130941

Optimization and comprehensive characterization of a faithful tissue culture model of the benign and malignant human prostate.

PubMed

Maund, Sophia Lisette; Nolley, Rosalie; Peehl, Donna Mae

2014-02-01

Few preclinical models accurately depict normal human prostate tissue or primary prostate cancer (PCa). In vitro systems typically lack complex cellular interactions among structured prostatic epithelia and a stromal microenvironment, and genetic and molecular fidelity are concerns in both in vitro and in vivo models. 'Tissue slice cultures' (TSCs) provide realistic preclinical models of diverse tissues and organs, but have not been fully developed or widely utilized for prostate studies. Problems encountered include degeneration of differentiated secretory cells, basal cell hyperplasia, and poor survival of PCa. Here, we optimized, characterized, and applied a TSC model of primary human PCa and benign prostate tissue that overcomes many deficiencies of current in vitro models. Tissue cores from fresh prostatectomy specimens were precision-cut at 300 μm and incubated in a rotary culture apparatus. The ability of varied culture conditions to faithfully maintain benign and cancer cell and tissue structure and function over time was evaluated by immunohistological and biochemical assays. After optimization of the culture system, molecular and cellular responses to androgen ablation and to piperlongumine (PL), purported to specifically reduce androgen signaling in PCa, were investigated. Optimized culture conditions successfully maintained the structural and functional fidelity of both benign and PCa TSCs for 5 days. TSCs exhibited androgen dependence, appropriately undergoing ductal degeneration, reduced proliferation, and decreased prostate-specific antigen expression upon androgen ablation. Further, TSCs revealed cancer-specific reduction of androgen receptor and increased apoptosis upon treatment with PL, validating data from cell lines. We demonstrate a TSC model that authentically recapitulates the structural, cellular, and genetic characteristics of the benign and malignant human prostate, androgen dependence of the native tissue, and cancer-specific response to a potentially new therapeutic for PCa. The work described herein provides a basis for advancing the experimental utility of the TSC model.

GTG mutation in the start codon of the androgen receptor gene in a family of horses with 64,XY disorder of sex development.

PubMed

Révay, T; Villagómez, D A F; Brewer, D; Chenier, T; King, W A

2012-01-01

Genetic sex in mammals is determined by the sex chromosomal composition of the zygote. The X and Y chromosomes are responsible for numerous factors that must work in close concert for the proper development of a healthy sexual phenotype. The role of androgens in case of XY chromosomal constitution is crucial for normal male sex differentiation. The intracellular androgenic action is mediated by the androgen receptor (AR), and its impaired function leads to a myriad of syndromes with severe clinical consequences, most notably androgen insensitivity syndrome and prostate cancer. In this paper, we investigated the possibility that an alteration of the equine AR gene explains a recently described familial XY, SRY + disorder of sex development. We uncovered a transition in the first nucleotide of the AR start codon (c.1A>G). To our knowledge, this represents the first causative AR mutation described in domestic animals. It is also a rarely observed mutation in eukaryotes and is unique among the >750 entries of the human androgen receptor mutation database. In addition, we found another quiet missense mutation in exon 1 (c.322C>T). Transcription of AR was confirmed by RT-PCR amplification of several exons. Translation of the full-length AR protein from the initiating GTG start codon was confirmed by Western blot using N- and C-terminal-specific antibodies. Two smaller peptides (25 and 14 amino acids long) were identified from the middle of exon 1 and across exons 5 and 6 by mass spectrometry. Based upon our experimental data and the supporting literature, it appears that the AR is expressed as a full-length protein and in a functional form, and the observed phenotype is the result of reduced AR protein expression levels. Copyright © 2011 S. Karger AG, Basel.

