FSHB and FSHR gene variants exert mild modulatory effect on reproductive hormone levels and testis size but not on semen quality: A study of 2020 men from the general Danish population.

BACKGROUND: Spermatogenesis depends on stimulation by follicle-stimulating hormone (FSH) which binds to FSH receptors (FSHR) on testicular Sertoli cells. Three FSH-related single-nucleotide polymorphisms (SNPs), FSHB -211G>T (rs10835638), FSHR -29G>A (rs1394205) and FSHR 2039A>G (rs6166) affect FSH action, and have been suggested to affect testicular function, but the evidence is uncertain. OBJECTIVE: To describe the associations between the three SNPs and testicular function in a large and well-characterised cohort of men from the general population. MATERIALS AND METHODS: A cross-sectional study of 2020 Danish men unselected regarding testicular function. Outcome variables were semen parameters, reproductive hormones and testis size. Genotyping was done by competitive allele-specific quantitative PCR. Differences in genotype frequencies were tested by chi-square test and associations between genotypes and outcomes were assessed by multivariate linear regressions. RESULTS: The SNPs affected serum FSH; carriers of the variant affecting FSH secretion (FSHB -211G>T) had lower FSH levels while carriers of variants affecting receptor expression (FSHR -29G>A) and receptor sensitivity (FSHR 2039A>G) had higher FSH levels. Carriers of FSHB -211G>T had lower calculated free testosterone/LH ratio. Although both FSHB -211G>T and FSHR 2039A>G were associated with smaller testis size, no clear association was detected in relation to any semen parameters, except a lower total number of morphologically normal spermatozoa in the heterozygous carriers of the FSHB -211G>T DISCUSSION AND CONCLUSION: The studied polymorphisms have only minor modulating influence on testis size and function in healthy men. We detected subtle effects of the three SNPs on FSH levels, but also effects of FSHB -211G>T on calculated free testosterone/LH ratio, compatible with altered Leydig cell function. Thus, the role of these FSH-related polymorphisms is complex and modest in men with normal testicular function, but the possible importance of FSH polymorphisms in men with impaired testicular function should be evaluated in future studies in more detail.

Clinical, genetic, biochemical, and testicular biopsy findings among 1,213 men evaluated for infertility.

OBJECTIVE: To study the pathologic findings among men evaluated for infertility. DESIGN: A retrospective, single-center, cross-sectional study. SETTING: University hospital-based research center. PARTICIPANT(S): We included data from 1,213 medical records from infertile men referred for diagnostic work-up from 2005 to 2009. INTERVENTIONS(S): None. MAIN OUTCOME MEASURE(S): Health history, clinical findings, chromosome/genetic aberrations, semen quality, reproductive hormones. RESULT(S): In total, 64.4% of the infertile men had one or more reproductive disorders or factors influencing fertility, leaving 35.6% diagnosed as idiopathic infertile. In 244 patients (20%), including seven cases of testicular cancer and/or germ cell neoplasia in situ, a pathologic finding was first detected during diagnostic work-up. Two hundred four patients (16.8%) had a history of cryptorchidism and 154 (12.7%) of varicocele (grade 2 and 3). Thirty-three patients had chromosomal abnormalities, including 16 with sex chromosome abnormalities (11 with 47,XXY). Y-chromosome microdeletions were detected in 65 patients (5.4%). One hundred thirty-three had azoospermia, of which 58 had testicular biopsy findings (Sertoli cell-only syndrome: n = 23; spermatogenic arrest: n = 7; impaired spermatogenesis and atrophy: n = 28). Additionally, in idiopathic infertile men and infertile men with additional symptoms of testicular dysgenesis syndrome, 22.5% presented with a degree of Leydig cell insufficiency, with the highest frequency (33.1%) among patients with sperm concentration <5 million/mL. CONCLUSION(S): We report pathologic findings that could explain the male-factor infertility in two-thirds of infertile men referred to our center. Thus, male infertility may be a sign of an underlying disease that warrants attention.

Is Sedentary Lifestyle Associated With Testicular Function? A Cross-Sectional Study of 1,210 Men.

