The ratio of the index and ring fingers (2D:4D ratio) is a proposed biomarker for prenatal sex hormone exposure. The higher ratio in women is associated with greater prenatal testosterone and lower estrogen exposure [1, 2]. It is also related to a wide range of diseases. Right and left hand 2D:4D ratios are lower in primary brain tumor patients relative to healthy individuals, with greater prenatal testosterone exposure in patients . And patients with coronary artery disease are likely to have higher 2D:4D ratio than controls in both hands . Ischemic stroke (IS) is recognized as a sexually dimorphic disorder, with a relatively lower stroke incidence in women . It usually induces disability and mortality among the encounters all over the world [6, 7]. Epidemiological and clinical studies have indicated the altered testosterone and estrogen levels in IS [5, 8]. The sex hormones may account for the stroke sensitivity of among the population. However, no studies are available to detect the relationship between 2D:4D ratio and IS. We here took this study to demonstrate the issue.
Materials and Methods
Written informed consent from all participants were obtained. This study was approved by the Ethics Committee of the institution in Wannan Medical College and was performed in accordance with the principles of Declaration of Helsinki. In this cross-sectional retrospective study, we recruited 100 subjects from the Department of Neurology, Yijishan Hospital between September 2016 and June 2017. Yijishan Hospital is a stroke center in East China Region, covering approximately 8 million people. All cases were form Han ethnic group. Individuals with former hand lesions, infertility, endocrine disorders, genetic diseases, and left handers were excluded. Patients with first ever IS were enrolled in patient group. An acute IS was confirmed by computed tomography or magnetic resonance imaging of the brain within 48 hours onset, on cases with neurological deficits. Subjects with IS and other central nervous system diseases history, that might influence the reliability of this study, were excluded. Two experienced physicians were responsible for inclusion and exclusion, independently. Any disagreement was determined by the senior neurologist (the corresponding author). The agreement between the two physicians were 96% for the inclusion and 95% for the exclusion.
Measurement of Finger Lengths and National Health Institute Stroke Scale (NIHSS)
Two independent examiners measured finger lengths, without acknowledgement of the medical diagnosis of the volunteers. The lengths of index and ring fingers were measured on the palmar surface of hands from the basal crease proximal to the palm to the tip of the finger, using electronic calipers as previously reported . Admission NIHSS was determined by two experienced stroke neurologists, who were not relevant to this study. The NIHSS includes the following domains: level of consciousness, eye movements, integrity of visual fields, facial movements, arm and leg muscle strength, sensation, coordination, language, speech and neglect. Each domain is scored on an ordinal scale ranging from 0-2, 0-3, or 0-4, with a total score from 0-42. Data were calculated, retested and recorded on computer. All these performers were blind to the design of the project and the further statistical analysis.
Statistical analyses were performed using the SPSS statistical software (SPSS 19.0, USA). The results were expressed as mean ± SD. Differences between the variables were determined by two-tailed Student’s t test. Receive operating characteristic (ROC) mode was used to detect predicting performance of 2D:4D ratios for IS. Spearman correlation analysis was used to study the relationship between 2D:4D ratios and NIHSS. P < 0.05 was regarded as statistically significant.
The baseline characteristics were shown in Table 1. 100 cases were included in this study, with 50 controls (25 males and 25 females, average age: 60.36 ± 12.29 years old) and 50 IS participants (25 males and 25 females, average As shown in Table 2, 2D:4D ratios of both age: 64.38 ± 13.36 years old). There were no hand were markedly higher than that in significant differences of age, atrial fibrillation controls (Pleft = 0.002; Pright = 0.006). The same and alcohol history between controls and trend was found in male ones (Pleft = 0.023; patients (P > 0.05). A significance was found Pright = 0.043). For females, left 2D:4D ratios in hypertension, diabetes, hyperlipemia, of patients were significantly higher over smoking between controls and sufferers healthy ones (P = 0.036), but not in right hand (P < 0.05). (P = 0.057).
