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Файл:Age endocrinology. Study aid for students of medical universities
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2. HYPOTHALAMUS-PITUITARY-THYROID AXIS:
CHANGE WITH AGE
A number of authors show that after exclusion from the study of people with
thyroid diseases and people with positive antibodies to thyroid tissue, normal aging is
accompanied by an increase in the concentration of serum thyroid-stimulating
hormone (TTH). However, changes in TTH concentration appear to depend on
regional iodine status. The level of free thyroxine (FT4) decreases with increasing
age, although a number of authors have reported its increase. The concentration of
free triiodothyronine (FT3) decreases throughout life. The authors acknowledge that
the nature of changes in thyroid function with aging varies greatly in the population.
For example, some people have elevated TTH and FT4 concentrations, while others
experience an increase in TTH followed by a fall in FT4 concentrations. These
various changes may be the result of hormone metabolism disorders due to associated
diseases, inflammation. In addition, during aging, the bioactivity of TTH or TTH
receptors may decrease. Finally, with age, the prevalence of autoimmune thyroid
lesions, nodules, increases, which can lead to changes in thyroid function.
The question of whether the increase in the prevalence of subclinical
hypothyroidism and hyperthyroidism in the elderly and senile age, as well as the
increase in TTH within the normal reference range, has clinical significance remains
debatable. European Data Thyroid Association show that subclinical hyperthyroidism
is associated with an increased risk of overall and cardiovascular mortality, especially
in older people with comorbidities. However, a number of authors have shown that in
individuals aged 85 years with subclinical hyperthyroidism, survival for 9 years was
not significantly worse than in their peers with euthyroidism. However, subclinical
hyperthyroidism is associated with an increased risk of atrial fibrillation, hip and
other bone fractures, and dementia, especially at TTH concentrations below
0.10 mIU/L. In contrast, older people with subclinical hypothyroidism or higher TTH
concentrations within the normal range have lower mortality than those with
euthyroidism or people with lower TTH concentrations. Although subclinical
hypothyroidism in individuals younger than 65 years of age is associated with an
increased risk of atherosclerosis, there is no such association in elderly patients with
TTH concentrations up to 10 mIU/L. However, according to some authors, people
aged 65–79 years with a TTH concentration above 10 mIU/l are also characterized by
a greater risk of developing coronary heart disease, while this risk was not high for
people over 80 years of age. Therefore, the risk of developing cardiovascular disease
22
with increasing TTH appears to decrease with age. Higher concentrations of TTH in
the reference range even reduce the risk of stroke.
These data suggest that decreased activity of the hypothalamic-pituitarythyroid axis is beneficial during the aging process. This hypothesis is also supported
by a number of studies that link low thyroid hormone concentrations with higher
physical function, while lower TTH concentrations predict future disability. This
potential adaptive mechanism could also be hereditary, contributing to longevity, as
centenarian offspring have been shown to have higher TTH levels and lower thyroid
hormone concentrations than offspring of parents who died at a younger age.
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3. HYPOTHYROIDISM IN THE ELDERLY
Worldwide, hypothyroidism is one of the most common chronic pathologies,
and levothyroxine is one of the ten most commonly prescribed drugs. It is widely
known that hypothyroidism is more common in the elderly, and its prevalence
increases with age. This trend is observed in both overt and subclinical
hypothyroidism. The age-related change in thyroid function seems to be an urgent
problem due to the increase in the proportion of older people in the total population
of the entire globe. This review of the literature collected data on the relationship of
hypothyroidism with a deterioration in the quality of life and the development of
various complications in the elderly, as well as on the effect of treatment with
levothyroxine on these indicators.
Studies in the past decades show that TTH in serum increases in the elderly.
