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Objective: To examine whether semen parameters are associated with live birth among couples seeking infertility treatment after accounting for semen parameter variability., Design: Folic Acid and Zinc Supplementation Trial (FAZST) prospective cohort., Setting: Four US reproductive endocrinology and infertility care study centers, 2013-2017., Patient(s): Couples (n = 2,369) seeking fertility consultations at 4 US infertility care study centers., Intervention(s): Semen volume, pH, sperm viability, morphology, progressive and total motility, concentration, count, and total and progressive motile count assessed at baseline and at 2, 4, and 6 months after enrollment., Main Outcome Measure(s): Log-binomial models stratified by fertility treatment received (in vitro fertilization [IVF], intrauterine insemination [IUI], ovulation induction [OI], or no treatment) estimated risk differences (RDs) between semen parameter quartiles and live birth and accounted for multiple semen assessments per person. We accounted for abstinence time, the biological interdependence of semen parameters, and potential selection bias because of loss to follow-up., Result(s): Among couples using OI only or no treatment, 39% had a live birth, and relative to the highest quartile, the lowest quartiles of morphology (RD, -19 [95% CI, -23 to -15] per 100 couples), motility (RD, -13 [95% CI, -17 to -9]), concentration (RD, -22 [95% CI, -26 to -19]), and total motile count (RD, -18 [95% CI, -22 to -14]) were associated with fewer live births. For IUI, 26% had a live birth, and the lowest quartiles of volume (RD, -6 [95% CI, -11 to -0.4]), concentration (RD, -6 [95% CI, -11 to -0.1]), count (RD, -10 [95% CI, -15 to -4]), and total motile count (RD, -7 [95% CI, -13 to -1]) were associated with fewer live births. For IVF, 61% had a live birth, and only morphology (Q1 RD, -7 [95% CI, -14 to 0.2]; Q2 RD, -10 [95% CI, -17 to -2.2]) was associated with live birth., Conclusion(s): Semen parameters are critical in couples undergoing OI/IUI. Only low morphology was important for live birth after IVF. Although data supporting the use of semen parameters are fragmented across differing populations, current findings are generalizable across the range of male fertility and couple fertility treatments, providing evidence about which semen parameters are most relevant in which settings., Clinical Trial Registration Number: NCT#01857310., (Published by Elsevier Inc.)

Objective: To determine if 6-month folic acid (5 mg) and zinc (30 mg) supplementation impacts sperm DNA methylation patterns., Design: A multicenter, double-blind, block randomized, placebo-controlled trial titled "The Folic Acid and Zinc Supplementation Trial (FAZST).", Setting: Infertility care centers., Patient(s): Male partners (18 years and older) from heterosexual couples (female partners aged 18-45 years) seeking fertility treatment were recruited., Intervention(s): Men were randomized 1:1 to receive folic acid (5 mg) and elemental zinc (30 mg) (n = 713) or a matching placebo (n = 757) daily for 6 months., Main Outcome Measure(s): Sperm DNA methylation was analyzed using the EPIC methylation array (Illumina) at 6 months. Differential sperm DNA methylation was assessed at multiple levels (regional, single cytosine phosphate guanine, etc.). We additionally assessed the impact of supplementation on epigenetic age., Result(s): No significant differences were identified between the treatment and placebo groups although some trends appeared to be present. To determine if these trends were noteworthy, we implemented various permutations and found that the patterns we identified were no more than would be expected by random chance., Conclusion(s): The data presented here strongly suggest that this supplementation regimen is not effective at altering sperm DNA methylation. These data comport well with previous findings from the FAZST study that found no impact of supplementation on basic semen analysis parameters or live birth., Clinical Trial Registration Number: ClinicalTrials.gov Identifier: NCT01857310., (Published by Elsevier Inc.)

