Extraovarian gonadotropin negative feedback revealed by aromatase inhibition in female marmoset monkeys.

Whereas the ovary produces the majority of estradiol (E) in mature female primates, extraovarian sources contribute to E synthesis and action, including the brain E-regulating hypothalamic gonadotropin-releasing hormone. In ovary-intact female rodent models, aromatase inhibition (AI) induces a polycystic ovary syndrome-like hypergonadotropic hyperandrogenism due to absent E-mediated negative feedback. To examine the role of extraovarian E on nonhuman primate gonadotropin regulation, the present study uses letrozole to elicit AI in adult female marmoset monkeys. Sixteen female marmosets (; >2 yr) were randomly assigned to ovary-intact or ovariectomy (OVX) conditions and subsequently placed on a daily oral regimen of either ~200 µl vehicle alone (ovary-intact Control, = 3; OVX, = 3) or 1 mg ⋅ kg ⋅ day letrozole in vehicle (ovary-intact AI, = 4; OVX + AI, = 6). Blood samples were collected every 10 days, and plasma chorionic gonadotropin (CG) and steroid hormone levels were determined by validated radioimmunoassay and liquid chromatography/tandem mass spectrometry, respectively. Ovary-intact, AI-treated and OVX females exhibited elevated CG ( < 0.01, = 0.004, respectively) compared with controls, and after 30 days, OVX + AI females exhibited a suprahypergonadotropic phenotype ( = 0.004) compared with ovary-intact + AI and OVX females. Androstenedione ( = 0.03) and testosterone ( = 0.05) were also elevated in ovary-intact, AI-treated females above all other groups. The current study thus confirms in a nonhuman primate that E depletion and diminished negative feedback in ovary-intact females engage hypergonadotropic hyperandrogenism. Additionally, we demonstrate that extraovarian estrogens, possibly neuroestrogens, contribute to female negative feedback regulation of gonadotropin release.