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 fertility workup. METHODS: A total of 146 men from infertile couples with unexplained impaired semen quality, characterized by sperm concentration < 20 million/mL, progressive motility < 50% or < 12% morphologically normal spermatozoa. Men with infertility due to a genetic etiology or a condition that could cause testicular damage were excluded. A total of 271 men from couples with an ongoing naturally conceived pregnancy served as a control group. Lumbar, femoral, and total body BMD were measured by dual X-ray absorptiometry. RESULTS: Infertile men had similar BMD compared with fertile men (Beta coefficient (g/cm2 ) and 95% confidence interval for the difference 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 measurements. Furthermore, BMD did not differ between infertile men with the lowest semen quality vs. infertile men with better semen quality 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.

EAA clinical practice guidelines-gynecomastia evaluation and management.

BACKGROUND: Gynecomastia (GM) is a benign proliferation of the glandular tissue of the breast in men. It is a frequent condition with a reported prevalence of 32-65%, depending on the age and the criteria used for definition. GM of infancy and puberty are common, benign conditions resolving spontaneously in the majority of cases. GM of adulthood is more prevalent among the elderly and proper investigation may reveal an underlying pathology in 45-50% of cases. OBJECTIVES: The aim was to provide clinical practice guidelines for the evaluation and management of GM. MATERIALS AND METHODS: A literature search of articles in English for the term 'gynecomastia' was conducted. Evidence-based recommendations were developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. RESULTS: A set of five statements and fifteen clinical recommendations was formulated. CONCLUSIONS: The purpose of GM assessment should be the detection of underlying pathological conditions, reversible causes (administration/abuse of aggravating substances), and the discrimination from other breast lumps, particularly breast cancer. Assessment should comprise a thorough medical history and physical examination of the breast and genitalia (including testicular ultrasound). A set of laboratory investigations may integrate the evaluation: testosterone (T), estradiol (E2), sex hormone-binding globulin (SHBG), luteinizing hormone (LH), follicular stimulating hormone (FSH), thyroid stimulating hormone (TSH), prolactin, human chorionic gonadotropin (hCG), alpha-fetal protein (AFP), liver and renal function tests. Breast imaging may be used whenever the clinical examination is equivocal. In suspicious lesions, core needle biopsy should be sought directly instead. Watchful waiting is recommended after treatment of underlying pathology or discontinuation of substances associated with GM. T treatment should be offered to men with proven T deficiency. The use of selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs) and non-aromatizable androgens is not justified in general. Surgical treatment is the therapy of choice for patients with long-lasting GM. SUMMARY OF STATEMENTS (S) AND RECOMMENDATIONS (R): S1. Gynecomastia (GM) is a benign proliferation of glandular tissue of the breast in males. S2. GM of infancy is a common condition that usually resolves spontaneously, typically within the first year of life. S3. GM of puberty is a common condition, affecting approximately 50% of mid-pubertal boys; in more than 90% of cases, it resolves spontaneously within 24 months. S4. The prevalence of GM in adulthood increases with increasing age; proper investigation may reveal an underlying pathology in approximately 45-50% of the cases. S5. Male breast cancer is rare; GM should not be considered a premalignant condition. The following recommendations are divided into 'strong', denoted by the number 1 and associated with the terminology 'we recommend', and 'weak' denoted by the number 2 and associated with the phrase 'we suggest'. The grading of the quality of evidence is denoted as follows: ⊕○○○ for very low-quality evidence; ⊕⊕○○ for low quality; ⊕⊕⊕○ for moderate quality; and ⊕⊕⊕⊕ for high quality. R1. The presence of an underlying pathology should be considered in GM of adulthood. We recommend that the identification of an apparent reason for GM in adulthood, including the use of medication known to be associated with GM, should not preclude a detailed investigation (1 ⊕⊕⊕○). R2. We suggest that the initial screening to rule out lipomastia, obvious breast cancer, or testicular cancer might be performed by a general practitioner or another non-specialist (2 ⊕○○○). R3. We recommend that in those cases where a thorough diagnostic workup is warranted, it should be performed by a specialist (1 ⊕○○○). R4. We recommend that the medical history should include information on the onset and duration of GM, sexual development and function, and administration or abuse of substances associated with GM (1 ⊕⊕⊕○). R5. We recommend that the physical examination should detect signs of under-virilization or systemic disease (1 ⊕⊕⊕⊕). R6. We recommend that breast examination should confirm the presence of palpable glandular tissue to discriminate GM from lipomastia (pseudo-gynecomastia) and rule out the suspicion of malignant breast tumor (1 ⊕⊕⊕⊕). R7. We recommend that the physical examination should include the examination of the genitalia to rule out the presence of a palpable testicular tumor and to detect testicular atrophy (1 ⊕⊕⊕⊕). R8. We recommend that genitalia examination is aided by a testicular ultrasound, as the detection of a testicular tumor by palpation has low sensitivity (1 ⊕⊕○○). R9. We suggest that a set of evaluations may include T, E2 , SHBG, LH, FSH, TSH, prolactin, hCG, AFP, and liver and renal function tests (2 ⊕⊕○○). R10. We suggest that breast imaging may offer assistance, where the clinical examination is equivocal (2 ⊕⊕○○). R11. We suggest that, if the clinical picture is suspicious for a malignant lesion, core needle biopsy should be performed (2 ⊕⊕○○). R12. We recommend watchful waiting after treatment of underlying pathology or discontinuation of the administration/abuse of substances associated with GM (1 ⊕⊕○○). R13. We recommend that T treatment should be offered only to men with proven testosterone deficiency (1 ⊕⊕⊕○). R14. We do not recommend the use of selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs), or non-aromatizable androgens in the treatment of GM in general (1 ⊕⊕○○). R15. We suggest surgical treatment only for patients with long-lasting GM, which does not regress spontaneously or following medical therapy. The extent and type of surgery depend on the size of breast enlargement, and the amount of adipose tissue (2 ⊕⊕○○).

