Search

International audience; Premature ovarian insufficiency (POI) is a rare pathology affecting 1-2% of under-40 year-old women, 1 in 1000 under-30 year-olds and 1 in 10,000 under-20 year-olds. There are multiple etiologies, which can be classified as primary (chromosomal, genetic, auto-immune) and secondary or iatrogenic (surgical, or secondary to chemotherapy and/or radiotherapy). Despite important progress in genetics, more than 60% of cases of primary POI still have no identifiable etiology; these cases are known as idiopathic POI. POI is defined by the association of 1 clinical and 1 biological criterion: primary or secondary amenorrhea or spaniomenorrhea of>4 months with onset before 40 year of age, and elevated follicle-stimulating hormone (FSH)>25IU/L on 2 assays at>4 weeks' interval. Estradiol level is low, and anti-Müllerian hormone (AMH) levels have usually collapsed. Initial etiological work-up comprises auto-immune assessment, karyotype, FMR1 premutation screening and gene-panel study. If all of these are normal, the patient and parents may be offered genome-wide analysis under the "France Génomique" project. The term ovarian insufficiency suggests that the dysfunction is not necessarily definitive. In some cases, ovarian function may fluctuate, and spontaneous pregnancy is possible in around 6% of cases. In confirmed POI, hormone replacement therapy is to be recommended at least up to the physiological menopause age of 51 years. Management in a rare diseases center may be proposed.

International audience; Hormones were largely used for undescended testis (UDT) during the 1900s. However, in the early 2000s the Nordic consensus no longer recommended hormonal treatment and instead advocated surgery as first line management of UDT.1 Based on 3 meta-analyses of randomized trials, the Nordic group found that human chorionic gonadotropin and gonadotropin-releasing hormone (GnRH) provided poor results and were associated with frequent testis reascension to a suprascrotal position. Some studies also raised suspicion about possible side effects such as temporary inflammatory changes in the testes, germ cell apoptosis and reduction in the number of germ cells in adulthood, especially when the treatment was given in children 1 to 3 years old.2 The American Urological Association3 and the Canadian Urological Association4 did not recommend hormonal therapy. Most guidelines subsequently focused on the timing of surgery, recommending that it be performed before age 1 year as the best way to preserve fertility in these children, although there is no guarantee of normal fertility later in life.5 Thus, hormonal treatment has been ignored for more than 15 years and has been overlooked by pediatric urologists.

International audience; Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder with a characteristic behavioural phenotype. A multidisciplinary approach to care is required to prevent multiple medical complications in individuals affected by PWS. The aim of this study was to describe the rehabilitation, medical care, educational and social support provided to school-aged French PWS patients with varying neuropsychological profiles. Data were obtained from a French multicentre study that included patients aged 4-20 years with diverse genetic syndromes. Nineteen PWS subjects with a mean age of 9.2 years were included. The mean full-scale intellectual quotient (IQ) was 58 (Wechsler scale). There were frequent dissociations between verbal and performance IQ that were not associated with a specific profile. We also observed lower autonomy and communication scores (5.3 years and 5.9 years equivalent, respectively, Vineland scale), the absence of hyperactivity (Conners scale), and the presence of behavioural abnormalities (CBCL scale). Multidisciplinary medical supervision was generally coordinated by the paediatric endocrinologist and did not always include follow-up with all of the recommended specialists, in particular with a paediatric psychiatrist. Analysis of multidisciplinary rehabilitation conducted in public and private-sector establishment revealed failings in psychological support, occupational therapy and dietary follow-up. Regarding education, most children younger than 10 years were in normal schools, while older individuals were often cared for in medico-social institutions. In conclusion, children and adolescents with PWS generally received appropriate care. Though there have been considerable improvements in the management of children with PWS, reference centres should continue reinforcing the coordination of multidisciplinary supervision.

Evidence of the benefits of screening for breast cancer using mammography after the age of 50 is considered sufficient. Information on the determinants of compliance to the recommendations on mammography is needed to identify women to which public health messages should be specifically addressed and also to interpret results from epidemiological data in which some breast cancer cases are detected through screening programmes and others are not. The general characteristics and dietary data of French women participating in the E3N cohort study were analysed. Odds ratios of the frequency of non-compliance to recommendations on breast cancer screening were computed in women over and under the age of 50. Non-compliant women over 50 (i.e. never attenders) had a poorer access to physicians and poorer health with regard to specific risk factors even after adjustment for age and educational level. Women who were used to referring to gynaecologists early in life were better attenders later on. Logically, women under 50 who were over-screened, as compared to public health recommendations, had the opposite characteristics. Public health recommendations should be designed specifically according to targeted subgroups of women. Determinants of attendance for screening should be kept in mind in the interpretation of epidemiological studies in which some cases may be over-screened and others not.

