Second to fourth digit ratio: a predictor of prostate-specific antigen level and the presence of prostate cancer

Authors


Tae Beom Kim, Department of Urology, Gachon University Gil Hospital, 1198 Guwol-Dong, Namdong-Gu, Incheon 405-760, Korea. e-mail: uroclinic@naver.com

Abstract

Study Type – Diagnostic (exploratory cohort) Level of Evidence 2b

What’s known on the subject? and What does the study add?

The Homeobox genes, Hox a and d, control urinogenital system differentiation and digit development. The patterns of digit formation may be related to gonad function and may be reflected in 2nd to 4th digit ratio (digit ratio). Digit ratio is negatively correlated with prenatal testosterone levels and androgen receptor activity which is related to the increased prostate cancer risk.

Patients with a lower digit ratio have a higher risk of prostate biopsy due to high PSA level, and of prostate cancer. Digit ratio could be a predictor of high PSA level and the presence of prostate cancer.

OBJECTIVE

To investigate the relationships between the 2nd to 4th digit ratio (digit ratio) and prostate volume, prostate-specific antigen (PSA) level, and the presence of prostate cancer.

PATIENTS AND METHODS

Of the men that presented with lower urinary tract symptoms (LUTS) at a single tertiary academic center, 366 men aged 40 or older with a PSA level ≤40 ng/mL were prospectively enrolled. Right-hand 2nd and 4th digit lengths were measured prior to the PSA determinations and transrectal ultrasonography (TRUS). Prostate volumes were measured by TRUS without information about digit length. Patients with a PSA level ≥3 ng/mL underwent prostate biopsy.

RESULTS

No relationship was found between prostate volume and digit ratio [correlation coefficient (r) =−0.038, P= 0.466]. But, significant negative correlations were found between digit ratio and PSA (r=−0.140, P= 0.007). When the patients were divided into two groups (Group A: digit ratio <0.95, n= 184; Group B: digit ratio ≥0.95, n= 182), Group A had a higher mean PSA level than Group B (3.26 ± 5.54 ng/mL vs 1.89 ± 2.24 ng/mL, P= 0.002) and had significantly higher risks of prostate biopsy [odds ratio (OR) = 1.75, 95% CI = 1.07–2.84] and prostate cancer (OR = 3.22, 95% CI = 1.33–7.78).

CONCLUSIONS

Patients with a lower digit ratio have higher risks of prostate biopsy and prostate cancer.

Abbreviations
AR

androgen receptor gene

PSAD

prostate-specific antigen density.

INTRODUCTION

The ratio of the 2nd to 4th digit length (digit ratio) of the right hand is known to be dependent on gender; men have lower ratios than women [1–3]. Furthermore, this gender difference is determined prenatally [4–6], and presumably under the control of the Hoxa gene, which is a key player in digit growth and form, and in the differentiation of testes and ovaries. This process starts in utero at about gestation week 14 [4].

It has been reported that the digit ratio of the right hand is negatively correlated with prenatal testosterone levels and positively correlated with prenatal oestrogen [7]. Accordingly, a high concentration of testosterone prenatally leads to a low digit ratio, which suggests high prenatal testicular activity. However, foetal response to prenatal testosterone is dependent on both the amount produced and foetal sensitivity to the hormone. Males and females with congenital adrenal hyperplasia (a trait associated with a high prenatal testosterone level) have lower digit ratios than controls [8,9].

Recently, it was suggested that the digit ratio of the right hand predicts the activity of the androgen receptor. Manning et al. demonstrated that the digit ratio of the right hand is positively correlated with the CAG repeat number of androgen receptor gene (AR), and that individuals with a low digit ratio possess AR alleles with low CAG repeat numbers [10]. Furthermore, it has been well established that a low AR CAG repeat number increases the risks of benign prostate hyperplasia (BPH) [11–13] and prostate cancer [14,15].

Based on the above-mentioned evidence, we considered that digit ratio might predict prostate volume and prostate–specific antigen (PSA) levels, and therefore, we investigated the relationship between it and prostate volume, PSA levels, and the presence of prostate cancer.

