Biomarkers of Stress and Male Fertility.

To study if stress, as measured by salivary alpha-amylase and cortisol, negatively impacts male fertility, as measured by semen parameters, pregnancy, and live birth rates. Prospective, cohort study of men enrolled in the Males, Antioxidants, and Infertility (MOXI) trial. One-hundred twelve infertile men provided first-morning salivary and semen samples at baseline. Salivary samples were analyzed for alpha-amylase and cortisol. Couples attempted to conceive naturally (months 1-3) and with clomiphene citrate/intrauterine insemination (months 4-6). The association between stress-related biomarkers and semen parameters including DNA fragmentation was assessed using linear regression models adjusting for male age. Salivary levels were dichotomized at the 80th percentile. Pregnancy/live birth rates in couples in the upper quintile were compared to remaining subjects using chi-square testing. Salivary levels of alpha-amylase were not associated with semen parameters or DNA fragmentation. Salivary cortisol levels were not correlated with DNA fragmentation or normal morphology. For every 1-unit increase in salivary cortisol, total sperm count increased by 13.9 million (95% CI: 2.5, 25.3) and total motile sperm count increased by 9.9 million (95% CI: 3.2-16.6). Couple pregnancy rates and live birth rates did not differ for males in the highest quintile of alpha-amylase (27% and 28%, p = 0.96; 23% and 21%, p = 0.87) or cortisol (40% and 26%, p = 0.22; 35% and 19%, p = 0.12), compared to males with lower values. Physiologic measures of high stress may not harm but actually improve semen parameters among men with male-factor infertility.

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.

Reservoir induced bladder rupture: a complication of inflatable penile prosthesis revision surgery.

Reservoir induced bladder rupture is a rare complication of inflatable penile prosthesis (IPP) revision surgery. Our aim is to review the literature and describe our experience with this complication using two case reports that involved reusing an in-situ reservoir. In each case, an episode of gross hematuria indicated that a bladder rupture had occurred. From our experience, we propose ways to possibly avoid and if necessary, manage this rare complication.

Male vitamin D status and male factor infertility.

OBJECTIVE: To determine the association between vitamin D levels in the male partner and fertility outcomes in couples with mild male factor infertility. DESIGN: Secondary analysis of a randomized, controlled trial. SETTING: Nine fertility centers in the United States. PATIENT(S): Men (n = 154) with sperm concentration between 5 and 15 million/mL, motility ≤40%, or normal morphology ≤4% were eligible. Female partners were ovulatory, ≤40 years old, and had documented tubal patency. INTERVENTION(S): Men provided semen and blood at baseline for semen analysis and 25-hydroxyvitamin D (25(OH)D) levels. They were randomly assigned to receive a vitamin formulation including vitamin D 2,000 IU daily or placebo for up to 6 months. Couples attempted to conceive naturally during the first 3 months and with clomiphene citrate with intrauterine insemination of the female partner in months 4 through 6. MAIN OUTCOME MEASURE(S): Primary: sperm concentration, motility, morphology, and DNA fragmentation at baseline. Secondary: cumulative pregnancy, miscarriage, and live birth rates. RESULT(S): Semen parameters and sperm DNA fragmentation were not statistically significantly different between men with vitamin D deficiency and men with 25(OH)D levels ≥20 ng/mL. In addition, clinical pregnancy and live birth rates were similar. Male 25(OH)D level <20 ng/mL was associated with a higher rate of pregnancy loss (adjusted odds ratio 9.0; 95% confidence interval 1.3 to 61.3). CONCLUSION(S): Vitamin D deficiency in the male partner did not significantly impact semen parameters or treatment outcomes. Further study is warranted to better characterize the rate of miscarriage in couples with male vitamin D deficiency.

One size does not fit all: variations by ethnicity in demographic characteristics of men seeking fertility treatment across North America.