International audience; The aim of this review is to examine the relationship between endocrine fluctuation and cognitive functioning. A plethora of in vitro and in vivo studies has demonstrated the neuroprotective role of estrogens and their impact on the neurotransmitter systems implicated in cognition. Recent hormonal replacement therapy (HRT) trials in non-demented post-menopausal women suggest a temporary positive effect (notably on verbal memory), and four recent meta-analyses converge to suggest a possible protective effect in relation to Alzheimer's disease (reducing risk by 29 to 44%). However, data from the only large randomised controlled trial published to date, the Women's Health Initiative Memory Study, did not confirm these observations and have even suggested an increase in dementia risk for women using HRT compared to controls. Several methodological differences between observation studies and controlled trials with regard to patient group, type, timing and duration of HRT, cognitive measures and analyses, are discussed to explain these discrepancies. The association between hormonal serum level and cognitive functioning remains controversial suggesting high inter-individual vulnerability in risk. Moreover, research on the impact of endocrine functioning on cognition during the female reproductive cycle suggests life-long fluctuations in vulnerability. Etiological models taking into account the interaction of clinical, reproductive, and menstrual events throughout life may provide a more valid approach in understanding the effects of steroids on the brain and in determining sub-groups at heightened risk. Cognitive disorders in the elderly are more likely be related to cumulated lifelong exposure to steroids, rather than to a specific exposure to a given steroid. Multifactorial models based on an exhaustive view of all hormonal events throughout reproductive life together with other risk factors (notably genetic risk factors related to estrogen receptor polymorphisms) should be explored to clarify the role of hormonal risk factors, or protective factors for cognitive dysfunction and dementia.

International audience; To describe the results of growth hormone (GH) therapy in adult GH-deficient patients treated in a tertiary referral center, with a focus on quality of life and adherence. Retrospective study of patients followed over a total period of 11 years. Quality of life (QOL) was assessed by the QOL-Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA) score and adherence to treatment was measured by a specific questionnaire. Clinical, biological, body composition and bone mineralization parameters were also analyzed. Data from 81 patients were analyzed. After a median treatment duration of 7 years, 2/3 of patients reported improved QOL (mean decrease of AGHDA score of 3.0 points, P

Women using menopausal hormone therapy (MHT) are at increased risk of developing breast cancer (BC). To detect genetic modifiers of the association between current use of MHT and BC risk, we conducted a meta-analysis of four genome-wide case-only studies followed by replication in 11 case–control studies. We used a case-only design to assess interactions between single-nucleotide polymorphisms (SNPs) and current MHT use on risk of overall and lobular BC. The discovery stage included 2920 cases (541 lobular) from four genome-wide association studies. The top 1391 SNPs showingPvalues for interaction (Pint) −3were selected for replication using pooled case–control data from 11 studies of the Breast Cancer Association Consortium, including 7689 cases (676 lobular) and 9266 controls. Fixed-effects meta-analysis was used to derive combinedPint. No SNP reached genome-wide significance in either the discovery or combined stage. We observed effect modification of current MHT use on overall BC risk by two SNPs on chr13 nearPOMP(combinedPint≤8.9×10−6), two SNPs inSLC25A21(combinedPint≤4.8×10−5), and three SNPs inPLCG2(combinedPint≤4.5×10−5). The association between lobular BC risk was potentially modified by one SNP inTMEFF2(combinedPint≤2.7×10−5), one SNP inCD80(combinedPint≤8.2×10−6), three SNPs on chr17 nearTMEM132E(combinedPint≤2.2×10−6), and two SNPs on chr18 nearSLC25A52(combinedPint≤4.6×10−5). In conclusion, polymorphisms in genes related to solute transportation in mitochondria, transmembrane signaling, and immune cell activation are potentially modifying BC risk associated with current use of MHT. These findings warrant replication in independent studies.

