This study aimed to determine the effect of metabolic syndrome (MS) on the reproductive function in fertile (FM) and male partners of infertile couples (MPIC). We performed a cross-sectional study ...formatting two study groups: partners of pregnant women (n = 238; mean age 32.0) as FM and male partners of infertile couples (n = 2642; mean age 32.6) as MPIC. A standard semen analysis was performed and clinical, laboratory and lifestyle data were analysed. The adapted NCEP-ATPIII criteria were used to define MS. 12.2% of FM and 17.8% of MPIC had MS. In both groups, men with MS were older, they were centrally obese and had higher triglycerides, systolic and diastolic blood pressure and decreased HDL cholesterol values as compared to men without MS. However, glucose concentrations as well as fasting insulin levels were significantly higher only in the MPIC-MS+ group. MS was not associated with semen parameters. Testosterone levels were negatively correlated to MS in both groups. This negative association persisted within the BMI categories between MPIC-MS- and MPIC-MS+ groups. LH was negatively correlated to MS but only in MPIC. FSH and oestradiol were not correlated to MS. Smoking and alcohol consumption were higher among men with MS. This study shows that except for testosterone, MS has no independent effect on major fertility parameters in different subgroups of men.
Infertility affects around 7% of men worldwide. Idiopathic non-obstructive azoospermia (NOA) is defined as the absence of spermatozoa in the ejaculate due to failed spermatogenesis. There is a high ...probability that NOA is caused by rare genetic defects. In this study, whole-exome sequencing (WES) was applied to two Estonian brothers diagnosed with NOA and Sertoli cell-only syndrome (SCOS). Compound heterozygous loss-of-function (LoF) variants in FANCM (Fanconi anemia complementation group M) were detected as the most likely cause for their condition. A rare maternally inherited frameshift variant p.Gln498Thrfs∗7 (rs761250416) and a previously undescribed splicing variant (c.4387−10A>G) derived from the father introduce a premature STOP codon leading to a truncated protein. FANCM exhibits enhanced testicular expression. In control subjects, immunohistochemical staining localized FANCM to the Sertoli and spermatogenic cells of seminiferous tubules with increasing intensity through germ cell development. This is consistent with its role in maintaining genomic stability in meiosis and mitosis. In the individual with SCOS carrying bi-allelic FANCM LoF variants, none or only faint expression was detected in the Sertoli cells. As further evidence, we detected two additional NOA-affected case subjects with independent FANCM homozygous nonsense variants, one from Estonia (p.Gln1701∗; rs147021911) and another from Portugal (p.Arg1931∗; rs144567652). The study convincingly demonstrates that bi-allelic recessive LoF variants in FANCM cause azoospermia. FANCM pathogenic variants have also been linked with doubled risk of familial breast and ovarian cancer, providing an example mechanism for the association between infertility and cancer risk, supported by published data on Fancm mutant mouse models.
Information about the use of flow cytometry in the diagnosis of male urethritis is scarce. The current study aims to evaluate the performance of flow cytometry on first-voided urine in males with ...infectious urethritis (Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma genitalium and Trichomonas vaginalis).
Male patients of the Andrology Centre (Tartu University Hospital, Estonia) were recruited during the period March 2015 -January 2018. Cases included 306 patients with infectious urethritis caused by Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma genitalium and/or Trichomonas vaginalis. The control group consisted of 192 patients without uro-genital complaints, negative tests for C. trachomatis, N. gonorrhoeae, M. genitalium and T. vaginalis from first-voided urine and no inflammation in first-voided urine, mid-stream urine and urine after prostate massage. C. trachomatis, N. gonorrhoeae, M. genitalium and T. vaginalis were detected from first-voided urine using polymerase chain reaction (PCR) method. First-voided urine was analysed using urine particle analyzer Sysmex UF-500i.
The most prevalent infection was chlamydia (64.1%), followed by Mycoplasma genitalium (20.9%), gonorrhoea (7.8%) and trichomoniasis (1.6%). Gonorrhoea caused the highest flow-cytometric leucocyte/bacteria count, followed by chlamydia and Mycoplasma genitalium. Trichomonas vaginalis showed nearly absent inflammation in first-voided urine. Using an empiric flow-cytometry diagnostic threshold for urethritis in first-voided urine (leucocytes ≥ 15/μl and bacteria ≥ 20/μl) the total calculated sensitivity was over 90%. However, when applying such criteria for deciding whether to perform first-voided urine PCR for C. trachomatis, N. gonorrhoeae, M. genitalium and T. vaginalis or not, we could miss 23 cases with infectious urethritis that makes up 7,5% of all proven cases.
