EFFECT OF CHRONIC OPIOID ANTAGONISM ON THE HYPOTHALAMIC-PITUITARY-OVARIAN AXIS IN HYPERPROLACTINEMIC WOMEN

Short term naloxone infusion studies have suggested that enhanced endo genous opioid activity may play a role in inhibiting GnRH and gonadotr opin secretion in hyperprolactinemic patients. Because it was not know n whether long term opioid antagonism would lead to persistent stimula tion of LH with a subsequent ovarian response, we administered the lon g-acting oral opiate antagonist, naltrexone (NTX), to six hyperprolact inemic amenorrheic women. Blood was drawn from all subjects every 15 m in for 10 h on a control day and again on the next day after the admin istration 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 fi rst NTX day compared to the control day (P < 0.02). Estradiol levels a lso 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 i n five of six patients, followed by a rise in estradiol in four of the se these five patients. This initial increase in estradiol was not sus tained in most cases, and the mean estradiol level during the entire N TX treatment period was not significantly different from the control l evel. One patient achieved an estradiol level of 187 pmol/L after 3 we eks of NTX treatment and reported withdrawal bleeding after stopping N TX. No patient ovulated. PRL levels did not change on the first NTX da y vs. the control day (166 +/- 79 vs. 167 +/- 67 mu g/L); however, PRL did increase over time with continued NTX treatment (P < 0.05). The m ean PRL level during chronic NTX treatment was 255 +/- 121 mu g/L. We conclude that treatment of hyperprolactinemic amenorrheic women with N TX results in a prompt partial reactivation of the hypothalamic-pituit ary-gonadal axis, as indicated by increased gonadotropin and subsequen t estradiol release. The effect of opioid antagonism, however, did not lead to a sustained increase in estradiol secretion with chronic trea tment. Thus, although endogenous opioids appear to play a key role in mediating PRL-induced gonadal suppression, chronic opioid antagonism w ith NTX does not appear to be an effective treatment for amenorrhea in these patients.