PMC:3649690 / 27276-30986 JSONTXT

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Gonadal Hormones, Depression, and Modulation of Neural Plasticity\nWomen are twice as likely as men to develop depression [148]. Sex differences are also seen in antidepressant efficacy as men have a better response to TCAs, while women have a better response to SSRIs [149], although these findings remain controversial. Any sex difference observed suggests that gonadal hormone levels are involved, and indeed there is evidence that androgens may protect males from the development of depression. Interestingly, there is an increased incidence of depression in males coinciding with the age related decline in testosterone levels [150–153]. Similarly, young hypogonadal males are more susceptible to developing depression [154], portending protective effects of testosterone against the development of depression. Testosterone has shown some antidepressant action as testosterone replacement therapies are efficacious in alleviating depressive symptoms in hypogonadal men [152, 155, 156]. Testosterone replacement also has efficacy as an adjunct treatment to clinical antidepressants in cases of treatment-resistant depression [155, 157]; however it should be noted that androgen therapies are not always seen to be effective for men suffering depression [158, 159].\nGonadal hormones in females are also likely a factor in the treatment and etiology of depression. Times of dramatic hormone fluctuation, such as during the postpartum and perimenopause, are associated with an increased incidence in depression [160, 161]. In addition hormonal replacement can show antidepressant effects during the postpartum and in peri- and postmenopausal women [162–164]. Consistent with clinical studies, gonadal hormones are also effective as an adjunct therapy to chronic antidepressant treatment in animal models. For example, chronic imipramine increases hippocampal neurogenesis in intact but not in ovariectomized rats [165]. Another study found that an SSRI decreased immobility in the FST in ovariectomized female rats, but only with adjunct estradiol treatment [166]. Similarly, testosterone potentiates the effects of imipramine in increasing cell proliferation and facilitates the alleviation of depressive-like behavioural phenotypes in castrated socially isolated male rats [167]. Consequently androgens and estrogens may have antidepressant properties which could impede the development of, or ameliorate, extant depressive disorders.\nInterestingly gonadal hormones modulate adult neurogenesis, BDNF levels, and PSA-NCAM expression in the hippocampus. Testosterone and its metabolite dihydrotestosterone (DHT) both serve to enhance hippocampal neurogenesis through improved cell survival via an androgen-dependent mechanism within the dentate gyrus [168]. Similarly, estrogens are able to increase adult neurogenesis via proliferation or survival depending on duration of treatment [169]. 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Gonadal Hormones, Depression, and Modulation of Neural Plasticity\nWomen are twice as likely as men to develop depression [148]. Sex differences are also seen in antidepressant efficacy as men have a better response to TCAs, while women have a better response to SSRIs [149], although these findings remain controversial. Any sex difference observed suggests that gonadal hormone levels are involved, and indeed there is evidence that androgens may protect males from the development of depression. Interestingly, there is an increased incidence of depression in males coinciding with the age related decline in testosterone levels [150–153]. Similarly, young hypogonadal males are more susceptible to developing depression [154], portending protective effects of testosterone against the development of depression. Testosterone has shown some antidepressant action as testosterone replacement therapies are efficacious in alleviating depressive symptoms in hypogonadal men [152, 155, 156]. 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Another study found that an SSRI decreased immobility in the FST in ovariectomized female rats, but only with adjunct estradiol treatment [166]. Similarly, testosterone potentiates the effects of imipramine in increasing cell proliferation and facilitates the alleviation of depressive-like behavioural phenotypes in castrated socially isolated male rats [167]. Consequently androgens and estrogens may have antidepressant properties which could impede the development of, or ameliorate, extant depressive disorders.\nInterestingly gonadal hormones modulate adult neurogenesis, BDNF levels, and PSA-NCAM expression in the hippocampus. Testosterone and its metabolite dihydrotestosterone (DHT) both serve to enhance hippocampal neurogenesis through improved cell survival via an androgen-dependent mechanism within the dentate gyrus [168]. Similarly, estrogens are able to increase adult neurogenesis via proliferation or survival depending on duration of treatment [169]. 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