Fetal, infant, adolescent and adult phenotypes of polycystic ovary syndrome in prenatally androgenized female rhesus monkeys

PubMed Central

Abbott, David H; Tarantal, Alice F; Dumesic, Daniel A

2010-01-01

Old World monkeys provide naturally-occurring and experimentally-induced phenotypes closely resembling the highly prevalent polycystic ovary syndrome (PCOS) in women. In particular, experimentally-induced fetal androgen excess in female rhesus monkeys produces a comprehensive adult PCOS-like phenotype that includes both reproductive and metabolic dysfunction found in PCOS women. Such a reliable experimental approach enables the use of the prenatally androgenized (PA) female rhesus monkey model to (1) examine fetal, infant and adolescent antecedents of adult pathophysiology, gaining valuable insight into early phenotypic expression of PCOS, and (2) to understand adult pathophysiology from a mechanistic perspective. Elevated circulating luteinizing hormone (LH) levels are the earliest indication of reproductive dysfunction in late gestation nonhuman primate fetuses and infants exposed to androgen excess during early (late first to second trimester) gestation. Such early gestation-exposed PA infants also are hyperandrogenic, with both LH hypersecretion and hyperandrogenism persisting in early gestation-exposed PA adults. Similarly, subtle metabolic abnormalities appearing in young nonhuman primate infants and adolescents precede the abdominal adiposity, hyperliplidemia, and increased incidence of type 2 diabetes that characterize early gestated-exposed PA adults. These new insights into the developmental origins of PCOS, and progression of the pathophysiology from infancy to adulthood, provide opportunities for clinical intervention to ameliorate the PCOS phenotype thus providing a preventive health care approach to PCOS-related abnormalities. For example, PCOS-like traits in PA monkeys, as in PCOS women, can improve with better insulin-glucose homeostasis, suggesting that lifestyle interventions preventing increased adiposity in adolescent daughters of PCOS mothers also may reduce their risk of acquiring many PCOS-related metabolic abnormalities in adulthood. PMID:19367587

Effects of the anti-androgen cyproterone acetate (CPA) on oocyte meiotic maturation in rainbow trout (Oncorhynchus mykiss).

PubMed

Rime, Hélène; Nguyen, Thaovi; Ombredane, Kevin; Fostier, Alexis; Bobe, Julien

2015-07-01

In the present study, we aimed at characterizing the effect of cyproterone acetate (CPA), an anti-androgenic compound, on oocyte meiotic maturation in a freshwater teleost fish species, the rainbow trout (Oncorhynchus mykiss). Fully-grown post-vitellogenic ovarian follicles were incubated in vitro with CPA, luteinizing hormone (Lh) or a combination of CPA and Lh. Incubations were also performed using a combination of Lh and testosterone (T). The occurrence of oocyte maturation (i.e., resumption of the meiotic process) was assessed by monitoring germinal vesicle breakdown (GVBD) after a 72h in vitro incubation. The effect of CPA on the production of 17,20β-dihydroxy-4-pregnen-3-one (17,20βP), the natural maturation-inducing steroid (MIS), was quantified by radioimmunoassay. Our results show that CPA dramatically inhibits Lh-induced oocyte maturation and MIS synthesis. We also observed a synergistic effect of Lh and T on oocyte maturation in highly competent oocytes (i.e., able to resume meiosis after stimulation by low doses of Lh). Our results also show that a combination of CPA and Lh inhibits phosphorylation of extracellular signal-regulated kinase (Erk), kinases that are associated with oocyte maturation in many species. As a whole, our results indicate that CPA has a potential to alter meiotic maturation in rainbow trout. Further analyses are, however, needed to determine the mechanisms by which this anti-androgen interferes with the meiotic process. Furthermore, the present study provides a framework for better understanding of the ecological consequences of exposure to anti-androgens and resulting meiotic maturation abnormalities observed in trout. Copyright © 2015 Elsevier B.V. All rights reserved.

The cortisol and androgen pathways cross talk in high temperature-induced masculinization: the 11β-hydroxysteroid dehydrogenase as a key enzyme.

PubMed

Fernandino, Juan Ignacio; Hattori, Ricardo Shohei; Kishii, Ai; Strüssmann, Carlos Augusto; Somoza, Gustavo Manuel

