Polymorphisms in <i>JMJD1C</i> are associated with pubertal onset in boys and reproductive function in men

Abstract JMJD1C, a member of the Jumonji-domain containing histone demethylases protein family, has been associated with levels of sex-hormone binding globulin (SHBG) and testosterone in men, and knock-out rodent models show age-dependent infertility. The objective of this study was to investigate whether single nucleotide polymorphisms (SNPs) nearby JMJD1C are associated with pubertal onset in boys and with male reproduction. 671 peri-pubertal boys, 1,027 young men, 315 fertile men, and 252 infertile men were genotyped for two JMJD1C SNPs (rs7910927 and rs10822184). rs7910927 and rs10822184 showed high linkage. Boys with the rs7910927 TT genotype entered puberty 3.6 months earlier than their peers (p = 2.5 × 10−2). In young men, the number of T alleles was associated with decreased levels of SHBG, follicle-stimulating hormone (FSH), testosterone, and testosterone x luteinizing hormone, as well as increased levels of Inhibin B, Inhibin B/FSH ratio, and testis size. No significant associations with semen parameters were observed and the genotype distribution was comparable among fertile and infertile men. In conclusion, genetic variation in the vicinity of JMJD1C had a surprisingly large impact on the age at pubertal onset in boys as well as levels of reproductive hormones and testis size in men, emphasizing the relationship between JMJD1C and reproductive functions

Development and validation of a mass spectrometry-based assay for quantification of insulin-like factor 3 in human serum

BACKGROUND: The circulating level of the peptide hormone insulin-like factor 3 (INSL3) is a promising diagnostic marker reflecting Leydig cell function in the male. Few commercial immunoassays of varying quality exist. Therefore, we decided to develop and validate a precise method for quantification of INSL3 by mass spectrometry. METHODS: We developed an assay in which the INSL3 A-chain is released from the INSL3 A-B heterodimer by chemical reduction and alkylation. The alkylated INSL3 A-chain is quantitated by liquid chromatography-tandem mass spectrometry (LC-MS/MS), as substitute for serum INSL3. The method was compared to a validated and sensitive in-house serum INSL3 immunoassay using 97 serum samples from 12 healthy boys during pubertal transition. Adult levels were determined based on sera from 72 adult healthy males aged 18-40 years. RESULTS: An LC-MS/MS assay with limit of detection and limit of quantification (LOQ) of 0.06 and 0.15 ng/mL, respectively, and intra-assay CVs <9% in the relevant ranges was obtained. The LC-MS/MS compared well with the in-house immunoassay (Deming regression slope: 1.28; Pearson correlation: R=0.86). INSL3 concentrations increased with pubertal maturation in healthy boys. INSL3 concentrations were above the LOQ in all samples from the adult men. The mean (±2 SD range)for serum INSL3 concentrations in the adult men was 2.2 (0.5-3.9) ng/mL. CONCLUSIONS: We have developed a robust and sensitive method suitable for quantitation of serum INSL3 in a clinical setting using LC-MS/MS instrumentation available in modern clinical laboratories. The method paves the way for future studies into the clinical role of serum INSL3 measurements

Bone mineral density is preserved in men with idiopathic infertility

Background:Lower semen quality is associated with increased mortality and morbidity, which may include osteoporosis.Objective:To assess whether infertile men have a lower bone mineral density (BMD) compared with fertile men at the time of fer-tility workup.Methods:A total of 146 men from infertile couples with unexplained impaired semen quality, characterized by sperm concentra-tion<20 million/mL, progressive motility<50% or<12% morphologically normal spermatozoa. Men with infertility due to agenetic etiology or a condition that could cause testicular damage were excluded. A total of 271 men from couples with an ongoingnaturally conceived pregnancy served as a control group. Lumbar, femoral, and total body BMD were measured by dual X-rayabsorptiometry.Results:Infertile men had similar BMD compared with fertile men (Beta coefficient (g/cm2) and 95% confidence interval for thedifference between the two groups: 0.02 ( 0.05; 0.01) for lumbar BMD, 0.02 ( 0.05; 0.01) for femoral neck BMD, 0.01 ( 0.04;0.02) for total femur BMD, and 0.01 ( 0.03; 0.01) for total body BMD). Semen parameters were not associated with BMD measure-ments. Furthermore, BMD did not differ between infertile men with the lowest semen quality vs. infertile men with better semenquality nor between infertile men with low testosterone vs. fertile men with normal testosterone levels.Conclusion:Bone mineral density is preserved in men with unexplained infertility at the time of fertility workup.status: Published onlin