Select Committee on Science and Technology Written Evidence

Memorandum by the Society for Endocrinology


  DHEA (dehydroepiandrosterone) is a steroid hormone produced by the human adrenal cortex. It is quite different from the other adrenal hormones for two reasons: first because most animal species do not produce DHEA so it is very much a "human hormone" and second, because of the striking changes in blood levels of DHEA through life. In childhood DHEA levels are low, then rise through adolescence and peak in the third decade of life. After this there is a steady decline in blood concentrations of DHEA, continuing into old age. Other adrenal steroids are produced at a relatively constant rate throughout life. It has also been shown that DHEA levels decrease in the presence of most chronic disease states, including diabetes, cancer, arthritis, heart disease etc.

  These findings have led to the suggestion that DHEA is a hormone of youth and "wellness" and it has even been suggested that old age may be a condition of "DHEA deficiency". There have been a few studies looking at the effects of replacing DHEA, both in older people and in people with adrenal failure. It is clear from these studies that DHEA will not be a universal panacea for all the diseases of older age, but it is also clear that giving DHEA has significant beneficial effects on the overall quality of life. The improvements in quality of life are seen in ratings of well-being, anxiety, depression, and self esteem and occur three to four months after starting treatment.

  The problem with carrying out studies on the effects of DHEA is that the pharmaceutical industry has no current interest in this hormone. DHEA and its active metabolites are all naturally occurring substances which have been well-characterised and crucially, do not offer the possibility of patentable products. This has caused a funding crisis in the area of DHEA clinical trials and much important research is therefore simply not possible. The most promising areas of research are: the use of long-term DHEA in older people, and the use of DHEA to treat anxiety disorders.

  One way to stimulate interest from the pharmaceutical industry would be to characterise the DHEA receptor, which would lead to the development of novel drugs which interact with the receptor. There is a clear need for funding to be directed towards this basic science research which is directly relevant to human disease and ageing.

  DHEA is inexpensive; it has few side effects when given in replacement doses. It has the potential to alleviate some of the health problems associated with ageing. However, non-commercial funding will be required to further our understanding of this hormone.


  Ageing is associated with a decline in the production of several key hormones. The most notable example is of course the menopausal loss of ovarian oestrogen production in women leading to effects on osteoporosis, which are described elsewhere in this report. However, other hormones that decline with ageing include the pineal gland hormone melatonin, pituitary growth hormone release, adrenal dehydroepiandrosterone (DHEA), and vitamin D. Changes in these hormones are likely to have diverse clinical consequences but one specific aspect of physiology that has attracted much recent attention is the Immune System. Along with hormone loss, ageing is associated with a parallel decline in immunity, otherwise known as immunesenscence, suggesting an important link between endocrinology and immunology. Although the precise impact of age-related hormone loss on immune-related diseases (autoimmune disease, susceptibility to infection etc) has yet to be fully defined, there is a growing body of evidence suggesting that this is an important consideration in the elderly. Specific examples are outlined below.


  Adrenal hormone production comprises three steroids of major importance: the glucocorticoid cortisol, the mineralocorticoid aldosterone, and the androgen precursor dehydroepiandrosterone (DHEA). DHEA is distinct from cortisol and aldosterone in declining with advancing age. This age-associated secretion pattern is only seen in humans and higher non-human primates. Individual maximum concentrations of DHEA and its sulphate ester (DHEAS) are achieved during the third decade, followed by a steady decline with advancing age so that levels in the "oldest-olds" are only 10-20 per cent of those seen in young adults. This decline has been termed "adrenopause" in spite of the fact that secretion of other adrenal hormones such as glucocorticoids does not change considerably with age. Adrenopause is independent of menopause and occurs in both sexes as a gradual process at similar ages.

