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Menopause

Thomas A. Klein, MD Professor, OB-GYN Has disclosed the following commercial relationships in relation to this content: Nothing to Disclose Questions: thomas.klein@jefferson.edu

Objectives Review the physiologic and clinical events which accompany menopause Review the long-term health consequences of menopause Review current research findings regarding the treatment of menopause Review various hormonal and non-hormonal approaches to the relief of menopausal symptoms

Per Cent of Female Population by Age

Menopause 2016: State of Affairs High prevalence: essentially 100 % of women (eventually) Symptoms often severe and multi-systemic Major economic impact Opportunities for prevention: osteoporosis, CHD Intense pharmaceutical industry research & marketing Large volume of research Inherently difficult and complex Contradictory results Large number of available therapeutic and preventive interventions Various drugs, combinations, doses, routes of administration Most affect more than one organ system: favorable and adverse effects Rapidly changing landscape

Menopause is defined as: Amenorrhea accompanied by vasomotor symptoms Infrequent light bleeding after the age of 48 Amenorrhea for more than 3 months in a patient with X-chromosome mosaicism 46XX/45X Permanent loss of menstruation, caused by cessation of ovarian estrogen secretion Presence of vasomotor symptoms in a woman over age 51, regardless of bleeding

Etiology Normal – Follicle exhaustion Iatrogenic Surgery Radiation therapy Chemotherapy Premature (< age 35) Genetic Autoimmune Idiopathic

Follicle Loss

Problems Accompanying Menopause Vasomotor symptoms (“hot flashes”) Coronary Heart Disease (CHD) Breast cancer Osteoporosis Urogenital atrophic symptoms (urinary symptoms, painful intercourse) Dementia

Osteoporosis: Impact 10 million people with osteoporosis, 80% women Current estimates (2009), in U.S.: 10 million people with osteoporosis, 80% women 34 million people with osteopenia 547,000 vertebral fractures per year 350,000 hip fractures per year 1,200,000 fractures at other sites per year 24 % mortality in year following hip fracture, in pts > age 50 About 65 % of women sustain permanent losses of function after hip fracture About $ 19 billion spent annually on osteoporotic fractures A major public health problem, largely preventable

Osteoporosis Risk Factors Female Personal or family history of fragility fracture Caucasian/fair/nordic; asian Slender: weight < 127 lb Early menopause Family history Alcohol/tobacco/caffiene Low calcium intake Sedentary lifestyle Medications, esp. glucocorticoids, for > 3 months

Osteoporosis: Preventive Measures Lifestyle changes, e.g., weight-bearing exercise, smoking cessation Nutritional changes: Calcium, Vitamin D Medications, e.g. bisphosphonates, estrogen

2. African-American ancestry 3. Use of antidepressants 4. BMI = 32 A 45-year-old peri-menopausal patient asks you whether she should take steps to prevent future osteoporosis. Her 77-year-old mother recently broke her hip. Which of the following are risk factors for osteoporosis: 1. Menopausal state 2. African-American ancestry 3. Use of antidepressants 4. BMI = 32 5. Hypertension

1. Calcium/Vitamin D supplements 2. Glucocorticoid therapy The preceding patient wants to take steps to prevent future osteoporosis. Which of the following would you recommend: 1. Calcium/Vitamin D supplements 2. Glucocorticoid therapy 3. Herbal estrogens 4. Progestin therapy 5. Weight loss regimen

Coronary Heart Disease (CHD) The leading cause of death Risk for men increases steadily with age Risk for women much lower until menopause, after which it rapidly approaches that of men A large body of animal and in vitro evidence shows a beneficial effect of estrogen on cardiovascular health A large number of carefully-designed retrospective and observational studies show that postmenopausal estrogen therapy results in a 50 % reduction in CHD-related events Main criticism: Selection bias – Women taking hormones may have a healthier lifestyle than those not on Rx

Women's Health Initiative (WHI) NIH-sponsored long-term multicenter placebo-controlled randomized prospective evaluation of HRT Designed to determine whether HRT could prevent CHD Major arms: 0.625 mg CEE/0.25 mg MPA daily vs placebo 0.625 mg CEE only vs placebo (hysterectomy) >100,000 women, > $1,000,000,000 External Data & Safety Monitoring Board Study stopped after average 5.2 years because of excessive risk of breast carcinoma

