scispace - formally typeset
Search or ask a question

Showing papers on "Testosterone published in 2011"


Journal ArticleDOI
04 Mar 2011-Cell
TL;DR: It is shown that, in males, bone acts as a regulator of fertility, and the physiological repertoire of osteocalcin is expanded, providing the first evidence that the skeleton is an endocrine regulator of reproduction.

540 citations


Journal ArticleDOI
TL;DR: It is reported that AR activity in castration-resistant VCaP tumor xenografts can be restored through CYP17A1-dependent de novo androgen synthesis, and that abiraterone treatment of these xenografteds imposes selective pressure for increased intratumoral expression of CYP 17A1, thereby generating a mechanism for development of resistance to CYP16A1 inhibitors.
Abstract: Relapse of castration-resistant prostate cancer (CRPC) that occurs after androgen deprivation therapy of primary prostate cancer can be mediated by reactivation of the androgen receptor (AR). One important mechanism mediating this AR reactivation is intratumoral conversion of the weak adrenal androgens DHEA and androstenedione into the AR ligands testosterone and dihydrotestosterone (DHT). DHEA and androstenedione are synthesized by the adrenals through the sequential actions of the cytochrome P450 enzymes CYP11A1 and CYP17A1, so that CYP17A1 inhibitors such as abiraterone are effective therapies for CRPC. However, the significance of intratumoral CYP17A1 and de novo androgen synthesis from cholesterol in CRPC, and the mechanisms contributing to CYP17A1 inhibitor resistance/relapse, remain to be determined. We report that AR activity in castration-resistant VCaP tumor xenografts can be restored through CYP17A1-dependent de novo androgen synthesis, and that abiraterone treatment of these xenografts imposes selective pressure for increased intratumoral expression of CYP17A1, thereby generating a mechanism for development of resistance to CYP17A1 inhibitors. Supporting the clinical relevance of this mechanism, we found that intratumoral expression of CYP17A1 was markedly increased in tumor biopsies from CRPC patients after CYP17A1 inhibitor therapy. We further show that CRPC cells expressing a progesterone responsive T877A mutant AR are not CYP17A1 dependent, but that AR activity in these cells is still steroid dependent and mediated by upstream CYP11A1 dependent intraturmoral pregnenolone/progesterone synthesis. Together, our results indicate that CRPCs resistant to CYP17A1 inhibition may remain steroid dependent and therefore responsive to therapies that can further suppress de novo intratumoral steroid synthesis.

414 citations


Journal ArticleDOI
TL;DR: Sex hormone concentrations were strongly associated with several established or suspected risk factors for breast cancer, and may mediate the effects of these factors on breast cancer risk.
Abstract: BACKGROUND: Breast cancer risk for postmenopausal women is positively associated with circulating concentrations of oestrogens and androgens, but the determinants of these hormones are not well understood. METHODS: Cross-sectional analyses of breast cancer risk factors and circulating hormone concentrations in more than 6000 postmenopausal women controls in 13 prospective studies. RESULTS: Concentrations of all hormones were lower in older than younger women, with the largest difference for dehydroepiandrosterone sulphate (DHEAS), whereas sex hormone-binding globulin (SHBG) was higher in the older women. Androgens were lower in women with bilateral ovariectomy than in naturally postmenopausal women, with the largest difference for free testosterone. All hormones were higher in obese than lean women, with the largest difference for free oestradiol, whereas SHBG was lower in obese women. Smokers of 15+ cigarettes per day had higher levels of all hormones than non-smokers, with the largest difference for testosterone. Drinkers of 20+ g alcohol per day had higher levels of all hormones, but lower SHBG, than non-drinkers, with the largest difference for DHEAS. Hormone concentrations were not strongly related to age at menarche, parity, age at first full-term pregnancy or family history of breast cancer. CONCLUSION: Sex hormone concentrations were strongly associated with several established or suspected risk factors for breast cancer, and may mediate the effects of these factors on breast cancer risk. British Journal of Cancer (2011) 105, 709-722. doi:10.1038/bjc.2011.254 www.bjcancer.com Published online 19 July 2011 (C) 2011 Cancer Research UK

