Short-Term Estradiol Replacement in Postmenopausal Women Selectively Mutes Somatostatin’s Dose-Dependent Inhibition of Fasting Growth Hormone Secretion1
M. J. Bray,
T. M. Vick,
N. Shah2,
S. M. Anderson,
L. W. Rice,
A. Iranmanesh,
W. S. Evans and
J. D. Veldhuis
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 humanis not
well understood. Here, we test the clinical hypothesisthat estradiol
stimulates GH secretion, in part, by opposingsomatostatin’s
inhibition of GH release. To this end,13 estrogen-withdrawn
postmenopausal women received placeboor 1 mg micronized
estradiol-17ß orally, twice dailyfor 14 days, in a prospectively
randomized, patient-blinded,within-subject cross-over design. For each
intervention, thedose-dependent suppressive actions of somatostatin
were evaluatedby infusing 0 (saline), 3, 10, 30, 100, or 300 µg/1.73
m2·hsomatostatin-14 continuously, iv, for 3 h, on
separate mornings,in the fasting state, 48 h apart. Blood was
sampled at 10-minintervals for 2 h before, for 3 h
concurrently with, and for1 h after each infusion. Serum GH
concentrations were quantitatedin an ultrasensitive
chemiluminescence-based assay (detectionthreshold, 0.005 µg/L). In
the estrogen-deficient milieu,constant iv somatostatin infusions
inhibited steady-state serumGH concentrations (valley mean during the
last 60 min of theinfusion interval) in a dose-dependent manner
(P < 10-4 interventional
effect).Maximally effective doses of somatostatin reduced the latter
by89 ± 6.1% (mean ± SEM) below the
subject-specificpreinfusion baseline. Estrogen administration
increased theserum 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
elevatedthe fasting (6-h mean) serum GH concentration from 0.41
±0.07 to 0.87 ± 0.27 (P = 0.011). Estradiol
supplementationdid not alter somatostatin’s maximal suppression of GH
by89 ± 4.7% (P <
10-4 below subject-specific preinfusion
baseline),thus signifying unchanging somatostatin efficacy. In
contrast,estradiol replacement significantly elevated the
half-maximallyinhibitory 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
inhibitorypotency. The latter inference was confirmed by a concomitant
4-folddecrease in the exponential steepness of the somatostatin
inhibitorydose-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).
Theforegoing effects were specific, because estrogen did not alter
somatostatin’sdose-dependent enhancement (P <
10-4) of the orderlinessof GH release
patterns, as quantitated via the approximate entropyregularity
statistic.
In summary, short-term replacement of estradiol to midfollicularphase
levels in postmenopausal women selectively reduces thepotency, but not
the efficacy, of somatostatin’s dose-dependentinhibition of GH
release. Estrogen supplementation does notmodify somatostatin’s
reciprocal enhancement of the quantifiableorderliness (approximate
entropy) of the GH secretory process.Accordingly, we postulate that
estradiol can facilitate pulsatileGH secretion, in part, by opposing
the repressive actions ofsomatostatin.
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