PATIENTS AND METHODS

Of the men that presented with lower urinary tract symptoms (LUTS) [Correction added after online publication 5 August 2010: lower urinary tract symptom (LUTS) has been changed to lower urinary tract symptoms (LUTS)] at a single tertiary academic center, 366 men aged 40 or older with a PSA level ≤40 ng/mL were prospectively enrolled in this study. All 366 patients underwent transrectal ultrasonography (TRUS) [Correction added after online publication 5 August 2010: transrectal ultrasonograph (TRUS) has been changed to transrectal ultrasonography (TURS)]. Men with a PSA level >40 ng/mL, or a history of α-blocker or 5α-reductase inhibitor medication, other malignancy, BPH surgery, or symptoms related to acute prostatitis, or who had fingers amputated were excluded.

Right-hand 2nd and 4th digit lengths were measured by an investigator prior to PSA determination and TRUS. Figure 1 shows how to measure digit length. Digit lengths were measured directly on ventral surface of fingers, from the crease proximal to the palm at the base of each digit to the digit tip, using a digital vernier caliper accurate to 0.01 mm [3]; this measurement has been previously reported to provide a high degree of repeatability [16,17] (Fig. 1). To minimize measurement errors, the mean values of duplicate measurements were used in the analysis.

Figure 1.

Measurement of digit length using vernier calipers. The 4th digit length is 7.304 cm.

Prostate volume measurements were taken by an uroradiologist unaware of finger lengths, and were calculated using the ellipsoid formula [prostrate volume (cc) =π/6 × lateral × anteroposterior × superoinferior diameters]. Those with a PSA level ≥3 ng/mL underwent a 12 core prostate biopsy after local anaesthesia induction with 5 mL 1% lidocaine, which was injected into both neurovascular bundles. Biopsies were performed transrectally using an 18-gauge biopsy needle and a biopsy gun under TRUS guidance to provide 17-mm-long tissue cores.

The relationships between the study variables were analysed using Pearson’s linear correlation. The Student’s t-test and the chi-square test were used to compare the variables of the two study groups divided by digit ratio. The analysis was performed using SPSS 12.0 (SPSS, Chicago, IL, USA) throughout, and differences were considered statistically significant when P values were less than 0.05.

RESULTS

Patients’ characteristics are summarized in Table 1. Mean patient age, testosterone level, prostate volume, PSA level and prostate-specific antigen density (PSAD) were 61.4 ± 10.5 years (mean ± SD), 445.59 ± 174.17 ng/dL, 35.05 ± 16.42 cc, 2.58 ± 4.28 ng/mL, and 0.066 ± 0.088 ng/mL/cc, respectively. Mean 2nd and 4th digit lengths, and digit ratio were 7.243 ± 0.490 cm, 7.612 ± 0.477 cm, and 0.952 ± 0.039, respectively. Of the 366 patients, 89 (24.3%) underwent a prostate biopsy, and 28 (7.7%) were found to have prostate cancer.

Table 1.  Characteristics of the study population
 Mean ± SDMedian (range)
  1. Digit ratio, 2nd digit length/4th digit length; PSA, prostate-specific antigen; PV, prostate volume; PSAD, prostate-specific antigen density.

Age (years)61.4 ± 10.5 62.0 (40.0–86.0)
2nd digit length (cm)7.243 ± 0.4907.211 (5.903–8.997)
4th digit length (cm)7.612 ± 0.4777.596 (6.198–9.198)
Digit ratio0.952 ± 0.0390.950 (0.827–1.089)
Testosterone (ng/dL)445.59 ± 174.17424.94 (150.15–919.86)
PV (cc)35.05 ± 16.4230.85 (13.46–108.27)
PSA (ng/mL)2.58 ± 4.281.08 (0.01–38.08)
PSAD (ng/mL/cc)0.066 ± 0.0880.035 (0.000–0.716)

Table 2 summarizes the relationships found between the variables investigated. No relationship was found between age and digit ratio [correlation coefficient (r) =−0.003, P= 0.959] and between prostate volume and digit ratio (r=−0.038, P= 0.466). However, PSA was negatively associated with digit ratio (r=−0.140, P= 0.007; Fig. 2).

Table 2.  Relationships between the study variables
  rP value
  1. Digit ratio, 2nd digit length/4th digit length; PSA, prostate-specific antigen; PV, prostate volume; PSAD, prostate-specific antigen density; r, correlation coefficient.

AgePV0.3370.000
AgePSA0.3110.000
AgePSAD0.2820.000
PVPSA0.4850.000
Digit ratioAge−0.0030.959
Digit ratioPV−0.0380.466
Digit ratioPSA−0.1400.007
Digit ratioPSAD−0.1210.021
Figure 2.