OBJECTIVE: To compare racial differences in male fertility history and treatment. DESIGN: Retrospective review of prospectively collected data. SETTING: North American reproductive urology centers. PATIENT(S): Males undergoing urologist fertility evaluation. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Demographic and reproductive Andrology Research Consortium data. RESULT(S): The racial breakdown of 6,462 men was: 51% White, 20% Asian/Indo-Canadian/Indo-American, 6% Black, 1% Indian/Native, <1% Native Hawaiian/Other Pacific Islander, and 21% "Other". White males sought evaluation sooner (3.5 ± 4.7 vs. 3.8 ± 4.2 years), had older partners (33.3 ± 4.9 vs. 32.9 ± 5.2 years), and more had undergone vasectomy (8.4% vs. 2.9%) vs. all other races. Black males were older (38.0 ± 8.1 vs. 36.5 ± 7.4 years), sought fertility evaluation later (4.8 ± 5.1 vs. 3.6 ± 4.4 years), fewer had undergone vasectomy (3.3% vs. 5.9%), and fewer had partners who underwent intrauterine insemination (8.2% vs. 12.6%) compared with all other races. Asian/Indo-Canadian/Indo-American patients were younger (36.1 ± 7.2 vs. 36.7 ± 7.6 years), fewer had undergone vasectomy (1.2% vs. 6.9%), and more had partners who underwent intrauterine insemination (14.2% vs. 11.9%). Indian/Native males sought evaluation later (5.1 ± 6.8 vs. 3.6 ± 4.4 years) and more had undergone vasectomy (13.4% vs. 5.7%). CONCLUSION(S): Racial differences exist for males undergoing fertility evaluation by a reproductive urologist. Better understanding of these differences in history in conjunction with societal and biologic factors can guide personalized care, as well as help to better understand and address disparities in access to fertility evaluation and treatment.

Clomiphene citrate improved testosterone and sperm concentration in hypogonadal males.

When considering empirical medical management (EMT) options for men with unexplained infertility (UI), clomiphene citrate (CC) has been shown to positively influence sperm parameters in hypogonadal men. Unfortunately, the optimal cut point for defining hypogonadism for this patient population has not been established. We hypothesized that hypogonadal men with UI having the lowest serum total testosterone (TT) (<265 ng/dL) would have a significant post-CC improvement in both TT and semen characteristics compared to those in the TT > 264 ng/dL group. We performed our study based on an IRB-approved retrospective chart review of 83 males with UI receiving more than 90 days of 50 mg daily CC. Serum TT and semen characteristics were studied in 83 patients before and in 23 patients after CC treatment. Median TT level increased from 256 ng/dL to 630 ng/dL (p < 0.001, n = 83) and SC increased from 6 ( 106 /ml) to 20 ( 106 /ml) (p < 0.016, n = 23). Overall, our results demonstrated the following: (1) CC treatment at all currently used serum TT cut-points resulted in significant improvement in both TT (p < 0.001) and sperm concentration (p = 0.03). No significant change in post-CC sperm motility or morphology was noted. (2) Correlation and linear regression analyses demonstrated that CC treatment significantly increased TT in 96% (22 of 23) of patients, and (3) when grouped as two cohorts (≤264 and >264 ng/dL), sperm concentration and TT improved 2.3 to 2.6-fold (p < 0.001) and 1.45 to 2.5-fold (p < 0.01) respectively. Thus, for hypogonadal men with UI, CC significantly improved TT and sperm concentration regardless of pre-treatment, baseline serum TT level. For this reason, CC treatment should be considered in men with UI having a TT < 400 ng/dL.

Defining hypogonadism in male partners of couples with unexplained infertility.

INTRODUCTION: Men with unexplained infertility (UI) should undergo an initial hormonal evaluation including serum FSH and total testosterone (TT). Unfortunately, there is no consensus regarding which TT cut point should be used to define hypogonadism in such men. To determine the best definition for hypogonadism, three different, literature-based TT cut points were used to assess associations between TT and semen parameters. The hypothesis was that the lowest TT cut point would associate with poorest sperm parameters. MATERIALS AND METHODS: We performed an IRB-approved retrospective chart review of 247 consecutive males presenting for evaluation of male factor infertility. After exclusions, basic statistics and correlation analysis of semen analysis parameters, TT, age, and body mass index (BMI) were evaluated on 128 men (age 34+/-33.5) categorized by three different TT cut points: 65 males were hypogonadal according to a TT cutoff of < 264; 16 with a cutoff of 264-300; 44 with a cutoff of 301-400; and 42 with a TT over 400 ng/dL. Basic statistics, one-way ANOVA and Levene comparative analysis were performed. Besides a negative correlation between TT and BMI, there was no significant association between the three TT literature-based cut points and the other studied parameters. These findings were further supported by multiple comparison analyses. RESULTS: For men with UI, regardless of how hypogonadism was defined, no relationship between semen parameters and TT was found. CONCLUSION: Conventional, TT-based definitions of male hypogonadism in the setting of UI need to be clarified. Clinically relevant, accurate and reproducible multivariable biomarkers need to be investigated to further advance best practices for treating men with UI.

