Undiagnosed RASopathies in infertile men.

RASopathies are syndromes caused by congenital defects in the Ras/mitogen-activated protein kinase (MAPK) pathway genes, with a population prevalence of 1 in 1,000. Patients are typically identified in childhood based on diverse characteristic features, including cryptorchidism (CR) in >50% of affected men. As CR predisposes to spermatogenic failure (SPGF; total sperm count per ejaculate 0-39 million), we hypothesized that men seeking infertility management include cases with undiagnosed RASopathies. Likely pathogenic or pathogenic (LP/P) variants in 22 RASopathy-linked genes were screened in 521 idiopathic SPGF patients (including 155 CR cases) and 323 normozoospermic controls using exome sequencing. All 844 men were recruited to the ESTonian ANDrology (ESTAND) cohort and underwent identical andrological phenotyping. RASopathy-specific variant interpretation guidelines were used for pathogenicity assessment. LP/P variants were identified in PTPN11 (two), SOS1 (three), SOS2 (one), LZTR1 (one), SPRED1 (one), NF1 (one), and MAP2K1 (one). The findings affected six of 155 cases with CR and SPGF, three of 366 men with SPGF only, and one (of 323) normozoospermic subfertile man. The subgroup "CR and SPGF" had over 13-fold enrichment of findings compared to controls (3.9% vs. 0.3%; Fisher's exact test, p = 5.5 × 10-3). All ESTAND subjects with LP/P variants in the Ras/MAPK pathway genes presented congenital genitourinary anomalies, skeletal and joint conditions, and other RASopathy-linked health concerns. Rare forms of malignancies (schwannomatosis and pancreatic and testicular cancer) were reported on four occasions. The Genetics of Male Infertility Initiative (GEMINI) cohort (1,416 SPGF cases and 317 fertile men) was used to validate the outcome. LP/P variants in PTPN11 (three), LZTR1 (three), and MRAS (one) were identified in six SPGF cases (including 4/31 GEMINI cases with CR) and one normozoospermic man. Undiagnosed RASopathies were detected in total for 17 ESTAND and GEMINI subjects, 15 SPGF patients (10 with CR), and two fertile men. Affected RASopathy genes showed high expression in spermatogenic and testicular somatic cells. In conclusion, congenital defects in the Ras/MAPK pathway genes represent a new congenital etiology of syndromic male infertility. Undiagnosed RASopathies were especially enriched among patients with a history of cryptorchidism. Given the relationship between RASopathies and other conditions, infertile men found to have this molecular diagnosis should be evaluated for known RASopathy-linked health concerns, including specific rare malignancies.

Abstinence for sperm sample collection and ART outcome: an unsubstantiated myth.

PURPOSE OF REVIEW: Semen analysis is a basic component of male evaluation. Reproductive centers typically instruct men to provide a semen specimen based on recommendations from WHO Standard for semen examination. Evidence that these recommendations optimize sperm reproductive capacity is lacking. Existing data to optimize sperm quality with shorter abstinence were reviewed. RECENT FINDINGS: Several recent studies have reviewed the effects of shorter ejaculatory abstinence of semen quality and assisted reproductive technology (ART) outcomes. Shorter abstinence was defined as 1 h-1 day in one review, and <4 h in the other systematic meta-analysis and review. SUMMARY: Prior instructions for male patients have not been designed to optimize fertility potential for semen analyses. Optimal sperm quality is obtained by instructing men to have a short abstinence (certainly <1 day, and preferably <4 h) for semen specimens used for in vitro fertilization (assisted reproduction).

Gabapentin for Postoperative Pain Control and Opioid Reduction in Scrotal Surgery: A Randomized Controlled Clinical Trial.

PURPOSE: To assess the safety and efficacy of gabapentin in reducing postoperative pain among patients undergoing scrotal surgery for male infertility by conducting a randomized, double-blind, placebo-controlled trial. MATERIALS AND METHODS: In this randomized, double-blind, placebo-controlled trial, healthy men undergoing scrotal surgery with a single surgeon were randomized to receive either (1) gabapentin 600 mg given 2 hours preoperatively and 300 mg taken 3 times a day postoperatively for 3 days, or (2) inactive placebo. The primary outcome measure was difference in postoperative pain scores. Secondary outcomes included differences in opioid usage, patient satisfaction, and adverse events. RESULTS: Of 97 patients screened, 74 enrolled and underwent randomization. Of these, 4 men were lost to follow-up, and 70 were included in the final analysis (35 gabapentin, 35 placebo). Both differences in initial postoperative mean pain score (-1.14, 95% CI -2.21 to -0.08, P = .035) and final mean pain score differences (-1.27, 95% CI -2.23 to -0.32, P = .0097) indicated lower gabapentin pain compared to placebo. There were no statistically significant differences in opioid usage, patient satisfaction, or adverse events. CONCLUSIONS: These data suggest that perioperative gabapentin results in a statistically and clinically significant decrease in pain following scrotal surgery. While there was no evidence of an impact on opioid usage or patient satisfaction, given the low risk of adverse events, it may be considered as part of a multimodal pain management strategy.

Age, Sperm Retrieval, and Testicular Histology in Klinefelter Syndrome.

