12. Endocrinology of aging Flashcards
Determinants of age
• Nutritional status • Insulin/glucose • Gonadal axis ○ Menopause/ andropause • GH-IGF system • Cortisol • DHEA • Thyroid function Diet Starvation Anorexia nervosa • Insulin/glucose • Leptin • Gonadal axis • GH-IGF system • Cortisol • Thyroid function
Different perspectives
• EVOLUTIONARY PERSPECTIVE • We are outliving our natural lifespan • Hormonal function: ○ ‘MENOPAUSE’ ○ ‘ANDROPAUSE’ § ‘ADAM’ ○ ‘SOMATOPAUSE’ ○ ‘ADRENOPAUSE’ • Cultural perspective ○ Anti-aging results in 2,940,000 Google hits • Pharma perspective ○ Enormous market, especially compared to endocrine market for testosterone/GH
Medicalisation of ageing
• Increased life expectancy may not equate to increased health expectancy • Usual ageing ○ Physiological - normal? ○ Pathological? ○ Optimal? • Boundaries of medicine? • Hormonal influence? ○ Dwarfed by: ○ Genetic, environmental, psychosocial, co-morbidities • Balance of benefit & harm of treatment ○ Risks esp cancer risk in elderly ○ Hassle - GH/testo not orally active ○ Costs
Association and causation
Similar phenotypes
• Hypogonadism/growth hormone deficiency/ aging
• Increased fat mass, increased visceral fat
• Sarcopaenia
• Decreased bone mineral density
• Decreased quality of life an mood
• Increased risk of cardiovascular disease
Phenotypes are non-specific, high prevalence - maybe universal
Age: nutritional status
Weight - increases from mid-30s up to 50-70
Lean body mass - decreased 6-8%/decade from mid 30s
Diet - trend towards decreased intake total energy and protein with increasing age
Age: insulin/glucose
• ↑ [insulin] and [glucose] with ↑ age
○ ↑ insulin resistance
○ ↓ peripheral glucose uptake
• ↑ prevalence metabolic syndrome with ↑ age
Metabolic syndrome
‘Constellation of closely associated CV risk factors’
• Visceral obesity
• Dyslipidaemia
• Hyperglycaemia
• Hypertension
INSULIN RESISTANCE is the underlying pathophysiological mechanism
Menopause
Menopause = ovarian failure • Oestrogen levels ○ Pre-menopausal: cycling ○ Post-menopausal: very low constant levels § ↓E2, ↑LH / FSH • ? Brain & ovary are ‘pacemakers’ ○ Age at menopause 50 ± 2 years • Symptoms: ○ Hot flushes, night sweats ○ Median duration of menopausal symptoms 7 years • Morbidity: ○ ↑ osteoporosis, ↑ CHD, ↑ sexual dysfunction
Post-menopausal HRT
Initial observational studies showed benefits
• ‘healthy user bias’
Some subsequent RCTs showed no benefits and increased risks
• However risk : benefit ratio depends on
○ Other risk factors
○ Age of woman and duration of HRT use
§ greater risk if >60 yrs, >10 year post-MP
○ Type of HRT (oestrogen, progestogen, route)
Post-menopausal HRT benefits and risks
Benefits:
• Rx menopausal Sx
• Decreased osteoperosis/fracture risk for duration Rx
Risks
• Increased venous thrombo-embolism
• Increased breast cancer (small) esp > 5 years
• Increased endometrial cancer if use unopposed E2
Post-menopausal hormone therapy treatment goals
Goal of treatment shifted back:
• From replacement to prevent disorders associated with post-menopausal oestrogen deficiency, like osteoperosis
• To treatment of menopausal symptoms - short term, lowest effective dose, younger menopausal women
Male gonadal axis
Different for men
Gradual decrease in testosterone with increased age
Wide range of normality at all ages
@75 years, mean [testo] is 2/3 that @ 25 years
Poor association between libido/erectile dysfunction and [testo]
Testosterone prescriptions increased 500% over the past decade
Age: male gonadal axis
Clinical hypogonadism
• ↓ sexual function
• ↑ osteoporosis
• ↓ muscle strength
Testosterone treatment effects on bones?
Bones
• Increase in bone mineral density if hypogonadal
• ? effect on fracture risk ?
• Bisphosphonates work, independent of androgen status
Testosterone treatment on body composition
- Increase in lean body mass
- Decrease in fat mass
- No convincing functional benefits demonstrated
- Increase in muscle strength with supra-physiological doses
Potential effects of testosterone treatment but not enough data
• Atherosclerosis / coronary artery disease
• Sexual function
○ Most erectile dysfunction is atherosclerotic
○ Drugs like sildenafil (‘Viagra’) may work
• Cognitive function
• Mood / quality of life
Risks of testosterone treatment
• Prostate (benign prostatic hypertrophy / cancer)
• Erythropoeisis (increase in haematocrit)
? Cardiovascular risk ?
