The ratio of 2nd to 4th digit length: A new predictor of disease predisposition?

doi:10.1054/mehy.1999.1150

Medical Hypotheses

Volume 54, Issue 5, May 2000, Pages 855-857

https://doi.org/10.1054/mehy.1999.1150 Get rights and content

Abstract

The ratio between the length of the 2nd and 4th digits is: (a) fixed in utero; (b) lower in men than in women; (c) negatively related to testosterone and sperm counts; and (d) positively related to oestrogen concentrations. Prenatal levels of testosterone and oestrogen have been implicated in infertility, autism, dyslexia, migraine, stammering, immune dysfunction, myocardial infarction and breast cancer. We suggest that 2D:4D ratio is predictive of these diseases and may be used in diagnosis, prognosis and in early life-style interventions which may delay the onset of disease or facilitate its early detection.

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Cited by (150)

2D:4D ratio, alexithymia, impulsivity, aggression, and ADHD in men with opioid and methamphetamine use disorders: A comparative analysis with healthy controls
2024, Early Human Development
Substance use disorder is an important mental health problem with increasing frequency. This study aims to investigate the 2D:4D ratio, Dr-I values (right-left differences), alexithymia, aggression, impulsivity, and attention deficit hyperactivity disorder (ADHD) symptoms in male patients with methamphetamine use disorder (MUD), opioid use disorder (OUD), and healthy controls. The study included a total of 57 male patients diagnosed with OUD, 42 male patients diagnosed with MUD, and 72 healthy male controls. The study indicated that the OUD and MUD patients were significantly different from the healthy controls in terms of the 2D:4D ratio, alexithymia, impulsivity, aggression, and ADHD. Compared to healthy controls, 2D:4D ratios, and Dr-I values were lower in OUD and MUD patients. OUD and MUD patients had higher scores of alexithymia, impulsivity, aggression, and ADHD compared to healthy controls. There were statistically significant negative correlations between the right-hand 2D:4D ratios and the ADHD, impulsivity, alexithymia and aggression scores and a significant negative correlation between Dr-I scores and the impulsivity scores of MUD and OUD patients. These findings contribute to the existing literature examining the complex relationship between prenatal testosterone exposure, substance use disorders and related psychological traits.
Patients with developmental dysplasia of the hip shows higher digit ratio (2D:4D)
2023, Early Human Development
Developmental dysplasia of the hip (DDH) encompasses a range of hip disorders, from dysplasia to dislocation. One key factor is sex, with women being four to eight times more susceptible to DDH than men. However, there have been no studies investigating the second-to-fourth digit ratio (2D:4D), a biomarker of prenatal sex steroid exposure, in DDH patients. This study aimed to explore whether there is an association between the 2D:4D ratio and DDH.
Digital calipers were used to measure the second and fourth finger lengths of 250 patients treated for DDH and 200 patients in the healthy control group between January 2020 and January 2023. The Mann-Whitney U test was used for non-normally distributed variables and two-way analysis of variance to assess differences in measurements between DDH patients based on sex, side, and the interaction of sex and side. The intraclass correlation coefficient (ICC) was used to assess measurement repeatability.
The median (min-max) age was 10.00 (6–16) years in the DDH group, 12.00 (6–16) years in the control group, and 10 (6–16) years for the whole cohort. There was no significant difference in terms of age between the patient and control groups (p = 0.083). When comparing the DDH group with controls the former showed higher right 2D:4D and Δ2D:4D and these differences were significant in both males and females. Among the patients, controlling for side of dysplasia did not affect right 2D:4D, left 2D:4D or Δ2D:4D.
There was a significant association between higher 2D:4D ratios (both right and left hands) and DDH in both men and women. This indicates that the 2D:4D ratio, a marker of intrauterine estrogen/testosterone balance, is associated with DDH.
Digital biomarker 2D:4D as a predictor of cancer: A systematic review
2022, Early Human Development
Citation Excerpt :
