Conserved roles of mouse DUX and human DUX4 in activating cleavage-stage genes and MERVL/HERVL retrotransposons.

To better understand transcriptional regulation during human oogenesis and preimplantation development, we defined stage-specific transcription, which highlighted the cleavage stage as being highly distinctive. Here, we present multiple lines of evidence that a eutherian-specific multicopy retrogene, DUX4, encodes a transcription factor that activates hundreds of endogenous genes (for example, ZSCAN4, KDM4E and PRAMEF-family genes) and retroviral elements (MERVL/HERVL family) that define the cleavage-specific transcriptional programs in humans and mice. Remarkably, mouse Dux expression is both necessary and sufficient to convert mouse embryonic stem cells (mESCs) into 2-cell-embryo-like ('2C-like') cells, measured here by the reactivation of '2C' genes and repeat elements, the loss of POU5F1 (also known as OCT4) protein and chromocenters, and the conversion of the chromatin landscape (as assessed by transposase-accessible chromatin using sequencing (ATAC-seq)) to a state strongly resembling that of mouse 2C embryos. Thus, we propose mouse DUX and human DUX4 as major drivers of the cleavage or 2C state.

Reproductive considerations in the setting of chronic viral illness.

Special considerations must be taken when patients with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C desire to become pregnant. Patients with chronic viral illnesses desire to have children at rates similar to the general population, and options are available to decrease both vertical transmission and viral transmission between partners. Preconception counseling or consultation with fertility specialists is imperative in patients with HIV, hepatitis B, and hepatitis C so that reproductive goals can be addressed and optimized. In couples in which one partner has HIV, the use of highly active antiretroviral therapy or preexposure prophylaxis can significantly reduce the risk of transmission between serodiscordant partners. The use of density gradient sperm-washing techniques and intrauterine insemination or in vitro fertilization results in an apparent lack of transmission of HIV between partners when the male partner is HIV-positive. Vertical transmission of HIV from mother to child can be reduced by use of highly active antiretroviral therapy regimens throughout pregnancy or by cesarean delivery in the setting of high maternal viral load. Transmission of hepatitis B between partners can be eliminated by vaccinating the uninfected partner. Vertical transmission from a hepatitis B-infected mother to a child can be reduced by vaccinating neonates with the standard hepatitis B vaccine series as well as hepatitis B immune globulin. Recent data have shown the antiviral medication tenofovir to be an effective way to reduce vertical transmission in the setting of high maternal viral load or the presence of hepatitis B e antigen. There are multiple antiviral medications available to treat chronic hepatitis C, although access to these medications often is limited by cost. Similar to HIV-positive patients, in settings in which the male partner is infected with hepatitis C, density gradient sperm washing can be used before intrauterine insemination or in vitro fertilization to reduce transmission of hepatitis C between partners. No safe and effective method exists to reduce vertical transmission of hepatitis C once a woman becomes pregnant, highlighting the importance of treatment of hepatitis C before pregnancy.

Female infertility, infertility-associated diagnoses, and comorbidities: a review.

PURPOSE: The purpose of the study is to evaluate existing literature for possible associations between female infertility, infertility-associated diagnoses, and the following areas of disease: psychiatric disorders, breast cancer, ovarian cancer, endometrial cancer, cardiovascular disease, and metabolic dysfunction. METHODS: The design of the study is a literature review. The patients were women included in 26 selected studies due to a diagnosis of infertility or a reproductive disorder associated with infertility. This study has no interventions, and the main outcome measure is the association between female infertility or a related diagnosis and psychiatric disorders, breast cancer, ovarian cancer, endometrial cancer, cardiovascular disease, and metabolic dysfunction. RESULTS: Female infertility and related reproductive disorders may have ramifications for women beyond reproductive health. An analysis of publications shows that women with infertility had higher rates of psychiatric disorders and endometrial cancer than the general population [1-10]. Data is conflicting about whether infertile women are at increased risk for breast cancer and ovarian cancer [7, 8, 10-20]. A generalized diagnosis of infertility was not clearly associated with an increased risk of cardiovascular disease or metabolic dysfunction, but women with infertility related to polycystic ovarian syndrome (PCOS) do appear more likely to develop cardiovascular disease and metabolic disorders such as diabetes than the general population [16, 21-26]. CONCLUSIONS: Female infertility and associated diagnoses have overall health implications. Beyond treatment of patients' immediate reproductive needs, healthcare professionals must be aware of the broader health impact of specific causes of infertility in order to provide accurate counseling regarding long-term risk.