Thus, the prevalence of subclinical hypothyroidism was significantly higher in people
over 60 years of age compared with younger patients. The results obtained from the
database of Scottish laboratories confirm the age-related increase in the upper
reference limit of serum TTH. What could be the reason for such phenomena? It is
assumed that a moderate increase in TTH in the elderly may not reflect subclinical
thyroid dysfunction, but rather be normal due to the fact that the hypothalamicpituitary-thyroid axis and its hormones undergo significant changes due to the
physiological aging process. Probably, in this case, a change in the sensitivity of the
pituitary gland or a violation of glycosylation of thyroid-stimulating hormone play a
role, which reduces its biological activity. At the same time, an increased level of
TTH accompanied by age-related resistance to thyroid hormones with laboratory
unchanged levels of thyroxine (T4) and triiodothyronine (T3). Age-related resistance
to thyroid hormones may be due to a decrease in their transport into tissues, a
decrease in the sensitivity of nuclear receptors, a deterioration in the conversion of T4
to T3, and changes in gene expression. The level of free T4 in the blood serum
usually does not change with aging, but the slowdown in its peripheral deiodination
leads to a gradual decrease in the concentration of T3. Current clinical evidence
suggests that age-related thyroid hormone resistance is largely an adaptive response
of the aging body. Interestingly, in persons over 80–85 years of age, there is a
nocturnal rise in TTH with a weakening of the inhibitory effect of corticosteroids,
which may indicate age-related insufficiency of the hypothalamus.
A number of studies have shown that TTH levels increase with age in women
after 45 years, but the same phenomenon was not observed in men. Subsequently, a
number of cross-sectional studies were carried out in different geographical locations,
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studying different age groups. In studies involving only the elderly (both women and
men), the prevalence of overt hypothyroidism ranged between 0.2–5.7% and
subclinical hypothyroidism between 1.5–12.5%. The wide variability in study results
is likely due to the heterogeneity of the populations assessed in terms of sex, age,
race, iodine intake, and the presence of already treated thyroid disease.
In addition, to the levels of TTH serum levels are also affected by genetic,
environmental, therapeutic factors, and trends in clinical practice. Despite this, in
routine clinical practice, patients are often treated using a single reference range for
serum TTH. (usually 0.4–4.5 mcU / ml) and not taking into account the age of the
patient. According to the guidelines of the European Thyroid Association (European
Thyroid Association — ETA) proposes to introduce age ranges for TTH, but there is
still no consensus, which makes it necessary to conduct an individual assessment
when interpreting test results in older people.
It is known that thyroid dysfunction affects the entire body, and the
cardiovascular system is one of the main targets of thyroid hormones. It is known that
an increase in TTH above 10 μIU/ml is associated with an increased risk of heart
failure and other adverse cardiovascular events. However, there is quite a lot of
conflicting data in the literature about the effect of hormone replacement therapy on
cardiovascular function. For example, in the work of Razvi S. et al. (2012) showed
that in the treatment of patients with subclinical hypothyroidism over 70 years of age
and TTH concentration more than 7 μIU/ml, positive cardiac effects were not
observed. These results are controversial, as evidenced by a recent meta-analysis that
demonstrated that subclinical hypothyroidism was associated with increased all-cause
mortality in patients over 65 years of age and an increased risk of cardiovascular
events.
It is not uncommon for elderly patients with thyroid dysfunction to suffer from
overtreatment and the adverse effects of levothyroxine. In the Somwaru study L. et al.
(2009) showed that 41 % of patients over 65 years of age taking levothyroxine had a
low TTH level. (less than 0.44 μIU/ml). Subsequently, these changes in hormones can
increase the risk of atrial fibrillation, heart failure, and coronary heart disease.
Overtreatment also increased the risk of osteoporotic fractures. However, recently
published data from a study by Gonzalez Rodriguez E. et al. (2020) demonstrated that
the use of levothyroxine for more than 1 year in the elderly had no effect on bone
health. Despite this, special attention must be paid to the interpretation of test results
and the treatment of hypothyroidism in order to avoid iatrogenic hyperthyroidism in
elderly patients.
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Interest in the function of the thyroid gland in the elderly is increasing due to
the fact that its status may be associated not only with the risk of cardiovascular
diseases, but also with an increase in disability and mortality in general, as well as a
deterioration in cognitive function. Recently, the results of a population-based
retrospective study were published that evaluated the performance of more than
2 000 patients with hypothyroidism over 65 years of age. Hypothyroidism was shown
to be associated with an increased risk of all-cause death (adjusted hazard ratio (aHR)
1.82; 95 % CI 1.68 to 1.98; p < 0.001) and patients with hypothyroidism on
replacement therapy levothyroxine had a lower risk of death than untreated (aHR
0.57; 95 % CI 0.49 to 0.66; p < 0.001). Seo SM data al. (2018) show a worse clinical
outcome in patients with acute myocardial infarction with elevated TTH levels (mean
age of patients 67.8±11.1 years). Moreover, an increase in the concentration of TTH
was a predictor of overall mortality in patients with acute myocardial infarction.
