1. Hormone Replacement Therapy 5/11/07 5/11/07Tanu

2. History of HRT Approximately 100years of research and 80 years of clinical practice Ovarian extracts used to treat dysmenorrhea and amenorrhea in 1900s The first commercially available injectable estrogen developed in 1928 The first orally active estrogen, Premarin available in the U.S. in 1942

3. Measurement of bone density available in 60s The association between unopposed ET and endometrial cancer in women with an intact uterus found in 70s HRT widely used for postmenopausal symptoms and prevention of osteoporosis in 80s Numerous observational studies in 90s showed cardioprotective effect of HRT History of HRT

4. The EPT arm of the Women’s Helath Initiative (WHI) prematurely halted because of increases in risk of breast cancer, VTE, stroke and CHD in 2002 The ET arm of WHI also prematurely discontinued, reporting that ET had increased risk of stroke and DVT in 2004 History of HRT

5. Recommended dose and duration of HRT have been changed considerably Daily dosages of conjugated estrogens 1.25mg to 2.5mg until mid 1970s The recommended dosage of CE today is 0.3mg HRT was recommended for long term use in 90s It is recommended to limit the use of HRT to the shortest duration History of HRT

6. Effects of HRT CHD Stroke VTE Breast Cancer Ovarian and Endometrial Cancer Osteoporotic fracture Colorectal Cancer Cognitive Function and dementia Gallbladder Diseases Menopausal Symptoms

7. Safety of HRT Observational studies in 90s showed protective effects of low and standard doses of ET/EPT on CHD (Grady D et al. Ann Intern Med. 1992) (Grodstein F et al. N Engl J Med. 1996) (Grodstein F et al. Ann Intern Med. 2000) Coronary Heart Disease

8. Safety of HRT Heart and Estrogen/progestin Replacement Study (HERS) reported that standard doses of EPT increased the risk of CHD in the first year of therapy and had no overall effect on CHD risk among women with h/o CHD (Hulley S et al. JAMA. 1998) (Grady D et al. JAMA. 2002) Coronary Heart Disease

9. Safety of HRT The EPT arm of the WHI reported a substantial elevation in the risk of CHD in year 1 (HR 1.81, 95%CI 1.09-3.01) and a small, statistically nonsignificant increase in the risk of CHD throughout the followup (HR1.24, 95%CI 0.97-1.60) (JoAnn E et al. N Engl J Med. 2003) Coronary Heart Disease

10. Safety of HRT The ET arm of the WHI reported the use of ET alone showed no increase in CHD risk (Anderson GL et al. JAMA. 2004) The population in the ET and EPT arms are older and largely free of menopausal symptoms (Rossouw JE et al. JAMA. 2002) Coronary Heart Disease

11. Safety of HRT The subanalyses of data from the WHI have shown that CHD risk may be reduced with hormone use in younger women and in women closer to the menopausal transition (Manson JE et al. N Engl J Med. 2003) (Hsia J et al. Arch Intern Med. 2006) (Grodstein F et al. J Womens Health. 2006) Coronary Heart Disease

12. Safety of HRT The secondary analysis of the WHI reported a statistically nonsignificant trend toward a reduction of the CHD risk in women who initiated hormone therapy closer to menopause compared to the women more distant from menopause (Rossouw JE et al. JAMA. 2007) Coronary Heart Disease

13. Copyright restrictions may apply. Rossouw, J. E. et al. JAMA 2007;297:1465-1477. Cardiovascular and Global Index Events by Age at Baseline

14. Copyright restrictions may apply. Rossouw, J. E. et al. JAMA 2007;297:1465-1477. Cardiovascular and Global Index Events by Years Since Menopause at Baseline

15. Copyright restrictions may apply. Rossouw, J. E. et al. JAMA 2007;297:1465-1477. Estimated Absolute Excess Risk per 10 000 Person-Years by Age Group at Baseline

16. Copyright restrictions may apply. Rossouw, J. E. et al. JAMA 2007;297:1465-1477. Estimated Absolute Excess Risk per 10 000 Person-Years by Years Since Menopause at Baseline

