Abstract
The anogenital distance (AGD) refers to the distance between the anus and the external genitalia. In mammals such as humans, mice, rats, and cats, the AGD is close to twice as long in males than in females. This sexual dimorphism is caused by the hormone-dependent sexual development in utero, where high androgen levels in male fetuses promote masculinization of the reproductive system and the body more generally. The absence of high androgen levels in female fetuses helps promote feminization of the reproductive system. This dependence of the sex steroid hormone milieu on establishing the sexual phenotypes, including the length of the AGD, has established AGD as a noninvasive biomarker for androgen action during fetal development. Importantly, suboptimal androgen levels in utero can lead to various male reproductive disorders such undescended testes, hypospadias, and infertility later in life. Thus, a short male AGD signals not only suboptimal androgen action during development but is also associated with male reproductive disorders more broadly. This fact is exploited in animal toxicity studies to screen for chemical substances suspected to be harmful to human reproductive health but is also used in some human epidemiology studies.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Abbreviations
- ADI:
-
Accepted daily Intake
- AGD:
-
Anogenital distance
- AGDi:
-
Anogenital distance index
- AR:
-
Androgen receptor
- DHT:
-
Dihydrotestosterone
- EDC:
-
Endocrine-disrupting chemical
- GD:
-
Gestational day
- LABC:
-
Levator ani/bulbocavernosus
- NOAEL:
-
No observed adverse effect level
- OECD:
-
Organization for Economic Cooperation and Development
- PND:
-
Postnatal day
- Sox9:
-
SRY-box transcription factor 9
- Sry:
-
Sex-determining region of the Y chromosome
- T:
-
Testosterone
- TDI:
-
Tolerable daily intake
- TG :
-
Test guideline
References
Abbott DH, Barnett DK, Bruns CM, Dumesic DA. Androgen excess fetal programming of female reproduction: a developmental aetiology for polycystic ovary syndrome? Hum Reprod Update. 2005;11:357–74.
Bornehag CG, Carlstedt F, Jönsson BA, Lindh CH, Jensen TK, Bodin A, Jonsson C, Janson S, Swan SH. Prenatal phthalate exposures and anogenital distance in Swedish boys. Environ Health Perspect. 2015;123:101–7.
Chang C, Saltzman A, Yeh S, Young W, Keller E, Lee HJ, Wang C, Mizokami A. Androgen receptor: an overview. Crit Rev Eukaryot Gene Expr. 1995;5:97–125.
Davey RA, Grossmann M. Androgen receptor structure, function and biology: from bench to bedside. Clin Biochem Rev. 2016;37:3–15.
Eisenberg ML, Hsieh MH, Walters RC, Krasnow R, Lipshultz LI. The relationship between anogenital distance, fatherhood, and fertility in adult men. PLoS One. 2011;6:e18973.
Eisenberg ML, Jensen TK, Walters RC, Skakkebaek NE, Lipshultz LI. The relationship between anogenital distance and reproductive hormone levels in adult men. J Urol. 2012;187:594–8.
Fischer MB, Ljubicic ML, Hagen CP, Thankamony A, Ong K, Hughes I, Jensen TK, Main KM, Petersen JH, Busch AS, Upners EN, Sathyanarayana S, Swan SH. Anogenital distance in healthy infants: method-, age- and sex-related reference ranges. J Clin Endocrinol Metab. 2020;105:2996–3004.
Gallavan RHJ, Holson JF, Stump DG, Knapp JF, Reynolds VL. Interpreting the toxicologic significance of alterations in anogenital distance: potential for confounding effects of progeny body weights. Reprod Toxicol. 1999;13:383–90.
Hsieh MH, Breyer BN, Eisenberg ML, Baskin LS. Associations among hypospadias, cryptorchidism, anogenital distance, and endocrine disruption. Curr Urol Rep. 2008;9:137–42.
Hsieh MH, Eisenberg ML, Hittelman AB, Wilson JM, Tasian GE, Baskin LS. Caucasian male infants and boys with hypospadias exhibit reduced anogenital distance. Hum Reprod. 2012;27:1577–80.
