Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Possible fetal determinants of male infertility

This article has been updated

Key Points

  • The fetal environment, which includes placental function, maternal metabolism and lifestyle factors (including maternal smoking), influences testicular development and function later in life

  • Endocrine disruption during fetal development might have important consequences for fertility

  • Testicular dysgenesis can result in impaired germ cell differentiation, cryptorchidism, hypospadias and a short anogenital distance at birth and later in life

  • Long-term consequences of testicular dysgenesis include male infertility, reduced levels of testosterone and testicular cancer

Abstract

Although common reproductive problems, such as male infertility and testicular cancer, present in adult life, strong evidence exists that these reproductive disorders might have a fetal origin. The evidence is derived not only from large epidemiological studies that show birth-cohort effects with regard to testicular cancer, levels of testosterone and semen quality, but also from histopathological observations. Many infertile men have histological signs of testicular dysgenesis, including Sertoli-cell-only tubules, immature undifferentiated Sertoli cells, microliths and Leydig cell nodules. The most severe gonadal symptoms occur in patients with disorders of sexual development (DSDs) who have genetic mutations, in whom even sex reversal of individuals with a 46,XY DSD can occur. However, patients with severe DSDs might represent only a small proportion of DSD cases, with milder forms of testicular dysgenesis potentially induced by exposure to environmental and lifestyle factors. Interestingly, maternal smoking during pregnancy has a stronger effect on spermatogenesis than a man's own smoking. Other lifestyle factors such as alcohol consumption and obesity might also have a role. However, increasing indirect evidence exists that exposure to ubiquitous endocrine disrupting chemicals, present at measurable concentrations in individuals, might affect development of human fetal testis. If confirmed, health policies to prevent male reproductive problems should not only target adult men, but also pregnant women and their children.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Sperm quality and neoplastic cells in ejaculate.
Figure 2: Testicular dysgenesis syndrome.
Figure 3: Histological features of severe oligozoospermia or azoospermia.
Figure 4: Measurement of anogenital distance in boys.
Figure 5: Relationship between levels of testosterone and fertility status.

Change history

  • 28 July 2014

    In the original version of this article published online the legend to Figure 3 was incorrect. 'CIS marker phospholipase A2-activating protein' should be 'CIS marker placental-like alkaline phosphatase'. This error has now been corrected in the HTML and PDF versions of the article.

References

  1. Skakkebæk, N. E., Rajpert-De Meyts, E. & Main, K. M. Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Hum. Reprod. 16, 972–978 (2001).

    PubMed  Google Scholar 

  2. Mocarelli, P. et al. Dioxin exposure, from infancy through puberty, produces endocrine disruption and affects human semen quality. Environ. Health Perspect. 116, 70–77 (2008).

    CAS  PubMed  Google Scholar 

  3. Klinefelter, H. F., Reifenstein, E. C. & Albright, F. Syndrome characterised by gynecomastia, aspermatogenesis, with A-Leydigism and increased excretion of follicle stimulating hormone. J. Clin. Endocrinol. 2, 615–627 (1942).

    CAS  Google Scholar 

  4. Aksglæde, L., Skakkebæk, N. E., Almstrup, K. & Juul, A. Clinical and biological parameters in 166 boys, adolescents and adults with nonmosaic Klinefelter syndrome: a Copenhagen experience. Acta Paediatr. 100, 793–806 (2011).

    PubMed  Google Scholar 

  5. Isidor, B. et al. Familial frameshift SRY mutation inherited from a mosaic father with testicular dysgenesis syndrome. J. Clin. Endocrinol. Metab. 94, 3467–3471 (2009).

    CAS  PubMed  Google Scholar 

  6. Lottrup, G. et al. Identification of a novel androgen receptor mutation in a family with multiple components compatible with the testicular dysgenesis syndrome. J. Clin. Endocrinol. Metab. 98, 2223–2229 (2013).

    CAS  PubMed  Google Scholar 

  7. Lindhardt Johansen, M. et al. 45,X/46,XY mosaicism: phenotypic characteristics, growth, and reproductive function—a retrospective longitudinal study. J. Clin. Endocrinol. Metab. 97, E1540–E1549 (2012).

    PubMed  Google Scholar 

  8. Jacobs, P. A. & Strong, J. A. A case of human intersexuality having a possible XXY sex-determining mechanism. Nature 183, 302–303 (1959).

    CAS  PubMed  Google Scholar 

  9. Dayangac, D. et al. Mutations of the CFTR gene in Turkish patients with congenital bilateral absence of the vas deferens. Hum. Reprod. 19, 1094–1100 (2004).

