Marco Gambacciani

Postmenopausal hormone therapy: An endocrine society scientific statement

OBJECTIVE Our objective was to provide a scholarly review of the published literature on menopausal hormonal therapy (MHT), make scientifically valid assessments of the available data, and grade the level of evidence available for each clinically important endpoint. PARTICIPANTS IN DEVELOPMENT OF SCIENTIFIC STATEMENT: The 12-member Scientific Statement Task Force of The Endocrine Society selected the leader of the statement development group (R.J.S.) and suggested experts with expertise in specific areas. In conjunction with the Task Force, lead authors (n = 25) and peer reviewers (n = 14) for each specific topic were selected. All discussions regarding content and grading of evidence occurred via teleconference or electronic and written correspondence. No funding was provided to any expert or peer reviewer, and all participants volunteered their time to prepare this Scientific Statement. EVIDENCE Each expert conducted extensive literature searches of case control, cohort, and randomized controlled trials as well as meta-analyses, Cochrane reviews, and Position Statements from other professional societies in order to compile and evaluate available evidence. No unpublished data were used to draw conclusions from the evidence. CONSENSUS PROCESS A consensus was reached after several iterations. Each topic was considered separately, and a consensus was achieved as to content to be included and conclusions reached between the primary author and the peer reviewer specific to that topic. In a separate iteration, the quality of evidence was judged using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) system in common use by The Endocrine Society for preparing clinical guidelines. The final iteration involved responses to four levels of additional review: 1) general comments offered by each of the 25 authors; 2) comments of the individual Task Force members; 3) critiques by the reviewers of the Journal of Clinical Endocrinology & Metabolism; and 4) suggestions offered by the Council and members of The Endocrine Society. The lead author compiled each individual topic into a coherent document and finalized the content for the final Statement. The writing process was analogous to preparation of a multiauthored textbook with input from individual authors and the textbook editors. CONCLUSIONS The major conclusions related to the overall benefits and risks of MHT expressed as the number of women per 1000 taking MHT for 5 yr who would experience benefit or harm. Primary areas of benefit included relief of hot flashes and symptoms of urogenital atrophy and prevention of fractures and diabetes. Risks included venothrombotic episodes, stroke, and cholecystitis. In the subgroup of women starting MHT between ages 50 and 59 or less than 10 yr after onset of menopause, congruent trends suggested additional benefit including reduction of overall mortality and coronary artery disease. In this subgroup, estrogen plus some progestogens increased the risk of breast cancer, whereas estrogen alone did not. Beneficial effects on colorectal and endometrial cancer and harmful effects on ovarian cancer occurred but affected only a small number of women. Data from the various Womens Health Initiative studies, which involved women of average age 63, cannot be appropriately applied to calculate risks and benefits of MHT in women starting shortly after menopause. At the present time, assessments of benefit and risk in these younger women are based on lower levels of evidence.

Phalangeal Osteosonogrammetry Study: Age‐Related Changes, Diagnostic Sensitivity, and Discrimination Power

Phalangeal osteosonogrammetry was introduced as a method for bone tissue investigation in 1992. It is based on the measure of the velocity of ultrasound (amplitude‐dependent speed of sound [AD‐SoS]) and on the interpretation of the characteristics of the ultrasound signal. In this study we have collected a database of 10,115 subjects to evaluate the performance of AD‐SoS and to develop a parameter that is able to quantify the signal characteristics: ultrasound bone profile index (UBPI). The database only includes females of which 4.5% had documented vertebral osteoporotic fractures, 16% lumbar spine dual X‐ray absorptiometry (DXA), and 6% hip DXA. The analysis of the ultrasound signal has shown that with aging the UBPI, first wave amplitude (FWA), and signal dynamics (SDy) follow a trend that is different from the one observed for AD‐SoS; that is, there is no increase during childhood. In the whole population, the risk of fracture per SD decrease for AD‐SOS was odds ratio (OR) 1.71 (CI, 1.58‐1.84). The AD‐SoS in fractured subjects was significantly lower than in a group of age‐matched nonfractured subjects (p < 0.0001). In a small cohort of hip‐fractured patients UBPI proved to be lower than in a control age‐matched group (p < 0.0001). When the World Health Organization (WHO) working group criteria were applied to this population to identify the T score value for osteoporosis, for AD‐SoS we found a T score of −3.2 and for UBPI we found a T score of −3.14. Sixty‐six percent of vertebral fractures were below the AD‐SoS −3.2 T score and 62% were below UBPI −3.14. We observed the highest incidence of fractures (63.6%) among subjects with AD‐SoS who had both DXA T score values below the threshold. We conclude from this study that ultrasound investigation at the hand phalanges is a valid methodology for osteoporosis assessment. It has been possible to quantify signal changes by means of UBPI, a parameter that will improve the possibility of investigating bone structure.

