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Testosterone Replacement Therapy in Hypogonadal Men at High Risk for Prostate Cancer: Results of 1 Year of Treatment in Men With Prostatic Intraepithelial Neoplasia
0022-5347/03/1706-2348/0 THE JOURNAL OF UROLOGY® Copyright © 2003 by AMERICAN UROLOGICAL ASSOCIATION
Vol. 170, 2348 –2351, December 2003 Printed in U.S.A.
DOI: 10.1097/01.ju.0000091104.71869.8e
TESTOSTERONE REPLACEMENT THERAPY IN HYPOGONADAL MEN AT HIGH RISK FOR PROSTATE CANCER: RESULTS OF 1 YEAR OF TREATMENT IN MEN WITH PROSTATIC INTRAEPITHELIAL NEOPLASIA ERNANI LUIS RHODEN
AND
ABRAHAM MORGENTALER*
From the Division of Urology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
ABSTRACT
Purpose: One of the greatest concerns among clinicians regarding testosterone replacement therapy (TRT) is the fear of causing or promoting prostate cancer. We evaluated prostatic changes in hypogonadal men with and without high grade prostatic intraepithelial neoplasia (PIN), which is considered a prostatic precancerous lesion, after 1 year of TRT. Materials and Methods: A total of 75 hypogonadal who completed 12 months of TRT were studied. All underwent prostate biopsy prior to initiating treatment. Of the men 55 had benign prostate biopsies (PIN⫺) and 20 had PIN without frank cancer (PIN⫹). All men with PIN underwent repeat biopsy to exclude cancer prior to the initiation of testosterone treatment. Prostate specific antigen (PSA), and total and free testosterone were determined prior to treatment and at 1 year. Repeat biopsy was performed for a change noted on digital rectal examination or for a PSA increase of 1 ng/l or greater. Results: PSA was similar at baseline in men with and without PIN (1.49 ⫾ 1.1 and 1.53 ⫾ 1.6 ng/dl, p ⬎0.05) and after 12 months of TRT (1.82 ⫾ 1.1 and 1.78 ⫾ 1.6 ng/dl, respectively, p ⬎0.05). A slight, similar increase in mean PSA was noted in the PIN⫺ and PIN⫹ groups (0.25 ⫾ 0.6 and 0.33 ⫾ 0.6 ng/dl, p ⬎0.05). One man in the PIN⫹ group had cancer after biopsy was performed due to abnormal digital rectal examination. Four additional men in the PIN⫺ group and 2 in the PIN⫹ group underwent re-biopsy for elevated PSA and none had cancer. No differences were noted between the PIN⫺ and PIN⫹ groups with regard to total and free testosterone at baseline and at 1 year (p ⫽ 0.267). Conclusions: After 1 year of TRT men with PIN do not have a greater increase in PSA or a significantly increased risk of cancer than men without PIN. These results indicate that TRT is not contraindicated in men with a history of PIN. KEY WORDS: prostate, prostatic neoplasms, testosterone, prostate-specific antigen, hypogonadism
There has been a great deal of recent interest in the topic of low testosterone in the older man, a condition referred to as andropause.1 Age related decreases in androgen levels occur gradually and vary considerably among individuals. Low testosterone has been implicated as a cause of changes in sexual, physical and behavioral capacity in aging men.2, 3 Several observational and interventional studies have demonstrated that androgens have important beneficial functions in body composition, muscle mass and strength, fat distribution, erythropoiesis, cognition, mood and bone density, and have a key role in male sexual function.2, 3 However, one of the greatest concerns among clinicians regarding testosterone replacement therapy (TRT) is the fear of causing or promoting prostate cancer. This fear is based on the fact that prostate cancer is hormonally responsive.4 Huggins et al reported 60 years ago that testosterone suppression causes prostate cancer regression5 and it is now commonplace for men with metastatic prostate cancer to undergo treatment designed to lower testosterone. However, the relationship between prostate cancer and testosterone is incompletely understood, particularly with regard to the promotion or development of new cancers. It
applies especially to high grade prostatic intraepithelial neoplasia (PIN), which has been postulated to be a precancerous condition. PIN has been identified in 0.5% to 27% of prostate biopsies and reports suggest that 25% to 51% of men with high grade PIN on initial biopsy have carcinoma on repeat biopsy.6, 7 An examination of prostates removed at radical prostatectomy for clinically localized cancer revealed high grade PIN in 86% of cases.7 Furthermore, a followup study of men with a history of PIN revealed that prostate cancer developed in 25% of these men within 3 years.8 These reports support the concept that PIN acts as a precancer and men with PIN are at high risk for subsequent frank cancer. Although to our knowledge the mechanisms by which PIN may progress to clinical cancer are not known, there has been concern that men with PIN should not undergo testosterone supplementation because of the theoretical risk of promoting prostate cancer due to the trophic effects of testosterone on prostate cancer. However, it is important to note that this concern is entirely theoretical since to our knowledge no data yet exist to link testosterone with the conversion of PIN to clinical prostate cancer. At our center a unique opportunity is provided to study the effects of TRT in men with and without PIN due to our practice of routinely performing prostate biopsy prior to initiating TRT, thus, providing a study population with welldefined baseline histology. We compared the effects of 12
