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*ESTRADIOL
*NALOXONE
The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 10 3501-3506
Copyright © 1998 by The Endocrine Society

From the Clinical Research Centers

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.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
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.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE ONSET of puberty is characterized by a nocturnal increase in gonadotropin secretion before the physical signs of pubertal maturation are evident (1, 2). This sleep-associated increase in gonadotropin secretion is associated with a decrease in the sensitivity of hypothalamic-pituitary axis to sex steroid negative feedback (3, 4). We have demonstrated previously in pubertal boys that the primary site of sex steroid negative feedback is at the level of hypothalamus, reflected by an inhibition of the nocturnal increase in LH and, by inference, GnRH pulse frequency (5, 6). As GnRH neurons are not thought to possess sex steroid receptors, estradiol (E2) inhibition of LH secretion is likely to occur through other inhibitory pathways. Endogenous opioid peptides have been shown to decrease LH secretion in some animal models (7, 8, 9, 10, 11, 12) and in adult humans (13, 14, 15) through inhibition of tonic secretion of GnRH from the hypothalamus (16, 17, 18, 19). In gonadectomized animals and in adult humans, naloxone fails to produce an increase in LH secretion (20, 21, 22, 23, 24), but sex steroid replacement restores the inhibitory tone of endogenous peptides on gonadotropin secretion (8, 20, 24). These observations suggest that the negative feedback effects of E2 on LH secretion may be mediated through opioitergic neurons. Although we have shown previously that naloxone fails to reverse the suppression of LH secretion by testosterone (T) or E2 infusion in mid- to late pubertal boys (5), the significant sex differences in neuroendocrine control of gonadotropin secretion during pubertal maturation in girls and boys (25) and the greater E2 exposure during childhood in girls compared to boys (26) suggest that the mechanisms controlling sex steroid negative feedback in girls and boys may differ significantly. Hence, we examined whether E2 inhibits LH pulse frequency and amplitude during pubertal maturation in girls and whether opioid blockade by naloxone administration could increase or reverse this blockade of LH secretion.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Ten healthy pubertal girls were recruited from the Pediatric Clinics of University of Michigan. The clinical characteristics of the girls are shown in Table 1Go. Two of the oldest girls (subjects 9 and 10) had established regular menstrual cycles, although the absence of increases in the serum progesterone concentration suggested that these cycles were not yet ovulatory. Only one girl (subject 3) had a progesterone concentration above 3 nmol/mL. None of the girls had received any hormonal medications before study.


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  		Table 1. Clinical characteristics of the subjects

 
Protocol

All studies were conducted at the General Clinical Research Center of the University of Michigan Hospitals after informed consent was obtained from a parent and assent was obtained from the subject. The protocol was approved by the institutional review board of the University of Michigan. The girls were admitted twice, 1 week apart, on the night before the study to acclimate them to the unit, except for subject 10, who was admitted on the day of the study. Lights were turned off at 2200 h, and girls were awakened at 0600 h. Sleep pattern was recorded by the trained nursing personnel. The protocol employed is shown in Fig. 1Go. An indwelling heparinized cannula was inserted into a forearm vein of each arm: one for infusion and the other for blood sampling. On the first weekend, all girls received a saline infusion at 10 cc/h starting at 1000 h until 1800 h on the following day. Blood samples were obtained every 15 min for serum LH and every 60 min for serum E2 and T determinations from 1200–1800 h and from 2200–1800 h on the following day. Four 1-cc iv boluses of saline were given hourly beginning at 1200 h, and four iv boluses of naloxone (0.1 mg/kg in 1 cc) were given hourly beginning at 1200 h on the following day. At the end of the infusion, 250 ng/kg synthetic GnRH (Factrel, Ayerst Laboratories, Rouses Point, NY) were administered as an iv bolus, and blood samples were obtained for serum LH determinations at 1800, 1820, and 1840 h. The same study was repeated a week later with infusion of 13.8 nmol/m2·h E2 instead of saline. Subject 3 received E2 at a rate of 4.6 nmol/m2·24 h. She had a decrease in the mean serum LH concentration of 16%, but the mean serum E2 concentrations before and during E2 infusion were similar. Exclusion of her data had no significant impact on interpretation of results, so her data were included in the analysis.



