Effects of Age and Diet on Endocrine Function

Question 1

Effects of age on endocrine function

• look at … status
• …/… levels
• … axis i.e. menopause, ‘andropause’
• GH-IGF system - what is this?
• … levels
• DHEA
• … function

Answer 1

• look at nutritional status
• Insulin/glucose levels
• Gonodal axis i.e. menopause, ‘andropause’
• GH-IGF system - growth hormone / IGF system
• Cortisol levels
• DHEA - dehydroepiandrosterone
• Thyroid function

Question 2

Effects of diet on endocrine function

• Starvation
• … Nervosa
  
  • …/glucose levels
  • L… levels
  • … axis
  • GH-IGF system - what is this
  • C… levels
  • … function

Answer 2

• Starvation
• Anorexia Nervosa
  
  • insulin/glucose levels
  • leptin levels
  • Gonodal axis
  • GH-IGF system - Growth hormone IGF system
  • Cortisol levels
  • Thyroid function

Question 3

Different perspectives on age, diet and endocrine function

• Evolutionary perspective is what?
  
  • Hormonal function:
    
    • …pause exists
    • ‘andropause’
    • ‘somatopause’
    • ‘adrenopause’
• Cultural perspective is what?
  
  • Anti-aging results in … google hits
• Pharma perspective is what?

Answer 3

• Evolutionary perspective
  
  • We are outliving our natural lifesan
  • Hormonal function:
    
    • menopause
    • ‘andropause’
    • ‘somatopause’
    • ‘adrenopause’
• Cultural perspective is what?
  
  • Anti-aging results in 3,000,000 google hits
• Pharma perspective is what?
  
  • enourmous market - especially compared to endocrine market for testosterone / GH

Question 4

Is 80 the new 60?

“Just because that happens doesnt mean that it’s health or inevitable … there must be a supplement or hormone that I can take to counteract it”

who said this?

Answer 4

healthy 76 yo compaining of loss of flexibility (yoga expert)

Question 5

‘Medicalisation’ - Aging and endocrine function

• Increased … expectancy may not equate to increased … expectancy
• ‘Usual ageing’ what does this mean?
  
  • physiological?
  • pathological?
  • optimal?
• Hormonal influence
  
  • dwarfed by other influences, what are these? (4)
• Balance of … and … of treatment
  
  • risks - esp … risk in elderly
  • … - GH/testo not … active
  • … involved

Answer 5

• Increased life expectancy may not equate to increased health expectancy
• Usual ageing
  
  • physiological?
  • pathological?
  • optimal?
• Hormonal influence
  
  • dwarfed by other influences, what are these? (4)
    
    • Genetic
    • Environmental
    • Psychosocial
    • Co-morbidities
    • • Balance of benefit and harm of treatment
  • risks - esp cancer risk in elderly
  • hassle - GH/testo not orally active
  • Costs involved

Question 6

Association and Causation - Aging and endocrine function

• Similar ‘phenotypes’ between …/… deficiency and aging
  
  • Increased … mass, increased … fat
  • Sarco…
  • Decreased bone … density
  • Decreased …/mood
  • Increased risk of … disease
• BUT:
  
  • Phenotypes are non-… and high …

Answer 6

• Similar ‘phenotypes’ between Hypogonadism/GH deficiency and aging
  
  • Increased fat mass, increased visceral fat
  • Sarcopaenia
  • Decreased bone mineral density
  • Decreased QOL/mood
  • Increased risk of CV disease
• BUT:
• Phenotypes are non-specific and high prevalence

Question 7

Age: Nutritional status

• Weight
  
  • increases from mid-…s
  • Plateau after age of … onwards
• Lean body mass
  
  • declines by approx …-…% / decade from mid …s
• Diet
  
  • trend towards (decrease or increase?) intake total energy and protein with increasing age

Answer 7

• Weight
  
  • increases from mid-30s
  • Plateau after age of 50-70
• Lean body mass
  
  • declines by approx 6-8% / decade from mid 30s
• Diet
  
  • trend towards decreased intake total energy and protein with increasing age

Question 8

Age: Insulin/glucose

• As you get older what happens to levels of insulin and glucose?
  
