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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 10 4776-4780
Copyright © 2003 by The Endocrine Society

Sexual Dimorphism of Growth Hormone (GH) Regulation in Humans: Endogenous GH-Releasing Hormone Maintains Basal GH in Women But Not in Men

Stacy K. Jessup, Eleni V. Dimaraki, Kathleen V. Symons and Ariel L. Barkan

Department of Internal Medicine (S.K.J., E.V.D., A.L.B.), Division of Endocrinology and Metabolism, University of Michigan Medical Center, and Department of Veterans Affairs Medical Center (K.V.S., A.L.B.), Ann Arbor, Michigan 48109

Address all correspondence and requests for reprints to: Ariel L. Barkan, M.D., University of Michigan Medical Center, 3920 Taubman Center, Box 0354, Ann Arbor, Michigan 48109-0354. E-mail: abarkan{at}umich.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
GH secretory patterns in humans are sexually dimorphic in terms of pulse regularity, amplitude of the diurnal rhythm, and magnitude of basal (trough) secretion. The neuroendocrine mechanisms of gender-specific GH regulation in humans are currently unknown, but the interpulse GH levels are generally assumed to be controlled by somatostatin. In rats, however, administration of antiserum to GHRH lowers GH interpulse levels in females but not males. In this study, using a competitive antagonist to GHRH in humans, we investigated whether endogenous GHRH has differential, gender-specific effects on the interpulse GH levels. Six healthy men and five healthy women (20–28 yr old) who were nonobese, did not smoke, and were on no medications known to influence GH secretion were studied. Each served as his or her own control during an infusion of GHRH antagonist or saline for a 27-h period. A control bolus of GHRH was given near the end of the infusion. In both sexes during GHRH antagonist infusion, mean GH, pulse amplitude, and GH response to GHRH decreased significantly, whereas pulse frequency remained unchanged. However, during the GHRH antagonist infusion, trough GH did not significantly change in men (P = 0.54) but significantly decreased in women (P = 0.008). Deconvolution analysis confirmed the lack of a significant change in basal secretion in men (P = 0.81) as opposed to women (P = 0.006). We conclude that sexual dimorphism in the neuroendocrine regulation of GH secretion in humans involves a differential role of endogenous GHRH in maintaining baseline GH.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE VAGARIES OF the neuroendocrine regulation of the somatotrophic axis continue to be gradually elucidated. Adult male and female GH profiles are easily distinguished at a glance with women having more uniform GH pulses throughout the day and men having a large nocturnal pulse and relatively low GH output over the rest of the day (1). However, the hypothalamic pituitary mechanisms controlling the sexual dimorphism have not been clearly defined. The relative roles of the two main central regulators of GH secretion, GHRH and somatostatin (SRIF) have been studied extensively in the rat in which gender specificity in GH profiles is striking.

Administration of GHRH antiserum reliably inhibited GH pulses in both sexes (2, 3, 4), indicating the crucial role of endogenous GHRH for GH pulse generation. SRIF antiserum in contrast did not alter GH pulse occurrence but increased interpulse GH levels, indicating that SRIF is important for the maintenance of basal GH secretion in both sexes. However, passive immunization to GHRH in males was ineffective in altering baseline GH but potently suppressed it in females (2). Thus, in the rat, endogenous GHRH has a sexually dimorphic role in terms of regulating basal GH output.

In previous studies a synthetic GHRH antagonist (N-Ac-Tyr1, D-Arg2) GHRH-(1–29) (GHRH antagonist) was found to significantly suppress nocturnal GH secretion in both men and women (5, 6). To investigate whether sexual dimorphism in baseline GH secretion is related to endogenous GHRH, we studied 24-h GH secretion in young normal men and women during a 24-h infusion of GHRH antagonist.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

The Institutional Review Board and the General Clinical Research Center at the University of Michigan Medical Center approved this study. Written consent was obtained from all participants before entry into the study. Six healthy men (age 23.3 ± 1.1 yr, body mass index 24.1 ± 0.65 kg/m2, IGF-I 309 ± 35 µg/liter, plasma testosterone 4.2 ± 0.6 µg/liter) and five healthy women in the midfollicular stage of the cycle (age 22.6 ± 0.9 yr, body mass index 21.6 ± 0.91 kg/m2, IGF-I 298 ± 34 µg/liter, plasma estradiol 39.4 ± 4.6 ng/liter) chose to participate. All subjects had unremarkable past medical histories. A screening physical exam and baseline hematological and biochemical tests were within normal limits. None of the subjects were receiving any medications known to influence GH secretion. The women specifically were not taking oral contraceptive pills and had naturally occurring regular menstrual cycles. A negative pregnancy test was confirmed before admission for all women. A negative urine ovulation test confirmed that the women were in the follicular phase of the menstrual cycle before each admission. All women had expected menstrual bleeding within 2–4 wk after each study.

