| androgen receptor | OKDB#: 100 |
| Symbols: | AR | Species: | human | ||
| Synonyms: | KD, AIS, AR8, TFM, DHTR, SBMA, HYSP1, NR3C4, SMAX1, HUMARA | Locus: | Xq12 in Homo sapiens | HPMR |
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| General Comment |
The gene encoding the androgen receptor, alternatively known as the dihydrotestosterone receptor, is located on the X chromosome. It is mutated in the X-linked androgen insensitivity syndrome formerly known as the testicular feminization syndrome (tfm), and in Kennedy spinal and bulbar muscular atrophy. Clinical variants of the androgen insensitivity syndrome (partial androgen insensitivity) include the Reifenstein syndrome.
//////A double-blind randomised controlled trial on the effect of dehydroepiandrosterone on ovarian reserve markers, ovarian response and number of oocytes in anticipated normal ovarian responders. Yeung T et al. (2015) To assess the effect of dehydroepiandrosterone (DHEA) on antral follicle count (AFC), ovarian response to a standard low dose of gonadotrophin stimulation and number of oocytes in anticipated normal responders undergoing in vitro fertilisation (IVF). Randomised, double-blind, placebo-controlled study. Tertiary reproductive unit. Seventy-two subfertile women with AFC of 5-15 scheduled for IVF. Eligible women were randomised into the DHEA group (n = 36), who received DHEA (GNC(®) , 25 mg three times a day), or the placebo group (n = 36), who received placebo, starting from 12 weeks before the scheduled IVF treatment according to a computer-generated randomisation list. Monthly assessment of AFC, serum anti-Mullerian hormone (AMH) and follicle-stimulating hormone (FSH) levels, ovarian response to a standard dose of gonadotrophin stimulation at week 8 and the number of oocytes obtained were compared. The primary outcome was AFC after 12 weeks of DHEA or placebo. DHEA for 12 weeks prior to IVF treatment in anticipated normal responders leads to significantly higher serum and follicular DHEA-S and testosterone relative to placebo. However, no significant differences in AFC, AMH and FSH, ovarian response to standard-dose ovarian stimulation and IVF cycle outcomes can be detected. No significant differences in AFC, ovarian response to a standard low dose of gonadotrophin stimulation and number of oocytes obtained were detected in anticipated normal responders receiving 12 weeks of DHEA prior to IVF treatment relative to placebo. No difference in ovarian response markers in normal responders receiving 12 weeks of DHEA.//////////////////
NCBI Summary: The androgen receptor gene is more than 90 kb long and codes for a protein that has 3 major functional domains: the N-terminal domain, DNA-binding domain, and androgen-binding domain. The protein functions as a steroid-hormone activated transcription factor. Upon binding the hormone ligand, the receptor dissociates from accessory proteins, translocates into the nucleus, dimerizes, and then stimulates transcription of androgen responsive genes. This gene contains 2 polymorphic trinucleotide repeat segments that encode polyglutamine and polyglycine tracts in the N-terminal transactivation domain of its protein. Expansion of the polyglutamine tract from the normal 9-34 repeats to the pathogenic 38-62 repeats causes spinal bulbar muscular atrophy (SBMA, also known as Kennedy's disease). Mutations in this gene are also associated with complete androgen insensitivity (CAIS). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2017] |
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| General function | Receptor | ||||
| Comment | Role of dehydroepiandrosterone in improving oocyte and embryo quality in IVF cycles. Zangmo R 2014 et al. The purpose of this study was to evaluate the role of dehydroepiandrosterone (DHEA) on the number and quality of oocytes and embryos in poor responders undergoing IVF cycles. A total of 50 patients with a history of poor ovarian response in the previous cycle(s) were enrolled in a prospective cohort study. They were treated with oral micronized DHEA 25mg three times a day for 4months. Oocyte and embryo number and quality were recorded before and after treatment. The results were analysed using Student's paired t-test. After treatment with DHEA, a significant increase in number of mature follicles was seen in the post treatment period (?35years P<0.001; ?36years P=0.002). There were significant increases in numbers of oocytes retrieved, fertilization rates and, consequently, the total number of embryos available. More embryos were vitrified among patients ?35years (P<0.001) post treatment, and clinical pregnancy rate in this group was 26.7%. DHEA treatment resulted in a higher number of oocytes retrieved, oocytes fertilized, embryos overall and of grade-I