Biol Reprod
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

BOR - Papers in Press, published online ahead of print April 28, 2004.
Biol Reprod 2004, 10.1095/biolreprod.104.027656
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
71/2/588    most recent
biolreprod.104.027656v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Wilson, M.E.
Right arrow Articles by Gould, K.G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wilson, M.E.
Right arrow Articles by Gould, K.G.
Agricola
Right arrow Articles by Wilson, M.E.
Right arrow Articles by Gould, K.G.
BIOLOGY OF REPRODUCTION 71, 588–597 (2004)
DOI: 10.1095/biolreprod.104.027656
© 2004 by the Society for the Study of Reproduction, Inc.

Neuroendocrinology

Reduced Growth Hormone Secretion Prolongs Puberty But Does Not Delay the Developmental Increase in Luteinizing Hormone in the Absence of Gonadal Negative Feedback1

M.E. Wilson2,3, K. Chikazawa3, J. Fisher3, D. Mook4,5, and K.G. Gould3

Yerkes National Primate Research Center,3 Department of Pathology,4 Division of Animal Resources,5 Emory University, Atlanta, Georgia 30322


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Previous studies have shown that the growth hormone (GH) axis is important for timing the later stages of puberty in female monkeys. However, it is not clear whether these growth-related signals are important for the initiation of puberty and early pubertal events. The present study, using female rhesus monkeys, used two approaches to answer this question. Experiment 1 tested the hypothesis that reduced GH secretion would blunt the rise in nocturnal LH secretion in young (17 mo; n = 7) but not older adolescent ovariectomized females (29 mo; n = 6). Reduced GH secretion was induced by treating females with the sustained release somatostatin analogue formulation, Sandostatin LAR (625 µg/kg). Morning (0900–0930 h) and evening (2200–2230 h) concentrations of bioactive LH were higher in older adolescent compared to young adolescent females. However, diurnal concentrations were not affected by the inhibition of GH secretion in either age group when compared to the placebo-treated, control condition. Experiment 2 tested the hypothesis that reduced GH secretion induced in young juvenile females would delay the initial increase in nocturnal LH secretion and subsequent early signs of puberty. In order to examine this hypothesis, puberty in control females (n = 7) was compared to those in which puberty had been experimentally arrested until a late adolescent age (29 mo) by the use of a depot GnRH analogue, Lupron (750 µg kg–1 mo–1; n = 7). Once the analogue treatment was discontinued, the progression of puberty was compared to a group treated in a similar fashion but made GH deficient by continuous treatment with Sandostatin LAR (n = 6). Puberty occurred as expected in control females with the initial rise in evening LH at 21 mo, menarche at 22 mo, and first ovulation at 30 mo. As expected, Lupron arrested reproductive maturation, but elevations in morning and evening LH and menarche occurred within 2 mo of the cessation of Lupron in both Lupron and Lupron-GH-suppressed females. In contrast, first ovulation was delayed significantly in the Lupron-GH-suppressed females (41 mo) compared to the Lupron-only females (36 mo). These data indicate that within this experimental model, reduced GH secretion does not perturb the early stages of puberty but supports previous observations that the GH axis is important for timing the later stages of puberty and attainment of fertility. Taken together, the data indicate that factors that reduce GH secretion may have a deleterious effect on the completion of puberty.

estradiol, growth hormone, luteinizing hormone, neuroendocrinology, puberty


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Despite an emerging understanding of the important neurochemical inputs to GnRH neurons that govern the developmental increase in gonadotropin secretion in primates [1, 2], the factors that are responsible for changing the nature of the neurochemical input to GnRH neurons are poorly understood. Since the seminal work of Frisch and colleagues [3–5], it has been hypothesized that growth and growth-related cues are important for the developmental changes in the reproductive axis [6]. A "somatometer" hypothesis suggests that a central growth-tracking device that is sensitive to circulating peripheral growth-related cues might underlie the increase in GnRH release at puberty [7]. Since bone age better predicts the timing of menarche than does chronological age [8], the growth hormone (GH) axis has been implicated in regulating puberty [9]. In children, GH deficiency delays puberty [8, 10] while GH therapy normalizes the progression of puberty but does not affect the appearance of secondary sex characteristics [11, 12]. Data from rodents indicate GH-derived increases in insulin-like growth factor (IGF)-I may be important. Mice deficient in GH have suppressed IGF-I levels, reduced postnatal growth, and delayed puberty, parameters that are normalized by IGF-I replacement [13]. In addition, hepatic [14] and median eminence expression of IGF-I [15, 16] increases prior to vaginal opening in rats. Although some studies report that neither IGF-I infusion [17] nor GH inhibition [18] affect puberty onset in female rats, ICV administration of IGF-I increases serum LH via GnRH and accelerates the onset of puberty [14]. These effects are supported by other rodent studies indicating that IGF-I stimulates GnRH from the ME in vitro [19] and the expression of GnRH mRNA in cell cultures [20].

Previous studies show that the GH axis, mediated through changes in peripheral IGF-I secretion, regulates the tempo of puberty in female monkeys. GH accelerates [21] while a somatostatin analogue [22] delays the occurrence of first ovulation compared to untreated control females when treatments are initiated during early puberty. This effect is likely mediated through changes in peripheral concentrations of IGF-I, as IGF-I administration advances the age at first ovulation relative to control females [23] by accelerating the decrease in the hypersensitivity to estradiol negative feedback inhibition of LH secretion [24]. However, treatments with IGF-I do not accelerate the developmental rise in daytime LH secretion in the absence of estradiol, an observation that supports data on the effects of GH administration to girls with Turner's syndrome [25].

