Editing Digit ratio (section)

==Effect of prenatal hormones==
It has been proposed that 2D:4D ratio is affected by [[fetus|fetal]] exposure to [[sex hormone]]s, in particular to [[testosterone]] and other [[androgen]]s. Lower 2D:4D is found to correlate with higher prenatal androgen exposure.<ref name="Zheng_2011">{{cite journal | vauthors = Zheng Z, Cohn MJ | title = Developmental basis of sexually dimorphic digit ratios | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 39 | pages = 16289–16294 | date = September 2011 | pmid = 21896736 | pmc = 3182741 | doi = 10.1073/pnas.1108312108 | doi-access = free }}</ref><ref name="Hönekopp_2007"/><ref name="Brown_2002" /><ref name="Okten_2002" /><ref>{{cite journal | vauthors = Rivas MP, Moreira LM, Santo LD, Marques AC, El-Hani CN, Toralles MB | title = New studies of second and fourth digit ratio as a morphogenetic trait in subjects with congenital adrenal hyperplasia | journal = American Journal of Human Biology | volume = 26 | issue = 4 | pages = 559–561 | year = 2014 | pmid = 24668932 | doi = 10.1002/ajhb.22545 | s2cid = 7711519 }}</ref><ref name="Manning_2013">{{cite journal | vauthors = Manning JT, Kilduff LP, Trivers R | title = Digit ratio (2D:4D) in Klinefelter's syndrome | journal = Andrology | volume = 1 | issue = 1 | pages = 94–99 | date = January 2013 | pmid = 23258636 | doi = 10.1111/j.2047-2927.2012.00013.x | s2cid = 4503281 }}</ref><ref>{{cite journal | vauthors = Ventura T, Gomes MC, Pita A, Neto MT, Taylor A | title = Digit ratio (2D:4D) in newborns: influences of prenatal testosterone and maternal environment | journal = Early Human Development | volume = 89 | issue = 2 | pages = 107–112 | date = February 2013 | pmid = 23017880 | doi = 10.1016/j.earlhumdev.2012.08.009 | hdl = 10400.17/772 | hdl-access = free }}</ref><ref>{{cite journal | vauthors = McIntyre MH | title = The use of digit ratios as markers for perinatal androgen action | journal = Reproductive Biology and Endocrinology | volume = 4 | pages = 10 | date = February 2006 | pmid = 16504142 | pmc = 1409789 | doi = 10.1186/1477-7827-4-10 | doi-access = free }}</ref> Therefore digit ratio could be considered a [[proxy variable]] (indirect measure) for prenatal androgen exposure. Various studies suggest that 2D:4D is also influenced by prenatal [[estrogen]] exposure, and that it correlates negatively, not with prenatal testosterone alone, but with the testosterone-to-estrogen ratio.<ref name="Lutchmaya_2004">{{cite journal | vauthors = Lutchmaya S, Baron-Cohen S, Raggatt P, Knickmeyer R, Manning JT | title = 2nd to 4th digit ratios, fetal testosterone and estradiol | journal = Early Human Development | volume = 77 | issue = 1–2 | pages = 23–28 | date = April 2004 | pmid = 15113628 | doi = 10.1016/j.earlhumdev.2003.12.002 }}</ref><ref name="Mayhew_2007" /><ref name="Malas_2006">{{cite journal | vauthors = Malas MA, Dogan S, Evcil EH, Desdicioglu K | title = Fetal development of the hand, digits and digit ratio (2D:4D) | journal = Early Human Development | volume = 82 | issue = 7 | pages = 469–475 | date = July 2006 | pmid = 16473482 | doi = 10.1016/j.earlhumdev.2005.12.002 }}</ref><ref>{{cite journal | vauthors = Dean A, Sharpe RM | title = Clinical review: Anogenital distance or digit length ratio as measures of fetal androgen exposure: relationship to male reproductive development and its disorders | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 98 | issue = 6 | pages = 2230–2238 | date = June 2013 | pmid = 23569219 | doi = 10.1210/jc.2012-4057 | doi-access = free }}</ref>

Prenatal hormone exposure can be measured via [[amniocentesis]] (usually performed between 14th and 20th weeks of pregnancy), maternal [[blood test|serum sampling]] and umbilical cord sampling at birth, the latter being a measure of exposure in late [[gestation]]. A 2024 meta-analysis has suggested that digit ratio may be related to amniotic fluid testosterone levels, but not umbilical cord levels, requiring further validation.<ref>{{Cite journal |last1=Sorokowski |first1=Piotr |last2=Kowal |first2=Marta |date=5 October 2023 |title=Relationship between the 2D : 4D and prenatal testosterone, adult level testosterone, and testosterone change: Meta-analysis of 54 studies |url=https://onlinelibrary.wiley.com/doi/10.1002/ajpa.24852 |journal=American Journal of Biological Anthropology |volume=183 |issue=1 |pages=20–38 |language=en |doi=10.1002/ajpa.24852 |pmid=37795916 |s2cid=263670473 |issn=2692-7691|url-access=subscription }}</ref> 

