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1
The Endocrinology
of Aging
MJ Rasaee
TMU 2022
Tehran
What is Aging?
2
GENERAL-hormone production altered
THYROID- decreased secretion
THYMUS-involution of thymus gland
CORTISOL- decrease anti-inflammatory hormone
PANCREAS- decrease secretion of enzymes & hormones
The gradual and spontaneous changes that occur in maturation from infant to young adult. These changes create a normal physiologic decline seen
in middle and late adulthood.The process by which a cell looses its ability to divide, grow, and function. This loss of function ultimately ends in death.
Biological clocks act through hormones to control the pace of aging. Hormones effects growth, metabolism, temperature, inflammation and stress.
Aging is not a disease
3
Overall, some hormones are decreased, some unchanged, and some increased
with age.
Hormones that are usually decreased include:
 Aldosterone
 Calcitonin
 growth hormone/insulin-like growth factor I axis (in somatopause)
 Renin
 Melatonine
 In women, estrogen (in menopause )and prolactin levels usually decrease.
 Testosterone (in andropause) levels usually decrease slightly as men age.
 Dehydroepiandrosterone and its sulphate (in adrenopause)
Hormones that may increase include:
 Follicle-stimulating hormone (FSH)
 Luteinizing hormone (LH)
 Norepinephrine
Hormones that remain unchanged or only slightly decreased include:
 Cortisol
 Epinephrine
 Insulin
 Parathyroid hormone
 Thyroid hormones T3 and T4
 25-hydroxyvitamin D
4
5
Endocrine, Physical, sexual, psychological.
Endocrine Symptoms:
 erectile dysfunction
 Increased abdominal fat/increased waist
size
 decreased vigor
 fatigue
 poor exercise tolerance
 diminished strength and muscle mass
 decrease in bone mineral density
 decreased body hair
Sexual Symptoms:
 decreased libido
 decreased sexual activity
 limited quality of orgasm
 reduced ejaculate strength
 reduced ejaculate volume
Psychological Symptoms:
Mood changes
Poor concentration
Loss of motivation
Reduced initiative
Memory impairment
Anxiety
Depression
Irritability
Insomnia
General reduction in intellectual activity
Poor work performance
6
The circulating levels of dehydroepiandrosterone (DHEA) and its
sulphate (DHEAS), which gradually decline with age, resulting
adrenopause.” The decline in DHEA(S) levels in both sexes contrasts
therefore with the maintenance of plasma cortisol levels and seems to be
caused by a selective decrease in the number of functional zona
reticularis cells in the adrenal cortex rather than regulated by a central
(hypothalamic) pacemaker of aging.
Steroidogenic acute regulatory protein (StAR) controls adrenal and
gonadal steroidogenesis. It was recently shown unequivocally that StAR
mRNA and protein are expressed within glia and neurons in discrete
regions of the mouse brain. Neurosteroids synthesized in the CNS appear
to attenuate age-relate memory and learning impairments.
The beneficial effects of PS and DHEA sulfate on age-related learning
and memory deficits appear to be mediated by NO-dependent pathway.
To determine whether the mechanism of attenuation was mediated
through the nitric oxide (NO) synthase (NOS) signal transduction
pathway, mice were pretreated with the NOS inhibitor, NG-nitrol-
arginine methyl ester (L-NAME). L-NAME inhibited the beneficial and
antiamnesic effects of PS and DHEA sulfate, and the effect of L-NAME
was blocked by the competitive substrate for NOS, L-arginine.
The adrenopause
7
 During aging, GnRH levels declined. but the number of
neurons expressing ppGnRH mRNA remained constant.
Aging had no effect on pituitary responsiveness to GnRH.
Despite this similar LH response, the stimulatory effect of
LH on testosterone production declined, LH circadian
rhythmicity was blunted, and testosterone levels over 24 h
declined progressively with age.
 Hence, deficits in testicular function during aging is
attributable, at least in part, to decreased GnRH rather than
decreased responsiveness of the anterior pituitary gland to
GnRH; this property and the attenuated circadian
rhythmicity of LH and testosterone secretion are
reminiscent of age dependent changes in the GH axis.
 Aging also has impact on the opioid control of
gonadotropin secretion. Naloxone (opiate antagonist)
produced a significant dose-dependent increase in the
release of GnRH from the hypothalamic tissue fragments
that was age dependent. These results suggest that age-
related changes in endogenous opioid systems likely
contribute to differences in secretion of GnRH, which in
turn affects the dynamics of LH secretion and testosterone
production.
8
• Excitatory amino acids also regulate pulsatile secretion of
hypothalamic GnRH and LH.
To explore the significance of aging on this pathway, the
effects of GnRH and the glutamate receptor agonist NMDA
on gonadotropin and prolactin release were investigated in
prepubertal,young, middle-aged, and old rats. The release of
gonadotropins in response to GnRH was not age dependent,
and NMDA increased LH, FSH and prolactin secretion in all
age groups. However, the NMDA enhancement of LH, FSH,
and prolactin release was lowest in old rats. To investigate
whether the reduced LH response to NMDA in old rats
occurred at the hypothalamic level, the direct effects of
NMDA on GnRH release were evaluated in tissue fragments
from the preoptic medial basal hypothalamus.
The magnitude of GnRH release from these fragments was
inversely related to age, and determination of amino acid
content showed that aged animals had the lowest
concentrations of glutamate, taurine, and GABA. Hence, the
attenuated responsiveness of GnRH neurons to NMDA and
reductions in excitatory amino acids likely contribute to the
diminished pulsatile LH secretion typically observed in old
rats.
Pathophysiology of Andropause
Hypothalamus
Pituitary
Testes
Reduced Leydig cell number
Impaired Leydig cell function
Lower GnRH pulse amplitude
Attenuation of diurnal pulsatility
More sensitive to negative feedback
T
E
The decline in testosterone as men age results in part from a reduction in Leydig cell number to be 44% lower in men between the ages of
50 and 76 when compared to the men who were aged 20 to 48 years. decline in age related steroidogenesis results from a reduction in
steroidogenic enzyme activity and a decrease in cholesterol transfer to the mitochondria. It has been demonstrated that older men have a
subnormal testosterone response to beta HCG as well as recombinant LH administration. In older men with low T, LH levels may
increase, but usually remain within the normal range. Overall, studies suggest heightened sensitivity of the hypothalamus to negative
feedback as men age. Studies have also provided evidence of reduced GnRH amplitude as men age. Moreover, the normal circadian
pattern of GnRH secretion is attenuated with aging. FSH on the other hand is regulated neg by testis inhibin as well as GnRH. Inhibin
production decrease with aging and in all forms of testis failure. Thus FSH levels tend to be elevated to a greater extent than LH in
older men with low T.
