Effects of preconception lifestyle intervention in infertile women with obesity: The FIT-PLESE randomized controlled trial

Background Women with obesity and infertility are counseled to lose weight prior to conception and infertility treatment to improve pregnancy rates and birth outcomes, although confirmatory evidence from randomized trials is lacking. We assessed whether a preconception intensive lifestyle intervention with acute weight loss is superior to a weight neutral intervention at achieving a healthy live birth. Methods and findings In this open-label, randomized controlled study (FIT-PLESE), 379 women with obesity (BMI ≥ 30 kg/m2) and unexplained infertility were randomly assigned in a 1:1 ratio to 2 preconception lifestyle modification groups lasting 16 weeks, between July 2015 and July 2018 (final follow-up September 2019) followed by infertility therapy. The primary outcome was the healthy live birth (term infant of normal weight without major anomalies) incidence. This was conducted at 9 academic health centers across the United States. The intensive group underwent increased physical activity and weight loss (target 7%) through meal replacements and medication (Orlistat) compared to a standard group with increased physical activity alone without weight loss. This was followed by standardized empiric infertility treatment consisting of 3 cycles of ovarian stimulation/intrauterine insemination. Outcomes of any resulting pregnancy were tracked. Among 191 women randomized to standard lifestyle group, 40 dropped out of the study before conception; among 188 women randomized to intensive lifestyle group, 31 dropped out of the study before conception. All the randomized women were included in the intent-to-treat analysis for primary outcome of a healthy live birth. There were no significant differences in the incidence of healthy live births [standard 29/191(15.2%), intensive 23/188(12.2%), rate ratio 0.81 (0.48 to 1.34), P = 0.40]. Intensive had significant weight loss compared to standard (−6.6 ± 5.4% versus −0.3 ± 3.2%, P < 0.001). There were improvements in metabolic health, including a marked decrease in incidence of the metabolic syndrome (baseline to 16 weeks: standard: 53.6% to 49.4%, intensive 52.8% to 32.2%, P = 0.003). Gastrointestinal side effects were significantly more common in intensive. There was a higher, but nonsignificant, first trimester pregnancy loss in the intensive group (33.3% versus 23.7% in standard, 95% rate ratio 1.40, 95% confidence interval [CI]: 0.79 to 2.50). The main limitations of the study are the limited power of the study to detect rare complications and the design difficulty in finding an adequate time matched control intervention, as the standard exercise intervention may have potentially been helpful or harmful. Conclusions A preconception intensive lifestyle intervention for weight loss did not improve fertility or birth outcomes compared to an exercise intervention without targeted weight loss. Improvement in metabolic health may not translate into improved female fecundity. Trial registration ClinicalTrials.gov NCT02432209

Human chromatin remodeler cofactor, RNA interactor, eraser and writer sperm RNAs responding to obesity

In the United States almost 33% of adults are considered obese (BMI > 30 kg/m2). Both animal models and to a lesser extent human studies, have associated BMI, a measure of obesity, with alterations in sperm DNA methylation and RNAs. Sperm RNAs from the Assessment of Multiple Gestations from Ovarian Stimulation trial, were isolated and sequenced. A Generalized Linear Model identified 487 BMI associated human sperm RNA elements (short exon-sized sequences). They partitioned into four patterns; a continual increase with BMI, increase once obese (BMI>30 kg/m2); a steady decrease with BMI; and decrease once overweight (BMI 25 - 30 kg/m2). Gene Ontology revealed a unique relationship between BMI and transcripts associated with chromosome organization, adipogenesis, cellular stress and obesity-related inflammation. Coregulatory networks linked by Chromatin remodeler cofactors, RNA interactors, Erasers and Writers (CREWs) were uncovered to reveal a hierarchical epigenetic response pathway

Robust and Operationally Simple Synthesis of Poly(bis(2,2,2-trifluoroethoxy) phosphazene) with Controlled Molecular Weight, Low PDI, and High Conversion

Synthetically straightforward conditions have been developed for the preparation of poly­(bis 2,2,2-trifluoroethoxy)­phosphazene with low PDI (<1.15) at high conversion (75–99%) and on a multigram scale. A combination of ³¹P NMR and GPC analyses demonstrate that molecular weight increases linearly as a function of monomer consumption, exhibiting first order kinetics with respect to monomer concentration up to high monomer conversion. Thus, the molecular weight can be controlled by varying the initiator (H₂O) to monomer ratio

Association between testosterone, semen parameters, and live birth in men with unexplained infertility in an intrauterine insemination population

