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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 12 6291-6296
Copyright © 2004 by The Endocrine Society

Contributions of Gender and Systemic Estradiol and Testosterone Concentrations to Maximal Secretagogue Drive of Burst-Like Growth Hormone Secretion in Healthy Middle-Aged and Older Adults

Johannes D. Veldhuis, James T. Patrie, Kimberly T. Brill, Judith Y. Weltman, Eugenio E. Mueller, Cyril Y. Bowers and Arthur Weltman

Department of Internal Medicine (J.D.V.), Mayo Medical and Graduate Schools of Medicine, General Clinical Research Center, Mayo Clinic, Rochester, Minnesota 55905; Departments of Health Evaluation Sciences (J.T.P.), Human Services (K.T.B., J.Y.W.), and Internal Medicine (A.W.), General Clinical Research Center, University of Virginia, Charlottesville, Virginia 22908; Department of Pharmacology and Toxicology (E.E.M.), University of Milan, 20129 Milan, Italy; and Tulane University Health Sciences Center (C.Y.B.), New Orleans, Louisiana 70112

Address all correspondence and requests for reprints to: Johannes D. Veldhuis, Division of Endocrinology and Metabolism, Department of Internal Medicine, Mayo Medical and Graduate Schools of Medicine, General Clinical Research Center, Mayo Clinic, Rochester, Minnesota 55905. E-mail: veldhuis.johannes{at}mayo.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
To test whether concentrations of estradiol and testosterone predict GH responses to mechanistically distinct secretagogues in healthy older adults, we studied 16 volunteers (n = 10 men, n = 6 women, age 49–72 yr) in each of six randomly ordered sessions as follows: 1) saline; 2) L-arginine; 3) aerobic exercise; 4) GHRH; 5) GH-releasing peptide (GHRP)-2; and 6) somatostatin-induced rebound. Statistical comparisons disclosed that stimulus type (P < 0.001) and the interaction between gender and stimulus type (P = 0.023) determine GH secretion. In women, each secretagogue, except exercise and somatostatin-induced rebound, stimulated GH secretion by 2.6- to 6.4-fold over saline/rest (P < 0.023). In men, somatostatin-induced rebound drove GH secretion by 4.6-fold (P = 0.004), exercise by 16-fold (P < 0.001), and other secretagogues by 18- to 109-fold over saline/rest (each P < 0.001). Gender comparisons disclosed greater GH secretion in men than women after somatostatin-induced rebound (P = 0.008) and GHRP-2 injection (P < 0.001) and conversely greater GH secretion in women than men after saline (P = 0.013). Regression analysis showed that individual concentrations of estradiol (r = 0.80, P = 0.002) and testosterone (r = 0.63, P = 0.008) and their combination (r = 0.86, P < 0.001) strongly predict responses to GHRP-2 only. We conclude that among healthy middle-aged and older adults, the action of GHRP is uniquely determined by gender and physiological concentrations of testosterone and estradiol.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
INTEGRATED CONCENTRATIONS AND daily secretion rates of GH fall progressively after young adulthood (1, 2). In cross-sectional analyses, GH production declines by 50% approximately every 7 y in men beginning in young adulthood (3, 4, 5). Gender comparisons have indicated that GH output decreases nearly 2-fold less rapidly in premenopausal women than comparably aged men (6, 7, 8, 9). Endogenously maintained GH release remains greater in women than men after age 50 yr (10). However, the basis for this consistent sex difference in unstimulated GH secretion has not been established. Moreover, how gender influences acute GH secretory responses to mechanistically separate secretagogues has not been elucidated.

The proximate neuroendocrine basis for diminished 24-h GH secretion in older individuals is a reduction in the mass of GH secreted per burst (3, 4, 5). The mass of GH secreted per burst is under the reciprocal control of peptidyl agonists and antagonists (11, 12, 13, 14). Important facilitative signals include GHRH and possibly ghrelin/GH-releasing peptide (GHRP), the actions of which are inhibited by somatostatin (1, 15, 16, 17). Accordingly, plausible mechanisms underlying diminished GH secretory-burst mass in healthy middle-aged and older adults could involve relative GHRH or ghrelin/GHRP deficiency and/or somatostatin excess. Evidence exists in support of all three considerations (18, 19). Nonetheless, to our knowledge, no clinical studies have compared GH secretion in response with mechanistically distinguishable secretagogues in the same cohort of middle-aged and older individuals.

