INTRODUCTION
 Top of page
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONFLICT OF INTEREST
 REFERENCES
The second to fourth digit ratio (hereafter the digit ratio) of the right hand is related to the activity of the androgen receptor (AR) [1,2]. Zheng et al. [1] reported that the digit ratio depends on the relative activity of the AR and oestrogen receptor (ER)α in the fourth digit. They found that AR and ERα activity is higher in the fourth digit than in the second digit. They also showed that, compared to ERα, the relatively high activity of the AR increases growth of the fourth digit, which leads to a lower digit ratio. Furthermore, they showed that the addition of androgen induces high activation of the AR rather than the ER [1].
Manning et al. [2] also suggested that the digit ratio may represent the activity of AR [2]. They showed that the digit ratio is positively correlated with the number of CAG repeats in the gene for AR [2]. A low number of CAG repeats in the gene for AR is known to related to high activity of the AR [3–5].
Testosterone is enzymatically converted to dihydrotestosterone (DHT) by 5αreductase; DHT also binds to the AR. This androgen (DHT) [6] and the AR [3–5] are known to be necessary for prostatic growth in BPH. It also has been well established that a high activity of AR increases the risks of BPH [3–5].
5αreductase inhibitor (5ARI) reduces prostatic growth by blocking the conversion of testosterone to DHT. The type 2selective 5ARI finasteride and the dual (types 1 and 2) 5ARI dutasteride are both approved for the treatment of BPH and provide longterm symptom relief, increase urinary flow, decrease prostate volume and reduce the risk of longterm complications, such as acute urinary retention and BPHrelated surgery [7,8].
In several studies, with respect to intraprostatic DHT levels from baseline, suppression rates of ∼85% and ∼95% have been reported with finasteride and dutasteride, respectively [9–11]. These findings mean that 5ARI does not always provide complete suppression of intraprostatic DHT levels in men with BPH. Namely, despite 5ARI treatment, unsuppressed DHT (>5%) remains in prostatic cells. If the activity of AR is very high, the unsuppressed DHT could bind to the AR, which may still have some function in the prostate.
Furthermore, in largescale placebocontrolled studies [7,12–14], a wide variation in sd was observed with respect to prostate volume reduction after 5ARI treatment, with reported mean (sd) decreases in prostate volume of −14.6 (13.5) mL [7], −24.4% (19.47%) [12], −12% (30%) [13] and −5.8 (18.4) mL [14]. These values indicate that patients with BPH do not always respond well to 5ARI treatment. To date, few studies are available to suggest reasons why the response of one patient to 5ARI differs from that of another patient.
Based on the evidence above, we hypothesized that the response of the prostate to 5ARI treatment (i.e. prostate volume reduction) may depend on AR activity. Therefore, the present study aimed to investigate the relationship between the digit ratio and prostate volume reduction by 5ARI (dutasteride) treatment.
RESULTS
 Top of page
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONFLICT OF INTEREST
 REFERENCES
Patient characteristics are summarized in Table 1. Mean age, digit ratio, prostate volume (PV1) and PSA level were 66.6 years, 0.951, 51.9 mL and 3.09 ng/mL, respectively. Mean duration of dutasteride treatment, prostate volume (PV2) and PSA level after dutasteride treatment were 10.2 months, 40.6 mL and 1.42 ng/mL, respectively. Mean reduced prostate volume (PV2–PV1) and reduced prostate volume ratio ([PV2–PV1]/PV1) were −11.3 mL and −21.0%, respectively. Mean reduction rate of prostate volume ([PV2–PV1]/duration) and the reduction rate of prostate volume ratio ([PV2–PV1]/PV1/duration) were −1.36 mL/month and −2.5%/month, respectively.