embryos. It can help in increasing pregnancy rate in poor responders. This study was performed to evaluate the role of dehydroepiandrosterone (DHEA) treatment on the number and quality of oocytes and embryos in poor responders undergoing IVF cycles. Fifty patients with a history of poor ovarian response in the previous cycle(s) were enrolled in the study and a prospective cohort study was performed. Patients were prescribed oral micronized DHEA 25mg three times a day for 4months. Oocytes and embryos in terms of both number and quality were measured before and after treatment. A significant increase in mean number of mature follicles was seen in the post-treatment group. There was a significant increase in the number of oocytes retrieved, fertilization rates and, consequently, in the total number of embryos available after treatment with DHEA. More embryos were vitrified post treatment and the overall pregnancy rate was 20%. DHEA resulted in a significant improvement in the numbers of oocytes retrieved, oocytes fertilized, embryos and grade-I embryos. DHEA can help improve pregnancy rate in poor responders with history of previous failed IVF cycles. ///////////////////////// | ||||
| Cellular localization | Cytoplasmic, Nuclear | ||||
| Comment | candidate123 | ||||
| Ovarian function | Follicle development, Preantral follicle growth, Antral follicle growth, Follicle atresia, Steroid metabolism, Luteinization, Oogenesis, Oocyte maturation | ||||
| Comment | Direct actions of androgen, estrogen and anti-Müllerian hormone on primate secondary follicle development in the absence of FSH in vitro. Baba T et al. (2017) What are effects of androgen, estrogen and anti-Müllerian hormone (AMH), independent of FSH action, on the development and function of primate follicles from the preantral to small antral stage in vitro? Androgen and estrogen, but not AMH, promote follicle survival and growth in vitro, in the absence of FSH. However, their growth-promoting effects are limited to the preantral to early antral stage. FSH supports primate preantral follicle development in vitro. Androgen and estrogen augment follicle survival and growth in the presence of FSH during culture. Nonhuman primate model; randomized, control versus treatment groups. Rhesus macaque (n = 6) secondary follicles (n = 24 per animal per treatment group) were cultured for 5 weeks. Follicles were encapsulated in 0.25% (w/v) alginate and cultured individually in modified alpha minimum essential media with (i) FSH (1 ng/ml; control), (ii) no FSH, (iii) no FSH + estradiol (E2; 100 pg/ml)/dihydrotestosterone (DHT; 50 ng/ml) and (iv) no FSH + AMH (50 ng/ml). In a second experiment, follicles were cultured with (i) FSH (1 ng/ml), (ii) no FSH, (iii) no FSH + E2 (1 ng/ml), (iv) no FSH + DHT (50 ng/ml) and (v) no FSH + E2/DHT. Follicle survival, antrum formation and growth pattern were evaluated. Progesterone (P4), E2 and AMH concentrations in culture media were measured. In the first experiment, FSH deprivation significantly decreased (P < 0.05) follicle survival rates in the no FSH group (16 ± 5%), compared to CTRL (66 ± 9%). E2/DHT (49 ± 5%), but not AMH (27 ± 8%), restored follicle survival rate to the CTRL level. Similarly, antrum formation rates were higher (P < 0.05) in CTRL (56 ± 6%) and E2/DHT groups (54 ± 14%), compared to no FSH (0 ± 0%) and AMH (11 ± 11%) groups. However, follicle growth rate after antrum formation and follicle diameter at week 5 was reduced (P < 0.05) in the E2/DHT group (405 ± 25 μm), compared to CTRL (522 ± 29 μm). Indeed, the proportion of fast-grow follicles at week 5 was higher in CTRL (29% ± 5), compared to E2/DHT group (10 ± 3%). No fast-grow follicles were observed in no FSH and AMH groups. AMH levels at week 3 remained similar in all groups. However, media concentrations of P4 and E2 at week 5 were lower (P < 0.05, undetectable) in no FSH, E2/DHT and AMH groups, compared to CTRL (P4 = 93 ± 10 ng/ml; E2 = 4 ± 1 ng/ml). In the second experiment, FSH depletion diminished follicle survival rate (66 ± 8% in control versus 45 ± 9% in no FSH, P = 0.034). E2 plus DHT (31.5 ± 11%) or DHT alone (69 ± 9%) restored follicle survival rate to the control (FSH) level as expected. Also, E2 plus DHT or DHT alone improved antrum formation rate. However, in the absence of FSH, E2 plus DHT or DHT alone did not support growth, in terms of follicle diameter, or steroid (P4 or E2) production after the antral stage. This study is limited to in vitro effects of E2, DHT and AMH during the interval from the secondary to small antral stage of macaque follicular development. In addition, the primate follicle pool is heterogeneous and differs between animals; therefore, even though only secondary follicles were selected, follicle growth and developmental outcomes might differ from one animal to another. This study provides novel information on the possible actions of estrogen and androgen during early follicular development in primates. Our results suggest that sequential exposure of preantral follicles to local factors, e.g. E2 and DHT, followed by gonadotropin once the follicle reaches the antral stage, may better mimic primate folliculogenesis in vivo. Research reported in this publication was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Center for Translational Research on Reproduction and Infertility 5P50HD071836, and the NIH Primate Centers Program 8P510D011092. There are no conflicts of interest.