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Файл:Age endocrinology. Study aid for students of medical universities
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5.1. CLINICAL MANIFESTATIONS OF ADRENAL AGING
Aging leads to a gradual decline in the functions of all human organs and
systems, including the adrenal glands. Inevitable clinical consequences include
changes in body composition such as loss of bone density, muscle mass and fat gain.
Such a transformation of the body may be associated with an increase in cortisol
levels with aging. Clinically, this can be manifested by cognitive impairment,
sarcopenia, osteopenia or osteoporosis, skin atrophy, etc.
The frailty syndrome is also associated with an increase in the daily level of
cortisol, which is a catabolic hormone, which explains weight loss, muscle loss and
anorexia. In contrast, lower daily cortisol levels have been found in centenarians.
Some of the most significant clinical manifestations of adrenal aging and
elevated cortisol levels are briefly discussed below.
Visceral obesity and muscle loss
Certain characteristic changes in body composition are observed in older
people. These include a decrease in total body weight, muscle mass and accumulation
of visceral fat, which lead to an increase in total adipose tissue mass and a decrease in
total muscle mass. The endocrine changes reflected in these rearrangements include
the aforementioned increase in cortisol levels (which is also due in part to an increase
in cortisol production by adipose tissue), insulin resistance, and a decrease in serum
testosterone levels. By the age of 80, the total muscle mass decreases by about 30 %,
sarcopenia develops — a geriatric syndrome that has serious medical and socioeconomic consequences. In particular, in a number of studies, muscle loss and fat
accumulation have been associated with increased urinary cortisol secretion. Ferrucci
L. et al. (2014) showed that a decrease in muscle mass and strength is partly due to
fatty infiltration of muscles, which leads to a change in their quality.
Diabetes
With aging, there are significant changes in glucose homeostasis due to a
decrease in insulin levels due to age-related dysfunction of β-cells and a gradual
increase in insulin resistance due to an increase in the amount of visceral fat, a
change in the ratio of adipose tissue and muscle mass, which, in general, is associated
with an increase in morbidity type 2 diabetes mellitus.
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Cortisol, as a catabolic hormone, significantly affects glucose metabolism.
Higher cortisol concentrations are associated with insulin resistance and increased
fasting glucose levels. It has also been demonstrated that the risk of developing type 2
diabetes in the elderly increases with an increase in the daily level of cortisol and a
change in its circadian secretion rhythm.
Osteopenia
One of the most obvious and inevitable consequences of aging is a decrease in
bone mineral density and deterioration of its quality due to an imbalance of two
simultaneous processes (formation and resorption of bone tissue), which leads to
osteopenia, osteoporosis and an increased risk of fractures. Excess cortisol during
aging contributes to the suppression of bone formation by stimulating apoptosis of
osteoblasts and osteocytes, and stimulating osteoclasts. The high affinity of
glucocorticoids to bone tissue is explained by the abundance of glucocorticoid
receptors on its cells.
The immune system
The immune system also undergoes age-related changes. So, there is atrophy of
the thymus, a decrease in the function of neutrophils, a decrease in the number of T
cells, a decrease in the production of antibodies by B cells. It should be noted that the
HPA axis plays one of the main roles in the changes in the immune system during
aging.
DHEA and cortisol modulate immune function but have opposite effects.
Although data remain conflicting, in general, cortisol plays an important role in
immunosuppression, while DHEA improves the immune response. Increasing the
cortisol/DHEA ratio may contribute to decreased immune function in the elderly.
Thus, the administration of DHEA preparations to elderly and senile patients may
have a beneficial effect on immune function, although this issue is not fully
understood. In addition to reducing stress, exercise lowers the cortisol/DHEA ratio,
thereby positively influencing the immune system.
5.2. ADRENAL AGING, BRAIN FUNCTION, STRESS RESPONSE
Chronological age is a significant predictor of the development of ageassociated chronic diseases. On the other hand, psychological stress appears to affect
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people's physical, mental and social health throughout life, and is a critical aspect in
promoting biological aging and the early development of age-related diseases. Over
the past decades, attention to the mechanisms of stress and the high incidence of
nosologies associated with it has increased all over the world. Evidence suggests that
there is a relationship between chronic stress and the development of depression,
anxiety, insulin resistance, dementia, and cardiovascular disease. However, the
mechanism of the detrimental effect of stress on organs and systems is not completely
clear.