The relationship between prostate-specific [Correction added after online publication 5 August 2010: prostate specific has been changed to prostate-specific] antigen (PSA) level and 2nd to 4th [Correction added after online publication 5 August 2010: 2nd to 4th has been changed to 2nd to 4th] digit ratio (digit ratio). PSA was found to be negatively associated with digit ratio. [Correlation coefficient (r) =−0.140, P= 0.007] (Correction added after online publication 5 August 2010: (Correlation coefficient(r) =−0.140, P= 0.007) has been changed to [Correlation coefficient(r) =−0.140, P= 0.007)].

The study subjects were allocated to two groups by digit ratio: to Group A (digit ratio <0.95; n= 184); or to Group B (digit ratio ≥0.95; n= 182). No intergroup difference was found for age, serum testosterone level or prostate volume. However, Group A had a higher mean PSA level than Group B (3.26 ± 5.54 ng/mL vs 1.89 ± 2.24 ng/mL, P= 0.002) and a higher mean PSAD level (0.077 ± 0.109 ng/mL/cc vs 0.055 ± 0.059 ng/mL/cc, P= 0.014). In Group A, a significantly greater proportion of patients underwent prostate biopsy than in Group B [54/184 (29.3%) vs 35/182 (19.2%), P= 0.024] and a greater number had prostate cancer [21/184 (11.4%) vs 7/182 (3.8%), P= 0.006; Table 3]. Proportions of men aged 65 or older were not significantly different in the two groups [82/184 (44.6%) vs 77/182 (42.3%), P= 0.663] and there were no significant differences in the proportion of men with prostate volume ≥35 cc [79/184 (42.9%) vs 63/182 (34.6%), P= 0.102; Table 4]. However, there were significant differences in the proportion of men with PSA level ≥3 ng/mL [54/184 (29.3%) in Group A vs 35/182 (19.2%) in Group B, P= 0.024], and prostate cancer [21/184 (11.4%) in Group A vs 7/182 (3.8%) in Group B, P= 0.006; Table 4]. Men in Group A were found to have a significantly higher risk of prostate biopsy because of an elevated PSA level [odds ratio (OR) = 1.75, 95% CI = 1.07–2.84], and of having prostate cancer (OR = 3.22, 95% CI = 1.33–7.78; Table 4).

Table 3.  Comparison of the variables between the two study groups
 Digit ratioP value
<0.950 (Group A)≥0.950 (Group B)
  1. Digit ratio, 2nd digit length/4th digit length; PV, prostate volume; PSA, prostate-specific antigen; PSAD, prostate-specific antigen density.

N184182 
Digit ratio 0.922 ± 0.020 0.983 ± 0.0280.000
Age (years)  61.8 ± 10.7  61.0 ± 10.20.448
Testosterone (ng/dL)465.35 ± 195.47419.24 ± 140.150.302
PV (cc) 36.17 ± 17.27 33.93 ± 15.470.193
PSA (ng/mL)  3.26 ± 5.54  1.89 ± 2.240.002
PSAD (ng/mL/cc) 0.077 ± 0.109 0.055 ± 0.0590.014
Prostate biopsy (%)54/184 (29.3%)35/182 (19.2%)0.024
Cancer (%)21/184 (11.4%) 7/182 (3.8%)0.006
Detection rate (%)21/54 (38.9%) 7/35 (20.0%)0.052
Table 4.  Relationship between digit ratios and study variables
 Digit ratioP valueOR95% CI
<0.950 (Group A)≥0.950 (Group B)
  1. Digit ratio, 2nd digit length/4th digit length; OR, odds ratio; PV, prostate volume; PSA, prostate-specific antigen; PSAD, prostate-specific antigen density.

Age (years)≥65 82 770.6631.0960.725–1.658
<65102105   
PV (cc)≥35 79 630.1021.4210.931–2.168
<35105 119   
PSA (ng/mL)≥3.0 54 350.0241.7451.073–2.838
<3.0130147   
PSAD (ng/mL/cc)≥0.10 36 230.0721.6820.952–2.971
<0.10148159   
Prostate biopsyDone 54 350.0241.7451.073–2.838
Not done130147   
CancerPresent 21  70.0063.2211.334–7.778
Absent163175   
Cancer detectionYes 21  70.0612.5450.943–6.868
No 33 28   

Table 5 shows the relationships between digit ratio and the biopsy findings such as number of cores involved, percentage involvement of core and Gleason score. No relationship was found between digit ratio and the biopsy findings revealing cancer (Table 5).

