MON-209 Systemic and Hypothalamic Hyperandrogenism Emerges Following Elimination of Ovarian and Extra-Ovarian Sources of Estradiol in Female Marmoset Monkeys

Abstract

In female nonhuman primates, ovarian and extra-ovarian estradiol (E2) contribute components of negative and positive feedback regulation of pituitary gonadotropin, as well as sexually receptive behavior. Little is known, however, about accompanying changes in brain steroid hormone content, particularly at the level of the hypothalamus. As part of a larger study investigating ovarian and extra-ovarian E2 regulation of reproductive, sexual and metabolic function, 13 adult female marmosets housed with well-established male pairmates were ovariectomized (OVX) and immediately assigned to one of three treatment groups: E2 SC capsule replacement (E2, n=5, mimicking peri-ovulatory circulating E2 levels), vehicle (VEH, n=4, daily PO 1ml/kg Ensure®), and aromatase inhibition (LET, n=4, daily PO 1mg/kg letrozole). At necropsy 8-9 months following treatment onset, plasma samples were obtained and hemi-hypothalami were harvested. Tissues and samples were placed in liquid nitrogen and frozen at -80C until assayed by LC-MS/MS (steroid hormones) or RIA (gonadotropin). LET females exhibited elevated (p=0.05) post-OVX circulating CG levels (marmoset LH equivalent) compared to E2 females. Circulating E2 levels were similarly diminished (p=0.01) in VEH and LET female groups compared to E2 females, while circulating levels of DHEA were comparably elevated (p<0.001) in VEH and LET compared to E2 females. Increased DHEA likely reflects absence of E2-inhibition of adrenal androgen biosynthesis and development of a zona reticularis. Circulating levels of testosterone (T), androstenedione (A4), progesterone (P4) and 17-hydroxyP4 (17OHP) were comparable between all three female groups. Changes in hypothalamic steroids, however, differed from circulating levels. Hypothalamic E2 was diminished (p<0.001) only in LET compared to E2 and VEH females. In contrast, hypothalamic A4 was increased in both VEH (p=0.03) and LET (p=0.05) compared to E2 females, while hypothalamic DHEA was increased (p=0.04) only in VEH compared to E2 and LET females. Hypothalamic T, P4 and 17OHP were comparable across treatment groups, not surprisingly producing a diminished (p<0.001) E2:T ratio in LET versus E2 females. Taken together, these results suggest E2 inhibition of adrenal and hypothalamic androgen biosynthesis and reveal potential contribution of hypothalamic E2 and androgens to physiological and behavioral function, translationally relevant when E2 production or action is impaired, such as in women with polycystic ovary syndrome.