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Hypospadias is a congenital malformation of penile urethra with unknown etiology in most cases. Persistent organic pollutant (POP) exposure may disrupt endocrine function during a critical window of development of male genitalia. In animal studies, POPs have been associated with male reproductive disorders, including hypospadias, but only few studies have assessed this relationship in humans. The aim of this study is to investigate the association between hypospadias and POP concentration levels in breast milk, as a proxy for prenatal exposure. This is a nested case-control study of Danish and Finnish mother-son pairs. Maternal breast milk samples were collected between 1997 and 2002, and they represent infant boys born with hypospadias [n = 33 (n = 22 Danish and n = 11 Finnish)] and their 1:1 matched controls. Breast milk samples were analyzed for six classes of POPs [including dioxins, polychlorinated biphenyls, flame retardants and perfluorinated alkylated substances (PFAS)]. We estimated odds ratios (ORs) and 95% confidence intervals (CI) for each chemical class using conditional logistic regression. In addition, a composite exposure score system was used to explore the effect of a POP mixture (four chemical classes): The composite score was categorized as low, moderate, or high exposure, and differences between cases and controls were tested with conditional logistic regression. No statistically significant associations were observed between the sums of the chemical classes and hypospadias in either country. The composite score was unable to detect differences in the risk of hypospadias between the tertiles of POP exposure. Levels of PFAS were significantly higher in Danish than in Finnish breast milk samples. This small study does not provide evidence for an association between hypospadias and exposure to POPs but adds information on quantitative exposures. Further development of multi-exposure models is needed for assessing the potential mixture effect ass

CONTEXT: Longitudinal data on levels of hypothalamic-pituitary-gonadal axis hormones and insulin-like growth factor I (IGF-I) during puberty in boys with a history of cryptorchidism are largely missing.OBJECTIVE: We aimed to compare pubertal hormone levels between boys with a history of congenital cryptorchidism who experienced spontaneous testicular descent or underwent orchiopexy and boys without a history of cryptorchidism.METHODS: This was a nested case-control study within a population-based birth cohort, with a prospective, longitudinal pubertal follow-up every 6 months (2005 to 2019). Participants were 109 Finnish boys, including boys with a history of unilateral cryptorchidism who underwent orchiopexy (n = 15), unilateral cryptorchidism who had spontaneous testicular descent (n = 15), bilateral cryptorchidism who underwent orchiopexy (n = 9), bilateral cryptorchidism who had spontaneous testicular descent (n = 7), and controls (n = 63). Serum reproductive hormone levels and testicular volumes were measured.RESULTS: From around onset of puberty, boys with bilateral cryptorchidism who underwent orchiopexy had significantly higher follicle-stimulating hormone (FSH) and lower inhibin B levels than controls. Boys with unilateral cryptorchidism who underwent orchiopexy had significantly higher FSH than controls, whereas inhibin B levels were similar. Testosterone, luteinizing hormone, insulin-like factor 3, and IGF-I were generally similar between groups. Testicular volume of boys with unilateral or bilateral cryptorchidism who underwent orchiopexy was smaller than that of the controls from 1 year after pubertal onset (P < 0.05).CONCLUSION: Cryptorchid boys, particularly those with bilateral cryptorchidism who underwent orchiopexy, had altered levels of serum biomarkers of Sertoli cells and germ cells and smaller testicular volumes compared with controls.

CONTEXT: It remains unknown how the postnatal activation of the hypothalamic-pituitary-gonadal axis in infancy, also known as 'minipuberty', relates to adult testis function.OBJECTIVE: To investigate how markers of reproductive function in three-month-old boys correlate with adult reproductive health parameters.DESIGN: Population-based birth cohort study (the Copenhagen Mother-Child cohort).SETTING: Copenhagen University Hospital, Denmark.PARTICIPANTS: 259 boys examined once around three months of age and again at 18-20 years.MAIN OUTCOME MEASURES: Reproductive hormones, penile length, testis volume, and semen quality. Minipubertal markers of testis function (by tertiles, T1-T3) were explored as predictors of adult semen quality using linear regression models. Associations between reproductive outcomes in infancy and young adulthood were estimated by intra-class correlation coefficients (ICCs), describing how well measurements in infancy correlate with those in adulthood.RESULTS: Serum testosterone concentration in infancy was positively associated with adult total sperm count. Median (IQR) total sperm count was 84 (54-138) million spermatozoa for boys in T1, 141 (81-286) million spermatozoa in T2, and 193 (56-287) million spermatozoa in T3. We found the highest ICC for FSH (0.41, 95% CI 0.26-0.57), while ICCs for inhibin B, SHBG, penile length, and testis volume ranged between 0.24 and 0.27. ICCs for LH, total and free testosterone were lower and statistically non-significant.CONCLUSIONS: Serum testosterone in infancy was a predictor of adult total sperm count. Other reproductive hormones and genital measures showed good correlation between infancy and adulthood, suggesting that an individual's reproductive setpoint starts shortly after birth in boys and persists until adulthood.

