The endocrine system and ageing

Complex changes occur within the endocrine system of ageing individuals. This article explores the changes that occur in the metabolism and production of various hormones and discusses the resulting clinical consequences.

As individuals age there is a decline in the peripheral levels of oestrogen and testosterone, with an increase in luteinizing hormone, follicle-stimulating hormone and sex hormone-binding globulin. Additionally there is a decline in serum concentrations of growth hormone, insulin-like growth factor-I and dehydroepiandrosterone and its sulphate-bound form. Even though there are complex changes within the hypothalmo-pituitary-adrenal/thyroid axis, there is minimal change in adrenal and thyroid function with ageing. The clinical significance of these deficiencies with age are variable and include reduced protein synthesis, decrease in lean body mass and bone mass, increased fat mass, insulin resistance, higher cardiovascular disease risk, increase in vasomotor symptoms, fatigue, depression, anaemia, poor libido, erectile deficiency and a decline in immune function. For each endocrine system, studies have been carried out in an attempt to reverse the effects of ageing by altering the serum hormonal levels of older individuals. However, the real benefits of hormonal treatment in older individuals are still being evaluated.

Introduction

In ageing individuals, endocrine changes result in a decline in endocrine function involving the responsiveness of tissues as well as reduced hormone secretion from peripheral glands. This is coupled with modifications in the central mechanisms controlling the temporal organization of hormone release, with a dampening of circadian hormonal and non‐hormonal rhythms. All endocrine glands are subject to the effects of ageing and many endocrine functions are so intertwined that reduced function in one gland adversely affects the remainder. With the ageing process there are associated alterations in body composition and a decline in functional status. Compared to younger individuals, healthy older individuals have decreased muscle mass, increased fat mass and decreased strength. With healthy ageing there are changes in endocrine systems, including oestrogen (menopause), testosterone (andropause), growth hormone/insulin‐like growth factor‐I axis (somatopause), hypothalamic–pituitary–thyroid axis, hypothalamic–pituitary–cortisol axis and dehydroepiandrosterone and its sulphate (adrenopause).

This review article attempts to delineate some aspects of the interplay between the regulation of endocrine function and the ageing process and explores the age‐related changes in hormone metabolism and production, with their clinical consequences. In evaluating the changes that occur in endocrine function, it is important to distinguish between the real effects of ageing on endocrine mechanisms from any confounding factors due to the higher prevalence of age‐related illness.

Menopause

By the mid‐sixth decade of life, all women experience the menopause. Ovulation frequency decreases by the age of 40, and reproductive ovarian function ceases in the vast majority of women within the next 15 years 1. In most women ovarian follicles function less well during this period, with serum oestradiol concentrations being lower and follicle‐stimulating hormone (FSH) concentrations higher than in younger women. Luteinizing hormone (LH) is unchanged 2. Eventually follicular activity ceases, oestrogen concentrations fall to postmenopausal values and LH and FSH levels rise above premenopausal concentrations 1. However, smaller amounts of a weaker oestrogen, oestrone, are still synthesized from androstenedione in the cortex of the adrenal gland and in the interstitial ovarian cells 3. Small amounts of this oestrone can be transformed into oestradiol. The changes in these serum concentrations result in a series of further changes, including an increased risk of cardiovascular events, rapid loss of skeletal mass, vasomotor instability, psychological symptoms and atrophy of oestrogen responsive tissue.

The risk of cardiovascular disease in premenopausal women is lower than in men, but during the postmenopausal period the risk increases and is equal to males of equivalent age and risk factor profile. Prior to this increase in risk, serum concentrations of atherogenic lipids deteriorate. Low‐density lipoprotein and total cholesterol increase, whereas high‐density lipoprotein decreases. This decrease in cardioprotective HDL is thought to be one of the causes of increased coronary heart disease, myocardial infarction and stroke in postmenopausal women 4. Hormone replacement alters biochemical markers favourably, but does not improve cardiovascular disease outcome 56.