The present investigation assesses the impact of gender and sex-steroid hormone concentrations on maximal feed-forward drive by injected GHRH acting directly on somatotrope cells (11, 20, 21, 22); infused GHRP-2, which opposes somatostatin inhibition in the hypothalamus, inducing GHRH release and stimulates GH secretion directly (23, 24, 25, 26, 27, 28, 29); endogenous GHRH, putatively released in response to exogenous infusion and withdrawal of somatostatin (29, 30, 31, 32, 33); acute somatostatin withdrawal, presumptively enforced by L-arginine infusion (34, 35, 36); and the complex physiological stimulus of aerobic exercise (37, 38).


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

Ten healthy older men and six estrogen-unreplaced postmenopausal women (age range, 49–72 yr) provided voluntary written informed consent, as approved by the institutional review board. Screening evaluation included a detailed medical history and physical examination, and biochemical exclusion of renal, hepatic, endocrine, hematologic, metabolic, and systemic disease. Subjects were nonsmokers and were not taking glucocorticoids, herbal supplements, hormones or medications other than acetaminophen, angiotensin-converting enzyme inhibitors, diuretics, or laxatives or using skin ointments or topical dermal or ophthalmic preparations.

Clinical protocol

Volunteers entered the General Clinical Research Center on the evening before study to allow overnight adaptation to the unit. To limit nutritional confounds, participants ingested a standardized evening meal at 1800 h (10 kcal/kg of 55% carbohydrate, 15% protein, and 30% fat) and then remained fasting until noon the next day. Lights were turned off at 2300 h and subjects remained at bed rest except for lavatory use until called to exercise the next morning or until 1200 h the next day. In the morning, bilateral iv catheters were placed in forearm veins at 0700 h to permit simultaneous blood sampling and secretagogue infusion (Fig. 1Go). Blood samples (1.5 ml) were withdrawn every 10 min for 4 h beginning at 0800 h.



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  		FIG. 1. Schematized outline of overall study paradigm.

 
Each subject undertook six randomly ordered, separate-day study sessions comprising: 1) saline infusion; 2) bolus injection of GHRH (1 µg/kg iv) at 0930 h; 3) bolus injection of GHRP-2 (1 µg/kg iv) at 0930 h; 4) constant infusion of L-arginine (30 g iv over 30 min) started at 0900 h; 5) continuous infusion of somatostatin (5 µg/kg/h over 90 min) initiated at 0800 h; and 6) 30 min of intensive exercise set at a power output midway between the individually predetermined lactate threshold and peak oxygen consumption and begun at 0900 h Thus, all interventions ended at 0930 h.

Hormone assays

Estradiol was quantitated by automated chemiluminescence assay (ACS 180, Bayer Corp., Norwood MA) with sensitivity 10 pg/ml (37 pmol/liter) and intra- and interassay coefficients of variation (CVs) of 5.3 and 6.4%; and total testosterone by solid-phase RIA (Coat-a Count, Diagnostic Products, Los Angeles, CA) with sensitivity 20 ng/dl (0.7 nmol/liter) and intra- and interassay CVs of 6.1% and CV of 7.9%, respectively (5, 39, 40). GH concentrations were measured by modified chemiluminescence assay (Nichols Laboratories, San Juan Capistrano, CA). This procedure has a sensitivity of 0.005 µg/liter for 22 kDa recombinant human GH standard and 30% cross-reactivity with 20 kDa GH (4, 41). In the present study, no GH measurements fell less than 0.025 µg/liter. Intraassay variance was defined as a power function (y = axb) of sample GH concentrations based on the dispersion in all observed replicates in any subject’s 4-h time series (1, 42).