A 2011 paper by Zhengui Zheng and Martin J. Cohn reports that "the 2D:4D ratio in mice is controlled by the balance of androgen to estrogen signaling during a narrow window of digit development".<ref name="Zheng_2011" /> The formation of the digits in humans, in utero, is thought to occur by 13 weeks, and the bone-to-bone ratio is consistent from this point into an individual's adulthood.<ref>{{cite journal | vauthors = Garn SM, Burdi AR, Babler WJ, Stinson S | title = Early prenatal attainment of adult metacarpal-phalangeal rankings and proportions | journal = American Journal of Physical Anthropology | volume = 43 | issue = 3 | pages = 327–332 | date = November 1975 | pmid = 1211429 | doi = 10.1002/ajpa.1330430305 | hdl = 2027.42/37557 | hdl-access = free }}</ref> If, during this period, the fetus is exposed to androgens (levels of which are usually far higher in male than female fetuses) the growth rate of the 4th digit is increased. In a 2006 study, digit ratio analysis of opposite-sex [[dizygotic twins]] found that the females in these pairings were born with significantly lower 2D:4D ratio, postulated to occur from exposure to excess androgens from their brothers in utero (the hormone-transfer theory).<ref>{{cite journal | vauthors = van Anders SM, Vernon PA, Wilbur CJ | title = Finger-length ratios show evidence of prenatal hormone-transfer between opposite-sex twins | journal = Hormones and Behavior | volume = 49 | issue = 3 | pages = 315–319 | date = March 2006 | pmid = 16143332 | doi = 10.1016/j.yhbeh.2005.08.003 | s2cid = 17288420 | hdl = 2027.42/83921 | hdl-access = free }}</ref> However, an attempt to replicate these findings with a larger sample of dizygotic twins (867 individuals) found no differences in the [[variance]] or [[co-variance]] of same-sex and opposite-sex pairings to support the theory, though it did confirm female 2D:4D to be significantly higher than male as expected.<ref>{{Cite journal |vauthors=Medland SE, Loehlin JC, Martin NG |date=1 April 2008 |title=No effects of prenatal hormone transfer on digit ratio in a large sample of same- and opposite-sex dizygotic twins |url=https://www.sciencedirect.com/science/article/pii/S0191886907004230 |journal=Personality and Individual Differences |language=en |volume=44 |issue=5 |pages=1225–1234 |doi=10.1016/j.paid.2007.11.017 |issn=0191-8869 |access-date=10 June 2023 |archive-date=28 November 2012 |archive-url=https://web.archive.org/web/20121128133338/http://www.sciencedirect.com/science/article/pii/S0191886907004230 |url-status=live |url-access=subscription }}</ref>

Researchers have raised concerns that, although the general trend points towards a correlation between digit ratio and early androgen exposure, many results have not been statistically significant.<ref name="Richards_2017">{{cite journal | vauthors = Richards G | title = Digit ratio (2D:4D) and prenatal/perinatal sex hormones: A response to Manning and Fink (2017) | journal = Early Human Development | volume = 113 | pages = 75–76 | date = October 2017 | pmid = 28917583 | doi = 10.1016/j.earlhumdev.2017.09.004 | url = https://eprint.ncl.ac.uk/fulltext.aspx?url=249530/77FA418E-6576-4475-A6B5-EEE33F7CAF94.pdf&pub_id=249530 }}</ref>

