EFFECTS OF AGE AND DIET__2022_studentcentral.pptx

EFFECTS OF AGE AND DIET ON ENDOCRINE FUNCTION Dr Anna Crown Age, diet and endocrine function Topics • Endocrine changes in old age. • Hormone treatment in the elderly. • Diet and endocrine disorders (obesity and anorexia nervosa). Learning Outcomes • To understand changes in the endocrine system...

EFFECTS OF AGE AND DIET ON ENDOCRINE FUNCTION Dr Anna Crown Age, diet and endocrine function Topics • Endocrine changes in old age. • Hormone treatment in the elderly. • Diet and endocrine disorders (obesity and anorexia nervosa). Learning Outcomes • To understand changes in the endocrine system associated with old age, the risk/benefit profile of hormone treatment in the elderly, and associations of diet with endocrine disorders EFFECTS OF AGE AND DIET ON ENDOCRINE FUNCTION • • • DIET ‘Hormone deficiencies in ageing’ – Is hormone treatment the elixir of youth? Starvation AGE Anorexia Nervosa – – – – – – – – – – – – – Nutritional status Insulin / glucose Insulin Leptin / glucose Gonadal Gonadal axis axis • Menopause GH – IGF system • ‘Andropause’ Cortisol GH – IGF system Thyroid function Cortisol DHEA Thyroid function NB: not referring to patients with ‘organic’ causes of endocrine diseases! DIFFERENT PERSPECTIVES • CULTURAL EVOLUTIONARY PERSPECTIVE PERSPECTIVE – ‘Anti-aging’ We are outliving results ourinnatural >500,000,000 lifespanGoogle – hits Hormonal function: • • ‘MENOPAUSE’ • ‘ANDROPAUSE’ PHARMA PERSPECTIVE – ‘ADAM’ – Enormous market • ‘SOMATOPAUSE’ •• Especially compared to ‘endocrine’ market for ‘ADRENOPAUSE’ testosterone / GH “80 is the new 60”? • ‘…..just because that happens doesn’t mean that it’s healthy or inevitable….. there must be a supplement or hormone that I can take to counteract it….’ – Healthy 76 year old woman (yoga expert) complaining of loss of flexibility – ‘An Aging Un-American’ » NEJM (2006) 355 1415 ‘MEDICALISATION’ • Hormonal life expectancy influence? may not equate to health expectancy – Dwarfed by • Genetic • ‘Usual ageing’ • Environmental – Physiological? • Psychosocial •• ‘Normal’? Co-morbidities – Pathological? • Balance of benefit & harm of treatment – – Optimal? Risks • Esp cancer risk in elderly • Boundaries – Hassle of medicine? • GH / testo not orally active – Costs ASSOCIATION & CAUSATION • ‘Phenotypes’ Similar ‘phenotypes’ are – Non-specific Hypogonadism / growth hormone deficiency / – aging High prevalence •• • • • •  fat mass,  visceral fat Universal? Sarcopaenia  Bone mineral density  QOL / mood  risk cardiovascular disease AGE: Nutritional status • WEIGHT – ↑ from mid-30s – → 50 – 70 • LEAN BODY MASS – ↓ 6-8% / decade from mid-30s • DIET – Trend towards ↓ intake total energy & protein with ↑ 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 Metabolic Syndrome Prevalence by AGE AND GENDER Men Women ALL 20-29 30-39 40-49 50-59 60-69 ≥70 JAMA (2002) 287 356 GONADAL AXIS AGE: MENOPAUSE • Menopause = ovarian failure – Oestrogen levels • Pre-menopausal: cycling • Post-menopausal: very low constant levels – ↓E2, ↑LH / FSH – ? Brain & ovary are ‘pacemakers’ • Average age at menopause 50 ± 2 years – Symptoms: • • • • Hot flushes, night sweats (‘vasomotor symptoms’) Genitourinary symptoms 8/10 women experience menopausal symptoms; 25% severe Typical duration of menopausal symptoms 2 - 5 years – ↓ bone mineral density after the menopause AGE: MENOPAUSE • 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 • RISKS BENEFITS – ↑Rxvenous menopausal thrombo-embolism Sx oral>transdermal – ↓•osteoporosis / fracture risk – ↑•breast Ca Rx for duration • ↑ risk with longer duration of treatment – ↑ endometrial Ca • if use unopposed E2 POST-MENOPAUSAL HRT First observational trials of HRT WHI trial 2002 ‘Davina McCall effect’ 2022 Future… ‘True