Increased hand digit length ratio (2D:4D) is associated with increased severity of hypospadias in pre-pubertal boys

  • Fardod O’KellyEmail author
  • Keara DeCotiis
  • Fadi Zu’bi
  • Walid A. Farhat
  • Martin A. Koyle
Original Article



Hypospadias is a common congenital male disorder, with much research focusing on prenatal androgen exposure as a causative factor. Whilst digit length ratios were apparent in sexual dimorphism since the nineteenth century, their role in hypospadias remains unknown. The objective of our study was to determine the correlation between digit length (2D:4D) ratio, hypospadias severity, and anogenital distance.


Pre-pubertal boys (<3 years old) seen intra/postoperatively following hypospadias repair (June 2018–January 2019 inc.) were included. These were age-matched to non-hypospadias controls. Anthropomorphic measurements of digit lengths, penile/glans width, and anogenital distance were measured using digital calipers.


Data measurements were collected for 105 boys with hypospadias (60 distal; 45 proximal) and 55 controls. There were significant differences in 2D:4D ratios in each hand (p < 0.001), as well as individual digits (p < 0.001), and a reduced anogenital distance (p < 0.001), when comparing the proximal group with distal or control groups. There were no significant differences in glans width, or between term- and preterm births.


This study is the first to demonstrate increased 2D:4D ratios with proximal hypospadias, which also correlate with a shortened anogenital distance. This may provide a non-invasive, potentially antenatal, anthropomorphic measurement, as an indirect indicator of aberrant urogenital development.


2D: 4D ratio Hypospadias Anogenital distance (AGD) Penile width Endocrine disruptor Male programming window (MPW) Testicular dysgenesis syndrome (TDS) 




Compliance with ethical standards

Conflict of interest:

All authors declare that there are no conflicts of interest.


