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Department of Anatomy and Neurobiology and The Animal Reproduction and Biotechnology Laboratory (K.J.S.), Colorado State University, Fort Collins, Colorado 80523; School of Health Sciences (C.R.P.), Duquesne University, Pittsburgh, Pennsylvania 15282; and Yerkes Primate Research Center (M.E.W.), Emory University, Lawrenceville Georgia 30043
Address correspondence and requests for reprints to: Mark E. Wilson, Yerkes Primate Research Center of Emory University, Field Station, 2409 Taylor Lane, Lawrenceville, Georgia 30043. E-mail: Markw{at}rmy
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(12, 13) within the mediobasal
hypothalamus (MBH). Despite our understanding of these putative
neurobiological mechanisms, the factor(s) responsible for the
developmental change in the nature of neurochemical inputs controlling
GnRH release in situ are not known (14). Factors that regulate and/or emanate from the rapid increments in skeletal and ponderal growth at the transition to puberty may be important in regulating the onset of puberty (15, 16, 17). These findings have lead to the so-called "somatometer" hypothesis, suggesting that a central growth-tracking device that is sensitive to circulating peripheral growth-related cues might underlie the increase in GnRH release at puberty (16). Two such growth-derived signals, leptin and insulin-like growth factor I (IGF-I), are leading candidates to regulate the developmental increase in GnRH secretion (17). Importantly, an increase in these growth-derived signals must be shown to be a prepubertal event independent of gonadal influence, temporally preceding the developmental increase in gonadotropin secretion, and the direct manipulation of these signals must alter the timing of the onset of puberty.
With respect to leptin, the prevailing hypothesis is that a developmental increase in leptin secretion initiates puberty by signaling the brain that energy stores are sufficient to support reproduction (18, 19, 20, 21, 22, 23). Indeed, maturational stage is a better predictor of serum leptin levels than chronological age (24). However, data obtained thus far on the role of leptin-initiating mammalian puberty are equivocal. Puberty is accelerated by leptin treatment to fed-mice in some studies (25, 26) and is normalized in diet-restricted rats (27). Moreover, studies of juvenile monkeys have failed to define a temporal relationship between daytime leptin levels and LH (28) or testosterone (29).
The GH axis has also been implicated in regulating puberty (15, 16). GH deficiency delays puberty (30), whereas GH therapy normalizes the progression of puberty (31, 32). In addition, GH-induced hepatic expression of IGF-I in rats increases before puberty, resulting in an increase in IGF-I messenger RNA (mRNA) in the median eminence (33). Moreover, bone age better predicts the timing of menarche than does chronological age (34), suggesting a link between bone development and sexual maturation. Although some studies report that IGF-I infusion does not affect puberty onset in female rats (35), intracerebroventricular administration of IGF-I increases serum LH via GnRH and initiates puberty in juvenile rats (33). However, it is believed that the endogenous developmental increases in GH-induced IGF-I secretion are caused, at least in part, by the maturational rise in gonadal secretion (36, 37), implying that any elevation in the GH axis occurs after the onset of puberty. In contrast, data from agonadal female monkeys has demonstrated that although estradiol augments the developmental increase in GH and IGF-I release, serum concentrations do increase developmentally in the absence of estradiol (38, 39). Accordingly, the precise relationship between increases in GH, IGF-I, and onset of puberty remains unclear.
To better understand the potential relationship between these growth-derived signals and the onset of puberty, the present analysis examined the hypothesis that the developmental increase in circulating leptin and/or GH and IGF-I levels occurs before the onset of puberty, defined as the increase in nocturnal pulsatile LH secretion. This hypothesis was tested by examining samples for leptin, GH, and IGF-I that were collected as a part of another study that clearly defined the onset of puberty in juvenile male rhesus monkeys (40). The same mechanism that results in the onset of the pubertal rise in LH secretion observed in the present study in agonadal animals likely is responsible for the reactivation of the hypothalamic-pituitary-testicular axis in intact animals.
