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Estradiol Negative Feedback Regulates Nocturnal Luteinizing Hormone and Follicle-Stimulating Hormone Secretion in Prepubertal Female Rhesus Monkeys

Division of Psychobiology, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia 30322

Address all correspondence and requests for reprints to: Mark E. Wilson, Yerkes National Primate Research Center, Emory University, 954 Gatewood Road, Atlanta, Georgia 30329. E-mail: markw{at}rmy.emory.edu.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In recent years, animal models of puberty in children have focused on factors responsible for the developmental increase in gonadotropin secretion independent of gonadal negative feedback. Although the testis may play little if any role in timing the initial increase in gonadotropin secretion in the male, the situation may be different for the female. The present study tested the hypothesis that removal of endogenous estradiol by ovariectomy would produce an immediate increase in nocturnal but not daytime LH and FSH concentrations, an effect reversed by estradiol replacement. Morning (1000 and 1030 h) and evening (2200 and 2230 h) concentrations of bioactive LH and, in selected samples, immunoreactive FSH were evaluated in young juvenile female rhesus monkeys (n = 7) before and after ovariectomy at 13 months of age. Evening but not morning concentrations of gonadotropins were significantly increased within 2 wk of ovariectomy, whereas estradiol replacement returned these to presurgical levels and to those observed in age-matched, gonadally intact females (n = 7). By 145 d after ovariectomy, or approximately 17 months of age, evening as well as morning concentrations of LH were significantly higher than concentrations seen immediately after surgery. Estradiol replacement at approximately 18 months of age suppressed both morning and evening LH but not to the degree seen during a similar treatment after ovariectomy. These data support the hypothesis that, for the female, the developmental rise in diurnal gonadotropin secretion is controlled by a gonad-independent mechanism as well as a gonadal negative feedback inhibition. The importance of gonadal restraint on gonadotropin secretion in young juvenile females is evident only in samples obtained during the evening. These data underscore the notion that, for the female puberty, onset, at least in terms of gonadotropin secretion, is a misnomer and that puberty reflects a progression in multiple control mechanisms that ultimately time the attainment of fertility.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
THE NOTION THAT the developmental increase in circulating gonadotropin secretion is regulated by a decrease in sensitivity to gonadal negative feedback suppression was originally described in children (1) and supported by data from girls with gonadal dysgenesis indicating that a functional ovary restrains the developmental increase gonadotropins (2, 3). This gonadostat hypothesis has since been evaluated in a number of nonhuman primate models. Data from male monkeys clearly show that the protracted period of hypogonadotropic hypogonadism, characteristic of the juvenile phase of development, occurs independent of gonadal regulation (4, 5, 6) and that the development of nocturnal pulsatile gonadotropin secretion is due to a change in central neuropeptide Y restraint (7) and/or glutamate stimulation (8, 9) independent of testicular negative feedback.

Data from female monkeys are less clear. Although prepubertal ovariectomy can result in a relatively immediate increase in daytime FSH concentrations (6, 10), analysis of serum LH suggests that, like the male, the ovary has little impact on the initial developmental increase in LH (11, 12). These data are supported by observations that GnRH secretion into the median eminence after prepubertal ovariectomy is delayed until an older juvenile age (13) after the sequential change in central -aminobutyric acid restraint and glutamate stimulation (14). It was argued that estradiol negative feedback suppression of GnRH becomes functionally important once these neurochemical changes have occurred (15) such that a decrease in sensitivity to estradiol inhibition regulates the late stages of puberty, timing the occurrence of first ovulation (12, 16). Although an earlier study did not observe a significant developmental difference in diurnal LH secretion in either gonadally intact (INT) or ovariectomized (OVX) prepubertal females (11), other reports indicate that nocturnal concentrations of LH are elevated relative to daytime levels in prepubertal OVX females (10, 17). These data would suggest that the prepubertal ovary, unlike the testis (17, 18), may indeed play a role in timing the emergence of nocturnal gonadotropin secretion.

