High Peak Estradiol Predicts Higher Miscarriage and Lower Live Birth Rates in High Responders Triggered with a GnRH Agonist in IVF/ICSI Cycles.

OBJECTIVE: To investigate parameters predictive of pregnancy outcomes in high responders undergoing fresh, autologous, GnRH antagonist IVF/ICSI cycles using a GnRH agonist trigger. STUDY DESIGN: Retrospective cohort study of all patients deemed high-risk for ovarian hyperstimulation syndrome who underwent fresh, autologous IVF/ICSI using a GnRH agonist trigger at an academic fertility center from 2010-2012. RESULTS: A total of 71 first cycles were analyzed. Rates of clinical pregnancy, live birth (LB), and total (clinical plus biochemical) miscarriage (MC) were 52%, 38%, and 25%, respectively. Mean peak estradiol (E2) and the number of oocytes retrieved were 3,701 pg/mL and 15.2, respectively. Peak E2 was significantly higher in those cycles resulting in clinical MC (p = 0.003). After adjusting for age, basal follicle stimulating hormone, and the number of oocytes retrieved, elevated peak E2 remained associated with increased clinical MC (p = 0.029) and trended towards a relationship with higher total MC (p = 0.062). When peak E2 was treated as a binary variable based on the threshold value of > 5,000 pg/mL, peak E2 above this value was associated with a higher rate of clinical MC (OR = 16.14 with 95% CI 1.25-209.35, p = 0.033) and total MC (OR = 6.81 with 95% CI 1.12-41.54, p = 0.037), as well as a lower LB rate (OR = 0.095 with 95% CI 0.01-0.90, p = 0.041). CONCLUSION: Clinicians should recognize most IVF/ICSI patients triggered with a GnRH agonist as inherently in danger of excessively high serum E2 and avoid peak levels > 5,000 pg/mL in order to avoid higher MC and lower LB rates.

Pregnancy rates in donor oocyte cycles compared to similar autologous in vitro fertilization cycles: an analysis of 26,457 fresh cycles from the Society for Assisted Reproductive Technology.

OBJECTIVE: To use a large US IVF database and compare pregnancy outcomes in fresh donor oocyte versus autologous IVF cycles in women age 20-30 years. DESIGN: Retrospective cohort study. SETTING: Not applicable. PATIENT(S): Women undergoing fresh autologous ovarian stimulation, and oocyte donors and recipients in the United States between 2008 and 2010. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Implantation, clinical pregnancy (CP), and live birth (LB) rates. RESULT(S): Despite similar demographics, stimulation, and embryo parameters, donor oocyte recipients had significantly higher rates of implantation, CP, and LB compared to those undergoing fresh autologous cycles. Odds ratios for implantation, CP, and LB significantly favored the donor oocyte group in all comparisons, including those limited to intracytoplasmic sperm injection cycles, intracytoplasmic sperm injection with male factor, unexplained infertility, cleavage stage embryo transfer, blastocyst transfer, elective single blastocyst transfer, and autologous patients with prior tubal ligation. CONCLUSION(S): Recent US data suggest that the hormonal environment resulting from autologous ovarian stimulation lowers IVF success rates. Further research is needed to determine when to avoid fresh embryo transfer in autologous patients.

Pregnancy outcomes decline in recipients over age 44: an analysis of 27,959 fresh donor oocyte in vitro fertilization cycles from the Society for Assisted Reproductive Technology.

