The luteal phase of the menstrual cycle is characterized by a progressive decrease in LH pulse frequency. Short term administration of opiate receptor antagonists during the luteal phase increases the release of both LH and PRL. However, the effects of prolonged opioid antagonism throughout the luteal phase are unknown and, hence, the precise role of endogenous opioid peptides in the reproductive cycle remains to be elucidated. In this study, we examine the ability of longer term opioid antagonism during the luteal phase to alter pulsatile LH and PRL release. Naltrexone (NTX), a long-acting oral opioid antagonist, at a dose of 50 mg, was administered daily for 7 days during the luteal phase in five women. Blood samples were obtained at intervals of 10 min starting at 0800 h for 11-12 h on matched days of the luteal phase of both a control and the experimental cycle. LH and PRL pulse frequencies were significantly increased at the end of the 7-day NTX administration period compared to those in the control cycle [LH, 0.22 +/- 0.04 (+/- SE) vs. 0.07 +/- 0.03 pulse/h (P less than 0.01); PRL, 0.20 +/- 0.02 vs. 0.13 +/- 0.02 pulse/h (P less than 0.05)]. The concordance between LH and PRL pulses increased from 50% in the control cycle to 70% in the NTX cycle, and there was a significant positive correlation between the amplitudes of the concomitant LH and PRL pulses (r = 0.72; P = 0.01). In conclusion, prolonged oral opioid antagonism increased pulsatile LH and PRL secretion during the luteal phase in normal women. The results underscore the important role of endogenous opioid peptides in controlling LH pulse frequency during the luteal phase of the cycle.