Prostate Cancer and Prostatic Disease (2014) 17, 132–143 & 2014 Macmillan Publishers Limited All rights reserved 1365-7852/14 www.nature.com/pcan
ORIGINAL ARTICLE
The effect of testosterone replacement therapy on prostate cancer: a systematic review and meta-analysis Y Cui, H Zong, H Yan and Y Zhang BACKGROUND: Testosterone replacement therapy (TRT) is a widely accepted form of treatment worldwide for aging men with late-onset hypogonadism syndrome. Urologists have been concerned about the possibility of TRT causing prostate cancer. The aim of this study was to assess the relationship between TRT and prostate cancer. METHODS: A literature review was performed to identify all published, randomized controlled trials (RCTs) of testosterone treatment for hypogonadism. The search included the MEDLINE, Embase and the Cochrane Controlled Trials Register databases. Fixed-effect model was chosen for homogeneous studies; otherwise, a random-effect model was used. Inconsistency was quantified by using the I2 statistic, which tests the proportion of heterogeneity across studies. RESULTS: Results of 22 RCTs involving a total of 2351 patients were analyzed. Eleven RCTs were short-term (o12 months) and 11 were long-term (12–36 months) comparisons of TRT with a placebo; TRT was administered transdermally, orally or by injection. Respective odds ratio (OR) and 95% confidence interval (CI) values for injection, transdermal administration and oral administration of short-term TRT were as follows: prostate cancer: 0.39 (0.06–2.45), 1.10 (0.26–4.65) and no oral; biopsy: 5.28 (0.24–113.87), 2.11 (0.32–13.73) and no oral; and prostate nodule: 1.01 (0.13–7.60), no injection and oral. Respective OR and 95% CI values for injection, transdermal administration and oral administration of long-term TRT were as follows: prostate cancer: 2.09 (0.18–24.73), 3.06 (0.12– 76.70) and 0.19 (0.01–4.03); biopsy: 2.09 (0.18–24.73), 3.65 (0.88–15.20) and 0.97 (0.13–7.03); and prostate nodule: 3.13 (0.12–80.68), 1.00 (0.06–16.41) and 0.97 (0.13–7.03). Though for some routes of administration and some end points, the OR associated with testosterone administration were 41 indicating increased risk, none of these reached or even approached statistical significance (all P40.10), which was consistent with the results of subgroup analyses and sensitivity analysis. Besides, sensitivity analysis indicated that short-term TRT was more likely to increase PSA levels than treatment with placebo (Po0.00001). CONCLUSIONS: This meta-analysis shows that regardless of the administration method, TRT is the short-term safety and does not promote prostate cancer development or progression but long-term data are warranted with justifiable end points. Prostate Cancer and Prostatic Disease (2014) 17, 132–143; doi:10.1038/pcan.2013.60; published online 21 January 2014 Keywords: testosterone; meta-analysis; randomized controlled trial
INTRODUCTION Testosterone deficiency in the aging male has become a topic of increasing interest and debate worldwide. Cross-sectional and longitudinal data indicate that testosterone levels are reduced progressively with age and that a significant percentage of men aged 460 years have serum testosterone levels that are below the lower limits of young adult men aged 20–30 years.1–3 Lateonset hypogonadism (LOH) is a clinical and biochemical syndrome associated with advancing age and characterized by a deficiency in serum testosterone levels, among other signs and symptoms.4,5 LOH may result in significant detriment to quality of life and adversely affect the function of multiple organ systems. Over the past decade, there has been a growing awareness of the health benefits of testosterone therapy for men with testosterone deficiency, including improved sexual desire and performance, improved mood, increased muscle mass and strength, decreased fat mass and improved bone mineral density.6 However, for approximately 70 years there has been a concern that higher serum testosterone represents a risk for prostate cancer.7 Many urologists are concerned that testosterone replacement therapy (TRT) may accelerate prostate growth not only in benign disease but also in cancer as well.
The goal of the present study was to perform a meta-analysis evaluating the effect of TRT on prostate cancer, which may resolve some of the current controversies over the use of the drug.
MATERIALS AND METHODS Search strategy Medline (1966 to Augest 2013), Embase (1974 to Augest 2013) and Cochrane Controlled Trials Register databases were searched to identify randomized controlled trials (RCTs) that referred to the impact of TRT on the prostate; we also searched the reference lists of the retrieved studies. The following search terms were used: testosterone, prostate cancer, and randomized controlled trials.
Inclusion criteria and trial selection RCTs that met the following criteria were included: (1) The study design included TRT; (2) the study provided accurate data that could be analyzed, including the total number of subjects and the values of each indication of prostate cancer, such as PSA levels’ change, number of people with elevated PSA, prostate nodule, biopsy and prostate cancer; and (3) the full text of the study could be accessed. When the same study was published in various journals or in different years, the most recent publication was
Department of Urology, Beijing Tian-Tan Hospital, Capital Medical University, Beijing, China. Correspondence: Dr Y Zhang, Department of Urology, Beijing Tian-Tan Hospital, Capital Medical University, No. 6 Tiantan Xi Li, Dong cheng Beijing 100050, China. E-mail: [email protected] Received 29 September 2013; revised 5 December 2013; accepted 6 December 2013; published online 21 January 2014
TRT and prostate cancer Y Cui et al
133 used for the meta-analysis. If the same group of researchers studied a group of subjects with multiple experiments, then each study was included. A flow diagram of the study selection process is presented in Figure 1.
Quality assessment The quality of the retrieved RCTs was assessed using the Jadad scale.8 All the identified RCTs were included in the meta-analysis regardless of the quality score. The methodological quality of each study was assessed according to how patients were allocated to the arms of the study, the concealment of allocation procedures, blinding and data loss due to attrition. The studies were then classified qualitatively according to the guidelines published in the Cochrane Handbook for Systematic Reviews of Interventions v.5.1.0.9 Based on the quality assessment criteria, each study was rated and assigned to one of the three following quality categories: A, if all quality criteria were adequately met, the study was deemed to have a low risk of bias; B, if X1 of the quality criteria was only partially met or was unclear, the study was deemed to have a moderate risk of bias; or C, if X1 of the criteria was not met or not included, the study was deemed to have a high risk of bias. Differences were resolved by discussion among the authors.
Data extraction The following information was collected for each study: (1) the name of the first author and the publication year; (2) the study design and sample size; (3) the therapy that the patients received; (4) the country in which the study was conducted; (5) data on the five indications of prostate cancer, that is, PSA levels, number of people with elevated PSA, prostate nodule, biopsy and prostate cancer; and (6) the TRT administration method and dosage.
Statistical analysis and meta-analysis The meta-analysis of comparable data was carried out using RevMan v.5.1.0 (Cochrane Collaboration, Oxford, UK).9 Changes in all five indications of prostate cancer were determined as differences between baseline (study entry) and study completion. We estimated the relative risk for dichotomous outcomes and the standardized mean difference (SMD) for continuous outcomes pooled across studies by using the DerSimonian and Laird10 random-effects model. We used a 95% confidence interval (CI). If the result of analysis showed P40.05, we considered the studies homogeneous and so chose a fixed-effect model for meta-analysis. Otherwise, a random-effect model was used. We quantified inconsistency using the I2 statistic, which describes the proportion of heterogeneity across studies that is not due to chance, thus describing the extent of true inconsistency
in results across trials.11 I2o25% reflects a small level of inconsistency, and I2450% reflects significant inconsistency.
Subgroup and sensitivity analysis To explore causes of inconsistency and subgroup treatment interactions, subgroup analyses were specified a priori according to the following factors: Participants: aged o65 or X65 years; total testosterone level at baseline
(testosterone level was considered low if o350 ng dl 1 or 12 nmol l 1); if total testosterone was not available, then the lower limit of normal for bioavailable or free testosterone levels was used; if neither total nor free testosterone levels were available, then studies were classified according to PSA levels; Interventions: testosterone formulation, route of administration; Outcome characteristic: duration of follow-up (o12 versus X12 months); and Study quality measure: proportion of patients lost to follow-up (p10% versus 410%), concealment of allocation, intention-to-treat analysis and blinding of patients.
RESULTS Characteristics of the individual studies The database search found 267 articles that could have been included in our meta-analysis. Based on the inclusion and exclusion criteria, 232 articles were excluded after reading the titles and abstracts of the articles. Thirteen articles lacked useful data. In all, 22 articles,12–33 reporting data from a total of 22 RCTs, were included in the analysis: 11 RCTs compared testosterone with a placebo over the short term (o12 months); and 11 RCTs compared testosterone with a placebo over the long term (12–36 months). Three different administration methods were used: oral, transdermal, and injection (Figure 1). The baseline characteristics of the studies included in our meta-analysis are listed in Table 1. All 22 RCTs included in our analysis involved rigorous, periodic monitoring of patients, and treatment was withdrawn when there were indications suspicious for prostate cancer or other serious complications. Few patients suffered serious complications, and all patients who withdrew from treatment had returned to normal at long-term assessment. Other than four short-term therapy RCTs, all of the 18 RCTs reported the baseline PSA levels, and only one patient from the studies31 suffered from BPH symptoms. In addition, for all 22 RCTs no patient had prostate enlargement at baseline, all patients had normal PSA levels at baseline (Table 1) and no patient had suspected or conformed diagnosis of prostate cancer at study entry. Quality of the individual studies All 22 RCTs were double blinded, and all described the randomization processes that they had used. All except Kenny et al.18 included a power calculation to determine the optimal sample size, and eight used intention-to-treat analysis (Table 2). The level of quality of each identified study was A (Table 2). The funnel plot provided a qualitative estimation of publication bias of the studies, and no evidence of bias was found (Figure 2).
