2. Hormones, Hot Flashes, & Highlights in Women’s Health Laura Davisson, MD Assistant Professor, Section of General Internal Medicine Clinical Care Co-Director, Center of Excellence in Women’s Health

3. History of Women’s Health

4. 1941: Diethylstilbestrol (DES) approved by FDA 1941: Diethylstilbestrol (DES) approved by FDA 1953: Study published showing ineffectiveness at preventing miscarriage 1953: Study published showing ineffectiveness at preventing miscarriage Until 1971: Continued to be aggressively marketed and routinely prescribed Until 1971: Continued to be aggressively marketed and routinely prescribed 1971: Identified as cause of vaginal clear cell adenocarcinoma in DES daughters 1971: Identified as cause of vaginal clear cell adenocarcinoma in DES daughters 1971: FDA advised physicians to stop prescribing to pregnant women and national effort begun to find women prescribed DES while pregnant 1971: FDA advised physicians to stop prescribing to pregnant women and national effort begun to find women prescribed DES while pregnant

5. History of Women’s Health Such tragedies in pregnant women led to fear of using women of childbearing age in trials Such tragedies in pregnant women led to fear of using women of childbearing age in trials 1970s: regulations restricted testing in women of reproductive age 1970s: regulations restricted testing in women of reproductive age Ultimately led to widespread exclusion of women from trials Ultimately led to widespread exclusion of women from trials Throughout most of 20 th century: treatments tested solely on men Throughout most of 20 th century: treatments tested solely on men 1990: GAO report brought to light under- representation of women in federally funded trials 1990: GAO report brought to light under- representation of women in federally funded trials

6. History of Women’s Health Now… Several Federal agencies have changed policies to promote inclusion of women in studies Several Federal agencies have changed policies to promote inclusion of women in studies Learning that women affected by some diseases at different rates than men Learning that women affected by some diseases at different rates than men Learning that women can present differently than men Learning that women can present differently than men There is emerging body of gender-specific research to guide practice in women’s health There is emerging body of gender-specific research to guide practice in women’s health

7. Today’s Goals Review literature regarding several important women’s health topics Review literature regarding several important women’s health topics Increase awareness of emerging discipline of women’s health Increase awareness of emerging discipline of women’s health

8. Outline Hormones Hormones Hot flashes Hot flashes Highlights Highlights

9. Preferred Terminology ET: estrogen therapy ET: estrogen therapy EPT: combined estrogen-progestogen therapy EPT: combined estrogen-progestogen therapy HT: Hormone therapy (encompasses both ET and EPT) HT: Hormone therapy (encompasses both ET and EPT) Note: hormone therapy (HT) as opposed to hormone replacement therapy Note: hormone therapy (HT) as opposed to hormone replacement therapy Progestogen encompasses both progesterone and progestin Progestogen encompasses both progesterone and progestin North American Menopause Society (NAMS), 2007 Position Statement

10. 1990’s Recommendations based on observational studies “Women who have coronary heart disease or who are at increased risk of coronary heart disease are likely to benefit from hormone therapy” American College of Physicians, 1992 “Probable beneficial effect of estrogen on heart disease” American College of Obstetricians and Gynecologists, 1992 “Estrogen replacement therapy does look promising as a long- term protection against heart attack” American Heart Association, 1996

11. Heart and Estrogen/Progestin Replacement Study (HERS) 1998

12. HERS Purpose: To evaluate secondary prevention of CHD with hormone therapy (HT) in postmenopausal women with known coronary disease

13. HERS Methods: Randomized, double blinded, placebo-controlled trial Randomized, double blinded, placebo-controlled trial Over 2700 women with CHD and intact uteri Over 2700 women with CHD and intact uteri Mean age 67 Mean age 67 Average follow-up: 4.1 years Average follow-up: 4.1 years Hormone formulation: conjugated equine estrogen (CEE) 0.625mg + medroxyprogesterone acetate (MPA) 2.5 mg daily Hormone formulation: conjugated equine estrogen (CEE) 0.625mg + medroxyprogesterone acetate (MPA) 2.5 mg daily

14. HERS Results: No significant differences in CHD found in treatment vs. placebo groups

15. HERS II (2002) Subsequent unblinded follow-up of HERS subjects Subsequent unblinded follow-up of HERS subjects Looked at long-term outcomes for 2.7 more years Looked at long-term outcomes for 2.7 more years Confirmed HERS findings that HT did NOT decrease risk of CHD in women with known history of CHD Confirmed HERS findings that HT did NOT decrease risk of CHD in women with known history of CHD