//////////////////Androgen potentiates the expression of FSH receptor and supports preantral follicle development in mice. Fujibe Y et al. (2019) Hyperandrogenism is one of the cardinal symptoms in polycystic ovary syndrome and plays a key role in the pathogenesis of polycystic ovary syndrome. However, the precise effects and mechanisms of excess androgen during follicular development are still unclear. Here we investigated the effects of androgen on mouse follicle development in vitro. Androgen did not affect the growth of follicles smaller than 160-180 μm in the presence of follicle-stimulating hormone (FSH). However, in the presence of low FSH, androgen supported the growth of follicles larger than 160-180 μm, a size at which growing follicles acquire FSH-dependency. Androgen did not change the mRNA expression of various growth-promoting factors but did increase mRNA expression of the FSH receptor. We suggest that androgen has a positive impact on follicle development by augmentation of the actions of FSH. Therefore, FSH-responsive but FSH-independent follicles grow in the presence of a certain level of FSH or androgen, and androgen compensates for FSH deficiency in FSH-dependent follicles.////////////////// Effects of testosterone on the expression levels of AMH, VEGF and HIF-1α in mouse granulosa cells. Zhang Y et al. (2016) The present study aimed to investigate the effects of testosterone on mouse granulosa cell morphology, and the expression levels of anti-Müllerian hormone (AMH), vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α (HIF-1α). Mouse granulosa cells were isolated and identified, and their morphology was examined using hematoxylin and eosin, F-actin, and follicle-stimulating hormone receptor staining. The mRNA expression levels of AMH, VEGF and HIF-1α were examined using reverse transcription-quantitative polymerase chain reaction, and their protein secretion levels were investigated using enzyme-linked immunosorbent assays. Testosterone treatment did not affect granulosa cell morphology; however, it significantly increased the mRNA expression levels of AMH and VEGF, and the protein secretion levels of AMH, VEGF and HIF-1α. These results suggested that testosterone was able to regulate the functions of granulosa cells by upregulating the expression levels of AMH, VEGF and HIF-1α.////////////////// The effect of androgens on ovarian follicle maturation: Dihydrotestosterone suppress FSH-stimulated granulosa cell proliferation by upregulating PPARγ-dependent PTEN expression. Chen MJ et al. (2015) Intraovarian hyperandrogenism is one of the determining factors of follicular arrest in women with polycystic ovary syndrome (PCOS). Using androgenized rat models, we investigated the effects of androgens on metabolism, as well as on factors involved in follicular arrest and the reduced number of estrus cycles. The dihydrotestosterone (DHT)-treated rats had fewer estrus cycles, higher numbers of large arrested follicles and an increased in body weight gain compared with the dehydroepiandrostenedione (DHEA)- and placebo-treated rats. In cultured rat granulosa cells, DHT suppressed follicle stimulating hormone (FSH)-induced granulosa cell proliferation and increased the accumulation of cells in the G2/M phase. DHT decreased phosphorylated Akt (p-Akt) and cyclin D1 levels through increasing PTEN. DHT-promoted PTEN expression was regulated by peroxisome proliferator-activated receptor gamma (PPARγ) in granulosa cells. Meanwhile, in the large follicles of the DHT-treated rats, the expressions of PPARγ and PTEN were higher, but the expression of p-Akt and proliferating cell nuclear antigen (PCNA) were lower. Conclusively, DHT and DHEA produced differential effects on metabolism in prepubertal female rats like clinical manifestations of women with PCOS. DHT treatment may affect ovarian follicular maturation by altering granulosa cell proliferation through the regulation of enhancing PPARγ dependent PTEN/p-Akt expression in the granulosa cells.