Is there a role for menopausal hormone therapy in the management of postmenopausal osteoporosis?

We provide an evidence base and guidance for the use of menopausal hormone therapy (MHT) for the maintenance of skeletal health and prevention of future fractures in recently menopausal women. Despite controversy over associated side effects, which has limited its use in recent decades, the potential role for MHT soon after menopause in the management of postmenopausal osteoporosis is increasingly recognized. We present a narrative review of the benefits versus risks of using MHT in the management of postmenopausal osteoporosis. Current literature suggests robust anti-fracture efficacy of MHT in patients unselected for low BMD, regardless of concomitant use with progestogens, but with limited evidence of persisting skeletal benefits following cessation of therapy. Side effects include cardiovascular events, thromboembolic disease, stroke and breast cancer, but the benefit-risk profile differs according to the use of opposed versus unopposed oestrogens, type of oestrogen/progestogen, dose and route of delivery and, for cardiovascular events, timing of MHT use. Overall, the benefit-risk profile supports MHT treatment in women who have recently (< 10 years) become menopausal, who have menopausal symptoms and who are less than 60 years old, with a low baseline risk for adverse events. MHT should be considered as an option for the maintenance of skeletal health in women, specifically as an additional benefit in the context of treatment of menopausal symptoms, when commenced at the menopause, or shortly thereafter, in the context of a personalized benefit-risk evaluation.

Assessment and hormonal management of osteoporosis.

Postmenopausal osteoporosis is a frequent health issue in women. Because osteoporosis-related fractures cause a significant increase in mortality and morbidity, it is clinically important to identify as soon as possible women at increased risk for future fracture so that preventive measures can be instituted. At the beginning of menopause, evaluation of the subsequent risk of fracture is not so easy. Most screening tools fail to accurately identify those women who will fracture within the next 10 years. A history of a prior fracture and low bone mineral density are the only major consistently found predictors for the risk of fracture. On the other hand, it is no longer a question whether menopause hormone therapy is efficient not only to prevent postmenopausal bone loss but also the incidence of fragility fracture. Over the last years, utility of menopause hormone therapy for the prevention of osteoporosis has been questioned due to safety concerns. In light of the most recent reports on a more favorable benefit/risk balance than was initially claimed in early postmenopausal women, this needs to be reconsidered. Prevention of bone loss in those women with a moderate or slightly high risk of fracture is likely a strategy to reduce fracture risk in older women. Menopause hormone therapy must be considered as a true primary preventive therapy more than an anti-fracture therapy at an age when the risk of fracture is likely much lower than later in life. Only thereafter should other anti-osteoporotic medications be discussed in women still at high risk for fracture.

[Women with a very high risk of breast cancer: Contraceptives, hormonal replacement therapy use and personalized screening]. / Femmes à très haut risque de cancer du sein : contraception, traitement hormonal substitutif et dépistage personnalisé.

Women with a high family risk of breast cancer are those with an identified genetic predisposition or those who have a suggestive family history without an identified germinal mutation, particularly for BRCA1 and BRCA2. Among these women with a very high risk of breast cancer, the fear of a potentially increased risk of breast cancer linked to some hormonal contraceptives and to the use of hormone replacement therapy, in connection with the general population data collected in literature, has led to certain reluctance to prescribe them to these women. Moreover, confusion often sets due to poor knowledge of the literature. Furthermore, the monitoring procedures consist of breast screening and strategies of risk reduction, based on recent recommendations. In order to improve the gynaecological monitoring throughout their lives, we offer here a review based on an analysis of recent literature and of the recommendations concerning personalized screening, contraception and hormone replacement therapy among women with a very high risk of breast cancer free from this illness.

Management of women with abnormal uterine bleeding: Clinical practice guidelines of the French National College of Gynaecologists and Obstetricians (CNGOF).