    CAS  PubMed  Google Scholar 

  10. Priskorn, L. et al. Increasing trends in childlessness in recent birth cohorts—a registry-based study of the total Danish male population born from 1945 to 1980. Int. J. Androl. 35, 449–455 (2012).

    CAS  PubMed  Google Scholar 

  11. Louis, J. F. et al. The prevalence of couple infertility in the United States from a male perspective: evidence from a nationally representative sample. Andrology 1, 741–748 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Schmidt, L., Münster, K. & Helm, P. Infertility and the seeking of infertility treatment in a representative population. Br. J. Obstet. Gynaecol. 102, 978–984 (1995).

    CAS  PubMed  Google Scholar 

  13. Schmidt, L. Infertility and assisted reproduction in Denmark. Epidemiology and psychosocial consequences. Dan. Med. Bull. 53, 390–417 (2006).

    PubMed  Google Scholar 

  14. Zegers-Hochschild, F. et al. The International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WHO) revised glossary on ART terminology, 2009. Hum. Reprod. 24, 2683–2687 (2009).

    CAS  PubMed  Google Scholar 

  15. Andersen, A. N. & Erb, K. Register data on assisted reproductive technology (ART) in Europe including a detailed description of ART in Denmark. Int. J. Androl. 29, 12–16 (2006).

    Google Scholar 

  16. Danish Fertility Society. Annual report 2013 [online], (2014).

  17. Jain, T. & Gupta, R. S. Trends in the use of intracytoplasmic sperm injection in the United States. N. Engl. J. Med. 357, 251–257 (2007).

    CAS  PubMed  Google Scholar 

  18. WHO. WHO laboratory manual for the examination and processing of human semen [online], (2010).

  19. Guzick, D. S. et al. Sperm morphology, motility, and concentration in fertile and infertile men. N. Engl. J. Med. 345, 1388–1393 (2001).

    CAS  PubMed  Google Scholar 

  20. Bonde, J. P. E. et al. Relation between semen quality and fertility: a population-based study of 430 first-pregnancy planners. Lancet 352, 1172–1177 (1998).

    CAS  PubMed  Google Scholar 

  21. Slama, R. et al. Time to pregnancy and semen parameters: a cross-sectional study among fertile couples from four European cities. Hum. Reprod. 17, 503–515 (2002).

    CAS  PubMed  Google Scholar 

  22. Sharpe, R. M. & Skakkebæk, N. E. Testicular dysgenesis syndrome: mechanistic insights and potential new downstream effects. Fertil. Steril. 89 (Suppl. 2), e33–e38 (2008).

    PubMed  Google Scholar 

  23. Welsh, M. et al. Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism. J. Clin. Invest. 118, 1479–1490 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. The Organization for Economic Co-operation and Development. OECD guideline for testing of chemicals. Reproduction/developmental toxicity screening test [online], (1995).

  25. Veeramachaneni, D. N., Palmer, J. S., Amann, R. P. & Pau, K. Y. Sequelae in male rabbits following developmental exposure to p,p'-DDT or a mixture of p,p'-DDT and vinclozolin: cryptorchidism, germ cell atypia, and sexual dysfunction. Reprod. Toxicol. 23, 353–365 (2007).

    CAS  PubMed  Google Scholar 

  26. Veeramachaneni, D. N., Amann, R. P. & Jacobson, J. P. Testis and antler dysgenesis in sitka black-tailed deer on Kodiak Island, Alaska: sequela of environmental endocrine disruption? Environ. Health Perspect. 114 (Suppl. 1), 51–59 (2006).

    PubMed  Google Scholar 

  27. Bay, K., Main, K. M., Toppari, J. & Skakkebæk, N. E. Testicular descent: INSL 3, testosterone, genes and the intrauterine milieu. Nat. Rev. Urol. 8, 187–196 (2011).

    CAS  PubMed  Google Scholar 

  28. Swaab, D. F. Sexual differentiation of the brain and behavior. Best Pract. Res. Clin. Endocrinol. Metab. 21, 431–444 (2007).

    PubMed  Google Scholar 

  29. Rajpert-De Meyts, E. Developmental model for the pathogenesis of testicular carcinoma in situ: genetic and environmental aspects. Hum. Reprod. Update 12, 303–323 (2006).

    CAS  PubMed  Google Scholar 

  30. Looijenga, L. H. J., de Munnik, H. & Oosterhuis, J. W. A molecular model for the development of germ cell cancer. Int. J. Cancer 83, 809–814 (1999).