Based on cross-sectional data on 1,210 healthy young Danish men, we investigated whether sedentary lifestyle was associated with testicular function (semen quality and reproductive hormones) independent of physical activity. The men were invited to participate in the study between 2008 and 2012, when they attended a compulsory medical examination to determine their fitness for military service. Information on sedentary behavior (television watching and computer time) and physical activity was obtained by questionnaire. The men had a physical examination, delivered a semen sample, and had a blood sample drawn. Time spent watching television, but not time sitting in front of a computer, was associated with lower sperm counts. Men who watched television more than 5 hours/day had an adjusted sperm concentration of 37 million/mL (95% confidence interval (CI): 30, 44) versus 52 million/mL (95% CI: 43, 62) among men who did not watch television; total sperm counts in those 2 groups were 104 million (95% CI: 84, 126) and 158 million (95% CI: 130, 189), respectively. Furthermore, an increase in follicle-stimulating hormone and decreases in testosterone and the testosterone/luteinizing hormone ratio were detected in men watching many hours of television. Self-rated physical fitness, but not time spent on physical activity, was positively associated with sperm counts.

Self-reported onset of puberty and subsequent semen quality and reproductive hormones in healthy young men.

STUDY QUESTION: Is there an association between pubertal onset and subsequent reproductive health in young men? SUMMARY ANSWER: Self-reported later onset of puberty was associated with reduced semen quality and altered serum levels of reproductive hormones among 1068 healthy, young Danish men. WHAT IS KNOWN ALREADY: The long-term effects of variations in the onset of male puberty on subsequent reproduction remain largely unstudied. STUDY DESIGN, SIZE, DURATION: In a cross-sectional study, young healthy Danish men were approached when they attended a compulsory medical examination to determine their fitness for military service from 2008 to 2012. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: A total of 1068 healthy, young Danish men (mean age 19 years) participated. They were asked to assess whether onset of penile and testicular growth, development of pubic hair and voice break occurred earlier, at the same time as or later than their peers. Their semen quality (semen volume, sperm concentration, total sperm count and percentages of motile and morphologically normal spermatozoa) and serum concentrations of sex hormones (LH, FSH, total testosterone, SHBG, inhibin B) and testicular size were determined. MAIN RESULTS AND THE ROLE OF CHANCE: The response rate was 29%. Of the 1068 men who then participated, 652 answered the questions about penile growth and pubic hair development and were therefore included in the analysis. Self-reported later onset of puberty was associated with a 25% reduction in sperm concentration (95% CI -41%; -4%), a 40% reduction in total sperm count (-55%; -21%), a 1.6% age point reduction in morphological normal spermatozoa (-2.9; -0.3) and a 1.6 ml reduction in testicular size (-2.4 and -0.8 ml), after adjustment for confounders. Self-reported later onset of puberty was also associated with a 9% (3%; 15%) reduction in free testosterone and a 16% (2%; 31%) increase in FSH, after adjustment for confounders. LIMITATIONS, REASON FOR CAUTION: Our study was cross-sectional and reverse causality cannot be ruled out. In addition, we cannot rule out the possibility that the men with late puberty onset had not yet fully matured although most were in Tanner stage 5. WIDER IMPLICATIONS OF THE FINDINGS: Approximately 15% of young Danish men have self-reported later onset of puberty than their peers. We found poorer testicular function in young men with a history of later pubertal development, suggesting that timing of pubertal onset may be a fundamental marker of male reproductive health. However, we cannot exclude the possibility that these men had not fully matured at the time of examination and therefore their semen quality may yet improve, which makes follow-up important. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the Danish Council for Strategic Research, Program Commission on Health, Food and Welfare (project number 2101-08-0058), Rigshospitalet (grants 961506336 and R42-A1326), European Union, DEER (grant agreement no 212844), the Danish Ministry of Health and the Danish Environmental Protection Agency and Kirsten and Freddy Johansens Foundation (grant 95-103-72087). There are no competing interests.

Phthalate excretion pattern and testicular function: a study of 881 healthy Danish men.