Figure 1. A flow diagram of the study selection process. RCT, randomized controlled trials. & 2014 Macmillan Publishers Limited
Short-term TRT versus placebo Prostate cancer. Only five RCTs, involving a total of 1168 participants (778 in the testosterone group and 390 in the control group), included prostate cancer data (Figure 3). Treatment was given by injection in one study and transdermally in four studies. It appears that in the TRT group there were 7 cancers in 778 men (0.90%), whereas in the placebo group there were 5 cancers in 390 men (1.28%). No heterogeneity was found between the trials (Figure 3). The odds ratio (OR) was 0.39 (95% CI, 0.06–2.45; P ¼ 0.32) for the study using delivery by injection and 1.10 (95% CI, Prostate Cancer and Prostatic Disease (2014), 132 – 143
12
Prostate Cancer and Prostatic Disease (2014), 132 – 143
Placebo
Placebo
Placebo
T
T
T
USA
UK
Japan
Italy
The Netherlands
Italy
USA
Australia
USA
USA
USA
USA
USA
New Zealand
USA
USA
USA
USA
USA
France
Sweden
USA
Country
96
108
23
40
104
27
17
33
24
45
12
214
106
114
21
6
307
37
7
6
11
6
Experimental
47
112
23
10
103
31
18
25
20
51
10
37
103
117
19
5
99
37
5
6
12
7
Control
Sample size
TT 3.4 ng ml
TT 350 ng dl
1
TT 11 nmol l 1
BT 11.8 pg ml
1
TT 11 nmol l 1
TT 13.7 nmol l 1
BT 3.6 nmol l 1
TT 12.1 nmol l 1
TT normal
BT 4.44 nmol l 1
TT 475 ng dl 1
BT 60 ng dl 1
TT 300 ng dl
1
At least two symptoms of hypogonadism IPSS47 and total prostate volume 420 ml Men had confirmed hypogonadism Community dwelling men with confirmed hypogonadism
Have evidence of limitations in mobility Hypogonadal but otherwise healthy men Normal liver function tests, PSA, and hematocrit Men had a bone mineral density of the lumbar spine below normal Men with late-onset hypogonadism symptoms Men with late-onset hypogonadism symptoms Men with late-onset hypogonadism symptoms Men had confirmed hypogonadism Men with late-onset hypogonadism symptoms
TT 350 ng dl 1
TT 12 nmol l 1
TT 300 ng dl 1
BT 128 ng dl 1
Men with low levels of TT andX1 symptoms of low T Folsteinini-Mental State Exam scores between 14 and 28 Men with late-onset hypogonadism symptoms Men with late-onset hypogonadism symptoms
Healthy, ambulatory, community-dwellig men
Healthy, older men
No history of diease, body mass index between 22–29 kg m 2 Men without urinary tract symptoms Men with low levels of TT
Other inclusion criteria
TT 10.4 nmol l 1
TT normal
TT 17 nmol l 1
1
TT normal
TT 12.1 nmol l
1
Testosterone cut off level for study entry
44
44
42
44
44.5
44
44
45
44
44
44
42.5
44
44
410
44
44
44
44
44
410
44
Exclusion of PSA levels (ng ml 1)
66.5
59.9
70.5
57
67
66.7
71
68.5
75.5
73
65
54.6
74
73.8
69
79.5
58
76.5
67.5
54.1
52
66.7
Age (median)
Long term
Long term
Long term
Long term
Long term
Long term
Long term
Long term
Long term
Long term
Long term
Short term
Short term
Short term
Short term
Short term
Short term
Short term
Short term
Short term
Short term
Short term
Short-term or longterm ART
T’
T’
I
T’
O
T’
I
O
T’
T’
I
T’
T’
T’
I
I
T’
I
I
T’
O
I
Administration method
125 mg day
1
2.5g per 2 weeks
1000 mg per 12 weeks 250 mg per 4 weeks 60 mg day 1
80 mg 2 day 1
200 mg per 2 weeks 5 mg day 1
80 mg 2 day
5 mg day
200 mg per 2 weeks 6 mg day 1
2.5g per 2 weeks
100 mg day 1
50 or 100 mg day 1 200 mg per 3 weeks 150 mg per 2 weeks 50 mg day 1
—
100 mg week 1
1
100 mg per 2 weeks 160 mg day 1
Dosage
1.5
1.6
1.06
1.07
1.6
1.6
0.9
2.5
2.0
1.7
1.0
0.85
—
1.5
1.55
0.88
1.30
—
1.4
—
1.28
2.1
T
1.4
1.2
1.06
1.1
1.7
1.4
1.4
2.5
2.0
1.6
1.5
0.89
—
1.5
0.97
1.30
1.13
—
1.2
—
0.72
2.1
P
Baseline PSA level (ng ml 1)
Abbreviations: ART, androgen-replacement therapy; BT, bioavailable testosterone; I, injection; IPSS, International Prostate Symptom Score; O, oral; P, placebo; T, testosterone; T’, transdermal; TT, total testosterone .
Placebo
T
Placebo
T
EmmelotVonk et al.29 Aversa et al.30 Shigehara et al.31 Jones et al.32 Hildreth et al.33
Placebo
T
Placebo
T
Placebo
Placebo
T
Placebo
Placebo
T
T
Placebo
T
T
Placebo
T
Placebo
Placebo
T
T
Placebo
T
Kenny et al.25 Wittert et al.26 Amory et al.27 Nair et al.28
Placebo
T
Placebo
Placebo
T
T
Placebo
T
Snyder et al.24
Placebo
Placebo
Therapy in control group
T
T
Therapy in experimental group
Study and patient characteristics
Holmang et al.13 Simon et al.14 Ferrando et al.15 Harman and Blackman16 Steidle et al.17 Kenny et al.18 Marks et al.19 SrinivasShankar et al.20 Basari et al.21 Kawfaman et al.22 Sih et al.23
Tenover
Study
Table 1.
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134
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TRT and prostate cancer Y Cui et al
135 Table 2.
Quality assessment of individual study
Study
Allocation sequence generation
Allocation concealment
Tenover12 Holmang et al.13 Simon et al.14 Ferrando et al.15 Harman and Blackman16 Steidle et al.17 Kenny et al.18 Marks et al.19 Srinivas-Shankar et al.20 Basari S21 Kawfaman et al.22 Sih et al.23 Snyder et al.24 Kenny et al.25 Wittert et al.26 Amory et al.27 Nair et al.28 Emmelot-Vonk et al.29 Aversa et al.30 Shigehara et al.31 Jones et al.32
B B B A B
Hildreth et al.33
Blinding
Loss to followup
Calculation of sample size
A A A A A
A A A A A
0 2 0 0 0
Yes Yes Yes Yes Yes
A B B A
A A A A
A A A A
6 0 21 31
Yes No Yes Yes
A A A A A A A A A A B A
A A A A A A A A A A A A
A A A A A A A A A A A A
3 23 10 12 24 18 13 4 16 0 6 15
Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
A
A
A
23
Yes
Statistical analysis
Intentiontotreat analysis
Level of quality
Analysis of variance Student’s t-test Student’s t-test Analysis of variance Analysis of variance
No No No No Yes
A A A A A
Fisher’s exact test Analysis of variance Paired t tests Analysis of covariance Student’s t-test Paired t tests Student’s t-test Analysis of variance Paired t tests Fisher’s exact test Student’s t-test Two-sided tests Unpaired t tests Analysis of variance Student’s t-test Analysis of covariance Analysis of variance
No No No Yes
A A A A
No No No Yes No Yes Yes No Yes No No Yes
A A A A A A A A A A A A
Yes
A
Abbreviation: ITT, intention-to-treat. A—all quality criteria met (adequate): low risk of bias. B—one or more of the quality criteria only partly met (unclear): moderate risk of bias. C—one or more criteria not met (inadequate or not used): high risk of bias.
0.26–4.65; P ¼ 0.90) for the study using transdermal delivery (Figure 3). Therefore, for either an injection or an transdermal administration method testosterone did not increase the number of prostate cancer confirmed diagnosis compared with placebo. Prostate biopsy. Only four RCTs, involving a total of 599 participants (387 in the testosterone group and 212 in the control group), included prostate biopsy data (Figure 3). Treatment was given by injection in one study and transdermally in three studies. It shows that in the TRT group there were 6 participants who needed prostate biospy in 387 men (1.55%) whereas in the placebo group there was 0 in 212 men. No heterogeneity was found between the trials (Figure 3). The OR was 5.28 (95% CI, 0.24– 113.87; P ¼ 0.29) for the study using delivery by injection and 2.11 (95% CI, 0.32–13.73; P ¼ 0.43) for the study using transdermal delivery (Figure 3). Therefore, for either an injection or an transdermal administration method testosterone did not increase the number of prostate biopsy compared with placebo. Prostate nodule. Only 2 of the included 11 RCTs reporting 274 participants (136 in the testosterone group and 138 in the control group) included the data for prostate nodule that used transdermal for administration of TRT or placebo. It shows that in the TRT group there were 1 participant with prostate nodule in 136 men (0.74%) while in the placebo group there were 1 in 138 men (0.72%). No heterogeneity was found between the trials using the transdermal method; the OR was 1.01 (95% CI, 0.13–7.60; P ¼ 0.99; Figure 3). These results demonstrate that TRT and placebo administered transdermally were similar in terms of the prostate nodule. & 2014 Macmillan Publishers Limited
Abnormal PSA levels. Five RCTs, representing 1033 participants (709 in the testosterone group and 324 in the control group), included data on abnormal PSA levels (Figure 3). Two trials used injection for administration and three used transdermal application. It appears that in the TRT group there were 20 participants with abnormal PSA levels in 709 men (2.82%) whereas in the placebo group there were 5 in 324 men (1.54%). No heterogeneity was found between the RCTs in which treatment was given by injection (Figure 3); the effect size for meta-analysis was denoted as the OR. The pooled estimate of OR was 1.45 (95% CI, 0.24–8.80; P ¼ 0.69; Figure 3). For the study that used transdermal treatment application, the OR was 1.54 (95% CI, 0.54–4.43; P ¼ 0.42; Figure 3). These results suggests that regardless of administration method comparing testosterone with a placebo revealed no apparent differences in abnormal PSA levels.