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

IMS Updated Recommendations on postmenopausal hormone therapy

The past decade has seen marked fluctuations inopinions concerning the merits and risks ofpostmenopausal hormone therapy. In July 2002,menopause management faced a major turningpoint when the first data from the Women’sHealth Initiative (WHI) trial were released. Thestudy was categorized as a primary preventiontrial for coronary heart disease, although the factthat mean age at recruitment was 63 years was notgiven enough importance at that time. WHIinvestigators concluded that hormone therapy(HT) was not cardioprotective, and, in fact, itsrisk–benefit ratio did not favor the use ofpostmenopausal hormones for prevention ofchronic diseases. As a result, there was a dramaticchange in prescription habits following recom-mendations to reserve HT for very symptomaticwomen, and to limit its use to the ‘shortestduration needed’ and ‘to the lowest effectivedosage’. This was the atmosphere in which theInternational Menopause Society (IMS) initiatedthe IMS Workshop held in Vienna (December2003) and the IMS Position Paper that was basedon the Workshop discussions. Looking at globalperspectives, and being independent of local orregional constraints imposed by official healthauthorities, this IMS Statement called for a morebalanced approach in the interpretation of thescientific data on hormone use that were availablein 2003. Since then, additional information hasbeen accumulated from both arms of the WHIstudy, observational trials and from other studies,allowing a more comprehensive review on allissues related to the use of hormones in thepostmenopausal period. In view of the above, theIMS Board decided that it is time to update the2004 Statement and to enlarge its scope tomenopause management and adult women’shealth in general. More than 30 experts from thevarious fields of menopause medicine reviewed thelatest information in a Workshop held in Budapestin February 2007.The following Recommendations express theviews of the IMS on the principles of hormonetherapy in the peri- and postmenopausal periods.Throughout the Recommendations, the term HTwill be used to cover all therapies includingestrogens, progestogens, combined therapies andtibolone.The previous IMS Statement in 2004 is stillvalid and serves as a basis for the current UpdatedRecommendations.We are aware of the geographical variationsrelated to different priorities of medical care,different prevalence of diseases, and country-specific attitudes of the public, the medicalcommunity and the health authorities towardmenopause management, which may all impacton hormone therapy. The following recommenda-tions, therefore, give a global and simple overviewthat serves as a common platform on issues relatedto the various aspects of hormone treatment.These Recommendations were reviewed and dis-cussed by representatives of more than 60National and Regional Menopause Societies fromall continents. These Recommendations can beeasily adapted and modified according to localneeds.

Prospective evaluation of body weight and body fat distribution in early postmenopausal women with and without hormonal replacement therapy

AIMS In order to assess the effects of menopause and hormonal replacement therapy (HRT) on body weight and body fat distribution (determined by dual energy X-ray), early postmenopausal women were given either oral calcium (500 mg/day, control group, n=13) or HRT, a combination of estradiol valerate (EV, 2 mg/day for 21 days) with cyproterone acetate (CPA, 1 mg/day in the last 10 days of the treatment cycle, n=18; Climen, Schering). RESULTS There were no differences in basal body weight and body fat distribution in the two groups before the study. In control group, a significant (P<0.05) increase in body weight (from 63.5+/-2.0 to 68.7+/-2.0 kg after 36 months) paralleled a shift to a prevalent central, android fat distribution with a slight but significant (P<0.05) increase in total body fat mass (from 23.4+/-2.1 to 29.1+/-2.1 kg), an increase in trunk (from 10.1+/-0.4 to 12.7+/-0.4 kg, P<0.05), arms (from 2.4+/-0.2 to 2.9+/-0.2 kg, P<0.05) and legs (from 6.5+/-0.4 to 7.8+/-0.4 kg, P<0.05) fat. In the HRT group total body bone mineral showed a significant increase (from 1086+/-21 to 1128+/-19 mg/cm(2), P<0.05) increase after 36 months, with no significant increase in body weight (from 62.6+/-1.8 to 65.0+/-1.9 kg), and no modifications in trunk (from 10.0+/-0.2 to 10.1+/-0.2 kg) and arms (from 2.4+/-0.1 to 2.6+/-0.1 kg) fat, but a significant increase in legs fat (from 6.9+/-0.3 to 9.9+/-0.4 kg, P<0.05). CONCLUSION Present results demonstrate that menopause is associated with an accelerated increase in body weight and body fat, with a prevalent central, android fat distribution, that can be counteracted at least in part by oral HRT.

Updated practical recommendations for hormone replacement therapy in the peri- and postmenopause.

Henry Burger, Australia; David Archer, USA; David Barlow, UK; Martin Birkhauser, Switzerland; Joaquim Calaf-Alsina, Spain; Marco Gambacciani, Italy; Andrea Genazzani, Italy; Peyman Hadji, Germany; Ole Erik Iversen, Norway; Herbert Kuhl, Germany; Rogerio A. Lobo, USA; Thierry Maudelonde, France; Manuel Neves e Castro, Portugal; Morris Notelovitz, USA; Santiago Palacios, Spain; Tomasz Paszkowski, Poland; Eitan Peer, Israel; Amos Pines, Israel; Goran Samsioe, Sweden; John Stevenson, UK; Sven Skouby, Denmark; David Sturdee, UK; Tobie de Villiers, South Africa; Malcolm Whitehead, UK; Olavi Ylikorkala, Finland