Objective: To explore the relation between bisphenol A and 14 phthalate metabolites and endometriosis., Design: Matched cohort design., Setting: Fourteen clinical centers., Patient(s): The operative cohort comprised 495 women undergoing laparoscopy/laparotomy, whereas the population cohort comprised 131 women matched on age and residence., Intervention(s): None., Main Outcome Measure(s): Surgically visualized or pelvic magnetic resonance imaging diagnosed endometriosis in the two cohorts, respectively., Result(s): Odds ratios (OR) and 95% confidence intervals (CIs) were estimated using logistic regression adjusting for age, body mass index, and creatinine. In the population cohort, six phthalate metabolites-mono-n-butyl phthalate, mono-[(2-carboxymethyl) hexyl] phthalate, mono (2-ethyl-5-carboxyphentyl) phthalate, mono (2-ethylhexyl) phthalate, mono (2-ethyl-5-hydroxyhexyl) phthalate, and mono (2-ethyl-5-oxohexyl) phthalate-were significantly associated with an approximately twofold increase in the odds of an endometriosis diagnosis. Two phthalates were associated with endometriosis in the operative cohort when restricting to visualized and histologic endometriosis (monooctyl phthalate; OR 1.38; 95% CI 1.10-1.72) or when restricting comparison women to those with a postoperative diagnosis of a normal pelvis [mono (2-ethylhexyl) phthalate; OR 1.35; 95% CI 1.03-1.78]., Conclusion(s): Select phthalates were associated with higher odds of an endometriosis diagnosis for women with magnetic resonance imaging-diagnosed endometriosis. The lack of consistency of findings across cohorts underscores the impact of methodology on findings., (Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To assess in utero exposures and the odds of an endometriosis diagnosis., Design: Matched cohort design., Setting: Fourteen participating clinical centers in geographically defined areas in Utah and California., Patient(s): Operative cohort comprised 473 women undergoing laparoscopy/laparotomy, and an age- and residence-matched population cohort comprising 127 women undergoing pelvic magnetic resonance imaging (MRI), 2007-2009., Intervention(s): None., Main Outcome Measure(s): Women completed standardized interviews before surgery or MRI regarding in utero exposures: mothers' lifestyle during the index pregnancy, and the index woman's gestation and birth size. Endometriosis was defined as visually confirmed disease in the operative cohort, and MRI visualized disease in the population cohort. The odds of an endometriosis diagnosis and corresponding 95% confidence intervals (CI) were estimated for each exposure by cohort using logistic regression and adjusting for current smoking, age at menarche, body mass index, and study site., Result(s): Endometriosis was diagnosed in 41% and 11% of women in the operative and population cohorts, respectively. In the primary analysis, adjust odds ratios (AORs) were elevated for maternal vitamin usage (1.27; 95% CI, 0.85-1.91), maternal cigarette smoking (1.16; 95% CI = 0.61-2.24), and low birth weight (1.1; 95% CI, 0.92-1.32). Reduced odds were observed for maternal usage of caffeine (0.99; 95% CI, 0.64-1.54), alcohol (0.82; 95% CI, 0.35-1.94), paternal cigarette smoking (0.72; 95% CI, 0.43-1.19), and preterm delivery (0.98; 95% CI, 0.47-2.03). Sensitivity analyses mostly upheld the primary results except for a decreased AOR for preterm birth (0.41; 95% CI, 0.18-0.94) when restricting to visualized and histologically confirmed endometriosis in the operative cohort., Conclusion(s): In utero exposures were not statistically significantly associated with the odds of an endometriosis diagnosis in either cohort., (Published by Elsevier Inc.)

