Metabolic Syndrome and Perimenopause

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Lecture at 2010 annual convention of Philippine Society of Climacteric Medicine

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Metabolic Syndrome and Perimenopause

  1. 1. Perimenopause & Metabolic Syndrome: Is there a link and what should be done about it? Iris Thiele Isip Tan MD, FPCP, FPSEM MS Health Informatics (cand.) Clinical Associate Professor, UP College of Medicine Section of Endocrinology, Diabetes & Metabolism Department of Medicine, UP-Philippine General Hospital
  2. 2. High triglycerides Hypertension Low HDL-C Obesity Glucose intolerance Metabolic Syndrome
  3. 3. Cross-sectional data MetSyn increases from premenopause to postmenopause, independent of age.
  4. 4. Low HDL-C Hypertension (Peri) Menopause High triglycerides Glucose intolerance Obesity
  5. 5. 2406 J Clin Endocrinol Metab, June 2003, 88(6):2404 –2411 risk diabetes hypertriglyceridemia small dense LDL hypertension CVD Estrogen promotes gluteo-femoral fat distribution Carr M et al JCEM 2003;88:2404-11 FIG. 1. Patterns of body fat distribution.
  6. 6. e the major determinant of the metabolic Changes in LDL with menopause high amounts of visceral fat have an excess ar mortality and associated metabolic abnor- Postmenopausal women have higher to Menopausal fat redistribution ➨ MetSyn When Pascot et al. (32) matched women for by CT scan) and menopausal status, the dif- LDL cholesterol, triglycerides (TG), and [Lp(a)] levels and lower HDL cholesterol l y found in very low density lipoprotein menopausal women (38 – 40). Although elev DL, large buoyant HDL2 particles, LDL par- a component of the metabolic syndrome, LDL glucose, C peptide, and blood pressure were by 10 –20% (23, 41) with menopause, and the action of genetic and environmental factors influences the manifestation of the metabolic syndrome. t (IAF) are associated with increased insulin resistance (IR) and FFA levels, and decreased adiponec eased secretion of apo B-containing particles, leading to hypertriglyceridemia and increased HL activity mall dense LDL particles and a reduction in the large antiatherogenic HDL2 particles. Carr M et al JCEM 2003;88:2404-11
  7. 7. Sex- and menopause-associated changes in body-fat distribution DEXA measurement Premenopausal women Men Regular menses 21-79 y No menopausal sx n = 103 19-51 y n = 61 - ?:, i . Postmenopausal Good health ): . . Amenorrhea Not obese 1. Elevated LH & FSH (BMI 18.8-28) ! 43-63 y No meds affecting n = 70 lipid/bone metabolism . - . Ley et al Am J Clin Nutr 1992;55:950-4
  8. 8. Increased android fat in menopause 2406 J Clin Endocrinol Metab, June 2003, 88(6):2404 –2411 *** p <0.001 60 eliminated, implying menopausal status a n = 103 Regional differences *** n = 70 tivity in postmenop 50 changes in fat accum n = 61 *** ing (33, 34). Adipone % *** may play a role in the are inversely related 40 ever, the only study revealed no differen (35). Menopause is als 30 mass (muscle) and t Pre- Post- physical activity (36) Males menopausal menopausal maximal oxygen con menopausal (VO2 m FIG. 1. Patterns of body fat distribution. Ley et al Am J Clin Nutr 1992;55:950-4 age-matched premen
  9. 9. Decreased gynoid fat in menopause ab, June 2003, 88(6):2404 –2411 Carr • Menopause and the eliminated, implying <0.001 differences in *** p that the 60 menopausal status accounted for the metab Regional differences in adipose tissue lipop tivity in postmenopause may account for n = 61 changes in fat accumulation, but results to *** 50 ing (33, 34).= 70 n Adiponectin, a novel adipocyte- may play a*** in the metabolic syndrome, a role % are inversely related n = obesity and insulin to 103 ever, the only study evaluating adiponecti *** 40 revealed no difference in pre- and postmen (35). Menopause is also associated with red mass (muscle) and this appears to be rela 30 physical activity (36). Lynch et al. (37) recentl Pre- Post- maximal oxygen consumption (VO2 max) in Males menopausal menopausal menopausal (VO2 max) women compared erns of body fat distribution. age-matched premenopausal women and f relationship betweenAm J Clin Nutr 1992;55:950-4 Ley et al visceral adiposity and gain, most studies do not reveal in-