2012-12-01

In many ectotherm species the gonadal fate is modulated by temperature early in life [temperature-dependent sex determination (TSD)] but the transducer mechanism between temperature and gonadal differentiation is still elusive. We have recently shown that cortisol, the glucocorticoid stress-related hormone in vertebrates, is involved in the TSD process of pejerrey, Odontesthes bonariensis. Particularly, all larvae exposed to a male-producing temperature (MPT, 29 C) after hatching showed increased whole-body cortisol and 11-ketotestosterone (11-KT; the main bioactive androgen in fish) levels and developed as males. Moreover, cortisol administration at an intermediate, mixed sex-producing temperature (MixPT, 24 C) caused increases in 11-KT and in the frequency of males, suggesting a relation between this glucocorticoid and androgens during the masculinization process. In order to clarify the link between stress and masculinization, the expression of hydroxysteroid dehydrogenase (hsd)11b2, glucocorticoid receptors gr1 and gr2, and androgen receptors ar1 and ar2 was analyzed by quantitative real time PCR and in situ hybridization in larvae reared at MPT, MixPT, and female-producing temperature (FPT, 17 C) during the sex determination period. We also analyzed the effects of cortisol treatment in larvae reared at MixPT and in adult testicular explants incubated in vitro. MPT and cortisol treatment produced significant increases in hsd11b2 mRNA expression. Also, gonadal explants incubated in the presence of cortisol showed increases of 11-KT levels in the medium. Taken together these results suggest that cortisol promotes 11-KT production during high temperature-induced masculinization by modulation of hsd11b2 expression and thus drives the morphogenesis of the testes.

Differential Response to Abiraterone Acetate and Di-n-butyl Phthalate in an Androgen-Sensitive Human Fetal Testis Xenograft Bioassay

PubMed Central

Boekelheide, Kim

2014-01-01

In utero exposure to antiandrogenic xenobiotics such as di-n-butyl phthalate (DBP) has been linked to congenital defects of the male reproductive tract, including cryptorchidism and hypospadias, as well as later life effects such as testicular cancer and decreased sperm counts. Experimental evidence indicates that DBP has in utero antiandrogenic effects in the rat. However, it is unclear whether DBP has similar effects on androgen biosynthesis in human fetal testis. To address this issue, we developed a xenograft bioassay with multiple androgen-sensitive physiological endpoints, similar to the rodent Hershberger assay. Adult male athymic nude mice were castrated, and human fetal testis was xenografted into the renal subcapsular space. Hosts were treated with human chorionic gonadotropin for 4 weeks to stimulate testosterone production. During weeks 3 and 4, hosts were exposed to DBP or abiraterone acetate, a CYP17A1 inhibitor. Although abiraterone acetate (14 d, 75mg/kg/d po) dramatically reduced testosterone and the weights of androgen-sensitive host organs, DBP (14 d, 500mg/kg/d po) had no effect on androgenic endpoints. DBP did produce a near-significant trend toward increased multinucleated germ cells in the xenografts. Gene expression analysis showed that abiraterone decreased expression of genes related to transcription and cell differentiation while increasing expression of genes involved in epigenetic control of gene expression. DBP induced expression of oxidative stress response genes and altered expression of actin cytoskeleton genes. PMID:24284787

17-ABAG, a novel geldanamycin derivative, inhibits LNCaP-cell proliferation through heat shock protein 90 inhibition

PubMed Central

LIN, ZHIYUAN; PENG, RUIXIAN; LI, ZHENYU; WANG, YANG; LU, CHUNHUA; SHEN, YUEMAO; WANG, JIFENG; SHI, GUOWEI

2015-01-01

Prostate cancer is one of the most common cancer types worldwide. In 2014, there were an estimated 233,000 new cases and 29,480 mortalities in the United States. Androgen deprivation therapy, also called androgen suppression therapy, targets androgen signaling and remains the standard treatment for patients with advanced prostate cancer; however, responses to treatment are not durable and most patients advance to castrate-resistant prostate cancer. Therefore, novel therapeutic strategies to treat prostate cancer are urgently required. Heat shock protein 90 (Hsp90) is a chaperone protein that has been shown to regulate the progression of tumor cells. Numerous Hsp90 inhibitors show anti-tumor activity and several of them have entered clinical trials. Geldanamycin (GA) was identified as the first Hsp90 inhibitor, but shows hepatotoxicity at its effective concentrations, limiting its clinical use. In previous studies by our group, the GA derivative 17-ABAG was designed and synthesized. The present study showed that 17-ABAG inhibits the proliferation and induces apoptosis of LNCaP, an androgen-dependent prostate cancer cell line, in vitro through a classic apoptotic pathway. 17-ABAG also downregulated the Hsp90 client protein and inhibited androgen receptor nuclear localization in LNCaP cells. In addition, 17-ABAG suppressed the growth of LNCaP xenograft tumors without any obvious side-effects. The present study demonstrated that 17-ABAG is a promising anti-tumor agent and warrants further validation in prospective studies. PMID:26059743