Table 1. Characteristics of the study populationCharacteristic  Mean (sd)  Median (range) 


Age (years)  66.6 (8.7)  68.0 (40.0–86.0) 
Second digit length (cm)  7.228 (0.512)  7.196 (6.000–8.600) 
Fourth digit length (cm)  7.604 (0.521)  7.515 (6.100–8.991) 
Digit ratio  0.951 (0.042)  0.950 (0.827–1.089) 
PV1 (mL)  51.9 (21.7)  44.8 (30.4–141.3) 
PSA1 (ng/mL)  3.09 (3.33)  1.77 (0.05–19.47) 
Duration (months)  10.2 (4.8)  9.0 (6.0–29.0) 
PV2 (mL)  40.6 (18.0)  36.3 (14.8–107.1) 
PSA2 (ng/mL)  1.42 (1.23)  1.03 (0.01–6.66) 
PV2–PV1 (mL)  −11.3 (11.2)  −9.8 (−42.0 to 16.0) 
(PV2–PV1)/PV1 (%)  −21.0 (19.0)  −24.5 (−68.7 to 48.5) 
(PV2–PV1)/duration (mL/month)  −1.36 (1.41)  −1.10 (−6.17 to 1.88) 
(PV2–PV1)/PV1/duration (%/month)  −2.5 (2.4)  −2.3 (−8.1 to 5.0) 
PSA2–PSA1 (ng/mL)  −1.67 (2.60)  −0.80 (−12.95 to 2.23) 
(PSA2–PSA1)/PSA1 (%)  −24.9 (90.7)  −50.2 (−98.8 to 637.1) 
(PSA2–PSA1)/duration (ng/mL/month)  −0.189 (0.306)  −0.077 (−1.666 to 0.198) 
(PSA2–PSA1)/PSA1/duration (%/month)  −3.1 (9.1)  −4.6 (−15.2 to 45.5) 
When the patients were divided into two groups according to digit ratio (group A: digit ratio <0.95, n= 71; group B: digit ratio ≥0.95, n= 71), group A had three times as many patients whose prostate volume increased despite dutasteride treatment (21.1% [15/71] vs 7.0% [5/71], P= 0.016; odds ratio [OR], 3.536; 95% CI, 1.209–10.338) (Table 2).
Table 2. Relationship between digit ratios and study variablesVariable  Volume change  P  Odds ratio  95% CI 

Decrease  Increase 


Age (years)  ≥65  71  14  0.318  1.676  0.603–4.656 
<65  51  6 
PV1 (mL)  ≥45  59  10  0.892  1.068  0.415–2.749 
<45  63  10 
PSA1 (ng/mL)  ≥1.75  59  13  0.168  1.983  0.740–5.311 
<1.75  63  7 
Duration (months)  ≥9  60  14  0.084  2.411  0.869–6.687 
<9  62  6 
Digit ratio  <0.95  56  15  0.016  3.536  1.209–10.338 
≥0.95  66  5 
In group B, there was a greater reduction in prostate volume compared to that in group A (PV2–PV1: −9.4 mL vs −13.2 mL, P= 0.042; [PV2–PV1]/PV1: −17.5% vs −24.5%, P= 0.027; [PV2–PV1]/duration: −1.1 mL/month vs −1.6 mL/month, P= 0.041; [PV2–PV1]/PV1/duration: −2.0%/month vs −3.0%/month, P= 0.016) (Table 3).
Table 3. Comparisons of study variables between the study groupsVariable  Digit ratio, mean (sd)  P 

<0.950 (n= 71)  ≥0.950 (n= 71) 


Age (years)  66.7 (8.2)  66.5 (9.3)  0.871 
Second digit length (cm)  7.113 (0.489)  7.342 (0.513)  0.007 
Fourth digit length (cm)  7.741 (0.503)  7.467 (0.505)  0.001 
Digit ratio  0.919 (0.024)  0.984 (0.028)  0.000 
PV1 (mL)  52.8 (23.6)  50.9 (19.6)  0.611 
PSA1 (ng/mL)  3.22 (3.29)  2.96 (3.39)  0.641 
Duration (months)  10.4 (4.8)  9.9 (4.8)  0.533 
PV2 (mL)  43.4 (20.5)  37.8 (14.7)  0.060 
PSA2 (ng/mL)  1.53 (1.21)  1.32 (1.25)  0.314 
PV2–PV1 (mL)  −9.4 (11.5)  −13.2 (10.7)  0.042 
(PV2–PV1)/PV1 (%)  −17.5 (19.1)  −24.5 (18.4)  0.027 
(PV2–PV1)/duration (mL/month)  −1.1 (1.5)  −1.6 (1.3)  0.041 
(PV2–PV1)/PV1/duration (%/month)  −2.0 (2.4)  −3.0 (2.3)  0.016 
PSA2–PSA1 (ng/mL)  −1.70 (2.68)  −1.64 (2.54)  0.904 
(PSA2–PSA1)/PSA1 (%)  −29.6 (59.9)  −20.3 (113.8)  0.544 
(PSA2–PSA1)/duration (ng/mL/month)  −0.19 (0.32)  −0.19 (0.30)  0.952 
(PSA2–PSA1)/PSA1/duration (%/month)  −3.2 (7.7)  −3.0 (10.4)  0.898 
Significant negative correlations were found between the digit ratio and the reduction rate ([PV2–PV1]/duration: r=−0.165, P= 0.049; [PV2–PV1]/PV1/duration: r=−0.191, P= 0.023) (Table 4). Figure 2 shows the relationship between the digit ratio and the reduction rate of prostate volume ratio ([PV2–PV1]/PV1/duration). The reduction rate of prostate volume ratio was found to be negatively associated with the digit ratio (r=−0.191, P= 0.023; y=−10.939x+ 7.888, where y is the reduction rate of the prostate volume ratio and x is the digit ratio) (Fig. 2).
