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1) 多嚢胞性卵巣症候群病態解明に向けた総合戦略(シンポジウム3:生殖「多嚢胞性卵巣症候群(PCOS)の病因・病態と管理」,第65回日本産科婦人科学会・学術講演会)

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Polycystic ovary syndrome (PCOS) is the predominant cause of anovulatory infertility, which is characterized by elevated plasma LH, hyperandrogenism and peripheral insulin resistance. The evidence of the strategy for PCOS has been accumulated as long as infertility treatments are concerned. However, most of these treatments belong to temporary and symptomatic treatments and outcomes of infertility treatments for PCOS are not very satisfying. On the other hand, the long-term health risk of PCOS, such as endometrial cancer and insulin resistance, has been becoming a non-negligible problem. Therefore, the pathogenesis of PCOS has yet to be elucidated in order to develop a more effective and pathogenesis-oriented approach. In this situation, we have been focusing on the abnormality of the gonadotropin secretion and the disturbance of folliculogenesis in PCOS. The molecular mechanisms of the disturbance folliculogenesis in PCOS is not fully revealed, although several authors have reported the cause of the polycystic formation in PCOS. The biological functions of growth factors on granulosa cell proliferation are mainly mediated by the PI3K-Akt pathway and MEK-ERK 1/2 pathway. PTEN antagonizes the activity of PI3K by dephosphorylating PIP3 to PIP2. Therefore, PTEN indirectly inhibits the phosphorylation of Akt. We found that the expression of PTEN was induced by hCG and insulin and that pretreatment with insulin or hCG attenuated the phosphorylation of Akt and proliferation of luteinized granulosa cells obtained from IVF treatments. We also demonstrated that PI3K inhibitor, not MEK inhibitor, inhibited the luteinized granulosa cell proliferation. In order to investigate further mechanisms of granulosa cell proliferation, we established the immortalized human non-luteinized granulosa cell line (HGrCl) by lentivirus-mediated transfer of oncogenic-genes. We found that the stimulation with insulin and androgens induced the expression of NPPC, which codes C-type natriuretic peptide (CNP). Recent studies demonstrated that CNP has the ability to stimulate cGMP production in cumulus cells to inhibit meiotic resumption of oocytes and promote early antral follicle growth. These results suggest that the PCOS-related molecules including LH, insulin and androgens are involved in the disturbance of folliculogenesis in PCOS via influence on the molecular mechanisms of the granulosa cells. Another aspect of the disturbance of folliculogenesis has been considered to be related with the alteration of the microenvironment of follicle growth. Insulin resistance is defined as a decrease in insulin sensitivity accompanying compensatory hyperinsulinemia and changes in the amount of adipokines secreted from adipose tissue. Therefore, we explored the follicular fluids in PCOS patients in comparison with normal controls. We measured the insulin concentration of the follicular fluids, and the found that the significance correlation between follicular-fluid insulin levels and the expression levels of PTEN in granulosa cells, which tend to be higher in PCOS patients than those in non-PCOS patients. We also found that the significantly high concentration of insulin in follicular fluid was observed in non-pregnant cycles of PCOS patients. Follicular fluid contains a variety of proteins that play important roles in follicle development and oocyte maturation and are thus thought to impact the outcome of in vitro fertilization. Therefore, conducting analyses of follicular fluid might be helpful in identifying molecules related with the pathogenesis of PCOS. We investigated the protein composition of human follicular fluid containing 12 females (n=4 of PCOS, n=8 of non-PCOS) undergoing IVF using proteomic analyses with LC/MS/MS. We found that 43 proteins exhibited significantly upregulated spectral counts in PCOS follicular fluid including fibronectin 1 and apolipoprotein M. GnRH neurons are the final common pathway to regulate the hypothalamus-pituitary-gonad axis. GnRH secretion occurs in a pulsatile manner and a surge, which is regulated negatively and positively by estrogen, respectively. Recent findings demonstrated the kisspeptin neurons in the arcuate nucleus (ARC) of hypothalamus serve as the central pacemaker to drive pulsatile GnRH secretion. These things suggest that the kisspeptin neurons in ARC might be involved in the hyper LH secretion in PCOS patients. Furthermore, neurokinin B (NKB) and dynorphin A (Dyn) have been reported to be co-expressed by kisspeptin neurons in ARC. Therefore, the kisspeptin neurons are now called KNDy neurons. In KNDy neurons, the rhythmic kisspeptin secretion is generally considered to be regulated positively by NKB and negatively by Dyn. We investigated the kisspeptin expression in ARC using PCOS-model rats. In adult cyclic rats, PCO is induced when RU486, a progesterone receptor antagonist, is given subcutaneously (4mg/day) for 12-16 consecutive days beginning on the first day of estrus. RU486-treated rats showed the persistent estrus with moderate estrogen levels and polycystic appearance of ovaries. We found that the expression of kisspeptin was upregulated in ARC compared to control intact rats. We also found that the LH pulsatile secretion tended to be increased in RU486-treated rats. The pathogenesis of PCOS consists of abnormalities in ovaries, CNS of GnRH secretion and insulin resistance. Three key molecules, insulin, LH, and androgens are involved in the disturbance of the folliculogenesis and GnRH pulsatile secretion. Our finding in the current study could be clues for elucidation of pathogenesis and development of novel therapeutic target in PCOS.

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