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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-0854
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 11 6006-6013
Copyright © 2005 by The Endocrine Society

Distinctive Inhibitory Mechanisms of Age and Relative Visceral Adiposity on Growth Hormone Secretion in Pre- and Postmenopausal Women Studied under a Hypogonadal Clamp

Johannes D. Veldhuis, Dana Erickson, Kristi Mielke, Leon S. Farhy, Daniel M. Keenan and Cyril Y. Bowers

Endocrine Research Unit, Department of Internal Medicine, Mayo School of Graduate Medical Education, General Clinical Research Center, Mayo Clinic (J.D.V., D.E., K.M.), Rochester, Minnesota 55905; Departments of Internal Medicine (L.S.F.) and Statistics (D.M.K.), University of Virginia, Charlottesville, Virginia 22904-4135; and Department of Medicine, Tulane University Health Sciences Center (C.Y.B.), New Orleans, Louisiana 70112

Address all correspondence and requests for reprints to: Dr. Johannes D. Veldhuis, Endocrine Research Unit, Department of Internal Medicine, Mayo School of Graduate Medical Education, 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
 
Background: Aging, body composition, and sex steroids jointly determine GH production. However, the actions of any given factor are confounded by the effects of the other two.

Hypothesis: Age and abdominal visceral fat (AVF) mass govern GH secretion via individually distinctive mechanisms, which can be unmasked by short-term sex steroid deprivation.

Design/Subjects: In a university setting, healthy pre- and postmenopausal volunteers underwent GnRH agonist-induced down-regulation for 6 wk to deplete ovarian sex steroids. GH secretion was evaluated by frequent blood sampling, saline vs. dual secretagogue infusions, an irregularity statistic, variable waveform deconvolution analysis, and a simplified feedback model. Computerized tomography was used to estimate AVF mass.

Outcomes/Measures: In the sex steroid-deficient milieu, postmenopausal compared with premenopausal women exhibited 1) lower concentrations of IGF-I (P = 0.028) and GH (P < 0.05); 2) reduced pulsatile, but elevated basal, GH secretion (P < 0.05); 3) more irregular GH patterns (P = 0.027); 4) an attenuated GH response to simultaneous GHRH/GH-releasing peptide-2 stimulation (P < 0.01); and 5) more rapid onset of GH release within secretory bursts (P < 0.01). In contrast, AVF negatively forecast GH responses to L-arginine/GH-releasing peptide-2 (r2 = 0.45; P < 0.001) and L-arginine/GHRH (r2 = 0.57; P = 0.007). From these marked contrasts, model-based analyses predicted distinguishable mechanisms by which aging and AVF alter pulsatile GH production.

Conclusion: Under limited confounding by sex steroids, age and body composition modulate GH secretion via highly selective peptidyl pathways in healthy women.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
EPIDEMIOLOGICAL STUDIES INDICATE that aging in women is marked by combined reductions in GH, IGF-I, estradiol, and testosterone concentrations and a relative increase in abdominal visceral fat mass (AVF) (1, 2, 3, 4, 5, 6, 7). The mechanisms mediating individual effects of age, AVF, and sex steroid concentrations have been difficult to parse, inasmuch as all three factors may be interrelated (8, 9). For example, GH secretion decreases with increasing premenopausal age, greater AVF mass, and decreasing estrogen availability (1, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21). Thus, unequal sex steroid drive in pre- and postmenopausal women (PRE and POST, respectively) would be a strong confounder in studies of how age and body composition separately modulate GH secretion.

In an effort to assess how age and AVF individually govern GH secretion, the present study implements an experimental regimen of reversible pituitary-ovarian suppression in healthy older (POST) and young (PRE) women. The goal was to maintain estradiol and testosterone concentrations in the POST range in healthy PRE volunteers. POST women underwent an identical down-regulation protocol to obviate any unexpected bias induced by the GnRH agonist. GH secretion was appraised by frequent blood sampling, high-sensitivity immunochemiluminometry, validated analytical methods, infusion of saline and pathway-selective GH secretagogues, and a simplified feedback model.