AIM: The aim was to assess the influence of dietary counselling on the pubertal development and hormonal status in healthy adolescents.METHODS: We used a subcohort of 193 healthy boys (52%) and girls (48%) from the Special Turku Coronary Risk Factor Intervention Project. Participants were recruited by nurses at the well-baby clinics in Turku Finland in 1990-1992 and randomised into intervention and control groups. Intervention children received low-saturated fat and low-cholesterol dietary counselling initiated at seven months of age. Participants were examined once a year with Tanner staging, anthropometric measurements and serial reproductive hormones from 10 to 19 years of age. In girls, postmenarcheal hormones were not analysed.RESULTS: Pubertal hormones in boys or girls did not differ between the intervention and control groups. However, we observed slight differences in pubertal progression by Tanner staging and in anthropometric parameters. The intervention boys progressed faster to G4 (p = 0.008), G5 (p = 0.008) and P5 (p = 0.03). The intervention boys were taller than control boys (p = 0.04), while weight and body mass index did not differ.CONCLUSION: Dietary intervention did not affect pubertal hormonal status. This finding supports the safety of implemented counselling in respect to puberty.

Context: Despite clinical guidelines calling for repetitive examination of testicular position during childhood, little is known of normal changes in testicular position during childhood, let alone factors that control it.Objective: To assess changes in and factors associated with testicular position during childhood.Design: Testicular position (the distance from the pubic bone to the upper pole of the testes) at birth, 3 months, 18 months, 36 months, and 7 years and reproductive hormones at 3 months were measured.Setting: Prenatally recruited, prospective longitudinal birth cohort.Participants: A total of 2545 boys were recruited prenatally in a Danish-Finnish birth cohort and had a testicular position examination available. A subset of 680 Danish and 362 Finnish boys had serum reproductive hormone concentrations and insulin-like growth factor I (IGF-I) determined at 3 months.Main Outcome Measures: Testicular distance to pubic bone (TDP), serum reproductive hormone, and IGF-I concentrations.Results: TDP increased from birth to 3 months and decreased thereafter. Length, gestational age, weight for gestational age, and penile length were positively associated with larger TDP and thus lower testicular position in a linear mixed-effect model. Furthermore, IGF-I concentration, inhibin B/follicle-stimulating hormone ratio, and testosterone/luteinizing hormone ratio were all independently and positively associated with longer TDP.Conclusions: We provide longitudinal data on postnatal changes in TDP. TDP is dynamic and associated with Leydig and Sertoli cell function as well as with IGF-I levels during the first months of life at mini-puberty of infancy. TDP may thus be a useful biomarker of postnatal testicular function.

STUDY QUESTION: Does semen quality improve during early adulthood?SUMMARY ANSWER: Semen variables change little during the third decade of life, however some improvement in sperm morphology and motility may occur.WHAT IS KNOWN ALREADY: A suspicion of deteriorating semen quality has been raised in several studies. The longitudinal development of semen quality in early adulthood is insufficiently understood.STUDY DESIGN, SIZE, DURATION: A longitudinal follow-up of two cohorts of volunteer young adult Finnish men representing the general population was carried out. Cohorts A (discovery cohort, born 1979-1981, n = 336) and B (validation cohort, born 1983, n = 197) were followed up from the age of 19 years onward for 10 years.PARTICIPANTS/MATERIALS, SETTING, METHODS: Inclusion criteria included that both the men and their mothers were born in Finland. Semen analysis was performed in cohorts A and B at 2-4 year intervals over a period of 10 years. Semen volume, sperm concentration, total sperm count, motility, total motile count and morphology were the variables assessed in the analysis. A physical examination was carried out at each visit to detect any significant andrological abnormalities. The overall participation rate was 13.4%.MAIN RESULTS AND THE ROLE OF CHANCE: During the follow-up, the percentage of sperm with normal morphology and the percentage of motile sperm increased significantly both in the discovery (A) (P < 0.001 at 19 versus 29 years for both) and validation (B) (P < 0.001 and P = 0.03 at 19 versus 29 years, respectively) cohort. Sperm concentration and total sperm count showed a significant increase with age only in cohort B (P = 0.03 at 21 versus 29 years, P = 0.009 at 19 versus 29 years, respectively).LIMITATIONS, REASONS FOR CAUTION: A limited number of men participated both in the first round and in the final fourth round (cohort A, n = 111 and cohort B, n = 90 men) and in all four rounds (cohort A

BACKGROUND: Present knowledge on the impact of varicoceles on testicular function is largely based on studies of subfertile and infertile men, making it difficult to extrapolate the impact of varicocele on the general population.OBJECTIVE: To describe associations between varicocele and testicular function assessed by semen analysis and reproductive hormones in men from the general population.DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional multicentre study of 7035 young men, median age 19 yr, from the general population in six European countries (Denmark, Finland, Germany, Estonia, Latvia, and Lithuania) were investigated from 1996 to 2010.OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We analysed results from physical examination, conventional semen variables, and serum reproductive hormones using multivariable regression analyses.RESULTS AND LIMITATIONS: A total of 1102 (15.7%) had grade 1-3 varicocele. Increasing varicocele grade was associated with poorer semen quality, even in grade 1 varicocele. In grade 3 varicocele, sperm concentration was less than half of that in men with no varicocele. Presence of varicocele was also associated with higher serum levels of follicle-stimulating hormone, lower inhibin B, and higher levels of luteinising hormone; testosterone and free testosterone were not significantly different between men with and without varicocele. This study cannot draw a conclusion on the progressiveness of varicocele or the effect of treatment.CONCLUSIONS: We demonstrated an adverse effect of increasing grade of varicocele on testicular function in men not selected due to fertility status.PATIENT SUMMARY: The presence and increasing grade of varicocele is adversely associated with semen quality and reproductive hormone levels in young men from the general population.