Low thrombin generation in postmenopausal women using estetrol.

OBJECTIVE: Estetrol (E4) represents a novel estrogen of interest to relieve vasomotor symptoms. E4 activates the nuclear estrogen receptor α (ERα) but antagonizes the estradiol ERα-dependent membrane-initiated steroid signaling pathway. The distinct pharmacological properties of E4 could explain its low impact on hemostasis. This study aimed to assess the effect of E4 on coagulation in postmenopausal women, using the thrombin generation assay (TGA). METHODS: Data were collected from a multicenter, randomized, placebo-controlled, dose-finding study in postmenopausal women (NCT02834312). Oral E4 (2.5 mg, n = 42; 5 mg, n = 29; 10 mg, n = 34; or 15 mg, n = 32) or placebo (n = 31) was administered daily for 12 weeks. Thrombograms and TGA parameters were extracted for each subject at baseline and after 12 weeks of treatment. RESULTS: After 12 weeks of treatment, all treatment groups showed a mean thrombogram (±95% confidence interval [CI] of the mean) within the reference ranges, that is, the 2.5th-97.5th percentile of all baseline thrombograms (n = 168), as well as for TGA parameters. CONCLUSIONS: The intake of E4 15 mg for 12 weeks led to significant but not clinically relevant changes compared to baseline as the mean values (±95% CI of the mean) remained within reference ranges, demonstrating a neutral profile of this estrogen on hemostasis.

Impact of estetrol (E4) on hemostasis, metabolism and bone turnover in postmenopausal women.

OBJECTIVE: This study aimed to determine the effects of estetrol (E4) on hemostasis, lipids, carbohydrate metabolism and bone turnover in postmenopausal women. METHODS: This study was a multicenter, randomized, double-blind placebo-controlled phase 2 trial. Participants (n = 180, age 43-64 years) received E4 2.5 mg, 5 mg, 10 mg and 15 mg or placebo once daily for 12 weeks. Changes from baseline at week 12 were evaluated versus placebo for hemostasis parameters, sex hormone binding globulin (SHBG), lipids, carbohydrate metabolism and bone markers. RESULTS: Changes for hemostasis parameters were minimal with a small increase only in the normalized activated protein C sensitivity ratio in the E4 15 mg group versus placebo. SHBG increased in the E4 5 mg, 10 mg and 15 mg groups versus placebo. High-density lipoprotein cholesterol increased in all E4 groups; changes were not consistent for other lipids. Significant decreases versus placebo were seen for insulin resistance (E4 10 mg group), hemoglobin A1c (E4 15 mg group) and type 1 collagen C-terminal telopeptide (E4 10 mg and 15 mg groups). Small decreases in osteocalcin in the E4 5 mg, 10 mg and 15 mg groups were significant versus the increase observed in placebo. CONCLUSION: E4 had limited impact on hemostasis and potentially beneficial effects on lipids, carbohydrate metabolism and bone turnover.

Estetrol-Drospirenone combination oral contraceptive: a clinical study of contraceptive efficacy, bleeding pattern and safety in Europe and Russia.

