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The ratio of 2nd to 4th digit length: A new predictor of disease predisposition?
Medical Hypotheses (2000) 54(5), 855–857 © 2000 Harcourt Publishers Ltd doi: 10.1054/mehy.1999.0000, available online at http://www.idealibrary.com on
The ratio of 2nd to 4th digit length: A new predictor of disease predisposition? J. T. Manning,1 P. E. Bundred2 1
School of Biological Sciences and 2Department of Primary Care, University of Liverpool, Liverpool, UK
Summary 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. © 2000 Harcourt Publishers Ltd
It has been known for some time that the relative lengths of the 2nd (index finger) and 4th (ring finger) digits differ between men and women (1). Men tend to have 4th digits longer than 2nd and women tend to have 2nd digits longer than 4th. This trait is best viewed as the ratio between 2nd and 4th digit length (2D:4D). In men 2D:4D ratio is negatively related to testosterone levels and sperm counts i.e. men with 4D>2D tend to produce more testosterone and more sperm than men with 4D<2D. In men and women 2D:4D ratio is positively related to oestrogen level i.e. individuals with 4D>2D produce less oestrogen than 4D<2D individuals (2). The bone-to-bone ratios of the digits are established by the end of week 13 of pregnancy (3) and there appears to be little change in the 2D:4D ratio at puberty (2). Therefore it is probable that 2D:4D ratios are correlated with prenatal levels of testosterone and oestrogen. The link between patterns of digit formation and prenatal testosterone and oestrogen may lie in the action of
Received 2 March 1999 Accepted 4 June 1999 Correspondence to: Dr J.T. Manning, School of Biological Sciences, University of Liverpool, Liverpool, L69 3BX UK. E-mail: [email protected]; Fax: +44 (0) 151 794 5094
Homeobox or Hox genes. In vertebrates, including humans, the Hox gene family is essential for the differentiation of both the urinogenital system (including the testes and ovaries) and the digit (4,5). In mice deregulation of Hoxd alters the relative lengths of digits and affects growth of the genial bud and differentiation of the penis (6). In humans the hand-foot-genital syndrome is characterised by defects in the digits, toes and genitalia and is the result of mutation of Hoxa (7). We suggest that the 2D:4D ratio is a marker for testosterone and oestrogen levels towards the end of the first trimester of pregnancy and reflects the action of Hox genes on differentiation during early pregnancy. The 2D:4D ratio may therefore be a predictor of fertility, the pattern of differentiation of the central nervous system (CNS) and the expression of a number of adult-onset diseases. 2D:4D RATIO AND FERTILITY The work of Manning et al (2) indicates the following (a) in men low 2D:4D ratio is associated with high sperm counts, high levels of testosterone and low levels of oestrogen. High 2D:4D ratios are correlated with low sperm counts and in extreme cases germ cell failure, low testosterone and high oestrogen concentrations. Men 855
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with low 2D:4D ratios are therefore likely to have elevated levels of fertility. Modern birth control methods and restriction of family size will obscure correlations between fertility and fecundity. However sub-fertile men who rarely use birth control are still unlikely to have large families. We predict 2D:4D ratio will be negatively related to offspring number i.e. men with low 2D:4D will on average have more children than men with high 2D:4D ratio. The relationship will be strongest in those cultures with large family size and minimal birth control. Men with low 2D:4D ratio may also show earlier reproduction (age at first child) and have their last child at a later age than high 2D:4D ratio men (b) in women oestrogen is positively related to 2D:4D ratio. High 2D:4D ratio women may have more children than low 2D:4D ratio women and the former group will have their first child earlier and their last child later than the latter group. 