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

Sen, Aritro; Hammes, Stephen R.

doi:10.1210/me.2010-0006

Cited by 270 publications

(138 citation statements)

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“…Increased body weight is accepted as a major risk factor for MS. Increased body mass and androgen levels were also known to be related to inflammatory response, and proinflammatory cytokine production like TNF-α also contributes to development of insulin resistance and metabolic syndrome in PCOS [18][19][20][21][22][23][24][25]. In accordance to literature, more than half of the Turkish PCOS adolescents were overweight in the present study.…”

Section: Discussionsupporting

confidence: 87%

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The incidence of metabolic syndrome in adolescents with different phenotypes of PCOS

et al. 2017

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Objectives: To evaluate the incidence of metabolic syndrome in Turkish adolescents with different phenotypes of polycystic ovary syndrome (PCOS). Material and methods:This cross-sectional study was performed on the Youth Center clinic of a tertiary referral hospital in Turkey. Adolescents with PCOS (n = 144) were classified into four phenotype groups according to the presence of oligo/anovulation (O), hyperandrogenism (H), and polycystic ovarian morphology (P) as follows: Phenotype A (O + H + P), Phenotype B (H + O), Phenotype C (H + P), Phenotype D (O + P). The adolescents gave early follicular phase blood samples for endocrine and metabolic tests. The incidence and the presence of parameters of metabolic syndrome were assessed among the four groups. Results:In total, 54.9% of the adolescents with PCOS were overweight and 25.7% had metabolic syndrome. The incidence of metabolic syndrome in Phenotypes A-D were as follows: 39.5%, 20.5%, 26.5%, and 15.2%, respectively. Although body mass index was higher in the Phenotype A group, insulin resistance was similar in all of the phenotype groups. The most common dyslipidemia was low HDL-C levels and this was present in more than half of the adolescents with PCOS. Both body mass index and total testosterone levels were significantly higher in adolescents with metabolic syndrome in comparison to those without metabolic syndrome. Conclusions:Although low HDL-C levels and insulin resistance are common PCOS findings in adolescents, the metabolic profile seems to be worse in Phenotype A than the other phenotypes. Therefore, screening programs should evaluate patients based on the known risk factors and phenotypes for adolescents with PCOS.

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Section: Discussionsupporting

confidence: 87%

“…Suggesting the role of insulin on ovarian function, patients having severe insulin resistance due to presence of insulin receptor mutations are accompanied by PCOS [18]. In these cases, extreme hyperinsulinemia might stimulate the insulin like growth factor-1 (IGF-1) that results increased androgen production in ovarian thecal cells.…”

Section: Discussionmentioning

confidence: 99%

The incidence of metabolic syndrome in adolescents with different phenotypes of PCOS

et al. 2017

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“…It is known that androgens have a stimulatory effect on follicular development in rodents and large farm animals, including ewes (Smith et al 2009. In fact, in the absence of functional ARs in granulosa cells, follicle progression from preantral to antral stage is inhibited and preantral follicles become atretic (Sen & Hammes 2010. Therefore, the decreased AR induction in response to oFSH specifically observed in antral follicles of DES-and BPA-exposed lambs could explain the lower follicular development found in these animals.…”

Section: Pnd30mentioning

confidence: 99%

Neonatal exposure to xenoestrogens impairs the ovarian response to gonadotropin treatment in lambs

Rivera¹,

Varayoud²,

Rodríguez³

et al. 2015

Reproduction

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Bisphenol A (BPA) and diethylstilbestrol (DES) are xenoestrogens, which have been associated with altered effects on reproduction. We hypothesized that neonatal xenoestrogen exposure affects the ovarian functionality in lambs. Thus, we evaluated the ovarian response to exogenous ovine FSH (oFSH) administered from postnatal day 30 (PND30) to PND32 in female lambs previously exposed to low doses of DES or BPA (BPA50: 50 mg/kg per day, BPA0.5: 0.5 mg/kg per day) from PND1 to PND14. We determined: i) follicular growth, ii) circulating levels of 17b-estradiol (E 2 ), iii) steroid receptors (estrogen receptor alpha, estrogen receptor beta, and androgen receptor (AR)) and atresia, and iv) mRNA expression levels of the ovarian bone morphogenetic protein (BMPs) system (BMP6, BMP15, BMPR1B, and GDF9) and FSH receptor (FSHR). Lambs neonatally exposed to DES or BPA showed an impaired ovarian response to oFSH with a lower number of follicles R2 mm in diameter together with a lower number of atretic follicles and no increase in E 2 serum levels in response to oFSH treatment. In addition, AR induction by oFSH was disrupted in granulosa and theca cells of lambs exposed to DES or BPA. An increase in GDF9 mRNA expression levels was observed in oFSH-primed lambs previously treated with DES or BPA50. In contrast, a decrease in BMPR1B was observed in BPA0.5-postnatally exposed lambs. The modifications in AR, GDF9, and BMPR1B may be associated with the altered ovarian function due to neonatal xenoestrogen exposure in response to an exogenous gonadotropin stimulus. These alterations may be the pathophysiological basis of subfertility syndrome in adulthood.Reproduction (2015) 149 645-655

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“…The development of ARKO mouse models (Yeh et al 2002, Hu et al 2004, Shiina et al 2006, Walters et al 2007, 2012a, Sen & Hammes 2010, Wu et al 2014) and PCOS models in rodents (Walters et al 2012b), sheep and primates (Abbott et al 2005) induced by excess androgen exposure provides unique mechanistic insights into the role for AR-mediated androgen actions in ovarian physiology function and the origins of PCOS. This review aims to provide a comprehensive integration of clinical observations with research findings from genetic and pharmacological studies based primarily on whole-animal models, to elucidate the specific roles of AR-mediated androgen actions in regulating normal and pathological ovarian function, and thereby female fertility.…”

Section: Introductionmentioning

confidence: 99%

Role of androgens in normal and pathological ovarian function

Walters

2015

Reproduction

132

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Androgens mediate their actions via the androgen receptor (AR), a member of the nuclear receptor superfamily. AR-mediated androgen action is essential in male reproductive development and function; however, only in the last decade has the suspected but unproven role for AR-mediated actions in female reproduction been firmly established. Deciphering the specific roles and precise pathways by which AR-mediated actions regulate ovarian function has been hindered by confusion on how to interpret results from pharmacological studies using androgens that can be converted into oestrogens, which exert actions via the oestrogen receptors. The generation and analysis of global and cell-specific female Ar knockout mouse models have deduced a role for AR-mediated actions in regulating ovarian function, maintaining female fertility, and have begun to unravel the mechanisms by which AR-mediated androgen actions regulate follicle health, development and ovulation. Furthermore, observational findings from human studies and animal models provide substantial evidence to support a role for AR-mediated effects not only in normal ovarian function but also in the development of the frequent ovarian pathological disorder, polycystic ovarian syndrome (PCOS). This review focuses on combining the findings from observational studies in humans, pharmacological studies and animal models to reveal the roles of AR-mediated actions in normal and pathological ovarian function. Together these findings will enable us to begin understanding the important roles of AR actions in the regulation of female fertility and ovarian ageing, as well as providing insights into the role of AR actions in the androgen-associated reproductive disorder PCOS.Reproduction (2015) 149 R193-R218

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

Cited by 270 publications

References 50 publications

The incidence of metabolic syndrome in adolescents with different phenotypes of PCOS

The incidence of metabolic syndrome in adolescents with different phenotypes of PCOS

Neonatal exposure to xenoestrogens impairs the ovarian response to gonadotropin treatment in lambs

Role of androgens in normal and pathological ovarian function

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