Sperm concentration is poorly associated with hypoandrogenism in infertile men.

OBJECTIVE: To evaluate the utility of routine hormone evaluation in all men presenting for infertility by understanding the relationship between sperm concentration and hypoandrogenism. METHODS: We performed a retrospective cross-sectional study between September 2013 and May 2014 at a tertiary referral center in Utah. Ninety-four men presenting for infertility consecutively between the ages of 18 and 55 years were identified. Our primary outcome was rate of hypoandrogenism among infertile men defined as the baseline total serum testosterone levels <300 ng/dL or bioavailable testosterone (BAT) levels <155 ng/dL. Secondary outcomes included association of normospermia, oligozoospermia, or azoospermia with biochemical or clinical hypoandrogenism. RESULTS: Thirty-nine men (41%) had a total serum testosterone level of <300 ng/dL, and 41 men (43%) had a BAT level <155 ng/dL. Biochemical and symptomatic hypoandrogenism was common; 17 men (18%) had a total testosterone level <300 ng/dL and ≥ 3 positive Androgen Deficiency in Aging Male (ADAM) responses, and 18 men (19%) had a BAT level of <155 ng/dL and ≥ 3 positive ADAM responses. Sperm concentration (normospermia, oligozoospermia, and azoospermia) was not associated with biochemical hypoandrogenism (total testosterone level <300 ng/dL or BAT level <155 ng/dL), symptomatic hypoandrogenism (≥ 3 positive ADAM responses), or sexual dysfunction (Sexual Health Inventory for Men score <21). CONCLUSION: Hypoandrogenism is common among infertile men, and routine hormonal evaluation may identify hypoandrogenism in many infertile men with otherwise normal semen analysis. Sperm concentration (normospermia, oligozoospermia, and azoospermia) is not well associated with hypoandrogenism in infertile men.

Increased urinary cobalt and whole blood concentrations of cadmium and lead in women with uterine leiomyomata: Findings from the ENDO Study.

Multiple trace elements have estrogen receptor activity, but the association of these elements with uterine leiomyoma has not been defined. A cohort of 473 women aged 18-44 undergoing surgery for benign gynecologic indications provided whole blood and urine specimens for trace element analysis, which was performed by inductively coupled plasma mass spectrometry. Twenty elements were analyzed in blood and 3 in urine. The surgeon documented whether fibroids were present. Geometric mean concentrations were compared between women with and without fibroids, and logistic regression models were generated to assess the impact of the concentration of each trace element on the odds of fibroids. In multivariate regressions, odds of a fibroid diagnosis were higher with increased whole blood cadmium (AOR 1.44, 95% CI 1.02, 2.04) and lead (AOR 1.31 95% CI 1.02, 1.69), and urine cobalt (AOR 1.31, 95% CI 1.02, 1.70). Urinary cadmium and lead were not related to fibroid diagnosis. Increased exposure to trace elements may contribute to fibroid growth, and fibroids may serve as a reservoir for these elements. Differences between urinary and whole blood findings merit further investigation, as urinary cadmium has been considered a superior marker of exposure.

Interrater and intrarater reliability in the diagnosis and staging of endometriosis.

