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Sex-Related Differences in Stimulated Hypothalamic-Pituitary-Adrenal Axis during Induced Gonadal Suppression

Office of Special Populations (C.A.R.), National Institute of Mental Health, Rockville, Maryland 20857; Behavioral Endocrinology Branch (P.J.S.), Geriatric Psychiatry Branch (K.P.), and Behavioral Endocrinology Branch (D.R.R.), National Institute of Mental Health, Bethesda, Maryland 20892; Department of Military and Emergency Medicine (P.A.D.), Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814; Clinical Center Nursing Department (M.A.D.), National Institutes of Health, Bethesda, Maryland 20892; Department of Psychiatry (M.A.), Weill Medical College of Cornell University, New York, New York 10021; and Developmental Endocrinology Branch (G.P.C.), and Pediatric and Reproductive Endocrinology Branch (L.K.N.), National Institute of Child Health and Human Development, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: David R. Rubinow, National Institute of Mental Health, Building 10-CRC, Room 6-5340, 10 Center Drive MSC 1276, Bethesda, Maryland 20892-1276. E-mail: rubinowd{at}mail.nih.gov.

Context: Sex-related differences in the stress response are well described in the animal literature but in humans are inconsistent and appear to reflect both the method used to stimulate the hypothalamic-pituitary-adrenal (HPA) axis and the age of the subjects. Sex-related differences in reproductive steroid levels further confound efforts to define the specific role of the sex of the individual in stress axis responsivity.

Objective: The aim of this study was to address this role independent of differences in reproductive steroid levels. We compared HPA axis response to pharmacological (CRH) and physiological (exercise) stressors in two groups of young to middle-aged (18–45 yr) men (n = 10 and 8) and women (n = 12 and 13) undergoing gonadal suppression with leuprolide acetate (monthly im injection of 7.5 mg in men and 3.75 mg in women).

Design: Exercise and CRH stimulation tests were performed during induced hypogonadal conditions.

Setting: The study was conducted at a National Institutes of Health Clinical Center Outpatient Clinic.

Patient or Other Participants: Male and female normal volunteers participated in the study.

Main Outcome Measures: The main outcome measures were stimulated ACTH and cortisol levels.

Results: Both CRH (1 µg/kg) stimulation and graded treadmill exercise stimulation occurred in the month after the second leuprolide injection to ensure gonadal suppression. Despite the absence of sex differences in estradiol or testosterone at the time of testing, men showed increased stimulated ACTH (repeated-measures ANOVA for CRH, P < 0.005) and cortisol (repeated-measures ANOVA for exercise, P < 0.05) compared with women. Among the summary measures, area under the curve (AUC) for cortisol was significantly greater in men than women after exercise. Although the AUC for ACTH was not significantly different across sexes, the initial AUC (0–30 min) was significantly greater in men for both procedures. No significant sex differences were found in a measure of adrenal responsivity, the cortisol to ACTH ratio, for either procedure. Cortisol-binding globulin levels did not differ between men and women and were not correlated with stimulated HPA axis measures. These data confirm earlier reports of sex differences in stimulated HPA axis activity and demonstrate that these differences exist even under induced hypogonadal conditions (i.e. in the absence of characteristic differences in reproductive steroids).

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