Fluoxymesterone-induced gynaecomastia in a patient with childhood aplastic anaemia

PubMed Central

Lo, Tom Edward Ngo; Andal, Zillien C; Lantion-Ang, Frances Lina

2015-01-01

Gynaecomastia is a benign condition characterised by enlargement of the male breast. Drug-induced gynaecomastia merits deep consideration as it may account for as many as 25% of all cases of gynaecomastia in adults. Although the mechanism is not fully clear, some mechanisms include oestrogen-like activities, stimulation of testicular production of oestrogens, inhibition of testosterone synthesis or blockade of androgen action. Anabolic steroids, in particular when used during the pubertal stage, may cause significant irreversible gynaecomastia. We report a case of 28-year-old Filipino man with persistent gynaecomastia from fluoxymesterone used for aplastic anaemia during his prepubertal stage. Hormonal work ups for gynaecomastia all turned out normal, thus isolating the drug as the cause. The patient was unable to undergo breast reconstruction surgery due to haematological contraindications, but eventually referred to psychiatry for counselling. This case will highlight the paradoxical effect of androgenic steroid used during childhood on male breast proliferation during puberty. PMID:25948845

Inducible model for β-six-mediated site-specific recombination in mammalian cells

PubMed Central

Servert, Pilar; Garcia-Castro, Javier; Díaz, Vicente; Lucas, Daniel; Gonzalez, Manuel A.; Martínez-A, Carlos; Bernad, Antonio

2006-01-01

The prokaryotic β recombinase catalyzes site-specific recombination between two directly oriented minimal six sites in chromatin-integrated substrates. Here, we demonstrate that an enhanced green fluorescent protein (EGFP)-fused version of β recombinase (β-EGFP) is fully active, retaining most specific activity. It is used to develop a recombination-dependent activatable gene expression (RAGE) system based on the androgen receptor (AR) ligand-binding domain (LBD). Two hybrid molecules, a direct fusion of the LBD-AR to the C-terminus of β recombinase (β-AR) and a triple fusion of β-EGFP to the same ligand-binding domain (β-EGFP-AR), were engineered and their subcellular behavior, stability and catalytic activity were evaluated. Both chimeric β recombinase proteins showed in vivo inducible recombinogenic activity dependent on addition of an androgen receptor agonist, although the β-AR fusion protein demonstrated more accurate ligand-dependent translocation from cytoplasm to nucleus. PMID:16394020

Brain connectivity aberrations in anabolic-androgenic steroid users.

PubMed

Westlye, Lars T; Kaufmann, Tobias; Alnæs, Dag; Hullstein, Ingunn R; Bjørnebekk, Astrid

2017-01-01

Sustained anabolic-androgenic steroid (AAS) use has adverse behavioral consequences, including aggression, violence and impulsivity. Candidate mechanisms include disruptions of brain networks with high concentrations of androgen receptors and critically involved in emotional and cognitive regulation. Here, we tested the effects of AAS on resting-state functional brain connectivity in the largest sample of AAS-users to date. We collected resting-state functional magnetic resonance imaging (fMRI) data from 151 males engaged in heavy resistance strength training. 50 users tested positive for AAS based on the testosterone to epitestosterone (T/E) ratio and doping substances in urine. 16 previous users and 59 controls tested negative. We estimated brain network nodes and their time-series using ICA and dual regression and defined connectivity matrices as the between-node partial correlations. In line with the emotional and behavioral consequences of AAS, current users exhibited reduced functional connectivity between key nodes involved in emotional and cognitive regulation, in particular reduced connectivity between the amygdala and default-mode network (DMN) and between the dorsal attention network (DAN) and a frontal node encompassing the superior and inferior frontal gyri (SFG/IFG) and the anterior cingulate cortex (ACC), with further reductions as a function of dependency, lifetime exposure, and cycle state (on/off).

The CAG polymorphism in androgen receptor (AR) gene impacts the moral permissibility of harmful behavior in females.