OBJECTIVE: To estimate the interrater and intrarater reliability of endometriosis diagnosis and severity of disease among gynecologic surgeons viewing operative digital images. METHODS: The study population comprised a random sample (n=148 [36%]) of women who participated in the Endometriosis: Natural History, Diagnosis and Outcomes study. Four academic expert and four local, specialized expert surgeons reviewed the images, diagnosed the presence or absence of endometriosis for each woman, and rated severity using the revised American Society for Reproductive Medicine (ASRM) criteria. Interrater-level and intrarater-level agreement were calculated for both endometriosis diagnosis and staging. RESULTS: The interrater reliability for endometriosis diagnosis among the eight surgeons was substantial: Fleiss κ=0.69 (95% confidence interval [CI] 0.64-0.74). Surgeons agreed on revised ASRM endometriosis staging criteria after experienced assessment in a majority of cases (mean 61%, range 52-75%) with moderate interrater reliability: Fleiss κ=0.44 (95% CI 0.41-0.47). The intrarater reliability for experienced assessment compared with computer-assisted revised ASRM staging was almost perfect (mean weighted κ=0.95, range 0.89-0.99). CONCLUSION: Substantial reliability was found for revised ASRM endometriosis diagnosis, whereas moderate reliability was observed for staging. Almost perfect reliability was observed for surgeons' rating of disease severity compared with computerized-assisted, checklist-based staging. Findings suggest that reliability in endometriosis diagnosis is not greatly altered by location or composition of surgeons, supporting the conduct of multisite studies or compilation of endometriosis data across clinical centers. Although surgeons appear to be skilled at assessing endometriosis stage intuitively, how staging of disease burden correlates with clinical outcomes remains to be developed.

Fertility-sparing management of endometrial adenocarcinoma.

UNLABELLED: Approximately 15% of patients with endometrial cancer are premenopausal. Previous studies largely support the conservative treatment of endometrial cancer in women desiring future fertility. From these studies, 75% to 80% of patients demonstrate a complete response to progestin therapy and the average recurrence rate is 30% to 35%. Conservative therapy should be reserved for women with International Federation of Gynecology and Obstetrics grade I tumors. Before conservative management, patients should be informed of the elevated risk (11%-29%) of concurrent ovarian cancer in cases of premenopausal endometrial cancer, and screening and ongoing surveillance during the treatment period is mandatory. A suggestion of myometrial invasion or metastatic disease is a contraindication to conservative management. Individuals meeting criteria for Lynch syndrome testing should be referred to genetic counseling. Fertility treatment should be individualized, and close surveillance is required during treatment. Staging hysterectomy is recommended after the completion of the childbearing period. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After participating in this activity, physicians should be better able to select appropriate candidates with endometrial cancer for fertility-sparing treatment. Educate patients with endometrial cancer regarding the risks and benefits of standard of care therapy and conservative therapy and screen appropriate patients for Lynch syndrome.

Conservative treatment of a Herlyn-Werner-Wunderlich müllerian anomaly variant, noncommunicating hemiuterus with Gartner duct pseudocyst.

Asymmetric obstructed uterus didelphys (Herlyn-Werner-Wunderlich syndrome) is a rare congenital müllerian anomaly consisting of uterus didelphys, hemivaginal septum, and ipsilateral renal agenesis. Herein is reported a case of incomplete Herlyn-Werner-Wunderlich syndrome diagnosed using 3-dimensional transvaginal ultrasound in a 14-year-old patient with absence of the hemivaginal septum. The most contributive diagnostic factors and appropriate therapeutic management in such cases are discussed.

A superior mesenteric vein thrombosis associated with in vitro fertilization.

OBJECTIVE: To describe a case of superior mesenteric vein thrombosis associated with IVF. DESIGN: Case report. SETTING: University teaching hospital. PATIENT(S): A 33-year-old female developed progressive abdominal pain several days after ET in her first IVF cycle. A computed tomography scan 12 days after ET showed a superior mesenteric vein thrombosis. INTERVENTION(S): Therapeutic anticoagulation. MAIN OUTCOME MEASURE(S): Resolution of the superior mesenteric vein thrombosis with therapeutic anticoagulation. RESULT(S): Early diagnosis and treatment of a superior mesenteric vein thrombosis associated with IVF led to a favorable outcome. CONCLUSION(S): Endocrine alterations consequent to controlled ovarian hyperstimulation for IVF place patients at risk for thromboembolic events. Thromboembolic events may occur during an IVF cycle in the absence of overt ovarian hyperstimulation, an inherited thrombophilia, or pregnancy. Early diagnosis and treatment of superior mesenteric vein thrombosis can lead to a favorable outcome. Treatment guidelines for superior mesenteric vein thrombosis in setting of IVF are discussed.