12. Endocrinology of aging Flashcards

1
Q

Determinants of age

A
• 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
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2
Q

Different perspectives

A
• 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
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3
Q

Medicalisation of ageing

A
• 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
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4
Q

Association and causation

A

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

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5
Q

Age: nutritional status

A

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

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6
Q

Age: insulin/glucose

A

• ↑ [insulin] and [glucose] with ↑ age
○ ↑ insulin resistance
○ ↓ peripheral glucose uptake
• ↑ prevalence metabolic syndrome with ↑ age

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7
Q

Metabolic syndrome

A

‘Constellation of closely associated CV risk factors’
• Visceral obesity
• Dyslipidaemia
• Hyperglycaemia
• Hypertension
INSULIN RESISTANCE is the underlying pathophysiological mechanism

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8
Q

Menopause

A
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
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9
Q

Post-menopausal HRT

A

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)

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10
Q

Post-menopausal HRT benefits and risks

A

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

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11
Q

Post-menopausal hormone therapy treatment goals

A

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

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12
Q

Male gonadal axis

A

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

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13
Q

Age: male gonadal axis

A

Clinical hypogonadism
• ↓ sexual function
• ↑ osteoporosis
• ↓ muscle strength

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14
Q

Testosterone treatment effects on bones?

A

Bones
• Increase in bone mineral density if hypogonadal
• ? effect on fracture risk ?
• Bisphosphonates work, independent of androgen status

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15
Q

Testosterone treatment on body composition

A
  • Increase in lean body mass
    • Decrease in fat mass
    • No convincing functional benefits demonstrated
    • Increase in muscle strength with supra-physiological doses
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16
Q

Potential effects of testosterone treatment but not enough data

A

• Atherosclerosis / coronary artery disease
• Sexual function
○ Most erectile dysfunction is atherosclerotic
○ Drugs like sildenafil (‘Viagra’) may work
• Cognitive function
• Mood / quality of life

17
Q

Risks of testosterone treatment

A

• Prostate (benign prostatic hypertrophy / cancer)
• Erythropoeisis (increase in haematocrit)
? Cardiovascular risk ?

18
Q

GH-IGF-I axis

A

Decreased integrated [GH] with increased age; Decreased [IGF-I] with ­ age
Wide variation in ‘normal range’

19
Q

GH treatment

A
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
20
Q

Cortisol and age

A
  • ↑ trough levels cortisol with ↑ age
    • ↑ average levels cortisol with ↑ age
    • Phase advance of diurnal rhythm
    • Time at trough and peak both earlier
21
Q

Sapolsky’s glucocorticoid cascade hypothesis

A

• ↓ 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

22
Q

DHEA (dehydropiandrosterone)

A

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

23
Q

Effect of age on DHEAS

A

↓[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

24
Q

Thyroid function

A

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

25
Q

Starvation/anorexia nervosa: insulin, glucose and leptin

A

↓ 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

26
Q

Starvation/AN: oestrogen/testosterone

A
↓ LH, ↓ FSH, 
↓ oestrogen / testosterone
↓ fertility, amenorrhoea
	• ‘hypothalamic amenorrhoea’
	• makes ‘evolutionary sense’ in times of famine
Osteoporosis
	• Rx HRT / COCP
27
Q

Links between metabolism and reproduction

A
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
28
Q

Central mediator: kisspeptin

A

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

29
Q

Starvation/AN: GH/IGF axis

A
• ‘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
30
Q

Starvation/AN: cortisol

A
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