L12 - Endocrinology of ageing Flashcards
Evolutionary perspective
We are outliving our natural lifespan
Hormonal function:
- menopause
- andropause
- 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
What is meant by ‘medicalisation’ of ageing?
Increased life expectancy may not equate to increased health expectancy
It is important to balance the benefit and harm of treatment
-especially cancer risk in elderly
Association and causation
Similar phenotypes: -hypogonadism/growth hormone deficiency/ageing =>^ fat mass ^ visceral fat =>sarcopenia =>decreased bone mineral density =>decreased mood/QOL =>^ risk CVD
Phenotypes are :
- non-specific
- high prevalence
Age: Nutritional status
Weight
- increases from mid 30s
- to 50-70yrs
Lean body mass
-decreases 6-8%/ decade from mid - 30s
Diet
-trend towards decreasing intake total energy and protein with increasing age
Age: insulin/glucose
increased insulin and glucose with increasing age
increases insulin resistance
decrease in peripheral glucose uptake
increase in prevalence of metabolic syndrome with increasing age
What is metabolic syndrome?
Constellation of closely associated CV risk factors
- visceral obesity
- dyslipidaemia
- hyperglycaemia
- hypertension
Insulin resistance is the underlying pathophysiological mechanism
Age: menopause definition
Menopause=ovarian failure
Oestrogen levels pre and post menopause
pre-menopausal: cycling
post-menopausal: very low constant levels
-decreased oestrogen, increased FSH and LH
Symptoms of menopause
hot flushes
night sweats
median duration of menopausal symptoms is 7 years
Age at menopause
approx 50 +/- 2 yrs
Morbidity associated with menopause
increased risk of osteoporosis, CHD and sexual dysfunction
Post-menopausal HRT: risks v benefits?
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 >60yrs, >10yrs post-MP
- type of HRT (oestrogen, progesterone, route)
Benefits of post-menopausal HRT
Rx menopausal Sx
Decreased osteoporosis/fracture risk
-for duration Rx
Risks of post-menopausal HRT
Increase venous thromboembolism
Increase breast cancer (small)
-esp > 5 years
Increase endometrial cancer
-if use unopposed oestrogen
Goal of post-menopausal HRT
shifted back from ‘replacement’ (to prevent disorders associated with post-menopausal oestrogen deficiency, like osteoporosis) to ‘treatment’ of menopausal symptoms
-short term, lowest effective dose, younger menopausal women
Male gonadal axis
Gradual decrease in testosterone with increasing age
Wide range of normality at all ages
At 75yrs, mean testosterone approx 2/3 of that at 25yrs
Poor association between libido/erectile dysfunction and testosterone
Testosterone prescriptions increased by 500% over the past decade
Clinical hypogonadism
decreased sexual function
increase osteoporosis
decreased muscle strength
Testosterone treatment: Bones
increase bone mineral density if hypogonadal
? effect on fracture risk ?
bisphosphonates work, independent androgen status
Testosterone treatment: body composition
increase lean body mass
decreased fat mass
no convincing functional benefits demonstrated
increase muscle strength with supra-physiological doses
Testosterone treatment: benefits and risks
Little/no evidence of benefit/insufficient data
- atherosclerosis/coronary artery disease
- sexual function
- most erectile dysfunction is atherosclerotic
- drugs like sildenafil (viagra) may work
- cognitive function
- mood/ QOL
Risks
- prostate (benign prostatic hypertrophy/cancer)
- erythropoeisis (increased haematocrit)
- ? cardiovascular risk ?
Effect of weight loss on testosterone
increase in total testosterone when increase in body weight loss
positive correlation
GH treatment
Body composition
- increased lean body mass approx 2kg
- decreased fat mass approx 2kg
- no convincing functional benefits demonstrated
No significant change
- bone mineral density
- lipids
Potential risks and side-effects of GH treatment
Potential risks
-increases risk of cancer: increases [IGF-1] in observational studies is associated with increase risk of non-smoking cancers such as prostate, colon and breast
Side-effects
- soft tissue oedema
- arthralgias
- carpal tunnel syndrome
Age: cortisol
↑ trough levels cortisol with ↑ age
↑ average levels cortisol with ↑ age
Phase advance of diurnal rhythm
-Time at trough and peak both earlier
DHEA
decline in men and women with age
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 of DHEA in men
Overwhelming excess of more potent circulating androgens
Contribution to androgenic effects in men ‘modest’ at most
DHEA in USA
Regulated by FDA
A food supplement, not a drug
Readily available
Decreased regulation
- Claims may be unsubstantiated
- Composition varies
- May contain 0 - 15% of amount stated on packet
DHEA benefits and adverse effects?
No evidence of beneficial effects on
- Body composition
- Physical performance
- Insulin sensitivity
- QOL
No adverse effects demonstrated
Multiple studies have not demonstrated any positive effect of DHEA in ageing individuals
No evidence for use
Age: 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/AN: 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] ↑ food intake, ↓ energy expenditure,
↓[leptin] ↓ 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
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
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
look at graphs
STARVATION / AN:
THYROID FUNCTION
TSH and T4 lower limit of normal
↓ T4 conversion to T3 ↓ T3 (active)
↑ T4 conversion to rT3 ↑ rT3 (inactive)
Consequences
- Lower basal metabolic rate
- Conserve energy