The hippocampus (HC), prefrontal cortex (PFC), and amygdala (AMYG) are
key brain regions involved in stress. Stress, in turn, causes profound structural and
functional changes in them. HC is an important link between the cortex and the
hypothalamus, partly regulates the cortisol circadian secretion, has a general
inhibitory effect on the activity of the HPA axis, serves as the main central target of
stress hormones and is extremely vulnerable to them. The key function of the PFC is
to temporarily store information to control subsequent behavior. PFC dysfunction
leads to mental disorders. The dorsolateral PFC (DLPFC) is involved in conscious
emotion regulation, reduces feelings of fear, and is involved in negative feedback
regulation of the HPA axis. The medial (M) PFC is involved in the pathogenesis of
muscular dystrophy and schizophrenia, affects the activity of the HPA axis, and plays
a central role in emotion regulation and goal-directed learning. The MPFC is closely
related to the DLPFC areas and the limbic system, especially the AMYG. AMYG
plays a central role in threat detection and fear generation. Unlike HC and PFC,
which decrease in volume after chronic stress, AMYG increases, which explains the
increased anxiety. During an emotional stimulus, PFC controls AMYG. Successful
and adequate emotion regulation is associated with an increase in PFC activity and a
decrease in AMYG activity.
Aging is accompanied by a decrease and deficit of autonomy, general health
and social status, which entails increased stress. In addition, acute and chronic stress
are known to affect the functioning of the HPA axis, causing individual
neurophysiological effects and the development of stress-related diseases.
A number of studies have shown that age-related changes in the HPA axis
affect the health status of older people, mainly through the daily secretion of cortisol.
Elevated levels of glucocorticoids correlate with chronic stress, are associated with
changes in spatial memory, hippocampal function, and cognitive status. Negative or
traumatic experiences at an early age contribute to a person's susceptibility to chronic
stress and therefore predisposition to depression, anxiety and other chronic diseases.
HPA hyperactivity is also associated with higher levels of anxiety and increased
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symptoms of depression. A decrease in DHEA and DHEA-S secretion is common in
patients with major depressive disorder, while an increase in DHEA-S is associated
with aggressive behavior. Stress resilience is an example of an interaction between
endogenous and exogenous factors, and is associated with HPA axis activity, aging,
emotion regulation, and social resources (e.g., social support), which in turn affect
HPA axis function and vice versa. Higher levels of cortisol have been identified in
people with low social support and poor stress resilience, which in turn is associated
with an increased risk of chronic disease and multiple biopsychosocial consequences.
Therefore, it is necessary to timely develop measures and programs for medical and
social support for the elderly in order to increase emotional stability, resistance to
stress and reduce the disruption of the HPA axis.
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6. HYPOTHALAMUS-PITUITARY-GONAD AXIS:
CHANGE WITH AGE
The aging of the reproductive system in women is characterized by a gradual
reduction in the ovarian reserve, which for a long time goes unnoticed due to the
maintenance of regular, predominantly ovulatory cycles. Finally, when the number of
follicles becomes insufficient, cycle irregularity occurs (more than 7 days longer than
previous cycles), signaling the onset of the early phase of the menopausal transition
at a mean age of 46 years (range 34–54 years). Lengthening the cycle duration
beyond 60 days, periods of amenorrhea signals the transition to the late phase of the
menopausal transition, ending with the almost complete depletion of the follicles in
the ovaries. The last menstrual cycle (determined retrospectively after 12 months of
amenorrhea) is identified as menopause at age 51 (range 40–60). Changes in the
secretion of gonadotropins during the menopausal transition and postmenopause are
characterized by increased LH and FSH impulse amplitude and the absence of a
preovulatory gonadotropin surge, which is caused by a decrease in the production of
sex steroids, inhibin A and inhibin B by the ovaries. During the reproductive life and
menopausal transition, an age-related downward trend is observed production of
DHEA and DHEA-S in the adrenal glands; and production of testosterone and
androstenedione by the adrenal glands and ovaries. The clinical consequences of
multiple organ hormonal changes that occur during the menopausal transition and
postmenopause, such as altered vasomotor regulation, bone metabolism, urogenital
status, articular syndrome, increased risk of fractures, etc., are mainly due to a
decrease in estrogen secretion. Estrogen replacement therapy can effectively suppress
the above undesirable effects, but the risk-benefit balance must be determined
individually.