  1. 1.
    Wan J, Rew KT (2010) Common penile problems. Prim Care 37:627–642PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Leung AKC, Robson WLM (2007) Hypospadias: an update. Asian J Androl 9:16–22PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Baskin LS, Ebbers MB (2006) Hypospadias: anatomy, etiology, and technique. J Pediatr Surg 41:463–472PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Lind DV, Main KM, Kyhl HB, Kristensen DM, Toppari J, Andersen HR, Andersen MS, Skakkebaek NE, Jensen TK (2017) Maternal use of mild analgesics during pregnancy associated with reduced anogenital distance in sons: a cohort study of 1027 mother-child pairs. Hum Reprod 32:223–231PubMedPubMedCentralGoogle Scholar
  5. 5.
    Fernández N, Perez J, Monterrey P, Poletta FA, Bagli DJ, Lorenzo AJ, Zarante I (2017) ECLAMC Study: prevalence patterns of hypospadias in South America: multi-national analysis over a 24-year period. Int Braz J Urol 43:325–334PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Fernández N, Henao-Mejía J, Monterrey P, Pérez J, Zarante I (2012) Association between maternal prenatal vitamin use and congenital abnormalities of the genitourinary tract in a developing country. J Pediatr Urol 8:121–126PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Aschim EL, Haugen TB, Tretli S, Daltveit AK, Grotmol T (2004) Risk factors for hypospadias in Norwegian boys-association with testicular dysgenesis syndrome? Int J Androl 27:213–221PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Drake AJ, Van den Driesche S, Scott HM, Hutchinson GR, Seckl JR, Sharpe RM (2009) Glucocorticoids amplify dibutyl phthalate-induced disruption of testosterone production and male reproductive development. Endocrinology 150:5055–5064PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Samtani R, Bajpai M, Vashisht K, Ghosh PK, Saraswathy KN (2011) Hypospadias risk and polymorphism in SRD5A2 and CYP17 genes: case-control study among Indian children. J Urol 185:2334–2339PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Bowman CJ, Barlow NJ, Turner KJ, Wallace DG, Foster PMD (2003) Effects of in utero exposure to finasteride on androgen-dependent reproductive development in the male rat. Toxicol Sci 74:393–406PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Zheng Z, Armfield BA, Cohn MJ (2015) Timing of androgen receptor disruption and estrogen exposure underlies a spectrum of congenital penile anomalies. Proc Natl Acad Sci USA 112:E7194–7203PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Welsh M, Saunders PT, Fisken M, Scott HM, Hutchinson GR, Smith LB, Sharpe RM (2008) Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism. J Clin Invest 118:1479–1490PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Welsh M, MacLeod DJ, Walker M, Smith LB, Sharpe RM (2010) Critical androgen-sensitive periods of rat penis and clitoris development. Int J Androl 33:e144–e152PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Nguyen T-V, Monnier P, Muckle G, Sathyanarayana S, Oullet E, Velez MP, Dodds L, Arbuckle TE (2019) Androgenic and estrogenic indices in human newborns and infants: the MIREC-ID study. J Dev Orig Health Dis 10(5):578–586PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Manning JT, Henzi P, Bundred PE (2001) The ratio of 2nd to 4th digit length: a proxy for testosterone, and susceptibility to HIV and AIDS? Med Hypotheses 57:761–763PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Manning JT, Scutt D, Wilson J, Lewis-Jones DI (1998) The ratio of 2nd to 4th digit length: a predictor of sperm numbers and concentrations of testosterone, luteinizing hormone and oestrogen. Hum Reprod 13:3000–3004PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Ronalds G, Phillips DIW, Godfrey KM, Manning JT (2002) The ratio of second to fourth digit lengths: a marker of impaired fetal growth? Early Hum Dev 68:21–26PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Lutchmaya S, Baron-Cohen S, Raggatt P, Knickmeyer R, Manning JT (2004) 2nd to 4th digit ratios, fetal testosterone and estradiol. Early Hum Dev 77:23–28PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Manning JT (2002) The ratio of 2nd to 4th digit length and performance in skiing. J Sports Med Phys Fitness 42:446–450PubMedPubMedCentralGoogle Scholar
  20. 20.
    Manning JT, Taylor RP (2001) Second to fourth digit ratio and male ability in sport: implications for sexual selection in humans. Evol Hum Behav 22:61–69PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Robinson SJ, Manning JT (2000) The ratio of 2nd to 4th digit length and male homosexuality. Evol Hum Behav 21:333–345PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Wallien MSC, Zucker KJ, Steensma TD, Kettenis PT (2008) 2D:4D finger-length ratios in children and adults with gender identity disorder. Horm Behav 54:450–454PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Brown WM, Hines M, Fane BA, Breedlove SM (2002) Masculinized finger length patterns in human males and females with congenital adrenal hyperplasia. Horm Behav 42:380–386PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Okten A, Kalyoncu M, Yariş N (2002) The ratio of second- and fourth-digit lengths and congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Early Hum Dev 70:47–54PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Dean A, Sharpe RM (2013) Clinical review: Anogenital distance or digit length ratio as measures of fetal androgen exposure: relationship to male reproductive development and its disorders. J Clin Endocrinol Metab 98:2230–2238PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Cox K, Kyriakou A, Amjad B, Toole S, Flett ME, Welsh M, Ahmed SF, Cascio S (2017) Shorter anogenital and anoscrotal distances correlate with the severity of hypospadias: A prospective study. J Pediatr Urol 13:57.e1–57.e5CrossRefGoogle Scholar