16. HERS I and II Interpretation of HERS trials: HT not effective in secondary prevention of CHD

17. WHI Women’s Health Initiative

18. WHI Observational Study Observational Study Clinical Trials: Clinical Trials: Hormone Therapy Hormone Therapy Dietary Modification Dietary Modification Calcium/Vitamin D Calcium/Vitamin D

19. Some of the 100+ WHI papers: Estrogen plus progestin and the risk of coronary heart disease. NEJM, 2003 Effect of estrogen plus progestin on stroke in postmenopausal women. The women’s health initiative: a randomized trial. JAMA, 2003 Estrogen plus progestin and colorectal cancer in postmenopausal women. NEJM, 2004 Estrogen plus progestin and risk of venous thrombosis. JAMA, 2004 Conjugated equine estrogens and coronary heart disease: the women’s health initiative. Arch Intern Med, 2006 Venous thrombosis and conjugated equine estrogen in women without a uterus. Arch Intern Med, 2006

20. WHI Multi-million dollar, 15-year project sponsored by NIH, NHLBI Multi-million dollar, 15-year project sponsored by NIH, NHLBI Over 160,000 women aged 50-79 Over 160,000 women aged 50-79 40 Clinical Centers across US 40 Clinical Centers across US One of most definitive, far-reaching clinical trials of post-menopausal women's health ever done One of most definitive, far-reaching clinical trials of post-menopausal women's health ever done

21. WHI Hormone Therapy Trial Long-term study to evaluate HT’s effects on CHD, osteoporotic fractures, and breast cancer in postmenopausal women Long-term study to evaluate HT’s effects on CHD, osteoporotic fractures, and breast cancer in postmenopausal women Two arms: Two arms: Estrogen plus Progestin (E+P) Estrogen plus Progestin (E+P) Estrogen Alone (E Alone) Estrogen Alone (E Alone)

22. WHI Hormone Therapy Trial: E+P arm

23. WHI: E+P arm Methods: Over 16,000 women with intact uteri Over 16,000 women with intact uteri Randomly assigned to E+P vs. placebo for 5 years (planned duration 8.5 years) Randomly assigned to E+P vs. placebo for 5 years (planned duration 8.5 years) Hormone formulation: CEE 0.625mg plus MPA 2.5mg daily Hormone formulation: CEE 0.625mg plus MPA 2.5mg daily

24. WHI: E+P arm Results: Trial halted early--July 2002 Trial halted early--July 2002 Overall harm found in treatment group Overall harm found in treatment group

25. WHI: E+P arm Decreased risk of: Colorectal cancer (34%) Colorectal cancer (34%) Hip fractures (34%) Hip fractures (34%) Outweighed by increased risk of: Breast cancer (26%) Breast cancer (26%) Pulmonary embolism (113%) Pulmonary embolism (113%) Coronary heart disease (29%) Coronary heart disease (29%) Strokes (41%) Strokes (41%)

26. WHI: E+P arm Absolute excess risks: Excess CHD events: 7/10,000 woman-years Excess stroke events : 8/10,000 woman-years Excess pulmonary emboli: 8/10,000 woman- years Excess invasive breast cancer: 8/10,000 woman- years

27. WHI: E+P arm Absolute Benefits: Fewer colorectal cancers: 6/10,000 woman- years Fewer hip fractures: 5/10,000 woman-years

28. WHI: E+P arm Summary of additional adverse events: 19 per 10,000 woman-years Summary of additional adverse events: 19 per 10,000 woman-years Number needed to harm for 5 years E+P use: 101 Number needed to harm for 5 years E+P use: 101

29. WHI Hormone Therapy Trial: E Alone arm

30. WHI: E Alone arm Methods: Over 10,000 women aged 50-79 with prior hysterectomy Over 10,000 women aged 50-79 with prior hysterectomy Randomly assigned to 0.625mg CEE vs. placebo Randomly assigned to 0.625mg CEE vs. placebo Followed for average 6.8 years Followed for average 6.8 years

31. WHI: E Alone arm Results: Trial halted one year early--February 2004 Trial halted one year early--February 2004 Increased risk of stroke among women in hormone group Increased risk of stroke among women in hormone group

