International geographic correlation study of the prevalence of disorders of male reproductive health

Inserm (Institut National de la Santé et de la Recherche Médicale) UMR 1085, IRSET (Institut de Recherche Santé Environnement & Travail), Campus de Beaulieu, Avenue du Général Leclerc Bât 13, Université de Rennes 1, Rennes Cedex F-35042, France.
Human Reproduction (Impact Factor: 4.57). 05/2013; 28(7). DOI: 10.1093/humrep/det111
Source: PubMed


STUDY QUESTION: Is there evidence at the population level of associations between different male genital disorders, outside Scandinavian countries? SUMMARY ANSWER: At an international scale, there is evidence for a number of correlations between rates of four male reproductive disorders (hypospadias, cryptorchidism, testicular cancer and low sperm concentration). WHAT IS KNOWN ALREADY: Some associations between these outcomes have been shown in studies focusing on individuals and mainly in Nordic European countries. These associations, together with histological evidence of a dysgenesis pattern in testicular tissue specimens, have generated the concept of the existence of a 'testicular dysgenesis syndrome' originating in utero. STUDY DESIGN, SIZE, DURATION: This is a geographical correlation study using cancer, malformations rates and sperm quality data collected between the years 1998 and 2005. PARTICIPANTS/MATERIALS, SETTING, METHODS: Incidence rates of testicular cancer were extracted from International Agency for Research on Cancer registries and Globocan, while cryptorchidism and hypospadias prevalence rates were obtained from EUROCAT and International Clearinghouse for Birth Defects Surveillance and Research registries. Sperm concentration data were extracted from recent studies using standardized methodology. A total of 39 registries and 9 sperm studies were selected. Non-parametric Spearman correlation tests were used to test the association between these four disorders. Correlations were computed for all registries together, for registries with high-quality matching coverage only and by continents. Sensitivity analyses were also conducted using data from prospective clinical studies to take into account potential bias related mainly to ascertainment of malformation rates. MAIN RESULTS AND THE ROLE OF CHANCE: We found positive correlations between testicular cancer and hypospadias (r = 0.32, P = 0.05) and between hypospadias and cryptorchidism (r = 0.70, P = 0.008). Stronger correlations were observed when using registries with high-quality matching coverage. Among these registries, differences between Europe and the rest of the world appeared (the positive correlation between testicular cancer and cryptorchidism was stronger outside Europe, r = 0.83, P = 0.01 compared with 0.40, P = 0.60 for European registries). A negative correlation between testicular cancer and sperm concentration was observed (r = -0.88, P = 0.002). These correlations support our initial hypothesis but remain only suggestive due to the intrinsic limitations in the study design (i.e. geographical correlation study) and do not allow causal inference. LIMITATIONS, REASONS FOR CAUTION: Differences in the ascertainment of malformations rates (definition, length of follow-up) make the international comparison difficult. The small number of registries for some conditions (cryptorchidism) or of studies (for sperm quality) and the absence of information about major risk factors such as ethnicity and socioeconomic status in the registries are also limitations. WIDER IMPLICATIONS OF THE FINDINGS: Our findings are in agreement with results of studies focusing on individuals and suggest that shared risk factors are present in the populations studied. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by Inserm (Institut National de la Santé et de la Recherche Médicale), the University of Rennes 1, EHESP (School of Public Health) and the Post-Grenelle 189 Program of INERIS (Institut National de l'Environnement industriel et des Risques). No competing interests were declared.