  10. 10. Is androgen dominance in menopause associated with development of MetSyn? Hallmark of menopausal transition is dramatic reduction in estradiol
  11. 11. SWAN Cohort & Metabolic Syndrome Study of the Women’s Health Across the Nation n = 949; 9-year follow-up Premenopause or early Primary outcome: perimenopause MetSyn (NCEP-ATP III) Reached menopause Secondary outcome: during the study MetSyn components Never took hormone therapy No diabetes or MetSyn at Serum T, SHBG and baseline estradiol Janssen I et al Arch Intern Med 2008;168(14):1568-75
  12. 12. Hormone Levels in SWAN Cohort With and Without MetSyn Hormone levels, Cohort without Cohort Total Cohort median (IQR) MetSyn with MetSyn 38.0 37.6 42.5* Testosterone, ng/dL (26.5-51.0) (25.8-50.4) (30.4-53.9) 3.13 2.89 4.52** Bioavailable T, ng/dL (1.78-5.32) (1.58-4.86) (2.48-7.08) 4.88 5.06 3.83* SHBG, ug/mL (3.37-6.80) (3.54-7.21) (2.52-5.46) 25.5 26.6 21.8** Estradiol, pg/mL (14.8-65.0) (14.7-69.5) (14.4-34.8) * p<0.05 ** p<0.001 Janssen I et al Arch Intern Med 2008;168(14):1568-75
  13. 13. SWAN Cohort & Metabolic Syndrome *Adjusted for age, age at final menstrual period, ethnicity, study site, baseline BMI, change in BMI from baseline, baseline education level, marital status and smoking New-onset MetSyn by final menstrual period: Odds of MetSyn increased by 13.7% 10% for every 1-SD increase in bioavailable T levels* Odds of MetSyn/year in perimenopause: 13% for every 1-SD decrease 1.45 (95%CI 1.35-1.56) in SHBG level* Janssen I et al Arch Intern Med 2008;168(14):1568-75
  14. 14. Body fat distribution and Metabolic Syndrome Exclusion criteria Diabetes, IHD, hypertension or chronic disease Matched for BMI use of OCP or HRT Medications affecting body Obesity clinic (Istanbul) composition/metabolism Retrospective Premenopausal Postmenopausal n= 405 n= 405 Overweight/obese (BMI>27) Overweight/obese (BMI>27) mean BMI 37.8 + 6.9 mean BMI 37.7 + 6.8 regular cycles abnormal menses x 12 mos FSH <30 IU/L FSH >30 IU/L Weight stable x 6 mos Excluded women with premature menopause Normal resting ECG Osbey et al Endoc J 2002;49(4):503-9
  15. 15. Postmenopausal women had more intra-abdominal fat Matched for BMI Premenopausal Postmenopausal p n = 405 n = 405 Age 33.28 + 7.62 52.36 + 7.50 <0.001 Weight (kg) 92.0 + 17.5 91.2 + 16.0 NS Height (cm) 155.9 + 5.3 155.6 + 5.8 NS BMI (kg/m2) 37.83 + 6.91 37.77 + 6.84 NS Waist circ (cm) 99.19 + 13.45 103.34 + 13.20 <0.001 Hip circ (cm) 123.10 + 13.10 123.83 + 13.09 NS WHR 0.80 + 0.07 0.84 + 0.08 <0.001 IAF (L) 3.19 + 1.42 3.97 + 2.17 <0.001 Osbey et al Endoc J 2002;49(4):503-9
  16. 16. MetSyn components higher in postmenopausal women Matched for BMI Premenopausal Postmenopausal p n = 405 n = 405 Age 33.28 + 7.62 52.36 + 7.50 <0.001 Systolic BP (mm Hg) 135.12 + 26.79 148.24 + 29.77 <0.001 Diastolic BP (mm Hg) 87.70 + 15.08 91.79 + 15.71 <0.001 Glucose (mg/dL) 99.41 + 19.19 109.68 + 33.62 <0.001 Uric acid (mg/dL) 4.34 + 1.12 4.78 + 1.47 <0.001 Cholesterol (mg/dL) 202.33 + 37.09 232.22 + 43.22 <0.001 HDL-C (mg/dL) 45.32 + 10.89 47.24 + 10.38 0.016 Triglyceride (mg/dL) 152.28 + 74.93 172.68 + 79.97 <0.001 Osbey et al Endoc J 2002;49(4):503-9
  17. 17. Increase in abdominal fat and unfavorable risk factors despite unchanged total body weight and BMI during menopause transition Menopause Osbey et al Endoc J 2002;49(4):503-9
