INTRODUCTION
The subject of neuroendocrinology is the interface between the nervous and endocrine systems within the brain. Their structural and functional interaction is bi-directional; that is, neuronal activity modulates endocrine secretion and, in turn, hormones influence brain function. Both neurons and endocrine cells transmit signals to distinct target cells by releasing a chemical mediator that is recognized by specific receptors. There is overlap, as some secreted substances serve as both neurotransmitter and hormone, for example arginine vasopressin (AVP, also called antidiuretic hormone, ADH) or vasoactive intestinal peptide (VIP). Virtually all neurotransmitting systems are involved in the neuroendocrine interaction, and jointly they regulate metabolic homeostasis, growth, development and reproductive function and they influence behaviour, learning, emotional and mental state.
Within the brain, the anatomical sites of closest interaction between the two systems are the hypothalamic-pituitary unit and the pineal gland. Peripherally, endocrine secretion is controlled either by direct innervation through autonomic secretomotor fibres or, indirectly, through the regulation of blood flow.
The endocrine effects on the CNS are widespread: the limbic system structures of hippocampus, amygdala, hypothalamus and cingulate gyrus, as well as the pre-frontal cortex and various other parts of the brain, are responsive to endocrine signals that may alter their morphology or functional behaviour.
The neuroendocrine interface is also linked closely to the body’s immunological responses, and the increasingly complex interactions have been described as a neuroendocrine-immune network. Significant immunological changes occur during the ageing process, in part as a consequence of these interactions; however, these aspects are beyond the scope of this chapter.
As in other regions of the brain, the number and function of certain hypothalamic neurons and neuroendocrine cells declines during senescence, while other cell populations remain intact or even hypertrophy1,2. Circadian rhythms of secretion undergo a phase shift or become less pronounced and increasingly irregular3. Some endocrine axes undergo a significant physiological decline in their activity as a consequence of altered central regulation, loss of peripheral endocrine secretory capacity, tissue responsiveness or post-receptor signalling changes. While the menopause is an established life event for women, the effects of the gradual decline of male sex hormone levels (sometimes termed ‘andropause’), of adrenal androgen production (‘adrenopause’) and of growth hormone (‘somatopause’) on healthy ageing are still the subjects of ongoing debate and research. In senescence, there are changes in body composition, loss of muscle strength, reduction in endurance and frequently a decline in cognitive, emotional and psychological function. Various hormonal changes contribute to these developments, and the chapter is arranged by endocrine axis and peripheral hormone. A brief overview of its physiology and CNS-related regulation is followed by a description of the changes occurring during senescence, and the implications for the ageing person.
The anterior, glandular lobe of the pituitary gland is derived from pharyngeal ectoderm rather than from neuroectoderm. It achieves a close functional relationship with its regulatory neurons through the capillary portal circulation that exists between the median eminence of the hypothalamus and the adenohypophysis. Releasing and inhibiting hormones thus reach the anterior pituitary gland to exert control over its secretion of hormones with a tropism for the peripheral endocrine glands. All anterior pituitary hormones are released in a pulsatile manner. While they provide feedback inhibition at hypothalamic neurons (short loop), the peripheral hormones exert negative feedback at pituitary and hypothalamic level to ensure stable plasma levels (long loop). The pituitary generally reduces in size during senescence4.
Somatopause
Growth hormone is synthesized by the somatotroph cell population of the anterior pituitary gland and released in pulsatile bursts with a peak after the onset of sleep. Two hormones are known to stimulate growth hormone synthesis and secretion: growth hormone-releasing hormone (GHRH) and ghrelin, both of which are produced in the hypothalamic arcuate nucleus. The former acts via its cognate GHRH receptor (GHRHR), and the latter via the growth hormone secretagogue receptor (GHSR). In addition, a range of other factors exert control over growth hormone release; such as metabolic substrates, physiological stimuli (sleep, exercise or stress) and certain neurotransmitters. Somatostatin, a hormone produced in the hypothalamic anterior paraventricular nucleus (PVN) inhibits growth hormone release, and the overall output effectively reflects an integration of all these stimuli. Under the influence of growth hormone, primarily the liver produces insulin-like growth factor 1 (IGF-1), which mediates many of the effects of growth hormone on target tissues. Metabolic effects of growth hormone are: increased muscle mass and strength, reduced fat mass, increased bone density and improved cholesterol levels5.
Growth hormone levels peak in adolescence and decline by 14% each decade, a process that is further accelerated in postmenopausal women. The amplitude of nocturnal growth hormone pulses falls and may disappear6. Since physiological ageing is associated with an increase in body fat and a reduction in muscle mass, as well as with a fall in bone density, there are similarities with adult growth hormone deficiency, and the term ‘somatopause’ has been used for this. A trial of supplementary growth hormone in a cohort of ageing men showed significant improvement in these parameters7. After 12 months of administration, however, side effects of carpal tunnel syndrome, gynaecomastia and hyperglycaemia became evident8. A meta-analysis concluded that, while growth hormone replacement was beneficial in growth hormone deficiency, supplementation in an otherwise healthy elderly person showed no evidence for improvements in maximal oxygen consumption, bone mineral density, lipid levels and fasting glucose and insulin levels. There was no suggestion that growth hormone prolonged life. Since there is also a theoretical risk of increased neoplastic disease, there are no grounds to advocate growth hormone supplementation in healthy ageing5.