32. WHI: E Alone arm Results: Reduced risk of hip fracture (39%) Reduced risk of hip fracture (39%) Increased risk of stroke (39%) Increased risk of stroke (39%) No effect on heart disease, breast cancer, pulmonary embolus, colorectal cancer, total mortality, or global index No effect on heart disease, breast cancer, pulmonary embolus, colorectal cancer, total mortality, or global index No overall benefit No overall benefit

33. WHI: E Alone arm Major Clinical Outcomes RR Hip fracture 0.61* Breast cancer 0.77 CHD0.91 Total Mortality 1.04 Colorectal cancer 1.08 CVA1.39*

34. Adapted from N Engl J Med 2006;355:2338-2347 WHI Hormone Therapy Trial Relative Risks and Absolute Risk Differences among Women 50-54 Outcome E+P RR (95% CI) Absolute Risk Difference E Alone RR (95% CI) Absolute Risk Difference CHD 1.29 (1.02-1.63) 0.26 0.91 (0.75-1.12) --- CVA 1.41 (1.07-1.85) 0.20 1.39 (1.10-1.77) 0.20 Pulmonary embolism 2.13 (1.39-3.25) 0.45 1.34 (0.87-2.06) --- Breast cancer 1.26 (1.00-1.59) 0.93 0.77 (0.59-1.01) --- Colon Cancer 0.63 (0.43-0.92) -0.18 1.08 (0.75-1.55) --- Hip fracture 0.66 (0.45-0.98) -0.10 0.61 (0.41-0.91) -0.12 Net outcomes per 1000 women years 1.560.08

35. WHI Hormone Therapy Trial: Divergent results Heart disease Heart disease Increased: E+P Increased: E+P Neutral: E Alone Neutral: E Alone Pulmonary embolism Pulmonary embolism Increased: E+P Increased: E+P Neutral: E Alone Neutral: E Alone Breast cancer Breast cancer Increased: E+P Increased: E+P Neutral: E Alone Neutral: E Alone Colorectal cancer Decreased: E+P Neutral: E Alone Global index Increased: E+P Neutral: E Alone

36. WHI Hormone Therapy Trial: Concordant results Increased: Increased: Strokes Strokes Dementia (>65) Dementia (>65) Gallstones Gallstones Urinary incontinence Urinary incontinence Decreased: Decreased: Fractures Fractures Vasomotor symptoms Vasomotor symptoms Diabetes Diabetes Neutral: Neutral: HRQOL HRQOL

37. WHI Hormone Therapy Trial Limitations: Only tested CEE and MPA hormone regimens Only tested CEE and MPA hormone regimens Early termination of trials can lead to bias Early termination of trials can lead to bias Average age mid-60’s, not typical 50 year-old women seeking relief from menopausal symptoms Average age mid-60’s, not typical 50 year-old women seeking relief from menopausal symptoms Possible that recently menopausal women with low baseline risk of heart disease may have more favorable balance of benefits and risks Possible that recently menopausal women with low baseline risk of heart disease may have more favorable balance of benefits and risks

38. WHI Hormone Therapy Trial Conclusions: HT should not be recommended for chronic disease prevention in postmenopausal women HT should not be recommended for chronic disease prevention in postmenopausal women Rate of adverse events was higher with E+P than Rate of adverse events was higher with E+P than E Alone Possible that progestins exacerbate risks Possible that progestins exacerbate risks Possible that other formulations, routes of administration, or lower doses might be associated with fewer adverse events (little supportive Possible that other formulations, routes of administration, or lower doses might be associated with fewer adverse events (little supportiveevidence)

39. Divergence of clinical trials from observational studies Highlights importance of randomized controlled clinical trials Highlights importance of randomized controlled clinical trials Confounding may explain lower heart disease rates in hormone users in observational studies because they were: Confounding may explain lower heart disease rates in hormone users in observational studies because they were: Leaner Leaner Less likely to smoke Less likely to smoke More physically active More physically active More likely to see doctors regularly More likely to see doctors regularly More highly educated More highly educated Another possible explanation for discrepancy: Another possible explanation for discrepancy: timing of initiation of HT

40. Timing of initiation of HT Emerging data suggests disparities may be related to timing of initiation of HT in relation to proximity of menopause Emerging data suggests disparities may be related to timing of initiation of HT in relation to proximity of menopause On average, women in WHI and HERS initiated HT more than a decade after menopause On average, women in WHI and HERS initiated HT more than a decade after menopause Insufficient numbers of younger, symptomatic, newly postmenopausal women to determine whether similar patterns apply to them Insufficient numbers of younger, symptomatic, newly postmenopausal women to determine whether similar patterns apply to them Trial results should be extrapolated to recently postmenopausal women only with caution Trial results should be extrapolated to recently postmenopausal women only with caution

