Studies in Rhesus Monkeys on the Site where Estrogen Inhibits Gonadotropins: Delivery of 17β-Estradiol to the Hypothalamus and Pituitary Gland*

Elevations in peripheral estradiol (E2) levels inhibit the pulsatile release of pituitary gonadotropins in ovariectomized rhesus monkeys. Efforts to determine the locus of E2 action [i.e. the medial basal hypothalamus (MBH) or the anterior pituitary gland (AP)] have been plagued by the diffusion of crystalline E2 from an implantation site within the MBH to the pituitary portal vasculature and, therefore, to the AP (implantation paradox). With an Alzet osmotic minipump, we delivered 10 ng E2/h to either the third ventricle or the AP of ovariectomized rhesus monkeys for a duration of 18 h, while monitoring changes in the peripheral gonadotropin concentrations. We also infused [3H]E2 into either site to determine the extent of [3H]-E2H]-E2 diffusion by the end of the infusion period. After infusion of [3H]E2 into the third ventricle for 18 h, only trace amounts of [3H]E2 were recovered from the AP. A small amount of [3H]E2 was recovered from the MBH after 18 h of delivery directly to the AP. Infusion of E2 into the third ventricle elicited a significant (P < 0.001) reduction in serum gonadotropin concentrations by 18 h. When monkeysof the E2-infused third ventricle group were challenged with 25 μg gonadotropin-releasing hormone (GnRH) at the end of the infusion,serum LH and FSH concentrations were 398 ±91% and 199 ±32% greater than prechallenge levels, respectively. When E2 was infused directly into the AP, mean serum gonadotropin levels were also decreased (P <0.05)compared with saline-treated controls. However, AP E2-treated monkeys exhibited no increase (P > 0.05)in serum levels of LH or FSH after a GnRH challenge at the termination of the experiment. Saline infusion into the third ventricle or AP had no significant effects on serum levels of gonadotropins, and GnRH administration elicited elevations in LH and FSH to 101 ± 12% and 98± 9% above preinjection levels, respectively. When infused into the third ventricle, E2 inhibited the pulsatile release of pituitary LH.When E2 was infused directly into the AP, pulsatile LH release was still observed. Thus, the MBH and AP responded to inhibition by E2 through different mechanisms. In the MBH, E2 appears to lessen the activity of the neural elements that regulate the pulsatile release of GnRH. In the AP, E2 may decrease the responsiveness of the gland to stimulation by GnRH.