At the time of the menopause there is rapid loss of bone, due to oestrogen withdrawal. This takes place within the background of age‐related bone loss that begins in the fourth decade of life. In the perimenopausal period, women lose 5–15% of their bone mass, with 80% of this loss being trabecular bone, which is more metabolically active than cortical bone 7. There is a modest rise in serum ionized calcium without any change in parathyroid hormone (PTH), indicating a possible change in PTH set‐point which is reversed by hormone action. There is also a fall in the oestrogen‐dependent components of intestinal calcium absorption and renal tubular reabsorption of calcium. The associated high bone resorption with normal PTH also suggests an increased sensitivity of bone to PTH. There is no change in serum 1,25‐vitamin D 8.

During the immediate menopausal period, when the rate of bone loss is greatest, oestrogen replacement maintains bone mass and reduces fracture risk 9. Drugs that have been demonstrated to maintain bone mass in postmenopausal women include bisphosphonates, which act by inhibiting bone resorption more than formation 10, and raloxifene, which is a selective oestrogen receptor modulator acting selectively on bone and lipid profiles 11.

Vasomotor symptoms originate in the hypothalamus, with a resetting and narrowing of the thermoregulatory system 1. The hot flush is preceded by an LH surge, although there is no associated change in serum oestradiol 4. Decreased oestrogen levels may reduce serotonin levels and thus cause an up‐regulation of the 5‐HT2A receptor in the hypothalamus. Additional serotonin is released, which causes activation of the 5‐HT2A receptor, thus changing the set point temperature and resulting in hot flushes 12. However, the full mechanism is not completely understood. Hormone replacement reduces but does not eliminate such episodes 13. Cognitive disturbances are reported at the menopause and certain aspects of cognition appear to be related to changes in oestrogen. Observational studies and clinical trials have examined the influence of oestrogen on cognitive function, particularly memory, in postmenopausal women, but the results are far from consistent 14. The vaginal mucosa atrophies in postmenopausal women, which may lead to bleeding, as the tissue is easily injured. In addition, oestrogen deprivation may lead to dysuria, urinary frequency and incontinence. These symptoms may respond to systemic or local oestrogen replacement therapy 15. Causes of a loss in libido in postmenopausal women may be due to a fall in both oestrogen and testosterone levels as ovarian function stops 16.

There has been considerable debate about the risk : benefit ratio of hormone replacement therapy, most notably with the recent publication of the results from the Women's Health Initiative (WHI) study. The study consisted of two parallel randomized, double‐blind, placebo‐controlled clinical trials of hormone therapy to determine whether conjugated equine oestrogen alone (for women with prior hysterectomy) or in combination with progestin would reduce cardiovascular events in mostly healthy postmenopausal women. The combined oestrogen and progestin component of the WHI was stopped early, as women taking hormonal therapy were determined to have an excessive risk of breast cancer 5. At the time the trial was stopped, risks of coronary heart disease, stroke and pulmonary embolism were significantly increased in the oestrogen + progestin group. Risks of colorectal cancer and of hip fracture were decreased and mortality risk was not significantly different. The unopposed oestrogen arm was continued and the results were similar to the combined conjugated equine oestrogen arm in terms of heart disease, stroke and thromboembolic events. A striking but not statistically significant decrease in the incidence of breast cancer was observed 17. Further analysis from the WHI study showed that oestrogen therapy alone or in combination with progestin treatment increased the risk of both dementia and mild cognitive impairment 18. Another multicentre, prospective, controlled trial of oestrogen + progestin in postmenopausal women with established coronary disease failed to support the use of hormone replacement therapy for the secondary prevention of heart disease 6. Patients need to understand that recent studies have shown that hormone replacement therapy can carry an increased risk of ischaemic stroke, coronary events, venous thrombosis and possibly breast cancer. In order to minimize these hazards, hormone replacement therapy should be considered only for severe menopausal symptoms and for the shortest possible time in women who are fully informed of these risks 19.

Andropause

Ageing is associated with changes in gonadal steroid production in men as well as women. As the population is living to an older age, there has been much interest in the study of the ageing male with reference to so called ‘rejuvenating hormones’, in particular androgens. For many years there was much debate as to whether serum total testosterone levels were truly lower in healthy older men, or whether this decline was attributable to the ageing process, with the observed decline occurring as a result of confounding effects due to chronic illness and medications. However, from cross‐sectional and longitudinal studies there is now agreement that in healthy men there is a gradual but progressive age‐dependent decline in testosterone levels, termed the andropause 2021. This is more marked for free testosterone than for total testosterone, due to an age‐associated increase of sex hormone‐binding globulin levels 22. The age‐related decline in testosterone level does not start at any specific point in older subjects and it varies from modest to severe (with unclear clinical consequences), which is different from the sharp reduction of oestrogen production in females at the menopause 23.