OBJECTIVES: To assess the contraceptive efficacy, bleeding pattern and safety of a combined oral contraceptive containing estetrol (E4) 15 mg and drospirenone (DRSP) 3 mg. DESIGN: Multicenter, open-label, phase 3 trial. SETTING: Sixty-nine sites in Europe and Russia. POPULATION: Sexually active women aged 18-50 years with regular menstrual cycles and body mass index ≤35 kg/m2 . METHODS: E4/DRSP was administered in a 24 active/4 placebo regimen for up to 13 cycles. Visits were scheduled during Cycles 2, 4, 7 and 10 and after completing treatment during which adverse events (AEs) were collected. Participants recorded medication intake, vaginal bleeding/spotting, use of other contraceptive methods and sexual intercourse on a daily diary. MAIN OUTCOME MEASURES: Pearl Index (PI) for women 18-35 years (overall and method-failure), bleeding pattern and AEs. RESULTS: A total of 1553 women aged 18-50 years, including 1353 from 18 to 35 years old, received the study medication. PI was 0.47 pregnancies/100 woman-years (95% CI 0.15-1.11); method failure PI was 0.29 pregnancies/100 woman-years (95% CI 0.06-0.83). Scheduled bleeding/spotting occurred in 91.9-94.4% of women over Cycles 1 to 12 and lasted a median of 4-5 days per cycle. The percentage of women with unscheduled bleeding/spotting episodes decreased from 23.5% in Cycle 1 to <16% from Cycle 6 onwards. The most common AEs were headache (7.7%), metrorrhagia (5.5%), vaginal haemorrhage (4.8%) and acne (4.2%). One treatment-related serious AE was reported, a lower extremity venous thromboembolism. One-hundred and forty-one (9.1%) women discontinued study participation because of treatment-related adverse events. CONCLUSION: E4/DRSP provides effective contraception, a predictable bleeding pattern and a favourable safety profile. TWEETABLE ABSTRACT: A phase 3 trial with E4/DRSP shows high contraceptive efficacy, a predictable bleeding pattern and favourable safety profile.

Clinical performance of a specific granulocyte colony stimulating factor ELISA to determine its concentration in follicular fluid as a predictor of implantation success during in vitro fertilization.

This study aimed to demonstrate the clinical performance of an ultra-sensitive follicular fluid (FF) granulocyte colony stimulating factor (G-CSF) immunoassay to confirm previous work, indicating a correlation between FF G-CSF concentration and live birth potential of the corresponding embryo after in vitro fertilization. This study was a noninterventional, prospective, diagnostic clinical multicentric study conducted between August 2012 and January 2014 with 396 single embryo transfers (SETs) from 278 subjects. During oocyte retrieval, FF was individually collected. Embryo morphology and implantation success were evaluated. The implantation success rate in the high G-CSF group (32.3%) was higher than the overall rate (27.5%). Similarly, for embryos with optimal morphology, implantation success rates were highest among those in the high G-CSF concentration category (34.5%) compared with low (19.6%) and intermediate (29.8%) G-CSF concentration categories. Significant differences in mean G-CSF concentrations were observed between the study sites. To minimize bias, analyses were repeated using data from the center with the largest number of SETs. In alignment with the overall analysis, this center demonstrated a 43% greater probability of implantation for optimal embryos with high G-CSF compared to the general implantation rate among optimal embryos and a 327% increase compared with the implantation rate of optimal embryos with low G-CSF.

Pharmacokinetics of the fetal estrogen estetrol in a multiple-rising-dose study in postmenopausal women.

OBJECTIVES: Estetrol (E4) is a natural fetal estrogen. In this open-label, multiple-rising-dose study, the pharmacokinetic effects of E4 in postmenopausal women were investigated as a secondary objective. METHODS: In total, 49 postmenopausal women were randomized to receive either 2 mg E4 or 2 mg estradiol valerate (E2V) for 28 days, or were (non-randomized) assigned to 10, 20, or 40 mg E4. The main outcome measures were: E4 plasma concentrations at trough, and on days 1 and 28; and E4 pharmacokinetic parameters AUC, Cmax and tmax on days 1 and 28. RESULTS: After oral administration, E4 showed a very fast absorption, followed by a multiphasic elimination with an initial rapid decline, gradually continuing with a slower elimination, suggesting a long terminal half-life. Steady state was reached within 2 weeks of dosing and pharmacokinetic results were generally proportional to the dose. Estetrol concentrations on day 28 were slightly higher compared to day 1, indicating some accumulation. CONCLUSION: The pharmacokinetic profile of estetrol is characterized by a very fast absorption phase, followed by an initial rapid decline, and a slow terminal elimination phase. Based on its kinetic properties, estetrol seems suitable for use as a once-daily oral drug.