PubMed

Gong, Pingyuan; Fang, Pengpeng; Yang, Xing; Ru, Wenzhao; Wang, Bei; Gao, Xiaocai; Liu, Jinting

2017-06-01

The moral permissibility of harm is strikingly varied among individuals. In light of the connection between testosterone levels and utilitarian moral judgment, this study examined to what extent a CAG polymorphism in the androgen receptor gene, a genetic polymorphism with the ability to regulate testosterone function, contributes to individual differences in moral judgment. Four hundred and thirty-nine Chinese Han participants completed permissibility ratings of harm in moral dilemmas and moral transgression scenarios. Results showed a significant association between the CAG polymorphism and moral permissibility of harm in females. Females with more copies of the S allele, which is associated with higher availability of testosterone, were more likely to judge harmful utilitarian acts and unintentionally harmful acts as permissible, while these effects were absent in males. The findings provide the first evidence for a link between the androgen receptor gene and moral judgment and highlight the role of androgens in moral foundations. Copyright © 2017 Elsevier Ltd. All rights reserved.

Practice Patterns Compared with Evidence-based Strategies for the Management of Androgen Deprivation Therapy-Induced Side Effects in Prostate Cancer Patients: Results of a European Web-based Survey.

PubMed

Bultijnck, Renée; Surcel, Cristian; Ploussard, Guillaume; Briganti, Alberto; De Visschere, Pieter; Fütterer, Jurgen; Ghadjar, Pirus; Giannarini, Gianluca; Isbarn, Hendrik; Massard, Christophe; Sooriakumaran, Prasanna; Valerio, Massimo; van den Bergh, Roderick; Ost, Piet

2016-12-01

Evidence-based recommendations are available for the management of androgen deprivation therapy (ADT)-induced side effects; however, there are no data on the implementation of the recommendations into daily practice patterns. To compare practice patterns in the management of ADT-induced side effects with evidence-based strategies. A European Web-based survey was conducted from January 16, 2015, to June 24, 2015. The 25-item questionnaire was designed with the aid of expert opinion and covered general respondent information, ADT preference per disease stage, patient communication on ADT-induced side effects, and strategies to mitigate side effects. All questions referred to patients with long-term ADT use. Reported practice patterns were compared with available evidence-based strategies. Following data collection, descriptive statistics were used for analysis. Frequency distributions were compiled and compared using a generalised chi-square test. In total, 489 eligible respondents completed the survey. Luteinising hormone-releasing hormone-agonist with or without an antiandrogen was the preferred method of ADT in different settings. Patients were well informed about loss of libido (90%), hot flushes (85%), fatigue (67%), and osteoporosis (63%). An osteoporotic and metabolic risk assessment prior to commencing ADT was done by one-quarter of physicians. The majority (85%) took preventive measures and applied at least one evidence-based strategy. Exercise was recommended by three-quarters of physicians who advocate its positive effects; however, only 25% of physicians had access to exercise programmes. Although the minimum sample size was set at 400 participants, the current survey remains susceptible to volunteer and nonresponder bias. Patients were well informed about several ADT-induced complications but uncommonly underwent an osteoporotic and metabolic risk assessment. Nevertheless, physicians partially provided evidence-based strategies for the management of the complications. Physicians often advised exercise to reduce ADT-induced side effects, but programmes were not widely available. Implementation of evidence-based strategies for androgen deprivation therapy-induced side effects in real-life practice patterns should be improved. Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Proteasomal degradation of sphingosine kinase 1 and inhibition of dihydroceramide desaturase by the sphingosine kinase inhibitors, SKi or ABC294640, induces growth arrest in androgen-independent LNCaP-AI prostate cancer cells.

