1. Rebecca C. Thurston, PhD Departments of Psychiatry, Psychology, and Epidemiology University of Pittsburgh

2. Outline  Introduction to hot flashes  Introduction to obesity  Obesity and hot flashes  Discussion/future directions

3. Hot Flashes  Sensation of intense heat, sweating, flushing  Hot flashes, night sweats (vasomotor symptoms)  Over 70% of women experience during menopausal transition  Can persist for decades

4. Hot Flashes Duration 0 80 51 Birth Death Final Menstrual Period % US women

5. Hot Flashes  Associated with pronounced impairments quality of life: Physical, social, emotional functioning Sleep disruption, irritability, depressed mood, poorer cognitive function

6. Hot Flashes  Leading cause of treatment seeking among midlife women  Findings of risk associated with hormone therapy (HT) Most effective treatment for hot flashes  Increased interest in physiology of, risk factors for, and new treatments for hot flashes  Underlying physiology not well-understood

7. Physiology of Hot Flashes Copyright ©2004 The Endocrine Society Randolph, J. F. et al. J Clin Endocrinol Metab 2004;89:1555-1561 Estradiol (E2) Follicle stimulating hormone (FSH) Hot Flashes

8. Physiology of Hot Flashes Sweating Shivering Thermoneutral zone TcTc TcTc AsymptomaticSymptomatic Shivering Sweating (Freedman, 2001)

9. Outline  Introduction to hot flashes  Introduction to obesity  Obesity and hot flashes  Discussion/future directions

10. Obesity: Major Health Issue for Midlife Women  Most midlife women in US overweight or obese (66%) BMI >= 25  Marked increase in obesity in recent decades  Projected that 87% of women will be overweight or obese by 2030

11. 2000 Obesity Trends* Among U.S. Adults BRFSS, 1990, 2000, 2010 (*BMI  30, or about 30 lbs. overweight for 5’4” person) 2010 1990 No Data <10% 10%–14 15%–19% 20%–24% 25%–29% ≥30% Source: CDC

12. Obesity: Major Health Issue for Midlife Women  Overweight/obesity associated with multiple health risks: cardiovascular disease, cancer, diabetes, mortality  Steady weight gain over midlife and the menopausal transition  Gain 1-2 pounds/year

13. What can we do about obesity?  Complex, multidimensional problem  Surgery, pharmacologic approaches, behavior changes  Behaviors: Reduce energy intake Increase physical activity

14. Outline  Introduction to hot flashes  Introduction to obesity  Obesity and hot flashes  Discussion/future directions

15. Adiposity and Hot Flashes: Two Perspectives Hormonal “Thin Hypothesis” Adipose tissue: convert androgens to estrogens Higher estrogen Lower risk of hot flashes Recent findings? Thermoregulatory Body fat: increased insulation Inhibit heat dissipation Increase risk of hot flashes Particularly subcutaneous fat

16. Subcutaneous and Visceral Fat

17. Study Questions  Abdominal adiposity associated with hot flashes?  Types of abdominal adiposity related to hot flashes? → Subcutaneous vs. Visceral  What role do reproductive hormones play in associations? → E2, FSH

18. Study of Women’s Health Across the Nation (SWAN) One Time Years 4-7: CT Scan: Abdominal Adiposity (Total, visceral, subcutaneous) SWAN Heart (N=557) Pittsburgh, Chicago SWAN (N = 3302) Annually: Demographic, Health behaviors, Affect Hot flashes Blood Draw: FSH, E2, SHBG Baseline 10 7 6 5 4 2 3 4 5 6 7 8 9 1

19. Abdominal Adiposity and Hot Flashes ** p < 0.01 Adjusted for age and site For every 1SD increase in adiposity Abdominal Adiposity ** (Thurston et al., 2008, Menopause)

20. * p < 0.05 For every 1 SD increase in adiposity Adjusted for age, site, race, education, menopausal status, smoking, HT use, antidepressant use, anxious sx Abdominal Adiposity and Hot Flashes: Fully Adjusted * Abdominal Adiposity * (Thurston et al., 2008, Menopause)

21. OR = 1.33** OR = 1.25* Abdominal Adiposity, Hot Flashes, and Hormones Hot Flashes Reproductive Hormones ? + *- ** E2 ** p < 0.01 * p < 0.05 Fully adjusted (Thurston et al., 2008, Menopause) Abdominal Adiposity

22.  Is this just about central adiposity?  What about total body fat? Questions

23. Study of Women’s Health Across the Nation (SWAN) Year 1 (N = 3302) Bioimpedance Analysis: %body fat, total fat mass, lean mass 10 2 3 4 5 6 7 8 9 (Thurston et al., 2008, Am J Epidemiology)

24. Adiposity and Vasomotor Symptoms N = 1764 p < 0.001 (Thurston et al., 2008, Am J Epidemiology) p < 0.05 + Covariates p < 0.05 + Covariates + Waist

25. OR = 1.21** Adiposity, Vasomotor Symptoms, and Hormones % Body FatVasomotor Sx Reproductive Hormones ? + ****- **** E2 **** 0 < 0.0001 ** p < 0.01 * p < 0.05 Fully Adjusted OR = 1.14* N = 1764 (Thurston et al., 2008, Am J Epidemiology)

26. Vasomotor Symptoms and Body Composition *** ***p < 0.001 For every 1SD increase fat or lean mass N = 1764 (Thurston et al., 2008, Am J Epidemiology)

27.  Does gaining fat increase hot flashes? Question

28. Study of Women’s Health Across the Nation (SWAN) SWAN (N = 3302) Annually: Demographic, Health behaviors, Affect Hot flashes Blood Draw: FSH, E2, SHBG Baseline 10 2 3 4 5 6 7 8 9 1 Years 6-9: Bioimpedance analysis: Total % body fat

