Variants in GCNA, X-linked germ-cell genome integrity gene, identified in men with primary spermatogenic failure.

Male infertility impacts millions of couples yet, the etiology of primary infertility remains largely unknown. A critical element of successful spermatogenesis is maintenance of genome integrity. Here, we present a genomic study of spermatogenic failure (SPGF). Our initial analysis (n = 176) did not reveal known gene-candidates but identified a potentially significant single-nucleotide variant (SNV) in X-linked germ-cell nuclear antigen (GCNA). Together with a larger follow-up study (n = 2049), 7 likely clinically relevant GCNA variants were identified. GCNA is critical for genome integrity in male meiosis and knockout models exhibit impaired spermatogenesis and infertility. Single-cell RNA-seq and immunohistochemistry confirm human GCNA expression from spermatogonia to elongated spermatids. Five identified SNVs were located in key functional regions, including N-terminal SUMO-interacting motif and C-terminal Spartan-like protease domain. Notably, variant p.Ala115ProfsTer7 results in an early frameshift, while Spartan-like domain missense variants p.Ser659Trp and p.Arg664Cys change conserved residues, likely affecting 3D structure. For variants within GCNA's intrinsically disordered region, we performed computational modeling for consensus motifs. Two SNVs were predicted to impact the structure of these consensus motifs. All identified variants have an extremely low minor allele frequency in the general population and 6 of 7 were not detected in > 5000 biological fathers. Considering evidence from animal models, germ-cell-specific expression, 3D modeling, and computational predictions for SNVs, we propose that identified GCNA variants disrupt structure and function of the respective protein domains, ultimately arresting germ-cell division. To our knowledge, this is the first study implicating GCNA, a key genome integrity factor, in human male infertility.

Preoperatively misclassified, surgically removed benign renal masses: a systematic review of surgical series and United States population level burden estimate.

PURPOSE: A significant proportion of renal masses removed for suspected malignancy are histologically benign with the probability inversely proportional to lesion size. To our knowledge the number of preoperatively misclassified benign renal masses treated with nephrectomy is currently unknown. Given the increasing incidence and decreasing average size of renal cell carcinoma, this burden is likely increasing. We estimated the population level burden of surgically removed, preoperatively misclassified benign renal masses in the United States. MATERIALS AND METHODS: We systematically reviewed the literature for studies of pathological findings of renal masses removed for suspected renal cell carcinoma based on preoperative imaging through July 1, 2014. We excluded studies that did not describe benign pathology and with masses not stratified by size, and in which pathology results were based on biopsy. SEER data were queried for the incidence of surgically removed renal cell carcinomas in 2000 to 2009. RESULTS: A total of 19 studies of tumor pathology based on size met criteria for review. Pooled estimates of the proportion of benign histology in our primary analysis (American studies only and 1 cm increments) were 40.4%, 20.9%, 19.6%, 17.2%, 9.2% and 6.4% for tumors less than 1, 1 to less than 2, 2 to less than 3, 3 to less than 4, 4 to 7 and greater than 7, respectively. The estimated number of surgically resected benign renal masses in the United States from 2000 to 2009 increased by 82% from 3,098 to 5,624. CONCLUSIONS: These estimates suggest that the population level burden of preoperatively misclassified benign renal masses is substantial and increasing rapidly, paralleling increases in surgically resected small renal cell carcinoma. This study illustrates an important and to our knowledge previously unstudied dimension of overtreatment that is not directly quantified in contemporary surveillance data.

Indications and characteristics of penile traction and vacuum erection devices.

