AGING OF THE AGING OF THE ENDOCRINE ENDOCRINE

SYSTEMSYSTEM

IEVA B. AKBARIEVA B. AKBAR

INTRODUCTIONINTRODUCTION

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

NEUROTRANSMITTER NEUROTRANSMITTER REGULATIONREGULATION

There is abundant evidence that There is abundant evidence that biogenic aminergic and peptidergic biogenic aminergic and peptidergic neurons strongly influence the neurons strongly influence the secretion of hypothalamic hormones. secretion of hypothalamic hormones. Those most studied are the “classic” Those most studied are the “classic” neurotransmitter dopamine, neurotransmitter dopamine, norepinephrine, epinephrine and norepinephrine, epinephrine and serotonine and the opioids. Other serotonine and the opioids. Other nioamines and peptides have been nioamines and peptides have been studied less extensively, and the data studied less extensively, and the data are somewhat confounding and are somewhat confounding and inconclusiveinconclusive

DOPAMINEDOPAMINE

Although histochemical studies have Although histochemical studies have shown the number of dopamine cell shown the number of dopamine cell bodies do not change with age in bodies do not change with age in rats, there is a marked decrease in rats, there is a marked decrease in the steady state concentration of the steady state concentration of dopamine and its rate-limiting dopamine and its rate-limiting biosynthetic enzyme tyrosine biosynthetic enzyme tyrosine hydroxylase and a decline in hydroxylase and a decline in dopamine turnover, a more reliable dopamine turnover, a more reliable index of dopaminergic activity in the index of dopaminergic activity in the hypothalamushypothalamus

Also the processing of dopamine by Also the processing of dopamine by the anterior pituitary decreases in the anterior pituitary decreases in aged animals, and these changes are aged animals, and these changes are not observed in longer living strains not observed in longer living strains of animals. Thus, with aging the of animals. Thus, with aging the amount of dopamine delivered to the amount of dopamine delivered to the pituitary is decreased. Since pituitary is decreased. Since dopamine exerts a tonic inhibitory dopamine exerts a tonic inhibitory action on prolactin, this may explain action on prolactin, this may explain the association of high plasma the association of high plasma prolactin levels in aged animals.prolactin levels in aged animals.

Aminergic and peptidergic

neurons

Hypothalamic peptidergic and

aminergic neurons

Depression

Steep

Stress

Exercise

Anterior pituitary hormones

End organ hormones

Ultrashort loopShort loop

Long loopShort loop

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

NOREPINEPHRINENOREPINEPHRINE

The hypothalamus is innervated by The hypothalamus is innervated by the dorsal and ventral noradrenergic the dorsal and ventral noradrenergic bundles that originate from brainstem bundles that originate from brainstem nuclei and send axons to several nuclei and send axons to several hypothalamic regions. Numerous hypothalamic regions. Numerous studies have shown that studies have shown that norepinephrine levels and turnover norepinephrine levels and turnover and its biosynthetic enzyme and its biosynthetic enzyme (dopamine-(dopamine-ββ-hydroxylase) decline with -hydroxylase) decline with age in rodents and other animal age in rodents and other animal species.species.

Also in aged female rats there is a Also in aged female rats there is a decreased ability of noradrenergic decreased ability of noradrenergic neurons to respond to ovarian neurons to respond to ovarian signals. The noradrenergic system signals. The noradrenergic system exert a stimulatory influence on exert a stimulatory influence on secretion of several pituitary secretion of several pituitary hormones, and its age-associated hormones, and its age-associated decline may be directly related to decline may be directly related to hyposecretion of these hormones.hyposecretion of these hormones.

