Digit ratio (2D:4D) and its relationship to foetal and maternal sex steroids: A mini-review.

The challenges of terrestrial existence may mean that the early development of tetrapod limb traits is linked to the development of the urogenital system and sex steroids. One such limb trait is the sex-dependent ratio of the lengths of the 2nd and 4th digits (2D:4D). Direct evidence for the association between early sex steroids and offspring 2D:4D can be obtained by manipulating foetal sex hormones. However, this is not ethically permissible in humans. It is widely accepted that 2D:4D is a biomarker for early foetal sex hormones in tetrapods but the link in humans remains controversial. Here we review the evidence that (i) manipulation of sex steroids in early development leads to sex-dependent changes in 2D:4D throughout the tetrapods, and (ii) maternal sex steroids cross the placenta and thus are associated with offspring 2D:4D in both non-human and human animals. We suggest a research focus on associations between human maternal sex steroids and offspring 2D:4D to clarify the link between 2D:4D and early sex steroids. A protocol is proposed to examine the correlation between 1st-trimester maternal sex steroids and offspring 2D:4D. Such an association may explain the existence and medium effect size of the human sex difference in 2D:4D.

The effects of sex, nation, ethnicity, age and self-reported pubertal development on participant-measured right-left 2D:4D (Dr-l) in the BBC internet study.

Digit ratio (2D:4D) - a proxy for prenatal sex steroids - shows sex, nationality and ethnic differences and is linked to pubertal onset. It is unclear whether right-left 2D:4D (Dr-l) also correlates with prenatal sex steroids, as evidence of these differences has been less conclusive. The present study examined the effects of sex, nation, ethnicity, age and self-reported pubertal development (i.e. the rate of physical development and age at menarche [females] or first shave [males]) on Dr-l in a large online study (the BBC internet study). Digit lengths were self-measured in 201,865 adults (110,955 males) and the sample of nations included 41 countries. Participants reported the self-perceived rate of physical pubertal development on a five-point scale (from very slow to very fast) and provided information on the age at menarche or first shave. Adult (>17 years) males had lower Dr-l than females with weak effect size across 41 nations (males-females; d = -.065, p < .0001). There were sex and ethnicity effects on Dr-l across seven ethnic groups with males < females and lower Dr-l in Whites and Middle/Near Eastern participants compared to Asian, Black and Chinese respondents. Considering age effects, the authors focused on participants >12 years; there were stable sex differences and a weak positive effect of age on Dr-l. Dr-l showed a positive relationship with the rate of physical development and a negative relationship with age at menarche or first shave. Relationships were present in males and females with stronger effects in the latter. It is concluded that Dr-l shows a weak sex difference (males < females) independent of nation, ethnicity and age, and suggest that Dr-l is a proxy for prenatal sex steroids.

Digit ratios and their asymmetries as risk factors of developmental instability and hospitalization for COVID-19.

COVID-19 presents with mild symptoms in the majority of patients but in a minority it progresses to acute illness and hospitalization. Here we consider whether markers for prenatal sex hormones and postnatal stressors on developmental instability, i.e. digit ratios and their directional and unsigned asymmetries, are predictive of hospitalization. We focus on six ratios: 2D:3D; 2D:4D; 2D:5D; 3D:4D; 3D:5D; 4D:5D and compare hospitalized patient and control means for right, and left ratios, directional asymmetries (right-left) and unsigned asymmetries [|(right-left)|]. There were 54 patients and 100 controls. We found (i) patients differed in their digit ratios from controls (patients > controls) in all three ratios that included 5D (2D:5D, 3D:5D and 4D:5D) with small to medium effect sizes (d = 0.3 to 0.64), (ii) they did not differ in their directional asymmetries, and (iii) patients had greater |(right-left)| asymmetry than controls for 2D:4D (d = .74) , and all ratios that included 5D; 2D:5D (d = 0.66), 3D:5D (d = .79), 4D:5D (d = 0.47). The Composite Asymmetry of the two largest effects (2D:4D + 3D:5D) gave a patient and control difference with effect size d = 1.04. All patient versus control differences were independent of sex. We conclude that digit ratio patterns differ between patients and controls and this was most evident in ratios that included 5D. Large |(right-left)| asymmetries in the patients are likely to be a marker for postnatal stressors resulting in developmental perturbations and for potential severity of COVID-19.