Increased TTH was associated with significantly higher all-cause mortality (26.0 %
vs 11.7%, p < 0.0001) and cardiac mortality (9.2 % vs 4.6 %, p = 0.014). Cox's
multivariate proportional hazards model determined that an increase in TTH is a
significant predictor of all-cause mortality (aHR 1.560, 95 % CI 1.017 to 2.392,
p = 0.041). It is known that both overt and subclinical hypothyroidism affect the lipid
profile. The study by Zhao M. et (2015) showed that this relationship is more
significant for patients aged 60–69 years than for those examined in the younger
group (40–49 years old).
The paucity of published research on hypothyroidism in the elderly severely
limits the understanding and treatment of this condition in this age group. One of the
features of the course of hypothyroidism in the elderly is that older patients report
fewer symptoms than younger people. A prospective study comparing the frequency
of reported symptoms found that hypothyroid patients older than 70 years of age were
significantly less likely to report weight gain, muscle cramps, or cold intolerance than
hypothyroid patients younger than 50 years of age. A study comparing patients with
hypothyroidism due to autoimmune thyroiditis and a euthyroid control group found
that while younger patients were more likely to report all 13 of the hypothyroidism
symptoms listed in the questionnaire, older patients reported only 3 of them (fatigue)
in most cases., apnea, hoarseness). The nonspecific pattern of hypothyroidism in the
elderly is further supported by screening studies for hypothyroidism in the elderly,
which have shown that only a small proportion of patients with biochemically
confirmed overt hypothyroidism have symptoms suggestive of the disease.
The relationship between hypothyroidism and cognitive impairment,
depression and other psychiatric manifestations has been considered for a long time.
26
Back in the middle of the last century, R. Asher (1949) introduced the term
“myxedema madness”, which was used to describe the combination of confusion,
disorientation and psychosis, which, as was noted, sometimes accompany long-term
hypothyroidism. These early observations were later supplemented by physiological
studies that showed changes in electroencephalograms, cerebral blood flow, and
visual evoked potentials in patients with hypothyroidism. Hypothyroidism in older
adults without dementia has been shown to be associated with impairments in various
neuropsychological tests of learning, verbal fluency, visuospatial ability, and mental
status.
In subclinical hypothyroidism, a number of studies have shown an association
with poor cognitive function in young people, but such results in the elderly are
contradictory. Cook study S.E. (2002), including participants with subclinical
hypothyroidism and a mean age of 74 years, showed a decrease in verbal memory
and cognitive performance, but no deterioration in working memory and processing
speed. The PAQUID survey of people aged over 65 found that increasing TTH
significantly associated with the presence of depressive symptoms, but not with
cognitive impairment.
Despite the high prevalence of hypothyroidism, there have been only a few
randomized clinical trials that have examined the results of levothyroxine
replacement therapy. While studies among middle-aged individuals showed an
improvement in cognitive function in individuals with subclinical hypothyroidism
with the use of levothyroxine, in older people such a significant relationship was not
observed. In a double-blind, randomized, placebo-controlled study by Stott DJ et al.
(2017), showed no improvement in symptoms as measured by the Quality of Life
Questionnaire for subclinical hypothyroidism in patients with a mean age of
74.4 years taking an average dose of levothyroxine 50 mcg compared with those
receiving placebo.
On the other hand, recent data obtained by Recker is of interest. S. et al.
(2019). The aim of this study was to investigate the effect of levothyroxine on quality
of life in young (under 40 years of age) and elderly (over 60 years of age) people with
newly diagnosed untreated subclinical hypothyroidism (with TTH). more than
8 mcU/ml). The authors found a significantly lower level of quality of life in both
young and elderly patients with subclinical hypothyroidism compared to healthy
people of the same age. Higher follow-up scores were found in all patients regardless
of age, indicating a better quality of life on levothyroxine therapy. Questionnaire
analysis showed that older patients experienced less emotional lability and fatigue
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while taking levothyroxine, while younger patients reported fewer cognitive
complaints compared to baseline.
In a small population-based study, Arinzon Z. et al. (2007) in elderly patients
with subclinical hypothyroidism during levothyroxine therapy, along with cognitive
status and quality of life, lipid profile indicators were assessed. The authors
demonstrated that, in addition to lowering total cholesterol, low-density lipoprotein
cholesterol, and triglycerides, patients with hypothyroidism treated with
levothyroxine reduced blood pressure, body mass index, and improved cognitive
function and quality of life. Interestingly, the response to therapy was better in
patients with subclinical thyroid dysfunction than in patients with overt
hypothyroidism.
