Niels E. Skakkebæk

Evidence for decreasing quality of semen during past 50 years.

OBJECTIVE--To investigate whether semen quality has changed during the past 50 years. DESIGN--Review of publications on semen quality in men without a history of infertility selected by means of Cumulated Index Medicus and Current List (1930-1965) and MEDLINE Silver Platter database (1966-August 1991). SUBJECTS--14,947 men included in a total of 61 papers published between 1938 and 1991. MAIN OUTCOME MEASURES--Mean sperm density and mean seminal volume. RESULTS--Linear regression of data weighted by number of men in each study showed a significant decrease in mean sperm count from 113 x 10(6)/ml in 1940 to 66 x 10(6)/ml in 1990 (p < 0.0001) and in seminal volume from 3.40 ml to 2.75 ml (p = 0.027), indicating an even more pronounced decrease in sperm production than expressed by the decline in sperm density. CONCLUSIONS--There has been a genuine decline in semen quality over the past 50 years. As male fertility is to some extent correlated with sperm count the results may reflect an overall reduction in male fertility. The biological significance of these changes is emphasised by a concomitant increase in the incidence of genitourinary abnormalities such as testicular cancer and possibly also cryptorchidism and hypospadias, suggesting a growing impact of factors with serious effects on male gonadal function.

Are oestrogens involved in falling sperm counts and disorders of the male reproductive tract

The incidence of disorders of development of the male reproductive tract has more than doubled in the past 30-50 years while sperm counts have declined by about half. Similar abnormalities occur in the sons of women exposed to diethylstilbestrol (DES) during pregnancy and can be induced in animals by brief exposure to exogenous oestrogen/DES during pregnancy. We argue that the increasing incidence of reproductive abnormalities in the human male may be related to increased oestrogen exposure in utero, and identify mechanisms by which this exposure could occur.

POSSIBLE CARCINOMA-IN-SITU OF THE TESTIS

Abstract Embryonal carcinoma of the testis was detected in two infertile men in whom testicular biopsies had revealed an abnormal seminiferous epithelium with atypical germ cells. The tumours occurred within 4 1 / 2 years of testicular biopsy. It is suggested that the atypical germ cells represented a carcinoma-in-situ.

European Consensus Conference on Diagnosis and Treatment of Germ Cell Cancer: A Report of the Second Meeting of the European Germ Cell Cancer Consensus group (EGCCCG): Part I

OBJECTIVES The first consensus report presented by the European Germ Cell Cancer Consensus Group (EGCCCG) in the year 2004 has found widespread approval by many colleagues throughout the world. In November 2006, the group met a second time under the auspices of the Department of Urology of the Amsterdam Medical Center, Amsterdam, The Netherlands. METHODS Medical oncologists, urological surgeons, radiation oncologists as well as pathologists from several European countries reviewed and discussed the data that had emerged since the 2002 conference, and incorporated the new data into updated and revised guidelines. As for the first meeting, the methodology of evidence-based medicine (EBM) was applied. The results of the discussion were compiled by the writing committee. All participants have agreed to this final update. RESULTS The first part of the consensus paper describes the clinical presentation of the primary tumor, its treatment, the importance and treatment of testicular intraepithelial neoplasia (TIN), histological classification, staging and prognostic factors, and treatment of stage I seminoma and non-seminoma. CONCLUSIONS Whereas the vast majority of the recommendations made in 2004 remain valid 3 yr later, refinements in the treatment of early- and advanced-stage testicular cancer have emerged from clinical trials. Despite technical improvements, expert clinical skills will continue to be one of the major determinants for the prognosis of patients with germ cell cancer. In addition, the particular needs of testicular cancer survivors have been acknowledged.

Human breast milk contamination with phthalates and alterations of endogenous reproductive hormones in infants three months of age.

