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Endocrinology and Aging

Endocrinology and Aging. The world is getting older. In the developed world, people >80 y/o are the fastest growing subset In the US, people over 60 will increase from 35 million (12.4%) to 71.6 million (19.6%) by 2030 Worldwide, lifespan expected to increase another 10 years by 2050

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Endocrinology and Aging

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  1. Endocrinology and Aging

  2. The world is getting older • In the developed world, people >80 y/o are the fastest growing subset • In the US, people over 60 will increase from 35 million (12.4%) to 71.6 million (19.6%) by 2030 • Worldwide, lifespan expected to increase another 10 years by 2050 • Therefore need to focus on healthy aging

  3. Aging Process • As people get older, parts don’t work as well • In the endocrine system, there is a decrease in feedback and feed-forward systems • Organs become less responsive to stimuli, and hormones are not released at the same levels

  4. Thyroid Axis

  5. Changes with Aging • Decreased pituitary responsiveness • Less TSH response to TRH • Less rise in TSH to low T4/T3 • Thyroid does not respond to TSH as well • Less T4 response to TSH surge • Decreased peripheral conversion of T4 to T3 due to decreased 5’ deiodinase activity • May be selenium dependent

  6. Change in TSH with Age Mariotto, et al. JCEM 1993: 77(5), 1130-1134

  7. Change in T4 and T3 Mariotto, et al. JCEM 1993: 77(5), 1130-1134

  8. Hypothyroidism • More common with advancing age • 7-14 % of elderly have TSH above nl range, more women than men • Higher incidence in iodine replete areas • Autoimmune is the most common cause, followed by surgical

  9. Elevated TSH with aging Canaris et al, Archives of Int Med: 2000;160:526

  10. Diagnosis • Symptoms can be the same as in younger patients, but more often ignored as they are attributed to “aging” • Fatigue and weakness were reported by more than 50%, but the following sxs were less commonly reported: • cold intolerance, weight gain, paresthesias, and muscle cramps • Can score lower on MMSE along with other memory and neurocognitive testing

  11. Associated Findings • PE: Bradycardia, diastolic hypertension, pericardial effusion • Labs: Elevated TSH, low FT4 • Other potential findings: • Hyponatremia • elevated CK • elevated LDL

  12. Treatment • Levothyroxine replacement • Start with lower dosage—0.25-0.5 mcg/kg instead of 1.6 mcg/kg as in young • See if tolerate, and then can increase by 12.5-25 mcg q 4-6 weeks • One study showed that if no cardiac dz present, elderly could tolerate full dose • If have underlying cardiac disease, may not be able to tolerate dose that would normalize TSH • Final dose may be 40 mcg lower than in comparable young

  13. Hyperthyroidism • Not as common as hypothyroidism • Prevalence < 0.5% of elderly • Subclinical hyperthyroidism is more common: 1-5%, but most studies say < 2.5%

  14. Presentation • Classically present with different symptoms • Weight loss, depression, and agitation dominate, leading to it being called “apathetic hyperthyroidism” • Sympathetic sxs less common like tremor or hyperactivity

  15. Cardiovascular Findings • A-fib occurs in 15% of pts with hyperthyroidism, but is more common in elderly • CV complications are more common in elderly: ischemic heart dz, dysrhythmias, hypertensive hd • So think about getting TFTs in pts presenting with atrial fibrillation, worsening heart failure, systolic hypertension, or deteriorating ischemic heart disease

  16. Effects on Bone • Leads to decreased BMD, especially in post-menopausal women • Treatment of hyperthyroidism improves BMD, but not back to baseline • One study showed a doubling of risk of death from fractured femur in treated pts • Need to get DXA and consider bisphosphonates in pts with hx of hyperthyroidism

  17. Thyroid Nodules • Incidence of nodules increases with age • Palpable nodules found in 5% of pts >60 • Autopsy studies show 90% in women >70 • U/S show 50% of women over 50 have nodules • Causes of goiter in older population • Nontoxic MNG: 51% • Toxic MNG: 23% • Single nodule: 8% • Graves: 5% • Hashimotos: 4%