PubMed

McNaughton, Melissa; Pitman, Melissa; Pitson, Stuart M; Pyne, Nigel J; Pyne, Susan

2016-03-29

Sphingosine kinases (two isoforms termed SK1 and SK2) catalyse the formation of the bioactive lipid sphingosine 1-phosphate. We demonstrate here that the SK2 inhibitor, ABC294640 (3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide) or the SK1/SK2 inhibitor, SKi (2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole)) induce the proteasomal degradation of SK1a (Mr = 42 kDa) and inhibit DNA synthesis in androgen-independent LNCaP-AI prostate cancer cells. These effects are recapitulated by the dihydroceramide desaturase (Des1) inhibitor, fenretinide. Moreover, SKi or ABC294640 reduce Des1 activity in Jurkat cells and ABC294640 induces the proteasomal degradation of Des1 (Mr = 38 kDa) in LNCaP-AI prostate cancer cells. Furthermore, SKi or ABC294640 or fenretinide increase the expression of the senescence markers, p53 and p21 in LNCaP-AI prostate cancer cells. The siRNA knockdown of SK1 or SK2 failed to increase p53 and p21 expression, but the former did reduce DNA synthesis in LNCaP-AI prostate cancer cells. Moreover, N-acetylcysteine (reactive oxygen species scavenger) blocked the SK inhibitor-induced increase in p21 and p53 expression but had no effect on the proteasomal degradation of SK1a. In addition, siRNA knockdown of Des1 increased p53 expression while a combination of Des1/SK1 siRNA increased the expression of p21. Therefore, Des1 and SK1 participate in regulating LNCaP-AI prostate cancer cell growth and this involves p53/p21-dependent and -independent pathways. Therefore, we propose targeting androgen-independent prostate cancer cells with compounds that affect Des1/SK1 to modulate both de novo and sphingolipid rheostat pathways in order to induce growth arrest.

Late-onset 3 beta-hydroxysteroid dehydrogenase deficiency with virilization induced by a large ovarian cyst.

PubMed

Heinrich, U; Eberlein-Gonska, M; Benz, G; Haack, D; Otto, H F

1993-01-01

A midpubertal girl presented with secondary amenorrhea and a rapidly progressive deepening of her voice as the only signs of virilization. Diagnostic work-up yielded an extremely elevated plasma testosterone (289 ng/dl), low estradiol (29 pg/ml) levels and a large solitary cyst of the right ovary, which was totally removed. Pathohistology was in keeping with a granulosa cyst with mild luteinization. Normalization of testosterone (to 27.3 ng/dl) and estradiol (to 62 pg/ml) and resumption of regular menses after 2 months clearly indicated an autonomous function of the cyst. A malignant tumor was unequivocally excluded. Basal and ACTH stimulated levels of adrenal androgens pointed to a late-onset 3 beta-hydroxysteroid dehydrogenase deficiency, which per se is known to induce polycystic ovarian changes, but to date has never been described to be accompanied with a large and autonomous follicular cyst.

Selective androgen receptor modulators in preclinical and clinical development.

PubMed

Narayanan, Ramesh; Mohler, Michael L; Bohl, Casey E; Miller, Duane D; Dalton, James T

2008-01-01

Androgen receptor (AR) plays a critical role in the function of several organs including primary and accessory sexual organs, skeletal muscle, and bone, making it a desirable therapeutic target. Selective androgen receptor modulators (SARMs) bind to the AR and demonstrate osteo- and myo-anabolic activity; however, unlike testosterone and other anabolic steroids, these nonsteroidal agents produce less of a growth effect on prostate and other secondary sexual organs. SARMs provide therapeutic opportunities in a variety of diseases, including muscle wasting associated with burns, cancer, or end-stage renal disease, osteoporosis, frailty, and hypogonadism. This review summarizes the current standing of research and development of SARMs, crystallography of AR with SARMs, plausible mechanisms for their action and the potential therapeutic indications for this emerging class of drugs.

Phthalate-induced testicular dysgenesis syndrome: Leydig cell influence.

PubMed

Hu, Guo-Xin; Lian, Qing-Quan; Ge, Ren-Shan; Hardy, Dianne O; Li, Xiao-Kun

2009-04-01

Phthalates, the most abundantly produced plasticizers, leach out from polyvinyl chloride plastics and disrupt androgen action. Male rats that are exposed to phthalates in utero develop symptoms characteristic of the human condition referred to as testicular dysgenesis syndrome (TDS). Environmental influences have been suspected to contribute to the increasing incidence of TDS in humans (i.e. cryptorchidism and hypospadias in newborn boys and testicular cancer and reduced sperm quality in adult males). In this review, we discuss the recent findings that prenatal exposure to phthalates affects Leydig cell function in the postnatal testis. This review also focuses on the recent progress in our understanding of how Leydig cell factors contribute to phthalate-mediated TDS.