Menopause and Hormone Replacement

1. Menopause and Hormone Replacement State of the Art, 2008

2. CONFUSION 1/3 of physicians regard HRT as dangerous, rarely indicated 1/3 of physicians regard HRT as safe for short term perimenopausal use 1/3 of physicians regard HRT as safe for long term post-menopausal use Wyeth reports return of sales volume

3. NAMS Position StatementJuly 2008 Much less specific than any previous “Use lowest possible dose for shortest possible time” no longer appears Categories of estrogen effects listed, and data discussed Plea for more research in almost all categories

4. Relevant Health Issues Cardiovascular disease Coronary disease Stroke Osteoporosis Alzheimer’s disease Breast Cancer Vaginal atrophy/bladder control All-cause mortality Quality of life Metabolic Syndrome/dyslipidemia Colon Cancer?

5. Principles for Understanding Understand the clinical question and the study goals RCT’s do not address the same questions as observational studies Observational studies appropriate for long-term clinical process improvement

6. Principles for Understanding Cardiovascular disease “It takes healthy vessels to respond to estrogen” Leon Speroff, MD Diseased vessels more susceptible to thrombosis

7. Principles for Understanding Breast Cancer Carcinogenesis requires 5-10 years Shorter term studies reflect recognition more than causation

8. Principles for Understanding Risk Levels (NAMS) Rare = <10 per 10,000 per year Very Rare = < 1 per 10 000 per year

9. Physiology of Menopause Depletion of primordial follicles in the ovary leads to loss of estrogen production That’s it!

10. Serendipity • National Cooperative Lipid Research Clinics—Cholesterol and All-cause mortality ca. 1983 • 2,269 females, 5.6 yr. Study (average) • Women who were estrogen deficient for any reason between ages 25 and 75 had double the mortality rate of age-matched women who were estrogen sufficient. This appeared to be primarily due to vascular disease (Ages 40-69 HR = .37)

11. Large Scale Observational Trials • Nurses Health Study • Walnut Creek • Leisure World • European Trials

12. Observational Trials • Less or no effect on stroke risk • Reduction in fragility fractures due to osteoporosis • 30-70% reduction in vascular disease, primarily CAD

13. Differences noted were: • Large • Consistent • Persistent through multi-variant analysis • Supported by lab studies • Primate models--Clarkson • Anti-oxidant effects of E2 • Lipid modification • Incr. HDL, Decr. LDL and TC

14. HERS study • RCT -- 1998 • Does estrogen – progestagen protect patients with pre-existing coronary artery disease? • Conclusion: NO----but look at the data

15. HERS STUDYPrimary CHD Events

17. HERS STUDY • Nonfatal MI p=.01 • CHD death p=.34 • Unstable angina • Or revasc. P=.42 • VTE p=.28

18. Enter WHI • Decision to perform RCT re efficacy of menopausal HRT • 1995 recruited patients who agreed to placebo vs. treatment and to detailed long-term follow-up. Approx. 25,000 patients. • In addition, began observational study of over 90,000 patients, 1/3 were on HRT at start of study

19. RCT dramatically cancelled Approx July 1, 2002 • DMSB cited excessive risk confirmed by Global Hazard Ratio • Some concern re breast cancer (not statistically significant) • Doubling of CAD risk in year 5

22. CAD rates in HRT users(annualized percentages)

23. CAD rates with controls

25. 1 ½ years later • Adjudicated data published—control group drop no longer present • Treatment and Control groups now statistically equal

26. WHI Observational Trial • 93,000 women enrolled • 3-month “wash-out” • On Combined HRT arm • 34,000 controls (not using at enrollment) • 17,000 users • Ave. age 60.5 • >60% of users used >5 yrs (<4% controls)

28. Role of RCTs • Requires randomizing patients some of whom are highly symptomatic, and requiring that they remain symptomatic for > 10 years (the lag-time in CAD incidence) • Requires avoidance of lipid lowering therapies