41. Meta-analysis: Mortality by treatment assignment and age group Adapted from J Gen Intern Med 2004;19:791-804 Group Odds Ratio (95% CI) for Mortality All ages 0.98 (0.87-1.18) <60 years 0.61 (0.39-0.95) >60 years 1.03 (0.90-1.18)

42. Rossouw, JE, et al. JAMA. Apr 4, 2007;297:1465-1477

43. Timing of initiation of HT Purpose: To explore whether the effects of HT on risk of cardiovascular disease vary by age or years since menopause began JAMA. Apr, 2007;297:1465-1477

44. Timing of initiation of HT Methods: Secondary analysis of WHI HT trial results Secondary analysis of WHI HT trial results Combined data from the two trial arms to improve statistical power to be able to examine trends across categories of age and years since menopause Combined data from the two trial arms to improve statistical power to be able to examine trends across categories of age and years since menopause Main outcome: CHD Main outcome: CHD Other outcomes: mortality and a global index Other outcomes: mortality and a global index JAMA. Apr, 2007;297:1465-1477

45. Timing of initiation of HT Results: Trend for reduced CHD risk in women closer to menopause but no subgroup met statistical significance Trend for reduced CHD risk in women closer to menopause but no subgroup met statistical significance Nonsignificant tendency for total mortality to be reduced among younger women (50-59) Nonsignificant tendency for total mortality to be reduced among younger women (50-59) Risk of stroke did not vary by age or time since menopause Risk of stroke did not vary by age or time since menopause JAMA. Apr, 2007;297:1465-1477

46. Timing of initiation of HT Conclusions: Offers reassurance that HT a reasonable option for short-term treatment of menopausal symptoms Offers reassurance that HT a reasonable option for short-term treatment of menopausal symptoms Raises the question of whether there may be a protective effect against CHD in younger, recently postmenopausal women Raises the question of whether there may be a protective effect against CHD in younger, recently postmenopausal women JAMA. Apr, 2007;297:1465-1477

47. Decrease in HT and Breast Cancer— Coincidence? After WHI (in 2002), HT use decreased by about 30% After WHI (in 2002), HT use decreased by about 30% Breast cancer incidence dropped 7% from 2002-2003 Breast cancer incidence dropped 7% from 2002-2003 It is suspected that the decreased use of HT may have led to decreased breast cancer incidence but causality cannot be determined from this data It is suspected that the decreased use of HT may have led to decreased breast cancer incidence but causality cannot be determined from this data Could also be from decreased mammography rates leading to decreased detection (mammography rates decreased 1% between 2000 and 2003) Could also be from decreased mammography rates leading to decreased detection (mammography rates decreased 1% between 2000 and 2003) Ravdin PM, Cronin KA, Howlander N, Chlebowski RT, Berry DA. 29 th Annual San Antonio Breast Cancer Symposium, Dec. 2006.

48. Hormone Therapy (HT): Current Guidelines

49. HT: current guidelines Indications by current labeling: Treatment of moderate-severe vasomotor symptoms Treatment of moderate-severe vasomotor symptoms Treatment of moderate-severe urogenital symptoms Treatment of moderate-severe urogenital symptoms Prevention of osteoporosis (not treatment) in women at significant risk Prevention of osteoporosis (not treatment) in women at significant risk

50. HT: current guidelines Per NAMS position statements: Limit use to short term menopausal symptom relief Limit use to short term menopausal symptom relief Lowest dose, shortest duration possible Lowest dose, shortest duration possible Avoid in women with history of breast cancer, uterine cancer, or thromboembolic disease Avoid in women with history of breast cancer, uterine cancer, or thromboembolic disease Must add progestin if patient has uterus Must add progestin if patient has uterus Do not initiate or continue to prevent CHD Do not initiate or continue to prevent CHD 2007 revision: benefits of short-term HT for treatment of perimenopausal symptoms likely outweigh risks for younger women 2007 revision: benefits of short-term HT for treatment of perimenopausal symptoms likely outweigh risks for younger women

