1. ¹Behavioral Endocrinology Branch, National Institute of Mental Health, Bethesda, MD, USA
2. ²Nursing Department, NIH Clinical Center, Bethesda, MD, USA
3. ³Geriatric Psychiatry Branch, National Institute of Mental Health, Bethesda, MD, USA
4. ⁴Clinical Endocrinology Branch, National Institute of Diabetes, Digestive and Kidney Disease, Bethesda, MD, USA
5. ⁵Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA

Correspondence: Dr DR Rubinow, NIMH, Bldg. 10-CRC, Room 6-5340 (SE), 10 Center Dr MSC 1276, Bethesda, MD 20892-1276, USA. Tel: +301 496 9675; Fax: +301 402 2588; E-mail: rubinowd@mail.nih.gov

Received 23 December 2004; Revised 7 March 2005; Accepted 8 March 2005; Published online 20 April 2005.

Abstract

Despite observations of age-dependent sexual dimorphisms in hypothalamic–pituitary–adrenal (HPA) axis activity, the role of androgens in the regulation of HPA axis activity in men has not been examined. We assessed this role by performing CRH stimulation tests in 10 men (ages 18–45 years) during gonadal suppression with leuprolide acetate and during testosterone addition to leuprolide. CRH-stimulated cortisol levels as well as peak cortisol and greatest cortisol excursion were significantly lower (p<0.05, 0.005, and 0.01, respectively) during testosterone replacement compared with the induced hypogonadal condition (leuprolide plus placebo); cortisol area under the curve was lower at a trend level (p<0.1). Paradoxically, CRH-stimulated corticotropin (ACTH) was increased significantly during testosterone replacement (p<0.05). The cortisol : ACTH ratio, a measure of adrenal sensitivity, was lower during testosterone replacement (p<0.1). A mixed effects regression model showed that testosterone but not estradiol or CBG significantly contributed to the variance of cortisol. These data demonstrate that testosterone regulates CRH-stimulated HPA axis activity in men, with the divergent effects on ACTH and cortisol suggesting a peripheral (adrenal) locus for the suppressive effects on cortisol. Our results further demonstrate that the enhanced stimulated HPA axis activity previously described in young men compared with young women cannot be ascribed to an activational upregulation of the axis by testosterone.