Protocol

The study was performed at the General Clinical Research Center of the University of Michigan. All subjects were admitted and studied twice. In random order, the subjects received either a continuous 27-h infusion of GHRH antagonist at 33 µg/kg·h or an infusion of normal saline at the same rate (15 ml/h). This dose was previously shown by us to provide a near-maximal inhibition of GH pulsatility both in men and in women (6, 7). In the men, the studies were performed with at least 1 wk between admissions, and in women at least a month had to lapse until their next menstrual cycle. All studies in women were performed on d 7.5 ± 0.56 (or d 5–10) after the onset of menstrual bleeding. Mealtimes were standardized, and snacking and napping were prohibited. Lights were turned on at 0700 h and turned off at 2300 h.

Subjects were admitted at 1800 h on d 1. Two heparinized cannulas were inserted into veins in both forearms for the purpose of blood drawing and the infusion. On d 2 at 0600 h, an infusion of GHRH antagonist or saline was begun and continued until 0900 h on d 3. Sampling for GH began at 0700 h on d 2 and continued every 10 min until 0900 h on d 3. The first hour of the infusion of GHRH antagonist or saline was used to allow for the decay in circulating GH concentration that was a result of GH secreted before the GHRH antagonist infusion. As a control a bolus of GHRH-44 (0.33 µg/kg, Bachem, Torrance, CA) was given on d 3 at 0700 h, and blood sampling was continued until 0900 h.

Assays

Plasma GH was measured in duplicate using a chemiluminometric assay (Nichols Institute Diagnostics, San Juan Capistrano, CA) with an assay sensitivity of 0.01 µg/liter as previously described (8). All samples from both admissions for a single subject were run in the same assay. Assays for screening labs [complete blood count, biochemical profile, TSH, IGF-I, and testosterone/estradiol] were performed by the Pathology Laboratories of the University of Michigan Medical Center using routine methodologies.

Data analysis

Analysis of GH pulsatility were performed by Cluster Program version 7.0 with a cluster size of 2 x 2 and a t statistic of 3 and 2 for detecting significant increases and decreases in GH, respectively. The minimum absolute peak value was set at 0.03 µg/liter. The mean pulse amplitude was calculated for each subject during both GHRH antagonist and saline as the average of the cluster-defined peaks greater than 0.03 µg/liter (9). Twenty-four-hour mean GH was calculated as the average of all GH values over the 24-h period. Twenty-four-hour trough GH was determined as the average of the lowest 5% of the GH values in the 24-h period. The GH response to GHRH was calculated using area under the curve of GH vs. time between 0700 and 0900 h.

The 24-h profiles were also analyzed by waveform-dependent deconvolution to estimate the total, pulsatile, and baseline GH secretion as well as GH half-life (10).

Data are shown as mean ± SEM. All comparisons between GHRH antagonist and saline protocols were made using two-tailed paired t tests. Data that were not normally distributed were logarithmically transformed before analysis. A P < 0.05 was assumed to indicate statistical significance.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Figure 1Go shows the composite picture of GH profiles in both sexes during saline and GHRH antagonist infusions. GHRH antagonist suppressed GH secretion in all subjects. Over the 24-h time period, men suppressed their area under the curve GH levels by 75 ± 3.5%, P = 0.0003, and women by 52.7 ± 14.0%, P = 0.039.



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  		FIG. 1. Mean (±SE) plasma GH concentrations in six men (upper panel) and five women (lower panel) during iv infusion of either normal saline (open symbols) or GHRH antagonist (closed symbols).

 
Table 1Go shows a comparison between the effects of GHRH antagonist and saline on discrete parameters of GH secretion. In all subjects by cluster analysis, the mean GH and mean pulse amplitude suppressed during GHRH antagonist infusion. Similarly, by deconvolution analysis total GH secretion and pulsatile GH secretion were similarly suppressed by GHRH antagonist, whereas GH half-life remained unchanged. GH responses to GHRH were significantly suppressed by GHRH antagonist in both sexes (Fig. 2Go).


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  		TABLE 1. Discrete parameters of GH secretion in six men and five women during normal saline or GHRH antagonist infusions

 


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  		FIG. 2. Plasma GH concentrations (M ± SE) in six men (left panel) and five women (right panel) in response to GHRH 0.33 µg/kg iv. The GHRH bolus was given during the infusion of either normal saline (open symbols) or GHRH antagonist (closed symbols).

 
Figure 3Go shows individual values of trough GH (by cluster) and basal GH secretion (by deconvolution) in all subjects. In men, trough GH did not change significantly during GHRH antagonist infusion: from 0.029 ± 0.008 to 0.022 ± 0.003 µg/liter (P = 0.54). In women, in contrast, trough GH declined significantly (P = 0.008) from 0.104 ± 0.021 to 0.066 ± 0.011 µg/liter, or 33.4 ± 5.6%.



