Anne Gompel

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

Ki-67: level of evidence and methodological considerations for its role in the clinical management of breast cancer: analytical and critical review

Clinicians can use biomarkers to guide therapeutic decisions in estrogen receptor positive (ER+) breast cancer. One such biomarker is cellular proliferation as evaluated by Ki-67. This biomarker has been extensively studied and is easily assayed by histopathologists but it is not currently accepted as a standard. This review focuses on its prognostic and predictive value, and on methodological considerations for its measurement and the cut-points used for treatment decision. Data describing study design, patients’ characteristics, methods used and results were extracted from papers published between January 1990 and July 2010. In addition, the studies were assessed using the REMARK tool. Ki-67 is an independent prognostic factor for disease-free survival (HR 1.05–1.72) in multivariate analyses studies using samples from randomized clinical trials with secondary central analysis of the biomarker. The level of evidence (LOE) was judged to be I-B with the recently revised definition of Simon. However, standardization of the techniques and scoring methods are needed for the integration of this biomarker in everyday practice. Ki-67 was not found to be predictive for long-term follow-up after chemotherapy. Nevertheless, high KI-67 was found to be associated with immediate pathological complete response in the neoadjuvant setting, with an LOE of II-B. The REMARK score improved over time (with a range of 6–13/20 vs. 10–18/20, before and after 2005, respectively). KI-67 could be considered as a prognostic biomarker for therapeutic decision. It is assessed with a simple assay that could be standardized. However, international guidelines are needed for routine clinical use.

Hormonal regulation of apoptosis in breast cells and tissues.

Few studies have referred to the implication of apoptotic processes following hormonal treatment. No data are available on the effects of progesterone in breast cells. In order to gain insights on the effects of the gonadal steroids and antiestrogens in breast cells, we have carried out studies on apoptosis in different breast materials. We have developed a model of normal breast cells in cultures that remain hormone-dependent. On these cells and in some hormone-dependent breast cancer cell lines (T-47-D, ZR75-1, MCF-7) we have observed an antiapoptotic effect of estradiol (E(2)) and a potent proapoptotic effect of some antiestrogens. Progestins were also proapoptotic in normal as well as in hormone-dependent breast cancer cells. In order to understand the mechanisms of these hormones on apoptosis, we studied the bcl-2 family proteins. We demonstrated that E(2) increased the antiapoptotic proteins, bcl-2 and bclx(L), whereas, the progestins drastically decreased bcl-2 expression and weakly bclx(L) levels. We investigated the mechanisms by which E(2) increased bcl-2 expression. Our results using quantitative RT-PCR showed that E(2) increased bcl-2 mRNA levels at 48 h of treatment via a transcriptional mechanism. None of the hormone treatments altered the proapoptotic protein levels, bax and bak. We also studied the in vivo expression of bcl-2 and other members of its family in biopsies of normal breast tissues according to the menstrual cycle. Bcl-2 displayed a strong cyclical variation and seemed to be the most hormone-dependent member of the family.

Treatment of Symptoms of the Menopause: An Endocrine Society Clinical Practice Guideline

OBJECTIVE The objective of this document is to generate a practice guideline for the management and treatment of symptoms of the menopause. PARTICIPANTS The Treatment of Symptoms of the Menopause Task Force included six experts, a methodologist, and a medical writer, all appointed by The Endocrine Society. EVIDENCE The Task Force developed this evidenced-based guideline using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe the strength of recommendations and the quality of evidence. The Task Force commissioned three systematic reviews of published data and considered several other existing meta-analyses and trials. CONSENSUS PROCESS Multiple e-mail communications, conference calls, and one face-to-face meeting determined consensus. Committees of The Endocrine Society, representatives from endorsing societies, and members of The Endocrine Society reviewed and commented on the drafts of the guidelines. The Australasian Menopause Society, the British Menopause Society, European Menopause and Andropause Society, the European Society of Endocrinology, and the International Menopause Society (co-sponsors of the guideline) reviewed and commented on the draft. CONCLUSIONS Menopausal hormone therapy (MHT) is the most effective treatment for vasomotor symptoms and other symptoms of the climacteric. Benefits may exceed risks for the majority of symptomatic postmenopausal women who are under age 60 or under 10 years since the onset of menopause. Health care professionals should individualize therapy based on clinical factors and patient preference. They should screen women before initiating MHT for cardiovascular and breast cancer risk and recommend the most appropriate therapy depending on risk/benefit considerations. Current evidence does not justify the use of MHT to prevent coronary heart disease, breast cancer, or dementia. Other options are available for those with vasomotor symptoms who prefer not to use MHT or who have contraindications because these patients should not use MHT. Low-dose vaginal estrogen and ospemifene provide effective therapy for the genitourinary syndrome of menopause, and vaginal moisturizers and lubricants are available for those not choosing hormonal therapy. All postmenopausal women should embrace appropriate lifestyle measures.