As an alternative, small molecules have been developed to act at the GHSR as a long-acting oral ghrelin analogue9. One trial was reported after one year to have achieved enhanced growth hormone pulsatility, restored IGF-1 values to juvenile levels, increased fatfree body mass and marginally lowered LDL-cholesterol. Observed side effects were a mild increase in fasted glucose, insulin resistance, cortisol levels and a weight gain of 2.7 kg vs. 0.8 kg in the placebo group10. Another compound improved lean body mass and functional strength, balance and coordination. Side effects were deterioration in parameters of insulin resistance, fatigue and insomnia11. Neither drug has reached the market.
Prolactin
Prolactin is structurally related to growth hormone, and its secretory regulation is unusual in that the pituitary lactotroph cells are under tonic inhibition by dopamine-producing hypothalamic neurons. Circulating prolactin levels comprise of a combination of basal and pulsatile release12. Prolactin levels rise in response to sleep to peak in the early hours13, and secretion is increased by stress and other stimuli. In men and non-pregnant women, prolactin concentrations gradually decline with advancing age. Frequent nocturnal sampling showed this to be a result of falling basal prolactin secretion that is associated with a reduced lactotroph cell mass or responsiveness, and also to be due to a reduction in hypothalamic stimuli for pulsatile bursts14. In ageing rats, the circadian rhythm of prolactin secretion loses the ability to adapt to changes in the light-dark cycle15.
In a large observational study of a cohort of middle-aged men (52 ± 12.9 years) attending for sexual dysfunction, the lowest quartile of prolactin concentrations was associated with increased risk for metabolic syndrome, atherogenic erectile dysfunction, premature ejaculation and anxiety. There also is evidence for immunemodulating properties of prolactin since, in mice, prolactin deficiency caused impaired lymphocyte function by reducing cytokine-induced macrophage activation16. However, the clinical relevance of reduced prolactin levels in senescence is unclear and no trials of replacement therapy in ageing humans have been conducted.
Menopause
The female cycle is under complex regulation by luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which are produced by the gonadotroph cell population of the anterior pituitary gland. Both are released in pulsatile fashion under control by hypothalamic gonadotrophin-releasing hormone (GnRH). In addition to the daily high-frequency pulsatility, their secretion is cyclical over the period of a lunar month. Complex feed-forward and feedback regulation between the hypothalamus, the pituitary gonadotroph cells and the ovary leads to the menstrual cycle during a woman’s fertile years. Oestrogen is produced mainly in the granulosa cells of the developing ovarian follicle from an androgenic precursor and is the main female sex steroid hormone.
Follicular depletion, however, is not the sole reason for the menopause. Studies in rats demonstrated that prior to any cycle irregularities there was an early decline in GnRH-neuron response and a consequently reduced LH surge in response to oestrogen around the time of ovulation. Thus the functional loss begins centrally at the level of hypothalamus and pituitary which, together with the changes at ovarian level, leads to the menopause17.
With the loss of follicular activity, which usually occurs around the mid-sixth decade of life, a rapid fall of oestrogen levels ensues and FSH and LH levels rise due to absence of feedback inhibition. Consequences of a lack of oestrogen are manifold: Atrophy of oestrogen-responsive tissues, rapid loss of bone mass, adverse changes to the lipid profile with increased atherogenic risk, depressive mood swings, lack of concentration, anxiety and loss of libido. Vasomotor symptoms of hot flashes not only impair quality of life, but also represent altered blood vessel physiology that is associated with increased cardiovascular risk18. Since the reduction in oestrogen leads to a narrowing of the ‘thermoneutral’ zone of temperature regulation in the hypothalamus, small changes in core body temperature can trigger symptoms19.
Oestrogen-containing hormone replacement therapy (HRT) can ameliorate vasogenic menopausal symptoms and delay biochemical changes. To avoid a concomitant excess risk of cardiovascular events, HRT should be taken early20 and for a limited period only to minimize the additional hazard of thromboembolism and breast cancer21. Contrary to expectations, HRT in elderly women did not preserve cognitive ability but was associated with an increased risk of dementia and global cognitive decline that correlated with a reduction in hippocampal, frontal lobe and total brain volumes22. It should be noted, however, that some of the noted CNS effects might be (i) specific to the hormone molecule used in the quoted studies, (ii) related to the late timing of HRT, and (iii) due to elevated levels of LH itself, rather than related to oestrogen deficiency23.
Andropause
Testosterone, the predominant male sex steroid hormone, is produced by testicular Leydig cells under the influence of LH and FSH. As in women, both gonadotrophins are released in pulses from the anterior pituitary gland under GnRH control. Testosterone levels in men follow a diurnal rhythm with peak concentrations occurring in the morning. At puberty, bioavailable testosterone levels begin to rise; they peak around the third decade of life and gradually fall thereafter at an annual rate of 1.3%24
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