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Department of Cell Biology and Physiology (K.J.S., T.M.P.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261; and School of Health Sciences (C.R.P.), Duquesne University, Pittsburgh, Pennsylvania 15282
Address all correspondence and requests for reprints to: Dr. Tony M. Plant, Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261. E-mail: plant1{at}vms.cis.pitt.edu
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Abstract |
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Before day zero, which was observed between 24 and 29 months of age, a stable, low frequency (<1 pulse/7 h), low amplitude pattern of pulsatile GnRH release was observed. Termination of the prepubertal mode of GnRH pulse generator activity was manifest as a relatively rapid nocturnal shift to a robust high-frequency pattern of activity. In some animals, the nocturnal acceleration to an adult GnRH pulse frequency (6–7 pulses/7 h) was attained within an epoch of only 30 days. Although initiation of the pubertal acceleration in nocturnal GnRH pulse generator activity seemed to be associated with an increase in GnRH pulse amplitude, it was not possible to decipher the subsequent developmental changes in this parameter. In some animals, the pattern of pulsatile GnRH release after the initiation of the pubertal acceleration was punctuated by periods of diminished activity, which seemed to be unrelated to the state of the pituitary-adrenal axis.
These findings demonstrate that the neurobiological mechanisms that lead to the termination of the prepubertal mode of diminished GnRH release, and that therefore initiate the insidious process of puberty, have the potential to unfold with a surprisingly rapid time course. The extent to which the intrinsic tempo of the pubertal acceleration of pulsatile GnRH release in the agonadal situation is dampened by testicular feedback in the intact monkey remains to be established.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Although the precise nature of the pubertal increase in the hypophysiotropic signal to the primate gonadotroph remains to be determined, frequency modulation of the intermittent pattern of GnRH secretion seems to be partially involved (see Ref.1). In the female monkey, the frequency of pulsatile GnRH release, as measured either directly or indirectly using hypothalamic perfusion and pituitary LH release, respectively, is slower in the prepubertal animal than in the pubertal or adult monkey (2, 6, 7, 8). To date, however, studies of male macaques have failed to provide evidence to support the notion of an acceleration in pulsatile GnRH release at the time of primate puberty (9, 10, 11).
In any event, the cross-sectional nature of the foregoing studies has necessarily failed to address the tempo at which the augmentation of pulsatile GnRH release unfolds during puberty. Therefore, the purpose of the present study was to describe, in the rhesus monkey, the dynamics of the pubertal augmentation of pulsatile GnRH release. The castrated male macaque was selected as the experimental model for the following reasons. First, the gonadal independent suppression of pulsatile GnRH release that occurs prepubertally seems markedly more intense in the male than in the female of comparable age (12, 13). It was therefore reasoned that the peripubertal increase in pulsatile GnRH release would be more pronounced in the male, and thus easier to track, for the first time, in this sex. Second, testicular steroids are known to modulate the frequency of pulsatile GnRH secretion (see Ref.14); and thus, an open-loop system was employed so that the fundamental ontogenetically patterned augmentation in pulsatile GnRH secretion could be described in the absence of secondary modulation by gonadal steroids.
GnRH discharges were identified indirectly, as previously described (15), using the LH response of the in situ pituitary, sensitized to endogenous GnRH release with an exogenous infusion of the decapeptide.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The animals were bilaterally orchidectomized between 12.5–20 months of age (BW, 2.0–2.9 kg), using a sterile technique, after sedation with ketamine hydrochloride (50 mg/animal, im; Vetlar, Parke-Davis, Morris Plains, NJ) and anesthesia with sodium pentobarbital (25 mg/kg BW, iv, plus 5-mg supplements, as required; Nembutal sodium solution, Abbott Laboratories, North Chicago, IL). Postsurgically, each animal was treated prophylactically with a single injection of penicillin (300,000 U, im; Bicillin L-A, Wyeth Laboratories, Inc., Philadelphia, PA).
