Problems in Postmenopausal Women

Menopausal Management: Where are we in 27? Marcelle I. Cedars, M.D. Professor and Director Division of Reproductive Endocrinology and Infertility UCSF Problems in Postmenopausal Women Vasomotor symptoms Genital atrophy Decrease in skin collagen Rapid bone loss Increase in coronary heart disease Increase in Alzheimer s disease Benefits of Menopausal HT: What We Thought We Knew before WHI Prevents or abolishes hot flashes Prevents or improves genital atrophy Prevents or slows bone loss Reduces risk of cardiovascular disease Improves cerebral blood flow May reduce risk of Alzheimer s disease May reduce risk of colon cancer Improves overall quality of life 1

Risks of Menopausal HT: What We Thought We Knew before WHI Breast cancer,?rr 1.1-1.5 Endometrial cancer, RR 4.-11. (unopposed estrogen) Venous thromboembolism 2 additional cases per 1, women Low mortality rate of 1% Gall bladder disease Menopausal HT/CVD Why we thought we knew it Observational studies (e.g. Nurse s Health Study) suggested ET/HT use associated with 5% reduction in CHD (Mikkola et al., Ann Med, 24) The NIH Lipid Research Clinics Trial Reported that ET normalized CHD risk for women with a CHD history (Bush et al., Circulation, 1987) Angiographic studies suggested that women with the Most Severe CHD derived the Most Benefit from ET/HT (Sullivan et al, Arch Int Med, 199) Clinical Studies Observational studies Retrospective Cohort (Prospective) Double-blind, randomized, placebocontrolled trials Publication of Clinical Trials in July, 22 Heart & Estrogen/Progestin Replacement Study (HERS) II JAMA 22;288:49-66 (July 3) Women s Health Initiative (WHI) JAMA 22;288:321-33 (July 17) 2

HERS Trial: Clinical Outcomes Outcome Total mortality Nonfatal and fatal MI CABG Percutaneous revascularization Stroke / TIA Venous thromboembolism Gallbladder disease All cancers Breast cancer RR (95% CI) 1.8 (.84-1.38).99 (.8-1.22).87 (.66-1.16).95 (.77-1.17) 1.13 (.85-1.48) 2.89 (1.5-5.58) 1.38 (1.-1.92) 1.12 (.84-1.5) 1.3 (.77-2.19) HERS: Conclusion HRT should not be used to reduce the risk of further CHD events in postmenopausal women with already established CHD Hulley S, et al. JAMA. 1998;28(7):65-613. Additional Supporting Cardiovascular Studies In the Women s Angiographic Vitamin and Estrogen (WAVE) trial, neither hormone therapy nor antioxidant vitamins provided any CV benefit to menopausal women with angiographic evidence of CHD, and potential for harm was suggested (Waters et al., JAMA 22;288:2432). The British ESPRIT (EStrogen in the Prevention of ReInfarction Trial), which randomly assigned menopausal women 5 to 69 who were heart attack survivors to estradiol vs. placebo, found no reduction in the overall risk of further cardiac events, reinfarction or cardiac death at 24 mos with hormone therapy (Lancet 22;36:21). Estrogen Replacement and Atherosclerosis (ERA) Study 39 women with documented coronary artery stenosis (mean age, 65 years) randomization Herrington et al, N Engl J Med, 2 Placebo n = 15 CEE only (.625 mg) n = 1 CEE (.625 mg) + MPA (2.5 mg) n = 14 Postmenopausal women with >3% coronary artery stenosis Mean follow-up 3.2 years Angiographic follow-up in 248 patients Mean cholesterol 216 mg/dl Compliance: 86% placebo, 84% HT, 74% ET 3

Change in diameter (mm) -.2 -.4 -.6 -.8 -.1 -.12 ERA Study Change in Minimal Lumen Diameter Placebo CEE CEE+MPA Modified from Herrington et al, N Engl J Med, 2 Progression of atherosclerosis Women s Health Initiative (WHI) Study design: Subjects: Interventions: Randomized, double-blind, placebocontrolled, primary prevention trial ET 1,739 surgically menopausal women HT 16,68 naturally postmenopausal women Both were 5 to 79 years old (mean age, 63.3 years) ET CEE.625 mg HT CEE.625 mg + MPA 2.5 mg daily or placebo 1 end point: Nonfatal MI or CHD death Time frame: Planned 8.5 years; terminated at 5.2 years Writing Group for the Women's Health Initiative Investigators, JAMA, 22 WHI HRT Study Cardiovascular Events (Cumulative) WHI HRT Study Disease Rates for Women on Estrogen + Progestin vs Placebo Cumulative Hazard Coronary Heart Disease Stroke Pulmonary Embolism 3% HR, 1.29 95% Cl, 1.2-1.63 2% 1% 1 2 3 4 5 6 7 3% HR, 1.41 95% Cl, 1.7-2% 1.85 1% 1 2 3 4 5 6 7 3% HR, 2.13 95% Cl, 1. 39-3.25 2% 1% 1 2 3 4 5 6 7 Number of Cases/year in 1, Women 6 5 4 3 2 1 + 7 + 8 Risks +31 + 8 Benefits - 11 + 8-6 - 5 Neutral Estrogen +Progestin Placebo Placebo Estrogen + Progestin CHD Stroke Breast Cancer PE Colorectal Cancer Hip Fracture Endometril Deaths Cancer HR: hazard ratio; Cl, confidence interval Writing Group for the Women s Health Initiative. JAMA. 22;288:321-333. Writing Group for the Women s Health Initiative. JAMA. 22;288:321-333. 4

