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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 5 2275-2280
Copyright © 2004 by The Endocrine Society

The Ontogeny of Pulsatile Growth Hormone Secretion and Its Temporal Relationship to the Onset of Puberty in the Agonadal Male Rhesus Monkey (Macaca mulatta)

K. J. Suter

Department of Biology, Emory University, Atlanta, Georgia 30322

Address all correspondence and requests for reprints to: Kelly J. Suter, Ph.D., Department of Biology, Emory University, Rollins Research Center, 1510 Clifton Road, Atlanta, Georgia 30322. E-mail: ksuter{at}learnlink.emory.edu.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The pubertal amplification of GH secretion in primates has been thought to reflect an increase in gonadal steroid hormones due to gonadotropin stimulation induced by hypothalamic GnRH release. Previous studies in agonadal, peripubertal, male rhesus monkeys have estimated the age of GnRH activation (defined as d 0) using analyses of nocturnal, pulsatile LH patterns derived from sequential blood samples. Using samples from these earlier studies, secretory patterns of GH were analyzed using Cluster at approximately 30-d intervals in the youngest prepubertal ages and at approximately 10- to 20-d intervals in the period immediately preceding and following the onset of puberty. Pulse frequency, amplitude, and mean GH increased significantly between early prepubertal ages (up to 30 d before d 0) and the late prepubertal period (between –20 d and d 0). Pulsatile GH activity increased earlier than pulsatile LH secretion in four of five animals. These findings support the conclusion that pulsatile GH secretion increases developmentally in the absence of gonadal steroids. Furthermore, the present observation that the developmental increase in GH secretion occurs earlier than previously reported is consistent with the possibility that GH itself either directly or indirectly participates in the pubertal reinitiation of GnRH pulse generator activity.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
SEXUAL MATURATION AND somatic growth are temporally related phenomena in human development. In children, sexual maturation occurs in response to an amplification of hypothalamic GnRH release, stimulating a corresponding increase in pulsatile gonadotropin secretion with subsequent activation of the gonads and the production of sex steroids (1). A similar, centrally mediated sequela takes place in the rhesus monkey, a representative higher primate. Studies of female monkeys indicate that the amplitude of GnRH pulses from the stalk-median eminence increases whereas the interpulse interval decreases from prepuberty to puberty in females (2). Furthermore, using pulsatile secretory patterns of pituitary LH as an index of hypothalamic GnRH release, the onset of puberty in male monkeys is characterized as an increase in GnRH from low, infrequent pulses (less than one per 7 h) to more frequent and perhaps higher amplitude pulses (two to five per 7 h) (3). Thus, increased discharge of GnRH is a necessary step for the initiation of puberty (4), a process that in the male monkey occurs largely independently of the gonad (5).

In contrast, the underlying neuroendocrine mechanism that results in the developmental increase in GH secretion is less well understood. It is clear that circulating levels of GH increase with advancing pubertal stage, as mean levels of GH are greater during late puberty than during prepuberty in both boys and girls (6, 7, 8). This pubertal increase in GH secretion is attributed to an enhancement of GH pulse amplitude (9, 10, 11) that may be initially limited to the evening hours (12, 13).

Moreover, the increase in GH secretion at the time of puberty is widely accepted to depend upon rising levels of gonadal steroids. For example, data derived primarily from cross-sectional studies indicate that the shift in amplitude of GH pulses is associated with increasing concentrations of gonadal steroids (7, 9, 10, 14, 15, 16). Several studies (17, 18, 19), but not all (20, 21, 22), report decreases in GH in girls with Turner’s syndrome, an effect reversed by the administration of ethinyl estradiol (23). Similarly, treatment of normal children with tamoxifen, a selective estrogen receptor antagonist, decreases GH levels (24). Taken together, these findings suggest that the increase in GH secretion at the time of puberty in children is due in large part to an increase in the activity of the gonad.

In contrast, little is known about GH secretion during the prepubertal interval and about developmental changes in GH in the absence of gonadal steroids. Data from female monkeys indicate that GH release increases developmentally in ovariectomized animals, albeit to a lesser degree than observed in estradiol-replaced animals (25, 26). Furthermore, a previous analysis indicates that mean circulating concentrations of both GH and IGF-I are significantly increased before the onset of puberty in agonadal male monkeys (27). However, the precise temporal relationship among puberty onset, the developmental increase in GH secretion, and the role of the gonad in this process remains unclear.