Flow cytometry of first-voided urine can be considered as a rapid and objective screening method in case of suspected male infectious urethritis.
The investigators sought evidence-based criteria for identifying late-onset hypogonadism in men between the ages of 40 and 79 years on the basis of the association between symptoms and a low ...testosterone level. The data suggest that late-onset hypogonadism can be defined by the presence of at least three sexual symptoms with a total testosterone level of less than 11 nmol per liter and a free testosterone level of less than 220 pmol per liter.
The data suggest that late-onset hypogonadism can be defined by the presence of at least three sexual symptoms with a total testosterone level of less than 11 nmol per liter and a free testosterone level of less than 220 pmol per liter.
The clinical importance of an age-related reduction in the testosterone level
1
–
3
remains controversial.
4
,
5
Because of the uncertainty regarding the nature of testosterone deficiency in aging men,
6
–
9
recent guidelines have suggested that so-called late-onset hypogonadism be regarded as a clinical and biochemical state with advancing age, characterized by particular symptoms and a low level of serum testosterone.
10
,
11
However, few data on hypogonadism in aging men are available
4
,
8
,
12
because of the lack of evidence regarding the exact criteria for identifying testosterone deficiency in older men who do not have pathological hypogonadism.
6
,
13
Although a familiar array . . .
The impact of sexually transmitted infections (STI) on male fertility is controversial. Aims: To investigate the prevalence of urethritis-associated STIs (chlamydia, gonorrhoeae,
, trichomoniasis) ...among infertile males; to analyze the effect of STIs on semen parameters and blood PSA. Case-control study. Study group (
= 2000): males with fertility problems or desire for fertility check. Control group (
= 248): male partners of pregnant women. Analyses: polymerase chain reaction for STI, seminal interleukin 6 (IL-6), semen and fractionated urine, blood analyses (PSA, reproductive hormones). The prevalence of
and chlamydia in the study group was 1.1% and 1.2%, respectively. The prevalence of chlamydia in the control group was 1.6%, while there were no
cases. No cases with gonorrhoeae or trichomoniasis or combined infections were observed in neither group. There was a higher seminal concentration of neutrophils and IL-6 among
positives compared with STI negatives. There was a trend toward a lower total count of spermatozoa and progressive motility among STI positives. No impact of STIs on PSA was found. The prevalence of STIs among infertile males is low.
is associated with seminal inflammation. The impact of STIs on semen parameters deserves further investigations.
Data on the clinical validity of DNA copy number variants (CNVs) in spermatogenic failure (SPGF) is limited. This study analyzed the genome-wide CNV profile in 215 men with idiopathic SPGF and 62 ...normozoospermic fertile men, recruited at the Andrology Clinic, Tartu University Hospital, Estonia. A two-fold higher representation of > 1 Mb CNVs was observed in men with SPGF (13%, n = 28) compared to controls (6.5%, n = 4). Seven patients with SPGF were identified as carriers of microdeletions (1q21.1; 2.4 Mb) or microduplications (3p26.3, 1.1 Mb; 7p22.3-p22.2, 1.56 Mb; 10q11.22, 1.42 Mb, three cases; Xp22.33; 2.3 Mb) linked to severe congenital conditions. Large autosomal CNV carriers had oligozoospermia, reduced or low-normal bitesticular volume (22-28 ml). The 7p22.3-p22.2 microduplication carrier presented mild intellectual disability, neuropsychiatric problems, and short stature. The Xp22.33 duplication at the PAR1/non-PAR boundary, previously linked to uterine agenesis, was detected in a patient with non-obstructive azoospermia. A novel recurrent intragenic deletion in testis-specific LRRC69 was significantly overrepresented in patients with SPGF compared to the general population (3.3% vs. 0.85%; χ
test, OR = 3.9 95% CI 1.8-8.4, P = 0.0001). Assessment of clinically valid CNVs in patients with SPGF will improve their management and counselling for general and reproductive health, including risk of miscarriage and congenital disorders in future offspring.