    CAS  PubMed  Google Scholar 

  31. Rørth, M. et al. Carcinoma in situ in the testis. Scand. J. Urol. Nephrol. 205, 166–186 (2000).

    Google Scholar 

  32. Skakkebæk, N. E., Berthelsen, J. G., Giwercman, A. & Müller, J. Carcinoma-in-situ of the testis: possible origin from gonocytes and precursor of all types of germ cell tumours except spermatocytoma. Int. J. Androl. 10, 19–28 (1987).

    PubMed  Google Scholar 

  33. Almstrup, K. et al. Embryonic stem cell-like features of testicular carcinoma in situ revealed by genome-wide gene expression profiling. Cancer Res. 64, 4736–4743 (2004).

    CAS  PubMed  Google Scholar 

  34. Skakkebæk, N. E. Carcinoma in situ of the testis: frequency and relationship to invasive germ cell tumours in infertile men. Histopathology 2, 157–170 (1978).

    PubMed  Google Scholar 

  35. Bergström, R. et al. Increase in testicular cancer incidence in six European countries: a birth cohort phenomenon. J. Natl Cancer Inst. 88, 727–733 (1996).

    PubMed  Google Scholar 

  36. Møller, H. Clues to the aetiology of testicular germ cell tumours from descriptive epidemiology. Eur. Urol. 23, 8–15 (1993).

    PubMed  Google Scholar 

  37. Müller, J., Skakkebæk, N. E., Ritzén, E. M., Plöen, L. & Petersen, K. E. Carcinoma in situ of the testis in children with 45,X/46,XY gonadal dysgenesis. J. Pediatr. 106, 431–436 (1985).

    PubMed  Google Scholar 

  38. Müller, J., Visfeldt, J. & Skakkebæk, N. E. Gonadoblastoma and invasive neoplasia in 2 girls with 46,XY gonadal dysgenesis. Horm. Res. 33 (Suppl. 3), 57 (1990).

    Google Scholar 

  39. Looijenga, L. H. et al. POU5F1 (OCT3/4) identifies cells with pluripotent potential in human germ cell tumors. Cancer Res. 63, 2244–2250 (2003).

    CAS  PubMed  Google Scholar 

  40. Cools, M. et al. Gonadal pathology and tumor risk in relation to clinical characteristics in patients with 45,X/46,XY mosaicism. J. Clin. Endocrinol. Metab. 96, E1171–E1180 (2011).

    CAS  PubMed  Google Scholar 

  41. Abdullah, N. A. et al. Birth prevalence of cryptorchidism and hypospadias in Northern England, 1993–2000. Arch. Dis. Child. 92, 576–579 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Jaffray, B., Moore, L. & Dickson, A. P. Prader–Willi syndrome and intratubular germ cell neoplasia. Med. Pediatr. Oncol. 32, 73–74 (1999).

    CAS  PubMed  Google Scholar 

  43. Berthelsen, J. G. & Skakkebæk, N. E. Gonadal function in men with testis cancer. Fertil. Steril. 39, 68–75 (1983).

    CAS  PubMed  Google Scholar 

  44. Berthelsen, J. G. Andrological aspects of testicular cancer. Int. J. Androl. 7, 451–483 (1984).

    CAS  PubMed  Google Scholar 

  45. Petersen, P. M., Skakkebæk, N. E., Vistisen, K., Rørth, M. & Giwercman, A. Semen quality and reproductive hormones before orchiectomy in men with testicular cancer. J. Clin. Oncol. 17, 941–947 (1999).

    CAS  PubMed  Google Scholar 

  46. Walsh, T. J., Croughan, M. S., Schembri, M., Chan, J. M. & Turek, P. J. Increased risk of testicular germ cell cancer among infertile men. Arch. Intern. Med. 169, 351–356 (2009).

    PubMed  PubMed Central  Google Scholar 

  47. Møller, H. & Skakkebaek, N. E. Risk of testicular cancer in subfertile men: case–control study. Br. Med. J. 318, 559–562 (1999).

    Google Scholar 

  48. Akre, O. & Richiardi, L. Does a testicular dysgenesis syndrome exist? Hum. Reprod. 24, 2053–2060 (2009).

    PubMed  Google Scholar 

  49. Asklund, C. et al. Semen quality, reproductive hormones and fertility of men operated for hypospadias. Int. J. Androl. 33, 80–87 (2010).

    CAS  PubMed  Google Scholar 

  50. Schnack, T. H., Poulsen, G., Myrup, C., Wohlfahrt, J. & Melbye, M. Familial coaggregation of cryptorchidism, hypospadias, and testicular germ cell cancer: a nationwide cohort study. J. Natl Cancer Inst. 102, 187–192 (2009).