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  		Figure 1. Schema of the study protocol. Shaded areas represent times when no blood samples were obtained.

 
Hormone assays

The serum LH concentration was measured in duplicate by RIA in subjects 3 and 7, as described previously (29). The assay sensitivity was 1.0 IU/L, and the intra- and interassay coefficients of variation (CVs) were 4% and 8%, respectively. The standard was WHO 78/549, and results are expressed in terms of the Second International Reference Preparation of human menopausal gonadotropin. In the remaining eight patients, the serum LH concentration was measured by immunofluorometric assay (IFMA) using Delfia kits obtained from Wallac, Inc. (Gaithersburg, MD). The standard was WHO 80/552, and results are expressed as Second International Standard units. The assay sensitivity was 0.05 IU/L, and intra- and interassay CVs were 5.7% and 6.9%, respectively. We have shown previously that detection of LH pulses and physiological conclusions obtained do not differ between the ultrasensitive IFMA and the RIA (30). IFMA values may be converted to RIA values by a multiplication factor of 2.7 for IFMA concentrations of 6 or greater, but the conversion is nonlinear at values approaching the assay sensitivity of the RIA (30). The data here are presented without conversion, because subjects served as their own controls.

Serum T and E2 concentrations were determined in duplicate using RIA kits obtained from Radioimmunoassay System Laboratories, Inc. (Carson, CA). The sensitivity of the T assay was 0.35 nmol/L, and intra- and interassay CVs were 5.0% and 8.5%, respectively. The sensitivity of the E2 assay was 18 pmol/L, and intra- and interassay CVs were 8% and 15%, respectively.

Two-hour pools made from blood obtained between 2200–0800 h were used to determine serum progesterone concentrations. Progesterone was measured by a double antibody RIA kit obtained from ICN (Costa Mesa, CA). The assay sensitivity was 0.64 nmol/L, and the intra- and interassay CVs were 5.2% and 8.1%, respectively.

Statistical analyses

LH pulses were identified by the Kushler-Brown algorithm (31), fitting exponential decay curves with a common half-life parameter to each down-slope: pulses are identified using an error sum of squares criterion starting from an initial set of pulses. Serum LH concentrations between 2200–1200 h during saline and E2 infusions were used for pulse analysis. Missing values comprised less than 1% of the samples; their values were linearly interpolated before the algorithm was applied. Samples below the assay sensitivity were assigned the value of assay sensitivity. In four series no pulses were detected; the four series are included in the estimation of pulse frequency (as zero) and the baseline, but not in the estimation of pulse amplitude or half-life.

Mean LH, LH pulse amplitude, baseline (LH values not in a pulse), and half-life were analyzed after logarithmic transformation and LH pulse frequency after square root transformation to reduce the heterogeneity of variances. Results are presented as the mean ± SE on the original scale and as 95% confidence intervals for the log-transformed variables. As the log transformation is not linear, the limits of the 95% confidence interval are transformed back to the original scale. Student’s paired t test applied to the transformed data was used to compare the infusions.

To analyze the effect of naloxone infusion on LH concentration, the area under the curve (AUC) for the 4-h period from 1200–1600 h was calculated using a trapezoid rule. Repeated measures ANOVA on the log of the AUC was used to test the differences between the conditions.

The pituitary responsiveness to GnRH was assessed by subtracting the serum LH concentration at baseline from the peak LH concentration after GnRH administration. Significance was determined using Student’s paired t test after logarithmic transformation of the data. P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Effects of E2 infusion on LH secretion

E2 infusion produced a significant increase in the mean serum E2 concentration from 44 ± 17 pmol/L during saline infusion to 112 ± 26 pmol/L (P < 0.01; subject 3 included). Neither mean serum T nor progesterone concentrations changed significantly during E2 infusion (data not shown).