These studies suggest that the GH axis is important for the timing of the latter stages of puberty, leading to first ovulation, in the female monkey. However, it is not clear whether these growth-related signals are involved in the neurochemical changes that initiate the rise in LH at the transition to adolescence, specifically in the absence of estradiol. Since a nocturnal elevation in LH heralds the initiation of the pubertal process in monkeys [26–28] as well as children [29], it is important to determine if the GH axis is involved in this key developmental process. The critical question is whether the GH axis influences the full developmental increase in LH secretion or whether it acts to time the later stages of puberty. The present study used two approaches to answer this question using female rhesus monkeys. Experiment 1 tested the hypothesis that a reduction in GH secretion would blunt the rise in nocturnal LH secretion in young but not older adolescent ovariectomized females. Older pubertal females were included as a positive control, as we have shown previously that IGF-I administration to ovariectomized females in this age range does not influence daytime LH secretion [24]. Experiment 2 tested the hypothesis that a reduction in GH secretion in young juvenile females would delay the initial increase in nocturnal LH secretion and subsequent early signs of puberty. In order to examine this hypothesis, puberty in normal females was compared to that in which puberty had been experimentally arrested until a late adolescent age by the use of a GnRH analogue. Once the analogue treatment was discontinued, the progression of puberty was compared to a group treated in a similar fashion but also treated with a somatostatin analogue to inhibit GH secretion. It was predicted that the reduction in GH secretion would further and significantly delay the initial developmental rise in nocturnal LH secretion as well as the early indices of puberty.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects were juvenile female rhesus monkeys (Macaca mulatta) born and raised at the Yerkes National Primate Research Center. Animals were born outdoors and moved indoors between 9 and 10 mo of age where they were housed under a fixed photoperiod (12L:12D) and temperature range (21–25°C). Animals were housed socially in small groups (n = 2– 4 females per caging unit) as described previously [30]. Animals were fed commercial monkey chow (Ralston Purina Company, St. Louis MO) ad libitum twice daily and received a daily supplement of fresh fruit and vegetables. 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."

Experiment 1

Thirteen ovariectomized females were studied at either 29 mo ("older" pubertal; n = 6) or 17 mo ("younger" pubertal; n = 7) of age. Females had been ovariectomized from 6 to 18 mo. Diurnal concentrations in bioactive LH were compared both during a placebo (saline) condition and during reduced GH secretion. GH secretion was reduced by treating each female with single dose of the sustained release formulation (30-day) of the somatostatin analogue, Sandostatin LAR (Novartis, Basel, Switzerland) at a dose (625 µg/kg, i.m.). This daily dose achieved by this approach (22 µg kg–1 day–1) was greater than that used in a previous study evaluating the effects of a reduction of GH secretion on the IGF-I axis in monkeys [31]. Diurnal hormone secretion was assessed in samples collected at 1000 and 1030 h and 2200 and 2230 h on Day 12 of the placebo and Day 12 of the Sandostatin LAR treatment periods. This approach was based on previous studies in monkeys using single morning and evening samples to assess developmental changes in LH [28, 32]. All subjects were habituated to conscious venipuncture as described previously [33]. Juvenile females readily adapt to these procedures, showing no adverse effects on growth or fertility [34].

Experiment 2

Twenty-one, gonadally-intact juvenile females were randomly assigned to one of three treatment groups: control (saline) (Con, n = 7), Lupron-treated (Lup, n = 7), and Sandostatin plus Lupron (Lup-GHx, n = 7). Treatments were initiated when each female reached 12 mo of age. Since continuous exposure to Lupron blocks the action of endogenous GnRH, puberty was experimentally arrested in Lup and Lup-GHx females. We employed this approach to standardize pubertal status, given inherent differences in rates of pubertal maturation in female monkeys [35], to assess the subsequent effects of a reduction in GH secretion of the progression of puberty. Depot Lupron (Tap Pharmaceuticals) was administered at a dose (750 µg kg–1 mo–1) used previously to suppress puberty in monkeys [36] and higher than the dose typically used to arrest precocious puberty in children [37]. Sandostatin was administered to reduce GH secretion using the same dose of Sandostatin LAR described for experiment 1. Lupron treatment was discontinued at 29 mo of age for both Lup and Lup-GHx females, whereas Sandostatin LAR treatment continued until the completion of the experiment (first ovulation for an individual female) in Lup-GHx females. Lupron was discontinued at 29 mo of age, as puberty is well under way in normal, unmanipulated females at this age [24], an observation that was concurrently verified in Con females. Following the cessation of Lupron treatment, the subsequent progression of puberty in Lup females to those that had been treated with Lupron but were still GH deficient (Lup-GHx) would test the hypothesis that normal GH secretion is important for puberty. Diurnal LH and GH secretion was assessed approximately every 90 days from 12 through 29 mo and in the weeks immediately following this age and the cessation of Lupron treatment in Lup and Lup-GHx females in samples collected at 1000, 1030, 2200, and 2230 h. Additionally, morning samples (0900 h) were obtained twice weekly for progesterone and LH analysis. As noted in experiment 1, all subjects were habituated to conscious venipuncture. First ovulation was inferred from a rise (>1.00 ng/ml) in serum progesterone. Ovulations with a normal luteal phase were those in which serum progesterone was elevated >3.00 ng/ml for 7–10 days [22, 23]. Ovulations with inadequate luteal phases were those with maximum serum progesterone levels of <2.00 ng/ml and with the sustained elevation in progesterone of <7 days [23]. Finally, the occurrence of perineal coloration and swelling as well as menstrual bleeding were assessed by daily visual inspection. Perineal changes in color and swelling are characteristic of perimenarchial rhesus monkeys [38] and are induced by increases in estradiol and activation of estrogen receptors [39].

In addition, auxological data were collected throughout the treatment period. Body weights were obtained monthly, while height, crown-rump length, and bone ages were assessed from hand and wrist radiographs using the Tanner-Whitehouse system [35] and were obtained every 90 days as described previously [30]. Body mass index (weight in kg divided by height in m, squared) was also calculated at each measurement point as an index of adiposity. Bone mineral content was also determined at these times using a dual energy X-ray absorptometer (DEXA, Norland XR-26 System, Fort Atkinson, WI) as described previously [40].

Assays

All assays were performed in the Yerkes Endocrine Core Lab. Serum IGF-I was determined by a commercially available ELISA (Diagnostic Systems Laboratory, Webster, TX). The assay has a sensitivity of 50 ng/ ml using 5 µl of serum with a inter- and intraassay coefficients of variation (CVs) of 5.89 and 4.5%, respectively. Serum progesterone was determined by a commercially available RIA (Diagnostics Products Corporation, Los Angeles, CA). The assay has a sensitivity of 0.15 ng/ml using 100 µl of serum with inter- and intraassay CVs of 10.26 and 9.08%, respectively. Serum GH was determined by a commercially available ELISA (Diagnostic Systems Laboratory). The assay has a sensitivity of 0.10 ng/ml using 20 µl of serum with inter- and intraassay CVs of 9.13 and 6.33%, respectively. LH concentrations were determined using the mouse interstitial cell bioassay [38]. The standard for the assay was the recombinant monkey LH (purchased from the National Hormone and Pituitary Program, NIDDK). Using 5 µl of serum, the LH bioassay has a sensitivity of 0.20 ng/ml with inter- and intraassay CVs of 12.00 and 10.31%, 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).

