Effects of clomiphene and raloxifene on gonadotrophin secretion in postmenopausal women: evidence of nongenomic action

Abstract

OBJECTIVE To evaluate the effect of raloxifene (R) and clomiphene (Cl) on FSH and LH secretion in postmenopausal women. DESIGN Postmenopausal volunteer women participated in two experimental (Exp) procedures. In Group 1, the women received R (180 mg/day orally) for 30 days plus oestradiol (E2) through skin patches (100 g/24 h) from days 21 to 30 (R-Exp). After a month's break the same women received Cl (150 mg/day orally) for 30 days plus E2 as above (Cl-Exp). In Group 2, the women received E2 for 30 days plus R from days 21 to 30 (R-Exp) and after a month's break they received E2 for 30 days plus Cl from days 21 to 30 (Cl-Exp). Daily doses were as in Group 1. A GnRH test (100 g intravenously) was performed in all women on days 0, 10, 20 and 30 of each experiment. PATIENTS Sixteen healthy postmenopausal women were divided into two groups (eight women in each group). MEASUREMENTS The area under the curve (AUC) of DeltaFSH and DeltaLH response to GnRH (net increase above the basal value) was calculated. RESULTS In Group 1, basal levels of FSH and LH did not change significantly during the R-Exp, while they decreased significantly in the Cl-Exp (P < 0.001). The addition of E2 did not have any effect. The AUC of LH response to GnRH increased significantly in the R-Exp (P < 0.05) and that of FSH in the Cl-Exp (P < 0.05). In Group 2, basal levels of FSH and LH declined significantly during treatment with E2 in both the R-Exp (P < 0.01) and the Cl-Exp (P < 0.001). However, the addition of Cl (for 10 days) interrupted this decrease, while the addition of R stimulated FSH levels significantly (P < 0.05). E2 suppressed significantly the AUC of LH in both experiments (P < 0.05). The addition of Cl did not affect the AUC in response to GnRH, while the addition of R increased the AUC of both LH and FSH (P < 0.05). CONCLUSIONS These results demonstrate for the first time that in contrast to Cl, R does not exert oestrogenic effects on basal gonadotrophin secretion. Although the antioestrogenic action of these drugs was evident only after pretreatment with E2, both R and Cl stimulated GnRH-induced gonadotrophin secretion in oestrogen-deprived women. It is hypothesized that these two compounds sensitize the pituitary to GnRH through mechanisms not involving the oestrogen receptor complex (nongenomic).