PSA levels’ change. Seven RCTs, representing 736 participants (472 in the testosterone group and 264 in the control group), included PSA data (Figure 3). Four studies used injection for administration, two used transdermal application and, in one, treatment was given orally. No heterogeneity was found among the trials (Figure 3). For the four RCTs using injected treatments, the fixed-effects estimate of the SMD was 0.52 (95% CI, 0.00–1.05; P ¼ 0.05; Figure 3). For the RCTs using transdermal application, the SMD was 0.33 (95% CI, 0.21–0.45; Po0.00001; Figure 3). For the study in which treatment was given orally, the SMD was 0.02 (95% CI, 0.64 to 0.60; P ¼ 0.95; Figure 3). This result suggests that TRT was more likely to result in increased PSA levels than treatment with a placebo when administered transdermally. Prostate Cancer and Prostatic Disease (2014), 132 – 143
TRT and prostate cancer Y Cui et al
136 Long-term TRT versus placebo Prostate cancer. The same, only three RCTs, involving a total of 379 participants (191 in the testosterone group and 188 in the control group), included prostate cancer data that used injection, transdermal and oral for administration of TRT or placebo (Figure 4). It appears that in the TRT group there were 3 cancers in 191 men (1.57%) while in the placebo group there were 3 cancers in 188 men (1.60%). No heterogeneity was found between the trials using the three methods; the OR was 0.99 (95% CI, 0.24– 4.02; P ¼ 0.99; Figure 4). These results demonstrate that TRT and placebo were similar in terms of the prostate cancer-confirmed diagnosis administered by injection, transdermally or orally.
Prostate biopsy. Only five RCTs, involving a total of 580 participants (314 in the testosterone group and 266 in the control group), included prostate biopsy data (Figure 4). Treatment was given by injection in one study, transdermally in three studies and orally in one study. It shows that in the TRT group there were 13 participants who need prostate biospy in 314 men (4.14%), whereas in the placebo group there were 5 in 266 men (1.88%). No heterogeneity was found between the trials (Figure 4). The OR was 2.37 (95% CI, 0.86–6.53; P ¼ 0.09; Figure 4). Therefore, for either an injection, a transdermal or an oral administration method, testosterone did not increase the number of prostate biopsy compared with placebo.
a
b
Figure 2. Forest plots showing changes in (a) prostate cancer, (b) prostate biopsy, (c) prostate node, (d) abnormal PSA levels and (e) PSA levels’ change in the short-term treatment studies. CI, confidence interval; IV, inverse variance; MH, mantel haenszel. Prostate Cancer and Prostatic Disease (2014), 132 – 143
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TRT and prostate cancer Y Cui et al
137
c
d
e
Figure 2.
Continued.
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Prostate Cancer and Prostatic Disease (2014), 132 – 143
TRT and prostate cancer Y Cui et al
138
a
b
Figure 3. Forest plots showing changes in (a) prostate cancer, (b) prostate biopsy, (c) prostate node, (d) abnormal PSA levels and (e) PSA levels’ change in the long-term treatment studies. CI, confidence interval; IV, inverse variance; MH, mantel haenszel.
Prostate Cancer and Prostatic Disease (2014), 132 – 143
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TRT and prostate cancer Y Cui et al
139
c
d
Figure 3.
Continued.
Prostate nodule. Only 3 of the included 11 RCTs reporting 379 participants (191 in the testosterone group and 188 in the control group) included the data for prostate nodule that used injection, transdermal and oral for administration of TRT or placebo. It shows that in the TRT group there were 4 participants with prostate nodule in 191 men (2.09%) while in the placebo & 2014 Macmillan Publishers Limited
group there were 3 in 188 men (1.60%). No heterogeneity was found between the trials using the three methods; the OR was 1.27 (95% CI, 0.31–5.23; P ¼ 0.74; Figure 4). These results demonstrate that TRT and placebo administered by injection, transdermally or orally were similar in terms of the prostate nodule. Prostate Cancer and Prostatic Disease (2014), 132 – 143
TRT and prostate cancer Y Cui et al
140
e
Figure 3.
Continued.
oral treatment application, the OR was 0.85 (95% CI, 0.33–2.19; P ¼ 0.74; Figure 4). These results suggests that regardless of the administration method, comparing testosterone with a placebo revealed no apparent differences in abnormal PSA levels.
Figure 4. Funnel plot of the studies represented in our metaanalysis. Although 22 articles are included in our study, the most articles that reported one of the indications of prostate cancer at the same time is 15. So 15 symbols are reported in the graph. MD, mean difference.
Abnormal PSA levels. Seven RCTs, representing 765 participants (385 in the testosterone group and 380 in the control group), included data on abnormal PSA levels (Figure 4). Two trials used injection for administration, three used transdermal application and two used oral application. It appears that in the TRT group there were 31 participants with abnormal PSA levels in 385 men (8.05%) while in the placebo group there were 21 in 380 men (5.53%). No heterogeneity was found between the RCTs in which treatment was given by injection (Figure 4). The pooled estimate of OR was 1.70 (95% CI, 0.22–13.37; P ¼ 0.61; Figure 4). For the study that used transdermal treatment application, the OR was 2.12 (95% CI, 0.94–4.78; P ¼ 0.07; Figure 4). For the study that used Prostate Cancer and Prostatic Disease (2014), 132 – 143
PSA levels’ change. Eight RCTs included PSA data for a total of 560 participants (300 in the testosterone group and 260 in the control group) (Figure 4). Three used injection for administration, three used transdermal administration and two gave treatments orally. According to our analysis, no heterogeneity was found among the trials (Figure 4). The SMDs were 0.15 (95% CI, 0.22 to 0.53; P ¼ 0.42), 0.01 (95% CI, 0.27 to 0.24; P ¼ 0.91) and 0.08 (95% CI, 0.36 to 0.20; P ¼ 0.57) for TRT administered by injection, transdermally and orally, respectively (Figure 4). These results indicate no apparent differences between TRT and placebo in changes in PSA levels regardless of how the treatments were administered. Subgroup analyses and sensitivity analysis. Subgroup analyses showed that all the results of determinants of prostate cancer in the TRT and placebo groups matched our findings (Table 3), except that TRT using the transdermal administration method was more likely to increase PSA levels than placebo (Po0.00001) in the group aged X65 years (Table 3). Sensitivity analysis was performed by removing the studies for which generation of allocation sequence was inadequate. By removing seven studies, our analysis indicated that short-term TRT was more likely to increase PSA levels than treatment with placebo (Po0.00001; Table 3). No differences were found between the TRT and placebo groups in the long-term studies regarding changes in PSA levels (P ¼ 0.91), abnormal PSA levels (P ¼ 0.24), prostate nodule (P ¼ 0.74), prostate biopsy (P ¼ 0.09) or prostate cancer (P ¼ 0.99) (Table 3). & 2014 Macmillan Publishers Limited
TRT and prostate cancer Y Cui et al
0.90 0.99 1.10 (0.26–4.65) 0.99 (0.24–4.02) 0.65 0.09
Abbreviations: CI, confidence interval; OR, odds ratio; SMD, standardized mean difference. Gold standard: tandem mass spectrometry and liquid chromatography. A level: all quality criteria met (adequate): low risk of bias.
1.69 (0.18–15.71) 2.37 (0.86–6.53) 0.51 0.74 — 1.27 (0.31–5.23) 0.42 0.24 1.54 (0.54–4.43) 1.42 (0.79–2.57) o0.00001 0.91 0.33 (0.21–0.45) 0.01 ( 0.19–0.17) Sensitivity analysis Short Long
0.74 0.77 0.81 (0.23–2.86) 0.84 (0.26–2.73) 0.11 0.17 2.27 (0.83–6.24) 3.10 (0.62–15.47) 0.99 0.47 0.99 (0.28–3.47) 3.55 (0.12–105.82) 0.15 0.48 0.38 o0.0001
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0.16 ( 0.20–0.53) 0.23 ( 0.12–0.34) Intention-to-treat analysis Yes No
1.55 (0.85–2.83) 1.35 (0.58–3.16)
0.94 0.32 1.04 (0.38–2.84) — 0.09 0.19 2.24 (0.89–5.64) 4.49 (0.46–43.43) 0.99 0.47 0.99 (0.28–3.47) — 0.16 0.47 o0.00001 0.25 Allocation sequence generation A level 0.23 (0.13–0.32) Non-A level 0.19 ( 0.13–0.51)
1.45 (0.87–2.43) 1.77 (0.37–8.43)
0.35 0.91 0.48 (0.11–2.19) 1.06 (0.37–3.07) 0.94 0.05 0.88 (0.04–18.75) 2.50 (0.99–6.33) — 0.78 — 1.18 (0.37–3.74) 0.76 0.30 0.46 o0.00001 0.30 ( 0.49–1.09) 0.22 (0.13–0.32) Testosterone assay types Gold standard Not gold standard
0.75 (0.11–4.95) 1.32 (0.78–2.24)
0.81 0.64 0.89 (0.33–2.38) 0.65 (0.11–3.94) 0.08 0.24 2.77 (0.88–8.75) 2.16 (0.60–7.77) 0.67 0.98 1.43 (0.27–7.53) 0.98 (0.20–4.94) 0.26 0.26 o0.00001 0.57 0.25 (0.14–0.35) 0.08 ( 0.19–0.34) Testosterone level Lower Normal
1.44 (0.76–2.72) 1.55 (0.72–3.32)
0.23 0.72 0.38 (0.08–1.85) 1.22 (0.41–3.61) 0.21 0.09 4.15 (0.46–37.69) 2.25 (0.89–5.70) 0.51 0.53 — 1.51 (0.42–5.46) 0.24 0.23 2.15 (0.60–7.70) 1.38 (0.81–2.36) 0.03 o0.0001 0.22 (0.02–0.41) 0.23 (0.12–0.33)
OR 95% CI OR 95% CI OR 95% CI P-value OR 95% CI P-value SMD 95% CI
PSA
Age, years o65 X65
Table 3.
