Eakate seksuaalsus: kas sellest peab vähihaigega rääkima?

Märkimisväärne osa inimestest jätkab seksuaalelu elamist vanemas eas ning ajas on see osakaal suurenenud. Seksuaalelu nõustamise korral on hea teada põhjalikumalt seksuaalelu mõistet, läheneda sellele avatult ja mittedualistlikult (erapooletult, kuid hoolivalt), et inimesi ja nende probleeme kuulata eelarvamustevabalt. Oluline on anda nõustamisel olulisimat – luba olla seksuaalne olend – ning seejärel nõustada patsienti professionaalsest pädevusest lähtudes. Koos seksuaalmeditsiini arenguga on tekkinud mitmeid patsientide aitamise võimalusi, kuid parim on siiski teha seda eri valdkondade koostöö kaudu. Nii nagu seksuaalelu elamist, tuleks erinevas vanuses aktsepteerida ka seksuaalelu mitteelamist, arutledes, mis inimesele (partnersuhtele) on tema seisukohalt parim. Laiema seksuaalsuse definitsiooni kohaselt hõlmab seksuaalsus põhivajadust puudutuse, läheduse ja inimliku kiindumuse järele ning seda vajab valdav osa inimesi kogu elu jooksul.Eesti Arst 2015; 94(10):624–62

Varikotseele ja teiste mehe suguelundeid mõjutavate haiguste levimus ning mõju munandi mahule

Sugutraktihaigused on kõige olulisemad ravitavad mehepoolse viljatuse riskitegurid. Töö eesmärgiks oli välja selgitada kliiniliselt väljendunud sugutraktihaiguste levimus lastetutel meestel võrreldes kontrollrühmaks võetud noorte Eesti meeste vastavate näitajatega. Ühtlasi uuriti munandikoti veenilaiendi kui kõige sagedamini mehe viljakust mõjutava haiguse mõju munandi mahule. Eesti Arst 2003; 82 (2): 80–8

Chromosomal scan of single sperm cells by combining fluorescence-activated cell sorting and next-generation sequencing

PurposeThe purpose of this study was to develop a feasible approach for single sperm isolation and chromosome analysis by next-generation sequencing (NGS).MethodsSingle sperm cells were isolated from semen samples of normozoospermic male and an infertile reciprocal translocation (RcT) carrier with the 46,XY,t(7;13)(p12;q12.1) karyotype using the optimized fluorescence-activated cell sorting (FACS) technique. Genome profiling was performed using NGS.ResultsFollowing whole-genome amplification, NGS,and quality control, the final chromosome analysis was performed on 31 and 6 single cell samples derived from the RcT carrier and normozoospermic male, respectively. All sperm cells from normozoospermic male showed a normal haploid 23-chromosome profile. For the RcT carrier, the sequencing data revealed that 64.5% of sperm cells harbored different variants of chromosome aberrations, involving deletion of 7p or 7q, duplication of 7p, and duplication of 13q, which is concordant with the expected chromosome segregation patterns observed in balanced translocation carriers. In one sample, a duplication of 9q was also detected.ConclusionsWe optimized FACS protocol for simple and efficient isolation of single human sperm cells that subsequently enabled a successful genome-wide chromosome profiling and identification of segmental aneuploidies from these individual cells, following NGS analysis. This approach may be useful for analyzing semen samples of infertile men or chromosomal aberration carriers to facilitate the reproductive risk assessment.Peer reviewe

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

Microdeletions and microduplications linked to severe congenital disorders in infertile men

Abstract 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%; χ2 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

Effect of the inferred <i>FSHR</i> gene haplotypes on tested male hormonal and testicular parameter distribution.

a<p><i>FSHR</i> gene haplotypes were inferred using genotype data on <i>FSHR</i> -29G/A (rs1394205; <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0094244#pone-0094244-t002" target="_blank">Table 2</a>) and <i>FSHR</i> 2039 A/G (rs6166, Asn680Ser; <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0094244#pone.0094244.s001" target="_blank">Table S1</a>; (16). Haplotype G-Asn is the combination of G- and Asn-alleles at the <i>FSHR</i> positions -29G/A and Asn680Ser, respectively, etc.</p>b<p><i>P</i>-value from omnibus test estimating the overall effect of <i>FSHR</i> haplotypes on tested parameter distribution <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0094244#pone.0094244-Rousset1" target="_blank">[30]</a> (<a href="http://pngu.mgh.harvard.edu/~purcell/plink/" target="_blank">http://pngu.mgh.harvard.edu/~purcell/plink/</a>).</p>c<p>Corrected empirical <i>P</i>-value from haplotype-based association test for individual haplotypes after correction for multiple haplotypes using max(T) permutation procedure (number of permutations, n = 10,000).</p>d<p>Effect of individual haplotypes is shown as the estimated linear regression (additive model) coefficient, β.</p>e<p>Among Estonian oligozoospermic infertile patients, Inhibin B values were available for 264 individuals.</p