Statistics

Data were summarized as mean ± SEM. Differences between Con, Lup, and Lup-GHx females throughout development were evaluated with analysis of variance models for repeated measures and group differences at specific ages, and time points were evaluated using the Fisher exact post hoc tests. Differences between groups on a single variable were evaluated with t-tests. To provide the best estimate of morning or evening hormone concentrations, the 1000 and 1030 h samples were averaged, as were the 2200 and 2230 h samples, and these data points were used in the statistical analyses. Statistical analyses were performed using SPSS (Chicago, IL) and tests having a P ≤ 0.05 were considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Experiment 1

Serum GH levels (Fig. 1) were significantly higher in evening compared with morning samples during both placebo and Sandostatin treatments (F1, 11 = 6.19, P = 0.030). Administration of Sandostatin significantly reduced serum GH (F1, 11 = 11.51, P = 0.006). However, GH levels were not different between the two different age-groups of pubertal females as a function of time of day or treatment (F1, 11 = 0.96, P = 0.348).



View larger version (27K):
[in this window]
[in a new window]
  		FIG. 1. Mean ± SEM GH concentrations in the morning (AM) and evening (PM) for younger (17 mo of age) and older (29 mo of age) pubertal females during placebo and Sandostatin LAR ("GHx") treatment conditions. As indicated, AM values of GH were significantly less than PM values for both groups of females. Bars with different letters within the AM and PM sampling times are significantly different from one another (P < 0.05)

The reduction in GH secretion resulting from Sandostatin treatment did not affect the diurnal pattern of LH secretion in either early or late juvenile females (Fig. 2). Serum levels of bioactive LH were significantly higher in evening compared with morning samples regardless of treatment condition or age (F1, 11 = 19.49, P = 0.001). Unlike GH concentrations, serum LH was significantly higher in older compared with younger pubertal females (F1, 11 = 13.67, P = 0.004). However, reduced GH secretion did not significantly affect either morning or evening LH levels in either early or late juvenile females (F1, 11 = 0.36, P = 0.560).



View larger version (30K):
[in this window]
[in a new window]
  		FIG. 2. Mean ± SEM bioactive LH concentrations in the morning (AM) and evening (PM) for younger (17 mo of age) and older (29 mo of age) pubertal females during placebo and Sandostatin LAR ("GHx") treatment conditions. As indicated, AM values of GH were significantly less than PM values for both groups of females. Bars with different letters within the AM and PM sampling times are significantly different from one another (P < 0.05)

Experiment 2

Efficacy of experimental model The somatostatin analogue treatment significantly suppressed GH secretion in all but one of the Lup-GHx females. Indeed, this animal's average evening GH level throughout the study (7.07 ng/ml) was 2.04 standard deviations above the mean of the other Lup-GHx females (4.22 ± 0.57 ng/ml; z-score) and was 0.28 standard deviations below the mean evening GH values of the Lup females (8.07 ± 1.34 ng/ml). Since the Sandostatin LAR treatment failed to suppress GH secretion in this animal, her data were excluded from the analysis; however, the reproductive endpoints for this animal are illustrated here, showing she was more similar to the Lup females in other developmental parameters in addition to GH secretion.

Serum concentrations of GH prior to the cessation of Lupron treatment at 29 mo varied significantly between the groups (Fig. 3; F1, 17 = 4.36, P = 0.029). Evening GH levels were consistently and significantly higher than morning values (F1, 17 = 24.66, P < 0.001), and this did not vary by treatment group (F2, 17 = 1.48, P = 0.255). Morning GH concentrations were similar between groups until 27 mo, when levels were consistently higher in Con compared with Lup-GHx females (Fig. 3). In contrast, evening GH levels were significantly higher in Con compared with Lup-GHx at every age studied (Fig. 3). Evening GH levels in Lup females were similar to Con and higher than Lup-GHx through 21 mo, after which concentrations were significantly higher in Con females.



View larger version (17K):
[in this window]
[in a new window]
  		FIG. 3. Mean ± SEM GH concentrations in the morning (AM) and evening (PM) for control (Con, n = 7), Lupron-treated (Lup, n = 7), and Lupron plus Sandostatin LAR-treated females (Lup-GHx, n = 6) at successive ages until the cessation of Lupron treatment at 29 mo. As indicated, AM values of GH were significantly less than PM values for all groups of females. Bars with different letters within the AM and PM sampling times are significantly different from one another (P < 0.05)

Serum levels of IGF-I also varied significantly through 29 mo of age (Fig. 4; F2, 17 = 4.68, P = 0.024). At every age, concentrations were significantly higher in Con compared to Lup-GHx. Other than the initial assessment at 14 mo, IGF-I concentrations were intermediate in Lup compared to Con and Lup-GHx females at 18 and 21 mo but significantly lower than Con and higher than Lup-GHx from 24 to 29 mo. Finally, a significant age-dependent increase in IGF-I was observed that varied between groups (Fig. 4; F10, 85 = 2.75, P = 0.005). In Con females, serum IGF-I rose significantly from 14 through 24 mo, coincident with menarche (see the following discussion) (F5, 60 = 15.01, P < 0.001). Serum IGF-I rose significantly in Lup females from 18 through 29 mo (F5, 30 = 6.60, P < 0.001). The increase was also significant for Lup-GHx females (F5, 25 = 6.20, P = 0.001) due primarily to the increase from 14 through 18 mo with little change thereafter.



View larger version (38K):
[in this window]
[in a new window]
  		FIG. 4. Mean ± SEM IGF-I concentrations for control (Con, n = 7), Lupron-treated (Lup, n = 7), and Lupron plus Sandostatin-treated females (Lup-GHx, n = 6) at successive ages through 29 mo. Also shown are IGF-I values for Lup and Lup-GHx females 1 mo after the cessation of Lupron treatment ("Post"). Bars with different letters are significantly different from one another (P < 0.05)

Lupron effectively suppressed LH secretion from 12 through 29 mo of age (Fig. 5). Serum levels of bioactive LH were significantly higher in Con compared to both Lup and Lup-GHx females (F1, 17 = 16.93, P < 0.001). Morning LH concentrations were significantly higher in Con at 24 and 29 mo of age, whereas evening LH concentrations were significantly higher in Con at every age assessed (Fig. 5). Morning LH concentrations were consistently and significantly lower than evening values but only in Con females (F2, 17 = 4.78, P = 0.023).