347 citations


Journal ArticleDOI
TL;DR: It is shown that the dominant route of DHT synthesis in CRPC bypasses testosterone, and instead requires 5α-reduction of androstenedione by SRD5A1 to 5 α-androstanedione, which is then converted to DHT.
Abstract: In the majority of cases, advanced prostate cancer responds initially to androgen deprivation therapy by depletion of gonadal testosterone. The response is usually transient, and metastatic tumors almost invariably eventually progress as castration-resistant prostate cancer (CRPC). The development of CRPC is dependent upon the intratumoral generation of the potent androgen, dihydrotestosterone (DHT), from adrenal precursor steroids. Progression to CRPC is accompanied by increased expression of steroid-5α-reductase isoenzyme-1 (SRD5A1) over SRD5A2, which is otherwise the dominant isoenzyme expressed in the prostate. DHT synthesis in CRPC is widely assumed to require 5α-reduction of testosterone as the obligate precursor, and the increased expression of SRD5A1 is thought to reflect its role in converting testosterone to DHT. Here, we show that the dominant route of DHT synthesis in CRPC bypasses testosterone, and instead requires 5α-reduction of androstenedione by SRD5A1 to 5α-androstanedione, which is then converted to DHT. This alternative pathway is operational and dominant in both human CRPC cell lines and fresh tissue obtained from human tumor metastases. Moreover, CRPC growth in mouse xenograft models is dependent upon this pathway, as well as expression of SRD5A1. These findings reframe the fundamental metabolic pathway that drives CRPC progression, and shed light on the development of new therapeutic strategies.

330 citations


Journal ArticleDOI
TL;DR: It is proposed that steroidogenesis in the brain, independent of peripherally derived precursors, may play a critical role in mammalian brain development of both sexes, beyond the establishment of sex differences.
Abstract: The prevailing view of sexual differentiation of mammalian brain is that androgen synthesized in the fetal and neonatal testis and aromatized centrally during a perinatal sensitive period is the sole source of brain estradiol and the primary determinant of sex differences. Subregions of the diencephalon are among the most sexually dimorphic in the brain, and there are well-established sex differences in the amount of testosterone and estradiol measured in the hypothalamus and preoptic area during the perinatal period. We previously reported unexpectedly high estradiol in the hippocampus and cortex of both male and female newborn rat. This prompted a thorough investigation of the developmental profile of steroids in the rat brain using RIA to quantify the level of estradiol, testosterone, and dihydrotestosterone in discrete subregions of the brain from embryonic d 19 to adulthood. Plasma estradiol levels from individual animals were assessed when sufficient sample was available. A significant sex differenc...

267 citations


Journal ArticleDOI
TL;DR: More work is needed to identify estrogens and associated signaling pathways in BPH in order to target BPH with dietary and therapeutic SERMs, and demonstrate that estrogen receptor signaling pathways may be important in the development and maintenance of BPH and LUTS.

255 citations


Journal ArticleDOI
TL;DR: Sex-specific relationships between normal, age-related depletion of androgens and estrogens in men and women, which may be relevant to development of AD, are demonstrated.

242 citations


Journal ArticleDOI
TL;DR: It is shown that females suffer a worse outcome from influenza A virus infection than males, which can be reversed by administration of high doses of estradiol to females and reflects differences in the induction of proinflammatory responses and not in virus load.
Abstract: Studies of the 1918 H1N1 influenza pandemic, the H5N1 avian influenza outbreak, and the 2009 H1N1 pandemic illustrate that sex and pregnancy contribute to severe outcome from infection, suggesting a role for sex steroids. To test the hypothesis that the sexes respond differently to influenza, the pathogenesis of influenza A virus infection was investigated in adult male and female C57BL/6 mice. Influenza infection reduced reproductive function in females and resulted in greater body mass loss, hypothermia, and mortality in females than males. Whereas lung virus titers were similar between the sexes, females had higher induction of proinflammatory cytokines and chemokines, including TNF-α, IFN-γ, IL-6, and CCL2, in their lungs than males. Removal of the gonads in both sexes eliminated the sex difference in influenza pathogenesis. Manipulation of testosterone or dihydrotestosterone concentrations in males did not significantly impact virus pathogenesis. Conversely, females administered high doses of estradiol had a ≥10-fold lower induction of TNF-α and CCL2 in the lungs and increased rates of survival as compared with females that had either low or no estradiol. The protective effects of estradiol on proinflammatory cytokines and chemokines, morbidity, and mortality were primarily mediated by signaling through estrogen receptor α (ERα). In summary, females suffer a worse outcome from influenza A virus infection than males, which can be reversed by administration of high doses of estradiol to females and reflects differences in the induction of proinflammatory responses and not in virus load.