2D:4D AND THE DIFFERENTIATION OF THE CNS There is evidence that testosterone has a major impact on the differentiation of the CNS. Geschwind and Galaburda (8) have hypothesised that prenatal testosterone slows the growth of certain areas of the left hemisphere and facilitates the growth of the homologous areas of the right hemisphere. They implicate high prenatal testosterone levels in the aetiology of left-handedness, autism, dyslexia, migraine, stammering and in disorders of the immune system resulting from effects on the thymus. Low 2D:4D ratios and their association with high testosterone levels therefore predict an elevated expression of these traits. This has been tested for one trait thus far. Manning et al. have shown that children with low 2D:4D ratios have greater leftward asymmetry in speed of hand performance than children with high 2D:4D ratios (9). 2D:4D may be measured at birth. This will facilitate the diagnosis of autism and dyslexia which are difficult to assess in early childhood. 2D:4D AND ADULT-ONSET DISEASES The intra-uterine hormonal environment is associated with the aetiology of a number of adult-onset diseases such as myocardial infarction (MI) and breast cancer. Several studies have shown that male survivors of MI have lower testosterone and higher oestradiol levels than age-matched controls (10–16). Prenatal conditions are likely to be powerful antecedents of coronary heart disease. First-trimester exposure to oestrogen and progesterone may lead to cardiovascular anomalies such as ventricular septal defect, atrial septal defect, pulmonic stenosis, patent ductus arteriosis and transposition of the great vessels (17–19). High 2D:4D ratios in men are therefore likely to be correlated with premature MI and to prognosis after MI. Medical Hypotheses (2000) 54(5), 855–857
Trichopoulos has suggested that exposure to high in utero levels of oestrogen is a risk factor for subsequent breast cancer (20). High birthweight is one correlate of prenatal oestrogen levels and this is associated with an increased risk of breast cancer (21). We suggest that 2D:4D ratio will be positively associated with breast cancer risk. Women with high 2D:4D ratio may present with breast tumours earlier than women with low 2D:4D ratio and prognosis may be worse for women in the former group compared to the latter. CONCLUSION The 2D:4D ratio may correlate with the incidence of infertility, autism, dyslexia, migraine, stammering, MI and breast cancer. It is fixed at birth and this will facilitate its early use in diagnosis and prognosis. It may also be useful in informing life-style interventions which may delay MI and in identification of high risk groups for whom early screening for breast cancer is approriate. REFERENCES 1. Baker F. Anthropological notes on the human hand. Am Anthropol 1888; 1: 51–76. 2. Manning J.T., Scutt D., Wilson J. et al. The ratio of 2nd to 4th digit length: a predictor of sperm numbers and concentrations of testosterone, luteinizing hormone and oestrogen. Hum Rep 1998; 13: 3000–3004. 3. Garn S.M., Burdi A.R., Babler W.J. et al. Early prenatal attainment of adult metacarpal-phalangeal rankings and proportions. Am J Phys Anthropol 1975; 43: 327–332. 4. Herault Y., Fradeau N., Zakany J. Ulnaless, A regulatory mutation inducing both loss-of-function and gain-of-function of posterior Hoxd genes. Development 1997; 124: 3493–3500. 5. Piechel C.L., Prabhakaran B., Vogt T.F. The mouse Ulnaless mutation deregulates posterior Hoxd gene expression and alters appendicular patterning. Development 1997; 124: 3481–3492. 6. Kondo T., Zakany J., Innis J.W. et al. Of fingers, toes and penises. Nature 1997; 390: 29. 7. Mortlock D.P., Innis J.W. Mutation of Hoxa13 in hand-footgenital syndrome. Nat Gen 1997; 15: 179–180. 8. Geschwind N., Galaburda A.M. Cerebral lateralisation. Biological mechanisms, association and pathology: a hypothesis and a program for research. Arch Neurol 1985; 43: 428–654. 9. Manning J.T., Trivers R.L., Thornhill R. et al. The 2nd to 4th digit ratio and asymmetry of hand performance in Jamaican children. Laterality 1999, in press. 10. Aksut S.V., Aksut G., Karamehmetoglu A. et al. The determination of serum estradiol, testosterone and progesterone in acute myocardial infarction. Jap Heart J 1986; 27: 825–837. 11. Sewardson M., Jailal I., Vythilingum S. et al. Sex hormone levels in young Indian patients with myocardial infarction. Arteriosclerosis 1986; 6: 418–421. 12. Swartz C.M., Young M.A. Low serum testosterone and myocardial infarction in geriatric male patients. J Amer Ger Soc 1987; 35: 39–44. 13. Sewardson M., Vylithingum S., Jailal I et al. Abnormalities in sex hormones are a risk factor for premature manifestation of coronary heart disease in South African Indian men. Athersc 1990; 83: 111–117.
