Pathology and genetics of tumours of the urinary system and male genital organs

Numerous reports have recently focused on various aspects of adverse trends in male reproductive health, such as the rising incidence of testicular cancer; low and probably declining semen quality; high and possibly increasing frequencies of undescended testis and hypospadias; and an apparently growing demand for assisted reproduction. Due to specialization in medicine and different ages at presentation of symptoms, reproductive problems used to be analysed separately by various professional groups, e.g. paediatric endocrinologists, urologists, andrologists and oncologists. This article summarizes existing evidence supporting a new concept that poor semen quality, testis cancer, undescended testis and hypospadias are symptoms of one underlying entity, the testicular dysgenesis syndrome (TDS), which may be increasingly common due to adverse environmental influences. Experimental and epidemiological studies suggest that TDS is a result of disruption of embryonal programming and gonadal development during fetal life. Therefore, we recommend that future epidemiological studies on trends in male reproductive health should not focus on one symptom only, but be more comprehensive and take all aspects of TDS into account. Otherwise, important biological information may be lost.

Testicular dysgenesis syndrome ; an increasingly common developmental disorder with environmental aspects

The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in The Netherlands. The study targets cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, oncological, and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. The findings of the Rotterdam Study have been presented in over a 1,000 research articles and reports (see www.erasmus-epidemiology.nl/rotterdamstudy). This article gives the rationale of the study and its design. It also presents a summary of the major findings and an update of the objectives and methods.

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The Rotterdam Study: Objectives and design update

https://apps.who.int/iris/bitstream/10665/78102/1/WHO_HSE_PHE_IHE_2013.1_eng.pdf

State of the Science of Endocrine Disrupting Chemicals - 2012

BACKGROUND Reported declines in sperm counts remain controversial today and recent trends are unknown. A definitive meta-analysis is critical given the predictive value of sperm count for fertility, morbidity and mortality. OBJECTIVE AND RATIONALE To provide a systematic review and meta-regression analysis of recent trends in sperm counts as measured by sperm concentration (SC) and total sperm count (TSC), and their modification by fertility and geographic group. SEARCH METHODS PubMed/MEDLINE and EMBASE were searched for English language studies of human SC published in 1981-2013. Following a predefined protocol 7518 abstracts were screened and 2510 full articles reporting primary data on SC were reviewed. A total of 244 estimates of SC and TSC from 185 studies of 42 935 men who provided semen samples in 1973-2011 were extracted for meta-regression analysis, as well as information on years of sample collection and covariates [fertility group ('Unselected by fertility' versus 'Fertile'), geographic group ('Western', including North America, Europe Australia and New Zealand versus 'Other', including South America, Asia and Africa), age, ejaculation abstinence time, semen collection method, method of measuring SC and semen volume, exclusion criteria and indicators of completeness of covariate data]. The slopes of SC and TSC were estimated as functions of sample collection year using both simple linear regression and weighted meta-regression models and the latter were adjusted for pre-determined covariates and modification by fertility and geographic group. Assumptions were examined using multiple sensitivity analyses and nonlinear models. OUTCOMES SC declined significantly between 1973 and 2011 (slope in unadjusted simple regression models -0.70 million/ml/year; 95% CI: -0.72 to -0.69; P < 0.001; slope in adjusted meta-regression models = -0.64; -1.06 to -0.22; P = 0.003). The slopes in the meta-regression model were modified by fertility (P for interaction = 0.064) and geographic group (P for interaction = 0.027). There was a significant decline in SC between 1973 and 2011 among Unselected Western (-1.38; -2.02 to -0.74; P < 0.001) and among Fertile Western (-0.68; -1.31 to -0.05; P = 0.033), while no significant trends were seen among Unselected Other and Fertile Other. Among Unselected Western studies, the mean SC declined, on average, 1.4% per year with an overall decline of 52.4% between 1973 and 2011. Trends for TSC and SC were similar, with a steep decline among Unselected Western (-5.33 million/year, -7.56 to -3.11; P < 0.001), corresponding to an average decline in mean TSC of 1.6% per year and overall decline of 59.3%. Results changed minimally in multiple sensitivity analyses, and there was no statistical support for the use of a nonlinear model. In a model restricted to data post-1995, the slope both for SC and TSC among Unselected Western was similar to that for the entire period (-2.06 million/ml, -3.38 to -0.74; P = 0.004 and -8.12 million, -13.73 to -2.51, P = 0.006, respectively). WIDER IMPLICATIONS This comprehensive meta-regression analysis reports a significant decline in sperm counts (as measured by SC and TSC) between 1973 and 2011, driven by a 50-60% decline among men unselected by fertility from North America, Europe, Australia and New Zealand. Because of the significant public health implications of these results, research on the causes of this continuing decline is urgently needed.

Temporal trends in sperm count: a systematic review and meta-regression analysis.

