Menopause hormone treatment after cancer.

Regular improvement in survival of women after treatment for cancer has been reached in these last years. Menopause hormone therapy (MHT) remains the most efficient treatment to alleviate climacteric symptoms and improve quality of life in symptomatic women. The long-term effects of estrogen deficiency can be, at least partially, prevented by MHT. However, using MHT in an oncologic context can be associated with contraindications. Patients who have experienced breast cancer frequently face severe climacteric symptoms, but results from randomized trials are not in favor of using MHT in these women. Three randomized trials are available in women treated by MHT after ovarian cancer, and report better survival rates in the active group of treatment, suggesting that, at least in serous high-grade ovarian carcinoma, MHT could be allowed. No robust data are available for MHT after endometrial carcinoma. According to various guidelines, MHT could be possible in low grades with good prognosis. Progestogen, however, is not contraindicated and can help to alleviate climacteric symptoms. Squamous cell cervical carcinoma is not hormone-dependent and therefore patients can be treated with MHT without restrictions, whereas cervical adenocarcinoma is likely to be estrogen-dependent, despite lack of robust data, and thus only progesterone or progestin might be potentially used. It is possible that, in future, better molecular characterization of genomic profiles of various cancers may allow MHT to be used with some patients.

Lack of evidence that progesterone in ovulatory cycles causes breast cancer.

A recent Perspective article asserted that progesterone secretion during ovulatory cycles is the cause of breast cancer. However, we challenge most of the evidence developed in this publication. First, there is a lack of evidence that progesterone is mutagenic for breast cells. Cause of a cancer should mean initiation by mutation, as opposed to promotion. Second, subclinical ovulatory disturbances occur rather frequently in normal-length menstrual cycles. Third, the authors attribute a potential carcinogenic effect to progesterone secreted during menstrual cycles but not to progesterone during pregnancy. They did not discuss breast cancer evidence from progesterone/progestin therapeutics. They argue that in genetic primary amenorrhea, a hypothetic lower risk of breast cancer could be due to the lack of progesterone, despite the progesterone/progestin in hormone replacements these women receive. Fourth, they advocate a regulatory effect of progesterone on several genes potentially involved in cancer genesis. In particular, they attribute a lower risk of breast cancer in women with Mayer-Rokitansky-Küster-Hauser syndrome to a defect in the progesterone-stimulated Wnt4 gene. However, this defect is only present in a small subset. Thus, the postulated progesterone breast cancer risk is unconvincing, which we discuss point by point in this commentary.

Menopausal symptoms in epithelial ovarian cancer survivors: a GINECO VIVROVAIRE2 study.

OBJECTIVE: We have previously shown that epithelial ovarian cancer (EOC) and its treatments have negative effects on long-term quality of life (QoL) and fatigue. The present multicenter study investigated the main menopausal symptoms and gynecological management of EOC survivors (EOCS). METHODS: 166 patients with relapse-free ≥3 years after the end of treatment attended a consultation with a gynecologist, including a questionnaire related to vasomotor symptoms (VMS) and sexuality, a clinical examination, a blood sample and an osteodensitometry. QoL, fatigue, insomnia and mood disorders were measured with validated questionnaires and correlated to VMS. VMS and QoL were assessed according to natural menopause (NM) or surgical menopause (SM). RESULTS: Mean age at the survey was 62 [21-83] years and stage III/IV (48%). Mean delay since the end of treatment was 6 years. Fifty-nine patients (36%) had SM. Half of patients reported VMS. Seventy-two percent of EOCS with SM had VMS compared to 41% with NM (P < .001). VMS were not associated with poor global QoL, fatigue, insomnia or mood disorders. Two-thirds of EOCS reported a decrease in libido. Patients with SM showed a greater decrease in libido than NM (P < .02). Fourteen percent of them had osteoporosis and 50% osteopenia. Among the 85 patients with VMS, 80 did not receive HRT after cancer treatment. At the time of the survey, only 7 (4%) patients were receiving hormone replacement therapy (HRT). CONCLUSIONS: VMS and sexual disorders are frequently reported by EOCS, particularly among patients with SM. Most EOCS with menopausal symptoms could benefit from HRT to improve these symptoms.

Systemic lupus erythematosus and menopause.

