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Sample records for androgen production function

  1. Control of adrenal androgen production.

    PubMed

    Odell, W D; Parker, L N

    The major adrenal androgens are dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulphate (DHEAS) and androstenedione (delta 4). Studies by Cutler et al in 1978 demonstrated that these androgens are detectable in blood of all domestic and laboratory animals studied, but that only 4 species show increase in one or more with sexual maturation: rabbit, dog, chimpanzee and man. Studies by Grover and Odell in 1975 show these androgens do not bind to the androgen receptor obtained from rat prostate and thus probably are androgens only by conversion to an active androgen in vivo. Thomas and Oake in 1974 showed human skin converted DHEA to testosterone. The control of adrenal androgen secretion is in part modulated by ACTH. However, other factors or hormones must exist also, for a variety of clinical observations show dissociation in adrenal androgen versus cortisol secretion. Other substances that have been said to be controllers of adrenal androgen secretion include estrogens, prolactin, growth hormone, gonadotropins and lipotropin. None of these appear to be the usual physiological modulator, although under some circumstances each may increase androgen production. Studies from our laboratory using in vivo experiments in the castrate dog and published in 1979 indicated that crude extracts of bovine pituitary contained a substance that either modified ACTH stimulation of adrenal androgen secretion, or stimulated secretion itself - Cortisol Androgen Stimulating Hormone. Parker et al in 1983 showed a 60,000 MW glycoprotein was extractable from human pituitaries, which stimulated DHA secretion by dispersed canine adrenal cells in vitro, but did not stimulate cortisol secretion. This material contained no ACTH by radioimmunoassay. In 1982 Brubaker et al reported a substance was also present in human fetal pituitaries, which stimulated DHA secretion, but did not effect cortisol. PMID:6100259

  2. Mono-2-ethylhexyl phthalate stimulates androgen production but suppresses mitochondrial function in mouse leydig cells with different steroidogenic potential.

    PubMed

    Savchuk, Iuliia; Söder, Olle; Svechnikov, Konstantin

    2015-05-01

    Numerous studies have reported on testicular toxicity of phthalates in different experimental paradigms and showed that Leydig cells (LCs) were one of the main targets of phthalate actions. Adverse effects of phthalates on LCs steroidogenesis have been attributed to their metabolites, monophthalates. This study focuses on investigation whether LCs responsiveness to monophthalates action is associated with their potential to produce androgens. We found that of 3 monophthalates investigated [ie, mono-2-ethylhexyl phthalate (MEHP), mono-n-butyl phthalate, and mono-n-benzyl phthalate] only MEHP caused biological effects on the mouse LCs function. This monophthalate stimulated basal steroidogenesis associated with upregulation of StAR protein expression with no effect on hCG-stimulated androgen production by LCs from CBA/Lac and C57BL/6j mouse genotypes were observed. Further, MEHP attenuated ATP production and increased superoxide generation by both phenotypes of mouse LCs that indicated on mitochondrial dysfunction induced by the monophthalate. All together, our data indicate that MEHP-mediated stimulation of steroidogenesis and perturbation in mitochondrial function are not associated with the capacity of the LCs to synthesize androgens. We suggest that this effect of MEHP observed in LCs of rodent origin needs to be taken into consideration in analysis of earlier start of puberty in boys and may highlight a possible influence of phthalates on reproductive health in males. PMID:25677926

  3. Functional link between bone morphogenetic proteins and insulin-like peptide 3 signaling in modulating ovarian androgen production

    PubMed Central

    Glister, Claire; Satchell, Leanne; Bathgate, Ross A. D.; Wade, John D.; Dai, Yanzhenzi; Ivell, Richard; Anand-Ivell, Ravinder; Rodgers, Raymond J.; Knight, Philip G.

    2013-01-01

    Bone morphogenetic proteins (BMPs) are firmly implicated as intra-ovarian regulators of follicle development and steroidogenesis. Here we report a microarray analysis showing that treatment of cultured bovine theca cells (TC) with BMP6 significantly (>twofold; P < 0.01) up- or down-regulated expression of 445 genes. Insulin-like peptide 3 (INSL3) was the most heavily down-regulated gene (−43-fold) with cytochrome P450, subfamily XVII (CYP17A1) and other key steroidogenic transcripts including steroidogenic acute regulatory protein (STAR), cytochrome P450 family 11, subfamily A1 (CYP11A1) and 3 beta-hydroxysteroid dehydrogenase type 1 (HSD3B1) also down-regulated. BMP6 also reduced expression of nuclear receptor subfamily 5A1 (NR5A1) known to target the promoter regions of the aforementioned genes. Real-time PCR confirmed these findings and also revealed a marked reduction in expression of INSL3 receptor, relaxin/insulin-like family peptide receptor 2 (RXFP2). Secretion of INSL3 protein and androstenedione were also suppressed suggesting a functional link between BMP and INSL3 pathways in controlling androgen synthesis. RNAi-mediated knockdown of INSL3 reduced INSL3 mRNA (75%) and protein (94%) level and elicited a 77% reduction in CYP17A1 mRNA and 83% reduction in androstenedione secretion. Knockdown of RXFP2 also reduced CYP17A1 expression (81%) and androstenedione secretion (88%). Conversely, treatment with exogenous (human) INSL3 increased androstenedione secretion ∼twofold. The CYP17A1 inhibitor abiraterone abolished androgen secretion and reduced expression of both INSL3 and RXFP2. Collectively, these findings indicate a positive autoregulatory role for INSL3 signaling in maintaining thecal androgen production, and visa versa. Moreover, BMP6-induced suppression of thecal androgen synthesis may be mediated, at least in part, by reduced INSL3-RXFP2 signaling. PMID:23530236

  4. Is androgen production in association with immune system activation potential evidence for existence of a functional adrenal/ovarian autoimmune system in women?

    PubMed Central

    2013-01-01

    Background Low functional ovarian reserve (FOR) is at all ages associated with low testosterone (T) levels. Causes are, however, unknown. We, therefore, investigate whether androgens with low FOR are associated with non-specific immune system activation. Methods 322 infertile women with low and normal FOR (controls) were assessed with a broadly based immune profile, which in previous studies has proven effective in differentiating infertile patients with and without immune system activation. Patients were either immune-positive (greater than or equal to one positive tested parameter) or immune negative (no positive test). 135 suffered from prematurely diminished FOR (POA/OPOI; < age 38), 155 from physiologic diminished FOR due to age (DOR; > age 40), and 32 were controls (< age 38 with normal age-specific FOR). Prevalence of immune-positive vs. negative was assessed in all 3 patient groups. Results Women with immune abnormalities, overall, demonstrated higher total T (TT, P = 0.004) and free T (FT, P < 0.001) levels than those without. The three clinical and two immunologic-defined patient groups demonstrated significant statistical interaction in mean TT (P = 0.008), with mean TT and FT in women with positive immune findings being significantly higher in control than in POA/OPOI and physiologic DOR patients (all 4 differences P < 0.001). No such differences between the three groups were seen in women without immune abnormalities. Conclusions In this study we used a definition of immune-positivity, which favors sensitivity over specificity, resulting in significant numbers of false-positives but likely only few false-negatives. The study allows suggesting the possibility of an immune system-derived androgen-production factor (APF), which maintains normal androgen levels but is deficient in women with low FOR and immune system inactivity. Existence of such an APF would suggest the presence of a still unknown functional adrenal autoimmune system

  5. Increase in collagen production with loss of androgen responsiveness in cultured androgen-responsive Shionogi carcinoma 115 cells.

    PubMed

    Terada, N; Wakimoto, H; Yamamoto, R; Uchida, N; Takatsuka, D; Takada, T; Taniguchi, H; Li, W; Kitamura, Y; Matsumoto, K

    1988-05-01

    The collagen production of androgen-responsive and -unresponsive Shionogi carcinoma 115 cells was investigated by culturing them in a medium with or without testosterone. Androgen-unresponsive cells were obtained by culturing a cloned androgen-responsive cell in a testosterone-free medium for 12 weeks. The collagen production of androgen-responsive cells slightly increased in the absence of testosterone, whereas testosterone did not affect the collagen production of androgen-unresponsive cells. Androgen-unresponsive cells produced 3-4 times more collagen than androgen-responsive cells. The major collagen produced by both androgen-responsive and - unresponsive cells migrated to the same position in sodium dodecylsulfate:polyacylamide gel electrophoresis. The present results indicate that the collagen production of androgen-responsive Shionogi carcinoma 115 cells increases with the loss of androgen responsiveness in culture. PMID:3169094

  6. Unveiling the crucial intermediates in androgen production.

    PubMed

    Mak, Piotr J; Gregory, Michael C; Denisov, Ilia G; Sligar, Stephen G; Kincaid, James R

    2015-12-29

    Ablation of androgen production through surgery is one strategy against prostate cancer, with the current focus placed on pharmaceutical intervention to restrict androgen synthesis selectively, an endeavor that could benefit from the enhanced understanding of enzymatic mechanisms that derives from characterization of key reaction intermediates. The multifunctional cytochrome P450 17A1 (CYP17A1) first catalyzes the typical hydroxylation of its primary substrate, pregnenolone (PREG) and then also orchestrates a remarkable C17-C20 bond cleavage (lyase) reaction, converting the 17-hydroxypregnenolone initial product to dehydroepiandrosterone, a process representing the first committed step in the biosynthesis of androgens. Now, we report the capture and structural characterization of intermediates produced during this lyase step: an initial peroxo-anion intermediate, poised for nucleophilic attack on the C20 position by a substrate-associated H-bond, and the crucial ferric peroxo-hemiacetal intermediate that precedes carbon-carbon (C-C) bond cleavage. These studies provide a rare glimpse at the actual structural determinants of a chemical transformation that carries profound physiological consequences. PMID:26668369

  7. Unveiling the crucial intermediates in androgen production

    PubMed Central

    Mak, Piotr J.; Gregory, Michael C.; Denisov, Ilia G.; Sligar, Stephen G.; Kincaid, James R.

    2015-01-01

    Ablation of androgen production through surgery is one strategy against prostate cancer, with the current focus placed on pharmaceutical intervention to restrict androgen synthesis selectively, an endeavor that could benefit from the enhanced understanding of enzymatic mechanisms that derives from characterization of key reaction intermediates. The multifunctional cytochrome P450 17A1 (CYP17A1) first catalyzes the typical hydroxylation of its primary substrate, pregnenolone (PREG) and then also orchestrates a remarkable C17–C20 bond cleavage (lyase) reaction, converting the 17-hydroxypregnenolone initial product to dehydroepiandrosterone, a process representing the first committed step in the biosynthesis of androgens. Now, we report the capture and structural characterization of intermediates produced during this lyase step: an initial peroxo-anion intermediate, poised for nucleophilic attack on the C20 position by a substrate-associated H-bond, and the crucial ferric peroxo-hemiacetal intermediate that precedes carbon–carbon (C-C) bond cleavage. These studies provide a rare glimpse at the actual structural determinants of a chemical transformation that carries profound physiological consequences. PMID:26668369

  8. In situ androgen and estrogen biosynthesis in endometrial cancer: focus on androgen actions and intratumoral production.

    PubMed

    Ito, Kiyoshi; Miki, Yasuhiro; Suzuki, Takashi; McNamara, Keely May; Sasano, Hironobu

    2016-07-01

    In situ estrogen biosynthesis is considered to play pivotal roles in the development and progression of human endometrial carcinoma. However, the biological roles of androgen have remained virtually unknown. Various epidemiological studies have revealed that elevated serum androgen levels are generally associated with an increased risk of developing endometrial carcinoma; however, studies directly examining androgens in carcinoma tissues are relatively rare and reviews summarizing this information are scarce. Therefore, we summarized recent studies on androgens in endometrial carcinoma, especially focusing androgen actions and in situ androgen biosynthesis. Among the enzymes required for local biosynthesis of androgen, 17β-hydroxysteroid dehydrogenase type 5 (conversion from androstenedione to testosterone) and 5α-reductase (reduction of testosterone to dihydrotestosterone (DHT)) are the principal enzymes involved in the formation of biologically most potent androgen, DHT. Both enzymes and androgen receptor were expressed in endometrial carcinoma tissues, and in situ production of DHT has been reported to exist in endometrial carcinoma tissues. However, testosterone is not only a precursor of DHT production, but also a precursor of estradiol synthesis, as a substrate of the aromatase enzyme. Therefore, aromatase could be another key enzyme serving as a negative regulator for in situ production of DHT by reducing amounts of the precursor. In an in vitro study, DHT was reported to exert antiproliferative effects on endometrial carcinoma cells. Intracrine mechanisms of androgens, the downstream signals of AR, which are directly related to anticancer progression, and the clinical significance of DHT-AR pathway in the patients with endometrial carcinoma have, however, not been fully elucidated. PMID:27287451

  9. 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

  10. Androgens induce sebaceous differentiation in sebocyte cells expressing a stable functional androgen receptor.

    PubMed

    Barrault, Christine; Garnier, Julien; Pedretti, Nathalie; Cordier-Dirikoc, Sevda; Ratineau, Emeline; Deguercy, Alain; Bernard, François-Xavier

    2015-08-01

    Androgens act through non-genomic and androgen receptor (AR)-dependent genomic mechanisms. AR is expressed in the sebaceous gland and the importance of androgens in the sebaceous function is well established. However, the in vitro models used to date have failed to evidence a clear genomic effect (e.g., modification of gene expression profile) of androgens on human sebocyte cells. In order to study the impact of active androgens in sebocytes, we constructed a stable human sebocyte cell line derived from SEBO662 [17] constitutively expressing a fully functional AR. In these SEBO662 AR+ cells, dihydrotestosterone (DHT) induced AR nuclear translocation and the strong modulation of a set of transcripts (RASD1, GREB1...) known to be androgen-sensitive in other androgenic cells and tissues. Moreover, we observed that DHT precociously down-regulated markers for immature follicular cells (KRT15, TNC) and for hair lineage (KRT75, FST) and up-regulated the expression of genes potentially related to sebocyte differentiation (MUC1/EMA, AQP3, FADS2). These effects were fully confirmed at the protein level. In addition, DHT-stimulated SEBO662 AR+, cultured in a low-calcium defined keratinocyte medium without serum or any complement, neosynthesize lipids, including sebum lipids, and store increased amounts of triglycerides in lipid droplets. DHT also induces morphological changes, increases cell size, and treatments over 7 days lead to a time-dependent increase in the population of apoptotic DNA-fragmented cells. Taken together, these results show for the first time that active androgens alone can engage immature sebocytes in a clear lipogenic differentiation process (Graphical abstract). These effects depend on the expression of a functional AR in these cells. This model should be of interest for revisiting the mechanisms of the sebaceous function in vitro and for the design of relevant pharmacological models for drug or compound testing. PMID:25864624

  11. Androgens.

    PubMed

    Iyer, Rakesh; Handelsman, David J

    2016-01-01

    Androgen abuse is the most potent and prevalent form of sports doping detected. It originated from the early years of the Cold War as an epidemic confined to drug cheating within elite power sports. In the decades following the end of the Cold War, it has become disseminated into an endemic based within the illicit drug subcultures serving recreational abusers seeking cosmetic body sculpting effects. Within sports, both direct androgen abuse (administration of androgens), as well as indirect androgen abuse (administration of nonandrogenic drugs to increase endogenous testosterone), is mostly readily detectable with mass spectrometry-based anti-doping urine tests. The ongoing temptation of fame and fortune and the effectiveness of androgen abuse in power sports continue to entice cheating via renewed approaches aiming to exploit androgens. These require ongoing vigilance, inventiveness in anti-doping science, and targeting coaches as well as athletes in order to build resilience against doping and maintain fairness in elite sport. The challenge of androgen abuse in the community among recreational abusers has barely been recognized and effective approaches remain to be developed. PMID:27347677

  12. Androgen receptor functions in castration-resistant prostate cancer and mechanisms of resistance to new agents targeting the androgen axis

    PubMed Central

    Yuan, X; Cai, C; Chen, S; Chen, S; Yu, Z; Balk, SP

    2016-01-01

    The metabolic functions of androgen receptor (AR) in normal prostate are circumvented in prostate cancer (PCa) to drive tumor growth, and the AR also can acquire new growth-promoting functions during PCa development and progression through genetic and epigenetic mechanisms. Androgen deprivation therapy (ADT, surgical or medical castration) is the standard treatment for metastatic PCa, but patients invariably relapse despite castrate androgen levels (castration-resistant PCa, CRPC). Early studies from many groups had shown that AR was highly expressed and transcriptionally active in CRPC, and indicated that steroids from the adrenal glands were contributing to this AR activity. More recent studies showed that CRPC cells had increased expression of enzymes mediating androgen synthesis from adrenal steroids, and could synthesize androgens de novo from cholesterol. Phase III clinical trials showing a survival advantage in CRPC for treatment with abiraterone (inhibitor of the enzyme CYP17A1 required for androgen synthesis that markedly reduces androgens and precursor steroids) and for enzalutamide (new AR antagonist) have now confirmed that AR activity driven by residual androgens makes a major contribution to CRPC, and led to the recent Food and Drug Administration approval of both agents. Unfortunately, patients treated with these agents for advanced CRPC generally relapse within a year and AR appears to be active in the relapsed tumors, but the molecular mechanisms mediating intrinsic or acquired resistance to these AR-targeted therapies remain to be defined. This review outlines AR functions that contribute to PCa development and progression, the roles of intratumoral androgen synthesis and AR structural alterations in driving AR activity in CRPC, mechanisms of action for abiraterone and enzalutamide, and possible mechanisms of resistance to these agents. PMID:23752196

  13. Androgen Receptor Structure, Function and Biology: From Bench to Bedside

    PubMed Central

    Davey, Rachel A; Grossmann, Mathis

    2016-01-01

    The actions of androgens such as testosterone and dihydrotestosterone are mediated via the androgen receptor (AR), a ligand-dependent nuclear transcription factor and member of the steroid hormone nuclear receptor family. Given its widespread expression in many cells and tissues, the AR has a diverse range of biological actions including important roles in the development and maintenance of the reproductive, musculoskeletal, cardiovascular, immune, neural and haemopoietic systems. AR signalling may also be involved in the development of tumours in the prostate, bladder, liver, kidney and lung. Androgens can exert their actions via the AR in a DNA binding-dependent manner to regulate target gene transcription, or in a non-DNA binding-dependent manner to initiate rapid, cellular events such as the phosphorylation of 2nd messenger signalling cascades. More recently, ligand-independent actions of the AR have also been identified. Given the large volume of studies relating to androgens and the AR, this review is not intended as an extensive review of all studies investigating the AR, but rather as an overview of the structure, function, signalling pathways and biology of the AR as well as its important role in clinical medicine, with emphasis on recent developments in this field. PMID:27057074

  14. 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. PMID:24742982

  15. 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

  16. Androgens and Male Sexual Function: A Review of Human Studies

    ERIC Educational Resources Information Center

    Schiavi, Raul C.; White, Daniel

    1976-01-01

    The scope of this article is a review and brief discussion of recently gathered information on androgens and sexual behavior in men. Current pharmacological research does not furnish specific evidence that administration of androgens or preprations that stimulate the secretion of endogenous androgens have beneficial effects on functional…

  17. Increased androgen levels in rats impair glucose-stimulated insulin secretion through disruption of pancreatic beta cell mitochondrial function.

    PubMed

    Wang, Hongdong; Wang, Xiaping; Zhu, Yunxia; Chen, Fang; Sun, Yujie; Han, Xiao

    2015-11-01

    Although insulin resistance is recognized to contribute to the reproductive and metabolic phenotypes of polycystic ovary syndrome (PCOS), pancreatic beta cell dysfunction plays an essential role in the progression from PCOS to the development of type 2 diabetes. However, the role of insulin secretory abnormalities in PCOS has received little attention. In addition, the precise changes in beta cells and the underlying mechanisms remain unclear. In this study, we therefore attempted to elucidate potential mechanisms involved in beta cell alterations in a rat model of PCOS. Glucose-induced insulin secretion was measured in islets isolated from DHT-treated and control rats. Oxygen consumption rate (OCR), ATP production, and mitochondrial copy number were assayed to evaluate mitochondrial function. Glucose-stimulated insulin secretion is significantly decreased in islets from DHT-treated rats. On the other hand, significant reductions are observed in the expression levels of several key genes involved in mitochondrial biogenesis and in mitochondrial OCR and ATP production in DHT-treated rat islets. Meanwhile, we found that androgens can directly impair beta cell function by inducing mitochondrial dysfunction in vitro in an androgen receptor dependent manner. For the first time, our study demonstrates that increased androgens in female rats can impair glucose-stimulated insulin secretion partly through disruption of pancreatic beta cell mitochondrial function. This work has significance for hyperandrogenic women with PCOS: excess activation of the androgen receptor by androgens may provoke beta cell dysfunction via mitochondrial dysfunction. PMID:26348137

  18. The androgen receptor mediates antiapoptotic function in myometrial cells.

    PubMed

    Li, H; Li, Y; Morin, D; Plymate, S; Lye, S; Dong, X

    2014-01-01

    During pregnancy, myometrial phenotype is programmed into three characteristic stages referred to as the early proliferative, the midterm hypertrophic, and the late contractile stage. Increased myometrial growth in the early and midterm of pregnancy involves a complex process of cell proliferation, antiapoptosis and differentiation. We have previously demonstrated that the androgen receptor (AR) is required for myometrial cell proliferation by modulating IGF-1 signaling during early pregnancy. Here, we report that AR also exerts its antiapoptotic function in human myometrial cells. Enhanced AR expression protects, whereas AR silencing sensitizes myometrial cells to both intrinsic and extrinsic apoptotic stimuli. AR agonist inhibits, whereas AR antagonist induces myometrial cells to undergo apoptotic cell death. Gene microarray analysis confirms that the central functions of AR in myometrial cells are to regulate cell cycling and apoptosis through three major gene groups involving the epidermal growth factor (EGF) signaling, RNA splicing and DNA repair processes. AR mediates its antiapoptotic function through two distinct pathways. In the receptor-dependent pathway, AR is required for the expression of several protein factors within the EGF signaling pathway. Through the PI3K/Akt pathway, AR enhances the expression of the antiapoptotic protein Mcl-1. In the ligand-dependent pathway, AR agonist triggers the activation of Src kinase, which in turn phosphorylates STAT3 to increase Mcl-1 expression. We conclude from these results that the AR signaling exerts antiapoptotic function in myometrial cells, further supporting its key role in programming of myometrial phenotype. PMID:25032861

  19. Bisphenol A affects androgen receptor function via multiple mechanisms

    PubMed Central

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

    2013-01-01

    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. PMID:23562765

  20. 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. PMID:23562765

  1. Ovarian overproduction of androgens

    MedlinePlus

    ... syndrome (PCOS) can both cause too much androgen production. Cushing's disease is a problem with the pituitary ... the adrenal glands can also cause too much production of androgens and can lead to male body ...

  2. INVESTIGATION OF TRANSFORMATION PRODUCTS FROM THE CHLORINATION OF ESTROGENIC AND ANDROGENIC COMPOUNDS- Poster

    EPA Science Inventory

    The objective of this research is to investigate chlorinated by-products of a selected number of steroids representing both estrogens and androgens. Highly controlled reaction conditions were used to ascertain product distribution. Bench-scale studies were conducted to identify...

  3. Effects of anabolic-androgens on brain reward function.

    PubMed

    Mhillaj, Emanuela; Morgese, Maria G; Tucci, Paolo; Bove, Maria; Schiavone, Stefania; Trabace, Luigia

    2015-01-01

    Androgens are mainly prescribed to treat several diseases caused by testosterone deficiency. However, athletes try to promote muscle growth by manipulating testosterone levels or assuming androgen anabolic steroids (AAS). These substances were originally synthesized to obtain anabolic effects greater than testosterone. Although AAS are rarely prescribed compared to testosterone, their off-label utilization is very wide. Furthermore, combinations of different steroids and doses generally higher than those used in therapy are common. Symptoms of the chronic use of supra-therapeutic doses of AAS include anxiety, depression, aggression, paranoia, distractibility, confusion, amnesia. Interestingly, some studies have shown that AAS elicited electroencephalographic changes similar to those observed with amphetamine abuse. The frequency of side effects is higher among AAS abusers, with psychiatric complications such as labile mood, lack of impulse control and high violence. On the other hand, AAS addiction studies are complex because data collection is very difficult due to the subjects' reticence and can be biased by many variables, including physical exercise, that alter the reward system. Moreover, it has been reported that AAS may imbalance neurotransmitter systems involved in the reward process, leading to increased sensitivity toward opioid narcotics and central stimulants. The goal of this article is to review the literature on steroid abuse and changes to the reward system in preclinical and clinical studies. PMID:26379484

  4. Effects of anabolic-androgens on brain reward function

    PubMed Central

    Mhillaj, Emanuela; Morgese, Maria G.; Tucci, Paolo; Bove, Maria; Schiavone, Stefania; Trabace, Luigia

    2015-01-01

    Androgens are mainly prescribed to treat several diseases caused by testosterone deficiency. However, athletes try to promote muscle growth by manipulating testosterone levels or assuming androgen anabolic steroids (AAS). These substances were originally synthesized to obtain anabolic effects greater than testosterone. Although AAS are rarely prescribed compared to testosterone, their off-label utilization is very wide. Furthermore, combinations of different steroids and doses generally higher than those used in therapy are common. Symptoms of the chronic use of supra-therapeutic doses of AAS include anxiety, depression, aggression, paranoia, distractibility, confusion, amnesia. Interestingly, some studies have shown that AAS elicited electroencephalographic changes similar to those observed with amphetamine abuse. The frequency of side effects is higher among AAS abusers, with psychiatric complications such as labile mood, lack of impulse control and high violence. On the other hand, AAS addiction studies are complex because data collection is very difficult due to the subjects' reticence and can be biased by many variables, including physical exercise, that alter the reward system. Moreover, it has been reported that AAS may imbalance neurotransmitter systems involved in the reward process, leading to increased sensitivity toward opioid narcotics and central stimulants. The goal of this article is to review the literature on steroid abuse and changes to the reward system in preclinical and clinical studies. PMID:26379484

  5. 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

  6. Androgens Modulate Structure and Function of the Suprachiasmatic Nucleus Brain Clock

    PubMed Central

    Karatsoreos, Ilia N.; Butler, Matthew P.; LeSauter, Joseph

    2011-01-01

    Gonadal hormones can modulate circadian rhythms in rodents and humans, and androgen receptors are highly localized within the core region of the mouse suprachiasmatic nucleus (SCN) brain clock. Although androgens are known to modulate neural plasticity in other CNS compartments, the role of androgens and their receptors on plasticity in the SCN is unexplored. In the present study, we ask whether androgens influence the structure and function of the mouse SCN by examining the effects of gonadectomy (GDX) on the structure of the SCN circuit and its responses to light, including induction of clock genes and behavioral phase shifting. We found that after GDX, glial fibrillary acidic protein increased with concomitant decreases in the expression of the synaptic proteins synaptophysin and postsynaptic density 95. We also found that GDX exerts effects on the molecular and behavioral responses to light that are phase dependent. In late night [circadian time (CT)21], GDX increased light-induced mPer1 but not mPer2 expression compared with intact (INT) controls. In contrast, in early night (CT13.5), GDX decreased light induced mPer2 but had no effect on mPer1. At CT13.5, GDX animals also showed larger phase delays than did INT. Treatment of GDX animals with the nonaromatizable androgen dihydrotestosterone restored glial fibrillary acidic protein, postsynaptic density 95, and synaptophysin in the SCN and reinstated the INT pattern of molecular and behavioral responses to light. Together, the results reveal a role for androgens in regulating circuitry in the mouse SCN, with functional consequences for clock gene expression and behavioral responses to photic phase resetting stimuli. PMID:21363939

  7. Improved effect of Pycnogenol on impaired spatial memory function in partial androgen deficiency rat model.

    PubMed

    Hasegawa, Noboru; Mochizuki, Miyako

    2009-06-01

    The improved effect of Pycnogenol on impaired spatial memory function was studied in orchidectomized rats. Endogenous testosterone levels were decreased by approximately one-half for 3 months after castration. In the radial arm maze, castration significantly impaired working and reference memory function without lowering motor function. Pycnogenol increased the NGF content in the hippocampus and cortex, and improved the spatial memory impairment. These observations confirmed that diagnostic accuracy can be improved by Pycnogenol in androgen-deficient rats. PMID:19142987

  8. Adrenal Androgen Production in Catarrhine Primates and the Evolution of Adrenarche

    PubMed Central

    Bernstein, Robin M.; Sterner, Kirstin N.; Wildman, Derek E.

    2015-01-01

    Adrenarche is a developmental event involving differentiation of the adrenal gland and production of adrenal androgens, and has been hypothesized to play a role in the extension of the preadolescent phase of human ontogeny. It remains unclear whether any nonhuman primate species shows a similar suite of endocrine, biochemical, and morphological changes as are encompassed by human adrenarche. Here, we report serum concentrations of the adrenal androgens dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) measured in 698 cross-sectional and mixed longitudinal serum samples from catarrhine primates ranging from 0.6 to 47 years of age. DHEAS in Pan is most similar to that of humans in both age-related pattern and absolute levels, and a transient early increase appears to be present in Gorilla. DHEA levels are highest in Cercocebus, Cercopithecus, and Macaca. We also tested for evidence of adaptive evolution in six genes that code for proteins involved in DHEA/S synthesis. Our genetic analyses demonstrate the protein-coding regions of these genes are highly conserved among sampled primates. We describe a tandem gene duplication event probably mediated by a retro-transposon that resulted in two 3-β-hydroxysteroid dehydrogenase/Delta 5-Delta 4 genes (HSD3B1 and HSD3B2) with tissue specific functions in catarrhines. In humans, HSD3B2 is expressed primarily in the adrenals, ovary, and testis, while HSD3B1 is expressed in the placenta. Taken together, our findings suggest that while adrenarche has been suggested to be unique to hominoids, the evolutionary roots for this developmental stage are more ancient. PMID:22271526

  9. Context-dependent effects of yolk androgens on nestling growth and immune function in a multibrooded passerine.

    PubMed

    Muriel, J; Salmón, P; Nunez-Buiza, A; de Salas, F; Pérez-Rodríguez, L; Puerta, M; Gil, D

    2015-08-01

    Female birds may adjust their offspring phenotype to the specific requirements of the environment by differential allocation of physiologically active substances into yolks, such as androgens. Yolk androgens have been shown to accelerate embryonic development, growth rate and competitive ability of nestlings, but they can also entail immunological costs. The balance between costs and benefits of androgen allocation is expected to depend on nestling environment. We tested this hypothesis in a multibrooded passerine, the spotless starling, Sturnus unicolor. We experimentally manipulated yolk androgen levels using a between-brood design and evaluated its effects on nestling development, survival and immune function. Both in first and replacement broods, the embryonic development period was shorter for androgen-treated chicks than controls, but there were no differences in second broods. In replacement broods, androgen-treated chicks were heavier and larger than those hatched from control eggs, but this effect was not observed in the other breeding attempts. Androgen exposure reduced survival with respect to controls only in second broods. Regarding immune function, we detected nonsignificant trends for androgen treatment to activate two important components of innate and adaptive immunity (IL-6 and Ig-A levels, respectively). Similarly, androgen-treated chicks showed greater lymphocyte proliferation than controls in the first brood and an opposite trend in the second brood. Our results indicate that yolk androgen effects on nestling development and immunity depend on the environmental conditions of each breeding attempt. Variation in maternal androgen allocation to eggs could be explained as the result of context-dependent optimal strategies to maximize offspring fitness. PMID:26079258

  10. Ca(2+)-Calmodulin regulation of testicular androgen production in Mozambique tilapia (Oreochromis mossambicus).

    PubMed

    Martins, Rute S T; Fuentes, Juan; Almeida, Olinda; Power, Deborah M; Canario, Adelino V M

    2009-06-01

    The Ca(2+)-Calmodulin (CaM) signaling pathway has previously been shown to be involved in the regulation of teleost fish ovarian steroidogenesis. However, a putative role of CaM in testicular steroidogenesis and potential targets has not been examined. To examine whether basal steroidogenesis is modulated by Ca(2+) and CaM levels in the testis of Mozambique tilapia (Oreochromis mossambicus) we have incubated testicular fragments in vitro under different conditions and analyzed steroid output. Calcium-free medium with or without EGTA did not affect testicular basal 11-ketotestosterone (11-KT) and testosterone (T) secretion. However, addition of 80microM the CaM inhibitor W7 significantly reduced basal 11-KT, T and androstenedione secretion. Interestingly, the decreased androgen production by 80microM of W7 was accompanied by increased 11-desoxicortisol output and by the activation of cortisol synthesis in the testis, the latter undetected in untreated tissues. However, production of 17,20alpha-dihydroxy-4-pregnen-3-one was unaltered by W7. This suggests that C17,20 desmolase, 21-hydroxylase and possibly 11beta-hydroxysteroid dehydrogenase are targets for CaM. In addition, androgen production was also found to be regulated by the level of cAMP since incubations with forskolin (FK) significantly increased 11-KT and T output. A cross-talk between the cAMP and Ca(2+)-CaM signaling pathways was detected since W7 administration also decreased FK stimulated androgen production. Altogether, these data show that both basal and cAMP stimulated androgen levels were modulated by intracellular Ca(2+)-dependent CaM and that possibly Ca(2+)-CaM determines the shift in steroidogenesis from C21 steroids to androgens. PMID:19341736

  11. Establishment of a novel immortalized human prostatic epithelial cell line stably expressing androgen receptor and its application for the functional screening of androgen receptor modulators

    SciTech Connect

    Yu, Shan; Wang, Ming-Wei; Yao, Xiaoqiang; Chan, F.L.

    2009-05-15

    In this study, we developed a human prostatic epithelial cell line BPH-1-AR stably expressing AR by lentiviral transduction. Characterization by immunoblot and RT-PCR showed that AR was stably expressed in all representative BPH-1-AR clones. Androgen treatment induced a secretory differentiation phenotype in BPH-1-AR cells but suppressed their cell proliferation. Treatments with AR agonists induced transactivation of a transfected PSA-gene promoter reporter in BPH-1-AR cells, whereas this transactivation was suppressed by an AR antagonist flutamide, indicating that the transduced AR in BPH-1-AR cells was functional. Finally, we utilized BPH-1-AR cells to evaluate the androgenic activities and growth effects of five newly developed non-steroidal compounds. Results showed that these compounds showed androgenic activities and growth-inhibitory effects on BPH-1-AR cells. Our results showed that BPH-1-AR cell line would be a valuable in vitro model for the study of androgen-regulated processes in prostatic epithelial cells and identification of compounds with AR-modulating activities.

  12. A novel approach to breast cancer prevention: reducing excessive ovarian androgen production in elderly women.

    PubMed

    Secreto, Giorgio; Sieri, Sabina; Agnoli, Claudia; Grioni, Sara; Muti, Paola; Zumoff, Barnett; Sant, Milena; Meneghini, Elisabetta; Krogh, Vittorio

    2016-08-01

    Minimizing endogenous estrogen production and activity in women at high risk for breast cancer is a prominent approach to prevention of the disease. A number of clinical trials have shown that the administration of selective-estrogen receptor modulators or aromatase inhibitors significantly reduces the incidence of breast cancer in healthy women. Unfortunately, these drugs often produce adverse effects on the quality of life and are, therefore, poorly accepted by many women, even those who are at high risk for breast cancer. We propose a novel alternative approach to decreasing estrogen production: suppression of ovarian synthesis of the androgen precursors of estrogens by administration of long-acting gonadotropin-releasing hormone analogs to women with ovarian stromal hyperplasia. The specific target population would be elderly postmenopausal women, at increased risk of breast cancer, and with high blood levels of testosterone, marker of ovarian hyperandrogenemia, and recognized factor of risk for breast cancer. Testosterone levels are measured at baseline to identify women at risk and during the follow-up to evaluate the effectiveness of therapy. The postmenopausal ovary is an important source of excessive androgen production which originates from the ovarian interstitial cell hyperplasia frequently present in breast cancer patients. We propose to counter the source of androgen excess in women with ovarian stromal hyperplasia, thus reducing the substrate for estrogen formation without completely inhibiting estrogen synthesis. Available evidence indicates that gonadotropin-releasing hormone analogs can be safely used for breast cancer prevention in postmenopausal women. PMID:27393623

  13. Protein kinase D1 (PKD1) influences androgen receptor (AR) function in prostate cancer cells

    SciTech Connect

    Mak, Paul; Jaggi, Meena; Chauhan, Subhash C.; Balaji, K.C.

    2008-09-05

    Protein kinase D1 (PKD1), founding member of PKD protein family, is down-regulated in advanced prostate cancer (PCa). We demonstrate that PKD1 and androgen receptor (AR) are present as a protein complex in PCa cells. PKD1 is associated with a transcriptional complex which contains AR and promoter sequence of the Prostate Specific Antigen (PSA) gene. Ectopic expression of wild type PKD1 and the kinase dead mutant PKD1 (K628W) attenuated the ligand-dependent transcriptional activation of AR in prostate cancer cells and yeast cells indicating that PKD1 can affect AR transcription activity, whereas knocking down PKD1 enhanced the ligand-dependent transcriptional activation of AR. Co-expression of kinase dead mutant with AR significantly inhibited androgen-mediated cell proliferation in both LNCaP and DU145 PC cells. Our data demonstrate for the first time that PKD1 can influence AR function in PCa cells.

  14. Androgen Modulates Functions of Endothelial Progenitor Cells through Activated Egr1 Signaling

    PubMed Central

    Ye, Yizhou; Li, Xizhe; Zhang, You; Shen, Zhenya; Yang, Junjie

    2016-01-01

    Researches show that androgens have important effects on migration of endothelial cells and endothelial protection in coronary heart disease. Endothelial progenitor cells (EPCs) as a progenitor cell type that can differentiate into endothelial cells, have a critical role in angiogenesis and endothelial protection. The relationship between androgen and the functions of EPCs has animated much interest and controversy. In this study, we investigated the angiogenic and migratory functions of EPCs after treatment by dihydrotestosterone (DHT) and the molecular mechanisms as well. We found that DHT treatment enhanced the incorporation of EPCs into tubular structures formed by HUVECs and the migratory activity of EPCs in the transwell assay dose dependently. Moreover, microarray analysis was performed to explore how DHT changes the gene expression profiles of EPCs. We found 346 differentially expressed genes in androgen-treated EPCs. Angiogenesis-related genes like Egr-1, Vcan, Efnb2, and Cdk2ap1 were identified to be regulated upon DHT treatment. Furthermore, the enhanced angiogenic and migratory abilities of EPCs after DHT treatment were inhibited by Egr1-siRNA transfection. In conclusion, our findings suggest that DHT markedly enhances the vessel forming ability and migration capacity of EPCs. Egr1 signaling may be a possible pathway in this process. PMID:26697079

  15. Fetal programming of adult Leydig cell function by androgenic effects on stem/progenitor cells

    PubMed Central

    Kilcoyne, Karen R.; Smith, Lee B.; Atanassova, Nina; Macpherson, Sheila; McKinnell, Chris; van den Driesche, Sander; Jobling, Matthew S.; Chambers, Thomas J. G.; De Gendt, Karel; Verhoeven, Guido; O’Hara, Laura; Platts, Sophie; Renato de Franca, Luiz; Lara, Nathália L. M.; Anderson, Richard A.; Sharpe, Richard M.

    2014-01-01

    Fetal growth plays a role in programming of adult cardiometabolic disorders, which in men, are associated with lowered testosterone levels. Fetal growth and fetal androgen exposure can also predetermine testosterone levels in men, although how is unknown, because the adult Leydig cells (ALCs) that produce testosterone do not differentiate until puberty. To explain this conundrum, we hypothesized that stem cells for ALCs must be present in the fetal testis and might be susceptible to programming by fetal androgen exposure during masculinization. To address this hypothesis, we used ALC ablation/regeneration to identify that, in rats, ALCs derive from stem/progenitor cells that express chicken ovalbumin upstream promoter transcription factor II. These stem cells are abundant in the fetal testis of humans and rodents, and lineage tracing in mice shows that they develop into ALCs. The stem cells also express androgen receptors (ARs). Reduction in fetal androgen action through AR KO in mice or dibutyl phthalate (DBP) -induced reduction in intratesticular testosterone in rats reduced ALC stem cell number by ∼40% at birth to adulthood and induced compensated ALC failure (low/normal testosterone and elevated luteinizing hormone). In DBP-exposed males, this failure was probably explained by reduced testicular steroidogenic acute regulatory protein expression, which is associated with increased histone methylation (H3K27me3) in the proximal promoter. Accordingly, ALCs and ALC stem cells immunoexpressed increased H3K27me3, a change that was also evident in ALC stem cells in fetal testes. These studies highlight how a key component of male reproductive development can fundamentally reprogram adult hormone production (through an epigenetic change), which might affect lifetime disease risk. PMID:24753613

  16. Perturbations of hypothalamic-pituitary-gonadal (HPG) axis and adrenal androgen (AA) functions in rheumatoid arthritis.

    PubMed

    Masi, A T; Da Silva, J A; Cutolo, M

    1996-05-01

    The available evidence reviewed does not allow definitive response to the question of a primary versus secondary role of sex hormone perturbations in RA. However, this conclusion should not be discouraging in view of the relatively recent focus upon this facet of the physiopathogenesis of RA and the enormous complexities of sex hormone biology and this disease. Specifically, data on the incidence of RA as well as life cycle changes in serum androgenic-anabolic (A-A) and sex hormone levels suggest important risk correlations. Furthermore, HLA-susceptibility markers for RA, gender, menopause and older age are all factors which significantly relate to the risk of developing RA and each has been shown to associate with sex hormone status. Whether or not HPG-AA hormonal status may modulate RA risk (or its course) primarily and independently or merely be predictive markers of other biological mechanisms was critically considered and requires further study. Sex hormone influences on cellular and humoral immunological reactivity and vascular pathogenetic mechanisms in RA were summarized. Androgens generally suppress immunoreactivity and cartilage responses to inflammation-mediated injury processes and may enhance synovial macrophage-like lining cell apoptosis. Oestrogens generally enhance immunoreactivity, offer some protection to inflammation-mediated cartilage damage (but less than androgens) and may inhibit apoptosis in certain in vitro cell models. Scant information is available on the balance of sex hormones (and glucocorticoids) in RA or its presumed pathogenetic mechanisms. Data were reviewed which support the concept of a spectrum of androgenicity in the normal population, particularly among women. A simplified schema of trophic and tropic steroidogenic mechanisms was proposed which could influence androgenic-anabolic (A-A) status and might relate to RA. Serum concentrations of DHAS (mumol/l), T (nmol/l) and O2 (pmol/l) span several orders of magnitude in normal

  17. Activin B is produced early in antral follicular development and suppresses thecal androgen production

    PubMed Central

    Young, J M; Henderson, S; Souza, C; Ludlow, H; Groome, N; McNeilly, A S

    2012-01-01

    Little is known about the role of activin B during folliculogenesis. This study investigated the expression levels of activin/inhibin subunits (βA, βB, and α), steroid enzyme, and gonadotrophin receptors in theca (TC) and granulosa cells (GC) by QPCR and activin A and B and inhibin A protein levels in follicular fluid (FF) of developing sheep follicles during estrus and anestrus. The effect of activin B on androgen production from primary TC cultures in vitro was also assessed. During folliculogenesis, in anestrus and estrus, FF activin B concentrations and thecal and GC activin βB mRNA levels decreased as follicle diameter increased from 1–3 to >6 mm regardless of estrogenic status. Estrogenic preovulatory follicles had reduced concentrations of FF activins B and A, and TC and GCs expressed higher levels of activin βA mRNA at 3–4 mm, and TCs more inhibin α mRNA at >4 mm stages of development compared with nonestrogenic follicles. Activin B decreased androstenedione production from primary TCs in vitro, an effect blocked by inhibin A. Thus, sheep follicles 1–3 mm in diameter contained high FF levels of activin B, which decreased as the follicle size increased, and, like activin A, suppressed thecal androgen production in vitro, an effect blocked by inhibin. Furthermore, the theca of large estrogenic follicles expressed high levels of inhibin α and activin βA mRNA suggesting local thecal derived inhibin A production. This would inhibit the negative effects of thecal activins B and A ensuring maximum androgen production for enhanced estradiol production by the preovulatory follicle(s). PMID:22450673

  18. Identification of the functional domains of ANT-1, a novel coactivator of the androgen receptor

    SciTech Connect

    Fan Shuli; Goto, Kiminobu; Chen Guangchun; Morinaga, Hidetaka; Nomura, Masatoshi; Okabe, Taijiro; Nawata, Hajime; Yanase, Toshihiko . E-mail: yanase@intmed3.med.kyushu-u.ac.jp

    2006-03-03

    Previously, we identified a transcriptional coactivator for the activation function-1 (AF-1) domain of the human androgen receptor (AR) and designated it androgen receptor N-terminal domain transactivating protein-1 (ANT-1). This coactivator, which contains multiple tetratricopeptide repeat (TPR) motifs from amino acid (aa) 294, is identical to a component of U5 small nuclear ribonucleoprotein particles and binds specifically to the AR or glucocorticoid receptor. Here, we identified four distinct functional domains. The AR-AF-1-binding domain, which bound to either aa 180-360 or 360-532 in AR-AF-1, clearly overlapped with TAU-1 and TAU-5. This domain and the subnuclear speckle formation domain in ANT-1 were assigned within the TPR motifs, while the transactivating and nuclear localization signal domains resided within the N-terminal sequence. The existence of these functional domains may further support the idea that ANT-1 can function as an AR-AF-1-specific coactivator while mediating a transcription-splicing coupling.

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

    PubMed

    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

  20. 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

  1. Androgen Receptor Coactivator ARID4B Is Required for the Function of Sertoli Cells in Spermatogenesis.

    PubMed

    Wu, Ray-Chang; Zeng, Yang; Pan, I-Wen; Wu, Mei-Yi

    2015-09-01

    Defects in spermatogenesis, a process that produces spermatozoa inside seminiferous tubules of the testis, result in male infertility. Spermatogenic progression is highly dependent on a microenvironment provided by Sertoli cells, the only somatic cells and epithelium of seminiferous tubules. However, genes that regulate such an important activity of Sertoli cells are poorly understood. Here, we found that AT-rich interactive domain 4B (ARID4B), is essential for the function of Sertoli cells to regulate spermatogenesis. Specifically, we generated Sertoli cell-specific Arid4b knockout (Arid4bSCKO) mice, and showed that the Arid4bSCKO male mice were completely infertile with impaired testis development and significantly reduced testis size. Importantly, severe structural defects accompanied by loss of germ cells and Sertoli cell-only phenotype were found in many seminiferous tubules of the Arid4bSCKO testes. In addition, maturation of Sertoli cells was significantly delayed in the Arid4bSCKO mice, associated with delayed onset of spermatogenesis. Spermatogenic progression was also defective, showing an arrest at the round spermatid stage in the Arid4bSCKO testes. Interestingly, we showed that ARID4B functions as a "coactivator" of androgen receptor and is required for optimal transcriptional activation of reproductive homeobox 5, an androgen receptor target gene specifically expressed in Sertoli cells and critical for spermatogenesis. Together, our study identified ARID4B to be a key regulator of Sertoli cell function important for male germ cell development. PMID:26258622

  2. Granulosa Cell-Specific Androgen Receptors Are Critical Regulators of Ovarian Development and Function

    PubMed Central

    Sen, Aritro; Hammes, Stephen R.

    2010-01-01

    The physiological significance of androgens in female reproduction was unclear until female mice with global knockout of androgen receptor (AR) expression were found to have reduced fertility with abnormal ovarian function. However, because ARs are expressed in a myriad of reproductive tissues, including the hypothalamus, pituitary, and various ovarian cells, the role of tissue-specific ARs in regulating female fertility remained unknown. To examine the importance of ovarian ARs in female reproduction, we generated granulosa cell (GC)- and oocyte-specific AR-knockout (ARKO) mice by crossing AR-flox mice with MisRIIcre (GC-specific) or growth differentiation factor growth differentiation factor-9cre (oocyte-specific) mice. Relative to heterozygous and wild-type mice, GC-specific ARKO mice had premature ovarian failure and were subfertile, with longer estrous cycles and fewer ovulated oocytes. In addition, ovaries from GC-specific knockout mice contained more preantral and atretic follicles, with fewer antral follicles and corpus lutea. Finally, in vitro growth of follicles from GC-specific AR-null mice was slower than follicles from wild-type animals. In contrast to GC-specific AR-null mice, fertility, estrous cycles, and ovarian morphology of oocyte-specific ARKO mice were normal, although androgens no longer promoted oocyte maturation in these animals. Together, our data indicate that nearly all reproductive phenotypes observed in global ARKO mice can be explained by the lack of AR expression in GCs. These GC-specific ARs appear to promote preantral follicle growth and prevent follicular atresia; thus they are essential for normal follicular development and fertility. PMID:20501640

  3. Oestradiol metabolism and androgen receptor genotypes are associated with right ventricular function

    PubMed Central

    Ventetuolo, Corey E.; Mitra, Nandita; Wan, Fei; Manichaikul, Ani; Barr, R. Graham; Johnson, Craig; Bluemke, David A.; Lima, Joao A.C.; Tandri, Hari; Ouyang, Pamela; Kawut, Steven M.

    2016-01-01

    Sex hormones are linked to right ventricular (RV) function, but the relationship between genetic variation in these pathways and RV function is unknown. We performed a cross-sectional study of 2761 genotyped adults without cardiovascular disease. The relationships between RV measures and single nucleotide polymorphisms (SNPs) in 10 candidate genes were assessed. Urinary oestradiol (E2) metabolites produced by cytochrome P4501B1 (CYP1B1) and serum testosterone were measured in women and men respectively. In African-American (AA) women, the CYP1B1 SNP rs162561 was associated with RV ejection fraction (RVEF), such that each copy of the A allele was associated with a 2.0% increase in RVEF. Haplotype analysis revealed associations with RVEF in AA (global p<7.2×10−6) and white (global p=0.05) women. In white subjects, higher E2 metabolite levels were associated with significantly higher RVEF. In men, androgen receptors SNPs (rs1337080; rs5918764) were significantly associated with all RV measures and modified the relationship between testosterone and RVEF. Genetic variation in E2 metabolism and androgen signalling was associated with RV morphology in a sex-specific manner. The CYP1B1 SNP identified is in tight linkage disequilibrium with SNPs associated with pulmonary hypertension and oncogenesis, suggesting these pathways may underpin sexual dimorphism in RV failure. PMID:26647441

  4. Oestradiol metabolism and androgen receptor genotypes are associated with right ventricular function.

    PubMed

    Ventetuolo, Corey E; Mitra, Nandita; Wan, Fei; Manichaikul, Ani; Barr, R Graham; Johnson, Craig; Bluemke, David A; Lima, Joao A C; Tandri, Hari; Ouyang, Pamela; Kawut, Steven M

    2016-02-01

    Sex hormones are linked to right ventricular (RV) function, but the relationship between genetic variation in these pathways and RV function is unknown.We performed a cross-sectional study of 2761 genotyped adults without cardiovascular disease. The relationships between RV measures and single nucleotide polymorphisms (SNPs) in 10 candidate genes were assessed. Urinary oestradiol (E2) metabolites produced by cytochrome P4501B1 (CYP1B1) and serum testosterone were measured in women and men respectively.In African-American (AA) women, the CYP1B1 SNP rs162561 was associated with RV ejection fraction (RVEF), such that each copy of the A allele was associated with a 2.0% increase in RVEF. Haplotype analysis revealed associations with RVEF in AA (global p<7.2×10(-6)) and white (global p=0.05) women. In white subjects, higher E2 metabolite levels were associated with significantly higher RVEF. In men, androgen receptors SNPs (rs1337080; rs5918764) were significantly associated with all RV measures and modified the relationship between testosterone and RVEF.Genetic variation in E2 metabolism and androgen signalling was associated with RV morphology in a sex-specific manner. The CYP1B1 SNP identified is in tight linkage disequilibrium with SNPs associated with pulmonary hypertension and oncogenesis, suggesting these pathways may underpin sexual dimorphism in RV failure. PMID:26647441

  5. PYK2 via S6K1 regulates the function of androgen receptors and the growth of prostate cancer cells.

    PubMed

    Hsiao, Yu-Hsuan; Huang, Yu-Ting; Hung, Chia-Yu; Kuo, Tzu-Chien; Luo, Fuh-Jinn; Yuan, Ta-Chun

    2016-08-01

    Androgen receptor (AR) is a steroid hormone receptor that functions as a transcription factor for regulating cell growth and survival. Aberrant AR function becomes a risk factor for promoting the progression of prostate cancer (PCa). In this study, we examined the roles of proline-rich tyrosine kinase 2 (PYK2) and ribosomal S6 kinase 1 (S6K1) in regulating AR expression and activity and growth properties in PCa cells. Compared with normal prostate tissues, PCa tumors exhibited high levels of PYK2 and S6K1 expression. Furthermore, the expression levels of PYK2 and S6K1 were significantly correlated with nuclear AR expression in PCa tissues. We further found the association between PYK2, S6K1, and AR in their protein expression and phosphorylation levels among normal prostate PZ-HPV-7 cells and prostate cancer LNCaP and 22Rv1 cells. Overexpression of the wild-type PYK2 in PZ-HPV-7 and LNCaP cells promoted AR and S6K1 expression and phosphorylation as well as enhanced cell growth. In contrast, expression of the mutated PYK2 or knockdown of PYK2 expression in LNCaP or 22Rv1 cells caused reduced expression or phosphorylation of AR and S6K1 as well as retarded cell growth. Under an androgen-deprived condition, PYK2-promoted AR expression and phosphorylation and PSA production in LNCaP cells can be abolished by knocking down S6K1 expression. In summary, our data suggested that PYK2 via S6K1 activation modulated AR function and growth properties in PCa cells. Thus, PYK2 and S6K1 may potentially serve as therapeutic targets for PCa treatment. PMID:27492635

  6. Regulation of Sclerostin Production in Human Male Osteocytes by Androgens: Experimental and Clinical Evidence.

    PubMed

    Di Nisio, Andrea; De Toni, Luca; Speltra, Elena; Rocca, Maria Santa; Taglialavoro, Giuseppe; Ferlin, Alberto; Foresta, Carlo

    2015-12-01

    In this study we aimed to elucidate a possible role of T in the regulation of sclerostin, a glycoprotein secreted by osteocytes known to regulate bone mass. To this end, we evaluated the effect of T stimulation on sclerostin production and gene expression in human cultured osteocytes. In addition, we evaluated serum sclerostin levels in a cohort of 20 hypogonadal male patients, compared with 20 age-matched eugonadal controls. Stimulation with DHT decreased sclerostin expression in cultured osteocytes in a time- and dose-dependent manner. Confirming a direct androgen receptor-mediated effect on sclerostin production, flutamide coincubation and silencing of androgen receptor gene in osteocytes abolished the DHT effects. In addition, hypogonadal patients showed higher serum sclerostin levels with respect to controls (145.87 ± 50.83 pg/mL vs 84.02 ± 32.15 pg/mL; P < .001) and in both probands and controls, serum T levels were negatively correlated with sclerostin (R = -0.664, P = 0.007, and R = -0.447, P = .045, respectively). Finally, multiple stepwise regression analysis showed that T represented the only independent predictor of sclerostin levels. In conclusion, by showing a direct correlation between T and sclerostin, both in vivo and in vitro, this study adds further support to the emerging clinical and experimental studies focusing on sclerostin as a therapeutic target for osteoporosis treatment. PMID:26393301

  7. Social modulation of androgen levels in male teleost fish.

    PubMed

    Oliveira, Rui F; Hirschenhauser, Katharina; Carneiro, Luis A; Canario, Adelino V M

    2002-05-01

    Androgens are classically thought of as the sex steroids controlling male reproduction. However, in recent years evidence has accumulated showing that androgens can also be affected by the interactions between conspecifics, suggesting reciprocal interactions between androgens and behaviour. These results have been interpreted as an adaptation for individuals to adjust their agonistic motivation and to cope with changes in their social environment. Thus, male-male interactions would stimulate the production of androgens, and the levels of androgens would be a function of the stability of its social environment ['challenge hypothesis', Gen. Comp. Endocrinol. 56 (1984) 417]. Here the available data on social modulation of androgen levels in male teleosts are reviewed and some predictions of the challenge hypothesis are addressed using teleosts as a study model. We investigate the causal link between social status, territoriality and elevated androgen levels and the available evidence suggests that the social environment indeed modulates the endocrine axis of teleosts. The association between higher androgen levels and social rank emerges mainly in periods of social instability. As reported in the avian literature, in teleosts the trade-off between androgens and parental care is indicated by the fact that during the parental phase breeding males decreased their androgen levels. A comparison of androgen responsiveness between teleost species with different mating and parenting systems also reveals that parenting explains the variation observed in androgen responsiveness to a higher degree than the mating strategy. Finally, the adaptive value of social modulation of androgens and some of its evolutionary consequences are discussed. PMID:11997222

  8. 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,...

  9. Cellular microenvironment dictates androgen production by murine fetal Leydig cells in primary culture.

    PubMed

    Carney, Colleen M; Muszynski, Jessica L; Strotman, Lindsay N; Lewis, Samantha R; O'Connell, Rachel L; Beebe, David J; Theberge, Ashleigh B; Jorgensen, Joan S

    2014-10-01

    Despite the fact that fetal Leydig cells are recognized as the primary source of androgens in male embryos, the mechanisms by which steroidogenesis occurs within the developing testis remain unclear. A genetic approach was used to visualize and isolate fetal Leydig cells from remaining cells within developing mouse testes. Cyp11a1-Cre mice were bred to mT/mG dual reporter mice to target membrane-tagged enhanced green fluorescent protein (GFP) within steroidogenic cells, whereas other cells expressed membrane-tagged tandem-dimer tomato red. Fetal Leydig cell identity was validated using double-labeled immunohistochemistry against GFP and the steroidogenic enzyme 3beta-HSD, and cells were successfully isolated as indicated by qPCR results from sorted cell populations. Because fetal Leydig cells must collaborate with neighboring cells to synthesize testosterone, we hypothesized that the fetal Leydig cell microenvironment defined their capacity for androgen production. Microfluidic culture devices were used to measure androstenedione and testosterone production of fetal Leydig cells that were cultured in cell-cell contact within a mixed population, were isolated but remained in medium contact via compartmentalized co-culture with other testicular cells, or were isolated and cultured alone. Results showed that fetal Leydig cells maintained their identity and steroidogenic activity for 3-5 days in primary culture. Microenvironment dictated proficiency of testosterone production. As expected, fetal Leydig cells produced androstenedione but not testosterone when cultured in isolation. More testosterone accumulated in medium from mixed cultures than from compartmentalized co-cultures initially; however, co-cultures maintained testosterone synthesis for a longer time. These data suggest that a combination of cell-cell contact and soluble factors constitute the ideal microenvironment for fetal Leydig cell activity in primary culture. PMID:25143354

  10. Cellular Microenvironment Dictates Androgen Production by Murine Fetal Leydig Cells in Primary Culture1

    PubMed Central

    Carney, Colleen M.; Muszynski, Jessica L.; Strotman, Lindsay N.; Lewis, Samantha R.; O'Connell, Rachel L.; Beebe, David J.; Theberge, Ashleigh B.; Jorgensen, Joan S.

    2014-01-01

    ABSTRACT Despite the fact that fetal Leydig cells are recognized as the primary source of androgens in male embryos, the mechanisms by which steroidogenesis occurs within the developing testis remain unclear. A genetic approach was used to visualize and isolate fetal Leydig cells from remaining cells within developing mouse testes. Cyp11a1-Cre mice were bred to mT/mG dual reporter mice to target membrane-tagged enhanced green fluorescent protein (GFP) within steroidogenic cells, whereas other cells expressed membrane-tagged tandem-dimer tomato red. Fetal Leydig cell identity was validated using double-labeled immunohistochemistry against GFP and the steroidogenic enzyme 3beta-HSD, and cells were successfully isolated as indicated by qPCR results from sorted cell populations. Because fetal Leydig cells must collaborate with neighboring cells to synthesize testosterone, we hypothesized that the fetal Leydig cell microenvironment defined their capacity for androgen production. Microfluidic culture devices were used to measure androstenedione and testosterone production of fetal Leydig cells that were cultured in cell-cell contact within a mixed population, were isolated but remained in medium contact via compartmentalized co-culture with other testicular cells, or were isolated and cultured alone. Results showed that fetal Leydig cells maintained their identity and steroidogenic activity for 3–5 days in primary culture. Microenvironment dictated proficiency of testosterone production. As expected, fetal Leydig cells produced androstenedione but not testosterone when cultured in isolation. More testosterone accumulated in medium from mixed cultures than from compartmentalized co-cultures initially; however, co-cultures maintained testosterone synthesis for a longer time. These data suggest that a combination of cell-cell contact and soluble factors constitute the ideal microenvironment for fetal Leydig cell activity in primary culture. PMID:25143354

  11. SUMO ligase PIAS1 functions as a target gene selective androgen receptor coregulator on prostate cancer cell chromatin.

    PubMed

    Toropainen, Sari; Malinen, Marjo; Kaikkonen, Sanna; Rytinki, Miia; Jääskeläinen, Tiina; Sahu, Biswajyoti; Jänne, Olli A; Palvimo, Jorma J

    2015-01-01

    Androgen receptor (AR) is a ligand-activated transcription factor that plays a central role in the development and growth of prostate carcinoma. PIAS1 is an AR- and SUMO-interacting protein and a putative transcriptional coregulator overexpressed in prostate cancer. To study the importance of PIAS1 for the androgen-regulated transcriptome of VCaP prostate cancer cells, we silenced its expression by RNAi. Transcriptome analyses revealed that a subset of the AR-regulated genes is significantly influenced, either activated or repressed, by PIAS1 depletion. Interestingly, PIAS1 depletion also exposed a new set of genes to androgen regulation, suggesting that PIAS1 can mask distinct genomic loci from AR access. In keeping with gene expression data, silencing of PIAS1 attenuated VCaP cell proliferation. ChIP-seq analyses showed that PIAS1 interacts with AR at chromatin sites harboring also SUMO2/3 and surrounded by H3K4me2; androgen exposure increased the number of PIAS1-occupying sites, resulting in nearly complete overlap with AR chromatin binding events. PIAS1 interacted also with the pioneer factor FOXA1. Of note, PIAS1 depletion affected AR chromatin occupancy at binding sites enriched for HOXD13 and GATA motifs. Taken together, PIAS1 is a genuine chromatin-bound AR coregulator that functions in a target gene selective fashion to regulate prostate cancer cell growth. PMID:25552417

  12. SUMO ligase PIAS1 functions as a target gene selective androgen receptor coregulator on prostate cancer cell chromatin

    PubMed Central

    Toropainen, Sari; Malinen, Marjo; Kaikkonen, Sanna; Rytinki, Miia; Jääskeläinen, Tiina; Sahu, Biswajyoti; Jänne, Olli A.; Palvimo, Jorma J.

    2015-01-01

    Androgen receptor (AR) is a ligand-activated transcription factor that plays a central role in the development and growth of prostate carcinoma. PIAS1 is an AR- and SUMO-interacting protein and a putative transcriptional coregulator overexpressed in prostate cancer. To study the importance of PIAS1 for the androgen-regulated transcriptome of VCaP prostate cancer cells, we silenced its expression by RNAi. Transcriptome analyses revealed that a subset of the AR-regulated genes is significantly influenced, either activated or repressed, by PIAS1 depletion. Interestingly, PIAS1 depletion also exposed a new set of genes to androgen regulation, suggesting that PIAS1 can mask distinct genomic loci from AR access. In keeping with gene expression data, silencing of PIAS1 attenuated VCaP cell proliferation. ChIP-seq analyses showed that PIAS1 interacts with AR at chromatin sites harboring also SUMO2/3 and surrounded by H3K4me2; androgen exposure increased the number of PIAS1-occupying sites, resulting in nearly complete overlap with AR chromatin binding events. PIAS1 interacted also with the pioneer factor FOXA1. Of note, PIAS1 depletion affected AR chromatin occupancy at binding sites enriched for HOXD13 and GATA motifs. Taken together, PIAS1 is a genuine chromatin-bound AR coregulator that functions in a target gene selective fashion to regulate prostate cancer cell growth. PMID:25552417

  13. Endostatin: A novel inhibitor of androgen receptor function in prostate cancer

    PubMed Central

    Lee, Joo Hyoung; Isayeva, Tatyana; Larson, Matthew R.; Sawant, Anandi; Cha, Ha-Ram; Chanda, Diptiman; Chesnokov, Igor N.; Ponnazhagan, Selvarangan

    2015-01-01

    Acquired resistance to androgen receptor (AR)-targeted therapies compels the development of novel treatment strategies for castration-resistant prostate cancer (CRPC). Here, we report a profound effect of endostatin on prostate cancer cells by efficient intracellular trafficking, direct interaction with AR, reduction of nuclear AR level, and down-regulation of AR-target gene transcription. Structural modeling followed by functional analyses further revealed that phenylalanine-rich α1-helix in endostatin—which shares structural similarity with noncanonical nuclear receptor box in AR—antagonizes AR transcriptional activity by occupying the activation function (AF)-2 binding interface for coactivators and N-terminal AR AF-1. Together, our data suggest that endostatin can be recognized as an endogenous AR inhibitor that impairs receptor function through protein–protein interaction. These findings provide new insights into endostatin whose antitumor effect is not limited to inhibiting angiogenesis, but can be translated to suppressing AR-mediated disease progression in CRPC. PMID:25605930

  14. Muscle function, physical performance and body composition changes in men with prostate cancer undergoing androgen deprivation therapy

    PubMed Central

    Storer, Thomas W; Miciek, Renee; Travison, Thomas G

    2012-01-01

    Prostate cancer (PCa) is the most common visceral malignancy in men with androgen deprivation therapy (ADT) the preferred therapy to suppress testosterone production and hence tumor growth. Despite its effectiveness in lowering testosterone, ADT is associated with side effects including loss of muscle mass, diminished muscle strength, decrements in physical performance, earlier fatigue and declining quality of life. This review reports a survey of the literature with a focus on changes in muscle strength, physical function and body composition, due to short-term and long-term ADT. Studies in these areas are sparse, especially well-controlled, prospective randomized trials. Cross-sectional and longitudinal data (up to 2 years) for men with PCa treated with ADT as well as patients with PCa not receiving ADT and age-matched healthy men are presented when available. Based on limited longitudinal data, the adverse effects of ADT on muscle function, physical performance and body composition occur shortly after the onset of ADT and tend to persist and worsen over time. Exercise training is a safe and effective intervention for mitigating these changes and initial guidelines for exercise program design for men with PCa have been published by the American College of Sports Medicine. Disparities in study duration, types of studies and other patient-specific variables such as time since diagnosis, cancer stage and comorbidities may all affect an understanding of the influence of ADT on health, physical performance and mortality. PMID:22367184

  15. INVESTIGATION OF TRANSFORMATION PRODUCTS FROM THE CHLORINATION OF ESTROGENIC AND ANDROGENIC COMPOUNDS

    EPA Science Inventory

    Drinking water sources are increasingly impacted by upstream anthropogenic activities, including wastewater discharge, concentrated animal feeding operations (CAFOs) and landfill leachate. Androgenic and estrogenic activities have been detected in surface waters downstream from ...

  16. 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. PMID:26373946

  17. Androgen insensitivity.

    PubMed

    Gottlieb, B; Pinsky, L; Beitel, L K; Trifiro, M

    1999-12-29

    The androgen receptor (AR) protein regulates transcription of certain genes. Usually, this activity depends upon a central DNA-binding domain that permits the binding of androgen-AR complexes to regulatory DNA sequences near or in a target gene. The AR also has a C-terminal androgen-binding domain (ABD) and an N-terminal modulatory domain. These domains interact among themselves and with coregulatory, nonreceptor proteins to determine vector control over a gene's transcription rate. The precise roles of these proteins are active research areas. Severe X-linked androgen receptor gene (AR) mutations cause complete androgen insensitivity, mild ones impair virilization with or without infertility, and moderate ones sometimes yield a wide phenotypic spectrum among sibs. Different expressivity may reflect variability of AR-interactive proteins. The family history must identify heterozygous XX females with sparse, delayed, or asymmetric pubic/axillary hair or delayed menarche and infertile XY maternal aunts or uncles. Mutation type and density vary along the length of the AR. N-terminal polyglutamine tract expansion limits AR transactivation, causing a form of mild androgen insensitivity. Analysis of ABD mutations that do not impair androgen binding or impair it selectively will illuminate its intradomain properties. For partial androgen insensitivity and mild androgen insensitivity, pharmacotherapy with certain androgens or other steroids may overcome some dysfunction of certain mutant ARs. Experience with this approach is limited; outcomes have been generally disappointing. PMID:10727996

  18. Androgen action.

    PubMed

    Werner, Ralf; Holterhus, Paul-Martin

    2014-01-01

    Androgens are important for male sex development and physiology. Their actions are mediated by the androgen receptor (AR), a ligand-dependent nuclear transcription factor. The activity of the AR is controlled at multiple stages due to ligand binding and induced structural changes assisted by the foldosome, compartmentalization, recruitment of coregulators, posttranslational modifications and chromatin remodeling, leading to subsequent transcription of androgen-responsive target genes. Beside these short-term androgen actions, there is phenomenological and experimental evidence of long-term androgen programming in mammals and in the human during sensitive programming time windows, both pre- and postnatally. At the molecular level, research into androgen insensitivity syndrome has unmasked androgen programming at the transcriptome level, in genital fibroblasts and peripheral blood mononuclear cells, and at the epigenome level. Androgens are crucial for male sex development and physiology during embryogenesis, at puberty and in adult life. Testosterone and its more potent metabolite, dihydrotestosterone, which is converted from testosterone within the target cell by 5α-reductase II, are the main androgens involved in male sex differentiation. Androgen action is mediated by a single AR. The AR belongs to the nuclear receptor 3 group C, composed of the glucocorticoid receptor (NR3C1), mineralocorticoid receptor (NR3C2), progesterone receptor (NR3C3) and AR (NR3C4), and acts as a ligand-dependent transcription factor. PMID:25247642

  19. Androgen induced acceleration of functional recovery after rat sciatic nerve injury.

    PubMed

    Brown, Todd J.; Khan, Talat; Jones, Kathryn J.

