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

Objective: 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.

Results: The patients were androgen deficient compared with controls (median, range), dehydroepiandrosterone sulphate (DHEAS): 185 (99-7800) nmol/l vs 4400 (820-13,000) nmol/l, P=or<0.001; androstenedione: 0.5 (0.1-7.1) nmol/l vs 4.3 (1.6-8.8) nmol/l, P=or<0.001; dihydrotestosterone (DHT): 0.13 (0.09-0.54) nmol/l vs 0.55 (0.09-0.89) nmol/l, P=or<0.001; testosterone: 0.28 (0.09-1.56) nmol/l vs 1.1 (0.71-2.24) nmol/l, (P=or<0.001); free testosterone: 0.004 (0.001-0.030) nmol/l vs 0.016 (0.001-0.030) nmol/l, P=or<0.001. The circulating levels of IGF-I, IGF-II, IGF-binding protein 1 (IGFBP-1), and IGFBP-3 did not differ between patients and controls. The subgroup of patients receiving hydrocortisone (HC) replacement (n=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=0.57, P=0.0005) as well as controls (r=0.43, P=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 microg/l, P=0.005 and IGFBP-3 (3887+/-139 vs 4309+/-138 microg/l, P=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=0.001) and a significant decrease in median (range) sex-hormone binding globulin (SHBG; 93 (11-278) vs 55.5 (20-142) nmol/l, P=0.001). DeltaIGF-I correlated with DeltaSHBG (r=-0.45 P=0.033) and DeltaIGFBP-3 (r=0.67 P=or<0.001). In a regression model DeltaE2, Deltatestosterone, DeltaSHBG and DeltaIGFBP-3 explained 93% of the variation in DeltaIGF-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 DeltaIGF-I correlated positively with Deltafree 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.