  No specific receptors for DHEA have been reported so it is possible that it achieves its effects via metabolism to sex hormones. Nevertheless, DHEA has been linked to a variety of immune responses. For example, in a number of studies DHEA supplementation has been used to modify immune functions and alter the course of immunopathies. Most studies have been performed in patients with the autoimmune disease lupus (SLE). The concept of using DHEA in the treatment of SLE was based on the observation that women are more often affected and that circulating androgens and DHEA concentrations are low in patients with SLE. Moreover, androgen treatment can modify the disease progression in an animal model of SLE.


  The active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), is a pluripotent hormone which has properties that extend well beyond its established role in calcium homeostasis. Sufficient bioavailability of active vitamin D is dependent on regular exposure to light and dietary intake. These conditions are generally not met in elderly populations, in particular in Northern countries, which leads to relative vitamin D insufficiency with ageing, particularly in nursing home populations. The consequences of severe vitamin D deficiency with respect to calcium status and bone disease (rickets/osteomalacia) have been recognised for many years and the recent resurgence in this disease amongst some children has attracted much attention. The possible impact of sustained vitamin D insufficiency is less well-known but may affect a substantial proportion of the UK population, particularly the elderly. Several researchers have proposed that chronic exposure to low levels of vitamin D results in a distinct bone disease referred to as hypovitaminosis D osteopathy (HVO).

  Another feature of vitamin D which may have significant health consequences is the immune modulatory actions of 1,25(OH)2D3 this has been described at several levels including the regulation of T-cell proliferation and function and may influence a diversity of tissues with the skin and gastrointestinal tract being good examples. Furthermore, these effects of 1,25(OH)2D3 involve mechanisms that are quite distinct from the renal/intestinal responses that are associated with classical calcium homeostasis. Dysregulated synthesis of 1,25(OH)2D3 is a feature of inflammatory disease but there may also be altered immune function associated with vitamin D insufficiency which is an increasingly prevalent problem in particularly at more northerly latitudes, and within elderly populations. Circulating levels of vitamin D have been linked to autoimmune diseases such as type 1 diabetes and multiple sclerosis and other related disorders such as Crohn's disease. At a cellular level there is much evidence suggesting that 1,25(OH)2D3 is a powerful immunosuppressive. Studies to date have focused on the application of this as treatment for autoimmune diseases and transplantation rejection but there is now growing awareness that vitamin D supplementation, particularly in the elderly, may also have considerable benefits in preventing immune disorders.


  Enzymatic conversion of serotonin by the serotonin-N-acetyltransferase (NAT) leads to the generation of melatonin. NAT expression is highest in the pineal gland and readily inhibited by light, with signal transduction from the retina via the hypothalamus to the pineal gland. This explains the diurnal rhythm of melatonin secretion with a maximum during night time hours (2-4 am). Intraindividual maximum levels are achieved during the first three years of life while young adults have 20 times lower levels. With ongoing ageing, melatonin secretion declines and the nightly peak level occurs one to two hours earlier.

  The main physiological function of melatonin is the regulation of the diurnal rhythm. It has been shown that melatonin is a sleep-inducing hormone and age-related insomnia may be improved by timed administration of melatonin. Recent studies have shown that human leukocytes express NAT and synthesize. Furthermore, inhibition of this process led to alterations in the secretion of immune-active cytokines. This suggests a potential role for melatonin in immune regulation.


  Growth hormone (GH) is released from anterior pituitary somatotrope cells in a pulsatile fashion. GH release is stimulated by GHRH and inhibited by somatostatin, which are produced in the hypothalamus. Pituitary growth hormone (GH) production reaches its maximum around 20 years of age, but shows attenuation with age, both with regard to total secretion and to amplitudes of pulsatile release. Studies suggest that spontaneous GH secretion falls by around 14 per cent per decade of adult life. GH has been reported to have a variety of immunomodulatory effects in vitro but the in vivo significance of this is unclear particularly as many of the effects of GH may be indirect.