  18. 18. e the major determinant of the metabolic Changes in LDL with menopause high amounts of visceral fat have an excess ar mortality and associated metabolic abnor- Postmenopausal women have higher to Unclear whether menopause is a CV risk When Pascot et al. (32) matched women for LDL cholesterol, triglycerides (TG), and factor for all women or only those with a by CT scan) and menopausal status, the dif- y found in very low density lipoprotein [Lp(a)] levels and lower HDL cholesterol l menopausal women (38 – 40). Although elev genetic predisposition to central obesity DL, large buoyant HDL2 particles, LDL par- glucose, C peptide, and blood pressure were a component of the metabolic syndrome, LDL by 10 –20% (23, 41) with menopause, and the action of genetic and environmental factors influences the manifestation of the metabolic syndrome. t (IAF) are associated with increased insulin resistance (IR) and FFA levels, and decreased adiponec eased secretion of apo B-containing particles, leading to hypertriglyceridemia and increased HL activity mall dense LDL particles and a reduction in the large antiatherogenic HDL2 particles. Carr M et al JCEM 2003;88:2404-11
  19. 19. Epidemiologic data Central fat distribution related to adverse psychological states (i.e. depression and anxiety) and to social difficulties (i.e. unemployment and divorce) Epel E et al Psychosomatic Med 2000;62:623-32
  20. 20. Depressive Symptoms and Stressful Life Events Predict MetSyn Healthy Women Study cohort n = 432; 15-year follow-up Enrolled at 3-y follow-up 254 (58.8%) premenopause 63 (14.6%) perimenopause Psychosocial measures 115 (26.6%) menopause Beck Depression Inventory Framingham Tension Scale Had MetSyn components at Spielberger Trait Anxiety Q 3-yr follow-up and at least Spielberger Anger Q one later examination Perceived Stress Scale Raikkonen et al Diabetes Care 2007;30:872-7
  21. 21. Psychosocial Factors and MetSyn Prevalence of MetSyn (ATP III) over 15-y follow-up Depressive None/mild vs at least Trait anger one very severe symptoms OR 1.40 stressful life event OR 1.39 (1.13-1.74) (1.11-1.74) OR 1.84 (1.20-2.81) Framingham Trait anxiety tension OR 1.03 OR 1.27 (0.83-1.28) (1.03-1.57) Perceived Adjusted for age, physical activity, alcohol stress consumption, current OR 1.19 smoking status, use of (0.96-1.47) HRT and level of education Raikkonen et al Diabetes Care 2007;30:872-7
  22. 22. Stress and Body Shape Hypothesis: Greater vulnerability to stress increases exposure to stress-induced cortisol ➜ central fat deposition Psychological/ Do women with cognitive measures: greater central fat • Coping (high WHR) adapt less • Mood effectively to repeated • Rosenberg Self- Esteem Scale stress over time than those with low WHR? Salivary cortisol Epel E et al Psychosomatic Med 2000;62:623-32
  23. 23. serve as a confounding factor. Whereas overweight women will inevitably have greater central fat as a WHR <0.75 WHR >0.79 result of their excess fat, lean women are less likely to Trier Social have central fat. One possible contributor to central fat n = 29 n = 30 Stress Test 45 mins/ Arithmetic session Serially subtract a prime number Stress Day 1 from a large session 1 number Stress Day 2 Visuospatial session 2 puzzle Replicate picture Stress Day 3 designs with session 3 blocks Control Speech Day 4 session Convince committee that she is best job applicant Epel E et al Psychosomatic Med 2000;62:623-32
