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Original Articles |
Departments of Obstetrics and Gynecology (M.J.B., T.M.V., S.M.A., L.W.R., J.D.V.) and Internal Medicine (N.S., W.S.E., J.D.V.), General Clinical Research Center, Center for Biomathematical Technology, University of Virginia School of Medicine, Charlottesville, Virginia 22908; and Endocrine Section (A.I.), Medical Service Veterans Affairs Medical Center, Salem, Virginia 24153
Address all correspondence and requests for reprints to: J. D. Veldhuis, M.D., Division of Endocrinology, Department of Internal Medicine, P.O. Box 800202, University of Virginia School of Medicine, Charlottesville, Virginia 22908. E-mail: jdv{at}virginia.edu
Abstract
How estradiol stimulates pulsatile GH secretion in the human is not well understood. Here, we test the clinical hypothesis that estradiol stimulates GH secretion, in part, by opposing somatostatin’s inhibition of GH release. To this end, 13 estrogen-withdrawn postmenopausal women received placebo or 1 mg micronized estradiol-17ß orally, twice daily for 14 days, in a prospectively randomized, patient-blinded, within-subject cross-over design. For each intervention, the dose-dependent suppressive actions of somatostatin were evaluated by infusing 0 (saline), 3, 10, 30, 100, or 300 µg/1.73 m2·h somatostatin-14 continuously, iv, for 3 h, on separate mornings, in the fasting state, 48 h apart. Blood was sampled at 10-min intervals for 2 h before, for 3 h concurrently with, and for 1 h after each infusion. Serum GH concentrations were quantitated in an ultrasensitive chemiluminescence-based assay (detection threshold, 0.005 µg/L). In the estrogen-deficient milieu, constant iv somatostatin infusions inhibited steady-state serum GH concentrations (valley mean during the last 60 min of the infusion interval) in a dose-dependent manner (P < 10-4 interventional effect). Maximally effective doses of somatostatin reduced the latter by 89 ± 6.1% (mean ± SEM) below the subject-specific preinfusion baseline. Estrogen administration increased the serum estradiol concentration from 12 ± 1 to 245 ± 35 pg/mL [42 ± 4 to 920 ± 110 pmol/L] (P < 10-4); decreased serum concentrations of LH (P = 0.018), FSH (P < 10-4), and insulin-like growth factor-I (P = 0.003); and elevated the fasting (6-h mean) serum GH concentration from 0.41 ± 0.07 to 0.87 ± 0.27 (P = 0.011). Estradiol supplementation did not alter somatostatin’s maximal suppression of GH by 89 ± 4.7% (P < 10-4 below subject-specific preinfusion baseline), thus signifying unchanging somatostatin efficacy. In contrast, estradiol replacement significantly elevated the half-maximally inhibitory dose of infused somatostatin by 13.5-fold, from 0.43 (0.38–0.48, 95% group statistical confidence intervals) (placebo) to 6.0 (5.2–7.0) (estradiol) µg/1.73 m2/h (P < 10-4), denoting muting of somatostatin’s inhibitory potency. The latter inference was confirmed by a concomitant 4-fold decrease in the exponential steepness of the somatostatin inhibitory dose-response function; viz., mean 1.42 (1.49 to 1.33) (placebo) vs. 0.34 (0.62 to 0.26) (estradiol) slope units (P < 10-4). The foregoing effects were specific, because estrogen did not alter somatostatin’s dose-dependent enhancement (P < 10-4) of the orderliness of GH release patterns, as quantitated via the approximate entropy regularity statistic.
In summary, short-term replacement of estradiol to midfollicular phase levels in postmenopausal women selectively reduces the potency, but not the efficacy, of somatostatin’s dose-dependent inhibition of GH release. Estrogen supplementation does not modify somatostatin’s reciprocal enhancement of the quantifiable orderliness (approximate entropy) of the GH secretory process. Accordingly, we postulate that estradiol can facilitate pulsatile GH secretion, in part, by opposing the repressive actions of somatostatin.