OBJECTIVE: To use a large and recent national registry to provide an updated report on the effect of recipient age on the outcome of donor oocyte in vitro fertilization (IVF) cycles. DESIGN: Retrospective cohort study. SETTING: United States national registry for assisted reproductive technology. PATIENT(S): Recipients of donor oocyte treatment cycles between 2008 and 2010, with cycles segregated into five age cohorts: ≤34, 35 to 39, 40 to 44, 45 to 49, and ≥50 years. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Implantation, clinical pregnancy, live-birth, and miscarriage rates. RESULT(S): In donor oocyte IVF cycles, all age cohorts ≤39 years had similar rates of implantation, clinical pregnancy, and live birth when compared with the 40- to 44-year-old reference group. Patients in the two oldest age groups (45 to 49, ≥50 years) experienced statistically significantly lower rates of implantation, clinical pregnancy, and live birth compared with the reference group. Additionally, all outcomes in the ≥50-year-old group were statistically significantly worse than the 45- to 49-year-old group, demonstrating progressive decline with advancing age. CONCLUSION(S): Recent national registry data suggest that donor oocyte recipients have stable rates of pregnancy outcomes before age 45, after which there is a small but steady and significant decline.

Oocyte number as a predictor for ovarian hyperstimulation syndrome and live birth: an analysis of 256,381 in vitro fertilization cycles.

OBJECTIVE: To investigate the association between oocyte number and the rates of ovarian hyperstimulation syndrome (OHSS) and live birth (LB) in fresh autologous in vitro fertilization (IVF) cycles. DESIGN: Retrospective cohort study. SETTING: An academic reproductive medicine practice. PATIENT(S): We analyzed data from 256,381 IVF cycles using the 2008-2010 Society for Assisted Reproductive Technology national registry. Patients were divided into five groups based on retrieved oocyte number. MAIN OUTCOME MEASURE(S): Rates of OHSS and LB were calculated for each group. A generalized estimating equation (GEE) was used to assess differences in OHSS and LB between groups. Receiver operating characteristic (ROC) curves were used to evaluate oocyte number as a predictor of OHSS and LB. INTERVENTION(S): None. RESULT(S): The LB rate increased up to 15 oocytes, then plateaued (0-5: 17%, 6-10: 31.7%; 11-15: 39.3%; 16-20: 42.7%; 21-25: 43.8%; and >25 oocytes: 41.8%). However, the rate of OHSS became much more clinically significant after 15 oocytes (0-5: 0.09%; 6-10: 0.37%; 11-15: 0.93%; 16-20: 1.67%; 21-25: 3.03%; and >25 oocytes: 6.34%). These trends remained after adjustment with the use of GEE. ROC curves revealed that although oocyte number is not useful in the prediction of LB, 15 retrieved oocytes is the number that best predicts OHSS risk. CONCLUSION(S): Retrieval of >15 oocytes significantly increases OHSS risk without improving LB rate in fresh autologous IVF cycles. In general, less aggressive stimulation protocols should be considered, especially in high-responders, to optimize outcomes.

Whole-genome sequences of DA and F344 rats with different susceptibilities to arthritis, autoimmunity, inflammation and cancer.

DA (D-blood group of Palm and Agouti, also known as Dark Agouti) and F344 (Fischer) are two inbred rat strains with differences in several phenotypes, including susceptibility to autoimmune disease models and inflammatory responses. While these strains have been extensively studied, little information is available about the DA and F344 genomes, as only the Brown Norway (BN) and spontaneously hypertensive rat strains have been sequenced to date. Here we report the sequencing of the DA and F344 genomes using next-generation Illumina paired-end read technology and the first de novo assembly of a rat genome. DA and F344 were sequenced with an average depth of 32-fold, covered 98.9% of the BN reference genome, and included 97.97% of known rat ESTs. New sequences could be assigned to 59 million positions with previously unknown data in the BN reference genome. Differences between DA, F344, and BN included 19 million positions in novel scaffolds, 4.09 million single nucleotide polymorphisms (SNPs) (including 1.37 million new SNPs), 458,224 short insertions and deletions, and 58,174 structural variants. Genetic differences between DA, F344, and BN, including high-impact SNPs and short insertions and deletions affecting >2500 genes, are likely to account for most of the phenotypic variation between these strains. The new DA and F344 genome sequencing data should facilitate gene discovery efforts in rat models of human disease.

How Obamacare will impact reproductive health.

