Menopause & Hormone Therapy Decisions

1. Menopause & Hormone Therapy Decisions Lisa Keller, M.D.

2. Limited goals for the next 45 minutes: • Define the syndrome, physiology, epidemiology. • Symptoms, potential pathophysiology. At-risk groups by age, time from menopause, as well as known risk profiles. • What we know about hormone therapy, what has shifted over the past decade, and where there is consensus. • What we don’t know, what appears likely, and how to synthesize all the above into therapeutic recommendations.

3. Why menopause? • So there can be grandmothers. Childbearing is a huge physiological burden. • Ovarian follicles: millions as fetus, thousands in youth, none by menopause. • Also CNS aging within the hypothalamic-pituitary axis, still being defined.

4. 100,000 90,000 80,000 70,000 60,000 50,000 40,000 30,000 20,000 10,000 0 Postmenopausal Women in US Age 65 years 60-64 years 55-59 years 50-54 years 45-49 years Population 2000 2010* 2020* 2030* 2040* 2050* Years *Projected estimate. US Census Bureau. Statistical Abstract of the United States. 2000:15.US Census Bureau. National population projections. Available at: http://www.census.gov/population/www/projections/natsum-T3.html. Accessed January 3, 2002.

5. Perimenopausal Transition Years 100 75 50 25 0 Reproductive Years Women (%) Postmenopause 60 50 55 35 40 45 30 Age (years)

6. Perimenopause • Reduction in viable ovarian follicles and follicular resistance to gonadotropins • Erratic hormonal milieu, erratic symptomatology • Although cycle length begins to shorten, potential for ovulation and pregnancy is preserved for a number of years

7. Menstrual Cycle Changes • Usually shorter cycle length (eg, by 2 to 7 days) • Longer or irregular later in transition • Changes in quality • Lighter volume. If heavier, more likely due to myomata or hyperplasia • Spotting prior to menses is common

8. Menopause-Related Changes • Vasomotor symptoms • Sleep quality • Mood changes • Urogenital symptoms • Sexual well-being • Skin changes • Bone loss • Coronary heart disease (CHD) risk increases • Eye dryness • Joint inflammation

9. Hormone Deficiency Effects Last period Vasomotor symptoms Sexual complaints Urogenital atrophy and symptoms Vascular and heart disease Bone loss/osteopenia Osteoporosis 40 45 90+ 50 55 60 65 70 75 80 85 Age (year)

10. Number of years women report having hot flushes as estimated by a survey of 501 untreated women who experienced hot flushes 0 2 4 6 8 10 12 14 16 18 20 22 24 28 30 36 41 Hot Flushes May Continue Years After Menopause Ages 29 to 82 Years Mean age of natural menopause was 49.5 years; mean age of surgical menopause was 43.7 years. Kronenberg F. Ann N Y Acad Sci. 1990;592:52-86. Used with permission.

11. Non-hormonal Therapies • Herbal therapy — black cohosh, St. John’s wort • Biologically based substances — phytoestrogens: isoflavones from soy protein or red clover (unknown breast effects) • Lifestyle modifications — relaxation, paced respiration, moderate physical activity, modulation of responsibilities, sleep time

12. Treatment of moderate to severe vasomotor symptoms • Prescription systemic hormone therapy, either as combined estrogen-progestogen therapy (EPT) or estrogen (ET), remains the gold standard for treatment in women without contraindications • Oral contraceptives are an option for perimenopausal women, especially those needing contraception

13. Genital Irritation, burning, pruritus Leukorrhea Dyspareunia Decreased vaginal secretions Shortening/lessening of vaginal distensibility Urinary Frequency, urgency Dysuria Nocturia Incontinence* Genitourinary Symptoms Associated With Menopause *Controversial.

14. Vaginal Cytology Premenopause Postmenopause

15. Risks and Benefits of HT It is known with good certainty that • Changes in the urogenital tract are among the most consistent hypoestrogenic features of the climacteric • HT administered vaginally or systemically provides effective relief from atrophic vaginitis, including reduction in vaginal dryness, irritation, pruritus, and dyspareunia ACOG Task Force on HT. Obstet Gynecol. 2004;104 (suppl 4):56s-61s.