The purpose of the present study was to measure pulsatile GH secretion in agonadal male monkeys and to determine the relationship of this hormone’s secretory patterns to the onset of puberty.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals

Five male rhesus monkeys (Macaca mulatta) born at the Center for Research in Reproductive Physiology, University of Pittsburgh, were bilaterally orchidectomized between 12.5 and 20 months of age. Animals were maintained in accordance with the NIH Guide for the Care and Use of Laboratory Animals. All procedures were approved by the institutional animal care and use committee at University of Pittsburgh. Daily care of the animals, surgical procedures (e.g. castration and catheter placement), and use of the GnRH-sensitized pituitary as a bioassay for episodic GnRH release have been previously described (3).

Experimental protocol

To determine the developmental changes in GH secretion associated with the onset of puberty, 53 series of sequential blood samples previously analyzed for LH pulses (3) were used to determine GH secretory profiles. These series were drawn from sample collections performed at 10-d intervals from approximately 20–35 months of age, except for one animal (monkey 2456) in which sampling was performed at 20-d intervals. In two animals (no. 2288 and 2289), sampling was also performed monthly at earlier prepubertal ages, beginning at 14 months. Each series consisted of sequential blood samples (0.8 ml) collected at 12-min intervals for 7 h (1900–0200 h). LH pulses were identified using the pulse detection program Pulsar (28), and the onset of puberty (d 0) was defined using an algorithm designed to detect the initiation of a developmental increase in hypophysiotropic drive to the gonadotrophs (3). Details of the pubertal increase and progression of pulsatile LH secretion using these samples have been previously reported (3).

Developmental changes in pulsatile GH secretion were examined in relation to the previously determined LH profiles obtained from the same samples. Developmental periods were defined in relation to LH d 0: early prepubertal (from the earliest assessments at approximately 14 months of age up to 30 d before d 0), late prepubertal (between –20 d and d 0), and postpubertal (after d 0). Because sample volumes at some of the younger ages had been depleted by the previous assays, our assessment of GH was performed, in general, at 30-d intervals in the youngest ages (up to ~20 months of age) and at 10- to 20-d intervals in the period immediately preceding and following the onset of puberty (i.e. d –50 through d 50 relative to d 0 as defined above). Mean concentrations of GH using these samples have been previously reported (27).

Assays

Plasma that had been frozen for approximately 3 yr was assayed for GH using a commercially available kit (Diagnostic Products Corp., Los Angeles, CA). The intra- and interassay coefficients of variation were 3.8% and 10.6%, respectively.

Data analysis and statistics

GH pulses were detected and evaluated for frequency and amplitude using Cluster (29), with t values selected for a constant false positive error rate of 1% on both up- and downstrokes and a cluster size of one for both peaks and nadirs. Series in which GH pulses were not detected were excluded from the calculation of group average amplitudes.

GH pulse parameters were compared between age groups using t tests. Calculated hormone maturation indexes for LH and GH were compared using Mann-Whitney U tests. Differences were considered statistically significant at P < 0.05. The Pearson correlation coefficient was determined between LH and GH levels within animals across development and on d 0.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Nocturnal patterns of circulating GH levels in two representative castrated male monkeys from the midprepubertal period until the late peripubertal phase of development are shown in Fig. 1Go. Average concentrations of GH before 23 months of age in the first animal ranged from 0.65–1.85 ng/ml. In the second animal, average concentrations ranged between 1.4 and 4.1 ng/ml. Developmental increases in GH were observed at 23.3 and 28.6 months of age, before the onset of puberty (d 0 = 24.1 and 28.9 months of age), as previously assessed with an algorithm that used LH concentrations in the same samples (3). During this peripubertal transition in the first animal (23.3–24.1 months of age), mean levels of GH rose to an average of 3.4 ng/ml. A corresponding increase in the frequency of GH pulses was also observed during this transition, from no detectable pulses at earlier ages to an average of 4.3 pulses/7 h. GH pulse amplitude remained stable during this interval, ranging from 4.4–5.2 ng/ml. In the second animal, mean levels of GH shifted from an average of 2.4 ng/ml during the early prepubertal period to 6.1 ng/ml at 28.6 months of age. An increase in amplitude, as opposed to frequency, was more prominent in this animal.