Intrauterine insemination performance characteristics and post-processing total motile sperm count in relation to live birth for couples with unexplained infertility in a randomised, multicentre clinical trial.

STUDY QUESTION: Are intrauterine insemination (IUI) performance characteristics and post-processing total motile sperm count (TMC) related to live birth rate in couples with unexplained infertility? SUMMARY ANSWER: Patient discomfort with IUI and lower inseminate TMC were associated with a reduced live birth rate, while time from hCG injection to IUI, sperm preparation method and ultrasound guidance for IUI were not associated with live birth success. WHAT IS ALREADY KNOWN: We previously determined that some baseline characteristics of couples with unexplained infertility, including female age, duration of infertility, history of prior loss and income, were related to live birth rate across a course of ovarian stimulation and IUI treatment. However, the relationship between treatment outcomes and per-cycle characteristics, including ultrasound guidance for IUI, timing of IUI relative to hCG injection, difficult or painful IUI and inseminate TMC, are controversial, and most prior investigations have not evaluated live birth outcome. STUDY DESIGN, SIZE, DURATION: This was a secondary analyses of 2462 cycles from the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) clinical trial. This prospective, randomised, multicentre clinical trial determined live birth rates following IUI after ovarian stimulation with clomiphene citrate, letrozole or gonadotropins in 854 couples with unexplained infertility. It was conducted between 2011 and 2014, and couples could undergo up to four consecutive treatment cycles. PARTICIPANTS/MATERIALS, SETTING, METHODS: AMIGOS was an NIH-sponsored Reproductive Medicine Network trial conducted at 12 clinical sites. Participants were women with unexplained infertility who were between 18 and 40 years of age. Cluster-weighted generalised estimating equations (GEE), which account for informative clustering of multiple IUI treatment cycles within the same patient, were used to determine associations between IUI performance characteristics, including inseminate TMC, and live birth rate. Efficiency curves were also generated to examine the relationship between inseminate TMC and live birth rate. MAIN RESULTS AND THE ROLE OF CHANCE: After adjustment for treatment group and baseline factors previously associated with live birth across a course of OS-IUI treatment, patient discomfort during the IUI procedure was associated with a reduction in live birth rate (aRR 0.40 (0.16-0.96)). Time from hCG trigger injection to IUI was not significantly associated with outcome. Higher TMC was associated with greater live birth rate (TMC 15.1-20.0 million (14.8%) compared to ≤5 million (5.5%)) (aRR 2.09 (1.31-3.33)). However, live births did occur with TMC ≤ 1 million (5.1%). LIMITATIONS, REASONS FOR CAUTION: This investigation is a secondary analysis, and AMIGOS was not designed to address the present question. Since timed intercourse was allowed as part of the AMIGOS trial, we cannot rule out the possibility that any given pregnancy resulted from intercourse rather than IUI. WIDER IMPLICATIONS OF THE FINDINGS: Most factors associated with the performance of IUI were not significantly related to obtaining live birth. Our findings suggest that higher TMC inseminated leads to an increase in live birth rate up to TMC ~20 million. However, there may be no reasonable threshold below which live birth is not possible with IUI. STUDY FUNDING/COMPETING INTEREST(S): Funding was received through grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): U10 HD077680, U10 HD39005, U10 HD38992, U10 HD27049, U10 HD38998, U10 HD055942, HD055944, U10 HD055936 and U10 HD055925. This research was made possible by funding by the American Recovery and Reinvestment Act. Dr Hansen reports grants from NIH/NICHD and Yale University during the conduct of the study, grants from Roche Diagnostics and grants from Ferring International Pharmascience Center US outside the submitted work. Dr Peck reports support from Ferring Pharmaceuticals outside the submitted work. Dr Coward has nothing to disclose. Dr Wild reports grants from NICHD during the conduct of the study. Dr Trussell has nothing to disclose. Dr Krawetz reports grants from NICHD during the conduct of the study, grants from Merck and support from Taylor and Frances and from Springer, outside the submitted work. Dr Diamond reports grants from NIH/NICHD, Yale University, during the conduct of the study and support from Advanced Reproductive Care AbbVie, Bayer and ObsEva, outside the submitted work. Dr Legro reports support from Bayer, Kindex, Odega, Millendo and AbbVie and grants and support from Ferring, outside the submitted work. Dr Coutifaris reports grants from NICHD/NIH and personal fees from American Society for Reproductive Medicine, outside the submitted work. Dr Alvero has nothing to disclose. Dr Robinson reports grants from NIH during the conduct of the study. Dr Casson has nothing to disclose. Dr Christman reports grants from NICHD during the conduct of the study. Dr Santoro reports grants from NIH during the conduct of the study. Dr Zhang reports grants from NIH during the conduct of the study and support from Shangdong University outside the submitted work. TRIAL REGISTRATION NUMBER: n/a.

