Hereditary Angioedema with and Without C1-Inhibitor Deficiency in Postmenopausal Women.

PURPOSE: Most types of hereditary angioedema (HAE) are worsened by endogenous or exogenous estrogens. Conversely, androgens can improve HAE with abnormal C1-Inhibitor (C1-INH) by increasing C1-INH concentrations. Menopause is associated with an extinction of ovarian estrogenic and androgenic secretion. There is currently insufficient information on postmenopausal women with HAE. The objective of this study was to describe the activity of HAE in postmenopausal women. METHODS: This was a French retrospective, multicenter study in postmenopausal women with HAE with or without C1-INH deficiency/dysfunction. The patients were classified before and after menopause with a previously validated HAE disease severity score. RESULTS: We included 65 women from 13 centers in France. The mean age was 62.7± 9.2 years, and the mean time between menopause and inclusion was 12.5± 9.1 years. HAE was associated with C1-INH deficiencyin 88% (n = 57) of the patients, a mutation of factor 12 in 8% (n = 5), a mutation in plasminogen gene in one, and unknown HAE for two. The HAE course was not different after menopause in 46.1% (n = 30), improved in 38.5% (n = 25), and worsened in 15.4% (n = 10). Improvement was correlated with estrogen sensitivity of angioedema before menopause (p = 0.06 for improvement vs no effect or worsening). In addition, we observed that only ten women received treatment (transdermal or oral estradiol+ progestogen) for their menopause symptoms. Among them, only 3 experienced worsening of symptoms (2 on transdermal and 1 on oral estradiol). CONCLUSION: Following menopause, most women with HAE remain stable but some worsen. Improvement was mainly observed in patients with previous estrogen sensitivity. More research is required in menopausal women with HAE to better understand how to manage climacteric symptoms.

Micronized progesterone, progestins, and menopause hormone therapy.

Treatment with estrogens alone in women without a uterus or in combination with progestins (PG) in women with a uterus is the most effective treatment for vasomotor symptoms in the peri or postmenopausal period. However, PGs differ by their biological activities, and it is likely that not all PGs will display a class effect. The type of PG is important regarding tolerance and cardiovascular and breast cancer risk. Some studies indicate that micronized progesterone (P) is safer than synthetic PGs with an acceptable metabolic profile. For that purpose, we conducted a narrative review on the balance between benefit/risk using P versus PGs in menopause hormone therapy (MHT) to aid clinician to choose the best regimens, specifically the PG component of hormone therapy, for women with bothersome menopausal symptoms and with a uterus.

Contraception in cancer survivors - an expert review Part I. Breast and gynaecological cancers.

Objective: The efficacy of treatment for many cancers has increased dramatically in recent decades and there are a growing number of cancer survivors who need effective contraception. In this paper, a group of experts from the European Society of Contraception set out to define the most frequent cancers in women and summarise the guidelines, reviews and studies that provide information and guidance on contraception for each cancer. Methods: Epidemiological studies were analysed to determine the frequency of cancers in women of reproductive age. A narrative review was performed for each cancer, collecting data about the treatment of the disease, its impact on fertility, and the efficacy, health risks, possible benefits and contraindications of the contraceptive methods available. The recommendations were then summarised. Results: Owing to a large amount of information, the results are presented in two parts. Part 1 includes contraception after breast and gynaecological cancers. Part 2 summarises the findings and recommendations regarding contraception in women with skin, gastrointestinal, haematological and endocrine cancers.

Contraception in cancer survivors - an expert review Part II. Skin, gastrointestinal, haematological and endocrine cancers.

Objective: The efficacy of treatment for many cancers has increased dramatically in recent decades and there is a growing number of cancer survivors who need effective contraception. In this paper, a group of experts from the European Society of Contraception set out to define the most frequent cancers in women and summarise the guidelines, reviews and studies that provide information and guidance on contraception for each cancer. Methods: Epidemiological studies were analysed to determine the frequency of cancers in women of reproductive age. A narrative review was performed for each cancer, collecting data about the treatment of the disease, its impact on fertility, and the efficacy, health risks, possible benefits and contraindications of the contraceptive methods available. The recommendations were then summarised. Results: Owing to the large amount of information the results are presented in two parts. Part 1 includes contraception after breast and gynaecological cancers. Part 2 summarises the findings and recommendations regarding contraception in women with skin, gastrointestinal, haematological and endocrine cancers.

Specialist Advice Support for Management of Severe Hereditary Angioedema Attacks: A Multicenter Cluster-Randomized Controlled Trial.

