Possible Involvement of Chemerin, a Novel Regulator in Follicular Growth and Steroidogenesis, in the Pathogenesis of Polycystic Ovarian Syndrome (PCOS).

Abstract

Polycystic ovarian syndrome (PCOS) is a heterogeneous syndrome associated with follicle growth arrest, dysregulated sex hormone profile, hyperthecosis and insulin resistance. Chemerin is a novel adipokine and is associated with obesity and metabolic syndrome. Although obese women and 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 ovarian follicular growth and steroidogenesis and gain insights in their dysregulation in the pathogenesis of PCOS. We hypothesize that chemerin is a novel regulator of follicular growth and steroidogenesis and contributes to the pathogenesis of PCOS. Using an immature rat model (day13-15 for follicle culture and day 21-24 for granulosa cells culture) and a chronically androgenized rat model [dihydrotestosterone (DHT); daily release dose 83μg from 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 capability. Chemerin and CMKLR1 were expressed in granulosa cells from immature rats and negatively regulated by gonadotropin in vivo and in vitro. Serum and ovarian chemerin levels in DHT-treated rats were elevated, which was associated with arrested follicular growth and decreased expression of p450 side-chain cleavage enzyme (p450scc), aromatase and hydroxysteroid dehydrogenases. Recombinant chemerin inhibited FSH-induced estradiol secretion in granulosa cells from DHT-treated rats in vitro. In addition, chemerin suppressed basal and FSH-induced follicle growth and estradiol/progesterone production in a concentration-dependent manner in preantral follicle cultures. Moreover, chemerin suppressed FSH-induced p450scc/aromatase expression and progesterone/estradiol secretion in immature rat granulosa cells in vitro. Conclusion: This study demonstrated, for the first time, that chemerin is a novel negative regulator in FSH-induced follicular growth and steroidogenesis. Our findings support the notion that the dysregulation of chemerin expression and function contributes to pathogenesis of PCOS and infertility associated with compromised follicular growth and differentiation. This research is supported by a grant from the CIHR (B.K.T.), CIHR-QTNPR (Q.W.) and CIHR-REDIH (K.X.) graduate scholarships and a CIHR-QTNPR postdoctoral fellowship (J.Y.K.).