Pregnancy registry: three-year follow-up of children conceived from letrozole, clomiphene, or gonadotropins.

OBJECTIVE: To study the development of children conceived from non-IVF infertility treatments consisting of gonadotropins, clomiphene, or letrozole. DESIGN: Prospective cohort study. SETTING: U.S. academic health centers. PATIENT(S): Children of women with polycystic ovary syndrome who conceived with letrozole (LTZ) or clomiphene (CC) in the PPCOS II study or women with unexplained infertility (AMIGOS study) who conceived with LTZ, CC, or gonadotropin (GN). INTERVENTION(S): Longitudinal annual follow-up from birth to age 3. MAIN OUTCOME MEASURE(S): Scores from Ages and Stages Developmental Questionnaire (ASQ), MacArthur-Bates Communicative Development Inventory (MCDI), and annual growth. RESULT(S): One hundred eighty-five children from 160 families participated in at least one follow-up evaluation from the two infertility trials. Most multiple gestations in the follow-up study resulted from GN treatment (n = 14) followed by CC (n = 6) and LTZ (n = 3). There were no significant differences among the three groups at any time point with respect to abnormal scores on the ASQ. On the MCDI Words and Gestures, the LTZ group scored significantly higher than the GN group for most items (phrases, early gestures, later gestures, and total gestures). Children in the CC group scored significantly higher than the GN group for the later gestures and total gestures items. CONCLUSION(S): Differences in growth and cognitive developmental rates among children conceived with first-line infertility therapies, including LTZ, are relatively minor and likely due to differences in multiple pregnancy rates.

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.

Reproductive endocrinologists are the gatekeepers for male infertility care in North America: results of a North American survey on the referral patterns and characteristics of men presenting to male infertility specialists for infertility investigations.

OBJECTIVE: To characterize the referral patterns and characteristics of men presenting for infertility evaluation using data obtained from the Andrology Research Consortium. DESIGN: Standardized male infertility questionnaire. SETTING: Male infertility centers. PATIENT(S): Men presenting for fertility evaluation. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Demographic, infertility history, and referral data. RESULT(S): The questionnaires were completed by 4,287 men, with a mean male age of 40 years ± 7.4 years and female partners age of 37 years ± 4.9 years. Most were Caucasian (54%) with other races being less commonly represented (Asian 18.6%, and African American 5.5%). The majority (59.7%) were referred by a reproductive gynecologist, 19.4% were referred by their primary care physician, 4.2% were self-referred, and 621 (14.5%) were referred by "other." Before the male infertility investigation, 12.1% of couples had undergone intrauterine insemination, and 4.9% of couples had undergone in vitro fertilization (up to six cycles). Among the male participants, 0.9% reported using finasteride (5α-reductase inhibitor) at a dose used for androgenic alopecia, and 1.6% reported exogenous testosterone use. CONCLUSION(S): This broad North American patient survey shows that reproductive gynecologists are the de facto gateway for most male infertility referrals, with most men being assessed in the male infertility service being referred by reproductive endocrinologists. Some of the couples with apparent male factor infertility are treated with assisted reproductive technologies before a male factor investigation. The survey also identified potentially reversible causes for the male infertility including lifestyle factors such as testosterone and 5α-reductase inhibitor use.

