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Age obesity

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Age obesity

  1. 1. Age obesity & osteoporosis Age 2 5 20 50 Milestones ………. happy not to pee your pants happy to have friends happy to have a licence happy to have sex happy to make money happy to have a career
  2. 2. Age 50 90 … .. Tombstones happy not to pee your pants happy to have friends happy to have a licence happy to have sex happy to still make money happy to still have a career
  3. 3. Declaration of conflict of interest Director of a publicly funded BMD unit Director of a publicly funded Endocrinology Unit No advisary boards No pharma associations other than co PI for studies performed through Sydney Menopause Centre (no financial interest) No speakers fee
  4. 4. Longevity & Disease Environmental / Accidental / Exposure infection / toxin / MVA / suicide Mutation / Unstable Genome malignancy Vascular CVD / DM / HT Neurodegenerative Alzheimers / Parkinsons / neuropathies Musculoskeletal DJD / osteoporosis OBESITY A G E
  5. 5. Calle E et al. N Engl J Med 1999;341:1097-1105 Multivariate Relative Risk of Death from All Causes among Men and Women According to Body-Mass Index, Smoking Status, and Disease Status
  6. 6. Calle E et al. N Engl J Med 1999;341:1097-1105 Rates and Relative Risks of Death from All Causes among Subjects Who Had Never Smoked and Who Had No History of Disease, According to Body-Mass Index, Race, and Sex
  7. 7. Calle E et al. N Engl J Med 1999;341:1097-1105 Multivariate Relative Risk of Death from CVD, Cancer & all other causes among Men & Women Who Had Never Smoked & Who Had No History of Disease at Enrollment, According to BMI
  8. 8. Calle E et al. N Engl J Med 1999;341:1097-1105 Rates and Relative Risks of Death from All Causes among Subjects Who Had Never Smoked and Who Had No History of Disease, According to Body-Mass Index, Sex, and Age
  9. 9. Ageing well ? Unknown factors decreased muscle mass bone mineral content GFR LVF increased body fat visceral fat Known factors/ accelerants disease Hypertension Diabetes CVD environment uv light tobacco alcohol
  10. 10. Ageing well ? <ul><li>Oxidative stress </li></ul><ul><li>DNA damage and repair </li></ul><ul><li>Impaired mitochondrial function </li></ul><ul><li>Non infectious inflammation / cytokine and adipocytokine </li></ul><ul><li>FFA increase and increased Insulin resistance </li></ul><ul><li>Garbage accumulation; AGEs and amyloid </li></ul><ul><li>Sympathoadrenal activation </li></ul><ul><li>AII activation </li></ul><ul><li>Postmitotic cell loss / apoptosis (muscle/neurone/osteocyte) </li></ul>
  11. 11. The Endocrinology of Ageing & Obesity <ul><li>Observations </li></ul><ul><ul><ul><ul><ul><li>Sarcopenic Obesity </li></ul></ul></ul></ul></ul><ul><li>Sex hormones </li></ul><ul><ul><ul><ul><ul><li>Women </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Men </li></ul></ul></ul></ul></ul><ul><li>Growth Hormone </li></ul><ul><li>Adrenal Hormones </li></ul><ul><li>Caloric restriction </li></ul>
  12. 12. The Endocrinology of Ageing & Obesity <ul><li>Observations of “sarcopenic obesity” (women > men) </li></ul><ul><li>reduced muscle mass / increased muscle fat (wagu beef) </li></ul><ul><ul><ul><li>Increased fat mass (until > 80) </li></ul></ul></ul><ul><ul><ul><li>Decreased resting metabolic rate </li></ul></ul></ul><ul><ul><ul><li>Decreased exercise & positive caloric balance </li></ul></ul></ul><ul><ul><ul><li>Increased inflammatory markers (THFa, IL6, CRP, ICAM1) </li></ul></ul></ul><ul><ul><ul><li>Decreased GH & IGF </li></ul></ul></ul><ul><ul><ul><li>Decreased DHEA cause or effect? </li></ul></ul></ul><ul><ul><ul><li>Decreased testosterone </li></ul></ul></ul><ul><ul><ul><li>Obligatory postmenopausal estrogen deficiency </li></ul></ul></ul>