Estrogen has been known for a long time to be a trigger on auto-immunity and may influence the course of lupus. Women experiencing systemic lupus are at high risk for premature ovarian insufficiency if using cyclophosphamide, of osteoporosis, arterial ischemic diseases and venous thrombosis at young age. In about 30% of them, an antiphospholipid/anticoagulant antibody can occur which is associated with very high risk of thrombosis. However, the severity of the disease may vary and some women with lupus could benefit from a menopausal hormone therapy (MHT). As a consequence, management of menopause symptoms needs to evaluate carefully the condition of the patient, her lupus history and cardiovascular risk. We will describe the effect of lupus on menopause, of menopause on lupus and report in detail the literature available on MHT and the risk of lupus or the risk of flares in women with lupus. Some other options than MHT for the management of climacteric symptoms will be discussed.

Long-term fatigue and quality of life among epithelial ovarian cancer survivors: a GINECO case/control VIVROVAIRE I study.

BACKGROUND: Few data are available on long-term fatigue (LTF) and quality of life (QoL) among epithelial ovarian cancer survivors (EOCS). In this case-control study, we compared LTF, symptoms and several QoL domains in EOCS relapse-free ≥3 years after first-line treatment and age-matched healthy women. PATIENTS AND METHODS: EOCS were recruited from 25 cooperative GINECO centers in France. Controls were randomly selected from the electoral rolls. All participants completed validated self-reported questionnaires: fatigue (FACIT-F), QoL (FACT-G/O), neurotoxicity (FACT-Ntx), anxiety/depression (HADS), sleep disturbance (ISI), and physical activity (IPAQ). Severe LTF (SLTF) was defined as a FACIT-F score <37/52. Univariate and multivariate logistic regressions were conducted to analyze SLTF and its influencing factors in EOCS. RESULTS: A total of 318 EOCS and 318 controls were included. EOCS were 63-year-old on average, with FIGO stage I/II (50%), III/IV (48%); 99% had received platinum and taxane chemotherapy, with an average 6-year follow-up. There were no differences between the two groups in socio-demographic characteristics and global QoL. EOCS had poorer FACIT-F scores (40 versus 45, P < 0.0001), lower functional well-being scores (18 versus 20, P = 0.0002), poorer FACT-O scores (31 versus 34 P < 0.0001), and poorer FACT-Ntx scores (35 versus 39, P < 0.0001). They also reported more SLTF (26% versus 13%, P = 0.0004), poorer sleep quality (63% versus 47%, P = 0.0003), and more depression (22% versus 13%, P = 0.01). Fewer than 20% of EOCS and controls exercised regularly. In multivariate analyses, EOCS with high levels of depression, neurotoxicity, and sleep disturbance had an increased risk of developing SLTF (P < 0.01). CONCLUSION: Compared with controls, EOCS presented similar QoL but persistent LTF, EOC-related symptoms, neurotoxicity, depression, and sleep disturbance. Depression, neuropathy, and sleep disturbance are the main conditions associated with severe LTF.

Progesterone, progestins and the endometrium in perimenopause and in menopausal hormone therapy.

It is well established that unopposed estrogen for hormone therapy in postmenopausal women (MHT) induces a dose-related stimulation of the endometrium associated with an increased risk of hyperplasia and endometrial cancer. Progesterone acts physiologically to counteract the proliferative effects of estradiol during the menstrual cycle. In MHT, progestogens protect the endometrium against the proliferative effects of estrogens in women with a uterus. Recent data suggest that, whereas micronized progesterone is apparently safer for the breast, it could be less efficient than synthetic progestin on the endometrium. An update on progestogen and endometrial safety in MHT is the subject of this review.

Progesterone, progestins and the breast in menopause treatment.

Breast cancer is the main risk associated with menopause hormone therapy (MHT). It is a hormone-dependent cancer. In postmenopausal women, about 80% of cases are estradiol receptor-positive. In cohort studies only estradiol receptor-positive breast cancers are promoted by MHT. Different levels of risk with estrogen-only treatment and combined treatment with estrogen + progestin are shown in randomized trials and observational studies. Several non-randomized studies show a lower risk with progesterone and retroprogesterone than with synthetic progestins. Progesterone and progestin are non-selective ligands for the progesterone receptor and bind also with other steroid receptors, with agonistic or antagonistic effects according to the structure of the molecule. Their half-life and metabolism are also different, progesterone being rapidly degraded with a short half-life. These aspects will be discussed in this review.