  24. 24. vivo, visceral fat deposits increased in a S. EPEL et a E. dose-depen- dent manner in rats and primates randomly assigned v to a chronic stress condition (40, 41). In vitro, cortisol d weight women, had we been able to use a more accu increases lipoprotein lipase (a fat-storing enzyme) in t rate measure of visceral fat. fat tissue but has an especiallythat genetics may playi It is also important to note exaggerated effect on visceral the tissue (11). role in fat stress– central fat relationship, although w f did not examine this in the current study. Genetics ca v account for up to AND of the variance in fat distribu CONCLUSIONS 50% IMPLICATIONS tion (36). That leaves another 50% of the variance theb Although our findings are strictly correlational, to shaped by environmental influences. There are als psychological and cortisol data are consistent with the hypothesis that greater psychological copingreactivity p genetic influences on life stress and stress with stres contributeandcentral fatreactivity (39), so it is possibl (37, 38) to cortisol among lean women. The con- h sistency of findings is striking: Vulnerabilitygeneticall that stress reactivity and central fat are to stress c linked. was noted across both psychological and physiological s measures among women with amanipulations of stres Nevertheless, experimental high WHR. There is w growing causal relationship between stress and fat dis show a recognition that overexposure to cortisol can m have pathophysiological consequences onof genetics. I tribution in animal models, regardless many organ g systems (42), stress-inducedincreased in a dose-depen vivo, visceral fat deposits damage that has been la- h beled manner in rats and primates randomly assigne dent “allostatic load” (43). Central fat among lean s to a chronic stress condition (40, 41). In vitro, allo- b women may serve as an indicator of one type ofcortiso increases physical lipase resulting from lack of w static load,lipoproteindamage (a fat-storing enzyme) i High-WHR vs low-WHR women fat tissue to stress, that can eventually result in dis- s adaptation but has an especially exaggerated effect o visceral Thus, lean women with a high WHR may be a ease (43). fat tissue (11). greater threat appraisal at higher risk of disease for two known and likely e (p=0.030) CONCLUSIONS greater exposure to cortisol and a interrelated factors, AND IMPLICATIONS exerted increasingly less effort possible metabolic aberrations associated with central i Although our findings are strictly correlational, th fat distribution, such as greater insulin resistance (2). p over time psychological and cortisol data are consistent with th (p=0.05) Only longitudinal and genetic studies will deter- f hypothesis that greater life stress and stress reactivit mine conclusively whether stress and central fat, with made more mistakes its related metabolic profile, are causally related con contribute to central fat among (p=0.002) The or m lean women. parallel phenomena. is striking: Vulnerability to stres sistency of findings Future research needs to better i was noted across both psychological and physiologica define levels of risk and appropriate treatments based p not only onamonggirth but also Medhigh WHR. causes d measuresE one’s women with a the multiple There i Epel et al Psychosomatic on 2000;62:623-32 of central recognition that overexposure to cortisol ca growing fat, such as genetics, behavior, general obe- n
  25. 25. Cross-sectional data Stress-induced cortisol secretion may contribute to central fat: link between psychological stress and risk for disease Epel E et al Psychosomatic Med 2000;62:623-32
  26. 26. Androgen Central Metabolic predominance (Menopausal obesity Syndrome transition) Environmental influence Genetic predisposition
  27. 27. Metabolic Syndrome in Community-based sample Copenhagen postmenopausal women Postmenopausal women and CV mortality n = 557 (48-76 years) 8.5 + 0.3 y follow-up Tanko et al Circulation 2005;111:1883-90
  28. 28. Enlarged waist with EWET confers 4.7-fold* (95%CI 2.2-9.8; p<0.001) elevated triglycerides increased risk of (EWET) and CV mortality fatal CV events * adjusted for age, smoking and LDL-C Tanko et al Circulation 2005;111:1883-90
  29. 29. What should be done about it? Identify women at risk for MetSyn.