View larger version (15K):
[in this window]
[in a new window]
  		FIG. 5. Mean ± SEM bioactive LH concentrations in the morning (AM) and evening (PM) for control (Con, n = 7), Lupron-treated (Lup, n = 7), and Lupron plus Sandostatin LAR-treated females (Lup-GHx, n = 6) at successive ages until the cessation of Lupron treatment at 29 mo. As indicated, AM values of LH were significantly less than PM values for the Con group only. Bars with different letters within the AM and PM sampling times are significantly different from one another (P < 0.05)

Post-Lupron Effects

Following the cessation of Lupron treatment at 29 mo of age for Lup and Lup-GHx females, diurnal hormone secretion was assessed at +2 and +4 wk. Both morning and evening GH levels were similar between Con and Lup females and significantly higher than Lup-GHx females (Fig. 6; F2, 17 = 3.60, P = 0.049). Morning GH did not differ significantly from evening GH during this interval (1.49, P = 0.239). The Lup-GHx female excluded from the analysis had a mean post-Lupron GH value (7.78 ng/ml) that was 1.66 standard deviations higher than the other Lup-GHx females (4.32 ± 0.85 ng/ml) and 0.29 standard deviations lower than Lup females (9.34 ± 2.00 ng/ml).



View larger version (16K):
[in this window]
[in a new window]
  		FIG. 6. Mean ± SEM GH concentrations in the morning (AM) and evening (PM) for control (Con, n = 7), Lupron-treated (Lup, n = 7), and Lupron plus Sandostatin LAR-treated females (Lup-GHx, n = 6) at 2 wk prior to the cessation of Lupron treatment at 29 mo and at 2 and 4 wk following the end of treatment. Morning values did not differ from evening values during this sampling interval. Bars with different letters within the AM and PM sampling times are significantly different from one another (P < 0.05)

IGF-I concentrations were significantly higher in Lup compared with Lup-GHx females in the month following the cessation of Lupron treatment (Fig. 4; t11 = 2.55, P = 0.027). Serum IGF-I rose significantly following the cessation of Lupron compared to vales at 29 mo in Lup (t6 = 2.38, P = 0.055) but not Lup-GHx females (t5 = 1.09, P = 0.324).

Bioactive levels of LH also changed significantly following the cessation of Lupron treatment (Fig. 7). Overall, levels of LH were significantly higher in Con compared with Lup and Lup-GHx (F2, 17 = 13.49, P < 0.001), but the pattern was different at the two post-Lupron assessments. LH levels were significantly higher in Con than Lup and Lup-GHx during both the morning and the evening 2 wk following the cessation of Lupron (Fig. 7). However, by 4 wk, LH levels were similar in Con and Lup females during both the morning and the evening. Although evening LH in Lup-GHx females were similar to other groups, morning LH concentrations were still significantly lower in Lup-GHx. However, morning LH values were significantly lower than evening values across all three groups (F1, 17 = 6.85, P = 0.018). The Lup-GHx female excluded from the analysis had a mean post-Lupron morning LH value (0.42 ng/ml) that was 7.45 standard deviations higher than the other Lup-GHx females (0.23 ± 0.01 ng/ml) and 0.29 standard deviations lower than Lup females (0.58 ± 0.21 ng/ ml). Evening LH levels for this female (1.05 ng/ml) were 2.35 standard deviations higher than other Lup-GHx females (0.44 ± 0.11) and 2.15 standard deviations higher than even the Lup females (0.53 ± 0.09 ng/ml).



View larger version (15K):
[in this window]
[in a new window]
  		FIG. 7. Mean ± SEM bioactive LH concentrations in the morning (AM) and evening (PM) for control (Con, n = 7), Lupron-treated (Lup, n = 7), and Lupron plus Sandostatin LAR-treated females (Lup-GHx, n = 6) at 2 wk prior to the cessation of Lupron treatment at 29 mo and at 2 and 4 wk following the end of treatment. As indicated, AM values of GH were significantly less than PM values for all groups of females. Bars with different letters within the AM and PM sampling times are significantly different from one another (P < 0.05)

As observed previously for our colony, secondary sexual characteristics were evident in Con females at approximately 24 mo of age (Table 1), long before the cessation of Lupron treatment in the other groups. Given the efficacy of the sustained Lupron treatment, the first evidence of perineal swelling as well as the age at menarche and first ovulation occurred significantly earlier in Con compared with both Lup and Lup-GHx females. Evidence of both perineal swelling and menarche occurred within 2 mo following the cessation of Lupron, and the age of these events did not differ between Lup and Lup-GHx females. However, age at first ovulation occurred significantly earlier in Lup compared with Lup-GHx females (Table 1 and Fig. 8). Furthermore the interval between menarche and first ovulation was significantly shorter in Lup (4.9 ± 1.6 mo) compared to Lup-GHx females (10.0 ± 0.5 mo), with the interval for Con females intermediate (7.2 ± 0.8 mo; F2, 20 5.16, P = 0.018). Luteal phase length and progesterone secretion at these first ovulations was normal in all Con and Lup-GHx females but only four of the seven Lup females. The Lup females that had the short luteal phases were the ones having first ovulation at the younger ages, closer to the cessation of Lupron treatment, compared to the Lup females that had a normal luteal phase (34 ± 2 mo vs. 38 ± 3 mo). As can be seen, the Lup-GHx female excluded from the analysis because of the failure of Sandostatin LAR to suppress GH secretion had first ovulation at an age 11.37 standard deviations below the mean of the other Lup-GHx females yet 0.97 standard deviations below the mean age for the Lup females. This female also had first ovulation 0.9 mo from menarche.


View this table:
[in this window]
[in a new window]
  		TABLE 1. Mean ± SEM ages at the initial appearance of perineal swelling as well as the occurrence of menarche and first ovulation for Con, Lup, and Lup-GHx females. Also shown is the percentage of females within each group that had a normal luteal phase at first ovulation. The data for the Lup-GHx female (RZq7) who was excluded from the analysis because of the failure of Sandostatin LAR to suppress GH secretion are also included. Lupron was discontinued at 29 mo for the Lup and Lup-GHx females



View larger version (19K):
[in this window]
[in a new window]
  		FIG. 8. Distribution (cumulative percentage) of the age at first ovulation in control (Con, n = 7), Lupron-treated (Lup, n = 7), and Lupron plus Sandostatin LAR-treated females (Lup-GHx, n = 6)

Auxological Parameters

Table 2 illustrates a between-group comparison of the auxological parameters assessed at the beginning of the study (12 mo of age) and the overall change in each measure calculated at 29 mo, at the time of cessation of Lupron treatment for the Lup and Lup-GHx females. The groups did not differ significantly from one another in any of the parameters at 12 mo of age. In terms of changes from 12 mo through the cessation of Lupron at 29 mo, Con females gained significantly more body weight than did Lup females. Weight gain in Lup-GHx females was intermediate statistically, being less than Con but more than Lup females. The increase in crown-rump length and body mass index (BMI) was significantly greater in Con compared to both Lup and Lup-GHx females. Finally, the increase in bone age was significantly greater in Con compared to Lup females and in turn was significantly greater than Lup-GHx females. Finally, the Lup-GHx female who was excluded from the analysis based on her GH values exceeded the average gain for all but BMI compared to the Lup-GHx females.