Effects of E2 infusion on LH pulse characteristics

Figure 2Go demonstrates the effect of E2 on LH pulse characteristics in pubertal girls. In four of the five youngest girls (bone age 11 yr or less), E2 infusion completely suppressed LH pulses. Subject 3, who had pulses apparent with E2 infusion, received one third of the E2 dose of the other girls. In the five older girls, E2 infusion resulted in a decline of pulse amplitude but not pulse frequency. Summary data are shown in Table 2Go. E2 infusion decreased the mean LH concentration from 3.2 ± 0.9 IU/L during saline infusion to 2.0 ± 0.7 IU/L (P = 0.014; 95% confidence interval ratio, 0.12, 0.64). There were 1.2 fewer LH pulses during E2 compared to saline infusion, but this change in LH pulse frequency did not achieve significance (P = 0.10). The baseline LH concentration between 2200–1200 h decreased significantly during E2 infusion (P = 0.019) to about half of that during saline infusion. LH pulse amplitude decreased significantly during E2 infusion to 58% of that during saline infusion (P = 0.0076). The LH half-life, a measurement of LH clearance, did not change significantly with infusion type (Table 2Go).



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  		Figure 2. LH profiles of 10 girls during the entire study period. Each panel represents one subject’s LH concentrations during saline infusion (closed circles) and E2 infusion (open circles). Arrows above the panels indicate the approximate time of saline or naloxone boluses. Mean E2 concentrations during saline and E2 infusion are indicated in sequence in the panels, as are the girls’ pubertal status (P) by the method of Tanner (28 ) and bone age (BA) in years. *, Subject 3 received one third of the E2 dose received by the remaining nine girls. Her E2 concentration did not increase, but her mean LH level declined by 16% after E2 infusion. Her results indicate the need for the higher dose of E2 infused in the remaining girls.

 

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  		Table 2. LH pulse characteristics during saline and E2 infusions

 
Pituitary responsiveness to GnRH

The effect of E2 infusion on pituitary responsiveness to GnRH was assessed by determining the increase in the LH concentration in response to 250 ng/kg GnRH, iv, at the end of the saline or E2 infusion. The mean increase in LH from baseline to peak response was 12.5 ± 2.3 after saline infusion and 13.4 ± 3.1 IU/L after E2 infusion (P = 0.73).

Effects of naloxone administration on LH secretion

The LH response to administration of naloxone is demonstrated in the LH profiles shown in Fig. 2Go. Although the youngest girls had no increase in serum LH concentration in response to naloxone during saline infusion, older girls had apparent augmentation of serum LH secretion in response to naloxone compared to saline boluses during saline infusion. The mean LH AUC during saline infusion was 1122 ± 375 IU/L during saline boluses and 1575 ± 403 IU/L during naloxone boluses, but the difference did not achieve statistical significance (Table 3Go; P = 0.39). In the absence of naloxone, E2 infusion suppressed the LH AUC from 1122 ± 375 IU/L during the saline infusion to 865 ± IU/L (P < 0.01; Table 3Go), and naloxone did not reverse the suppression of LH AUC by E2 infusion in any girl, regardless of the degree of maturation or the dose of E2 given.


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  		Table 3. LH response to naloxone during saline and E2 infusions

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Puberty in both boys and girls is characterized by an increase in nocturnal LH secretion (1, 2). Our prior studies in both boys and girls indicate that this nocturnal LH rise is characterized by an increase in both LH pulse frequency and amplitude, a finding that has been robust in the face of changes in LH assay sensitivity or the pulse detection algorithm (4, 25). Boys exhibit a decrease in LH pulse frequency, but not amplitude, in response to infusion of either T or E2 at the adult male production rate (6, 32). Thus, it is surprising to find that in girls, E2 infusion suppresses LH pulse amplitude, whereas the decrease in pulse frequency is not significant. This finding must be tempered by the fact that the number of subjects is small, and the results of subjects variable. It may be that E2 decreases pulse frequency in young pubertal girls and amplitude in older girls. A lower concentration of E2 may be needed to discern whether E2 has a greater effect on LH pulse amplitude or frequency in very early pubertal subjects.

