Sex-specific effects of low-dose hydrocortisone on threat detection in HIV

One sex differences in the perception of emotion is that females, particularly those with high anxiety, often show heightened identification of fearful faces. To better understand the causal role of glucocorticoids in this sex difference, we examine these associations in people with HIV(PWH) where emotion perception is impaired and mental health disorders are frequent. In a double-blind, placebo-controlled, cross-over study, we used a single low-dose of hydrocortisone (10 mg; LDH) as a mechanistic probe of the effects of elevated glucocorticoids on negative emotion perception in 65 PWH (31 women). The primary outcome was accuracy in identifying emotional expressions on the Facial Emotion Perception Test (FEPT). Salivary cortisol, self-reported stress/anxiety, and childhood trauma were also assessed. LDH increased salivary cortisol levels versus placebo. The effect of LDH versus placebo on FEPT accuracy depended on the combined influence of facial expression and sex (P = 0.03). LDH influenced accuracy only for women (P = 0.03), specifically for fearful faces (Cohen's d = 0.44, P = 0.04). Women's enhanced threat detection varied with psychological burden (mood, anxiety, and post-traumatic stress symptoms), more pronounced among those with lower burden and trauma (P < 0.05). This result suggests a role of the HPA axis in sex differences for perception of fearful faces in women with HIV, potentially due to changes in glucocorticoid receptor availability/activity, or improved integration of signals from facial recognition and emotion processing regions. The blunting of this effect in men and in individuals with more severe trauma suggests that the mechanisms underlying threat detection differ by sex and trauma history and warrant further investigation.