Full-text preview

Available from:
    • "Much evidence points to the fact that changes to the intrauterine environment can elevate the risk of health disorders in adulthood (Aiken and Ozanne, 2014). In males, disruption of foetal development, particularly androgen-sensitive parameters, are thought to contribute towards an array of male gonadal development disorders and decline in reproductive health, collectively explained by the Testicular Dysgenesis Syndrome hypothesis, (Serrano et al., 2013;Skakkebaek et al., 2001). Several studies suggest that female reproductive health is suffering from a similar decline, partly due to cultural changes (e.g. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Studies report that foetal exposure to paracetamol by maternal consumption can interfere with male reproductive development. Moreover, recent biomonitoring data report widespread presence of paracetamol in German and Danish populations, suggesting exposure via secondary (non-pharmaceutical) sources such as metabolic conversion from the ubiquitous industrial compound aniline. In this study we investigated the extent to which paracetamol and aniline can interfere with female reproductive development. Intrauterine exposure to paracetamol by gavage of pregnant dams resulted in shortening of the anogenital distance in adult offspring, suggesting that foetal hormone signalling had been disturbed. Female offspring of paracetamol-exposed mothers had ovaries with diminished follicle reserve and reduced fertility. Foetal gonads of exposed animals had also reduced gonocyte numbers, suggesting that the reduced follicle count in adults could be due to early disruption of germ cell development. However, ex vivo cultures of ovaries from 12.5 days post coitum foetuses showed no decrease in proliferation or expression following exposure to paracetamol. This suggests that the effect of paracetamol occurs prior to this developmental stage. Accordingly, using embryonic stem cells as a proxy for primordial germ cells we show that paracetamol is an inhibitor of cellular proliferation, but without cytotoxic effects. Collectively, our data show that intrauterine exposure to paracetamol at levels commonly observed in pregnant women, as well as its precursor aniline, may block primordial germ cell proliferation, ultimately leading to reduced follicle reserves and compromised reproductive capacity later in life.
    No preview · Article · Jan 2016 · Toxicological Sciences
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: Kartagener's syndrome (KS) is characterized by the classic triad of chronic sinusitis, bronchiectasis and situs inversus. This is caused by dynein arm defects in axonemal microtubules in ciliary and flagellar structures. Male patients are invariably infertile because of the immotility of spermatozoa. We report a healthy birth that was achieved by intracytoplasmic sperm injection (ICSI) using ejaculated spermatozoa from a patient with KS. Case report: The wife of the patient was a 33-year-old woman with infertility of one-year duration.Her diagnostic infertility work-ups were normal. Her husband was 33 years old. He had normal secondary sex characteristics and both testicular volumes were normal. His serum FSH, LH, testosterone and prolactin levels were all within normal limits. He had dextrocardia and dysosmia as well as a history of chronic bronchitis and sinusitis, the classic triad disorders of KS, and was therefore diagnosed with KS. Several semen analyses showed sperm concentration of 77-87 × 10 6 /ml and ejaculated volume of 3.5-4.0 ml. However, only 2-28 motile spermatozoa were observed in the whole field with a Makler Counting Chamber. After eosin staining, 30% of the sperm were viable with unremarkable morphology. Transmission electron microscopy (TEM) of the sperm tail showed the absence of both inner and outer dynein arms. After counseling for this condition and suitability for ICSI, the couple proceeded with ICSI using ejaculated spermatozoa. In August 2005, after ovarian stimulation by a long protocol using GnRHa / hMG, twenty-one oocytes were obtained, and 18 metaphase II oocytes were retrieved. Fresh semen samples were obtained after masturbation. The sperm concentration was 57.2 × 10 6 /ml and the volume was 3.5 ml. Total motility was 0.3%, and no spermatozoa showed straight progressive motility. After swim-up preparation, we observed a few motile spermatozoa that appeared morphologically normal, and these motile spermatozoa were selected for ICSI. Thirteen oocytes were fertilized. All embryos were cryopreserved in the cleavage stage to prevent development of ovarian hyperstimulation syndrome. In October 2005, two--step embryo transfer was performed in the hormone replacement (HR) cycle. A twin pregnancy was achieved, one resulting in missed abortion but the other being uneventful. A healthy female infant was delivered in June 2006 at a gestation age of 37 weeks and weighing 2675 g. In April 2008, the couple was referred to our clinic for a second pregnancy. Four cycles of single blastocyst transfer using a cryopreserved-thawed blastocyst were repeatedly performed. Pregnancy tests were positive in three cycles, but all of the three pregnancies resulted in chemical abortion. In January 2009, after using an ovarian stimulation protocol similar to that used in the first cycle, five metaphase II oocytes were retrieved. Sperm concentration and total motility were 68.1 × 10 6 /ml and 0.1%, respectively, and a few progressive motile sperm were observed. The intracytoplasmic morphologically selected sperm injection (IMSI) procedure was performed with the progressive motile sperm. All oocytes were fertilized. One embryo was cryopreserved in the cleavage stage and the other four embryos were cultured for three more days, but no blastocyst was obtained. In March 2009, cryopreserved-thawed embryo transfer was performed in the HR cycle, but pregnancy was not achieved. Conclusion: This case report demonstrates that successful pregnancy after ICSI in couples with Kartagener's syndrome is possible with ejaculated spermatozoa. Our results suggest that even for KS patients, if motile sperm are observed, a fertilization rate comparable to that with ICSI of the other male factor can be expected. KS is a heterogeneous group of disorders with similar clinical presentations, and treatment should be individualized depending on sperm motility.
    Full-text · Article · Jun 2010 · Human Reproduction
  • [Show abstract] [Hide abstract]
    ABSTRACT: Studies over the last years show an increase in testicular cancer, hypospadias and cryptorchidism in industrial countries, leading to the concept of Testicular dysgenesis syndrome (TDS). It is hypothesized that TDS is caused by estrogen and antiandrogen exposure during fetal life, accompanied by incomplete maturation of testicular Sertoli Cells (SC). However, it is not known if SC disruption is a primary cause or a response to fetal Leydig cell testosterone production changes. To determine if SC differentiation is directly affected by estrogens, we compared SC maturation between adult gender reassignment cases exposed to estrogen and antiandrogen therapy, and those of typical TDS in adult cryptorchidism. We found similar expression of immature SC markers M2A antigen, inhibin bodies and Anti Mullerian Hormone, and the absence of maturation marker androgen receptor in SC of both types of patients. These data supports the occurrence of true SC dedifferentiation caused by estrogen exposure in adult humans. Our data also suggests that SC maturation is directly disrupted in TDS.
    No preview · Article · Sep 2013 · Reproductive Toxicology
Show more