The ROCs analyzing showed that the area under the curve (AUC) of left 2D:4D in all was 0.635 (95%CI: 0.527-0.743, P = 0.020), and it was 0.647 for right hand (95%CI: 0.539-0.755, P = 0.011) (Figure 1). The optimal cutoff point of left 2D:4D ratio for AIS was 0.9570 with sensitivity of 68.0% and specificity of 54.0%. For right hand, the point was 0.9445 with sensitivity of 74.0% and specificity of 52.0%. We discovered that AUCs of 2D:4D ratio in male were 0.667 (95%CI: 0.514-0.820, P = 0.043) (left) and 0.670 (95%CI: 0.519-0.822, P = 0.039) (right) (Figure 2). The optimal cutoff points of 2D:4D value for male were 0.9570 with 60.0% sensitivity and 72.0% specificity (left), and 0.9445 with sensitivity of 76.0% and specificity of 60.0% (right). However, AUCs of both hands in female were not statistically significant (Pleft = 0.109, Pright = 0.138).
We also assessed the relationship between 2D:4D ratios and NIHSS. No differences were found between 2D:4D ratios and NIHSS (All: 4.90±5.50, Pleft = 0.803, Pright = 0.565; Male: 5.40±7.12, Pleft = 0.960, Pright = 0.710; Female: 4.40±3.24, Pleft = 0.984, Pright = 0.592).
The current study was the first to study the association between 2D:4D ratio and IS. We found that stroke patients had a higher 2D:4D ratio in both hands. The same trends were found in both hands of male, and in female left hand.
2D:4D ratio is affected by prenatal sex hormones exposure and it acts as the symbol of sexual orientation of adults . The ratio tends to be higher in female, being associated with greater prenatal testosterone and lower estrogen exposure. Epidemiological and clinical studies have indicated men intend to have a higher incidence of IS [11, 12]. The most common biological explanation for this phenomenon may be attributed to sex hormones. Atherosclerosis of intracranial artery and thrombus formation is the core features of IS. Testosterone increases platelet aggregation and subsequent arterial thrombus formation . Estrogen has very potent effects on endothelial cells through promoting dilation and blood flow . An extremely lower endogenous testosterone was associated with higher risk of IS . And postmenopausal women receiving estrogen therapy had a lower IS rate than those without intervention . Also, sex hormones lead to microglia and astrocyte activation [17, 18], which are major contributing cells in neuroinflammation in response to various insults [19, 20, 21]. The inflammatory status would exacerbate the atherosclerosis in vascular arteries . Some researchers have confirmed the link between 2D:4D ratio and arterial atherosclerosis through biopsy .
We believed that there might be connections between 2D:4D and IS. The present study indicated that men tended to have a higher 2D:4D ratio in both hands. This is consistent with the previous findings in coronary heart disease. In that study, men with coronary heart disease shared a higher ratio of 2D:4D [24, 25]. This might be attributed to the cause of atherosclerosis changes in both disorders. However, the same trends only existed in left, but not right hand among women, indicating potential sex differences in this disease. More studies should be done to discover this matter. Also, we used electronic calipers to directly measure the lengths of fingers, instead of calculating them from photocopies and scans. This ensured the reliability and accuracy, as previously proved in a recent review .
NIHSS is a common tool for the assessment of stroke severity. It was originally developed in 1989  and now widely applied in various studies [28-30]. It was used to assess the relationship between 2D:4D ratios and stroke severity. It indicated that 2D:4D was not associated with the severity. It worked as a qualitative, not a quantitative tool for brain ischemia. High 2D:4D ratio is a possible biomarker for IS. Further research is required to validate this association in different populations in screening of patients’ susceptibility to develop IS.
A significant association was not found between 2D:4D ratio and IS in the current study. ROC analysis indicated its role in the diagnostic role of 2D:4D ratio in IS, but with limited sensitivity and specificity. It only indicated the possible place of it in the early understanding of the disorder.
The current study indicated that stroke patients had a higher 2D:4D ratio in both hands. The diagnostic value of 2D:4D ratio was limited in IS. Further research is required to explore the role of it in screening IS.