Objective: To estimate the incidence of endometriosis in an operative cohort of women seeking clinical care and in a matched population cohort to delineate more fully the scope and magnitude of endometriosis in the context of and beyond clinical care., Design: Matched-exposure cohort design., Setting: Surgical centers in the Salt Lake City, Utah, and San Francisco, California, areas., Patient(s): The operative cohort comprised 495 women undergoing laparoscopy/laparotomy between 2007 and 2009, and the population cohort comprised 131 women from the surgical centers' catchment areas., Intervention(s): None., Main Outcome Measure(s): Incidence of endometriosis by diagnostic method in the operative cohort and by pelvic magnetic resonance imaged (MRI) disease in the population cohort., Result(s): Endometriosis incidence in the operative cohort ranged by two orders of magnitude by diagnostic method: 0.7% for only histology, 7% for only MRI, and 41% for visualized disease. Endometriosis staging was skewed toward minimal (58%) and mild disease (15%). The incidence of MRI-diagnosed endometriosis was 11% in the population cohort., Conclusion(s): Endometriosis incidence is dependent on the diagnostic method and choice of sampling framework. Conservatively, 11% of women have undiagnosed endometriosis at the population level, with implications for the design and interpretation of etiologic research., (Published by Elsevier Inc.)

Objective: To assess the methylation patterns of four pluripotency gene promoters in mouse oocytes after in vivo maturation, in vitro maturation (IVM), and vitrification followed by IVM., Design: Experimental study., Setting: Research laboratory., Animal(s): Three populations of metaphase II mouse oocytes were analyzed after in vivo maturation, IVM, and vitrification followed by IVM (V-IVM). Cumulus cells and blastocyst embryos were controls., Intervention(s): The CpG methylation patterns (overall and CpG specific) in the promoters of four pluripotency genes (Oct4, Nanog, Foxd3, and Sox2) were analyzed for each cell type by traditional DNA bisulfite sequencing., Main Outcome Measure(s): Differences for overall methylation were evaluated using the Student's t-test and for individual CpG sites by χ2 analysis., Result(s): Significantly lower levels of overall methylation in promoters of Oct4 (25%) and Sox2 (4.5%) were noted in V-IVM oocytes compared with in vivo-matured oocytes (62.5% and 8.5%, respectively). Cumulus cell promoters were generally hypomethylated at Nanog, Foxd3. and Sox2, but hypermethylated at Oct4., Conclusion(s): The methylation status of Oct4 and Sox2 promoters of V-IVM mouse oocytes are altered when compared with in vivo-matured oocytes. The biological risk and significance of these changes are unknown and this study indicates caution and that further analyses are warranted., (Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

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., (Published by Elsevier Inc.)

