In Pubertal Girls, Naloxone Fails to Reverse the Suppression of Luteinizing Hormone Secretion by Estradiol1
Ayse Pinar Cemeroglu,
Gad B. Kletter2,
Wensheng Guo,
Morton B. Brown,
Robert P. Kelch3,
John C. Marshall,
Vasantha Padmanabhan and
Carol M. Foster
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 examinedin 10 pubertal girls, testing the hypothesis
that E2 suppressesLH pulse frequency and amplitude through
opioid pathways. At1000 h, a 32-h saline infusion was given,
followed 1 week laterby an E2 infusion at 13.8
nmol/m2·h. During both infusions,four iv boluses of
saline were given hourly beginning at 1200h, and four naloxone iv
boluses (0.1 mg/kg each) were givenhourly beginning at 1200 h on
the following day. Blood was obtainedevery 15 min for LH determination
and every 60 min for E2 determinationfrom 1200 h to
the end of the infusion. E2 infusion increasedthe mean
serum E2 concentration from 44 ± 17 to 112 ±26
pmol/L (P < 0.01). The mean LH concentration
between 2200–1200h 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 were1.2 fewer pulses
during E2 infusion compared to saline infusion,differences
did not reach significance (P = 0.1; 95%
confidenceinterval for the difference, -3.5, 1.1). Pituitary
responsivenessto GnRH, assessed at the end of the infusion by
administering250 ng/kg GnRH iv, did not change during E2
infusion. The effectof naloxone blockade of opioid activity on LH
secretion wasdetermined by assessing the area under the curve (AUC)
from1200–1600 h. During saline infusion, the LH AUC was 1122±
375 IU/L during saline boluses and 1575 ± 403IU/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
pubertalgirls: 1) E2 decreases the LH concentration and LH
pulse amplitude;2) the main site of negative feedback effect of
E2 appears tobe at the level of the hypothalamus; 3) an
increase in LH secretionafter naloxone administration could not be
demonstrated in thesegirls and may depend on the maturity of the
hypothalamic-pituitary-gonadalaxis; and 4) opioid receptor blockade
does not reverse the E2inhibition of LH secretion even in
the most mature girls. Thus,E2 suppression of LH secretion
in pubertal girls appears tobe mediated by a decrease in hypothalamic
GnRH secretion thatis independent of opioid pathways.
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