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

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. 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 ¼ , 0.001; androstenedione: 0.5 (0.1 – 7.1) nmol/l vs 4.3 (1.6 – 8.8) nmol/l, P ¼ , 0.001; dihydrotestosterone (DHT): 0.13 (0.09 – 0.54) nmol/l vs 0.55 (0.09 – 0.89) nmol/l, P ¼ , 0.001; testosterone: 0.28 (0.09 – 1.56) nmol/l vs 1.1 (0.71 – 2.24) nmol/l, (P ¼ , 0.001); free testosterone: 0.004 (0.001 – 0.030) nmol/l vs 0.016 (0.001 – 0.030) nmol/l, P ¼ , 0.001. The circulating levels of IGF-I, IGFII, 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 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 206^14mg/l, P ¼ 0.005 and IGFBP-3 (3887^139 vs 4309^138mg/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; 93 (11 – 278) vs 55.5 (20 – 142) 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.