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

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

DTIC Science & Technology

2006-10-01

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

Androgen imprinting of the brain in animal models and humans with intersex disorders: review and recommendations.

PubMed

Hrabovszky, Zoltan; Hutson, John M

2002-11-01

Psychosexual development, gender assignment and surgical treatment in patients with intersex are controversial issues in the medical literature. Some groups are of the opinion that gender identity and sexual orientation are determined prenatally secondary to the fetal hormonal environment causing irreversible development of the nervous system. We reviewed the evidence in animal and human studies to determine the possible role of early postnatal androgen production in gender development. An extensive literature review was performed of data from animal experiments and human studies. RESULTS Many animal studies show that adding or removing hormonal stimulus in early postnatal life can profoundly alter gender behavior of the adult animal. Human case studies show that late intervention is unable to reverse gender orientation from male to female. Most studies have not permitted testing of whether early gender assignment and treatment as female with suppression/ablation of postnatal androgen production leads to improved concordance of the gender identity and sex of rearing. Animal studies support a role for postnatal androgens in brain/behavior development with human studies neither completely supportive nor antagonistic. Therefore, gender assignment in infants with intersex should be made with the possibility in mind that postnatal testicular hormones at ages 1 to 6 months may affect gender identity. A case-control study is required to test the hypothesis that postnatal androgen exposure may convert ambisexual brain functions to committed male behavior patterns.

MicroRNAs Are Mediators of Androgen Action in Prostate and Muscle

PubMed Central

Narayanan, Ramesh; Jiang, Jinmai; Gusev, Yuriy; Jones, Amanda; Kearbey, Jeffrey D.; Miller, Duane D.; Schmittgen, Thomas D.; Dalton, James T.

2010-01-01

Androgen receptor (AR) function is critical for the development of male reproductive organs, muscle, bone and other tissues. Functionally impaired AR results in androgen insensitivity syndrome (AIS). The interaction between AR and microRNA (miR) signaling pathways was examined to understand the role of miRs in AR function. Reduction of androgen levels in Sprague-Dawley rats by castration inhibited the expression of a large set of miRs in prostate and muscle, which was reversed by treatment of castrated rats with 3 mg/day dihydrotestosterone (DHT) or selective androgen receptor modulators. Knockout of the miR processing enzyme, DICER, in LNCaP prostate cancer cells or tissue specifically in mice inhibited AR function leading to AIS. Since the only function of miRs is to bind to 3′ UTR and inhibit translation of target genes, androgens might induce miRs to inhibit repressors of AR function. In concordance, knock-down of DICER in LNCaP cells and in tissues in mice induced the expression of corepressors, NCoR and SMRT. These studies demonstrate a feedback loop between miRs, corepressors and AR and the imperative role of miRs in AR function in non-cancerous androgen-responsive tissues. PMID:21048966

PAPSS2 Deficiency Causes Androgen Excess via Impaired DHEA Sulfation—In Vitro and in Vivo Studies in a Family Harboring Two Novel PAPSS2 Mutations

PubMed Central

Oostdijk, Wilma; Idkowiak, Jan; Mueller, Jonathan W.; House, Philip J.; Taylor, Angela E.; O'Reilly, Michael W.; Hughes, Beverly A.; de Vries, Martine C.; Kant, Sarina G.; Santen, Gijs W. E.; Verkerk, Annemieke J. M. H.; Uitterlinden, André G.; Wit, Jan M.; Losekoot, Monique

2015-01-01

Context: PAPSS2 (PAPS synthase 2) provides the universal sulfate donor PAPS (3′-phospho-adenosine-5′-phosphosulfate) to all human sulfotransferases, including SULT2A1, responsible for sulfation of the crucial androgen precursor dehydroepiandrosterone (DHEA). Impaired DHEA sulfation is thought to increase the conversion of DHEA toward active androgens, a proposition supported by the previous report of a girl with inactivating PAPSS2 mutations who presented with low serum DHEA sulfate and androgen excess, clinically manifesting with premature pubarche and early-onset polycystic ovary syndrome. Patients and Methods: We investigated a family harboring two novel PAPSS2 mutations, including two compound heterozygous brothers presenting with disproportionate short stature, low serum DHEA sulfate, but normal serum androgens. Patients and parents underwent a DHEA challenge test comprising frequent blood sampling and urine collection before and after 100 mg DHEA orally, with subsequent analysis of DHEA sulfation and androgen metabolism by mass spectrometry. The functional impact of the mutations was investigated in silico and in vitro. Results: We identified a novel PAPSS2 frameshift mutation, c.1371del, p.W462Cfs*3, resulting in complete disruption, and a novel missense mutation, c.809G>A, p.G270D, causing partial disruption of DHEA sulfation. Both patients and their mother, who was heterozygous for p.W462Cfs*3, showed increased 5α-reductase activity at baseline and significantly increased production of active androgens after DHEA intake. The mother had a history of oligomenorrhea and chronic anovulation that required clomiphene for ovulation induction. Conclusions: We provide direct in vivo evidence for the significant functional impact of mutant PAPSS2 on DHEA sulfation and androgen activation. Heterozygosity for PAPSS2 mutations can be associated with a phenotype resembling polycystic ovary syndrome. PMID:25594860

Anti-müllerian hormone and sertoli cell function in paediatric male hypogonadism.

PubMed

Grinspon, Romina P; Rey, Rodolfo A

2010-01-01

In the prepubertal male, Sertoli cells are the most active testicular cell population. Without stimulation tests, prepubertal hypogonadism can only be evidenced if Sertoli cell function is assessed. Anti-müllerian hormone (AMH) is a distinctive marker of the prepubertal Sertoli cell. Serum AMH is high from fetal life until puberty. In postnatal life, AMH testicular production is stimulated by FSH and potently inhibited by androgens. In anorchid patients, AMH is undetectable. In prepubertal males with fetal- or childhood-onset primary or central hypogonadism affecting the whole gonad, serum AMH is low. Conversely, when hypogonadism only affects Leydig cells (i.e., LH/human chorionic gonadotrophin receptor or steroidogenic enzyme defects), serum AMH is normal/high. AMH is also normal/high in patients with androgen insensitivity. In patients of pubertal age with central hypogonadism, AMH is low for Tanner stage - reflecting lack of FSH stimulus, - but high for age - reflecting lack of testosterone inhibitory effect. FSH treatment results in serum AMH rise, whereas human chorionic gonadotrophin treatment increases testosterone levels which inhibit AMH production. In conclusion, AMH determination is helpful in assessing gonadal function, without need for stimulation tests, and orientates the aetiological diagnosis of paediatric male hypogonadism. Furthermore, serum AMH is an excellent marker of FSH and androgen action in the testis. Copyright 2010 S. Karger AG, Basel.

A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids.

PubMed

Pretorius, Elzette; Arlt, Wiebke; Storbeck, Karl-Heinz

2017-02-05

The abundant adrenal C19 steroid 11β-hydroxyandrostenedione (11OHA4) has been written off as a dead-end product of adrenal steroidogenesis. However, recent evidence has demonstrated that 11OHA4 is the precursor to the potent androgenic 11-oxygenated steroids, 11-ketotestosterone and 11-ketodihydrotestosterone, that bind and activate the human androgen receptor similarly to testosterone and DHT. The significance of this discovery becomes apparent when considering androgen dependent diseases such as castration resistant prostate cancer and diseases associated with androgen excess, e.g. congenital adrenal hyperplasia and polycystic ovary syndrome. In this review we describe the production and metabolism of 11-oxygenated steroids. We subsequently discuss their androgenic activity and highlight the putative role of these androgens in disease states. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

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

PubMed Central

O’Connell, Matthew DL; Wu, Frederick CW

2014-01-01

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

Adiponectin and Its Receptors in the Ovary: Further Evidence for a Link between Obesity and Hyperandrogenism in Polycystic Ovary Syndrome

PubMed Central

Comim, Fabio V.; Hardy, Kate; Franks, Stephen

2013-01-01

Polycystic ovary syndrome (PCOS), characterized by ovarian androgen excess, is the commonest endocrine disorder in women. Obesity increases androgen synthesis, a phenomenon attributed to the accompanying hyperinsulinemia. Our hypothesis was that adipokines, fat cell-derived hormones, play a direct role in modulating ovarian androgen secretion. Therefore, the aims of this study were to explore the effects of adipokines (in particular, adiponectin) on ovarian steroidogenesis and compare the expression of adiponectin receptors in ovaries from women with and without PCO. Sections of archived human ovaries (nine from women with normal ovaries and 16 with PCOS, classified histologically, with reference to menstrual history and ultrasound) were analysed by quantitative morphometry and the proportion of positive-labelling cells compared. In addition, studies of androgen production in relation to adipokine function in primary bovine theca cell culture were also performed. A significantly lower proportion of theca cells expressed adiponectin receptors 1 and 2 (AdipoR1, AdipoR2) in polycystic ovaries than in normal ovaries. In cultured theca cells, adiponectin suppressed androstenedione production and gene expression of LH receptor and key enzymes in the androgen synthesis pathway. Moreover, knockdown of genes for AdipoR1 and AdipoR2 was associated with increased androstenedione secretion by bovine theca cells. These results provide evidence for a direct link between fat cell metabolism and ovarian steroidogenesis, suggesting that disruption of adiponectin and/or its receptors plays a key role in pathogenesis of hyperandrogenism in PCOS. PMID:24260388

Development of cell-penetrating bispecific antibodies targeting the N-terminal domain of androgen receptor for prostate cancer therapy.

PubMed

Goicochea, Nancy L; Garnovskaya, Maria; Blanton, Mary G; Chan, Grace; Weisbart, Richard; Lilly, Michael B

2017-12-01

Castration-resistant prostate cancer cells exhibit continued androgen receptor signaling in spite of low levels of ligand. Current therapies to block androgen receptor signaling act by inhibiting ligand production or binding. We developed bispecific antibodies capable of penetrating cells and binding androgen receptor outside of the ligand-binding domain. Half of the bispecific antibody molecule consists of a single-chain variable fragment of 3E10, an anti-DNA antibody that enters cells. The other half is a single-chain variable fragment version of AR441, an anti-AR antibody. The resulting 3E10-AR441 bispecific antibody enters human LNCaP prostate cells and accumulates in the nucleus. The antibody binds to wild-type, mutant and splice variant androgen receptor. Binding affinity of 3E10-AR441 to androgen receptor (284 nM) was lower than that of the parental AR441 mAb (4.6 nM), but could be improved (45 nM) through alternative placement of the affinity tags, and ordering of the VH and VK domains. The 3E10-AR441 bispecific antibody blocked genomic signaling by wild-type or splice variant androgen receptor in LNCaP cells. It also blocked non-genomic signaling by the wild-type receptor. Furthermore, bispecific antibody inhibited the growth of C4-2 prostate cancer cells under androgen-stimulated conditions. The 3E10-AR441 biAb can enter prostate cancer cells and inhibits androgen receptor function in a ligand-independent manner. It may be an attractive prototype agent for prostate cancer therapy. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Polycystic ovarian disease: the adrenal connection.

PubMed

Marouliss, George B; Triantafillidis, Ioannis K

2006-01-01

Polycystic ovarian disease (PCOD) is characterized by hyperandrogenemia, ovulatory dysfunction and polycystic ovaries (PCO). The increased androgen production in PCOD comes primarily from the ovaries. However, in about 40% of patients there is excessive adrenal androgen production (DHEA, DHEA-Sulfate, Androstenedione, Testosterone and Dihydrotestosterone). The contribution of the adrenal in the PCOD is suggested by the presence of adrenal androgen excess in PCO, the presence of PCO in women with enzymatic adrenal hyperplasia as well as in women with adrenal tumors. However, the cause of adrenal androgen hypersecretion is not yet fully understood but it may include endogenous hypersecretion of the zona reticularis of unclear cause, hypersecretion of cortical-androgen-stimulating hormone (CASH), stress, hyperprolactinemia, adrenal enzymatic defects etc. This short review covers the aspects of adrenal androgen hypersecretion in PCOD.

Androgen receptor-related diseases: what do we know?

PubMed

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

2016-05-01

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

Genomic and non-genomic effects of androgens in the cardiovascular system: clinical implications

PubMed Central

Lucas-Herald, Angela K.; Alves-Lopes, Rheure; Montezano, Augusto C.; Ahmed, S. Faisal

2017-01-01

The principle steroidal androgens are testosterone and its metabolite 5α-dihydrotestosterone (DHT), which is converted from testosterone by the enzyme 5α-reductase. Through the classic pathway with androgens crossing the plasma membrane and binding to the androgen receptor (AR) or via mechanisms independent of the ligand-dependent transactivation function of nuclear receptors, testosterone induces genomic and non-genomic effects respectively. AR is widely distributed in several tissues, including vascular endothelial and smooth muscle cells. Androgens are essential for many developmental and physiological processes, especially in male reproductive tissues. It is now clear that androgens have multiple actions besides sex differentiation and sexual maturation and that many physiological systems are influenced by androgens, including regulation of cardiovascular function [nitric oxide (NO) release, Ca2+ mobilization, vascular apoptosis, hypertrophy, calcification, senescence and reactive oxygen species (ROS) generation]. This review focuses on evidence indicating that interplay between genomic and non-genomic actions of testosterone may influence cardiovascular function. PMID:28645930

In Silico Analysis Identifies a Novel Role for Androgens in the Regulation of Human Endometrial Apoptosis

PubMed Central

Marshall, Elaine; Lowrey, Jacqueline; MacPherson, Sheila; Maybin, Jacqueline A.; Collins, Frances; Critchley, Hilary O. D.

2011-01-01

Context: The endometrium is a multicellular, steroid-responsive tissue that undergoes dynamic remodeling every menstrual cycle in preparation for implantation and, in absence of pregnancy, menstruation. Androgen receptors are present in the endometrium. Objective: The objective of the study was to investigate the impact of androgens on human endometrial stromal cells (hESC). Design: Bioinformatics was used to identify an androgen-regulated gene set and processes associated with their function. Regulation of target genes and impact of androgens on cell function were validated using primary hESC. Setting: The study was conducted at the University Research Institute. Patients: Endometrium was collected from women with regular menses; tissues were used for recovery of cells, total mRNA, or protein and for immunohistochemistry. Results: A new endometrial androgen target gene set (n = 15) was identified. Bioinformatics revealed 12 of these genes interacted in one pathway and identified an association with control of cell survival. Dynamic androgen-dependent changes in expression of the gene set were detected in hESC with nine significantly down-regulated at 2 and/or 8 h. Treatment of hESC with dihydrotestosterone reduced staurosporine-induced apoptosis and cell migration/proliferation. Conclusions: Rigorous in silico analysis resulted in identification of a group of androgen-regulated genes expressed in human endometrium. Pathway analysis and functional assays suggest androgen-dependent changes in gene expression may have a significant impact on stromal cell proliferation, migration, and survival. These data provide the platform for further studies on the role of circulatory or local androgens in the regulation of endometrial function and identify androgens as candidates in the pathogenesis of common endometrial disorders including polycystic ovarian syndrome, cancer, and endometriosis. PMID:21865353

Prenatal Androgen Exposure Causes Hypertension and Gut Microbiota Dysbiosis.

PubMed

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

2018-02-22

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

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

DTIC Science & Technology

2016-10-01

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

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

PubMed

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

2012-04-01

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

Enrichment of putative prostate cancer stem cells after androgen deprivation: upregulation of pluripotency transactivators concurs with resistance to androgen deprivation in LNCaP cell lines.

PubMed

Seiler, Daniel; Zheng, Junying; Liu, Gentao; Wang, Shunyou; Yamashiro, Joyce; Reiter, Robert E; Huang, Jiaoti; Zeng, Gang

2013-09-01

Prostate cancer stem cells (PCSC) offer theoretical explanations to many clinical and biological behaviors of the disease in human. In contrast to approaches of using side populations and cell-surface markers to isolate and characterize the putative PCSC, we hypothesize that androgen deprivation leads to functional enrichment of putative PCSC. Human prostate cancer lines LNCaP, LAPC4 and LAPC9 were depleted of androgen in cell cultures and in castrated SCID mice. The resultant androgen deprivation-resistant or castration-resistant populations, in particular in LNCaP and its derivative cell lines, displayed increased expression of pluripotency transactivators and significantly higher tumorigenicity. Individual tumor cell clones were isolated from castration-resistant bulk cultures of LNCaP (CR-LNCaP) and tested for tumorigenicity in male SCID mice under limiting dilution conditions. As few as 200 cells were able to form spheres in vitro, and generate tumors with similar growth kinetics as 10(6) LNCaP or 10(4) CR-LNCaP cells in vivo. These putative PCSC were CD44(+) /CD24(-) and lack the expression of prostate lineage proteins. When transplanted into the prostate of an intact male SCID mouse, these putative PCSC seemed to show limited differentiation into Ck5(+) , Ck8(+) , Ck5(+) /Ck8(+) , and AR(+) cells. On the other hand, stable transduction of LNCaP with retrovirus encoding Sox2 led to androgen-deprivation resistant growth and down-regulation of major prostate lineage gene products in vitro. Concurrence of overexpression of pluripotency transactivators and resistance to androgen deprivation supported the role of putative PCSC in the emergence of prostate cancer resistant to androgen deprivation. © 2013 Wiley Periodicals, Inc.

Genomic and non-genomic effects of androgens in the cardiovascular system: clinical implications.

PubMed

Lucas-Herald, Angela K; Alves-Lopes, Rheure; Montezano, Augusto C; Ahmed, S Faisal; Touyz, Rhian M

2017-07-01

The principle steroidal androgens are testosterone and its metabolite 5α-dihydrotestosterone (DHT), which is converted from testosterone by the enzyme 5α-reductase. Through the classic pathway with androgens crossing the plasma membrane and binding to the androgen receptor (AR) or via mechanisms independent of the ligand-dependent transactivation function of nuclear receptors, testosterone induces genomic and non-genomic effects respectively. AR is widely distributed in several tissues, including vascular endothelial and smooth muscle cells. Androgens are essential for many developmental and physiological processes, especially in male reproductive tissues. It is now clear that androgens have multiple actions besides sex differentiation and sexual maturation and that many physiological systems are influenced by androgens, including regulation of cardiovascular function [nitric oxide (NO) release, Ca 2+ mobilization, vascular apoptosis, hypertrophy, calcification, senescence and reactive oxygen species (ROS) generation]. This review focuses on evidence indicating that interplay between genomic and non-genomic actions of testosterone may influence cardiovascular function. © 2017 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

Increased androgen response to follicle-stimulating hormone administration in women with polycystic ovary syndrome.

PubMed

Wachs, Deborah S; Coffler, Mickey S; Malcom, Pamela J; Shimasaki, Shunichi; Chang, R Jeffrey

2008-05-01

In women with polycystic ovary syndrome (PCOS), excess ovarian androgen production is driven by increased LH secretion. Studies conducted in animals suggest that the granulosa cell may influence LH-stimulated theca cell androgen production. The objective of this study was to determine whether FSH enhances androgen production in women with PCOS compared with that of normal women. A prospective study was conducted to compare androgen production in response to FSH in two groups of women. The study was conducted in a General Clinical Research Center in a tertiary academic medical center. Women with PCOS, 18-35 yr (n = 20), and normal ovulatory controls, 18-35 yr (n = 10), were recruited for study. Serial blood samples were obtained over a 24-h period after an iv injection of recombinant human FSH (150 IU). The main outcome measures were serum 17-hydroxyprogesterone (17-OHP), androstenedione (A), dehydroepiandrosterone (DHEA), testosterone (T), and inhibin B (Inh B) responses after FSH administration. Basal serum 17-OHP, A, and T levels were markedly increased in women with PCOS compared with that observed in normal women. Basal DHEA and Inh B levels were similar to those of normal controls. After FSH injection, PCOS women demonstrated enhanced production of 17-OHP, A, DHEA, and Inh B, whereas in normal women no increases were observed. T levels declined slightly in both groups. These findings provide evidence that, in PCOS women, theca cell androgen production is enhanced by FSH administration and suggest a granulosa-theca cell paracrine mechanism.

A novel selective androgen receptor modulator (SARM) MK-4541 exerts anti-androgenic activity in the prostate cancer xenograft R-3327G and anabolic activity on skeletal muscle mass & function in castrated mice.

PubMed

Chisamore, Michael J; Gentile, Michael A; Dillon, Gregory Michael; Baran, Matthew; Gambone, Carlo; Riley, Sean; Schmidt, Azriel; Flores, Osvaldo; Wilkinson, Hilary; Alves, Stephen E

2016-10-01

The androgen receptor (AR) is a member of the nuclear hormone receptor super family of transcription factors. Androgens play an essential role in the development, growth, and maintenance of male sex organs, as well as the musculoskeletal and central nervous systems. Yet with advancing age, androgens can drive the onset of prostate cancer, the second leading cause of cancer death in males within the United States. Androgen deprivation therapy (ADT) by pharmacologic and/or surgical castration induces apoptosis of prostate cells and subsequent shrinkage of the prostate and prostate tumors. However, ADT is associated with significant musculoskeletal and behavioral adverse effects. The unique pharmacological activity of selective androgen receptor modulator (SARM) MK-4541 recently has been reported as an AR antagonist with 5α-reductase inhibitor function. The molecule inhibits proliferation and induces apoptosis in AR positive, androgen dependent prostate cancer cells. Importantly, MK-4541 inhibited androgen-dependent prostate growth in male rats yet maintained lean body mass and bone formation following ovariectomy in female rats. In the present study, we evaluated the effects of SARM MK-4541 in the androgen-dependent Dunning R3327-G prostate carcinoma xenograft mouse model as well as on skeletal muscle mass and function, and AR-regulated behavior in mice. MK-4541 significantly inhibited the growth of R3327-G prostate tumors, exhibited anti-androgen effects on the seminal vesicles, reduced plasma testosterone concentrations in intact males, and inhibited Ki67 expression. MK-4541 treated xenografts appeared similar to xenografts in castrated mice. Importantly, we demonstrate that MK-4541 exhibited anabolic activity in androgen deficient conditions, increasing lean body mass and muscle function in adult castrated mice. Moreover, MK-4541 treatment restored general activity levels in castrated mice. Thus, MK-4541 exhibits an optimum profile as an adjuvant therapy to ADT which may provide potent anti-androgenic activity at the prostate yet protective activity on skeletal muscle and behavior in patients. Copyright © 2016 Elsevier Ltd. All rights reserved.

Androgen Effects on Adipose Tissue Architecture and Function in Nonhuman Primates

PubMed Central

Varlamov, Oleg; White, Ashley E.; Carroll, Julie M.; Bethea, Cynthia L.; Reddy, Arubala; Slayden, Ov; O'Rourke, Robert W.

2012-01-01

The differential association of hypoandrogenism in men and hyperandrogenism in women with insulin resistance and obesity suggests that androgens may exert sex-specific effects on adipose and other tissues, although the underlying mechanisms remain poorly understood. Moreover, recent studies also suggest that rodents and humans may respond differently to androgen imbalance. To achieve better insight into clinically relevant sex-specific mechanisms of androgen action, we used nonhuman primates to investigate the direct effects of gonadectomy and hormone replacement on white adipose tissue. We also employed a novel ex vivo approach that provides a convenient framework for understanding of adipose tissue physiology under a controlled tissue culture environment. In vivo androgen deprivation of males did not result in overt obesity or insulin resistance but did induce the appearance of very small, multilocular white adipocytes. Testosterone replacement restored normal cell size and a unilocular phenotype and stimulated adipogenic gene transcription and improved insulin sensitivity of male adipose tissue. Ex vivo studies demonstrated sex-specific effects of androgens on adipocyte function. Female adipose tissue treated with androgens displayed elevated basal but reduced insulin-dependent fatty acid uptake. Androgen-stimulated basal uptake was greater in adipose tissue of ovariectomized females than in adipose tissue of intact females and ovariectomized females replaced with estrogen and progesterone in vivo. Collectively, these data demonstrate that androgens are essential for normal adipogenesis in males and can impair essential adipocyte functions in females, thus strengthening the experimental basis for sex-specific effects of androgens in adipose tissue. PMID:22547568

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

DTIC Science & Technology

2017-10-01

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

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...

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

PubMed

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

2011-12-01

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

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.

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

PubMed

Hu, Jieping; Wang, Gongxian; Sun, Ting

2017-05-01

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

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

PubMed Central

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

2011-01-01

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

Uncarboxylated Osteocalcin and Gprc6a Axis Produce Intratumoral Androgens in Castration-Resistant Prostate Cancer

DTIC Science & Technology

2016-05-01

multiple pathways, despite castrate levels of testosterone . One such adaptive mechanism is the “intracrine” production of androgens in the primary...despite castrate levels of testosterone . One such adaptive mechanism is the “intracrine” production of androgens in the primary tumor and/or at... testosterone . Thus, just as the skeleton regulates fertility in an endocrine fashion, and it may also promote bone metastasis via an “intracrine” mechanism

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

PubMed

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

2017-07-01

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

Morphological and functional maturation of Leydig cells: from rodent models to primates.

PubMed

Teerds, Katja J; Huhtaniemi, Ilpo T

2015-01-01

Leydig cells (LC) are the sites of testicular androgen production. Development of LC occurs in the testes of most mammalian species as two distinct growth phases, i.e. as fetal and pubertal/adult populations. In primates there are indications of a third neonatal growth phase. LC androgen production begins in embryonic life and is crucial for the intrauterine masculinization of the male fetal genital tract and brain, and continues until birth after which it rapidly declines. A short post-natal phase of LC activity in primates (including human) termed 'mini-puberty' precedes the period of juvenile quiescence. The adult population of LC evolves, depending on species, in mid- to late-prepuberty upon reawakening of the hypothalamic-pituitary-testicular axis, and these cells are responsible for testicular androgen production in adult life, which continues with a slight gradual decline until senescence. This review is an updated comparative analysis of the functional and morphological maturation of LC in model species with special reference to rodents and primates. Pubmed, Scopus, Web of Science and Google Scholar databases were searched between December 2012 and October 2014. Studies published in languages other than English or German were excluded, as were data in abstract form only. Studies available on primates were primarily examined and compared with available data from specific animal models with emphasis on rodents. Expression of different marker genes in rodents provides evidence that at least two distinct progenitor lineages give rise to the fetal LC (FLC) population, one arising from the coelomic epithelium and the other from specialized vascular-associated cells along the gonad-mesonephros border. There is general agreement that the formation and functioning of the FLC population in rodents is gonadotrophin-responsive but not gonadotrophin-dependent. In contrast, although there is in primates some controversy on the role of gonadotrophins in the formation of the FLC population, there is consensus about the essential role of gonadotrophins in testosterone production. Like the FLC population, adult Leydig cells (ALC) in rodents arise from stem cells, which have their origin in the fetal testis. In contrast, in primates the ALC population is thought to originate from FLC, which undergo several cycles of regression and redifferentiation before giving rise to the mature ALC population, as well as from differentiation of stem cells/precursor cells. Despite this difference in origin, both in primates and rodents the formation of the mature and functionally active ALC population is critically dependent on the pituitary gonadotrophin, LH. From studies on rodents considerable knowledge has emerged on factors that are involved besides LH in the regulation of this developmental process. Whether the same factors also play a role in the development of the mature primate LC population awaits further investigation. Distinct populations of LC develop along the life span of males, including fetal, neonatal (primates) and ALC. Despite differences in the LC lineages of rodents and primates, the end product is a mature population of LC with the main function to provide androgens necessary for the maintenance of spermatogenesis and extra-gonadal androgen actions. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Overlapping dose responses of spermatogenic and extragonadal testosterone actions jeopardize the principle of hormonal male contraception

PubMed Central

Oduwole, Olayiwola O.; Vydra, Natalia; Wood, Nicholas E. M.; Samanta, Luna; Owen, Laura; Keevil, Brian; Donaldson, Mandy; Naresh, Kikkeri; Huhtaniemi, Ilpo T.

2014-01-01

Testosterone (T), alone or in combination with progestin, provides a promising approach to hormonal male contraception. Its principle relies on enhanced negative feedback of exogenous T to suppress gonadotropins, thereby blocking the testicular T production needed for spermatogenesis, while simultaneously maintaining the extragonadal androgen actions, such as potency and libido, to avoid hypogonadism. A serious drawback of the treatment is that a significant proportion of men do not reach azoospermia or severe oligozoospermia, commensurate with contraceptive efficacy. We tested here, using hypogonadal luteinizing hormone/choriongonadotropin receptor (LHCGR) knockout (LHR−/−) mice, the basic principle of the T-based male contraceptive method, that a specific T dose could maintain extragonadal androgen actions without simultaneously activating spermatogenesis. LHR−/− mice were treated with increasing T doses, and the responses of their spermatogenesis and extragonadal androgen actions (including gonadotropin suppression and sexual behavior) were assessed. Conspicuously, all dose responses to T were practically superimposable, and no dose of T could be defined that would maintain sexual function and suppress gonadotropins without simultaneously activating spermatogenesis. This finding, never addressed in clinical contraceptive trials, is not unexpected in light of the same androgen receptor mediating androgen actions in all organs. When extrapolated to humans, our findings may jeopardize the current approach to hormonal male contraception and call for more effective means of inhibiting intratesticular T production or action, to achieve consistent spermatogenic suppression.—Oduwole, O. O., Vydra, N., Wood, N. E. M., Samanta, L., Owen, L., Keevil, B., Donaldson, M., Naresh, K., Huhtaniemi, I. T. Overlapping dose responses of spermatogenic and extragonadal testosterone actions jeopardize the principle of hormonal male contraception. PMID:24599970

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

PubMed

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

2010-06-01

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

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...

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

DTIC Science & Technology

2016-10-01

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

Premature adrenarche: etiology, clinical findings, and consequences.

PubMed

Voutilainen, Raimo; Jääskeläinen, Jarmo

2015-01-01

Adrenarche means the morphological and functional change of the adrenal cortex leading to increasing production of adrenal androgen precursors (AAPs) in mid childhood, typically at around 5-8 years of age in humans. The AAPs dehydroepiandrosterone (DHEA) and its sulfate conjugate (DHEAS) are the best serum markers of adrenal androgen (AA) secretion and adrenarche. Normal ACTH secretion and action are needed for adrenarche, but additional inherent and exogenous factors regulate AA secretion. Inter-individual variation in the timing of adrenarche and serum concentrations of DHEA(S) in adolescence and adulthood are remarkable. Premature adrenarche (PA) is defined as the appearance of clinical signs of androgen action (pubic/axillary hair, adult type body odor, oily skin or hair, comedones, acne, accelerated statural growth) before the age of 8 years in girls or 9 years in boys associated with AAP concentrations high for the prepubertal chronological age. To accept the diagnosis of PA, central puberty, adrenocortical and gonadal sex hormone secreting tumors, congenital adrenal hyperplasia, and exogenous source of androgens need to be excluded. The individually variable peripheral conversion of circulating AAPs to biologically more active androgens (testosterone, dihydrotestosterone) and the androgen receptor activity in the target tissues are as important as the circulating AAP concentrations as determinants of androgen action. PA has gained much attention during the last decades, as it has been associated with small birth size, the metabolic and polycystic ovarian syndrome (PCOS), and thus with an increased risk for type 2 diabetes and cardiovascular diseases in later life. The aim of this review is to describe the known hormonal changes and their possible regulators in on-time and premature adrenarche, and the clinical features and possible later health problems associating with PA. Copyright © 2014 Elsevier Ltd. All rights reserved.

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

PubMed

DePriest, Adam D; Fiandalo, Michael V; Schlanger, Simon; Heemers, Frederike; Mohler, James L; Liu, Song; Heemers, Hannelore V

2016-01-01

Androgen receptor (AR) is a ligand-activated transcription factor that is the main target for treatment of non-organ-confined prostate cancer (CaP). Failure of life-prolonging AR-targeting androgen deprivation therapy is due to flexibility in steroidogenic pathways that control intracrine androgen levels and variability in the AR transcriptional output. Androgen biosynthesis enzymes, androgen transporters and AR-associated coregulators are attractive novel CaP treatment targets. These proteins, however, are characterized by multiple transcript variants and isoforms, are subject to genomic alterations, and are differentially expressed among CaPs. Determining their therapeutic potential requires evaluation of extensive, diverse datasets that are dispersed over multiple databases, websites and literature reports. Mining and integrating these datasets are cumbersome, time-consuming tasks and provide only snapshots of relevant information. To overcome this impediment to effective, efficient study of AR and potential drug targets, we developed the Regulators of Androgen Action Resource (RAAR), a non-redundant, curated and user-friendly searchable web interface. RAAR centralizes information on gene function, clinical relevance, and resources for 55 genes that encode proteins involved in biosynthesis, metabolism and transport of androgens and for 274 AR-associated coregulator genes. Data in RAAR are organized in two levels: (i) Information pertaining to production of androgens is contained in a 'pre-receptor level' database, and coregulator gene information is provided in a 'post-receptor level' database, and (ii) an 'other resources' database contains links to additional databases that are complementary to and useful to pursue further the information provided in RAAR. For each of its 329 entries, RAAR provides access to more than 20 well-curated publicly available databases, and thus, access to thousands of data points. Hyperlinks provide direct access to gene-specific entries in the respective database(s). RAAR is a novel, freely available resource that provides fast, reliable and easy access to integrated information that is needed to develop alternative CaP therapies. Database URL: http://www.lerner.ccf.org/cancerbio/heemers/RAAR/search/. © The Author(s) 2016. Published by Oxford University Press.

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

PubMed

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

2018-03-01

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

Involvement of androgens in ovarian health and disease

PubMed Central

Lebbe, M.; Woodruff, T.K.

2013-01-01

In women, ovary and adrenal gland produce androgens. Androgens are essential drivers of the primordial to antral follicle development, prior to serving as substrate for estrogen production in the later stages of folliculogenesis. Androgens play a crucial role in the follicular–stromal intertalk by fine tuning the extracellular matrix and vessel content of the ovarian stroma. Local auto-and paracrine factors regulate androgen synthesis in the pre-antral follicle. Androgen excess is a hallmark of polycystic ovary syndrome and is a key contributor in the exaggerated antral follicle formation, stromal hyperplasia and hypervascularity. Hyperandrogenaemia overrides the follicular–stromal dialog, resulting in follicular arrest and disturbed ovulation. On the other hand, androgen deficiency is likely to have a negative impact on fertility as well, and further research is needed to examine the benefits of androgen-replacement therapy in subfertility. PMID:24026057

IN UTERO EXPOSURE TO THE FUNGICIDE PROCYMIDONE AND DIBUTYL PHTHALATE PRODUCE DOSE ADDITIVE DISRUPTIONS OF MALE RAT SEXUAL DIFFERENTIATION

EPA Science Inventory

Procymidone (PRO) and dibutyl phthalate (DBP) alter male rat sexual differentiation by disrupting the androgen-signaling pathway via distinctly different cellular mechanisms of toxicity. DBP inhibits fetal Leydig cell androgen production whereas PRO binds AR and blocks androgen a...

[Neuronal and hormonal regulatory mechanisms of tears production and secretion].

PubMed

Mrugacz, Małgorzata; Zywalewska, Nella; Bakunowicz-Lazarczyk, Alina

2005-01-01

The ocular surface, tear film, lacrimal glands act as a functional unit to preserve the quality of the refractive surface of the eye, and to resist injury and protect the eye against bodily and environmental conditions. Homeostasis of this functional unit involves neuronal and hormonal regulatory mechanisms. The eye appears to be a target organ for sex hormones particulary the androgen, as they modulate the immune system and trophic functions of the lacrimal and Meibomian glands.

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

PubMed Central

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

2009-01-01

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

Androgens: basic biology and clinical implication.

PubMed

Orwoll, E S

2001-10-01

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

Androgen biosynthesis during minipuberty favors the backdoor pathway over the classic pathway: Insights into enzyme activities and steroid fluxes in healthy infants during the first year of life from the urinary steroid metabolome.

PubMed

Dhayat, Nasser A; Dick, Bernhard; Frey, Brigitte M; d'Uscio, Claudia H; Vogt, Bruno; Flück, Christa E

2017-01-01

The steroid profile changes dramatically from prenatal to postnatal life. Recently, a novel backdoor pathway for androgen biosynthesis has been discovered. However, its role remains elusive. Therefore, we investigated androgen production from birth to one year of life with a focus on minipuberty and on production of androgens through the backdoor pathway. Additionally, we assessed the development of the specific steroid enzyme activities in early life. To do so, we collected urine specimens from diapers in 43 healthy newborns (22 females) at 13 time points from birth to one year of age in an ambulatory setting, and performed in house GC-MS steroid profiling for 67 steroid metabolites. Data were analyzed for androgen production through the classic and backdoor pathway and calculations of diagnostic ratios for steroid enzyme activities were performed. Analysis revealed that during minipuberty androgen production is much higher in boys than in girls (e.g. androsterone (An)), originates largely from the testis (An boys -An girls ), and uses predominantly the alternative backdoor pathway (An/Et; Δ5<Δ4 lyase activity). Modelling of steroid enzyme activities showed age-related effects for 21-, 11-, 17-hydroxylase and P450 oxidoreductase activities as well as 3β-hydroxysteroid dehydrogenase, 11β-hydroxylase type 1/2 and 5α-reductase activities. Sex-related characteristics were found for 21-hydroxylase and 5α-reductase activities. Overall, our study shows that androgen biosynthesis during minipuberty favors the backdoor pathway over the classic pathway. Calculations of specific diagnostic ratios for enzyme activities seem to allow the diagnosis of specific steroid disorders from the urinary steroid metabolome. Copyright © 2016 Elsevier Ltd. All rights reserved.

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 of 10 randomly surveyed herbal extracts on sex performance enhancers did not contain the right compositions as stated in the manual brochures. The addition of illegal chemicals to herbal extracts and traditional herbs which has been proclaimed as sex tonics (erectogenics) or other health conditions (analgetics, cortisone) found in the market.

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

PubMed Central

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

2011-01-01

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

Androgen Receptor Signaling in Bladder Cancer

PubMed Central

Li, Peng; Chen, Jinbo; Miyamoto, Hiroshi

2017-01-01

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

Increased protein expression of LHCG receptor and 17α-hydroxylase/17-20-lyase in human polycystic ovaries.

PubMed

Comim, F V; Teerds, K; Hardy, K; Franks, S

2013-11-01

Does the expression of LHCG receptor (LHCGR) protein and key enzymes in the androgen biosynthetic pathway differ in normal human versus polycystic ovarian tissue? LHCGR and 17α-hydroxylase/17-20-lyase (CYP17A1) protein levels are increased in polycystic ovaries (PCOs). The predominant source of excess androgen secretion in women with polycystic ovary syndrome (PCOS) is ovarian theca cells but few studies have directly assessed the presence and abundance of protein for key molecules involved in androgen production by theca, including LHCGR and the rate-limiting enzyme in androgen production, CYP17A1. This is a laboratory-based, cross-sectional study comparing protein expression of key molecules in the androgen biosynthetic pathway in archived ovarian tissue from women with normal ovaries (n = 10) with those with PCOs (n = 16). A quantitative morphometric study was performed using sections of archived human ovaries (n = 26) previously characterized as normal or polycystic. The distribution and abundance of LHCGR, CYP17A1, 3β-hydroxysteroid dehydrogenase type 2 (3βHSDII) and 17β-hydroxysteroid dehydrogenase type 5 (17βHSD5) proteins were evaluated by immunohistochemistry and quantified. A higher proportion of theca cells from anovulatory PCO expressed LHCGR protein when compared with control ovaries (P = 0.01). A significant increase in the intensity of immunostaining for CYP17A1 was identified in antral follicles in sections of PCO compared with ovaries from normal women (P = 0.04). As the study used formalin-fixed ovarian tissue sections, it was not possible to carry out studies 'in vitro' using the same ovarian tissues in order to also demonstrate increased functional activity of LHCGR and CYP17A1. The data are in keeping with the results of previous studies in isolated theca cells and support the notion of an intrinsic abnormality of theca cell androgen production in women with PCOS. The research was supported by a Programme Grant, G0802782, from the Medical Research Council (MRC) UK and by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London. F.V.C was supported by Capes Foundation (Brazilian Ministry of Education). The authors have no conflicts of interest to disclose.

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

PubMed

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

2016-06-01

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

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

DTIC Science & Technology

2017-10-01

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

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

PubMed

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

2015-03-31

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

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

PubMed Central

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

2012-01-01

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

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.

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

PubMed

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

2014-04-28

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

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

PubMed

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

2011-09-01

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

Mouse Leydig Cells with Different Androgen Production Potential Are Resistant to Estrogenic Stimuli but Responsive to Bisphenol A Which Attenuates Testosterone Metabolism

PubMed Central

Savchuk, Iuliia; Söder, Olle; Svechnikov, Konstantin

2013-01-01

It is well known that estrogens and estrogen-like endocrine disruptors can suppress steroidogenic gene expression, attenuate androgen production and decrease differentiation of adult Leydig cell lineage. However, there is no information about the possible link between the potency of Leydig cells to produce androgens and their sensitivity to estrogenic stimuli. Thus, the present study explored the relationship between androgen production potential of Leydig cells and their responsiveness to estrogenic compounds. To investigate this relationship we selected mouse genotypes contrasting in sex hormone levels and differing in testosterone/estradiol (T/E2) ratio. We found that two mouse genotypes, CBA/Lac and C57BL/6j have the highest and the lowest serum T/E2 ratio associated with increased serum LH level in C57BL/6j compared to CBA/Lac. Analysis of steroidogenic gene expression demonstrated significant upregulation of Cyp19 gene expression but coordinated suppression of LHR, StAR, 3βHSDI and Cyp17a1 in Leydig cells from C57BL/6j that was associated with attenuated androgen production in basal and hCG-stimulated conditions compared to CBA/Lac mice. These genotype-dependent differences in steroidogenesis were not linked to changes in the expression of estrogen receptors ERα and Gpr30, while ERβ expression was attenuated in Leydig cells from C57BL/6j compared to CBA/Lac. No effects of estrogenic agonists on steroidogenesis in Leydig cells from both genotypes were found. In contrast, xenoestrogen bisphenol A significantly potentiated hCG-activated androgen production by Leydig cells from C57BL/6j and CBA/Lac mice by suppressing conversion of testosterone into corresponding metabolite 5α-androstane-3α,17β-diol. All together our data indicate that developing mouse Leydig cells with different androgen production potential are resistant to estrogenic stimuli, while xenoestrogen BPA facilitates hCG-induced steroidogenesis in mouse Leydig cells via attenuation of testosterone metabolism. This cellular event can cause premature maturation of Leydig cells that may create abnormal intratesticular paracrine milieu and disturb proper development of germ cells. PMID:23967237

Anti and Androgenic Activities in MDA-KB2 Cells: A Comparison of Performance in 96 Well Versus HTS Assays

EPA Science Inventory

We developed the MDA-kb2 cell line to screen androgen agonists/antagonists (Wilson et al., ToxSci 66:69, 2002). MDA-kb2 has been used to quantify anti- and androgenic activities of chemicals, mixtures, combustion by-products, oil dispersants and waste, source and drinking water s...

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

DTIC Science & Technology

2017-10-01

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

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

DTIC Science & Technology

2016-10-01

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

Androgens in health and disease: An overview

PubMed Central

Jordan, Cynthia L.; DonCarlos, Lydia

2009-01-01

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

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

PubMed

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

2009-10-01

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

Androgen abuse in the community.

PubMed

Melnik, Bodo C

2009-06-01

To provide information of the current prevalence of illicit use of androgens by individuals of the community. Prevalence of abuse of androgens in individuals of the general population has reached alarming dimensions. Use of androgens is no longer limited to competitive sports, but has spread to leisure and fitness sports, bodybuilding, and nonathletes motivated to increase muscular mass and physical attractiveness. Alarming studies from Germany demonstrated that members of the healthcare systems provide illegal androgens to 48.1% of abusers visiting fitness centers. The new trend to combine androgens with growth hormone, insulin, and insulinotropic milk protein-fortified drinks may potentiate health risks of androgen abuse. The use of androgens has changed from being a problem restricted to sports to one of public health concern. The potential health hazards of androgen abuse are underestimated in the medical community, which unfortunately contributes to illegal distribution of androgens. Both the adverse effects of current androgen abuse especially in young men as well as the chronic toxicity from past long-term abuse of now middle-aged men has to be considered as a growing public health problem. In the future, an increasing prevalence of androgen misuse in combination with other growth-promoting hormones and insulinotropic milk protein products has to be expected, which may have further promoting effects on the prevalence of chronic western diseases.

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

PubMed Central

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

2010-01-01

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

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

PubMed Central

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

2009-01-01

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

Androgenic/estrogenic balance in the male rat cerebral circulation: metabolic enzymes and sex steroid receptors

PubMed Central

Gonzales, Rayna J; Ansar, Saema; Duckles, Sue P; Krause, Diana N

2008-01-01

Tissues from males can be regulated by a balance of androgenic and estrogenic effects because of local metabolism of testosterone and expression of relevant steroid hormone receptors. As a critical first step to understanding sex hormone influences in the cerebral circulation of males, we investigated the presence of enzymes that metabolize testosterone to active products and their respective receptors. We found that cerebral blood vessels from male rats express 5α-reductase type 2 and aromatase, enzymes responsible for conversion of testosterone into dihydrotestosterone (DHT) and 17β-estradiol, respectively. Protein levels of these enzymes, however, were not modulated by long-term in vivo hormone treatment. We also showed the presence of receptors for both androgens (AR) and estrogens (ER) from male cerebral vessels. Western blot analysis showed bands corresponding to the full-length AR (110 kDa) and ERα (66 kDa). Long-term in vivo treatment of orchiectomized rats with testosterone or DHT, but not estrogen, increased AR levels in cerebral vessels. In contrast, ERα protein levels were increased after in vivo treatment with estrogen but not testosterone. Fluorescent immunostaining revealed ERα, AR, and 5α-reductase type 2 in both the endothelial and smooth muscle layers of cerebral arteries, whereas aromatase staining was solely localized to the endothelium. Thus, cerebral vessels from males are target tissues for both androgens and estrogen. Furthermore, local metabolism of testosterone might balance opposing androgenic and estrogenic influences on cerebrovascular as well as brain function in males. PMID:17406656

The Pathogenesis of Polycystic Ovary Syndrome (PCOS): The Hypothesis of PCOS as Functional Ovarian Hyperandrogenism Revisited

PubMed Central

Ehrmann, David A.

2016-01-01

Polycystic ovary syndrome (PCOS) was hypothesized to result from functional ovarian hyperandrogenism (FOH) due to dysregulation of androgen secretion in 1989–1995. Subsequent studies have supported and amplified this hypothesis. When defined as otherwise unexplained hyperandrogenic oligoanovulation, two-thirds of PCOS cases have functionally typical FOH, characterized by 17-hydroxyprogesterone hyperresponsiveness to gonadotropin stimulation. Two-thirds of the remaining PCOS have FOH detectable by testosterone elevation after suppression of adrenal androgen production. About 3% of PCOS have a related isolated functional adrenal hyperandrogenism. The remaining PCOS cases are mild and lack evidence of steroid secretory abnormalities; most of these are obese, which we postulate to account for their atypical PCOS. Approximately half of normal women with polycystic ovarian morphology (PCOM) have subclinical FOH-related steroidogenic defects. Theca cells from polycystic ovaries of classic PCOS patients in long-term culture have an intrinsic steroidogenic dysregulation that can account for the steroidogenic abnormalities typical of FOH. These cells overexpress most steroidogenic enzymes, particularly cytochrome P450c17. Overexpression of a protein identified by genome-wide association screening, differentially expressed in normal and neoplastic development 1A.V2, in normal theca cells has reproduced this PCOS phenotype in vitro. A metabolic syndrome of obesity-related and/or intrinsic insulin resistance occurs in about half of PCOS patients, and the compensatory hyperinsulinism has tissue-selective effects, which include aggravation of hyperandrogenism. PCOS seems to arise as a complex trait that results from the interaction of diverse genetic and environmental factors. Heritable factors include PCOM, hyperandrogenemia, insulin resistance, and insulin secretory defects. Environmental factors include prenatal androgen exposure and poor fetal growth, whereas acquired obesity is a major postnatal factor. The variety of pathways involved and lack of a common thread attests to the multifactorial nature and heterogeneity of the syndrome. Further research into the fundamental basis of the disorder will be necessary to optimally correct androgen levels, ovulation, and metabolic homeostasis. PMID:27459230

The Pathogenesis of Polycystic Ovary Syndrome (PCOS): The Hypothesis of PCOS as Functional Ovarian Hyperandrogenism Revisited.

PubMed

Rosenfield, Robert L; Ehrmann, David A

2016-10-01

Polycystic ovary syndrome (PCOS) was hypothesized to result from functional ovarian hyperandrogenism (FOH) due to dysregulation of androgen secretion in 1989-1995. Subsequent studies have supported and amplified this hypothesis. When defined as otherwise unexplained hyperandrogenic oligoanovulation, two-thirds of PCOS cases have functionally typical FOH, characterized by 17-hydroxyprogesterone hyperresponsiveness to gonadotropin stimulation. Two-thirds of the remaining PCOS have FOH detectable by testosterone elevation after suppression of adrenal androgen production. About 3% of PCOS have a related isolated functional adrenal hyperandrogenism. The remaining PCOS cases are mild and lack evidence of steroid secretory abnormalities; most of these are obese, which we postulate to account for their atypical PCOS. Approximately half of normal women with polycystic ovarian morphology (PCOM) have subclinical FOH-related steroidogenic defects. Theca cells from polycystic ovaries of classic PCOS patients in long-term culture have an intrinsic steroidogenic dysregulation that can account for the steroidogenic abnormalities typical of FOH. These cells overexpress most steroidogenic enzymes, particularly cytochrome P450c17. Overexpression of a protein identified by genome-wide association screening, differentially expressed in normal and neoplastic development 1A.V2, in normal theca cells has reproduced this PCOS phenotype in vitro. A metabolic syndrome of obesity-related and/or intrinsic insulin resistance occurs in about half of PCOS patients, and the compensatory hyperinsulinism has tissue-selective effects, which include aggravation of hyperandrogenism. PCOS seems to arise as a complex trait that results from the interaction of diverse genetic and environmental factors. Heritable factors include PCOM, hyperandrogenemia, insulin resistance, and insulin secretory defects. Environmental factors include prenatal androgen exposure and poor fetal growth, whereas acquired obesity is a major postnatal factor. The variety of pathways involved and lack of a common thread attests to the multifactorial nature and heterogeneity of the syndrome. Further research into the fundamental basis of the disorder will be necessary to optimally correct androgen levels, ovulation, and metabolic homeostasis.

PROSTATE REGULATION: MODELING ENDOGENOUS ...

EPA Pesticide Factsheets

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

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

PubMed Central

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

2016-01-01

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

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

PubMed

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

2011-02-01

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

Development of 17β-hydroxysteroid dehydrogenase type 3 as a target in hormone-dependent prostate cancer therapy.

PubMed

Ning, Xiaohui; Yang, Yan; Deng, Hong; Zhang, Qihao; Huang, Yadong; Su, Zhijian; Fu, Yongmei; Xiang, Qi; Zhang, Shu

2017-05-01

17β-Hydroxysteroid dehydrogenase type 3 (17β-HSD3) is expressed almost exclusively in the testes and specifically converts the weak androgenic androstenedione to active testosterone (T) in the presence of NADPH. Additionally, studies have demonstrated that 17β-HSD3 is over-expressed in hormone-dependent prostate cancer. T, which interacts with the androgen receptor (AR), eventually stimulates the growth of prostate cancer cells. Defects in T synthesis or action impair the development of the male phenotype during embryogenesis and cause the autosomal recessive disorder male pseudohermaphroditism. Affected individuals are often born with female-appearing external genitalia and are reared as females. Since 17β-HSD3 plays a central role in T production, it has been recognized as a promising therapeutic target to reduce the circulating level of androgens and to suppress androgen-sensitive tumor proliferation. In recent decades, improvements have been made in the development of 17β-HSD3 inhibitors. Herein, we give an overview of the main structure and function of human 17β-HSD3 and summarize steroidal and non-steroidal inhibitors of 17β-HSD3, which can be a potential target for prostate cancer. Copyright © 2017 Elsevier Inc. All rights reserved.

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

PubMed

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

2017-08-01

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

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

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

PubMed

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

2017-07-01

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

PTTG1, A novel androgen responsive gene is required for androgen-induced prostate cancer cell growth and invasion

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

Zhang, Zheng; Jin, Bo; Jin, Yaqiong

Androgens (AR) play an important role in initiation and progression of prostate cancer. It has been shown that AR exert their effects mainly through the androgen-activated AR which binds to androgen response elements (AREs) in the regulatory regions of target genes to regulate the transcription of androgen-responsive genes, thus, identification of AR downstream target gene is critical to understand androgen function in prostate cancer. In this study, our results showed that androgen treatment of LNCaP cells induced PTTG1 expression, which was blocked by the androgen receptor antagonist, Casodex. Bioinformatics analysis and experiments using PTTG1 promoter deletion mutants showed that themore » PTTG1 promoter contains a putative androgen response element (ARE), which localizes in the −851 to −836 region of the promoter. Androgen activated androgen receptor (AR) binding to this ARE was confirmed by Chromatin immunoprecipitation (ChIP) assay. Furthermore, Knockdown of PTTG1 expression using short hairpin RNA significantly reduced androgen-induced LNCaP cell growth and invasion. In addition, we showed PTTG1 is highly expressed in metastasis prostate cancer tissue. These results suggest that PTTG1 is a novel downstream target gene of androgen receptor and take part in prostate cancer proliferation and metastasis. - Highlights: • Androgen treatment of LNCaP cells induced PTTG1 expression. • Knockdown of PTTG1 expression significantly reduced androgen-induced LNCaP cell growth and invasion. • PTTG1 is highly expressed in metastasis prostate cancer tissue. • PTTG1 is a novel downstream target gene of androgen receptor.« less

Human Prostatic Acid Phosphatase: Structure, Function and Regulation

PubMed Central

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

2013-01-01

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

Cellular and Animal Studies: Insights into Pathophysiology and Therapy of PCOS.

PubMed

Indran, Inthrani Raja; Lee, Bao Hui; Yong, Eu-Leong

2016-11-01

Basic science studies have advanced our understanding of the role of key enzymes in the steroidogenesis pathway and those that affect the pathophysiology of PCOS. Studies with ovarian theca cells taken from women with PCOS have demonstrated increased androgen production due to increased CYP17A1 and HSD3B2 enzyme activities. Furthermore, overexpression of DENND1A variant 2 in normal theca cells resulted in a PCOS phenotype with increased androgen production. Notably, cellular steroidogenesis models have facilitated the understanding of the mechanistic effects of pharmacotherapies, including insulin sensitizers (e.g., pioglitazone and metformin) used for the treatment of insulin resistance in PCOS, on androgen production. In addition, animal models of PCOS have provided a critical platform to study the effects of therapeutic agents in a manner closer to the physiological state. Indeed, recent breakthroughs have demonstrated that natural derivatives such as the dietary medium-chain fatty acid decanoic acid (DA) can restore estrous cyclicity and lower androgen levels in an animal model of PCOS, thus laying the platform for novel therapeutic developments in PCOS. This chapter reviews the current understanding on the pathways modulating androgen biosynthesis, and the cellular and animal models that form the basis for preclinical research in PCOS, and sets the stage for clinical research. Copyright © 2016. Published by Elsevier Ltd.

Androgen Stimulates Growth of Mouse Preantral Follicles In Vitro: Interaction With Follicle-Stimulating Hormone and With Growth Factors of the TGFβ Superfamily

PubMed Central

Laird, Mhairi; Thomson, Kacie; Fenwick, Mark; Mora, Jocelyn; Hardy, Kate

2017-01-01

Androgens are essential for the normal function of mature antral follicles but also have a role in the early stages of follicle development. Polycystic ovary syndrome (PCOS), the most common cause of anovulatory infertility, is characterized by androgen excess and aberrant follicle development that includes accelerated early follicle growth. We have examined the effects of testosterone and dihydrotestosterone (DHT) on development of isolated mouse preantral follicles in culture with the specific aim of investigating interaction with follicle-stimulating hormone (FSH), the steroidogenic pathway, and growth factors of the TGFβ superfamily that are known to have a role in early follicle development. Both testosterone and DHT stimulated follicle growth and augmented FSH-induced growth and increased the incidence of antrum formation among the granulosa cell layers of these preantral follicles after 72 hours in culture. Effects of both androgens were reversed by the androgen receptor antagonist flutamide. FSH receptor expression was increased in response to both testosterone and DHT, as was that of Star, whereas Cyp11a1 was down-regulated. The key androgen-induced changes in the TGFβ signaling pathway were down-regulation of Amh, Bmp15, and their receptors. Inhibition of Alk6 (Bmpr1b), a putative partner for Amhr2 and Bmpr2, by dorsomorphin resulted in augmentation of androgen-stimulated growth and modification of androgen-induced gene expression. Our findings point to varied effects of androgen on preantral follicle growth and function, including interaction with FSH-activated growth and steroidogenesis, and, importantly, implicate the intrafollicular TGFβ system as a key mediator of androgen action. These findings provide insight into abnormal early follicle development in PCOS. PMID:28324051

Androgen Stimulates Growth of Mouse Preantral Follicles In Vitro: Interaction With Follicle-Stimulating Hormone and With Growth Factors of the TGFβ Superfamily.

PubMed

Laird, Mhairi; Thomson, Kacie; Fenwick, Mark; Mora, Jocelyn; Franks, Stephen; Hardy, Kate

2017-04-01

Androgens are essential for the normal function of mature antral follicles but also have a role in the early stages of follicle development. Polycystic ovary syndrome (PCOS), the most common cause of anovulatory infertility, is characterized by androgen excess and aberrant follicle development that includes accelerated early follicle growth. We have examined the effects of testosterone and dihydrotestosterone (DHT) on development of isolated mouse preantral follicles in culture with the specific aim of investigating interaction with follicle-stimulating hormone (FSH), the steroidogenic pathway, and growth factors of the TGFβ superfamily that are known to have a role in early follicle development. Both testosterone and DHT stimulated follicle growth and augmented FSH-induced growth and increased the incidence of antrum formation among the granulosa cell layers of these preantral follicles after 72 hours in culture. Effects of both androgens were reversed by the androgen receptor antagonist flutamide. FSH receptor expression was increased in response to both testosterone and DHT, as was that of Star, whereas Cyp11a1 was down-regulated. The key androgen-induced changes in the TGFβ signaling pathway were down-regulation of Amh, Bmp15, and their receptors. Inhibition of Alk6 (Bmpr1b), a putative partner for Amhr2 and Bmpr2, by dorsomorphin resulted in augmentation of androgen-stimulated growth and modification of androgen-induced gene expression. Our findings point to varied effects of androgen on preantral follicle growth and function, including interaction with FSH-activated growth and steroidogenesis, and, importantly, implicate the intrafollicular TGFβ system as a key mediator of androgen action. These findings provide insight into abnormal early follicle development in PCOS.

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

PubMed

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

2016-01-21

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

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

PubMed

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

2016-12-01

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

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

PubMed Central

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

2016-01-01

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

Early Hormonal Influences on Cognitive Functioning in Congenital Adrenal Hyperplasia.

ERIC Educational Resources Information Center

Resnick, Susan M.; And Others

1986-01-01

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

Increased and mistimed sex hormone production in night shift workers.