Results of the subgroup and sensitivity analysis
Abnormal PSA levels
Prostate nodule
P-value
Prostate biopsy
P-value
Prostate cancer
P-value
141 DISCUSSION Prostate growth is dependent on the presence of testosterones; conversely, antiandrogen and orchidectomy can decrease prostate volume in patients with BPH.34 There is abundant evidence that androgens influence the development of prostate cancer.35–37 Although the risk that testosterone treatment triggers prostate cancer was not fully recognized. Resolving this question will inform methods of treating LOH accompanied by prostatic problems. The 22 placebo-controlled, randomized studies included in this meta-analysis provide direct comparasions of the indications of prostate cancer (PSA levels’ change, abnormal PSA levels, prostate nodule, prostate biopsy) and the incidence of new prostate cancer, which are all relative sensitive indicators for prostate cancer in testosterone therapy and placebo. In all, only 12, 5, 9 and 8 of the included 22 RCTs reported the incidence of abnormal PSA levels, prostate nodule, prostate biopsy and new prostate cancer, respectively. Namely, less than half of the included 22 RCTs reported the incidence of the indications of prostate cancer or new prostate cancer. It showed that neither short-term nor longterm TRT increased the risk of prostate cancer. In our analysis, short-term TRT delivered by transdermal application was more likely to increase PSA levels than treatment with a placebo. A section of urologists consider that testosterone has a linear effect on prostate growth, and prostate dysfunction as an adverse effect of this was the dominant theory in the past. A new paradigm has been put forward: the saturation model of testosterone and the prostate.38 The theory holds that testosterone’s effect on the prostate reaches a saturation point well below the physiological testosterone levels encountered in the clinical setting, beyond which additional testosterone does not have an increased effect. The inclusion criteria for patients receiving transdermal treatment included PSA level o1.5 ng ml 1, which was much lower than normal (Table 1). This may be the reason leading to increased PSA levels in the short term. But as to the incidence of new prostate cancer, prostate biopsy, prostate nodule and abnormal PSA levels, there was no apparent difference between testosterone with placebo, especially in transdermal administration method. Our study also evaluated the safety of long-term TRT (12–36 months) for prostate cancer. All 22 RCTs included in our analysis involved rigorous, periodic monitoring of patients, and treatment was withdrawn when there were indications suspicious for prostate cancer or other serious complications. In addition, for all 22 RCTs no patient had prostate enlargement at baseline, all patients had normal PSA levels at baseline and one RCT reported patients who underwent prostate biopsy at study entry and at the end of the study, which implicated that testosterone can not be a prostate cancer stimulus. Consequently, short-term TRT is safe in terms of prostate cancer under judicious and careful monitoring. The fact that all 22 RCTs included rigorous periodic monitoring of patients and withdrew patients when they suspected prostate cancer might be the reason why the meta-analysis failed to detect an increased hazards of prostate cancer among those treated with TRT. Our conclusion is based on the fact that TRT has no adverse effect on prostate cancer in patients without prostatic hyperplasia. Whether or not TRT will increase the risk for prostate cancer in patients with BPH needs further investigation in larger, highquality studies. Although difference resided in the baseline level of testosterone included in 22 RCTs, the cohorts of 17 of the 22 studies in our meta-analysis were diagnosed as LOH. Controversy surrounds setting a lower limit of normal testosterone. There is also no generally accepted lower limits of normal testosterone level in aging males. It was demonstrated that demographic differences in testosterone level within population of aging male exist.39 Although different methods and dosages were used in the Prostate Cancer and Prostatic Disease (2014), 132 – 143
TRT and prostate cancer Y Cui et al
142 selected RCTs, all patients in the 22 RCTs achieved normal testosterone levels and supraphysiological levels were avoided. The 22 RCTs included in this meta-analysis were all doubleblinded. According to the quality-assessment scale that we developed, the quality of the individual studies in the meta-analysis was high. The results of this analysis are important from a scientific standpoint, and they apply to everyday clinical practice, particularly because data were analyzed by method of TRT delivery. The results of the subgroup and sensitivity analyses are in accordance with our findings, indicating that our results are robust and reliable. Nevertheless, there are some limitations to our analysis. Data in the studies covered by this meta-analysis are insufficient to determine whether more severe grades of prostate cancer are found with testosterone treatment versus without testosterone treatment. Major limitations include heterogeneity in the populations examined (Table 1), testosterone dosage used (Table 1) and baseline PSA levels. LOH is a clinical and biochemical syndrome that adversely affects the function of multiple organ systems. The presence of symptoms associated with LOH was not consistent across the included studies, and this may have contributed to the heterogeneous population. Although we conducted subgroup and sensitivity analyses to assess the quality of the studies, the problem of heterogeneity still could not be completely avoided. Although 21 of the 22 RCTs drew morning blood samples to measure testosterone levels, 17 of the 22 studies reported six measurement assay methods that included tandem mass spectrometry-liquid chromatography, mass spectroscopy, chemiluminescent immunoassay, radioimmunoassay, fluoroimmunoassay and electrochemiluminescence. It is generally known that the first method is the gold standard. Although the results of subgroup analysis by testosterone assay types (gold standard and not gold standard) matched our findings, this made inclusion of studies using different testosterone assays problematic and potentially influenced the results of the meta-analysis. CONCLUSIONS This meta-analysis shows that regardless of the administration method, TRT is the short-term safety and does not promote prostate cancer development or progression but long-term data are warranted with justifiable end points. CONFLICT OF INTEREST The authors declare no conflict of interest.
ACKNOWLEDGEMENTS Financial support for our studies from the Research Fund of Capital Medical Development (No.2009-2069) and from the Urological Backbone Fund of Beijing Municipal Health Bureau (No.2009-3-15) is gratefully acknowledged.
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6 Wang C, Cunningham G, Dobs A, Iranmanesh A, Matsumoto AM, Snyder PJ et al. Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone density in hypogonadal men. J Clin Endocrinol Metab 2004; 89: 2085–2098. 7 Morgentaler A. Testosterone and prostate cancer: an historical perspective on a modern myth. Eur Urol 2006; 50: 935–939. 8 Jadad AR. Randomised Controlled Trials. BMJ Publishing Group: London, UK, 1998. 9 Higgins JPT, Green S (eds). Cochrane handbook for systematic reviews of interventions, v.5.1 [updated March 2011]. Cochrane Collaboration Web site http:// www.cochrane-handbook.org/. 10 DerSimonian R, Laird N. Meta-analysis in clinical trials. Controlled Clinical Trials 1986; 7: 177–188. 11 Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in metaanalyses. BMJ 2003; 327: 557–560. 12 Tenover JS. Effects of testosterone supplementation in the aging male. 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The effects of growth hormone and sex steroid on lean body mass, fat mass, muscle strength, cardiovascular endurance and adverse events in healthy elderly women and men. Horm Res 2003; 60: 121–124. 17 Steidle C, Schwartz S, Jacoby K, Sebree T, Smith T, Bachand R. AA2500 testosterone gel normalizes androgen levels in aging males with improvements in body composition and sexual function. J Clin Endocrinol Metab 2003; 88: 2673–2681. 18 Kenny AM, Fabregas G, Song C, Biskup B, Bellantonio S. Effects of testosterone on behavior, depression, and cognitive function in older men with mild cognitive loss. J Gerontol A Biol Sci Med Sci 2004; 591: 75–78. 19 Marks LS, Mazer NA, Mostaghel E, Hess DL, Dorey FJ, Epstein JI et al. Effect of testosterone replacement therapy on prostate tissue in men with late-onset hypogonadism. AMA 2006; 296: 2351–2361. 20 Srinivas-Shanker U, Roberts SA, Connolly MJ, O’Connell MD, Adams JE, Oldham JA et al. Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab 2010; 95: 639–650. 21 Basaria S, Coviello AD, Travison TG, Storer TW, Farwell WR, Jette AM et al. Adverse events associated with testosterone administration. N Engl J Med 2010; 363: 109–122. 22 Kaufman JM, Miller MG, Garwin JL, Fitzpatrick S, McWhirter C, Brennan JJ. Efficacy and safety study of 1.62% testosterone gel for the treatment of hypogonadal men. J Sex Med 2011; 8: 2079–2089. 23 Sih R, Morlet JE, Kaiser FE, Perry HM, Rd, Patrick P, Ross C. Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. J Clin Endocrinol Metab 1997; 82: 1661–1667. 24 Snyder PJ, Peachey H, Hannoush P, Berlin JA, Loh L, Holmes JH et al. Effect of testosterone treatment on bone mineral density in men over 65 years of age. J Clin Endocrinol Metab 1999; 84: 1966–1972. 25 Kenny AM, Prestwood KM, Gruman CA, Marcello KM, Raisz LG. Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels. J Gerontol A Biol Sci Med Sci 2001; 565: 266–272. 26 Wittert GA, Chapman IM, Haren MT, Mackintosh, Coates P, Morley JE. Oral testosterone supplementation increases muscle and decreases fat mass in healthy elderly males with low–normal gonadal status. J Gerontol A Biol Sci Med Sci 2003; 587: 618–625. 27 Amory JK, Watts NB, Easley KA, Sutton PR, Anawalt BD, Matsumoto AM et al. Exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone. J Clin Endocrinol Metab 2004; 89: 503–510. 28 Nair KS, Rizza RA, O’Brien P, Dhatariya K, Short KR, Nehra A et al. DHEA in elderly women and DHEA or testosterone in elderly men. N Engl J Med 2006; 355: 1647–1659. 29 Emmelot-Vonk MH, Verhaar HJJ, Pour HRN, Aleman A, Lock TM, Bosch JL et al. Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men. AMA 2008; 299: 39–52. 30 Aversa A, Bruzziches R, Francomano D, Rosano G, Isidori AM, Lenzi A et al. Effects of testosterone undecanoate on cardiovascular risk factors and atherosclerosis in middle-aged men with late-onset hypogonadism and metabolic syndrome:
