Menopausal Management: Where are we in 21? 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 Case 1 34 y/o stops oral contraceptive pills to attempt conception. She fails to menstruate and ultimately is diagnosed with premature ovarian failure. She is started on hormone replacement therapy and ultimately adopts a child. She presents for her well woman visit at age 4 having been on HRT for 5 years. How would you advise her re: continuing treatment at this time? 1
Case 2 Benefits of Menopausal HT: What We Thought We Knew before WHI 46y/o woman presents with complaints of difficulty sleeping and premenstrual migraines. She has noted some increased irregularity in her cycles, but continues to bleed. Her last period was 3 months before this visit. What would be your evaluation? If the evaluation is negative, would you offer any treatments 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 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) 2
Publication of Clinical Trials in July, 22 HERS: Conclusion 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) HRT should not be used to reduce the risk of further CHD events in postmenopausal women with already established CHD 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
ERA Study Change in Minimal Lumen Diameter -.2 WHI HRT Study Cardiovascular Events (Cumulative) Coronary Heart Disease Stroke Pulmonary Embolism Change in diameter (mm) -.4 -.6 -.8 -.1 -.12 Placebo CEE CEE+MPA Progression of atherosclerosis Cumulative Hazard 3% HR, 1.29 95% Cl, 1.2-1.63 2% 1% 1 2 3 4 5 6 7 Placebo 3% HR, 1.41 95% Cl, 1.7-2% 1.85 1% 1 2 3 4 5 6 7 1% Estrogen + Progestin 3% HR, 2.13 95% Cl, 1. 39-3.25 2% 1 2 3 4 5 6 7 Modified from Herrington et al, N Engl J Med, 2 HR: hazard ratio; Cl, confidence interval Writing Group for the Women s Health Initiative. JAMA. 22;288:321-333. WHI HRT Study Disease Rates for Women on Estrogen + Progestin vs Placebo Number of women needing to take HT for one extra adverse or protective event per year: Number of Cases/year in 1, Women 6 5 4 3 2 1 + 7 + 8 Risks +31 + 8 CHD Stroke Breast Cancer PE Benefits - 11 + 8-6 - 5 Colorectal Cancer Neutral Hip Fracture Endometril Deaths Cancer Estrogen +Progestin Placebo 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 Writing Group for the Women s Health Initiative. JAMA. 22;288:321-333. 4
Observations about the WHI Study 97.5% of subjects had no adverse events Were subjects not as healthy as thought at entry Introduction of the timing hypothesis 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. Preliminary analyses suggest lower hazard ratios (for CVD) in women aged 5 to 59 years. What s different? Reconciling observational studies and clinical trials 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 5
WHI vs. Observational studies WHI vs. Observational studies Cardiovascular Disease Biological explanations Clinical characteristics of the populations healthier users timing of initiation of treatment Characteristics of hormone therapy type and dosage Manson JE, et al. 26; 13:139 Mean age 63 BMI 28.5 kg/m 2 Past User 2% Current User 6% Hormone Use Prior to Study Entry 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 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 6
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 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 6 MMP-9 (ng/ml) 4 2 p=.2 p=.36 2 15 1 5 Gelatinolytic Activity (densitometric units) Oral CEE Transdermal 2 E Oral CEE Transdermal E 2 6 mos 12 mos Modified from Decensi et al, Circulation, 22 Placebo HT Placebo HT Modified from Zanger et al, J Am Coll Cardiol, 2 7
Metalloproteinase and Gelatinolytic Activity of Human Coronary Artery Atherosclerotic Plaques Adventitia Media Internal Elastic Lamina Fatty Streak/Plaque VASCULAR BIOLOGIST'S DEFINITION OF PRIMARY PREVENTION Fibrous Cap Plaque CARDIOLOGIST'S DEFINITION OF MMP-9 PRIMARY PREVENTION Fibrous Cap Plaque Event From Galis et al, J Clin Invest, 1994 Necrotic Core Effect of Statin Treatment on Plasma MMP-9 of Patients with Coronary Heart Disease Plasma MMP-9 (ng/ml) 14 12 1 8 6 4 Incidence (%) 2 15 1 5 Effects of Statins on Early CVD Events in HERS With CEE/MPA With Placebo No Statin Use Statin Use 2 Prudent Diet Prudent Diet + Simvastatin 1 2 3 4 5 Follow-up (years) From Koh et al, Cor Artery Dis, 21 Herrington et al, Circulation, 22 8
Effect of Statins on CHD Among HT Users in WHI Statin Use Hazard Ratio for CHD..5 1. 1.5 2. 2.5 3. 3.5 4. Adventitia Media Internal Elastic Lamina Estrogen Effects on the Natural History of Atherosclerosis Fatty Streak/Plaque Fibrous Cap Plaque Fibrous Cap Plaque Necrotic Core Fibrous Cap Plaque Necrotic Core MMP-9.99 Yes No Manson et al, N Engl J Med, 23 1.27 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 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 Adverse effects of estrogen on atherosclerosis/chd 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 9
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 Umetani et al. Nature Med 27 >65 15 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* Estrogen and Breast Cancer Breast Cancer Reanalysis Lancet, 1997:35:147 Current/recent use HT: 2.3%/year Delay in menopause: 2.8%/year Chen, W. Y. et al. Arch Intern Med 26;166:127-132. Copyright restrictions may apply. 1
Breast Cancer Impact of change in HT From 21-2 to 25-6 reductions up to 2% strongest for women 5-6years old strongest for ER+/PR+ cancers accelerated growth with attendant earlier detection by 3-5 years after stopping no increased risk Verkooijen HM, et al, 29 Maturitas 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 before menopause - and last long after Symptoms and the Menopausal Transition Hot flushes and night sweats Stiff or painful joints Difficulty sleeping Poor/fair self-rated health Depression Headache Urinary incontinence Berecki-Gisolf J, et al. Menopause 29 11