The selection of the dose of levothyroxine in elderly patients also has its own
characteristics and requires consideration of some factors. Dose of Levothyroxine to
Normalize TTH in serum, in elderly patients may be lower than in young people,
which is associated with a change in thyroxine metabolism due to an age-related
decrease in lean body mass. Other factors, such as reduced absorption, other
medications, and the presence of comorbidities, can also affect thyroid hormone
metabolism. Another feature that must be considered in the treatment of elderly
patients is low compliance. For example, according to a study by Kim S. et al.
(2018), 20–40 % of comorbid patients with thyroid pathology did not comply with
the drug regimen. Compliance with therapy is complicated by the fact that
levothyroxine is traditionally recommended to be taken in the morning
30–60 minutes before meals. However, studies have been conducted that have shown
that alternative administration of levothyroxine in the evening is not inferior in
effectiveness to the traditional regimen. Previous studies were conducted mainly in
groups of children and middle-aged people. Giassi K. et al. (2019) conducted a study
involving older people over 60 years old, but at the moment its results are not yet
available for review. It is known that the effectiveness of taking levothyroxine 60
minutes before breakfast and 60 minutes after dinner was compared.
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4. SOMATOTROPIC AXIS: CHANGE WITH AGE
Somatotropic axis — the hypothalamic-pituitary axis that produces growth
hormone (somatotropin) by pituitary somatotropes with subsequent stimulation of the
secretion of insulin-like growth factor-1 (IGF-1). Growth hormone is a single-chain
protein of 191 amino acids and belongs to the family of polypeptide hormones.
Secreted by somatotrophs of the anterior pituitary gland in a pulsed mode in response
to stimulation of somatotropin-releasing hormone, ghrelin, hypoglycemia, food
protein and amino acids (arginine, ornithine, lysine, glutamine). The secretion of STH
is inhibited in a feedback manner by IGF-1, as well as by somatostatin and other
neuroendocrine signals, including insulin, which act by binding to the appropriate
receptors. Although growth hormone is the main regulator of IGF-1 expression in the
liver, IGF-1 is also secreted by meso- and ectodermal tissues and acts autocrine and
paracrine. Insulin has also been shown to potentiate hepatic IGF-1 secretion in
response to growth hormone through activation of its receptors.
Growth hormone has a variety of functions: stimulation of bone growth,
regulation of carbohydrate, protein, lipid metabolism, metabolic function of the liver
and energy balance. At the cellular level, STH regulates cell growth, differentiation,
apoptosis, and cytoskeletal reorganization. The effects of this protein hormone may
be indirectly mediated through insulin-like growth factor 1 (IGF-1), a 70 amino acid
circulating peptide that is produced in the liver and other tissues in response to STH.
IGF-1-dependent effects of growth hormone include the regulation of growth,
carbohydrate and protein metabolism. The action of STH in target tissues can also be
direct, independent of IGF-1, such as stimulation of insulin secretion, lipolysis and
gluconeogenesis.
STH acts through a receptor known as the growth hormone receptor. It is the
only transmembrane protein in target tissues, consisting of 620 amino acids. Binding
of somatotropin to the receptor leads to receptor homodimerization, which seems to
be a prerequisite for the biological activity of the hormone, since receptor
dimerization precedes signal transduction, activation of intracellular signaling
pathways, and expression of a diverse set of genes, which allows STH to manifest its
pleiotropic effect. However, growth hormone and insulin-like growth factor 1 act
differently on glucose and lipid metabolism: STH blocks the action of insulin,
promotes lipolysis, and interferes with lipogenesis, while IGF-1 has the opposite
effect.
Decreases in growth hormone synthesis and secretion are characteristic of
normal aging in all mammalian species studied to date. The circulating peak of STH
29
and IGF-1 levels is characteristic of the second decade of life — a time of significant
cell proliferation and linear growth, then their concentration progressively decreases
by the sixth decade, reaching a low plateau. Accordingly, with a decrease in STH
secretion, there is a concomitant decrease in IGF-1 levels. This phenomenon is called
somatopause. In humans, as well as in other mammalian species, with age, a decrease
in activation of the STH/IGF-1 axis correlates with an increase in body weight and
visceral fat, a decrease in muscle mass, physical activity, immune system functions,
and concentrations of sex hormones (estrogens and androgens). Thus, the natural
decline in STH and IGF-1 levels, and the activity of the STH/IGF-1 axis, is the cause
of age-related degenerative changes. In this regard, in 1990 Rudman D. et al.