PubMed

Papantoniou, Kyriaki; Pozo, Oscar J; Espinosa, Ana; Marcos, Josep; Castaño-Vinyals, Gemma; Basagaña, Xavier; Juanola Pagès, Elena; Mirabent, Joan; Martín, Jordi; Such Faro, Patricia; Gascó Aparici, Amparo; Middleton, Benita; Skene, Debra J; Kogevinas, Manolis

2015-05-01

Night shift work has been associated with an increased risk for breast and prostate cancer. The effect of circadian disruption on sex steroid production is a possible underlying mechanism, underinvestigated in humans. We have assessed daily rhythms of sex hormones and melatonin in night and day shift workers of both sexes. We recruited 75 night and 42 day workers, ages 22 to 64 years, in different working settings. Participants collected urine samples from all voids over 24 hours on a working day. Urinary concentrations of 16 sex steroid hormones and metabolites (estrogens, progestagens, and androgens) and 6-sulfatoxymelatonin were measured in all samples. Mean levels and peak time of total and individual metabolite production were compared between night and day workers. Night workers had higher levels of total progestagens [geometric mean ratio (GMR) 1.65; 95% confidence intervals (CI), 1.17-2.32] and androgens (GMR: 1.44; 95% CI, 1.03-2.00), compared with day workers, after adjusting for potential confounders. The increased sex hormone levels among night shift workers were not related to the observed suppression of 6-sulfatoxymelatonin. Peak time of androgens was significantly later among night workers, compared with day workers (testosterone: 12:14 hours; 10:06-14:48 vs. 08:35 hours; 06:52-10:46). We found increased levels of progestagens and androgens as well as delayed peak androgen production in night shift workers compared with day workers. The increase and mistiming of sex hormone production may explain part of the increased risk for hormone-related cancers observed in night shift workers. ©2015 American Association for Cancer Research.

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.

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

PubMed

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

2014-11-28

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

Metabolic effects of obesity on reproduction.

PubMed

Pasquali, Renato; Gambineri, Alessandra

2006-05-01

Obese women are characterized by similar comorbidities to men, particularly type 2 diabetes mellitus and cardiovascular diseases. Moreover, they also develop some specific problems, including fertility-related disorders and some hormone-dependent forms of cancer. The relationship between excess body fat and reproductive disturbances appears to be stronger for early-onset obesity. Early onset of obesity, particularly during adolescence, favours the development of menses irregularities, chronic oligo-anovulation and infertility in adulthood. Moreover, obesity in women can increase the risk of miscarriage and impair the outcome of assisted reproductive technologies. The main factor implicated in the association between obesity and fertility-related disorders is insulin excess, which accompanies insulin resistance. Hyperinsulinaemia may be directly responsible for the development of androgen excess, through its effects in reducing sex hormone-binding globulin synthesis and circulating concentrations, and in stimulating ovarian androgen production rates. Androgen excess, in turn, represents one of the major factors leading to altered ovarian physiology and associated ovulatory disturbances. Obesity-associated hyperleptinaemia may represent an additional factor involved in anovulation, not only through the induction of insulin resistance, but also through a direct impairment of ovarian function.

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. Copyright © 2014 Elsevier B.V. All rights reserved.

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

EPA Science Inventory

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

A Major Population of Functional KLRG1- ILC2s in Female Lungs Contributes to a Sex Bias in ILC2 Numbers.

PubMed

Kadel, Sapana; Ainsua-Enrich, Erola; Hatipoglu, Ibrahim; Turner, Sean; Singh, Simar; Khan, Sohaib; Kovats, Susan

2018-02-01

Humans show significant sex differences in the incidence and severity of respiratory diseases, including asthma and virus infection. Sex hormones contribute to the female sex bias in type 2 inflammation associated with respiratory diseases, consistent with recent reports that female lungs harbor greater numbers of GATA-3-dependent group 2 innate lymphoid cells (ILC2s). In this study, we determined whether sex hormone levels govern sex differences in the numbers, phenotype, and function of ILC2s in the murine lung and bone marrow (BM). Our data show that lungs of female mice harbor significantly greater ILC2 numbers in homeostasis, in part due to a major subset of ILC2s lacking killer-cell lectin like receptor G1 (KLRG1), a population largely absent in male lungs. The KLRG1 - ILC2s were capable of type 2 cytokine production and increased with age after sexual maturity, suggesting that a unique functional subset exists in females. Experiments with gonadectomized mice or mice bearing either global or lymphocyte restricted estrogen receptor α ( Esr1 ) deficiency showed that androgens rather than estrogens regulated numbers of the KLRG1 - ILC2 subset and ILC2 functional capacity in the lung and BM, as well as levels of GATA-3 expression in BM ILC2s. Furthermore, the frequency of BM PLZF + ILC precursors was higher in males and increased by excess androgens, suggesting that androgens act to inhibit the transition of ILC precursors to ILC2s. Taken together, these data show that a functional subset of KLRG1 - ILC2s in females contributes to the sex bias in lung ILC2s that is observed after reproductive age.

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 ...

Synthesis and chemical reactions of the steroidal hormone 17α-methyltestosterone.

PubMed

El-Desoky, El-Sayed Ibrahim; Reyad, Mahmoud; Afsah, Elsayed Mohammed; Dawidar, Abdel-Aziz Mahmoud

2016-01-01

Structural modifications of natural products with complex structures like steroids require great synthetic effort. A review of literature is presented on the chemistry of the steroidal hormone 17α-methyltestosterone that is approved by Food and Drug Administration (FDA) in the United States as an androgen for estrogen-androgen hormone replacement therapy treatment. The analog also offers special possibilities for the prevention/treatment of hormone-sensitive cancers. The testosterone skeleton has important functionalities in the molecule that can act as a carbonyl component, an active methylene compound, α,β-unsaturated enone and tertiary hydroxyl group in various chemical reactions to access stereoisomeric steroidal compounds with potent activity. In addition, microbiological methods of synthesis and transformation of this hormone are presented. Copyright © 2015 Elsevier Inc. All rights reserved.

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

PubMed

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

2014-11-01

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

Androgen receptor signaling and mutations in prostate cancer

PubMed Central

Koochekpour, Shahriar

2010-01-01

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

Development of Novel Drugs That Target Coactivation Sites of the Androgen Receptor for Treatment of Antiandrogen-Resistant Prostate Cancer

DTIC Science & Technology

2015-12-01

quantifying their effect on the production of the prostate specific antigen (PSA) in prostate cancer cell lines (11). PSA is AR-regulated serine protease and... products . The hydroxylation products were observed in lesser amounts. The IV and IP serum profiles of VPC-13566 suggest that it could be administered IP...Glucocorticoid, mineralocorticoid, progesterone , and androgen receptors. Pharmacological Reviews. 2006;58:782-97. 2. Denmeade SR, Isaacs JT. A

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

PubMed

English, Robert S

2018-02-01

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

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

PubMed

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

2007-06-01

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

Mode of action: inhibition of androgen receptor function--vinclozolin-induced malformations in reproductive development.

PubMed

Kavlock, Robert; Cummings, Audrey

2005-01-01

Vinclozolin is a fungicide that has been shown to cause Leydig cell tumors and atrophy of the accessory sex glands in adult rodents. In addition, exposure of rats during pregnancy causes a pattern of malformations in the male urogenital tract. A wealth of standard toxicological studies and targeted research efforts is available related to this adverse effect, and these were used to evaluate the Human Relevance Framework (HRF) for noncancer health effects. Vinclozolin and two of its metabolites, designated M1 and M2, have been shown to bind and inhibit the function of the rat and human androgen receptor. Other means of interfering with androgen receptor function (e.g., by exposure to the pharmaceutical agent flutamide) lead to similar adverse health outcomes. There is direct in vivo evidence in the rat prostate that androgen-dependent gene expression changes occur after exposure to vinclozolin. There are no proposed alternatives to the androgen receptor-mediated mode of action. Based on what is known about kinetic and dynamic factors, confidence is high that the animal mode of action (MOA) for vinclozolin-induced malformation of the male reproductive tract is highly plausible in humans.

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

PubMed

Zhu, Yuan-shan; Cai, Li-qun

2006-04-01

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

Evidence that cytochrome b{sub 5} acts as a redox donor in CYP17A1 mediated androgen synthesis

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

Duggal, Ruchia; Liu, Yilin; Gregory, Michael C.

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 C−C lyase step, at the expense of glucocorticoid production. Cytochrome b{sub 5} (cyt b{sub 5}) 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 b{sub 5} increases androgen biosynthesis. Cyt b{sub 5} could act as an allosteric effector, binding to CYP17A1 and eithermore » changing its selective substrate affinity or altering the conformation of the P450 to increase the catalytic rate or decrease unproductive uncoupling channels. Alternatively, cyt b{sub 5} 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 b{sub 5}, we generated a redox-inactive form of cyt b{sub 5}, in which the heme is replaced with a Manganese-protoporphyrin IX (Mn-b{sub 5}), 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 b{sub 5} were enhanced ∼5 fold as compared to reactions in the absence of cyt b{sub 5}. We also performed resonance Raman measurements on ferric CYP17A1 bound to Mn-b{sub 5}. Upon addition of Mn-b{sub 5} to Nanodisc reconstituted CYP17A1, we observed clear evidence for the formation of a b{sub 5}-CYP17A1 complex, as noted by changes in the porphyrin modes and alteration in the proximal Fe−S vibrational frequency. Thus, although Mn-b{sub 5} binds to CYP17A1, it is unable to enhance the lyase reaction, strongly suggesting that cyt b{sub 5} has a redox effector role in enhancement of the CYP17A1 mediated lyase reaction necessary for androgen synthesis. - Highlights: • Cyt b{sub 5} role in human CYP17A1 mediated androgen synthesis was probed in Nanodiscs. • Native cyt b{sub 5} enhances androgen synthesis by CYP17A1. • Redox inactive Mn cyt b{sub 5} does not enhance androgen synthesis by CYP17A1. • Interactions with Cyt b{sub 5} perturb Fe−S and heme Raman modes of CYP17A1. • Cyt b{sub 5} acts as a redox donor for CYP17A1 mediated androgen synthesis.« less

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

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

Yu, Shan; Wang, Ming-Wei; Yao, Xiaoqiang

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 newlymore » 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.« less

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

PubMed Central

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

2012-01-01

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

Partial androgen insensitivity syndrome caused by a deep intronic mutation creating an alternative splice acceptor site of the AR gene.

PubMed

Ono, Hiroyuki; Saitsu, Hirotomo; Horikawa, Reiko; Nakashima, Shinichi; Ohkubo, Yumiko; Yanagi, Kumiko; Nakabayashi, Kazuhiko; Fukami, Maki; Fujisawa, Yasuko; Ogata, Tsutomu

2018-02-02

Although partial androgen insensitivity syndrome (PAIS) is caused by attenuated responsiveness to androgens, androgen receptor gene (AR) mutations on the coding regions and their splice sites have been identified only in <25% of patients with a diagnosis of PAIS. We performed extensive molecular studies including whole exome sequencing in a Japanese family with PAIS, identifying a deep intronic variant beyond the branch site at intron 6 of AR (NM_000044.4:c.2450-42 G > A). This variant created the splice acceptor motif that was accompanied by pyrimidine-rich sequence and two candidate branch sites. Consistent with this, reverse transcriptase (RT)-PCR experiments for cycloheximide-treated lymphoblastoid cell lines revealed a relatively large amount of aberrant mRNA produced by the newly created splice acceptor site and a relatively small amount of wildtype mRNA produced by the normal splice acceptor site. Furthermore, most of the aberrant mRNA was shown to undergo nonsense mediated decay (NMD) and, if a small amount of aberrant mRNA may have escaped NMD, such mRNA was predicted to generate a truncated AR protein missing some functional domains. These findings imply that the deep intronic mutation creating an alternative splice acceptor site resulted in the production of a relatively small amount of wildtype AR mRNA, leading to PAIS.

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

2016-04-07

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.

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

EPA Science Inventory

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

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

PubMed

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

2016-04-01

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

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

PubMed

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

2015-04-01

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

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

PubMed Central

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

2011-01-01

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

Regulation of steroidogenesis in fetal bovine ovaries: differential effects of LH and FSH.

PubMed

Allen, J J; Herrick, S L; Fortune, J E

2016-11-01

In cattle, primordial follicles form before birth. Fetal ovarian capacity to produce progesterone and estradiol is high before follicle formation begins and decreases around the time follicles first appear (around 90 days of gestation). However, mechanisms that regulate steroid production during this time remain unclear. We hypothesized that LH stimulates progesterone and androgen production and that FSH stimulates aromatization of androgens to estradiol. To test this, we cultured pieces from fetal bovine ovaries for 10 days without or with exogenous hormones and then measured the accumulation of steroids in the culture medium by RIA. LH (100 ng/mL) alone increased the accumulation of progesterone, androstenedione, testosterone and estradiol. FSH (100 ng/mL) alone increased both progesterone and estradiol accumulation, but had no effect on androgens. Exogenous testosterone (0.5 µM) alone greatly increased estradiol accumulation and the combination of testosterone + FSH, but not testosterone + LH, increased estradiol relative to testosterone alone. Interestingly, exogenous testosterone and estradiol decreased progesterone accumulation in a dose-dependent manner. Because the highest dose of estradiol (0.5 µM) decreased progesterone accumulation, but increased both pregnenolone and androstenedione in the same cultures, endogenous estradiol may be a paracrine regulator of steroid synthesis. Together, these results confirm our initial hypotheses and indicate that LH stimulates androgen production in fetal bovine ovaries via the Δ 5 pathway, whereas FSH stimulates aromatization of androgens to estradiol. These results are consistent with the two-cell, two-gonadotropin model of estradiol production by bovine preovulatory follicles, which suggests that the mechanisms regulating ovarian steroid production are established during fetal life. © 2016 Society for Endocrinology.

Aberrant AR Signaling as a Function of Declining Androgen

DTIC Science & Technology

2006-08-01

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

Androgens in pregnancy: roles in parturition

PubMed Central

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

2014-01-01

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

Androgens in pregnancy: roles in parturition.

PubMed

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

2014-01-01

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

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...

Role of Hsp90 in Androgen-Refractory Prostate Cancer

DTIC Science & Technology

2010-03-01

designed siRNA sequence using Intergrated DNA Technologies RNAi online software tool (IDT, Coralville, IA). The sequence of siRNA specific for...proliferation and production of prostate-specific antigen in androgen-sensitive pros- tatic cancer cells, LNCaP, by dihydrotestosterone. Endocrinology 136

Virilization caused by an ectopic adrenal tumor located behind the iliopsoas muscle.

PubMed

Mavroudis, Konstantinos; Aloumanis, Kyriakos; Papapetrou, Peter D; Voros, Dionisios; Spanos, Iraklis

2007-06-01

Virilization due to androgen-secreting neoplasms in women is a result of androgen overproduction from benign or malignant tumors that are found in the ovaries or rarely in the adrenal glands. Virilizing tumors that arise from ectopic adrenal tissue are extremely rare. We describe a very rare case of an ectopic androgen-producing adrenal tumor. Case report study. Endocrinology outpatient department of university-affiliated teaching hospital. A 45-year-old woman with symptoms of virilization of abrupt onset and rapid progression, with high serum androgen hormone levels and normal glucocorticoid secretion. Basal hormonal levels, stimulation and suppression tests, imaging techniques, and selective venous sampling. Localization and surgical removal of the source of androgen production. An ectopic mass was detected behind the left iliopsoas muscle. The patient was operated on and an oblong-shaped lesion, weighing 6 g, was removed. Histologically, the tissue was identified to be of adrenal origin. Postoperatively the androgen levels decreased to normal levels. This case illustrates difficulties in detecting and localizing the rare contingence of an ectopic adrenocortical androgen-secreting tumor.

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.

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

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

PubMed

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

2013-12-01

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

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,...

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

PubMed

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

2017-01-01

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

Systems Genetics Reveals the Functional Context of PCOS Loci and Identifies Genetic and Molecular Mechanisms of Disease Heterogeneity.

PubMed

Jones, Michelle R; Brower, Meredith A; Xu, Ning; Cui, Jinrui; Mengesha, Emebet; Chen, Yii-Der I; Taylor, Kent D; Azziz, Ricardo; Goodarzi, Mark O

2015-08-01

Genome wide association studies (GWAS) have revealed 11 independent risk loci for polycystic ovary syndrome (PCOS), a common disorder in young women characterized by androgen excess and oligomenorrhea. To put these risk loci and the single nucleotide polymorphisms (SNPs) therein into functional context, we measured DNA methylation and gene expression in subcutaneous adipose tissue biopsies to identify PCOS-specific alterations. Two genes from the LHCGR region, STON1-GTF2A1L and LHCGR, were overexpressed in PCOS. In analysis stratified by obesity, LHCGR was overexpressed only in non-obese PCOS women. Although not differentially expressed in the entire PCOS group, INSR was underexpressed in obese PCOS subjects only. Alterations in gene expression in the LHCGR, RAB5B and INSR regions suggest that SNPs in these loci may be functional and could affect gene expression directly or indirectly via epigenetic alterations. We identified reduced methylation in the LHCGR locus and increased methylation in the INSR locus, changes that are concordant with the altered gene expression profiles. Complex patterns of meQTL and eQTL were identified in these loci, suggesting that local genetic variation plays an important role in gene regulation. We propose that non-obese PCOS women possess significant alterations in LH receptor expression, which drives excess androgen secretion from the ovary. Alternatively, obese women with PCOS possess alterations in insulin receptor expression, with underexpression in metabolic tissues and overexpression in the ovary, resulting in peripheral insulin resistance and excess ovarian androgen production. These studies provide a genetic and molecular basis for the reported clinical heterogeneity of PCOS.

Androgens and menopause.

PubMed

Shulman, L P

2009-12-01

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

RNA splicing and splicing regulator changes in prostate cancer pathology.

PubMed

Munkley, Jennifer; Livermore, Karen; Rajan, Prabhakar; Elliott, David J

2017-09-01

Changes in mRNA splice patterns have been associated with key pathological mechanisms in prostate cancer progression. The androgen receptor (abbreviated AR) transcription factor is a major driver of prostate cancer pathology and activated by androgen steroid hormones. Selection of alternative promoters by the activated AR can critically alter gene function by switching mRNA isoform production, including creating a pro-oncogenic isoform of the normally tumour suppressor gene TSC2. A number of androgen-regulated genes generate alternatively spliced mRNA isoforms, including a prostate-specific splice isoform of ST6GALNAC1 mRNA. ST6GALNAC1 encodes a sialyltransferase that catalyses the synthesis of the cancer-associated sTn antigen important for cell mobility. Genetic rearrangements occurring early in prostate cancer development place ERG oncogene expression under the control of the androgen-regulated TMPRSS2 promoter to hijack cell behaviour. This TMPRSS2-ERG fusion gene shows different patterns of alternative splicing in invasive versus localised prostate cancer. Alternative AR mRNA isoforms play a key role in the generation of prostate cancer drug resistance, by providing a mechanism through which prostate cancer cells can grow in limited serum androgen concentrations. A number of splicing regulator proteins change expression patterns in prostate cancer and may help drive key stages of disease progression. Up-regulation of SRRM4 establishes neuronal splicing patterns in neuroendocrine prostate cancer. The splicing regulators Sam68 and Tra2β increase expression in prostate cancer. The SR protein kinase SRPK1 that modulates the activity of SR proteins is up-regulated in prostate cancer and has already given encouraging results as a potential therapeutic target in mouse models.

Evaluation of Triclosan in the Hershberger and H295R Steroidogenesis Assays

EPA Science Inventory

Triclosan (TCS) is an antibacterial widely used in personal care products that exhibits endocrine disrupting activity in several species with reports of altered thyroid, estrogen and androgen signaling pathways. To evaluate the androgen mode of action, TCS was evaluated for and...

In utero virilization secondary to a maternal Krukenberg tumor: case report and review of literature.

PubMed

Bustamante, Carmen; Hoyos-Martínez, Alfonso; Pirela, Daniela; Díaz, Alejandro

2017-07-26

Krukenberg tumors are ovarian metastatic adenocarcinomas with a primary origin usually located in the stomach, colon, gallbladder, pancreas, or breast. Occasionally, these tumors produce virilization in the affected individual due to androgen production by luteinization of the tumoral stroma. It is believed that during pregnancy these tumors are more likely to increase androgen production due to the elevated levels of human chorionic gonadotropin (hCG). High maternal androgens can cross the placenta producing virilization of the female fetus. A 46,XX newborn female, whose mother was diagnosed with a metastatic ovarian tumor during her second trimester of gestation associated with worsening hirsutism and acne, was found to have ambiguous genitalia at birth. Testosterone levels in both the mother and infant were elevated. Follow-up laboratory tests showed progressive normalization of circulating androgens after delivery. Krukenberg tumors are rare and may produce virilization of the mother and the female fetus when present during pregnancy.

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

PubMed Central

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

2013-01-01

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

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

DTIC Science & Technology

2007-10-01

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

Androgen circle of polycystic ovary syndrome.

PubMed

Homburg, Roy

2009-07-01

Although the aetiology of polycystic ovary syndrome (PCOS) is still not known and the search for causative genes is proving elusive, it is generally agreed that hyperandrogenism is at the heart of the syndrome. Here, it is proposed that excess androgens are the root cause of PCOS starting from their influence on the female fetus in programming gene expression, producing the characteristic signs and symptoms which are then exacerbated by a propagation of excess ovarian androgen production from multiple small follicles, anovulation and insulin resistance in the reproductive life-span, thus setting up a vicious perpetual circle of androgen excess. This opinion paper, rather than being a full-scale review, is intentionally biased in support of this hypothesis that androgen excess is the 'root of all evil' in PCOS; in the hope that its acceptance could lead to more direct treatment of the syndrome in all its facets rather than the symptomatic treatment of side effects of androgen excess that we are addressing today.

Efficient discovery of bioactive scaffolds by activity-directed synthesis

NASA Astrophysics Data System (ADS)

Karageorgis, George; Warriner, Stuart; Nelson, Adam

2014-10-01

The structures and biological activities of natural products have often provided inspiration in drug discovery. The functional benefits of natural products to the host organism steers the evolution of their biosynthetic pathways. Here, we describe a discovery approach—which we term activity-directed synthesis—in which reactions with alternative outcomes are steered towards functional products. Arrays of catalysed reactions of α-diazo amides, whose outcome was critically dependent on the specific conditions used, were performed. The products were assayed at increasingly low concentration, with the results informing the design of a subsequent reaction array. Finally, promising reactions were scaled up and, after purification, submicromolar ligands based on two scaffolds with no previous annotated activity against the androgen receptor were discovered. The approach enables the discovery, in tandem, of both bioactive small molecules and associated synthetic routes, analogous to the evolution of biosynthetic pathways to yield natural products.

Interactions between androgens, FSH, anti-Müllerian hormone and estradiol during folliculogenesis in the human normal and polycystic ovary.

PubMed

Dewailly, Didier; Robin, Geoffroy; Peigne, Maëliss; Decanter, Christine; Pigny, Pascal; Catteau-Jonard, Sophie

2016-11-01

Androgens, FSH, anti-Müllerian hormone (AMH) and estradiol (E2) are essential in human ovarian folliculogenesis. However, the interactions between these four players is not fully understood. The purpose of this review is to highlight the chronological sequence of the appearance and function of androgens, FSH, AMH and E2 and to discuss controversies in the relationship between FSH and AMH. A better understanding of this interaction could supplement our current knowledge about the pathophysiology of the polycystic ovary syndrome (PCOS). A literature review was performed using the following search terms: androgens, FSH, FSH receptor, anti-Mullerian hormone, AMHRII, estradiol, follicle, ovary, PCOS, aromatase, granulosa cell, oocyte. The time period searched was 1980-2015 and the databases interrogated were PubMed and Web of Science. During the pre-antral ('gonadotropin-independent') follicle growth, FSH is already active and promotes follicle growth in synergy with theca cell-derived androgens. Conversely, AMH is inhibitory by counteracting FSH. We challenge the hypothesis that AMH is regulated by androgens and propose rather an indirect effect through an androgen-dependent amplification of FSH action on granulosa cells (GCs) from small growing follicles. This hypothesis implies that FSH stimulates AMH expression. During the antral ('gonadotropin-dependent') follicle growth, E2 production results from FSH-dependent activation of aromatase. Conversely, AMH is inhibitory but the decline of its expression, amplified by E2, allows full expression of aromatase, characteristic of the large antral follicles. We propose a theoretical scheme made up of two triangles that follow each other chronologically. In PCOS, pre-antral follicle growth is excessive (triangle 1) because of intrinsic androgen excess that renders GCs hypersensitive to FSH, with consequently excessive AMH expression. Antral follicle growth and differentiation are disturbed (triangle 2) because of the abnormally persisting inhibition of FSH effects by AMH that blocks aromatase. Beside anovulation, this scenario may also serve to explain the higher receptiveness to gonadotropin therapy and the increased risk of ovarian hyperstimulation syndrome (OHSS) in patients with PCOS. Within GCs, the balance between FSH and AMH effects is pivotal in the shift from androgen- to oestrogen-driven follicles. Our two triangles hypothesis, based on updated data from the literature, offers a pedagogic template for the understanding of folliculogenesis in the normal and polycystic ovary. It opens new avenues for the treatment of anovulation due to PCOS. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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

PubMed

Riedl, Marc A

2015-04-01

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

Polycystic ovary syndrome, adipose tissue and metabolic syndrome.

PubMed

Delitala, Alessandro P; Capobianco, Giampiero; Delitala, Giuseppe; Cherchi, Pier Luigi; Dessole, Salvatore

2017-09-01

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder that affects women of reproductive age and is characterized by ovulatory dysfunction and/or androgen excess or polycystic ovaries. Women with PCOS present a number of systemic symptoms in addition to those related to the reproductive system. It has been associated with functional derangements in adipose tissue, metabolic syndrome, type 2 diabetes, and an increased risk of cardiovascular disease (CVD). A detailed literature search on Pubmed was done for articles about PCOS, adipokines, insulin resistance, and metabolic syndrome. Original articles, reviews, and meta-analysis were included. PCOS women are prone to visceral fat hypertrophy in the presence of androgen excess and the presence of these conditions is related to insulin resistance and worsens the PCO phenotype. Disturbed secretion of many adipocyte-derived substances (adipokines) is associated with chronic low-grade inflammation and contributes to insulin resistance. Abdominal obesity and insulin resistance stimulate ovarian and adrenal androgen production, and may further increase abdominal obesity and inflammation, thus creating a vicious cycle. The high prevalence of metabolic disorders mainly related to insulin resistance and CVD risk factors in women with PCOS highlight the need for early lifestyle changes for reducing metabolic risks in these patients.

EFFECTS OF ENVIRONMENTAL ANTIANDROGENS IN EXPERIMENTAL ANIMALS

EPA Science Inventory

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

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

PubMed Central

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

2009-01-01

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

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

PubMed

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

2008-05-01

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

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

DTIC Science & Technology

2011-07-01

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

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

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

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

1994-09-01

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

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

PubMed

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

2011-12-01

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

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

PubMed Central

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

2011-01-01

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

Disordered follicle development

PubMed Central

Chang, R. Jeffrey; Cook-Andersen, Heidi

2013-01-01

Alterations of ovarian follicle morphology and function have been well documented in women with PCOS. These include increased numbers of growing preantral follicles, failure of follicle growth beyond the mid-antral stage, evidence of granulosa call degeneration, and theca cell hyperplasia. Functional abnormalities include paradoxical granulosa cell hyperresponsiveness to FSH which is clinically linked to ovarian hyperstimulation during ovulation induction. In addition, there is likely a primary theca cell defect that accounts for the majority of excess androgen production in this disorder. The precise mechanisms responsible for altered follicle function are not completely clear. However, several factors appear to influence normal advancement of follicle development as well as impair ovarian steroidogenesis. These include intra- as well as extraovarian influences that distort normal ovarian growth and disrupt steroid production by follicle cells. PMID:22874072

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

PubMed

Traish, Abdulmaged M

2017-01-01

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

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

PubMed

Wibowo, Erik

2017-01-01

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

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

PubMed

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

1994-04-01

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

Baicalein suppresses the androgen receptor (AR)-mediated prostate cancer progression via inhibiting the AR N-C dimerization and AR-coactivators interaction.

PubMed

Xu, Defeng; Chen, Qiulu; Liu, Yalin; Wen, Xingqiao

2017-12-01

Androgen receptor (AR) plays a critical role in prostate cancer (PCa) development and progression. Androgen deprivation therapy with antiandrogens to reduce androgen biosynthesis or prevent androgens from binding to AR are widely used to suppress AR-mediated PCa growth. However, most of ADT may eventually fail with development of the castration resistance after 12-24 months. Here we found that a natural product baicalein can effectively suppress the PCa progression via targeting the androgen-induced AR transactivation with little effect to AR protein expression. PCa cells including LNCaP, CWR22Rv1, C4-2, PC-3, and DU145, were treated with baicalein and luciferase assay was used to evaluate their effect on the AR transactivation. Cell growth and IC 50 were determined by MTT assay after 48 hrs treatment. RT-PCR was used to evaluate the mRNA levels of AR target genes including PSA, TMPRSS2, and TMEPA1. Western blot was used to determine AR and PSA protein expression. The natural product of baicalein can selectively inhibit AR transactivation with little effect on the other nuclear receptors, including ERα, and GR. At a low concentration, 2.5 μM of baicalein effectively suppresses the growth of AR-positive PCa cells, and has little effect on AR-negative PCa cells. Mechanism dissection suggest that baicalein can suppress AR target genes (PSA, TMPRSS2, and TMEPA1) expression in both androgen responsive LNCaP cells and castration resistant CWR22Rv1 cells, that may involve the inhibiting the AR N/C dimerization and AR-coactivators interaction. Baicalein may be developed as an effective anti-AR therapy via its ability to inhibit AR transactivation and AR-mediated PCa cell growth.

EFFECTS OF ENVIRONMENTAL ANTIANDROGENS ON REPRODUCTIVE DEVELOPMENT IN EXPERIMENTAL ANIMALS

EPA Science Inventory

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

THE HERBICIDE LINURON REDUCES FETAL TESTOSTERONE PRODUCTION DURING BOTH IN UTERO AND IN VITRO EXPOSURES

EPA Science Inventory

Linuron, a urea-based herbicide, is a weak antagonist for the androgen receptor. Previous studies in our lab have shown that in utero exposureresults in malformations of androgen dependent tissues in adult male offspring. The pattern of malformations, however, differs somewha...

Androgen action in the masculinization programming window and development of male reproductive organs.

PubMed

Macleod, D J; Sharpe, R M; Welsh, M; Fisken, M; Scott, H M; Hutchison, G R; Drake, A J; van den Driesche, S

2010-04-01

We have shown previously that deficient androgen action within a masculinization programming window (MPW; e15.5-e18.5 in rats) is important in the origin of male reproductive disorders and in programming male reproductive organ size, but that androgen action postnatally may be important to achieve this size. To further investigate importance of the MPW, we used two rat models, in which foetal androgen production or action was impaired during the MPW by exposing in utero to either di(n-butyl) phthalate (DBP) or to flutamide. Reduced anogenital distance (AGD) was used as a monitor of androgen production/action during the MPW. Offspring were evaluated in early puberty (Pnd25) to establish if reproductive organ size was altered. The testes, penis, ventral prostate (VP) and seminal vesicles (SV) were weighed and penis length measured. Both DBP and flutamide exposure in the MPW significantly reduced penis, VP and SV size along with AGD at Pnd25; AGD and organ size were highly correlated. In DBP-, but not flutamide-, exposed animals, testis weight was also reduced and correlated with AGD. Intratesticular testosterone was also measured in control and DBP-exposed males during (e17.5) or after (e21.5) the MPW and related to AGD at e21.5. To evaluate the importance of postnatal androgen action in reproductive organ growth, the effect of combinations of prenatal and postnatal maternal treatments on AGD and penis size at Pnd25 was evaluated. In prenatally DBP-exposed animals, further postnatal exposure to either DBP or flutamide significantly reduced AGD and penis size in comparison with prenatal DBP exposure alone. In comparison, rats exposed postnatally to testosterone propionate after prenatal vehicle-exposure showed considerable increase in these parameters vs. controls. In conclusion, we show that the size of all male reproductive organs is programmed by androgen exposure in the MPW, but that growth towards this size is dependent on androgen action postnatally.

Rational design of a topical androgen receptor antagonist for the suppression of sebum production with properties suitable for follicular delivery.

PubMed

Mitchell, Lorna H; Johnson, Theodore R; Lu, Guang Wei; Du, Daniel; Datta, Kaushik; Grzemski, Felicity; Shanmugasundaram, Veerabahu; Spence, Julie; Wade, Kim; Wang, Zhi; Sun, Kevin; Lin, Kristin; Hu, Lain-Yen; Sexton, Karen; Raheja, Neil; Kostlan, Catherine; Pocalyko, David

2010-06-10

A novel nonsteroidal androgen receptor antagonist, (R)-4-(1-benzyl-4,4-dimethyl-2-oxopyrrolidin-3-yloxy)-2-(trifluoromethyl)benzonitrile (1), for the topical control of sebum production is reported. This compound, which is potent, selective, and efficacious in the clinically validated golden Syrian hamster ear animal model, was designed to be delivered to the pilosebaceous unit, the site of action, preferentially by the follicular route.

Potential prostate cancer drug target: bioactivation of androstanediol by conversion to dihydrotestosterone.

PubMed

Mohler, James L; Titus, Mark A; Wilson, Elizabeth M

2011-09-15

High-affinity binding of dihydrotestosterone (DHT) to the androgen receptor (AR) initiates androgen-dependent gene activation, required for normal male sex development in utero, and contributes to prostate cancer development and progression in men. Under normal physiologic conditions, DHT is synthesized predominantly by 5α-reduction of testosterone, the major circulating androgen produced by the testis. During androgen deprivation therapy, intratumoral androgen production is sufficient for AR activation and prostate cancer growth, even though circulating testicular androgen levels are low. Recent studies indicate that the metabolism of 5α-androstane-3α, 17β-diol by 17β-hydroxysteroid dehydrogenase 6 in benign prostate and prostate cancer cells is a major biosynthetic pathway for intratumoral synthesis of DHT, which binds AR and initiates transactivation to promote prostate cancer growth during androgen deprivation therapy. Drugs that target the so-called backdoor pathway of DHT synthesis provide an opportunity to enhance clinical response to luteinizing-hormone-releasing hormone (LHRH) agonists or antagonists, AR antagonists, and inhibitors of 5α-reductase enzymes (finasteride or dutasteride), and other steroid metabolism enzyme inhibitors (ketoconazole or the recently available abiraterone acetate). ©2011 AACR.

Comparison between testosterone oenanthate-induced azoospermia and oligozoospermia in a male contraceptive study. IV. Suppression of endogenous testicular and adrenal androgens.

PubMed

Anderson, R A; Wallace, A M; Kicman, A T; Wu, F C

1997-08-01

Administration of supraphysiological doses of testosterone to normal men causes inhibition of spermatogenesis, but while most become azoospermic, 30-55% maintain a low rate of spermatogenesis. We have investigated whether there are differences in endogenous androgen production, of testicular and adrenal origin, which may be related to the degree of suppression of spermatogenesis. Thirty-three healthy Caucasian men were given weekly i.m. injections of 200 mg testosterone oenanthate (TE), 18 became azoospermic, while 15 remained oligozoospermic. Urinary excretion of epitestosterone, a specific testicular product, was reduced to <10% of pretreatment values, with no differences between the groups. Similar results were obtained for other markers of testicular steroidogenesis. Urinary and plasma adrenal androgens were also reduced during TE treatment: a statistically significant decrease in both (P < 0.001 and P < 0.05 respectively) was seen in the azoospermic but not oligozoospermic responders. These results suggest that testicular steroidogenesis is decreased to <10% by the administration of supraphysiological doses of exogenous testosterone. Differences in the degree of ongoing steroidogenesis in the testis do not appear to account for incomplete suppression of spermatogenesis, thus differences in androgen metabolism may underlie this heterogeneous response. A small but significant reduction in secretion of adrenal androgens was also detectable, the relevance of which is unclear.

Dietary sources of cumulative phthalates exposure among the U.S. general population in NHANES 2005-2014.

PubMed

Varshavsky, Julia R; Morello-Frosch, Rachel; Woodruff, Tracey J; Zota, Ami R

2018-06-01

Anti-androgenic phthalates are reproductive toxicants that may have additive effects on male development. Diet is the primary exposure source for most phthalates, which contaminate the food supply through food contact materials and industrialized production. To compare dietary sources of cumulative phthalates exposure between "food at home" (e.g. food consumed from a grocery store) and "food away from home" (e.g. food consumed from fast food/restaurants and cafeterias) in the U.S. general population. We estimated cumulative phthalates exposure by calculating daily intake from metabolite concentrations in urinary spot samples for 10,253 participants (≥6 years old) using National Health and Nutrition Examination Survey (NHANES, 2005-2014) data. We constructed a biologically relevant metric of phthalates daily intake (∑androgen-disruptor, μg/kg/day) by converting phthalates into anti-androgen equivalent terms prior to their summation. Particular foods and the percent of total energy intake (TEI) consumed from multiple dining out sources were ascertained from 24-h recall surveys. Associations with ∑androgen-disruptor levels were estimated for children, adolescents, and adults using multivariable linear regression. We observed a consistent positive association between dining out and Σandrogen-disruptor levels across the study population (p-trend <0.0001). Among adolescents, high consumers of foods outside the home had 55% (95% CI: 35%, 78%) higher Σandrogen-disruptor levels compared to those who only consumed food at home. The contribution of specific dining out sources to Σandrogen-disruptor levels varied by age group. For example, cafeteria food was associated with 15% (95% CI: 4.0%, 28%) and 64% (95% CI: 40%, 92%) higher Σandrogen-disruptor levels in children and adults, respectively. Particular foods, especially sandwiches (i.e. cheeseburgers), were associated with increased Σandrogen-disruptor levels only if they were purchased away from home (p < 0.01). Dining out may be an important source of biologically relevant cumulative phthalates exposure among the U.S. Future studies should evaluate modifiable production practices that remove phthalates from the food supply in addition to the efficacy of interventions that promote eating fresh foods prepared at home. Copyright © 2018 Elsevier Ltd. All rights reserved.

INTERACTION OF ORGANOPHOSPHATE PESTICIDES AND RELATED COMPOUNDS WITH THE ANDROGEN RECEPTOR

EPA Science Inventory

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

Gynecomastia: Clinical evaluation and management

PubMed Central

Cuhaci, Neslihan; Polat, Sefika Burcak; Evranos, Berna; Ersoy, Reyhan; Cakir, Bekir

2014-01-01

Gynecomastia is the benign enlargement of male breast glandular tissue and is the most common breast condition in males. At least 30% of males will be affected during their life. Since it causes anxiety, psychosocial discomfort and fear of breast cancer, early diagnostic evaluation is important and patients usually seek medical attention. Gynecomastia was reported to cause an imbalance between estrogen and androgen action or an increased estrogen to androgen ratio, due to increased estrogen production, decreased androgen production or both. Evaluation of gynecomastia must include a detailed medical history, clinical examination, specific blood tests, imaging and tissue sampling. Individual treatment requirements can range from simple reassurance to medical treatment or even surgery. The main aim of any intervention is to relieve the symptoms and exclude other etiological factors. PMID:24741509

Visualising Androgen Receptor Activity in Male and Female Mice

PubMed Central

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

2013-01-01

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

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

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

PubMed Central

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

2011-01-01

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

Synergistic killing effect of chloroquine and androgen deprivation in LNCaP cells

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

Kaini, Ramesh R.; Hu, Chien-An A., E-mail: AHu@salud.unm.edu

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 showedmore » 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.« less

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 enhance the lyase reaction, strongly suggesting that cyt b5 has a redox effector role in enhancement of the CYP17A1 mediated lyase reaction necessary for androgen synthesis. Published by Elsevier Inc.

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

PubMed

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

2018-05-14

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

Systems Genetics Reveals the Functional Context of PCOS Loci and Identifies Genetic and Molecular Mechanisms of Disease Heterogeneity

PubMed Central

Xu, Ning; Cui, Jinrui; Mengesha, Emebet; Chen, Yii-Der I.; Taylor, Kent D.; Azziz, Ricardo; Goodarzi, Mark O.

2015-01-01

Genome wide association studies (GWAS) have revealed 11 independent risk loci for polycystic ovary syndrome (PCOS), a common disorder in young women characterized by androgen excess and oligomenorrhea. To put these risk loci and the single nucleotide polymorphisms (SNPs) therein into functional context, we measured DNA methylation and gene expression in subcutaneous adipose tissue biopsies to identify PCOS-specific alterations. Two genes from the LHCGR region, STON1-GTF2A1L and LHCGR, were overexpressed in PCOS. In analysis stratified by obesity, LHCGR was overexpressed only in non-obese PCOS women. Although not differentially expressed in the entire PCOS group, INSR was underexpressed in obese PCOS subjects only. Alterations in gene expression in the LHCGR, RAB5B and INSR regions suggest that SNPs in these loci may be functional and could affect gene expression directly or indirectly via epigenetic alterations. We identified reduced methylation in the LHCGR locus and increased methylation in the INSR locus, changes that are concordant with the altered gene expression profiles. Complex patterns of meQTL and eQTL were identified in these loci, suggesting that local genetic variation plays an important role in gene regulation. We propose that non-obese PCOS women possess significant alterations in LH receptor expression, which drives excess androgen secretion from the ovary. Alternatively, obese women with PCOS possess alterations in insulin receptor expression, with underexpression in metabolic tissues and overexpression in the ovary, resulting in peripheral insulin resistance and excess ovarian androgen production. These studies provide a genetic and molecular basis for the reported clinical heterogeneity of PCOS. PMID:26305227

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...

Androgens and bone.

PubMed

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

2012-12-01

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

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

Artificial masculinization in tilapia involves androgen receptor activation.

PubMed

Golan, Matan; Levavi-Sivan, Berta

2014-10-01

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

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

PubMed Central

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

1994-01-01

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

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

EPA Science Inventory

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

Dihydrotestosterone inhibits hair growth in mice by inhibiting insulin-like growth factor-I production in dermal papillae.

PubMed

Zhao, Juan; Harada, Naoaki; Okajima, Kenji

2011-10-01

We demonstrated that insulin-like growth factor-I (IGF-I) production in dermal papillae was increased and hair growth was promoted after sensory neuron stimulation in mice. Although the androgen metabolite dihydrotestosterone (DHT) inhibits hair growth by negatively modulating growth-regulatory effects of dermal papillae, relationship between androgen metabolism and IGF-I production in dermal papillae is not fully understood. We examined whether DHT inhibits IGF-I production by inhibiting sensory neuron stimulation, thereby preventing hair growth in mice. Effect of DHT on sensory neuron stimulation was examined using cultured dorsal root ganglion (DRG) neurons isolated from mice. DHT inhibits calcitonin gene-related peptide (CGRP) release from cultured DRG neurons. The non-steroidal androgen-receptor antagonist flutamide reversed DHT-induced inhibition of CGRP release. Dermal levels of IGF-I and IGF-I mRNA, and the number of IGF-I-positive fibroblasts around hair follicles were increased at 6h after CGRP administration. DHT administration for 3weeks decreased dermal levels of CGRP, IGF-I, and IGF-I mRNA in mice. Immunohistochemical expression of IGF-I and the number of proliferating cells in hair follicles were decreased and hair re-growth was inhibited in animals administered DHT. Co-administration of flutamide and CGRP reversed these changes induced by DHT administration. These observations suggest that DHT may decrease IGF-I production in dermal papillae by inhibiting sensory neuron stimulation through interaction with the androgen receptor, thereby inhibiting hair growth in mice. Copyright © 2011 Elsevier Ltd. All rights reserved.

[Neuroendocrine differentiation in prostate adenocarcinoma].

PubMed

Ramírez-Balderrama, Lázaro; López-Briones, Sergio; Daza-Benítez, Leonel; Macías, Maciste H; López-Gaytán, Teresa; Pérez-Vázquez, Victoriano

2013-01-01

The human prostate is a gland composed of many types of cells and extracellular components with specific functions. The stromal compartment includes nerve tissue, fibroblasts, lymphocytes, macrophages, endothelial cells, and smooth muscular cells. The epithelial compartment is composed of luminal epithelial cells, basal cells, and a lesser number of neuroendocrine cells, which are transcendental in growth regulation, differentiation, and secretory function. In prostate cancer, neuroendocrine cells replicate especially in high grade and advanced stage, and hormonally treated tumoral cells adopt characteristics that make them resistant to hormonal deprivation. Androgen receptors have a crucial role in tumorigenesis of prostate adenocarcinoma. Deprivation hormone therapy blocks the expression of androgen receptors in the prostatic epithelial cells. Neuroendocrine cells lack androgen receptors; their growth is hormonally independent and that is why deprivation hormonal therapy does not eliminate the neoplasic neuroendocrine cells. In contrast, these types of cells proliferate after therapy and make a paracrine network, stimulating the proliferation of androgen-independent neoplastic cells, which finally lead to tumoral recurrence. In this work we describe the neuroendocrine function in normal tissue and in prostatic adenocarcinoma, including neoplasic proliferation stimulation, invasion, apoptosis resistance, and angiogenesis, and describe some molecular pathways involved in this neuroendocrine differentiation.

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.

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

Increased acid ceramidase expression depends on upregulation of androgen-dependent deubiquitinases, USP2, in a human prostate cancer cell line, LNCaP.

PubMed

Mizutani, Naoki; Inoue, Minami; Omori, Yukari; Ito, Hiromi; Tamiya-Koizumi, Keiko; Takagi, Akira; Kojima, Tetsuhito; Nakamura, Mitsuhiro; Iwaki, Soichiro; Nakatochi, Masahiro; Suzuki, Motoshi; Nozawa, Yoshinori; Murate, Takashi

2015-10-01

Acid ceramidase (ACDase) metabolizes ceramide to sphingosine, leading to sphingosine 1-phosphate production. Reportedly, ACDase has been upregulated in prostate cancer. However, its regulatory mechanism remains unclear. LNCaP (androgen-sensitive prostate cancer cell line) but not PC3 and DU-145, (androgen-unresponsive cell lines) exhibited the highest ACDase protein. Among three cell lines, ASAH1 mRNA level was not correlated with ACDase protein expression, and the 5'-promoter activity did not show androgen dependency, suggesting the post-transcriptional regulation of ACDase in LNCaP cells. Based on these results, LNCaP was analysed further. Casodex, androgen receptor antagonist, and charcoal-stripped FCS (CS-FCS) decreased ACDase protein and activity, whereas dihydrotestosterone in CS-FCS culture increased ACDase protein and enzyme activity. MG132, a proteasome inhibitor, prevented the decrease of ACDase protein when cultured in CS-FCS, suggesting the involvement of ubiquitin/proteasome system. Reportedly, USP2, a deubiquitinase, plays an important role in LNCaP cells. USP2 siRNA decreased ACDase protein, whereas USP2 overexpression increased ACDase protein of LNCaP cells. However, SKP2, an ubiquitin E3 ligase known to be active in prostate cancer, did not affect androgen-dependent ACDase expression in LNCaP cells. Thus, ACDase regulation by androgen in androgen-sensitive LNCaP cells is mainly due to its prolonged protein half-life by androgen-stimulated USP2 expression. © The Authors 2015. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.

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...

PRESENTED AT SOCIETY OF TOXICOLOGY 2006: THE HERBICIDE LINURON REDUCES FETAL TESTOSTERONE PRODUCTION DURING BOTH IN UTERO AND IN VITRO EXPOSURES

EPA Science Inventory

Previous studies in our lab have shown that in utero exposure to Linuron, a urea-based herbicide, results in malformations of androgen dependent tissues in adult male offspring. The pattern of malformations, however, differs somewhat from that typically seen with a pure androgen...

Androgens and endometrium: New insights and new targets.

PubMed

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

2018-04-15

Androgens are synthesised in both the ovary and adrenals in women and play an important role in the regulation of female fertility, as well as in the aetiology of disorders such as polycystic ovarian syndrome, endometriosis and endometrial cancer. The endometrium is an androgen target tissue and the impact of AR-mediated effects has been studied using human endometrial tissue samples and rodent models. In this review we highlight recent evidence that endometrial androgen biosynthesis and intracrine action is important in preparation of a tissue microenvironment that can support implantation and establishment of pregnancy. The impact of androgens on endometrial cell proliferation, in repair of the endometrial wound at the time of menstruation and in endometrial disorders is discussed. Future directions for research focused on AR function as a therapeutic target are considered. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

Testosterone and Erectile Function: From Basic Research to a New Clinical Paradigm for Managing Men with Androgen Insufficiency and Erectile Dysfunction

PubMed Central

Traish, Abdulmaged M.; Goldstein, Irwin; Kim, Noel N.

2007-01-01

Objectives Androgens are essential for the development and growth of the penis, and they regulate erectile physiology by multiple mechanisms. Our goal is to provide a concise overview of the basic research and how this knowledge can be translated into a new clinical paradigm for patient management. In addition, this new paradigm may serve as a basis for stimulating constructive debate regarding the use of testosterone in men, and to promote new, innovative basic and clinical research to further understand the underlying mechanisms of androgen action in restoring erectile physiology. Methods A literature review was performed utilizing the US National Library of Medicine's PubMed database. Results On the basis of evidence derived from laboratory animal studies and clinical data, we postulate that androgen insufficiency disrupts cellular-signaling pathways and produces pathologic alterations in penile tissues, leading to erectile dysfunction. In this review, we discuss androgen-dependent cellular, molecular, and physiologic mechanisms modulating erectile function in the animal model, and the implication of this knowledge in testosterone use in the clinical setting to treat erectile dysfunction. The new clinical paradigm incorporates many of the consensed points of view discussed in traditional consensed algorithms exclusively designed for men with androgen insufficiency. There are, however, novel and innovative differences with this new clinical paradigm. This paradigm represents a fresh effort to provide mandatory and optional management strategies for men with both androgen insufficiency and erectile dysfunction. Conclusions The new clinical paradigm is evidence-based and represents one of the first attempts to address a logical management plan for men with concomitant hormonal and sexual health concerns. PMID:17329016

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

PubMed

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

2016-06-01

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

Androgen replacement therapy in late-onset hypogonadism: current concepts and controversies - a mini-review.

PubMed

Mäkinen, Juuso I; Huhtaniemi, Ilpo

2011-01-01

Normal testicular function is essential for the maintenance of male physical strength and behaviour irrespective of age. A new term of late-onset hypogonadism (LOH) has been coined for the condition of decreased testosterone (T) and hypogonadal symptoms in ageing men. The most important testicular hormone, T, is responsible for the gender-specific androgenic-anabolic effects in men. Testicular T production remains stable until around the age of 40 years after which it declines by 1-2% annually. Despite this age-related decline, serum T levels in most older men remain within the reference range of younger men. The decreasing androgen levels are paralleled by well-defined objective biological and nonspecific subjective signs and symptoms of ageing. Because these symptoms are similar to those observed in young men with documented hypogonadism, androgen replacement therapy (ART) has been considered a logical way to treat them. A thorough review of the existing literature was performed to evaluate the current concepts and controversies related to ageing men and ART. Although it is intuitively logical that the symptoms of LOH are due to the ageing-related deficiency of T, and that they can be reversed by ART, the evidence for this is still variable and often weak. In particular, evidence-based information about long-term benefits and risks of ART in ageing men is largely missing. Despite widespread use, evidence-based proof for the objective benefits and side effects of ART of elderly men is still scanty, and such treatments should be considered experimental. Copyright © 2010 S. Karger AG, Basel.

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

PubMed

Iwatani, N; Kodama, M; Seto, H

1992-06-01

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

Androgens and innate immunity in rehabilitated semi-captive orangutans (Pongo pygmaeus morio) from Malaysian Borneo.

PubMed

Prall, Sean P; Ambu, Laurentius; Nathan, Senthilvel; Alsisto, Sylvia; Ramirez, Diana; Muehlenbein, Michael P

2015-06-01

Despite the implications for the development of life-history traits, endocrine-immune trade-offs in apes are not well studied. This is due, in part, to difficulty in sampling wild primates, and lack of methods available for immune measures using samples collected noninvasively. Evidence for androgen-mediated immune trade-offs in orangutans is virtually absent, and very little is known regarding their pattern of adrenal development and production of adrenal androgens. To remedy both of these deficiencies, sera were collected from orangutans (Pongo pygmaeus morio) (N = 38) at the Sepilok Orangutan Rehabilitation Centre, Sabah, Malaysia, during routine health screenings. Testosterone, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone-sulfate (DHEA-S) were assayed, along with two measures of functional innate immunity. DHEA-S concentrations, but not DHEA, increased with age in this sample of 1-18 year old animals. DHEA concentrations were higher in animals with higher levels of serum bacteria killing ability, while DHEA-S and testosterone concentrations were higher in animals with reduced complement protein activity. Patterns of DHEA-S concentration in this sample are consistent with patterns of adrenarche observed in other apes. Results from this study suggest that in addition to testosterone, DHEA and DHEA-S may have potent effects on immunological activity in this species. © 2015 Wiley Periodicals, Inc.

Androgen and androgen metabolite levels in serum and urine of East African chimpanzees (Pan troglodytes schweinfurthii): comparison of EIA and LC-MS analyses.

PubMed

Preis, Anna; Mugisha, Lawrence; Hauser, Barbara; Weltring, Anja; Deschner, Tobias

2011-12-01

The primary male androgen testosterone (T) is often used as an endocrinological marker to investigate androgen-behaviour interactions in males. In chimpanzees and bonobos, studies investigating the relationship between T levels and dominance rank or aggressive behaviour have revealed contradictory results. The immunoassays used in these studies were originally developed for the measurement of steroids in serum. Their application to non-invasively collected samples, however, can lead to methodological problems due to cross-reacting metabolites, which might occur in urine or faeces but not in blood. The overall aim of this study, therefore, is to clarify whether a T enzyme immunoassay (EIA) is an applicable method to monitor testicular function in adult male chimpanzees. To estimate the impact of cross-reacting androgens on the used T EIA, we compared the results of an EIA measurement with a set of androgen metabolite levels measured by LC-MS. In urine from male chimpanzees, cross-reactivities appear to exist mainly with T and its exclusive metabolites, 5α-dihydrotestosterone (5α-DHT) and 5α-androstanediol (androstanediol). Both urinary and serum T levels of male chimpanzees were significantly higher than female T levels when measured with the T EIA, indicating a reliable measurement of testicular androgens and their exclusive metabolites with the used EIA. In urine from female chimpanzees, the comparison between LC-MS and T EIA results indicated a higher impact of cross-reactions with adrenal androgen metabolites. Therefore, the investigation of urinary T levels in female chimpanzees with a T EIA seems to be problematic. Overall our results show that a T EIA can be a reliable method to monitor testicular function in male chimpanzee urine and that LC-MS is a valuable tool for the validation of immunoassays. Copyright © 2011 Elsevier Inc. All rights reserved.

Expression profiles and functional associations of endogenous androgen receptor and caveolin-1 in prostate cancer cell lines.

PubMed

Bennett, Nigel C; Hooper, John D; Johnson, David W; Gobe, Glenda C

2014-05-01

In prostate cancer (PCa) patients, the protein target for androgen deprivation and blockade therapies is androgen receptor (AR). AR interacts with many proteins that function to either co-activate or co-repress its activity. Caveolin-1 (Cav-1) is not found in normal prostatic epithelium, but is found in PCa, and may be an AR co-regulator protein. We investigated cell line-specific signatures and associations of endogenous AR and Cav-1 in six PCa cell lines of known androgen sensitivity: LNCaP (androgen sensitive); 22Rv1 (androgen responsive); PC3, DU145, and ALVA41 (androgen non-reliant); and RWPE1 (non-malignant). Protein and mRNA expression profiles were compared and electron microscopy used to identify cells with caveolar structures. For cell lines expressing both AR and Cav-1, knockdown techniques using small interfering RNA against AR or Cav-1 were used to test whether diminished expression of one affected the other. Co-sedimentation of AR and Cav-1 was used to test their association. A reporter assay for AR genomic activity was utilized following Cav-1 knockdown. AR-expressing LNCaP and 22Rv1 cells had low endogenous Cav-1 mRNA and protein. Cell lines that expressed little or no AR (DU145, PC3, ALVA41, and RWPE1) expressed high endogenous levels of Cav-1. AR knockdown in LNCaP cells had little effect on Cav-1, but Cav-1 knockdown inhibited AR expression and genomic activity. These data show endogenous AR and Cav-1 mRNA and protein expression is inversely related in PCa cells, with Cav-1 acting on the androgen/AR signaling axis possibly as an AR co-activator, demonstrated by diminished AR genomic activity following Cav-1 knockdown. © 2013 Wiley Periodicals, Inc.

Brain and gonadal aromatase activity and steroid hormone levels in female and polymorphic males of the peacock blenny Salaria pavo.

PubMed

Gonçalves, David; Teles, Magda; Alpedrinha, João; Oliveira, Rui F

2008-11-01

In the peacock blenny Salaria pavo large males with well-developed secondary sexual characters establish nests and attract females while small "sneaker" males mimic female sexual displays in order to approach the nests of larger males and parasitically fertilize eggs. These alternative reproductive tactics are sequential, as sneakers irreversibly switch into nesting males. This transition involves major morphologic and behavioral changes and is likely to be mediated by hormones. This study focuses on the role of aromatase, an enzyme that catalyses the conversion of androgens into estrogens, in the regulation of male sexual polymorphism in S. pavo. For this, sex steroid plasma levels and aromatase activity (AA) in gonads, whole brain and brain macroareas were determined in sneakers, transitional males (i.e. sneakers undergoing the transition into nesting males), nesting males and females collected in the field. AA was much higher in ovarian tissue than in testicular tissue and accordingly circulating estradiol levels were highest in females. This supports the view that elevated AA and estradiol levels are associated with the development of a functional ovary. Transitional males are in a non-reproductive phase and had underdeveloped testes when compared with sneakers and nesting males. Testicular AA was approximately 10 times higher in transitional males when compared with sneakers and nesting males, suggesting high AA has a suppressive effect on testicular development. Nesting males had significantly higher plasma levels of both testosterone (T) and 11-ketotestosterone when compared with the other male morphs and previous studies demonstrated that these androgens suppress female-like displays in sneakers. In the brain, AA was highest in macroareas presumably containing hypothalamic nuclei traditionally associated with the regulation of reproductive behaviors. Overall, females presented the highest levels of brain AA. In male morphs AA increased from sneakers, to transitional males, to nesting males in all brain macroareas. These results suggest that the transition into the nesting male tactic is accompanied both by an increase in testicular androgen production and by a higher conversion of androgens into estrogens in the brain. The increase in androgen production is likely to mediate the development of male secondary sexual characters while the increase in brain AA may be related to the behavioral changes associated with tactic transition.

Classifying chemical mode of action using gene networks and machine learning: a case study with the herbicide linuron.

PubMed

Ornostay, Anna; Cowie, Andrew M; Hindle, Matthew; Baker, Christopher J O; Martyniuk, Christopher J

2013-12-01

The herbicide linuron (LIN) is an endocrine disruptor with an anti-androgenic mode of action. The objectives of this study were to (1) improve knowledge of androgen and anti-androgen signaling in the teleostean ovary and to (2) assess the ability of gene networks and machine learning to classify LIN as an anti-androgen using transcriptomic data. Ovarian explants from vitellogenic fathead minnows (FHMs) were exposed to three concentrations of either 5α-dihydrotestosterone (DHT), flutamide (FLUT), or LIN for 12h. Ovaries exposed to DHT showed a significant increase in 17β-estradiol (E2) production while FLUT and LIN had no effect on E2. To improve understanding of androgen receptor signaling in the ovary, a reciprocal gene expression network was constructed for DHT and FLUT using pathway analysis and these data suggested that steroid metabolism, translation, and DNA replication are processes regulated through AR signaling in the ovary. Sub-network enrichment analysis revealed that FLUT and LIN shared more regulated gene networks in common compared to DHT. Using transcriptomic datasets from different fish species, machine learning algorithms classified LIN successfully with other anti-androgens. This study advances knowledge regarding molecular signaling cascades in the ovary that are responsive to androgens and anti-androgens and provides proof of concept that gene network analysis and machine learning can classify priority chemicals using experimental transcriptomic data collected from different fish species. © 2013.

