AGING OF THE
ENDOCRINE SYSTEM
IEVA B. AKBAR
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)
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
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
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.
Depression
Aminergic and
peptidergic neurons
Stress
Steep
Exercise
Hypothalamic peptidergic
and aminergic neurons
Short loop
Ultrashort 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
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-βhydroxylase) decline with age in rodents
and other animal species.
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.
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
OPIOIDS
There is evidence that the steady state
levels of proopiomelanocortin-derived
peptides (ACTH, β-endorphin, βlipotropin, and a 16 kDa fragment)
decline with age. Also, the
posttranslational processing of βendorphin is decreased in old rats.
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.
THE HYPOTHALAMIC-PITUITARY
ADRENAL AXIS
1.
2.
3.
Corticotropin-releasing hormone (CRH or
CRF)
Corticotropin (ACTH, adrecorticotropic
hormone) secreted by anterior pituitary
corticotropes into the circulation
Adrenal hormone, primarily
glucocorticoids, from the adrenal cortex.
Stress
Biogenic amines
+
-
CRF _
Figure 2. The hypothalamicpituitary-adrenal axis.
Inhibitory feedback pathways
are represented by broken line
+
ACTH
-
Corticosteroids
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 :
1.
2.
Maintain homeostasis and control the
response to exogenous and endogenous
stimuli (i.e. stress response)
Generate hormonal secretory rhythms
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.
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.
During Aging




Menopause : E2 
Andropause : T 
Andrenopause: DHEA 
Somatopause : GH/IGF-1 
EFFECT OF AGING ON THE HPA
o
o
o
o
ACTH and glucocorticoid secretion
Pituitary and adrenal involvement
Stress activation and feedback
inhibition
CRH in Alzheimer’s disease
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 HPAmediated homeostasis. The significance of
decrease brain CRH levels in the pathogenesis
and treatment of Alzheimer’s disease is currently
under investigation.
EFFECT OF AGING ON THE
GROWTH HORMONE
o
o
o
Physiologic secretion
Sites of involvement
Feedback inhibition and peripheral
effect
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.
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.
EFFECT OF AGING ON THE
HYPOTHALAMIC-PITUITARYTESTICULAR AXIS (HPT)
Testicular function
Pituitary and feedback regulation
Hypothalamic factors :
o
o
o
o
o
o
GnRH
Opioids
Prolactin
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
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
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.
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.
o
Hypothalamic-Pituitary Disorders
a.
b.
c.
o
o
Hypopituitarism
Acromegali
Gynecomastia
Testicular disorders
Disorder of the adrenal gland
a.
b.
c.
Glucocorticoid excess
Mineralocorticoid excess
Adrenal insufficiency
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
Tabel 1. General Age-Related Change
Structure Gland
Affected
Change
Most Gland
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
Target tissues of most
gland
Hypothalamus, pituitary
Progressive loss of sensitivity to feedback
control
GH : Fails to be supressed by nutrients
FSH : Increase 10-14 x after estrogen
begin to decline
LH : Similar pattern with FSH
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.
ADH



Decrease ability to concentrate urine
Increasing renal tubular resistance to
antidiuretic hormone
Decrease tubular sensitivity
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
Adrenal Cortex



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



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
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).
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)
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, maglinancygenerated 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.
Endocrine Disorders Associated with
Advanced age
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
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Diabetes Mellitus
Thyrotoxicosis
Hypothyroidism
Cushing’s Disease
Addison’s Disease
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