////////////////// Differential effects of estrogen and progesterone on development of primate secondary follicles in a steroid-depleted milieu in vitro. Ting AY et al. (2015) What are the direct effects of progesterone (P4) and estradiol (E2) on the development and function of primate follicles in vitro from the pre-antral to early antral stage? In a steroid-depleted milieu, E2 improved follicle survival, growth, antrum formation and oocyte health, whereas P4 exerted minimal beneficial effects on follicle survival and reduced oocyte health. Effects of P4 and E2 on follicle development have been studied primarily in large antral and pre-ovulatory follicles. Chronic P4 exposure suppresses antral follicle growth, but acute P4 exposure promotes oocyte maturation in pre-ovulatory follicles. Effects of E2 can be stimulatory or inhibitory depending upon species, dose and duration of exposure. Non-human primate model, randomized, control versus treatment. Macaque (n = 6) secondary follicles (n = 24 per animal per treatment group) were cultured for 5 weeks. Adult rhesus macaque secondary follicles were encapsulated in 0.25% alginate and cultured individually in media containing follicle stimulating hormone plus (i) vehicle, (ii) a steroid-synthesis inhibitor, trilostane (TRL, 250 ng/ml), (iii) TRL + low E2 (100 pg/ml) or progestin (P, 10 ng/ml R5020) and (iv) TRL + high E2 (1 ng/ml E2) or P (100 ng/ml R5020). Follicles reaching the antral stage (≥750 µm) were treated with human chorionic gonadotrophin for 34 h. End-points included follicle survival, antrum formation, growth pattern, plus oocyte health and maturation status, as well as media concentrations of P4, E2 and anti-Müllerian hormone (AMH). In a steroid-depleted milieu, low dose, but not high dose, P improved (P < 0.05) follicle survival, but had no effect (P > 0.05) on antrum formation and AMH production. Low-dose P increased (P < 0.05) P4 production in fast-grow follicles, and both doses of P elevated (P < 0.05) E2 production in slow-grow follicles. Additionally, low-dose P increased (P < 0.05) the percentage of no-grow follicles, and high-dose P promoted oocyte degeneration. In contrast, E2, in a steroid-depleted milieu, improved (P < 0.05) follicle survival, growth, antrum formation and oocyte health. E2 had no effect on P4 or E2 production. Follicles exposed to E2 yielded mature oocytes capable of fertilization and early cleavage, at a rate similar to untreated control follicles. This study is limited to in vitro effects of P and E2 during the interval from the secondary to small antral stage of macaque follicles. This study provides novel information on the direct actions of P4 and E2 on primate pre-antral follicle development. Combined with our previous report on the actions of androgens, our findings suggest that androgens appear to be a survival factor but hinder antral follicle differentiation, E2 appears to be a survival and growth factor at the pre-antral and early antral stage, whereas P4 may not be essential during early folliculogenesis in primates. NIH P50 HD071836 (NCTRI), NIH ORWH/NICHD 2K12HD043488 (BIRCWH), ONPRC 8P51OD011092. There are no conflicts of interest.////////////////// Direct actions of androgens on the survival, growth and secretion of steroids and anti-Müllerian hormone by individual macaque follicles during three-dimensional culture. Rodrigues JK et al. (2015) What are the direct effects of androgens on primate follicular development and function at specific stages of folliculogenesis? Androgen addition altered primate follicle survival, growth, steroid and anti-Müllerian hormone (AMH) production, and oocyte quality in vitro, in a dose- and stage-dependent manner. Androgens have local actions in the ovary, particularly in the developing follicles. It is hypothesized that androgen promotes early follicular growth, but becomes detrimental to the antral follicles in primates. In vitro follicle maturation was performed using rhesus macaques. Secondary (125-225 µm) follicles were mechanically isolated from 14 pairs of ovaries, encapsulated into alginate (0.25% w/v), and cultured for 40 days. Individual follicles were cultured in a 5% O2 environment, in alpha minimum essential medium supplemented with recombinant human FSH. Follicles were randomly assigned to experiments of steroid ablation by trilostane (TRL), testosterone (T) replacement and dihydrotestosterone (DHT) replacement. Follicle survival and growth were assessed. Follicles with diameters ≥500 μm at Week 5 were categorized as fast-grow follicles. Pregnenolone (P5), progesterone (P4), estradiol (E2) and AMH concentrations in media were measured. Meiotic maturation and fertilization of oocytes from recombinant human chorionic gonadotrophin-treated follicles were assessed at the end of culture. Compared with controls, TRL exposure reduced (P < 0.05) follicle survival, antrum formation rate and follicle