SEROTONINSEROTONIN

The indoleamine serotonin has a The indoleamine serotonin has a purported role in neuroendocrine purported role in neuroendocrine regulation. Serotoninergic neurons in regulation. Serotoninergic neurons in the ventral and dprsal raphe nuclei of the ventral and dprsal raphe nuclei of the brainstem project axons to the brainstem project axons to hypothalamic structures. Although hypothalamic structures. Although tyrosine hydroxylase, the rate-limiting tyrosine hydroxylase, the rate-limiting enzyme for sertonin synthesis, decline enzyme for sertonin synthesis, decline with age, the data on brain serotonin with age, the data on brain serotonin levels are conflicting. Thus to date, levels are conflicting. Thus to date, there is no consistent age-related there is no consistent age-related effect on serotonineffect on serotonin

OPIOIDSOPIOIDS

There is evidence that the There is evidence that the steady state levels of steady state levels of proopiomelanocortin-derived proopiomelanocortin-derived peptides (ACTH, peptides (ACTH, ββ-endorphin, -endorphin, ββ--lipotropin, and a 16 kDa lipotropin, and a 16 kDa fragment) decline with age. fragment) decline with age. Also, the posttranslational Also, the posttranslational processing of processing of ββ-endorphin is -endorphin is decreased in old rats.decreased in old rats.

Because decreased brain Because decreased brain concentrations could reflect concentrations could reflect diminished synthesis or enhanced diminished synthesis or enhanced release, Simpkins and Millard have release, Simpkins and Millard have hypothesized that old rats may be hypothesized that old rats may be “hypo or hyperopioid”. It remains to “hypo or hyperopioid”. It remains to be determined which, if either, be determined which, if either, condition occurs with aging. Both condition occurs with aging. Both states could provide an explanation states could provide an explanation for some of the neuroendocrine for some of the neuroendocrine manifestations of aging, including manifestations of aging, including discruption of autonomic nervous discruption of autonomic nervous system function.system function.

THE HYPOTHALAMIC-THE HYPOTHALAMIC-PITUITARY ADRENAL AXISPITUITARY ADRENAL AXIS

1.1. Corticotropin-releasing hormone Corticotropin-releasing hormone (CRH or CRF)(CRH or CRF)

2.2. Corticotropin (ACTH, Corticotropin (ACTH, adrecorticotropic hormone) adrecorticotropic hormone) secreted by anterior pituitary secreted by anterior pituitary corticotropes into the circulationcorticotropes into the circulation

3.3. Adrenal hormone, primarily Adrenal hormone, primarily glucocorticoids, from the adrenal glucocorticoids, from the adrenal cortex.cortex.

Stress

Biogenic amines

+ -

CRF _

+ ACTH-

Corticosteroids

Figure 2. The hypothalamic-pituitary-adrenal axis.

Inhibitory feedback pathways are represented by broken line

The HPA is considered by many to The HPA is considered by many to be the “quint essential” be the “quint essential” neuroendocrine system because it neuroendocrine system because it most clearly portrays complex most clearly portrays complex interactions between the brain and interactions between the brain and the endocrine system to :the endocrine system to :

1.1. Maintain homeostasis and control the Maintain homeostasis and control the response to exogenous and response to exogenous and endogenous stimuli (i.e. stress endogenous stimuli (i.e. stress response)response)

2.2. Generate hormonal secretory rhythmsGenerate hormonal secretory rhythms

ADRENAL HORMONEADRENAL HORMONE

Cortisol is the principal Cortisol is the principal glucocorticoid secreted in humans. glucocorticoid secreted in humans. ACTH has a direct effect on ACTH has a direct effect on glucocorticoid-containing cells to glucocorticoid-containing cells to cause immediate release of cortisol. cause immediate release of cortisol. The half-life of cortisol in plasma is The half-life of cortisol in plasma is 60 to 90 minutes and approximately 60 to 90 minutes and approximately 10 percent circulates in the free 10 percent circulates in the free form, which is available to cells.form, which is available to cells.

Cortisol has effects on cell Cortisol has effects on cell membranes and the genes that code membranes and the genes that code for regulatory enzymes that regulate for regulatory enzymes that regulate lipid, corbohydrate, and protein lipid, corbohydrate, and protein metabolism and stimulate cell metabolism and stimulate cell differentiation. ACTH also stimulates differentiation. ACTH also stimulates androcorticoids androcorticoids (dehydroepiandrosterone) and the (dehydroepiandrosterone) and the mineralororticoid aldosterone. mineralororticoid aldosterone. Adrenal androgen are converted to Adrenal androgen are converted to testosterone is primarily under testosterone is primarily under control by the reninangiotensin control by the reninangiotensin system.system.

