Exogenous human menopausal gonadotropin (hMG) therapy produces transient hyperprolactinemia during ovulation induction or ovarian hyperstimulation for in vitro fertilization, and hyperprolactinemia has been linked to decreased fertility. Coadministration of clomiphene citrate (CC) with hMG is often used to decrease the total amount of hMG used in such patients, but whether this results in less hyperprolactinemia is not known. As the hyperprolactinemia in this setting is a threshold phenomenon dependent on the strength and duration of estrogen exposure, we investigated whether CC acted as an estrogen to enhance PRL secretion or as an antiestrogen deterring estradiol (E2)- and progesterone (P4)-induced hyperprolactinemia in nonhuman primates. Normally cycling (control) monkeys (n = 4) received E2 benzoate (12.5 micrograms/kg, im, daily) on menstrual cycle days 6-33 and continuous crystalline P4 via Silastic implants on days 20-33, a regimen known to initiate hyperprolactinemia. Treated monkeys (n = 5) received the same regimen, except that oral CC (15 mg daily) was given on days 6-33. Daily serum samples were assayed for E2, P4, and PRL. Both treatments caused significant (P less than 0.05) increases in serum PRL concentrations during P4 administration. The CC-treated monkeys had significantly smaller increases in mean PRL [21 +/- 1.5 (+/- SEM) vs. 44 +/- 6.3 ng/mL (micrograms/L); P less than 0.05] and smaller mean area under the PRL response curve [288 +/- 35 (+/- SEM) vs. 588 +/- 121 ng/day.mL (micrograms/day.L); P less than 0.05] than the control monkeys. We conclude that CC attenuates the hyperprolactinemia response to E2/P4 synergy in monkeys by acting as an antiestrogen. If coadministered with hMG for ovulation induction or ovarian hyperstimulation for in vitro fertilization, CC should attenuate hMG-induced hyperprolactinemia, thereby reducing its potentially adverse effects on fertility.