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CD146 is an adhesion molecule essentially located in the vascular system, which has been described to play an important role in angiogenesis. A soluble form of CD146, called sCD146, is detected in the bloodstream and is known as an angiogenic factor. During placental development, CD146 is selectively expressed in extravillous trophoblasts. A growing body of evidence shows that CD146 and, in particular, sCD146, regulate extravillous trophoblasts migration and invasion both in vitro and in vivo . Hereby, we review expression and functions of CD146/sCD146 in the obstetrical field, mainly in pregnancy and in embryo implantation. We emphasized the relevance of quantifying sCD146 in the plasma of pregnant women or in embryo supernatant in the case of in vitro fertilization (IVF) to predict pathological pregnancy such as preeclampsia or implantation defect. This review will also shed light on some major results that led us to define CD146/sCD146 as a biomarker of placental development and paves the way toward identification of new therapeutic targets during implantation and pregnancy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bouvier, Kaspi, Joshkon, Paulmyer-Lacroix, Piercecchi-Marti, Sharma, Leroyer, Bertaud, Gris, Dignat-George, Blot-Chabaud and Bardin.)

Although progress was made in in vitro fertilization (IVF) techniques, the majority of embryos transferred fail to implant. Morphology embryo scoring is the standard procedure for most of IVF centres for choosing the best embryo, but remains limited since even the embryos classified as "top quality" may not implant. As it has been shown that i) CD146 is involved in embryo implantation and ii) membrane form is shed to generate soluble CD146 (sCD146), we propose that sCD146 in embryo supernatants may constitute a new biomarker of embryo selection. Immunocytochemical staining showed expression of CD146 in early embryo stages and sCD146 was detected by ELISA and Western-blot in embryo supernatants from D2. We retrospectively studied 126 couples who underwent IVF attempt. The embryo culture medium from each transferred embryo (n = 222) was collected for measurement of sCD146 by ELISA. Significantly higher sCD146 concentrations were present in embryo supernatants that did not implant (n = 185) as compared to those that successfully implanted (n = 37) (1310 +/- 1152 pg.mL-1 vs. 845+/- 1173 pg.mL-1, p = 0.024). Sensitivity analysis performed on single embryo transfers (n = 71) confirmed this association (p = 0.0054). The computed ROC curve established that the optimal sCD146 concentration for embryo implantation is under 1164 pg.mL-1 (sensitivity: 76%, specificity: 48%, PPV: 25% and NPV: 92%). Over this sCD146 threshold, the implantation rate was significantly lower (9% with sCD146 levels >1164 pg.ml-1 vs. 22% with sCD146 levels ≤ 1164 pg.mL-1, p = 0.01). Among the embryos preselected by morphologic scoring, sCD146 determination could allow a better selection of the embryo(s), thus improving the success of elective single embryo transfer. This study establishes the proof of concept for the use of sCD146 as a biomarker for IVF by excluding the embryo with the highest sCD146 level. A multicentre prospective study will now be necessary to further establish its use in clinical practice.