16. 44 42 40 38 36 34 At Oophorectomy 3 Years After Oophorectomy 6 Years After Oophorectomy 0 2 4 6 8 10 12 14 16 Effect of Delayed Initiation of HT on Bone Loss Metacarpal Bone Mineral Content (mg/mm) Years Blue area represents placebo-treated population of oophorectomized women. Lindsay R, et al. Lancet. 1976;1:1038-41.

17. 0.5 1.0 2.0 WHI: Reduction in Fracture Risk With E+P and E Alone Hip Vertebral Lower Arm/Wrist All Fractures CEE/MPA (95% nCI) CEE alone (95% nCI) Hazard Ratio

18. WHI Fracture Results:Clinical Implications • Women treated with E alone or E+P for menopausal symptoms do not need another antiresorptive agent • HT is the only therapy that has been demonstrated to prevent fractures in a population of postmenopausal women at relatively low risk of fracture ACOG Task Force on HT. Obstet Gynecol. 2004;104(suppl 4):66s-76s. AACE Osteoporosis Task Force. Endocrine Pract. 2003;9:544-64.

19. Menopause, HT, & Depression • Several observational studies report increased risk for onset of major depression during perimenopause • Perimenopause seems associated with increased risk of clinically significant depressive illness for subgroup of women • Some prospective studies, although not all, have demonstrated improvements of ~ 80% in newly depressed perimenopausal women started on HT (placebo 20%) • Insufficient evidence to support HT use for depression treatment , but consider in new onset

20. Contraindications To HT • Estrogen-dependent neoplasms (endometrial carcinoma, hyperplasia, breast cancer), venous or arterial thrombosis, high risk of cardiovascular disease, and/or liver disorders. • Oral conjugated equine estrogen (CEE) significantly increases triglyceride levels. So, oral estrogen therapy is not optimal for women with elevated triglycerides. But these patients may benefit from transdermal estriadol therapy. • Oral estrogen is not recommended for heavy smokers.

21. Consistent Terminology Urged • ET — Estrogen therapy • EPT — Combined estrogen-progestogen therapy • HT — Hormone therapy (encompassing both ET and EPT) • CC-EPT — Continuous-combined estrogen-progestogen therapy (daily administration of both estrogen and progestogen) • CS-EPT — Continuous-sequential estrogen-progestogen therapy (estrogen daily, with progestogen added on set sequence) • Progestogen — Both progesterone and progestin

22. Observational Trial Results • 1976: Lowers risk of osteoporosis • 1981: CHD benefit, inconclusive for stroke • 1988: Reduction in mortality • 1994: Reduction in Alzheimer’s risk • Accelerated use of hormone therapy

23. Women’s Health Initiative (WHI) Clinical Trials of HT • >27,000 postmenopausal women randomized and enrolled from 1993 to 1998 • Mean age at baseline, ~63 years • Women with vasomotor symptoms discouraged from participating • Primary outcomes: CHD, breast cancer • E+P trial stopped in July 2002 • Breast cancer crossed monitoring boundary • E alone trial stopped February 2004 • Trend toward increased stroke

24. WHI Limitations • Only one estrogen was used (CEE, alone and with MPA) and only one progestogen (MPA) • Only one route of administration was used (oral) and only one dosage (0.625 mg/2.5 mg) • Subjects were: • Older (mean age, 63 years) • Most more than 10 years beyond menopause • Had more risk factors than younger women who typically use HT for menopausal symptoms • Largely asymptomatic

25. WHI E+P: Absolute Risks & Benefits No Significant Difference in # of Cases CEE/MPA Placebo More Cases in E+P Group Fewer Cases in E+P Group Number per Year per 10,000 Women CHD* Stroke Breast Cancer VTE PE Endometrial Cancer Total Deaths Colorectal Cancer Hip Fractures

26. CEE Placebo Strokes VTE CHD Breast Cancer PE Colorectal Cancer Total Deaths Hip Fractures WHI E Alone: Absolute Risks & Benefits Fewer Cases in EGroup More Cases in EGroup No Significant Difference in # of Cases Number per Year per 10,000 Women