Androgen deficiency: association with increased anxiety and depression symptom severity in anorexia nervosa.

PubMed

Miller, Karen K; Wexler, Tamara L; Zha, Alicia M; Lawson, Elizabeth A; Meenaghan, Erinne M; Misra, Madhusmita; Binstock, Anna B; Herzog, David B; Klibanski, Anne

2007-06-01

Anorexia nervosa is associated with a high prevalence of psychiatric comorbidities, including anxiety and depression, and with endocrine dysfunction, including relative androgen deficiency compared with healthy young women. Because androgens are known to affect mood and behavior, we hypothesized that low endogenous androgen production in anorexia nervosa would predict anxiety and depression severity. Serum androgen levels and severity of depression (Hamilton Rating Scale for Depression) and anxiety (Hamilton Rating Scale for Anxiety) were measured in 43 community-dwelling women with DSM-IV-defined anorexia nervosa from May 2004 to July 2006. Strong inverse associations were observed between both total and free testosterone and anxiety and depression severity, independent of weight. Free testosterone was also inversely associated with 4 eating-disordered thinking and behavior subscales of the Eating Disorder Inventory 2 (EDI-2). Mean free testosterone blood levels were lower in women with clinically significant anxiety and in women with clinically significant depression, compared with those without. In stepwise regression models, free testosterone was an important predictor of anxiety and depression severity. EDI-2 ineffectiveness, perfectionism, interpersonal distress, and social insecurity scores were also inversely associated with androgen levels, independent of weight. Our data suggest that low androgen levels may contribute to anxiety, depression, and eating-disordered thinking and behavior in women with anorexia nervosa and form the basis for future studies to investigate the effectiveness of androgen replacement therapy. ClinicalTrials.gov identifier NCT00089843.

Species comparisons in molecular and functional attributes of the androgen and estrogen receptor

EPA Science Inventory

While endocrine disrupting compounds (EDCs) have the potential to act via several mechanisms of action, one of the most widely studied is the ability of environmental chemicals to interact directly with either the estrogen (ER) or androgen receptor (AR). In vitro screening assay...

Identification of Androgen Receptor Antagonists in Fish Using a Simple Bioassay with the Fathead Minnow Pimephales promelas .

EPA Science Inventory

Considerable effort has been expended on the development of bioassays to detect chemicals that affect endocrine function controlled by the vertebrate hypothalamic-pituitary-gonadal (HPG) axis via different mechanisms/modes of action (MOA). Antagonism of the androgen receptor (AR)...

Targeting androgen receptor and JunD interaction for prevention of prostate cancer progression.

PubMed

Mehraein-Ghomi, Farideh; Kegel, Stacy J; Church, Dawn R; Schmidt, Joseph S; Reuter, Quentin R; Saphner, Elizabeth L; Basu, Hirak S; Wilding, George

2014-05-01

Multiple studies show that reactive oxygen species (ROS) play a major role in prostate cancer (PCa) development and progression. Previously, we reported an induction of Spermidine/Spermine N(1) -Acetyl Transferase (SSAT) by androgen-activated androgen receptor (AR)-JunD protein complex that leads to over-production of ROS in PCa cells. In our current research, we identify small molecules that specifically block AR-JunD in this ROS-generating metabolic pathway. A high throughput assay based on Gaussia Luciferase reconstitution was used to identify inhibitors of the AR-JunD interaction. Selected hits were further screened using a fluorescence polarization competitor assay to eliminate those that bind to the AR Ligand Binding Domain (LBD), in order to identify molecules that specifically target events downstream to androgen activation of AR. Eleven molecules were selected for studies on their efficacy against ROS generation and growth of cultured human PCa cells by DCFH dye-oxidation assay and DNA fluorescence assay, respectively. In situ Proximity Ligation Assay (PLA), SSAT promoter-luciferase reporter assay, and western blotting of apoptosis and cell cycle markers were used to study mechanism of action of the lead compound. Selected lead compound GWARJD10 with EC(50) 10 μM against ROS production was shown to block AR-JunD interaction in situ as well as block androgen-induced SSAT gene expression at IC(50) 5 μM. This compound had no effect on apoptosis markers, but reduced cyclin D1 protein level. Inhibitor of AR-JunD interaction, GWARJD10 shows promise for prevention of progression of PCa at an early stage of the disease by blocking growth and ROS production. © 2014 Wiley Periodicals, Inc.

Development and exploitation of a novel mutant androgen receptor modelling strategy to identify new targets for advanced prostate cancer therapy

PubMed Central

O'Neill, Daniel; Jones, Dominic; Wade, Mark; Grey, James; Nakjang, Sirintra; Guo, Wenrui; Cork, David; Davies, Barry R.; Wedge, Steve R.; Robson, Craig N.; Gaughan, Luke

2015-01-01

The persistence of androgen receptor (AR) signalling in castrate-resistant prostate cancer (CRPC) highlights the unmet clinical need for the development of more effective AR targeting therapies. A key mechanism of therapy-resistance is by selection of AR mutations that convert anti-androgens to agonists enabling the retention of androgenic signalling in CRPC. To improve our understanding of these receptors in advanced disease we developed a physiologically-relevant model to analyse the global functionality of AR mutants in CRPC. Using the bicalutamide-activated ARW741L/C mutation as proof of concept, we demonstrate that this mutant confers an androgenic-like signalling programme and growth promoting phenotype in the presence of bicalutamide. Transcriptomic profiling of ARW741L highlighted key genes markedly up-regulated by the mutant receptor, including TIPARP, RASD1 and SGK1. Importantly, SGK1 expression was found to be highly expressed in the KUCaP xenograft model and a CRPC patient biopsy sample both of which express the bicalutamide-activated receptor mutant. Using an SGK1 inhibitor, ARW741L transcriptional and growth promoting activity was reduced indicating that exploiting functional distinctions between receptor isoforms in our model may provide new and effective therapies for CRPC patients. PMID:26267320

An alternate pathway for androgen regulation of brain function: Activation of estrogen receptor beta by the metabolite of dihydrotestosterone, 5α-androstane 3β, 17β diol

PubMed Central

Handa, Robert J.; Pak, Toni R.; Kudwa, Andrea E.; Lund, Trent D.; Hinds, Laura

2008-01-01

The complexity of gonadal steroid hormone actions is reflected in their broad and diverse effects on a host of integrated systems including reproductive physiology, sexual behavior, stress responses, immune function, cognition, and neural protection. Understanding the specific contributions of androgens and estrogens in neurons that mediate these important biological processes is central to the study of neuroendocrinology. Of particular interest in recent years has been the biological role of androgen metabolites. The goal of this review is to highlight recent data delineating the specific brain targets for the dihydrotestosterone metabolite, 5α-androstane, 3β, 17β-diol (3β-Diol). Studies using both in vitro and in vivo approaches provide compelling evidence that 3β-Diol is an important modulator of the stress response mediated by the hypothalmo-pituitary-adrenal axis. Further, the actions of 3β-Diol are mediated by estrogen receptors, and not androgen receptors, often through a canonical estrogen response element in the promoter of a given target gene. These novel findings compel us to re-evaluate the interpretation of past studies and the design of future experiments aimed at elucidating the specific effects of androgen receptor signaling pathways. PMID:18067894

Allosteric alterations in the androgen receptor and activity in prostate cancer.

PubMed

Uo, Takuma; Plymate, Stephen R; Sprenger, Cynthia C

2017-09-01

Organisms have evolved to generate biological complexity in their proteome and transcriptome from a limited number of genes. This concept holds true for the androgen receptor, which displays a diversity of inclusion/exclusion events in its structural motifs as a mechanism of resistance to the most forefront anti-androgen therapies. More than 20 androgen receptor variants that lack various portions of ligand-binding domain have been identified in human prostate cancer (PCa) samples. Most of the variants are inactive on their own, with a few exceptions displaying constitutive activity. The full-length receptor and one or more variants can be co-expressed in the same cell under many circumstances, which raises the question of how these variants physically and functionally interact with the full-length receptor or one another in the course of PCa progression. To address this issue, in this review, we will characterize and discuss androgen receptor variants, including the novel variants discovered in the last couple of years (i) individually, (ii) with respect to their physical and functional interaction with one another and (iii) in clinical relevance. Here, we also introduce the very recent understanding of AR-Vs obtained through successful development of some AR-V-specific antibodies as well as identification of novel AR-Vs by data mining approaches. © 2017 Society for Endocrinology.

Evolution of the androgen-induced male phenotype.

PubMed

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

2018-01-01

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

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

Histological and transcriptomic effects of 17α-methyltestosterone on zebrafish gonad development.

PubMed

Lee, Stephanie Ling Jie; Horsfield, Julia A; Black, Michael A; Rutherford, Kim; Fisher, Amanda; Gemmell, Neil J

2017-07-24

Sex hormones play important roles in teleost ovarian and testicular development. In zebrafish, ovarian differentiation appears to be dictated by an oocyte-derived signal via Cyp19a1a aromatase-mediated estrogen production. Androgens and aromatase inhibitors can induce female-to-male sex reversal, however, the mechanisms underlying gonadal masculinisation are poorly understood. We used histological analyses together with RNA sequencing to characterise zebrafish gonadal transcriptomes and investigate the effects of 17α-methyltestosterone on gonadal differentiation. At a morphological level, 17α-methyltestosterone (MT) masculinised gonads and accelerated spermatogenesis, and these changes were paralleled in masculinisation and de-feminisation of gonadal transcriptomes. MT treatment upregulated expression of genes involved in male sex determination and differentiation (amh, dmrt1, gsdf and wt1a) and those involved in 11-oxygenated androgen production (cyp11c1 and hsd11b2). It also repressed expression of ovarian development and folliculogenesis genes (bmp15, gdf9, figla, zp2.1 and zp3b). Furthermore, MT treatment altered epigenetic modification of histones in zebrafish gonads. Contrary to expectations, higher levels of cyp19a1a or foxl2 expression in control ovaries compared to MT-treated testes and control testes were not statistically significant during early gonad development (40 dpf). Our study suggests that both androgen production and aromatase inhibition are important for androgen-induced gonadal masculinisation and natural testicular differentiation in zebrafish.

Disrupting androgen production of Leydig cells by resveratrol via direct inhibition of human and rat 3β-hydroxysteroid dehydrogenase.

PubMed

Li, Ling; Chen, Xiaomin; Zhu, Qiqi; Chen, Dongxin; Guo, Jingjing; Yao, Wenwen; Dong, Yaoyao; Wei, Jia; Lian, Qingquan; Ge, Ren-Shan; Yuan, Bo

2014-04-07

Resveratrol is a polyphenol produced by several plants. It has been demonstrated that it has anti-inflammatory, antitumor, and anti-diabetic effects in animal models. However, its side effects are generally unclear. In the present study, we reported that resveratrol inhibited luteinizing hormone-stimulated androgen production in rat immature Leydig cells. Further analysis demonstrated that it was a competitive inhibitor of rat and human 3β-hydroxysteroid dehydrogenase with IC₆₀ values of 3.87 ± 0.06 and 8.48 ± 0.04 μM, respectively. The inhibition on 3β-hydroxysteroid dehydrogenase was specific since it did not inhibit another hydroxysteroid dehydrogenase 17β-hydroxysteroid dehydrogenase 3 at the highest concentration (100 μM) tested. In conclusion, resveratrol potentially interferes with androgen biosynthesis of rat Leydig cells. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

ERG Expression Levels in Prostate Tumors Reflect Functional Status of the Androgen Receptor (AR) as a Consequence of Fusion of ERG with AR Regulated Gene Promoters

DTIC Science & Technology

2010-01-01

mathematically defined in the following formulas. ARGI = Σ (I PMEPA1 + IPSA +INKX3.1+IODC1+IAMD1) ARFI=CI=ARGI+IERG Detection of TMPRSS2-ERG Fusion Junctions...ERG expression into the Androgen Receptor Function Index, ARFI. ARGI = Σ (I PMEPA1 + IPSA +INKX3.1+IODC1+IAMD1) ARFI=CI=ARGI+IERG In the high ERG

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.

Endocrine Activities of Pesticides During Ozonation of Waters.

PubMed

Westlund, Paul; Isazadeh, Siavash; Therrien, Alexandre; Yargeau, Viviane

2018-01-01

Two yeast-based bioassays were used to assess the endocrine activity potential of transformation products formed during the ozonation of water containing a variety of pesticides (propiconazole, atrazine, 2,4-dichlorophenoxyacetic acid [2,4-D], tebuconazole, climbazole, myclobutanil, irgarol, terbutryn, dicamba, mecoprop and diuron). Ozone experiments were conducted first in reverse osmosis water to isolate the effects of the pesticides and then in synthetic wastewater and wastewater effluent to investigate whether the results translated to more complex matrices. The findings demonstrate the recalcitrant nature of most pesticides during ozonation, with removals below 50%, except for irgarol, terbutryn and climbazole with removals up to 70%. This study is the first one to investigate the removal of the fungicides myclobutanil and tebuconazole by ozonation and is one of the first studies to investigate the androgenic activity of ozonation transformation products of contaminants of emerging concern. These findings also demonstrated that during ozonation the initial anti-androgenic activity was removed while the estrogenic activity remained undetected and the androgenic activity increased to levels up to 60% of the anti-androgenic activity of the DHT control. These results indicate that bioactivity should be considered in the evaluation of treatment performance and risks assessment associated to wastewater discharges.

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

PubMed Central

Yang, Fu-Chun; Chen, Yi-Lung; Tang, Sen-Lin; Yu, Chang-Ping; Wang, Po-Hsiang; Ismail, Wael; Wang, Chia-Hsiang; Ding, Jiun-Yan; Yang, Cheng-Yu; Yang, Chia-Ying; Chiang, Yin-Ru

2016-01-01

Steroid hormones, such as androgens, are common surface-water contaminants. However, literature on the ecophysiological relevance of steroid-degrading organisms in the environment, particularly in anoxic ecosystems, is extremely limited. We previously reported that Steroidobacter denitrificans anaerobically degrades androgens through the 2,3-seco pathway. In this study, the genome of Sdo. denitrificans was completely sequenced. Transcriptomic data revealed gene clusters that were distinctly expressed during anaerobic growth on testosterone. We isolated and characterized the bifunctional 1-testosterone hydratase/dehydrogenase, which is essential for anaerobic degradation of steroid A-ring. Because of apparent substrate preference of this molybdoenzyme, corresponding genes, along with the signature metabolites of the 2,3-seco pathway, were used as biomarkers to investigate androgen biodegradation in the largest sewage treatment plant in Taipei, Taiwan. Androgen metabolite analysis indicated that denitrifying bacteria in anoxic sewage use the 2,3-seco pathway to degrade androgens. Metagenomic analysis and PCR-based functional assays showed androgen degradation in anoxic sewage by Thauera spp. through the action of 1-testosterone hydratase/dehydrogenase. Our integrative ‘omics' approach can be used for culture-independent investigations of the microbial degradation of structurally complex compounds where isotope-labeled substrates are not easily available. PMID:26872041

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

PubMed

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

2005-12-01

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

Inflammation in Polycystic Ovary Syndrome: Underpinning of insulin resistance and ovarian dysfunction

PubMed Central

González, Frank

2012-01-01

Chronic low-grade inflammation has emerged as a key contributor to the pathogenesis of Polycystic Ovary Syndrome (PCOS). A dietary trigger such as glucose is capable of inciting oxidative stress and an inflammatory response from mononuclear cells (MNC) of women with PCOS, and this phenomenon is independent of obesity. This is important because MNC-derived macrophages are the primary source of cytokine production in excess adipose tissue, and also promote adipocyte cytokine production in a paracrine fashion. The proinflammatory cytokine tumor necrosis factor-α (TNFα) is a known mediator of insulin resistance. Glucose-stimulated TNFα release from MNC along with molecular markers of inflammation are associated with insulin resistance in PCOS. Hyperandrogenism is capable of activating MNC in the fasting state, thereby increasing MNC sensitivity to glucose; and this may be a potential mechanism for promoting diet-induced inflammation in PCOS. Increased abdominal adiposity is prevalent across all weight classes in PCOS, and this inflamed adipose tissue contributes to the inflammatory load in the disorder. Nevertheless, glucose ingestion incites oxidative stress in normal weight women with PCOS even in the absence of increased abdominal adiposity. In PCOS, markers of oxidative stress and inflammation are highly correlated with circulating androgens. Chronic suppression of ovarian androgen production does not ameliorate inflammation in normal weight women with the disorder. Furthermore, in vitro studies have demonstrated the ability of pro-inflammatory stimuli to upregulate the ovarian theca cell steroidogenic enzyme responsible for androgen production. These findings support the contention that inflammation directly stimulates the polycystic ovary to produce androgens. PMID:22178787

Group management influences reproductive function of the male cheetah (Acinonyx jubatus).

PubMed

Koester, Diana C; Freeman, Elizabeth W; Wildt, David E; Terrell, Kimberly A; Franklin, Ashley D; Meeks, Karen; Crosier, Adrienne E

2017-03-01

Although the free-ranging cheetah is generally socially solitary, as many as 60% of males live in same-sex (usually sibling) coalitions. Under ex situ conditions, the cheetah experiences low reproductive success with only ~18% of males having ever produced young. Most male cheetahs (85%) are managed in captivity in coalitions, but with no data on the influence of social grouping on reproductive parameters. We examined the influence of singleton versus coalition management on various male cheetah physiological traits, including ejaculate quality and gonadal and adrenal hormone metabolite concentrations. We also assessed behaviour within coalitions for evidence of social hierarchy through initiation of interactions with group mates and relatedness to physiological traits. Ejaculate quality (including total motile and structurally normal spermatozoa per ejaculate) and androgen concentration profiles were higher (P<0.05) in coalition compared with singleton males. These results support the conclusion that testis function in the cheetah, specifically related to the development of normal, motile spermatozoa and androgen production, is influenced by management with same-sex conspecifics. The findings have implications for ex situ conservation breeding programs by suggesting that reproductive quality can be enhanced through group maintenance of cheetah males.

SPECIES DIFFERENCES IN ANDROGEN AND ESTROGEN RECEPTOR STRUCTURE AND FUNCTION AMONG VERTEBRATES AND INVERTEBRATES FOR INTERSPECIES EXTRAPOLATION OF ENDOCRINE DISRUPTING CHEMICALS

EPA Science Inventory

In vitro screening assays designed to identify hormone minics or antagonists, including the EDSTAC Tier 1 Screening (TIS) Battery, typically use only mammalian estrogen (ER) and androgen receptors (AR). However, there is uncertainty concerning species differences in binding affin...

EFFECT OF THE ANTI-ANDROGENIC ENDOCRINE DISRUPTOR VINCLOZOLIN ON EMBRYONIC TESTIS CORD FORMATION AND POSTNATAL TESTIS DEVELOPMENT AND FUNCTION. (R827405)

EPA Science Inventory

Vinclozolin is a systemic dicarboximide fungicide that is used on fruits, vegetables, ornamental plants, and turf grass. Vinclozolin and its metabolites are known to be endocrine disruptors and act as androgen receptor antagonists. The hypothesis tested in the current study is...

Identification of a new androgen receptor (AR) co-regulator BUD31 and related peptides to suppress wild-type and mutated AR-mediated prostate cancer growth via peptide screening and X-ray structure analysis.

PubMed

Hsu, Cheng-Lung; Liu, Jai-Shin; Wu, Po-Long; Guan, Hong-Hsiang; Chen, Yuh-Ling; Lin, An-Chi; Ting, Huei-Ju; Pang, See-Tong; Yeh, Shauh-Der; Ma, Wen-Lung; Chen, Chung-Jung; Wu, Wen-Guey; Chang, Chawnshang

2014-12-01

Treatment with individual anti-androgens is associated with the development of hot-spot mutations in the androgen receptor (AR). Here, we found that anti-androgens-mt-ARs have similar binary structure to the 5α-dihydrotestosterone-wt-AR. Phage display revealed that these ARs bound to similar peptides, including BUD31, containing an Fxx(F/H/L/W/Y)Y motif cluster with Tyr in the +5 position. Structural analyses of the AR-LBD-BUD31 complex revealed formation of an extra hydrogen bond between the Tyr+5 residue of the peptide and the AR. Functional studies showed that BUD31-related peptides suppressed AR transactivation, interrupted AR N-C interaction, and suppressed AR-mediated cell growth. Combination of peptide screening and X-ray structure analysis may serve as a new strategy for developing anti-ARs that simultaneously suppress both wt and mutated AR function. Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Functional behavior and reproduction in androgenic sex reversed zebrafish (Danio rerio).

PubMed

Larsen, Mia G; Baatrup, Erik

2010-08-01

Endocrine-disrupting chemicals released into natural watercourses may cause biased sex ratios by sex reversal in fish populations. The present study investigated the androgenic sex reversal of zebrafish (Danio rerio) exposed to the androgenic compound 17beta-trenbolone (TB) and whether sex-changed females would revert to the female phenotype after cessation of TB exposure. 17beta-Trenbolone is a metabolite of trenbolone acetate, an anabolic steroid used as a growth promoter in beef cattle. 17beta-Trenbolone in runoff from cattle feedlots may reach concentrations that affect fish sexual development. Zebrafish were exposed to a concentration of 20 ng/L TB in a flow-through system for five months from egg until sexual maturity. This resulted in an all-male population. It was further found that all these phenotypic males displayed normal male courtship behavior and were able to reproduce successfully, implying that the sex reversal was complete and functional. None of the phenotypic males developed into females after six months in clean water, demonstrating that androgenic sex reversal of zebrafish is irreversible. Copyright 2010 SETAC

Progesterone receptor in the prostate: A potential suppressor for benign prostatic hyperplasia and prostate cancer.

PubMed

Chen, RuiQi; Yu, Yue; Dong, Xuesen

2017-02-01

Advanced prostate cancer undergoing androgen receptor pathway inhibition (ARPI) eventually progresses to castrate-resistant prostate cancer (CRPC), suggesting that (i) androgen receptor (AR) blockage is incomplete, and (ii) there are other critical molecular pathways contributing to prostate cancer (PCa) progression. Although most PCa occurs in the epithelium, prostate stroma is increasingly believed to play a crucial role in promoting tumorigenesis and facilitating tumor progression. In the stroma, sex steroid hormone receptors such as AR and estrogen receptor-α are implicated to have important functions, whereas the progesterone receptor (PR) remains largely under-investigated despite the high sequence and structural similarities between PR and AR. Stromal progesterone/PR signaling may play a critical role in PCa development and progression because not only progesterone is a critical precursor for de novo androgen steroidogenesis and an activator of mutant androgen receptors, but also PR functions in a ligand-independent manner in various important pathways. In fact, recent progress in our understanding of stromal PR function suggests that this receptor may exert an inhibitory effect on benign prostatic hyperplasia (BPH), reactive stroma development, and PCa progression. These early findings of stromal PR warrant further investigations as this receptor could be a potential biomarker and therapeutic target in PCa management. Copyright © 2016 Elsevier Ltd. All rights reserved.

Concept and viability of androgen annihilation for advanced prostate cancer.

PubMed

Mohler, James L

2014-09-01

There remains no standard of care for patients with a rising prostate-specific antigen level after radical prostatectomy or radiotherapy but who have no radiographic metastases, even though this is the second largest group of patients with prostate cancer (CaP) in the United States. Androgen deprivation therapy (ADT) may cure some men with advanced CaP based on single-institution series and a randomized clinical trial of immediate versus delayed ADT for men found to have pelvic lymph node metastasis at the time of radical prostatectomy. ADT may be more effective when initiated for minimal disease burden, which can be detected using PSA after radical prostatectomy or radiotherapy, and if more complete disruption of the androgen axis using newer agents decreases the chance that androgen-sensitive cells survive to adapt to a low-androgen environment. Androgens may be "annihilated" simultaneously using a luteinizing hormone-releasing hormone antagonist or agonist to inhibit testicular production of testosterone, a P45017A1 (CYP17A1) inhibitor to diminish metabolism of testosterone via the adrenal pathway and dihydrotestosterone (DHT) via the backdoor pathway, a 5α-reductase (SRD5A) inhibitor to diminish testosterone reduction to DHT and backdoor metabolism of progesterone substrates to DHT, and a newer antiandrogen to compete better with DHT for the androgen receptor ligand-binding domain. Early initiation of androgen annihilation for induction as part of planned intermittent ADT should be safe, may reduce tumor burden below a threshold that allows eradication by the immune system, and may cure many men who have failed definitive local therapy. © 2014 American Cancer Society.

Sexual function in infertile women with polycystic ovary syndrome and unexplained infertility.

PubMed

Diamond, Michael P; Legro, Richard S; Coutifaris, Christos; Alvero, Ruben; Robinson, Randal D; Casson, Peter A; Christman, Gregory M; Huang, Hao; Hansen, Karl R; Baker, Valerie; Usadi, Rebecca; Seungdamrong, Aimee; Bates, G Wright; Rosen, R Mitchell; Schlaff, William; Haisenleder, Daniel; Krawetz, Stephen A; Barnhart, Kurt; Trussell, J C; Santoro, Nanette; Eisenberg, Esther; Zhang, Heping

2017-08-01

While female sexual dysfunction is a frequent occurrence, characteristics in infertile women are not well delineated. Furthermore, the impact of infertility etiology on the characteristics in women with differing androgen levels observed in women with polycystic ovary syndrome and unexplained infertility has not been assessed. The objective of the study was to determine the characteristics of sexual dysfunction in women with polycystic ovary syndrome and unexplained infertility. A secondary data analysis was performed on 2 of Eunice Kennedy Shriver National Institute of Child Health and Human Development Cooperative Reproductive Medicine Networks clinical trials: Pregnancy in Polycystic Ovary Syndrome Study II and Assessment of Multiple Intrauterine Gestations From Ovarian Stimulation. Both protocols assessed female sexual function using the Female Sexual Function Inventory and the Female Sexual Distress Scale. Women with polycystic ovary syndrome had higher weight and body mass index than women with unexplained infertility (each P < .001), greater phenotypic (Ferriman-Gallwey hirsutism score, sebum score, and acne score; each P < .001), and hormonal (testosterone, free testosterone, and dehydroepiandrosterone; each P < .001) evidence of androgen excess. Sexual function scores, as assessed by the Female Sexual Function Inventory, were nearly identical. The Female Sexual Distress Scale total score was higher in women with polycystic ovary syndrome. The mean Female Sexual Function Inventory total score increased slightly as the free androgen index increased, mainly as a result of the desire subscore. This association was more pronounced in the women with unexplained infertility. Reproductive-age women with infertility associated with polycystic ovary syndrome and unexplained infertility, despite phenotypic and biochemical differences in androgenic manifestations, do not manifest clinically significant differences in sexual function. Copyright © 2017 Elsevier Inc. All rights reserved.

Bypass Mechanisms of the Androgen Receptor Pathway in Therapy-Resistant Prostate Cancer Cell Models

PubMed Central

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

2010-01-01

Background Prostate cancer is initially dependent on androgens for survival and growth, making hormonal therapy the cornerstone treatment for late-stage tumors. However, despite initial remission, the cancer will inevitably recur. The present study was designed to investigate how androgen-dependent prostate cancer cells eventually survive and resume growth under androgen-deprived and antiandrogen supplemented conditions. As model system, we used the androgen-responsive PC346C cell line and its therapy-resistant sublines: PC346DCC, PC346Flu1 and PC346Flu2. Methodology/Principal Findings Microarray technology was used to analyze differences in gene expression between the androgen-responsive and therapy-resistant PC346 cell lines. Microarray analysis revealed 487 transcripts differentially-expressed between the androgen-responsive and the therapy-resistant cell lines. Most of these genes were common to all three therapy-resistant sublines and only a minority (∼5%) was androgen-regulated. Pathway analysis revealed enrichment in functions involving cellular movement, cell growth and cell death, as well as association with cancer and reproductive system disease. PC346DCC expressed residual levels of androgen receptor (AR) and showed significant down-regulation of androgen-regulated genes (p-value = 10−7). Up-regulation of VAV3 and TWIST1 oncogenes and repression of the DKK3 tumor-suppressor was observed in PC346DCC, suggesting a potential AR bypass mechanism. Subsequent validation of these three genes in patient samples confirmed that expression was deregulated during prostate cancer progression. Conclusions/Significance Therapy-resistant growth may result from adaptations in the AR pathway, but androgen-independence may also be achieved by alternative survival mechanisms. Here we identified TWIST1, VAV3 and DKK3 as potential players in the bypassing of the AR pathway, making them good candidates as biomarkers and novel therapeutical targets. PMID:20976069

Mass spectrometry of selective androgen receptor modulators.

PubMed

Thevis, Mario; Schänzer, Wilhelm

2008-07-01

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

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

[Growth in puberty].

PubMed

Bierich, J R

1985-01-01

During puberty growth velocity increases within 3 years from a prepubertal nadir to a maximum, in male to 9-10 cm/year, in female to 7-9 cm/year. This spurt is triggered by the androgenic steroids, in male mainly by testicular testosterone. In patients with anorchia the pubertal growth spurt is missing. The androgens have a dual effect. 1. As comes forth from observations in hypopituitary dwarfs being treated with constant replacement doses of hGH, these steroids potentiate the growth-stimulatory effect of hGH. In order to continue growing at all, these dwarfs need the additional medication of androgenic or anabolic steroids if they are hypogonadotrophic. 2. As demonstrated by our measurements of the nocturnal hGH secretion, androgenic steroids enhance the spontaneous production of hGH by a factor of 2-3. Biologically active androgens appear to be a conditio sine qua non for longitudinal growth after age 11-12. This is in concordance with the statement that adult male castrates are no giants as has often been claimed. The rather tall eunuchs in Istanbul were no Turks but as a rule Sudanese negroes who are racially much taller than Turks.

Androgen receptor CAG repeat polymorphism and hypothalamic-pituitary-gonadal function in Filipino young adult males

PubMed Central

Ryan, Calen P.; McDade, Thomas W; Gettler, Lee T.; Eisenberg, Dan T.A.; Rzhetskaya, Margarita; Hayes, M. Geoffey; Kuzawa, Christopher W.

2016-01-01

Objectives Testosterone (T), the primary androgenic hormone in males, is stimulated through pulsatile secretion of LH and regulated through negative feedback inhibition at the hypothalamus and pituitary. The hypothalamic-pituitary-gonadal (HPG) axis also controls sperm production through the secretion of follicle-stimulating hormone (FSH). Negative feedback in the HPG axis is achieved in part through the binding of T to the androgen receptor (AR), which contains a highly variable trinucleotide repeat polymorphism (AR-CAGn). The number of repeats in the AR-CAGn inversely correlates with transcriptional activity of the AR. Thus, we predicted longer AR-CAGn to be associated with higher T, LH, and FSH levels. Methods We examined the relationship between AR-CAGn and total plasma T, LH, and FSH, as well as 'bioavailable' morning (AM-T) and evening (PM-T) testosterone in 722 young (21.5 ± 0.5 years) Filipino males. Results There was no relationship between AR-CAGn and total T, AM-T, or LH (P > 0.25 for all). We did observe a marginally non-significant (P = 0.066) correlation between AR-CAGn and PM-T in the predicted direction, and a negative correlation between AR-CAGn and FSH (P = 0.005). Conclusions Our results both support and differ from previous findings in this area, and study parameters that differ between our study and others, such as participant age, sample time, and the role of other hormones should be considered when interpreting our findings. While our data point to a modest effect of AR-CAGn on HPG regulation at best, the AR-CAGn may still affect somatic traits by regulating androgenic activity at peripheral tissues. PMID:27417274

Novel mutations of the SRD5A2 and AR genes in Thai patients with 46, XY disorders of sex development.

PubMed

Ittiwut, Chupong; Pratuangdejkul, Jaturong; Supornsilchai, Vichit; Muensri, Sasipa; Hiranras, Yodporn; Sahakitrungruang, Taninee; Watcharasindhu, Suttipong; Suphapeetiporn, Kanya; Shotelersuk, Vorasuk

2017-01-01

Abnormalities of dihydrotestosterone conversion [5α-reductase deficiency: online Mendelian inheritance in man (OMIM) 607306] or actions of androgens [partial androgen insensitivity syndrome (PAIS): OMIM 312300] during the 8th-12th weeks of gestation cause varying degrees of undervirilized external genitalia in 46, XY disorders of sex development (DSD) with increased testosterone production. The objective of the study was to determine clinical and genetic characteristics of Thai patients with 46, XY DSD. A cross-sectional study was conducted in 46, XY DSD with increased testosterone production (n=43) evaluated by a human chorionic gonadotropin (hCG) stimulation test or clinical features consistent with 5α-reductase deficiency or PAIS. PCR sequencing of the entire coding regions of the SRD5A2 and AR genes was performed. Molecular modeling analysis of the androgen receptor-ligand-binding domain (AR-LBD) of a novel mutation was constructed. Mutations were found in seven patients (16.3%): five (11.6%) and two (4.7%) patients had mutations in SRD5A2 and AR, respectively. Two novel mutations, SRD5A2 c.383A>G (p.Y128C) and AR c.2176C>T (p.R726C), were identified. Dimensional structural analysis of the novel mutated AR (p.R726C) revealed that it affected the co-activator binding [binding function-3 (BF-3)], not the testosterone binding site. Short phallus length was associated with 5α-reductase deficiency. Around 16.3% of our patients with 46, XY DSD had 5α-reductase deficiency or PAIS. Two novel mutations of SRD5A2 and AR were identified. The novel mutated AR (p.R726C) might affect the co-activator binding (BF-3), not the testosterone binding site.

Screening of synthetic and natural product databases: Identification of novel androgens and antiandrogens.

PubMed

Bobach, Claudia; Tennstedt, Stephanie; Palberg, Kristin; Denkert, Annika; Brandt, Wolfgang; de Meijere, Armin; Seliger, Barbara; Wessjohann, Ludger A

2015-01-27

The androgen receptor is an important pharmaceutical target for a variety of diseases. This paper presents an in silico/in vitro screening procedure to identify new androgen receptor ligands. The two-step virtual screening procedure uses a three-dimensional pharmacophore model and a docking/scoring routine. About 39,000 filtered compounds were docked with PLANTS and scored by Chemplp. Subsequent to virtual screening, 94 compounds, including 28 steroidal and 66 nonsteroidal compounds, were tested by an androgen receptor fluorescence polarization ligand displacement assay. As a result, 30 compounds were identified that show a relative binding affinity of more than 50% in comparison to 100 nM dihydrotestosterone and were classified as androgen receptor binders. For 11 androgen receptor binders of interest IC50 and Ki values were determined. The compound with the highest affinity exhibits a Ki value of 10.8 nM. Subsequent testing of the 11 compounds in a PC-3 and LNCaP multi readout proliferation assay provides insights into the potential mode of action. Further steroid receptor ligand displacement assays and docking studies on estrogen receptors α and β, glucocorticoid receptor, and progesterone receptor gave information about the specificity of the 11 most active compounds. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

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

PubMed Central

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

2010-01-01

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

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

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

Kharlyngdoh, Joubert Banjop; Asnake, Solomon; Prad

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

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

PubMed

Lundqvist, Johan; Tringali, Corrado; Oskarsson, Agneta

2017-11-01

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

Quality of life, self-esteem, fatigue, and sexual function in young men after cancer: a controlled cross-sectional study.

PubMed

Greenfield, Diana M; Walters, Stephen J; Coleman, Robert E; Hancock, Barry W; Snowden, John A; Shalet, Stephen M; DeRogatis, Leonard R; Ross, Richard J M

2010-03-15

Androgen deficiency is increasingly recognized in young male cancer survivors; however, its impact on quality of life (QOL) is not established. The authors investigated the relationship between androgen levels, QOL, self-esteem, fatigue, and sexual function in young male cancer survivors compared with control subjects. A cross-sectional, observational study of 176 male cancer survivors and 213 male controls aged 25 to 45 years was performed. Subjects completed 3 QOL scales (Medical Outcomes Study 36-Item Short-Form Health Survey version 2, the 12-item General Health Questionnaire [GHQ-12], and Aging Male Scale), and measures of self-esteem (Rosenberg Self-Esteem Scale), fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue), and sexual function (Derogatis Interview for Sexual Functioning-II Self-Report-Male). Cancer survivors had lower scores for all components of the Short-Form Health Survey, Aging Male Scale, and Functional Assessment of Chronic Illness Therapy-Fatigue, and for 4 of 5 subsections of the Derogatis Interview for Sexual Functioning than controls. The majority of these differences remained after adjusting by linear regression analysis. Levels of psychiatric disorder or self-esteem did not differ between the 2 groups. In cancer survivors, those with androgen deficiency (serum testosterone < or = 10 nmol/L) had lower scores than those without for all components of the Short-Form Health Survey, the General Health Questionnaire, Functional Assessment of Chronic Illness Therapy-Fatigue, and the Derogatis Interview for Sexual Functioning. Serum testosterone only weakly correlated with health measures. Young male cancer survivors self-report a marked impairment in QOL, energy levels, and quality of sexual functioning, and this was exacerbated in those with androgen deficiency. However, psychological distress was not elevated, self-esteem was normal, and sexual relationships were not impaired. The relationship with testosterone is complex, and appears dependent on a threshold level rather than direct correlation. Interventional trials are needed to determine whether testosterone replacement would improve QOL in young male cancer survivors.

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.

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

PubMed

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

2006-01-01

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

Androgen regulation of the human hair follicle: the type I hair keratin hHa7 is a direct target gene in trichocytes.

PubMed

Jave-Suarez, Luis F; Langbein, Lutz; Winter, Hermelita; Praetzel, Silke; Rogers, Michael A; Schweizer, Juergen

2004-03-01

Previous work had shown that most members of the complex human hair keratin family were expressed in terminal scalp hairs. An exception to this rule was the type I hair keratin hHa7, which was only detected in some but not all vellus hairs of the human scalp (Langbein et al, 1999). Here we show that hHa7 exhibits constitutive expression in medullary cells of all types of male and female sexual hairs. Medullated beard, axillary, and pubic hairs arise during puberty from small, unmedullated vellus hairs under the influence of circulating androgens. This suggested an androgen-controlled expression of the hHa7 gene. Further evidence for this assumption was provided by the demonstration of androgen receptor (AR) expression in the nuclei of medullary cells of beard hairs. Moreover, homology search for the semipalindromic androgen receptor-binding element (ARE) consensus sequence GG(A)/(T)ACAnnnTGTTCT in the proximal hHa7 promoter revealed three putative ARE motifs. Electrophoretic mobility shift assays demonstrated the specific binding of AR to all three hHa7 AREs. Their function as AR-responsive elements, either individually or in concert within the hHa7 promoter, could be further confirmed by transfection studies with or without an AR expression vector in PtK2 and prostate PC3-Arwt cells, respectively in the presence or absence of a synthetic androgen. Our study detected hHa7 as the first gene in hair follicle trichocytes whose expression appears to be directly regulated by androgens. As such, hHa7 represents a marker for androgen action on hair follicles and might be a suitable tool for investigations of androgen-dependent hair disorders.

Spatiotemporal dynamics of androgen signaling underlie sexual differentiation and congenital malformations of the urethra and vagina

PubMed Central

Larkins, Christine E.; Enriquez, Ana B.; Cohn, Martin J.

2016-01-01

Disorders of sex development (DSDs) are congenital anomalies that affect sexual differentiation of genitourinary organs and secondary sex characters. A common cause of female genital virilization is congenital adrenal hyperplasia (CAH), in which excess androgen production during development of 46XX females can result in vaginal atresia, masculinization of the urethra, a single urogenital sinus, and clitoral hypertrophy or ambiguous external genitalia. Development of the vagina depends on sexual differentiation of the urogenital sinus ridge, an epithelial thickening that forms where the sex ducts attach to the anterior urethra. In females, the sinus ridge descends posteriorly to allow the vaginal opening to form in the vulva, whereas in males and in females with CAH, androgens inhibit descent of the sinus ridge. The mechanisms that regulate development of the female urethra and vagina are largely unknown. Here we show that the timing and duration of, and the cell population targeted by, androgen signaling determine the position of vaginal attachment to the urethra. Manipulations of androgen signaling in utero reveal a temporal window of development when sinus ridge fate is determined. Cell type-specific genetic deletions of androgen receptor (Ar) identify a subpopulation of mesenchymal cells that regulate sinus ridge morphogenesis. These results reveal a common mechanism that coordinates development of the vagina and feminization of the urethra, which may account for development of a single urogenital sinus in females exposed to excessive androgen during a critical period of prenatal development. PMID:27821748

Spatiotemporal dynamics of androgen signaling underlie sexual differentiation and congenital malformations of the urethra and vagina.

PubMed

Larkins, Christine E; Enriquez, Ana B; Cohn, Martin J

2016-11-22

Disorders of sex development (DSDs) are congenital anomalies that affect sexual differentiation of genitourinary organs and secondary sex characters. A common cause of female genital virilization is congenital adrenal hyperplasia (CAH), in which excess androgen production during development of 46XX females can result in vaginal atresia, masculinization of the urethra, a single urogenital sinus, and clitoral hypertrophy or ambiguous external genitalia. Development of the vagina depends on sexual differentiation of the urogenital sinus ridge, an epithelial thickening that forms where the sex ducts attach to the anterior urethra. In females, the sinus ridge descends posteriorly to allow the vaginal opening to form in the vulva, whereas in males and in females with CAH, androgens inhibit descent of the sinus ridge. The mechanisms that regulate development of the female urethra and vagina are largely unknown. Here we show that the timing and duration of, and the cell population targeted by, androgen signaling determine the position of vaginal attachment to the urethra. Manipulations of androgen signaling in utero reveal a temporal window of development when sinus ridge fate is determined. Cell type-specific genetic deletions of androgen receptor (Ar) identify a subpopulation of mesenchymal cells that regulate sinus ridge morphogenesis. These results reveal a common mechanism that coordinates development of the vagina and feminization of the urethra, which may account for development of a single urogenital sinus in females exposed to excessive androgen during a critical period of prenatal development.

Melatonin Decreases Glucose Metabolism in Prostate Cancer Cells: A 13C Stable Isotope-Resolved Metabolomic Study.

PubMed

Hevia, David; Gonzalez-Menendez, Pedro; Fernandez-Fernandez, Mario; Cueto, Sergio; Rodriguez-Gonzalez, Pablo; Garcia-Alonso, Jose I; Mayo, Juan C; Sainz, Rosa M

2017-07-26

The pineal neuroindole melatonin exerts an exceptional variety of systemic functions. Some of them are exerted through its specific membrane receptors type 1 and type 2 (MT1 and MT2) while others are mediated by receptor-independent mechanisms. A potential transport of melatonin through facilitative glucose transporters (GLUT/ SLC2A ) was proposed in prostate cancer cells. The prostate cells have a particular metabolism that changes during tumor progression. During the first steps of carcinogenesis, oxidative phosphorylation is reactivated while the switch to the "Warburg effect" only occurs in advanced tumors and in the metastatic stage. Here, we investigated whether melatonin might change prostate cancer cell metabolism. To do so, 13 C stable isotope-resolved metabolomics in androgen sensitive LNCaP and insensitive PC-3 prostate cancer cells were employed. In addition to metabolite 13 C-labeling, ATP/AMP levels, and lactate dehydrogenase or pentose phosphate pathway activity were measured. Melatonin reduces lactate labeling in androgen-sensitive cells and it also lowers 13 C-labeling of tricarboxylic acid cycle metabolites and ATP production. In addition, melatonin reduces lactate 13 C-labeling in androgen insensitive prostate cancer cells. Results demonstrated that melatonin limits glycolysis as well as the tricarboxylic acid cycle and pentose phosphate pathway in prostate cancer cells, suggesting that the reduction of glucose uptake is a major target of the indole in this tumor type.

Stromal Androgen Receptor in Prostate Cancer Development and Progression

PubMed Central

Leach, Damien A.; Buchanan, Grant

2017-01-01

Prostate cancer development and progression is the result of complex interactions between epithelia cells and fibroblasts/myofibroblasts, in a series of dynamic process amenable to regulation by hormones. Whilst androgen action through the androgen receptor (AR) is a well-established component of prostate cancer biology, it has been becoming increasingly apparent that changes in AR signalling in the surrounding stroma can dramatically influence tumour cell behavior. This is reflected in the consistent finding of a strong association between stromal AR expression and patient outcomes. In this review, we explore the relationship between AR signalling in fibroblasts/myofibroblasts and prostate cancer cells in the primary site, and detail the known functions, actions, and mechanisms of fibroblast AR signaling. We conclude with an evidence-based summary of how androgen action in stroma dramatically influences disease progression. PMID:28117763

Atypical onset of bicalutamide-induced liver injury.

PubMed

Yun, Gee Young; Kim, Seok Hyun; Kim, Seok Won; Joo, Jong Seok; Kim, Ju Seok; Lee, Eaum Seok; Lee, Byung Seok; Kang, Sun Hyoung; Moon, Hee Seok; Sung, Jae Kyu; Lee, Heon Young; Kim, Kyung Hee

2016-04-21

Anti-androgen therapy is the leading treatment for advanced prostate cancer and is commonly used for neoadjuvant or adjuvant treatment. Bicalutamide is a non-steroidal anti-androgen, used during the initiation of androgen deprivation therapy along with a luteinizing hormone-releasing hormone agonist to reduce the symptoms of tumor-related flares in patients with advanced prostate cancer. As side effects, bicalutamide can cause fatigue, gynecomastia, and decreased libido through competitive androgen receptor blockade. Additionally, although not as common, drug-induced liver injury has also been reported. Herein, we report a case of hepatotoxicity secondary to bicalutamide use. Typically, bicalutamide-induced hepatotoxicity develops after a few days; however, in this case, hepatic injury occurred 5 mo after treatment initiation. Based on this rare case of delayed liver injury, we recommend careful monitoring of liver function throughout bicalutamide treatment for prostate cancer.

Androgen deficiency in male patients diagnosed with ANCA-associated vasculitis: a cause of fatigue and reduced health-related quality of life?

PubMed

Tuin, Janneke; Sanders, Jan-Stephan F; Buhl, Birgit M; van Beek, André P; Stegeman, Coen A

2013-01-01

Low testosterone levels in men are associated with fatigue, limited physical performance and reduced health-related quality of life (HRQOL); however, this relationship has never been assessed in patients with anti-neutrophil cytoplasmic antibodies (ANCA) -associated vasculitides (AAV). The aim of this study was to assess the prevalence of androgen deficiency and to investigate the role of testosterone in fatigue, limited physical condition and reduced HRQOL in men with AAV. Male patients with AAV in remission were included in this study. Fatigue and HRQOL were assessed by the multi-dimensional fatigue inventory (MFI)-20 and RAND-36 questionnaires. Seventy male patients with a mean age of 59 years (SD 12) were included. Scores of almost all subscales of both questionnaires were significantly worse in patients compared to controls. Mean total testosterone and free testosterone levels were 13.8 nmol/L (SD 5.6) and 256 pmol/L (SD 102), respectively. Androgen deficiency (defined according to Endocrine Society Clinical Practice Guidelines) was present in 47% of patients. Scores in the subscales of general health perception, physical functioning and reduced activity were significantly worse in patients with androgen deficiency compared to patients with normal androgen levels. Testosterone and age were predictors for the RAND-36 physical component summary in multiple linear regression analysis. Testosterone, age, vasculitis damage index (VDI) and C-reactive protein (CRP) were associated with the MFI-20 subscale of general fatigue. This study showed that androgen deficiency was present in a substantial number of patients with AAV. Testosterone was one of the predictors for physical functioning and fatigue. Testosterone may play a role in fatigue, reduced physical performance and HRQOL in male patients with AAV.

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

PubMed

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

2013-03-01

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

Conversion of blood androgens to estrogens in normal adult men and women

PubMed Central

Longcope, Christopher; Kato, Tatsuo; Horton, Richard

1969-01-01

Continuous infusions of Δ4-androstenedione-7-3H and testosterone-7-3H have been used to demonstrate that these androgens are converted to estrone and 17β-estradiol, and contribute to the circulating blood levels of these estrogens in normal males and females. The conversion ratio (ratio of concentrations of radioactivity of free product steroid [χ-PRO] and free precursor steroid [χ-PRE], both corrected for recoveries, after an infusion of radioactive precursor steroid) for androstenedione (precursor) to estrone (product) is 0.013 in males and 0.007 in females, and the conversion ratio for testosterone (precursor) to estradiol (product) is 0.0018 in males and 0.005 in females. The transfer constant, [ρ]BBAE1, for androstenedione conversion to estrone ([ρ]BBAE1 = per cent of infused androstenedione, precursor, converted to estrone, product, when infusion and measurement are both in blood) is 1.35% in males and 0.74% in females, and the transfer constant, [ρ]BBTE2, for testosterone conversion to estradiol is 0.39% in males and 0.15% in females. Whether measured as conversion ratio or transfer constant, the peripheral aromatization of androstenedione takes place to a greater degree than that of testosterone, and, for the respective androgens, both the conversion ratio and [ρ]BB value are greater in males than females. For the androgen interconversions, [ρ]BBAT is 4.5% in males and 2.2% in females; [ρ]BBTA is 8.2% in males and 12.0% in females. Studies on the distribution coefficients (effective concentration in red cells/plasma) for precursor radioactivity were also made. In both males and females the distribution coefficient for androstenedione is 0.16-0.17 while that of testosterone is 0.01-0.03. PMID:5355335

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. Copyright © 2014. Published by Elsevier Ltd.

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.

Association of Androgen Metabolism Gene Polymorphisms with Prostate Cancer Risk and Androgen Concentrations: Results from the Prostate Cancer Prevention Trial

PubMed Central

Price, Douglas K.; Chau, Cindy H.; Till, Cathee; Goodman, Phyllis J.; Leach, Robin J.; Johnson-Pais, Teresa L.; Hsing, Ann W.; Hoque, Ashraful; Parnes, Howard L.; Schenk, Jeannette M.; Tangen, Catherine M.; Thompson, Ian M.; Reichardt, Juergen K.V.; Figg, William D.

2016-01-01

Background Prostate cancer is highly influenced by androgens and genes. We investigated whether genetic polymorphisms along the androgen biosynthesis and metabolism pathways are associated with androgen concentrations or risk of prostate cancer or high-grade disease from finasteride treatment. Methods A nested case-control study from the Prostate Cancer Prevention Trial using cases drawn from men with biopsy-proven prostate cancer and biopsy-negative, frequency-matched controls was conducted to investigate the association of 51 single nucleotide polymorphisms (SNPs) in 12 genes of the androgen pathway with total, low-grade, and high-grade prostate cancer incidence and serum hormone concentrations. Results There were significant associations of genetic polymorphisms in SRD5A1 (rs3736316, rs3822430, rs1560149, rs248797, and rs472402) and SRD5A2 (rs2300700) with risk of high-grade prostate cancer in the placebo arm of the PCPT; two SNPs were significantly associated with increased risk (SRD5A1 rs472402 [OR, 1.70; 95% CI, 1.05-2.75, Ptrend=0.03]; SRD5A2 rs2300700 [OR, 1.94; 95% CI, 1.19-3.18, Ptrend=0.01]). Eleven SNPs in SRD5A1, SRD5A2, CYP1B1, and CYP3A4 were found to be associated with modifying mean serum androgen and sex hormone-binding globulin concentrations; two SNPs (SRD5A1 rs824811 and CYP1B1 rs10012, Ptrend<0.05) consistently and significantly altered all androgen concentrations. Several SNPs (rs3822430, rs2300700; CYP3A43 rs800672; CYP19 rs700519; Ptrend<0.05) were significantly associated with both circulating hormone levels and prostate cancer risk. Conclusion Germline genetic variations of androgen-related pathway genes are associated with serum androgen concentrations and risk of prostate cancer. Further studies to examine the functional consequence of novel causal variants are warranted. PMID:27164191

Determination of the source of androgen excess in functionally atypical polycystic ovary syndrome by a short dexamethasone androgen-suppression test and a low-dose ACTH test.

PubMed

Rosenfield, Robert L; Mortensen, Monica; Wroblewski, Kristen; Littlejohn, Elizabeth; Ehrmann, David A

2011-11-01

Polycystic ovary syndrome (PCOS) patients typically have 17-hydroxyprogesterone (17OHP) hyperresponsiveness to GnRH agonist (GnRHa) (PCOS-T). The objective of this study was to determine the source of androgen excess in the one-third of PCOS patients who atypically lack this type of ovarian dysfunction (PCOS-A). Aged-matched PCOS-T (n= 40), PCOS-A (n= 20) and controls (n= 39) were studied prospectively in a General Clinical Research Center. Short (4 h) and long (4-7 day) dexamethasone androgen-suppression tests (SDAST and LDAST, respectively) were compared in subsets of subjects. Responses to SDAST and low-dose adrenocorticotropic hormone (ACTH) were then evaluated in all. Testosterone post-SDAST correlated significantly with testosterone post-LDAST and 17OHP post-GnRHa (r = 0.671-0.672), indicating that all detect related aspects of ovarian dysfunction. An elevated dehydroepiandrosterone peak in response to ACTH, which defined functional adrenal hyperandrogenism, was similarly prevalent in PCOS-T (27.5%) and PCOS-A (30%) and correlated significantly with baseline dehydroepiandrosterone sulfate (DHEAS) (r = 0.708). Functional ovarian hyperandrogenism was detected by subnormal testosterone suppression by SDAST in most (92.5%) PCOS-T, but significantly fewer PCOS-A (60%, P< 0.01). Glucose intolerance was absent in PCOS-A, but present in 30% of PCOS-T (P < 0.001). Most of the PCOS-A cases with normal testosterone suppression in response to SDAST (5/8) lacked evidence of adrenal hyperandrogenism and were obese. Functional ovarian hyperandrogenism was not demonstrable by SDAST in 40% of PCOS-A. Most of these cases had no evidence of adrenal hyperandrogenism. Obesity may account for most hyperandrogenemic anovulation that lacks a glandular source of excess androgen, and the SDAST seems useful in making this distinction.

Determination of the source of androgen excess in functionally atypical polycystic ovary syndrome by a short dexamethasone androgen-suppression test and a low-dose ACTH test

PubMed Central

Rosenfield, Robert L.; Mortensen, Monica; Wroblewski, Kristen; Littlejohn, Elizabeth; Ehrmann, David A.

2011-01-01

BACKGROUND Polycystic ovary syndrome (PCOS) patients typically have 17-hydroxyprogesterone (17OHP) hyperresponsiveness to GnRH agonist (GnRHa) (PCOS-T). The objective of this study was to determine the source of androgen excess in the one-third of PCOS patients who atypically lack this type of ovarian dysfunction (PCOS-A). METHODS Aged-matched PCOS-T (n= 40), PCOS-A (n= 20) and controls (n= 39) were studied prospectively in a General Clinical Research Center. Short (4 h) and long (4–7 day) dexamethasone androgen-suppression tests (SDAST and LDAST, respectively) were compared in subsets of subjects. Responses to SDAST and low-dose adrenocorticotropic hormone (ACTH) were then evaluated in all. RESULTS Testosterone post-SDAST correlated significantly with testosterone post-LDAST and 17OHP post-GnRHa (r = 0.671–0.672), indicating that all detect related aspects of ovarian dysfunction. An elevated dehydroepiandrosterone peak in response to ACTH, which defined functional adrenal hyperandrogenism, was similarly prevalent in PCOS-T (27.5%) and PCOS-A (30%) and correlated significantly with baseline dehydroepiandrosterone sulfate (DHEAS) (r = 0.708). Functional ovarian hyperandrogenism was detected by subnormal testosterone suppression by SDAST in most (92.5%) PCOS-T, but significantly fewer PCOS-A (60%, P< 0.01). Glucose intolerance was absent in PCOS-A, but present in 30% of PCOS-T (P < 0.001). Most of the PCOS-A cases with normal testosterone suppression in response to SDAST (5/8) lacked evidence of adrenal hyperandrogenism and were obese. CONCLUSIONS Functional ovarian hyperandrogenism was not demonstrable by SDAST in 40% of PCOS-A. Most of these cases had no evidence of adrenal hyperandrogenism. Obesity may account for most hyperandrogenemic anovulation that lacks a glandular source of excess androgen, and the SDAST seems useful in making this distinction. PMID:21908468

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

PubMed

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

2017-10-01

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

TESTOSTERONE AND SPORT: CURRENT PERSPECTIVES

PubMed Central

Wood, Ruth I.; Stanton, Steven J.

2011-01-01

Testosterone and other anabolic-androgenic steroids enhance athletic performance in men and women. As a result, exogenous androgen is banned from most competitive sports. However, due to variability in endogenous secretion, and similarities with exogenous testosterone, it has been challenging to establish allowable limits for testosterone in competition. Endogenous androgen production is dynamically regulated by both exercise and winning in competition. Furthermore, testosterone may promote athletic performance, not only through its long-term anabolic actions, but also through rapid effects on behavior. In women, excess production of endogenous testosterone due to inborn disorders of sexual development (DSD) may convey a competitive advantage. For many years, female competitors have been subject to tests of sexual genotype and phenotype known as gender verification. Although gender verification has not identified any normal man competing as a woman, this process has identified women athletes with DSD. As understanding of DSD has expanded in recent years, women with DSD are increasingly able to continue athletic competition. PMID:21983229

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

PubMed

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

2017-08-14

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

Endocrine-disrupting chemicals-Mechanisms of action on male reproductive system.

PubMed

Sidorkiewicz, Iwona; Zaręba, Kamil; Wołczyński, Sławomir; Czerniecki, Jan

2017-07-01

Endocrine-disrupting chemicals (EDCs) are exogenous compounds that can cause disturbances in the endocrine system and have multiple harmful effects on health by targeting different organs and systems in the human body. Mass industrial production and widespread use of EDCs have resulted in worldwide contamination. Accumulating evidence suggest that human exposure to EDCs is related to the impairment of male reproductive function and can interrupt other hormonally regulated metabolic processes, particularly if exposure occurs during early development. Investigation of studies absent in previous reviews and meta-analysis of adverse effects of EDCs on functioning of the male reproductive system is the core of this work. Four main modes of action of EDCs on male fertility have been summarized in this review. First, studies describing estrogen- pathway disturbing chemicals are investigated. Second, androgen-signaling pathway alterations and influence on androgen sensitive tissues are examined. Third, evaluation of steroidogenesis dysfunction is discussed by focusing on the steroid hormone biosynthesis pathway, which is targeted by EDCs. Last, the reportedly destructive role of reactive oxygen species (ROS) on sperm function is discussed. Spermatogenesis is a remarkably complex process, hence multiple studies point out various dysfunctions depending on the development state at which the exposure occurred. Collected data show the need to account for critical windows of exposure such as fetal, perinatal and pubertal periods as well as effects of mixtures of several compounds in future research.

Minoxidil may suppress androgen receptor-related functions.

PubMed

Hsu, Cheng-Lung; Liu, Jai-Shin; Lin, An-Chi; Yang, Chih-Hsun; Chung, Wen-Hung; Wu, Wen-Guey

2014-04-30

Although minoxidil has been used for more than two decades to treat androgenetic alopecia (AGA), an androgen-androgen receptor (AR) pathway-dominant disease, its precise mechanism of action remains elusive. We hypothesized that minoxidil may influence the AR or its downstream signaling. These tests revealed that minoxidil suppressed AR-related functions, decreasing AR transcriptional activity in reporter assays, reducing expression of AR targets at the protein level, and suppressing AR-positive LNCaP cell growth. Dissecting the underlying mechanisms, we found that minoxidil interfered with AR-peptide, AR-coregulator, and AR N/C-terminal interactions, as well as AR protein stability. Furthermore, a crystallographic analysis using the AR ligand-binding domain (LBD) revealed direct binding of minoxidil to the AR in a minoxidil-AR-LBD co-crystal model, and surface plasmon resonance assays demonstrated that minoxidil directly bound the AR with a K(d) value of 2.6 µM. Minoxidil also suppressed AR-responsive reporter activity and decreased AR protein stability in human hair dermal papilla cells. The current findings provide evidence that minoxidil could be used to treat both cancer and age-related disease, and open a new avenue for applications of minoxidil in treating androgen-AR pathway-related diseases.