Table 4. Relationships between the study variablesVariable  Digit ratio  PV1  PSA1 


PV2–PV1 
r  −0.144  −0.557  −0.123 
P  0.088  0.000  0.145 
(PV2–PV1)/PV1 
r  −0.145  −0.092  0.124 
P  0.086  0.274  0.143 
(PV2–PV1)/duration 
r  −0.165  −0.537  −0.083 
P  0.049  0.000  0.327 
(PV2–PV1)/PV1/duration 
r  −0.191  −0.104  0.129 
P  0.023  0.218  0.127 
The reduced prostate volume and reduced prostate volume ratio were not statistically correlated with the digit ratio (PV2–PV1: r=−0.144, P= 0.088; [PV2–PV1]/PV1: r=−0.145, P= 0.086) (Table 4). Although the reduced prostate volume ratio ([PV2–PV1]/PV1) was not statistically correlated with the digit ratio, Fig. 3 shows that men with a higher digit ratio tend to have a higher reduced prostate volume ratio (r=−0.145, P= 0.086; y=−66.305x+ 42.060, where y is the reduced prostate volume ratio and x is the digit ratio) (Fig. 3).
Additionally, significant negative correlations were found between PV1 and reduced prostate volume (PV2–PV1) and the reduction rate of prostate volume ([PV2–PV1]/duration) (PV2–PV1: r=−0.557, P= 0.000; [PV2–PV1]/duration: r=−0.537, P= 0.000) (Table 4).
DISCUSSION
 Top of page
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONFLICT OF INTEREST
 REFERENCES
The digit ratio differs between men and women, with women having larger digit ratios than men [17,21,22]. This sex difference may evolve through changes in prenatal steroid concentrations [17,21,22]. Thus, the digit ratio is determined mostly during embryo development [23–26] and changes little after sexual maturation [24].
Furthermore, it was suggested that the digit ratio may be reflective of AR activity among individuals [1,2]. There are two studies showing a relationship between the digit ratio and prostate cancer risk [15,27]. Jung et al. [15] found a significant negative association between the digit ratio and PSA level (r=−0.140, P= 0.007) and men with a lower digit ratio had a higher mean PSA level (3.26 vs 1.89, P= 0.002), as well as a higher risk of prostate biopsy (OR, 1.75; 95% CI, 1.07–2.84) and prostate cancer (OR, 3.22; 95% CI, 1.33–7.78). Similarly, Rahman et al. [27] also found that men with a higher digit ratio had a statistically significant decreased prostate cancer risk (OR, 0.67; 95% CI, 0.57–0.80) [27]. The means that the digit ratio may represent a simple marker for prostate cancer risk, suggesting a relationship between the digit ratio and AR activity.
