Mohammed T. Abou-Saleh

Principles and Practice of Geriatric Psychiatry.Editors: Professor John R. M. Copeland, Dr Mohammed T. Abou-Saleh and Professor Dan G. BlazerCopyright & 2002 John Wiley & Sons LtdPrint ISBN 0-471-98197-4 Online ISBN 0-470-84641-09Neuroendocrinology of AgeingR. A. Burns and Mohammed T. Abou-SalehDepartment of Addictive Behaviour and Psychological Medicine, St George’s Hospital Medical School, London, UKINTRODUCTIONNeuroendocrinology is the study of interactions between thenervous and endocrine systems. Such interactions occur viacomplex mechanisms involving the cerebral cortex, limbic system,brain stem, hypothalamus, pituitary and periphery with regulatoryfeedback by many hormones to the pituitary, hypothalamusand probably higher centres such as the hippocampus. Observationsof neuroendocrine dysfunction and disorders of behaviourhave helped to improve our understanding of mental illness andwill be discussed later in this chapter.Despite a surge of research over the last 25 years, many gapsremain in our understanding of neuroendocrinology, especiallythat of central secretion and neural control of hormone release.The complex interrelationships between monoamines, neuropeptidesand hormones have not been elucidated 1 . Hormones suchas insulin and cortisol, once thought to exist only peripherally,are now believed to have central functions as neurotransmittersor neuromodulators 2 . Neuropeptides such as opioids andvasoactive intestinal peptide (VIP) are found centrally andperipherally and some, such as thyrotropin releasing hormone(TRH), can be secreted from the same nerve terminals asclassical neurotransmitters, thus also acting as neuromodulators3 . Some neurotransmitters, once thought to act solely viathe hypothalamus, may directly affect the pituitary, bypassingthe hypothalamus 4 . The hypothalamus remains the fulcrum ofneuroendocrine activity. In response to primarily centralstimuli, the hypothalamus acts either: (a) via release ofneuropeptide releasing or inhibiting factors into the portalcirculation to the anterior pituitary; or (b) via the direct releaseof neuropeptides to the posterior pituitary. Thus adrenocorticotrophichormone (ACTH), thyroid stimulating hormone(TSH), growth hormone (GH), follicle stimulating hormone(FSH), luteinizing hormone (LH) and prolactin are releasedfrom the anterior pituitary and vasopressin (antidiuretichormone (ADH)) and oxytocin from the posterior pituitary.There is an intricate multilevel system of feedback mechanismsbetween adjacent and even distant steps in the process ofhormonal secretion. Description of peripheral endocrine effectsare beyond the scope of this chapter.Like other systems, the neuroendocrine system undergoes adegree of decline during senescence, although by varyingdegrees and different mechanisms. Ageing may affect the neuralcontrol of hormones; the endocrine cells themselves, theirhormones, hormone receptors and post-receptor events in targetcells 5 . Most commonly there is a reduction in receptor cellnumbers but hormone-receptor coupling mechanisms have alsobeen implicated 6,7 . As some symptoms of hormonal disordermimic the symptoms of advancing age it is not surprising thatthe hypothalamus and endocrine system have been linked ascausative agents to the ageing process. Such organ system-basedtheories of ageing assume the presence of an ‘‘organal pacemaker’’for ageing which initiates the chain of events seen insenescence 8 . The failure of organ systems, with the loss ofhomeostasis, is important to many of these theories. Some ideashave focused on more peripheral endocrine glands, e.g. thehypothyroid hypotheses, but there has been a more recent shiftto central structures, such as the hypothalamus 9 . Dilman andothers have proposed that an elevated hypothalamic thresholdto negative feedback is an important element in the ‘‘deviationof homeostasis’’ after the completion of growth, and that arelative hypersecretion of, among others, growth hormonerenders the internal environment inconsistent with survival byaltering glucose and fatty acid metabolism and resulting invascular disease, diabetes mellitus and other forms of morbidity10 . Work by Frolkis et al 11 in Kiev has shown that thehypothalamo–pituitary axis plays a role in the regulation ofRNA synthesis and in the induction of some enzymes ofcarbohydrate and protein metabolism. They found that thesefunctions deteriorated with age and their work suggests thathomeostatic and repair mechanisms may be influenced, whichgives some support for an aetiological role for the neuroendocrinesystem in ageing. Possibly a more integrated theoryinvolves a more circular mechanism. Genetic programmingcombines with the internal and external environment to resultin impairment of all cells with ageing, including cells of theendocrine system. Impairment of the endocrine system altershomeostatic function and thus accelerates impairment of theremainder of the organism 4 . Given the complexity of theinterrelationships within the internal environment, it is unlikelythat the debate generated by these theories will be resolved inthe near future.Much of the initial research on ageing and endocrine functionwas with animal studies which, although helpful, may not beentirely applicable to humans, as there are important differences12,13 . However, techniques such as immunoassay haveenabled us to measure hormone levels directly in humans, buteven with this technique a high level of quality control is essential,as is the reliability of measurement. In human studies, too, wemust remember that most samples are cross-sectional and we aretherefore measuring age differences rather than age changes;longitudinal studies are therefore desirable. Nevertheless, in spiteof these difficulties, greater sophistication and reliability in ourmeasurement techniques, as well as the ability to synthesizehypothalamic releasing factors, have enhanced our understandingof neuroendocrinology and the effect of ageing.Principles and Practice of Geriatric Psychiatry, 2nd edn. Edited by J. R. M. Copeland, M. T. Abou-Saleh and D. G. Blazer&2002 John Wiley & Sons, Ltd