Number of women needing to take HT for one extra adverse or protective event per year: 11 for myocardial infarction 12 for stroke 6 for serious thromboembolism 13 for invasive breast cancer 2 to prevent a hip fracture 17 to prevent a colon cancer Observations about the WHI Study 97.5% of subjects had no adverse events Subjects not as healthy as thought at entry, i.e., not well designed as a primary prevention trial The WHI Estrogen-Alone Trial (JAMA 24:291:171-1712) Only strokes and hip fractures were significantly impacted in 1,739 postmenopausal women aged 5-79 over 6.8 years: There was an absolute excess risk of 12 additional strokes and 6 fewer hip fractures per 1, person-years. A possible reduction in breast cancer risk, inconsistent with other studies, requires further investigation. Reconciling observational studies and clinical trials Preliminary analyses suggest lower hazard ratios (for CVD) in women aged 5 to 59 years. Menopausal women should be reassured that estrogen remains a viable treatment option for the treatment of symptoms of estrogen deficiency. 5

What s different? WHI vs. Observational studies Methodological explanations: Confounding intrinsic biases of observational studies Incomplete capture of early clinical events attenuation of risk Biological explanations Clinical characteristics of the populations timing of initiation of treatment Characteristics of hormone therapy type and dosage Manson JE, et al. 26; 13:139 WHI vs. Observational studies Biological explanations Clinical characteristics of the populations timing of initiation of treatment Characteristics of hormone therapy type and dosage Mean age 63 BMI 28.5 kg/m 2 Past User 2% Current User 6% WHI HRT Study: Patient Characteristics Never User 74% % of Enrolled Population 5 4 3 2 1 N=5522 N=751 5-59 6-69 7-79 Age N=3576 Hormone Use Prior to Study Entry 6

The Effect of Body Mass on the Risk of CHD: Putting the WHI Results in Perspective RH for CVD 4. 3.5 3. 2.5 2. 1.5 1..5. 22 24 27 >29 BMI (kg/m 2 ) WHI* *Mean BMI 28.5 kg/m 2. BMI data from Willett et al, JAMA, 1995 WHI data from Writing Group for the Women s Health Initiative Investigators, JAMA, 22 4. 3.5 3. 2.5 2. 1.5 1..5. RH for CVD Inflammatory Biomarkers, HT, and Coronary Heart Disease (CHD) in the WHI (Pradhan et al., JAMA 22;288:98) Median baseline levels of CRP and interleukin-6 (IL-6) were significantly higher in 34 women with incident CHD than in matched controls Both inflammatory markers were associated with a 2-fold increase in odds for CHD events HT use increased CRP but not IL-6 Use or non-use of HRT had less importance as a predictor of cardiovascular risk than did baseline levels of either CRP or IL-6 Age-Adjusted Relative Risk of Future Cardiovascular Events According to C-Reactive Protein Quintile at Baseline Among Postmenopausal Women That Were Nonusers (n=15,745) and Users (n=12,139) of HT 6 5 4 3 2 1 Non HRT Users HRT Users 1 2 3 4 5 Baseline Quintile of C-Reactive Protein Modified from Ridker et al, N Engl J Med, 22 Comparison of C-Reactive Protein Increases of Postmenopausal Women Treated with Oral CEE or Transdermal 2 E (Mean change ± 95% Confidence Interval) Change from Baseline in CRP Concentrations (%) 1 9 8 7 6 5 4 3 2 1-1 -2 Oral CEE Transdermal 2 E Oral CEE Transdermal 2 E 6 mos 12 mos Modified from Decensi et al, Circulation, 22 7