In general, both dutasteride and finasteride were effective in reducing prostate volume, leading to a ∼25% reduction at 2 years [7,8,12,28–30]. However, not all patients with BPH respond well to 5ARI treatment. In largescale placebocontrolled studies [7,12–14], a wide variation in sd was observed with respect to prostate volume reduction after 5ARI treatment, indicating that these results were problematic. In particular, the sd was twofold higher than the mean value in the Medical Therapy of Prostatic Symptoms study [13]. If the data of the placebocontrolled study with 5ARI follow a normal distribution, >15% of all patients treated with 5ARI had a reduction in prostate volume >40%, whereas >15% of all patients with 5ARI treatment had a reduction in prostate volume <5%. This means that some patients had a large reduction in prostate volume, whereas others did not.
Similar to the results reported in previous studies [7,8,12,28–30], in the present study, the mean decrease in prostate volume was −11.3 mL or −21.0%. Additionally, a wide value of sd was observed with respect to prostate volume reduction after 5ARI treatment. Mean (sd, range) reduced prostate volume (PV2–PV1) and mean (sd, range) reduced prostate volume ratio ([PV2–PV1]/PV1) were −11.3 (11.2, −42.0 to 16.0) mL and −21.0% (19.0%, −68.7% to 48.5%), respectively (Table 1). Furthermore, in the present study, the proportion of patients whose prostate volume increased despite dutasteride treatment was 14.1% (20/142) (Table 2).
To date, despite the diversity of responses to 5ARI treatment, few studies have identified the reasons why different patients have different responses to 5ARI. We consider that the present study identifies one reason for individual variation in the response to 5ARI treatment.
According to the results of previous studies [9–11], despite 5ARI treatment, unsuppressed DHT (>5%) remains in prostatic cells. We consider that, if the AR activity is very high, unsuppressed DHT (>5%) could bind to the AR, which may still have some function in the prostate. Therefore, we hypothesize that the response of the prostate to 5ARI (i.e. prostate volume reduction) may depend on AR activity. Therefore, we investigated the relationship between the response to dutasteride treatment (prostate volume reduction) and the digit ratio, which is related to AR activity [1,2].
Employing a similar hypothesis, Mostaghel et al. [31] suggested that AR levels may predict the cancer preventive efficacy of 5ARI [31]. In two largescale studies investigating the preventive effects of 5ARI on cancer, namely the Prostate Cancer Prevention Trial [32] and the Reduction of Dutasteride of Prostate Cancer Events study [33], significant variations in cancer preventive activity were observed between individual men [32,33]. It is not known why 5ARI was ineffective in all individuals, nor what factors underlie the variable outcomes observed. The study by Mostaghel et al. [31] shows one of the reasons for this phenomenon by showing that, under conditions of relative androgen depletion, high AR levels in benign prostate epithelium can maintain AR transcriptional network activity, whereas low AR levels cannot compensate for low ligand concentrations. It was also suggested that pretreatment tissue AR levels may predict the response to 5ARI therapies, which means that variation in the molecular programme concerning regulation of the gene for AR has important implications for the optimal use of 5ARI in prostate cancer prevention and treatment [31].
A novel finding of the present study was that the response to dutasteride treatment, as measured by prostate volume reduction, is related to the digit ratio, which is reflective of the activity of AR among individuals. The lower digit ratio group had three times as many patients whose prostate volume increased despite dutasteride treatment (Table 2). Furthermore, in the higher digit ratio group, there was a greater reduction in mean prostate volume compared to the lower digit ratio group (Table 3). In the correlation study, significant negative relationships were observed between the righthand digit ratio and the reduction rate of prostate volume ratio ([PV2–PV1]/PV1/duration) (Fig. 2 and Table 4). These results suggest that the digit ratio is a predictor of response to dutasteride treatment.
The present study was designed to investigate not only the change in prostate volume or PSA level, but also the change in the ratio of prostate volume or PSA level. The change in the ratio of prostate volume or PSA level was defined as (PV2–PV1)/PV1 or (PSA2–PSA1)/PSA1, respectively.
From the data obtained in the present study, after dutasteride treatment, prostate volume decreased by −21.8% or −11.3 mL (from 51.9 mL to 40.6 mL). Similarly, the mean value of the change in prostate volume ratio was −21%. Although the PSA level decreased by −54.0% or −1.67 ng/mL (from 3.09 ng/mL to 1.42 ng/mL), the mean value of the change in PSA ratio was −24.9% (Table 1).
In other words, the mean and median values of the change in PSA ratio were significantly different from each other (−24.9% vs −50.2%), whereas the mean and median values of the change in prostate volume ratio were similar to each other (−21.0% vs −24.5%) (Table 1).
