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      Sex Steroids and the Growth Hormone/Insulin-Like Growth Factor-I Axis in Adults

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          In healthy adults insulin-like growth factor (IGF)-I levels do not differ between males and females, whereas spontaneous growth hormone (GH) secretion is approximately twofold higher in females. Untreated GH-deficient (GHD) women exhibit lower IGF-I levels compared with men and the increase in serum IGF-I during GH replacement is also significantly less. These data suggest a resistance to GH in women, which in healthy subjects is compensated for by increased GH secretion. Administration of oral oestrogen in healthy postmenopausal women suppresses hepatic IGF-I production and increases pituitary GH release, and oral oestrogen replacement in women with GHD lowers IGF-I concentrations and increases the amount of GH necessary to achieve IGF-I target levels during treatment. These data clearly suggest that hepatic suppression of IGF-I production by oestrogen subserves the gender difference in GH sensitivity, but it is also likely that sex steroids may interact with the GH/IGF axis at other levels. There is also circumstantial evidence to indicate that testosterone stimulates IGF-I production and it is speculated that a certain threshold level of androgens is essential to ensure hepatic IGF-I production. Whether these data should translate into earlier discontinuation of oestrogen replacement therapy in women with hypopituitarism merits consideration.

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          Most cited references 11

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          Effects of sex and age on the 24-hour profile of growth hormone secretion in man: importance of endogenous estradiol concentrations.

          We undertook a study of the separate and combined effects of age and sex on the pulsatile pattern of GH secretion. The 24-h secretory profile of GH was generated by 20-min sampling in 10 young women (aged 18-33 yr), 10 young men (aged 18-33 yr), 8 postmenopausal women (aged greater than 55 yr), and 8 older men (aged greater than 55 yr). A computer-assisted pulse analysis program was used to assess both total GH secretion, as reflected in the 24-h integrated GH concentration (IGHC), and pulsatile secretion, as denoted by pulse frequency, duration, amplitude, and the fraction of GH secreted in pulses during the 24-h period (FGHP). IGHC was significantly greater in women than in men (P less than 0.025) and greater in the young than in the old (P less than 0.003). The mean pulse amplitude, duration, and FGHP were each greater in the young (P less than 0.006, P less than 0.03, and P less than 0.0001, respectively), but not significantly different between the sexes. The mean pulse frequency was not affected by sex or age. The serum concentration of free estradiol, but not free testosterone, correlated with IGHC (r = 0.46; P less than 0.005), pulse amplitude (r = 0.53; P less than 0.001), and FGHP (r = 0.59; P less than 0.0002). After correcting for the effects of estradiol, neither sex nor age influenced IGHC or mean pulse amplitude, while the effect of age on FGHP was reduced from 81% to 29%. Of the indices of GH secretion, FGHP had the strongest correlation (r = 0.43; P less than 0.006) with somatomedin-C. Somatomedin-C declined significantly with age in both sexes. Our results indicate that sex and age have independent and interrelated effects on GH secretion. These effects can be largely accounted for by corresponding variations in endogenous estradiol levels. These observations suggest an amplifying action of estradiol on the neuroendocrine regulation of pulsatile GH release.
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            Estrogen inhibits GH signaling by suppressing GH-induced JAK2 phosphorylation, an effect mediated by SOCS-2.

            Oral estrogen administration attenuates the metabolic action of growth hormone (GH) in humans. To investigate the mechanism involved, we studied the effects of estrogen on GH signaling through Janus kinase (JAK)2 and the signal transducers and activators of transcription (STATs) in HEK293 cells stably expressing the GH receptor (293GHR), HuH7 (hepatoma) and T-47D (breast cancer) cells. 293GHR cells were transiently transfected with an estrogen receptor-alpha expression plasmid and luciferase reporters with binding elements for STAT3 and STAT5 or the beta-casein promoter. GH stimulated the reporter activities by four- to sixfold. Cotreatment with 17beta-estradiol (E(2)) resulted in a dose-dependent reduction in the response of all three reporters to GH to a maximum of 49-66% of control at 100 nM (P < 0.05). No reduction was seen when E(2) was added 1-2 h after GH treatment. Similar inhibitory effects were observed in HuH7 and T-47D cells. E(2) suppressed GH-induced JAK2 phosphorylation, an effect attenuated by actinomycin D, suggesting a requirement for gene expression. Next, we investigated the role of the suppressors of cytokine signaling (SOCS) in E(2) inhibition. E(2) increased the mRNA abundance of SOCS-2 but not SOCS-1 and SOCS-3 in HEK293 cells. The inhibitory effect of E(2) was absent in cells lacking SOCS-2 but not in those lacking SOCS-1 and SOCS-3. In conclusion, estrogen inhibits GH signaling, an action mediated by SOCS-2. This paper provides evidence for regulatory interaction between a sex steroid and the GHJAKSTAT pathway, in which SOCS-2 plays a central mechanistic role.
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              Effects of different oral oestrogen formulations on insulin-like growth factor-I, growth hormone and growth hormone binding protein in post-menopausal women.

              Insulin like growth factor-I (IGF-I) levels in post-menopausal women are reduced by oral administration of the synthetic oestrogen ethinyl oestradiol but increased by transdermal delivery of 17 beta-oestradiol. Since these oestrogen types are different, the aim of this study was to clarify whether reduction in IGF-I is a specific effect of ethinyl oestradiol or common to other oral oestrogen formulations.

                Author and article information

                Horm Res Paediatr
                Hormone Research in Paediatrics
                S. Karger AG
                November 2005
                15 November 2005
                : 64
                : Suppl 2
                : 37-40
                Medical Department M (Endocrinology and Diabetes) and Department of Gynecology and Obstetrics, Århus University Hospital, Århus, Denmark
                87752 Horm Res 2005;64:37–40
                © 2005 S. Karger AG, Basel

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                Page count
                Figures: 2, References: 16, Pages: 4
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