A novel approach toward the generation of oocytes by direct diploid cell haploidization.

Oocyte-mediated somatic cell haploidization is a process in which a diploid cell halves its chromosomal content by segregating its homologue within the ooplasm. Replacing the donor oocyte nucleus with a patient's female diploid somatic nucleus can generate patient-genotyped oocytes. Insemination of these resulting constructs enables their activation and induces a reductive meiotic division, haploidizing the diploid female donor cell that can subsequently support syngamy with the male genome and create a zygote. So far, experimental data for this method have been limited and have not consistently proven the generation of chromosomally normal embryos. Overall, we achieved reconstruction of murine oocytes with a micromanipulation survival rate of 56.5%, and a correct haploidization and fertilization rate of 31.2%, resulting in a 12.7% blastocyst rate. Time-lapse analysis revealed that reconstructed embryos underwent a timely polar body extrusion and pronuclear appearance followed by a satisfactory embryonic cleavage, comparable with the control. Whole genome sequencing of the analyzed embryos indicated that 27.3% (6/22) were properly diploid. Our findings suggest that diploid cell haploidization may be a feasible technique for creating functional gametes in mammals.

Comparison of fresh and frozen ejaculated spermatozoa in sibling oocyte recipient cycles.

RESEARCH QUESTION: Do IVF and intracytoplasmic sperm injection cycles using fresh and frozen ejaculated spermatozoa result in similar pregnancy outcomes in couples with non-male factor infertility? DESIGN: Retrospective cohort study; patients undergoing donor egg recipient cycles, in which oocytes from a single ovarian stimulation were split between two recipients, were reviewed. Two recipients of oocytes from a single donor were paired and categorized based on the type of ejaculated spermatozoa (fresh/frozen). Outcomes included delivery rate, implantation, pregnancy, pregnancy loss and fertilization rates. RESULTS: Of the 408 patients who received oocytes from a split donor oocyte cycle, 45 pairs of patients used discrepant types of ejaculated spermatozoa and were included in the study. Fertilization rate: fresh (74.8%); frozen (68.6%) (P = 0.13). Pregnancy rate: fresh (76%); frozen (67%); delivery rate: fresh (69%); frozen (44%); implantation rate was significantly higher: fresh (64%); frozen (36%) (P = 0.04). Rate of pregnancy loss was significantly higher in the frozen group compared with the fresh group (33% versus 5.9%, P = 0.013). Adjusted odds for delivery was 67% lower in the frozen group (95% CI 0.12, 0.89). Adjusted odds of pregnancy (adjusted OR 0.67, 95% CI 0.20, 2.27) and implantation (adjusted OR 0.5, 95% CI 0.12, 2.12) were not significantly different between the frozen and fresh sperm groups. CONCLUSION: In this model that controls for oocyte quality by using paired recipients from the same donor, frozen ejaculated spermatozoa resulted in lower delivery rates than those using fresh spermatozoa.

Is increasing paternal age negatively associated with donor oocyte recipient success? A paired analysis using sibling oocytes.

OBJECTIVE: To determine if increasing paternal age has an adverse effect on pregnancy outcomes in paired donor egg recipients who received oocytes from the same donor in the same stimulation cycle. DESIGN: Retrospective cohort study. SETTING: Reproductive Medicine Center. PATIENT(S): The study included 154 recipients who received oocytes from a split donor oocyte cycle and received sperm from men in discrepant age groups (group A: <45 years old; group B: ≥45 years old). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Implantation rate, pregnancy loss rate, pregnancy rate, and live birth rate. RESULT(S): The median paternal age was 41 years old for group A and 48 years old for group B. The pregnancy rate was 81% in group A compared with 69% in group B. The live birth rate was 65% in group A compared with 53% in group B. The rate of pregnancy loss was 19% in group A and 23% in group B. The implantation rate was 69% in group A compared with 66% in group B. The adjusted odds of pregnancy were found to be 65% lower for patients in the older partner age group (95% confidence interval [CI], 0.13, 0.95). The adjusted odds of live birth rate (odds ratio [OR], 0.45; 95% CI, 0.20, 1.00), implantation rate (OR, 0.91; 95% CI, 0.43, 1.92), and rate of pregnancy loss (OR, 1.5; 95% CI, 0.5, 4.5) favored the younger partner age group; however, these results were not statistically significant. CONCLUSION(S): In this model that controlled for oocyte quality to the greatest degree possible by using paired recipients from the same donor from the same stimulation cycle, we found that increased paternal age had a negative effect on pregnancy rates.