Remote access to the venous circulation
The monkeys were first adapted, for 3–4 weeks, to a jacket and
tether system that was subsequently employed to protect indwelling
venous catheters. One to 9 weeks after castration, each monkey was
implanted with an indwelling jugular or femoral vein catheter (0.040
inches id, 0.085 inches od; Sil-med Corp., Tauton, MA), under
pentobarbital anesthesia. The venous catheter, tunneled sc to the
scapular region and protruding through a cutaneous fistula protected by
a sterile dressing coated with antibiotic cream (Neosporin; Burroughs
Wellcome, Research Triangle Park, NC), was extended through the jacket
and tether to the swivel. Polyvinyl chloride tubing was connected to
the external port of the swivel and passed through the wall of the
animal room into an adjacent laboratory, so that infusion and blood
sampling could be performed remotely (16). Post catheterization, each
animal was treated with an im injection of penicillin, and with
cephalosporin (100 mg/animal, iv; Cefazolin sodium; Eli Lilly Co.,
Indianapolis, IN) and an analgesic, meperidine hydrochloride (1 mg/kg,
iv; Demerol, Winthrop Pharmaceuticals, New York, NY), twice daily for 4
days. Patency of catheters was maintained by continuous infusions of
heparinized saline (4 U/ml, 2 ml/h) and was restored, when necessary,
by surgically repositioning or replacing the catheter. When catheter
patency was permanently lost, additional veins were catheterized.
Animals were lightly sedated with ketamine hydrochloride once a week to determine body weight, to clean the scapular fistula, and to change the protective sterile dressing. All animals were supplemented monthly with iron dextran (25 mg, im; Phoenix Pharmaceuticals, Inc., St. Joseph, MO). After collection of sequential blood samples, blood cells were suspended in 0.9% saline and returned to the animals, which were also treated prophylactically with cephalosporin (100 mg, iv) twice a day for 4 days.
In situ GnRH bioassay
To enhance the responsiveness of the pituitary of prepubertal
monkeys to endogenously released GnRH, animals received an intermittent
iv infusion of synthetic GnRH (0.05 µg/min for 3 min every h;
LH-FSH-RH, chloride form, batch no. 2, AY-24–031-A26, from the
National Hormone and Pituitary Program) for 3–7 weeks using a
peristaltic pump controlled by a programmable timer (Chrontrol,
Lindburg Enterprises, Inc., San Diego, CA). The initial effectiveness
of the exogenous GnRH infusion in heightening gonadotroph
responsiveness was tracked, in most animals, by measuring circulating
LH concentrations at approximately weekly intervals. The pituitary was
considered to be sufficiently responsive to examine spontaneous GnRH
release when LH concentrations approached 50 ng/ml or more, which, in
the majority of animals, was observed after 28–45 days of pulsatile
GnRH treatment. To identify endogenous GnRH discharges, the exogenous
GnRH infusion was temporarily interrupted for 4 days. On the fourth day
of GnRH interruption, sequential blood samples (0.8 ml) were collected
at 12-min intervals for 7 h to assess circulating levels of LH. At
the end of the assessment window, the LH response to an iv bolus
injection of 300 ng GnRH was examined to provide an index of pituitary
responsiveness to GnRH (defined as the increment in plasma LH after
injection of GnRH). After the initial assessment of GnRH release,
repetitive 10-day priming cycles of intermittent GnRH infusion were
imposed to maintain the sensitivity of the gonadotrophs to GnRH. Each
cycle consisted of 6 days of pulsatile GnRH infusion followed by 4 days
of saline infusion. This priming regimen allowed for the potential of
assessing endogenous GnRH release every 10 days. A discharge of GnRH
was inferred whenever an LH secretory episode was identified by a
pulse-detection algorithm.
The progressive enhancement of pituitary responsiveness to GnRH during
the first 32 days of pulsatile GnRH stimulation was systematically
studied in two monkeys.2 In
these two animals, the iv bolus of 300 ng GnRH was administered before
initiation of GnRH priming, and it failed to elicit a robust discharge
of LH (Fig. 1
). In contrast, the same
GnRH stimulus, administered 4 days after the end of 38 days of priming,
increased plasma LH levels from 8 ng/ml before the challenge to 50–200
ng/ml at the peak of the response.