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Materials and Methods |
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Samples from five agonadal male rhesus monkeys (Macaca mulatta) in which the time of the pubertal increase in pulsatile LH release had been previously determined (40) were analyzed. For the study, animals were maintained in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Surgical procedures, daily care, and collection of blood samples from these chronically catheterized animals has been described in detail (40). To define the age of the pubertal increase in GnRH release, the animals received an intermittent infusion of GnRH to sensitize the pituitary to endogenous stimulation. In four subjects, samples were taken at 10-day intervals, whereas in one subject samples were collected every 20 days. At each sampling, samples were collected every 12 min from 1900–0200 h after the GnRH infusion had been temporarily interrupted for 96 h. Because the same mechanism that results in the activation of the pituitary-gonadal axis in intact animals likely results in the increase in LH secretion observed in agonadal animals, for purposes of analysis and discussion such changes are referred to as "pubertal." Accordingly, samples were analyzed for LH, and an algorithm (based on developmental changes in mean levels of LH) was used to define the onset of puberty or day 0 (40). With the exception of one male, morning samples (1000 and 1030 h) and evening samples (2200 and 2230 h) were also obtained 36 and 48 h, respectively, after the interruption of GnRH infusion.
Plasma concentrations of leptin were determined in the morning and evening samples obtained before the collection of the sequential samples. If the evening samples were not available, the 2200-h sample from the sequential bleeds was used. Leptin was measured using a primate-specific RIA (Linco Research, Inc., St. Charles, MO). The assay has a sensitivity of 0.50 ng/mL using 100 µl of sample. The intra-assay and interassay coefficient of variation (CV) were 5.2% and 11.1%, respectively. Plasma concentrations of IGF-I were determined in the evening samples or, if not available, the morning samples. Although concentrations of IGF-I decrease after the morning meal, differences between morning and evening samples are less than 8% (M. E. Wilson and S. Lackey, unpublished observations). Total IGF-I levels were measured using a previously validated RIA following removal of IGF binding proteins (41). The assay has a sensitivity of 50 ng/mL using 0.25-µL equivalents of sample. The intra-assay and interassay CV were 4.1% and 12.1%, respectively. GH concentrations were determined in the sequential nocturnal samples. Since these samples had been assayed previously (40), volumes were limited. Consequently, some of the early (<day -40) and later age points (>day +30) were not available for every subject. The assay was performed using a commercially available kit (Diagnostic Products Corp. Los Angeles, CA). The intra-assay and interassay CV were 3.8% and 10.6%, respectively. For the purpose of the present analysis, the mean GH level across each sequential bleed was determined for each animal.
Data were aligned to the onset of puberty, day 0, in 10-day increments from day -60 through day +50 for IGF-I and leptin. Sample volumes at the youngest ages, however, were limited for the GH assay. Therefore, GH data are expressed in 10-day increments from day -20 onward and 20-day increments before day -20. Data were expressed as mean ± SEM. Data were grouped in three intervals for analysis: early prepubertal (EPP) (day -60 through Day -40), late prepubertal (LPP), and postpubertal (PP) [day 0 through day +40 (GH) or 50 (leptin and IGF-I)]. The LPP interval is the period in which the acceleration of nocturnal LH pulse frequency seems to be initiated (40). All animals contributed data points to the analysis of these interval data. Given the small sample size, overall developmental changes were evaluated with the Friedman nonparametric statistic, which tests the hypothesis that the values come from the same population. To test the hypothesis that these growth-related signals increased before puberty, concentrations from the EPP were compared with the LPP period, whereas concentrations from the LPP were compared with either the EPP or PP using paired t tests or Wilcoxon matched pair tests. Statistical values having a probability of 0.05 or less were considered significant.