PURPOSE: We sought to examine sperm retrieval and testicular histology in males of different ages with Klinefelter syndrome. MATERIALS AND METHODS: We identified all males with Klinefelter syndrome who underwent microdissection testicular sperm extraction at our institution from 1995 to 2020. Patients were divided into adolescent (<20 years) and adult (≥20 years) cohorts. Histology and sperm retrieval were compared using chi-square statistics. Multivariable logistic regression models were used to examine factors associated with successful sperm retrieval. RESULTS: We identified 217 males with Klinefelter syndrome, of whom 59 were adolescents and 158 were adults. Adults were stratified into 10-year groupings (20-29 years, n = 62; 30-39 years, n = 88; ≥40 years, n = 8). Approximately 17% of adolescents had testis histology containing germ cells compared with 15% of the 20 to 29-year cohort, 14% of the 30 to 39-year cohort, and 0% over 40 years. In comparison to adolescents (53%), the sperm retrieval rate was significantly higher in the 20 to 29-year cohort (71%, P = .04) and lower in the ≥40-year cohort (13%, P = .03). In multivariable analysis, the presence of hypospermatogenesis on testis biopsy (OR 5.8, P = .03) was associated with higher odds of successful sperm retrieval. CONCLUSIONS: Younger males more frequently had germ cell-containing testis histology, however this finding was not associated with a higher odds of sperm retrieval. Reproductive urologists should counsel azoospermic males with Klinefelter syndrome that sperm retrieval during adolescence for fertility preservation is not required and can be performed in young adulthood.

Can sperm quality affect reproductive outcomes?

Current clinical evaluation of male factors poorly predicts assisted reproductive technology outcome. Sperm DNA fragmentation is useful. More advanced analysis of sperm structure and genetics could better assess male reproductive competence.

Successful cryptozoospermia management with multiple semen specimen collection.

OBJECTIVE: To determine the prevalence of sperm suitable for intracytoplasmic sperm injection (ICSI) in fresh ejaculated semen samples provided by men scheduled for a microdissection testicular sperm extraction (mTESE) procedure. Secondary objectives included an evaluation of the effect of a short abstinence period on semen quality and ICSI outcomes for men with cryptozoospermia. DESIGN: Retrospective cohort study. SETTING: Academic medical center. PATIENTS: All men were scheduled to undergo a mTESE procedure by a single, high-volume surgeon at an academic center from September 1, 2015, to May 1, 2021. INTERVENTION: Presence of sperm suitable for ICSI in the ejaculate on the day of scheduled mTESE. MAIN OUTCOME MEASURES: Prevalence of sperm suitable for ICSI in the ejaculate among previously diagnosed men with azoospermia. Secondary outcomes included changes in semen parameters, clinical pregnancy rate, and live birth rate. RESULTS: Of 727 planned mTESE procedures, 69 (9.5%) were canceled because sperm suitable for ICSI were identified in a fresh ejaculated sample produced on the day of scheduled surgery (typically one day before oocyte retrieval). Overall, 50 men (50/727, 6.9%) used these rare, ejaculated sperm for ICSI. Semen samples obtained with <24 hours of abstinence were more likely to have better motility than the sample initially provided on the day of the planned mTESE. The live birth rate per ICSI attempt using these rare, ejaculated sperm was 36% (19/53). CONCLUSION: Providing a fresh ejaculated semen sample on the day of mTESE allows nearly 10% of men with azoospermia to avoid surgery with satisfactory ICSI outcomes. Providing multiple ejaculated samples over a short period of time does not adversely affect sperm concentration and may enhance sperm motility in men with cryptozoospermia.

Acute testicular infarction in the setting of SARS-CoV-2 infection and diabetic vasculopathy.

Acute testicular pain with no arterial flow on Doppler ultrasonography is highly consistent with testicular torsion. In adults, there are rare etiologies of testicular infarction other than torsion, including infection, vasculitis, and trauma. We describe a 41-year-old man with type 2 diabetes complicated by severe vasculopathy and positive SARS-CoV-2 status presenting with acute right testicular pain. Surgical exploration and pathology were concerning for arteriosclerosis and vasculitis. These observations suggest that medically complex patients presenting with acute testicular pain in the setting of COVID-19 infection could be at risk for ischemia; causes of testicular pain beyond torsion should be considered.

Sperm DNA Damage and Its Relevance in Fertility Treatment: A Review of Recent Literature and Current Practice Guidelines.

Sperm deoxyribonucleic acid (DNA) damage has recently emerged as one of the most controversial topics in male reproductive medicine. While level I evidence indicates that abnormal sperm DNA damage has substantial adverse effects on reproductive outcomes (including chance of pregnancy and risk of miscarriage), there is limited consensus on how sperm DNA fragmentation (SDF) testing should be performed and/or interpreted in clinical practice. In this article, we review: (1) how SDF is assessed, (2) cumulative evidence regarding its impact on reproductive outcomes, (3) methods for mitigating high SDF, and (4) the most recent practice guidelines available for clinicians regarding the use and interpretation of SDF testing.

Modern surgical treatment of azoospermia.

PURPOSE OF REVIEW: To review noteworthy research from the last 2 years on surgical management of azoospermia. RECENT FINDINGS: The recommended treatments for nonobstructive and obstructive azoospermia have not appreciably changed. However, recent level-1 evidence has reinforced superiority of micro-dissection testicular sperm extraction over sperm aspiration in men with nonobstructive azoospermia, and several studies have identified genetic and other clinical factors that may aid in selecting candidates for testicular sperm extraction. Machine learning technology has shown promise as a decision support system for patient selection prior to sperm retrieval as well a tool to aid in sperm identification from testis tissue. SUMMARY: Most men with obstructive azoospermia who desire fertility can be offered either surgical reconstruction or sperm retrieval. For men with nonobstructive azoospermia, sperm retrieval with microdissection testicular sperm extraction remains the gold standard treatment. Uncovering more genetic causes of nonobstructive azoospermia may aid in properly counseling and selecting patients for microdissection testicular sperm extraction. Neural networks and deep learning may have a future role in patient selection for surgical sperm retrieval and postprocedural sperm identification.