Anogenital distance is associated with semen quality but not reproductive hormones in 1106 young men from the general population.

STUDY QUESTION: Is anogenital distance (AGD) associated with semen quality and reproductive hormones in men from the general population? SUMMARY ANSWER: Short AGD measured from the anus to the base of scrotum (AGDAS) was associated with reduced sperm counts and morphology but not with sperm motility or reproductive hormones. WHAT IS KNOWN ALREADY: AGD is longer in males than in females. In rodents, AGD is a well-established and sensitive marker of disruption during the masculinization programming window in utero and it has been suggested to be so in humans as well. Therefore, the average AGD would be expected to be shorter in men with poor semen quality, which some studies have confirmed while others have not. STUDY DESIGN, SIZE, DURATION: This cross-sectional population-based study was of 1106 men included between 2012 and 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: Men from the general Danish population (median age 19 years), unselected with regard to fertility status and semen quality, delivered a semen sample, had a blood sample drawn, which was analyzed for concentrations of reproductive hormones, and answered a comprehensive questionnaire. They also had a physical examination performed including determination of AGD measured as the distance between anus and scrotum (AGDAS) and penis (AGDAP). Odds ratios (OR) and 95% CI were estimated for a man having abnormal semen parameters according to the World Health Organization's reference values or a low/high concentration of reproductive hormones (defined as the lowest or highest 10%) depending on AGD. AGD was categorized in four strata: ≤10th percentile, 10th-30th percentile, 30th-50th percentile and >50th percentile. MAIN RESULTS AND THE ROLE OF CHANCE: Men with the 10% shortest AGDAS had a more than doubled risk (OR: 2.19, 95% CI: 1.40-3.42) of being in the subfertile range for either sperm concentration (<15 million/mL) or sperm morphology (<4%) compared to men with AGDAS above the median (reference). Men in the 10th-30th percentile also had an increased OR of 1.48 (95% CI: 1.06-2.08) but not men in the 30th-50th percentile (OR: 1.14, 95% CI: 0.81-1.62). AGDAP was only weakly related to semen quality. AGD was not associated with testicular volume or any of the reproductive hormones. LIMITATIONS, REASONS FOR CAUTION: Limitations include the potential non-differential misclassification of reproductive outcomes based on a single semen and blood sample and some between-examiner differences in AGD measurements which introduces noise and may result in an underestimation of observed associations. WIDER IMPLICATIONS OF THE FINDINGS: Our study of men from the general population confirmed associations between AGD and semen quality, supporting the hypothesis that AGD in humans could be a marker of fetal testicular development. This suggests that the low semen quality in Danish men may partly be explained by prenatal factors. STUDY FUNDING/COMPETING INTEREST(S): The study has received financial support from the ReproUnion (L.P.); the Research fund of Rigshospitalet, Copenhagen University Hospital (N.J.); Grants R01ES016863-04 and R01ES016863-02S4; National Institute of Environmental Health Sciences (NIEHS) and National Institute of Environmental Health Sciences grant (P30ES023515) (S.S.); the European Union (Contract numbers BMH4-CT96-0314, QLK4-CT-1999-01422, QLK4-CT-2002-00603, FP7/2007-2013, DEER Grant agreement no. 212844); the Danish Ministry of Health; the Danish Environmental Protection Agency; A.P. Møller and wife Chastine McKinney Møllers foundation; and Svend Andersens Foundation. None of the funders had any role in the study design, collection, analysis or interpretation of data, writing of the paper or publication decisions. The authors have nothing to declare. TRIAL REGISTRATION NUMBER: N/A.

