Changes of the endocrine system and metabolism Part I

1. 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 Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011

2. 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 Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011 Márta Balaskó-Erika Pétervári Molecular and Clinical Basics of Gerontology – Lecture 13 Changes of theendocrinesystem and metabolismPart I

3. 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.

4. Common endocrine alterations in theelderly Menopause Estrogen  (Progesterone?) Andro“pause” Testosterone  DHT Somatopause GH  Sarcopenia leanbody mass (appetite: CCK) Adreno“pause” DHEA  DHEAS  Cortisol  ACTH FSH  LH Failinglibido depression osteoporosis QOL issues Immuno-neuro-endocrine correlations Metabolic alterations Insulin resistance, IGT Metabolic syndrome (Carcinogenesis) “Synchropause” Melatonin Sleep(?) QOL issues certain autoimmune processes  (inflammageing) Not “normal” ageing process, but common:subclinical hypo- and hyperthyroidism in theelderly

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

6. Ghrelin administration improves the somatotropic system in the elderly • Growth hormone (GH) secretagogues (ghrelin, MK-0677) act on arcuateneurons, • 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 brain • Administration of GH secretagogues may improve age-related symptoms, buttheyhaveserioussideeffects.

7. Functions of the suprarenal glands in the elderly • 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.

8. Adrenopause • Following the second and third decade of life, there is a continuous decline of adrenal androgen production (“adrenopause”). • Adrenal androgens, dehydro-epiandrosterone (DHEA) and itssulphate (DHEA-S), are the most abundant steroid hormones in the human bodywithlargelyunknownphysiologicalfunctions. • Studies utilizing supplementation of DHEA demonstratedclear benefits: e.g. in autoimmune diseases,inAddison's disease, inprevention of diabetes mellitus, inobesity, cancer, heart disease. • The issue of replacing DHEA in elderly stillremains controversial. • Elderly men with a physiological decline of DHEA did not benefit from DHEA replacement in contrast to women with adrenal failure.

9. Sex steroids in the elderly • 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.

10. Menopause • Concentrations 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)

11. Premenopausal thermoregulation Stabilized thermoregulatory set point External factors Presynaptic neuron Hypothalamus Normalthermoregulatory response Euthermia(vasodilatation or constriction) Ovary Postsynaptic neuron Estrogens Adrenal gland Hyperthemicperception Hypothermicperception 5-HT 5-HT1a receptor 5-HT2 receptor 5-HT reuptake site

12. Peri/postmenopausalthermoregulation Destabilized thermoregulatory set point, 5-HT?, imbalance of 5-HT1a/5-HT2 receptors? External factors Presynaptic neuron Hypothalamus Alteredthermoregulatory response Menopause Anti-estrogens Aromatase inhibitors LHRH agonists Hot flushes(vasodilatation) Ovary Postsynaptic neuron Estrogens Adrenal gland Hyperthemicperception Hypothermicperception 5-HT 5-HT1a receptor 5-HT2 receptor 5-HT reuptake site

13. Andropause in the elderly • 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.)

14. Benign prostate hyperplasia (BPH) in the elderly • 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.) • Pathogenesis • In 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. • Complications • hesitant, interrupted, weak stream of urine, urgency and leaking, more frequent (night-time) urination, urine retention, infections

15. Benignprostatehyperplasia(BPH): invariably common in elderly Cross of andropause 35 2,500 30 2,000 25 1,500 20 Testosterone nmol/L () FSH ng/L () 15 1,000 10 500 5 0 0 young old

16. Benign prostate hyperplasia(BPH): mechanisms GnRH FSH Testes Pituitary PRL/GH LH/FSH FSH-R Testosterone Estrogens PRL/GH-R Endocrine Autocrine Paracrine Endocrine Exocrine Auto/Paracrine Aromatase Androgens Estrogens Prostate

17. “Synchropause”:definition, symptoms • Definition • Healthy 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)

18. “Synchropause”:pathogenesis, treatment • Pathogenesis is unknown • Decline in melatonin production of the pineal gland is assumed. • Low day-time activity, prolonged daily bed-rest • Therapeutical measures • There 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

19. Thyroid dysfunctions in the elderly • 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. • Thesedysfunctions, especiallyhyperthyroidismmust always be treated!