WHI: Summary of Results Combination Therapy Arm Outcome HR C.I. Events/yr/10,000 pts. HRT Placebo Coronary HD 1.29 1.02 - 1.63 37 30 Stroke 1.41 1.07 - 1.85 29 21 VTE 2.11 1.58 - 2.82 34 16 Breast Ca 1.26 1.00 - 1.59 38 30 Colon Ca 0.63 0.43 - 0.92 10 16 Hip fracture 0.66 0.45 - 0.98 10 15 JAMA 2002;288:321

WHI - Criticisms Relatively advanced age of many subjects Exclusion of women with vasomotor symptoms Relatively advanced age of many subjects Average age 63 Average time since menopause 10 years Internal vs. external validity Results conflict with biological and in vitro data supporting beneficial effects of estrogens Nevertheless, WHI indicates that use of HRT in older women, or for long periods of time, increases the risk of breast cancer and CHD. “Estrogen Forever” no longer recommended

She is right; non-hormonal therapy is much safer A 50-year-old patient has been having severe vasomotor symptoms for several months. She has read about the Women’s Health Initiative (WHI) on the internet and is concerned that estrogen therapy may increase her risk of breast cancer. You tell her that: She is right; non-hormonal therapy is much safer The results of the WHI do not apply to her The WHI is a retrospective study and may not be valid Her risk of breast cancer will be minimal if she uses non-oral estrogen therapy Her risk of breast cancer will be lower if she adds a progestin to the estrogen therapy

HRT: Contraindications Absolute: Current breast or endometrial cancer Past history of breast or endometrial cancer (??) Undiagnosed vaginal bleeding Pregnancy Acute or chronic liver disease Active venous thrombosis or thromboembolic disease Relative: History of thrombosis or thromboembolism Strong family history of breast cancer

Which of the following is an absolute contraindication to estrogen replacement therapy? Varicose veins Positive hepatitis B surface antigen test Hypertension Fibrocystic breast change Undiagnosed vaginal bleeding

Oral combined (estrogen + progestin) therapy No hormonal therapy A 49-year-old patient is requesting estrogen therapy for severe “hot flashes.” Her last menstrual period was 6 months ago. She has a history of chronic hypertension and migraine headaches. What would you recommend? Oral combined (estrogen + progestin) therapy No hormonal therapy Oral progestin therapy only Oral estrogen therapy only Vaginal estrogen therapy

Non-Hormonal Therapies Vasomotor Symptoms Clonidine SSRI’s Herbal estrogens, Vitamin E (?) Osteoporosis SERM’s Bisphosphonates Calcitonin Calcium, Vitamin D, weight-bearing exercise, smoking cessation Coronary Heart Disease Statins Aspirin Control hypertension, diabetes Diet, exercise, smoking cessation

Treatment of Menopause: Issues to Consider Age, menopausal status, potential duration of therapy Severity and impact of symptoms Lifestyle and likelihood of change Smoking, diet, exercise Other medical problems and medications Risk factors for coronary heart disease Diabetes, hypertension, dyslipidemia Risk factors for breast Ca - ? Gail model Risk factors for osteoporosis Risk factors for DVT, VTE Likelihood of compliance with medication(s) Patient’s tolerance for risk Cost of treatment; insurance coverage

HRT: Current Situation ERT is safe and effective in most women for at least 5 years, when begun at time of menopause HRT should not be given to women at increased risk for CHD, breast cancer or DVT/VTE. This includes age > 60 years Risk of CHD and breast cancer increases with age and duration of HRT Use the lowest effective dose of HRT for the shortest necessary time

HRT: Current Situation HRT should not be used without a clear indication and careful consideration of risk/benefit ratio FDA-approved indications: Relief of vasomotor and vulvovaginal symptoms and prevention of osteoporosis Non-oral routes of administration may be preferable, to avoid DVT Benefits of HRT may also be achieved with non- hormonal therapy

Prevention of Alzheimer’s disease Prevention of osteoporosis Which of the following is an FDA-approved indication for postmenopausal hormone replacement therapy (HRT)? Prevention of Alzheimer’s disease Prevention of osteoporosis Prevention of coronary heart disease Prevention of deep vein thrombosis (DVT) Prevention of cerebrovascular disease

Menopause: Summary A “normal” hypoestrogenic state with multisystem effects, mostly adverse Estrogen replacement therapy corrects most of these effects, but with small risk of serious consequences, related to age, dose, duration of use and individual patient risk factors However, estrogen replacement therapy can relieve suffering and improve quality of life with relatively little risk, when appropriately administered The concept of “estrogen forever” is discredited The decision to administer estrogen replacement therapy requires a thorough and detailed evaluation of the patient’s situation, as well as non-estrogenic alternative therapies