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

OBJECTIVE: To determine whether men with unexplained infertility and low total T (TT) have abnormal spermatogenesis and lower fecundity. DESIGN: Secondary analysis of the prospective, randomized, multicenter clinical trial, Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS). SETTING: Infertility clinics. PATIENT(S): 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. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): 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. RESULT(S): 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 were less likely to have normal (≥4% strict Kruger) morphology (unadjusted odds ratio [OR], 0.56; 95% confidence interval [CI], 0.34, 0.92; adjusted OR, 0.59; 95% CI, 0.35, 0.99). There was no association between low TT and semen volume < 1.5 mL, sperm concentration < 15 × 106/mL, or motility < 40%. Among couples whose male partner had low TT, 21 (18.8%) had a live birth, compared with 184 (27.5%) live births in couples with a male partner having 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). CONCLUSION(S): In couples with unexplained infertility, low TT in the male partner was associated with abnormal sperm morphology and lower live birth rates. CLINICAL TRIAL REGISTRATION NUMBER: NCT01044862.

Fertility Related Quality of Life, Gonadal Function and Erectile Dysfunction in Male Partners of Couples with Unexplained Infertility.

PURPOSE: We sought to determine whether lower fertility related quality of life or depression in men of couples with unexplained infertility is associated with low total testosterone levels, abnormal semen quality or erectile dysfunction. MATERIALS AND METHODS: This study is a secondary analysis of a large, multicenter, randomized controlled trial in couples with unexplained infertility. Male partners underwent baseline semen analysis with measurement of fasting total testosterone and gonadotropin. They also completed surveys, including the FertiQOL (Fertility Quality of Life), the PHQ-9 (Patient Health Questionnaire-9) and the IIEF (International Index of Erectile Function). The primary study outcomes were total testosterone with low total testosterone defined as less than 264 ng/dl, semen parameters and the IIEF score. We performed multivariable logistic regression analyses adjusted for patient age, race, body mass index, education, smoking, alcohol use, infertility duration and comorbidity. RESULTS: A total of 708 men with a mean ± SD age of 34.2 ± 5.6 were included in study. Of the men 59 (8.3%) had a PHQ-9 score of 5 or greater, which was consistent with depression, 99 (14.0%) had low total testosterone and 63 (9.0%) had mild or worse erectile dysfunction. Neither the FertiQOL score nor depression was associated with total testosterone or any semen parameter. The FertiQOL score was inversely associated with erectile dysfunction (for every 5-point score decline AOR 1.30, 95% CI 1.16-1.46). Depressed men were significantly more likely to have erectile dysfunction than nondepressed men (AOR 6.31, 95% CI 3.12-12.77). CONCLUSIONS: In men in couples with unexplained infertility lower fertility related quality of life and depression are strongly associated with erectile dysfunction. However, neither is associated with spermatogenesis or testosterone levels. Erectile dysfunction in infertile men merits longitudinal investigation in future studies.

The efficiency of single institutional review board review in National Institute of Child Health and Human Development Cooperative Reproductive Medicine Network-initiated clinical trials.

BACKGROUND/AIMS: Timely review of research protocols by institutional review boards leads to more rapid initiation of clinical trials, which is critical to expeditious translation from bench to bedside. This observational study examined the impact of a single institutional review board on time and efforts required to initiate clinical trials by the National Institute of Child Health and Human Development Cooperative Reproductive Medicine Network. METHODS: Collection of data from the same six main clinical sites for three current clinical trials and two past clinical trials, including time from institutional review board submission to approval, pages submitted, consent form length, number of required attachments, other regulatory requirements, order of review at central or local sites, and language in documents at individual participating sites. Results from two past clinical trials were also included. RESULTS: While time required for actual institutional review board submission's review and initial approval was reduced with use of a single institutional review board for multicenter trials (from a mean of 66.7-24.0 days), total time was increased (to a mean of 111.2 or 123.3 days). In addition to single institutional review board approval, all institutions required local approval of some components (commonly consent language and use of local language), which varied considerably. The single institutional review board relied on local institutions for adding or removing personnel, conflict of interest review, and auditing of activities. CONCLUSION: A single institutional review board reduced time for initial review and approval of protocols and informed consents, although time for the entire process was increased, as individual institutions retained oversight of components of required regulatory review. In order to best achieve the National Institute of Health's goals for improved efficiency in initiation and conduct of multisite clinical research, greater coordination with local institutional review boards is key to streamlining and accelerating initiation of multisite clinical research.