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Results |
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. Daytime leptin concentrations (ng/mL)
decreased significantly (Friedman statistic, P = 0.02)
from the EPP interval (0.88 ± 0.08) to the LPP interval
(0.70 ± 0.04; P = 0.04, Wilcoxon test). However,
this difference was not significant when evaluated with a t
test (t3 = 2.36). After the onset of puberty,
daytime leptin concentrations (PP; 1.17 ± 0.20) were similar to
values observed during the EPP (t3 = 1.07 or
Wilcoxon P = 0.34). In contrast, nocturnal leptin
concentrations (ng/mL) increased significantly from the EPP (0.82
± 0.10) to LPP period (1.23 ± 0.16; Friedman statistic,
P = 0.02 and t4 = 4.31). This
prepubertal elevation in nocturnal leptin was sustained following
puberty (1.90 ± 0.47) with values statistically similar between
LPP and PP (t4 = 1.25). The developmental change
in nocturnal leptin showed large individual variations (e.g.
one animal’s values ranged from 0.78–2.64 ng/mL, whereas another’s
ranged from 0.60–7.15 ng/mL. Consequently, individual mean
concentrations during LPP and PP were also expressed as the
percentage change from EPP (Fig. 2). The percentage change in daytime
leptin from EPP to LPP was significant (t3 =
2.76), and the change from EPP to PP was not significant
(t3 = 1.18). Importantly, the percentage
increase in nocturnal leptin from EPP to LPP and from EPP to PP was
significant (t4 = 4.39; t4
= 3.42, respectively), whereas the change from LPP compared to that of
PP was not significant (t4 = 1.39). Finally,
daytime values (ng/mL) of leptin (0.92 ± 0.07) were significantly
lower than nocturnal concentrations (1.60 ± 0.33;
P = 0.04, Wilcoxon test).
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. There was a significant increase in
mean nocturnal GH concentrations from prepuberty through the
postpubertal period (Friedman statistic, P = 0.02). GH
levels (ng/mL) increased significantly from the EPP (1.20 ± 0.10)
to the LPP interval (2.15 ± 0.36; t4 =
3.42), and this increase was sustained through the PP period (2.50
± 0.76; t4 = 1.86). The developmental change in
circulating IGF-I concentrations also followed a similar pattern (Fig. 3; Friedman statistic, P = 0.00). Levels (ng/mL)
increased significantly from the EPP (178 ± 30) to the LPP
interval (238 ± 36), and this increase, too, was sustained
through the PP period (266 ± 26; t4 =
0.87).
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. Indicated in each panel are
concentrations of leptin, GH, and IGF-I at the same time points. These
data illustrate that all three growth-related signals increase prior to
the defined day of the onset of puberty.
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. Increments in weight did not
differ significantly between day -30 and day +40 (P =
0.52).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The identification of leptin has provided a mechanism to account for the long-standing hypothesis that puberty is initiated by an accumulation of body fat (42, 43). Accumulating fat mass during maturation results in an increased secretion of leptin from the adipocyte (44), and correlational studies in children suggest that a developmental increase in leptin secretion initiates puberty by signaling the brain that energy stores, composed in part by fat depots, are sufficient to support reproduction (18, 19, 20, 21, 22, 23). Although body fat was not measured in the present analysis, the subjects were actively growing and showed a significant increment in body weight from early prepuberty to the period prior to the increase in pulsatile LH secretion. Accordingly, the increase in leptin observed in the present study, may reflect changes in body composition.
The finding in the present study of a significant prepubertal elevation in nocturnal leptin levels supports the hypothesis that leptin may be an important signal to the brain for the initiation of puberty. Other analyses suggest that leptin acts as a gate, permitting puberty to proceed (45). Indeed, the first significant rise in leptin, when normalized to prepubertal levels, occurred at the time when the acceleration in LH pulse frequency seemed to be initiated (i.e. days -30 through -10; Ref. 40). Moreover, it is interesting that the robust increase in nocturnal leptin concentrations after the onset of puberty in the present study is associated with the transition to rapid, high amplitude LH pulses (40). Data from women (46) indicate that nocturnal pulsatile leptin secretion may induce and synchronize LH and, presumably, GnRH pulses. If this were the case, then the prepubertal and early postpubertal rises in leptin observed in the present study might also underlie a similar synchronization of GnRH release during this critical phase of development.