BACKGROUND: In animals, some phthalates impair male reproductive development and function. Epidemiological studies have reported inconsistent evidence of associations between phthalates and markers of human testicular function. OBJECTIVES: We aimed to provide estimates of the effects of phthalate exposure on reproductive hormone levels and semen quality in healthy men. METHODS: A total of 881 men gave urine, serum, and semen samples. Serum levels of testosterone, estradiol (E2), sex hormone-binding globulin (SHBG), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and inhibin-B; semen quality; and urinary concentrations of 14 phthalate metabolites, including metabolites of di(2-ethylhexyl) phthalate (DEHP) and diisononyl phthalate (DiNP), were assessed. The proportions of DEHP and DiNP excreted as their respective primary metabolites [mono(2-ethylhexyl) phthalate (MEHP) and mono-isononyl phthalate (MiNP)] were calculated and expressed as percentages (%MEHP and %MiNP, respectively). RESULTS: The free androgen index was 15% lower [95% confidence interval (CI): -23, -8%] for men in the highest %MiNP quartile compared to the lowest quartile (p < 0.001) after adjusting for confounders, and 9% lower (95% CI: -16, -1%) in the highest %MEHP quartile (p = 0.02). %MEHP and %MiNP were negatively associated with the ratio of testosterone/LH and testosterone/FSH. %MEHP was negatively associated with total testosterone, free testosterone, and ratio of testosterone/E(2). %MiNP was positively associated with SHBG. There was little evidence of associations between urinary phthalate metabolites or sums of phthalates with reproductive hormones or semen quality. CONCLUSION: Our data suggest that both testosterone production and pituitary-hypothalamic feedback may be compromised in individuals excreting a high proportion of primary metabolites of long-chained phthalates relative to the proportion of secondary metabolites.

Human semen quality in the new millennium: a prospective cross-sectional population-based study of 4867 men.

OBJECTIVES: Considerable interest and controversy over a possible decline in semen quality during the 20th century raised concern that semen quality could have reached a critically low level where it might affect human reproduction. The authors therefore initiated a study to assess reproductive health in men from the general population and to monitor changes in semen quality over time. DESIGN: Cross-sectional study of men from the general Danish population. Inclusion criteria were place of residence in the Copenhagen area, and both the man and his mother being born and raised in Denmark. Men with severe or chronic diseases were not included. SETTING: Danish one-centre study. PARTICIPANTS: 4867 men, median age 19 years, included from 1996 to 2010. OUTCOME MEASURES: Semen volume, sperm concentration, total sperm count, sperm motility and sperm morphology. RESULTS: Only 23% of participants had optimal sperm concentration and sperm morphology. Comparing with historic data of men attending a Copenhagen infertility clinic in the 1940s and men who recently became fathers, these two groups had significantly better semen quality than our study group from the general population. Over the 15 years, median sperm concentration increased from 43 to 48 million/ml (p=0.02) and total sperm count from 132 to 151 million (p=0.001). The median percentage of motile spermatozoa and abnormal spermatozoa were 68% and 93%, and did not change during the study period. CONCLUSIONS: This large prospective study of semen quality among young men of the general population showed an increasing trend in sperm concentration and total sperm count. However, only one in four men had optimal semen quality. In addition, one in four will most likely face a prolonged waiting time to pregnancy if they in the future want to father a child and another 15% are at risk of the need of fertility treatment. Thus, reduced semen quality seems so frequent that it may impair the fertility rates and further increase the demand for assisted reproduction.

Testicular dysgenesis syndrome and the origin of carcinoma in situ testis.

Recent increases in male reproductive disorders have been linked to exposure to environmental factors leading to the testicular dysgenesis syndrome (TDS). Testicular cancer is the most severe condition in TDS and studies have shown a clear correlation between risk of testicular cancer and other components of TDS and that the geographical location of the mother during pregnancy can be a risk factor. This suggests that the dysgenesis has its origin in utero and that TDS is initiated by environmental factors, including possibly hormone-disrupting compounds that act on the mother and the developing foetus, but the genetic background may also play a role. The morphological similarity of carcinoma in situ (CIS) cells (the precursor of the majority of invasive testicular cancers) with primordial germ cells and gonocytes, and overlap in expression of protein markers suggests an origin of CIS from primordial germ cells or gonocytes. CIS cells and germ cell-derived cancers of the human type have so far not been described in any animal model of TDS, which could be caused by species differences in the development of the male gonad. Regardless of this, it is plausible that the dysgenesis, and hence the development of CIS cells, is a result of disturbed signalling between nurse cells and germ cells that allow embryonic germ cells to survive in the pre-pubertal and adult testis. The post-pubertal proliferation of CIS cells combined with aberrant signalling then leads to an accumulation of genetic changes in the CIS cells, which eventually results in the development of invasive testicular cancer in the adult.