In pubertal girls, naloxone fails to reverse the suppression of luteinizing hormone secretion by estradiol

Estradiol (E-2) negative feedback on LH secretion was examined in 10 pubertal girls, testing the hypothesis that E-2 suppresses LH pulse frequency and amplitude through opioid pathways. At 1000 h, a 32-h saline infusion was given, followed 1 week later by an E-2 infusion at 13.8 nmol/m(2).h. During both infusions, four iv boluses of saline were given hourly beginning at 1200 h, and four naloxone iv boluses (0.1 mg/kg each) were given hourly beginning at 1200 h on the following day. Blood was obtained every 15 min for LH determination and every 60 min for E-2 determination from 1200 h to the end of the infusion. E-2 infusion increased the mean serum E-2 concentration fi om 44 +/- 17 to 112 +/- 26 pmol/L (P < 0.01). The mean LH concentration between 2200-1200 h decreased from 3.19 +/- 0.89 to 1.99 +/- 0.65 IU/L (P = 0.014), and LH pulse amplitude decreased from 3.4 +/- 0.6 to 2.6 +/- 0.5 IU/L (P = 0.0076). Although there were 1.2 fewer pulses during E-2 infusion compared to saline infusion, differences did not reach significance (P = 0.1; 95% confidence interval for the difference, -3.5, 1.1). Pituitary responsiveness to GnRH, assessed at the end of the infusion by administering 250 ng/kg GnRH iv, did not change during E-2 infusion. The effect of naloxone blockade of opioid activity on LH secretion was determined by assessing the area under the curve (AUC) from 1200-1600 h. During saline infusion, the LH AUC was 1122 +/- 375 IU/L during saline boluses and 1575 +/- 403 IU/L during naloxone boluses (P = 0.39). When E-2 was infused, the LH AUCs during saline and naloxone boluses were 865 +/- 249 and 866 +/- 250 IU/L, respectively. Thus, in pubertal girls: 1) E-2 decreases the LH concentration and LH pulse amplitude; 2) the main site of negative feedback effect of E-2 appears to be at the level of the hypothalamus; 3) an increase in LH secretion after naloxone administration could not be demonstrated in these girls and may depend on the maturity of the hypothalamic-pituitary-gonadal axis; and 4) opioid receptor blockade does not reverse the E-2 inhibition of LH secretion even in the most mature girls. Thus, E-2 suppression of LH secretion in pubertal girls appears to be mediated by a decrease in hypothalamic GnRH secretion that is independent of opioid pathways.