The effect of androgens on ovarian follicle maturation: Dihydrotestosterone suppress FSH-stimulated granulosa cell proliferation by upregulating PPARγ-dependent PTEN expression.

Mei-Jou Chen,Wei-Shiung Yang,Yu-Shih Yang,Hong-Nerng Ho,Chia-Hung Chou,Shee-Uan Chen

doi:10.1038/srep18319

Mei-Jou Chen, Wei-Shiung Yang + Show 4 more

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https://doi.org/10.1038/srep18319

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Abstract

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.

Highlights

Intraovarian hyperandrogenism is one of the determining factors of follicular arrest in women with polycystic ovary syndrome (PCOS)
This study shows that the chronic exposure of prepubertal female rats to DHT, but not DHEA, induced significant increases in body weight and adiposity
Such findings confirm the results of previous studies suggesting that differential androgen levels in women with PCOS may lead to opposing phenotypes, including visceral obesity, insulin resistance and the risk of metabolic disorders[6,7,9,10,11]

Summary

Introduction

Intraovarian hyperandrogenism is one of the determining factors of follicular arrest in women with polycystic ovary syndrome (PCOS). 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 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. DHT-treated rodent models exhibit many reproductive and metabolic features similar to those of obese women with PCOS, including irregular estrus cycles, increased numbers of large atretic follicles, increased body weight and visceral fat, dyslipidemia, and aggravated insulin resistance[13,14,15]. Little is known about the mechanisms underlying the reduced numbers of estrus cycles and follicle arrest observed in androgenized rats

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