Adventitia Media Internal Elastic Lamina Fatty Streak/Plaque Fibrous Cap Plaque Necrotic Core VASCULAR BIOLOGIST'S DEFINITION OF PRIMARY PREVENTION Fibrous Cap Plaque CARDIOLOGIST'S DEFINITION OF MMP-9 PRIMARY PREVENTION Event Adventitia Media Internal Elastic Lamina Estrogen Effects on the Natural History of Atherosclerosis Fatty Streak/Plaque Fibrous Cap Plaque Estrogen Effects in Atherogenesis LDL oxidation LDL atherogenicity LDL binding/accum lesion progression CAMs monocyte adhesion/ macrophage accumulation SMC proliferation lesion progression Endothelial function vasodilation Benefits of estrogen on atherosclerosis prevention Fibrous Cap Plaque Necrotic Core Fibrous Cap Plaque Necrotic Core MMP-9 Estrogen Effects in Established Plaques Inflammation PQ instability lesion progression MMP expression PQ instability/rupture Neovascularization PQ hemorrhage Loss of Estrogen Benefits Expression of estrogen receptors Vascular responsivity Potentially adverse effects of estrogen on atherosclerosis/chd Effect of ET and HT on CHD in Postmenopausal Women Age 5-59 6-69 7-79 Years Since Menopause < 1 1-19 2 Hazard Ratio for CHD (ET Arm*)..5 1. 1.5 2. 2.5 3..56.92 1.4 Hazard Ratio for CHD (HT Arm**)..5 1. 1.5 2. 2.5 3..89 1.22 1.71 *The Women s Health Initiative Steering Committee, JAMA, 24 **Manson et al, N Engl J Med, 23 Metalloproteinase and Gelatinolytic Activity of Human Coronary Artery Atherosclerotic Plaques From Galis et al, J Clin Invest, 1994 8

Plasma Expression of Matrix Metalloproteinase-9 (MMP-9) and Gelatinolytic Activity of Postmenopausal Women (Av. Age 66 yrs) Treated Either with Placebo or HT (.625 mg CEE and 2.5 mg MPA per day) 8 p=.2 p=.36 2 Effect of Statin Treatment on Plasma MMP-9 of Patients with Coronary Heart Disease 14 12 6 MMP-9 (ng/ml) 4 15 1 Gelatinolytic Activity (densitometric units) Plasma MMP-9 (ng/ml) 1 8 6 4 2 5 2 Placebo HT Placebo HT Modified from Zanger et al, J Am Coll Cardiol, 2 Prudent Diet From Koh et al, Cor Artery Dis, 21 Prudent Diet + Simvastatin Effects of Statins on Early CVD Events in HERS Effect of Statins on CHD Among HT Users in WHI Incidence (%) 2 15 1 5 With CEE/MPA With Placebo No Statin Use Statin Use Statin Use Yes No Hazard Ratio for CHD..5 1. 1.5 2. 2.5 3. 3.5 4..99 1.27 1 2 3 4 5 Follow-up (years) Manson et al, N Engl J Med, 23 Herrington et al, Circulation, 22 9

Patient Characteristics: Age Grodstein et al. J Womens Health 26 Nurse s Health Study: evaluating time from menopause women near menopause reduced CV risk (RR.66 CI:.54-.8) Manson et al. NEJM 27 WHI: coronary calcium women 5-59, coronary calcium score lower in women on ET vs. placebo (OR.69 CI:.48-.98) Patient Characteristics: Age 27 Hydroxycholesterol SERM Competitive inhibitor of the estrogen receptor Accumulates in vessels in low estrogenic state Umetani et al. Nature Med 27 27HC inhibition of vasoprotective effect of estrogen Age In Years HYPOTHETICAL RATIONALE FOR KEEPS 35-45 45-55 55 55-65 Early Intervention (KEEPS) MHT No MHT Adventitia Media Internal Elastic Lamina Fatty Streak/Plaque Fibrous Cap Plaque Late Intervention (HERS, WHI) 5 1 Years Post- menopause Necrotic Core MHT MMP-9 >65 15 Umetani et al. Nature Med 27 1

ELITE Trial Early vs. Late Hodis FN (Los Angeles, CA) Drug Effect of 17β-estradiol Primary endpoint Carotid IMT Timing Perimenopausal women > 6 years post menopausal The Menopausal Syndrome Almost all signs and symptoms result from decreased circulating estrogen Symptoms: Hot flushes, paresthesias, cold hands and feet, headache, vertigo, irritability, anxiety, nervousness, depression, fatigue, weight gain, insomnia, night sweats, forgetfulness Signs: Depressed menstrual bleeding, relocation of fat deposits, decreased skin elasticity, osteoporosis in 25%, genital tract atrophy Some signs and symptoms may begin long before menopause HRT/ET and Neuroprotection WHIMS (Shumaker et al., JAMA 23;289:2651-62; Rapp et al., JAMA 23;289:2663-72) increased cognitive impairment and dementia in the oldest population Observational/animal studies role of timing, type improvement in certain skills (memory and verbal fluency) impact of smoking role of oxidative stress, inflammation HRT/ET and Neuroprotection Impact of timing Suzuki et al. PNAS 27 Mouse model Estradiol exerted a profound neuroprotective action when administered immediately upon ovariectomy (attenuating proinflammatory cytokines) Benefit lost is given remote from ovariectomy 11

