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In Pubertal Girls, Naloxone Fails to Reverse the Suppression of Luteinizing Hormone Secretion by Estradiol¹

Department of Pediatrics/Division of Endocrinology, University of Michigan Medical School (A.P.C., R.P.K., G.B.K., V.P., C.M.F.), and the Department of Biostatistics, School of Public Health (W.G., M.B.B.), Ann Arbor, Michigan 48109; and the Department of Internal Medicine, University of Virginia (J.C.M.), Charlottesville, Virginia 22908

Address all correspondence and requests for reprints to: Carol M. Foster, M.D., D3252 MPB, Box 0718, Ann Arbor, Michigan 48109.

Estradiol (E₂) negative feedback on LH secretion was examined in 10 pubertal girls, testing the hypothesis that E₂ 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 E₂ infusion at 13.8 nmol/m²·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 E₂ determination from 1200 h to the end of the infusion. E₂ infusion increased the mean serum E₂ concentration from 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 E₂ 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 E₂ 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 E₂ was infused, the LH AUCs during saline and naloxone boluses were 865 ± 249 and 866 ± 250 IU/L, respectively. Thus, in pubertal girls: 1) E₂ decreases the LH concentration and LH pulse amplitude; 2) the main site of negative feedback effect of E₂ 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 E₂ inhibition of LH secretion even in the most mature girls. Thus, E₂ suppression of LH secretion in pubertal girls appears to be mediated by a decrease in hypothalamic GnRH secretion that is independent of opioid pathways.

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