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On those occasions when pulsatile GnRH profiles were unaccountably dampened, an estimate of stress was sought by monitoring circulating levels of cortisol.
Assays
Plasma LH was measured in duplicate using a cynomolgus
LH-anti-human CG (R13, Pool D) RIA system, with rhesus preparation
WP-XV-20 (NIH rh-LH-RP-1) as standard (18). Minimum detectable
concentrations ranged between 6 and 14 ng/ml. Interassay coefficients
of variation were 10.9%, 7.1%, and 8.0% at 79%, 49%, and 26%
binding, respectively. The corresponding intraassay coefficients of
variation were 5.7%, 2.8%, and 3.3%, respectively. LH was also
measured in selected series of samples, with a more sensitive bioassay
that employed the same standard as the RIA and used testosterone
production by gerbil Leydig cells. This assay, which was performed in
the laboratory of Dr. Ernst Knobil, has been previously described (19).
The minimum detectable concentration with this assay was 0.8 ng/ml.
Inter- and intraassay coefficients of variation were 4.7% and 8.2%,
respectively.
Cortisol was measured by RIA, in duplicate, by a previously described assay (20), with antiserum F-3–314 (Endocrine Sciences, Tarzana, CA). The minimum detectable concentration was 2.4–5.4 ng/ml. Inter- and intraassay coefficients of variation were 6.7% and 6.4%, respectively.
LH Pulse detection
Pulses during 7 h of sequential sampling were identified by
the pulse detection algorithm, Pulsar, using G values that produce a
1% false positive rate: G(1) = 4.4, G(2) = 2.6, G(3) = 1.96, G(4) =
1.46, and G(5) = 1.13 (21). This program was used to determine the
number of pulses in each sampling period (frequency) and the average
amplitude of LH pulses. Experimental series in which LH pulses were not
detected were excluded from numerical analysis of LH pulse amplitude.
For purposes of calculation, the assay limit of detection was
substituted for undetectable samples.
For the quantitative analysis of LH pulsatility throughout development,
only LH measurements obtained by RIA were used. However, in
anticipation of low or undetectable immunoactive LH levels before the
development of augmented pulsatile release, Pulsar analysis was also
performed on selected profiles of bioactive LH levels. Representative
comparisons of moment-to-moment changes in immuno- and bioactive LH
concentrations are shown in Fig. 2. Where
profiles of immunoactive LH were at or near the minimal detectable
concentration, thus requiring caution for interpretation of pulse
analysis outcomes, bioactive LH levels were measurable and, moreover,
reflected only a low level of pulsatile GnRH release (Fig. 2).
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On occasion, when it was necessary to correlate cortisol and LH levels in specific assessment windows, an integrated level for the steroid in the 36 samples for the relevant windows was first calculated. The Pearson product-moment correlation coefficient was then obtained between integrated LH and integrated cortisol concentrations.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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shows sequential windows of
nocturnal pulsatile GnRH release, as reflected by pituitary LH
discharges, in two individual castrated male rhesus monkeys from 21–30
months of age, a time during which the initiation of puberty would have
been anticipated had the animals remained intact (12). The monkeys
shown in Fig. 3 were orchidectomized at 13 and 20 months of age; and in
both instances, evidence for robust pulsatile GnRH release was first
obtained at approximately 24 months of age.
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). In two of the remaining three
animals, robust pulsatile GnRH release was already evident at the time
of the first assessment window (age, 21.8 and 23.6 months; BW, 3.3 and
3.4 kg, respectively). In the last animal, evidence of GnRH pulsatility
was absent at 22.6 and 23.0 months of age (BW, 3.3 kg). For technical
reasons, however, GnRH release in this animal was not assessed again
until 26.5 months of age (BW, 3.7 kg), at which time robust pulsatility
was observed.