Non-obstructive azoospermia (NOA) is the most severe form of male infertility and typically incurable. Defining the genetic basis of NOA has proven challenging, and the most advanced classification ...of NOA subforms is not based on genetics, but simple description of testis histology. In this study, we exome-sequenced over 1000 clinically diagnosed NOA cases and identified a plausible recessive Mendelian cause in 20%. We find further support for 21 genes in a 2-stage burden test with 2072 cases and 11,587 fertile controls. The disrupted genes are primarily on the autosomes, enriched for undescribed human "knockouts", and, for the most part, have yet to be linked to a Mendelian trait. Integration with single-cell RNA sequencing data shows that azoospermia genes can be grouped into molecular subforms with synchronized expression patterns, and analogs of these subforms exist in mice. This analysis framework identifies groups of genes with known roles in spermatogenesis but also reveals unrecognized subforms, such as a set of genes expressed across mitotic divisions of differentiating spermatogonia. Our findings highlight NOA as an understudied Mendelian disorder and provide a conceptual structure for organizing the complex genetics of male infertility, which may provide a rational basis for disease classification.
Male infertility is a prevalent condition, affecting 5-10% of men. So far, few genetic factors have been described as contributors to spermatogenic failure. Here, we report the first re-sequencing ...study of the Y-chromosomal
(
) region, combined with gene dosage analysis of the multicopy
, and
genes and Y-haplogroup determination. In analysing 2324 Estonian men, we uncovered a novel structural variant as a high-penetrance risk factor for male infertility. The Y lineage R1a1-M458, reported at >20% frequency in several European populations, carries a fixed ~1.6 Mb
inversion, destabilizing the
region and predisposing to large recurrent microdeletions. Such complex rearrangements were significantly enriched among severe oligozoospermia cases. The carrier vs non-carrier risk for spermatogenic failure was increased 8.6-fold (p=6.0×10
). This finding contributes to improved molecular diagnostics and clinical management of infertility. Carrier identification at young age will facilitate timely counselling and reproductive decision-making.
Objectives
To profile the seminal microbiome applying next generation sequencing.
Methods
Semen samples of 67 men were involved in the study (21 men with and 46 men without prostatitis). Seminal ...microbiomes were profiled applying the method that uses combinatorial sequence tags attached to polymerase chain reaction primers that amplify the ribosomal ribonucleic acid V6 region. Amplified polymerase chain reaction products were sequenced using an Illumina paired‐end protocol on HiSeq2000 platform.
Results
The most abundant phylum in semen was Firmicutes, comprising nearly half of the sequences found (median 41.7%, quartiles 28.5–47.2%) followed by Bacteroidetes, Proteobacteria and Actinobacteria. The counts of lactobacilli were higher in healthy men than prostatitis patients (27% 20.2–34.6% vs 20.2% 4.9–25.0%; P = 0.05), especially for Lactobacillus iners. Proteobacteria comprised higher proportions in prostatitis patients than healthy men. The species richness was higher in prostatitis patients than healthy men (inverted Simpson index 13.5 ± 5.8 vs 10.3 ± 4.0).
Conclusions
The semen of chronic prostatitis patients contains fewer health‐supporting lactobacilli, and has higher species diversity than that of healthy men. Firmicutes (especially lactobacilli), Bacteroidetes, Proteobacteria and Actinobacteria comprise the highest proportion of seminal microbiome.
Context: The cause of declining testosterone (T) in aging men and their relationships with risk factors are unclear.
Objective: The objective of the study was to investigate the relationships between ...lifestyle and health with reproductive hormones in aging men.
Design: This was a baseline cross-sectional survey on 3200 community-dwelling men aged 40–79 yr from a prospective cohort study in eight European countries.
Results: Four predictors were associated with distinct modes of altered function: 1) age: lower free T (FT; −3.12 pmol/liter·yr, P < 0.001) with raised LH, suggesting impaired testicular function; 2) obesity: lower total T (TT; −2.32 nmol/liter) and FT (−17.60 pmol/liter) for body mass index (BMI; ≥ 25 to < 30 kg/m2) and lower TT (−5.09 nmol/liter) and FT (−53.72 pmol/liter) for BMI 30 kg/m2 or greater (P < 0.001–0.01, referent: BMI < 25 kg/m2) with unchanged/decreased LH, indicating hypothalamus/pituitary dysfunction; 3) comorbidity: lower TT (−0.80 nmol/liter, P < 0.01) with unchanged LH in younger men but higher LH in older men; and 4) smoking: higher SHBG (5.96 nmol/liter, P < 0.001) and LH (0.77 U/liter, P < 0.01) with increased TT (1.31 nmol/liter, P < 0.001) but not FT, compatible with a resetting of T-LH-negative feedback due to elevated SHBG.
Conclusions: Complex multiple alterations in the hypothalamic-pituitary-testicular axis function exist in aging men against a background of progressive age-related testicular impairment. These changes are differentially linked to specific risk factors. Some risk factors operate independently of but others interact with age, in contributing to the T decline. These potentially modifiable risk factors suggest possible preventative measures to maintain T during aging in men.
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