    1999-01-01

    PURPOSE: Testosterone (T) treatment accelerates recovery from facial paralysis after facial nerve crush in hamsters. In this study, we extended those studies to another injury model and asked the following question: Will T treatment accelerate recovery from lower limb paralysis following sciatic nerve crush in the rat? METHODS: Castrated adult male rats received a right side sciatic nerve crush at the level of the sciatic notch, with the left side serving as control. Half the animals received a subcutaneous implant of a propionated form of T (TP), the others were sham-implanted. Weekly testing using the Sciatic Functional Index (SFI), a quantitative measure of locomotion, was done for 7 weeks postoperative (wpo). RESULTS: Between 3 and 5 weeks post-op, the average SFI score of the TP-treated group was higher than controls. This difference was significant at 4 wpo, indicating an accelerated degree of functional recovery. At these timepoints, the differences were attributable to the footprint or paw length and associated with calf muscle reinnervation rather than the toespreading component associated with intrinsic foot muscle rein-nervation. Beyond 5 wpo, there were no differences in the SFI scores. CONCLUSION: The results indicate that, as with facial nerve regeneration in the hamster, testosterone accelerates functional recovery from hind limb paralysis following sciatic nerve injury in the rat. While the responses of spinal motoneurons to injury can differ from those of cranial motoneurons, in this case it appears that they share a similar response to the trophic actions of androgen. This is important in the context of designing therapeutic strategies for dealing with direct trauma to motoneurons resulting from both peripheral and central nervous system trauma, such as spinal cord injury. PMID:12671219

  20. Abnormal Mitochondrial Function and Impaired Granulosa Cell Differentiation in Androgen Receptor Knockout Mice

    PubMed Central

    Wang, Ruey-Sheng; Chang, Heng-Yu; Kao, Shu-Huei; Kao, Cheng-Heng; Wu, Yi-Chen; Yeh, Shuyuan; Tzeng, Chii-Reuy; Chang, Chawnshang

    2015-01-01

    In the ovary, the paracrine interactions between the oocyte and surrounded granulosa cells are critical for optimal oocyte quality and embryonic development. Mice lacking the androgen receptor (AR−/−) were noted to have reduced fertility with abnormal ovarian function that might involve the promotion of preantral follicle growth and prevention of follicular atresia. However, the detailed mechanism of how AR in granulosa cells exerts its effects on oocyte quality is poorly understood. Comparing in vitro maturation rate of oocytes, we found oocytes collected from AR−/− mice have a significantly poor maturating rate with 60% reached metaphase II and 30% remained in germinal vesicle breakdown stage, whereas 95% of wild-type AR (AR+/+) oocytes had reached metaphase II. Interestingly, we found these AR−/− female mice also had an increased frequency of morphological alterations in the mitochondria of granulosa cells with reduced ATP generation (0.18 ± 0.02 vs. 0.29 ± 0.02 µM/mg protein; p < 0.05) and aberrant mitochondrial biogenesis. Mechanism dissection found loss of AR led to a significant decrease in the expression of peroxisome proliferator-activated receptor γ (PPARγ) co-activator 1-β (PGC1-β) and its sequential downstream genes, nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM), in controlling mitochondrial biogenesis. These results indicate that AR may contribute to maintain oocyte quality and fertility via controlling the signals of PGC1-β-mediated mitochondrial biogenesis in granulosa cells. PMID:25941928

  1. MECHANISMS IN ENDOCRINOLOGY: Medical consequences of doping with anabolic androgenic steroids: effects on reproductive functions.

    PubMed

    Nieschlag, Eberhard; Vorona, Elena

    2015-08-01

    Anabolic androgenic steroids (AASs) are appearance and performance-enhancing drugs (APEDs) used in competitive athletics, in recreational sports, and by body-builders. The global lifetime prevalence of AASs abuse is 6.4% for males and 1.6% for women. Many AASs, often obtained from the internet and dubious sources, have not undergone proper testing and are consumed at extremely high doses and in irrational combinations, also along with other drugs. Controlled clinical trials investigating undesired side effects are lacking because ethical restrictions prevent exposing volunteers to potentially toxic regimens, obscuring a causal relationship between AASs abuse and possible sequelae. Because of the negative feedback in the regulation of the hypothalamic-pituitary-gonadal axis, in men AASs cause reversible suppression of spermatogenesis, testicular atrophy, infertility, and erectile dysfunction (anabolic steroid-induced hypogonadism). Should spermatogenesis not recover after AASs abuse, a pre-existing fertility disorder may have resurfaced. AASs frequently cause gynecomastia and acne. In women, AASs may disrupt ovarian function. Chronic strenuous physical activity leads to menstrual irregularities and, in severe cases, to the female athlete triad (low energy intake, menstrual disorders and low bone mass), making it difficult to disentangle the effects of sports and AASs. Acne, hirsutism and (irreversible) deepening of the voice are further consequences of AASs misuse. There is no evidence that AASs cause breast carcinoma. Detecting AASs misuse through the control network of the World Anti-Doping Agency (WADA) not only aims to guarantee fair conditions for athletes, but also to protect them from medical sequelae of AASs abuse. PMID:25805894

  2. [Epigenetic Regulation by Androgen Receptor and Possible Function in Bone Metabolism].

    PubMed

    Imai, Yuuki

    2016-07-01

    Epigenetic regulation underlying AR(Androgen receptor)mediated transcription is important component to understand pathophysiology of osteoporosis in men. In this commentary, it is reported recent findings related to epigenetic landscape governed by AR and its cofactors including lysine-specific demethylase 1 (LSD1), and possible implication for bone metabolism. PMID:27346313

  3. 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...

  4. Profiling of androgen response in rainbow trout pubertal testis: relevance to male gonad development and spermatogenesis.

    PubMed

    Rolland, Antoine D; Lardenois, Aurélie; Goupil, Anne-Sophie; Lareyre, Jean-Jacques; Houlgatte, Rémi; Chalmel, Frédéric; Le Gac, Florence

    2013-01-01

    The capacity of testicular somatic cells to promote and sustain germ cell differentiation is largely regulated by sexual steroids and notably androgens. In fish species the importance of androgens is emphasized by their ability to induce sex reversal of the developing fries and to trigger spermatogenesis. Here we studied the influence of androgens on testicular gene expression in trout testis using microarrays. Following treatment of immature males with physiological doses of testosterone or 11-ketotestosterone, 418 genes that exhibit changes in expression were identified. Interestingly, the activity of testosterone appeared stronger than that of 11-ketotestosterone. Expression profiles of responsive genes throughout testis development and in isolated germ cells confirmed androgens to mainly affect gene expression in somatic cells. Furthermore, specific clusters of genes that exhibit regulation coincidently with changes in the natural circulating levels of androgens during the reproductive cycle were highlighted, reinforcing the physiological significance of these data. Among somatic genes, a phylogenetic footprinting study identified putative androgen response elements within the proximal promoter regions of 42 potential direct androgen target genes. Finally, androgens were also found to alter the germ line towards meiotic expression profiles, supporting the hypothesis of a role for the somatic responsive genes in driving germ cell fate. This study significantly increases our understanding of molecular pathways regulated by androgens in vertebrates. The highly cyclic testicular development in trout together with functions associated with regulated genes reveal potential mechanisms for androgen actions in tubule formation, steroid production, germ cell development and sperm secretion. PMID:23301058

  5. Mechanism of androgen receptor action.

    PubMed

    Li, Jin; Al-Azzawi, Farook

    2009-06-20

    Recent research provides a much more detailed understanding of the role of the androgen receptor in normal human development and physiology, its structure, and its functioning. This review discusses genomic and non-genomic actions of the androgen receptor, as well as their co-regulators. We also explore several clinically relevant aspects of the molecular biology of the androgen receptor and its co-regulators. PMID:19372015

  6. β-Catenin Binds to the Activation Function 2 Region of the Androgen Receptor and Modulates the Effects of the N-Terminal Domain and TIF2 on Ligand-Dependent Transcription

    PubMed Central

    Song, Liang-Nian; Herrell, Roger; Byers, Stephen; Shah, Salimuddin; Wilson, Elizabeth M.; Gelmann, Edward P.

    2003-01-01

    β-Catenin is a multifunctional molecule that is activated by signaling through WNT receptors. β-Catenin can also enhance the transcriptional activity of some steroid hormone receptors such as the androgen receptor and retinoic acid receptor α. Androgens can affect nuclear translocation of β-catenin and influence its subcellular distribution. Using mammalian two-hybrid binding assays, analysis of reporter gene transcription, and coimmunoprecipitation, we now show that β-catenin binds to the androgen receptor ligand-binding domain (LBD) and modulates the transcriptional effects of TIF2 and the androgen receptor N-terminal domain (NTD). In functional assays, β-catenin bound to androgen receptor only in the presence of ligand agonists, not antagonists. β-Catenin binding to the androgen receptor LBD was independent of and cooperative with the androgen receptor NTD and the p160 coactivator TIF2, both of which bind to the activation function 2 (AF-2) region of the androgen receptor. Different mutations of androgen receptor helix 3 amino acids disrupted binding of androgen receptor NTD and β-catenin. β-Catenin, androgen receptor NTD, and TIF2 binding to the androgen receptor LBD were affected similarly by a subset of helix 12 mutations, but disruption of two sites on helix 12 affected only binding of β-catenin and not of TIF2 or the androgen receptor NTD. Mutational disruption of each of five LXXLL peptide motifs in the β-catenin armadillo repeats did not disrupt either binding to androgen receptor or transcriptional coactivation. ICAT, an inhibitor of T-cell factor 4 (TCF-4), and E-cadherin binding to β-catenin also blocked binding of the androgen receptor LBD. We also demonstrated cross talk between the WNT and androgen receptor signaling pathways because excess androgen receptor could interfere with WNT signaling and excess TCF-4 inhibited the interaction of β-catenin and androgen receptor. Taken together, the data show that β-catenin can bind to the

  7. 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...

  8. Hormonal influence on the secretory immune system of the eye: androgen control of secretory component production by the rat exorbital gland.

    PubMed Central

    Sullivan, D A; Bloch, K J; Allansmith, M R

    1984-01-01

    Androgens are known to regulate the level of secretory component (SC) in tears of male rats. The purpose of the present study was to explore the underlying mechanism of this hormone action by (i) identifying the ocular tissue(s) involved in SC production; and (ii) determining whether androgens increase SC production by this tissue. We also examined whether androgen administration influenced the concentration of SC in tears of female rats. Ocular tissues from adult Sprague-Dawley rats were cultured in the presence or absence of cycloheximide in the incubation medium. Secretory component in the culture media was measured by an RIA which detects primarily free SC. Analysis of media obtained after incubation of exorbital (lacrimal) glands, 'lid' tissues, globes, and Harderian glands revealed that only exorbital glands released substantial amounts of SC. This exorbital gland production of SC, which was significantly greater in tissues from male rats, as compared to those of female rats, was reduced by approximately 50% when cycloheximide was present in the culture medium. To determine whether SC production by exorbital glands was influenced by androgens, orchiectomized glands was influenced by androgens, orchiectomized rats were administered either saline or testosterone (2.0 mg/day for 4 days), and exorbital glands were cultured 24 hr after the last injection. Testosterone treatment in vivo induced a significant, cycloheximide-sensitive increase in SC production in vitro, compared to the glandular SC output of saline-injected controls. It is interesting that similar androgen treatment of ovariectomized females also resulted in elevated tear SC concentrations and enhanced output of SC by their exorbital glands in vitro. These findings indicate that the exorbital gland is primarily responsible for SC production in the rat eye and that androgens may modulate the synthesis of SC in this gland. PMID:6735436

  9. The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function.

    PubMed Central

    Chamberlain, N L; Driver, E D; Miesfeld, R L

    1994-01-01

    Some transcription factors contain stretches of polyglutamine encoded by repeats of the trinucleotide CAG. Expansion of the CAG repeat in the androgen receptor (AR) has been correlated with the incidence and severity of X-linked spinal and bulbar muscular atrophy (Kennedy's disease). In order to understand the relationship of this mutation to AR function, we constructed ARs that varied in the position and size of the polyglutamine tract, and assayed for the abilities of these mutant receptors to bind androgen and to activate transcription of several different AR-responsive reporter genes. Elimination of the tract in both human and rat AR resulted in elevated transcriptional activation activity, strongly suggesting that the presence of the polyglutamine tract is inhibitory to transactivation. Progressive expansion of the CAG repeat in human AR caused a linear decrease of transactivation function. Importantly, expansion of the tract did not completely eliminate AR activity. We postulate that this residual AR activity may be sufficient for development of male primary and secondary sex characteristics, but may fall below a threshold level of activity necessary for normal maintenance of motor neuron function. This functional abnormality may be representative of other genetic diseases that are associated with CAG expansion mutations in open reading frames, such as spinocerebellar ataxia type I and Huntington's disease. Images PMID:8065934

  10. Androgens Regulate Gene Expression in Avian Skeletal Muscles

    PubMed Central

    Fuxjager, Matthew J.; Barske, Julia; Du, Sienmi; Day, Lainy B.; Schlinger, Barney A.

    2012-01-01

    Circulating androgens in adult reproductively active male vertebrates influence a diversity of organ systems and thus are considered costly. Recently, we obtained evidence that androgen receptors (AR) are expressed in several skeletal muscles of three passeriform birds, the golden-collared manakin (Manacus vitellinus), zebra finch (Taenopygia guttata), and ochre-bellied flycatcher (Mionectes oleagieus). Because skeletal muscles that control wing movement make up the bulk of a bird’s body mass, evidence for widespread effects of androgen action on these muscles would greatly expand the functional impact of androgens beyond their well-characterized effects on relatively discrete targets throughout the avian body. To investigate this issue, we use quantitative PCR (qPCR) to determine if androgens alter gene mRNA expression patterns in wing musculature of wild golden-collared manakins and captive zebra finches. In manakins, the androgen testosterone (T) up-regulated expression of parvalbumin (PV) and insulin-like growth factor I (IGF-I), two genes whose products enhance cellular Ca2+ cycling and hypertrophy of skeletal muscle fibers. In T-treated zebra finches, the anti-androgen flutamide blunted PV and IGF-I expression. These results suggest that certain transcriptional effects of androgen action via AR are conserved in passerine skeletal muscle tissue. When we examined wing muscles of manakins, zebra finches and ochre-bellied flycatchers, we found that expression of PV and IGF-I varied across species and in a manner consistent with a function for AR-dependent gene regulation. Together, these findings imply that androgens have the potential to act on avian muscle in a way that may enhance the physicality required for successful reproduction. PMID:23284699

  11. 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

  12. Environmental stress-induced testis differentiation: androgen as a by-product of cortisol inactivation.

    PubMed

    Fernandino, Juan I; Hattori, Ricardo S; Moreno Acosta, Omar D; Strüssmann, Carlos A; Somoza, Gustavo M

    2013-10-01

    This review deals with the gonadal masculinization induced by thermal stress in fish with focus on the action of 11β-hydroxysteroid dehydrogenase (11β-HSD) as this mechanism key transducer. High temperatures have been reported to produce male-skewed sex ratios in several species with TSD (temperature-dependent sex determination), and in some of them, this process was reported to be associated with high levels of cortisol, the hormone-related stress in vertebrates, during early gonad development. In addition, in pejerrey larvae reared at high-masculinizing temperatures, 11-ketotestosterone (11-KT), the main and most potent androgen in fish, was also detected at high levels. In testicular explants, cortisol induced the synthesis of 11-KT, suggesting that its synthesis could be under the control of the stress axis at the time of gonadal fate determination. 11β-HSD is one of the enzymes shared by the glucocorticoid and androgen pathways; this enzyme converts cortisol to cortisone and also participates in the finals steps of the synthesis of the 11-oxigenated androgens. Based on these data and literature information, here we propose that the masculinization induced by thermal stress can be considered as a consequence of cortisol inactivation and the concomitant synthesis of 11-KT and discussing this as a possible mechanism of masculinization induced by different types of environmental stressors. PMID:23770022

  13. Human Checkpoint Protein hRad9 Functions as a Negative Coregulator To Repress Androgen Receptor Transactivation in Prostate Cancer Cells

    PubMed Central

    Wang, Liang; Hsu, Cheng-Lung; Ni, Jing; Wang, Peng-Hui; Yeh, Shuyuan; Keng, Peter; Chang, Chawnshang

    2004-01-01

    Positive responses to combined androgen elimination therapy and radiation therapy have been well documented in the treatment of prostate cancer patients. The detailed mechanisms how androgen-androgen receptor (AR) cross talks to the radiation-related signal pathways, however, remain largely unknown. Here we report the identification of hRad9, a key member of the checkpoint Rad protein family, as a coregulator to suppress androgen-AR transactivation in prostate cancer cells. In vivo and in vitro interaction assays using Saccharomyces cerevisiae two-hybrid, mammalian two-hybrid, glutathione S-transferase pull-down, and coimmunoprecipitation methods prove that AR can interact with the C terminus of hRad9 via its ligand binding domain. The FXXLF motif within the C terminus of hRad9 interrupts the androgen-induced interaction between the N terminus and C terminus of AR. This interaction between AR and hRad9 may result in the suppression of AR transactivation, demonstrated by the repressed AR transactivation in androgen-induced luciferase reporter assay and the reduced endogenous prostate-specific antigen expression in Western blot assay. Addition of small interfering RNA of hRad9 can reverse hRad9 suppression effects, which suggests that hRad9 functions as a repressor of AR transactivation in vivo. Together, our data provide the first linkage between androgen-AR signals and radiation-induced responses. Further studies of the influence of hRad9 on prostate cancer growth may provide potential new therapeutic approaches. PMID:14966297

  14. Hypochlorite oxidation of select androgenic steroids.

    PubMed

    Mash, Heath; Schenck, Kathleen; Rosenblum, Laura

    2010-03-01

    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 synthetic analogs released from agricultural activities and wastewater discharge may be introduced into drinking water sources. The fate of androgenic steroids during drinking water treatment, specifically the use of chlorine for biological control, has not been extensively studied. As such, this study focuses on the hypochlorite oxidation of a select number of androgenic compounds that vary in their structural composition. Where a favorable reaction is observed, we also attempt to describe the product distribution. The results show compounds that possess a ketonic functional group conjugated with a double bond inhibit oxidation by hypochlorite in the absence of biological or indirect oxidative pathways. Oxidative reactivity in the presence of hypochlorite was favorably correlated with the presence of isolated unsaturated carbon bonds and resulted in various transformation products. PMID:20031185

  15. Polycystic ovary syndrome patients with high BMI tend to have functional disorders of androgen excess: a prospective study.

    PubMed

    Yuan, Chun; Liu, Xiaoqiang; Mao, Yundong; Diao, Feiyang; Cui, Yugui; Liu, Jiayin

    2016-05-01

    Biochemical or clinical changes of hyperandrogenism are important elements of polycystic ovary syndrome (PCOS). There is currently no consensus on the definition and diagnostic criteria of hyperandrogenism in PCOS. The aim of this study was to investigate the complex symptoms of hyperandrogenic disorders and the correlations between metabolism and hyperandrogenism in patients with PCOS from an outpatient reproductive medicine clinic in China. We conducted a case control study of 125 PCOS patients and 130 controls to evaluate differences in body mass index (BMI), total testosterone (TT), modified Ferriman-Gallwey hirsutism score, sex hormone binding globulin (SHBG), homeostasis model assessment-estimated insulin resistance (HOMA-IR) and free androgen index (FAI) between PCOS patients and controls and subgroups of PCOS. The prevalence of acne and hirsutism did not differ significantly between the hyperandrogenic and non-hyperandrogenic subgroup. Patients with signs of hyperandrogenism had significantly higher BMI (P < 0.05), but differences in TT, SHBG, FAI and waist/hip ratio were insignificant. The odds ratio of overweight was calculated for all PCOS patients. Our results suggest that PCOS patients with high BMI tend to have functional disorders of androgen excess; therefore, BMI may be a strong predictor of hyperandrogenism in PCOS. PMID:27526961

  16. Polycystic ovary syndrome patients with high BMI tend to have functional disorders of androgen excess: a prospective study

    PubMed Central

    Yuan, Chun; Liu, Xiaoqiang; Mao, Yundong; Diao, Feiyang; Cui, Yugui; Liu, Jiayin

    2016-01-01

    Abstract Biochemical or clinical changes of hyperandrogenism are important elements of polycystic ovary syndrome (PCOS). There is currently no consensus on the definition and diagnostic criteria of hyperandrogenism in PCOS. The aim of this study was to investigate the complex symptoms of hyperandrogenic disorders and the correlations between metabolism and hyperandrogenism in patients with PCOS from an outpatient reproductive medicine clinic in China. We conducted a case control study of 125 PCOS patients and 130 controls to evaluate differences in body mass index (BMI), total testosterone (TT), modified Ferriman-Gallwey hirsutism score, sex hormone binding globulin (SHBG), homeostasis model assessment-estimated insulin resistance (HOMA-IR) and free androgen index (FAI) between PCOS patients and controls and subgroups of PCOS. The prevalence of acne and hirsutism did not differ significantly between the hyperandrogenic and non-hyperandrogenic subgroup. Patients with signs of hyperandrogenism had significantly higher BMI (P < 0.05), but differences in TT, SHBG, FAI and waist/hip ratio were insignificant. The odds ratio of overweight was calculated for all PCOS patients. Our results suggest that PCOS patients with high BMI tend to have functional disorders of androgen excess; therefore, BMI may be a strong predictor of hyperandrogenism in PCOS. PMID:27526961

  17. Mechanisms Mediating Spinal and Bulbar Muscular Atrophy: Investigations into Polyglutamine-Expanded Androgen Receptor Function and Dysfunction

    PubMed Central

    Beitel, Lenore K.; Alvarado, Carlos; Mokhtar, Shaza; Paliouras, Miltiadis; Trifiro, Mark

    2013-01-01

    Spinal and bulbar muscular atrophy (SBMA, Kennedy’s disease), a late-onset neuromuscular disorder, is caused by expansion of the polymorphic polyglutamine tract in the androgen receptor (AR). The AR is a ligand-activated transcription factor, but plays roles in other cellular pathways. In SBMA, selective motor neuron degeneration occurs in the brainstem and spinal cord, thus the causes of neuronal dysfunction have been studied. However, pathogenic pathways in muscles may also be involved. Cultured cells, fly and mouse models are used to study the molecular mechanisms leading to SBMA. Both the structure of the polyglutamine-expanded AR (polyQ AR) and its interactions with other proteins are altered relative to the normal AR. The ligand-dependent translocation of the polyQ AR to the nucleus appears to be critical, as are interdomain interactions. The polyQ AR, or fragments thereof, can form nuclear inclusions, but their pathogenic or protective nature is unclear. Other data suggests soluble polyQ AR oligomers can be harmful. Post-translational modifications such as phosphorylation, acetylation, and ubiquitination influence AR function and modulate the deleterious effects of the polyQ AR. Transcriptional dysregulation is highly likely to be a factor in SBMA; deregulation of non-genomic AR signaling may also be involved. Studies on polyQ AR-protein degradation suggest inhibition of the ubiquitin proteasome system and changes to autophagic pathways may be relevant. Mitochondrial function and axonal transport may also be affected by the polyQ AR. Androgens, acting through the AR, can be neurotrophic and are important in muscle development; hence both loss of normal AR functions and gain of novel harmful functions by the polyQ AR can contribute to neurodegeneration and muscular atrophy. Thus investigations into polyQ AR function have shown that multiple complex mechanisms lead to the initiation and progression of SBMA. PMID:23720649

  18. CACUL1 functions as a negative regulator of androgen receptor in prostate cancer cells.

    PubMed

    Choi, Hanbyeul; Lee, Sang Hyup; Um, Soo-Jong; Kim, Eun-Joo

    2016-07-01

    The androgen receptor (AR) plays a critical role in the initiation and progression of prostate cancer (PCa), and thus its regulation is an important tool in PCa therapy. Here, we report that CDK2-associated cullin 1 (CACUL1) directly associates with AR and suppresses AR transcriptional activity. In addition, CACUL1 represses histone demethylase LSD1-mediated AR transactivation by competing with LSD1 for AR binding. Depletion of CACUL1 enhances the LSD1 occupancy of the AR-target promoter, accompanied by decreased accumulation of H3K9me2, a repressive transcriptional marker. CACUL1 and LSD1 oppositely regulate CDX-induced cell death in AR-positive LNCaP and metastatic castrate-resistant LNCaP-LN3 cells. These data suggest that CACUL1 impairs LSD1-mediated activation of AR, thereby implicating it as a potential antitumor target in PCa. PMID:27085459

  19. Alternatively Spliced Androgen Receptor Variants

    PubMed Central

    Dehm, Scott M.; Tindall, Donald J.

    2011-01-01

    Alternative splicing is an important mechanism for increasing functional diversity from a limited set of genes. De-regulation of this process is common in diverse pathologic conditions. The androgen receptor (AR) is a steroid receptor transcription factor with functions critical for normal male development as well as the growth and survival of normal and cancerous prostate tissue. Studies of AR function in androgen insensitivity syndrome (AIS) and prostate cancer (PCa) have demonstrated loss-of-function AR alterations in AIS, and gain-of-function AR alterations in PCa. Over the past two decades, AR gene alterations have been identified in various individuals with AIS, which disrupt normal AR splicing patterns and yield dysfunctional AR protein variants. More recently, altered AR splicing patterns have been identified as a mechanism of PCa progression and resistance to androgen-depletion therapy. Several studies have described the synthesis of alternatively spliced transcripts encoding truncated AR isoforms that lack the ligand-binding domain, which is the ultimate target of androgen depletion. Many of these truncated AR isoforms function as constitutively active, ligand-independent transcription factors that can support androgen-independent expression of AR target genes, as well as the androgen-independent growth of PCa cells. In this review, we will summarize the various alternatively spliced AR variants that have been discovered, with a focus on their role and origin in the pathologic conditions of AIS and PCa. PMID:21778211

  20. Ligand fishing using new chitosan based functionalized Androgen Receptor magnetic particles.

    PubMed

    Marszałł, Michał Piotr; Sroka, Wiktor Dariusz; Sikora, Adam; Chełminiak, Dorota; Ziegler-Borowska, Marta; Siódmiak, Tomasz; Moaddel, Ruin

    2016-08-01

    Superparamagnetic nanoparticles with chemically modified chitosan has been proposed as a potential support for the immobilization of the androgen receptor (AR). The study involved comparison of different AR carriers like commercially available magnetic beads coated with silica (BcMag) and chitosan coated nanoparticles with different amount of amino groups. The immobilization was carried out through covalent immobilization of the AR through the terminal amino group or through available carboxylic acids. The initial characterization of the AR coated magnetic beads was carried out with dihydrotestosterone, a known AR ligand. Subsequently, chitosan modified nanporticles with long-distanced primary amino groups (Fe3O4CS-(NH2)3) (upto 8.34mM/g) were used for further study to isolate known AR ligands (bicalutamide, flutamide, hydroxyflutamide and levonogestrel) from a mixture of tested compounds in ammonium acetate buffer [10mM, pH 7.4]. The results showed that the selected nanoparticles are a promising semi-quantitative tool for the identification of high affinity compounds to AR and might be of special importance in the identification of novel agonists or antiandrogens. PMID:27156644

  1. 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

  2. Tissue- and cell-specific functions of the androgen receptor revealed through conditional knockout models in mice.

    PubMed

    De Gendt, Karel; Verhoeven, Guido

    2012-04-16

    This review aims to evaluate the contribution of individual cell-selective knockout models to our current understanding of androgen action. Cre/loxP technology has allowed the generation of cell-selective knockout models targeting the androgen receptor (AR) in distinct putative target cells in a wide variety of organs and tissues including: testis, ovary, accessory sex tissues, muscle, bone, fat, liver, skin and myeloid tissue. In some androgen-regulated processes such as spermatogenesis and folliculogenesis this approach has lead to the identification of a key cellular mediator of androgen action (Sertoli and granulosa cells, respectively). In many target tissues, however, the final response to androgens appears to be more complex. Here, cell-selective knockout technology offers a platform upon which we can begin to unravel the more complex interplay and signaling pathways of androgens. A prototypic example is the analysis of mesenchymal-epithelial interactions in many accessory sex glands. Furthermore, for some actions of testosterone, in which part of the effect is mediated by the active metabolite 17β-estradiol, conditional knockout technology offers a novel strategy to study the relative contribution of AR and estrogen receptor-mediated signaling. The latter approach has already resulted in a better understanding of androgen action in brain and bone. Finally, cell-selective knockout technology has generated valuable models to search for AR-controlled molecular mediators of androgen action, a strategy that has successfully been applied to the study of androgen action in the testis and in the epididymis. Although some conditional knockout models have provided clear answers to physiologic questions, it should be noted that others have pointed to unexpected complexities or technical limitations confounding interpretation of the results. PMID:21871526

  3. Cryptotanshinone Suppresses Androgen Receptor-mediated Growth in Androgen Dependent and Castration Resistant Prostate Cancer Cells

    PubMed Central

    Xu, Defeng; Lin, Tzu-Hua; Li, Shaoshun; Da, Jun; Wen, Xing-Qiao; Ding, Jiang; Chang, Chawnshang; Yeh, Shuyuan

    2012-01-01

    Androgen receptor (AR) is the major therapeutic target for the treatment of prostate cancer (PCa). Anti-androgens to reduce or prevent androgens binding to AR are widely used to suppress AR-mediated PCa growth; however, the androgen depletion therapy is only effective for a period of time. Here we found a natural product/Chinese herbal medicine cryptotanshinone (CTS), with a structure similar to dihydrotestosterone (DHT), can effectively inhibit the DHT-induced AR transactivation and prostate cancer cell growth. Our results indicated that 0.5 µM CTS effectively suppresses the growth of AR-positive PCa cells, but has little effect on AR negative PC-3 cells and non-malignant prostate epithelial cells. Furthermore, our data indicated that CTS could modulate AR transactivation and suppress the DHT-mediated AR target genes (PSA, TMPRSS2, and TMEPA1) expression in both androgen responsive PCa LNCaP cells and castration resistant CWR22rv1 cells. Importantly, CTS selective inhibits AR without repressing the activities of other nuclear receptors, including ERα, GR, and PR. The mechanistic studies indicate that CTS functions as an AR inhibitor to suppress androgen/AR-mediated cell growth and PSA expression by blocking AR dimerization and the AR–coregulator complex formation. Furthermore, we showed that CTS effectively inhibits CWR22Rv1 cell growth in the xenograft animal model. The previously un-described mechanisms of CTS may explain how CTS inhibits the growth of PCa cells and help us to establish new therapeutic concepts for the treatment of PCa. PMID:22154085

  4. Autocrine androgen action is essential for Leydig cell maturation and function, and protects against late-onset Leydig cell apoptosis in both mice and men

    PubMed Central

    O’Hara, Laura; McInnes, Kerry; Simitsidellis, Ioannis; Morgan, Stephanie; Atanassova, Nina; Slowikowska-Hilczer, Jolanta; Kula, Krzysztof; Szarras-Czapnik, Maria; Milne, Laura; Mitchell, Rod T.; Smith, Lee B.

    2015-01-01

    Leydig cell number and function decline as men age, and low testosterone is associated with all “Western” cardio-metabolic disorders. However, whether perturbed androgen action within the adult Leydig cell lineage predisposes individuals to this late-onset degeneration remains unknown. To address this, we generated a novel mouse model in which androgen receptor (AR) is ablated from ∼75% of adult Leydig stem cell/cell progenitors, from fetal life onward (Leydig cell AR knockout mice), permitting interrogation of the specific roles of autocrine Leydig cell AR signaling through comparison to adjacent AR-retaining Leydig cells, testes from littermate controls, and to human testes, including from patients with complete androgen insensitivity syndrome (CAIS). This revealed that autocrine AR signaling is dispensable for the attainment of final Leydig cell number but is essential for Leydig cell maturation and regulation of steroidogenic enzymes in adulthood. Furthermore, these studies reveal that autocrine AR signaling in Leydig cells protects against late-onset degeneration of the seminiferous epithelium in mice and inhibits Leydig cell apoptosis in both adult mice and patients with CAIS, possibly via opposing aberrant estrogen signaling. We conclude that autocrine androgen action within Leydig cells is essential for the lifelong support of spermatogenesis and the development and lifelong health of Leydig cells.—O’Hara, L., McInnes, K., Simitsidellis, I., Morgan, S., Atanassova, N., Slowikowska-Hilczer, J., Kula, K., Szarras-Czapnik, M., Milne, L., Mitchell, R. T., Smith, L. B. Autocrine androgen action is essential for Leydig cell maturation and function, and protects against late-onset Leydig cell apoptosis in both mice and men. PMID:25404712

  5. Strength Training Induces Muscle Hypertrophy and Functional Gains in Black Prostate Cancer Patients Despite Androgen Deprivation Therapy

    PubMed Central

    Hurley, Ben F.

    2013-01-01

    Background. Androgen deprivation therapy (ADT) for prostate cancer (PCa) is associated with weakness, fatigue, sarcopenia, and reduced quality of life (QoL). Black men have a higher incidence and mortality from PCa than Caucasians. We hypothesized that despite ADT, strength training (ST) would increase muscle power and size, thereby improving body composition, physical function, fatigue levels, and QoL in older black men with PCa. Methods. Muscle mass, power, strength, endurance, physical function, fatigue perception, and QoL were measured in 17 black men with PCa on ADT before and after 12 weeks of ST. Within-group differences were determined using t tests and regression models. Results. ST significantly increased total body muscle mass (2.7%), thigh muscle volume (6.4%), power (17%), and strength (28%). There were significant increases in functional performance (20%), muscle endurance (110%), and QoL scores (7%) and decreases in fatigue perception (38%). Improved muscle function was associated with higher functional performance (R 2 = 0.54) and lower fatigue perception (R 2 = 0.37), and both were associated with improved QoL (R 2 = 0.45), whereas fatigue perception tended to be associated with muscle endurance (R 2 = 0.37). Conclusions. ST elicits muscle hypertrophy even in the absence of testosterone and is effective in counteracting the adverse functional consequences of ADT in older black men with PCa. These improvements are associated with reduced fatigue perception, enhanced physical performance, and improved QoL. Thus, ST may be a safe and well-tolerated therapy to prevent the loss of muscle mass, strength, and power commonly observed during ADT. PMID:23089339

  6. Coactivator MYST1 regulates nuclear factor-κB and androgen receptor functions during proliferation of prostate cancer cells.

    PubMed

    Jaganathan, Anbalagan; Chaurasia, Pratima; Xiao, Guang-Qian; Philizaire, Marc; Lv, Xiang; Yao, Shen; Burnstein, Kerry L; Liu, De-Pei; Levine, Alice C; Mujtaba, Shiraz

    2014-06-01

    In prostate cancer (PCa), the functional synergy between androgen receptor (AR) and nuclear factor-κ B (NF-κB) escalates the resistance to therapeutic regimens and promotes aggressive tumor growth. Although the underlying mechanisms are less clear, gene regulatory abilities of coactivators can bridge the transcription functions of AR and NF-κB. The present study shows that MYST1 (MOZ, YBF2 and SAS2, and TIP60 protein 1) costimulates AR and NF-κB functions in PCa cells. We demonstrate that activation of NF-κB promotes deacetylation of MYST1 by sirtuin 1. Further, the mutually exclusive interactions of MYST1 with sirtuin 1 vs AR regulate the acetylation of lysine 16 on histone H4. Notably, in AR-lacking PC3 cells and in AR-depleted LNCaP cells, diminution of MYST1 activates the cleavage of poly(ADP-ribose) polymerase and caspase 3 that leads to apoptosis. In contrast, in AR-transformed PC3 cells (PC3-AR), depletion of MYST1 induces cyclin-dependent kinase (CDK) N1A/p21, which results in G2M arrest. Concomitantly, the levels of phospho-retinoblastoma, E2F1, CDK4, and CDK6 are reduced. Finally, the expression of tumor protein D52 (TPD52) was unequivocally affected in PC3, PC3-AR, and LNCaP cells. Taken together, the results of this study reveal that the functional interactions of MYST1 with AR and NF-κB are critical for PCa progression. PMID:24702180

  7. Spatial function in adolescents and young adults with congenital adrenal hyperplasia: clinical phenotype and implications for the androgen hypothesis.

    PubMed

    Hampson, Elizabeth; Rovet, Joanne F

    2015-04-01

    Females with the classic form of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency are said to perform better than unaffected female controls on tests of mental rotation or other visuospatial abilities, but findings are conflicting. We studied 31 adolescents and young adults with CAH and 19 unaffected sibling controls, who were given standardized spatial tests and tests of other sexually differentiated cognitive functions (verbal fluency, perceptual speed). The possible role of CAH subtype (salt-wasting or simple-virilizing) was evaluated. Only females with the more severe, salt-wasting form of CAH, but not females with the simple-virilizing form, performed significantly better than sex-matched sibling controls on measures of mental rotation. Subtype differences were not significant for verbal fluency or perceptual speed. Severity of prenatal genital virilization, but not postnatal age when medication was started, predicted accuracy on the Mental Rotations Test. Results are consistent with the possibility of an organizational effect of androgens in the central nervous system that impacts the development of spatial abilities. Implications for the timing of the hypothetical critical period are discussed. PMID:25686803

  8. Novel protein ADTRP regulates TFPI expression and function in human endothelial cells in normal conditions and in response to androgen

    PubMed Central

    Zhu, Hua; Popescu, Narcis I.; Wren, Jonathan D.; Lupu, Florea

    2011-01-01

    Thrombosis and cardiovascular disease (CVD) represent major causes of morbidity and mortality. Low androgen correlates with higher incidence of CVD/thrombosis. Tissue Factor Pathway Inhibitor (TFPI) is the major inhibitor of tissue factor-factor VIIa (TF-FVIIa)–dependent FXa generation. Because endothelial cell (EC) dysfunction leading to vascular disease correlates with low EC-associated TFPI, we sought to identify mechanisms that regulate the natural expression of TFPI. Data mining of NCBI's GEO microarrays revealed strong coexpression between TFPI and the uncharacterized protein encoded by C6ORF105, which is predicted to be multispan, palmitoylated and androgen-responsive. We demonstrate that this protein regulates both the native and androgen-enhanced TFPI expression and activity in cultured ECs, and we named it androgen-dependent TFPI-regulating protein (ADTRP). We confirm ADTRP expression and colocalization with TFPI and caveolin-1 in ECs. ADTRP-shRNA reduces, while over-expression of ADTRP enhances, TFPI mRNA and activity and the colocalization of TF-FVIIa–FXa-TFPI with caveolin-1. Imaging and Triton X-114–extraction confirm TFPI and ADTRP association with lipid rafts/caveolae. Dihydrotestosterone up-regulates TFPI and ADTRP expression, and increases FXa inhibition by TFPI in an ADTRP- and caveolin-1-dependent manner. We conclude that the ADTRP-dependent up-regulation of TFPI expression and activity by androgen represents a novel mechanism of increasing the anticoagulant protection of the endothelium. PMID:21868574

  9. 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. PMID:9165014

  10. Androgen receptor genomic regulation

    PubMed Central

    Jin, Hong-Jian; Kim, Jung

    2013-01-01

    The transcriptional activity of the androgen receptor (AR) is not only critical for the normal development and function of the prostate but also pivotal to the onset and progression of prostate cancer (PCa). The studies of AR transcriptional regulation were previously limited to a handful of AR-target genes. Owing to the development of various high-throughput genomic technologies, significant advances have been made in recent years. Here we discuss the discoveries of genome-wide androgen-regulated genes in PCa cell lines, animal models and tissues using expression microarray and sequencing, the mapping of genomic landscapes of AR using Combining Chromatin Immunoprecipitation (ChIP)-on-chip and ChIP-seq assays, the interplay of transcriptional cofactors in defining AR binding profiles, and the genomic regulation and AR reprogramming in advanced PCa. PMID:25237629

  11. Genetic basis of endocrine disease 4: The spectrum of mutations in the androgen receptor gene that causes androgen resistance

    SciTech Connect

    McPhaul, M.J.; Marcelli, M.; Zoppi, S.; Griffin, J.E.; Wilson, J.D. )

    1993-01-01

    Mutations in the androgen receptor gene cause phenotypic abnormalities of male sexual development that range from a female phenotype (complete testicular feminization) to that of undervirilized or infertile men. Using the tools of molecular biology, the authors have analyzed androgen receptor gene mutations in 31 unrelated subjects with androgen resistance syndromes. Most of the defects are due to nucleotide changes that cause premature termination codons or single amino acid substitutions within the open reading frame encoding the androgen receptor, and the majority of these substitutions are localized in three regions of the androgen receptor: the DNA-binding domain and two segments of the androgen-binding domain. Less frequently, partial or complete gene deletions have been identified. Functional studies and immunoblot assays of the androgen receptors in patients with androgen resistance indicate that in most cases the phenotypic abnormalities are the result of impairment of receptor function or decreases in receptor abundance or both. 34 refs., 2 figs.

  12. Androgen-Forming Stem Leydig cells: Identification, Function and Therapeutic Potential

    PubMed Central

    Zhang, Yunhui; Ge, Renshan; Hardy, Matthew P.

    2008-01-01

    Leydig cells are the primary source of testosterone in the male, and differentiation of Leydig cells in the testes is one of the primary events in the development of the male body and fertility. Stem Leydig cells (SLCs) exist in the testis throughout postnatal life, but a lack of cell surface markers previously hindered attempts to obtain purified SLC fractions. Once isolated, the properties of SLCs provide interesting clues for the ontogeny of these cells within the embryo. Moreover, the clinical potential of SLCs might be used to reverse age-related declines in testosterone levels in aging men, and stimulate reproductive function in hypogonadal males. This review focuses on the source, identification and outlook for therapeutic applications of SLCs. Separate pools of SLCs may give rise to fetal and adult generations of Leydig cell, which may account for their observed functional differences. These differences should in turn be taken into account when assessing the consequences of environmental pollutants such as the phthalate ester, diethylhexylphthalate (DEHP). PMID:18525122

  13. Androgen actions on the human hair follicle: perspectives.

    PubMed

    Inui, Shigeki; Itami, Satoshi

    2013-03-01

    Androgens stimulate beard growth but suppress hair growth in androgenetic alopecia (AGA). This condition is known as 'androgen paradox'. Human pilosebaceous units possess enough enzymes to form the active androgens testosterone and dihydrotestosterone. In hair follicles, 5α-reductase type 1 and 2, androgen receptors (AR) and AR coactivators can regulate androgen sensitivity of dermal papillae (DP). To regulate hair growth, androgens stimulate production of IGF-1 as positive mediators from beard DP cells and of TGF-β1, TGF-β2, dickkopf1 and IL-6 as negative mediators from balding DP cells. In addition, androgens enhance inducible nitric oxide synthase from occipital DP cells and stem cell factor for positive regulation of hair growth in beard and negative regulation of balding DP cells. Moreover, AGA involves crosstalk between androgen and Wnt/β-catenin signalling. Finally, recent data on susceptibility genes have provided us with the impetus to investigate the molecular pathogenesis of AGA. PMID:23016593

  14. Signaling pathway of nitric oxide production induced by ginsenoside Rb1 in human aortic endothelial cells: a possible involvement of androgen receptor.

    PubMed

    Yu, Jing; Eto, Masato; Akishita, Masahiro; Kaneko, Akiyo; Ouchi, Yasuyoshi; Okabe, Tetsuro

    2007-02-16

    Ginsenosides have been shown to stimulate nitric oxide (NO) production in aortic endothelial cells. However, the signaling pathways involved have not been well studied in human aortic endothelial cells. The present study was designed to examine whether purified ginsenoside Rb1, a major active component of ginseng could actually induce NO production and to clarify the signaling pathway in human aortic endothelial cells. NO production was rapidly increased by Rb1. The rapid increase in NO production was abrogated by treatment with nitric oxide synthetase inhibitor, L-NAME. Rb1 stimulated rapid phosphorylation of Akt (Ser473), ERK1/2 (Thr202/Thr204) and eNOS (Ser1177). Rapid phosphorylation of eNOS (Ser1177) was prevented by SH-5, an Akt inhibitor or wortmannin, PI3-kinase inhibitor and partially attenuated by PD98059, an upstream inhibitor for ERK1/2. Interestingly, NO production and eNOS phosphorylation at Ser1177 by Rb1 were abolished by androgen receptor antagonist, nilutamide. The results suggest that PI3kinase/Akt and MEK/ERK pathways and androgen receptor are involved in the regulation of acute eNOS activation by Rb1 in human aortic endothelial cells. PMID:17196933

  15. Androgen receptors in prostate cancer.

    PubMed

    Culig, Z; Klocker, H; Bartsch, G; Hobisch, A

    2002-09-01

    The androgen receptor (AR), a transcription factor that mediates the action of androgens in target tissues, is expressed in nearly all prostate cancers. Carcinoma of the prostate is the most frequently diagnosed neoplasm in men in industrialized countries. Palliative treatment for non-organ-confined prostate cancer aims to down-regulate the concentration of circulating androgen or to block the transcription activation function of the AR. AR function during endocrine therapy was studied in tumor cells LNCaP subjected to long-term steroid depletion; newly generated sublines could be stimulated by lower concentrations of androgen than parental cells and showed up-regulation of AR expression and activity as well as resistance to apoptosis. Androgenic hormones regulate the expression of key cell cycle regulators, cyclin-dependent kinase 2 and 4, and that of the cell cycle inhibitor p27. Inhibition of AR expression could be achieved by potential chemopreventive agents flufenamic acid, resveratrol, quercetin, polyunsaturated fatty acids and interleukin-1beta, and by the application of AR antisense oligonucleotides. In the clinical situation, AR gene amplification and point mutations were reported in patients with metastatic disease. These mutations generate receptors which could be activated by other steroid hormones and non-steroidal antiandrogens. In the absence of androgen, the AR could be activated by various growth-promoting (growth factors, epidermal growth factor receptor-related oncogene HER-2/neu) and pleiotropic (protein kinase A activators, interleukin-6) compounds as well as by inducers of differentiation (phenylbutyrate). AR function is modulated by a number of coactivators and corepressors. The three coactivators, TIF-2, SRC-1 and RAC3, are up-regulated in relapsed prostate cancer. New experimental therapies for prostate cancer are aimed to down-regulate AR expression and to overcome difficulties which occur because of the acquisition of agonistic properties

  16. The role of androgens in species recognition and sperm production in Atlantic mollies (Poecilia mexicana).

    PubMed

    Gabor, Caitlin R; Aspbury, Andrea S; Ma, Jacqueline; Nice, Chris C

    2012-02-01

    Much is known about the role of hormones in the regulation of vertebrate mating behavior, including receptivity, and several components of mate choice. Hormones may modulate reproductive behavior in such a way to increase or decrease the individual's motivation, and therefore hormones may be important in mediating behavior associated with reproductive isolation. The mating complex of the all female gynogenetic Amazon mollies, Poecilia formosa, and their parental species (sailfin mollies, P. latipinna, and Atlantic mollies, P. mexicana) is a model system for studying ultimate mechanisms of species recognition. However, proximate mechanisms, such as variation in hormone levels, and the effect of hormones on sperm production have not been extensively examined. We predict that one or more of the sex steroid hormones in teleost fish (11-ketotestosterone (KT), testosterone (T), and estradiol (E)) will play a role in species recognition (during mate choice and/or sperm priming) for Atlantic mollies (the maternal parental species) that are sympatric with Amazon mollies. We sequentially paired male Atlantic mollies with female conspecifics and Amazon mollies and obtained water-borne hormone samples before and after mating for all fish. We measured circulating KT, T, and E from the water samples. Although we did not find an overall KT response to mating with conspecifics as has been found previously in sailfin mollies, male Atlantic mollies that mated more with conspecific females had lower postmating T levels. Additionally, males attempted to mate more with conspecific females that had lower postmating E levels, but attempted to mate more with Amazon mollies that had higher postmating KT levels. We also examined the effect of KT on sperm priming (a mechanism of premating mate choice), and found that KT levels of male Atlantic mollies prior to mating are correlated with the sperm priming response when males were paired with conspecific females, but this correlation was not

  17. Luteinizing hormone release and androgen production of avian hybrids in response to luteinizing hormone releasing hormone injection.

    PubMed

    Mathis, G F; Burke, W H; McDougald, L R

    1983-04-01

    The levels of luteinizing hormone (LH) and androgens were measured in sterile avian hybrids. Guinea fowl-chicken and peafowl-guinea fowl hybrids were bled before and after injection with LH- releasing hormone (LHRH). The preinjection LH levels for the guinea fowl-chicken hybrids were below or at the very lower limit of the assay sensitivity and the peafowl-guinea fowl hybrids averaged 1.3 ng/ml. Within 10 min after LHRH injection, LH had increased dramatically in both hybrids and then began to slowly decline. Androgen levels in the guinea fowl-chicken hybrids increased from 16.2 pg/ml to 95.2 pg/ml and continued to increase, reaching 287 pg/ml at the last bleeding 60 min after injection. PMID:6346309

  18. Synergistic androgenic effect of a petroleum product caused by the joint action of at least three different types of compounds.

    PubMed

    Jonker, Michiel T O; Candido, Angelica; Vrabie, Cozmina M; Scarlett, Alan G; Rowland, Steven J

    2016-02-01

    In a previous study, we found a dose-dependent synergistic effect in recombinant yeast stably transfected with the human androgen receptor (AR), in response to co-exposure to testosterone and a commercially-available lubricant (engine) oil for cars. As there is relatively little knowledge on synergistic toxic effects and causative compounds, particularly for the androgenic system, the objective of the present study was to investigate this oil in more detail. The oil was fractionated into SARA fractions (so-called 'saturates', 'aromatics', 'resins', and 'asphaltenes') by open column chromatography. Surprisingly, when exposing the recombinant AR yeast to testosterone in combination with the separate SARA fractions, the synergistic effect could not be reproduced fully. After pooling the fractions again however, the full synergism returned. From subsequent exposures to combinations of two or three SARA fractions, it appeared that both the 'saturates' and the 'resins' fraction were required for obtaining the synergistic response with testosterone. This clearly demonstrates a synergistic effect related to the androgenic system caused by the joint action of at least three chemically-distinct compounds, or groups of compounds (i.e. testosterone, 'resins' and 'saturates'). Although detailed chemical analyses could not reveal the identity of the causative compounds and the in vivo relevance of the present results remains unclear, the results do add to the growing body of evidence on the potentially extremely complex character of mixture effects. PMID:26461438

  19. Effect of inter-cycle interval on oocyte production in humans in the presence of the weak androgen DHEA and follicle stimulating hormone: a case-control study

    PubMed Central

    2014-01-01

    Background In various animal models androgens have been demonstrated to enhance follicle stimulating hormone (FSH) activity on granulosa cells during small growing follicle stages. To assess whether similar synergism may also exist in humans we investigated women on androgen (dehydroepiandrosterone, DHEA) supplementation with varying concomitant FSH exposure. Methods In a case controlled cohort study we determine if time interval between IVF cycles of IVF treatment with FSH had an effect on ovarian response to ovulation induction in women supplemented with DHEA. Among 85 women with known low functional ovarian reserve (LFOR), supplemented with DHEA, and undergoing at least 3 consecutive IVF cycles, 68 demonstrated short (<120 days) intervals between repeated cycles (Group 1) and were, therefore, considered to have consistent FSH exposure. In contrast 17 women (Group 2) demonstrated long (> = 120 days) intervals between repeated cycles and, therefore, were considered to demonstrate inconsistent FSH exposure. Trends in oocyte yields were compared between these groups, utilizing mixed model repeated measures ANOVA, adjusted for initial age and FSH dose. Results Only women in Group I demonstrated a linear increase in oocyte yields across their three cycles of treatments (F = 7.92; df 1, 68.6; p = 0.017). Moreover, the analysis revealed a significant interaction between the two patient groups and cycle number for retrieved oocytes (F = 6.32, df = 2, 85.9, p = 0.003). Conclusions This study offers preliminary confirmatory evidence that repeated short interval exposure to androgens in combination with FSH improves human FOR. A higher level of evidence will require prospectively randomized studies. PMID:25048047

  20. 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

  1. Regulators of Androgen Action Resource: a one-stop shop for the comprehensive study of androgen receptor action

    PubMed Central

    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

  2. Disruption of androgen regulation in the prostate by the environmental contaminant hexachlorobenzene.

    PubMed Central

    Ralph, Jody L; Orgebin-Crist, Marie-Claire; Lareyre, Jean-Jacques; Nelson, Colleen C

    2003-01-01

    Hexachlorobenzene (HCB) is a persistent environmental contaminant that has the potential to interfere with steroid hormone regulation. The prostate requires precise control by androgens to regulate its growth and function. To determine if HCB impacts androgen action in the prostate, we used a number of methods. Our in vitro cell-culture-based assay used a firefly luciferase reporter gene driven by an androgen-responsive promoter. In the presence of dihydrotestosterone, low concentrations (0.5-5 nM) of HCB increased the androgen-responsive production of firefly luciferase and high concentrations of HCB (> 10 microM) suppressed this transcriptional activity. Results from a binding assay showed no evidence of affinity between HCB and the androgen receptor. We also tested HCB for in vivo effects using transgenic mice in which the transgene was a prostate-specific, androgen-responsive promoter upstream of a chloramphenicol acetyl transferase (CAT) reporter gene. In 4-week-old mice, the proportion of dilated prostate acini, a marker of sexual maturity, increased in the low HCB dose group and decreased in the high HCB dose mice. In the 8-week-old mice, there was a significant decrease in both CAT activity and prostate weight upon exposure to 20 mg/kg/day HCB. Therefore, in vitro and in vivo data suggest that HCB weakly agonizes androgen action, and consequently, low levels of HCB enhanced androgen action but high levels of HCB interfered. Environmental contaminants have been implicated in the rising incidence of prostate cancer, and insight into the mechanisms of endocrine disruption will help to clarify their role. PMID:12676599

  3. Synthesis of novel C17 steroidal carbamates. Studies on CYP17 action, androgen receptor binding and function, and prostate cancer cell growth.

    PubMed

    Moreira, Vânia M A; Vasaitis, Tadas S; Guo, Zhiyong; Njar, Vincent C O; Salvador, Jorge A R

    2008-11-01

    We have exploited the reaction of 1,1'-carbonylbis(2-methylimidazole) (CBMI) with several 17beta-hydroxy androstanes to synthesize a series of novel C17 steroidal carbamates. Structural elucidation features have been provided for the final compounds based on 1D and 2D NMR techniques, IR spectroscopy, and related literature. The new compounds were tested for inhibition of human cytochrome 17alpha-hydroxylase-C17,20-lyase (CYP17) and androgen receptor (AR) binding and function effects. Their inhibitory potential against PC-3 cell proliferation was also evaluated. Compounds 11 and 23 were found to inhibit CYP17 with IC50 values of 17.1 and 11.5 microM, respectively. The carbamate moiety at C17 allowed tight binding of the synthesized compounds to both wild-type (wt-) and mutated AR. When bound to the mutated AR, the compounds were found to have a dual effect, stimulating transcription at low concentrations while almost fully blocking it at the higher concentrations tested, in the presence of the natural androgen dihydrotestosterone (DHT). Compounds 8 and 12 were the most active against PC-3 cell proliferation with EC50 values of 2.2 and 0.2 microM, respectively. PMID:18582482

  4. Endothelial Cell Death, Angiogenesis, and Microvascular Function after Castration in an Androgen-Dependent Tumor: Role of Vascular Endothelial Growth Factor

    NASA Astrophysics Data System (ADS)

    Jain, Rakesh K.; Safabakhsh, Nina; Sckell, Axel; Chen, Yi; Jiang, Ping; Benjamin, Laura; Yuan, Fan; Keshet, Eli

    1998-09-01

    The sequence of events that leads to tumor vessel regression and the functional characteristics of these vessels during hormone--ablation therapy are not known. This is because of the lack of an appropriate animal model and monitoring technology. By using in vivo microscopy and in situ molecular analysis of the androgen-dependent Shionogi carcinoma grown in severe combined immunodeficient mice, we show that castration of these mice leads to tumor regression and a concomitant decrease in vascular endothelial growth factor (VEGF) expression. Androgen withdrawal is known to induce apoptosis in Shionogi tumor cells. Surprisingly, tumor endothelial cells begin to undergo apoptosis before neoplastic cells, and rarefaction of tumor vessels precedes the decrease in tumor size. The regressing vessels begin to exhibit normal phenotype, i.e., lower diameter, tortuosity, vascular permeability, and leukocyte adhesion. Two weeks after castration, a second wave of angiogenesis and tumor growth begins with a concomitant increase in VEGF expression. Because human tumors often relapse following hormone--ablation therapy, our data suggest that these patients may benefit from combined anti-VEGF therapy.

  5. Antioxidants Abrogate Alpha-Tocopherylquinone-Mediated Down-Regulation of the Androgen Receptor in Androgen-Responsive Prostate Cancer Cells

    PubMed Central

    Fajardo, Alexandra M.; MacKenzie, Debra A.; Olguin, Sarah L.; Scariano, John K.; Rabinowitz, Ian; Thompson, Todd A.

    2016-01-01

    Tocopherylquinone (TQ), the oxidation product of alpha-tocopherol (AT), is a bioactive molecule with distinct properties from AT. In this study, AT and TQ are investigated for their comparative effects on growth and androgenic activity in prostate cancer cells. TQ potently inhibited the growth of androgen-responsive prostate cancer cell lines (e.g., LAPC4 and LNCaP cells), whereas the growth of androgen-independent prostate cancer cells (e.g., DU145 cells) was not affected by TQ. Due to the growth inhibitory effects induced by TQ on androgen-responsive cells, the anti-androgenic properties of TQ were examined. TQ inhibited the androgen-induced activation of an androgen-responsive reporter and inhibited the release of prostate specific antigen from LNCaP cells. TQ pretreatment was also found to inhibit AR activation as measured using the Multifunctional Androgen Receptor Screening assay. Furthermore, TQ decreased androgen-responsive gene expression, including TM4SF1, KLK2, and PSA over 5-fold, whereas AT did not affect the expression of androgen-responsive genes. Of importance, the antiandrogenic effects of TQ on prostate cancer cells were found to result from androgen receptor protein down-regulation produced by TQ that was not observed with AT treatment. Moreover, none of the androgenic endpoints assessed were affected by AT. The down-regulation of androgen receptor protein by TQ was abrogated by co-treatment with antioxidants. Overall, the biological actions of TQ were found to be distinct from AT, where TQ was found to be a potent inhibitor of cell growth and androgenic activity in androgen-responsive prostate cancer cells. PMID:26986969

  6. Long-term effects of perinatal androgenization on reproductive parameters of male rat offspring androgenization and male rat reproduction.

    PubMed

    Guerra, M T; Perobelli, J E; Sanabria, M; Anselmo-Franci, J A; Kempinas, W De Grava

    2013-08-01

    It is known that during sex differentiation, fetal androgens are critical determinants of the male phenotype. Although testosterone is necessary for normal development of male sexual behavior, perinatal androgen treatment can result in disruption of normal male sexual reproduction. Pregnant Wistar rats were administered either corn oil (vehicle) or testosterone propionate at 0.2 mg/kg from gestational day 12 until the end of lactation and the reproductive function of male offspring was evaluated at 90 (adulthood) and 270 (middle age) days of age. Perinatal androgenization in the rat provoked a reduction in sperm production and reserves in adulthood that did not affect fertility and did not persist at more advanced ages, as shown by the results at post-natal day 270. If perinatal androgenization promotes similar effects in humans of reproductive age, the results of the present work can impact male reproduction health, given the less efficient spermatogenesis and lower sperm reserves in the human epididymis, compared to rodents. PMID:23549673

  7. Genetic ablation of androgen receptor signaling in fetal Leydig cell lineage affects Leydig cell functions in adult testis.

    PubMed

    Kaftanovskaya, Elena M; Lopez, Carolina; Ferguson, Lydia; Myhr, Courtney; Agoulnik, Alexander I

    2015-06-01

    It is commonly accepted that androgen-producing fetal Leydig cells (FLC) are substituted by adult Leydig cells (ALC) during perinatal testis development. The mechanisms influencing this process are unclear. We used mice with a retinoid acid receptor 2 promoter-Cre recombinase transgene (Rarb-cre) expressed in embryonic FLC precursors, but not in postnatal testis, and a dual fluorescent Cre recombinase reporter to label FLC and ALC in vivo. All FLC in newborn testis had the recombinant, whereas the majority of LC in adult testis had the nonrecombinant reporter. Primary LC cultures from adult testis had either recombinant (20%) or nonrecombinant (80%) cells, demonstrating that the FLC survive in adult testis and their ontogeny is distinct from ALC. Conditional inactivation of androgen receptor (AR) allele using the Rarb-cre transgene resulted in a 50% increase of AR-negative LC in adult testis. The mutant males became infertile with age, with all LC in older testis showing signs of incomplete differentiation, such as a large number of big lipid droplets, an increase of finger-like protrusions, and a misexpression of steroidogenic or FLC- and ALC-specific genes. We propose that the antiandrogenic exposure during early development may similarly result in an increase of FLC in adult testis, leading to abnormal LC differentiation. PMID:25713029

  8. Estrogen receptor (ER) agonists and androgen receptor (AR) antagonists in effluents from Norwegian North Sea oil production platforms.

    PubMed

    Tollefsen, Knut-Erik; Harman, Christopher; Smith, Andy; Thomas, Kevin V

    2007-03-01

    The in vitro estrogen receptor (ER) agonist and androgen receptor (AR) antagonist potencies of offshore produced water effluents collected from the Norwegian Sector were determined using recombinant yeast estrogen and androgen screens. Solid phase extraction (SPE) concentrates of the effluents showed E2 agonist activities similar to those previously reported for the United Kingdom (UK) Continental Shelf (<0.1-4 ng E2 L(-1)). No activity was detected in the filtered oil droplets suggesting that produced water ER activity is primarily associated with the dissolved phase. Targeted analysis for methyl- to nonyl-substituted alkylphenol isomers show the occurrence of known ER agonists in the analysed samples. For the first time, AR antagonists were detected in both the dissolved and oil associated phase at concentrations of between 20 and 8000 microg of flutamide equivalents L(-1). The identity of the AR antagonists is unknown, however this represents a significant input into the marine environment of unknown compounds that exert a known biological effect. It is recommended that further analysis using techniques such as bioassay-directed analysis is performed to identify the compounds/groups of compounds that are responsible in order to improve the assessment of the risk posed by produced water discharges to the marine environment. PMID:17258235

  9. 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

  10. Evidence that obesity and androgens have independent and opposing effects on gonadotropin production from puberty to maturity.

    PubMed

    Rosenfield, Robert L; Bordini, Brian

    2010-12-10

    Optimal fat mass is necessary for normal gonadotropin levels in adults, and both undernutrition and overnutrition suppress gonadotropins: thus, the gonadotropin response to relative adipose mass is biphasic. Adult obesity is associated with blunted luteinizing hormone (LH) pulse amplitude that is partially attributable to increased LH clearance rate. Testosterone appears to have a biphasic effect on gonadotropin production in females. Moderate elevations of testosterone appear to stimulate LH production at both the hypothalamic and pituitary level, while very high levels of testosterone suppress LH. Thus, obesity per se appears to suppress gonadotropin production, and moderate hyperandrogenemia in women appears to stimulate LH. The ordinary hypergonadotropic hyperandrogenism of obese women appears to be an exception to this model because it is usually due to polycystic ovary syndrome (PCOS), a condition in which intrinsic functional ovarian hyperandrogenism and excess adiposity share a common origin that involves insulin-resistant hyperinsulinemia. LH elevation seems to be secondary to hyperandrogenemia and is absent in the most obese cases. Overweight early pubertal girls have significant blunting of sleep-related LH production, which is the first hormonal change of puberty. The data are compatible with the possibility that excess adiposity may paradoxically subtly suppress hypothalamic-pituitary-gonadal function in early puberty although it is known to contribute to the early onset of puberty. PMID:20816944

  11. Disruption of Androgen Receptor Signaling in Males by Environmental Chemicals

    PubMed Central

    Luccio-Camelo, Doug C.; Prins, Gail S

    2011-01-01

    Androgen-disruptors are environmental chemicals in that interfere with the biosynthesis, metabolism or action of endogenous androgens resulting in a deflection from normal male developmental programming and reproductive tract growth and function. Since male sexual differentiation is entirely androgen-dependent, it is highly susceptible to androgen-disruptors. Animal models and epidemiological evidence link exposure to androgen disrupting chemicals with reduced sperm counts, increased infertility, testicular dysgenesis syndrome, and testicular and prostate cancers. Further, there appears to be increased sensitivity to these agents during critical developmental windows when male differentiation is at its peak. A variety of in vitro and in silico approaches have been used to identify broad classes of androgen disrupting molecules that include organochlorinated pesticides, industrial chemicals, and plasticizers with capacity to ligand the androgen receptor. The vast majority of these synthetic molecules act as anti-androgens. This review will highlight the evidence for androgen disrupting chemicals that act through interference with the androgen receptor, discussing specific compounds for which there is documented in vivo evidence for male reproductive tract perturbations. PMID:21515368

  12. Effects of aromatase inhibition and androgen activity on serotonin and behavior in male macaques.

    PubMed

    Bethea, Cynthia L; Reddy, Arubala P; Robertson, Nicola; Coleman, Kristine

    2013-06-01

    Aggression in humans and animals has been linked to androgens and serotonin function. To further our understanding of the effect of androgens on serotonin and aggression in male macaques, we sought to manipulate circulating androgens and the activity of aromatase; and to then determine behavior and the endogenous availability of serotonin. Male Japanese macaques (Macaca fuscata) were castrated for 5-7 months and then treated for 3 months with (a) placebo; (b) testosterone (T); (c) T + Dutasteride (5a reductase inhibitor; AvodartTM); (d) T + Letrozole (nonsteroidal aromatase inhibitor; FemeraTM); (e) Flutamide + ATD (androgen antagonist plus steroidal aromatase inhibitor); or (f) dihydrotestosterone (DHT) + ATD (n = 5/group). Behavioral observations were made during treatments. At the end of the treatment period, each animal was sedated with propofol and administered a bolus of fenfluramine (5 mg/kg). Fenfluramine causes the release of serotonin proportional to endogenous availability and in turn, serotonin stimulates the secretion of prolactin. Therefore, serum prolactin concentrations reflect endogenous serotonin. Fenfluramine significantly increased serotonin/prolactin in all groups (p < .0001). Fenfluramine-induced serotonin/prolactin in the T-treated group was significantly higher than the other groups (p < .0001). Castration partially reduced the serotonin/prolactin response and Letrozole partially blocked the effect of T. Complete inhibition of aromatase with ATD, a noncompetitive inhibitor, significantly and similarly reduced the fenfluramine-induced serotonin/prolactin response in the presence or absence of DHT. Neither aggressive behavior nor yawning (indicators of androgen activity) correlated with serotonin/prolactin, but posited aromatase activity correlated significantly with prolactin (p < .0008; r² = 0.95). In summary, androgens induced aggressive behavior but they did not regulate serotonin. Altogether, the data suggest that aromatase activity

  13. Aberrant splicing of androgenic receptor mRNA results in synthesis of a nonfunctional receptor protein in a patient with androgen insensitivity

    SciTech Connect

    Ris-Stalpers, C.; Kuiper, G.G.J.M.; Faber, P.W.; van Rooij, H.C.J.; Degenhart, H.J.; Trapman, J.; Brinkmann, A.O. ); Schweikert, H.U. ); Zegers, N.D. ); Hodgins, M.B. )

    1990-10-01

    Androgen insensitivity is a disorder in which the correct androgen response in an androgen target cell is impaired. The clinical symtpoms of this X chromosome-linked syndrome are presumed to be caused by mutations in the androgen receptor gene. The authors report a G {r arrow} T mutation in the splice donor site of intron 4 of the androgen receptor gene of a 46, XY subject lacking detectable androgen binding to the receptor and with the complete form of androgen insensitivity. This point mutation completely abolishes normal RNA splicing at the exon 4/intron 4 boundary and results in the activation of a cryptic splice donor site in exon 4, which leads to the deletion of 123 nucleotides from the mRNA. Translation of the mutant mRNA results in an androgen receptor protein {approx}5 kDa smaller than the wild type. This mutated androgen receptor protein was unable to bind androgens and unable to activate transcription of an androgen-regulated reporter gene construct. This mutation in the human androgen receptor gene demonstrates the importance of an intact steroid-binding domain for proper androgen receptor functioning in vivo.

  14. Androgen Receptor Coactivators in Regulation of Growth and Differentiation in Prostate Cancer.

    PubMed

    Culig, Zoran

    2016-02-01

    Androgen receptor (AR) is a key factor in regulation of growth and differentiation in normal and malignant prostate. Endocrine therapies for prostate cancer include inhibition of androgen production either by analogs of luteinizing hormone releasing hormone or abiraterone acetate and/or use of anti-androgens such as hydroxyflutamide, bicalutamide, and enzalutamide. Castration therapy-resistant cancer develops inevitably in patients who undergo treatment. AR coactivators are proteins which interact with one or more regions of the AR thus enhancing its function. Although several functions of AR coactivators may be redundant, specific functions have been identified and analyzed. The p160 group of coactivators, SRC-1, -2, and -3 not only potentiate the activation of the AR, but are also implicated in potentiation of function of insulin-like growth factor-I and activation of the Akt pathway. Transcriptional integrators p300 and CBP are up-regulated by androgen ablation and may influence antagonist/agonist balance of non-steroidal anti-androgens. A therapy approach designed to target p300 in prostate cancer revealed its role in regulation of proliferation of migration of androgen-sensitive and -insensitive prostate cancer cells. Coactivators p300 and SRC-1 are required for AR activation by interleukin-6 (IL-6), a cytokine that is overexpressed in castration therapy-resistant prostate cancer. Some coactivators, such as Vav3, are involved in regulation of transcriptional activity of truncated AR, which emerge during endocrine thrapy. Stimulation of cellular migration and invasion by AR coactivators has also been described. Translational studies with aim to introduce anti-AR coactivator therapy have not been successfully implemented in the clinic so far. PMID:26201947

  15. Androgens and prostate disease

    PubMed Central

    Cooper, Lori A; Page, Stephanie T

    2014-01-01

    A growing body of literature has established the anabolic benefits of testosterone (T) therapy in hypogonadal men. However, there remains a paucity of data regarding the risks of exogenous androgen use in older men and the potential for adverse effects on the prostate gland. Whether T therapy in older, hypogonadal men might worsen lower urinary tract symptoms or exacerbate, unmask, or even incite prostate cancer development has tempered enthusiasm for T therapy, while known prostatic disease has served as a relative contraindication to T therapy. Androgens are necessary for the development and maintenance of the prostate gland. However, epidemiologic studies do not consistently find a positive relationship between endogenous serum androgen concentrations and the risk of prostate disease. Recent data demonstrate that 5α-reductase inhibitors decrease the risk of low-grade prostate cancer, suggesting that modifying androgen metabolism may have beneficial effects on prostate health, yet similar reductions in high-grade disease have not been observed, thereby questioning the true clinical benefits of these agents for chemoprevention. Knowing how to best investigate the relationship between androgens and the development of prostate disease given the lack of large, randomized trials is difficult. Accumulating data challenges the assumption that alterations in serum androgens have parallel effects within the prostate hormonal environment or change androgen-regulated processes within the gland. Long-term intervention studies are needed to truly ascertain the effects of androgen manipulation on prostate tissue and disease risk. However, available data do not support the notion that restoring serum androgens to normal physiologic ranges drives prostate disease. PMID:24407178

  16. Androgen levels and female social dominance in Lemur catta.

    PubMed

    von Engelhardt, N; Kappeler, P M; Heistermann, M

    2000-08-01

    Morphological and behavioural traits which improve agonistic power are subject to intrasexual selection and, at the proximate level, are influenced by circulating androgens. Because intrasexual selection in mammals is more intense among males, they typically dominate females. Female social dominance is therefore unexpected and, indeed, rare. Ring-tailed lemurs (Lemur catta) are sexually monomorphic primates in which all adult females dominate all males. The goal of our study was to test the prediction that female dominance in this species is associated with high androgen levels. Using two captive groups, we collected data on agonistic behaviour and non-invasively assessed their androgen concentrations in faeces and saliva by enzyme immunoassay. We found that adult female L. catta do not have higher androgen levels than males. However, during the mating season there was a twofold increase in both the androgen levels and conflict rates among females. This seasonal increase in their androgen levels was probably not due to a general increase in ovarian hormone production because those females showing the strongest signs of follicular development tended to have low androgen concentrations. At the individual level neither the individual aggression rates nor the proportion of same-sexed individuals dominated were correlated with their androgen levels. We conclude that female dominance in ring-tailed lemurs is neither based on physical superiority nor on high androgen levels and that it is equally important to study male subordination and prenatal brain priming effects for a complete understanding of this phenomenon. PMID:11007329

  17. 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...

