AGING OF THE ENDOCRINE SYSTEM

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AGING OF THE ENDOCRINE SYSTEM

• IEVA B. AKBAR

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INTRODUCTION

• The aging process can alter neuroendocrine
  function at multiple levels (i.e. through its
  effects on biogenic aminergic and peptidergic
  neurons, anterior pituitary cells and end organs)

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NEUROTRANSMITTER REGULATION
There is abundant evidence that biogenic
aminergic and peptidergic neurons strongly
influence the secretion of hypothalamic hormones.
Those most studied are the classic
neurotransmitter dopamine, norepinephrine,
epinephrine and serotonine and the opioids. Other
nioamines and peptides have been studied less
extensively, and the data are somewhat
confounding and inconclusive
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DOPAMINE
Although histochemical studies have shown the
number of dopamine cell bodies do not change with
age in rats, there is a marked decrease in the
steady state concentration of dopamine and its
rate-limiting biosynthetic enzyme tyrosine
hydroxylase and a decline in dopamine turnover, a
more reliable index of dopaminergic activity in
the hypothalamus
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Also the processing of dopamine by the anterior
pituitary decreases in aged animals, and these
changes are not observed in longer living strains
of animals. Thus, with aging the amount of
dopamine delivered to the pituitary is decreased.
Since dopamine exerts a tonic inhibitory action
on prolactin, this may explain the association of
high plasma prolactin levels in aged animals.
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Aminergic and peptidergic neurons
Depression
Stress
Steep
Exercise
Hypothalamic peptidergic and aminergic neurons
Ultrashort loop
Short loop
Anterior pituitary hormones
Long loop
Short loop
End organ hormones
Figure 1. The hypothalamic-pituitary unit and
factors that affect its activity, including
inputs from other brain regions and feedback
regulatory systems at deveral levels
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NOREPINEPHRINE
The hypothalamus is innervated by the dorsal and
ventral noradrenergic bundles that originate from
brainstem nuclei and send axons to several
hypothalamic regions. Numerous studies have shown
that norepinephrine levels and turnover and its
biosynthetic enzyme (dopamine-ß-hydroxylase)
decline with age in rodents and other animal
species.
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Also in aged female rats there is a decreased
ability of noradrenergic neurons to respond to
ovarian signals. The noradrenergic system exert a
stimulatory influence on secretion of several
pituitary hormones, and its age-associated
decline may be directly related to hyposecretion
of these hormones.
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SEROTONIN
The indoleamine serotonin has a purported role
in neuroendocrine regulation. Serotoninergic
neurons in the ventral and dprsal raphe nuclei of
the brainstem project axons to hypothalamic
structures. Although tyrosine hydroxylase, the
rate-limiting enzyme for sertonin synthesis,
decline with age, the data on brain serotonin
levels are conflicting. Thus to date, there is no
consistent age-related effect on serotonin
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OPIOIDS
There is evidence that the steady state levels
of proopiomelanocortin-derived peptides (ACTH,
ß-endorphin, ß-lipotropin, and a 16 kDa fragment)
decline with age. Also, the posttranslational
processing of ß-endorphin is decreased in old
rats.
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Because decreased brain concentrations could
reflect diminished synthesis or enhanced release,
Simpkins and Millard have hypothesized that old
rats may be hypo or hyperopioid. It remains to
be determined which, if either, condition occurs
with aging. Both states could provide an
explanation for some of the neuroendocrine
manifestations of aging, including discruption of
autonomic nervous system function.
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THE HYPOTHALAMIC-PITUITARY ADRENAL AXIS

1. Corticotropin-releasing hormone (CRH or CRF)
2. Corticotropin (ACTH, adrecorticotropic hormone)
   secreted by anterior pituitary corticotropes into
   the circulation
3. Adrenal hormone, primarily glucocorticoids, from
   the adrenal cortex.

