Response to stress is dysregulated in psychosis (PSY). fMRI studies showed hyperactivity in hypothalamus (HYPO), hippocampus (HIPP), amygdala (AMYG), anterior cingulate (ACC), orbital and medial prefrontal (OFC; mPFC) cortices, with some studies reporting sex differences. We predicted abnormal steroid hormone levels in PSY would be associated with sex differences in hyperactivity in HYPO, AMYG, and HIPP, and hypoactivity in PFC and ACC, with more severe deficits in men. We studied 32 PSY cases (50.0% women) and 39 controls (43.6% women) using a novel visual stress challenge while collecting blood. PSY males showed BOLD hyperactivity across all hypothesized regions, including HYPO and ACC by FWE-correction. Females showed hyperactivity in HIPP and AMYG and hypoactivity in OFC and mPFC, the latter FWE-corrected. Interaction of group by sex was significant in mPFC (F=7.00, p=0.01), with PSY females exhibiting the lowest activity. Male hyperactivity in HYPO and ACC was significantly associated with hypercortisolemia post-stress challenge, and mPFC with low androgens. Steroid hormones and neural activity were dissociated in PSY women. Findings suggest disruptions in neural circuitry-hormone associations in response to stress are sex-dependent in psychosis, particularly in prefrontal cortex.
• Using fMRI, sex differences exist in stress circuitry deficits in psychoses.
• Male cases were hyperactive across subcortical and cortical stress circuitry.
• Female cases were hypoactive in prefrontal cortex.
• Brain activity deficits in medial prefrontal cortex were significant by sex.
• Neural-steroid hormone associations under stress are sex-dependent in psychosis.
“Brain regions that respond to negatively valenced stimuli also regulate the hypothalamic-pituitary-adrenal (HPA) and HP-gonadal (HPG) systems, which are dysregulated in schizophrenia. Gonadal hormones, such as estradiol, modulate risk of psychotic illness across the lifespan. Likewise HPA dysregulation, at the adrenal, pituitary and central nervous system levels, contribute to the pathophysiology and etiology of schizophrenia. Hippocampus, amygdala, hypothalamus, and anterior cingulate cortex are linked to endocrine function and neuroprotective and neurotoxic responses to reproductive steroid exposures. Glucocorticoid receptors are located in the hippocampus, hypothalamus, prefrontal and anterior cingulate cortices, areas that are dense in sex steroid hormone receptors. The hypothalamus, hippocampus and amygdala are involved in the regulation of HPA and HPG hormones, and anterior cingulate, medial, and dorsolateral prefrontal cortices influence autonomic and endocrine function integrating bodily states and goal-directed behavior. These brain regions are some of the most highly sexually dimorphic regions in the brain, demonstrating in vivo sex differences in brain volumes and brain activity in healthy populations, and schizophrenia.
Compared with control males, males with psychoses expressed hyperactivity in most of the hypothesized stress response regions, demonstrating substantial effect sizes that were present regardless of psychosis type. In contrast, females with psychoses compared with healthy females showed hyperactivity in subcortical stress response regions and anterior cingulate cortex, and hypoactivity in orbital and medial prefrontal cortices, the latter of which were significantly different from males. We had adequate statistical power to test for sex differences in psychoses, and the sample presented here was generally representative of the population from which they were drawn…
We further found that differences across group (psychoses vs. healthy controls) and sex were differentially associated with steroid hormone abnormalities. Hypercortisolemia was present in male and female cases compared to their healthy counterparts, but had a differential effect on brain activity deficits in prefrontal cortex in males and females. Hypercortisolemia was associated with hyperactivity across stress response regions in men with psychoses, including prefrontal cortices. In contrast, hypercortisolemia was associated with hypoactivity in medial prefrontal (and orbitofrontal) cortices in females with psychoses, a difference that was not present among male and female controls. Not surprising, hypercortisolemia in cases was associated with low gonadal hormone expression regardless of sex (i.e, for male cases, low free androgen, and for female cases, low estradiol). The impact of low androgens on explaining hyperactivity in prefrontal cortex in male cases was only, in part, explained by hypercortisolemia, whereas the variance accounting for hypoactivity in prefrontal cortices in female cases was explained through its relationship to hypercortisolemia. These findings suggest adrenal and gonadal hormone abnormalities are associated with brain activity deficits in stress response regions but have differential effects on brain dependent on sex.
Neural-hormone deficits are not surprising given that stress response circuitry regions, such as anterior hypothalamus, amygdala, and hippocampus, are governed by the coordinated action of HPG and HPA axis hormones. They are regions dense in estrogen, progesterone, androgen, and glucocorticoid receptors In fact, as evident in the cases in this study, HPA dysregulation, i.e., hypercortisolemia, had a significant impact on attenuating HPG response (i.e., lower gonadal hormone expression). There is a long history to the idea that HPA dysregulation is implicated in schizophrenia, described as hypercortisolemic and hyper-responsive to stress, physiologic responses attributed to bipolar psychoses as well. Previous work, including our own, also demonstrated abnormalities in gonadal hormone levels (lower in cases) and endocrine function.
fMRI and PET studies of emotional arousal in schizophrenia, particularly response to negatively-valenced stimuli or the so-called stress response, have consistently shown increased activation in hippocampus, amygdala and anterior cingulate cortex, coupled with decreased activation in prefrontal cortex
The magnitude of hyperarousal varied across the menstrual cycle in women, with attenuation of hyperactivity in response to stress during mid-cycle compared with early follicular and increased prefrontal and anterior cingulate cortices during the luteal phase, when progesterone was heightened
Hyperactivity of hypothalamus in healthy men vs. women was consistent across studies, controlled for menstrual cycle status and negatively correlated with estradiol levels.
Low estradiol was associated with hypercortisolemia in female cases with little correlation among the controls (Spearman׳s r=−0.49 vs. −0.07, respectively). However, low estradiol did not account for variance in the impact on prefrontal cortex over and above hypercortisolemia in female cases vs. controls.
Impact of low free androgen levels on hyperactivity in medial prefrontal cortex among the male cases vs. controls was significant (β=0.10, p<0.05), an effect that was, in part, accounted for by the high cortisol:DHEAS levels in male cases.
Jacobs et al.  have found that 17β estradiol was significantly related to attenuation of BOLD activity in key subcortical stress response regions in healthy women, but no modulation by 17β estradiol in depressed women was found.
A recent study has found that progesterone mediates brain functional connectivity changes during the menstrual cycle .
Sex differences in depressive and socioemotional responses to an inflammatory challenge have been investigated .
Hernaus et al. have investigated psychotic reactivity to daily life stress and the dopamine system  and found that there is no evidence for attenuated stress-induced extrastriatal dopamine signaling in psychotic disorder .
Sex-specific restoration of MK-801-induced sensorimotor gating deficit by environmental enrichment has been reported in rats .