1. Hormone Therapy for Menopause: Current Data Jan Shepherd, MD, FACOG

2. Objectives Discuss data on the risks and benefits of HT generated since the initial publication from the Women’s Health Initiative. Discuss current evidence regarding the effect of HT on cardiovascular and breast cancer risk. Apply current evidence regarding HT to clinical practice.

3. Case A 52 year-old Caucasian female g2p2, LMP 6 months ago, presents with significant hot flashes interfering with her daily activities and sleep. She has read that HT can cause breast cancer and heart attacks. What is your initial advice?

4. Hormone Therapy (HT or MHT) Combination Therapy (EPT, was HRT) – replacing estrogen and progesterone –Progesterone necessary to protect uterus Estrogen Therapy (ET, was ERT) – replacing estrogen alone –Used in women who have had a hysterectomy Until 2002, thought to be almost always beneficial

5. Symptoms of the Climacteric Menstrual Changes Vaginal Dryness and Genital Tract Atrophy Hot Flashes Sleep Disturbances Mood Changes Cognitive Changes Other

7. Osteoporosis

8. Osteoporosis

10. Sequelae of the Menopause Heart disease Women relatively protected until menopause –Adverse lipid changes –Vascular effects

11. Menopause Symptoms can interfere with women functioning to their full physical and mental abilities Health risks –An important time of life for health interventions Can replacing estrogen address both of these issues?

13. The Women’s Health Initiative Randomized, double-blind, placebo- controlled study of Premarin and Provera (Prempro) Enrolled 16,600 postmenopausal women at 40 sites in the US Halted after 5.2 years because breast cancer risk reached a predetermined threshold

14. JAMA 2002;288:321 Results of WHI PremproPlacebo RR (95%CI)% Change CHD 37 30 1.29 (1.02-1.63)  29% Strokes 29 21 1.41 (1.07-1.85)  41% DVT/PE 34 16 2.11 (1.58-2.82) ↑ 111% Breast Ca 38 30 1.26 (1.00-1.59)  26% Colon Ca 10 16 0.63 (0.42-0.92)  37% Hip fracture 10 15 0.66 (0.45-0.98)  34% Incidents per 10,000 women/year

15. July 22, 2002

16. Annual Prescriptions:1995-2003 JAMA 2004; 291:47-53.

17. Questions Raised about WHI Average age 63 (only 3.4% were 50-55), asymptomatic patients – does this data apply to newly menopausal women? One-size-fits-all approach – does this data apply to all forms and doses of HT? Only E+P studied - does progestin play a role in risk?

18. JAMA 2004;291:1701 WHI Premarin-Only Arm (10,739 women post hysterectomy) Premarin PlaceboRR (95% CI)% Change CHD 49 54 0.91 (.75-1.12) ↓ 9% Stroke 44 32 1.39 (1.1-1.77) ↑ 39% DVT or PE 28 21 1.33 (.99-1.79) ↑ 33% Breast Ca 26 33 0.77 (.59-1.01) ↓ 23% Colon Ca 17 16 1.08 (.75-1.55) ↑ 8% Hip fracture 11 17 0.61 (.41-.91) ↓ 39% Incidents per 10,000 women/year

19. What do we think we learned? RISKS Venous thrombosis Stroke CHD (combined therapy) ↑ Breast cancer (combined therapy) BENEFITS Symptom relief Sexual function Osteoporosis and fracture prevention ↓ Colon cancer (combined therapy)

20. Newer Data Diabetes Heart Disease Stroke Breast Cancer

21. Reduced Onset Type 2 Diabetes RR95% CI% Change HERS 1 0.650.48-0.89- 35% WHI/HT 2 0.790.67-0.93- 21% WHI/ET 3 0.880.77-1.01- 12% 1. Ann Intern Med 2003;138:1-19. 2. Diabetalogia 2004;47:1175-87. 3. Diabetalogia 2006;49:459-68. Etiology uncertain May  insulin sensitivity May be secondary to  centripetal weight gain

22. Circulation 2002;106:913 Effects of Estrogen on Vasculature Direct –Binds to endothelial β 2 -adrenergic receptors → NO release → Vasodilation –  Platelet aggregation,  thromboxane Biochemical –↑ HDL-C, ↓ LDL, ↑ triglycerides (oral) –↑ C-reactive protein (oral only)

23. Thrombogenic Effects of Estrogen First-pass effects –↑ Factors VII and X, APC resistance –↓ Antithrombin, Proteins C and S Explains increased DVT/VTE Some oral estrogens may be more thrombogenic than others 1 No increase in DVT/VTE shown with transdermal preparations 2,3 1. JAMA 2004;292:1581 2. Lancet 2003;362:428 3. Circulation 2007;115:840

25. Potential Effects of Progestin Can reverse estrogen’s positive effect on lipid profile May block estrogen’s positive effect on vasculature

26. J Cinical Endocrin Metab;2001;86:5396 HT and Atherosclerosis in Monkeys

28. Further Analysis of WHI (Both arms combined) For women < 10 years since menopause,  CHD risk (RR.76, 95% CI 0.50-1.16) For women < age 60,  mortality risk (RR.70, 95% CI 0.51-0.96) JAMA 2007;297:1465-1477.