  Testosterone deficiency in younger men is associated with a variety of symptoms including, diminished libido, erectile dysfunction, fatigue and decreased vitality, reduced muscle mass with increased central obesity, reduced bone density, decreased cognitive function, depression and anaemia. All or the majority of these symptoms can be improved/restored by testosterone replacement. Replacement therapy is now available using much more acceptable methods via patches, gels and gum pellets as well as the more traditional methods of injections or implants.

  Blood levels of Testosterone including free or bioavailable Testosterone fall in the ageing male. Studies have also suggested an association between low testosterone and patients with diabetes and increased cardiovascular risk. Many of the symptoms of hypogonadism are similar to the "normal" ageing process inviting the question as to whether testosterone replacement could be beneficial for the elderly male, improving quality of life, cognitive function and reducing the risk of chronic disorders such as cardiovascular disease or osteoporosis.

  Unfortunately testosterone therapy may be associated with significant risks to health. The increased risk of cardiovascular disease in males has been attributed to testosterone although there is no evidence to support this. Excessive replacement can be associated with increased red-cell mass and polycythaemia which might contribute to circulatory problems. It could be expected that the development of androgen dependent tumours especially the prostate might be increased but again there is no confirmatory evidence.

  At present we know that there are a proportion of elderly men with detectable but low levels of testosterone especially when compared to the younger male. Many have symptoms compatible with testosterone deficiency but we have no evidence as to the risk/benefit of replacement therapy. This has resulted in recent position statements from both the US (United States National Academy of Science, Institute of Medicine) and the UK (Society for Endocrinology) urging caution before commencing treatment and emphasising the need for proper controlled trials. The UK would be in an excellent position to undertake such research. Such a trial would almost certainly not be funded by the pharmaceutical industry and will depend on central government funding such as the MRC.


  A large number of skeletal diseases are associated with the ageing process. Although there is some research to inform many of these agendas a lot of this has been ignored by health policy makers and as a result of the morbidity and mortality associated with the skeletal disease in the elderly is substantial.

  The primary skeletal problem associated with ageing is the occurrence of bone fractures. This has been known for many years. Furthermore it is generally accepted that the incidence of fracture is likely to increase over the coming years. This is predominantly the effect of an ageing population. In addition to their own problems of pain and immobility fractures are associated with a significant decrease in quality of life. Furthermore, vertebral fractures are associated with a significantly increased mortality. Following a fracture, in addition to the increased death rate, there is also significant evidence pointing to a loss of independence: only 50 per cent of people following hip fracture returned to previous level of independence. As a consequence the national health and personal social service costs of these fractures are substantial. It has been estimated these are currently in the region of £2 billion per year and that this figure is likely to increase with the passage of time.

  Although there has been a significant research effort in the field of osteoporosis this has been predominantly driven by the needs of the pharmaceutical industry and issues not related to drug therapies have received much less high profile attention.

  Although the prevention of falls on fractures was considered within the National Service Framework for older people this has not lead to major change in provision for the prevention and treatment of osteoporosis. Several topics around the field of osteoporosis are currently under review by the National Institute for Clinical Excellence but current provision for osteoporosis is fragmentary. A recent EU report indicates that the United Kingdom has the lowest provision for bone densitometry (the means of diagnosing osteoporosis) of any of the member states. Although we understand the committee is not primarily considering health care issues it can be seen that this low level of provision indicates how poorly the results of research have been translated into practical provision within the United Kingdom.


  Vitamin D deficiency is a further important cause of skeletal morbidity in the elderly. It is now well established that for the healthy population even in temperate climates such as the United Kingdom the vast majority of vitamin D is formed within the body as the result of the action of sunlight on the skin. In the elderly population exposure to sunlight is reduced and therefore this source of vitamin D is less readily obtained. This presents a particular problem in institutionalised or housebound elderly. Low levels of vitamin D have been well documented to lead to muscle weakness together with softening of the bones (osteomalacia). The combination of these leads to an increased risk of fracture. Several studies have indicated that giving vitamin D and calcium supplementation to elderly institutionalised individuals is associated with a significant reduction in the occurrence of fractures. There is no public health policy guiding such supplementation in the United Kingdom even in high-risk institutionalised elderly patients. Again this shows a lack of willingness of the public health authorities to put lessons which had been learnt from clinical research into practice for the benefit of the elderly population.