They show that this biomarker is a potentially useful indicator that may be associated with gestational T levels, T/E, or prenatal hormonal disruption of the uterine microenvironment [17]. Manning and Bundred [19], in 2000, suggested that the intra-uterine hormonal environment is associated with the etiology of several adult-onset diseases and that digital ratio is predictive of some diseases [19]. A review carried out in 2014 [20] highlights three fronts of studies on 2D:4D: psychological traits, body performance and susceptibility to diseases in adult life [20].
The digital ratio between the second and fourth digits of the hands, known as 2D:4D, is sexually dimorphic. It has been suggested that a low 2D:4D indicates high exposure to prenatal testosterone and low estrogen exposure while a high 2D:4D indicates the inverse. The 2D:4D may be predictive of cancer susceptibility, and this may be particularly true in cancers that show differences between sexes in their occurrence.
To conduct a systematic review of published epidemiological literature examining the association between 2D:4D and cancer.
This review was carried out according to criteria recommended for the systematic review of Statement PRISMA. We enrolled 25 papers involving eleven cancer topographies with 4,569 cases and 19,416 controls from Europe, America, Asia and Australia.
We noticed variations and discrepancies in the results of the association between 2D:4D and cancer among the studies, either in those that had evaluated the same or different types of cancer, or in the same or distinct lateralities. However, a high 2D:4D was considered a likely predictor of cancer risk in 11 of 25 studies, a low 2D:4D was suggested as a predictor of risk in eight papers, and five of the twenty-five studies did not demonstrate any association.
Although this biomarker has the advantage of being easy to measure, it is noted that its relationship with sex hormone levels at specific stages of life has not yet been well quantified, and it has still been questioned. Hence, it is suggested that those findings from studies involving 2D:4D as a proxy for foetal hormone exposure should be interpreted with caution, as well as those studies which claim its association with cancer. Thus, this review shows the need for a greater number of epidemiological studies using more homogeneous methodology and techniques to better investigate the strength of the findings.
Association between the 2d:4d and cardiovascular risk factors: Body mass index, blood pressure and body fat
2020, Early Human Development
Citation Excerpt :
This study advocated that digit ratio of Greek men may act as potential biomarker for predicting their likelihood of MI [7]. A study reported that men with higher ratio tended to have their first MI early in life than their counterparts with lesser 2d:4d [8]. Dalton et al. suggests that, the relationship between 2d:4d and HTN in males can be a predictor for cardiovascular diseases with a connection to prenatal sex hormones [9].
To examine the relationship between the cardiovascular risk factors such as obesity as measured by Body mass index (BMI), body fat and blood pressure with the second to fourth digit ratio (2d:4d); a prenatal testosterone exposure marker.
The 2d:4d for both hands were measured for the Indian male subjects' (n = 1217). Subject's anthropometric parameters such as height, weight, skinfold thicknesses at various regions and blood pressure measurements were collected in a cross-sectional study with a convenient sampling approach. The association between digit ratio and the other variables were examined using analysis of variance, Pearson's correlation test and linear regression methods.
The study included 1193 subjects and all were males aged 19.69 ± 5.38 years (range 13 to 40 years). The subjects' body mass index (BMI) was 19.45 ± 3.82 and right and left hand 2d:4d were 0.958 ± 0.054, and 0.958 ± 0.061 respectively. The systolic blood pressure (SBP) and BMI significantly differed between the higher and lower half of right 2d:4d. The left hand 2d:4d was significantly correlated with SBP (r = 0.075, p = 0.028) and significantly differed between different hypertensive groups (p < 0.003, F = 3.552, df = 5).
The study observed an association between 2d:4d with hypertension and BMI among young Indian population, emphasizing the effect of prenatal testosterone on late life cardiovascular risk factor.
Decreased second to fourth digit ratios in female multiple sclerosis patients
2020, Early Human Development
Citation Excerpt :