HYPOTHALAMIC SIGNALS, SUCH as GHRH (a stimulatory 44-amino-acid peptide) and somatostatin (an inhibitory tetradecapeptide) act coordinately to supervise basal, pulsatile, entropic (pattern-sensitive), and 24-h rhythmic GH secretion (1, 2, 3, 4). GHRH stimulates rapid exocytotic discharge of intracellular GH stores, acute transcription of the GH gene, and delayed somatotrope-cell growth and proliferation (5). In contrast, somatostatin blocks the immediate release of accumulated GH without impeding further de novo biosynthesis (1, 6). Synthetic GH-releasing peptides (GHRPs) are also highly effective cosecretagogues. However, the precise roles of a recently cloned endogenous 3Ser-octanoylated 28-amino-acid GHRP, ghrelin, and the cognate receptor-specific signaling pathway in the human are not yet clear (4, 7, 8, 9). The foregoing core tripeptidyl model, along with GH/insulin-like growth factor-I (GH/IGF-I) negative feedback, provides an ensemble of regulatory signals, which putatively mediate the impact of various internal and external cues on GH production (10, 11).
Age, gender, and sex steroids are important determinants of the endogenous production rate of GH and IGF-I in humans and experimental animals (1, 2, 12, 13). For example, estrogen-sufficient young women secrete 2- to 7-fold more GH than do prepubertal girls, men, or estrogen-deficient postmenopausal women (11, 13, 14, 15, 16, 17, 18, 19, 20). Daily GH output correlates with the serum estradiol concentration in pubertal children, men, and women (15, 17, 18, 21), increases nearly 2-fold during the estrogen-enriched preovulatory phase of the menstrual cycle (6, 15, 21, 22), and rises concomitantly with increasing estrogen secretion in puberty. Oral estrogen administration and higher-dose transdermal estradiol delivery stimulate GH secretion by 1.5- to 2.8-fold in girls and women, and diethylstilbestrol ingestion drives GH production in men (1, 11, 12, 23, 24, 25).
Recent mechanistic analyses indicate that estrogen stimulates GH output principally by augmenting the amount (mass) of GH released within each secretory burst, without evidently altering GH pulse frequency, secretory event duration, basal/nonpulsatile GH release, or the GH half-life (12, 23, 25). The foregoing specificity of estrogen’s amplification of GH secretory burst mass could indicate that this sex steroid: 1) opposes somatostatinergic restraint of GH secretion; 2) potentiates GHRH or GHRP’s stimulation of somatotropes; 3) drives pituitary GH gene expression directly; and/or 4) decreases the in vivo distribution volume or metabolic clearance rate of GH. Few clinical or experimental data support either of the last two conjectures (1, 2, 20, 25, 26). Estrogen supplementation does not typically facilitate GHRH production or its acute pituitary actions in the rat or human (1, 2, 12, 13). However, normal puberty and administration of estrogen enhance GH release stimulated by synthetic GHRPs under some (but not all) clinical conditions (9, 27, 28, 29). Thus, an important unresolved mechanistic issue is whether estradiol modulates the potency and/or efficacy of somatostatin’s inhibition of GH secretion. Accordingly, the present study appraises the ability of short-term estradiol supplementation to relieve infused somatostatin’s dose-dependent suppression of GH secretion in healthy postmenopausal women.
Materials and Methods
Subjects
Thirteen healthy postmenopausal women participated in the study, after providing voluntary written informed consent approved by the Institutional Review Board of the University of Virginia. Criteria for inclusion included healthy, unmedicated, postmenopausal women withdrawn from any prior estrogen replacement therapy for at least 4 weeks, with an unremarkable detailed medical history and complete physical examination. Volunteers had normal screening biochemical tests of hematological, renal, hepatic, metabolic, and thyroid function. Menopausal status was confirmed biochemically by documenting serum concentrations of estradiol less than 20 pg/mL and of FSH more than 35 IU/L. Exclusion criteria included the use of prescription medications, acute or chronic systemic disease, neuropsychiatric illness, drug or alcohol abuse, clinical contraindications to estrogen replacement (e.g. estrogen-responsive neoplasms, nondiuretic-controlled hypertension, or type IV hyperlipidemia), recent transmeridian travel (more than three time zones within 10 days), acute weight change (>2 kg loss or gain over 3 weeks), or lack of voluntary written informed consent.
Protocol design
Each volunteer was admitted to the University of Virginia General Clinical Research Center for a total of eight study sessions. There were two sets of four admissions (one set after pretreatment with placebo and another after estrogen). Each set comprised randomly ordered somatostatin doses given on alternate days (below).
Estrogen was administered as micronized 17ß-estradiol (1 mg orally, twice daily for 14 days). Placebo vs. estrogen was given in a single-blind manner after at least 4 weeks of hormone-free washout. Infusion sessions were prescheduled for days 8, 10, 12, and 14 of placebo or estrogen intervention, because oral estrogen supplementation stimulates GH secretion consistently within 5–7 days (23, 25).