diameters at Week 5. While P5 concentrations increased (P < 0.05) following TRL treatment, P4 levels decreased (P < 0.05) in fast-grow follicles at Week 5. Few healthy oocytes were retrieved from antral follicles developed in the presence of TRL. T replacement with TRL increased (P < 0.05) follicle survival and antrum formation at Week 5, compared with TRL alone, to levels comparable to controls. However, high-dose T with TRL decreased (P < 0.05) diameters of fast-grow follicles. Although P4 concentrations produced by fast-grow follicles were not altered by T in the presence of TRL, there was a dose-dependent increase (P < 0.05) in E2 levels at Week 5. High-dose T with TRL decreased (P < 0.05) AMH production by fast-grow follicles at Week 3. More healthy oocytes were retrieved from antral follicles developed in TRL+T compared with TRL alone. DHT had the similar effects to those of high-dose T, except that DHT replacement decreased (P < 0.05) E2 concentrations produced by fast-grow follicles at Week 5 regardless of TRL treatment. This study reports T and DHT actions on in vitro-developed individual primate (macaque) follicles, which are limited to the interval from the secondary to small antral stage. The above findings provide novel information on the role(s) of androgens in primate follicular development and oocyte maturation. We hypothesize that androgens promote pre-antral follicle development, but inhibit antral follicle growth and function in primates. While androgens can act positively, excess levels of androgens may have negative impacts on primate folliculogenesis. NIH U54 RR024347/RL1HD058294/PL1EB008542 (Oncofertility Consortium), NIH U54 HD071836 (SCCPIR), NIH ORWH/NICHD 2K12HD043488 (BIRCWH), NIH FIC TW/HD-00668, ONPRC 8P51OD011092. There are no conflicts of interest.////////////////// The role of androgen hormones in early follicular development. Gerv?o CG 2014 et al. Background. Although chronic hyperandrogenism, a typical feature of polycystic ovary syndrome, is often associated with disturbed reproductive performance, androgens have been shown to promote ovarian follicle growth in shorter exposures. Here, we review the main effects of androgens on the regulation of early folliculogenesis and the potential of their application in improving follicular in vitro growth. Review. Androgens may affect folliculogenesis directly via androgen receptors (ARs) or indirectly through aromatization to estrogen. ARs are highly expressed in the granulosa and theca cells of early stage follicles and slightly expressed in mature follicles. Short-term androgen exposure augments FSH receptor expression in the granulosa cells of developing follicles and enhances the FSH-induced cAMP formation necessary for the transcription of genes involved in the control of follicular cell proliferation and differentiation. AR activation also increases insulin-like growth factor (IGF-1) and its receptor gene expression in the granulosa and theca cells of growing follicles and in the oocytes of primordial follicles, thus facilitating IGF-1 actions in both follicular recruitment and subsequent development. Conclusion. During the early and intermediate stages of follicular maturation, locally produced androgens facilitate the transition of follicles from the dormant to the growing pool as well as their further development. ///////////////////////// Androgens regulate ovarian follicular development by increasing follicle stimulating hormone receptor and microRNA-125b expression. Sen A 2014 et al. Although androgen excess is considered detrimental to women's health and fertility, global and ovarian granulosa cell-specific androgen-receptor (AR) knockout mouse models have been used to show that androgen actions through ARs are actually necessary for normal ovarian function and female fertility. Here we describe two AR-mediated pathways in granulosa cells that regulate ovarian follicular development and therefore female fertility. First, we show that androgens attenuate follicular atresia through nuclear and extranuclear signaling pathways by enhancing expression of the microRNA (miR) miR-125b, which in turn suppresses proapoptotic protein expression. Second, we demonstrate that, independent of transcription, androgens enhance follicle-stimulating hormone (FSH) receptor expression, which then augments FSH-mediated follicle growth and development. Interestingly, we find that the scaffold molecule paxillin regulates both processes, making it a critical regulator of AR actions in the ovary. Finally, we report that low doses of exogenous androgens enhance gonadotropin-induced ovulation in mice, further demonstrating the critical role that androgens play in follicular development and fertility. These data may explain reported positive effects of androgens