  27. 27.
    Thankamony A, Lek N, Carroll D, Williams M, Dunger DB, Acerini CL, Ong KK, Hughes IA (2014) Anogenital distance and penile length in infants with hypospadias or cryptorchidism: comparison with normative data. Environ Health Perspect 122:207–211PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Hsieh MH, Eisenberg ML, Hittelman AB, Wilson JM, Tasian GE, Baskin LS (2012) Caucasian male infants and boys with hypospadias exhibit reduced anogenital distance. Hum Reprod 27:1577–1580PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Eisenberg ML, Hsieh MH, Walters RC, Krasnow R, Lipshultz LI (2011) The relationship between anogenital distance, fatherhood, and fertility in adult men. PLoS ONE ONE 6:e18973CrossRefGoogle Scholar
  30. 30.
    Cárceles AB, Sanchez-Rodriguez C, Vera-Porras EM, -Gonzalo JJ, Celdran J, Samper-Mateo P, Escudero D, Torres-Roca M, Martinez-Diaz F, Mendiola J, Cantero AM (2017) Anogenital distance, a biomarker of prenatal androgen exposure is associated with prostate cancer severity. Prostate 77:406–411PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Van den Driesche S, Kilcoyne KR, Wagner I, Rebourcet D, Boyle A, Mitchell R, McKinnell C, Macpherson S, Donat R, Shukla CJ, Jorgensen A, Meyts ER, Skakkebaek NE, Sharpe RM (2017) Experimentally induced testicular dysgenesis syndrome originates in the masculinization programming window. JCI Insight 2(6):e91204PubMedPubMedCentralGoogle Scholar
  32. 32.
    Abbo O, Ferdynus C, Kalfa N, Huiart L, Sauvat F, Harper LH (2015) Male infants with hypospadias and/or cryptorchidism show a lower 2D/4D digit ratio than normal boys. Arch Dis Child 100:643–647PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Saillenfait A-M, Sabate JP, Robert A, Cossec B, Roudot AC, Denis F, Burgart M (2013) Adverse effects of diisooctyl phthalate on the male rat reproductive development following prenatal exposure. Reprod Toxicol 42:192–202PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Cunha GR, Sinclair A, Risbridger G, Hutson J, Baskin LS (2015) Current understanding of hypospadias: relevance of animal models. Nat. Rev. Urol. 12:271–280PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Kim TS, Jung KK, Kim SS, Kang IH, Baek JH, Nam HS, Hong SK, Lee BM, Hong JT, Oh KW, Kim HS, Han SY, Kang TS (2010) Effects of in utero exposure to DI(n-Butyl) phthalate on development of male reproductive tracts in Sprague-Dawley rats. J Toxicol Environ Health A 73:1544–1559PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Wen K, Zhou X, Yang J, Zhu Y (2018) Effect of flutamide exposed during pregnancy on reproductive organs development and oxidative stress responsein in male mice offspring. Wei Sheng Yan Jiu 47:974–978PubMedPubMedCentralGoogle Scholar
  37. 37.
    Arbuckle TE, Agarwal A, MacPherson SH, Fraser WD, Sathyanarayana S, Ramsay T, Dodds L, Muckle G, Fisher M, Foster W, Walker M, Monnier P (2018) Prenatal exposure to phthalates and phenols and infant endocrine-sensitive outcomes: The MIREC study. Environ Int 120:572–583PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Richards G, Gomes M, Ventura T (2019) Testosterone measured from amniotic fluid and maternal plasma shows no significant association with directional asymmetry in newborn digit ratio (2D:4D). J Dev Orig Health Dis 10:362–367PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Sharpe RM (2003) The ’oestrogen hypothesis’- where do we stand now? Int J Androl 26:2–15PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Takahashi T, Shimotakahara A, Miyahara K, Lane GJ, Yamataka A (2013) Activating transcription factor 3 is not up-regulated in hypospadias patients in Japan. Afr J Paediatr Surg 10:371–373PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Manno FAM (2008) Measurement of the digit lengths and the anogenital distance in mice. Physiol Behav 93:364–368PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Zhou Y-J, Wei J-F, Zhang L-F, Wang Y, Zhang W (2012) Expression of Notch1 in the genital tubercle of male rats with hypospadias induced by Di-n-butyl phthalate. Zhonghua Nan Ke Xue 18:222–226PubMedPubMedCentralGoogle Scholar
  43. 43.
    Kluth D, Fiegel HC, Geyer C, Metzger R (2011) Embryology of the distal urethra and external genitals. Semin Pediatr Surg 20:176–187PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Sonne SB, -Hansen CE, Fisher JS, Leffers H, Meyts E, Skakkebaek NE (2004) Do environmental factors play a role in the aetiology of carcinoma in situ testis and the testicular dysgenesis syndrome? Verh Dtsch Ges Pathol 88:144–151PubMedPubMedCentralGoogle Scholar
  45. 45.
    Wohlfahrt-Veje C, Main KM, Skakkebaek NE (2009) Testicular dysgenesis syndrome: foetal origin of adult reproductive problems. Clin Endocrinol (Oxf) 71:459–465CrossRefGoogle Scholar
  46. 46.
    Faasse MA, Josnson EK, Bowen DK, Lindgren BW, Maizels M, Marcus CR, Jovanovic BD, Yerkes EB (2016) Is glans penis width a risk factor for complications after hypospadias repair? J Pediatr Urol 12:202.e1–202.e5CrossRefGoogle Scholar
  47. 47.
    Bush NC, Villanueva C, Snodgrass W (2015) Glans size is an independent risk factor for urethroplasty complications after hypospadias repair. J Pediatr Urol 11:355.e1–355.e5CrossRefGoogle Scholar
  48. 48.
    Snodgrass WT, Villanueva C, Granberg C, Bush NC (2014) Objective use of testosterone reveals androgen insensitivity in patients with proximal hypospadias. J Pediatr Urol 10:118–122PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Fardod O’Kelly
    • 1
    Email author
  • Keara DeCotiis
    • 1
  • Fadi Zu’bi
    • 1
  • Walid A. Farhat
    • 1
  • Martin A. Koyle
    • 1
  1. 1.Division of UrologyThe Hospital for Sick ChildrenTorontoCanada

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