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

A total of 15 healthy PRE (n = 7) and POST (n = 8) women enrolled in and completed all four study sessions (see below). Participants provided voluntary written informed consent, approved by the Mayo institutional review board. The protocol was approved by the U.S. Food and Drug Administration under an investigator-initiated new drug number. Exclusion criteria were recent transmeridian travel (within 10 d), nightshift work, significant weight change (≥3 kg in 1 month), body mass index less than 19 or more than 29 kg/m2, acute or chronic systemic illness, anemia, psychiatric treatment or substance abuse, and failure to provide informed consent. Volunteers were nonsmokers and free of known or suspected cardiac, cerebral, or peripheral arterial or venous thromboembolic disease; breast cancer; or untreated gallstones. None was receiving neuroactive medications. Inclusion criteria were an unremarkable medical history and physical examination, and normal screening laboratory tests of hepatic, renal, endocrine, metabolic, and hematological function.

The mean ± SEM age was 28 ± 1.0 yr (range, 24–31 yr) and 62 ± 3.1 yr (range, 51–78 yr) in PRE and POST volunteers, respectively. Corresponding body mass indices were 26 ± 2.0 (range, 19–29) and 25 ± 1.5 (range, 20–29) kg/m2 (P = NS). PRE women did not use oral contraceptives and had normal menarchal and menstrual histories and a negative pregnancy test. POST status was confirmed by concentrations of FSH greater than 50 IU/liter, LH greater than 20 IU/liter, and estradiol less than 30 pg/ml (<81 pmol/liter). POST volunteers discontinued any hormone replacement at least 6 wk before study (three subjects). Two POST subjects had undergone ovariectomy after clinical menopause (at age 50 and 59 yr) for histologically benign disease.

Overall design

The study was a parallel cohort design. Saline and combined secretagogue infusions were scheduled in a prospectively randomized, placebo-controlled, patient-blinded, within-subject, crossover design.

Hypogonadal clamp

Volunteers received two im injections of leuprolide acetate (3.75 mg) 3 wk apart in the early follicular phase (PRE). Infusion sessions were scheduled 38–42 d after the first leuprolide injection.

Sampling paradigm

Volunteers stayed overnight in the unit after a constant meal (500 kcal) at 2000 h. Participants then remained fasting overnight until 1400 h the next day. At 0800 h, plasma samples (1.5 ml) were collected every 10 min for 6 h while subjects were fasting.

Infusions

Infusions comprised iv delivery of 1) saline (1000–1400 h); 2) L-arginine (30 g) over 30 min (1000–1030 h), followed immediately by bolus GHRH (1 µg/kg; GRF, Serono, Norwalk, MA); 3) L-arginine (see above), followed by a bolus of GH-releasing peptide-2 (GHRP-2; 3 µg/kg); and 4) both GHRH and GHRP-2 (1 µg/kg·h each, 1000–1400 h). These doses are maximally stimulatory (22, 23).

Hormone assays

Plasma GH concentrations were measured in duplicate by automated, ultrasensitive, double-monoclonal, immunoenzymatic, magnetic particle-capture chemiluminescence assay using 22-kDa recombinant human GH as the assay standard (Sanofi Diagnostics Pasteur Access, Chaska, MN). All samples (n = 148) from any given subject were analyzed together. The sensitivity of the assay was 0.010 µg/liter (defined as 3 SD above the zero dose tube). Interassay coefficients of variation were 7.9% and 6.3%, respectively, at GH concentrations of 3.4 and 12.1 µg/liter. The intraassay coefficients of variation were 4.9% at 1.12 µg/liter and 4.5% at 20 µg/liter. No values fell below 0.020 µg/liter. Cross-reactivity with GH-binding protein or 20-kDa GH is less than 5%. Serum LH, FSH, estradiol, and testosterone concentrations were quantitated by automated competitive chemiluminescent immunoassay (ACS Corning, Bayer, Tarrytown, NY), and total IGF-I, prolactin, and SHBG concentrations were measured by immunoradiometric assay, as described previously (7, 24).

Visceral fat mass

Intraabdominal visceral fat mass was estimated by single-slice abdominal computed tomography (CT) scan at L3, exactly as previously reported (1).

Approximate entropy (ApEn)

ApEn (1, 20%) provides a scale- and model-independent regularity statistic to quantitate the orderliness of serial measurements (25). Higher ApEn denotes greater relative randomness or disorderliness of subpatterns. Mathematical models and clinical experiments establish that increased irregularity predicts altered feedforward and/or feedback coupling within a neuroendocrine axis with high sensitivity and specificity (both >90%) (26, 27).