Table 5.  Relationships between digit ratio and the biopsy findings revealing cancer
 rP value
Correlation StudyDigit ratioNo of cores involved−0.1930.325
Digit ratio% involvement of core−0.1560.429
Digit ratioSum of GS−0.0960.627
Digit ratioPrimary GS−0.1430.469
Digit ratioSecondary GS−0.0310.876
 Digit ratioP value
<0.950 (Group A)≥0.950 (Group B)
  1. Digit ratio, 2nd digit length/4th digit length; GS, Gleason score; r, correlation coefficient. [Correction added after online publication 5 August 2010: Group A <0.950, Group B ≥0.950 has been changed to <0.950 (Group A), ≥0.950 (Group B)]

Comparison StudyN21 7 
No of cores involved 6.00 ± 3.77 5.86 ± 3.630.931
% involvement of core (%)29.04 ± 24.6621.36 ± 16.710.452
Sum of GS 6.81 ± 1.08 6.43 ± 0.980.416
Primary GS 3.43 ± 0.60 3.14 ± 0.380.158
Secondary GS 3.38 ± 0.67 3.29 ± 0.760.754

DISCUSSION

The Homeobox genes, Hox a and d, control urinogenital system differentiation, and may therefore indirectly influence the prenatal production of testicular androgens and digit development [5,6,18]. This observation has led to the suggestion that patterns of digit formation may be related to gonad function [3,19] and, thus, to the suggestion that this may be reflected in 2nd to 4th digit ratio (digit ratio).

Several studies have shown that males have a lower digit ratio than females [1–3,20]. In addition, accumulated evidence suggests that some sex-dependent behaviours are also correlated with 2nd to 4th digit ratio. For example, some behavioural traits associated with the male gender have been shown to be associated with low value digit ratios, e.g. a left hand preference [21], good visual-spatial ability [22], and autism and Asperger’s syndrome [23]. On the other hand, traits more associated with a female gender, e.g. verbal fluency and emotional behaviour [24], have been associated with a high digit ratio. It has been suggested that this gender difference in digit ratio is determined prenatally, and that digit ratio is negatively related to prenatal testosterone and positively to prenatal oestrogen, and is a marker of sex steroid levels during brain organization [3]. Relative digit lengths are established as early as gestation week 14 [3,4], and are little changed at puberty. Moreover, individuals with congenital adrenal hyperplasia (a condition associated with high prenatal androgen) have lower digit ratios than controls [1,8,9].

Recently, Lutchmaya et al. [7] showed that digit ratio is negatively associated with prenatal testosterone levels and positively associated with prenatal oestrogen levels. This may mean that digit ratio is sensitive to the effects of relative foetal testosterone and foetal oestrogen concentrations, and that a high concentration of testosterone leads to a low digit ratio and suggests high prenatal testicular activity [25]. It is well known testosterone and AR play central roles in prostate growth and prostate cancer development, and that variations in the X-linked AR determine sensitivity to testosterone. More specifically, the transactivational activities of AR alleles with low numbers of CAG triplets respond sensitively to testosterone, whereas alleles with high numbers of CAG triplets are less sensitive, which means that CAG length is negatively related to testosterone sensitivity [26,27]. Furthermore, the effect of androgen is likely to be dependent on the amount of hormone produced and the activity of the AR. CAG repeat lengths of the AR normally range from 6 to 39 repeats, where a shorter length is correlated with greater transactivational activity. Furthermore, short CAG repeat length has been reported to be associated with the aetiologies of BPH [11–13] and prostate cancer [14,15].

Recently, Manning et al. [10] showed right-hand digit ratio is positively correlated with CAG repeat number of AR, and that individuals with a lower right-hand vs left-hand digit ratio had AR alleles with low CAG repeat numbers. They showed in a sample of 50 men (49 Caucasian subjects, and 1 Caucasian/Chinese subject) that digit ratio is a phenotypic correlate of AR structure, that right-hand digit ratio is positively correlated with CAG number, and that individuals with lower right than left hand digit ratio possessed AR alleles with lower CAG numbers [10].

