Journal of Neuroendocrinology, 1997, Vol. 9, 129–134 Activational Effects of Gonadal Steroids on Hypothalamo-Pituitary- Adrenal Regulation in the Rat Disclosed by Response to Dexamethasone Suppression Osborne F. X. Almeida*, Virginie Canoine*, Sinan Ali†, Florian Holsboer* and Vladimir K. Patchev* *Department of Neuroendocrinology, Max Planck Institute of Psychiatry, Clinical Institute, 80804 Munich, Germany. †School of Biological Sciences, Macquarie University, New South Wales, 2109 Australia. Key words: corticosterone, ACTH, CRH, glucocorticoid receptors, sexual differentiation. Abstract Previous studies demonstrated that gonadal steroids secreted during perinatal life permanently ‘organize’ the mechanisms governing hypothalamo-pituitary-adrenal (HPA) function, leading to sexually differentiated patterns of pituitar y-adrenal activity under basal and stress conditions. In this paper, we show that gonadal steroids can also exert ‘activational’ effects upon the HPA system. Examination of the ability of different doses of dexamethasone to suppress the nocturnal increase in corticosterone secretion and to attenuate the gene expression of CRH in the hypothalamic paraventricular nucleus of intact and gonadectomized male and female rats revealed that ovarian steroids make an important contribution to the higher sensitivity of the pituitary-adrenal axis in females to glucocorticoid suppression, whereas testicular steroids may be causal to the male’s moderate responsiveness to glucocorticoid feedback. These findings may be implicated in a number of psychiatric and neurological disease states commonly associated with impaired HPA regulation, but which may be primarily rooted in altered gonadal steroid secretion. Basal secretory activity in the hypothalamo-pituitary-adrenal 1960s ( 8–10) and ample evidence for the causal involvement of gonadal hormones in these phenomena has accumulated (HPA) system, and the magnitude of the endocrine response to stress, are tightly controlled by circulating glucocorticoids. The (11–14). More recent studies have revealed that several compon- ents of the HPA cascade are responsive to gonadal steroids, thus sensitivity of neural circuits involved in HPA regulation to glucocorticoid feedback determines the organism’s capacity to pointing at potential targets at which the latter might act to influence HPA function. Briefly, the synthesis of the major adequately respond to stressful stimuli. Impairment in corticos- teroid feedback mechanisms is a frequent symptom of certain secretagogues of ACTH, CRH ( 15–19) and arginine-vasopressin (AVP) (20, 21), are influenced by gonadal steroids; at the same psychiatric (e.g. anxiety, major depression) and neurological (e.g. multiple sclerosis) disorders. In addition, the resulting hyper- time, gonadal steroids are suggested to affect the synthesis and binding properties of corticosteroid receptors in brain centres corticalism and inability to terminate the adrenocortical secretory response to stress are believed to cause further neural impairments, concerned with HPA regulation ( 13, 22–25). Nevertheless, the factors leading to sexually differentiated responses in HPA leading to an exacerbation of clinical symptoms and neuroendo- crine dysregulation (1–3). Although epidemiological studies sug- activity are relatively poorly defined, mainly due to the dual— ‘organizing’ and ‘activating’—actions of gonadal steroids in the gest a preponderance of affective disorders and multiple sclerosis in women (4–6 ), little is known about sex differences in the CNS (26 ). We recently provided the initial demonstration that sex steroid-dependent brain organization may also extend to sensitivity of the HPA system to the physiological and patholo- gical effects of glucocorticoids. However, recently, Heuser et al. mechanisms that determine the pituitary-adrenal response to stress (27 ). On the other hand, a growing body of evidence ( 7) demonstrated that male-female differences in the respons- iveness of the pituitary-adrenal system to dexamethasone suppres- points to the ‘activating’ role of sex steroids in the regulation of the HPA axis (14, 17, 19, 23, 25 ). In this paper, we describe the sion and stimulation by corticotropin-releasing hormone (CRH ) may become apparent, especially, in elderly subjects. results from a study designed to define the ‘activating’ role of gonadal hormones in determining glucocorticoid feedback Male-female differences in basal and stress-induced pituitary- adrenal secretions in the rat were described as early as in the thresholds in male and female rats. Correspondence to: Osborne F. X. Almeida, Department of Neuroendocrinology, Max Planck Institute of Psychiatry, Clinical Institute, Kraepelinstr. 2, 80804 Munich, Germany. © 1997 Blackwell Science Ltd