Analysis of GH secretion

Multiple-parameter deconvolution analysis was applied to compute GH secretory burst mass (amount of hormone secreted per pulse per unit distribution volume, micrograms per liter), frequency, the basal secretion rate, and the slow-phase GH half-life (43, 44). The biexponential kinetic model consisted of a fixed rapid-phase half-life (3.5 min) and a variable (fitted) slow phase half-life (apportioned as 63% of the total decay amplitude). The entire 4-h GH profile (0800–1200 h) was fit initially. Thereafter the mass of GH secreted in bursts was summed over the 2.5-h interval after each stimulus (0930–1200 h). This analytical strategem allows valid partitioning of basal and secretagogue-induced GH secretion.

Statistical analysis

Logarithmically transformed deconvolution parameters were analyzed in a mixed-effects, two-way ANOVA repeated-measures randomized-block design (45). Model specification included gender (two factors), intervention type (six factors), and their interaction and random effects representing between and within-subject error terms. The variance-covariance matrix was estimated by the Huber and White empirical sandwich estimator (46). Post hoc contrasts were based on the Tukey’s honestly significantly different criterion and an a priori experiment-wise type I error rate of 0.05.

Bivariate regression was applied to relate the natural logarithm of the sum of GH secretory-burst mass (micrograms per liter per 2.5 h) to concurrent concentrations of estradiol and testosterone in the combined cohorts (n = 16). Logarithmic transformation of the biologic response is relevant because GH secretion is asymptotically maximal under any stimulus.

Clinical characteristics of the study subjects were compared between genders using an unpaired two-tailed Student’s t test (46).

Data are given as the arithmic mean ± SEM of untransformed data.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Table 1Go summarizes screening baseline characteristics of the two cohorts. Men and women did not differ by age or fasting (0800 h) serum concentrations of glucose, insulin, IGF-I, or estradiol. Testosterone concentrations were higher in men (P = 0.003), and body mass index was lower in women (P < 0.01).


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  		TABLE 1. Clinical characteristics of volunteers

 
Figure 2Go gives mean cohort profiles of GH concentrations sampled every 10 min under all six conditions separately in men and women. Deconvolution analysis was applied to quantitate stimulated GH secretory-burst mass (micrograms per liter per 2.5 h) (Fig. 3Go). Two-way ANOVA revealed that secretagogue type (P < 0.001) and the interaction between stimulus type and gender (P = 0.023) significantly determined the summed mass of GH secreted in 2.5 h. In both genders, secretagogue type was a significant determinant of GH secretion (P < 0.01 in men and women).



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  		FIG. 2. Mean GH concentration time plots in 10 men (A) and six women (B) before and after stimulation with saline, GHRP-2, GHRH, L-arginine, exercise, and somatostatin-induced rebound GH release. Data are the mean ± SEM (see Subjects and Methods).

 


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  		FIG. 3. Impact of gender and specific secretagogue type on the mass of GH secreted in bursts in older men and estrogen-unreplaced postmenopausal women. Data are the arithmetic mean ± SEM (micrograms per liter per 2.5 h). Indicated significance levels were determined by two-way ANOVA (see Subjects and Methods). Post hoc gender contrasts are denoted by individual P values above paired bars. See Results for comparisons among secretagogue types.

 
In women, stimulated GH secretion exceeded that observed in the control state (saline/rest) in three circumstances only: 1) L-arginine by 5.5 (1.5–20)-fold (P = 0.011); 2) GHRH by 4.5 (1.2–17)-fold (P = 0.023); and 3) GHRP-2 by 6.4 (1.7–24)-fold (P = 0.006). GH responses to exercise [2.6 (0.9–9.4)-fold] and somatostatin-induced rebound [0.48 (0.13–1.8)-fold] did not differ significantly from control values. Post hoc comparisons in women disclosed that exercise evoked 5.2 (1.5–24)-fold (P = 0.012) more GH release than somatostatin-induced rebound and stimulation by L-arginine, GHRH, and GHRP-2 did not differ.