Estradiol and Depressive Disorders (Soares et al., Arch Gen Psychiatry 21;58:529) 5 perimenopausal women aged 4-55 with irregular menstrual periods and FSH > 25 IU/L meeting criteria for major depressive, dysthymic, or minor depressive disorder by DSM-IV blindly randomized to transdermal estradiol (.1 mg) or placebo for 12 wks Remission of depression observed in 17 of 25 (68%) on E 2 and 5% on placebo Regardless of DSM-IV diagnosis, subjects responded similarly to E 2 Estrogen, Menopause, and the Aging Brain: How basic neuroscience can inform hormone therapy in women HT/ET at the menopausal transition and afterward could have beneficial effects on neurological symptoms Disconnect with WHI and WHIMS Animal and pre-clinical data supporting benefit Timing of treatment Administration formulations Morrison, Brinton, Schmidt, Gore: J Neuroscience: 26:1332 Risks of Menopausal HT: What We Think We Know Now Breast cancer RR 1.1-1.5 (all forms of estrogen) increased with progestogen (especially continuous) Endometrial cancer R 4.-11. (unopposed estrogen) reduced by progestin Venous Thromboembolism (oral therapy) 2 additional cases per 1, Mortality low, 1% Gall bladder disease CVD increased risk with existing disease and remote from menopause Risk of Invasive Breast Cancer by Duration of ET Use Among All Postmenopausal Women Who Had Undergone Hysterectomy and Those With ER+/PR+ Cancers Only* Copyright restrictions may apply. Chen, W. Y. et al. Arch Intern Med 26;166:127-132. 12

Estrogen and Breast Cancer Breast Cancer Reanalysis Lancet, 1997:35:147 Current/recent use HT: 2.3%/year Delay in menopause: 2.8%/year Does the Route of Estrogen Therapy Affect the Risk of Venous Thromboembolism (VTE)? (Scarabin et al., Lancet 23;362:428) Multicenter, case-control study of women of mean age 62 yr from France 155 cases of first VTE and 381 matched controls Overall 32 (21%) cases and 27 (7%) controls were current users of oral estrogen, whereas 3 (19%) cases and 93 (24%) controls were current users of transdermal estrogen After adjustment the odds ratio in current users of estrogen was 3.5 for oral and.9 for transdermal, respectively a 4-fold greater risk for oral compared to transdermal Menopausal Hormone Therapy and Osteoporosis Estrogen and estrogen/progestin are indicated for prevention of osteoporosis only. Yet the WHI is the first study not specifically designed with fracture as a primary endpoint to document a decrease in fractures. Cumulative Hazard for Hip Fracture WHI Results: Effect of HRT on Risk of Hip Fracture.3.2.1 Kaplan-Meier Estimate HR =.66 95% ncl =.45.98 95% aci =.33 1.33 1 2 3 4 5 6 7 Time (year) Placebo HRT HR = hazard ratio; nci = nominal confidence interval; aci = adjusted confidence interval. Writing Group for the Women s Health Initiative Investigators. JAMA. 22;288:321-33. 13

JAMA 26; 295:257 JAMA 26; 295:257 Menopause 25; 12:18 14

Suvanto-Luukkonen, et al. Obstet Gynecol 26; 18:41 Reddy SY, et al. Reddy SY, et al. 15

Current Truths Regarding Menopausal HT and CVD The public is largely unaware that CVD is the primary cause of mortality in women. Women should not take estrogen to prevent CVD. Women with known CVD should not begin HT for treatment of heart disease. Current Truths Regarding HRT and CVD (cont.) A statin is the drug of choice for any woman with hypercholesterolemia. In selecting HT, consideration should be given to the lipid profile because different HT regimens have different effects on various lipoproteins. First-line therapies for women with known CVD include risk factor modifications, aspirin, β- blockers, statins, and angiotensin-converting enzyme inhibitors, just as in men. Benefits of Menopausal HT: What We Think We Know Now Prevents or abolishes hot flashes Prevents or improves genital atrophy Prevents or slows bone loss May reduce risk of Alzheimer s disease May reduce risk of colon cancer May improve overall quality of life Alternatives and Future Directions for Research Estrogen Therapy progestagen-iud for uterine protection transdermal estrogen Raloxifene no change in CRP lowers homocysteine increased VTE Tibolone decrease in MMP-9 decrease in PAI-1 New SERMs Neurospecific action Bone specific action 16

So Just When Is Menopausal HT Indicated Now? For symptomatic women For prevention of osteoporosis in those where other drugs may be contraindicated?in women with new onset depression?for those who feel better taking estrogen 17