STUDY OBJECTIVE: Hereditary angioedema is a rare disease associated with unpredictable, recurrent attacks of potentially life-threatening edema. Management of severe attacks is currently suboptimal because emergency medical teams are often unaware of new specific treatments. The objective of this trial is to test whether a dedicated national telephone care-management strategy would reduce resource use during severe hereditary angioedema attacks. METHODS: We conducted a cluster-randomized multicenter prospective trial of patients with a documented diagnosis of hereditary angioedema (type I, II or FXII hereditary angioedema). Participants were enrolled between March 2013 and June 2014 at 8 participating reference centers. The randomized units were the reference centers (clusters). Patients in the intervention arm were given a national free telephone number to call in the event of a severe attack. Emergency physicians in the SOS-hereditary angiœdema (SOS-HAE) call center were trained to advise or prescribe specific treatments. The primary outcome was number of admissions for angioedema attacks. Economic evaluation was also performed. RESULTS: We included 100 patients in the SOS-HAE group and 100 in the control group. During the 2 years, there were 2,368 hereditary angioedema attacks among 169 patients (85%). Mean number of hospital admissions per patient in the 2-year period was significantly greater in the usual-practice group (mean 0.16 [range 0 to 2] versus 0.03 [range 0 to 1]); patient risk difference was significant: -0.13 (95% confidence interval -0.22 to -0.04; P=.02). Probabilistic sensitivity graphic analysis indicated a trend toward increased quality-adjusted life-years in the SOS-HAE group. CONCLUSION: A national dedicated call center for management of severe hereditary angioedema attacks is associated with a decrease in hospital admissions and may be cost-effective if facilities and staff are available to deliver the intervention alongside existing services.

Pain management in the Ehlers-Danlos syndromes.

Chronic pain in the Ehlers-Danlos syndromes (EDS) is common and may be severe. According to one study, nearly 90% of patients report some form of chronic pain. Pain, which is often one of the first symptoms to occur, may be widespread or localized to one region such as an arm or a leg. Studies on treatment modalities are few and insufficient to guide management. The following is a discussion of the evidence regarding the underlying mechanisms of pain in EDS. The causes of pain in this condition are multifactorial and include joint subluxations and dislocations, previous surgery, muscle weakness, proprioceptive disorders, and vertebral instability. Affected persons may also present with generalized body pain, fatigue, headaches, gastrointestinal pain, temporomandibular joint pain, dysmenorrhea, and vulvodynia. Pain management strategies may be focused around treating the cause of the pain (e.g., dislocation of a joint, proprioceptive disorder) and minimizing the sensation of pain. Management strategies for chronic pain in EDS includes physical therapy, medications, as well as durable medical equipment such as cushions, compressive garments, and braces. The different modalities are discussed in this paper. © 2017 Wiley Periodicals, Inc.

First mutation in the FSHR cytoplasmic tail identified in a non-pregnant woman with spontaneous ovarian hyperstimulation syndrome.

BACKGROUND: Spontaneous ovarian hyperstimulation syndrome (sOHSS) is a rare event occurring mostly during natural pregnancy. Among described etiologies, some activating mutations of FSH receptor (FSHR) have been identified. CASE PRESENTATION: We report hereby the case of a non-pregnant women with three episodes of sOHSS. Hormonal evaluation was normal and no pituitary adenoma was detected. However, genetic analysis identified a novel heterozygous FSHR mutation (c.1901 G > A). This R634H mutation is the first described in the cytoplasmic tail of the receptor. Functional analysis failed to reveal constitutive activity of the mutant but a decreased cAMP production in response to FSH. The weak activity of this mutant is correlated with a markedly reduced cell surface expression. CONCLUSION: Pathophysiology of non gestationnal sOHSS is still ill established. The molecular characterization of this new mutant indicates that it might not be at play. Therefore, further investigations are needed to improve knowledge of the molecular mechanism of this syndrome.

Erratum to: Loss of glucocorticoid receptor activation is a hallmark of BRCA1-mutated breast tissue.

Erratum to: Breast Cancer Res Treat (2013),142:283­296,DOI 10.1007/s10549-013-2722-8. In the original publication of the article, the blot corresponding to the total P38 protein content for the conditions siCtl and siBRCA1 in Fig. 7a was incorrectly laid out. The corrected Fig. 7a is given in this erratum.The

Inhibin A and inhibin B producing ovarian fibrothecoma revealed by suppression of follicle stimulating hormone (FSH) in a post-menopausal woman: report of the first case.