17. Copyright restrictions may apply. Rossouw, J. E. et al. JAMA 2007;297:1465-1477. Cardiovascular and Global Index Events in Subgroup of Participants with Moderate or Severe Vasomotor Symptoms at Baseline in the Combined Trials

18. Copyright restrictions may apply. Rossouw, J. E. et al. JAMA 2007;297:1465-1477. Cardiovascular and Global Index Events in Subgroup of Participants With Moderate or Severe Vasomotor Symptoms at Baseline in the Combined Trials

19. Safety of HRT Lower dose of HRT? The Nurses' Health Study reported that women beginning ET/EPT near menopause had a significantly reduced risk of CHD, and women beginning therapy 10 years or more after menopause showed no reduction in risk. (Grodstein F et al. J Womens Health. 2006) Coronary Heart Disease

20. Safety of HRT Lower dose of HRT? The analysis from two large clinical trials reported no MI or CV death were observed among patients receiving ET/EPT (Lobo RA et al. Arch Intern Med. 2004 ) Coronary Heart Disease

21. Safety of HRT WHI study has indicated that both ET and EPT are associated with a small but statistically significant increase in the risk of stroke (ET; HR 1.39 95%CI 1.10-1.77, EPT; HR 1.41 95%CI 1.07-1.85) (Wassertheil-Smoller S et al. JAMA. 2003 ) The effect of HRT on stroke risk was similar in all categories of years since menopause (Rossouw JE et al. JAMA. 2007) Stroke

22. Safety of HRT The Nurses' Health Study showed the risk of stroke was related to the daily dose of estrogen. (HR for 0.625 mg/d of CE, 1.35; 95% CI, 1.08-1.68; RR for >=1.25 mg/d of CE, 1.63; 95% CI, 1.18-2.26). Women who used 0.3 mg/d of CE showed no increase in risk of stroke (RR, 0.54; 95% CI, 0.28-1.06). (Grodstein F et al. J Womens Health. 2006) Stroke

23. Safety of HRT The EPT arm of WHI study demonstrated it increased the risk of PE and DVT (Grodstein F et al. J Womens Health. 2006) The ET arm of WHI study showed only the increased risk of DVT reached the statistical significance (Anderson GL et al. JAMA. 2004) Venous Thromboembolic Events

24. Safety of HRT One case study showed a clear dose response in the risk of VTE associated with ET/EPT. The matched RR estimates for estrogen users of 0.325 mg, 0.625 mg, and 1.25 mg or more daily were 2.1, 3.3, and 6.9, respectively (Jick H et al. Lancet. 1996) Venous Thromboembolic Events

25. Safety of HRT The WHI Memory Study (WHIMS) showed EPT did not improve cognitive function. More women in the EPT arm had a substantial and clinically important decline in MMSE score (6.7% vs 4.8%, p=.008). (Rapp SR et al. JAMA. 2003) Cognitive Function and Dementia

26. Safety of HRT The WHI Memory Study (WHIMS) showed EPT did increase the risk for probable dementia. (HR 2.05, 95% CI 1.21-3.48, p=.01). It would result in an additional 23 cases of dementia per 10,000 women per year. (Shumaker SA et al. JAMA. 2003) Cognitive Function and Dementia

27. Safety of HRT The ET arm in the WHIMS showed similar results, increased risk of probable dementia (HR, 1.49; 95% CI, 0.83-2.66), no improved cognitive function, tendency to have significant decrease in MMSE (HR1.47, 95% CI 1.04-2.07) among women with ET. (Espeland MA et al. JAMA. 2004) (Shumaker SA et al. JAMA. 2004) Cognitive Function and Dementia

28. Safety of HRT The substudy of the Nurses’ Health Study found little difference in mean cognitive decline between current hormone users and never users. But increased risk of substantial decline observed on most cognitive tests among long term users of ET/EPT. (Kang JH et al. Neurology 2004) Cognitive Function and Dementia

29. Safety of HRT One 15-year prospective and cross- sectional study failed to show any consistent association between performance on tests of cognitive function and baseline, past, current, or never estrogen use; estrogen dose; or duration of use. (Matthews K et al. J Am Geriatr Soc 1999 ) Cognitive Function and Dementia