proposed recombinant human growth hormone as a potent anti-aging therapeutic
agent that positively affects body composition, bone mineral density and skin
thickness. Researchers have shown that administration of recombinant STH for 6
months returns changes in lean body mass and adipose tissue mass to levels
characteristic of younger people by an average of 10–20 years. The findings sparked
a buzz around recombinant growth hormone as an anti-aging agent, with some
proponents hailing it as a “fountain of youth”. Congenital deficiency of STH, which
is accompanied by dwarfism, significantly reduces life expectancy. These findings
have led to the widespread use of hormone therapy as an anti-aging treatment.
There is no doubt that the introduction of hormone replacement therapy in
individuals with growth hormone deficiency is important for health. However, there
are no good data on the benefit of restoring “young” levels of growth hormone to
endocrinologically healthy aging individuals. Thus, a debate arises as to whether this
decrease in general can be considered beneficial or detrimental for aging and agerelated diseases. Abnormally high levels of STH, characteristic of acromegaly, have
been shown to increase morbidity and mortality in both rodents and humans.
However, the data obtained on the effect of restored STH levels do not reveal all the
possible effects of increased STH levels on aging and the progression of age-related
diseases. While the benefits of STH administration are varied and well documented,
it is also clear that not all clinical outcomes of growth hormone restoration are
favorable. So it is reported that even low doses of recombinant STH increase the risk
of impaired carbohydrate metabolism, diabetes and mortality. In 2007, a metaanalysis of the use of recombinant STH in the elderly (mean age 69 years) found that
the drug had little benefit for body composition, but had large risks of developing
diabetes.
STH/IGF-1 axis has been shown to prolong lifespan in a wide range of species,
including worms, fruit flies, yeast, and mice. Caloric restriction, which is one of the
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most effective ways to increase lifespan in most species, also reduces the activity of
the STH/IGF-1 axis. Some studies also support an increase in human life expectancy
with reduced levels of STH and IGF-1. The results of such studies raise the question
of whether reduced activity of the STH/IGF-1 axis could be beneficial in extending
human lifespan.
Thus, two concepts, namely, high or low levels of growth hormone and IGF-1
slow down aging and increase life expectancy, are the focus of modern scientists.
Much new information about the effects of somatotropin has come from
studies of transgenic giant mice that were generated in several laboratories using a
then novel procedure for injecting cloned DNA encoding high production of growth
hormone into the pronuclei of mouse zygotes. Since the expression of the hormone
was stimulated by such promoters as metallothionein I or phosphoenolpyruvate
carboxykinase, STH in these mice was produced in large quantities throughout life in
various organs and tissues, primarily in the liver, kidneys and intestines. In addition,
the rate of STH secretion is not subject to the control of IGF-1 and the law of
negative feedback. Given the anabolic, diabetogenic, and lipolytic effects of the
hormone, transgenic mice were very thin and remained so throughout their lives,
unlike wild-type mice. The surprising giant phenotype of transgenic mice attracted
the attention of scientists, and therefore these animals have been and continue to be
used in numerous studies of the action of STH. During experiments, it was noticed
that transgenic mice are characterized by a reduced lifespan of about 30–40 %
compared to wild-type mice. Many physiological characteristics of these animals
strikingly resemble the symptoms of aging in genetically normal mice: kyphosis,
early decline in cognitive function and hypothalamic neurotransmitter metabolism,
graying of the hair, increased incidence of cancer. In addition, the anti-insulin activity
of STH leads to high insulin levels and the development of insulin resistance in
transgenic mice. Thus, a combination of insulin resistance and histopathological
changes in organs and tissues is a likely cause of premature death in these animals.
Acromegaly syndrome, which develops in humans as a result of excessive
production of STH by an anterior pituitary adenoma (somatotropinoma), has been
shown to be associated with an increased risk of hypertension, diabetes, and cancer,
as well as a reduced life expectancy, which together can be considered as signs of
accelerated aging. However, it should be noted that the acceleration of normal aging
is very difficult to distinguish from the various pathological processes associated with
high levels of STH in transgenic animals and in patients with acromegaly or
gigantism. This is why the above-described effects of growth hormone are not usually
taken as evidence that high levels of STH contribute to aging. However, despite the
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