Zheng Z, Cohn MJ. Developmental basis of sexually dimorphic digit ratios. Proc Natl Acad Sci U S A 2011 2011-09-27;108(39):16289-94. Google Scholar
Manning JT. Resolving the role of prenatal sex steroids in the development of digit ratio. Proc Natl Acad Sci U S A 2011 2011-09-27;108(39):16143-4. Google Scholar
Bunevicius A, Tamasauskas S, Deltuva VP, Tamasauskas A, Sliauzys A, Bunevicius R. Digit ratio (2D:4D) in primary brain tumor patients: A case-control study. Early Hum Dev 2016 2016-12-01;103:205-8. Google Scholar
Lu H, Ma Z, Zhao J, Huo Z. Second to fourth digit ratio (2D:4D) and coronary heart disease. Early Hum Dev 2015 2015-07-01;91(7):417-20. Google Scholar
Suzuki S, Brown CM, Wise PM. Neuroprotective effects of estrogens following ischemic stroke. Front Neuroendocrinol 2009 2009-07-01;30(2):201-11. Google Scholar
Christophe BR, Mehta SH, Garton AL, Sisti J, Connolly EJ. Current and future perspectives on the treatment of cerebral ischemia. Expert Opin Pharmacother 2017 2017-04-01;18(6):573-80. Google Scholar
Cruz-Flores S. Acute Stroke and Transient Ischemic Attack in the Outpatient Clinic. Med Clin North Am 2017 2017-05-01;101(3):479-94. Google Scholar
Jeppesen LL, Jorgensen HS, Nakayama H, Raaschou HO, Olsen TS, Winther K. Decreased serum testosterone in men with acute ischemic stroke. Arterioscler Thromb Vasc Biol 1996 1996-06-01;16(6):749-54. Google Scholar
Fink B, Manning JT, Neave N. The 2nd-4th digit ratio (2D:4D) and neck circumference: implications for risk factors in coronary heart disease. Int J Obes (Lond) 2006 2006-04-01;30(4):711-4. Google Scholar
Ventura T, Gomes MC, Pita A, Neto MT, Taylor A. Digit ratio (2D:4D) in newborns: influences of prenatal testosterone and maternal environment. Early Hum Dev 2013 2013-02-01;89(2):107-12.Google Scholar
Barker-Collo S, Bennett DA, Krishnamurthi RV, Parmar P, Feigin VL, Naghavi M, et al. Sex Differences in Stroke Incidence, Prevalence, Mortality and Disability-Adjusted Life Years: Results from the Global Burden of Disease Study 2013. Neuroepidemiology 2015 2015-01-20;45(3):203-14. Google Scholar
Yatsuya H, Folsom AR, Yamagishi K, North KE, Brancati FL, Stevens J. Race- and sex-specific associations of obesity measures with ischemic stroke incidence in the Atherosclerosis Risk in Communities (ARIC) study. Stroke 2010 2010-03-01;41(3):417-25. Google Scholar
Glueck CJ, Wang P. Testosterone therapy, thrombosis, thrombophilia, cardiovascular events. Metabolism 2014 2014-08-01;63(8):989-94. Google Scholar
Tarhouni K, Guihot AL, Vessieres E, Procaccio V, Grimaud L, Abraham P, et al. Estrogens are needed for the improvement in endothelium-mediated dilation induced by a chronic increase in blood flow in rat mesenteric arteries. Vascul Pharmacol 2016 2016-05-01;80:35-42. Google Scholar
Holmegard HN, Nordestgaard BG, Jensen GB, Tybjaerg-Hansen A, Benn M. Sex Hormones and Ischemic Stroke: A Prospective Cohort Study and Meta-Analyses. J Clin Endocrinol Metab 2016 2016-01-01;101(1):69-78. Google Scholar
Wassertheil-Smoller S, Hendrix SL, Limacher M, Heiss G, Kooperberg C, Baird A, et al. Effect of estrogen plus progestin on stroke in postmenopausal women: the Women’s Health Initiative: a randomized trial. JAMA 2003 2003-05-28;289(20):2673-84. Google Scholar
Drew PD, Chavis JA. Female sex steroids: effects upon microglial cell activation. J Neuroimmunol 2000 2000-11-01;111(1-2):77-85. Google Scholar