  • What happens to insulin resistance?
  • What happens to peripheral glucose uptake?
• Increased prevalence of … syndrome with increased age

Answer 8

• As you get older what happens to levels of insulin and glucose? insulin and glucose levels increase
  
  • What happens to insulin resistance? - increases
  • What happens to peripheral glucose uptake? - decreases
• Increased prevalence of metabolic syndrome with increased age

Question 9

Metabolic syndrome

• ‘Constellation of closely associated … risk factors’
  
  • These are … (4)
• … resistance is the underlying pathophysiological mechanism

Answer 9

• ‘Constellation of closely associated CV risk factors’
  
  • These are … (4)
    
    • Visceral obesity
    • Dyslipidaemia
    • Hyperglycaemia
    • Hypertension
• Insulin resistance is the underlying pathophysiological mechanism

Question 10

This graph shows that the prevalence of … syndrome goes up by age

Answer 10

metabolic syndrome

Question 11

What axis is shown?

Answer 11

Gonadal axis

Question 12

Age: Menopause

• Menopause means what?
  
  • Oestrogen levels:
    
    • Pre-menopausal: there is a …
    • Post-menopausal: levels are … meaning levels of LH and FSH are … - why?
  • ? What causes menopause
  • Average age of menopause is roughly … with a standard deviation of 2 years
  • Symptoms of menopause include … (2)
  • Symptoms median duration is … years
  • Morbidity:
    
    • Increased chance of osteo… increased CHD - what is this? increased sexual …

Answer 12

• Menopause means ovarian failure
  
  • Oestrogen levels:
    
    • Pre-menopausal: there is a cycle
      
      • Post-menopausal: levels are very low meaning levels of LH and FSH are constantly high - why? - because of the lack of negative feedback
      • ? What causes menopause - brain and ovary are ‘pacemakers’
      • Average age of menopause is roughly 50 with a standard deviation of 2 years
      • Symptoms of menopause include hot flushes, night sweat
      • Symptoms median duration is 7 years
      • Morbidity:
        
        • Increased osteoporosis increased CHD (coronary heart disease)increased sexualdysfunction

Question 13

Age: Menopause - Post-Menopausal HRT

• Hormone replacement therapy
  
  • Initial observational studies showed benefits (… user bias)
  • Some subsequent RCTs showed what?
  • However, ratio depends on
    
    • other risk factors
    • … of woman and … of use
      
      • greater risk if >…yrs, >…yrs post-MP
    • … of HRT (oestrogen, progestogen, route)

Answer 13

• Hormone replacement therapy
  
  • 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 use
      
      • greater risk if >60yrs, >10yrs post-MP
    • Type of HRT (oestrogen, progestogen, route)

Question 14

Post-menopausal HRT

• Benefits
  
  • Treatment of menopausal symptoms
  • decreased risk of … / fracture risk
    
    • for … of treatment only
• Risks
  
  • increased risk of venous …-…
  • increased … cancer risk (esp >5yrs)
  • increased … cancer if unopposed oestrogen is used

Answer 14

• Benefits
  
  • Treatment of menopausal symptoms
  • decreased osteoporosis / fracture risk
    
    • for duration of treatment
• Risks
  
  • increased risk of venous thrombo-embolism - particularly smokers
  • increased breast cancer risk (esp >5yrs)
  • increased endometrial cancer - if use unopposed oestrogen used

Question 15

Post-menopausal HRT - goals of treatment

• Goals have shifted back:
  
  • from … (to prevent disorders associated with post-menopausal oestrogen deficiency, like osteoporosis)
  • To … of menopausal …
    
    • … term, … effective dose, … menopausal women

Answer 15

• 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

Question 16

Male Gonadal Axis

• Gradual testosterone … with increased age
• Wide range of … at all ages
• @ 75 years, mean testosterone is …/… that @ 25years
• … association between libido / erectile dysfunction and testosterone
• Testosterone prescriptions increased by …% over the past decade

Answer 16

• Gradual testosterone decrease with increased age
• Wide range of normality at all ages
• @ 75 years, mean testosterone is 2/3 that @ 25years
• Poor association between libido / erectile dysfunction and testosterone
• Testosterone prescriptions increased by 500% over the past decade

Question 17

What does this figure illustrate?

Answer 17

The gradual decline in testosterone with age

Question 18

What is this table showing?

Answer 18

Testosterone range for 95% of healthy men

Question 19

Age - Male Gonodal Axis

• Clinical hypo…
  
  • … sexual function
  • … risk of osteoporosis
  • … muscle strength
• Questions
  
  • are some features of ageing secondary … deficiency
  • Would treatment be beneficial or risky?