To reconcile these differences and provide a clearer understanding of the role of estradiol in timing of diurnal LH and FSH secretion, we examined diurnal patterns in LH and FSH concentrations before and immediately after ovariectomy in prepubertal rhesus monkeys and determined how estradiol may differentially affect these diurnal patterns with advancing age. We tested the hypothesis that removal of endogenous estradiol by ovariectomy would produce an immediate increase in nocturnal but not daytime LH and FSH concentrations, an effect reversed by estradiol replacement.

	Subjects and Methods

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Female rhesus monkeys (Macaca mulatta) born at the Yerkes National Primate Research were subjects. Animals were housed indoors in pairs or trios under a fixed photoperiod (12 h light, 12 h dark) and temperature (25 ± 2 C). Animals were fed a commercial monkey diet ad libitum twice daily (Lab Diet, number 5038; Purina, St. Louis, MO) and fresh fruit and vegetables once daily. The protocol was approved by the Emory University Institutional Animal Care and Use Committee in accordance with the Animal Welfare Act and the U.S. Department of Health and Human Services Guide for Care and Use of Laboratory Animals.

Two groups of females were used in the study. One group (OVX; n = 7) was studied before and after ovariectomy at 13 months of age. Blood samples were obtained at 1000, 1030, 2200, and 2230 h to assess diurnal secretion of serum LH and, in selected samples, FSH. Samples were collected 21 and 7 d before and 14 and 28 d after ovariectomy. This time frame (12–14 months) corresponds to the early prepubertal period, occurring some 12 months before the age of menarche in animals from our colony housed indoors (19). On d 31 after ovariectomy, females received a sc implant of estradiol to release a dose of 2 µg/kg·d for 21 d (Innovative Research of America, Sarasota, FL). Additional samples for diurnal hormone analysis were collected on d 10 and 25 after the estradiol implant, corresponding to 14.3 and 14.8 months of age. Finally, diurnal samples were again collected in the absence of estradiol (d 145) and on d 160, 10 d after the implantation of an estradiol pellet that released similar amounts of the hormone as the first treatment (2 µg/kg·d for 21 d). These later ages (17.8 and 18.3 months) correspond to the approximate age of the first sustained increase in daytime LH in OVX females from our colony (12). Thus, this approach allowed us to compare diurnal LH and FSH secretion before and after ovariectomy in prepubertal females and how these patterns were affected by low-dose replacement. However, given limitations on serum volumes, FSH was analyzed only in samples collected at –21, – 7, +14, +28, and +41 d (d 10 of estradiol treatment) from ovariectomy.

A second cohort of females who were not OVX (INT, n = 7) was used to compare diurnal hormone secretion during the prepubertal period to that observed in the OVX females. Diurnal samples (1000, 1030, 2200, and 2230 h) were obtained in this subset of animals at 13.5 months and again at 18 months of age.

Blood samples were obtained from unanesthetized females who had been habituated to the handling procedures. Previous studies show that these procedures in acclimated subjects do not compromise growth, puberty, or reproductive function (19, 20, 21). Serum was harvested and stored at –20 C until analysis. Estradiol was measured in selected samples using a modification of a commercially available kit (Diagnostic Products Corp., Los Angeles, CA). Using 100 µl serum, the assay has a sensitivity of 5 pg/ml. The intra- and interassay coefficients of variation (CV) are 5.2 and 11.1%, respectively. LH concentrations were determined using the mouse interstitial cell bioassay (22). The standard for the assay was the recombinant monkey LH (purchased from the National Hormone and Peptide Program, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, and Dr. A. F. Parlow, University of California-Los Angeles, Torrance, CA). Using 5 µl serum, the LH bioassay had a sensitivity of 0.20 ng/ml with intra- and interassay CV of 9.23 and 12.65%, respectively. The LH potency in the standards, control, and unknown samples was based on the production of testosterone in the incubates. Testosterone was determined using a commercially available RIA (Diagnostic Systems Laboratory, Webster, TX). FSH was determined by RIA using the homologous monkey assay reagents distributed by National Hormone and Pituitary Program, National Institute of Diabetes and Digestive and Kidney Diseases, and Dr. A. F. Parlow. Using 200 µl serum, the assay has a sensitivity of 0.5 ng/ml. The intra- and interassay CV are 4.2 and 10.9%, respectively. Because the FSH assay requires 200 µl serum in duplicate for maximum sensitivity and sample volumes were limited, samples collected from –21 through +41 d after ovariectomy for the OVX females and samples collected at 14 months for INT females were analyzed for FSH.