Phthalates adversely affect the male reproductive system in animals. We investigated whether phthalate monoester contamination of human breast milk had any influence on the postnatal surge of reproductive hormones in newborn boys as a sign of testicular dysgenesis. Design We obtained biologic samples from a prospective Danish–Finnish cohort study on cryptorchidism from 1997 to 2001. We analyzed individual breast milk samples collected as additive aliquots 1–3 months postnatally (n = 130; 62 cryptorchid/68 healthy boys) for phthalate monoesters [mono-methyl phthalate (mMP), mono-ethyl phthalate (mEP), mono-n-butyl phthalate (mBP), mono-benzyl phthalate (mBzP), mono-2-ethylhexyl phthalate (mEHP), mono-isononyl phthalate (miNP)]. We analyzed serum samples (obtained in 74% of all boys) for gonadotropins, sex-hormone binding globulin (SHBG), testosterone, and inhibin B. Results All phthalate monoesters were found in breast milk with large variations [medians (minimum–maximum)]: mMP 0.10 (< 0.01–5.53 μg/L), mEP 0.95 (0.07–41.4 μg/L), mBP 9.6 (0.6–10,900 μg/L), mBzP 1.2 (0.2–26 μg/L), mEHP 11 (1.5–1,410 μg/L), miNP 95 (27–469 μg/L). Finnish breast milk had higher concentrations of mBP, mBzP, mEHP, and Danish breast milk had higher values for miNP (p = 0.0001–0.056). No association was found between phthalate monoester levels and cryptorchidism. However, mEP and mBP showed positive correlations with SHBG (r = 0.323, p = 0.002 and r = 0.272, p = 0.01, respectively); mMP, mEP, and mBP with LH:free testosterone ratio (r = 0.21–0.323, p = 0.002–0.044) and miNP with luteinizing hormone (r = 0.243, p = 0.019). mBP was negatively correlated with free testosterone (r = −0.22, p = 0.033). Other phthalate monoesters showed similar but nonsignificant tendencies. Conclusions Our data on reproductive hormone profiles and phthalate exposures in newborn boys are in accordance with rodent data and suggest that human Leydig cell development and function may also be vulnerable to perinatal exposure to some phthalates. Our findings are also in line with other recent human data showing incomplete virilization in infant boys exposed to phthalates prenatally.

Recent Decline in Age at Breast Development: The Copenhagen Puberty Study

OBJECTIVE. Recent publications showing unexpectedly early breast development in American girls created debate worldwide. However, secular trend analyses are often limited by poor data comparability among studies performed by different researchers in different time periods and populations. Here we present new European data systematically collected from the same region and by 1 research group at the beginning and end of the recent 15-year period. METHODS. Girls (N = 2095) aged 5.6 to 20.0 years were studied in 1991–1993 (1991 cohort; n = 1100) and 2006–2008 (2006 cohort; n = 995). All girls were evaluated by palpation of glandular breast, measurement of height and weight, and blood sampling (for estradiol, luteinizing hormone, and follicle-stimulating hormone). Age distribution at entering pubertal breast stages 2 through 5, pubic hair stages 2 through 5, and menarche was estimated for the 2 cohorts. RESULTS. Onset of puberty, defined as mean estimated age at attainment of glandular breast tissue (Tanner breast stage 2+), occurred significantly earlier in the 2006 cohort (estimated mean age: 9.86 years) when compared with the 1991 cohort (estimated mean age: 10.88 years). The difference remained significant after adjustment for BMI. Estimated ages at menarche were 13.42 and 13.13 years in the 1991 and 2006 cohorts, respectively. Serum follicle-stimulating hormone and luteinizing hormone did not differ between the 2 cohorts at any age interval, whereas significantly lower estradiol levels were found in 8- to 10-year-old girls from the 2006 cohort compared with similarly aged girls from the 1991 cohort. CONCLUSIONS. We found significantly earlier breast development among girls born more recently. Alterations in reproductive hormones and BMI did not explain these marked changes, which suggests that other factors yet to be identified may be involved.