9
10
Controlled trials of testosterone therapy in elderly males with low-normal testosterone levels
Age (years) Baseline T
(nmol/l)
T
administratio
n
Duration
(months)
Effects Side-effects
12.7 2.7 (SD)
[T <16.5]
Testosterone
(Testoderm,
scrotal patch)
6 mg/24 h
36 Lean body
mass -
,perception of
physical
functioning ,fat
mass. No
overall effect
on muscle
trength, BMD
(spine and hip),
lipids, and
bone markers
PSA (from 1.5
to 2.0
ng/ml) Hct
(>52% in
3 out of 54
subjects)
51 (22-78) 2.7 2.7 (SD)
[T <8.7]
Testosterone
(Testoderm,
scrotal patch),
6 mg/24 h
36 Libido, BMD
(L2-L4)
No effect on
muscle
strength, BMD
(hip), and
lipids
Hct (>52% in
1 out of
18 subjects) No
change
in PSA
76 ± 4 13.5[6.0]
[BT <4.4]
Testosterone
(transdermal
patch) 5.0
mg/day
12 Femoral BMD
, lean
body mass ,
body fat ¯
No effect on
muscle
strength
PSA (from 2.0
to 2.6
ng/ml) No
effect on Hct
11
Testosterone levels decline by about 100 ng/dL
per decade.
higher rate of ‘prostate events’ with
testosterone treatment.
GH levels decline by about 14% per decade, but
the risks of GH therapy outweigh the benefits
in non-GH-deficient people.
Although serum levels of many hormones
decline with age, additional research is needed
to prove that these declining levels are
pathologic and that hormone replacement
actually affects the aging process.
Testosterone Decrease in fat mass and increase in lean
mass and bone mineral density Mixed data
on the effect on cognition.
Dehydroepiandr
osterone
Inconsistent data on muscle mass, fat mass,
and strength. Insufficient evidence for
improvement in cognition.
Growth
hormone
Increase in lean body mass; decrease in fat
mass. Increase in bone mineral density.
Increase in mortality.
Vitamin D May improve muscle function
HORMONAL THERAPY  Testosterone replacement also has the
potential to inhibit neurodegeneration by
maintaining expression of BDNF
in the aging brain.This is particularly important
because of the importance of BDNF in
maintaining noradrenergic
innervations during aging as well as its proposed
significance in Parkinson’s disease and AD.
12
 Hormonal decline may be the most important
major contributor to aging. Physical changes during
aging have been considered physiologic, but there is
evidence that some of these changes are related to this
decline in hormonal activity.
 For men - it is so gradual that men often reach their
mid-forties or fifties without noticing the negative
changes that have taken place in their body.
 For women - hormonal changes can begin as early
as the mid to late thirties. The decline in hormones for
men is more gradual unlike in women’s menopause, which
is a more abrupt event.
In women, the amount of TSH produced does not decrease
with time, but it does in men.
With aging, the thyroid often becomes lumpy (nodular)
Metabolism gradually declines, beginning around age 20.
Less thyroid hormone may be produced, but there is also
less body mass (because of loss of muscle and bone tissue).
This means that thyroid function tests usually show results
within the normal range.
13
The somatopause
• Pituitary function, LH, FSH, and TSH decline
with age. therefore, that GH also has been
reported to decline with age beginning in the
third decade. This decrease is associated with
decreased insulin-like growth factor
concentrations. Pathologically decreased GH
is associated with decreased concentrations of
gonadal steroids in serum. Thus,
pathologically decreased GH is associated
with increasing fat, decreasing muscle mass,
and decreasing bone mass, all of which are
seen as age increases.
14
Body
fat
Lean body
mass
Strength Skeleton Cholesterol
Estrogen
deficiency in
healthy
women
no effect — —
Testosterone
deficiency in
healthy men
GH deficiency
in
healthy
individuals
15
It is now well established that there is a physiological decline in food intake over the
life span. This has been termed the anorexia of aging hormones play a major. This
physiology of aging represents a major reason why older persons have a greater
propensity than younger ones to lose weight when they have a disease. Older persons
tend to have early satiation. This is due to two factors.
1. decrease in compliance of the fundus of the stomach with aging.
This occurs because food fails to cause appropriate release of nitric
oxide to relax the smooth muscles of the fundus.
2. CCK is a potent satiating agent. Older persons produce more CCK in
the duodenum both basally and in response to fat. The increase in
CCK is predominantly due to slower clearance in older persons than in
younger persons.
Leptin is anorectic and increases metabolic rate. Thus, it is a catabolic hormone.
Men develop a greater physiological anorexia of aging than do women. Beyond the
age of 70, fat mass declines in men. This would be expected to lead to a decline in
leptin levels, but a longitudinal study showed that leptin levels increase in older men.
This increase in leptin levels was related to the fall in testosterone levels that occurs
with aging.
Ghrelin Recently a peptide hormone called ghrelin was isolated from the fundus of
the stomach. Ghrelin causes the release of growth hormone and an increase in
feeding. Ghrelin or an analog appears to have potential as a therapy for the anorexia
of aging.
16
thyroid function is imperative for normal
development in human aging.
cretinism, deficiencies in iodine and thyroid,
the link between thyroid hormones
and cognition.
At any age, low thyroid function is also
associated with cognitive decline, since
hypothyroidism is associated with brain hypo
metabolism.
In the aging population, low uptake of
glucose associated with Alzheimer’s disease
and may even present decades prior to any
clinical symptoms of neurodegeneration.
cognitive decline product of the aging
process and physiological effects in thyroid
function
With aging there is:
 a decline in thyroxine production rate
 small decline in triiodothyronine (T3) levels
 Thyroid stimulating hormone (TSH) levels are
increased
antibodies to thyroid peroxidase increase with aging.
 There is emerging evidence that, with aging, thyroid
hormone tends to be less capable of activating a number of
postreceptor biomarkers of thyroid function.
Excess and deficiency of thyroid hormone are two classical
examples of atypical presentation of disease in older
persons. Thus, early hypothyroidism is a biochemical
diagnosis in older persons.
Older persons often develop the low T3 syndrome or the
euthyroid sick syndrome. In these persons, T3 is markedly
decreased and thyroxine may be normal or decreased. TSH
levels may be decreased, unchanged, or increased. There is
no evidence that thyroid replacement improves outcomes in
this condition.
These abnormalities are mainly caused by autoimmunity and
are therefore an expression of age-associated disease rather
than a consequence of the aging process.
17
18
With ageing as well as body weight, thyroid volume increases slightly.
Other factors, : cigarette smoking, chronic kidney disease, acute hepatic disease, and seasonal changes, increase thyroid volume.
no age-related changes of serum free and total T4 levels.
In aging, nocturnal pulses of TSH secretion in comparison to their younger counterparts
since aging TSH secretion, this effect is counter balanced, leading to unchanged T4 levels.
T3 levels also remain stable with aging.
Malnutrition and chronic illness important confounders in assessing thyroid function in the elderly.
Both cause serum T3 levels in absence of thyroid disease
other non-thyroidal illnesses with aging can decrease T4 conversion to T3
medications an important role in thyroid function in the elderly.
