T. J. de Villiers

Global Consensus Statement on Menopausal Hormone Therapy

The following Consensus Statement is endorsed by The American Society for Reproductive Medicine, The Asia Pacific Menopause Federation, The Endocrine Society, The European Menopause and Andropause Society, The International Menopause Society, The International Osteoporosis Foundation and The North American Menopause Society.

Updated 2013 International Menopause Society recommendations on menopausal hormone therapy and preventive strategies for midlife health

MediClinic Panorama and Department of Obstetrics and Gynecology, Stellenbosch University, Cape Town, South Africa; * Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; † Queen Charlotte ’ s & Chelsea Hospital, and Chelsea and Westminster Hospital, London, UK; ‡ Department of Obstetrics and Gynecology, Pisa University Hospital, Pisa, Italy; * * Jones Institute, Eastern Virginia Medical School, Norfolk, VA, USA; † † Sydney Medical School, The University of Sydney, NSW, Australia; ‡ ‡ Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia; * * * UF de Gyn e cologie, Universit e Paris Descartes, AP-HP, H o tel-Dieu, Paris, France; † † † Departments of Health Research & Policy (Epidemiology) and of Neurology & Neurological Sciences, Stanford University, Stanford, CA, USA; ‡ ‡ ‡ Associate Dean for Clinical and Translational Research and Professor of Family Medicine-Las Vegas, University of Nevada School of Medicine, Las Vegas, NV, USA; * * * * Department of Obstetrics and Gynecology, Columbia University, New York, NY, USA; † † † † Unit e de Gyn e cologie M e dicale, H o tel Dieu, Paris, France; ‡ ‡ ‡ ‡ Heart of England NHS Foundation Trust, Solihull Hospital, Birmingham, UK

Menopausal hot flushes and night sweats: where are we now?

ABSTRACT Objective An overview of the current knowledge on the etiology and treatment of vasomotor symptoms in postmenopausal women. Materials and methods Acknowledged experts in the field contributed a brief assessment of their areas of interest which were combined and edited into the final manuscript. Results Women around the world experience vasomotor symptoms as they enter and complete the menopause transition. Vasomotor symptoms, specifically hot flushes, are caused by a narrowing of the thermoneutral zone in the brain. This effect, although related to estrogen withdrawal, is most likely related to changes in central nervous system neurotransmitters. Peripheral vascular reactivity is also altered in symptomatic women. Estrogen replacement therapy is the most effective treatment for hot flushes. Of the other interventions investigated, selective serotonin and selective norepinephrine reuptake inhibitors and gabapentin show efficacy greater than placebo. Objective monitoring of hot flushes indicates a robust improvement with hormone replacement therapy but little to no change with placebo. These data suggest that the subjective assessment of responses to therapy for vasomotor symptom results in inaccurate data. Hot flushes have recently been associated with increased cardiovascular risks and a lower incidence of breast cancer, but these data require confirmation. Conclusions Vasomotor symptoms are experienced by women of all ethnic groups. They are caused by changes in the central nervous system associated with estrogen withdrawal and are best treated with estrogen replacement therapy. Objective monitoring of hot flushes indicates that placebo has little to no effect on their improvement. Subjective assessments of hot flushes in clinical trials may be inaccurate based on objective measurement of the frequency of hot flushes. Based on preliminary reports, women experiencing hot flushes have an increased risk of cardiovascular disease and a reduced incidence of breast cancer.

Prevention of diseases after menopause.

