Memorandum by the Society for Endocrinology
BIOLOGICAL PROCESSES
AND AGEING
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.

HORMONES, AGEING AND THE IMMUNE SYSTEM: DR
MARTIN HEWISON AND DR WIEBKE ARLT, THE UNIVERSITY OF BIRMINGHAM
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 STEROIDS
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.
VITAMIN D
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.
MELATONIN
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
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 AND THE AGEING MALE: DR COLIN
JOHNSTON, WEST HERTFORDSHIRE TR
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.
SKELETAL DISEASES: DR PETER SELBY, UNIVERSITY
OF MANCHESTER
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
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
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: DR ANDREW TOOGOOD, UNIVERSITY
OF BIRMINGHAM
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
|