Objective: To study the correlation between indices of air pollution and sperm parameters., Design: Ecological study., Setting: Contained geographic area., Patient(s): Resident men presenting for semen analysis or artificial insemination., Intervention(s): Analysis of levels of particulate air pollution (particulate matter [PM] 2.5) over a five-year period in relation to sperm parameters obtained from semen analyses and separately in relation to sequences of sperm parameters at the time of semen preparations for artificial insemination. To account for the duration of spermatogenesis (72 days), "corrected" variables were created by shifting backward 1, 2, 3 and 4 months each of the semen parameters. The final analysis corrected for season of the year and current temperature., Main Outcome Measure(s): Sperm concentration, sperm motility and sperm morphology., Result(s): The study included 1,699 semen analyses and 877 inseminations. PM 2.5 levels were highest in the winter months, when the ambient temperature was the lowest. Semen analysis data showed that values of PM 2.5 were negatively correlated to sperm motility two months and three months following the recording of the PM 2.5 values. Artificial insemination data also showed that sperm motility correlated negatively with PM 2.5 values recorded three months previously., Conclusion(s): Both semen analysis and sperm parameters data obtained from men presenting for multiple inseminations over time showed that air pollution is associated with reduced sperm motility two to three month after exposure., (Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To compare the effect of two oxygen concentrations used during days 3-5 of human embryo culture on embryo quality and pregnancy outcome., Design: Retrospective analysis of the use of two culture conditions., Setting: University-based infertility clinic., Patient(s): Three hundred eighty-two patients undergoing IVF., Intervention(s): Embryos were cultured in 5% CO(2) balanced ( approximately 20% O(2)) gas phase until day 3 then assigned to approximately 20% or reduced (5%) oxygen concentration groups and cultured until ET., Main Outcome Measure(s): Embryo quality, pregnancy rates, and implantation rates., Result(s): There were no differences in demographic features (age, type of infertility) between the two groups. The embryo scores at day 3 and day 5, blastulation rate, and transfer score did not differ between groups. No differences were observed between the 5% and 20% oxygen concentrations in the chemical pregnancy rate (71.27% vs. 78.72%), clinical pregnancy rate (58.56% vs. 64.36%), or implantation rate (44.06% vs. 44.16%)., Conclusion(s): Reduced oxygen concentration in the gas mixture from day 3 until ET did not support better embryo development or result in higher pregnancy or implantation rates. These data do not support the hypothesis that beneficial effects of reduced oxygen concentration can be gained by employing the strategy during the latter stages of embryo culture (days 3-5) only and highlight the need for further studies through all stages of in vitro culture., (Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the current understanding of the effects and potential mechanisms of obesity on male fertility., Design: Literature review of articles pertaining to obesity and male infertility., Result(s): Recent population-based studies suggest an elevated risk for subfertility among couples in which the male partner is obese and an increased likelihood of abnormal semen parameters among heavier men. Male factor infertility is associated with a higher incidence of obesity in the male partner. Obese men exhibit reduced androgen and SHBG levels accompanied by elevated estrogen levels. Reduced inhibin B levels correlate with degree of obesity and are not accompanied by compensatory increases in FSH. This complexly altered reproductive hormonal profile suggests that endocrine dysregulation in obese men may explain the increased risk of altered semen parameters and infertility. Additional features of male obesity that may contribute to an increased risk for infertility are altered retention and metabolism of environmental toxins, altered lifestyle factors, and increased risks for sexual dysfunction. Neither reversibility of obesity-associated male infertility with weight loss nor effective therapeutic interventions have been studied yet., Conclusion(s): The increasing prevalence of obesity calls for greater clinician awareness of its effects on fertility, better understanding of underlying mechanisms, and eventually avenues for mitigation or treatment.

Objective: To evaluate whether aberrant sperm P1/P2 ratios are predictive of abnormal fertilizing ability and are related to in vitro fertilization (IVF) outcome., Design: Prospective case-control study., Setting: University-based infertility and IVF clinic., Patient(s): Forty-three male infertility patients with an abnormally reduced P1/P2 ratio, 251 patients with a normal P1/P2 ratio, and 121 patients with an abnormally elevated P1/P2 ratio., Intervention(s): Human IVF, the sperm penetration assay (SPA), and sperm protamine quantification via nuclear protein extraction, gel electrophoresis, and densitometry analysis., Main Outcome Measure(s): Sperm P1/P2 ratios; P1 and P2 quantities; SPA scores; and IVF-fertilization, embryo-quality, pregnancy, delivery, and spontaneous-abortion rates., Result(s): Standard IVF fertilization rates and SPA scores were significantly reduced in patients with abnormally low and high P1/P2 ratios. In vitro fertilization embryo quality was comparable between these groups, but pregnancy rates were significantly reduced in patients with abnormally reduced P1/P2 ratios., Conclusion(s): The P1/P2 ratio has a significant relationship to sperm fertilization ability. The relationship between protamines and fertilization ability is not understood but may be either a reflection of generalized abnormalities during spermiogenesis or an indication of protamine deficiency acting as a regulator or checkpoint of spermatogenesis.

Failed fertilization and the appearance of immature oocytes are common in IVF practice; rescue intracytoplasmic sperm injection can be used as a therapy. However, this study indicates that embryos created after in vitro maturation and delayed intracytoplasmic sperm injection contain an increase in aneuploidy (79.7%) over control embryos (60.5%). Therefore, patients should be informed of the possible risk when presented with delayed intracytoplasmic sperm injection.