Average sperm count remains unchanged despite reduction in maternal smoking: results from a large cross-sectional study with annual investigations over 21 years.

STUDY QUESTION: How are temporal trends in lifestyle factors, including exposure to maternal smoking in utero, associated to semen quality in young men from the general population? SUMMARY ANSWER: Exposure to maternal smoking was associated with lower sperm counts but no overall increase in sperm counts was observed during the study period despite a decrease in this exposure. WHAT IS KNOWN ALREADY: Meta-analyses suggest a continuous decline in semen quality but few studies have investigated temporal trends in unselected populations recruited and analysed with the same protocol over a long period and none have studied simultaneous trends in lifestyle factors. STUDY DESIGN, SIZE, DURATION: Cross-sectional population-based study including ~300 participants per year (total number = 6386) between 1996 and 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study is based on men from the Greater Copenhagen area, Denmark, with a median age of 19 years, and unselected with regard to fertility status and semen quality. The men delivered a semen sample, had a blood sample drawn and a physical examination performed and answered a comprehensive questionnaire, including information on lifestyle and the mother's pregnancy. Temporal trends in semen quality and lifestyle were illustrated graphically, and trends in semen parameters and the impact of prenatal and current lifestyle factors were explored in multiple regression analyses. MAIN RESULTS AND THE ROLE OF CHANCE: Throughout the study period, 35% of the men had low semen quality. Overall, there were no persistent temporal trends in semen quality, testicular volume or levels of follicle-stimulating hormone over the 21 years studied. The men's alcohol intake was lowest between 2011 and 2016, whereas BMI, use of medication and smoking showed no clear temporal trends. Parental age increased, and exposure in utero to maternal smoking declined from 40% among men investigated in 1996-2000 to 18% among men investigated in 2011-2016. Exposure to maternal smoking was associated with lower sperm counts but no overall increase in sperm counts was observed despite the decrease in this exposure. LIMITATIONS, REASONS FOR CAUTION: Information of current and prenatal lifestyle was obtained by self-report, and the men delivered only one semen sample each. WIDER IMPLICATIONS OF THE FINDINGS: The significant decline in in utero exposure to maternal smoking, which was not reflected in an overall improvement of semen quality at the population level, suggest that other unknown adverse factors may maintain the low semen quality among Danish men. STUDY FUNDING/COMPETING INTEREST(S): The study has received financial support from the ReproUnion; the Research fund of Rigshospitalet, Copenhagen University Hospital; the European Union (Contract numbers BMH4-CT96-0314,QLK4-CT-1999-01422, QLK4-CT-2002-00603, FP7/2007-2013, DEER Grant agreement no. 212844); the Danish Ministry of Health; the Danish Environmental Protection Agency; A.P. Møller and wife Chastine McKinney Møllers foundation; and Svend Andersens Foundation. None of the funders had any role in the study design, collection, analysis or interpretation of data, writing of the paper or publication decisions. TRIAL REGISTRATION NUMBER: N/A.

Is the FSHR 2039A>G variant associated with susceptibility to testicular germ cell cancer?