To determine whether men with unexplained infertility and low total T (TT) have abnormal spermatogenesis and lower fecundity. Secondary analysis of the prospective, randomized, multicenter clinical trial, Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS). Infertility clinics. Nine hundred couples with unexplained infertility enrolled in AMIGOS. Semen analysis with an ejaculate of at least 5 million total motile sperm was required for enrollment. For inclusion in this secondary analysis, a fasting TT was required. None. Logistic regression, adjusted for age and body mass index, assessed the association between low TT (defined as <264 ng/dL), semen parameters, and pregnancy outcome. Seven hundred eighty-one men (mean age, 34.2 ± 5.7 years) with a median (interquartile range) TT of 411 (318–520) ng/dL were included. Men with TT 264 ng/dL. The odds of live birth decreased by 40% in couples whose male partner had low TT (unadjusted OR, 0.60; 95% CI, 0.36, 1.00; adjusted OR, 0.65; 95% CI, 0.38, 1.12). In couples with unexplained infertility, low TT in the male partner was associated with abnormal sperm morphology and lower live birth rates. NCT01044862. Asociación entre la testosterona, los parámetros seminales, y los nacidos vivos en hombres con infertilidad inexplicable en una población de inseminación intrauterina Determinar si los hombres con infertilidad inexplicable y testosterona total (TT) baja tienen espermatogénesis anormal y menor fecundidad. Análisis secundario del ensayo clínico prospectivo, aleatorizado, multicéntrico, Evaluación de Gestaciones Intrauterinas Múltiples a partir de Estimulación Ovárica (AMIGOS). Clínicas de infertilidad. Novecientas parejas con infertilidad inexplicada inscritas en AMIGOS. Análisis de semen con una eyaculación con al menos 5 millones de espermatozoides móviles totales para la participación en el estudio. Para su inclusión en este análisis secundario, se requirió una muestra en ayunas de TT. Ninguna. Regresión logística, ajustada por edad e índice de masa corporal, evaluando la asociación entre TT baja (definido como <264 ng/dL), parámetros del semen y resultado del embarazo. Se incluyeron setecientos ochenta y un hombres (edad media, 34.2 ± 5.7 años) con una mediana (rango intercuartil) de TT de 411 (318–520) ng / dL. Los hombres con TT 264 ng/dL. Las probabilidades de nacidos vivos disminuyeron en un 40% en las parejas cuyo compañero masculino tenía TT baja (OR no ajustada, 0.60; IC del 95%, 0.36; 1.00; OR ajustada, 0.65; IC del 95%, 0.38; 1.12). En parejas con infertilidad inexplicable, la TT baja en la pareja masculina se asoció con una morfología anormal de los espermatozoides y menores tasas de nacidos vivos

Recruitment challenges of a multicenter randomized controlled varicocelectomy trial

Objective: To review reasons for suboptimal recruitment for a randomized controlled trial (RCT) of varicocelectomy versus intrauterine insemination (IUI) for treatment of male infertility and to suggest means for improving future study recruitment. Design: Survey of Reproductive Medicine Network (RMN) participating sites. Setting: Reproductive Medicine Network. Patient(s): None. Intervention(s): None. Main Outcome Measure(s): Ascertain reasons for inadequate recruitment and suggest improvements for future varicocelectomy trails. Result(s): This study screened seven and enrolled three couples, with the first couple randomized on June 30, 2010. The study was subsequently stopped on March 30, 2011. The following themes were cited most frequently by sites and therefore determined to be most likely to have played a role in suboptimal recruitment: [1] men must be screened at the beginning of a couple's infertility evaluation, [2] inclusion of infertile women who had failed previous fertility interventions appeared to be associated with the couple's intolerance of a placebo arm, and [3] an apparent bias against the use of unstimulated IUI cycles indicated a prejudicial preference for surgical intervention in the male partner. Conclusion(s): Improved recruitment may be realized through screening infertile men as early as possible while minimizing study-related time commitments. Focused patient education may promote improved equipoise and acceptance of a placebo arm in male infertility studies. Creative approaches to implementing varicocelectomy trials must be considered in addition to having a network of motivated researchers who carry a high volume of possible study participants because very large numbers may need to be screened to complete the clinical trial enrollment. (Fertil Steril (R) 2011;96:1299-305. (c) 2011 by American Society for Reproductive Medicine.

Total Testosterone Assays in Women with Polycystic Ovary Syndrome: Precision and Correlation with Hirsutism

Context: There is no standardized assay of testosterone in women. Liquid chromatography mass spectrometry (LC/MS) has been proposed as the preferable assay by an Endocrine Society Position Statement