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results from a 24-month, randomized, double-blind, placebo-controlled study. J Sex Med 2010; 7: 3495–3503. Shigehara K, Sugimoto K, Konaka H, Iijima M, Fukushima M, Maeda Y et al. Androgen replacement therapy contributes to improving lower urinary tract symptoms in patients with hypogonadism and benign prostate hypertrophy: a randomised controlled study. Aging Male 2011; 14: 53–58. Jones TH, Arver S, Behre HM, Buvat J, Meuleman E, Moncada I et al. Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care 2011; 34: 828–837. Hildreth KL, Barry DW, Moreau KL, Vande GJ, Meacham RB, Nakamura T et al. Effects of testosterone and progressive resistance exercise in healthy, highly functioning older men with low-normal testosterone levels. J Clin Endocrinol Metab 2013; 98: 1891–1900. Roehrborn CG, Siami P, Barkin J, Damiao R, Major-Walker K, Nandy I et al. The effects of combination therapy with dutasteride and tamsulosin on clinical
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outcomes in men with symptomatic benign prostatic hyperplasia: 4-year results from the CombAT Study. Eur Urol 2010; 57: 123–131. Hsing AW, Reichardt JK, Stanczyk FZ. Hormones and prostate cancer: current perspectives and future directions. Prostate 2002; 52: 213–235. Ross RK, Bernstein L, Lobo RA, Henderson BE, Lobo RA, Stanczyk FZ et al. 5-Alphareductase activity and risk of prostate cancer among Japanese and US white and black males. Lancet 1992; 339: 887–889. Giovannucci E, Stampfer MJ, Krithivas K, Brown M, Dahl D, Brufsky A et al. The CAG repeat within the androgen receptor gene and its relationship to prostate cancer. Proc Natl Acad Sci USA 1997; 94: 3320–3323. Morgentaler A, Traish AM. Shifting the paradigm of testosterone and prostate cancer: the saturation model and the limits of androgen-dependent growth. Eur Urol 2009; 55: 310–320. Nieschlag E, Swerdloff R, Behre HM, Gooren LJ, Kaufman JM, Legros JJ et al. Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, and EAU recommendations. J Androl 2006; 27: 135–137.
Prostate Cancer and Prostatic Disease (2014), 132 – 143
ORIGINAL ARTICLE
The effect of testosterone replacement therapy on prostate cancer: a systematic review and meta-analysis Y Cui, H Zong, H Yan and Y Zhang BACKGROUND: Testosterone replacement therapy (TRT) is a widely accepted form of treatment worldwide for aging men with late-onset hypogonadism syndrome. Urologists have been concerned about the possibility of TRT causing prostate cancer. The aim of this study was to assess the relationship between TRT and prostate cancer. METHODS: A literature review was performed to identify all published, randomized controlled trials (RCTs) of testosterone treatment for hypogonadism. The search included the MEDLINE, Embase and the Cochrane Controlled Trials Register databases. Fixed-effect model was chosen for homogeneous studies; otherwise, a random-effect model was used. Inconsistency was quantified by using the I2 statistic, which tests the proportion of heterogeneity across studies. RESULTS: Results of 22 RCTs involving a total of 2351 patients were analyzed. Eleven RCTs were short-term (o12 months) and 11 were long-term (12–36 months) comparisons of TRT with a placebo; TRT was administered transdermally, orally or by injection. Respective odds ratio (OR) and 95% confidence interval (CI) values for injection, transdermal administration and oral administration of short-term TRT were as follows: prostate cancer: 0.39 (0.06–2.45), 1.10 (0.26–4.65) and no oral; biopsy: 5.28 (0.24–113.87), 2.11 (0.32–13.73) and no oral; and prostate nodule: 1.01 (0.13–7.60), no injection and oral. Respective OR and 95% CI values for injection, transdermal administration and oral administration of long-term TRT were as follows: prostate cancer: 2.09 (0.18–24.73), 3.06 (0.12– 76.70) and 0.19 (0.01–4.03); biopsy: 2.09 (0.18–24.73), 3.65 (0.88–15.20) and 0.97 (0.13–7.03); and prostate nodule: 3.13 (0.12–80.68), 1.00 (0.06–16.41) and 0.97 (0.13–7.03). Though for some routes of administration and some end points, the OR associated with testosterone administration were 41 indicating increased risk, none of these reached or even approached statistical significance (all P40.10), which was consistent with the results of subgroup analyses and sensitivity analysis. Besides, sensitivity analysis indicated that short-term TRT was more likely to increase PSA levels than treatment with placebo (Po0.00001). CONCLUSIONS: This meta-analysis shows that regardless of the administration method, TRT is the short-term safety and does not promote prostate cancer development or progression but long-term data are warranted with justifiable end points. Prostate Cancer and Prostatic Disease (2014) 17, 132–143; doi:10.1038/pcan.2013.60; published online 21 January 2014 Keywords: testosterone; meta-analysis; randomized controlled trial
INTRODUCTION Testosterone deficiency in the aging male has become a topic of increasing interest and debate worldwide. Cross-sectional and longitudinal data indicate that testosterone levels are reduced progressively with age and that a significant percentage of men aged 460 years have serum testosterone levels that are below the lower limits of young adult men aged 20–30 years.1–3 Lateonset hypogonadism (LOH) is a clinical and biochemical syndrome associated with advancing age and characterized by a deficiency in serum testosterone levels, among other signs and symptoms.4,5 LOH may result in significant detriment to quality of life and adversely affect the function of multiple organ systems. Over the past decade, there has been a growing awareness of the health benefits of testosterone therapy for men with testosterone deficiency, including improved sexual desire and performance, improved mood, increased muscle mass and strength, decreased fat mass and improved bone mineral density.6 However, for approximately 70 years there has been a concern that higher serum testosterone represents a risk for prostate cancer.7 Many urologists are concerned that testosterone replacement therapy (TRT) may accelerate prostate growth not only in benign disease but also in cancer as well.
The goal of the present study was to perform a meta-analysis evaluating the effect of TRT on prostate cancer, which may resolve some of the current controversies over the use of the drug.
MATERIALS AND METHODS Search strategy Medline (1966 to Augest 2013), Embase (1974 to Augest 2013) and Cochrane Controlled Trials Register databases were searched to identify randomized controlled trials (RCTs) that referred to the impact of TRT on the prostate; we also searched the reference lists of the retrieved studies. The following search terms were used: testosterone, prostate cancer, and randomized controlled trials.
Inclusion criteria and trial selection RCTs that met the following criteria were included: (1) The study design included TRT; (2) the study provided accurate data that could be analyzed, including the total number of subjects and the values of each indication of prostate cancer, such as PSA levels’ change, number of people with elevated PSA, prostate nodule, biopsy and prostate cancer; and (3) the full text of the study could be accessed. When the same study was published in various journals or in different years, the most recent publication was
Department of Urology, Beijing Tian-Tan Hospital, Capital Medical University, Beijing, China. Correspondence: Dr Y Zhang, Department of Urology, Beijing Tian-Tan Hospital, Capital Medical University, No. 6 Tiantan Xi Li, Dong cheng Beijing 100050, China. E-mail: [email protected] Received 29 September 2013; revised 5 December 2013; accepted 6 December 2013; published online 21 January 2014
TRT and prostate cancer Y Cui et al
133 used for the meta-analysis. If the same group of researchers studied a group of subjects with multiple experiments, then each study was included. A flow diagram of the study selection process is presented in Figure 1.
Quality assessment The quality of the retrieved RCTs was assessed using the Jadad scale.8 All the identified RCTs were included in the meta-analysis regardless of the quality score. The methodological quality of each study was assessed according to how patients were allocated to the arms of the study, the concealment of allocation procedures, blinding and data loss due to attrition. The studies were then classified qualitatively according to the guidelines published in the Cochrane Handbook for Systematic Reviews of Interventions v.5.1.0.9 Based on the quality assessment criteria, each study was rated and assigned to one of the three following quality categories: A, if all quality criteria were adequately met, the study was deemed to have a low risk of bias; B, if X1 of the quality criteria was only partially met or was unclear, the study was deemed to have a moderate risk of bias; or C, if X1 of the criteria was not met or not included, the study was deemed to have a high risk of bias. Differences were resolved by discussion among the authors.
Data extraction The following information was collected for each study: (1) the name of the first author and the publication year; (2) the study design and sample size; (3) the therapy that the patients received; (4) the country in which the study was conducted; (5) data on the five indications of prostate cancer, that is, PSA levels, number of people with elevated PSA, prostate nodule, biopsy and prostate cancer; and (6) the TRT administration method and dosage.