Minoxidil may suppress androgen receptor-related functions

PubMed Central

Hsu, Cheng-Lung; Liu, Jai-Shin; Lin, An-Chi; Yang, Chih-Hsun; Chung, Wen-Hung; Wu, Wen-Guey

2014-01-01

Although minoxidil has been used for more than two decades to treat androgenetic alopecia (AGA), an androgen-androgen receptor (AR) pathway-dominant disease, its precise mechanism of action remains elusive. We hypothesized that minoxidil may influence the AR or its downstream signaling. These tests revealed that minoxidil suppressed AR-related functions, decreasing AR transcriptional activity in reporter assays, reducing expression of AR targets at the protein level, and suppressing AR-positive LNCaP cell growth. Dissecting the underlying mechanisms, we found that minoxidil interfered with AR-peptide, AR-coregulator, and AR N/C-terminal interactions, as well as AR protein stability. Furthermore, a crystallographic analysis using the AR ligand-binding domain (LBD) revealed direct binding of minoxidil to the AR in a minoxidil-AR-LBD co-crystal model, and surface plasmon resonance assays demonstrated that minoxidil directly bound the AR with a Kd value of 2.6 μM. Minoxidil also suppressed AR-responsive reporter activity and decreased AR protein stability in human hair dermal papilla cells. The current findings provide evidence that minoxidil could be used to treat both cancer and age-related disease, and open a new avenue for applications of minoxidil in treating androgen-AR pathway-related diseases. PMID:24742982

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

PubMed

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

2008-11-01

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

Endocrine correlates of musth in free-ranging Asian elephants (Elephas maximus) determined by non-invasive faecal steroid hormone metabolite measurements.

PubMed

Ghosal, Ratna; Ganswindt, André; Seshagiri, Polani B; Sukumar, Raman

2013-01-01

The occurrence of musth, a period of elevated levels of androgens and heightened sexual activity, has been well documented for the male Asian elephant (Elephas maximus). However, the relationship between androgen-dependent musth and adrenocortical function in this species is unclear. The current study is the first assessment of testicular and adrenocortical function in free-ranging male Asian elephants by measuring levels of testosterone (androgen) and cortisol (glucocorticoid--a physiological indicator of stress) metabolites in faeces. During musth, males expectedly showed significant elevation in faecal testosterone metabolite levels. Interestingly, glucocorticoid metabolite concentrations remained unchanged between musth and non-musth periods. This observation is contrary to that observed with wild and captive African elephant bulls and captive Asian bull elephants. Our results show that musth may not necessarily represent a stressful condition in free-ranging male Asian elephants.

Expression of the androgen receptor in the testes and the concentrations of gonadotropins and sex steroid hormones in male turkeys (Meleagris gallopavo) during growth and development.

PubMed

Kiezun, J; Leska, A; Kaminska, B; Jankowski, J; Dusza, L

2015-04-01

Androgens, including testosterone (T) and androstenedione (A4), are essential for puberty, fertility and sexual functions. The biological activity of those hormones is mediated via the androgen receptor (AR). The regulation of androgen action in birds is poorly understood. Therefore, the present study analysed mRNA and protein expression of AR in the testes, plasma concentrations of the luteinizing hormone (LH), follicle-stimulating hormone (FSH), T, A4 and oestradiol (E2), as well as the levels of T, A4 and E2 in testicular homogenates of male turkeys (Meleagris gallopavo) at the age of 4, 8, 12, 16, 20, 24 and 28weeks. Plasma concentrations of LH and FSH, as well as plasma and testicular levels of T and A4 began to increase at 20weeks of age. The lowest plasma levels of E2 were noted at 20weeks relative to other growth stages. The 20th week of life seems to be the key phase in the development of the reproductive system of turkeys. The AR protein was found in the nuclei of testicular cells in all examined growth stages. Higher expression of AR protein in the testes beginning at 20weeks of age was accompanied by high plasma concentrations of LH and high plasma and testicular levels of androgens. This relationship seems to be necessary to regulate male sexual function. Copyright © 2014 Elsevier Inc. All rights reserved.

Critical role of androgen receptor in the postnatal period in male sexual behavior in rats.

PubMed

Yamada, Shunji; Ohoya, Miku; Takanami, Keiko; Matsuda, Ken Ichi; Kawata, Mitsuhiro

2015-11-16

Gonadal hormones have a developmental role in organization of the nervous system that regulates sexually dimorphic behavior. It is well known that androgen secreted from testes in the perinatal period is converted to estrogen by aromatase in rodent brain, and that estrogen and its receptor play a pivotal role in masculinization of brain structure and function. Treatment with flutamide, an androgen receptor (AR) antagonist, during the perinatal period inhibits development of malespecific brain structure and function, suggesting that androgen signaling via AR also influences brain masculinization. In this study, we investigated which stage during the postnatal period is critical for androgen signaling in brain masculinization. The postnatal period was designated as postnatal days (PD) 0-22, and divided into stages I (PD 0-7), II (PD 8-14), and III (PD 15-22). Newborn male rats were given flutamide subcutaneously in each stage. After adulthood, the effects of postnatal flutamide treatment on brain masculinization were evaluated byanalysis of male sexual behavior. Continuous inhibition of AR throughout stages I and II caused a robust reduction of the intromission ratio and ejaculation frequency compared with other groups. AR inhibition in stage I, II, or III did not cause any change. AR inhibition had no effect onmount behavior. These results show that stage-specific AR activation in the first two postnatal weeks may contribute to brain masculinization mediating male sexual behavior in adulthood. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

A Recurrent Germline Mutation in the 5'UTR of the Androgen Receptor Causes Complete Androgen Insensitivity by Activating Aberrant uORF Translation.

PubMed

Hornig, Nadine C; de Beaufort, Carine; Denzer, Friederike; Cools, Martine; Wabitsch, Martin; Ukat, Martin; Kulle, Alexandra E; Schweikert, Hans-Udo; Werner, Ralf; Hiort, Olaf; Audi, Laura; Siebert, Reiner; Ammerpohl, Ole; Holterhus, Paul-Martin

2016-01-01

A subset of patients with monogenic disorders lacks disease causing mutations in the protein coding region of the corresponding gene. Here we describe a recurrent germline mutation found in two unrelated patients with complete androgen insensitivity syndrome (CAIS) generating an upstream open reading frame (uORF) in the 5' untranslated region (5'-UTR) of the androgen receptor (AR) gene. We show in patient derived primary genital skin fibroblasts as well as in cell-based reporter assays that this mutation severely impacts AR function by reducing AR protein levels without affecting AR mRNA levels. Importantly, the newly generated uORF translates into a polypeptide and the expression level of this polypeptide inversely correlates with protein translation from the primary ORF of the AR thereby providing a model for AR-5'UTR mediated translational repression. Our findings not only add a hitherto unrecognized genetic cause to complete androgen insensitivity but also underline the importance of 5'UTR mutations affecting uORFs for the pathogenesis of monogenic disorders in general.

A Recurrent Germline Mutation in the 5’UTR of the Androgen Receptor Causes Complete Androgen Insensitivity by Activating Aberrant uORF Translation

PubMed Central

Hornig, Nadine C.; de Beaufort, Carine; Denzer, Friederike; Cools, Martine; Wabitsch, Martin; Ukat, Martin; Kulle, Alexandra E.; Schweikert, Hans-Udo; Werner, Ralf; Hiort, Olaf; Audi, Laura; Siebert, Reiner; Ammerpohl, Ole; Holterhus, Paul-Martin

2016-01-01

A subset of patients with monogenic disorders lacks disease causing mutations in the protein coding region of the corresponding gene. Here we describe a recurrent germline mutation found in two unrelated patients with complete androgen insensitivity syndrome (CAIS) generating an upstream open reading frame (uORF) in the 5’ untranslated region (5’-UTR) of the androgen receptor (AR) gene. We show in patient derived primary genital skin fibroblasts as well as in cell-based reporter assays that this mutation severely impacts AR function by reducing AR protein levels without affecting AR mRNA levels. Importantly, the newly generated uORF translates into a polypeptide and the expression level of this polypeptide inversely correlates with protein translation from the primary ORF of the AR thereby providing a model for AR-5′UTR mediated translational repression. Our findings not only add a hitherto unrecognized genetic cause to complete androgen insensitivity but also underline the importance of 5′UTR mutations affecting uORFs for the pathogenesis of monogenic disorders in general. PMID:27110943

Androgen responsiveness of Renilla luciferase reporter vectors is promoter, transgene, and cell line dependent.

PubMed

Mulholland, David J; Cox, Michael; Read, Jason; Rennie, Paul; Nelson, Colleen

2004-05-01

Renilla based reporters are frequently used as transfection controls for luciferase transcriptional reporter assays. However, recent evidence suggests that a commonly used reporter (HSV-thymidine kinase driven Renilla) is responsive to androgen receptor (AR) and glucocorticoid receptors in the presence of the cognate ligands, dihydrotestosterone (DHT) and dexamethasone (DEX), respectively [1]. We further validate this important technical difficulty by illustrating that in LNCaP prostate cancer cells, spurious Renilla luciferase activity is a function of (a) the promoter driving Renilla expression, (b) the presence of co-transfected transgenes, and (c) the androgen responsiveness of the cell line used. Using inhibitors of transcription and translation we showed that transcript interference or translational modulation is not a major means by which androgens affect Renilla luciferase activity. As luciferase reporter assays are a frequent means of studying transcriptional co-regulation in the highly androgen dependent LNCaP cell line, our data serves as a cautionary note that alternative normalization techniques should be employed to avoid misinterpretation of data. Copyright 2004 Wiley-Liss, Inc.

Androgenic correlates of genetic variation in the gene encoding 5alpha-reductase type 1.

PubMed

Ellis, Justine A; Panagiotopoulos, Sianna; Akdeniz, Aysel; Jerums, George; Harrap, Stephen B

2005-01-01

Androgens determine male secondary sexual characteristics and influence a variety of metabolic pathways. Circulating levels of androgens are highly heritable; however, the genes involved are largely unknown. The 5alpha-reductase enzymes types 1 and 2 responsible for converting testosterone to the more potent androgen dihydrotestosterone are encoded by the SRD5A1 and SRD5A2 genes, respectively. We performed indirect genetic association studies of SRD5A1 and SRD5A2 and the dihydrotestosterone/testosterone ratio that reflects the activity of 5alpha-reductase in 57 males with type 2 diabetes. We found evidence of significant association between a single nucleotide polymorphism in SRD5A1 and the dihydrotestosterone/testosterone ratio (median 0.10, interquartile range 0.08 vs. median 0.06, interquartile range 0.04, P = 0.009). The polymorphism was not associated with any diabetic phenotypes. These results suggest that functional genetic variants might exist in or around SRD5A1 that affect the activity of the 5alpha-reductase enzyme type 1 and influence androgen levels.

Androgen Regulation of 5α-Reductase Isoenzymes in Prostate Cancer: Implications for Prostate Cancer Prevention

PubMed Central

Li, Jin; Ding, Zhiyong; Wang, Zhengxin; Lu, Jing-Fang; Maity, Sankar N.; Navone, Nora M.; Logothetis, Christopher J.; Mills, Gordon B.; Kim, Jeri

2011-01-01

The enzyme 5α-reductase, which converts testosterone to dihydrotestosterone (DHT), performs key functions in the androgen receptor (AR) signaling pathway. The three isoenzymes of 5α-reductase identified to date are encoded by different genes: SRD5A1, SRD5A2, and SRD5A3. In this study, we investigated mechanisms underlying androgen regulation of 5α-reductase isoenzyme expression in human prostate cells. We found that androgen regulates the mRNA level of 5α-reductase isoenzymes in a cell type–specific manner, that such regulation occurs at the transcriptional level, and that AR is necessary for this regulation. In addition, our results suggest that AR is recruited to a negative androgen response element (nARE) on the promoter of SRD5A3 in vivo and directly binds to the nARE in vitro. The different expression levels of 5α-reductase isoenzymes may confer response or resistance to 5α-reductase inhibitors and thus may have importance in prostate cancer prevention. PMID:22194926

Role of Stromal Paracrine Signals in Proliferative Diseases of the Aging Human Prostate

PubMed Central

Takahashi, Sanai; Sugimura, Yoshiki

2018-01-01

Androgens are essential for the development, differentiation, growth, and function of the prostate through epithelial–stromal interactions. However, androgen concentrations in the hypertrophic human prostate decrease significantly with age, suggesting an inverse correlation between androgen levels and proliferative diseases of the aging prostate. In elderly males, age- and/or androgen-related stromal remodeling is spontaneously induced, i.e., increased fibroblast and myofibroblast numbers, but decreased smooth muscle cell numbers in the prostatic stroma. These fibroblasts produce not only growth factors, cytokines, and extracellular matrix proteins, but also microRNAs as stromal paracrine signals that stimulate prostate epithelial cell proliferation. Surgical or chemical castration is the standard systemic therapy for patients with advanced prostate cancer. Androgen deprivation therapy induces temporary remission, but the majority of patients eventually progress to castration-resistant prostate cancer, which is associated with a high mortality rate. Androgen deprivation therapy-induced stromal remodeling may be involved in the development and progression of castration-resistant prostate cancer. In the tumor microenvironment, activated fibroblasts stimulating prostate cancer cell proliferation are called carcinoma-associated fibroblasts. In this review, we summarize the role of stromal paracrine signals in proliferative diseases of the aging human prostate and discuss the potential clinical applications of carcinoma-associated fibroblast-derived exosomal microRNAs as promising biomarkers. PMID:29614830

Menstrual cycle-related changes in circulating androgens in healthy women with self-reported normal sexual function.

PubMed

Salonia, Andrea; Pontillo, Marina; Nappi, Rossella E; Zanni, Giuseppe; Fabbri, Fabio; Scavini, Marina; Daverio, Rita; Gallina, Andrea; Rigatti, Patrizio; Bosi, Emanuele; Bonini, Pier Angelo; Montorsi, Francesco

2008-04-01

There is currently neither a clinically useful, reliable and inexpensive assay to measure circulating levels of free testosterone (T) in the range observed in women, nor is there agreement on the serum free T threshold defining hypoandrogenism that is associated with female-impaired sexual function. Following the Clinical and Laboratory Standards Institute guidelines, we generated clinically applicable ranges for circulating androgens during specific phases of the menstrual cycle in a convenience sample of 120 reproductive-aged, regularly cycling healthy European Caucasian women with self-reported normal sexual function. All participants were asked to complete a semistructured interview and fill out a set of validated questionnaires, including the Female Sexual Function Index, the Female Sexual Distress Scale, and the 21-item Beck's Inventory for Depression. Between 8 am and 10 am, a venous blood sample was drawn from each participant during the midfollicular (day 5 to 8), the ovulatory (day 13 to 15), and the midluteal phase (day 19 to 22) of the same menstrual cycle. Serum levels of total and free testosterone, Delta(4)-androstenedione, dehydroepiandrosterone sulphate and sex hormone-binding globulin during the midfollicular, ovulatory and midluteal phase of the same menstrual cycle. Total and free T levels showed significant fluctuations, peaking during the ovulatory phase. No significant variation during the menstrual cycle were observed for Delta(4)-androstenedione and dehydroepiandrosterone sulphate. Despite the careful selection of participants that yielded an homogeneous group of women without sexual disorders, we observed a wide range of distribution for each of the circulating androgens measured in this study. This report provides clinically applicable ranges for androgens throughout the menstrual cycle in reproductive-aged, regularly cycling, young healthy Caucasian European women with self-reported normal sexual function.

Changes in amount and intracellular distribution of androgen receptor in human foreskin as a function of age.

PubMed Central

Roehrborn, C G; Lange, J L; George, F W; Wilson, J D

1987-01-01

To provide insight into the factors that control growth of the penis we measured the amount and intracellular distribution of specific high affinity androgen receptor in foreskins obtained at circumcision from 49 males varying in age from newborn to 59 yr. Total (cytosolic plus nuclear extract) androgen receptor decreased from approximately 40 fmol/g tissue weight in newborn foreskins to approximately 25 fmol/g by 1 yr of age. The amount of receptor rose in childhood to approximately 180 fmol/g in the late teenage years and fell thereafter to approximately 20-40 fmol/g in men older than 40 yr. The amount of receptor in the nuclear fraction increased at the time of puberty and subsequently decreased in parallel with the decline in total receptor level. These changes in androgen-receptor amount are similar when expressed per milligram DNA or per milligram protein. Images PMID:3491838

Endocrine Disrupting Chemicals Mediated through Binding Androgen Receptor Are Associated with Diabetes Mellitus

PubMed Central

Sakkiah, Sugunadevi; Wang, Tony; Zou, Wen; Wang, Yuping; Pan, Bohu; Tong, Weida; Hong, Huixiao

2017-01-01

Endocrine disrupting chemicals (EDCs) can mimic natural hormone to interact with receptors in the endocrine system and thus disrupt the functions of the endocrine system, raising concerns on the public health. In addition to disruption of the endocrine system, some EDCs have been found associated with many diseases such as breast cancer, prostate cancer, infertility, asthma, stroke, Alzheimer’s disease, obesity, and diabetes mellitus. EDCs that binding androgen receptor have been reported associated with diabetes mellitus in in vitro, animal, and clinical studies. In this review, we summarize the structural basis and interactions between androgen receptor and EDCs as well as the associations of various types of diabetes mellitus with the EDCs mediated through androgen receptor binding. We also discuss the perspective research for further understanding the impact and mechanisms of EDCs on the risk of diabetes mellitus. PMID:29295509

Short poly-glutamine repeat in the androgen receptor in New World monkeys.

PubMed

Hiramatsu, Chihiro; Paukner, Annika; Kuroshima, Hika; Fujita, Kazuo; Suomi, Stephen J; Inoue-Murayama, Miho

2017-12-01

The androgen receptor mediates various physiological and developmental functions and is highly conserved in mammals. Although great intraspecific length polymorphisms in poly glutamine (poly-Q) and poly glycine (poly-G) regions of the androgen receptor in humans, apes and several Old World monkeys have been reported, little is known about the characteristics of these regions in New World monkeys. In this study, we surveyed 17 species of New World monkeys and found length polymorphisms in these regions in three species (common squirrel monkeys, tufted capuchin monkeys and owl monkeys). We found that the poly-Q region in New World monkeys is relatively shorter than that in catarrhines (humans, apes and Old World monkeys). In addition, we observed that codon usage for poly-G region in New World monkeys is unique among primates. These results suggest that the length of polymorphic regions in androgen receptor genes have evolved uniquely in New World monkeys.

Do androgens play a beneficial role in the regulation of vascular tone? Nongenomic vascular effects of testosterone metabolites

PubMed Central

Perusquía, Mercedes

2010-01-01

The marked sexual dimorphism that exists in human cardiovascular diseases has led to the dogmatic concept that testosterone (Tes) has deleterious effects and exacerbates the development of cardiovascular disease in males. While some animal studies suggest that Tes does exert deleterious effects by enhancing vascular tone through acute or chronic mechanisms, accumulating evidence suggests that Tes and other androgens exert beneficial effects by inducing rapid vasorelaxation of vascular smooth muscle through nongenomic mechanisms. While this effect frequently has been observed in large arteries at micromolar concentrations, more recent studies have reported vasorelaxation of smaller resistance arteries at nanomolar (physiological) concentrations. The key mechanism underlying Tes-induced vasorelaxation appears to be the modulation of vascular smooth muscle ion channel function, particularly the inactivation of L-type voltage-operated Ca2+ channels and/or the activation of voltage-operated and Ca2+-activated K+ channels. Studies employing Tes analogs and metabolites reveal that androgen-induced vasodilation is a structurally specific nongenomic effect that is fundamentally different than the genomic effects on reproductive targets. For example, 5α-dihydrotestosterone exhibits potent genomic-androgenic effects but only moderate vasorelaxing activity, whereas its isomer 5β-dihydrotestosterone is devoid of androgenic effects but is a highly efficacious vasodilator. These findings suggest that the dihydro-metabolites of Tes or other androgen analogs devoid of androgenic or estrogenic effects could have useful therapeutic roles in hypertension, erectile dysfunction, prostatic ischemia, or other vascular dysfunctions. PMID:20228257

New perspectives in the diagnosis of pediatric male hypogonadism: the importance of AMH as a Sertoli cell marker.

PubMed

Grinspon, Romina P; Rey, Rodolfo A

2011-11-01

Sertoli cells are the most active cell population in the testis during infancy and childhood. In these periods of life, hypogonadism can only be evidenced without stimulation tests, if Sertoli cell function is assessed. AMH is a useful marker of prepubertal Sertoli cell activity and number. Serum AMH is high from fetal life until mid-puberty. Testicular AMH production increases in response to FSH and is potently inhibited by androgens. Serum AMH is undetectable in anorchidic patients. In primary or central hypogonadism affecting the whole gonad and established in fetal life or childhood, serum AMH is low. Conversely, when hypogonadism affects only Leydig cells (e.g. LHβ mutations, LH/CG receptor or steroidogenic enzyme defects), serum AMH is normal or high. In pubertal males with central hypogonadism, AMH is low for Tanner stage (reflecting lack of FSH stimulus), but high for the age (indicating lack of testosterone inhibitory effect). Treatment with FSH provokes an increase in serum AMH, whereas hCG administration increases testosterone levels, which downregulate AMH. In conclusion, assessment of serum AMH is helpful to evaluate gonadal function, without the need for stimulation tests, and guides etiological diagnosis of pediatric male hypogonadism. Furthermore, serum AMH is an excellent marker of FSH and androgen action on the testis.

Effect of ovarian aging on androgen biosynthesis in a cynomolgus macaque model

PubMed Central

Ethun, K. F.; Wood, C. E.; Parker, C. R.; Kaplan, J. R.; Chen, H.; Appt, S. E.

2013-01-01

Objective The role of androgens in chronic disease pathogenesis, cognitive function and libido during menopause is of increasing interest. The aim of this study was to characterize the distribution and expression of androgenic proteins in the macaque ovary and to investigate the relationship between serum androgen concentrations, follicle number, and the persistence of androgenesis in the aging macaque ovary. Methods The subjects were 26 adult female cynomolgus macaques. Ovaries were immunostained for cytochrome P450 17α-hydroxylase/17–20 lyase (P450c17), 3β-hydroxysteroid dehydrogenase (3βHSD), and cytochrome b5 (cytb5). Based on primordial follicle counts, animals were divided into tertiles (low (≤200), intermediate (226–1232), and high (2372–4356)) to evaluate differences in androgen staining and changes in serum androgen concentrations following ovariectomy. Results Positive immunostaining for P450c17 and cytb5 within the theca interna layer of growing follicles persisted in advanced atretic follicles and secondary interstitial cells (residual stromal cells). Ovaries with low follicle numbers had less staining for all androgenic proteins compared to ovaries with higher numbers of growing follicles. Immunostaining for cytb5 was the most reliable marker for persistent androgenesis in ovaries with minimal primordial follicle numbers (<100) and residual stromal cells. Following ovariectomy, a significant decrease in testosterone (−27.7%, −30.8%, −27.5%; p < 0.01) and androstenedione (−33.4%, −35.7%, −46.0%; p < 0.01) was observed in monkeys with low, intermediate, and high primordial follicle counts, respectively. Conclusions Despite low follicle numbers, the aging macaque ovary retains the necessary proteins for androgenesis within residual stromal cells and contributes to peripheral androgen concentrations. PMID:21864136

Diethylstilbesterol revisited: androgen deprivation, osteoporosis and prostate cancer.

PubMed

Scherr, Douglas; Pitts, W Reid; Vaughn, E Darracott

2002-02-01

It is well described in the urological literature that androgen deprivation can result in accelerated bone breakdown and osteoporosis. Therefore, we evaluate the degree of bone breakdown in patients on conventional androgen deprivation with those on diethylstilbesterol alone or in conjunction with luteinizing hormone releasing hormone agonists or orchiectomy. During an 18-month period a total of 54 patients with clinically localized prostate cancer and 24 with benign prostatic hyperplasia were evaluated. All patients with prostate cancer were either treated with external beam radiotherapy without androgen deprivation or were started on androgen deprivation therapy. All patients were prospectively followed and evaluated for serum testosterone and estradiol along with urinary collagen type I cross-linked N-telopeptides. Three separate morning urine samples on 3 separate months were collected on each patient and analyzed for N-telopeptides. To correct for different levels of renal function, all N-telopeptides were measured as a ratio of urinary N-telopeptides/urine creatinine. All patients with any bone or skeletal abnormalities were excluded from study as were those with osseous metastatic disease. There was a statistically significant (p < 0.05) higher level of urinary N-telopeptides/creatinine in patients on androgen deprivation therapy who were not treated with diethylstilbesterol. The estrogenic effect of diethylstilbesterol protects one from bone resorption. Patients on diethylstilbesterol did not have any higher levels of bone breakdown than patients with benign prostatic hyperplasia or those who never received any androgen deprivation. Rapid bone turnover and resorption can be prevented with 1 mg. diethylstilbesterol alone or in conjunction with other modes of androgen deprivation. Therefore, diethylstilbesterol should be considered as monotherpy in men who require long-term antiandrogen therapy.

Cardiac Nitric Oxide Synthases and Na⁺/K⁺-ATPase in the Rat Model of Polycystic Ovary Syndrome Induced by Dihydrotestosterone.

PubMed

Tepavčević, S; Milutinović, D V; Macut, D; Stanišić, J; Nikolić, M; Božić-Antić, I; Rodaljević, S; Bjekić-Macut, J; Matić, G; Korićanac, G

2015-05-01

Nitric oxide synthases (NOSs) and Na(+)/K(+)-ATPase are enzymes essential for regular functioning of the heart. Since both enzymes are under insulin and androgen regulation and since insulin action and androgen level were disturbed in polycystic ovary syndrome (PCOS), we hypothesized that cardiac nitric oxide (NO) production and sodium/potassium transport would be deteriorated in PCOS. To test our hypothesis we introduced animal model of PCOS based on dihydrotestosterone (DHT) treatment of female Wistar rats and analyzed protein expression, phosphorylation or subcellular localization of endothelial NOS (eNOS), inducible NOS (iNOS) and alpha subunits of Na(+)/K(+)-ATPase in the heart. Obtained results indicate that DHT treatment significantly decreased cardiac eNOS protein level and activating phosphorylation at serine 1,177, while inhibitory phosphorylation at threonine 495 was increased. In contrast to expression of eNOS, iNOS protein level in the heart of DHT-treated rats was significantly elevated. Furthermore, cardiac protein level of alpha 1 subunit of the ATPase, as well as its plasma membrane content, were decreased in rats with PCOS. In line with this, alpha 2 subunit protein level in fraction of plasma membranes was also significantly below control level. In conclusion, DHT treatment impaired effectiveness of NOSs and Na(+)/K(+)-ATPase in the female rat heart. Regarding the importance of NO production and sodium/potassium transport in the cardiac contraction and blood flow regulation, it implicates strong consequences of PCOS for heart functioning. © Georg Thieme Verlag KG Stuttgart · New York.

Plasmacytoid dendritic cell interferon-α production to R-848 stimulation is decreased in male infants.

PubMed

Wang, Jennifer P; Zhang, Lei; Madera, Rachel F; Woda, Marcia; Libraty, Daniel H

2012-07-06

Sex differences in response to microbial infections, especially viral ones, may be associated with Toll-like receptor (TLR)-mediated responses by plasmacytoid dendritic cells (pDCs). In this study, we identified sex differences in human infant pDC interferon-α production following challenge with the TLR7/8 agonist R-848. Male pDC responses were significantly lower than those of females during early infancy. This difference may be attributed to the androgen surge experienced by males during the early infancy period. Pretreatment of human pDCs with dihydrotestosterone produced a significant reduction in interferon-α production following R-848 challenge. Androgen-mediated regulation of pDC TLR7-driven innate immune responses may contribute to the observed sex differences in response to infections during early infancy.

Endocrine Disruption in Human Fetal Testis Explants by Individual and Combined Exposures to Selected Pharmaceuticals, Pesticides, and Environmental Pollutants

PubMed Central

Gaudriault, Pierre; Mazaud-Guittot, Séverine; Lavoué, Vincent; Coiffec, Isabelle; Lesné, Laurianne; Dejucq-Rainsford, Nathalie; Scholze, Martin; Kortenkamp, Andreas

2017-01-01

Background: Numerous chemicals are capable of disrupting androgen production, but the possibility that they might act together to produce effects greater than those of the most effective component in the mixture has not been studied directly in human tissues. Suppression of androgen synthesis in fetal life has been associated with testis maldescent, malformations of the genitalia at birth, and poor semen quality later in life. Objectives: Our aim was to investigate whether chemicals can act together to disrupt androgen production in human fetal testis explants and to evaluate the importance of mixture effects when characterizing the hazard of individual chemicals. Methods: We used an organotypic culture system of human fetal testes explants called FEtal Gonad Assay (FEGA) with tissue obtained at 10 and 12 gestational wk (GW 10–12), to screen 27 chemicals individually for their possible anti-androgenic effect. Based on the results of the screen, we selected 11 compounds and tested them as mixtures. Results: We evaluated mixtures composed of four and eight antiandrogens that contained the pharmaceuticals ketoconazole and theophylline and several previously untested chemicals, such as the pesticides imazalil and propiconazole. Mixtures of antiandrogens can suppress testosterone synthesis in human fetal testicular explants to an extent greater than that seen with individual chemicals. This revealed itself as a shift towards lower doses in the dose–response curves of individual antiandrogens that became more pronounced as the number of components increased from four to eight. Conclusions: Our results with the FEGA provide the foundations of a predictive human mixture risk assessment approach for anti-androgenic exposures in fetal life. https://doi.org/10.1289/EHP1014 PMID:28796631

Endocrine Disruption in Human Fetal Testis Explants by Individual and Combined Exposures to Selected Pharmaceuticals, Pesticides, and Environmental Pollutants.

PubMed

Gaudriault, Pierre; Mazaud-Guittot, Séverine; Lavoué, Vincent; Coiffec, Isabelle; Lesné, Laurianne; Dejucq-Rainsford, Nathalie; Scholze, Martin; Kortenkamp, Andreas; Jégou, Bernard

2017-08-04

Numerous chemicals are capable of disrupting androgen production, but the possibility that they might act together to produce effects greater than those of the most effective component in the mixture has not been studied directly in human tissues. Suppression of androgen synthesis in fetal life has been associated with testis maldescent, malformations of the genitalia at birth, and poor semen quality later in life. Our aim was to investigate whether chemicals can act together to disrupt androgen production in human fetal testis explants and to evaluate the importance of mixture effects when characterizing the hazard of individual chemicals. We used an organotypic culture system of human fetal testes explants called FEtal Gonad Assay (FEGA) with tissue obtained at 10 and 12 gestational wk (GW 10-12), to screen 27 chemicals individually for their possible anti-androgenic effect. Based on the results of the screen, we selected 11 compounds and tested them as mixtures. We evaluated mixtures composed of four and eight antiandrogens that contained the pharmaceuticals ketoconazole and theophylline and several previously untested chemicals, such as the pesticides imazalil and propiconazole. Mixtures of antiandrogens can suppress testosterone synthesis in human fetal testicular explants to an extent greater than that seen with individual chemicals. This revealed itself as a shift towards lower doses in the dose-response curves of individual antiandrogens that became more pronounced as the number of components increased from four to eight. Our results with the FEGA provide the foundations of a predictive human mixture risk assessment approach for anti-androgenic exposures in fetal life. https://doi.org/10.1289/EHP1014.

Targeting Androgen Receptor-Driven Resistance to CYP17A1 Inhibitors

DTIC Science & Technology

2016-11-01

unlimited The views, opinions and/or findings contained in this report are those of the author(s) and should not be construed as an official Department of...chemo- and radiotherapies that are efficacious against primary, androgen sensitive (AS)-CaP. CR-CaP progresses to metastatic disease in local lymph... AR ) protein, called AR -V, is directly responsible for malignancy of CR-CaP, and moreover, that ENZ or ABI treatment actually enhances production of AR

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

PubMed

Ghosal, Ratna; Sorensen, Peter W

2016-06-01

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

Key structural features of nonsteroidal ligands for binding and activation of the androgen receptor.

PubMed

Yin, Donghua; He, Yali; Perera, Minoli A; Hong, Seoung Soo; Marhefka, Craig; Stourman, Nina; Kirkovsky, Leonid; Miller, Duane D; Dalton, James T

2003-01-01

The purposes of the present studies were to examine the androgen receptor (AR) binding ability and in vitro functional activity of multiple series of nonsteroidal compounds derived from known antiandrogen pharmacophores and to investigate the structure-activity relationships (SARs) of these nonsteroidal compounds. The AR binding properties of sixty-five nonsteroidal compounds were assessed by a radioligand competitive binding assay with the use of cytosolic AR prepared from rat prostates. The AR agonist and antagonist activities of high-affinity ligands were determined by the ability of the ligand to regulate AR-mediated transcriptional activation in cultured CV-1 cells, using a cotransfection assay. Nonsteroidal compounds with diverse structural features demonstrated a wide range of binding affinity for the AR. Ten compounds, mainly from the bicalutamide-related series, showed a binding affinity superior to the structural pharmacophore from which they were derived. Several SARs regarding nonsteroidal AR binding were revealed from the binding data, including stereoisomeric conformation, steric effect, and electronic effect. The functional activity of high-affinity ligands ranged from antagonist to full agonist for the AR. Several structural features were found to be determinative of agonist and antagonist activities. The nonsteroidal AR agonists identified from the present studies provided a pool of candidates for further development of selective androgen receptor modulators (SARMs) for androgen therapy. Also, these studies uncovered or confirmed numerous important SARs governing AR binding and functional properties by nonsteroidal molecules, which would be valuable in the future structural optimization of SARMs.

21 CFR 310.528 - Drug products containing active ingredients offered over-the-counter (OTC) for use as an...

Code of Federal Regulations, 2012 CFR

2012-04-01

..., testosterone, vitamins, yohimbine, yohimbine hydrochloride, and yohimbinum have been present as ingredients in such drug products. Androgens (e.g., testosterone and methyltestosterone) and estrogens are powerful...

21 CFR 310.528 - Drug products containing active ingredients offered over-the-counter (OTC) for use as an...

Code of Federal Regulations, 2014 CFR

2014-04-01

..., testosterone, vitamins, yohimbine, yohimbine hydrochloride, and yohimbinum have been present as ingredients in such drug products. Androgens (e.g., testosterone and methyltestosterone) and estrogens are powerful...

21 CFR 310.528 - Drug products containing active ingredients offered over-the-counter (OTC) for use as an...

Code of Federal Regulations, 2013 CFR

2013-04-01

..., testosterone, vitamins, yohimbine, yohimbine hydrochloride, and yohimbinum have been present as ingredients in such drug products. Androgens (e.g., testosterone and methyltestosterone) and estrogens are powerful...

21 CFR 310.528 - Drug products containing active ingredients offered over-the-counter (OTC) for use as an...

Code of Federal Regulations, 2011 CFR

2011-04-01

..., testosterone, vitamins, yohimbine, yohimbine hydrochloride, and yohimbinum have been present as ingredients in such drug products. Androgens (e.g., testosterone and methyltestosterone) and estrogens are powerful...

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

..., testosterone, vitamins, yohimbine, yohimbine hydrochloride, and yohimbinum have been present as ingredients in such drug products. Androgens (e.g., testosterone and methyltestosterone) and estrogens are powerful...

Androgen Receptor-Mediated Escape Mechanisms from Androgen Ablation Therapy

DTIC Science & Technology

2005-10-01

intestinal polyps, the precursor of invasive carcinoma and colon cancer. Also, fain-of-function, truncated forms of 3-catenin occurring in metastatic prostate...STATEMENT: Approved for Public Release; Distribution Unlimited The views, opinions and/or findings contained in this report are those of the author(s) and...should not be construed as an official Department of the Army position, policy or decision unless so designated by other documentation. 20060503040

Relating Androgen Receptor Conformation to Function in Prostate Cancer Cells

DTIC Science & Technology

2005-01-01

line development , but have made progress towards resolving these issues and in development of alternate strategies. Task 1. Development of AR and...conformation. Task 2. Development of LNCaP Cells to Express Human AR mutants. We experienced unexpected difficulties in Task 2. We transfected the TET...Coactivators in AR Transactivation Summary Androgens drive sex differentiation, bone and muscle development , and promote growth of hormone dependent cancers

Altered cortisol metabolism in polycystic ovary syndrome: insulin enhances 5alpha-reduction but not the elevated adrenal steroid production rates.

PubMed

Tsilchorozidou, Tasoula; Honour, John W; Conway, Gerard S

2003-12-01

Androgen excess in women with polycystic ovary syndrome (PCOS) may be ovarian and/or adrenal in origin, and one proposed contributing mechanism is altered cortisol metabolism. Increased peripheral metabolism of cortisol may occur by enhanced inactivation of cortisol by 5alpha-reductase (5alpha-R) or impaired reactivation of cortisol from cortisone by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) resulting in decreased negative feedback suppression of ACTH secretion maintaining normal plasma cortisol concentrations at the expense of androgen excess. We have tested whether any enzyme dysregulation was related to circulating insulin or androgen concentrations in women with PCOS and have sought to clarify their relationship with obesity. First, to avoid obesity-related effects on cortisol metabolism, 18 lean women with PCOS were compared with 19 lean controls who were closely matched for body mass index (BMI). Second, the impact of obesity was studied in a cross-section of 42 PCOS women of a broad range of BMI. We measured 24-h urinary excretion of steroid metabolites by gas chromatography/mass spectrometry and fasting metabolic and hormone profiles. Urinary excretion of androgens [androsterone (P = 0.003), etiocholanolone (P = 0.02), and C19 steroid sulfates (P = 0.009)], cortisone metabolites [tetrahydrocortisone (THE) (P = 0.02), alpha-cortolone (P < 0.001), beta-cortol + beta-cortolone (P < 0.001), cortolones (P < 0.001), and E metabolites (P < 0.001)], and TCM (P = 0.002) were raised in lean PCOS subjects when compared with controls. A significantly higher 5alpha-tetrahydrocortisol (5alpha-THF)/5beta-THF ratio (P = 0.04) and a significantly lower alpha-THF + THF + alpha-cortol/THE + cortolones ratio (P = 0.01) were found in lean PCOS women compared with lean controls, indicating both enhanced 5alpha-R and reduced 11beta-HSD1 activities. A decreased THE/cortolones ratio (P = 0.03) was also found in lean PCOS women compared with lean controls, indicating increased 20 alpha/beta-HSD activity. In the group of 42 PCOS subjects, measures of 5alpha/5beta reduction were positively correlated with the homeostasis model insulin resistance index (HOMA-R): alpha-THF/THF and HOMA-R (r = 0.34; P = 0.03), androsterone/etiocholanolone and HOMA-R (r = 0.32; P = 0.04), and total 5alpha /total 5beta and HOMA-R (r = 0.37; P = 0.02). A positive correlation was also found between measures of 5alpha-R and BMI (r = 0.37; P = 0.02). No correlation was found between measures of 11beta-HSD1 activity and indices of insulin sensitivity or BMI. We have demonstrated that there is an increased production rate of cortisol and androgens as measured in vivo in lean PCOS women. Insulin seems to enhance 5alpha reduction of steroids in PCOS but was not associated with the elevated cortisol production rate. The changes in 5alpha-R, 11beta-HSD1, and 20alpha/beta-HSD enzyme activities observed in PCOS may contribute to the increased production rates of cortisol and androgens, supporting the concept of a widespread dysregulation of steroid metabolism. This dysregulation does not seem to be the primary cause of PCOS because no correlation was found between serum androgen levels or urinary excretion of androgens with measurements of either 5alpha-R or 11beta-HSD1 activities.

Transcriptional regulation of core autophagy and lysosomal genes by the androgen receptor promotes prostate cancer progression

PubMed Central

Blessing, Alicia M.; Rajapakshe, Kimal; Reddy Bollu, Lakshmi; Shi, Yan; White, Mark A.; Pham, Alexander H.; Lin, Chenchu; Jonsson, Philip; Cortes, Constanza J.; Cheung, Edwin; La Spada, Albert R.; Bast, Robert C.; Merchant, Fatima A.; Coarfa, Cristian; Frigo, Daniel E.

2017-01-01

ABSTRACT AR (androgen receptor) signaling is crucial for the development and maintenance of the prostate as well as the initiation and progression of prostate cancer. Despite the AR's central role in prostate cancer progression, it is still unclear which AR-mediated processes drive the disease. Here, we identified 4 core autophagy genes: ATG4B, ATG4D, ULK1, and ULK2, in addition to the transcription factor TFEB, a master regulator of lysosomal biogenesis and function, as transcriptional targets of AR in prostate cancer. These findings were significant in light of our recent observation that androgens promoted prostate cancer cell growth in part through the induction of autophagy. Expression of these 5 genes was essential for maximal androgen-mediated autophagy and cell proliferation. In addition, expression of each of these 5 genes alone or in combination was sufficient to increase prostate cancer cell growth independent of AR activity. Further, bioinformatic analysis demonstrated that the expression of these genes correlated with disease progression in 3 separate clinical cohorts. Collectively, these findings demonstrate a functional role for increased autophagy in prostate cancer progression, provide a mechanism for how autophagy is augmented, and highlight the potential of targeting this process for the treatment of advanced prostate cancer. PMID:27977328

Association of Androgen Excess with Glucose Intolerance in Women with Polycystic Ovary Syndrome.

PubMed

Zhang, Bingjie; Wang, Jing; Shen, Shanmei; Liu, Jiayi; Sun, Jie; Gu, Tianwei; Ye, Xiao; Zhu, Dalong; Bi, Yan

2018-01-01

Women with polycystic ovary syndrome (PCOS) show high prevalence of glucose intolerance. This study aimed to investigate the association of androgen excess with glucose intolerance in PCOS. A total of 378 women with PCOS participated in the study. Free androgen index (FAI) was selected as indicator of hyperandrogenism. Insulin sensitivity was assessed by 1/homeostasis model assessment of insulin resistance (1/HOMA-IR) and Matsuda insulin sensitivity index (ISI M ); β -cell function was assessed by disposition index (DI). We found that women with glucose intolerance had higher FAI levels compared to women with normal glucose tolerance (NGT) (prediabetes 6.2, T2DM 7.9 versus NGT 5.0, resp.; p < 0.001). Furthermore, there was a direct association between FAI levels and frequency of glucose intolerance (OR = 2.480, 95% CI 1.387-4.434), even after adjusting for age, BMI, waist circumference, hypertension, fasting insulin, testosterone, SHBG, and family history of diabetes. In addition, with FAI increase, glycosylated hemoglobin (HbA1c), plasma glucose concentrations, and serum insulin levels increased, while insulin sensitivity and β -cell function decreased. Our results suggested that androgen excess indicated by high FAI levels might serve as indicator of glucose intolerance, as it might promote insulin resistance and β -cell dysfunction in women with PCOS.

A dual yet opposite growth-regulating function of miR-204 and its target XRN1 in prostate adenocarcinoma cells and neuroendocrine-like prostate cancer cells

PubMed Central

Ding, Miao; Lin, Biaoyang; Li, Tao; Liu, Yuanyuan; Li, Yuhua; Zhou, Xiaoyu; Miao, Maohua; Gu, Jinfa; Pan, Hongjie; Yang, Fen; Li, Tianqi; Liu, Xin Yuan; Li, Runsheng

2015-01-01

Androgen deprivation therapy in prostate cancer (PCa) causes neuroendocrine differentiation (NED) of prostatic adenocarcinomas (PAC) cells, leading to recurrence of PCa. Androgen-responsive genes involved in PCa progression including NED remain largely unknown. Here we demonstrated the importance of androgen receptor (AR)-microRNA-204 (miR-204)-XRN1 axis in PCa cell lines and the rat ventral prostate. Androgens downregulate miR-204, resulting in induction of XRN1 (5′-3′ exoribonuclease 1), which we identified as a miR-204 target. miR-204 acts as a tumor suppressor in two PAC cell lines (LNCaP and 22Rv1) and as an oncomiR in two neuroendocrine-like prostate cancer (NEPC) cell lines (PC-3 and CL1). Importantly, overexpression of miR-204 and knockdown of XRN1 inhibited AR expression in PCa cells. Repression of miR-34a, a known AR-targeting miRNA, contributes AR expression by XRN1. Thus we revealed the AR-miR-204-XRN1-miR-34a positive feedback loop and a dual function of miR-204/XRN1 axis in prostate cancer. PMID:25797256

Transcriptional regulation of core autophagy and lysosomal genes by the androgen receptor promotes prostate cancer progression.

PubMed

Blessing, Alicia M; Rajapakshe, Kimal; Reddy Bollu, Lakshmi; Shi, Yan; White, Mark A; Pham, Alexander H; Lin, Chenchu; Jonsson, Philip; Cortes, Constanza J; Cheung, Edwin; La Spada, Albert R; Bast, Robert C; Merchant, Fatima A; Coarfa, Cristian; Frigo, Daniel E

2017-03-04

AR (androgen receptor) signaling is crucial for the development and maintenance of the prostate as well as the initiation and progression of prostate cancer. Despite the AR's central role in prostate cancer progression, it is still unclear which AR-mediated processes drive the disease. Here, we identified 4 core autophagy genes: ATG4B, ATG4D, ULK1, and ULK2, in addition to the transcription factor TFEB, a master regulator of lysosomal biogenesis and function, as transcriptional targets of AR in prostate cancer. These findings were significant in light of our recent observation that androgens promoted prostate cancer cell growth in part through the induction of autophagy. Expression of these 5 genes was essential for maximal androgen-mediated autophagy and cell proliferation. In addition, expression of each of these 5 genes alone or in combination was sufficient to increase prostate cancer cell growth independent of AR activity. Further, bioinformatic analysis demonstrated that the expression of these genes correlated with disease progression in 3 separate clinical cohorts. Collectively, these findings demonstrate a functional role for increased autophagy in prostate cancer progression, provide a mechanism for how autophagy is augmented, and highlight the potential of targeting this process for the treatment of advanced prostate cancer.

Cumulative and antagonistic effects of a mixture of the antiandrogens vinclozolin and iprodione in the pubertal male rat.

PubMed

Blystone, Chad R; Lambright, Christy S; Cardon, Mary C; Furr, Johnathan; Rider, Cynthia V; Hartig, Phillip C; Wilson, Vickie S; Gray, Leon E

2009-09-01

Vinclozolin and iprodione are dicarboximide fungicides that display antiandrogenic effects in the male rat, which suggests that a mixture would lead to cumulative effects on androgen-sensitive end points. Iprodione is a steroid synthesis inhibitor, but androgen receptor antagonist activity, which is displayed by vinclozolin, has not been fully evaluated. Here, we demonstrate that iprodione binds to the human androgen receptor (IC(50) = 86.0 microM), reduces androgen-dependent gene expression, and reduces androgen-sensitive tissue weights in castrated male rats (Hershberger assay). Since vinclozolin and iprodione affect common targets in the pubertal male rat, we tested the hypothesis that a mixture would have cumulative antiandrogenic effects. An iprodione dose, that does not significantly affect androgen-dependent morphological end points, was combined with vinclozolin doses (2 x 5 factorial design). Sprague-Dawley rats were dosed by gavage with vinclozolin at 0, 10, 30, 60, and 100 mg/kg/day with and without 50 mg iprodione/kg/day from postnatal day (PND) 23 to 55-57 (n = 8 per group). The age at puberty (preputial separation [PPS]), organ weights, serum hormones, and ex vivo testis steroid hormone production were measured. Vinclozolin delayed PPS, reduced androgen-sensitive organ weights, and increased serum testosterone. The addition of iprodione enhanced the vinclozolin inhibition of PPS (PND 47.5 vs.49.1; two-way ANOVA: iprodione main effect p = 0.0002). The dose response for several reproductive and nonreproductive organ weights was affected in a cumulative manner. In contrast, iprodione antagonized the vinclozolin-induced increase in serum testosterone. These results demonstrate that these fungicides interact on common targets in a tissue-specific manner when coadministered to the pubertal male rat.

Developmental programming of polycystic ovary syndrome (PCOS): prenatal androgens establish pancreatic islet α/β cell ratio and subsequent insulin secretion.

PubMed

Ramaswamy, S; Grace, C; Mattei, A A; Siemienowicz, K; Brownlee, W; MacCallum, J; McNeilly, A S; Duncan, W C; Rae, M T

2016-06-06

Exogenous androgenic steroids applied to pregnant sheep programmes a PCOS-like phenotype in female offspring. Via ultrasound guidance we applied steroids directly to ovine fetuses at d62 and d82 of gestation, and examined fetal (day 90 gestation) and postnatal (11 months old) pancreatic structure and function. Of three classes of steroid agonists applied (androgen - Testosterone propionate (TP), estrogen - Diethystilbesterol (DES) and glucocorticoid - Dexamethasone (DEX)), only androgens (TP) caused altered pancreatic development. Beta cell numbers were significantly elevated in prenatally androgenised female fetuses (P = 0.03) (to approximately the higher numbers found in male fetuses), whereas alpha cell counts were unaffected, precipitating decreased alpha:beta cell ratios in the developing fetal pancreas (P = 0.001), sustained into adolescence (P = 0.0004). In adolescence basal insulin secretion was significantly higher in female offspring from androgen-excess pregnancies (P = 0.045), and an exaggerated, hyperinsulinaemic response to glucose challenge (P = 0.0007) observed, whereas prenatal DES or DEX treatment had no effects upon insulin secretion. Postnatal insulin secretion correlated with beta cell numbers (P = 0.03). We conclude that the pancreas is a primary locus of androgenic stimulation during development, giving rise to postnatal offspring whose pancreas secreted excess insulin due to excess beta cells in the presence of a normal number of alpha cells.

Developmental programming of polycystic ovary syndrome (PCOS): prenatal androgens establish pancreatic islet α/β cell ratio and subsequent insulin secretion

PubMed Central

Ramaswamy, S.; Grace, C.; Mattei, A. A.; Siemienowicz, K.; Brownlee, W.; MacCallum, J.; McNeilly, A. S.; Duncan, W. C.; Rae, M. T.

2016-01-01

Exogenous androgenic steroids applied to pregnant sheep programmes a PCOS-like phenotype in female offspring. Via ultrasound guidance we applied steroids directly to ovine fetuses at d62 and d82 of gestation, and examined fetal (day 90 gestation) and postnatal (11 months old) pancreatic structure and function. Of three classes of steroid agonists applied (androgen - Testosterone propionate (TP), estrogen - Diethystilbesterol (DES) and glucocorticoid - Dexamethasone (DEX)), only androgens (TP) caused altered pancreatic development. Beta cell numbers were significantly elevated in prenatally androgenised female fetuses (P = 0.03) (to approximately the higher numbers found in male fetuses), whereas alpha cell counts were unaffected, precipitating decreased alpha:beta cell ratios in the developing fetal pancreas (P = 0.001), sustained into adolescence (P = 0.0004). In adolescence basal insulin secretion was significantly higher in female offspring from androgen-excess pregnancies (P = 0.045), and an exaggerated, hyperinsulinaemic response to glucose challenge (P = 0.0007) observed, whereas prenatal DES or DEX treatment had no effects upon insulin secretion. Postnatal insulin secretion correlated with beta cell numbers (P = 0.03). We conclude that the pancreas is a primary locus of androgenic stimulation during development, giving rise to postnatal offspring whose pancreas secreted excess insulin due to excess beta cells in the presence of a normal number of alpha cells. PMID:27265420

Suspected ontogeny of a recently described hypo-androgenic PCOS-like phenotype with advancing age.

PubMed

Gleicher, Norbert; Kushnir, Vitaly A; Darmon, Sarah K; Wang, Qi; Zhang, Lin; Albertini, David F; Barad, David H

2018-03-01

A recent report described a new PCOS-like phenotype in lean older infertile women, and was characterized by high age-specific anti-Müllerian hormone (AMH) but hypo- rather than the expected hyper-androgenism. The hypo-androgenism was, furthermore, characterized of, likely, adrenal origin and autoimmune etiology. We extracted data on 708 consecutive infertility patients, and separated them into three age-strata, <35, 36-42, and >42 years. In each stratum, we investigated how levels of anti-Müllerian hormone (AMH) and testosterone (T) interrelate between high-AMH (AMH ≥ 75th quantile) and normal AMH (25th-75th quantile) and low-T (total testosterone ≤19.0 ng/dL), normal-T (19.0-29.0 ng/dL) and high-T (>29.0 ng/dL). High-AMH cycles were presumed to reflect PCOS-like patients. Routine in vitro fertilization (IVF) cycle outcomes and clinical phenotypes of patients were then compared between groups with AMH and T as statistical variables. This hypo-androgenic PCOS-like phenotype already exists in age stratum <35 years. It appears to arise from a lean, at very young ages hyper-androgenic PCOS phenotype that develops in comparison to controls (likely autoimmune-induced) insufficiency of the adrenal zona reticularis (low-T and low-DHEAS) and zona fasciculata (low-C), and is characterized by frequent evidence of autoimmunity. A degree of adrenal insufficiency, thus, concomitantly appears to affect adrenal androgen and, to lesser degrees, glucocorticoid production (mineralocorticoids were not investigated). Here investigated new PCOS-like phenotype demonstrates features compatible with what under Rotterdam criteria has been referred to as PCOS phenotype-D. If confirmed, the observation that the ontogeny of this phenotype already at young ages is, likely, driven by adrenal autoimmunity, supports the position of the androgen excess and PCOS society that the etiology of phenotype-D differs from that of classical hyper-androgenic PCOS of mostly ovarian etiology.

Effects of model aromatizable (17α-methyltestosterone) and non-aromatizable (5α-dihydrotestosterone) androgens on the adult mummichog (Fundulus heteroclitus) in a short-term reproductive endocrine bioassay.

PubMed

Rutherford, Robert; Lister, Andrea; Hewitt, L Mark; MacLatchy, Deborah

2015-04-01

Androgens originating from pulp mill processing, sewage treatment facilities and agricultural activities have the potential for discharge into aquatic receiving environments. To assess androgen effects on reproductive endocrine status in fish in estuarine environments, male and female adult northern mummichog (Fundulus heteroclitus macrolepidotus) were exposed to an aromatizable androgen (17α-methyltestosterone; MT) and a non-aromatizable androgen (5α-dihydrotestosterone; DHT) in a short-term reproductive endocrine bioassay. Fish were nominally exposed to 10 μg/L or 100 μg/L DHT, or 0.1 μg/L or 1 μg/L MT for 14 days during gonadal recrudescence. Actual concentrations of androgens, as measured by enzyme immunoassay (EIA), were 10-49% of nominal MT 0.1, 3-6% of nominal MT 1, 5-10% of nominal DHT 10 and 3-25% of nominal DHT 100. Female mummichog were impacted to a greater degree by androgen exposure, with increased plasma testosterone (T) at 100 μg/L DHT, depressed plasma 17β-estradiol (E2) at both DHT concentrations and at 1 μg/L MT, as well as depressed in vitro E2 at both MT concentrations and 100 μg/L DHT. Males had depressed plasma T in the 10 μg/L DHT treatment and depressed in vitro 11-ketotestosterone production for both MT concentrations and 10 μg/L DHT. Ovarian aromatase gene expression was induced in females exposed to 1 μg/L MT. DHT at 100 μg/L increased hepatic vitellogenin-1 (VTG1) expression in males and depressed VTG1 expression in females. The range of responses between sexes and among species provides evidence for modes of actions and potential impacts of androgens in aquatic receiving environments. Copyright © 2015 Elsevier Inc. All rights reserved.

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

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

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

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

Degradation of 17α-methyltestosterone by Rhodococcus sp. and Nocardioides sp. isolated from a masculinizing pond of Nile tilapia fry.

PubMed

Homklin, Supreeda; Ong, Say Kee; Limpiyakorn, Tawan

2012-06-30

17α-Methyltestosterone (MT), a synthetic anabolic androgenic steroid, is widely used in aquafarming for the production of an all male fish population such as Nile tilapia. This study isolated, identified and characterized MT-degrading bacteria in the sediment and water from a masculinizing pond of Nile tilapia fry. Based on the phylogeny, physiological properties and cell morphology, the three isolated MT-degrading bacteria were related closely to Rhodococcus equi, Nocardioides aromaticivorans, and Nocardioides nitrophenolicus. Growth of the three isolated strains was found to be inhibited for MT concentrations in the range of 1.0-10mg/L. The inhibition of cell growth was found to be modeled using the Haldane's substrate inhibition model. The kinetic constants ranged from 0.13 to 0.19h(-1) for μ(max), 0.7-24.8mg/L for K(s) and 19.6-76.2mg/L for K(i). Androgenic activity using β-galactosidase assay showed that all strains degraded MT to the products with no androgenic potency. Copyright © 2012 Elsevier B.V. All rights reserved.

Nrdp1-Mediated ErbB3 Increase During Androgen Ablation and Its Contribution to Androgen-Independence

DTIC Science & Technology

2011-09-01

after the first day. Cell lysates were immunoblotted with anti-Nrdp1 and anti-tubulin antibodies. 7 Differential regulation of Nrdp1 by...Prostate Cancer PDGFR Platelet -derived growth factor receptor PI3K Phosphatidylinositol 3-kinase PKC Protein Kinase C pRB Retinoblastoma gene product PSA... glioma . Cancer Res. 2007; 67(17):7960–7965. [PubMed: 17804702] 131. Junttila TT, Akita RW, Parsons K, Fields C, Lewis Phillips GD, Friedman LS, Sampath D

Androgen deprivation by adrenal suppression using low-dose hydrocortisone for the treatment of breast carcinoma with apocrine features: a case report illustrating this new paradigm.

PubMed

Jongen, Lynn; Paridaens, Robert; Floris, Giuseppe; Wildiers, Hans; Neven, Patrick

2016-02-01

We report on a postmenopausal patient with a secondary metastatic apocrine breast cancer successfully treated with low-dose hydrocortisone only following several lines of chemotherapy. The tumor cells in the primary and metastatic lesion exhibited a 'triple-negative' status (estrogen receptor (ER)-, progesterone receptor (PR)-, and human epidermal growth factor receptor 2 (HER2)-negative); the androgen receptor (AR) was strongly expressed. Twenty milligrams of hydrocortisone, a low substitution dose known to suppress adrenal steroid production, twice daily led to a clinical benefit lasting for one year, with symptom control, radiologically stable disease, and steady decrease in CA15.3. Our observation demonstrates that an AR-expressing apocrine breast cancer may respond to androgen deprivation, as an ER-positive breast cancer may benefit from estrogen deprivation. It highlights the importance of further research targeting the AR pathway in apocrine carcinoma, for which androgens represent the sole (known) steroid hormone stimulating tumor growth. Future clinical trials should not only focus on AR inhibitors like enzalutamide, but also on ablative modalities like low-dose hydrocortisone aiming at medical adrenalectomy. This method of androgen deprivation is largely available, cheap, and nearly devoid of toxicity.