Deconvolution analyses of basal (nonpulsatile), pulsatile, and secretagogue-stimulated burst-like GH secretion

Pulsatile and basal GH secretion was estimated from each 6-h GH concentration time series using a new flexible waveform deconvolution model (28). This approach yields a maximum-likelihood solution statistically conditioned on biexponential kinetics and a priori estimates of pulse-onset times (29, 30). The rapid- and slow-phase half-lives of GH were assumed to be 6.93 and 20.8 min, respectively, with fractional contributions of 37% and 63% (31). Pulse times were identified independently as previously described (28). The distribution of interburst intervals was represented algebraically as a Weibull probability density defined by a pulse rate (number of events per 24 h, {lambda}) and interpulse interval regularity ({gamma}) (32). A value of {gamma} > 1.0 signifies greater regularity than that of the classic Poisson distribution of random event times, wherein the coefficient of variation definitionally equals 100%. The waveform of secretory bursts (shape of plot of instantaneous secretion rate over time) was represented by a three-parameter generalized {gamma} function, thus allowing for either symmetric or variably asymmetric bursts (29, 30). One measure of shape is the modal time (minutes) required to reach maximal secretion within bursts (28). All seven PRE (and analogously eight POST) GH concentration-times series from any given infusion session (protocol) were analyzed together to estimate 1) a cohort-specific secretory burst waveform, 2) a cohort-specific basal (nonpulsatile) GH secretion rate, and 3) pulsatile GH secretion in each subject (represented algebraically by individual random effects of burst mass about the cohort mean). The SE of the mode and mean were derived analytically for waveform and basal secretion parameters, as summarized in the Appendix of Refs.33 and 34).

Model-assisted interpretations

Structure of three-peptide ensemble. For modeling purposes, interactions among GH, GHRH, GHRP/ghrelin, and somatostatin assumed that 1) somatostatin withdrawal after a pulse of GH evokes rebound-like secretion of GHRH and GH; 2) GHRP directly stimulates GH release; and 3) GHRP opposes somatostatin’s inhibition of both GHRH secretion by the arcuate nucleus and GH release by the pituitary gland (35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45).

Hypotheses. Model-based simulations were used to test whether one of the following basic mechanisms in POST women could, in principle, account for the observed contrasts in GH secretion: 1) reduced GHRH efficacy, 2) decreased GHRP/ghrelin efficacy, and 3) greater somatostatin secretion (23, 46, 47, 48).

Other statistical comparisons

An unpaired, two-tailed Student’s t test was used to compare statistically independent measures (49). Bivariate linear regression analysis was applied to examine the relationship between saline- or secretagogue-stimulated pulsatile GH secretion and AVF or age in the combined cohorts (n = 15) (50). In view of the need to perform four linear regressions, significance was construed at protected P ≤ 0.0125 (51). Data are presented as the mean ± SEM.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Table 1Go shows fasting hormone concentrations. Concentrations of GH, IGF-I, and estradiol were higher in PRE than POST volunteers; FSH was higher in POST, and SHBG, prolactin, LH, and testosterone did not differ by age.


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  		TABLE 1. Fasting hormone concentrations in PRE and POST women

 
Figure 1Go illustrates GH concentration profiles in four PRE and POST women during saline infusion. Figure 2Go shows that 1) unstimulated GH secretory burst mass was 56% lower in POST than PRE volunteers (P < 0.05); 2) GH interburst intervals were comparable, viz. 50 ± 4.7 min (POST) and 55 ± 5.0 min (PRE; not significantly different); 3) interpulse variability was similar ({gamma} = 2.2 and 2.4); and 4) basal GH secretion was higher in POST subjects (P < 0.01).



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  		FIG. 1. Illustrative GH concentration profiles (continuous lines) obtained in the morning fasting during saline infusion in four PRE and four POST healthy women (above, PRE; below, POST). Asterisks on the x-axis mark pulse onset times. The three insets are rescaled to visualize smaller GH pulses. Volunteers were studied in a low sex steroid milieu induced by administration of leuprolide beginning 6 wk earlier. Interrupted curves are predicted by flexible waveform deconvolution analysis. GH was measured by high-sensitivity immunochemiluminometric assay of plasma samples collected every 10 min for 6 h (0800–1400 h).