Statistical analysis and meta-analysis The meta-analysis of comparable data was carried out using RevMan v.5.1.0 (Cochrane Collaboration, Oxford, UK).9 Changes in all five indications of prostate cancer were determined as differences between baseline (study entry) and study completion. We estimated the relative risk for dichotomous outcomes and the standardized mean difference (SMD) for continuous outcomes pooled across studies by using the DerSimonian and Laird10 random-effects model. We used a 95% confidence interval (CI). If the result of analysis showed P40.05, we considered the studies homogeneous and so chose a fixed-effect model for meta-analysis. Otherwise, a random-effect model was used. We quantified inconsistency using the I2 statistic, which describes the proportion of heterogeneity across studies that is not due to chance, thus describing the extent of true inconsistency
in results across trials.11 I2o25% reflects a small level of inconsistency, and I2450% reflects significant inconsistency.
Subgroup and sensitivity analysis To explore causes of inconsistency and subgroup treatment interactions, subgroup analyses were specified a priori according to the following factors: Participants: aged o65 or X65 years; total testosterone level at baseline
(testosterone level was considered low if o350 ng dl 1 or 12 nmol l 1); if total testosterone was not available, then the lower limit of normal for bioavailable or free testosterone levels was used; if neither total nor free testosterone levels were available, then studies were classified according to PSA levels; Interventions: testosterone formulation, route of administration; Outcome characteristic: duration of follow-up (o12 versus X12 months); and Study quality measure: proportion of patients lost to follow-up (p10% versus 410%), concealment of allocation, intention-to-treat analysis and blinding of patients.
RESULTS Characteristics of the individual studies The database search found 267 articles that could have been included in our meta-analysis. Based on the inclusion and exclusion criteria, 232 articles were excluded after reading the titles and abstracts of the articles. Thirteen articles lacked useful data. In all, 22 articles,12–33 reporting data from a total of 22 RCTs, were included in the analysis: 11 RCTs compared testosterone with a placebo over the short term (o12 months); and 11 RCTs compared testosterone with a placebo over the long term (12–36 months). Three different administration methods were used: oral, transdermal, and injection (Figure 1). The baseline characteristics of the studies included in our meta-analysis are listed in Table 1. All 22 RCTs included in our analysis involved rigorous, periodic monitoring of patients, and treatment was withdrawn when there were indications suspicious for prostate cancer or other serious complications. Few patients suffered serious complications, and all patients who withdrew from treatment had returned to normal at long-term assessment. Other than four short-term therapy RCTs, all of the 18 RCTs reported the baseline PSA levels, and only one patient from the studies31 suffered from BPH symptoms. In addition, for all 22 RCTs no patient had prostate enlargement at baseline, all patients had normal PSA levels at baseline (Table 1) and no patient had suspected or conformed diagnosis of prostate cancer at study entry. Quality of the individual studies All 22 RCTs were double blinded, and all described the randomization processes that they had used. All except Kenny et al.18 included a power calculation to determine the optimal sample size, and eight used intention-to-treat analysis (Table 2). The level of quality of each identified study was A (Table 2). The funnel plot provided a qualitative estimation of publication bias of the studies, and no evidence of bias was found (Figure 2).
Figure 1. A flow diagram of the study selection process. RCT, randomized controlled trials. & 2014 Macmillan Publishers Limited
Short-term TRT versus placebo Prostate cancer. Only five RCTs, involving a total of 1168 participants (778 in the testosterone group and 390 in the control group), included prostate cancer data (Figure 3). Treatment was given by injection in one study and transdermally in four studies. It appears that in the TRT group there were 7 cancers in 778 men (0.90%), whereas in the placebo group there were 5 cancers in 390 men (1.28%). No heterogeneity was found between the trials (Figure 3). The odds ratio (OR) was 0.39 (95% CI, 0.06–2.45; P ¼ 0.32) for the study using delivery by injection and 1.10 (95% CI, Prostate Cancer and Prostatic Disease (2014), 132 – 143
12
Prostate Cancer and Prostatic Disease (2014), 132 – 143
Placebo
Placebo
Placebo
T
T
T
USA
UK
Japan
Italy
The Netherlands
Italy
USA
Australia
USA
USA
USA
USA
USA
New Zealand
USA
USA
USA
USA
USA
France
Sweden
USA
Country
96
108
23
40
104
27
17
33
24
45
12
214
106
114
21
6
307
37
7
6
11
6
Experimental
47
112
23
10
103
31
18
25
20
51
10
37
103
117
19
5
99
37
5
6
12
7
Control
Sample size
TT 3.4 ng ml
TT 350 ng dl
1
TT 11 nmol l 1
BT 11.8 pg ml
1
TT 11 nmol l 1
TT 13.7 nmol l 1
BT 3.6 nmol l 1
TT 12.1 nmol l 1
TT normal
BT 4.44 nmol l 1
TT 475 ng dl 1
BT 60 ng dl 1
TT 300 ng dl
1
At least two symptoms of hypogonadism IPSS47 and total prostate volume 420 ml Men had confirmed hypogonadism Community dwelling men with confirmed hypogonadism
Have evidence of limitations in mobility Hypogonadal but otherwise healthy men Normal liver function tests, PSA, and hematocrit Men had a bone mineral density of the lumbar spine below normal Men with late-onset hypogonadism symptoms Men with late-onset hypogonadism symptoms Men with late-onset hypogonadism symptoms Men had confirmed hypogonadism Men with late-onset hypogonadism symptoms
TT 350 ng dl 1
TT 12 nmol l 1
TT 300 ng dl 1
BT 128 ng dl 1
Men with low levels of TT andX1 symptoms of low T Folsteinini-Mental State Exam scores between 14 and 28 Men with late-onset hypogonadism symptoms Men with late-onset hypogonadism symptoms
Healthy, ambulatory, community-dwellig men
Healthy, older men
No history of diease, body mass index between 22–29 kg m 2 Men without urinary tract symptoms Men with low levels of TT
Other inclusion criteria
TT 10.4 nmol l 1
TT normal
TT 17 nmol l 1
1
TT normal
TT 12.1 nmol l
1
Testosterone cut off level for study entry
44
44
42
44
44.5
44
44
45
44
44
44
42.5
44
44
410
44
44
44
44
44
410
44
Exclusion of PSA levels (ng ml 1)
66.5
59.9
70.5
57
67
66.7
71
68.5
75.5
73
65
54.6
74
73.8
69
79.5
58
76.5
67.5
54.1
52
66.7
Age (median)
Long term
Long term
Long term
Long term
Long term
Long term
Long term
Long term
Long term
Long term
Long term
Short term
Short term
Short term
Short term
Short term
Short term
Short term
Short term
Short term
Short term
Short term
Short-term or longterm ART
T’
T’
I
T’
O
T’
I
O
T’
T’
I
T’
T’
T’
I
I
T’
I
I
T’
O
I
Administration method
125 mg day
1
2.5g per 2 weeks
1000 mg per 12 weeks 250 mg per 4 weeks 60 mg day 1
80 mg 2 day 1
200 mg per 2 weeks 5 mg day 1
80 mg 2 day
5 mg day
200 mg per 2 weeks 6 mg day 1
2.5g per 2 weeks
100 mg day 1
50 or 100 mg day 1 200 mg per 3 weeks 150 mg per 2 weeks 50 mg day 1
—
100 mg week 1
1
100 mg per 2 weeks 160 mg day 1
Dosage
1.5
1.6
1.06
1.07
1.6
1.6
0.9
2.5
2.0
1.7
1.0
0.85
—
1.5
1.55
0.88
1.30
—
1.4
—
1.28
2.1
T
1.4
1.2
1.06
1.1
1.7
1.4
1.4
2.5
2.0
1.6
1.5
0.89
—
1.5
0.97
1.30
1.13
—
1.2
—
0.72
2.1
P
Baseline PSA level (ng ml 1)
Abbreviations: ART, androgen-replacement therapy; BT, bioavailable testosterone; I, injection; IPSS, International Prostate Symptom Score; O, oral; P, placebo; T, testosterone; T’, transdermal; TT, total testosterone .
Placebo
T
Placebo
T
EmmelotVonk et al.29 Aversa et al.30 Shigehara et al.31 Jones et al.32 Hildreth et al.33
Placebo
T
Placebo
T
Placebo
Placebo
T
Placebo
Placebo
T
T
Placebo
T
T
Placebo
T
Placebo
Placebo
T
T
Placebo
T
Kenny et al.25 Wittert et al.26 Amory et al.27 Nair et al.28
Placebo
T
Placebo
Placebo
T
T
Placebo
T
Snyder et al.24
Placebo
Placebo
Therapy in control group
T
T
Therapy in experimental group
Study and patient characteristics
Holmang et al.13 Simon et al.14 Ferrando et al.15 Harman and Blackman16 Steidle et al.17 Kenny et al.18 Marks et al.19 SrinivasShankar et al.20 Basari et al.21 Kawfaman et al.22 Sih et al.23
Tenover
Study
Table 1.