OBJECTIVE: To provide French guidelines for the management of women with abnormal uterine bleeding (AUB). DESIGN: A consensus committee of 26 experts was formed. A formal conflict-of-interest policy was developed at the beginning of the process and enforced throughout. The entire guidelines process was conducted independently of any industry funding (i.e. pharmaceutical or medical device companies). The authors were advised to follow the rules of the Grading of Recommendations Assessment, Development and Evaluation (GRADE®) system to guide assessment of quality of evidence. The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasized. METHODS: The last guidelines from the Collège National des Gynécologues et Obstétriciens Français on the management of women with AUB were published in 2008. The literature seems now sufficient for an update. The committee studied questions within 7 fields (diagnosis; adolescents; idiopathic AUB; endometrial hyperplasia and polyps; type 0-2 fibroids; type 3 or higher fibroids; and adenomyosis). Each question was formulated in a PICO (Patients, Intervention, Comparison, Outcome) format and evidence profiles were compiled. The GRADE® methodology was applied to the literature review and the formulation of recommendations. RESULTS: The experts' synthesis work and the application of the GRADE method resulted in 36 recommendations. Among the formalized recommendations, 19 are strong and 17 weak. No response was found in the literature for 14 questions. We chose to abstain from recommendations rather than providing advice based solely on expert clinical experience. CONCLUSIONS: The 36 recommendations make it possible to specify the diagnostic and therapeutic strategies for various clinical situations practitioners encounter, from the simplest to the most complex.

Quality of life of patients with bilateral oophorectomy before the age of 45 for the treatment of endometriosis.

INTRODUCTION: The study aimed to evaluate the quality of life and associated factors among women who underwent bilateral oophorectomy (BO) before the age of 45 for the treatment of deep infiltrating endometriosis (DIE). MATERIALS AND METHODS: This cross-sectional study was carried out in 52 women who were treated from January 2014 to December 2019 in 2 public and private DIE surgical centers in Toulouse. All women answered the Menopausal Quality of Life questionnaire (MenQOL). Mean MenQOL scores were compared according to age at BO, smoking, BMI, level of education, delay between BO and the survey and post-BO hormone replacement therapy (HRT) using Mann-Whitney and Anova tests. Spearman's correlation coefficient was used to analyze the correlations between all the MEnQOL domain scores and clinical variables. The variables associated with the outcomes in univariate analyses with p < 0.2 were jointly evaluated using multiple linear regression. RESULTS: The mean age at the time of the survey was 43.4 ± 3.4 years while the mean age at BO was 40.5 ± 3.4 years. The mean MenQOL score was 3.96 (± 1.45), with the highest scores in the sexual (4.77) and vasomotor (4.01) domains. BMI and smoking were independently and significantly associated with the mean total MenQOL score, all domain scores being significantly higher in overweight/obese women. A trend towards worse MenQOL scores was found in patients who had BO before the age of 41. We did not find any difference according to whether or not they were taking HRT. CONCLUSION: This is a first study evaluating quality of life in a specific population of oophorectomized women under the age of 45 using MenQOL for DIE. While BO is effective in relieving pain in women with severe DIE, the induced premature menopause is associated with a poor quality of life, which deserves further attention.

Management of postmenopausal women: Collège National des Gynécologues et Obstétriciens Français (CNGOF) and Groupe d'Etude sur la Ménopause et le Vieillissement (GEMVi) Clinical Practice Guidelines.

AIM: The aim of these recommendations is to set forth an individualized approach to the management of early postmenopausal women (i.e., within the first 10 years after natural menopause) covering all aspects of lifestyle and therapeutic management, with or without menopause hormone therapy (MHT). MATERIALS AND METHODS: Literature review and consensus of French expert opinion. Recommendations were graded according to the HAS methodology and levels of evidence derived from the international literature, except when there was no good-quality evidence. SUMMARY RECOMMENDATIONS: The beginning of menopause is an ideal time for each woman to evaluate her health status by assessing her bone, cardiovascular, and cancer-related risk factors that may be amplified by postmenopausal estrogen deficiency and by reviewing her lifestyle habits. Improving lifestyle, including nutrition and physical activity, and avoiding risk factors (notably smoking), should be recommended to all women. MHT remains the most effective treatment for vasomotor symptoms but it could be also recommended as first-line treatment for the prevention of osteoporosis in early postmenopausal women at low to moderate risk for fracture. The risks of MHT differ depending on its type, dose, duration of use, route of administration, timing of initiation, and whether a progestogen is used. There is reasonable evidence that using transdermal estradiol in association with micronized progesterone or dydrogesterone may limit both the venous thromboembolic risk associated with oral estrogens and the risk of breast cancer associated with synthetic progestins. Treatment should be individualized to each woman, by using the best available evidence to maximize benefits and minimize risks, with periodic reevaluation of its benefit-risk balance. For bothersome genitourinary syndrome of menopause (GSM) symptoms, vaginal treatment with lubricants and moisturizers is recommended as first-line treatment together with low-dose vaginal estrogen therapy, depending on the clinical course. No recommendation of an optimal duration of MHT can be made, but it must take into consideration the initial indication for MHT as well as each woman's benefit-risk balance. Management of gynecological side-effects of MHT is also examined. These recommendations are endorsed by the Groupe d'Etude sur la Ménopause et le Vieillissement hormonal (GEMVI) and the Collège National des Gynécologues-Obstétriciens Français (CNGOF).

