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Division of Endocrinology and Metabolism (J.D.V.), Department of Internal Medicine, Mayo Medical and Graduate Schools of Medicine, General Clinical Research Center, Mayo Clinic, Rochester, Minnesota 55905; Division of Endocrinology (S.M.A.), Department of Internal Medicine, General Clinical Research Center, Department of Statistics (D.M.K.), University of Virginia, Charlottesville, Virginia 22908; Department of Internal Medicine (P.K.), Leiden University Medical Center, Leiden, The Netherlands; Endocrine Service (A.I.), Medical Section, Salem Veterans Affairs Medical Center, Salem, Virginia 24153; and Institute of Experimental Clinical Research (J.F., H.Ø.), Medical Research Laboratory, Aarhus University Hospital, Aarhus, Denmark DK-8000
Address all correspondence and requests for reprints to: J. 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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In summary, compared with Pl, E2 supplementation in postmenopausal women: 1) amplifies endogenously driven GH secretory-burst mass; 2) initiates rapid onset of GHRH-stimulated GH release; and 3) potentiates IGF-I-dependent suppression of unstimulated GH concentrations. Based upon companion modeling data, we postulate that E2 facilitates the upstroke and IGF-I enforces the downstroke of high-amplitude GH secretory bursts in estrogen-replete individuals.
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Introduction |
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Blood-borne IGF-I mediates negative feedback on GH secretion. For example, in transgenic mice, molecular silencing of hepatic IGF-I gene expression lowers IGF-I concentrations by 70–80% and elevates GH concentrations by 4- to 10-fold (8, 9). In young men and women, sc injection of a potent and selective GH-receptor antagonist (pegvisomant) decreases total IGF-I concentrations by 34% and stimulates pulsatile GH secretion by 77% within 72 h (10). In a patient with partial truncational mutation of the IGF-I gene and markedly reduced IGF-I concentrations, GH concentrations exceeded 100 µg/liter and were suppressible by treatment with recombinant human (rh)IGF-I (11). And infusion of rhIGF-I in patients with GH-receptor defects (Laron syndrome) and healthy fasting adults lowers GH concentrations rapidly (12, 13, 14, 15).
An apparent feedback paradox emerges in estradiol (E2)-sufficient pubertal girls and late-follicular-phase young women, in whom IGF-I concentrations and pulsatile GH secretion rise concomitantly (5, 16, 17, 18). Conversely, in states of estrogen deficiency, GH and IGF-I concentrations fall pari passu. A plausible explanation for the foregoing associations is that E2 not only facilitates central drive of pulsatile GH secretion (see Discussion) but also antagonizes negative feedback by systemic IGF-I. The present study tests the latter regulatory hypothesis.
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Subjects and Methods |
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Eight postmenopausal volunteers enrolled in and completed all four infusion sessions. Participants provided written informed consent approved by the Institutional Review Board. The project was reviewed by the National Institutes of Health and United States Food and Drug Administration under an investigator-initiated investigational new drug for the use of rhIGF-I by iv infusion. Exclusion criteria included known or suspected cardiac, cerebrovascular, peripheral arterial, or venous thromboembolic disease; a history of chronic smoking; personal history of breast or endometrial cancer; concomitant or recent use of neuroactive medications; anemia; and failure to provide written informed consent. There was no recent transmeridian travel (within 10 d), night-shift work, significant weight change (
2 kg in 3 wk), acute or chronic disease, psychiatric illness requiring treatment, and alcohol or drug abuse. Some enrollees continued to take multivitamins and ferrous sulfate, and one volunteer each was using triamcinolone nasal spray or receiving stable T4 replacement. Inclusion criteria required an unremarkable medical history and physical examination and normal screening laboratory tests of hepatic, renal, endocrine, metabolic, and hematologic function.
The mean (± SEM) age was 62 ± 3 yr; and body mass index, 25 ± 0.8 kg/m2. Individuals were clinically postmenopausal for at least 1 yr, and ovariprival status was confirmed by elevated (screening) concentrations of FSH (82 ± 7.7 IU/liter) and LH (37 ± 4.0 IU/liter) and a concentration of E2 less than 30 pg/ml (<10 pmol/liter). Subjects discontinued any hormone replacement at least 4 wk before participation.
