Sex steroid regulation of growth hormone secretion and action

Evidence that oestrogen is involved in the regulation of the somatotrophic axis in adult humans is provided by the observations that mean growth hormone (GH) levels are higher in women than men, that the fall in GH and insulin-like growth factor-1 (IGF-1) with aging are correlated to oestradiol levels and that oestrogen increases the GH responses to provocative stimuli. To investigate whether oestrogen modulates GH secretion and action in adult life, we studied the impact of oestrogen replacement on circulating GH and IGF-1 levels in postmenopausal women. Since the liver is the major source of circulating IGF-1 and the oral route of oestrogen delivery causes nonphysiologic effects on hepatic proteins, we compared the effects of oral and transdermal routes of delivery. Oral ethinyl oestradiol administration resulted in a significant fall in mean IGF-1 levels and a threefold increase in mean 24-hour GH. Transdermal administration of 17 beta-oestradiol resulted in a slight increase in serum IGF-1 but no change in mean 24-hour GH levels. To determine whether differences in oestrogen type rather than in the route of delivery caused the different effects on the GH/IGF-1 axis, we compared the effects of three oral oestrogen formulations. Ethinyl oestradiol, conjugated equine oestrogen and oestradiol valerate each induced a fall in IGF-1 and a rise in mean 24-hour GH levels in postmenopausal women. To determine the significance of oestrogen-induced changes on IGF-1, we studied effects on markers of connective and bone tissue activity. We found that propeptide concentrations of type III and type I collagen, and osteocalcin rose and fell in parallel with IGF-1 during oral or transdermal oestrogen therapy. Oestrogen causes distinct, route-dependent effects on the somatotrophic axis. The dissociation of the GH/IGF-1 axis by the oral route is likely to arise from impaired hepatic IGF-1 production which causes increased GH secretion through reduced feedback inhibition. Oestrogen treatment may have longer-term metabolic effects on hypogonadal women exerted through effects on the somatotrophic axis.