Contrasting effects of oral and transdermal routes of estrogen replacement therapy on 24-hour growth hormone (GH) secretion, insulin-like growth factor I, and GH-binding protein in postmenopausal women

Abstract

Estrogen deficiency may account for lower circulating GH and insulin-like growth factor I (IGF-I) concentrations in the menopause. Since the liver is the major source of circulating IGF-I and oral estrogens have nonphysiological effects on hepatic function, we have compared GH secretion over 24 h from 20 min sampling and serum IGF-I levels in premenopausal women (n = 7, follicular phase) and postmenopausal women before and after 2 months of cyclical replacement therapy with either oral ethinyl estradiol (EE, 20 μg daily; n = 7) or transdermal 17β-estradiol (E2, 100 μg patches applied twice weekly; n = 7). The extent of GH binding to its serum binding protein was also examined by measuring the percent specific binding of [125I] GH in serum. Mean 24-h serum GH and serum IGF-I were significantly lower (P < 0.05) in postmenopausal than in premenopausal women. Oral and transdermal estrogen therapy resulted in a comparable degree of gonadotropin suppression. Oral EE treatment increased mean 24-h serum GH (2.0 ± 0.4 to 7.0 ± 0.6 mIU/L, P < 0.0005) and mean pulse amplitude (5.3 ± 1.2 to 11.2 ± 2.5 mIU/L, P < 0.01) but significantly reduced circulating IGF-I (0.70 ± 0.09 to 0.47 ± 0.04 U/mL, P < 0.02) levels. Oral EE increased the percent specific binding of [125I]GH (22.0 ± 1.6 to 32.0 ± 1.9%, P < 0.0005), however the derived mean 24-h free serum GH concentrations were significantly higher (P < 0.0005) after treatment. By contrast, transdermal E2 administration, which restored circulating E2 concentrations to the midfollicular range, increased circulating IGF-I (0.86 ± 0.15 to 1.10 ± 0.14 U/mL, P < 0.005) to levels that were not significantly different from those of premenopausal women (1.41 ± 0.21 U/ mL). This was not accompanied by changes in 24-h GH secretion or the percent specific binding of [125I]GH in serum. The route of administration is a major determinant of the effects of exogenous estrogens on the GH/IGF-I axis. Oral estrogen administration inhibits hepatic IGF-I synthesis and increases GH secretion through reduced feedback inhibition. Reduced GH secretion in the menopause is not explained by estrogen deficiency since GH secretion is not restored by the attainment of physiological E2 concentrations using the transdermal route. The contrasting route dependent IGF-I responses have important implications for the long-term benefit of hormone replacement therapy in the menopause.