Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of DebrecenIdentification number: TÁMOP-4.1.2-08/1/A-2009-0011

CHANGES OF THE ENDOCRINE SYSTEM AND METABOLISMPART I

Márta Balaskó-Erika PéterváriMolecular and Clinical Basics of Gerontology – Lecture 13

Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of DebrecenIdentification number: TÁMOP-4.1.2-08/1/A-2009-0011

TÁMOP-4.1.2-08/1/A-2009-0011

Age-related alterations in the endocrine system • The function of most endocrine organs change (declines) in the course of

aging. • Both baseline and reserve functions become limited. • Signal transduction mechanisms grow diminished, hormone release and

hormone-induced responses are suppressed.• However, age-related alterations in complex regulatory feed-back circles lead

to elevation of some hormone levels.• These changes are not predictable, age-specific “normal” values can not be

determined.

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QOL issues

MenopauseEstrogen

(Progesterone?)

Andro“pause”Testosterone

DHT

SomatopauseGH

Sarcopenia leanbody mass

(appetite: CCK)

Adreno“pause”DHEA DHEAS Cortisol

ACTH

FSH LH

Failing libidodepression

osteoporosisQOL issues

Immuno-neuro-endocrine

correlationscertain

autoimmune processes

Metabolicalterations

Insulin resistance, IGT

Metabolic syndrome

(Carcinogenesis)

“Synchropause”MelatoninSleep(?)

(inflammageing)

Not “normal” ageing process, but common:subclinical hypo- and hyperthyroidism in the elderly

Common endocrine alterations in the elderly

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Age is associated with:• a decline in spontaneous overnight GH-secretion,• a reduced GH amplitude and low serum insulin-like growth factor-I (IGF-I) levels.

Changes in body composition with age are similar to those observed in patients with the adult GH deficiency syndrome. Administration of GH to the latter group of patients has significantly improved body composition, muscle strength, functional performance and quality of life.

The somatotropic hormone system in the elderly: aging vs. growth hormone (GH)

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• Growth hormone (GH) secretagogues (ghrelin, MK-0677) act on arcuate neurons,

• they restore the amplitude of GH pulsatility in old animals, thus GH target tissues are exposed to young-adult GH pulsatility.

• Functional benefits include increased lean mass, bone density and modest improvements in strength,

• partially restored thymus function, • partially restored hepatic function (e.g.

gluconeogenesis)• amplification of dopamine signaling in the brainAdministration of GH secretagogues may improve age-related symptoms, but they have serious side effects.

Ghrelin administration improves the somatotropic system in the elderly

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• Function of the hypothalamo-pituitary-adrenal (HPA) axis is not only maintained, but rather enhanced in the elderly possibly contributing [via central actions of hypothalamic corticotropin-releasing-factor (CRF)] to prevalent anxiety in old populations.

• Diurnal rhythms of adrenocorticotrop hormone (ACTH) and cortisol are maintained, their release is enhanced.

• This slight hyperfunction may contribute to adiposity, osteoporosis and suppression of the immune response.

• Usually, these alterations are considered to be mild, therefore no therapy is indicated.

Functions of the suprarenal glands in the elderly

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• Following the second and third decade of life, there is a continuous decline of adrenal androgen production (“adrenopause”).

• Adrenal androgens, dehydro-epiandrosterone (DHEA) and its sulphate (DHEA-S), are the most abundant steroid hormones in the human body with largely unknown physiological functions.

• Studies utilizing supplementation of DHEA demonstrated clear benefits: e.g. in autoimmune diseases, in Addison's disease, in prevention of diabetes mellitus, in obesity, cancer, heart disease.

• The issue of replacing DHEA in elderly still remains controversial.

• Elderly men with a physiological decline of DHEA did not benefit from DHEA replacement in contrast to women with adrenal failure.

Adrenopause

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Sex steroids (estrogens and androgens present in both gender) affect multiple physiological functions from food intake, metabolic rate and body composition to thermoregulation and neuronal functions.There is an age-associated reductions in sex steroids in both genders.• In females, this reduction is rapid leading to menopause and infertility between

the ages of 45-55 years (mean 51 years).• In males, a slow progressive decline of sex steroids is observed. Fertility is

maintained until very old age.

Sex steroids in the elderly

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MenopauseConcentrations of estrogens and progesterone rapidly decline, those of pituitary gonadotrop hormones follicle stimulating and luteinizing hormones (FSH and LH) rise.Some estrogen is produced by fat tissue aromatase from adrenal cortex derived androgens. Consequences include:thermoregulatory disorders (hot flashes), atrophy of estrogen-sensitive tissues, rapid decline of bone mass, augmented cardiovascular risk (due to loss of protective effects), psychological disturbances (irritability, anxiety, depression)

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5-HT1a receptor

External factors

Normalthermoregulatory

response

Euthermia(vasodilatation or

constriction)Postsynaptic neuronOvary

Adrenal gland Estro

gens

Presynaptic neuron

5-HT5-HT2 receptor 5-HT reuptake site

Hypothermicperception

Hyperthemicperception

Premenopausal thermoregulation

Hypothalamus

Stabilized thermoregulatory set point

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Destabilized thermoregulatory set point, 5-HT?, imbalance of 5-HT1a/5-HT2 receptors?

