Sex differences in psychopathology: of gonads, adrenals and mental illness

Stress-related disorders such as anxiety and depression are disproportionately prevalent in women. Women are more likely to experience depression and anxiety disorders during periods of marked hormonal fluctuations, suggesting that gonadal hormones are involved in stress pathology. Depression and anxiety are both associated with aberrant secretion of glucocorticoids, which also show marked fluctuations across the reproductive cycle and in response to gonadal steroids. Thus, interactions between gonadal and stress hormones may play a major role in predisposing females to stress-related disease. The purpose of this brief review is to highlight preclinical data regarding the role of estrogens in depression and anxiety-like behaviors. While it is evident the exogenous estrogens modulate affective behavior in rodents, there is some disagreement in the literature, perhaps related to experimental designs that vary with respect to administration parameters and stress. Beneficial effects of estrogens on mood are most likely due to estrogen receptor (ER)beta signaling. The antidepressant and anxiolytic effects of ERbeta are consistent with its role in attenuating glucocorticoid responses to stress, suggesting that estrogens, acting at ERbeta, may improve mood by suppressing glucocorticoid hyperactivity. However, additional studies demonstrate that ERbeta signaling in the hippocampus is sufficient to induce antidepressant and anxiolytic behaviors. Thus, ERbeta may improve mood via primary actions on hypothalamic (i.e., paraventricular nucleus) and/or extra-hypothalamic sites. Overall, the preclinical research suggests that selective ER modulators targeting ERbeta may be an attractive alternative or adjunct treatment to currently prescribed antidepressants or anxiolytics.