Abstract Women may expect to spend more than a third of their lives after menopause. Beginning in the sixth decade, many chronic diseases will begin to emerge, which will affect both the quality and quantity of a womans life. Thus, the onset of menopause heralds an opportunity for prevention strategies to improve the quality of life and enhance longevity. Obesity, metabolic syndrome and diabetes, cardiovascular disease, osteoporosis and osteoarthritis, cognitive decline, dementia and depression, and cancer are the major diseases of concern. Prevention strategies at menopause have to begin with screening and careful assessment for risk factors, which should also include molecular and genetic diagnostics, as these become available. Identification of certain risks will then allow directed therapy. Evidence-based prevention for the diseases noted above include lifestyle management, cessation of smoking, curtailing excessive alcohol consumption, a healthy diet and moderate exercise, as well as mentally stimulating activities. Although the most recent publications from the follow-up studies of the Womens Health Initiative do not recommend menopause hormonal therapy as a prevention strategy, these conclusions may not be fully valid for midlife women, on the basis of the existing data. For healthy women aged 50–59 years, estrogen therapy decreases coronary heart disease and all-cause mortality; this interpretation is entirely consistent with results from other randomized, controlled trials and observational studies. Thus. as part of a comprehensive strategy to prevent chronic disease after menopause, menopausal hormone therapy, particularly estrogen therapy may be considered as part of the armamentarium.

Revised Global Consensus Statement on Menopausal Hormone Therapy

The following Consensus Statement is endorsed by The International Menopause Society, The North American Menopause Society, The Endocrine Society, The European Menopause and Andropause Society, The...

Cancer-associated bone disease

Bone is commonly affected in cancer. Cancer-induced bone disease results from the primary disease, or from therapies against the primary condition, causing bone fragility. Bone-modifying agents, such as bisphosphonates and denosumab, are efficacious in preventing and delaying cancer-related bone disease. With evidence-based care pathways, guidelines assist physicians in clinical decision-making. Of the 57 million deaths in 2008 worldwide, almost two thirds were due to non-communicable diseases, led by cardiovascular diseases and cancers. Bone is a commonly affected organ in cancer, and although the incidence of metastatic bone disease is not well defined, it is estimated that around half of patients who die from cancer in the USA each year have bone involvement. Furthermore, cancer-induced bone disease can result from the primary disease itself, either due to circulating bone resorbing substances or metastatic bone disease, such as commonly occurs with breast, lung and prostate cancer, or from therapies administered to treat the primary condition thus causing bone loss and fractures. Treatment-induced osteoporosis may occur in the setting of glucocorticoid therapy or oestrogen deprivation therapy, chemotherapy-induced ovarian failure and androgen deprivation therapy. Tumour skeletal-related events include pathologic fractures, spinal cord compression, surgery and radiotherapy to bone and may or may not include hypercalcaemia of malignancy while skeletal complication refers to pain and other symptoms. Some evidence demonstrates the efficacy of various interventions including bone-modifying agents, such as bisphosphonates and denosumab, in preventing or delaying cancer-related bone disease. The latter includes treatment of patients with metastatic skeletal lesions in general, adjuvant treatment of breast and prostate cancer in particular, and the prevention of cancer-associated bone disease. This has led to the development of guidelines by several societies and working groups to assist physicians in clinical decision making, providing them with evidence-based care pathways to prevent skeletal-related events and bone loss. The goal of this paper is to put forth an IOF position paper addressing bone diseases and cancer and summarizing the position papers of other organizations.