During AgingDuring Aging MenopauseMenopause : E: E22 Andropause Andropause : T : T AndrenopauseAndrenopause : DHEA : DHEA SomatopauseSomatopause : GH/IGF-1 : GH/IGF-1

EFFECT OF AGING ON THE EFFECT OF AGING ON THE HPAHPA

o ACTH and glucocorticoid ACTH and glucocorticoid secretionsecretion

o Pituitary and adrenal Pituitary and adrenal involvementinvolvement

o Stress activation and feedback Stress activation and feedback inhibitioninhibition

o CRH in Alzheimer’s diseaseCRH in Alzheimer’s disease

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

EFFECT OF AGING ON THE EFFECT OF AGING ON THE GROWTH HORMONEGROWTH HORMONE

o Physiologic secretionPhysiologic secretiono Sites of involvementSites of involvemento Feedback inhibition and Feedback inhibition and

peripheral effectperipheral effect

Investigation of the age-related decline in Investigation of the age-related decline in episodec GH secretion point to several sites episodec GH secretion point to several sites in the hypothalamic-pituitary axis where in the hypothalamic-pituitary axis where there may be disruption of regulatory there may be disruption of regulatory mechanism. At the extrahypothalamic level, mechanism. At the extrahypothalamic level, there is evidence for diminished there is evidence for diminished catecholamine neurotransmission that could catecholamine neurotransmission that could cause decreased stimulation of GHRH or cause decreased stimulation of GHRH or enhanced suppression of somatostatin enhanced suppression of somatostatin release. At the hypothalamic level, a large release. At the hypothalamic level, a large number of studies provides convincing number of studies provides convincing evidence that somatostatin release is evidence that somatostatin release is increased in aged animals, and the increased in aged animals, and the proportion of the more potent and longer proportion of the more potent and longer lasting form, somatostatin-28 increase with lasting form, somatostatin-28 increase with age.age.

It is not clear if the synthesis and/or It is not clear if the synthesis and/or release of GHRH decline with age. At the release of GHRH decline with age. At the pituitary level, some studies suggest that pituitary level, some studies suggest that the pituitary responsiveness to GHRH is the pituitary responsiveness to GHRH is decreased, possible due to a loss of decreased, possible due to a loss of functional GHRH receptors. However, this functional GHRH receptors. However, this may be due to the age-associated decline may be due to the age-associated decline in pituitary GH content. Evidence from in pituitary GH content. Evidence from developmental studies indicates that the developmental studies indicates that the inhibitory influence of somatostatin on inhibitory influence of somatostatin on pituitary somatotropes is facilitated pituitary somatotropes is facilitated during the aging process. Finally, there is during the aging process. Finally, there is no evidence to indicate that feedback no evidence to indicate that feedback inhibition, plasma clearance, or the inhibition, plasma clearance, or the peripheral actions of GH are significantly peripheral actions of GH are significantly altered in aged animal.altered in aged animal.

EFFECT OF AGING ON THE EFFECT OF AGING ON THE HYPOTHALAMIC-PITUITARY-HYPOTHALAMIC-PITUITARY-

TESTICULAR AXIS (HPT)TESTICULAR AXIS (HPT)

o Testicular functionTesticular functiono Pituitary and feedback Pituitary and feedback

regulationregulationo Hypothalamic factors :Hypothalamic factors :

o GnRHGnRHo OpioidsOpioidso ProlactinProlactin

There is considerable evidence that normal There is considerable evidence that normal aging is accompained by primary testicular aging is accompained by primary testicular failure that is modest in degree in most failure that is modest in degree in most individuals. This age-related testicular failure individuals. This age-related testicular failure result in diminished availability of testosterone result in diminished availability of testosterone and inhibin as well as a decrease in sperm and inhibin as well as a decrease in sperm production. While there is a gonadotropin production. While there is a gonadotropin response to this testicular failure, there is response to this testicular failure, there is growing evidence for subtle defects in growing evidence for subtle defects in hypothalamic-pituitary regulation that may hypothalamic-pituitary regulation that may contribute to the age-related decline in contribute to the age-related decline in testicular function. Because of the role that the testicular function. Because of the role that the central neurotransmitter norepinephrine and central neurotransmitter norepinephrine and opioids play in regulation of the hypothalamic opioids play in regulation of the hypothalamic pituitary axis, alterations in these central pituitary axis, alterations in these central neurotrnsmitters with aging may contribute to neurotrnsmitters with aging may contribute to the hypothalamic-pituitary alterations observedthe hypothalamic-pituitary alterations observed