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  		FIG. 3. Trough GH concentrations (upper panels) and basal GH secretion (lower panels) in six men and five women during the normal saline (NS) and GHRH antagonist infusions.

 
Using the deconvolution analysis, there was no decline in the basal GH secretion in men (1.97 ± 0.47 vs. 1.56 ± 0.23 µg/liter·min, P = 0.81). In contrast, the same analysis in women disclosed significant suppression of basal GH secretion in women: from 5.24 ± 1.08 to 2.90 ± 0.56 µg/liter·min (P = 0.006), with the average suppression of 43.3 ± 7.1%.

GHRH antagonist was well tolerated in all subjects. Subjects were blinded to the infusion and could not distinguish between the GHRH antagonist and saline when questioned on d 3.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Sexual dimorphism in the somatotrophic axis has been clearly demonstrated in rats in which distinct divergence in GH profiles has been attributed to differences in neuroendocrine timing influence. The pulsatility of GH secretion in the male rat vs. the relative continuity of the GH release in female rats has been shown to determine differences in somatic growth, cytochrome P450 enzymes, IGF-I mRNA content in different tissues, and circulating GH-binding protein levels (11, 12, 13). The differential parameters of GH secretion (pulses vs. baseline secretion) may carry specific messages that are tissue specific and possess major biological significance. In this context, elucidation of the neuroendocrine mechanisms responsible for the generation of GH pulses or the maintenance of the interpulse GH output acquires practical value. Whether the same can be said for the importance of the endogenous pattern of GH profiles in humans is still uncertain, but the early data by Jorgensen et al. (14) and Jaffe et al. (15) suggest that it may be the case.

To investigate the role of endogenous GHRH in humans, we employed a competitive GHRH antagonist that has been shown to significantly suppress GH secretion. Using this tool, we could draw some general conclusions regarding the role of GHRH in GH pulsatility and could specifically ascertain whether GHRH secretion in humans is sexually dimorphic.

In this study, we chose to examine young healthy women during the midfollicular phase of the menstrual cycle, at the time of the maximal GH output (16, 17).

The GH profiles of young men and women during the early follicular phase of the menstrual cycle have been previously studied, and although no gender-based differences were found in total GH secretion, dissimilarity in the pattern of GH secretion in men and women were observed (1). Specifically, mean valley GH concentrations were twice as high in women. Furthermore, whereas men had virtually absent GH inputs and GH pulse occurrence during the morning and early afternoon hours, GH pulsatility at that time was very active in women. Divergence between genders was also shown with respect to suppressibility of spontaneous and GHRH-stimulated GH secretion by recombinant human IGF-I (1). These data suggest that gender-specific differences in human GH secretion likely reflect set differences in the timing of a delicate neuroendocrine balance of positive and negative influences on GH secretion (namely, GHRH and SRIF).

The current protocol allowed us to study discrete parameters of GH pulsatility in men and women over a 24-h time period under baseline conditions and during an infusion of GHRH antagonist. The differences between the responses of GH pulses and the interpulse levels in men and women permitted us to ascertain the relative role of GHRH in both sexes. Despite employing a relatively high dose of GHRH antagonist (6, 17), we could not achieve a complete elimination of the pituitary responsiveness to GHRH, as evidenced by the diminished but still present GH responses to a physiological dose of exogenous GHRH. This may explain the persistence of GH pulses in both sexes albeit at a markedly diminished amplitude, or the pulses could have been due to a non-GHRH stimulus as demonstrated in patients with genetic GHRH resistance (18). Diminished pulse amplitude was the main determinant of suppressed daily GH output in both sexes.

The main finding of this study was the sexually dimorphic role of GHRH in the maintenance of baseline GH secretion. This was demonstrated by two independent assessments: direct calculation of the trough GH and estimation of the baseline GH secretion using deconvolution methodology. One could argue that the baseline GH levels in men were very low to start with, and additional suppression by the GHRH antagonist could not be technically detected, similar to what was observed in male rats (2). However, even trough GH concentrations in men were at least twice the assay sensitivity, and their reliable measurement was not a technical problem. In addition, we have shown previously that octreotide infusion in young men causes a reliable decline in the trough GH levels that was easily detectable by the immunochemiluminometric assay (19). Thus, the lack of basal GH suppression in men is not a technical artifact but a true biological phenomenon. In contrast, GHRH antagonist reliably suppressed baseline GH levels in women similar to the effect observed in rats under the influence of GHRH antiserum (2, 3). There still remains a possibility that the lack of obvious decline in the basal GH secretion in men was due to the relatively small size of the study group. A power analysis using the existing data has shown that at least 35–75 subjects would be needed to have an 80% chance of reaching a level of statistical significance. Thus, even if physiologically present, the role of endogenous GHRH in the maintenance of basal GH secretion is minor.