Migraine, hormones and the menopausal transition.

Migraine is a common, disabling and incapacitating headache disorder that may be triggered by many factors, such as hormones especially during the perimenopausal period, where large alterations in estradiol levels can occur. The evidence implies that hormonal fluctuations are one of the important triggers of migraine. During reproductive life and during hormonal contraception, the course of migraine can be impacted. Different types of migraine with and without aura can be variously influenced by hormones. Migraine can constitute a risk factor for stroke and this must be taken in account for menopause hormone therapy. Hormone therapy is a possible approach to prevent migraine that happens during the menopause transition. Scarce data on the various regimens and types of hormone therapy are available. Transdermal estradiol displays a more favorable profile on migraine than oral estrogens because it may provide more constant levels of estrogens.

Hereditary angioedema with normal C1 inhibitor and factor XII mutation: a series of 57 patients from the French National Center of Reference for Angioedema.

Hereditary angioedema (HAE) is a rare disease associated with either a quantitative or qualitative deficiency in C1-inhibitor (C1-INH) or normal C1-INH. HAE with normal C1-INH is associated in 20% of cases with mutations in the gene for factor XII (FXII) or FXII-HAE. A recent review described 41 families, including 14 German and 15 Spanish families. We have constructed a register of French patients and their characteristics. A national survey was launched through the French National Center of Reference for Angioedema (CREAK) to study the clinical, biological and therapeutic characteristics of patients with HAE linked to a mutation of FXII gene. Fifty-seven patients were identified from 24 different families. In most cases they were young women (mean age at diagnosis: 31 years, mean age at first symptom: 21 years, female/male ratio: 76%). Twenty-one per cent of the patients experienced angioedema attacks only during pregnancy or when on oestrogen contraception. Sixty-three per cent had attacks at all times, but they were more severe during these same periods. Male carriers of the mutation were more frequently asymptomatic than females (P = 0·003). C1-INH concentrate and icatibant were both effective for treating attacks. The prophylactic use of tranexamic acid led to a 64% decrease in the number of attacks. This is one of the largest series reported of HAE patients with FXII mutation. The therapeutic management appeared to be identical to that of HAE with C1-INH deficiency.

Chronic urticaria and hormones: Is there a link?

BACKGROUND: While the role of oestrogens in bradykinin angioedema (AE) has been clearly demonstrated, scarce data are available about the role of sex hormones in chronic urticaria (CU). OBJECTIVES: To gather information from a population of women with various forms of CU [chronic spontaneous urticaria (CSU), including a subtype of isolated histaminic AE and a classic subtype of association of wheals and AE, and exclusive inducible urticaria (IU)] about the impact of sex hormones and reproductive factors on their symptoms. METHODS: This was a cross-sectional study comprising interviews of 200 women consulting for CU at nine centres throughout France between May and July 2013. The dermatologists filled in an online questionnaire on the impact of reproductive factors (puberty, contraception and pregnancy) and hormonal treatments on the course of CU, including CSU and IU, in the presence of the women. RESULTS: Most of the women did not experience CU before puberty and if so, puberty did not influence the course of CU. Only 16 women had experienced a pregnancy during CU which caused a worsening of symptoms in four. Hormonal contraception was associated with aggravation in a minority of women, mostly women with CSU (10%). Women with isolated histaminic AE did not exhibit any female sex hormone dependency. CONCLUSIONS: It would appear that sex hormones act as a trigger in only a small subset of women with CU. Nevertheless, this should be taken into account to improve patient management.

Chikungunya virus and West Nile virus infections imported into Belgium, 2007-2012.

Arboviral infections are emerging among tourists travelling to (sub)tropical regions. This study aims to describe the importation of chikungunya virus (CHIKV) and West Nile virus (WNV) into Belgium over a 6-year period from 2007 to 2012. Clinical samples were obtained from travellers presenting at the outpatient clinic of the Institute of Tropical Medicine (ITM), Antwerp, Belgium or submitted to the Central Laboratory for Clinical Biology of the ITM. Testing was performed by serology and/or by real-time reverse transcriptase-polymerase chain reaction. A total of 1288 returning travellers were investigated for CHIKV infection resulting in 34 confirmed and two probable diagnoses (2·80%). Out of 899 patients, four confirmed and one probable imported WNV infections were diagnosed (0·55%). No locally acquired cases have been registered in Belgium until now and the geographical origin of the imported infections reflects the global locations where the viruses are circulating.

A Commentary on a recent update of the ovarian cancer risk attributable to menopausal hormone therapy.

The incidence of ovarian cancer is tenfold lower than that of breast cancer. The goal of the recently published meta-analysis by Beral and colleagues, using 'individual participant datasets from 52 epidemiological studies', was to provide an updated assessment of the effect of menopausal hormone therapy (MHT) on ovarian cancer risk. The relative risk generated from the cited prospective studies was significantly increased but the relative risk from the retrospective studies was not. This is quite unusual since retrospective studies usually display higher levels of relative risk. No further increase was observed with increasing duration. Moreover, a number of the studies could not be adjusted for important ovarian cancer risk factors. From the meta-analysis, it can be calculated that the absolute excess risk of 5 years of MHT for a 50-year-old UK woman is 1 in 10 000 per year, indicating a very low risk. We conclude that this meta-analysis mostly reflects the previously published data from the Million Women Study, from which the majority of this new publication is derived.

Tranexamic acid as maintenance treatment for non-histaminergic angioedema: analysis of efficacy and safety in 37 patients.

Angioedema (AE) is a clinical syndrome characterized by localised swelling lasting several hours. The swelling is often recurring and can be lethal if it is located in the laryngeal region. Much progress has been made recently in the treatment of acute episodes, but no consensus has been reached on maintenance treatment. We have performed a national retrospective observational study to assess the use of tranexamic acid (TA) as maintenance treatment for non-histaminergic AE [hereditary AE (HAE) or idiopathic non-histaminergic AE]. Records for 64 cases were collected from 1 October 2012 to 31 August 2013; 37 of these were included (12 HAE with C1-inhibitor deficiency, six with HAE with normal C1-inhibitor and 19 idiopathic non-histaminergic AE). When treated with TA over six months, the number of attacks was reduced by 75% in 17 patients, 10 patients showed a lower level of reduction and 10 had the same number of attacks. In no instances were symptoms increased. No thromboembolic events were observed, and the main side effects were digestive in nature. Thus, TA, which is well tolerated and inexpensive, appears to be an effective maintenance treatment for some patients with HAE or idiopathic non-histaminergic AE.

Prevention of diseases after menopause.

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 woman's 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 Women's 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.

Benefits of progestin contraception in non-allergic angioedema.

BACKGROUND: Hereditary angioedema attacks can be induced or worsened by oral contraceptive containing oestrogens. OBJECTIVES: The purpose of this study was to assess the impact of progestin contraceptives on angioedema attacks. METHODS: We conducted a French retrospective, multi-centre study of progestin contraception in women with non-allergic angioedema, including hereditary angioedema type I, II and III and idiopathic angioedema. Patients were classified into four groups according to frequency of attacks. We evaluated the effects of progestin on the mean number of attacks and compared the number of patients in each group before and under progestin contraception. The influence of hormonal factors on the course of angioedema was also assessed. RESULTS: Fifty-five women were included: mean age was 32.1 years (16-52) and mean follow-up 32.4 months (SD:29). Fourteen women were classified as type I (25.4%), two as type II (3.6%) and 19 as type III (34%) and 20 were idiopathic (36%). Seventeen patients were taking a low dose progestin-only pill (POP), 24 antigonadotropic progestins (AGP) and 14 both successively. Total or partial improvement was observed in 81.8% (45/55) of the patients and more frequently in those on an AGP agent (34 patients, 89.5%) than on POP (19 patients, 61.3%) (P = 0.013). CONCLUSIONS & CLINICAL RELEVANCE: This is the first study evaluating the interest of antigonadotropic progestin contraception in a series of women with non-allergic angioedema. Progestins, especially antigonadotropic progestins, appear to convey a marked benefit in most cases. Antigonadotropic progestins could thus be recommended as adjuvant treatment in childbearing women with non-allergic angioedema.

Oncology in midlife and beyond.