  18. Pilot Study on the Effect of Botanical Medicine (Tribulus terrestris) on Serum Testosterone Level and Erectile Function in Aging Males With Partial Androgen Deficiency (PADAM).

    PubMed

    Roaiah, Mohamed Farid; El Khayat, Yasser Ibrahim; GamalEl Din, Sameh Fayek; Abd El Salam, Mohamed Ahmed

    2016-05-18

    This study was conducted on 30 consecutive male patients presenting to Kasr-Al Ainy Andrology outpatient clinic complaining of manifestations of partial androgen deficiency in aging males (PADAM). In this study (750 mg/day) of Tribulus terrestris in 3 divided doses, each of 250 mg, as an endogenous testosterone enhancer had been tried for a duration of 3 months and the evaluation of its effect had been monitored for each patient concerning its effect on serum testosterone (total and free) and luteinizing hormone (LH), as well as its impact on erectile function, which was evaluated by the International Index of Erectile Function-5 (IIEF-5) questionnaire for those patients. Results showed a statistically significant difference in the level of testosterone (total and free) and IIEF-5, but no statistically significant difference in the level of LH before and after treatment. Also, the study showed statistically significant correlation between testosterone (total and free) and IIEF-5, but no statistically significant correlation between the level of LH and the IIEF-5 before and after treatment. PMID:25849625

  19. 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. PMID:26991422

  20. Production Function Geometry with "Knightian" Total Product

    ERIC Educational Resources Information Center

    Truett, Dale B.; Truett, Lila J.

    2007-01-01

    Authors of principles and price theory textbooks generally illustrate short-run production using a total product curve that displays first increasing and then diminishing marginal returns to employment of the variable input(s). Although it seems reasonable that a temporary range of increasing returns to variable inputs will likely occur as…

  1. Distinguishing seasonal androgen responses from male-male androgen responsiveness-revisiting the Challenge Hypothesis.

    PubMed

    Goymann, Wolfgang; Landys, Meta M; Wingfield, John C

    2007-04-01

    Androgen levels show strong patterns throughout the year in male vertebrates and play an important role in the seasonal modulation of the frequency, intensity and persistence of aggression. The Challenge Hypothesis (Wingfield, J.C., Hegner, R.E., Dufty, A.M., Ball, G.F., 1990. The "Challenge Hypothesis": Theoretical implications for patterns of testosterone secretion, mating systems, and breeding strategies. Am. Nat. 136, 829-846) predicts that seasonal patterns in androgen levels vary as a function of mating system, male-male aggression and paternal care. Although many studies have addressed these predictions, investigators have often assumed that the ratio of the breeding season maximum and breeding baseline concentrations (termed "androgen responsiveness") reflects hormonal responses due to social stimulation. However, increasing evidence suggests that seasonal androgen elevations are not necessarily caused by social interactions between males. Here, we separate the seasonal androgen response (R(seasonal)) and the androgen responsiveness to male-male competition (R(male-male)) to begin to distinguish between different kinds of hormonal responses. We demonstrate that R(seasonal) and R(male-male) are fundamentally different and should be treated as separate variables. Differences are particularly evident in single-brooded male birds that show no increase in plasma androgen levels during simulated territorial intrusions (STIs), even though R(seasonal) is elevated. In multiple-brooded species, STIs typically elicit a rise in androgens. We relate these findings to the natural history of single- and multiple-brooded species and suggest a research approach that could be utilized to increase our understanding of the factors that determine different types of androgen responses. This approach does not only include R(seasonal) and R(male-male), but also the androgen responsiveness to receptive females (R(male-female)) and to non-social environmental cues (R

  2. Social modulation of androgens in male birds.

    PubMed

    Goymann, Wolfgang

    2009-09-01

    Most seasonally reproducing vertebrates show pronounced changes in testosterone levels throughout the year. The Challenge Hypothesis [Wingfield, J.C., Hegner, R.E., Dufty, A.M., Ball, G. F., 1990. The "challenge hypothesis": theoretical implications for patterns of testosterone secretion, mating systems, and breeding strategies. Am. Nat. 136, 829-846] predicts that seasonal patterns in circulating androgen concentrations vary as a function of mating system, male-male aggression and paternal care. In most comparative studies, the predictions of the Challenge Hypothesis have been tested primarily by calculating the ratio between breeding peak and breeding baseline testosterone concentrations, using this ratio as a proxy for the effect that social interactions have on testosterone levels (androgen responsiveness R). Recently, we suggested that it is preferable to separate the seasonal testosterone response (R(season)) from the androgen responsiveness to male-male interactions (R(male-male)), as these two measures do not correlate and can differ both in magnitude and direction [Goymann, W., Landys, M.M., Wingfield, J.C., 2007. Distinguishing seasonal androgen responses from male-male androgen responsiveness-revisiting the Challenge Hypothesis. Horm. Behav. 51, 463-476]. Here, I discuss several methodological and ecological factors that may explain why R(season) and R(male-male) differ. Furthermore, I describe three other kinds of androgen responsiveness, namely the androgen responsiveness of males to receptive females (R(male-female)), to non-social environmental cues (R(environment)), and the potential androgen responsiveness (R(potential)). The latter is measured before and after an injection of gonadotropin releasing hormone (GnRH), which typically leads to a maximal release of testosterone from the testes. I argue that separation of different kinds of androgen responsiveness and putting them into context with the natural history and ecology of a study species may

  3. PROCHLORAZ INHIBITS TESTOSTERONE PRODUCTION AT DOSAGE BELOW THOSE THAT AFFECT ANDROGEN-DEPENDENT ORGAN WEIGHTS OR THE ONSET OF PUBERTY IN THE MALE SPRAGUE DAWLEY RAT

    EPA Science Inventory

    ABSTRACT: Since prochloraz (PCZ) is an imidazole fungicide that inhibits gonadal steroidogenesis and antagonizes the androgen receptor (AR), we hypothesized that pubertal exposure to PCZ would delay male rat reproductive development. Sprague Dawley rats were dosed by gavage with...

  4. Cytochrome b5 Activates the 17,20-Lyase Activity of Human Cytochrome P450 17A1 by Increasing the Coupling of NADPH Consumption to Androgen Production.

    PubMed

    Peng, Hwei-Ming; Im, Sang-Choul; Pearl, Naw May; Turcu, Adina F; Rege, Juilee; Waskell, Lucy; Auchus, Richard J

    2016-08-01

    Human cytochrome P450 17A1 is required for all androgen biosynthesis and is the target of abiraterone, a drug used widely to treat advanced prostate cancer. P450 17A1 catalyzes both 17-hydroxylation and subsequent 17,20-lyase reactions with pregnenolone, progesterone, and allopregnanolone. The presence of cytochrome b5 (b5) markedly stimulates the 17,20-lyase reaction, with little effect on 17-hydroxylation; however, the mechanism of this b5 effect is not known. We determined the influence of b5 on coupling efficiency-defined as the ratio of product formation to NADPH consumption-in a reconstituted system using these 3 pairs of substrates for the 2 reactions. Rates of NADPH consumption ranged from 4 to 13 nmol/min/nmol P450 with wild-type P450 17A1. For the 17-hydroxylase reaction, progesterone oxidation was the most tightly coupled (∼50%) and negligibly changed upon addition of b5. Rates of NADPH consumption were similar for the 17-hydroxylase and corresponding 17,20-lyase reactions for each steroid series, and b5 only slightly increased NADPH consumption. For the 17,20-lyase reactions, b5 markedly increased product formation and coupling in parallel with all substrates, from 6% to 44% with the major substrate 17-hydroxypregnenolone. For the naturally occurring P450 17A1 mutations E305G and R347H, which impair 17,20-lyase activity, b5 failed to rescue the poor coupling with 17-hydroxypregnenolone (2-4%). When the conserved active-site threonine was mutated to alanine (T306A), both the activity and coupling were markedly decreased with all substrates. We conclude that b5 stimulation of the 17,20-lyase reaction primarily derives from more efficient use of NADPH for product formation rather than side products. PMID:27426448

  5. What do urologists think patients need to know when starting on androgen deprivation therapy? The perspective from Canada versus countries with lower gross domestic product

    PubMed Central

    Rot, Irena; Wassersug, Richard J.

    2016-01-01

    Background Androgen deprivation therapy (ADT) side effects are numerous and negatively impact prostate cancer patients’ quality of life. There is considerable discrepancy though among Canadian urologists regarding what ADT side effects and side effect management strategies. Little is known about global differences in ADT patient education. Methods International respondents were recruited via online posting and at an international urology conference. Hypotheses suggest that economic and cultural differences influence patient education practices; therefore, international respondents were divided into 3 categories (high, medium, and low gross domestic product). Results No differences were found between responses from Canadian urologists and high GDP countries. Compared to responses from low GDP countries, Canadian urologists are more likely to endorse informing patients about: osteoporosis, loss of muscle mass, weight gain, fatigue/sleep disturbance, relationship changes, cognitive changes, and loss of body hair. Infertility was the only side effect more often disclosed by urologists in low GDP counties. Recommended management strategies for hot flashes are more likely to be pharmaceutical in Canada, and behavioral in low GDP countries. Management strategies for gynecomastia are emphasized more in low GDP countries. Physical exercise is endorsed consistently more often by Canadian urologists. Conclusions ADT educational practices vary greatly between Canada and lower GDP countries. Factors that could contribute to differences include economics (e.g., ADT drug costs), differences in side effect presentation due to different ADT drugs used, racial differences in perceived side effect burden, disease status at ADT commencement, and cultural differences in patient-physician shared-decision making. PMID:27141453

  6. Leptin and androgens in male obesity: evidence for leptin contribution to reduced androgen levels.

    PubMed

    Isidori, A M; Caprio, M; Strollo, F; Moretti, C; Frajese, G; Isidori, A; Fabbri, A

    1999-10-01

    Leptin circulates in plasma at concentrations that parallel the amount of fat reserves. In obese males, androgen levels decline in proportion to the degree of obesity. Recently, we have shown that in rodent Leydig cells leptin inhibits hCG-stimulated testosterone (T) production via a functional leptin receptor isoform; others have found that leptin inhibits basal and hCG-induced T secretion by testis from adult rats. In this study, we further investigated the relationship linking leptin and androgens in men. Basal and hCG-stimulated leptin and sex hormone levels were studied in a large group of men ranging from normal weight to very obese (body mass index, 21.8-55.7). Initial cross-sectional studies showed that circulating leptin and fat mass (FM) were inversely related with total and free T (r = -0.51 and r = -0.38, P < 0.01 and P < 0.05, respectively). Multiple regression analysis indicated that the correlation between leptin or FM and T was not lost after controlling for SHBG and/or LH and/or estradiol (E2) levels and that leptin was the best hormonal predictor of the lower androgen levels in obesity. Dynamic studies showed that in obese men the area under the curve of T and free T to LH/hCG stimulation (5000 IU i.m.) was 30-40% lower than in controls and inversely correlated with leptin levels (r = -0.45 and r = -0.40, P < 0.01 and P < 0.05, respectively). Also, LH/hCG-stimulation caused higher increases in 17-OH-progesterone to T ratio in obese men than in controls, whereas no differences were observed between groups either in stimulated E2 levels or in the E2/T ratio. In all subjects, the percentage increases from baseline in the 17-OH-progesterone to T ratio were directly correlated with leptin levels or FM (r = 0.40 and r = 0.45, P < 0.01), but not with E2 or other hormonal variables. In conclusion, our studies, together with previous in vitro findings, indicate that excess of circulating leptin may be an important contributor to the development of reduced

  7. Neurotropic action of androgens: principles, mechanisms and novel targets.

    PubMed

    Patchev, Vladimir K; Schroeder, Jens; Goetz, Franziska; Rohde, Wolfgang; Patchev, Alexandre V

    2004-01-01

    The importance of androgen signaling is well recognized for numerous aspects of central nervous system (CNS) function, ranging from sex-specific organization of neuroendocrine and behavioral circuits to adaptive capacity, resistance and repair. Nonetheless, concepts for the therapeutic use of androgens in neurological and mental disorders are far from being established. This review outlines some critical issues which interfere with decisions on the suitability of androgens as therapeutic agents for CNS conditions. Among these, sex-specific organization of neural substrates and resulting differential responsiveness to endogenous gonadal steroids, convergence of steroid hormone actions on common molecular targets, co-presence of different sex steroid receptors in target neuronal populations, and in situ biotransformation of natural androgens apparently pose the principal obstacles for the characterization of specific neurotropic effects of androgens. Additional important, albeit less explored aspects consist in insufficient knowledge about molecular targets in the CNS which are under exclusive or predominant androgen control. Own experimental data illustrate the variability of pharmacological effects of natural and synthetic androgens on CNS functions of adaptive relevance, such as sexual behavior, anxiety and endocrine responsiveness to stress. Finally, we present results from an analysis of the consequences of aging for the rat brain transcriptome and examination of the influence of androgens on differentially expressed genes with presumable significance in neuropathology. PMID:15582281

  8. MicroRNA Library-Based Functional Screening Identified Androgen-Sensitive miR-216a as a Player in Bicalutamide Resistance in Prostate Cancer

    PubMed Central

    Miyazaki, Toshiaki; Ikeda, Kazuhiro; Sato, Wataru; Horie-Inoue, Kuniko; Okamoto, Koji; Inoue, Satoshi

    2015-01-01

    Prostate cancer is a major hormone-dependent tumor affecting men, and is often treated by hormone therapy at the primary stages. Despite its initial efficiency, the disease eventually acquires resistance, resulting in the recurrence of castration-resistant prostate cancer. Recent studies suggest that dysregulation of microRNA (miRNA) function is one of the mechanisms underlying hormone therapy resistance. Identification of critical miRNAs involved in endocrine resistance will therefore be important for developing therapeutic targets for prostate cancer. In the present study, we performed an miRNA library screening to identify anti-androgen bicalutamide resistance-related miRNAs in prostate cancer LNCaP cells. Cells were infected with a lentiviral miRNA library and subsequently maintained in media containing either bicalutamide or vehicle for a month. Microarray analysis determined the amounts of individual miRNA precursors and identified 2 retained miRNAs after one-month bicalutamide treatment. Of these, we further characterized miR-216a, because its function in prostate cancer remains unknown. miR-216a could be induced by dihydrotestosterone in LNCaP cells and ectopic expression of miR-216a inhibited bicalutamide-mediated growth suppression of LNCaP cells. Furthermore, a microarray dataset revealed that the expression levels of miR-216a were significantly higher in clinical prostate cancer than in benign samples. These results suggest that functional screening using an miRNA expression library could be useful for identifying novel miRNAs that contribute to bicalutamide resistance in prostate cancer. PMID:26506397

  9. 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

  10. Steroidogenic pathways involved in androgen biosynthesis in eumenorrheic women and patients with polycystic ovary syndrome.

    PubMed

    Saito, Kazuki; Matsuzaki, Toshiya; Iwasa, Takeshi; Miyado, Mami; Saito, Hidekazu; Hasegawa, Tomonobu; Homma, Keiko; Inoue, Eisuke; Miyashiro, Yoshimichi; Kubota, Toshiro; Irahara, Minoru; Ogata, Tsutomu; Fukami, Maki

    2016-04-01

    The conventional Δ5 and Δ4 steroidogenic pathways mediate androgen production in females. While multiple non-conventional pathways to dihydrotestosterone (DHT) have recently been postulated in humans, the functional significance of these pathways remains to be elucidated. The aim of this study was to clarify the origin of androgens in healthy women and in patients with polycystic ovary syndrome (PCOS), a multifactorial disorder characterized by androgen overproduction. We measured 13 steroids in blood samples of 31 eumenorrheic females and 28 PCOS patients using liquid chromatography-tandem mass spectrometry and chemiluminescent enzyme immunoassay. We found that 17-hydroxy (17-OH) progesterone (17-OHP), androstenedione (Δ4A), testosterone, androstanedione, androsterone, and androstanediol levels were higher in the patient group than in the eumenorrheic group, while levels of other steroids were comparable between the two groups. In the eumenorrheic group, DHT levels were correlated with testosterone, androstanedione, and androstanediol. Quantitative correlations were also observed among 17-OH allopregnanolone, androsterone, androstanediol, and DHT, and among Δ4A, androstanedione, androsterone, and androstanediol. In the patient group, DHT levels were correlated with testosterone levels, but not with androstanedione or androstanediol levels. Δ4A and testosterone paralleled 17-OHP. Androstanedione, androsterone, androstanediol, and 17-OH allopregnanolone were quantitatively correlated. In both groups, multivariable linear regression analyses suggested relationships between androsterone and androstanedione, as well as between androsterone and 17-OH allopregnanolone. These results indicate that multiple androgen biosynthesis pathways are operating in eumenorrheic females and PCOS patients. In PCOS patients, excessive androgens are produced primarily via the conventional pathways, while two alternative pathways; i.e., an androstanedione-mediated pathway and a so

  11. Androgen receptors and experimental bone loss - an in vivo and in vitro study.

    PubMed

    Steffens, Joao Paulo; Coimbra, Leila Santana; Rossa, Carlos; Kantarci, Alpdogan; Van Dyke, Thomas E; Spolidorio, Luis Carlos

    2015-12-01

    Testosterone is a sex hormone that exhibits many functions beyond reproduction; one such function is the regulation of bone metabolism. The role played by androgen receptors during testosterone-mediated biological processes associated with bone metabolism is largely unknown. This study aims to use a periodontal disease model in vivo in order to assess the involvement of androgen receptors on microbial-induced inflammation and alveolar bone resorption in experimental bone loss. The impact of hormone deprivation was tested through both orchiectomy and chemical blockage of androgen receptor using flutamide (FLU). Additionally, the direct effect of exogenous testosterone, and the role of the androgen receptor, on osteoclastogenesis were investigated. Thirty male adult rats (n=10/group) were subjected to: 1-orchiectomy (OCX); 2-OCX sham surgery; or 3-OCX sham surgery plus FLU, four weeks before the induction of experimental bone loss. Ten OCX sham-operated rats were not subjected to experimental bone loss and served as healthy controls. The rats were euthanized two weeks later, so as to assess bone resorption and the production of inflammatory cytokines in the gingival tissue and serum. In order to study the in vitro impact of testosterone, osteoclasts were differentiated from RAW264.7 cells and testosterone was added at increasing concentrations. Both OCX and FLU increased bone resorption, but OCX alone was observed to increase osteoclast count. IL-1β production was increased only in the gingival tissue of OCX animals, whereas FLU-treated animals presented a decreased expression of IL-6. Testosterone reduced the osteoclast formation in a dose-dependent manner, and significantly impacted the production of TNF-α; FLU partially reversed these actions. When taken together, our results indicate that testosterone modulates experimental bone loss, and that this action is mediated, at least in part, via the androgen receptor. PMID:26450018

  12. Androgen receptor modulates Foxp3 expression in CD4+CD25+Foxp3+ regulatory T-cells

    PubMed Central

    Walecki, Magdalena; Eisel, Florian; Klug, Jörg; Baal, Nelli; Paradowska-Dogan, Agnieszka; Wahle, Eva; Hackstein, Holger; Meinhardt, Andreas; Fijak, Monika

    2015-01-01

    CD4+CD25+Foxp3+ regulatory T (Treg) cells are able to inhibit proliferation and cytokine production in effector T-cells and play a major role in immune responses and prevention of autoimmune disease. A master regulator of Treg cell development and function is the transcription factor Foxp3. Several cytokines, such as TGF-β and IL-2, are known to regulate Foxp3 expression as well as methylation of the Foxp3 locus. We demonstrated previously that testosterone treatment induces a strong increase in the Treg cell population both in vivo and in vitro. Therefore we sought to investigate the direct effect of androgens on expression and regulation of Foxp3. We show a significant androgen-dependent increase of Foxp3 expression in human T-cells from women in the ovulatory phase of the menstrual cycle but not from men and identify a functional androgen response element within the Foxp3 locus. Binding of androgen receptor leads to changes in the acetylation status of histone H4, whereas methylation of defined CpG regions in the Foxp3 gene is unaffected. Our results provide novel evidence for a modulatory role of androgens in the differentiation of Treg cells. PMID:26063731

  13. The RNA-binding protein Sam68 regulates expression and transcription function of the androgen receptor splice variant AR-V7

    PubMed Central

    Stockley, Jacqueline; Markert, Elke; Zhou, Yan; Robson, Craig N.; Elliott, David J.; Lindberg, Johan; Leung, Hing Y.; Rajan, Prabhakar

    2015-01-01

    Castration-resistant (CR) prostate cancer (PCa) partly arises due to persistence of androgen receptor (AR) transcriptional activity in the absence of cognate ligand. An emerging mechanism underlying the CRPCa phenotype and predicting response to therapy is the expression of the constitutively-active AR-V7 splice variant generated by AR cryptic exon 3b inclusion. Here, we explore the role of the RNA-binding protein (RBP) Sam68 (encoded by KHDRBS1), which is over-expressed in clinical PCa, on AR-V7 expression and transcription function. Using a minigene reporter, we show that Sam68 controls expression of exon 3b resulting in an increase in endogenous AR-V7 mRNA and protein expression in RNA-binding-dependent manner. We identify a novel protein-protein interaction between Sam68 and AR-V7 mediated by a common domain shared with full-length AR, and observe these proteins in the cell nucleoplasm. Using a luciferase reporter, we demonstrate that Sam68 co-activates ligand-independent AR-V7 transcriptional activity in an RNA-binding-independent manner, and controls expression of the endogenous AR-V7-specific gene target UBE2C. Our data suggest that Sam68 has separable effects on the regulation of AR-V7 expression and transcriptional activity, through its RNA-binding capacity. Sam68 and other RBPs may control expression of AR-V7 and other splice variants as well as their downstream functions in CRPCa. PMID:26310125

  14. The RNA-binding protein Sam68 regulates expression and transcription function of the androgen receptor splice variant AR-V7.

    PubMed

    Stockley, Jacqueline; Markert, Elke; Zhou, Yan; Robson, Craig N; Elliott, David J; Lindberg, Johan; Leung, Hing Y; Rajan, Prabhakar

    2015-01-01

    Castration-resistant (CR) prostate cancer (PCa) partly arises due to persistence of androgen receptor (AR) transcriptional activity in the absence of cognate ligand. An emerging mechanism underlying the CRPCa phenotype and predicting response to therapy is the expression of the constitutively-active AR-V7 splice variant generated by AR cryptic exon 3b inclusion. Here, we explore the role of the RNA-binding protein (RBP) Sam68 (encoded by KHDRBS1), which is over-expressed in clinical PCa, on AR-V7 expression and transcription function. Using a minigene reporter, we show that Sam68 controls expression of exon 3b resulting in an increase in endogenous AR-V7 mRNA and protein expression in RNA-binding-dependent manner. We identify a novel protein-protein interaction between Sam68 and AR-V7 mediated by a common domain shared with full-length AR, and observe these proteins in the cell nucleoplasm. Using a luciferase reporter, we demonstrate that Sam68 co-activates ligand-independent AR-V7 transcriptional activity in an RNA-binding-independent manner, and controls expression of the endogenous AR-V7-specific gene target UBE2C. Our data suggest that Sam68 has separable effects on the regulation of AR-V7 expression and transcriptional activity, through its RNA-binding capacity. Sam68 and other RBPs may control expression of AR-V7 and other splice variants as well as their downstream functions in CRPCa. PMID:26310125

  15. Are the Endocrine Society's Clinical Practice Guidelines on Androgen Therapy in Women misguided? A commentary.

    PubMed

    Traish, Abdulmaged; Guay, Andre T; Spark, Richard F

    2007-09-01

    The Endocrine Society Clinical Guidelines on Androgen Therapy in Women (henceforth referred to as the Guidelines) do not necessarily represent the opinion held by the many health-care professionals and clinicians who are specialized in the evaluation, diagnosis, and treatment of women's health in androgen insufficiency states. The recommendations provided in the published Guidelines are neither accurate nor complete. We disagree with the therapeutic nihilism promoted by these Guidelines. The members of the Guidelines Panel (henceforth referred to as the Panel), in their own disclaimer, stated that the Guidelines do not establish a standard of care. Based on data available in the contemporary literature, on the role of androgens in women's health, we provide in this commentary a point-by-point discussion of the arguments made by the Panel in arriving at their recommendations. It is our view that the Guidelines are not based on the preponderance of scientific evidence. Health-care professionals, physicians, and scientists often disagree when determining how best to address and manage new and emerging clinical issues. This is where we stand now as we endeavor to understand the role of androgens in a woman's health and welfare. Indeed, some basic facts are not in contention. All agree that dehydroepiandrosterone sulfate (DHEA-S) production from the adrenal gland begins during the preteen years, peaks in the mid 20s, then declines progressively over time. In contrast, ovarian androgen (i.e., testosterone) secretion commences at puberty, is sustained during a woman's peak reproductive years and declines as a woman ages, with a more rapid and steep decrease after surgical menopause. However, there are ample data to suggest that adrenal androgens play a role in the development of axillary and pubic hair, and that testosterone is critical for women's libido and sexual function. We take this opportunity to invite members of the Panel on Androgen Therapy in Women to discuss

  16. 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...

  17. Sex steroids do not affect muscle weight, oxidative metabolism or cytosolic androgen reception binding of functionally overloaded rat Plantaris muscles

    NASA Technical Reports Server (NTRS)

    Max, S. R.; Rance, N.

    1983-01-01

    The effects of sex steroids on muscle weight and oxidative capacity of rat planaris muscles subjected to functional overload by removal of synergistic muscles were investigated. Ten weeks after bilateral synergist removal, plantaris muscles were significantly hypertrophic compared with unoperated controls. After this period, the ability of the muscles to oxide three substrates of oxidative metabolism was assessed. Experimental procedures are discussed and results are presented herein. Results suggest a lack of beneficial effect of sex hormone status on the process of hypertrophy and on biochemical changes in overloaded muscle. Such findings are not consistent with the idea of synergistic effects of sex steroids and muscle usage.

  18. PROCHLORAZ INHIBITS TESTOSTERONE PRODUCTION AT DOSAGE LEVELS BELOW THOSE THAT AFFECT ANDROGEN-DEPENDENT ORGAN WEIGHTS OR THE ONSET OF MALE RAT PUBERTY

    EPA Science Inventory

    Prochloraz (PCZ) is an imidazole fungicide that has several endocrine modes of action. In vitro, PCZ inhibits steroidogenesis and acts as an androgen receptor (AR) antagonist. We hypothesized that pubertal exposure to prochloraz would delay preputial separation and growth of an...

  19. Novel, potent anti-androgens of therapeutic potential: recent advances and promising developments.

    PubMed

    Vasaitis, Tadas S; Njar, Vincent C O

    2010-04-01

    The beneficial effect of androgen ablation has been well established in prostate cancer therapy. Despite the initial response, patients typically relapse with a more aggressive form described as castration-resistant prostate cancer (CRCP), driven by continued androgen receptor (AR) signaling. This review details the current state of anti-androgen therapy, mainly for CRPC, with major emphasis on the most potent and promising compounds under development. Anti-androgen failure has been linked to elevated AR expression, increased expression of coactivator proteins, AR mutations, ligand-independent AR activation and persistent intraprostatic androgens. MDV3100, BMS-641988 and VN/124-1 were developed to overcome these mechanisms. In CRCP, prostate cancer cells still rely on intracellular androgens and, to a greater extent, on active AR for growth and survival. Therefore, potent anti-androgens that efficiently disrupt the functions (signaling) of AR are envisioned to be effective drugs for all types of prostate cancers. PMID:21426013

  20. A case of androgen-secreting adrenal carcinoma with non-classical congenital adrenal hyperplasia.

    PubMed

    Varma, Tarun; Panchani, Roopal; Goyal, Ashutosh; Maskey, Robin

    2013-10-01

    Androgen excess is one of the most common and disturbing endocrine disorder of reproductive-aged women, affecting approximately 7% of this population Androgen excess results in the development of androgenic features in the women affected, with the development of hirsutism, androgenic alopecia, ovulatory dysfunction, and, if extreme, even virilization and masculinization. Adrenocortical carcinoma (ACC) is a rare malignancy accounting for 0.02% of all annual cancers reported. About 60% are functional tumors secreting hormones, with its consequent clinical manifestations, the Cushing's syndrome due to cortisone, virilization due to androgens, feminization due to estrogens, or hypertension due to aldosterone. Adrenal tumors that secrete androgens exclusively are extremely rare. Here, we present a rare case of androgen-secreting adrenocortical carcinoma with non-classical congenital adrenal hyperplasia. PMID:24251173

  1. Androgen receptor polymorphism (CAG repeats) and androgenicity.

    PubMed

    Canale, D; Caglieresi, C; Moschini, C; Liberati, C D; Macchia, E; Pinchera, A; Martino, E

    2005-09-01

    Objective Polymorphism of the androgen receptor (AR) has been related to various pathophysiological conditions, such as osteoporosis and infertility. The objectives of this study were to evaluate the frequency of distribution in a normal Italian population and to assess CAG repeats (CAGr) in other conditions, such as hypoandrogenism, potentially influenced by AR polymorphism. Patients and measurements CAGr polymorphism was determined in a group of 91 healthy normoandrogenized subjects, 29 hypoandrogenized patients (hypoplasia of prostate and seminal vesicles, reduced beard or body hair, etc.) and 29 infertile patients by direct sequencing. Results The mean (+/- SD) number of CAG repeats [(CAGr)n] was 21.5 (+/- 1.7) in the control group, 21.4 (+/- 2.0) in the infertile patients and 24.0 (+/- 2.9) in the hypoandrogenic males. The difference was statistically significant between this last group and the other two (P < 0.0001), while there was no difference between normal controls and infertile patients. The frequency distribution showed a shift towards higher CAG length in hypoandrogenized patients compared to controls and infertile patients. If we used a cut-off point of 24.9 (2 SD above the mean), the percentage of patients with 25 or more CAGr repeats was 38% among hypoandrogenized patients, 7% among infertile patients and 5% among the control group. In hypoandrogenized subjects (CAGr)n correlated slightly with testis and prostate volume. The number of CAG repeats was not associated with any of the hormonal parameters, including testosterone, evaluated in the three groups. Conclusions Our normal population, representing subjects from Central Italy, is superimposable on other European populations with regard to (CAGr)n distribution. Hypoandrogenic males have a shift in the frequency distribution towards longer (CAGr)n. Infertile patients are not statistically different from the control group. These findings suggest that, given the same amount of circulating

  2. [The mechanisms of prostate cancer progression through androgen receptor].

    PubMed

    Goto, Yusuke; Sakamoto, Shinichi; Ichikawa, Tomohiko

    2016-01-01

    Androgen receptor(AR) has a critical role in prostate cancer(PCa) progression and targeting AR axis signaling by androgen deprivation therapy is a standard treatment for advanced PCa. Recently, the role of AR even in castration-resistant PCa(CRPC) is well recognized and emerging evidence suggests survival advantages of treatment by targeting AR in CRPC. This review outlines AR functions that contribute to PCa progression, AR structural alterations and AR activation via intracrine, co-factors, and kinase pathways in CRPC. Finally, we describe about recently reported bipolar androgen therapy as a novel treatment for CRPC targeting AR. PMID:26793880

  3. The role of mesenchymal stem cells in promoting the transformation of androgen-dependent human prostate cancer cells into androgen-independent manner

    PubMed Central

    Cheng, Jiwen; Yang, Keqin; Zhang, Qingyun; Yu, Yang; Meng, Qinggui; Mo, Ning; Zhou, Yang; Yi, Xianlin; Ma, Chengzhong; Lei, Aming; Liu, Yan

    2016-01-01

    Mesenchymal stem cells (MSCs) play an important role in the development of human prostate cancer (PCa). However, the role of MSCs in the transformation of androgen-dependent human PCa cells into androgen-independent manner has been poorly understood. In this study, we investigated the underlying mechanism of MSCs in promoting PCa cells from androgen-dependent into androgen-independent manner. Firstly, we demonstrated that MSCs could affect the transformation of androgen-dependent human PCa cells into androgen-independent manner in vivo and in vitro. Then we found a substantial expression of TGF-β in MSCs. TGF-β blockade could significantly inhibit the promotive function of MSCs in PCa cells. Besides that, we also demonstrated androgen might inhibit the expression of TGF-β in MSCs. Furthermore, we found that either overexpression of SSEA-4 or the number of SSEA-4 positive MSCs in PCa tissues was associated with a shorter cancer-free survival interval (CFSI) and a worse overall survival (OS). Our results suggest that androgen blockade treatment in clinical PCa therapy may elicit the expression of TGF-β in MSCs, which will result in the transformation of androgen-dependent human PCa cells into androgen-independent manner. PMID:26787499

  4. Cooperative demethylation by JMJD2C and LSD1 promotes androgen receptor-dependent gene expression.

    PubMed

    Wissmann, Melanie; Yin, Na; Müller, Judith M; Greschik, Holger; Fodor, Barna D; Jenuwein, Thomas; Vogler, Christine; Schneider, Robert; Günther, Thomas; Buettner, Reinhard; Metzger, Eric; Schüle, Roland

    2007-03-01

    Posttranslational modifications of histones, such as methylation, regulate chromatin structure and gene expression. Recently, lysine-specific demethylase 1 (LSD1), the first histone demethylase, was identified. LSD1 interacts with the androgen receptor and promotes androgen-dependent transcription of target genes by ligand-induced demethylation of mono- and dimethylated histone H3 at Lys 9 (H3K9) only. Here, we identify the Jumonji C (JMJC) domain-containing protein JMJD2C as the first histone tridemethylase regulating androgen receptor function. JMJD2C interacts with androgen receptor in vitro and in vivo. Assembly of ligand-bound androgen receptor and JMJD2C on androgen receptor-target genes results in demethylation of trimethyl H3K9 and in stimulation of androgen receptor-dependent transcription. Conversely, knockdown of JMJD2C inhibits androgen-induced removal of trimethyl H3K9, transcriptional activation and tumour cell proliferation. Importantly, JMJD2C colocalizes with androgen receptor and LSD1 in normal prostate and in prostate carcinomas. JMJD2C and LSD1 interact and both demethylases cooperatively stimulate androgen receptor-dependent gene transcription. In addition, androgen receptor, JMJD2C and LSD1 assemble on chromatin to remove methyl groups from mono, di and trimethylated H3K9. Thus, our data suggest that specific gene regulation requires the assembly and coordinate action of demethylases with distinct substrate specificities. PMID:17277772

  5. Mutational analysis of the androgen receptor gene in two Chinese families with complete androgen insensitivity syndrome

    PubMed Central

    WANG, SONG; XU, HAIKUN; AN, WEI; ZHU, DECHUN; LI, DEJUN

    2016-01-01

    Androgens are essential for normal male sex differentiation and are responsible for the normal development of male secondary sexual characteristics at puberty. The physiological effects of androgens are mediated by the androgen receptor (AR). Mutations in the AR gene are the most common cause of androgen insensitivity syndrome. The present study undertook a genetic analysis of the AR gene in two unrelated families affected by complete androgen insensitivity syndrome (CAIS) in China. In family 1, a previously reported nonsense mutation (G-to-A; p.W751X) was identified in exon 5 of the AR gene. In addition, a novel missense mutation was detected in exon 6 of the AR gene from family 2; this mutation resulted in a predicted amino acid change from phenylalanine to serine at codon 804 (T-to-C; p.F804S) in the ligand-binding domain (LBD) of AR. Computer simulation of the structural changes generated by the p.F804S substitution revealed marked conformational alterations in the hydrophobic core responsible for the stability and function of the AR-LBD. In conclusion, the present study identified two mutations from two unrelated Chinese families affected by CAIS. The novel mutation (p.F804S) may provide insights into the molecular mechanism underlying CAIS. Furthermore, it expands on the number of mutational hot spots in the international AR mutation database, which may be useful in the future for prenatal diagnosis and genetic counseling. PMID:27284311

  6. Production of recombinant insulin-like androgenic gland hormones from three decapod species: In vitro testicular phosphorylation and activation of a newly identified tyrosine kinase receptor from the Eastern spiny lobster, Sagmariasus verreauxi.

    PubMed

    Aizen, Joseph; Chandler, Jennifer C; Fitzgibbon, Quinn P; Sagi, Amir; Battaglene, Stephen C; Elizur, Abigail; Ventura, Tomer

    2016-04-01

    In crustaceans the insulin-like androgenic gland hormone (IAG) is responsible for male sexual differentiation. To date, the biochemical pathways through which IAG exerts its effects are poorly understood and could be elucidated through the production of a functional recombinant IAG (rIAG). We have successfully expressed glycosylated, biologically active IAG using the Pichia pastoris yeast expression system. We co-expressed recombinant single-chain precursor molecules consisting of the B and A chains (the mature hormone) tethered by a flexible linker, producing rIAGs of the following commercially important species: Eastern spiny lobster Sagmariasus verreauxi (Sv), redclaw crayfish Cherax quadricarinatus (Cq) and giant freshwater prawn Macrobrachium rosenbergii (Mr). We then tested the biological activity of each, through the ability to increase phosphorylation in the testis; both Sv and Cq rIAGs significantly elevated phosphorylation specific to their species, and in a dose-dependent manner. Mr rIAG was tested on Macrobrachium australiense (Ma), eliciting a similar response. Moreover, using bioinformatics analyses of the de novo assembled spiny lobster transcriptome, we identified a spiny lobster tyrosine kinase insulin receptor (Sv-TKIR). We validated this discovery with a receptor activation assay in COS-7 cells expressing Sv-TKIR, using a reporter SRE-LUC system designed for RTKs, with each of the rIAG proteins acting as the activation ligand. Using recombinant proteins, we aim to develop specific tools to control sexual development through the administration of IAG within the critical sexual differentiation time window. The biologically active rIAGs generated might facilitate commercially feasible solutions for the long sought techniques for sex-change induction and monosex population culture in crustaceans and shed new light on the physiological mode of action of IAG in crustaceans. PMID:26883686

  7. Interactions of methoxyacetic acid with androgen receptor

    SciTech Connect

    Bagchi, Gargi; Hurst, Christopher H.; Waxman, David J.

    2009-07-15

    Endocrine disruptive compounds (EDC) alter hormone-stimulated, nuclear receptor-dependent physiological and developmental processes by a variety of mechanisms. One recently identified mode of endocrine disruption is through hormone sensitization, where the EDC modulates intracellular signaling pathways that control nuclear receptor function, thereby regulating receptor transcriptional activity indirectly. Methoxyacetic acid (MAA), the primary, active metabolite of the industrial solvent ethylene glycol monomethyl ether and a testicular toxicant, belongs to this EDC class. Modulation of nuclear receptor activity by MAA could contribute to the testicular toxicity associated with MAA exposure. In the present study, we evaluated the impact of MAA on the transcriptional activity of several nuclear receptors including the androgen receptor (AR), which plays a pivotal role in the development and maturation of spermatocytes. AR transcriptional activity is shown to be increased by MAA through a tyrosine kinase signaling pathway that involves PI3-kinase. In a combinatorial setting with AR antagonists, MAA potentiated the AR response without significantly altering the EC{sub 50} for androgen responsiveness, partially alleviating the antagonistic effect of the anti-androgens. Finally, MAA treatment of TM3 mouse testicular Leydig cells markedly increased the expression of Cyp17a1 and Shbg while suppressing Igfbp3 expression by {approx} 90%. Deregulation of these genes may alter androgen synthesis and action in a manner that contributes to MAA-induced testicular toxicity.

  8. Steroid Sulfatase Deficiency and Androgen Activation Before and After Puberty

    PubMed Central

    Idkowiak, Jan; Taylor, Angela E.; Subtil, Sandra; O'Neil, Donna M.; Vijzelaar, Raymon; Dias, Renuka P.; Amin, Rakesh; Barrett, Timothy G.; Shackleton, Cedric H. L.; Kirk, Jeremy M. W.; Moss, Celia

    2016-01-01

    represent a fine tuning mechanism for tissue-specific androgen activation preparing for the major changes in androgen production during puberty. PMID:27003302

  9. The validity of androgen assays

    PubMed Central

    Carruthers, Malcolm; Trinick, Tom R.; Wheeler, Michael J.

    2007-01-01

    Problems in the measurement of androgens and in interpreting results have been reviewed and classified as follows: Preanalytical factors The exact sampling conditions in relation to circadian and seasonal variations, diet, alcohol, physical activity and posture. Physiological and medical factors Androgen levels vary according to the patient's general health, stress, sexual activity and smoking habits. Analytical variables Sample preservation and storage variables are often unknown. The different androgen assays used have widely differing accuracy and precision and are subject to large inter-laboratory variation, which especially in women and children can render the results of routinely available direct immunoassays meaningless. Interpretation of results Laboratory reference ranges vary widely, largely independent of methodology, and fail to take into account the log-normal distribution of androgen values, causing errors in clinical diagnosis and treatment. Other unknowns are antagonists such as SHBG, estrogens, catecholamines, cortisol, and anti-androgens. As well as age, androgen receptor polymorphisms play a major role in regulating androgen levels and resistance to their action. Conclusions Though laboratory assays can support a diagnosis of androgen deficiency in men, they should not be used to exclude it. It is suggested that there needs to be greater reliance on the history and clinical features, together with careful evaluation of the symptomatology, and where necessary a therapeutic trial of androgen treatment given. PMID:17701661

  10. Regulation of androgen action during establishment of pregnancy.

    PubMed

    Gibson, Douglas A; Simitsidellis, Ioannis; Saunders, Philippa T K

    2016-07-01

    During the establishment of pregnancy, the ovarian-derived hormones progesterone and oestradiol regulate remodelling of the endometrium to promote an environment that is able to support and maintain a successful pregnancy. Decidualisation is characterised by differentiation of endometrial stromal cells that secrete growth factors and cytokines that regulate vascular remodelling and immune cell influx. This differentiation process is critical for reproduction, and inadequate decidualisation is implicated in the aetiology of pregnancy disorders such as foetal growth restriction and preeclampsia. In contrast to progesterone and oestradiol, the role of androgens in regulating endometrial function is poorly understood. Androgen receptors are expressed in the endometrium, and androgens are reported to regulate both the transcriptome and the secretome of endometrial stromal cells. In androgen-target tissues, circulating precursors are activated to mediate local effects, and recent studies report that steroid concentrations detected in endometrial tissue are distinct to those detected in the peripheral circulation. New evidence suggests that decidualisation results in dynamic changes in the expression of androgen biosynthetic enzymes, highlighting a role for pre-receptor regulation of androgen action during the establishment of pregnancy. These results suggest that such enzymes could be future therapeutic targets for the treatment of infertility associated with endometrial dysfunction. In conclusion, these data support the hypothesis that androgens play a beneficial role in regulating the establishment and maintenance of pregnancy. Future studies should be focussed on investigating the safety and efficacy of androgen supplementation with the potential for utilisation of novel therapeutics, such as selective androgen receptor modulators, to improve reproductive outcomes in women. PMID:27067639

  11. Sensitization of androgen refractory prostate cancer cells to anti-androgens through re-expression of epigenetically repressed androgen receptor - Synergistic action of quercetin and curcumin.

    PubMed

    Sharma, Vikas; Kumar, Lokesh; Mohanty, Sujit K; Maikhuri, Jagdamba P; Rajender, Singh; Gupta, Gopal

    2016-08-15

    Epigenetic repression of Androgen Receptor (AR) gene by hypermethylation of its promoter causes resistance in prostate cancer (CaP) to androgen deprivation therapy with anti-androgens. Some dietary phytocompounds like quercetin (Q) and curcumin (C) with reported DNMT-inhibitory activity were tested for their ability to re-express the AR in AR-negative CaP cell lines PC3 and DU145. Combined treatment with Q+C was much more effective than either Q or C in inhibiting DNMT, causing global hypomethylation, restoring AR mRNA and protein levels and causing apoptosis via mitochondrial depolarization of PC3 and DU145. The functional AR protein expressed in Q+C treated cells sensitized them to dihydrotestosterone (DHT)-induced proliferation, bicalutamide-induced apoptosis, bound to androgen response element to increase luciferase activity in gene reporter assay and was susceptible to downregulation by AR siRNA. Bisulfite sequencing revealed high methylation of AR promoter CpG sites in AR-negative DU145 and PC3 cell lines that was significantly demethylated by Q+C treatment, which restored AR expression. Notable synergistic effects of Q+C combination in re-sensitizing androgen refractory CaP cells to AR-mediated apoptosis, their known safety in clinical use, and epidemiological evidences relating their dietary consumption with lower cancer incidences indicate their potential for use in chemoprevention of androgen resistance in prostate cancer. PMID:27132804

  12. Production Decline Analysis Using Influence Functions

    SciTech Connect

    Zais, Elliot J.

    1980-12-16

    We previously reported (Zais, 1979) that Arps's exponential equation works quite well on geothermal production data. The hyperbolic equation should probably not be used. In this paper we show the progress made i n using influence functions t o describe reservoir production behavior.

  13. Functional chromatographic technique for natural product isolation†

    PubMed Central

    Lau, Eric C.; Mason, Damian J.; Eichhorst, Nicole; Engelder, Pearce; Mesa, Celestina; Kithsiri Wijeratne, E. M.; Gunaherath, G. M. Kamal B.; Leslie Gunatilaka, A. A.

    2015-01-01

    Natural product discovery arises through a unique interplay between chromatographic purification and biological assays. Currently, most techniques used for natural product purification deliver leads without a defined biological action. We now describe a technique, referred to herein as functional chromatography, that deploys biological affinity as the matrix for compound isolation. PMID:25588099

  14. Vocal cues to male androgen levels in giant pandas.

    PubMed

    Charlton, Benjamin D; Keating, Jennifer L; Kersey, David; Rengui, Li; Huang, Yan; Swaisgood, Ronald R

    2011-02-23

    Little is known about the potential of non-human mammal vocalizations to signal information on the hormonal status of the caller. In the current study, we used endocrine data and acoustic analyses to determine whether male giant panda bleats provide reliable information about the caller's current androgen levels. Our results revealed significant relationships between acoustic features of male giant panda bleats and the caller's faecal androgen metabolite concentrations. To our knowledge, this constitutes the first demonstration that the acoustic structure of a non-human mammal call has the potential to yield information about the caller's current androgen levels. We go on to discuss the anatomical basis for our findings and the potential functional relevance of signalling information on male androgen levels in giant panda sexual communication. PMID:20810426

  15. Anti-androgens act jointly in suppressing spiggin concentrations in androgen-primed female three-spined sticklebacks - prediction of combined effects by concentration addition.

    PubMed

    Pottinger, T G; Katsiadaki, I; Jolly, C; Sanders, M; Mayer, I; Scott, A P; Morris, S; Kortenkamp, A; Scholze, M

    2013-09-15

    Increasing attention is being directed at the role played by anti-androgenic chemicals in endocrine disruption of wildlife within the aquatic environment. The co-occurrence of multiple contaminants with anti-androgenic activity highlights a need for the predictive assessment of combined effects, but information about anti-androgen mixture effects on wildlife is lacking. This study evaluated the suitability of the androgenised female stickleback screen (AFSS), in which inhibition of androgen-induced spiggin production provides a quantitative assessment of anti-androgenic activity, for predicting the effect of a four component mixture of anti-androgens. The anti-androgenic activity of four known anti-androgens (vinclozolin, fenitrothion, flutamide, linuron) was evaluated from individual concentration-response data and used to design a mixture containing each chemical at equipotent concentrations. Across a 100-fold concentration range, a concentration addition approach was used to predict the response of fish to the mixture. Two studies were conducted independently at each of two laboratories. By using a novel method to adjust for differences between nominal and measured concentrations, good agreement was obtained between the actual outcome of the mixture exposure and the predicted outcome. This demonstrated for the first time that androgen receptor antagonists act in concert in an additive fashion in fish and that existing mixture methodology is effective in predicting the outcome, based on concentration-response data for individual chemicals. The sensitivity range of the AFSS assay lies within the range of anti-androgenicity reported in rivers across many locations internationally. The approach taken in our study lays the foundations for understanding how androgen receptor antagonists work together in fish and is essential in informing risk assessment methods for complex anti-androgenic mixtures in the aquatic environment. PMID:23792627

  16. A double-blind, placebo-controlled, randomized clinical trial of recombinant human chorionic gonadotropin on muscle strength and physical function and activity in older men with partial age-related androgen deficiency.

    PubMed

    Liu, Peter Y; Wishart, Susan M; Handelsman, David J

    2002-07-01

    changes in hemoglobin, osteocalcin, or prostate-specific antigen, and the International Prostate Symptom Score did not change. Three men developed nipple tenderness that did not progress to gynecomastia. We conclude that 3 months of treatment with twice weekly r-hCG demonstrates sustained androgenic effects on hormones and muscle mass but has no effect on muscle strength or physical functioning. PMID:12107212

  17. Androgen receptor roles in hepatocellular carcinoma, cirrhosis, and hepatitis

    PubMed Central

    Ma, Wen-Lung; Lai, Hsueh-Chou; Yeh, Shuyuan; Cai, Xiujun; Chang, Chawnshang

    2014-01-01

    Summary Androgen/androgen receptor (AR) signaling plays important roles in normal liver function and in progression of liver diseases. In studies of non-cancerous liver diseases, AR knockout mouse models of liver disease have revealed that androgen/AR signaling suppresses the development of steatosis, virus-related hepatitis, and cirrhosis. In addition, studies have shown that targeting AR in bone marrow-derived mesenchymal stem cells (BM-MSCs) improves their self-renewal and migration potentials, thereby increasing the efficacy of BM-MSC transplantation as a way to control the progression of cirrhosis. Androgen/AR signaling is known to be involved in the initiation of carcinogen- or Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). However, studies have demonstrated that AR, rather than androgen, plays the dominant role in cancer initiation. Therefore, targeting AR might be an appropriate therapy for patients with early-stage HCC. In contrast, androgen/AR signaling has been shown to suppress metastasis of HCC in patients with late-stage disease. In addition, there is evidence that therapy comprising Sorafenib and agents that enhance the functional expression of AR may suppress the progression of late-stage HCC. PMID:24424503

  18. 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. PMID:18385897

  19. Classical androgen receptors in non-classical sites in the brain

    PubMed Central

    Sarkey, Sara; Azcoitia, Iñigo; Garcia-Segura, Luis Miguel; Garcia-Ovejero, Daniel; DonCarlos, Lydia L.

    2008-01-01

    Androgen receptors are expressed in many different neuronal populations in the central nervous system where they often act as transcription factors in the cell nucleus. However, recent studies have detected androgen receptor immunoreactivity in neuronal and glial processes of the adult rat neocortex, hippocampal formation, and amygdala as well as in the telencephalon of Eastern Fence and green anole lizards. This review discusses previously published findings on extranuclear androgen receptors, as well as new experimental results that begin to establish a possible functional role for androgen receptors in axons within cortical regions. Electron microscopic studies have revealed that androgen receptor immunoreactive processes in the rat brain correspond to axons, dendrites and glial processes. New results show that lesions of the dorsal CA1 region by local administration of ibotenic acid reduce the density of androgen receptor immunoreactive axons in the cerebral cortex and the amygdala, suggesting that these axons may originate in the hippocampus. Androgen receptor immunoreactivity in axons is also decreased by the intracerebroventricular administration of colchicine, suggesting that androgen receptor protein is transported from the perikaryon to the axons by fast axonal transport. Androgen receptors in axons located in the cerebral cortex and amygdala and originating in the hippocampus may play an important role in the rapid behavioral effects of androgens. PMID:18402960

  20. Molecular evolution of the androgenic hormone in terrestrial isopods.

    PubMed

    Cerveau, Nicolas; Bouchon, Didier; Bergès, Thierry; Grève, Pierre

    2014-04-25

    In crustaceans, the androgenic gland (AG), thanks to the synthesis of the androgenic gland hormone (AGH), controls the differentiation of the primary and secondary male sexual characters. In this study, we amplified 12 new AGH cDNAs in species belonging to five different families of the infra-order Ligiamorpha of terrestrial isopods. Putative essential amino acids for the production of a functional AGH protein exhibit signatures of negative selection and are strictly conserved including typical proteolytic cleavage motifs, a putative N-linked glycosylation motif on the A chains and the eight Cys positions. An insulin-like growth factor motif was also identified in Armadillidium AGH sequences. The phylogenetic relationships of AGH sequences allowed one to distinguish two main clades, corresponding to members of the Armadillidiidae and the Porcellionidae families which are congruent with the narrow specificity of AG heterospecific grafting. An in-depth understanding of the regulation of AGH expression would help deciphering the interaction between Wolbachia, widespread feminizing endosymbiotic bacteria in isopods, and the sex differentiation of their hosts. PMID:24561051

  1. Cell proliferation, DNA repair, and p53 function are not required for programmed death of prostatic glandular cells induced by androgen ablation.

    PubMed Central

    Berges, R R; Furuya, Y; Remington, L; English, H F; Jacks, T; Isaacs, J T

    1993-01-01

    Androgen ablation induces programmed death of androgen-dependent prostatic glandular cells, resulting in fragmentation of their genomic DNA and the cells themselves into apoptotic bodies. Twenty percent of prostatic glandular cells undergo programmed death per day between day 2 and 5 after castration. During this same period, < 1% of prostatic glandular cells enter the S phase of the cell cycle, documenting that > 95% of these die in G0. During the programmed death of these G0 glandular cells, a futile DNA repair process is induced secondary to the DNA fragmentation. This futile DNA repair is not required, however, since inhibition of this process by > 90% with an appropriately timed hydroxy-urea dosing regimen had no effect upon the extent of the programmed death of these cells after castration. Likewise, p53 gene expression is not required since the same degree of cell death occurred in prostates and seminal vesicles after castration of wild-type and p53-deficient mice. PMID:8415631

  2. Androgens and sexuality.

    PubMed

    Hutchinson, K A

    1995-01-16

    A review of the literature reveals that the endocrine determinants of female sexuality are complex and difficult to characterize. In adolescent males, free testosterone directly affects sexual motivation, with social factors exerting little or no effect. In adolescent girls, by contrast, societal and peer pressure play a pivotal role in the appearance of certain sexual behaviors. Throughout a woman's life, hormonal and psychosocial factors are critical influences. It is possible that cyclic patterns of testosterone are less important for female sexual behavior than the "tonic" effect of overall testosterone levels. Although the estrogen dependence of the vaginal epithelium--important for postmenopausal women--has been clearly established, the role of other hormonal factors and treatments, particularly those involving androgens, in human female sexual behavior remains enigmatic. The search for an understanding of these relationships is not merely an interesting academic exercise but is necessary to determine what role, if any, androgens may play in the treatment of sexual dysfunction during the female reproductive years. PMID:7825630

  3. Identification of novel genes that regulate androgen receptor signaling and growth of androgen-deprived prostate cancer cells

    PubMed Central

    Levina, Elina; Ji, Hao; Chen, Mengqiang; Baig, Mirza; Oliver, David; Ohouo, Patrice; Lim, Chang-uk; Schools, Garry; Carmack, Steven; Ding, Ye; Broude, Eugenia V.; Roninson, Igor B.

    2015-01-01

    Prostate cancer progression to castration refractory disease is associated with anomalous transcriptional activity of the androgen receptor (AR) in an androgen-depleted milieu. To identify novel gene products whose downregulation transactivates AR in prostate cancer cells, we performed a screen of enzymatically-generated shRNA lenti-libraries selecting for transduced LNCaP cells with elevated expression of a fluorescent reporter gene under the control of an AR-responsive promoter. The shRNAs present in selected populations were analyzed using high-throughput sequencing to identify target genes. Highly enriched gene targets were then validated with siRNAs against selected genes, testing first for increased expression of luciferase from an AR-responsive promoter and then for altered expression of endogenous androgen-regulated genes in LNCaP cells. We identified 20 human genes whose silencing affected the expression of exogenous and endogenous androgen-responsive genes in prostate cancer cells grown in androgen-depleted medium. Knockdown of four of these genes upregulated the expression of endogenous AR targets and siRNAs targeting two of these genes (IGSF8 and RTN1) enabled androgen-independent proliferation of androgen-dependent cells. The effects of IGSF8 appear to be mediated through its interaction with a tetraspanin protein, CD9, previously implicated in prostate cancer progression. Remarkably, homozygous deletions of IGSF8 are found almost exclusively in prostate cancers but not in other cancer types. Our study shows that androgen independence can be achieved through the inhibition of specific genes and reveals a novel set of genes that regulate AR signaling in prostate cancers. PMID:26036626

  4. [Osteoporosis in men and androgen replacement therapy].

    PubMed

    Tsujimura, Akira; Okuyama, Akihiko

    2003-11-01

    Androgen plays an important role in bone maturation and maintenance of bone mass. Androgen deficiency associated with aging causes osteoporosis for men. With respect to this disease, androgen replacement treatment has been performed for aging male. However, available preparations of androgen are limited in Japan and each of them has both merit and demerit. Establishment of guideline for androgen replacement treatment including criteria of serum testosterone concentration is the problem, which now confronts us. PMID:15775234

  5. 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

  6. Water Production Functions for High Plains Crops

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Water Production Functions for High Plains Crops Water consumptive use by a crop can be reduced through limited (deficit) irrigation. If the reduced consumptive use (CU) can be quantified, the saved water can be transferred to other users. If the value of the transferred water is greater than the fa...

  7. AB69. Phyto-androgenic androgens in men’s health, sex and aging FX

    PubMed Central

    Adimoelja, Arif; Siauw, Ali Fuchih

    2014-01-01

    Protodioscin is a Herbal Steroid Saponin extract derived mainly from Tribulus terristris L. grown mainly in Bulgaria. This herbal plant begun well known in main stream medicine since the periods around 1972 in Indonesia when this phyto-steroid compound has been proven of having the ability to be converted to DHEA and further to another androgenic androgen (T) in hypogonadal men in the presence of 5-alpha-dehydrogenase (A. Adimoelja, 1976, 1978). Biogenic androgens and androgenic androgens Testosterone as a product of the male gonads from blood serum cholesterol. Cholesterol is further converted to DHEA. This product is identified as one of the biogenic or endogenic androgens (testosterone, pregnenolone, progesterone, aldosterone, androstendione). Health disorders are often hampered by the tendencies of men or women to conceal their health (sexual health) conditions due to fear and/or embarrassments. If these conditions are not being soonest medically diagnosed and left to be untreated, another un-healthy condition may appear. (hypertension, high blood serum cholesterol, decrease HDL, CVD). Decrease libido, sex arousal and ED are the first expression of the down-degraded health conditions which may appear (A. Adimoelja 1985). Prescription of phytopharmaceuticals in mainstream medicine Surprisingly more phyto-pharmaceuticals in mainstream medicine were unconsciously prescribed by physicians (25% of prescriptions, WHO, 1908). Prescriptions were made to support health conditions and promote sexual health problems, most common as aphrodisiacs. Prtodioscin and health enhancers Protodioscin indeed promote health condition in hypogonadic men (A.Adimoelja and Tjahjo Djojo Tanojo, 2009). Regretfully most herbal products whih has been promoted as health foods in the market, or sex-tonics are combined with other chemical product(s), some of which combined with erectogenics (W. Pangkahila, 2010). Sharlip ID (USA) too reported in the “Newark Star Ledger in 2002” that 9 out

  8. Functional cyclic AMP response element in the breast cancer resistance protein (BCRP/ABCG2) promoter modulates epidermal growth factor receptor pathway- or androgen withdrawal-mediated BCRP/ABCG2 transcription in human cancer cells.

    PubMed

    Xie, Yi; Nakanishi, Takeo; Natarajan, Karthika; Safren, Lowell; Hamburger, Anne W; Hussain, Arif; Ross, Douglas D

    2015-03-01

    Phosphorylated cyclic-AMP (cAMP) response element binding protein (p-CREB) is a downstream effector of a variety of important signaling pathways. We investigated whether the human BCRP promoter contains a functional cAMP response element (CRE). 8Br-cAMP, a cAMP analogue, increased the activity of a BCRP promoter reporter construct and BCRP mRNA in human carcinoma cells. Epidermal growth factor receptor (EGFR) pathway activation also led to an increase in p-CREB and in BCRP promoter reporter activity via two major downstream EGFR signaling pathways: the phosphotidylinositol-3-kinase (PI3K)/AKT pathway and the mitogen-activated protein kinase (MAPK) pathway. EGF treatment increased the phosphorylation of EGFR, AKT, ERK and CREB, while simultaneously enhancing BCRP mRNA and functional protein expression. EGF-stimulated CREB phosphorylation and BCRP induction were diminished by inhibition of EGFR, PI3K/AKT or RAS/MAPK signaling. CREB silencing using RNA interference reduced basal levels of BCRP mRNA and diminished the induction of BCRP by EGF. Chromatin immunoprecipitation assays confirmed that a putative CRE site on the BCRP promoter bound p-CREB by a point mutation of the CRE site abolished EGF-induced stimulation of BCRP promoter reporter activity. Furthermore, the CREB co-activator, cAMP-regulated transcriptional co-activator (CRTC2), is involved in CREB-mediated BCRP transcription: androgen depletion of LNCaP human prostate cancer cells increased both CREB phosphorylation and CRTC2 nuclear translocation, and enhanced BCRP expression. Silencing CREB or CRTC2 reduced basal BCRP expression and BCRP induction under androgen-depletion conditions. This novel CRE site plays a central role in mediating BCRP gene expression in several human cancer cell lines following activation of multiple cancer-relevant signaling pathways. PMID:25615818

  9. Clinical, cytogenetic and molecular analysis of androgen insensitivity syndromes from south Indian cohort and detection and in-silico characterization of androgen receptor gene mutations.

    PubMed

    V G, Abilash; S, Radha; K M, Marimuthu; K, Thangaraj; S, Arun; S, Nishu; A, Mohana Priya; J, Meena; D, Anuradha

    2016-01-30

    Rare cases of 9 complete androgen insensitivity syndromes, 9 cases of partial androgen insensitivity syndromes and equal number of male control samples were selected for this study. Few strong variations in clinical features were noticed; Giemsa banded metaphase revealed a 46,XY karyotype and the frequency of chromosome aberrations were significantly higher when compared with control samples. DNA sequence analysis of the androgen receptor gene of androgen insensitivity syndromes revealed three missense mutations - c.C1713>G resulting in the replacement of a highly conserved histidine residue with glutamine p.(His571Glu) in DNA-binding domain, c.A1715>G resulting in the replacement of a highly conserved tyrosine residue with cysteine p.(Tyr572Cys) in DNA-binding domain and c.G2599>A resulting in the replacement of a highly conserved valine residue with methionine p.(Val867Met) in ligand-binding domain of androgen receptor gene respectively. The heterozygous type of mutations c.C1713>G and c.G2599>A observed in mothers of the patients for familial cases concluding that the mutation was inherited from the mother. The novel mutation c.C1713>G is reported first time in androgen insensitivity syndrome. In-silico analysis of mutations observed in androgen receptor gene of androgen insensitivity syndrome predicted that the substitution at Y572C and V867M could probably disrupt the protein structure and function. PMID:26688387

  10. Mixture effects at very low doses with combinations of anti-androgenic pesticides, antioxidants, industrial pollutant and chemicals used in personal care products.

    PubMed

    Orton, Frances; Ermler, Sibylle; Kugathas, Subramaniam; Rosivatz, Erika; Scholze, Martin; Kortenkamp, Andreas

    2014-08-01

    Many xenobiotics have been identified as in vitro androgen receptor (AR) antagonists, but information about their ability to produce combined effects at low concentrations is missing. Such data can reveal whether joint effects at the receptor are induced at low levels and may support the prioritisation of in vivo evaluations and provide orientations for the grouping of anti-androgens in cumulative risk assessment. Combinations of 30 AR antagonists from a wide range of sources and exposure routes (pesticides, antioxidants, parabens, UV-filters, synthetic musks, bisphenol-A, benzo(a)pyrene, perfluorooctane sulfonate and pentabromodiphenyl ether) were tested using a reporter gene assay (MDA-kb2). Chemicals were combined at three mixture ratios, equivalent to single components' effect concentrations that inhibit the action of dihydrotesterone by 1%, 10% or 20%. Concentration addition (CA) and independent action were used to calculate additivity expectations. We observed complete suppression of dihydrotestosterone effects when chemicals were combined at individual concentrations eliciting 1%, 10% or 20% AR antagonistic effect. Due to the large number of mixture components, the combined AR antagonistic effects occurred at very low concentrations of individual mixture components. CA slightly underestimated the combined effects at all mixture ratios. In conclusion, large numbers of AR antagonists from a wide variety of sources and exposure routes have the ability of acting together at the receptor to produce joint effects at very low concentrations. Significant mixture effects are observed when chemicals are combined at concentrations that individually do not induce observable AR antagonistic effects. Cumulative risk assessment for AR antagonists should apply grouping criteria based on effects where data are available, rather than on criteria of chemical similarity. PMID:24055644

  11. Mixture effects at very low doses with combinations of anti-androgenic pesticides, antioxidants, industrial pollutant and chemicals used in personal care products

    SciTech Connect

    Orton, Frances; Ermler, Sibylle; Kugathas, Subramaniam; Rosivatz, Erika; Scholze, Martin; Kortenkamp, Andreas

    2014-08-01

    Many xenobiotics have been identified as in vitro androgen receptor (AR) antagonists, but information about their ability to produce combined effects at low concentrations is missing. Such data can reveal whether joint effects at the receptor are induced at low levels and may support the prioritisation of in vivo evaluations and provide orientations for the grouping of anti-androgens in cumulative risk assessment. Combinations of 30 AR antagonists from a wide range of sources and exposure routes (pesticides, antioxidants, parabens, UV-filters, synthetic musks, bisphenol-A, benzo(a)pyrene, perfluorooctane sulfonate and pentabromodiphenyl ether) were tested using a reporter gene assay (MDA-kb2). Chemicals were combined at three mixture ratios, equivalent to single components' effect concentrations that inhibit the action of dihydrotesterone by 1%, 10% or 20%. Concentration addition (CA) and independent action were used to calculate additivity expectations. We observed complete suppression of dihydrotestosterone effects when chemicals were combined at individual concentrations eliciting 1%, 10% or 20% AR antagonistic effect. Due to the large number of mixture components, the combined AR antagonistic effects occurred at very low concentrations of individual mixture components. CA slightly underestimated the combined effects at all mixture ratios. In conclusion, large numbers of AR antagonists from a wide variety of sources and exposure routes have the ability of acting together at the receptor to produce joint effects at very low concentrations. Significant mixture effects are observed when chemicals are combined at concentrations that individually do not induce observable AR antagonistic effects. Cumulative risk assessment for AR antagonists should apply grouping criteria based on effects where data are available, rather than on criteria of chemical similarity. - Highlights: • Mixtures of AR antagonists at low individual concentrations cause complete inhibition.

  12. Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletion

    PubMed Central

    Harris, William P; Mostaghel, Elahe A; Nelson, Peter S; Montgomery, Bruce

    2010-01-01

    SUMMARY Androgen deprivation therapy remains a critical component of treatment for men with advanced prostate cancer, and data supports its use in metastatic disease and in conjunction with surgery or radiation in specific settings. Alternatives to standard androgen deprivation therapy, such as intermittent androgen suppression and estrogen therapy, hold the potential to improve toxicity profiles while maintaining clinical benefit. Current androgen deprivation strategies seem to incompletely suppress androgen levels and androgen-receptor-mediated effects at the tissue level. Advances in the understanding of mechanisms that contribute to castration-resistant prostate cancer are leading to rationally designed therapies targeting androgen metabolism and the androgen receptor. The results of large trials investigating the optimization of primary androgen deprivation therapy, including evaluation of intermittent androgen suppression and estrogen patch assessment, as well as phase III studies of novel androgen synthesis inhibitors, such as abiraterone acetate, are eagerly awaited. PMID:19198621

  13. Molecular cloning, characterization, and expression profiles of androgen receptors in spotted scat (Scatophagus argus).

