Discontinuation of estrogen replacement therapy in GH-treated hypopituitary women alters androgen status and IGF-I

Abstract

Objective and design: Compared with their male counterparts, healthy females secrete more growth hormone (GH) and those with GH-deficiency have lower insulin-like growth factor I (IGF-I) levels and are less responsive to GH substitution. To test whether this gender difference is related to sex hormones we measured androgen status and IGF-I related parameters in 38 hypopituitary women (mean (range) age 41.5 (20-58) years) during continued GH substitution as compared with a control group of 38 healthy women matched for age and menopausal status. Twenty six patients were studied twice: with estrogen replacement and after 28 days of estrogen discontinuation in a randomised design. (IGFBP-1), and IGFBP-3 did not differ between patients and controls. The subgroup of patients receiving hydrocortisone (HC) replacement (n ¼ 24) had significantly lower levels of androgens (suppressed by 80-100%) as well as IGF-I and IGFBP-3 as compared with the patients not receiving HC. IGF-I was correlated to free testosterone in patients (r ¼ 0.57, P ¼ 0.0005) as well as controls (r ¼ 0.43, P ¼ 0.008), and free testosterone was a significant positive predictor of IGF-I. Estrogen discontinuation induced an increase in IGF-I (167^15 vs 206^14 mg/l, P ¼ 0.005 and IGFBP-3 (3887^139 vs 4309^138 mg/l, P ¼ 0.0005). Estrogen discontinuation was associated with a significant increase in median (range) free testosterone (0.004 (0 -0.02) vs 0.0065 (0 -0.03) nmol/l, P ¼ 0.001) and a significant decrease in median (range) sex-hormone binding globulin (SHBG;) nmol/l, P ¼ 0.001). DIGF-I correlated with DSHBG (r ¼ 2 0.45 P ¼ 0.033) and DIGFBP-3 (r ¼ 0.67 P ¼ ,0.001). In a regression model DE2, Dtestosterone, DSHBG and DIGFBP-3 explained 93% of the variation in DIGF-I. Conclusions: Androgen levels are low in hypopituitary women and free testosterone correlates with IGF-I. Discontinuation of estrogen replacement in these patients induces elevations in IGF-I as well as free testosterone, and DIGF-I correlated positively with Dfree testosterone. These effects may contribute to the gender differences observed in the GH -IGF axis in healthy adults as well as in the responsiveness of hypopituitary patients to GH substitution.

Administration route-dependent effects of estrogens on IGF-I levels during fixed GH replacement in women with hypopituitarism

“…Serum SHBG concentrations correlated negatively with IGF-I concentrations, as reported by others in healthy subjects and in GHD (6,26). Moreover, SHBG levels were lower during transdermal administration of 100 mg estradiol when compared with oral administration of 2 mg estradiol, despite similar circulating estradiol concentrations.…”

“…Conversely, discontinuation of oral estrogen substitution increases IGF-I levels during continued substitution with rhGH in female patients with hypopituitarism (6). The route of estrogen administration also affects IGF-I levels.…”

Conventional and novel biomarkers of treatment outcome in patients with acromegaly: discordant results after somatostatin analog treatment compared with surgery

“…This notion is supported by the fact that GH dose requirements are higher in females as compared with male patients with adult GH deficiency (43). Several lines of evidence suggest that the elevated GH levels in females represent an increase in GH secretion to compensate for a suppressive effect of estrogen on hepatic IGF1 production (44,45), but the genderspecific difference in patients with acromegaly is also reported in elderly subjects and is not fully accounted for by estrogen status (9). The observation made from that study, which did not include patients on medical treatment, was replicated in our population, and both dataset suggest that additional factors such as abdominal adiposity may contribute to the relative increase in GH levels in females as compared with males (46).…”

Insulin-like growth factor I concentrations in infancy predict differential gains in body length and adiposity: the Cambridge Baby Growth Study

“…During infancy there is a major change in the regulation of IGF-I generation, which gradually comes more under the control of GHs. The appearance of a sex difference in IGF-I and IGFBP-3 concentrations between ages 3 and 12 mo might reflect the gradual postnatal emergence of GH regulation of growth, as GH sensitivity is influenced by sex and sex steroid concentrations (30,31). In contrast to the sex differences in both IGF-I and IGFBP-3 concentrations, formula milk feeding was associated with higher concentrations of IGF-I but not of IGFBP-3, which indicates that infant milk feeding affects free IGF-I concentrations and IGF-I bioavailability.…”