Impact of follicular G-CSF quantification on subsequent embryo transfer decisions: a proof of concept study.

BACKGROUND: Previous experiments have shown that granulocyte colony-stimulating factor (G-CSF), quantified in the follicular fluid (FF) of individual oocytes, correlates with the potential for an ongoing pregnancy of the corresponding fertilized oocytes among selected transferred embryos. Here we present a proof of concept study aimed at evaluating the impact of including FF G-CSF quantification in the embryo transfer decisions. METHODS: FF G-CSF was quantified with the Luminex XMap technology in 523 individual FF samples corresponding to 116 fresh transferred embryos, 275 frozen embryos and 131 destroyed embryos from 78 patients undergoing ICSI. RESULTS: Follicular G-CSF was highly predictive of subsequent implantation. The receiving operator characteristics curve methodology showed its higher discriminatory power to predict ongoing pregnancy in multivariate logistic regression analysis for FF G-CSF compared with embryo morphology [0.77 (0.69-0.83), P < 0.001 versus 0.66 (0.58-0.73), P = 0.01)]. Embryos were classified by their FF G-CSF concentration: Class I over 30 pg/ml (a highest positive predictive value for implantation), Class II from 30 to 18.4 pg/ml and Class III <18.4 pg/ml (a highest negative predictive value). Embryos derived from Class I follicles had a significantly higher implantation rate (IR) than those from Class II and III follicles (36 versus 16.6 and 6%, P < 0.001). Embryos derived from Class I follicles with an optimal morphology reached an IR of 54%. Frozen-thawed embryos transfer derived from Class I follicles had an IR of 37% significantly higher than those from Class II and III follicles, respectively, of 8 and 5% (P < 0.001). Thirty-five per cent of the frozen embryos but also 10% of the destroyed embryos were derived from G-CSF Class I follicles. Non-optimal embryos appear to have been transferred in 28% (22/78) of the women, and their pregnancy rate was significantly lower than that of women who received at least one optimal embryo (18 versus 36%, P = 0.04). CONCLUSIONS: Monitoring FF G-CSF for the selection of embryos with a better potential for pregnancy might improve the effectiveness of IVF by reducing the time and cost required for obtaining a pregnancy.

Curcumin-cyclodextrin complexes potentiate gemcitabine effects in an orthotopic mouse model of lung cancer.

BACKGROUND: Overall clinical outcome for advanced lung cancer remains very disappointing despite recent advances in treatment. Curcumin has been reported as potentially active against cancer. METHODS: Owing to poor curcumin solubility, we have used cyclodextrins (CD) as an excipient allowing a considerable increase of aqueous solubility and bioavailability of curcumin. The effects of solubilised curcumin have been evaluated in cell cultures as well as in an in vivo orthotopic lung tumour mouse model. RESULTS: Cell proliferation was reduced while apoptosis rates were increased when lung epithelial tumour cells were cultured in the presence of curcumin-CD complexes. For in vivo experiments, cells were grafted into lungs of C57Bl/6 mice treated by an oral administration of a non-soluble form of curcumin, CDs alone or curcumin-CD complexes, combined or not with gemcitabine. The size of orthotopically implanted lung tumours was reduced upon curcumin complex administration as compared with treatments with placebo or non-solubilised curcumin. Moreover, curcumin potentiated the gemcitabine-mediated antitumour effects. CONCLUSION: Our data demonstrate that curcumin, when given orally in a CD-solubilised form, reduces lung tumour size in vivo. In vitro experiments show impaired tumour cell proliferation and increased cell apoptosis. Moreover, our data underline a potential additive effect of curcumin with gemcitabine thus providing an efficient therapeutic option for antilung cancer therapy.

Adverse obstetrical outcomes after treatment of precancerous cervical lesions: a Belgian multicentre study.

