논문 상세보기
Polycystic Ovarian Syndrome: Dysregulation at the Reproductive-Metabolic Interphase
- 언어ENG
- URLhttps://db.koreascholar.com/Article/Detail/213293
Polycystic ovarian syndrome (PCOS) is a heterogeneous syndrome associated with follicle growth arrest, dysregulated sex hormone profile, hyperthecosis and insulin resistance. Chemerin, a novel adipokine, is associated with obesity and metabolic syndrome. Although obese women and in PCOS subjects have elevated plasma chemerin levels, whether and how chemerin is involved in the regulation of follicular growth/steroidogenesis and pathogenesis of PCOS is unknown. Our objective is to better understand the complex regulatory mechanisms involved in the control of these processes and gain insights in their dysregulation in the pathogenesis of PCOS. We hypothesize that: (a) hyperandrogenism induces small and medium antral follicle growth arrest and ovarian structural changes, resulting from granulosa cell and oocyte apoptosis and theca cell survival, and (b) chemerin regulates follicular growth and steroidogenesis and contributes to the pathogenesis of PCOS. Using immature rats (day 13～15 for follicle culture and day 21～24 for granulosa cells culture) and a chronically androgenized rat model [dihydrotestosterone (DHT); 83 μg daily, day 21～105] which recapitulates the reproductive and metabolic phenotypes of human PCOS, we have examined the granulosa cell expression patterns of chemerin and its receptor CMKLR1 and their steroidogenic and follicle growth capability. DHT treatment resulted in decreased follicle numbers in preantral to preovulatory stages and absence of corpus luteum, but increased numbers of condensed atypical follicles. Atypical follicles, constituted predominantly of theca cells, exhibited high expression of calpain and down‐regulation of the cytoskeletal protein substrates vimentin, fodrin and β‐tubulin. Granulosa cell aromatase expression was significantly down‐regulated, a response accompanied by increased activated caspase‐3 content and DNA fragmentation. While PTEN levels were considerably higher in granulosa cells in the PCOS rats than controls, phospho‐Akt (Ser473) content was lower. In addition, DHT also activated granulosa cell caspase‐3, decreased XIAP, PARP and phospho‐Akt contents and induced apoptosis in vitro, responses that could be attenuated by forced expression of XIAP. These findings are consistent with our hypothesis that dysregulated follicular growth in PCOS is associated with changes in follicular growth dynamics and follicle cell fate, a consequence of dysregulated interactions of pro‐survival (p‐Akt, XIAP, PARP) and proapoptotic (calpain, PTEN, caspase‐3) modulators in a cell‐specific manner. Chemerin and CMKLR1 were expressed in granulosa cells and negatively regulated by gonadotropin in vivo and in vitro. Serum and ovarian chemerin levels in DHT‐treated rats were elevated, and associated with arrested early antral follicular growth, remodeling of the follicle wall and decreased expression of p450 side‐chain cleavage enzyme (p450- scc), aromatase and hydroxysteroid dehydrogenases. Recombinant chemerin inhibited FSH ‐ induced estradiol secretion in granulosa cells from DHT‐treated rats in vitro. Chemerin also suppressed basal and FSH‐ and GDF9‐induced follicle growth and estradiol/ progesterone production in preantral follicle cultures. Moreover, chemerin suppressed FSH‐induced p450scc/aromatase expression and progesterone/estradiol secretion in immature rat granulosa cells in vitro. These studies demonstrate that chemerin is a novel negative regulator in FSH‐induced follicular growth and steroidogenesis and support the notion that the dysregulation of chemerin expression and function contributes to pathogenesis of PCOS. Our observations also suggest that this chronically androgenized rat model may be useful not only for studies on the long term effects of androgen on folliculogenesis, but also on the pathophysiology of PCOS. * This work was supported by grants from the Canadian Institutes of Health Research (CIHR; MOP‐119381) and the World Class University (WCU) program through the Ministry of Education, Science and Technology funded by the National Research Foundation of Korea (R31‐10056).