    PubMed

    Chen, H P; Deng, S P; Dai, M L; Zhu, C H; Li, G L

    2016-01-01

    Androgen plays critical roles in vertebrate reproductive systems via androgen receptors (ARs). In the present study, the full-length spotted scat (Scatophagus argus) androgen receptor (sAR) cDNA sequence was cloned from testis. The sAR cDNA measured 2448 bp in length with an open-reading frame of 2289 bp, encoding 763 amino acids. Amino acid alignment analyses showed that the sARs exhibited highly evolutionary conserved functional domains. Phylogenetically, the sARs clustered within the ARβ common vertebrate group. Real-time polymerase chain reaction (RT-PCR) revealed that sAR expression varied in level and distribution throughout the tissues of both females and males. sAR expression was detected during testicular development by quantitative RT-PCR. The results showed that the highest transcription of sARs was observed in the mid-testicular stage, and remained at a high expression level until the late-testicular stage. In addition, the effects of 17α-methyltestosterone (MT) and estrogen (E2) on the expression of sARs in ovaries were determined using quantitative RT-PCR. sAR expression increased at 12 and 24 h post-MT treatment and decreased with E2 treatment. The present study provides preliminary evidence indicating gonadal plasticity of spotted scat under exogenous steroidal hormone treatments. It also provides a theoretical basis for sex reversal and production of artificial pseudo-males for female monosex breeding. PMID:27173207

  14. Restoration of spermatogenesis and male fertility using an androgen receptor transgene.

    PubMed

    Walker, William H; Easton, Evan; Moreci, Rebecca S; Toocheck, Corey; Anamthathmakula, Prashanth; Jeyasuria, Pancharatnam

    2015-01-01

    Androgens signal through the androgen receptor (AR) to regulate male secondary sexual characteristics, reproductive tract development, prostate function, sperm production, bone and muscle mass as well as body hair growth among other functions. We developed a transgenic mouse model in which endogenous AR expression was replaced by a functionally modified AR transgene. A bacterial artificial chromosome (BAC) was constructed containing all AR exons and introns plus 40 kb each of 5' and 3' regulatory sequence. Insertion of an internal ribosome entry site and the EGFP gene 3' to AR allowed co-expression of AR and EGFP. Pronuclear injection of the BAC resulted in six founder mice that displayed EGFP production in appropriate AR expressing tissues. The six founder mice were mated into a Sertoli cell specific AR knockout (SCARKO) background in which spermatogenesis is blocked at the meiosis stage of germ cell development. The AR-EGFP transgene was expressed in a cyclical manner similar to that of endogenous AR in Sertoli cells and fertility was restored as offspring were produced in the absence of Sertoli cell AR. Thus, the AR-EGFP transgene under the control of AR regulatory elements is capable of rescuing AR function in a cell selective, AR-null background. These initial studies provide proof of principle that a strategy employing the AR-EGFP transgene can be used to understand AR functions. Transgenic mice expressing selective modifications of the AR-EGFP transgene may provide crucial information needed to elicit the molecular mechanisms by which AR acts in the testis and other androgen responsive tissues. PMID:25803277

  15. Genetics of androgen metabolism in women with infertility and hypoandrogenism.

    PubMed

    Shohat-Tal, Aya; Sen, Aritro; Barad, David H; Kushnir, Vitaly; Gleicher, Norbert

    2015-07-01

    Hypoandrogenism in women with low functional ovarian reserve (LFOR, defined as an abnormally low number of small growing follicles) adversely affects fertility. The androgen precursor dehydroepiandrosterone (DHEA) is increasingly used to supplement treatment protocols in women with LFOR undergoing in vitro fertilization. Due to differences in androgen metabolism, however, responses to DHEA supplementation vary between patients. In addition to overall declines in steroidogenic capacity with advancing age, genetic factors, which result in altered expression or enzymatic function of key steroidogenic proteins or their upstream regulators, might further exacerbate variations in the conversion of DHEA to testosterone. In this Review, we discuss in vitro studies and animal models of polymorphisms and gene mutations that affect the conversion of DHEA to testosterone and attempt to elucidate how these variations affect female hormone profiles. We also discuss treatment options that modulate levels of testosterone by targeting the expression of steroidogenic genes. Common variants in genes encoding DHEA sulphotransferase, aromatase, steroid 5α-reductase, androgen receptor, sex-hormone binding globulin, fragile X mental retardation protein and breast cancer type 1 susceptibility protein have been implicated in androgen metabolism and, therefore, can affect levels of androgens in women. Short of screening for all potential genetic variants, hormonal assessments of patients with low testosterone levels after DHEA supplementation facilitate identification of underlying genetic defects. The genetic predisposition of patients can then be used to design individualized fertility treatments. PMID:25942654

  16. Association of androgen receptor GGN repeat length polymorphism and male infertility in Khuzestan, Iran

    PubMed Central

    Moghadam, Mohamad; Khatami, Saied Reza; Galehdari, Hamid

    2015-01-01

    Background: Androgens play critical role in secondary sexual and male gonads differentiations such as spermatogenesis, via androgen receptor. The human androgen receptor (AR) encoding gene contains two regions with three nucleotide polymorphic repeats (CAG and GGN) in the first exon. Unlike the CAG repeats, the GGN has been less studied because of technical difficulties, so the functional role of these polymorphic repeats is still unclear. Objective: The goal of this study was to investigate any relationship between GGN repeat length in the first exon of AR gene and idiopathic male infertility in southwest of Iran. Materials and Methods: This is the first study on GGN repeat of AR gene in infertile male in Khuzestan, Iran. We used polymerase chain reaction (PCR) and polyacrylamide gel electrophoresis to categorize GGN repeat lengths in 72 infertile and 72 fertile men. Afterwards we sequenced the PCR products to determine the exact length of GGN repeat in each category. Our samples included 36 azoospermic and 36 oligozoospermic men as cases and 72 fertile men as control group. Results: We found that the numbers of repeats in the cases range from 18 to 25, while in the controls this range is from 20 to 28. The results showed a significant relation between the length of GGN repeat and fertility (p=0.015). The most frequent alleles were alleles with 24 and 25 repeats respectively in case and control groups. On the other hand no significant differences were found between Arab and non-Arab cases by considering GGN repeat lengths (p=0.234). Conclusion: Due to our results, there is a significant association between the presence of allele with 24 repeats and susceptibility to male infertility. Therefore this polymorphism should be considered in future studies to clarify etiology of disorders related to androgen receptor activity. PMID:26221130

  17. A clinical data validated mathematical model of prostate cancer growth under intermittent androgen suppression therapy

    NASA Astrophysics Data System (ADS)

    Portz, Travis; Kuang, Yang; Nagy, John D.

    2012-03-01

    Prostate cancer is commonly treated by a form of hormone therapy called androgen suppression. This form of treatment, while successful at reducing the cancer cell population, adversely affects quality of life and typically leads to a recurrence of the cancer in an androgen-independent form. Intermittent androgen suppression aims to alleviate some of these adverse affects by cycling the patient on and off treatment. Clinical studies have suggested that intermittent therapy is capable of maintaining androgen dependence over multiple treatment cycles while increasing quality of life during off-treatment periods. This paper presents a mathematical model of prostate cancer to study the dynamics of androgen suppression therapy and the production of prostate-specific antigen (PSA), a clinical marker for prostate cancer. Preliminary models were based on the assumption of an androgen-independent (AI) cell population with constant net growth rate. These models gave poor accuracy when fitting clinical data during simulation. The final model presented hypothesizes an AI population with increased sensitivity to low levels of androgen. It also hypothesizes that PSA production is heavily dependent on androgen. The high level of accuracy in fitting clinical data with this model appears to confirm these hypotheses, which are also consistent with biological evidence.

  18. Increased adrenal androgen secretion with inhibition of 11beta-hydroxylase in HIV-infected women.

    PubMed

    Koutkia, Polyxeni; Berry, Jacqueline; Eaton, Kristina; Breu, Jeff; Grinspoon, Steven

    2006-05-01

    Adrenal androgen production is reduced in association with disease severity in HIV-infected women. This response may be maladaptive in terms of maintenance of lean body mass, functional status, and immune function. The aim of this study was to assess whether the use of an adrenal enzyme inhibitor of 11beta-hydroxylase might increase androgen production in this population. We conducted a randomized, double-blind, placebo-controlled study of metyrapone (500 mg p.o. qid) or placebo for 2 wk in 10 HIV-infected women with AIDS wasting [weight <90% ideal body weight (IBW) or weight loss >10%] and reduced androgen levels. Basal and ACTH-stimulated androgen, mineralocorticoid, and glucocorticoid levels were measured at baseline and after 14 days of treatment. Subjects were similar in age (40.9 +/- 0.9 yr), weight (91.7 +/- 3.5% IBW) and hormone concentrations at study entry. Total testosterone (84 +/- 54 vs. -0.4 +/- 2 ng/dl, P = 0.024), free testosterone (6.5 +/- 2.8 vs. 0.1 +/- 0.1 pg/ml, P = 0.024), DHEA (5.0 +/- 3.2 vs. -0.6 +/- 0.5 microg/l, P = 0.024), and 11-deoxycortisol (2,145 +/- 820 vs. -14 +/- 22 ng/dl, P = 0.024) levels increased in response to metyrapone compared with placebo treatment. In response to ACTH, significant increases in the DHEA/cortisol ratio (174 +/- 48 vs. 3 +/- 3, P = 0.008) were seen in the metyrapone group compared with placebo. Blood pressure and electrolytes did not change, and signs of adrenal insufficiency were not apparent. These data demonstrate that inhibition of 11beta-hydroxylase with metyrapone increases adrenal androgen secretion in HIV-infected women. Further studies are needed to assess the physiological effects of this strategy to increase anabolic hormone levels in severe stress, including detailed testing to rule out the potential risk of concomitant adrenal insufficiency. PMID:16303845

  19. Androgen response element of the glycine N-methyltransferase gene is located in the coding region of its first exon.

    PubMed

    Lee, Cheng-Ming; Yen, Chia-Hung; Tzeng, Tsai-Yu; Huang, Yu-Zen; Chou, Kuan-Hsien; Chang, Tai-Jay; Arthur Chen, Yi-Ming

    2013-01-01

    Androgen plays an important role in the pathogenesis of PCa (prostate cancer). Previously, we identified GNMT (glycine N-methyltransferase) as a tumour susceptibility gene and characterized its promoter region. Besides, its enzymatic product-sarcosine has been recognized as a marker for prognosis of PCa. The goals of this study were to determine whether GNMT is regulated by androgen and to map its AREs (androgen response elements). Real-time PCR analyses showed that R1881, a synthetic AR (androgen receptor) agonist induced GNMT expression in AR-positive LNCaP cells, but not in AR-negative DU145 cells. In silico prediction showed that there are four putative AREs in GNMT-ARE1, ARE2 and ARE3 are located in the intron 1 and ARE4 is in the intron 2. Consensus ARE motif deduced from published AREs was used to identify the fifth ARE-ARE5 in the coding region of exon 1. Luciferase reporter assay found that only ARE5 mediated the transcriptional activation of R1881. ARE3 overlaps with a YY1 [Yin and Yang 1 (motif (CaCCATGTT, +1118/+1126)] that was further confirmed by antibody supershift and ChIP (chromatin immunoprecipitation) assays. EMSA (electrophoretic mobility shift assay) and ChIP assay confirmed that AR interacts with ARE5 in vitro and in vivo. In summary, GNMT is an AR-targeted gene with its functional ARE located at +19/+33 of the first exon. These results are valuable for the study of the influence of androgen on the gene expression of GNMT especially in the pathogenesis of cancer. PMID:23883094

  20. Identification and Characterization of the Androgen Receptor From the American Alligator, Alligator mississippiensis

    PubMed Central

    Miyagawa, Shinichi; Yatsu, Ryohei; Kohno, Satomi; Doheny, Brenna M.; Ogino, Yukiko; Ishibashi, Hiroshi; Katsu, Yoshinao; Ohta, Yasuhiko; Guillette, Louis J.

    2015-01-01

    Androgens are essential for the development, reproduction, and health throughout the life span of vertebrates, particularly during the initiation and maintenance of male sexual characteristics. Androgen signaling is mediated by the androgen receptor (AR), a member of the steroid nuclear receptor superfamily. Mounting evidence suggests that environmental factors, such as exogenous hormones or contaminants that mimic hormones, can disrupt endocrine signaling and function. The American alligator (Alligator mississippiensis), a unique model for ecological research in that it exhibits environment-dependent sex determination, is oviparous and long lived. Alligators from a contaminated environment exhibit low reproductive success and morphological disorders of the testis and phallus in neonates and juveniles, both associated with androgen signaling; thus, the alterations are hypothesized to be related to disrupted androgen signaling. However, this line of research has been limited because of a lack of information on the alligator AR gene. Here, we isolated A mississippiensis AR homologs (AmAR) and evaluated receptor-hormone/chemical interactions using a transactivation assay. We showed that AmAR responded to all natural androgens and their effects were inhibited by cotreatment with antiandrogens, such as flutamide, p,p′-dichlorodiphenyldichloroethylene, and vinclozolin. Intriguingly, we found a spliced form of the AR from alligator cDNA, which lacks seven amino acids within the ligand-binding domain that shows no response to androgens. Finally, we have initial data on a possible dominant-negative function of the spliced form of the AR against androgen-induced AmAR. PMID:25974402

  1. Identification and Characterization of the Androgen Receptor From the American Alligator, Alligator mississippiensis.

    PubMed

    Miyagawa, Shinichi; Yatsu, Ryohei; Kohno, Satomi; Doheny, Brenna M; Ogino, Yukiko; Ishibashi, Hiroshi; Katsu, Yoshinao; Ohta, Yasuhiko; Guillette, Louis J; Iguchi, Taisen

    2015-08-01

    Androgens are essential for the development, reproduction, and health throughout the life span of vertebrates, particularly during the initiation and maintenance of male sexual characteristics. Androgen signaling is mediated by the androgen receptor (AR), a member of the steroid nuclear receptor superfamily. Mounting evidence suggests that environmental factors, such as exogenous hormones or contaminants that mimic hormones, can disrupt endocrine signaling and function. The American alligator (Alligator mississippiensis), a unique model for ecological research in that it exhibits environment-dependent sex determination, is oviparous and long lived. Alligators from a contaminated environment exhibit low reproductive success and morphological disorders of the testis and phallus in neonates and juveniles, both associated with androgen signaling; thus, the alterations are hypothesized to be related to disrupted androgen signaling. However, this line of research has been limited because of a lack of information on the alligator AR gene. Here, we isolated A mississippiensis AR homologs (AmAR) and evaluated receptor-hormone/chemical interactions using a transactivation assay. We showed that AmAR responded to all natural androgens and their effects were inhibited by cotreatment with antiandrogens, such as flutamide, p,p'-dichlorodiphenyldichloroethylene, and vinclozolin. Intriguingly, we found a spliced form of the AR from alligator cDNA, which lacks seven amino acids within the ligand-binding domain that shows no response to androgens. Finally, we have initial data on a possible dominant-negative function of the spliced form of the AR against androgen-induced AmAR. PMID:25974402

  2. Anti-androgen treatments.

    PubMed

    Bachelot, Anne; Chabbert-Buffet, Nathalie; Salenave, Sylvie; Kerlan, Véronique; Galand-Portier, Marie-Béatrice

    2010-02-01

    1. Estrogen plus progestin contraceptives (EPP) are the first-line treatment of moderate hirsutism and acne in women of child bearing age (grade C). 2. CPA, 50mg/day, 20 days out of 28, associated with estrogen is the first-line treatment of "moderate to severe hirsutism" in women of childbearing age (grade C). 3. Spironolactone, given as a contraceptive, can be proposed as a second-line treatment in case of side effects or counter-indications to CPA in moderate to severe hirsutism (grade C) in women of childbearing age. No market authorization in this indication. 4. Flutamide or Finasteride are "only" to be used under the guise of contraception as a "thirdline therapy" in cases of severe hirsutism, the presence of side effects or counter-indications to EPP, CPA 50mg/day or spironolactone (grade C). No market authorization in this indication 5. There is no indication for GnRH analogs as an anti-androgen treatment in women of childbearing age given the current therapeutic alternatives (grade C) 6. Only long-term hair removal treatments can be proposed (grade C): electrolysis or laser hair removal. PMID:20096826

  3. Rapid effects of androgens in macrophages.

    PubMed

    Benten, W Peter M; Guo, Z; Krücken, J; Wunderlich, F

    2004-08-01

    We investigated the existence of membrane receptors for testosterone (mAR) in mouse macrophages of the cell lines IC-21 and RAW 264.7 as well as their roles in nongenomic pathways, gene expression and cell functioning. Both cell lines lack intracellular androgen receptors (iARs) and respond to testosterone with rapid rises in [Ca2+]i. These rises in [Ca2+]i can neither be inhibited by iAR- nor by iER blockers, but are rather mediated through mAR. Pharmacological approaches suggest that the mAR belongs to the class of membrane receptors which are coupled to phospholipase C via pertussis toxin (PTX) sensitive G-proteins. The mAR can be localized as specific surface binding sites for testosterone-BSA-FITC by confocal laser scanning microscopy (CLSM)and flow cytometry, and are characterized by their agonist-sequestrability. In order to examine a possible role of the testosterone-induced rise in [Ca2+]i on gene expression, a c-fos promoter reporter gene construct was transfected into RAW 264.7 macrophages. The increase in [Ca2+]i induced by testosterone cannot significantly activate the c-fos promoter directly. Also, no significant activation of ERK1/2, JNK/SAPK and p38 can be observed following testosterone-stimulation alone. However, testosterone-induced rises in [Ca2+]i do have specific effects on gene expression in context with lipopolysaccharide (LPS)-induced genotropic signaling: testosterone specifically down-regulates LPS-induced activation of c-fos promoter, p38 MAPK and NO production. In fetal calf serum (FCS)-induced genotropic signaling, the situation is reversed, i.e. testosterone augments the activation of c-fos promoter and ERK1/2. Our studies demonstrate a cross-talk between the testosterone-induced nongenomic Ca2+ signaling and the genotropic signaling induced by LPS and FCS in macrophages. PMID:15288774

  4. Androgens are powerful non-genomic inducers of calcium sensitization in visceral smooth muscle.

    PubMed

    González-Montelongo, Maria C; Marín, Raquel; Gómez, Tomás; Díaz, Mario

    2010-01-01

    Androgens are recognized as genotropic inducers of a number of physiological functions mainly associated with the development of sexual characteristics. However, as in the case of estrogens, the number of studies evidencing androgen actions in non-reproductive tissues has steadily grown over the past years. Here, we show that androgens acutely ( approximately 30min) alter the frequency spectrum of peristaltic activity of intestinal smooth muscle and augment the amplitude agonist-induced contractile activity. Maximal stimulation occurred at physiological concentrations of androgens with EC(50) values in the picomolar range. Androgen-induced potentiation was prevented by preincubation with androgen receptor (AR) antagonists but unaffected by cycloheximide plus actinomycin D, indicating that potentiation was mediated by ARs via a non-genomic mechanism. The effects of androgens were mimicked by polyamines and were completely blocked by inhibitors of polyamine synthesis. Using ionomycin-permeabilized intestinal smooth muscle preparations, we demonstrate that androgens exert their effects by inducing a mechanism of sensitization to calcium and not by altering intracellular calcium homeostasis. Correspondingly, the potentiation of mechanical activity induced by androgens was accompanied by an increase in the phosphorylation of the regulatory myosin light chain (LC(20)) within the same time-course than calcium sensitization and mechanical potentiation. The pursuit of potential signalling pathways linking androgen receptor activation with calcium sensitization revealed that mechanical potentiation of intestinal muscle by androgens involve activation of the Rho pathway, whose downstream effector, Rho-associated kinase (ROCK), is eventually responsible for displacement of the phosphorylation/dephosphorylation state of LC(20) towards its phosphorylated form. PMID:19800357

  5. Molecular targets of androgen signaling that characterize skeletal muscle recovery and regeneration.

    PubMed

    MacKrell, James G; Yaden, Benjamin C; Bullock, Heather; Chen, Keyue; Shetler, Pamela; Bryant, Henry U; Krishnan, Venkatesh

    2015-01-01

    The high regenerative capacity of adult skeletal muscle relies on a self-renewing depot of adult stem cells, termed muscle satellite cells (MSCs). Androgens, known mediators of overall body composition and specifically skeletal muscle mass, have been shown to regulate MSCs. The possible overlapping function of androgen regulation of muscle growth and MSC activation has not been carefully investigated with regards to muscle regeneration.Therefore, the aim of this study was to examine coinciding androgen-mediated genetic changes in an in vitro MSC model and clinically relevant in vivo models. A gene signature was established via microarray analysis for androgen-mediated MSC engagement and highlighted several markers including follistatin (FST), IGF-1, C-X-C chemokine receptor 4 (CXCR4), hepatocyte growth factor (HGF) and glucocorticoid receptor (GR). In an in vivo muscle atrophy model, androgen re-supplementation significantly increased muscle size and expression of IGF-1, FST, and HGF, while significantly decreasing expression of GR. Biphasic gene expression profiles over the 7-day re-supplementation period identified temporal androgen regulation of molecular targets involved in satellite cell engagement into myogenesis. In a muscle injury model, removal of androgens resulted in delayed muscle recovery and regeneration. Modifications in the androgen signaling gene signature, along with reduced Pax7 and MyoD expression, suggested that limited MSC activation and increased inflammation contributed to the delayed regeneration. However, enhanced MSC activation in the androgen-deplete mouse injury model was driven by an androgen receptor (AR) agonist. These results provide novel in vitro and in vivo evidence describing molecular targets of androgen signaling, while also increasing support for translational use of AR agonists in skeletal muscle recovery and regeneration. PMID:26457071

  6. Role of 5α-reductase inhibitors in androgen-stimulated skin disorders.

    PubMed

    Azzouni, Faris; Zeitouni, Nathalie; Mohler, James

    2013-02-01

    5α-reductase (5α-R) isozymes are ubiquitously expressed in human tissues. This enzyme family is composed of 3 members that perform several important biologic functions. 5α-R isozymes play an important role in benign prostate hyperplasia, prostate cancer, and androgen-stimulated skin disorders, which include androgenic alopecia, acne, and hirsutism. Discovery of 5α-R type 2 deficiency in 1974 sparked interest in development of pharmaceutical agents to inhibit 5α-R isozymes, and 2 such inhibitors are currently available for clinical use: finasteride and dutasteride. 5α-R inhibitors are US Food and Drug Administration (FDA)-approved for the treatment of benign prostate hyperplasia. Only finasteride is FDA-approved for treatment of male androgenic alopecia. This article reviews the pathophysiology of androgen-stimulated skin disorders and the key clinical trials using 5α-R inhibitors in the treatment of androgen-stimulated skin disorders. PMID:23377402

  7. Crosstalk between RON and androgen receptor signaling in the development of castration resistant prostate cancer

    PubMed Central

    Batth, Izhar; Yun, Huiyoung; Hussain, Suleman; Meng, Peng; Osumulski, Powel; Huang, Tim Hui-Ming; Bedolla, Roble; Profit, Amanda; Reddick, Robert; Kumar, Addanki

    2016-01-01

    Castrate-resistant prostate cancer (CRPC) is the fatal form of prostate cancer. Although reactivation of androgen receptor (AR) occurs following androgen deprivation, the precise mechanism involved is unclear. Here we show that the receptor tyrosine kinase, RON alters mechanical properties of cells to influence epithelial to mesenchymal transition and functions as a transcription factor to differentially regulate AR signaling. RON inhibits AR activation and subset of AR-regulated transcripts in androgen responsive LNCaP cells. However in C4-2B, a castrate-resistant sub-line of LNCaP and AR-negative androgen independent DU145 cells, RON activates subset of AR-regulated transcripts. Expression of AR in PC-3 cells leads to activation of RON under androgen deprivation but not under androgen proficient conditions implicating a role for RON in androgen independence. Consistently, RON expression is significantly elevated in castrate resistant prostate tumors. Taken together our results suggest that RON activation could aid in promoting androgen independence and that inhibition of RON in combination with AR antagonist(s) merits serious consideration as a therapeutic option during hormone deprivation therapy. PMID:26872377

  8. Androgen receptor targeted therapies in castration-resistant prostate cancer: Bench to clinic.

    PubMed

    Imamura, Yusuke; Sadar, Marianne D

    2016-08-01

    The androgen receptor is a transcription factor and validated therapeutic target for prostate cancer. Androgen deprivation therapy remains the gold standard treatment, but it is not curative, and eventually the disease will return as lethal castration-resistant prostate cancer. There have been improvements in the therapeutic landscape with new agents approved, such as abiraterone acetate, enzalutamide, sipuleucel-T, cabazitaxel and Ra-223, in the past 5 years. New insight into the mechanisms of resistance to treatments in advanced disease is being and has been elucidated. All current androgen receptor-targeting therapies inhibit the growth of prostate cancer by blocking the ligand-binding domain, where androgen binds to activate the receptor. Persuasive evidence supports the concept that constitutively active androgen receptor splice variants lacking the ligand-binding domain are one of the resistant mechanisms underlying advanced disease. Transcriptional activity of the androgen receptor requires a functional AF-1 region in its N-terminal domain. Preclinical evidence proved that this domain is a druggable target to forecast a potential paradigm shift in the management of advanced prostate cancer. This review presents an overview of androgen receptor-related mechanisms of resistance as well as novel therapeutic agents to overcome resistance that is linked to the expression of androgen receptor splice variants in castration-resistant prostate cancer. PMID:27302572

  9. Loss of exogenous androgen dependence by prostate tumor cells is associated with elevated glucuronidation potential.

    PubMed

    Zimmer, Brenna M; Howell, Michelle E; Wei, Qin; Ma, Linlin; Romsdahl, Trevor; Loughman, Eileen G; Markham, Jonathan E; Seravalli, Javier; Barycki, Joseph J; Simpson, Melanie A

    2016-08-01

    Prostate epithelial cells control the potency and availability of androgen hormones in part by inactivation and elimination. UDP-glucose dehydrogenase (UGDH) catalyzes the NAD(+)-dependent oxidation of UDP-glucose to UDP-glucuronate, an essential precursor for androgen inactivation by the prostate glucuronidation enzymes UGT2B15 and UGT2B17. UGDH expression is androgen stimulated, which increases the production of UDP-glucuronate and fuels UGT-catalyzed glucuronidation. In this study, we compared the glucuronidation potential and its impact on androgen-mediated gene expression in an isogenic LNCaP model for androgen-dependent versus castration-resistant prostate cancer. Despite significantly lower androgen-glucuronide output, LNCaP 81 castration-resistant tumor cells expressed higher levels of UGDH, UGT2B15, and UGT2B17. However, the magnitude of androgen-activated UGDH and prostate-specific antigen (PSA) expression, as well as the androgen receptor (AR)-dependent repression of UGT2B15 and UGT2B17, was blunted several-fold in these cells. Consistent with these results, the ligand-activated binding of AR to the PSA promoter and subsequent transcriptional activation were also significantly reduced in castration-resistant cells. Analysis of the UDP-sugar pools and flux through pathways downstream of UDP-glucuronate production revealed that these glucuronidation precursor metabolites were channeled through proteoglycan and glycosaminoglycan biosynthetic pathways, leading to increased surface expression of Notch1. Knockdown of UGDH diminished Notch1 and increased glucuronide output. Overall, these results support a model in which the aberrant partitioning of UDP-glucuronate and other UDP-sugars into alternative pathways during androgen deprivation contributes to the loss of prostate tumor cell androgen sensitivity by promoting altered cell surface proteoglycan expression. PMID:27307252

  10. Life's Impact on the Soil Production Function

    NASA Astrophysics Data System (ADS)

    Harrison, Emma; Willenbring, Jane; Brocard, Gilles

    2016-04-01

    Soil melds life and lithology, but the top-down production of soil by the incorporation of organic matter has typically been viewed through a lens of soil biogeochemistry and the bottom-up weathering of bedrock viewed from a geomorphologic perspective. We merge these perspectives by developing a variation on the classic geomorphological soil production function [1] that accounts for the influence of top-down soil production by additions of organic material. In the classic view [1], production rate of soil from bedrock weathering is a function of the thickness of the soil horizon. Under steady state conditions, this thickness is controlled by a constant coefficient of diffusion and by the hillslope curvature. Across the globe, equilibrium landscapes can be hard to find. We explore the many ways that biota influence the upper soil horizons and move the soil-hillslope system out of steady state using measurements of in situ 10Be at depth in soil profiles. Our empirical case study is in the Luquillo Critical Zone Observatory of northeastern Puerto Rico, where long term ecological monitoring suggests an average of 375 m My-1 of litter fall [2] and as much as 17.5 m My-1 of dust [3] is contributed to the forest floor. This substantial volume of material forms an active surficial layer, functionally increasing the residence time of grains deeper in the soil profile. Litter recycling influences the cosmogenic dose rate to be higher by increasing the residence time of grains and to be lower by increasing environmental shielding. In unconstrained systems, probabilistic modeling can determine a range of solutions for the ages of grains determined with 10Be depth profiles[4]. We compare the probabilistic outcomes to actual measurements of the in situ 10Be at depth in soil profiles from the Luquillo Mountains. Life living in the soil, rather than on it, is of equal importance in the Luquillo Mountains. On average, the soil is occupied by 200 individual earthworms per m2 [5

  11. ADVERSE EFFECTS OF ENVIRONMENTAL ANTIANDROGENS AND ANDROGENS ON REPRODUCTIVE DEVELOPMENT IN MAMMALS

    EPA Science Inventory

    Within the last decade, several classes of chemicals have been shown in laboratory studies to disrupt reproductive development by acting as androgen receptor (AR) antagonists and/or inhibitors of fetal Leydig cell testosterone production. Some phthalate esters alter gubernacular...

  12. Cephalopod Ink: Production, Chemistry, Functions and Applications

    PubMed Central

    Derby, Charles D.

    2014-01-01

    One of the most distinctive and defining features of coleoid cephalopods—squid, cuttlefish and octopus—is their inking behavior. Their ink, which is blackened by melanin, but also contains other constituents, has been used by humans in various ways for millennia. This review summarizes our current knowledge of cephalopod ink. Topics include: (1) the production of ink, including the functional organization of the ink sac and funnel organ that produce it; (2) the chemical components of ink, with a focus on the best known of these—melanin and the biochemical pathways involved in its production; (3) the neuroecology of the use of ink in predator-prey interactions by cephalopods in their natural environment; and (4) the use of cephalopod ink by humans, including in the development of drugs for biomedical applications and other chemicals for industrial and other commercial applications. As is hopefully evident from this review, much is known about cephalopod ink and inking, yet more striking is how little we know. Towards closing that gap, future directions in research on cephalopod inking are suggested. PMID:24824020

  13. Targeting intratumoral androgens: statins and beyond.

    PubMed

    Schweizer, Michael T; Yu, Evan Y

    2016-09-01

    While initially effective, androgen deprivation therapy (ADT) is not curative, and nearly all men with advanced prostate cancer will eventually progress to the more resistant, and ultimately lethal form of the disease, so called castration-resistant prostate cancer (CRPC). The maintenance of androgens within the prostate cancer microenvironment likely represents one of the key mechanisms by which this transition from hormone-sensitive to CRPC occurs. This can be accomplished either through intratumoral androgen biosynthesis or the active transport of androgens and androgenic precursors into the tumor microenvironment. More recently, preclinical and clinical data supported therapeutic strategies that seek to target these two mechanisms, either through the use of drugs that impair androgen biosynthesis (e.g. inhibiting the steroidogenic enzymes CYP17 and AKR1C3 with abiraterone and indomethacin, respectively) or drugs that inhibit the SLCO transporters responsible for importing androgens (e.g. statins). PMID:27583031

  14. Androgen action in cultured dermal papilla cells from human hair follicles.

    PubMed

    Randall, V A; Thornton, M J; Hamada, K; Messenger, A G

    1994-01-01

    Androgens are major regulators of human hair growth with paradoxically different effects on hair follicles depending on their body site. They stimulate terminal growth in many regions including the face, have no effect on eyelashes, but may cause inhibition and balding on the scalp in genetically disposed individuals. How this occurs is unknown. However, androgens may act on the hair follicle via the cells of the dermal papilla; these would then influence the other cells of the hair follicle by altering the production of regulatory substances such as growth factors and/or extracellular matrix components. Therefore, primary lines of dermal papilla cells have been established from androgen-sensitive hair follicles, such as beard, and control, relatively androgen-independent, non-balding scalp cells and their mechanism of androgen action has been compared. Isolated beard dermal papillae were larger than those from scalp follicles. Although dermal papilla cells did not respond to in vitro androgens by alterations in growth, androgen-dependent dermal papilla cells contained higher levels of specific, low capacity, high affinity androgen receptors than non-balding scalp cells. The ability of the cells to metabolise testosterone to 5 alpha-dihydrotestosterone in culture also varied in parallel to that predicted from studies of hair growth in the 5 alpha-reductase deficiency syndrome. These results support the hypothesis that androgens act via the dermal papilla. They also show that dermal papilla cells retain differences in gene expression in culture which appear to correspond with their androgenic response in vivo. Further studies of such cells should help elucidate why bald men can grow beards! PMID:8003318

  15. Anoxic Androgen Degradation by the Denitrifying Bacterium Sterolibacterium denitrificans via the 2,3-seco Pathway

    PubMed Central

    Wang, Po-Hsiang; Yu, Chang-Ping; Lee, Tzong-Huei; Lin, Ching-Wen; Ismail, Wael; Wey, Shiaw-Pyng; Kuo, An-Ti

    2014-01-01

    The biodegradation of steroids is a crucial biochemical process mediated exclusively by bacteria. So far, information concerning the anoxic catabolic pathways of androgens is largely unknown, which has prevented many environmental investigations. In this work, we show that Sterolibacterium denitrificans DSMZ 13999 can anaerobically mineralize testosterone and some C19 androgens. By using a 13C-metabolomics approach and monitoring the sequential appearance of the intermediates, we demonstrated that S. denitrificans uses the 2,3-seco pathway to degrade testosterone under anoxic conditions. Furthermore, based on the identification of a C17 intermediate, we propose that the A-ring cleavage may be followed by the removal of a C2 side chain at C-5 of 17-hydroxy-1-oxo-2,3-seco-androstan-3-oic acid (the A-ring cleavage product) via retro-aldol reaction. The androgenic activities of the bacterial culture and the identified intermediates were assessed using the lacZ-based yeast androgen assay. The androgenic activity in the testosterone-grown S. denitrificans culture decreased significantly over time, indicating its ability to eliminate androgens. The A-ring cleavage intermediate (≤500 μM) did not exhibit androgenic activity, whereas the sterane-containing intermediates did. So far, only two androgen-degrading anaerobes (Sterolibacterium denitrificans DSMZ 13999 [a betaproteobacterium] and Steroidobacter denitrificans DSMZ 18526 [a gammaproteobacterium]) have been isolated and characterized, and both of them use the 2,3-seco pathway to anaerobically degrade androgens. The key intermediate 2,3-seco-androstan-3-oic acid can be used as a signature intermediate for culture-independent environmental investigations of anaerobic degradation of C19 androgens. PMID:24657867

  16. Molecular cloning and characterization of a nuclear androgen receptor activated by 11-ketotestosterone

    PubMed Central

    Olsson, Per-Erik; Berg, A Håkan; von Hofsten, Jonas; Grahn, Birgitta; Hellqvist, Anna; Larsson, Anders; Karlsson, Johnny; Modig, Carina; Borg, Bertil; Thomas, Peter

    2005-01-01

    Although 11-ketotestosterone is a potent androgen and induces male secondary sex characteristics in many teleosts, androgen receptors with high binding affinity for 11-ketotestosterone or preferential activation by 11-ketotestosterone have not been identified. So, the mechanism by which 11-ketotestosterone exhibits such high potency remains unclear. Recently we cloned the cDNA of an 11-ketotestosterone regulated protein, spiggin, from three-spined stickleback renal tissue. As spiggin is the only identified gene product regulated by 11-ketotestosterone, the stickleback kidney is ideal for determination of the mechanism of 11-ketotestosterone gene regulation. A single androgen receptor gene with two splicing variants, belonging to the androgen receptor-β subfamily was cloned from stickleback kidney. A high affinity, saturable, single class of androgen specific binding sites, with the characteristics of an androgen receptor, was identified in renal cytosolic and nuclear fractions. Measurement of ligand binding moieties in the cytosolic and nuclear fractions as well as to the recombinant receptor revealed lower affinity for 11-ketotestosterone than for dihydrotestosterone. Treatment with different androgens did not up-regulate androgen receptor mRNA level or increase receptor abundance, suggesting that auto-regulation is not involved in differential ligand activation. However, comparison of the trans-activation potential of the stickleback androgen receptor with the human androgen receptor, in both human HepG2 cells and zebrafish ZFL cells, revealed preferential activation by 11-ketotestosterone of the stickleback receptor, but not of the human receptor. These findings demonstrate the presence of a receptor preferentially activated by 11-ketotestosterone in the three-spined stickleback, so far the only one known in any animal. PMID:16107211

  17. 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...

  18. Retinoic acid receptor beta and angiopoietin-like protein 1 are involved in the regulation of human androgen biosynthesis

    PubMed Central

    Udhane, Sameer S.; Pandey, Amit V.; Hofer, Gaby; Mullis, Primus E.; Flück, Christa E.

    2015-01-01

    Androgens are essential for sexual development and reproduction. However, androgen regulation in health and disease is poorly understood. We showed that human adrenocortical H295R cells grown under starvation conditions acquire a hyperandrogenic steroid profile with changes in steroid metabolizing enzymes HSD3B2 and CYP17A1 essential for androgen production. Here we studied the regulatory mechanisms underlying androgen production in starved H295R cells. Microarray expression profiling of normal versus starved H295R cells revealed fourteen differentially expressed genes; HSD3B2, HSD3B1, CYP21A2, RARB, ASS1, CFI, ASCL1 and ENC1 play a role in steroid and energy metabolism and ANGPTL1, PLK2, DUSP6, DUSP10 and FREM2 are involved in signal transduction. We discovered two new gene networks around RARB and ANGPTL1, and show how they regulate androgen biosynthesis. Transcription factor RARB stimulated the promoters of genes involved in androgen production (StAR, CYP17A1 and HSD3B2) and enhanced androstenedione production. For HSD3B2 regulation RARB worked in cooperation with Nur77. Secretory protein ANGPTL1 modulated CYP17A1 and DUSP6 expression by inducing ERK1/2 phosphorylation. By contrast, our studies revealed no evidence for hormones or cell cycle involvement in regulating androgen biosynthesis. In summary, these studies establish a firm role for RARB and ANGPTL1 in the regulation of androgen production in H295R cells. PMID:25970467

  19. Androgen receptor mutations in carcinoma of the prostate: significance for endocrine therapy.

    PubMed

    Culig, Z; Klocker, H; Bartsch, G; Hobisch, A

    2001-01-01

    Endocrine therapy for advanced prostate cancer involves androgen ablation (orchiectomy or application of luteinizing hormone releasing hormone analogs) and/or blockade of the androgen receptor (AR) with either steroidal (cyproterone acetate) or nonsteroidal (hydroxyflutamide, bicalutamide and nilutamide) antiandrogens. These antagonists prevent androgen-induced conformational change and activation of the AR. During long term androgen ablation, the AR adapts to an environment with low androgen concentrations and becomes hypersensitive to low concentrations of androgens, either alone or in combination with various cellular regulators. Bicalutamide can switch from antagonist to agonist during long-term androgen withdrawal, as shown in prostate cancer LNCaP cells. AR point mutations were detected in metastatic lesions from human prostate cancer more frequently than in primary tumors. Although functional characterization of only some mutant AR detected in prostate cancer tissue has been performed, data available suggest that they are activated by dihydrotestosterone, its precursors and metabolites, synthetic androgens, estrogenic and progestagenic steroids and hydroxyflutamide. A direct association between AR mutations and endocrine withdrawal syndrome has been investigated in only one study thus far. There is no evidence at present that activation of any of the mutant AR genes detected in prostate cancer is enhanced in the presence of a nonsteroidal AR stimulator. Coactivators of the AR are proteins that associate with the receptor, possess histone acetylase activity and facilitate AR activation. The coregulatory proteins ARA70 and ARA160 differentially affected the activity of the mutated AR Glu(231)-->Gly, which was discovered in a mouse authochthonous prostate tumor. ARA70 enhanced receptor activation by both androgen and estradiol, whereas ARA160 augmented only androgen-induced AR activity. Novel experimental therapies that down-regulate AR expression have been

  20. Water Production Functions for Central Plains Crops

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Sustaining irrigated agriculture with limited water supplies requires maximizing productivity per unit of water. Relationships between crop production and water consumed are basic information required to maximize productivity. This information can be used to determine if deficit irrigation is eco...

  1. Water Production Function For Central Plains Crops

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Sustaining irrigated agriculture with limited water supplies requires maximizing productivity per unit of water. Relationships between crop production and water consumed are basic information required to maximize productivity. This information can be used to determine if deficit irrigation is econ...

  2. Effects of androgen and leptin on behavioral and cellular responses in female rats.

    PubMed

    Feng, Yi; Shao, Ruijin; Weijdegård, Birgitta; Wang, Tienpei; Johansson, Julia; Sun, Shan; Wang, Wei; Egecioglu, Emil; Billig, Håkan; Stener-Victorin, Elisabet

    2011-09-01

    The causes of anxiety and depression in women with polycystic ovary syndrome (PCOS) remain elusive. To identify steps linking androgen signaling to the regulation of affective symptoms in vivo, we compared behavioral responses in female rats continuously exposed to DHT from puberty (a model of DHT-induced PCOS) and in rats exposed to DHT for 1week. Continuous and 1week of DHT exposure resulted in a general decrease in locomotor activity and time spent on the open arms in the elevated plus maze, indicating anxiety-like behavior. Rats with DHT-induced PCOS have increases in adiposity and circulating leptin levels accompanied by leptin resistance. One week of DHT exposure decreased androgen receptor (AR) expression in the hypothalamus and leptin synthesis and function in adipocytes; it also inhibited signal transducer and activator of transcription 3 (STAT3) and attenuated leptin activity by increasing levels of soluble leptin receptor, a leptin-binding protein, in the hypothalamus. This may affect the androgen-induced anxiety-related behavior in female rats. In conclusion, our results highlight the central role of androgens in behavioral function in female rats and suggest that androgens directly regulate the AR by decreasing its hypothalamic expression. Androgens also increase leptin synthesis in adipocytes, which drives central leptin signaling, and may regulate anxiety-related behaviors. Elucidating mechanisms by which androgens modulate female anxiety-like behavior may uncover useful approaches for treating women with PCOS who have symptoms of anxiety. PMID:21819988

  3. Functions of Carotenoid Metabolites and Breakdown Products

    NASA Astrophysics Data System (ADS)

    Britton, George

    It is not only intact carotenoids but also fragments of carotenoid molecules that have important natural functions and actions. The electron-rich polyene chain of the carotenoids is very susceptible to oxidative breakdown, which may be enzymic or non-enzymic. Central cleavage gives C20 compounds, retinoids, as described in Chapter 16. Cleavage at other positions gives smaller fragments, notably C10, C13 and C15 compounds that retain the carotenoid end group. The formation of these is described in Chapter 17 and in Volume 3, Chapter 4. Oxidative breakdown can also take place during storage, processing and curing of plant material, and the products contribute to the desired aroma/flavour properties of, for example, tea, wine and tobacco. The importance of vitamin A (C20) in animals is well known. Vitamin A deficiency is still a major concern in many parts of the world. It can lead to blindness and serious ill-health or death, especially in young children. Volatile smaller carotenoid fragments (`norisoprenoids') are widespread scent/flavour compounds in plants.

  4. Androgen and FSH synergistically stimulate lipoprotein degradation and utilization by ovary granulosa cells

    SciTech Connect

    Schreiber, J.R.; Nakamura, K.; Schmit, V.; Weinstein, D.B.

    1984-01-01

    Androgen can directly modulate the induction of steroidogenic enzymes by FSH (follicle stimulating hormone) in ovary granulosa cells. In studies of its mechanism of action, the authors examined the androgen effect on granulosa cell interaction with lipoproteins, the physiologic source of cholesterol. After granulosa cells were cultured for 48 hours with and without androgen and/or FSH, the cells were incubated for 24 hours with /sup 125/I-lipoproteins (human high density lipoprotein (HDL), rat HDL, or human low density lipoprotein (LDL)). The media were then analyzed for lipoprotein protein coat degradation products (mainly /sup 125/I-monoiodotyrosine) and progestin (mainly 20 alpha-dihydroprogesterone (20 alpha-DHP)). In the absence of FSH and androgen, 2 X 10(5) granulosa cells degraded basal levels of all three lipoproteins, but produced no measurable 20 alpha-DHP. The addition of 10(-7) M androstenedione (A), testosterone (T), or 5 alpha-dihydrotestosterone (DHT) had no effect on lipoprotein protein degradation or 20 alpha-DHP production. FSH alone stimulated lipoprotein protein degradation by 50 to 300% while the addition of androgen synergistically augmented the FSH-stimulated 20 alpha-DHP production as well as protein coat degradation of all three lipoproteins. DHT and T were both effective, indicating that androgens themselves, and not estrogen products, were responsible for the effect on lipoprotein protein degradation and 20 alpha-DHP production.

  5. Loss of exogenous androgen dependence by prostate tumor cells is associated with elevated glucuronidation potential

    PubMed Central

    Zimmer, Brenna M.; Howell, Michelle E.; Wei, Qin; Ma, Linlin; Romsdahl, Trevor; Loughman, Eileen G.; Markham, Jonathan E.; Seravalli, Javier; Barycki, Joseph J.; Simpson, Melanie A.

    2016-01-01

    Prostate epithelial cells control the potency and availability of androgen hormones in part by inactivation and elimination. UDP-glucose dehydrogenase (UGDH) catalyzes the NAD+-dependent oxidation of UDP-glucose to UDP-glucuronate, an essential precursor for androgen inactivation by the prostate glucuronidation enzymes UGT2B15 and UGT2B17. UGDH expression is androgen stimulated, which increases the production of UDP-glucuronate, and fuels UGT-catalyzed glucuronidation. In this study, we compared the glucuronidation potential and its impact on androgen-mediated gene expression in an isogenic LNCaP model for androgen dependent versus castration resistant prostate cancer. Despite significantly lower androgen-glucuronide output, LNCaP 81 castration resistant tumor cells expressed higher levels of UGDH, UGT2B15, and UGT2B17. However, the magnitude of androgen-activated UGDH and PSA expression, as well as the AR-dependent repression of UGT2B15 and UGT2B17, was blunted several-fold in these cells. Consistent with these results, the ligand-activated binding of AR to the PSA promoter and subsequent transcriptional activation were also significantly reduced in castration resistant cells. Analysis of the UDP-sugar pools and flux through pathways downstream of UDP-glucuronate production revealed that these glucuronidation precursor metabolites were channeled through proteoglycan and glycosaminoglycan biosynthetic pathways, leading to increased surface expression of Notch 1. Knockdown of UGDH diminished Notch1 and increased glucuronide output. Overall, these results support a model in which the aberrant partitioning of UDP-glucuronate and other UDP-sugars into alternative pathways during androgen deprivation contributes to the loss of prostate tumor cell androgen sensitivity by promoting altered cell surface proteoglycan expression. PMID:27307252

  6. 4-Nitro-3-phenylphenol has both androgenic and anti-androgenic-like effects in rats.

    PubMed

    Trisomboon, Jiratthiya; Li, ChunMei; Suzuki, Akira; Watanabe, Gen; Taya, Kazuyoshi

    2015-01-01

    To investigate the effect of endocrine disruption of 4-nitro-3-phenylphenol (PNMPP) on immature male Wistar-Imamichi rats, the rat pituitary was exposed to PNMPP (10(-5)-10(-9) M) for 24 h with or without gonadotropin-releasing hormone (GnRH) in experiment I. In addition, the Leydig cells (10(-5)-10(-9) M) were exposed to PNMPP for 24 h with or without human chronic gonadotropin (hCG) in experiment II. Our results showed that the PNMPP at 10(-5)-10(-7) M suppressed follicle-stimulating hormone (FSH) and luteinizing hormone (LH) productions from GnRH-stimulated pituitary cells. At the same time, PNMPP 10(-5)-10(-7) M induced an increase in testosterone production from the Leydig cells treated with or without hCG. Based on our results, it can be concluded that that PNMPP might have both androgen agonist action by decreasing FSH and LH production in the pituitary and anti-androgenic action by increasing testosterone production in the Leydig cell. PMID:25736398

  7. CCAAT/Enhancer binding protein β controls androgen-deprivation-induced senescence in prostate cancer cells.

    PubMed

    Barakat, D J; Zhang, J; Barberi, T; Denmeade, S R; Friedman, A D; Paz-Priel, I

    2015-11-26

    The processes associated with transition to castration-resistant prostate cancer (PC) growth are not well understood. Cellular senescence is a stable cell cycle arrest that occurs in response to sublethal stress. It is often overcome in malignant transformation to confer a survival advantage. CCAAT/Enhancer Binding Protein (C/EBP) β function is frequently deregulated in human malignancies and interestingly, androgen-sensitive PC cells express primarily the liver-enriched inhibitory protein isoform. We found that C/EBPβ expression is negatively regulated by androgen receptor (AR) activity and that treatment of androgen-sensitive cell lines with anti-androgens increases C/EBPβ mRNA and protein levels. Accordingly, we also find that C/EBPβ levels are significantly elevated in primary PC samples from castration-resistant compared with therapy-naive patients. Chromatin immunoprecipitation demonstrated enhanced binding of the AR to the proximal promoter of the CEBPB gene in the presence of dihydroxytestosterone. Upon androgen deprivation, induction of C/EBPβ is facilitated by active transcription as evident by increased histone 3 acetylation at the C/EBPβ promoter. Also, the androgen agonist R1881 suppresses the activity of a CEBPB promoter reporter. Loss of C/EBPβ expression prevents growth arrest following androgen deprivation or anti-androgen challenge. Accordingly, suppression of C/EBPβ under low androgen conditions results in reduced expression of senescence-associated secretory genes, significantly decreased number of cells displaying heterochromatin foci and increased numbers of Ki67-positive cells. Ectopic expression of C/EBPβ caused pronounced morphological changes, reduced PC cell growth and increased the number of senescent LNCaP cells. Lastly, we found that senescence contributes to PC cell survival under androgen deprivation, and C/EBPβ-deficient cells were significantly more susceptible to killing by cytotoxic chemotherapy following androgen

  8. 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

  9. Prostate cancer stem cells: the role of androgen and estrogen receptors.

    PubMed

    Di Zazzo, Erika; Galasso, Giovanni; Giovannelli, Pia; Di Donato, Marzia; Di Santi, Annalisa; Cernera, Gustavo; Rossi, Valentina; Abbondanza, Ciro; Moncharmont, Bruno; Sinisi, Antonio Agostino; Castoria, Gabriella; Migliaccio, Antimo

    2016-01-01

    Prostate cancer is one of the most commonly diagnosed cancers in men, and androgen deprivation therapy still represents the primary treatment for prostate cancer patients. This approach, however, frequently fails and patients develop castration-resistant prostate cancer, which is almost untreatable.Cancer cells are characterized by a hierarchical organization, and stem/progenitor cells are endowed with tumor-initiating activity. Accumulating evidence indicates that prostate cancer stem cells lack the androgen receptor and are, indeed, resistant to androgen deprivation therapy. In contrast, these cells express classical (α and/or β) and novel (GPR30) estrogen receptors, which may represent new putative targets in prostate cancer treatment.In the present review, we discuss the still-debated mechanisms, both genomic and non-genomic, by which androgen and estradiol receptors (classical and novel) mediate the hormonal control of prostate cell stemness, transformation, and the continued growth of prostate cancer. Recent preclinical and clinical findings obtained using new androgen receptor antagonists, anti-estrogens, or compounds such as enhancers of androgen receptor degradation and peptides inhibiting non-genomic androgen functions are also presented. These new drugs will likely lead to significant advances in prostate cancer therapy. PMID:26506594

  10. Prostate cancer stem cells: the role of androgen and estrogen receptors

    PubMed Central

    Di Zazzo, Erika; Galasso, Giovanni; Giovannelli, Pia; Di Donato, Marzia; Di Santi, Annalisa; Cernera, Gustavo; Rossi, Valentina; Abbondanza, Ciro; Moncharmont, Bruno; Sinisi, Antonio Agostino; Castoria, Gabriella; Migliaccio, Antimo

    2016-01-01

    Prostate cancer is one of the most commonly diagnosed cancers in men, and androgen deprivation therapy still represents the primary treatment for prostate cancer patients. This approach, however, frequently fails and patients develop castration-resistant prostate cancer, which is almost untreatable. Cancer cells are characterized by a hierarchical organization, and stem/progenitor cells are endowed with tumor-initiating activity. Accumulating evidence indicates that prostate cancer stem cells lack the androgen receptor and are, indeed, resistant to androgen deprivation therapy. In contrast, these cells express classical (α and/or β) and novel (GPR30) estrogen receptors, which may represent new putative targets in prostate cancer treatment. In the present review, we discuss the still-debated mechanisms, both genomic and non-genomic, by which androgen and estradiol receptors (classical and novel) mediate the hormonal control of prostate cell stemness, transformation, and the continued growth of prostate cancer. Recent preclinical and clinical findings obtained using new androgen receptor antagonists, anti-estrogens, or compounds such as enhancers of androgen receptor degradation and peptides inhibiting non-genomic androgen functions are also presented. These new drugs will likely lead to significant advances in prostate cancer therapy. PMID:26506594

  11. [Androgenic treatment of male hypogonadism].

    PubMed

    Kuhn, Jean-Marc; Prévost, Gaëtan

    2014-02-01

    The diagnosis of male hypogonadism should be clearly established on a clinical and biological basis before considering the initiation of a substitutive treatment with androgens. A careful evaluation of advantages, constraints and limitations of the treatment should be done previously. The potential advantages of an androgenic substitution include an improvement of the symptoms of hypogonadism and the prevention of its bone and metabolic consequences. Absolute (namely prostatic) or relative contraindications should be detected before starting any substitution. The modalities of treatment will be adapted to both the patient's age and the goals to reach. The different available formulations do not induce a similar pattern of plasma testosterone levels. Patches, gel applications and long-acting intramuscular formulations [injected every 3 months] result in stable plasma levels in the physiologic range. The main limitation to their use is linked to a financial aspect as they are not the object of any refund. A careful survey (on clinical, biological and radiological basis) should be established after starting the substitutive treatment with androgens. PMID:24268959

  12. Androgens and erythropoiesis: past and present.

    PubMed

    Shahani, S; Braga-Basaria, M; Maggio, M; Basaria, S

    2009-09-01

    Association between androgens and erythropoiesis has been known for more than seven decades. Androgens stimulate hematopoietic system by various mechanisms. These include stimulation of erythropoietin release, increasing bone marrow activity and iron incorporation into the red cells. Before the discovery of recombinant erythropoietin (rhEpo), androgens were used in the treatment of anemia associated with renal disease, bone marrow suppression, and hypopituitarism. Anabolism is an additional advantage of androgen therapy. Furthermore, in light of recent reports regarding adverse effects of rhEpo, the role of androgen therapy in various types of anemias should be readdressed. Polycythemia remains a known side effect of androgen therapy. In this review, we will briefly discuss the initial animal and human studies which demonstrated the role of androgens in the treatment of anemia, their mechanism of action, a detailed account of the efficacy of androgens in the treatment of various anemias, the erythropoietic side effects of androgens and finally, the relationship between hematocrit levels and cardiovascular disease. PMID:19494706

  13. 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

  14. Orexin Decreases Aromatase Gene Expression in The Hypothalamus of Androgenized Female Rats

    PubMed Central

    Salimi, Maliheh; Alishah, Zahra; Khazali, Homayoun; Mahmoudi, Fariba

    2016-01-01

    Background Orexin is a hypothalamic orexigenic neuropeptide, which third cerebral injection of it mainly exerts inhibitory effects on reproductive functions. It increases significantly the Aromatase (Cyp19) gene expression in the hypothalamus of male rats. Aromatase is an enzyme which converts androgens to estradiol in the hypothalamus of rats. Prenatal or neonatal exposure of females to testosterone masculinizes the pattern of Cyp19 mRNA levels in adulthood. In the present study the effects of central injections of orexin-A on hypothalamic Cyp19 gene expression of adult female rats were investigated, while they had been androgenized on third day of postnatal life. Materials and Methods In this experimental study, twenty female Wistar rats received subcutaneous injections of testosterone propionate (50 µg/100 µl) on their third day of postnatal life. Adult androgenized rats weighing 180-220 g, received either 3 µl saline or one of 2, 4 or 8 µg/3 µl concentration of orexin via third cerebral ventricle. Five non-androgenized rats, as control group, received intra cerebral ventricle (ICV) injection of 3 µl saline. The hypothalamuses were dissected out and mean Cyp19 mRNA levels were determined by semi-quantitative real time-polymerase chain reaction (PCR) method. Data were analyzed by unpaired t test and one-way ANOVA using SPSS software, version 16. Results Mean relative Cyp19 mRNA level was significantly increased in the hypothalamus of androgenized compared to non-androgenized female rats. Central injec- tions of 2, 4 or 8 µg/3 µl orexin decreased significantly the hypothalamic Cyp19 mRNA level of androgenized rats compared to androgenized-control groups. Conclusion The results suggested that the orexin may exert inhibitory effects on the gene expression of Cyp19 in the hypothalamus of neonatal androgenized female rats in adulthood. PMID:27441052

  15. Survival Advantage of AMPK Activation to Androgen-Independent Prostate Cancer Cells During Energy Stress

    PubMed Central

    Chhipa, Rishi Raj; Wu, Yue; Mohler, James L.; Ip, Clement

    2016-01-01

    Androgen-independent prostate cancer usually develops as a relapse following androgen ablation therapy. Removing androgen systemically causes vascular degeneration and nutrient depletion of the prostate tumor tissue. The fact that the malignancy later evolves to androgen-independence suggests that some cancer cells are able to survive the challenge of energy/nutrient deprivation. AMP-activated protein kinase (AMPK) is an important manager of energy stress. The present study was designed to investigate the role of AMPK in contributing to the survival of the androgen-independent phenotype. Most of the experiments were carried out in the androgen-dependent LNCaP cells and the androgen-independent C4-2 cells. These two cell lines have the same genetic background, since the C4-2 line is derived from the LNCaP line. Glucose deprivation (GD) was instituted to model energy stress encountered by these cells. The key findings are as follows. First, the activation of AMPK by GD was much stronger in C4-2 cells than in LNCaP cells, and the robustness of AMPK activation was correlated favorably with cell viability. Second, the response of AMPK was specific to energy deficiency rather than to amino acid deficiency. The activation of AMPK by GD was functional, as demonstrated by appropriate phosphorylation changes of mTOR and mTOR downstream substrates. Third, blocking AMPK activation by chemical inhibitor or dominant negative AMPK led to increased apoptotic cell death. The observation that similar results were found in other androgen-independent prostate cancer cell lines, including CW22Rv1 abd VCaP, provided further assurance that AMPK is a facilitator on the road to androgen-independence of prostate cancer cells. PMID:20570728

  16. Canonical Estimation of Joint Educational Production Functions.

    ERIC Educational Resources Information Center

    Chizmar, John F.; Zak, Thomas A.

    1984-01-01

    This article views learning and attitude formation within the context of joint production. Tables show summary statistics and estimated marginal products and rates for each output. These estimates reveal trade-offs within the learning process that differ for men and women. (PB)

  17. 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

    SciTech Connect

    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 transfected 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.

  18. Anogenital distance as a marker of androgen exposure in humans.

    PubMed

    Thankamony, A; Pasterski, V; Ong, K K; Acerini, C L; Hughes, I A

    2016-07-01

    Abnormal foetal testis development has been proposed to underlie common disorders of the male reproductive system such as cryptorchidism, hypospadias, reduced semen quality and testicular germ cell tumour, which are regarded as components of a 'testicular dysgenesis syndrome'. The increasing trends and geographical variation in their incidence have been suggested to result from in utero exposure to environmental chemicals acting as endocrine disruptors. In rodents, the anogenital distance (AGD), measured from the anus to the base of genital tubercle, is a sensitive biomarker of androgen exposure during a critical embryonic window of testis development. In humans, several epidemiological studies have shown alterations in AGD associated with prenatal exposure to several chemicals with potential endocrine disrupting activity. However, the link between AGD and androgen exposure in humans is not well-defined. This review focuses on the current evidence for such a relationship. As in rodents, a clear gender difference is detected during foetal development of the AGD in humans which is maintained thereafter. Reduced AGD in association with clinically relevant outcomes of potential environmental exposures, such as cryptorchidism or hypospadias, is in keeping with AGD as a marker of foetal testicular function. Furthermore, AGD may reflect variations in prenatal androgen exposure in healthy children as shorter AGD at birth is associated with reduced masculine play behaviour in preschool boys. Several studies provide evidence linking shorter AGD with lower fertility, semen quality and testosterone levels in selected groups of adults attending andrology clinics. Overall, the observational data in humans are consistent with experimental studies in animals and support the use of AGD as a biomarker of foetal androgen exposure. Future studies evaluating AGD in relation to reproductive hormones in both infants and adults, and to gene polymorphisms, will help to further delineate

  19. Androgen synthesis inhibitors in the treatment of castration-resistant prostate cancer

    PubMed Central

    Stein, Mark N; Patel, Neal; Bershadskiy, Alexander; Sokoloff, Alisa; Singer, Eric A

    2014-01-01

    Suppression of gonadal testosterone synthesis represents the standard first line therapy for treatment of metastatic prostate cancer. However, in the majority of patients who develop castration-resistant prostate cancer (CRPC), it is possible to detect persistent activation of the androgen receptor (AR) through androgens produced in the adrenal gland or within the tumor itself. Abiraterone acetate was developed as an irreversible inhibitor of the dual functional cytochrome P450 enzyme CYP17 with activity as a 17α-hydroxylase and 17,20-lyase. CYP17 is necessary for production of nongonadal androgens from cholesterol. Regulatory approval of abiraterone in 2011, based on a phase III trial showing a significant improvement in overall survival (OS) with abiraterone and prednisone versus prednisone, represented proof of principle that targeting AR is essential for improving outcomes in men with CRPC. Inhibition of 17α-hydroxylase by abiraterone results in accumulation of upstream mineralocorticoids due to loss of cortisol-mediated suppression of pituitary adrenocorticotropic hormone (ACTH), providing a rationale for development of CYP17 inhibitors with increased specificity for 17,20-lyase (orteronel, galeterone and VT-464) that can potentially be administered without exogenous corticosteroids. In this article, we review the development of abiraterone and other CYP17 inhibitors; recent studies with abiraterone that inform our understanding of clinical parameters such as drug effects on quality-of-life, potential early predictors of response, and optimal sequencing of abiraterone with respect to other agents; and results of translational studies providing insights into resistance mechanisms to CYP17 inhibitors leading to clinical trials with drug combinations designed to prolong abiraterone benefit or restore abiraterone activity. PMID:24759590

  20. New insights into the androgen biotransformation in prostate cancer: A regulatory network among androgen, androgen receptors and UGTs.

    PubMed

    Qin, Xuan; Liu, Mingyao; Wang, Xin

    2016-04-01

    Androgen, as one kind of steroid hormones, is pivotal in the hormone-sensitive cancer, such as prostate cancer (PCa). The synthesis, elimination, and bioavailability of androgen in prostate cells have been proved to be a main cause of the carcinogenesis, maintenance and deterioration of PCa. This review illustrates the outlines of androgen biotransformation, and further discusses the different enzymes, especially UDP-glucuronyltransferases (UGTs) embedded in both benign and malignant prostate cells, which catalyze the reactions. Although many inhibitors of the enzymes responsible for the synthesis of androgens have been developed into drugs to fight against PCa, the elimination procedures metabolized by the UGTs are less emphasized. Thus the regulatory network among androgen, androgen receptors (AR) and UGTs is carefully reviewed in this article, indicating the determinant effects of UGTs on prostatic androgens and the regulation of AR. Finally, the hypothesis is also put forward that the regulators of UGTs may be developed to accelerate the androgen elimination and benefit PCa therapy. PMID:26926093

  1. Effect of cinnamon (Cinnamomum zeylanicum) bark oil on heat stress-induced changes in sperm production, testicular lipid peroxidation, testicular apoptosis, and androgenic receptor density in developing Japanese quails.

    PubMed

    Türk, Gaffari; Şimşek, Ülkü G; Çeribaşı, Ali O; Çeribaşı, Songül; Özer Kaya, Şeyma; Güvenç, Mehmet; Çiftçi, Mehmet; Sönmez, Mustafa; Yüce, Abdurrauf; Bayrakdar, Ali; Yaman, Mine; Tonbak, Fadime

    2015-08-01

    The aim of this study was to investigate the effect of cinnamon bark oil (CBO) on heat stress (HS)-induced changes in sperm production, testicular lipid peroxidation, testicular apoptosis, and androgenic receptor (AR) density in developing Japanese quails. Fifteen-day-old 90 male chicks were assigned to two main groups. The first group (45 chicks) was kept in a thermoneutral room at 22 °C for 24 h/day. The second group (45 chicks) was kept in a room with high ambient temperature at 34 °C for 8 h/day (from 9 AM-5 PM) and at 22 °C for 16 h/day. Each of these two main groups was then divided into three subgroups (CBO groups 0, 250, 500 ppm) consisting of 15 chicks (six treatment groups in 2 × 3 factorial order). Each of subgroups was replicated for three times and each replicate included five chicks. Heat stress caused significant decreases in body weight, spermatid and testicular sperm numbers, the density of testicular Bcl-2 (antiapoptotic marker) and AR immunopositivity, and significant increases in testicular lipid peroxidation level, the density of testicular Bax (apoptotic marker) immunopositivity, and a Bax/Bcl-2 ratio along with some histopathologic damages. However, 250 and 500 ppm CBO supplementation provided significant improvements in HS-induced increased level of testicular lipid peroxidation, decreased number of spermatid and testicular sperm, decreased densities of Bcl-2 and AR immunopositivity, and some deteriorated testicular histopathologic lesions. In addition, although HS did not significantly affect the testicular glutathione level, addition of both 250 and 500 ppm CBO to diet of quails reared in both HS and thermoneutral conditions caused a significant increase when compared with quails without any consumption of CBO. In conclusion, HS-induced lipid peroxidation causes testicular damage in developing male Japanese quails and, consumption of CBO, which has antiperoxidative effect, protects their testes against HS. PMID:25913274

  2. The Role of Androgen and Androgen Receptor in the Skin-Related Disorders

    PubMed Central

    Lai, Jiann-Jyh; Chang, Philip; Lai, Kuo-Pao; Chen, Lumin; Chang, Chawnshang

    2013-01-01

    Androgen and androgen receptor (AR) may play important roles in several skin related diseases, such as androgenetic alopecia and acne vulgaris. Current treatments for these androgen/AR-involved diseases, which target the synthesis of androgens or prevent its binding to AR, can cause significant adverse side effects. Based on the recent studies using AR knockout mice, it has been suggested that AR and androgens play distinct roles in the skin pathogenesis, and AR seems to be a better target than androgens for the treatment of these skin diseases. Here we review recent studies of androgen/AR roles in several skin-related disorders, including acne vulgaris, androgenetic alopecia, and hirsutism, as well as cutaneous wound healing. PMID:22829074

  3. Identification of an anabolic selective androgen receptor modulator that actively induces death of androgen-independent prostate cancer cells.

    PubMed

    Schmidt, Azriel; Meissner, Robert S; Gentile, Michael A; Chisamore, Michael J; Opas, Evan E; Scafonas, Angela; Cusick, Tara E; Gambone, Carlo; Pennypacker, Brenda; Hodor, Paul; Perkins, James J; Bai, Chang; Ferraro, Damien; Bettoun, David J; Wilkinson, Hilary A; Alves, Stephen E; Flores, Osvaldo; Ray, William J

    2014-09-01

    Prostate cancer (PCa) initially responds to inhibition of androgen receptor (AR) signaling, but inevitably progresses to hormone ablation-resistant disease. Much effort is focused on optimizing this androgen deprivation strategy by improving hormone depletion and AR antagonism. However we found that bicalutamide, a clinically used antiandrogen, actually resembles a selective AR modulator (SARM), as it partially regulates 24% of endogenously 5α-dihydrotestosterone (DHT)-responsive genes in AR(+) MDA-MB-453 breast cancer cells. These data suggested that passive blocking of all AR functions is not required for PCa therapy. Hence, we adopted an active strategy that calls for the development of novel SARMs, which induce a unique gene expression profile that is intolerable to PCa cells. Therefore, we screened 3000 SARMs for the ability to arrest the androgen-independent growth of AR(+) 22Rv1 and LNCaP PCa cells but not AR(-) PC3 or DU145 cells. We identified only one such compound; the 4-aza-steroid, MK-4541, a potent and selective SARM. MK-4541 induces caspase-3 activity and cell death in both androgen-independent, AR(+) PCa cell lines but spares AR(-) cells or AR(+) non-PCa cells. This activity correlates with its promoter context- and cell-type dependent transcriptional effects. In rats, MK-4541 inhibits the trophic effects of DHT on the prostate, but not the levator ani muscle, and triggers an anabolic response in the periosteal compartment of bone. Therefore, MK-4541 has the potential to effectively manage prostatic hypertrophic diseases owing to its antitumor SARM-like mechanism, while simultaneously maintaining the anabolic benefits of natural androgens. PMID:24565564

  4. Single-Chain Probes for Illuminating Androgenicity of Chemicals.

    PubMed

    Kim, Sung-Bae; Tao, Hiroaki

    2016-01-01

    The present protocol introduces a single-chain probe carrying a functional peptide in the N-terminal domain of the androgen receptor (AR NTD) for illuminating androgenicity of ligands. In the single-chain probe, a functional peptide in the AR NTD was genetically fused to the ligand-binding domain of AR (AR LBD) via a flexible linker, and then sandwiched between the N- and C-terminal fragments of split-firefly luciferase (FLuc) dissected at D415. This single-chain probe exerts (1) a high signal-to-background ratio and (2) sensitive discrimination between agonists and antagonists, where the dimerization of AR LBD is not involved. The present protocol guides a fundamental methodology on how to discriminate weak protein-protein (peptide) binding, and provides a new insight into the intramolecular folding inside monomeric AR. PMID:27424901

  5. Exercise and Serum Androgens in Women.

    ERIC Educational Resources Information Center

    Westerlind, Kim C.; And Others

    1987-01-01

    This study examining the effect of a 10-week hydraulic resistance exercise program on serum androgen levels, strength, and lean body weight in 18 college women revealed that training did not result in significant increases in androgen hormones, although there were significant gains in strength. (Author/CB)

  6. Water Production Functions For High Plains Crops

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Declining water supplies is the critical resource issue for irrigated agriculture in the High Plains and much of the western U.S. Farmers need to maximize production per unit water consumed to remain economically viable and sustain irrigated agriculture. The Agricultural Research Service (ARS) Wat...

