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 two randomized,
crossover studies show that oral estrogen replacement therapy suppresses
the biological actions of growth hormones in GH-deficient women, the researchers
concluded.
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.
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, the researchers report.
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 researchers
conclude 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.
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