Objective: To identify the prognostic factors for pregnancy after intrauterine insemination with the husband's sperm (IUI-H)., Design: Retrospective study., Setting: A single university medical center., Patient(s): 851 couples, for 2,019 IUI-H cycles., Intervention(s): After controlled ovarian stimulation, IUI-H performed 36 hours after ovulation triggering or 24 hours after a spontaneous luteinizing hormone (LH) surge., Main Outcome Measure(s): Clinical pregnancy rate per cycle (PR) and delivery rate per cycle (DR)., Result(s): The overall PR was 14.8% and DR 10.8%. Higher PR and DR were observed for patients presenting with ovulation disorders (particularly polycystic ovary syndrome) or with male infertility. Secondary infertility in the woman appeared to be a positive prognostic factor as did a basal follicle-stimulating hormone (FSH) level ≤ 7 IU/L and ovulation triggering over spontaneous LH rise. The other parameters influencing the results were the women's age, the number of mature follicles obtained (≥ 2), the endometrial thickness (10-11 mm), and the number of progressive motile spermatozoa inseminated (>1 million)., Conclusion(s): In women aged ≤ 38 years, IUI-H should be considered as an option, particularly in cases of female infertility from ovulation disorders, in cases of a normal ovarian reserve, in cases of secondary infertility, or when ≥ 1 million progressive sperm are inseminated. Bifollicular stimulation is required. In other cases, in vitro fertilization should be discussed as the first-line treatment., (Copyright © 2014 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Implantation failure could be related to antiphospholipid antibodies (aPL). We retrospectively analyzed the usefulness of aPL determination in women undergoing IVF. Conventional aPL of the antiphospholipid syndrome, lupus anticoagulant (LA), anticardiolipin antibodies (aCL), anti-β2glycoprotein I (a β2GPI) antibodies, and IgG and IgM isotypes as well as IgA isotype were analyzed in women presenting with at least two implantation failures after in vitro fertilization (IVF). In a population of 40 IVF patients, a total prevalence of 20% (8/40) of aPL was found, significantly different from that of the control population (100 healthy blood donors, P < 0.0005). Among the panels of aPL tested, a β2GPI IgA antibodies were the most prevalent (62.5% 5/8), significantly higher in IVF patients (12.5%, 5/40) than in controls (1%, 1/100) (P = 0.01). No difference according to the numbers of IVF attempts and success of embryo implantation was found between aPL positive and negative IVF patients. In contrast, no accomplished pregnancy with full-term live birth was observed in aPL positive IVF patients. Altogether our data led us to propose aPL assessment, in particular a β2GPI IgA antibodies, in support of IVF treated women. In a perspective way, an early aPL detection could be the basis for defining novel therapeutic strategy.

We compared the abilities of two commonly used semen preparation techniques to decrease the amount of benzo(a)pyrene-diol-epoxide (BPDE)-DNA adducts in the spermatozoa of ten smokers. Semen processing by swim-up or discontinuous gradient centrifugation recovered spermatozoa showing an equally significantly lower amount of BPDE-DNA adducts than in unprepared spermatozoa from neat semen., (Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Epicardial white adipose tissue (eWAT) is in close contact with coronary vessels and therefore could alter coronary homeostasis. Adrenomedullin (AM) is a potent vasodilatator and antioxidative peptide which has been shown to play a cytoprotective role in experimental models of acute myocardial infarction. We studied, using immunohistochemistry and qRT-PCR, the expression of AM and its receptors calcitonin receptor-like receptor (CRLR), and receptor activity-modifying protein (RAMP)2 and -3 in paired biopsies of subcutaneous WAT (sWAT) and eWAT obtained from patients with coronary artery disease (CAD) or without CAD (NCAD). In eWAT obtained from NCAD or CAD patients, immunoreactivity for AM, CRLR, and RAMP2 and -3 was detected in blood vessel walls and isolated stromal cells close to adipocytes. Some of the AM positive stromal cells colocalized CD68 immunoreactivity. eWAT from CAD patients showed increased AM immunoreactivity and AM gene expression. CRLR mRNA levels were comparable in sWAT of both groups and decreased by 40-50% in eWAT, irrespectively of the coronary status. RAMP2 mRNA concentrations did not change while RAMP3 mRNA levels increased in sWAT from CAD patients. There was a positive linear relationship between eWAT 11beta-hydroxysteroid dehydrogenase type 1 mRNA (11beta-HSD-1, the enzyme that converts inactive to active glucocorticoids) and AM mRNA. In conclusion, we demonstrate that AM and its receptors are expressed in eWAT. Our data suggest that eWAT AM, which could originate from macrophages, is related to 11beta-HSD-1 expression. AM synthesis, which is increased in eWAT during chronic CAD in humans, can play a cardioprotective role.