In this report, we describe the first case ever reported in the literature, of an inhibin-A (INHA) and inhibin-B (INHB) producing fibrothecoma. A post-menopausal woman was referred to our unit because of follicle stimulating hormone (FSH) level below the reference interval for postmenopausal women. By contrast luteinizing hormone, hCG, and estradiol levels were within normal range. This discrepancy suggested the secretion of FSH inhibitory factors. INHB and INHA levels were markedly elevated for age, 475 pg/mL and 100 pg/mL, respectively. Ultrasonography and MRI showed a pelvic mass of indeterminate nature. Abnormal inhibin secretion is generally observed in granulosa cell tumors. In this case this etiology was unlikely because of low estradiol and AMH levels. Surgical exploration revealed a 10 cm mass of the left ovary proven histologically to be an ovarian fibrothecoma (OFT). After tumor removal, INHB and INHA levels decreased rapidly. Only three cases of OFT with an important secretion of INHB have been reported to date. INHA secretion has never been associated with OFT. There is a need to develop coupled hormone and imaging strategies to diagnose the source of INH secretion in case of FSH/LH discrepancy.

Progesterone receptor A predominance is a discriminator of benefit from endocrine therapy in the ATAC trial.

Progesterone receptor (PR) function, while essential in normal human breast, is also implicated in breast cancer risk. The two progesterone receptors, PRA and PRB, are co-expressed at equivalent levels in normal breast, but early in carcinogenesis normal levels of PRA:PRB are frequently disrupted, and predominance of one isoform, usually PRA, results. In model systems, PRA and PRB have different activities, and altering the PRA:PRB ratio in cell lines alters PR signaling. The purpose of this study was to determine whether hormonal or reproductive factors contribute to imbalanced PRA:PRB expression in breast tumors and the impact of PRA:PRB imbalance on disease outcome. The relative expression of PRA and PRB proteins was determined by dual immunofluorescence histochemistry in archival breast tumors and associations with clinical and reproductive history assessed. PRA:PRB expression was not influenced by reproductive factors, whereas exogenous hormone use (menopausal hormone treatment, MHT) favored PRB expression (p < 0.035). The PRA:PRB ratio may be a discriminator of response to endocrine therapy in the TransATAC sample collection, with high PRA:PRB ratio predicting earlier relapse for women on tamoxifen, but not anastrozole (mean lnPRA:PRB ratio; HR (95 % CI) tamoxifen 2.45 (1.20-4.99); p value 0.02; anastrozole 0.80 (0.36-1.78); p value 0.60). The results of this study show that PRA:PRB imbalance in breast cancers is not associated with lifetime endogenous endocrine and reproductive factors, but is associated with MHT use, and that PRA predominance can discriminate those women who will relapse earlier on tamoxifen treatment. These data support a role for imbalanced PRA:PRB expression in breast cancer progression and relative benefit from endocrine treatment.

Factors associated with hospital admission in hereditary angioedema attacks: a multicenter prospective study.

BACKGROUND: Acute attacks of hereditary angioedema are characterized by recurrent localized edema. These attacks can be life threatening and are associated with substantial morbidity and mortality. OBJECTIVE: To determine factors associated with hospital admission of patients with an acute attack of hereditary angioedema presenting at the emergency department. METHODS: This was a multicenter prospective observational study of consecutive patients (January 2011 through December 2013) experiencing an acute hereditary angioedema attack and presenting at the emergency department at 1 of 4 French reference centers for bradykinin-mediated angioedema. Attacks requiring hospital admission were compared with those not requiring admission. RESULTS: Of 57 attacks in 29 patients, 17 (30%) led to hospital admission. In multivariate analysis, laryngeal and facial involvements were associated with hospital admission (odds ratio 18.6, 95% confidence interval 3.9-88; odds ratio 7.7, 95% confidence interval 1.4-43.4, respectively). Self-injection of icatibant at home was associated with non-admission (odds ratio 0.06, 95% confidence interval 0.01-0.61). The course was favorable in all 57 cases. No upper airway management was required. CONCLUSION: Most patients attended the emergency department because they were running out of medication and did not know that emergency treatment could be self-administered. Risk factors associated with hospital admission were laryngeal and facial involvement, whereas self-injection of icatibant was associated with a return home.

Are we overestimating the stroke risk related to contraceptive pills?