29. Applicability of RCTs • Internally consistent—”follow the rules” • WHI usually given good marks here, but: • Non-random subset of population (asymptomatic) • Excessive drop-out and cross-over (not as critical) • Differential use of statins and othe risk-factor modifiers without statistical correction

30. Applicability of RCTs • Can be Generalized to Relevant Clinical Population • Fails—looks at non-random subset of a population 15 years post-menopause—closer to HERS study • Reassuring except raises questions re DVT/Stroke

31. Reflects the Implied Clinical Question RCT’s: What happens when women with vascular disease are treated with hormones for 5-7 years? Observational Trials: Does the pre-menopausal protection from vascular disease that women have continue if estrogen levels are prevented from dropping at menopause?

32. Alzheimer’s—Cache Co. UTNovember, 2002 Hazard Ratios Female:Male overall: 2.11 HRT vs non: 0.59 >10 yrs HRT vs non: 0.41

33. Breast Cancer and HRT

34. Oregonian (LA-Times, Washington Post) August 2008 “The study of more than 15,000 women who took the hormones for more than 5 years found that the chance of developing Ca remained elevated well after they quit….while the increased risk of heart attacks, blood clots and strokes appeared to vanish as soon as women got off the drugs”

35. Oregonian, July 2007 “Breast cancer rates in NW women have plummeted since 2002 when thousands abruptly quit taking hormone medications…” (actual annual risk changes quoted: < 0.025%: 1.51/1000 vs. 1.23/1000)

36. Breast Cancer and HRT • In multiple studies, including WHI, hazard ratios scatter around 1 • Patients with breast cancer diagnosed while on HRT have a reduced mortality rate. • Dr. Pommier at OHSU: due to biological properties of tumor, not differences in screening or care

39. HRT after Breast Cancer NCI Study May, 2001 (Jour. N.C.I.) 2755 patients, 174 HRT users Each user matched to 4 controls 2-19 year followup

40. HRT after Breast Cancer • Recurrence: • 17 per 1000 person-years, HRT • 30 per 1000 person-years non-users • Adj rel risk 0.50 ( 0.3 – 0.85) • Death (cancer related) • 5/ 1000 person yrs HRT • 15/ 1000 person yrs non • Adj rel risk 0.34 (0.13-0.91)

41. HRT after Breast Cancer • Death (total-all cause) • 16 per thousand person yrs. HRT • 30 per thousand person yrs. Non HRT • 0.48 (0.29-0.78)

42. Hypothesis • If carcinogenesis to clinical recognition requires 5-8 years: • Most published studies look at effect of hormones on pre-existing malignant processes • Hormones may accelerate clinical recognition of these cancers with consequent improvement in outcome

43. Hypothesis • Estrogen functions as a growth hormone (regulator) and not a primary carcinogen

44. Clinical Management • Two factors which create confusion: • 1) Perimenopausal ovaries respond to estrogen • 2) Androgens play a significant role in the bioavailability of estrogens

45. Perimenopausal Ovary • Primordial follicles have FSH receptors • FSH receptors maintained by estrogen • This accounts for increased fluctuation of both gonadotropins and estrogen in perimenopause • May be packing-density issue

46. Also accounts for fact that apparently menopausal patients may start cycling upon initiation of HRT, and/or complain of xs estrogen symptoms (headache, bloating, breast tenderness) • Interferes with assessment of low-dose HRT preparations

47. Clinical Practice • In symptomatic perimenopausal patients, initiate therapy with low dose unopposed estrogen (something with long half-life) • Graduate to HRT when periods stop (or stop again)

48. Monitoring • Offered when standard therapy doesn’t help • ? Should be universal—would you treat thyroid disease with one standard dose and not monitor??

49. Monitor FSH and E2 • FSH correlates with symptoms better than E2 level • FSH (depends on lab) <15-20 usually will eliminate symptoms • E2 physiologic levels 80-200 • <50 consistently associated with bone loss

50. Estrogen levels • Dose-response curves are linear for most end-points: • Bone mineral density • HDL • (-)LDL • (-)TC • (-) Insulin