1. Hormone Replacement Therapy and Alternatives after WHI Dawn E. DeWitt MD, MSc University of Washington MEDEX GRAND ROUNDS 2003

2. “This fundamentally changes everything we know about elephants!”

3. Overview n Breast cancer n Vasomotor symptoms n Alternative therapies n Genitourinary symptoms n Osteoporosis n CAD n Recommendations

4. A 54 y.o. postmenopausal woman asks you about a recent article in the paper on hormones and cancer. She has been taking HRT for two years because her mother has osteoporosis. Her bone density is normal. She does not smoke and takes 1000 mg of calcium daily. She has no family history of breast cancer. Regarding her risk of breast cancer A. The risk is only increased for estrogen-only use B. The risk clearly applies to combined HRT C. HRT only increases the risk in patients with a family history of breast cancer D. If she stops in 5 years her risk will not be increased. E. The risk in only increased in obese women.

5. A. The risk is only increased for estrogen-only use B. The risk clearly applies to combined HRT C. HRT only increases the risk in patients with a family history of breast cancer D. If she stops in 5 years her risk will not be increased. E. The risk in only increased in obese women.

6. Myth and Reality

7. 1997: Association of HRT with Lower All Cause Mortality n < 5 years of use does not increase cancer risk n Risk returns to never used after 5 years n Protective effect detectable at 10 years Nurses Health Study 121,000 x 18 yrs Grodstein, NEJM. 1997;336:1769.

8. 1997: HRT Decision Analysis n Greatest gain in life = 41 mos for high CAD risk and low breast cancer risk n HRT did not improve life expectancy for low CAD risk and high breast cancer risk Col et al. JAMA. 1997;277:1140.

9. HRT and Breast Cancer Risk Impact n Largest increase risk in USC study n RR 1.38 with 5 years of cyclic therapy n 50 y.o. woman has a 2.4% risk by age 60 n Increase risk by 38% = 3.3% total risk n NNH = 100 –Treat 100 women between 50 and 55 for > 5 years and possibly expect <1 additional case »Feuer et al. J Natl Cancer Inst, 1993.

10. Breast Cancer Demonstration Project 2000 –Cohort of 46,355 women n NNH Estrogen + Progesterone = 862 n NNH Estrogen only = 2624 n Caveats –Still no increased risk early –Heavier women less affected –Data are suggestive but confidence intervals overlap »Schairer et al, JAMA, 2000—283:485.

11. HRT Breast Cancer Risk 2002-WHI n Excess breast cancers detected at 3 years with safety threshold exceeded at 5 years n Experts suspect a cumulative duration effect n Absolute risk of invasive cancer: –8/10,000 person-years –NNH=1250

12. A 50 y.o. woman requests HRT advice because of hot flushes that are keeping her awake and embarrass her in her job as an ad executive. Her mother died of hip fracture complications, her father had an MI at age 45, and she has no family history of breast cancer. Her cholesterol is 210, HDL 45. The best therapy is A. daily calcium 1500 mg, vitamin D 400IU B. soy milk 1 glass a day C. alendronate 10 mg and simvastatin 10 mg, PO QD D. estrogen 1 mg and progesterone 2.5 mg, PO QD E. raloxifene 60 mg PO QD

13. A. daily calcium 1500 mg, vitamin D 400IU B. soy milk 1 glass a day C. alendronate 10 mg and simvastatin 10 mg, PO QD D. estrogen 1 mg and progesterone 2.5 mg, PO QD E. raloxifene 60 mg PO QD

14. Vasomotor symptoms are the only clear indication for HRT n Hot flushes affect 75% of perimenopausal women n Oral estrogen is still the most effective treatment of hot flushes and associated sleep disturbances n Combined HRT recommended with uterus –65-78% of women have spotting in the first year –75% amenorrheic at one year –Withdrawal bleeds q 3 mo result in hyperplasia and are not recommended n SERMS result in increased hot flushes in a substantial number of women and do not treat hot flushes

15. Estrogen versus Raloxifene

16. A 52 year old school teacher with hot flashes who had her last period 3 months ago seeks your opinion about “natural” therapy for menopause. You tell her that the best remedy is A. Evening primrose oil 3-4 gm/day (9% GLA) B. Don Quai (Angelica sinensis) C. Chaste Tree berry 0.5% agnuside 200 mg/day D. Phytoestrogens (soy 60 gm/day) E. Black Cohosh 2 tabs BID

17. A. Evening primrose oil 3-4 gm/day (9% GLA) B. Don Quai (Angelica sinensis) C. Chaste Tree berry 0.5% agnuside 200 mg/day D. Phytoestrogens (soy 60 gm/day) E. Black Cohosh 2 tabs BID

19. Complementary/Alternative Therapy Show me the data… n Evening Primrose oil-breast tenderness, PMS— meta-analysis no effect, probably safe n Don Quai-PMS—no good data probably not effective in one trial for menopausal sx, interferes with warfarin n Chaste Tree berry-PMS—unclear, caution with ocp’s or dopaminergic medications n Black Cohosh-menopause sx—well-tolerated, possibly effective, more data needed n Recommended: Kronenberg, Annals Intern Med, 2002.