 


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  		FIG. 2. Impact of PRE vs. POST status on pulsatile and basal GH secretion evaluated during saline infusion during experimentally imposed sex-steroid depletion. Data are the mean ± SEM (n = 7, PRE; n = 8, POST). P values reflect unpaired parametric comparisons after log transformation. P = NS denotes P > 0.05.

 
Figure 3Go presents the mean (±SEM) GH concentration profiles for all four interventions, as quantitated in Fig. 4AGo. Sequential infusion of L-arginine/GHRP-2 drove pulsatile GH secretion by 16-fold in PRE and by 20-fold in POST subjects, conferring comparable absolute responses (P > 0.10). Combined GHRH/GHRP-2 infusion stimulated GH release by 23- and 24-fold in PRE and POST women, respectively, yielding a 2.0-fold greater absolute response in PRE volunteers (P < 0.01). L-Arginine/GHRH infusion increased pulsatile GH secretion by 19-fold (PRE) and 48-fold (POST), resulting in similar absolute maxima (P > 0.60).



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  		FIG. 3. Mean (±SEM) GH concentration profiles in seven PRE and eight POST women. Volunteers underwent frequent (10-min) blood sampling for 6 h in the morning fasting after pituitary-ovarian down-regulation. Infusions of saline and sequential or combined secretagogue pairs were begun after 2 h of baseline sampling (see Subjects and Methods). Note rescaling of the y-axis for the two saline/saline sessions.

 


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  		FIG. 4. A, Impact of infusion of saline and paired secretagogues on pulsatile GH secretion (micrograms per liter per hour) in PRE and POST women in an experimentally imposed, hypogonadal milieu. Data are presented otherwise as described in the text. B, Mean GH secretory burst shape (normalized waveform) in each of the four infusion conditions in PRE (top) and POST (bottom) cohorts. Curves depict the estimated time course of instantaneous GH secretion beginning with the onset of a burst. The modal time to achieve maximal GH secretion provides a statistical measure of the rapidity of onset of burst-like GH release (see Table 2Go).

 
Variable waveform deconvolution analysis allowed estimation of the apparent shape (time evolution) of underlying GH secretory bursts (Fig. 4BGo). POST women exhibited significantly (1.9-fold; P < 0.01) accelerated GH release within individual bursts during saline, viz. under endogenous drive (Table 2Go). Sequential infusion of L-arginine and either GHRH or GHRP-2 significantly abbreviated the latency to maximal GH release in PRE volunteers (P < 0.01), such that mean burst shape no longer differed from that in POST volunteers. Responses to combined GHRH/GHRP-2 stimulation in PRE women were intermediate.


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  		TABLE 2. Modal times to maximal secretion in GH secretory bursts

 
ApEn was used to quantitate the feedback-dependent orderliness or regularity of sample by sample GH release in the saline-infused session. GH secretion was markedly more irregular (disorderly) in POST women, as defined by their higher ApEn (P = 0.027) and lower absolute z-score (SD removed from maximally random; P = 0.017).

Linear regression analysis was applied to relate GH secretion to CT estimates of AVF mass in the combined cohorts (n = 15). A higher AVF forecast lower GH secretory responses to stimulation with L-arginine/GHRP-2 (P < 0.001; r2 = 0.57) and L-arginine/GHRH (P = 0.007; r2 = 0.45; Fig. 5Go). AVF tended to correlate negatively with pulsatile GH secretion during the infusion of saline (P = 0.029; r2 = 0.32) and GHRH/GHRP-2 (P = 0.021; r2 = 0.34). Bivariate regression of pulsatile GH secretion on AVF and age indicated that AVF negatively determines GH responses during consecutive infusion of L-arginine and GHRP-2 (P < 0.001) or GHRH (P = 0.002) independently of age (P < 0.043). Conversely, age (P = 0.004) more than AVF (P = 0.022) predicts GH responses to GHRH/GHRP-2.



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  		FIG. 5. Linear regression of pulsatile GH secretion (micrograms per liter per hour) on AVF in the combined cohorts of PRE and POST women (n = 15) studied in four interventional contexts, as indicated. Responses to secretagogues were regressed on AVF mass estimated by CT scan.

