Thyroid diseases and second to fourth digit ratio in Polish adults

The association between second to fourth finger ratio and thyroid diseases is unexplained. There is a possible interaction between prenatal exposition to sex hormone and thyroid functions in the adulthood. The study included 175 adults investigated in Łódź in the central Poland. It consisted of two main parts: a survey including questions about occurrence of thyroid gland dysfunction and anthropometric measurements (body mass and height and length of the second and fourth finger, waist and hip circumferences). The women who had thyroid disease had higher 2D:4D digit ratio (left hand) (mean = 1.004; SD = 0.036) than healthy ones (mean = 0.989; SD = 0.030) (t = − 2105; p = 0.038; d = 0.707). The association between thyroid diseases occurrence and prenatal steroid hormone exposition is noticed. Only females who had thyroid diseases tend to have higher 2D:4D digit ratio, for left hand.

Estrogens and androgens are two of the five classes of the steroid hormones. Women and men have them in significantly different amounts that affect their sexual traits and physiology 1 . The widely known fingers ratio-2D:4D was identified with proportion of estrogen and androgens in prenatal life 2 , but also with current level of the sex hormones 3,4 . However, some studies pointed out that association between the second to fourth finger is only prenatal effect and current sex hormone concentration in this mechanism is questionable [5][6][7] .
The association between thyroid hormones and sex hormones is noticed. In the cells of thyroid tissue are located sex hormone receptors, thus thyroid diseases may be linked with level of sex hormones 8 . The thyroid is a gland which produces hormones regulating metabolism-triiodothyronine (T3) and thyroxine (T4). The thyroid regulation is under control of HPA axis. The proper hormonal balance is crucial for the body homeostasis. Inappropriate thyroid hormones concentration may stem from thyroid diseases such as overactive thyroid gland or hypothyroidism 9 .
There are also studies which linked sex hormones concentrations with the thyroid diseases. Hypothyroidism is more common among individuals with increased estrogen levels 10 , thus hypothyroidism is less frequently observed in men than in women 11 .
Additionally, thyroid cancer is associated with excess of estrogens [12][13][14][15][16] . Moreover, thyroid autoimmune diseases are observed in men with increased estrogen levels 10,17,18 . There are few studies which evaluated link between digit ratio and thyroid diseases. Tabachnik et al. 19 pointed out that thyroid disorders were more common among women with higher 2D:4D. The prenatal programing of thyroid and sex hormones stays tentative. Wilcoxon and Redei 20 showed in the animal studies that among adults, thyroid function is programmed in utero, however that might be triggered by sex steroids in the adulthood.
Moreover, body mass index (BMI) seems to be an important factor associated with sex hormones proportions and thyroid diseases. Female pattern of 2D:4D finger ratio is associated with elevated BMI, as presented Fink et al. 21 among males and Bagepally et al. 22 among both sexes. Facing the problem of thyroid dysfunctions and body mass dysregulation the direct association is uncertain. In the case of more common hypothyroidism the patients tend to have higher BMI and fat mass 23,24 . It relates to lower cell metabolism triggered by lower T4 value and leptin interaction 25 .
In this study we have examined the association between second to fourth finger ratio and thyroid diseases, due to possible sex hormone prenatal exposition and interaction with thyroid hormones in the adulthood taking into account body mass index (BMI) and waist to hip ratio (WHR).