209 citations


Journal ArticleDOI
01 Jan 2011-Steroids
TL;DR: The hypothesis that the changes in T and DHT that occur across the cycle may reflect changes in SHBG and estrogen, whereas in menopause, androgen levels decrease is supported.

200 citations


Journal ArticleDOI
TL;DR: It is hypothesized that the effects of BPA on reproductive dysfunction may be due to its actions on gonadal steroidogenesis and so the anomalous releases of endogenous steroid hormones in the HPG-axis.

199 citations


Journal ArticleDOI
TL;DR: The role of androgen biosynthesis in the progression of prostate cancer and the impact of CYP17 inhibitors, such as ketoconazole, abiraterone acetate, VN/124-1 (TOK-001) and TAK-700 in the clinic and in clinical development are highlighted.

Journal ArticleDOI
TL;DR: An immunomodulatory and protective effect of testosterone substitution in the pathogenesis of EAO is shown and suggests androgens as a new factor in the differentiation of regulatory T cells.
Abstract: Despite the immune-privileged status of the male genital tract, infection and inflammation of the male genital tract are important etiological factors in male infertility. A common observation in clinical and experimental orchitis as well as in systemic infection and inflammation are decreased levels of testosterone. Emerging data point to an immunosuppressive role of testosterone. In our study, we substituted testosterone levels in experimental autoimmune orchitis (EAO) in rat by s.c. testosterone implants. EAO development was reduced to 17% when animals were treated with low-dose testosterone implants (3 cm long, EAO+T3) and to 33% when rats were supplied with high-dose testosterone implants (24 cm, EAO+T24) compared with 80% of animals developing disease in the EAO control group. In the testis, testosterone replacement in EAO animals prevented the accumulation of macrophages and significantly reduced the number of CD4+ T cells with a strong concomitant increase in the number of regulatory T cells (CD4+CD25+Foxp3+) compared with EAO control. In vitro testosterone treatment of naive T cells led to an expansion of the regulatory T cell subset with suppressive activity and ameliorated MCP-1–stimulated chemotaxis of T lymphocytes in a Transwell assay. Moreover, expression of proinflammatory mediators such as MCP-1, TNF-α, and IL-6 in the testis and secretion of Th1 cytokines such as IFN-γ and IL-2 by mononuclear cells isolated from testicular draining lymph nodes were decreased in the EAO+T3 and EAO+T24 groups. Thus, our study shows an immunomodulatory and protective effect of testosterone substitution in the pathogenesis of EAO and suggests androgens as a new factor in the differentiation of regulatory T cells.

Journal ArticleDOI
TL;DR: Data show that BPA targets the estradiol biosynthesis pathway in the ovary, and pregnenolone was unable to protect follicles from BPA induced inhibition of steroidogenic enzymes compared with the DMSO control.

Journal ArticleDOI
TL;DR: The most current data regarding non-ligand-mediated activation of the AR in prostate cancer cells is summarized to more clearly elucidate the signals that drive AR activity independently of androgens in CR disease so that better therapeutic targets can be developed for patients with this stage of highly aggressive prostate cancer.
Abstract: Advanced prostate tumors, which are androgen dependent, are often initially treated in the clinic with hormone ablation therapy, either through surgical castration or administration of small-molecule antiandrogens. Most tumors respond favorably to these treatments, exhibiting regression of the tumor, amelioration of symptoms, and a decrease of prostate-specific antigen in patient sera. However, with time, the majority of tumors recur in a more aggressive, castration-resistant (CR) phenotype. Currently, no effective treatment exists for this stage of the cancer, and patients ultimately succumb to metastatic disease. The androgen receptor (AR), which is a member of the nuclear hormone receptor superfamily of proteins, is the transcription factor that is responsible for mediating the effects of androgens upon target tissues, and it has been demonstrated to play a central role in the development and progression of prostate cancer. Despite CR tumor cells being able to continue to grow after hormonal therapy in which testosterone and dihydrotestosterone are markedly reduced, they still require the expression and activity of the AR. The AR can become transactivated in this low-androgen environment through a number of different mechanisms, including amplification and mutation of the receptor, cross talk with other signaling pathways, and altered regulation by coregulatory proteins. This review will summarize the most current data regarding non-ligand-mediated activation of the AR in prostate cancer cells. Developing work in this field aims to more clearly elucidate the signals that drive AR activity independently of androgens in CR disease so that better therapeutic targets can be developed for patients with this stage of highly aggressive prostate carcinoma.