We consider that the mean value of the change in PSA ratio is different from the expected value (−50%) because of the exaggerated values of the change in PSA ratio ([PSA2–PSA1]/PSA1) as a result of the relatively lower values of PSA1 compared to those of PV1.
From the data obtained in the present study, the values of PSA1 range from 0.05 ng/mL to 19.47 ng/mL, whereas the values of PV1 range from 30.4 mL to 141.3 mL. Although the minimal value of PV1 is 30.4 mL, the minimal value of PSA1 is 0.05 ng/mL (Table 1). This means that, if the value of PSA1 is very low and close to zero, the value of the change in PSA ratio could be greatly exaggerated to a relatively higher value according to its definition ([PSA2–PSA1]/PSA1).
For example, the PSA level in one patient increased from 0.05 ng/mL to 0.25 ng/mL. Although the change in PSA level (PSA2–PSA1) is only 0.2 ng/mL, the change in PSA ratio ([PSA2–PSA1]/PSA1) is as much as 400%. Indeed, from data obtained in the present study, the maximum value of the change in PSA ratio is +637.1% (Table 1).
In addition, from the data obtained in the present study, out of a total of 142 men, the PSA level of 25 men (25/142; 17.6%) increased despite dutasteride treatment as the prostate volume of 20 men (20/142; 14.1%) did. Most of the patients whose PSA level increased had very low values of PSA1, which were close to zero. Therefore, according to the definition, the values of the change in PSA ratio were greatly exaggerated to higher values. We consider that these exaggerated values of the change in PSA ratio may lead to the positive shift of its mean value from −50% to −25%.
From the data obtained in the present study, the median value of the change in PSA ratio was −50.2%, which is similar to the expected value (−50%) (Table 1). This means that, if the value of PSA1 is sufficiently high, the mean value of the change in PSA ratio could be close to the expected value (−50%).
The present study was performed based on the assumption that the digit ratio is reflective of AR activity among individuals and that, under conditions of relative androgen depletion as a result of treatment with 5ARI, the relative AR activity among individuals may predict the response to 5ARI treatment. Thus, we did not investigate directly the diversity of AR activity among individuals. Instead, we investigated the digit ratios of individuals based on the assumption that the digit ratio is reflective of AR activity among individuals. In essence, we investigated indirectly the relationship between a reduction in prostate volume and AR activity, which is related to the righthand digit ratio. This may represent one of the limitations of the present study. Nevertheless, based on the evidence outlined above, we consider that the results obtained in the present study provide sufficient evidence concerning the relationship between the activity of the AR and the response to 5ARI among individuals.
Another limitation of the present study is that we did not measure serum androgen (DHT and testosterone) levels before and after 5ARI treatment. The change in serum androgen levels after 5ARI treatment is well known. In previous studies, with respect to serum DHT levels from baseline, suppression rates of ∼85% and ∼95% have been reported with finasteride and dutasteride, respectively [7,9–12,30,34,35]. The decrease in DHT levels with 5ARI was accompanied by a reciprocal increase in serum testosterone levels. Serum testosterone had increased by a mean of 25% at month 48 in the dutasteride treatment groups [7,9,12,30,35]. Mean and median testosterone values remained within the normal physiological range [12,30,35].
Most previous studies also showed that there was no relationship between adult serum testosterone levels and the digit ratio in the normal population [36,37]. In the present study, when patients were divided into two groups according to the digit ratio, no intergroup difference was found for age (mean [sd], 66.7 [8.2] years vs 66.5 [9.3] years, P= 0.871) (Table 3), which is one of the important predictors of adult serum testosterone level. Furthermore, no significant correlation was found between the digit ratio and age (r= 0.053, P= 0.531). This means that, although we did not measure serum androgen levels, it is acceptable that serum androgen levels may have no influence on the digit ratio.
In conclusion, the findings obtained in the present study show that patients with a higher digit ratio respond well to dutasteride treatment. Additionally, significant negative relationships were observed between the righthand digit ratio and the reduction rate of prostate volume ratio ([PV2–PV1]/PV1/duration). These results suggest that the digit ratio may be a predictor of the response to dutasteride treatment.