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). During the period from day -70 to
day -30, mean GnRH pulse frequency, as reflected by LH pulse
frequency, was very low (<1 pulse/7 h) and similar to that observed
when this parameter was first assessed at 14 (two monkeys) and 21–22
(three monkeys) months of age (i.e. 300–100 days before day
zero). Although not statistically significant until day zero, an
increase in GnRH pulse frequency seemed to be initiated by day -20.
Subsequently, mean GnRH pulse frequency showed a rapid acceleration,
which interestingly, achieved a maximal value within 40 days (day -30
to day +10), producing a plateau by day +10 of approximately 4 pulses/7
h. An adult frequency (6–7 pulses/7 h) was attained by days +10, +20,
+30, and +80 in four of the animals. In the fifth animal, the maximal
GnRH pulse frequency, observed during the 6-month period after day
zero, was five pulses/7 h.
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. Until day -10, the
maximum mean LH pulse amplitude was 11 ng/ml. An abrupt and striking
increase in LH pulse amplitude was seen on day zero. LH pulse amplitude
showed a further increase, to reach a maximum value of 81 ng/ml on day
+20.
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). On day
zero, LH levels increased abruptly and remained elevated throughout the
next 50 days.
Pituitary responsiveness to GnRH, as reflected by the LH response
to an iv bolus of 300 ng GnRH administered at the end of each window of
assessment of endogenous GnRH release (Fig. 6), was relatively stable throughout the
phase of development when an increase in hypophysiotropic drive to the
pituitary gonadotroph was unfolding (day -30 to day +20).
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.
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. In this monkey, as in all animals
in which day zero was identified, the termination of the prepubertal
mode of truncated GnRH release was abrupt; within the 20-day period
between 25.1 and 25.8 months of age, a marked increase in GnRH pulse
frequency and pulse amplitude was apparent. However, the progressive
developmental increase in the hypophysiotropic drive to the gonadotroph
of this monkey was not sustained but, instead, was interrupted
(particularly at 27.1 and 28.8 months of age) by periods of less robust
pulsatile GnRH release. Similar periods of decreased pulsatile GnRH
release were not observed at older ages. In the three animals in which
this phenomenon was observed, diminished GnRH activity was not
associated with elevated cortisol secretion, as reflected by the lack
of correlation (r = 0.08) between integrated cortisol and LH
concentrations in assessment windows exhibiting robust and attenuated
patterns of pulsatile GnRH release.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The recognized value of employing moment-to-moment changes in circulating LH concentrations as an index of GnRH pulse generator activity in the open-loop situation in adult animals is graphically illustrated by studies of the ovariectomized ewe (22), describing the temporal relationship between fluctuations in the concentration of the decapeptide in hypophysial portal plasma with those of the gonadotropin in the peripheral circulation. Indeed, perfection of portal blood collection in the ovariectomized ewe indicates that the fidelity of the relationships between pulsatile GnRH and LH release is exceedingly high (23, 24); and therefore, the interpretation of silent GnRH pulses reported initially requires caution. Although analogous studies have not been conducted in the monkey, the application of push-pull perfusion to assess GnRH release in the median eminence of castrated female macaques has revealed that GnRH discharges and peripheral LH pulses were significantly cross-correlated (25). The notion that an episode of pituitary LH release in agonadal postpubertal animals may be equated to a discharge of hypothalamic GnRH is further supported by the finding that, in the ovariectomized rat, goat, and monkey, pulsatile LH release is robustly correlated with abrupt increases in hypothalamic multiunit activity, an electrophysiological correlate of the GnRH pulse generator (26, 27, 28). The poor responsiveness to GnRH of the gonadotrophs in the prepubertal monkey (15, 29), however, necessitated that the juvenile monkeys be primed with an intermittent iv infusion of the synthetic decapeptide before the in situ pituitary could be used to describe developmental changes in GnRH pulse generator activity.