Recently Low et al. (20) demonstrated that SRIF knock-out male mice exhibit feminized GH secretory patterns. Thus, the role of endogeneous SRIF as an important mediator of sexual dimorphism of GH secretion is undisputed. Additional studies with a somatostatin antagonist (21) in humans might be helpful to further investigate the neuroendocrine balance involved in the sexual dimorphism of the somatotrophic axis. Traditionally, conclusions about the potential involvement of SRIF in the regulation of GH pulsatility in humans were inferred from the classical model of Plotsky and Vale (4) obtained in male rats. Based on that model, all alterations in the baseline GH release were ascribed to the changes in SRIF secretion. Our data show that although such a conclusion is likely to be correct in men, it is no longer applicable to women because either SRIF increase or GHRH decrease may equally explain the altered baseline or interpulse GH secretion. We have shown recently that plasma ghrelin concentrations are about 3-fold higher in women in the mid- to late follicular phase than in men (22). Because ghrelin is a known potentiater of GHRH action, its role in the sexual dimorphism of GH secretory profiles will have to be addressed in more detailed studies in the future.

We conclude that endogenous GHRH has differential roles in maintaining baseline GHRH in women and men and propose a model of sexually dimorphic patterns of GHRH secretion. Our previous data have shown that nocturnal GHRH output was lower in women than men, explaining the relatively lower magnitude of their nocturnal GH rise (5). Our current data indicate that GHRH is tonically secreted during the daytime in women but not men. Thus, we suggest that the female pattern of GHRH secretion is characterized by GHRH pulses superimposed on tonically elevated GHRH levels during the day and by relatively blunted nocturnal GHRH release. In contrast, the male pattern of GHRH secretion consists of acute periodic GHRH bursts arising from a near-zero GHRH background and of powerful nocturnal GHRH output.


   Footnotes
 
This work was supported by the Endocrine Fellowship Foundation Grant (to S.K.J.); a Veterans Affairs Medical Research Service grant (to A.L.B.); and National Institutes of Health Grant MO1-RR-00042 (General Clinical Research Center).

Abbreviation: SRIF, Somatostatin.

Received February 13, 2003.

Accepted July 14, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Jaffe CA, Ocampo-Lim B, Guo W, Drueger K, Sugahara I, DeMott-Friberg R, Bermann M, Barkan AL 1998 Regulatory mechanisms of growth hormone secretion are sexually dimorphic. J Clin Invest 102:153–164[Medline]
  2. Painson J-C, Tannenbaum GS 1991 Sexual dimorphism of somatostatin and growth hormone-releasing factor signaling in the control of pulsatile growth hormone secretion in the rat. Endocrinology 128:2858–2866[Abstract]
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  6. Orrego JJ, Russell-Aulet M, DeMott-Friberg R, Barkan AL 2001 Semiquantification of hypothalamic GH-releasing hormone output in women: evidence for sexual dimorphism in the mechanism of the somatopause. J Clin Endocrinol Metab 86:5485–5490[Abstract/Free Full Text]
  7. Russell-Aulet M, Jaffe CA, Demott-Friberg R, Barkan AL 1999 In vivo semiquantification of hypothalamic growth hormone-releasing hormone (GHRH) output in humans: evidence for relative GHRH deficiency in aging. J Clin Endocrinol Metab 84:3490–3497[Abstract/Free Full Text]
  8. Jaffe CA, DeMott-Friberg R, Barkan AL 1993 Suppression of growth hormone (GH) secretion by a selective GH-releasing hormone (GHRH) antagonist. J Clin Invest 92:695–701
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  11. Legraverend C, Mode A, Wells T, Robinson ICAF, Gustafsson J-A 1992 Hepatic steroid dehydroxylating enzymes are controlled by the sexually-dimorphic pattern of growth hormone secretion in both normal and dwarf rats. FASEB J 6:711–718[Abstract]
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  15. Jaffe CA, Turgeon DK, Lown K, DeMott-Friberg R, Watkins PB 2002 Growth hormone secretion pattern is an independent regulator of growth hormone actions in humans. Am J Physiol Endocrinol Metab 283:E1008–E1015
  16. Faria ACS, Bekenstein LW, Booth Jr RB, Vaccaro VA, Asplin CM, Veldhuis JD, Thorner MO, Evans WS 1992 Pulsatile growth hormone release in normal women during the menstrual cycle. Clin Endocrinol (Oxf) 36:591–596[Medline]
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  20. Low MJ, Otero-Corchon V, Parlow AF, Ramirez JL, Kumar U, Patel YC, Rubinstein M 2001 Somatostatin is required for masculinization of growth hormone-regulated hepatic gene expression but not of somatic growth. J Clin Invest 107:1571–1580[Medline]
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