For many years, health care delivery in the United States was accomplished through a complicated and evolving series of publicly and privately available insurance programs. In recent years, the increasing cost of health care as well as the relatively large number of individuals without any health care insurance coverage has prompted repeated attempts to modify or overhaul the current health care delivery paradigm. The largest legislative change to this system occurred on March 23, 2010, when President Barack Obama signed into law the Patient Protection and Affordable Care Act (PPACA).The PPACA is a multifaceted and sweeping piece of legislation. The law introduces a myriad number of changes into both public and private health insurance. Understanding the law, its implications, and how to navigate through these changes is essential to provide high-quality health care to patients. Although the law or parts of it are still at risk of being modified either through judicial or political action, it is important to recognize the current aspects of the law to understand any future modifications. Providing health care coverage in the United States is sure to be as it has always been: a constantly changing and evolving set of private and public policies that carry with them significant complexities and challenges. Health care providers must constantly strive to maximize access to and quality of medical care in whatever paradigm evolves in the future.

A truncated progesterone receptor (PR-M) localizes to the mitochondrion and controls cellular respiration.

The cDNA for a novel truncated progesterone receptor (PR-M) was previously cloned from human adipose and aortic cDNA libraries. The predicted protein sequence contains 16 unique N-terminal amino acids, encoded by a sequence in the distal third intron of the progesterone receptor PR gene, followed by the same amino acid sequence encoded by exons 4 through 8 of the nuclear PR. Thus, PR-M lacks the N terminus A/B domains and the C domain for DNA binding, whereas containing the hinge and hormone-binding domains. In this report, we have localized PR-M to mitochondria using immunofluorescent localization of a PR-M-green fluorescent protein (GFP) fusion protein and in Western blot analyses of purified human heart mitochondrial protein. Removal of the putative N-terminal mitochondrial localization signal obviated association of PR-M with mitochondria, whereas addition of the mitochondrial localization signal to green fluorescent protein resulted in mitochondrial localization. Immunoelectron microscopy and Western blot analysis after mitochondrial fractionation identified PR-M in the outer mitochondrial membrane. Antibody specificity was shown by mass spectrometry identification of a PR peptide in a mitochondrial membrane protein isolation. Cell models of overexpression and gene silencing of PR-M demonstrated a progestin-induced increase in mitochondrial membrane potential and an increase in oxygen consumption consistent with an increase in cellular respiration. This is the first example of a truncated steroid receptor, lacking a DNA-binding domain that localizes to the mitochondrion and initiates direct non-nuclear progesterone action. We hypothesize that progesterone may directly affect cellular energy production to meet the increased metabolic demands of pregnancy.

Hyperglycosylated human chorionic gonadotropin does not increase progesterone production by luteinized granulosa cells.

CONTEXT: Trophoblast-derived human chorionic gonadotropin (hCG) promotes corpus luteum progesterone (P4) production, and wide ranges of serum P4 levels are noted in various pregnancy outcomes, despite similar hCG concentrations. There are five unique biologically active hCG variants in human pregnancy urine, and previous studies of P4 production in response to hCG have used only preparations containing all isoforms. Understanding exactly which hCG variant is primarily responsible for stimulating corpus luteum steroidogenesis may have great clinical and diagnostic implications, including in the setting of ectopic pregnancy. OBJECTIVE: Our objective was to delineate the role of the standard and hyperglycosylated (H)-hCG isoforms in stimulating P4 production by luteinized granulosa cells. DESIGN AND SETTING: Cell culture, ELISA, and fluorometric-based protein assays were done at Duke University Medical Center. PATIENTS: Patients were anonymous oocyte donors. INTERVENTION: Cultured luteinized granulosa cells were treated with 0.25, 0.5, and 1.0 ng/ml total hCG, which contains all isoforms, purified standard hCG (37.1 kDa), and purified H-hCG (42.8 kDa). MAIN OUTCOME MEASURE: P4 produced per total cellular protein (nanograms per microgram) was measured via ELISA and fluorometric protein determination kits. RESULTS: Both total hCG (P = 0.0003) and purified standard hCG (P < 0.0001) stimulated a dose-dependent increase in P4 production. Purified H-hCG did not change the P4 produced per total cellular protein response (P value not significant). CONCLUSIONS: Standard hCG stimulated P4 production by cultured granulosa cells and likely supports corpus luteum function via interactions with the LH/hCG receptor. In contrast, H-hCG did not increase P4 production, which indicates a nonsteroidogenic role for this protein during early gestation.