Detection of early placental hormone production in embryo transfer cycles lacking a corpus luteum.

PURPOSE: This study sought to identify the initiation of placental hormonal production as defined by the production of endogenous estradiol (E2) and progesterone (P4) in a cohort of patients undergoing programmed endometrial preparation cycles with single embryo transfers resulting in live-born singletons. METHODS: In this retrospective cohort study, patients undergoing either programmed frozen-thawed embryo transfer (FET) with autologous oocytes or donor egg recipient (DER) cycles with fresh embryos were screened for inclusion. Only patients who underwent a single embryo transfer, had a single gestational sac, and a resultant live-born singleton were included. All patients were treated with E2 patches and intramuscular progesterone injections. Main outcome measures were serial E2 and P4, with median values calculated for cycle days 28 (baseline), or 4w0d gestational age (GA), through 60, or 8w4d GA. The baseline cycle day (CD) 28 median value was compared to each daily median cycle day value using the Wilcoxon signed rank test. RESULTS: A total of 696 patients, 569 using autologous oocytes in programmed FET cycles and 127 using fresh donor oocytes, from 4/2013 to 4/2019 met inclusion criteria. Serum E2 and P4 levels stayed consistent initially and then began to increase daily. Compared to baseline CD 28 E2 (415 pg/mL), the serum E2 was significantly elevated at 542 pg/mL (P < 0.001) beginning on CD 36 (5w1d GA). With respect to baseline CD 28 P4 (28.1 ng/mL), beginning on CD 48 (6w6d GA), the serum P4 was significantly elevated at 31.6 ng/mL (P < 0.001). CONCLUSION: These results demonstrate that endogenous placental estradiol and progesterone production may occur by CD 36 and CD 48, respectively, earlier than traditionally thought.

Body mass index is not associated with donor oocyte recipient success: an ideal study using a paired analysis of sibling-oocytes.

OBJECTIVE: To determine whether a higher body mass index (BMI) adversely affects endometrial receptivity. DESIGN: Retrospective cohort study. SETTING: Academic medical center. PATIENTS: All donor egg recipients (DERs) who received fresh sibling-oocytes (oocytes from a donor that were retrieved from a single controlled ovarian hyperstimulation [COH] cycle and split between two recipients) at our center over a 7-year period were included. INTERVENTIONS: COH of a donor with fresh embryo transfer to recipients of differing BMI. The two recipients of the sibling-oocytes were paired and categorized based on BMI: group A (normal weight, BMI 18.5-24.9 kg/m2) and group B (overweight/obese, BMI >25.0 kg/m2). MAIN OUTCOME MEASURES: The primary outcome was implantation rate. Secondary outcomes were positive pregnancy rate and live birth rate. RESULTS: A total of 408 patients had received oocytes from a split donor oocyte cycle. There were 71 pairs of patients (142 recipients) that had discrepant BMI categories and were analyzed. Implantation rates were similar for the two groups (54.5%±5.3% vs. 56.3%±4.8% for group A and B, respectively, P=0.72). The positive pregnancy rate (77.5% vs. 80.3%, P=0.28) and live birth rate (54.9% vs. 60.6%, P=0.33) for groups A and B were also found to be similar. CONCLUSIONS: In this idealized model that controls to the greatest degree possible for factors that would impact implantation, we found that a higher BMI did not reduce implantation, positive pregnancy, or delivery rates. These findings suggest that a higher BMI does not adversely affect uterine receptivity.

Contemporary Management of Polycystic Ovarian Syndrome.

PCOS remains one of the most intriguing endocrine disorders that physicians encounter even though it was first described over 80 years ago. Although the diagnostic criteria, nomenclature, and ideal therapeutic strategies are areas of active and ongoing debate, there is no doubt that we have made tremendous progress in improving the quality of life and reproductive outcomes of women who suffer from this wide-ranging disorder.