51. Outline Hormones Hormones Hot flashes Hot flashes Highlights Highlights

52. Definition of natural menopause Retrospectively defined: no menstrual period for 12 months Retrospectively defined: no menstrual period for 12 months Average age: 51-52 years Average age: 51-52 years

53. Perimenopause Around ages 42-52 years Around ages 42-52 years Irregular cycles: shorter or longer; heavier or lighter; missed completely Irregular cycles: shorter or longer; heavier or lighter; missed completely Vasomotor symptoms: hot flashes, night sweats Vasomotor symptoms: hot flashes, night sweats Urogenital symptoms: dryness, itching, dyspareunia, incontinence, increased bladder infections Urogenital symptoms: dryness, itching, dyspareunia, incontinence, increased bladder infections FSH rises (often normal range during perimenopause) FSH rises (often normal range during perimenopause)

54. Perimenopause Many vasomotor symptoms will improve within several months Many vasomotor symptoms will improve within several months Most will resolve within 4-5 years Most will resolve within 4-5 years Substantial minority (10-15%) continue to have troublesome symptoms for years Substantial minority (10-15%) continue to have troublesome symptoms for years

55. Treatment of vasomotor symptoms Data to guide therapy is lacking Data to guide therapy is lacking Studies complicated by high rate of placebo effect (around 25%) Studies complicated by high rate of placebo effect (around 25%) Trials have been small and brief, providing little information about long-term efficacy and risks Trials have been small and brief, providing little information about long-term efficacy and risks

56. Treatment of vasomotor symptoms: Estrogen

57. Treatment of vasomotor symptoms: estrogen Multiple randomized trials have demonstrated its efficacy Multiple randomized trials have demonstrated its efficacy All types and routes of administration markedly improve frequency and severity of hot flashes All types and routes of administration markedly improve frequency and severity of hot flashes Dose-related improvement Dose-related improvement

58. Adapted from N Engl J Med 2006;355:2338-2347 Efficacy of Treatment of Hot Flushes with Various Doses of Estrogen, as Compared with Placebo Type/dose of estrogen % Reduction in hot flash frequency Oral conjugated equine estrogen 0.625mg 94 Oral conjugated equine estrogen 0.45mg 78 Oral conjugated equine estrogen 0.3mg 78 Oral 17 Beta-Estradiol 2 mg 96 Oral 17 Beta-Estradiol 1 mg 89 Oral 17 Beta-Estradiol 0.5 mg 79 Oral 17 Beta-Estradiol 0.25 mg 59 Transdermal 17 Beta-Estradiol 0.1mg 96 Transdermal 17 Beta-Estradiol 0.05 mg 96 Transdermal 17 Beta-Estradiol 0.025 mg 86

59. Nelson, HD, Vesco KK, Haney E, et al. Nonhormonal therapies for menopausal hot flashes: Systematic review and meta-analysis. JAMA. 2006;295:2057-2071

60. Methods 10 trials of antidepressants (SSRI’s or SNRI’s) 10 trials of antidepressants (SSRI’s or SNRI’s) 10 trials of clonidine 10 trials of clonidine 6 trials of other prescribed medications 6 trials of other prescribed medications 17 trials of isoflavone extracts 17 trials of isoflavone extracts JAMA. 2006;295:2057-2071

61. Results and Conclusions Isoflavone extracts: no definite evidence of benefit Isoflavone extracts: no definite evidence of benefit SSRI’s, SNRI’s, clonidine, gabapentin: some evidence of efficacy but less than estrogen SSRI’s, SNRI’s, clonidine, gabapentin: some evidence of efficacy but less than estrogen Few trials of non-hormonal therapies have been published Few trials of non-hormonal therapies have been published Most have methodological deficiencies Most have methodological deficiencies Generalizability limited Generalizability limited JAMA. 2006;295:2057-2071

62. Evidence of Efficacy of Non-hormonal Prescription Drugs for Treatment of Hot Flashes from Randomized, Controlled Clinical Trials Adapted from N Engl J Med 2006; 355:2338-2347 Treatment Evidence of Benefit MPAYes MegestrolYes GabapentinYes ClonidineMixed MethyldopaNo CitalopramNo FluoxetineMixed ParoxetineYes SertralineNo VenlafaxineMixed

63. Nedrow A, Miller J, Walker M, Nygren P, Huffman LH, Nelson HD. Complementary and alternative therapies for the management of menopause-related symptoms: A systematic evidence review. Arch Intern Med. 2006;166:1453-1465