Accepted for publication July 25, 2003. Supported by Fundac¸a˜o Coordenacao de Aperfeic¸oamento de Pessoal de Nivel Superior-Brazil. * Corresponding author: 1 Brookline Pl., Suite 624, Brookline, Massachusetts 02445 (telephone: 617-277-5000; FAX: 617-277-5444; e-mail: [email protected]). 2348
2349
TESTOSTERONE REPLACEMENT IN HYPOGONADAL MEN AT RISK FOR PROSTATE CANCER
months of TRT in men with and without PIN with specific attention to changes suggestive of prostate cancer. METHODS
The charts of 75 hypogonadal men who completed 1 year of TRT between 1998 and 2001 were reviewed. All men presented initially with sexual symptoms, consisting of erectile dysfunction and/or decreased libido. Prostate biopsy was performed in all men prior to beginning treatment. There were 55 men with benign biopsy results (PIN⫺) and 20 with 1 or more foci of high grade PIN (PIN⫹). Digital rectal examination (DRE) was performed at the beginning of treatment and at 12 months of followup. All patients presented with hypogonadal symptoms and had documented low total testosterone (TT) or free testosterone (FT). Men were excluded from study if they were on medication known to decrease prostate specific antigen (PSA) (finasteride), had undergone previous prostatic surgery or had a history of prostate cancer, chronic prostatitis, urinary infection or another condition that might cause alterations in PSA. Men who had received previous treatment with testosterone replacement therapy were also excluded from this analysis. Serum determinations of TT and FT were obtained during the clinical hours of 8:00 a.m. to 5:00 p.m. TT and FT were measured by radioimmunoassay (Diagnostic Products Corp., Los Angeles, California) with a stated reference range of TT and FT of 270 to 1,100 and 1.5 to 3.5 ng/dl, respectively. TT less than 300 ng/dl was considered subnormal for study purposes. PSA was determined by radioimmunoassay using the IMX (Abbot Laboratories, Abbot Park, Illinois) kit. All PSA determinations were performed at the same laboratory (normal 0 to 4 ng/dl). DRE of the prostate was performed in all patients by a single urologist (AM). The absence of nodularity, asymmetry or unusual firmness of the prostate defined a normal DRE result. Biopsies were performed with transaxial and sagittal transrectal ultrasound scanning using a 7.0 MHz end-fire transducer. Transrectal ultrasound guided prostate needle biopsies were performed with an automatic Biopty (Bard Urological, Covington, Georgia) device using an 18 gauge needle. Six cores were routinely obtained, which was increased to as many as 12 if there were palpable or ultrasound abnormalities. Hypoechoic or otherwise suspicious areas on ultrasound were also biopsied. Biopsy specimens were reviewed by the clinical pathology staff at our institution.
TABLE 1. Patient characteristics No. pts Mean age ⫾ SD (range) Mean ng/dl PSA ⫾ SD (range) Mean ng/dl TT ⫾ SD (range) Mean ng/dl FT ⫾ SD (range) No. biopsy: Without PIN With PIN
75 59.6 ⫾ 9.0 (42–77) 1.54 ⫾ 1.5 (0.3–9.4) 295.9 ⫾ 119.3 (74–776) 1.04 ⫾ 0.33 (0.4–1.9) 55 20
The mode of TRT administration was intramuscular injection of testosterone enanthate in 32 men (58.2%) in the PIN⫺ group with transdermal gel given in the remaining 23 (41.8%). In the PIN⫹ group 11 of the 20 men (55%) were treated with injections and 9 (45%) received gel. Clinical evaluation at 12 months included DRE, and serum TT, FT and PSA determinations in all individuals. In men receiving testosterone injections serum TT and FT were measured 7 to 10 days after the last treatment. Individuals with an increase in PSA of above 1.0 ng/dl or with changes on DRE underwent repeat prostate biopsy. Statistical analysis was performed using the Student t and chi-square tests to assess the differences between groups with p ⬍0.05 considered significant. RESULTS
Table 1 lists study group characteristics. Mean age in the study group was 59.6 years and there was no significant difference between the PIN⫹ and PIN⫺ groups (62.3 and 58.3, respectively, p ⬎0.05). The PIN⫹ group consisted of 12 men with low FT, and 8 with low FT and TT. In the PIN⫺ group there were 18 men with low FT only, 2 cases with low TT only, and 35 with low FT and low TT. There were no differences between groups in the mean number of cores ⫾ SD at initial biopsy (6.8 ⫾ 1.2 and 7.1 ⫾ 1.4, p ⬎0.05). However, extended repeat biopsies (mean 10.2 ⫾ 1.6 cores) were subsequently performed in men with PIN at initial biopsy. Two men (10%) in the PIN⫹ group and 3 (6%) in the PIN⫺ group had PSA greater than 4.0 ng/ml. DRE was initially abnormal in 7 men (12.7%) in the PIN⫺ group and in 4 (20%) in the PIN⫹ group. Baseline TT was similar in the PIN⫺ and PIN⫹ groups (294 ⫾ 126.7 and 298.1 ⫾ 92.3 ng/dl, p ⫽ 0.897) and no differences were noted between groups after 12 months of TRT (641.8 ⫾ 324.3 and 616.6 ⫾ 270.4 ng/dl, respectively, p ⫽ 0.76). Similarly