International audience; INTRODUCTION: Venous thromboembolism (VTE) is a common disease. The incidence rises markedly with increasing age; over the age of 75, the annual incidence reaches 1 per 100. BACKGROUND: Besides major risk factors (surgery, trauma and acute medical illness), four risk factors have to be taken into account in the management of VTE: increasing age, cancer, previous history of VTE and pregnancy. To date, with the exception of the antiphospholipid syndrome and antithrombin deficiency, "thrombophilias" do not appear to change the management of VTE. VIEWPOINTS: "Thrombophilias" are useful tools for understanding the pathophysiology of VTE. Therefore, further studies are needed to identify new biological anomalies and their impact on the risk of VTE. Recently, links between VTE and atherosclerosis have been demonstrated, leading to new concept of pan-vascular disease and prevention. CONCLUSIONS: VTE is a major public health problem. The knowledge of VTE risk factors is of major importance in identifying high-risk patients and in reducing the incidence and mortality of VTE.

International audience; BACKGROUND: The association between hormone treatment (HT) and mortality remains controversial. This study aimed to determine whether the risk of mortality associated with HT use varies depending on the specific characteristics of treatment and genetic variability in terms of the estrogen receptor. METHODOLOGY/PRINCIPAL FINDINGS: A prospective, population-based study of 5135 women aged 65 years and older who were recruited from three cities in France and followed over six years. Detailed information related to HT use was obtained and five estrogen receptor polymorphisms were genotyped. The total follow-up was 25,436 person-years and during this time 352 women died. Cancer (36.4%) and cardiovascular disease (19.3%) were the major causes of death. Cox proportional hazards models adjusted for age, education, centre, living situation, comorbidity, depression, physical and mental incapacities, indicated no significant association between HT and mortality, regardless of the type or duration of treatment, or the age at initiation. However, the association between HT and all-cause or cancer-related mortality varied across women, with significant interactions identified with three estrogen receptor polymorphisms (p-values = 0.004 to 0.03) in adjusted analyses. Women carrying the C allele of ESR1 rs2234693 had a decreased risk of all-cause mortality with HT (HR: 0.42, 95% CI: 0.18-0.97), while in stark contrast, those homozygous for the T allele had a significantly increased risk of cancer-related mortality (HR: 3.18, 95% CI: 1.23-8.20). The findings were similar for ESR1 rs9340799 and ESR2 rs1271572. CONCLUSIONS/SIGNIFICANCE: The risk of mortality was not associated with HT duration, type or age at initiation. It was however not equal across all women, with some women appearing genetically more vulnerable to the effects of HT in terms of their estrogen receptor genotype. These findings, if confirmed in another independent study, may help explain the differential susceptibility of women to the beneficial or adverse effects of HT.

International audience; PURPOSE: This prospective study evaluated the recurrence rate in 715 patients with differentiated thyroid cancer who had no evidence of persistent disease after total thyroidectomy and lymph node dissection in 94% of them followed up by radioiodine ablation (30-100 mCi) and assessed the predictive value of the initial thyroglobulin (Tg) levels for detecting recurrence, both during levothyroxine (LT4) treatment and after TSH stimulation. PATIENTS AND METHODS: Patients had Tg determinations performed at 3 months on LT4 treatment (Tg1) and at 9-12 months after stimulation by either thyroid hormone withdrawal or recombinant human TSH (Tg2); the Access kit was used (functional sensitivity of 0.11 ng/ml); they had undetectable anti-Tg antibodies. Patients were followed up annually. Predictive values were calculated by comparing Tg levels (Tg1 and Tg2) and the outcome in terms of recurrence. RESULTS: During the median follow-up of 6.2 yr, 32 patients had a recurrence. Assuming a cutoff level for Tg1 at 0.27 ng/ml, Tg1 sensitivity and specificity reached 72 and 86%, respectively, whereas predictive positive and negative values were 20 and 99%, respectively. With a cutoff level for Tg2 at 1.4 ng/ml, sensitivity and specificity reached 78 and 90%, respectively, whereas positive and negative predictive values were 26 and 99%, respectively. CONCLUSION: This large prospective cohort of patients presented a low rate of recurrence. Initial Tg measurements allow to predict long-term recurrence with an excellent specificity. Stimulated Tg determination presented a slightly higher sensitivity than Tg determination on LT4. TSH stimulation may be avoided when Tg measured 3 months after ablation is less than 0.27 ng/ml during LT4 treatment.