Sexual function in infertile women with polycystic ovary syndrome and unexplained infertility.

BACKGROUND: While female sexual dysfunction is a frequent occurrence, characteristics in infertile women are not well delineated. Furthermore, the impact of infertility etiology on the characteristics in women with differing androgen levels observed in women with polycystic ovary syndrome and unexplained infertility has not been assessed. OBJECTIVE: The objective of the study was to determine the characteristics of sexual dysfunction in women with polycystic ovary syndrome and unexplained infertility. STUDY DESIGN: A secondary data analysis was performed on 2 of Eunice Kennedy Shriver National Institute of Child Health and Human Development Cooperative Reproductive Medicine Networks clinical trials: Pregnancy in Polycystic Ovary Syndrome Study II and Assessment of Multiple Intrauterine Gestations From Ovarian Stimulation. Both protocols assessed female sexual function using the Female Sexual Function Inventory and the Female Sexual Distress Scale. RESULTS: Women with polycystic ovary syndrome had higher weight and body mass index than women with unexplained infertility (each P < .001), greater phenotypic (Ferriman-Gallwey hirsutism score, sebum score, and acne score; each P < .001), and hormonal (testosterone, free testosterone, and dehydroepiandrosterone; each P < .001) evidence of androgen excess. Sexual function scores, as assessed by the Female Sexual Function Inventory, were nearly identical. The Female Sexual Distress Scale total score was higher in women with polycystic ovary syndrome. The mean Female Sexual Function Inventory total score increased slightly as the free androgen index increased, mainly as a result of the desire subscore. This association was more pronounced in the women with unexplained infertility. CONCLUSION: Reproductive-age women with infertility associated with polycystic ovary syndrome and unexplained infertility, despite phenotypic and biochemical differences in androgenic manifestations, do not manifest clinically significant differences in sexual function.

Fertility-related quality of life from two RCT cohorts with infertility: unexplained infertility and polycystic ovary syndrome.