Subjects were admitted to the General Clinical Research Center, the evening before sampling and infusion, to allow overnight adaptation to the Unit. To limit nutritional confounds, a standardized snack was administered at 1800 h (12 kcal/kg; 55% carbohydrate, 15% protein, and 30% fat). Volunteers then remained fasting until 1400 h the next day. At 0700 h the next morning, two indwelling cannulae were placed in contralateral forearm veins for later repetitive blood sampling and saline/somatostatin infusion. At 0800 h, a fasting blood sample was withdrawn for later assay of baseline serum estradiol, FSH, LH, and IGF-I concentrations (below). Thereafter, blood was sampled (1.0 mL per sample) every 10 min for 6 h, from 0800 h until 1400 h. The first 2 h served as a preinfusion baseline. At 1000 h, one of the following randomly ordered doses of synthetic somatostatin-14 (Serono Laboratories, Inc., Serono, Canada, used under an investigator-initiated FDA Investigator New Drug file) was infused iv continuously for 3 h: 0 (saline, 13 women); 3, 10, or 30 (4 women); and 30, 100, or 300 µg/1.73 m2·h (9 women). The infusion was stopped at 1300 h, and blood sampling was continued for 1 additional hour until 1400 h. Volunteers were then given lunch and discharged from the Unit. Subjects remained at bedrest except for lavatory use during sampling and infusions. Blood glucose was monitored hourly (below).
Hormone assays
Serum GH concentrations were determined in each sample, in duplicate, by a robotics-assisted ultrasensitive chemiluminescence-based assay (Nichols Institute Diagnostics, San Juan Capistrano, CA) using 22-kDa recombinant human GH as standard (4, 30, 31). All serum samples from a given subject (n = 289) were analyzed in one run. The sensitivity of the GH assay (defined as 3 SDs above the zero dose tube) was 0.005 µg/L (30, 31). The median intra- and interassay coefficients of variation (CVs) were 6.5% and 8.7%, respectively, at the GH concentrations measured here. Estradiol was quantitated by RIA with a sensitivity of 8 pg/mL and within-assay CV of 6.2% (Coat-A-Count, Diagnostic Products, Los Angeles, CA). Serum LH and FSH concentrations were measured by immunoradiometric assay (IRMA) (Nichols Institute Diagnostics), using the First and Second International Reference Preparations, respectively, as standards (25). The corresponding sensitivities and intraassay CVs were 0.5 and 2.0 IU/L, and 6.3 and 7.4%. Interassay CVs were less than 10%. Serum IGF-I was assayed by RIA after acid-ethanol extraction (Nichols Institute Diagnostics), with intra- and interassay CVs of 10.3% and 12% (25). Glucose was measured by an automated glucose oxidase technique.
Statistical analysis
ANOVA with repeated measures was used to contrast the impact of varying somatostatin doses on various measures of GH release. To this end, the first sample at 0800 h was assigned a time of 10 min, and the baseline serum GH concentration was calculated as the mean 2-h preinfusion value over the time interval 10–130 min. The primary calculated comparison measures included: 1) the mean steady-state valley serum GH concentration (average over the last 60 min of the continuous 3-h somatostatin infusion, corresponding to a time window of 250–310 min); and 2) the percentage decrease in the valley serum GH concentration in relation to each subject- and session-specific baseline (baseline-valley/baseline x 100%).
Serum concentrations of estradiol, FSH, LH, and IGF-I were measured in single samples collected at 0800 h on admission days 8, 10, 12, and 14. Because the foregoing means were statistically invariant within each set of four placebo or estrogen-replacement sessions, daily values were averaged within intervention. A paired, two-tailed Student’s t test was used to assess estrogen’s effects on the resultant means.
Data are given in text and figures as the mean ±
SEM. P values 
0.05 were construed as
statistically significant.
Dose-response analysis
A simple 4-parameter logistic (sigmoidal) model was applied to quantitate the dose-dependent inhibitory effects of somatostatin (0, 3, 10, 30, 100, or 300 µg/1.73 m2·h) on valley serum GH concentrations (defined above) and the approximate entropy (ApEn) of GH release (below). Thereby, one estimates the group potency or ID50 (median half-maximally inhibitory dose of somatostatin), the exponential slope (steepness) of inhibition at the ID50 value, and the efficacy (maximally suppressive effect of somatostatin), along with asymptotic 95% statistical confidence intervals for each parameter (32).
