DR [page 6] [Dermatology Reports 2016; 8:6386] Digit-length ratios (2D:4D) as a phenotypic indicator of in utero androgen exposure is not prognostic for androgenic alopecia: a descriptive-analytic study of 1200 Iranian men. Amir Feily,1 Masoomeh Hosseinpoor,1 Ali Bakhti,1 Mohamad Nekuyi,1 Saeed Sobhanian,2 Zahra Fathinezhad,3 Reza Sahraei,4 Marigdalia K. Ramirez-Fort5 1Department of Dermatology, Jahrom University of Medical Sciences, Jahrom, Iran; 2Hormozgan University of Medical Sciences, Bandarabas, Iran; 3Department of Community Health, Jahrom University of Medical Sciences, Jahrom, Iran; 4Department of Anesthesiology, Jahrom University of Medical Sciences, Jahrom Iran; 5Department of Dermatology, Tufts Medical Center, Boston, MA, USA Abstract The etiology of androgenic alopecia (AGA) involves several factors, including genetics, androgens, age and nutrition. Digit-length ratio of the index and ring finger (2D:4D) is an indicator of prenatal exposure to sex hor- mones. There is a paucity of studies that sys- temically review the possible positive predic- tive value of 2D:4D in the development of AGA. We performed a single-site, descriptive-analyt- ical study among a racially homogeneous pop- ulation. Our results revealed that no signifi- cant association was determined between right 2D:4D and AGA severity within our entire population (P=0.384, r=0.025), however a pos- itive correlation coefficient was identified in subjects above the age of 40. Based on the receiver operating characteristic curve analy- sis, 2D:4D does not predict the development of AGA. AGA is truly a multifactorial disease. Further, our findings suggest that increased in utero exposure to androgens as a fetus does not predispose men to develop AGA. Introduction Androgenic alopecia (AGA) is the most com- mon type of progressive hair loss. The etiology of AGA involves several factors, including genetics, androgens, age and nutrition.1-4 Some evidence suggests that the digit-length ratio of the index and ring finger (2D:4D) is an indicator of prenatal exposure to sex hor- mones, with a lower 2D:4D being suggestive of a greater androgen exposure.5-8 Digit-length ratios have been utilized to determine the effects of prenatal androgen exposure a variety of phenotypic expres- sions.5,6,8 However, there is a paucity of studies that systemically review the possible positive predictive value of 2D:4D in the development of AGA. Materials and Methods The study was initiated after approval by the research and ethics committee of Jahrom University of Medical Sciences, approval ID: JUMS.REC.1393.017. All participants signed an informed consent prior to participating in the study. We performed a single-site, descriptive- analytical study between June 2013 and February 2014 among a racially homogeneous population that they were selected by stratified and randomized sampling. Participants did not have a significant history of other types of alopecia (e.g. iatrogenic scarring alopecia, alopecia areata, etc.). A trained team per- formed digit-length measurements of both hands with vernier calipers and subsequently calculated the 2D:4D. A single trained techni- cian graded baldness using the Hamilton- Norwood Classification scale; for simplicity these grades were further divided into four stages: no baldness (I), mild (II, III), moderate (IV, V) and severe baldness (VI, VII). Associations between 2D:4D and AGA were determined with SPSS version 16. The quanti- tative results are presented as a mean±stan- dard deviation (SD). A Pearson linear correla- tion was performed to assess relationships between 2D:4D and age; a Spearman linear correlation to assess relationships between 2D:4D and AGA severity, and ROCs mode was used to measure the validity of 2D:4D as a pre- dictive test for AGA. Statistical significance was assigned at P<0.05. Results A total of 1200 men between 20 to 60 years of age with a mean age of 33.2 (SD: 0.28), enrolled in the study. The prevalence of AGA among the study population was 45.4%. A total of 53.4% of the participants had normal hair distribution (aged 29.95±8.4 years), 26.16% had mild hair loss (aged 34.97±10.11 years), 15.19% had moderate (aged 40.35±9.43 years) and 4.32% had severe hair loss (aged 42.28±9.92 years). The mean ratio of the right 2D:4D was 0.992 (SD: 0.0024), while the left was 0.982 (SD: 0.0017). No significant differences were iden- tified between left and right hand 2D:4D per subject (Table 1). There was significant asso- ciation between age and AGA(r=-0.426, P=0.001). No significant