Margery Gass

Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials.

IMPORTANCE Menopausal hormone therapy continues in clinical use but questions remain regarding its risks and benefits for chronic disease prevention. OBJECTIVE To report a comprehensive, integrated overview of findings from the 2 Womens Health Initiative (WHI) hormone therapy trials with extended postintervention follow-up. DESIGN, SETTING, AND PARTICIPANTS A total of 27,347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers. INTERVENTIONS Women with an intact uterus received conjugated equine estrogens (CEE; 0.625 mg/d) plus medroxyprogesterone acetate (MPA; 2.5 mg/d) (n = 8506) or placebo (n = 8102). Women with prior hysterectomy received CEE alone (0.625 mg/d) (n = 5310) or placebo (n = 5429). The intervention lasted a median of 5.6 years in CEE plus MPA trial and 7.2 years in CEE alone trial with 13 years of cumulative follow-up until September 30, 2010. MAIN OUTCOMES AND MEASURES Primary efficacy and safety outcomes were coronary heart disease (CHD) and invasive breast cancer, respectively. A global index also included stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and death. RESULTS During the CEE plus MPA intervention phase, the numbers of CHD cases were 196 for CEE plus MPA vs 159 for placebo (hazard ratio [HR], 1.18; 95% CI, 0.95-1.45) and 206 vs 155, respectively, for invasive breast cancer (HR, 1.24; 95% CI, 1.01-1.53). Other risks included increased stroke, pulmonary embolism, dementia (in women aged ≥65 years), gallbladder disease, and urinary incontinence; benefits included decreased hip fractures, diabetes, and vasomotor symptoms. Most risks and benefits dissipated postintervention, although some elevation in breast cancer risk persisted during cumulative follow-up (434 cases for CEE plus MPA vs 323 for placebo; HR, 1.28 [95% CI, 1.11-1.48]). The risks and benefits were more balanced during the CEE alone intervention with 204 CHD cases for CEE alone vs 222 cases for placebo (HR, 0.94; 95% CI, 0.78-1.14) and 104 vs 135, respectively, for invasive breast cancer (HR, 0.79; 95% CI, 0.61-1.02); cumulatively, there were 168 vs 216, respectively, cases of breast cancer diagnosed (HR, 0.79; 95% CI, 0.65-0.97). Results for other outcomes were similar to CEE plus MPA. Neither regimen affected all-cause mortality. For CEE alone, younger women (aged 50-59 years) had more favorable results for all-cause mortality, myocardial infarction, and the global index (nominal P < .05 for trend by age). Absolute risks of adverse events (measured by the global index) per 10,000 women annually taking CEE plus MPA ranged from 12 excess cases for ages of 50-59 years to 38 for ages of 70-79 years; for women taking CEE alone, from 19 fewer cases for ages of 50-59 years to 51 excess cases for ages of 70-79 years. Quality-of-life outcomes had mixed results in both trials. CONCLUSIONS AND RELEVANCE Menopausal hormone therapy has a complex pattern of risks and benefits. Findings from the intervention and extended postintervention follow-up of the 2 WHI hormone therapy trials do not support use of this therapy for chronic disease prevention, although it is appropriate for symptom management in some women. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00000611.

Evaluation of bazedoxifene/conjugated estrogens for the treatment of menopausal symptoms and effects on metabolic parameters and overall safety profile

OBJECTIVE To evaluate the effects of a tissue-selective estrogen complex (TSEC) composed of bazedoxifene/conjugated estrogens (BZA/CE) on menopausal symptoms, metabolic parameters, and overall safety. DESIGN Multicenter, double-blind, placebo- and active-controlled phase 3 trial (Selective estrogens, Menopause, And Response to Therapy [SMART]-1). SETTING Outpatient clinical. PATIENT(S) Healthy, postmenopausal women (n = 3,397) age 40 to 75 with an intact uterus. INTERVENTION(S) Single tablets of BZA (10, 20, or 40 mg), each with CE (0.625 or 0.45 mg); raloxifene 60 mg; or placebo taken daily for 2 years. MAIN OUTCOME MEASURE(S) Hot flushes, breast pain, vaginal atrophy, metabolic parameters, and adverse events. RESULT(S) BZA (20 mg)/CE (0.625 or 0.45 mg) significantly reduced the frequency and severity of hot flushes and improved measures of vaginal atrophy compared with placebo. At week 12, the daily number of hot flushes decreased by 51.7% to 85.7% with all BZA/CE doses vs. 17.1% for placebo. BZA/CE improved lipid parameters and homocysteine levels, did not significantly change carbohydrate metabolism, and had only minor effects on some coagulation parameters. The incidences of breast pain and adverse events were similar between BZA/CE and placebo. CONCLUSION The TSEC composed of BZA (20 mg)/CE (0.625 or 0.45 mg) is an effective and safe treatment for menopausal symptoms.

