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Mindy Goldman, MD Clinical Professor Dept Managing Menopause Medically and Naturally Mindy Goldman, MD Clinical Professor Dept. of Ob/Gyn and Reproductive Sciences Director, Women’s Cancer Care Program, UCSF Breast Care Center and Women’s Health University of California, San Francisco I have nothing to disclose –Mindy Goldman, MD CASE STUDY 50 yr. old G2P2 peri-menopausal woman presents with complaints of significant night sweats interfering with her ability to sleep. She has mild hot flashes during the day. She has never had a bone mineral density test but her mother had a hip fracture at age 62 due to osteoporosis. Her 46 yr. old sister was diagnosed with breast cancer at age 43, treated with lumpectomy and radiation and currently is doing well. There is no other family history of cancer. Questions 1. Would you offer her MHT? 2. If yes, how long would you continue it? 3. If no, what would you offer for alternative treatments? 4. Would your treatment differ if you knew she had underlying heart disease? Is it safe? How long can I take it? What about Mymy Bones?bones? Will it protect my heart? MHT - 2015 What about my brain? Will I get breast cancer? What about my hot flashes? Menopausal Symptoms Hot flashes Night sweats Sleep disturbances Vaginal dryness/Sexual dysfunction Mood disturbances How to Treat Menopausal Symptoms Hormone therapy Alternatives to hormones Complementary and Integrative Techniques Prior to Women’s Health Initiative Hormone therapy primary treatment of menopausal hot flashes Few women would continue hormones past one year By 1990’s well known that progestins protect against uterine cancer, so women with a uterus prescribed HRT and women with prior hysterectomy prescribed ERT Hormone therapy primary treatment of osteopenia and osteoporosis Prior to Women’s Health Initiative Vast majority of observational studies showed hormones protected against heart disease, so women with cardiac risks most often prescribed HRT/ERT (primary prevention) Many women took hormones for protection against Alzheimer's Disease Were the benefits of HRT/ERT overestimated? Women’s Health Initiative – What was it Prospective primary prevention RCT – designed to see if hormones protected against heart disease Hormone Therapy Trial (HT) (27,347) Dietary Modification Trial (DM) (48,835) Calcium/Vitamin D Supplementation Trial (CaD) (36,282) Observational Study (OS) RCT/OS Participants: – From 40 Clinical Centers (CC) nationwide – 161,808 women aged 50-79; 68,132 in RCT 93,676 in OS 10 – 17.5% overall minority recruitment: Women’s Health Initiative – What was it . Women with a uterus randomized to CEE .625 plus 2.5 medroxyprogesterone acetate vs. placebo (prempro) . Women with hysterectomy randomized to conjugated equine estrogen .625 vs. placebo (premarin) . 16,000 women enrolled in CEE + MPA vs. placebo . 11,000 in the CEE vs. placebo . Average age 63 (range 50 -79 years) . 10% of subjects were 50 to 54 years old . 16% of subjects were less than 5 years past the onset of menopause WHI – Study characteristics At entry, 7.7% had prior CVD 36% had hypertension 49% were current or past smokers 34% had a body mass index ≥30 Was not designed to study effects on menopausal symptoms WHI – What Happened Combination HRT study terminated early in May 2002 because of increased risk of breast cancer, heart attacks, stroke and DVT Study of Estrogen only did not find an increased risk of breast cancer and continued. It terminated 1 year early in 2004 because of an increased risk of stroke and no protection for heart disease WHI: In Graphic - Numerical Terms 14 Gold Standard – but Criticisms of WHI Relative risks used instead of absolute which would take into account incidence rates After randomization the women were free to decide whether to continue their assigned treatment or whether to undergo diagnostic procedures The rate of unblinding in the E+P group was 45%, so almost ½ of women knew their treatment group High drop out rates - 43% of treated group and 38% of placebo group stopped their medication Average age of patient 10-15 yrs. above average age of menopause Media “took off” with results WHI Data - Where are we now? Fun Hawaii Facts Residents of Hawaii live longer than in any other state, average life expectancy of 81.5 years, about three years longer than the country’s average of 78.8 years Hawaii’s official state fish is the trigger fish called humuhumunukunukuāpuaʻa” (also one of the longest words in the Hawaiian language and the name is thought to be longer than the fish!) Called the Humuhumu,” for short, and is a “fish that grunts like a pig,” and named for the sounds it makes when cornered or caught. WHI Extension Study 2005-2010, 2010-2015 Annual updates on health outcomes are collected by mail, with