Jain VG, Singal AK. Shorter anogenital distance correlates with undescended testis: a detailed genital anthropometric analysis in human newborns. Hum Reprod. 2013;28:2343–9.
MacLeod DJ, Sharpe RM, Welsh M, Fisken M, Scott HM, Hutchison GR, Drake AJ, van den Driesche S. Androgen action in the masculinization programming window and development of male reproductive organs. Int J Androl. 2010;33:279–87.
Mendiola J, Stahlhut RW, Jorgensen N, Liu F, Swan SH. Shorter anogenital distance predicts poorer semen quality in young men in Rochester, New York. Environ Health Perspect. 2011;119:958–63.
Mira-Escolano MP, Mendiola J, MÃnguez-Alarcón L, Melgarejo M, Cutillas-TolÃn A, Roca M, López-EspÃn JJ, Noguera-Velasco JA, Torres-Cantero AM. Longer anogenital distance is associated with higher testosterone levels in women: a cross-sectional study. BJOG. 2014;121:1359–64.
Moreno-Mendoza D, Casamonti E, Riera-Escamilla A, Pietroforte S, Corona G, Ruiz-Castañe E, Krausz C. Short anogenital distance is associated with testicular germ cell tumour development. Andrology. 2020;8:1770–8.
OECD. Guidance document on mammalian reproductive toxicity testing and assessment. OECD series on testing and assessment no. 43. 2008.
OECD. Test no. 414: prenatal development toxicity study, OECD guidelines for the testing of chemicals, section 4. Paris: OECD Publishing; 2018.
Salazar-Martinez E, Romano-Riquer P, Yanez-Marquez E, Longnecker MP, Hernandez-Avila M. Anogenital distance in human male and female newborns: a descriptive, cross-sectional study. Environ Health. 2004;3:8.
Schwartz CL, Christiansen S, Vinggaard AM, Axelstad M, Hass U, Svingen T. Anogenital distance as a toxicological or clinical marker for fetal androgen action and risk for reproductive disorders. Arch Toxicol. 2019;93:253–72.
Sharpe M. Androgens and the masculinization programming window: human–rodent differences. Biochem Soc Trans. 2020;48:1725–35.
Sharpe RM. Phthalate exposure during pregnancy and lower anogenital index in boys: wider implications for the general population? Environ Health Perspect. 2005;113:A504–5.
Svingen T, Koopman P. Building the mammalian testis: origins, differentiation, and assembly of the component cell populations. Genes Dev. 2013;27:2409–26.
Swan SH, Main KM, Liu F, et al. Decrease in anogenital distance among male infants with prenatal phthalate exposure [published correction appears in Environ Health Perspect. 2005;113(9):A583]. Environ Health Perspect. 2005;113(8):1056–1061. https://doi.org/10.1289/ehp.8100
Thankamony A, Lek N, Carroll D, Williams M, Dunger DB, Acerini CL, Ong KK, Hughes IA. Anogenital distance and penile length in infants with hypospadias or cryptorchidism: comparison with normative data. Environ Health Perspect. 2014;122:207–11.
Thankamony A, Pasterski V, Ong KK, Acerini CL, Hughes IA. Anogenital distance as a marker of androgen exposure in humans. Andrology. 2016;4:616–25.
Welsh M, Saunders PT, Fisken M, Scott HM, Hutchison GR, Smith LB, Sharpe RM. Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism. J Clin Invest. 2008;118:1479–90.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2023 Springer Nature Switzerland AG
About this entry
Cite this entry
Svingen, T., Hass, U., Schwartz, C.L., Christiansen, S. (2023). Anogenital Distance: Features, Measures, and Uses as a Biomarker for Toxicity In Utero. In: Patel, V.B., Preedy, V.R., Rajendram, R. (eds) Biomarkers in Toxicology. Biomarkers in Disease: Methods, Discoveries and Applications. Springer, Cham. https://doi.org/10.1007/978-3-031-07392-2_37
Download citation
DOI: https://doi.org/10.1007/978-3-031-07392-2_37
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-031-07391-5
Online ISBN: 978-3-031-07392-2
eBook Packages: Biomedical and Life SciencesReference Module Biomedical and Life Sciences