Differential Effects of the Hormonal and Copper Intrauterine Device on the Endometrial Transcriptome.

The contraceptive effectiveness of intrauterine devices (IUDs) has been attributed in part to a foreign body reaction in the endometrium. We performed this study to better understand mechanisms of action of contraceptives of by studying their effects on endometrial and cervical transcriptomes. We collected endometrial and cervical biopsies from women using the levonorgestrel-releasing intrauterine system (LNG-IUS, n = 11), copper intrauterine device (cu-IUD, n = 13) or levonorgestrel-containing combined oral contraceptives (COC, n = 12), and from women not using contraceptives (control group, n = 11). Transcriptional profiling was performed with Affymetrix arrays, Principal Component Analysis and the bioconductor package limma. In endometrial samples from cu-IUD users, there were no genes with statistically significant differential expression compared to controls. In LNG-IUS users, 2509 genes were differentially expressed and mapped predominantly onto immune and inflammatory pathways. The cervical samples showed no statistically significant differential gene expression compared to controls. Hormonal and copper IUDs have significantly different effects on the endometrial transcriptome, with the LNG-IUS transcriptome showing pronounced inflammation and immune activation compared to controls whereas the cu-IUD transcriptome was indistinguishable from luteal phase endometrium. These findings argue against a foreign body reaction as a common mechanism of action of IUDs

Progestins Related to Progesterone and Testosterone Elicit Divergent Human Endometrial Transcriptomes and Biofunctions.

Progestins are widely used for the treatment of gynecologic disorders and alone, or combined with an estrogen, are used as contraceptives. While their potencies, efficacies and side effects vary due to differences in structures, doses and routes of administration, little is known about their effects on the endometrial transcriptome in the presence or absence of estrogen. Herein, we assessed the transcriptome and pathways induced by progesterone (P4) and the three most commonly used synthetic progestins, medroxyprogesterone acetate (MPA), levonorgestrel (LNG), and norethindrone acetate (NETA), on human endometrial stromal fibroblasts (eSF), key players in endometrial physiology and reproductive success. While there were similar transcriptional responses, each progestin induced unique genes and biofunctions, consistent with their structural similarities to progesterone (P4 and MPA) or testosterone (LNG and NETA), involving cellular proliferation, migration and invasion. Addition of estradiol (E2) to each progestin influenced the number of differentially expressed genes and biofunctions in P4 and MPA, while LNG and NETA signatures were more independent of E2. Together, these data suggest different mechanisms of action for different progestins, with progestin-specific altered signatures when combined with E2. Further investigation is warranted for a personalized approach in different gynecologic disorders, for contraception, and minimizing side effects associated with their use

Stanniocalcin-1 expression in normal human endometrium and dysregulation in endometriosis

Objective To determine expression of stanniocalcin-1 (STC1) in human endometrium with and without endometriosis and its regulation by steroid hormones. Design Laboratory study. Setting University. Patient(s) Nineteen women with endometriosis and 33 control women. Intervention(s) Endometrial biopsy and fluid sampling. Main Outcome Measure(s) Analysis of early secretory (ESE) and midsecretory (MSE) endometrial secretomes from fertile women with the use of nano–liquid chromatography–dual mass spectrometry; real-time quantitative polymerase chain reaction, and immunohistochemistry for STC1 and its receptor calcium-sensing receptor (CASR) mRNA and proteins in endometrium with and without endometriosis; evaluation of STC1 and CASR mRNA expression in endometrial stromal fibroblasts (eSF) from women with and without endometriosis decidualized with the use of E2P or 8-bromo-cyclic adenosine monophosphate (cAMP). Result(s) STC1 protein was strongly up-regulated in MSE versus ESE in endometrial fluid of fertile women. STC1 mRNA significantly increased in MSE from women with, but not from those without, endometriosis, compared with proliferative endometrium or ESE, with no significant difference throughout the menstrual cycle between groups. STC1 mRNA in eSF from control women increased >230-fold on decidualization with the use of cAMP versus 45-fold from women with endometriosis, which was not seen on decidualization with E2/P. CASR mRNA did not exhibit significant differences in any condition and was not expressed in isolated eSF. STC1 protein immunoexpression in eSF was significantly lower in women with endometriosis compared with control women. Conclusion(s) STC1 protein is significantly up-regulated in MSE endometrial fluid and is dysregulated in eutopic endometrial tissue from women with endometriosis. It is likely regulated by cAMP and may be involved in the pathogenesis of decidualization defects

Effects of the levonorgestrel-releasing intrauterine device on the immune microenvironment of the human cervix and endometrium

There is little information regarding the impact of the intrauterine device on immune parameters of the upper female reproductive tract related to risk of HIV acquisition

Dirac Gauginos, Negative Supertraces and Gauge Mediation

In an attempt to maximize General Gauge Mediated parameter space, I propose simple models in which gauginos and scalars are generated from disconnected mechanisms. In my models Dirac gauginos are generated through the supersoft mechanism, while independent R-symmetric scalar masses are generated through operators involving non-zero messenger supertrace. I propose several new methods for generating negative messenger supertraces which result in viable positive mass squareds for MSSM scalars. The resultant spectra are novel, compressed and may contain light fermionic SM adjoint fields.Comment: 16 pages 3 figure

Molecular probe technology detects bacteria without culture

<p>Abstract</p> <p>Background</p> <p>Our ultimate goal is to detect the entire human microbiome, in health and in disease, in a single reaction tube, and employing only commercially available reagents. To that end, we adapted molecular inversion probes to detect bacteria using solely a massively multiplex molecular technology. This molecular probe technology does not require growth of the bacteria in culture. Rather, the molecular probe technology requires only a sequence of forty sequential bases unique to the genome of the bacterium of interest. In this communication, we report the first results of employing our molecular probes to detect bacteria in clinical samples.</p> <p>Results</p> <p>While the assay on Affymetrix GenFlex Tag16K arrays allows the multiplexing of the detection of the bacteria in each clinical sample, one Affymetrix GenFlex Tag16K array must be used for each clinical sample. To multiplex the clinical samples, we introduce a second, independent assay for the molecular probes employing Sequencing by Oligonucleotide Ligation and Detection. By adding one unique oligonucleotide barcode for each clinical sample, we combine the samples after processing, but before sequencing, and sequence them together.</p> <p>Conclusions</p> <p>Overall, we have employed 192 molecular probes representing 40 bacteria to detect the bacteria in twenty-one vaginal swabs as assessed by the Affymetrix GenFlex Tag16K assay and fourteen of those by the Sequencing by Oligonucleotide Ligation and Detection assay. The correlations among the assays were excellent.</p

Persistent Lipophilic Environmental Chemicals and Endometriosis: The ENDO Study

Background: An equivocal literature exists regarding the relation between persistent organochlorine pollutants (POPs) and endometriosis in women, with differences attributed to methodologies