30. Safety of HRT The WHI study showed EPT use was associated with a small increase in the risk of invasive breast cancer (RR, 1.24; 95% CI, 1.01-1.54). The risk for breast cancer increased with the duration of EPT use and was higher in women with prior EPT use (Chlebowski RT et al. JAMA. 2003 ) Breast Cancer

31. Safety of HRT In contrast, the ET-only arm of the WHI study experienced a statistically- nonsignificant decrease in breast cancer risk. (RR, 0.77; 95% CI, 0.59-1.01; P=.06). (Anderson GL et al. JAMA. 2004 ) Breast Cancer

32. Safety of HRT The Women's Health Study showed the RR of breast cancer increased with the dose of estrogen. low-dosage estrogen use (<=0.3 mg/d) was not associated with an increase in risk (RR, 0.87; 95% CI, 0.44-1.73). No association between progestin dose and breast cancer risk was observed (Porch JV et al. Cancer Causes Control. 2002) Breast Cancer

33. Safety of HRT A nonsignificant increase in the risk of ovarian cancer was observed in the EPT arm of the WHI study.(HR 1.6, 95% CI 0.8 -3.2). Data from the ET arm not published yet. (Anderson GL et al. JAMA. 2003) Ovarian and Endometrial Cancer

34. Safety of HRT A nonsignificant reduction in the risk of endometrial cancer was observed among women with intact uteruses in the EPT group of the WHI study (HR 0.83, 95% CI 0.47-1.47), though more women in the EPT group experienced vaginal bleeding. (Anderson GL et al. JAMA. 2003) Ovarian and Endometrial Cancer

35. Safety of HRT The risk of osteoporotic fracture with EPT in the WHI study was reduced at the hip (HR 0.67, 95% CI 0.47-0.96) and at the vertebrae and wrist (HR 0.65, 95% CI 0.46 - 0.92; and HR 0.71, 95% CI 0.59-0.85, respectively) (Cauley JA et al. JAMA. 2003) Similar results were observed in the ET arm. (Anderson GL et al. JAMA. 2004) Osteoporotic fracture

36. Safety of HRT In the WHI, the risk of colorectal cancer was reduced with EPT use (HR 0.56, 95% CI 0.38-0.81) (Chlebowski RT et al. N Engl J Med 2004.) No significant risk reduction was observed in the ET arm (HR 1.08, 95% CI 0.75-1.55) (Anderson GL et al. JAMA 2004.) Colorectal Cancer

37. Safety of HRT A secondary analysis of data from the WHI found a significantly increased risk of biliary tract disease among women using ET/EPT (ET: HR, 1.67; 95% CI, 1.35-2.06; EPT: HR, 1.59; 95% CI, 1.28-1.97) (Cirillo DJ et al. JAMA. 2005) Gallbladder Disease

38. Efficacy of HRT Both standard-dose ET/EPT and low-dose ET/EPT provide significant relief of hot flashes. (Utian WH et al. Fertil Steril. 2001 ) (Utian WH et al. Am J Obstet Gynecol. 1999 ) Menopausal Symptoms

39. Summary ETEPT CVDSafe in women closer to menopause StrokeIncreased risk VTEIncreased risk of DVT Increased risk of PE and DVT Breast Cancer Reduced risk?Increased risk

40. Summary ETEPT DementiaIncreased risk Ovarian CapendingIncreased risk? Endometrial CaN/AReduced risk?? Osteoporotic FxReduced risk Colorectal CaReduced risk?Reduced risk Gall bladder dzIncreased risk

41. The Women’s Health Initiave Study is the largest trial to date on the risks and benefits of the standard-dose hormone replacement therapy. Women closer to menopause may benefit from the hormone replacement therapy especially if they are symptomatic Summary

42. Data on the safety of the low-dose hormone replacement therapy are largely limited to observational studies The low dose hormone replacement therapy is as effective as the standard dose HRT, and may have a favorable side effect profile Summary

43. Use of the Hormone replacement therapy should be discouraged for elderly population The hormone replacement therapy may be beneficial in young, healthy postmenopausal women The lower dose should be recommended The use should be limited to the shortest duration Summary