Androgen receptor (AR) pathophysiological roles in androgen-related diseases in skin, bone/muscle, metabolic syndrome and neuron/immune systems: lessons learned from mice lacking AR in specific cells

PubMed Central

Chang, Chawnshang; Yeh, Shuyuan; Lee, Soo Ok; Chang, Ta-min

2013-01-01

The androgen receptor (AR) is expressed ubiquitously and plays a variety of roles in a vast number of physiological and pathophysiological processes. Recent studies of AR knockout (ARKO) mouse models, particularly the cell type- or tissue-specific ARKO models, have uncovered many AR cell type- or tissue-specific pathophysiological roles in mice, which otherwise would not be delineated from conventional castration and androgen insensitivity syndrome studies. Thus, the AR in various specific cell types plays pivotal roles in production and maturation of immune cells, bone mineralization, and muscle growth. In metabolism, the ARs in brain, particularly in the hypothalamus, and the liver appear to participate in regulation of insulin sensitivity and glucose homeostasis. The AR also plays key roles in cutaneous wound healing and cardiovascular diseases, including atherosclerosis and abdominal aortic aneurysm. This article will discuss the results obtained from the total, cell type-, or tissue-specific ARKO models. The understanding of AR cell type- or tissue-specific physiological and pathophysiological roles using these in vivo mouse models will provide useful information in uncovering AR roles in humans and eventually help us to develop better therapies via targeting the AR or its downstream signaling molecules to combat androgen/AR-related diseases. PMID:24653668

Optimization and comprehensive characterization of a faithful tissue culture model of the benign and malignant human prostate.

PubMed

Maund, Sophia Lisette; Nolley, Rosalie; Peehl, Donna Mae

2014-02-01

Few preclinical models accurately depict normal human prostate tissue or primary prostate cancer (PCa). In vitro systems typically lack complex cellular interactions among structured prostatic epithelia and a stromal microenvironment, and genetic and molecular fidelity are concerns in both in vitro and in vivo models. 'Tissue slice cultures' (TSCs) provide realistic preclinical models of diverse tissues and organs, but have not been fully developed or widely utilized for prostate studies. Problems encountered include degeneration of differentiated secretory cells, basal cell hyperplasia, and poor survival of PCa. Here, we optimized, characterized, and applied a TSC model of primary human PCa and benign prostate tissue that overcomes many deficiencies of current in vitro models. Tissue cores from fresh prostatectomy specimens were precision-cut at 300 μm and incubated in a rotary culture apparatus. The ability of varied culture conditions to faithfully maintain benign and cancer cell and tissue structure and function over time was evaluated by immunohistological and biochemical assays. After optimization of the culture system, molecular and cellular responses to androgen ablation and to piperlongumine (PL), purported to specifically reduce androgen signaling in PCa, were investigated. Optimized culture conditions successfully maintained the structural and functional fidelity of both benign and PCa TSCs for 5 days. TSCs exhibited androgen dependence, appropriately undergoing ductal degeneration, reduced proliferation, and decreased prostate-specific antigen expression upon androgen ablation. Further, TSCs revealed cancer-specific reduction of androgen receptor and increased apoptosis upon treatment with PL, validating data from cell lines. We demonstrate a TSC model that authentically recapitulates the structural, cellular, and genetic characteristics of the benign and malignant human prostate, androgen dependence of the native tissue, and cancer-specific response to a potentially new therapeutic for PCa. The work described herein provides a basis for advancing the experimental utility of the TSC model.

GTG mutation in the start codon of the androgen receptor gene in a family of horses with 64,XY disorder of sex development.

PubMed

Révay, T; Villagómez, D A F; Brewer, D; Chenier, T; King, W A

2012-01-01

Genetic sex in mammals is determined by the sex chromosomal composition of the zygote. The X and Y chromosomes are responsible for numerous factors that must work in close concert for the proper development of a healthy sexual phenotype. The role of androgens in case of XY chromosomal constitution is crucial for normal male sex differentiation. The intracellular androgenic action is mediated by the androgen receptor (AR), and its impaired function leads to a myriad of syndromes with severe clinical consequences, most notably androgen insensitivity syndrome and prostate cancer. In this paper, we investigated the possibility that an alteration of the equine AR gene explains a recently described familial XY, SRY + disorder of sex development. We uncovered a transition in the first nucleotide of the AR start codon (c.1A>G). To our knowledge, this represents the first causative AR mutation described in domestic animals. It is also a rarely observed mutation in eukaryotes and is unique among the >750 entries of the human androgen receptor mutation database. In addition, we found another quiet missense mutation in exon 1 (c.322C>T). Transcription of AR was confirmed by RT-PCR amplification of several exons. Translation of the full-length AR protein from the initiating GTG start codon was confirmed by Western blot using N- and C-terminal-specific antibodies. Two smaller peptides (25 and 14 amino acids long) were identified from the middle of exon 1 and across exons 5 and 6 by mass spectrometry. Based upon our experimental data and the supporting literature, it appears that the AR is expressed as a full-length protein and in a functional form, and the observed phenotype is the result of reduced AR protein expression levels. Copyright © 2011 S. Karger AG, Basel.

Hormone therapy in acne.

PubMed

Lakshmi, Chembolli

2013-01-01

Underlying hormone imbalances may render acne unresponsive to conventional therapy. Relevant investigations followed by initiation of hormonal therapy in combination with regular anti-acne therapy may be necessary if signs of hyperandrogenism are present. In addition to other factors, androgen-stimulated sebum production plays an important role in the pathophysiology of acne in women. Sebum production is also regulated by other hormones, including estrogens, growth hormone, insulin, insulin-like growth factor-1, glucocorticoids, adrenocorticotropic hormone, and melanocortins. Hormonal therapy may also be beneficial in female acne patients with normal serum androgen levels. An understanding of the sebaceous gland and the hormonal influences in the pathogenesis of acne would be essential for optimizing hormonal therapy. Sebocytes form the sebaceous gland. Human sebocytes express a multitude of receptors, including receptors for peptide hormones, neurotransmitters and the receptors for steroid and thyroid hormones. Various hormones and mediators acting through the sebocyte receptors play a role in the orchestration of pathogenetic lesions of acne. Thus, the goal of hormonal treatment is a reduction in sebum production. This review shall focus on hormonal influences in the elicitation of acne via the sebocyte receptors, pathways of cutaneous androgen metabolism, various clinical scenarios and syndromes associated with acne, and the available therapeutic armamentarium of hormones and drugs having hormone-like actions in the treatment of acne.

Status-Relevant Experiences and Conspicuous Consumption - the Moderating Role of Prenatal Androgen Exposure.

PubMed

Cornelissen, Gert; Palacios-Fenech, Javier

2016-09-20

In this paper we study consumers' interest in acquiring and displaying expensive luxury products. Based on recent insights in consumer psychology, which build on developments in evolutionary biology, we consider luxury products as "costly signals": wasteful and costly goods, whose purpose is to communicate one's biological fitness, and social status, to others. In line with previous research, we show that experiences that trigger mate attraction goals (Study 1: Exposure to others in bathing outfit) or status display goals (Study 2: Experiencing a vicarious victory of one's favorite sports team) can increase people's interest in luxury products. However, we demonstrate that some individuals are predictably more responsive to those experiences than others. We used a physiological measure (the proportion of the length of the index finger and ring finger of the right hand, 2D:4D) as a proxy for individual differences in exposure to prenatal androgens (i.e., testosterone). This measure has been related to dominant and competitive behavior later in life. We predict and find that individuals with a low 2D:4D (i.e., high exposure to prenatal androgens) were more responsive to the status-relevant experiences: they became more interested in luxury goods after these experiences. This was not the case for high 2D:4D individuals.

Selection shaped the evolution of mouse androgen-binding protein (ABP) function and promoted the duplication of Abp genes.

PubMed

Karn, Robert C; Laukaitis, Christina M

2014-08-01

In the present article, we summarize two aspects of our work on mouse ABP (androgen-binding protein): (i) the sexual selection function producing incipient reinforcement on the European house mouse hybrid zone, and (ii) the mechanism behind the dramatic expansion of the Abp gene region in the mouse genome. Selection unifies these two components, although the ways in which selection has acted differ. At the functional level, strong positive selection has acted on key sites on the surface of one face of the ABP dimer, possibly to influence binding to a receptor. A different kind of selection has apparently driven the recent and rapid expansion of the gene region, probably by increasing the amount of Abp transcript, in one or both of two ways. We have shown previously that groups of Abp genes behave as LCRs (low-copy repeats), duplicating as relatively large blocks of genes by NAHR (non-allelic homologous recombination). The second type of selection involves the close link between the accumulation of L1 elements and the expansion of the Abp gene family by NAHR. It is probably predicated on an initial selection for increased transcription of existing Abp genes and/or an increase in Abp gene number providing more transcriptional sites. Either or both could increase initial transcript production, a quantitative change similar to increasing the volume of a radio transmission. In closing, we also provide a note on Abp gene nomenclature.

Transition from androgenic to neurosteroidal action of 5α-androstane-3α, 17β-diol through the type A γ-aminobutyric acid receptor in prostate cancer progression.

PubMed

Xia, Ding; Lai, Doan V; Wu, Weijuan; Webb, Zachary D; Yang, Qing; Zhao, Lichao; Yu, Zhongxin; Thorpe, Jessica E; Disch, Bryan C; Ihnat, Michael A; Jayaraman, Muralidharan; Dhanasekaran, Danny N; Stratton, Kelly L; Cookson, Michael S; Fung, Kar-Ming; Lin, Hsueh-Kung

2018-04-01

Androgen ablation is the standard of care prescribed to patients with advanced or metastatic prostate cancer (PCa) to slow down disease progression. Unfortunately, a majority of PCa patients under androgen ablation progress to castration-resistant prostate cancer (CRPC). Several mechanisms including alternative intra-prostatic androgen production and androgen-independent androgen receptor (AR) activation have been proposed for CRPC progression. Aldo-keto reductase family 1 member C3 (AKR1C3), a multi-functional steroid metabolizing enzyme, is specifically expressed in the cytoplasm of PCa cells; and positive immunoreactivity of the type A γ-aminobutyric acid receptor (GABA A R), an ionotropic receptor and ligand-gated ion channel, is detected on the membrane of PCa cells. We studied a total of 72 radical prostatectomy cases by immunohistochemistry, and identified that 21 cases exhibited positive immunoreactivities for both AKR1C3 and GABA A R. In the dual positive cancer cases, AKR1C3 and GABA A R subunit α 1 were either expressed in the same cells or in neighboring cells. Among several possible substrates, AKR1C3 reduces 5α-dihydrotesterone (DHT) to form 5α-androstane-3α, 17β-diol (3α-diol). 3α-diol is a neurosteroid that acts as a positive allosteric modulator of the GABA A R in the central nervous system (CNS). We examined the hypothesis that 3α-diol-regulated pathological effects in the prostate are GABA A R-dependent, but are independent of the AR. In GABA A R-positive, AR-negative human PCa PC-3 cells, 3α-diol significantly stimulated cell growth in culture and the in ovo chorioallantoic membrane (CAM) xenograft model. 3α-diol also up-regulated expression of the epidermal growth factor (EGF) family of growth factors and activation of EGF receptor (EGFR) and Src as measured by quantitative polymerase chain reaction and immunoblotting, respectively. Inclusion of GABA A R antagonists reversed 3α-diol-stimulated tumor cell growth, expression of EGF family members, and activation of EGFR and Src to the level observed in untreated cells. Results from the present study suggest that 3α-diol may act as an alternative intra-prostatic neurosteroid that activates AR-independent PCa progression. The involvement of AKR1C3-mediated steroid metabolisms in modulating GABA A R activation and promoting PCa progression requires continued studies. Copyright © 2017 Elsevier Ltd. All rights reserved.

Plasmacytoid dendritic cell interferon-α production to R-848 stimulation is decreased in male infants

PubMed Central

2012-01-01

Background Sex differences in response to microbial infections, especially viral ones, may be associated with Toll-like receptor (TLR)-mediated responses by plasmacytoid dendritic cells (pDCs). Results In this study, we identified sex differences in human infant pDC interferon-α production following challenge with the TLR7/8 agonist R-848. Male pDC responses were significantly lower than those of females during early infancy. This difference may be attributed to the androgen surge experienced by males during the early infancy period. Pretreatment of human pDCs with dihydrotestosterone produced a significant reduction in interferon-α production following R-848 challenge. Conclusions Androgen-mediated regulation of pDC TLR7-driven innate immune responses may contribute to the observed sex differences in response to infections during early infancy. PMID:22769054

Inhibin removes the inhibitory effects of activin on steroid enzyme expression and androgen production by normal ovarian thecal cells

PubMed Central

Young, J M; McNeilly, A S

2012-01-01

Activin and inhibin are important local modulators of theca cell steroidogenesis in the ovary. Using a serum-free primary theca cell culture system, this study investigated the effects of inhibin on theca cell androgen production and expression of steroidogenic enzymes. Androstenedione secretion from theca cells cultured in media containing activin, inhibin and follistatin was assessed by RIA over 144 h. Activin (1–100 ng/ml) suppressed androstenedione production. Inhibin (1–100 ng/ml) blocked the suppressive effects of added activin, but increased androstenedione production when added alone, suggesting it was blocking endogenous activin produced by theca cells. Addition of SB-431542 (activin receptor inhibitor) and follistatin (500 ng/ml) increased androstenedione production, supporting this concept. Infection of theca cells with adenoviruses expressing inhibitory Smad6 or 7 increased androstenedione secretion, confirming that the suppressive effects of activin required activation of the Smad2/3 pathway. Activin decreased the expression levels of steroidogenic acute regulatory protein (STAR), whereas STAR expression was increased by inhibin and SB-431542, alone and in combination. CYP11A was unaffected. The expression of CYP17 encoding 17α-hydroxylase was unaffected by activin but increased by inhibin and SB-431542, and when added in combination the effect was further enhanced. The expression of 3β-hydroxysteroid dehydrogenase (3β-HSD) was significantly decreased by activin, while inhibin alone and in combination with SB-431542 both potently increased the expression of 3β-HSD. In conclusion, activin suppressed theca cell androstenedione production by decreasing the expression of STAR and 3β-HSD. Inhibin and other blockers of activin action reversed this effect, supporting the concept that endogenous thecal activin modulates androgen production in theca cells. PMID:22082494

Seminal Plasma Proteins as Androgen Receptor Coregulators Promote Prostate Cancer Growth

DTIC Science & Technology

2014-10-01

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

Selective androgen receptor modulators as function promoting therapies.

PubMed

Bhasin, Shalender; Jasuja, Ravi

2009-05-01

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

Brain connectivity aberrations in anabolic-androgenic steroid users.

PubMed

Westlye, Lars T; Kaufmann, Tobias; Alnæs, Dag; Hullstein, Ingunn R; Bjørnebekk, Astrid

2017-01-01

Sustained anabolic-androgenic steroid (AAS) use has adverse behavioral consequences, including aggression, violence and impulsivity. Candidate mechanisms include disruptions of brain networks with high concentrations of androgen receptors and critically involved in emotional and cognitive regulation. Here, we tested the effects of AAS on resting-state functional brain connectivity in the largest sample of AAS-users to date. We collected resting-state functional magnetic resonance imaging (fMRI) data from 151 males engaged in heavy resistance strength training. 50 users tested positive for AAS based on the testosterone to epitestosterone (T/E) ratio and doping substances in urine. 16 previous users and 59 controls tested negative. We estimated brain network nodes and their time-series using ICA and dual regression and defined connectivity matrices as the between-node partial correlations. In line with the emotional and behavioral consequences of AAS, current users exhibited reduced functional connectivity between key nodes involved in emotional and cognitive regulation, in particular reduced connectivity between the amygdala and default-mode network (DMN) and between the dorsal attention network (DAN) and a frontal node encompassing the superior and inferior frontal gyri (SFG/IFG) and the anterior cingulate cortex (ACC), with further reductions as a function of dependency, lifetime exposure, and cycle state (on/off).

The CAG polymorphism in androgen receptor (AR) gene impacts the moral permissibility of harmful behavior in females.

PubMed

Gong, Pingyuan; Fang, Pengpeng; Yang, Xing; Ru, Wenzhao; Wang, Bei; Gao, Xiaocai; Liu, Jinting

2017-06-01

The moral permissibility of harm is strikingly varied among individuals. In light of the connection between testosterone levels and utilitarian moral judgment, this study examined to what extent a CAG polymorphism in the androgen receptor gene, a genetic polymorphism with the ability to regulate testosterone function, contributes to individual differences in moral judgment. Four hundred and thirty-nine Chinese Han participants completed permissibility ratings of harm in moral dilemmas and moral transgression scenarios. Results showed a significant association between the CAG polymorphism and moral permissibility of harm in females. Females with more copies of the S allele, which is associated with higher availability of testosterone, were more likely to judge harmful utilitarian acts and unintentionally harmful acts as permissible, while these effects were absent in males. The findings provide the first evidence for a link between the androgen receptor gene and moral judgment and highlight the role of androgens in moral foundations. Copyright © 2017 Elsevier Ltd. All rights reserved.

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.

Next-generation steroidogenesis inhibitors, dutasteride and abiraterone, attenuate but still do not eliminate androgen biosynthesis in 22RV1 cells in vitro.

PubMed

Pham, Steven; Deb, Subrata; Ming, Dong Sheng; Adomat, Hans; Hosseini-Beheshti, Elham; Zoubeidi, Amina; Gleave, Martin; Guns, Emma S Tomlinson

2014-10-01

Castration resistant prostate cancer (CRPC) is often lethal and inevitably develops after androgen ablation therapy. However, in the majority of cases it remains androgen dependent. CRPC tumors have the ability to synthesize their own androgens from cholesterol by engaging in de novo steroidogenesis. We investigated the potential of 22RV1 prostate cancer cells to convert the supplemented steroid precursors within this pathway under the effects of current clinical steroidogenesis inhibitors such as abiraterone and dutasteride, either alone or in combination. Under steroid starved conditions, enzymes responsible for de novo steroidogenesis were upregulated. Testosterone and dihydrotestosterone (DHT) were formed by using both dehydroepiandrosterone (DHEA) and progesterone as substrates. Formation of testosterone and DHT was higher following incubation with DHEA compared to progesterone. Progesterone decreased the mRNA expression of enzymes responsible for steroidogenesis. Abiraterone treatment decreased testosterone production but increased several precursor steroids in both classical and backdoor pathways in the presence of progesterone. In contrast, the DHT levels were elevated following treatment with abiraterone when progesterone was absent. Dutasteride decreased the formation of testosterone, DHT and precursor steroids in the backdoor pathway but increased steroid precursors in the classical steroidogenesis pathway. The combination of abiraterone and dutasteride decreased testosterone and DHT in the presence of progesterone but increased DHT in the absence of progesterone. Abiraterone inhibited androgen receptor (AR) activation but not to the same extent as MDV3100. However, abiraterone and dutasteride treatment, either alone or in combination, were more effective in decreasing prostate specific antigen secretion into the media than MDV3100. Thus, while interventions with these drugs alone or in combination fail to completely inhibit steroidogenesis in the 22RV1 cells, the combined inhibition of androgen production and blockade of AR can exceed the effect of MDV3100. Further characterization of bypass mechanisms that may develop as a response to these inhibitors is necessary to achieve optimal suppression of testosterone and DHT synthesis as a part of therapeutic regimens for the treatment of CRPC. Copyright © 2014 Elsevier Ltd. All rights reserved.

Sphingosine kinase-1 mediates androgen-induced osteoblast cell growth

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

Martin, Claire; Universite de Toulouse, UPS, IPBS, Toulouse F-31000; Lafosse, Jean-Michel

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.

Selective androgen receptor modulators in preclinical and clinical development.

PubMed

Narayanan, Ramesh; Mohler, Michael L; Bohl, Casey E; Miller, Duane D; Dalton, James T

2008-01-01

Androgen receptor (AR) plays a critical role in the function of several organs including primary and accessory sexual organs, skeletal muscle, and bone, making it a desirable therapeutic target. Selective androgen receptor modulators (SARMs) bind to the AR and demonstrate osteo- and myo-anabolic activity; however, unlike testosterone and other anabolic steroids, these nonsteroidal agents produce less of a growth effect on prostate and other secondary sexual organs. SARMs provide therapeutic opportunities in a variety of diseases, including muscle wasting associated with burns, cancer, or end-stage renal disease, osteoporosis, frailty, and hypogonadism. This review summarizes the current standing of research and development of SARMs, crystallography of AR with SARMs, plausible mechanisms for their action and the potential therapeutic indications for this emerging class of drugs.

A giant ovarian cyst in a neonate with classical 21-hydroxylase deficiency with very high testosterone levels demonstrating a high-dose hook effect.

PubMed

Güran, Tülay; Yeşil, Gözde; Güran, Ömer; Cesur, Suna; Bosnalı, Oktav; Celayir, Ayşenur; Topçuoğlu, Sevilay; Bereket, Abdullah

2012-09-01

Congenital adrenal hyperplasia (CAH) is a group of disorders affecting the adrenal steroid synthesis. The most common form, 21-hydroxylase deficiency (21-OHD), leads to decreased production of cortisol and aldosterone with increased androgen secretion. In classic CAH, glucocorticoid treatment can be life-saving and serves to bring the symptoms under control. However, the treatment challenge is to effectively control the excess androgen effect by using the lowest possible glucocorticoid dose. Previous studies suggested a relationship between ovarian cyst formation and adrenal androgen excess, but neonatal large ovarian cysts have been very rarely reported in newborns with CAH. Here, we present the unique case of a neonate with classical 21-OHD who underwent surgery for a giant (10x8x7 cm) unilateral solitary ovarian follicular cyst on the 2nd postnatal day. Hormonal evaluation of the patient revealed high-dose hook effect for serum testosterone levels for the first time by a two-site immunoradiometric assay. Possible mechanisms by which androgen excess may cause ovarian cyst formation are discussed.

Methyltestosterone-induced transient hyperthyroidism in a hypothyroid patient.

PubMed

Krysiak, R; Okopien, B

2013-01-01

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

Selective modulation of the androgen receptor AF2 domain rescues degeneration in spinal bulbar muscular atrophy.

PubMed

Badders, Nisha M; Korff, Ane; Miranda, Helen C; Vuppala, Pradeep K; Smith, Rebecca B; Winborn, Brett J; Quemin, Emmanuelle R; Sopher, Bryce L; Dearman, Jennifer; Messing, James; Kim, Nam Chul; Moore, Jennifer; Freibaum, Brian D; Kanagaraj, Anderson P; Fan, Baochang; Tillman, Heather; Chen, Ping-Chung; Wang, Yingzhe; Freeman, Burgess B; Li, Yimei; Kim, Hong Joo; La Spada, Albert R; Taylor, J Paul

2018-05-01

Spinal bulbar muscular atrophy (SBMA) is a motor neuron disease caused by toxic gain of function of the androgen receptor (AR). Previously, we found that co-regulator binding through the activation function-2 (AF2) domain of AR is essential for pathogenesis, suggesting that AF2 may be a potential drug target for selective modulation of toxic AR activity. We screened previously identified AF2 modulators for their ability to rescue toxicity in a Drosophila model of SBMA. We identified two compounds, tolfenamic acid (TA) and 1-[2-(4-methylphenoxy)ethyl]-2-[(2-phenoxyethyl)sulfanyl]-1H-benzimidazole (MEPB), as top candidates for rescuing lethality, locomotor function and neuromuscular junction defects in SBMA flies. Pharmacokinetic analyses in mice revealed a more favorable bioavailability and tissue retention of MEPB compared with TA in muscle, brain and spinal cord. In a preclinical trial in a new mouse model of SBMA, MEPB treatment yielded a dose-dependent rescue from loss of body weight, rotarod activity and grip strength. In addition, MEPB ameliorated neuronal loss, neurogenic atrophy and testicular atrophy, validating AF2 modulation as a potent androgen-sparing strategy for SBMA therapy.

Comparison of the Effects of Dibutyl and Monobutyl Phthalates on the Steroidogenesis of Rat Immature Leydig Cells

PubMed Central

Li, Linxi; Chen, Xiaomin; Hu, Guoxin; Wang, Sicong; Xu, Renai; Zhu, Qiqi; Li, Xiaoheng; Wang, Mingcang; Lian, Qing-Quan; Ge, Ren-Shan

2016-01-01

Dibutyl phthalate (DBP) is a widely used synthetic phthalic diester and monobutyl phthalate (MBP) is its main metabolite. DBP can be released into the environment and potentially disrupting mammalian male reproductive endocrine system. However, the potencies of DBP and MBP to inhibit Leydig cell steroidogenesis and their possible mechanisms are not clear. Immature Leydig cells isolated from rats were cultured with 0.05–50 μM DBP or MBP for 3 h in combination with testosterone synthesis regulator or intermediate. The concentrations of 5α-androstanediol and testosterone in the media were measured, and the mRNA levels of the androgen biosynthetic genes were detected by qPCR. The direct actions of DBP or MBP on CYP11A1, CYP17A1, SRD5A1, and AKR1C14 activities were measured. MBP inhibited androgen production by the immature Leydig cell at as low as 50 nM, while 50 μM was required for DBP to suppress its androgen production. MBP mainly downregulated Cyp11a1 and Hsd3b1 expression levels at 50 nM. However, 50 μM DBP downregulated Star, Hsd3b1, and Hsd17b3 expression levels and directly inhibited CYP11A1 and CYP17A1 activities. In conclusion, DBP is metabolized to more potent inhibitor MBP that downregulated the expression levels of some androgen biosynthetic enzymes. PMID:27148549

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

Exercise improves quality of life in androgen deprivation therapy-treated prostate cancer: systematic review of randomised controlled trials.

PubMed

Teleni, Laisa; Chan, Raymond J; Chan, Alexandre; Isenring, Elisabeth A; Vela, Ian; Inder, Warrick J; McCarthy, Alexandra L

2016-02-01

Men receiving androgen deprivation therapy (ADT) for prostate cancer (PCa) are likely to develop metabolic conditions such as diabetes, cardiovascular disease, abdominal obesity and osteoporosis. Other treatment-related side effects adversely influence quality of life (QoL) including vasomotor distress, depression, anxiety, mood swings, poor sleep quality and compromised sexual function. The objective of this study was to systematically review the nature and effects of dietary and exercise interventions on QoL, androgen deprivation symptoms and metabolic risk factors in men with PCa undergoing ADT. An electronic search of CINAHL, CENTRAL, Medline, PsychINFO and reference lists was performed to identify peer-reviewed articles published between January 2004 and December 2014 in English. Eligible study designs included randomised controlled trials (RCTs) with pre- and post-intervention data. Data extraction and assessment of methodological quality with the Cochrane approach was conducted by two independent reviewers. Seven exercise studies were identified. Exercise significantly improved QoL, but showed no effect on metabolic risk factors (weight, waist circumference, lean or fat mass, blood pressure and lipid profile). Two dietary studies were identified, both of which tested soy supplements. Soy supplementation did not improve any outcomes. No dietary counselling studies were identified. No studies evaluated androgen-deficiency symptoms (libido, erectile function, sleep quality, mood swings, depression, anxiety and bone mineral density). Evidence from RCTs indicates that exercise enhances health- and disease-specific QoL in men with PCa undergoing ADT. Further studies are required to evaluate the effect of exercise and dietary interventions on QoL, androgen deprivation symptoms and metabolic risk factors in this cohort. © 2016 Society for Endocrinology.

Revascularization with percutaneous coronary intervention does not affect androgen status in males with chronic stable angina pectoris.

PubMed

Gosai, J N; Charalampidis, P; Nikolaidou, T; Parviz, Y; Morris, P D; Channer, K S; Jones, T H; Grech, E D

2016-05-01

There is a clear association between low serum testosterone and coronary artery disease (CAD) in men. Hypotestosteronaemia is associated with accelerated atherosclerosis and a quarter of men with CAD are biochemically hypogonadal. Amongst those with CAD, hypotestosteronaemia is associated with increased mortality. Testosterone vasodilates coronary arteries, and exogenous testosterone reduces ischaemia. Whether hypotestosteronaemia is a cause or a consequence of CAD remains unanswered. The aim of this prospective observational study was to investigate whether coronary revascularization affected androgen status in men with stable angina pectoris. Twenty five men (mean age 62.7, SD 9.18) with angiographically significant CAD and symptomatic angina underwent full coronary revascularization by percutaneous coronary intervention. Androgen status and symptoms of angina, stress, depression and sexual function were assessed before, and at one and 6 months after the coronary revascularization. All patients underwent complete revascularization which was associated with a significant reduction in angina symptoms and ischaemia. No significant difference was seen in total testosterone (11.33 nmol/L baseline; 12.56, 1 month post; 13.04 at 6 months; p = 0.08). A significant and sustained rise in sex hormone-binding globulin was seen (33.99 nm/L baseline; 36.11 nm/L 1 month post PCI; 37.94 nm/L at 6 months; p = 0.03) Overall, there was no significant alteration in any other marker of androgen status including free testosterone or bioavailable testosterone. There was no change in symptoms of anxiety, depression or sexual function. Coronary revascularization has no sustained effect on androgen status. This supports the hypothesis that hypotestosteronaemia is not a consequence of angina pectoris or myocardial ischaemia. © 2016 American Society of Andrology and European Academy of Andrology.

Gain in Transcriptional Activity by Primate-specific Coevolution of Melanoma Antigen-A11 and Its Interaction Site in Androgen Receptor*

PubMed Central

Liu, Qiang; Su, Shifeng; Blackwelder, Amanda J.; Minges, John T.; Wilson, Elizabeth M.

2011-01-01

Male sex development and growth occur in response to high affinity androgen binding to the androgen receptor (AR). In contrast to complete amino acid sequence conservation in the AR DNA and ligand binding domains among mammals, a primate-specific difference in the AR NH2-terminal region that regulates the NH2- and carboxyl-terminal (N/C) interaction enables direct binding to melanoma antigen-A11 (MAGE-11), an AR coregulator that is also primate-specific. Human, mouse, and rat AR share the same NH2-terminal 23FQNLF27 sequence that mediates the androgen-dependent N/C interaction. However, the mouse and rat AR FXXLF motif is flanked by Ala33 that evolved to Val33 in primates. Human AR Val33 was required to interact directly with MAGE-11 and for the inhibitory effect of the AR N/C interaction on activation function 2 that was relieved by MAGE-11. The functional importance of MAGE-11 was indicated by decreased human AR regulation of an androgen-dependent endogenous gene using lentivirus short hairpin RNAs and by the greater transcriptional strength of human compared with mouse AR. MAGE-11 increased progesterone and glucocorticoid receptor activity independently of binding an FXXLF motif by interacting with p300 and p160 coactivators. We conclude that the coevolution of the AR NH2-terminal sequence and MAGE-11 expression among primates provides increased regulatory control over activation domain dominance. Primate-specific expression of MAGE-11 results in greater steroid receptor transcriptional activity through direct interactions with the human AR FXXLF motif region and indirectly through steroid receptor-associated p300 and p160 coactivators. PMID:21730049

Ornithine Decarboxylase Activity Is Required for Prostatic Budding in the Developing Mouse Prostate

PubMed Central

Gamat, Melissa; Malinowski, Rita L.; Parkhurst, Linnea J.; Steinke, Laura M.; Marker, Paul C.

2015-01-01

The prostate is a male accessory sex gland that produces secretions in seminal fluid to facilitate fertilization. Prostate secretory function is dependent on androgens, although the mechanism by which androgens exert their effects is still unclear. Polyamines are small cationic molecules that play pivotal roles in DNA transcription, translation and gene regulation. The rate-limiting enzyme in polyamine biosynthesis is ornithine decarboxylase, which is encoded by the gene Odc1. Ornithine decarboxylase mRNA decreases in the prostate upon castration and increases upon administration of androgens. Furthermore, testosterone administered to castrated male mice restores prostate secretory activity, whereas administering testosterone and the ornithine decarboxylase inhibitor D,L-α-difluromethylornithine (DFMO) to castrated males does not restore prostate secretory activity, suggesting that polyamines are required for androgens to exert their effects. To date, no one has examined polyamines in prostate development, which is also androgen dependent. In this study, we showed that ornithine decarboxylase protein was expressed in the epithelium of the ventral, dorsolateral and anterior lobes of the adult mouse prostate. Ornithine decarboxylase protein was also expressed in the urogenital sinus (UGS) epithelium of the male and female embryo prior to prostate development, and expression continued in prostatic epithelial buds as they emerged from the UGS. Inhibiting ornithine decarboxylase using DFMO in UGS organ culture blocked the induction of prostatic buds by androgens, and significantly decreased expression of key prostate transcription factor, Nkx3.1, by androgens. DFMO also significantly decreased the expression of developmental regulatory gene Notch1. Other genes implicated in prostatic development including Sox9, Wif1 and Srd5a2 were unaffected by DFMO. Together these results indicate that Odc1 and polyamines are required for androgens to exert their effect in mediating prostatic bud induction, and are required for the expression of a subset of prostatic developmental regulatory genes including Notch1 and Nkx3.1. PMID:26426536

Maternal gestational androgens are associated with decreased juvenile play in white-faced marmosets (Callithrix geoffroyi)

PubMed Central

Birnie, Andrew K.; Hendricks, Shelton E.; Smith, Adam S.; Milam, Ross; French, Jeffrey A.

2013-01-01

Exposure to androgens during prenatal development shapes both physiological and behavioral developmental trajectories. Notably, in rhesus macaques, prenatal androgen exposure has been shown to increase rough-and-tumble play, a prominent behavioral feature in males during the juvenile period in primates. While macaques are an Old World, polygamous species with marked sexually dimorphic behavior, New World callitrichine primates (marmosets and tamarins) live in cooperative breeding groups and are considered to be socially monogamous and exhibit minimal sexual dimorphism in social play, which suggests that androgen may affect this species in different ways compared to macaques. In addition, we previously described considerable variation in maternal androgen production during gestation in marmosets. Here we tested the association between this variation and variation in offspring rough-and-tumble play patterns in both males and females. We measured testosterone and androstenedione levels in urine samples collected from pregnant marmoset mothers and then observed their offspring's play behavior as juveniles (5–10 months of age). In contrast to findings in rhesus macaques, hierarchical regression analyses showed that higher gestational testosterone levels, primarily in the second semester, were associated with decreased rough-and-tumble play in juveniles, and this relationship appears to be driven more so by males than females. We found no reliable associations between gestational androstenedione and juvenile play behavior. Our findings provide evidence to suggest that normative variation in levels of maternal androgen during gestation may influence developmental behavioral trajectories in marmosets in a way that contradicts previous findings in Old World primates. PMID:22705955

A new highly specific and robust yeast androgen bioassay for the detection of agonists and antagonists

PubMed Central

Helsdingen, Richard J. R.; Hamers, Astrid R. M.; van Duursen, Majorie B. M.; Nielen, Michel W. F.; Hoogenboom, Ron L. A. P.

2007-01-01

Public concern about the presence of natural and anthropogenic compounds which affect human health by modulating normal endocrine functions is continuously growing. Fast and simple high-throughput screening methods for the detection of hormone activities are thus indispensable. During the last two decades, a panel of different in vitro assays has been developed, mainly for compounds with an estrogenic mode of action. Here we describe the development of an androgen transcription activation assay that is easy to use in routine screening. Recombinant yeast cells were constructed that express the human androgen receptor and yeast enhanced green fluorescent protein (yEGFP), the latter in response to androgens. Compared with other reporters, the yEGFP reporter protein is very convenient because it is directly measurable in intact living cells, i.e., cell wall disruption and the addition of a substrate are not needed. When yeast was exposed to 17β-testosterone, the concentration where half-maximal activation is reached (EC50) was 50 nM. The relative androgenic potencies, defined as the ratio between the EC50 of 17β-testosterone and the EC50 of the compound, of 5α-dihydrotestosterone, methyltrienolone, and 17β-boldenone are 2.3, 1.4, and 0.15 respectively. The results presented in this paper demonstrate that this new yeast androgen bioassay is fast, sensitive, and very specific and also suited to detect compounds that have an antiandrogenic mode of action. PMID:17849102

CaM kinase kinase beta-mediated activation of the growth regulatory kinase AMPK is required for androgen-dependent migration of prostate cancer cells.

PubMed

Frigo, Daniel E; Howe, Matthew K; Wittmann, Bryan M; Brunner, Abigail M; Cushman, Ian; Wang, Qianben; Brown, Myles; Means, Anthony R; McDonnell, Donald P

2011-01-15

While patients with advanced prostate cancer initially respond favorably to androgen ablation therapy, most experience a relapse of the disease within 1-2 years. Although hormone-refractory disease is unresponsive to androgen-deprivation, androgen receptor (AR)-regulated signaling pathways remain active and are necessary for cancer progression. Thus, both AR itself and the processes downstream of the receptor remain viable targets for therapeutic intervention. Microarray analysis of multiple clinical cohorts showed that the serine/threonine kinase Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ) is both highly expressed in the prostate and further elevated in prostate cancers. Using cellular models of prostate cancer, we have determined that androgens (a) directly increase the expression of a CaMKKβ splice variant and (b) increase functional CaMKKβ protein levels as determined by the phosphorylation of both CaMKI and AMP-activated protein kinase (AMPK), two of CaMKKβ's primary substrates. Importantly, inhibition of the CaMKKβ-AMPK, but not CaMKI, signaling axis in prostate cancer cells by pharmacological inhibitors or siRNA-mediated knockdown blocks androgen-mediated migration and invasion. Conversely, overexpression of CaMKKβ alone leads to both increased AMPK phosphorylation and cell migration. Given the key roles of CaMKKβ and AMPK in the biology of prostate cancer cells, we propose that these enzymes are potential therapeutic targets in prostate cancer. © 2010 AACR.

Male patients with partial androgen insensitivity syndrome: a longitudinal follow-up of growth, reproductive hormones and the development of gynaecomastia.

PubMed

Hellmann, Philip; Christiansen, Peter; Johannsen, Trine Holm; Main, Katharina M; Duno, Morten; Juul, Anders

2012-05-01

To describe the natural history of phenotype, growth and gonadal function in patients with partial androgen insensitivity syndrome. Tertiary paediatric endocrine centre. Retrospective evaluation of 14 male patients with partial androgen insensitivity syndrome (PAIS) with verified androgen receptor (AR) mutations. The authors recorded phenotypic characteristics at birth and external masculinisation score (EMS), registered longitudinal growth, circulating levels of testosterone, estradiol, luteinising hormone (LH), follicle-stimulating hormone (FSH), inhibin-B and sex hormone binding globulin (SHBG), in addition to phenotype at postpubertal follow up. The EMS ranged from 5 to 12 in PAIS at birth. Six patients were born with hypospadias and all patients developed gynaecomastia in puberty. Eight of the patients received testosterone treatment. At follow-up penile size was impaired irrespective of EMS at birth, but responded to pubertal androgen therapy in some of the patients. Serum levels of testosterone, estradiol, SHBG and LH, but not FSH and inhibin B, were markedly elevated in puberty. Final height was 181.3 cm (165.7-190.5 cm) corresponding to an SD score of 0.7 (-2.1 to +2.1 SD, n=10). Gynaecomastia and impaired phallic growth are frequently observed in adults with PAIS, but may be ameliorated by androgen therapy. The authors suggest that male patients presenting with gynaecomastia in puberty, and elevated circulating levels of testosterone, estradiol and LH in puberty, but normal FSH, should be suspected of having PAIS and undergo genetic testing for AR mutations.

Androgen excess in women: experience with over 1000 consecutive patients.

PubMed

Azziz, R; Sanchez, L A; Knochenhauer, E S; Moran, C; Lazenby, J; Stephens, K C; Taylor, K; Boots, L R

2004-02-01

The objective of the present study was to estimate the prevalence of the different pathological conditions causing clinically evident androgen excess and to document the degree of long-term success of suppressive and/or antiandrogen hormonal therapy in a large consecutive population of patients. All patients presenting for evaluation of symptoms potentially related to androgen excess between October 1987 and June 2002 were evaluated, and the data were maintained prospectively in a computerized database. For the assessment of therapeutic response, a retrospective review of the medical chart was performed, after the exclusion of those patients seeking fertility therapy only, or with inadequate follow-up or poor compliance. A total of 1281 consecutive patients were seen during the study period. Excluded from analysis were 408 patients in whom we were unable to evaluate hormonal status, determine ovulatory status, or find any evidence of androgen excess. In the remaining population of 873 patients, the unbiased prevalence of androgen-secreting neoplasms was 0.2%, 21-hydroxylase-deficient classic adrenal hyperplasia (CAH) was 0.6%, 21-hydroxylase-deficient nonclassic adrenal hyperplasia (NCAH) was 1.6%, hyperandrogenic insulin-resistant acanthosis nigricans (HAIRAN) syndrome was 3.1%, idiopathic hirsutism was 4.7%, and polycystic ovary syndrome (PCOS) was 82.0%. Fifty-nine (6.75%) patients had elevated androgen levels and hirsutism but normal ovulation. A total of 257 patients were included in the assessment of the response to hormonal therapy. The mean duration of follow-up was 33.5 months (range, 6-155). Hirsutism improved in 86%, menstrual dysfunction in 80%, acne in 81%, and hair loss in 33% of patients. The major side effects noted were irregular vaginal bleeding (16.1%), nausea (13.0%), and headaches (12.6%); only 36.6% of patients never complained of side effects. In this large study of consecutive patients presenting with clinically evident androgen excess, specific identifiable disorders (NCAH, CAH, HAIRAN syndrome, and androgen-secreting neoplasms) were observed in approximately 7% of subjects, whereas functional androgen excess, principally PCOS, was observed in the remainder. Hirsutism, menstrual dysfunction, or acne, but not alopecia, improved in the majority of patients treated with a combination suppressive therapy; although more than 60% experienced side effects.

Putative Prostate Cancer Risk SNP in an Androgen Receptor‐Binding Site of the Melanophilin Gene Illustrates Enrichment of Risk SNPs in Androgen Receptor Target Sites

PubMed Central

Bu, Huajie; Narisu, Narisu; Schlick, Bettina; Rainer, Johannes; Manke, Thomas; Schäfer, Georg; Pasqualini, Lorenza; Chines, Peter; Schweiger, Michal R.; Fuchsberger, Christian

2015-01-01

ABSTRACT Genome‐wide association studies have identified genomic loci, whose single‐nucleotide polymorphisms (SNPs) predispose to prostate cancer (PCa). However, the mechanisms of most of these variants are largely unknown. We integrated chromatin‐immunoprecipitation‐coupled sequencing and microarray expression profiling in TMPRSS2‐ERG gene rearrangement positive DUCaP cells with the GWAS PCa risk SNPs catalog to identify disease susceptibility SNPs localized within functional androgen receptor‐binding sites (ARBSs). Among the 48 GWAS index risk SNPs and 3,917 linked SNPs, 80 were found located in ARBSs. Of these, rs11891426:T>G in an intron of the melanophilin gene (MLPH) was within a novel putative auxiliary AR‐binding motif, which is enriched in the neighborhood of canonical androgen‐responsive elements. T→G exchange attenuated the transcriptional activity of the ARBS in an AR reporter gene assay. The expression of MLPH in primary prostate tumors was significantly lower in those with the G compared with the T allele and correlated significantly with AR protein. Higher melanophilin level in prostate tissue of patients with a favorable PCa risk profile points out a tumor‐suppressive effect. These results unravel a hidden link between AR and a functional putative PCa risk SNP, whose allele alteration affects androgen regulation of its host gene MLPH. PMID:26411452

Human PIRH2 Enhances Androgen Receptor Signaling through Inhibition of Histone Deacetylase 1 and Is Overexpressed in Prostate Cancer

PubMed Central

Logan, Ian R.; Gaughan, Luke; McCracken, Stuart R. C.; Sapountzi, Vasileia; Leung, Hing Y.; Robson, Craig N.

2006-01-01

The androgen receptor (AR) is a hormone-dependent transcription factor critically involved in human prostate carcinogenesis. Optimal transcriptional control of androgen-responsive genes by AR may require complex interaction among multiple coregulatory proteins. We have previously shown that the AR coregulator TIP60 can interact with human PIRH2 (hPIRH2). In this study, we uncover important new functional role(s) for hPIRH2 in AR signaling: (i) hPIRH2 interacts with AR and enhances AR-mediated transcription with a dynamic pattern of recruitment to androgen response elements in the prostate-specific antigen (PSA) gene; (ii) hPIRH2 interacts with the AR corepressor HDAC1, leading to reduced HDAC1 protein levels and inhibition of transcriptional repression; (iii) hPIRH2 is required for optimal PSA expression; and (iv) hPIRH2 is involved in prostate cancer cell proliferation. In addition, overexpression of hPIRH2 protein was detected in 73 of 82 (89%) resected prostate cancers, with a strong correlation between increased hPIRH2 expression and aggressive disease, as signified by high Gleason sum scores and the presence of metastatic disease (P = <0.0001 and 0.0004, respectively). Collectively, our data establish hPIRH2 as a key modulator of AR function, opening a new direction for targeted therapy in aggressive human prostate cancer. PMID:16914734

Human PIRH2 enhances androgen receptor signaling through inhibition of histone deacetylase 1 and is overexpressed in prostate cancer.

PubMed

Logan, Ian R; Gaughan, Luke; McCracken, Stuart R C; Sapountzi, Vasileia; Leung, Hing Y; Robson, Craig N

2006-09-01

The androgen receptor (AR) is a hormone-dependent transcription factor critically involved in human prostate carcinogenesis. Optimal transcriptional control of androgen-responsive genes by AR may require complex interaction among multiple coregulatory proteins. We have previously shown that the AR coregulator TIP60 can interact with human PIRH2 (hPIRH2). In this study, we uncover important new functional role(s) for hPIRH2 in AR signaling: (i) hPIRH2 interacts with AR and enhances AR-mediated transcription with a dynamic pattern of recruitment to androgen response elements in the prostate-specific antigen (PSA) gene; (ii) hPIRH2 interacts with the AR corepressor HDAC1, leading to reduced HDAC1 protein levels and inhibition of transcriptional repression; (iii) hPIRH2 is required for optimal PSA expression; and (iv) hPIRH2 is involved in prostate cancer cell proliferation. In addition, overexpression of hPIRH2 protein was detected in 73 of 82 (89%) resected prostate cancers, with a strong correlation between increased hPIRH2 expression and aggressive disease, as signified by high Gleason sum scores and the presence of metastatic disease (P = <0.0001 and 0.0004, respectively). Collectively, our data establish hPIRH2 as a key modulator of AR function, opening a new direction for targeted therapy in aggressive human prostate cancer.

Regulation of androgen receptor and histone deacetylase 1 by Mdm2-mediated ubiquitylation.

PubMed

Gaughan, Luke; Logan, Ian R; Neal, David E; Robson, Craig N

2005-01-01

The androgen receptor (AR) is a member of the nuclear hormone receptor family of transcription factors and plays a critical role in regulating the expression of genes involved in androgen-dependent and -independent tumour formation. Regulation of the AR is achieved by alternate binding of either histone acetyltransferase (HAT)-containing co-activator proteins, or histone deacetylase 1 (HDAC1). Factors that control AR stability may also constitute an important regulatory mechanism, a notion that has been confirmed with the finding that the AR is a direct target for Mdm2-mediated ubiquitylation and proteolysis. Using chromatin immunoprecipitation (ChIP) and re-ChIP analyses, we show that Mdm2 associates with AR and HDAC1 at the active androgen-responsive PSA promoter in LNCaP prostate cancer cells. Furthermore, we demonstrate that Mdm2-mediated modification of AR and HDAC1 catalyses protein destabilization and attenuates AR sactivity, suggesting that ubiquitylation of the AR and HDAC1 may constitute an additional mechanism for regulating AR function. We also show that HDAC1 and Mdm2 function co-operatively to reduce AR-mediated transcription that is attenuated by the HAT activity of the AR co-activator Tip60, suggesting interplay between acetylation status and receptor ubiquitylation in AR regulation. In all, our data indicates a novel role for Mdm2 in regulating components of the AR transcriptosome.

Neural Activation During Mental Rotation in Complete Androgen Insensitivity Syndrome: The Influence of Sex Hormones and Sex Chromosomes.

PubMed

van Hemmen, Judy; Veltman, Dick J; Hoekzema, Elseline; Cohen-Kettenis, Peggy T; Dessens, Arianne B; Bakker, Julie

2016-03-01

Sex hormones, androgens in particular, are hypothesized to play a key role in the sexual differentiation of the human brain. However, possible direct effects of the sex chromosomes, that is, XX or XY, have not been well studied in humans. Individuals with complete androgen insensitivity syndrome (CAIS), who have a 46,XY karyotype but a female phenotype due to a complete androgen resistance, enable us to study the separate effects of gonadal hormones versus sex chromosomes on neural sex differences. Therefore, in the present study, we compared 46,XY men (n = 30) and 46,XX women (n = 29) to 46,XY individuals with CAIS (n = 21) on a mental rotation task using functional magnetic resonance imaging. Previously reported sex differences in neural activation during mental rotation were replicated in the control groups, with control men showing more activation in the inferior parietal lobe than control women. Individuals with CAIS showed a female-like neural activation pattern in the parietal lobe, indicating feminization of the brain in CAIS. Furthermore, this first neuroimaging study in individuals with CAIS provides evidence that sex differences in regional brain function during mental rotation are most likely not directly driven by genetic sex, but rather reflect gonadal hormone exposure. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Association of androgen metabolism gene polymorphisms with prostate cancer risk and androgen concentrations: Results from the Prostate Cancer Prevention Trial.

PubMed

Price, Douglas K; Chau, Cindy H; Till, Cathee; Goodman, Phyllis J; Leach, Robin J; Johnson-Pais, Teresa L; Hsing, Ann W; Hoque, Ashraful; Parnes, Howard L; Schenk, Jeannette M; Tangen, Catherine M; Thompson, Ian M; Reichardt, Juergen K V; Figg, William D

2016-08-01

Prostate cancer is highly influenced by androgens and genes. The authors investigated whether genetic polymorphisms along the androgen biosynthesis and metabolism pathways are associated with androgen concentrations or with the risk of prostate cancer or high-grade disease from finasteride treatment. A nested case-control study from the Prostate Cancer Prevention Trial using data from men who had biopsy-proven prostate cancer (cases) and a group of biopsy-negative, frequency-matched controls was conducted to investigate the association of 51 single nucleotide polymorphisms (SNPs) in 12 genes of the androgen pathway with overall (total), low-grade, and high-grade prostate cancer incidence and serum hormone concentrations. There were significant associations of genetic polymorphisms in steroid 5α-reductase 1 (SRD5A1) (reference SNPs: rs3736316, rs3822430, rs1560149, rs248797, and rs472402) and SRD5A2 (rs2300700) with the risk of high-grade prostate cancer in the placebo arm of the Prostate Cancer Prevention Trial; 2 SNPs were significantly associated with an increased risk (SRD5A1 rs472402 [odds ratio, 1.70; 95% confidence interval, 1.05-2.75; Ptrend = .03] and SRD5A2 rs2300700 [odds ratio, 1.94; 95% confidence interval, 1.19-3.18; Ptrend = .01]). Eleven SNPs in SRD5A1, SRD5A2, cytochrome P450 family 1, subfamily B, polypeptide 1 (CYP1B1), and CYP3A4 were associated with modifying the mean concentrations of serum androgen and sex hormone-binding globulin; and 2 SNPs (SRD5A1 rs824811 and CYP1B1 rs10012; Ptrend < .05) consistently and significantly altered all androgen concentrations. Several SNPs (SRD5A1 rs3822430, SRD5A2 rs2300700, CYP3A43 rs800672, and CYP19 rs700519; Ptrend < .05) were significantly associated with both circulating hormone levels and prostate cancer risk. Germline genetic variations of androgen-related pathway genes are associated with serum androgen concentrations and the risk of prostate cancer. Further studies to examine the functional consequence of novel causal variants are warranted. Cancer 2016;122:2332-2340. © 2016 American Cancer Society. © 2016 American Cancer Society.

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

PubMed Central

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

2014-01-01

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

Regulation of apical blebbing in the porcine epididymis.

PubMed

Hughes, Jennifer R; Berger, Trish

2018-03-01

Apical blebbing, a non-classical secretion mechanism, occurs in the mature porcine epididymis as part of its normal function. Proteins secreted by this mechanism contribute to the modification of the sperm plasma membrane during epididymal transit and are thought to contribute to acquisition of fertilizing ability. However, little is known about the regulation of this secretion mechanism in an in vivo model. Previous work demonstrated apical blebbing in the epididymis developed pubertally, suggesting androgens, sperm or other luminal factors regulated this process. Hence, the objective was to evaluate the hypothesized regulation of apical blebbing in the epididymis of pubertal boars by androgens and luminal factors. Androgen receptor blockade (flutamide) and surgical interventions (efferent duct ligation, orchidectomy or transection of the caput epididymis) were used to alter signaling, and the subsequent effects on apical blebbing were evaluated histologically. Apical blebbing was not altered by androgen receptor blockade with flutamide, but was significantly reduced 24 h after efferent duct ligation and after orchidectomy, treatments that eliminated luminal flow from the testis (P < 0.05). Like efferent duct ligation, epididymal transection altered luminal flow without removing the androgen source and significantly reduced the appearance of apical blebbing (P < 0.05). In conclusion, apical blebbing in the porcine epididymis appears to be regulated by luminal factors. © 2017 Anatomical Society.

Synthetic anabolic agents: steroids and nonsteroidal selective androgen receptor modulators.

PubMed

Thevis, Mario; Schänzer, Wilhelm

2010-01-01

The central role of testosterone in the development of male characteristics, as well as its beneficial effects on physical performance and muscle growth, has led to the search for synthetic alternatives with improved pharmacological profiles. Hundreds of steroidal analogs have been prepared with a superior oral bioavailability, which should also possess reduced undesirable effects. However, only a few entered the pharmaceutical market due to severe toxicological incidences that were mainly attributed to the lack of tissue selectivity. Prominent representatives of anabolic-androgenic steroids (AAS) are for instance methyltestosterone, metandienone and stanozolol, which are discussed as model compounds with regard to general pharmacological aspects of synthetic AAS. Recently, nonsteroidal alternatives to AAS have been developed that selectively activate the androgen receptor in either muscle tissue or bones. These so-called selective androgen receptor modulators (SARMs) are currently undergoing late clinical trials (IIb) and will be prohibited by the World Anti-Doping Agency from January 2008. Their entirely synthetic structures are barely related to steroids, but particular functional groups allow for the tissue-selective activation or inhibition of androgen receptors and, thus, the stimulation of muscle growth without the risk of severe undesirable effects commonly observed in steroid replacement therapies. Hence, these compounds possess a high potential for misuse in sports and will be the subject of future doping control assays.

Identification of candidate reference chemicals for in vitro steroidogenesis assays.

PubMed

Pinto, Caroline Lucia; Markey, Kristan; Dix, David; Browne, Patience

2018-03-01

The Endocrine Disruptor Screening Program (EDSP) is transitioning from traditional testing methods to integrating ToxCast/Tox21 in vitro high-throughput screening assays for identifying chemicals with endocrine bioactivity. The ToxCast high-throughput H295R steroidogenesis assay may potentially replace the low-throughput assays currently used in the EDSP Tier 1 battery to detect chemicals that alter the synthesis of androgens and estrogens. Herein, we describe an approach for identifying in vitro candidate reference chemicals that affect the production of androgens and estrogens in models of steroidogenesis. Candidate reference chemicals were identified from a review of H295R and gonad-derived in vitro assays used in methods validation and published in the scientific literature. A total of 29 chemicals affecting androgen and estrogen levels satisfied all criteria for positive reference chemicals, while an additional set of 21 and 15 chemicals partially fulfilled criteria for positive reference chemicals for androgens and estrogens, respectively. The identified chemicals included pesticides, pharmaceuticals, industrial and naturally-occurring chemicals with the capability to increase or decrease the levels of the sex hormones in vitro. Additionally, 14 and 15 compounds were identified as potential negative reference chemicals for effects on androgens and estrogens, respectively. These candidate reference chemicals will be informative for performance-based validation of in vitro steroidogenesis models. Copyright © 2017. Published by Elsevier Ltd.

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

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.

The effects of simvastatin and dipentyl phthalate on fetal cholesterol and testosterone production

EPA Science Inventory

Sex differentiation of the male reproductive tract in mammals is driven, in part, by fetal androgen production. In utero, some phthalate esters (PEs) alter fetal Leydig cell differentiation, reducing the expression of genes associated with steroid synthesis/transport, and conseq...

Sex differences in the effects of androgens acting in the central nervous system on metabolism

PubMed Central

Morford, Jamie; Mauvais-Jarvis, Franck

2016-01-01

One of the most sexually dimorphic aspects of metabolic regulation is the bidirectional modulation of glucose and energy homeostasis by testosterone in males and females. Testosterone deficiency predisposes men to metabolic dysfunction, with excess adiposity, insulin resistance, and type 2 diabetes, whereas androgen excess predisposes women to insulin resistance, adiposity, and type 2 diabetes. This review discusses how testosterone acts in the central nervous system, and especially the hypothalamus, to promote metabolic homeostasis or dysfunction in a sexually dimorphic manner. We compare the organizational actions of testosterone, which program the hypothalamic control of metabolic homeostasis during development, and the activational actions of testosterone, which affect metabolic function after puberty. We also discuss how the metabolic effect of testosterone is centrally mediated via the androgen receptor. PMID:28179813

[The impact of the androgen receptor splice variant AR-V7 on the prognosis and treatment of advanced prostate cancer].

PubMed

Thelen, P; Taubert, H; Duensing, S; Kristiansen, G; Merseburger, A S; Cronauer, M V

2018-01-25

A recently discovered mechanism enabling prostate cancer cells to escape the effects of endocrine therapies consists in the synthesis of C-terminally truncated, constitutively active androgen receptor (AR) splice variants (AR-V). Devoid of a functional C-terminal hormone/ligand binding domain, various AR-Vs are insensitive to therapies targeting the androgen/AR signalling axis. Preliminary studies suggest that AR-V7, the most common AR-V, is a promising predictive tumour marker and a relevant selection marker for the treatment of advanced prostate cancer. This review critically outlines recent advances in AR-V7 diagnostics and presents an overview of current AR-V7 targeted therapies. © Georg Thieme Verlag KG Stuttgart · New York.

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

Childhood Obesity and Its Impact on the Development of Adolescent PCOS

PubMed Central

Anderson, Amy D.; Solorzano, Christine M. Burt; McCartney, Christopher R.

2014-01-01

Obesity exacerbates the reproductive and metabolic manifestations of polycystic ovary syndrome (PCOS). The symptoms of PCOS often begin in adolescence, and the rising prevalence of peripubertal obesity has prompted concern that the prevalence and severity of adolescent PCOS is increasing in parallel. Recent data have disclosed a high prevalence of hyperandrogenemia among peripubertal adolescents with obesity, suggesting that such girls are indeed at risk for developing PCOS. Obesity may impact the risk of PCOS via insulin resistance and compensatory hyperinsulinemia, which augments ovarian/adrenal androgen production and suppresses sex hormone–binding globulin (SHBG), thereby increasing androgen bioavailability. Altered luteinizing hormone (LH) secretion plays an important role in the pathophysiology of PCOS, and although obesity is generally associated with relative reductions of LH, higher LH appears to be the best predictor of increased free testosterone among peripubertal girls with obesity. Other potential mechanisms of obesity-associated hyperandrogenemia include enhanced androgen production in an expanded fat mass and potential effects of abnormal adipokine/cytokine levels. Adolescents with PCOS are at risk for comorbidities such as metabolic syndrome and impaired glucose tolerance, and concomitant obesity compounds these risks. For all of these reasons, weight loss represents an important therapeutic target in obese adolescents with PCOS. PMID:24715515

Evaluation of effects of an oral contraceptive containing ethinylestradiol combined with drospirenone on adrenal steroidogenesis in hyperandrogenic women with polycystic ovary syndrome.

