Mohammed T. Abou-Saleh

esponse to stress 37 (see below). Overall, findings suggest a mildreduction, if any, in basal functioning but with an alteredregulatory capacity, an important factor in the stress response.Plasma total cortisol, plasma cortisol binding, plasma and urinaryfree cortisol and plasma ACTH are unchanged. Diurnal variationof cortisol secretion persists but may occur later in the day. BothACTH and cortisol show decreased responsivity to provocativestimulation in older individuals and a degree of loss of theinhibitory feedback response 38 . Several studies have shownattenuation of the cortisol response to ACTH, possibly as aresult of altered functioning of ACTH-stimulated cAMP glucocorticoidreceptors, whose numbers also diminish with age 39 .NEUROENDOCRINOLOGY OF AGEING 53POSTERIOR PITUITARYMorphologically, animal studies have revealed subcellularchanges in the posterior pituitary. In humans, earlier evidencesuggesting non-alteration of posterior pituitary hormones 40 mustbe tempered by the more recent evidence of a tendency toincreased secretion of vasopressin in the elderly with elevatedbasal levels. Diminished secretion by ageing hypophyseal tissue isoffset by elevation of vasopressin levels as a result of a reductionin renal tubule sensitivity to vasopressin 41 . Animal studies suggestthat ageing may result in the loss of a particular group ofhippocampal cells normally inhibitory to vasopressin secretion.Oxytocin levels also decrease with age.AGEING AND STRESS‘‘Stress’’ may be defined in many ways but implies demands uponan organism threatening to overwhelm it and resulting in aphysiological response. Human physiological responses to stress,either physical or psychological, are characteristic and involveinitial adrenal medullary sympathetic activity which is latersuperseded by activity of the HPA axis during the ‘‘adaptation’’phase. The HPA axis and its response to stress is outlined inFigure 9.1. Thus, in situations of stress, there is centrallystimulated hypersecretion of ACTH and cortisol, along withfacilitatory vasopressin. The HPA axis also plays a major role inthe homeostasis of stress and it has been postulated that itachieves this by blunting the organism’s persisting and potentiallyharmful physiological reaction to stress. The repeated aetiologicallinkage of stress to psychiatric illness has led over the last 25 yearsto much investigation of the HPA axis in stress and psychiatricillness, resulting in a mushrooming of the concept ofpsychoneuroendocrinology or behavioural endocrinology andthe search for neuroendocrine markers for psychiatric illness.The concept of the neuroendocrine interface as ‘‘the window intothe brain’’, although not fulfilling initial expectations, has led toneuroendocrinological techniques becoming powerful researchtools and valuable diagnostic aids in psychiatry 42 .With ageing it appears that the physiological stress mechanismbecomes compromised and there is also evidence that stressfulstimuli can accelerate ageing 43 . At the neurochemical level, ratexperiments have suggested changes in monoamine metabolismand poor habituation to stress occurring with increasing age 44 .Such a loss of habituation may be a result of an age-inducedreduction of benzodiazepine binding sites 45 (thus increasingvulnerability to anxiety-induced mechanisms) or may be aconsequence of a reduction of inhibitory hippocampal cortisolreceptor numbers 46 . Despite inconsistent findings there appears tobe a diminished maximal response of the HPA axis to stressfulstimuli, denoting a reduction in reserve capacity in ageinghumans.Figure 9.1 The HPA axis and its response to stress. 5-HT, 5-hydroxytrytamine; ACh, acetylcholine; NA, noradrenaline; GABA, g-aminobytyric acid; CRH, corticotrophin releasing hormone; CCK,cholecystokinin; AVP, arginine asopressin; VIP, vasoactive intestinalpeptide; ACTH, adrenocorticotropin; ADR, adrenal glandAGE AND PSYCHONEUROENDOCRINE MARKERSAs a result of research carried out over the last 25 years, it is nowfirmly established that mental illness is associated with a highincidence of endocrine abnormality in both young and old. Themost commonly investigated endocrine axis in psychologicaldisturbance is the HPA axis, which in depression characteristicallyshows hyperactivity with elevated circulating ACTH-cortisol andnon-suppression by dexamethasone, a powerful synthetic steroidthat, in normal individuals, inhibits the secretion of ACTH andhence cortisol. In younger individuals, dexamethasone nonsuppressionis not truly specific for depression and is commonin other affective psychosis and acute schizophrenia, with a lowerincidence in anxiety, panic disorder and anorexia nervosa 47 .Dexamethasone suppression is also influenced by age (amongother variables), with the healthy elderly showing a tendencytowards non-suppression. However, non-suppression is morepronounced in the elderly depressed and those with Alzheimer’sdisease. In the elderly, as in the young, the dexamethasonesuppression test (DST) is still a useful aid when used with carefulclinical assessment 48 . It is helpful in differentiating depressiveillness from minor psychiatric conditions and chronic schizophrenia,and reports have also suggested uses in identifyingdepressive pseudodementia and demented patients with depression49 . In depression, the DST is a good predictor of long-termoutcome, with greater risk of relapse in non-suppressors 50 . The