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134
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TRT and prostate cancer Y Cui et al
135 Table 2.
Quality assessment of individual study
Study
Allocation sequence generation
Allocation concealment
Tenover12 Holmang et al.13 Simon et al.14 Ferrando et al.15 Harman and Blackman16 Steidle et al.17 Kenny et al.18 Marks et al.19 Srinivas-Shankar et al.20 Basari S21 Kawfaman et al.22 Sih et al.23 Snyder et al.24 Kenny et al.25 Wittert et al.26 Amory et al.27 Nair et al.28 Emmelot-Vonk et al.29 Aversa et al.30 Shigehara et al.31 Jones et al.32
B B B A B
Hildreth et al.33
Blinding
Loss to followup
Calculation of sample size
A A A A A
A A A A A
0 2 0 0 0
Yes Yes Yes Yes Yes
A B B A
A A A A
A A A A
6 0 21 31
Yes No Yes Yes
A A A A A A A A A A B A
A A A A A A A A A A A A
A A A A A A A A A A A A
3 23 10 12 24 18 13 4 16 0 6 15
Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
A
A
A
23
Yes
Statistical analysis
Intentiontotreat analysis
Level of quality
Analysis of variance Student’s t-test Student’s t-test Analysis of variance Analysis of variance
No No No No Yes
A A A A A
Fisher’s exact test Analysis of variance Paired t tests Analysis of covariance Student’s t-test Paired t tests Student’s t-test Analysis of variance Paired t tests Fisher’s exact test Student’s t-test Two-sided tests Unpaired t tests Analysis of variance Student’s t-test Analysis of covariance Analysis of variance
No No No Yes
A A A A
No No No Yes No Yes Yes No Yes No No Yes
A A A A A A A A A A A A
Yes
A
Abbreviation: ITT, intention-to-treat. A—all quality criteria met (adequate): low risk of bias. B—one or more of the quality criteria only partly met (unclear): moderate risk of bias. C—one or more criteria not met (inadequate or not used): high risk of bias.
0.26–4.65; P ¼ 0.90) for the study using transdermal delivery (Figure 3). Therefore, for either an injection or an transdermal administration method testosterone did not increase the number of prostate cancer confirmed diagnosis compared with placebo. Prostate biopsy. Only four RCTs, involving a total of 599 participants (387 in the testosterone group and 212 in the control group), included prostate biopsy data (Figure 3). Treatment was given by injection in one study and transdermally in three studies. It shows that in the TRT group there were 6 participants who needed prostate biospy in 387 men (1.55%) whereas in the placebo group there was 0 in 212 men. No heterogeneity was found between the trials (Figure 3). The OR was 5.28 (95% CI, 0.24– 113.87; P ¼ 0.29) for the study using delivery by injection and 2.11 (95% CI, 0.32–13.73; P ¼ 0.43) for the study using transdermal delivery (Figure 3). Therefore, for either an injection or an transdermal administration method testosterone did not increase the number of prostate biopsy compared with placebo. Prostate nodule. Only 2 of the included 11 RCTs reporting 274 participants (136 in the testosterone group and 138 in the control group) included the data for prostate nodule that used transdermal for administration of TRT or placebo. It shows that in the TRT group there were 1 participant with prostate nodule in 136 men (0.74%) while in the placebo group there were 1 in 138 men (0.72%). No heterogeneity was found between the trials using the transdermal method; the OR was 1.01 (95% CI, 0.13–7.60; P ¼ 0.99; Figure 3). These results demonstrate that TRT and placebo administered transdermally were similar in terms of the prostate nodule. & 2014 Macmillan Publishers Limited
Abnormal PSA levels. Five RCTs, representing 1033 participants (709 in the testosterone group and 324 in the control group), included data on abnormal PSA levels (Figure 3). Two trials used injection for administration and three used transdermal application. It appears that in the TRT group there were 20 participants with abnormal PSA levels in 709 men (2.82%) whereas in the placebo group there were 5 in 324 men (1.54%). No heterogeneity was found between the RCTs in which treatment was given by injection (Figure 3); the effect size for meta-analysis was denoted as the OR. The pooled estimate of OR was 1.45 (95% CI, 0.24–8.80; P ¼ 0.69; Figure 3). For the study that used transdermal treatment application, the OR was 1.54 (95% CI, 0.54–4.43; P ¼ 0.42; Figure 3). These results suggests that regardless of administration method comparing testosterone with a placebo revealed no apparent differences in abnormal PSA levels.
PSA levels’ change. Seven RCTs, representing 736 participants (472 in the testosterone group and 264 in the control group), included PSA data (Figure 3). Four studies used injection for administration, two used transdermal application and, in one, treatment was given orally. No heterogeneity was found among the trials (Figure 3). For the four RCTs using injected treatments, the fixed-effects estimate of the SMD was 0.52 (95% CI, 0.00–1.05; P ¼ 0.05; Figure 3). For the RCTs using transdermal application, the SMD was 0.33 (95% CI, 0.21–0.45; Po0.00001; Figure 3). For the study in which treatment was given orally, the SMD was 0.02 (95% CI, 0.64 to 0.60; P ¼ 0.95; Figure 3). This result suggests that TRT was more likely to result in increased PSA levels than treatment with a placebo when administered transdermally. Prostate Cancer and Prostatic Disease (2014), 132 – 143
TRT and prostate cancer Y Cui et al
136 Long-term TRT versus placebo Prostate cancer. The same, only three RCTs, involving a total of 379 participants (191 in the testosterone group and 188 in the control group), included prostate cancer data that used injection, transdermal and oral for administration of TRT or placebo (Figure 4). It appears that in the TRT group there were 3 cancers in 191 men (1.57%) while in the placebo group there were 3 cancers in 188 men (1.60%). No heterogeneity was found between the trials using the three methods; the OR was 0.99 (95% CI, 0.24– 4.02; P ¼ 0.99; Figure 4). These results demonstrate that TRT and placebo were similar in terms of the prostate cancer-confirmed diagnosis administered by injection, transdermally or orally.
Prostate biopsy. Only five RCTs, involving a total of 580 participants (314 in the testosterone group and 266 in the control group), included prostate biopsy data (Figure 4). Treatment was given by injection in one study, transdermally in three studies and orally in one study. It shows that in the TRT group there were 13 participants who need prostate biospy in 314 men (4.14%), whereas in the placebo group there were 5 in 266 men (1.88%). No heterogeneity was found between the trials (Figure 4). The OR was 2.37 (95% CI, 0.86–6.53; P ¼ 0.09; Figure 4). Therefore, for either an injection, a transdermal or an oral administration method, testosterone did not increase the number of prostate biopsy compared with placebo.
a
b
Figure 2. Forest plots showing changes in (a) prostate cancer, (b) prostate biopsy, (c) prostate node, (d) abnormal PSA levels and (e) PSA levels’ change in the short-term treatment studies. CI, confidence interval; IV, inverse variance; MH, mantel haenszel. Prostate Cancer and Prostatic Disease (2014), 132 – 143
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TRT and prostate cancer Y Cui et al
137
c
d
e
Figure 2.
Continued.
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Prostate Cancer and Prostatic Disease (2014), 132 – 143
TRT and prostate cancer Y Cui et al
138
a
b
Figure 3. Forest plots showing changes in (a) prostate cancer, (b) prostate biopsy, (c) prostate node, (d) abnormal PSA levels and (e) PSA levels’ change in the long-term treatment studies. CI, confidence interval; IV, inverse variance; MH, mantel haenszel.
Prostate Cancer and Prostatic Disease (2014), 132 – 143
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TRT and prostate cancer Y Cui et al
139
c
d
Figure 3.
Continued.
Prostate nodule. Only 3 of the included 11 RCTs reporting 379 participants (191 in the testosterone group and 188 in the control group) included the data for prostate nodule that used injection, transdermal and oral for administration of TRT or placebo. It shows that in the TRT group there were 4 participants with prostate nodule in 191 men (2.09%) while in the placebo & 2014 Macmillan Publishers Limited
group there were 3 in 188 men (1.60%). No heterogeneity was found between the trials using the three methods; the OR was 1.27 (95% CI, 0.31–5.23; P ¼ 0.74; Figure 4). These results demonstrate that TRT and placebo administered by injection, transdermally or orally were similar in terms of the prostate nodule. Prostate Cancer and Prostatic Disease (2014), 132 – 143
TRT and prostate cancer Y Cui et al
140
e
Figure 3.
Continued.
oral treatment application, the OR was 0.85 (95% CI, 0.33–2.19; P ¼ 0.74; Figure 4). These results suggests that regardless of the administration method, comparing testosterone with a placebo revealed no apparent differences in abnormal PSA levels.
Figure 4. Funnel plot of the studies represented in our metaanalysis. Although 22 articles are included in our study, the most articles that reported one of the indications of prostate cancer at the same time is 15. So 15 symbols are reported in the graph. MD, mean difference.
Abnormal PSA levels. Seven RCTs, representing 765 participants (385 in the testosterone group and 380 in the control group), included data on abnormal PSA levels (Figure 4). Two trials used injection for administration, three used transdermal application and two used oral application. It appears that in the TRT group there were 31 participants with abnormal PSA levels in 385 men (8.05%) while in the placebo group there were 21 in 380 men (5.53%). No heterogeneity was found between the RCTs in which treatment was given by injection (Figure 4). The pooled estimate of OR was 1.70 (95% CI, 0.22–13.37; P ¼ 0.61; Figure 4). For the study that used transdermal treatment application, the OR was 2.12 (95% CI, 0.94–4.78; P ¼ 0.07; Figure 4). For the study that used Prostate Cancer and Prostatic Disease (2014), 132 – 143
PSA levels’ change. Eight RCTs included PSA data for a total of 560 participants (300 in the testosterone group and 260 in the control group) (Figure 4). Three used injection for administration, three used transdermal administration and two gave treatments orally. According to our analysis, no heterogeneity was found among the trials (Figure 4). The SMDs were 0.15 (95% CI, 0.22 to 0.53; P ¼ 0.42), 0.01 (95% CI, 0.27 to 0.24; P ¼ 0.91) and 0.08 (95% CI, 0.36 to 0.20; P ¼ 0.57) for TRT administered by injection, transdermally and orally, respectively (Figure 4). These results indicate no apparent differences between TRT and placebo in changes in PSA levels regardless of how the treatments were administered. Subgroup analyses and sensitivity analysis. Subgroup analyses showed that all the results of determinants of prostate cancer in the TRT and placebo groups matched our findings (Table 3), except that TRT using the transdermal administration method was more likely to increase PSA levels than placebo (Po0.00001) in the group aged X65 years (Table 3). Sensitivity analysis was performed by removing the studies for which generation of allocation sequence was inadequate. By removing seven studies, our analysis indicated that short-term TRT was more likely to increase PSA levels than treatment with placebo (Po0.00001; Table 3). No differences were found between the TRT and placebo groups in the long-term studies regarding changes in PSA levels (P ¼ 0.91), abnormal PSA levels (P ¼ 0.24), prostate nodule (P ¼ 0.74), prostate biopsy (P ¼ 0.09) or prostate cancer (P ¼ 0.99) (Table 3). & 2014 Macmillan Publishers Limited
TRT and prostate cancer Y Cui et al
0.90 0.99 1.10 (0.26–4.65) 0.99 (0.24–4.02) 0.65 0.09
Abbreviations: CI, confidence interval; OR, odds ratio; SMD, standardized mean difference. Gold standard: tandem mass spectrometry and liquid chromatography. A level: all quality criteria met (adequate): low risk of bias.