ApEn
ApEn was used as a model-independent regularity statistic, which is a barometer of feedback control of time-series orderliness. ApEn was applied to the last 90 min of each 3-h infusion to quantify the subpattern reproducibility of serial GH release (33). ApEn parameters of m = 1 (window length) and r = 75% of each series SD (de facto threshold) were used here, as earlier validated. This normalized ApEn statistic, ApEn (1, 75%), is thus scale-invariant and suitable for application to short series. Increased ApEn (at equal time series lengths and similar parameter values, as used here) indicates greater irregularity of successive patterns, as reported for GH profiles in acromegaly (34), midpuberty (33), and women compared with men (35).
Results
The mean (± SEM) age at study was 58 ± 3.1 yr, and the duration of clinical menopause was 8 ± 2.2 yr. The body mass index averaged 27 ± 0.8 kg/m2.
Administration of estradiol-17ß orally for 14 days was well tolerated. All women completed eight admissions. Three women reported breast tenderness, mild fluid retention, and/or altered mood. No serious adverse events were observed. Each volunteer completed all eight admissions in the within-subject cross-over design. No ill effects were attributed to the somatostatin infusions, with one exception, in which the dose dispensed was too high by a factor of 1.73. In this case, the volunteer experienced transient abdominal cramps, nausea, and headache. The session was stopped and repeated, on another day, using the correct dose of somatostatin. Hourly plasma glucose concentrations did not increase during any of the infusions.
Estradiol replacement for 8–14 days increased the morning (0800 h) serum estradiol concentration to 245 ± 35 pg/mL (920 ± 130 pmol/L), compared with a mean postplacebo (basal) value of 12 ± 1 pg/mL (42 ± 4 pmol/L) (P = 10-4). Concomitantly, serum concentrations of FSH declined from 84 ± 11 (placebo) to 50 ± 9.2 (estrogen) IU/L (P < 10-4), LH from 45 ± 8.3 to 35 ± 7.8 IU/L (P = 0.018), and IGF-I from 190 ± 18 (normal range, 79–280) to 133 ± 16 µg/L (P = 0.003).
On the control day (saline infusion), mean 6-h fasting serum GH
concentrations averaged 0.41 ± 0.07 (placebo) and 0.87 ±
0.27 µg/L (estradiol) (P = 0.012). Preinfusion (2-h)
baseline serum GH levels rose commensurately (approximately 2-fold)
(P < 0.01). Attendant (mean ±
SEM) serum GH concentration profiles for all 13
study subjects are shown in Fig. 1
.
Somatostatin infusions suppressed mean valley (steady-state) serum GH
concentrations dose-dependently during both placebo and estrogen
replacement (each P <
10-4 by ANOVA) (Fig. 2). Maximal suppression of valley serum
GH concentrations was statistically comparable at 89 ± 6.1%
during placebo and 89 ± 4.7% during estradiol treatment (n
= 13 for saline; n = 4 for 3, 10 or 30; and n = 9 for 30, 100
and 300 µg/1.73 m2·h). Serum GH
concentrations remained detectable in the chemiluminescence assay in
all 10-min samples in each 6-h infusion session in all 13 women.
|
|
, top subpanel). The
exponential slope (steepness) of the somatostatin inhibition curve fell
from 1.42 (1.49 to 1.33) (placebo) to 0.34 (0.62 to 0.26) (estradiol)
slope units (P <
10-4) (Fig. 3, middle panel). In contrast, asymptotically maximal
inhibition of serum GH concentrations was comparable during randomly
ordered placebo and estradiol pretreatment; i.e. the
predicted minimal valley serum GH concentration was 0.028
(0.025–0.033) (control) and 0.044 (0.031–0.056) µg/L (estradiol)
(Fig. 3, bottom subpanel). These values are, respectively,
5.3 and 7.9-fold higher than the GH assay threshold (Materials
and Methods).
|
).
|
Discussion
The present clinical investigation corroborates the neuroregulatory hypothesis that estrogen stimulates pulsatile GH secretion in postmenopausal women, in part, by reducing somatostatin’s potency (but not efficacy) of inhibiting GH secretion. In this paradigm, short-term (8–14 days of) oral estradiol-17ß replacement achieved the equivalent of mid- to late-follicular phase estradiol concentrations (15, 21, 25) and concomitantly doubled fasting serum GH concentrations. Studies were carried out in which fasting was used to limit confounding that would otherwise result from variable amounts of endogenous somatostatin, the release of which is suppressed by food withdrawal in humans (1, 2). Under these conditions, continuous iv infusion of somatostatin-14 suppressed GH release, dose-dependently, to new steady-state (valley) concentrations after 1.5–2 h. This time course is in keeping with the known half-life of GH (12–20 min) and a rapid onset of inhibition by somatostatin (1, 2, 26).