Testicular dysgenesis syndrome: mechanistic insights and potential new downstream effects

Reproductive disorders of newborn (cryptorchidism, hypospadias) and young adult males (low sperm counts, testicular germ cell cancer) are common and/or increasing in incidence. It has been hypothesized that these disorders may comprise a testicular dysgenesis syndrome (TDS) with a common origin in fetal life. This has been supported by findings in an animal model of TDS involving fetal exposure to n(dibutyl) phthalate, as well as by new clinical studies. Recent advances in understanding from such studies have led to refinement of the TDS hypothesis, highlighting the central role that deficient androgen production/action during fetal testis development, may play in the origin of downstream disorders.

Risk of testicular cancer in men with abnormal semen characteristics: cohort study

Abstract Objective: To explore the associations between semen characteristics and subsequent risk of testicular cancer. Design: Cohort study. Participants: 32 442 men who had a semen analysis done at the Sperm Analysis Laboratory in Copenhagen during 1963-95. Main outcome measure: Standardised incidence ratios of testicular cancer compared with total population of Danish men. Results: Men in couples with fertility problems were more likely to develop testicular cancer than other men (89 cases, standardised incidence ratio 1.6; 95% confidence interval 1.3 to 1.9). The risk was relatively constant with increasing time between semen analysis and cancer diagnosis. Analysis according to specific semen characteristics showed that low semen concentration (standardised incidence ratio 2.3), poor motility of the spermatozoa (2.5), and high proportion of morphologically abnormal spermatozoa (3.0) were all associated with an increased risk of testicular cancer. The only other cancer group that showed increased incidence was “peritoneum and other digestive organs” (six cases; 3.7, 1.3 to 8.0). Of these, two cases were probably and two cases were possibly extragonadal germ cell tumours. Conclusions: The results point towards the existence of common aetiological factors for low semen quality and testicular cancer. Low semen quality may also be associated with increased incidence of extragonadal germ cell tumours.

Public Health Implications of Altered Puberty Timing

Changes in puberty timing have implications for the treatment of individual children, for the risk of later adult disease, and for chemical testing and risk assessment for the population. Children with early puberty are at a risk for accelerated skeletal maturation and short adult height, early sexual debut, potential sexual abuse, and psychosocial difficulties. Altered puberty timing is also of concern for the development of reproductive tract cancers later in life. For example, an early age of menarche is a risk factor for breast cancer. A low age at male puberty is associated with an increased risk for testicular cancer according to several, but not all, epidemiologic studies. Girls and, possibly, boys who exhibit premature adrenarche are at a higher risk for developing features of metabolic syndrome, including obesity, type 2 diabetes, and cardiovascular disease later in adulthood. Altered timing of puberty also has implications for behavioral disorders. For example, an early maturation is associated with a greater incidence of conduct and behavior disorders during adolescence. Finally, altered puberty timing is considered an adverse effect in reproductive toxicity risk assessment for chemicals. Recent US legislation has mandated improved chemical testing approaches for protecting childrens health and screening for endocrine-disrupting agents, which has led to changes in the US Environmental Protection Agencys risk assessment and toxicity testing guidelines to include puberty-related assessments and to the validation of pubertal male and female rat assays for endocrine screening.

Risk of testicular cancer in subfertile men: case›control study

Abstract Objective: To evaluate the association between subfertility in men and the subsequent risk of testicular cancer. Design: Population based case-control study. Setting: The Danish population. Participants: Cases were identified in the Danish Cancer Registry; controls were randomly selected from the Danish population with the computerised Danish Central Population Register. Men were interviewed by telephone; 514men with cancer and 720controls participated. Outcome measure: Occurrence of testicular cancer. Results: A reduced risk of testicular cancer was associated with paternity (relative risk 0.63; 95% confidence interval 0.47 to 0.85). In men who before the diagnosis of testicular cancer had a lower number of children than expected on the basis of their age, the relative risk was 1.98(1.43to 2.75). There was no corresponding protective effect associated with a higher number of children than expected. The associations were similar for seminoma and non-seminomaand were not influenced by adjustment for potential confounding factors. Conclusion: These data are consistent with the hypothesis that male subfertility and testicular cancer share important aetiological factors.