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.

Expression of neurotensin and NT1 receptor in human breast cancer: a potential role in tumor progression.

Emerging evidence supports neurotensin as a trophic and antiapoptotic factor, mediating its control via the high-affinity neurotensin receptor (NT1 receptor) in several human solid tumors. In a series of 51 patients with invasive ductal breast cancers, 34% of all tumors were positive for neurotensin and 91% positive for NT1 receptor. We found a coexpression of neurotensin and NT1 receptor in a large proportion (30%) of ductal breast tumors, suggesting a contribution of the neurotensinergic signaling cascade within breast cancer progression. Functionally expressed NT1 receptor, in the highly malignant MDA-MB-231 human breast cancer cell line, coordinated a series of transforming functions, including cellular migration, invasion, induction of the matrix metalloproteinase (MMP)-9 transcripts, and MMP-9 gelatinase activity. Disruption of NT1 receptor signaling by silencing RNA or use of a specific NT1 receptor antagonist, SR48692, caused the reversion of these transforming functions and tumor growth of MDA-MB-231 cells xenografted in nude mice. Our findings support the contribution of neurotensin in human breast cancer progression and point out the utility to develop therapeutic molecules targeting neurotensin or NT1 receptor signaling cascade. These strategies would increase the range of therapeutic approaches and be beneficial for specific patients.

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.

Type III hereditary angio-oedema: clinical and biological features in a French cohort

To cite this article: Vitrat‐Hincky V, Gompel A, Dumestre‐Perard C, Boccon‐Gibod I, Drouet C, Cesbron JY, Lunardi J, Massot C, Bouillet L. Type III hereditary angio‐oedema: clinical and biological features in a French cohort. Allergy 2010; 65: 1331–1336.

In vitro studies of tibolone in breast cells.

OBJECTIVE To investigate the effects of tibolone and its main metabolites on breast homeostasis. DESIGN In vitro studies in primary cultures of normal breast cells and in breast cancer cell lines. SETTING Hospital-based academic research center. PATIENT(S) Human breast cells were obtained from women undergoing surgery for hypermastia. Breast cancer cell lines (MCF-7, T47-D, and ZR75-1) were routinely obtained from subcultures. INTERVENTION(S) Cells were incubated with tibolone, its various metabolites, the pure pregnane Org 2058, and the androgen dihydrotestosterone. MAIN OUTCOME MEASURE(S) Proliferation was determined by using a morphometric growth index, apoptosis by using morphologic analysis and flow cytometry, and antiapoptotic proteins bcl-2 and bclx(L) by using Western blot assay. Activity of 17beta-hydroxysteroid dehydrogenase was measured as an epithelial differentiation marker. RESULT(S) Tibolone and its delta(4) isomer were antiproliferative in normal breast cells. Tibolone and its delta(4) isomer increased apoptosis in breast cells. These proapoptotic effects were at least partially mediated through decreased expression of the antiapoptotic proteins bcl-2 and bclx(L). An increase in HSD activity was observed after tibolone administration. CONCLUSION(S) Tibolone is antiproliferative and proapoptotic and induces differentiation in normal breast cells. It is also proapoptotic in breast cancer cell lines.

Progestogen-Only Contraceptives and the Risk of Stroke A Meta-Analysis

Background and Purpose— The association between combined oral contraceptives (OC) use and increased risk of stroke has been reported. While progestogen-only contraceptives (POC) are commonly used worldwide, their impact on cardiovascular disease remains unclear. Methods— A meta-analysis based on EMBASE and MEDLINE referenced literature corresponding to OCs marketed since 1960 was carried out. Eligible articles assessing the risk of stroke in relation to OC or POC were reviewed, and relevant studies were extracted. All types of POC and routes of administration were taken into account in the meta-analysis. Results— Six case–control studies were identified. The combined odd ratio (OR) showed no increase in the risk of stroke among POC users (OR=0.96; 95% confidence interval: 0.70 to 1.31). This result was similar according to the route of administration (either implant or injectable or oral POC). Conclusion— Data from observational studies show that POC use is not associated with an increased risk of stroke. However, these results are based on limited data. Further investigations are needed in women with risk factors of stroke.