E2 suppresses pulse amplitude more than frequency in the older girls in our study, similar to its reported effects in adult men, but in adult men, E2 appears to suppress gonadotropin secretion principally by decreasing pituitary sensitivity to GnRH (33). In contrast to studies in adults, a 32-h E2 infusion does not suppress the pituitary LH response to GnRH in either older or younger girls, implying that the major site of action of E2 negative feedback during puberty is at the level of the hypothalamus. As girls become mature, it appears that the primary site of E2 suppression of gonadotropin secretion may shift from the hypothalamus to the pituitary as the hypothalamus develops progressive resistance to negative feedback from sex steroids. The dose of GnRH is an intermediate dose, which could have pharmacological activity. Yet, development of resistance and subsequent shift of the site of sex steroid negative feedback have been demonstrated in comparative studies of sex steroid infusion in boys and men (5, 33).

Pubertal development seems to represent a recrudescence of LH secretion after early and midchildhood restraint of active fetal and neonatal GnRH secretion by as yet unknown neuroendocrine factors. It has long been hypothesized that opioid pathways might participate in restraining GnRH secretion during childhood (11, 16). Opioid pathways are appealing candidates for suppression of LH secretion, because naloxone blockade produces a prompt increase in LH secretion in some animal models (7, 8, 9, 10, 11, 12) and in adult humans (13, 14, 15) by action at the level of the hypothalamus rather than at the pituitary (16, 17, 18, 19). Earlier studies of the ability of naloxone to disinhibit restraint of LH secretion in childhood have used lower doses or differing protocols for administration compared to the high dose bolus regimen used here (34, 35). The girls in this study failed to demonstrate a consistent increase in LH AUC in response to naloxone. This may have been expected in the youngest subjects, as sex steroid, particularly E2, exposure appears to be needed to express opioid receptors in GnRH neurons. It is surprising that naloxone did not consistently increase the LH AUC in our older subjects. This may be due to the fact that opioid activity in adult women seems to vary with the menstrual cycle (36, 37). Although naloxone enhances LH secretion in the follicular to luteal transition and during the luteal phase, it is difficult to demonstrate any naloxone effect on LH secretion during the follicular phase (37). As progesterone concentrations were low in all of our subjects, suggesting that none was having ovulatory cycles, it may be that further reproductive maturation must take place in girls before opioid pathways become fully developed or fully functional. Alternatively, even larger doses of naloxone than those used in this study (20 times the dose for reversal of narcotic overdose) may be needed to see an effect. A full examination of the development of opioid regulation of LH secretion in pubertal girls will also require a far larger number of subjects than examined here.

Our study supports the idea that E2 decreases hypothalamic GnRH secretion. The data are consistent with the idea that pulse frequency declines in younger girls and pulse amplitude in older girls, but subject numbers are not sufficient to provide statistical proof. The data are sufficient to conclude that E2 suppresses daytime LH AUC between 1200–1600 h, and naloxone is ineffective in reversing that inhibition. These results are similar to those we have seen in boys, in whom naloxone is ineffective in counteracting the suppression of LH secretion by either T or E2 (5, 32). Naloxone is also ineffective in reversing T suppression of LH secretion in adult men (33). Thus, sex steroid negative feedback effects on LH secretion are unlikely to be mediated through opioid pathways in boys or girls.


   Acknowledgments
 
We gratefully acknowledge the expert technical assistance of Ms. Alice Rolfes-Curl and Ms. Pamela Olton, and the secretarial assistance of Ms. Julie Grimes.


   Footnotes
 
1 This work was supported by NIH Grant HD-16000 and General Clinical Research Center Grant MO1-RR-00042. Presented in part at the 77th Annual Meeting of The Endocrine Society, Washington, D.C., June 1995. Back

2 Current address: Department of Pediatrics, University of Washington, Seattle, Washington 98105. Back

3 Current address: University of Iowa College of Medicine, Iowa City, Iowa 52245-1101. Back

Received November 14, 1997.

Revised June 23, 1998.

Accepted July 13, 1998.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals