Intra-individual changes in sperm parameters and total motile count with time among infertile men.

BACKGROUND: Paternal age association with sperm parameters has been previously studied, demonstrating a decrease in semen volume, sperm motility, and sperm morphology, but not in sperm concentration. However, scarce data exists on the individual intra-personal changes in semen parameters with time. STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To evaluate the changes in semen parameters and total motile count of infertile men over time. MATERIALS AND METHODS: In this retrospective cohort study, infertile men without known risk factors for sperm quality deterioration and at least two semen analyses done > 3 months apart, between 2005 and 2021, were evaluated. Allocation to groups was according to time between first and last semen analyses - 3-12 months, 1-3 years, 3-5 years, and > 5 years. Basic characteristics and first and last semen analyses were compared. The primary outcome was the change in sperm parameters and the secondary outcome was the occurrence of a total motile count < 5 million in men with an initial total motile count > 10 million. RESULTS: A total of 2018 men were included in the study. The median age at first semen analyses was 36.2 (interquartile range: 32.8-40.1) years and the median time between semen analyses was 323 days (range 90-5810 days). The overall trend demonstrated an increase in concentration in the 3-12 months and the 1-3 years groups, whereas volume, motility, and morphology remained similar in these time groups. Semen analyses done more than 5 years apart showed decreased volume (p < 0.05), motility (p < 0.05) morphology (p < 0.05), and steady sperm concentration. Significant declines in TMCs were found over time (p < 0.001), with 18% and 22% of infertile men with an initial total motile count > 10 million dropping to < 5 million after 3 and 5 years, respectively. The factors independently predictive of total motile count < 5 M in the last semen analyses in men with an initial total motile count of > 10 M in a multivariate logistic regression model were baseline volume (odds ratio 0.80, p = 0.03), baseline total motile count (odds ratio 0.98, p = 0.01) and time between semen analyses - 3-5 years (odds ratio 3.79, p < 0.001) and > 5 years (odds ratio 3.49, p = 0.04) DISCUSSION: Our study demonstrates, at the individual level, that while improvement in sperm concentration is observed in the first year and between 1 and 3 years, possibly due to fertility treatments, fertility-related counseling, and lifestyle changes, semen parameters decline with time over 3 years in individuals. Of significance, close to 22% of men with an initial total motile count > 10 million (a range where spontaneous pregnancy is attainable) declined to < 5 million (a range usually indicating a need for in-vitro fertilization/intracytoplasmic sperm injection) over 5 years. This data could contribute to individualized family planning for infertile men regarding the mode and timing of conception and the need for sperm banking, in order to minimize the need for future fertility treatments.

Temporal Trends in Semen Quality, Hormone Levels, and Substance Use Among Infertile Men in Pre- and Post-Cannabis Legalization Eras in Canada.

Background: The Cannabis Act (Bill C-45) was enacted in 2018, to legalize and regulate the use, production, and sale of nonmedical cannabis in Canada. While public health and safety implications of cannabis legalization have yet to be elucidated, the wide availability of cannabis necessitates health care providers to be knowledgeable about therapeutic potential and side effects of use. This study aimed to examine the temporal trends over two decades and the impact of the Cannabis Act in Canada, implemented in October 2018, on substance use, semen parameters, and testosterone levels of infertile men. Methods: We conducted a retrospective cohort study from a prospectively maintained database of a single infertility clinic. Demographic, fertility, and substance use history were correlated with semen and hormone assessments. Temporal trends in cannabis use and semen quality between 2001 and 2021 were investigated and compared between pre-cannabis legalization eras (PRCL) and post-cannabis legalization eras (POCL). Results: Our cohort included 11,630 patients (9411 PRCL and 2230 POCL). Cannabis use increased by 8.4% per year (p<0.001), while alcohol and tobacco consumption declined (0.8% and 1.5% per year, p<0.05 and p=0.004, respectively). Similar trends were noticed in the POCL, with higher rates of cannabis use (22.4% vs. 12.9%, p<0.001) and decreased tobacco and alcohol intake (15.2% vs. 17.7%, p=0.005 and 50.5% vs. 55.2%, p<0.001, respectively) compared to the PRCL group. Semen concentration was lower in the POCL group (24.8±44.8 vs. 28.7±48.3 million/mL, p=0.03). Testosterone did not differ between the cohorts. Comparison between cannabis users (n=1715) and nonusers (n=9924) demonstrated a slight increase in sperm motility (25.9%±15.3% vs. 23.9%±15.0%, p=0.002) and decreased sperm concentration among users (27.6±53.5 vs. 23.9±15.0 million/mL, p=0.03). Conclusion: A nearly 10% rise in cannabis use in the POCL era was observed among men being investigated for infertility. Our data suggest cannabis use may be associated with an increase in testosterone, slightly improved sperm motility, and decreased sperm concentration.

Biomarkers of Iron Are Associated with Anterior-Pituitary-Produced Reproductive Hormones in Men with Infertility.

Approximately 16% of North American couples are affected by infertility, with 30% of cases being attributable to male factor infertility. The regulation of reproductive hormones via the hypothalamic-pituitary-gonadal axis is important for spermatogenesis and subsequently male fertility. Maintaining iron homeostasis is critical to normal reproductive physiological function. This cross-sectional study's objective was to determine the association between serum biomarkers of iron and reproductive hormones. Men experiencing infertility (n = 303) were recruited from Mount Sinai Hospital, Toronto. Serum was analyzed for iron and ferritin as biomarkers of iron status and reproductive hormones (follicle-stimulating hormone, luteinizing hormone, testosterone, estradiol, and prolactin), which were the primary outcome. Associations were determined using non-parametric Spearman's rank correlation coefficient, linear regressions, and logistic regressions. A significant independent monotonic inverse relationship between serum iron and prolactin (p = 0.0002) was found. In linear regression analyses, iron was inversely associated with luteinizing hormone (unadjusted p = 0.03, adjusted p = 0.03) and prolactin (unadjusted p = 0.001 and adjusted p = 0.003). Serum ferritin was inversely associated with both gonadotropins, follicle-stimulating hormone (adjusted p = 0.03), and luteinizing hormone (adjusted p = 0.02). These findings suggest that biomarkers of iron are associated with pituitary-produced reproductive hormones, which play a role in the hypothalamic-pituitary-gonadal signaling pathway involved in spermatogenesis, testicular testosterone production, and male fertility.

Improved sperm DNA fragmentation levels in infertile men following very short abstinence of 3-4 hours.

Background: Limited data exists on possible approaches to improve sperm DNA fragmentation index (DFI) when no identifiable cause is found. The effect of short abstinence on sperm parameters has been extensively studied, but rarely reported on the effect on DFI in infertile men. In this study, we aimed to determine whether a second ejaculate provided after very short abstinence demonstrates lower DFI rates in infertile men. Methods: This prospective cohort study was conducted at Mount Sinai Hospital, Toronto, Canada, a tertiary university affiliated hospital. All men having DFI testing in addition to the standard semen analysis were identified via a prospectively collected database. Infertile men were instructed to provide two semen samples 3-4 hours apart (the first sample was given after 2-5 days of abstinence) to test the effect on DFI levels. Data analysis was performed for the comparison of the change in sperm parameters and DFI between samples and between men with DFI above and under 30%. Results: A total of 52 men provided double ejaculates 3-4 hours apart. In the entire group, DFI decreased from 38.9%±21.4% to 35.1%±21.6% in the second sample (P<0.001). Semen volume was lower on the second sample (2.3±1.4 vs. 1.5±0.9 mL, P<0.001), while the remaining parameters did not change. Forty out of 52 patients (76.9%) had improved DFI (average of 6.0±4.0 percentage points). Change in DFI varied with 22/52 (42.3%) and 7/52 (13.5%) of patients found to have decreases in DFI >5% and >10% in the second ejaculate, respectively. For men with DFI of 30-40%, 64% (7/11) of DFIs reduced to the under 30% range. First DFI value was the only parameter associated with DFI decrease to under 30% in multivariate models [odds ratio (OR), 0.62; 95% confidence interval (CI): 0.39-0.98; P=0.04]. Conclusions: This study identified significant improvements in DFI in infertile men providing a second sample after 3-4 hours. Controlled trials are needed to determine if reproductive outcomes are improved using a second ejaculate for infertile men with high initial sperm DFI values.

Practice and development of male contraception: European Academy of Andrology and American Society of Andrology guidelines.

BACKGROUNDS: Despite a wide spectrum of contraceptive methods for women, the unintended pregnancy rate remains high (45% in the US), with 50% resulting in abortion. Currently, 20% of global contraceptive use is male-directed, with a wide variation among countries due to limited availability and lack of efficacy. Worldwide studies indicate that >50% of men would opt to use a reversible method, and 90% of women would rely on their partner to use a contraceptive. Additional reasons for novel male contraceptive methods to be available include the increased life expectancy, sharing the reproductive risks among partners, social issues, the lack of pharma industry involvement and the lack of opinion makers advocating for male contraception. AIM: The present guidelines aim to review the status regarding male contraception, the current state of the art to support the clinical practice, recommend minimal requirements for new male contraceptive development and provide and grade updated, evidence-based recommendations from the European Society of Andrology (EAA) and the American Society of Andrology (ASA). METHODS: An expert panel of academicians appointed by the EAA and the ASA generated a consensus guideline according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) system. RESULTS: Sixty evidence-based and graded recommendations were produced on couple-centered communication, behaviors, barrier methods, semen analysis and contraceptive efficacy, physical agents, surgical methods, actions before initiating male contraception, hormonal methods, non-hormonal methods, vaccines, and social and ethical considerations. CONCLUSION: As gender roles transform and gender equity is established in relationships, the male contribution to family planning must be facilitated. Efficient and safe male-directed methods must be evaluated and introduced into clinical practice, preferably reversible, either hormonal or non-hormonal. From a future perspective, identifying new hormonal combinations, suitable testicular targets, and emerging vas occlusion methods will produce novel molecules and products for male contraception.

Intra-individual changes in sperm DNA fragmentation levels over short and long time periods.

PURPOSE: We aimed to examine the longitudinal, intra-personal changes in DNA fragmentation index (DFI) over time. METHODS: Men who performed at least two DFI measurements (using sperm chromatin structure assay (SCSA) between 2003 and 2019 were included in this study and allocated to groups by time between DFI tests: < 1 year, 1-3 years, 3-5 years, and > 5 years. An analysis of DFI change over time according to age groups was additionally performed. Regression models were developed to predict changes in DFI with time. RESULTS: Overall, 225 patients had two or more DFI measurements done at least a month apart (mean of 586.7± 710.0 days). The < 1 year (n = 124) and 1-3 years (n = 68) groups demonstrated decreased DFI levels, while an increase in DFI was shown in 3-5 years (n = 21) and more than 5 years (n = 12) groups - 7.1 ± 14.9%, - 4.5 ± 13.4%, + 3.2 ± 8.4%, and + 10.8 ± 18.0%, respectively, p < 0.001). This trend was similarly shown in age subgroups of under 40 years and 40-50 years at baseline DFI. Linear regression models showed that the factors predictive of DFI increase are baseline DFI and > 3 years between DFI tests. CONCLUSION: This study shows that DFI, in men being investigated for infertility, initially decreases in the first 3 years of follow-up, and then increases over time with the highest increase occurring after 5 years interval (an average increase of 10.8%). Testing infertile men's DFI levels at first evaluation may contribute to personalized consult regarding future reproductive outcomes.

Ascorbic acid is associated with favourable hormonal profiles among infertile males.

Introduction: Infertility affects about 16% of North American couples, with the male factor contributing to ∼30% of cases. Reproductive hormones play an integral role in regulating the reproductive system and consequently, fertility. Oxidative stress reduces testosterone synthesis, and reduction in oxidative stress can improve hormone profiles. Ascorbic acid is a potent antioxidant that accounts for up to 65% of seminal antioxidant activity; however, its effects on reproductive hormones in humans are unknown. Methods: The objective was to determine the association between serum ascorbic acid concentrations and male reproductive hormones. We conducted a cross-sectional study involving infertile males (n = 302) recruited from Mount Sinai Hospital, Toronto. Serum was analyzed for ascorbic acid, luteinizing hormone (LH), follicular stimulating hormone (FSH), total testosterone (TT), prolactin and estradiol. Statistical analyses included Spearman's rank correlations, linear regressions, logistic regressions, simple slope and Johnson-Neyman procedures. Results: After adjusting for covariates, ascorbic acid was inversely associated with LH (P = 0.01). Ascorbic acid was positively associated with TT only among males over the age of 41.6 years (P = 0.01). Discussion: Our findings show that ascorbic acid is associated with higher testosterone levels and improved androgenic status in infertile males, and some of the effects appear to be age dependent.

Uncovering the Association Between Complete AZFc Microduplications and Spermatogenic Ability: The First Reported Series.

Purpose This article aims to report the first series of men with complete AZFc microduplications and their clinical and reproductive characteristics. Methods We sampled 3000 men who presented for reproductive urology evaluation from 2012-2020, of which 104 men underwent high-resolution Y-chromosome microarray testing, and five men were identified to have complete AZFc microduplications. Medical, surgical, and reproductive histories were obtained. Semen and hormonal parameters as well as response to fertility therapies were recorded. Results Five men were identified as having complete AZFc microduplications. The mean age was 33.75 years, representing 0.2% (5/3000) of men presenting for fertility investigation, 4.8% (5/104) of men undergoing microarray testing, and 21% (5/24) of men with AZFc abnormalities. Two of the men had prior undescended testicles and one had several autoimmune processes. The mean follicle-stimulating hormone (FSH) was 5.5 IU/L, luteinizing hormone (LH) 3.6 IU/L, and testosterone 14.56 nmol/L. One man was azoospermic, one man alternated between severe oligospermia and rare non-motile sperm, one had variable parameters, with one semen analysis demonstrating azoospermia and a second demonstrating a total motile sperm count (TMSC) of 4 ×106, one man was persistently oligospermic with TMSCs ranging 3.96-12.6 ×106, and one man initially had severe oligospermia, with a mean TMSC of 1.5 ×106, which increased to 21.7 ×106 after intervention (varicocele embolization, clomiphene citrate). This last man then fathered a spontaneous pregnancy. Conclusion AZFc complete microduplications are a rare cause of spermatogenic failure but not an uncommon form of AZFc abnormality. Clinically, they represent a heterogeneous group, having a variable reproductive potential. Cases should be managed on an individual basis.

How far will they go? Distance and driving times that north American men travel to see a reproductive urologist.

Male factor infertility affects about 50% of infertile couples. However, male factor infertility is largely under-evaluated due to multiple reasons. This study is to determine the time men travel for fertility evaluation, and factors associated with driving longer. Data from the Andrology Research Consortium were analysed. Driving distance and time were calculated by comparing "patient postal code" with "clinic postal code", then stratified into quartiles. Patients with the longest driving times (> 75th percentile [Q4]) were compared with those having shorter driving times. Logistic regression analysis was used to identify factors associated with longer driving times. Sixteen clinics and 3029 men were included. The median driving distance was 18.1 miles, median driving time was 32 min, and Q4 driving time was 49 min. Factors correlated with having Q4 driving time were age > 30 years, native Indian and Caucasian race, body mass index (BMI) > 30 kg/m2 , history of miscarriage, children with previous partner, self-referral, prior vasectomy, and prior marijuana use. On logistic regression, males aged < 30 years were more likely to be in Q4 for driving time versus older males. Blacks and Asians were less likely to travel further than Caucasians. Overweight/obese men, those having children with previous partner, and with prior vasectomy were more likely to be in Q4 travelling time. Factors correlated with longer driving times include younger age, native Indian and Caucasian race, higher BMI, children with prior partner, and prior vasectomy. These may reflect groups that drive long distances for reproductive care. The study provides an opportunity to better access these groups and minimise their barriers to fertility care.

"Who needs an app? Fertility patients' use of a novel mobile health app".