In contrast to the findings of the present study, previous studies of juvenile monkeys have not found a relationship between daytime leptin levels and LH (28) or testosterone (29). The discrepancy between these data and the present results may reflect methodological differences. In the one study (28), puberty was defined by the increase in daytime LH levels. However, the onset of puberty as assessed with nocturnal LH pulses by sequential sampling from a GnRH-sensitized pituitary, precedes the daytime increase as assessed from a single sample by as much as 5 months (40, 47). These data suggest that increases in daytime LH secretion do not accurately reflect, as do nocturnal estimates, the underlying hypothalamic event initiating puberty. Accordingly, reliance on daytime samples or down-stream gonadal responses (28, 29) may over-estimate the age of the onset of puberty and miss any transient changes in leptin secretion, such as those associated with puberty in boys (19).
The present study found a diurnal variation in leptin secretion during the 110 days surrounding the onset of puberty. This diurnal variation in leptin concentrations during the pre- and early pubertal period in the agonadal monkeys supports previous data from monkeys (28) in children (48, 49, 50). Other studies suggest that the diurnal leptin rhythm occurs independent of age and may be the result of the daytime pattern of food intake (51, 52); however, the absolute increase in leptin within this rhythm reflects the degree of sc fat (53). The absence of a more robust diurnal rhythm in the present study may reflect the limited number of animals and the high variability in leptin levels among individuals.
If, indeed, leptin is an important signal initiating puberty, the mechanism of action has yet to be defined. Leptin receptors are found in the lining of the third ventricle, as well as in the MBH, and are localized on NPY (54, 55, 56, 57) and opioid (55). Leptin receptors are expressed in a model GnRH neuronal system (i.e. GT1–7 cells; 56, 58), and leptin application in this system results in GnRH release (58). However, hypothalamic GnRH neurons do not express leptin receptors (55). Accordingly, it is likely that any effect of leptin on GnRH release is mediated through an intermediary system such as NPY neurons. In this regard, some data from monkeys suggest that NPY regulates GnRH after but not before puberty (59), whereas most recent data suggest that a diminution in NPY inhibition of GnRH cell bodies may be responsible for the transitional increase in GnRH at the onset of puberty (10, 11). The observation that leptin decreases NPY gene expression and activity in the MBH of rodents (60) provides a possible functional link in the prepubertal increase in leptin observed in the present study and the concomitant pubertal shift in episodic LH release (40). In contrast to a direct effect on neuromodulators, other evidence suggests that leptin may increase GnRH indirectly by increasing intracellular metabolic fuel oxidation within the MBH (17, 61), as well as insulin sensitivity and glucose utilization (62). Thus, it remains to be determined whether changes in diurnal leptin secretion drive diurnal changes in LH (and GnRH) and whether leptin stimulates LH secretion in prepubertal monkeys, regardless of degree of adiposity and metabolic fuel stores (17).
In addition to a significant prepubertal elevation in nocturnal leptin secretion, the present analysis also shows that nocturnal GH and IGF-I rise before the onset of puberty. Data from children indicate the developmental rise in GH-induced IGF-I secretion is a post-onset phenomenon, resulting from an increase of gonadal steroid secretion (36, 37). Previous data from ovariectomized monkeys indicate that GH and IGF-I levels increase developmentally and that estradiol replacement enhances this increase (38, 39). The present analysis unequivocally demonstrates that the rise in GH and IGF-I is a prepubertal event that occurs before the developmental increase in nocturnal LH secretion and is largely independent of gonadal influence. At this time, it is not known what accounts for this prepubertal increase in GH, which ultimately controls IGF-I release (63). Although differences in the regulation of GH pulsatility between prepubescent and pubertal children have been extensively investigated (see Ref. 64 for review), little attention has focused on the prepubertal interval itself. It is tempting to speculate that leptin may be involved as data from rodents suggest that leptin stimulates GH release in a number of contexts (65, 66). However, leptin may actually inhibit GH secretion in humans (67), analogous to other differences in metabolic regulation between rodents and primates (66). Consequently, the prepubertal increase in leptin and GH may not be causally linked. Finally, it is not clear what would account for the earlier pre-onset rise in IGF-I compared to GH observed in the present study. As previously noted, only limited plasma was available for GH analysis at the youngest age, preventing us from performing a robust analysis of this issue. It is likely that a prospective analysis of dedicated samples would show a coincident rise in pulsatile GH secretion and IGF-I during the prepubertal interval. A better understanding of what factors regulate prepubertal changes in GH and IGF-I secretion would not only elucidate their potential role in the onset of puberty but would also help account for the significant increments in skeletal growth and acquisition of bone mineral density that occur prior to puberty (16).