© 2000 Harcourt Publishers Ltd
Ratio of 2nd to 4th digit length
14. Mendoza S.G., Carrasco H., Zerpa A. et al. Effect of physical training on lipids, lipoproteins, apolipoproteins, lipases, and endogenous hormones in men with premature mycardial infarction. Met Clin Exper 1991; 40: 368–377. 15. Rice T., Sprecher D.L., Borecki et al. Cincinnati myocardial infarction and hormone family study: family resemblance for testosterone in random and MI families. Am J Med Gen 1993; 47: 542–549. 16. Phillips G.B., Pinkernell B.H., Jing T.Y. The association of hypotesteronemia with coronary artery disease in men. Arteriosc Thromb 1994; 14: 701–706. 17. Levy E.P., Cohen A., Fraser F.C. Hormone treatment during pregnancy and congenital heart defects. Lancet 1973; 1: 611.
© 2000 Harcourt Publishers Ltd
857
18. Nora J.J., Nora A.H., Perinchief A.G. et al. Congenital abnormalities and first-trimester exposure to progestagen/oestrogen. Lancet 1976; 1: 313–314. 19. Heinonen O.P., Slone D., Monson R.R. et al. Cardiovascular birth defects and antenatal exposure to female hormones. N Eng J Med 1977; 296: 67–70. 20. Trichopoulos D. Hypothesis: does breast cancer originate in utero? Lancet 1990; 335: 939–940. 21. Sanderson M., Williams M.A., Malone K.E. et al. Perinatal factors and risk of breast cancer. Epidemiol 1996; 7: 34–37.
Medical Hypotheses (2000) 54(5), 855–857
The ratio of 2nd to 4th digit length: A new predictor of disease predisposition? J. T. Manning,1 P. E. Bundred2 1
School of Biological Sciences and 2Department of Primary Care, University of Liverpool, Liverpool, UK
Summary 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. © 2000 Harcourt Publishers Ltd
It has been known for some time that the relative lengths of the 2nd (index finger) and 4th (ring finger) digits differ between men and women (1). Men tend to have 4th digits longer than 2nd and women tend to have 2nd digits longer than 4th. This trait is best viewed as the ratio between 2nd and 4th digit length (2D:4D). In men 2D:4D ratio is negatively related to testosterone levels and sperm counts i.e. men with 4D>2D tend to produce more testosterone and more sperm than men with 4D<2D. In men and women 2D:4D ratio is positively related to oestrogen level i.e. individuals with 4D>2D produce less oestrogen than 4D<2D individuals (2). The bone-to-bone ratios of the digits are established by the end of week 13 of pregnancy (3) and there appears to be little change in the 2D:4D ratio at puberty (2). Therefore it is probable that 2D:4D ratios are correlated with prenatal levels of testosterone and oestrogen. The link between patterns of digit formation and prenatal testosterone and oestrogen may lie in the action of
Received 2 March 1999 Accepted 4 June 1999 Correspondence to: Dr J.T. Manning, School of Biological Sciences, University of Liverpool, Liverpool, L69 3BX UK. E-mail: [email protected]; Fax: +44 (0) 151 794 5094
Homeobox or Hox genes. In vertebrates, including humans, the Hox gene family is essential for the differentiation of both the urinogenital system (including the testes and ovaries) and the digit (4,5). In mice deregulation of Hoxd alters the relative lengths of digits and affects growth of the genial bud and differentiation of the penis (6). In humans the hand-foot-genital syndrome is characterised by defects in the digits, toes and genitalia and is the result of mutation of Hoxa (7). We suggest that the 2D:4D ratio is a marker for testosterone and oestrogen levels towards the end of the first trimester of pregnancy and reflects the action of Hox genes on differentiation during early pregnancy. The 2D:4D ratio may therefore be a predictor of fertility, the pattern of differentiation of the central nervous system (CNS) and the expression of a number of adult-onset diseases. 2D:4D RATIO AND FERTILITY The work of Manning et al (2) indicates the following (a) in men low 2D:4D ratio is associated with high sperm counts, high levels of testosterone and low levels of oestrogen. High 2D:4D ratios are correlated with low sperm counts and in extreme cases germ cell failure, low testosterone and high oestrogen concentrations. Men 855
