Endothelin-Dependent Vasoconstriction in Human Uterine Artery: Application to Preeclampsia

BACKGROUND: Reduced uteroplacental perfusion, the initiating event in preeclampsia, is associated with enhanced endothelin-1 (ET-1) production which feeds the vasoconstriction of uterine artery. Whether the treatments of preeclampsia were effective on ET-1 induced contraction and could reverse placental ischemia is the question addressed in this study. We investigated the effect of antihypertensive drugs used in preeclampsia and of ET receptor antagonists on the contractile response to ET-1 on human uterine arteries. METHODOLOGY/PRINCIPAL FINDINGS: Experiments were performed, ex vivo, on human uterine artery samples obtained after hysterectomy. We studied variations in isometric tension of arterial rings in response to the vasoconstrictor ET-1 and evaluated the effects of various vasodilators and ET-receptor antagonists on this response. Among antihypertensive drugs, only dihydropyridines were effective in blocking and reversing the ET-1 contractile response. Their efficiency, independent of the concentration of ET-1, was only partial. Hydralazine, alpha-methyldopa and labetalol had no effect on ET-1 induced contraction which is mediated by both ET(A) and ET(B) receptors in uterine artery. ET receptors antagonists, BQ-123 and BQ-788, slightly reduced the amplitude of the response to ET-1. Combination of both antagonists was more efficient, but it was not possible to reverse the maximal ET-1-induced contraction with antagonists used alone or in combination. CONCLUSION: Pharmacological drugs currently used in the context of preeclampsia, do not reverse ET-1 induced contraction. Only dihydropyridines, which partially relax uterine artery previously contracted with ET-1, might offer interesting perspectives to improve placental perfusion

Transcriptome Analysis during Human Trophectoderm Specification Suggests New Roles of Metabolic and Epigenetic Genes

In humans, successful pregnancy depends on a cascade of dynamic events during early embryonic development. Unfortunately, molecular data on these critical events is scarce. To improve our understanding of the molecular mechanisms that govern the specification/development of the trophoblast cell lineage, the transcriptome of human trophectoderm (TE) cells from day 5 blastocysts was compared to that of single day 3 embryos from our in vitro fertilization program by using Human Genome U133 Plus 2.0 microarrays. Some of the microarray data were validated by quantitative RT-PCR. The TE molecular signature included 2,196 transcripts, among which were genes already known to be TE-specific (GATA2, GATA3 and GCM1) but also genes involved in trophoblast invasion (MUC15), chromatin remodeling (specifically the DNA methyltransferase DNMT3L) and steroid metabolism (HSD3B1, HSD17B1 and FDX1). In day 3 human embryos 1,714 transcripts were specifically up-regulated. Besides stemness genes such as NANOG and DPPA2, this signature included genes belonging to the NLR family (NALP4, 5, 9, 11 and 13), Ret finger protein-like family (RFPL1, 2 and 3), Melanoma Antigen family (MAGEA1, 2, 3, 5, 6 and 12) and previously unreported transcripts, such as MBD3L2 and ZSCAN4. This study provides a comprehensive outlook of the genes that are expressed during the initial embryo-trophectoderm transition in humans. Further understanding of the biological functions of the key genes involved in steroidogenesis and epigenetic regulation of transcription that are up-regulated in TE cells may clarify their contribution to TE specification and might also provide new biomarkers for the selection of viable and competent blastocysts

Hormonal treatment increases the response of the reward system at the menopause transition: a counterbalanced randomized placebo-controlled fMRI study

International audiencePreclinical research using rodent models demonstrated that estrogens play neuroprotective effects if they are administered during a critical period near the time of cessation of ovarian function. In women, a number of controversial epidemiological studies reported that a neuroprotective effect of estradiol may be obtained on cognition and mood-related disorders if hormone therapy (HT) begins early at the beginning of menopause. Yet, little is known about the modulatory effects of early HT administration on brain activation near menopause. Here, we investigated whether HT, initiated early during the menopause transition, increases the response of the reward system, a key brain circuit involved in motivation and hedonic behavior. We used fMRI and a counterbalanced, double-blind, randomized and crossover placebo-controlled design to investigate whether sequential 17beta-estradiol plus oral progesterone modulate reward-related brain activity. Each woman was scanned twice while presented with images of slot machines, once after receiving HT and once under placebo. The fMRI results demonstrate that HT, relative to placebo, increased the response of the striatum and ventromedial prefrontal cortex, two areas that have been shown to be respectively involved during reward anticipation and at the time of reward delivery. Our neuroimaging results bridge the gap between animal studies and human epidemiological studies of HT on cognition. These findings establish a neurobiological foundation for understanding the neurofunctional impact of early HT initiation on reward processing at the menopause transition