no differences were noted for FT at baseline (1.03 ⫾ 0.4 and 1.07 ⫾ 0.2 ng/dl, p ⫽ 0.671) and at 12 months (2.1 ⫾ 1.0 and 2.1 ⫾ 0.9 ng/dl, respectively, p ⫽ 1.0). Testosterone and PSA were similar regardless of the injection or transdermal treatment mode (p ⬎0.05) (tables 2 and 3). Mean PSA was almost identical in the PIN⫺ and PIN⫹ groups at baseline (1.53 ⫾ 1.6 and 1.49 ⫾ 1.1 ng/dl, p ⫽ 0.918) and after 12 months of TRT (1.78 ⫾ 1.6 and 1.82 ⫾ 1.1 ng/dl, respectively, p ⫽ 0.898). There was also no difference in the increase in PSA after 12 months of TRT between the PIN⫺ and PIN⫹ groups (0.25 ⫾ 0.6 and 0.33 ⫾ 0.6 ng/dl, respectively, p ⫽ 0.949, table 4). In the entire study group only a 57 year-old man in the PIN⫹ group was identified with cancer, which occurred 1 year after the initiation of TRT. Initial DRE became abnormal on followup. PSA increased from 1.7 to 2.6 ng/dl. Gleason score of the cancer was 7 (4 ⫹ 3). Testosterone treatment was discontinued when cancer was identified. Four men in the PIN⫺ group underwent biopsy for an increase in PSA of greater than 1.0 ng/dl but none had prostate cancer. In the PIN⫹ group 2 men had a PSA elevation of greater than 1.0
TABLE 2. Baseline and change in testosterone in men with and without PIN who received TRT Groups
No. Pts
Without PIN: Injection Gel Totals With PIN: Injection Gel
Mean TT ⫾ SD (ng/dl)
Mean FT ⫾ SD (ng/dl)
Before TRT
At 12 Mos
Before TRT
At 12 Mos
32 23
297.7 ⫾ 156.6 292.7 ⫾ 89.7
622.3 ⫾ 379.1 641.4 ⫾ 243.2
0.9 ⫾ 0.4 1.1 ⫾ 0.3
2.0 ⫾ 1.2 2.0 ⫾ 0.8
55
294.8 ⫾ 126.7
641.8 ⫾ 324.3
1.0 ⫾ 0.4
2.1 ⫾ 1.0
11 9
305.7 ⫾ 105.6 293.1 ⫾ 70.8
604.7 ⫾ 292.6 654.0 ⫾ 242.6
1.0 ⫾ 0.3 1.1 ⫾ 0.2
2.1 ⫾ 1.2 2.1 ⫾ 0.6
616.6 ⫾ 270.4
1.1 ⫾ 0.2
2.1 ⫾ 0.9
Totals 20 298.1 ⫾ 92.3 For all comparisons between the PIN⫺ and PIN⫹ groups p ⬎0.05.
2350
TESTOSTERONE REPLACEMENT IN HYPOGONADAL MEN AT RISK FOR PROSTATE CANCER TABLE 3. PSA changes 1 year after TRT No. Pts
Without PIN: Injection Gel With PIN: Injection Gel Totals
Mean PSA ⫾ SD (ng/dl)
Change
Before TRT
At 12 Mos
32 23
1.54 ⫾ 1.6 1.52 ⫾ 1.8
1.82 ⫾ 1.4 1.86 ⫾ 1.9
0.28 ⫾ 0.7 0.34 ⫾ 0.5
11 9
1.24 ⫾ 0.6 1.78 ⫾ 1.5
1.56 ⫾ 0.9 2.12 ⫾ 1.4
0.32 ⫾ 0.6 0.34 ⫾ 0.6
75
1.54 ⫾ 1.5
1.81 ⫾ 1.5
0.27 ⫾ 0.6
TABLE 4. PSA change before to 1 year after TRT in men with and without PIN who underwent TRT No. pts Mean age ⫾ SD Mean PSA ⫾ SD (ng/dl): Before TRT At 12 mos Change
Without PIN
PIN
55 58.3 ⫾ 8.9
20 62.3 ⫾ 8.7
1.53 ⫾ 1.6 1.78 ⫾ 1.6 0.25 ⫾ 0.6
1.49 ⫾ 1.1 1.82 ⫾ 1.1 0.33 ⫾ 0.6
ng/l. One patient underwent repeat biopsy, which again demonstrated PIN but no cancer, while the other refused rebiopsy. Overall after 12 months of TRT 1 of 20 men had cancer in the PIN⫹ group and 0 of 55 had cancer in the PIN⫺ group (p ⫽ 0.267). The cancer rate in the entire study population of 75 men was 1 of 75 (1.3%) after 1 year of TRT. DISCUSSION
The risk of TRT with regard to prostate cancer remains a highly controversial issue. We addressed an aspect of this topic by investigating the impact of TRT in a set of men considered to be at high risk for subsequent prostate cancer. PIN is found to coexist in the majority of prostate cancer cases and subsequent followup of PIN cases reveals cancer in a high percentage.9 Specific concerns regarding TRT in hypogonadal men are that testosterone may cause progression of already existing but undiagnosed prostate cancer and it may convert precancerous lesions such as PIN to frank carcinoma. However, there are little if any compelling data indicating that TRT does in fact promote prostate cancer, even in men with PIN. In this report we present our data on the prostatic effects of 12 months of TRT in men with and without PIN. At the end of the study period we found no differences in mean PSA between the 2 groups. Moreover, the mean increase in PSA in men with PIN was the same as in men without PIN. The increase in PSA was quite modest in each group and consistent with that in other published TRT studies.10 The mean PSA increase of less than 0.3 ng/dl during 1 year supports existing literature that TRT causes an increase that may be statistically significant in groups but has minimal clinical significance in individuals undergoing treatment.10 TT and FT were similar between the 2 groups at the beginning and end of the study period, excluding the possibility that the lack of observed differences between groups was due to differences in the degree of prostate hormonal stimulation. Peak and trough hormone levels were not determined in the injection group and, therefore, these value differed from the relatively stable levels obtained with testosterone gel. Overall only 1 cancer (1.3%) was identified in the 75 treated men. This rate of cancer is similar to that identified in other TRT studies. In a compilation of testosterone replacement therapy studies only 5 of 461 men (1.1%) were identified with prostate cancer during a followup of 6 to 36 months.2, 3, 10 –14 Although the single case of cancer occurred in the PIN⫹
