Gonadotropin-releasing hormone agonist in premenopausal women does not alter hypothalamic-pituitary-adrenal axis response to corticotropin-releasing hormone

Abstract

Sex hormones appear to play a role in the regulation of hypothalamic-pituitary-adrenal (HPA) axis activity. The objective was to isolate the effects of estradiol (E 2 ) on central activation of the HPA axis. We hypothesized that the HPA axis response to corticotropin-releasing hormone (CRH) under dexamethasone (Dex) suppression would be exaggerated in response to chronic ovarian hormone suppression and that physiologic E 2 add-back would mitigate this response. Thirty premenopausal women underwent 20 wk of gonadotropin-releasing hormone agonist therapy (GnRH AG ) and transdermal E 2 (0.075 mg per day, GnRH AG + E 2 , n = 15) or placebo (PL) patch (GnRH AG + PL, n = 15). Women in the GnRH AG + PL and GnRH AG + E 2 groups were of similar age (38 (SD 5) yr vs. 36 (SD 7) yr) and body mass index (27 (SD 6) kg/m 2 vs. 27 (SD 6) kg/m 2 ). Serum E 2 changed differently between the groups (P = 0.01); it decreased in response to GnRH AG + PL (77.9 ± 17.4 to 23.2 ± 2.6 pg/ml; P = 0.008) and did not change in response to GnRH AG + E 2 (70.6 ± 12.4 to 105 ± 30.4 pg/ml; P = 0.36). The incremental area under the curve (AUC INC ) responses to CRH were different between the groups for total cortisol (P = 0.03) and cortisone (P = 0.04) but not serum adrenocorticotropic hormone (ACTH) (P = 0.28). When examining within-group changes, Gn-RH AG + PL did not alter the HPA axis response to Dex/CRH, but GnRH AG + E 2 decreased the AUC INC for ACTH (AUC INC , 1,623 ± 257 to 1,211 ± 236 pg/ml·min, P = 0.004), cortisone (1,795 ± 367 to 1,090 ± 281 ng/ml·min, P = 0.009), and total cortisol (7,008 ± 1,387 to 3,893 ± 1,090 ng/ml·min, P = 0.02). Suppression of ovarian hormones by GnRH AG therapy for 20 wk did not exaggerate the HPA axis response to CRH, but physiologic E 2 add-back reduced HPA axis activity compared with preintervention levels.