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  		FIG. 1. Developmental progression of nocturnal, episodic patterns of GH and LH in two agonadal male monkeys (no. 2288 and 2289) in which enhanced pituitary responsiveness to GnRH had been established and subsequently sustained between sampling periods with an intermittent iv infusion of synthetic GnRH. Asterisks indicate increments in circulating hormone concentrations identified as significant peaks by Cluster (GH) or Pulsar (LH). The onset of puberty (d 0) was defined by an algorithm designed to detect the initiation of increased hypophysiotropic drive to LH secretion. These animals were bilaterally orchidectomized at 13 months of age, and priming was initiated 2 wk later. LH data shown for ages 21.0–24.3 months for the first animal have been reproduced from Ref.3 with permission (1998, ©The Endocrine Society). In this animal, d 0 was 24.1 months of age; in the second animal, d 0 was 28.9 months of age.

 
LH pulses in the first animal (Fig. 1Go) occurred only rarely up to 23.3 months of age, increased slightly at 23.7 months, and then appeared to be firmly established by 24.1 months of age (d 0), after which their frequency and amplitude continued to rise. Likewise, in the second animal, LH pulses were limited before d 0. Episodic secretion emerged at 28.9 months of age.

Profiles of nocturnal GH concentrations in three other monkeys are shown in Fig. 2Go. In two animals, an established secretory pattern of GH increased in frequency and amplitude before d 0 (Fig. 2Go, top and middle profiles). These animals, like that in Fig. 1Go, are representative of four (of five) of the monkeys examined, in which pulsatile patterns of GH were unambiguous before d 0. In the fifth animal, episodic GH secretion was observed before d 0, but did not appear to increase with development at the ages studied (Fig. 2Go, bottom).



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  		FIG. 2. Progression of episodic GH in three agonadal male monkeys (top, no. 2207; middle, no. 2219; bottom, no. 2456) immediately before d 0. Chronological ages for d 0 in these animals were 24.5 months (no. 2207), 25.5 months (no. 2219), and 27.9 months (no. 2456). LH data for ages 21.6–23.5 months for the first animal and 25.1 and 25.5 months for the second animal have been reproduced from Ref.3 with permission (1998, ©The Endocrine Society).

 
Developmental changes in GH pulse frequency, pulse amplitude, and mean concentrations are summarized in Fig. 3Go. At late prepubertal ages (–20 d until d 0), average values for these parameters of pulsatile secretion were significantly higher than those observed during the early prepubertal period. These significant increases were sustained into the postpubertal period for GH pulse amplitude and mean concentration. Developmental increases in LH and GH were correlated across development (r = 0.235) and on d 0 (r = 0.383).



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  		FIG. 3. Composite of developmental changes in average GH pulse frequency, amplitude, and mean integrated GH concentrations. Data from the five individual agonadal monkeys were aligned to d 0, which marks the onset of puberty (see Fig. 1Go). Developmental periods were then defined in relation to d 0: early prepubertal (from ~14 months of age to 30 d before d 0), late prepubertal (between –20 d and d 0), and postpubertal (after d 0). The number of observations for each period varies from 5–13 for pulse amplitude and 9–15 for pulse frequency and mean concentrations. Asterisks indicate significant differences from the early prepubertal period (P < 0.05). Data for early prepubertal period are based on 16 sample series (2–4 per animal). Data for late prepubertal period are based on 15 sample series (3 per animal). Data for postpubertal period are based on 23 sample series (3–5 per animal).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Notwithstanding the absence of gonadal steroids, peripubertal secretory patterns of pituitary LH and hypothalamic GnRH are known to occur with normal timing in castrated monkeys (3, 5). Thus, the initial shift in neuroendocrine activity that drives the developmental increase in GnRH release appears to be largely unaffected by the absence of the gonad. By extension, it is reasonable to regard the GH secretory patterns observed in the present study as reflecting the developmental progression of steroid-independent mechanisms that control pituitary GH secretion during the peripubertal period. Accordingly, the present findings support the conclusion that pulsatile GH secretion increases developmentally in the absence of gonadal steroids.

The observed timing of this progression suggests that steroid-independent GH secretion may actually precede GnRH and LH release. For four of five animals, visual inspection of nocturnal patterns of LH and GH suggests a strong tendency for pulsatile GH activity to increase earlier than pulsatile LH activity. This is consistent with our previous analysis of average plasma GH concentrations in these animals (27).

