2D:4D Digit Ratios in Adults with Gender Dysphoria: A Comparison to Their Unaffected Same-Sex Heterosexual Siblings, Cisgender Heterosexual Men, and Cisgender Heterosexual Women

2D:4D Digit Ratios in Adults with Gender Dysphoria: A Comparison to Their Unaffected Same-Sex Heterosexual Siblings, Cisgender Heterosexual Men, and Cisgender Heterosexual Women. Şenol Turan, Murat Boysan, Mahmut Cem Tarakçıoğlu, Tarık Sağlam, Ahmet Yassa, Hasan Bakay, Ömer Faruk Demirel & Musa Tosun. Archives of Sexual Behavior, Mar 10 2021, https://link.springer.com/article/10.1007%2Fs10508-021-01938-5

Abstract: We compared gender dysphoria (GD) patients and their same-sex siblings in terms of their 2D:4D ratios, which may reflect prenatal exposure to androgen, one of the possible etiological mechanisms underlying GD. Sixty-eight GD patients (46 Female-to-Male [FtM]; 22 Male-to-Female [MtF]), 68 siblings (46 sisters of FtMs; 22 brothers of MtFs), and 118 heterosexual controls (62 female; 56 male) were included in the study. FtMs were gynephilic and MtFs were androphilic. We found that 2D:4D ratios in the both right hand (p < .001) and the left hand (p = .003) were lower in male controls than in female controls. Regarding right hands, FtM GD patients had lower 2D:4D ratios than female controls (p < .001) but their ratios did not differ from those of their sisters or male controls. FtM GD patients had no significant difference in their left-hand 2D:4D ratios compared to their sisters or female and male controls. While there was no significant difference in right hands between FtM's sisters and male controls, left-hand 2D:4D ratios were significantly higher in FtM's sisters (p = .017). MtF GD patients had lower right-hand 2D:4D ratios than female controls (p <.001), but their right-hand ratios did not differ from those of their brothers and male controls. There was no significant difference in left-hand 2D:4D ratios between MtF GD patients, and their brothers, or female and male controls. FtM GD patients showed significantly masculinized right-hand 2D:4D ratios, while there was no evidence of feminization in MtF GD patients.

Discussion

The 2D:4D ratio is thought to be determined during critical periods of prenatal development under the influence of sex hormones. Here, we conducted a case-control study of the 2D:4D ratio, which is thought to be indicative of prenatal exposure to sex hormones, in patients with GD, their unaffected same-sex heterosexual siblings, and cisgender heterosexual male and female controls. We observed that patients with FtM GD had lower right-hand 2D:4D ratios than cisgender heterosexual female controls and they did not significantly differ from cisgender heterosexual male controls. Although they had lower right-hand 2D:4D ratios than their unaffected heterosexual sisters, the difference was not significant. Furthermore, the left-hand 2D:4D ratios in patients with FtM GD did not differ significantly from that of their unaffected heterosexual sisters, cisgender heterosexual male or female controls. Patients with MtF GD had lower right-hand 2D:4D ratios than cisgender heterosexual female controls but they did not show a significant difference from their unaffected heterosexual brothers or cisgender heterosexual male controls. There was no significant difference in the left-hand 2D:4D ratios between patients with MtF GD and their unaffected heterosexual brothers, as well as the cisgender heterosexual male or cisgender heterosexual male controls.