STUDY QUESTION: Does fertility-related quality of life (FertiQOL) differ by infertility diagnosis between women with polycystic ovary syndrome (PCOS) and their partners, compared with couples with unexplained infertility (UI)? SUMMARY ANSWER: Women with PCOS report lower QOL than those with UI, whereas males with UI report lower QOL than males with PCOS partners. WHAT IS KNOWN ALREADY: The fertility-specific QOL survey, FertiQOL, has been used to examine fertility-related QOL in a number of worldwide cohorts. Few data have addressed fertility-related QOL as a function of infertility diagnosis. Overall, men report better QOL than women with infertility, and there is variation in FertiQOL scores across different samples from different countries. STUDY DESIGN, SIZE, DURATION: This was a prospective, cohort study derived from two concurrent, randomized clinical trials, and designed to examine QOL in infertile females with PCOS and UI at the time of enrollment compared with each other and their male partners; to compare concordance FertiQOL scores in this study across other worldwide cohorts; and to determine if baseline FertiQOL was associated with pregnancy outcome. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with PCOS and their partners (n = 733 and n = 641, respectively), and couples with UI (n = 865 women and 849 men) completed a validated fertility-specific QOL survey (FertiQOL) at the time of the study screening visit. PCOS women were randomized to either clomiphene citrate or letrozole treatment; couples with UI were randomized to clomiphene citrate, letrozole or gonadotrophin plus IUI. FertiQOL results were compiled by diagnosis (PCOS or UI) and compared by diagnosis and sex using Wilcoxon Rank-Sum testing. Relationships between baseline FertiQOL and pregnancy outcomes were examined using logistic regression. Multivariable models were performed to assess the association between FertiQOL scores and key participant characteristics. MAIN RESULTS AND THE ROLE OF CHANCE: Women with PCOS had lower total FertiQOL scores (72.3 ± 14.8) than those with UI (77.1 ± 12.8; P < 0.001); this was true for each domain (except Relational). These differences were largely explained by variation in BMI, hirsutism, household income and age. Women had lower overall FertiQOL scores than their male partners. Males with PCOS partners had higher scores than males with UI (84.9 ± 10.2 versus 83.3 ± 10.8; P = 0.003). Scores were not consistently associated with conception or pregnancy outcome. LIMITATIONS, REASONS FOR CAUTION: The use of multiple tests of association may have resulted in spurious statistically significant findings. Inherent sociodemographic differences between women with PCOS and those with UI largely account for the lower QOL in women with PCOS. Our study was unable to assess if changes in QOL affected pregnancy outcome as FertiQOL data were collected prior to treatment. Finally, the participants for both studies represent their local communities, but are not a population-based sample and thus firm conclusions about how representative these couples are to the general population must be made with caution. WIDER IMPLICATIONS OF THE FINDINGS: Women with PCOS with elevated BMI and hirsutism scores and with lower socioeconomic status may require more, targeted psychosocial support than those with other diagnoses. Possible attribution of infertility to the male partner appears to result in a lower QOL. There appears to be substantial national variation in FertiQOL scores, with US-based cohorts reporting overall higher QOL. STUDY FUNDING/COMPETING INTERESTS: This work was supported by National Institutes of Health (NIH)/Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Grants U10 HD39005 (to M.D.), U10 HD38992 (to R.S.L.), (to C.C.), U10 HD38998 (to R.A.), U10 HD055942 (to R.D.R.), HD055944 (to P.C.), U10 HD055936 (to G.C.), U10HD055925 (to H.Z.); and U10 U54-HD29834 (to the University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core of the Specialized Cooperative Centers Program in Reproduction and Infertility Research). Most importantly, this research was made possible by the funding by American Recovery and Reinvestment Act. N.S., E.E., J.C.T., C.G., H.H., R.A., P.C., G.C., C.C., M.D., S.J., W.D.S. and H.Z. report no conflicts of interests/disclosures. L.B.C. reports research support from Ferring Pharmaceuticals and Roche Diagnostics; R.S.L. reports receipt of consulting fees from AstraZeneca, Euroscreen, Sprout Pharmaceuticals, Taken, Kindex, Clarus and Bayer, Inc., and research support from AstraZeneca and Ferring Pharmaceuticals. R.D.R. reports research support from AbbVie. TRIAL REGISTRATION NUMBER: Pregnancy in Polycystic Ovary Syndrome II (PPCOS II), NCT00719186; Assessment of Multiple Intrauterine Gestations in Ovulation Stimulation (AMIGOS) NCT01044862, clinicaltrials.gov. TRIAL REGISTRATION DATE: PPCOS II 17 July 2008; AMIGOS 7 January 2010. DATE OF FIRST PATIENT'S ENROLMENT: PPCOS II 19 February 2009; AMIGOS 2 August 2010.

Retroperitoneal fluid collection following anterior spine surgery--differential and management.

Iatrogenic ureteral injuries are rare and must be accurately identified to minimizing the risk for additional complications. Anterior lumbar interbody fusion (ALIF) is a valuable technique utilized in spine surgery, with its own unique set of complications. For example, retroperitoneal fluid collections, following ALIF surgery are rare and may result in back pain, radicular pain, nausea, and even death. It is important to rapidly identify the nature of the fluid collection to clarify appropriate management options. The purpose of this case report is to present a differential diagnosis for a delayed presentation of an extremely large retroperitoneal fluid collection following anterior lumbar surgery, as well as to provide discussion on this rare complication. Specifically, a 51-year-old female with a history of numerous previous abdominal surgeries underwent an L3-S1 ALIF through a paramedian retroperitoneal approach. Postoperatively, she developed a large retroperitoneal fluid collection heralded by unilateral left lower extremity swelling and paresthesias. Fluid aspiration suggested a urine leak, but no specific injury was identified on retrograde pyelogram, most likely due to hardware obscuration in the area of presumed injury. A presumptive ureteral injury resulted in a ureteral stent placement, with resolution of the fluid collection and hydronephrosis. A high index of suspicion allowed for proper treatment, healing, and ultimately, a satisfactory outcome.

Letrozole, Gonadotropin, or Clomiphene for Unexplained Infertility.