Answer 19

• Clinical hypogonadism
  
  • decreased sexual function
  • increased risk of osteoporosis
  • decreased muscle strength
• Questions
  
  • are some features of ageing secondary androgen deficiency
  • Would treatment be beneficial or risky?

Question 20

Testosterone treatment in older men

• Are there improvements in sexual function?
  
  • most erectile dysfunction in older age is …
  • drugs like sildenafil (‘…’) may work
• Little or no evidence of benefit or insufficient data that testosterone improves… (3)
• Potential risks
  
  • … (benign prostatic hypertrophy / cancer)
  • … (increased haematocrit)
  • ? … risk (MI/strokes)

Answer 20

• There are small improvements in sexual function
  
  • most erectile dysfunction in older age is atherosclerotic
  • drugs like sildenafil (‘viagra’) may work
• Little or no evidence of benefit or insufficient data
  
  • physical function, including energy & vitality
  • cognitive function
  • mood/QOL
• Potential risks
  
  • prostate (benign prostatic hypertrophy / cancer)
  • erythropoeisis (increased haematocrit)
  • ? CVS risk (MI/strokes)

Question 21

Testosterone treatment in older men (2)

• Bones
  
  • increased bone … … if hypogonadal
  • What is the effect on fractures?
  • … work, independent of androgen status
• Body composition
  
  • … lean body mass
  • … fat mass
  • no convincing functional benefits demonstrated
  • increased muscle … with supra-physiological doses

Answer 21

• Bones
  
  • increased bone mineral density if hypogonadal
  • ? Effect on fractures - unknown
  • Bisphosphonates work, independent of androgen status
• Body composition
  
  • increased lean body mass
  • decreased fat mass
  • no convincing functional benefits demonstrated
  • increased muscle strength with supra-physiological doses

Question 22

What are these quotes discussing treatment of?

Answer 22

Testosterone treatment in older men

Question 23

What axis is shown here?

Answer 23

GH-IGF-1-axis

Question 24

GH-IGF-1-Axis - age

• … integrated GH with increased age, … IGF-1 with increased age
• Wide variation in … range

Answer 24

• decreased integrated GH with increased age, decreased IGF-1 with increased age
• Wide variation in normal range

Question 25

_GH treatment in older individuals_ * Body composition * Lean body mass? * Fat mass? * Overall are there benefits for this? * Is there a significant change in * bone mineral density? * Lipids?

Answer 25

* Body composition * Lean body mass? - **increases by about 2kg** * Fat mass? - **decreases by about 2kg** * Overall are there benefits for this? - **no convincing functional benefits demonstrated** * Is there a significant change in * bone mineral density? - **no** * Lipids? - **slight improvement in total cholesterol levels (reduced)**

Question 26

_Risks of GH treatment in older adults_ * What are the potential risks? (2) * higher IGF-1 is associated with... * increased risk of type ... * What are the side-effects? (3)

Answer 26

* Potential risks include: * increased risk of cancer (increased IFG-1) in observational studies is associated with increased risk non-smoking related cancer (i.e. prostate, colon, breast) * also increased risk of T2 DM * Side effects: * soft tissue oedema * arthralgias * carpal tunnel syndrome

Question 27

What is this quote discussing?

Answer 27

Growth hormone

Question 28

What axis is this?

Answer 28

Hypothalamic-pituitary-adrenal axis

Question 29

_Effects of age on cortisol levels_ * ... trough levels cortisol with increased age * ... average levels with increased age * phase advance of ... rhythm * time at trough and peak both earlier or later?

Answer 29

* **Increased** trough levels cortisol with increased age * **increased** average levels with increased age * phase advance of **diurnal** rhythm * time at trough and peak both **earlier**

Question 30

_Sapolsky's glucocorticoid cascade hypothesis_ * ... hippocampal glucocorticoid and mineralocorticoid receptors with increasing age * ... sensitivity to glucocorticoid negative feedback * Hippocampal ... vulnerable to damage * 'feed forward cascade' * volume hippocampus ... on MRI - no differences in volume of adjacent structures * Hippocampus roles include learning and memory * Therefore cortisol associated with **what?**

Answer 30

* Decreased hippocampal glucocorticoid and mineralocorticoid receptors with increasing age * Decreased sensitivity to glucocorticoid negative feedback * Hippocampal neurons vulnerable to damage * 'feed forward cascade' * volume hippocampus decreased on MRI - no differences in volume of adjacent structures * Hippocampus roles include learning and memory * Therefore cortisol associated with **increased decline of cognitive function**

Question 31

DHEAS is an ... androgen

Answer 31

DHEAS is an **adrenal** androgen

Question 32

What happens to levels of DHEA with age?