Fernandez-Galaz MC, Morschl E, Chowen JA, Torres-Aleman I, Naftolin F, Garcia-Segura LM. Role of astroglia and insulin-like growth factor-I in gonadal hormone-dependent synaptic plasticity. Brain Res Bull 1997 1997-01-19;44(4):525-31. Google Scholar
Xu X, Cai X, Zhu Y, He W, Wu Q, Shi X, et al. MFG-E8 inhibits Abeta-induced microglial production of cathelicidin-related antimicrobial peptide: A suitable target against Alzheimer’s disease. Cell Immunol 2018 2018-05-24. Google Scholar
Shi X, Cai X, Di W, Li J, Xu X, Zhang A, et al. MFG-E8 Selectively Inhibited Abeta-Induced Microglial M1 Polarization via NF-kappaB and PI3K-Akt Pathways. Mol Neurobiol 2017 2017-12-01;54(10):7777-88. Google Scholar
Shao YY, Li B, Huang YM, Luo Q, Xie YM, Chen YH. Thymoquinone Attenuates Brain Injury via an Anti-oxidative Pathway in a Status Epilepticus Rat Model. Transl Neurosci 2017 2017-01-01;8:9-14. Google Scholar
Xing J, Lu J. Effects of mTOR on Neurological Deficits after Transient Global Ischemia. Transl Neurosci 2017 2017-01-20;8:21-6. Google Scholar
Ozdogmus O, Cakmak YO, Coskun M, Verimli U, Cavdar S, Uzun I. The high 2D:4D finger length ratio effects on atherosclerotic plaque development. Atherosclerosis 2010 2010-03-01;209(1):195-6. Google Scholar
Kyriakidis I, Papaioannidou P, Pantelidou V, Kalles V, Gemitzis K. Digit ratios and relation to myocardial infarction in Greek men and women. Gend Med 2010 2010-12-01;7(6):628-36. Google Scholar
Wu XL, Yang DY, Chai WH, Jin ML, Zhou XC, Peng L, et al. The ratio of second to fourth digit length (2D:4D) and coronary artery disease in a Han Chinese population. Int J Med Sci 2013 2013-01-20;10(11):1584-8. Google Scholar
Ribeiro E, Neave N, Morais RN, Manning JT. Direct versus indirect measurement of digit ratio (2D: 4D) a critical review of the literature and new data. Evolutionary Psychology 2016 2016-01-01;14(1):2125747160. Google Scholar
Nilanont Y, Komoltri C, Saposnik G, Cote R, Di Legge S, Jin Y, et al. The Canadian Neurological Scale and the NIHSS: development and validation of a simple conversion model. Cerebrovasc Dis 2010 2010-01-20;30(2):120-6. Google Scholar
Martin-Schild S, Albright KC, Tanksley J, Pandav V, Jones EB, Grotta JC, et al. Zero on the NIHSS does not equal the absence of stroke. Ann Emerg Med 2011 2011-01-01;57(1):42-5.Google Scholar
Braksick SA, Wijdicks EF. An NIHSS of 0 and a Very Disabling Stroke. Neurocrit Care 2016 2016-10-26.Google Scholar
Guo C, Shi X, Ding X, Zhou Z. Analysis of Radiation Effects in Digital Subtraction Angiography of Intracranial Artery Stenosis. World Neurosurg 2018 2018-04-21. Google Scholar
About the article
Published Online: 2018-11-12
Conflict of interest None of the authors has a conflict of interest to declare.
Funding This study was supported by grants from Talent Scientific Research Start-up Foundation of Yijishan Hospital, Wannan Medical College (Grant No. YR201603), Youth and Middle Foundation of Wannan Medical College (Grant No. KY86700312) and National Natural Science Foundation of China (Grant No. 81701061).
Citation Information: Translational Neuroscience, Volume 9, Issue 1, Pages 142–146, ISSN (Online) 2081-6936, DOI: https://doi.org/10.1515/tnsci-2018-0021.
© 2018 Ke Yang et al., published by De Gruyter. This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License. BY-NC-ND 4.0