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Division of Endocrinology and Metabolism (D.E., K.M., K.B., J.M.M., J.D.V.), Department of Internal Medicine, Mayo Medical and Graduate Schools of Medicine, General Clinical Research Center, Mayo Clinic, Rochester, Minnesota 55905; Department of Statistics (D.M.K.), University of Virginia, Charlottesville, Virginia 22904; and Department of Medicine (C.Y.B.), Tulane University Health Sciences Center, New Orleans, Louisiana 70112
Address all correspondence and requests for reprints to: Dr. 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
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Abstract |
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Introduction |
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The present study examines GH secretion in pre- and postmenopausal women in an experimentally defined estradiol-enriched milieu. To achieve comparable estrogen repletion and minimize possible confounding by unequal testosterone and progesterone concentrations, a GnRH agonist was administered first to down-regulate the gonadal axis (see Subjects and Methods). To enhance interpretation of GH secretory responses to peptidyl secretagogues, individual agonists were delivered during putative somatostatin withdrawal induced by L-arginine infusion (12, 13, 14). This investigative paradigm was used to test the hypothesis that pre- and postmenopausal individuals differ in endogenously driven and exogenous peptide-stimulated GH secretion despite commensurate short-term systemic estradiol drive. A subsidiary postulate was that abdominal visceral fat mass contributes to the variability in GH secretory responsiveness in a somatostatin-withdrawn and estrogen-sufficient milieu (15).
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Healthy premenopausal (n = 10) and postmenopausal (n = 8) women completed the four study sessions (see below). Participants provided 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 2 wk), night-shift work, significant weight change (
3 kg in 1 month), body mass index 30 kg/m2, acute or chronic illness, psychiatric treatment, or substance abuse. 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. Some enrollees continued to take multivitamins, ferrous sulfate, calcium carbonate, aspirin, and ibuprofen on nonstudy days. Each subject had an unremarkable medical history and physical examination and normal screening laboratory tests of hepatic, renal, endocrine, metabolic, and hematological function.
The mean (± SD) age was 26 ± 4.7 and 63 ± 2.7 yr, respectively, in pre- and postmenopausal volunteers. Corresponding body mass index was comparable and averaged 23 ± 3.5 and 25 ± 3.1 kg/m2, respectively. Premenopausal women were studied after documenting a normal menarchal and menstrual history. In postmenopausal women, ovariprival status was confirmed by concentrations of FSH greater than 50 IU/liter, LH greater than 20 IU/liter, and estradiol less than 20 pg/ml (<74 pmol/liter). Volunteers discontinued any hormone replacement at least 6 wk before study.
Statistical design
The study was a parallel-cohort design. The order of secretagogue infusions was prospectively randomized, placebo-controlled, and patient-blinded within the cohort.
Estradiol clamp
Each volunteer received two consecutive im injections of leuprolide acetate 3.75 mg 3 wk apart. In young women, leuprolide was given in the early follicular phase (within 7 d of menses onset) after establishing a negative blood pregnancy test. Beginning on the day of the second leuprolide injection, transdermal estradiol was administered in graded amounts of 0.05, 0.10, 0.15, and 0.20 mg/d. The intent was to achieve a gradual stepwise and minimally symptomatic increase to late follicular-phase estradiol concentrations over a 2-wk interval. A given dose was administered each evening (starting on d 1) for four consecutive nights before dose escalation. The 0.2-mg dose was continued for 7 d (d 15–21). To ensure stable estradiol concentrations on study days, infusion sessions were scheduled on any 4 of the last 5 d of the 0.2-mg estradiol intervention (viz., d 17–21, inclusive). After the last sampling session, progesterone was administered (100 mg orally for 12 d) to women with an intact uterus according to good standards of clinical practice.