Management of gynecologic surgery in the patient with factor XI deficiency: a review of the literature.

UNLABELLED: Factor XI deficiency is a rare bleeding disorder that is more commonly found in Ashkenazi Jews. Bleeding manifestations of this disorder are varied and poorly correlate with factor XI levels. Spontaneous bleeding is uncommon, whereas delayed postoperative bleeding is often the presentation of factor XI deficiency. To date, there are no standard recommendations for prophylactic treatment in women undergoing gynecologic surgery. Here, we review published cases of gynecological surgery in women with factor XI deficiency and discuss the risks and benefits of various therapeutic options. TARGET AUDIENCE: Obstetricians And Gynecologists. LEARNING OBJECTIVES: After participating in this activity, physicians should be better able to identify the pathophysiology of factor XI deficiency. Compare previous outcomes of prophylactic treatment in patients with factor XI deficiency undergoing gynecological surgery. Implement possible prophylactic therapies for patients with factor XI deficiency undergoing gynecological surgery.

A feasibility study to evaluate pelvic peritoneal anatomy with a saline intraperitoneal sonogram (SIPS).

OBJECTIVE: To prove the safety and feasibility of evaluating pelvic anatomy with a new imaging technique called saline intraperitoneal sonogram (SIPS). DESIGN: Prospective clinical case series. SETTING: Outpatient fertility clinic. PATIENT(S): Ten women with unexplained infertility and normal hysterosalpingograms (HSG). Five women with no known risk factors and five women with known risk factors for adhesive disease were enrolled. INTERVENTION(S): Step 1 required performing a sonohysterogram. Step 2 involved directing a 17-g oocyte retrieval needle into a pocket of peritoneal fluid under ultrasound guidance and infusing normal saline. The pelvic anatomy was evaluated with the three-dimensional and four-dimensional mode on pelvic ultrasound. MAIN OUTCOME MEASURE(S): Technical feasibility, safety, time, fluid infusion, and deficit volumes. RESULT(S): All 10 patients successfully completed the protocol. One of the five women with no risk factors for adhesive disease and a normal HSG was discovered to have a unilateral hydrosalpinx and filmy adhesive disease on SIPS. Both findings were confirmed on laparoscopy. Three out of the five women with known risk factors had abnormal SIPS imaging and were confirmed on laparoscopy to have significant adhesive disease. The average procedure time was 45 minutes (±15 minutes). CONCLUSION(S): This study demonstrates that SIPS is a safe, quick, and potentially cost-effective method for evaluating pelvic adhesive disease in an outpatient facility in women with unexplained infertility and a normal HSG.

Early polycystic ovary syndrome as a possible etiology of unexplained premenarcheal ovarian torsion.

STUDY OBJECTIVE: To study evidence of polycystic ovary syndrome (PCOS) in premenarcheal adolescents with unexplained ovarian torsion. DESIGN: Retrospective observational case series. SETTING: Tertiary university clinical center PARTICIPANTS: Six premenarcheal adolescents and six adults with acute ovarian torsion INTERVENTION: A chart review. MAIN OUTCOME MEASURES: Contralateral ovarian size, operative findings, ovarian pathology, hormone testing RESULTS: Five of the six premenarcheal cases had no pathologic explanation for their ovarian torsion. In four of the cases, size measurements of the contralateral ovary were noted to be larger than the criterion of their respective age group. Three of the four cases had either an ovarian volume (28.5 cm(3)) or an area (16.0 cm(2) and 57.6 cm(2)) that was above the size criterion for a polycystic ovary (volume >10 cm(3) or area>5.5 cm(2)). Pathology of a wedge biopsy of one of the contralateral ovaries suggested evidence of polycystic ovary. Finally, hormone testing available in three of the cases revealed elevated testosterone levels in two. Among the adults, half of the cases had a pathologic explanation for ovarian torsion. One out of the five cases had a contralateral ovary that was significantly enlarged and this was noted in a woman with a diagnosis of PCOS. The remaining two cases had extensive necrosis of the torsed ovary and no other diagnosis was made. CONCLUSION: We propose that premenarcheal girls presenting with ovarian torsion, without obvious ovarian pathology, be screened for ultrasound and biochemical evidence of PCOS. In those with evidence of PCOS, treatment with oral contraceptives should be considered taking into account the age and pubertal development, to decrease ovarian volume.