The decline in serum testosterone concentrations is mainly due to decreased production rates in older men 24 and this is a result of abnormalities at all levels of the hypothalamic–pituitary–testicular axis 25. In longitudinal studies, serum LH and FSH levels show an age‐related increase. However, serum LH concentrations often do not reciprocate the decline in testosterone with age 26—most likely a result of impaired gonadotrophin‐releasing hormone secretion and alterations in gonadal steroid feedback mechanisms 27. The testosterone response to LH and human chorionic gonadotrophin decreases with ageing 28and the circadian rhythm of plasma testosterone secretion, with higher levels in the morning than in the evening, is generally lost in older men 29.

The clinical features associated with reduced testosterone levels in ageing men include increased fat mass, loss of muscle and bone mass, fatigue, depression, anaemia, poor libido, erectile deficiency 20, insulin resistance 30 and higher cardiovascular risk 31. These are similar to changes associated with testosterone deficiency in young men, so the syndrome of androgen deficiency of the ageing male (ADAM) has been proposed. However, each of these clinical features may also occur in older men with normal androgen levels and so the ADAM syndrome has not been universally accepted 32.

As there is a certain proportion of middle‐aged and older men with serum total testosterone levels below the reference range for young adult males, there is a suggestion that supplementing testosterone in older men with low testosterone levels into a range that is mid‐normal for healthy, young men may prevent or reverse the effects of ageing 33. Over the last decade, several clinical studies have been undertaken to determine whether testosterone supplementation in ageing is beneficial. Despite several trials examining various parameters, including body composition, muscle strength, bone density, metabolism and lipid profile, there is still no consensus as to whether androgen treatment is beneficial to men over 50. Much of the uncertainty is due to the brief duration of many of the protocols, such that the effects of prolonged testosterone replacement are not clear.

Growth hormone–insulin‐like growth factor‐I axis

Growth hormone (GH) is both anabolic and lipolytic and the action of growth hormone on peripheral tissues is mediated, in part, by circulating (hepatic‐generated) or paracrine insulin‐like growth factor‐I (IGF‐I) 34. The secretion of GH undergoes dramatic changes during life. GH output is relatively low before puberty, but with sexual maturation and adolescence there is a period of high GH output and accelerated somatic growth 35. With ageing, numerous studies have shown that GH secretion and serum GH concentrations fall, both basally and in response to stimuli, and this is paralleled by a decline in IGF‐I 34. GH production and IGF‐I concentrations decline by more than 50% in healthy older adults 36. The progressive decline in GH secretion has been termed the ‘somatopause’. In older subjects the decrease in GH secretion is known to cause a reduction of protein synthesis, a decrease in lean body mass and bone mass and a decline in immune function 34.

The neuroendocrine mechanisms of the somatopause are uncertain. Early studies suggesting senescent changes in the pituitary 3738 have not been supported by the observations that there is no decrease in the number of pituitary somatotroph cells 39 or that exogenous growth hormone‐releasing hormone (GHRH) 4041 or GH‐releasing peptide analogues 42 are able to rejuvenate GH output and plasma IGF‐I levels in older individuals. Consequently, attention has shifted to potential alterations of the hypothalamic regulation of GH secretion, with data suggesting an age‐dependent decrease in endogenous hypothalamic GHRH output, contributing to the age‐associated GH decline 43. Low physical fitness and higher adiposity in older individuals also contributes to the decreased GH secretion 44, although the mechanisms underlying these observations are not clear. Low IGF‐I levels reflect decreased GH secretion rather than a loss of hepatic responsiveness to the hormone, as circulating IGF‐I levels increase similarly in young and old men after exogenous administration of either GH or GHRH 34.