  18. Thyroid Cancer • See same cancers as in young, but some differences • Ratio of Papillary:Follicular goes from 4:1 to 2:1 • Female:male ratio narrows • Decreased 10 yr survival with older age • Women <20 have 100% • Women >60 have <5%

  19. Thyroid Cancer • Increased recurrance rate in older pts • PTC/Follicular risk of recurrance and death • <50: 10% and 3% • >50: 32% and 30% • Direct extension worse in elderly • 67% recurrance, 60% death in older • 12% and 4% in young • Distant mets more deadly in older • 96% vs 63% Cady B, Sedgwick CE, Meissner WA, et al. Risk factor analysis in differentiated thyroid cancer. Cancer 43:810-820, 1979

  20. Anaplastic Thyroid Cancer • Peak incidence in 60’s, and more than 65% occur in pts older than 65 • 1-2% of all thyroid cancers • Usually presents as a rapidly growing mass with local sxs • Often caused by transformation of pre-existing differentiated thyroid cancer or longstanding goiter • Older pts have worse prognosis • 5 yr survival of 7%, mean survival of 11 months

  21. Thyroid Lymphoma • Only .5-5% of all thyroid cancers • Peak incidence form 50-80 • Presents as rapidly enlarging goiter, usually in someone with long standing Hashimoto’s • Dx can be difficult since FNA will just show lymphocytes. Can do flow cytometry • Treatment is chemotherapy

  22. Androgens • Testosterone levels in men decline continuously starting at age 30 • There is no abrupt decrease similar to menopause • Testosterone is lower in men with chronic illness, obesity, metabolic syndrome, etc • SHBG goes up in elderly, lowering free T even more

  23. Longitudinal Changes in Testosterone 20 (177) 18 (144) (151) 16 Testosterone (nmol/L) (109) 14 (43) (158) 12 10 30 40 50 60 70 80 90 Age (Years) Adapted from Harman SM, et al. J Clin Endocrinol Metab. 2001;86:724-731.

  24. Incidence • Not every man develops low T, unlike women who all go through menopause • Incidence varies in different studies • 50% of men >70 y/o vs. • 3% of healthy men • Health status may be a significant factor

  25. Physiology • Testosterone production decreases with age • All levels of the HPT axis are affected • LH/FSH are higher than in younger men, but not as high as expected for degree of low T, indicating loss of normal feedback • LH/FSH response to GnRH not as coordinated • Less synchrony in LH pulses and T production • Decreased ability of testes to make T

  26. Effects of Low Testosterone • Decreased muscle mass and strength • Decreased bone mineral density • Decreased libido and sexual functioning • Low nitric oxide synthase is seen in hypogonadal men. NOS needed for PDE to work • Increased fat mass • Anemia • Dysthymia

  27. Testosterone and Mortality • Several studies have shown decreased survival in men with lower T • Rancho Bernardo study showed that men in the lowest quartile of testosterone (<241 ng/dL) were 40% more likely to die over the next 20 years than those with higher levels • The increased risk of death in men with low testosterone levels was independent of multiple risk factors, including age, adiposity, and lifestyle • No studies have shown replacement increases survival. Unclear is cause:effect or association Araujo AB, Kupelian V, Page ST, Handelsman DJ, Bremner WJ, McKinlay JB.Sex steroids and all-cause and cause-specific mortality in men. Arch Intern Med. 2007 Jun 25;167(12):1252-60

  28. Effect of T on Survival Shores MM, Matsumoto AM, Sloan KL, Kivlahan DR.Low serum testosterone and mortality in male veterans. Arch Intern Med. 2006 Aug 14-28;166(15):1660-5

  29. Definition and Diagnosis • Normal ranges of T based on young men • Does this correlate to elderly? • Draw total T before 0900 • >350 ng/dl—no deficiency • <230 mg/dl—deficient • 230-350 ng/dl: need to check free T