group, it would be difficult to implicate TRT as an etiological factor since prostate cancer develops in as many as 25.8% of PIN cases within 3 years.8 Our 5% cancer rate in men with PIN⫹ after 1 year of TRT appears to be no higher than the reported rate of cancer in untreated men, although admittedly the number with PIN⫹ in this series is small. However, despite this limited population size these data are reassuring that at least in the short term TRT in hypogonadal men with PIN does not appear to increase the risk of prostate cancer. Longer term followup of this group is planned to determine if there are further changes with time. Clinical concerns regarding the use of TRT in hypogonadal men with PIN stem from a generalized concern that testosterone supplementation may trigger prostate cancer. However, we have been unable to identify any published reports that directly address the effects of TRT on PIN. On the other hand, a number of reports describe the effects of antiandrogen therapy on PIN with conflicting results.15 One study showed a decrease in the prevalence and extent of high grade PIN after chemical castration with the combination of leuprolide and flutamide.16 In contrast, a study with finasteride, which decreases intracellular dihydrotestosterone without decreasing serum testosterone, showed little or no effect on PIN.17 Moreover, another study indicated that the incidence of PIN was unchanged after 1 year of finasteride and there was a significant increase in the number of patients with subsequent cancer on biopsy after this treatment.18 To our knowledge our study appears to be the first in which men with known PIN underwent TRT and were monitored for changes in PSA and DRE. At our center a unique opportunity is provided for such study due to our routine practice of performing prostate biopsy prior to TRT.19 However, the population of men in this study may differ slightly from other groups in which PIN is diagnosed since most of our patients underwent biopsy only because of low testosterone and not for the usual indications of elevated PSA or abnormal DRE. Nevertheless, pathological study of men in whom cancer was diagnosed only because of low testosterone showed no apparent differences in grade, stage or disease extent compared with men in whom cancer was diagnosed due to traditional indications,20 suggesting that the disease process may be the same regardless of the original reason for biopsy. A limitation of the current study is the followup period of only 1 year. It is entirely possible that longer follow up is necessary to detect new cancers in these men. Nevertheless, if TRT truly increased cancer progression in men with PIN, one would expect that any worrisome PSA increase would occur shortly after correcting an androgen deficient environment. There is little theoretical basis to expect that men receiving TRT would differ in cancer development from men with similar, naturally occurring testosterone after testosterone normalization has been established. Another limitation of the current study is the relatively small sample size. A large multicenter study would be required to detect subtle increases in cancer risk and we would strongly support the development of such a study. However, the low incidence of cancer progression in the current study represents reassuring data that no major early effect occurs. CONCLUSIONS
This study does not demonstrate an increased risk of progression to prostate cancer in hypogonadal men with PIN treated with testosterone for 1 year. PIN does not appear to be a contraindication to TRT. REFERENCES
1. Tenover, J. L.: Male hormone replacement therapy including “andropause”. Endocrinol Metabol Clin North Am, 27: 969, 1998
TESTOSTERONE REPLACEMENT IN HYPOGONADAL MEN AT RISK FOR PROSTATE CANCER 2. Snyder, P. J., Peachey, H., Berlin, J. A., Hannoush, P., Haddad, G., Dlewati, A. et al: Effects of testosterone replacement in hypogonadal men. J Clin Endocrinol Metab, 85: 2670, 2000 3. Sih, R., Morley, J. E., Kaiser, F. E., Perry, H. M., 3rd, Patrick, P. and Ross, C.: Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. J Clin Endocrinol Metab, 82: 1661, 1997 4. Basaria, S. and Dobs, A. S.: Risks versus benefits of testosterone therapy in elderly men. Drugs Aging, 15: 131, 1999 5. Huggins, C. B., Stevens, R. B. and Hodges, C. V.: The effects of castration on advanced carcinoma of the prostate gland. Arch Surg, 43: 209, 1941 6. Bostwick, D. G., Qian, J. and Frankel, K.: The incidence of high grade prostatic intraepithelial neoplasia in needle biopsies. J Urol, 154: 1791, 1996 7. Bostwick, D. G., Pacelli, A. and Lopez-Beltran, A.: Molecular biology of prostate intraepithelial neoplasia. Prostate, 29: 117, 1996 8. Lefkowitz, G. K., Taneja, S. S., Brown, J., Melamed, J. and Lepor, H.: Followup interval prostate biopsy 3 years after diagnosis of high grade prostatic intraepithelial neoplasia is associated with high likelihood of prostate cancer, independent of change in prostate specific antigen levels. J Urol, 168: 1415, 2002 ´ ., Wojno, K. J. and Oesterling, 9. Ha¨ ggman, M. J., Macoska, J. A J. E.: The relationship between prostatic intraepithelial neoplasia and prostate cancer: critical issues. J Urol, 158: 12, 1997 10. Wang, C., Swedloff, R. S., Iranmanesh, A., Dobs, A., Snyder, P. J., Cunningham, G. et al: Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. Testosterone Gel Study Group. J Clin Endocrinol Metab, 85: 2839, 2000 11. Kenny, A. M., Prestwood, K. M., Gruman, C. A., Marcello, K. M. and Raisz, L. G.: Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels. J Gerontol A Biol Sci Med Sci, 56: M266, 2001 12. Dobs, A. S., Meikle, A. W., Arver, S., Sanders, S. W., Caramelli,