Material and methods
The study included 175 adults (101 females and 74 males) investigated between July 2020 and September 2020 in Łódź (population 680,000) in the central Poland. It consisted of two main parts: a survey and anthropological measurements. The survey was filled in by the probants during measurements and contained information about: occurrence of thyroid diseases and the family' history of the thyroid diseases. Among all patients 37 declared thyroid diseases (hypothyroidism or Hashimoto's disease), the rest 138 did not declare any thyroid diseases. The second part of the investigation including the following anthropological measurements performed according to Martin procedure 26 by qualified staff received standardized training for each type of measurements: body weight (with an accuracy of 0.1 kg) using a scale, body height (with an accuracy of 0.001 m) using an anthropometer, waist and hip circumferences using (with an accuracy of 0.001 m) using an anthropometric tape, the length (from a midpoint of the flexure-crease proximal to the palm to the tip of the finger) of the second and the fourth digits in both hands (with an accuracy of 0.001 m) directly by hands using a sliding calliper (Vernier calliper). All measurements were repeated twice and that the average value was taken to minimize the measurements error.
Some of the measurements were used to calculate the following indexes: the 2D:4D digit ratio [the quotient of the length of the second digit and the fourth digit (mm)], the BMI-the body mass index [the quotient of body mass (kg) and the square of height (m 2 )], the WHR-the waist to hip ratio [the quotient of waist circumference (cm)] and hip waist circumference.
This study was conducted according to the guidelines of the Declaration of Helsinki, and all procedures involving research study participants were approved by the consent of the Bioethics Committee at the Medical University of Lodz (RNN/374/19/KE). Written informed consent was obtained from all participants.
Statistical analysis. The Shapiro-Wilk test was used to verify the distribution of the continuous variables.
Finger ratio 2D:4D for right and left hand and BMI were normally distributed (box-cox transformation was used due to the skewness of BMI) thus parametric tests were applied for the further analysis.
The Spearman correlation was used to evaluate association between age, BMI, WHR versus 2D:4D finger ratio for both hands separately for healthy and ill man and women.
The Chi 2 test was used to check frequency differences between BMI categories according to WHO among investigated individuals and frequency differences between investigated individuals who reported and those who did not report thyroid diseases in the 2D:4D digit ratio categories (below 1-male pattern, above or equal 1-female pattern) for the both hands. Odds ratio was calculated to asses if female or male hand pattern is a risk factor in thyroid diseases.
The student t-tests were used to investigate the age, BMI (after Box-Cox transformation), WHR and finger ratio (right, left hand) differences depending on sex and occurrence of thyroid diseases. Additionally, student t-test for independent samples were used to verify differences between 2D:4D digit ratio for right and left hand. There were statistically significant differences between 2D:4D digit ratio for right and left hand, (t = − 2.668; p = 0.008), thus the further analyses were conducted separately for the right and left hand. To calculate effect size for each comparisons Cohen's d value were calculated.
Multiple regression models were applied to verify which variables importantly explain variability of the 2D:4D for both hands.
The Statistica ver. 12.0 software was used to perform all calculations.
The Table 2 showed that among individuals with thyroid diseases obesity and overweight were more frequent than among healthy ones. 57.97% of females without thyroid diseases had normal weight and 40.58% were overweight or obese, but among females who had thyroid diseases 37.50% had normal weight and 62.5% were overweight or obese. In the case of men without thyroid diseases 24.64% had normal weight and 73.92% were overweight or obese, but among males who had thyroid diseases 20.00% had normal weight and 80.00% were overweight or obese. Independently on thyroid diseases occurrence, men more frequently had overweight or obesity than women. Table 3 presented non statically significant frequency differences between investigated individuals who reported and those who did not report thyroid diseases in the two 2D:4D digit ratio categories (below 1-male pattern, above or equal 1-female pattern) for the both hands. Odds ratio showed that female hand pattern in the right hand reduced the risk of thyroid diseases for the both sexes. In contrary to right hand for the left hand the results were contradictory, female hand pattern was a risk factor of thyroid diseases for both sexes, however the p value did not allow to interpret this result as a statistically significant.
The Spearman correlations presented in the Table 4 showed statistically significant results between BMI and WHR among all investigated individuals. BMI was negatively correlated with 2D:4D digit ratio (L) and BMI among males who had thyroid diseases. Among healthy women age was positively correlated with BMI and WHR. Only among males who had thyroid diseases there were negative correlation between the 2D:4D digit ratio (R) and age and between the 2D:4D digit ratio (L) and BMI.
BMI, age and WHR were not statistically significantly different among individuals who had thyroid diseases and healthy females and males (Table 5). Moreover, the 2D:4D digit ratio for both hands were not statistically significant among men who have thyroid disease and healthy one, but also for 2D:4D (R) among women have www.nature.com/scientificreports/ thyroid disease and healthy one. The differences between females who had thyroid diseases and healthy ones were observed only in the case of 2D:4D digit ratio (left hand). The women who had thyroid disease had higher 2D:4D digit ratio (left hand) (mean = 1.004; SD = 0.036) than healthy ones (mean = 0.989; SD = 0.030) (t = − 2105; p = 0.038; d = 0.707) ( Table 5, Fig. 1). The regression models explaining variability of 2D:4D (R) and (L) were performed separately for males and females. The following variables were included in the model: age, BMI, WHR and occurrence of the thyroid diseases. Neither for males nor for females' models for each hand were statistically significant (Supplementary data).