[Management of women with abnormal uterine bleeding: Clinical practice guidelines of the French National College of Gynecologists and Obstetricians (CNGOF)]. / Prise en charge des ménorragies : recommandations pour la pratique clinique du Collège national des gynécologues et obstétriciens français (CNGOF).

OBJECTIVE: To provide French guidelines for the management of women with abnormal uterine bleeding (AUB). DESIGN: A consensus committee of 26 experts was formed. A formal conflict-of-interest (COI) policy was developed at the beginning of the process and enforced throughout. The entire guidelines process was conducted independently of any industrial funding (i.e. pharmaceutical, or medical devices). The authors were advised to follow the rules of the Grading of Recommendations Assessment, Development and Evaluation (GRADE®) system to guide assessment of quality of evidence. The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasized. METHODS: The last guidelines from the Collège national des gynécologues et obstétriciens français (CNGOF) on the management of women with AUB was published in 2008. The literature seems now sufficient for an update. The committee studied questions within 7 fields (diagnosis; adolescent; idiopathic AUB; endometrial hyperplasia and polyps; fibroids type 0 to 2; fibroids type 3 and more; adenomyosis). Each question was formulated in a PICO (Patients, Intervention, Comparison, Outcome) format and the evidence profiles were produced. The literature review and recommendations were made according to the GRADE® methodology. RESULTS: The experts' synthesis work and the application of the GRADE method resulted in 36 recommendations. Among the formalized recommendations, 19 present a strong agreement and 17 a weak agreement. Fourteen questions did not find any response in the literature. We preferred to abstain from recommending instead of providing expert advice. CONCLUSIONS: The 36 recommendations made it possible to specify the diagnostic and therapeutic strategies of various clinical situations managed by the practitioner, from the simplest to the most complex.

[Menopause, menopause hormone therapy and osteoporosis. Postmenopausal women management: CNGOF and GEMVi clinical practice guidelines]. / Ménopause, traitement hormonal de ménopause et ostéoporose. RPC Les femmes ménopausées du CNGOF et du GEMVi.

Postmenopausal osteoporosis is a frequent clinical condition, which affects nearly 1 in 3 women. Estrogen deficiency leads to rapid bone loss, which is maximal within the first years after the menopause transition and can be prevented by menopause hormone therapy (MHT). Assessment of the individual risk of osteoporosis is primarily based on the measurement of bone mineral density (BMD) at the spine and femur by DXA. Clinical risk factors (CRFs) for fractures taken either alone or in combination in the FRAX score were shown not to reliably predict fractures and/or osteoporosis (as defined by a T-score<-2.5) in early postmenopausal women. If DXA measurement is indicated in all women with CRFs for fractures, it can be proposed on a case-by-case basis, when knowledge of BMD is likely to condition the management of women at the beginning of menopause, particularly the benefit-risk balance of MHT. MHT prevents both bone loss and degradation of the bone microarchitecture in early menopause. It significantly reduces the risk of fracture at all bone sites by 20 to 40% regardless of basal level of risk with an estrogen-dependent dose-effect. Given the inter-individual variability in bone response, individual monitoring of the bone effect of MHT is warranted when prescribed for the prevention of osteoporosis. This monitoring is based on repeated measurement of lumbar and femoral BMD (on the same DXA measurement system) after 2years of MHT, the response criterion being no significant bone loss. Discontinuation of treatment is associated with a resumption of transient bone loss although there is a large variability in the rate of bone loss among women. Basically, there is a return to the level of fracture risk comparable to that of in untreated woman of the same age within 2 to 5years. Therefore, when MHT is prescribed for the prevention of osteoporosis in women with an increased risk at the beginning of menopause, measurement of BMD is recommended when MHT is stopped in order to consider further management of the risk of fracture whenever necessary (with possibly another anti-osteoporotic treatment).