In younger GH‐deficient adults there are alterations in body composition, including physical performance, psychological well‐being and substrate metabolism, which resemble the ageing phenotype. These features are improved by long‐term hormone replacement with recombinant human GH 45. This had led to the suggestion that the elderly have genuine GH deficiency and, by implication, would benefit from GH treatment. There are many unanswered questions about the use of GH in older individuals. A study published in 1990 showed that 6 months treatment of recombinant GH in 12 healthy 61–81 year‐old men who had serum IGF‐I concentrations below those of healthy younger men resulted in an increase in lean body mass by 9% and a decrease in adipose tissue mass by 15% 46. However, the weekly dose of GH was approximately twice as high as the dose used in non‐elderly GH‐deficient adults, the study was not double‐blinded and there was no assessment of muscle strength, exercise endurance or quality of life 47. A double‐blind placebo‐controlled study showed that GH with or without sex steroids in healthy women (n = 57) and men (n = 74) aged 65–88 years increased lean body mass and decreased fat mass 48. However, there was no change in muscle strength or maximal oxygen uptake during exercise. These findings were similar to a previous randomized, controlled, double‐blind trial in 1996, in which 52 healthy men aged > 69 years with well‐preserved functional ability but low baseline IGF‐1 levels were given 6 months of physiological doses of GH 49. Body composition improved but functional ability did not. A further study recruited 18 healthy older men (aged 65–82 years) who initially underwent progressive weight training for 14 weeks to invoke a trained state, then were randomized to receive GH or placebo while continuing a further 10 weeks of strength training 50. The results suggested that supplementation with GH does not augment the response to strength training in older men.

Data have also suggested that the age‐related decline in testosterone seen in men may contribute to the reduction in GH secretion; thus, testosterone may act synergistically with GH in reversing this GH secretion decline. Non‐pharmacological doses of combined GH and testosterone in older men have been shown to improve selected aspects of physical performance and increased muscle IGF‐I gene expression without measurably changing body composition or muscle strength 51. In a more recent study, co‐administration of low‐dose GH with testosterone resulted in beneficial changes in mid‐thigh muscle and aerobic capacity 52.

The initial enthusiasm for the potential benefits of GH replacement in aged individuals has been severely dampened by its known adverse side‐effects, including arthralgia, carpal tunnel syndrome, oedema and hyperglycaemia. There are also particular concerns over the links between the GH–IGF–I axis and the development of cancer in the normal population 4748. Studies to date have been for a maximum of 12 months, so long‐term safety data are not available. Currently there is no ‘magic pill’ that reverses the process of ageing, and GH therapy for ‘anti‐ageing’ has currently not been proved to be effective 47. Long‐term studies are required to determine the efficacy and safety of GH treatment in older adults who are not GH‐deficient. It remains to be seen whether GH secreatagogues are beneficial in the elderly.

Hypothalmo–pituitary–thyroid axis

The hypothalmo–pituitary–thyroid axis undergoes a significant number of complex physiological alterations associated with ageing. However, direct age‐related changes need to be distinguished from indirect alterations caused by simultaneous thyroid or non‐thyroidal illness, or other physiological or pathophysiological states whose incidence increases with age. Several changes formerly believed to be a direct result of the ageing process have subsequently been shown to be due to the increased prevalence of subclinical thyroid disease and/or the result of non‐thyroidal illness. This makes interpretation of thyroid function tests difficult in the elderly 53. Thyroid hormone clearance decreases with age, but thyroid hormone secretion is also reduced, leading to unchanged total and free serum thyroxine (T4) concentrations 54. In contrast to thyroxine, serum total and free triiodothyronine (T3) concentrations decrease with ageing. This reduction is believed to be mostly due to reduced peripheral conversion of T4 to T3, due either to the direct effect of non‐thyroidal illness or to ageing itself 53.

In older, apparently euthyroid patients, serum thyroid‐stimulating hormone (TSH) concentrations may be reduced 5556, but this is usually a pathological finding indicating either exogenous or endogenous thyrotoxicosis 57. However, in elderly patients without clinical or subclinical hyperthyroidism, slightly decreased serum TSH is seen 5658. An age‐dependent reduction of daily TSH secretion rate has been reported 59. The reason for such age‐dependent reduction of TSH secretion is uncertain. It may be due to supersensitivity of thyrotrophs to the negative feedback from T4, but other theories, such as reduced hypothalamic thyroid‐releasing hormone secretion, have not been excluded 53. The amplitude of the nocturnal pulses of TSH secretion, which results in the majority of 24 h TSH secretion, is lower in older subjects 60. This decrease probably results in decreased T4 secretion in response to the decrease in T4 clearance in older individuals 54.