  7. Evidence that cytochrome b5 acts as a redox donor in CYP17A1 mediated androgen synthesis.

    PubMed

    Duggal, Ruchia; Liu, Yilin; Gregory, Michael C; Denisov, Ilia G; Kincaid, James R; Sligar, Stephen G

    2016-08-19

    Cytochrome P450 17A1 (CYP17A1) is an important drug target for castration resistant prostate cancer. It is a bi-functional enzyme, catalyzing production of glucocorticoid precursors by hydroxylation of pregnene-nucleus, and androgen biosynthesis by a second CC lyase step, at the expense of glucocorticoid production. Cytochrome b5 (cyt b5) is known to be a key regulator of the androgen synthesis reaction in vivo, by a mechanism that is not well understood. Two hypotheses have been proposed for the mechanism by which cyt b5 increases androgen biosynthesis. Cyt b5 could act as an allosteric effector, binding to CYP17A1 and either changing its selective substrate affinity or altering the conformation of the P450 to increase the catalytic rate or decrease unproductive uncoupling channels. Alternatively, cyt b5 could act as a redox donor for supply of the second electron in the P450 cycle, reducing the oxyferrous complex to form the reactive peroxo-intermediate. To understand the mechanism of lyase enhancement by cyt b5, we generated a redox-inactive form of cyt b5, in which the heme is replaced with a Manganese-protoporphyrin IX (Mn-b5), and investigated enhancement of androgen producing lyase reaction by CYP17A1. Given the critical significance of a stable membrane anchor for all of the proteins involved and the need for controlled stoichiometric ratios, we employed the Nanodisc system for this study. The redox inactive form was observed to have no effect on the lyase reaction, while reactions with the normal heme-iron containing cyt b5 were enhanced ∼5 fold as compared to reactions in the absence of cyt b5. We also performed resonance Raman measurements on ferric CYP17A1 bound to Mn-b5. Upon addition of Mn-b5 to Nanodisc reconstituted CYP17A1, we observed clear evidence for the formation of a b5-CYP17A1 complex, as noted by changes in the porphyrin modes and alteration in the proximal FeS vibrational frequency. Thus, although Mn-b5 binds to CYP17A1, it is unable to

  8. The effects of model androgen 5α-dihydrotestosterone on mummichog (Fundulus heteroclitus) reproduction under different salinities.

    PubMed

    Glinka, Chelsea O; Frasca, Salvatore; Provatas, Anthony A; Lama, Tanya; DeGuise, Sylvain; Bosker, Thijs

    2015-08-01

    Endocrine disrupting substances (EDSs) have the potential to disturb sensitive hormone pathways, particularly those involved in development and reproduction. Both fresh and estuarine water bodies receive inputs of EDSs from a variety of sources, including sewage effluent, industrial effluent and agricultural runoff. Based on current literature, freshwater species appear to respond to lower levels of EDSs than estuarine or marine species. Therefore, effects elicited by EDSs in freshwater teleosts may not be an accurate representation of how EDSs affect teleosts in estuarine and marine environments. To address this potential difference, a short-term reproductive bioassay was conducted under conditions of low and high salinity using mummichog (Fundulus heteroclitus), a euryhaline species that is native to the east coast of North America. The goals of this study were to determine the response of mummichog when exposed to an androgenic EDS and whether salinity affected the response. A model androgen, 5α-dihydrotestosterone (DHT), was selected for this experiment. Impacts on reproduction were evaluated at multiple biological levels, including physiological (sex steroid levels), organismal (gonad size and gonad morphology), and functional (egg production) endpoints. Under conditions of high salinity, egg production was significantly reduced at all exposure concentrations. Under conditions of low salinity, there were no significant differences based on DHT treatment; however, egg production in all treatment groups including the control were significantly reduced relative to the high salinity control group. Other reproductive endpoints, such as sex steroid production, showed stronger correlation to fecundity in females than males. This study demonstrates that mummichog fecundity is sensitive to androgenic endocrine disruption while also underscoring the importance of how changes in salinity, an environmental variable, can impact reproduction. PMID:26141585

  9. In Vitro Androgen Bioassays as a Detection Method for Designer Androgens

    PubMed Central

    Cooper, Elliot R.; McGrath, Kristine C. Y.; Heather, Alison K.

    2013-01-01

    Androgens are the class of sex steroids responsible for male sexual characteristics, including increased muscle mass and decreased fat mass. Illicit use of androgen doping can be an attractive option for those looking to enhance sporting performance and/or physical appearance. The use of in vitro bioassays to detect androgens, especially designer or proandrogens, is becoming increasingly important in combating androgen doping associated with nutritional supplements. The nutritional sports supplement market has grown rapidly throughout the past decade. Many of these supplements contain androgens, designer androgens or proandrogens. Many designer or proandrogens cannot be detected by the standard highly-sensitive screening methods such as gas chromatography-mass spectrometry because their chemical structure is unknown. However, in vitro androgen bioassays can detect designer and proandrogens as these assays are not reliant on knowing the chemical structure but instead are based on androgen receptor activation. For these reasons, it may be advantageous to use routine androgen bioassay screening of nutraceutical samples to help curb the increasing problem of androgen doping. PMID:23389345

  10. Androgens in human evolution. A new explanation of human evolution.

    PubMed

    Howard, J

    2001-01-01

    Human evolution consists of chronological changes in gene regulation of a continuous and relatively stable genome, activated by hormones, the production of which is intermittently affected by endogenous and exogenous forces. Periodic variations in the gonadal androgen, testosterone, and the adrenal androgen, dehydroepiandrosterone (DHEA), significantly participated in all hominid transformations. The hominid characteristics of early Australopithecines are primarily a result of increased testosterone. The first significant cold of the early Pleistocene resulted in an increase in DHEA that simultaneously produced Homo and the robust Australopithecines. Subsequent Pleistocene climatic changes and differential reproduction produced changes in DHEA and testosterone ratios that caused extinction of the robust Australopithecines and further changes and continuation of Homo. Changes in testosterone and DHEA produce allometric and behavioral changes that are identifiable and vigorous in modern populations. PMID:11702658

  11. Microfluidic production of polymeric functional microparticles

    NASA Astrophysics Data System (ADS)

    Jiang, Kunqiang

    This dissertation focuses on applying droplet-based microfluidics to fabricate new classes of polymeric microparticles with customized properties for various applications. The integration of microfluidic techniques with microparticle engineering allows for unprecedented control over particle size, shape, and functional properties. Specifically, three types of microparticles are discussed here: (1) Magnetic and fluorescent chitosan hydrogel microparticles and their in-situ assembly into higher-order microstructures; (2) Polydimethylsiloxane (PDMS) microbeads with phosphorescent properties for oxygen sensing; (3) Macroporous microparticles as biological immunosensors. First, we describe a microfluidic approach to generate monodisperse chitosan hydrogel microparticles that can be further connected in-situ into higher-order microstructures. Microparticles of the biopolymer chitosan are created continuously by contacting an aqueous solution of chitosan at a microfluidic T-junction with a stream of hexadecane containing a nonionic detergent, followed by downstream crosslinking of the generated droplets by a ternary flow of glutaraldehyde. Functional properties of the microparticles can be easily varied by introducing payloads such as magnetic nanoparticles and/or fluorescent dyes into the chitosan solution. We then use these prepared microparticles as "building blocks" and assemble them into high ordered microstructures, i.e. microchains with controlled geometry and flexibility. Next, we describe a new approach to produce monodisperse microbeads of PDMS using microfluidics. Using a flow-focusing configuration, a PDMS precursor solution is dispersed into microdroplets within an aqueous continuous phase. These droplets are collected and thermally cured off-chip into soft, solid microbeads. In addition, our technique allows for direct integration of payloads, such as an oxygen-sensitive porphyrin dye, into the PDMS microbeads. We then show that the resulting dye

  12. Protective effect of androgens against inflammation induced cartilage degradation in male rodents.

    PubMed Central

    Da Silva, J A; Larbre, J P; Spector, T D; Perry, L A; Scott, D L; Willoughby, D A

    1993-01-01

    OBJECTIVES--Rheumatoid arthritis (RA) is a disease which predominantly affects women. Interestingly, low serum androgen levels and clinical improvement with androgen replacement have been reported in male patients. The aetiopathogenic role of sex hormones in arthritis and their potential long term effects on joint destruction and disability remains unclear, however. This study was designed to investigate the potential influence of sex hormones on inflammation induced cartilage degradation in male rodents. METHODS--An in vivo model of cotton wrapped cartilage implants was used to assess the effects of androgen, oestradiol, and progesterone on inflammation induced cartilage degradation, and in vitro techniques were used to investigate the direct actions on cartilage metabolism and cytokine production in male animals. RESULTS--Orchidectomy resulted in accelerated cartilage damage which was reversed by replacement of physiological levels of androgens. Granulomatous tissue from castrated male rodents produced higher amounts of interleukin 1. Sex hormones reduced spontaneous proteoglycan loss in vitro but did not interfere with the effects of interleukin 1 on cultured cartilage. CONCLUSIONS--Androgens appear to protect cartilage from inflammation induced breakdown in male animals. These results support a pathogenic role for hypoandrogenism in rheumatoid arthritis and suggest that long term androgen replacement may help prevent joint damage and disability. PMID:8484695

  13. MiR137 is an androgen regulated repressor of an extended network of transcriptional coregulators

    PubMed Central

    Whitchurch, Jonathan; McWilliam, Andrew; Ødum, Niels; Persson, Jenny L.; Heery, David M.; Gudas, Lorraine J.; Mongan, Nigel P.

    2015-01-01

    Androgens and the androgen receptor (AR) play crucial roles in male development and the pathogenesis and progression of prostate cancer (PCa). The AR functions as a ligand dependent transcription factor which recruits multiple enzymatically distinct epigenetic coregulators to facilitate transcriptional regulation in response to androgens. Over-expression of AR coregulators is implicated in cancer. We have shown that over-expression of KDM1A, an AR coregulator, contributes to PCa recurrence by promoting VEGFA expression. However the mechanism(s) whereby AR coregulators are increased in PCa remain poorly understood. In this study we show that the microRNA hsa-miR-137 (miR137) tumor suppressor regulates expression of an extended network of transcriptional coregulators including KDM1A/LSD1/AOF1, KDM2A/JHDM1A/FBXL11, KDM4A/JMJD2A, KDM5B JARID1B/PLU1, KDM7A/JHDM1D/PHF8, MED1/TRAP220/DRIP205 and NCoA2/SRC2/TIF2. We show that expression of miR137 is increased by androgen in LnCaP androgen PCa responsive cells and that the miR137 locus is epigenetically silenced in androgen LnCaP:C4-2 and PC3 independent PCa cells. In addition, we found that restoration of miR137 expression down-regulates expression of VEGFA, an AR target gene, which suggests a role of miR137 loss also in cancer angiogenesis. Finally we show functional inhibition of miR137 function enhanced androgen induction of PSA/KLK3 expression. Our data indicate that miR137 functions as an androgen regulated suppressor of androgen signaling by modulating expression of an extended network of transcriptional coregulators. Therefore, we propose that epigenetic silencing of miR137 is an important event in promoting androgen signaling during prostate carcinogenesis and progression. PMID:26461474

  14. MiR137 is an androgen regulated repressor of an extended network of transcriptional coregulators.

    PubMed

    Nilsson, Emeli M; Laursen, Kristian B; Whitchurch, Jonathan; McWilliam, Andrew; Ødum, Niels; Persson, Jenny L; Heery, David M; Gudas, Lorraine J; Mongan, Nigel P

    2015-11-01

    Androgens and the androgen receptor (AR) play crucial roles in male development and the pathogenesis and progression of prostate cancer (PCa). The AR functions as a ligand dependent transcription factor which recruits multiple enzymatically distinct epigenetic coregulators to facilitate transcriptional regulation in response to androgens. Over-expression of AR coregulators is implicated in cancer. We have shown that over-expression of KDM1A, an AR coregulator, contributes to PCa recurrence by promoting VEGFA expression. However the mechanism(s) whereby AR coregulators are increased in PCa remain poorly understood. In this study we show that the microRNA hsa-miR-137 (miR137) tumor suppressor regulates expression of an extended network of transcriptional coregulators including KDM1A/LSD1/AOF1, KDM2A/JHDM1A/FBXL11, KDM4A/JMJD2A, KDM5B JARID1B/PLU1, KDM7A/JHDM1D/PHF8, MED1/TRAP220/DRIP205 and NCoA2/SRC2/TIF2. We show that expression of miR137 is increased by androgen in LnCaP androgen PCa responsive cells and that the miR137 locus is epigenetically silenced in androgen LnCaP:C4-2 and PC3 independent PCa cells. In addition, we found that restoration of miR137 expression down-regulates expression of VEGFA, an AR target gene, which suggests a role of miR137 loss also in cancer angiogenesis. Finally we show functional inhibition of miR137 function enhanced androgen induction of PSA/KLK3 expression. Our data indicate that miR137 functions as an androgen regulated suppressor of androgen signaling by modulating expression of an extended network of transcriptional coregulators. Therefore, we propose that epigenetic silencing of miR137 is an important event in promoting androgen signaling during prostate carcinogenesis and progression. PMID:26461474

  15. Targeting Alternative Sites on the Androgen Receptor to Treat Castration-Resistant Prostate Cancer

    PubMed Central

    Lallous, Nada; Dalal, Kush; Cherkasov, Artem; Rennie, Paul S.

    2013-01-01

    Recurrent, metastatic prostate cancer continues to be a leading cause of cancer-death in men. The androgen receptor (AR) is a modular, ligand-inducible transcription factor that regulates the expression of genes that can drive the progression of this disease, and as a consequence, this receptor is a key therapeutic target for controlling prostate cancer. The current drugs designed to directly inhibit the AR are called anti-androgens, and all act by competing with androgens for binding to the androgen/ligand binding site. Unfortunately, with the inevitable progression of the cancer to castration resistance, many of these drugs become ineffective. However, there are numerous other regulatory sites on this protein that have not been exploited therapeutically. The regulation of AR activity involves a cascade of complex interactions with numerous chaperones, co-factors and co-regulatory proteins, leading ultimately to direct binding of AR dimers to specific DNA androgen response elements within the promoter and enhancers of androgen-regulated genes. As part of the family of nuclear receptors, the AR is organized into modular structural and functional domains with specialized roles in facilitating their inter-molecular interactions. These regions of the AR present attractive, yet largely unexploited, drug target sites for reducing or eliminating androgen signaling in prostate cancers. The design of small molecule inhibitors targeting these specific AR domains is only now being realized and is the culmination of decades of work, including crystallographic and biochemistry approaches to map the shape and accessibility of the AR surfaces and cavities. Here, we review the structure of the AR protein and describe recent advancements in inhibiting its activity with small molecules specifically designed to target areas distinct from the receptor’s androgen binding site. It is anticipated that these new classes of anti-AR drugs will provide an additional arsenal to treat

  16. Selective androgen receptor modulators in preclinical and clinical development

    PubMed Central

    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. PMID:19079612

  17. Sphingosine kinase-1 mediates androgen-induced osteoblast cell growth.

    PubMed

    Martin, Claire; Lafosse, Jean-Michel; Malavaud, Bernard; Cuvillier, Olivier

    2010-01-01

    Herein we report that the lipid kinase sphingosine kinase-1 (SphK1) is instrumental in mediating androgen-induced cell proliferation in osteoblasts. Dihydrotestosterone (DHT) triggered cell growth in steroid-deprived MC3T3 cells, which was associated with a rapid stimulation of SphK1 and activation of both Akt and ERK signaling pathways. This mechanism relied on functional androgen receptor/PI3K/Akt nongenotropic signaling as pharmacological antagonists could block SphK1 stimulation by DHT and its consequences. Finally, SphK1 inhibition not only abrogated DHT-induced ERK activation but also blocked cell proliferation, while ERK inhibition had no impact, suggesting that SphK1 was critical for DHT signaling yet independently of the ERK. PMID:19932089

  18. Sphingosine kinase-1 mediates androgen-induced osteoblast cell growth

    SciTech Connect

    Martin, Claire; Lafosse, Jean-Michel; Malavaud, Bernard; Cuvillier, Olivier

    2010-01-01

    Herein we report that the lipid kinase sphingosine kinase-1 (SphK1) is instrumental in mediating androgen-induced cell proliferation in osteoblasts. Dihydrotestosterone (DHT) triggered cell growth in steroid-deprived MC3T3 cells, which was associated with a rapid stimulation of SphK1 and activation of both Akt and ERK signaling pathways. This mechanism relied on functional androgen receptor/PI3K/Akt nongenotropic signaling as pharmacological antagonists could block SphK1 stimulation by DHT and its consequences. Finally, SphK1 inhibition not only abrogated DHT-induced ERK activation but also blocked cell proliferation, while ERK inhibition had no impact, suggesting that SphK1 was critical for DHT signaling yet independently of the ERK.

  19. Research Resource: Hormones, Genes, and Athleticism: Effect of Androgens on the Avian Muscular Transcriptome.

    PubMed

    Fuxjager, Matthew J; Lee, Jae-Hyung; Chan, Tak-Ming; Bahn, Jae Hoon; Chew, Jenifer G; Xiao, Xinshu; Schlinger, Barney A

    2016-02-01

    Male vertebrate social displays vary from physically simple to complex, with the latter involving exquisite motor command of the body and appendages. Studies of these displays have, in turn, provided substantial insight into neuromotor mechanisms. The neotropical golden-collared manakin (Manacus vitellinus) has been used previously as a model to investigate intricate motor skills because adult males of this species perform an acrobatic and androgen-dependent courtship display. To support this behavior, these birds express elevated levels of androgen receptors (AR) in their skeletal muscles. Here we use RNA sequencing to explore how testosterone (T) modulates the muscular transcriptome to support male manakin courtship displays. In addition, we explore how androgens influence gene expression in the muscles of the zebra finch (Taenopygia guttata), a model passerine bird with a limited courtship display and minimal muscle AR. We identify androgen-dependent, muscle-specific gene regulation in both species. In addition, we identify manakin-specific effects that are linked to muscle use during the manakin display, including androgenic regulation of genes associated with muscle fiber contractility, cellular homeostasis, and energetic efficiency. Overall, our results point to numerous genes and gene networks impacted by androgens in male birds, including some that underlie optimal muscle function necessary for performing acrobatic display routines. Manakins are excellent models to explore gene regulation promoting athletic ability. PMID:26745669

  20. Influencing factors on color and product-function association.

    PubMed

    Ko, Ya-Hsien

    2011-06-01

    The associations of age, sex, and matching types with color and product-function were examined in a real-world product scenario (shampoo) among 128 volunteers (M age = 29.3 yr.; SD = 15.6). A pilot study identified eight popular colors and eight product-functions. The association between color and product-function was explored in the main sample. Responses suggested seven pairings of color/product-functions: Red/Hot oil treatment, Yellow/Bright and shiny hair, Green/Herbal extracts, Blue/Deep cleaning, Purple/Soothing, Black/Antiseptic, and White/Anti-dandruff. Analyses indicated that adult participants required more repetitions for retention, as did memorization with random pairing compared to participant-selected pairings. There were statistically significant correlations of responses to colors and product functions. With known color/product-function associations, manufacturers might promote their products more effectively. It is suggested that the associations might be sex- or culture-specific. PMID:21879633

  1. The androgen receptor in health and disease.

    PubMed

    Matsumoto, Takahiro; Sakari, Matomo; Okada, Maiko; Yokoyama, Atsushi; Takahashi, Sayuri; Kouzmenko, Alexander; Kato, Shigeaki

    2013-01-01

    Androgens play pivotal roles in the regulation of male development and physiological processes, particularly in the male reproductive system. Most biological effects of androgens are mediated by the action of nuclear androgen receptor (AR). AR acts as a master regulator of downstream androgen-dependent signaling pathway networks. This ligand-dependent transcriptional factor modulates gene expression through the recruitment of various coregulator complexes, the induction of chromatin reorganization, and epigenetic histone modifications at target genomic loci. Dysregulation of androgen/AR signaling perturbs normal reproductive development and accounts for a wide range of pathological conditions such as androgen-insensitive syndrome, prostate cancer, and spinal bulbar muscular atrophy. In this review we summarize recent advances in understanding of the epigenetic mechanisms of AR action as well as newly recognized aspects of AR-mediated androgen signaling in both men and women. In addition, we offer a perspective on the use of animal genetic model systems aimed at eventually developing novel therapeutic AR ligands. PMID:23157556

  2. Structure and Function of Macroalgal Natural Products.

    PubMed

    Young, Ryan M; Schoenrock, Kathryn M; von Salm, Jacqueline L; Amsler, Charles D; Baker, Bill J

    2015-01-01

    Since the initial discovery of marine phyco-derived secondary metabolites in the 1950s there has been a rapid increase in the description of new algal natural products. These metabolites have multiple ecological roles as well as commercial value as potential drugs or lead compounds. With the emergence of resistance to our current arsenal of drugs as well as the development of new chemotherapies for currently untreatable diseases, new compounds must be sourced. As outlined in this chapter algae produce a diverse range of chemicals many of which have potential for the treatment of human afflictions.In this chapter we outline the classes of metabolites produced by this chemically rich group of organisms as well as their respective ecological roles in the environment. Algae are found in nearly every environment on earth, with many of these organisms possessing the ability to shape the ecosystem they inhabit. With current challenges to climate stability, understanding how these important organisms interact with their environment as well as one another might afford better insight into how they respond to a changing climate. PMID:26108497

  3. Adolescents and Androgens, Receptors and Rewards

    PubMed Central

    Sato, Satoru M.; Schulz, Kalynn M.; Sisk, Cheryl L.; Wood, Ruth I.

    2008-01-01

    Adolescence is associated with increases in pleasure-seeking behaviors, which, in turn, are shaped by the pubertal activation of the hypothalamo-pituitary-gonadal axis. In animal models of naturally rewarding behaviors, such as sex, testicular androgens contribute to the development and expression of the behavior in males. To effect behavioral maturation, the brain undergoes significant remodeling during adolescence, and many of the changes are likewise sensitive to androgens, presumably acting through androgen receptors (AR). Given the delicate interaction of gonadal hormones and brain development, it is no surprise that disruption of hormone levels during this sensitive period significantly alters adolescent and adult behaviors. In male hamsters, exposure to testosterone during adolescence is required for normal expression of adult sexual behavior. Males deprived of androgens during puberty display sustained deficits in mating. Conversely, androgens alone are not sufficient to induce mating in prepubertal males, even though brain AR are present before puberty. In this context, wide-spread use of anabolic-androgenic steroids (AAS) during adolescence is a significant concern. AAS abuse has the potential to alter both the timing and the levels of androgens in adolescent males. In hamsters, adolescent AAS exposure increases aggression, and causes lasting changes in neurotransmitter systems. In addition, AAS are themselves reinforcing, as demonstrated by self-administration of testosterone and other AAS. However, recent evidence suggests that the reinforcing effects of androgens may not require classical AR. Therefore, further examination of interactions between androgens and rewarding behaviors in the adolescent brain is required for a better understanding of AAS abuse. PMID:18343381

  4. 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. PMID:18469090

  5. Androgen-responsive gene database: integrated knowledge on androgen-responsive genes.

    PubMed

    Jiang, Mei; Ma, Yunsheng; Chen, Congcong; Fu, Xuping; Yang, Shu; Li, Xia; Yu, Guohua; Mao, Yumin; Xie, Yi; Li, Yao

    2009-11-01

    Androgen signaling plays an important role in many biological processes. Androgen Responsive Gene Database (ARGDB) is devoted to providing integrated knowledge on androgen-controlled genes. Gene records were collected on the basis of PubMed literature collections. More than 6000 abstracts and 950 original publications were manually screened, leading to 1785 human genes, 993 mouse genes, and 583 rat genes finally included in the database. All the collected genes were experimentally proved to be regulated by androgen at the expression level or to contain androgen-responsive regions. For each gene important details of the androgen regulation experiments were collected from references, such as expression change, androgen-responsive sequence, response time, tissue/cell type, experimental method, ligand identity, and androgen amount, which will facilitate further evaluation by researchers. Furthermore, the database was integrated with multiple annotation resources, including National Center for Biotechnology Information, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathway, to reveal the biological characteristics and significance of androgen-regulated genes. The ARGDB web site is mainly composed of the Browse, Search, Element Scan, and Submission modules. It is user friendly and freely accessible at http://argdb.fudan.edu.cn. Preliminary analysis of the collected data was performed. Many disease pathways, such as prostate carcinogenesis, were found to be enriched in androgen-regulated genes. The discovered androgen-response motifs were similar to those in previous reports. The analysis results are displayed in the web site. In conclusion, ARGDB provides a unified gateway to storage, retrieval, and update of information on androgen-regulated genes. PMID:19762544

  6. Ecological Production Functions: A Theoretical and Practical Exploration

    EPA Science Inventory

    Ecological production functions characterize relationships between ecosystem condition, management practices, and the delivery of economically valuable ecosystem services. Many in the ecosystem service research community view ecological research directed toward developing ecolog...

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

    PubMed

    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; Schumacher, Michael; Ghandour, M Said

    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

  8. Synthetic androgens as designer supplements.

    PubMed

    Joseph, Jan Felix; Parr, Maria Kristina

    2015-01-01

    Anabolic androgenic steroids (AAS) are some of the most common performance enhancing drugs (PED) among society. Despite the broad spectrum of adverse effects and legal consequences, AAS are illicitly marketed and distributed in many countries. To circumvent existing laws, the chemical structure of AAS is modified and these designer steroids are sold as nutritional supplements mainly over the Internet. Several side effects are linked with AAS abuse. Only little is known about the pharmacological effects and metabolism of unapproved steroids due to the absence of clinical studies. The large number of designer steroid findings in dietary supplements and the detection of new compounds combined with legal loopholes for their distribution in many countries show that stricter regulations and better information policy are needed. PMID:26074745

  9. Synthetic Androgens as Designer Supplements

    PubMed Central

    Joseph, Jan Felix; Parr, Maria Kristina

    2015-01-01

    Anabolic androgenic steroids (AAS) are some of the most common performance enhancing drugs (PED) among society. Despite the broad spectrum of adverse effects and legal consequences, AAS are illicitly marketed and distributed in many countries. To circumvent existing laws, the chemical structure of AAS is modified and these designer steroids are sold as nutritional supplements mainly over the Internet. Several side effects are linked with AAS abuse. Only little is known about the pharmacological effects and metabolism of unapproved steroids due to the absence of clinical studies. The large number of designer steroid findings in dietary supplements and the detection of new compounds combined with legal loopholes for their distribution in many countries show that stricter regulations and better information policy are needed. PMID:26074745

  10. Expression of androgen receptor splice variants in clinical breast cancers

    PubMed Central

    Dvinge, Heidi; Tarulli, Gerard A.; Hanson, Adrienne R.; Ryan, Natalie K.; Pickering, Marie A.; Birrell, Stephen N.; Hu, Dong Gui; Mackenzie, Peter I.; Russell, Roslin; Caldas, Carlos; Raj, Ganesh V.; Dehm, Scott M.; Plymate, Stephen R.; Bradley, Robert K.; Tilley, Wayne D.; Selth, Luke A.

    2015-01-01

    The importance of androgen receptor (AR) signaling is increasingly being recognized in breast cancer, which has elicited clinical trials aimed at assessing the efficacy of androgen deprivation therapy (ADT) for metastatic disease. In prostate cancer, resistance to ADT is frequently associated with the emergence of androgen-independent splice variants of the AR (AR variants, AR-Vs) that lack the LBD and are constitutively active. Women with breast cancer may be prone to a similar phenomenon. Herein, we show that in addition to the prototypical transcript, the AR gene produces a diverse range of AR-V transcripts in primary breast tumors. The most frequently and highly expressed variant was AR-V7 (exons 1/2/3/CE3), which was detectable at the mRNA level in > 50% of all breast cancers and at the protein level in a subset of ERα-negative tumors. Functionally, AR-V7 is a constitutively active and ADT-resistant transcription factor that promotes growth and regulates a transcriptional program distinct from AR in ERα-negative breast cancer cells. Importantly, we provide ex vivo evidence that AR-V7 is upregulated by the AR antagonist enzalutamide in primary breast tumors. These findings have implications for treatment response in the ongoing clinical trials of ADT in breast cancer. PMID:26554309

  11. Expression of androgen receptor splice variants in clinical breast cancers.

    PubMed

    Hickey, Theresa E; Irvine, Connie M; Dvinge, Heidi; Tarulli, Gerard A; Hanson, Adrienne R; Ryan, Natalie K; Pickering, Marie A; Birrell, Stephen N; Hu, Dong Gui; Mackenzie, Peter I; Russell, Roslin; Caldas, Carlos; Raj, Ganesh V; Dehm, Scott M; Plymate, Stephen R; Bradley, Robert K; Tilley, Wayne D; Selth, Luke A

    2015-12-29

    The importance of androgen receptor (AR) signaling is increasingly being recognized in breast cancer, which has elicited clinical trials aimed at assessing the efficacy of androgen deprivation therapy (ADT) for metastatic disease. In prostate cancer, resistance to ADT is frequently associated with the emergence of androgen-independent splice variants of the AR (AR variants, AR-Vs) that lack the LBD and are constitutively active. Women with breast cancer may be prone to a similar phenomenon. Herein, we show that in addition to the prototypical transcript, the AR gene produces a diverse range of AR-V transcripts in primary breast tumors. The most frequently and highly expressed variant was AR-V7 (exons 1/2/3/CE3), which was detectable at the mRNA level in > 50% of all breast cancers and at the protein level in a subset of ERα-negative tumors. Functionally, AR-V7 is a constitutively active and ADT-resistant transcription factor that promotes growth and regulates a transcriptional program distinct from AR in ERα-negative breast cancer cells. Importantly, we provide ex vivo evidence that AR-V7 is upregulated by the AR antagonist enzalutamide in primary breast tumors. These findings have implications for treatment response in the ongoing clinical trials of ADT in breast cancer. PMID:26554309

  12. Opioid-Induced Androgen Deficiency (OPIAD): Diagnosis, Management, and Literature Review.

    PubMed

    O'Rourke, Timothy K; Wosnitzer, Matthew S

    2016-10-01

    Opioid-induced androgen deficiency (OPIAD) was initially recognized as a possible consequence of opioid use roughly four decades ago. Long-acting opioid use carries risks of addiction, tolerance, and systemic side effects including hypogonadotropic hypogonadism with consequent testosterone depletion leading to multiple central and peripheral effects. Hypogonadism is induced through direct inhibitory action of opioids on receptors within the hypothalamic-pituitary-gonadal (HPG) and hypothalamic-pituitary-adrenal (HPA) axes as well as testosterone production within the testes. Few studies have systematically investigated hormonal changes induced by long-term opioid administration or the effects of testosterone replacement therapy (TRT) in patients with OPIAD. Clomiphene citrate, a selective estrogen receptor modulator (SERM), is a testosterone enhancement treatment which upregulates endogenous hypothalamic function. This review will focus on the pathophysiology, diagnosis, and management of OPIAD, including summary of literature evaluating OPIAD treatment with TRT, and areas of future investigation. PMID:27586511

  13. Genetics Home Reference: androgen insensitivity syndrome

    MedlinePlus

    ... typically raised as females and have a female gender identity. Affected individuals have male internal sex organs ( ... and may have a male or a female gender identity. People with mild androgen insensitivity are born ...

  14. Androgen deprivation treatment of sexual behavior.

    PubMed

    Houts, Frederick W; Taller, Inna; Tucker, Douglas E; Berlin, Fred S

    2011-01-01

    Gonadotropin-releasing hormone agonists are underutilized in patients seeking diminution of problematic sexual drives. This chapter reviews the literature on surgical castration of sex offenders, anti-androgen use and the rationale for providing androgen deprivation therapy, rather than selective serotonin reuptake inhibitors or more conservative interventions, for patients with paraphilias and excessive sexual drive. Discussions of informed consent, side effects, contraindications and case examples are provided. PMID:22005210

  15. A Modification of Lotka's Function for Scientific Productivity.

    ERIC Educational Resources Information Center

    Fang, P. H.; Fang, John M.

    1995-01-01

    Examines the validity of Lotka's function for a measurement of scientific productivity. A systematic deviation of this function from numerical examples has been found by introducing a different least-square formulation instead of a logarithmic linearization. Therefore, a modification of the measurement of the publication frequencies is proposed.…

  16. Identification of an educational production function for diverse technologies

    NASA Technical Reports Server (NTRS)

    Mcclung, R. L.

    1977-01-01

    Production function analysis used to estimate the cost effectiveness of three alternative technologies in higher education: traditional instruction, instructional television, and computer-assisted instruction is presented. Criteria and selection of a functional form are outlined and a general discussion of variable selection and measurement is presented.

  17. Renormdynamics, multiparticle production, negative binomial distribution, and Riemann zeta function

    NASA Astrophysics Data System (ADS)

    Makhaldiani, N. V.

    2013-09-01

    After short introduction, we consider different aspects of the renormdynamics. Then scaling functions of the multiparticle production processes and corresponding stochastic dynamics are considered. Nonperturbative quasi-particle dynamics is considered on the base of the toy QCD- O( N)-sigma model. Last section concerns to the NBD-Riemann zeta function connection.

  18. Detection of persistent organic pollutants binding modes with androgen receptor ligand binding domain by docking and molecular dynamics

    PubMed Central

    2013-01-01

    Background Persistent organic pollutants (POPs) are persistent in the environment after release from industrial compounds, combustion productions or pesticides. The exposure of POPs has been related to various reproductive disturbances, such as reduced semen quality, testicular cancer, and imbalanced sex ratio. Among POPs, dichlorodiphenyldichloroethylene (4,4’-DDE) and polychlorinated biphenyls (PCBs) are the most widespread and well-studied compounds. Recent studies have revealed that 4,4’-DDE is an antagonist of androgen receptor (AR). However, the mechanism of the inhibition remains elusive. CB-153 is the most common congener of PCBs, while the action of CB-153 on AR is still under debate. Results Molecular docking and molecular dynamics (MD) approaches have been employed to study binding modes and inhibition mechanism of 4,4’-DDE and CB-153 against AR ligand binding domain (LBD). Several potential binding sites have been detected and analyzed. One possible binding site is the same binding site of AR natural ligand androgen 5α-dihydrotestosterone (DHT). Another one is on the ligand-dependent transcriptional activation function (AF2) region, which is crucial for the co-activators recruitment. Besides, a novel possible binding site was observed for POPs with low binding free energy with the receptor. Detailed interactions between ligands and the receptor have been represented. The disrupting mechanism of POPs against AR has also been discussed. Conclusions POPs disrupt the function of AR through binding to three possible biding sites on AR/LBD. One of them shares the same binding site of natural ligand of AR. Another one is on AF2 region. The third one is in a cleft near N-terminal of the receptor. Significantly, values of binding free energy of POPs with AR/LBD are comparable to that of natural ligand androgen DHT. PMID:24053684

  19. Promoter-dependent activity on androgen receptor N-terminal domain mutations in androgen insensitivity syndrome.

    PubMed

    Tadokoro-Cuccaro, Rieko; Davies, John; Mongan, Nigel P; Bunch, Trevor; Brown, Rosalind S; Audi, Laura; Watt, Kate; McEwan, Iain J; Hughes, Ieuan A

    2014-01-01

    Androgen receptor (AR) mutations are associated with androgen insensitivity syndrome (AIS). Missense mutations identified in the AR-N-terminal domain (AR-NTD) are rare, and clinical phenotypes are typically mild. We investigated 7 missense mutations and 2 insertion/deletions located in the AR-NTD. This study aimed to elucidate the pathogenic role of AR-NTD mutants in AIS and to use this knowledge to further define AR-NTD function. AR-NTD mutations (Q120E, A159T, G216R, N235K, G248V, L272F, and P380R) were introduced into AR-expression plasmids. Stably expressing cell lines were established for del57L and ins58L. Transactivation was measured using luciferase reporter constructs under the control of GRE and Pem promoters. Intrinsic fluorescence spectroscopy and partial proteolysis studies were performed for mutations which showed reduced activities by using a purified AR-AF1 protein. Pem-luciferase reporter activation was reduced for A159T, N235K, and G248V but not the GRE-luciferase reporter. Protein structure analysis detected no significant change in the AR-AF1 region for these mutations. Reduced cellular expression and transactivation activity were observed for ins58L. The mutations Q120E, G216R, L272F, P380R, and del57L showed small or no detectable changes in function. Thus, clinical and experimental analyses have identified novel AR-signalling defects associated with mutations in the structurally disordered AR-NTD domain in patients with AIS. PMID:25500996

  20. Mechanistic relationship between androgen receptor polyglutamine tract truncation and androgen-dependent transcriptional hyperactivity in prostate cancer cells.

    PubMed

    Wang, Qianben; Udayakumar, T S; Vasaitis, Tadas S; Brodie, Angela M; Fondell, Joseph D

    2004-04-23

    Androgen receptor (AR) signaling pathways mediate critical events in normal and neoplastic prostate growth. Shortening of the polymorphic N-terminal polyglutamine (poly(Q)) tract of the AR gene leads to transcriptional hyperactivity and has been correlated with an increased risk of prostate cancer. The underlying mechanisms for these effects are poorly understood. We show here that androgen-dependent cellular proliferation and transcription in prostate cancer cells is inversely correlated to the length of the AR poly(Q) region. We further show that AR proteins containing a shortened poly(Q) region functionally respond to lower concentrations of androgens than wild type AR. Whereas DNA binding activity is relatively unaffected by AR poly(Q) variation, we found that ligand binding affinity and the ligand-induced NH(2)- to COOH-terminal intramolecular interaction is enhanced when the poly(Q) region is shortened. Importantly, we show that AR proteins containing a shortened poly(Q) region associate in vivo with higher levels of specific p160 coactivators and components of the SWI/SNF chromatin remodeling complex as compared with the wild type AR. Collectively, our findings suggest that the AR transcriptional hyperactivity associated with shortened poly(Q) length stems from altered ligand-induced conformational changes that enhance coactivator recruitment. PMID:14966121

  1. 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...

  2. EVALUATION OF THE MODEL ANTI-ANDROGEN FLUTAMIDE FOR ASSESSING THE MECHANISTIC BASIS OF RESPONSES TO AN ANDROGEN IN THE FATHEAD MINNOW

    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 as...

  3. Cross-talk between androgen receptor/filamin A and TrkA regulates neurite outgrowth in PC12 cells

    PubMed Central

    Di Donato, Marzia; Bilancio, Antonio; D'Amato, Loredana; Claudiani, Pamela; Oliviero, Maria Antonietta; Barone, Maria Vittoria; Auricchio, Alberto; Appella, Ettore; Migliaccio, Antimo; Auricchio, Ferdinando; Castoria, Gabriella

    2015-01-01

    Steroids and growth factors control neuronal development through their receptors under physiological and pathological conditions. We show that PC12 cells harbor endogenous androgen receptor (AR), whose inhibition or silencing strongly interferes with neuritogenesis stimulated by the nonaromatizable synthetic androgen R1881 or NGF. This implies a role for AR not only in androgen signaling, but also in NGF signaling. In turn, a pharmacological TrkA inhibitor interferes with NGF- or androgen-induced neuritogenesis. In addition, androgen or NGF triggers AR association with TrkA, TrkA interaction with PI3-K δ, and downstream activation of PI3-K δ and Rac in PC12 cells. Once associated with AR, filamin A (FlnA) contributes to androgen or NGF neuritogenesis, likely through its interaction with signaling effectors, such as Rac. This study thus identifies a previously unrecognized reciprocal cross-talk between AR and TrkA, which is controlled by β1 integrin. The contribution of FlnA/AR complex and PI3-K δ to neuronal differentiation by androgens and NGF is also novel. This is the first description of AR function in PC12 cells. PMID:26063730

  4. Androgen-dependent protein interactions within an intron 1 regulatory region of the 20-kDa protein gene.

    PubMed

    Avellar, M C; Gregory, C W; Power, S G; French, F S

    1997-07-11

    The 20-kDa protein gene is androgen regulated in rat ventral prostate. Intron 1 contains a 130-base pair complex response element (D2) that binds androgen (AR) and glucocorticoid receptor (GR) but transactivates only with AR in transient cotransfection assays in CV1 cells using the reporter vector D2-tkCAT. To better understand the function of this androgen-responsive unit, nuclear protein interactions with D2 were analyzed by DNase I footprinting in ventral prostate nuclei of intact or castrated rats and in vitro with ventral prostate nuclear protein extracts from intact, castrated, and testosterone-treated castrated rats. Multiple androgen-dependent protected regions and hypersensitive sites were identified in the D2 region with both methods. Mobility shift assays with 32P-labeled oligonucleotides spanning D2 revealed specific interactions with ventral prostate nuclear proteins. Four of the D2-protein complexes decreased in intensity within 24 h of castration. UV cross-linking of the androgen-dependent DNA binding proteins identified protein complexes of approximately 140 and 55 kDa. The results demonstrate androgen-dependent nuclear protein-DNA interactions within the complex androgen response element D2. PMID:9211911

  5. Structure of the ligand-binding domain (LBD) of human androgen receptor in complex with a selective modulator LGD2226

    SciTech Connect

    Wang, Feng; Liu, Xiao-qin; Li, He; Liang, Kai-ni; Miner, Jeffrey N.; Hong, Mei; Kallel, E. Adam; Oeveren, Arjan van; Zhi, Lin; Jiang, Tao

    2006-11-01

    Crystal structure of the ligand-binding domain of androgen receptor in complex with LGD2226. The androgen receptor (AR) is a ligand-inducible steroid hormone receptor that mediates androgen action, determining male sexual phenotypes and promoting spermatogenesis. As the androgens play a dominant role in male sexual development and function, steroidal androgen agonists have been used clinically for some years. However, there is a risk of potential side effects and most steroidal androgens cannot be dosed orally, which limits the use of these substances. 1,2-Dihydro-6-N,N-bis(2,2,2-trifluoroethyl) amino-4-trifluoromethyl-2-quinolinone (LGD2226) is a synthetic nonsteroidal ligand and a novel selective AR modulator. The crystal structure of the complex of LGD2226 with the androgen receptor ligand-binding domain (AR LBD) at 2.1 Å was solved and compared with the structure of the AR LBD–R1881 complex. It is hoped that this will aid in further explaining the selectivity of LGD2226 observed in in vitro and in vivo assays and in developing more selective and effective therapeutic agents.

  6. Effects of androgenic-anabolic steroids in athletes.

    PubMed

    Hartgens, Fred; Kuipers, Harm

    2004-01-01

    Androgenic-anabolic steroids (AAS) are synthetic derivatives of the male hormone testosterone. They can exert strong effects on the human body that may be beneficial for athletic performance. A review of the literature revealed that most laboratory studies did not investigate the actual doses of AAS currently abused in the field. Therefore, those studies may not reflect the actual (adverse) effects of steroids. The available scientific literature describes that short-term administration of these drugs by athletes can increase strength and bodyweight. Strength gains of about 5-20% of the initial strength and increments of 2-5 kg bodyweight, that may be attributed to an increase of the lean body mass, have been observed. A reduction of fat mass does not seem to occur. Although AAS administration may affect erythropoiesis and blood haemoglobin concentrations, no effect on endurance performance was observed. Little data about the effects of AAS on metabolic responses during exercise training and recovery are available and, therefore, do not allow firm conclusions. The main untoward effects of short- and long-term AAS abuse that male athletes most often self-report are an increase in sexual drive, the occurrence of acne vulgaris, increased body hair and increment of aggressive behaviour. AAS administration will disturb the regular endogenous production of testosterone and gonadotrophins that may persist for months after drug withdrawal. Cardiovascular risk factors may undergo deleterious alterations, including elevation of blood pressure and depression of serum high-density lipoprotein (HDL)-, HDL2- and HDL3-cholesterol levels. In echocardiographic studies in male athletes, AAS did not seem to affect cardiac structure and function, although in animal studies these drugs have been observed to exert hazardous effects on heart structure and function. In studies of athletes, AAS were not found to damage the liver. Psyche and behaviour seem to be strongly affected by AAS

  7. Assessment of estrogenic and anti-androgenic activities of the mycotoxin zearalenone and its metabolites using in vitro receptor-specific bioassays.

    PubMed

    Molina-Molina, José-Manuel; Real, Macarena; Jimenez-Diaz, Inmaculada; Belhassen, Hidaya; Hedhili, Abderazzak; Torné, Pablo; Fernández, Mariana F; Olea, Nicolás

    2014-12-01

    Zearalenone (ZEN) is a well-known mycotoxin present in numerous agricultural products. Humans and animals are therefore at a risk of exposure to zearalenone through consumption of contaminated food. After intake, ZEN is reduced to α- and β-zearalenol (α-ZEL and β-ZEL), zearalanone (ZAN), and α- and β-zearalanol (α-ZAL and β-ZAL). Although their estrogenicity has been well characterized, much less is known about their interaction with other nuclear receptors. This study was undertaken to investigate interactions of ZEN and its five metabolites, with the human androgen receptor (hAR) and estrogen receptor alpha (hERα). Their ability to induce hAR-mediated reporter gene expression was examined in androgen-sensitive PALM cells, whereas the effects on hERα function were assessed in MCF-7 cells using the E-Screen bioassay. We confirm that ZEN and its metabolites are full agonists for hERα and demonstrate that all six compounds tested possess hAR-mediated antagonistic activity in PALM cells, in which ZAN, α-ZAL, and β-ZAL were the most effective hAR antagonists. Overall, the observed estrogenic and anti-androgenic potencies of ZEN and its metabolites suggest that these compounds may interfere with the endocrine system by various modes of action and that further investigation is warranted into their role as endocrine disrupters in animals and humans. PMID:25455890

  8. A Role for Androgens in Epithelial Proliferation and Formation of Glands in the Mouse Uterus.

    PubMed

    Simitsidellis, Ioannis; Gibson, Douglas A; Cousins, Fiona L; Esnal-Zufiaurre, Arantza; Saunders, Philippa T K

    2016-05-01

    The endometrium consists of stromal and epithelial compartments (luminal and glandular) with distinct functions in the regulation of uterine homeostasis. Ovarian sex steroids, namely 17β-estradiol and progesterone, play essential roles in modulating uterine cell proliferation, stromal-epithelial cross-talk and differentiation in preparation for pregnancy. The effect of androgens on uterine function remains poorly understood. The current study investigated the effect of the non-aromatizable androgen dihydrotestosterone (DHT) on mouse endometrial function. Ovx female mice were given a single sc injection (short treatment) or 7 daily injections (long treatment) of vehicle alone (5% ethanol, 0.4% methylcellulose) or vehicle with the addition of 0.2 mg DHT (n=8/group) and a single injection of bromodeoxyuridine 2 hours prior to tissue recovery. Treatment with DHT increased uterine weight, the area of the endometrial compartment and immunoexpression of the androgen receptor in the luminal and glandular epithelium. Treatment-dependent proliferation of epithelial cells was identified by immunostaining for MKi67 and bromodeoxyuridine. Real-time PCR identified significant DHT-dependent changes in the concentrations of mRNAs encoded by genes implicated in the regulation of the cell cycle (Wee1, Ccnd1, Rb1) and stromal-epithelial interactions (Wnt4, Wnt5a, Wnt7a, Cdh1, Vcl, Igf1, Prl8, Prlr) as well as a striking effect on the number of endometrial glands. This study has revealed a novel role for androgens in regulating uterine function with an effect on the glandular compartment of the endometrium. This previously unrecognized role for androgens has implications for our understanding of the role of androgens in regulation of endometrial function and fertility in women. PMID:26963473

  9. A Role for Androgens in Epithelial Proliferation and Formation of Glands in the Mouse Uterus

    PubMed Central

    Simitsidellis, Ioannis; Gibson, Douglas A.; Cousins, Fiona L.; Esnal-Zufiaurre, Arantza

    2016-01-01

    The endometrium consists of stromal and epithelial compartments (luminal and glandular) with distinct functions in the regulation of uterine homeostasis. Ovarian sex steroids, namely 17β-estradiol and progesterone, play essential roles in modulating uterine cell proliferation, stromal-epithelial cross-talk and differentiation in preparation for pregnancy. The effect of androgens on uterine function remains poorly understood. The current study investigated the effect of the non-aromatizable androgen dihydrotestosterone (DHT) on mouse endometrial function. Ovx female mice were given a single sc injection (short treatment) or 7 daily injections (long treatment) of vehicle alone (5% ethanol, 0.4% methylcellulose) or vehicle with the addition of 0.2 mg DHT (n=8/group) and a single injection of bromodeoxyuridine 2 hours prior to tissue recovery. Treatment with DHT increased uterine weight, the area of the endometrial compartment and immunoexpression of the androgen receptor in the luminal and glandular epithelium. Treatment-dependent proliferation of epithelial cells was identified by immunostaining for MKi67 and bromodeoxyuridine. Real-time PCR identified significant DHT-dependent changes in the concentrations of mRNAs encoded by genes implicated in the regulation of the cell cycle (Wee1, Ccnd1, Rb1) and stromal-epithelial interactions (Wnt4, Wnt5a, Wnt7a, Cdh1, Vcl, Igf1, Prl8, Prlr) as well as a striking effect on the number of endometrial glands. This study has revealed a novel role for androgens in regulating uterine function with an effect on the glandular compartment of the endometrium. This previously unrecognized role for androgens has implications for our understanding of the role of androgens in regulation of endometrial function and fertility in women. PMID:26963473

  10. Drug Insight: testosterone and selective androgen receptor modulators as anabolic therapies for chronic illness and aging

    PubMed Central

    Bhasin, Shalender; Calof, Olga M; Storer, Thomas W; Lee, Martin L; Mazer, Norman A; Jasuja, Ravi; Montori, Victor M; Gao, Wenqing; Dalton, James T

    2007-01-01

    SUMMARY Several regulatory concerns have hindered development of androgens as anabolic therapies, despite unequivocal evidence that testosterone supplementation increases muscle mass and strength in men; it induces hypertrophy of type I and II muscle fibers, and increases myonuclear and satellite cell number. Androgens promote differentiation of mesenchymal multipotent cells into the myogenic lineage and inhibit their adipogenic differentiation, by facilitating association of androgen receptors with β-catenin and activating T-cell factor 4. Meta-analyses indicate that testosterone supplementation increases fat-free mass and muscle strength in HIV-positive men with weight loss, glucocorticoid-treated men, and older men with low or low-normal testosterone levels. The effects of testosterone on physical function and outcomes important to patients have not, however, been studied. In older men, increased hematocrit and increased risk of prostate biopsy and detection of prostate events are the most frequent, testosterone-related adverse events. Concerns about long-term risks have restrained enthusiasm for testosterone use as anabolic therapy. Selective androgen-receptor modulators that are preferentially anabolic and that spare the prostate hold promise as anabolic therapies. We need more studies to determine whether testosterone or selective androgen-receptor modulators can induce meaningful improvements in physical function and patient-important outcomes in patients with physical dysfunction associated with chronic illness or aging. PMID:16932274

  11. Androgen Receptor as a Driver of Therapeutic Resistance in Advanced Prostate Cancer

    PubMed Central

    Kahn, Barbara; Collazo, Joanne; Kyprianou, Natasha

    2014-01-01

    The role of the androgen receptor (AR) signaling axis in the progression of prostate cancer is a cornerstone to our understanding of the molecular mechanisms causing castration-resistant prostate cancer (CRPC). Resistance of advanced prostate cancer to available treatment options makes it a clinical challenge that results in approximately 30,000 deaths of American men every year. Since the historic discovery by Dr. Huggins more than 70 years ago, androgen deprivation therapy (ADT) has been the principal treatment for advanced prostate cancer. Initially, ADT induces apoptosis of androgen-dependent prostate cancer epithelial cells and regression of androgen-dependent tumors. However, the majority of patients with advanced prostate cancer progress and become refractory to ADT due to emergence of androgen-independent prostate cancer cells driven by aberrant AR activation. Microtubule-targeting agents such as taxanes, docetaxel and paclitaxel, have enjoyed success in the treatment of metastatic prostate cancer; although new, recently designed mitosis-specific agents, such as the polo-kinase and kinesin-inhibitors, have yielded clinically disappointing results. Docetaxel, as a first-line chemotherapy, improves prostate cancer patient survival by months, but tumor resistance to these therapeutic agents inevitably develops. On a molecular level, progression to CRPC is characterized by aberrant AR expression, de novo intraprostatic androgen production, and cross talk with other oncogenic pathways. Emerging evidence suggests that reactivation of epithelial-mesenchymal-transition (EMT) processes may facilitate the development of not only prostate cancer but also prostate cancer metastases. EMT is characterized by gain of mesenchymal characteristics and invasiveness accompanied by loss of cell polarity, with an increasing number of studies focusing on the direct involvement of androgen-AR signaling axis in EMT, tumor progression, and therapeutic resistance. In this article, we

  12. Constitutive Activity of the Androgen Receptor

    PubMed Central

    Chan, Siu Chiu; Dehm, Scott M.

    2014-01-01

    Prostate cancer (PCa) is the most frequently diagnosed cancer in the United States. The androgen receptor (AR) signaling axis is central to all stages of PCa pathophysiology and serves as the main target for endocrine-based therapy. The most advanced stage of the disease, castration resistant prostate cancer (CRPC), is presently incurable and accounts for most PCa mortality. In this review, we highlight the mechanisms by which the AR signaling axis can bypass endocrine-targeted therapies and drive progression of CRPC. These mechanisms include alterations in growth factor, cytokine, and inflammatory signaling pathways, altered expression or activity of transcriptional co-regulators, AR point mutations, and AR gene amplification leading to AR protein overexpression. Additionally, we will discuss the mechanisms underlying the synthesis of constitutively active AR splice variants (AR-Vs) lacking the COOH-terminal ligand binding domain, as well as the role and regulation of AR-Vs in supporting therapeutic resistance in CRPC. Finally, we summarize the ongoing development of inhibitors targeting discrete AR functional domains as well as the status of new biomarkers for monitoring the AR signaling axis in patients. PMID:24931201

  13. Seasonal analysis of semen characteristics, serum testosterone and fecal androgens in the ocelot (Leopardus pardalis), margay (L. wiedii) and tigrina (L. tigrinus).

    PubMed

    Morais, R N; Mucciolo, R G; Gomes, M L F; Lacerda, O; Moraes, W; Moreira, N; Graham, L H; Swanson, W F; Brown, J L

    2002-05-01

    Captive adult male ocelots (Leopardus pardalis, n = 3), margays (L. wiedii, n = 3) and tigrinas (L. tigrinus, n = 4) in two locations in southern Brazil were studied for 14 consecutive months to evaluate the effect of season on testicular function. Reproductive evaluations, including testicular measurements, electroejaculation and blood collection were conducted monthly. Fecal samples were collected weekly for androgen metabolite analysis to assess testicular steroidogenic activity. Ocelots had the highest number of motile spermatozoa in the ejaculate (114.7+/-15.8 x 10(6); P < 0.05), the highest percentage of morphologically normal spermatozoa (82.4+/-1.2%; P < 0.05) and the highest concentration of fecal androgens (1.71 vs. 0.14 microg/g; P < 0.05). Margays and tigrinas had lower numbers of motile spermatozoa (23.4+/-2.8 x 10(6), 74.2+/-8.9 x 10(6), respectively), lower percentages of morphologically normal spermatozoa (57.4+/-2.8, 59.2+/-3.5%, respectively), and lower fecal androgen concentrations (0.15+/-0.01, 0.23+/-0.01 microg/g, respectively). Serum testosterone concentrations were similar among the three species. Fecal androgen concentrations were not affected by season, with the exception of the ocelot where concentrations were higher (P < 0.05) in the summer. Ejaculates were collected throughout the year; however, peaks in average sperm production were observed during the summer for all species. In summary, this study has identified several species differences in male testicular traits among ocelots, margays and tigrinas. Results of longitudinal reproductive assessments suggest males of each species are capable of breeding throughout the year. PMID:12066863

  14. Androgen receptors in the bonnethead, Sphyrna tiburo: cDNA cloning and tissue-specific expression in the male reproductive tract.

    PubMed

    Tyminski, John P; Gelsleichter, James J; Motta, Philip J

    2015-12-01

    As demonstrated in past studies, androgens appear to play critical roles in regulating reproduction in male sharks. However, little is known about the cell-specific actions of androgens in these fishes. To address this, this study examined androgen targets in reproductive organs of a seasonally reproducing shark, the bonnethead (Sphyrna tiburo). A partial bonnethead AR cDNA clone was isolated and found to exhibit strong homology with known vertebrate ARs. Using RT-PCR and in situ hybridization, AR was found to be expressed in multiple cell types in the male bonnethead testis (premeiotic germ cells, Leydig-like interstitial cells, Sertoli cells, peritubular myoid cells, and mature spermatozoa) and gonadal ducts (stromal cells, luminal epithelial cells, mature spermatozoa). Furthermore, AR expression in these organs was found to vary temporally in relation to the seasonal reproductive cycle. Based on immunocytochemistry, the presence of AR protein in male bonnethead reproductive organs was largely consistent with patterns of AR gene expression with the single exception of mature spermatozoa, which exhibited consistently strong mRNA expression but only inconsistent and weak AR protein immunoreactivity. These results suggest important roles for androgens in regulating germ cell proliferation, hormone production, spermatid elongation, spermiation, and gonadal duct function in male bonnetheads. In addition, high abundance of AR mRNA in bonnethead spermatozoa suggest the potential for de novo protein synthesis following spermiation/copulation and/or a role for AR mRNA in early embryonic development, both of which have been proposed to explain the occurrence of mRNA transcripts in spermatozoa from various vertebrates. PMID:26320857

  15. Identification and characterization of membrane androgen receptors in the ZIP9 zinc transporter subfamily: I. Discovery in female atlantic croaker and evidence ZIP9 mediates testosterone-induced apoptosis of ovarian follicle cells.

    PubMed

    Berg, A Håkan; Rice, Charles D; Rahman, Md Saydur; Dong, Jing; Thomas, Peter

    2014-11-01

    Rapid, cell surface-initiated, pregenomic androgen actions have been described in various vertebrate cells, but the receptors mediating these actions remain unidentified. We report here the cloning and expression of a cDNA from Atlantic croaker (Micropogonias undulatus) ovaries encoding a 33-kDa, seven-transmembrane protein with binding and signaling characteristics of a membrane androgen receptor that is unrelated to any previously described steroid receptor. Instead, croaker membrane androgen receptor has 81-93% amino acid sequence identity with zinc transporter ZIP9 (SLC39A9) subfamily members, indicating it is a ZIP9 protein. Croaker ZIP9 is expressed in gonadal tissues and in brain and is up-regulated in the ovary by reproductive hormones. Croaker ZIP9 protein is localized to plasma membranes of croaker granulosa cells and human breast cancer (SKBR-3) cells stably transfected with ZIP9. Recombinant croaker ZIP9 has a high affinity (dissociation constant, Kd, 12.7 nM), limited capacity (maximal binding capacity 2.8 nM/mg protein), displaceable, single binding site-specific for androgens, characteristic of steroid receptors. Testosterone activates a stimulatory G protein coupled to ZIP9, resulting in increased cAMP production. Testosterone promotes serum starvation-induced cell death and apoptosis in transfected cells and in croaker ovarian follicle cells that is associated with rapid increases in intracellular free zinc concentrations, suggesting an involvement of zinc in this nonclassical androgen action to promote apoptosis. These responses to testosterone are abrogated by treatment with ZIP9 small interfering RNA. The results provide the first evidence that zinc transporter proteins can function as specific steroid membrane receptors and indicate a previously unrecognized signaling pathway mediated by steroid receptors involving alterations in intracellular zinc. PMID:25014354

  16. Androgen Control in Prostate Cancer.

    PubMed

    Pelekanou, Vasiliki; Castanas, Elias

    2016-10-01

    Research on prostate cancer has extensively advanced in the past decade, through an improved understanding for its genetic basis and risk-stratification. Molecular classification of prostate cancer into distinct subtypes and the recognition of new histologic entities promise the development of tailored-made management strategies of patients. Nowadays, various alternatives are available for clinical management of localized disease ranging from observation alone through radical prostatectomy. In patients with castration-resistant prostate cancer, the approval of new drugs for the management of metastatic disease has offered promising results improving the survival of these patients. In this context, androgen receptors (AR) remain at the epicenter of prostate cancer research holding a prominent role in the biology and therapeutic regimens of prostate cancer. As many of castration-resistant tumors retain hormone-responsiveness, AR is a clinical relevant, druggable target. However, AR paradoxically remains neglected as a prostate cancer biomarker. The great advancements in prostate cancer preclinical and clinical research, imply further improvement in clinical and translational data, for patient selection and treatment optimization. For a precision medicine-guided clinical management of prostate cancer, AR evaluation has to be implemented in companion and complementary diagnostics, as discussed here. J. Cell. Biochem. 117: 2224-2234, 2016. © 2016 Wiley Periodicals, Inc. PMID:27104784

  17. 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. PMID:25284435

  18. Anti-androgenic activity of 3-methyl-4-nitrophenol in diesel exhaust particles.

    PubMed

    Li, ChunMei; Taneda, Shinji; Suzuki, Akira K; Furuta, Chie; Watanabe, Gen; Taya, Kazuyoshi

    2006-08-14

    In our continuing studies on nitrophenol derivatives as vasodilators in diesel exhaust particles, we have reported that nitrophenols in diesel exhaust particles possess not only vasodilatory activity but also estrogenic activity in vitro and in vivo, as well as anti-androgenic activity in vitro. Our efforts here were focused on the in vitro and in vivo anti-androgenic activity of 3-methyl-4-nitrophenol (4-nitro-m-cresol; PNMC), known a degradation product of the insecticide fenitrothion, in diesel exhaust particles. We investigated its anti-androgenic activity using an in vitro recombinant yeast screen and in vivo Hershberger assays. Recombinant yeast screen assay showed that PNMC possesses anti-androgenic activity at low concentrations. Furthermore, castrated 28-day-old immature male rats each implanted with a 5-mm-long silastic tube containing crystalline testosterone and injected with PNMC subcutaneously at doses from as low as 0.01 and 0.1 mg/kg up to 1 mg/kg for 5 consecutive days showed significantly decreased weights of the seminal vesicles, ventral prostate, and glans penis. Plasma follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were significantly increased in the 0.1 mg/kg PNMC treatment group. Our results demonstrate that PNMC in diesel exhaust particles clearly has anti-androgenic activity both in vitro and in vivo and can therefore be considered as an endocrine-disrupting chemical. PMID:16822498

  19. Widely used pharmaceuticals present in the environment revealed as in vitro antagonists for human estrogen and androgen receptors.

    PubMed

    Ezechiáš, Martin; Janochová, Jana; Filipová, Alena; Křesinová, Zdena; Cajthaml, Tomáš

    2016-06-01

    A considerable amount of scientific evidence indicates that a number of pharmaceuticals that could be detected in the environment can contribute towards the development of problems associated with human reproductive systems, as well as those of wildlife. We investigated the estrogenic and androgenic effects of select pharmaceuticals with high production volume and environmental relevance. We examined the receptor-binding activities of these pharmaceuticals in the T47D human cell line using altered secretion of cytokine CXCL12. Functional yeast-luciferase reporter gene assays were also employed to confirm the mechanism of receptor binding by estrogen and androgen. Non-steroidal anti-inflammatory drugs, namely ibuprofen, diclofenac and antiarrhythmic agent amiodarone showed strong anti-estrogenic effects in the T47D cell line. In the yeast-luciferase assay, these anti-inflammatory drugs also demonstrated anti-estrogenic potency and inhibited the E2 response in a concentration-dependent manner. Amiodarone did not exhibit any response in the yeast-luciferase assay; therefore, the endocrine disruption presumably occurred at a different level without directly involving the receptor. All the anti-inflammatory drugs considered in this study, including ketoprofen, naproxen and clofibrate, exhibited a dose-dependent antagonism towards the androgen receptor in the yeast-luciferase assays. Several other drugs, including the stimulant caffeine, did not show any response in the tests that were employed. A risk assessment analysis using 'Hazard Quotient' suggested a potential risk, especially in the cases of ibuprofen, ketoprofen, diclofenac and clofibrate. The results reveal the intrinsic endocrine disrupting nature of several pharmaceuticals and thus could contribute towards explaining a number of adverse health effects on humans and wildlife. PMID:26978704

  20. Using Plant Functional Traits to Explain Diversity–Productivity Relationships

    PubMed Central

    Roscher, Christiane; Schumacher, Jens; Gubsch, Marlén; Lipowsky, Annett; Weigelt, Alexandra; Buchmann, Nina; Schmid, Bernhard; Schulze, Ernst-Detlef

    2012-01-01

    Background The different hypotheses proposed to explain positive species richness–productivity relationships, i.e. selection effect and complementarity effect, imply that plant functional characteristics are at the core of a mechanistic understanding of biodiversity effects. Methodology/Principal Findings We used two community-wide measures of plant functional composition, (1) community-weighted means of trait values (CWM) and (2) functional trait diversity based on Rao’s quadratic diversity (FDQ) to predict biomass production and measures of biodiversity effects in experimental grasslands (Jena Experiment) with different species richness (2, 4, 8, 16 and 60) and different functional group number and composition (1 to 4; legumes, grasses, small herbs, tall herbs) four years after establishment. Functional trait composition had a larger predictive power for community biomass and measures of biodiversitity effects (40–82% of explained variation) than species richness per se (<1–13% of explained variation). CWM explained a larger amount of variation in community biomass (80%) and net biodiversity effects (70%) than FDQ (36 and 38% of explained variation respectively). FDQ explained similar proportions of variation in complementarity effects (24%, positive relationship) and selection effects (28%, negative relationship) as CWM (27% of explained variation for both complementarity and selection effects), but for all response variables the combination of CWM and FDQ led to significant model improvement compared to a separate consideration of different components of functional trait composition. Effects of FDQ were mainly attributable to diversity in nutrient acquisition and life-history strategies. The large spectrum of traits contributing to positive effects of CWM on biomass production and net biodiversity effects indicated that effects of dominant species were associated with different trait combinations. Conclusions/Significance Our results suggest that the

  1. Estren promotes androgen phenotypes in primary lymphoid organs and submandibular glands

    PubMed Central

    Islander, Ulrika; Hasséus, Bengt; Erlandsson, Malin C; Jochems, Caroline; Skrtic, Sofia Movérare; Lindberg, Marie; Gustafsson, Jan-Åke; Ohlsson, Claes; Carlsten, Hans

    2005-01-01

    Background Estrogens and androgens have extensive effects on the immune system, for example they suppress both T and B lymphopoiesis in thymus and bone marrow. Submandibular glands are sexually dimorphic in rodents, resulting in larger granular convoluted tubules in males compared to females. The aim of the present experiments was to investigate the estrogenic and androgenic effects of 4-estren-3α,17β-diol (estren) on thymus, bone marrow and submandibular glands, and compare the effects to those of 17β-estradiol (E2) and 5α-dihydrotestosterone (DHT), respectively. Estrogen receptors (ERs) were blocked by treatment of mice with the ER-antagonist ICI 182,780; also, knock-out mice lacking one or both ERs were used. Results As expected, the presence of functional ERs was mandatory for all the effects of E2. Similar to DHT-treatment, estren-treatment resulted in decreased thymus weight, as well as decreased frequency of bone marrow B cells. Treatment with estren or DHT also resulted in a shift in submandibular glands towards an androgen phenotype. All the effects of estren and DHT were independent of ERs. Conclusion Our study is the first to show that estren has similar effects as the androgen DHT on lymphopoiesis in thymus and bone marrow, and on submandibular glands, and that these effects are independent of estrogen receptors. This supports the hypothesis of estren being able to signal through the androgen receptor. PMID:16011795

  2. Dose-Dependent Effects of Androgens on the Circadian Timing System and Its Response to Light

    PubMed Central

    Butler, Matthew P.; Karatsoreos, Ilia N.; LeSauter, Joseph

    2012-01-01

    The hypothalamic suprachiasmatic nucleus (SCN) is the locus of a master clock that regulates circadian rhythms in physiology and behavior. Gonadectomy in male mice lengthens the period of circadian rhythms and increases the day-to-day variability of activity onset time. Both of these responses are rescued by the nonaromatizable androgen dihydrotestosterone. Androgen receptors (AR) are localized in SCN neurons that receive direct retinal input. To explore how androgens affect circadian clock function and its responsiveness to photic cues, we measured wheel-running behavior and SCN AR expression in intact, gonadectomized, and testosterone-replaced mice, held under various photic conditions. Gonadectomy lengthened circadian period in constant dim light but not in constant darkness. Increasing intensities of constant light parametrically increased circadian period, and this was potentiated at all intensities by gonadectomy. In contrast, gonadectomy did not alter light-induced pupil constriction, suggesting a nonretinal locus of hormone action. In hormone-replaced animals housed in constant darkness, T concentration was positively correlated with precision of activity onset and with SCN AR expression and negatively correlated with duration of activity. We infer the existence of two androgenic mechanisms: one modulates SCN responsiveness to light, and the second modulates SCN timekeeping and locomotor activity in a dose-dependent manner. Finally, the effects of androgens on period are a result of hormonal modulation of the SCN's response to photic input rather than to a change in the inherent period of oscillators in the absence of light. PMID:22492303

  3. Increased androgenic sensitivity in the hind limb muscular system marks the evolution of a derived gestural display.

    PubMed

    Mangiamele, Lisa A; Fuxjager, Matthew J; Schuppe, Eric R; Taylor, Rebecca S; Hödl, Walter; Preininger, Doris

    2016-05-17

    Physical gestures are prominent features of many species' multimodal displays, yet how evolution incorporates body and leg movements into animal signaling repertoires is unclear. Androgenic hormones modulate the production of reproductive signals and sexual motor skills in many vertebrates; therefore, one possibility is that selection for physical signals drives the evolution of androgenic sensitivity in select neuromotor pathways. We examined this issue in the Bornean rock frog (Staurois parvus, family: Ranidae). Males court females and compete with rivals by performing both vocalizations and hind limb gestural signals, called "foot flags." Foot flagging is a derived display that emerged in the ranids after vocal signaling. Here, we show that administration of testosterone (T) increases foot flagging behavior under seminatural conditions. Moreover, using quantitative PCR, we also find that adult male S. parvus maintain a unique androgenic phenotype, in which androgen receptor (AR) in the hind limb musculature is expressed at levels ∼10× greater than in two other anuran species, which do not produce foot flags (Rana pipiens and Xenopus laevis). Finally, because males of all three of these species solicit mates with calls, we accordingly detect no differences in AR expression in the vocal apparatus (larynx) among taxa. The results show that foot flagging is an androgen-dependent gestural signal, and its emergence is associated with increased androgenic sensitivity within the hind limb musculature. Selection for this novel gestural signal may therefore drive the evolution of increased AR expression in key muscles that control signal production to support adaptive motor performance. PMID:27143723

  4. 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.

  5. Production Functions Revisited in the Context of Educational Reform.

    ERIC Educational Resources Information Center

    MacPhail-Wilcox, Bettye; King, Richard A.

    1986-01-01

    Educational reform depends more on clearly defined missions and operational efficiency than on improved teacher quality. This article defines adequacy, equality, equity, and efficiency; examines numerous production function studies of teacher characteristics and policy and administrative structures; and summarizes seven policy implications.…

  6. Development of US EPA's Ecological Production Function Library

    EPA Science Inventory

    US EPA is developing a library of ecological production functions (EPFs) to help communities plan for sustainable access to ecosystem goods and services (EGS). Several databases already compile information about the value of EGS. However, they focus on static representations of...