  30. Benefits of Replacement • Benefit only shown in men who have low T • Decreases fat mass and increases muscle mass, but not dramatic • Improved sexual functioning and libido • Improves bone mineral density, but no fracture data • No good data on cognition • Can improve quality of life

  31. Should We Replace? • An expert panel of the Endocrine Society recommended against testosterone therapy for all older men with low testosterone levels. • Instead the panel suggested that “clinicians consider offering testosterone therapy on an individualized basis to older men with consistently low testosterone levels on more than one occasion and significant symptoms of androgen deficiency, after appropriate discussion of the uncertainties of the risks and benefits of testosterone therapy in older men”. • The panel’s recommendations were guided by the recognition of the paucity and low quality of evidence, and that high quality evidence of the efficacy and safety will not be available for a very long time.

  32. Androgen deficiency in Women • As in men, testosterone levels decline with aging, particularly after oophorectomy or adrenal failure • By age 40, T levels are 50% of age 20 • However, levels don’t fall at menopause like estrogen does • Hard to biochemically define because free T assays are not good at the lower range and total not as reliable due to more SHBG variation • Testosterone levels not associated with sexual functioning in some studies

  33. Benefits of Replacement? • Controversial that disorder even exists • Decreased sexual desire is reported in 25-53% of women, but not always perceived as a problem • Maybe improvement in BMD • Conflicting results on body mass

  34. Androgen Replacement • Multiple studies looked at transdermal testosterone replacement in surgically and naturally menopausal women on estrogen • Patch of 300 mcg worn for 24 weeks increased satisfying sexual encounters by 1-2 episodes per month—statistically significant • Other measures of mood, sense of well being, libido, and distress had mixed outcomes • No long term safety data

  35. Outcomes • Treatment effect was not dependent on baseline testosterone levels • No significant difference in surgical or natural menopausal women except for number of satisfying encounters • Women in the 300 mcg group had testosterone levels at or above the upper range of normal

  36. Summary • 300 mcg testosterone patch modestly improved sexual functioning, but this is clinically meaningful • Baseline testosterone had no bearing on outcome, so not useful for diagnosing “androgen deficiency”

  37. Growth Hormone • Similar properties to sex steroids • Improve lean body mass and muscle strength • Decrease fat mass • Improve BMD • Improve sense of well being

  38. Growth Hormone Deficiency • Increased fat and decreased lean mass • Sarcopenia • Increased lipids • Increased CV disease, impaired cardiac function • Decreased BMD

  39. GH Changes with Aging • GH Declines as we age • Sex steroids have a significant impact on GH levels • The higher the testosterone, the higher the GH levels • Obesity also is a factor • The more overweight a person is, the lower their GH levels

  40. Relationship of Age, Weight and Testosterone to GH Iranmanesh, A, et al, Eur J Endo 1998;139:59-71

  41. GH and Aging • Since muscle and strength decline with age, would supplementing GH be beneficial? • GH supplementation in pts who are deficient has been shown to: • improve QOL • Increase lean body mass • Decrease fat mass--especially central • Increase BMD

  42. Risks of Supplementation • Possible increased risk of malignancy • Increased insulin resistance • Increased edema, arthralgias, and carpal tunnel syndrome • Some studies showed critically ill pts (ICU, CHF) had higher mortality when treated with GH

  43. Answer? • Don’t know if decline in GH with aging is adaptive or maladaptive • GH secretogogues may be an answer in the future • Currently, can’t recommend GH replacement for average aging patient

  44. Osteoporosis • Peak bone mass is attained by age 20 • Thereafter, bone is lost at a steady rate • In women, there is an increase in BMD loss for the 5-10 years after menopause

  45. Rate of bone Loss Dashed=trabecular Solid=cortical Khosla, et al. Pathophysiology of Age Related Bone Loss and Osteoporosis. Endo Metab Clin N Amer, DEC 2005: 1015-1030

  46. Fracture Incidence Khosla, et al. Pathophysiology of Age Related Bone Loss and Osteoporosis. Endo Metab Clin N Amer, DEC 2005: 1015-1030

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