Digit ratio (2D:4D) and body mass index in the BBC Internet Study: prenatal sex steroids and a Trivers-Willard effect on body composition.

Digit ratio - a putative measure of prenatal sex steroids - may be related to body mass index (BMI). However, reports of correlations between 2D:4D and BMI have yielded mixed results with some studies showing no relationship while others have reported positive associations in men or women only. This study considers associations between self-reported 2D:4D and BMI in a large online survey (i.e. the BBC Internet Study). At the individual level, there was a weak positive association between 2D:4D and BMI in both sexes with greater effect sizes in women. Body mass index was positively related to age and negatively related to parental income; however, the relationship between 2D:4D and BMI was independent of both variables. At the national level, mean 2D:4D per country showed positive associations with mean national BMI but those correlations were restricted to females. It is concluded that BMI is positively related to low prenatal testosterone and high prenatal oestrogen. Parental income inequality may influence both prenatal sex steroids (through a 'Trivers-Willard' effect) and BMI such that increases in inequality result in reductions in prenatal testosterone and increases in BMI at the individual and national level.

Parental income inequality and children's digit ratio (2D:4D): a 'Trivers-Willard' effect on prenatal androgenization?

Income inequality is associated positively with disease prevalence and mortality. Digit ratio (2D:4D) - a negative proxy for prenatal testosterone and a positive correlate of prenatal oestrogen - is related to several diseases. This study examined the association of income inequality (operationalized as relative parental income) and children's 2D:4D. Participants self-measured finger lengths (2D=index finger, and 4D=ring finger) in a large online survey conducted in July 2005 (the BBC Internet Study) and reported their parents' income. Children of parents of above-average income had low 2D:4D (high prenatal testosterone, low prenatal oestrogen) while the children of parents of below-average income had high 2D:4D (low prenatal testosterone, high prenatal oestrogen). The effects were significant in the total sample, present among Whites (the largest group in the sample), in the two largest national samples (UK and USA) and were greater for males than females. The findings suggest a Trivers-Willard effect, such that high-income women may prenatally masculinize their sons at the expense of the fitness of their daughters. Women with low income may prenatally feminize their daughters at the fitness expense of their sons. The effect could, in part, explain associations between low income, high 2D:4D (low prenatal testosterone) and some major causes of mortality such as cardiovascular disease.

Digit ratio (2D:4D) in women and men with lung cancer.

A prenatal sex steroid environment of high prenatal testosterone and low prenatal oestrogen inhibits lung development and may predispose individuals to be vulnerable to lung disease in later life. Therefore, the aim of this report was to investigate whether there is an association between right and left 2D:4D (biomarker of prenatal sex steroids exposure) and primary lung cancer in women and men. Also, we considered the relationship between right-left 2D:4D (Δ2D:4D, a negative correlate of high prenatal testosterone and low prenatal oestrogen) and the age of lung cancer diagnosis. The study included 109 patients (61 men) with lung cancer and 197 controls (78 men). In the study we found that: (i) women with lung cancer have lower 2D:4D compared to controls (the effect was independent of smoking), (ii) among women with cancer, age at diagnosis was positively related to 2D:4D, i.e. women with masculinized 2D:4D present earlier with the cancer than women with feminized 2D:4D, (iii) among men with lung cancer, those with the most aggressive form (small-cell lung cancer) had masculinized (low) Δ2D:4D compared to those with the less aggressive form (non-small cell lung cancer). The data suggests that masculinized right 2D:4D and Δ2D:4D are associated with a predisposition to lung cancer and/or the more aggressive forms of lung cancer.

Radiographic digit ratios (2D:4D) of Afro-Caribbean children: Comparisons with published data from white children.

BACKGROUND: Digit ratio (2D:4D) from soft-tissue measurements of fingers from children and adults from Black and White ethnic groups show sex differences (males

Digit ratio (2D:4D) in Klinefelter's syndrome.