27. More Recent WHI Analyses of Younger Women (50-59 years) • 7% decrease in CHD with ET or EPT (2 fewer cases per 10,000 per year of use) • 24% increase in breast cancer with EPT (9 more cases per 10,000 per year of use) • 20% decrease in breast cancer with ET (7 fewer cases per 10,000 per year of use) • 30% decrease in total mortality with ET or EPT (10 fewer deaths per 10,000 per year of use) ET = CE; EPT = CE + MPA

28. WHI: Effect of CEE Alone on Risk of CHD by Age Group Age 0.63 50–59 y 0.94 60–69 y 1.11 70–79 y 0.0 0.5 1.0 1.5 2.0 Dotted vertical line represents the HR for CHD in the overall cohort (0.95; 95% CI = 0.79-1.16) P = .07 for interaction with age Hsia J, et al. Arch Intern Med. 2006;166:357-65.

29. Effect of E+P on CHD in Postmenopausal Women Hazard Ratio for CHD 0.0 0.5 1.0 1.5 2.0 2.5 3.0 Age (years) 1.27 50–59 1.05 60–69 1.44 70–79 Years Since Menopause Hazard Ratio for CHD 0.0 0.5 1.0 1.5 2.0 2.5 3.0 0.89 <10 1.22 10–19 1.71 >20 Manson JE, et al. N Engl J Med. 2003;349:523-34.

30. WHI Cardiovascular Summary Effects per 10,000 women/year of ET use (50-59 yrs) • 10 fewer deaths • 10 fewer CHD events • 2 fewer strokes • 4 additional VTE Effects per 10,000 women/year of EPT use (<10 years postmenopause) • 6 fewer deaths • 4 fewer CHD events • 5 more strokes • 11 additional VTE

31. Risks and Benefits of HT It is known with good certainty that • HT does not increase CHD risk in women who initiate therapy close to the onset of menopause (within ~ 9 years of last menses) • HT does not prevent and may increase the risk of CHD in women who initiate therapy years after menopause

32. 0.5 1.0 2.0 5.0 WHI HT Trials: Increased Risk of Venous Thromboembolism HR (95% CI) E+P1 2.06 (1.57, 2.70) E alone2 1.33 (0.99, 1.79) Hazard Ratio 1Cushman M, et al. JAMA. 2004;292:1573-80. 2Women's Health Initiative Steering Committee. JAMA. 2004;291:1701-12.

33. Risks and Benefits of HT Additional research of HT on risk of stroke is needed to clarify the effect • Meta-analyses find a small increased risk of stroke in postmenopausal women taking HT • Whether this increased risk is modified by hormone preparation, dose, or route of administration has not been established by randomized controlled trials • The risk of stroke for women taking HT increases with age, but the risk for younger women does not appear to be insignificant (still “rare” by WHO criterion) ACOG Task Force on HT. Obstet Gynecol. 2004;104(suppl 4): 97s-105s.

34. HT and Venous Thromboembolism • Significant increase in VTE risk in postmenopausal women using systemic HT • Risk increased with both EPT and ET • VTE risk appears during first 1-2 years after therapy initiation and decreases over time • Transdermal 17ß-estradiol and oral therapies may have different risk • Lower doses of oral estrogens may be safer than higher doses

35. WHI and Breast Cancer Risk With EPT use • Relative risk = 1.24 (24% increased risk) • Absolute risk = 9 more cancers per 10,000 women per year of EPT use With ET use • Relative risk = 0.80 (20% decreased risk) • Absolute risk = 7 fewer cancers per 10,000 women per year of ET use • 33% statistically significant decreased risk when adherent to treatment (i.e., used ET 80% of the time)

36. Million Women Study: Breast Cancer Relative Risks Mortality 1.22 Current use 1.66 Implanted estrogen 1.65 Transdermal estrogen 1.24 Oral estrogen 1.32 Tibolone 1.45 2 E + P 1.3 Estrogen only 1 1.5 2 Lancet. 2003;362:419-427.