Answer 32

Declining levels with age

Question 33

_DHEA - regulation of action_ * regulation of action of DHEA - unclear * ?stimulated same as cortisol, by ... * ?Action via androgen and/or oestrogen receptors * '...-hormone' * Potential for adverse effects of treatment (... , ... tissue) - not demonstrated

Answer 33

* regulation of action of DHEA - unclear * ?**ACTH** - same as cortisol * ?Action via androgen and/or oestrogen receptors * '**pro**-hormone' * Potential for adverse effects of treatment (**prostate**, **breast**) - not demonstrated

Question 34

_DHEA - importance in men?_ * Overwhelming excess of more potent circulating ... * Contribution to androgenic effects in men '...' at most

Answer 34

* Overwhelming excess of more potent **circulating** androgens * Contribution to androgenic effects in men '**modest**' at most

Question 35

_DHEAS - age_ * Levels ... with age * by 70-80, DHEAS is ...% of peak * Observational studies have suggested increased DHEAS is associated with increased ... (2) and decreased ... (2) * Decreased DHEA is a non-specific marker of ... health * associations may not be ... * decreased DHEA / DHEA:cortisol ratio found in ... (4 conditions/diseases)

Answer 35

* Levels **d****ecrease** with age * by 70-80, DHEAS is **5-10**% of peak * Observational studies have suggested increased DHEAS is associated with increased **QOL and bone mineral density** (2) and decreased **cognitive decline and coronary heart disease**(2) * Decreased DHEA is a non-specific marker of **ill** health * associations may not be **causal** * decreased DHEA / DHEA:cortisol ratio found in **cancer, inflammatory disease, T2DM, CV disease**

Question 36

_DHEA - USA_ * Is it regulated? * Is it a drug or supplement? * Is it readily available? * Is it well regulated?

Answer 36

* Is it regulated - **Yes - FDA** * Is it a drug or supplement - **Food Supplement** * Is it readily available? - **yes** * Is it well regulated? - no - **composition** varies - may contain **0-15**% of amount stated on packet

Question 37

_DHEA - overview_ * Is there evidence of beneficial effects on: * body composition? * physical performance? * insulin sensitivity? * QOL? * Are there any adverse effects demonstrated? * Have studies demonstrated any positive effect of DHEA in aging individuals ? * evidence for use?

Answer 37

* Is there evidence of beneficial effects on: * **body composition? - no** * **physical performance? - no** * **insulin sensitivity? - no** * **QOL? - no** * Are there any adverse effects demonstrated? - **no** * **Multiple** studies have **not** demonstrated any positive effect of DHEA in aging individuals * **No evidence for use**

Question 38

What axis is shown?

Answer 38

Thyroid axis

Question 39

_Age: Thyroid function_ * Slight ... TSH with age * T4 levels? * ... peripheral T4 -\> T3 conversion with age * ... T3 with age * evidence for beneficial effect of T4 treatment ? * may do ... * What are 3 risks?

Answer 39

* Slight **increase** TSH with age * T4 levels? - **stay more or less same** * **Decreased** peripheral T4 -\> T3 conversion with age * **Decreased** T3 with age * **No evidence for beneficial effect of T4 treatment** * may do **harm** * risk of **osteoporosis**, **atrial fibrillation** * **risk in elderly with atherosclerotic coronaries**

Question 40

_Starvation/AN - insulin, glucose and leptin_ * What happens to Insulin and glucose levels and insulin sensitivity? * Leptin is produced by ... * leptin correlates with ... * reports ... information to the hypothalamus * '... signal' signals energy availability * ... leptin = increase food intake, decrease energy expenditure * decrease leptin = decreased ... * permissive factor for initiation of ...