According to the above evidence, digit ratio may be a predictor of prostate volume, PSA levels and the presence of prostate cancer. In the present study, we found a significant negative association between right-hand digit ratio and PSA (r=−0.140, P= 0.007; Fig. 2). However, we found no significant correlation between digit ratio and prostate volume (r=−0.038, P= 0.466). Furthermore, we found that those with lower digit ratios had a higher PSA level (3.26 ± 5.54 ng/mL vs 1.89 ± 2.24 ng/mL, P= 0.002) and a higher mean PSAD level (0.077 ± 0.109 ng/mL/cc vs 0.055 ± 0.059 ng/mL/cc, P= 0.014). In Group A, a significantly greater proportion of patients underwent prostate biopsy [54/184 (29.3%) vs 35/182 (19.2%), P= 0.024] and had prostate cancer [21/184 (11.4%) vs 7/182 (3.8%), P= 0.006; Table 3]. However, we found that there was no significant difference of prostate volume between those with lower digit ratios and those with higher digit ratios (36.17 ± 17.27 vs 33.93 ± 15.47, P= 0.193). These results suggest that digit ratio may predict PSA level and the presence of prostate cancer rather than prostate volume.

In 1988, Henderson et al. [28] proposed the possible relationship between later development of prostate cancer and prenatal androgen exposure. Our results also show the significant relationships between the two. In our data digit ratio, which is reflective of prenatal androgen exposures and in utero milieu, can predict the presence of prostate cancer. However, it cannot predict BPH (prostate volume). So far, little is known about the evidence that shows directly that in utero milieu (prenatal androgen exposure) has a higher effect on prostate cancer development than on BPH development in male offspring. However, the discordance between prostate cancer and BPH as found in our study can also be found indirectly in the studies about the racial difference of prostate cancer and BPH between white and black men. In utero milieu of black males is different from that of white males. Black women have higher maternal testosterone levels than white women [28,29]. In addition, short CAG repeat length on the AR was associated with black rather than white men [30] and the digit ratio of black people is lower than that of white people [31]. This in utero milieu of black males might be related to the increased risk of prostate cancer. However, the in utero milieu of black males is not related to the increased risk of BPH as the histopathological concept [32].

Black men are 2.5 times more likely to die of prostate cancer than white men [33]. And, prostate cancer incidence was higher in black than in white men for all age groups (age-adjusted relative risk = 1.8, 95% CI = 1.4–2.3) [Correction added after online publication 5 August 2010: CI 1.4–2.3 has been changed to CI = 1.4–2.3][34]. However, in contrast to prostate cancer, there is much evidence about the similarity of BPH between black and white people. Black men were at no increased risk for BPH compared with white men [34–36]. Furthermore, there were no differences in prostate volume between black men and white men [37–39] and no significant differences were found in cellular composition of BPH [40]. In terms of AR expression in prostate cancer epithelial nuclei, black men exhibited 38% higher levels of AR immunostaining than white men. However, intensity of AR immunostaining was similar between races in benign prostate[41]. In prostatic tissue without cancer, levels of testosterone and dihydrotestosterone (DHT) were similar in black men and white men [42]. From this evidence, we can hypothesize that in utero milieu (prenatal androgen exposure) has a higher effect on prostate cancer development of the peripheral zone in male offspring than on the BPH development of the transitional zone.

In the present study, we found no significant correlation between digit ratio and age (r=−0.003, P= 0.959). This means that digit ratio had even distribution in each age bracket of this study population and that patient age, which is one of the important predictors of BPH, high PSA and prostate cancer, had no influence on digit ratio. These results support several previous studies that relative digit length is established as early as the 14th gestational week in utero[3,4], and changes little with age.

No difference was found between serum testosterone levels in the two study groups, which is in agreement with the findings of previous studies about the relation between digit ratio and adult sex hormone levels. Manning et al. [43] found that adult levels of testosterone may be related to digit ratio in men with a compromised testicular function, but not in men from normative samples. In addition, in a study conducted by Hönekopp et al. [44], digit ratio was not found to be associated with adult sex hormone levels in the normal population.

We found that prostate biopsy findings were not related to digit ratio (Table 5). However, the total number of patients who had prostate cancer was 28 which we think is not sufficient to reveal the relationship of digit ratio to biopsy findings. Another limitation of our study is that it was not based on a normal population, rather participants were recruited from among patients that presented with LUTS. Nevertheless, we believe that our results present sufficient evidence that a relationship exists between digit ratio and PSA and prostate cancer.

In conclusion, significant negative relationships were observed between right-hand digit ratio and PSA level. Patients with a lower digit ratio had a higher risk of prostate biopsy due to high PSA level, and of prostate cancer. These results suggest that digit ratio is a predictor of high PSA level and the presence of prostate cancer.

CONFLICT OF INTEREST

None declared.

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