Date were expressed as mean ± SEM and were analyzed by ANOVA for repeated measures (SPSS version 11, SPSS Inc., Chicago, IL). Post hoc tests (Fisher’s least squared difference) were performed to determine how gonadotropin concentrations differed at specific time points for OVX females and between OVX and INT females. F values are listed with appropriate degrees of freedom expressed for each test lists as subscripts. To provide a better estimate of morning or evening hormone concentrations, the 1000- and 1030-h samples were averaged as were the 2200- and 2230-h samples. Statistical tests with P < 0.05 were considered significant.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
For OVX females, serum estradiol was below the sensitivity of the assay (<5 pg/ml) before ovariectomy (d –21 and –7) and after ovariectomy during assessments when estradiol was not replaced (d +14, +28, and +145). Estradiol replacement at approximately 14 months of age produced serum concentrations of 31 ± 8 and 14 ± 5 pg/ml on d 10 and 25 after estradiol replacement, respectively (corresponding to assessments days from ovariectomy of +41 and +56). Subsequent replacement with estradiol for the assessment on d +160 produced serum levels of 40 ± 6 pg/ml. Serum estradiol for INT females was 17 ± 4 and 26 ± 7 pg/ml at 13.5 and 18.3 months, respectively.

Serum concentrations of bioactive LH varied significantly between morning and evening samples across the assessment periods for the OVX females (Fig. 1; F_(7,42) = 18.55; P < = 0.01), with evening values consistently elevated above those in the morning [F_(1,6) = 28.96; P < 0.01]. Morning LH concentrations did not significantly increase from pre-OVX levels until some 145 d after ovariectomy, corresponding to 17.8 months [F_(7,42) = 20.15; P < 0.01]. Concentrations were not significantly different before ovariectomy compared with values observed immediately after ovariectomy (d +14 and +28) and 10 and 25 d after the initiation of estradiol treatment (d 41 and 56, respectively). By d 145, morning LH values had risen significantly compared with all previous morning vales. Subsequent assessment at d 160 during estradiol replacement revealed LH concentrations were significantly reduced compared with d 145; however, values were nonetheless higher than previous morning concentrations.

View larger version (12K): [in this window] [in a new window]   FIG. 1. Mean ± SEM bioactive LH concentrations in serum for OVX females before and after ovariectomy obtained from samples collected in the morning (AM, mean of 1000 and 1030 h; open bar) and evening (PM, mean of 2200 and 2230 h; closed bar). Estradiol was administered 10 d before the assessment on d 48 and 161. Morning time points with a different letter (x, y, or z) and evening time points with a different letter (a, b, or c) are significantly different from one another (P < 0.05).

The comparison of bioactive LH levels from OVX females with those of INT females at 13.5 and 18.3 months of age further shows the importance of ovarian estradiol. In the absence of estradiol replacement for the OVX females, serum LH varied significantly depending on time of day and age [Table 1; F_(1,12) = 4.98; P = 0.04]. Post hoc analyses revealed that morning concentrations were not different between OVX and INT females at 13.5 months but were significantly elevated in OVX compared with INT females in evening samples at 14 months and in both morning and evening samples at 18.3 months of age (P < 0.05). In contrast, LH concentrations were not significantly different at either age or time of day between INT females and OVX females treated with estradiol [F_(1,12) = 0.16; P = 0.69].