View this table:
[in this window]
[in a new window]
  		TABLE 2. Mean ± SEM ages of auxological measures for Con, Lup, and Lup-GHx females at 12 mo of age and the overall change through 29 mo of age. Also shown are the data for the Lup-GHx female (RZq7) who was excluded from the analysis because of the failure of Sandostatin LAR to suppress GH secretion

Body weight at first ovulation was significantly lower in Con (4.52 ± 0.23 kg) than either Lup (5.19 ± 0.20 kg) or Lup-GHx (5.70 ± 0.30 kg; F2, 17 = 5.64, P = 0.013). The difference between Lup and Lup-GHx females was not significant. The Lup-GHx female excluded from the analysis because of the failure of Sandostatin LAR to suppress GH secretion had a weight at first ovulation 1.33 standard deviations below the mean of the other Lup-GHx females and 0.88 standard deviations below the mean for the Lup females.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The results of experiment 1 do not support the hypothesis that a reduction in GH secretion delays the nocturnal rise in LH secretion in ovariectomized females juvenile females. The somatostatin analogue treatment effectively reduced GH secretion with no effect on nocturnal LH secretion. Furthermore, the results from experiment 2 do not support the hypothesis that a reduction in GH, and consequently IGF-I, secretion perturbs the initiation of puberty. As observed in experiment 1, the somatostatin analogue treatment effectively reduced GH secretion and Lupron arrested puberty as evidenced by an absence of gonadotropin secretion and other signs of pubertal development. Once Lupron was removed, females progressed through puberty with first ovulation delayed by a reduction in GH secretion, confirming previous data [22] that this condition prolongs the final stages of puberty and delays the onset of fertility.

We had predicted that nocturnal LH secretion would be compromised in young adolescent females whose GH secretion was reduced by treatment with a somatostatin analogue. We compared their response to a reduction in GH secretion to that of an older group of adolescent females. Importantly, the experiment was designed to determine if a reduction in GH secretion would compromise LH secretion in the absence of estradiol negative feedback, as we had previously shown that the GH axis, specifically IGF-I, decrease the efficacy of estradiol negative feedback inhibition of LH secretion as adolescent females progress through puberty [24]. The data from experiment 1 clearly show that the GH axis is not involved in the regulation of LH secretion in the absence of estradiol negative feedback in either young or older juvenile animals. Rather, GH or, more likely, IGF-I attenuates, through some as of yet undefined mechanism, the hypersensitivity to estradiol negative feedback characteristic of adolescent females [24, 41]. Although experiment 1 was not designed to assess estradiol negative feedback efficacy while GH secretion was reduced, preliminary data from another cohort of monkeys indicate negative feedback is more robust in GH-deficient females. Nocturnal LH concentrations are similar between ovariectomized controls (4.09 ± 0.25 ng/ml; n = 2, age 25 mo) and ovariectomized females made GH deficient with Sandostatin LAR (4.07 ± 1.04 ng/ml; n = 6, age 25 mo). Treatment with low dose estradiol to achieve serum levels of 65 pg/ml decreased nocturnal LH in both control (1.46 ± 0.20 ng/ml) and GH-deficient females (0.46 ± 0.16 ng/ml), but the decrease was greater in GH-deficient animals (65 ± 3% vs. 87 ± 4%). Inadequate sample sizes preclude appropriate statistical analyses, but these preliminary data support the hypothesis that GH regulates estradiol negative feedback efficacy during adolescence in female monkeys. This is not trivial, as this change in feedback efficacy is what determines the timing of the onset of fertile, ovulatory cycles [41].

Although experiment 2 did not assess estradiol negative feedback efficacy, the results support the hypothesis that the GH axis is important in timing these later stages of puberty. The parameters of puberty observed in control females were consistent with previous data from our facility in monkeys housed in an indoor, photoperiod-controlled environment [23, 35]. We used a GnRH analogue to experimentally arrest puberty. Treatment was purposefully stopped at 29 mo of age, coincident with the later stages of puberty in nonanalogue, control monkeys. Indeed, all control females had shown clear elevations in nocturnal LH by this age, all had experienced menarche, and first ovulation was rapidly approaching. We reasoned that if a reduction in GH secretion had a deleterious effect on the early stages of puberty, the initial increase in nocturnal LH secretion and the appearance of secondary sexual signs including menarche would be delayed in GH-deficient females after the removal of Lupron compared with females that had been on Lupron treatment only. Although both morning and evening LH secretion was still significantly lower in both Lup and Lup-GHx females compared with control animals 2 wk after the cessation of Lupron treatment, nocturnal levels were similar between all groups at 4 wk. However, morning LH concentrations were still significantly lower in Lup-GHx compared with controls but not different from Lup females. Importantly, the appearance of secondary sexual characteristics and menarche did not differ between the two Lupron-treated groups. We conclude from these data that a reduction in GH secretion does not affect the early change in the neuroendocrine reproductive axis that time the initial stages of puberty. However, the results from experiment 2 support the conclusions inferred from the data in experiment 1, namely, that reduced GH secretion prolongs the final stages of puberty. First ovulation was significantly delayed and the interval between menarche and first ovulation significantly lengthened in the GH-deficient females compared to the Lupron-only treated counterparts. Taken together, these data are consistent with the effects of somatostatin analogue-only treatment, which did not affect age at menarche but delayed first ovulation compared to control females [22].

The experimental arrest of puberty in the two Lupron-treated groups is consistent with the clinical use of Lupron and other GnRH analogues in the treatment of precocious puberty [42, 43]. Importantly, the data show that blocking the action of endogenous GnRH by the analogue does not hinder neuroendocrine development, as morning and evening LH were increased by 4 wk following termination of treatment and perineal swelling and menarche occurred, on the average, within 2 mo of ending the Lupron treatments, a situation analogous to girls coming off of Lupron therapy for precocious puberty [44]. Furthermore, the initial signs of perineal swelling and the occurrence of menarche occurred, on the average, within 2 mo of the cessation of Lupron treatment in both groups. If Lupron itself had delayed the neurobiological maturation of the GnRH pulse generator, these parameters of puberty should have been delayed further following Lupron termination. Although the duration of the interval between menarche and first ovulation was shorter in Lup (4.9 mo) compared to Con females (7.2 mo), the difference was not significant. These data indicate that the neuroendocrine changes that are responsible for early pubertal events are progressing during Lupron treatment but that their expression is simply masked, whereas the final maturation of the GnRH pulse generator or its downstream effects are slightly affected by Lupron. In support of this, Lupron administration did appear to affect the quality of the luteal phase of the first ovulation in females that ovulated soon after the cessation of Lupron treatment. The present study was not designed to determine if this was a carryover affect at the level of the pituitary and the integrity of pulsatile gonadotropin secretion or ovarian sensitivity to gonadotropic stimulation. Pharmacokinetic data suggest that sustained-release formulations of Lupron as administered in the present study do remain in circulation in the weeks following the cessation of treatment [45].