    PubMed  Google Scholar 

  51. Cools, M. & Looijenga, L. H. Tumor risk and clinical follow-up in patients with disorders of sex development. Pediatr. Endocrinol. Rev. 9 (Suppl. 1), 519–524 (2011).

    PubMed  Google Scholar 

  52. Rud, C. N. et al. Sperm concentration, testicular volume and age predict risk of carcinoma-in-situ in contralateral testis of men with testicular germ-cell cancer. J. Urol. 190, 2074–2080 (2013).

    PubMed  Google Scholar 

  53. Olesen, I. A. et al. Testicular carcinoma in situ in subfertile Danish men. Int. J. Androl. 30, 406–412 (2007).

    PubMed  Google Scholar 

  54. Høi-Hansen, C. E., Holm, M., Rajpert-De Meyts, E. & Skakkebæk, N. E. Histological evidence of testicular dysgenesis in contralateral biopsies from 218 patients with testicular germ cell cancer. J. Pathol. 200, 370–374 (2003).

    Google Scholar 

  55. Yong, E. L., Loy, C. J. & Sim, K. S. Androgen receptor gene and male infertility. Hum. Reprod. Update 18, 1–7 (2003).

    Google Scholar 

  56. Ferlin, A., Arredi, B. & Foresta, C. Genetic causes of male infertility. Reprod. Toxicol. 30, 133–141 (2006).

    Google Scholar 

  57. Hellmann, P. et al. Male patients with partial androgen insensitivity syndrome: a longitudinal follow-up of growth, reproductive hormones and the development of gynaecomastia. Arch. Dis. Child. 97, 403–409 (2012).

    PubMed  Google Scholar 

  58. Aksglæde, L. et al. Natural history of seminiferous tubule degeneration in Klinefelter syndrome. Hum. Reprod. Update 12, 39–48 (2006).

    PubMed  Google Scholar 

  59. Skakkebæk, N. E. Two types of tubules containing only Sertoli cells in adults with Klinefelter's syndrome. Nature 223, 643–645 (1969).

    PubMed  Google Scholar 

  60. McLachlan, R. I., Rajpert-De Meyts, E., Høi-Hansen, C. E., De Kretser, D. M. & Skakkebæk, N. E. Histological evaluation of the human testis—approaches to optimizing the clinical value of the assessment: mini review. Hum. Reprod. 22, 2–16 (2007).

    CAS  PubMed  Google Scholar 

  61. Mehta, A., Paduch, D. A. & Schlegel, P. N. Successful testicular sperm retrieval in adolescents with Klinefelter syndrome treated with at least 1 year of topical testosterone and aromatase inhibitor. Fertil. Steril. 100, e27 (2013).

    PubMed  Google Scholar 

  62. Vorona, E., Zitzmann, M., Gromoll, J., Schuring, A. N. & Nieschlag, E. Clinical, endocrinological, and epigenetic features of the 46,XX male syndrome, compared with 47,XXY Klinefelter patients. J. Clin. Endocrinol. Metab. 21, 3458–3465 (2007).

    Google Scholar 

  63. Ottesen, A. M. et al. Increased number of sex chromosomes affects height in a nonlinear fashion: a study of 305 patients with sex chromosome aneuploidy. Am. J. Med. Genet. A 152A, 1206–1212 (2010).

    PubMed  PubMed Central  Google Scholar 

  64. Leppig, K. A. & Disteche, C. M. Ring X and other structural X chromosome abnormalities: X inactivation and phenotype. Semin. Reprod. Med. 19, 147–157 (2001).

    CAS  PubMed  Google Scholar 

  65. Richardson, M. E., Bleiziffer, A., Tuttelmann, F., Gromoll, J. & Wilkinson, M. F. Epigenetic regulation of the RHOX homeobox gene cluster and its association with human male infertility. Hum. Mol. Genet. 23, 12–23 (2014).

    CAS  PubMed  Google Scholar 

  66. Le Cornet, C. et al. Testicular cancer incidence to rise by 25% by 2025 in Europe? Model-based predictions in 40 countries using population-based registry data. Eur. J. Cancer 50, 831–839 (2014).

    PubMed  Google Scholar 

  67. Main, K. M., Jensen, R. B., Asklund, C., Høi-Hansen, C. E. & Skakkebæk, N. E. Low birth weight and male reproductive function. Horm. Res. 65 (Suppl. 3), 116–122 (2006).