Early studies of 2D:4D ratios in patients with GD found that patients with MtF GD have higher right-hand 2D:4D ratios than those of male controls, while differences in 2D:4D ratios between patients with FtM GD and female controls were not significant (Kraemer et al., 2007; Schneider et al., 2006). However, subsequent studies found results contradicting with the findings of these two first studies. Wallien et al. (2008) found a lower 2D:4D ratio in patients with FtM GD in comparison with female controls, but no significant difference between patients with MtF GD and male controls. Vujovic et al. (2014) echoed and extended the finding reported by Hisasue et al. (2012) that patients with FtM GD had the lowest left-hand 2D:4D ratios, as measured by X-rays, in comparison with both male and female controls. In a similar vein, Leinung and Wu (2017) found a low dominant-hand 2D:4D ratio in patients with FtM GD compared to female controls; however, a feminized 2D:4D (higher) in patients with MtF GD in comparison with male controls was not observed. In another more recent study, Sağlam et al. (2020) found a lower right-hand 2D:4D ratio in patients with FtM GD in comparison with female controls, but no significant difference between patients with MtF GD and male controls in both hands. In a meta-analytic study, Voracek, Kaden, Kossmeier, Pietschnig, and Tran (2018) concluded that patients with MtF GD showed feminized right-hand 2D:4D digit ratios, while the identical effect for the left-hand digit ratio was not significant. However, the study findings underscored that patients with FtM GD had neither masculinized right-hand 2D:4D ratios nor left-hand 2D:4D digit ratios. In another meta-analytic study conducted by Sadr et al. (2020), it was shown that 2D:4D digit ratios of patients with MtF GD (transwomen) were higher (feminized) than male controls and this finding was consistent across studies and both hands, but the effect sizes were small (left hand: d = .19, p = .010; right hand: d = .29, p = .0009). For patients with FtM GD (transmen), they had a lower (masculinized) 2D:4D digit ratio in both hands than female controls, while it was detected that the effect sizes were not statistically significant (left hand: d = − .20, p = .195; right hand: d = − .36, p = .123). The latest meta-analytic study conducted by Siegmann et al. (2020) showed that the 2D:4D digit ratios of patients with MtF GD were significantly higher than male controls (Hedge’s g = .153), and this effect is even more pronounced if the diagnosis was made by a clinician (Hedge’s g = .193). They did not detect any significant difference between patients with FtM GD and female controls.

In the present study, we found that patients with FtM GD had lower right-hand 2D:4D ratios than cisgender heterosexual female controls, but did not have lower ratios than cisgender heterosexual male controls. Previous studies have concluded that in humans the right-hand 2D:4D ratios are more sensitive to early prenatal androgen exposure than the left 2D:4D ratios (Hönekopp & Watson, 2010; Manning, 2002; Manning, Scutt, Wilson, & Lewis-Jones, 1998; Xu & Zheng, 2015). In keeping with the previous literature (Hönekopp et al., 2010; Kraemer et al., 2007; McFadden et al., 2005; Schneider et al., 2006), the differences appear to be more pronounced in the right-hand 2D:4D ratios in our study. To account for this finding, we may suggest that increased levels of prenatal steroid exposure may be associated with greater lateralization toward the left hemisphere (Grimshaw, Bryden, & Finegan, 1995; Jackson, 2008; Witelson & Nowakowski, 1991) which may make the differences in finger length ratios more visible in the right hand. Thus, ICC analyses showed that the 2D:4D ratios of patients with FtM GD and their unaffected heterosexual sisters revealed moderate resemblance in both the right hand and in the left hand, with a stronger correlation for the right hand. Adding to this perspective, an animal model put forth by Zheng and Cohn (2011) suggested that the 2D:4D ratios of the right paw are more sensitive to prenatal androgen exposure than the 2D:4D ratios of the left paw. Emerging evidence and the consistency of relevant findings appear to give credence to the increased sensitivity of the right hand to prenatal androgen exposure (Schneider et al., 2006). In addition to this, we also found no significant difference in the left-hand 2D:4D ratios between patients with FtM GD and cisgender heterosexual male controls. Vujovic et al. (2014) reported that patients with FtM GD showed the lowest left-hand 2D:4D ratio compared to both the control males and females. These findings may be interpreted as meaning that both the right and left hand may be affected by prenatal androgen exposure to a certain degree, but that this influence may be stronger for the right hand. However, there is no credible explanation for an underlying mechanism that specifies a different association of the right and the left finger lengths with prenatal androgen levels, and thus, the mechanism underlying this needs further investigation (Hisasue et al., 2012).

Growing evidence from family and twin studies demonstrates that genetic factors contribute to the development of GD (Gomez-Gil et al., 2010; Heylens et al., 2012; Polderman et al., 2018; Turan & Demirel, 2017), but a strong candidate gene accounting for the development of GD is yet to be identified (Zucker et al., 2016). In human beings, many traits and diseases have a polygenic architecture (Zucker et al., 2016), and many genotypical characteristics evolve into phenotypical traits through interactions with the environment. GD is most likely a complex condition that results from a combination of multiple genetic and environmental factors. In this context, the term endophenotype, meaning measurable components unseen by the unaided eye along the pathway between disease and genotype, has arisen as an important concept in the investigation of complex psychiatric diseases (Gottesman & Gould, 2003). An endophenotype is a quantitative biological trait which shows greater prevalence in unaffected first-degree parents of GD patients than in the general population ((Flint & Munafo, 2007; Kendler & Neale, 2010) and may be neurophysiological, biochemical, endocrinological, neuroanatomical, cognitive, or neuropsychological in nature (Gottesman & Gould, 2003).