This prepubertal increase in GH and IGF-I secretion in male monkeys supports data from other species that this axis, in particular IGF-I, is important for the onset of puberty. GH-induced hepatic expression of IGF-I increases before puberty, resulting in an increase in IGF-I mRNA in the median eminence (33). Although some studies report that IGF-I infusion does not affect puberty onset in female rats (35), intracerebroventricular administration of IGF-I increases serum LH via GnRH and initiates puberty in juvenile rats (33). These effects are supported by other rodent studies indicating IGF-I stimulates GnRH from the median eminence in vitro (68), the expression of GnRH mRNA in cell cultures (69, 70), and increases process extensions of GnRH neurons and cell-cell contacts (71). A series of studies using a female monkey model indicates that a somatostatin analog delays age at first ovulation (72), whereas GH or IGF-I accelerates age at first ovulation (73, 74) by decreasing the sensitivity to gonadal negative feedback inhibition of LH secretion (75). Because these manipulations did not affect age at menarche, one could conclude that the GH axis may regulate the tempo of sexual maturation but not the onset of puberty. However, these treatments in monkeys were initiated at an age after the increase in GnRH pulsatility had likely occurred (76, 77). Manipulations of the GH axis at juvenile ages will produce a more definitive test of the hypothesis that IGF-I initiates puberty.
In conclusion, the findings of the present study are the first to demonstrate an increase in nocturnal leptin and GH-induced IGF-I secretion before the onset of puberty in the agonadal male monkey, providing justification for further investigation of the role of leptin and the GH axis, in particular IGF-I, in regulating developmental increases in pulsatile GnRH secretion. It is not clear whether one signal may have a more prominent role or whether redundancy is present with respect to growth-related signals to guarantee fertility is attained. Even in this limited analysis, it is intriguing that the maximum prepubertal increase in leptin and IGF-I occurred simultaneously in four of the five animals studied. The observation that this maximum increase varied between 10 and 30 days before the onset of puberty among the animals emphasizes the need to define more carefully the temporal relationship between the secretion of GnRH and these growth-related cues. Unlike other mammals, the interval between the onset of puberty and fertility in monkeys and children is extended and is susceptible to perturbations. Accordingly, what maintains the developmental drive in GnRH secretion is as important as what is responsible for its initiation, marking the transition to puberty. This underscores the need to not only identify the signal(s) that initiates puberty, but also how these signals sustain the developmental increase in GnRH secretion that ultimately results in fertility.
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Acknowledgments |
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Footnotes |
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Received June 30, 1999.
Revised September 22, 1999.
Accepted October 20, 1999.
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References |
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eds. The neurobiology of puberty. Bristol, UK: J Endocrinol
Ltd.; 103–117.
with the
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)
and nocturnal leptin concentrations (
) from 60 days before and 50
days after the onset of puberty (day 0). For analysis, data were
grouped in three intervals: early EPP, LPP, and PP. The shaded
area encompasses the LPP period in which the prepubertal
acceleration in pulsatile LH occurs (Ref. 41). Differences between
intervals that are significant indicated by "<"
(P < 0.05), whereas those that are not significant
are indicated by " = ."