    CAS  PubMed  Google Scholar 

  68. Nordenvall, A. S., Frisen, L., Nordenstrom, A., Lichtenstein, P. & Nordenskjold, A. A population-based nationwide study of hypospadias in Sweden, 1973–2009: incidence and risk factors. J. Urol. 191, 783–789 (2013).

    PubMed  Google Scholar 

  69. Virtanen, H. E. & Toppari, J. Epidemiology and pathogenesis of cryptorchidism. Hum. Reprod. Update 14, 49–58 (2008).

    CAS  PubMed  Google Scholar 

  70. Depue, R. H., Pike, M. C. & Henderson, B. E. Birth weight and the risk of testicular cancer. J. Natl Cancer Inst. 77, 829–830 (1986).

    Google Scholar 

  71. Møller, H. & Skakkebæk, N. E. Testicular cancer and cryptorchidism in relation to prenatal factors: case–control studies in Denmark. Cancer Causes Control 8, 904–912 (1997).

    PubMed  Google Scholar 

  72. Francois, I., De Zegher, F., Spiessens, C., D'Hooge, T. & Vanderschueren, D. Low birth weight and subsequent male subfertility. Pediatr. Res. 42, 899–901 (1997).

    CAS  PubMed  Google Scholar 

  73. Cicognani, A. et al. Low birth weight for gestational age and subsequent male gonadal function. J. Pediatr. 141, 376–380 (2002).

    PubMed  Google Scholar 

  74. Vanbillemont, G. et al. Birth weight in relation to sex steroid status and body composition in young healthy male siblings. J. Clin. Endocrinol. Metab. 95, 1587–1594 (2010).

    CAS  PubMed  Google Scholar 

  75. Jensen, R. B. et al. Pituitary–gonadal function in adolescent males born appropriate or small for gestational age with or without intrauterine growth restriction. J. Clin. Endocrinol. Metab. 92, 1353–1357 (2007).

    CAS  PubMed  Google Scholar 

  76. Kerkhof, G. F. et al. Influence of preterm birth and birth size on gonadal function in young men. J. Clin. Endocrinol. Metab. 94, 4243–4250 (2009).

    CAS  PubMed  Google Scholar 

  77. Damgaard, I. N. et al. Risk factors for congenital cryptorchidism in a prospective birth cohort study. PLoS ONE. 3, e3051 (2008).

    PubMed  PubMed Central  Google Scholar 

  78. Virtanen, H. E. et al. Mild gestational diabetes as a risk factor for congenital cryptorchidism. J. Clin. Endocrinol. Metab. 91, 4862–4865 (2006).

    CAS  PubMed  Google Scholar 

  79. van Rooij, I. A. et al. Risk factors for different phenotypes of hypospadias: results from a Dutch case-control study. BJU Int. 112, 121–128 (2013).

    PubMed  Google Scholar 

  80. Carmichael, S. L. et al. Hypospadias and maternal intake of phytoestrogens. Am. J. Epidemiol. 178, 434–440 (2013).

    PubMed  PubMed Central  Google Scholar 

  81. Thorup, J., Cortes, D. & Petersen, B. L. The incidence of bilateral cryptorchidism is increased and the fertility potential is reduced in sons born to mothers who have smoked during pregnancy. J. Urol. 176, 734–737 (2006).

    CAS  PubMed  Google Scholar 

  82. Ravnborg, T. L. et al. Prenatal and adult exposures to smoking are associated with adverse effects on reproductive hormones, semen quality, final height and body mass index. Hum. Reprod. 26, 1000–1011 (2011).

    CAS  PubMed  Google Scholar 

  83. Ratcliffe, J. M., Gladen, B. C., Wilcox, A. J. & Herbst, A. L. Does early exposure to maternal smoking affect future fertility in adult males? Reprod. Toxicol. 6, 297–307 (1992).

    CAS  PubMed  Google Scholar 

  84. Jensen, T. K. et al. Adult and prenatal exposures to tobacco smoke as risk indicators of fertility among 430 Danish couples. Am. J. Epidemiol. 148, 992–997 (1998).

    CAS  PubMed  Google Scholar 

  85. Storgaard, L. et al. Does smoking during pregnancy affect sons' sperm counts? Epidemiology 14, 278–286 (2003).

    PubMed  Google Scholar 

  86. Jensen, T. K. et al. Association of in utero exposure to maternal smoking with reduced semen quality and testis size in adulthood: a cross-sectional study of 1,770 young men from the general population in five European countries. Am. J. Epidemiol. 159, 49–58 (2004).

    PubMed  Google Scholar 

  87. Ramlau-Hansen, C. H. et al. Maternal smoking in pregnancy and reproductive hormones in adult sons. Int. J. Androl. 31, 565–572 (2008).