PubMed

De Leo, Vincenzo; Morgante, Giuseppe; Piomboni, Paola; Musacchio, Maria Concetta; Petraglia, Felice; Cianci, Antonio

2007-07-01

To investigate whether the administration of an oral contraceptive containing the new antiandrogenic drospirenone is associated with reduced adrenal androgen synthesis in hyperandrogenic women with diagnosis of polycystic ovary syndrome. Drospirenone, an analogue of spironolactone and aldosterone antagonist, is a novel progestin under clinical development that is similar to the natural hormone progesterone, combining potent progestogenic with antimineralocorticoid and antiandrogenic activities. Prospective study. Healthy volunteers in University Department of Obstetrics and Gynecology. Fifteen women ages 18 to 28 years with the diagnosis of polycystic ovary syndrome. Three months of contraceptive use (30 mcg ethinylestradiol, 3 mg drospirenone). An adrenocorticotropic hormone test was performed before and after the study. Adrenal production of cortisol was unchanged after therapy with oral contraceptives. An interesting observation was reduced basal concentrations of androgens such as androstenedione, dehydroepiandrosterone sulfate, testosterone, and free testosterone during therapy. The ratios of the areas of substrates to products before and after oral contraceptive administration were compared for differences in 17alpha-hydroxylase (17-hydroxyprogesterone/progesterone) and 17,20-lyase (androstenedione/17-hydroxyprogesterone); activities were significantly reduced, indicating a reduction in the activities of these enzymes. The present results show for the first time that oral contraceptives containing drospirenone affect adrenal steroidogenesis by reducing synthesis and release of androgens in response to adrenocorticotropic hormone, leaving adrenal production of cortisol unchanged.

Androgen and glucocorticoid production in the male killer whale (Orcinus orca): influence of age, maturity, and environmental factors.

PubMed

O'Brien, J K; Steinman, K J; Fetter, G A; Robeck, T R

2017-01-01

Circulating concentrations of testosterone and its precursor androstenedione, as well as dehydroepiandrosterone (DHEA) and the adrenal hormones cortisol and corticosterone were measured at monthly intervals in 14 male killer whales (Orcinus orca) aged 0.8-38 years. Analyses were performed for examination of the relationships of age, sexual maturation status (STATUS), season, and environmental temperature (monthly air ambient temperature, A-TEMP) with hormone production using a mixed effects linear regression model with animal ID as the random variable. Hormone profiles, derived from enzyme immunoassay procedures validated herein, established that simultaneous up-regulation of androstenedione and testosterone production occurs at puberty, when males are aged 8-12 years. Androgen (testosterone and androstenedione) production in pubertal and adult males was influenced by season, with highest (p < 0.01) concentrations observed in spring and summer months. A significant effect of STATUS and season on DHEA production was also documented, with higher (p < 0.05) concentrations in pubertal and adult males compared to juvenile males, and higher (p < 0.05) concentrations in the months of summer than the fall. Among adult males (≥13 years), those classified as aged (≥31 years) had concentrations of testosterone and both glucocorticoids that were lower (p < 0.05), and those of androstenedione that were higher (p < 0.05) than their younger counterparts. The cortisol:corticosterone ratio for adult males was 7 : 1, and both glucocorticoids were affected by STATUS (p < 0.05), but not season or A-TEMP. Results of this research enhance our understanding of reproductive and adrenocortical function in healthy male killer whales and provide baseline profiles of hormone production for use in the species' health assessment and conservation. © 2016 American Society of Andrology and European Academy of Andrology.

Elevated serum progastrin-releasing peptide (31-98) in metastatic and androgen-independent prostate cancer patients.

PubMed

Yashi, Masahiro; Muraishi, Osamu; Kobayashi, Yutaka; Tokue, Akihiko; Nanjo, Hiroshi

2002-05-01

Increases in neuroendocrine phenotype and secretory products are closely correlated with tumor progression and androgen independence in prostate cancer. In this study, we explored this correlation using serum progastrin-releasing peptide (ProGRP), a carboxy-terminal region common to three subtypes of precursors for gastrin-releasing peptide (GRP), which is released from the neuroendocrine phenotype to act as a growth factor. In 60 patients with benign prostatic hyperplasia (BPH) and 200 with prostate cancer, serum ProGRP levels were determined with an enzyme-linked immunosorbent assay (ELISA) kit and evaluated in relation to clinical stage, hormonal treatment, and prostate-specific antigen (PSA) values. Fourteen randomly selected patients were entered in the follow-up study. Additionally, expression of ProGRP as determined by immunohistochemical analysis was compared to that of chromogranin-A (CgA) in tissue samples from several subjects. We found a positive correlation between PSA and ProGRP in patients with untreated prostate cancer; no correlation was found in the treated groups. The increases in the ProGRP value and in the percentage of patients with higher than normal values were significant (P < 0.0001), especially in the androgen-independent group (P < 0.0001). A longitudinal study showed that, in a subset of patients, the ProGRP values tended to increase transiently when the cancer became androgen independent, but remained unchanged or decreased at the androgen-dependent stage. Positive staining for ProGRP occurred in a different distribution in neuroendocrine tissues than that of staining for CgA. The clinical results demonstrated the existence of a regulatory mechanism for GRP, which to date had only been observed in cell lines. These findings suggest that GRP is a growth factor potentially upregulated by androgen but that does not rely principally on androgen modulation. The large overlap in levels of ProGRP among the groups limits the use of this value as a monitoring tool. Measurement of ProGRP, however, does have potential as an independent parameter to evaluate androgen-independent progression and to facilitate a new therapeutic strategy that may compensate for current limitations of diagnosis based on PSA alone. Copyright 2002 Wiley-Liss, Inc.

Environmental concentrations of an androgenic progestin disrupts the seasonal breeding cycle in male three-spined stickleback (Gasterosteus aculeatus).

PubMed

Svensson, Johan; Fick, Jerker; Brandt, Ingvar; Brunström, Björn

2014-02-01

Synthetic steroid hormones from contraceptive pharmaceuticals have become global aquatic contaminants. Progestins, the synthetic analogs to progesterone, are receiving increasing attention as contaminants and have been shown to impair reproduction in fish and amphibians at low ng L(-1) concentrations. Certain progestins, such as levonorgestrel have androgenic properties and seem to be several orders of magnitude more potent in terms of reproductive impairment in fish than non-androgenic progestins and progestagens. We recently reported that levonorgestrel has strong androgenic effects in female three-spined sticklebacks (Gasterosteus aculeatus), including induction of the normally male-specific glue protein spiggin and suppression of vitellogenesis. In light of this we investigated if exposure to levonorgestrel could disrupt the highly androgen-dependent seasonal reproductive cycle in male sticklebacks. Male sticklebacks that were in the final stage of a breeding period were exposed to various concentrations of levonorgestrel for six weeks in winter conditions in terms of light and temperature, after which reproductive status was evaluated from gross morphology, histology and key gene transcript levels. During the experimental period the controls had transitioned from full breeding condition into the non-breeding state, including regression of secondary sex characteristics, cessation of spiggin production in the kidney, and resumption of spermatogenesis in the testes. This is ascribed to the natural drop in plasma androgen levels after breeding. However, in the groups concurrently exposed to levonorgestrel, transition to the non-breeding condition was dose-dependently inhibited. Our results show that levonorgestrel can disrupt the seasonal breeding cycle in male sticklebacks. The fitness costs of such an effect could be detrimental to natural stickleback populations. Some effects occurred at a levonorgestrel concentration of 6.5 ng L(-1), well within the range of levonorgestrel levels in surface waters and may therefore occur in progestin-contaminated waters. Furthermore, the effects by levonorgestrel in the present study were likely mediated mainly by its androgenic activity, and the low concentration at which they occurred makes levonorgestrel one of the most potent androgenic contaminants known. Copyright © 2013 Elsevier B.V. All rights reserved.

Aberrant AR Signaling as a Function of Declining Androgen

DTIC Science & Technology

2005-03-01

The first was represented as PSA or hAIAK/GAPD1t1 mRNA ratios, sense, 5’-AUG UCA ACU CCA GGA UGC UTT-3’ and antisense, 5’-AGC AUC Transient... advertisement in accordance indirect effects are general transcription factors like SP1 or with 18 U.S.C. Section 1734 solely to indicate this fact. We thank...Targeting the androgen receptor: improvi 1989,17:71-7. growth vs . expression of prostate specific differentiation comes for castration-resistant

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

PubMed

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

2018-04-01

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

The influence of combined oral contraceptives containing drospirenone on hypothalamic-pituitary-adrenocortical axis activity and glucocorticoid receptor expression and function in women with polycystic ovary syndrome.

PubMed

Macut, Djuro; Božić Antić, Ivana; Nestorov, Jelena; Topalović, Vladanka; Bjekić Macut, Jelica; Panidis, Dimitrios; Kastratović Kotlica, Biljana; Papadakis, Efstathios; Matić, Gordana; Vojnović Milutinović, Danijela

2015-01-01

Most women with PCOS have increased adrenal androgen production, enhanced peripheral metabolism of cortisol and elevation in urinary excretion of its metabolites. Increased cortisol clearance in PCOS is followed by a compensatory overdrive of the hypothalamic-pituitary-adrenocortical (HPA) axis. We hypothesized that oral contraceptives containing ethinylestradiol and drospirenone (EE-DRSP) could modulate glucocorticoid receptor (GR) expression and function and thus affect HPA axis activity in PCOS patients. We analyzed 12 women with PCOS (age 24.17±4.88 years; body mass index 22.05±3.97 kg/m²) treated for 12 months with EE-DRSP and 20 BMI matched controls. In all subjects testosterone, dehydroepiandrosterone sulfate (DHEAS), sex hormone binding globulin (SHBG), cortisol (basal and after dexamethasone), concentrations of GR protein, phospo-GR211 protein, number of GR per cell (B(max) and its equilibrium dissociation constant (K(D)) were measured. Before treatment, increased concentrations of testosterone and DHEAS (p<0.001, respectively), unaltered basal cortisol and an increased sensitivity (p<0.05) of the HPA axis to dexamethasone were observed in PCOS women in comparison to controls. After treatment, testosterone (p<0.01), DHEAS (p<0.05) and cortisol suppression after dexamethasone (p<0.01) were decreased in PCOS women. There were no changes in GR protein concentration, GR phosphorylation nor in the receptor functional parameters B(max) and K(D) in women with PCOS before and after the therapy, and in comparison to controls. Prolonged treatment with EE-DRSP in PCOS women decreased serum androgens and increased cortisol in the presence of decreased sensitivity of the HPA axis and did not exert changes in GR expression and function.

MEASUREMENT OF PHTHALATE LEVELS IN HUMAN MILK IN THE US EPA MAMA STUDY

EPA Science Inventory

Phthalates are plasticizers used to impart flexibility in products including PVC, plastic toys, and medical devices. These products are widely used by the general population. Phthalates act as anti-androgens and in utero or perinatal exposure in laboratory animal models leads to ...

HYDROLOGIC CONDITIONS AFFECTING THE TROPOSPHERIC FLUX OF VINCLOZOLIN AND ITS DEGRADATION PRODUCTS

EPA Science Inventory

A laboratory chamber was used to determine hydrologic conditions that lead to the tropospheric flux of a suspected anti-androgenic dicarboximide fungicide, vinclozolin (3-(3,5-dichlorophenyl)-5-methyl-5-vinyl-oxzoli-dine-2,4-dione) and three degradation products from sterilized...

Male hypogonadism.

PubMed

Basaria, Shehzad

2014-04-05

Male hypogonadism is a clinical syndrome that results from failure to produce physiological concentrations of testosterone, normal amounts of sperm, or both. Hypogonadism may arise from testicular disease (primary hypogonadism) or dysfunction of the hypothalamic-pituitary unit (secondary hypogonadism). Clinical presentations vary dependent on the time of onset of androgen deficiency, whether the defect is in testosterone production or spermatogenesis, associated genetic factors, or history of androgen therapy. The clinical diagnosis of hypogonadism is made on the basis of signs and symptoms consistent with androgen deficiency and low morning testosterone concentrations in serum on multiple occasions. Several testosterone-replacement therapies are approved for treatment and should be selected according to the patient's preference, cost, availability, and formulation-specific properties. Contraindications to testosterone-replacement therapy include prostate and breast cancers, uncontrolled congestive heart failure, severe lower-urinary-tract symptoms, and erythrocytosis. Treatment should be monitored for benefits and adverse effects. Copyright © 2014 Elsevier Ltd. All rights reserved.

Elevated YKL40 is associated with advanced prostate cancer (PCa) and positively regulates invasion and migration of PCa cells

PubMed Central

Jeet, Varinder; Tevz, Gregor; Lehman, Melanie; Hollier, Brett; Nelson, Colleen

2014-01-01

Chitinase 3-like 1 (CHI3L1 or YKL40) is a secreted glycoprotein highly expressed in tumours from patients with advanced stage cancers, including prostate cancer (PCa). The exact function of YKL40 is poorly understood, but it has been shown to play an important role in promoting tumour angiogenesis and metastasis. The therapeutic value and biological function of YKL40 are unknown in PCa. The objective of this study was to examine the expression and function of YKL40 in PCa. Gene expression analysis demonstrated that YKL40 was highly expressed in metastatic PCa cells when compared with less invasive and normal prostate epithelial cell lines. In addition, the expression was primarily limited to androgen receptor-positive cell lines. Evaluation of YKL40 tissue expression in PCa patients showed a progressive increase in patients with aggressive disease when compared with those with less aggressive cancers and normal controls. Treatment of LNCaP and C4-2B cells with androgens increased YKL40 expression, whereas treatment with an anti-androgen agent decreased the gene expression of YKL40 in androgen-sensitive LNCaP cells. Furthermore, knockdown of YKL40 significantly decreased invasion and migration of PCa cells, whereas overexpression rendered them more invasive and migratory, which was commensurate with an enhancement in the anchorage-independent growth of cells. To our knowledge, this study characterises the role of YKL40 for the first time in PCa. Together, these results suggest that YKL40 plays an important role in PCa progression and thus inhibition of YKL40 may be a potential therapeutic strategy for the treatment of PCa. PMID:24981110

Elevated YKL40 is associated with advanced prostate cancer (PCa) and positively regulates invasion and migration of PCa cells.

PubMed

Jeet, Varinder; Tevz, Gregor; Lehman, Melanie; Hollier, Brett; Nelson, Colleen

2014-10-01

Chitinase 3-like 1 (CHI3L1 or YKL40) is a secreted glycoprotein highly expressed in tumours from patients with advanced stage cancers, including prostate cancer (PCa). The exact function of YKL40 is poorly understood, but it has been shown to play an important role in promoting tumour angiogenesis and metastasis. The therapeutic value and biological function of YKL40 are unknown in PCa. The objective of this study was to examine the expression and function of YKL40 in PCa. Gene expression analysis demonstrated that YKL40 was highly expressed in metastatic PCa cells when compared with less invasive and normal prostate epithelial cell lines. In addition, the expression was primarily limited to androgen receptor-positive cell lines. Evaluation of YKL40 tissue expression in PCa patients showed a progressive increase in patients with aggressive disease when compared with those with less aggressive cancers and normal controls. Treatment of LNCaP and C4-2B cells with androgens increased YKL40 expression, whereas treatment with an anti-androgen agent decreased the gene expression of YKL40 in androgen-sensitive LNCaP cells. Furthermore, knockdown of YKL40 significantly decreased invasion and migration of PCa cells, whereas overexpression rendered them more invasive and migratory, which was commensurate with an enhancement in the anchorage-independent growth of cells. To our knowledge, this study characterises the role of YKL40 for the first time in PCa. Together, these results suggest that YKL40 plays an important role in PCa progression and thus inhibition of YKL40 may be a potential therapeutic strategy for the treatment of PCa. © 2014 The authors.

Selective androgen receptor modulators for the prevention and treatment of muscle wasting associated with cancer.

PubMed

Dalton, James T; Taylor, Ryan P; Mohler, Michael L; Steiner, Mitchell S

2013-12-01

This review highlights selective androgen receptor modulators (SARMs) as emerging agents in late-stage clinical development for the prevention and treatment of muscle wasting associated with cancer. Muscle wasting, including a loss of skeletal muscle, is a cancer-related symptom that begins early in the progression of cancer and affects a patient's quality of life, ability to tolerate chemotherapy, and survival. SARMs increase muscle mass and improve physical function in healthy and diseased individuals, and potentially may provide a new therapy for muscle wasting and cancer cachexia. SARMs modulate the same anabolic pathways targeted with classical steroidal androgens, but within the dose range in which expected effects on muscle mass and function are seen androgenic side-effects on prostate, skin, and hair have not been observed. Unlike testosterone, SARMs are orally active, nonaromatizable, nonvirilizing, and tissue-selective anabolic agents. Recent clinical efficacy data for LGD-4033, MK-0773, MK-3984, and enobosarm (GTx-024, ostarine, and S-22) are reviewed. Enobosarm, a nonsteroidal SARM, is the most well characterized clinically, and has consistently demonstrated increases in lean body mass and better physical function across several populations along with a lower hazard ratio for survival in cancer patients. Completed in May 2013, results for the Phase III clinical trials entitled Prevention and treatment Of muscle Wasting in patiEnts with Cancer1 (POWER1) and POWER2 evaluating enobosarm for the prevention and treatment of muscle wasting in patients with nonsmall cell lung cancer will be available soon, and will potentially establish a SARM, enobosarm, as the first drug for the prevention and treatment of muscle wasting in cancer patients.

Comparing the Effects of Combined Oral Contraceptives Containing Progestins With Low Androgenic and Antiandrogenic Activities on the Hypothalamic-Pituitary-Gonadal Axis in Patients With Polycystic Ovary Syndrome: Systematic Review and Meta-Analysis

PubMed Central

Amiri, Mina; Nahidi, Fatemeh; Kabir, Ali; Azizi, Fereidoun

2018-01-01

Background Different products of combined oral contraceptives (COCs) can improve clinical and biochemical findings in patients with polycystic ovary syndrome (PCOS) through suppression of the hypothalamic-pituitary-gonadal (HPG) axis. Objective This systematic review and meta-analysis aimed to compare the effects of COCs containing progestins with low androgenic and antiandrogenic activities on the HPG axis in patients with PCOS. Methods We searched PubMed, Scopus, Google Scholar, ScienceDirect, and Web of Science databases (1980-2017) to identify randomized controlled trials or nonrandomized studies investigating the effect of COCs containing progestins with low androgenic and antiandrogenic activities, including the products containing desogestrel, cyproterone acetate, and drospirenone, on the HPG axis in patients with PCOS. In this meta-analysis, fixed and random effect models were used. Outcomes of interest were weighted mean differences (WMD) of hormonal parameters, including the follicle-stimulating hormone (FSH), luteinizing hormone (LH), LH-to-FSH ratio, estradiol, total testosterone, and sex hormone–binding globulin. Potential sources of heterogeneity were investigated using meta-regression and subgroup analyses. Subgroup analyses were performed based on the used progestin compound and treatment duration. We assessed quality of included studies and their risk of bias using Cochrane guidelines. Publication bias was assessed using Egger test and funnel plot. Results COC use was significantly associated with a decrease in gonadotropin levels, including FSH and LH. Use of products containing cyproterone acetate was associated with a decrease in FSH levels after 3 months (WMD=−0.48; 95% CI −0.81 to −0.15), 6 months (WMD=−2.33; 95% CI −3.48 to −1.18), and 12 months (WMD=−4.70; 95% CI −4.98 to −4.42) and a decrease in LH levels after 3 months (WMD=−3.57; 95% CI −5.14 to −1.99), 6 months (WMD=−5.68; 95% CI −9.57 to −1.80), and 12 months (WMD=−11.60; 95% CI −17.60 to −5.60). Use of COCs containing drospirenone for 6 months decreased FSH (WMD=−0.93; 95% CI −1.79 to −0.08) and LH (WMD=−4.59; 95% CI −7.53 to −1.66) levels. Data for products containing desogestrel were few, but this compound generally had no statistically significant influence on gonadotropin levels similar to that observed with COCs containing cyproterone acetate and drospirenone. Use of COCs was not associated with any significant change in LH-to-FSH ratio. COCs containing cyproterone acetate showed maximum effect on gonadotropin suppression. COCs containing cyproterone acetate significantly decreased estradiol concentrations, whereas those containing drospirenone exhibited no such effect. All COCs demonstrated improvement in androgenic profile and had the same effects on total testosterone and sex hormone–binding globulin concentrations. Progestin compound and treatment duration had no statistically significant effects on changing total testosterone and sex hormone–binding globulin levels. Conclusions COCs containing cyproterone acetate can effectively suppress gonadotropins, leading to a decrease in androgenic parameters. Although different products of COCs could significantly suppress the androgenic profile, it seems that products containing cyproterone acetate are more effective in suppressing gonadotropin and estradiol levels in patients with PCOS. PMID:29695378

Comparing the Effects of Combined Oral Contraceptives Containing Progestins With Low Androgenic and Antiandrogenic Activities on the Hypothalamic-Pituitary-Gonadal Axis in Patients With Polycystic Ovary Syndrome: Systematic Review and Meta-Analysis.

PubMed

Amiri, Mina; Ramezani Tehrani, Fahimeh; Nahidi, Fatemeh; Kabir, Ali; Azizi, Fereidoun

2018-04-25

Different products of combined oral contraceptives (COCs) can improve clinical and biochemical findings in patients with polycystic ovary syndrome (PCOS) through suppression of the hypothalamic-pituitary-gonadal (HPG) axis. This systematic review and meta-analysis aimed to compare the effects of COCs containing progestins with low androgenic and antiandrogenic activities on the HPG axis in patients with PCOS. We searched PubMed, Scopus, Google Scholar, ScienceDirect, and Web of Science databases (1980-2017) to identify randomized controlled trials or nonrandomized studies investigating the effect of COCs containing progestins with low androgenic and antiandrogenic activities, including the products containing desogestrel, cyproterone acetate, and drospirenone, on the HPG axis in patients with PCOS. In this meta-analysis, fixed and random effect models were used. Outcomes of interest were weighted mean differences (WMD) of hormonal parameters, including the follicle-stimulating hormone (FSH), luteinizing hormone (LH), LH-to-FSH ratio, estradiol, total testosterone, and sex hormone-binding globulin. Potential sources of heterogeneity were investigated using meta-regression and subgroup analyses. Subgroup analyses were performed based on the used progestin compound and treatment duration. We assessed quality of included studies and their risk of bias using Cochrane guidelines. Publication bias was assessed using Egger test and funnel plot. COC use was significantly associated with a decrease in gonadotropin levels, including FSH and LH. Use of products containing cyproterone acetate was associated with a decrease in FSH levels after 3 months (WMD=-0.48; 95% CI -0.81 to -0.15), 6 months (WMD=-2.33; 95% CI -3.48 to -1.18), and 12 months (WMD=-4.70; 95% CI -4.98 to -4.42) and a decrease in LH levels after 3 months (WMD=-3.57; 95% CI -5.14 to -1.99), 6 months (WMD=-5.68; 95% CI -9.57 to -1.80), and 12 months (WMD=-11.60; 95% CI -17.60 to -5.60). Use of COCs containing drospirenone for 6 months decreased FSH (WMD=-0.93; 95% CI -1.79 to -0.08) and LH (WMD=-4.59; 95% CI -7.53 to -1.66) levels. Data for products containing desogestrel were few, but this compound generally had no statistically significant influence on gonadotropin levels similar to that observed with COCs containing cyproterone acetate and drospirenone. Use of COCs was not associated with any significant change in LH-to-FSH ratio. COCs containing cyproterone acetate showed maximum effect on gonadotropin suppression. COCs containing cyproterone acetate significantly decreased estradiol concentrations, whereas those containing drospirenone exhibited no such effect. All COCs demonstrated improvement in androgenic profile and had the same effects on total testosterone and sex hormone-binding globulin concentrations. Progestin compound and treatment duration had no statistically significant effects on changing total testosterone and sex hormone-binding globulin levels. COCs containing cyproterone acetate can effectively suppress gonadotropins, leading to a decrease in androgenic parameters. Although different products of COCs could significantly suppress the androgenic profile, it seems that products containing cyproterone acetate are more effective in suppressing gonadotropin and estradiol levels in patients with PCOS. ©Mina Amiri, Fahimeh Ramezani Tehrani, Fatemeh Nahidi, Ali Kabir, Fereidoun Azizi. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 25.04.2018.

Influence of androgen receptor repeat polymorphisms on personality traits in men

PubMed Central

Westberg, Lars; Henningsson, Susanne; Landén, Mikael; Annerbrink, Kristina; Melke, Jonas; Nilsson, Staffan; Rosmond, Roland; Holm, Göran; Anckarsäter, Henrik; Eriksson, Elias

2009-01-01

Background Testosterone has been attributed importance for various aspects of behaviour. The aim of our study was to investigate the potential influence of 2 functional polymorphisms in the amino terminal of the androgen receptor on personality traits in men. Methods We assessed and genotyped 141 men born in 1944 recruited from the general population. We used 2 different instruments: the Karolinska Scales of Personality and the Temperament and Character Inventory. For replication, we similarly assessed 63 men recruited from a forensic psychiatry study group. Results In the population-recruited sample, the lengths of the androgen receptor repeats were associated with neuroticism, extraversion and self-transcendence. The association with extraversion was replicated in the independent sample. Limitations Our 2 samples differed in size; sample 1 was of moderate size and sample 2 was small. In addition, the homogeneity of sample 1 probably enhanced our ability to detect significant associations between genotype and phenotype. Conclusion Our results suggest that the repeat polymorphisms in the androgen receptor gene may influence personality traits in men. PMID:19448851

Management of adolescents with congenital adrenal hyperplasia

PubMed Central

Merke, Deborah P; Poppas, Dix P

2014-01-01

The management of congenital adrenal hyperplasia involves suppression of adrenal androgen production, in addition to treatment of adrenal insufficiency. Management of adolescents with congenital adrenal hyperplasia is especially challenging because changes in the hormonal milieu during puberty can lead to inadequate suppression of adrenal androgens, psychosocial issues often affect adherence to medical therapy, and sexual function plays a major part in adolescence and young adulthood. For these reasons, treatment regimen reassessment is indicated during adolescence. Patients with non-classic congenital adrenal hyperplasia require reassessment regarding the need for glucocorticoid drug treatment. No clinical trials have compared various regimens for classic congenital adrenal hyperplasia in adults, thus therapy is individualised and based on the prevention of adverse outcomes. Extensive patient education is key during transition from paediatric care to adult care and should include education of females with classic congenital adrenal hyperplasia regarding their genital anatomy and surgical history. Common issues for these patients include urinary incontinence, vaginal stenosis, clitoral pain, and cosmetic concerns; for males with classic congenital adrenal hyperplasia, common issues include testicular adrenal rest tumours. Transition from paediatric to adult care is most successful when phased over many years. Education of health-care providers on how to successfully transition patients is greatly needed. PMID:24622419

Integrated assessment of runoff from livestock farming operations: analytical chemistry, in vitro bioassays, and in vivo fish exposures

USGS Publications Warehouse

Cavallin, Jenna E.; Durhan, Elizabeth J.; Evans, Nicola; Jensen, Kathleen M.; Kahl, Michael D.; Kolpin, Dana W.; Kolodziej, Edward P.; Foreman, William T.; LaLone, Carlie A.; Makynen, Elizabeth A.; Seidl, Sara M.; Thomas, Linnea M.; Villeneuve, Daniel L.; Weberg, Matthew A.; Wilson, Vickie S.; Ankley, Gerald T.

2014-01-01

Animal waste from livestock farming operations can contain varying levels of natural and synthetic androgens and/or estrogens, which can contaminate surrounding waterways. In the present study, surface stream water was collected from 6 basins containing livestock farming operations. Aqueous concentrations of 12 hormones were determined via chemical analyses. Relative androgenic and estrogenic activity was measured using in vitro cell assays (MDA-kb2 and T47D-Kbluc assays, respectively). In parallel, 48-h static-renewal in vivo exposures were conducted to examine potential endocrine-disrupting effects in fathead minnows. Mature fish were exposed to surface water dilutions (0%, 25%, 50%, and 100%) and 10-ng/L of 17α-ethynylestradiol or 50-ng/L of 17β-trenbolone as positive controls. Hepatic expression of vitellogenin and estrogen receptor α mRNA, gonadal ex vivo testosterone and 17β-estradiol production, and plasma vitellogenin concentrations were examined. Potentially estrogenic and androgenic steroids were detected at low nanogram per liter concentrations. In vitro estrogenic activity was detected in all samples, whereas androgenic activity was detected in only 1 sample. In vivo exposures to the surface water had no significant dose-dependent effect on any of the biological endpoints, with the exception of increased male testosterone production in 1 exposure. The present study, which combines analytical chemistry measurements, in vitro bioassays, and in vivo fish exposures, highlights the integrated value and future use of a combination of techniques to obtain a comprehensive characterization of an environmental chemical mixture. 

Salivary testosterone and a trinucleotide (CAG) length polymorphism in the androgen receptor gene predict amygdala reactivity in men.

PubMed

Manuck, Stephen B; Marsland, Anna L; Flory, Janine D; Gorka, Adam; Ferrell, Robert E; Hariri, Ahmad R

2010-01-01

In studies employing functional magnetic resonance imaging (fMRI), reactivity of the amygdala to threat-related sensory cues (viz., facial displays of negative emotion) has been found to correlate positively with interindividual variability in testosterone levels of women and young men and to increase on acute administration of exogenous testosterone. Many of the biological actions of testosterone are mediated by intracellular androgen receptors (ARs), which exert transcriptional control of androgen-dependent genes and are expressed in various regions of the brain, including the amygdala. Transactivation potential of the AR decreases (yielding relative androgen insensitivity) with expansion a polyglutamine stretch in the N-terminal domain of the AR protein, as encoded by a trinucleotide (CAG) repeat polymorphism in exon 1 of the X-chromosome AR gene. Here we examined whether amygdala reactivity to threat-related facial expressions (fear, anger) differs as a function of AR CAG length variation and endogenous (salivary) testosterone in a mid-life sample of 41 healthy men (mean age=45.6 years, range: 34-54 years; CAG repeats, range: 19-29). Testosterone correlated inversely with participant age (r=-0.39, p=0.012) and positively with number of CAG repeats (r=0.45, p=0.003). In partial correlations adjusted for testosterone level, reactivity in the ventral amygdala was lowest among men with largest number of CAG repeats. This inverse association was seen in both the right (r(p)=-0.34, p<0.05) and left (r(p)=-0.32, p<0.05) hemisphere. Activation of dorsal amygdala, correlated positively with individual differences in salivary testosterone, also in right (r=0.40, p<0.02) and left (r=0.32, p<0.05) hemisphere, but was not affected by number of CAG repeats. Hence, androgenic influences on threat-related reactivity in the ventral amygdala may be moderated partially by CAG length variation in the AR gene. Because individual differences in salivary testosterone also predicted dorsal amygdala reactivity and did so independently of CAG repeats, it is suggested that androgenic influences within this anatomically distinct region may be mediated, in part, by non-genomic or AR-independent mechanisms.

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

PubMed

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

2015-02-01

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

Targeting the relaxin hormonal pathway in prostate cancer.

PubMed

Neschadim, Anton; Summerlee, Alastair J S; Silvertown, Joshua D

2015-11-15

Targeting the androgen signalling pathway has long been the hallmark of anti-hormonal therapy for prostate cancer. However, development of androgen-independent prostate cancer is an inevitable outcome to therapies targeting this pathway, in part, owing to the shift from cancer dependence on androgen signalling for growth in favor of augmentation of other cellular pathways that provide proliferation-, survival- and angiogenesis-promoting signals. This review focuses on the role of the hormone relaxin in the development and progression of prostate cancer, prior to and after the onset of androgen independence, as well as its role in cancers of other reproductive tissues. As the body of literature expands, examining relaxin expression in cancerous tissues and its role in a growing number of in vitro and in vivo cancer models, our understanding of the important involvement of this hormone in cancer biology is becoming clearer. Specifically, the pleiotropic functions of relaxin affecting cell growth, angiogenesis, blood flow, cell migration and extracellular matrix remodeling are examined in the context of cancer progression. The interactions and intercepts of the intracellular signalling pathways of relaxin with the androgen pathway are explored in the context of progression of castration-resistant and androgen-independent prostate cancers. We provide an overview of current anti-hormonal therapeutic treatment options for prostate cancer and delve into therapeutic approaches and development of agents aimed at specifically antagonizing relaxin signalling to curb tumor growth. We also discuss the rationale and challenges utilizing such agents as novel anti-hormonals in the clinic, and their potential to supplement current therapeutic modalities. © 2014 UICC.

Excess androgen during puberty disrupts circadian organization in female rats.

PubMed

Sellix, Michael T; Murphy, Zachary C; Menaker, Michael

2013-04-01

Circadian clocks have been described in each tissue of the hypothalamo-pituitary-ovarian axis. Although a role for the clock in the timing of ovulation is indicated, the impact of diseases that disrupt fertility on clock function or the clocks' role in the etiology of these pathologies has yet to be fully appreciated. Polycystic ovary syndrome (PCOS) is a particularly devastating endocrinopathy, affecting approximately 10% of women at childbearing age. Common features of PCOS are a polycystic ovary, amenorrhea, and excess serum androgen. Approximately 40% of these women have metabolic syndrome, including hyperinsulinemia, dyslipidemia, and hyperleptinemia. It has been suggested that excess androgen is a critical factor in the etiology of PCOS. We have examined the effects of androgen excess during puberty on the phase of circadian clocks in tissues of the metabolic and hypothalamo-pituitary-ovarian axes. Female period1-luciferase (per1-luc) rats were exposed to androgen (5α-dihydrotestosterone [DHT]) or placebo for 4-6 weeks (short term) or 9-15 weeks (long term). As expected, DHT-treated animals gained more weight than controls and had disrupted estrous cycles. At the end of treatment, tissues, including the liver, lung, kidney, white adipose, cornea, pituitary, oviduct, and ovarian follicles, were cultured, and per1-luc expression in each was recorded. Analysis of per1-luc expression revealed that DHT exposure increased phase distribution of multiple oscillators, including ovarian follicles, liver, and adipose, and altered phase synchrony between animals. These data suggest that excess androgen during puberty, a common feature of PCOS, negatively affects internal circadian organization in both the reproductive and metabolic axes.

Excess Androgen During Puberty Disrupts Circadian Organization in Female Rats

PubMed Central

Murphy, Zachary C.; Menaker, Michael

2013-01-01

Circadian clocks have been described in each tissue of the hypothalamo-pituitary-ovarian axis. Although a role for the clock in the timing of ovulation is indicated, the impact of diseases that disrupt fertility on clock function or the clocks' role in the etiology of these pathologies has yet to be fully appreciated. Polycystic ovary syndrome (PCOS) is a particularly devastating endocrinopathy, affecting approximately 10% of women at childbearing age. Common features of PCOS are a polycystic ovary, amenorrhea, and excess serum androgen. Approximately 40% of these women have metabolic syndrome, including hyperinsulinemia, dyslipidemia, and hyperleptinemia. It has been suggested that excess androgen is a critical factor in the etiology of PCOS. We have examined the effects of androgen excess during puberty on the phase of circadian clocks in tissues of the metabolic and hypothalamo-pituitary-ovarian axes. Female period1-luciferase (per1-luc) rats were exposed to androgen (5α-dihydrotestosterone [DHT]) or placebo for 4-6 weeks (short term) or 9-15 weeks (long term). As expected, DHT-treated animals gained more weight than controls and had disrupted estrous cycles. At the end of treatment, tissues, including the liver, lung, kidney, white adipose, cornea, pituitary, oviduct, and ovarian follicles, were cultured, and per1-luc expression in each was recorded. Analysis of per1-luc expression revealed that DHT exposure increased phase distribution of multiple oscillators, including ovarian follicles, liver, and adipose, and altered phase synchrony between animals. These data suggest that excess androgen during puberty, a common feature of PCOS, negatively affects internal circadian organization in both the reproductive and metabolic axes. PMID:23417420

Histological characterization of peppermint shrimp ( Lysmata wurdemanni) androgenic gland

NASA Astrophysics Data System (ADS)

Liu, Xin; Zhang, Dong; Lin, Tingting

2017-12-01

The androgenic gland (AG) is an important endocrine gland for male reproductive function in crustaceans. In the present study, we investigated the histological characteristics of the androgenic gland of peppermint shrimp, Lysmata wurdemanni. The peppermint shrimp matures as male first, then some individuals may become euhermaphrodite after several moltings (transitional phase). Euhermaphrodite-phase shrimp acts as male at intermolts. However, it can be fertilized as a female immediately after molting. Considering the male reproductive function acts in its lifespan except for at larval stages, and female reproductive system starts to develop at transitional phase, we hypothesized that AG activity might be reduced to allow and promote vitellogenesis onset in early transitional phase and the following euhermaphrodite phase. So AG cell structure might be different in three phases in L. wurdemanni. The results showed that AG exists in the male in transitional and euhermaphrodite phases. The gland cell clusters surrounding the ejaculatory ducts locate at the roots of the fifth pereopods. The nucleus diameters are similar in the three phases while the nucleus- to-cell ratio is the lowest in euhermaphrodite phase. Our results indicated that for the individuals that will become euhermaphrodite, the cellular structure of AG changes since transitional phase. Male reproductive function which is still available in euhermaphrodite-phase shrimp should be due to the existence of the gland.

Negative regulation of parathyroid hormone-related protein expression by steroid hormones

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

Kajitani, Takashi; Tamamori-Adachi, Mimi; Okinaga, Hiroko

Highlights: {yields} Steroid hormones repress expression of PTHrP in the cell lines where the corresponding nuclear receptors are expressed. {yields} Nuclear receptors are required for suppression of PTHrP expression by steroid hormones, except for androgen receptor. {yields} Androgen-induced suppression of PTHrP expression appears to be mediated by estrogen receptor. -- Abstract: Elevated parathyroid hormone-related protein (PTHrP) is responsible for humoral hypercalcemia of malignancy (HHM), which is of clinical significance in treatment of terminal patients with malignancies. Steroid hormones were known to cause suppression of PTHrP expression. However, detailed studies linking multiple steroid hormones to PTHrP expression are lacking. Here wemore » studied PTHrP expression in response to steroid hormones in four cell lines with excessive PTHrP production. Our study established that steroid hormones negatively regulate PTHrP expression. Vitamin D receptor, estrogen receptor {alpha}, glucocorticoid receptor, and progesterone receptor, were required for repression of PTHrP expression by the cognate ligands. A notable exception was the androgen receptor, which was dispensable for suppression of PTHrP expression in androgen-treated cells. We propose a pathway(s) involving nuclear receptors to suppress PTHrP expression.« less

Sex steroids and the GH axis: Implications for the management of hypopituitarism.

PubMed

Birzniece, Vita; Ho, Ken K Y

2017-02-01

Growth hormone (GH) regulates somatic growth, substrate metabolism and body composition. Sex hormones exert profound effect on the secretion and action of GH. Estrogens stimulate the secretion of GH, but inhibit the action of GH on the liver, an effect that occurs when administered orally. Estrogens suppress GH receptor signaling by stimulating the expression proteins that inhibit cytokine receptor signaling. This effect of estrogens is avoided when physiological doses of estrogens are administered via a non-oral route. Estrogen-like compounds, such as selective estrogen receptor modulators, possess dual properties of inhibiting the secretion as well as the action of GH. In contrast, androgens stimulate GH secretion, driving IGF-1 production. In the periphery, androgens enhance the action of GH. The differential effects of estrogens and androgens influence the dose of GH replacement in patients with hypopituitarism on concomitant treatment with sex steroids. Where possible, a non-oral route of estrogen replacement is recommended for optimizing cost-benefit of GH replacement in women with GH deficiency. Adequate androgen replacement in conjunction with GH replacement is required to achieve the full anabolic effect in men with hypopituitarism. Copyright © 2017 Elsevier Ltd. All rights reserved.

Biotransformation of 17α-methyltestosterone in sediment under different electron acceptor conditions.

PubMed

Homklin, Supreeda; Ong, Say Kee; Limpiyakorn, Tawan

2011-03-01

17α-Methyltestosterone (MT), an anabolic androgenic steroid, is used widely in inducing an all male population in aquaculture farming of fish, such as Nile tilapia (Oreochromis niloticus). Current understanding of the occurrence and fate of MT in the sediments and the surrounding areas of the aquaculture ponds are very limited. Bioassay tests showed that MT was biotransformed under aerobic and sulfate-reducing conditions with a half-life of 3.8d and 5.3d, respectively, with complete disappearance of androgenic activity. However, under methanogenic condition, MT was found to biotransform but the androgenic activity continued to persist even after 45 d of incubation. In contrast, MT was found to transform slowly under iron(III)-reducing condition and was hardly transformed under nitrate-reducing condition. A possible reason for the lack of transformation of MT under nitrate-reducing condition is the presence of the methyl group at the C-17 position. The results of this study suggest that MT and its degradation products with androgenic activity may potentially accumulate in the sediments of fish farming ponds under iron(III)-reducing, nitrate-reducing and methanogenic conditions. Copyright © 2010 Elsevier Ltd. All rights reserved.

Androgens and Psychosocial Factors Related to Sexual Dysfunctions in Premenopausal Women∗: ∗2016 ISSM Female Sexual Dysfunction Prize.

PubMed

Wåhlin-Jacobsen, Sarah; Kristensen, Ellids; Pedersen, Anette Tønnes; Laessøe, Nanna Cassandra; Cohen, Arieh S; Hougaard, David M; Lundqvist, Marika; Giraldi, Annamaria

2017-03-01

The female sexual response is complex and influenced by several biological, psychological, and social factors. Testosterone is believed to modulate a woman's sexual response and desire, because low levels are considered a risk factor for impaired sexual function, but previous studies have been inconclusive. To investigate how androgen levels and psychosocial factors are associated with female sexual dysfunction (FSD), including hypoactive sexual desire disorder (HSDD). The cross-sectional study included 428 premenopausal women 19 to 58 years old who completed a questionnaire on psychosocial factors and had blood sampled at days 6 to 10 in their menstrual cycle. Logistic regression models were built to test the association among hormone levels, psychosocial factors, and sexual end points. Five different sexual end points were measured using the Female Sexual Function Index and the Female Sexual Distress Scale: impaired sexual function, sexual distress, FSD, low sexual desire, and HSDD. Serum levels of total and free testosterone, androstenedione, dehydroepiandrosterone sulfate, and androsterone glucuronide were analyzed using mass spectrometry. After adjusting for psychosocial factors, women with low sexual desire had significantly lower mean levels of free testosterone and androstenedione compared with women without low sexual desire. None of the androgens were associated with FSD in general or with HSDD in particular. Relationship duration longer than 2 years and mild depressive symptoms increased the risk of having all the sexual end points, including FSD in general and HSDD in particular in multivariate analyses. In this large cross-sectional study, low sexual desire was significantly associated with levels of free testosterone and androstenedione, but FSD in general and HSDD in particular were not associated with androgen levels. Length of relationship and depression were associated with FSD including HSDD. Wåhlin-Jacobsen S, Kristensen E, Tønnes Pedersen A, et al. Androgens and Psychosocial Factors Related to Sexual Dysfunctions in Premenopausal Women. J Sex Med 2017;14:366-379. Copyright © 2017 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

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

PubMed

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

2010-08-01

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

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

PubMed

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

2013-09-01

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

MEASUREMENT AND MODELING OF THE TRANSPORT OF ENDOCRINE DISRUPTING DICARBOXIMIDES AND DEGRADATION PRODUCTS FROM THE SOIL TO THE LOWER TROPOSPHERE

EPA Science Inventory

This research addresses the environmental fate, transport, exposure and potential risks from dicarboximides, a widely used class of agricultural fungicides. Certain dicarboximide fungicides and degradation products have been found to be anti-androgenic; i. e., exposure to these...

MEASURING AND MODELING THE TRANSPORT OF ENDOCRINE DISRUPTING DICARBOXIMIDES AND DEGRADATION PRODUCTS FROM THE SOIL TO THE LOWER TROPOSPHERE

EPA Science Inventory

This research addresses the environmental fate, transport, exposure and potential risks from dicarboximides, a widely used class of agricultural fungicides. Certain dicarboximide fungicides and degradation products have been found to be anti-androgenic; i. e., exposure to these...

Comparison of ex vivo DSP and in vitro MBP Exposures on Fetal Testis Testosterone Production

EPA Science Inventory

In utero exposure to di‐butyl phthalate (DBP) during sex differentiation reduces androgen production and produces a characteristic profile of gene expression changes in the fetal testis. The DPB metabolite mono‐butyl phthalate (MBP) is hypothesized to produce these changes by ...

The herbicide linuron reduces testosterone production from the fetal rat testis both in utero and in vitro

EPA Science Inventory

In utero exposure to linuron, an urea-based herbicide, results in a pattern of malformations of androgen-dependent tissues in adult male rat offspring resembling that produced by some phthalate esters which are known to decrease fetal testosterone production. This study investiga...

Local estrogenic/androgenic balance in the cerebral vasculature

PubMed Central

Krause, Diana N.; Duckles, Sue P.; Gonzales, Rayna J.

2011-01-01

Reproductive effects of sex steroids are well-known, however it is increasingly apparent that these hormones have important actions on non-reproductive tissues such as the vasculature. The latter effects can be relevant throughout the lifespan, not just limited to reproductive years, and are not necessarily restricted to one sex or the other. Our work has established that cerebral blood vessels are a non-reproductive target tissue for sex steroids. We have found that estrogen and androgens alter vascular tone, endothelial function, oxidative stress and inflammatory responses in cerebral vessels. Often the actions of estrogen and androgens oppose each other. Moreover, it is clear that cerebral vessels are directly targeted by sex steroids as they express specific receptors for these hormones. Interestingly, cerebral blood vessels also express enzymes that metabolize sex steroids. These findings suggest that local synthesis of 17β-estradiol and dihydrotestosterone can occur within the vessel wall. One of the enzymes present, aromatase, converts testosterone to 17β-estradiol, which would alter the local balance of androgenic and estrogenic influences. Thus cerebral vessels are affected by circulating sex hormones as well as locally synthesized sex steroids. The presence of vascular endocrine effector mechanisms has important implications for male-female differences in cerebrovascular function and disease. Moreover, the cerebral circulation is a target for gonadal hormones as well as anabolic steroids and therapeutic drugs used to manipulate sex steroid actions. The long-term consequences of these influences have yet to be determined. PMID:21535417

Seasonality of fecal androgen and glucocorticoid metabolite excretion in male goral (Naemorhedus griseus) in Thailand.

PubMed

Khonmee, Jaruwan; Brown, Janine L; Rojanasthien, Suvichai; Thumasanukul, Dissakul; Kongphoemphun, Adisorn; Siriaroonrat, Boripat; Tipkantha, Wanlaya; Punyapornwithaya, Veerasak; Thitaram, Chatchote

2014-04-01

There is no information on the endocrinology of Chinese goral (Naemorhedus griseus), a high priority species for captive breeding and reintroduction in Thailand. This study characterized fecal androgen and glucocorticoid metabolites in male goral at Omkoi Wildlife Sanctuary to investigate seasonal relationships. Fecal samples were collected 3 days/week for 1 year from eight adult males. Mean androgen metabolite concentrations were greater (P<0.05) during the rainy season (289.82±9.18ng/g) and winter (224.09±11.97ng/g) compared to the summer (195.48±8.23ng/g), and were related to breeding activity. A similar pattern was observed for glucocorticoid concentrations (22.10±0.72ng/g compared to 21.98±0.98ng/g compared to 15.30±0.48ng/g), respectively, and this resulted in a positive correlation between the two hormones (P<0.05). There also were positive correlations between fecal androgen metabolite concentrations and temperature (P<0.05) and day length (P<0.05). In summary, this is the first study to assess endocrine function in male goral, and results showed seasonal variation in testicular and adrenal steroidogenic function, with greater activity in the rainy season and winter. Given that resources for captive male goral are consistent throughout the year, reproduction may be regulated primarily by photoperiod in this species. Copyright © 2014 Elsevier B.V. All rights reserved.

FBI-1 functions as a novel AR co-repressor in prostate cancer cells.

PubMed

Cui, Jiajun; Yang, Yutao; Zhang, Chuanfu; Hu, Pinliang; Kan, Wei; Bai, Xianhong; Liu, Xuelin; Song, Hongbin

2011-03-01

The pro-oncogene FBI-1, encoded by Zbtb7a, is a transcriptional repressor that belongs to the POK (POZ/BTB and Krüppel) protein family. In this study, we investigated a potential interaction between androgen receptor (AR) signaling and FBI-1 and demonstrated that overexpression of FBI-1 inhibited ligand-dependent AR activation. A protein-protein interaction was identified between FBI-1 and AR in a ligand-dependent manner. Furthermore, FBI-1, AR and SMRT formed a ternary complex and FBI-1 enhanced the recruitment of NCoR and SMRT to endogenous PSA upstream sequences. Our data also indicated that the FBI-1-mediated inhibition of AR transcriptional activity is partially dependent on HDAC. Interestingly, FBI-1 plays distinct roles in regulating LNCaP (androgen-dependent) and PC-3 cell (androgen-independent) proliferation.

Nandrolone decreases mu opioid receptor expression in SH-SY5Y human neuroblastoma cells.

PubMed

Guarino, Goffredo; Spampinato, Santi

2008-07-16

Nandrolone and other anabolic androgenic steroids alter the expression and function of neurotransmitter systems and contribute to drug dependence. Nandrolone treatment (10-10 M) caused a time-dependent and concentration-dependent downregulation of mu opioid receptor (MOPr) transcripts in SH-SY5Y human neuroblastoma cells. This effect was prevented by the androgen receptor antagonist hydroxyflutamide. Receptor binding assays confirmed a decrease in MOPr of approximately 40% in nandrolone-treated cells. Treatment with actinomycin D (10 (-5)M), a transcription inhibitor, revealed that nandrolone might regulate MOPr mRNA stability. In SH-SY5Y cells transfected with a human MOPr luciferase promoter/reporter construct, nandrolone did not alter the rate of gene transcription. These results suggest that nandrolone may regulate MOPr expression through posttranscriptional mechanisms requiring the androgen receptor.

Is androgen receptor targeting an emerging treatment strategy for triple negative breast cancer?

PubMed

Anestis, Aristomenis; Karamouzis, Michalis V; Dalagiorgou, Georgia; Papavassiliou, Athanasios G

2015-06-01

Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype. The absence of expression and/or amplification of estrogen and progesterone receptor as well as ERBB-2 prevent the use of currently available endocrine options and/or ERBB-2-directed drugs and indicates chemotherapy as the main current therapy. TNBC represents approximately 15% of breast cancer cases with high index of heterogeneity. Here, we review the role of androgen receptor in breast carcinogenesis and its association with alterations in the expression pattern and functional roles of regulatory molecules and signal transduction pathways in TNBC. Additionally, based on the so far preclinical and clinical published data, we evaluate the perspectives for using and/or developing androgen receptor targeting strategies for specific TNBC subtypes. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

PubMed

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

2005-07-18

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

The role of androgen receptor activity mediated by the CAG repeat polymorphism in the pathogenesis of PCOS.

PubMed

Baculescu, N

2013-03-15

Polycystic ovary syndrome (PCOS), one of the most common and complex endocrine disorders affecting up to 15 % of reproductive age women, is considered a predominantly hyperandrogenic syndrome according to the Androgen Excess Society. It is generally accepted that androgens determine the characteristic features of PCOS; in this context, a hyperactive androgen receptor (AR) at the levels of the GnRH pulse generator in the hypothalamus and at the granulosa cells in the ovary, skeletal muscle or adipocytes senses initially normal testosterone and dihydrotestosterone as biochemical hyperandrogenism and might be a crucial connection between the vicious circles of the PCOS pathogenesis. Polymorphism of the AR gene has been associated with different androgen pattern diseases. Several studies have demonstrated an association between AR with increased activity encoded by shorter CAG repeat polymorphism in the exon 1 of the AR gene and PCOS, although there are conflicting results in this field. The phenomenon is more complex because the AR activity is determined by the epigenetic effect of X chromosome inactivation (XCI). Moreover, we must evaluate the AR as a dynamic heterocomplex, with a large number of coactivators and corepressors that are essential to its function, thus mediating tissue-specific effects. In theory, any of these factors could modify the activity of AR, which likely explains the inconsistent results obtained when this activity was quantified by only the CAG polymorphism in PCOS.

Quantifying the impact of androgen therapy on the female larynx.

PubMed

Damrose, Edward J

2009-02-01

To describe the timing of changes in fundamental frequency of the female voice following androgen therapy during female to male gender reassignment. A 33-year-old female semi-professional singer undergoing gender reassignment and intramuscular androgen injections was examined at monthly intervals to monitor the impact of therapy on the voice. Laryngostroboscopy and acoustic analysis were performed simultaneously to monitor for potential laryngeal pathology. Pretreatment mean fundamental frequency (MF(0)) was 228.45 Hz and ranged from 140.26 Hz to 430.64 Hz. Between month 3 and month 4 of treatment, MF(0) declined to 116.52 Hz and ranged from 90.75 Hz to 201.07 Hz. Shimmer increased from 3.4% to 7.8%. Noise to harmonics ratio (NHR) also increased from 0.12 to 0.17. The patient has continued to sing semi-professionally despite these changes in laryngeal function. Androgen therapy exerted a profound change on mean fundamental frequency between the third and fourth months of treatment. In addition, pitch range was reduced in a commensurate fashion. Patients undergoing androgen therapy may undergo a significant change in speaking voice between the third and fourth months of therapy. Moreover, though these changes may exert a profound impact on the singing voice, patients undergoing gender reassignment may still be able to achieve personal and professional success in their singing careers.

Dimethandrolone (7α,11β-dimethyl-19-nortestosterone) and 11β-methyl-19-nortestosterone are not converted to aromatic A-ring products in the presence of recombinant human aromatase☆

PubMed Central

Attardi, Barbara J.; Pham, Trung C.; Radler, Lisa M.; Burgenson, Janet; Hild, Sheri A.; Reel, Jerry R.

2008-01-01

Dimethandrolone undecanoate (DMAU: 7α,11β-dimethyl-19-nortestosterone 17β-undecanoate) is a potent orally active androgen in development for hormonal therapy in men. Cleavage of the 17β-ester bond by esterases in vivo leads to liberation of the biologically active androgen, dimethandrolone (DMA), a 19-norandrogen. For hormone replacement in men, administration of C19 androgens such as testosterone (T) may lead to elevations in circulating levels of estrogens due to aromatization. As several reports have suggested that certain 19-norandrogens may serve as substrates for the aromatase enzyme and are converted to the corresponding aromatic A-ring products, it was important to investigate whether DMA, the related compound, 11β-methyl-19-nortestosterone (11β-MNT), also being tested for hormonal therapy in men, and other 19-norandrogens can be converted to aromatic A-ring products by human aromatase. The hypothetical aromatic A-ring product corresponding to each substrate was obtained by chemical synthesis. These estrogens bound with high affinity to purified recombinant human estrogen receptors (ER) α and β in competitive binding assays (IC50's: 5−12 × 10−9 M) and stimulated transcription of 3XERE-luciferase in T47Dco human breast cancer cells with a potency equal to or greater than that of estradiol (E2) (EC50's: 10−12 to 10−11 M). C19 androgens (T, 17α-methyltestosterone (17α-MT), androstenedione (AD), and 16α-hydroxyandrostenedione (16α-OHAD)), 19-norandrogens (DMA, 11β-MNT, 19-nortestosterone (19-NT), and 7α-methyl-19-nortestosterone (MENT)) or the structurally similar 19-norprogestin, norethindrone (NET) were incubated at 50 μM with recombinant human aromatase for 10−180 min at 37 °C. The reactions were terminated by extraction with acetonitrile and centrifugation, and substrate and potential product were separated by HPLC. Retention times were monitored by UV absorption, and UV peaks were quantified using standard curves. Aromatization of the positive controls, T, AD, and 16α-OHAD was linear for 40−60 min, and conversion of T or AD was complete by 120 min. The nonsteroidal aromatase inhibitor, letrozole, demonstrated concentration-dependent suppression of T aromatization. Under the same conditions, there was no detectable conversion of DMA, 11β-MNT, or NET to their respective hypothetical aromatic A-ring products during incubation times up to 180 min. Aromatization of MENT and 19-NT proceeded slowly and was limited. Collectively, these data support the notion that in the absence of the C19-methyl group, which is the site of attack by oxygen, aromatization of androgenic substrates proceeds slowly or not at all and that this reaction is impeded by the presence of a methyl group at the 11β position. PMID:18555683

Differential Response to Abiraterone Acetate and Di-n-butyl Phthalate in an Androgen-Sensitive Human Fetal Testis Xenograft Bioassay

PubMed Central

Boekelheide, Kim

2014-01-01

In utero exposure to antiandrogenic xenobiotics such as di-n-butyl phthalate (DBP) has been linked to congenital defects of the male reproductive tract, including cryptorchidism and hypospadias, as well as later life effects such as testicular cancer and decreased sperm counts. Experimental evidence indicates that DBP has in utero antiandrogenic effects in the rat. However, it is unclear whether DBP has similar effects on androgen biosynthesis in human fetal testis. To address this issue, we developed a xenograft bioassay with multiple androgen-sensitive physiological endpoints, similar to the rodent Hershberger assay. Adult male athymic nude mice were castrated, and human fetal testis was xenografted into the renal subcapsular space. Hosts were treated with human chorionic gonadotropin for 4 weeks to stimulate testosterone production. During weeks 3 and 4, hosts were exposed to DBP or abiraterone acetate, a CYP17A1 inhibitor. Although abiraterone acetate (14 d, 75mg/kg/d po) dramatically reduced testosterone and the weights of androgen-sensitive host organs, DBP (14 d, 500mg/kg/d po) had no effect on androgenic endpoints. DBP did produce a near-significant trend toward increased multinucleated germ cells in the xenografts. Gene expression analysis showed that abiraterone decreased expression of genes related to transcription and cell differentiation while increasing expression of genes involved in epigenetic control of gene expression. DBP induced expression of oxidative stress response genes and altered expression of actin cytoskeleton genes. PMID:24284787

Androgen replacement for women.

PubMed Central

Basson, R.

1999-01-01

OBJECTIVES: To determine whether a postmenopausal syndrome comprising specific changes in sexual desire and response associated with low free testosterone exists. To determine whether this syndrome is ameliorated by testosterone replacement. QUALITY OF EVIDENCE: Literature documenting that replacement of physiological levels of testosterone is beneficial and safe is scant. Only one randomized prospective blinded study examines sexual outcome in detail. MAIN MESSAGE: Testosterone is an important metabolic and sex hormone produced by the ovary throughout life. The variable reduction in ovarian testosterone production coincident with menopause is sometimes associated with a syndrome of specific changes in sexual desire and sexual response. Estrogen deficiency also impairs sexual response, but its replacement will not improve and might exacerbate sexual symptoms from androgen loss. Diagnosis of androgen deficiency is clinical, based on accurate assessment of a woman's sexual status before and after menopause and only confirmed (rather than diagnosed) by a low level of free testosterone. Partial androgen replacement restores much of the sexual response and facilitates sexual desire that is triggered by external cues. Avoiding supraphysiological levels of testosterone lessens risk of masculinization. Avoiding alkylated testosterone lessens hepatic or lipid impairment. CONCLUSION: Further prospective randomized studies of replacement of physiological levels of testosterone in women with androgen deficiency syndrome are needed, using formulations of testosterone available in Canada. The consistency of sexual changes, the associated personal and relationship distress, together with our clinical experience of the gratifying response to physiological replacement, make further studies urgently needed. PMID:10509222

Mechanistic basis for estrogenic effects in fathead minnow (Pimephales promelas) following exposure to the androgen 17alpha-methyltestosterone: conversion of 17alpha-methyltestosterone to 17alpha-methylestradiol.