The prevalence of thyroid disease increases with age and all forms of thyroid disease are encountered. However, the clinical manifestations are different from those encountered in younger patients. In the elderly, autoimmune hypothyroidism is particularly prevalent. Hyperthyroidism is mainly characterized by cardiovascular symptoms and is frequently due to toxic nodular goitres. Thyroid carcinoma is also more aggressive 61. Ageing is also associated with the appearance of thyroid autoantibodies, but the biological and clinical significance of this is still unknown. Some data have shown that these thyroid autoantibodies are rare in healthy centenarians and in other highly selected aged populations, whereas they are frequently observed in unselected or hospitalized elderly patients, thus suggesting that these autoantibodies are not the consequence of the ageing process itself, but rather are related to age‐associated disease 62.

A major, unresolved issue is whether and to what extent the complex physiological changes seen in the hypothalmo–pituitary–thyroid axis contributes to the pathogenesis of age‐associated diseases such as atherosclerosis, coronary heart disease and neurological disorders 53.

Hypothalmo–pituitary–adrenal axis

The hypothalamo–pituitary–adrenal (HPA) axis is involved in life‐sustaining homeostatic and allostatic adjustments to internal and external stressors. This stress‐adaptive axis is a dynamic feedback network with circadian rhythmicity and pulsatile neurohormone secretion 63. However, how ageing causes changes in the axis is incompletely understood. With age there are variable changes in the effects of cortisol on ACTH secretion or of ACTH on cortisol secretion 64. However, there appears to be no deficiency of adrenal production of corticosteroids in ageing 65. Healthy ageing likely disrupts neuroendocrine mechanisms that coordinate within axis pulsatile and 24 h rhythmic cortisol release, and also alters the inter‐axis mechanisms that link LH and cortisol release. In older subjects, serum cortisol secretion concentrations may vary more within a 24 h period as compared to younger subjects 63. There is a 20–50% increase in 24 h mean cortisol levels between 20 and 80 years of age 66. The evening nadir in serum cortisol concentrations may be higher and earlier in older subjects 6667. Levels of corticosteroid binding globulin have not been shown to alter with age 68. With dexamethasone, inhibiton of ACTH and cortisol secretion is similar to younger individuals 64, but this inhibition may be slower in onset 69. In older women, serum cortisol concentrations increase more with exogenous ACTH 64. The rise in serum concentrations in fasting older and younger men are similar and serum cortisol response to stress is prolonged in older individuals 63. Several studies have shown gender‐specific, age‐related alterations in the HPA axis. With healthy ageing there is an increase in the cortisol response to challenge from CRH and diminished hypothalamic–pituitary sensitivity to glucocorticoid feedback inhibition. However, this is more profound in older women than older men 68.

Age‐related changes in the HPA axis may have far‐reaching physiological significance. There is growing evidence supporting the view that chronic cortisol excess may lead to hippocampal atrophy and cognitive impairment during ageing. The alterations in cortisol circadian amplitude and phase could be involved in the aetiology of sleep disorders in the elderly 66. Additionally, in older females increasing levels of HPA axis activity, as measured by urinary free cortisol excretion, are associated with a decline in memory performance 70. In healthy older men, cortisol levels are inversely related to bone mineral density and the rate of bone loss, suggesting that bone density and the rate of involutional bone loss in healthy individuals might also be regulated by the HPA axis 71. Furthermore, in both men and women cortisol levels are strongly associated with a risk of clinical fractures 72. Lastly, there is an association between 24 h cortisol production rate and increased body fat in older men. Thus, the increase in HPA axis activity may play a role in the alterations in body composition and central fat distribution that are seen in ageing 73.