64. Complementary and Alternative Therapies Systematic review included randomized controlled trials and meta-analyses Systematic review included randomized controlled trials and meta-analyses Phytoestrogens: mixed results Phytoestrogens: mixed results Black cohosh: mixed results Black cohosh: mixed results Mind-body, energy, manipulative, body-based therapies and whole medical systems: little benefit Mind-body, energy, manipulative, body-based therapies and whole medical systems: little benefit Data insufficient to support effectiveness of any therapy in this review Data insufficient to support effectiveness of any therapy in this review Arch Intern Med. 2006;166:1453-1465

65. Treatment of vasomotor symptoms: black cohosh 2006: longest and largest placebo-controlled, double-blind trial to date of black cohosh 2006: longest and largest placebo-controlled, double-blind trial to date of black cohosh Showed no improvement in vasomotor symptoms Showed no improvement in vasomotor symptoms In combination with other studies provides strong evidence that black cohosh ineffective In combination with other studies provides strong evidence that black cohosh ineffective Ann Intern Med. 2006;145:869-879.

66. Treatment of vasomotor symptoms No convincing evidence of efficacy for treatment of vasomotor symptoms for: Evening primrose oil Evening primrose oil Ginseng Ginseng Wild yam cream Wild yam cream Yoga Yoga Chinese herbs Chinese herbs Dong quai Dong quai Kava Kava Red clover extract Red clover extract Vitamin E Vitamin E ANY complementary and alternative therapy ANY complementary and alternative therapy

67. “Bioidentical” hormone replacement

68. Term “bioidentical” not defined, has no scientific meaning Term “bioidentical” not defined, has no scientific meaning These products made by compounding pharmacies These products made by compounding pharmacies Individualized dosage determined by salivary hormone levels Individualized dosage determined by salivary hormone levels Promoted by patient testimonials, often celebrities, as safer and more effective than conventional therapy Promoted by patient testimonials, often celebrities, as safer and more effective than conventional therapy Not produced according to federal Good Manufacturing Practice, not approved by FDA Not produced according to federal Good Manufacturing Practice, not approved by FDA No evidence of effectiveness or safety No evidence of effectiveness or safety Cannot be recommended Cannot be recommended

69. Practical/behavioral measures Paced respirations Paced respirations Dress in layers Dress in layers Lower ambient temperature Lower ambient temperature Avoid turtlenecks, down comforters, alcohol, spicy foods, bright lights Avoid turtlenecks, down comforters, alcohol, spicy foods, bright lights

70. Summary of Treatment Options for Vasomotor Symptoms Practical/behavioral measures—first line for mild symptoms Practical/behavioral measures—first line for mild symptoms HT for moderate to severe symptoms—most effective HT for moderate to severe symptoms—most effective Topical treatment if urogenital symptoms only Topical treatment if urogenital symptoms only Non-hormonal drugs can be tried if want to avoid estrogens (off-label): Non-hormonal drugs can be tried if want to avoid estrogens (off-label): Antidepressants including venlafaxine, fluoxetine, paroxetine Antidepressants including venlafaxine, fluoxetine, paroxetine Gabapentin Gabapentin Clonidine Clonidine

71. Treatment of vasomotor symptoms—if HT used: Follow NAMS guidelines (avoid use in patients with contraindications, use low doses/short durations) Follow NAMS guidelines (avoid use in patients with contraindications, use low doses/short durations) Reasonable to try discontinuing every 6-12 months since vasomotor symptoms are usually temporary Reasonable to try discontinuing every 6-12 months since vasomotor symptoms are usually temporary Possible that women will have recurrence of symptoms after stopping Possible that women will have recurrence of symptoms after stopping If symptoms recur, try gradually tapering dose or number of days per week used (no guidelines) If symptoms recur, try gradually tapering dose or number of days per week used (no guidelines)

72. Outline Hormones Hormones Hot flashes Hot flashes Highlights Highlights

73. Low-Fat Dietary Pattern and Risk of Colorectal Cancer Low-Fat Dietary Pattern and Risk of Invasive Breast Cancer The Women’s Health Initiative Randomized Controlled Dietary Modification Trial JAMA, February 8, 2006;295

74. WHI Dietary Modification Trial Background: Observational data suggests association of dietary fat intake with breast cancer, cardiovascular disease, and colorectal cancer Observational data suggests association of dietary fat intake with breast cancer, cardiovascular disease, and colorectal cancer Purpose: to evaluate effectiveness of low-fat diet Purpose: to evaluate effectiveness of low-fat diet