Given these data, the key question is what regulates neurochemical changes responsible for the transition to adolescence, that is, the onset of puberty. We recently reported that leptin administration to prepubertal female monkeys advances the initial elevation in nocturnal LH, the appearance of secondary sexual characteristics, menarche, and first ovulation compared with untreated controls [30]. These data suggest that a developmental increase in leptin may be important for timing the initial stages of puberty in females but perhaps not in males [46]. However, this conclusion is tempered by the observation that nocturnal LH concentration in age-matched ovariectomized females not treated with leptin were significantly elevated compared to leptin-treated, gonadally intact females [30]. These comparisons lead to the hypothesis that the developmental rise in leptin altered the efficacy of estradiol negative feedback at these initial stages of puberty, leading to acceleration in the pubertal progression. Since leptin also stimulates nocturnal GH secretion, it was not clear whether this acceleration was due to a direct effect of leptin or a leptin stimulation of GH. However, data from the present study would suggest that this might be a direct effect of leptin, as the reduction in GH secretion began at the same age as leptin administration had no effect on these early pubertal events. Although the role for leptin in primate puberty is quite controversial [46], it may interact with IGF-I to diminish the hypersensitivity to estradiol negative feedback. Prospective studies must dissociate effects of leptin and GH/IGF-I on these developmental parameters. Whether other growth or metabolic cues are responsible for the initial drive to gonadotropin secretion absent gonadal negative feedback remains a question.

The consequence of the Lupron and somatostatin analogue treatments on growth in experiment 2 were not a primary focus of the study but rather was used to verify treatment efficacy. Morning as well as evening GH secretion was significantly attenuated by the Sandostatin LAR treatment. GH concentrations were similar in control and Lupron-only-treated females up through 24 mo of age, after which GH was higher in control females, likely because of the augmentation by rising estradiol concentrations [48, 49]. However, with the exception of bone age, body weight, crown-rump length, and BMI were equally reduced in Lup and Lup-GHx females, suggesting that Lupron suppression of the developing reproductive axis was the key manipulation. These data are consistent with data from precocious children on Lupron therapy [50–52] as well as monkeys treated with a similar dose of Lupron [36]. The lower bone ages induced by Lupron treatment, of course, provides the rationale for slowing epiphyseal closure in children with precocious puberty by inducing hypoestrogenism [42, 53– 55]. The data also indicate that a reduction in GH secretion exacerbates the attenuation in bone age induced by Lupron. This too underscores the rationale for treating children with GH deficiency with Lupron [56], as if puberty is further delayed by GnRH analogue treatment, epiphyses close more slowly and more height is accumulated.

The reason one of the Lup-GHx females was unresponsive to Sandostatin LAR treatment is unknown. Although sensitivity to this treatment has been assessed in acromegalic patients [57], little is known on responsivity in normal pituitary individuals. This female did respond to Lupron treatment as indicated by the suppression of diurnal LH secretion and rapid pubertal progression once Lupron was discontinued. Indeed, most of her developmental parameters were within one standard deviation of the mean for the Lup group. The exception was this female's post-Lupron nocturnal LH concentrations, which were 2.35 standard deviation above the mean of the Lup-GHx group and 2.15 standard deviations above that of the Lupron-only females. Of all the Lupron-treated females, this female had the earliest age at first ovulation.

The results of this study suggest that the GH axis plays an important role timing the neuroendocrine changes that are responsible for the final stages of puberty leading to fertility in female monkeys. Despite the accumulation of evidence in monkeys that the developmental increase in the GH axis attenuates the hypersensitivity to estradiol negative feedback [21–24], the mechanism by which GH or, more likely, IGF-I has these effects is unknown. Nevertheless, the results indicate that factors that compromise GH secretion during primate maturation may have a deleterious effect not only on growth but also on the onset of fertility.


   ACKNOWLEDGMENTS
 
We appreciate the technical assistance of R. Yoda, A. Legendre, J. Johnson-Ward, and J. Brown. The assays were performed in the Endocrine Core at the YNPRC. We would like to thank Dr. C. Pohl (Duquesne University) for helpful comments on the experimental design of these studies. The YNPRC is fully accredited by the Association for the Assessment and Accreditation of Laboratory Animal Care International.


   FOOTNOTES
 
1 Supported by NIH grant HD37583 and, in part, RR00165. Back

2 Correspondence: M.E. Wilson, Yerkes Primate Research Center Field Station, Emory University, 2409 Taylor La., Lawrenceville, GA 30043. FAX: 404 727 9069; markw{at}rmy.emory.edu Back

Received: 22 January 2004.

First decision: 6 February 2004.