The lowest serum GH concentrations attained during somatostatin exposure remained at least 5-fold above the detection limit of the chemiluminescence-based GH assay. This technical feature ensured valid computation of somatostatin’s inhibitory potency and efficacy. Administration of estradiol selectively attenuated somatostatin potency, as quantified by a 13.5-fold-higher ID50 and 4-fold-lower slope of the somatostatin dose-inhibition curve. This in vivo finding mirrors in vitro data in single somatotrope cells from the adult rat, wherein gender influences somatostatin’s potency rather than efficacy (36). From a physiological perspective, the ability of estradiol to mute the repressive actions of submaximally inhibitory amounts of somatostatin would be particularly important, because maximal restraint of GH secretion probably is rarely, if ever, achieved in normal healthy individuals.
Estradiol’s reduction of somatostatin’s inhibitory potency could arise by way of either direct or indirect mechanisms. A direct mechanism might entail estradiol-induced down-regulation of pituitary somatostatin receptor signaling. However, this notion is unlikely, in view of estrogen’s tendency to amplify somatostatin binding and actions in animal and cell-culture models (37, 38), and the presently observed sparing by estrogen of somatostatin’s putatively direct enhancement of orderly GH release (below). An alternative hypothesis is that estrogen promotes the release and/or activity of one or more somatostatin-opposing GH secretagogues. In this regard, GHRH and GHRPs both partially antagonize somatostatin’s inhibition of GH release at the somatotrope level (1, 2), whereas GHRPs also oppose certain hypothalamic actions of somatostatin (1, 2, 7, 8). Accordingly, we postulate that estradiol relieves somatostatin’s repression of GH secretion in postmenopausal women by facilitating the release and/or actions of endogenous GH secretagogues (Introduction).
Plasma IGF-I concentrations declined by approximately 25% in the oral estrogen-replaced state, presumptively reflecting down-regulation of hepatic IGF-I production (39, 40). The oral route of estrogen delivery is especially, but not solely, effective in stimulating GH secretion, because higher-dose transdermal estradiol administration can do likewise (12). In principle, reduced peripheral IGF-I availability might contribute to estrogen-stimulated GH production because of partial withdrawal of negative feedback (1, 2). However, the precise role of circulating IGF-I in regulating GH secretion has been questioned by recent studies in genetically engineered liver-specific disruption of the IGF-I gene in growing mice and acute GH-receptor blockade with pegvisomant in young men (41, 42). Alternatively, the ability of IGF-I deficiency to reduce hypothalamic somatostatin production in the rat (43) might indirectly increase the amount of exogenously infused somatostatin required to suppress GH submaximally.
The present experiments examine the actions of exogenous, rather than
the release of endogenous, somatostatin. At the level of the
hypothalamus, estradiol (unlike testosterone or 5
-dihydrotestosterone) does not consistently regulate in
situ somatostatin gene or peptide expression in the rat (1, 2, 10, 44, 45, 46, 47). Although comparable histochemical data are not
available in humans, clinical studies have used
L-arginine as a GH secretagogue to probe
hypothalamic somatostatin release (1). Interestingly,
L-arginine tends to exert a greater effect in
healthy women than men, with maximal secretory activity evident in the
late follicular phase of the menstrual cycle (11, 22, 48, 49). Thus, an estrogen-enriched milieu may heighten hypothalamic
somatostatin availability and/or enhance an unknown (e.g.
nitric-oxide or other nonsomatostatinergic) stimulatory effect of
L-arginine (1, 2). Such inferential
actions of estrogen on the central somatostatinergic system in the
human should be distinguished from the relief of pituitary inhibition
by any given amount of available somatostatin under estrogen drive, as
demonstrated here.