Objective: The number of couples experiencing infertility treatment has increased, as has the number of women and men experiencing infertility treatment-related stress and anxiety. Therefore, there is a need to provide information and support to both men and women facing fertility concerns. To achieve this goal, we designed a mhealth app, Infotility, that provided men and women with tailored medical, psychosocial, lifestyle, and legal information. Methods: This study specifically examined how fertility factors (e.g. time in infertility treatment, parity), socio-demographic characteristics (e.g. gender, education, immigrant status), and mental health characteristics (e.g. stress, depression, anxiety, fertility-related quality of life) were related to male and female fertility patients' patterns of use of the Infotility app. Results: Overall, the lifestyle section of the app was the most highly used section by both men and women. In addition, women without children and highly educated women were more likely to use Infotility. No demographic, mental health or fertility characteristics were significantly associated with app use for men. Conclusion: This study shows the feasibility of a mhealth app to address the psychosocial and informational needs of fertility patients.

Evaluation of a Mobile Health App Offering Fertility Information to Male Patients With Cancer: Usability Study.

BACKGROUND: Cancer and its treatment can adversely affect male fertility. Although sperm banking is an effective fertility preservation method, there is an unmet need for information and support surrounding these issues. OBJECTIVE: This usability study evaluates a mobile health app providing male patients with cancer with credible information about the impact of cancer and its treatment on fertility and fertility preservation. METHODS: Participants were recruited by a market research firm. Eligibility criteria were men who were 18-45 years of age, identified as male, diagnosed with new or recurring cancer within 1 year, not in fertility treatment, able to read and write in English or French, and had internet access. App usage was tracked for 2 weeks. After app use, participants provided qualitative feedback about their experiences using the app as well as quantitative data regarding their sperm banking decisions, perceived change in fertility knowledge, evaluation of the app's information on the Information Assessment Method, and the app's quality on the user version of the Mobile App Rating Scale. RESULTS: The sample included 40 men aged 27-45 years. Approximately 68% (27/40) indicated that no one had previously spoken to them about the impact of cancer on fertility, and 85% (34/40) had not received information on fertility preservation. Approximately 83% (33/40) found the app's information relevant, and 85% (34/40) said that it increased their fertility knowledge. Approximately 23% (9/40) made a decision about sperm banking after using the app. Participants rated the app's quality highly, with mean scores (out of 5) of 4.14 for information, 4.06 for functionality, 3.84 for aesthetics, and 3.63 for engagement. CONCLUSIONS: The app proved to be useful for male patients with cancer, suggesting that mobile health resources could be beneficial to incorporate into clinical care to enable shared decision-making about fertility.

Risky Business: Increasing Fertility Knowledge of Men in the General Public Using the Mobile Health Application Infotility XY.

Male infertility presents a public health concern. As most men wish to become fathers, it is important to increase men's awareness of infertility risk factors. We developed a mobile health application (mHealth app), Infotility XY, to promote men's reproductive health. This study evaluates whether use of the app led to increased knowledge of infertility risk factors, and whether knowledge change was associated with participants' sociodemographic characteristics and/or app usage. Participants were recruited between August and October 2020. Eligibility criteria included: identified as male; 18-45 years old; childless; no infertility history; able to read and write in English/French; had internet access. We assessed participants' fertility knowledge before and after app use. App usage data were captured during the 2-week intervention period. Our sample included 49 men aged 18-45. Seventy-eight percent of participants had not previously sought fertility information. Participants viewed on average 75% of the app's articles, and 96% of participants said the app increased their fertility knowledge. Before app use, 55% of men said they were aware of infertility risk factors, compared to 96% after app use. Men correctly identified more risk factors after app use compared to before, t(48) = 8.28, p < .001. Participants' sociodemographic characteristics and amount of app usage were not associated with knowledge change. This study provides evidence of the feasibility of an mHealth app to improve men's awareness of infertility risk factors. Given the positive relationship between male reproductive health and overall health, increased awareness of infertility risk factors may lead to men's improved overall health.

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.

The impact of cannabis use on male sexual function: A 10-year, single-center experience.