Accepted: 5 April 2004.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Plant TM. Neurobiological bases underlying the control of the onset of puberty in the rhesus monkey: a representative higher primate. Front Neuroendocrinol 2001 22:107-139[CrossRef][Medline]
  2. Terasawa E, Fernandez DL. Neurobiological mechanisms of the onset of puberty in primates. Endocr Rev 2001 22:111-151[Abstract/Free Full Text]
  3. Johnston FE, Malina RM, Galbraith MA, Frisch RE, Revelle R, Cook S. Height, weight and age at menarche and the "critical weight" hypothesis. Science 1971 174:1148-1149[Free Full Text]
  4. Frisch RE. Influences on age of menarche. Lancet 1973 1:1007
  5. Frisch RE. Body fat, puberty and fertility. Biol Rev Camb Philos Soc 1984 59:161-188[Medline]
  6. Foster DL, Nagatani S. Physiological perspectives on leptin as a regulator of reproduction: role in timing puberty. Biol Reprod 1999 60: : 205-215[Abstract/Free Full Text]
  7. Plant TM, Fraser MO, Medhamurthy R, Gay VL. Somatogenic control of GnRH neuronal synchronization during development in primates: a speculation. In: Delemarre-van de Waal HA, Plant TM, van Rees JM, Schoemaker J (eds.), Control of the Onset of Puberty III. Amsterdam: Elsevier; 1989:111–121
  8. Tanner JM, Whitehouse RH. A note on the bone age at which patients with true isolated growth hormone deficiency enter puberty. J Clin Endocrinol Metab 1975 41:788-790[Abstract]
  9. Wilson ME. The impact of the GH-IGF-I axis on gonadotropin secretion: inferences from animal models. J Pediatr Endocrinol Metab 2001 14:115-140[Medline]
  10. Ogilvy-Stuart AL, Shalet SM. Growth hormone and puberty. J Endocrinol 1992 135:405-406[Medline]
  11. Darendeliler F, Hindmarsh PC, Preece MA, Cox L, Brook CG. Growth hormone increases rate of pubertal maturation. Acta Endocrinol (Copenh) 1990 122:414-416[Medline]
  12. Stanhope R, Albanese A, Hindmarsh P, Brook CG. The effects of growth hormone therapy on spontaneous sexual development. Horm Res 1992 38:suppl 19-13
  13. Danilovich N, Wernsing D, Coschigano KT, Kopchick JJ, Bartke A. Deficits in female reproductive function in GH-R-KO mice; role of IGF-I. Endocrinology 1999 140:2637-2640[Abstract/Free Full Text]
  14. Hiney JK, Srivastava V, Nyberg CL, Ojeda SR, Dees WL. Insulin-like growth factor I of peripheral origin acts centrally to accelerate the initiation of female puberty. Endocrinology 1996 137:3717-3728[Abstract]
  15. Daftary SS, Gore AC. Developmental changes in hypothalamic insulin-like growth factor-1: relationship to gonadotropin-releasing hormone neurons. Endocrinology 2003 144:2034-2045[Abstract/Free Full Text]
  16. Miller BH, Gore AC. Alterations in hypothalamic insulin-like growth factor-I and its associations with gonadotropin releasing hormone neurones during reproductive development and ageing. J Neuroendocrinol 2001 13:728-736[CrossRef][Medline]
  17. Gruaz NM, d'Alleves V, Charnay Y, Skottner A, Ekvarn S, Fryklund L, Aubert ML. Effects of constant infusion with insulin-like growth factor-I (IGF-I) to immature female rats on body weight gain, tissue growth and sexual function: evidence that such treatment does not affect sexual maturation of fertility. Endocrine 1997 6:11-19[Medline]
  18. Gruaz NM, Arsenijevic Y, Wehrenberg WB, Sizonenko PC, Aubert ML. Growth hormone (GH) deprivation induced by passive immunization against rat GH-releasing factor does not disturb the course of sexual maturation and fertility in the female rat. Endocrinology 1994; 135:509-519[Abstract]
  19. Hiney JK, Ojeda SR, Dees WL. Insulin-like growth factor I: a possible metabolic signal involved in the regulation of female puberty. Neuroendocrinology 1991 54:420-423[Medline]
  20. Longo KM, Sun Y, Gore AC. Insulin-like growth factor-I effects on gonadotropin-releasing hormone biosynthesis in GT1–7 cells. Endocrinology 1998 139:1125-1132[Abstract/Free Full Text]
  21. Wilson ME, Gordon TP, Rudman CG, Tanner JM. Effects of growth hormone on the tempo of sexual maturation in female rhesus monkeys. J Clin Endocrinol Metab 1989 68:29-38[Abstract]
  22. Wilson ME, Tanner JM. Somatostatin analog treatment slows growth and the tempo of reproductive maturation in female rhesus monkeys. J Clin Endocrinol Metab 1994 79:495-501[Abstract]
  23. Wilson ME. Premature elevation in serum insulin-like growth factor-I advances first ovulation in rhesus monkeys. J Endocrinol 1998 158: : 247-257[Abstract]
  24. Wilson ME. IGF-I administration advances the decrease in hypersensitivity to oestradiol negative feedback inhibition of serum LH in adolescent female rhesus monkeys. J Endocrinol 1995 145:121-130[Abstract]
  25. Bourguignon JP, Gerard A, Deby-Dupont G, Franchimot P. Effects of growth hormone therapy on the developmental changes of follicle-stimulating hormone and insulin-like growth factor serum concentrations in Turner's syndrome. Clin Endocrinol 1993 39:85-89[Medline]
  26. Suter KJ, Pohl CR, Plant TM. The pattern and tempo of the pubertal reaugmentation of open-loop pulsatile gonadotropin-releasing hormone release assessed indirectly in the male rhesus monkey (Macaca mulatta). Endocrinology 1998 139:2774-2783[Abstract/Free Full Text]
  27. Suter KJ, Pohl CR, Plant TM. Indirect assessment of pulsatile gonadotropin-releasing hormone release in agonadal prepubertal rhesus monkeys (Macaca mulatta). J Endocrinol 1999 160:35-41[Abstract]
  28. Terasawa E, Bridson WE, Nass TE, Noonan JJ, Dierschke DJ. Developmental changes in the luteinizing hormone secretory pattern in peripubertal female rhesus monkeys: comparisons between gonadally intact and ovariectomized animals. Endocrinology 1984 115:2233-2240[Abstract]
  29. Grumbach MM. The neuroendocrinology of human puberty revisited. Horm Res 2002 57:suppl 22-14
  30. Wilson ME, Fisher J, Chikazawa K, Yoda R, Legendre A, Mook D, Gould KG. Leptin administration increases nocturnal concentrations of luteinizing hormone and growth hormone in juvenile female rhesus monkeys. J Clin Endocrinol Metab 2003 88:4874-4883[Abstract/Free Full Text]
  31. Wilson ME. Effects of estradiol and exogenous insulin-like growth factor I (IGF-I) on the IGF-I axis during growth hormone inhibition and antagonism. J Clin Endocrinol Metab 1998 83:4013-4021[Abstract/Free Full Text]
  32. Pohl CR, deRidder CM, Plant TM. Gonadal and nongonadal mechanisms contribute to the prepubertal hiatus in gonadotropin secretion in the female rhesus monkey (Macaca mulatta). J Clin Endocrinol Metab 1995 80:2094-2101[Abstract]
