J.M. Hotaling

Teratozoospermia and asthenozoospermia are associated with specific epigenetic signatures.

Semen analysis is commonly used as a tool to assess the fertility potential of a male, despite its relatively low predictive power. In this study, we have assessed associations between semen analysis findings (low count, low motility, low viability, poor sperm penetration assay results, poor morphology, and increased DNA damage) and DNA methylation patterns in mature spermatozoa. DNA methylation patterns in the mature spermatozoa are thought to be indicative of patterns in the adult germline stem cells and may offer insight into potential perturbations to cellular pathways involved in spermatogenesis. In this study, sperm DNA methylation at >480,000 CpGs was assessed in 94 men using the Illumina 450k HumanMethylation Array and compared to standard measures of sperm quality. We did not identify any global changes to methylation profiles that were associated with reduced semen parameters. Similarly, we found no significant difference in methylation variability that was associated with any abnormal semen analysis parameter, although sperm displaying abnormal parameters tended to have an increased coefficient of variability, suggesting that, in some samples, this may be a contributing factor. Analysis of methylation at single CpGs and genomic regions did identify associations for low viability and low motility, and to a smaller extent, low count. Interestingly, based on GO Term analysis, differentially methylated regions associated with low viability were over‐represented in regions important in meiosis, spermatogenesis, and genomic imprinting. These results suggest that while there are not global alterations to the sperm methylome associated with semen abnormalites, some viability associated regional alterations do exist that may be indicative of perturbed cellular pathways during spermatogenesis.

Cardiovascular autonomic neuropathy, erectile dysfunction and lower urinary tract symptoms in men with type 1 diabetes: findings from the DCCT/EDIC.

PURPOSE We evaluated the association between cardiovascular autonomic neuropathy, and erectile dysfunction and lower urinary tract symptoms in men with type 1 diabetes. MATERIALS AND METHODS Male type 1 diabetes participants (635) in the DCCT/EDIC were studied. Cardiovascular autonomic neuropathy was assessed by standardized cardiovascular reflex tests including changes in respiratory rate variation with deep breathing, Valsalva maneuver (Valsalva ratio) and changes in supine to standing diastolic blood pressure. Erectile dysfunction was assessed by a proxy item from the International Index of Erectile Function, and lower urinary tract symptoms were assessed with the AUASI (American Urological Association Symptom Index). Multivariable logistic regression models estimated the association between cardiovascular autonomic neuropathy and erectile dysfunction and/or lower urinary tract symptoms, adjusting for time weighted glycemic control, blood pressure, age and other covariates. RESULTS Men in whom erectile dysfunction and/or lower urinary tract symptoms developed during EDIC had a significantly lower respiratory rate variation and Valsalva ratio at DCCT closeout and EDIC year 16/17 compared to those without erectile dysfunction or lower urinary tract symptoms. In adjusted analysis, participants with cardiovascular autonomic neuropathy had 2.65 greater odds of erectile dysfunction and lower urinary tract symptoms (95% CI 1.47-4.79). CONCLUSIONS These data suggest that cardiovascular autonomic neuropathy predicts the development of urological complications in men with long-standing type 1 diabetes. Studies evaluating the mechanisms contributing to these interactions are warranted for targeting effective prevention or treatment.

Sperm DNA damage output parameters measured by the alkaline Comet assay and their importance.

The alkaline Comet assay has shown high diagnostic value to determine male reproductive health and prognostic ability to predict ART success. Here, spermatozoon was analysed in 47 fertile donors and 238 patients, including 132 couples undergoing ART [semen was collected: Group I – within 3 months of their treatment (n = 79); and Group II – 3 months prior to their treatment (n = 53)]. We introduce four Comet distribution plots (A, B1, B2 and C) by plotting the level of DNA damage (x‐axis) and percentage of comets (y‐axis). Fertile donors had low mean DNA damage, olive tail moment and per cent of spermatozoa with damage and increased type A plots. Comet parameters were associated with clinical pregnancies in Group I. About 66% of couples with type A distribution plot were successful after ART, whereas couples with type B1, B2 and C distribution plots achieved 56%, 44% and 33% pregnancies respectively. The efficiency of the Comet assay was due to complete decondensation process, where the compact sperm nuclear DNA (28.2 ± 0.2 μm3) is decondensed to ~63 μm3 (before lysis) and ~1018 μm3 (after lysis). A combinational analysis of all the Comet output parameters may provide a comprehensive evaluation of patients reproductive health as these parameters measure different aspects of DNA damage within the spermatozoa.

Glycaemic control and risk of incident urinary incontinence in women with Type 1 diabetes: results from the Diabetes Control and Complications Trial and Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study

To study the impact of glycaemic control on urinary incontinence in women who participated in the Diabetes Control and Complications Trial (DCCT; 1983–1993) and its observational follow‐up study, the Epidemiology of Diabetes Interventions and Complications (EDIC; 1994–present).

A call for standardized outcomes in microTESE

In his letter to the Editor, Dr. Song mentions a number of concerns regarding sperm retrieval techniques in men with nonobstructive azoospermia (NOA). At large academic fertility meetings, we find many series reported of sperm retrieval procedures, most notably microdissection testicular sperm extraction (microTESE), and these series commonly have high success rates. Dr. Song voices concern that the reported successes and experiences with microTESE that are reported are not widely seen among clinical urologists in practice. We also share many of Dr. Song’s concerns. We agree that standardization of definitions of patients to be included in NOA series needs to be strict. For instance, if patients with cryptozoospermia are included in something described as microTESE (Alrabeeah et al., 2016), for instance, this would elevate the success rate, as these men do not have NOA. Patient inclusion and exclusion criteria in reports are variable and need to be standardized. Another area of variation from center to center is the laboratory handling of the specimens. In high-volume microTESE centers, the impact of assigning multiple laboratory technicians to examine testis tissue for many hours cannot be understated. This may be one explanation of higher sperm retrieval rates in such locations. However, this may not be practical in a freestanding clinical practice where there may be only one technician, and limited time to examine the tissue, as other tasks also need to be done. Finally, almost all large reports of microTESE are free-standing case series. There may have been reports of simple biopsies done in the past, but drawing conclusions about the efficacy of microTESE in this setting is difficult, as prior treatment has been done by multiple providers with many different prior biopsy techniques. Therefore, stating that microTESE has a certain high success rate, even in the face of prior failed biopsy, is questionable without a standardized treatment plan prior to the microTESE. In a paper published by some of the authors of this letter (Jensen et al., 2016), percutaneous needle biopsy was performed with 50–100 needle passes, sampling all areas of the testis as an initial method of sperm retrieval. Those who failed initial needle biopsy were offered microTESE with a success rate of only 11%. With no well-designed comparative studies between microTESE and other sperm retrieval techniques, it remains difficult to really assess the relative advantages and disadvantages of the various approaches. Such a trial would have to adhere to a strict definition of NOA (Anderson & Hotaling, 2015) and randomize people to either initial microTESE or an alternative procedure, perhaps a very difficult thing to convince patients to do. However, only with strictly controlled, randomized, comparative studies would we finally be able to define the place of different sperm retrieval techniques in the management of NOA.