The North American Menopause Society recommendations for clinical care of midlife women

In celebration of the 25th anniversary of The North American Menopause Society (NAMS), the Society has compiled a set of key points and clinical recommendations for the care of midlife women. NAMS has always been a premier source of information about menopause for both healthcare providers and midli

Global Consensus Statement on menopausal hormone therapy.

MediClinic Panorama and Department of Obstetrics and Gynecology, Stellenbosch University, Cape Town, South Africa; * Department of Surgery, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University School of Medicine, Cleveland, OH, USA; † Department of Obstetrics and Gynecology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR; ‡ Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; * * Department of Obstetrics and Gynecology, Columbia University, New York, NY, USA; † † University of Geneva, Switzerland; ‡ ‡ Reader Emeritus, University of Oxford, UK

Why the product labeling for low-dose vaginal estrogen should be changed

This commentary summarizes the activities of several clinicians and researchers to encourage modifications to the labeling of low-dose vaginal estrogen. Motivated by concerns of practicing clinicians that the boxed warning on the labels and package inserts for these products overstate potential risk

Algorithm and mobile app for menopausal symptom management and hormonal/non-hormonal therapy decision making: a clinical decision-support tool from The North American Menopause Society.

OVERVIEW The Menopause Decision-Support Algorithm (Fig. 1) and companion MenoPro iPhone/iPad app, developed in collaboration with The North American Menopause Society (NAMS), are designed to help clinicians decide which patients are candidates for pharmacologic treatment of menopausal symptoms, understand what the treatment options are, and gain experience deciding among the options. Menopausal symptoms vary dramatically among women. Some women are good candidates for hormonal treatments and others, due to their personal preferences or risk factor profiles, are not appropriate candidates and should consider non-hormonal options. One of the most complex health care decisions facing women in mid-life is whether to use prescription medications for menopausal symptom management, and the array of pharmacologic options has expanded markedly in recent years. The new MenoPro app, which can be downloaded free of charge on a mobile phone or tablet device, helps clinicians and patients work together to Bpersonalize[ treatment decisions, based on risk stratification and the patient_s personal preferences. The mobile app has two modes, one for clinicians and a companion mode for patients, to facilitate shared decision making and patient-centered care. The algorithm and MenoPro mobile app address options for Bmoderate to severe[ hot flashes and/or night sweats (defined as bothersome enough to interfere with daily activities, impair quality of life, and/or interrupt sleep), as well as genitourinary symptoms (including vaginal dryness or pain with intercourse or other sexual activities). Convenient links provide information about treatment options, formulations and doses, and contraindications to therapy. The app calculates an atherosclerotic cardiovascular disease (CVD) risk score for each patient, which is relevant to the decision regarding initiation of systemic menopausal hormone therapy (HT). Women at high risk of, or with significant concern about, breast cancer should be informed about availability of non hormonal therapies. Once the clinician becomes familiar with the algorithm, personalized decision-making for most patients will require only 2-3 minutes, and the app provides a summary at the end that can be printed out or directly emailed to the patient. The tool can be used for women with menopausal symptoms who are ages Q45 years old. The algorithm can also be used for women who have had removal of both ovaries, regardless of age. Women below age 45 or those who are not clearly menopausal, as well as women who have had endometrial ablation, progestinreleasing intrauterine device/system, or hysterectomy without removal of ovaries, may need additional clinical evaluation before applying this algorithm (evaluation may include hCG, FSH, TSH, prolactin, and other tests). The algorithm encourages all patients to try lifestyle modifications for at least 3 months before beginning HT or other pharmacologic therapies. For information on lifestyle modifications, cognitive behavioral therapy, and/or alternative remedies, clinicians may want to print out the materials for the patient at the below link (or send the link by email via the app): http://www.menopause.org/docs/for-women/ mnflashes.pdf. Women at high risk of osteoporotic fracture and unable to tolerate standard preventive medications may also be candidates for HT (NAMS Hormone Therapy Position Statement: http://www.menopause.org/docs/default-document-library/ psht12.pdf ?sfvrsn=2). The algorithm also addresses considerations relevant to decisions about duration of treatment, including balancing risks of breast cancer, cardiovascular disease, and osteoporosis. Each step of the algorithm should be reassessed at least once every 12 months or if health status changes.