The ratio of second to fourth digit length (2D:4D) is a correlate of prenatal testosterone. High 2D:4D is associated with low prenatal testosterone, and reduced sensitivity to testosterone. Klinefelter's syndrome (KS; 47 XXY) affects the endocrine system, such that low testosterone levels are found in KS foetuses, new-borns and adults. To date, there are no published data regarding the pattern of 2D:4D in KS males. Here we consider 2D:4D in KS individuals (n = 51), their relatives (16 fathers and 15 mothers) and an unaffected control sample of 153 men and 153 women. Adult KS individuals were taller than their fathers and had shorter fingers than fathers and male controls. Compared with fathers, male controls and mothers, KS males had shorter fingers relative to height. With regard to 2D:4D, KS individuals had higher 2D:4D than fathers (right and left hands), male controls (right and left hands) and mothers (left hands). Among KS males older than 13 years there were 34 individuals currently prescribed testosterone and nine not prescribed. In comparison to the former, the latter individuals had higher right 2D:4D and higher right-left 2D:4D. We conclude that KS males have mean 2D:4D values similar to those found in female population norms. In addition, testosterone supplementation in KS males may be most common for individuals with low right 2D:4D.

Second to fourth digit ratio (2D:4D), breast cancer risk factors, and breast cancer risk: a prospective cohort study.

BACKGROUND: We aimed to assess whether 2D:4D measures are associated with breast cancer risk. METHODS: We derived the ratio of the lengths of the index and ring fingers (2D:4D), and right minus left 2D:4D (Δ(r-l)) from digit lengths measured from photocopies of participants' hands collected during a recent follow-up of the Melbourne Collaborative Cohort Study, a prospective study including 24 469 women. Of the 9044 women with available data, we identified 573 incident breast cancer cases. Hazard ratios (HR) and 95% confidence intervals (CI) for a one standard deviation difference in 2D:4D measures were obtained from Weibull survival models, and linear regression models were used to examine potential associations between 2D:4D measures and age at menarche and menopause. RESULTS: We found a direct association between left 2D:4D and breast cancer risk, an inverse association between Δ(r-l) and risk of breast cancer, but no association between right 2D:4D and breast cancer risk. Among breast cancer cases, both right 2D:4D and Δ(r-l) were inversely associated with age at diagnosis. We also observed associations between both right 2D:4D and Δ(r-l) and age at menopause, with increasing digit ratio measures related to earlier mean age at menopause. CONCLUSION: Digit ratio measures might be associated with breast cancer risk and age at onset of breast cancer. If confirmed in other studies, this suggests that lower exposure or sensitivity to prenatal testosterone might be associated with lower risk of breast cancer.

Second to fourth digit ratio (2D:4D) and prostate cancer risk in the Melbourne Collaborative Cohort Study.

BACKGROUND: The ratio of the lengths of index and ring fingers (2D:4D) is a marker of prenatal exposure to sex hormones, with low 2D:4D being indicative of high prenatal androgen action. Recent studies have reported a strong association between 2D:4D and risk of prostate cancer. METHODS: A total of 6258 men participating in the Melbourne Collaborative Cohort Study had 2D:4D assessed. Of these men, we identified 686 incident prostate cancer cases. Hazard ratios (HRs) and confidence intervals (CIs) were estimated for a standard deviation increase in 2D:4D. RESULTS: No association was observed between 2D:4D and prostate cancer risk overall (HRs 1.00; 95% CIs, 0.92-1.08 for right, 0.93-1.08 for left). We observed a weak inverse association between 2D:4D and risk of prostate cancer for age <60, however 95% CIs included unity for all observed ages. CONCLUSION: Our results are not consistent with an association between 2D:4D and overall prostate cancer risk, but we cannot exclude a weak inverse association between 2D:4D and early onset prostate cancer risk.

Digit ratio (2D:4D) and performance in elite rugby players.