Men don't go through the equivalent of menopause. many have wellmaintained production of sex hormones and fertility into old age. However, aging
affects the male reproductive system. The volume of the testicle in men over 75 years
of age decreases by 30%, and the number of Sertolli cells also decreases. Changes in
sperm quality are characterized by a moderate decrease in ejaculate volume and
suboptimal mobility and impaired sperm morphology; increased DNA damage,
which contributes to age-related decline in fertility. However, although these changes
are associated with aging, they can also be caused by other factors such as obesity,
increased intervals between ejaculations.
In healthy men aged 75 years, there is a slow and gradual decrease in the
concentration of testosterone in the morning serum by 25 % compared with 25-year-
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olds, which is associated with a decrease in testicular secretion of the hormone and is
not fully compensated by a decrease in metabolic clearance. In addition, sex
hormone-binding globulin (SHBG) concentrations increase by approximately 1 % per
year, resulting in a faster decline in serum biologically active free testosterone
concentrations than total testosterone, by approximately 50 % by age 25 up to 75
years old. Serum concentrations of total and free dihydrotestosterone (20 % produced
in the testicles and 80 % converted from testosterone by 5α-reductase type 2 in
peripheral tissues), testosterone precursor androstenedione (produced in both the
testes and adrenal glands) also decrease with age. In addition, urinary excretion of the
metabolite androstenediol glucuronide (70 % converted from testosterone and 30%
from DHEAS) is also reduced. However, serum concentrations of estradiol with
aging do not generally decrease due to the aromatization of testosterone and
androstenedione in adipose and muscle tissues.
In response to a decrease in free and total testosterone, there is a progressive
increase in FSH and LH concentrations. In addition, body weight has a major impact
on the secretion of sex hormones, so overweight (BMI 25–29 kg/m2) in the blood
serum, the concentration of SHBG and total testosterone is lower than in normal body
weight, in obesity (BMI ≥30 kg/m2) the concentration of total and free testosterone
decreases as a result of hypothalamic dysfunction.
The relative contribution of aging, as well as clinical and subclinical
comorbidities, to changes in sex hormone secretion and function in older men
remains a matter of debate. Although many of the clinical signs of aging in older men
resemble those of hypogonadism in younger men, their association with sex steroid
concentrations is generally weak, and causation is difficult to explain. In addition,
clinical manifestations may be partly the cause, and not the result of changes in the
level of sex steroids. Low testosterone levels in the elderly have been proven to be a
sign of poor general health, sexual dysfunction, and are associated with a high risk of
death. Hormone levels for symptoms such as reduced libido and erectile dysfunction
are at the lower end of the reference range for young men, i.e. total testosterone
concentrations are below 320 ng/dL (11 nmol/L), and free testosterone is below
6–4 ng/L. dl (0–22 nmol/l). Of greater importance is the role of testosterone as a
precursor of estradiol, which has important physiological effects in men, such as the
effect on bone homeostasis. The positive effects of testosterone therapy on muscle,
bone, sexual function, and general well-being have only been described in older men
who initially had low testosterone levels. However, these benefits appear to be
modest, and long-term data on issues such as prostate and cardiovascular safety are
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lacking. Therefore, the administration of testosterone to older men without ruling out
an organic cause of hypogonadism is controversial.
Estrogens and androgens play an important role in the development,
maintenance of mass and function of bone and muscle tissues in men and women.
Sex steroid deficiency may contribute to age-related bone loss, possibly through
increased oxidative stress, effects on the immune system, increased glycation end
products, and inflammation. In older men, estrogen is the dominant sex steroid
regulating bone resorption, and both estrogen and testosterone are important in
maintaining bone formation. In men, low serum estradiol levels predicted accidental
fractures, but the highest risk was in men with additionally low testosterone levels
and high SHBG concentrations.
6.1. SEX HORMONES AND COGNITION:
IS THERE AN IMPACT?