75. WHI Dietary Modification Trial Methods: Over 48,000 women, aged 50-79 Over 48,000 women, aged 50-79 Subjects randomized to low-fat/high fruit, vegetable, grain diet vs. usual eating pattern Subjects randomized to low-fat/high fruit, vegetable, grain diet vs. usual eating pattern Followed for mean of 8.1 years Followed for mean of 8.1 years

76. WHI Dietary Modification Trial Results--no significant reduced risk of any outcome: Breast cancer Breast cancer Colorectal cancer Colorectal cancer Stroke Stroke CHD CHD

77. WHI Dietary Modification Trial Limitations: Did not specify types fats--potential for benefit of diet lower in saturated and trans fat Did not specify types fats--potential for benefit of diet lower in saturated and trans fat Few met target of 20% calories from fat--may have been underpowered to detect difference Few met target of 20% calories from fat--may have been underpowered to detect difference Positive trend toward decreased coronary heart disease, breast cancer, and colon polyps as trial progressed—did not reach statistical significance Positive trend toward decreased coronary heart disease, breast cancer, and colon polyps as trial progressed—did not reach statistical significance Health implications of diet may take years to be fully realized--benefits may show up in future follow-up Health implications of diet may take years to be fully realized--benefits may show up in future follow-up

78. Women’s Intervention Nutrition Study (WINS) Randomized, prospective, multicenter clinical trial Randomized, prospective, multicenter clinical trial Tested dietary intervention for reducing recurrence of breast cancer Tested dietary intervention for reducing recurrence of breast cancer Intervention: decrease fat intake to 15% of calories (30% at baseline) Intervention: decrease fat intake to 15% of calories (30% at baseline) Over 2000 women with resected, early-stage breast cancer receiving conventional cancer management Over 2000 women with resected, early-stage breast cancer receiving conventional cancer management Analysis performed after median follow-up of 60 months Analysis performed after median follow-up of 60 months J Natl Cancer Inst. 2006 Dec 20;98(24):1767-76

79. Women’s Intervention Nutrition Study (WINS) Results: Intervention group achieved fat intake of 20% of calories (29% in control group) Intervention group achieved fat intake of 20% of calories (29% in control group) Intervention group weighed 6 pounds less than control group (same at baseline) Intervention group weighed 6 pounds less than control group (same at baseline) 24% risk reduction for relapse in intervention group 24% risk reduction for relapse in intervention group Number needed to treat: 38 Number needed to treat: 38 Subgroup analysis suggested most benefit in hormone receptor negative cancers (not statistically significant) Subgroup analysis suggested most benefit in hormone receptor negative cancers (not statistically significant) J Natl Cancer Inst. 2006 Dec 20;98(24):1767-76

80. Women’s Intervention Nutrition Study (WINS) Limitations: Effect could have been from weight loss rather than the dietary fat on its own Effect could have been from weight loss rather than the dietary fat on its own Generalizability of benefit of low fat diet is limited: only studied recurrence of breast cancer in women with previous breast cancer history Generalizability of benefit of low fat diet is limited: only studied recurrence of breast cancer in women with previous breast cancer history J Natl Cancer Inst. 2006 Dec 20;98(24):1767-76

81. Interpretation of these trials: Should women bother eating a low-fat diet? Studies need to be interpreted with caution because conducting clinical trials of lifestyle changes is difficult Studies need to be interpreted with caution because conducting clinical trials of lifestyle changes is difficult WINS study suggests that reduced dietary fat intake with influence on weight may benefit breast cancer patients WINS study suggests that reduced dietary fat intake with influence on weight may benefit breast cancer patients WHI Dietary Modification trial did not show benefit, but experts are not recommending change in current recommendations WHI Dietary Modification trial did not show benefit, but experts are not recommending change in current recommendations Longer follow-up of these trials will answer more questions about its benefit Longer follow-up of these trials will answer more questions about its benefit Low-fat diet still recommended for overall health Low-fat diet still recommended for overall health

82. Conclusions Hormones Hormones HT trials HT trials Limited role for HT Limited role for HT Hot flashes Hot flashes Menopause/perimenopause Menopause/perimenopause Limited options for vasomotor symptoms Limited options for vasomotor symptoms Highlights Highlights Low-fat diet trials Low-fat diet trials Several recent trials have changed treatment of women Several recent trials have changed treatment of women