Sampling paradigm
Volunteers were admitted to the General Clinical Research Center on the evening before study to allow overnight adaptation to the Unit. Sleep was deferred until 2200 h. To obviate food-related confounds, subjects were given a constant meal (turkey sandwich or vegetarian alternative) of 500 kcal containing 55% carbohydrate, 15% protein, and 30% fat at 2000 h. Participants then remained fasting overnight until 1400 h the next day. On the day of sampling and infusion(s), two iv catheters were inserted in contralateral forearm veins at 0700 h. Blood was withdrawn for later assay of serum estradiol, testosterone, progesterone, and IGF-I concentrations. Samples (1.5 ml) were collected in chilled plastic tubes containing calcium chelator every 10 min for 6 h between 0800 and 1400 h for GH measurements. Plasma was separated on ice and frozen at –70 C within 30 min. Lunch was provided at 1400 h before discharge.
Infusions
Infusion studies were performed on separate mornings after fasting. The four protocols comprised iv delivery of 1) saline (0800–1400 h); 2) L-arginine, 30 g over 30 min (0930–1000 h), followed immediately by bolus GHRH (1 µg/kg; GRF, Serono, Norwalk, MA); 3) L-arginine (see above) followed by bolus GH-releasing peptide (GHRP)-2 (3 µg/kg); and 4) combined GHRH and GHRP-2 at a constant rate of 1 µg/kg·h each (1000 and 1400 h). The foregoing peptide doses are maximally stimulatory in dose-response analyses in postmenopausal women (12, 16).
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 assay standard (Sanofi Diagnostics Pasteur Access, Chaska, MN). All samples (n = 148) from any given subject were analyzed together. Sensitivity is 0.010 µg/liter (defined as 3 SD above the zero-dose tube). Interassay coefficients of variation (CVs) were 7.9 and 6.3%, respectively, at GH concentrations of 3.4 µg/liter and 12.1 µg/liter. The intraassay CVs 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 20-kDa GH is less than 5%. Serum LH and FSH concentrations were quantitated by automated chemiluminescence assay (ACS 180, Bayer, Norwood, MA), using as standards the First and Second International Reference Preparations, respectively. Procedural sensitivities for LH and FSH are 0.2 and 0.4 IU/liter. Intraassay CVs for LH were 4.7, 3.5, and 3.8%, and interassay CVs were 8, 3.7, and 4.7% at 4.4, 18.2, and 38.8 IU/liter, respectively. For FSH measurements, the intraassay CVs were 5.6, 4.3, and 3.5%, and interassay CVs were 6, 4, and 2.8% at 4.6, 25.4, and 61.7 IU/liter, respectively. Estradiol, testosterone, and progesterone were quantitated by automated competitive chemiluminescent immunoassay (ACS Corning, Bayer, Tarrytown, NY). For estradiol, intraassay CVs were 4.1% at 173 pg/ml and 3.9% at 371 pg/ml. Interassay CVs were 7% at 71.2 pg/ml and 4% at 261 pg/ml (multiply by 3.67 for pmol/liter). For testosterone, mean intra- and interassay CVs were 6.8 and 8.3%, with an assay sensitivity of 8 ng/dl (multiply by 0.0347 for nmol/liter). For progesterone, corresponding values were 5.7, 6.9, and 0.2 ng/ml (multiply by 3.18 for nmol/liter). Total IGF-I concentrations were measured by immunoradiometric assay after extraction (Diagnostic Systems Laboratories, Webster, TX). Interassay CVs were 9% at 64 µg/liter and 6.2% at 157 µg/liter. Intraassay CVs were 3.4, 55.4, and 1.5% at 9.4, 55.4, and 264 µg/liter, respectively.
Visceral fat mass
Intraabdominal visceral fat mass was estimated exactly as described by single-slice abdominal computed tomography (CT) scan at L5 (15).
Deconvolution analyses of basal (nonpulsatile) and GHRH-stimulated burst-like GH secretion
Earlier deconvolution methods in some cases yield nonunique estimates of basal hormone secretion and elimination rates (17). To address this technical issue, basal and pulsatile GH secretion were estimated simultaneously using a variable-waveform model statistically conditioned on biexponential kinetics and estimated pulse times, as recently validated (18, 19, 20). Thereby, we explore the impact of age stratum on saline and GHRH and/or GHRP-2-stimulated GH secretory-burst mass and waveform (shape). See the supplemental data published on The Endocrine Society’s Journals Online web site at http://jcem.endojournals.org.