29. Gain in Body Fat and Hot Flashes * Relative to stable body fat Adjusted for site, age, race, menopausal status, anxiety, smoking status, parity, education N = 1585 (Thurston et al., 2009, Am J Epidemiology) OR=1.23 (1.02-1.48), p=0.03OR=1.26 (1.03-1.53), p=0.02 +E2 Relative to stable body fat Adjusted for site, age, race, menopausal status, anxiety, smoking status, parity, education, E2

30. Adiposity gain and hot flashes OR (95% CI) Hot Flashes +E2+FSH+FEI Change in Body Fat Gain Lose Stable 1.26* (1.09-1.53) 1.09 (0.89-1.33) - 1.25* (1.02-1.52) 1.08 (0.88-1.32) - 1.24* (1.02-1.50) 1.07 (0.88-1.31) - *p<0.05, Adjusted for age, site, race, education, smoking, parity, anxiety, menopausal stage-cycle day of blood draw (Thurston et al., 2009, AJE)

31. Adiposity and hot flashes  Cross-sectional and longitudinal  Endocrine and thermoregulatory role of body fat  Strongest support for thermoregulatory model  Challenges long-held “thin hypothesis”

32. Adiposity and Hot Flashes

33. A Note about Measurement  Epidemiologic studies use questionnaire measures of hot flashes  Crude, memory and reporting influences  Physiologic, diary measures of hot flashes  Data in “real time”  More precise  Insight into reporting influences

34. Physiologic Measurement of Hot Flashes

35. Hot Flash Diary  Occurrence  Severity  Bothersome  Location on body  Aura  Emotions  Health behaviors…

36. “False Positive” Hot Flash Reporting Physiologic Reported (Diary) YesNo Yes347208 No394--

37. “False Positive” Hot Flash Self-report … But no skin conductance change

38. Psychological Factors Associated with False Positive Hot Flashes (Thurston et al., 2005, Psychosom Med) * * † † p < 0.1 * p < 0.05

39. Emotional Antecedents of “False Positive” Hot Flashes Frustration Sadness StressTiredHappyRelaxed In Control * * * p < 0.05 (Thurston et al., 2005, Psychosom Med)

40. Mood and Hot Flash reporting  Hot flash reporting, like any physical symptom, influenced by mood  More negative affect, more reporting of hot flashes  Particularly those not detected physiologically  Consider when using self-report measures only

41. Study Questions Adiposity Hot flashes? (measured physiologically) E2?

42. SWAN FLASHES 52 Pittsburgh SWAN participants (ages 54-64), with hot flashes/night sweats, no HT, SSRI/SNRIs Bioimpedance body fat, BMI, waist circumference 96 hours ambulatory skin conductance monitoring with electronic diary Screening Body fat, Waist circumference BMI 96 hours hot flash monitoring

43.  Higher BMI, body fat, waist circumference associated with fewer hot flashes  But the association varied by age Surprising Finding

44. Association between body fat and hot flashes varies by age **** ****p<0.0001 Covariates: age, race/ethnicity, anxiety (Thurston et al., 2011, J Clinical Endocrinology and Metabolism)

45. Relation between BMI and hormones varies by age E2SHBGFree E2 Index Age 54-56 -0.22-0.160.03 Age 57-59 0.13-0.160.12 Age 60-63 0.56**-0.72**0.75** **p<0.01 Adjusted for cycle day of blood draw, age, time difference between measures, race/ethnicity (Thurston et al., 2001, J Clinical Endocrinology and Metabolism)

46.  Impact of obesity on reproductive function may vary by age  Younger midlife women, obesity anovulatory cycles, lower E2  Older women, body fat main source of estrogen What’s age got to do with it?

47. Relation between obesity and E2 over the transition

48. Adiposity and Hot Flashes  Possible endocrine & thermoregulatory role of body fat  Endocrine impact of body fat vary by age

49. Outline  Introduction to hot flashes  Introduction to obesity  Obesity and hot flashes  Discussion

50. Weight Loss  Women can lose weight behaviorally  Behavioral weight loss associated with 7-10% reduction in body weight over 6 months  Clinically-significant improvements in multiple cardiovascular risk factors

51. The Science of Behavioral Weight Loss  Single best method: keep a food diary  Write down everything eat and calculate caloric content (great online resources)  To keep weight off, maintain high level of exercise (60 min, 5 days/wk brisk walking)

52. Implications?  Better understand physiology of hot flashes  Weight Loss  Multiple health benefits  Improve health of midlife women

53. SWAN has grant support from the NIH, DHHS, through the NIA, NINR, NHLBI, ORWH (NR004061; AG012505, AG012535, AG012531, AG012539, AG012546, AG012553, AG012554, AG012495, HL065581, HL06551) Pittsburgh Mind Body Center/NIH (HL076852/076858) Thurston: K23 AG029216 American Federation for Aging Research University of Pittsburgh Institute on Aging The content of this presentation is solely the responsibility of the authors and does not necessarily represent the official views of the NIA, NINR, ORWH or the NIH. Karen Matthews, PhD Kim Sutton-Tyrrell, DrPH Rachel Hess, MD, MSc Samar El Khoudary, PhD Faith Selzer, PhD Susan Everson-Rose, PhD, MPH Ellen Gold, PhD Imke Janssen, PhD Lynda Powell, PhD Israel Christie, PhD Carolyn Crandall, MD, MS Barbara Sternfeld, PhD Acknowledgements

54. Thank you!

55. Questions?