Answer 40

* What happens to Insulin and glucose levels and insulin sensitivity? - **glucose and insulin levels decrease, insulin sensitivity increases** * Leptin is produced by **white adipose tissue** * leptin correlates with **BMI and body fat** * reports **nutritional** information to the hypothalamus * '**starvation** signal' signals energy availability * **decreased** leptin = increase food intake, decrease energy expenditure * decrease leptin = decreased **fertility** * permissive factor for initiation of **puberty**

Question 41

_Starvation/AN - oestrogen/testosterone_ * .... LH and FSH * ... oestrogen and testosterone * ... fertility, amenorrhoea * termed 'hypothalamic amenorrhoea' * makes evolutionary sense in times of ... * osteo... - treatment HRT / COCP

Answer 41

* **Decreased** LH and FSH * **Decreased** oestrogen and testosterone * **Decreased** fertility, amenorrhoea * 'hypothalamic amenorrhoea' * makes evolutionary sense in times of **famine** * **osteoporosis** - treatment HRT / COCP

Question 42

_Links between metabolism and reproduction_ * Ob Ob mouse * hyperphagic and obese * Also had: * low ...trophins * incomplete development of ... organs * does not reach ... maturity * fertile? * ... - treatment * reduced obesity * Also: * restored ... secretion * ... gonad * induced ... * restored ...

Answer 42

* Ob Ob mouse * hyperphagic and obese * Also: * low **gonadotrophins** * incomplete development of **reproductive** organs * does not reach **sexual** maturity * **infertile** * **Leptin** - treatment * reduced obesity * Also: * restored **GN** secretion * **mature** gonad * induced **puberty** * restored **fertility**

Question 43

_Central mediator: kisspeptin_ * A ... secretagogue - at the apex of the reproductive axis in the hypothalamus * KISS1 neurons highly responsive to ..., implicated in both + and - central feedback of sex steroids on GnRH production * Metabolic influences on reproduction: * mediated by ...: permissive effect * via the kisspeptin system * puberty and reproduction

Answer 43

* A **GnRH** secretagogue - at the apex of the reproductive axis in the hypothalamus * 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**: permissive effect * via the kisspeptin system * puberty and reproduction

Question 44

What does this show the permissive effect of?

Answer 44

Permissive effect of leptin on kisspeptin

Question 45

_Starvation/AN: GH/IGF axis_ * GH ... * ... GH, ... IGF-1 * Seen in acute ... and in AN * ? down-regulation hepatic GH receptor and / or post-receptor defect * Reversible with ...

Answer 45

* GH **resistance** * **high** GH, **low** IGF-1 * Seen in acute **starvation** and in AN * ? down-regulation hepatic GH receptor and / or post-receptor defect * Reversible with **re-feeding**

Question 46

_Starvation/AN: cortisol_ * Left (Individual data) = fed state * Right (Individual data) = fasting state * What happens to cortisol in fasting state?

Answer 46

* In fasting state - starvation - stress response - increased cortisol pulses - loss of diurnal trough - get increased pulsatility of cortisol

Question 47

_Starvation/AN: Thyroid function_ * TSH and T4 ... limit of normal * ... T4 conversion to T3 - (active) * ... T4 conversion to rT3 (inactive) * Consequences?

Answer 47

* TSH and T4 **lower** limit of normal * **Less** T4 conversion to T3 - (active) * **More** T4 conversion to rT3 (inactive) * Consequences? * **lower basal metabolic rate** * **conserve energy**

Question 48

Do you treat issues with thyroid function during starvation/ anorexia nervosa with thyroxine?

Answer 48

* no - treat starvation / AN * body is trying to conserve energy

Question 49

With increasing age: decrease or increase * E2/T levels ... * DHEA levels ... * FSH (women) levels ... * GH/IGF-1 levels ... * Cortisol levels ... * T3 levels ... * Insulin/glucose levels ...

Answer 49

* **E2/T - decrease** * **DHEA - decrease** * **FSH (women) - increase** * **GH/IGF-1 - decrease** * **Cortisol - increase** * **T3 - decrease** * **Insulin/glucose - decrease**

Question 50

_During starvation/AN: high or low_ * E2/T levels ... * Leptin levels ... * FSH/LH levels ... * GH levels ... * IGF-1 levels ... * Cortisol levels ... * T3 - active levels .. inactive levels..

Answer 50

* E2/T - low * Leptin - low * FSH/LH - low * GH - high * IGF-1- low * Cortisol - high * T3 - low active, high inactive