GH-IGF-I axis
Decreased integrated [GH] with increased age; Decreased [IGF-I] with age
Wide variation in ‘normal range’
GH treatment
Body composition • increase lean body mass ~ 2 kg • Decrease in fat mass ~ 2 kg • No convincing functional benefits demonstrated No significant change • Bone mineral density • Lipids ○ Decrease in T Chol N.S. after adjusting for change in body composition • Potential risks ○ ↑ cancer: ↑ [IGF-I] in observational studies is associated with ↑ risk non-smoking related Ca ○ prostate, colon, breast • Increase in T2 DM Side-effects • Soft tissue oedema • Arthralgias Carpal tunnel syndrome
Cortisol and age
- ↑ trough levels cortisol with ↑ age
- ↑ average levels cortisol with ↑ age
- Phase advance of diurnal rhythm
- Time at trough and peak both earlier
Sapolsky’s glucocorticoid cascade hypothesis
• ↓ hippocampal glucocorticoid & mineralocorticoid receptors
• ↓ sensitivity to glucocorticoid negative feedback
• ↑ [glucocorticoids]
• Þ hippocampal neurons vulnerable to damage
• ‘feed forward cascade’
○ ↓ volume hippocampus on MRI – no differences in volume of adjacent structures
• Other roles of hippocampus: learning, memory
○ ↑ cortisol associated with ↑ decline cognitive function
DHEA (dehydropiandrosterone)
Decline in DHEA with age in men and women
Regulation / action of DHEA
? ACTH +
? Action via androgen and/or oestrogen R ?
• ‘Pro-hormone’
• Potential for adverse effects of treatment (prostate, breast) –
not demonstrated
? Importance in men
• Overwhelming excess of more potent circulating androgens
• Contribution to androgenic effects in men ‘modest’ at most
Effect of age on DHEAS
↓[DHEAS] with age
• By 70-80 yrs, [DHEAS] ~ 5-10% of peak
• Observational studies have suggested ↑[DHEAS] is associated with:
○ ↑QOL, ↑bone mineral density,
○ ↓cognitive decline, ↓ coronary heart disease
• ?↓[DHEA] is a non-specific marker of ill health
○ Associations may not be not causal
○ ↓[DHEA] / ↓ [DHEA]:cortisol ratio found in cancer, inflammatory diseases, T2DM, CV disease
• USA
• Regulated by FDA, a food supplement, not a drug
• Readily available
• ¯Regulation
○ Claims may be unsubstantiated
○ Composition varies - may contain 0 - 15% of amount stated on packet
Thyroid function
Slight increase [TSH] with age
T4 →
↓ peripheral T4 → T3 conversion with age
↓ [T3] with age
No evidence for beneficial effect of T4 treatment!
May do harm
• ?↑ risk osteoporosis, atrial fibrillation
? risk in elderly with atherosclerotic coronaries
Starvation/anorexia nervosa: insulin, glucose and leptin
↓ insulin, ↓ glucose, ↑ insulin sensitivity
LEPTIN
• Produced by white adipose tissue
○ [leptin] correlates with BMI and body fat
• Reports nutritional information to the hypothalamus
○ ‘Starvation signal’: signals energy availability
○ ↓[leptin] Þ ↑ food intake, ↓ energy expenditure,
○ ↓[leptin] Þ ↓ fertility
§ Permissive factor for initiation of puberty
Starvation/AN: oestrogen/testosterone
↓ LH, ↓ FSH, ↓ oestrogen / testosterone ↓ fertility, amenorrhoea • ‘hypothalamic amenorrhoea’ • makes ‘evolutionary sense’ in times of famine Osteoporosis • Rx HRT / COCP
Links between metabolism and reproduction
Ob/Ob mouse • Hyperphagic & obese Also • Low gonadotrophins • Incomplete development of reproductive organs • Does not reach sexual maturity • Infertile
Ob Ob mouse: • Hyperphagic & obese ALSO • Low gonadotrophins • Incomplete development of reproductive organs • Does not reach sexual maturity • Infertile
Leptin Rx: • Reduce obesity ALSO • Restore Gn secretion • Mature gonad • Induce puberty • Restore fertility
Central mediator: kisspeptin
A GnRH secretagogue
KISS1 neurons highly responsive to oestrogen, implicated in both + and – central feedback of sex steroids on GnRH production
Metabolic influences on reproduction mediated by leptin via the kisspeptin system
• Puberty
• Reproduction
Oestrogen can +/- kiss neurons depending on their location and the developmental stage of the animal
Starvation/AN: GH/IGF axis
• ‘GH resistance’ ○ ↑ GH, ↓ IGF-I • Seen in acute starvation and in AN • ? down-regulation hepatic GH receptor and / or post-receptor defect • Reversible with re-feeding
Starvation/AN: cortisol
TSH and T4 lower limit of normal ↓ T4 conversion to T3 Þ ↓ T3 (active) ↑ T4 conversion to rT3 Þ ↑ rT3 (inactive) Consequences • Lower basal metabolic rate • Conserve energy