OBJECTIVE: To assess the impact of cervical intraepithelial neoplasia (CIN) treatment on the risk of (spontaneous) preterm delivery (PD) and small for gestational age (SGA) at birth. DESIGN: A multicentre cohort study. SETTING: Maternity wards of four academic hospitals in Belgium. POPULATION: Ninety-seven exposed pregnant women (with a CIN treatment history) and 194 nonexposed pregnant women (without a history of CIN treatment). METHODS: A questionnaire and check of obstetrical files included socio-demographic characteristics, risk factors for PD, obstetrical history for all women and characteristics of the CIN treatment for exposed women. Pregnancy outcomes were recorded after delivery. The influence of previous treatment of CIN on pregnancy outcomes, adjusted for confounding variables, was assessed by Cox regression and lifetables (for the outcome gestational age at birth) and by logistic regression (for the outcomes PD and SGA at birth). MAIN OUTCOME MEASURES: Occurrence of PD and SGA at birth. RESULTS: Seventy-nine per cent of the women in the database were multiparous; 16.3% of women with a previous excisional treatment spontaneously delivered preterm, compared with 8.1% of unexposed women [odds ratio (OR), 2.19; 95% confidence interval (CI), 0.97-4.99]. When adjusting for confounding factors (ethnicity, HIV status, education, age, smoking and parity), the OR for PD was 2.33 (95% CI, 0.99-5.49). Excisional treatment did not have an impact on SGA at birth (OR, 0.94; 95% CI,0.41-2.15). The depth of the cone was >10 mm in 63.5% of the documented cases. Large cones, more than 10 mm deep, were associated with a significantly increased risk of PD (adjusted OR, 4.55; 95% CI, 1.32-15.65) compared with untreated women, whereas smaller cones (≤ 10 mm) were not significantly associated with PD (OR, 2.77; 95% CI, 0.28-27.59). The associations seen for PD with respect to the cone size did not hold for SGA at birth. CONCLUSIONS: There was an increased risk of (spontaneous) PD after excision of CIN, in particular when the cone depth exceeded 10 mm.

[Premature ovarian failure, from genetics to clinical]. / Insuffisance ovarienne prématurée: de la génétique à la clinique.

Premature Ovarian Failure (POF) is a condition with complicated clinical presentation. An estimated 1% of the population is affected before the age of 40, with 0.1% affected prior to the age of 30. There are many causes of POI: genetic aberrations, auto-immune ovarian damage, iatrogenic factors following surgery, radiotherapy or chemotherapy, environmental factors (viruses, toxins, smoking) and metabolic. The majority of POF cases have idiopathic etiologies.

[Obstetrical epidural analgesia and postpartum backache]. / Analgésie péridurale obstétricale et lombalgie du post-partum: un lien de cause a effet?

Backache is a common problem in the general population. The prevalence of backpain is increased during pregnancy and after delivery. Early studies have suggested that labor epidural analgesia might be associated with an increased incidence of backache in the postpartum period. However, these initial studies were retrospective and their design included several methodological deficiencies. All the prospective studies published afterwards (prospective cohort studies and 3 randomized controlled trials) yield the same result: there is no relationship between labor epidural analgesia and long-term postpartum backpain. Pregnant women must be aware of this in order to make an informed and appropriate choice about labor epidural analgesia, the most effective technique for intrapartum pain relief.

[Herpes hepatic failure during the third quarter of pregnancy]. / Le cas clinique du mois. Hépatite herpétique au 3eme trimestre de la grossesse.

Acute liver diseases of pregnancy are common and usually transient and reversible. Given the number of different possible diagnoses, performing a large biological screening and a proper iconographic documentation is key. It makes sure no etiology fatal to the mother and her fetus is missed.

Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization.

Acquisition of invasive/metastatic potential through protease expression is an essential event in tumor progression. High levels of components of the plasminogen activation system, including urokinase, but paradoxically also its inhibitor, plasminogen activator inhibitor 1 (PAI1), have been correlated with a poor prognosis for some cancers. We report here that deficient PAI1 expression in host mice prevented local invasion and tumor vascularization of transplanted malignant keratinocytes. When this PAI1 deficiency was circumvented by intravenous injection of a replication-defective adenoviral vector expressing human PAI1, invasion and associated angiogenesis were restored. This experimental evidence demonstrates that host-produced PAI is essential for cancer cell invasion and angiogenesis.

Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions.

Vascular endothelial growth factor (VEGF) stimulates angiogenesis by activating VEGF receptor-2 (VEGFR-2). The role of its homolog, placental growth factor (PlGF), remains unknown. Both VEGF and PlGF bind to VEGF receptor-1 (VEGFR-1), but it is unknown whether VEGFR-1, which exists as a soluble or a membrane-bound type, is an inert decoy or a signaling receptor for PlGF during angiogenesis. Here, we report that embryonic angiogenesis in mice was not affected by deficiency of PlGF (Pgf-/-). VEGF-B, another ligand of VEGFR-1, did not rescue development in Pgf-/- mice. However, loss of PlGF impaired angiogenesis, plasma extravasation and collateral growth during ischemia, inflammation, wound healing and cancer. Transplantation of wild-type bone marrow rescued the impaired angiogenesis and collateral growth in Pgf-/- mice, indicating that PlGF might have contributed to vessel growth in the adult by mobilizing bone-marrow-derived cells. The synergism between PlGF and VEGF was specific, as PlGF deficiency impaired the response to VEGF, but not to bFGF or histamine. VEGFR-1 was activated by PlGF, given that anti-VEGFR-1 antibodies and a Src-kinase inhibitor blocked the endothelial response to PlGF or VEGF/PlGF. By upregulating PlGF and the signaling subtype of VEGFR-1, endothelial cells amplify their responsiveness to VEGF during the 'angiogenic switch' in many pathological disorders.

[Invasion and metastatic dissemination in breast cancer: mechanisms]. / Invasion et dissémination métastatiques dans le cancer du sein: mécanismes.

Metastases formation is a complex process involving genetic and epigenetic modifications leading to several molecular pathway dysfunctions and alterations in the production and fonction of a panel of molecular mediators. Recent studies have shed light on the importance of multiple interactions occuring between tumor cells and host cells involved in the elaboration of a microenvironment permissive for tumor cell survival and growth. These tumor-host interactions are decisive, not only in the primary tumor, but also in secondary sites colonized by tumor cells. Cancer appears more and more as a sytemic disease in which tumor cell is one of the pawn in the game. System of defense are rapidly overwhelmed and tumor cells hijack host cells to promote their dissemination that likely occurs at earlier stages than initially anticipated. In the present review, we describe the novel concepts of metastases formation based on recent transcriptomic analyses and new insights acquired on the tumor microenvironment in the primary tumor and in secondary foci.

[Circulating tumor cells: detection, characterization and clinical impact]. / Cellules tumorales circulantes: détection, caractérisation et intérêts cliniques.

The metastatic process generates circulating tumor cells (CTCs) and disseminated tumor cells (DTCs) in bone marrow and other organs which can remain as occult metastases. Various methods and systems have been developed to allow the isolation and identification of those cells but major technical limitations still exist. Research on CTCs is a nevertheless tremendously growing field of cancer research because of their potential clinical applications. CTCs indeed convey predictive information for the development of metastasis and recurrence, and prognostic information regarding patient survival. CTCs enumeration could also be used to monitor the effectiveness of adjuvant treatments. Moreover, enhancing our basic understanding of the metastatic process, CTCs, and DTCs in particular, are thought to contain subpopulations of cells with stem cells properties that would be responsible for relapses.

[Clinical case of the month. Unfavourable outcome of a triplet gestation]. / Issue d favorable d'une grossesse triple.

Body stalk anomaly is rarely described in triplet gestation after medically assisted procreation. The relationship between congenital anomaly, multiple pregnancy, and medically assisted procreation is briefly discussed.