Protocol design
The design was a prospectively randomized, placebo (Pl)-controlled, patient-blinded, within-subject crossover intervention. Each woman underwent a total of four admissions (two during Pl and two during estrogen supplementation). Estrogen was administered as 1 mg of micronized 17 ß-E2 (Estrace, Bristol-Myers Squibb, Princeton, NJ) orally twice daily for 10 d. Infusion sessions were performed on the morning of d 10 of Pl or E2 supplementation. Each intervention was separated by a minimum of 4 wk. Thus, individual study duration was 4–6 months.
Volunteers were admitted to the General Clinical Research Center (GCRC) in the evening of d 9 of Pl or E2 administration (above) to allow overnight adaptation to the Unit. To obviate food-related confounds, subjects received a constant evening meal (turkey sandwich or vegetarian alternative) of 500 kcal containing 55% carbohydrate, 15% protein, and 30% fat at 1800 h. Participants remained fasting overnight and until 1400 h the next day. Caffeinated beverages, sleep, and vigorous exercise were disallowed during the sampling session.
Infusions
At 0600 h on the morning of sampling and infusions, two iv catheters were inserted in (contralateral) forearm veins. Blood was withdrawn at 0600 h for later assay of E2, FSH, LH, and prolactin (PRL) concentrations and then sampled (2 ml) every 10 min for a total of 8 h (to 1400 h). After 2 h of baseline sampling, saline (50 ml/h) or rhIGF-I (10 µg/kg·h) (Genentech, Inc., South San Francisco, CA) was infused continuously iv for 6 h during the interval 0800–1400 h. To stimulate GH secretion, a single iv bolus of GHRH (1.0 µg/kg) (Geref, Serono, Rockland, MA) was injected at 1200 h (4 h after onset and 2 h before termination of sampling and infusion). As safety considerations, serum concentrations of potassium and phosphorus were measured at baseline screening and at the end of rhIGF-I infusion; and continuous electrocardiographic monitoring and hourly plasma glucose measurements were performed throughout the infusion.
Hormone assays
Serum concentrations of GH (10-min samples) were measured in duplicate by automated ultrasensitive chemiluminescence-based assay (modified Nichols Chemiluminescent hGH assay, Nichols Institute Diagnostics, San Juan Capistrano, CA) using 22-kDa rhGH as assay standard (19, 20). The entire set of GH samples (n = 196) in any given subject were analyzed together. Sensitivity of the GH assay is 0.005 µg/liter (defined as 3 SDs above the zero-dose tube), and median intra- and interassay coefficients of variation (CVs) were 5.2% and 6.3%, respectively, at the GH concentrations measured here (19, 20). No GH values fell less than 0.020 µg/liter. LH, FSH, and PRL concentrations were quantitated by automated chemiluminescence assay (ACS 180, Bayer, Norwood, MA) as described (21). E2 concentrations were quantitated in a single batch (32 samples) by double-antibody RIA with a sensitivity of 2.5 pg/ml and a within-assay CV of 4.0% (Diagnostic Systems Laboratories, Baxter, TX).
Total (acid-ethanol extractable) IGF-I concentrations were quantitated by time-resolved monoclonal immunofluorometric assay of hourly pooled sera. Sensitivity is 0.00025 µg/liter; IGF-II cross-reactivity is less than 0.0002%; and intraassay and interassay CVs are 1.3–4.8% and 8.6%, respectively. Free IGF-I concentrations were determined analogously after centrifugal ultrafiltration of undiluted serum at 37 C, pH 7.4 (22).
Deconvolution analyses of basal (nonpulsatile) and GHRH-stimulated GH secretion
Basal (nonpulsatile) GH secretion was estimated by waveform-independent deconvolution analysis assuming a priori biexponential kinetics (23, 24).
Pulsatile GH secretion was quantitated by a recently validated deconvolution procedure (25, 26). The latter technique formulates allowably asymmetric secretory bursts, whereby we explore the impact of E2 and rhIGF-I on GHRH-driven burst shape (below).