The principal analytical outcomes compared by menopausal status are 1) basal and pulsatile GH secretion during saline infusion (µg/liter·6 h), 2) the mass of GH secreted in bursts after saline or dual-secretagogue injection (µg/liter·4 h), and 3) the modal time latency (minutes) for a given secretagogue pair to elicit maximal GH secretion within the stimulated burst.
Other statistical comparisons
An unpaired two-tailed Student’s t test was used to compare data in the two age groups. Bonferroni correction was applied whenever hypotheses and/or biological outcomes were not independent a priori (21). Linear regression analysis was applied to examine the relationship between GH secretory-burst mass and abdominal visceral fat mass (CT cross-sectional area) in the combined cohorts (22).
Data are presented as the arithmetic mean ± SEM.
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Results |
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Table 1
summarizes mean fasting hormone concentrations in the two age cohorts. Estradiol concentrations were similar (by ANOVA) among the four separate admissions in each study group and thus were pooled within individual. Values averaged (pg/ml) 161 ± 3 in post- and 152 ± 22 in premenopausal women (P = not significant; multiply by 3.67 for units of pmol/liter). The SHBG concentration was higher in post- than premenopausal volunteers, but the mean molar estradiol/SHBG ratio was comparable. Mean GH and IGF-I concentrations were 78 and 57% lower in post- compared with premenopausal individuals. LH and FSH concentrations were suppressed to less than 0.5 IU/liter and less than 1.4 IU/liter. Testosterone and progesterone were comparably low in both age strata. In absolute terms, concentrations of prolactin and FSH were slightly higher in older than young volunteers (Table 1).
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illustrates mean cohort-specific GH concentration time series in the four study conditions in post- and premenopausal women. Deconvolution analysis was applied to the 6-h control (saline infusion) session to examine the basis for reduced mean GH concentrations in post- compared with premenopausal subjects. As shown in Fig. 2, postmenopausal volunteers had significantly lower fasting (unstimulated) 6-h mean GH concentrations and reduced basal, pulsatile, and total GH secretion (mean percentage decrement in post- compared with premenopausal), as follows: 1) 70% for basal GH secretion (P < 0.001), 2) 78% for pulsatile GH secretion (P < 0.01), and 3) 78% for total (pulsatile plus basal) GH secretion (P < 0.005). The foregoing contrasts were specific in that age did not influence the mean inter-secretory-burst interval (time in minutes between consecutive GH pulses), viz., 67 ± 6.1 (postmenopausal) vs. 65 ± 3.6 (premenopausal).
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presents GH secretory responses to specific secretagogue pairs for each of the four interventions. The quantitative endpoint is the summed mass of GH secreted in pulses (µg/liter·4 h) after saline or the dual stimulus. A priori motivated age comparisons demonstrated that the mass of burst-like GH secretion was significantly reduced in older compared with young subjects by the following percentage amounts: 1) saline, 78% (P < 0.01); 2) L-arginine/GHRH, 53% (P < 0.025); 3) L-arginine/GHRP-2, 63% (P < 0.01); and 4) GHRH/GHRP-2, 45% (P < 0.025). Relative efficacy of the three secretagogue pairs was 1) L-arginine/GHRP-2 more than L-arginine/GHRH only in premenopausal (P < 0.05); 2) combined GHRH/GHRP-2 more than L-arginine/GHRH in premenopausal (P < 0.05) and postmenopausal (P < 0.025); and 3) combined GHRH/GHRP-2 equals L-arginine/GHRP-2 in both pre- and postmenopausal.