 
Simulation analyses were conducted under the assumptions of an interlinked three-peptide model of GH regulation (see Subjects and Methods). Hypothesis testing indicated that the collective responses to saline and paired secretagogues could not be attributed facilely to an isolated decrease in either GHRH or GHRP efficacy or an increase in GH feedback-induced secretion of somatostatin in POST compared with PRE women. A plausible minimal formulation in POST subjects comprised attenuation of the efficacy of GHRP’s antagonism of basal somatostatinergic inhibition of 1) GH release by somatotropes, and 2) GHRH secretion by the arcuate nucleus (Fig. 6Go). The formulation thereby predicts that POST individuals would have smaller GH pulses, more rapid GH exocytosis, greater interpulse GH secretion, less GHRH secretion from the arcuate nucleus, and impaired direct pituitary stimulation by GHRP. Corollary predictions include higher basal (nonpulsatile) and lower pulsatile (burst-like) somatostatin release.



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  		FIG. 6. Model-based predictions of mechanisms mediating selective diminution in saline- and GHRH/GHRP-2-stimulated pulsatile GH secretion in POST compared with PRE women studied in a low sex steroid milieu. The model embodies 1) reduction in GHRP’s opposition to increased basal somatostatinergic (SS) inhibition of hypothalamic GHRH and pituitary GH release, and 2) impairment of GH feedback-induced pulsatile SS release. The outcomes are small, irregular, and brief GH pulses during saline infusion; reduced efficacy of GHRH/GHRP-2 in the absence of SS withdrawal; and preserved efficacy of GHRH or GHRP-2 in a low-SS milieu (after L-arginine exposure).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The present investigation used an experimental paradigm of short-term suppression of ovarian sex steroid secretion in healthy POST and PRE women to dissect how age and body composition regulate GH secretion. By design, the GnRH agonist maintained estradiol and testosterone concentrations in the POST range in both age strata. In the sex steroid-depleted milieu, POST compared with PRE volunteers manifested lower GH and IGF-I concentrations, smaller GH secretory bursts, higher basal GH secretion, reduced GH responses to simultaneous GHRH/GHRP-2 stimulation, and more rapid evolution of GH release within secretory bursts. In the combined cohorts, differences in AVF forecast 45–57% of the interindividual variability in GH responses to L-arginine/GHRH and L-arginine/GHRP-2, whereas age predicted 32–34% of the variance in saline- and GHRH/GHRP-stimulated GH secretion. The collective outcomes indicate that age and AVF modulate pulsatile GH secretion via mechanistically selective pathways in healthy women.

POST women had lower IGF-I concentrations and secreted 56% less GH in pulses than PRE women in an ovariprival milieu. Decreased systemic IGF-I concentrations disinhibit pulsatile GH secretion in young adults (52). Accordingly, failure of POST women to generate high-amplitude GH pulses despite reduced IGF-I suggests that age-associated factors attenuate stimulatory and/or accentuate inhibitory inputs to somatotropes. Stimulatory peptides include GHRH and GHRP/ghrelin, and a major inhibitory peptide is somatostatin (8, 10, 44, 45, 47, 53, 54, 55, 56, 57, 58, 59). Because the effects of these regulatory signals are interdependent, a strategy of dual secretagogue infusions was used to probe their interactions, as illustrated recently in other settings (22, 23, 34).

Combined continuous GHRH/GHRP stimulation was used as an indirect test of the idea that age or AVF heightens somatostatin outflow (combined secretion and action). The prediction was that increased basal (nonpulsatile) somatostatin outflow, if present in older women, would attenuate simultaneous two-peptide drive of pulsatile GH secretion (38, 53, 60, 61). Consistent with this hypothesis, combined GHRH/GHRP-2 stimulation was 50% less effective in POST than PRE volunteers. Thus, aging, independently of the short-term sex steroid milieu, may elevate basal somatostatin secretion or potentiate somatostatin inhibition.

Age stratum did not determine GH secretory responses to L-arginine/GHRH or L-arginine/GHRP-2. Power estimates for both comparisons exceeded 85% to detect a unit SD difference in GH secretory responses at P < 0.05. Thus, assuming that infusion of L-arginine decreases hypothalamic somatostatin release (8, 62, 63), we infer that maximal actions of GHRH and GHRP-2 do not differ greatly by age when assessed in a low sex steroid milieu. The outcomes do not contradict the independent abilities of estradiol to decrease the inhibitory potency of somatostatin, augment the potency of GHRH, and enhance the efficacy of GHRP-2 in POST individuals (23, 34, 64, 65, 66).

