News Release

Oral administration of estrogen replacement therapy suppresses the biological actions of growth hormones in GH-deficient women

Peer-Reviewed Publication

American Physiological Society

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.

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Source: American Journal of Physiology: Endocrinology and Metabolism, December 2001

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.


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