Objective: To identify high-risk categories for high-order multiple pregnancy (HMP) in in vitro fertilization (IVF), establish clinic-specific HMP risk data for counseling use, and verify their utility in reducing HMP., Design: Before and after intervention study., Setting: Two IVF programs using the same embryology laboratory and IVF protocols., Patient(s): All IVF patients undergoing fresh embryo transfers., Intervention(s): Use of clinic-specific age, diagnosis, and embryo score (ES) risk data in assessing individual HMP risk during informed consent., Main Outcome Measure(s): HMP and pregnancy outcomes., Result(s): In determining clinic-specific high risk categories and developing outcomes-based HMP risk data for counseling, the good outcome rate (GR) was defined as the percentage of singleton or twin deliveries per cycle and the bad outcome rate included no pregnancy or nondelivered pregnancies (miscarriages, multifetal reduction) and HMP per cycle. During 1995 to 1999, age <35 years, calculated morphologic ES, and donor egg (DE) cycles were factors shown by logistic regression to statistically significantly affect the GR. The optimal GRs for DE <35 and >or=35 years (donor age), and non-DE cycles <35 years were achieved with two (57.7%), three (43.2%), and three (43.2%) embryos transferred, respectively. A DE <35 years with >or=3 embryos transferred had the highest risk for HMP. The GR correlated (0.91) with the ES according to the formula: GR = 3.3 + 2.0 ES, when ES range was between 4 and 26. Clinic-specific risks for HMP based on age, diagnosis, and ES were developed and considered while counseling for ET during 2004. The clinic-specific HMP risk data made for a reduction in the HMP rate of 90.9% for DE-IVF (11.8% to 1%) and 53.8% for all IVF (9.1% to 4.2%), without decreases in clinical pregnancy or delivery rates. Physicians showing the greatest decline (64%) in HMP had no reduction in pregnancy or delivery rates., Conclusion(s): The use of clinic-specific HMP risk data in counseling based on age, diagnosis, and ES provided a 53% to 64% reduction in HMP without affecting rates of pregnancy or delivery. The clinic-specific ES system correlated closely with good outcomes. A standardized ES system may provide useful information for counseling during ET informed consent.

Objective: To evaluate variability in donor semen quality between seven commercial donor sperm banks, within sperm banks, and between intracervical insemination and intrauterine insemination., Design: Prospective, randomized, blind evaluation of commercially available donor semen samples., Setting: An academic andrology laboratory., Patient(s): Seventy-five cryopreserved donor semen samples were evaluated., Intervention(s): Samples were coded, then blindly evaluated for semen quality., Main Outcome Measure(s): Standard semen quality parameters, including concentration, motility parameters, World Health Organization criteria morphology, and strict criteria morphology., Result(s): Significant differences were observed between donor semen banks for most semen quality parameters analyzed in intracervical insemination samples. In general, the greatest variability observed between banks was in percentage progressive sperm motility (range, 8.8 +/- 5.8 to 42.4 +/- 5.5) and normal sperm morphology (strict criteria; range, 10.1 +/- 3.3 to 26.6 +/- 4.7). Coefficients of variation within sperm banks were generally high., Conclusion(s): These data demonstrate the variability of donor semen quality provided by commercial sperm banks, both between banks and within a given bank. No relationship was observed between the size or type of sperm bank and the degree of variability. The data demonstrate the lack of uniformity in the criteria used to screen potential semen donors and emphasize the need for more stringent screening criteria and strict quality control in processing samples.