  33. Walker M, Gordon TP, Wilson M. Reproductive performance of capture acclimated female rhesus monkeys. J Med Primatol 1982 11: : 291-302[Medline]
  34. Wilson ME. Premature elevation in serum insulin-like growth factor-I advances first ovulation in rhesus monkeys. J Endocrinol 1998 158: : 247-257
  35. Wilson ME, Gordon TP, Rudman CG, Tanner JM. Effects of a natural versus artificial environment on the tempo of maturation in female rhesus monkeys. Endocrinology 1988 123:2653-2661[Abstract]
  36. Golub MS, Styne DM, Wheeler MD, Keen CL, Hendrickx AG, Moran F, Gershwin ME. Growth retardation in premenarchial female rhesus monkeys during chronic administration of a GnRH agonist (leuprolode acetate). J Med Primatol 1997 26:248-256[Medline]
  37. Mul D, de Muinck Keizer-Schrama SM, Oostdijk W, Drop SL. Auxological and biochemical evaluation of pubertal suppression with the GnRH agonist leuprolide acetate in early and precocious puberty. Horm Res 1999 51:270-276[CrossRef][Medline]
  38. Wilson ME, Gordon TP, Collins DC. Ontogeny of luteinizing hormone secretion and first ovulation in seasonal breeding rhesus monkeys. Endocrinology 1986 118:293-301[Abstract]
  39. Bentley JP, Brenner RM, Linstedt AD, West NB, Carlisle KS, Rokosova BC, MacDonald N. Increased hyaluronate and collagen biosynthesis and fibroblast estrogen receptors in macaque sex skin. J Invest Dermatol 1986 87:668-673[CrossRef][Medline]
  40. Mann DR, Akinbami MA, Gould KG, Castracane VD. A longitudinal study of leptin during development in the male rhesus monkey: the effect of body composition and season on circulating leptin levels. Biol Reprod 2000 62:285-291[Abstract/Free Full Text]
  41. Rapisarda JJ, Bergman KS, Steiner RA, Foster DL. Response to estradiol inhibition of tonic luteinizing hormone secretion decreases during the final stage of puberty in the rhesus monkey. Endocrinology 1983 112:1172-1179[Abstract]
  42. Carel JC, Lahlou N, Jaramillo O, Montauban V, Teinturier C, Colle M, Lucas C, Chaussain JL. Treatment of central precocious puberty by subcutaneous injections of leuprorelin 3-month depot (11.25 mg). J Clin Endocrinol Metab 2002 87:4111-4116[Abstract/Free Full Text]
  43. Schroeter M, Baus I, Sippell WG, Partsch CJ. Long-term suppression of pituitary-gonadal function with three-month depot of leuprorelin acetate in a girl with central precocious puberty. Horm Res 2002 58: : 292-296[CrossRef][Medline]
  44. Clemons RD, Kappy MS, Stuart TE, Perelman AH, Hoekstra FT. Long-term effectiveness of depot gonadotropin-releasing hormone analogue in the treatment of children with central precocious puberty. Am J Dis Child 1993 147:653-657[Abstract]
  45. Periti P, Mazzei T, Mini E. Clinical pharmacokinetics of depot leuprorelin. Clin Pharmacokinet 2002 41:485-504[CrossRef][Medline]
  46. Barker-Gibb ML, Sahu A, Pohl CR, Plant TM. Elevating circulating leptin in prepubertal male rhesus monkeys (Macaca mulatta) does not elicit precocious gonadotropin-releasing hormone release, assessed indirectly. J Clin Endocrinol Metab 2002 87:4976-4983[Abstract/Free Full Text]
  47. Mann DR, Plant TM. Leptin and pubertal development. Semin Reprod Med 2002 20:93-102[CrossRef][Medline]
  48. Mauras N, Blizzard RM, Link K, Johnson ML, Rogol AD, Veldhuis JD. Augmentation of growth hormone secretion during puberty: evidence for a pulse amplitude-modulated phenomenon. J Clin Endocrinol Metab 1987 64:596-601[Abstract]
  49. Wilson ME, Gordon TP, Tanner JM. Constant low-dose oestradiol replacement accelerates skeletal maturation and growth in ovariectomized adolescent rhesus monkeys. J Endocrinol 1993 137:519-527[Abstract]
  50. van der Sluis IM, Boot AM, Krenning EP, Drop SL, de Muinck Keizer-Schrama SM. Longitudinal follow-up of bone density and body composition in children with precocious or early puberty before, during and after cessation of GnRH agonist therapy. J Clin Endocrinol Metab 2002 87:506-512[Abstract/Free Full Text]
  51. Sklar CA, Rothenberg S, Blumberg D, Oberfield SE, Levine LS, David R. Suppression of the pituitary-gonadal axis in children with central precocious puberty: effects on growth, growth hormone, insulin-like growth factor-I, and prolactin secretion. J Clin Endocrinol Metab 1991 73:734-738[Abstract]
  52. DiMartino-Nardi J, Wu R, Fishman K, Saenger P. The effect of long-acting analog of luteinizing hormone-releasing hormone on growth hormone secretory dynamics in children with precocious puberty. J Clin Endocrinol Metab 1991 73:902-906[Abstract]
  53. Boepple PA, Mansfield MJ, Crawford JD, Crigler JF Jr, Blizzard RM, Crowley WF Jr. Gonadotrophin-releasing hormone agonist treatment of central precocious puberty: an analysis of growth data in a developmental context. Acta Paediatr Scand Suppl 1990 367:38-43[Medline]
  54. Boepple PA, Crowley WF Jr. Gonadotrophin-releasing hormone analogues as therapeutic probes in human growth and development: evidence from children with central precocious puberty. Acta Paediatr Scand Suppl 1991 372:33-38[Medline]
  55. Neely EK, Hintz RL, Parker B, Bachrach LK, Cohen P, Olney R, Wilson DM. Two-year results of treatment with depot leuprolide acetate for central precocious puberty. J Pediatr 1992 121:634-640[CrossRef][Medline]
  56. Mul D, Wit JM, Oostdijk W, Van den Broeck J. The effect of pubertal delay by GnRH agonist in GH-deficient children on final height. J Clin Endocrinol Metab 2001 86:4655-4656[Free Full Text]
  57. Colao A, Ferone D, Lastoria S, Marzullo P, Cerbone G, Di Sarno A, Longobardi S, Merola B, Salvatore M, Lombardi G. Prediction of efficacy of octreotide therapy in patients with acromegaly. J Clin Endocrinol Metab 1996 81:2356-2362[Abstract]



This article has been cited by other articles:


Home page
 Biol. Reprod.Home page
M. E. Wilson and B. Kinkead
Gene-Environment Interactions, Not Neonatal Growth Hormone Deficiency, Time Puberty in Female Rhesus Monkeys
Biol Reprod, April 1, 2008; 78(4): 736 - 743.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
71/2/588    most recent
biolreprod.104.027656v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Wilson, M.E.
Right arrow Articles by Gould, K.G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wilson, M.E.
Right arrow Articles by Gould, K.G.
Agricola
Right arrow Articles by Wilson, M.E.
Right arrow Articles by Gould, K.G.