In contrast, earlier studies in children support the idea that the increase in GH secretion is a postpubertal event in girls (6, 7) and boys (9) and have lead to the conclusion that the pubertal amplification of GH secretion reflects the earlier activation of the pituitary-gonadal axis. The findings of the present study challenge this idea by demonstrating an unambiguous rise in GH secretion in castrated animals around the time when puberty onset would have occurred had the animals remained gonad-intact. These findings suggest that a shift in the hypothalamic control of episodic GH secretion occurs before or near the time of the pubertal reawakening of the GnRH pulse generator. Although it is difficult to temporally define the onset of puberty with absolute accuracy, the technique employed in these studies, using the GnRH-sensitized pituitary in castrates, detects hypothalamic secretion of GnRH at ages consistent with known ages of puberty onset in gonad-intact animals (3) and thus provides a reasonable index of the earliest secretory activity in this system for longitudinal and contemporaneous hormone analysis.

Studies in children have suggested that the increase in GH secretion at the time of puberty is principally an amplitude-modulated event (6, 10). However, the present findings in agonadal rhesus monkeys reveal a clear acceleration of the frequency of GH pulses in addition to rises in amplitude. Whereas previous studies have examined GH secretion in the adult rhesus monkey (30, 31, 32), developmental data in nonhuman primates of the type presented here are unavailable. One study in gonad-intact male monkeys found a nocturnal slowing in GH pulse frequency between young and aged male monkeys (33). Thus, developmental changes in GH secretion may be both frequency and amplitude modulated. The subsequent actions on pulsatile GH release of rising concentrations of steroid hormones during puberty remain to be clarified. Gonadal steroids presumably modulate and amplify pituitary and hypothalamic control mechanisms that, based upon the present study, appear to already be active at the onset of puberty.

The finding of a gonad-independent, developmental augmentation of episodic GH release, particularly the observed increase in GH pulse frequency, suggests the participation of hypothalamic control mechanisms. Hypothalamic neurotransmitters such as neuropeptide-Y (34, 35), glutamate (36, 37, 38), and {gamma}-aminobutyric acid (38, 39, 40) have been implicated in the pubertal activation of GnRH release, but their roles in GHRH release are unknown. The temporal lag in the onset of GnRH output relative to GHRH output observed in the present study might reflect different properties of the separate populations of neurosecretory cells. Electrophysiological studies in single neurons indicate that GHRH-containing neurons express repetitive action potentials (the mode of firing that facilitates neuropeptide release) (41) in response to brief injections of depolarizing current (42). In contrast, GnRH neurons exhibit only single action potentials in response to brief injections of current (43). Thus, in response to the same stimulatory input, GHRH neurons would be more likely to release their peptide product than GnRH neurons. Finally, the observation that the developmental increase in GH secretion occurs much earlier than previously reported is consistent with the possibility that GH itself either directly or indirectly participates in the pubertal reinitiation of GnRH pulse generator activity.


   Acknowledgments
 
All experimental components of this study were undertaken in the laboratory of Dr. Tony M. Plant. I acknowledge the expert technical assistance of Deborah Bolette, Deborah Berger, and the staff of the Primate Core of the Center for Research in Reproductive Physiology, University of Pittsburgh. I am grateful to Drs. Johannes D. Veldhuis and Michael L. Johnson for generously providing the Cluster program to Clifford R. Pohl of Duquesne University, who performed the pulse analysis for this study and earlier studies using these samples. Assays of LH used to define the onset of puberty were performed by the Assay Core of the Center for Research in Reproductive Physiology, University of Pittsburgh. Assays of GH were performed by the Assay Services Core at Yerkes Primate Research Center. Dr. Vernon L. Gay and Ms. Wendy Bell (Department of Cell Biology and Physiology, University of Pittsburgh) facilitated the transfer of samples to Yerkes Primate Research Center.


   Footnotes
 
This work was supported by National Institutes of Health Grants HD-13254, HD-08610, HD-16305 (to Tony M. Plant) and HD37583 (to M.E.W.), and RR-00165 (to the Yerkes Primate Research Center).

Received November 21, 2003.

Accepted February 18, 2004.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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