From a technical perspective, there are four interventional assignments involving Pl/E2 and/or saline/rhIGF-I, here denoted as k = 1–4. Each of eight subjects, j = 1–8, was sampled every 10 min for 8 h under each condition. At a given time t, the GH secretion rate (unobserved) and the GH concentration (measured) in subject j in condition k are given by Zj(k) (t) and Xj(k) (t), respectively, and basal GH secretion by 
(k). Pulsatile GH secretion after GHRH injection at time T is described by two terms: 1) the waveform or instantaneous (unit-area normalized) rate of secretion over time, 
(·); and 2) the mass of GH released per unit distribution volume in the burst (µg/liter), M (26, 27). Waveform (burst shape) is defined by the generalized probability density:
 | (1) |
The present analyses reconstruct: 1) a common -function for the cohort of eight subjects, one in each of four interventions, k; and 2) a cohort- and intervention-specific mean amount of GH secreted after GHRH, M(k). The mass in any subject is M(k) plus a random variation, Aj(k). The total (basal and pulsatile) GH secretion rate in subject j under condition k is:
 | (2) |
 | (3) |
1 and 2 are rate constants of rapid and slow elimination, and X(0) is the starting hormone concentration (25). Here, 1 is fixed at the shortest half-life estimable for 10-min sampling, 6.93 min, and 2 at the reported value of 20.8 min (24)
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i:
 | (5) |
(k):
 | (6) |
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Variances and covariances of parameters are obtained explicitly from the inverse of the estimated information matrix:
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(k).
Thereby, SEMs are calculated directly for basal secretion, 
(k), and waveform parameters, 
1(k), 2(k), and 3(k). The mode of the maximal GH secretion rate is given as 
Variance is computed by the multivariate 
method as:
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1(k), 2(k), 3(k)), where 
i,j(k) is the (i, j) element of 
(k). Primary outcomes
The principal outcomes reported are: 1) pulsatile GH secretion (sum of nonbasal burst mass) during saline infusion before GHRH injection (µg/liter·6 h); 2) the total mass of GH secreted after GHRH injection (µg/liter·2 h); and 3) the time latency (min) for GHRH to elicit maximal GH secretion.
Other statistical comparisons
One-way ANOVA in a repeated-measures design was used to compare baseline hormone concentrations followed by post hoc contrasts using Tukey’s honestly significantly different criterion (28). Linear regression analysis was applied to estimate: 1) the rate of decline of maximal-to-nadir serum GH concentrations during rhIGF-I infusion; and 2) the rate of rise of hourly IGF-I concentrations.
Data are cited as the mean ± SEM or 95% statistical confidence intervals (CIs).
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Results |
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Compared with Pl, E2: 1) elevated 0600-h E2 (pg/ml) from 4.4 ± 0.77 to 367 ± 28 (P < 0.001) (to convert to pmol/liter, multiply by 3.67), GH (µg/liter, 6-h mean ± SEM) from 0.80 ± 0.04 to 1.2 ± 0.06 (P < 0.01), and PRL (µg/liter) from 14 ± 1.8 to 22 ± 3.2 (P = 0.002); 2) suppressed FSH (IU/liter) from 75 ± 5.9 to 39 ± 3.8 and LH (IU/liter) from 31 ± 2.4 to 21 ± 1.4 (both P < 0.001); 3) lowered total IGF-I concentrations (µg/liter) from 91 ± 6.4 to 64 ± 4.1 (P < 0.01); and 4) tended to reduce free IGF-I concentrations (P = 0.069) (Table 1
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depicts 10-min GH concentration profiles for each intervention. Statistical comparisons showed that E2 vs. Pl augmented: 1) pulsatile GH secretion (µg/liter/6 h) from 12 ± 3.3 to 18 ± 4.6 (paired- comparison, 6 ± 2.8, P < 0.05); 2) the IGF-I-enforced decrement in GH concentrations (µg/liter) from 0.73 ± 0.21 to 1.6 ± 0.25; and 3) the absolute value of the negative slope of GH concentrations during IGF-I infusion by 3.3-fold (P < 0.001) (Fig. 2).
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Figure 3 presents analytically reconstructed GHRH-stimulated GH secretory rates (Panel A); the mass of GH secreted above basal release (Panel B); and, the predicted asymmetric waveform (time-plot) of normalized GH secretion rates within a burst (Panel C). E2, compared with Pl, reduced the time latency to maximal GHRH-evoked GH release by 50% (P < 0.01). Infusion of rhIGF-I suppressed the mass of GHRH-stimulated GH secretion but did not modify the capability of E2 to reduce the time delay to peak GH secretion.