point’ of pendulum? POST-MENOPAUSAL HRT • Menopause is a ‘life stage’ not a ‘deficiency state’ • HRT should not be used without a clear indication • HRT should not be used for the sole purpose of disease prevention • Menopause should not be compared to conditions such as hypothyroidism / T1DM Post-menopausal HRT • Goal of treatment shifted back: – from ‘replacement’ (to prevent disorders associated with post-menopausal oestrogen deficiency, like osteoporosis) – to ‘treatment’ of menopausal symptoms • Individualised risk:benefit assessment • Short term, lowest effective dose (annual review) • Consider the route and type of oestrogen and progestogen to minimize risks • Younger menopausal women MALE GONADAL AXIS • DIFFERENT FOR MEN! – – – – Gradual [testosterone] with ↑ age Wide range of normality at all ages @ 75 yrs, mean [testo] ~ 2/3rds that @ 25 yrs Poor association between libido / erectile dysfunction and [testo] – Testosterone prescriptions 500% over the past decade ‘Mature’ dads…… DECLINE IN TESTOSTERONE WITH AGE FREE TESTOSTERONE TOTAL TESTOSTERONE Age & Fountain of Youth Hormones Paul Stewart NEJM (2006) 355 1724-6 Testosterone range for 95% of healthy men AGE / years 40s 50s 60s 70s 2.5TH 8.7 CENTILE [T TESTO] / nmol/l 7.5 6.8 5.4 97.5TH 31.7 CENTILE [T TESTO] / nmol/l 30.4 29.8 28.4 Clin Endo (2005) 62 64-73 AGE: MALE GONADAL AXIS • Clinical hypogonadism – ↓ sexual function – ↑ osteoporosis – ↓ muscle strength • QUESTIONS – Are some features of ageing 2androgen deficiency – Would treatment be beneficial? – Would treatment be risky? NOT A NEW IDEA – Claimed he’d personally experienced • Brown-Sequard effects on virility and well-being – beneficial Lancet 2 (1889) – …..though his ‘watery’ extract of guinea pig & – ‘Note on the effects produced on man by dog testes is unlikely to have contained any subcutaneous injections of a liquid obtained androgens….. from the testicles of animals’ Testosterone treatment in older men • 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 / quality of life • Potential risks – Prostate (benign prostatic hypertrophy / cancer) – Erythropoeisis ( haematocrit) – ? Cardiovascular risk ? (MI / strokes) Annals Int Med 2020 172:126-133 Testosterone treatment in older men • Bones – bone mineral density if hypogonadal – ? effect on fracture risk ? – Bisphosphonates work, independent of androgen status • Body composition – – – – lean body mass fat mass No convincing functional benefits demonstrated muscle strength with supra-physiological doses Testosterone treatment in older men • ‘The ‘As todiagnosis the clinical of picture, partial androgen in view ofdeficiency its low specificity in elderly and males, the high&prevalence certainly the of decision symptoms to possibly implement associated any potentially with hypogonadism harmful intervention, in the elderlyshould population, be approached one should with pragmatism avoid suggesting&orappropriate soliciting symptoms’ reserve’ The decline of androgen levels in elderly men and its clinical and therapeutic implications Kaufman & vermeulen Endo Reviews (2005) 26: 833-876 GH – IGF-I axis GH – IGF-I AXIS integrated [GH] with age; [IGF-I] with age Wide variation in ‘normal range’ Human growth hormone and human aging Endocrine Reviews Corpas, Harman & Blackman (1993) 14 20-39 GH TREATMENT • Body composition – lean body mass ~ 2 kg – fat mass ~ 2 kg – No convincing functional benefits demonstrated • No significant change – Bone mineral density – Lipids • T Chol N.S. after adjusting for change in body composition Systematic review: the safety & efficacy of GH in the healthy elderly Annals of Internal Medicine (2007) 146 104 GH TREATMENT • Potential risks – ↑ cancer: ↑ [IGF-I] in observational studies is associated with ↑ risk non-smoking related Ca • prostate, colon, breast – T2 DM • Side-effects – Soft tissue oedema – Arthralgias – Carpal tunnel syndrome Systematic review: the safety & efficacy of GH in the healthy elderly Annals of Internal Medicine (2007) 146 104 ‘GH – ready for prime time?’ • ‘this agent has captured the fancy of many people who, in quest of greater muscle strength and vitality, appear to have little difficulty obtaining hormone from entrepreneurial physicians, notwithstanding the failure of the scientific literature to support these uses’ • ‘It would be unfortunate if such physicians seized upon [these results] as another profitable alternative to diet and exercise.’ Marcus & Reaven Editorial JCEM (1997) 82 725-726 Hypothalamic-pituitary-adrenal axis AGE: CORTISOL Bergendahl et al, JCEM, 2000 • ↑ trough levels cortisol with ↑ age – ↑ average levels cortisol with ↑ age – Phase advance of diurnal rhythm • Time at trough and peak both earlier AGE: CORTISOL – Sapolsky’s glucocorticoid cascade hypothesis • ↓ hippocampal glucocorticoid & mineralocorticoid receptors with age • ↓ sensitivity to glucocorticoid negative feedback • ↑ [glucocorticoids] • 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 DHEAS: an adrenal androgen Adrenal glands DHEAS ANDROSTENEDIONE Testes Aromatase TESTOSTERONE 5- -reductase DIHYDROTESTOSTERONE OESTROGEN DECLINE IN DEHYDROEPIANDROSTERONE WITH AGE Sulphated DHEA (men & women) Age & Fountain of Youth Hormones Paul Stewart NEJM (2006) 355 1724-6 DHEA • ? Importance Regulation /in action men of DHEA – Overwhelming ? ACTH + excess of more potent – circulating ? Action viaandrogens androgen and/or oestrogen R ? – Contribution • ‘Pro-hormone’ to androgenic effects in men • Potentialatfor ‘modest’ most adverse effects of treatment (prostate, breast) – not demonstrated DHEA • ↓[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 DHEA • 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 DHEA • No Multiple evidence studies of beneficial have not demonstrated effects on – Body any positive effect of DHEA in aging composition – Physical performance individuals. – Insulin sensitivity – QOL • No evidence for use • No adverse effects demonstrated THYROID AXIS AGE: THYROID FUNCTION • • • • Slight [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 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 Metabolism and Reproduction • Leptin Ob Ob Rx: mouse: – Reduce Hyperphagic obesity & obese • ALSO – Restore Low gonadotrophins Gn secretion – Mature Incomplete gonad development of reproductive – organs Induce puberty – notfertility reach sexual maturity – Does Restore – Infertile Central mediator: kisspeptin • 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 & reproduction Kisspeptin system Arcuate nucleus & anteroventral periventricular nucleus Oestrogen can +/- Kiss neurons depending on their location and the developmental stage of the animal Kisspeptin, metabolism & reproduction Permissive effect of leptin on kisspeptin Hameed S et al. 2011;208:97-105 ©2011 by BioScientifica 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 Mean data Individual data Bergendahl et al, JCEM, 2000 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 EFFECTS OF AGE AND DIET ON ENDOCRINE FUNCTION • • • DIET ‘Hormone deficiencies in ageing’ – Is hormone treatment the elixir of youth? Starvation AGE Anorexia Nervosa – – – – – – – – – – – – – Nutritional status Insulin / glucose Insulin Leptin / glucose Gonadal Gonadal axis axis • Menopause GH – IGF system • ‘Andropause’ Cortisol GH – IGF system Thyroid function Cortisol DHEA Thyroid function QUIZ QUIZ • With increasing age: E2 / T DHEA FSH (women) GH / IGF-I Cortisol T3 Insulin / glucose QUIZ • Starvation / AN: Leptin LH / FSH E2 / T GH IGF-I Cortisol T3 THANK-YOU! Questions?