  13. 13. ERT, deficiency & Obesity Postmenopausal weight gain is age related Postmenopausal women redistribute fat in an android pattern ERT does not cause weight gain (PEPI) ERT type may cause changes in body composition (hepatic metabolism of IGF BPs / GHBP)
  14. 14. The “other” hormone replacement therapies at the menopause Androgen replacement therapy DHEA replacement Growth hormone replacement Thyroxine replacement
  15. 15. Classification of evidence A RCT A1 many trials/ consistent results A2 one trial/ one result B Population based observational B1 prospective longitudinal B2 case control C Cross sectional Case series D Expert opinion
  16. 16. Mrs DT 58 TAHSPO at age 38 Estrogen implant 6/12 post surgery Symptomatic menopause Continues Premia continuous and plans to do so indefinitely Mammogram normal Hypertension on tritace Husband ED Diminished libido but “unfortunate but its not an issue”
  17. 17. Mrs AW 45 Chemotherapy for AML/BMT/GVHD 6 months amenorrhoea flushes irritable moodiness decreased libido marked BMD deficits T scores 2.6/2.1 Commences livial Symptomatic improvement except libido “ I don’t really care but I really would like to give him a little present”
  18. 18. Ms CS 38 G2P2 (12yr & 22 months) Normal menstrual cycles 28/4 No flushes irritable & moody, not related to menstrual cycles Depressed, out of character Weight gain No libido Commenced Zoloft Some improvement except libido “ I miss it and I want it back”
  19. 19. Ms HSW 51 approx 9 months amenorrhoea Perimenopausal Infrequent hot flushes Tried HRT, bloated, weight gain concerned about risks Ceased HRT Feels somewhat more fatigued than previously Cant seem to do as much as before Libido unchanged, stable relationship Concerned about rapid ageing No major health concerns No medications but takes numerous herbal remedies Enthusiast for natural therapies “ should I be taking DHEA”
  20. 20. Basic Endocrinology you need to know 1) Cholesterol Progesterone DHEA/S Estriol Androstenedione Estrone Testosterone Estradiol DHT 2) SHBG + Free Testosterone Bound Testosterone 3) 50% arises from peripheral conversion of androstenedione
  21. 21. <ul><li>Problems in defining Androgen deficiency in women </li></ul><ul><ul><li>Lack of validated assays </li></ul></ul><ul><ul><li>Lack of age based normative data </li></ul></ul><ul><ul><li>No correlation between HSDD & androgen levels </li></ul></ul>Syndromes of probable androgen deficiency bilateral ovariectomy addisons hypopituitarism Syndromes of possible androgen deficiency ?OCP (but progestational agents may be androgenic) steroid therapy (ACTH suppression of adrenal precursors) HRT ( ? via increased SHBG)
  22. 22. To convert nmol/liter to ng/dl or pmol/liter to pg/dl, divide by 0.0347; to convert µmol/liter to µg/dl, divide by 0.027. Age grouping (yr) 18–24 25–34 35–44 45–54 55–64 65–75 n 22 97 153 140 74 109 Total T (nmol/liter)      Mean 1.58 1.11 0.92 0.81 0.66 0.71      Median 1.55 1.00 0.80 0.70 0.55 0.60      SD 0.55 0.45 0.45 0.41 0.40 0.48      Minimum 0.60 0.30 0.10 0.10 0.10 0.10      10th centile 0.86 0.58 0.50 0.40 0.20 0.30      90th centile 2.47 1.70 1.40 1.30 1.25 1.10      Maximum 2.90 2.30 3.20 2.60 2.00 4.00 Free T (pmol/liter)      Mean 23.61 17.25 13.67 11.82 10.81 9.76      Median 20.52 15.27 12.36 9.87 8.31 8.75      SD 10.44 9.70 7.43 7.68 8.01 6.92      Minimum 5.77 3.02 1.55 1.81 2.03 1.36      10th centile 12.91 8.17 5.80 5.25 3.69 3.43      90th centile 38.64 31.70 23.52 21.28 20.88 17.26      Maximum 46.32 58.24 47.92 43.60 49.28 52.87 DHEAS (µmol/liter)      Mean 