INTRODUCTION: Despite increasing consumption rates in much of the world, the impact of cannabis use on various components of male sexual function remains poorly established. The purpose of this study was to further evaluate the relationship between cannabis use and reproductive and sexual function using a large patient cohort from a single academic andrology clinic. METHODS: This is a historical cohort study from a single academic center andrology clinic. Patients from 2008-2017 were included. Intake questionnaires provided baseline demographic information, as well as data regarding substance use and various sexual function parameters. Subjects were categorized as cannabis users or non-users. Cannabis users and non-users were compared using descriptive statistics and Chi-squared tests, and regression analyses were performed to test for association. RESULTS: A total of 7809 males were included in the study; 993 (12.7%) were cannabis users and 6816 (87.3%) were non-users. Cannabis users had a higher mean Sexual Health Inventory for Men (SHIM) score (21.9±4.4 vs. 21.2±4.8, p<0.001) and mean serum total testosterone (13.4±12.0 nmol/L vs. 12.6±11.8 nmol/L, p=0.04) than non-users, although they also had a higher rate of positive Androgen Deficiency in the Aging Male (ADAM) scores (52% vs. 46%, p<0.001). Cannabis users also reported higher sexual frequency compared to non-users (8.8 events/month vs. 7.8 events/month, p<0.05). On multivariate analysis, cannabis use was not associated with SHIM score or serum testosterone concentration. Cannabis use was associated with positive ADAM scores. CONCLUSIONS: Cannabis use was not associated with clinically significant deleterious effects on male sexual parameters in this cohort.

Predictors of infertility-related concerns in a Canadian survey of men and women seeking fertility treatment.

OBJECTIVE: To examine if and how factors associated with infertility-related concerns and opportunity to discuss concerns differ between male and female fertility patients. METHODS: A cross-sectional survey of 313 female and 254 male patients recruited from Canadian fertility clinics. An online survey asked about sociodemographic characteristics, psychological distress, the severity of psychosocial concerns on a scale of 0 (not concerned) to 5 (very concerned) related to fertility treatment, and their opportunity and desire to discuss concerns with healthcare providers (HCPs). RESULTS: For women, higher stress, educational attainment and being childless were associated with higher concern (F(6, 287) = 14.73, p < .001). For men, higher stress, being religious and longer treatment duration were associated with higher concern (F(8, 222) = 9.87, p < .001). No significant difference existed between men's and women's average concern scores (t(558) = -1.62, p = .11) or opportunity to discuss concerns (t(149) = 0.28, p = .78). CONCLUSION: Our results indicate an unmet need and desire for support among subgroups of patients who were concerned about psychosocial issues related to infertility, but did not have the opportunity to discuss these issues with HCPs. PRACTICE IMPLICATIONS: There is a need to tailor resources to address the concerns of male and female fertility patients from diverse sociodemographic backgrounds and with different fertility histories.

A noninvasive urine-based methylation biomarker panel to detect bladder cancer and discriminate cancer grade.

BACKGROUND: Highly sensitive and specific urinary biomarkers for the early detection of bladder cancer (BC) to improve the performance of urinary cytology are needed. OBJECTIVE: To investigate the usefulness of methylation markers in voided urine to identify BC presence and grade. DESIGN, SETTINGS, AND PARTICIPANTS: Using genome-wide methylation strategies in Toronto, Canada and Liège, Belgium, we have identified differentially methylated genes (TWIST1, RUNX3, GATA4, NID2, and FOXE1) in low-grade vs. high-grade BC tissue and urine. We accrued urine samples from 313 patients using a 2:1 ratio in a case-control setting from Toronto, Canada, Halifax, Canada, and Zurich, Switzerland. We studied the usefulness of these 5 methylated genes to identify BC and discriminate cancer grade in voided urine specimens. Urinary cell sediment DNA was evaluated using qPCR-based MethyLight assay. Multivariable logistic regression prediction models were created. RESULTS AND LIMITATIONS: We included 211 BC patients (180 nonmuscle invasive) and 102 controls. In univariate analyses, all methylated genes significantly predicted BC vs. no BC, and high grade vs. low grade (all P < 0.05). In multivariable analysis, NID2, TWIST1, and age were independent predictors of BC (all P < 0.05). Sensitivity of NID2 and TWIST1 to predict BC and BC grade was 76.2% and 77.6%, respectively, whereas specificity was 83.3% and 61.1%, respectively. Multivariable models predicting BC overall and discriminating between high-grade and low-grade BC reached area under the receiver operating characteristics curves of 0.89 and 0.78, respectively. CONCLUSIONS: This multi-centric study in a real life scenario (different countries, techniques, and pathologists) supports the promise of epigenetic urinary markers in noninvasively detecting BC. With sensitivities and specificities in the range of 80%, the overall performance characteristics of this panel of methylated genes probably does not allow such signature to significantly alter clinical care at this stage but is worth further studying for instance in BC surveillance or screening in high-risk populations.