BACKGROUND: The standard therapy for women with unexplained infertility is gonadotropin or clomiphene citrate. Ovarian stimulation with letrozole has been proposed to reduce multiple gestations while maintaining live birth rates. METHODS: We enrolled couples with unexplained infertility in a multicenter, randomized trial. Ovulatory women 18 to 40 years of age with at least one patent fallopian tube were randomly assigned to ovarian stimulation (up to four cycles) with gonadotropin (301 women), clomiphene (300), or letrozole (299). The primary outcome was the rate of multiple gestations among women with clinical pregnancies. RESULTS: After treatment with gonadotropin, clomiphene, or letrozole, clinical pregnancies occurred in 35.5%, 28.3%, and 22.4% of cycles, and live birth in 32.2%, 23.3%, and 18.7%, respectively; pregnancy rates with letrozole were significantly lower than the rates with standard therapy (gonadotropin or clomiphene) (P=0.003) or gonadotropin alone (P<0.001) but not with clomiphene alone (P=0.10). Among ongoing pregnancies with fetal heart activity, the multiple gestation rate with letrozole (9 of 67 pregnancies, 13%) did not differ significantly from the rate with gonadotropin or clomiphene (42 of 192, 22%; P=0.15) or clomiphene alone (8 of 85, 9%; P=0.44) but was lower than the rate with gonadotropin alone (34 of 107, 32%; P=0.006). All multiple gestations in the clomiphene and letrozole groups were twins, whereas gonadotropin treatment resulted in 24 twin and 10 triplet gestations. There were no significant differences among groups in the frequencies of congenital anomalies or major fetal and neonatal complications. CONCLUSIONS: In women with unexplained infertility, ovarian stimulation with letrozole resulted in a significantly lower frequency of multiple gestation but also a lower frequency of live birth, as compared with gonadotropin but not as compared with clomiphene. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01044862.).

Impact of Male and Female Weight, Smoking, and Intercourse Frequency on Live Birth in Women With Polycystic Ovary Syndrome.

CONTEXT: Obese men with normal semen parameters exhibit reduced fertility but few prospective data are available. OBJECTIVE: This study aimed to determine the effect of male factors and body mass among the Pregnancy in Polycystic Ovary Syndrome II (PPCOS II) participants. METHODS: This is a secondary analysis of the PPCOS II trial. A total of 750 infertile women with polycystic ovary syndrome (PCOS) were randomly assigned to up to receive five cycles of letrozole or clomiphene citrate. Females were 18-39-years-old and had a male partner with sperm concentration of at least 14 million/mL who consented to regular intercourse. Analysis was limited to couples with complete male partner information (n = 710). RESULTS: Male body mass index (BMI) was higher in couples who failed to conceive (29.5 kg/m(2) vs 28.2 kg/m(2); P = .039) as well as those who did not achieve a live birth (29.5 kg/m(2) vs 28.1 kg/m(2); P = .047). At least one partner was obese in 548 couples (77.1%). A total of 261 couples were concordant for obesity (36.8%). After adjustment for female BMI, the association of male BMI with live birth was no longer significant (odds ratio [OR] = 0.85; 95 % confidence interval [CI], 0.68-1.05; P = .13). Couples in which both partners smoked had a lower chance of live birth vs nonsmokers (OR = 0.20; 95 % CI, 0.08-0.52; P = .02), whereas there was not a significant effect of female or male smoking alone. Live birth was more likely in couples with at least three sexual intercourse attempts over the previous 4 weeks (reported at baseline) as opposed to couples with lesser frequency (OR = 4.39; 95 % CI, 1.52-12. 4; P < .01). CONCLUSIONS: In this large cohort of obese women with PCOS, effect of male obesity was explained by female BMI. Lower chance of success was seen among couples where both partners smoked. Obesity and smoking are common among women with PCOS and their partners and contribute to a decrease in fertility treatment success.

On-label and off-label drugs used in the treatment of male infertility.

Infertility affects 6.1 million U.S. couples-representing 10% of reproductive-age adults and 15% of all couples trying to conceive. Half of the time, infertility is the result of an abnormal semen analysis or other male factors, with 40%-50% of these infertile men diagnosed with idiopathic or nonclassifiable infertility. While the role of hormone therapy for men with an identified abnormality is well defined, the literature remains inconclusive and controversial regarding hormone manipulation using empirical (off-label) medical therapies for men with idiopathic infertility. This manuscript reviews the commonly used off-label medications used to treat idiopathic male factor infertility: clomiphene citrate, letrozole/anastrozole, exogenous androgens, and pentoxifylline.