DISORDERS OF THE DISORDERS OF THE NEUROENDOCRINE SYSTEMNEUROENDOCRINE SYSTEM

Disorders of the neuroendocrine Disorders of the neuroendocrine system have clinical features system have clinical features related to hormone excess, hormone related to hormone excess, hormone deficiency, or local physical effect deficiency, or local physical effect from endocrine tumors. Particularly from endocrine tumors. Particularly in the area of hormone deficiency in the area of hormone deficiency states. There may be some states. There may be some challenge to clinical recognition in challenge to clinical recognition in an elderly patients populationan elderly patients population

Symptoms of adrenal, testicular or Symptoms of adrenal, testicular or pituitary insufficiency tend to be pituitary insufficiency tend to be nonspecific and include weight loss, nonspecific and include weight loss, fatigue, loss of appetite, muscle fatigue, loss of appetite, muscle wasting, and impaired sexual wasting, and impaired sexual function. As any of these findings may function. As any of these findings may be manifestations of chronic illness in be manifestations of chronic illness in an older person, it is understandable an older person, it is understandable that an endocrine cause for such that an endocrine cause for such symptoms, which would be relatively symptoms, which would be relatively rare, can be overlooked.rare, can be overlooked.

The diagnostic challenge is The diagnostic challenge is further compounded by age-further compounded by age-related changes in related changes in neuroendocrine function, as neuroendocrine function, as detailed previously, since detailed previously, since decreased growth hormone and decreased growth hormone and testosterone production occur testosterone production occur with age in the absence of with age in the absence of neuroendocrine disease.neuroendocrine disease.

o Hypothalamic-Pituitary DisordersHypothalamic-Pituitary Disordersa.a. HypopituitarismHypopituitarism

b.b. AcromegaliAcromegali

c.c. GynecomastiaGynecomastiao Testicular disordersTesticular disorderso Disorder of the adrenal glandDisorder of the adrenal gland

a.a. Glucocorticoid excessGlucocorticoid excess

b.b. Mineralocorticoid excessMineralocorticoid excess

c.c. Adrenal insufficiencyAdrenal insufficiency

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

GENERAL AGE-RELATED CHANGEGENERAL AGE-RELATED CHANGE

Tabel 1. General Age-Related Tabel 1. General Age-Related ChangeChangeStructure GlandStructure Gland

AffectedAffected

ChangeChange

Most GlandMost Gland

Target tissues of most Target tissues of most

glandgland

Hypothalamus, pituitaryHypothalamus, pituitary

Some degree of glandular atrophy and fibrosisSome degree of glandular atrophy and fibrosis

Decreased rate of secretionDecreased rate of secretion

Decreased rate metabolic destruction of Decreased rate metabolic destruction of

hormone produced. Circulating hormone hormone produced. Circulating hormone

levels remain fairly constant because of this levels remain fairly constant because of this

decrease, or decreased excretion through decrease, or decreased excretion through

the kidneysthe kidneys

Change in sensitivityChange in sensitivity

Progressive loss of sensitivity to feedback Progressive loss of sensitivity to feedback

controlcontrol

GHGH : Fails to be supressed by : Fails to be supressed by nutrientsnutrients

FSHFSH : Increase 10-14 x after : Increase 10-14 x after estrogen estrogen

begin to declinebegin to decline

LHLH : Similar pattern with FSH: Similar pattern with FSH

Growth HormoneGrowth Hormone Decline about 50% of level early Decline about 50% of level early

adulthood by age 65adulthood by age 65 Replacement – favorablr effects : Replacement – favorablr effects :

increased body mass, skin increased body mass, skin thickness, bone densitythickness, bone density

GH decline could be a significant GH decline could be a significant feature in aging process.feature in aging process.