Various findings have also challenged the general trend. One study of 66 children that attempted to replicate the findings of a frequently cited paper on the topic<ref name="Lutchmaya_2004" /> found no association between prenatal testosterone and estrogen levels and 2D:4D in childhood.<ref name="Richards_2021">{{cite journal | vauthors = Richards G, Browne WV, Constantinescu M | title = Digit ratio (2D:4D) and amniotic testosterone and estradiol: an attempted replication of Lutchmaya ''et al.'' (2004) | journal = Journal of Developmental Origins of Health and Disease | volume = 12 | issue = 6 | pages = 859–864 | date = December 2021 | pmid = 33472723 | doi = 10.1017/S2040174420001294 | s2cid = 231664924 | url = https://repository.uel.ac.uk/download/80146174549c10eed26a47263c60f382cfb6cac134adaa6fa3e297afd005044b/349843/Richards%2C%20Brown%20and%20Constantinescu.pdf | access-date = 23 March 2022 | archive-date = 2 April 2022 | archive-url = https://web.archive.org/web/20220402034729/https://repository.uel.ac.uk/download/80146174549c10eed26a47263c60f382cfb6cac134adaa6fa3e297afd005044b/349843/Richards%2C%20Brown%20and%20Constantinescu.pdf | url-status = live }}</ref> Another paper also found no relationship between 2D:4D ratios and umbilical cord androgen and estrogen levels.<ref name="research-repository.uwa.edu.au">{{cite journal | vauthors = Hollier LP, Keelan JA, Jamnadass ES, Maybery MT, Hickey M, Whitehouse AJ | title = Adult digit ratio (2D:4D) is not related to umbilical cord androgen or estrogen concentrations, their ratios or net bioactivity | journal = Early Human Development | volume = 91 | issue = 2 | pages = 111–117 | date = February 2015 | pmid = 25594498 | doi = 10.1016/j.earlhumdev.2014.12.011 | url = https://research-repository.uwa.edu.au/en/publications/b3d44281-0fcf-499c-9743-7daac128c486 }}</ref> A large meta-analysis studying genomic correlations was unable to find evidence for 2D:4D being a marker for prenatal androgen exposure, but did not exclude the possibility given constraints in genomic knowledge (with 3.8% of the variance in 2D:4D ratio accounted for genetically).<ref>{{cite journal | vauthors = Warrington NM, Shevroja E, Hemani G, Hysi PG, Jiang Y, Auton A, Boer CG, Mangino M, Wang CA, Kemp JP, McMahon G, Medina-Gomez C, Hickey M, Trajanoska K, Wolke D, Ikram MA, Montgomery GW, Felix JF, Wright MJ, Mackey DA, Jaddoe VW, Martin NG, Tung JY, Davey Smith G, Pennell CE, Spector TD, van Meurs J, Rivadeneira F, Medland SE, Evans DM | display-authors = 6 | title = Genome-wide association study identifies nine novel loci for 2D:4D finger ratio, a putative retrospective biomarker of testosterone exposure in utero | journal = Human Molecular Genetics | volume = 27 | issue = 11 | pages = 2025–2038 | date = June 2018 | pmid = 29659830 | pmc = 5961159 | doi = 10.1093/hmg/ddy121 }}</ref>

===Developmental disorders===
Women with [[congenital adrenal hyperplasia]] (CAH), who have elevated androgen levels before birth, have lower (more masculine) 2D:4D on average<ref name="Brown_2002">{{cite journal | vauthors = Brown WM, Hines M, Fane BA, Breedlove SM | title = Masculinized finger length patterns in human males and females with congenital adrenal hyperplasia | journal = Hormones and Behavior | volume = 42 | issue = 4 | pages = 380–386 | date = December 2002 | pmid = 12488105 | doi = 10.1006/hbeh.2002.1830 | s2cid = 8886238 }}</ref><ref name="Okten_2002">{{cite journal | vauthors = Okten A, Kalyoncu M, Yariş N | title = The ratio of second- and fourth-digit lengths and congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Early Human Development | volume = 70 | issue = 1–2 | pages = 47–54 | date = December 2002 | pmid = 12441204 | doi = 10.1016/s0378-3782(02)00073-7 }}</ref><ref name="Ciumas_2009">{{cite journal | vauthors = Ciumas C, Lindén Hirschberg A, Savic I | title = High fetal testosterone and sexually dimorphic cerebral networks in females | journal = Cerebral Cortex | volume = 19 | issue = 5 | pages = 1167–1174 | date = May 2009 | pmid = 18854582 | doi = 10.1093/cercor/bhn160 | doi-access = free }}</ref> along with other possible physiological effects such as an enlarged [[clitoris]] and shallow [[vagina]].<ref>{{cite book| vauthors = McAnulty RD, Burnette MM |year= 2006| url= https://books.google.com/books?id=KBi9aG0pQAkC&pg=PA165 |title= Sex and sexuality | volume = 1 | publisher= [[Greenwood Publishing Group]]| page= 165| isbn= 9780313049194}}</ref> Males with CAH also express lower digit ratios than [[case–control study|controls]].<ref name="Brown_2002" /><ref name="Okten_2002" /> Amniocentesis samples in males with CAH show that prenatal levels of testosterone are in the high-normal range and levels of the weaker androgen [[androstenedione]] are several fold higher than in controls,<ref name="Pang_1980">{{cite journal | vauthors = Pang S, Levine LS, Cederqvist LL, Fuentes M, Riccardi VM, Holcombe JH, Nitowsky HM, Sachs G, Anderson CE, Duchon MA, Owens R, Merkatz I, New MI | display-authors = 6 | title = Amniotic fluid concentrations of delta 5 and delta 4 steroids in fetuses with congenital adrenal hyperplasia due to 21 hydroxylase deficiency and in anencephalic fetuses | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 51 | issue = 2 | pages = 223–229 | date = August 1980 | pmid = 6447160 | doi = 10.1210/jcem-51-2-223 }}</ref><ref name="Dörr_1993">{{cite journal | vauthors = Dörr HG, Sippell WG | title = Prenatal dexamethasone treatment in pregnancies at risk for congenital adrenal hyperplasia due to 21-hydroxylase deficiency: effect on midgestational amniotic fluid steroid levels | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 76 | issue = 1 | pages = 117–120 | date = January 1993 | doi = 10.1210/jcem.76.1.8421074 | pmid = 8421074 }}</ref><ref name="Wudy_1999">{{cite journal | vauthors = Wudy SA, Dörr HG, Solleder C, Djalali M, Homoki J | title = Profiling steroid hormones in amniotic fluid of midpregnancy by routine stable isotope dilution/gas chromatography-mass spectrometry: reference values and concentrations in fetuses at risk for 21-hydroxylase deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 84 | issue = 8 | pages = 2724–2728 | date = August 1999 | doi = 10.1210/jcem.84.8.5870 | pmid = 10443667 | doi-access = free }}</ref> indicating that males with CAH are exposed to greater prenatal concentrations of total androgens.