International audience; DEFINITION: Congenital hypopituitarism is characterized by multiple pituitary hormone deficiency, including somatotroph, thyrotroph, lactotroph, corticotroph or gonadotroph deficiencies, due to mutations of pituitary transcription factors involved in pituitary ontogenesis. INCIDENCE: Congenital hypopituitarism is rare compared with the high incidence of hypopituitarism induced by pituitary adenomas, transsphenoidal surgery or radiotherapy. The incidence of congenital hypopituitarism is estimated to be between 1:3000 and 1:4000 births. CLINICAL SIGNS: Clinical presentation is variable, depending on the type and severity of deficiencies and on the age at diagnosis. If untreated, main symptoms include short stature, cognitive alterations or delayed puberty. DIAGNOSIS: A diagnosis of combined pituitary hormone deficiency (CPHD) must be suspected when evident causes of hypopituitarism (sellar tumor, postsurgical or radioinduced hypopituitarism...) have been ruled out. Clinical, biological and radiological work-up is very important to better determine which transcription factor should be screened. Confirmation is provided by direct sequencing of the transcription factor genes. AETIOLOGY: Congenital hypopituitarism is due to mutations of several genes encoding pituitary transcription factors. Phenotype varies with the factor involved: PROP1 (somatolactotroph, thyrotroph, gonadotroph and sometimes corticotroph deficiencies; pituitary hyper and hypoplasia), POU1F1 (somatolactotroph and thyrotroph deficiencies, pituitary hypoplasia), HESX1 (variable pituitary deficiencies, septo-optic dysplasia), and less frequently LHX3 (somatolactotroph, thyrotroph and gonadotroph deficiencies, limited head and neck rotation) and LHX4 (variable pituitary deficiencies, ectopic neurohypophysis, cerebral abnormalities). MANAGEMENT: An appropriate replacement of hormone deficiencies is required. Strict follow-up is necessary because patients develop new deficiencies (for example late onset corticotroph deficiency in patients with PROP1 mutations). GENETIC COUNSELLING: Type of transmission varies with the factor and the mutation involved (recessive transmission for PROP1 and LHX3, dominant for LHX4, autosomal or recessive for POU1F1 and HESX1). PROGNOSIS: It is equivalent to patients without pituitary deficiencies if treatment is started immediately when diagnosis is confirmed, and if a specialized follow-up is performed.

International audience; OBJECTIVE: This review aimed to examine evidence for the role of hormonal changes in the onset and course of depressive symptomatology and to assess the possible future role of hormonal therapies in the treatment of depression. METHODS: A Medline and PsycINFO search of the literature published between 1965 and 2006 was made of studies of depressive symptoms and hormonal treatment in women at all stages of reproductive life. RESULTS: The cyclic fluctuation of gonadal steroids at menarche coincides with the beginning of gender-based differences in depression rates, which continue throughout reproductive life until menopause. Modifications in hormonal status, whether related to endogenous or exogenous exposure or to hormone deprivation, appear to be associated with affective disorder in a subgroup of women. For these women, a growing body of evidence indicates a biological pattern of vulnerability to mood disorders in response to hormonal fluctuations. This could have three major implications: that women vary in vulnerability to mood disorder when abrupt change in steroid levels occur, that these effects could be cumulative across the female life span, and that women do not arrive at menopause with equal risk of mood disorders or equal susceptibility to the effects of hormonal replacement therapy as has been assumed by current clinical research and practice. CONCLUSION: While hormonal therapies could have positive effects in the treatment and prevention of depressive disorders, further research is required to differentiate hormone-responsive subgroups of women for whom specific hormonal treatments may be most beneficial. To this end, we suggest that a multifactorial model of cumulative vulnerability, which takes into account hormonal exposure throughout life, genetic vulnerability, and environmental factors, may provide better prediction of treatment response.

International audience; OBJECTIVE: This review aimed to examine evidence for the role of hormonal changes in the onset and course of depressive symptomatology and to assess the possible future role of hormonal therapies in the treatment of depression. METHODS: A Medline and PsycINFO search of the literature published between 1965 and 2006 was made of studies of depressive symptoms and hormonal treatment in women at all stages of reproductive life. RESULTS: The cyclic fluctuation of gonadal steroids at menarche coincides with the beginning of gender-based differences in depression rates, which continue throughout reproductive life until menopause. Modifications in hormonal status, whether related to endogenous or exogenous exposure or to hormone deprivation, appear to be associated with affective disorder in a subgroup of women. For these women, a growing body of evidence indicates a biological pattern of vulnerability to mood disorders in response to hormonal fluctuations. This could have three major implications: that women vary in vulnerability to mood disorder when abrupt change in steroid levels occur, that these effects could be cumulative across the female life span, and that women do not arrive at menopause with equal risk of mood disorders or equal susceptibility to the effects of hormonal replacement therapy as has been assumed by current clinical research and practice. CONCLUSION: While hormonal therapies could have positive effects in the treatment and prevention of depressive disorders, further research is required to differentiate hormone-responsive subgroups of women for whom specific hormonal treatments may be most beneficial. To this end, we suggest that a multifactorial model of cumulative vulnerability, which takes into account hormonal exposure throughout life, genetic vulnerability, and environmental factors, may provide better prediction of treatment response.