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Discussion |
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To our knowledge, the present clinical experiment provides the first analysis of the impact of estrogen depletion and repletion on IGF-I negative feedback. In an earlier investigation restricted to young men, overnight iv infusion of rhIGF-I inhibited GHRH-evoked GH release the next morning (13). Suppression in this context could reflect somatostatin release due to breakfast 4 h earlier, TRH injection 2 h earlier, and/or elevated IGF-I concentrations. In three women and five men, iv infusion of rhIGF-I reduced the peak GH response to L-arginine by 55% (29). Observed inhibition may denote IGF-I’s repression of GHRH release, stimulation of somatostatin outflow, and/or direct antagonism of pituitary GH release. In premenopausal women, sc injection of rhIGF-I blunted individual GH responses to GHRH or hexarelin (a GH-releasing peptide) by 45% and 55%, respectively, but did not inhibit synergy between L-arginine and GHRH (15, 30). The last outcome supports in vivo laboratory data showing that IGF-I elicits somatostatin outflow and represses GHRH release, and limits the significance of in vitro direct inhibition of somatotrope secretion (see introduction to this manuscript). In one comparison by gender, constant iv infusion of rhIGF-I for 24 h: 1) elevated IGF-I concentrations more in women than men (mean absolute difference, 300 µg/liter); 2) decreased GH concentrations more in women than men in the daytime awake fed state but did the opposite during overnight sleep when fasting; and 3) inhibited the effect of GHRH more in men than women (14). However, GHRH was injected 2 h after a noontime meal and 2 h after stopping the IGF-I infusion. The foregoing confounding factors make facile interpretation of gender differences in IGF-I negative feedback difficult.
The mechanisms by which E2 and IGF-I conjointly regulate activity of the human hypothalamo-pituitary-GH unit are not established. In the rodent, E2 increases: 1) hypothalamic gene transcripts encoding IGF-I peptide and receptor; 2) intracellular signaling by neuronal IGF-I receptors; 3) IGF-I binding in the pituitary gland; and 4) pituitary content of IGF-I peptide, IGFBP-2 protein, and IGFBP-2 mRNA (31, 32). Because systemic estrogens and intact insulinomimetic peptides have access to the hypothalamus and pituitary gland (1, 8, 33), available data do not allow unique localization of the site(s) of interaction of IGF-I and estrogen in mediating enhanced negative feedback, as observed here.
Administration of estrogen (in the absence of a synthetic progestin) via oral, higher-dose transdermal, iv, intranasal, im, or intravaginal routes can reduce total IGF-I concentrations in hypogonadal girls and women, male-to-female transsexual patients, and men with prostatic carcinoma (1, 18). E2 given orally also elevates IGFBP-1 concentrations (34). This effect may account for apparent lowering of dialyzably free IGF-I concentrations (P = 0.069). Accordingly, greater availability of free IGF-I cannot account for E2’s potentiation of negative feedback by rhIGF-I.
A novel deconvolution technique was applied to estimate the mass (amount) and waveform (shape) of GHRH-stimulated GH secretory bursts (25, 26). This analysis disclosed that: 1) rhIGF-I suppresses GHRH-evoked GH secretory-burst mass by 50%, whether or not E2 is present; and 2) E2 reduces the time required for GHRH to evoke maximal GH release by 50%, whether or not IGF-I negative feedback is enforced exogenously. We speculate that inferred attainment of peak GH secretion rates within 10 min in the estrogen-enriched state, compared with 20 min otherwise, may reflect facilitation of the exocytotic phase of GH release. Other recent investigations have documented physiological control of both the mass and waveform of LH, TSH, and ACTH secretory bursts (35, 36, 37).
In summary, E2 supplementation in healthy postmenopausal women potentiates the inhibitory effect of rhIGF-I on fasting GH concentrations and accelerates the attainment of peak GH secretory rates in GHRH-induced secretory bursts. In theoretical models, such reciprocal actions could facilitate the rapid onset and prompt offset of the high-amplitude GH release episodes that typify physiological GH pulsatility in estrogen-replete individuals.
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Acknowledgments |
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Footnotes |
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Abbreviations: CI, Confidence interval; CV, coefficient of variation; E2, estradiol; GCRC, General Clinical Research Center; Pl, placebo; PRL, prolactin; rh, recombinant human.
Received August 26, 2003.
Accepted November 17, 2003.
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) in the normalized secretory-burst waveform (C).