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K. E. and Mazer, N. A.: Pharmacokinetics, efficacy, and safety of a permeation-enhanced testosterone transdermal system in comparison with bi-weekly injections of testosterone enanthate for the treatment of hypogonadal men. J Clin Endocrinol Metab, 84: 3469, 1999 Snyder, P. J., Peachey, H., Hannoush, P., Berlin, J. A., Loh, L., Holmes, J. H. et al: Effect of testosterone treatment on bone mineral density in men over 65 years of age. J Clin Endocrinol Metab, 84: 1966, 1999 Hajjar, R. R., Kaiser, F. E. and Morley, J. E.: Outcomes of long-term testosterone replacement in older hypogonadal males: a retrospective analysis. J Clin Endocrinol Metab, 82: 3793, 1997 Clark, L. C. and Marshall, J. R.: Randomized, controlled chemoprevention trials in populations at very high risk for prostate cancer: elevated prostate-specific antigen and high-grade prostatic intraepithelial neoplasia. Urology, 57: 185, 2001 Balaji, K. C., Rabbani, F., Tsai, H., Bastar, A. and Fair, W. R.: Effect of neoadjuvant hormonal therapy on prostatic intraepithelial neoplasia and its prognostic significance. J Urol, 162: 753, 1999 Yang, X. J., Lecksell, K., Short, K., Gottesman, J., Peterson, L., Bannow, J. et al: Does long-term finasteride therapy affect the histologic features of benign prostatic tissue and prostate cancer on needle biopsy? PLESS Study Group. Proscar Long-Term Efficacy and Safety Study. Urology, 53: 696, 1999 Salem, C. E., Cote, R. J., Skinner, E. C., Pike, M. C,. Stanczyk, F. Z. and Ross, R. K.: The effect of finasteride on prostate gland peripheral zone histology and proliferation rates in men at risk for prostate cancer. J Urol, suppl., 157: 229, abstract 891, 1997 Morgentaler, A., Bruning, C. O., III and DeWolf, W. C.: Occult prostate cancer in men with low serum testosterone levels. JAMA, 276: 1904, 1996 Zhang, P. L., Bubley, G., Upton, M., Morgentaler, A., DeWolf, W. C. and Rosen, S.: Pathologic features of occult prostatic carcinoma in hypogonadal men. Prostate J, 2: 74, 2000
Vol. 170, 2348 –2351, December 2003 Printed in U.S.A.
DOI: 10.1097/01.ju.0000091104.71869.8e
TESTOSTERONE REPLACEMENT THERAPY IN HYPOGONADAL MEN AT HIGH RISK FOR PROSTATE CANCER: RESULTS OF 1 YEAR OF TREATMENT IN MEN WITH PROSTATIC INTRAEPITHELIAL NEOPLASIA ERNANI LUIS RHODEN
AND
ABRAHAM MORGENTALER*
From the Division of Urology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
ABSTRACT
Purpose: One of the greatest concerns among clinicians regarding testosterone replacement therapy (TRT) is the fear of causing or promoting prostate cancer. We evaluated prostatic changes in hypogonadal men with and without high grade prostatic intraepithelial neoplasia (PIN), which is considered a prostatic precancerous lesion, after 1 year of TRT. Materials and Methods: A total of 75 hypogonadal who completed 12 months of TRT were studied. All underwent prostate biopsy prior to initiating treatment. Of the men 55 had benign prostate biopsies (PIN⫺) and 20 had PIN without frank cancer (PIN⫹). All men with PIN underwent repeat biopsy to exclude cancer prior to the initiation of testosterone treatment. Prostate specific antigen (PSA), and total and free testosterone were determined prior to treatment and at 1 year. Repeat biopsy was performed for a change noted on digital rectal examination or for a PSA increase of 1 ng/l or greater. Results: PSA was similar at baseline in men with and without PIN (1.49 ⫾ 1.1 and 1.53 ⫾ 1.6 ng/dl, p ⬎0.05) and after 12 months of TRT (1.82 ⫾ 1.1 and 1.78 ⫾ 1.6 ng/dl, respectively, p ⬎0.05). A slight, similar increase in mean PSA was noted in the PIN⫺ and PIN⫹ groups (0.25 ⫾ 0.6 and 0.33 ⫾ 0.6 ng/dl, p ⬎0.05). One man in the PIN⫹ group had cancer after biopsy was performed due to abnormal digital rectal examination. Four additional men in the PIN⫺ group and 2 in the PIN⫹ group underwent re-biopsy for elevated PSA and none had cancer. No differences were noted between the PIN⫺ and PIN⫹ groups with regard to total and free testosterone at baseline and at 1 year (p ⫽ 0.267). Conclusions: After 1 year of TRT men with PIN do not have a greater increase in PSA or a significantly increased risk of cancer than men without PIN. These results indicate that TRT is not contraindicated in men with a history of PIN. KEY WORDS: prostate, prostatic neoplasms, testosterone, prostate-specific antigen, hypogonadism