37. European Trials — HT after BCA • One (HABITS) with continuous E+P showed ^ BCA recurrence risk • Other (Scandinavian trial) with ET and only intermittent P, showed 18% < BCA recurrence risk

38. Risks and Benefits of HT It is known with good certainty that • E+P use >5 years is associated with an increased risk of breast cancer1,2 • Absolute risk is small; about 2 additional cases per 1000 women using E+P for 5 years1 • Use of unopposed E does not increase breast cancer risk in women with previous hysterectomy3 1ACOG Task Force on HT. Obstet Gynecol. 2004;104(suppl 4):11s-6s.

39. Risks and Benefits of HT Research is ongoing to determine the effects of HT on cognitive function and dementia • Like CHD, findings from observational studies and the WHI do not agree. Stratification by age and the “healthy cell bias” may explain discrepancy • HT initiation in older postmenopausal women appears to increase risk of dementia

40. HT in the Woman With Premature Ovarian Failure (POF) • POF is associated with premature osteoporosis and increased CV morbidity and mortality • Effective management involves early identification of POF, use of HT to relieve symptoms and prevent osteoporosis, and regular monitoring for associated conditions Nelson LM, et al. Fertil Steril. 2005;83:1327-32.

41. Conclusions • Extrapolate with caution WHI date when considering risks of HT during or soon after the menopausal transition • Future research is critical to clarify optimal timing and duration of HT • WHI data do not address benefits and risks in women with premature menopause ACOG Task Force on HT. Obstet Gynecol. 2004;104(suppl 4):1s-4s. North American Menopause Society (NAMS). Menopause. 2003;10:497-506.

42. Progestins Steroids Natural Found in Nature Synthetic Laboratory Synthesized Structurally Related to Progesterone Structurally Related to Testosterone • Native  Synthetic • Progesterone • Ethinylated • Norethindrone • Norethynodrel • Lynestrenol • Norethindrone acetate (NETA) • Tibolone • Ethynodiol acetate • Levonorgestrel • Desogestrel • Norgestimate • Gestodene • Pregnane Derivatives • MPA • Megestrol acetate • Cyproterone acetate • Chlormadinone acetate • Medrogestone • Dydrogesterone • 19-Norpregnane Derivatives • Nomegestrol acetate • Demegestone • Trimegestone • Promegestone • Nesterone • Non-ethinylated • Dienogest • Drospirenone Stanczyk FZ. Rev Endocr Metab Disord. 2002;3:211-24.

43. EPIC Fournier et al, Int J Cancer, 2004.

44. Medroxyprogesterone Acetate • Most common progestin used in USA • Most intensely studied progestin • Only progestin with substantial data proving ability to prevent endometrial cancer long term • Challenges regarding cardiac, thrombotic and breast effects Gradyan D, Obstet Gynecol. 1995 Feb;85(2):304-13.

45. O OCCH2 C CH O Norethindrone Acetate • Synthetic, patented in 1950 • Pro-drug, rapidly converted to norethindrone • NETA long half life • Most common progestin in EU • NETA converts to ethinyl estradiol • In high dose, 0.7 - 1% • 6 micrograms EE/1 milligram NETA

46. CH3 O C O Natural Progesterone • Bioidentical • Several formulations • Short half life • No long term safety outcomes

47. 0.3 0.3 0.2 0.2 Coronary Plaque Size (mm2) 0.1 0.1 0 0 No TX E2 E2 + P No TX CEE CEE + MPA MPA Primary Prevention of Coronary Atherosclerosis with CEE and MPA vs Estradiol and Progesterone Adams et al. Arterioscler Thromb Vasc Biol. 1997;17:217 Adams et al. Arteriosclerosis. 1990;10:1051.

48. Coronary Artery Vasospasm in Monkeys Treated With E2 and Progesterone or MPA Parameter E2 + Progesterone E2 + MPA Number of vasospasms 6/6 0/6 Minimum coronary artery diameter .37 ± .02 .15 ± .04 Miyagawa et al. Nature Med. 1997;3:324.

49. Alternative Progestins

50. Breast vs Endometrial Risk Million Women, Lancet 2005; 365: 1543–51