29. Evidence Suggests: Estrogen may have a negative effect on damaged endothelium A positive effect of estrogen, if it occurs, requires a healthy endothelium HT and risk of CHD –May ↑ risk when started postmenopausally –May ↓ risk when begun at menopause

30. New Data on Stroke Risk Population-based case control study from UK Database (15,710 cases of stroke matched to 59,958 controls) CasesControlsRR (95% CI) Transdermal1034410.95 (0.75-1.20) < 50 μg estradiol763840.81 (0.62-1.05) > 50 μg estradiol27571.89 (1.15-3.11) Oral61820251.28 (1.15-1.42) <.625mg CE, 2mg E 51517531.25 (1.12-1.40) >.625mg CE, 2mg E 1032721.48 (1.16-1.90) BMJ 2010;340:c2519.

31. Effects of E and P on the Breast Persistent high endogenous estrogen is known to be associated with breast cancer Mitotic activity in the breast peaks during the luteal phase (progesterone-dominant)

32. HT and Risk of Breast Cancer Observational studies –Average RR 1.35 –↑ Risk with ↑ duration of therapy –Little or no risk with estrogen alone WHI –RR 1.24 (CI 1.00 – 1.59) –No risk with estrogen alone

33. N Engl J Med 2007; 356:1670-1674. SEER Data

34. Newer Data from WHI New Engl J Med 2009;360:573-587.

35. Evidence Suggests: There is a small increased risk of breast cancer with combination HT, which likely increases with increased duration of use E alone may have less impact HT may potentiate tumors that are already present Withdrawal of HT may lead to regression of preclinical cancers

36. Relative Risk of Breast Cancer Relative risk of breast cancer Family history BRCA1-2 mutation Early menarche Late age at birth of 1st child Benign breast disease Hormone replacement therapy Alcohol use

37. Hormone Therapy and Mortality Meta-Analysis for Women < Age 60 Am J Med 2009;122:1016-22.

38. What do we think we know about HT? RISKS Venous thrombosis (oral) Stroke CAD (combined therapy, older women) Breast cancer (esp. combined therapy, prolonged use) BENEFITS Symptom relief Sexual function Osteoporosis prevention ↓ Diabetes May ↓ CAD (younger women) May  mortality (if begun before age 60)

39. Menopause 2010;17(2):242-255. 2010 NAMS Statement Treatment of moderate to severe vasomotor symptoms remains the primary indication for HT When vulvovaginal atrophy is the sole indication, first- line therapy should be topical Oral HT increases the risk of VTE, particularly in the first 1-2 years and in women over age 60 Data show a reduction in CHD with HT initiated within 10 years of menopause and an increase after 10 years ET/HT in early menopause for primary prevention of CHD needs further evaluation; HT should not be used for secondary prevention of CHD

40. 2010 NAMS Statement Initiating HT after age 65 for prevention of dementia is not recommended; data for early menopause insufficient Both ET and HT may increase risk of stroke Both ET and HT appear to reduce diabetes risk Breast cancer risk is slightly increased with HT use beyond 5 years (4-6/10,000 women) –There is no difference in mortality from breast cancer between HT users and nonusers –Estrogen alone may have less impact There is definitive evidence that HT and ET reduce osteoporosis risk, and both may still be considered for women at high fracture risk

41. 2010 NAMS Statement Use the lowest effective dose consistent with treatment goals, benefits, and risks Extended use is acceptable if informed patient believes benefits outweigh risks Specific regimens and forms of administration may have different outcomes, but evidence is insufficient There is inadequate evidence on endometrial safety to recommend alternatives to standard EPT regimens Compounded “bioidentical” hormones should be used with caution http://www.menopause.org

42. How well do women understand the research on HT? Women aged 45-65 - UF Women’s Clinics Dramatically overestimated the risks of HT –1/3 believed HT increases risk of CHD 10-30% –1/2 believed HT increases risk of breast cancer 10-30% Actual increases were.07% &.08%, respectively Am J Obstet Gynecol 2004;191:641-7.

43. What can we tell our patients? Clarify misconceptions resulting from media coverage Help each woman understand the risks and benefits for her individual situation

45. NAMS