To determine the effect of administration of a progestin alone on endogenous opioid peptide activity, we infused naloxone (2 mg/h for 4 h) into seven estrogen-deficient postmenopausal women before and after oral medroxyprogesterone acetate (Provera; 20 mg) daily for 30 days. Baseline serum LH levels were significantly decreased by the Provera therapy [70.3 +/- 6.6 (+/- SE) vs. 27.5 +/- 1.7 mIU/ml; P less than 0.001]. Naloxone infusion before Provera treatment had no effect on serum LH levels. In contrast, after Provera therapy, a significant (P less than 0.001) increase in LH levels toward the pre-Provera baseline occurred with naloxone infusion. These findings suggest that progestins exert their negative feedback effects on LH at least in part through an opioid peptide-mediated mechanism and that progestin treatment alone can reestablish opiatergic control of LH.