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depicts cohort- and intervention-specific analytical estimates of the (unit-area normalized) GH secretory-burst waveform. The latter is defined as the time evolution of secretion within a discrete burst, viz., underlying secretory-pulse shape (see the supplemental data). Shape estimates are statistically independent of secretory-burst mass (Fig. 3
) (see Subjects and Methods). A separate waveform is determined in relation to each secretagogue pair in a given cohort. The outcome is the modal (most commonly occurring) time delay in minutes to maximal GH secretion after onset of the secretory burst. Statistical comparisons disclosed 50–61% abbreviation of the modal time latency to achieve peak GH secretion after stimulation by L-arginine/GHRH, L-arginine/GHRP-2, and GHRH/GHRP-2 (absolute range, 14–20 min) compared with saline (range, 32–36 min) (each P < 0.001 vs. saline). The particular secretagogue combination did not modulate this novel effect of peptide stimulation. A possible exception occurred after combined infusion of GHRH/GHRP-2, wherein modal burst duration was slightly prolonged at 20 ± 0.63 min in post- compared with 18 ± 0.34 min in premenopausal (P < 0.033 after Bonferroni adjustment).
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). Correlation strength did not differ significantly among stimuli; viz., individual R values were –0.480 (saline), –0.478 (GHRP-2), –0.490 (GHRH), and –0.499 (GHRH/GHRP-2) (each P < 0.05 assuming independence of the distinct secretagogue relationships). Thus, R2 varied from 0.23–0.25 (see Discussion).
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Discussion |
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Impoverished pulsatile, total, and maximally effective peptide-stimulated GH secretion in estradiol-replete postmenopausal women occurred despite significantly lower peripheral IGF-I concentrations. The latter distinction is pertinent, in that midphysiological IGF-I concentrations exert negative feedback on the human hypothalamo-pituitary unit. In fact, a 32% reduction in systemic total IGF-I concentrations induced pharmacologically over 60–70 h in young adults stimulates basal and pulsatile GH secretion by 1.8- and 2.0-fold, respectively (23, 24). Given this negative-feedback relationship, we reason that reduced IGF-I concentrations in post- compared with premenopausal subjects in the estradiol-sufficient paradigm should augment rather than blunt pulsatile GH secretion. Therefore, by inference, burst-like GH secretion is diminished both absolutely and according to feedback expectations in postmenopausal individuals in an estrogen-enriched milieu. The contrast might have been more prominent if assessed overnight when GH secretion increases physiologically. Although the primary mechanisms have not been elucidated, attenuated GH output in aging individuals could reflect impaired secretagogue feedforward, reduced somatotrope biosynthetic capacity, excessive somatostatinergic inhibition, and/or heightened feedback by IGF-I and GH (25). In relation to some of these considerations, recent mechanistic studies in postmenopausal volunteers show that estradiol compared with placebo administration 1) augments recombinant human (rh) IGF-I-induced suppression of fasting pulsatile (but not GHRH-stimulated) GH secretion, 2) mutes rh GH-enforced autoinhibition of GHRP-2-enhanced (but not saline, GHRH, or exercise-enhanced) GH secretion (26), 3) potentiates the individual feedforward actions of submaximal GHRH and maximal GHRP-2 (27), and 4) relieves the submaximally suppressive effects of infused somatostatin-14 (28).