1.69 (0.18–15.71) 2.37 (0.86–6.53) 0.51 0.74 — 1.27 (0.31–5.23) 0.42 0.24 1.54 (0.54–4.43) 1.42 (0.79–2.57) o0.00001 0.91 0.33 (0.21–0.45) 0.01 ( 0.19–0.17) Sensitivity analysis Short Long
0.74 0.77 0.81 (0.23–2.86) 0.84 (0.26–2.73) 0.11 0.17 2.27 (0.83–6.24) 3.10 (0.62–15.47) 0.99 0.47 0.99 (0.28–3.47) 3.55 (0.12–105.82) 0.15 0.48 0.38 o0.0001
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0.16 ( 0.20–0.53) 0.23 ( 0.12–0.34) Intention-to-treat analysis Yes No
1.55 (0.85–2.83) 1.35 (0.58–3.16)
0.94 0.32 1.04 (0.38–2.84) — 0.09 0.19 2.24 (0.89–5.64) 4.49 (0.46–43.43) 0.99 0.47 0.99 (0.28–3.47) — 0.16 0.47 o0.00001 0.25 Allocation sequence generation A level 0.23 (0.13–0.32) Non-A level 0.19 ( 0.13–0.51)
1.45 (0.87–2.43) 1.77 (0.37–8.43)
0.35 0.91 0.48 (0.11–2.19) 1.06 (0.37–3.07) 0.94 0.05 0.88 (0.04–18.75) 2.50 (0.99–6.33) — 0.78 — 1.18 (0.37–3.74) 0.76 0.30 0.46 o0.00001 0.30 ( 0.49–1.09) 0.22 (0.13–0.32) Testosterone assay types Gold standard Not gold standard
0.75 (0.11–4.95) 1.32 (0.78–2.24)
0.81 0.64 0.89 (0.33–2.38) 0.65 (0.11–3.94) 0.08 0.24 2.77 (0.88–8.75) 2.16 (0.60–7.77) 0.67 0.98 1.43 (0.27–7.53) 0.98 (0.20–4.94) 0.26 0.26 o0.00001 0.57 0.25 (0.14–0.35) 0.08 ( 0.19–0.34) Testosterone level Lower Normal
1.44 (0.76–2.72) 1.55 (0.72–3.32)
0.23 0.72 0.38 (0.08–1.85) 1.22 (0.41–3.61) 0.21 0.09 4.15 (0.46–37.69) 2.25 (0.89–5.70) 0.51 0.53 — 1.51 (0.42–5.46) 0.24 0.23 2.15 (0.60–7.70) 1.38 (0.81–2.36) 0.03 o0.0001 0.22 (0.02–0.41) 0.23 (0.12–0.33)
OR 95% CI OR 95% CI OR 95% CI P-value OR 95% CI P-value SMD 95% CI
PSA
Age, years o65 X65
Table 3.
Results of the subgroup and sensitivity analysis
Abnormal PSA levels
Prostate nodule
P-value
Prostate biopsy
P-value
Prostate cancer
P-value
141 DISCUSSION Prostate growth is dependent on the presence of testosterones; conversely, antiandrogen and orchidectomy can decrease prostate volume in patients with BPH.34 There is abundant evidence that androgens influence the development of prostate cancer.35–37 Although the risk that testosterone treatment triggers prostate cancer was not fully recognized. Resolving this question will inform methods of treating LOH accompanied by prostatic problems. The 22 placebo-controlled, randomized studies included in this meta-analysis provide direct comparasions of the indications of prostate cancer (PSA levels’ change, abnormal PSA levels, prostate nodule, prostate biopsy) and the incidence of new prostate cancer, which are all relative sensitive indicators for prostate cancer in testosterone therapy and placebo. In all, only 12, 5, 9 and 8 of the included 22 RCTs reported the incidence of abnormal PSA levels, prostate nodule, prostate biopsy and new prostate cancer, respectively. Namely, less than half of the included 22 RCTs reported the incidence of the indications of prostate cancer or new prostate cancer. It showed that neither short-term nor longterm TRT increased the risk of prostate cancer. In our analysis, short-term TRT delivered by transdermal application was more likely to increase PSA levels than treatment with a placebo. A section of urologists consider that testosterone has a linear effect on prostate growth, and prostate dysfunction as an adverse effect of this was the dominant theory in the past. A new paradigm has been put forward: the saturation model of testosterone and the prostate.38 The theory holds that testosterone’s effect on the prostate reaches a saturation point well below the physiological testosterone levels encountered in the clinical setting, beyond which additional testosterone does not have an increased effect. The inclusion criteria for patients receiving transdermal treatment included PSA level o1.5 ng ml 1, which was much lower than normal (Table 1). This may be the reason leading to increased PSA levels in the short term. But as to the incidence of new prostate cancer, prostate biopsy, prostate nodule and abnormal PSA levels, there was no apparent difference between testosterone with placebo, especially in transdermal administration method. Our study also evaluated the safety of long-term TRT (12–36 months) for prostate cancer. All 22 RCTs included in our analysis involved rigorous, periodic monitoring of patients, and treatment was withdrawn when there were indications suspicious for prostate cancer or other serious complications. In addition, for all 22 RCTs no patient had prostate enlargement at baseline, all patients had normal PSA levels at baseline and one RCT reported patients who underwent prostate biopsy at study entry and at the end of the study, which implicated that testosterone can not be a prostate cancer stimulus. Consequently, short-term TRT is safe in terms of prostate cancer under judicious and careful monitoring. The fact that all 22 RCTs included rigorous periodic monitoring of patients and withdrew patients when they suspected prostate cancer might be the reason why the meta-analysis failed to detect an increased hazards of prostate cancer among those treated with TRT. Our conclusion is based on the fact that TRT has no adverse effect on prostate cancer in patients without prostatic hyperplasia. Whether or not TRT will increase the risk for prostate cancer in patients with BPH needs further investigation in larger, highquality studies. Although difference resided in the baseline level of testosterone included in 22 RCTs, the cohorts of 17 of the 22 studies in our meta-analysis were diagnosed as LOH. Controversy surrounds setting a lower limit of normal testosterone. There is also no generally accepted lower limits of normal testosterone level in aging males. It was demonstrated that demographic differences in testosterone level within population of aging male exist.39 Although different methods and dosages were used in the Prostate Cancer and Prostatic Disease (2014), 132 – 143
TRT and prostate cancer Y Cui et al
142 selected RCTs, all patients in the 22 RCTs achieved normal testosterone levels and supraphysiological levels were avoided. The 22 RCTs included in this meta-analysis were all doubleblinded. According to the quality-assessment scale that we developed, the quality of the individual studies in the meta-analysis was high. The results of this analysis are important from a scientific standpoint, and they apply to everyday clinical practice, particularly because data were analyzed by method of TRT delivery. The results of the subgroup and sensitivity analyses are in accordance with our findings, indicating that our results are robust and reliable. Nevertheless, there are some limitations to our analysis. Data in the studies covered by this meta-analysis are insufficient to determine whether more severe grades of prostate cancer are found with testosterone treatment versus without testosterone treatment. Major limitations include heterogeneity in the populations examined (Table 1), testosterone dosage used (Table 1) and baseline PSA levels. LOH is a clinical and biochemical syndrome that adversely affects the function of multiple organ systems. The presence of symptoms associated with LOH was not consistent across the included studies, and this may have contributed to the heterogeneous population. Although we conducted subgroup and sensitivity analyses to assess the quality of the studies, the problem of heterogeneity still could not be completely avoided. Although 21 of the 22 RCTs drew morning blood samples to measure testosterone levels, 17 of the 22 studies reported six measurement assay methods that included tandem mass spectrometry-liquid chromatography, mass spectroscopy, chemiluminescent immunoassay, radioimmunoassay, fluoroimmunoassay and electrochemiluminescence. It is generally known that the first method is the gold standard. Although the results of subgroup analysis by testosterone assay types (gold standard and not gold standard) matched our findings, this made inclusion of studies using different testosterone assays problematic and potentially influenced the results of the meta-analysis. CONCLUSIONS This meta-analysis shows that regardless of the administration method, TRT is the short-term safety and does not promote prostate cancer development or progression but long-term data are warranted with justifiable end points. CONFLICT OF INTEREST The authors declare no conflict of interest.
ACKNOWLEDGEMENTS Financial support for our studies from the Research Fund of Capital Medical Development (No.2009-2069) and from the Urological Backbone Fund of Beijing Municipal Health Bureau (No.2009-3-15) is gratefully acknowledged.
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