Heterotopic cervical pregnancy treated with transvaginal ultrasound-guided aspiration resulting in cervical site varices within the myometrium.

OBJECTIVE: To report a case of successful treatment of a heterotopic cervical pregnancy from IVF-embryo transfer and intracytoplasmic sperm injection (ICSI) that resulted in uterine varices at the cervical site. DESIGN: Case report. SETTING: Tertiary university clinical center. PATIENT(S): A 34-year-old with a history of infertility associated with oligospermia who developed a heterotopic cervical pregnancy diagnosed at 7 weeks gestation. INTERVENTION(S): Transvaginal ultrasound (TVS)-guided aspiration of the cervical pregnancy; preoperative placement of bilateral hypogastric artery occlusion balloons; cesarean section. MAIN OUTCOME MEASURE(S): Successful delivery of intrauterine pregnancy; conservation of the uterus. RESULT(S): Successful termination of the cervical site pregnancy was achieved with TVS-guided aspiration. However, the pregnancy was then complicated by development of uterine varices at the cervical site noted on serial obstetric ultrasounds and magnetic resonance imaging (MRI). Successful management of the pregnancy required a multidisciplinary approach and preoperative placement of bilateral hypogastric artery occlusion balloons. A scheduled high fundal classic cesarean section at 37 weeks allowed for safe delivery of a healthy infant. Complete spontaneous resolution of the uterine varices was noted after the delivery. CONCLUSION(S): It is unclear whether residual ectopic tissue contributed to this later complication; however, it cannot be ignored that the locations of the aborted site and the prominence of dilated venous vasculature in this same location suggests a correlation. The interventions applied are reasonable conservative treatments of a cervical heterotopic pregnancy and a management strategy for uterine varices.

Breast cancer cell-targeted oxidative stress: enhancement of cancer cell uptake of conjugated linoleic acid, activation of p53, and inhibition of proliferation.

We investigated the mechanism of inhibition of cell proliferation by mixed isomers of CLA (9-cis, 11-trans CLA; 10-trans, 12-cis CLA) on human, non-tumorigenic MCF10A cells that were derived from mammary ductal epithelial cells and MCF7 cells that were derived from a well differentiation mammary adenocarcinoma. When treated in the log phase of growth, the uptake of CLA by MCF7 exceeded the levels measured in MCF10A cells. Treatment with CLA in the presence of HPO doubled the incorporation of CLA in MCF7 cells, independent of the isomer, but reduced the incorporation of CLA by MCF10A cells. CLA caused tumor cell-targeted increased expression of 4-hydroxy-2-nonenal (4HNE), a product of lipid peroxidation, and decreased proliferation in MCF7 cells, as measured by the incorporation of bromodeoxyuridine (BrdU) and expression of phosphorylated histone H3, and the effects of CLA in combination with HPO on mitosis were greater than the effects of either agent alone. Decreased cell proliferation in CLA-treated MCF7 cells coincided with increased nuclear localization of phosphorylated, activated p53 protein, and decreased nuclear localization of the transcription factor FKHRSer256. Importantly, CLA-treated MCF7 cells were more sensitive than MCF10A cells to HPO-induced 4HNE, expression of p53, and decreased mitotic activity. These studies suggest that tumor cell-targeted increased sensitivity to oxidative stress and activation of p53 play important roles in the regulation of human breast cancer cell proliferation by CLA.