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.
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 of 22 RCTs involving a total of 2351 patients were analyzed. Eleven RCTs were short-term (<12 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 >1 indicating increased risk, none of these reached or even approached statistical significance (all P>0.10), 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 (P<0.00001).
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.
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 >60 years have serum testosterone levels that are below the lower limits of young adult men aged 20–30 years.1, 2, 3 Late-onset 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
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 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.
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.22.214.171.124 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 ⩾1 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 ⩾1 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.
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 P>0.05, 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 I2<25% reflects a small level of inconsistency, and I2>50% 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 <65 or ⩾65 years; total testosterone level at baseline (testosterone level was considered low if <350 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 (<12 versus ⩾12 months); and
Study quality measure: proportion of patients lost to follow-up (⩽10% versus >10%), concealment of allocation, intention-to-treat analysis and blinding of patients.
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, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 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 (<12 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).
Short-term TRT versus placebo
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=0.32) for the study using delivery by injection and 1.10 (95% CI, 0.26–4.65; P=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.
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=0.29) for the study using delivery by injection and 2.11 (95% CI, 0.32–13.73; P=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.
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=0.99; Figure 3). These results demonstrate that TRT and placebo administered transdermally were similar in terms of the prostate nodule.
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=0.69; Figure 3). For the study that used transdermal treatment application, the OR was 1.54 (95% CI, 0.54–4.43; P=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=0.05; Figure 3). For the RCTs using transdermal application, the SMD was 0.33 (95% CI, 0.21–0.45; P<0.00001; Figure 3). For the study in which treatment was given orally, the SMD was −0.02 (95% CI, −0.64 to 0.60; P=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.
Long-term TRT versus placebo
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=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.
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=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.
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 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=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.
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=0.61; Figure 4). For the study that used transdermal treatment application, the OR was 2.12 (95% CI, 0.94–4.78; P=0.07; Figure 4). For the study that used oral treatment application, the OR was 0.85 (95% CI, 0.33–2.19; P=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.
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=0.42), −0.01 (95% CI, −0.27 to 0.24; P=0.91) and −0.08 (95% CI, −0.36 to 0.20; P=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 (P<0.00001) in the group aged ⩾65 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 (P<0.00001; Table 3). No differences were found between the TRT and placebo groups in the long-term studies regarding changes in PSA levels (P=0.91), abnormal PSA levels (P=0.24), prostate nodule (P=0.74), prostate biopsy (P=0.09) or prostate cancer (P=0.99) (Table 3).
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, 36, 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 long-term 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 <1.5 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, high-quality 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 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 double-blinded. 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.
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.
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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.
The authors declare no conflict of interest.
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Cui, Y., Zong, H., Yan, H. et al. The effect of testosterone replacement therapy on prostate cancer: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis 17, 132–143 (2014). https://doi.org/10.1038/pcan.2013.60
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Questioning the evidence behind the Saturation Model for testosterone replacement therapy in prostate cancer
Investigative and Clinical Urology (2020)
No evidence found for an association between trial characteristics and treatment effects in randomized trials of testosterone therapy in men: a meta-epidemiological study
Journal of Clinical Epidemiology (2020)