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.

https://www.bmj.com/content/bmj/321/7264/789.full.pdf

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

Fertility status may predict later mortality, but no studies have examined the effect of semen quality on subsequent mortality. Men referred to the Copenhagen Sperm Analysis Laboratory by general practitioners and urologists from 1963 to 2001 were, through a unique personal identification number, linked to the Danish central registers that hold information on all cases of cancer, causes of death, and number of children in the Danish population. The men were followed until December 31, 2001, death, or censoring, whichever occurred first, and the total mortality and cause-specific mortality of the cohort were compared with those of all age-standardized Danish men or according to semen characteristics. Among 43,277 men without azospermia referred for infertility problems, mortality decreased as the sperm concentration increased up to a threshold of 40 million/mL. As the percentages of motile and morphologically normal spermatozoa and semen volume increased, mortality decreased in a dose-response manner (P(trend) < 0.05). The decrease in mortality among men with good semen quality was due to a decrease in a wide range of diseases and was found among men both with and without children; therefore, the decrease in mortality could not be attributed solely to lifestyle and/or social factors. Semen quality may therefore be a fundamental biomarker of overall male health.

Good semen quality and life expectancy: a cohort study of 43,277 men.

Background: The widespread use of cellular telephones has heightened concerns about possible adverse health effects. The objective of this study was to investigate cancer risk among Danish cellular telephone users who were followed for up to 21 years. Methods: This study is an extended follow-up of a large nationwide cohort of 420 095 persons whose fi rst cellular telephone subscription was between 1982 and 1995 and who were followed through 2002 for cancer incidence. Standardized incidence ratios (SIRs) were calculated by dividing the number of observed cancer cases in the cohort by the number expected in the Danish population. Results: A total of 14 249 cancers were observed (SIR = 0.95; 95% confi dence interval [CI] = 0.93 to 0.97) for men and women combined. Cellular telephone use was not associated with increased risk for brain tumors (SIR = 0.97), acoustic neuromas (SIR = 0.73), salivary gland tumors (SIR = 0.77), eye tumors (SIR = 0.96), or leukemias (SIR = 1.00). Among long-term subscribers of 10 years or more, cellular telephone use was not associated with increased risk for brain tumors (SIR = 0.66, 95% CI = 0.44 to 0.95), and there was no trend with time since fi rst subscription. The risk for smoking-related cancers was decreased among men (SIR = 0.88, 95% CI = 0.86 to 0.91) but increased among women (SIR = 1.11, 95% CI = 1.02 to 1.21). Additional data on income and smoking prevalence, primarily among men, indicated that cellular telephone users who started subscriptions in the mid-1980s appeared to have a higher income and to smoke less than the general population. Conclusions: We found no evidence for an association between tumor risk and cellular telephone use among either short-term or longterm users. Moreover, the narrow confi dence intervals provide evidence that any large association of risk of cancer and cellular telephone use can be excluded. [J Natl Cancer Inst 2006;98: 1707 – 13 ]

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Cellular Telephone Use and Cancer Risk: Update of a Nationwide Danish Cohort

Analysis of the effect of multiple birth, birth order, age of parents and the sexes of preceding siblings on the secondary sex ratio was performed for 815 891 children, born in Denmark, 1980-1993. The proportion of males was analysed as a function of multiple birth, birth order, age of parents and the sexes of preceding siblings, using contingency tables, chi(2) tests and logistic regression analysis. The secondary sex ratio decreased with increased number of children per plural birth and with paternal age, whereas no independent effect was observed for maternal age, birth order, the sex of the preceding child, or the combination of sexes of previously born children in the family.

Natural variation in the human sex ratio

Impaired semen quality and testicular cancer may be linked through a testicular dysgenesis syndrome of foetal origin. The incidence of testis cancer has been shown to increase among Finnish men, whereas there is no recent publication describing temporal trends in semen quality. Therefore, we carried out a prospective semen quality study and a registry study of testis cancer incidence among Finnish men to explore recent trends. A total of 858 men were investigated in the semen quality study during 1998–2006. Median sperm concentrations were 67 (95% CI 57–80) million/mL, 60 (51–71) and 48 (39–60) for birth cohorts 1979–81, 1982–83 and 1987; total sperm counts 227 (189–272) million, 202 (170–240) and 165 (132–207); total number of morphologically normal spermatozoa 18 (14–23) million, 15 (12–19) and 11 (8–15). Men aged 10–59 years at the time of diagnosis with testicular cancer during 1954–2008 were included in the registry study, which confirmed the increasing incidence of testicular cancer in recent cohorts. These simultaneous and rapidly occurring adverse trends suggest that the underlying causes are environmental and, as such, preventable. Our findings necessitate not only further surveillance of male reproductive health but also research to detect and remove the underlying factors.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2605.2010.01133.x

Rune Jacobsen

Papers

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

Good semen quality and life expectancy: a cohort study of 43,277 men.

Cellular Telephone Use and Cancer Risk: Update of a Nationwide Danish Cohort

Natural variation in the human sex ratio

Recent adverse trends in semen quality and testis cancer incidence among Finnish men