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The results of the present study clearly show that the prepubertal ovary restrains gonadotropin secretion in the female monkey. These data extend previous studies (10, 17) by using animals as their own control and assessing diurnal gonadotropin secretion in the weeks surrounding prepubertal ovariectomy in the presence and absence of estradiol replacement. These data support the hypothesis that, for the female, the developmental rise in diurnal gonadotropin secretion is controlled by a gonad-independent mechanism as well as a gonadal negative feedback inhibition.

The data support previous observations from monkeys (5, 10, 11, 17) as well as children (23, 24, 25, 26) that there is a distinct diurnal rhythm in gonadotropin and GnRH secretion (27) during development with nocturnal levels increasing before elevations in daytime concentrations. In the present study, prepubertal ovariectomy resulted in an immediate (within 14 d) elevation in nocturnal but not morning concentrations of LH and FSH. By 145 d after ovariectomy, or approximately 17 months of age, evening and morning concentrations of both LH were significantly higher than concentrations seen immediately after surgery. Unfortunately, sample volumes were insufficient to assay FSH at these later ages. This reflects the developmental drive of the nongonadal mechanism regulating gonadotropin and by inference GnRH secretion (13). Previous data of OVX monkeys show that both morning and evening concentrations of LH further increase through 24 months of age (28), the approximate age of menarche in gonadally INT females from our colony (12, 19, 28). After this age, morning values are similar to those observed in agonadal adult females (12).

Estradiol replacement within 2 months of ovariectomy returned evening levels to presurgical values and to those observed in gonadally INT, age-matched females, whereas a similar treatment some 5 months later suppressed both morning and evening LH but not to the degree seen at an earlier age. The diurnal pattern of LH at this later developmental age in estradiol-replaced females again matched that of gonadally INT controls. The estradiol replacement to the OVX females produced serum levels slightly higher than the age-matched gonadally INT controls. The values for the INT females are similar to those published previously (11, 19). Despite the difference, the serum estradiol concentrations produced by the replacement therapy were still within the physiological range of premenarchial female rhesus monkeys. Although LH values at 14 months after estradiol replacement were at or near the sensitivity of the bio-LH assay, LH concentrations at 18 months in response to estradiol were not. Thus, higher, less physiological levels of estradiol than those attained in the current protocol would have likely suppressed LH further and below that observed in gonadally INT controls.

The observation that estradiol restrains gonadotropin secretion in early juvenile females contrasts conclusions reached assessing developmental changes in GnRH release into the stalk-median eminence (13, 15). Ovariectomy of females defined as prepubertal does not increase GnRH release in either morning or evening samples, whereas it does in older, more adolescent females, and this is most evident in evening samples (13). Based on these observations, it was inferred that the ovary was unimportant at this age. We reached the same conclusion in previous assessments of morning LH concentrations (12, 29), as have others (6, 11), and would have done so again in the present study if only daytime samples had been evaluated. Importantly, the effect of ovariectomy at these young ages is only evident in evening samples, whereas it produces increases in both morning and evening concentrations at older developmental ages (10, 11, 17). It is difficult to reconcile data on GnRH release after ovariectomy of young female monkeys with those on gonadotropin release from this and other studies (6, 10, 17). Approaches are different (chaired monkeys for GnRH measurement vs. freely mobile monkeys). Furthermore, given the vast individual differences in rates of maturation of monkeys housed in different environments (19), sampling groups of monkeys at a specific age does guarantee homogeneity of the data. Nevertheless, data from children (23, 24, 25, 26) clearly show that developmental increases in gonadotropin secretion emerge initially in evening samples, an observation evident in data from the estradiol replacement conditions and gonadally INT females in the present study and in previous experiments with monkeys (11, 28). Although this pattern has been attributed to a diurnal change in estradiol secretion from the prepubertal ovary (23, 24), the observation that this pattern is present in OVX monkeys receiving constant estradiol replacement suggests that the neuroendocrine drive to GnRH and, thus, gonadotropin secretion is greater at night than during the morning. This is not to say that a diurnal rhythm in low concentrations of estradiol in young females is not important but may operate more to reduce the absolute concentrations of gonadotropins in both the morning and evening.