A greater (more feminine) digit ratio occurs for men with [[Klinefelter's syndrome]], who have reduced testosterone secretion throughout life compared to their fathers or to controls.<ref name=Manning_2013/>

Digit ratio in men may correlate with genetic variation in the [[androgen receptor]] gene.<ref name="Manning_2003">{{Cite journal |doi=10.1016/S1090-5138(03)00052-7 |title=The second to fourth digit ratio and variation in the androgen receptor gene |year=2003 |vauthors = Manning JT, Bundred PE, Newton DJ, Flanagan BF |journal=Evolution and Human Behavior |volume=24 |pages=399–405 |issue=6 |bibcode=2003EHumB..24..399M }}</ref> Men with genes that produce androgen receptors that are less sensitive to testosterone (because they have more [[CAG repeats]]) have greater digit ratios, though there have also been reports of failure in replicating this finding.<ref>{{Cite journal| vauthors = Hampson E, Sankar JS |title=Re-examining the Manning hypothesis: androgen receptor polymorphism and the 2D:4D ratio |journal=Evol Hum Behav |volume=33 | issue= 5|pages=557–561 |year=2012 |doi=10.1016/j.evolhumbehav.2012.02.003|bibcode=2012EHumB..33..557H }}</ref> Men with less sensitive androgen receptors may compensate for this by secreting more testosterone via reduced inhibitory feedback on [[gonadotropins]].<ref>{{cite journal | vauthors = Crabbe P, Bogaert V, De Bacquer D, Goemaere S, Zmierczak H, Kaufman JM | title = Part of the interindividual variation in serum testosterone levels in healthy men reflects differences in androgen sensitivity and feedback set point: contribution of the androgen receptor polyglutamine tract polymorphism | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 92 | issue = 9 | pages = 3604–3610 | date = September 2007 | pmid = 17579205 | doi = 10.1210/jc.2007-0117 | s2cid = 33761349 | doi-access = free }}</ref> Thus, it is not clear that 2D:4D would be expected to correlate with CAG repeats, even if it accurately reflects prenatal androgen.

XY individuals with [[androgen insensitivity syndrome]] due to a dysfunctional gene for the androgen receptor present as women and have greater digit ratios on average, as would be predicted if androgenic hormones affect digit ratios. This finding suggests that the sex difference in digit ratios may be unrelated to the [[Y chromosome]] per se.<ref>{{cite journal | vauthors = Berenbaum SA, Bryk KK, Nowak N, Quigley CA, Moffat S | title = Fingers as a marker of prenatal androgen exposure | journal = Endocrinology | volume = 150 | issue = 11 | pages = 5119–5124 | date = November 2009 | pmid = 19819951 | pmc = 2775980 | doi = 10.1210/en.2009-0774 }}</ref>