Journal ArticleDOI
TL;DR: This review outlines one clinically important mechanism contributing to this AR reactivation, which is increased intratumoral synthesis of testosterone and DHT from weak androgens produced by the adrenal glands and possibly de novo from cholesterol.
Abstract: The majority of prostate cancers (PCa) express high levels of androgen receptor (AR) and are dependent for their growth on testosterone produced by the testes, which is reduced in the prostate to the higher affinity ligand 5α-dihydrotestosterone (DHT). PCa growth can be suppressed by androgen deprivation therapy, which involves removal of testicular androgens (surgical or medical castration) or treatment with an AR antagonist (or a combination of both), but patients invariably relapse with tumors that have been termed castration recurrent/resistant PCa (CRPC). Importantly, AR transcriptional activity becomes reactivated at this CRPC stage of the disease and remains essential for tumor growth. The objective of this review is to outline one clinically important mechanism contributing to this AR reactivation, which is increased intratumoral synthesis of testosterone and DHT from weak androgens produced by the adrenal glands and possibly de novo from cholesterol. Early studies showed that a substantial fraction of CRPC patients responded to adrenalectomy or medical suppression of adrenal androgen synthesis using agents such as ketoconazole (CYP17A1 inhibitor), and a recent phase III study of a more potent and selective CYP17A1 inhibitor (abiraterone) has demonstrated an improvement in survival. With the pending FDA approval of abiraterone for CRPC, defining the molecular mechanisms contributing to CYP17A1 inhibitor resistance/relapse and AR reactivation is now critical to build on these advances.

Journal ArticleDOI
TL;DR: Postnatal HPG axis activation in infancy is increased in PT boys and associated with faster testicular and penile growth compared with FT boys, and possible long-term consequences of hyperandrogenism in PT infant boys warrant further research.
Abstract: Context: Transient activation of the hypothalamic-pituitary-gonadal (HPG) axis is observed in boys during the first months of life. Previous research suggests increased HPG axis activation in premature infants, but the physiological significance of this has not been studied. Objective: The objective of this study was to evaluate the differences in reproductive hormone levels and their biological effects between full-term (FT) and preterm (PT) infant boys. Study Design and Participants: Twenty-five FT and 25 PT (gestational age 24.7–36.6 wk) boys were recruited at birth and followed up monthly from 1 wk to 6 months of age (d 7, months 1–6). Nineteen FT and 20 PT boys were reexamined at 14 months of age. Main Outcome Measures: Urinary gonadotropins and testosterone were measured in serial urine samples and compared with testicular and penile growth. Urinary prostate-specific antigen was measured as an androgen biomarker. Results: LH and testosterone levels were higher in PT boys (P < 0.001 for both) than FT...

Journal ArticleDOI
TL;DR: Male and female cortical astrocytes respond differentially to an inflammatory challenge and this may be predetermined by perinatal testosterone exposure.
Abstract: Numerous neurological and psychiatric disorders show sex differences in incidence, age of onset, symptomatology or outcome. Astrocytes, one of the glial cell types of the brain, show sex differences in number, differentiation and function. Since astrocytes are involved in the response of neural tissue to injury and inflammation, these cells may participate in the generation of sex differences in the response of the brain to pathological insults. To explore this hypothesis, we have examined whether male and female astrocytes show a different response to an inflammatory challenge and whether perinatal testosterone influences this response. Cortical astrocyte cultures were prepared from postnatal day 1 (one day after birth) male or female CD1 mice pups. In addition, cortical astrocyte cultures were also prepared from female pups that were injected at birth with 100 μg of testosterone propionate or vehicle. Cultures were treated for 5 hours with medium containing lipopolysaccharide (LPS) or with control medium. The mRNA levels of IL6, interferon-inducible protein 10 (IP10), TNFα, IL1β, Toll-like receptor 4 (TLR4), steroidogenic acute regulatory protein and translocator protein were assessed by quantitative real-time polymerase chain reaction. Statistical significance was assessed by unpaired t-test or by one-way analysis of variance followed by the Tukey post hoc test. The mRNA levels of IL6, TNFα and IL1β after LPS treatment were significantly higher in astrocytes derived from male or androgenized females compared to astrocytes derived from control or vehicle-injected females. In contrast, IP10 mRNA levels after LPS treatment were higher in astrocytes derived from control or vehicle-injected females than in those obtained from males or androgenized females. The different response of male and female astrocytes to LPS was due neither to differences in the basal expression of the inflammatory molecules nor to differences in the expression of the LPS receptor TLR4. In contrast, the different inflammatory response was associated with increased mRNA levels of translocator protein, a key steroidogenic regulator, in female astrocytes that were treated with LPS. Male and female cortical astrocytes respond differentially to an inflammatory challenge and this may be predetermined by perinatal testosterone exposure.