7.49 4.72 4.31 3.42 2.36 1.76      Median 7.30 4.50 3.90 2.85 2.15 1.50      SD 2.63 2.08 2.11 2.01 1.57 1.40      Minimum 4.00 0.90 0.80 0.30 0.30 0.30      10th centile 4.03 2.20 1.86 1.30 0.70 0.50      90th centile 10.78 7.90 7.31 6.20 5.30 3.10      Maximum 14.90 11.20 12.50 12.00 6.20 8.00 Androstenedione (nmol/liter)      Mean 8.46 6.44 5.15 4.17 3.14 3.07      Median 7.95 6.30 4.50 3.80 2.80 2.80      SD 3.09 2.46 2.39 2.14 1.76 1.86      Minimum 4.40 1.70 1.60 1.20 0.50 0.50      10th centile 4.86 3.00 2.64 2.00 1.30 1.30      90th centile 13.72 9.46 8.48 6.29 5.10 5.40      Maximum 14.70 14.80 18.80 16.50 10.60 11.80
  23. 23. Copyright ©2005 The Endocrine Society Davison, S. L. et al. J Clin Endocrinol Metab 2005;90:3847-3853 FIG. 2. Relationship between age and individual androgens for the reference group
  24. 24. Copyright ©2005 The Endocrine Society Davison, S. L. et al. J Clin Endocrinol Metab 2005;90:3847-3853 FIG. 4. Androgen levels for premenopausal and postmenopausal women in the reference group between 45 and 54 yr
  25. 25. Mean (SD), oophorectomized women Mean (SD), reference women Mean difference 95% CI for mean difference P value 55–64 yr, oophorectomized, n = 11; reference, n = 74      Total T (nmol/liter) 0.38 (0.26) 0.66 (0.40) – 0.27 – 0.52, –0.03 0.029      Free T (pmol/liter) 5.54 (4.40) 10.81 (8.01) – 5.27 – 10.20, –0.34 0.037      DHEAS (µmol/liter) 1.89 (1.50) 2.37 (1.57) – 0.48 – 1.48, 0.53 0.347      Androstenedione (nmol/liter) 2.15 (1.28) 3.14 (1.76) – 1.0 – 2.10, 0.10 0.075 65–75 yr, oophorectomized, n = 16; reference women, n = 109      Total T (nmol/liter) 0.39 (0.22) 0.71 (0.48) – 0.32 – 0.56, –0.07 0.011      Free T (pmol/liter) 6.06 (3.33) 9.76 (6.92) – 3.70 – 7.19, –0.21 0.038      DHEAS (µmol/liter) 1.13 (0.64) 1.76 (1.40) – 0.63 – 1.33, 0.08 0.081      Androstenedione (nmol/liter) 2.93 (2.00) 3.07 (1.86) – 0.14 – 1.14, 0.86 0.782
  26. 26. Copyright ©2000 The Endocrine Society Laughlin, G. A. et al. J Clin Endocrinol Metab 2000;85:645-651 Rancho Bernardo Study
  27. 27. Copyright ©2000 The Endocrine Society Laughlin, G. A. et al. J Clin Endocrinol Metab 2000;85:645-651
  28. 28. Copyright ©2000 The Endocrine Society Burger, H. G. et al. J Clin Endocrinol Metab 2000;85:2832-2838 SHBG in perimenopausal women
  29. 29. <ul><li>Sherwin et al (A) </li></ul><ul><ul><li>53 postmenopausal women TAHSPO </li></ul></ul><ul><ul><li>16 week study </li></ul></ul><ul><ul><li>ERT/ART/ERT+ART/placebo </li></ul></ul><ul><ul><li>Increased libido/arousal/fantasies > placebo </li></ul></ul><ul><ul><li>ERT+ART > ERT or ART </li></ul></ul>
  30. 30. <ul><li>Shifrin et al NEJM 2000 (A) </li></ul><ul><ul><li>75 postmenopausal women TAHSPO & HSDD </li></ul></ul><ul><ul><li>12 week study </li></ul></ul><ul><ul><li>CEE 0.625 + placebo/ 150mcg/ 300mcg transdermal patch </li></ul></ul><ul><ul><ul><li>4.2 +/- 2.8 13.5 +/- 8.3 20.5 +/-16.6 </li></ul></ul></ul><ul><ul><li>Increased libido/arousal/fantasies/sexual activity </li></ul></ul><ul><ul><li>Considerable placebo response </li></ul></ul><ul><ul><li>Increased further with ART </li></ul></ul><ul><ul><li>most significantly with 300 mcg/dose </li></ul></ul><ul><ul><li>Raising levels to upper end of premenopausal range </li></ul></ul>
  31. 31. <ul><li>Buster et al Obstet Gynaecol 2005 (A) </li></ul><ul><ul><li>533 postmenopausal women TAHSPO & HSDD </li></ul></ul><ul><ul><li>24 week study </li></ul></ul><ul><ul><li>CEE 0.625 + placebo/ 300mcg transdermal patch </li></ul></ul><ul><ul><li>Increased satisfactory sexual activity (1 extra episode / 2 weeks) </li></ul></ul><ul><ul><li>Increased sexual desire </li></ul></ul><ul><ul><li>Improved well being and diminished personal distress </li></ul></ul><ul><ul><li>Increased total and bioavailable testosterone </li></ul></ul>
