Sex and stress hormones are reciprocally regulated and have opposing neurobiological effects (Sinclair et al, 2014). Molecular changes in brain sex and stress hormone receptors indicate that these systems are out of balance in people with schizophrenia. Furthermore, increased stress can precipitate the onset or trigger the relapse of psychosis, while low levels of estrogen can exacerbate symptoms in females with schizophrenia (Heringa et al, 2015). Also, the sex and stress hormone signaling systems are both activated at a time of increased risk for first developing schizophrenia, during human adolescence, when the prefrontal cortex appears primed to respond to cortisol (Sinclair et al, 2011) and when sex steroids are flooding the brain. While we often study these major hormonal systems individually, there is greater awareness that they work in concert and should be considered together.

When the source of peripheral sex steroids are removed, male and female rats will alter their glucocorticoid secretion in response to stress in a gender-specific manner. Thus, one way to modulate the body’s reaction to stress is to change sex steroid levels. In addition, high levels of cortisol promote neuronal damage, whereas sex steroids, in particular estrogen, act as neuroprotectants. Males and females have equivalent estrogen receptor (ER) Alpha levels in one of the most stress responsive areas of the brain: the human prefrontal cortex (Perlman et al, 2005). Thus, stimulation of ER in both males and females may potentially buffer some of the damaging effects of stress.

Historically, the field has approached estrogen as a potential therapy for schizophrenia based on the clinical observation that women can sometimes first manifest the symptoms of schizophrenia later in adult life (>50 years). Because of the known drop in circulating estrogen during female menopause, the obvious strategy was to replace estrogen in these women to test if this could lead to clinical improvement. Most studies suggest that adjunctive estrogens can reduce positive, negative and general symptoms of older women with schizophrenia (Heringa et al. 2015). However, long-term estrogen treatment can increase the risk of adverse events. The selective ER modulator raloxifene is an alternative estrogen-based treatment, which has been shown to preserve neural activity and cognition in healthy older men and women. Given that men and women with schizophrenia can express abnormal cerebral cortical ERs (Weickert et al., 2008) and raloxifene could overcome the dominant negative effect of these abnormal receptors on wild-type ER in men and women, we administered raloxifene as an adjunctive treatment to antipsychotics in men and women with schizophrenia to determine the extent to which raloxifene would improve cognitive deficits in schizophrenia. We found that adjunctive raloxifene significantly improved memory and attention and increased hippocampal activity during learning in men and women with schizophrenia (Weickert et al, 2015;Kindler et al, 2015). Since raloxifene acts as an ER agonist in brain, but can act as an ER antagonist in the periphery, it remains an open question as to how raloxifene may impact stress hormone signaling in schizophrenia.

We do know that estrogen actions are complex. Estrogen can exaggerate stress effects and can augment prefrontal dysfunction during stress in females, but can also protect adolescent females from deleterious effects of social stress (Sinclair et al, 2014). In males, testosterone inhibits glucocorticoid secretion. Since raloxifene has potential to increase circulating testosterone levels in men with schizophrenia, it is possible that this increase in testosterone could attenuate the response to stress in men with schizophrenia either directly via testosterone’s action on androgen receptor or indirectly on ER via conversion of testosterone to estradiol by aromatase.

FUNDING AND DISCLOSURE

CSW declares no conflict of interest in relation to this work; however, over the past 3 years she has received funds as a consultant for Lundbeck and Roche. TWW declares no conflict of interest in relation to this work; however, over the past three years his wife has received funds as a consultant for Lundbeck and Roche.