Modulation of growth hormone action by sex steroids

Abstract

SummaryGrowth hormone (GH) is a major regulator of growth, somatic development and body composition. Sex steroids can act centrally by regulating GH secretion and peripherally modulating GH responsiveness. This review addresses data of potential clinical relevance on how sex steroids modulate GH secretion and action, aiming to increase the understanding of sex steroid/GH interactions and leading to improved management of patients. Sex steroids regulate GH secretion directly as well as indirectly through IGF-I modulation. Testosterone stimulates GH secretion centrally, an effect dependent on prior aromatization to oestrogen. Oestrogen stimulates GH secretion indirectly by reducing IGF-I feedback inhibition. Whether oestrogen stimulates GH secretion centrally in females is unresolved.Gonadal steroids modify the metabolic effects of GH. Testosterone amplifies GH stimulation of IGF-I, sodium retention, substrate metabolism and protein anabolism while exhibiting similar but independent actions of its own. Oestrogen attenuates GH action by inhibiting GH-regulated endocrine function of the liver. This is a concentration-dependent phenomenon that arises invariably from oral administration of therapeutic doses of oestrogen, an effect that can be avoided by using a parenteral route.This strong modulatory effect of gonadal steroids on GH responsiveness provides insights into the biological basis of sexual dimorphism in growth, development and body composition and practical information for the clinical endocrinologist. It calls for an appraisal of the diagnostic criteria for GH deficiency of GH stimulation tests, which currently are based on arbitrary cut-offs that do not take into account the shifting baseline from the changing gonadal steroid milieu. In the management of GH deficiency in the hypopituitary female, oestrogen should be administered by a nonoral route. In hypopituitary men, androgens should be replaced concurrently to maximize the benefits of GH. In the general population, the metabolic consequences of long-term treatment of women with oral oestrogen compounds, including selective oestrogen receptor modulators, are largely unknown and warrant study.

Estrogens in the Control of Growth Hormone Actions in Liver

“…Therefore, estrogen-GH interactions are relevant because physiological roles these hormones have in mammals, and the widespread use of estrogen and estrogen-related compounds in human. These have been supported from clinical observations where administration of pharmacological doses of estrogens to human impairs GH-regulated endocrine and metabolic functions in liver (Meinhardt and Ho, 2006). Thus, deficiency of GH or E2 activities as well as estrogen-GH interactions may cause a dramatic impact in liver physiology during development as well as in adulthood.…”

GH signaling in skeletal muscle and adipose tissue in healthy human subjects: impact of gender and age

“…It is well established that estrogen status is an important determinant of GH secretion although it does not fully account for the sexual dimorphism (2,11,29). One mechanism of estrogen in this regard is direct suppression of hepatic IGF1 production, where the subsequent decline in serum IGF1 levels is assumed to stimulate GH secretion secondary to reduced feedback inhibition (11).…”

“…Both spontaneous and stimulated GH secretion in midlife adults are determined by abdominal adiposity rather than chronological age (5,6), and weight loss partly restores impaired GH secretion in obesity (7). It is also well known that sex steroids regulate GH secretion at the pituitary level and also modulate peripheral IGF1 generation (2). In adult males, testosterone stimulates GH secretion (2) and some but not all studies suggest that testosterone enhances GH-induced IGF1 stimulation (8,9).…”

“…The activity of the growth hormone (GH)-insulin-like growth factor 1 (IGF1) axis in human subjects is determined by several factors including age and gender, but the causeeffect relationship remains uncertain (1,2,3).…”

The role of estrogen in bone growth and formation: changes at puberty

“…42 Conversely, human pubertal data have emerged demonstrating that a substantial portion of testosterone's effect is mediated through its aromatization to estrogen by the enzyme aromatase. 34,36,[43][44][45] Estrogens are responsible for the development of secondary sexual characteristics and play a major role in reproductive function in women. Estrogens are known to have a biphasic effect on pubertal skeletal growth.…”