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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 Therefore need to focus on healthy aging 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 Thyroid Axis 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 Change in TSH with Age Mariotto, et al. JCEM 1993: 77(5), 1130-1134 Change in T4 and T3 Mariotto, et al. JCEM 1993: 77(5), 1130-1134 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 Elevated TSH with aging Canaris et al, Archives of Int Med: 2000;160:526 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 Associated Findings PE: Bradycardia, diastolic hypertension, pericardial effusion Labs: Elevated TSH, low FT4 Other potential findings: Hyponatremia elevated CK elevated LDL 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 Hyperthyroidism Not as common as hypothyroidism Prevalence < 0.5% of elderly Subclinical hyperthyroidism is more common: 1-5%, but most studies say < 2.5% 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 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 Effects on Bone Leads to decreased BMD, especially in postmenopausal 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 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% 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% 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 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 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 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 Longitudinal Changes in Testosterone Testosterone (nmol/L) 20 18 (177) (144) (151) 16 (109) 14 (43) (158) 12 10 30 40 50 60 Age (Years) Adapted from Harman SM, et al. J Clin Endocrinol Metab. 2001;86:724-731. 70 80 90 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 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 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 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 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 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 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 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. 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 Benefits of Replacement? Controversial that disorder even exists Decreased sexual desire is reported in 2553% of women, but not always perceived as a problem Maybe improvement in BMD Conflicting results on body mass 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 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 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” Growth Hormone Similar properties to sex steroids Improve lean body mass and muscle strength Decrease fat mass Improve BMD Improve sense of well being Growth Hormone Deficiency Increased fat and decreased lean mass Sarcopenia Increased lipids Increased CV disease, impaired cardiac function Decreased BMD 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 Relationship of Age, Weight and Testosterone to GH Iranmanesh, A, et al, Eur J Endo 1998;139:59-71 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 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 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 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 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 Fracture Incidence Khosla, et al. Pathophysiology of Age Related Bone Loss and Osteoporosis. Endo Metab Clin N Amer, DEC 2005: 1015-1030 Post-menopausal Osteoporosis After menopause, estradiol levels fall to 10-15% of previous levels Bone resorption increases by 90%, while formation increases by 45% Estrogen inhibits osteoclast function and multiple cytokines that increase bone resorption. Without estrogen, these processes increase Post-menopausal Osteoporosis Other contributing factors: Vit D deficiency Secondary hyperparathyroidism Decreased calcium intake and increased calcium secretion Never attaining good peak BMD Decreased GH levels Secondary causes Also have impaired bone formation due to GH defic, estrogen defic, Osteoporosis in Men Men lose half as much bone as women and have 1/3 the number of fractures Main cause is decreased testosterone, but estrogen has the main effect on bone Therefore do not want to give aromatase inhibitors to men on androgen therapy— will decrease bone benefit Estrogen Effect on BMD in Men Khosla, et al. Pathophysiology of Age Related Bone Loss and Osteoporosis. Endo Metab Clin N Amer, DEC 2005: 1015-1030 Screening 1. 2. 3. 4. 5. The NOF recommends offering BMD testing to the following women: All postmenopausal women under age 65 who have one or more additional risk factors for osteoporosis (besides menopause). All women aged 65 and older regardless of additional risk factors. Postmenopausal women who present with fractures (to confirm diagnosis and determine disease severity). Women who are considering therapy for osteoporosis, if BMD testing would facilitate the decision. Women who have been on hormone replacement therapy for prolonged periods. Screening in Men NOF does not give specific guidelines ACP recommends: clinicians periodically perform individualized assessment of risk factors for osteoporosis in older men clinicians obtain DXA for men who are at increased risk for osteoporosis and are candidates for drug therapy Main risk factors: age >70, low BMI, weight loss, previous fracture, steroid use, inactivity, hypogonadism Cortisol Axis Age does not have a significant effect on CRH, ACTH, or cortisol levels However, diurnal pattern seems to be altered, with higher levels later in the day CRH evokes a greater ACTH and cortisol response in older pts Stress response ACTH and cortisol release are actually 2-fold greater—seems to be a decreased sensitivity to negative feedback by cortisol This is more prominent in women DHEA DHEA is not active, but it is converted to other androgens that are active By age 80, DHEA levels are <10 % of young adult levels ACTH which stimulates release of DHEA remain stable over this time Likely due to decreased adrenal enzyme activity, like 3ß-HSD DHEA Over Time DHEA and Mortality Multiple studies have shown that older men with lower levels of DHEA have increased mortality and lower functional status There was no correlation seen in women DHEA replacement in adrenally insufficient pts has shown improvement in a number of areas However, replacement in healthy elderly showed no benefit in multiple studies It has improved sense of well being in pts with depression, schizophrenia, and some immune mediated dzs like SLEc Diabetes Prevalence of DM increases with aging Changes that occur with aging Decreased insulin secretion Decreased insulin action/increased resistance Alteration of hepatic glucose output Increased obesity Change in diet These changes associated with genetic background increase DM in the elderly Prevalence of DM Third NHANES Survey 1988-1994 Presentation May not be classic Glycemic threshold in kidney higher so may not have polyuria Have impaired thirst drive so may not have polydypsia Complaints may be more non-specific Often will present with a complication like CVA, HONK, or MI Hypoglycemia The risk of severe hypoglycemia with oral agents or insulin increases exponentially in the elderly Due to: Impaired secretion of counter-regulatory hormones like glucagon Reduced awareness of autonomic symptoms Decreased ability to function with a low sugar which decreases their ability to treat themselves Primary treatment is prevention! Goals of Treatment Need to be individualized Don’t need to be as aggressive in pts with shorter life expectancy or significant comorbidities For some, goal is to prevent hyperglycemic sxs: Fasting sugar <180 Post-prandial <250 Medications If mild hyperglycemia, consider meds that will not cause hypoglycemia: Metformin (as long as GFR>60) α-glucosidase inhibitors DPP4 inhibitors Caution with TZDs Caution with sulfonylureas and meglitinides Glyburide Elimination is decreased with age Leads to more glucose lowering effect in elderly than in young Cleared renally Metabolites are active All this leads to increased risk of severe hypoglycemia Other sulfonlyureas do not have these properties Questions?