[Menopause hormone treatment in practice. Postmenopausal women management: CNGOF and GEMVi clinical practice guidelines]. / Le traitement hormonal de la ménopause en pratique. RPC Les femmes ménopausées du CNGOF et du GEMVi.

Menopause Hormonal Treatment (MHT) was initially developed to correct the climacteric symptoms induced by postmenopausal estrogen deficiency. In non-hysterectomized women, MHT combines estrogens and a progestogen, the latter opposing the negative impact of estrogen on endometrial proliferation. In France, and contrary to the USA and Northern European countries, MHT mainly combines 17ß-estradiol, which is the physiological estrogen produced by the ovary, and progesterone or its derivative, dihydrogesterone. France has been a pioneer in the development of cutaneous administration routes (gel or transdermal patch) for estradiol, allowing better metabolic tolerance and a reduction of the risk of venous thromboembolism compared to the oral route. The choice of the doses as well as the treatment regimen is underpinned by tolerance as well as acceptance and compliance. The risk of breast cancer, which is one of the main risks of MHT, is higher with estro-progestogen combinations than with estrogens alone ; the preferential use of progesterone or dihydrogesterone being likely to limit the excess risk of breast cancer associated with MHT at least for duration of treatment of less than 5 to 7 years. The question of the optimal duration of MHT remains an issue and must take into account the initial indication of treatment as well as the benefit-risk balance, which is specific to each woman. Continuation of MHT is conditioned by the benefit-risk balance, which must be evaluated regularly, but also by the evolution of symptoms when MHT is stopped as well as menopause-related health risks or induced by MHT. After stopping MHT, it is necessary to maintain a medical follow-up to be adapted to the clinical situation of each woman and in particular, her cardiovascular and gynecological risk factors.

Long-Term Effects of Roux-en-Y Gastric Bypass and Sleeve Gastrectomy on Bone Mineral Density: a 4-Year Longitudinal Study.

INTRODUCTION: Bone mineral density (BMD) declines in the initial years after bariatric surgery, but long-term skeletal effects are unclear and comparisons between sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) are rare. DESIGN AND METHODS: An observational longitudinal study of obese patients undergoing SG or RYGB was performed. Whole-body (WB) BMD, along with BMD of the total hip (TH), femoral neck (FN), and lumbar spine (LS), was measured by dual-energy X-ray absorptiometry (DXA) before surgery and yearly thereafter for 4 years. Calciotropic hormones were also measured. RESULTS: Forty-seven patients undergoing RYGB surgery and 28 patients undergoing SG were included. Four years after RYGB, BMD declined by 2.8 ± 5.8% in LS, 8.6 ± 5% in FN, 10.9 ± 6.3% in TH, and 4.2 ± 6.2% in WB, relative to baseline. For SG, BMD declined by 8.1 ± 5.5% in FN, 7.7 ± 6% in TH, 2.0 ± 7.2% in LS, and 2.5 ± 6.4% in WB after 4 years, relative to baseline. Vitamin D levels increased with supplementation in both groups. Whereas parathyroid hormone levels increased slightly in the RYGB group, they decreased modestly in the SG group (P < 0.05 in both groups). CONCLUSIONS: Bone loss after 4 years was comparable between the two procedures, although RYGB was associated with a slightly greater decrease at the TH than SG. Bone health should therefore be monitored after both RYGB and SG.

Assessment of Cardiovascular Safety of Anti-Osteoporosis Drugs.