signed release to obtain medical records if needed Heart Disease Absolute risks seen in WHI low: 19 additional events per year per 10,000 women with HRT versus placebo Analysis of WHI showed excess risks seen primarily in older women with combination HRT No increased risks with ERT and some suggestion of benefit in younger women, < 10 yrs. from menopause Increasing data that synthetic progestins may negate some of the beneficial effects of estrogen on lipids and endothelial function 13 yr follow up from WHI showed net neutral effects on CHD in both HRT and ET groups Timing Hypothesis and Heart Disease Various CHD events -nonfatal MI, coronary death, angina, and coronary artery revascularization were significantly reduced by 34% to 45% in the ET group relative to placebo in women aged 50 to 59, but not women aged 60 to 69 or 70 to 79 Number of studies since WHI including coronary angiography study, calcification study, and meta-analysis showed <10 yrs. since menopause or age 50-59 did not have increased CHD risks and suggestion of benefit Large prospective RCT Danish Osteoporosis Prevention Study (2012) showed 52% reduction death, MI, heart failure in HRT users, average age 50, over 10 year period (also found no increased breast ca or stroke risks) No major organization has said to use hormones for primary prevention Heart Disease “ Timing Hypothesis” most studies now suggest timing since menopause affects risk of CHD Types of estrogen may effect risks of CHD, transdermals have more favorable effects on markers for CHD No data that suggests that MHT should be used for secondary prevention in women with CHD Stroke In a meta-analysis of randomized trials (including HERS, WEST, and WHI), both ERT and HRT associated with an increase in ischemic stroke, but not hemorrhagic stroke Increases in all age groups but in younger women 50-59 no absolute increased risks Studies have shown a trend toward more fatal strokes in women on oral ERT Studies have shown low dose transdermal not thought to increase risk of stroke VTE Risks Meta-analysis have showed that oral MHT use causes about 2 fold increased risk of DVT/PE Studies suggest older age and obesity affects risks Data from WHI show risks not changed by smoking, ASA use or statins 3-7 fold higher if Factor V Leiden VTE Risks- Type and Dose of MHT Type of estrogen may matter: small studies have shown that conjugated estrogens, but not esterified (plant-derived) estrogens, increase risk Meta-analysis showed that transdermal routes not associated with increased VTE risks – oral, but not transdermal elevate CRP levels which is a marker for CHD risks low-dose MHT, (0.3 mg conjugated estrogen) has less effects on coagulation and inflammatory markers than standard dose therapy and lower VTE risks Type of progestin may matter- large Million Women Study showed higher risks with MPA Mortality When WHI reanalyzed by age, a significant 30 percent mortality reduction was seen in women under 60 years of age using MHT Absolute reductions: 5.3 and 5 fewer deaths per 1000 per five years of combined estrogen-progestin or unopposed estrogen use, respectively meta-analysis showed overall mortality not reduced with MHT in women over age 60 Meta-analysis of 19 RCT of MHT for women under 60 showed 27 percent reduced mortality with HT when compared with placebo , absolute risks: 1 in every 119 women treated with HT did not die at five years compared with untreated patients Breast Cancer Risk of breast ca in HRT users seen in year 3 for prior users and year 4 for first time users, absolute risk 8 excess cases per 10,000 person-years. Persistent increased risks in 13 yr fu in HRT group but decreased over time Epidemiologic studies have shown risks of breast cancer drop off when HRT discontinued Trend toward lower risk of breast ca in ERT arm, HR .79, and that has persisted with long-term follow up (13 years) Breast Cancer Not clear if starting hormones closer to menopause is associated with greater risks Length of ERT and risk? In Nurses Health Study long-term ERT associated with risk of breast ca (>15 yrs.) but not short term Studies have shown than breast cancer risk is not furthered increased in women with a family history- mainly independent risk factors Why would ERT alone be associated with decreased risk of breast cancer? One hypothesis is that in menopausal women with low endogenous estrogen maybe exogenous estrogens induce apoptosis in existing tumors What about ovarian status - women using ERT alone have had a hysterectomy with possible oophorectomy, which decreases risk of hormone positive breast cancer MHT and Breast Cancer Prognosis Impact of HT on breast cancer prognosis and mortality unclear 2010 follow-up analysis of WHI showed similar grade and histology but more
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