Lithium (hyperthyroidism), amiodarone (hyperthyroidism), estrogens and glucocorticoids (thyroid binding globulin status) can affect thyroid
function.
with age, increased prevalence of anti-thyroperoxidase and anti-thyroglobulin antibodies, especially in females above 60 years of age.
in centennials ، thyroid antibodies are rare in comparison to hospitalized patients
decrease in free T3/free T4 ratio with age in males, but not females, suggesting impaired T4 to T3 conversion in males.
increase T3 resistance index with age in males, but not females.
elevated TSH levels with age along with normal T4 levels a question about subclinical hypothyroidism
Ischemic heart disease and its association with thyroid function: any association
19
prevalence of ischemic heart disease in individuals with subclinical hypothyroidism is
higher in younger compared to ages 65 and older
treatment of subclinical hypothyroidism has been shown to be associated with fewer
events of ischemic heart disease in the younger but not in older than age 70.
inverse correlation between subclinical hypothyroidism and ischemic heart disease.
These indicate TSH levels play a cardiovascular protective role.
high TSH levels and low T4 levels associated with a lower mortality survival
centenarians have significantly higher median serum TSH levels and lower T4 levels
compared with control group of thyroid disease-free individuals (median age of 68 years).
Hyperthyroidism, is not as common as hypothyroidism, but its prevalence does increase
in the elderly.
Depending on iodine intake in the given area, Grave’s disease and toxic multinodular
goiter are most common causes.
lower metabolic rate caloric restriction improve mortality rates in animals
20
Thyroid hormone regulates metabolism via adrenergic stimulation
and glucose uptake. It plays a role in mitochondrial gene expression,
affecting mitochondrial oxidation in skeletal muscle. Effects of
hypothyroidism with aging can lead to lipid accumulation.
compromising metabolic activity. This can result in insulin resistance
and other features of metabolic syndrome. increased metabolic rate
has shown to cause early mortality by accelerating aging.
Basal metabolic rate usually declines with aging indicating a healthier
functional status and low energy requirements for maintaining
homeostasis. basal metabolic rates in the young and older individuals it
has been shown that the higher the metabolic rate in the younger
predictability the higher mortality. independent of other risk factors such
as body mass index, smoking status, daily physical activity, blood
pressure and diabetes In older individuals who fail to down regulate the
metabolic rate with age usually have poor health status and shown to
have higher risk of mortality.
atrial fibrillation due to hyperthyroidism is higher in the elderly but
other symptoms such as heat intolerance, tremors, and ocular
manifestations are less frequent .Non-thyroidal illness, fasting, and
drug-induced causes must be ruled out before making the diagnosis.
Pathophysiology of diabetes mellitus in older persons
The prevalence of type 2 diabetes is age-related. As age increases, on average, a small
increase in fasting hepatic glucose output is reported, with impairment of non-insulin-
dependent glucose disposal. In addition, insulin secretion is impaired with age, with less
insulin being released in the early and late phase after challenges. insulin resistance
increases with age. Other endocrine changes, particularly in adrenal function with age, may
also play a role in this process . In addition, dietary intake, activity, and body composition
alter with age and may play a role in increasing insulin resistance in older individuals.
21
The sex steroids, dopamine,
oxytocin, and 5-HT regulate
sexual behavior through
actions in the CNS. Because
the production of these
hormones and
neurotransmitters declines
during aging, it is hardly
surprising that aging is
commonly associated with a
decline in libido and sexual
performance.
Sexual Behavior and Aging
Adrenal Function
Adrenal medullary function and baseline serum
epinephrine and norepinephrine concentrations
apparently increase with advancing age. the
increasing incidence of type 2 diabetes and peripheral
insulin resistance undoubtedly is exacerbated by the
constant increased basal concentrations of epinephrine
and norepinephrine.
Adrenal cortical function also appears to increase
with age. Thus, mean glucocorticoid and
mineralocorticoid serum concentrations are higher
in older compared with younger individuals. The
target organ for mineralocorticoid activity (kidney),
however, becomes less responsive as age progresses,
and sodium losses become more fixed as age
progresses.
Increased basal adrenal medullary and cortical activity
reduces the functional reserve for either epinephrine/
norepinephrine or steroid hormones. This
circumstance provides less ability to respond to stress,
corresponding to an initial frailty syndrome. 22
Decreased skeletal mass associated with increasing age is
the result of a series of changes associated with aging:
 Calcium absorption/transport in the intestinal mucosa
decreases with age
 calcium intake also generally decreases with age
 Renal function, including 1-α- hydroxylase activity,
decreases with age
1- α -Hydroxylase catalyzes the conversion of 25OHD to
1,25(OH)2D, the active metabolite of vitamin D.
Decreased 1,25(OH)2D leads to further diminution of
vitamin D sensitive calcium absorption.
decreasing calcium absorption from the gut:
(a) decreased calcium intake
(b) decreased calcium absorption
(c) decreased vitamin D-dependent calcium absorption
(d) The result of decreased calcium absorption is
increased dependence on skeletal calcium as a source
of needed calcium
Other changes related to age occur in mineral metabolism.
As renal function declines with age, PTH increases.
Increasing PTH is associated with increased osteoclastic
and osteoblastic activity. Such increased activity is
probably associated with more rapid loss of bone.
Skeletal/Mineral Metabolism
23
Glucocorticoid Hormone
glucocorticoid secretion shows a strong 24-h rhythm with peak concentrations in the early morning and a trough in the late
afternoon. Glucocorticoids are known to play a role in the regulation of peripheral glucose mobilization and metabolism.
cortisol is essential for cognitive appraisal and affects numerous cognitive domains, including attention, perception, memory,
and emotional processing in humans. Glucocorticoids play an important role in many neural functions that are mediated by
classic genomic effects via intracellular glucocorticoid receptors or nongenomic mechanisms.
Cortisol also participates in energy metabolism and gene expression in the brain, and it coordinates behavioral adaptation to
the environmental and internal conditions through the regulation of many neurotransmitters and neural circuits. A progressive
increase in levels of circulating cortisol occurs with increasing age, as well as in brain degenerative processes, for instance in
Alzheimer’s disease. This has been interpreted as a malfunction of the hypothalamo-pituitary-adrenal axis, and, according to
the glucocorticoid-cascade hypothesis, is considered as a main agent of injury to the hippocampus and to lead to the
cognitive impairment of the elderly, and as an added pathogenic factor in brain degeneration.
Cortisol may affect the intracellular concentrations of Ca2+ by membrane receptors or ion channels, which is one of the
important accessory factors in axonal transport. It has been shown that increasing free intracellular calcium may induce the
phosphorylation of tau proteins, which belong to the family of MAP, and influence the axonal transport. Glucocorticoid
resistance exists in AD brain, and is related to the degree of neuropathological changes, suggesting that glucocorticoid
resistance in AD brain may contribute to neuroendocrinal changes, neuropathological mechanisms and dementia.
Glucocorticoid resistance in AD may disturb not only the neural functions but also the negative feedback regulation via
different brain areas such as hippocampus and result in an activation of the HPA-axis and contribute to the pathogenetic
process of AD and induce cascade changes, such as the loss of neuronal Ca2+ homeostasis, abnormal production and
degradation of amyloid β-peptide (Aβ), development of NFT and neuronal degeneration. A potential injury to the hippocampus
has been postulated by the “glucocorticoid cascade hypothesis” as deriving from the life-long exposure to the stress
glucocorticoid hormone.