[The usefulness of combined gynecologic and endocrinologic consultation in pediatrics: a retrospective study of the reasons for consultation and the practical approach]. / De l'utilité d'une consultation conjointe de gynécologie- endocrinologie pédiatrique: etude rétrospective des motifs de consultation et approche pratique.

The gynaecological issues encountered in children and teenagers lay at the intersection of paediatric endocrinology and gynaecology. More than ten years ago, an outpatient clinic in paediatric endocrinology and gynaecology has been created. Here, we review the last 6 years. 214 girls were included, considering only the first visit for each patient. Collected data are initial concern for this consultation, age at first consultation and confirmed or suspected diagnosis. A classification is done according to the initial concern of patients in six categories. Principal queries concern pubertal development, precocious pilosity or abnormalities in menstrual cycles. Vulvovaginitis and morphologic abnormalities are also frequently encountered. This consultation suggests a paediatric approach with a child feeling confident and a gynaecological examination with a specialist knowing the anatomy particularities and the development of the children. This article focuses on the importance of specific gynaecological examination in children and reviews the main diseases encountered.

Antibodies to laminin in Chagas' disease.

We have found that sera from humans with Chagas' disease and Rhesus monkeys infected with Trypanosoma cruzi contain IgM and IgG antibodies, which react with structures in a variety of connective tissues. These antibodies react with laminin but not with various other purified connective tissue components like collagen types I, III, IV, and V, fibronectin, heparan sulfate (BM-1) proteoglycan, or chondronectin. The tissue-reacting antibodies were isolated by absorption to a laminin-Sepharose column. The bound fraction contained all the tissue-reacting antibodies. These antibodies strongly stained trypomastigotes and amastigotes, but weakly stained epimastigotes. These studies show that sera from T. cruzi-infected primates contain antilaminin antibodies, which may be produced by those host in response to a laminin-like molecule present in the parasite.

Maternal plasma soluble endoglin at 11-13 weeks' gestation in pre-eclampsia.

OBJECTIVES: To examine the performance of screening for pre-eclampsia (PE) by a combination of maternal factors, soluble endoglin (sEng), pregnancy associated plasma protein-A (PAPP-A), placental growth factor (PlGF) and uterine artery lowest pulsatility index (L-PI) at 11-13 weeks' gestation. METHODS: Uterine artery L-PI, sEng, PAPP-A and PlGF were measured at 11-13 weeks in 90 singleton pregnancies that subsequently developed PE, including 30 that required delivery before 34 weeks (early PE) and 60 with late PE, and 180 unaffected controls. Screening performance for PE by maternal factors, sEng, PAPP-A, PlGF and uterine artery L-PI and their combinations was determined. RESULTS: In early PE, compared to controls, plasma sEng and uterine L-PI were significantly increased and serum PAPP-A and PlGF were decreased. In late PE, compared to controls, serum PlGF was decreased and uterine L-PI was increased but plasma sEng and serum PAPP-A were not significantly different. In screening for early PE, the detection rate for a 10% false-positive rate was 46.7% for sEng alone and 96.3% for a combination of maternal factors, sEng, PlGF and uterine artery L-PI. CONCLUSIONS: Effective screening for early PE can be provided by a combination of maternal factors, sEng, PlGF and uterine artery L-PI at 11-13 weeks' gestation.

[Non-observance and therapeutic inertia in obstetrics]. / D'efaut d'observance et inertie thérapeutique en obstétrique.

Observance around pregnancy includes two parts: what can be done before conception and what must be done during pregnancy. Preconception care, if efficaciously performed, offerss real benefits for foetal and child development. Its efficacy will depends on the involvement and motivation of physicians and particularly also on the patient's observance. In this article we summarize essential pieces of advice to be given to each patient before pregnancy. Therapeutic inertia in obstetrics presents two differents aspects: on the one hand, the delay to initiate a therapeutic strategy when a complication arises such as a postpartum hemorrhage; on the other hand, the continuation of obsolete practices, such as the therapy of uterine hypersystolia.