Estrogen and the Brain Direct effects Enhances synaptic plasticity, neurite growth, hippocampal nurogenesis and long-term potentiation (memory) Protects against apoptosis and neural injury Stimulates aceytlcholine (memory), serotonin, noradrenalin Decrease deposition of β-amyloid Promotes morphological and electrophysiological correlates of learning and memory Indirect effects Vasculature Immune system NIA Frontiers proposal Bench to Bedside Estrogen as a case-study (29) Estrogen and the Brain Natural menopause Does not seem to be associated with decreased memory Surgical menopause Estrogen administration improves episodic memory Estrogen and the Brain Alzheimer Disease Early and consistent symptom loss of episodic memory (failing to recall appointments and events) In the laboratory: estrogen reduces the formation of β-amyloid formation and diminishes hyperphosphorylation of tau protein Estrogen and the Brain Alzheimer Disease Observational studies suggest protection Meta-analyses suggest risk reduction of approximately 1/3 Contradicted by the WHIMS trial (ages 65-79) Risk of dementia increased two-fold with combined HRT Impact noted within a few years, suggesting impact primarily on the vasculature Past history of use associated with lowered incident risk of dementia (including Alzheimer Disease) Initiation in older women WITH disease is no beneficial 12
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 Estrogen, Menopause, and the Aging Brain: How basic neuroscience can inform hormone therapy in women Disconnect with WHI and WHIMS Animal and pre-clinical data supporting benefit Timing of treatment Administration formulations HT/ET at the menopausal transition and afterward could have beneficial effects on neurological symptoms 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 Morrison, Brinton, Schmidt, Gore: J Neuroscience: 26:1332 13
Route of Estrogen Therapy Blood pressure impaired endothelial function Small impact of oral; no impact for transdermal beneficial impact suggested with estradiol and drospirenone Metabolic syndrome menopause diabetogenic Reduced DM and insulin resistance with estrogen Advantage of natural progesterone/non-androgenic progestins (drospeirenone, dydrogesterone) Route of Estrogen Therapy CVD CRP increased with oral and not transdermal; worsening affect with MPA first pass effect on the liver (lipids) endothelial function - improved with both (inhibited by MPA and NET) MMP-9 increased by oral and not by transdermal Thromboembolic events Increased risk with oral No increase with transdermal Route of Estrogen Therapy Neuroprotection No differences available between oral and transdermal Breast cancer No differences available between oral and transdermal Increased risk with combined progestational agent Risks of Menopausal HT: What We Think We Know Now Breast cancer RR 1.1-1.5 (all forms of estrogen) 8 additional cases/1,; 1 additional death/13 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 14
Current Truths Regarding Menopausal HT and CVD Endocrine Society 21 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. Endocrine Society 21 Assessment of Perimenopausal women BP Fasting lipid profile Fasting glucose TSH Assess for metabolic syndrome (decrease in insulin sensitivity; increase in central obesity) Counsel re: maintenance of healthy weight Assess sleep quality Screen for depression Vitamin D deficiency IMPORTANCE OF LIFESTYLE 15
Current Truths Regarding HRT and CVD A statin is the drug of choice for any woman with hypercholesterolemia First-line therapies for women with known CVD disease include risk-factor modification, 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 still the most effect treatment 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 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 Alternatives and Future Directions for Research Estrogen/Progestin Therapy progestagen-iud for uterine protection transdermal estrogen lower dosages new progestational agent 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 anti-estrogenic at breast and uterus 16
Case 1 34 y/o stops oral contraceptive pills to attempt conception. She fails to menstruate and ultimately is diagnosed with premature ovarian failure. She is started on hormone replacement therapy and ultimately adopts a child. She presents for her well woman visit at age 4 having been on HRT for 5 years. How would you advise her re: continuing treatment at this time? Case 2 46y/o woman presents with complaints of difficulty sleeping and premenstrual migraines. She has noted some increased irregularity in her cycles, but continues to bleed. Her last period was 3 months before this visit. What would be your evaluation? If the evaluation is negative, would you offer any treatments Effect of ET and HT on CHD in Postmenopausal Women Age 5-59 6-69 7-79 Hazard Ratio for CHD (ET Arm*)..5 1. 1.5 2. 2.5 3..56.92 1.4 Years Since Menopause < 1 1-19 2 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 17
Clinical Studies Observational studies Retrospective Cohort (Prospective) Double-blind, randomized, placebocontrolled trials 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 Does the Route of Estrogen Therapy Affect the Risk of Venous Thromboembolism (VTE)? 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 Heiss, et al. JAMA 28 Scarabin et al., Lancet 23;362:428 18