PURPOSE OF REVIEW: Hormonal contraceptives are used by million of women worldwide. Ischemic stroke is one of the major harmful effects of hormonal contraceptives, but remains a very uncommon disease before menopause. The increased risk of stroke under third and fourth-generation contraceptive pills and nonoral contraceptives has been recently highlighted. Given the benefits associated with combined hormonal contraceptives (COCs), it is important to properly evaluate their risks in order to provide a better benefit/risk balance to young women. RECENT FINDINGS: Scarce studies addressing the rates of stroke in young women suggest that the fraction attributable to the contraceptive pill remains low. In contrast, there is abundant literature on the relative risks of stroke under COCs. The risk of arterial disease seems to be similar among users of second and third-generation pills, drospirenone-containing pills and nonoral hormonal contraceptives. Progestin-only contraceptives do not appear to be associated with an increased risk of stroke. SUMMARY: New formulations of hormonal contraceptives are not safer than second-generation COCs. Even if the absolute numbers of strokes attributable to hormonal contraceptives is very low, stringent selection of patients should help to reduce the events still more, and progestin-only contraceptives/nonhormonal methods should be preferred in cases of associated risk factors.

Loss of glucocorticoid receptor activation is a hallmark of BRCA1-mutated breast tissue.

Glucocorticoids (GCs) regulate cell homeostasis and can affect carcinogenesis. An inherited germline mutation in the BRCA1 gene, a tumor suppressor gene, confers a predisposition to breast and ovarian cancers. BRCA1 participates in the maintenance of genome stability through DNA repair, in cellular homeostasis through gene transcription, and in signaling regulation. The interaction between BRCA1 and the glucocorticoid receptor (GR) signaling pathway was studied in normal breast tissues and triple-negative breast cancers from BRCA1 mutation carriers. A loss of the active Ser211 phosphorylated form of GR was found in the mutant as compared to the non-mutant. In in vitro studies, the BRCA1 status in breast cancer cell lines regulates GC-dependent proliferation/apoptosis and impacts GC-dependent gene expression. The lack of BRCA1 inhibited dexamethasone actions on its target genes' expression and the opposite effect was seen with BRCA1 overexpression. BRCA1 overexpression enhances MAPK p38 phosphorylation, resulting in an amplification of GR phosphorylation on Ser 211 and GR basal expression. Our results indicate that BRCA1 is essential to develop an efficient GC signalization. GR P-Ser211 levels may constitute an important diagnostic factor for screening BRCA1 loss of expression in tumors from BRCA1 mutation carriers as well as in sporadic BRCAness tumors. This marker may help to optimize therapeutic strategies.

Hereditary angioedema with C1 inhibitor deficiency: clinical presentation and quality of life of 193 French patients.

BACKGROUND: Hereditary angioedema (HAE) is a rare and potentially life-threatening disease. New specific treatments are available. OBJECTIVE: To identify patients' features and patients' best therapeutic option. METHODS: A 1-year, multicenter, retrospective study was performed. The primary objective was to examine the clinical presentation of HAE. Secondary objectives included patient characteristics, management of HAE over 12 months, and health-related quality of life using the SF-36v2 questionnaire. RESULTS: One hundred ninety-three patients were included, and 69.4% were women. In the 12-month period, the mean number of HAE attacks was 7.6. Among the 568 reported attacks, localizations were the abdomen (57.1%), peripheral limbs (42.5%), upper airway (7.9%), and face (6.9%); 31.6% of attacks were severe and occurred statistically more often in women (P < .02). Compared with a population of allergic patients, all age- and sex-adjusted scores were significantly lower in patients with HAE (P < .05) except for the physical component summary. Health-related quality of life negatively correlated with the annual number of attacks and was markedly altered for patients having more than 5 attacks per year (P < .05 for all dimensions). CONCLUSION: HAE is a severe disease that places a heavy burden on quality of life.

International consensus and practical guidelines on the gynecologic and obstetric management of female patients with hereditary angioedema caused by C1 inhibitor deficiency.

BACKGROUND: There are a limited number of publications on the management of gynecologic/obstetric events in female patients with hereditary angioedema caused by C1 inhibitor deficiency (HAE-C1-INH). OBJECTIVE: We sought to elaborate guidelines for optimizing the management of gynecologic/obstetric events in female patients with HAE-C1-INH. METHODS: A roundtable discussion took place at the 6th C1 Inhibitor Deficiency Workshop (May 2009, Budapest, Hungary). A review of related literature in English was performed. RESULTS: Contraception: Estrogens should be avoided. Barrier methods, intrauterine devices, and progestins can be used. Pregnancy: Attenuated androgens are contraindicated and should be discontinued before attempting conception. Plasma-derived human C1 inhibitor concentrate (pdhC1INH) is preferred for acute treatment, short-term prophylaxis, or long-term prophylaxis. Tranexamic acid or virally inactivated fresh frozen plasma can be used for long-term prophylaxis if human plasma-derived C1-INH is not available. No safety data are available on icatibant, ecallantide, or recombinant human C1-INH (rhC1INH). Parturition: Complications during vaginal delivery are rare. Prophylaxis before labor and delivery might not be clinically indicated, but pdhC1INH therapeutic doses (20 U/kg) should be available. Nevertheless, each case should be treated based on HAE-C1-INH symptoms during pregnancy and previous labors. pdhC1INH prophylaxis is advised before forceps or vacuum extraction or cesarean section. Regional anesthesia is preferred to endotracheal intubation. Breast cancer: Attenuated androgens should be avoided. Antiestrogens can worsen angioedema symptoms. In these cases anastrozole might be an alternative. Other issues addressed include special features of HAE-C1-INH treatment in female patients, genetic counseling, infertility, abortion, lactation, menopause treatment, and endometrial cancer. CONCLUSIONS: A consensus for the management of female patients with HAE-C1-INH is presented.