Objective: To evaluate pregnancy rates (PRs) in women undergoing artificial insemination with sperm alternately prepared by one of five techniques: sperm washing, Percoll gradient centrifugation, swim-up, swim-down, or refrigeration/heparin treatment., Design: Each treatment group alternated in a different order through the five sperm preparations. Pregnancy rates were compared for each sperm preparation., Setting: Two infertility centers, one located in an academic institution and the other a regional hospital., Patient(s): Three hundred sixty-three women undergoing 898 artificial inseminations with husband semen with a progressive motile sperm count of >20 million sperm per mL were randomly placed in the five treatment groups., Main Outcome Measure(s): Pregnancy rates., Result(s): The overall ongoing PR per insemination was 9.7% (87/898), including 6.12% for natural cycles (n = 196), 12.8% for clomiphene citrate-stimulated cycles (n = 101), and 10.3% for gonadotropin-stimulated cycles (n = 601). The highest ongoing PRs for sperm preparations followed the swim-up technique (13.2%, 26/197) and the Percoll gradient centrifugation technique (12.7%, 26/204)., Conclusion(s): These data suggest that the swim-up and Percoll gradient preparations result in higher PRs than the wash, swim-down, and refrigeration/heparin techniques.

Objectives: To determine whether one to four cycles of ovulation induction with hMG and IUI or one cycle of IVF results in the highest pregnancy rate and is least expensive and whether published pregnancy rates for one to four cycles of hMG and IUI results in a higher pregnancy rate than rates for one cycle of IVF, zygote intrafallopian transfer (ZIFT), or GIFT., Design: Prospective, nonrandomized, cohort study. Patients were excluded who were infertile for < 18 months, had a significant male factor, had greater than mild endometriosis, or had bilateral nonpatency of the fallopian tubes. Cohort groups included 47 hMG and IUI patients (99 cycles), 19 IVF patients (19 cycles), and 21 patients (210 cycles) receiving no treatment. A meta-analysis on accumulated hMG and IUI data using similar entry criteria was also performed. Theoretical calculations were performed and stable fecundity assumed to compare with national data on IVF, ZIFT, and GIFT., Setting: Fertility Center, Division of Reproductive Endocrinology, University of Utah, Salt Lake City, Utah., Results: A course of therapy with one to four cycles of hMG and IUI was just as effective as one cycle of IVF in achieving pregnancy. No significant difference in pregnancy rates was found between one IVF cycle and one to four cycles of hMG and IUI in our population. In vitro fertilization was more expensive than four cycles of hMG and IUI. Both IVF and hMG and IUI were more effective than no therapy. Published data also suggest that four cycles of hMG and IUI theoretically result in higher pregnancy rates than one cycle of IVF, ZIFT, or GIFT., Conclusion: Cost-benefit analysis comparing hMG and IUI, IVF, and no therapy in infertility patients may favor a course of four cycles of hMG and IUI as the first line of therapy. Using meta-analysis and theoretical assumptions, the pregnancy rate for one cycle of hMG and IUI is inferior to IVF, GIFT, or ZIFT; two cycles are comparable to IVF or ZIFT and inferior to GIFT; three cycles are superior to IVF or ZIFT and comparable to GIFT; and four cycles are theoretically superior to all techniques.

In summary, we report a case of secondary infertility attributed to pseudomyxoma peritonei caused by ruptured appendiceal mucocele. Resection of the tumor and visible mucinous ascites resulted in spontaneous conception. We hypothesize secondary infertility was caused by significant peritoneal inflammation and inhibition of sperm-oocyte interaction from the ascites.

Objective: To select in vitro fertilization (IVF) patients with a low sperm penetration assay (SPA) value and to determine if the penetration rate, fertilization rate, and the pregnancy rate (PR) can be improved in these patients by treating sperm with refrigeration, calcium ionophore A23187, prostaglandin E1, prostaglandin E2, or heparin., Design: The study consists of three parts: identification of patients with poor SPA values, analysis of treatments to improve the SPA value, and evaluation of the treatments to improve fertilization and PRs., Results: The data indicate that treatment of sperm with refrigeration can improve fertilization and PRs during IVF in selected patients previously shown to have an improved SPA value with the treatment., Conclusions: Three points are emphasized: (1) the treatments analyzed in this study can improve SPA values in some of the patients with low sperm penetration capacity; (2) of the treatments studied, sperm refrigeration resulted in the largest improvement in sperm penetration capacity; and (3) sperm refrigeration can increase fertilization and PRs during IVF in this select group of patients.