During placebo administration, somatostatin infusion consistently lowered GH ApEn, which change quantitates more orderly patterns of GH release enforced by negative feedback. The dissociation between estradiol’s antagonism of somatostatin’s effects on GH secretory output, but not the orderliness of GH release, could indicate that estrogen also alters nonsomatostatinergic signaling inputs to somatotropes. This notion would follow from earlier studies showing that estrogen supplementation alone elevates GH ApEn (4, 9, 25, 33, 50). The failure of estradiol, in the presence of somatostatin infusions, to elevate GH ApEn would indicate the dominance of somatostatin as a regulator of orderly GH secretion.
In summary, the present clinical investigation demonstrates that short-term oral estradiol supplementation opposes exogenous somatostatin’s dose-dependent inhibition of fasting GH secretion in postmenopausal women. Estrogen acts specifically to attenuate somatostatin’s inhibitory potency (i.e. reduce pituitary sensitivity to this suppressive peptide) without altering its efficacy (i.e. alter the degree of maximal inhibition of GH release). Thus, estradiol replacement in postmenopausal women may amplify pulsatile GH secretion, in part, by opposing endogenous somatostatin’s ability to repress GH release. Based on an ensemble concept of multipeptidyl control of GH production, we postulate that estrogen achieves such evident disinhibition from somatostatin restraint by augmenting the release and/or actions of endogenous GHRH, GHRP, and/or other co-secretagogues of GH.
Acknowledgments
We thank Patsy Craig for skillful preparation of the manuscript; Paula P. Azimi for deconvolution analysis, data management, and graphics; Brenda Grisso and Ginger Bauler for performance of the immunoassays; Dr. Michael O. Thorner for providing initial access to his Investigator New Drug file for application in some of the pilot somatostatin infusions; and Sandra Jackson and the expert nursing staff at the University of Virginia General Clinical Research Center for conduct of the research protocols. This focused report necessarily omits many primary references because of editorial constraints. We therefore acknowledge numerous colleagues, who have made earlier foundational observations.
Footnotes
1 Supported in part by NIH National Center for Research
Resources Grant MO1-RR-00847 (to the General Clinical Research
Center of the University of Virginia Health System), Center for
Biomathematical Technology, an NIH Clinical Research Scholar’s Award
(to N.S.), a Clinical Associate Physician Award (to S.M.A.), and
National Institute on Aging Grant AG-14799 (to J.D.V.). 
2 Present address: West Eau Gallie Boulevard, Suite 200, Melbourne,
Florida 32935.
Received November 30, 2000.
Revised February 26, 2001.
Accepted March 14, 2001.
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J. D. Veldhuis, J. Patrie, L. Wideman, M. Patterson, J. Y. Weltman, and A. Weltman Contrasting Negative-Feedback Control of Endogenously Driven and Exercise-Stimulated Pulsatile Growth Hormone Secretion in Women and Men J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 840 - 846. [Abstract] [Full Text] [PDF]
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 N. R. Biermasz, A. M. Pereira, M. Frolich, J. A. Romijn, J. D. Veldhuis, and F. Roelfsema Octreotide represses secretory-burst mass and nonpulsatile secretion but does not restore event frequency or orderly GH secretion in acromegaly Am J Physiol Endocrinol Metab, January 1, 2004; 286(1): E25 - E30. [Abstract] [Full Text]
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E. Richmond, A. D. Rogol, D. Basdemir, O. L. Veldhuis, W. Clarke, C. Y. Bowers, and J. D. Veldhuis Accelerated Escape from GH Autonegative Feedback in Midpuberty in Males: Evidence for Time-Delimited GH-Induced Somatostatinergic Outflow in Adolescent Boys J. Clin. Endocrinol. Metab., August 1, 2002; 87(8): 3837 - 3844. [Abstract] [Full Text] [PDF]
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J. Svensson, J. D. Veldhuis, A. Iranmanesh, B.-A. Bengtsson, and G. Johannsson Increased Orderliness of Growth Hormone (GH) Secretion in GH-Deficient Adults with Low Serum Insulin-Like Growth Factor I J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2863 - 2869. [Abstract] [Full Text] [PDF]
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L. S. Farhy, M. Straume, M. L. Johnson, B. Kovatchev, and J. D. Veldhuis Unequal autonegative feedback by GH models the sexual dimorphism in GH secretory dynamics Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2002; 282(3): R753 - R764. [Abstract] [Full Text] [PDF]
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A. Gentili, T. Mulligan, M. Godschalk, J. Clore, J. Patrie, A. Iranmanesh, and J. D. Veldhuis Unequal Impact of Short-Term Testosterone Repletion on the Somatotropic Axis of Young and Older Men J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 825 - 834. [Abstract] [Full Text] [PDF]
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