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

HRT in the early menopause: scientific evidence and common perceptions

Hormone replacement therapy (HRT) remains the first-line and most effective treatment for menopausal symptoms. But, despite massive, goodquality clinical outcome data on efficacy and safety when HRT is begun for symptoms in the early postmenopause, many physicians and lay people believe that hormones are risky and undesired even in the most appropriate case scenarios. Many misconceptions and misperceptions play roles in this complicated situation: some are purely scientific, others are cultural or social. The importance of the media and internet as effective, but unmonitored, means for dissemination of information, interpretation and recommendations cannot be ignored. Actual scientific facts and data have become trivialized in the mass media, often receiving less editorial scrutiny than normal journalism. Furthermore, many HRT prescribers and users do not attempt to broaden their knowledge on menopause and its treatment beyond capturing headlines or short commentaries, often produced by unqualified or prejudiced sources or unprofessional people. As a result, a gap has formed between the actual clinical evidence and the way it is perceived by all concerned. The results of the Women’s Health Initiative (WHI), a very large, government-sponsored study of hormone treatment regardless of indications (in contradistinction to normal practice that is based on clinical symptoms and signs), were prematurely released before the study was completed and before the results could be properly evaluated. As a result, the results were over-interpreted and negatively slanted. It was viewed as a negative study by its investigators and failed to emphasize the data, which pointed at the vast importance of age and time since menopause as major determinants of the benefit–risk equilibrium of HRT and the many benefits from timely employment of HRT. This was a catalyst for negative sentiments toward HRT. By the time that more detailed analyses from the WHI study could be published in the past 2 years, much ground was lost for all concerned and much remains to be set right for patients and caregivers, alike. At present, it is clear that the WHI showed that properly timed HRT is safe for healthy women in their early postmenopause and has major preventative effects against fractures. It reduces mortality and this may be, in large part, due to prevention of heart disease. The premature evaluation of the WHI includes statements and warnings from many health authorities, such as the US Preventive Services Task Force (USPSTF) and the European Agency for the Evaluation of Medicinal Products (EMEA), that sent a message that still prevails: the use of HRT is dangerous and therefore should be avoided, unless there is a substantial reduction in quality of life because of menopausal symptoms, in which case treatment should be given for the

The WHI: The effect of hormone replacement therapy on fracture prevention

ABSTRACT The Womens Health Initiative (WHI) randomized, controlled trial was the first study to prove that hormone replacement therapy (HRT) reduces the incidence of all osteoporosis-related fractures in postmenopausal women, even those at low risk of fracture. The study authors concluded that the bone-friendly aspect of HRT was limited in clinical practice as possible adverse effects outweighed possible benefit. On the strength of these publications, regulatory authorities downgraded the use of HRT for the prevention of fracture to second-line therapy. This article examines the original and subsequent evidence presented by the WHI study and concludes that the restrictions placed on HRT as a bone-specific drug by regulatory bodies have not withstood the test of time and are not supported by the data of the WHI.

Randomized placebo- and active-controlled study of desvenlafaxine for menopausal vasomotor symptoms

ABSTRACT Objective To evaluate the efficacy and safety of desvenlafaxine (administered as desvenlafaxine succinate) vs. tibolone and placebo for menopausal vasomotor symptoms and the incidence of uterine bleeding. Methods This 12-week, double-blind, randomized, controlled trial was conducted at 35 sites in Europe, two sites in South Africa, and one site in Mexico. Postmenopausal women with ≥50 moderate or severe hot flushes per week (n = 485) were randomized to desvenlafaxine 100 mg/day, tibolone 2.5 mg/day, or placebo. Reduction in the average daily number of moderate and severe hot flushes at weeks 4 and 12 (primary endpoint) was evaluated using analysis of covariance. Safety assessments included incidence of uterine bleeding, adverse events, laboratory values, and vital signs. Results At week 12, no statistically significant difference was observed in reduction of the average daily number of moderate and severe hot flushes for desvenlafaxine (−5.78) vs. placebo (−5.82; p = 0.921), although time to 50% reduction was significantly less than placebo (13 vs. 26 days, p = 0.006). Hot flush reduction with tibolone (−8.21) was significantly greater than placebo (p < 0.001). Nausea was the most common adverse event with desvenlafaxine, was generally mild to moderate, and resolved within the first 2 weeks. Significantly more subjects experienced bleeding with tibolone (23%) vs. desvenlafaxine (12%; p < 0.024) or placebo (9%; p < 0.001). Conclusions Desvenlafaxine did not separate from placebo in reducing the number of moderate to severe hot flushes at week 12, although it did allow women to achieve 50% reduction sooner than placebo. Tibolone did separate from placebo, but with smaller than expected effect. The placebo effect was high (57%). Adverse drug reactions were consistent with the known safety profile of desvenlafaxine, and significantly more women who received tibolone experienced episodes of bleeding compared with women who received desvenlafaxine or placebo.