on ovulation rates in women with diminished ovarian reserve. Furthermore, this study demonstrates mechanisms that might contribute to the unregulated follicle growth seen in diseases of excess androgens such as polycystic ovary syndrome. ///////////////////////// Reproductive and Metabolic Phenotype of a Mouse Model of PCOS. van Houten EL et al. Polycystic ovary syndrome (PCOS), the most common endocrine disorder in women in their reproductive age, is characterized by both reproductive and metabolic features. Recent studies in human, nonhuman primates, and sheep suggest that hyperandrogenism plays an important role in the development of PCOS. We investigated whether chronic dihydrotestosterone (DHT) exposure in mice reproduces both features of PCOS. Such a model would allow us to study the mechanism of association between the reproductive and metabolic features in transgenic mice. In this study, prepubertal female mice received a 90 d continuous release pellet containing the nonaromatizable androgen DHT or vehicle. At the end of the treatment period, DHT-treated mice were in continuous anestrous, their ovaries contained an increased number of atretic follicles, with the majority of atretic antral follicles having a cyst-like structure. Chronic DHT-exposed mice had significantly higher body weights (21%) than vehicle-treated mice. In addition, fat depots of DHT-treated mice displayed an increased number of enlarged adipocytes (P < 0.003). Leptin levels were elevated (P < 0.013), adiponectin levels were diminished (P < 0.001), and DHT-treated mice were glucose intolerant (P < 0.001). In conclusion, a mouse model of PCOS has been developed showing reproductive and metabolic characteristics associated with PCOS in women.//////////Stimulation of aromatase activity by follicle stimulating hormone in rat granulosa cells in vivo and in vitro. Erickson GF 1979 et al. The FSH actionis dependent on androgens. ///////////////////////// The number of primary follicles was significantly increased over time in testosterone-treated rhesus monkeys. In situ hybridization showed that androgen treatment resulted in an increase to 3-fold in insulin-like growth factor I (IGF-I) and to 5-fold in IGF-I receptor mRNA in primordial follicle oocytes. DHT effects were comparable to those of testosterone, showing that these are androgen receptor-mediated phenomena (Vendola et al., 1998 and 1999). In addition, androgen treatment significantly increased granulosa cell FSH-receptor mRNA abundance (Weil et al., 1999). Granulosa cell aromatase induction/activation by FSH is an androgen receptor-regulated process in vitro (Hillier et al., 1981). Androgens augment FSH-induced progesterone secretion by cultured rat granulosa cells (Armstrong and Dorrington, 1976). The antiatretogenic effect of estrogen was blocked by treatment with testosterone, which increased ovarian apoptotic DNA fragmentation in DES-treated rats. In situ examination showed that androgen treatment increased apoptosis in granulosa cells in a subpopulation of early antral and preantral rat follicles (Billig et al., 1993). Dihydroxytestosterone reduced the ovulation rate by decreasing the number of granulosa cells/follicle and by altering the oestrogen synthetic abilities of the cells. All follicles, regardless of size, were sensitive to androgen treatment (Conway et al, 1990). Furthermore, androgens exert a direct stimulatory role on the growth and development of mouse antral follicles, in vitro (Murray et al., 1998). Effect of androgens on the development of mouse follicles growing in vitro. Murray AA 1998 et al. The effects of androgens on ovarian follicular development have been investigated using a whole follicle culture system. Follicles obtained from mouse ovaries and cultured in the presence of anti-androgen serum grew more slowly than control follicles. This effect was reversed by the addition of androstenedione to the medium. A similar effect was obtained when receptor-mediated effects of androgens were blocked using an androgen receptor antagonist. When follicles were grown in concentrations of FSH that are marginal for follicle development, they developed faster in the presence of a non-aromatizable androgen, dihydroxytestosterone. The results indicate that androgens exert a direct, stimulatory role on the growth and development of mouse antral follicles, in vitro. ///////////////////////// Lutz LB,et al 2001 reported that androgens are the primary steroids produced by Xenopus laevis ovaries and may signal through the classical androgen receptor to promote oocyte maturation. Steroid-induced maturation of Xenopus oocytes has long served as a model for studying meiosis. Progesterone has been considered the relevant steroid controlling maturation, perhaps through interactions