Effect of chronic opioid antagonism on the hypothalamic-pituitary-ovarian axis in hyperprolactinemic women

Short term naloxone infusion studies have suggested that enhanced endogenous opioid activity may play a role in inhibiting GnRH and gonadotropin secretion in hyperprolactinemic patients. Because it was not known whether long term opioid antagonism would lead to persistent stimulation of LH with a subsequent ovarian response, we administered the long-acting oral opiate antagonist, naltrexone (NTX), to six hyperprolactinemic amenorrheic women. Blood was drawn from all subjects every 15 min for 10 h on a control day and again on the next day after the administration of 50 mg NTX. Five subjects continued NTX (50 mg daily) for 3-8 weeks. There was a significant increase in the mean concentration of LH (6.7 +/- 1.1 to 12.2 +/- 1.6 IU/L), area under the LH curve (200%), and LH pulse amplitude (3.2 +/- 0.6 to 7.2 +/- 1.0 IU/L) on the first NTX day compared to the control day (P < 0.02). Estradiol levels also increased on the first NTX day (P < 0.01). The mean peak estradiol level increased from 76 +/- 9.9 pmol/L on the control day to 138 +/- 21 pmol/L during NTX treatment (P < 0.02). NTX stimulated LH release in five of six patients, followed by a rise in estradiol in four of these five patients. This initial increase in estradiol was not sustained in most cases, and the mean estradiol level during the entire NTX treatment period was not significantly different from the control level. One patient achieved an estradiol level of 187 pmol/L after 3 weeks of NTX treatment and reported withdrawal bleeding after stopping NTX. No patient ovulated. PRL levels did not change on the first NTX day vs. the control day (166 +/- 79 vs. 167 +/- 67 micrograms/L); however, PRL did increase over time with continued NTX treatment (P < 0.05). The mean PRL level during chronic NTX treatment was 255 +/- 121 micrograms/L. We conclude that treatment of hyperprolactinemic amenorrheic women with NTX results in a prompt partial reactivation of the hypothalamic-pituitary-gonadal axis, as indicated by increased gonadotropin and subsequent estradiol release. The effect of opioid antagonism, however, did not lead to a sustained increase in estradiol secretion with chronic treatment. Thus, although endogenous opioids appear to play a key role in mediating PRL-induced gonadal suppression, chronic opioid antagonism with NTX does not appear to be an effective treatment for amenorrhea in these patients.