Examples of neurodegenerative disease:
• Alzheimer’s disease
• Parkinson’s disease
• Frontotemporal dementia
• Amyotrophic lateral sclerosis
(Lou Gehrig’s disease)
• Spinocerebellar ataxia
• Huntington’s disease
24
Alzheimer’s disease is an irreversible, progressive brain disease that slowly
destroys memory and thinking skills. Once considered a rare disorder, is now seen
as a major public health problem that is seriously affecting millions of older
population . Although the risk of developing AD increases with age – in most
people with AD, symptoms first appear after age 60 – AD is not a part of normal
aging. It is caused by a fatal disease that affects the brain.
25
 estrogens have neuroprotective effects, including inhibition of
β-amyloid formation from its precursor protein. This may be
due partly to reduced accumulation of reactive oxygen and
nitrogen species.
 Glucocorticoid-induced hippocampal neuronal damage also
seems to be reduced.
 Neuroimaging studies in humans have implicated that estrogen
influences the pattern of brain activation during memory
processing, with regional increments in cerebral blood flow
and glucose metabolism and with modulation of activity in
specific brain regions affected during the early stages of AD.
This may be partly related to direct effects on cerebral blood
flow by estrogens.
 Epidemiological studies have suggested that estrogen is
protective against the development and/ or progression of
neurodegenerative disorders. Thus, low circulating levels of
estrogen have been associated with an increased risk of AD.
 The estrogen β-receptor ERb has a clear role in the
development of the cerebral cortex and also in survival of
hippocampal neurons after exposure to excitatory
neurotoxins.
 In contrast, Era is the major receptor subtype expressed in
basal forebrain cholinergic neurons. Thus, estrogen probably
acts via ERa to enhance cognitive functions through the
production of acetylcholine. On the other hand, ERb is the
only estrogen receptor expressed in the dorsal raphe nucleus
suggesting important effects on the serotonin system,
indirectly affecting neuronal plasticity.
Altered CNS function appears to precede the metabolic,
reproductive, and cognitive deficiencies associated with
aging. neuroendocrine changes characterized by:
altered biological rhythms
reduced amplitude
altered frequency, and decreased orderliness of hormone,
neuropeptide, and neurotransmitter release.
Decline in activity of the brain during aging. The
amplitude of release of neurotransmitters and
neuropeptides declines and the rhythms of release
become more erratic. Experiments using tissue
transplants from fetal brain and administration of L-
dopa and GHS-R ligands show the feasibility of
reversing certain aspects of aging through
therapeutic intervention.
26
Senile plaques
• Extracellular deposits
• Plaques described as “diffuse”,
“neuritic”, or “cored”
• These may represent different ages of
plaque
• Neuritic plaques are one of the
pathologic criteria for diagnosis of
Alzheimer’s disease
• Composed chiefly of beta amyloid
Beta amyloid is a 39-43 amino acid peptide
Derived from 700 amino acid amyloid precursor
protein (APP), may be processed to “amyloidogenic”
or “non-amyloidogenic” pathways
Beta amyloid
27
In the menopausal transition, menstrual cycle regularity is progressively lost due to
insufficient numbers of FSH-sensitive follicles present at any time in the ovaries .
Cycles become persistently shorter first, due to advanced dominant follicle selection with
shorter duration of the follicular phase. Later, cycles may also become lengthened with
delayed initiation of dominant follicle growth or anovulatory bleeding after estrogen
withdrawal without evidence of corpus luteum function.
The complete loss of cyclic ovarian follicular activity is defined as the final menstrual period
followed by 12 consecutive months of amenorrhea (menopause).
1. Hot flushes are a sensation of warmth, often accompanied by skin flushing and
sweating. Hot flushes are thought to be related to the rate of oestrogen withdrawal and
the resulting vasomotor instability.Many women experience palpitations, or a sensation
of pressure within the head, frequently accompanied by weakness, fainting or vertigo
before the flush begins. Treatment (Hormone replacement therapy, Clonidine,
Progesterone)
2-Urinary incontinence
The lining of the urethra is responsive to oestrogen, and the postmenopausal fall in oestrogen
results in physical changes that can increase rates of urinary incontinenceTreatment (Pelvic
floor exercises and bladder training, Hormone replacement therapy)
3-Vaginal atrophy
4-Mood, depression and cognitive function
Frequent hot flushes and the resulting insomnia .declining oestrogen levels.Midlife is often a
time of social and emotional upheaval
5-wound inflammation :roles of estrogens
6-increased prevalence and severity of atherosclerosis :antiatherosclerotic properties of
estrogens
7-osteoporosis :decrease in Inh B level
28
• The reproductive aging process is thought to be dominated by a gradual decrease in
both the quantity and the quality of the oocytes residing within the follicles present in
the ovarian cortex.Menopause is the final step in the process referred to as ovarian
ageing. The age related decrease in follicle numbers dictates the onset of cycle
irregularity and the final cessation of menses.
• At the fourth month of fetal development, the ovaries contain some 6–7 million
oocytes surrounded by a layer of flat granulosa cells to form the primordial follicle
pool .
• Due to a rapid loss of the great majority of the primordial follicles via apoptosis in the
second half of fetal life, at birth only 1–2 million primordial follicles remain.
• After birth, this high rate of follicle loss slows down somewhat, so that at menarche at
least 300,000 to 400,000 primordial follicles remain.
• below 1000 at the time of menopause
• Along with the decrease in follicle number, oocyte quality also diminishes (at least
after the age of 31 yr).
• The loss of oocyte quality is believed to be due to:
1- an increase in meiotic nondisjunction,
2-resulting in an increasing rate of aneuploidy in the early embryo at higher female ages.
3-accumulated damage of oocytes in the course of a woman’s life
4- age-related changes in the quality of the granulosa cells surrounding the oocyte.
Despite the profound changes in numbers and quality of follicles during the third
and fourth decade of life, the process of ovarian aging remains largely unnoticed.
From several sources, it has become clear that monthly fecundity gradually
decreases from the mean age of 30 yr onward.
Number of primordial follicles present in the ovaries
and the chromosomal quality of oocytes in relation to
female age and corresponding reproductive events.
A number of terms including ‘climacteric’,
‘perimenopause’, ‘menopausal transition’,
‘postmenopause’ and ‘menopause’ have been
used to refer to the stages of reproductive
aging surrounding the final menstrual period
(FMP).
The first standardized classification
guidelines for female reproductive aging were
proposed in 2001 at the Stages of
Reproductive Aging Workshop (STRAW).
The stages were nominated using the FMP as
a reference point, and were based on changes
in the pattern of menstrual cycles levels of
follicle-stimulating hormone (FSH).
The STRAW criteria
29
The Stages of Reproductive Aging (STRAW) criteria
The proposed STRAW criteria were deemed unsuitable
for application in women who: smoked, were obese or
underweight (body mass index <18 or >30), participated
in intense regular physical training, had chronic
menstrual irregularities ,had abnormal reproductive
anatomy
30
Fecundity per cycle according to female age. Mean rate for women aged 20–30 was
scaled as 1.00. For a woman aged 33 yr, the relative rate of 0.75 indicates that she has in
each cycle 75% of the chance of a woman aged 20–30 of getting pregnant.