856
Manning and Bundred
with low 2D:4D ratios are therefore likely to have elevated levels of fertility. Modern birth control methods and restriction of family size will obscure correlations between fertility and fecundity. However sub-fertile men who rarely use birth control are still unlikely to have large families. We predict 2D:4D ratio will be negatively related to offspring number i.e. men with low 2D:4D will on average have more children than men with high 2D:4D ratio. The relationship will be strongest in those cultures with large family size and minimal birth control. Men with low 2D:4D ratio may also show earlier reproduction (age at first child) and have their last child at a later age than high 2D:4D ratio men (b) in women oestrogen is positively related to 2D:4D ratio. High 2D:4D ratio women may have more children than low 2D:4D ratio women and the former group will have their first child earlier and their last child later than the latter group. 2D:4D AND THE DIFFERENTIATION OF THE CNS There is evidence that testosterone has a major impact on the differentiation of the CNS. Geschwind and Galaburda (8) have hypothesised that prenatal testosterone slows the growth of certain areas of the left hemisphere and facilitates the growth of the homologous areas of the right hemisphere. They implicate high prenatal testosterone levels in the aetiology of left-handedness, autism, dyslexia, migraine, stammering and in disorders of the immune system resulting from effects on the thymus. Low 2D:4D ratios and their association with high testosterone levels therefore predict an elevated expression of these traits. This has been tested for one trait thus far. Manning et al. have shown that children with low 2D:4D ratios have greater leftward asymmetry in speed of hand performance than children with high 2D:4D ratios (9). 2D:4D may be measured at birth. This will facilitate the diagnosis of autism and dyslexia which are difficult to assess in early childhood. 2D:4D AND ADULT-ONSET DISEASES The intra-uterine hormonal environment is associated with the aetiology of a number of adult-onset diseases such as myocardial infarction (MI) and breast cancer. Several studies have shown that male survivors of MI have lower testosterone and higher oestradiol levels than age-matched controls (10–16). Prenatal conditions are likely to be powerful antecedents of coronary heart disease. First-trimester exposure to oestrogen and progesterone may lead to cardiovascular anomalies such as ventricular septal defect, atrial septal defect, pulmonic stenosis, patent ductus arteriosis and transposition of the great vessels (17–19). High 2D:4D ratios in men are therefore likely to be correlated with premature MI and to prognosis after MI. Medical Hypotheses (2000) 54(5), 855–857
Trichopoulos has suggested that exposure to high in utero levels of oestrogen is a risk factor for subsequent breast cancer (20). High birthweight is one correlate of prenatal oestrogen levels and this is associated with an increased risk of breast cancer (21). We suggest that 2D:4D ratio will be positively associated with breast cancer risk. Women with high 2D:4D ratio may present with breast tumours earlier than women with low 2D:4D ratio and prognosis may be worse for women in the former group compared to the latter. CONCLUSION The 2D:4D ratio may correlate with the incidence of infertility, autism, dyslexia, migraine, stammering, MI and breast cancer. It is fixed at birth and this will facilitate its early use in diagnosis and prognosis. It may also be useful in informing life-style interventions which may delay MI and in identification of high risk groups for whom early screening for breast cancer is approriate. REFERENCES 1. Baker F. Anthropological notes on the human hand. Am Anthropol 1888; 1: 51–76. 