No abstract

We have shown that inhibition of mTOR in granulosa cells and ovarian follicles results in compromised granulosa proliferation and reduced follicle growth. Further analysis here using spontaneously immortalized rat granulosa cells has revealed that mTOR pathway activity is enhanced during M-phase of the cell cycle. mTOR specific phosphorylation of p70S6 kinase and 4E-BP, and expression of Raptor are all enhanced during M-phase. The predominant effect of mTOR inhibition by the specific inhibitor Rapamycin (RAP) was a dose-responsive arrest in the G1 cell cycle stage. The fraction of granulosa cells that continued to divide in the presence of RAP exhibited a dose-dependent increase in aberrant mitotic figures known as anaphase bridges. Strikingly, estradiol consistently decreased the incidence of aberrant mitotic figures. In mice treated with RAP, the mitotic index was reduced compared to controls, and a similar increase in aberrant mitotic events was noted. RAP injected during a superovulation regime resulted in a dose-dependent reduction in the numbers of eggs ovulated. Implications for the real-time regulation of follicle growth and dominance, including the consequences of increased numbers of aneuploid granulosa cells, are discussed.

The conserved target of rapamycin (TOR) proteins are involved in sensing nutrient levels and/or stress and the resultant control of cell growth, size, and survival. The authors assess mammalian TOR (mTOR) kinase expression in the mouse ovary and also the expression of its cofactors, Raptor, Rictor, and LST8. In granulosa cells, mTOR demonstrates high cytoplasmic/perinuclear expression. The kinase-active serine 2448-phosphorylated form of mTOR (P-mTOR) is present at very high levels during the M-phase. P-mTOR was enriched on or near the mitotic spindle and also near the contractile ring during cytokinesis. Rapamycin inhibition of mTOR resulted in both reduced granulosa cell proliferation and reduced follicle growth in vitro, each in a dose-dependent fashion. Follicles cultured in rapamycin did not undergo atresia. mTOR inhibition results in a reduction in granulosa cell proliferation, supporting a model in which stress and nutritional cues may directly influence ovarian follicle growth.

Polycystic ovary syndrome (PCOS) is complex heterogeneous disorder that has several aspects in terms of pathology such as metabolic, endocrine, reproductive, and psychological. However, the etiology of PCOS remains poorly understood. Several studies suggest that insulin resistance and hyperandrogenism play a central role in the progression of PCOS pathophysiology. Therefore, common treatment strategies of PCOS are based on lifestyle modification, which include exercise, diet, and nutrient supplementation therapy. Recent studies have recommended some nutrients such as vitamins, minerals, and vitamin-like nutrients for the therapy of PCOS because each has at least one functional property in PCOS-induced pathways. Therefore, it is claimed that the cause of PCOS could be vitamin or mineral deficiency. This review aims to provide a critical literature survey on nutritional supplementation for the treatment of PCOS-associated endocrine and metabolic dysfunctions and discuss the role of nutrients in the management of PCOS in view of the clinical trials and experimental studies.

Polycystic ovary syndrome (PCOS) is a common and complex endocrine disorder affecting 5-10% of women in reproductive age that is characterized by hyperandrogenism, oligo- or anovulation and infertility. However 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. Therefore, we hypothesized that mTORC1 and/or 2 may have important role in proliferation of theca and granulosa cells in PCOS. In the present study, we sought to determine the mTOR signaling pathway in PCOS mouse ovary. We designed 3 groups: Control (C, no treatment), PCOS (P, The injection of DHEA (6 mg/100 g BW in 0.1 ml of sesame oil) (s.c) for 20 consecutive days), Vehicle (V, daily (s.c) sesame oil alone injection). Our results showed that mTORC1 and mTORC2-mediated signaling may play a role in PCOS mouse ovary. These findings provide evidence that mTORC1 and mTORC2 may have responsibility in 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.

Aim Endometriosis is an estrogen‐dependent chronic inflammatory condition which causes pain, infertility, and predisposition for ovarian cancer. Endometriosis generates a unique microenvironment for survivability of endometriotic lesions which includes cell proliferation, differentiation, migration, and apoptosis. For these cellular activities, cascading activations of intracellular kinases are needed. Many kinase signaling pathways, IKKβ/NK‐κB pathway, PI3K/AKT/mTOR, and the mitogen‐activated protein kinase (MAPK) pathways (ERK1/2, p38, and JNK), are activated in endometriosis. In this review, we focus on the role of MAPK pathways in endometriosis. Methods To identify the role of MAP Kinase signaling pathway in endometriosis we searched the Pubmed database using the search terms in various combinations “endometriosis,” “endometrium,” “ovary,” “MAPK pathway,” “ERK pathway,” “p38 pathway,” “JNK pathway,” “estrogen,” and “progesterone.” Results According to the current literature, MAPK signaling pathway has various roles in generating microenvironment and survival of endometriosis. Abnormal MAPK activation in migration, implantation, growth, invasion into the pelvic structures, proliferation, and apoptosis leads to the form of endometriosis and to worsen the condition in patients with endometriosis. Conclusion To further investigations on the effective and long‐term endometriosis treatment, MAPK signaling pathways may be targeted. Molecular mechanism of MAPK signaling pathway in endometriosis should be more deeply understood and clinical trials should be more commonly performed for possible new endometriosis treatments to improve fertility and rescue endometriosis irreversibly.

No abstract

No abstract