Medical Biotechnology Master’s Programmes
at the University of Pécs and at the University of Debrecen
Identification number: TÁMOP-4.1.2-08/1/A-2009-0011
CHANGES OF THE
ENDOCRINE SYSTEM AND METABOLISM
PART I
Márta Balaskó-Erika Pétervári
Molecular and Clinical Basics of Gerontology – Lecture 13
Medical Biotechnology Master’s Programmes
at the University of Pécs and at the University of Debrecen
Identification number: 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.
QOL issues Menopause
Estrogen (Progesterone?)
Andro“pause”
Testosterone DHT
Somatopause GH
Sarcopenia lean body mass
(appetite: CCK)
Adreno“pause”
DHEA DHEAS Cortisol
ACTH
FSH LH
Failing libido depression osteoporosis
QOL issues
Immuno-neuro- endocrine correlations certain autoimmune
processes Metabolic
alterations Insulin resistance,
IGT Metabolic syndrome (Carcinogenesis)
“Synchropause”
Melatonin Sleep(?) (inflammageing)
Not “normal” ageing process, but common:
subclinical hypo- and hyperthyroidism in the elderly
Common endocrine alterations in the
elderly
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)
• 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 brain
Administration of GH secretagogues may improve age- related symptoms, but they have serious side effects.
Ghrelin administration improves the
somatotropic system 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.
Functions of the suprarenal glands in
the elderly
• 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
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
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)
5-HT1a receptor
External factors
Normal
thermoregulatory response
Euthermia (vasodilatation or
constriction) Postsynaptic neuron
Ovary
Adrenal gland Estrogens
Presynaptic neuron
5-HT
5-HT2 receptor 5-HT reuptake site
Hypothermic perception Hyperthemic
perception
Premenopausal thermoregulation
Hypothalamus
Stabilized thermoregulatory set point
Destabilized thermoregulatory set point, 5-HT?, imbalance of 5-HT1a/5-HT2 receptors?
5-HT1a receptor
External factors
Altered
thermoregulatory response
Hot flushes (vasodilatation) Postsynaptic neuron
Ovary Adrenal gland
Estrogens
Hypothalamus
Presynaptic neuron
5-HT
5-HT2 receptor 5-HT reuptake site
Hypothermic perception Hyperthemic
perception
Peri/postmenopausal thermoregulation
Menopause Anti-estrogens Aromatase inhibitors
LHRH agonists
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
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
Benign prostate hyperplasia (BPH) in
the elderly
Cross of andropause
young
Testosterone nmol/L () FSH ng/L ()
0 old
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
GnRH
Testosterone Estrogens
LH/FSH
Testes Pituitary
Endocrine
Exocrine Auto/Paracrine
FSH PRL/GH FSH-R PRL/GH-R
Benign prostate hyperplasia (BPH):
mechanisms
Androgens Estrogens Prostate
Aromatase
Autocrine Paracrine
Endocrine
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)
“Synchropause”:
definition, symptoms
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
“Synchropause”:
pathogenesis, treatment
• Thyroid dysfunctions (especially of autoimmune origin) are frequent, often without specific, characteristic symptoms.
• Hyperthyroidism
Atrial 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!