  7. Preface: Biocatalysis and Biotechnology for Functional Foods and Industrial Products

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This book was assembled with the intent of bringing together current advances and in-depth review of biocatalysis and biotechnology with emphasis on functional foods and industrial products. Biocatalysis and biotechnology defined in this book include enzyme catalysis, biotransformation, bioconversi...

  8. Production of modern functional materials based on renewable vegetable resources

    NASA Astrophysics Data System (ADS)

    Onishchenko, D. V.; Reva, V. P.

    2013-05-01

    An energy-saving technology for production of variously structured carbon modifications from a renewable vegetable raw material, i.e., the waste of agricultural crops and peat moss, has been developed. Promising functional materials — refractory compounds (tungsten and titanium carbides) and oil sorbents possessing a combination of high operating characteristics — have been formed on the basis of the synthesized carbon modifications.

  9. Functionality of alternative protein in gluten-free product development.

    PubMed

    Deora, Navneet Singh; Deswal, Aastha; Mishra, Hari Niwas

    2015-07-01

    Celiac disease is an immune-mediated disease triggered in genetically susceptible individuals by ingested gluten from wheat, rye, barley, and other closely related cereal grains. The current treatment for celiac disease is life-long adherence to a strict gluten-exclusion diet. The replacement of gluten presents a significant technological challenge, as it is an essential structure-building protein, which is necessary for formulating high-quality baked goods. A major limitation in the production of gluten-free products is the lack of protein functionality in non-wheat cereals. Additionally, commercial gluten-free mixes usually contain only carbohydrates, which may significantly limit the amount of protein in the diet. In the recent past, various approaches are attempted to incorporate protein-based ingredients and to modify the functional properties for gluten-free product development. This review aims to the highlight functionality of the alternative protein-based ingredients, which can be utilized for gluten-free product development both functionally as well as nutritionally. PMID:26048849

  10. [Transdisciplinary Approach for Sarcopenia. Appication of selective androgen receptor modulator to the therapy of sarcopenia].

    PubMed

    Yanase, Toshihiko; Tanabe, Makito; Nomiyama, Takashi

    2014-10-01

    The research to develop a drug, so called selective androgen receptor modulator (SARM) , which shows beneficial androgenic action on bone and muscle, but hardly possesses the stimulatory action on prostate has been making a progress. However, no drug is available in the market at present. Most of such drugs are developed, aiming at the application to age-related muscle reduction (sarcopenia) and osteoporosis. Recently, in a clinical trial of SARM (enbosarm) administration to healthy elderly men, a promising data showing the increase of lean body mass and physical function has been reported. Future clinical applications of SARMs are expected. PMID:25266096

  11. Steroidogenic enzyme profile in an androgen-secreting adrenocortical oncocytoma associated with hirsustism

    PubMed Central

    Tetsi Nomigni, Milène; Ouzounian, Sophie; Benoit, Alice; Vadrot, Jacqueline; Tissier, Frédérique; Renouf, Sylvie; Lefebvre, Hervé; Christin-Maitre, Sophie; Louiset, Estelle

    2015-01-01

    Hirsutism induced by hyperandrogenism can be associated with polycystic ovary syndrome, 21-hydroxylase (OH) deficiency or androgen-secreting tumors, including ovarian and adrenal tumors. Adrenal androgen-secreting tumors are frequently malignant. Adrenal oncocytomas represent rare causes of hyperandrogenism. The aim of the study was to investigate steroidogenic enzyme expression and steroid secretion in an androgen-secreting adrenal oncocytoma in a young woman presenting with hirsutism. Hyperandrogenism was diagnosed on the basis of elevated plasma Δ4-androstenedione and testosterone levels. Pelvic ultrasound was normal, CT scanning revealed a right adrenal mass. Androgens were assessed in adrenal and ovarian vein samples and proved a right adrenal origin. Adrenalectomy normalized androgen levels and the adrenal tumor was diagnosed as an oncocytoma. Real time-PCR, immunohistochemistry and cell culture studies were performed on tumor explants to investigate the steroid secretion profile. Among enzymes required for cortisol synthesis, 17α-OH and 3β-hydroxysteroid dehydrogenase 2 (3β-HSD2) were highly expressed whereas 21-OH and 11β-OH were weakly produced at the mRNA and/or protein levels. Enzymes involved in testosterone production, 17β-HSD5 and 17β-HSD3, were also detected. ACTH receptor was present in the tissue. Cortisol, Δ4-androstenedione and testosterone secretions by cultured cells were increased by ACTH. These results provide the first demonstration, to our knowledge, of abnormal expression profile of steroidogenic enzymes in an adrenocortical oncocytoma. Our results also indicate that Δ4-androstenedione hypersecretion resulted from high 17α-OH and 3β-HSD2 expression in combination with low expression of 21-OH and 11β-OH. Testosterone production was ascribed to occurrence of 17β-HSD5 and 17β-HSD3. Finally, our results indicate that androgen secretion was stimulated by ACTH. PMID:26034121

  12. Androgen-Dependent Regulation of Human MUC1 Mucin Expression

    PubMed Central

    Mitchell, Stephen; Abel, Paul; Madaan, Sanjeev; Jeffs, James; Chaudhary, Khurram; Stamp, Gordon; Lalani, El-Nasir

    2002-01-01

    Abstract MUC1 mucin is transcriptionally regulated by estrogen, progesterone, and glucocorticoids. Our objective was to determine whether androgen receptor (AR) activation regulates expression of MUC1. The following breast and prostatic cell lines were phenotyped and grouped according to AR and MUC1 protein expression: 1) AR+MUC1+ [DAR17+19 (AR transfectants of DU-145), ZR-75-1, MDA-MB-453, and T47D]; 2) AR-MUC1+ [DZeo1 (AR-vector control), DU-145, BT20,MDA-MB-231, and MCF7]; 3) AR+MUC1- (LNCaP and LNCaP-r). Cell proliferation was determined using the MTT assay in the presence of synthetic androgen R1881, 0.1 pM to 1 µM. Cell surface MUC1 expression was determined by flow cytometry in the presence or absence of oestradiol, medroxy progesterone acetate or R1881, with and without 4 hydroxy-flutamide (4-OH), a nonsteroidal AR antagonist. The functional significance of MUC1 expression was investigated with a cell-cell aggregation assay. Only AR+ MUC1+ cell lines showed a significant increase in MUC1 expression with AR activation (P (range) =.01 to.0001), reversed in the presence of 4-OHF. Cell proliferation was unaffected. Increased expression of MUC1 was associated with a significant (P (range) =.002 to.001) reduction in cell-cell adhesion. To our knowledge, this is the first description of androgen-dependent regulation of MUC1 mucin. This is also functionally associated with decreased cell-cell adhesion, a recognised feature of progressive malignancy. These findings have important implications for physiological and pathological processes. PMID:11922395

  13. Functions of the gene products of Escherichia coli.

    PubMed Central

    Riley, M

    1993-01-01

    A list of currently identified gene products of Escherichia coli is given, together with a bibliography that provides pointers to the literature on each gene product. A scheme to categorize cellular functions is used to classify the gene products of E. coli so far identified. A count shows that the numbers of genes concerned with small-molecule metabolism are on the same order as the numbers concerned with macromolecule biosynthesis and degradation. One large category is the category of tRNAs and their synthetases. Another is the category of transport elements. The categories of cell structure and cellular processes other than metabolism are smaller. Other subjects discussed are the occurrence in the E. coli genome of redundant pairs and groups of genes of identical or closely similar function, as well as variation in the degree of density of genetic information in different parts of the genome. PMID:7508076

  14. Biosynthesis and Function of Polyacetylenes and Allied Natural Products

    PubMed Central

    Minto, Robert E.; Blacklock, Brenda J.

    2008-01-01

    Polyacetylenic natural products are a substantial class of often unstable compounds containing a unique carbon-carbon triple bond functionality, that are intriguing for their wide variety of biochemical and ecological functions, economic potential, and surprising mode of biosynthesis. Isotopic tracer experiments between 1960 and 1990 demonstrated that the majority of these compounds are derived from fatty acid and polyketide precursors. During the past decade, research into the metabolism of polyacetylenes has swiftly advanced, driven by the cloning of the first genes responsible for polyacetylene biosynthesis in plants, moss, fungi, and actinomycetes, and the initial characterization of the gene products. The current state of knowledge of the biochemistry and molecular genetics of polyacetylenic secondary metabolic pathways will be presented together with an up-to-date survey of new terrestrial and marine natural products, their known biological activities, and a discussion of their likely metabolic origins. PMID:18387369

  15. Androgen receptor in human endothelial cells

    PubMed Central

    Torres-Estay, Verónica; Carreño, Daniela V; San Francisco, Ignacio F; Sotomayor, Paula; Godoy, Alejandro S; Smith, Gary J

    2015-01-01

    Androgen receptor (AR) is a ligand-inducible transcription factor, and a member of the steroid-thyroid-retinoid receptor superfamily, that mediates the biological effects of androgens in a wide range of physiological and pathological processes. AR expression was identified in vascular cells nearly 20 years ago, and recent research has shown that AR mediates a variety of actions of androgens in endothelial and vascular smooth muscle cells. In this mini-review, we review evidence indicating the importance of AR in human endothelial cell (HUVEC) homeostatic and pathogenic processes. Although a role for AR in the modulation of HUVEC biology is evident, the molecular mechanisms by which AR regulates HUVEC homeostasis and disease processes are not fully understood. Understanding these mechanisms could provide critical insights into the processes of pathogenesis of diseases ranging from cardiovascular disease to cancer that are major causes of human morbidity and mortality. PMID:25563353

  16. Partial Androgen Insensitivity Syndrome Presenting with Gynecomastia

    PubMed Central

    Lee, Sung Won; Kwak, Dong Shin; Jung, In Sub; Kwak, Joo Hee; Park, Jung Hwan; Hong, Sang Mo; Lee, Chang Bum; Park, Yong Soo; Kim, Dong Sun; Choi, Woong Hwan

    2015-01-01

    Gynecomastia is a benign enlargement of the male breast caused by the proliferation of glandular breast tissue. Determining the various causes of gynecomastia such as physiological causes, drugs, systemic diseases, and endocrine disorders is important. Androgen insensitivity syndrome (AIS) is a rare endocrine disorder presenting with gynecomastia and is a disorder of male sexual differentiation caused by mutations within the androgen receptor gene. All individuals with AIS have the 46 XY karyotype, although AIS phenotypes can be classified as mild, partial or complete and can differ among both males and females including ambiguous genitalia or infertility in males. We experienced a case of partial AIS presenting with gynecomastia and identified the androgen receptor gene mutation. PMID:25433660

  17. Microfluidic production of multiple emulsions and functional microcapsules.

    PubMed

    Lee, Tae Yong; Choi, Tae Min; Shim, Tae Soup; Frijns, Raoul A M; Kim, Shin-Hyun

    2016-09-21

    Recent advances in microfluidics have enabled the controlled production of multiple-emulsion drops with onion-like topology. The multiple-emulsion drops possess an intrinsic core-shell geometry, which makes them useful as templates to create microcapsules with a solid membrane. High flexibility in the selection of materials and hierarchical order, achieved by microfluidic technologies, has provided versatility in the membrane properties and microcapsule functions. The microcapsules are now designed not just for storage and release of encapsulants but for sensing microenvironments, developing structural colours, and many other uses. This article reviews the current state of the art in the microfluidic-based production of multiple-emulsion drops and functional microcapsules. The three main sections of this paper discuss distinct microfluidic techniques developed for the generation of multiple emulsions, four representative methods used for solid membrane formation, and various applications of functional microcapsules. Finally, we outline the current limitations and future perspectives of microfluidics and microcapsules. PMID:27470590

  18. Functional and Behavioral Product Information Representation and Consistency Validation for Collaboration in Product Lifecycle Activities

    ERIC Educational Resources Information Center

    Baysal, Mehmet Murat

    2012-01-01

    Information models that represent the function, assembly and behavior of artifacts are critical in the conceptual development of a product and its evaluation. Much research has been conducted in this area; however, existing models do not relate function, behavior and structure in a comprehensive and consistent way. In this work, NIST's Core…

  19. Synergistic killing effect of chloroquine and androgen deprivation in LNCaP cells

    SciTech Connect

    Kaini, Ramesh R.; Hu, Chien-An A.

    2012-08-24

    Highlights: Black-Right-Pointing-Pointer Chloroquine synergistically killed LNCaP cells during androgen deprivation treatment. Black-Right-Pointing-Pointer Chloroquine inhibited the function of autolysosomes and decreases the cytosolic ATP. Black-Right-Pointing-Pointer Chloroquine induced nuclear and DNA fragmentation in androgen deprived LNCaP. Black-Right-Pointing-Pointer Chloroquine may be an useful adjuvant in hormone ablation therapy in PCa patients. -- Abstract: Modulation of autophagy is a new paradigm in cancer therapeutics. Recently a novel function of chloroquine (CLQ) in inhibiting degradation of autophagic vesicles has been revealed, which raises the question whether CLQ can be used as an adjuvant in targeting autophagic pro-survival mechanism in prostate cancer (PCa). We previously showed that autophagy played a protective role during hormone ablation therapy, in part, by consuming lipid droplets in PCa cells. In addition, blocking autophagy by genetic and pharmacological means in the presence of androgen deprivation caused cell death in PCa cells. To further investigate the importance of autophagy in PCa survival and dissect the role of CLQ in PCa death, we treated hormone responsive LNCaP cells with CLQ in combination with androgen deprivation. We observed that CLQ synergistically killed LNCaP cells during androgen deprivation in a dose- and time-dependent manner. We further confirmed that CLQ inhibited the maturation of autophagic vesicles and decreased the cytosolic ATP. Moreover, CLQ induced nuclear condensation and DNA fragmentation, a hallmark of apoptosis, in androgen deprived LNCaP cells. Taken together, our finding suggests that CLQ may be an useful adjuvant in hormone ablation therapy to improve the therapeutic efficacy.

  20. Joint pricing and production management: a geometric programming approach with consideration of cubic production cost function

    NASA Astrophysics Data System (ADS)

    Sadjadi, Seyed Jafar; Hamidi Hesarsorkh, Aghil; Mohammadi, Mehdi; Bonyadi Naeini, Ali

    2014-08-01

    Coordination and harmony between different departments of a company can be an important factor in achieving competitive advantage if the company corrects alignment between strategies of different departments. This paper presents an integrated decision model based on recent advances of geometric programming technique. The demand of a product considers as a power function of factors such as product's price, marketing expenditures, and consumer service expenditures. Furthermore, production cost considers as a cubic power function of outputs. The model will be solved by recent advances in convex optimization tools. Finally, the solution procedure is illustrated by numerical example.

  1. Androgen-metabolizing enzymes: A structural perspective.

    PubMed

    Manenda, Mahder Seifu; Hamel, Charles Jérémie; Masselot-Joubert, Loreleï; Picard, Marie-Ève; Shi, Rong

    2016-07-01

    Androgen-metabolizing enzymes convert cholesterol, a relatively inert molecule, into some of the most potent chemical messengers in vertebrates. This conversion involves thermodynamically challenging reactions catalyzed by P450 enzymes and redox reactions catalyzed by Aldo-Keto Reductases (AKRs). This review covers the structures of these enzymes with a focus on active site interactions and proposed mechanisms. Due to their role in a number of diseases, particularly in cancer, androgen-metabolizing enzymes have been targets of drug design. Hence we will also highlight how existing knowledge of structure is being used to this end. PMID:26924584

  2. IN VIVO CONFIRMATION OF THE ANTI-ANDROGENIC NATURE OF FLUTAMIDE IN THE FATHEAD MINNOW

    EPA Science Inventory

    A short-term reproduction assay with the fathead minnow has been developed to detect chemicals with the potential to disrupt reproductive endocrine function controlled by estrogen- and androgen-mediated pathways. As part of characterizing the assay, tests have been conducted wit...

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

    PubMed

    Morooka, Nobukatsu; Ueguri, Kei; Yee, Karen Kar Lye; Yanase, Toshihiko; Sato, Takashi

    2016-09-01

    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 inflammatory 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. PMID:27392713

  4. 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.

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

    PubMed Central

    Bird, Ian M.; Dumesic, Daniel A.; Abbott, David H.

    2005-01-01

    Context: Adrenal androgen excess is found in ∼25-60%% of women with polycystic ovary syndrome (PCOS), but the mechanisms underlying PCOS-related adrenal androgen excess are unclear. Objective: To determine whether adrenal androgen excess is manifest in a nonhuman primate model for PCOS, Participants: Six prenatally androgenized (PA) and 6 control female rhesus monkeys of similar age, body weight and BMI were studied during days 2-6 of two menstrual cycles or anovulatory 30-day periods. Interventions: Pre-dexamethasone adrenal steroid levels were assessed in the first cycle (cycle 1). In a subsequent cycle (cycle 2), occurring 1-3 cycles following cycle 1, adrenal steroids were determined 14.5-16.0h after an i.m. injection of 0.5mg/kg dexamethasone [post-dexamethasone levels] and following an i.v. injection of 50μg ACTH1-39. Results: Both before and after dexamethasone, serum levels of dehydroepiandrosterone (DHEA) in PA females exceeded those in controls. Following ACTH injection, PA females exhibited higher circulating levels of DHEA, androstenedione and corticosterone, but comparable levels of 17α-hydroxyprogesterone, cortisol, DHEAS, and testosterone, compared to controls. Conclusion: 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 to 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 re-programming of adrenocortical function. PMID:16174719

  6. [Role of androgen in the elderly. Current status of development of selective androgen receptor modulator].

    PubMed

    Yanase, Toshihiko

    2013-08-01

    The research to develop a drug, so called selective androgen receptor modulator (SARM) , which shows beneficial androgenic action on bone and muscle, but hardly possesses the stimulatory action on prostate has been making a progress. However, no drug is available in the market at present. Most of such drugs are developed, aiming at the application to age-related muscle reduction (sarcopenia) and osteoporosis. We are now trying to develop a SARM which may have beneficial effect on metabolic syndrome. PMID:23892218

  7. A Mathematical Model of Intermittent Androgen Suppression for Prostate Cancer

    NASA Astrophysics Data System (ADS)

    Ideta, Aiko Miyamura; Tanaka, Gouhei; Takeuchi, Takumi; Aihara, Kazuyuki

    2008-12-01

    For several decades, androgen suppression has been the principal modality for treatment of advanced prostate cancer. Although the androgen deprivation is initially effective, most patients experience a relapse within several years due to the proliferation of so-called androgen-independent tumor cells. Bruchovsky et al. suggested in animal models that intermittent androgen suppression (IAS) can prolong the time to relapse when compared with continuous androgen suppression (CAS). Therefore, IAS has been expected to enhance clinical efficacy in conjunction with reduction in adverse effects and improvement in quality of life of patients during off-treatment periods. This paper presents a mathematical model that describes the growth of a prostate tumor under IAS therapy based on monitoring of the serum prostate-specific antigen (PSA). By treating the cancer tumor as a mixed assembly of androgen-dependent and androgen-independent cells, we investigate the difference between CAS and IAS with respect to factors affecting an androgen-independent relapse. Numerical and bifurcation analyses show how the tumor growth and the relapse time are influenced by the net growth rate of the androgen-independent cells, a protocol of the IAS therapy, and the mutation rate from androgen-dependent cells to androgen-independent ones.

  8. Integrated multi-omics analyses reveal the biochemical mechanisms and phylogenetic relevance of anaerobic androgen biodegradation in the environment.

    PubMed

    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

    2016-08-01

    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

  9. Androgen receptor expression and morphology of forebrain and neuromuscular systems in male green anoles displaying individual differences in sexual behavior.

    PubMed

    Neal, Jennifer K; Wade, Juli

    2007-08-01

    Investigating individual differences in sexual performance in unmanipulated males is important for understanding natural relationships between behavior and morphology, and the mechanisms regulating them. Among male green anole lizards, some court and copulate frequently (studs) and others do not (duds). To evaluate potential factors underlying differences in the level of these behaviors, morphology and androgen receptor expression in neuromuscular courtship and copulatory structures, as well as in the preoptic area and amygdala, were compared in males displaying varying degrees of sexual function. This study revealed that individual differences in behavior among unmanipulated males, in particular the extension of a throat fan (dewlap) used during courtship, were positively correlated with the size of fibers in the associated muscle and with soma size in the amygdala. The physiological response to testosterone, as indicated by the height of cells in an androgen-sensitive portion of the kidney, was also correlated with male sexual behavior, and predicted it better than plasma androgen levels. Androgen receptor expression was not related to the display of courtship or copulation in any of the tissues examined. The present data indicate that higher levels of male courtship behavior result in (or are the result of) enhanced courtship muscle and amygdala morphology, and that androgen-sensitive tissue in studs may be more responsive to testosterone than duds. However, some mechanism(s) other than androgen receptor expression likely confer this difference in responsiveness. PMID:17531996

  10. Androgen receptor expression and morphology of forebrain and neuromuscular systems in male green anoles displaying individual differences in sexual behavior

    PubMed Central

    Neal, Jennifer K.; Wade, Juli

    2010-01-01

    Investigating individual differences in sexual performance in unmanipulated males is important for understanding natural relationships between behavior and morphology, and the mechanisms regulating them. Among male green anole lizards, some court and copulate frequently (studs) and others do not (duds). To evaluate potential factors underlying differences in the level of these behaviors, morphology and androgen receptor expression in neuromuscular courtship and copulatory structures, as well as in the preoptic area and amygdala, were compared in males displaying varying degrees of sexual function. This study revealed that individual differences in behavior among unmanipulated males, in particular the extension of a throat fan (dewlap) used during courtship, were positively correlated with the size of fibers in the associated muscle and with soma size in the amygdala. The physiological response to testosterone, as indicated by the height of cells in an androgen-sensitive portion of the kidney, was also correlated with male sexual behavior, and predicted it better than plasma androgen levels. Androgen receptor expression was not related to the display of courtship or copulation in any of the tissues examined. The present data indicate that higher levels of male courtship behavior result in (or are the result of) enhanced courtship muscle and amygdala morphology, and that androgen-sensitive tissue in studs may be more responsive to testosterone than duds. However, some mechanism(s) other than androgen receptor expression likely confer this difference in responsiveness. PMID:17531996

  11. The androgen-binding protein gene is expressed in male and female rat brain.

    PubMed

    Wang, Y M; Bayliss, D A; Millhorn, D E; Petrusz, P; Joseph, D R

    1990-12-01

    Extracellular androgen-binding proteins (ABP) are thought to modulate the regulatory functions of androgens and the trans-acting nuclear androgen receptor. Testicular ABP and plasma sex hormone-binding globulin (SHBG), which is produced in liver, are encoded by the same gene. We have now found that the ABP-SHBG gene is also expressed in male and female rat brain. Immunoreactive ABP was found to be present in neuronal cell bodies throughout the brain as well as in fibers of the hypothalamic median eminence. The highest concentrations of immunoreactive cell bodies were located in the supraoptic and paraventricular nuclei. Likewise, ABP mRNA was present in all brain regions examined. Analysis of cDNA clones representing brain ABP mRNAs revealed amino acid sequence differences in brain and testicular ABPs. The protein encoded by an alternatively processed RNA has sequence characteristics suggesting that the protein could act as a competitior of ABP binding to cell surface receptors. These data and gene-sequencing experiments indicate that a specific ABP gene promoter is used for transcription initiation in brain. ABP may function in brain as an androgen carrier protein; however, in view of the widespread presence of ABP and ABP mRNA in brain, the protein may have a much broader, yet unknown, function. PMID:1701136

  12. Current studies on physiological functions and biological production of lactosucrose.

    PubMed

    Mu, Wanmeng; Chen, Qiuming; Wang, Xiao; Zhang, Tao; Jiang, Bo

    2013-08-01

    Lactosucrose (O-β-D-galactopyranosyl-(1,4)-O-α-D-glucopyranosyl-(1,2)-β-D-fructofuranoside) is a trisaccharide formed from lactose and sucrose by enzymatic transglycosylation. This rare trisaccharide is a kind of indigestible carbohydrate, has good prebiotic effect, and promotes intestinal mineral absorption. It has been used as a functional ingredient in a range of food products which are approved as foods for specified health uses in Japan. Using lactose and sucrose as substrates, lactosucrose can be produced through transfructosylation by β-fructofuranosidase from Arthrobacter sp. K-1 or a range of levansucrases, or through transgalactosylation by β-galactosidase from Bacillus circulans. This article presented a review of recent studies on the physiological functions of lactosucrose and the biological production from lactose and sucrose by different enzymes. PMID:23828605

  13. Androgen Receptors in a Cichlid Fish, Astatotilapia burtoni: Structure, Localization, and Expression Levels

    PubMed Central

    HARBOTT, LENE K.; BURMEISTER, SABRINA S.; WHITE, RICHARD B.; VAGELL, MIKE; FERNALD, RUSSELL D.

    2009-01-01

    Androgens are an important output of the hypothalamic-pituitary-gonadal (HPG) axis that controls reproduction in all vertebrates. In male teleosts two androgens, testosterone and 11-ketotestosterone, control sexual differentiation and development in juveniles and reproductive behavior in adults. Androgenic signals provide feedback at many levels of the HPG axis, including the hypothalamic neurons that synthesize and release gonadotropin-releasing hormone 1 (GnRH1), but the precise cellular site of androgen action in the brain is not known. Here we describe two androgen receptor subtypes, ARα and ARβ, in the cichlid Astatotilapia burtoni and show that these subtypes are differentially located throughout the adult brain in nuclei known to function in the control of reproduction. ARα was expressed in the ventral part of the ventral telencephalon, the preoptic area (POA) of the hypothalamus and the ventral hypothalamus, whereas ARβ was more widely expressed in the dorsal and ventral telencephalon, the POA, and the ventral and dorsal hypothalamus. We provide the first evidence in any vertebrate that the GnRH1-releasing neurons, which serve as the central control point of the HPG axis, express both subtypes of AR. Using quantitative real-time PCR, we show that A. burtoni AR subtypes have different expression levels in adult tissue, with ARα showing significantly higher expression than ARβ in the pituitary, and ARβ expressed at a higher level than ARα in the anterior and middle brain. These data provide important insight into the role of androgens in regulating the vertebrate reproductive axis. PMID:17614300

  14. Androgen Deficiency Exacerbates High-Fat Diet-Induced Metabolic Alterations in Male Mice.

    PubMed

    Dubois, Vanessa; Laurent, Michaël R; Jardi, Ferran; Antonio, Leen; Lemaire, Katleen; Goyvaerts, Lotte; Deldicque, Louise; Carmeliet, Geert; Decallonne, Brigitte; Vanderschueren, Dirk; Claessens, Frank

    2016-02-01

    Androgen deficiency is associated with obesity, metabolic syndrome, and type 2 diabetes mellitus in men, but the mechanisms behind these associations remain unclear. In this study, we investigated the combined effects of androgen deficiency and high-fat diet (HFD) on body composition and glucose homeostasis in C57BL/6J male mice. Two models of androgen deficiency were used: orchidectomy (ORX) and androgen receptor knockout mice. Both models displayed higher adiposity and serum leptin levels upon HFD, whereas no differences were seen on a regular diet. Fat accumulation in HFD ORX animals was accompanied by increased sedentary behavior and occurred in spite of reduced food intake. HFD ORX mice showed white adipocyte hypertrophy, correlated with decreased mitochondrial content but not function as well as increased lipogenesis and decreased lipolysis suggested by the up-regulation of fatty acid synthase and the down-regulation of hormone-sensitive lipase. Both ORX and androgen receptor knockout exacerbated HFD-induced glucose intolerance by impairing insulin action in liver and skeletal muscle, as evidenced by the increased triglyceride and decreased glycogen content in these tissues. In addition, serum IL-1β levels were elevated, and pancreatic insulin secretion was impaired after ORX. Testosterone but not dihydrotestosterone supplementation restored the castration effects on body composition and glucose homeostasis. We conclude that sex steroid deficiency in combination with HFD exacerbates adiposity, insulin resistance, and β-cell failure in 2 preclinical male mouse models. Our findings stress the importance of a healthy diet in a clinical context of androgen deficiency and may have implications for the prevention of metabolic alterations in hypogonadal men. PMID:26562264

  15. Effects of androgen on immunohistochemical localization of androgen receptor and Connexin 43 in mouse ovary.

    PubMed

    Yang, Mei; Li, Jianhua; An, Yulin; Zhang, Shuiwen

    2015-10-01

    Androgens have essential roles in the regulation of follicular development and female fertility. Androgen excess is the leading defect in polycystic ovary syndrome (PCOS) patients and involved in the ovarian dysfunction. The aim of this study was to elucidate the regarding regulatory role of androgen in the follicular development of female mouse. Immunohistochemical staining and Western blot analyses were performed to detect androgen receptor (AR) and Connexin 43 (Cx43) expression in ovaries from both control and testosterone-treated group mice. In this study, localizations of AR and Cx43 were dramatically altered in testosterone-treated mouse ovaries. In addition, AR expression was significantly increased, whereas Cx43 expression was markedly decreased after testosterone treatment. Alterations of AR and Cx43 expression by testosterone with concomitant reduction of MII oocytes. Overall, these results suggest the involvement of androgen in the regulation of AR and Cx43 localizations in mouse ovary. Alterations of AR and Cx43 expression by testosterone may affect normal folliculogenesis. Together these findings will enable us to begin understanding the important roles of AR and Cx43 actions in the regulation of follicular development, as well as providing insights into the role of AR and Cx43 actions in the androgen-associated reproductive diseases such as PCOS. PMID:26206424

  16. Racial differences in the androgen/androgen receptor pathway in prostate cancer.

    PubMed Central

    Pettaway, C. A.

    1999-01-01

    Pathologic and epidemiologic data suggest that while little racial variation exists in prostate cancer prevalence ("autopsy cancer"), striking racial variation exists for the clinically diagnosed form of the disease. A review of the available literature was performed to define whether racial differences in serum androgen levels or qualitative or quantitative differences in the androgen receptor were correlated with prostate cancer incidence or severity. Black men were found to be exposed to higher circulating testosterone levels from birth to about age 35 years. Such differences were not consistently noted among older men. Significant differences also were found for dihydrotestosterone metabolites among black, white, and Asian men. Unique racial genetic polymorphisms were noted for the gene for 5 alpha-reductase type 2 among black and Asian men. Novel androgen receptor mutations recently have been described among Japanese, but not white, men with latent prostate cancer. Finally, androgen receptor gene polymorphisms leading to shorter or longer glutamine and glycine residues in the receptor protein are correlated with racial variation in the incidence and severity of prostate cancer. This same polymorphism also could explain racial variation in serum prostate-specific antigen levels. Collectively, these data strongly suggest racial differences within the androgen/androgen receptor pathway not only exist but could be one cause of clinically observed differences in the biology of prostate cancer among racial groups. Images Figure 1 PMID:10628124

  17. Review: Production and functionality of active peptides from milk.

    PubMed

    Muro Urista, C; Álvarez Fernández, R; Riera Rodriguez, F; Arana Cuenca, A; Téllez Jurado, A

    2011-08-01

    In recent years, research on the production of active peptides obtained from milk and their potential functionality has grown, to a great extent. Bioactive peptides have been defined as specific protein fragments that have a positive impact on body functions or conditions, and they may ultimately have an influence on health. Individual proteins of casein or milk-derived products such as cheese and yogurt have been used as a protein source to study the isolation and activity of peptides with several applications. Currently, the milk whey waste obtained in the production of cheese also represents a protein source from which active peptides could be isolated with potential industrial applications. The active properties of milk peptides and the results found with regard to their physiological effects have led to the classification of peptides as belonging to the group of ingredients of protein nature, appropriate for use in functional foods or pharmaceutical formulations. In this study, the main peptides obtained from milk protein and the past research studies about its production and biological activities will be explained. Second, an analysis will be made on the methods to determinate the biological activities, the separation of bioactive peptides and its structure identification. All of these form the base required to obtain synthetic peptides. Finally, we explain the experimental animal and human trials done in the past years. Nevertheless, more research is required on the design and implementation of equipment for the industrial production and separation of peptides. In addition, different authors suggest that more emphasis should therefore be given to preclinical studies, proving that results are consistent and that effects are demonstrated repeatedly by several research human groups. PMID:21917640

  18. Migratory constraints on yolk precursors limit yolk androgen deposition and underlie a brood reduction strategy in rockhopper penguins.

    PubMed

    Crossin, Glenn T; Poisbleau, Maud; Demongin, Laurent; Chastel, Olivier; Williams, Tony D; Eens, Marcel; Quillfeldt, Petra

    2012-12-23

    Hormonally mediated maternal effects link maternal phenotype and environmental conditions to offspring phenotype. The production of lipid-rich maternal yolk precursors may provide a mechanism by which lipophilic steroid hormones can be transported to developing yolks, thus predicting a positive correlation between yolk precursors in mothers and androgen levels in eggs. Using rockhopper penguins (Eudyptes chrysocome), which produce a two-egg clutch characterized by extreme egg-size dimorphism, reversed hatching asynchrony and brood-reduction, we examined correlations between circulating concentrations of the primary yolk-precursor vitellogenin (VTG) and levels of yolk androgens. Previous work in Eudyptes penguins has shown that egg-size dimorphism is the product of migratory constraints on yolk precursor production. We predicted that if yolk precursors are constrained, androgen transport to developing yolks would be similarly constrained. We reveal positive linear relationships between maternal VTG and androgens in small A-eggs but not larger B-eggs, which is consistent with a migratory constraint operating on the A-egg. Results suggest that intra-clutch variation in total yolk androgen levels depends on the production and uptake of yolk precursors. The brood reduction strategy common to Eudyptes might thus be best described as the result of a migratory constraint. PMID:22809718

  19. Clinical outcomes of anti-androgen withdrawal and subsequent alternative anti-androgen therapy for advanced prostate cancer following failure of initial maximum androgen blockade

    PubMed Central

    MOMOZONO, HIROYUKI; MIYAKE, HIDEAKI; TEI, HIROMOTO; HARADA, KEN-ICHI; FUJISAWA, MASATO

    2016-01-01

    The present study aimed to investigate the significance of anti-androgen withdrawal and/or subsequent alternative anti-androgen therapy in patients with advanced prostate cancer (PC) who relapsed after initial maximum androgen blockade (MAB). The present study evaluated the clinical outcomes of 272 consecutive advanced PC patients undergoing anti-androgen withdrawal and/or subsequent alternative anti-androgen therapy with flutamide following the failure of initial MAB using bicalutamide. With the exception of 41 patients (15.1%) who did not undergo anti-androgen withdrawal due to the characteristics of PC suggesting aggressive diseases, prostate-specific antigen (PSA) declined from the baseline value in 83 patients (35.9%), including 18 (7.8%) with PSA decline >50%, but not in the remaining 148 (64.1%). No significant difference in the overall survival (OS) or cancer-specific survival (CSS) among the three groups was observed based on the response to anti-androgen withdrawal. Following the introduction of alternative anti-androgen therapy with flutamide, PSA decline was observed in 185 patients (68.0%), including 103 (37.9%) who achieved a PSA reduction of >50%; however, the PSA level continued to elevate in the remaining 87 (32.0%). Furthermore, of the numerous factors examined, only the duration of the initial MAB therapy was shown to be significantly correlated with the PSA decline following alternative anti-androgen therapy. Multivariate analysis of several factors identified revealed that only PSA decline following alternative anti-androgen therapy was an independent predictor of CSS and OS. If initial MAB is effective, the introduction of alternative anti-androgen therapy may be considered; however, anti-androgen withdrawal should be omitted, irrespective of the characteristics of advanced PC. PMID:27123292

  20. Demand for functional and nutritional enhancements in specialty milk products.

    PubMed

    Gulseven, Osman; Wohlgenant, Michael

    2014-10-01

    This article investigates the socio-demographic determinants affecting the demand for functional and nutritional enhancements in milk products based on a two-stage model. In order to derive the implicit market values of these enhancements, first we estimated the relationship between the prices of differentiated dairy products and the amount or respectively the presence of specific characteristics in these products. Next, using these implicit prices along with the information on households' demographic background, we analyzed the socio-demographic factors that affect consumer demand for specific functional and nutritional enhancements. The model is estimated using a combined panel data set based on AC Nielsen Retail Homescan Panel and the USDA Nutrient Database. Our results indicate that being lactose/cholesterol free (LFCF) and organic implies substantially higher price premiums, whereas soy has a negative price. Socio-demographic factors such as income, racial profile, presence of children; education level and age have significant effects on the demand for functional enhancements. Specialty milk consumption increases with age, education, and presence of kids, whereas it declines with income. The ratio of specialty milk consumption to total milk consumption is substantially higher among Hispanic, Asian and African-American households. PMID:24997409

  1. Is lactate an undervalued functional component of fermented food products?

    PubMed Central

    Garrote, Graciela L.; Abraham, Analía G.; Rumbo, Martín

    2015-01-01

    Although it has been traditionally regarded as an intermediate of carbon metabolism and major component of fermented dairy products contributing to organoleptic and antimicrobial properties of food, there is evidence gathered in recent years that lactate has bioactive properties that may be responsible of broader properties of functional foods. Lactate can regulate critical functions of several key players of the immune system such as macrophages and dendritic cells, being able to modulate inflammatory activation of epithelial cells as well. Intraluminal levels of lactate derived from fermentative metabolism of lactobacilli have been shown to modulate inflammatory environment in intestinal mucosa. The molecular mechanisms responsible to these functions, including histone deacetylase dependent-modulation of gene expression and signaling through G-protein coupled receptors have started to be described. Since lactate is a major fermentation product of several bacterial families with probiotic properties, we here propose that it may contribute to some of the properties attributed to these microorganisms and in a larger view, to the properties of food products fermented by lactic acid bacteria. PMID:26150815

  2. Resist charging effect correction function qualification for photomasks production

    NASA Astrophysics Data System (ADS)

    Sidorkin, Vadim; Finken, Michael; Wandel, Timo; Nakayamada, Noriaki; Cantrell, G. R.

    2014-10-01

    We quantitatively evaluate Nuflare's latest resist charging effect correction (CEC) model for advanced photomask production using e-beam lithography. Functionality of this CEC model includes the simulation of static and timedependent charging effects together with an improved calibration method. CEC model calibration is performed by polynomial fitting of image placement distortions induced by various beam scattering effects on a special test design with writing density variations. CEC model parameters can be fine tuned for different photomask blank materials facilitating resist charging compensation maps for different product layers. Application of this CEC model into production yields a significant reduction in photomask image placement (IP), as well as improving photomask overlay between critical neighbouring layers. The correlations between IP improvement facilitated by this CEC model and single mask parameters are presented and discussed. The layer design specifics, resist and blank materials, coupled with their required exposure parameters are observed to be the major influences on CEC model performance.

  3. Affected functional networks associated with sentence production in classic galactosemia.

    PubMed

    Timmers, Inge; van den Hurk, Job; Hofman, Paul Am; Zimmermann, Luc Ji; Uludağ, Kâmil; Jansma, Bernadette M; Rubio-Gozalbo, M Estela

    2015-08-01

    Patients with the inherited metabolic disorder classic galactosemia have language production impairments in several planning stages. Here, we assessed potential deviations in recruitment and connectivity across brain areas responsible for language production that may explain these deficits. We used functional magnetic resonance imaging (fMRI) to study neural activity and connectivity while participants carried out a language production task. This study included 13 adolescent patients and 13 age- and gender-matched healthy controls. Participants passively watched or actively described an animated visual scene using two conditions, varying in syntactic complexity (single words versus a sentence). Results showed that patients recruited additional and more extensive brain regions during sentence production. Both groups showed modulations with syntactic complexity in left inferior frontal gyrus (IFG), a region associated with syntactic planning, and in right insula. In addition, patients showed a modulation with syntax in left superior temporal gyrus (STG), whereas the controls did not. Further, patients showed increased activity in right STG and right supplementary motor area (SMA). The functional connectivity data showed similar patterns, with more extensive connectivity with frontal and motor regions, and restricted and weaker connectivity with superior temporal regions. Patients also showed higher baseline cerebral blood flow (CBF) in right IFG and trends towards higher CBF in bilateral STG, SMA and the insula. Taken together, the data demonstrate that language abnormalities in classic galactosemia are associated with specific changes within the language network. These changes point towards impairments related to both syntactic planning and speech motor planning in these patients. PMID:25979518

  4. 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. PMID:26899179

  5. AB46. Screening and identification for the target genes of androgen receptor in mouse Sertoli cells

    PubMed Central

    Gui, Yaoting; Mou, Lisha; Zhang, Qiaoxia; Yang, Lihua; Wang, Yadong; Cai, Zhiming

    2014-01-01

    ubiquitylation, while downregulation of UBE2B blocked the testosterone-induced H2A ubiquitylation. The ubiquitylation of H2A was markedly decreased in the testes of S-AR mice by immunohistochemistry. Digital gene expression analysis showed that 113 genes were significantly down-regulated and 71 were up-regulated by UBE2B in TM4 cells. These results suggest that Ube2b, as a direct AR transcriptional target in Sertoli cells, mediates the function of AR in spermatogenesis by promoting H2A ubiquitylation. Our previous digital gene expression analysis data also showed that heat shock transcription factors 1 (HSF1) was regulated by androgen in mouse Sertoli cells. We found that the expression of Hsf1 was increased in the testes of S-AR mice compared with wild-type mice by quantitative real-time PCR and the expression of HSF1 in the S-ARSertoli cells was significantly increased as examined by immunofluorescence analysis. Besides, in vitro study showed that testosterone repressed the expression of Hsf1 in TM4 cells. Moreover, luciferase assay, electrophoretic mobility shift assay and chromatin immunoprecipitation assay showed that testosterone repressed Hsf1 expression by facilitating the binding of androgen receptor to Hsf1 promoter. Our experiment also demonstrated that testosterone downregulated the expression of heat shock protein HSP105 and HSP60 by inhibiting the transcription of Hsf1. Taken together, these results reveal that HSF1 is a novel target of androgen receptor in mouse Sertoli Cells, and testosterone and its receptor regulate the process of spermatogenesis partially by inhibiting HSF1 expression.

  6. The effect of anabolic-androgenic steroids on aromatase activity and androgen receptor binding in the rat preoptic area.

    PubMed

    Roselli, C E

    1998-05-11

    The level of aromatase in the preoptic area of rats is transcriptionally regulated through a specific androgen-receptor mediated mechanism and can be used as a measure of central androgenic effect. Therefore, several commonly abused anabolic-androgenic steroids (AAS) were tested for their ability to induce aromatase activity in the preoptic area of castrated rats. In addition, we determined the relative binding affinities of these compounds for the androgen receptor, as well as their ability to bind androgen receptor in vivo following subcutaneous injections. All of the AAS compounds tested significantly stimulated POA aromatase activity above castrate levels. The compounds that produced the greatest stimulation of aromatase activity were those that bound most avidly to the androgen receptor in vitro (i.e., testosterone, dihydrotestosterone and nandrolone). In contrast, the 17alpha-alkylated compounds that were tested (stanozolol, danazol, methandrostenolone) modestly stimulated aromatase and were weak competitors for the androgen receptor. The subcutaneous injection of AAS compounds increased the concentrations of occupied nuclear androgen receptors in the brain, but the magnitude of effect was not related to their potency for inducing aromatase or their relative binding affinity for the androgen receptor suggesting that androgen receptor occupancy in POA is not correlated with the action of androgen on aromatase. The present results help explain the behavioral effects of AAS compounds in rats. PMID:9593936

  7. Double Parton Fragmentation Function and its Evolution in Quarkonium Production

    NASA Astrophysics Data System (ADS)

    Kang, Zhong-Bo

    2014-01-01

    We summarize the results of a recent study on a new perturbative QCD factorization formalism for the production of heavy quarkonia of large transverse momentum pT at collider energies. Such a new factorization formalism includes both the leading power (LP) and next-to-leading power (NLP) contributions to the cross section in the mQ2/p_T^2 expansion for heavy quark mass mQ. For the NLP contribution, the so-called double parton fragmentation functions are involved, whose evolution equations have been derived. We estimate fragmentation functions in the non-relativistic QCD formalism, and found that their contribution reproduce the bulk of the large enhancement found in explicit NLO calculations in the color singlet model. Heavy quarkonia produced from NLP channels prefer longitudinal polarization, in contrast to the single parton fragmentation function. This might shed some light on the heavy quarkonium polarization puzzle.

  8. Metformin Inhibits Androgen-Induced IGF-IR Up-Regulation in Prostate Cancer Cells by Disrupting Membrane-Initiated Androgen Signaling

    PubMed Central

    Malaguarnera, Roberta; Sacco, Antonella; Morcavallo, Alaide; Squatrito, Sebastiano; Migliaccio, Antimo; Morrione, Andrea; Maggiolini, Marcello

    2014-01-01

    We have previously demonstrated that, in prostate cancer cells, androgens up-regulate IGF-I receptor (IGF-IR) by inducing cAMP-response element-binding protein (CREB) activation and CREB-dependent IGF-IR gene transcription through androgen receptor (AR)-dependent membrane-initiated effects. This IGF-IR up-regulation is not blocked by classical antiandrogens and sensitizes cells to IGF-I-induced biological effects. Metformin exerts complex antitumoral functions in various models and may inhibit CREB activation in hepatocytes. We, therefore, evaluated whether metformin may affect androgen-dependent IGF-IR up-regulation. In the AR+ LNCaP prostate cancer cells, we found that metformin inhibits androgen-induced CRE activity and IGF-IR gene transcription. CRE activity requires the formation of a CREB-CREB binding protein-CREB regulated transcription coactivator 2 (CRTC2) complex, which follows Ser133-CREB phosphorylation. Metformin inhibited Ser133-CREB phosphorylation and induced nuclear exclusion of CREB cofactor CRTC2, thus dissociating the CREB-CREB binding protein-CRTC2 complex and blocking its transcriptional activity. Similarly to metformin action, CRTC2 silencing inhibited IGF-IR promoter activity. Moreover, metformin blocked membrane-initiated signals of AR to the mammalian target of rapamycin/p70S6Kinase pathway by inhibiting AR phosphorylation and its association with c-Src. AMPK signals were also involved to some extent. By inhibiting androgen-dependent IGF-IR up-regulation, metformin reduced IGF-I-mediated proliferation of LNCaP cells. These results indicate that, in prostate cancer cells, metformin inhibits IGF-I-mediated biological effects by disrupting membrane-initiated AR action responsible for IGF-IR up-regulation and suggest that metformin could represent a useful adjunct to the classical antiandrogen therapy. PMID:24437490

  9. Biocatalysis for the production of industrial products and functional foods from rice and other agricultural produce.

    PubMed

    Akoh, Casimir C; Chang, Shu-Wei; Lee, Guan-Chiun; Shaw, Jei-Fu

    2008-11-26

    Many industrial products and functional foods can be obtained from cheap and renewable raw agricultural materials. For example, starch can be converted to bioethanol as biofuel to reduce the current demand for petroleum or fossil fuel energy. On the other hand, starch can also be converted to useful functional ingredients, such as high fructose and high maltose syrups, wine, glucose, and trehalose. The conversion process involves fermentation by microorganisms and use of biocatalysts such as hydrolases of the amylase superfamily. Amylases catalyze the process of liquefaction and saccharification of starch. It is possible to perform complete hydrolysis of starch by using the fusion product of both linear and debranching thermostable enzymes. This will result in saving energy otherwise needed for cooling before the next enzyme can act on the substrate, if a sequential process is utilized. Recombinant enzyme technology, protein engineering, and enzyme immobilization are powerful tools available to enhance the activity of enzymes, lower the cost of enzyme through large scale production in a heterologous host, increase their thermostability, improve pH stability, enhance their productivity, and hence making it competitive with the chemical processes involved in starch hydrolysis and conversions. This review emphasizes the potential of using biocatalysis for the production of useful industrial products and functional foods from cheap agricultural produce and transgenic plants. Rice was selected as a typical example to illustrate many applications of biocatalysis in converting low-value agricultural produce to high-value commercial food and industrial products. The greatest advantages of using enzymes for food processing and for industrial production of biobased products are their environmental friendliness and consumer acceptance as being a natural process. PMID:18942836

  10. Heterodimers and homodimers of inhibin subunits have different paracrine action in the modulation of luteinizing hormone-stimulated androgen biosynthesis

    SciTech Connect

    Hsueh, A.J.W.; Dahl, K.D.; Vaughan, J.; Tucker, E.; Rivier, J.; Bardin, C.W.; Vale, W.

    1987-07-01

    Inhibin, a gonadal hormone capable of preferential suppression of pituitary follicle-stimulating hormone (FSH) secretion, has recently been purified. The major form of this protein is an ..cap alpha beta.. heterodimer encoded by two separate genes. In contrast to the FSH-suppressing action of the ..cap alpha beta.. heterodimer, the ..beta beta.. homodimer stimulates FSH secretion. Luteinizing hormone (LH)-secreting pituitary cells and gonadal androgen-producing cells have long been shown to form a closed-loop feedback axis. Based on recent studies demonstrated the FSH stimulation of inhibin biosynthesis by ovarian granulosa and testis Sertoli cells, an additional closed-loop feedback axis exists between pituitary FSH- and gonadal inhibin-producing cells. Because uncharacterized Sertoli cell factors have been suggested to either stimulate or inhibit androgen production by testicular Leydig cells, the authors have tested the intragonadal paracrine actions of heterodimers and homodimers of inhibin subunits. In primary cultures of testis cells, the ..cap alpha beta.. heterodimer of inhibin enhances Leydig cell androgen biosynthesis stimulated by LH, whereas the ..beta beta.. homodimer suppresses androgen production. The data indicate that the inhibin-related gene products synthesized by Sertoli and granulosa cells may form heterodimers or homodimers to serve as intragonadal paracrine signals in the modulation of LH-stimulated androgen biosynthesis and allow cross-communication between the two feedback loops.

  11. Sarcopenia and Androgens: A Link between Pathology and Treatment

    PubMed Central

    Basualto-Alarcón, Carla; Varela, Diego; Duran, Javier; Maass, Rodrigo; Estrada, Manuel

    2014-01-01

    Sarcopenia, the age-related loss of skeletal muscle mass and function, is becoming more prevalent as the lifespan continues to increase in most populations. As sarcopenia is highly disabling, being associated with increased risk of dependence, falls, fractures, weakness, disability, and death, development of approaches to its prevention and treatment are required. Androgens are the main physiologic anabolic steroid hormones and normal testosterone levels are necessary for a range of developmental and biological processes, including maintenance of muscle mass. Testosterone concentrations decline as age increase, suggesting that low plasma testosterone levels can cause or accelerate muscle- and age-related diseases, as sarcopenia. Currently, there is increasing interest on the anabolic properties of testosterone for therapeutic use in muscle diseases including sarcopenia. However, the pathophysiological mechanisms underlying this muscle syndrome and its relationship with plasma level of androgens are not completely understood. This review discusses the recent findings regarding sarcopenia, the intrinsic, and extrinsic mechanisms involved in the onset and progression of this disease and the treatment approaches that have been developed based on testosterone deficiency and their implications. PMID:25566189

  12. Fish protein hydrolysates: production, biochemical, and functional properties.

    PubMed

    Kristinsson, H G; Rasco, B A

    2000-01-01

    Considerable amounts of fish processing byproducts are discarded each year. By developing enzyme technologies for protein recovery and modification, production of a broad spectrum of food ingredients and industrial products may be possible. Hydrolyzed vegetable and milk proteins are widely used food ingredients. There are few hydrolyzed fish protein foods with the exception of East Asian condiments and sauces. This review describes various manufacturing techniques for fish protein hydrolysates using acid, base, endogenous enzymes, and added bacterial or digestive proteases. The chemical and biochemical characteristics of hydrolyzed fish proteins are discussed. In addition, functional properties of fish protein hydrolysates are described, including solubility, water-holding capacity, emulsification, and foam-forming ability. Possible applications of fish protein hydrolysates in food systems are provided, and comparison with other food protein hydrolysates where pertinent. PMID:10674201

  13. Linking geophysics and soil function modelling - biomass production

    NASA Astrophysics Data System (ADS)

    Krüger, J.; Franko, U.; Werban, U.; Fank, J.

    2012-04-01

    The iSOIL project aims at reliable mapping of soil properties and soil functions with various methods including geophysical, spectroscopic and monitoring techniques. The general procedure contains three steps (i) geophysical monitoring, (ii) generation of soil property maps and (iii) process modelling. The objective of this work is to demonstrate the mentioned procedure with a focus on process modelling. It deals with the dynamics of soil water and the direct influence on crop biomass production. The new module PLUS extends CANDY to simulate crop biomass production based on environmental influences. A soil function modelling with an adapted model parameterisation based on data of ground penetration radar (GPR) and conductivity (EM38) was realized. This study shows an approach to handle heterogeneity of soil properties with geophysical data used for biomass production modelling. The Austrian field site Wagna is characterised by highly heterogenic soil with fluvioglacial gravel sediments. The variation of thickness of topsoil above a sandy subsoil with gravels strongly influences the soil water balance. EM38, mounted on a mobile platform, enables to rapidly scan large areas whereas GPR requires a greater logistical effort. However, GPR can detect exact soil horizon depth between topsoil and subsoil, the combination of both results in a detailed large scale soil map. The combined plot-specific GPR and field site EM38 measurements extends the soil input data and improves the model performance of CANDY PLUS for plant biomass production (Krüger et al. 2011). The example demonstrates how geophysics provides a surplus of data for agroecosystem modelling which identifies and contributes alternative options for agricultural management decisions. iSOIL - "Interactions between soil related sciences - Linking geophysics, soil science and digital soil mapping" is a Collaborative Project (Grant Agreement number 211386) co-funded by the Research DG of the European Commission

  14. Universal microscopic correlation functions for products of truncated unitary matrices

    NASA Astrophysics Data System (ADS)

    Akemann, Gernot; Burda, Zdzislaw; Kieburg, Mario; Nagao, Taro

    2014-06-01

    We investigate the spectral properties of the product of M complex non-Hermitian random matrices that are obtained by removing L rows and columns of larger unitary random matrices uniformly distributed on the group U(N + L). Such matrices are called truncated unitary matrices or random contractions. We first derive the joint probability distribution for the complex eigenvalues of the product matrix for fixed N, L, and M, given by a standard determinantal point process in the complex plane. The weight however is non-standard and can be expressed in terms of the Meijer G-function. The explicit knowledge of all eigenvalue correlation functions and the corresponding kernel allows us to take various large N (and L) limits at fixed M. At strong non-unitarity, with L/N finite, the eigenvalues condense on a domain inside the unit circle. At the edge and in the bulk we find the same universal microscopic kernel as for a single complex non-Hermitian matrix from the Ginibre ensemble. At the origin we find the same new universality classes labeled by M as for the product of M matrices from the Ginibre ensemble. Keeping a fixed size of truncation, L, when N goes to infinity leads to weak non-unitarity, with most eigenvalues on the unit circle as for unitary matrices. Here we find a new microscopic edge kernel that generalizes the known results for M = 1. We briefly comment on the case when each product matrix results from a truncation of different size Lj.

  15. Production of functional proteins: balance of shear stress and gravity

    NASA Technical Reports Server (NTRS)

    Goodwin, Thomas John (Inventor); Hammond, Timothy Grant (Inventor); Kaysen, James Howard (Inventor)

    2011-01-01

    A method for the production of functional proteins including hormones by renal cells in a three dimensional culturing process responsive to shear stress uses a rotating wall vessel. Natural mixture of renal cells expresses the enzyme 1-.alpha.-hydroxylase which can be used to generate the active form of vitamin D: 1,25-diOH vitamin D.sub.3. The fibroblast cultures and co-culture of renal cortical cells express the gene for erythropoietin and secrete erythropoietin into the culture supernatant. Other shear stress response genes are also modulated by shear stress, such as toxin receptors megalin and cubulin (gp280). Also provided is a method of treating an in-need individual with the functional proteins produced in a three dimensional co-culture process responsive to shear stress using a rotating wall vessel.

  16. Functional cereals for production in new and variable climates.

    PubMed

    Henry, Robert J; Rangan, Parimalan; Furtado, Agnelo

    2016-04-01

    Adaptation of cereal crops to variable or changing climates requires that essential quality attributes are maintained to deliver food that will be acceptable to human consumers. Advances in cereal genomics are delivering insights into the molecular basis of nutritional and functional quality traits in cereals and defining new genetic resources. Understanding the influence of the environment on expression of these traits will support the retention of these essential functional properties during climate adaptation. New cereals for use as whole grain or ground to flour for other food products may be based upon the traditional species such as rice and wheat currently used in these food applications but may also include new options exploiting genomics tools to allow accelerated domestication of new species. PMID:26828379

  17. Production of functional proteins: balance of shear stress and gravity

    NASA Technical Reports Server (NTRS)

    Goodwin, Thomas John (Inventor); Hammond, Timothy Grant (Inventor); Kaysen, James Howard (Inventor)

    2007-01-01

    The present invention provides a method for production of functional proteins including hormones by renal cells in a three dimensional co-culture process responsive to shear stress using a rotating wall vessel. Natural mixture of renal cells expresses the enzyme 1-a-hydroxylase which can be used to generate the active form of vitamin D: 1,25-diOH vitamin D3. The fibroblast cultures and co-culture of renal cortical cells express the gene for erythropoietin and secrete erythropoietin into the culture supernatant. Other shear stress response genes are also modulated by shear stress, such as toxin receptors megalin and cubulin (gp280). Also provided is a method of treating in-need individual with the functional proteins produced in a three dimensional co-culture process responsive to shear stress using a rotating wall vessel.

  18. Production of functional proteins: balance of shear stress and gravity

    NASA Technical Reports Server (NTRS)

    Goodwin, Thomas John (Inventor); Hammond, Timothy Grant (Inventor); Kaysen, James Howard (Inventor)

    2004-01-01

    The present invention provides a method for production of functional proteins including hormones by renal cells in a three dimensional co-culture process responsive to shear stress using a rotating wall vessel. Natural mixture of renal cells expresses the enzyme 1-a-hydroxylase which can be used to generate the active form of vitamin D: 1,25-diOH vitamin D3. The fibroblast cultures and co-culture of renal cortical cells express the gene for erythropoietin and secrete erythropoietin into the culture supernatant. Other shear stress response genes are also modulated by shear stress, such as toxin receptors megalin and cubulin (gp280). Also provided is a method of treating in-need individual with the functional proteins produced in a three dimensional co-culture process responsive to shear stress using a rotating wall vessel.

  19. Comparative Study of Antioxidant Status in Androgenic Embryos of Aesculus hippocastanum and Aesculus flava

    PubMed Central

    Štajner, Dubravka; Popović, Boris M.; Ćalić, Dušica; Štajner, Marijana

    2014-01-01

    In vivo (leaves and seed embryos) and in vitro (androgenic embryos) antioxidant scavenging activity of Aesculus hippocastanum and Aesculus flava medical plants was examined. Here we report antioxidant enzyme activities of superoxide dismutase, catalase, guaiacol peroxidase and glutathione peroxidase, reduced glutathione quantity, flavonoids, soluble protein contents, quantities of malondialdehyde, and •OH radical presence in the investigated plant samples. Total antioxidant capacity of all the samples of A. hippocastanum and A. flava was determined using FRAP, DPPH, and NO• radical scavenger capacity. The leaves of A. flava collected from the botanical garden exhibited stronger antioxidant activity (higher activities of SOD, and higher quantities of GSH, TSH, TPC, and scavenging abilities of DPPH and NO•, and higher FRAP values and lowest quantities of •OH and MDA) than in vitro obtained cultures. However, the leaves of A. flava showed higher antioxidant activity than the leaves of A. hippocastanum, and therefore they have a stronger tolerance of oxidative stress. Androgenic embryos of both species had low amount of antioxidants due to controlled in vitro environmental conditions (T, photoperiod, humidity, nutritive factors, and pathogen-free). Our results confirmed that we found optimal in vitro conditions for producing androgenic embryos of both Aesculus species. Also, we assume that horse chestnut androgenic embryos can be used as an alternative source for large-scale aescin production. PMID:24672369

  20. Comparative study of antioxidant status in androgenic embryos of Aesculus hippocastanum and Aesculus flava.

    PubMed

    Štajner, Dubravka; Popović, Boris M; Ćalić, Dušica; Št, Marijana

    2014-01-01

    In vivo (leaves and seed embryos) and in vitro (androgenic embryos) antioxidant scavenging activity of Aesculus hippocastanum and Aesculus flava medical plants was examined. Here we report antioxidant enzyme activities of superoxide dismutase, catalase, guaiacol peroxidase and glutathione peroxidase, reduced glutathione quantity, flavonoids, soluble protein contents, quantities of malondialdehyde, and (•)OH radical presence in the investigated plant samples. Total antioxidant capacity of all the samples of A. hippocastanum and A. flava was determined using FRAP, DPPH, and NO(•) radical scavenger capacity. The leaves of A. flava collected from the botanical garden exhibited stronger antioxidant activity (higher activities of SOD, and higher quantities of GSH, TSH, TPC, and scavenging abilities of DPPH and NO(•), and higher FRAP values and lowest quantities of (•)OH and MDA) than in vitro obtained cultures. However, the leaves of A. flava showed higher antioxidant activity than the leaves of A. hippocastanum, and therefore they have a stronger tolerance of oxidative stress. Androgenic embryos of both species had low amount of antioxidants due to controlled in vitro environmental conditions (T, photoperiod, humidity, nutritive factors, and pathogen-free). Our results confirmed that we found optimal in vitro conditions for producing androgenic embryos of both Aesculus species. Also, we assume that horse chestnut androgenic embryos can be used as an alternative source for large-scale aescin production. PMID:24672369

  1. Androgens and Androgen Derivatives: Science, Myths, and Theories: Explored From a Special Operations Perspective.

    PubMed

    Givens, Melissa L; Deuster, Patricia

    2015-01-01

    Androgen use outside of legitimate medical therapy is a perceived concern that is drawing attention across military and specifically Special Operations Forces (SOF) communities. For leadership and the medical community to properly address the issue and relate to those individuals who are using or considering use, it will be crucial to understand the scope of the problem. Limited data suggest that the prevalence of androgen use may be increasing, and inferences made from the scientific literature suggest that SOF may be a population of concern. While risks of androgen use are well known, there are little data specific to military performance that can be applied to a rigorous risk:benefit analysis, allowing myths and poorly supported theories to perpetuate within the community. Further efforts to define the potential benefits balanced against the short- and long-term risks should be undertaken. Providers within the SOF community should arm themselves with information to engage androgen users and leadership in meaningful discussion regarding androgen use. PMID:26360363

  2. Gene expression profile of androgen modulated genes in the murine fetal developing lung

    PubMed Central

    2010-01-01

    Background Accumulating evidences suggest that sex affects lung development. Indeed, a higher incidence of respiratory distress syndrome is observed in male compared to female preterm neonates at comparable developmental stage and experimental studies demonstrated an androgen-related delay in male lung maturation. However, the precise mechanisms underlying these deleterious effects of androgens in lung maturation are only partially understood. Methods To build up a better understanding of the effect of androgens on lung development, we analyzed by microarrays the expression of genes showing a sexual difference and those modulated by androgens. Lungs of murine fetuses resulting from a timely mating window of 1 hour were studied at gestational day 17 (GD17) and GD18, corresponding to the period of surge of surfactant production. Using injections of the antiandrogen flutamide to pregnant mice, we hunted for genes in fetal lungs which are transcriptionally modulated by androgens. Results Results revealed that 1844 genes were expressed with a sexual difference at GD17 and 833 at GD18. Many genes were significantly modulated by flutamide: 1597 at GD17 and 1775 at GD18. Datasets were analyzed by using in silico tools for reconstruction of cellular pathways. Between GD17 and GD18, male lungs showed an intensive transcriptional activity of proliferative pathways along with the onset of lung differentiation. Among the genes showing a sex difference or an antiandrogen modulation of their expression, we specifically identified androgen receptor interacting genes, surfactant related genes in particularly those involved in the pathway leading to phospholipid synthesis, and several genes of lung development regulator pathways. Among these latter, some genes related to Shh, FGF, TGF-beta, BMP, and Wnt signaling are modulated by sex and/or antiandrogen treatment. Conclusion Our results show clearly that there is a real delay in lung maturation between male and female in this period

  3. Relationships Between Androgens, Serotonin Gene Expression and Innervation in Male Macaques

    PubMed Central

    Bethea, Cynthia L.; Coleman, Kristine; Phu, Kenny; Reddy, Arubala P.; Phu, Andy

    2014-01-01

    Androgen administration to castrated individuals was purported to decrease activity in the serotonin system. However, we found that androgen administration to castrated male macaques increased fenfluramine-induced serotonin release as reflected by increased prolactin secretion. In this study, we sought to define the effects of androgens and aromatase inhibition on serotonin-related gene expression in the dorsal raphe, as well as serotonergic innervation of the LC. Male Japanese macaques (Macaca fuscata) were castrated for 5–7 months and then treated for 3 months with [1] placebo, [2] testosterone (T), [3] dihydrotestosterone (DHT; non- aromatizable androgen) and ATD (steroidal aromatase inhibitor), or [4] Flutamide (FLUT; androgen antagonist) and ATD (n=5/group). This study reports the expression of serotonin-related genes: tryptophan hydroxylase 2 (TPH2), serotonin reuptake transporter (SERT) and the serotonin 1A autoreceptor (5HT1A) using digoxigenin-ISH and image analysis. To examine the production of serotonin and the serotonergic innervation of a target area underlying arousal and vigilance, we measured the serotonin axon density entering the LC with ICC and image analysis. TPH2 and SERT expression were significantly elevated in T- and DHT+ATD- treated groups over placebo- and FLUT+ATD- treated groups in the dorsal raphe (p<0.007). There was no difference in 5HT1A expression between the groups. There was a significant decrease in the pixel area of serotonin axons and in the number of varicosities in the LC across the treatment groups with T > placebo >DHT+ATD = FLUT+ATD treatments. Comparatively, T- and DHT+ATD -treated groups had elevated TPH2 and SERT gene expression, but the DHT+ATD group had markedly suppressed serotonin axon density relative to the T-treated group. Further comparison with previously published data indicated that TPH2 and SERT expression reflected yawning and basal prolactin secretion. The serotonin axon density in the LC agreed with the

  4. Probiotics and its functionally valuable products-a review.

    PubMed

    Kanmani, Paulraj; Satish Kumar, R; Yuvaraj, N; Paari, K A; Pattukumar, V; Arul, Venkatesan

    2013-01-01

    During the past two decades probiotic bacteria have been increasingly proposed as health promoting bacteria in variety of food system, because of its safety, functional, and technological characteristics. Commonly, Lactobacillus spp., Bifidobacterium spp., Saccharomyces boulardii, and some other microorganisms have been considered as probiotic strains. Possibly these bacterial strains exerted several beneficial effects into gastrointestinal tract of host while administered with variety of food system. Lactic acid bacteria (LAB) usually produce antimicrobial substances like bacteriocin which have broad spectrum of antagonist effect against closely related Gram positive and Gram negative pathogens. LAB strains often produce polymeric substances such as exopolysaccharides (EPS) which increase the colonization of probiotic bacteria by cell-cell interactions in gastrointestinal tract. LAB also produces biosurfactant which showed that the wide range of antimicrobial activity against bacterial pathogen as well as its antiadhesive properties reduces the adhesion of pathogens into gastric wall membrane. Furthermore, LAB strains have also been reported for production of antioxidants which are ability to scavenge the free radicals such as superoxide anions and hydroxyl radicals. For this sense, this review article is mainly focused on the ecology, biosynthesis, genetics, target sites, and applications of bacteriocins and EPS from LAB strains. Moreover, this review discusses about the production and functions of nutritive essential element folate and iron chelating agent such as siderophores from LAB. PMID:23627505

  5. Design of smart functional apparel products for moxa moxibustion

    NASA Astrophysics Data System (ADS)

    Li, Li; Au, Wai-man; Ding, Feng; Wong, Kwok-shing

    2013-08-01

    Moxa Moxibustion is a common traditional Chinese therapy in which burning Moxa is applied to affected body areas. This method has been employed for thousands of years to achieve certain medical objectives, such as pain relief or antibacterial and anti-inflammatory effects. Its therapeutic effectiveness has been demonstrated successfully both in research and clinical studies. However, this traditional approach may cause undesirable side effects, for example: 1) burning of Moxa produces by-products such as smoke and ash; 2) patients are at risk of being burnt; 3) the active ingredients of the Moxa leaf oil are volatile, odorous, unstable in air and easy to dissipate, and difficult to store and transport; 4) it is inconvenient to operate. These side effects limit its further high-potential and high-value applications. This study is aimed at developing a multi-functional smart textile system that will adopt smart fabrics containing encapsulated Moxa oil integrated with thermally conductive materials to replace the conventional Moxa products. This will efficiently deliver the active ingredients of Moxa to a human body at optimum conditions, i.e., in a precise and controllable way, with maximum convenience and a high level of comfort. Doing so would solve the existing problems mentioned above. Both garment design skill and textile technology will be applied to Moxa Moxibustion textile to enhance the aesthetics and functionality. The smart garment performance will be assessed subjectively in a clinical trial and objectively by a number of instrumental methods.