Discussion
Among plenty of studies which discussed the association between second to third digit ratio and some of the human traits or diseases [27][28][29][30] , there is a lack of studies which investigated an association with thyroid diseases. Only Tabachnik et al. 19 found that women with higher 2D:4D had more frequently thyroid disorders. Our results are partially in line with Tabachnik's outcomes, as we also showed that females with higher 2D:4D (left hand) more commonly had thyroid diseases. Interestingly, we did not find it for the right hand. Some studies underline that right hand is more representative for digit ratio calculation 31 .
The relationship between prenatal programming of thyroid functions and sex hormones remains unclear, however Wilcoxon and Redei 20 claimed that thyroid function is programmed in utero and might be regulated by sex steroids in the adulthood. Table 3. Frequency differences between investigated individuals who reported and those who did not report thyroid diseases in the 2D:4D digit ratio categories (below 1-male pattern, above or equal 1-female pattern) for the both hands.  Table 4. Association between age, BMI, WHR versus 2D:4D finger ratio for both hands separately for healthy and ill man and women. Bold indicates statistically significant results (p < 0.05). www.nature.com/scientificreports/ Thyroid hormones are transported by specific protein: thyroxine-binding globulin (TBG). Estrogen causes increase in the concentration of TBG which leads to increase concentration thyroid hormone (T4). However, there are evidences that thyroid disorders may be a consequence of direct estrogen's influence on hypothalamicpituitary-thyroid axis (HPT) and unrelated to TBG e.g. elevated TSH 32,33 .

Pair of variables
There are studies which consider thyroid diseases and sex hormone proportions. Elevated estrogen levels seem to occur more commonly among individuals with hypothyroidism 10 , that is less frequently observed in men than in women 11 .
In contrary, some studies presented the link between the occurrence of the thyroid diseases and PCOS, that is connected with estrogen, progesterone and androgens imbalance. Some of the studies showed that elevated level of androgens may relate to PCOS and hypothyroidisms 10,11,34,35 . Similarly, female with lower estrogen level during menopausal period more frequently had hypothyroidism as Abdel-Dayem, M.M. and M.S. Elgendy showed in rats' studies 34 .
Additionally, there are some suspicions that elevated testosterone level might be associated with excess of thyroid functions. The levels of testosterone in Chinese male patients with TPP-thyreotoxic periodic paralysis (elevated thyroid hormone production) was higher compared to those with only hyperthyroidism 36 .
Among adults there was not observed correlation between age and 2D:4D finger ratio 37 , although we presented the negative correlation between age and 2D:4D finger ratio but only for the right hand among man who had thyroid diseases, thus more study is needed in this area.
We did not replicate the results of the study performed by Bagepally et al. 22 who presented that higher 2D:4D finger ratio is associated with elevated BMI. We showed only dimorphic differences-women had statistically significantly lower BMI and less frequently had overweight and obesity than men, that is in line with other studies around the world 38,39 . Women are more familiar with healthy lifestyle than men that results in lower BMI among women than in men 40 . However, worldwide the prevalence of obesity is higher among women than in men independently on country development status [41][42][43] . These results lead to the conclusion that extreme cases of excessive body mass are more common among women but simultaneously the women are more likely to take Table 5. Differences in age, BMI, 2D:4D (R), 2D:4D (L) among individuals who had thyroid diseases and healthy one separately for females and males. Bold indicates statistically significant results (p < 0.05).  www.nature.com/scientificreports/