The present study tracked the ontogeny of pulsatile GnRH release in agonadal male rhesus monkeys from as early as 14 months of age until 24–36 months of age, the time at which an increase in nocturnal testosterone secretion, an early herald of the onset of puberty, would have been anticipated had the animals remained intact (12). Therefore, the emergence of an enhanced open-loop GnRH drive to the gonadotroph that was observed between approximately 2–21/2 yr of age was to be expected. Although the present study was performed in agonadal monkeys, there is no reason to suspect that the neurobiological mechanism triggering the reaugmentation of open-loop GnRH release is fundamentally different from that underlying the pubertal reactivation of the hypothalamic-pituitary-testicular axis in the gonadally intact model. Accordingly, in the discussion that follows, the changes in pulsatile GnRH secretion that were observed at approximately 2–21/2 yr of age are referred to as pubertal.
Developmental changes in the activity of the GnRH pulse generator were
formally evaluated with a simple algorithm, which equated
hypophysiotropic drive to pituitary LH output, and objectively applied
a subjective criterion (see Results) to identify the age at
which the pubertal increase in hypophysiotropic drive to the
gonadotroph was initiated (defined as day zero). Although arbitrary,
the algorithm seemed to identify, with reasonable accuracy, the
termination of the prepubertal mode of pulsatile GnRH release: before
day zero, integrated LH concentrations (index for GnRH drive) were
stable and varied, between windows of assessment, by less than 8%,
which contrasted with a sharp 64% increase in this parameter on day
zero (Fig. 5). Regardless of whether the accuracy of the algorithm is
accepted or challenged (see below), the procedure defined an objective
point of reference, on which to align data for individual animals, to
describe the overall tempo of the peripubertal transition in GnRH pulse
generator activity.
Interestingly, the age at which the pubertal reaugmentation of pulsatile GnRH release was observed in the present study, with tethered monkeys bearing indwelling venous catheters (i.e. range <22–29 months), was similar to that (range < 23–33 months) inferred from an earlier study of unrestrained, agonadal male monkeys in which nocturnal gonadotropin secretion by the unprimed pituitary was monitored at weekly intervals (12). Moreover, the body weights at this critical stage of development in the restrained animals studied here (range, 3.1–4.1 kg) and in the unrestrained monkeys studied earlier (range, 2.8–4.3 kg) were comparable. Taken together, these findings suggest that neither growth, nor the control system regulating the ontogeny of pulsatile GnRH release, was impaired by chronic catheterization and tethering. Similarly, because the age at which a pubertal mode of GnRH release became manifest was unrelated to the duration of the preceding intermittent infusion of exogenous GnRH used to maintain pituitary responsiveness, it may be argued that the ontogeny of GnRH pulse generator activity was not perturbed by the priming treatment. This issue was of some concern at the outset of the study because an anatomical substrate for a potential action of the synthetic decapeptide on the developmental pattern of endogenous GnRH release had been indicated by the finding that, in the monkey, as in other species, GnRH perikarya and dendrites receive synaptic input from GnRH neurons (30, 31). A more recent study of the monkey, however, failed to reveal autoregulatory synapses on GnRH neurons in this species (32). Whatever the case may be, the failure of GnRH priming to influence the ontogeny of pulsatile GnRH release is consistent with the finding that, in the adult monkey, electrophysiological correlates of GnRH pulse generator activity are not influenced by treatment with GnRH receptor ligands (33).
During prepubertal development, the GnRH pulse generator exhibited a stable, low-frequency (<1 pulse/7 h), low-amplitude mode of activity. From the time observations began, which was as early as 14 months of age in two animals, until 20 days before termination of the prepubertal mode of GnRH release, there was no evidence for either frequency or amplitude modulation of the GnRH pulse generator. Though estimates of hypothalamic GnRH release during the prepubertal period were restricted to the nighttime hours, it is likely that GnRH pulse generator activity during the remainder of the 24-h cycle showed a similar or more marked quiescence. Previous work has demonstrated that the activity of the GnRH pulse generator during the transition into and out of the prepubertal phase of development in the male monkey is diurnally modulated, with maximal activity characteristically observed at night (12, 34). Likewise, a similar diurnal modulation of the GnRH pulse generator is also present during prepubertal development in the female monkey (13) and in children (see Ref.1).