  6. Mental rotation in intellectually gifted boys is affected by the androgen receptor CAG repeat polymorphism.

    PubMed

    Durdiaková, Jaroslava; Lakatošová, Silvia; Kubranská, Aneta; Laznibatová, Jolana; Ficek, Andrej; Ostatníková, Daniela; Celec, Peter

    2013-08-01

    Testosterone was shown to organize brain and modulate cognitive functions. It is currently unknown whether mental rotation is also associated with prenatal testosterone exposure and testosterone-related genetic polymorphisms. The aim of our study was to analyze associations between mental rotation performance, the actual testosterone levels, the prenatal testosterone level (expressed as 2D:4D ratio) and the androgen receptor CAG repeat polymorphism in intellectually gifted boys. One hundred forty-seven boys aged 10-18 years with IQ>130 were enrolled. Saliva samples were collected and used for ELISA of actual levels of salivary testosterone. The 2D:4D finger length ratio as an indicator of prenatal testosterone was measured on both hands and averaged. Amthauer mental rotation test was used for the assessment of this spatial ability. The CAG repeat polymorphism in the androgen receptor gene was analyzed using PCR and capillary electrophoresis. Linear regression revealed that 2D:4D finger length ratio and the number of CAG repeats in the androgen receptor gene were associated with mental rotation. Actual levels of testosterone did not correlate significantly with mental rotation. Multivariate analysis of covariance revealed that after adjustment of age as a confounding variable, only the effect of the genetic polymorphism was significant. The results are in line with our previous genetic analysis of intellectually gifted boys showing the importance of CAG repeat polymorphism in the androgen receptor gene. Details of the interactions between androgen signaling, testosterone levels and its metabolism especially during the prenatal development of brain function remain to be elucidated. PMID:23727571

  7. Androgen receptor gene polymorphism in zebra species

    PubMed Central

    Ito, Hideyuki; Langenhorst, Tanya; Ogden, Rob; Inoue-Murayama, Miho

    2015-01-01

    Androgen receptor genes (AR) have been found to have associations with reproductive development, behavioral traits, and disorders in humans. However, the influence of similar genetic effects on the behavior of other animals is scarce. We examined the loci AR glutamine repeat (ARQ) in 44 Grevy's zebras, 23 plains zebras, and three mountain zebras, and compared them with those of domesticated horses. We observed polymorphism among zebra species and between zebra and horse. As androgens such as testosterone influence aggressiveness, AR polymorphism among equid species may be associated with differences in levels of aggression and tameness. Our findings indicate that it would be useful to conduct further studies focusing on the potential association between AR and personality traits, and to understand domestication of equid species. PMID:26236645

  8. Rheumatoid arthritis, the contraceptive pill, and androgens.

    PubMed

    James, W H

    1993-06-01

    Evidence is accumulating that low androgen concentrations are a cause of rheumatoid arthritis. This would explain a number of established features of the epidemiology of the disease. These include: (a) the variation of disease activity with pregnancy; (b) the variation of age at onset by sex; (c) the variation by sex with HLA-B15; (d) the association with bone mineral density; and (e) the differing time trends in incidence rates by sex. It is argued, moreover, that if one makes a plausible assumption--namely, that women who choose oral contraceptives have high androgen concentrations at the time they first make this choice--then an explanation becomes available for the confusion about the relation between rheumatoid arthritis and oral contraception. Grounds are adduced for that assumption. If this line of reasoning is substantially correct it also has implications for the relations between rheumatoid arthritis and smoking and consumption of alcohol. PMID:8323402

  9. Molecular cloning of canine co-chaperone small glutamine-rich tetratricopeptide repeat-containing protein α (SGTA) and investigation of its ability to suppress androgen receptor signalling in androgen-independent prostate cancer.

    PubMed

    Kato, Yuiko; Ochiai, Kazuhiko; Michishita, Masaki; Azakami, Daigo; Nakahira, Rei; Morimatsu, Masami; Ishiguro-Oonuma, Toshina; Yoshikawa, Yasunaga; Kobayashi, Masato; Bonkobara, Makoto; Kobayashi, Masanori; Takahashi, Kimimasa; Watanabe, Masami; Omi, Toshinori

    2015-11-01

    Although the morbidity of canine prostate cancer is low, the majority of cases present with resistance to androgen therapy and poor clinical outcomes. These pathological conditions are similar to the signs of the terminal stage of human androgen-independent prostate cancer. The co-chaperone small glutamine-rich tetratricopeptide repeat-containing protein α (SGTA) is known to be overexpressed in human androgen-independent prostate cancer. However, there is little information about the structure and function of canine SGTA. In this study, canine SGTA was cloned and analysed for its ability to suppress androgen receptor signalling. The full-length open reading frame (ORF) of the canine SGTA gene was amplified by RT-PCR using primers designed from canine-expressed sequence tags that were homologous to human SGTA. The canine SGTA ORF has high homology with the corresponding human (89%) and mouse (81%) sequences. SGTA dimerisation region and tetratricopeptide repeat (TPR) domains are conserved across the three species. The ability of canine SGTA to undergo homodimerisation was demonstrated by a mammalian two-hybrid system and a pull-down assay. The negative impact of canine SGTA on androgen receptor (AR) signalling was demonstrated using a reporter assay in androgen-independent human prostate cancer cell lines. Pathological analysis showed overexpression of SGTA in canine prostate cancer, but not in hyperplasia. A reporter assay in prostate cells demonstrated suppression of AR signalling by canine SGTA. Altogether, these results suggest that canine SGTA may play an important role in the acquisition of androgen independence by canine prostate cancer cells. PMID:26346258

  10. Androgens modulate gene expression and specific DNA methylation pattern of steroid 5α-reductases in the frog Silurana tropicalis.

    PubMed

    Bissegger, Sonja; Langlois, Valerie S

    2016-08-01

    In vertebrates, androgens are essential in many biological functions, including reproduction, immune system, metabolism, cardiovascular function, and the central nervous system. The most potent androgen 5α-dihydrotestosterone (5α-DHT), which is actively involved in sexual differentiation and development, is converted from testosterone (T) by the steroid 5α-reductases type 1, 2, and 3 (Srd5α1, Srd5α2, and Srd5α3). Alternatively, steroid 5β-reductase (Srd5β) converts T to 5β-dihydrotestosterone (5β-DHT), a metabolite believed to be involved in steroid clearance. Recent studies suggested that Srd5 isoforms are targets for endocrine disruption. Thus, understanding the regulation of Srd5 is important to expand our knowledge on how exogenous compounds can interfere with these enzymes. In this study, we exposed frog brain, liver, and gonads ex vivo to T, 5α-DHT, and 5β-DHT in order to investigate the regulation of srd5 in response to androgens as a simulation of endocrine disrupting chemicals with androgenic properties. Androgens did not modulate srd5α2, suggesting that this isoform is not regulated by T and 5α-DHT in frogs. However, the DNA methylation of srd5α2 increased following 5α-DHT treatment suggesting that androgens can modulate epigenetic mechanisms in amphibians. In contrast, the DNA methylation of srd5α1 and srd5α3 remained stable after androgen exposure, but the mRNA levels of srd5α1 and srd5α3 were modulated by T, 5α-DHT, and 5β-DHT in a sex- and tissue-specific manner. While T positively regulates srd5α1 and srd5α3 in testes, T negatively regulates srd5α3 in ovaries. Moreover, exposure to T also increased the mRNA level of srd5β in the male brain suggesting a mechanism to protect the brain from androgen action by elimination of T into 5β-DHT. Thus, exogenous compounds with androgenic properties potentially interact with srd5 transcription and DNA methylation pattern, which could adversely affect biological functions of vertebrates

  11. Position stand on androgen and human growth hormone use.

    PubMed

    Hoffman, Jay R; Kraemer, William J; Bhasin, Shalender; Storer, Thomas; Ratamess, Nicholas A; Haff, G Gregory; Willoughby, Darryn S; Rogol, Alan D

    2009-08-01

    Hoffman, JR, Kraemer, WJ, Bhasin, S, Storer, T, Ratamess, NA, Haff, GG, Willoughby, DS, and Rogol, AD. Position stand on Androgen and human growth hormone use. J Strength Cond Res 23(5): S1-S59, 2009-Perceived yet often misunderstood demands of a sport, overt benefits of anabolic drugs, and the inability to be offered any effective alternatives has fueled anabolic drug abuse despite any consequences. Motivational interactions with many situational demands including the desire for improved body image, sport performance, physical function, and body size influence and fuel such negative decisions. Positive countermeasures to deter the abuse of anabolic drugs are complex and yet unclear. Furthermore, anabolic drugs work and the optimized training and nutritional programs needed to cut into the magnitude of improvement mediated by drug abuse require more work, dedication, and preparation on the part of both athletes and coaches alike. Few shortcuts are available to the athlete who desires to train naturally. Historically, the NSCA has placed an emphasis on education to help athletes, coaches, and strength and conditioning professionals become more knowledgeable, highly skilled, and technically trained in their approach to exercise program design and implementation. Optimizing nutritional strategies are a vital interface to help cope with exercise and sport demands (). In addition, research-based supplements will also have to be acknowledged as a strategic set of tools (e.g., protein supplements before and after resistance exercise workout) that can be used in conjunction with optimized nutrition to allow more effective adaptation and recovery from exercise. Resistance exercise is the most effective anabolic form of exercise, and over the past 20 years, the research base for resistance exercise has just started to develop to a significant volume of work to help in the decision-making process in program design (). The interface with nutritional strategies has been less

  12. Binding kinetics and physical properties of androgen receptor in androgen-dependent Shionogi mammary carcinoma 115.

    PubMed

    Nohno, T

    1981-02-01

    The characteristics of the androgen receptor in the cytoplasmic fraction of Shionogi carcinoma 115 were studied in vitro by means of charcoal adsorption assay, sucrose density gradient centrifugation, and polyacrylamide gel electrophoresis. The equilibrium dissociation constant for [3H]dihydrotestosterone (Kd = (2-5) X 10(-11) M) was estimated from independently determined rates of association and dissociation, and was lower by one order of magnitude than the value obtained by saturation analysis (Kd = (2-8) X 10(-10) M). Evaluation of the effect of temperature on receptor binding of androgen allowed the estimation of several thermodynamic parameters, including activation energies of association (4 kcal/mol) and dissociation (14 kcal/mol), the apparent free energy (-13 kcal/mol), enthalpy (-9 kcal/mol), and entropy (+14 cal/mol per K). The receptor was greatly stabilized when bound with androgen. The results indicate how the lability of the unbound receptor and slow rate of dihydrotestosterone-receptor interaction can influence the estimation of dissociation constants by usual saturation analysis. The sedimentation coefficient of androgen receptor in freshly prepared cytosol was 6S, and became 7S after storage for 2 months at -80 degrees C. The 7S conversion of the receptor was reversed by treatment with heparin. In all cases, a single 5S peak was obtained in the presence of 0.5 M KCl. On electrophoresis in heparin-containing polyacrylamide gel, protein-bound radioactive androgen migrated as a single peak (Rf = 0.5 in 5% gel). Differences in reported values for the sedimentation coefficient of androgen receptor in cytosol of Shionogi carcinoma 115 appear to be derived from aggregation of the receptor protein during the assay procedure. PMID:7240130

  13. When color fails: illicit blue tablets containing anabolic androgen steroids.

    PubMed

    Favretto, Donata; Castagna, Franca; Maietti, Sergio; Boscolo-Berto, Rafael; Ferrara, Santo Davide

    2013-09-01

    The necessity of specific, confirmatory tests in the identification of seized illicit products was highlighted by the analysis of eighteen heart shaped, blue tablets confiscated by Police at a street control in the North East of Italy. The tablets responded as amphetamines to a preliminary color test (Marquis); a subsequent, confirmatory assay by gas chromatography-mass spectrometry revealed the presence of two anabolic androgen steroids (AAS), methandienone and methyltestosterone, in concentration of 1.7 and 1.5mg respectively per tablet; no trace of amphetamine-like or nitrogen containing compounds was found. The observed orange coloration was due to the reaction of concentrated sulphuric acid, contained in the Marquis reagent, with the Δ(4) C-3 keto group of steroids. The two AAS, banned under the world antidoping code, are not considered as psychoactive drugs of abuse in most countries, although their trafficking may entangle severe public health concerns. PMID:23770638

  14. Natural Product Discovery through Improved Functional Metagenomics in Streptomyces.

    PubMed

    Iqbal, Hala A; Low-Beinart, Lila; Obiajulu, Joseph U; Brady, Sean F

    2016-08-01

    Because the majority of environmental bacteria are not easily culturable, access to many bacterially encoded secondary metabolites will be dependent on the development of improved functional metagenomic screening methods. In this study, we examined a collection of diverse Streptomyces species for the best innate ability to heterologously express biosynthetic gene clusters. We then optimized methods for constructing high quality metagenomic cosmid libraries in the best Streptomyces host. An initial screen of a 1.5 million-membered metagenomic library constructed in Streptomyces albus, the species that exhibited the highest propensity for heterologous expression of gene clusters, led to the identification of the novel natural product metatricycloene (1). Metatricycloene is a tricyclic polyene encoded by a reductive, iterative polyketide-like gene cluster. Related gene clusters found in sequenced genomes appear to encode a largely unexplored collection of structurally diverse, polyene-based metabolites. PMID:27447056

  15. Androgen mediated translational and postranslational regulation of IGFBP-2 in androgen-sensitive LNCaP human prostate cancer cells

    PubMed Central

    DeGraff, David J; Aguiar, Adam A; Chen, Qian; Adams, Lisa K; Williams, B. Jill; Sikes, Robert A

    2010-01-01

    The insulin-like growth factor (IGF) axis is associated intimately with prostate cancer (PCa) development, growth, survival and metastasis. In particular, increased levels of IGFBP-2 expression are associated with advanced PCa, bone metastasis, and the development of castrate resistant PCa. Previously, we reported that androgen treatment decreased intracellular and extracellular IGFBP-2 in the androgen sensitive (AS) PCa cell line, LNCaP. Nonetheless, the mechanism by which androgen treatment decreases expression of IGFBP-2 is not clear. Since elevated IGFBP-2 is associated with a variety of advanced cancers, including PCa, coupled with the fact that hormone ablation is the customary treatment modality for advanced PCa, a complete understanding of the influence of androgens on IGFBP-2 expression is essential. Androgen treatment initially increased steady state IGFBP-2 mRNA levels in LNCaP cells. Extended androgen treatment on LNCaP resulted in a time-dependent decrease in both steady state IGFBP-2 mRNA and protein. Polysomal mRNA analysis showed no difference in IGFBP-2 association with a given fraction; however, Q-PCR revealed less IGFBP-2 mRNA in each androgen-treated fraction. In addition, there was an overall decrease in polysome mRNA after androgen treatment. Extracellular proteolysis of IGFBP-2 was prevented in the presence of serine protease inhibitors. These data indicate that androgen acts via multiple levels to down-regulate IGFBP-2 in LNCaP PCa cells. PMID:20407609

  16. Effect of AQP9 Expression in Androgen-Independent Prostate Cancer Cell PC3

    PubMed Central

    Chen, Qiwei; Zhu, Liang; Zheng, Bo; Wang, Jinliang; Song, Xishuang; Zheng, Wei; Wang, Lina; Yang, Deyong; Wang, Jianbo

    2016-01-01

    It is known that aquaporin 9 (AQP9) in the prostate was strictly upregulated by androgen and may represent a novel therapeutic target for several cancers, but whether AQP9 plays a role in the regulation of androgen-independent prostate cancer still remains unclear. In the present study, AQP9 was determined in prostate cancer and adjacent cancer tissues; AQP9-siRNA was applied to silencing AQP9 in androgen-independent prostate cancer cell PC3 cell line. Western blot and flow cytometry analysis were employed to detect changes in related-function of control and AQP9-siRNA groups. The results showed that AQP9 is significantly induced in cancer tissues than that in adjacent cancer tissues. Moreover, knockdown of AQP9 in PC3 androgen-independent prostate cancer cell prostate cancer cells increased inhibition rates of proliferation. In addition, knockdown of AQP9 resulted in a significant decrease in the expression of the Bcl-2 and with a notable increase in the expression of Bax and cleaved caspase 3, indicated that AQP9 knockdown promoted apoptosis in prostate cancer cells. From wound healing assay and matrigel invasion, we suggested that AQP9 expression affects the motility and invasiveness of prostate cancer cells. Moreover, In order to explore the pathway may be involved in AQP9-mediated motility and invasion of prostate cancer cells, the phosphorylation of ERK1/2 was significant suppressed in AQP9 siRNA-transfected cells compared with that in control cells, suggesting that AQP9 is involved in the activation of the ERK pathway in androgen-independent prostate cancer cells. PMID:27187384

  17. Role of androgen and vitamin D receptors in endothelial cells from benign and malignant human prostate

    PubMed Central

    Chung, Ivy; Montecinos, Viviana P.; Buttyan, Ralph; Johnson, Candace S.; Smith, Gary J.

    2013-01-01

    Forty years ago, Judah Folkman (Folkman. N Engl J Med 285: 1182–1186, 1971) proposed that tumor growth might be controlled by limiting formation of new blood vessels (angiogenesis) needed to supply a growing tumor with oxygen and nutrients. To this end, numerous “antiangiogenic” agents have been developed and tested for therapeutic efficacy in cancer patients, including prostate cancer (CaP) patients, with limited success. Despite the lack of clinical efficacy of lead anti-angiogenic therapeutics in CaP patients, recent published evidence continues to support the idea that prostate tumor vasculature provides a reasonable target for development of new therapeutics. Particularly relevant to antiangiogenic therapies targeted to the prostate is the observation that specific hormones can affect the survival and vascular function of prostate endothelial cells within normal and malignant prostate tissues. Here, we review the evidence demonstrating that both androgen(s) and vitamin D significantly impact the growth and survival of endothelial cells residing within prostate cancer and that systemic changes in circulating androgen or vitamin D drastically affect blood flow and vascularity of prostate tissue. Furthermore, recent evidence will be discussed about the expression of the receptors for both androgen and vitamin D in prostate endothelial cells that argues for direct effects of these hormone-activated receptors on the biology of endothelial cells. Based on this literature, we propose that prostate tumor vasculature represents an unexplored target for modulation of tumor growth. A better understanding of androgen and vitamin D effects on prostate endothelial cells will support development of more effective angiogenesis-targeting therapeutics for CaP patients. PMID:23548616

  18. Androgens increase spine synapse density in the CA1 hippocampal subfield of ovariectomized female rats.

    PubMed

    Leranth, Csaba; Hajszan, Tibor; MacLusky, Neil J

    2004-01-14

    The effects of androgen on the density of spine synapses on pyramidal neurons in the CA1 area of the hippocampus were studied in ovariectomized (OVX) adult female rats. Treatment of OVX rats with testosterone propionate (TP; 500 microg/d, s.c., 2 d) significantly increased spine synapse density (from 0.661 +/- 0.016 spine synapse/microm3 in OVX rats to 1.081 +/- 0.018 spine synapse/microm3 after TP treatment). A smaller, but still statistically significant, increase in synapse density (0.955 +/- 0.029 spine synapse/microm3) was observed in OVX animals after treatment with the nonaromatizable androgen dihydrotestosterone (DHT; 500 microg/d, s.c., 2 d). Administration of 1 mg of letrozole, a powerful nonsteroidal aromatase inhibitor, 1 hr before the steroid injections almost completely blocked the synaptic response to testosterone, resulting in a mean synapse density (0.723 +/- 0.003 spine synapse/microm3) only slightly higher than in OVX control rats. By contrast, the response to DHT was unaffected by letrozole pretreatment. These data suggest that androgen secretion during the female reproductive cycle may contribute to cyclical changes in hippocampal synaptic density. They also indicate that androgen treatment may be as effective as estrogen replacement in reversing the decline in hippocampal CA1 spine synapses that follows loss of ovarian function. Induction of hippocampal synapse formation by androgen is not mediated entirely via intracerebral estrogen biosynthesis, however, because aromatase-independent mechanisms also significantly affect CA1 spine synapse density. PMID:14724248

  19. TRPM8 channel as a novel molecular target in androgen-regulated prostate cancer cells.

    PubMed

    Asuthkar, Swapna; Velpula, Kiran Kumar; Elustondo, Pia A; Demirkhanyan, Lusine; Zakharian, Eleonora

    2015-07-10

    The cold and menthol receptor TRPM8 is highly expressed in prostate and prostate cancer (PC). Recently, we identified that TRPM8 is as an ionotropic testosterone receptor. The TRPM8 mRNA is expressed in early prostate tumors with high androgen levels, while anti-androgen therapy greatly reduces its expression. Here, from the chromatin-immunoprecipitation (ChIP) analysis, we found that an androgen response element (ARE) mediates androgen regulation of trpm8. Furthermore, using immunofluorescence, calcium-imaging and planar lipid bilayers, we identified that TRPM8 channel is functionally regulated by androgens in the prostate. Although TRPM8 mRNA is expressed at high levels, we found that the TRPM8 protein undergoes ubiquitination and degradation in PC cells. The mass-spectrometry analysis of TRPM8, immunoprecipitated from LNCaP cells identified ubiquitin-like modifier-activating enzyme 1 (UBA1). PYR-41, a potent inhibitor of initial enzyme in the ubiquitination cascade, UBA1, increased TRPM8 activity on the plasma membrane (PM) of LNCaP cells. Furthermore, PYR-41-mediated PMTRPM8 activity was accompanied by enhanced activation of p53 and Caspase-9. Interestingly, we found that the trpm8 promoter possesses putative binding sites for p53 and that the overexpression of p53 increased the TRPM8 mRNA levels. In addition to the genomic regulation of TRPM8 by AR and p53, our findings indicate that the testosterone-induced PMTRPM8 activity elicits Ca2+ uptake, subsequently causing apoptotic cell death. These findings support the strategy of rescuing PMTRPM8 expression as a new therapeutic application through the regulation of PC cell growth and proliferation. PMID:25980497

  20. TRPM8 channel as a novel molecular target in androgen-regulated prostate cancer cells

    PubMed Central

    Asuthkar, Swapna; Velpula, Kiran Kumar; Elustondo, Pia A.; Demirkhanyan, Lusine; Zakharian, Eleonora

    2015-01-01

    The cold and menthol receptor TRPM8 is highly expressed in prostate and prostate cancer (PC). Recently, we identified that TRPM8 is as an ionotropic testosterone receptor. The TRPM8 mRNA is expressed in early prostate tumors with high androgen levels, while anti-androgen therapy greatly reduces its expression. Here, from the chromatin-immunoprecipitation (ChIP) analysis, we found that an androgen response element (ARE) mediates androgen regulation of trpm8. Furthermore, using immunofluorescence, calcium-imaging and planar lipid bilayers, we identified that TRPM8 channel is functionally regulated by androgens in the prostate. Although TRPM8 mRNA is expressed at high levels, we found that the TRPM8 protein undergoes ubiquitination and degradation in PC cells. The mass-spectrometry analysis of TRPM8, immunoprecipitated from LNCaP cells identified ubiquitin-like modifier-activating enzyme 1 (UBA1). PYR-41, a potent inhibitor of initial enzyme in the ubiquitination cascade, UBA1, increased TRPM8 activity on the plasma membrane (PM) of LNCaP cells. Furthermore, PYR-41-mediated PMTRPM8 activity was accompanied by enhanced activation of p53 and Caspase-9. Interestingly, we found that the trpm8 promoter possesses putative binding sites for p53 and that the overexpression of p53 increased the TRPM8 mRNA levels. In addition to the genomic regulation of TRPM8 by AR and p53, our findings indicate that the testosterone-induced PMTRPM8 activity elicits Ca2+ uptake, subsequently causing apoptotic cell death. These findings support the strategy of rescuing PMTRPM8 expression as a new therapeutic application through the regulation of PC cell growth and proliferation. PMID:25980497

  1. Pharmacological characterization of an imidazolopyrazole as novel selective androgen receptor modulator.

    PubMed

    Zhang, Xuqing; Allan, George F; Tannenbaum, Pamela; Sbriscia, Tifanie; Linton, Olivia; Lai, Muh-Tsann; Haynes-Johnson, Donna; Bhattacharjee, Sheela; Lundeen, Scott G; Sui, Zhihua

    2013-03-01

    Selective androgen receptor modulators (SARMs) are androgens with tissue-selective activity. SARMs that have anabolic activity on muscle while having minimal stimulatory activity on prostate are classified as SARM agonists. They can be used to prevent the loss of lean body mass that is associated with cancer, immunodeficiency, renal disease and aging. They may also have anabolic activity on bone; thus, unlike estrogens, they may reverse the loss of bone strength associated with aging or hypogonadism. Our in-house effort on SARM program discovers a nonsteroidal androgen receptor ligand with a unique imidazolopyrazole moiety in its structure. In vitro, this compound is a weak androgen receptor binder and a weak androgen agonist. Despite this, in orchidectomized mature rats it is an effective SARM agonist, with an ED(50) on levator ani muscle of 3.3mg/kg and an ED(50) on ventral prostate of >30mg/kg. It has its maximal effect on muscle at the dose of 10mg/kg. In addition, this compound has mixed agonistic and antagonistic activities on prostate, reducing the weight of that tissue in intact rats by 22% at 10mg/kg. The compound does not have significant effect on gonadotropin levels or testosterone levels in both orchidectomized and intact male rats. It does not have notable progestin, estrogen or glucocorticoid agonistic or antagonistic activity in rats. In a female sexual behavior model, it improves the sexual desire of ovariectomized female rats for sexually mature intact males over nonsexually ovariectomized females. Overall, the imidazolopyrazole is a potent prostate-sparing candidate for development as a SARM agonist with an appropriate pharmacological profile for clinical benefit in muscle-wasting conditions and female sexual function disorders. PMID:23098693

  2. Groundwater productivity potential mapping using evidential belief function.

    PubMed

    Park, Inhye; Kim, Yongsung; Lee, Saro

    2014-09-01

    The evidential belief function (EBF) model was applied and validated for analysis of groundwater-productivity potential (GPP) in Boryeong and Pohang cities, agriculture region in Korea using geographic information systems (GIS). Data about related factors, including topography, lineament, geology, forest, soil, and groundwater data were collected and input into a spatial database. Additionally, in the Boryeong area, specific capacity (SPC) data not lower than 4.55 m3 /d/m were collected, corresponding to 300 m3 /d yield from 72 well locations. In the Pohang area, SPC data of ≥ 6.25 m3 /d/m were collected, corresponding to a yield of 500 m3 /d from 44 well locations. By using the constructed spatial database, 19 factors related to groundwater productivity were extracted. The relationships between the well locations and the factors were identified and quantified by using the EBF model. Four relationships were calculated: belief (Bel), disbelief (Dis), uncertainty (Unc), and plausibility (Pls). The relationships were used as factor ratings in the overlay analysis to create GPP indices and maps. The resulting GPP maps showed 83.41% and 77.53% accuracy in Boryeong and Pohang areas, respectively. The EBF model was found to be more effective in terms of prediction accuracy. PMID:24841077

  3. Impact of bioenergy production on carbon storage and soil functions

    NASA Astrophysics Data System (ADS)

    Prays, Nadia; Franko, Uwe

    2016-04-01

    An important renewable energy source is methane produced in biogas plants (BGPs) that convert plant material and animal excrements to biogas and a residue (BGR). If the plant material stems from crops produced specifically for that purpose, a BGP have a 'footprint' that is defined by the area of arable land needed for the production of these energy crops and the area for distributing the BGRs. The BGR can be used to fertilize these lands (reducing the need for carbon and nitrogen fertilizers), and the crop land can be managed to serve as a carbon sink, capturing atmospheric CO2. We focus on the ecological impact of different BGPs in Central Germany, with a specific interest in the long-term effect of BGR-fertilization on carbon storage within the footprint of a BGP. We therefore studied nutrient fluxes using the CANDY (CArbon and Nitrogen Dynamics) model, which processes site-specific information on soils, crops, weather, and land management to compute stocks and fluxes of carbon and nitrogen for agricultural fields. We used CANDY to calculated matter fluxes within the footprints of BGPs of different sizes, and studied the effect of the substrate mix for the BGP on the carbon dynamics of the soil. This included the land requirement of the BGR recycling when used as a fertilizer: the footprint of a BGP required for the production of the energy crop generally differs from its footprint required to take up its BGR. We demonstrate how these findings can be used to find optimal cropping choices and land management for sustainable soil use, maintaining soil fertility and other soil functions. Furthermore, site specific potentials and limitations for agricultural biogas production can be identified and applied in land-use planning.

  4. Inactivation of ATM/ATR DNA Damage Checkpoint Promotes Androgen Induced Chromosomal Instability in Prostate Epithelial Cells

    PubMed Central

    Chiu, Yung-Tuen; Liu, Ji; Tang, Kaidun; Wong, Yong-Chuan; Khanna, Kum Kum; Ling, Ming-Tat

    2012-01-01

    The ATM/ATR DNA damage checkpoint functions in the maintenance of genetic stability and some missense variants of the ATM gene have been shown to confer a moderate increased risk of prostate cancer. However, whether inactivation of this checkpoint contributes directly to prostate specific cancer predisposition is still unknown. Here, we show that exposure of non-malignant prostate epithelial cells (HPr-1AR) to androgen led to activation of the ATM/ATR DNA damage response and induction of cellular senescence. Notably, knockdown of the ATM gene expression in HPr-1AR cells can promote androgen-induced TMPRSS2: ERG rearrangement, a prostate-specific chromosome translocation frequently found in prostate cancer cells. Intriguingly, unlike the non-malignant prostate epithelial cells, the ATM/ATR DNA damage checkpoint appears to be defective in prostate cancer cells, since androgen treatment only induced a partial activation of the DNA damage response. This mechanism appears to preserve androgen induced autophosphorylation of ATM and phosphorylation of H2AX, lesion processing and repair pathway yet restrain ATM/CHK1/CHK2 and p53 signaling pathway. Our findings demonstrate that ATM/ATR inactivation is a crucial step in promoting androgen-induced genomic instability and prostate carcinogenesis. PMID:23272087

  5. Mold-Ripened Soft Cheeses Fortified with Date Palm Fruit Product as Functional Dairy Products.

    PubMed

    Al-Otaibi, Mutlag M; Haddadin, Jamal S; Haddadin, Malik S Y

    2016-01-01

    Date fruit based products are gaining popularity among the consumers in almost all date growing countries due to its added nutritional value. Therefore, novel products were developed by combining two types of foods i.e., soft ripened cheeses and date fruit syrups or date powder. This study is the first to report the surface mold-ripened cheese production with date syrup and date powder. Model cheeses were prepared from pasteurized milk inoculated with Streptococcus thermophilus, Penicillium camemberti and Geotrichum candidum. Date syrup-1, date syrup-2, date powder or the date mixture were added at the stage of curdling. Based on the kinetic growth of the microbial groups in all the treatments, there was no change in the growth of these in various date palm product. On the contrary It may be said that addition of the date fruit product supports their growth. After 35 days, the amounts of total poly phenols were 128.3 ± 1.01, 81.8 ± 1.11, 33.5 ± 2.19, 156.23 ± 1.27 mg GAE/100 g in the cheeses support with date syrup-1, date syrup-2, date powder or the date mixture, respectively. Antioxidant activity of date fruits ranged from 80.13 IC50 (date syrup-2) to 82.23 IC50 (date syrup-1). Based on the chemical characteristics and sensory analysis, the study results showed the potential for innovative application of date products for developing new functional dairy products as an ideal medium for the delivery of biological active compounds with beneficial health effects over. PMID:26930796

  6. Molecular pathways: targeting resistance in the androgen receptor for therapeutic benefit.

    PubMed

    Mostaghel, Elahe A; Plymate, Stephen R; Montgomery, Bruce

    2014-02-15

    Androgen receptor signaling is critical in the development and progression of prostate cancer, leading to intensive efforts to elucidate all potential points of inflection for therapeutic intervention. These efforts have revealed new mechanisms of resistance and raise the possibility that known mechanisms may become even more relevant in the context of effective androgen receptor suppression. These mechanisms include tumoral appropriation of alternative androgen sources, alterations in androgen receptor expression, androgen receptor mutations, truncated androgen receptor variants, alterations and cross-talk in recruitment of cofactors to androgen receptor binding sites in the genome, and androgen receptor-driven oncogenic gene fusions. New agents such as enzalutamide, EPI-001, androgen receptor-specific peptidomimetics, novel HSP90 inhibitors, and PARP inhibitors, as well as new approaches to cotargeting the androgen receptor pathway, point to the potential for more complete and durable control of androgen receptor-mediated growth. PMID:24305618

  7. Identification of a novel androgen receptor agonist (or “androgen mimic”) of environmental concern: spironolactone

    EPA Science Inventory

    Spironolactone is a pharmaceutical that acts as an androgen receptor (AR) antagonist in humans to treat certain conditions such as hirsutism, various dermatologic afflictions, and female pattern hair loss. The drug is also used to treat hypertension as a diuretic. With this commo...

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

    PubMed

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

    2014-10-15

    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

  9. 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

  10. 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. PMID:27110943

  11. ASSESSMENT OF IN VITRO ANDROGENIC ACTIVITY IN KRAFT MILL EFFLUENT

    EPA Science Inventory

    Detection of In Vitro Androgenic Activity in Feedlot Effluent. Lambright, CS 1 , Guillette, LJ, Jr.2, Gray, LE, Jr.1 , 1USEPA, NHEERL, RTP, NC, 2 University of Florida, Dept. of Zoology, Gainesville FL

    Recent studies have shown the presence of androgenic activity in water...

  12. Novel structures in secreting the androgenic gland hormone.

    PubMed

    Negishi, S; Hasegawa, Y; Nakajima, Y

    2001-12-01

    The secretory granules in the androgenic gland of the terrestrial isopod Armadillidium vulgare, which have been indistinct for long time because of vulnerable structures, were revealed by using the rapid-freezing and freeze-substitution method. The fine structure of the androgenic gland is conspicuous by the distribution of numerous particular organelles in the cytoplasm consisting of the endoplasmic reticulum and the Golgi complex, and by having a number of highly organized structures developed between the androgenic gland cells. The structures connect to the intercellular space, which is seen as intercellular canaliculi for exporting the androgenic gland hormone. The plasma membranes near the particular structure of the intercellular canaliculi in the androgenic gland are often specialized to form cellular junctions. The secretory granules including the electron-dense materials, which are supposed to be peptides of androgenic gland hormone, are distributed beside the particular structure of the intercellular canaliculi. Some of the granules are seen to fuse with the plasma membranes. This observation suggests that, in the Armadillidium vulgare, the secretory granules containing androgenic gland hormone are transferred to the extracellular space through the intercellular canaliculi particularly developed for exporting the peptide hormone. This is the first evidence to show the secretory mechanism of the androgenic gland hormone in the Isopoda. PMID:11911080

  13. Illicit Use of Androgens and Other Hormones: Recent Advances

    PubMed Central

    Kanayama, Gen; Pope, Harrison G.

    2012-01-01

    Purpose of review To summarize recent advances in studies of illicit use of androgens and other hormones. Recent findings Androgens and other appearance- and performance-enhancing substances are widely abused worldwide. Three notable clusters of findings have emerged in this field in recent years. First, studies almost unanimously find that androgen users engage in polypharmacy, often ingesting other hormones (e.g., human growth hormone, thyroid hormones, and insulin), ergo/thermogenic drugs (e.g., caffeine, ephedrine, clenbuterol), and classical drugs of abuse (e.g., cannabis, opiates, and cocaine). Second, reports of long-term psychiatric and medical adverse effects of androgens continue to accumulate. In cardiovascular research particularly, controlled studies have begun to supersede anecdotal evidence, strengthening the case that androgens (possibly acting synergistically with other abused drugs) may cause significant morbidity and even mortality. Third, it is increasingly recognized that androgen use may lead to a dependence syndrome with both psychological and physiological origins. Androgen dependence likely affects some millions of individuals worldwide, and arguably represents the least studied major class of illicit drug dependence. Summary Given mounting evidence of the adverse effects of androgens and associated polypharmacy, this topic will likely represent an expanding area of research and an issue of growing public-health concern. PMID:22450858

  14. ENVIRONMENTAL ANDROGENS AND ANTIANDROGENS: AN EXPANDING CHEMICAL UNIVERSE

    EPA Science Inventory

    Within the last ten years, awareness has grown about environmental chemicals that display antiandrogenic or androgenic activity. While studies in the early 1990s focused on pesticides that acted as androgen receptor (AR) antagonists, it soon became evident that this was not the ...

  15. The functional role of some tomato products on lipid profile and liver function in adult rats.

    PubMed

    Ibrahim, Hoda Salama; Ahmed, Lamiaa Ali; El-din, Maha Mohamed Essam

    2008-09-01

    This study was carried out to investigate the functional role of lycopene obtained from powder prepared from fresh tomato, tomato paste, and ketchup that contained equal amounts of lycopene based on levels of intake on body weight gain (BWG), feed intake, feed efficiency ratio (FER), lipid profiles, atherogenic index, and liver enzymes of hyperlipidemic rats. Forty-eight male albino rats were divided into two main groups: the first group (n = 6 rats) was kept on the basal diet as a normal control, while the second group (n = 42 rats) was fed a hyperlipidemic diet for 5 weeks to induce hyperlipidemia. The latter group was divided into seven subgroups: the first subgroup was the positive control group, while the others were supplemented with one of the tomato products at one of two levels (10 or 20 mg of lycopene/kg of diet). BWG, feed intake, and FER were calculated, and blood samples were collected to determine total lipids, total cholesterol, triglycerides, lipoprotein fractions, atherogenic index, and liver function in sera. Relative organ weights were also calculated. Results revealed that administration of various tomato products produced a significant reduction in feed intake except for the hyperlipidemic group that supplemented with the lower lycopene level from tomato paste. In addition, BWG and FER were not influenced by addition of tomato products at any level of intake. Hyperlipidemic rats supplemented with tomato powder, tomato paste, or ketchup showed significant improvement in almost all the parameters studied compared to the positive control group. Results showed that the higher lycopene level from tomato paste produced significant improvement in all lipid parameters, followed by 10 mg of lycopene/kg from tomato paste, which caused significant elevation in high-density lipoprotein cholesterol comparable to that of the negative control group. The lowest atherogenic index was achieved by addition of the lower lycopene level from tomato paste followed by

  16. Increased androgenic sensitivity in the hind limb muscular system marks the evolution of a derived gestural display

    PubMed Central

    Mangiamele, Lisa A.; Fuxjager, Matthew J.; Schuppe, Eric R.; Taylor, Rebecca S.; Hödl, Walter; Preininger, Doris

    2016-01-01

    Physical gestures are prominent features of many species’ multimodal displays, yet how evolution incorporates body and leg movements into animal signaling repertoires is unclear. Androgenic hormones modulate the production of reproductive signals and sexual motor skills in many vertebrates; therefore, one possibility is that selection for physical signals drives the evolution of androgenic sensitivity in select neuromotor pathways. We examined this issue in the Bornean rock frog (Staurois parvus, family: Ranidae). Males court females and compete with rivals by performing both vocalizations and hind limb gestural signals, called “foot flags.” Foot flagging is a derived display that emerged in the ranids after vocal signaling. Here, we show that administration of testosterone (T) increases foot flagging behavior under seminatural conditions. Moreover, using quantitative PCR, we also find that adult male S. parvus maintain a unique androgenic phenotype, in which androgen receptor (AR) in the hind limb musculature is expressed at levels ∼10× greater than in two other anuran species, which do not produce foot flags (Rana pipiens and Xenopus laevis). Finally, because males of all three of these species solicit mates with calls, we accordingly detect no differences in AR expression in the vocal apparatus (larynx) among taxa. The results show that foot flagging is an androgen-dependent gestural signal, and its emergence is associated with increased androgenic sensitivity within the hind limb musculature. Selection for this novel gestural signal may therefore drive the evolution of increased AR expression in key muscles that control signal production to support adaptive motor performance. PMID:27143723

  17. N-Aryl-oxazolidin-2-imine Muscle Selective Androgen Receptor Modulators Enhance Potency through Pharmacophore Reorientation

    SciTech Connect

    Nirschl, Alexandra A.; Zou, Yan; Krystek, Jr., Stanley R.; Sutton, James C.; Simpkins, Ligaya M.; Lupisella, John A.; Kuhns, Joyce E.; Seethala, Ramakrishna; Golla, Rajasree; Sleph, Paul G.; Beehler, Blake C.; Grover, Gary J.; Egan, Donald; Fura, Aberra; Vyas, Viral P.; Li, Yi-Xin; Sack, John S.; Kish, Kevin F.; An, Yongmi; Bryson, James A.; Gougoutas, Jack Z.; DiMarco, John; Zahler, Robert; Ostrowski, Jacek; Hamann, Lawrence G.

    2010-11-09

    A novel selective androgen receptor modulator (SARM) scaffold was discovered as a byproduct obtained during synthesis of our earlier series of imidazolidin-2-ones. The resulting oxazolidin-2-imines are among the most potent SARMs known, with many analogues exhibiting sub-nM in vitro potency in binding and functional assays. Despite the potential for hydrolytic instability at gut pH, compounds of the present class showed good oral bioavailability and were highly active in a standard rodent pharmacological model.

  18. Dithiafulvalene functionalized diketopyrrolopyrrole based sensitizers for efficient hydrogen production.

    PubMed

    Narayanaswamy, K; Tiwari, Amritanjali; Mondal, Indranil; Pal, Ujjwal; Niveditha, S; Bhanuprakash, K; Singh, Surya Prakash

    2015-05-28

    We have designed and synthesized two new diketopyrrolopyrrole (DPP) based organic sensitizers (DPPCA and DPPCN) with the dithiafulvalene (DTF) unit as donor and cyanoacrylic acid/malononitrile as acceptor moieties. These dyes showed excellent efficiency of photocatalytic hydrogen production over a Pt-TiO2 composite via solar-induced water splitting. The sensitizers showed broad absorptions over the wide visible regime (500-800 nm). In DPPCN, the malononitrile moiety led to strong intra-molecular charge transfer, as evidenced by red shifted (∼24 nm) absorption maxima with highly enhanced molar absorptivity (108 190 M(-1) cm(-1)). The electrochemical characterization of as-prepared sensitizers confirmed the feasible electron injection from the dye to the TiO2 conduction band (CB) which has been further validated by theoretical studies. In this study, the rate of the photocatalytic activity was found to be dependent on the acceptor part of the dye molecule as DPPCN sensitized Pt-TiO2 (DNPT) exhibited remarkable (1208 μmol) hydrogen evolution yield in comparison to DPPCA sensitized Pt-TiO2 (DAPT) (840 μmol). The rigid DPP core made the sensitizers significantly photo-stable as affirmed by their high hydrogen production efficiency over 80 h of prolonged irradiation. As predicted from density functional theory (DFT) calculations, ground state geometry of the dyes was almost planar, facilitating continuous conjugation throughout the molecule. Time-dependent DFT (TD-DFT) calculations were also carried out to make clear the understanding of charge transfer transition of the dye molecules. PMID:25942447

  19. Honokiol Inhibits Androgen Receptor Activity in Prostate Cancer Cells

    PubMed Central

    Hahm, Eun-Ryeong; Karlsson, A. Isabella; Bonner, Michael Y.; Arbiser, Jack L.; Singh, Shivendra V.

    2014-01-01

    BACKGROUND We have shown previously that honokiol (HNK), a bioactive component of the medicinal plant Magnolia officinalis, inhibits growth of human prostate cancer cells in vitro and in vivo. However, the effect of HNK on androgen receptor (AR) signaling is not known. METHODS LNCaP, C4-2, and TRAMP-C1 cells were used for various assays. Trypan blue dye exclusion assay or clonogenic assay was performed for determination of cell viability. The effects of HNK and/or its analogs on protein levels of AR and its target gene product prostate specific antigen (PSA) were determined by western blotting. RNA interference of p53 was achieved by transient transfection. Reverse transcription-polymerase chain reaction was performed for mRNA expression of AR. Nuclear translocation of AR was visualized by microscopy. Apoptosis was quantified by DNA fragmentation assay or flow cytometry after Annexin V-propidium iodide staining. RESULTS HNK and its dichloroacetate analog (HDCA) were relatively more effective in suppressing cell viability and AR protein level than honokiol epoxide or biseugenol. Nuclear translocation of AR stimulated by a synthetic androgen (R1881) was markedly suppressed in the presence of HNK. Downregulation of AR protein resulting from HNK exposure was attributable to transcriptional repression as well as proteasomal degradation. HNK-mediated suppression of AR protein was maintained in LNCaP cells after knockdown of p53 protein. HNK-induced apoptosis was not affected by R1881 treatment. CONCLUSIONS The present study demonstrates, for the first time, that HNK inhibits activity of AR in prostate cancer cells regardless of the p53 status. PMID:24338950

  20. [Recent aspects of therapy with androgenic and anabolic steroids].

    PubMed

    Schambach, H; Nitschke, U; Kröhne, H J

    1983-11-15

    From the pharmacology of the therapeutically available androgen preparations and the clinical experience results that a highly dosed androgen long-term therapy is effectively possible only by testosterone esters which are to be injected intramuscularly (e.g. testosterone oenanthate). It is indicated in all forms of endocrine hypogonadism, certain aplastic anaemias and if necessary in extreme male high growth. In partial androgen deficiency (pubertas tarda, Klinefelter's syndrome, climacterium virile and others) orally applicable androgens such as testosterone-undecanoate (Andriol) and mesterolone (Vistimon) can be used. The latter is to be preferred when a hyperoestrogenism is present, e.g. in liver cirrhosis. When 17-alpha-alkylated oral androgens are used, their often not sufficiently confirmed anabolic effect and their potential liver toxicity should more be taken into consideration. PMID:6666179

  1. Structural and functional properties of hemp seed protein products.

    PubMed

    Malomo, Sunday A; He, Rong; Aluko, Rotimi E

    2014-08-01

    The effects of pH and protein concentration on some structural and functional properties of hemp seed protein isolate (HPI, 84.15% protein content) and defatted hemp seed protein meal (HPM, 44.32% protein content) were determined. The HPI had minimum protein solubility (PS) at pH 4.0, which increased as pH was decreased or increased. In contrast, the HPM had minimum PS at pH 3.0, which increased at higher pH values. Gel electrophoresis showed that some of the high molecular weight proteins (>45 kDa) present in HPM were not well extracted by the alkali and were absent or present in low ratio in the HPI polypeptide profile. The amino acid composition showed that the isolation process increased the Arg/Lys ratio of HPI (5.52%) when compared to HPM (3.35%). Intrinsic fluorescence and circular dichroism data indicate that the HPI proteins had a well-defined structure at pH 3.0, which was lost as pH value increased. The differences in structural conformation of HPI at different pH values were reflected as better foaming capacity at pH 3.0 when compared to pH 5.0, 7.0, and 9.0. At 10 and 25 mg/mL protein concentrations, emulsions formed by the HPM had smaller oil droplet sizes (higher quality), when compared to the HPI-formed emulsions. In contrast at 50 mg/mL protein concentration, the HPI-formed emulsions had smaller oil droplet sizes (except at pH 3.0). We conclude that the functional properties of hemp seed protein products are dependent on structural conformations as well as protein concentration and pH. PMID:25048774

  2. Androgens Alter the Tuning of Electroreceptors

    NASA Astrophysics Data System (ADS)

    Harlan Meyer, J.; Zakon, Harold H.

    1982-08-01

    Weakly electric fish possess electroreceptors that are tuned to their individual electric organ discharge frequencies. One genus, Sternopygus, displays both ontogenetic and seasonal shifts in these frequencies, possibly because of endocrine influences. Systemic treatment with androgens lowers the discharge frequencies in these animals. Concomitant with these changes in electric organ discharge frequencies are decreases in electroreceptor best frequencies; hence the close match between discharge frequency and receptor tuning is maintained. These findings indicate that the tuning of electroreceptors is dynamic and that it parallels natural shifts in electric organ discharge frequency.

  3. 17β-trenbolone, an anabolic–androgenic steroid as well as an environmental hormone, contributes to neurodegeneration

    SciTech Connect

    Ma, Fucui; Liu, Daicheng

    2015-01-01

    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-trenbolone 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 17

  4. Androgen receptor- and PIAS1-regulated gene programs in molecular apocrine breast cancer cells.

    PubMed

    Malinen, Marjo; Toropainen, Sari; Jääskeläinen, Tiina; Sahu, Biswajyoti; Jänne, Olli A; Palvimo, Jorma J

    2015-10-15

    We have analyzed androgen receptor (AR) chromatin binding sites (ARBs) and androgen-regulated transcriptome in estrogen receptor negative molecular apocrine breast cancer cells. These analyses revealed that 42% of ARBs and 39% androgen-regulated transcripts in MDA-MB453 cells have counterparts in VCaP prostate cancer cells. Pathway analyses showed a similar enrichment of molecular and cellular functions among AR targets in both breast and prostate cancer cells, with cellular growth and proliferation being among the most enriched functions. Silencing of the coregulator SUMO ligase PIAS1 in MDA-MB453 cells influenced AR function in a target-selective fashion. An anti-apoptotic effect of the silencing suggests involvement of the PIAS1 in the regulation of cell death and survival pathways. In sum, apocrine breast cancer and prostate cancer cells share a core AR cistrome and target gene signature linked to cancer cell growth, and PIAS1 plays a similar coregulatory role for AR in both cancer cell types. PMID:26219822

  5. Androgen receptor-mediated regulation of adrenocortical activity in the sand rat, Psammomys obesus.

    PubMed

    Benmouloud, Abdelouafi; Amirat, Zaina; Khammar, Farida; Patchev, Alexandre V; Exbrayat, Jean M; Almeida, Osborne F X

    2014-12-01

    The wild sand rat, Psammomys obesus, displays seasonal variations in adrenocortical activity that parallel those of testicular activity, indicating functional cross-talk between the hypothalamo-pituitary-adrenal and hypothalamo-pituitary-gonadal axes. In the present study, we examined androgen receptor (AR)-mediated actions of testicular steroids in the regulation of adrenocortical function in the sand rat. Specifically, we examined the expression of AR in the adrenal cortex, as well as adrenal apoptosis in male sand rats that had been surgically castrated or castrated and supplemented with testosterone; biochemical indices of adrenocortical function and hormone profiles were also measured. Orchiectomy was followed by an increase in adrenocorticotropic hormone secretion from the anterior pituitary and subsequently, increased adrenocortical activity; the latter was evidenced by orchiectomy-induced increases in the adrenal content of cholesterol and lipids as well as adrenal hypertrophy (seen as an elevation of the RNA/DNA ratio). Further, androgen deprivation respectively up- and downregulated the incidence of apoptosis within the glucocorticoid-producing zona fasciculata and sex steroid-producing zona reticularis. Interestingly, orchiectomy resulted in increased expression of AR in the zona fasciculata. All of the orchiectomy-induced cellular and biochemical responses were reversible after testosterone substitution therapy. Together, these data suggest that adrenocortical activity in the sand rat is seasonally modulated by testicular androgens that act through AR located in the adrenal cortex itself. PMID:25179180

  6. RAINBOW TROUT ANDROGEN RECEPTOR ALPHA AND THE HUMAN ANDROGEN RECEPTOR: COMPARISONS IN THE COS WHOLE CELL BINDING ASSAY

    EPA Science Inventory

    Rainbow Trout Androgen Receptor Alpha And Human Androgen Receptor: Comparisons in the COS Whole Cell Binding Assay
    Mary C. Cardon, L. Earl Gray, Jr. and Vickie S. Wilson
    U.S. Environmental Protection Agency, ORD, NHEERL, Reproductive Toxicology Division, Research Triangle...

  7. RAINBOW TROUT ANDROGEN RECEPTOR ALPHA AND THE HUMAN ANDROGEN RECEPTOR: COMPARISONS IN THE COS WHOLE CELL BINDING ASSAY

    EPA Science Inventory

    RAINBOW TROUT ANDROGEN RECEPTOR ALPHA AND HUMAN ANDROGEN RECEPTOR: COMPARISONS IN THE COS WHOLE CELL BINDING ASSAY.
    MC Cardon, PC Hartig,LE Gray, Jr. and VS Wilson.
    U.S. EPA, ORD, NHEERL, RTD, Research Triangle Park, NC, USA.
    Typically, in vitro hazard assessments for ...

  8. 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)...

  9. Bacterial cellulose biosynthesis: diversity of operons, subunits, products and functions

    PubMed Central

    Römling, Ute; Galperin, Michael Y.

    2015-01-01

    Summary Recent studies of bacterial cellulose biosynthesis, including structural characterization of a functional cellulose synthase complex, provided the first mechanistic insight into this fascinating process. In most studied bacteria, just two subunits, BcsA and BcsB, are necessary and sufficient for the formation of the polysaccharide chain in vitro. Other subunits – which differ among various taxa – affect the enzymatic activity and product yield in vivo by modulating expression of biosynthesis apparatus, export of the nascent β-D-glucan polymer to the cell surface, and the organization of cellulose fibers into a higher-order structure. These auxiliary subunits play key roles in determining the quantity and structure of the resulting biofilm, which is particularly important for interactions of bacteria with higher organisms that lead to rhizosphere colonization and modulate virulence of cellulose-producing bacterial pathogens inside and outside of host cells. Here we review the organization of four principal types of cellulose synthase operons found in various bacterial genomes, identify additional bcs genes that encode likely components of the cellulose biosynthesis and secretion machinery, and propose a unified nomenclature for these genes and subunits. We also discuss the role of cellulose as a key component of biofilms formed by a variety of free-living and pathogenic bacteria and, for the latter, in the choice between acute infection and persistence in the host. PMID:26077867

  10. Bacterial cellulose biosynthesis: diversity of operons, subunits, products, and functions.

    PubMed

    Römling, Ute; Galperin, Michael Y

    2015-09-01

    Recent studies of bacterial cellulose biosynthesis, including structural characterization of a functional cellulose synthase complex, provided the first mechanistic insight into this fascinating process. In most studied bacteria, just two subunits, BcsA and BcsB, are necessary and sufficient for the formation of the polysaccharide chain in vitro. Other subunits - which differ among various taxa - affect the enzymatic activity and product yield in vivo by modulating (i) the expression of the biosynthesis apparatus, (ii) the export of the nascent β-D-glucan polymer to the cell surface, and (iii) the organization of cellulose fibers into a higher-order structure. These auxiliary subunits play key roles in determining the quantity and structure of resulting biofilms, which is particularly important for the interactions of bacteria with higher organisms - leading to rhizosphere colonization and modulating the virulence of cellulose-producing bacterial pathogens inside and outside of host cells. We review the organization of four principal types of cellulose synthase operon found in various bacterial genomes, identify additional bcs genes that encode components of the cellulose biosynthesis and secretion machinery, and propose a unified nomenclature for these genes and subunits. We also discuss the role of cellulose as a key component of biofilms and in the choice between acute infection and persistence in the host. PMID:26077867

  11. AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS, AMERICAN COLLEGE OF ENDOCRINOLOGY, AND ANDROGEN EXCESS AND PCOS SOCIETY DISEASE STATE CLINICAL REVIEW: GUIDE TO THE BEST PRACTICES IN THE EVALUATION AND TREATMENT OF POLYCYSTIC OVARY SYNDROME--PART 1.

    PubMed

    Goodman, Neil F; Cobin, Rhoda H; Futterweit, Walter; Glueck, Jennifer S; Legro, Richard S; Carmina, Enrico

    2015-11-01

    Polycystic Ovary Syndrome (PCOS) is recognized as the most common endocrine disorder of reproductive-aged women around the world. This document, produced by the collaboration of the American Association of Clinical Endocrinologists (AACE) and the Androgen Excess and PCOS Society (AES) aims to highlight the most important clinical issues confronting physicians and their patients with PCOS. It is a summary of current best practices in 2015. PCOS has been defined using various criteria, including menstrual irregularity, hyperandrogenism, and polycystic ovary morphology (PCOM). General agreement exists among specialty society guidelines that the diagnosis of PCOS must be based on the presence of at least two of the following three criteria: chronic anovulation, hyperandrogenism (clinical or biological) and polycystic ovaries. There is need for careful clinical assessment of women's history, physical examination, and laboratory evaluation, emphasizing the accuracy and validity of the methodology used for both biochemical measurements and ovarian imaging. Free testosterone (T) levels are more sensitive than the measurement of total T for establishing the existence of androgen excess and should be ideally determined through equilibrium dialysis techniques. Value of measuring levels of androgens other than T in patients with PCOS is relatively low. New ultrasound machines allow diagnosis of PCOM in patients having at least 25 small follicles (2 to 9 mm) in the whole ovary. Ovarian size at 10 mL remains the threshold between normal and increased ovary size. Serum 17-hydroxyprogesterone and anti-Müllerian hormone are useful for determining a diagnosis of PCOS. Correct diagnosis of PCOS impacts on the likelihood of associated metabolic and cardiovascular risks and leads to appropriate intervention, depending upon the woman's age, reproductive status, and her own concerns. The management of women with PCOS should include reproductive function, as well as the care of hirsutism

  12. Study on Capturing Functional Requirements of the New Product Based on Evolution

    NASA Astrophysics Data System (ADS)

    Liu, Fang; Song, Liya; Bai, Zhonghang; Zhang, Peng

    In order to exist in an increasingly competitive global marketplace, it is important for corporations to forecast the evolutionary direction of new products rapidly and effectively. Most products in the world are developed based on the design of existing products. In the product design, capturing functional requirements is a key step. Function is continuously evolving, which is driven by the evolution of needs and technologies. So the functional requirements of new product can be forecasted based on the functions of existing product. Eight laws of function evolution are put forward in this paper. The process model of capturing the functional requirements of new product based on function evolution is proposed. An example illustrates the design process.

  13. Pituitary Androgen Receptor Signalling Regulates Prolactin but Not Gonadotrophins in the Male Mouse

    PubMed Central

    O’Hara, Laura; Curley, Michael; Tedim Ferreira, Maria; Cruickshanks, Lyndsey; Milne, Laura; Smith, Lee B.

    2015-01-01

    Production of the androgen testosterone is controlled by a negative feedback loop within the hypothalamic-pituitary-gonadal (HPG) axis. Stimulation of testicular Leydig cells by pituitary luteinising hormone (LH) is under the control of hypothalamic gonadotrophin releasing hormone (GnRH), while suppression of LH secretion by the pituitary is controlled by circulating testosterone. Exactly how androgens exert their feedback control of gonadotrophin secretion (and whether this is at the level of the pituitary), as well as the role of AR in other pituitary cell types remains unclear. To investigate these questions, we exploited a transgenic mouse line (Foxg1Cre/+; ARfl/y) which lacks androgen receptor in the pituitary gland. Both circulating testosterone and gonadotrophins are unchanged in adulthood, demonstrating that AR signalling is dispensable in the male mouse pituitary for testosterone-dependent regulation of LH secretion. In contrast, Foxg1Cre/+; ARfl/y males have a significant increase in circulating prolactin, suggesting that, rather than controlling gonadotrophins, AR-signalling in the pituitary acts to suppress aberrant prolactin production in males. PMID:25799562

  14. Developmental changes in serum androgen levels of Eastern Screech-Owls (Megascops asio)

    USGS Publications Warehouse

    Kozlowski, Corinne P.; Hahn, D. Caldwell

    2010-01-01

    We studied androgen production during development in nestling Eastern Screech-Owls (Megascops asio) and hypothesized that gender and hatch order might influence serum levels of testosterone and androstenedione. Testosterone levels were highest immediately after hatching and declined significantly in the 4 weeks leading to fledging. The average level of testosterone for 1-7 day-old owls was 3.99 - 0.68 ng/ml. At 22-28 days of age, the average testosterone level for nestling owls was 0.83 - 0.18 ng/ml. Testosterone levels did not differ between males or females. The average testosterone level for male nestlings was 2.23 - 0.29 ng/ml and 2.39 - 0.56 ng/ml for female nestlings. The average level of androstenedione for nestling owls was 1.92 - 0.11 ng/ml and levels remained constant throughout development. Levels were significantly higher in males than females. The average androstenedione level was 1.77 - 0.16 ng/ml for male nestlings and 1.05 - 0.24 ng/ml for female nestlings. Hatching order did not affect levels of either androgen. Our results provide a foundation for future studies of androgen production by nestling owls.

  15. Assessing the transferability of ecosystem service production estimates and functions

    EPA Science Inventory

    Estimates of ecosystem service (ES) production, and their responses to stressors or policy actions, may be obtained by direct measurement, other empirical studies, or modeling. Direct measurement is costly and often impractical, and thus many studies transfer ES production estim...

  16. Androgens and estrogens in skeletal sexual dimorphism.

    PubMed

    Laurent, Michaël; Antonio, Leen; Sinnesael, Mieke; Dubois, Vanessa; Gielen, Evelien; Classens, Frank; Vanderschueren, Dirk

    2014-01-01

    Bone is an endocrine tissue expressing androgen and estrogen receptors as well as steroid metabolizing enzymes. The bioactivity of circulating sex steroids is modulated by sex hormone-binding globulin and local conversion in bone tissue, for example, from testosterone (T) to estradiol (E2) by aromatase, or to dihydrotestosterone by 5α-reductase enzymes. Our understanding of the structural basis for gender differences in bone strength has advanced considerably over recent years due to increasing use of (high resolution) peripheral computed tomography. These microarchitectural insights form the basis to understand sex steroid influences on male peak bone mass and turnover in cortical vs trabecular bone. Recent studies using Cre/LoxP technology have further refi ned our mechanistic insights from global knockout mice into the direct contributions of sex steroids and their respective nuclear receptors in osteoblasts, osteoclasts, osteocytes, and other cells to male osteoporosis. At the same time, these studies have reinforced the notion that androgen and estrogen defi ciency have both direct and pleiotropic effects via interaction with, for example, insulin-like growth factor 1, inflammation, oxidative stress, central nervous system control of bone metabolism, adaptation to mechanical loading, etc., This review will summarize recent advances on these issues in the fi eld of sex steroid actions in male bone homeostasis. PMID:24385015

  17. Stress and Androgen Activity During Fetal Development

    PubMed Central

    Swan, Shanna H.

    2015-01-01

    Prenatal stress is known to alter hypothalamic-pituitary-adrenal axis activity, and more recent evidence suggests that it may also affect androgen activity. In animal models, prenatal stress disrupts the normal surge of testosterone in the developing male, whereas in females, associations differ by species. In humans, studies show that (1) associations between prenatal stress and child outcomes are often sex-dependent, (2) prenatal stress predicts several disorders with notable sex differences in prevalence, and (3) prenatal exposure to stressful life events may be associated with masculinized reproductive tract development and play behavior in girls. In this minireview, we examine the existing literature on prenatal stress and androgenic activity and present new, preliminary data indicating that prenatal stress may also modify associations between prenatal exposure to diethylhexyl phthalate, (a synthetic, antiandrogenic chemical) and reproductive development in infant boys. Taken together, these data support the hypothesis that prenatal exposure to both chemical and nonchemical stressors may alter sex steroid pathways in the maternal-placental-fetal unit and ultimately alter hormone-dependent developmental endpoints. PMID:26241065

  18. Stress and Androgen Activity During Fetal Development.

    PubMed

    Barrett, Emily S; Swan, Shanna H

    2015-10-01

    Prenatal stress is known to alter hypothalamic-pituitary-adrenal axis activity, and more recent evidence suggests that it may also affect androgen activity. In animal models, prenatal stress disrupts the normal surge of testosterone in the developing male, whereas in females, associations differ by species. In humans, studies show that (1) associations between prenatal stress and child outcomes are often sex-dependent, (2) prenatal stress predicts several disorders with notable sex differences in prevalence, and (3) prenatal exposure to stressful life events may be associated with masculinized reproductive tract development and play behavior in girls. In this minireview, we examine the existing literature on prenatal stress and androgenic activity and present new, preliminary data indicating that prenatal stress may also modify associations between prenatal exposure to diethylhexyl phthalate, (a synthetic, antiandrogenic chemical) and reproductive development in infant boys. Taken together, these data support the hypothesis that prenatal exposure to both chemical and nonchemical stressors may alter sex steroid pathways in the maternal-placental-fetal unit and ultimately alter hormone-dependent developmental endpoints. PMID:26241065

  19. Evaluation Strategies as a Function of Product Development Stages.

    ERIC Educational Resources Information Center

    Hess, Robert J.; Wright, William J.

    There are issues in evaluation and stages of product development that demand the use of experimental or quasi-experimental designs. To counteract criticism of evaluation efforts, an approach to the examination of the multiple issues involved in curriculum product evaluation across the usual developmental cycle of educational products was…

  20. Secretion of Unconjugated Androgens and Estrogens by the Normal and Abnormal Human Testis before and after Human Chorionic Gonadotropin

    PubMed Central

    Weinstein, R. L.; Kelch, R. P.; Jenner, M. R.; Kaplan, S. L.; Grumbach, M. M.

    1974-01-01

    The secretion of androgens and estrogens by normal and abnormal testes was compared by determining the concentrations of dehydroepiandrosterone (DHEA), androstenedione (Δ4A), testosterone (T), estrone (E1), and 17β-estradiol (E2) in peripheral and spermatic venous plasma samples from 14 normal men and 5 men with unilateral testicular atrophy. Four normal men and one patient with unilateral atrophy of the testis were given human chorionic gonadotropin (HCG) before surgery. Plasma estrogens were determined by radioimmunoassay; plasma androgens were measured by the double-isotope dilution derivative technique. Peripheral concentrations of these steroids before and after HCG were similar in both the normal men and the patients with unilateral testicular atrophy. In normal men, the mean ±SE spermatic venous concentrations were DHEA, 73.1±11.7 ng/ml; Δ4A, 30.7±7.9 ng/ml; T, 751±114 ng/ml; E1, 306±55 pg/ml; and E2, 1298±216 pg/ml. Three of four subjects with unilateral testicular atrophy had greatly diminished spermatic venous levels of androgens and estrogens. HCG treatment increased the testicular secretion of DHEA and T fivefold, Δ4A threefold, E1 sixfold, and E2 eightfold in normal men. In the single subject with an atrophic testis who received HCG, the spermatic venous concentrations of androgens and estrogens were much less than in normal men similarly treated. We conclude that: (a) E1 is secreted by the human testis, but testicular secretion of E1 accounts for less than 5% of E1 production in normal men; (b) HCG stimulation produces increases in spermatic venous estrogens equal to or greater than the changes in androgens, including testosterone; and (c) strikingly decreased secretion of androgen and estrogen by unilateral atrophic human tests cannot be appreciated by analyses of peripheral steroid concentrations. PMID:4271572

  1. 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. PMID:27131392

  2. Structural Stereochemistry of Androstene Hormones Determines Interactions with Human Androgen, Estrogen, and Glucocorticoid Receptors

    PubMed Central

    Shaak, Thomas L.; Wijesinghe, Dayanjan S.; Chalfant, Charles E.; Diegelmann, Robert F.; Ward, Kevin R.; Loria, Roger M.

    2013-01-01

    DHEA, 17α-AED, 17β-AED, and 17β-AET exhibit strong biological activity that has been attributed to androgenic, estrogenic, or antiglucocorticoid activity in vivo and in vitro. This study compared DHEA, 17α-AED, 17β-AED, and 17β-AET for their ability to activate the human AR, ER, and GR and determine the relative androgenicity, estrogenicity, and glucocorticoid activity. The results show that, at the receptor level, these androstene hormones are weak AR and even weaker ER activators. Direct androstene hormone activation of the human AR, ERα, and ERβ may not be essential for their biological function. Similarly, these hormones indirectly activated the human GR, only in the presence of high dexamethasone concentrations. These results underscore the major difference between androstene hormone interactions with these nuclear receptors and their biological effects. PMID:24729874

  3. Neonatal Androgenization Exacerbates Alcohol-Induced Liver Injury in Adult Rats, an Effect Abrogated by Estrogen

    PubMed Central

    Ellefson, Whitney M.; Lakner, Ashley M.; Hamilton, Alicia; McKillop, Iain H.; Bonkovsky, Herbert L.; Steuerwald, Nury M.; Huet, Yvette M.; Schrum, Laura W.

    2011-01-01

    Alcoholic liver disease (ALD) affects millions of people worldwide and is a major cause of morbidity and mortality. However, fewer than 10% of heavy drinkers progress to later stages of injury, suggesting other factors in ALD development, including environmental exposures and genetics. Females display greater susceptibility to the early damaging effects of ethanol. Estrogen (E2) and ethanol metabolizing enzymes (cytochrome P450, CYP450) are implicated in sex differences of ALD. Sex steroid hormones are developmentally regulated by the hypothalamic-pituitary-gonadal (HPG) axis, which controls sex-specific cycling of gonadal steroid production and expression of hepatic enzymes. The aim of this study was to determine if early postnatal inhibition of adult cyclic E2 alters ethanol metabolizing enzyme expression contributing to the development of ALD in adulthood. An androgenized rat model was used to inhibit cyclic E2 production. Control females (Ctrl), androgenized females (Andro) and Andro females with E2 implants were administered either an ethanol or isocalorically-matched control Lieber-DeCarli diet for four weeks and liver injury and CYP450 expression assessed. Androgenization exacerbated the deleterious effects of ethanol demonstrated by increased steatosis, lipid peroxidation, profibrotic gene expression and decreased antioxidant defenses compared to Ctrl. Additionally, CYP2E1 expression was down-regulated in Andro animals on both diets. No change was observed in CYP1A2 protein expression. Further, continuous exogenous administration of E2 to Andro in adulthood attenuated these effects, suggesting that E2 has protective effects in the androgenized animal. Therefore, early postnatal inhibition of cyclic E2 modulates development and progression of ALD in adulthood. PMID:22206017

  4. Novel Stably Transfected Human Reporter Cell Line AIZ-AR as a Tool for an Assessment of Human Androgen Receptor Transcriptional Activity

    PubMed Central

    Bartonkova, Iveta; Novotna, Aneta; Dvorak, Zdenek

    2015-01-01

    Androgen receptor plays multiple physiological and pathological roles in human organism. In the current paper, we describe construction and characterization of a novel stably transfected human reporter cell line AIZ-AR for assessment of transcriptional activity of human androgen receptor. Cell line AIZ-AR is derived from human prostate carcinoma epithelial cell line 22Rv1 that was transfected with reporter plasmid containing 3 copies of androgen response regions (ARRs) followed by a single copy of androgen response element (ARE) from the promoter region of human prostate specific antigen (PSA) gene. AIZ-AR cells remained fully functional for more than 60 days and over 25 passages in the culture and even after cryopreservation. Time-course analyses showed that AIZ-AR cells allow detection of AR ligands as soon as after 8 hours of the treatment. We performed dose-response analyses with 23 steroids in 96-well plate format. We observed activation of AR by androgens, but not by estrogens and mineralocorticoids. Some glucocorticoids and progesterone also induced luciferase, but their potencies were 2-3 orders of magnitude weaker as compared to androgens. Taken together, we have developed a rapid, sensitive, selective, high-throughput and reproducible tool for detection of human AR ligands, with potential use in pharmacological and environmental applications. PMID:25811655

  5. CCAR1 promotes chromatin loading of androgen receptor (AR) transcription complex by stabilizing the association between AR and GATA2

    PubMed Central

    Seo, Woo-Young; Jeong, Byong Chang; Yu, Eun Ji; Kim, Hwa Jin; Kim, Seok-Hyung; Lim, Joung Eun; Kwon, Ghee Young; Lee, Hyun Moo; Kim, Jeong Hoon

    2013-01-01

    Androgen receptor (AR), a ligand-dependent transcription factor, plays a critical role in prostate cancer onset and progression, and its transcriptional function is mediated largely by distinct nuclear receptor co-regulators. Here, we show that cell cycle and apoptosis regulator 1 (CCAR1) functions as an AR co-activator. CCAR1 interacted with and enhanced the transcriptional activity of AR. Depletion of CCAR1 caused reduction in androgen-dependent expression of a subset of AR target genes. We further showed that CCAR1 is required for recruitment of AR, MED1 and RNA polymerase II to the enhancers of AR target genes and for androgen-induced long-range prostate specific antigen enhancer–promoter interaction. The molecular mechanism underlying CCAR1 function in AR-mediated transcription involves CCAR1-mediated enhanced recruitment of GATA2, a pioneer factor for AR, to AR-binding sites. CCAR1 stabilized the interaction between AR and GATA2 by interacting directly with both proteins, thereby facilitating AR and GATA2 occupancy on the enhancers. Furthermore, CCAR1 depletion inhibited the growth, migration, invasion of prostate cancer cells and reduced the tumorigenicity of prostate cancer cells in vivo. Our results firmly established CCAR1 as an AR co-activator that plays a key role in AR transcription complex assembly and has an important physiological role in androgen signaling and prostate tumorigenesis. PMID:23887938

  6. Persistence of Reduced Androgenic Glands after Protandric Sex Change Suggests a Basis for Simultaneous Hermaphroditism in a Caridean Shrimp.