The incidence of osteoporosis and cardiovascular disease increases with age, and there are potentially shared mechanistic associations between the two conditions. It is therefore highly relevant to understand the cardiovascular implications of osteoporosis medications. These are presented in this narrative review. Calcium supplementation could theoretically cause atheroma formation via calcium deposition, and in one study was found to be associated with myocardial infarction, but this has not been replicated. Vitamin D supplementation has been extensively investigated for cardiac benefit, but no consistent effect has been found. Despite findings in the early 21st century that menopausal hormone therapy was associated with coronary artery disease and venous thromboembolism (VTE), this therapy is now thought to be potentially safe (from a cardiac perspective) if started within the first 10 years of the menopause. Selective estrogen receptor modulators (SERMs) are associated with increased risk of VTE and may be related to fatal strokes (a subset of total strokes). Bisphosphonates could theoretically provide protection against atheroma. However, data from randomised trials and observational studies have neither robustly supported this nor consistently demonstrated the potential association with atrial fibrillation. Denosumab does not appear to be associated with cardiovascular disease and, although parathyroid hormone analogues are associated with palpitations and dizziness, no association with a defined cardiovascular pathology has been demonstrated. Finally, romosozumab has been shown to have a possible cardiovascular signal, and therefore post-market surveillance of this therapy will be vital.

[How to prevent early postmenopausal fracture risk? Proposition of a strategy]. / Proposition d'une stratégie de prévention du risque fracturaire en début de ménopause.

Postmenopausal osteoporosis is a chronic disease, which justifies long-term treatment in those women with an increased risk of fracture. The current disponibility of various drugs, which have demonstrated their efficacy in reducing the incidence of fracture, has raised the question of the best treatment strategy in a woman who would begin her postmenopausal period with an increased risk for fracture. Indeed, for most treatments (with the exception of hormonal replacement therapy [HRT]), their efficacy in reducing the risk of fracture has been mainly demonstrated in higher risk elderly women (above 65 years) with prevalent vertebral fractures. There is uncertainty concerning their cost-effectiveness in younger women for a true primary prevention of the risk of fracture. Furthermore, current guidelines recommend a 5-year period of treatment which has led us to considering treatment strategies which would be based on various sequential treatment periods over time, the selection of each specific sequence being determined by the clinical situation of the woman, the level of her fracture risk and the expected skeletal (in terms of spectrum of bone effects) and potential extraskeletal benefits of drugs. In this regard, HRT or raloxifene, which allows a more global approach of the menopause-induced consequences of estrogen deficiency than the sole prevention of osteoporosis, should be privileged within the first 10 years of treatment or so in those youngest women at increased risk for subsequent fracture. Use of bisphosphonate or strontium ranelate should be thus reserved at a more advanced age, when the prevention of hip fracture becomes mandatory.

Bone mineral density at menopause does not predict breast cancer incidence.

UNLABELLED: In this prospective study in 2,137 perimenopausal and early postmenopausal women who were followed over a 13.1-year period of time, we observed no association between bone mineral density measured at the beginning of menopause and the subsequent risk of breast cancer. INTRODUCTION: This study aimed to investigate the relationship between BMD and the risk of breast cancer (BC) in young postmenopausal women. METHODS: As part of a clinical research program, 2,137 women who were perimenopausal or within their 5 first postmenopausal years were scanned between 1988-1990 and reviewed on average 13.1 years after their initial examination. Ninety-eight incident BC cases were recorded throughout the follow-up. RESULTS: Women with incident BC significantly differed from those who had never had BC with regard to age at menarche, age of birth of 1st child, familial history of BC and postmenopausal hormone therapy (PHT) use. There was no significant difference between the two groups for baseline DXA of the spine. There was a trend for BC cases for having lower femoral neck BMD compared to women without BC. However, women with low BMD were more likely to have taken PHT by the end of the study. In Cox multivariate analyses the relationship between BC risk and femoral neck BMD no longer existed. CONCLUSIONS: There was no relationship between BMD measured within the first postmenopausal years and the risk of BC, which makes unlikely the possibility of using BMD as a predictor factor for BC in early postmenopausal women.

Role of inflammatory cytokines in the effect of estradiol on atheroma.

