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

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) 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 add-back would mitigate this response. Thirty premenopausal women underwent 20 wk of gonadotropin-releasing hormone agonist therapy (GnRH) and transdermal E (0.075 mg per day, GnRH + E, n = 15) or placebo (PL) patch (GnRH + PL, n = 15). Women in the GnRH + PL and GnRH + E groups were of similar age (38 (SD 5) yr vs. 36 (SD 7) yr) and body mass index (27 (SD 6) kg/m vs. 27 (SD 6) kg/m). Serum E changed differently between the groups ( P = 0.01); it decreased in response to GnRH + PL (77.9 ± 17.4 to 23.2 ± 2.6 pg/ml; P = 0.008) and did not change in response to GnRH + E (70.6 ± 12.4 to 105 ± 30.4 pg/ml; P = 0.36). The incremental area under the curve (AUC) 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, GnRH + PL did not alter the HPA axis response to Dex/CRH, but GnRH + E decreased the AUC for ACTH (AUC, 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 therapy for 20 wk did not exaggerate the HPA axis response to CRH, but physiologic E add-back reduced HPA axis activity compared with preintervention levels.