MTOR (The Mammalian Target of Rapamycin) Mechanism in Polycystic Over Syndrome (PCOS)

Polycystic ovary syndrome (PCOS) is a common and complex endocrine disorder affecting 5-10% of women in reproductive age. It is characterized by hyperandrogenism, oligo- or anovulation and infertility. But the pathophysiology of PCOS still remains unknown.The mammalian target of rapamycin (mTOR) is a central component that regulates various processes including cell growth, proliferation, metabolism, and angiogenesis. mTOR signaling cascade has recently been examined in ovarian follicles where it regulates granulosa cell proliferation and differentiation. mTOR functions as two complexes, mTOR complex 1 and 2 (mTORC1 (mTOR, P-mTOR (Serine-2448), Raptor, GBetaL) and mTORC 2 (mTOR, P-mTOR (Serine-2481), Rictor, GBetaL)). mTORC1 phosphorylates p70S6 kinase (S6K1) and mTORC2 phosphorylates PKCalpha. We hypothesized that mTORC 1 and/or 2 may have role in proliferation of theca and granulosa cells in PCOS mouse model. In the present study, we sought to determine the mTOR signaling pathway in PCOS mouse ovary.25 days old 30 BalbC female mice were used and designed 3 groups (n=10): Control (no treatment), PCOS (The injection of DHEA (6 mg/100g BW in 0.1 ml of sesame oil) (s.c) for 20 consecutive days), Vehicle (daily (s.c) sesame oil alone enjection). To show the morphological difference between PCOS and control mouse ovary, sections stained with haematoxylin and eosin for histological analysis of cyst formation. Mouse PCOS model were confirmed by ELISA technique. Serum samples from each animals before and after treatment were collected. Then we evaluated estradiol and progesterone levels. mTOR and P-mTOR (serine 2448) antibodies were used for immunohistochemistry showing proliferating ovarian follicular cells. We used mTORC1, mTORC2 and P70S6K, phospho- P70S6K and PKCalpha, phosphor- PKCalpha antibodies for western blott technique presenting mTOR signal protein complexes. PCNA were used as a proliferation marker. RT-PCR technique also used for present mTORC1 and mTORC2 mRNA levels. Statistical analyses were carried out using the Sigma Stat 3.0. Student t-test was used for comparisons between value of groups; P <0.05 was considered significant.Here, we provide evidence for the first time mTORC1 and mTORC2 in PCOS mouse ovary. Our results showed that upregulating mTORC1 and mTORC2-mediated signaling may plays a crucial role in PCOS mouse ovary. All these findings provide an evidence that mTORC1 and mTORC2 affects increased ovarian follicular cell proliferation and growth in PCOS.Consequently, these results suggest that the mTOR signaling pathways (mTORC1 and mTORC 2) may create new clinical strategies to optimize developmental competence of PCOS should target correction of the entire follicle growth, oocyte development process and anovulatory infertility in PCOS.