Symptomatic Fibroid Management: Systematic Review of the Literature.

BACKGROUND AND OBJECTIVES: Symptomatic uterine fibroids are a societal and healthcare burden with no clear consensus among medical professionals as to which procedural treatment is most appropriate for each symptomatic patient. Our purpose was to determine whether recommendations can be made regarding best practice based on review and analysis of the literature since 2006. DATABASE: A systematic search of journal articles relevant to the treatment of symptomatic uterine fibroids was performed within PubMed, clinical society websites, and medical device manufacturers' websites. All clinical trials published in English, representing original research, and reporting clinical outcomes associated with interventions for the management of symptomatic uterine fibroids were considered. Each article was screened and selected based on study type, content, relevance, American College of Obstetricians and Gynecologists score, and internal/external validity. Outcomes of interest were patient baseline characteristics, fibroid characteristics, procedural details, complications, and long-term follow-up. Random-effects meta-analyses were used to test the quantitative data. Assessment of 143 full-length articles through January 2016 produced 45 articles for the quantitative analysis. The weighted combined results from hysterectomy trials were compared with those from uterine-preserving fibroid studies (myomectomy, uterine artery embolization, laparoscopic radiofrequency ablation, and magnetic resonance-guided focused ultrasound). CONCLUSION: We explored trends that might guide clinicians when counseling patients who need treatment of symptomatic fibroids. We found that fibroid therapy is trending toward uterine-conserving treatments and outcomes are comparable across those treatments. Since minimally invasive options are increasing, it is important for the clinician to provide the patient with evidence-based therapeutic strategies.

Replacing single frozen-thawed euploid embryos in a natural cycle in ovulatory women may increase live birth rates compared to medicated cycles in anovulatory women.

PURPOSE: The goal of this study was to compare pregnancy outcomes between natural frozen embryo transfer (FET) cycles in ovulatory women and programmed FET cycles in anovulatory women after undergoing in vitro fertilization with preimplantation genetic screening (IVF-PGS). METHODS: This was a retrospective cohort study performed at an academic medical center. Patients undergoing single FET IVF-PGS cycles between October 2011 and December 2014 were included. Patients were stratified by type of endometrial replacement: programmed cycles with estrogen/progesterone replacement and natural cycles. IVF-PGS with 24-chromosome screening was performed on all included patients. Those patients with euploid embryos had single embryo transfer in a subsequent FET. The primary study outcome was live birth/ongoing pregnancy rate. Secondary outcomes included implantation, biochemical pregnancy, and miscarriage rates. RESULTS: One hundred thirteen cycles met inclusion criteria: 65 natural cycles and 48 programmed cycles. The programmed FET group was younger (35.9 ± 4.5 vs. 37.5 ± 3.7, P = 0.03) and had a higher AMH (3.95 ± 4.2 vs. 2.37 ± 2.4, P = 0.045). The groups were similar for BMI, gravidity, parity, history of uterine surgery, and incidence of Asherman's syndrome. There was also no difference in embryo grade at biopsy or transfer, and proportion of day 5 and day 6 transfers. Implantation rates were higher in the natural FET group (0.66 ± 0.48 vs. 0.44 ± 0.50, P = 0.02). There was no difference in the rates of biochemical pregnancy or miscarriage. After controlling for age, live birth/ongoing pregnancy rate was higher in natural FETs with an adjusted odds ratio of 2.68 (95% CI 1.22-5.87). CONCLUSIONS: Natural FET in ovulatory women after IVF-PGS is associated with increased implantation and live birth rates compared to programmed FET in anovulatory women. Further investigation is needed to determine whether these findings hold true in other patient cohorts.

The Accuracy of Web Sites and Cellular Phone Applications in Predicting the Fertile Window.

