Contribution of sex hormones to gender differences in schizophrenia: A review

• Fair-moderate evidence for mediating effects of sex hormones on gender differences.
• Estrogen has most notable role; progesterone, testosterone and DHEA(S) lesser parts.
• Preliminary data supports further exploration of their benefit as treatment options.

Female patients with schizophrenia tend to have a more benign course and better outcomes than males. One proposed explanation is the differential influence of male and female sex hormones, including estrogen, progesterone, testosterone, and dehydroepiandrosterone (DHEA) and its sulfate (DHEAS). Such benefit may be mediated by their effects on neurotransmitters and neuroprotection. Besides altered estrogen and DHEA/DHEAS levels in female patients, data is equivocal on hormonal differences between patients and controls. However, several reports note a mostly negative correlation between estrogen levels and symptom severity in both genders, and a positive correlation between estrogen levels and neurocognition but mainly in females. Adjunctive estrogen appears to improve symptoms in both genders. Progesterone levels have inconsistent links to symptom severity in both genders, and correlate positively with neurocognition but only in males. Estrogen-progesterone combination shows preliminary benefits as augmentation for both symptoms and neurocognition in females. Testosterone levels correlate inversely with negative symptoms in males and have inconsistent associations with neurocognition in both genders. Testosterone augmentation reduced negative symptoms in male patients in a pilot investigation, but has not been evaluated for neurocognition in either gender. DHEA/DHEAS have mixed results for their association with, and clinical utility for, symptoms and neurocognition in both genders. Overall, data on the impact of sex hormones on clinical course or as treatment for schizophrenia is limited, but estrogen has most evidence for positive influence and clinical benefit. The possibly greater tolerability and broader impact of these hormones versus existing medications support further exploration of their use.