1. Although hormonal therapy (HT) may increase the risk of coronary heart disease (CHD) and stroke in postmenopausal women, epidemiological studies (protection in premenopausal women) suggest and experimental studies (prevention of fatty streak development in animals) demonstrate a major atheroprotective action of estradiol (E2). The understanding of the deleterious and beneficial effects of oestrogens is thus required. 2. The immuno-inflammatory system plays a key role in the development of fatty streak deposit as well as in the rupture of the atherosclerotic plaque. Although E2 favours an anti-inflammatory effect in vitro (cultured cells), it rather elicits a pro-inflammatory response in vivo involving several subpopulations of the immuno-inflammatory system, which could contribute to plaque destabilization. The functional role of several cytokines was explored in hypercholesterolemic mice. The atheroprotective effect of E2 was fully maintained in mice deficient in interferon-g or interleukin-12, as well as IL-10. In contrast, the protective effect of estradiol was abolished and even reversed in hypercholesterolemic mice given a neutralizing anti-transforming growth factor-b (TGF-b) antibody. Endothelium is another important target for E2, since it not only potentiates endothelial nitric oxide and prostacyclin production, but also controls trafficking of the populations of the immuno-inflammatory system. 3. To conclude, the respective actions of oestrogens on the cell populations involved in the pathophysiology of atherothrombosis may be influenced, among others, by the timing of HT initiation, the status of the vessel wall and, as recently demonstrated the status of the TGF-b pathway.

Frailty, osteoporosis and hip fracture: causes, consequences and therapeutic perspectives.

OBJECTIVE: The aim of this review of the literature is to report the factors which both contribute to the frailty syndrome and increase hip fracture risk in the elderly. This work is the fruit of common reflection by geriatricians, endocrinologists, gynecologists and rheumatologists, and seeks to stress the importance of detection and management of the various components of frailty in elderly subjects who are followed and treated for osteoporosis. It also sets out to heighten awareness of the need for management of osteoporosis in the frail elderly. DESIGN: The current literature on frailty and its links with hip fracture was reviewed and discussed by the group. RESULTS: The factors and mechanisms which are common to both osteoporosis and frailty (falls, weight loss, sarcopenia, low physical activity, cognitive decline, depression, hormones such as testosterone, estrogens, insulin-like growth factor-I (IGF-I), growth hormone (GH), vitamin D and pro-inflammatory cytokines) were identified. The obstacles to access to diagnosis and treatment of osteoporosis in the frail elderly population and common therapeutic pathways for osteoporosis and frailty were discussed. CONCLUSION: Future research including frail subjects would improve our understanding of how management of frailty can can contribute to lower the incidence of fractures. In parallel, more systematic management of osteoporosis should reduce the risk of becoming frail in the elderly population.

[Postmenopausal osteoporosis: when is it necessary to perform laboratory testing? Which testing strategy?]. / Ostéoporose postménopausique: quand faut-il demander un bilan biologique? En quoi consiste-t-il?

Causes of secondary osteoporosis represent 10 to 20% of all postmenopausal osteoporosis causes. Accordingly, laboratory testing needs to be performed to exclude those conditions before any therapeutic strategy. It is particularly the case in women with a recent fragility fracture or in otherwise healthy women with unexplained low bone mineral density. While there is no consensus for a simple testing strategy, evaluation of serum and urine calcium, phosphate, creatinine with 25-hydroxyvitamin D and complete blood count including erythrocyte sedimentation rate and possibly protein electrophoresis and serum thyroid-stimulating hormone could be recommended.

Understanding the controversy about hormonal replacement therapy: insights from estrogen effects on experimental and clinical atherosclerosis.

Whereas hormonal replacement/menopause therapy (HRT) in post-menopausal women increases the coronary artery risk, epidemiological studies (protection in pre-menopaused women) suggest and experimental studies (prevention of the development of fatty streaks in animals) demonstrate a major atheroprotective action of estradiol (E2). The understanding of the deleterious and beneficial effects of estrogens is thus required. The immuno-inflammatory system plays a key role in the development of fatty streak deposit as well as in the atherosclerotic plaque rupture. Whereas E2 favors an anti-inflammatory effect in vitro (cultured cells), it rather elicits pro-inflammation in vivo, at the level of several subpopulations of the immuno-inflammatory system, which could contribute to plaque destabilization. Endothelium is another important target for E2, since it stimulates endothelial NO and prostacyclin production, thus promoting beneficial effects of vasorelaxation and platelet aggregation inhibition. Prostacyclin, but not NO, appears to be involved in the atheroprotective effect of E2. Estradiol accelerates also endothelial regrowth, thus favoring vascular healing. Finally, most of these effects of E2 are mediated by estrogen receptor alpha, and are independent of estrogen receptor beta. In summary, a better understanding of the mechanisms of estrogen action is required not only on the normal and atheromatous arteries, but also on innate and adaptive immune responses. This should help cardiovascular disease prevention optimization after menopause. These mouse models should help to screen existing and future Selective Estrogen Receptor Modulators (SERMs).

