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Oral Administration of Estrogen Replacement Therapy
Suppresses The Biological Actions of Growth Hormones in GH-Deficient Women
Findings demonstrate for the first time that the impact
of oral estrogen extends beyond effects on circulating IGF-I levels as GH-induced
stimulation of fat oxidation, protein metabolism also affected
November 25, 2001 -- Bethesda, Md.— The American Journal of
Physiology: Endocrinology and Metabolism, one of the 14 peer-reviewed
journals published by the American Physiological Society (APS), spotlights
recent research findings designed to improve and understand human well-being
and health. The December edition includes a twin pair of crossover studies
that find oral administration of estrogen replacement therapy (ERT)
suppresses the biological actions of the growth hormone in women with key
hormonal deficiencies.
Background
Growth hormones have recently been approved for replacement treatment in
adults in several countries. They play an important role in regulating body
composition and physical and psychological well-being in adult life.
However, there is limited information regarding the interaction of growth
hormones with other hormones during replacement therapy. Accordingly,
observations in postmenopausal women raised the question as to whether the
traditional oral route of estrogen replacement reduces the biological
effects of growth hormones.
Two studies were undertaken comparing the effects of oral and transdermal
estrogen administration on the biological actions of growth hormones. Doses
employed are those routinely used in the therapy of women with
hypopituitarism. The first study investigated insulin-like growth factor I (IGF-I)
responses to three different doses of GH (dose-response study). The second
study investigated metabolic effects of growth hormone GH on lipid oxidation
and whole body protein metabolism (metabolic study).
The authors of the studies, “Oral Estrogen Antagonizes the Metabolic
Actions of Growth Hormone In Growth Hormone-Deficient Women,” are Troels
Wolthers, David M. Hoffman, Ailish G. Nugent, and Ken K. Y. Ho, all from The
Garvan Institute of Medical Research, St. Vincent's Hospital and Biomedical
Mass Spectrometry Unit, University of New South Wales, Sydney, Australia;
and Mark W. Duncan and Margot Umpleby, both from The Endocrine and Diabetic
Unit, St. Thomas's Hospital, London.
Protocols
Ten hypopituitary GH-deficient women with hypogonadism were recruited
from the Endocrine Outpatient Clinic at St. Vincent's Hospital (Sydney,
Australia). They were randomized into two separate studies, which were
separated by at least three months. Six subjects participated in both
studies. Growth hormone deficiency was confirmed by a peak GH response of <3
ng/ml during an insulin tolerance test. The duration of hypopituitarism was
at least one year, and no subjects had received GH before. All hypopituitary
subjects were receiving stable hormone replacement for other deficiencies,
except for one subject of postmenopausal age who did not receive sex steroid
replacement.
Study Design
Eight subjects participated in each study. Both studies were of
open-label, randomized, crossover design, allowing for differences in
treatment effect (i.e., route of estrogen administration) to be compared
during estrogen therapy. Each subject was randomized to 2 mg/day oral
estradiol valerate or transdermal estrogen patches delivering 100 µg of
17estradiol daily for eight weeks. The subjects then crossed over to the
alternate estrogen treatment for an additional eight weeks. The estrogen
dosages used were based on data indicating equivalent biological activity,
as measured by gonadotropin suppression and vaginal cytology.
Medroxyprogesterone acetate (10 mg daily) was coadministered on the last
12 days of each four-week cycle of estrogen treatment to induce withdrawal
bleeding.
The Dose-Response Study
The growth hormone Genotropin was administered in a stepwise incremental
regimen during the second month of each estrogen phase, at a dose of 0.5 IU/day
(0.17 mg/day) for the first week, one IU/day (0.33 mg/day) for the second
week, and two IU/day (0.67 mg/day) for the third week. The growth hormone
was administered daily by self-injection at 2000. Blood was withdrawn for
IGF-I measurements before initiation of estrogen therapy, during estrogen
phases immediately before initiation of GH administration, and again on the
seventh day of each increment in the growth hormone.
The Metabolic Study
This study design was the same as in the dose-response study except that
patients received a daily dose of growth hormone from weeks four to six
during each estrogen phase. On the basis of the IGF-I data obtained in the
dose-response study, a GH dose of 2 IU (0.67 mg) was administered daily by
self-injection at 2000. Serum IGF-I, lipid oxidation, and protein metabolism
were measured just before GH was started and at the end of the second week
of GH treatment during each estrogen phase.
Results
The Dose-Response Study
The mean IGF-I level fell significantly from baseline (11.2 ± 1.54 nmol/l)
during oral (P < 0.05, 8.7 ± 1.3 nmol/l) but not transdermal (11.2 ± 1.6 nmol/l)
treatment. GH administration significantly increased IGF-I levels in a
stepwise, dose-dependent manner during both estrogen treatments; however,
mean IGF-I levels were significantly lower during oral estrogen treatment.
