A retrospective study was performed to evaluate how the prostate-specific antigen (PSA) response to testosterone replacement therapy (TRT) varies with age, mode of testosterone treatment, and baseline levels of PSA and testosterone. In total, 48 consecutive hypogonadal men who completed 1 year of TRT were evaluated. All men had a negative prostate biopsy obtained prior to initiating TRT. Men received TRT in the form of intramuscular injections (n=33) or topical gel (n=25) based on clinical response. Comparisons in the change in PSA after 1 year of TRT were made based on various thresholds for age and baseline values of PSA, total testosterone (TT), and free testosterone (FT). Baseline levels of TT (297.7±156.6 vs 292.7±89.7 ng/dl; P=0.88) and FT (0.95±0.3 vs 1.1±0.3 ng/dl; P=0.08) were similar for the injection and transdermal groups, and both groups also had similar baseline PSA values (1.92±1.9 vs 1.71±1.9 ng/ml, respectively; P=0.67). After 1 year of TRT, mean PSA values did not differ significantly between groups, nor did the mean increase in PSA (P>0.05). The overall mean increase in PSA was 0.31±0.76 ng/ml. After one year of TRT, PSA was decreased in 21%, unchanged in 22%, and increased in 57%. Only 24% of the entire group demonstrated a PSA increase of 0.5 ng/ml or greater. No statistical difference was found in the change in PSA based on patient age, baseline PSA levels, or baseline levels of TT or FT. TRT causes only a mild increase in PSA in most hypogonadal men, and does not appear to be influenced by the mode of TRT, age, or baseline levels of PSA or testosterone.
There are now numerous studies demonstrating the beneficial effect of testosterone replacement therapy in hypogonadal men, such as improvements in body composition,1, 2, 3 muscle mass and strength, fat distribution,1, 2, 4 erythropoesis,1, 5 cognition,6 mood,6 bone density,4, 6 and sexual function.1, 2, 7 However, there remains considerable concern among clinicians that testosterone replacement therapy (TRT) may possibly promote prostate cancer. For this reason, monitoring of the prostate with prostate-specific antigen (PSA) and digital rectal exam is recommended at regular intervals for men receiving TRT, with biopsy indicated for digital rectal exam (DRE) changes or a substantial rise in PSA.
Unfortunately, there exists limited published literature defining the PSA response to TRT. It has been argued that a substantial rise in PSA following initiation of TRT may be a sign of prostate cancer, but there is little information as to what constitutes a normal, or worrisome, rise in PSA following TRT.8, 9 Furthermore, it is as yet unknown what may be the effect of age on the PSA response to TRT, as well as whether men with lower baseline testosterone values might demonstrate a more exaggerated PSA increase compared to men with milder degrees of hypogonadism. In order to properly evaluate what may be a worrisome rise in PSA with TRT, it is necessary to determine the impact of demographic or biochemical characteristics on this response.
In this study, we examined the impact of age, mode of TRT, baseline PSA, and total and free testosterone levels on the PSA response in a group of hypogonadal men, all of whom had negative prostate biopsy prior to initiation of TRT.
Materials and methods
The study group consisted of 58 consecutive men who were enrolled in a program of TRT between June 2000 and December 2001 and completed 1 year of treatment. All had a negative prostate biopsy obtained prior to initiation of TRT. All men presented with hypogonadal symptoms, and had confirmatory blood tests demonstrating low levels of either total testosterone (TT), free testosterone (FT), or both. TT levels <300 ng/ml and FT levels <1.5 ng/dl were categorized as low.
Serum determinations of TT and FT were obtained during clinical hours ranging from 0080 to 1700 hours. TT and FT levels were measured by radioimmunoassay (Diagnostic Products Corp., Los Angeles, CA, USA). All PSA tests were performed in the same laboratory, using the Abbot IMX radioimmunoassay kit (Abbot Laboratories, Abbot Park, III). Normal PSA values were defined as 0–4.0 ng/ml.
Men taking medications known to lower PSA level (finasteride) or who had undergone previous prostate surgery, as well as cases of prostate cancer, known chronic prostatitis, urinary infection, or other condition that can interfere in the PSA levels as well as previous treatments with TRT were excluded from this analysis. Also excluded from the present study were individuals whose biopsies revealed prostatic intraepithelial neoplasia.
DRE of the prostate was performed in all men by a single urologist (AM). The absence of nodularity, asymmetry, or unusual firmness of the prostate defined a normal DRE result.