International audience; OBJECTIVE: This review aimed to examine evidence for the role of hormonal changes in the onset and course of depressive symptomatology and to assess the possible future role of hormonal therapies in the treatment of depression. METHODS: A Medline and PsycINFO search of the literature published between 1965 and 2006 was made of studies of depressive symptoms and hormonal treatment in women at all stages of reproductive life. RESULTS: The cyclic fluctuation of gonadal steroids at menarche coincides with the beginning of gender-based differences in depression rates, which continue throughout reproductive life until menopause. Modifications in hormonal status, whether related to endogenous or exogenous exposure or to hormone deprivation, appear to be associated with affective disorder in a subgroup of women. For these women, a growing body of evidence indicates a biological pattern of vulnerability to mood disorders in response to hormonal fluctuations. This could have three major implications: that women vary in vulnerability to mood disorder when abrupt change in steroid levels occur, that these effects could be cumulative across the female life span, and that women do not arrive at menopause with equal risk of mood disorders or equal susceptibility to the effects of hormonal replacement therapy as has been assumed by current clinical research and practice. CONCLUSION: While hormonal therapies could have positive effects in the treatment and prevention of depressive disorders, further research is required to differentiate hormone-responsive subgroups of women for whom specific hormonal treatments may be most beneficial. To this end, we suggest that a multifactorial model of cumulative vulnerability, which takes into account hormonal exposure throughout life, genetic vulnerability, and environmental factors, may provide better prediction of treatment response.

Objectives To estimate the number of women aged 50–69 years treated by hormone therapy (HT) in France before Women's Health Initiative's (WHI) results and to evaluate the potential decrease of HT prescriptions since the publication of WHI clinical trial. Methods We used data from eight computerized databases of French cohort studies providing information on HT and constituted by women aged over 50 years living in metropolitan France. From these, we used direct standardization on the French population to estimate the prevalence of HT users across 5 years age groups. Data from the National Health Insurance Agency on two time-periods November 2002–January 2003 and November 2003–January 2004 were used to evaluate the evolution of HT prescriptions since WHI's publication among women aged 50–69 years living in the Rhone-Alpes region. Results The crude prevalence of HT users among women aged 50–69 years was 52.3% (51.8–52.8) and corresponds to a standardized prevalence of 35.7% (35.1–36.4), that is about 2.56 (2.51–2.59) million women. Standardized prevalence was the highest in 50–54 years age group then it decreased significantly across the older age groups ( p −6 ). HT reimbursements decreased significantly between the two studied time-periods in the Rhone-Alpes region ( p −6 ) from −14 to −45%, depending on the considered age groups (65–69 or 50–54 years). Conclusions Although WHI results have been criticized by French professional societies based on the fact that treatments used were different in France – mainly transdermal estrogens – and that French postmenopausal women were at lower vascular risk than those of the WHI, the release of this study had effect on the prescription before the French regulatory agency (AFSSAPS) edited limiting recommendations for HT prescription. Further efforts have to be made to collect systematically information on preventive treatments used at menopause followed by evaluation studies.

Objective: To assess postmenopausal breast cancer risk in relation to particular patterns of oral contraceptive (OC) use according to hormone replacement therapy (HRT) exposure. Methods: Time-dependent Cox regression models were used to analyse information on postmenopausal women from a large-scale French cohort. Among a total of 68,670 women born between 1925 and 1950, 1405 primary invasive postmenopausal breast cancer cases were identified from 1992 to 2000. Results: A non-significant decrease in risk of around 10% was associated with ever OC use as compared to never OC use in postmenopausal women. No significant interaction was found between OC and HRT use on postmenopausal breast cancer risk. Breast cancer risk decreased significantly with increasing time since first OC use (test for trend: p = 0.01); this was consistent after adjustment for duration of use or for time since last use. Conclusion: No increase in breast cancer risk was associated with previous OC exposure among postmenopausal women, probably because the induction window had closed. Some women may develop breast cancer soon after exposure to OCs, leading to a deficit of cases of older women. Further investigation is therefore required to identify young women at high risk.