Journal ArticleDOI
TL;DR: Findings represent a paradigm shift when thinking about the role of sex steroids in neuroprotection clinically after TBI, as increased estradiol and testosterone levels over time were associated with increased mortality and worse global outcome for both men and women.
Abstract: Experimental traumatic brain injury (TBI) studies report the neuroprotective effects of female sex steroids on multiple mechanisms of injury, with the clinical assumption that women have hormonally mediated neuroprotection because of the endogenous presence of these hormones. Other literature indicates that testosterone may exacerbate injury. Further, stress hormone abnormalities that accompany critical illness may both amplify or blunt sex steroid levels. To better understand the role of sex steroid exposure in mediating TBI, we 1) characterized temporal profiles of serum gonadal and stress hormones in a population with severe TBI during the acute phases of their injury; and 2) used a biological systems approach to evaluate these hormones as biomarkers predicting global outcome. The study population was 117 adults (28 women; 89 men) with severe TBI. Serum samples (n=536) were collected for 7 days post-TBI for cortisol, progesterone, testosterone, estradiol, luteinizing hormone (LH), and follicle-stimulating hormone (FSH). Hormone data were linked with clinical data, including acute care mortality and Glasgow Outcome Scale (GOS) scores at 6 months. Hormone levels after TBI were compared to those in healthy controls (n=14). Group based trajectory analysis (TRAJ) was used to develop temporal hormone profiles that delineate distinct subpopulations in the cohort. Structural equations models were used to determine inter-relationships between hormones and outcomes within a multivariate model. Compared to controls, acute serum hormone levels were significantly altered after severe TBI. Changes in the post-TBI adrenal response and peripheral aromatization influenced hormone TRAJ profiles and contributed to the abnormalities, including increased estradiol in men and increased testosterone in women. In addition to older age and greater injury severity, increased estradiol and testosterone levels over time were associated with increased mortality and worse global outcome for both men and women. These findings represent a paradigm shift when thinking about the role of sex steroids in neuroprotection clinically after TBI.

Journal ArticleDOI
TL;DR: Klinefelter syndrome is the most frequent sex chromosome disorder in males, but the phenotype varies greatly and is therefore highly under‐diagnosed, and the phenotypic characteristics throughout life from clinical follow-up of patients with KS are described.
Abstract: Aim: Klinefelter syndrome (KS) is the most frequent sex chromosome disorder in males, but the phenotype varies greatly and is therefore highly under-diagnosed. We aimed at describing the phenotypic characteristics throughout life from clinical follow-up of our large cohort of patients with KS. Methods: A retrospective observational study of 166 males with nonmosaic 47,XXY KS aged 0.3―80.3 years. Data on phenotype, growth, body composition, bone mineral density, sex hormones, lipids, glycosylated haemoglobin (HbA1C) and prostate-specific antigen were recorded. In addition, histological examination of testicular biopsies from 29 patients was performed. Results: Patients with Klinefelter were taller already in childhood. All patients had smaller testicular volume and elevated luteinizing hormone (LH) and follicle-stimulating hormone levels in adulthood. Cryptorchidism was reported in 14%, gynaecomastia in 44%, and 36% required speech therapy or educational support. The abnormal biochemical parameters became evident after onset of puberty and correlated with histological findings of a gradual deterioration of seminiferous tubules and massive Leydig cell hyperplasia in adults. Conclusion: Our patients presented with a wide spectrum of the classical Klinefelter symptoms. In adulthood, two features were consistently present in every patient: small testes and high LH/testosterone ratio, often despite normal testosterone levels. Such biochemical parameters combined with small testes should lead to a suspicion of KS.