The aim of this study was to describe the association between various percentages of macronuclear spermatozoa (MNSs), sperm chromosomal abnormalities, and reproductive failure in 4 patients. One patient had a familial history of perinatal deaths. Patients were selected according to the coexistence of normal-sized spermatozoa and MNSs (19%, 22%, 29.5%, and 49.7%). Fluorescent in situ hybridization (FISH) on spermatozoa and semiautomated analysis of nuclear surface were assessed. All patients were characterized by an oligoasthenozoospermia. Three patients had a prevalence of irregular MNSs and prevalence of nondisjunction at the first meiotic division. One patient had a prevalence of regular MNSs and a prevalence of nondisjunction at the second meiotic division. FISH also showed a high rate of polyploidy and various rates of aneuploid sperm. The percentage of sperm with abnormal chromosome complements (25.6%, 43.6%, 51.4%, 71.7% with 3-color FISH) was higher than the percentage of MNSs. A population of apparently normal-sized spermatozoa that could be used for intracytoplasmic sperm injection (ICSI) was aneuploid. Sperm nuclear surface analysis revealed either a shift toward elevated values or distinguished 2 sperm subpopulations: normal and macronuclear. Patients underwent 7 ICSI cycles. The fertilization rate was low for 3 patients (50%, 40%, 50%) and normal for 1 patient (83.3%). Pregnancy rate per transfer was low (14.3%). The present study shows that the macronuclear phenotype can manifest a variety of clinical aspects. It is also shown that mild rates of MNSs impair fertility and constitute a risk of chromosomal abnormality for the embryos and a risk of perinatal death. We suggest conducting FISH on spermatozoa and genetic counseling for a couple when the percentage of MNSs reaches 20% in at least 1 spermiogram.

Objective: Glucocorticoids may be a pathophysiological mediator for the development of visceral obesity. In obese patients, adipose tissue reactivation of cortisone to cortisol is enhanced. In addition, changes in glucocorticoid receptor (GR) could also be important, either at the central nervous system level, by modulating the negative glucocorticoid feedback, or at a peripheral level, by regulating adipose tissue activity., Research Methods and Procedures: Using quantitative reverse transcriptase-polymerase chain reaction, we studied the expression of the GR mRNA isoforms (active, GRalpha; inactive, GRbeta) in circulating mononuclear leukocytes (in which GR shares the same regulation with central nervous system GR) obtained from normal weight women (n = 65) and patients with gluteofemoral (n = 26) or visceral (n = 39) obesity. Using in situ hybridization, we measured GRalpha mRNA levels in adipose tissue from control (n = 10) or obese (n = 15) patients., Results: The mean alpha/beta ratio was decreased in mononuclear leukocytes from obese patients (2.6, 9.2, and 32.1, respectively). GRalpha mRNA levels were significantly decreased in subcutaneous abdominal adipose tissue obtained from obese patients compared with nonobese ones, suggesting the existence of a downregulation of GR gene expression. This phenomenon was not found in visceral adipose tissue., Discussion: This suggests that, in obese patients, the relative insensitivity to the negative glucocorticoid feedback is, at least in part, subsequent to a dysregulation of the GRalpha/GRbeta ratio and that visceral, but not subcutaneous, adipose tissue retains a full capacity to respond to increased local generation of cortisol.

Glucocorticoids are implicated as a pathophysiological mediator of obesity and its accompanying metabolic and cardiovascular complications. Obese patients exhibit normal circulating cortisol levels, related to increased glucocorticoid production and degradation. However, it has been demonstrated that local production of active cortisol from inactive cortisone driven by 11 beta-hydroxysteroid dehydrogenase type 1 is exaggerated in adipose tissue of obese subjects. Such local hypercortisolism may be responsible for increased adipocyte differentiation and enhanced secretion of free fatty acids and other substances involved in the metabolic and cardiovascular complications observed in obesity.