The effect of menopause on blood lipid and lipoprotein levels

There is increasing evidence from epidemiological studies that exogenous estrogen (hormone replacement therapy) protects against the elevated risk of cardiovascular disease in women after the menopause. However, it is still uncertain whether the postmenopausal decrease in endogenous estrogen in itself contributes significantly to this increase in risk. Most of the studies that have provided evidence linking cardiovascular disease with menopause have involved North American women, who may differ significantly from Europeans in terms of lifestyle and diet. ICARUS (Italian Climacteric Research Group Study) is an observational study that involves Italian Menopause Clinics, with the objective of collecting observational data on menopause and its management. The results of a cross-sectional analysis of 9309 women, free from any hormonal treatment and enrolled up to March 1997, are reported here. Data show that the menopause has a marked effect on the circulating levels of lipids and lipoproteins. From pre- to post-menopause there are significant increases in total cholesterol (6.9% before and 4.4% after adjustment for covariates including chronological age, educational level, center, BMI, smoking habits, hypertension and diabetes, previous contraceptive use, and time since menopause), LDL (7.5% before, 4.0% after), and triglycerides (9.0% before, 3.2% (ns) after). However, there is no significant change in HDL. Among postmenopausal women, no effect on lipid profile of time since menopause was observed.

Determinants of age at menopause in Italy: results from a large cross-sectional study

OBJECTIVE To identify the determinants of age at menopause in an Italian population, using data from the Italian Climacteric Research Group Study (ICARUS). METHODS ICARUS is a prospective study of the effect of menopause on womens health that has been running in menopause clinics throughout Italy since 1995. A total of 4300 women with spontaneous menopause, aged 55 years or more and observed for the first time at the participating centres are included in the present analysis. RESULTS The mean age at menopause in the total population was 50.9 years. After taking into account potential covariates, the women reported smoking, had a slightly lower mean age at menopause than non smokers 50.4 versus 50.9 years; P = 0.01. The mean age at menopause in nulliparae was 50.0 years, and, respectively 50.4, 50.6, 50.9, 51.2 and 50.9 years in those reporting 1, 2, 3, 4 and 5 or more births (P < 0.01). A low body mass index and an early age at menarche were associated with early menopause in the crude analysis, but these associations disappeared after taking into account the confounding factors. CONCLUSIONS This study offers an estimate of the mean age at menopause of women attending menopause clinics in Italy, on the basis of the data obtained from a large sample. It also indicates that smoking and nulliparity are associated with early menopause.

Effects of low-dose, continuous combined estradiol and noretisterone acetate on menopausal quality of life in early postmenopausal women

OBJECTIVES To describe the effects of low dose hormonal replacement therapy (LD-HRT) on quality of life in early postmenopausal women, since the postmenopausal estrogen deprivation in mid age women often brings along a series of changes and symptoms, which may greatly affect quality of life. METHODS Fifty normal postmenopausal women were recruited and randomly treated with LD-HRT, 17beta-estradiol (1 mg/day) and norethisterone acetate (0.5 mg/day) (LD-HRT) or calcium supplement (controls). No significant differences in age, age at menopause, the presence of chronic diseases and socio-economic status were present in the two groups. The Womens Health Questionnaire (WHQ), a validated quality-of-life instrument for perimenopausal and postmenopausal women, was administered at baseline and after 6 and 12 weeks of treatment in both groups. RESULTS At baseline no significant differences in WHQ scores were present in the two groups. In the control group the scores in all different areas showed no significant modification either after 6 and 12 weeks of observation. Conversely, the LD-HRT group showed a significant decrease in the scores of vasomotor symptoms, somatic symptoms, anxiety/fear, depressed mood and sleep problem items. No effects on memory/concentration and menstrual symptoms areas were evident. CONCLUSION Although quality of life is also and may be mainly influenced by socio-economic and cultural factors, LD-HRT definitively can improve not only vasomotor symptoms, but also more general aspects of physical and psychological well-being of symptomatic postmenopausal women.

Evidence that Estrogens Inhibit LH Secretion through Opioids in Postmenopausal Women Using Naloxone

To evaluate whether ovarian steroid environment may modify endogenous opioid activity at hypothalamic-pituitary level, the effects of naloxone infusion (1.2 mg/h for 4 h) on gonadotropin secretion were studied in 5 postmenopausal women who had natural menopause 3-5 years before the study. In addition, naloxone infusion was repeated in the same subjects after chronic oral treatment with conjugated estrogens (1.25 mg/day in two divided doses for 20 days). Before treatment, both the circulating levels of estrogens and plasma gonadotropins were in the normal range for postmenopausal women and naloxone infusion did not induce any significant modification of gonadotropin secretion. In contrast, after estrogen therapy, and the consequent rise in estrogen plasma levels, naloxone infusion induced a significant LH increase (p less than 0.01) starting during the last hour of treatment. These findings seem to confirm that endogenous opioid peptides may modulate the inhibitory effect exerted by estrogens on LH secretion, in humans.