The absence of robust pulsatility during the prepubertal period cannot be attributed to a pituitary that was insensitive to endogenous GnRH release because the heightened response to the exogenous GnRH test stimulus at the end of each window of GnRH assessment was maintained during this phase of development. Thus, it is reasonable to conclude that the diminished hypophysiotropic drive to the gonadotroph, during prepubertal development in the male monkey, results from a combination of a slow frequency and low amplitude of pulse generator activity. Application of a sensitive immunofluorometric assay to the measurement of plasma LH concentrations in agonadal prepubertal boys suggests that a similar situation exists in man (35). The possibility that very-low-amplitude GnRH pulses escaped detection in the present study of the monkey and in the earlier clinical investigation, however, cannot be unequivocally excluded.
Termination of the stable low-frequency, low-amplitude prepubertal mode
of operation of the GnRH pulse generator was manifest as an abrupt and
unambiguous shift to a robust high-frequency pattern of activity. The
acceleration in frequency of GnRH pulse generator activity was
particularly rapid, increasing from less than 1 pulse/7 h to
approximately 4 pulses/7 h, over a 40-day epoch between day -30 and
day +10 (Fig. 4). The LH response to exogenous GnRH at this time was
stable (Fig. 6); and therefore, the increased number of GnRH pulses
detected during this critical phase of development cannot be accounted
for by a concomitant enhancement in pituitary responsiveness. Although
a significant increase in GnRH pulse frequency coincided with day zero,
the acceleration of the GnRH pulse generator seemed to be initiated
some 20–30 days earlier (Fig. 4). This observation indicates that (in
contrast to the present algorithm, which was unbiased, with respect to
frequency and amplitude) models based on frequency alone may prove, in
the future, more accurate for identifying the onset of the pubertal
mode of pulsatile GnRH release.
The relatively rapid acceleration in frequency that characterized the shift to the pubertal mode of pulsatile GnRH release was associated also with a rise in LH pulse amplitude on day zero, although the increment in this parameter did not attain statistical significance until day +20. Because there was no increase in pituitary responsiveness to exogenous GnRH during this critical phase of development, it must be concluded that the increased LH amplitude reflects increased GnRH pulse amplitude. A similar developmental increase in this parameter of GnRH pulse generator activity has been reported previously in studies employing direct assessment of GnRH release in the ovariectomized monkey (7, 36).
Although assessment of pulsatile GnRH release, during the early phase of the transition to the pubertal state, was conducted only at night, it may be assumed that the acceleration in pulse frequency and enhancement in pulse amplitude observed on these occasions was primarily restricted to nighttime hours. The reasons for this are as follows. First, when differences between daytime and nighttime were initially examined, 50–150 days after day zero, pulsatile GnRH release during the day was still markedly less robust than that at night. Second, pubertal increases in LH and testosterone in normal male monkeys are first observed in the evening hours (12). The pubertal activation of this neuroendocrine axis in man is also subject to similar diurnal modulation (see Ref.1).
After the relatively rapid initiation of the pubertal acceleration in GnRH pulse frequency between day -30 and day +10, the subsequent progression of GnRH pulse generator activity was variable. In the majority of monkeys, an adult GnRH pulse frequency was attained either during or shortly after completion of the initial phase of acceleration (day +30 or before). In one monkey, however, attainment of a frequency of 1 pulse/h was not achieved until day +80; and in another, a frequency of 5 pulses/7 h was not reached until several months after day zero. Moreover, in some of the animals, the early progression of the pubertal reaugmentation in GnRH pulse generator activity was interrupted by periods of diminished GnRH release. The finding that these punctuations in the developmental progression of GnRH pulse generator activity were not correlated with elevated cortisol levels suggests that they were unrelated to changing degrees of stress. Whether the foregoing temporal pattern of GnRH pulse generator activity is a characteristic of pubertal development in the monkey or is independent of this developmental process remains to be determined.