PubMed

Hornung, Michael W; Jensen, Kathleen M; Korte, Joseph J; Kahl, Michael D; Durhan, Elizabeth J; Denny, Jeffrey S; Henry, Tala R; Ankley, Gerald T

2004-01-07

Exposure of adult fathead minnows (Pimephales promelas) to the androgen 17alpha-methyltestosterone (MT) produces both androgenic and estrogenic effects, manifested as nuptial tubercle formation in females, and vitellogenin production in males and females, respectively. The present study was conducted to determine if the unanticipated estrogenic effects are produced by conversion of MT via aromatase activity to 17alpha-methylestradiol (ME2). Aromatase activity at the end of a 7-day waterborne MT exposure (20, 200microg/l) was significantly decreased in ovarian microsomes and brain homogenates from exposed fish, to about 30-50% of control activity. Although aromatase activity was decreased by 7 days, it is possible that the conversion of MT to ME2 occurred soon after initial exposure. In support of this, ME2 was detected in plasma samples of the fish following the 7-day exposure, confirming their ability convert the androgen MT to the estrogen ME2. The concentration of ME2 in plasma was within the range of plasma 17ss-estradiol (E2) found in control female fathead minnows (4-5ng/ml). These results, in conjunction with competitive binding assays that indicate ME2 binds to the fathead minnow estrogen receptor with a relative binding affinity of 68.3% of E2, support the hypothesis that aromatization of MT to ME2 contributes to the estrogenic effects in fathead minnows following exposure to this androgen.

Chemical Suppression of the Reactivated Androgen Signaling Pathway in Androgen-Independent Prostate Cancer

DTIC Science & Technology

2014-01-08

Prostate Cancer, Castration Resistant Disease, Hedgehog Signaling, Smoothened, Gli, Cyclopamine, Androgen Signaling, Androgen Biosynthesis, Androgen...role of Hedgehog /Gli Signaling in generating the androgen-independent growth phenotype of castration resistant prostate cancer and will test the ability...of drugs that target Hedgehog /Gli as a means to suppress the androgen independent growth behavior associated with castration resistant prostate

Public health impact of androgens.

PubMed

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

2018-06-01

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

Androgen Receptor (AR) in Cardiovascular Diseases

PubMed Central

Huang, Chiung-Kuei; Lee, Soo Ok; Chang, Eugene; Pang, Haiyan; Chang, Chawnshang

2016-01-01

Cardiovascular diseases (CVDs) are still the highest leading cause of death worldwide. Several risk factors have been linked to CVDs, including smoking, diabetes, hyperlipidemia, and gender among others. Sex hormones, especially the androgen and its receptor, androgen receptor (AR), have been linked to many diseases with a clear gender difference. Here, we summarize androgen/AR effects on CVDs, including hypertension, stroke, atherosclerosis, abdominal aortic aneurysm (AAA), myocardial hypertrophy, and heart failure, as well as metabolic syndrome/diabetes and their impacts on CVDs. Androgen/AR signaling exacerbates hypertension and anti-androgens may suppress hypertension. Androgen/AR signaling plays dual roles in strokes, depending on different kinds of factors, but generally males have a higher incidence of strokes than females. Androgen and AR differentially modulate atherosclerosis. Androgen deficiency causes elevated lipid accumulation to enhance atherosclerosis, but targeting AR in selective cells without altering serum androgen levels would suppress atherosclerosis progression. Androgen/AR signaling is crucial in AAA development and progression, and targeting androgen/AR profoundly restricts AAA progression. Men have increased cardiac hypertrophy as compared to age-matched women that may be due to androgens. Finally, androgen/AR plays important roles in contributing to obesity and insulin/leptin resistance to increase the metabolic syndrome. PMID:26769913

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

PubMed

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

2017-04-01

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

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

PubMed Central

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

2015-01-01

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

Enzalutamide inhibits androgen receptor-positive bladder cancer cell growth.

PubMed

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

2016-10-01

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

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

Inhibitors for Androgen Receptor Activation Surfaces

DTIC Science & Technology

2008-09-01

such as FKBP52 or HSP90 bind in vivo, and started a collaboration with Marc Cox at UT El Paso to test these possibilities. Our assays of mutated amino...will complete testing the compounds in full length AR constructs and publish the results. We have begun two collaborations, one with Marc Cox on...Prof. Marc Cox and Dr. Paul Rennie to identify proteins that bind to BF3 so that we may form crystals of the receptor with these proteins and learn more about function of the human androgen receptor.

Embodied masculinity and androgen deprivation therapy.

PubMed

Oliffe, John

2006-05-01

This paper describes the findings from an ethnographic study of 16 Anglo-Australian men treated with androgen deprivation therapy (ADT) for advanced prostate cancer. Utilising a social constructionist gendered analysis, participants' experiences, particularly in relation to embodied masculinity, are described in the context of reduced testosterone that accompany ADT. The findings indicated that participants reformulated many ideals of hegemonic masculinity in response to functional body changes. However, hegemonic masculinity strongly influenced participants' philosophical resolve to "fight" prostate cancer. The findings are considered in broader ongoing debates about essentialist sex and the social construction of gender.

Integrin-Mediated Signaling in Prostate Cancer: Role of KAI1/CD82 in Regulating Integrin and Androgen Receptor Function During Metastasis

DTIC Science & Technology

2007-09-01

models of prostate cancer, Clusterin antisense improved the efficacy of chemotherapy, radiation, and androgen withdrawal [Miyake et al., 2000]. Hsp27 ...and phosphorylation of Hsp27 , thereby increasing the network of actin stress fibers and numbers of focal adhesions. Thus, an advantage of the Hsp27 ...Prostatic Dis 6:174–181. Jia Y, Ransom RF, Shibanuma M, Liu C, Welsh MJ, Smoyer WE. 2001. Identification and characterization of hic-5/ARA55 as an hsp27

Ketoconazole inhibition of testicular secretion of testosterone and displacement of steroid hormones from serum transport proteins.

PubMed Central

Grosso, D S; Boyden, T W; Pamenter, R W; Johnson, D G; Stevens, D A; Galgiani, J N

1983-01-01

In vivo perfusion of canine testes with ketoconazole inhibited the stimulation of testosterone production by human chorionic gonadotropin in a dose-dependent manner. Ketoconazole also selectively displaced steroids from serum-binding globulins. Dihydrotestosterone and estradiol binding to sex hormone-binding globulin were inhibited by ketoconazole. Cortisol binding to corticosteroid-binding globulin was unaffected. The concentrations of ketoconazole that inhibited human chorionic gonadotropin stimulation of testicular androgen production and displaced sex steroids from sex hormone-binding globulin were in the range of blood levels found in patients on higher therapeutic dosage regimens. Suppression of testicular testosterone synthesis and displacement of estrogens from sex hormone-binding globulin may decrease the androgen/estrogen ratio of the blood and contribute to the development of gynecomastia that has been reported in some ketoconazole-treated patients. PMID:6301363

The neuroendocrine genesis of polycystic ovary syndrome: A role for arcuate nucleus GABA neurons.

PubMed

Moore, Aleisha M; Campbell, Rebecca E

2016-06-01

Polycystic ovary syndrome (PCOS) is a prevalent and distressing endocrine disorder lacking a clearly identified aetiology. Despite its name, PCOS may result from impaired neuronal circuits in the brain that regulate steroid hormone feedback to the hypothalamo-pituitary-gonadal axis. Ovarian function in all mammals is controlled by the gonadotropin-releasing hormone (GnRH) neurons, a small group of neurons that reside in the pre-optic area of the hypothalamus. GnRH neurons drive the secretion of the gonadotropins from the pituitary gland that subsequently control ovarian function, including the production of gonadal steroid hormones. These hormones, in turn, provide important feedback signals to GnRH neurons via a hormone sensitive neuronal network in the brain. In many women with PCOS this feedback pathway is impaired, resulting in the downstream consequences of the syndrome. This review will explore what is currently known from clinical and animal studies about the identity, relative contribution and significance of the individual neuronal components within the GnRH neuronal network that contribute to the pathophysiology of PCOS. We review evidence for the specific neuronal pathways hypothesised to mediate progesterone negative feedback to GnRH neurons, and discuss the potential mechanisms by which androgens may evoke disruptions in these circuits at different developmental time points. Finally, this review discusses data providing compelling support for disordered progesterone-sensitive GABAergic input to GnRH neurons, originating specifically within the arcuate nucleus in prenatal androgen induced forms of PCOS. Copyright © 2015 Elsevier Ltd. All rights reserved.

Skeletal muscle growth and fiber composition in mice are regulated through the transcription factors STAT5a/b: linking growth hormone to the androgen receptor.

PubMed

Klover, Peter; Chen, Weiping; Zhu, Bing-Mei; Hennighausen, Lothar

2009-09-01

In skeletal muscle, STAT5a/b transcription factors are critical for normal postnatal growth, whole-animal glucose homeostasis, and local IGF-1 production. These observations have led us to hypothesize that STAT5a/b are critical for maintenance of normal muscle mass and function. To investigate this, mice with a skeletal muscle-specific deletion of the Stat5a/b genes (Stat5MKO) were used. Stat5MKO mice displayed reduced muscle mass, altered fiber-type distribution and reduced activity. On a molecular level, gene expression in skeletal muscle of Stat5MKO and control mice was analyzed by microarrays and real-time PCR, both in the presence and absence of growth hormone (GH) stimulation. Expression of several genes involved in muscle growth and fiber type were significantly changed. Specifically, in the quadriceps, a muscle almost exclusively composed of type II fibers, the absence of STAT5a/b led to increased expression of several genes associated with type I fibers and the de novo appearance of type I fibers. In addition, it is shown here that expression of the androgen receptor gene (Ar) is controlled by GH through STAT5a/b. The link between STAT5a/b and Ar gene is likely through direct transcriptional regulation, as chromatin immunoprecipitaion of the Ar promoter region in C2C12 myoblasts was accomplished by antibodies against STAT5a. These experiments demonstrate an important role for STAT5a/b in skeletal muscle physiology, and they provide a direct link to androgen signaling.

Mechanism of Action of Bolandiol (19-Nortestosterone-3β,17β-Diol), a Unique Anabolic Steroid with Androgenic, Estrogenic, and Progestational Activities*

PubMed Central

Attardi, Barbara J.; Page, Stephanie T.; Hild, Sheri A.; Coss, Christopher C.; Matsumoto, Alvin M.

2009-01-01

Bolandiol is a synthetic anabolic steroid that increases lean body mass and bone mineral density without significant stimulation of sex accessory glands in castrate adult male rats. Since bolandiol suppresses gonadotropins and endogenous testosterone (T) production, we investigated its mechanism of action. We compared the potency of bolandiol in vitro and in vivo with T, 5α-dihydrotestosterone (DHT), 19-nortestosterone (19-NT) and estradiol (E2). Bolandiol bound with lower affinity to the recombinant rat androgen receptor (AR) than the other androgens and had low, but measurable, affinity for recombinant human progestin receptors (PR-A, PR-B), and estrogen receptors (ERα and β-1). Functional agonist activity was assessed in transcription assays mediated by AR, PR, or ER. Bolandiol was stimulatory in all these assays, but only 4–9% as potent as T, DHT, and 19-NT via AR, 1% as potent as progesterone via PR, and 3% and 1% as potent as E2 acting through ERα or ERβ, respectively. In immature castrate rats, bolandiol was equipotent to T in stimulating growth of the levator ani muscle but less potent than T in stimulating growth of the sex accessory glands. Bolandiol also stimulated uterine weight increases in immature female rats, which were partly blocked by ICI 182,780, but it was not aromatized in vitro by recombinant human aromatase. In contrast to T, stimulation of sex accessory gland weights by bolandiol was not inhibited by concomitant treatment with the dual 5α-reductase inhibitor dutasteride. As bolandiol exhibits tissue selectivity in vivo, it may act via AR, PR, and/or ER, utilize alternative signaling pathway(s) or transcriptional coregulators, and/or be metabolized to a more potent selective steroid. PMID:19941958

Historical determinants of contemporary attributes of African descendants in the Americas: the androgen receptor holds the key.

PubMed

Aiken, W D

2011-12-01

It is hypothesised that seemingly disparate and unrelated phenomena clustering in persons of African descent living in the Americas such as outstanding sprinting ability and high prostate cancer incidence and mortality are in fact related and emerge from enhanced testosterone responsiveness in descendants of African slaves surviving the transatlantic trade in Africans. It is postulated that the ability to have survived the middle passage was positively correlated with greater responsiveness of the androgen receptor to its primary ligands dihydrotestosterone and testosterone, and that slaves possessing more responsive androgen receptors experienced a survival advantage engendered by the enhanced anabolic effects which accrued such as increased red cell mass and therefore greater oxygen carrying capacity and tissue oxygen delivery enabling these slaves to tolerate stifling conditions in the hull of the slave ship, increased lean muscle mass and therefore greater surface area to volume ratio resulting in easier ability to dissipate heat and remain cool, and increased skin thickness and sebum production resisting the macerating effect of lying in admixed bodily fluids below deck. These androgen effects as well as others would have produced a survival advantage under the severe selection pressure created by the inhumane and physiologically challenging circumstances under which the slaves were transported from the interior of the African continent and West Africa to the 'New World'. This would result in a population shift favouring increased androgen receptor responsiveness in descendants of African slaves populating the Americas and a corresponding geographic and racial distribution of androgen related phenomena such as sprinting prowess and prostate cancer. African-Americans having the highest prostate cancer incidence rate and the Caribbean having the highest prostate cancer mortality rates in the world are consistent with this hypothesis as is the observation that the 10 fastest men and 9 fastest women of all time are exclusively the descendants of West African slaves who survived the middle passage. It is predicted that as yet undiscovered as well as known biological correlates of enhanced androgen receptor responsiveness such as relatively short CAG-repeats in the poly Q tail of exon 1 of the androgen receptor gene will be more prevalent among African-Americans and Afro-Caribbean peoples than among West Africans. It is also predicted that African-Americans and Afro-Caribbean peoples will have relatively shorter CAG-repeats in the androgen receptor gene compared to West Africans. Copyright © 2011 Elsevier Ltd. All rights reserved.

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, alopecia, and acne. Cycle length >35 days suggests chronic anovulation, but cycle length slightly longer than normal (32 to 35 days) or slightly irregular (32 to 35-36 days) needs assessment for ovulatory dysfunction. Ovulatory dysfunction is associated with increased prevalence of endometrial hyperplasia and endometrial cancer, in addition to infertility. In PCOS, hirsutism develops gradually and intensifies with weight gain. In the neoplastic virilizing states, hirsutism is of rapid onset, usually associated with clitoromegaly and oligomenorrhea. Girls with severe acne or acne resistant to oral and topical agents, including isotretinoin (Accutane), may have a 40% likelihood of developing PCOS. Hair loss patterns are variable in women with hyperandrogenemia, typically the vertex, crown or diffuse pattern, whereas women with more severe hyperandrogenemia may see bitemporal hair loss and loss of the frontal hairline. Oral contraceptives (OCPs) can effectively lower androgens and block the effect of androgens via suppression of ovarian androgen production and by increasing sex hormone-binding globulin. Physiologic doses of dexamethasone or prednisone can directly lower adrenal androgen output. Anti-androgens can be used to block the effects of androgen in the pilosebaceous unit or in the hair follicle. Anti-androgen therapy works through competitive antagonism of the androgen receptor (spironolactone, cyproterone acetate, flutamide) or inhibition of 5α-reductase (finasteride) to prevent the conversion of T to its more potent form, 5α-dihydrotestosterone. The choice of antiandrogen therapy is guided by symptoms. The diagnosis of PCOS in adolescents is particularly challenging given significant age and developmental issues in this group. Management of infertility in women with PCOS requires an understanding of the pathophysiology of anovulation as well as currently available treatments. Many features of PCOS, including acne, menstrual irregularities, and hyperinsulinemia, are common in normal puberty. Menstrual irregularities with anovulatory cycles and varied cycle length are common due to the immaturity of the hypothalamic-pituitary-ovarian axis in the 2- to 3-year time period post-menarche. Persistent oligomenorrhea 2 to 3 years beyond menarche predicts ongoing menstrual irregularities and greater likelihood of underlying ovarian or adrenal dysfunction. In adolescent girls, large, multicystic ovaries are a common finding, so ultrasound is not a first-line investigation in women <17 years of age. Ovarian dysfunction in adolescents should be based on oligomenorrhea and/or biochemical evidence of oligo/anovulation, but there are major limitations to the sensitivity of T assays in ranges applicable to young girls. Metformin is commonly used in young girls and adolescents with PCOS as first-line monotherapy or in combination with OCPs and anti-androgen medications. In lean adolescent girls, a dose as low as 850 mg daily may be effective at reducing PCOS symptoms; in overweight and obese adolescents, dose escalation to 1.5 to 2.5 g daily is likely required. Anti-androgen therapy in adolescents could affect bone mass, although available short-term data suggest no effect on bone loss.

Androgenic signaling systems and their role in behavioral evolution.

PubMed

Fuxjager, Matthew J; Schuppe, Eric R

2018-06-05

Sex steroids mediate the organization and activation of masculine reproductive phenotypes in diverse vertebrate taxa. However, the effects of sex steroid action in this context vary tremendously, in that steroid action influences reproductive physiology and behavior in markedly different ways (even among closely related species). This leads to the idea that the mechanisms underlying sex steroid action similarly differ across vertebrates in a manner that supports diversification of important sexual traits. Here, we highlight the Evolutionary Potential Hypothesis as a framework for understanding how androgen-dependent reproductive behavior evolves. This idea posits that the cellular mechanisms underlying androgenic action can independently evolve within a given target tissue to adjust the hormone's functional effects. The result is a seemingly endless number of permutations in androgenic signaling pathways that can be mapped onto the incredible diversity of reproductive phenotypes. One reason this hypothesis is important is because it shifts current thinking about the evolution of steroid-dependent traits away from an emphasis on circulating steroid levels and toward a focus on molecular mechanisms of hormone action. To this end, we also provide new empirical data suggesting that certain cellular modulators of androgen action-namely, the co-factors that dynamically adjust transcritpional effects of steroid action either up or down-are also substrates on which evolution can act. We then close the review with a detailed look at a case study in the golden-collared manakin (Manacus vitellinus). Work in this tropical bird shows how androgenic signaling systems are modified in specific parts of the skeletal muscle system to enhance motor performance necessary to produce acrobatic courtship displays. Altogether, this paper seeks to develop a platform to better understand how steroid action influences the evolution of complex animal behavior. Copyright © 2018 Elsevier Ltd. All rights reserved.

The prohibitin-repressive interaction with E2F1 is rapidly inhibited by androgen signalling in prostate cancer cells

PubMed Central

Koushyar, S; Economides, G; Zaat, S; Jiang, W; Bevan, C L; Dart, D A

2017-01-01

Prohibitin (PHB) is a tumour suppressor molecule with pleiotropic activities across several cellular compartments including mitochondria, cell membrane and the nucleus. PHB and the steroid-activated androgen receptor (AR) have an interplay where AR downregulates PHB, and PHB represses AR. Additionally, their cellular locations and chromatin interactions are in dynamic opposition. We investigated the mechanisms of cell cycle inhibition by PHB and how this is modulated by AR in prostate cancer. Using a prostate cancer cell line overexpressing PHB, we analysed the gene expression changes associated with PHB-mediated cell cycle arrest. Over 1000 gene expression changes were found to be significant and gene ontology analysis confirmed PHB-mediated repression of genes essential for DNA replication and synthesis, for example, MCMs and TK1, via an E2F1 regulated pathway—agreeing with its G1/S cell cycle arrest activity. PHB is known to inhibit E2F1-mediated transcription, and the PHB:E2F1 interaction was seen in LNCaP nuclear extracts, which was then reduced by androgen treatment. Upon two-dimensional western blot analysis, the PHB protein itself showed androgen-mediated charge differentiation (only in AR-positive cells), indicating a potential dephosphorylation event. Kinexus phosphoprotein array analysis indicated that Src kinase was the main interacting intracellular signalling hub in androgen-treated LNCaP cells, and that Src inhibition could reduce this AR-mediated charge differentiation. PHB charge change may be associated with rapid dissociation from chromatin and E2F1, allowing the cell cycle to proceed. The AR and androgens may deactivate the repressive functions of PHB upon E2F1 leading to cell cycle progression, and indicates a role for AR in DNA replication licensing. PMID:28504694

Rational design and synthesis of androgen receptor-targeted nonsteroidal anti-androgen ligands for the tumor-specific delivery of a doxorubicin-formaldehyde conjugate.

PubMed

Cogan, Peter S; Koch, Tad H

2003-11-20

The synthesis and preliminary evaluation of a doxorubicin-formaldehyde conjugate tethered to the nonsteroidal antiandrogen, cyanonilutamide (RU 56279), for the treatment of prostate cancer are reported. The relative ability of the targeting group to bind to the human androgen receptor was studied as a function of tether. The tether served to attach the antiandrogen to the doxorubicin-formaldehyde conjugate via an N-Mannich base of a salicylamide derivative. The salicylamide was selected to serve as a trigger release mechanism to separate the doxorubicin-formaldehyde conjugate from the targeting group after it has bound to the androgen receptor. The remaining part of the tether consisted of a linear group that spanned from the 5-position of the salicylamide to the 3'-position of cyanonilutamide. The structures explored for the linear region of the tether were derivatives of di(ethylene glycol), tri(ethylene glycol), N,N'-disubstituted-piperazine, and 2-butyne-1,4-diol. Relative binding affinity of the tethers bound to the targeting group for human androgen receptor were measured using a (3)H-Mibolerone competition assay and varied from 18% of nilutamide binding for the butynediol-based linear region to less than 1% for one of the piperazine derivatives. The complete targeted drug with the butynediol-based linear region has a relative binding affinity of 10%. This relative binding affinity is encouraging in light of the cocrystal structure of human androgen receptor ligand binding domain bound to the steroid Metribolone which predicts very limited space for a tether connecting the antiandrogen on the inside to the cytotoxin on the outside.

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. Copyright © 2012 Elsevier Ltd. All rights reserved.

Effect of androgen replacement therapy on atherosclerotic risk markers in young-to-middle-aged men with idiopathic hypogonadotropic hypogonadism.

PubMed

Doğan, Berçem Ayçiçek; Karakılıç, Ersen; Tuna, Mazhar Müslüm; Arduç, Ayşe; Berker, Dilek; Güler, Serdar

2015-03-01

Idiopathic hypogonadotropic hypogonadism is a rare disorder. This study evaluated the effect of androgen replacement therapy on atherosclerotic risk markers in young-to-middle-aged men with this disorder. Forty-three male patients aged 30 (range: 24-39 years) who were newly diagnosed with idiopathic hypogonadotropic hypogonadism and 20 age-, sex- and weight-matched controls (range: 26-39 years) were included in the study. Androgen replacement therapy was given according to the Algorithm of Testosterone Therapy in Adult Men with Androgen Deficiency Syndromes (2010; Journal of Clinical Endocrinology and Metabolism, 95, 2536). The patients were assessed at a pretreatment visit and 3 and 6 months after the treatment. Inflammatory markers and lipid parameters were evaluated. Endothelial function was assessed with brachial flow-mediated dilation of a brachial artery and high-resolution ultrasonography of the carotid intima-media thickness. The carotid intima-media thickness (P < 0·001) was higher and the brachial flow-mediated diameter (P = 0·002) was lower in patients with idiopathic hypogonadotropic hypogonadism compared to the control subjects at the pretreatment visit. There was a negative correlation between the total testosterone level and carotid intima-media thickness (r = -0·556, P = <0·001). The carotid intima-media thickness and per cent flow-mediated diameter were significantly improved in the patient group 6 months after the androgen replacement therapy (P = 0·002 and 0·026, respectively). This study indicated that low total testosterone levels can be considered a significant marker of atherosclerosis in patients with idiopathic hypogonadotropic hypogonadism and that androgen replacement therapy significantly reduces atherosclerotic risk markers in these patients after 6 months. © 2014 John Wiley & Sons Ltd.

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

Childhood obesity and its impact on the development of adolescent PCOS.

PubMed

Anderson, Amy D; Solorzano, Christine M Burt; McCartney, Christopher R

2014-05-01

Obesity exacerbates the reproductive and metabolic manifestations of polycystic ovary syndrome (PCOS). The symptoms of PCOS often begin in adolescence, and the rising prevalence of peripubertal obesity has prompted concern that the prevalence and severity of adolescent PCOS is increasing in parallel. Recent data have disclosed a high prevalence of hyperandrogenemia among peripubertal adolescents with obesity, suggesting that such girls are indeed at risk for developing PCOS. Obesity may impact the risk of PCOS via insulin resistance and compensatory hyperinsulinemia, which augments ovarian/adrenal androgen production and suppresses sex hormone-binding globulin (SHBG), thereby increasing androgen bioavailability. Altered luteinizing hormone (LH) secretion plays an important role in the pathophysiology of PCOS, and although obesity is generally associated with relative reductions of LH, higher LH appears to be the best predictor of increased free testosterone among peripubertal girls with obesity. Other potential mechanisms of obesity-associated hyperandrogenemia include enhanced androgen production in an expanded fat mass and potential effects of abnormal adipokine/cytokine levels. Adolescents with PCOS are at risk for comorbidities such as metabolic syndrome and impaired glucose tolerance, and concomitant obesity compounds these risks. For all of these reasons, weight loss represents an important therapeutic target in obese adolescents with PCOS. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Antimüllerian hormone levels are independently related to ovarian hyperandrogenism and polycystic ovaries.

PubMed

Rosenfield, Robert L; Wroblewski, Kristen; Padmanabhan, Vasantha; Littlejohn, Elizabeth; Mortensen, Monica; Ehrmann, David A

2012-07-01

To determine the relationship of antimüllerian hormone (AMH) levels to polycystic ovaries and ovarian androgenic function. Prospective case-control study. General clinical research center. Eumenorrheic asymptomatic volunteers without (V-NO; n = 19; reference population) or with (V-PCO; n = 28) a polycystic ovary and hyperandrogenemic anovulatory subjects grouped according to ovarian function into typical PCOS (PCOS-T; n = 37) and atypical PCOS (PCOS-A; n = 18). Pelvic ultrasonography, short dexamethasone androgen-suppression test (SDAST), and GnRH agonist (GnRHag) test. Baseline AMH levels were related to polycystic ovary status, testosterone response to SDAST, and 17-hydroxyprogesterone response to GnRHag test. AMH levels correlated with SDAST and GnRHag test outcomes. AMH was elevated (>6.2 ng/mL) in 32% of V-PCO versus 5% V-NO. The 21% of V-PCO who met Rotterdam PCOS criteria all had functional ovarian hyperandrogenism, but AMH levels were similar to nonhyperandrogenic V-PCO. AMH >10.7 ng/mL discriminated V-PCO from PCOS with 96% specificity and 41% sensitivity for PCOS-T, and insignificantly for PCOS-A. AMH levels are independently related to ovarian androgenic function and polycystic ovaries. Very high AMH levels are specific but insensitive for PCOS. In the absence of hyperandrogenism, moderate AMH elevation in women with normal-variant polycystic ovaries seems to indicate an enlarged oocyte pool. Copyright © 2012 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Antimüllerian hormone levels are independently related to ovarian hyperandrogenism and polycystic ovaries

PubMed Central

Rosenfield, Robert L.; Wroblewski, Kristen; Padmanabhan, Vasantha; Littlejohn, Elizabeth; Mortensen, Monica; Ehrmann, David A.

2013-01-01

Objective To determine the relationship of antimüllerian hormone (AMH) levels to polycystic ovaries and ovarian androgenic function. Design Prospective case-control study. Setting General clinical research center. Participant(s) Eumenorrheic asymptomatic volunteers without (V-NO; n = 19; reference population) or with (V-PCO; n = 28) a polycystic ovary and hyperandrogenemic anovulatory subjects grouped according to ovarian function into typical PCOS (PCOS-T; n = 37) and atypical PCOS (PCOS-A; n = 18). Intervention(s) Pelvic ultrasonography, short dexamethasone androgen-suppression test (SDAST), and GnRH agonist (GnRHag) test. Main Outcome Measure(s) Baseline AMH levels were related to polycystic ovary status, testosterone response to SDAST, and 17-hydroxyprogesterone response to GnRHag test. Result(s) AMH levels correlated with SDAST and GnRHag test outcomes. AMH was elevated (>6.2 ng/mL) in 32% of V-PCO versus 5% V-NO. The 21% of V-PCO who met Rotterdam PCOS criteria all had functional ovarian hyperandrogenism, but AMH levels were similar to nonhyperandrogenic V-PCO. AMH >10.7 ng/mL discriminated V-PCO from PCOS with 96% specificity and 41% sensitivity for PCOS-T, and insignificantly for PCOS-A. Conclusion(s) AMH levels are independently related to ovarian androgenic function and polycystic ovaries. Very high AMH levels are specific but insensitive for PCOS. In the absence of hyperandrogenism, moderate AMH elevation in women with normal-variant polycystic ovaries seems to indicate an enlarged oocyte pool. PMID:22541936

A Perspective on Middle-Aged and Older Men With Functional Hypogonadism: Focus on Holistic Management.

PubMed

Grossmann, Mathis; Matsumoto, Alvin M

2017-03-01

Middle-aged and older men (≥50 years), especially those who are obese and suffer from comorbidities, not uncommonly present with clinical features consistent with androgen deficiency and modestly reduced testosterone levels. Commonly, such men do not demonstrate anatomical hypothalamic-pituitary-testicular axis pathology but have functional hypogonadism that is potentially reversible. Literature review from 1970 to October 2016. Although definitive randomized controlled trials are lacking, evidence suggests that in such men, lifestyle measures to achieve weight loss and optimization of comorbidities, including discontinuation of offending medications, lead to clinical improvement and a modest increase in testosterone. Also, androgen deficiency-like symptoms and end-organ deficits respond to targeted treatments (such as phosphodiesterase-5 inhibitors for erectile dysfunction) without evidence that hypogonadal men are refractory. Unfortunately, lifestyle interventions remain difficult and may be insufficient even if successful. Testosterone therapy should be considered primarily for men who have significant clinical features of androgen deficiency and unequivocally low testosterone levels. Testosterone should be initiated either concomitantly with a trial of lifestyle measures, or after such a trial fails, after a tailored diagnostic work-up, exclusion of contraindications, and appropriate counseling. There is modest evidence that functional hypogonadism responds to lifestyle measures and optimization of comorbidities. If achievable, these interventions may have demonstrable health benefits beyond the potential for increasing testosterone levels. Therefore, treatment of underlying causes of functional hypogonadism and of symptoms should be used either as an initial or adjunctive approach to testosterone therapy.

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

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

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

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

The Polycystic Ovary Morphology-Polycystic Ovary Syndrome Spectrum

PubMed Central

Rosenfield, Robert L.

2014-01-01

Background Polycystic ovary syndrome (PCOS) is the most common cause of chronic hyperandrogenic anovulation. Two-thirds of PCOS patients have functionally typical PCOS, with typical functional ovarian hyperandrogenism manifest as 17-hydroxyprogesterone hyper-responsiveness to gonadotropin stimulation. Most, but not all, of the remainder have atypical functional ovarian hyperandrogenism. Many asymptomatic volunteers with polycystic ovary morphology (PCOM) have similar abnormalities. Objective The objective of this paper is to review the relationship of biochemical ovarian function to the clinical spectrum observed in PCOS and in normal volunteers with PCOM. Findings Adolescents and adults with PCOS are similar clinically and biochemically. Ninety-five percent of functionally typical PCOS have classic PCOS, ie, hyperandrogenic anovulation with PCOM. In addition to having more severe hyperandrogenism and a greater prevalence of PCOM than other PCOS, they have a significantly greater prevalence of glucose intolerance although insulin resistance is similarly reduced. Half of normal-variant PCOM have PCOS-related steroidogenic dysfunction, which suggests a PCOS carrier state. Conclusions There is a spectrum of ovarian androgenic dysfunction that ranges from subclinical hyperandrogenemia in some normal-variant PCOM to severe ovarian hyperandrogenism in most classic PCOS. A minority of mild PCOS cases do not fall on this spectrum of ovarian androgenic dysfunction, but rather seem to have obesity as the basis of their hyperandrogenism, or, less often, isolated adrenal androgenic dysfunction. Half of normal-variant PCOM also do not fall on the PCOS spectrum, and some of these seem to have excessive folliculogenesis as a variant that may confer mild prolongation of the reproductive lifespan. Improved understanding of PCOM in young women is needed. PMID:25840648

Overexpression of Aldo-Keto Reductase 1C3 (AKR1C3) in LNCaP Cells Diverts Androgen Metabolism towards Testosterone Resulting in Resistance to the 5α-Reductase Inhibitor Finasteride

PubMed Central

Byrns, Michael C.; Mindnich, Rebekka; Duan, Ling; Penning, Trevor M.

2012-01-01

Type 5 17β-hydroxysteroid dehydrogenase (AKR1C3) is the major enzyme in the prostate that reduces 4-androstene-3,17-dione (Δ4-Adione) to the androgen receptor (AR) ligand testosterone. AKR1C3 is upregulated in prostate cancer (PCa) and castrate resistant prostate cancer (CRPC) that develops after androgen deprivation therapy. PCa and CRPC often depend on intratumoral androgen biosynthesis and upregulation of AKR1C3 could contribute to intracellular synthesis of AR ligands and stimulation of proliferation through AR signalling. To test this hypothesis, we developed an LNCaP prostate cancer cell line overexpressing AKR1C3 (LNCaP-AKR1C3) and compared its metabolic and proliferative responses to Δ4-Adione treatment with that of the parental, AKR1C3 negative LNCaP cells. In LNCaP and LNCaP-AKR1C3 cells, metabolism proceeded via 5α-reduction to form 5α-androstane-3,17-dione and then (epi)androsterone-3-glucuronide. LNCaP-AKR1C3 cells made significantly higher amounts of testosterone-17β-glucuronide. When 5α-reductase was inhibited by finasteride, the production of testosterone-17β-glucuronide was further elevated in LNCaP-AKR1C3 cells. When AKR1C3 activity was inhibited with indomethacin the production of testosterone-17β-glucuronide was significantly decreased. Δ4-Adione treatment stimulated cell proliferation in both cell lines. Finasteride inhibited LNCaP cell proliferation, consistent with 5α-androstane-3,17-dione acting as the major metabolite that stimulates growth by binding to the mutated AR. However, LNCaP-AKR1C3 cells were resistant to the growth inhibitory properties of finasteride, consistent with the diversion of Δ4-Adione metabolism from 5α-reduced androgens to increased formation of testosterone. Indomethacin did not result in differences in Δ4-Adione induced proliferation since this treatment led to the same metabolic profile in LNCaP and LNCaP-AKR1C3 cells. We conclude that AKR1C3 overexpression diverts androgen metabolism to testosterone that results in proliferation in androgen sensitive prostate cancer. This effect is seen despite high levels of uridine glucuronosyl transferases suggesting that AKR1C3 activity can surmount the effects of this elimination pathway. Treatment options in prostate cancer that target 5α-reductase where AKR1C3 co-exists may be less effective due to the diversion of Δ4-Adione to testosterone. PMID:22265960

Simultaneous determination of androgenic and estrogenic endpoints in the threespine stickleback (Gasterosteus aculeatus) using quantitative RT-PCR.

PubMed

Hogan, Natacha S; Wartman, Cheryl A; Finley, Megan A; van der Lee, Jennifer G; van den Heuvel, Michael R

2008-12-11

A method to evaluate the expression of three hormone responsive genes, vitellogenin (estrogens), spiggin (androgens), and an androgen receptor (ARbeta) using real-time PCR in threespine stickleback is presented. Primers were designed from previously characterised spiggin and ARbeta sequences, while a homology cloning strategy was used to isolate a partial gene sequence for stickleback vitellogenin (Vtg). Spiggin mRNA was significantly higher in kidneys of field-caught males compared to females by greater than five orders of magnitude while ARbeta levels were only 1.4-fold higher in males. Female fish had four order of magnitude higher liver Vtg expression than wild-captured males. To determine the sensitivity of these genes to induction by hormones, male and female sticklebacks were exposed to 1, 10 and 100 ng/L of methyltestosterone (MT) or estradiol (E2) in a flow-through exposure system for 7 days. Spiggin induction in females, and Vtg induction in males were both detectable at 10 ng/L of MT and E2, respectively. MT exposure did not induce ARbeta expression in the kidneys of female stickleback. In vitro gonadal steroid hormones production was measured in testes and ovaries of exposed stickleback to compare gene expression endpoints to an endpoint of hormonal reproductive alteration. Reduction in testosterone production in ovaries at all three MT exposure concentrations, and ovarian estradiol synthesis at the 100 ng/L exposure were the only effects observed in the in vitro steroidogenesis for either hormone exposure. Application of these methods to assess both androgenic, estrogenic, and anti-steroidogenic properties of environmental contaminants in a single fish species will be a valuable tool for identifying compounds causing reproductive dysfunction in fishes.

Sex steroids and personality traits in the middle luteal phase of healthy normally menstruating young professional women.

PubMed

Avgoustinaki, Pavlina D; Mitsopoulou, Effrosyni; Chlouverakis, Gregorios; Triantafillou, Theoni; Venihaki, Maria; Koukouli, Sofia; Margioris, Andrew N

2012-01-01

Sex steroids affect human behavior. The aim of the present study was to determine the associations, if any, between the circulating levels of gonadal and adrenal sex steroids in the mid luteal phase (21st day of a normal menstrual cycle, MC) of young professional women and psychometric parameters as assessed by the Minnesota Multiphasic Personality Inventory (MMPI). Our results are as follows: (a) The metabolic product of activated adrenal and gonadal androgens, 3alpha-diolG, was modestly but significantly associated with the social introversion scale (10-SI) (r=0.36, p<0.05), independently accounting for 13% of its variation across participants (R²=0.13, F(1,45)=6.58, p=0.014). (b) Total testosterone was significantly associated with the paranoia scale (6-Pa) (r=0.27, p<0.05). Multiple regression analyses indicated that 10% of the variability in paranoia scores could be independently explained by total testosterone levels (R²=0.10, F(1,57)=6.23, p=0.016). We were unable to find any association between the circulating androgens and scores on the masculinity-femininity scale (Mf). We were also unable to document any association between the weak adrenal androgens DHEA and DHEA-S and depression in contrast to several published reports. (c) Our data suggest a marginally significant association between progesterone and scores on the 7-Pt (obsessive/compulsive/psychasthenia) scale (r=0.27, p<0.05). However, only 7% of the 7-Pt variance was explained by progesterone (R²=0.071, F(1,50)=3.81, p=0.057). We have found that total testosterone was associated with the paranoia score, the metabolic product of activated androgens, 3alpha-diolG, to social introversion and, finally, progesterone to obsessive-compulsive behavior.

Phase 1b study of orteronel in postmenopausal women with hormone-receptor positive (HR+) metastatic breast cancer

PubMed Central

Rampurwala, Murtuza; Wisinski, Kari B; Burkard, Mark E; Ehsani, Sima; O’Regan, Ruth M; Carmichael, Lakeesha; Kim, KyungMann; Kolesar, Jill; Tevaarwerk, Amye J

2017-01-01

Intro Suppressing both androgens and estrogens may circumvent hormone receptor resistance in breast cancer by reducing androgen receptor stimulation. Selective inhibition of the 17, 20-lyase enzyme by orteronel leads to decreased androgen production in men and would be anticipated to reduce estrogen and androgen production in women. Thus, we conducted a phase 1b study of orteronel in postmenopausal women with hormone-receptor positive (HR+) metastatic breast cancer. Methods The primary objective was to identify the recommended phase 2 dose (R2PD) of orteronel in women; escalation was via standard 3+3 design. The initial dose was 300 mg BID and escalated to 400 mg BID. Cycle length was 28 days. Enrolled patients had HR+ metastatic breast cancer and were evaluated every 8 weeks for disease progression. Results Eight heavily pre-treated women enrolled [median age: 57 yo (range 47–73)]. Four received 300 mg BID at dose level 1; 4 received 400 mg BID at dose level 2. No dose limiting toxicities (DLTs) were observed. Adverse events (AE) at least possibly related to orteronel included grade 1–2 nausea (n=4) and bone pain (n=3), and grade 1 hypokalemia, hot flashes, myalgia and AST elevation (n=2). The only grade 3 AE was hypertension (n=2) with 8 patients receiving 34 cycles of treatment. No objective responses were seen; clinical benefit was seen in 2 patients with stable disease for more than 6 months. Serum estrogens and testosterone were suppressed from baseline on both doses of orteronel. Conclusions Orteronel 400 mg BID is well tolerated in postmenopausal women, and significantly suppresses serum estrogens and testosterone. Clinical benefit was seen among heavily pretreated postmenopausal women with HR+ metastatic breast cancer. PMID:27826831

Androgens as double-edged swords: Induction and suppression of follicular development.

PubMed

Pan, Jie-Xue; Zhang, Jun-Yu; Ke, Zhang-Hong; Wang, Fang-Fang; Barry, John A; Hardiman, Paul J; Qu, Fan

2015-01-01

Androgens, which are mediated via the androgen receptor (AR), play important roles in normal follicular development and female fertility. However, just like a double-edged sword, besides the positive effects of androgen on follicular development, abnormal androgen levels, especially as in hyperandrogenism, seriously suppress normal follicular development. A crucial balance exists between the importance of androgens in follicular development and their negative effects when in excess. As the first meiotic division and epigenetic reprogramming are two critical events in oogenesis, abnormal androgen levels or deficiency in androgen/AR signaling in the ovary may affect these vital events. Oocytes have a tendency to develop genomic instability, thus resulting in an increasing incidence of unpredictable adult diseases. Although many studies have explored the effects of androgens and AR on follicular development, the conclusions are controversial and there has been no thorough review of this topic. This review focuses on the roles of androgens in the physiological process of follicular development, summarizes new insights into the roles of androgens in the arrested development of follicles, and discusses the potential risk of adult diseases originating from abnormal follicular androgen levels or androgen receptor signals, which may determine areas for future studies.

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

[Panhypopituitarism caused by an intrasellar cystic mass in late-onset hypogonadism clinic].

PubMed

Yamamoto, Yoshiyuki; Takada, Shingo; Kinjo, Takanori; Nonomura, Daichi; Yoneda, Suguru; Nomura, Hironori; Tei, Norihide; Matsumiya, Kiyomi; Okusu, Takahiro

2013-10-01

A 74-year-old man who was referred to our late onset hypogonadism clinic presented with sweating and loss of appetite. His aging males' symptoms (AMS) and international index of erectile function (IIEF-5) scores were 59 and 2, respectively. His hormonal examination revealed extremely low free testosterone values. The patient was started on androgen replacement therapy, but his symptoms did not improve. Additional hormonal examinations revealed low values for other anterior pituitary hormones. Magnetic resonance imaging revealed an intrasellar cystic mass with suprasellar extension. We considered this mass caused hypothalamic hypopituitarism. A load test for anterior pituitary hormones revealed panhypogonadism. His symptoms improved after administration of adrenal and thyroid hormones and androgen. Five months after start of drug administration, his AMS score improved to 29, but IIEF-5 score showed little change. As a matter of course, not only androgen but all pituitary-related hormones are needed for hypopituitarism patients.

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

PubMed Central

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

2005-01-01

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

Selective androgen receptor modulators for the treatment of late onset male hypogonadism.

PubMed

Coss, Christopher C; Jones, Amanda; Hancock, Michael L; Steiner, Mitchell S; Dalton, James T

2014-01-01

Several testosterone preparations are used in the treatment of hypogonadism in the ageing male. These therapies differ in their convenience, flexibility, regional availability and expense but share their pharmacokinetic basis of approval and dearth of long-term safety data. The brevity and relatively reduced cost of pharmacokinetic based registration trials provides little commercial incentive to develop improved novel therapies for the treatment of late onset male hypogonadism. Selective androgen receptor modulators (SARMs) have been shown to provide anabolic benefit in the absence of androgenic effects on prostate, hair and skin. Current clinical development for SARMs is focused on acute muscle wasting conditions with defi ned clinical endpoints of physical function and lean body mass. Similar regulatory clarity concerning clinical deficits in men with hypogonadism is required before the beneficial pharmacology and desirable pharmacokinetics of SARMs can be employed in the treatment of late onset male hypogonadism.

Selective androgen receptor modulators for the treatment of late onset male hypogonadism

PubMed Central

Coss, Christopher C; Jones, Amanda; Hancock, Michael L; Steiner, Mitchell S; Dalton, James T

2014-01-01

Several testosterone preparations are used in the treatment of hypogonadism in the ageing male. These therapies differ in their convenience, flexibility, regional availability and expense but share their pharmacokinetic basis of approval and dearth of long-term safety data. The brevity and relatively reduced cost of pharmacokinetic based registration trials provides little commercial incentive to develop improved novel therapies for the treatment of late onset male hypogonadism. Selective androgen receptor modulators (SARMs) have been shown to provide anabolic benefit in the absence of androgenic effects on prostate, hair and skin. Current clinical development for SARMs is focused on acute muscle wasting conditions with defined clinical endpoints of physical function and lean body mass. Similar regulatory clarity concerning clinical deficits in men with hypogonadism is required before the beneficial pharmacology and desirable pharmacokinetics of SARMs can be employed in the treatment of late onset male hypogonadism. PMID:24407183

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

PubMed Central

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

2010-01-01

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

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

PubMed

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

2017-09-01

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

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

PubMed Central

Schiffer, Lina; Kempegowda, Punith; Arlt, Wiebke

2017-01-01

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

Osteopenia as a feature of the androgen insensitivity syndrome.

PubMed

Soule, S G; Conway, G; Prelevic, G M; Prentice, M; Ginsburg, J; Jacobs, H S

1995-12-01

The syndrome of androgen insensitivity, a paradigm of a hormone resistance syndrome, manifests as failure of masculinization despite normal or high concentrations of serum testosterone. The defect in these 46 XY patients resides in the androgen receptor gene, with consequent defective androgen action and abnormal sexual differentiation. We sought to evaluate whether the adverse sequelae of androgen resistance may extend to skeletal tissue by measuring bone mineral density in six patients with androgen insensitivity. A cross-sectional retrospective study. Bone mineral density was measured by means of a Dexa (Hologic QDR 1000 scanner). The diagnosis of androgen insensitivity was confirmed in each patient by karyotype and assay of sex hormones. The five adult patients with androgen insensitivity had been exposed to both defective androgen action and variable periods of oestrogen deficiency. The latter resulted from the low circulating oestrogen concentrations (for premenopausal females) before gonadectomy and inadequate oestrogen replacement after gonadectomy. All five adults with androgen insensitivity had osteopenia in both the lumbar spine (T-score -1.52 to -3.85) and femoral neck (T-score -1.34 to -4.91). Osteopenia in patients with androgen insensitivity may relate to defective androgen action, oestrogen deficiency or a combination of the two. These observations have implications for the management of patients with androgen insensitivity and may provide insight into the effects of androgens on the female as well as the male skeleton.

Habitual physical activity is associated with improved anthropometric and androgenic profile in PCOS: a cross-sectional study.

PubMed

Mario, F M; Graff, S K; Spritzer, P M

2017-04-01

To examine the effect of habitual physical activity (PA) on the metabolic and hormonal profiles of women with polycystic ovary syndrome. Anthropometric, metabolic and hormonal assessment and determination of habitual PA levels with a digital pedometer were evaluated in 84 women with PCOS and 67 age- and body mass index (BMI)-matched controls. PA status was defined according to number of steps (≥7500 steps, active, or <7500 steps, sedentary). BMI was lower in active women from both groups. Active PCOS women presented lower waist circumference (WC) and lipid accumulation product (LAP) values versus sedentary PCOS women. In the control group, active women also had lower WC, lower values for fasting and 120-min insulin, and lower LAP than sedentary controls. In the PCOS group, androgen levels were lower in active versus sedentary women (p = 0.001). In the control group, free androgen index (FAI) was also lower in active versus sedentary women (p = 0.018). Homeostasis model assessment of insulin resistance and 2000 daily step increments were independent predictors of FAI. Each 2000 daily step increment was associated with a decrease of 1.07 in FAI. Habitual PA was associated with a better anthropometric and androgenic profile in PCOS.

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.

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. © 2014 S. Karger AG, Basel.

Chronic Exposure to Anabolic Androgenic Steroids Alters Neuronal Function in the Mammalian Forebrain via Androgen Receptor- and Estrogen Receptor-Mediated Mechanisms

PubMed Central

Penatti, Carlos A A; Porter, Donna M; Henderson, Leslie P

2009-01-01

Anabolic androgenic steroids (AAS) can promote detrimental effects on social behaviors for which γ-aminobutyric acid type A (GABAA) receptor-mediated circuits in the forebrain play a critical role. While all AAS bind to androgen receptors (AR), they may also be aromatized to estrogens and thus potentially impart effects via estrogen receptors (ER). Chronic exposure of wild type male mice to a combination of chemically distinct AAS increased action potential (AP) frequency, selective GABAA receptor subunit mRNAs, and GABAergic synaptic current decay in the medial preoptic area (mPOA). Experiments performed with pharmacological agents and in AR-deficient Tfm mutant mice suggest that the AAS-dependent enhancement of GABAergic transmission in wild type mice is AR-mediated. In AR-deficient mice, the AAS elicited dramatically different effects, decreasing AP frequency, sIPSC amplitude and frequency and the expression of selective GABAA receptor subunit mRNAs. Surprisingly, in the absence of AR signaling, the data indicate that the AAS do not act as ER agonists, but rather suggest a novel in vivo action in which the AAS inhibit aromatase and impair endogenous ER signaling. These results show that the AAS have the capacity to alter neuronal function in the forebrain via multiple steroid signaling mechanisms and suggest that effects of these steroids in the brain will depend not only on the balance of AR- vs. ER-mediated regulation for different target genes, but also on the ability of these drugs to alter steroid metabolism and thus the endogenous steroid milieu. PMID:19812324

Self-Perceived Weight and Anabolic Steroid Misuse Among US Adolescent Boys

PubMed Central

Jampel, Jonathan D.; Murray, Stuart B.; Griffiths, Scott; Blashill, Aaron J.

2016-01-01

Purpose Anabolic steroid misuse is a growing concern among adolescent boys, and chronic misuse is associated with multisystemic health consequences. However, little is known about weight related predictors of anabolic steroid misuse. We examined the prediction of lifetime anabolic steroid misuse as a function of self-perceived weight status among US adolescent boys. Methods Analysis was undertaken using the 2013 Youth Risk Behavior Survey, a nationally representative data set sampling public and private high school students throughout the United States. Data from a total of 6,000 US adolescent boys were used in the present study. Results The prevalence of ever misusing anabolic androgenic steroids was 12.6% among boys who viewed themselves as very underweight, 11.9% for boys who viewed themselves as very overweight, compared with 3.8% for boys who viewed themselves as about the right weight. Compared to boys who viewed themselves as about the right weight, boys who self-perceived themselves as very underweight (adjusted odds ratio = 6.9, 95% confidence interval: 2.7–17.7, p < .001) and very overweight (adjusted odds ratio = 3.8, 95% confidence interval: 1.8–7.7, p < .001) were significantly associated with increased risk of anabolic androgenic steroid misuse. Conclusions Large effect size estimates were revealed, suggesting that anabolic androgenic steroid misuse is not solely a function of boys desiring increased mass; boys who desire leanness are also likely to misuse anabolic androgenic steroids. Future prevention efforts should target not only boys who view themselves as underweight but also those who perceive themselves as overweight. PMID:26598061

Transcriptional networks associated with the immune system are disrupted by organochlorine pesticides in largemouth bass (Micropterus salmoides) ovary.

PubMed

Martyniuk, Christopher J; Doperalski, Nicholas J; Feswick, April; Prucha, Melinda S; Kroll, Kevin J; Barber, David S; Denslow, Nancy D

2016-08-01

Largemouth bass (Micropterus salmoides) inhabiting Lake Apopka, Florida are exposed to high levels of persistent organochlorine pesticides (OCPs) and dietary uptake is a significant route of exposure for these apex predators. The objectives of this study were to determine the dietary effects of two organochlorine pesticides (p, p'-dichlorodiphenyldichloroethylene; p, p' DDE and methoxychlor; MXC) on the reproductive axis of largemouth bass. Reproductive bass (late vitellogenesis) were fed one of the following diets: control pellets, 125ppm p, p'-DDE, or 10ppm MXC (mg/kg) for 84days. Due to the fact that both p,p' DDE and MXC have anti-androgenic properties, the anti-androgenic pharmaceutical flutamide was fed to a fourth group of largemouth bass (750ppm). Following a 3 month exposure, fish incorporated p,p' DDE and MXC into both muscle and ovary tissue, with the ovary incorporating 3 times more organochlorine pesticides compared to muscle. Endpoints assessed were those related to reproduction due to previous studies demonstrating that these pesticides impact the reproductive axis and we hypothesized that a dietary exposure would result in impaired reproduction. However, oocyte distribution, gonadosomatic index, plasma vitellogenin, and plasma sex steroids (17β-estradiol, E2 and testosterone, T) were not different between control animals and contaminant-fed largemouth bass. Moreover, neither p, p' DDE nor MXC affected E2 or T production in ex vivo oocyte cultures from chemical-fed largemouth bass. However, both pesticides did interfere with the normal upregulation of androgen receptor that is observed in response to human chorionic gonadotropin in ex vivo cultures, an observation that may be related to their anti-androgenic properties. Transcriptomics profiling in the ovary revealed that gene networks related to cell processes such as leukocyte cell adhesion, ossification, platelet function and inhibition, xenobiotic metabolism, fibrinolysis, and thermoregulation were altered by p, p' DDE, MXC, and flutamide. Interestingly, immune-related gene networks were suppressed by all three chemicals. The data suggest that p, p' DDE and flutamide affected more genes in common with each other than either chemical with MXC, consistent with studies suggesting that p, p' DDE is a more potent anti-androgen than MXC. These data demonstrate that reproductive health was not affected by these specific dietary treatments, but rather the immune system, which may be a significant target of organochlorine pesticides. The interaction between the reproductive and immune systems should be considered in future studies on these legacy and persistent pesticides. Copyright © 2016 Elsevier B.V. All rights reserved.

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

Proteomic Comparison and MRM-Based Comparative Analysis of Metabolites Reveal Metabolic Shift in Human Prostate Cancer Cell Lines.

PubMed

Shu, Qingbo; Cai, Tanxi; Chen, Xiulan; Zhu, Helen He; Xue, Peng; Zhu, Nali; Xie, Zhensheng; Wei, Shasha; Zhang, Qing; Niu, Lili; Gao, Wei-Qiang; Yang, Fuquan

2015-08-07

One of the major challenges in prostate cancer therapy remains the development of effective treatments for castration-resistant prostate cancer (CRPC), as the underlying mechanisms for its progression remain elusive. Previous studies showed that androgen receptor (AR) is crucially involved in regulation of metabolism in prostate cancer (PCa) cells throughout the transition from early stage, androgen-sensitive PCa to androgen-independent CRPC. AR achieves such metabolic rewiring directively either via its transcriptional activity or via interactions with AMP-activated protein kinase (AMPK). However, due to the heterogeneous expression and activity status of AR in PCa cells, it remains a challenge to investigate the links between AR status and metabolic alterations. To this end, we compared the proteomes of three pairs of androgen-sensitive (AS) and androgen-independent (AI) PCa cell lines, namely, PC3-AR(+)/PC3, 22Rv1/Du145, and LNCaP/C42B, using an iTRAQ labeling approach. Our results revealed that most of the differentially expressed proteins between each pair function in metabolism, indicating a metabolic shift between AS and AI cells, as further validated by multiple reaction monitoring (MRM)-based quantification of nucleotides and relative comparison of fatty acids between these cell lines. Furthermore, increased adenylate kinase isoenzyme 1 (AK1) in AS relative to AI cells may result in activation of AMPK, representing a major regulatory factor involved in the observed metabolic shift in PCa cells.

Gender role behavior in children with XY karyotype and disorders of sex development.

PubMed

Jürgensen, Martina; Hiort, Olaf; Holterhus, Paul-Martin; Thyen, Ute

2007-03-01

Children exhibit gender-typical preferences in play, toys, activities and interests, and playmates. Several studies suggest that high concentrations of pre- and postnatal androgens contribute to male-typical behavior development, whereas female-typical behavior develops in the absence of high androgens levels. This study aims to explore the consequences of hypoandrogenization on gender-typical behavior in children who have an XY karyotype and disorder of sex development (DSD). Participants included 33 children (ages 2-12 years) with an XY karyotype and DSD; 21 reared as girls and 12 reared as boys. Children's preferred activities and interests and playmate preferences were assessed with parent report questionnaires, a structured free-play task, and choice of a toy to keep as a gift. Participant's responses were compared to those of children recruited in a pre-school and elementary school survey (N=166). In this study, the degree of hypoandrogenization as indicated by genital stage and diagnosis showed a significant relationship to nearly all of the gender-related behaviors assessed, supporting the hypothesis that masculinization of gender role behavior is a function of prenatal androgen exposure. Despite the fact that children with partial androgen effects reared as girls showed increased "boyish" behaviors, they did not show increased signs of gender identity confusion or instability on a group level. We conclude that androgen exposure plays a decisive role in the development of gender-typical behavior in children with XY karyotype and DSD conditions.

The ErbB family and androgen receptor signaling are targets of Celecoxib in prostate cancer.

PubMed

Brizzolara, Antonella; Benelli, Roberto; Venè, Roberta; Barboro, Paola; Poggi, Alessandro; Tosetti, Francesca; Ferrari, Nicoletta

2017-08-01

Inflammation plays a central role in prostate cancer (PCa) development through significant crosstalk between the COX-2-ErbB family receptor network and androgen receptor (AR)-EGFR signaling pathways. The purpose of this work was to determine the ability of the COX-2 inhibitor Celecoxib to modulate the EGFR-AR signaling pathway in androgen-dependent PCa cells and to provide a rationale for its beneficial use in chemopreventive strategies. Functional studies of Celecoxib activity were performed on LNCaP prostate cancer cells. Western blotting, gene expression analysis, dual-luciferase reporter assay and ELISA were applied to assess the Celecoxib mechanisms of action. We found that Celecoxib, through EGF and amphiregulin (AREG) induction, caused EGFR and ErbB2 activation and consequent degradation associated with the inhibition of androgenic signaling. By upregulating the E3 ubiquitin ligase Nrdp1, Celecoxib also efficiently downregulated ErbB3, which is strongly implicated in castration-resistant prostate cancer. Lastly, Celecoxib directly regulated AR transcription and translation independent of ErbB activation by downregulating the RNA binding protein heterogeneous nuclear ribonucleoprotein K (hnRNP K). The simultaneous suppression of ErbB kinases and androgen signaling by Celecoxib represents a novel strategy to interrupt the vicious cycle of AR/ErbB cross-talk with the primary purpose of undermining their resilient signaling in prostate cancer progression. Our data provide important premises for the chemopreventive use of Celecoxib in the clinical management of prostate cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

Association between FTO gene polymorphisms and type 2 diabetes mellitus, serum levels of apelin and androgen hormones among Iranian obese women.

PubMed

Ghafarian-Alipour, Farzaneh; Ziaee, Shayan; Ashoori, Mohamad Reza; Zakeri, Mir Saeid; Boroumand, Mohammad Ali; Aghamohammadzadeh, Naser; Abbasi-Majdi, Maryam; Shool, Fatemeh; Asbaghi, Navid Sarakhs; Mohammadi, Abolghasem; Zarghami, Nosratollah

2018-01-30

Recent studies show that FTO single nucleotide polymorphisms (SNPs) are associated with obesity and type 2 diabetes mellitus (T2DM). On the other hand, many animal models and clinical studies have demonstrated that apelin, an adipocytokine, is related to the obesity and T2DM. Additionally, obese women are at risk of Hyperandrogenemia. So, the aim of this study was to investigate the relationship between FTO variants (rs763967273, rs759031579, rs141115189, rs9926289, rs76804286 and rs9939609) with T2DM, serum apelin and androgenic hormones in Iranian obese women. 197 obese women (123 women with T2DM and 74 women as healthy control) were participated in this study. Anthropometrical and biochemical characteristics were measured. Serum apelin and androgen hormones levels were determined in 66 subjects consisting of 33 cases and 33 controls. PCR were carried out and subsequently, the PCR production was genotyped by Sanger sequencing assay. Our observations showed that all SNPs are related to T2DM. The rs9926289 FTO variant had a strong association with serum apelin and dehydroepiandrosterone-sulfate levels (P=0.04 and P=0.03, respectively) among SNPs. In addition, apelin and androgenic hormones were correlated with T2DM. Two polymorphisms including rs9939609 and rs9926289 had a strong Linkage disequilibrium (r 2 =1). FTO variants not only were associated with T2DM, but also some variants had a strong association with apelin and androgenic hormones profile. Copyright © 2017 Elsevier B.V. All rights reserved.

