Oestrogens may modulate the activity of the hypothalamic-pituitary-adrenal (HPA) axis. The present study was to investigate whether the activity of the HPA axis in mood disorders might be directly modulated by oestrogens via oestrogen receptors (ORs) in the corticotropin-releasing hormone (CRH) neurons of the human hypothalamic paraventricular nucleus (PVN). Brains of 13 subjects ranging in age between 45 and 79 years suffering from major depression/major depressive disorder (eight cases) or bipolar disorder (five cases) and of 13 controls, matched for sex, age, brain weight, post-mortem delay, fixation time and season and clock time at death, were studied with double-label immunocytochemistry. The total number of CRH-immunoreactive (IR) neurons, CRH neurons that colocalized ORalpha in the neuronal nucleus and the number of only nuclear ORalpha-containing neurons in the PVN were measured using an image analysis system. In addition, the volume of the PVN delineated on the basis of CRH neurons was determined. It was found that the total number of CRH-IR neurons in patients with mood disorders was nearly 1.7 times higher than in controls (P = 0.034). A novel finding was that the total number of CRH-IR neurons and the number of CRH-nuclear ORalpha double-staining neurons in the PVN were strongly correlated both in controls and in patients with mood disorders (P < 0.001 and P = 0.022, respectively). The ratio of the CRH-nuclear-ORalpha double-staining neurons to the total CRH-IR neurons in patients with mood disorders was similar to that in the controls (P = 0.448). The volume of the sub-region of the PVN that was delineated on the basis of CRH neurons was significantly larger in patients with mood disorders than in controls (P = 0.022). Another novel finding was the large population of extra-hypothalamic CRH neurons that was found in the thalamus. In summary, oestrogens may directly influence CRH neurons in the human PVN. The increased numbers of neurons expressing CRH in mood disorders is accompanied by increased ORalpha colocalization in the nucleus of these neurons. These changes seem to be trait- rather than state-related.