With the exception of the dramatic increase in LH pulse amplitude on day zero (which, as discussed above, presumably reflects an increase in GnRH pulse amplitude in association with the initial pubertal acceleration of the GnRH pulse generator), the subsequent changes in this parameter were unremarkable. However, because LH pulse amplitude, in response to intermittent stimulation with constant doses of synthetic GnRH, is inversely related to the frequency of the exogenous hypophysiotropic stimulus (37), it would be imprudent to conclude that the pubertal acceleration of the GnRH pulse generator is not accompanied by a progressive increase in GnRH pulse amplitude. Indeed, in the ovariectomized monkey, direct assessment of GnRH pulse generator activity in hypothalamic perfusates indicates a progressive increase in GnRH pulse amplitude during this phase of development (36).
In concluding, it might be expected that the rapid tempo by which the pubertal reaugmentation of pulsatile GnRH release unfolds in the agonadal male monkey will be modulated, and most likely dampened, in the normal situation, by testicular inputs, which are activated as a result of the endocrine cascade that is set in motion by the primary neurobiological event in the hypothalamus. Data on developmental changes in LH pulse profiles in the intact male monkey are scant (9, 11); and therefore, the superior results obtained from boys (38, 39, 40, 41, 42, 43, 44, 45) must be used to explore this issue. As discussed above, the relationship between LH pulse amplitude and GnRH pulse amplitude is complex; and in the clinical studies, it is further confounded by the fact that pituitary responsiveness to GnRH was not clamped by exogenous GnRH priming. Thus, a discussion of the potential role of the testis in modulating the reaugmentation of GnRH pulse generator activity will be limited to frequency. Paradoxically, in this regard, the application (in several of the foregoing clinical studies) of highly sensitive immunofluorometric and related assay techniques for the measurement of circulating LH concentrations raises an additional caveat that must be considered when GnRH pulse frequencies are inferred from episodes of LH secretion. Specifically, the finding, with such an assay, that low-amplitude LH pulses are observed in both patients with Kallmann’s syndrome and prepubertal boys with an intact neuroendocrine hypothalamus (46), suggests that these pulses may not reflect hypothalamic secretion of GnRH. Notwithstanding, it is interesting to note that, in normal boys, the pubertal acceleration in GnRH pulse frequency (as reflected by LH discharges), which has been reported by many (38, 40, 41, 42, 43, 44) but not all investigators (39, 45), also seems to be restricted to the early phase of this protracted developmental event. Indeed, in the cross-sectional study of Wu et al. (44), this acceleration occurred primarily during transition between phases of development termed midchildhood and prepubertal, and it was completed before physical changes were observed. Taking the foregoing considerations together, it seems reasonable to propose that, in male primates, the acceleration of the GnRH pulse generator, during puberty, represents an early and a rapidly completed neurobiological event in the initiation of this critical phase of development.
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Acknowledgments |
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Footnotes |
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2 These animals were not used to assess endogenous
GnRH release.