    CAS  PubMed  Google Scholar 

  88. Toppari, J. et al. Male reproductive health and environmental xenoestrogens. Environ. Health Perspect. 104, 741–803 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. MacLeod, D. J. et al. Androgen action in the masculinization programming window and development of male reproductive organs. Int. J. Androl. 33, 279–287 (2010).

    CAS  PubMed  Google Scholar 

  90. Fisher, J. S., Macpherson, S., Marchetti, N. & Sharpe, R. M. Human “testicular dysgenesis syndrome”: a possible model using in-utero exposure of the rat to dibutyl phthalate. Hum. Reprod. 18, 1383–1394 (2003).

    CAS  PubMed  Google Scholar 

  91. Hass, U. et al. Combined exposure to anti-androgens exacerbates disruption of sexual differentiation in the rat. Environ. Health Perspect. 115 (Suppl. 1), 122–128 (2007).

    PubMed  PubMed Central  Google Scholar 

  92. Hardell, L. et al. Increased concentrations of polychlorinated biphenyls, hexachlorobenzene, and chlordanes in mothers of men with testicular cancer. Environ. Health Perspect. 111, 930–934 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Krysiak-Baltyn, K. et al. Country-specific chemical signatures of persistent environmental compounds in breast milk. Int. J. Androl. 33, 270–278 (2010).

    CAS  PubMed  Google Scholar 

  94. Kortenkamp, A. Ten years of mixing cocktails: a review of combination effects of endocrine-disrupting chemicals. Environ. Health Perspect. 115 (Suppl. 1), 98–105 (2007).

    PubMed  PubMed Central  Google Scholar 

  95. Orton, F., Rosivatz, E., Scholze, M. & Kortenkamp, A. Widely used pesticides with previously unknown endocrine activity revealed as in vitro antiandrogens. Environ. Health Perspect. 119, 794–800 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Kristensen, D. M. et al. Intrauterine exposure to mild analgesics is a risk factor for development of male reproductive disorders in human and rat. Hum. Reprod. 26, 235–244 (2011).

    CAS  PubMed  Google Scholar 

  97. Mazaud-Guittot, S. et al. Paracetamol, aspirin, and indomethacin induce endocrine disturbances in the human fetal testis capable of interfering with testicular descent. J. Clin. Endocrinol. Metab. 98, E1757–E1767 (2013).

    CAS  PubMed  Google Scholar 

  98. Snijder, C. A. et al. Intrauterine exposure to mild analgesics during pregnancy and the occurrence of cryptorchidism and hypospadia in the offspring: the Generation R Study. Hum. Reprod. 27, 1191–1201 (2012).

    PubMed  Google Scholar 

  99. Jensen, M. S. et al. Analgesics during pregnancy and cryptorchidism: additional analyses. Epidemiology 22, 610–612 (2011).

    PubMed  Google Scholar 

  100. Andersen, H. R. et al. Impaired reproductive development in sons of women occupationally exposed to pesticides during pregnancy. Environ. Health Perspect. 116, 566–572 (2008).

    PubMed  PubMed Central  Google Scholar 

  101. Wohlfahrt-Veje, C. et al. Smaller genitals at school age in boys whose mothers were exposed to non-persistent pesticides in early pregnancy. Int. J. Androl. 35, 265–272 (2012).

    CAS  PubMed  Google Scholar 

  102. Chul, K. S., Kyoung, K. S. & Pyo, H. Y. Trends in the incidence of cryptorchidism and hypospadias of registry-based data in Korea: a comparison between industrialized areas of petrochemical estates and a non-industrialized area. Asian J. Androl. 13, 715–718 (2011).

    Google Scholar 

  103. Krysiak-Baltyn, K. et al. Association between chemical pattern in breast milk and congenital cryptorchidism: modelling of complex human exposures. Int. J. Androl. 35, 294–302 (2012).

    CAS  PubMed  Google Scholar 

  104. Rantakokko, P. et al. Association of placenta organotin concentrations with congenital cryptorchidism and reproductive hormone levels in 280 newborn boys from Denmark and Finland. Hum. Reprod. 28, 1647–1660 (2013).

    CAS  PubMed  Google Scholar 

  105. Virtanen, H. E. et al. Associations between congenital cryptorchidism in newborn boys and levels of dioxins and PCBs in placenta. Int. J. Androl. 35, 283–293 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Main, K. M. et al. Human breast milk contamination with phthalates and alterations of endogenous reproductive hormones in three months old infants. Environ. Health Perspect. 114, 270–276 (2006).