31
higher risk of cardiovascular disease
elevated serum triglycerides
prothrombotic effects
increased hepatic synthesis of
vascular inflammatory markers
risk of stroke increases,
venous thromboembolism increase
Estrogen treatment in women with severe
postmenopausal symptoms.
Estrogen :orally or topically, with transdermal
patch, or intravaginally.
Low-dose estrogen in relieving hot flashes.
first The lowest dose to decrease adverse effects
of HRT.
HDL does play a protective role in menopausal
women

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The Endocrinology of Aging.ppt

  • 1. 1 The Endocrinology of Aging MJ Rasaee TMU 2022 Tehran
  • 2. What is Aging? 2 GENERAL-hormone production altered THYROID- decreased secretion THYMUS-involution of thymus gland CORTISOL- decrease anti-inflammatory hormone PANCREAS- decrease secretion of enzymes & hormones The gradual and spontaneous changes that occur in maturation from infant to young adult. These changes create a normal physiologic decline seen in middle and late adulthood.The process by which a cell looses its ability to divide, grow, and function. This loss of function ultimately ends in death. Biological clocks act through hormones to control the pace of aging. Hormones effects growth, metabolism, temperature, inflammation and stress. Aging is not a disease
  • 3. 3
  • 4. Overall, some hormones are decreased, some unchanged, and some increased with age. Hormones that are usually decreased include:  Aldosterone  Calcitonin  growth hormone/insulin-like growth factor I axis (in somatopause)  Renin  Melatonine  In women, estrogen (in menopause )and prolactin levels usually decrease.  Testosterone (in andropause) levels usually decrease slightly as men age.  Dehydroepiandrosterone and its sulphate (in adrenopause) Hormones that may increase include:  Follicle-stimulating hormone (FSH)  Luteinizing hormone (LH)  Norepinephrine Hormones that remain unchanged or only slightly decreased include:  Cortisol  Epinephrine  Insulin  Parathyroid hormone  Thyroid hormones T3 and T4  25-hydroxyvitamin D 4
  • 5. 5 Endocrine, Physical, sexual, psychological. Endocrine Symptoms:  erectile dysfunction  Increased abdominal fat/increased waist size  decreased vigor  fatigue  poor exercise tolerance  diminished strength and muscle mass  decrease in bone mineral density  decreased body hair Sexual Symptoms:  decreased libido  decreased sexual activity  limited quality of orgasm  reduced ejaculate strength  reduced ejaculate volume Psychological Symptoms: Mood changes Poor concentration Loss of motivation Reduced initiative Memory impairment Anxiety Depression Irritability Insomnia General reduction in intellectual activity Poor work performance
  • 6. 6
  • 7. The circulating levels of dehydroepiandrosterone (DHEA) and its sulphate (DHEAS), which gradually decline with age, resulting adrenopause.” The decline in DHEA(S) levels in both sexes contrasts therefore with the maintenance of plasma cortisol levels and seems to be caused by a selective decrease in the number of functional zona reticularis cells in the adrenal cortex rather than regulated by a central (hypothalamic) pacemaker of aging. Steroidogenic acute regulatory protein (StAR) controls adrenal and gonadal steroidogenesis. It was recently shown unequivocally that StAR mRNA and protein are expressed within glia and neurons in discrete regions of the mouse brain. Neurosteroids synthesized in the CNS appear to attenuate age-relate memory and learning impairments. The beneficial effects of PS and DHEA sulfate on age-related learning and memory deficits appear to be mediated by NO-dependent pathway. To determine whether the mechanism of attenuation was mediated through the nitric oxide (NO) synthase (NOS) signal transduction pathway, mice were pretreated with the NOS inhibitor, NG-nitrol- arginine methyl ester (L-NAME). L-NAME inhibited the beneficial and antiamnesic effects of PS and DHEA sulfate, and the effect of L-NAME was blocked by the competitive substrate for NOS, L-arginine. The adrenopause 7
  • 8.  During aging, GnRH levels declined. but the number of neurons expressing ppGnRH mRNA remained constant. Aging had no effect on pituitary responsiveness to GnRH. Despite this similar LH response, the stimulatory effect of LH on testosterone production declined, LH circadian rhythmicity was blunted, and testosterone levels over 24 h declined progressively with age.  Hence, deficits in testicular function during aging is attributable, at least in part, to decreased GnRH rather than decreased responsiveness of the anterior pituitary gland to GnRH; this property and the attenuated circadian rhythmicity of LH and testosterone secretion are reminiscent of age dependent changes in the GH axis.  Aging also has impact on the opioid control of gonadotropin secretion. Naloxone (opiate antagonist) produced a significant dose-dependent increase in the release of GnRH from the hypothalamic tissue fragments that was age dependent. These results suggest that age- related changes in endogenous opioid systems likely contribute to differences in secretion of GnRH, which in turn affects the dynamics of LH secretion and testosterone production. 8 • Excitatory amino acids also regulate pulsatile secretion of hypothalamic GnRH and LH. To explore the significance of aging on this pathway, the effects of GnRH and the glutamate receptor agonist NMDA on gonadotropin and prolactin release were investigated in prepubertal,young, middle-aged, and old rats. The release of gonadotropins in response to GnRH was not age dependent, and NMDA increased LH, FSH and prolactin secretion in all age groups. However, the NMDA enhancement of LH, FSH, and prolactin release was lowest in old rats. To investigate whether the reduced LH response to NMDA in old rats occurred at the hypothalamic level, the direct effects of NMDA on GnRH release were evaluated in tissue fragments from the preoptic medial basal hypothalamus. The magnitude of GnRH release from these fragments was inversely related to age, and determination of amino acid content showed that aged animals had the lowest concentrations of glutamate, taurine, and GABA. Hence, the attenuated responsiveness of GnRH neurons to NMDA and reductions in excitatory amino acids likely contribute to the diminished pulsatile LH secretion typically observed in old rats.
  • 9. Pathophysiology of Andropause Hypothalamus Pituitary Testes Reduced Leydig cell number Impaired Leydig cell function Lower GnRH pulse amplitude Attenuation of diurnal pulsatility More sensitive to negative feedback T E The decline in testosterone as men age results in part from a reduction in Leydig cell number to be 44% lower in men between the ages of 50 and 76 when compared to the men who were aged 20 to 48 years. decline in age related steroidogenesis results from a reduction in steroidogenic enzyme activity and a decrease in cholesterol transfer to the mitochondria. It has been demonstrated that older men have a subnormal testosterone response to beta HCG as well as recombinant LH administration. In older men with low T, LH levels may increase, but usually remain within the normal range. Overall, studies suggest heightened sensitivity of the hypothalamus to negative feedback as men age. Studies have also provided evidence of reduced GnRH amplitude as men age. Moreover, the normal circadian pattern of GnRH secretion is attenuated with aging. FSH on the other hand is regulated neg by testis inhibin as well as GnRH. Inhibin production decrease with aging and in all forms of testis failure. Thus FSH levels tend to be elevated to a greater extent than LH in older men with low T. 9
  • 10. 10
  • 11. Controlled trials of testosterone therapy in elderly males with low-normal testosterone levels Age (years) Baseline T (nmol/l) T administratio n Duration (months) Effects Side-effects 12.7 2.7 (SD) [T <16.5] Testosterone (Testoderm, scrotal patch) 6 mg/24 h 36 Lean body mass - ,perception of physical functioning ,fat mass. No overall effect on muscle trength, BMD (spine and hip), lipids, and bone markers PSA (from 1.5 to 2.0 ng/ml) Hct (>52% in 3 out of 54 subjects) 51 (22-78) 2.7 2.7 (SD) [T <8.7] Testosterone (Testoderm, scrotal patch), 6 mg/24 h 36 Libido, BMD (L2-L4) No effect on muscle strength, BMD (hip), and lipids Hct (>52% in 1 out of 18 subjects) No change in PSA 76 ± 4 13.5[6.0] [BT <4.4] Testosterone (transdermal patch) 5.0 mg/day 12 Femoral BMD , lean body mass , body fat ¯ No effect on muscle strength PSA (from 2.0 to 2.6 ng/ml) No effect on Hct 11 Testosterone levels decline by about 100 ng/dL per decade. higher rate of ‘prostate events’ with testosterone treatment. GH levels decline by about 14% per decade, but the risks of GH therapy outweigh the benefits in non-GH-deficient people. Although serum levels of many hormones decline with age, additional research is needed to prove that these declining levels are pathologic and that hormone replacement actually affects the aging process.
  • 12. Testosterone Decrease in fat mass and increase in lean mass and bone mineral density Mixed data on the effect on cognition. Dehydroepiandr osterone Inconsistent data on muscle mass, fat mass, and strength. Insufficient evidence for improvement in cognition. Growth hormone Increase in lean body mass; decrease in fat mass. Increase in bone mineral density. Increase in mortality. Vitamin D May improve muscle function HORMONAL THERAPY  Testosterone replacement also has the potential to inhibit neurodegeneration by maintaining expression of BDNF in the aging brain.This is particularly important because of the importance of BDNF in maintaining noradrenergic innervations during aging as well as its proposed significance in Parkinson’s disease and AD. 12
  • 13.  Hormonal decline may be the most important major contributor to aging. Physical changes during aging have been considered physiologic, but there is evidence that some of these changes are related to this decline in hormonal activity.  For men - it is so gradual that men often reach their mid-forties or fifties without noticing the negative changes that have taken place in their body.  For women - hormonal changes can begin as early as the mid to late thirties. The decline in hormones for men is more gradual unlike in women’s menopause, which is a more abrupt event. In women, the amount of TSH produced does not decrease with time, but it does in men. With aging, the thyroid often becomes lumpy (nodular) Metabolism gradually declines, beginning around age 20. Less thyroid hormone may be produced, but there is also less body mass (because of loss of muscle and bone tissue). This means that thyroid function tests usually show results within the normal range. 13
  • 14. The somatopause • Pituitary function, LH, FSH, and TSH decline with age. therefore, that GH also has been reported to decline with age beginning in the third decade. This decrease is associated with decreased insulin-like growth factor concentrations. Pathologically decreased GH is associated with decreased concentrations of gonadal steroids in serum. Thus, pathologically decreased GH is associated with increasing fat, decreasing muscle mass, and decreasing bone mass, all of which are seen as age increases. 14 Body fat Lean body mass Strength Skeleton Cholesterol Estrogen deficiency in healthy women no effect — — Testosterone deficiency in healthy men GH deficiency in healthy individuals
  • 15. 15 It is now well established that there is a physiological decline in food intake over the life span. This has been termed the anorexia of aging hormones play a major. This physiology of aging represents a major reason why older persons have a greater propensity than younger ones to lose weight when they have a disease. Older persons tend to have early satiation. This is due to two factors. 1. decrease in compliance of the fundus of the stomach with aging. This occurs because food fails to cause appropriate release of nitric oxide to relax the smooth muscles of the fundus. 2. CCK is a potent satiating agent. Older persons produce more CCK in the duodenum both basally and in response to fat. The increase in CCK is predominantly due to slower clearance in older persons than in younger persons. Leptin is anorectic and increases metabolic rate. Thus, it is a catabolic hormone. Men develop a greater physiological anorexia of aging than do women. Beyond the age of 70, fat mass declines in men. This would be expected to lead to a decline in leptin levels, but a longitudinal study showed that leptin levels increase in older men. This increase in leptin levels was related to the fall in testosterone levels that occurs with aging. Ghrelin Recently a peptide hormone called ghrelin was isolated from the fundus of the stomach. Ghrelin causes the release of growth hormone and an increase in feeding. Ghrelin or an analog appears to have potential as a therapy for the anorexia of aging.
  • 16. 16 thyroid function is imperative for normal development in human aging. cretinism, deficiencies in iodine and thyroid, the link between thyroid hormones and cognition. At any age, low thyroid function is also associated with cognitive decline, since hypothyroidism is associated with brain hypo metabolism. In the aging population, low uptake of glucose associated with Alzheimer’s disease and may even present decades prior to any clinical symptoms of neurodegeneration. cognitive decline product of the aging process and physiological effects in thyroid function
  • 17. With aging there is:  a decline in thyroxine production rate  small decline in triiodothyronine (T3) levels  Thyroid stimulating hormone (TSH) levels are increased antibodies to thyroid peroxidase increase with aging.  There is emerging evidence that, with aging, thyroid hormone tends to be less capable of activating a number of postreceptor biomarkers of thyroid function. Excess and deficiency of thyroid hormone are two classical examples of atypical presentation of disease in older persons. Thus, early hypothyroidism is a biochemical diagnosis in older persons. Older persons often develop the low T3 syndrome or the euthyroid sick syndrome. In these persons, T3 is markedly decreased and thyroxine may be normal or decreased. TSH levels may be decreased, unchanged, or increased. There is no evidence that thyroid replacement improves outcomes in this condition. These abnormalities are mainly caused by autoimmunity and are therefore an expression of age-associated disease rather than a consequence of the aging process. 17
  • 18. 18 With ageing as well as body weight, thyroid volume increases slightly. Other factors, : cigarette smoking, chronic kidney disease, acute hepatic disease, and seasonal changes, increase thyroid volume. no age-related changes of serum free and total T4 levels. In aging, nocturnal pulses of TSH secretion in comparison to their younger counterparts since aging TSH secretion, this effect is counter balanced, leading to unchanged T4 levels. T3 levels also remain stable with aging. Malnutrition and chronic illness important confounders in assessing thyroid function in the elderly. Both cause serum T3 levels in absence of thyroid disease other non-thyroidal illnesses with aging can decrease T4 conversion to T3 medications an important role in thyroid function in the elderly. Lithium (hyperthyroidism), amiodarone (hyperthyroidism), estrogens and glucocorticoids (thyroid binding globulin status) can affect thyroid function. with age, increased prevalence of anti-thyroperoxidase and anti-thyroglobulin antibodies, especially in females above 60 years of age. in centennials ، thyroid antibodies are rare in comparison to hospitalized patients decrease in free T3/free T4 ratio with age in males, but not females, suggesting impaired T4 to T3 conversion in males. increase T3 resistance index with age in males, but not females. elevated TSH levels with age along with normal T4 levels a question about subclinical hypothyroidism Ischemic heart disease and its association with thyroid function: any association
  • 19. 19 prevalence of ischemic heart disease in individuals with subclinical hypothyroidism is higher in younger compared to ages 65 and older treatment of subclinical hypothyroidism has been shown to be associated with fewer events of ischemic heart disease in the younger but not in older than age 70. inverse correlation between subclinical hypothyroidism and ischemic heart disease. These indicate TSH levels play a cardiovascular protective role. high TSH levels and low T4 levels associated with a lower mortality survival centenarians have significantly higher median serum TSH levels and lower T4 levels compared with control group of thyroid disease-free individuals (median age of 68 years). Hyperthyroidism, is not as common as hypothyroidism, but its prevalence does increase in the elderly. Depending on iodine intake in the given area, Grave’s disease and toxic multinodular goiter are most common causes. lower metabolic rate caloric restriction improve mortality rates in animals
  • 20. 20 Thyroid hormone regulates metabolism via adrenergic stimulation and glucose uptake. It plays a role in mitochondrial gene expression, affecting mitochondrial oxidation in skeletal muscle. Effects of hypothyroidism with aging can lead to lipid accumulation. compromising metabolic activity. This can result in insulin resistance and other features of metabolic syndrome. increased metabolic rate has shown to cause early mortality by accelerating aging. Basal metabolic rate usually declines with aging indicating a healthier functional status and low energy requirements for maintaining homeostasis. basal metabolic rates in the young and older individuals it has been shown that the higher the metabolic rate in the younger predictability the higher mortality. independent of other risk factors such as body mass index, smoking status, daily physical activity, blood pressure and diabetes In older individuals who fail to down regulate the metabolic rate with age usually have poor health status and shown to have higher risk of mortality. atrial fibrillation due to hyperthyroidism is higher in the elderly but other symptoms such as heat intolerance, tremors, and ocular manifestations are less frequent .Non-thyroidal illness, fasting, and drug-induced causes must be ruled out before making the diagnosis.
