No abstract

Between 1996 and 1999, the authors invited all young men from five European countries who were undergoing compulsory medical examination for possible military service to participate in a study on male reproductive health. The participation rate was 19% in two cities in Denmark (n = 889), 17% in Oslo, Norway (n = 221), 13% in Turku, Finland (n = 313), 14% in Kaunas, Lithuania (n = 157), and 19% in Tartu, Estonia (n = 190). Each man provided a semen sample, was examined by a physician, and, in collaboration with his mother, completed a questionnaire about general and reproductive health, current smoking habits, and exposure to smoking in utero. After adjustment for confounding factors, men exposed to smoking in utero had a reduction in sperm concentration of 20.1% (95% confidence interval (CI): 6.8, 33.5) and a reduction in total sperm count of 24.5% (95% CI: 9.5, 39.5) in comparison with unexposed men. Percentages of motile and morphologically normal sperm cells were 1.85 (95% CI: 0.46, 3.23) and 0.64 (95% CI: -0.02, 1.30) percentage points lower, respectively, among men exposed in utero, and exposed men had a 1.15-ml (95% CI: 0.66, 1.64) smaller testis size. The associations were present when data from the study centers were analyzed separately (though not in Lithuania, where only 1% of mothers smoked during pregnancy), although the strength of the association varied. Maternal smoking may have long-term implications for the reproductive health of the offspring. This is another good reason to advise pregnant women to avoid smoking.

Recent prospective studies of male reproductive health have shown differences between several European countries. Our objective was to evaluate the current situation in the two Baltic States Estonia and Lithuania. In 1997-99 we investigated semen parameters, levels of reproductive hormones and general health factors of 196 men from the general population in Lithuania; from Estonia, 79 men from the general population and 118 soldiers were investigated. Adjusted for interlaboratory differences and abstinence period, sperm concentration of Lithuanian and Estonian men from the general populations were shown to be 55 and 67 million/mL, respectively. The Estonian soldiers had the highest sperm concentration, 82 million/mL. The frequencies of morphologically normal spermatozoa were 6.2, 7.7 and 9.6%, respectively. In contrast to the semen qualities, highest Inhibin B levels were detected in the Lithuanians (233 pg/mL) followed by Estonian men from the general population (220 pg/mL) and Estonian soldiers (185 pg/mL). The soldiers had also the lowest level of testosterone and oestradiol. The sperm counts of the Estonian and Lithuanian men investigated here are higher than recently shown for Norwegian, Danish, Estonian and Finnish men. Comparisons should be cautiously drawn as the groups are not completely comparable. Still, even within the Baltic region, geographically close and sharing common recent social history, differences in semen quality and levels of reproductive hormones are apparent.

We detected lower frequency of cryptorchidism at birth in Lithuanian boys than in Danes (9.0%), but higher than in Finns (2.4%). We had expected the frequencies in Lithuania and Finland to be relatively similar because the other symptoms of TDS (incidence of testicular cancer and semen quality) are close in these countries.

All funding sources were non-profitable and sponsors of this study played no role in the study design, in data collection, analysis, or interpretation, or in the writing of the article. The authors have no conflicts of interest.

Follicle-Stimulating Hormone Receptor (FSHR) -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 FSHR -29G/A variants in men. In Baltic young male cohort (n = 982; Estonians, Latvians, Lithuanians; aged 20.2±2.0 years), the FSHR -29 A-allele was significantly associated with higher serum FSH (linear regression: effect 0.27 IU/L; P = 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 FSHR gene haplotypes determined by the allelic combination of FSHR -29G/A and a well-studied variant c.2039 A/G (Asn680Ser, exon 10). Among the FSHR -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 (FSHB -211G/T; FSHR -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 FSHR -29G/A nor FSHR 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 FSHR -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 FSHR SNPs (FSHR -29G/A, c.2039 A/G) in combination with FSHB -211G/T testing.

Inter-observer variation in andrological examination by 10 clinical investigators from five Nordic and Baltic countries was investigated. In addition, information on intra-observer variation was obtained for six of the 10 investigators. Testicular size was measured using Prader's orchidometer and one of the investigators also performed an ultrasound estimate of testicular size. A highly significant difference (p < 0.001) between observers was found with an inter-observer error of 16% in estimating testicular size in 23 young men. The difference in the estimate tended to increase with increasing testicular size. There was no significant intra-observer difference in two measurements performed on consecutive days. Only differences in median testis size, which were greater than 31% between measurements by two investigators, were found to be significant at the 5% level. The ultrasound estimate of testicular size was significantly lower than the orchidometer estimate, with a mean difference of 3.6 mL for the left testis and 4.3 mL for the right testis. Tanner staging of genitalia and diagnosis of a varicocele was subject to great inter-observer variation, and for the diagnosis of varicocele only one-third of the investigators was able to reproduce their results on a second examination. In conclusion, it was found that the clinical andrological examination of young men is subject to great inter-observer variation. This should be kept in mind when results from different studies are compared as well as in daily clinical practice.

Follicle-stimulating hormone receptor (FSHR) contains two common linked polymorphisms, Thr307Ala (rs6165) and Asn680Ser (rs6166), shown to modulate ovarian function in women. The effect on male fertility and reproductive parameters has been inconclusive. We studied FSHR Asn680Ser polymorphism in a large study group (n = 1790) from the Baltic countries. The population-based Baltic male cohort (Estonians, Latvians, Lithuanians; n = 1052) and Estonian oligo-/azoospermic (sperm concentration <20 × 106/mL) idiopathic infertile patients (n = 738) were genotyped for the FSHR Asn680Ser using PCR-RFLP. Genetic associations were tested using linear regression under additive model and results were combined in meta-analysis. No statistical difference was detected in allelic distribution of the FSHR Asn680Ser between the Baltic cohort and Estonian male infertility group. A consistent significant association was detected between the FSHR Ser680 allele and lower total testes volume in both, the Baltic cohort (p = 0.010, effect = −1.16 mL) and Estonian idiopathic infertility group (p = 0.007, effect = −1.77 mL). In meta-analysis, the statistical significance was enhanced (p = 0.000066, effect = −1.40 mL). Meta-analysis supported further associations with moderate effect between the FSHR Ser680 variant and higher serum FSH (p = 0.072), lower Inhibin B (p = 0.037) and total testosterone (p = 0.034). No statistically significant associations were identified with serum LH and estradiol, and sperm parameters. In conclusion, the study in 1790 Baltic men shows statistically highly significant association of the FSHR Asn680Ser with total testes volume and supportive association with serum reproductive hormone levels indicative to the functional effect of the alternative FSHR variants on male reproductive physiology.