5-HT1a receptor

External factors

Alteredthermoregulatory

response

Hot flushes(vasodilatation)Postsynaptic neuronOvary

Adrenal gland Estro

gens

Hypothalamus

Presynaptic neuron

5-HT5-HT2 receptor 5-HT reuptake site

Hypothermicperception

Hyperthemicperception

Peri/postmenopausal thermoregulation

MenopauseAnti-estrogens

Aromatase inhibitors

LHRH agonists

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Reduction in male sex steroids with aging:• may lead to alterations in body composition and

performance (frailty) similar to those observed in non-elderly hypogonadal men.

• does not prevent benign prostatic hyperplasia (BPH), very frequently seen in elderly men [dihydro-testosterone (DHT) stimulate prostate cell proliferation].

• may allow for somewhat enhanced estrogen production leading prostate hyperplasia in animal experiments.

Administration of testosterone has been reported to increase muscle mass in both groups, and to improve strength in hypogonadal men. (As a side effect it may aggravate BPH.)

Andropause in the elderly

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Definition, prevalence• Benign hyperplasia of prostatic stromal and epithelial cells

leading to compression of the urethra.• BPH rarely causes symptoms before the age 40, but

prevalence of prostatic enlargement may reach more than 50% above 60 years and as high as 80% above the age of 80 years. (Enlargement does not mean clinical symptoms.)

PathogenesisIn addition to life-long androgene production (especially that of DHT), age-related hormonal changes (e.g. a significant rise in FSH production and a relative increase in estrogen release) promote cellular hyperplasia. Complicationshesitant, interrupted, weak stream of urine, urgency and leaking, more frequent (night-time) urination, urine retention, infections

Benign prostate hyperplasia (BPH) in the elderly

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Cross of andropause

young

Test

oste

rone

nm

ol/L

()

FSH ng/L ()

old0

5

10

15

20

25

30

35

0

500

1,000

1,500

2,000

2,500

Benign prostate hyperplasia (BPH): invariably common in elderly

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GnRH

TestosteroneEstrogens

LH/FSHTestes Pituitary

Endocrine

ExocrineAuto/Paracrine

FSHPRL/GHFSH-RPRL/GH-R

Benign prostate hyperplasia (BPH): mechanisms

Androgens EstrogensProstate

Aromatase

AutocrineParacrine

Endocrine

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DefinitionHealthy young individuals (humans and mammals) show characteristic circadian rhythm regarding body temperature, activity, blood pressure (BP), endocrine functions (e.g. release of GH, ACTH, etc.), sleep, etc. In the elderly such circadian rhythmicity becomes disturbed, most frequently affecting sleep, activity, blood pressure.Symptoms• disturbances of sleep (advanced sleep-phase syndrome,

delayed sleep-phase syndrome)• non-dipper BP pattern (night-time BP is higher and not

lower than day-time value)• in animal studies circadian rhythm of food intake was

also disturbed (food intake of old rodents was not restricted to the night)

“Synchropause”:definition, symptoms

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Pathogenesis is unknown• Decline in melatonin production of the pineal gland is

assumed.• Low day-time activity, prolonged daily bed-restTherapeutical measuresThere is no cure for aging-associated disturbances of circadian rhythm.Benefits were shown using: • bright light therapy • behavior and chronoterapy (adjusting

activity/light and avoiding coffee/nicotine and other stimulation before desired sleeping time)

• an increased level of physical activity (e.g. fitness training program for 3 months)

• melatonin (hormone of the pineal gland, reaching its peak at night) administration in the evening

“Synchropause”:pathogenesis, treatment

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• Thyroid dysfunctions (especially of autoimmune origin) are frequent, often without specific, characteristic symptoms.

• HyperthyroidismAtrial fibrillation or cardiac decompensation may be the first sign, eventually heat intolerance may develop. Loss of BW is not necessarily observed.

• Hypothyroidism often appears as depression, confusion or dementia. Constipation is also a characteristic finding. Osteoporosis is a frequent long-term complication.

• Diagnosis and treatment are important. • Upon treatment, hypothyroidism-associated cognitive

dysfunctions are reversible, hyperthyroidism-associated cardiovascular risks are diminished.

These dysfunctions, especially hyperthyroidism must always be treated!

Thyroid dysfunctions in the elderly