The relative length of the second and fourth digits (2D:4D) is a putative marker for prenatal testosterone. Low 2D:4D has been reported to correlate with high performance in sport in general. Here, for the first time, we examine the relationship between 2D:4D and performance in elite rugby players. The 44 players (28 forwards, 16 backs) were drawn from the Ospreys Rugby Union Club and 44 age-matched controls. The measures of performance comprised age-adjusted number of international performances (caps) for Wales, a comparison of coaches' first-choice League team with others, and the number of tries scored by backs in club matches. Compared with controls, players were larger and had lower 2D:4D for the right and left hand. With regard to number of caps, players with low 2D:4D in their right hand and low right 2D:4D compared with their left (right - left 2D:4D difference) had high numbers of caps. First-choice players did not differ significantly from second-choice players in their 2D:4D but they did have a lower right - left 2D:4D difference than second-choice players. Low right 2D:4D and low right - left 2D:4D difference were significantly linked with large numbers of tries. We conclude that low right 2D:4D and low right - left 2D:4D difference are predictors of high rugby performance.

Perturbations in finger length and digit ratio (2D:4D) in ICSI children.

Intracytoplasmic sperm injection (ICSI) is used to overcome severe male-factor infertility where males are azoospermic or have poor quality spermatozoa. Perturbations of finger length (short finger length adjusted for height and high second-to-fourth digit ratio, or 2D:4D) have been described in azoospermic men and men who are rated as having low sexual attractiveness. High 2D:4D has been described in women with high fecundity. Such perturbations may be related to endocrine regulation of some homeobox genes. This study compared finger length and 2D:4D in singleton children conceived with the help of ICSI with those in naturally conceived singleton controls. Participants were recruited from centres in Germany and the UK. There were 211 children conceived by ICSI and 195 controls. Finger length was measured from photocopies of the ventral surface of the hand. In comparison to controls, male and female ICSI children had shorter fingers after correction for height. There was also evidence that female ICSI children may have higher 2D:4D than female controls. Perturbations in finger length in ICSI children may be inherited from their fathers and, in the case of boys, could be associated with lower fertility and reduced sexual attractiveness. For ICSI females, increased 2D:4D may be associated with increased fertility.

Digit ratio (2D:4D) and hand preference for writing in the BBC Internet Study.

The ratio of the length of the second to the fourth digit (2D:4D) may be negatively correlated with prenatal testosterone. Hand preference has been linked with prenatal testosterone and 2D:4D. Here we show that 2D:4D is associated with hand preference for writing in a large internet sample (n>170,000) in which participants self-reported their finger lengths. We replicated a significant association between right 2D:4D and writing hand preference (low right 2D:4D associated with left hand preference) as well as a significant correlation between writing hand preference and the difference between left and right 2D:4D or Dr-l (low Dr-l associated with left hand preference). A new significant correlation between left 2D:4D and writing hand preference was also shown (high left 2D:4D associated with left hand preference). There was a clear interaction between writing hand preference and 2D:4D: The left 2D:4D was significantly larger than the right 2D:4D in male and female left-handed writers, and the right hand 2D:4D was significantly larger than the left hand 2D:4D in male and female right-handed writers.

Digit ratio (2D:4D) and sprinting speed in boys.

Digit ratio (2D:4D), a putative correlate of prenatal testosterone, has been found to relate to performance in sport and athletics such that low 2D:4D (high prenatal testosterone) correlates with high performance. Speed in endurance races is strongly related to 2D:4D, and may be one factor that underlies the link between sport and 2D:4D, but nothing is known of the relationship between 2D:4D and sprinting speed. Here we show that running times over 50 m were positively correlated with 2D:4D in a sample of 241 boys (i.e. runners with low 2D:4D ran faster than runners with high 2D:4D). The relationship was also found for 50 m split times (at 20, 30, and 40 m) and was independent of age, BMI, and an index of maturity. However, associations between 2D:4D and sprinting speed were much weaker than those reported for endurance running. This suggests that 2D:4D is a relatively weak predictor of strength and a stronger predictor of efficiency in aerobic exercise. We discuss the effect sizes for relationships between 2D:4D and sport and target traits in general, and identify areas of strength and weakness in digit ratio research.

The androgen receptor gene: a major modifier of speed of neuronal transmission and intelligence?