In men, the effect of each secretagogue significantly exceeded that of saline/rest as follows: 1) L-arginine by 18 (6.5–49)-fold (P < 0.001); 2) exercise by 16 (5.9–45)-fold (P < 0.001); 3) GHRH by 19 (7.0–53)-fold (P < 0.001); 4) GHRP-2 by 49 (40–53)-fold (P < 0.001); and 5) somatostatin-induced rebound by 4.6 (1.7–13)-fold (P = 0.004). Post hoc comparisons in the male disclosed that stimulation by GHRP-2 was greater than that of L-arginine by 6.1 (2.2–17)-fold (P < 0.001), exercise by 6.7 (2.4–18)-fold (P < 0.001), and GHRH by 5.6 (2.1–15)-fold (P < 0.001). Somatostatin-induced rebound GH secretion was the least effective intervention, in that the following stimuli were more effective: GHRP-2 by 23 (8.4–67)-fold (P < 0.001), L-arginine by 3.9 (1.4–11)-fold (P = 0.009), exercise by 3.7 (1.3–9.8)-fold (P = 0.014), and GHRH by 4.2 (1.2–12)-fold (P = 0.042).

Statistical contrasts by gender identified three major distinctions: women maintained a higher mass of GH secreted in bursts at baseline (saline/rest) than men (P = 0.013); and men achieved greater burst-like GH release than women after somatostatin rebound (P = 0.008) and GHRP-2 infusion (P < 0.001). Absolute GH secretory responses to exercise, L-arginine, and GHRH did not differ significantly by gender.

Bivariate linear regression analysis was used to relate the natural logarithm of GH secretory-burst mass (dependent variable) to concentrations of testosterone and estradiol (independent variables) in the combined cohorts (n = 16) (Fig. 4Go). The amount of GH secreted after bolus GHRP-2 injection was jointly determined by testosterone and estradiol concentrations (r = 0.860, P < 0.001). Both sex steroids contributed significantly to the overall correlation; viz., testosterone, partial r = 0.795 [95% confidence interval (CI), 0.701–0.862] (P < 0.001) and estradiol, partial r = 0.627 (95% CI, 0.478–0.741) (P = 0.012). Comparison of 95% CIs indicated that testosterone and estradiol contribute individually, and comparably, with the bivariate relationship. No other secretagogue manifested significant (protected P < 0.01) correlations with either sex steroid.



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  		FIG. 4. Relationship of GHRP-2-stimulated GH secretory-burst mass (y-axis) to concentrations of testosterone (x-axis, top) and estradiol (x-axis,bottom) in a cohort of 16 healthy middle-aged and older adults. Overall r for the joint dependence of GH secretion on testosterone and estradiol concentrations was +0.860 (r2 = 0.74, P < 0.001).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
According to the present analyses, gender and sex steroid concentrations jointly determine maximally stimulatory effects of certain but not other GH secretagogues in healthy individuals aged 49–72 yr. In particular, somatostatin-induced rebound and GHRP-2 stimulated pulsatile GH release to a severalfold greater degree in men than women. In contrast, under endogenous secretagogue drive (saline infusion at rest), women secrete 5.6-fold more GH in bursts than comparably aged men. All three of the foregoing principal gender differences might be subsumed under the parsimonious hypotheses that women maintain lesser somatostatin outflow and/or greater spontaneous fasting GHRH release and effectiveness than men and men sustain greater postsomatostatin rebound-like and GHRP-induced GHRH outflow than comparably aged women. In principle, mechanistic gender distinctions could be due to relatively elevated systemic estradiol concentrations (in women) and in situ availability of testosterone for aromatization to estradiol (in men).

Aging impairs responses to the majority of clinically used individual GH secretagogues, except insulin-induced hypoglycemia (1, 2, 47). Earlier studies have established that, compared with young controls, older adults have diminished L-arginine, aerobic exercise, GHRH, GHRP-2, and somatostatin-induced GH secretion (1, 2, 30, 48, 49, 50). Complementary to such approaches, the current paradigm examined all five secretagogues in the same middle-aged and older individuals. This strategy unveiled a descending rank order of secretagogue efficacy (maximal stimulation) of the following: GHRP-2 >> GHRH = L-arginine = exercise > somatostatin rebound. The relative order of secretagogue actions did not differ by gender.