  • 21. Pathophysiology of diabetes mellitus in older persons The prevalence of type 2 diabetes is age-related. As age increases, on average, a small increase in fasting hepatic glucose output is reported, with impairment of non-insulin- dependent glucose disposal. In addition, insulin secretion is impaired with age, with less insulin being released in the early and late phase after challenges. insulin resistance increases with age. Other endocrine changes, particularly in adrenal function with age, may also play a role in this process . In addition, dietary intake, activity, and body composition alter with age and may play a role in increasing insulin resistance in older individuals. 21 The sex steroids, dopamine, oxytocin, and 5-HT regulate sexual behavior through actions in the CNS. Because the production of these hormones and neurotransmitters declines during aging, it is hardly surprising that aging is commonly associated with a decline in libido and sexual performance. Sexual Behavior and Aging
  • 22. Adrenal Function Adrenal medullary function and baseline serum epinephrine and norepinephrine concentrations apparently increase with advancing age. the increasing incidence of type 2 diabetes and peripheral insulin resistance undoubtedly is exacerbated by the constant increased basal concentrations of epinephrine and norepinephrine. Adrenal cortical function also appears to increase with age. Thus, mean glucocorticoid and mineralocorticoid serum concentrations are higher in older compared with younger individuals. The target organ for mineralocorticoid activity (kidney), however, becomes less responsive as age progresses, and sodium losses become more fixed as age progresses. Increased basal adrenal medullary and cortical activity reduces the functional reserve for either epinephrine/ norepinephrine or steroid hormones. This circumstance provides less ability to respond to stress, corresponding to an initial frailty syndrome. 22 Decreased skeletal mass associated with increasing age is the result of a series of changes associated with aging:  Calcium absorption/transport in the intestinal mucosa decreases with age  calcium intake also generally decreases with age  Renal function, including 1-α- hydroxylase activity, decreases with age 1- α -Hydroxylase catalyzes the conversion of 25OHD to 1,25(OH)2D, the active metabolite of vitamin D. Decreased 1,25(OH)2D leads to further diminution of vitamin D sensitive calcium absorption. decreasing calcium absorption from the gut: (a) decreased calcium intake (b) decreased calcium absorption (c) decreased vitamin D-dependent calcium absorption (d) The result of decreased calcium absorption is increased dependence on skeletal calcium as a source of needed calcium Other changes related to age occur in mineral metabolism. As renal function declines with age, PTH increases. Increasing PTH is associated with increased osteoclastic and osteoblastic activity. Such increased activity is probably associated with more rapid loss of bone. Skeletal/Mineral Metabolism
  • 23. 23 Glucocorticoid Hormone glucocorticoid secretion shows a strong 24-h rhythm with peak concentrations in the early morning and a trough in the late afternoon. Glucocorticoids are known to play a role in the regulation of peripheral glucose mobilization and metabolism. cortisol is essential for cognitive appraisal and affects numerous cognitive domains, including attention, perception, memory, and emotional processing in humans. Glucocorticoids play an important role in many neural functions that are mediated by classic genomic effects via intracellular glucocorticoid receptors or nongenomic mechanisms. Cortisol also participates in energy metabolism and gene expression in the brain, and it coordinates behavioral adaptation to the environmental and internal conditions through the regulation of many neurotransmitters and neural circuits. A progressive increase in levels of circulating cortisol occurs with increasing age, as well as in brain degenerative processes, for instance in Alzheimer’s disease. This has been interpreted as a malfunction of the hypothalamo-pituitary-adrenal axis, and, according to the glucocorticoid-cascade hypothesis, is considered as a main agent of injury to the hippocampus and to lead to the cognitive impairment of the elderly, and as an added pathogenic factor in brain degeneration. Cortisol may affect the intracellular concentrations of Ca2+ by membrane receptors or ion channels, which is one of the important accessory factors in axonal transport. It has been shown that increasing free intracellular calcium may induce the phosphorylation of tau proteins, which belong to the family of MAP, and influence the axonal transport. Glucocorticoid resistance exists in AD brain, and is related to the degree of neuropathological changes, suggesting that glucocorticoid resistance in AD brain may contribute to neuroendocrinal changes, neuropathological mechanisms and dementia. Glucocorticoid resistance in AD may disturb not only the neural functions but also the negative feedback regulation via different brain areas such as hippocampus and result in an activation of the HPA-axis and contribute to the pathogenetic process of AD and induce cascade changes, such as the loss of neuronal Ca2+ homeostasis, abnormal production and degradation of amyloid β-peptide (Aβ), development of NFT and neuronal degeneration. A potential injury to the hippocampus has been postulated by the “glucocorticoid cascade hypothesis” as deriving from the life-long exposure to the stress glucocorticoid hormone.
  • 24. Examples of neurodegenerative disease: • Alzheimer’s disease • Parkinson’s disease • Frontotemporal dementia • Amyotrophic lateral sclerosis (Lou Gehrig’s disease) • Spinocerebellar ataxia • Huntington’s disease 24 Alzheimer’s disease is an irreversible, progressive brain disease that slowly destroys memory and thinking skills. Once considered a rare disorder, is now seen as a major public health problem that is seriously affecting millions of older population . Although the risk of developing AD increases with age – in most people with AD, symptoms first appear after age 60 – AD is not a part of normal aging. It is caused by a fatal disease that affects the brain.
