sirolimus and Polycystic-Ovary-Syndrome

The mammalian target of rapamycin, mTOR, is a serine-threonine protein kinase downstream of the phosphatidylinositol 3-kinase (PI3K)-AKT axis. The pathway can regulate cell growth, proliferation, and survival by activating ribosomal kinases. Recent studies have implicated the mTOR signaling pathway in ovarian neoplasms, polycystic ovary syndrome (PCOS) and premature ovarian failure (POF). Preclinical investigations have demonstrated that the PI3K/AKT/mTOR pathway is frequently activated in the control of various ovarian functions. mTOR allows cancer cells to escape the normal biochemical system and regulates the balance between apoptosis and survival. Some recent studies have suggested that involvement of the mTOR signaling system is an important pathophysiological basis of PCOS. Overexpression of the mTOR pathway can impair the interaction of cumulus cells, lead to insulin resistance, and affect the growth of follicles directly. The roles of mTOR signaling in follicular development have been extensively studied in recent years; abnormalities in this process lead to a series of pathologies such as POF and infertility. To improve understanding of the role of the mTOR signaling pathway in the pathogenesis and development of ovarian diseases, here we review the roles of mTOR signaling in such diseases and discuss the corresponding therapeutic strategies that target this pathway. Clin. Anat. 31:891-898, 2018. © 2018 Wiley Periodicals, Inc.

Topics: Female; Humans; Immunosuppressive Agents; Ovarian Follicle; Ovarian Neoplasms; Polycystic Ovary Syndrome; Primary Ovarian Insufficiency; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

The purpose of this study was to explore the potential molecular mechanisms of excess homocysteine in relation to autophagic activity in the ovarian tissue of polycystic ovarian syndrome (PCOS) with hyperandrogenism.A PCOS model was constructed using ICR mice. ELISA was used to detect the Hcy levels in the serum and ovarian tissues of PCOS model. The expression level of key enzymes (Methionine synthase and Betaine-homocysteine methyltransferase, MTR and BHMT) in homocysteine metabolism and autophagy-related proteins were detected in ovarian tissues and mouse granulosa cells (mGCs) that were treated with homocysteine, androgen, autophagy inhibitors or BHMT-expressing plasmid by western blot and immunohistochemistry. Electron microscope experiments were used to evaluate autophagosomes in Hcy-treated mGCs. The prenatally androgenized (PNA) PCOS mouse model showed hyperhomocysteinemia and hyperandrogenism. Homocysteine levels displayed a significant increase, while its metabolic enzymes levels were significantly decreased in ovarian tissues of PCOS mice and dihydrotestosterone (DHT)-stimulated mGCs. The LC3II and Beclin1 expression levels were increased and the P62 and p-mTOR levels were decreased in vivo in ovarian tissue from the PCOS mice. The in vitro data were similarly with the in vivo by stimulation of mGCs with DHT or homocysteine. These effects could be diminished by the autophagy inhibitor (MHY1485), androgen receptor antagonists (ARN509) or BHMT-expressing plasmid. Androgen increases homocysteine concentration by downregulating the key enzymes in homocysteine metabolism. And then Hcy promotes GCs autophagy via the mTOR signal pathway.

Topics: Androgens; Animals; Autophagy; Female; Granulosa Cells; Homocysteine; Humans; Hyperandrogenism; Male; Mammals; Mice; Mice, Inbred ICR; Polycystic Ovary Syndrome; Sirolimus; TOR Serine-Threonine Kinases

Polycystic ovary syndrome (PCOS) is a multifactorial endocrinopathy that affects reproduction and metabolism. Mammalian target of rapamycin (mTOR) has been shown to participate in female reproduction under physiological and pathological conditions. This study aimed to investigate the role of mTOR complex 1 (mTORC1) signaling in dehydroepiandrosterone (DHEA)-induced PCOS mice.. Female C57BL/6J mice were randomly assigned into three groups: control group, DHEA group, and DHEA + rapamycin group. All DHEA-treated mice were administered 6 mg/100 g DHEA for 21 consecutive days, and the DHEA + rapamycin group was intraperitoneally injected with 4 mg/kg rapamycin every other day for the last 14 days of the DHEA treatment. There was no obvious change in the expression of mTORC1 signaling in the ovaries of the control and DHEA groups. Rapamycin did not protect against DHEA-induced acyclicity and PCO morphology, but impeded follicle development and elevated serum testosterone levels in DHEA-induced mice, which was related with suppressed Hsd3b1, Cyp17a1, and Cyp19a1 expression. Moreover, rapamycin also exacerbated insulin resistance but relieved lipid metabolic disturbance in the short term.. Rapamycin exacerbated reproductive imbalance in DHEA-induced PCOS mice, which characterized by elevated testosterone levels and suppressed steroid synthesis. This underscores the need for new mTORC1-specific and tissue-specific mTOR-related drugs for reproductive disorders.

Topics: Animals; Dehydroepiandrosterone; Disease Models, Animal; Female; Humans; Mice; Polycystic Ovary Syndrome; Reproduction; Sirolimus; Testosterone

Immunosuppression medications contribute to posttransplant diabetes mellitus in patients and can cause insulin resistance in male rats. Tacrolimus (TAC)-sirolimus (SIR) immunosuppression is also associated with appearance of ovarian cysts in transplant patients. Because insulin resistance is observed in patients with polycystic ovary syndrome, we hypothesized that TAC or SIR may induce reproductive abnormalities.. We monitored estrus cycles of adult female rats treated daily with TAC, SIR, and combination of TAC-SIR, or diluent (control) for 4 weeks. Animals were then challenged with oral glucose to determine their glucose and insulin responses, killed, and their blood and tissues, including ovaries and uteri harvested.. TAC and TAC-SIR treatments increased mean random glucose concentrations (P<0.05). TAC, SIR, and TAC-SIR treatments also increased the glucose response to oral glucose challenge (P<0.05). The insulin response to glucose was significantly higher in rats treated with SIR compared with TAC (P<0.05). TAC, SIR and TAC-SIR treatments reduced number of estrus cycles (P<0.05). The ovaries were smaller after SIR and TAC-SIR treatment compared with controls. The TAC and TAC-SIR treatment groups had fewer preovulatory follicles. Corpora lutea were present in all groups. Ovarian aromatase expression was reduced in the SIR and TAC-SIR treatment groups. A significant (P<0.05) reduction in uterine size was observed in all treatment groups when compared with controls.. In a model of immunosuppressant-induced hyperglycemia, both TAC and SIR induced reproductive abnormalities in adult female rats, likely through different mechanisms.

Topics: Animals; Aromatase; Blood Glucose; Estrus; Female; Gene Expression Regulation, Enzymologic; Glucose; Hyperglycemia; Immunosuppressive Agents; Insulin Resistance; Ovary; Phenotype; Polycystic Ovary Syndrome; Rats; Rats, Sprague-Dawley; Sirolimus; Tacrolimus; Uterus