Reproductive Physiology in Young Men Is Cumulatively Affected by FSH-Action Modulating Genetic Variants: <i>FSHR</i> -29G/A and c.2039 A/G, <i>FSHB</i> -211G/T

<div><p><i>Follicle-Stimulating Hormone Receptor</i> (<i>FSHR</i>) -29G/A polymorphism (rs1394205) was reported to modulate gene expression and reproductive parameters in women, but data in men is limited. We aimed to bring evidence to the effect of <i>FSHR</i> -29G/A variants in men. In Baltic young male cohort (n = 982; Estonians, Latvians, Lithuanians; aged 20.2±2.0 years), the <i>FSHR</i> -29 A-allele was significantly associated with higher serum FSH (linear regression: effect 0.27 IU/L; <i>P</i> = 0.0019, resistant to Bonferroni correction for multiple testing) and showed a non-significant trend for association with higher LH (0.19 IU/L) and total testosterone (0.93 nmol/L), but reduced Inhibin B (−7.84 pg/mL) and total testes volume (effect −1.00 mL). Next, we extended the study and tested the effect of <i>FSHR</i> gene haplotypes determined by the allelic combination of <i>FSHR</i> -29G/A and a well-studied variant c.2039 A/G (Asn680Ser, exon 10). Among the <i>FSHR</i> -29A/2039G haplotype carriers (A-Ser; haplotype-based linear regression), this genetic effect was enhanced for FSH (effect 0.40 IU/L), Inhibin B (−16.57 pg/mL) and total testes volume (−2.34 mL). Finally, we estimated the total contribution of three known FSH-action modulating SNPs (<i>FSHB</i> -211G/T; <i>FSHR</i> -29G/A, c.2039 A/G) to phenotypic variance in reproductive parameters among young men. The major FSH-action modulating SNPs explained together 2.3%, 1.4%, 1.0 and 1.1% of the measured variance in serum FSH, Inhibin B, testosterone and total testes volume, respectively. In contrast to the young male cohort, neither <i>FSHR</i> -29G/A nor <i>FSHR</i> haplotypes appeared to systematically modulate the reproductive physiology of oligozoospermic idiopathic infertile patients (n = 641, Estonians; aged 31.5±6.0 years). In summary, this is the first study showing the significant effect of <i>FSHR</i> -29G/A on male serum FSH level. To account for the genetic effect of known common polymorphisms modulating FSH-action, we suggest haplotype-based analysis of <i>FSHR</i> SNPs (<i>FSHR</i> -29G/A, c.2039 A/G) in combination with <i>FSHB</i> -211G/T testing.</p></div

General characteristics of the study groups.

a<p>Data for BMI available for 324 patients of the oligozoospermic study group.</p>b<p>Data presented as percentage with number of allele/genotype carriers in brackets.</p>c<p><i>P</i>-value from χ²-test for differences in <i>FSHR</i> -29G/A allele and genotype distribution between Estonian oligozoospermic infertile patients and Baltic male cohort.</p>d<p>Hardy-Weinberg Equilibrium test <i>P</i>-value of  = 0.4.</p>e<p>Hardy-Weinberg Equilibrium test <i>P</i>-value of  = 1.0.</p

Marker-trait association analysis and clinical parameters of the two study samples stratified into subgroups based on the <i>FSHR</i> -29G/A (rs1394205) genotypes of the participants.

a<p>Baltic young men cohort, n = 982, A-allele frequency 25.4%, HWE test <i>P</i> = 0.40; Estonian oligozoospermic men, n = 641, A-allele frequency 22.9%, HWE test <i>P</i> = 1.0.</p>b<p><i>FSHR</i> -29 A-allele effect is shown as the estimated linear regression (additive model) statistic beta (β), standard error of the regression (SE) is shown in brackets. Asterisk (*) indicates a significant association, <i>P</i><0.05 after Bonferroni correction for multiple testing.</p

Effect of the carrier status of <i>FSHR</i> -29G/A and Asn680Ser genotype combinations on reproductive parameters.

<p>Effect of the <i>FSHR</i> -29G/A (rs1394205) and <i>FSHR</i> Asn680Ser (c.2039A>G, rs6166) genotype combinations on (<b>A</b>) serum FSH level (IU/L; mean ± SD) and (<b>B</b>) total testes volume (mL; mean ± SD) among the Baltic male cohort sample (n = 982). The -29G/A and Asn680Ser variants form nine possible <i>FSHR</i> genotype combinations: GG-AsnSer (n = 271), GG-AsnAsn (n = 189), AG-AsnSer (n = 170), AG-AsnAsn (n = 144), GG-SerSer (n = 92), AG-SerSer (n = 48), AA-AsnSer (n = 29), AA-AsnAsn (n = 22), AA-SerSer (n = 17). The prevalence of each genotype combination (%) is shown in brackets.</p