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Stress Biogenic amines
- CRF _
ACTH -
Figure 2. The hypothalamic-pituitary-adrenal
axis. Inhibitory feedback pathways are
represented by broken line
Corticosteroids
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• The HPA is considered by many to be the quint
  essential neuroendocrine system because it most
  clearly portrays complex interactions between the
  brain and the endocrine system to
• Maintain homeostasis and control the response to
  exogenous and endogenous stimuli (i.e. stress
  response)
• Generate hormonal secretory rhythms

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ADRENAL HORMONE
Cortisol is the principal glucocorticoid
secreted in humans. ACTH has a direct effect on
glucocorticoid-containing cells to cause
immediate release of cortisol. The half-life of
cortisol in plasma is 60 to 90 minutes and
approximately 10 percent circulates in the free
form, which is available to cells.
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Cortisol has effects on cell membranes and the
genes that code for regulatory enzymes that
regulate lipid, corbohydrate, and protein
metabolism and stimulate cell differentiation.
ACTH also stimulates androcorticoids
(dehydroepiandrosterone) and the
mineralororticoid aldosterone. Adrenal androgen
are converted to testosterone is primarily under
control by the reninangiotensin system.
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• During Aging
• Menopause E2 ?
• Andropause T ?
• Andrenopause DHEA ?
• Somatopause GH/IGF-1 ?

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EFFECT OF AGING ON THE HPA

• ACTH and glucocorticoid secretion
• Pituitary and adrenal involvement
• Stress activation and feedback inhibition
• CRH in Alzheimers disease

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This bulk of evidence indicates that of the
alterations in the HPA that develop with aging,
the one most clearly demonstrable is a diminution
in feedback inhibition of ACTH and/or CRH systems
by glucocorticoids. Thus, there appears to be a
prolonged response to HPA activation by stressful
stimuli, suggesting an imbalance in the recovery
phase of HPA-mediated homeostasis. The
significance of decrease brain CRH levels in the
pathogenesis and treatment of Alzheimers disease
is currently under investigation.
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EFFECT OF AGING ON THE GROWTH HORMONE

• Physiologic secretion
• Sites of involvement
• Feedback inhibition and peripheral effect

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Investigation of the age-related decline in
episodec GH secretion point to several sites in
the hypothalamic-pituitary axis where there may
be disruption of regulatory mechanism. At the
extrahypothalamic level, there is evidence for
diminished catecholamine neurotransmission that
could cause decreased stimulation of GHRH or
enhanced suppression of somatostatin release. At
the hypothalamic level, a large number of studies
provides convincing evidence that somatostatin
release is increased in aged animals, and the
proportion of the more potent and longer lasting
form, somatostatin-28 increase with age.
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It is not clear if the synthesis and/or release
of GHRH decline with age. At the pituitary level,
some studies suggest that the pituitary
responsiveness to GHRH is decreased, possible due
to a loss of functional GHRH receptors. However,
this may be due to the age-associated decline in
pituitary GH content. Evidence from developmental
studies indicates that the inhibitory influence
of somatostatin on pituitary somatotropes is
facilitated during the aging process. Finally,
there is no evidence to indicate that feedback
inhibition, plasma clearance, or the peripheral
actions of GH are significantly altered in aged
animal.
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EFFECT OF AGING ON THE HYPOTHALAMIC-PITUITARY-TEST
ICULAR AXIS (HPT)

• Testicular function
• Pituitary and feedback regulation
• Hypothalamic factors
• GnRH
• Opioids
• Prolactin

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There is considerable evidence that normal aging
is accompained by primary testicular failure that
is modest in degree in most individuals. This
age-related testicular failure result in
diminished availability of testosterone and
inhibin as well as a decrease in sperm
production. While there is a gonadotropin
response to this testicular failure, there is
growing evidence for subtle defects in
hypothalamic-pituitary regulation that may
contribute to the age-related decline in
testicular function. Because of the role that the
central neurotransmitter norepinephrine and
opioids play in regulation of the hypothalamic
pituitary axis, alterations in these central
neurotrnsmitters with aging may contribute to the
hypothalamic-pituitary alterations observed
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DISORDERS OF THE NEUROENDOCRINE SYSTEM
Disorders of the neuroendocrine system have
clinical features related to hormone excess,
hormone deficiency, or local physical effect from
endocrine tumors. Particularly in the area of
hormone deficiency states. There may be some
challenge to clinical recognition in an elderly
patients population
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Symptoms of adrenal, testicular or pituitary
insufficiency tend to be nonspecific and include
weight loss, fatigue, loss of appetite, muscle
wasting, and impaired sexual function. As any of
these findings may be manifestations of chronic
illness in an older person, it is understandable
that an endocrine cause for such symptoms, which
would be relatively rare, can be overlooked.
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The diagnostic challenge is further compounded
by age-related changes in neuroendocrine
function, as detailed previously, since decreased
growth hormone and testosterone production occur
with age in the absence of neuroendocrine disease.
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• Hypothalamic-Pituitary Disorders
• Hypopituitarism
• Acromegali
• Gynecomastia
• Testicular disorders
• Disorder of the adrenal gland
• Glucocorticoid excess
• Mineralocorticoid excess
• Adrenal insufficiency