The increment in IGF-I induced by GH was also less during the oral phase
compared with the transdermal phase at each of the three different GH
dosages. The impact of the route of estrogen administration was gauged by
comparing mean IGF-I levels achieved across GH doses between estrogen
treatments.
The mean IGF-I level in response to 1.0 IU GH during oral estrogen
therapy was indistinguishable from that observed at baseline and during the
transdermal phase before commencing GH. Administration of 2.0 IU GH during
oral estrogen therapy resulted in a mean IGF-I level similar to that
observed with one-half of this dose during the transdermal phase. Comparable
IGF-I levels between estrogen treatments were obtained at a GH dosage ~1.0
IU higher during oral estrogen treatment.
The Metabolic Study
IGF-I results confirmed the findings of the dose-response study. Thus,
mean baseline IGF-I concentration during oral estrogen was significantly
lower than during transdermal estrogen. GH administration increased IGF-I
levels during both estrogen treatments, with a mean IGF-I level lower during
oral estrogen treatment. Furthermore, the increase in IGF-I induced by GH
was also of lower magnitude during the oral phase compared with the
transdermal phase.
Lipid oxidation
Fasting lipid oxidation was not influenced by the route of estrogen
administration. Ingestion of a standardized meal significantly suppressed
lipid oxidation during both estrogen treatment. When compared with the
transdermal route, oral estrogen administration resulted in a greater
suppression of lipid oxidation during the 1st h after ingestion of the
standardized meal. Fasting and postmeal lipid oxidation was significantly
increased by growth hormone treatments, although the meal once again induced
a decline in lipid oxidation during both estrogen treatments. However,
postmeal lipid oxidation during GH treatment was again suppressed to a
greater degree in the first hour with oral treatment. The magnitude of GH-induced
stimulation of lipid oxidation during fasting or in the postmeal state was
not influenced by the route of estrogen. Thus oral estrogen reduces early
postprandial lipid oxidation both before and during GH administration.
Protein metabolism
When compared with the transdermal phase, leucine incorporation into
protein was significantly lower during the oral phase. Mean leucine turnover
was lower during oral therapy, although the difference failed to reach
statistical significance. Leucine oxidation was not significantly different
between estrogen treatments. GH administration did not significantly affect
leucine turnover but induced a significant fall in leucine oxidation. This
was accompanied by a rise in leucine incorporation into protein, which
increased significantly. However, during GH treatment, leucine
incorporation into protein remained significantly lower with oral estrogen
compared with the transdermal route.
Discussion and Conclusions
These two randomized, crossover studies show that oral estrogen
replacement therapy suppresses the biological actions of growth hormones in
GH-deficient women:
In the first study, mean IGF-I across all three GH doses was
significantly lower, and the rise in IGF-I during oral estrogen was
significantly less than that observed during transdermal therapy.
In the metabolic study, postprandial lipid oxidation and leucine
incorporation into protein were stimulated by GH treatment but remained
significantly lower during the oral estrogen phase.
Moreover, the route-dependent effects of estrogen on IGF-I, fat
oxidation, and protein metabolism were evident even before GH
administration. Thus, in GH-deficient, hypogonadal women, oral estrogen
exhibits intrinsic metabolic actions that are opposite those of GH and are
not overcome by replacement doses of GH currently used in clinical practice,
indicating the physiological importance of these observations.
The findings demonstrate for the first time that the impact of oral
estrogen extends beyond effects on circulating IGF-I levels in that GH-induced
stimulation of fat oxidation and protein metabolism are also affected.
Although fat oxidation was stimulated by GH, it remained suppressed to a
greater degree postprandially during the oral estrogen treatment. Similarly,
although GH stimulated protein metabolism, leucine incorporation into
protein was significantly lower during oral estrogen therapy. These
observations in postmenopausal women strongly suggest that similar
detrimental changes may occur with conventional oral estrogen therapy in
untreated GH-deficient women.
The study concludes that:
Estrogen at a therapeutic dose exerts significant route-dependent effects
on GH action in women with organic GH deficiency.
Compared with the transdermal route, oral estrogen aggravates metabolic
abnormalities of GH deficiency and attenuates the metabolic effects of GH
therapy. Thus oral estrogen may worsen the body composition abnormalities of
GH deficiency and limit the benefits of GH replacement therapy in GH-deficient
women.
The route of estrogen administration is an important consideration both
before and during GH replacement therapy in hypogonadal GH-deficient women.
Source: American Journal of Physiology: Endocrinology and
Metabolism, December 2001
-end-
The American Physiological Society (APS) was founded in
1887 to foster basic and applied science, much of it relating to human
health. The Bethesda, MD-based Society has more than 10,000 members and
publishes 3,800 articles in its 14 peer-reviewed journals every year.
***
Editor’s Note: For the full
text of the research cited above, or to set up an interview with a member of
the research team, please contact Donna Krupa at 703.527.7357 (direct dial),
703.967.2751 (cell) or djkrupa1@aol.com.
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