  30. 30. Screening for CV risk in Perimenopause Assess all perimenopausal women seeking medical help for menopausal symptoms for risk of ‣ developing CVD ‣ complications in the presence of existing disease Management of Cardiovascular Risk in the Perimenopausal Woman: A Consensus Statement of European cardiologists and gnyecologists.Collins et al Eur Heart J 2007;28:2028-40
  31. 31. Menopausal Symptoms and CV Risk Factors Eindhoven Perimenopausal Osteoporosis Study cohort n = 5523 women aged 46 to 57 years Self-reported data Do women with Night sweats 38% vasomotor symptoms Flushing 39% differ from those Measurements without with respect total cholesterol to CV risk factors? blood pressure BMI Gerrie-Cor et al Hypertension 2008;51:1492-8
  32. 32. Menopausal Symptoms and CV Risk Factors Eindhoven Perimenopausal Osteoporosis Study cohort n = 5523 women aged 46 to 57 years Women with flushing ↑ cholesterol (0.27 mmol/L [95%CI 0.15-0.39]) ↑ BMI (0.60 kg/m2 [95%CI 0.35-0.84]) ↑ SBP (1.59 mm Hg [95%CI 0.52-2.67]) Hypercholesterolemia ↑ DBP (1.09 mm Hg [95%CI 0.48-1.69]) OR 1.52 (95%CI 1.25-1.84) Hypertension OR 1.20 (95%CI 1.07-1.34) Gerrie-Cor et al Hypertension 2008;51:1492-8
  33. 33. What should be done about it? Address the obesity.
  34. 34. Abdominal Obesity NCEP ATP III (Waist circ.) Men >102 cm (40 in) Women >88 cm (>35 in) IDF (Waist circ.) Men >90 cm Women >80 cm
  35. 35. Nutritional Risk and MetSyn in Women Selected macronutrients Framingham Offspring-Spouse Study • Energy 300 healthy women (aged 30-69 y) free of • Protein MetSyn risk factors at baseline • MUFA • PUFA 12-y follow-up Risk nutrients Protective Tertiles of nutritional • Total fat nutrients risk based on intake • Saturated fat • CHO Dietary fiber of 19 nutrients • • Alcohol • Calcium • Cholesterol Outcomes: • Sodium • Selenium • Vit C, B6, B12, E Abdominal obesity • Folate MetSyn • β-carotene Millen et al Am J Clin Nutr 2000;62:623-32
  36. 36. Age-adjusted proportions of women who complied with NCEP-ATP III dietary guidelines Nutritional risk tertile 100 1 2 3 75 % 50 25 0 Saturated fat Total fat CHO Fiber CHON Cholesterol <7% 25-35% 50-60% 20-30 g/d 15% <200 mg/d Millen et al Am J Clin Nutr 2000;62:623-32
  37. 37. Nutritional Risk and MetSyn in Women Nutritional Risk Score Tertile 1 2 3 Outcome (n = 91) (n = 109) (n = 100) Abdominal obesity RR 1.1 RR 2.3 1.0 (ref) (WC >88 cm) (95%CI 0.6-1.9) (95%CI 1.2-4.3) Metabolic RR 0.8 RR 3.0 1.0 (ref) Syndrome (95%CI 0.3-2.5) (95%CI 1.2-7.6) Multivariate logistic regression model adjusted for age, smoking, physical activity and menopausal status Millen et al Am J Clin Nutr 2000;62:623-32
  38. 38. Physical Activity and Changes in Weight and Waist Circumference in Midlife Women Study of Women’s Health Across the Nation cohort n = 3064 women aged 42 to 52 years; 3-y follow-up Change in weight and Exposure variables waist circumference Age absolute difference: Menopausal status baseline and 3 years Physical activity relative difference: % baseline value Sternfeld et al Am J Epidemiol 2004;160:912-22
  39. 39. Mean within-woman weight change between baseline and year 3 Physical Activity and Weight and Waist Change 917 accdg to change in level of sports/exercise Study of Women’s Health Across the Nation cohort n = 3064 women rts/exer- rd error, p <0.01 y, a one- me (beta with a he influ- routine standard within- standard ld/care- ough an sociated c differ- Scale of 1-5 he mean for FIGUREage, baseline within-woman weight change between baseline * Adjusted baseline 1. Mean level of sports/exercise, race/ethnicity,(1996–1997)of chronic conditions and study according to change in the the presence and year 3 (1999–2000) site Ameri- level of sports/exercise (on a scale of 1–5), Study of Women’s Health ) in the Sternfeld et al Am J Epidemiol 2004;160:912-22 Across the Nation. Results were adjusted for baseline age, baseline er time,