Journal ArticleDOI
TL;DR: An overview of the regulation of the HPT axis is provided with an emphasis on the changes that occur with aging and the measurement of gonadal steroids, including hormone pulsatility, within-subject and circadian variations.

Journal ArticleDOI
TL;DR: The expression of Kiss1 is reported in the amygdala, predominantly in the medial nucleus of the amygdala (MeA), a region implicated in social and emotional behaviors as well as various aspects of reproduction.
Abstract: Kisspeptin (encoded by the Kiss1 gene) is an important regulator of reproduction. In rodents, Kiss1 is expressed in two hypothalamic regions, the arcuate nucleus and anteroventral periventricular/ periventricular continuum, where it is regulated by sex steroids. However, the distribution, regulation, and functional significance of neural kisspeptin outside of the hypothalamus have not been studied and are poorly understood. Here, we report the expression of Kiss1 in the amygdala, predominantly in the medial nucleus of the amygdala (MeA), a region implicated in social and emotional behaviors as well as various aspects of reproduction. In gonadally intact rats and mice, Kiss1-expressing neurons were identified in the MeA of both sexes, with higher Kiss1 expression levels in adult males than females in diestrus. In rats, Kiss1 expression in the MeA changed as a function of the estrous cycle, with highest levels at proestrus. Next, we tested whether Kiss1 in the MeA is regulated by the circulating sex steroid milieu. Kiss1 levels in the MeA were low in gonadectomized mice and rats of both sexes, and treatment with either testosterone or estradiol amplified Kiss1 expression in this region. Testosterone's inductive effect on Kiss1 expression in the MeA likely occurs via estrogen receptor-dependent pathways, not through the androgen receptor, because dihydrotestosterone (a nonaromatizable androgen) did not affect MeA Kiss1 levels. Thus, in rodents, Kiss1 is expressed and regulated by sex steroids in the MeA of both sexes and may play a role in modulating reproduction or brain functions that extend beyond reproduction.

Journal ArticleDOI
TL;DR: Many endocrine disruptors act as antiandrogens via directly inhibiting one or more enzymes for testosterone biosynthesis and metabolic activation, including industrial materials and pesticides/biocides and plant constituents.
Abstract: The Leydig cells of the testis have the capacity to biosynthesize testosterone from cholesterol. Testosterone and its metabolically activated product dihydrotestosterone are critical for the development of male reproductive system and spermatogenesis. At least four steroidogenic enzymes are involved in testosterone biosynthesis: Cholesterol side chain cleavage enzyme (CYP11A1) for the conversion of cholesterol into pregnenolone within the mitochondria, 3β-hydroxysteroid dehydrogenase (HSD3B), for the conversion of pregnenolone into progesterone, 17α-hydroxylase/17,20-lyase (CYP17A1) for the conversion of progesterone into androstenedione and 17β-hydroxysteroid dehydrogenase (HSD17B3) for the formation of testosterone from androstenedione. Testosterone is also metabolically activated into more potent androgen dihydrotestosterone by two isoforms 5α-reductase 1 (SRD5A1) and 2 (SRD5A2) in Leydig cells and peripheral tissues. Many endocrine disruptors act as antiandrogens via directly inhibiting one or more enzymes for testosterone biosynthesis and metabolic activation. These chemicals include industrial materials (perfluoroalkyl compounds, phthalates, bisphenol A and benzophenone) and pesticides/biocides (methoxychlor, organotins, 1,2-dibromo-3-chloropropane and prochloraz) and plant constituents (genistein and gossypol). This paper reviews these endocrine disruptors targeting steroidogenic enzymes.