  An alternative approach to this problem would involve the fortification of certain foodstuffs with vitamin D. Although this is done some extent with spreading fats this is not undertaken in the United Kingdom to anything like the same extent as in other countries of Europe or the United States. The reasons for this are generally attributed to the possibility of over treatment leading to hypercalcaemia. However, in places where supplementation is routine this has only occurred rarely.


  Paget's disease is a poorly understood condition which leads to a marked increase in turnover in discrete bones within the skeleton. As a result of this it can lead to, deformity, and fracture. It has recently been estimated that Paget's disease affects two percent of the population over the age of 55. The consequences of Paget's disease are less well understood. A large multicentre trial examined the effect of treatment of Paget's disease on specific endpoint such as fracture and arthritis is currently under way. This study (the Paget's prism study) is jointly funded by arc and the National association for the relief of Paget's disease. Little if any cognisance of the needs of patients with Paget's disease appears to be taken by those responsible for health care planning.


  Growth hormone (GH) is produced by the anterior pituitary gland in a pulsatile fashion, with the majority being released during sleep, however the amount of GH released changes over the course of the human lifespan. GH release is maximal during puberty when it promotes linear growth, but thereafter secretion declines by approximately 14 per cent per decade of adult life. Although GH does have direct effects upon some tissues, many of its actions are mediated via insulin-like growth factor-I (IGF-I), a peptide produced predominantly in the liver. In parallel with GH, IGF-I levels also fall with increasing age. As a consequence of these changes, old age is a state of relative GH insufficiency, frequently referred to as the "somatopause".

  In addition to changes in hormone secretion, the aging process results in adverse changes in body composition, particularly a decline in muscle mass and an increase in fat mass; bone mineral density declines and the risk of fracture increases; physical performance deteriorates and there is an increased risk of falls. Furthermore, ageing is associated with a worsening cardiovascular risk profile and increased morbidity and mortality from cardiovascular and cerebrovascular disease.

  GH deficiency in younger adults causes similar changes to those outlined above associated with the ageing process, which has led to the suggestion that the elderly are GH deficient and would benefit from GH treatment. Randomised controlled studies have demonstrated modest benefits when GH has been used alone or in combination with exercise or sex steroids. Body composition improves, and there is some improvement in strength and exercise capacity. These data have provided the basis for the use of GH as an anti-ageing compound, particularly in the United States and increasingly in the United Kingdom, a practice not accepted by the mainstream endocrine community.

  There is some evidence that treatment targeted at specific groups may improve function. One study of GH therapy given during the perioperative period to patients undergoing hip replacement increased the four-minute walking time compared to placebo. Such changes may improve recovery and reduce the time to independent living following similar operative procedures. Other groups where the benefits of the anabolic effects of GH are not known is in patients at risk of falls or those undergoing knee replacement surgery.

  The benefits of GH treatment in the elderly are limited to changes in body composition and improvements in exercise capacity. These benefits are offset by a high frequency of side effects and concerns regarding the long-term safety of GH treatment in this age group. There are no long-term data that indicate whether the benefits are permanent or whether they extend the period of independent living. Furthermore there are no data that determine the cost effectiveness of GH treatment in healthy ageing adults. Future work must determine what is meant by the term somatopause; no single person or professional body to date has defined this clinical state or physiological process. Work is required to identify subject groups that will benefit from either short term or chronic GH treatment and what parameters should be assessed to demonstrate GH treatment is actually providing significant functional or health benefits. As the population ages and places increasing pressure on the Health Services small changes in functional ability may result in significant savings in bed occupancy and cost.

October 2004

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