In keeping with the literature, the most salient finding of the current data was that patients with FtM GD’s right-hand 2D:4D ratios had significant and strong intraclass correlation with their unaffected heterosexual sisters’ right 2D:4D ratios (r = 0.55). The same was also true for the left-hand 2D:4D ratios, but with a relatively more modest intraclass correlation coefficient (r = 0.36). In contrast, neither the intraclass correlation coefficients for the right-hand nor the left-hand 2D:4D ratios of patients with MtF GD and their unaffected heterosexual brothers were substantial. Moreover, patients with FtM GD and their unaffected heterosexual sisters did not significantly differ in their right 2D:4D ratios from cisgender heterosexual male controls.

These results may be interpreted as further evidence for significant associations between prenatal testosterone exposure and the gender-related behaviors previously suggested in the literature (Brown, Hines, Fane, & Breedlove, 2002; Grimbos et al., 2010; Hines, 2006; Lutchmaya, Baron-Cohen, Raggatt, Knickmeyer, & Manning, 2004; Voracek, Dressler, & Manning, 2007). To the best of our knowledge, relying on the present results, which were consistent with the preceding data (Manning, Bundred, Newton, & Flanagan, 2003; van Anders, Vernon, & Wilbur, 2006), the right-hand 2D:4D digit ratios, in particular, can be considered an endophenotype for masculinization in biological females, which may result in GD.

In this study, we found that patients with MtF GD had lower right-hand 2D:4D digit ratios than cisgender heterosexual female controls, but the mean difference from cisgender heterosexual female controls for the left-hand digit ratios was not significant. On the other hand, unlike patients with MtF GD, the unaffected heterosexual brothers of MtF GD patients had significantly lower left-hand 2D:4D ratios than cisgender heterosexual female controls. These findings are partly consistent with those of previous studies (Kraemer et al., 2007; Schneider et al., 2006; Vujovic et al., 2014) showing that patients with MtF GD seem to also be affected by prenatal androgen exposure, with the exception of the direction of the hand, in which right-hand sensitivity has been widely highlighted. The masculinization in patients with MtF GD might be conceived of as a “ceiling effect” in which males are exposed to sufficient levels of androgen stimulation during the prenatal period (Breedlove, 2010), and the right hand may be more affected from this exposure. However, the 2D:4D digit ratios did not show an endophenotypic characteristic for patients with MTF, when their unaffected heterosexual siblings, cisgender heterosexual male controls, and cisgender heterosexual female controls were considered.

Our study had several limitations that should be considered. First, the sample sizes were relatively small in all groups, which compromise the generalizability of the current results. Second, the measurement method of finger length was indirect. Previous studies showed that indirect finger length measurement methods such as photocopies tended to produce lower 2D:4D ratios than direct measurements (Manning, Fink, Neave, & Caswell, 2005; Ribeiro, Neave, Morais, & Manning, 2016; Xu & Zheng, 2015). Therefore, it has been suggested that indirect measurements may not be the best method to investigate sex or gender effects in 2D:4D ratios (Manning, 2017). However, it has been argued that indirect measurement methods can be used as long as 2D:4D ratios obtained with different digit measurement methods are combined within one study (Xu & Zheng, 2015). Third, because siblings were recruited by patients with GD, it can be said that we have a biased sample. Finally, the absence of patients with FtM GD who were sexually attracted to men and patients with MtF GD who were sexually attracted to women make it difficult to distinguish the effect of sexual orientation and gender identity on digit ratio. As a matter of fact, in the meta-analysis study conducted by Grimbos et al. (2010), similar to the results of our study, while homosexual women had a lower 2D:4D ratio than did heterosexual women, no significant difference was found between homosexual and heterosexual men.

In conclusion, patients with FtM GD had significantly masculinized right-hand 2D:4D ratios. The unaffected heterosexual sisters of patients with FtM GD measured between the digit ratios of cisgender heterosexual male and females in terms of right-hand 2D:4D ratio. This could be indicative of an endophenotype for prenatal exposure to androgens that has long been considered a significant antecedent of this phenomenon of the right-hand 2D:4D digit ratio. In contrast, we did not find prominent evidence pointing to feminization in the 2D:4D ratio in patients with MtF GD. Patients with MtF GD seemed to follow different developmental pathways in the early period. Further studies with larger samples should be conducted to develop a more sophisticated understanding of the potential underpinnings of GD in relation to the 2D:4D ratio.