    CAS  PubMed  Google Scholar 

  107. Damgaard, I. N. et al. Persistent pesticides in human breast milk and cryptorchidism. Environ. Health Perspect. 114, 1133–1138 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Main, K. M. et al. Flame retardants in placenta and breast milk and cryptorchidism in newborn boys. Environ. Health Perspect. 115, 1519–1526 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Swan, S. H. et al. Decrease in anogenital distance among male infants with prenatal phthalate exposure. Environ. Health Perspect. 113, 1056–1061 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Longnecker, M. P. et al. Maternal serum level of 1,1-dichloro-2, 2-bis(p-chlorophenyl)ethylene and risk of cryptorchidism, hypospadias, and polythelia among male offspring. Am. J. Epidemiol. 155, 313–322 (2002).

    PubMed  Google Scholar 

  111. Brucker-Davis, F. et al. Cryptorchidism at birth in Nice area (France) is associated with higher prenatal exposure to PCBs and DDE, as assessed by colostrum concentrations. Hum. Reprod. 23, 1708–1718 (2008).

    CAS  PubMed  Google Scholar 

  112. Pierik, F. H., Klebanoff, M. A., Brock, J. W. & Longnecker, M. P. Maternal pregnancy serum level of heptachlor epoxide, hexachlorobenzene, and β-hexachlorocyclohexane and risk of cryptorchidism in offspring. Environ. Res. 105, 364–369 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. van der Zanden, L. F. et al. Exploration of gene–environment interactions, maternal effects and parent of origin effects in the etiology of hypospadias. J. Urol. 188, 2354–2360 (2012).

    PubMed  PubMed Central  Google Scholar 

  114. Qin, X. Y. et al. Individual variation of the genetic response to bisphenol a in human foreskin fibroblast cells derived from cryptorchidism and hypospadias patients. PLoS ONE 7, e52756 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Andersen, H. R. et al. Paraoxonase–1 polymorphism and prenatal pesticide exposure associated with adverse cardiovascular risk profiles at school age. PLoS ONE 7, e36830 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Joensen, U. N. et al. Associations of filaggrin gene loss-of-function variants with urinary phthalate metabolites and testicular function in young Danish men. Environ. Health Perspect. 122, 345–350 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Swan, S. H. Prenatal phthalate exposure and anogenital distance in male infants. Environ. Health Perspect. 114, A88–A89 (2006).

    PubMed  PubMed Central  Google Scholar 

  118. Thankamony, A. et al. Anogenital distance and penile length in infants with hypospadias or cryptorchidism: comparison with normative data. Environ. Health Perspect. 122, 207–211 (2014).

    PubMed  Google Scholar 

  119. Hsieh, M. H., Breyer, B. N., Eisenberg, M. L. & Baskin, L. S. Associations among hypospadias, cryptorchidism, anogenital distance, and endocrine disruption. Curr. Urol. Rep. 9, 137–142 (2008).

    PubMed  Google Scholar 

  120. Gray, L. E. Jr et al. Adverse effects of environmental antiandrogens and androgens on reproductive development in mammals. Int. J. Androl. 29, 96–104 (2006).

    CAS  PubMed  Google Scholar 

  121. Scott, H. M. et al. Relationship between androgen action in the “male programming window,” fetal Sertoli cell number, and adult testis size in the rat. Endocrinology 149, 5280–5287 (2008).

    CAS  PubMed  Google Scholar 

  122. Suzuki, Y., Yoshinaga, J., Mizumoto, Y., Serizawa, S. & Shiraishi, H. Foetal exposure to phthalate esters and anogenital distance in male newborns. Int. J. Androl. 35, 236–244 (2012).

    CAS  PubMed  Google Scholar 

  123. Miao, M. et al. In utero exposure to bisphenol-A and anogenital distance of male offspring. Birth Defects Res. A Clin. Mol. Teratol. 91, 867–872 (2011).

    CAS  PubMed  Google Scholar 

  124. Hotchkiss, A. K. et al. A mixture of the “antiandrogens” linuron and butyl benzyl phthalate alters sexual differentiation of the male rat in a cumulative fashion. Biol. Reprod. 71, 1852–1861 (2004).

    CAS  PubMed  Google Scholar 

  125. Mendiola, J., Stahlhut, R. W., Jørgensen, N., Liu, F. & Swan, S. H. Shorter anogenital distance predicts poorer semen quality in young men in Rochester, New York. Environ. Health Perspect. 119, 958–963 (2011).