Neurokinin 3 receptor antagonists for menopausal vasomotor symptoms, an appraisal.

Fezolinetant is a neurokinin 3 receptor antagonist under investigation for treatment of menopausal symptoms. In a recent study, Lederman and colleagues1 reported the safety and efficacy of fezolinetant for the treatment of moderate-to-severe vasomotor symptoms associated with menopause.

Contraception in breast cancer survivors from the FEERIC case-control study (performed on behalf of the Seintinelles research network).

OBJECTIVE: To compare the prevalence of contraception in breast cancer (BC) patients at risk of unintentional pregnancy (i.e. not currently pregnant or trying to get pregnant) and matched controls. STUDY DESIGN: The FEERIC study (Fertility, Pregnancy, Contraception after BC in France) is a prospective, multicenter case-control study, including localized BC patients aged 18-43 years, matched for age and parity to cancer-free volunteer controls in a 1:2 ratio. Data were collected through online questionnaires completed on the Seintinelles research platform. RESULTS: In a population of 1278 women at risk of unintentional pregnancy, the prevalence of contraception at study inclusion did not differ significantly between cases (340/431, 78.9%) and controls (666/847, 78.6%, p = 0.97). Contrarily, the contraceptive methods used were significantly different, with a higher proportion of copper IUD use in BC survivors (59.5% versus 25.0% in controls p < 0.001). For patients at risk of unintentional pregnancy, receiving information about chemotherapy-induced ovary damage at BC diagnosis (OR = 2.47 95%CI [ 1.39-4.37] and anti-HER2 treatment (OR = 2.46, 95% CI [ 1.14-6.16]) were significantly associated with the use of a contraception in multivariate analysis. CONCLUSION: In this large French study, BC survivors had a prevalence of contraception use similar to that for matched controls, though almost one in five women at risk of unintentional pregnancy did not use contraception. Dedicated consultations at cancer care centers could further improve access to information and contraception counseling.

Glucocorticoid receptor activity discriminates between progesterone and medroxyprogesterone acetate effects in breast cells.

The purpose of this article is to determine the tumorigenic potential of estradiol treatment (E2) when combined with either progesterone (P4) or medroxyprogesterone acetate (MPA) in normal luminal human breast cells (HBE) and in human breast cancer cells (T47-D, MCF-7). Proliferation profiles were evaluated, along with the gene transactivation activity between the progesterone and glucocorticoid receptors (PR, GR) in HBE, T47-D, and MCF-7 cells treated by E2 + P4 or E2 + MPA. High throughput transcriptome analysis was performed on RNA from HBE cells treated by E2, E2 + MPA and E2 + P4. GR content was analyzed in normal breast cells as well. In HBE cells, E2 + P4 treatment was antiproliferative and promoted cellular differentiation. In contrast, E2 + MPA displayed mitogenic, antiapoptotic effects in HBE cells and did not influence cellular differentiation. The effect of P4 and MPA on cell proliferation was, however, variable in breast cancer cells. In cells containing GR or/and PR, MPA decreased proliferation whereas P4 antiproliferative effect needed the presence of PR. In HBE cells, the regulation of genes by E2 + P4, and E2 + MPA was significantly different, particularly in cell proliferation and cell death gene families. Further analysis revealed a modulation of the glucocorticoid receptor gene expression pathway by E2 + MPA. Predominant MPA glucocorticoid activity in normal and breast cancer cells was demonstrated using a glucocorticoid antagonist and the down-regulation of the GR by RNA interference. In normal luminal breast cells and in breast cancer cells, P4 and MPA combined with E2 treatment have opposing mitogenic effects due to GR. The consequences of MPA glucocorticoid potencies as well as the importance of GR in breast tissue merit a reappraisal.

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

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