Peripheral and Central Sex Steroids Have Differential Effects on the HPA Axis of Male and Female Rats

Abstract

Sex differences in hypothalamic-pituitary-adrenal (HPA) function were examined in gonadectomized male and female rats given equivalent sex hormone replacement regimens either using subcutaneous silastic implants (Experiment 1) or cannula implants in the medial preoptic area (MPOA) (Experiment 2) containing either dihydrotestosterone (DHT), testosterone propionate (TP), estradiol benzoate (EB), or left empty (control). Plasma was obtained before and after 20 min of restraint stress to determine plasma ACTH, corticosterone, and CBG levels as measures of HPA function. Consistent with the literature, androgens decreased, and estrogen increased these measures of HPA function, although peripheral implants were more effective than MPOA implants. Gonadectomy and sex hormone treatment did not eliminate sex differences; overall, females had higher levels than males on measures of HPA function. Analyses of variance (ANOVA) indicated interactions of sex and sex hormone treatment on CBG levels and post-stress corticosterone levels in Expt. 1. The results suggest that sexual dimorphisms influence HPA function even when males and females are given equivalent physiological doses of gonadal steroids, and that the relevant sexual dimorphisms involve both the periphery and the CNS.

An alternate pathway for androgen regulation of brain function: Activation of estrogen receptor beta by the metabolite of dihydrotestosterone, 5α-androstane-3β,17β-diol

“…This hyperreactivity of the female stress response is characterized by a greater and prolonged secretion of ACTH and corticosterone suggesting enhanced stimulus as well as a reduced negative feedback (Burgess and Handa, 1992). Consistent with these findings, females also have higher levels of corticosteroid binding globulin (CBG), a liver-derived plasma protein that binds and sequesters corticosterone from its receptor (McCormick et al 2002). Moreover, evidence that sex steroid hormones can interact with the regulatory elements of the HPA axis comes from studies showing that gonadectomy of both males and females reduces the sex difference and hormone replacement to gonadectomized animals can reinstate the sex difference (Handa et al, 1994a,b).…”

Environmental enrichment reduces the mnemonic and neural benefits of estrogen

“…However, the combination of estrogen and enrichment may have elevated corticosterone levels beyond optimal levels, impairing memory as a result. Alternatively, estrogen-induced increases in the synthesis of corticosterone binding globulin may have blunted enrichment-mediated increases in basal free corticosterone, resulting in suboptimal elevations in this glucocorticoid and corresponding mnemonic deficits (Kempermann et al, 2002;McCormick et al, 2002). Because serum samples were not collected, corticosterone levels were not measured in the present study and thus the hypothesized effects of combined estrogen and enrichment on corticosterone-mediated changes in memory are speculative.…”

Sex Differences in Salivary Cortisol Responses to Sex-Linked Stressors: A Test of the Tend-and-Befriend Model

“…Substantial evidence suggests that reproductive steroids modulate the response to stress. Supportive data include observations of sex differences in hypothalamic-pituitary-adrenal (HPA) axis activity/responsivity (McCormick et al 2002;Roelfsema et al 1993;Greenspan et al 1993) and demonstration of acute regulatory effects of gonadal steroids on the HPA axis in animal castration and replacement studies (Burgess and Handa 1992;Critchlow et al 1963;Bingaman et al 1994). Free testosterone in particular would serve as an excellent candidate biomarker for elucidating the unexpected decreases in cortisol observed in young men exposed to the MS prime and out-group threat.…”