  40. 40. n mean The results of the multivariable logistic regression anal- nge in yses are summarized in table 3. In general, these results are = 0.14Mean within-woman of the longitudinal analysis. Riskbaseline consistent with those waist change between of ively). and year 3 accdg to change in level of sports/exercise , waist lightly Study of Women’s Health Across the Nation cohort n = 3064 women signifi- n addi- p <0.05 weight, s were condi- nge in woman nt cate- ctivity, Scale of 1-5 n these evel* of Adjusted for baseline2. Mean within-woman change in waist circumference FIGURE age, baseline level of sports/exercise, quares race/ethnicity, the presence of chronic conditions and study (1999–2000) according to between baseline (1996–1997) and year 3 site .2, 3.3) change in the level of sports/exercise (on a scale ofet al Am Study of 2004;160:912-22 Sternfeld 1–5), J Epidemiol .8) for Women’s Health Across the Nation. Results were adjusted for base-
  41. 41. Mean within-woman weight change between baseline and Sternfeld et al. change in level of daily routine activity 918 year 3 by Study of Women’s Health Across the Nation cohort n = 3064 women Walking or daily exercise and p <0.01 with lower risk, bu biking statistically sign was for transportation significantly associa Hours of TV gain or substantial included in the mo viewing significantly associa only 54 women ga inclusion of this va (data not shown). DISCUSSION Scale of 1-5 In this study of a significant increase * Adjusted for 3. Mean within-woman weight routine activity, FIGURE baseline age, baseline level of daily change between baseline race/ethnicity, the presence of3 (1999–2000) according to change in the (1996–1997) and year chronic conditions and study site ence occurred over Sternfeld et al of risk factor for weigh level of daily routine physical activity (on a scale of 1–5), Study Am J Epidemiol 2004;160:912-22 Women’s Health Across the Nation. Results were adjusted for base- was not, whether th
  42. 42. gain. Furthermore, and change in daily routine activity. Of the factors associated and waist circumfe with substantial gain in waist circumference, the most Mean was the 32 percent increase in risk associated with a baseline notable within-woman waist change between gorical change in and increase3 by change in over time indaily routine activity activity had the le 1-kg year in weight. Increases level of the sports/ decreased their acti Study of Women’s Health Across the Nation cohort n = 3064 women The finding that period is consisten Walking or tends to that weight p <0.05 aged adults (31, 3 biking for weight gai woman transportation tha slightly lower Healthy Women’s Hours of TV women, over a sim viewing than the in greater year follow-up peri imply that women average, expect to per year during the initial body size, o Scale of 1-5 was a large degree o gain weight over ti * Adjusted for baseline age, baseline level ofchange in waist circumference daily routine activity, women lost at least FIGURE 4. Mean within-woman race/ethnicity,baseline (1996–1997) conditions3 (1999–2000) according to between the presence of chronic and year and study site the 3-year follow-u change in the level of daily routine physical activity (on a scale of Am J Epidemiol 2004;160:912-22 d Sternfeld et al 1– In this study, 5), Study of Women’s Health Across the Nation. Results were domains of both s
  43. 43. Maintain or increase physical activity in midlife to prevent or attenuate increase in weight and waist circumference
  44. 44. Androgen Central Metabolic predominance (Menopausal obesity Syndrome transition) Environmental Genetic influence predisposition
  45. 45. Thank You http://www.endocrine-witch.info

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