    PubMed  PubMed Central  Google Scholar 

  126. Eisenberg, M. L., Hsieh, M. H., Walters, R. C., Krasnow, R. & Lipshultz, L. I. The relationship between anogenital distance, fatherhood, and fertility in adult men. PLoS ONE 6, e18973 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Eisenberg, M. L., Jensen, T. K., Walters, R. C., Skakkebæk, N. E. & Lipshultz, L. I. The relationship between anogenital distance and reproductive hormone levels in adult men. J. Urol. 187, 594–598 (2012).

    CAS  PubMed  Google Scholar 

  128. Eisenberg, M. L., Shy, M., Walters, R. C. & Lipshultz, L. I. The relationship between anogenital distance and azoospermia in adult men. Int. J. Androl. 35, 726–730 (2012).

    PubMed  Google Scholar 

  129. Travison, T. G., Araujo, A. B., O'Donnell, A. B., Kupelian, V. & McKinlay, J. B. A population-level decline in serum testosterone levels in American men. J. Clin. Endocrinol. Metab. 92, 196–202 (2007).

    CAS  PubMed  Google Scholar 

  130. Andersson, A. M. et al. Secular decline in male testosterone and sex hormone binding globulin serum levels in Danish population surveys. J. Clin. Endocrinol. Metab. 92, 4696–4705 (2007).

    CAS  PubMed  Google Scholar 

  131. Perheentupa, A. et al. A cohort effect on serum testosterone levels in Finnish men. Eur. J. Endocrinol. 168, 227–233 (2013).

    CAS  PubMed  Google Scholar 

  132. Jørgensen, N. et al. Human semen quality in the new millennium: a prospective cross-sectional population-based study of 4,867 men. BMJ Open 2, e000990 (2012).

    PubMed  PubMed Central  Google Scholar 

  133. Aksglæde, L. et al. Primary testicular failure in Klinefelter's syndrome: the use of bivariate luteinizing hormone-testosterone reference charts. Clin. Endocrinol. 66, 276–281 (2007).

    Google Scholar 

  134. Andersson, A. M., Jørgensen, N., Larsen, L. F., Rajpert-De Meyts, E. & Skakkebæk, N. E. Impaired Leydig cell function in infertile men: a study of 357 idiopathic infertile men and 318 proven fertile controls. J. Clin. Endocrinol. Metab. 89, 3161–3167 (2004).

    CAS  PubMed  Google Scholar 

  135. Gracia, J., Zalabardo, J. S., Garcia, J. S., Garcia, C. & Ferrandez, A. Clinical, physical, sperm and hormonal data in 251 adults operated on for cryptorchidism in childhood. BJU Int. 85, 1100–1103 (2000).

    CAS  PubMed  Google Scholar 

  136. Werder, E. A. et al. Gonadal function in young adults after surgical treatment of cryptorchidism. Br. Med. J. 2, 1357–1359 (1976).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Blanc, T. et al. Testicular function and physical outcome in young adult males diagnosed with idiopathic 46 XY disorders of sex development during childhood. Eur. J. Endocrinol. 165, 907–915 (2011).

    CAS  PubMed  Google Scholar 

  138. Suomi, A.-M. et al. Hormonal changes in 3-month-old cryptorchid boys. J. Clin. Endocrinol. Metab. 91, 953–958 (2006).

    CAS  PubMed  Google Scholar 

  139. Pierik, F. H. et al. The hypothalamus–pituitary–testis axis in boys during the first six months of life: a comparison of cryptorchidism and hypospadias cases with controls. Int. J. Androl. 32, 453–461 (2008).

    PubMed  Google Scholar 

  140. Sathyanarayana, S., Beard, L., Zhou, C. & Grady, R. Measurement and correlates of ano-genital distance in healthy, newborn infants. Int. J. Androl. 33, 317–323 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors acknowledge the Kirsten and Freddy Johansen Foundation for supporting the start of the International Research and Research Training Centre in Male Reproduction and Child Health (EDMaRC).

Author information

Authors and Affiliations

Authors

Contributions

A.J., K.A., A.-M.A., T.K.J., N.J., K.M.M., E.R.-D.M., J.T. and N.E.S. researched the data for the article, provided substantial contribution to discussions of the content and wrote the article. A.J., K.A., A.-M.A., N.J., K.M.M., E.R.-D.M., J.T. and N.E.S. reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Anders Juul.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Juul, A., Almstrup, K., Andersson, AM. et al. Possible fetal determinants of male infertility. Nat Rev Endocrinol 10, 553–562 (2014). https://doi.org/10.1038/nrendo.2014.97

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrendo.2014.97

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing