Extravillous trophoblast cell lineage development is associated with active remodeling of the chromatin landscape.

The extravillous trophoblast cell lineage is a key feature of placentation and successful pregnancy. Knowledge of transcriptional regulation driving extravillous trophoblast cell development is limited. Here, we map the transcriptome and epigenome landscape as well as chromatin interactions of human trophoblast stem cells and their transition into extravillous trophoblast cells. We show that integrating chromatin accessibility, long-range chromatin interactions, transcriptomic, and transcription factor binding motif enrichment enables identification of transcription factors and regulatory mechanisms critical for extravillous trophoblast cell development. We elucidate functional roles for TFAP2C, SNAI1, and EPAS1 in the regulation of extravillous trophoblast cell development. EPAS1 is identified as an upstream regulator of key extravillous trophoblast cell transcription factors, including ASCL2 and SNAI1 and together with its target genes, is linked to pregnancy loss and birth weight. Collectively, we reveal activation of a dynamic regulatory network and provide a framework for understanding extravillous trophoblast cell specification in trophoblast cell lineage development and human placentation.

Case Report: Uterine Didelphys and Cervical Agenesis in an 18 Year-Old Woman Presenting with a Pelvic Mass.

BACKGROUND: Although Müllerian anomalies are relatively common they can be easily misdiagnosed as other gynecologic conditions leading to inappropriate treatment. CASE: An 18-year-old woman presented to the hospital with abdominal pain and was found to have a 17-cm pelvic mass and absence of the cervix. Because of concern for recurrent endometrioma formation in the setting of a Müllerian anomaly, she underwent a hysterectomy. During surgery, she was noted to have complete uterine didelphys with cervical agenesis and a normal vagina. SUMMARY AND CONCLUSION: This extremely rare Müllerian anomaly represents one of the only descriptions to date of uterine didelphys with cervical agenesis and normal vaginal development. Appropriate identification and management of Müllerian anomalies is essential for guiding the care of these young, complex patients.

Luteal phase HCG support for unexplained recurrent pregnancy loss - a low hanging fruit?

Recurrent pregnancy loss (RPL) is defined by two or more failed pregnancies and accounts for only 1-5% of pregnancy failures. Treatment options for unexplained RPL (uRPL) are limited. Previous studies suggest a link between delayed implantation and pregnancy loss. Based on this, a timely signal for rescue of the corpus luteum (CL) using human chorionic gonadotrophin (HCG) could improve outcomes in women with uRPL. This retrospective cohort study included 98 subjects with uRPL: 45 underwent 135 monitored cycles without HCG support; and 53 underwent 142 cycles with a single mid-luteal HCG injection. Based on Log-rank Mantel-Cox survival curves, miscarriage rate and time to pregnancy decreased in the HCG group (P = 0.0005). Women receiving luteal HCG support had an increased chance of an ongoing pregnancy compared with those not receiving it (RR = 2.4; 95% CI 1.4-3.6; number need to treat (NNT) = 7; 95% CI 4-18). Subjects receiving HCG support had a significant absolute risk reduction (ARR) of miscarriage (P < 0.001; ARR = 11.5%; 95% CI 3.6-19.5; NNT = 9(5-27). These data suggest restoration of synchrony and CL support improves outcomes in women with RPL. Further randomized controlled trials of luteal-phase HCG in women with RPL appears warranted.

Prospective assessment of midsecretory endometrial leukemia inhibitor factor expression versus ανß3 testing in women with unexplained infertility.

OBJECTIVE: To evaluate endometrial leukemia inhibitor factor (LIF) expression as a marker of endometrial receptivity in women with unexplained infertility (UI). DESIGN: Prospective case-control study. SETTING: University-associated infertility clinics. PATIENT(S): Women with UI for more than 1 year and healthy control women. INTERVENTION(S): Endometrial biopsy. MAIN OUTCOME MEASURE(S): Time to pregnancy was compared between patients with UI who were evaluated for endometrial LIF protein as well as ανß3 integrin expression. Endometrium was evaluated using immunohistochemistry (IHC) and messenger RNA by real time reverse transcriptase-polymerase chain reaction (PCR) (quantitative real-time reverse transcriptase-PCR) in samples from women with UI as well as healthy control women. RESULT(S): Leukemia inhibitor factor was expressed in epithelial cells in a cyclic fashion in controls, and overall expression in the secretory phase was similar between controls and women with UI, whereas ανß3 integrin expression was reduced. However, using quantitative real-time PCR, LIF messenger RNA abundance was 4.4-fold lower in women with low levels of ανß3 integrin expression compared with samples with normal integrins. By immunohistochemistry, ανß3 integrin expression was always lacking when the histology was out of phase, whereas LIF expression was only negative in a subset of those samples. Reduced endometrial LIF expression was strongly associated with poor reproductive outcomes. CONCLUSION(S): Endometrial LIF expression peaks in the midsecretory phase and is reduced in some women with UI. The use of LIF in combination with ανß3 integrin as biomarkers appears to be superior to integrin testing alone when evaluating endometrial receptivity, primarily because of its earlier pattern of expression during the secretory phase.

Endometriosis and infertility.

Endometriosis is an enigmatic disease affecting up to 10% of reproductive-aged women causing pain and infertility. Up to 50% of women with endometriosis are infertile, and agreement about treatment options has been difficult to establish. The association between endometriosis and infertility is derived from comparisons of fertile and infertile women, animal models, donor sperm studies, and in vitro fertilization results. Diagnostic approaches based on endometrial changes associated with endometriosis are also providing insights into possible mechanisms of infertility, especially in women with milder forms of the disease. Treatment of endometriosis, including surgical ablation or resection, is cost-effective and offers the potential for improvement in cycle fecundity. Medical management of endometriosis-associated infertility has not been proven outside of in vitro fertilization.

Premature ovarian failure: a phenotypic expression of fragile X premutation.

Fragile X syndrome is the most common cause of mental retardation in the male. Historically, fragile X premutation was considered to be phenotypically silent. In recent reports the premutation has been associated with premature ovarian failure and fragile X-associated tremor/ataxia syndrome. This case describes a 24-year-old woman who presented with irregular menstrual cycles secondary to premature ovarian failure. Subsequent genetic analysis confirmed that she has a premutation for fragile X with 70 CGG trinucleotide repeats.