2. Manning J.T., Scutt D., Wilson J. et al. The ratio of 2nd to 4th digit length: a predictor of sperm numbers and concentrations of testosterone, luteinizing hormone and oestrogen. Hum Rep 1998; 13: 3000–3004. 3. Garn S.M., Burdi A.R., Babler W.J. et al. Early prenatal attainment of adult metacarpal-phalangeal rankings and proportions. Am J Phys Anthropol 1975; 43: 327–332. 4. Herault Y., Fradeau N., Zakany J. Ulnaless, A regulatory mutation inducing both loss-of-function and gain-of-function of posterior Hoxd genes. Development 1997; 124: 3493–3500. 5. Piechel C.L., Prabhakaran B., Vogt T.F. The mouse Ulnaless mutation deregulates posterior Hoxd gene expression and alters appendicular patterning. Development 1997; 124: 3481–3492. 6. Kondo T., Zakany J., Innis J.W. et al. Of fingers, toes and penises. Nature 1997; 390: 29. 7. Mortlock D.P., Innis J.W. Mutation of Hoxa13 in hand-footgenital syndrome. Nat Gen 1997; 15: 179–180. 8. Geschwind N., Galaburda A.M. Cerebral lateralisation. Biological mechanisms, association and pathology: a hypothesis and a program for research. Arch Neurol 1985; 43: 428–654. 9. Manning J.T., Trivers R.L., Thornhill R. et al. The 2nd to 4th digit ratio and asymmetry of hand performance in Jamaican children. Laterality 1999, in press. 10. Aksut S.V., Aksut G., Karamehmetoglu A. et al. The determination of serum estradiol, testosterone and progesterone in acute myocardial infarction. Jap Heart J 1986; 27: 825–837. 11. Sewardson M., Jailal I., Vythilingum S. et al. Sex hormone levels in young Indian patients with myocardial infarction. Arteriosclerosis 1986; 6: 418–421. 12. Swartz C.M., Young M.A. Low serum testosterone and myocardial infarction in geriatric male patients. J Amer Ger Soc 1987; 35: 39–44. 13. Sewardson M., Vylithingum S., Jailal I et al. Abnormalities in sex hormones are a risk factor for premature manifestation of coronary heart disease in South African Indian men. Athersc 1990; 83: 111–117.
© 2000 Harcourt Publishers Ltd
Ratio of 2nd to 4th digit length
14. Mendoza S.G., Carrasco H., Zerpa A. et al. Effect of physical training on lipids, lipoproteins, apolipoproteins, lipases, and endogenous hormones in men with premature mycardial infarction. Met Clin Exper 1991; 40: 368–377. 15. Rice T., Sprecher D.L., Borecki et al. Cincinnati myocardial infarction and hormone family study: family resemblance for testosterone in random and MI families. Am J Med Gen 1993; 47: 542–549. 16. Phillips G.B., Pinkernell B.H., Jing T.Y. The association of hypotesteronemia with coronary artery disease in men. Arteriosc Thromb 1994; 14: 701–706. 17. Levy E.P., Cohen A., Fraser F.C. Hormone treatment during pregnancy and congenital heart defects. Lancet 1973; 1: 611.
© 2000 Harcourt Publishers Ltd
857
18. Nora J.J., Nora A.H., Perinchief A.G. et al. Congenital abnormalities and first-trimester exposure to progestagen/oestrogen. Lancet 1976; 1: 313–314. 19. Heinonen O.P., Slone D., Monson R.R. et al. Cardiovascular birth defects and antenatal exposure to female hormones. N Eng J Med 1977; 296: 67–70. 20. Trichopoulos D. Hypothesis: does breast cancer originate in utero? Lancet 1990; 335: 939–940. 21. Sanderson M., Williams M.A., Malone K.E. et al. Perinatal factors and risk of breast cancer. Epidemiol 1996; 7: 34–37.
Medical Hypotheses (2000) 54(5), 855–857