A GWAS in Idiopathic/Unexplained Infertile Men Detects a Genomic Region Determining Follicle-Stimulating Hormone Levels.

CONTEXT: Approximately 70% of infertile men are diagnosed with idiopathic (abnormal semen parameters) or unexplained (normozoospermia) infertility, with the common feature of lacking etiologic factors. Follicle-stimulating hormone (FSH) is essential for initiation and maintenance of spermatogenesis. Certain single-nucleotide variations (SNVs; formerly single-nucleotide polymorphisms [SNPs]) (ie, FSHB c.-211G > T, FSHR c.2039A > G) are associated with FSH, testicular volume, and spermatogenesis. It is unknown to what extent other variants are associated with FSH levels and therewith resemble causative factors for infertility. OBJECTIVE: We aimed to identify further genetic determinants modulating FSH levels in a cohort of men presenting with idiopathic or unexplained infertility. METHODS: We retrospectively (2010-2018) selected 1900 men with idiopathic/unexplained infertility. In the discovery study (n = 760), a genome-wide association study (GWAS) was performed (Infinium PsychArrays) in association with FSH values (Illumina GenomeStudio, v2.0). Minor allele frequencies (MAFs) were analyzed for the discovery and an independent normozoospermic cohort. In the validation study (n = 1140), TaqMan SNV polymerase chain reaction was conducted for rs11031005 and rs10835638 in association with andrological parameters. RESULTS: Imputation revealed 9 SNVs in high linkage disequilibrium, with genome-wide significance (P < 4.28e-07) at the FSHB locus 11p.14.1 being associated with FSH. The 9 SNVs accounted for up to a 4.65% variance in FSH level. In the oligozoospermic subgroup, this was increased up to 6.95% and the MAF was enhanced compared to an independent cohort of normozoospermic men. By validation, a significant association for rs11031005/rs10835638 with FSH (P = 4.71e-06/5.55e-07) and FSH/luteinizing hormone ratio (P = 2.08e-12/6.4e-12) was evident. CONCLUSIONS: This GWAS delineates the polymorphic FSHB genomic region as the main determinant of FSH levels in men with unexplained or idiopathic infertility. Given the essential role of FSH, molecular detection of one of the identified SNVs that causes lowered FSH and therewith decreases spermatogenesis could resolve the idiopathic/unexplained origin by this etiologic factor.

Testicular Microlithiasis Is Associated with Impaired Spermatogenesis in Patients with Unexplained Infertility.

INTRODUCTION: Testicular microlithiasis (TML) was shown to be associated with an increased risk of infertility. However, the association of TML with spermatogenesis in patients with unexplained infertility is still unknown. In this study, we therefore investigated the effect of TML on hormones and sperm parameters in a large cohort of infertile men without major factors for impaired fertility and azoospermic men serving for comparison. METHODS: Over a period of 10 years, we retrospectively analyzed 2,914 patients who attended our centre with the diagnosis of unexplained infertility and sperm count >1 million/ejaculate, as well as 281 patients with unexplained azoospermia. From the 2,914 patients, we identified 218 patients with TML as revealed by ultrasound imaging. Further, 26 out of 281 azoospermic patients showed TML. Subsequently, we performed a thorough analysis of reproductive parameters and their association with TML. RESULTS: The overall incidence of TML in patients with unexplained infertility and in unexplained azoospermic men was 7.5 and 9.3%, respectively. Patients with unexplained infertility and TML showed significantly smaller testicular volume, elevated FSH level, and lower sperm count and motility. Impaired spermatogenesis was not associated with the amount of microlithiasis, considered after classification into subgroups (<5 vs. ≥5 microliths/testis), and instead was associated with presence or absence of TML. TML in unexplained infertile azoospermic patients was not significantly associated neither with andrological reproductive parameters nor with sperm retrieval rate in microsurgical testicular sperm extraction. DISCUSSION/CONCLUSION: TML itself, and not the number of microliths, is associated with impaired spermatogenesis in patients with unexplained infertility. The parameter TML alone is not sufficient to predict spermatogenic impairment in azoospermic patients. This study highlights the importance of ultrasound imaging in the clinical evaluation of infertile men, taking into account that TML is a negative co-factor for male fertility.

[The G8 questionnaire as a geriatric screening tool in urooncology]. / Der G8-Fragebogen als geriatrisches Screening-Tool in der Uroonkologie.

The G8 questionnaire is a geriatric screening tool recommended by the SIOG and the EAU. To save time and resources, it can precede a comprehensive geriatric assessment (CGA) in a two-step evaluation. Based on our experience, this 8-item questionnaire is easy and fast to perform (4 - 5 minutes), even by medical staff untrained in geriatrics. The G8 questionnaire has become an established screening tool also in geriatric oncology. It has been shown in several studies that it provides an independent prognostic indicator for the overall survival of cancer patients. However, some critical aspects remain: its low specificity (60 %), its focus on nutritional aspects, and possible interobserver differences. These aspects should be known and taken into account by clinicians.