20. Does soy really work? n Conflicting data on soy estrogen- advise trial of 25 gm of soy per day (8 oz = 5 gm soy protein) –66% had a reduction > 50% vs. 34% in placebo using 70 mg genistin/daidzin per day »Faure et al, Menopause, 2002. n Red clover isoflavones (Promensil®) –16% reduction with placebo; double-blind had further decrease of 44% hot flushes per day with no further decrease in placebo group »Van de Weijer, Maturitas, 2002.

21. Phytoestrogens n Americans eat < 5 gm/day n 25-60 gm/day to see effect—8 weeks significant decrease in hot flushes –4 glasses soy milk, 1/3 brick of tofu,1 half cup edamame, 1 serving soy protein powder in a shake, soy convenience foods »Victoria Rand, UCSF/ACP 2001. Albertazzi OB Gyn 1998. n Breast cancer risk –OR 0.85 in high soy— WU. Cancer Epidem Biom. 1996. –RR 0.27-0.36 in high phytoestrogen— Ingram. Lancet. 1997.

22. Other alternatives to HRT/ERT n Progestational agents (SE bleeding, wt gain, CTS) –Medroxyprogesterone acetate (20 mg/day) –tibolone (2.5 mg/d)-partial estrogen agonist –megestrol acetate 20 mg/day (74% vs 27%) –Topical progesterone is not absorbed; not effective n Venlafaxine: 61% reduction in 75 or 150 mg/day (27% placebo); 37% in 37.5 mg-start at 37.5 mg/d n  -agonists: modest effect, clonidine 0.1 mg/d n SSRIs-pilot data only, limited effect?

23. A 58 y.o. woman on HRT developed breast cancer and. her HRT was stopped. She returns 6 months later with severe vaginal dryness and dyspareunia. She is having decreasing hot flushes, but increasing dysuria, urinary frequency, and stress incontinence. UA is normal. You recommend A. Vaginal estrogen cream, 1 gm prn B. Vaginal estrogen cream, 1 gm qhs C. Lubricant and Kegel exercises D. Raloxifene 60 mg po qd E. Vaginal Estring, 1 q3 months

24. A. Vaginal estrogen cream, 1 gm prn B. Vaginal estrogen cream, 1 gm qhs C. Lubricant and Kegel exercises D. Raloxifene 60 mg po qd E. Vaginal Estring, 1 q3 months

25. Topical Estrogen n Topical estrogen is usually effective for vaginal and urinary symptoms n Vaginal estrogen cream is absorbed and serum levels are detectable –undesirable in breast cancer patients n Estring does not generate detectable serum estrogen levels –probably safe for breast cancer patients

26. Vaginal and Urinary Symptoms n Pelvic exam for tissue status, urethral caruncle, and bladder prolapse –Pearl: use lower half of speculum alone n Check a UA and cultures as appropriate n Remember latex allergy n Water-based lubricants (e.g. Astroglide) n Kegel exercises n Low dose imipramine

27. A 59 y.o. woman presents after a fall that resulted in ankle and Colles’ fractures, DEXA T score is –1.9. She is s/p hysterectomy (fibroids), and had a breast biopsy showing fibroadenoma. Her LDL is 202, HDL 45 and FH is positive for premature CAD. The best treatment at this time is A. Estrogen 0.3 mg po qd and a statin B. Raloxifene 60 mg po qd C. Calcitonin 200IU spray qd and niacin D. Estrogen 0.625 mg po qd and diet E. Alendronate 70 mg q week and a statin

28. A. Estrogen 0.3 mg po qd and a statin B. Raloxifene 60 mg po qd C. Calcitonin 200IU spray qd and niacin D. Estrogen 0.625 mg po qd and diet E. Alendronate 70 mg q week and a statin

29. Osteoporosis: bare bones n 6-9 million women in the U.S.; 1.3 million fx/yr n 16% are hip fractures –12-40% die of related conditions within 6 mo. –50% are institutionalized n Risk: sedentary, family history, low estrogen, low calcium intake n DEXA at spine and hip n T score < -2.5 or < 1.0 with fx over age 40

30. Osteoporosis: Pills, Pills, Pills

31. Low Dose Estrogen: Good Enough? n 406 postmenopausal women: 54% completed n 0.3, 0.625, or 1.25 mg (unopposed) n Endometrium: 1.25 mg  hyperplasia; 0.3 stable n Lipids: Dose-related  LDL(6-9),  HDL (5) n Symptoms: placebo and 0.3 mg ineffective n Osteoporosis: Dose-related  spine BMD -2.52 1.762.815.10 Genant. Arch Intern Med. 1997;157:2609.