Motor development in individuals with congenital adrenal hyperplasia: strength, targeting, and fine motor skill.

PubMed

Collaer, Marcia L; Brook, Charles G D; Conway, Gerard S; Hindmarsh, Peter C; Hines, Melissa

2009-02-01

This study investigated early androgen influence on the development of human motor and visuomotor characteristics. Participants, ages 12-45 years, were individuals with congenital adrenal hyperplasia (CAH), a disorder causing increased adrenal androgen production before birth (40 females, 29 males) and their unaffected relatives (29 females, 30 males). We investigated grip strength and visuomotor targeting tasks on which males generally outperform females, and fine motor pegboard tasks on which females generally outperform males. Physical characteristics (height and weight) were measured to explore whether body parameters could explain differences in motor skills. Females with CAH were stronger and showed better targeting than unaffected females and showed reduced fine visuomotor skill on one pegboard measure, with no difference on the other. Males with CAH were weaker than unaffected males in grip strength but did not differ on the targeting or pegboard measures. Correction for body size could not explain the findings for females, but suggests that the reduced strength of males with CAH may relate to their smaller stature. Further, the targeting advantage in females with CAH persisted following adjustment for their greater strength. Results in females support the hypothesis that androgen may masculinize, or promote, certain motor characteristics at which males excel, and contribute to defeminization of certain fine motor characteristics at which females excel. Thus, these data suggest that organizational effects of androgens on behavior during prenatal life may extend to motor characteristics and may contribute to general sex differences in motor-related behaviors; however, alternative explanations based on activational influences of androgen or altered experiential factors cannot be excluded without further study.

Effects of Tribulus terrestris on endocrine sensitive organs in male and female Wistar rats.

PubMed

Martino-Andrade, Anderson J; Morais, Rosana N; Spercoski, Katherinne M; Rossi, Stefani C; Vechi, Marina F; Golin, Munisa; Lombardi, Natália F; Greca, Cláudio S; Dalsenter, Paulo R

2010-01-08

Investigate the possible effects of Tribulus terrestris (TT) on endocrine sensitive organs in intact and castrated male rats as well as in a post-menopausal rat model using ovariectomized females. Three different dose levels of TT (11, 42 and 110 mg/kg/day) were administered to castrated males for 7 days and to intact males and castrated females for 28 days. In addition to TT treatment, all experiments also included a group of rats treated with dehydroepiandrosterone (DHEA). In experiments using castrated males and females we also used testosterone and 17 alpha-ethynylestradiol, respectively, as positive controls for androgenicity and estrogenicity. Neither DHEA nor TT was able to stimulate androgen sensitive tissues like the prostate and seminal vesicle in both intact and castrated male rats. In addition, administration of TT to intact male rats for 28 days did not change serum testosterone levels as well as did not produce any quantitative change in the fecal excretion of androgenic metabolites. However, a slight increase in the number of homogenization-resistant spermatids was observed in rats treated with 11 mg/kg/day of TT extract. In ovariectomized females, TT did not produce any stimulatory effects in uterine and vaginal epithelia. Tribulus terrestris was not able to stimulate endocrine sensitive tissues such as the prostate, seminal vesicle, uterus and vagina in Wistar rats, indicating lack of androgenic and estrogenic activity in vivo. We also showed a positive effect of TT administration on rat sperm production, associated with unchanged levels of circulating androgens. Copyright 2009 Elsevier Ireland Ltd. All rights reserved.

Persistent müllerian duct syndrome and prostate cancer.

PubMed

Mitre, Anuar Ibrahim; Castilho, Lisias Nogueira; Avarese de Figueiredo, Andre; Arap, Sami

2002-10-01

A localized Gleason score 6 (3 + 3) prostate cancer was found in a 56-year-old man with bilateral cryptorchidism. Radical laparoscopic prostatectomy was performed. However, at the beginning of the procedure, a uterus, two fallopian tubes, and two intra-abdominal gonads were endoscopically identified. The müllerian rests were excised and the gonads biopsied. The histologic examination showed testicular tissue. The association of prostate cancer and persistent müllerian duct syndrome to our knowledge has not previously been reported. Prostate cancer is an androgen-dependent neoplasm, and patients with male pseudohermaphroditism have poor androgen production that should provide protection against it.

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.

A substitutional mutation in the DNA binding domain of the androgen receptor causes complete androgen insensitivity syndrome.

PubMed

Komori, S; Sakata, K; Kasumi, H; Tsuji, Y; Hamada, K; Koyama, K

1999-10-01

DNA analysis of the androgen receptor gene in a patient with complete androgen insensitivity syndrome identified a substitutional mutation (tyrosine converted to cysteine at position 571) in the DNA binding domain. In vitro transfection experiments with the patients' androgen receptor gene, indicated normal expression of the androgen receptor in transfected COS-7 cells compared to the wild type gene. There was also no evidence of impaired thermal stability of the 5 alpha-dihydrotestosterone-androgen receptor complex. However, the capacity of the androgen receptor to activate target gene transcription was found to be completely disrupted in a luciferase assay. These results confirmed that only one substitutional mutation in the DNA binding domain was related to the pathogenesis of the complete androgen insensitivity syndrome.

Peripheral auditory processing changes seasonally in Gambel’s white-crowned sparrow

PubMed Central

Caras, Melissa L.; Brenowitz, Eliot; Rubel, Edwin W

2010-01-01

Song in oscine birds is a learned behavior that plays important roles in breeding. Pronounced seasonal differences in song behavior, and in the morphology and physiology of the neural circuit underlying song production are well documented in many songbird species. Androgenic and estrogenic hormones largely mediate these seasonal changes. While much work has focused on the hormonal mechanisms underlying seasonal plasticity in songbird vocal production, relatively less work has investigated seasonal and hormonal effects on songbird auditory processing, particularly at a peripheral level. We addressed this issue in Gambel’s white-crowned sparrow (Zonotrichia leucophrys gambelii), a highly seasonal breeder. Photoperiod and hormone levels were manipulated in the laboratory to simulate natural breeding and non-breeding conditions. Peripheral auditory function was assessed by measuring the auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAEs) of males and females in both conditions. Birds exposed to breeding-like conditions demonstrated elevated thresholds and prolonged peak latencies compared with birds housed under non-breeding-like conditions. There were no changes in DPOAEs, however, which indicates that the seasonal differences in ABRs do not arise from changes in hair cell function. These results suggest that seasons and hormones impact auditory processing as well as vocal production in wild songbirds. PMID:20563817

Rapid effects of the aromatase inhibitor fadrozole on steroid production and gene expression in the ovary of female fathead minnows (Pimephales promelas)

EPA Science Inventory

Cytochrome P450 aromatase catalyzes conversion of C19 androgens to C18 estrogens and is critical for normal reproduction in female vertebrates. Fadrozole is a well-studied aromatase inhibitor that has been shown to suppress estrogen production in the ovaries of fish. However, l...

Simvastatin and Dipentyl Phthalate Display Different Mechanisms of Action but Exhibit Dose Additive Effects on Fetal Testicular Testosterone Production in Sprague Dawley Rats

EPA Science Inventory

Sex differentiation of the male reproductive tract in mammals is driven, in part, by fetal androgen production. In utero exposure to some phthalate esters (PEs) alters fetal Leydig cell differentiation, reducing the expression of several genes associated with steroid synthesis/tr...

JS-K, a glutathione/glutathione S-transferase-activated nitric oxide releasing prodrug inhibits androgen receptor and WNT-signaling in prostate cancer cells.

PubMed

Laschak, Martin; Spindler, Klaus-Dieter; Schrader, Andres J; Hessenauer, Andrea; Streicher, Wolfgang; Schrader, Mark; Cronauer, Marcus V

2012-03-30

Nitric oxide (NO) and its oxidative reaction products have been repeatedly shown to block steroid receptor function via nitrosation of zinc finger structures in the DNA-binding domain (DBD). In consequence NO-donors could be of special interest for the treatment of deregulated androgen receptor(AR)-signaling in castration resistant prostate cancer (CRPC). Prostate cancer (PCa) cells were treated with JS-K, a diazeniumdiolate derivate capable of generating large amounts of intracellular NO following activation by glutathione S-transferase. Generation of NO was determined indirectly by the detection of nitrate in tissue culture medium or by immunodetection of nitrotyrosine in the cytoplasm. Effects of JS-K on intracellular AR-levels were determined by western blotting. AR-dimerization was analyzed by mammalian two hybrid assay, nuclear translocation of the AR was visualized in PCa cells transfected with a green fluorescent AR-Eos fusion protein using fluorescence microscopy. Modulation of AR- and WNT-signalling by JS-K was investigated using reporter gene assays. Tumor cell proliferation following JS-K treatment was measured by MTT-Assay. The NO-releasing compound JS-K was shown to inhibit AR-mediated reporter gene activity in 22Rv1 CRPC cells. Inhibition of AR signaling was neither due to an inhibition of nuclear import nor to a reduction in AR-dimerization. In contrast to previously tested NO-donors, JS-K was able to reduce the intracellular concentration of functional AR. This could be attributed to the generation of extremely high intracellular levels of the free radical NO as demonstrated indirectly by high levels of nitrotyrosine in JS-K treated cells. Moreover, JS-K diminished WNT-signaling in AR-positive 22Rv1 cells. In line with these observations, castration resistant 22Rv1 cells were found to be more susceptible to the growth inhibitory effects of JS-K than the androgen dependent LNCaP which do not exhibit an active WNT-signaling pathway. Our results suggest that small molecules able to inhibit WNT- and AR-signaling via NO-release represent a promising platform for the development of new compounds for the treatment of CRPC.

JS-K, a glutathione/glutathione S-transferase-activated nitric oxide releasing prodrug inhibits androgen receptor and WNT-signaling in prostate cancer cells

PubMed Central

2012-01-01

Background Nitric oxide (NO) and its oxidative reaction products have been repeatedly shown to block steroid receptor function via nitrosation of zinc finger structures in the DNA-binding domain (DBD). In consequence NO-donors could be of special interest for the treatment of deregulated androgen receptor(AR)-signaling in castration resistant prostate cancer (CRPC). Methods Prostate cancer (PCa) cells were treated with JS-K, a diazeniumdiolate derivate capable of generating large amounts of intracellular NO following activation by glutathione S-transferase. Generation of NO was determined indirectly by the detection of nitrate in tissue culture medium or by immunodetection of nitrotyrosine in the cytoplasm. Effects of JS-K on intracellular AR-levels were determined by western blotting. AR-dimerization was analyzed by mammalian two hybrid assay, nuclear translocation of the AR was visualized in PCa cells transfected with a green fluorescent AR-Eos fusion protein using fluorescence microscopy. Modulation of AR- and WNT-signalling by JS-K was investigated using reporter gene assays. Tumor cell proliferation following JS-K treatment was measured by MTT-Assay. Results The NO-releasing compound JS-K was shown to inhibit AR-mediated reporter gene activity in 22Rv1 CRPC cells. Inhibition of AR signaling was neither due to an inhibition of nuclear import nor to a reduction in AR-dimerization. In contrast to previously tested NO-donors, JS-K was able to reduce the intracellular concentration of functional AR. This could be attributed to the generation of extremely high intracellular levels of the free radical NO as demonstrated indirectly by high levels of nitrotyrosine in JS-K treated cells. Moreover, JS-K diminished WNT-signaling in AR-positive 22Rv1 cells. In line with these observations, castration resistant 22Rv1 cells were found to be more susceptible to the growth inhibitory effects of JS-K than the androgen dependent LNCaP which do not exhibit an active WNT-signaling pathway. Conclusions Our results suggest that small molecules able to inhibit WNT- and AR-signaling via NO-release represent a promising platform for the development of new compounds for the treatment of CRPC. PMID:22462810

Can estrogens be considered as key elements of the challenge hypothesis? The case of intrasexual aggression in a cichlid fish.

PubMed

Scaia, María Florencia; Morandini, Leonel; Noguera, CristobalAlejandro; Trudeau, Vance L; Somoza, Gustavo Manuel; Pandolfi, Matías

2018-06-20

Territorial aggression has been widely studied in males and it has been historically suggested that androgens are key mediators of this behavior. However, more recent evidence suggests that it is the aromatization to estrogens, rather than androgens themselves, that is key to regulating this behavior. Females also display aggressive behaviors, but the physiological regulation of female aggression is still understudied when compared to males. In this context, the challenge hypothesis postulates that male-male aggressive interactions stimulate the production of androgens in males in periods of social instability. Here we determine plasma sex steroid levels in Cichlasoma dimerus to assess whether estrogens are related to aggressive behavior and to test the challenge hypothesis in both males and females. We set-up challenge trials as intrasexual dyadic encounters and determined androgen and estrogen levels before and after the trial in both winners and losers. Even though there were no differences in initial estradiol-17β plasma levels between male winners and losers, initial levels were higher (p = .046) in female winners than in losers, while there were no differences in testosterone or 11-ketotestosterone levels. After trials, both males and females showed elevated levels of estradiol-17β and both androgens, but only males exhibited a significant 1.45, 5.42 and 3.2-fold increase in estradiol-17β, testosterone and 11-ketotestosterone, respectively (p = .023, p = .016, p = .018). Moreover, changes in circulating levels of estradiol-17β in females after the trials do not depend on their reproductive status or on the outcome of the contest. We suggest that female aggression is associated with initial levels of estradiol-17β, and that the challenge hypothesis, originally defined for androgens, could also be extended to estrogens. Copyright © 2018. Published by Elsevier Inc.

ERG/AKR1C3/AR Constitutes a Feed-Forward Loop for AR Signaling in Prostate Cancer Cells.

PubMed

Powell, Katelyn; Semaan, Louie; Conley-LaComb, M Katie; Asangani, Irfan; Wu, Yi-Mi; Ginsburg, Kevin B; Williams, Julia; Squire, Jeremy A; Maddipati, Krishna R; Cher, Michael L; Chinni, Sreenivasa R

2015-06-01

Intratumoral androgen synthesis in prostate cancer contributes to the development of castration-resistant prostate cancer (CRPC). Several enzymes responsible for androgen biosynthesis have been shown to be overexpressed in CRPC, thus contributing to CRPC in a castrated environment. The TMPRSS2-ERG transcription factor has been shown to be present in primary prostate cancer tumors as well as CRPC tumors. We hypothesize that TMPRSS2-ERG fusions regulate androgen biosynthetic enzyme (ABE) gene expression and the production of androgens, which contributes to the development of CRPC. We used a panel of assays, including lentivirus transduction, gene expression, chromatin immunoprecipitation and sequencing, liquid chromatography-mass spectrometric quantitation, immunocytochemistry, immunohistochemistry, and bioinformatics analysis of gene microarray databases, to determine ERG regulation of androgen synthesis. We found that ERG regulated the expression of the ABE AKR1C3 in prostate cancer cells via direct binding to the AKR1C3 gene. Knockdown of ERG resulted in reduced AKR1C3 expression, which caused a reduction in both DHT synthesis and PSA expression in VCaP prostate cancer cells treated with 5α-androstanedione (5α-Adione), a DHT precursor metabolite. Immunohistochemical staining revealed that ERG was coexpressed with AKR1C3 in prostate cancer tissue samples. These data suggest that AKR1C3 catalyzes the biochemical reduction of 5α-Adione to DHT in prostate cancer cells, and that ERG regulates this step through upregulation of AKR1C3 expression. Elucidation of ERG regulation of ABEs in CRPC may help to stratify TMPRSS2-ERG fusion-positive prostate cancer patients in the clinic for anti-androgen receptor-driven therapies; and AKR1C3 may serve as a valuable therapeutic target in the treatment of CRPC. ©2015 American Association for Cancer Research.

Steroid receptor RNA activator (SRA1): unusual bifaceted gene products with suspected relevance to breast cancer

PubMed Central

Leygue, Etienne

2007-01-01

The steroid receptor RNA activator (SRA) is a unique modulator of steroid receptor transcriptional activity, as it is able to mediate its coregulatory effects as a RNA molecule. Recent findings, however, have painted a more complex picture of the SRA gene (SRA1) products. Indeed, even though SRA was initially thought to be noncoding, several RNA isoforms have now been found to encode an endogenous protein (SRAP), which is well conserved among Chordata. Although the function of SRAP remains largely unknown, it has been proposed that, much like its corresponding RNA, the protein itself might regulate estrogen and androgen receptor signaling pathways. As such, data suggest that both SRA and SRAP might participate in the mechanisms underlying breast, as well as prostate tumorigenesis. This review summarizes the published literature dealing with these two faces of the SRA gene products and underscores the relevance of this bifaceted system to breast cancer development. PMID:17710122

Nicotine affects rat Leydig cell function in vivo and vitro via down-regulating some key steroidogenic enzyme expressions.

PubMed

Guo, Xiaoling; Wang, Huang; Wu, Xiaolong; Chen, Xianwu; Chen, Yong; Guo, Jingjing; Li, Xiaoheng; Lian, Qingquan; Ge, Ren-Shan

2017-12-01

Nicotine is consumed largely as a component of cigarettes and has a potential effect on pubertal development of Leydig cells in males. To investigate its effects, 49-day-old male Sprague Dawley rats received intraperitoneal injections of nicotine (0.5 or 1 mg/kg/day) for 2 weeks and immature Leydig cells were isolated from the testes of 35-day-old rats and treated with nicotine (0.05-50 μM). Serum hormones, Leydig cell number and related gene expression levels after in vivo treatment were determined and medium androgen levels were measured and cell cycle, apoptosis, mitochondrial membrane potential (△Ψm), and reactive oxygen species (ROS) of Leydig cells after in vitro treatment were measured. In vivo exposure to nicotine lowered serum luteinizing hormone, follicle stimulating hormone, and testosterone levels and reduced Leydig cell number and gene expression levels. Nicotine in vitro inhibited androgen production in Leydig cells by downregulating the expression levels of P450 cholesterol side cleavage enzyme, 3β-hydroxysteroid dehydrogenase 1, and steroidogenic factor 1 at different concentration ranges. In conclusion, nicotine disrupts Leydig cell steroidogenesis during puberty possibly via down-regulating some key steroidogenic enzyme expressions. Copyright © 2017. Published by Elsevier Ltd.

Fetal programming of adrenal androgen excess: lessons from a nonhuman primate model of polycystic ovary syndrome.

PubMed

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

2008-01-01

Adrenal androgen excess is found in adult female rhesus monkeys previously exposed to androgen treatment during early gestation. In adulthood, such prenatally androgenized female monkeys exhibit elevated basal circulating levels of dehydroepiandrosterone sulfate (DHEAS), typical of polycystic ovary syndrome (PCOS) women with adrenal androgen excess. Further androgen and glucocorticoid abnormalities in PA female monkeys are revealed by acute ACTH stimulation: DHEA, androstenedione and corticosterone responses are all elevated compared to responses in controls. Pioglitazone treatment, however, diminishes circulating DHEAS responses to ACTH in both prenatally androgenized and control female monkeys, while increasing the 17-hydroxyprogesterone response and reducing the DHEA to 17-hydroxyprogesterone ratio. Since 60-min post-ACTH serum values for 17-hydroxyprogesterone correlate negatively with basal serum insulin levels (all female monkeys on pioglitazone and placebo treatment combined), while similar DHEAS values correlate positively with basal serum insulin levels, circulating insulin levels may preferentially support adrenal androgen biosynthesis in both prenatally androgenized and control female rhesus monkeys. Overall, our findings suggest that differentiation of the monkey adrenal cortex in a hyperandrogenic fetal environment may permanently upregulate adult adrenal androgen biosynthesis through specific elevation of 17,20-lyase activity in the zona fasciculata-reticularis. As adult prenatally androgenized female rhesus monkeys closely emulate PCOS-like symptoms, excess fetal androgen programming may contribute to adult adrenal androgen excess in women with PCOS.

Fetal programming of adrenal androgen excess: lessons from a nonhuman primate model of polycystic ovary syndrome

PubMed Central

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

2008-01-01

Adrenal androgen excess is found in adult female rhesus monkeys previously exposed to androgen treatment during early gestation. In adulthood, such prenatally androgenized female monkeys exhibit elevated basal circulating levels of DHEAS, typical of PCOS women with adrenal androgen excess. Further androgen and glucocorticoid abnormalities in PA female monkeys are revealed by acute ACTH stimulation: DHEA, androstenedione and corticosterone responses are all elevated compared to responses in controls. Pioglitazone treatment, however, diminishes circulating DHEAS responses to ACTH in both prenatally androgenized and control female monkeys, while increasing the 17-hydroxyprogesterone response and reducing the DHEA to 17-hydroxyprogesterone ratio. Since 60-min post-ACTH serum values for 17-hydroxyprogesterone correlate negatively with basal serum insulin levels (all female monkeys on pioglitazone and placebo treatment combined), while similar DHEAS values correlate positively with basal serum insulin levels, circulating insulin levels may preferentially support adrenal androgen biosynthesis in both prenatally androgenized and control female rhesus monkeys. Overall, our findings suggest that differentiation of the monkey adrenal cortex in a hyperandrogenic fetal environment may permanently upregulate adult adrenal androgen biosynthesis through specific elevation of 17,20-lyase activity in the zona fasciculata-reticularis. As adult prenatally androgenized female rhesus monkeys closely emulate PCOS-like symptoms, excess fetal androgen programming may contribute to adult adrenal androgen excess in women with PCOS. PMID:18493139

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

Androgen Receptor Content of the Normal and Hyperplastic Canine Prostate

PubMed Central

Shain, Sydney A.; Boesel, Robert W.

1978-01-01

A procedure was developed for measurement of androgen receptors in cytoplasmic extracts of prostates from intact dogs. The protocol utilized exchange saturation analysis at 15°C employing the synthetic androgen R1881 (17β-hydroxy-17α-methylestra-4,9,11-trien-3-one) as the ligand probe and quantitatively detected total cytoplasmic androgen receptor (Rc, androgen-free receptor, and RcA, androgen-occupied receptor) present at the initiation of the assay. This protocol was employed in conjunction with a tissue mince saturation analysis procedure (for quantitation of nuclear androgen receptor) to quantitate total androgen receptor content of normal and hyperplastic prostates obtained from young (2.5- or 4.6-yr old) and aged (12.5-yr old) purebred dogs of known birth date. The total cytoplasmic androgen receptor content (picomoles per prostate) of hyperplastic prostates was 4.6-fold greater than that of normal prostates. The total nuclear androgen receptor content of hyperplastic prostates (picomoles per prostate measured in crude nuclear preparations) was either 5.0- (4.6-yr-old dogs) or 7.8-fold (2.5-yr-old dogs) greater than that of normal prostates. However, androgen receptor content per cell was identical for hyperplastic and normal canine prostates, with the exception that nuclear androgen receptor was diminished in prostates from 2.5-yr-old dogs. The cell content per gram dry weight was identical for hyperplastic and normal canine prostates. We conclude that canine prostate hyperplasia is characterized by coordinate proliferation of androgen receptor-positive and androgen receptor-negative cells and is not a consequence of increased accumulation of 5α-dihydrotestosterone due to proliferation of androgen receptors per prostate cell. PMID:76635

Neurotensin is an autocrine trophic factor stimulated by androgen withdrawal in human prostate cancer.

PubMed Central

Sehgal, I; Powers, S; Huntley, B; Powis, G; Pittelkow, M; Maihle, N J

1994-01-01

After therapeutic hormone deprivation, prostate cancer cells often develop androgen-insensitive growth through mechanisms thus far undefined. Neuropeptides have been previously implicated as growth factors in some prostate cancers. Here, we demonstrate that androgen-sensitive LNCaP human prostate cancer cells produce and secrete neurotensin following androgen withdrawal. We show that while LNCaP cells express the neurotensin receptor, only androgen-deprived cells exhibit a growth response to exogenous neurotensin. We further demonstrate that androgen-stimulated cells may be refractory to exogenous neurotensin due to androgen induction of a metalloprotease active toward neurotensin. Thus, prostate cancer cells deprived of androgen develop an alternative autocrine growth mechanism involving neurotensin. Images PMID:8197117

Genetic Variations in the Androgen Receptor Are Associated with Steroid Concentrations and Anthropometrics but Not with Muscle Mass in Healthy Young Men

PubMed Central

De Naeyer, Hélène; Bogaert, Veerle; De Spaey, Annelies; Roef, Greet; Vandewalle, Sara; Derave, Wim; Taes, Youri; Kaufman, Jean-Marc

2014-01-01

Objective The relationship between serum testosterone (T) levels, muscle mass and muscle force in eugonadal men is incompletely understood. As polymorphisms in the androgen receptor (AR) gene cause differences in androgen sensitivity, no straightforward correlation can be observed between the interindividual variation in T levels and different phenotypes. Therefore, we aim to investigate the relationship between genetic variations in the AR, circulating androgens and muscle mass and function in young healthy male siblings. Design 677 men (25–45 years) were recruited in a cross-sectional, population-based sibling pair study. Methods Relations between genetic variation in the AR gene (CAGn, GGNn, SNPs), sex steroid levels (by LC-MS/MS), body composition (by DXA), muscle cross-sectional area (CSA) (by pQCT), muscle force (isokinetic peak torque, grip strength) and anthropometrics were studied using linear mixed-effect modelling. Results Muscle mass and force were highly heritable and related to age, physical activity, body composition and anthropometrics. Total T (TT) and free T (FT) levels were positively related to muscle CSA, whereas estradiol (E2) and free E2 (FE2) concentrations were negatively associated with muscle force. Subjects with longer CAG repeat length had higher circulating TT, FT, and higher E2 and FE2 concentrations. Weak associations with TT and FT were found for the rs5965433 and rs5919392 SNP in the AR, whereas no association between GGN repeat polymorphism and T concentrations were found. Arm span and 2D:4D finger length ratio were inversely associated, whereas muscle mass and force were not associated with the number of CAG repeats. Conclusions Age, physical activity, body composition, sex steroid levels and anthropometrics are determinants of muscle mass and function in young men. Although the number of CAG repeats of the AR are related to sex steroid levels and anthropometrics, we have no evidence that these variations in the AR gene also affect muscle mass or function. PMID:24465978

Genetic variations in the androgen receptor are associated with steroid concentrations and anthropometrics but not with muscle mass in healthy young men.

PubMed

De Naeyer, Hélène; Bogaert, Veerle; De Spaey, Annelies; Roef, Greet; Vandewalle, Sara; Derave, Wim; Taes, Youri; Kaufman, Jean-Marc

2014-01-01

The relationship between serum testosterone (T) levels, muscle mass and muscle force in eugonadal men is incompletely understood. As polymorphisms in the androgen receptor (AR) gene cause differences in androgen sensitivity, no straightforward correlation can be observed between the interindividual variation in T levels and different phenotypes. Therefore, we aim to investigate the relationship between genetic variations in the AR, circulating androgens and muscle mass and function in young healthy male siblings. 677 men (25-45 years) were recruited in a cross-sectional, population-based sibling pair study. Relations between genetic variation in the AR gene (CAGn, GGNn, SNPs), sex steroid levels (by LC-MS/MS), body composition (by DXA), muscle cross-sectional area (CSA) (by pQCT), muscle force (isokinetic peak torque, grip strength) and anthropometrics were studied using linear mixed-effect modelling. Muscle mass and force were highly heritable and related to age, physical activity, body composition and anthropometrics. Total T (TT) and free T (FT) levels were positively related to muscle CSA, whereas estradiol (E2) and free E2 (FE2) concentrations were negatively associated with muscle force. Subjects with longer CAG repeat length had higher circulating TT, FT, and higher E2 and FE2 concentrations. Weak associations with TT and FT were found for the rs5965433 and rs5919392 SNP in the AR, whereas no association between GGN repeat polymorphism and T concentrations were found. Arm span and 2D:4D finger length ratio were inversely associated, whereas muscle mass and force were not associated with the number of CAG repeats. Age, physical activity, body composition, sex steroid levels and anthropometrics are determinants of muscle mass and function in young men. Although the number of CAG repeats of the AR are related to sex steroid levels and anthropometrics, we have no evidence that these variations in the AR gene also affect muscle mass or function.

The in utero programming effect of increased maternal androgens and a direct fetal intervention on liver and metabolic function in adult sheep.

PubMed

Hogg, Kirsten; Wood, Charlotte; McNeilly, Alan S; Duncan, W Colin

2011-01-01

Epigenetic changes in response to external stimuli are fast emerging as common underlying causes for the pre-disposition to adult disease. Prenatal androgenization is one such model that results in reproductive and metabolic features that are present in conditions such as polycystic ovary syndrome (PCOS). We examined the effect of prenatal androgens on liver function and metabolism of adult sheep. As non-alcoholic fatty liver disease is increased in PCOS we hypothesized that this, and other important liver pathways including metabolic function, insulin-like growth factor (IGF) and steroid receptivity, would be affected. Pregnant ewes received vehicle control (C; n = 5) or testosterone propionate (TP; n = 9) twice weekly (100 mg; i.m) from d62-102 (gestation 147 days). In a novel treatment paradigm, a second cohort received a direct C (n = 4) or TP (20 mg; n = 7) fetal injection at d62 and d82. In adults, maternal TP exposure resulted in increased insulin secretion to glucose load (P<0.05) and the histological presence of fatty liver (P<0.05) independent of central obesity. Additionally, hepatic androgen receptor (AR; P<0.05), glucocorticoid receptor (GR; P<0.05), UDP- glucose ceramide glucosyltransferase (UGCG; P<0.05) and IGF1 (P<0.01) expression were upregulated. The direct fetal intervention (C and TP) led to early fatty liver changes in all animals without differential changes in insulin secretion. Furthermore, hepatic phosphoenolpyruvate carboxykinase (PEPCK) was up-regulated in the fetal controls (P<0.05) and this was opposed by fetal TP (P<0.05). Hepatic estrogen receptor (ERα; P<0.05) and mitogen activated protein kinase kinase 4 (MAP2K4; P<0.05) were increased following fetal TP exposure. Adult liver metabolism and signaling can be altered by early exposure to sex steroids implicating epigenetic regulation of metabolic disturbances that are common in PCOS.

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.

Modulation of AKR1C2 by curcumin decreases testosterone production in prostate cancer.

PubMed

Ide, Hisamitsu; Lu, Yan; Noguchi, Takahiro; Muto, Satoru; Okada, Hiroshi; Kawato, Suguru; Horie, Shigeo

2018-04-01

Intratumoral androgen biosynthesis has been recognized as an essential factor of castration-resistant prostate cancer. The present study investigated the effects of curcumin on the inhibition of intracrine androgen synthesis in prostate cancer. Human prostate cancer cell lines, LNCaP and 22Rv1 cells were incubated with or without curcumin after which cell proliferation was measured at 0, 24, 48 and 72 hours, respectively. Prostate tissues from the transgenic adenocarcinoma of the mouse prostate (TRAMP) model were obtained after 1-month oral administration of 200 mg/kg/d curcumin. Testosterone and dihydrotestosterone concentrations in LNCaP prostate cancer cells were determined through LC-MS/MS assay. Curcumin inhibited cell proliferation and induced apoptosis of prostate cancer cells in a dose-dependent manner. Curcumin decreased the expression of steroidogenic acute regulatory proteins, CYP11A1 and HSD3B2 in prostate cancer cell lines, supporting the decrease of testosterone production. After 1-month oral administration of curcumin, Aldo-Keto reductase 1C2 (AKR1C2) expression was elevated. Simultaneously, decreased testosterone levels in the prostate tissues were observed in the TRAMP mice. Meanwhile, curcumin treatments considerably increased the expression of AKR1C2 in prostate cancer cell lines, supporting the decrease of dihydrotestosterone. Taken together, these results suggest that curcumin's natural bioactive compounds could have potent anticancer properties due to suppression of androgen production, and this could have therapeutic effects on prostate cancer. © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Effects of immunization against LHRH and treatment with trenbolone acetate on reproductive function of beef bulls and steers

USDA-ARS?s Scientific Manuscript database

The objectives of this study were (1) to evaluate the ability of trenbolone acetate (TBA) administered in tandem with LHRH immunization to suppress reproductive function in beef bulls and (2) to examine the effects of LHRH and androgen (TBA) signaling on pituitary function. In order to address thes...

Relationship Between 17-Hydroxyprogesterone Responses to Human Chorionic Gonadotropin and Markers of Ovarian Follicle Morphology in Women With Polycystic Ovary Syndrome

PubMed Central

Maas, Kevin H.; Chuan, Sandy S.; Cook-Andersen, Heidi; Su, H. Irene; Duleba, A.

2015-01-01

Context: Women with polycystic ovary syndrome (PCOS) have increased 17-hydroxyprogesterone (17-OHP) responses to gonadotropin stimulation although individual variability is substantial, as reflected by exaggerated as well as normal responses. The relationship between 17-OHP responses to gonadotropin stimulation and markers of ovarian function has not been assessed. Objective: To determine whether 17-OHP responses are associated with antral follicle count (AFC), anti-Mullerian hormone (AMH), or inhibin B (Inh B) levels in PCOS and normal women. Design: Prospective study. Setting: Research center at an academic medical center. Participants: Women with PCOS (n = 18) and normal controls (n = 18). Interventions: Blood samples were obtained before and 24 hours after administration of 25 μg recombinant-human chorionic gonadotropin. Ovarian imaging was conducted with three-dimensional pelvic ultrasound. Main Outcome Measures: Basal and stimulated levels of 17-OHP, androgens, estrogen, AMH, Inh B, and AFC. Results: In women with PCOS, 17-OHP responses were heterogeneous and inversely correlated with AMH and Inh B levels, but not AFC. In a subgroup of PCOS women with exaggerated 17-OHP responses, AMH levels were equivalent to that of normal women. In PCOS women with normal 17-OHP responses, AMH levels were markedly elevated. Conclusion: Based on heterogeneous 17-OHP responses to human chorionic gonadotropin in women with PCOS, AMH levels are inversely linked to ovarian androgen production while positively correlated with AFC. These findings suggest that in PCOS, AMH production may reflect redistribution of the follicle population or regulation by intraovarian mechanisms. PMID:25313914

Seasonal changes in testicular steroidogenesis in the toad Bufo arenarum H.

PubMed

Canosa, L F; Ceballos, N R

2002-02-15

The biosynthesis of androgens in Bufo arenarum takes place through the 5-ene pathway that includes 5-androstane-3beta,17beta-diol as intermediate in testosterone biosynthesis. Besides testosterone and 5alpha-dihydrotestosterone, testes are able to synthesize 5alpha-pregnan-3,20-dione and several 3alpha- and 20alpha-reduced derivatives. Steroid biosynthesis changes during the breeding period (spring and early summer), turning from androgen to C21 steroid production. During the reproductive season, the production of progesterone, 5alpha-pregnan-3alpha,20alpha-diol, 3alpha-hydroxy-5alpha-pregnan-20-one, and 5alpha-pregnan-3,20-dione increases significantly. The function of most of these steroids in amphibians remains unknown. However, 5alpha-androstan-3alpha,17beta-diol and 3alpha-hydroxy-5alpha-pregnan-20-one were shown to be neuroactive in mammals, modulating sexual behavior. Thus, 5alpha/3alpha-reduced steroids could be involved in the regulation of the reproductive behavior in B. arenarum, a species with a dissociated reproductive pattern. Percentage contribution of each enzymes to the total metabolism reveals that neither 3beta-hydroxysteroid dehydrogenase/isomerase nor 5alpha-reductase change throughout the reproductive cycle. However, a strong reduction in 17-hydroxylase-C(17-20) lyase activity occurs in the reproductive season, suggesting that this enzyme could represent a key enzyme in the regulation of the seasonal change of steroidogenesis. Also, 3alpha-hydroxysteroid dehydrogenase and 20-hydroxysteroid dehydrogenase activities increase during the reproductive period, implying that steroid metabolism is clearly focused on C21-reduced steroids. (C)2002 Elsevier Science (USA).

The Polycystic Ovary Morphology-Polycystic Ovary Syndrome Spectrum.

PubMed

Rosenfield, Robert L

2015-12-01

Polycystic ovary syndrome (PCOS) is the most common cause of chronic hyperandrogenic anovulation. Two-thirds of PCOS patients have functionally typical PCOS, with typical functional ovarian hyperandrogenism manifest as 17-hydroxyprogesterone hyper-responsiveness to gonadotropin stimulation. Most, but not all, of the remainder have atypical functional ovarian hyperandrogenism. Many asymptomatic volunteers with polycystic ovary morphology (PCOM) have similar abnormalities. The objective of this paper is to review the relationship of biochemical ovarian function to the clinical spectrum observed in PCOS and in normal volunteers with PCOM. Adolescents and adults with PCOS are similar clinically and biochemically. Ninety-five percent of functionally typical PCOS have classic PCOS, ie, hyperandrogenic anovulation with PCOM. In addition to having more severe hyperandrogenism and a greater prevalence of PCOM than other PCOS, they have a significantly greater prevalence of glucose intolerance although insulin resistance is similarly reduced. Half of normal-variant PCOM have PCOS-related steroidogenic dysfunction, which suggests a PCOS carrier state. There is a spectrum of ovarian androgenic dysfunction that ranges from subclinical hyperandrogenemia in some normal-variant PCOM to severe ovarian hyperandrogenism in most classic PCOS. A minority of mild PCOS cases do not fall on this spectrum of ovarian androgenic dysfunction, but rather seem to have obesity as the basis of their hyperandrogenism, or, less often, isolated adrenal androgenic dysfunction. Half of normal-variant PCOM also do not fall on the PCOS spectrum, and some of these seem to have excessive folliculogenesis as a variant that may confer mild prolongation of the reproductive lifespan. Improved understanding of PCOM in young women is needed. Copyright © 2015 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.

Androgen Receptor Functional Analyses by High Throughput Imaging: Determination of Ligand, Cell Cycle, and Mutation-Specific Effects

PubMed Central

Szafran, Adam T.; Szwarc, Maria; Marcelli, Marco; Mancini, Michael A.

2008-01-01

Background Understanding how androgen receptor (AR) function is modulated by exposure to steroids, growth factors or small molecules can have important mechanistic implications for AR-related disease therapies (e.g., prostate cancer, androgen insensitivity syndrome, AIS), and in the analysis of environmental endocrine disruptors. Methodology/Principal Findings We report the development of a high throughput (HT) image-based assay that quantifies AR subcellular and subnuclear distribution, and transcriptional reporter gene activity on a cell-by-cell basis. Furthermore, simultaneous analysis of DNA content allowed determination of cell cycle position and permitted the analysis of cell cycle dependent changes in AR function in unsynchronized cell populations. Assay quality for EC50 coefficients of variation were 5–24%, with Z' values reaching 0.91. This was achieved by the selective analysis of cells expressing physiological levels of AR, important because minor over-expression resulted in elevated nuclear speckling and decreased transcriptional reporter gene activity. A small screen of AR-binding ligands, including known agonists, antagonists, and endocrine disruptors, demonstrated that nuclear translocation and nuclear “speckling” were linked with transcriptional output, and specific ligands were noted to differentially affect measurements for wild type versus mutant AR, suggesting differing mechanisms of action. HT imaging of patient-derived AIS mutations demonstrated a proof-of-principle personalized medicine approach to rapidly identify ligands capable of restoring multiple AR functions. Conclusions/Significance HT imaging-based multiplex screening will provide a rapid, systems-level analysis of compounds/RNAi that may differentially affect wild type AR or clinically relevant AR mutations. PMID:18978937

A Perspective on Middle-Aged and Older Men With Functional Hypogonadism: Focus on Holistic Management

PubMed Central

Matsumoto, Alvin M.

2017-01-01

Abstract Context: Middle-aged and older men (≥50 years), especially those who are obese and suffer from comorbidities, not uncommonly present with clinical features consistent with androgen deficiency and modestly reduced testosterone levels. Commonly, such men do not demonstrate anatomical hypothalamic–pituitary–testicular axis pathology but have functional hypogonadism that is potentially reversible. Evidence Acquisition: Literature review from 1970 to October 2016. Evidence Synthesis: Although definitive randomized controlled trials are lacking, evidence suggests that in such men, lifestyle measures to achieve weight loss and optimization of comorbidities, including discontinuation of offending medications, lead to clinical improvement and a modest increase in testosterone. Also, androgen deficiency–like symptoms and end-organ deficits respond to targeted treatments (such as phosphodiesterase-5 inhibitors for erectile dysfunction) without evidence that hypogonadal men are refractory. Unfortunately, lifestyle interventions remain difficult and may be insufficient even if successful. Testosterone therapy should be considered primarily for men who have significant clinical features of androgen deficiency and unequivocally low testosterone levels. Testosterone should be initiated either concomitantly with a trial of lifestyle measures, or after such a trial fails, after a tailored diagnostic work-up, exclusion of contraindications, and appropriate counseling. Conclusions: There is modest evidence that functional hypogonadism responds to lifestyle measures and optimization of comorbidities. If achievable, these interventions may have demonstrable health benefits beyond the potential for increasing testosterone levels. Therefore, treatment of underlying causes of functional hypogonadism and of symptoms should be used either as an initial or adjunctive approach to testosterone therapy. PMID:28359097

Effects of Synthetic Androgens on Liver Function Using the Rabbit as a Model*†

PubMed Central

Hild, Sheri Ann; Attardi, Barbara J.; Koduri, Sailaja; Till, Bruce A.; Reel, Jerry R.

2010-01-01

The objective of this study was to determine if the rabbit was a suitable model to test new synthetic androgens for potential liver toxicity within a short dosing interval. Adult male rabbits were dosed orally daily on days 0–13 with 17α-methyltestosterone (MT), as a positive control, and testosterone (T), as a negative control, to validate this model. Synthetic androgens tested were: 7α-methyl-19-nortestosterone (MENT), dimethandrolone-undecanoate (DMAU), and 11β-methyl-19-nortestosterone-17β-dodecylcarbonate (11β-MNTDC). Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transpeptidase (GGT), and sorbitol dehydrogenase (SDH), as well as clearance of intravenous injected bromsulfonphthalein (BSP) from serum on days 0, 7 and 14, were determined. As expected, T (10 mg/kg/day) did not adversely affect BSP retention or serum liver enzymes. MT (10 mg/kg/day) increased BSP retention, and AST, ALT, GGT, and SDH levels indicating that this model could detect androgens known to be hepatotoxic. DMAU and MENT (10 mg/kg/day), increased BSP retention, and all 4 serum liver enzymes as well, but the effects were less than those observed with MT at the same dose. All parameters returned to baseline 2 weeks after cessation of dosing. 11β-MNTDC at 10 mg/kg/day did not have an effect on BSP retention or liver enzymes, but a slight increase in serum GGT levels was observed in rabbits treated with 25 mg/kg/day. For the androgens that exhibited liver toxicity at 10 mg/kg/day (MT, DMAU, and MENT), a no observed effect level (NOEL) of 1 mg/kg/day was established. Overall ranking of the synthetic androgens from most to least hepatotoxic based on %BSP retention was: MT ≫ DMAU > MENT > 11β-MNTDC. Hence, the rabbit appears to be a promising model for detection of potential liver toxicity by synthetic androgens using BSP clearance and serum liver enzyme levels as early indicators of injury. PMID:20378929

The role of androgens and polymorphisms in the androgen receptor in the epidemiology of breast cancer

PubMed Central

Lillie, Elizabeth O; Bernstein, Leslie; Ursin, Giske

2003-01-01

Testosterone binds to the androgen receptor in target tissue to mediate its effects. Variations in testosterone levels and androgen receptor activity may play a role in the etiology of breast cancer. Here, we review the epidemiologic evidence linking endogenous testosterone to breast cancer risk. Paradoxically, results from observational studies that have examined polymorphisms in the androgen receptor suggest that the low-activity androgen receptor increases breast cancer risk. We review the quality of this evidence and conclude with a discussion of how the androgen receptor and testosterone results coincide. PMID:12793900

Selective androgen receptor modulators: in pursuit of tissue-selective androgens.

PubMed

Omwancha, Josephat; Brown, Terry R

2006-10-01

The androgen receptor mediates the androgenic and anabolic activity of the endogenous steroids testosterone and 5alpha-dihydrotestosterone. Current knowledge of the androgen receptor protein structure, and the molecular mechanisms surrounding the binding properties and activities of agonists and antagonists has led to the design and development of novel nonsteroidal ligands with selected tissue-specific androgen receptor agonist and antagonist activities. The activity of these compounds, termed selective androgen receptor modulators (SARMs), is directed toward the maintenance or enhancement of anabolic effects on bone and muscle with minimal androgenic effects on prostate growth. SARMs are of potential therapeutic value in the treatment of male hypogonadism, osteoporosis, frailty and muscle wasting, burn injury and would healing, anemia, mood and depression, benign prostatic hyperplasia and prostate cancer.

Neuroendocrine Consequences of Androgen Excess in Female Rodents

PubMed Central

Foecking, Eileen M.; McDevitt, Melissa A.; Acosta-Martínez, Maricedes; Horton, Teresa H.; Levine, Jon E.

2008-01-01

Androgens exert significant organizational and activational effects on the nervous system and behavior. Despite the fact that female mammals generally produce low levels of androgens, relative to the male of the same species, increasing evidence suggests that androgens can exert profound effects on the normal physiology and behavior of females during fetal, neonatal, and adult stages of life. This review examines the effects of exposure to androgens at three stages of development – as an adult, during early postnatal life and as a fetus, on reproductive hormone secretions in female rats. We examine the effects of androgen exposure both as a model of neuroendocrine sexual differentiation and with respect to the role androgens play in the normal female. We then discuss the hypothesis that androgens may cause epigenetic modification of estrogen target genes in the brain. Finally we consider the clinical consequences of excess androgen exposure in women. PMID:18374922

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

PubMed

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

2017-08-15

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

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

PubMed Central

Rosenfield, Robert L; Bordini, Brian

2010-01-01

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

Effect of rejuvenation hormones on spermatogenesis.

PubMed

Moss, Jared L; Crosnoe, Lindsey E; Kim, Edward D

2013-06-01

To review the current literature for the effect of hormones used in rejuvenation clinics on the maintenance of spermatogenesis. Review of published literature. Not applicable. Men who have undergone exogenous testosterone (T) and/or anabolic androgenic steroid (AAS) therapies. None. Semen analysis, pregnancy outcomes, and time to recovery of spermatogenesis. Exogenous testosterone and anabolic androgenic steroids suppress intratesticular testosterone production, which may lead to azoospermia or severe oligozoospermia. Therapies that protect spermatogenesis involve human chorionic gonadotropin (hCG) therapy and selective estrogen receptor modulators (SERMs). The studies examining the effect of human growth hormone (HGH) on infertile men are uncontrolled and unconvincing, but they do not appear to negatively impact spermatogenesis. At present, routine use of aromatase inhibitors is not recommended based on a lack of long-term data. The use of hormones for rejuvenation is increasing with the aging of the Baby Boomer population. Men desiring children at a later age may be unaware of the side-effect profile of hormones used at rejuvenation centers. Testosterone and anabolic androgenic steroids have well-established detrimental effects on spermatogenesis, but recovery may be possible with cessation. Clomiphene citrate, human growth hormone (HGH)/insulin-like growth factor-1 (IGF-1), human chorionic gonadotropin (hCG), and aromatase inhibitors do not appear to have significant negative effects on sperm production, but quality data are lacking. Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

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

PubMed

Corbould, A

2008-10-01

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

11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome.

PubMed

O'Reilly, Michael W; Kempegowda, Punith; Jenkinson, Carl; Taylor, Angela E; Quanson, Jonathan L; Storbeck, Karl-Heinz; Arlt, Wiebke

2017-03-01

Androgen excess is a defining feature of polycystic ovary syndrome (PCOS), but the exact origin of hyperandrogenemia remains a matter of debate. Recent studies have highlighted the importance of the 11-oxygenated C19 steroid pathway to androgen metabolism in humans. In this study, we analyzed the contribution of 11-oxygenated androgens to androgen excess in women with PCOS. One hundred fourteen women with PCOS and 49 healthy control subjects underwent measurement of serum androgens by liquid chromatography-tandem mass spectrometry. Twenty-four-hour urinary androgen excretion was analyzed by gas chromatography-mass spectrometry. Fasting plasma insulin and glucose were measured for homeostatic model assessment of insulin resistance. Baseline demographic data, including body mass index, were recorded. As expected, serum concentrations of the classic androgens testosterone (P < 0.001), androstenedione (P < 0.001), and dehydroepiandrosterone (P < 0.01) were significantly increased in PCOS. Mirroring this, serum 11-oxygenated androgens 11β-hydroxyandrostenedione, 11-ketoandrostenedione, 11β-hydroxytestosterone, and 11-ketotestosterone were significantly higher in PCOS than in control subjects, as was the urinary 11-oxygenated androgen metabolite 11β-hydroxyandrosterone. The proportionate contribution of 11-oxygenated to total serum androgens was significantly higher in patients with PCOS compared with control subjects [53.0% (interquartile range, 48.7 to 60.3) vs 44.0% (interquartile range, 32.9 to 54.9); P < 0.0001]. Obese (n = 51) and nonobese (n = 63) patients with PCOS had significantly increased 11-oxygenated androgens. Serum 11β-hydroxyandrostenedione and 11-ketoandrostenedione correlated significantly with markers of insulin resistance. We show that 11-oxygenated androgens represent the majority of circulating androgens in women with PCOS, with close correlation to markers of metabolic risk.

11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome

PubMed Central

O’Reilly, Michael W.; Kempegowda, Punith; Jenkinson, Carl; Taylor, Angela E.; Quanson, Jonathan L.; Storbeck, Karl-Heinz

2017-01-01

Context: Androgen excess is a defining feature of polycystic ovary syndrome (PCOS), but the exact origin of hyperandrogenemia remains a matter of debate. Recent studies have highlighted the importance of the 11-oxygenated C19 steroid pathway to androgen metabolism in humans. In this study, we analyzed the contribution of 11-oxygenated androgens to androgen excess in women with PCOS. Methods: One hundred fourteen women with PCOS and 49 healthy control subjects underwent measurement of serum androgens by liquid chromatography-tandem mass spectrometry. Twenty-four–hour urinary androgen excretion was analyzed by gas chromatography-mass spectrometry. Fasting plasma insulin and glucose were measured for homeostatic model assessment of insulin resistance. Baseline demographic data, including body mass index, were recorded. Results: As expected, serum concentrations of the classic androgens testosterone (P < 0.001), androstenedione (P < 0.001), and dehydroepiandrosterone (P < 0.01) were significantly increased in PCOS. Mirroring this, serum 11-oxygenated androgens 11β-hydroxyandrostenedione, 11-ketoandrostenedione, 11β-hydroxytestosterone, and 11-ketotestosterone were significantly higher in PCOS than in control subjects, as was the urinary 11-oxygenated androgen metabolite 11β-hydroxyandrosterone. The proportionate contribution of 11-oxygenated to total serum androgens was significantly higher in patients with PCOS compared with control subjects [53.0% (interquartile range, 48.7 to 60.3) vs 44.0% (interquartile range, 32.9 to 54.9); P < 0.0001]. Obese (n = 51) and nonobese (n = 63) patients with PCOS had significantly increased 11-oxygenated androgens. Serum 11β-hydroxyandrostenedione and 11-ketoandrostenedione correlated significantly with markers of insulin resistance. Conclusions: We show that 11-oxygenated androgens represent the majority of circulating androgens in women with PCOS, with close correlation to markers of metabolic risk. PMID:27901631

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.

Androgens and androgenic activity in broiler manure assessed by means of chemical analyses and in vitro bioassays.

PubMed

Valdehita, Ana; Fernández-Cruz, María-Luisa; González-Gullón, María Isabel; Becerra-Neira, Eduardo; Delgado, María Mar; García-González, Mari Cruz; Navas, José María

2017-07-01

The use of manure as an agricultural amendment is increasing the release of steroid hormones into the environment. Most research in this field has focused on estrogenic phenomena, with less attention paid to androgenic substances. The present study assessed androgenic activity in broiler manure using in vitro approaches based on cells stably transfected with androgen receptor. Leaching experiments were also performed to observe whether endocrine disruptors present in manure pass through a soil column and potentially reach groundwater. In parallel, an analytical chemistry method was used to determine the contribution of the most important natural androgens to androgenicity. Samplings were performed at 4 farms in 2 seasons. All but 2 samples showed androgen activity. In leakage experiments, however, no androgenic activity was detectable in leachates or in soils after leaching. According to the analytical results, androgenicity can be attributed mainly (but not completely) to androstenedione, and dihydrotestosterone. Similarly to the bioassays, chemical analysis did not reveal the presence of any androgen in leachates or soils. These results point to a rapid degradation of the substances responsible for androgenic activity in soils under the experimental conditions of the present study. However, the long-term effects associated with the constant and intensive application of manure to agricultural land require further attention. Environ Toxicol Chem 2017;36:1746-1754. © 2016 SETAC. © 2016 SETAC.

The role of estrogen and androgen receptors in bone health and disease

PubMed Central

2014-01-01

Mouse models with cell-specific deletion of the estrogen receptor (ER) α, the androgen receptor (AR) or the receptor activator of nuclear factor κB ligand (RANKL), as well as cascade-selective estrogenic compounds have provided novel insights into the function and signalling of ERα and AR. The studies reveal that the effects of estrogens on trabecular versus cortical bone mass are mediated by direct effects on osteoclasts and osteoblasts, respectively. The protection of cortical bone mass by estrogens is mediated via ERα, using a non-nucleus-initiated mechanism. By contrast, the AR of mature osteoblasts is indispensable for the maintenance of trabecular bone mass in male mammals, but not required for the anabolic effects of androgens on cortical bone. Most unexpectedly, and independently of estrogens, ERα in osteoblast progenitors stimulates Wnt signalling and periosteal bone accrual in response to mechanical strain. RANKL expression in B lymphocytes, but not T lymphocytes, contributes to the loss of trabecular bone caused by estrogen deficiency. In this Review, we summarize this evidence and discuss its implications for understanding the regulation of trabecular and cortical bone mass; the integration of hormonal and mechanical signals; the relative importance of estrogens versus androgens in the male skeleton; and, finally, the pathogenesis and treatment of osteoporosis. PMID:24042328

Androgen Receptor (AR) Physiological Roles in Male and Female Reproductive Systems: Lessons Learned from AR-Knockout Mice Lacking AR in Selective Cells1

PubMed Central

Chang, Chawnshang; Lee, Soo Ok; Wang, Ruey-Sheng; Yeh, Shuyuan; Chang, Ta-Min

2013-01-01

ABSTRACT Androgens/androgen receptor (AR) signaling is involved primarily in the development of male-specific phenotypes during embryogenesis, spermatogenesis, sexual behavior, and fertility during adult life. However, this signaling has also been shown to play an important role in development of female reproductive organs and their functions, such as ovarian folliculogenesis, embryonic implantation, and uterine and breast development. The establishment of the testicular feminization (Tfm) mouse model exploiting the X-linked Tfm mutation in mice has been a good in vivo tool for studying the human complete androgen insensitivity syndrome, but this mouse may not be the perfect in vivo model. Mouse models with various cell-specific AR knockout (ARKO) might allow us to study AR roles in individual types of cells in these male and female reproductive systems, although discrepancies are found in results between labs, probably due to using various Cre mice and/or knocking out AR in different AR domains. Nevertheless, no doubt exists that the continuous development of these ARKO mouse models and careful studies will provide information useful for understanding AR roles in reproductive systems of humans and may help us to develop more effective and more specific therapeutic approaches for reproductive system-related diseases. PMID:23782840

A selective androgen receptor modulator with minimal prostate hypertrophic activity enhances lean body mass in male rats and stimulates sexual behavior in female rats.

PubMed

Allan, George F; Tannenbaum, Pamela; Sbriscia, Tifanie; Linton, Olivia; Lai, Muh-Tsann; Haynes-Johnson, Donna; Bhattacharjee, Sheela; Zhang, Xuqing; Sui, Zhihua; Lundeen, Scott G

2007-08-01

Androgen receptor (AR) ligands with tissue selectivity (selective androgen receptor modulators, or SARMs) have potential for treating muscle wasting, hypogonadism of aging, osteoporosis, female sexual dysfunction, and other indications. JNJ-28330835 is a nonsteroidal AR ligand with mixed agonist and antagonist activity in androgen-responsive cell-based assays. It is an orally active SARM with muscle selectivity in orchidectomized rat models. It stimulated growth of the levator ani muscle, stimulating maximal growth at a dose of 10 mg/kg. At the same time, JNJ-28330835 reduced prostate weight in intact rats by a mean of 30% at 10 mg/kg, while having no inhibitory effect on muscle. Using magnetic resonance imaging (MRI) to monitor body composition, it prevented half of the loss of lean body mass associated with orchidectomy, and restored about 30% of lost lean mass to aged orchidectomized rats. It had agonist effects on markers of both osteoclast and osteoblast activity, suggesting that it reduces bone turnover. In a model of sexual behavior, JNJ-28330835 enhanced the preference of ovariectomized female rats for sexually intact male rats over nonsexual orchidectomized males. JNJ-28330835 is a prostate-sparing SARM with the potential for clinically beneficial effects in muscle-wasting diseases and sexual function disorders.

Hyperandrogenism in adolescent girls: relationship with the somatotrophic axis.

PubMed

Hernandez, María Isabel; López, Patricia; Gaete, Ximena; Villarroel, Claudio; Cavada, Gabriel; Avila, Alejandra; Iñiguez, German; Cassorla, Fernando

2017-05-01

During puberty there is a physiologic increase in adrenal and ovarian androgens. It has been suggested that the somatotrophic axis may be related to the development of hyperandrogenism and anovulation in non-obese adult women with polycystic ovarian syndrome (PCOS). The objective of the study was to investigate whether ovarian androgen secretion in young postmenarchal girls is related to the function of their somatotropic axis. This was a cross-sectional study of adolescent girls. We studied non-obese adolescent girls with hyperandrogenism (HA; n = 21) matched with control girls (C; n = 25) for chronological age, age at menarche and body mass index. We obtained a fasting blood sample for measurement of serum glucose, insulin, 17-hydroxyprogesterone (17OH-Prog), dehydroepiandrosterone-sulfate (DHEA-S), androstenedione, sex hormone-binding globulin (SHBG), total testosterone, IGF-I, IGF-II, IGFBP-1, IGFBP-3, ghrelin, leptin, AMH (antiMüllerian hormone), luteinizing hormone (LH) and follicle stimulating hormone (FSH) during the follicular phase of the menstrual period. We performed an oral glucose tolerance test to determine blood glucose, insulin and ghrelin levels and urine samples to measure urinary GH (growth hormone) levels. As expected, the hyperandrogenic girls had significantly higher Ferriman scores, basal total testosterone, free androgen index (FAI), androstenedione, AMH, and basal LH levels compared with the girls in controls. Serum IGF-I, IGF-II, IGFBP-3 and urinary GH did not differ between HA and C. There was a correlation between urinary GH and FAI in all girls (r 0.29, p < 0.05). In addition, in HA girls FAI correlated with insulin, homeostasis model assessment (HOMA) and ghrelin. We observed a correlation between urinary GH and FAI in the hyperandrogenic and control girls, suggesting that the function of the somatotrophic axis may influence the secretion of androgens in adolescent girls.