Dehydroepiandrosterone

Dehydroepiandrosterone (DHEA) and its sulphate‐bound form (DHEAS) are the most abundant steroid hormones, although their physiological functions have not been fully delineated. As well as an abdundant circulating adrenal androgen, DHEA(S) is also thought to act directly as a neurosteroid that may have cardioprotective, antidiabetic, anti‐obesity and immuno‐enhancing properties 74. There has been much debate on the anti‐ageing properties of DHEA and its potential as a ‘hormone of youth’ 75. Unlike the relatively unaffected cortisol biosynthesis, the major age‐related change in the human adrenal cortex is a striking decrease in the biosynthesis of DHEA(S) 667677. The blood level of DHEA, most of which is present in the sulphated form (DHEAS), peaks at approximately 20 years of age and declines rapidly and markedly after the age of 25 76. By the age of 80, patients have DHEA levels 10–20% of those of younger counterparts 78. Histomorphological analysis of adrenal specimens suggests that ageing results in alterations within the adrenal cortex, resulting in a reduction in the size of the zona reticularis, this being responsible for the diminished production of DHEA 79.

The physiological consequences of a decline in DHEA with age are not fully understood. Many have speculated that administration of DHEA may reverse ageing effects and there is widespread commercial availability of DHEA outside the regular pharmaceutical networks, without adequate scientific evidence 80. Cross‐sectional studies have noted an association between the decline in DHEAS levels and cardiovascular disease, breast cancer, low bone mineral density, depressed mood, type 2 diabetes and Alzheimer's disease. However, this may reflect the ageing process per se rather than there being a causal relationship 81.

This age‐related decline in circulating DHEA(S) has led to a number of randomized trials assessing the effect of oral DHEA in otherwise healthy older subjects. In the first randomized placebo‐controlled cross‐over trial, 50 mg DHEA was administered to 13 men and 17 women aged 40–70 years for 6 months. There was an improvement in well‐being and no change in insulin sensitivity or body composition. Bioavailable IGF‐I increased slightly, whereas HDL cholesterol decreased in women 82. In the largest study to date, a double‐blind randomized parallel study of 140 men and 140 women aged 60–79 years, who were given 50 mg DHEA or placebo daily, showed no improvement in well‐being or cognition 83. In the study, women > 70 years had increased libido, and slight but significant gains in bone mineral density were observed in women but not in men. Other trials have failed to demonstrate any benefit of DHEA on well‐being, mood, cognition or activities of daily living 84-86. From these studies, it can be concluded that the decline in DHEA concentrations does not necessarily lead to impaired well‐being, cognition or sexuality per se 80.

In healthy ageing there is a marked sexual dimorphism in adrenal hormone regulation. In older women, lower DHEA(S) and higher cortisol levels are seen compared to older men, which persists into advanced age. This is in contrast to cortisol levels in men and women, which show a progressive, parallel increase with ageing. The consequence of sexual dimorphism in adrenal hormones may have implications for age‐related changes in cardiovascular disease, brain function and bone metabolism 68.

In summary, there is no clear clinical consequence of the age‐related decrease in serum concentration of DHEA and there are no clear benefits of DHEA replacement in older individuals 80.

Conclusion

Complex changes are seen in many endocrine systems with ageing that occur independently of factors associated with the higher prevalence of age‐related illnesses. Endocrine deficiencies in older individuals include a decrease in the peripheral levels of oestrogen and testosterone, with an increase in LH, FSH and sex hormone‐binding globulin. In addition there is a decline in serum concentrations of GH, IGF‐I and DHEA(S). The endocrine functions that are essential to life, such as adrenal and thyroid functions, show a minimal overall change in basal levels with ageing, even though there are complex changes that do occur within the hypothalmo–pituitary–adrenal/thyroid axis.

The clinical significance of these deficiencies with age are variable and are still being evaluated. The menopause results in a series of changes in lipid metabolism, bone loss, vasomotor symptoms and possible changes in cognition. Likewise, declines in gonadal function in men are associated with increased fat mass, loss of muscle and bone mass, fatigue, depression, anaemia, poor libido, erectile deficiency, insulin resistance and higher cardiovascular disease risk. Similarly, a decline in the GH–IGF–I axis results in reduced protein synthesis, decrease in lean body mass and bone mass and a deterioration in immune function. Changes in adrenal hormones have variable clinical significance.

For each endocrine system there have been many studies trying to reverse the effects of ageing by restoring the serum hormonal levels of older individuals back into ‘younger ranges’. However, currently it is unclear whether treatment of many of these aged‐related changes is ultimately beneficial. So far research has not found the ‘magic pill’ to reverse the process of ageing and the quest for a ‘hormone of youth’ still carries on.

Chahal HS, Drake WM.

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