A decade after the Women's Health Initiative—the experts do agree

Cynthia A. Stuenkel, M.D., N.C.M.P., Margery L. S. Gass, M.D., N.C.M.P., JoAnn E. Manson, M.D., Dr.PH., N.C.M.P., Rogerio A. Lobo, M.D., Lubna Pal, M.B.B.S., M.R.C.O.G., M.Sc., N.C.M.P., Robert W. Rebar, M.D., and Janet E. Hall, M.D. a Clinical Professor of Medicine, Endocrinology and Metabolism, University of California, San Diego, California; b Executive Director, The North American Menopause Society, Consultant, Cleveland Clinic Center for Specialized Womens Health, Clinical Professor, Department of Reproductive Biology, Case Western Reserve University School of Medicine, Cleveland, Ohio; c Professor of Medicine and the Michael and Lee Bell Professor of Womens Health, Harvard Medical School, Chief of Preventive Medicine, Co-Director, Connors Center for Womens Health and Gender Biology, Brigham and Womens Hospital, Boston, Massachusetts; d Professor, Department of Obstetrics and Gynecology, Columbia University, New York, New York; e Associate Professor, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, Director, Program for Polycystic Ovarian Syndrome, Director, Program for Reproductive Aging and Bone Health, New Haven, Connecticut; f Executive Director, American Society for Reproductive Medicine, Birmingham, Alabama; and g Professor, Department of Medicine, Harvard Medical School, Boston, Massachusetts

A Decade after the Women's Health Initiative—The Experts Do Agree

Cynthia A. Stuenkel, M.D., N.C.M.P., Margery L. S. Gass, M.D., N.C.M.P., JoAnn E. Manson, M.D., Dr.PH., N.C.M.P., Rogerio A. Lobo, M.D., Lubna Pal, M.B.B.S., M.R.C.O.G., M.Sc., N.C.M.P., Robert W. Rebar, M.D., and Janet E. Hall, M.D. a Clinical Professor of Medicine, Endocrinology and Metabolism, University of California, San Diego, California; b Executive Director, The North American Menopause Society, Consultant, Cleveland Clinic Center for Specialized Womens Health, Clinical Professor, Department of Reproductive Biology, Case Western Reserve University School of Medicine, Cleveland, Ohio; c Professor of Medicine and the Michael and Lee Bell Professor of Womens Health, Harvard Medical School, Chief of Preventive Medicine, Co-Director, Connors Center for Womens Health and Gender Biology, Brigham and Womens Hospital, Boston, Massachusetts; d Professor, Department of Obstetrics and Gynecology, Columbia University, New York, New York; e Associate Professor, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, Director, Program for Polycystic Ovarian Syndrome, Director, Program for Reproductive Aging and Bone Health, New Haven, Connecticut; f Executive Director, American Society for Reproductive Medicine, Birmingham, Alabama; and g Professor, Department of Medicine, Harvard Medical School, Boston, Massachusetts

The effect of low-dose conjugated equine estrogens and cyclic MPA on bone density

OBJECTIVE to compare the effect of 0.3 and 0.625 mg conjugated equine estrogens on bone mineral density (BMD) in a private practice setting. METHODS postmenopausal women interested in hormone replacement therapy were prescribed either 0.3 or 0.625 mg conjugated equine estrogens daily with 10 mg medroxyprogesterone acetate days 1-12 of the month. All women were given calcium citrate 1000 mg/day and vitamin D 400 IU/day. DEXA bone mineral density studies of the spine and hip were performed at baseline and 1 year. RESULTS there was no significant difference in BMD at the spine, the trochanter or the femoral neck compared with baseline in either the 0.625 or 0.3 mg group. The mean percent increase in BMD for the 0.3 versus 0.625 mg group was: spine 2.6 versus 3.8%, femoral neck 1.8 versus 1.5%, and trochanter 0.5 versus 2.6%. CONCLUSION both the 0.625 mg dose and the 0.3 mg dose of conjugated equine estrogens preserved BMD at the spine and hip over one year in early postmenopausal women who were also given cyclic medroxyprogesterone acetate, calcium citrate and vitamin D.

Reassessing Benefits and Risks of Hormone Therapy

Recent randomized clinical trials of postmenopausal hormone therapy have informed clinical decision making and provided insights that help identify appropriate candidates for treatment. A decline in the use of hormone therapy began precipitously in 2002 with publication of data from the Womens Health Initiative. This review examines the scientific literature surrounding this major change in practice and comments on the equilibrating process now taking place. Notably, the incidence of most of the medical conditions adversely affected by hormone therapy increases with age. As a result, recently menopausal women—those most interested in using hormone therapy—are at lower absolute risk of adverse events than older women. A critical mass of data now suggests that age and time since menopause may also modify relative risks of selected outcomes with use of hormone therapy, but this warrants further study. Duration of hormone therapy use also appears to influence risk, with the occurrence of certain outcomes (such as venous thrombosis) being highest in the first 1 or 2 years of hormone therapy use and others (such as breast cancer) increasing with longer duration of hormone therapy use. The conflicting results for some outcomes from the estrogen arm and the estrogen-progestin arm of the Womens Health Initiative suggest that progestins influence risk of several diseases, particularly breast cancer. Quantifying the benefits and risks of estrogen and estrogen-progestin by age group makes it possible to discuss pros and cons of hormone therapy in a more clinically relevant manner with patients. Hormone therapy remains a viable short-term option for the management of moderate to severe vasomotor symptoms in recently menopausal women who are in generally good health. However, due to known risks, it should not be initiated or continued for the express purpose of preventing cardiovascular disease or other chronic diseases.