Journal ArticleDOI
TL;DR: Using morphometric analysis and the rat model, changes in epithelial cell height and lumen diameter are identified and IGF1 and EGF receptors were found to be important mediators of androgen receptor-mediated activation of the MAPK/ERK pathways.
Abstract: Androgens are responsible for maintaining epididymal structure and functions. However, little is known about how androgen action is mediated and the mechanisms underlying the restoration of the integrity of epididymal cells after androgen deprivation. We first provide an overview of what is known about androgen action in this tissue and then present data on the initial and sequential roles of androgens in altering cellular architecture and function in an androgen-deprived condition. Using morphometric analysis and the rat model, we identified changes in epithelial cell height and lumen diameter, as well as in the numbers of proliferating cells in different regions and at various time points after androgen withdrawal and replacement. The sequence of gene activation or suppression that occurred in the androgen-deprived tissue was examined upon the readministration of the 2 active metabolites of testosterone, dihydrotestosterone (DHT) and estradiol. Although few genes were regulated by estradiol, many were affected by DHT. Epidermal growth factor (EGF) and insulinlike growth factor-1 (IGF1) appear to play an important role in the early response pathway activated by DHT because of their function in the regulation of the expression of many other genes. The intracellular signaling pathway involved in mediating the action of androgen in restoring epididymal epithelial cell integrity was investigated using the PC-1 epididymal cell line. IGF1 and EGF receptors were found to be important mediators of androgen receptor-mediated activation of the MAPK/ERK pathways. Together, these studies provide a greater understanding of the mechanisms of androgen action in the epididymis.

Journal ArticleDOI
TL;DR: Further research is needed to establish through which molecular pathways, and during which evolutionary stages of development, androgens and estrogens can promote the occurrence of both receptor-positive and -negative clinical breast tumors.
Abstract: Prediagnostic endogenous sex steroid hormone levels have well established associations with overall risk of breast cancer. While evidence toward the existence of distinct subtypes of breast cancer accumulates, few studies have investigated the associations of sex steroid hormone levels with risk of hormone receptor [estrogen receptor (ER) and/or progesterone receptor (PR)] defined breast cancer. In a case-control study nested within the EPIC cohort (European Prospective Investigation into Cancer and Nutrition), estradiol, testosterone, and sex hormone-binding globulin levels were measured in prediagnostic serum samples from postmenopausal women not using hormone replacement therapy at blood donation. A total of 554 women who developed invasive breast cancer with information on receptor status were matched with 821 control subjects. Conditional logistic regression models estimated breast cancer risk with hormone concentrations according to hormone receptor status of the tumor. Sex steroid hormones were associated with risks of not only ER+PR+ breast cancer [estradiol OR for highest vs. lowest tertile = 2.91 (95% CI: 1.62-5.23), P(trend) = 0.002; testosterone OR = 2.27 (95% CI: 1.35-3.81), P(trend) = 0.002] but also of ER-PR- breast cancer [estradiol OR = 2.11 (95% CI: 1.00-4.46), P(trend) = 0.05; testosterone OR = 2.06 (95% CI: 0.95-4.46), P(trend) = 0.03], with associations appearing somewhat stronger in the receptor-positive disease. Serum androgens and estrogens are associated with risks of both hormone receptor-negative as well as receptor-positive breast tumors. Further research is needed to establish through which molecular pathways, and during which evolutionary stages of development, androgens and estrogens can promote the occurrence of both receptor-positive and -negative clinical breast tumors.

Journal ArticleDOI
TL;DR: It is found that castration of adult male rats resulted in decreased AVP mRNA expression and increased methylation of specific CpG sites within the AVP promoter in the BST, which suggests that the DNA promoter methylation status of some steroid responsive genes in the adult brain is actively maintained by the presence of circulating steroid hormones.
Abstract: Although some DNA methylation patterns are altered by steroid hormone exposure in the developing brain, less is known about how changes in steroid hormone levels influence DNA methylation patterns in the adult brain. Steroid hormones act in the adult brain to regulate gene expression. Specifically, the expression of the socially relevant peptide vasopressin (AVP) within the bed nucleus of the stria terminalis (BST) of adult brain is dependent upon testosterone exposure. Castration dramatically reduces and testosterone replacement restores AVP expression within the BST. As decreases in mRNA expression are associated with increases in DNA promoter methylation, we explored the hypothesis that AVP expression in the adult brain is maintained through sustained epigenetic modifications of the AVP gene promoter. We find that castration of adult male rats resulted in decreased AVP mRNA expression and increased methylation of specific CpG sites within the AVP promoter in the BST. Similarly, castration significantly increased estrogen receptor α (ERα) mRNA expression and decreased ERα promoter methylation within the BST. These changes were prevented by testosterone replacement. This suggests that the DNA promoter methylation status of some steroid responsive genes in the adult brain is actively maintained by the presence of circulating steroid hormones. The maintenance of methylated or demethylated states of some genes in the adult brain by the presence of steroid hormones may play a role in the homeostatic regulation of behaviorally relevant systems.