In the combined cohorts, AVF correlated negatively with responses to L-arginine/GHRH and L-arginine/GHRP-2. There were similar trends between AVF and both unstimulated and GHRH/GHRP-2-stimulated GH secretion. In an analysis in men, AVF was also a prominent negative determinant of GH secretion driven by repeated iv pulses of GHRH (67). To the degree that L-arginine limits somatostatin outflow (8, 62, 63), the foregoing correlations imply that AVF does not act solely by augmenting inhibition by somatostatin, but appears also to reduce individual GHRH and GHRP efficacy in a sex steroid-depleted milieu.

ApEn was employed as a sensitive (>90%) and specific (>90%) barometer of feedback control within the GH axis (26, 68, 69). ApEn analysis unveiled less orderly (more irregular) GH secretion in fasting POST than PRE women in the sex steroid-deficient context. Reduced regularity signifies impaired negative feedback in mathematical models and clinical experiments (27, 43, 44, 45, 47, 53, 67, 70, 71). In this regard, model-based analyses predicted greater basal somatostatin release (at the onset of a GH pulse) and lesser burst-like somatostatin outflow (induced by feedback from each GH pulse) in POST women. The first postulate leads to higher basal (nonpulsatile) GH secretion and reduced efficacy of GHRH/GHRP-2, whereas the second yields abbreviated GH secretory bursts and impaired feedback-evoked GH pulse renewal in POST individuals. Stated alternatively, small, irregular, and brief GH pulses with high interpulse GH secretion in POST women would signify diminished secretagogue antagonism of basal somatostatin outflow (45, 53, 72). In this construction, reduced efficacy of any single secretagogue would not be detectable in the low-somatostatin milieu associated with L-arginine/GHRP-2 or L-arginine/GHRH infusion, but would emerge during combined GHRH/GHRP drive. An untested prediction is that triple infusion of L-arginine/GHRH/GHRP would abolish the age difference.

Analytical reconstruction of the time course of GH secretion within spontaneous secretory bursts disclosed 1.9-fold more rapid initial GH release in POST (18 min) than PRE (35 min) individuals. This novel distinction points to more rapid exocytosis of pituitary GH stores in POST subjects. Infusion of L-arginine with GHRH or GHRP-2 in PRE women abolished the age contrast, consistent with the model prediction of greater GH feedback-evoked somatostatin release in PRE volunteers.

Several caveats should be considered. First, gonadal down-regulation was restricted to an ethically acceptable interval of 6 wk, given that increased bone resorption can be detected within 2 wk of GnRH agonist exposure in young women (73). Second, the present paradigm was not intended to discriminate between effects of low estrogen and low androgen. Third, mean estradiol concentrations were less than 20 pg/ml (73 pmol/liter) in both cohorts, but absolute values were higher in PRE than POST volunteers. Whether such levels influence GH secretion is not known. Fourth, the current protocol evaluated secretagogue efficacy, but not potency or sensitivity. And, fifth, the assumption that L-arginine can suppress somatostatin outflow does not exclude other (unknown) actions of this amino acid (8, 62, 63, 74).

In summary, a low sex steroid milieu unveils prominent contrasts in fasting GH and IGF-I concentrations, the mass and waveform of GH secretory bursts, basal and orderly GH secretion, and hypothalamo-pituitary responses to simultaneous GHRH/GHRP stimulation in PRE and POST women. Regression analyses also establish that age and AVF are distinguishable determinants of GH secretion.


   Acknowledgments
 
We thank Kris Nunez and Kandace Bradford for excellent support of manuscript preparation and graphical presentation, the Mayo Immunochemical Laboratory for assay assistance, and the Mayo Research Pharmacy and nursing staff for conducting the protocol.


   Footnotes
 
This work was supported by General Clinical Research Center Grant MO1-RR-00585 to the Mayo Clinic and Foundation from the National Center for Research Resources (Rockville, MD), National Institutes of Health Grants K25-HD-01474 and R01-NIA-AG-14799.

First Published Online August 9, 2005

Abbreviations: ApEn, Approximate entropy; AVF, abdominal visceral fat; CT, computed tomography; GHRP-2, GH-releasing peptide-2; PRE, premenopausal; POST, postmenopausal.

Received April 18, 2005.

Accepted August 1, 2005.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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