  • 25. 25  estrogens have neuroprotective effects, including inhibition of β-amyloid formation from its precursor protein. This may be due partly to reduced accumulation of reactive oxygen and nitrogen species.  Glucocorticoid-induced hippocampal neuronal damage also seems to be reduced.  Neuroimaging studies in humans have implicated that estrogen influences the pattern of brain activation during memory processing, with regional increments in cerebral blood flow and glucose metabolism and with modulation of activity in specific brain regions affected during the early stages of AD. This may be partly related to direct effects on cerebral blood flow by estrogens.  Epidemiological studies have suggested that estrogen is protective against the development and/ or progression of neurodegenerative disorders. Thus, low circulating levels of estrogen have been associated with an increased risk of AD.  The estrogen β-receptor ERb has a clear role in the development of the cerebral cortex and also in survival of hippocampal neurons after exposure to excitatory neurotoxins.  In contrast, Era is the major receptor subtype expressed in basal forebrain cholinergic neurons. Thus, estrogen probably acts via ERa to enhance cognitive functions through the production of acetylcholine. On the other hand, ERb is the only estrogen receptor expressed in the dorsal raphe nucleus suggesting important effects on the serotonin system, indirectly affecting neuronal plasticity. Altered CNS function appears to precede the metabolic, reproductive, and cognitive deficiencies associated with aging. neuroendocrine changes characterized by: altered biological rhythms reduced amplitude altered frequency, and decreased orderliness of hormone, neuropeptide, and neurotransmitter release. Decline in activity of the brain during aging. The amplitude of release of neurotransmitters and neuropeptides declines and the rhythms of release become more erratic. Experiments using tissue transplants from fetal brain and administration of L- dopa and GHS-R ligands show the feasibility of reversing certain aspects of aging through therapeutic intervention.
  • 26. 26 Senile plaques • Extracellular deposits • Plaques described as “diffuse”, “neuritic”, or “cored” • These may represent different ages of plaque • Neuritic plaques are one of the pathologic criteria for diagnosis of Alzheimer’s disease • Composed chiefly of beta amyloid Beta amyloid is a 39-43 amino acid peptide Derived from 700 amino acid amyloid precursor protein (APP), may be processed to “amyloidogenic” or “non-amyloidogenic” pathways Beta amyloid
  • 27. 27 In the menopausal transition, menstrual cycle regularity is progressively lost due to insufficient numbers of FSH-sensitive follicles present at any time in the ovaries . Cycles become persistently shorter first, due to advanced dominant follicle selection with shorter duration of the follicular phase. Later, cycles may also become lengthened with delayed initiation of dominant follicle growth or anovulatory bleeding after estrogen withdrawal without evidence of corpus luteum function. The complete loss of cyclic ovarian follicular activity is defined as the final menstrual period followed by 12 consecutive months of amenorrhea (menopause). 1. Hot flushes are a sensation of warmth, often accompanied by skin flushing and sweating. Hot flushes are thought to be related to the rate of oestrogen withdrawal and the resulting vasomotor instability.Many women experience palpitations, or a sensation of pressure within the head, frequently accompanied by weakness, fainting or vertigo before the flush begins. Treatment (Hormone replacement therapy, Clonidine, Progesterone) 2-Urinary incontinence The lining of the urethra is responsive to oestrogen, and the postmenopausal fall in oestrogen results in physical changes that can increase rates of urinary incontinenceTreatment (Pelvic floor exercises and bladder training, Hormone replacement therapy) 3-Vaginal atrophy 4-Mood, depression and cognitive function Frequent hot flushes and the resulting insomnia .declining oestrogen levels.Midlife is often a time of social and emotional upheaval 5-wound inflammation :roles of estrogens 6-increased prevalence and severity of atherosclerosis :antiatherosclerotic properties of estrogens 7-osteoporosis :decrease in Inh B level
  • 28. 28 • The reproductive aging process is thought to be dominated by a gradual decrease in both the quantity and the quality of the oocytes residing within the follicles present in the ovarian cortex.Menopause is the final step in the process referred to as ovarian ageing. The age related decrease in follicle numbers dictates the onset of cycle irregularity and the final cessation of menses. • At the fourth month of fetal development, the ovaries contain some 6–7 million oocytes surrounded by a layer of flat granulosa cells to form the primordial follicle pool . • Due to a rapid loss of the great majority of the primordial follicles via apoptosis in the second half of fetal life, at birth only 1–2 million primordial follicles remain. • After birth, this high rate of follicle loss slows down somewhat, so that at menarche at least 300,000 to 400,000 primordial follicles remain. • below 1000 at the time of menopause • Along with the decrease in follicle number, oocyte quality also diminishes (at least after the age of 31 yr). • The loss of oocyte quality is believed to be due to: 1- an increase in meiotic nondisjunction, 2-resulting in an increasing rate of aneuploidy in the early embryo at higher female ages. 3-accumulated damage of oocytes in the course of a woman’s life 4- age-related changes in the quality of the granulosa cells surrounding the oocyte. Despite the profound changes in numbers and quality of follicles during the third and fourth decade of life, the process of ovarian aging remains largely unnoticed. From several sources, it has become clear that monthly fecundity gradually decreases from the mean age of 30 yr onward.
  • 29. Number of primordial follicles present in the ovaries and the chromosomal quality of oocytes in relation to female age and corresponding reproductive events. A number of terms including ‘climacteric’, ‘perimenopause’, ‘menopausal transition’, ‘postmenopause’ and ‘menopause’ have been used to refer to the stages of reproductive aging surrounding the final menstrual period (FMP). The first standardized classification guidelines for female reproductive aging were proposed in 2001 at the Stages of Reproductive Aging Workshop (STRAW). The stages were nominated using the FMP as a reference point, and were based on changes in the pattern of menstrual cycles levels of follicle-stimulating hormone (FSH). The STRAW criteria 29
  • 30. The Stages of Reproductive Aging (STRAW) criteria The proposed STRAW criteria were deemed unsuitable for application in women who: smoked, were obese or underweight (body mass index <18 or >30), participated in intense regular physical training, had chronic menstrual irregularities ,had abnormal reproductive anatomy 30 Fecundity per cycle according to female age. Mean rate for women aged 20–30 was scaled as 1.00. For a woman aged 33 yr, the relative rate of 0.75 indicates that she has in each cycle 75% of the chance of a woman aged 20–30 of getting pregnant.
  • 31. 31 higher risk of cardiovascular disease elevated serum triglycerides prothrombotic effects increased hepatic synthesis of vascular inflammatory markers risk of stroke increases, venous thromboembolism increase Estrogen treatment in women with severe postmenopausal symptoms. Estrogen :orally or topically, with transdermal patch, or intravaginally. Low-dose estrogen in relieving hot flashes. first The lowest dose to decrease adverse effects of HRT. HDL does play a protective role in menopausal women