32. Everybody do it! n Physical activity – very active women over 65 (top 40%): hip fracture RRR 0.36 –moderate activity reduced hip (42%) and vertebral (33%) fractures n Calcium and Vitamin D –NNT = 14 x 1 year –500 mg Ca 2+ and 700 IU vit D Gregg. Ann Intern Med. 1998;129. Dawson-Hughes. NEJM. 1997;337.

33. Calcium: Of cows and others n 1200 mg/day for adults –Milk = 300 mg/8 oz glass –Supplemented OJ (Minute Maid) = 300 mg/8 oz –Chewable supplements Tums EX = 300 mg Ca/tablet (get sugarfree) –cheap, low lead Viactiv = 500 mg/chew (chocolate, caramel) –$8/month Yes, CaGluconate > absorption than CaCarbonate Avoid oystershell, dolomite (high lead)

34. Postmenopausal Lipid Therapy *estrogen patch does not increase TG, but less beneficial

35. What to put in the water—Statins? n CC of US women > 60 –OR 0.48 for all fractures if >13 months prescriptions n NCC of UK women > 50 –OR 0.55 for fractures in women taking statins but not other cholesterol-lowering agents n NJ Medicare/Medicaid pts > 65 –OR hip fx 0.50-0.57 (180 days to 3 years) –Current use OR 0.29 (statins not other agents) Chan, Lancet;355:2185. Meier, JAMA, 283:3205. Wang, JAMA, 283:3211.

36. A 62 year-old woman comes in to your office having been on ERT for several years for hot flashes and prevention of heart disease. She is concerned about the data from the WHI. As you are discussing the risks and benefits, you tell her that her risk of heart disease on ERT is A. Increased in a dose-effect manner B. Decreased since ERT increases HDL C. Increased only for the first 6 months of use D. Unclear at present E. Is not increased since she doesn’t have known CAD

37. A. Increased in a dose-effect manner B. Decreased since ERT increases HDL C. Increased only for the first 6 months of use D. Unclear at present E. Is not increased since she doesn’t have known CAD

38. The HERS Study: HRT & Secondary CAD Prevention n RPCT of 2763 women with CAD (66.7 y.o.) n 4.1 years, 75% compliance n 11% lower LDL, 10% higher HDL n No difference in MI or CHD death n Trend to early increase in thrombotic events (2.5% vs 0.9%) Hulley. JAMA. 1998;280:605.

39. ERT and atherosclerosis: “EPAT” n Over 40 observational studies: HRT decreases M&M; most in healthy pm women on ERT n DBRPCT, 222 women > 45 without CAD; LDL > 130 n Unopposed 17ß-estradiol 1 mg/day; lipid tx if LDL > 160 n Intima-media US thickness progression slower in HRT –same as lipid rx patients n ERA study of CAD using angio showed no diff, but results consistent with HERS data and observational data n Conclusion-ERT may slow CAD progression in healthy women without CAD. Form of estrogen and ERT vs HRT yet to be defined. »Hodis, Ann Intern Med, 2001. Herrington, NEJM, 2000.

40. Heart disease and WHI n WHI was stopped due to Breast Cancer risk not CAD n Combined HRT: cee + medroxyprogesterone n H.R. for CV mortality is 1.03 with confidence intervals crossing 1 n Increases CHD risk (H.R. 1.29) n Absolute risk 7/10,000NNH 1429 n Stroke A. R. 8/10,000NNH1250 n HRT is clearly not indicated for primary or secondary CHD prevention n ERT-it remains to be seen

41. Alzeimer Disease n Controversial n May be effective for prevention with long term use –Cache county study H.R. 0.41 n Overall ~30% risk reduction in major studies

42. The Bottom Line n Symptoms –Hot flushes- estrogen (1-2 years) –Vaginal or urinary symptoms-local estrogen n Breast Cancer risk –Combined HRT= NNH 1250 –Raloxifene probably decreases risk ~75% n CAD risk –Combined HRT increases risk; NNH 1100 –Do not start HRT in women with known CAD n Osteoporosis risk-Calcium and Vit D-NNT = 14 –Hip fx decrease with RR 0.66 from WHI n Dementia-data are inconclusive –Estrogen?, statins?

43. Risks and Benefits* USPSTF (WHI) USPSTF, Annals, 2002;137:834 Benefits n Vertebral fracture 0.60 n Hip fracture 0.76 n Colorectal cancer 0.80 n ?Dementia 0.66 n Diabetes 0.65 NNT 30 Risks n CAD 0.91 (1.29) n CVA 1.12 (1.41 NS) n DVT/TE 2.14 1 st yr 3.49 n Breast ca > 5 yrs 1.23 (1.26) < 5 yrs 1.0-1.14 n Cholecystitis 1.8-2.5 n Asthma *R.R. or O.R.

44. “Since the food you serve is not organically grown, is it safe to assume that the meat is laced with antibiotics and the salad is chockful of pesticides!” You know, there are times in life when prescription drugs are entirely appropriate.