• Dick F Swaab, Ai-Min Bao, and Paul J Lucassen.
• Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ Amsterdam, The Netherlands. d.f.swaab@nih.knaw.nl
• Ageing Res. Rev. 2005 May 1;4(2):141-94.

AbstractCorticotropin-releasing hormone (CRH) plays a central role in the regulation of the hypothalamic-pituitary-adrenal (HPA)-axis, i.e., the final common pathway in the stress response. The action of CRH on ACTH release is strongly potentiated by vasopressin, that is co-produced in increasing amounts when the hypothalamic paraventricular neurons are chronically activated. Whereas vasopressin stimulates ACTH release in humans, oxytocin inhibits it. ACTH release results in the release of corticosteroids from the adrenal that, subsequently, through mineralocorticoid and glucocorticoid receptors, exert negative feedback on, among other things, the hippocampus, the pituitary and the hypothalamus. The most important glucocorticoid in humans is cortisol, present in higher levels in women than in men. During aging, the activation of the CRH neurons is modest compared to the extra activation observed in Alzheimer's disease (AD) and the even stronger increase in major depression. The HPA-axis is hyperactive in depression, due to genetic factors or due to aversive stimuli that may occur during early development or adult life. At least five interacting hypothalamic peptidergic systems are involved in the symptoms of major depression. Increased production of vasopressin in depression does not only occur in neurons that colocalize CRH, but also in neurons of the supraoptic nucleus (SON), which may lead to increased plasma levels of vasopressin, that have been related to an enhanced suicide risk. The increased activity of oxytocin neurons in the paraventricular nucleus (PVN) may be related to the eating disorders in depression. The suprachiasmatic nucleus (SCN), i.e., the biological clock of the brain, shows lower vasopressin production and a smaller circadian amplitude in depression, which may explain the sleeping problems in this disorder and may contribute to the strong CRH activation. The hypothalamo-pituitary thyroid (HPT)-axis is inhibited in depression. These hypothalamic peptidergic systems, i.e., the HPA-axis, the SCN, the SON and the HPT-axis, have many interactions with aminergic systems that are also implicated in depression. CRH neurons are strongly activated in depressed patients, and so is their HPA-axis, at all levels, but the individual variability is large. It is hypothesized that particularly a subgroup of CRH neurons that projects into the brain is activated in depression and induces the symptoms of this disorder. On the other hand, there is also a lot of evidence for a direct involvement of glucocorticoids in the etiology and symptoms of depression. Although there is a close association between cerebrospinal fluid (CSF) levels of CRH and alterations in the HPA-axis in depression, much of the CRH in CSF is likely to be derived from sources other than the PVN. Furthermore, a close interaction between the HPA-axis and the hypothalamic-pituitary-gonadal (HPG)-axis exists. Organizing effects during fetal life as well as activating effects of sex hormones on the HPA-axis have been reported. Such mechanisms may be a basis for the higher prevalence of mood disorders in women as compared to men. In addition, the stress system is affected by changing levels of sex hormones, as found, e.g., in the premenstrual period, ante- and postpartum, during the transition phase to the menopause and during the use of oral contraceptives. In depressed women, plasma levels of estrogen are usually lower and plasma levels of androgens are increased, while testosterone levels are decreased in depressed men. This is explained by the fact that both in depressed males and females the HPA-axis is increased in activity, parallel to a diminished HPG-axis, while the major source of androgens in women is the adrenal, whereas in men it is the testes. It is speculated, however, that in the etiology of depression the relative levels of sex hormones play a more important role than their absolute levels. Sex hormone replacement therapy indeed seems to improve mood in elderly people and AD patients. Studies of rats have shown that high levels of cumulative corticosteroid exposure and rather extreme chronic stress induce neuronal damage that selectively affects hippocampal structure. Studies performed under less extreme circumstances have so far provided conflicting data. The corticosteroid neurotoxicity hypothesis that evolved as a result of these initial observations is, however, not supported by clinical and experimental observations. In a few recent postmortem studies in patients treated with corticosteroids and patients who had been seriously and chronically depressed no indications for AD neuropathology, massive cell loss, or loss of plasticity could be found, while the incidence of apoptosis was extremely rare and only seen outside regions expected to be at risk for steroid overexposure. In addition, various recent experimental studies using good stereological methods failed to find massive cell loss in the hippocampus following exposure to stress or steroids, but rather showed adaptive and reversible changes in structural parameters after stress. Thus, the HPA-axis in AD is only moderately activated, possibly due to the initial (primary) hippocampal degeneration in this condition. There are no convincing arguments to presume a causal, primary role for cortisol in the pathogenesis of AD. Although cortisol and CRH may well be causally involved in the signs and symptoms of depression, there is so far no evidence for any major irreversible damage in the human hippocampus in this disorder.

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