The synthesis and secretion of sex steroid hormones (estrogens, progesterone
and androgens) are regulated by the HPG axis. Thus, the hypothalamus secretes
GRH, which stimulates the anterior pituitary gland to produce and secrete
gonadotropins (LH and FSH) into the bloodstream. LH stimulates the release of sex
steroids (androgens and estrogens) from the gonads. Peripheral sex steroids complete
the endocrine feedback cycle by inhibiting GRH release. It is well known that the role
of gonadal hormones goes beyond the regulation and development of reproductive
functions.
There is a relatively large database, mostly derived from rodent studies,
demonstrating that estrogens can influence cognition through effects on multiple
signaling pathways in the brain through activation both genomic (via ER-α and ER-β
estrogen receptors) and and rapid non-genomic mechanisms (through membranebound ER-α and ER-β and G-protein-linked estrogen receptors in cognitively
significant areas of the brain, including the hippocampus and prefrontal regions of the
brain. Estrogens promote the synthesis of neurotrophins; modulate cholinergic and
dopaminergic neurotransmitter systems and protect the brain stress and inflammation
Animal studies have provided evidence that exogenous administration of estrogen
(specifically 17β-estradiol, as opposed to estrone) can improve cognitive function,
especially in the areas of learning and memory. post-me therapy nopause showed that
estradiol administration was generally associated with a positive effect on verbal
working memory and attention, and it is believed that this effect is mediated through
the prefrontal regions of the brain.
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Like estradiol, progesterone has a trophic effect on brain development during
adolescence and adulthood. Estrogens and progesterones are thought to work together
to improve neuronal function through mechanisms such as synapse formation and
repair, increased synaptic transmission, and neuroprotective effects. Progesterone
receptors have also been found in cognitively relevant areas of the brain, including
the frontal lobe, hypothalamus, thalamus, hippocampus, amygdala, and cerebellum.
Animal studies evaluating the effects of progesterone administration in
ovariectomized rats show a beneficial effect on spatial cognition of progestins and
progesterone, dependent on the time of administration and the type of
progestin/progesterone. Studies of postmenopausal women taking hormone
replacement therapy and women of childbearing age taking birth control pills show
that the type of progestin is related to cognitive effects.
Gonadotropin levels, including LH and FSH, are also associated with cognitive
function and contribute to its decline. Endogenous LH may regulate learning and
memory through LH receptors, which have been identified in cognitively relevant
areas of the brain such as the hippocampus, or indirectly through the ability of
estrogen to regulate LH activity. Fewer studies have been done investigating the
relationship between FSH and cognition. Preliminary research suggests that there is a
positive relationship between FSH and cognitive performance.
Thus, the above data indicate the effect of sex hormones and gonadotropins on
cognitive functions.
6.2. CHANGES IN SEX HORMONES AND COGNITIVE FUNCTIONS
THROUGHOUT LIFE: PRENATAL PERIOD, PUBERTY, REPRODUCTIVE AGE
Sex differences in cognitive functions are widely discussed in the literature. So,
on average, men are superior to women in spatial abilities, and women are superior to
men in speech. It is important to note that these sex differences are based on average
data and do not apply to each individual separately.
is believed to begin in utero, when brain development in men and women
occurs in response to androgen production, but with some differences. The male fetus
shows an increase in testosterone levels between 8 and 24 weeks of gestation, and a
less pronounced increase in testosterone levels approximately 3 to 4 months after
birth. During the prenatal period, testosterone levels in male fetuses are 2.5 times
higher than in female fetuses, and this is considered a “critical window” in which
hormones can influence brain development, forming the basis for cognitive
functioning.