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GENERAL AGE-RELATED CHANGE

• The pituitary gland begins to atrophy after
  middle age but show no decrease in growth
  hormones secreting cells or prolactin secreting
  cells

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Tabel 1. General Age-Related Change
Structure Gland Affected Change
Most Gland Target tissues of most gland Hypothalamus, pituitary Some degree of glandular atrophy and fibrosis Decreased rate of secretion Decreased rate metabolic destruction of hormone produced. Circulating hormone levels remain fairly constant because of this decrease, or decreased excretion through the kidneys Change in sensitivity Progressive loss of sensitivity to feedback control
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GH Fails to be supressed by nutrients FSH
Increase 10-14 x after estrogen
begin to decline LH Similar pattern with FSH
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• Growth Hormone
• Decline about 50 of level early adulthood by age
  65
• Replacement favorablr effects increased body
  mass, skin thickness, bone density
• GH decline could be a significant feature in
  aging process.
• Consider as therapy cancer, pancreas problem.

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• ADH
• Decrease ability to concentrate urine
• Increasing renal tubular resistance to
  antidiuretic hormone
• Decrease tubular sensitivity

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• Thyroid
• Infiltration of lymphocytes and decrease in
  glandular cells.
• Associated in part with autoimmune destruction of
  the gland
• Antithyroglobin antibodies
• Nodularity thyroid (postmortem 27)
• Hypothyroidism accurs in 3 to 4 elderly
• Hyperthyroidism 1
• More common in woman
• Difficult to diagnosis (symptoms cause of other
  factors
• Iodine uptake little change
• Drug interaction ? distort thyroid function tests

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• Adrenal Cortex
• Cortisol decline by 25 in elderly
• Plasma cortisol level are unchanged
• Renal clearance of cortisol are diminished
• Responsiveness to ACTH does not decline
• Pituitary to cortisol feedback not does
• Progesterone aldosterone decrease with age
• Affect attitudes, behavior are related physical
  factors
• Renin-aldosterone mechanism also decline with age

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Adrenal Medulla The adrenal medulla may increase
its catecholamine and norepinephrine production
in elderly subjects, but the cardiovascular
response to norepinephrine may decline. Nerve
ending production of norepinephrine may decline
in some patients, producing a delayed blood
pressure response to moving to an upright posture
(orthostatic hypotension).
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• Pancreas
• The islets Langerhans show little age-related
  change
• Substantial decline in glucose tolerance
• Caused by decreased islets response to high blood
  glucose
• In adequate insulin production
• Decreased cell membrane responsiveness to insulin
• Increased insulin level in response to oral
  glucose (in some affected elderly)

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Change of Gastrin and Secretion Diabetes
mellitus and thyroid dysfunction are two most
important general categories of
endocrine/metabolic disorders in the elderly.
They are followed by the consequences of
menopause in women, hypocalcemia and
hypercalcemia (either dietary-absorptive or
parathyroid in origin), electrolyte problems
related to adrenal or renal changes,
maglinancy-generated imbalances, and drug-related
endocrine problems. One reseacher has observed
that there is likely to be, on average, at least
one endocrine related problem in each new elderly
patient.
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• Endocrine Disorders Associated with
• Advanced age
• Diabetes Mellitus
• Thyrotoxicosis
• Hypothyroidism
• Cushings Disease
• Addisons Disease

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• ANDROPAUSE
• The aging of reproductive system
• Sexual activity among elderly people
• Disease and condition associated with advancing
  age
• Impotence
• Gynecomastia
• Adenocarcinoma
• Hypertrophy prostate
• Testicular cancer