  32. 32. <ul><li>Dobs et al JCEM 2002 (A) </li></ul><ul><ul><li>40 unselected postmenopausal women </li></ul></ul><ul><ul><li>16 week study </li></ul></ul><ul><ul><li>ERT 1.25 (CEE) vs ERT +2.5mg methyltestosterone </li></ul></ul><ul><ul><li>Increased muscle mass (1.2 kg) and strength </li></ul></ul><ul><ul><li>reduced body fat (0.9 kg) </li></ul></ul><ul><ul><li>QOL / sexual function > placebo </li></ul></ul><ul><li>Lobo et al (A) </li></ul><ul><ul><li>218 postmenopausal women complaining of HSDD </li></ul></ul><ul><ul><li>16 week study </li></ul></ul><ul><ul><li>ERT 0.625 (CEE) + placebo </li></ul></ul><ul><ul><li>ERT 0.625 + 1.25 mg methyltestosterone </li></ul></ul><ul><ul><li>Increased FAI/decreased SHBG/decreased HDL/Increased acne </li></ul></ul><ul><ul><li>Improved desire and responsiveness & proportional to change in FAI </li></ul></ul>
  33. 33. Summary (D) ART plus ERT or ERPT for postmenopausal women is controversial. Clearest indication for ART is in patients with symptomatic androgen insufficiency & bilateral oophorectomy. possibly in association with hypopituitarism adrenal insufficiency premature ovarian failure ? Role for ART alone ? ART in premenopausal HSDD
  34. 34. ? Androgens may significantly improve sexual functioning in select postmenopausal women. ? Improved cognitive function data are not compelling. ? Androgen may have a beneficial effect on bone, ? due to the additional estrogen formed from the administered androgen studies with nonaromatizable androgens could resolve this question. ? Serum HDL cholesterol concentrations decline slightly in postmenopausal women receiving oral testosterone therapy it is not known if the change substantially affects overall cardiovascular risk. Cosmetic side effects such as hirsutism and acne are usually mild and are well tolerated and irreversible virilizing changes are rare.
  35. 35. DHEA; Androgen, estrogen or unique? Peaks at Birth and at the adrenarche Decline from age 30 Replacement; decrease SHBG & HDL (androgenic) increase T and DHT increase estriol increase insulin resistance increase IGF1 My bias; it is acting as a weak androgenic precursor
  36. 36. Basic Endocrinology you need to know 1) Cholesterol Progesterone DHEA/S Estriol Androstenedione Estrone Testosterone Estradiol DHT 2) SHBG + Free Testosterone Bound Testosterone 3) 50% arises from peripheral conversion of androstenedione
  37. 37. <ul><li>Barnhart et al JCEM 1999 (A) </li></ul><ul><ul><li>66 postmenopausal women ( 2-12 months amenorrhoea) </li></ul></ul><ul><ul><li>Mean age 48 </li></ul></ul><ul><ul><li>12 week study </li></ul></ul><ul><ul><li>50 mg DHEA v placebo </li></ul></ul><ul><ul><li>Not on HRT (& none within 6 months) </li></ul></ul><ul><ul><li>No steroids/No antidepressants/not sick </li></ul></ul>
  38. 38. Copyright ©1999 The Endocrine Society Barnhart, K. T. et al. J Clin Endocrinol Metab 1999;84:3896-3902
  39. 39. <ul><li>Barnhart et al (A) </li></ul><ul><li>DHEA alone to postmenopausal women </li></ul><ul><li>Despite increased DHEA and testosterone levels </li></ul><ul><li>No improvement </li></ul><ul><li>perimenopausal symptoms </li></ul><ul><li>mood </li></ul><ul><li>dysphoria </li></ul><ul><li>libido </li></ul><ul><li>cognition </li></ul><ul><li>memory </li></ul><ul><li>well-being </li></ul>
  40. 40. ARLT et al (A) 24 women 14 primary adrenal failure & 10 secondary adrenal failure Double-blind RCT, crossover design; 50 mg DHEA vs. placebo treatment for 4 months, 4 wk washout estrogen replete or deficient Improved Symptom Checklist-90 VAS sex activity score Similar results in other studies, small numbers, mixed male female, primary and secondary adrenal insufficiency