Before starting testosterone replacement therapy, all men underwent transrectal ultrasound of the prostate together with ultrasound-guided prostate needle biopsy. Transaxial and saggital ultrasound scanning was performed with a 7.0-MHz end-fire transducer, and transrectal ultrasound-guided prostate needle biopsies were performed with an automatic device (Biopty, Bard Urological, Covington, GA, USA) using an 18-gauge needle. Six cores were routinely obtained, increasing to as much as 12 cores if there were palpable or ultrasound abnormalities. Hypoechoic or otherwise suspicious areas noted by ultrasound also underwent biopsy. Biopsy specimens were reviewed by the clinical pathology staff at Beth Israel Deaconess Medical Center. Men with abnormal DRE or PSA at baseline with negative prostate biopsy were monitored according to the same routine as the remainder of the group.
After 12 monthS of TRT, blood tests were repeated for PSA, TT, and FT. Men with a PSA increase greater than 1.0 ng/ml underwent repeat prostate biopsy.
In all, 33 men received intramuscular injections of testosterone, and 25 used testosterone gel, either Androgel (Solvay) or Testim (Auxilium).
The study group was divided into subgroups to determine whether there were differences in the PSA response to TRT after 1 year, based on age, mode of TRT, or baseline levels of PSA, TT, and FT. Statistical analysis was performed using Student's t-test analysis to assess the differences between groups. A level of P<0.05 was considered as significant.
The characteristics of the study group are shown in Table 1. The mean age of the entire group was 58.3 years, ranging from 42 to 77. Baseline PSA ranged from 0.3 to 9.4 ng/ml with a mean of 1.83 ng/ml. Baseline mean levels of TT and FT were 295.6 and 1.02 ng/dl, respectively.
Baseline levels of TT between men who received testosterone by injections and transdermal delivery systems were similar (297.7±156.6 vs 292.7±89.7; P=0.0887), as were TT levels after 12 months of TRT (612.9±357.2 vs 641.4±243.2; P=0.728). FT baseline levels were similar between individuals who received injection and transdermal testosterone (0.95±0.3 vs 1.10±0.3; P=0.089), respectively, and the mean levels in the two groups after 12 months on TRT were also similar (1.92±1.1 vs 2.01±0.8; P=0.672). These data are expressed in Table 2.
The mean baseline level of PSA for the entire study group was 1.83±1.9 ng/ml. After 12 months of TRT, the mean PSA increased by 17% to 2.14±2.0 ng/ml, representing a mean increase of 0.31±0.76 ng/ml (Table 3). In all, 12 men had a decrease in PSA, 13 were unchanged, and 33 increased. Overall, a PSA rise of 0.50 ng/ml or greater was noted in only 14 of 58 men (24%) (Figure 1).
The characteristics for men whose PSA declined were as follows: the mean age was 59.6 years, baseline PSA was 2.72 ng/ml, baseline TT was 321.9 ng/dl, and baseline FT was 1.11 ng/dl. The mean values for men whose PSA rose by >1.0 ng/ml were similar: age 59.1 years, baseline PSA 2.76 ng/ml, baseline TT was 359.6 ng/dl, and FT was 0.98 ng/dl (P>0.05 for all comparisons).
Six men (10.3%) had a PSA increase >1.0 ng/ml after 12 months of TRT. Four of these men underwent repeat prostate biopsy, and one of these had prostate cancer. He was 55-year-old with a baseline PSA of 5.5 ng/ml that rose to 8.2 ng/ml after 12 months of TRT, an increase of 2.7 ng/ml. An additional five men underwent repeat biopsy due to changes noted on DRE; however, no new cases of prostate cancer were identified in these men.
Comparisons of subgroups based on demographic and biochemical parameters are presented in Table 3. The increase in PSA for men 40–60 years of age (n=38) was 0.34 ng/ml compared to an increase of 0.23 ng/ml for men >60 years (n=20) (P>0.05).
Comparisons of groups based on initial TT values were made at thresholds of 200 and 250 ng/dl. Men whose baseline TT values were <250 ng/dl (n=25) demonstrated a rise in PSA of 0.33 ng/ml compared to a PSA increase of 0.25 ng/ml for men whose baseline TT was 250 ng/dl or greater (n=33) (P>0.05). In addition, no statistically significant difference was seen when 200 ng/dl was used as the dividing point. Comparison of subgroups based on baseline FT also failed to show significant differences in the rise in PSA following TRT.
When stratified by baseline levels of PSA, the mean effect of TRT on PSA were, respectively, 0.29, 0.32, and 0.42 ng/ml for individuals with PSA ranging from 0 to 2, 2 to 4, and >4 ng/ml. These values were not significantly different from each other (ANOVA, P=0.90) (Table 4).
