About 25% of patients with PCOS exhibit mildly elevated prolactin levels, which may result from abnormal estrogen feedback to the pituitary gland. In some patients with PCOS, bromocriptine has reduced LH levels and restored ovulatory function (56).
Polycystic ovary syndrome is a complex multigenetic disorder that results from the interaction between multiple genetic and environmental factors. Genetic studies of PCOS reported allele sharing in large PCOS patient populations and linkage studies focused on candidate genes most likely to be involved in the pathogenesis of PCOS. These genes can be grouped in four categories: (i) insulin resistance–related genes, (ii) genes that interfere with the biosynthesis and the action of androgens, (iii) genes that encode inﬂammatory cytokines, and (iv) other candidate genes (57).
Linkage studies identified the follistatin, CYP11A, Calpain 10, IRS-1 and IRS-2 regions and loci near the insulin receptor (19p13.3), SHBG, TCF7L2, and the insulin genes, as likely PCOS candidate genes (58–64). A polymorphic variant, D19S884, in FBN3 was found to be associated with risk of PCOS (65). Using theca cells derived from women with PCOS elevated mRNA levels was noted for CYP11A, 3BHSD2, and CYP17 genes with corresponding overproduction of testosterone, 17-α-hydroxyprogesterone, and progesterone. Despite the characteristically heightened steroidogenesis in POCS, the STARB gene was not overexpressed (58). Microarray data using theca cells from PCOS women did not identify any genes near the 19p13.3 locus that were differentially expressed; however, the mRNAs of several genes that map to 19p13.3, including the insulin receptor, p114-Rho-GEF, and several expressed sequence tags, were detected in both PCOS and normal theca cells. Those studies identified new factors that might impact theca cell steroidogenesis and function, including cAMP-GEFII, genes involved in all-transretinoic acid (atRA) synthesis signaling, genes that participate in the Wnt signal transduction pathway, and transcription factor GATA6. These findings suggest that a 19p13.3 locus or some other candidate gene may be a signal transduction gene that results in overexpression of a suite of genes downstream that may affect steroidogenic activity (66). Polymorphisms in major folliculogenesis genes, GDF9, BMP15, AMH, and AMHR2, are not associated with PCOS susceptibility (67).
Insulin Resistance Patients with PCOS frequently exhibit insulin resistance and hyperinsulinemia. Insulin resistance and hyperinsulinemia participate in the ovarian steroidogenic dysfunction of PCOS. Insulin alters ovarian steroidogenesis independent of gonadotropin secretion in PCOS. Insulin and insulin-like growth factor I (IGF-I) receptors are present in the ovarian stromal cells. A specific defect in the early steps of insulin receptor–mediated signaling (diminished autophosphorylation) was identified in 50% of women with PCOS (68).
Insulin has direct and indirect roles in the pathogenesis of hyperandrogenism in PCOS. Insulin in collaboration with LH enhances the androgen production of theca cells. Insulin inhibits the hepatic synthesis of sex hormone–binding globulin, the main circulating protein that binds to testosterone, thus increasing the proportion of unbound or bioavailable testosterone (13).