Successive exposure to and withdrawal of somatostatin will trigger rebound-like secretion of a burst of GH in vivo and both hypothalamic GHRH and pituitary GH in vivo (29, 30, 32, 51). If these basic concepts apply to the human, then the greater mass of GH released after somatostatin infusion and withdrawal in men than women may reflect expansion of releasable GH stores or accentuation of GHRH outflow and/or action. In relation to these interpretations, estrogen supplementation enhances submaximally stimulatory actions of GHRH in the human (52) and augments pituitary GH stores in the autotransplanted pituitary gland of the rat (53). In principle, testosterone might mediate such actions in men after aromatization in relevant target tissues (1).

Partial molecular silencing of the neuronal ghrelin/GHRP receptor in transgenic mice reduces GH pulse amplitude and IGF-I concentrations in the adult female (but not male) animal (54). On the other hand, in the present clinical comparison, GHRP-2 evoked several times more GH secretion in middle-aged and older men than women. The mechanisms mediating this prominent gender difference have not been elucidated. However, we observed that estradiol and testosterone concentrations individually and jointly predicted maximal responsiveness to GHRP-2 in the combined cohort of 16 volunteers (joint r2 = 0.74). This outcome leaves only 26% of the interindividual variability in GHRP-2 action unaccounted for. Factors such as sleep patterns, diet, relative adiposity, physical fitness, and negative feedback might contribute to the residual (26%) unexplained variability in absolute GH secretory responses to GHRP-2 (1). None of the four other secretagogues tested here exhibited a significant dependence on sex-steroid concentrations. The selectivity of the GHRP-2 association is consistent with the capability of aromatizable androgen or estradiol to potentiate GHRP stimulation and the in vitro capacity of estradiol to induce transcription of the human GHRP-receptor gene (55, 56, 57, 58).

By way of qualification, the present inferences apply to acute stimulation by maximally effective individual peptidyl and nonpeptidyl secretagogues in healthy middle-aged and older adults. In contradistinction, continuous sc infusion of GHRP-2 for 30 d amplifies burst-like GH secretion 2-fold more in estrogen-replaced postmenopausal women than men of similar age (59). In another comparison, constant iv infusion of GHRP-2 augmented pulsatile GH release more in female than male patients with protracted critical illness (60). In both of these contexts, estrogen availability was enhanced by way of either exogenous replacement or endogenous metabolism. This point raises the consideration that in situ generation of estradiol from testosterone in the male cohort studied here contributes to their enhanced responsiveness to GHRP-2 (1). Analyses of the effects of exogenous estradiol in postmenopausal women support the concept of a key role for estrogen in facilitating GHRP action (56, 57). However, at present the relative influence of systemically delivered and locally synthesized estrogen in augmenting GHRP action is not known (61). Moreover, inferences in the human depend on mechanisms developed in basic experiments.

In summary, the present analyses in healthy estrogen-unreplaced postmenopausal women and comparably aged men indicate that: 1) women secrete more GH in pulses than men in the morning when fasting at rest; 2) men secrete more GH than women in response to somatostatin-induced rebound and GHRP-2 infusion but not in response to L-arginine, GHRH, or aerobic exercise; and 3) concentrations of testosterone and estradiol jointly and selectively account for significant (74%) interindividual variability in acute hypothalamopituitary responses to GHRP-2 in the middle-aged and older adult.


   Acknowledgments
 
The authors are grateful to Kandace Bradford for manuscript preparation; Dr. Peter O’Brien (Department of Statistics, Mayo Medical School) for statistical advice; the nursing staff in the General Clinical Research Center for conducting the protocols; Dr. S. M. Anderson, who screened, saw, and injected patients on a fee-for-service basis; Dr. Fred Wagner (BioNebraska Inc., Lincoln, NE) for providing recombinant human GHRH-1,44-NH2; and Kaken Pharmaceutical Co. (Tokyo, Japan) for supplying GHRP-2.


   Footnotes
 
This work was supported in part by the National Center for Research Resources (Rockville, MD) and National Institutes of Health (Bethesda, MD) via General Clinical Research Center Grants M01 RR00585, RR00847, RO1 AG14799, and AG19695.

Abbreviations: CI, Confidence interval; CV, coefficient of variation; GHRP, GH-releasing peptide.

Received April 5, 2004.

Accepted September 20, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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