The effect of ethnicity on semen analysis and hormones in the infertile patient.

INTRODUCTION: We aimed to study the association of ethnicity on semen parameters and hormones in patients presenting with infertility. METHODS: Data from men presenting for infertility assessment were prospectively collected and retrospectively reviewed. Demographic and clinical history was self-reported. Semen analysis included volume, count, motility, morphology, and vitality. The 2010 World Health Organization cutoffs were used. Baseline total testosterone and follicle-stimulating hormone (FSH) levels were recorded. Ethnicity data was classified as Caucasian, African Canadian, Asian, Indo-Canadian, Native Canadian, Hispanic, and Middle Eastern. All patients with complete data were included and statistical analysis was performed. RESULTS: A total of 9079 patients were reviewed, of which 3956 patients had complete data. Of these, 839 (21.2%) were azoospermic. After adjusting for age, African Canadians (odds ratio [OR] 1.70; 95% confidence interval [CI] 1.28-2.25) and Asians (1.34; 95% CI 1.11-1.62) were more likely to be azoospermic compared to Caucasians. Similarly, African Canadians (OR 1.75; 95% CI 1.33-2.29) were more likely to be oligospermic and Asians (OR 0.82; 95% CI 0.70-0.97) less likely to be oligospermic. Low volume was found in African Canadian (OR 1.42; 95% CI 1.05-1.91), Asians (OR 1.23; 95% CI 1.01-1.51), and Indo-Canadians (OR 1.47; 95% CI 1.01-2.13). Furthermore, Asians (OR 0.73; 95% CI 0.57-0.93) and Hispanics (OR 0.58; 95% CI 034-0.99) were less likely to have asthenospermia. Asians (OR 0.73; 95% CI 0.57-0.94) and Indo-Canadians (OR 0.58; 95% CI 0.35-0.99) were less likely to have teratozospermia. No differences were seen for vitality. No differences were seen for FSH levels, however, Asians (p<0.01) and Indo-Canadians (p<0.01) were more likely to have lower testosterone. CONCLUSIONS: Our study illustrates that variations in semen analyses and hormones exist in men with infertility. This may provide insight into the workup and management for infertile men from different ethnicities.

Searching the Internet for Infertility Information: A Survey of Patient Needs and Preferences.

BACKGROUND: Given the complexity of infertility diagnoses and treatments and the convenience of the internet for finding health-related information, people undergoing infertility treatments often use Web-based resources to obtain infertility information and support. However, little is known about the types of information and support resources infertility patients search for on the internet and whether these resources meet their needs. OBJECTIVE: The aims of this study were to (1) examine what individual factors, namely, demographic characteristics and distress, are associated with searching the internet for different types of infertility-related information and support resources and (2) determine whether Web-based resources meet the needs of patients. METHODS: Men and women seeking infertility care responded to a survey assessing use of Web-based resources for accessing infertility-related information and support. The survey further assessed satisfaction with Web-based resources as well as perceived stress and depressive symptomatology. RESULTS: A total of 567 participants, including 254 men and 313 women, completed the survey. Most participants (490/558, 87.8%) had searched the internet for infertility information and support. Searchers were more likely to be women (P<.001), highly educated (P=.04), long-term patients (P=.03), and more distressed (P=.04). Causes of infertility, treatment options, and scientific literature about infertility were the three most frequently searched topics, whereas ways to discuss treatment with family and friends as well as surrogacy and ways to find peer support were the three least searched topics. Of those who searched the internet, 70.9% (346/488) indicated that their needs were met by Web-based information, whereas 29.1% (142/488) said that their needs were not met. Having unmet needs was related to greater levels of perceived stress (P=.005) and depressive symptomatology (P=.03). CONCLUSIONS: This study provides evidence for the important role of the internet in accessing infertility information and support and for the ability of Web-based resources to meet patients' needs. However, although distressed patients reported particularly high rates of searching, their needs were not always met, suggesting that they may benefit from alternative sources of information and support or guidance from health care providers when searching the internet.

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.