    PubMed

    Bortolini, José Luis; Bauer, Raymond T

    2016-04-01

    The caridean shrimp Lysmata wurdemanni is a protandric simultaneous hermaphrodite. These individuals go through a male phase (MP) before changing sex to become female-phase simultaneous hermaphrodites (FPSH). The latter have an externally female phenotype, but retain a reduced male reproductive system and both male and female reproductive function. Previous studies have reported that the androgenic glands (AGs), whose hormones stimulate development of male characteristics in decapod crustaceans, are absent in the female phase of purely protandric species. We tested the hypothesis of androgenic gland persistence in FPSHs of L. wurdemanni by dissection and histology on the ejaculatory ducts. These glands were observed in FPSHs, although in a variably atrophied form. Androgenic glands of L. wurdemanni MPs are compact and replete with well developed cells, with large, deeply stained (hematoxylin-eosin) nuclei, as in males of gonochoric and protandric species. The AGs of simultaneous hermaphrodites were more reticulate in appearance due to the apparent breakdown and loss of cells, resulting in vacuolated areas, or empty spaces in the gland surrounded by connective tissue fibers or cell remnants. However, all FPSHs possessed numerous, or at least some possibly functional cells. The greatest atrophy of AGs was observed in the largest (i.e., oldest) FPSHs. However, the ovotestes of all FPSHs retained a small testicular portion with well developed ejaculatory ducts containing sperm. Our results suggest that the reduced androgenic glands of female-phase simultaneous hermaphrodites of L. wurdemanni allow them to maintain male reproductive function after sex change. PMID:27132133

  7. Testosterone and Vascular Function in Aging

    PubMed Central

    Lopes, Rhéure A. M.; Neves, Karla B.; Carneiro, Fernando S.; Tostes, Rita C.

    2012-01-01

    Androgen receptors are widely distributed in several tissues, including vascular endothelial and smooth muscle cells. Through classic cytosolic androgen receptors or membrane receptors, testosterone induces genomic and non-genomic effects, respectively. Testosterone interferes with the vascular function by increasing the production of pro-inflammatory cytokines and arterial thickness. Experimental evidence indicates that sex steroid hormones, such as testosterone modulate the synthesis and bioavailability of NO and, consequently, endothelial function, which is key for a healthy vasculature. Of interest, aging itself is accompanied by endothelial and vascular smooth muscle dysfunction. Aging-associated decline of testosterone levels is accompanied by age-related diseases, such as metabolic and cardiovascular diseases, indicating that very low levels of androgens may contribute to cardiovascular dysfunction observed in these age-related disorders or, in other words, that testosterone may have beneficial effects in the cardiovascular system. However, testosterone seems to play a negative role in the severity of renal disease. In this mini-review, we briefly comment on the interplay between aging and testosterone levels, the vascular actions of testosterone and its implications for vascular aging. Renal effects of testosterone and the use of testosterone to prevent vascular dysfunction in elderly are also addressed. PMID:22514541

  8. Androgen biosynthesis in castration-resistant prostate cancer

    PubMed Central

    Penning, Trevor M

    2014-01-01

    Prostate cancer is the second leading cause of death in adult males in the USA. Recent advances have revealed that the fatal form of this cancer, known as castration-resistant prostate cancer (CRPC), remains hormonally driven despite castrate levels of circulating androgens. CRPC arises as the tumor undergoes adaptation to low levels of androgens by either synthesizing its own androgens (intratumoral androgens) or altering the androgen receptor (AR). This article reviews the major routes to testosterone and dihydrotestosterone synthesis in CRPC cells and examines the enzyme targets and progress in the development of isoform-specific inhibitors that could block intratumoral androgen biosynthesis. Because redundancy exists in these pathways, it is likely that inhibition of a single pathway will lead to upregulation of another so that drug resistance would be anticipated. Drugs that target multiple pathways or bifunctional agents that block intratumoral androgen biosynthesis and antagonize the AR offer the most promise. Optimal use of enzyme inhibitors or AR antagonists to ensure maximal benefits to CRPC patients will also require application of precision molecular medicine to determine whether a tumor in a particular patient will be responsive to these treatments either alone or in combination. PMID:24829267

  9. Development of a novel cell based androgen screening model.

    PubMed

    Campana, Carmela; Rege, Juilee; Turcu, Adina F; Pezzi, Vincenzo; Gomez-Sanchez, Celso E; Robins, Diane M; Rainey, William E

    2016-02-01

    The androgen receptor (AR) mediates the majority of androgen effects on target cells. The DNA cis-regulatory elements that respond to AR share sequence similarity with cis-regulatory elements for glucocorticoid, mineralocorticoid and progesterone receptors (GR, MR and PR, respectively). As a result, many of the current AR screening models are complicated by inaccurate activation of reporters by one of these receptor pathways. Identification of more selective androgen testing systems would be beneficial for clinical, pharmacological and toxicologic screening of AR activators. The present study describes the development of a selective androgen-responsive reporter cell line that expresses AR but does not express GR, MR and PR. CV1 cells were stably transduced to express human AR and an androgen-responsive gaussia luciferase gene. Clonal populations of AR expressing cells were isolated. Quantitative RT-PCR (qPCR) and western analysis confirmed stable integration of AR in the most responsive clonal line which was named 'CV1-ARluc'. Stimulation of CV1AR-luc with androgenic ligands (testosterone and 5α-dihydrotestosterone) for 18h caused an increase in luciferase activity in a dose-dependent manner. Other steroid hormones including aldosterone, cortisol, and progesterone did not stimulate luciferase response. The CV1-ARluc also increased luciferase activity when treated with human serum extracts. In conclusion, the CV1-ARluc cells provide a novel model system for screening of new AR agonists and antagonists and can determine the androgenic activity of human serum samples. PMID:26581480

  10. 21 CFR 310.528 - Drug products containing active ingredients offered over-the-counter (OTC) for use as an...

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... drug product. Anise, cantharides, don qual, estrogens, fennel, ginseng, golden seal, gotu kola, Korean... such drug products. Androgens (e.g., testosterone and methyltestosterone) and estrogens are...

  11. Blood androgen levels in male baboons throughout the year

    SciTech Connect

    Taranov, A.G.; Goncharov, N.P.

    1986-04-01

    This paper describes a study of possible dependence of the androgen level in male baboons on the time of year. Plasma was obtained by centrifugation of the blood at 3000 rpm and the following androgens were determined by radioimmunoassay, using chromatographic separation of the steroids on columns with celite: testosterone, 5s-dihydrotestosterone, and dehydroepiandrosterone. Plasma steriod concentrations were calculated and the results were subjected to statistical analysis by Students test. Seasonal change in the concentration of steroids in the animals' blood plasma were discovered. The results of androgen assay throughout the year and determination of their mean annual concentrations are shown.

  12. A simplified method for extracting androgens from avian egg yolks

    USGS Publications Warehouse

    Kozlowski, C.P.; Bauman, J.E.; Hahn, D.C.

    2009-01-01

    Female birds deposit significant amounts of steroid hormones into the yolks of their eggs. Studies have demonstrated that these hormones, particularly androgens, affect nestling growth and development. In order to measure androgen concentrations in avian egg yolks, most authors follow the extraction methods outlined by Schwabl (1993. Proc. Nat. Acad. Sci. USA 90:11446-11450). We describe a simplified method for extracting androgens from avian egg yolks. Our method, which has been validated through recovery and linearity experiments, consists of a single ethanol precipitation that produces substantially higher recoveries than those reported by Schwabl.

  13. Indirect androgen doping by oestrogen blockade in sports

    PubMed Central

    Handelsman, D J

    2008-01-01

    Androgens can increase muscular mass and strength and remain the most frequently abused and widely available drugs used in sports doping. Banning the administration of natural or synthetic androgens has led to a variety of strategies to circumvent the ban of the most effective ergogenic agents for power sports. Among these, a variety of indirect androgen doping strategies aiming to produce a sustained rise in endogenous testosterone have been utilized. These include oestrogen blockade by drugs that act as oestrogen receptor antagonists (antioestrogen) or aromatase inhibitors. The physiological and pharmacological basis for the effects of oestrogen blockade in men, but not women, are reviewed. PMID:18500381

  14. The Historical Role of the Production Function in Economics and Business

    ERIC Educational Resources Information Center

    Gordon, David; Vaughan, Richard

    2011-01-01

    The production function explains a basic technological relationship between scarce resources, or inputs, and output. This paper offers a brief overview of the historical significance and operational role of the production function in business and economics. The origin and development of this function over time is initially explored. Several…

  15. Mars: New Determination of Impact Crater Production Function Size Distribution

    NASA Astrophysics Data System (ADS)

    Hartmann, William K.

    2006-12-01

    Several authors have questioned our knowledge of Martian impact crater production function size-frequency distribution (PFSFD), especially at small diameters D. Plescia (2005) questioned whether any area of Mars shows size distributions used for estimating crater retention ages on Mars. McEwen et al. (2005) and McEwen and Bierhaus (2006) suggested existing PFSFD’s are hopelessly confused by the presence of secondaries, and that my isochrons give primary crater densities off by factors of several thousand at small D. In 2005, I addressed some of these concerns, noting my curves do not estimate primary crater densities per se, but show total numbers of primaries + semi-randomly “distant secondaries” (negating many McEwen et al. critiques). In 2006 I have conducted new crater counts on a PFSFD test area suggested by Ken Tanaka. This area shows young lava flows of similar crater density, west of Olympus Mons (around 30 deg N, 100 deg W). Multiple crater counts were made on several adjacent Odyssey THEMIS images and MGS MOC images, giving the SFD over a range of 11m

  16. Motivation and Productivity as a Function of Corporate Climate.

    ERIC Educational Resources Information Center

    Hellweg, Susan A.

    The current status of productivity and motivation research, particularly as they relate to communication studies and climate studies, is delineated in this paper, largely by a review of literature in these areas. In the section following the introduction, the problems of defining productivity and its relation to performance and communication are…

  17. The PPAR{gamma} ligand ciglitazone regulates androgen receptor activation differently in androgen-dependent versus androgen-independent human prostate cancer cells

    SciTech Connect

    Moss, Patrice E.; Lyles, Besstina E.; Stewart, LaMonica V.

    2010-12-10

    The androgen receptor (AR) regulates growth and progression of androgen-dependent as well as androgen-independent prostate cancer cells. Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) agonists have been reported to reduce AR activation in androgen-dependent LNCaP prostate cancer cells. To determine whether PPAR{gamma} ligands are equally effective at inhibiting AR activity in androgen-independent prostate cancer, we examined the effect of the PPAR{gamma} ligands ciglitazone and rosiglitazone on C4-2 cells, an androgen- independent derivative of the LNCaP cell line. Luciferase-based reporter assays and Western blot analysis demonstrated that PPAR{gamma} ligand reduced dihydrotestosterone (DHT)-induced increases in AR activity in LNCaP cells. However, in C4-2 cells, these compounds increased DHT-induced AR driven luciferase activity. In addition, ciglitazone did not significantly alter DHT-mediated increases in prostate specific antigen (PSA) protein or mRNA levels within C4-2 cells. siRNA-based experiments demonstrated that the ciglitazone-induced regulation of AR activity observed in C4-2 cells was dependent on the presence of PPAR{gamma}. Furthermore, overexpression of the AR corepressor cyclin D1 inhibited the ability of ciglitazone to induce AR luciferase activity in C4-2 cells. Thus, our data suggest that both PPAR{gamma} and cyclin D1 levels influence the ability of ciglitazone to differentially regulate AR signaling in androgen-independent C4-2 prostate cancer cells.

  18. Advantages and Limitations of Androgen Receptor-Based Methods for Detecting Anabolic Androgenic Steroid Abuse as Performance Enhancing Drugs

    PubMed Central

    Bailey, Kathy; Yazdi, Tahmineh; Masharani, Umesh; Tyrrell, Blake; Butch, Anthony; Schaufele, Fred

    2016-01-01

    Testosterone (T) and related androgens are performance enhancing drugs (PEDs) abused by some athletes to gain competitive advantage. To monitor unauthorized androgen abuse, doping control programs use mass spectrometry (MS) to detect androgens, synthetic anabolic-androgenic steroids (AASs) and their metabolites in an athlete’s urine. AASs of unknown composition will not be detected by these procedures. Since AASs achieve their anabolic effects by activating the Androgen Receptor (AR), cell-based bioassays that measure the effect of a urine sample on AR activity are under investigation as complementary, pan-androgen detection methods. We evaluated an AR BioAssay as a monitor for androgen activity in urine pre-treated with glucuronidase, which releases T from the inactive T-glucuronide that predominates in urine. AR BioAssay activity levels were expressed as ‘T-equivalent’ concentrations by comparison to a T dose response curve. The T-equivalent concentrations of androgens in the urine of hypogonadal participants supplemented with T (in whom all androgenic activity should arise from T) were quantitatively identical to the T measurements conducted by MS at the UCLA Olympic Analytical Laboratory (0.96 ± 0.22). All 17 AASs studied were active in the AR BioAssay; other steroids were inactive. 12 metabolites of 10 commonly abused AASs, which are used for MS monitoring of AAS doping because of their prolonged presence in urine, had reduced or no AR BioAssay activity. Thus, the AR BioAssay can accurately and inexpensively monitor T, but its ability to monitor urinary AASs will be limited to a period immediately following doping in which the active AASs remain intact. PMID:26998755

  19. Advantages and Limitations of Androgen Receptor-Based Methods for Detecting Anabolic Androgenic Steroid Abuse as Performance Enhancing Drugs.

    PubMed

    Bailey, Kathy; Yazdi, Tahmineh; Masharani, Umesh; Tyrrell, Blake; Butch, Anthony; Schaufele, Fred

    2016-01-01

    Testosterone (T) and related androgens are performance enhancing drugs (PEDs) abused by some athletes to gain competitive advantage. To monitor unauthorized androgen abuse, doping control programs use mass spectrometry (MS) to detect androgens, synthetic anabolic-androgenic steroids (AASs) and their metabolites in an athlete's urine. AASs of unknown composition will not be detected by these procedures. Since AASs achieve their anabolic effects by activating the Androgen Receptor (AR), cell-based bioassays that measure the effect of a urine sample on AR activity are under investigation as complementary, pan-androgen detection methods. We evaluated an AR BioAssay as a monitor for androgen activity in urine pre-treated with glucuronidase, which releases T from the inactive T-glucuronide that predominates in urine. AR BioAssay activity levels were expressed as 'T-equivalent' concentrations by comparison to a T dose response curve. The T-equivalent concentrations of androgens in the urine of hypogonadal participants supplemented with T (in whom all androgenic activity should arise from T) were quantitatively identical to the T measurements conducted by MS at the UCLA Olympic Analytical Laboratory (0.96 ± 0.22). All 17 AASs studied were active in the AR BioAssay; other steroids were inactive. 12 metabolites of 10 commonly abused AASs, which are used for MS monitoring of AAS doping because of their prolonged presence in urine, had reduced or no AR BioAssay activity. Thus, the AR BioAssay can accurately and inexpensively monitor T, but its ability to monitor urinary AASs will be limited to a period immediately following doping in which the active AASs remain intact. PMID:26998755

  20. Determination of escin content in androgenic embryos and hairy root culture of Aesculus hippocastanum.

    PubMed

    Calić-Dragosavac, Dusica; Zdravković-Korać, Snezana; Savikin-Fodulović, Katarina; Radojević, Ljiljana; Vinterhalter, Branka

    2010-05-01

    Escin, a group of chemically related triterpenic glycosides, is widely used in commercial preparations for the treatment of venous insufficiency. Since the zygotic embryo cotyledons accumulate the highest amount of escin, it is currently extracted from the seeds of horse chestnut, Aesculus hippocastanum L. (Hippocastanaceae), on a large scale. As this material is available during only short period of the year, we studied the possibility of using plant tissue culture to obtain escin. For this purpose, the content of escin in androgenic embryos and hairy root cultures of horse chestnut was studied. Escin content was found to be dependent on the stage of androgenic embryo development and the type of phytoregulator supplemented to the nutritive medium. In the absence of phytoregulators, androgenic embryos at the globular stage of development contained approximately four times less escin than those at the cotyledonary stage. Inclusion of various phytoregulators in the nutritive media stimulated escin production. Among them, 2,4-dichlorophenoxyacetic acid (2,4-D) showed the most pronounced effect, with escin content almost reaching that found in zygotic embryos (6.77% versus 6.96%). Two hairy root clones produced substantial amounts of escin (3.57% and 4.09%), less than zygotic embryos, but higher than cotyledonary embryos on phytoregulator-free medium. PMID:20645800

  1. Androgenic and spermatogenic activity of alkylamide-rich ethanol solution extract of Anacyclus pyrethrum DC.

    PubMed

    Sharma, Vikas; Boonen, Jente; Spiegeleer, Bart De; Dixit, V K

    2013-01-01

    Anacyclus pyrethrum (A. pyrethrum) has been used as Vajikaran Rasayana (aphrodisiac) in traditional Indian ayurvedic medicine to treat male sexual dysfunction, including infertility. Aphrodisiac activity may be due to an increase in the production or effect of androgens, so this study sought to evaluate the androgenic and spermatogenic potential of the alkylamide-rich ethanol solution extract. Male Wistar strain rats weighing between 150 and 180 g were completely randomized divided into five groups. The ethanol solution extract of A. pyrethrum was administered to groups of rats in 50, 100, and 150 mg/kg doses for a period of 28 days, and the action was compared with control and testosterone-treated rats. Thirteen N-alkylamides were detected in the extract by using HPLC/UV/electrospray ionization mass spectrometry method. Extract administration at all the doses produced significant increase in body weight, sperm count, motility, and viability along with serum testosterone, luteinizing hormone, and follicle-stimulating hormone concentrations. Histoarchitecture of testis revealed increased spermatogenic activities. Seminal fructose content was also significantly increased after 28 days of treatment. Our results suggest that the ethanol solution extract of the roots of A. pyrethrum has androgenic potential and may improve male fertility by enhancing spermatogenesis. PMID:22473789

  2. Androgen modulation of social decision-making mechanisms in the brain: an integrative and embodied perspective

    PubMed Central

    Oliveira, Gonçalo A.; Oliveira, Rui F.

    2014-01-01

    Apart from their role in reproduction androgens also respond to social challenges and this response has been seen as a way to regulate the expression of behavior according to the perceived social environment (Challenge hypothesis, Wingfield et al., 1990). This hypothesis implies that social decision-making mechanisms localized in the central nervous system (CNS) are open to the influence of peripheral hormones that ultimately are under the control of the CNS through the hypothalamic-pituitary-gonadal axis. Therefore, two puzzling questions emerge at two different levels of biological analysis: (1) Why does the brain, which perceives the social environment and regulates androgen production in the gonad, need feedback information from the gonad to adjust its social decision-making processes? (2) How does the brain regulate gonadal androgen responses to social challenges and how do these feedback into the brain? In this paper, we will address these two questions using the integrative approach proposed by Niko Tinbergen, who proposed that a full understanding of behavior requires its analysis at both proximate (physiology, ontogeny) and ultimate (ecology, evolution) levels. PMID:25100938

  3. Redirecting abiraterone metabolism to fine-tune prostate cancer anti-androgen therapy.

    PubMed

    Li, Zhenfei; Alyamani, Mohammad; Li, Jianneng; Rogacki, Kevin; Abazeed, Mohamed; Upadhyay, Sunil K; Balk, Steven P; Taplin, Mary-Ellen; Auchus, Richard J; Sharifi, Nima

    2016-05-26

    Abiraterone blocks androgen synthesis and prolongs survival in patients with castration-resistant prostate cancer, which is otherwise driven by intratumoral androgen synthesis. Abiraterone is metabolized in patients to Δ(4)-abiraterone (D4A), which has even greater anti-tumour activity and is structurally similar to endogenous steroidal 5α-reductase substrates, such as testosterone. Here, we show that D4A is converted to at least three 5α-reduced and three 5β-reduced metabolites in human serum. The initial 5α-reduced metabolite, 3-keto-5α-abiraterone, is present at higher concentrations than D4A in patients with prostate cancer taking abiraterone, and is an androgen receptor agonist, which promotes prostate cancer progression. In a clinical trial of abiraterone alone, followed by abiraterone plus dutasteride (a 5α-reductase inhibitor), 3-keto-5α-abiraterone and downstream metabolites were depleted by the addition of dutasteride, while D4A concentrations rose, showing that dutasteride effectively blocks production of a tumour-promoting metabolite and permits D4A accumulation. Furthermore, dutasteride did not deplete the three 5β-reduced metabolites, which were also clinically detectable, demonstrating the specific biochemical effects of pharmacological 5α-reductase inhibition on abiraterone metabolism. Our findings suggest a previously unappreciated and biochemically specific method of clinically fine-tuning abiraterone metabolism to optimize therapy. PMID:27225130

  4. Effects of triclocarban on intact immature male rat: augmentation of androgen action.

    PubMed

    Duleba, Antoni J; Ahmed, Mohamed I; Sun, Meng; Gao, Allen C; Villanueva, Jesus; Conley, Alan J; Turgeon, Judith L; Benirschke, Kurt; Gee, Nancy A; Chen, Jiangang; Green, Peter G; Lasley, Bill L

    2011-02-01

    Triclocarban (TCC; 3,4,4'-trichlorocarbanilide) is an antimicrobial agent used widely in various personal hygiene products including soaps. Recently, TCC has been shown to enhance testosterone-induced effects in vitro and to enlarge accessory sex organs in castrated male rats. This study was designed to evaluate the effects of TCC on intact age-matched male rats and on human prostate LNCaP and C4-2B cells. Seven-week-old male Sprague-Dawley rats received either a normal diet or a diet supplemented with TCC (0.25% in diet) for 10 days. Triclocarban induced hyperplasia of accessory sex organs in the absence of significant qualitative histological changes. Serum luteinizing hormone (LH) and testosterone were not significantly altered by TCC treatment. In prostate cancer-derived LNCaP and C4-2B cells, TCC potentiated androgen actions via androgen receptor-dependent actions. In conclusion, TCC significantly affects intact male reproductive organs and potentiates androgen effects in prostate cancer cells. PMID:20889956

  5. Structural analysis of complementary DNA and amino acid sequences of human and rat androgen receptors

    SciTech Connect

    Chang, C.; Kokontis, J.; Liao, S. )

    1988-10-01

    Structural analysis of cDNAs for human and rat androgen receptors (ARs) indicates that the amino-terminal regions of ARs are rich in oligo- and poly(amino acid) motifs as in some homeotic genes. The human AR has a long stretch of repeated glycines, whereas rat AR has a long stretch of glutamines. There is a considerable sequence similarity among ARs and the receptors for glucocorticoids, progestins, and mineralocorticoids within the steroid-binding domains. The cysteine-rich DNA-binding domains are well conserved. Translation of mRNA transcribed from AR cDNAs yielded 94- and 76-kDa proteins and smaller forms that bind to DNA and have high affinity toward androgens. These rat or human ARs were recognized by human autoantibodies to natural Ars. Molecular hybridization studies, using AR cDNAs as probes, indicated that the ventral prostate and other male accessory organs are rich in AR mRNA and that the production of AR mRNA in the target organs may be autoregulated by androgens.

  6. Androgen Receptor Targeted Conjugate for Bimodal Photodynamic Therapy of Prostate Cancer in Vitro.

    PubMed

    Rapozzi, Valentina; Ragno, Daniele; Guerrini, Andrea; Ferroni, Claudia; della Pietra, Emilia; Cesselli, Daniela; Castoria, Gabriella; Di Donato, Marzia; Saracino, Emanuela; Benfenati, Valentina; Varchi, Greta

    2015-08-19

    Prostate cancer (PC) represents the most common type of cancer among males and is the second leading cause of cancer death in men in Western society. Current options for PC therapy remain unsatisfactory, since they often produce uncomfortable long-term side effects, such as impotence (70%) and incontinence (5-20%) even in the first stages of the disease. Light-triggered therapies, such as photodynamic therapy, have the potential to provide important advances in the treatment of localized and partially metastasized prostate cancer. We have designed a novel molecular conjugate (DR2) constituted of a photosensitizer (pheophorbide a, Pba), connected to a nonsteroidal anti-androgen molecule through a small pegylated linker. This study aims at investigating whether DR2 represents a valuable approach for PC treatment based on light-induced production of single oxygen and nitric oxide (NO) in vitro. Besides being able to efficiently bind the androgen receptor (AR), the 2-trifluoromethylnitrobenzene ring on the DR2 backbone is able to release cytotoxic NO under the exclusive control of light, thus augmenting the general photodynamic effect. Although DR2 is similarly internalized in cells expressing different levels of androgen receptor, the AR ligand prevents its efflux through the ABCG2-pump. In vitro phototoxicity experiments demonstrated the ability of DR2 to kill cancer cells more efficiently than Pba, while no dark toxicity was observed. Overall, the presented approach is very promising for further development of AR-photosensitizer conjugates in the multimodal photodynamic treatment of prostate cancer. PMID:26108715

  7. Selective activity of deguelin identifies therapeutic targets for androgen receptor-positive breast cancer.

    PubMed

    Robles, Andrew J; Cai, Shengxin; Cichewicz, Robert H; Mooberry, Susan L

    2016-06-01

    Triple-negative breast cancers (TNBC) are aggressive malignancies with no effective targeted therapies. Recent gene expression profiling of these heterogeneous cancers and the classification of cell line models now allows for the identification of compounds with selective activities against molecular subtypes of TNBC. The natural product deguelin was found to have selective activity against MDA-MB-453 and SUM-185PE cell lines, which both model the luminal androgen receptor (LAR) subtype of TNBC. Deguelin potently inhibited proliferation of these cells with GI50 values of 30 and 61 nM, in MDA-MB-453 and SUM-185PE cells, respectively. Deguelin had exceptionally high selectivity, 197 to 566-fold, for these cell lines compared to cell lines representing other TNBC subtypes. Deguelin's mechanisms of action were investigated to determine how it produced these potent and selective effects. Our results show that deguelin has dual activities, inhibiting PI3K/Akt/mTOR signaling, and decreasing androgen receptor levels and nuclear localization. Based on these data, we hypothesized that the combination of the mTOR inhibitor rapamycin and the antiandrogen enzalutamide would have efficacy in LAR models. Rapamycin and enzalutamide showed additive effects in MDA-MB-453 cells, and both drugs had potent antitumor efficacy in a LAR xenograft model. These results suggest that the combination of antiandrogens and mTOR inhibitors might be an effective strategy for the treatment of androgen receptor-expressing TNBC. PMID:27255535

  8. Heterodimers and homodimers of inhibin subunits have different paracrine action in the modulation of luteinizing hormone-stimulated androgen biosynthesis.

    PubMed Central

    Hsueh, A J; Dahl, K D; Vaughan, J; Tucker, E; Rivier, J; Bardin, C W; Vale, W

    1987-01-01

    Inhibin, a gonadal hormone capable of preferential suppression of pituitary follicle-stimulating hormone (FSH) secretion, has recently been purified. The major form of this protein is an alpha beta heterodimer encoded by two separate genes. In contrast to the FSH-suppressing action of the alpha beta heterodimer, the beta beta homodimer stimulates FSH secretion. Luteinizing hormone (LH)-secreting pituitary cells and gonadal androgen-producing cells have long been shown to form a closed-loop feedback axis. Based on recent studies demonstrating the FSH stimulation of inhibin biosynthesis by ovarian granulosa and testis Sertoli cells, an additional closed-loop feedback axis exists between pituitary FSH- and gonadal inhibin-producing cells. Because uncharacterized Sertoli cell factors have been suggested to either stimulate or inhibit androgen production by testicular Leydig cells, we have tested the intragonadal paracrine actions of heterodimers and homodimers of inhibin subunits. In primary cultures of testis cells, the alpha beta heterodimer of inhibin enhances Leydig cell androgen biosynthesis stimulated by LH, whereas the beta beta homodimer suppresses androgen production. Furthermore, similar modulatory actions of inhibin-related proteins were found in cultured ovarian theca-interstitial cells and theca explants treated with LH. In contrast, treatment with the inhibin-related proteins alone did not affect gonadal steroidogenesis. Our data indicate that the inhibin-related gene products synthesized by Sertoli and granulosa cells may form heterodimers or homodimers to serve as intragonadal paracrine signals in the modulation of LH-stimulated androgen biosynthesis and allow cross-communication between the two feedback loops. PMID:3474640

  9. The model anti-androgen flutamide suppresses the expression of typical male stickleback reproductive behaviour.

    PubMed

    Sebire, Marion; Allen, Yvonne; Bersuder, Philippe; Katsiadaki, Ioanna

    2008-10-20

    Over the past 15 years considerable attention has been given to the presence in the environment of endocrine disrupting chemicals (EDCs) that may have harmful effects on organisms. Specific test guidelines for the detection of EDCs used for short-term fish screening assays have been developed by the Organisation for Economic Cooperation and Development (OECD). Compared to the core species used in the OECD guidelines, the three-spined stickleback (Gasterosteus aculeatus) has an additional and unique endpoint for (anti-)androgenic substances through the androgen-dependent glue protein (spiggin) used in the nest building. Here we describe a specific behavioural assay that was developed in parallel to the OECD protocol, utilising unique behavioural features of sticklebacks. In the assay, a photoperiod of 16L:8D (light:dark) and a temperature of 17+/-1 degrees C was used to induce breeding in quiescent male sticklebacks that were simultaneously exposed for a 21-day period to the mammalian anti-androgen flutamide (FL) at 100, 500 and 1000 microg/l (plus a water control). Spiggin production and the reproductive behaviour (nest building and courtship) of male sticklebacks were the main measured endpoints. The control fish entered an active breeding cycle including nest building and courtship behaviours as expected due to the stimulating temperature and photoperiodic conditions. The FL-exposed males showed significantly lower spiggin levels at 500 and 1000 microg/l. In addition, there was a significant decrease in the number of nests built by the FL-treated males at 100 microg/l with no nest built at 500 and 1000 microg/l. Finally, FL affected the courtship behaviour of the males with a significant reduction of the number of zigzags towards the female. When the breeding status of the stickleback males is controlled, the behavioural assay developed here is a suitable tool for the detection of androgen antagonists. PMID:18809216

  10. Peripheral androgen receptors sustain the acrobatics and fine motor skill of elaborate male courtship.

    PubMed

    Fuxjager, Matthew J; Longpre, Kristy M; Chew, Jennifer G; Fusani, Leonida; Schlinger, Barney A

    2013-09-01

    Androgenic hormones regulate many aspects of animal social behavior, including the elaborate display routines on which many species rely for advertisement and competition. One way that this might occur is through peripheral effects of androgens, particularly on skeletal muscles that control complex movements and postures of the body and its limbs. However, the specific contribution of peripheral androgen-muscle interactions to the performance of elaborate behavioral displays in the natural world has never been examined. We study this issue in one of the only natural physiological models of animal acrobatics: the golden-collared manakin (Manacus vitellinus). In this tropical bird, males compete with each other and court females by producing firecracker-like wing- snaps and by rapidly dancing among saplings over the forest floor. To test how activation of peripheral androgen receptors (AR) influences this display, we treat reproductively active adult male birds with the peripherally selective antiandrogen bicalutamide (BICAL) and observe the effects of this manipulation on male display performance. We not only validate the peripheral specificity of BICAL in this species, but we also show that BICAL treatment reduces the frequency with which adult male birds perform their acrobatic display maneuvers and disrupts the overall structure and fine-scale patterning of these birds' main complex wing-snap sonation. In addition, this manipulation has no effect on the behavioral metrics associated with male motivation to display. Together, our findings help differentiate the various effects of peripheral and central AR on the performance of a complex sociosexual behavioral phenotype by indicating that peripheral AR can optimize the motor skills necessary for the production of an elaborate animal display. PMID:23782945

  11. Anabolic androgenic steroid-induced hepatotoxicity.

    PubMed

    Bond, Peter; Llewellyn, William; Van Mol, Peter

    2016-08-01

    Anabolic androgenic steroids (AAS) have been abused for decades by both professional and amateur athletes in order to improve physical performance or muscle mass. AAS abuse can cause adverse effects, among which are hepatotoxic effects. These effects include cholestatic icterus and possibly peliosis hepatis and hepatocellular carcinoma or adenoma. In particular, 17α-alkylated AAS appear to be hepatotoxic, whereas nonalkylated AAS appear not to be. The 17α-alkyl substitution retards hepatic metabolism of the AAS rendering it orally bioavailable. The mechanism responsible for the hepatotoxicity induced by 17α-alkylated AAS remains poorly understood. However, oxidative stress has been repeatedly shown to be associated with it. In this manuscript we present a hypothesis which describes a potential mechanism responsible for AAS-induced hepatotoxicity, based on several observations from the literature which suggest oxidative stress being a causal factor. PMID:27372877

  12. [Control measures for anabolic androgenic steroid medicines].

    PubMed

    Vázquez-Mourelle, Raquel; Carracedo-Martínez, Eduardo; Ces Gens, Eugenio; Cadórniga Valiño, Luis; Álvaro Esteban, Pilar; Pose Reino, José Manuel

    2015-01-01

    Anabolic androgenic steroids (AAS) can cause serious adverse effects when used without a therapeutic purpose. This article aims to show that the AAS are susceptible to being sold on the black market. We also aim to describe how certain limitations on the health inspection services of the Galician health service to pursue these illegal actions prompted a regulatory initiative demanding that additional actions be granted to community pharmacies when dispensing AAS. Four pharmacy inspections detected the diversion of a total of 3118 packages of AAS, which led to the opening of four disciplinary proceedings. In two of these, specialized police forces were called in as there was sufficient evidence of possible diversion to gymnasiums, resulting in a police operation called Operation Fitness. PMID:25778637

  13. Androgenic alopecia in women: an Indian perspective.

    PubMed

    Sehgal, Virendra N; Srivastava, Govind; Aggarwal, Ashok K; Midha, Reshmi

    2013-01-01

    The authors sought to investigate androgenic alopecia (AA) utilizing clinical and investigative procedures to establish the pattern of AA in the Indian subcontinent. A total of 35 consecutive women presenting with AA were included. After obtaining informed consent, a detailed history/examination, hair pull test, trichogram, and a scalp biopsy were performed in patients. AA classification was attempted across Ludwig and Norwood guidelines. Of 35 women, 16 had grade I, 10 had grade II, and 1 had grade III Ludwig classification. In addition, 6 other women had Christmas tree baldness: 1 each of fronto-parietal and male pattern baldness. Several investigations including hormonal profile were inconclusive; however, hair pull test and trichogram may be helpful in understanding the sequence in AA in women. AA has infrequently been reported, particularly India and in Asia in general. PMID:24517037

  14. A case of postmenopausal androgen excess.

    PubMed

    Lambrinoudaki, Irene; Dafnios, Nikos; Kondi-Pafiti, Agathi; Triantafyllou, Nikos; Karopoulou, Evangelia; Papageorgiou, Anastasia; Augoulea, Areti; Armeni, Eleni; Creatsa, Maria; Vlahos, Nikolaos

    2015-10-01

    Ovarian steroid cell tumors are very rare but potentially life-threatening neoplasms. They represent less than 0.1% of all ovarian tumors, typically present in premenopausal women and frequently manifest with virilization. Signs of hyperandrogenism may appear in postmenopausal women due to tumorοus and non-tumorοus adrenal and ovarian causes as well due to the normal aging process. In any case, steroid cell tumor should be suspected in postmenopausal women who present with rapid progressive androgen excess symptoms. This report describes a case of a 67-year-old postmenopausal woman with signs of hyperandrogenism, where an ovarian steroid cell tumor was diagnosed and treated by laparoscopic bilateral salpingo-oophorectomy and synchronous hysterectomy. PMID:26287476

  15. [Treatment of androgenic alopecia with topical minoxidil].

    PubMed

    Brenner, S; Tamir, A

    1991-11-01

    Minoxidil, a vasodilator, was first marketed in 1979 as an oral antihypertensive. Since hypertrichosis occurred as an adverse effect in most patients treated, a 2% topical solution was developed for use in men with androgenic alopecia. It was approved by the American Food and Drug Administration and by the Israel Ministry of Health. A follow-up of 30 cases treated with the preparation is presented. Efficacy of treatment was assessed by hair counts in a marked area on the balding scalp, as well as by subjective evaluations of patients and physicians. The treatment was beneficial in 63%: balding was slowed in most, while in a minority hair density actually increased. However, in only 6.6% was dramatic cosmetic improvement achieved. PMID:1800277

  16. Research of the degradation products of chitosan's angiogenic function

    NASA Astrophysics Data System (ADS)

    Wang, Jianyun; Chen, Yuanwei; Ding, Yulong; Shi, Guoqi; Wan, Changxiu

    2008-11-01

    Angiogenesis is of great importance in tissue engineering and has gained large attention in the past decade. But how it will be influenced by the biodegradable materials, especially their degradation products, remains unknown. Chitosan (CS) is a kind of naturally occurred polysaccharide which can be degraded in physiological environment. In order to gain some knowledge of the influences of CS degradation products on angiogenesis, the interaction of vascular endothelial cells with the degradation products was investigated in the present study. The CS degradation products were prepared by keeping CS sample in physiological saline aseptically at 37 °C for 120 days. Endothelial cells were co-cultured with the degradation products and the angiogenic cell behaviors, including cell proliferation, migration and tube-like structure (TLS) formation, were tested by MTT assay, cell migration quantification method (CMQM), and tube-like structure quantification method (TLSQM) respectively. Furthermore, mRNA expressions of vascular endothelial growth factor (VEGF) and matrix metallo proteinase (MMP-2) were determined by real-time reverse transcriptional polymerase chain reaction (RT-PCR). Physiological saline served as a negative control. As the results showed, the degradation products obtained from 20th to 60th day significantly inhibited the proliferation, migration, and TLS formation of endothelial cells. However, degradation products of the first 14 days and the last 30 days were found to be proangiogenic. At the molecular level, the initial results indicated that the mRNA expressions of VEGF and MMP-2 were increased by the degradation products of 7th day, but were decreased by the ones of 60th day. According to all the results, it could be concluded that the angiogenic behaviors of endothelial cells at both cellular and molecular level could be significantly stimulated or suppressed by the degradation products of CS and the influences are quite time-dependent.

  17. Propagation of spectral functions and dilepton production at SIS energies

    SciTech Connect

    Wolf, Gy.; Kaempfer, B.; Zetenyi, M.

    2012-06-15

    The time evolution of vector meson spectral functions is studied within a BUU-type transport model. Applications focus on {rho} and {omega} mesons being important pieces for the interpretation of the dielectron invariant mass spectrum. Since the evolution of the spectral functions is driven by the local density, the inmedium modifications turn out to compete, in this approach, with the known vacuum contributions.

  18. Aneuploidy among androgenic progeny of hexaploid triticale (XTriticosecale Wittmack).

    PubMed

    Oleszczuk, Sylwia; Rabiza-Swider, Julita; Zimny, Janusz; Lukaszewski, Adam J

    2011-04-01

    Doubled haploids are an established tool in plant breeding and research. Of several methods for their production, androgenesis is technically simple and can efficiently produce substantial numbers of lines. It is well suited to such crops as hexaploid triticale. Owing to meiotic irregularities of triticale hybrids, aneuploidy may affect the efficiency of androgenesis more severely than in meiotically stable crops. This study addresses the issue of aneuploidy among androgenic regenerants of triticale. Plant morphology, seed set and seed quality were better predictors of aneuploidy, as determined cytologically, than flow cytometry. Most aneuploids were hypoploids and these included nullisomics, telosomics, and translocation lines; among 42 chromosome plants were nulli-tetrasomics. Rye chromosomes involved in aneuploidy greatly outnumbered wheat chromosomes; in C(0) rye chromosomes 2R and 5R were most frequently involved. While the frequency of nullisomy 2R was fairly constant in most cross combinations, nullisomy 5R was more frequent in the most recalcitrant combination, and its frequency increased with time spent in culture with up to 70% of green plants recovered late being nullisomic 5R. Given that 5R was not involved in meiotic aberrations with an above-average frequency, it is possible that its absence promotes androgenesis or green plant regeneration. Overall, aneuploidy among tested combinations reduced the average efficiency of double haploid production by 35% and by 69% in one recalcitrant combination, seriously reducing the yield of useful lines. PMID:21170716

  19. Temperature regulates methane production through the function centralization of microbial community in anaerobic digestion.

    PubMed

    Lin, Qiang; De Vrieze, Jo; He, Guihua; Li, Xiangzhen; Li, Jiabao

    2016-09-01

    Temperature is crucial for the performance of anaerobic digestion process. In this study of anaerobic digestion of swine manure, the relationship between the microbial gene expression and methane production at different temperatures (25-55°C) was revealed through metatranscriptomic analysis. Daily methane production and total biogas production increased with temperature up to 50°C, but decreased at 55°C. The functional gene expression showed great variation at different temperatures. The function centralization (opposite to alpha-diversity), assessed by the least proportions of functional pathways contributing for at least 50% of total reads positively correlated to methane production. Temperature regulated methane production probably through reducing the diversity of functional pathways, but enhancing central functional pathways, so that most of cellular activities and resource were invested in methanogenesis and related pathways, enhancing the efficiency of conversion of substrates to methane. This research demonstrated the importance of function centralization for efficient system functioning. PMID:27236402

  20. Threat perception and familiarity moderate the androgen response to competition in women

    PubMed Central

    Oliveira, Gonçalo A.; Uceda, Sara; Oliveira, Tânia; Fernandes, Alexandre; Garcia-Marques, Teresa; Oliveira, Rui F.

    2013-01-01

    Social interactions elicit androgen responses whose function has been posited to be the adjustment of androgen-dependent behaviors to social context. The activation of this androgen response is known to be mediated and moderated by psychological factors. In this study we tested the hypothesis that the testosterone (T) changes after a competition are not simply related to its outcome, but rather to the way the subject evaluates the event. In particular we tested two evaluative dimensions of a social interaction: familiarity with the opponent and the subjective evaluation of the outcome as threat or challenge. Challenge/threat occurs in goal relevant situations and represent different motivational states arising from the individuals’ subjective evaluation of the interplay between the task demands and coping resources possessed. For challenge the coping resources exceed the task demands, while threat represents a state where coping resources are insufficient to meet the task demands. In this experiment women competed in pairs, against a same sex opponent using the number tracking test as a competitive task. Losers appraised the competition outcome as more threatening than winners, and displayed higher post-competition T levels than winners. No differences were found either for cortisol (C) or for dehydroepiandrosterone. Threat, familiarity with the opponent and T response were associated only in the loser condition. Moderation analysis suggests that for the women that lost the competition the effect of threat on T is moderated by familiarity with the opponent. PMID:23847564

  1. Effects of testosterone on synaptic plasticity mediated by androgen receptors in male SAMP8 mice.

    PubMed

    Jia, Jian-Xin; Cui, Cheng-Li; Yan, Xu-Sheng; Zhang, Bai-Feng; Song, Wei; Huo, Dong-Sheng; Wang, He; Yang, Zhan-Jun

    2016-01-01

    Synaptic changes are closely associated with cognitive deficits. In addition, testosterone (T) is known to exert regulative effects on synaptic plasticity. T may improve cognitive deficits in Alzheimer's disease (AD) patients, but the underlying mechanisms of androgenic action on cognitive performance remain unclear. The aim of this study was thus to examine the protective mechanism attributed to T on cognitive performance in an AD senescence, accelerated mouse prone 8 (SAMP8) animal model. Using Golgi staining to quantify the dendritic spine density in hippocampal CA1 region, molecular biomarkers of synapse function were analyzed using immunohistochemistry and western blot. T significantly increased the dendritic spine density in hippocampal CA1 region, while flutamide (F) inhibited these T-mediated effects. Immunohistochemistry and western blot analysis showed that the expression levels of brain derived neurotrophic factor (BDNF), postsynaptic density 95 (PSD-95), and p-cyclic-AMP response element binding protein (CREB)/CREB levels were significantly elevated in the T group, but F reduced the T-induced effects in these biomarkers to control levels. There were no significant differences in the expression levels of PSD-95, BDNF, and p-CREB/CREB between C and F. These findings indicate that the effects of T on improvement in synaptic plasticity were mediated via androgen receptor (AR). It is conceivable that new treatments targeted toward preventing synaptic pathology in AD may involve the use of androgen-acting drugs. PMID:27599230

  2. FOXA1 regulates androgen receptor variant activity in models of castrate-resistant prostate cancer

    PubMed Central

    Nakjang, Sirintra; Chaytor, Lewis; Grey, James; Robson, Craig N.; Gaughan, Luke

    2015-01-01

    Retention of androgen receptor (AR) signalling in castrate-resistant prostate cancer (CRPC) highlights the requirement for the development of more effective AR targeting therapies. A key mechanism of resistance to anti-androgens is through expression of constitutively active AR variants (AR-Vs) that are refractory to next-generation therapies, including Enzalutamide and Abiraterone. By maintaining an androgenic gene signature, AR-Vs drive tumour survival and progression in castrate conditions. Critically, however, our understanding of the mechanics of AR-V-driven transcription is limited, particularly with respect to dependency on pioneer factor function. Here we show that depletion of FOXA1 in the CWR22Rv1 CRPC cell line abrogates the oncogenic potential of AR-Vs. Gene expression profiling reveals that approximately 41% of the AR-V transcriptome requires FOXA1 and that depletion of FOXA1 attenuates AR-V binding at a sub-set of analysed co-regulated genes. Interestingly, AR-V levels are elevated in cells depleted of FOXA1 as a consequence of attenuated negative feedback on the AR gene, but is insufficient to maintain cell growth as evidenced by marked anti-proliferative effects in FOXA1 knockdown cells. In all, our data suggests that AR-Vs are dependent on FOXA1 for sustaining a pro-proliferative gene signature and agents targeting FOXA1 may represent novel therapeutic options for CRPC patients. PMID:26336819

  3. Seasonal expression of androgen receptor in scented gland of muskrat (Ondatra zibethicus).

    PubMed

    Lu, Lu; Liu, Shuqiang; Li, Qinglin; Huang, Shiyang; Bao, Lihong; Sheng, Xia; Han, Yingying; Watanabe, Gen; Taya, Kazuyoshi; Weng, Qiang

    2014-08-01

    Muskrat is a seasonal breeder, males of which secret musk from paired perineal scented glands found beneath the skin at the ventral base of the tail for attracting female during the breeding season. The aim of this study was to investigate the seasonal changes of expression of androgen receptor (AR) in the scented gland of muskrat during the breeding and nonbreeding seasons. Histologically, glandular cells, interstitial cells and excretory tubules were identified in scented glands in both seasons, whereas epithelial cells were sparse in the nonbreeding season. AR was observed in glandular cells of scented glands during the breeding and nonbreeding seasons with stronger immunostaining during the breeding season compared to the nonbreeding season. Consistent with the immunohistochemical results, AR protein level was higher in the scented glands of the breeding season, and then decreased to a relatively low level in the nonbreeding season. The mean mRNA level of Ar was significantly higher in the breeding season than in the nonbreeding season. In addition, plasma gonadotropins and testosterone concentrations were remarkably higher in the breeding season than those in the nonbreeding season. These results suggested that muskrat scented gland was the direct target organ of androgen, and stronger expression of AR in scented glands during the breeding season suggested that androgens may directly influence scented glandular function of the muskrats and also courtship behavior as we inferred. PMID:24818970

  4. RNA Editing of Androgen Receptor Gene Transcripts in Prostate Cancer Cells*S⃞

    PubMed Central

    Martinez, Harryl D.; Jasavala, Rohini J.; Hinkson, Izumi; Fitzgerald, Latricia D.; Trimmer, James S.; Kung, Hsing-Jien; Wright, Michael E.

    2008-01-01

    Reactivation of the androgen receptor (AR) signaling pathway represents a critical step in the growth and survival of androgen-independent (AI) prostate cancer (CaP). In this study we show the DU145 and PC3 AI human CaP cell lines respond to androgens and require AR expression for optimal proliferation in vitro. Interestingly, AR gene transcripts in DU145 and PC3 cells harbored a large number of single base pair nucleotide transitions that resulted in missense mutations in selected AR codons. The most notable lesion detected in AR gene transcripts included the oncogenic codon 877T→A gain-of-function mutation. Surprisingly, AR gene transcript nucleotide transitions were not genome-encoded substitutions, but instead the mutations co-localized to putative A-to-I, U-to-C, C-to-U, and G-to-A RNA editing sites, suggesting the lesions were mediated through RNA editing mechanisms. Higher levels of mRNA encoding the A-to-I RNA editing enzymes ADAR1 and ADARB1 were observed in DU145 and PC3 cells relative to the androgen-responsive LNCaP and 22Rv1 human CaP cell lines, which correlated with higher levels of AR gene transcript A-to-I editing detected in DU145 and PC3 cells. Our results suggest that AR gene transcripts are targeted by different RNA editing enzymes in DU145 and PC3 cells. Thus RNA editing of AR gene transcripts may contribute to the etiology of hormone-refractory phenotypes in advanced stage AI CaP. PMID:18708348

  5. Effects of testosterone replacement in men with opioid-induced androgen deficiency: a randomized controlled trial.

    PubMed

    Basaria, Shehzad; Travison, Thomas G; Alford, Daniel; Knapp, Philip E; Teeter, Kjersten; Cahalan, Christine; Eder, Richard; Lakshman, Kishore; Bachman, Eric; Mensing, George; Martel, Marc O; Le, Dillon; Stroh, Helene; Bhasin, Shalender; Wasan, Ajay D; Edwards, Robert R

    2015-02-01

    Symptomatic androgen deficiency is common in patients taking opioid analgesics, as these drugs potently suppress the hypothalamic-pituitary-gonadal axis. However, the efficacy of testosterone replacement in this setting remains unclear. The objective of this trial was to evaluate the efficacy of testosterone replacement on pain perception and other androgen-dependent outcomes in men with opioid-induced androgen deficiency. We conducted a randomized, double-blind, parallel placebo-controlled trial at an outpatient academic research center. Participants were men aged 18 to 64 years on opioid analgesics for chronic noncancer pain, and total testosterone levels were <350 ng/dL. Participants were randomly assigned to 14 weeks of daily transdermal gel that contained 5 g of testosterone or placebo. Primary outcomes were changes in self-reported clinical pain and objectively assessed pain sensitivity. Sexual function, quality of life, and body composition were also assessed. The mean age was 49 years. The median total and free testosterone levels at baseline were 243 ng/dL and 47 pg/mL and 251 ng/dL and 43 pg/mL in the testosterone and placebo arm, respectively. Of the 84 randomized participants, 65 had follow-up data on efficacy outcomes. Compared with men assigned to the placebo arm, those assigned to testosterone replacement experienced greater improvements in pressure and mechanical hyperalgesia, sexual desire, and role limitation due to emotional problems. Testosterone administration was also associated with an improvement in body composition. There were no between-group differences in changes in self-reported pain. In conclusion, in men with opioid-induced androgen deficiency, testosterone administration improved pain sensitivity, sexual desire, body composition, and aspects of quality of life. PMID:25599449

  6. Towards a non-animal risk assessment for anti-androgenic effects in humans.

    PubMed

    Dent, Matthew P; Carmichael, Paul L; Jones, Kevin C; Martin, Francis L

    2015-10-01

    Toxicology testing is undergoing a transformation from a system based on high-dose studies in laboratory animals to one founded primarily on in vitro methods that evaluate changes in normal cellular signalling pathways using human-relevant cells or tissues. We review the tools and approaches that could be used to develop a non-animal safety assessment for anti-androgenic effects in humans, with a focus on the molecular initiating events (MIEs) that human disorders indicate critical for normal functioning of the hypothalamus-pituitary-testicular (HPT) axis. In vitro test systems exist which can be used to characterize the effects of test chemicals on some MIEs such as androgen receptor antagonism, inhibition of steroidogenic enzymes or 5α-reductase inhibition. When used alongside information describing the pharmacokinetics of a specific chemical exposure, these could be used to inform a pathways-based safety assessment. However, some parts of the HPT axis such as events occurring in the hypothalamus or pituitary are not well represented by accepted in vitro methods. In vitro tools to characterize perturbations in these events need to be developed before a fully integrated model of the HPT axis can be described. Knowledge gaps also exist which prevent us from using in vitro data to predict the type and severity of in vivo effect(s) that could arise from a given level of in vitro anti-androgenic activity. This means that more work is needed to reliably link an MIE with an adverse outcome. However, especially for chemicals with low anti-androgenic activity, human exposure data can be used to put in vitro mode of action data into context for risk-based safety decision-making. PMID:26115536

  7. Targeting of androgen receptor in bone reveals a lack of androgen anabolic action and inhibition of osteogenesis A model for compartment-specific androgen action in the skeleton

    PubMed Central

    Wiren, Kristine M.; Semirale, Anthony A.; Zhang, Xiao-Wei; Woo, Adrian; Tommasini, Steven M.; Price, Christopher; Schaffler, Mitchell B.; Jepsen, Karl J.

    2008-01-01

    Androgens are anabolic hormones that affect many tissues, including bone. However, an anabolic effect of androgen treatment on bone in eugonadal subjects has not been observed and clinical trials have been disappointing. The androgen receptor (AR) mediates biological responses to androgens. In bone tissue, both AR and the estrogen receptor (ER) are expressed. Since androgens can be converted into estrogen, the specific role of the AR in maintenance of skeletal homoeostasis remains controversial. The goal of this study was to use skeletally targeted overexpression of AR in differentiated osteoblasts as a means of elucidating the specific role(s) for AR transactivation in the mature bone compartment. Transgenic mice overexpressing AR under the control of the 2.3-kb α1(I)-collagen promoter fragment showed no difference in body composition, testosterone, or 17β-estradiol levels. However, transgenic males have reduced serum osteocalcin, CTx and TRAPC5b levels, and a bone phenotype was observed. In cortical bone, high-resolution micro-computed tomography revealed no difference in periosteal perimeter but a significant reduction in cortical bone area due to an enlarged marrow cavity. Endocortical bone formation rate was also significantly inhibited. Biomechanical analyses showed decreased whole bone strength and quality, with significant reductions in all parameters tested. Trabecular morphology was altered, with increased bone volume comprised of more trabeculae that were closer together but not thicker. Expression of genes involved in bone formation and bone resorption was significantly reduced. The consequences of androgen action are compartment-specific; anabolic effects are exhibited exclusively at periosteal surfaces, but in mature osteoblasts androgens inhibited osteogenesis with detrimental effects on matrix quality, bone fragility and whole bone strength. Thus, the present data demonstrate that enhanced androgen signaling targeted to bone results in low bone

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

    PubMed

    Kharlyngdoh, Joubert Banjop; Asnake, Solomon; Pradhan, Ajay; Olsson, Per-Erik

    2016-09-15

    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 ART877A mutation, which is frequently detected mutation in PCa tumors and the ARW741C 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. In the present study we investigated the effect of AR mutations (ARW741C and ART877A) 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 ART877A 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 (ART877A) compared to T-47D cells (ARWT) following TBECH exposure. Furthermore, AR knockdown experiments confirmed the AR dependency of these responses. The higher sensitivity of ART877A and ARW741C to low levels of TBECH suggests that cells with these AR mutations are more susceptible to androgenic endocrine disrupters. PMID:27473015

  9. Does Dietary Mitigation of Enteric Methane Production Affect Rumen Function and Animal Productivity in Dairy Cows?

    PubMed Central

    Veneman, Jolien B.; Muetzel, Stefan; Hart, Kenton J.; Faulkner, Catherine L.; Moorby, Jon M.; Perdok, Hink B.; Newbold, Charles J.

    2015-01-01

    It has been suggested that the rumen microbiome and rumen function might be disrupted if methane production in the rumen is decreased. Furthermore concerns have been voiced that geography and management might influence the underlying microbial population and hence the response of the rumen to mitigation strategies. Here we report the effect of the dietary additives: linseed oil and nitrate on methane emissions, rumen fermentation, and the rumen microbiome in two experiments from New Zealand (Dairy 1) and the UK (Dairy 2). Dairy 1 was a randomized block design with 18 multiparous lactating cows. Dairy 2 was a complete replicated 3 x 3 Latin Square using 6 rumen cannulated, lactating dairy cows. Treatments consisted of a control total mixed ration (TMR), supplementation with linseed oil (4% of feed DM) and supplementation with nitrate (2% of feed DM) in both experiments. Methane emissions were measured in open circuit respiration chambers and rumen samples were analyzed for rumen fermentation parameters and microbial population structure using qPCR and next generation sequencing (NGS). Supplementation with nitrate, but not linseed oil, decreased methane yield (g/kg DMI; P<0.02) and increased hydrogen (P<0.03) emissions in both experiments. Furthermore, the effect of nitrate on gaseous emissions was accompanied by an increased rumen acetate to propionate ratio and consistent changes in the rumen microbial populations including a decreased abundance of the main genus Prevotella and a decrease in archaeal mcrA (log10 copies/ g rumen DM content). These results demonstrate that methane emissions can be significantly decreased with nitrate supplementation with only minor, but consistent, effects on the rumen microbial population and its function, with no evidence that the response to dietary additives differed due to geography and different underlying microbial populations. PMID:26509835

  10. Androgen receptor and histone lysine demethylases in ovine placenta.

    PubMed

    Cleys, Ellane R; Halleran, Jennifer L; Enriquez, Vanessa A; da Silveira, Juliano C; West, Rachel C; Winger, Quinton A; Anthony, Russell V; Bruemmer, Jason E; Clay, Colin M; Bouma, Gerrit J

    2015-01-01

    Sex steroid hormones regulate developmental programming in many tissues, including programming gene expression during prenatal development. While estradiol is known to regulate placentation, little is known about the role of testosterone and androgen signaling in placental development despite the fact that testosterone rises in maternal circulation during pregnancy and in placenta-induced pregnancy disorders. We investigated the role of testosterone in placental gene expression, and focused on androgen receptor (AR). Prenatal androgenization decreased global DNA methylation in gestational day 90 placentomes, and increased placental expression of AR as well as genes involved in epigenetic regulation, angiogenesis, and growth. As AR complexes with histone lysine demethylases (KDMs) to regulate AR target genes in human cancers, we also investigated if the same mechanism is present in the ovine placenta. AR co-immunoprecipitated with KDM1A and KDM4D in sheep placentomes, and AR-KDM1A complexes were recruited to a half-site for androgen response element (ARE) in the promoter region of VEGFA. Androgenized ewes also had increased cotyledonary VEGFA. Finally, in human first trimester placental samples KDM1A and KDM4D immunolocalized to the syncytiotrophoblast, with nuclear KDM1A and KDM4D immunostaining also present in the villous stroma. In conclusion, placental androgen signaling, possibly through AR-KDM complex recruitment to AREs, regulates placental VEGFA expression. AR and KDMs are also present in first trimester human placenta. Androgens appear to be an important regulator of trophoblast differentiation and placental development, and aberrant androgen signaling may contribute to the development of placental disorders. PMID:25675430

  11. Nur77 inhibits androgen-induced bladder cancer growth.

    PubMed

    Wu, Jianping; Liu, Jun; Jia, Ruipeng; Song, Hongbin

    2013-12-01

    Currently, bladder cancer ranks as the second most common genitourinary malignancy which is exacting significant morbidity and mortality worldwide. Although there are abundant epidemiological and basic studies which strongly suggest the role of androgen hormone in bladder cancer, the underlying mechanism is not fully understood. In the current study, we sought to identify a new competitive inhibitor for androgen receptor in bladder cancer cells. Our results showed that Nur77 hyperexpression inhibits UM-UC-3 cell growth and cell cycle progression while Nur77 knockdown exerts the opposite effect. In our cell culture model, we also demonstrated that Nur77 competitively inhibits androgen-dependent transcription activity and more specifically, Nur77 competes with androgen receptor for binding to src-1, a well-known coactivator for steroids. More importantly, we also showed that a small molecule agonist for Nur77, Cytosporone B, significantly inhibits androgen-dependent bladder cancer cell growth in two different cell lines. These data provide a good proof-of-principle that Nur77 signaling machinery could be a new target for growth control of androgen-dependent bladder cancer cells. PMID:24299210

  12. The Role of Androgen Hormones in Early Follicular Development

    PubMed Central

    Gervásio, Catiele Garcia; Bernuci, Marcelo Picinin; Silva-de-Sá, Marcos Felipe; Rosa-e-Silva, Ana Carolina Japur de Sá

    2014-01-01

    Background. Although chronic hyperandrogenism, a typical feature of polycystic ovary syndrome, is often associated with disturbed reproductive performance, androgens have been shown to promote ovarian follicle growth in shorter exposures. Here, we review the main effects of androgens on the regulation of early folliculogenesis and the potential of their application in improving follicular in vitro growth. Review. Androgens may affect folliculogenesis directly via androgen receptors (ARs) or indirectly through aromatization to estrogen. ARs are highly expressed in the granulosa and theca cells of early stage follicles and slightly expressed in mature follicles. Short-term androgen exposure augments FSH receptor expression in the granulosa cells of developing follicles and enhances the FSH-induced cAMP formation necessary for the transcription of genes involved in the control of follicular cell proliferation and differentiation. AR activation also increases insulin-like growth factor (IGF-1) and its receptor gene expression in the granulosa and theca cells of growing follicles and in the oocytes of primordial follicles, thus facilitating IGF-1 actions in both follicular recruitment and subsequent development. Conclusion. During the early and intermediate stages of follicular maturation, locally produced androgens facilitate the transition of follicles from the dormant to the growing pool as well as their further development. PMID:25006485

  13. Enhanced evaluation of selective androgen receptor modulators in vivo.

    PubMed

    Otto-Duessel, M; He, M; Adamson, T W; Jones, J O

    2013-01-01

    Selective androgen receptor modulators (SARMs) are a class of drugs that control the activity of the androgen receptor (AR), which mediates the response to androgens, in a tissue-selective fashion. They are specifically designed to reduce the possible complications that result from the systemic inhibition or activation of AR in patients with diseases that involve androgen signalling. However, there are no ideal in vivo models for evaluating candidate SARMs. Therefore, we created a panel of androgen-responsive genes in clinically relevant AR expressing tissues including prostate, skin, bone, fat, muscle, brain and kidney. We used select genes from this panel to compare transcriptional changes in response to the full agonist dihydrotestosterone (DHT) and the SARM bolandiol at 16 h and 6 weeks. We identified several genes in each tissue whose expression at each of these time points correlates with the known tissue-specific effects of these compounds. For example, in the prostate we found four genes whose expression was much lower in animals treated with bolandiol compared with animals treated with DHT for 6 weeks, which correlated well with differences in prostate weight. We demonstrate that adding molecular measurements (androgen-regulated gene expression) to the traditional physiological measurements (tissue weights, etc.) makes the evaluation of potential SARMs more accurate, thorough and perhaps more rapid by allowing measurement of selectivity after only 16 h of drug treatment. PMID:23258627

  14. Recent advances in the elucidation of enzymatic function in natural product biosynthesis

    PubMed Central

    Tan, Gao-Yi; Deng, Zixin; Liu, Tiangang

    2016-01-01

    With the successful production of artemisinic acid in yeast, the promising potential of synthetic biology for natural product biosynthesis is now being realized. The recent total biosynthesis of opioids in microbes is considered to be another landmark in this field. The importance and significance of enzymes in natural product biosynthetic pathways have been re-emphasized by these advancements. Therefore, the characterization and elucidation of enzymatic function in natural product biosynthesis are undoubtedly fundamental for the development of new drugs and the heterologous biosynthesis of active natural products. Here, discoveries regarding enzymatic function in natural product biosynthesis over the past year are briefly reviewed. PMID:26989472

  15. Fungal Laccases: Production, Function, and Applications in Food Processing

    PubMed Central

    Brijwani, Khushal; Rigdon, Anne; Vadlani, Praveen V.

    2010-01-01

    Laccases are increasingly being used in food industry for production of cost-effective and healthy foods. To sustain this trend widespread availability of laccase and efficient production systems have to be developed. The present paper delineate the recent developments that have taken place in understanding the role of laccase action, efforts in overexpression of laccase in heterologous systems, and various cultivation techniques that have been developed to efficiently produce laccase at the industrial scale. The role of laccase in different food industries, particularly the recent developments in laccase application for food processing, is discussed. PMID:21048859

  16. Language Production as a Function of Social Distance.

    ERIC Educational Resources Information Center

    Silverman, Thalia Pappas

    The need to find which social contexts elicit children's fullest language repertoire generated this study of the effects of three social distance variables on language production, as measured by mean length of communication unit, vocabulary diversity, and use of black English. The social distance variables investigated included race and sex of…

  17. Properties of amaranth flour with functional oat products

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Amaranth flour containing the essential amino acid, lysine, was composited with oat products that contain ß-glucan known for lowering blood cholesterol and preventing heart disease. The pasting and rheological properties of amaranth-oat composites were evaluated. The amaranth-Nutrim composites showe...

  18. Examining the Function of Visual Feedback in Text Production.

    ERIC Educational Resources Information Center

    Hull, Glynda A.; Smith, William L.

    Composing is controlled by information feedback from prior behavior which serves to influence future behavior. This model posits movement toward a desired end product through a continual interchange of writing and examining and evaluating what has been written against internal standards. A study was conducted to determine the extent to which…

  19. No androgenic/anti-androgenic effects of bisphenol-A in Hershberger assay using immature castrated rats.

    PubMed

    Kim, Hyung Sik; Han, Soon Young; Kim, Tae Sung; Kwack, Seung Jun; Lee, Rhee Da; Kim, In Young; Seok, Ji-Hyun; Lee, Byung Mu; Yoo, Sun Dong; Park, Kui Lea

    2002-09-01

    Several studies have demonstrated that bisphenol A (BPA) exhibited weak estrogenic activity in the 3-day uterotrophic assay using ovariectomized (OVX) and immature rats (Toxicol. Lett. 115 (2000) 231; Regul. Toxicol. Pharmacol. 32 (2000) 118; J. Toxicol. Sci. 26 (2001) 111) and BPA also possessed anti-androgenic activity in in vitro yeast based assays (J. Endocrinol. 158 (1998) 327). To investigate anti-androgenic effects of BPA. a rodent Hershberger assay was carried out using immature Sprague-Dawley male rats. An androgen agonist, testosterone (0.4 mg/kg per day), was administered for 7 consecutive days by subcutaneous (s.c.) injection as a positive control. Additionally, a pure androgen antagonist, flutamide (1, 5. 10 mg/kg per day. oral) was co-administered with testosterone (0.4 mg/kg per day s.c.). BPA was also administered orally with or without testosterone (0.4 mg/kg per day, s.c.) for 7 consecutive days. In the testosterone treated groups, glans penis, seminal vesicles, ventral prostate, and levator ani plus bulbocavernosus muscles (LABC) weights were significantly increased compared with control. However. flulamide dose-dependently inhibited the testosterone-induced re-growth of seminal vesicles, ventral prostate, and LABC, with a significant decrease at flutamide 1.0 mg/kg and above (P<0.05). Serum LH levels were also significantly increased (5 mg/kg and above, P<0.05), but no changes in serum testosterone levels. In contrast, BPA had no effects on the re-growth of seminal vesicles, ventral prostate and LABC induced by testosterone, and no significant differences were observed in serum LH and testosterone levels. In summary, the Hershberger assay could be a sensitive method for detecting androgenic or anti-androgenic chemicals, but BPA did not exhibit any androgenic or anti-androgenic activities in Hershberger assay. PMID:12243870

  20. Estrogenic and androgenic activities of TBBA and TBMEPH, metabolites of novel brominated flame retardants, and selected bisphenols, using the XenoScreen XL YES/YAS assay.

    PubMed

    Fic, Anja; Žegura, Bojana; Gramec, Darja; Mašič, Lucija Peterlin

    2014-10-01

    The present study investigated and compared the estrogenic and androgenic activities of the three different classes of environmental pollutants and their metabolites using the XenoScreen XL YES/YAS assay, which has advantages compared with the original YES/YAS protocol. Contrary to the parent brominated flame retardants TBB and TBPH, which demonstrated no or very weak (anti)estrogenic or (anti)androgenic activities, their metabolites, TBBA and TBMEPH, exhibited anti-estrogenic (IC50 for TBBA=31.75 μM and IC50 for TBMEPH=0.265 μM) and anti-androgenic (IC50 for TBBA=73.95 μM and IC50 for TBMEPH=2.92 μM) activities. These results reveal that metabolism can enhance the anti-estrogenic and anti-androgenic effects of these two novel brominated flame retardants. Based on the activities of BPAF, BPF, BPA and MBP, we can conclude that the XenoScreen XL YES/YAS assay gives comparable results to the (anti)estrogenic or (anti)androgenic assays that are reported in the literature. For BPA, it was confirmed previously that the metabolite formed after an ipso-reaction (hydroxycumyl alcohol) exhibited higher estrogenic activity compared with the parent BPA, but this was not confirmed for BPAF and BPF ipso-metabolites, which were not active in the XenoScreen YES/YAS assay. Among the substituted BPA analogues, bis-GMA exhibited weak anti-estrogenic activity, BADGE demonstrated weak anti-estrogenic and anti-androgenic activities (IC50=13.73 μM), and the hydrolysed product BADGE·2H2O demonstrated no (anti)estrogenic or (anti)androgenic activities. PMID:25048928

  1. A Critical Analysis of the Use of Production Functions in School Finance.

    ERIC Educational Resources Information Center

    Gilman, David A.

    1988-01-01

    This article discusses the uses of production function models and describes the role of inferential statistics for making predictions in school finance. Specifically, the analysis evaluates types, suggests uses, explains the advantages and disadvantages, and lists the statistical complexities of production functions. (JAM)

  2. Changes in circulating androgens during short term carbamazepine therapy.

    PubMed Central

    Connell, J M; Rapeport, W G; Beastall, G H; Brodie, M J

    1984-01-01

    Serum concentrations of testosterone, androstenedione, dehydroepiandrosterone sulphate (DHAS), sex hormone binding globulin (SHBG) and luteinising hormone (LH) were measured before, during and after 21 days treatment with carbamazepine (CBZ)400 mg daily in six