Consider as therapy : cancer, Consider as therapy : cancer, pancreas problem. pancreas problem.

ADHADH Decrease ability to concentrate Decrease ability to concentrate

urineurine Increasing renal tubular Increasing renal tubular

resistance to antidiuretic resistance to antidiuretic hormonehormone

Decrease tubular sensitivityDecrease tubular sensitivity

ThyroidThyroid Infiltration of lymphocytes and decrease in Infiltration of lymphocytes and decrease in

glandular cells.glandular cells. Associated in part with autoimmune Associated in part with autoimmune

destruction of the glanddestruction of the gland Antithyroglobin antibodiesAntithyroglobin antibodies Nodularity thyroid (postmortem : 27%)Nodularity thyroid (postmortem : 27%) Hypothyroidism accurs in 3% to 4% elderlyHypothyroidism accurs in 3% to 4% elderly Hyperthyroidism 1%Hyperthyroidism 1% More common in womanMore common in woman Difficult to diagnosis (symptoms cause of other Difficult to diagnosis (symptoms cause of other

factorsfactors Iodine uptake little changeIodine uptake little change Drug interaction Drug interaction distort thyroid function distort thyroid function

teststests

Adrenal CortexAdrenal Cortex Cortisol decline by 25% in elderlyCortisol decline by 25% in elderly Plasma cortisol level are unchangedPlasma cortisol level are unchanged Renal clearance of cortisol are Renal clearance of cortisol are

diminisheddiminished Responsiveness to ACTH does not declineResponsiveness to ACTH does not decline Pituitary to cortisol feedback : not doesPituitary to cortisol feedback : not does Progesterone – aldosterone : decrease Progesterone – aldosterone : decrease

with age with age Affect attitudes, behavior are related Affect attitudes, behavior are related

physical factorsphysical factors Renin-aldosterone mechanism also Renin-aldosterone mechanism also

decline with agedecline with age

Adrenal MedullaAdrenal Medulla

The adrenal medulla may increase The adrenal medulla may increase its catecholamine and its catecholamine and norepinephrine production in elderly norepinephrine production in elderly subjects, but the cardiovascular subjects, but the cardiovascular response to norepinephrine may response to norepinephrine may decline. Nerve ending production of decline. Nerve ending production of norepinephrine may decline in some norepinephrine may decline in some patients, producing a delayed blood patients, producing a delayed blood pressure response to moving to an pressure response to moving to an upright posture (orthostatic upright posture (orthostatic hypotension).hypotension).

PancreasPancreas The islets Langerhans show little age-The islets Langerhans show little age-

related changerelated change Substantial decline in glucose Substantial decline in glucose

tolerancetolerance Caused by decreased islets response Caused by decreased islets response

to high blood glucoseto high blood glucose In adequate insulin productionIn adequate insulin production Decreased cell membrane Decreased cell membrane

responsiveness to insulinresponsiveness to insulin Increased insulin level in response to Increased insulin level in response to

oral glucose (in some affected elderly)oral glucose (in some affected elderly)

Change of Gastrin and SecretionChange of Gastrin and Secretion

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

Endocrine Disorders Endocrine Disorders Associated with Associated with

Advanced ageAdvanced age Diabetes MellitusDiabetes Mellitus ThyrotoxicosisThyrotoxicosis HypothyroidismHypothyroidism Cushing’s DiseaseCushing’s Disease Addison’s DiseaseAddison’s Disease

ANDROPAUSE :ANDROPAUSE : The aging of reproductive systemThe aging of reproductive system Sexual activity among elderly Sexual activity among elderly

peoplepeople Disease and condition associated Disease and condition associated

with advancing age :with advancing age : ImpotenceImpotence GynecomastiaGynecomastia AdenocarcinomaAdenocarcinoma Hypertrophy prostateHypertrophy prostate Testicular cancerTesticular cancer