Unified minimal model of polycystic ovary syndrome pathophysiology

(A) FOH is nearly universal in PCOS and can account for all of the cardinal clinical features of the syndrome: hyperandrogenemia, oligo-anovulation, and polycystic ovaries (step 1). Pituitary LH secretion is necessary to sustain the ovarian androgen excess but is not sufficient to cause it.
(B) Approximately one-half of patients with FOH have an abnormal degree of insulin-resistant hyperinsulinism (step 2). Insulin-resistant hyperinsulinism acts on theca cells to aggravate hyperandrogenism, synergizes with androgen to prematurely luteinize granulosa cells, and stimulates fat accumulation. The increased hyperandrogenemia provokes LH excess, which then acts on both theca and luteinized granulosa cells to worsen hyperandrogenism (step 3). LH also stimulates luteinized granulosa cells to secrete estradiol (step 4), which suppresses FSH secretion. These hyperinsulinism-initiated changes in granulosa cell function further exacerbate PCOM and further hinder ovulation. Obesity increases insulin-resistance, and the resultant increased hyperinsulinism further aggravates hyperandrogenism (step 5). Bold and enlarged fonts represent greater severity.
Both FOH and insulin resistance typically have an intrinsic basis. This model does not exclude the possibility that the unknown intrinsic ovarian defects that underpin the ovarian steroidogenic dysfunction also involve granulosa cell folliculogenesis and other systems as well. The figure also does not depict other associated defects, such as the functional adrenal hyperandrogenism that often accompanies the ovarian hyperandrogenism and the contribution of excess adiposity to peripheral androgen production and gonadotropin suppression.