OBJECTIVE: To evaluate the validity of fertility web sites and applications (apps) by comparing the predicted fertile window of these modalities to the actual fertile window of a standard 28-day cycle. METHODS: This was a descriptive study. The top resulting free web sites and electronic apps downloadable to a cellular phone that provide calendars for fertility and ovulation prediction were assessed. Cycles were standardized to 28 days in length, 4 days of menses, and the last menstrual period was set to January 1, 2015. The predicted date of ovulation and fertility window generated were compared with an actual estimated date of ovulation on cycle day 15, January 15, and a fertile window consisting of cycle day 10 to cycle day 15, the day of ovulation plus the preceding 5 cycle days, January 10-15. RESULTS: Data from 20 web sites and 33 apps were collected. Of all the web sites and apps used, one web site and three apps predicted the precise fertile window. CONCLUSION: Web sites and electronic apps used by the general public to predict fertile windows are generally inaccurate, although the clinical effect of this inaccuracy is unknown. Although they all include the most fertile cycle day, the range of the fertility window varies widely. Patients who are trying to conceive with the assistance of calendars generated from web sites and electronic apps should be counseled on the inaccuracy of these modalities.

Robot-Assisted Myomectomy for Large Uterine Myomas: A Single Center Experience.

Objective. To determine if robot-assisted myomectomy (RAM) is feasible for women with large uterine myomas. Methods. Retrospective review of one gynecologic surgeon's RAM cases between May 2010 and July 2013. Large uterine myomas, defined as the largest myoma ≥9 cm by preoperative magnetic resonance imaging, was age- and time-matched to controls with the largest myoma <9 cm. Primary surgical outcomes compared were operative time and estimated blood loss (EBL). Results. 207 patients were included: 66 (32%) patients were in the ≥9 cm group, while 141 (68%) patients were in the <9 cm group. There was a statistically significant increase in the operative time (130 min versus 92 min) and EBL (100 mL versus 25 mL) for the ≥9 cm group compared to the <9 cm group. Ten (4.8%) patients had the largest myoma measuring ≥15 cm, and 11 (5.3%) patients had a specimen weight >900 gm, of which no major adverse outcomes were observed. All patients in the study cohort were discharged on the same day after surgery. Conclusion. RAM is a feasible surgical approach for patients with myomas ≥9 cm. Patients with large myomas undergoing RAM are also candidates for same-day discharge after surgery.

Is anti-Müllerian hormone associated with IVF outcomes in young patients with diminished ovarian reserve?

AIM: To investigate whether anti-Müllerian hormone (AMH) is associated with IVF cycle outcomes in young patients with diminished ovarian reserve. MATERIALS & METHODS: Retrospective study of patients <35 years of age undergoing fresh IVF who had at least two 8-cell, day-3 embryos transferred with grades 1, 1.5 or 2. Patients were subgrouped, a priori, based on serum AMH levels: <1 or >1 ng/ml and <0.5 or >0.5 ng/ml. RESULTS: In total, 1005 patients were included. Patients in the >1 ng/ml group required lesser gonadotropins compared with the <1 ng/ml and the <0.5 ng/ml group. More oocytes were retrieved from the same group compared with the latter two (p < 0.001). Despite these differences, the overall rates of clinical pregnancy, spontaneous abortion and live birth were comparable between the two groups. CONCLUSION: In patients with diminished ovarian reserve who have good quality embryos, AMH is not associated with clinical pregnancy, spontaneous miscarriage or live birth rates.

Fibrate therapy: an update.

Fibrates are a class of lipid-lowering medication primarily used as second-line agents behind statins. Acting via the peroxisome proliferators-activated receptor-alpha, their main lipoprotein effects are to lower serum triglyceride levels and to raise high-density lipoprotein-cholesterol, with modest effects on low-density lipoprotein-cholesterol. However, many clinical trials indicate that fibrates may have benefits beyond simply altering one's lipid profile. Several angiographic studies show retardation in the progression of atherosclerotic lesions in coronary vessels. Although clinical trials have failed to show a reduction in mortality with fibrates, several post hoc analyses indicate that there may be a mortality benefit in patients with features of the metabolic syndrome. Given that fibrates are often used as second-line agents, it is essential they are safe to be given in combination with other agents, particularly statins and ezetimibe. Although the side-effect profile of fibrates includes gastrointestinal symptoms, increased liver function tests, a reversible rise in creatinine and myositis, in general, fibrates seem to be safe to use in combination with other lipid lowering medications. Thus far, fibrates have not shown a mortality benefit in randomized clinical trials; as a result, they cannot be considered first-line medication for the primary or secondary prevention of coronary artery disease.