There has been a great deal of recent interest in the topic of low testosterone in the older man, a condition referred to as andropause.1 Age related decreases in androgen levels occur gradually and vary considerably among individuals. Low testosterone has been implicated as a cause of changes in sexual, physical and behavioral capacity in aging men.2, 3 Several observational and interventional studies have demonstrated that androgens have important beneficial functions in body composition, muscle mass and strength, fat distribution, erythropoiesis, cognition, mood and bone density, and have a key role in male sexual function.2, 3 However, one of the greatest concerns among clinicians regarding testosterone replacement therapy (TRT) is the fear of causing or promoting prostate cancer. This fear is based on the fact that prostate cancer is hormonally responsive.4 Huggins et al reported 60 years ago that testosterone suppression causes prostate cancer regression5 and it is now commonplace for men with metastatic prostate cancer to undergo treatment designed to lower testosterone. However, the relationship between prostate cancer and testosterone is incompletely understood, particularly with regard to the promotion or development of new cancers. It
applies especially to high grade prostatic intraepithelial neoplasia (PIN), which has been postulated to be a precancerous condition. PIN has been identified in 0.5% to 27% of prostate biopsies and reports suggest that 25% to 51% of men with high grade PIN on initial biopsy have carcinoma on repeat biopsy.6, 7 An examination of prostates removed at radical prostatectomy for clinically localized cancer revealed high grade PIN in 86% of cases.7 Furthermore, a followup study of men with a history of PIN revealed that prostate cancer developed in 25% of these men within 3 years.8 These reports support the concept that PIN acts as a precancer and men with PIN are at high risk for subsequent frank cancer. Although to our knowledge the mechanisms by which PIN may progress to clinical cancer are not known, there has been concern that men with PIN should not undergo testosterone supplementation because of the theoretical risk of promoting prostate cancer due to the trophic effects of testosterone on prostate cancer. However, it is important to note that this concern is entirely theoretical since to our knowledge no data yet exist to link testosterone with the conversion of PIN to clinical prostate cancer. At our center a unique opportunity is provided to study the effects of TRT in men with and without PIN due to our practice of routinely performing prostate biopsy prior to initiating TRT, thus, providing a study population with welldefined baseline histology. We compared the effects of 12
Accepted for publication July 25, 2003. Supported by Fundac¸a˜o Coordenacao de Aperfeic¸oamento de Pessoal de Nivel Superior-Brazil. * Corresponding author: 1 Brookline Pl., Suite 624, Brookline, Massachusetts 02445 (telephone: 617-277-5000; FAX: 617-277-5444; e-mail: [email protected]). 2348
2349
TESTOSTERONE REPLACEMENT IN HYPOGONADAL MEN AT RISK FOR PROSTATE CANCER
months of TRT in men with and without PIN with specific attention to changes suggestive of prostate cancer. METHODS
The charts of 75 hypogonadal men who completed 1 year of TRT between 1998 and 2001 were reviewed. All men presented initially with sexual symptoms, consisting of erectile dysfunction and/or decreased libido. Prostate biopsy was performed in all men prior to beginning treatment. There were 55 men with benign biopsy results (PIN⫺) and 20 with 1 or more foci of high grade PIN (PIN⫹). Digital rectal examination (DRE) was performed at the beginning of treatment and at 12 months of followup. All patients presented with hypogonadal symptoms and had documented low total testosterone (TT) or free testosterone (FT). Men were excluded from study if they were on medication known to decrease prostate specific antigen (PSA) (finasteride), had undergone previous prostatic surgery or had a history of prostate cancer, chronic prostatitis, urinary infection or another condition that might cause alterations in PSA. Men who had received previous treatment with testosterone replacement therapy were also excluded from this analysis. Serum determinations of TT and FT were obtained during the clinical hours of 8:00 a.m. to 5:00 p.m. TT and FT were measured by radioimmunoassay (Diagnostic Products Corp., Los Angeles, California) with a stated reference range of TT and FT of 270 to 1,100 and 1.5 to 3.5 ng/dl, respectively. TT less than 300 ng/dl was considered subnormal for study purposes. PSA was determined by radioimmunoassay using the IMX (Abbot Laboratories, Abbot Park, Illinois) kit. All PSA determinations were performed at the same laboratory (normal 0 to 4 ng/dl). DRE of the prostate was performed in all patients by a single urologist (AM). The absence of nodularity, asymmetry or unusual firmness of the prostate defined a normal DRE result. Biopsies were performed with transaxial and sagittal transrectal ultrasound scanning using a 7.0 MHz end-fire transducer. Transrectal ultrasound guided prostate needle biopsies were performed with an automatic Biopty (Bard Urological, Covington, Georgia) device using an 18 gauge needle. Six cores were routinely obtained, which was increased to as many as 12 if there were palpable or ultrasound abnormalities. Hypoechoic or otherwise suspicious areas on ultrasound were also biopsied. Biopsy specimens were reviewed by the clinical pathology staff at our institution.