From a technical vantage, we evaluated the basis for reduced GH concentrations in the experimentally estradiol-predominant milieu in post- compared with premenopausal volunteers by way of a recently developed variable-waveform biexponential deconvolution technique (18, 20, 29). This analytical methodology was developed to 1) quantitate possible asymmetry of hormone secretory bursts determined by specific agonist type and pathophysiology and 2) ensure valid discrimination among in vivo elimination kinetics, basal secretion, secretory-burst mass pulse locations, and random measurement errors contributing to fluctuating GH concentrations (19, 20). In fact, reliable dissection of all five interrelated factors is not necessarily accomplished by earlier technology (17). Statistical verification was by formal mathematical proof of unbiased maximum-likelihood estimation of the parameter set, and physiological validation was by frequent (5 min) and extended (4–12 h) direct cavernous-sinus and internal-jugular venous sampling of hypothalamo-pituitary hormone secretion in the awake unrestrained horse and sheep (18, 19, 20, 27, 29). Based upon this analytical platform, we infer that the secretagogue pairs evaluated here control the time course of GH release within a given secretory burst (viz., the underlying pulse shape or waveform) (Fig. 4). In particular, compared with saline infusion, stimulation by sequential L-arginine and GHRH or GHRP-2 and combined GHRH/GHRP-2 abbreviated the modal time latency to maximal GH secretion by 50–61%. Postmenopausal status did not affect peptide-induced rapid initial GH release, except for a small (17%) prolongation of secretory-burst evolution associated with dual GHRH/GHRP-2 drive. In a recent study, GHRH stimulation without previous L-arginine infusion also evoked prompt GH secretion in an estrogen-rich but not estrogen-poor milieu. A parsimonious hypothesis to account for these outcomes is that feedforward by GHRH and GHRP during estrogen exposure evokes prompt exocytotic release of presynthesized GH stores. This postulate would be consistent with the reported capabilities of estradiol in the laboratory animal to regulate receptors for each of somatostatin, GHRH, and GHRP and to augment GH synthesis and storage over several days in vitro and in ectopically placed pituitary tissue in vivo (30, 31, 32, 33, 34).
Estimates of the distribution volume of rh GH are comparable in young women and men; pre-, mid-, and postpubertal boys; and postmenopausal women receiving estradiol and placebo (26, 35, 36). Such data are important on analytical grounds, because GH secretion is quantitated as the mass of hormone (micrograms) released per unit distribution volume (liters). At similar distribution volumes, the inferred reduction in fasting- and secretagogue-stimulated burst-like GH release in post- compared with premenopausal individuals at similar estradiol concentrations should signify a true age-related diminution in pulsatile GH secretion rates.
GHRH and GHRP transduce feedforward drive, whereas somatostatin and possibly neuropeptide Y mediate feedback restraint, of GH secretion by responsive somatotrope cells (37, 38, 39). The interplay among such agonists and inhibitors appears to determine the mass of GH released per burst (40, 41, 42, 43). In relation to inhibitory inputs, concentrations of hypothalamic somatostatin peptide and gene transcripts are higher in the aged than young rodent. Thus, in an effort to minimize interpretative confounding by unequal hypothalamic somatostatin outflow, we infused L-arginine immediately before bolus injection of a maximally effective dose of GHRH (1 µg/kg) or GHRP-2 (3 µg/kg) (12, 27). L-Arginine provides one means to presumptively limit hypothalamic somatostatin release (13, 14). Combined administration of all three of estradiol, L-arginine, and either GHRH or GHRP-2 stimulated approximately 2-fold more GH secretion in post- than premenopausal women. Therefore, factors associated with postmenopausal status attenuate hypothalamo-pituitary responses to individually maximal feedforward drive by GHRH and GHRP in a putatively low somatostatin and demonstrably high estrogen milieu.
Simultaneous stimulation with GHRH and GHRP-2 (without L-arginine pretreatment) evoked significantly greater GH secretion in young than older estrogen-replete women. Impaired responsiveness in postmenopausal subjects could reflect reduced maximal pituitary secretory capacity, impaired individual secretagogue action (above), and/or accentuated somatostatinergic inhibition (44, 45). In the first regard, diminished somatotrope secretory capacity seems unlikely, in that Arvat et al. (46) observed similar peak and integrated GH concentrations in young and older adults after triple infusion of L-arginine, GHRH, and GHRP. In the second context, one study reported reduced central nervous system GHRP binding capacity in the older human (47), which in principle could contribute to lesser efficacy of GHRP-2. In addition, GH secretion after single or repeated GHRH stimuli is blunted in older compared with young adults (present data and Refs.48, 49, 50). Impaired GHRH action in aging individuals would predictively also attenuate stimulation by GHRP, because GHRH synergizes with GHRP (51, 52). And, in relation to the third issue, we cannot exclude the conjecture that inferentially accentuated somatostatinergic restraint in aging is only partially overcome by previous L-arginine infusion (8).