association was determined between right 2D:4D and AGA severity within our entire population (P=0.384, r=0.025), also there was no signifi- cant association between left 2D:4D and AGA severity (P=0.495, r=0.028), however a corre- lation coefficient was identified in subjects above the age of 40. The receiver operating characteristic (ROC) analysis of subjects age 40 and above demon- strated the area under curve (AUC) as 0.502 (95%CI 0.391 to 0.613) and 0.480 (95% CI 0.371 to 0.590) for right and left 2D:4D, respec- tively, as a predictive test for AGA (Figure 1). Dermatology Reports 2016; volume 8:6386 Correspondence: Masoomeh Hosseinpoor, Department of Dermatology, Jahrom University of Medical Sciences, Shahid Motahhari Blvd, Jahrom, Iran. Tel.: +98.937.6925988. E-mail: masoomehosseinpoor@yahoo.com Key words: Androgenic alopecia; hair loss; digit- length ratio; predictive value. Contributions: the authors contributed equally. Conflict of interest: the authors declare no poten- tial conflict of interest. Received for publication: 24 December 2015. Accepted for publication: 4 April 2016. This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0). ©Copyright Amir Feily et al., 2016 Licensee PAGEPress, Italy Dermatology Reports 2016; 8:6386 doi:10.4081/dr.2016.6386 Figure 1. Receiver operating characteristic curve analysis of right and left 2D:4D with androgenetic alopecia gold standard. No n c om me rci al us e o nly [Dermatology Reports 2016; 8:6386] [page 7] Discussion and Conclusions Herein, is the largest study to date aimed to explore the utility of a phenotypic expression of in utero androgen exposure in predicting the development of AGA. The prevalence of AGA was 45.4%, similar to worldwide reports.9,10 The prevalence of AGA trended upwards as participant age increased. Although there was no significant association between right 2D:4D and AGA (P=0.384, r=0.025), there was a correlation coefficient identified in subjects above the age of 40. With increasing of age the AGA severity increases especially in participants above the age of 40. In clinical practice, most patients generally express AGA by age 40. Therefore, we attempt- ed to evaluate the utility of 2D:4D as a predic- tive test for AGA. Based on the ROC curve analysis, 2D:4D does not predict the develop- ment of AGA. AGA is truly a multifactorial dis- ease. Further, our findings suggest that increased in utero exposure to androgens does not predispose men to develop AGA. References 1. Trueb RM. Molecular mechanisms of androgenetic alopecia. Exp Gerontol 2002;37:981-90. 2. Stárka L, Cermáková I, Dusková M, et al. Hormonal profile of men with premature balding. Exp Clin Endocrinol Diabetes 2004;112:24-8. 3. Chumlea WC, Rhodes T, Girman CJ, et al. Family history and risk of hair loss. Dermatology 2004;209:33-9. 4. Inui S, Itami S. Androgen actions on the human hair follicle: perspectives. Exp Dermatol 2012;22:168-71. 5. Honekopp J, Manning TJ, Muller C. Digit ratio (2D:4D) and physical fitness in males and females: evidence for effects of prenatal androgens on sexually selected traits. Horm Behav 2006;49:545-9. 6. Honekopp J, Voracek M, Manning JT. 2nd to 4th digit ratio (2D:4D) and number of sex partners: evidence for effects of prena- tal testosterone in men. Psychoneuroen - docrinology 2006;31:30-7. 7. Manning JT, Wood S, Vang E, et al. Second to fourth digit ratio (2D:4D) and testos- terone in men. Asian J Androl 2004;6:211- 5. 8. Rivas MP, Moreira LM, Santo LD, et al. New studies of second and fourth digit ratio as a morphogenetic trait in subjects with congenital adrenal hyperplasia. Am J Hum Biol 2014;26:559-61. 9 . Severi G, Sinclair R, Hopper JL, et al. Androgenetic alopecia in men aged 40-69 years: revalence and risk factors. Br J Dermatol 2003;149:1207-13. 10. Yeo IK, Jang WS, Min PK, et al. An epi- demiological study of androgenic alopecia in 3114 Korean patients. Clin Exp Dermatol 2014;39:25-9. Article Table 1. Mean of 2d:4d ratio compared to androgenetic alopecia stage severity. AA stages Mean SD 95% CI Sum of squares Df Mean square F Sig. Right ratio 0.009 3 0.003 0.409 0.747 Normal 0.9919 0.08179 0.9855-0.9982 Mild 0.9952 0.06994 0.9874-1.0030 Moderate 0.9913 0.09576 0.9770-1.0057 Severe 0.9810 0.13942 0.9391-1.0229 Left ratio 0.012 3 0.004 1.127 0.337 Normal 0.9853 0.06019 0.9806-0.9899 Mild 0.9781 0.04175 0.9735-0.9828 Moderate 0.9795 0.09040 0.9659-0.9931 Severe 0.9812 0.03508 0.9707-0.9918 AA, androgenetic alopecia; SD; standard deviation; CI, confidence interval. No n c om me rci al us e o nly