  41. 41. GROWTH HORMONE REPLACEMENT & postmenopausal women <ul><li>Background </li></ul><ul><li>GH levels decline with age </li></ul><ul><li>nutrition </li></ul><ul><li>slow wave sleep </li></ul><ul><li>estrogen deficiency </li></ul><ul><li>central adiposity & visceral fat & increased FFAs </li></ul><ul><li>downregulated response to Ghrelin </li></ul><ul><li>GH decline is more marked in men than women </li></ul><ul><li>Decline in GH principally due to less GH per “burst” </li></ul><ul><li>Gender differences in response to secretogogues; </li></ul><ul><li>women can have 6 fold greater burst amplitude basally </li></ul><ul><li>men exhibit greater amplitude response to some stimuli (GHRH) </li></ul><ul><li>GH replacement in the GHD adult </li></ul><ul><li>increased lean muscle mass (?LVF) </li></ul><ul><li>decreased fat mass </li></ul><ul><li>improved psychological well being </li></ul>
  42. 42. Estrogens facilitate GH release but the route of estrogen administration influences GH action Oral estrogen; hepatic effects on circulating GH & IGF binding proteins reduced fat oxidation Mechanistic explanation for effect of oral ERT increased fat mass decreased lean mass Observed in postmenopausal women on ERT ERT in hypopituitary patients who receive exogenous GH
  43. 43. Copyright ©2005 The Endocrine Society Franco, C. et al. J Clin Endocrinol Metab 2005;90:1466-1474 FIG. 1. Trial profile
  44. 44. Variable Group Baseline 6 months 12 months P (0–1 yr) Weight (kg) GH 86.0 (2.4) 86.1 (2.6) 87.2 ( 2.5) 1 0.9   Placebo 80.9 (2.2) 80.7 (2.3) 81.8 (2.3) 1   Waist (cm) GH 104 (1.4) 103 (1.5) 104 (1.6) 0.7   Placebo 102 (1.6) 102 (1.8) 102 (2.0)       W/H ratio GH 0.93 (0.01) 0.92 (0.01) 0.93 (0.01) 0.3   Placebo 0.94 (0.012) 0.94 (0.01) 0.93 (0.01)  
  45. 45. Thigh muscle area (cm 2 ) GH 110.4 (2.7)   113.0 (2.5) 3 0.002   Placebo 110.9 (3.4)   110.7 (3.2)   Abdominal sc AT area (cm 2 ) GH 430.2 (20.2)   432.0 (22.3) 0.8   Placebo 400.9 (20.8)   400.5 (22.0)   Visceral AT area (cm 2 ) GH 177.2 (8.7)   170.6 (10.0) 0.003   Placebo 161.0 (7.9)   172.0 (8.9) 2  
  46. 46. Growth Hormone replacement Side effects contraindicated in intracranial hypertension malignancy retinopathy oedema arthralgia transient impaired insulin sensitivity Dose 0.15-0.3 mg/day initially and titrate to IGF1 But IGF1 cannot be reliably used for diagnosis
  47. 47. Longevity & Disease Environmental / Accidental / Exposure infection / toxin / MVA / suicide Mutation / Unstable Genome malignancy Vascular CVD / DM / HT Neurodegenerative Alzheimers / Parkinsons / neuropathies Musculoskeletal DJD / osteoporosis OSTEOPOROSIS A G E
  48. 49. Remodelling is not the enemy…. but the loss of balance is. <ul><li>Increased activation frequency </li></ul><ul><li>Preferentially occurring at sites of fatigue and repair </li></ul><ul><li>Subsequently replacing less than removed </li></ul><ul><li>Accentuated potential for fatigue / stress risers </li></ul><ul><li>Accelerated bone loss & treatment implications </li></ul>
  49. 50. It is more important to identify the right patient Than the right treatment
  50. 51. Several factors assist in identifying those at risk Age BMD prior fracture falls www.garvan.org.au/promotions/bone-fracture-risk/ www.fractureriskcalculator.com
  51. 52. Australian Fracture Risk Calculator 12.5 40.5 10-y risk (%): 6.7 21.5 5-y risk (%): Any fracture 5.2 21.0 10-y risk (%): 2.7 11.1 5-y risk (%): Hip fracture YOUR RISK OF 0 0 Fall in the last 12 mo: 0 1 Prior fracture: -2.9 -3.6 BMD T-scores: 67 63 Age (y): Men Women Gender:

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