Although there are conflicting results regarding this relationship, these studies at least may provide some clue to a possible relationship between in utero hormonal environment and development of several diseases. Many studies suggest that the 2D:4D ratio is determined by the level of prenatal androgen, although it is more likely to reflect the balance between androgen and estrogen activity [12–14,27]. Higher androgen and also estrogen receptor activity has been shown in digit 4 than in digit 2, and the growth of the fourth digit under the influence of the balance between androgen and estrogen activity may therefore affect gender differences in the 2D: 4D ratio [12,13].
Sex-related differences in multiple sclerosis (MS) suggest a possible role of prenatal sex hormones in the pathogenesis. The aim of this study was to investigate whether the 2D:4D ratio, considered a predictor of prenatal hormonal exposure, in MS patients differ from that in healthy controls.
Two hundred MS patients and one hundred seventy healthy control subjects with similar age and sex distribution enrolled. All participants were right-handed. The right hands of all participants were scanned using a digital scanner. Measurements of second and fourth digit lengths were made from digital scans. The 2D:4D ratio was calculated by dividing the length of the second digit by the length of the fourth digit.
A total of 171 MS patients' and 159 healthy controls' digit scans included in the study. The MS group consisted of 94 females (mean age 38.32 ± 10.5) and 77 males (mean age 42.06 ± 11.8) and the control group of 86 females (mean age 40.24 ± 9.7) and 73 males (mean age 38.49 ± 11.6). 2D:4D ratios of female MS patients were significantly lower than those of healthy females (p=0.004). Although 2D:4D ratios of male patients with MS were lower than those of healthy males, this difference was not statistically significant (p=0.33). There was no significant correlation between the 2D:4D ratio, EDSS levels or duration of the disease in male or female MS patients (p<0.05).
Although our results suggest that a prenatal hormonal balance in favor of androgenic activity may be a risk factor for MS, complex factors mediating the actions of sex hormones on target cells should always be considered when evaluating the effects of sex hormones.
The association between digit ratio (2D:4D) and overweight or obesity among Chinese children and adolescents: A cross-sectional study
2019, Early Human Development
The aim of this study was to analyze the relationship between 2D:4D and childhood overweight or obesity, which might indirectly show the role of prenatal hormone in childhood overweight or obesity.
Using stratified cluster sampling approach, a school-based cross-sectional investigation was undertaken among 687 children and adolescents aged 8–15 years. Each participant's index finger (2D) and ring finger (4D) length, height, weight, testosterone, and estradiol levels were measured, and their dietary behaviors, physical and sedentary activities were also surveyed.
The prevalence of overweight or obesity among children and adolescents aged 8- and 12–15 years was 36.0% and 25.9%, respectively (P < 0.05). There were no associations between 2D:4D and overweight or obesity in both boys and girls (P > 0.05). However, 2D and multiplying index of digit ratio and length (MIDRL) associated directly with overweight or obesity among boys (OR (95%CI) were 1.45 (1.00, 2.14), 1.46 (1.01, 2.11), respectively), and was indirectly related to overweight or obesity by testosterone (OR were 1.30, 1.26, respectively).
In boys, 2D and MIDRL were directly related to overweight or obesity, and indirectly associated with overweight or obesity by testosterone, which suggested that prenatal hormone exposure might associate with overweight or obesity among boys.

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Regular ArticleThe ratio of 2nd to 4th digit length: A new predictor of disease predisposition?

Abstract

Met Clin Exper

Lancet

Lancet

Lancet

Anthropological notes on the human hand

Am Anthropol

The ratio of 2nd to 4th digit length: a predictor of sperm numbers and concentrations of testosterone, luteinizing hormone and oestrogen

Hum Rep

Early prenatal attainment of adult metacarpal-phalangeal rankings and proportions

Am J Phys Anthropol

Ulnaless, A regulatory mutation inducing both loss-of-function and gain-of-function of posterior Hoxd genes

Development

The mouse Ulnaless mutation deregulates posterior Hoxd gene expression and alters appendicular patterning

Development

Of fingers, toes and penises

Nature

Regular Article
The ratio of 2nd to 4th digit length: A new predictor of disease predisposition?