Deconvolution analysis disclosed comparable mean GH intersecretory-burst intervals in estradiol-sufficient post and premenopausal volunteers. Thus, GH pulse frequency appears to be highly stable across age and between genders (53, 54, 55, 56). On the other hand, basal (time-invariant) GH secretion was reduced by 78% in estradiol-replaced older compared with young women. At present, little is known about the in vivo determinants of basal GH release (57). Technical artifact is unlikely, in view of combined statistical verification and physiological validation of the biexponential deconvolution methodology implemented here (18, 19, 20). Earlier studies suggest that constant infusion of GHRH or GHRP may elevate, whereas acute injection of octreotide or somatostatin may lower, estimated basal GH secretion (50, 58, 59, 60, 61). If pertinent to endogenous peptidyl signals, such outcomes could indicate that aging depresses basal GH secretion by impairing feedforward by GHRH or ghrelin and/or accentuating feedback by somatostatin.
Regression analysis revealed a negative correlation between GH secretory-burst mass and CT estimates of abdominal visceral fat content in the combined post- and premenopausal cohorts. The association accounted for less than or equal to 25% of interindividual differences in saline and dual secretagogue-stimulated GH secretion. An analogous inverse relationship has been recognized between unstimulated GH secretion and abdominal visceral fat (15). We demonstrate this negative association in the face of fixed young-adult estradiol availability and maximal single or dual peptidyl stimulation. Albeit important, the body-compositional correlation leaves up to 75% of the variability in GH secretory-burst mass unexplained in healthy young and aging women. Epidemiological associations suggest that other covariates of GH production include age, gender, ethnicity, physical fitness, sleep stage, stress, nutritional status, and concentrations of progesterone and testosterone (3, 4, 5, 10, 50, 62, 63).
Several caveats should be considered. The accompanying analyses do not establish 1) whether comparable repletion of estradiol in post- and premenopausal women for a prolonged interval might reduce the age-related difference in GH production (64); 2) how supplementation with nonestrogenic sex steroids would affect GH secretion in young and older women (65), and 3) whether chronic secretagogue administration could augment GH secretion further in elderly individuals under estrogen-sufficient conditions. The last question arises because 30 d of continuous sc GHRP-2 infusion and 3 months of twice-daily GHRH injection can elevate GH production by 2- to 6-fold in older adults (64).
In summary, the present study contrasts GH secretion in post- and premenopausal women studied in an estrogen-enriched milieu enforced by concomitant GnRH-agonist administration and transdermal estradiol addback. This investigative strategy yields age-comparable concentrations of estradiol and molar estradiol/SHBG ratios. However, postmenopausal subjects evince significantly depressed GH and IGF-I concentrations, impoverished fasting basal and pulsatile GH secretion, and reduced burst-like GH release driven by a maximally stimulatory pulse of GHRH or GHRP-2 infused individually after L-arginine exposure and together continuously. In contrast, menopausal status does not alter the unique capability of peptidyl stimuli to induce 2-fold more rapid initial GH release in the estradiol-enriched milieu. Abdominal visceral fat mass predicts 23–25% of the variability in pulsatile GH secretion among the pre- and postmenopausal individuals studied here, thus leaving up to 75% of secretory differences unexplained. These ensemble findings indicate that age-related factors other than short-term systemic estrogen availability and relative visceral adiposity strongly determine fasting and maximal secretagogue-stimulated GH secretion in healthy women.
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Acknowledgments |
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Footnotes |
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Abbreviations: CT, Computed tomography; CV, coefficient of variation; GHRP, GH-releasing peptide; rh, recombinant human.
Received March 2, 2004.
Accepted June 16, 2004.
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) women sampled every 10 min for 6 h on d 17–21 of an experimental systemic estradiol clamp. The indicated secretagogue pairs were infused after 120 min of baseline sampling (see Subjects and Methods).