with classical progesterone receptors. In this study, the authors provide evidence that androgens, rather than progesterone, are the physiologic mediators of Xenopus oocyte maturation. Androgens were equal or more potent activators of maturation in vitro relative to progesterone and were significantly more abundant in the serum and ovaries of beta-human chorionic growth hormone-stimulated frogs. Androgen action appeared to be mediated by classical androgen receptors (ARs) expressed in oocytes, as androgen-induced maturation and signaling was specifically attenuated by AR antagonists. Interestingly, we found that progesterone was rapidly converted to the androgen androstenedione in isolated oocytes by the enzyme CYP17, suggesting that androgens may be promoting maturation even under conditions typical for "progesterone-mediated" maturation assays. Androgens are thought to play an important role in ovarian development as well as pathology, and signaling through the AR may prove to be a major regulatory mechanism mediating these processes. | ||||
| Expression regulated by | FSH, Steroids | ||||
| Comment | Direct actions of androgens on the survival, growth and secretion of steroids and anti-Müllerian hormone by individual macaque follicles during three-dimensional culture. Rodrigues JK et al. (2015) What are the direct effects of androgens on primate follicular development and function at specific stages of folliculogenesis? Androgen addition altered primate follicle survival, growth, steroid and anti-Müllerian hormone (AMH) production, and oocyte quality in vitro, in a dose- and stage-dependent manner. Androgens have local actions in the ovary, particularly in the developing follicles. It is hypothesized that androgen promotes early follicular growth, but becomes detrimental to the antral follicles in primates. In vitro follicle maturation was performed using rhesus macaques. Secondary (125-225 µm) follicles were mechanically isolated from 14 pairs of ovaries, encapsulated into alginate (0.25% w/v), and cultured for 40 days. Individual follicles were cultured in a 5% O2 environment, in alpha minimum essential medium supplemented with recombinant human FSH. Follicles were randomly assigned to experiments of steroid ablation by trilostane (TRL), testosterone (T) replacement and dihydrotestosterone (DHT) replacement. Follicle survival and growth were assessed. Follicles with diameters ≥500 μm at Week 5 were categorized as fast-grow follicles. Pregnenolone (P5), progesterone (P4), estradiol (E2) and AMH concentrations in media were measured. Meiotic maturation and fertilization of oocytes from recombinant human chorionic gonadotrophin-treated follicles were assessed at the end of culture. Compared with controls, TRL exposure reduced (P < 0.05) follicle survival, antrum formation rate and follicle diameters at Week 5. While P5 concentrations increased (P < 0.05) following TRL treatment, P4 levels decreased (P < 0.05) in fast-grow follicles at Week 5. Few healthy oocytes were retrieved from antral follicles developed in the presence of TRL. T replacement with TRL increased (P < 0.05) follicle survival and antrum formation at Week 5, compared with TRL alone, to levels comparable to controls. However, high-dose T with TRL decreased (P < 0.05) diameters of fast-grow follicles. Although P4 concentrations produced by fast-grow follicles were not altered by T in the presence of TRL, there was a dose-dependent increase (P < 0.05) in E2 levels at Week 5. High-dose T with TRL decreased (P < 0.05) AMH production by fast-grow follicles at Week 3. More healthy oocytes were retrieved from antral follicles developed in TRL+T compared with TRL alone. DHT had the similar effects to those of high-dose T, except that DHT replacement decreased (P < 0.05) E2 concentrations produced by fast-grow follicles at Week 5 regardless of TRL treatment. This study reports T and DHT actions on in vitro-developed individual primate (macaque) follicles, which are limited to the interval from the secondary to small antral stage. The above findings provide novel information on the role(s) of androgens in primate follicular development and oocyte maturation. We hypothesize that androgens promote pre-antral follicle development, but inhibit antral follicle growth and function in primates. While androgens can act positively, excess levels of androgens may have negative impacts on primate folliculogenesis. NIH U54 RR024347/RL1HD058294/PL1EB008542 (Oncofertility Consortium), NIH U54 HD071836 (SCCPIR), NIH ORWH/NICHD 2K12HD043488 (BIRCWH), NIH FIC TW/HD-00668, ONPRC 8P51OD011092. There are no conflicts of interest.