Testicular germ cell cancer (TGCC) is derived from germ cell neoplasia in situ (GCNIS), which arises due to niche disturbances affecting the Sertoli cells. It is believed that exogenous endocrine factors have a crucial role in governing neoplastic transformation but on a strong hereditary background. Follicle-stimulating hormone (FSH) is the major regulatory hormone of the Sertoli cells. FSH signalling-related single-nucleotide polymorphisms (SNPs) have previously been shown to affect FSH action in men at different levels. We aimed to investigate whether three FSH-related SNPs (FSHR 2039A>G, FSHR -29G>A and FSHB -211G>T) are associated with development of TGCC. A total of 752 Danish and German patients with TGCC from two tertiary andrological referral centres were included. Three control groups comprising 2020 men from the general population, 679 fertile men and 417 infertile men, were also included. Chi-squared test was performed to compare genotype- and allele frequencies. Kruskal-Wallis test was performed to compare age at diagnosis. Patients with TGCC had a higher frequency of the A-allele of FSHR 2039A>G compared to the group of fertile men with an AA-genotype frequency of 30.2% vs. 22.0%, respectively, p = 0.002. This variant is associated with higher FSH receptor activity. The distribution of the FSHR 2039A>G did not differ significantly between the patients with TGCC and the infertile or the general population. The frequency of the two other SNPs did not differ between patient with TGCC and any of the control groups. No differences were detected between genotypes and age distribution or histological subtype of the tumours. In conclusion, we observed that a genetic variant associated with FSHR activity may modulate the susceptibility to TGCC.

Possible involvement of the glucocorticoid receptor (NR3C1) and selected NR3C1 gene variants in regulation of human testicular function.

Perceived stress has been associated with decreased semen quality but the mechanisms have not been elucidated. It is not known whether cortisol, the major stress hormone in humans, can act directly via receptors in the testis, and whether variants in the gene encoding the glucocorticoid receptor (NR3C1) can possibly modulate the effect. To address these questions, we investigated the expression of the glucocorticoid receptor in human testicular tissue, including adult and fetal samples (n = 20) by immunohistochemical staining, and in silico analysis of publicly available datasets. In the adult testis NR3C1 protein was detected in peritubular cells, a subset of Leydig cells, Sertoli cells (weak), and spermatogonia, but not in spermatids. The NR3C1 expression pattern in fetal testis samples differed by a notably stronger reaction in Sertoli cells, lack of staining in gonocytes but the presence in a subset of pro-spermatogonia, and the almost absent reaction in nascent peritubular cells. In parallel, we explored the association between adult testicular function and three single nucleotide NR3C1 polymorphisms (BcII [rs41423247], 9ß [rs6198], and Tth111I [rs10052957]) affecting glucocorticoid sensitivity. Testicular function was determined by semen analysis and reproductive hormone profiling in 893 men from the general population. The NR3C1 SNP BclI was associated with semen quality in an over-dominant manner with heterozygotes having better semen parameters compared to both homozygote constellations, and with sperm motility showing the strongest association. This association was supported by a higher inhibin B and inhibin B/FSH ratio, as well as a lower FSH in BclI heterozygotes. The SNPs 9ß and Tth111I were not associated with semen parameters. Although the clinical impact of the findings is limited, the results substantiate a suggested link between stress and testicular function. Hence this investigation should be regarded as a discovery study generating hypotheses for future studies.

A study of finger lengths, semen quality and sex hormones in 360 young men from the general Danish population.

BACKGROUND: It has been suggested that finger length may correlate with function or disorders of the male reproductive system. This is based on the HOXA and HOXD genes' common embryological control of finger development and differentiation of the genital bud. The objective of this study was to explore the association between the ratio of 2nd to 4th finger length (2D:4D ratio) and testis function in a sample of young Danish men from the general population. METHODS: Semen samples and finger measurements were obtained from a total of 360 young Danish men in addition to blood samples for sex hormone analysis to describe the possible association between 2D:4D and semen and sex-hormone parameters. RESULTS: A statistically significant inverse association with the 2D:4D was found only in relation to hormone levels of FSH in the group of young men with a 2D:4D >1 (P = 0.036) and a direct association with the total sperm count in the group of young men with a 2D:4D < or = 1 (P = 0.045). CONCLUSION: The statistically significant results may be 'false positives' (type I error) rather than representing true associations. This relatively large study of young, normal Danish men shows no reliable association between 2D:4D finger ratio and testicular function. Measurements of finger lengths do not have the power to predict the testicular function of adult men.