TABLE 1. Patient characteristics No. pts Mean age ⫾ SD (range) Mean ng/dl PSA ⫾ SD (range) Mean ng/dl TT ⫾ SD (range) Mean ng/dl FT ⫾ SD (range) No. biopsy: Without PIN With PIN
75 59.6 ⫾ 9.0 (42–77) 1.54 ⫾ 1.5 (0.3–9.4) 295.9 ⫾ 119.3 (74–776) 1.04 ⫾ 0.33 (0.4–1.9) 55 20
The mode of TRT administration was intramuscular injection of testosterone enanthate in 32 men (58.2%) in the PIN⫺ group with transdermal gel given in the remaining 23 (41.8%). In the PIN⫹ group 11 of the 20 men (55%) were treated with injections and 9 (45%) received gel. Clinical evaluation at 12 months included DRE, and serum TT, FT and PSA determinations in all individuals. In men receiving testosterone injections serum TT and FT were measured 7 to 10 days after the last treatment. Individuals with an increase in PSA of above 1.0 ng/dl or with changes on DRE underwent repeat prostate biopsy. Statistical analysis was performed using the Student t and chi-square tests to assess the differences between groups with p ⬍0.05 considered significant. RESULTS
Table 1 lists study group characteristics. Mean age in the study group was 59.6 years and there was no significant difference between the PIN⫹ and PIN⫺ groups (62.3 and 58.3, respectively, p ⬎0.05). The PIN⫹ group consisted of 12 men with low FT, and 8 with low FT and TT. In the PIN⫺ group there were 18 men with low FT only, 2 cases with low TT only, and 35 with low FT and low TT. There were no differences between groups in the mean number of cores ⫾ SD at initial biopsy (6.8 ⫾ 1.2 and 7.1 ⫾ 1.4, p ⬎0.05). However, extended repeat biopsies (mean 10.2 ⫾ 1.6 cores) were subsequently performed in men with PIN at initial biopsy. Two men (10%) in the PIN⫹ group and 3 (6%) in the PIN⫺ group had PSA greater than 4.0 ng/ml. DRE was initially abnormal in 7 men (12.7%) in the PIN⫺ group and in 4 (20%) in the PIN⫹ group. Baseline TT was similar in the PIN⫺ and PIN⫹ groups (294 ⫾ 126.7 and 298.1 ⫾ 92.3 ng/dl, p ⫽ 0.897) and no differences were noted between groups after 12 months of TRT (641.8 ⫾ 324.3 and 616.6 ⫾ 270.4 ng/dl, respectively, p ⫽ 0.76). Similarly no differences were noted for FT at baseline (1.03 ⫾ 0.4 and 1.07 ⫾ 0.2 ng/dl, p ⫽ 0.671) and at 12 months (2.1 ⫾ 1.0 and 2.1 ⫾ 0.9 ng/dl, respectively, p ⫽ 1.0). Testosterone and PSA were similar regardless of the injection or transdermal treatment mode (p ⬎0.05) (tables 2 and 3). Mean PSA was almost identical in the PIN⫺ and PIN⫹ groups at baseline (1.53 ⫾ 1.6 and 1.49 ⫾ 1.1 ng/dl, p ⫽ 0.918) and after 12 months of TRT (1.78 ⫾ 1.6 and 1.82 ⫾ 1.1 ng/dl, respectively, p ⫽ 0.898). There was also no difference in the increase in PSA after 12 months of TRT between the PIN⫺ and PIN⫹ groups (0.25 ⫾ 0.6 and 0.33 ⫾ 0.6 ng/dl, respectively, p ⫽ 0.949, table 4). In the entire study group only a 57 year-old man in the PIN⫹ group was identified with cancer, which occurred 1 year after the initiation of TRT. Initial DRE became abnormal on followup. PSA increased from 1.7 to 2.6 ng/dl. Gleason score of the cancer was 7 (4 ⫹ 3). Testosterone treatment was discontinued when cancer was identified. Four men in the PIN⫺ group underwent biopsy for an increase in PSA of greater than 1.0 ng/dl but none had prostate cancer. In the PIN⫹ group 2 men had a PSA elevation of greater than 1.0
TABLE 2. Baseline and change in testosterone in men with and without PIN who received TRT Groups
No. Pts
Without PIN: Injection Gel Totals With PIN: Injection Gel
Mean TT ⫾ SD (ng/dl)
Mean FT ⫾ SD (ng/dl)
Before TRT
At 12 Mos
Before TRT
At 12 Mos
32 23
297.7 ⫾ 156.6 292.7 ⫾ 89.7
622.3 ⫾ 379.1 641.4 ⫾ 243.2
0.9 ⫾ 0.4 1.1 ⫾ 0.3
2.0 ⫾ 1.2 2.0 ⫾ 0.8
55
294.8 ⫾ 126.7
641.8 ⫾ 324.3
1.0 ⫾ 0.4
2.1 ⫾ 1.0
11 9
305.7 ⫾ 105.6 293.1 ⫾ 70.8
604.7 ⫾ 292.6 654.0 ⫾ 242.6
1.0 ⫾ 0.3 1.1 ⫾ 0.2
2.1 ⫾ 1.2 2.1 ⫾ 0.6
616.6 ⫾ 270.4
1.1 ⫾ 0.2
2.1 ⫾ 0.9
Totals 20 298.1 ⫾ 92.3 For all comparisons between the PIN⫺ and PIN⫹ groups p ⬎0.05.