In this study, the mean increase in PSA was 0.3 ng/ml, rising from a baseline PSA of 1.8–2.1 ng/ml after 12 months of TRT, representing an overall increase of 17%. Not only is this mean PSA response quite modest, but a breakdown of individual responses revealed that over 75% of men demonstrated an increase in PSA of 0.5 ng/ml or less. Indeed, 43% of the entire group demonstrated either no increase at all, or even a decline in PSA.
The mean increase in PSA noted in this study is well within the range of reported values for PSA following TRT, with published1, 2, 7, 10, 11, 12, 13, 14 data ranging from a decline of 0.01 to an increase of 1.0 ng/ml (Table 4). However, none of those reports have attempted to examine the influence of baseline characteristics on the PSA response to TRT. Since a substantial rise in PSA is considered a worrisome indicator of possible prostate cancer, there is substantial value in determining the range of PSA response and the factors that might influence it.15
In theory, testosterone injection therapy might stimulate greater increase in PSA due to the high testosterone levels obtained via this modality, particularly as supraphysiologic levels routinely occur for the first several days after injection.8, 9 This effect from a greater testosterone delivery appears to be responsible for the higher incidence of erythrocytosis among men receiving injection therapy compared to those receiving transdermal treatment. In this study, men receiving injection therapy had a rise in PSA that was double the value among men receiving transdermal therapy (0.41 vs 0.18 ng/ml); however, this difference was not statistically significant due to large standard deviations in the data.
Given that production of PSA is an androgen-dependent process, with an androgen response element in the PSA gene, one might theorize that lower baseline levels of TT or FT might predispose an individual to a larger PSA response to TRT.16 Again, a numerically greater PSA response was seen for men with lower testosterone levels; however no comparison reached statistical significance, even when a number of thresholds were used to create comparison groups. It is possible that analysis of larger study populations might reveal significant differences in this regard.
Age also did not appear to be a significant factor with regard to the PSA response to TRT, with an increase of 0.34 ng/ml for men 40–60 years old, and 0.23 ng/ml for men older than 60. However, as a percentage increase over baseline values, the PSA rose 21% for the younger group and only 9% for the older men. Similarly, the level of PSA at baseline did not predict a greater numerical increase in the PSA response to TRT, although as a percentage of the baseline value, men who began with a PSA of 2.0 ng/ml or less increased their PSA by 30% over the course of 12 months of TRT, compared to only an 8% increase for men with baseline PSA of >2.0 ng/ml.
A major strength of this study is the performance of prostate biopsy in all subjects prior to initiation of TRT. Although prostate biopsy cannot completely remove the possibility that an occult cancer may exist in a given individual, it does provide some reassurance that no man with large volume disease has been included in the analysis. This factor separates this study from nearly all other reports, in which prostate biopsy was reserved for men who demonstrated significant increases in PSA or change in DRE. Our own work has shown that approximately 14% of hypogonadal men with a PSA of 4.0 or less have biopsy-detectable prostate cancer. Although the PSA response to TRT in these men is unknown, the elimination of such men from this study reduces a major potential confounding factor.
Despite a negative prostate biopsy as an inclusion criterion in this study, one individual did develop prostate cancer over the course of 1 year of TRT. This individual had an elevated PSA at baseline, and the highest increase in PSA (2.7 ng/ml) observed in the entire study group. Published recommendations for monitoring men on TRT have suggested that a rise of >1.0 ng/ml within the first of year of treatment requires prostate biopsy,15, 17, 18, 19 and this case affirms the merit of those recommendations. Nevertheless, it should be noted that nine men in this study underwent repeat prostate biopsy, including four due to a PSA increase of >1.0 ng/ml, with cancer detected in only one case (11%).
There are two main limitations of this study. The first is the lack of a control group, which would ideally consist of hypogonadal men who did not receive TRT. However, the inclusion requirement of a negative prostate biopsy would make it problematic to include such a control group. The other limitation is the size of the study population. In several analyses, there were numerical differences between subgroups that might possibly have achieved statistical significance in a larger study. Further research in larger populations would be beneficial in this regard.
In conclusion, we found no significant differences in the PSA response to TRT with regard to age, mode of therapy, or baseline levels of TT, FT, or PSA.
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We acknowledge the support for Dr Rhoden by CAPES of Brazil and Conselho Nacional de Pesquisa (CNPq) Brazil.
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Rhoden, E., Morgentaler, A. Influence of demographic factors and biochemical characteristics on the prostate-specific antigen (PSA) response to testosterone replacement therapy. Int J Impot Res 18, 201–205 (2006). https://doi.org/10.1038/sj.ijir.3901394
- prostate cancer
- total testosterone
- free testosterone
- prostate-specific antigen
- aging men
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