Humans show considerable additive genetic variance in cognitive ability or general intelligence (g) but the genes that influence this variation are largely unknown. It is suggested here that the X-linked androgen receptor gene (AR) has a major modifying effect on speed of neuronal transmission and thus on g. The AR is polymorphic in its N-terminal transactivation domain which encodes a polyglutamine tract (CAGn) with a parametric mean of n=21 CAG repeats and normal variation between n=11 and n=30 repeats . Very low repeat numbers are associated with mental retardation, repeat numbers above 30 with reduced cognitive function, and CAGn greater than 40 with spinal and bulbar muscular atrophy. Within the range of 11-30 repeats short CAG chains are associated with high androgen sensitivity and high sperm counts. Despite this, all human populations contain many individuals with n>21 repeats. I suggest that within the range of 11-30 repeats there is a positive association with speed of neuronal transmission and values of g. The advantage of high g and the consequent spread of alleles for high CAGn will be countered by the negative effects on sperm production. Below CAGn=11 and above CAGn=30 neuronal speed may reduce, thus leading to reductions in g and loss of function of neurons. In support of the model I discuss the link between the X-chromosome and g, the comparative structure of the AR gene in the primates, and the variation in CAGn and g in human ethnic groups.

Maternal smoking during pregnancy and possible effects of in utero testosterone: evidence from the 2D:4D finger length ratio.

OBJECTIVES: Maternal smoking during pregnancy is linked to high fetal testosterone (FT), and an increased risk in offspring for autism, ADHD, conduct disorder, antisocial behaviour and criminal outcomes. The ratio of the length of the 2nd and 4th fingers (2D:4D) is thought to be negatively related to FT concentration, and is related to autism, hyperactivity, poor social behaviour, and physical aggression. We compare the 2D:4D ratio of children whose mothers smoked during pregnancy with the 2D:4D of children whose mother did not smoke. METHOD: Cross-sectional survey in two primary schools. Questionnaires were distributed to 710 children and 546 were returned. Of these the 2nd and 4th digits of 520 children (259 females and 261 males) were measured. The main outcome measures were 2nd and 4th digit length, smoking history of mother and father. RESULTS: Boys had lower mean 2D:4D than girls and right 2D:4D was lower than left. Among boys, those whose mother's smoked during pregnancy had lower right hand 2D:4D ratio than those whose mother did not smoke. The difference remained significant after the effects of age, height, weight and birth weight were removed. Other household smoking patterns were not associated with male offspring 2D:4D. Female offspring 2D:4D did not differ on the basis of maternal smoking. CONCLUSIONS: Maternal smoking during pregnancy was associated with low right 2D:4D in children, but the effect was restricted to boys. A link between maternal smoking during pregnancy and 2D:4D supports a causal association between FT and such behaviours as hyperactivity and conduct disorder.

The 2nd-4th digit ratio (2D:4D) and neck circumference: implications for risk factors in coronary heart disease.

BACKGROUND: The ratio of the lengths of the 2nd and 4th digit (2D:4D) is negatively related to prenatal and adult concentrations of testosterone (T). Testosterone appears to be a protective against myocardial infarction (MI) in men as men with low 2D:4D are older at first MI than men with high 2D:4D, and men with coronary artery disease have lower T levels than men with normal angiograms. Neck circumference (NC), a simple and time-saving screening measure to identify obesity is reported to be positively correlated with the factors of the metabolic syndrome, a complex breakdown of normal physiology characterized by obesity, insulin resistance, hyperlipidemia, and hypertension, and is therefore likely to increase the risk of coronary heart disease (CHD). OBJECTIVE: To investigate possible associations between 2D:4D ratios and NC in men and women. RESEARCH METHODS AND PROCEDURES: 2D:4D ratios, NC, along with measures of waist and hip circumferences, body mass index (BMI), and waist-to-hip ratio was recorded from 127 men and 117 women. RESULTS: A significant positive correlation between 2D:4D and NC and was found for men but not for women after controlling for body mass index (BMI); the higher the ratio the higher the NC. DISCUSSION: This finding supports the suggestion of NC to serve as a predictor for increased risk for CHD as previously suggested. In addition, the present association suggests a predisposition for men towards CHD via 2D:4D as proxy to early sex-steroid exposure.