2350
TESTOSTERONE REPLACEMENT IN HYPOGONADAL MEN AT RISK FOR PROSTATE CANCER TABLE 3. PSA changes 1 year after TRT No. Pts
Without PIN: Injection Gel With PIN: Injection Gel Totals
Mean PSA ⫾ SD (ng/dl)
Change
Before TRT
At 12 Mos
32 23
1.54 ⫾ 1.6 1.52 ⫾ 1.8
1.82 ⫾ 1.4 1.86 ⫾ 1.9
0.28 ⫾ 0.7 0.34 ⫾ 0.5
11 9
1.24 ⫾ 0.6 1.78 ⫾ 1.5
1.56 ⫾ 0.9 2.12 ⫾ 1.4
0.32 ⫾ 0.6 0.34 ⫾ 0.6
75
1.54 ⫾ 1.5
1.81 ⫾ 1.5
0.27 ⫾ 0.6
TABLE 4. PSA change before to 1 year after TRT in men with and without PIN who underwent TRT No. pts Mean age ⫾ SD Mean PSA ⫾ SD (ng/dl): Before TRT At 12 mos Change
Without PIN
PIN
55 58.3 ⫾ 8.9
20 62.3 ⫾ 8.7
1.53 ⫾ 1.6 1.78 ⫾ 1.6 0.25 ⫾ 0.6
1.49 ⫾ 1.1 1.82 ⫾ 1.1 0.33 ⫾ 0.6
ng/l. One patient underwent repeat biopsy, which again demonstrated PIN but no cancer, while the other refused rebiopsy. Overall after 12 months of TRT 1 of 20 men had cancer in the PIN⫹ group and 0 of 55 had cancer in the PIN⫺ group (p ⫽ 0.267). The cancer rate in the entire study population of 75 men was 1 of 75 (1.3%) after 1 year of TRT. DISCUSSION
The risk of TRT with regard to prostate cancer remains a highly controversial issue. We addressed an aspect of this topic by investigating the impact of TRT in a set of men considered to be at high risk for subsequent prostate cancer. PIN is found to coexist in the majority of prostate cancer cases and subsequent followup of PIN cases reveals cancer in a high percentage.9 Specific concerns regarding TRT in hypogonadal men are that testosterone may cause progression of already existing but undiagnosed prostate cancer and it may convert precancerous lesions such as PIN to frank carcinoma. However, there are little if any compelling data indicating that TRT does in fact promote prostate cancer, even in men with PIN. In this report we present our data on the prostatic effects of 12 months of TRT in men with and without PIN. At the end of the study period we found no differences in mean PSA between the 2 groups. Moreover, the mean increase in PSA in men with PIN was the same as in men without PIN. The increase in PSA was quite modest in each group and consistent with that in other published TRT studies.10 The mean PSA increase of less than 0.3 ng/dl during 1 year supports existing literature that TRT causes an increase that may be statistically significant in groups but has minimal clinical significance in individuals undergoing treatment.10 TT and FT were similar between the 2 groups at the beginning and end of the study period, excluding the possibility that the lack of observed differences between groups was due to differences in the degree of prostate hormonal stimulation. Peak and trough hormone levels were not determined in the injection group and, therefore, these value differed from the relatively stable levels obtained with testosterone gel. Overall only 1 cancer (1.3%) was identified in the 75 treated men. This rate of cancer is similar to that identified in other TRT studies. In a compilation of testosterone replacement therapy studies only 5 of 461 men (1.1%) were identified with prostate cancer during a followup of 6 to 36 months.2, 3, 10 –14 Although the single case of cancer occurred in the PIN⫹
group, it would be difficult to implicate TRT as an etiological factor since prostate cancer develops in as many as 25.8% of PIN cases within 3 years.8 Our 5% cancer rate in men with PIN⫹ after 1 year of TRT appears to be no higher than the reported rate of cancer in untreated men, although admittedly the number with PIN⫹ in this series is small. However, despite this limited population size these data are reassuring that at least in the short term TRT in hypogonadal men with PIN does not appear to increase the risk of prostate cancer. Longer term followup of this group is planned to determine if there are further changes with time. Clinical concerns regarding the use of TRT in hypogonadal men with PIN stem from a generalized concern that testosterone supplementation may trigger prostate cancer. However, we have been unable to identify any published reports that directly address the effects of TRT on PIN. On the other hand, a number of reports describe the effects of antiandrogen therapy on PIN with conflicting results.15 One study showed a decrease in the prevalence and extent of high grade PIN after chemical castration with the combination of leuprolide and flutamide.16 In contrast, a study with finasteride, which decreases intracellular dihydrotestosterone without decreasing serum testosterone, showed little or no effect on PIN.17 Moreover, another study indicated that the incidence of PIN was unchanged after 1 year of finasteride and there was a significant increase in the number of patients with subsequent cancer on biopsy after this treatment.18 To our knowledge our study appears to be the first in which men with known PIN underwent TRT and were monitored for changes in PSA and DRE. At our center a unique opportunity is provided for such study due to our routine practice of performing prostate biopsy prior to TRT.19 However, the population of men in this study may differ slightly from other groups in which PIN is diagnosed since most of our patients underwent biopsy only because of low testosterone and not for the usual indications of elevated PSA or abnormal DRE. Nevertheless, pathological study of men in whom cancer was diagnosed only because of low testosterone showed no apparent differences in grade, stage or disease extent compared with men in whom cancer was diagnosed due to traditional indications,20 suggesting that the disease process may be the same regardless of the original reason for biopsy. A limitation of the current study is the followup period of only 1 year. It is entirely possible that longer follow up is necessary to detect new cancers in these men. Nevertheless, if TRT truly increased cancer progression in men with PIN, one would expect that any worrisome PSA increase would occur shortly after correcting an androgen deficient environment. There is little theoretical basis to expect that men receiving TRT would differ in cancer development from men with similar, naturally occurring testosterone after testosterone normalization has been established. Another limitation of the current study is the relatively small sample size. A large multicenter study would be required to detect subtle increases in cancer risk and we would strongly support the development of such a study. However, the low incidence of cancer progression in the current study represents reassuring data that no major early effect occurs. CONCLUSIONS
This study does not demonstrate an increased risk of progression to prostate cancer in hypogonadal men with PIN treated with testosterone for 1 year. PIN does not appear to be a contraindication to TRT. REFERENCES
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