Most epidemiological studies have shown an increase in breast cancer risk related to hormone replacement therapy (HRT) use. A recent large cohort study showed effects of similar magnitude for different types of progestogens and for different routes of administration of estrogens evaluated. Further investigation of these issues is of importance. We assessed the risk of breast cancer associated with HRT use in 54,548 postmenopausal women who had never taken any HRT 1 year before entering the E3N-EPIC cohort study (mean age at inclusion: 52.8 years); 948 primary invasive breast cancers were diagnosed during follow-up (mean duration: 5.8 years). Data were analyzed using multivariate Cox proportional hazards models. In this cohort where the mean duration of HRT use was 2.8 years, an increased risk in HRT users compared to nonusers was found (relative risk (RR) 1.2 [95% confidence interval 1.1–1.4]). The RR was 1.1 [0.8 –1.6] for estrogens used alone and 1.3 [1.1–1.5] when used in combination with oral progestogens. The risk was significantly greater (p

Many studies have analysed the relation between hormone replacement therapy use and breast cancer risk. We performed a synthesis of their results based on a meta-analysis published in 1997, on fifteen observational studies published afterwards, and on a recent randomised trial. The accumulated evidence shows a higher risk of breast cancer among HRT ever users compared to non users. The risk increases with treatment duration and disappears a few years after the end of the treatment. Furthermore, recent observational studies showed that this risk may be higher when progestational agents are added to estrogens than when estrogens are used alone. This may be important in terms of public health since combination therapy with estrogen and progestational agents have become the standard of care among women with an intact uterus and are now commonly used. The effects of the treatments used in France, that are not those widely studied until now, must be evaluated, ideally through a randomized trial.

International audience; Deep vein thrombosis is a frequent disease with an annual incidence reaching 5 per thousand among subjects over 75 years. Major acquired risk factors for venous thrombosis include surgery, neoplasm, reduced mobility or paresis, and a previous episode of deep vein thrombosis. Among women, hormonal status (pregnancy, oral contraceptive, hormone replacement therapy) is responsible for the majority of all venous thrombotic events. The impact of other factors is controversial: obesity, tobacco use and varicose veins. Venous thrombosis is a multifactorial disease and analysis of the interactions between acquired and inherited risk factors is an extremely interesting field of investigation.

International audience; OBJECTIVES: Many epidemiological studies have analysed the relation between hormonal replacement therapy and risk of breast cancer. We present here a synthesis of the available results. MATERIAL AND METHODS: In 1997, a meta-analysis synthesised 90% of the data available at the time, obtained from 15 cohort and 36 case-control studies. This meta-analysis collected 53,000 breast cancers, 22% of these breast cancers having been observed in cohort studies. Since the publication of this meta-analysis, six studies totalling 8,000 cases (32% from cohort studies) have been published: two of these studies were partially included in the meta-analysis and the other four provided entirely new data. RESULTS: The conclusion, based on the available evidence, is that the risk of breast cancer diagnosis is higher among women who have used hormonal replacement therapy than among women who have not. The risk increases with treatment duration, is reduced when treatment is stopped and disappears almost completely a few years (5 in the meta-analysis) after the end of the treatment. The increase in the risk of breast cancer may be larger with estrogen-progestogen therapy than with estrogen alone. What are the consequences in terms of public health? From the results of the meta-analysis, one can estimate that the use of replacement therapy for 10 years between age 50 and 60 by 1,000 women will lead to the diagnosis of 6 extra breast cancers. This corresponds to the observation of 69 cases per 1,000 treated women after 20 years follow-up, as compared to the 63 cases expected among 1,000 untreated women. DISCUSSION: These results require confirmation. The observed increase in the risk of breast cancer is open to biases, particularly to a screening bias if women receiving hormonal replacement therapy have a more intensive surveillance than other women. Overall, the total number of women, across studies, who have received estrogen-progestogen therapy is small and their treatment was usually a combination of natural estrogens and medroxy progesterone acetate; therefore, the long term consequences of the treatments commonly used in France (synthetic estrogens and a variety of progestogens) have not been evaluated, this evaluation is much needed. CONCLUSION: What is needed is a global view of the risks and benefits of hormonal replacement therapy, and more epidemiologic data are required to reach this goal. In the present state of knowledge, the moderate excess risk of breast cancer observed does not justify a change in medical practice, neither in the selection of women to whom hormonal replacement therapy should be offered nor in the duration of their treatment.