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It is hypothesized that prenatal androgens influence brain lateralization and
behavior, with males developing right hemisphere dominance, which may aid spatial
task performance (given that visuospatial cognition is associated with greater right
hemisphere involvement). Several hypotheses have been proposed to explain how
prenatal androgens contribute to right hemisphere dominance, collectively suggesting
that increased prenatal testosterone exposure contributes to slower left hemisphere
development with compensatory or enhanced right hemisphere development. A metaanalysis examining the strength of the main hypotheses associated with prenatal
exposure to androgens on brain lateralization found that the available evidence
remains insufficient and further research is needed. Support for the idea that prenatal
androgens enhance spatial ability comes from studies of groups of people with
hyperandrogenemia and healthy people. Thus, women with congenital adrenal
hyperplasia (CAH), a condition characterized by prenatal overproduction of
androgens by the adrenal glands, have an advantage in spatial thinking compared to
men with CAH, which may be due to the fact that there are optimal levels of prenatal
androgens for the development of this function. Female and male fraternal twins also
exhibit superior spatial abilities, which are related to intrauterine androgen action. It
is believed that prenatal androgens are also involved in shaping male-pattern behavior
and may therefore indirectly influence mental rotation abilities by influencing early
childhood interests. Therefore, the advantage of men in the dominance of the right
hemisphere may be due to the influence of sex hormones.
The second stage of sex hormone-dependent neuronal organization occurs
during adolescence. After the first year of life, the HPG axis remains in an inactive
state until the onset of puberty (gonadarch). Schulz K.M. et al created a two-stage
model suggesting that gonadal steroid hormones can affect the developing brain both
in the prenatal period and during adolescence. They suggest that prenatal and puberty
are periods during which gonadal hormones rise and play a role in brain organization
through mechanisms such as cell proliferation and survival, and synapse formation
and removal. Empirical research examining the association of puberty and sex
hormones with cognition and brain development is limited. Herting M.M. et al in a
study of 126 adolescents (63 girls) showed that sex hormones, regardless of age, are
unambiguously associated with changes in the volume of the cerebral cortex and
subcortical structures. The greatest changes in the volume of the cortex and subcortex
were seen at the beginning of puberty, with lesser changes at the end. Changes were
also specific to sex and brain region (for example, testosterone was associated with a
decrease in right amygdala volume, seen in boys but increased in girls). An analysis
of structural and functional neuroimaging studies associated with puberty revealed
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sex differences and the effect of gonadal hormones during puberty on amygdala (and
to a lesser extent hippocampal) volume. Puberty has also been associated with an
increase in white matter density/volume, especially in the frontal and temporal lobes,
as well as in the cortical-cortical and cortical-subcortical association tracts that link
these areas.
A number of authors have studied the relationship of puberty (assessed
retrospectively) with cognitive abilities in young people. They demonstrated that the
time of puberty was not associated with cognitive functions in women, but in men, on
the contrary, it is clear.
For women of reproductive age, studies of the menstrual cycle and the use of
contraceptives provide an opportunity to further study the effect of endogenous and
exogenous levels of sex hormones on cognitive function. For women, the average
length of the menstrual cycle is 25 to 31 days. As a rule, the first seven days of the
menstrual cycle (early follicular phase) are characterized by low levels of estradiol
and progesterone in the blood serum. Estradiol levels then rise rapidly during the
second week of the cycle (late follicular phase) to a pre-ovulatory estradiol surge
followed by an LH surge that is a precursor to ovulation (marking the middle of the
cycle). The luteal phase (often divided into early and late) is the time from the LH
surge to your period. Progesterone levels rise during the luteal phase and peak around
day 21 (on a standard 28-day cycle) and gradually fall. The dominant theory in
research on menstrual cycle phases and cognition suggests that the early follicular
phase (low estrogen, low progesterone) is associated with better measures of malespecific cognition, such as spatial ability, and cycle phases with elevated estrogen
and/or progesterone (for example, late follicular or mid-luteal), is characterized by an
improvement in the cognitive abilities inherent in women, such as speech fluency and
verbal memory.
Sundstrom Poromaa I.; Gingnell M. reviewed 13 studies that assessed verbal
ability in relation to cycle phases, and while most studies (9 of 13) found no effect of
phase, 4 studies showed an association between an early follicular or low estrogen
phase and improved measures of spatial reasoning. Women with polycystic ovary
syndrome (PCOS), a condition characterized by elevated testosterone levels, also
performed better on spatial reasoning tasks than female controls. Therefore, current
evidence does not support a significant effect of the phases of the menstrual cycle on
cognitive function, although circulating testosterone levels may be associated with
mental performance.
Research on contraceptives provides an opportunity to study the effects of
exogenous hormones on cognitive function in women of reproductive age. Oral
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