////////////////// FSH treatment increased granulosa androgen receptor mRNA levels only in primary follicles (Weil et al., 1999). Identification of androgen receptor phosphorylation in the primate ovary in vivo. McEwan IJ et al. The androgen receptor (AR) is a member of the nuclear receptor superfamily and is important for both male and female reproductive health. The receptor is a target for a number of post-translational modifications including phosphorylation, which has been intensively studied in vitro. However, little is known about the phosphorylation status of the receptor in target tissues in vivo. The common marmoset is a useful model for studying human reproductive functions and comparison of the AR primary sequence from this primate shows high conservation of serines known to be phosphorylated in the human receptor and corresponding flanking amino acids. We have used a panel of phosphospecific antibodies to study AR phosphorylation in the marmoset ovary throughout the follicular phase and after treatment with GnRH antagonist or testosterone propionate. In normal follicular phase ovaries total AR (both phosphorylated and non-phosphorylated forms) immunopositive staining was observed in several cell types including granulosa cells of developing follicles, theca cells and endothelial cells lining blood vessels. Receptor phosphorylation at serines 81, 308 and 650 was detected primarily in the granulosa cells of developing follicles, surface epithelium and vessel endothelial cells. Testosterone treatment lead to a modest increase, in AR staining in all stages of follicle studied while GnRH antagonist had no effect. Neither treatment significantly altered the pattern of phosphorylation compared to the control group. These results demonstrate that phosphorylation of the AR occurs, at a subset of serine residues, in a reproductive target tissue in vivo, which appears refractory to hormonal manipulations. | ||||
| Ovarian localization | Oocyte, Granulosa, Theca, Luteal cells, Stromal cells | ||||
| Comment | Androgen receptor mRNA is found in granulosa cells of healthy preantral follicles in the primate ovary. Theca interna and stromal cells also expressed androgen receptor mRNA, but to a lesser degree than granulosa cells (Weil et al., 1999). Luteinizing granulosa cells of the periovulatory follicle and luteal cells from the early and midluteal phase stained intensely for androgen receptor. Regressing corpora lutea of the late luteal phase also stained for androgen receptor; however, fully regressed corpora lutea in the early follicular phase of the next cycle did not exhibit receptor staining (Hild-Petito et al., 1991).Szoltys M, et al reported that during the oocyte growth AR translocates from the oocyte cytoplasm to GV, and then to the nucleolus, which seems to become the main target for this receptor. A possible role of AR in the GV nucleolus is obscure. However, nucleolus contains rRNA genes and is the site of an active transcription, so the role of AR as a ligand-activated, transcriptional factor cannot be excluded. | ||||
| Follicle stages | Primary, Secondary, Preovulatory, Corpus luteum | ||||
| Comment | Primordial and primary follicles did not express androgen receptor. In granulosa and thecal cells of secondary follicles there was weak nuclear staining for androgen receptor. Granulosa cells of dominant follicles showed moderate nuclear staining for androgen receptor, which was stronger than that in thecal cells. In the luteal phase, the staining intensity for androgen receptor was strongest in the early luteal phase just after ovulation and declined gradually thereafter (Horie et al., 1992). Tetsuka and Hillier (1996) show that a down-regulation of androgen receptor mRNA expression takes place in granulosa cells of preovulatory follicles. FSH was not directly responsible for this and androgen down-regulates AR mRNA expression in immature granulosa cells, and this effect is reversed by FSH. They conclude that androgen and FSH jointly regulate AR mRNA expression in rat granulosa cells. | ||||
| Phenotypes |
PCO (polycystic ovarian syndrome) POF (premature ovarian failure) |
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| Mutations |
19 mutations
Species: mouse
Species: mouse
Species: mouse
Species: mouse
Species: mouse
Species: human
Species: human
Species: mouse
Species: human
Species: human
Species: mouse
Species: human
Species: mouse
Species: mouse
Species: human
Species: human
Species: human
Species: human
Species: human
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| Genomic Region | show genomic region | ||||
| Phenotypes and GWAS | show phenotypes and GWAS | ||||
| Links |
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| created: | Aug. 20, 1999, midnight | by: |
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| last update: | Dec. 9, 2020, 11:04 p.m. | by: | hsueh email: |
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