A variety of devices are available for the management of patients with erectile dysfunction, Peyronie's disease, penile dysmorphophobia, for support before and after penile prosthesis insertion, and after radical prostatectomy. Traction devices include, but are not limited to, Penimaster PRO (MSP Concept, Berlin, Germany), Andropenis and Andropeyronie (Andromedical, Madrid, Spain), and the Restorex (PathRight Medical, Plymouth, USA). The other type of devices are vacuum devices such the Osbon ErecAid (Timm Medical, MN, USA). Different devices are optimal for different clinical applications, and robust and contemporary clinical data show a variety of strengths and weaknesses for each device. Research currently favours the use of traction devices for improvement of penile curvature and erectile function in patients with Peyronie's disease compared with vacuum devices; Penimaster Pro and Restorex have been shown to be associated with the best outcomes in this indication. Vacuum devices are favoured for treatment of erectile dysfunction and penile length loss after radical prostatectomy; the Osbon ErecAid is the most well-studied device for this indication. Research into other uses of vacuum and traction devices, such as for penile dysmorphophobia or before and after penile prosthesis, is very limited. Compliance, cost and availability remain substantial challenges, and further high-quality evidence is required to clarify the role of traction devices in urology and sexual medicine.

Recent advances in clinical diagnosis and treatment of male factor infertility.

Infertility is a significant global health issue affecting around 8-12% of couples worldwide with male factor infertility accounting for a substantial proportion of these cases. Despite significant advances within the past few decades, an etiology for male factor infertility cannot be identified in up to 80% of patients and thus, this continues to be an area of active study. This review aims to provide an update on recent advances in the field of male infertility including semen analysis and at-home semen testing, genetics, DNA fragmentation, surgical approaches, and the rise of telemedicine in the era of COVID19.

Penile dimensions: What are surgeons measuring?

Penile dimensions and related dissatisfaction, may have significant impact upon patients whom undergo andrological surgeries. Whilst penile dimension assessment is performed as part of the andrological evaluation, little is known regarding the surgeons' opinions nor contemporary practices. This study was designed to gain further insights into the opinions and practices of clinicians regarding penile measurement and is the first paper in the literature of its kind. The study was performed by inviting clinicians at andrological/urological conferences to participate in a voluntary 10 point survey concerning penile dimensions. Of 126 responses recorded, 56% (71/126) were andrologists. Of the responders, 45% (56/122) did not routinely perform penile measurement prior to treatment nor were they aware of the standardised method (93/123). The majority 64%(81/126) would measure the penile length from the pubic bone to the tip (79/123) with the penis in a stretched position (99/125). A goniometer was the most common way of assessing penile curvature (37/73) and the length would be measured mostly on the convex side (46/119). Responders felt that, from the patients perspective, a combination of length, girth and shape (51/123), or length only (50/123), were the more important aspects of penile dimensions. As responders were recruited based on their interest in andrological aspects of urology, it may not be representative of the general urological community. In conclusion, attitudes and methods of penile measurement are quite varied amongst surgeons, thus further discussion and investigation of this aspect of andrological care ought to occur.

Metachronous Bilateral Testicular Leydig-Like Tumors Leading to the Diagnosis of Congenital Adrenal Hyperplasia (Adrenogenital Syndrome).

A 33-year-old male with a history of left testis Leydig cell tumor (LCT), 3-month status after left radical orchiectomy, presented with a rapidly enlarging (0.6 cm to 3.7 cm) right testicular mass. He underwent a right radical orchiectomy, sections interpreted as showing a similar Leydig cell-like oncocytic proliferation, with a differential diagnosis including metachronous bilateral LCT and metachronous bilateral testicular tumors associated with congenital adrenal hyperplasia (a.k.a. "testicular adrenal rest tumors" (TARTs) and "testicular tumors of the adrenogenital syndrome" (TTAGS)). Additional workup demonstrated a markedly elevated serum adrenocorticotropic hormone (ACTH) and elevated adrenal precursor steroid levels. He was diagnosed with congenital adrenal hyperplasia, 3ß-hydroxysteroid dehydrogenase deficiency (3BHSD) type, and started on treatment. Metachronous bilateral testicular masses in adults should prompt consideration of adult presentation of CAH. Since all untreated CAH patients are expected to have elevated serum ACTH, formal exclusion of CAH prior to surgical resection of a testicular Leydig-like proliferation could be accomplished by screening for elevated serum ACTH.