Reproducibility over time of measurements of androgens, estrogens and hydroxy estrogens in urine samples from post-menopausal women

Sex steroid concentrations in urine samples from post-menopausal women have been associated with risk of various chronic diseases. The basic requirement for the assessment of risk in such largescale epidemiological studies is that subjects be ranked accurately by their average, long-term hormone levels. We examined the reproducibility over time of measurements of urinary testosterone (T), 5a-androstane-3a, 17b-diol (ADIOL), estrone (E1), estradiol (E2), 2-hydroxy estrone and 2-hydroxy estradiol, (2(OH)-E), 16a-hydroxyestrone (16a(OH)-E1) and the ratio of 2(OH)-E and 16a(OH)-E1, in a representative sub-sample of post-menopausal women (n ¼ 43) participating in an ongoing prospective cohort study. Women collected three first morning urine voids on different occasions, with average time difference between the first and the third urine sample of 5.1 years. T, ADIOL, E1 and E2 were measured by radio immunoassay after enzymatic hydrolysis, solidphase extraction and HPLC purification of the samples, while 2(OH)-E and 16a(OH)-E1 were assayed by solid-phase enzyme immunoassay after enzymatic hydrolysis. Intra-class correlation co-efficients (ICCs) over time were very good for T (r ¼ 0.85), acceptable for E2, E1 and ADIOL (r > 0.55), but low for 2(OH)-E, 16a(OH)-E1 and their ratio (r < 0.46). The adjustment for creatinine concentrations did not increase these correlations

Involvement of BCL2 family members in the regulation of human oocyte and early embryo survival and death: gene expression and beyond

In women, up to 99.9% of the oocyte stockpile formed during fetal life is decimated by apoptosis. Apoptotic features are also detected in human preimplantation embryos both in vivo and in vitro. Despite the important consequences of cell death processes to oocyte competence and early embryonic development, little is known about its genetic and molecular control. B cell lymphoma-2 (BCL2) family proteins are major regulators of cell death and survival. Here, we present a literature review on BCL2 family expression and protein distribution in human and animal oocytes and early embryos. Most of the studies focused on the expression of two antagonistic members: the founding and survival family member BCL2 and its proapoptotic homolog BAX. However, recent transcriptomic analyses have identified novel candidate genes related to oocyte and/or early embryonic viability (such as BCL2L10) or commitment to apoptosis (e.g. BIK). Interestingly, some BCL2 proteins appear to be differentially distributed at the subcellular level during oocyte maturation and early embryonic development, a process probably linked to the functional compartmentalization of the ooplasm and blastomere. Assessment of BCL2 family involvement in regulating the survival of human oocytes and embryos may be of particular value for diagnosis and assisted reproductive technology. We suggest that implications of not only aberrant gene expression but also abnormal subcellular protein redistribution should be established in pathological conditions resulting in infertility

Comparative protein expression profiling in human cumulus cells in relation to oocyte fertilization and ovarian stimulation protocol.

International audienc

Bisphenol A differentially affects male reproductive function biomarkers in a reference population and agro pesticides users from Djutitsa, Cameroon

The consequences of bisphenol A (BPA) exposure on male reproductive function were studied in two populations from Cameroon, farmers using agro pesticides in Djutitsa (rural area) and townsmen in Yaounde (urban area, Centre region). Urinary BPA concentration from all participants was measured, and the values were correlated with biochemical markers of male reproductive function. The data showed that BPA could be detected in 92.6% of urine participants, with an average concentration of 2.18 +/- 1.97 microg/g creatinine but with no significant difference between the urinary BPA concentration from rural and urban populations. From BPA urinary concentration, the BPA average daily intake was estimated to be 0.06 +/- 0.05 mug/kg/day (3.51 microg/day per individual) in the Cameroon population. Interestingly, free and bioavailable testosterone concentrations and estradiol/testosterone ratio correlated with BPA levels in the overall population. When data were analysed according to residence, BPA correlated with total testosterone levels ( r = -0.433) and estradiol/testosterone ratio ( r = 0.338) in the urban residents only, while the rural population exhibited significant increases in sex-hormone-binding globulin with increased BPA exposure. Our data showed that the male Cameroon population is exposed to BPA but that inconstant BPA association to endocrine reproductive markers suggests that other environmental factors in combination with BPA exposure might influence testicular function