The mechanism by which nocturnal gonadotropin secretion merges initially at night is not fully understood. The marked diurnal difference is age dependent because LH secretion is greater at night than during the day in girls going through puberty compared with adult females, independent of ovarian estradiol secretion (30). The emergence of nocturnal gonadotropin secretion during development in children is sleep entrained (31). In adults, sleep, regardless of the time of day, augments GH and LH secretion but does not alter the circadian pattern of cortisol secretion in young men (32). Sleep slows LH pulses and increases the amplitude of the pulse during the early follicular phase in women (33). However, this increased amplitude during sleep appears to be unrelated to any change in pituitary responsiveness to GnRH (34). Because GnRH mRNA expression does not vary by time of day during puberty in female rats, the diurnal rhythm of GnRH is likely the result of posttranslational effects or factors regulating GnRH release (35). The association between sleep and gonadotropin secretion, particularly during development, suggests a functional link between neuroendocrine control mechanisms, activity cycles, and, thus, energy homeostasis (33). Food intake to maintain energy balance is obviously tied to sleep-wake cycles but is driven by a complex coordination of orexigenic and anorexic peripheral and central peptides and neurotransmitters (36). The nocturnal emergence of gonadotropin secretion in the diurnal primate may be more a consequence of developmental changes in these factors that alternate between cycles of vigilance—food intake and rest. Developmental increases in nocturnal leptin secretion (37, 38), reflecting increasing fat mass (39, 40), have been suggested to be one such signal (39). Daily late-afternoon administration of leptin to prepubertal female monkeys increases both morning and evening circulating leptin concentrations and advances the developmental increase in both morning and evening bioactive LH concentrations (28). Although the role of leptin in primate puberty is controversial (41), it is possible that this metabolic signal directly (42, 43) or indirectly, perhaps by a suppression of NPY (7, 44, 45), may be responsible for the initial augmentation of nocturnal followed by enhanced daytime gonadotropin secretion. Studies to clarify these questions are difficult in primates and must take into consideration food intake, activity cycles and energy expenditure, and corresponding diurnal changes in metabolic hormones.

A limitation of the approach used in the present study is the reliance on dual morning and evening rather than frequent samples to assess how ovariectomy and estradiol replacement affect the diurnal secretion of gonadotropins in young females. Although assessment of episodic hormone secretion patterns yields significant information on how gonadotropin secretion is regulated (17, 46), the data derived from the present study nonetheless provide evidence of the importance of the ovary and estradiol in the juvenile regulation of gonadotropin secretion. A longitudinal assessment of the nongonadal drive and response to estradiol-negative feedback from birth through the age coincident with the attainment of fertility begs to be done. Cross-sectional or between-group comparisons will not provide the same answers given inherent individual differences in development and patterns of gonadotropin secretion (29, 47, 48). These data underscore the notion that, for the female puberty, onset, at least in terms of gonadotropin secretion, is a misnomer and that puberty reflects a progression in multiple control mechanisms that ultimately time the attainment of fertility.

	Acknowledgments

	Footnotes

 
This work was supported by NIH Grant HD37583 and, in part, Grant RR00165.

Abbreviations: CV, Coefficient(s) of variation; INT, gonadally intact; OVX, ovariectomized.

Received January 30, 2004.

Accepted April 27, 2004.

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Top Abstract Introduction Subjects and Methods Results Discussion References

 

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