Journal ArticleDOI
TL;DR: It is found that NTFs display a masculinized energy intake and ARC POMC expression and innervation as observed in CMs, which can be mimicked by neonatal exposure to the androgen receptor agonist dihydrotestosterone (DHT).
Abstract: In mammals, males consume more food, which is considered a masculinized behavior, but the underlying mechanism of this sex-specific feeding behavior is unknown. In mice, neonatal testosterone (NT) is critical to masculinize the developing brain, leading to sex differences in reproductive physiology. The proopiomelanocortin (POMC) neurons of the hypothalamic arcuate nucleus (ARC) are critical to suppress energy intake and POMC innervation of hypothalamic feeding circuits develops to a large extent neonatally. We hypothesized that NT programs the masculinization of energy intake by programming POMC neurons. We tested this hypothesis by comparing control females and control males (CMs) with female mice neonatally androgenized with testosterone (NTFs). We show that increased food intake in CMs is associated with reduced POMC expression and decreased intensity of neuronal projections from POMC neurons within the ARC compared with control females. We found that NTFs display a masculinized energy intake and ARC POMC expression and innervation as observed in CMs, which can be mimicked by neonatal exposure to the androgen receptor agonist dihydrotestosterone (DHT). NTFs also exhibit hyperleptinemia and a decreased ability of leptin to up-regulate POMC, suppress food intake, and prevent adipose tissue accumulation, independent of signal transducer and activator of transcription 3. However, this leptin resistance is specific to NTFs, is not a consequence of masculinization, and is reproduced by neonatal exposure to estrogen but not DHT. Thus, NT programs a sexual differentiation of POMC neurons in female mice via DHT but also predisposes to leptin resistance and obesity in an estrogen-dependent manner.

Journal ArticleDOI
TL;DR: Results indicate that perinatal OMC-exposure can affect both the reproductive and neurological development of rat offspring, which may be a cause of concern, as humans are systematically exposed to the compound through usage of sunscreens and other cosmetics.

Journal ArticleDOI
TL;DR: Data show that the suppression of the hypothalamo-hypophyseal-gonadal axis in patients with subnormal free testosterone concentrations and type 2 diabetes is not associated with increased estradiol concentrations.
Abstract: OBJECTIVE It has been suggested that the high prevalence of subnormal free testosterone concentrations, along with low or inappropriately normal gonadotropins in men with type 2 diabetes, may be the result of an increase in plasma estradiol concentrations secondary to an increase in aromatase activity in the adipose tissue that leads to the suppression of the hypothalamo-hypophyseal-gonadal axis. RESEARCH DESIGN AND METHODS To investigate this hypothesis, plasma estradiol, testosterone, leutinizing hormone, follicle-stimulating hormone, and sex hormone–binding globulin (SHBG) concentrations were measured in fasting blood samples of 240 men with type 2 diabetes. Free estradiol concentrations were either calculated ( n = 198) using total estradiol and SHBG measured by immunoassay or directly measured by liquid chromatography tandem mass spectrometry (LC-MS/MS) and equilibrium dialysis ( n = 102). RESULTS The calculated free estradiol concentration in men with subnormal free testosterone concentrations was lower than that in men with normal free testosterone concentrations (median 0.047 vs. 0.063 ng/dL, P P = 0.008). Free estradiol concentrations were directly related to free testosterone but not to BMI or age. CONCLUSIONS These data show that the suppression of the hypothalamo-hypophyseal-gonadal axis in patients with subnormal free testosterone concentrations and type 2 diabetes is not associated with increased estradiol concentrations. The pathogenesis of subnormal free testosterone concentrations in type 2 diabetes needs to be investigated further.

Journal ArticleDOI
TL;DR: Chronic low-dose treatment with microcystin-LR results in substantial toxicity to male reproduction, causing declines in sperm quality, decreased levels of serum testosterone, and injury to the testis.