The onset of the menopause is often a time when women's concerns can act as a powerful trigger to encourage healthy modifications in lifestyle which will maintain, or improve, their general health. This document aims to help women to understand their potential risks, to encourage them to find proactive preventive strategies by modifying some of their attitudes, and to use health resources (when available) to be screened. Cancer is an important cause of death but not the primary cause of mortality. Cardio/circulatory diseases represent 35-40% of causes of death in most developed countries and 20-25% of women will die from cancers in Western Europe, Australasia, high-income North America, high-income Asia Pacific, East Asia and Southern Latin America. Breast cancer, lung cancer and colorectal cancer are prevalent in most regions of the world. Cervical cancer remains a hallmark of low access to health care. Preventive strategies (decreasing smoking and alcohol consumption, losing weight, eating a healthy diet and undertaking physical activity) and implementation of screening could help to significantly decrease the incidence of and mortality from cancer. The mortality/incidence ratio is higher in developing countries compared to high-income regions as well as in subgroups of populations in developed countries with lower socioeconomic levels. Implementation of better diagnostic methods and management of cancer according to the local resources will help to decrease the mortality rate in developing countries, and effort has to be made to decrease social inequities and improve access to health care for low-income groups. In conclusion, cancer incidence is increasing as a consequence of longer life expectancy all over the world. National health programs are mandatory to implement screening and to improve individual management. Finally, educating women so that they are aware of ways to improve their general health, to minimize their own risk factors and to identify signs of change in their own health which may be markers of impending cancer will help to reduce the burden of disease and improve the prognosis for tumors detected at an earlier stage.

Heat-shock protein 70 gene sequencing for Leishmania species typing in European tropical infectious disease clinics.

We describe Leishmania species determination on clinical samples on the basis of partial sequencing of the heat-shock protein 70 gene (hsp70), without the need for parasite isolation. The method is especially suited for use in non-endemic infectious disease clinics dealing with relatively few cases on an annual basis, for which no fast high throughput diagnostic tests are needed. We show that the results obtained from this gene are in nearly perfect agreement with those from multilocus enzyme electrophoresis, which is still considered by many clinicians and the World Health Organization (WHO) as the gold standard in Leishmania species typing. Currently, 203 sequences are available that cover the entire hsp70 gene region analysed here, originating from a total of 41 leishmaniasis endemic countries, and representing 15 species and sub-species causing human disease. We also provide a detailed laboratory protocol that includes a step-by-step procedure of the typing methodology, to facilitate implementation in diagnostic laboratories.

Micronized progesterone and its impact on the endometrium and breast vs. progestogens.

It is well established that progestogens protect the endometrium against the proliferative effects of estrogens in postmenopausal women receiving hormone replacement therapy (HRT). Therefore, micronized progesterone and progestogens are recommended as part of combined HRT in women with an intact uterus. The protective effect of progestogens against hyperplasia and endometrial cancer does not appear to differ with different progestogens (micronized progesterone or progestogens), but appears to be affected by the regimen and thus the dose, with continuous combined treatment conferring better protection. However, the protective effect of progestogens seen in the endometrium is not replicated in the breast. Progestogens combined with estrogens are generally associated with a small increase in the risk of invasive breast cancer, which is believed to be due to a promoter effect. However, all progestogens are not equivalent in their effects on the breast and breast cancer risk. Micronized progesterone does not increase cell proliferation in breast tissue in postmenopausal women compared with synthetic medroxyprogesterone acetate (MPA). Experimental evidence suggests that the opposing effects of MPA and micronized progesterone on breast tissue are related to the non-specific effects of MPA, including glucocorticoid activity and differences in the regulation of gene expression. Therefore, for women with an intact uterus, micronized progesterone may be the optimal choice as part of combined HRT.

Hormone therapy and breast cancer risk 10 years after the WHI.

Ten years after the publication of the first Women's Health Initiative (WHI) report, a substantial decrease in hormone replacement therapy (HRT) has been observed world-wide. Fear of developing breast cancer represents one of the reasons for an important shift toward alternatives for treatment of menopause symptoms or abstention from therapy altogether. Many publications in the scientific and lay press have emphasized the magnitude of the relative risk of breast cancer but have not focused on excess or attributable risk. Since the original report of the WHI study, new information has been published on risk factors for breast cancer related to hormone therapy use. Accordingly, we believe it important to review current data and examine excess rather than relative or absolute risk. A balanced perspective on excess risk determined from existing data suggests that the benefits of HRT for quality of life can outweigh the risks in management of a large number of postmenopausal women. In addition, alternative strategies for relief of menopausal symptoms are not as effective as HRT in treating the climacteric symptoms.

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

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.