Sex differences in the ACTH and cortisol response to pharmacological probes are stressor-specific and occur regardless of alcohol dependence history

Abstract

Women and men differ in their risk for developing stress-related conditions such as alcohol use and anxiety disorders and there are gender differences in the typical sequence in which these disorders co-occur. However, the neural systems underlying these gender-biased psychopathologies and clinical course modifiers in humans are poorly understood and may involve both central and peripheral mechanisms regulating the limbic-hypothalamic-pituitary-adrenal axis. In the present randomized, double blind, placebo-controlled, triple-dummy crossover study, we juxtaposed a centrally-acting, citalopram (2 mg/unit BMI) neuroendocrine stimulation test with a peripherally-acting, dexamethasone (Dex) (1.5 mg)/corticotropin-releasing factor (CRF) (1 μg/kg) test in euthymic women (N = 38) and men (N = 44) with (54%) and without histories of alcohol dependence to determine whether sex, alcohol dependence or both influenced the adrenocorticotropic hormone (ACTH) and cortisol responses to the pharmacological challenges and to identify the loci of these effects. We found that central serotonergic mechanisms, along with differences in pituitary and adrenal sensitivity, mediated sexually-diergic ACTH and cortisol responses in a stressor-specific manner regardless of a personal history of alcohol dependence. Specifically, women exhibited a greater response to the Dex/CRF test than they did the citalopram test while men exhibited the opposite pattern of results. Women also had more robust ACTH, cortisol and body temperature responses to Dex/CRF than men, and exhibited a shift in their adrenal glands' sensitivity to ACTH as measured by the cortisol/log (ACTH) ratio during that session in contrast to the other test days. Our findings indicate that central serotonergic and peripheral mechanisms both play roles in mediating sexually dimorphic, stressor-specific endocrine responses in humans regardless of alcohol dependence history.

Keywords: Alcohol use disorder; Citalopram stimulation test; Cortisol; Dex/CRF test; Serotonin (5-HT); Sex differences.

Fig. 1.

A and B Overall Study Design (1A) - Randomized, double-blind, triple dummy, crossover study conducted in adult men and women with and without histories of alcohol dependence. The 82 randomized participants received each of 3 separate challenge tests (i.e., placebo, citalopram stimulation test [Citalopram, 2 mg/unit BMI], and the combined dexamethasone [1.5 mg]/corticotropin-releasing factor [1 μ/kg] [DEX/CRF] stimulation test) in counterbalanced order as detailed in 1.B. Outcomes from the 3-month follow-up visit assessing relapse versus continued abstinence are presented in other manuscripts.

Fig. 2.

A and B Baseline, resting AM hormonal (ACTH = upper panel, 2A; cortisol = lower panel, 2B) concentrations on each of the 3 test days. Regardless of alcoholism status, women had significantly lower ACTH concentrations than men on the placebo day. Baseline cortisol levels did not differ across the groups on any test day. Abbreviations: AD = alcohol dependent; CIT = citalopram day; DEX/CRF = combined dexamethasone/corticotropin-releasing factor day; and PLA = placebo day. Mean ± SEM shown.

Fig. 3.

A and B Unadjusted hormonal (ACTH - upper panel, 3A; cortisol = lower panel, 3B) concentrations on the placebo test day. After adjusting for baseline effects, corticotropin levels in women increased over time compared with men (Sex x Time interaction, p < 0.006). Morning cortisol concentrations were significantly lower in women than men (main Sex effect, p < 0.04), but gradually increased over time (Sex x Time interaction, p < 0.03). Mean ± SEM shown.

Fig. 4.

A-D ACTH (left panels, 4A and 4C) and cortisol (right panels, 4B and 4D) responses to the citalopram and DEX/CRF stimulation tests, respectively, demonstrate sex- and pharmacological stressor-specificity. There was a trend for women to have more robust ACTH responses to DEX/CRF than citalopram (upper left panel, Fig. 4A), whereas for cortisol (upper right panel, Fig. 4B), both the stressor-specific and the sexually-dimorphic response to the DEX/CRF test were clearly observed. The corollary of these findings is shown in the lower panels where peak Δ hormonal responses are displayed: men had significantly greater ACTH (lower left panel, Fig. 4C) and cortisol (lower right panel, Fig. 4D) responses following citalopram stimulation than after DEX/CRF. Women’s peak Δ responses to the DEX/ CRF test were significantly greater than men’s. Mean ± SEM shown.

Fig. 5.

A-C Cortisol to log (ACTH) ratios - an indirect measure of adrenal sensitivity - indicated that men’s adrenal glands were more sensitive to ACTH than women’s on the Citalopram (upper panel, Fig. 5A) and Placebo (lower panel, Fig. 5C) test days. Asterisks (*) signify specific time points where significant Sex X Time interaction effects were found. An opposite pattern (i.e., women’s ratios > men’s) was observed on the DEX/CRF test day (middle panel, Fig. 5B). Mean ± SEM shown.