FIG. 4.

The “two-hit” hypothesis of PCOS. The “two-hit” hypothesis of polycystic ovary syndrome (PCOS) suggests that two insults are required for the syndrome's full phenotypic expression. For the first “hit,” one or more of a number of different mechanisms, including: (1) Primary adrenal, ovarian, and/or neuroendocrine abnormalities; (2) insulin resistance and hyperinsulinemia; and/or (3) prenatal, immediate postnatal, and/or peripubertal androgen exposure, lead to increased androgen production. For the second “hit,” the preexisting hyperandrogenism reduces the sensitivity of the gonadotropin-releasing hormone (GnRH) pulse generator to progesterone-mediated slowing during pubertal maturation, thereby initiating a series of changes in the hypothalamic–pituitary–ovarian (HPO) axis that result in ovulatory dysfunction and sustained hyperandrogenism. Thus, a cycle is established whereby the presence of hyperandrogenism, the final common pathway for the development of PCOS, begets more hyperandrogenism. E₂, Estradiol; LH, luteinizing hormone; FSH, follicle stimulating hormone; E₂, estradiol. (Figure based on ref. 32.)