Underlying mechanisms mediating the antidepressant effects of estrogens

There is an increased risk for depressive symptoms and affective disorders in individuals who experience drastic drops or fluctuations of gonadal hormones. Moreover, clinical studies indicate that estrogens have the potential to be effective in treating depression.

Possible underlying mechanisms for the antidepressant activity of estrogens are reviewed and discussed.

Estrogens exert their antidepressant activity via a multimodal mechanism of action by regulating several pathways and functions associated with antidepressive effects. Estrogens increase serotonergic activity by regulating the synthesis and degradation of serotonin, as well as spontaneous firing of the serotonergic neurons in the raphe nuclei. Both pre- and postsynaptic serotonin receptors are shown to be regulated by estrogens. In addition, estrogens are neurotrophic and promote neuroplasticity and neurogenesis. Similar effects are also observed after treatment with current antidepressant therapies. However in stark contrast to current therapies which must be administered chronically to produce an effect, the responses to estrogens are often observed after a single dose. Many of these estrogenic effects, including antidepressant and anxiolytic responses in behavioral models in rodents, appear to be mediated via the estrogen receptor beta subtype.

The rapid onset of action combined with the multifactorial mechanism of action of estrogens indicates that estrogen treatment could complement currently available therapies for depression. Considering safety aspects, selective estrogen receptor beta agonists would probably be the optimal estrogenic therapy.