Wednesday, February 8, 2012

Gender and Selective Estrogen Receptor Modulator (SERM) Regulation of GH Axis

Estrogen regulates the secretion and action of GH in both men and women. GH secretion is stimulated by estradiol derived locally from aromatization of testosterone. In hypogonadal men, testosterone treatment results in a significant increase in GH levels. This effect is blocked by central estrogen receptor antagonist tamoxifen, which indicates that testosterone stimulation of GH secretion requires prior aromatization to estradiol. Recently, we showed in women that local estrogen also stimulates GH secretion. Thus, estrogen plays a major role in the central stimulation ofGHsecretion in both men and women.

In contrast to its central stimulatory effect, estrogen antagonizes the signaling of the GH receptor. When estrogen is administered orally, the liver is exposed to supraphysiological concentrations, resulting in a fall in circulating IGF-I levels. Thus, estrogen exerts complex effects on the GH-IGF axis—central stimulatory and peripheral inhibitory effects.

Tamoxifen and raloxifene are selective estrogen receptor modulators (SERMs) in wide therapeutic use. Both antagonize central estrogen action but exert estrogen-like effects in the liver. Therefore, these SERMs simultaneously block the central paracrine effects of estrogen while exerting a peripheral endocrine agonist effect. It can be predicted that by blocking central estrogen action, SERMs reduce GH secretion, and by exerting hepatic agonistic effects, they reduce IGF-I production.

Researchers reported recently that in women tamoxifen reduced GH and IGF-I levels. However, the effects of other SERMs such as raloxifene have not been studied. In men, estrogen plays a major role not only in the regulation of the GH-IGF-I axis, but also in the pituitary gonadal axis. Testosterone-mediated negative feedback on LH secretion requires aromatization to estradiol.  Researchers recently reported that central estrogen blockade with SERMs results in stimulation of the pituitary-gonadal axis, enhancing LH secretion and increasing testosterone levels. The higher testosterone levels may in turn result in secondary stimulation of GH secretion. Therefore, it is conceivable that central estrogen blockade may result in an effect on the GH-IGF-I axis in men that is different from women.

The present investigation tests the hypothesis that the effects of estrogen receptor modulation on the GH-IGF-I axis differ between men and women. They have undertaken a prospective, randomized, two-phase crossover study comparing the effects of the two most commonly used SERMs, tamoxifen and raloxifene.

In women, tamoxifen attenuates estrogen-stimulated GH secretion by blocking central estrogen receptors. In the liver, it exerts estrogen-like effect to further reduce IGF-I production.

In men, tamoxifen treatment stimulates LH, which is followed by an increase in testosterone levels. The increase in testosterone will result in greater substrate availability for aromatization to estradiol, which counteracts the inhibitory effect of tamoxifen on GH secretion. As a consequence, there is no net effect on GH secretion, contrary to that in women. Tamoxifen, by exerting an estrogen-like effect on the liver, reduces IGF-I levels similar to that in women.

ER, Estrogen receptor; T, testosterone.

Birzniece V, Sutanto S, Ho KKY. Gender Difference in the Neuroendocrine Regulation of Growth Hormone Axis by Selective Estrogen Receptor Modulators. Journal of Clinical Endocrinology & Metabolism.

Context: In men, GH secretion is stimulated by estradiol derived locally from aromatization of testosterone. Recently, we showed that local estrogen also plays a major role in the central regulation of GH secretion in women. Tamoxifen and raloxifene are selective estrogen receptor modulators (SERMs), drugs that block central estrogen action but exert estrogen-like effects in the liver, inhibiting hepatic IGF-I production. The relative impact of SERMs on the GH-IGF-I axis in men and women has not been investigated.

Objective: The aim of the study was to determine whether there is a gender difference in the impact of SERMs on the GH-IGF-I axis.

Design: We conducted a comparative, randomized, open-label, crossover study of tamoxifen and raloxifene.

Patients and Intervention: Ten healthy postmenopausal women and ten healthy men were randomized to 2-wk sequential treatment with tamoxifen (10 and 20 mg/d) and raloxifene (60 and 120 mg/d) with a washout of 2 wk between treatments.

Main Outcome Measures: The GH response to arginine, IGF-I, testosterone, and SHBG was measured.

Results: In women, but not in men, tamoxifen significantly attenuated the GH response to arginine. The GH response was not significantly blunted by raloxifene in both sexes. Both SERMs significantly reduced mean IGF-I levels to a similar degree in men and women. In men, both SERMs significantly increased LH and testosterone levels.

Conclusions: In summary, GH secretion was blunted by tamoxifen in women in the face of reduced IGF-I feedback inhibition but not in men in whom the gonadal axis was stimulated. We conclude that potential blunting of GH secretion in men by SERMs was counteracted by concomitant central stimulation of GH secretion by testosterone. In therapeutic doses, tamoxifen may induce detrimental metabolic effects in women, but not men.