Received January 8, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-concentrations in infant, prepubertal and
adult rhesus monkeys (Macaca mulatta) and in juvenile males
during premature initiation of puberty with pulsatile
gonadotropin-releasing hormone treatment. Endocrinology 125:250–256This article has been cited by other articles:
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 T. M Plant The role of KiSS-1 in the regulation of puberty in higher primates Eur. J. Endocrinol., November 1, 2006; 155(suppl_1): S11 - S16. [Abstract] [Full Text] [PDF]
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S. B. Seminara, M. J. DiPietro, S. Ramaswamy, W. F. Crowley Jr., and T. M. Plant Continuous Human Metastin 45-54 Infusion Desensitizes G Protein-Coupled Receptor 54-Induced Gonadotropin-Releasing Hormone Release Monitored Indirectly in the Juvenile Male Rhesus Monkey (Macaca mulatta): A Finding with Therapeutic Implications Endocrinology, May 1, 2006; 147(5): 2122 - 2126. [Abstract] [Full Text] [PDF]
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K. J. Suter The Ontogeny of Pulsatile Growth Hormone Secretion and Its Temporal Relationship to the Onset of Puberty in the Agonadal Male Rhesus Monkey (Macaca mulatta) J. Clin. Endocrinol. Metab., May 1, 2004; 89(5): 2275 - 2280. [Abstract] [Full Text] [PDF]
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M. J. Cunningham, M. Shahab, K. L. Grove, J. M. Scarlett, T. M. Plant, J. L. Cameron, M. S. Smith, D. K. Clifton, and R. A. Steiner Galanin-Like Peptide as a Possible Link between Metabolism and Reproduction in the Macaque J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1760 - 1766. [Abstract] [Full Text] [PDF]
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 T. M. Plant and M. L. Barker-Gibb Neurobiological mechanisms of puberty in higher primates Hum. Reprod. Update, January 1, 2004; 10(1): 67 - 77. [Abstract] [Full Text] [PDF]
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D. R. Simorangkir, G. R. Marshall, and T. M. Plant Sertoli Cell Proliferation during Prepubertal Development in the Rhesus Monkey (Macaca mulatta) Is Maximal during Infancy when Gonadotropin Secretion Is Robust J. Clin. Endocrinol. Metab., October 1, 2003; 88(10): 4984 - 4989. [Abstract] [Full Text] [PDF]
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G. C. Harris and J. E. Levine Pubertal Acceleration of Pulsatile Gonadotropin-Releasing Hormone Release in Male Rats as Revealed by Microdialysis Endocrinology, January 1, 2003; 144(1): 163 - 171. [Abstract] [Full Text] [PDF]
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M. L. Barker-Gibb, A. Sahu, C. R. Pohl, and T. M. Plant Elevating Circulating Leptin in Prepubertal Male Rhesus Monkeys (Macaca mulatta) Does Not Elicit Precocious Gonadotropin-Releasing Hormone Release, Assessed Indirectly J. Clin. Endocrinol. Metab., November 1, 2002; 87(11): 4976 - 4983. [Abstract] [Full Text] [PDF]
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M. R. Palmert and P. A. Boepple Variation in the Timing of Puberty: Clinical Spectrum and Genetic Investigation J. Clin. Endocrinol. Metab., June 1, 2001; 86(6): 2364 - 2368. [Abstract] [Full Text] [PDF]
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T. M. Plant Leptin, Growth Hormone, and the Onset of Primate Puberty J. Clin. Endocrinol. Metab., January 1, 2001; 86(1): 459 - 460. [Full Text]
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K. J. Suter, C. R. Pohl, and M. E. Wilson Growth Signals and Puberty J. Clin. Endocrinol. Metab., January 1, 2001; 86(1): 460 - 460. [Full Text]
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S. M. Hileman, D. D. Pierroz, and J. S. Flier Leptin, Nutrition, and Reproduction: Timing Is Everything J. Clin. Endocrinol. Metab., February 1, 2000; 85(2): 804 - 807. [Full Text]
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K. J. Suter, C. R. Pohl, and M. E. Wilson Circulating Concentrations of Nocturnal Leptin, Growth Hormone, and Insulin-Like Growth Factor-I Increase before the Onset of Puberty in Agonadal Male Monkeys: Potential Signals for the Initiation of Puberty J. Clin. Endocrinol. Metab., February 1, 2000; 85(2): 808 - 814. [Abstract] [Full Text]
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M. E. Majdoubi, A. Sahu, S. Ramaswamy, and T. M. Plant Neuropeptide Y: A hypothalamic brake restraining the onset of puberty in primates PNAS, May 23, 2000; 97(11): 6179 - 6184. [Abstract] [Full Text] [PDF]
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