[Hormone replacement therapy in postmenopausal women: all the treatments are not the same]. / Traitement hormonal chez les femmes ménopausées: tous les traitements sont-ils équivalents?

Different estrogens combined with various progestins, administered are used in hormone therapy (HT) for postmenopausal women. All these compounds, which do not have the same chemical structure and the same pharmacokinetic behavior as the bio-identicals hormones, estradiol 17beta and progesterone, have intrinsic properties which can lead to tangible differences in therapeutic results. Recent biological and clinical data strongly suggest that the coronary and venous thromboembolic risk as well as the breast cancer risk attributed to HT use would not be the same according to the therapeutic scheme used. This article will briefly review the general principle of a true "hormone replacement therapy" and will discuss the recent data supporting the hypothesis that the cardiovascular and breast cancer risks might be lower with bio-identical hormones than with other therapeutic schemes.

Understanding the oestrogen action in experimental and clinical atherosclerosis.

Whereas hormone replacement/menopause therapy (HRT) in postmenopausal women increases the coronary artery risk, epidemiological studies (protection in premenopaused women) suggest and experimental studies (prevention of the development of fatty streaks in animals) demonstrate a major atheroprotective action of oestradiol (E2). The understanding of the deleterious and beneficial effects of oestrogens is thus required. The immuno-inflammatory system plays a key role in the development of fatty streak deposit as well as in the rupture of the atherosclerotic plaque. Whereas E2 favours an anti-inflammatory effect in vitro (cultured cells), it rather elicits in vivo a proinflammation at the level of several subpopulations of the immuno-inflammatory system, which could contribute to plaque destabilization. Endothelium is another important target for E2, as it potentiates endothelial NO and prostacyclin production, thus promoting the beneficial effects as vasorelaxation and inhibition of platelet aggregation. Prostacyclin, but not NO, appears to be involved in the atheroprotective effect of E2. E2 also accelerates endothelial regrowth, thus favouring vascular healing. Finally, most of these effects of E2 are mediated by oestrogen receptor alpha, and are independent of oestrogen receptor beta. In summary, a better understanding of the mechanisms of oestrogen action not only on the normal and atheromatous arteries, but also on innate and adaptive immune responses is required and should help to optimize the prevention of cardiovascular disease after menopause. These mouse models should help to screen existing and future selective oestrogen receptor modulators.

[Raloxifene in postmenopausal women]. / Indications du raloxifène chez la femme ménopausée.

Since the diffusion of the WHI's trial and MWS results, which reported a negative risk/benefit balance of hormone therapy, the management of postmenopausal women has deeply changed over the last 2-3 years. In particular, for the prevention of osteoporosis, the use of other efficient agents tends now to be more widely recommended rather than estrogens. The SERMs with raloxifene are new molecules that have estrogen agonist effects on bone and estrogen antagonist or neutral effects on endometrial and breast tissue. The efficacy of raloxifene to inhibit postmenopausal bone loss as well as to reduce the incidence of vertebral fractures has been demonstrated in women at high risk for osteoporosis through a large randomized placebo-controlled trial involving several thousands of postmenopausal women (MORE trial). Furthermore, the extraskeletal effects of raloxifene might represent an advantage for a global management approach of postmenopausal women, although to date, its exclusive indication is namely the prevention of osteoporosis. However, the estrogen antagonist effects of raloxifene on breast tissue as well as its good safety profile with regard to both the endometrium and the risk of heart diseases are likely to make raloxifene of particular interest for women around the age of 60 years old. Adverse events associated with raloxifene only included an increase in the absolute risk of venous thromboembolism in a comparable manner as with estrogen therapy. Also, its lack of efficacy in reducing hot flushes or preventing vaginal dryness may limit its use in young symptomatic postmenopausal women. Also, its lack of reimbursement in women with no prior fragility fracture must be taken into account.