Introduction

Testosterone therapy has been administered for male hypogonadism for decades^{1, 2, 3, 4} and has seen increasing use in part because of the availability of well-tolerated testosterone formulations.^{5, 6, 7, 8, 9, 10} When administered cautiously, testosterone therapy is safe and effective in mitigating the signs and symptoms of hypogonadism,¹¹ which include lower libido; erectile dysfunction; fatigue; decreased muscle strength, bone mineral density and body hair; increased body fat; anemia; hot flushes; and mood changes.^{10, 12, 13} Testosterone therapy may also have beneficial effects on the lipid profile and cardiovascular system.¹⁴

Testosterone therapy for male hypogonadism is generally safe, with possible adverse effects of benign prostatic hyperplasia, erythrocytosis, sleep apnea, gynecomastia, testicular atrophy, fluid retention and local reactions at sites of buccal, topical, subcutaneous and intramuscular administration.¹⁵ There is, however, an important and unresolved question of whether testosterone therapy increases the risk of new prostate cancer or the recurrence or progression of prostate cancer.

Long-standing concerns about testosterone treatment for hypogonadism are derived from Huggins and Hodges' landmark observation in 1941 stating that testosterone reduction causes regression of metastatic prostate cancer and testosterone administration causes prostate cancer growth.¹⁶ Huggins and Hodges' conclusion about exogenous testosterone and cancer growth was drawn from observation of just one patient without prior castration. The precise relationship of endogenous testosterone and exogenous testosterone therapy and the risk of prostate cancer, as well as prostate cancer progression, has not yet been made clear.^{15, 17, 18}

Recently published opinions regarding this question have stated that an association cannot be confirmed.^{13, 17, 19, 20, 21, 22, 23, 24} The Institute of Medicine Committee on Assessing the Need for Clinical Trials of Testosterone Replacement Therapy in 2004 advised against starting a long-term study of the risks associated with testosterone therapy in older men unless short-term studies conclusively demonstrated the benefit of such therapy.²⁵ It has been estimated that a long-term, randomized, placebo-controlled study would involve following 6000 elderly hypogonadal men for 6 years to determine whether treatment increases the risk of prostate cancer.¹⁹ In the absence of such a study, it is worthwhile to address the unresolved question regarding the potential association of testosterone therapy and the risk of developing or promoting the recurrence or progression of prostate cancer.

This article distills findings from the literature in an effort to provide as authoritative an answer as possible to the question of whether the risk of prostate cancer is higher in hypogonadal men treated with testosterone than in hypogonadal men who have not received testosterone treatment.

Materials and methods

Search strategy

The electronic databases MEDLINE and EMBASE were searched for studies published in the English language from 1970 through 2008, using as keywords and key phrases testosterone combined with cypionate, enanthate, proprionate, gel, patch, oral, therapy, prostate cancer risk and prostate-specific antigen (PSA). A supplemental search was conducted of references cited in journal articles, conference proceedings and books. Study investigators were queried for additional references.

Selection of studies for systematic review

As indicated in Figure 1, titles and abstracts of the studies retrieved by the literature search were reviewed by medical staff. For studies that appeared relevant and for which full text reports were available, a decision was made whether to analyze them further, based on their clinical features and quality of study methods.

Figure 1.

Process to select studies for systematic review.

Full figure and legend (29K)

To maximize data, many types of reports were accepted, from single and multiple case reports to studies that were randomized or nonrandomized; open- or closed-label; placebo-, active- or noncontrolled; prospective or retrospective; sequential, parallel, or crossover; blinded or not blinded; conducted in one or more clinics or private practices; and pharmacokinetic or pharmacodynamic. Also, studies of men with or without a history of prostate cancer were accepted.

Inclusion and exclusion criteria

Inclusion required that each study involve adult men who received testosterone therapy for signs and symptoms of hypogonadism or had abnormally low or low-normal testosterone levels of any etiology. Included studies had defined criteria of hypogonadism and required histologic confirmation of prostate cancer. Excluded from this investigation were review articles, meta-analyses, and reports of studies in which testosterone therapy was not administered as monotherapy or outcomes had no apparent relevance to the association between the risk of prostate cancer and testosterone therapy in hypogonadal men. Meta-analyses and review articles were referred to as a source of data to identify individual articles that met the scope and methodology of this systematic review.

Review and data extraction methods

For each study uncovered by the broad search, details concerning the study's objectives, design, subjects, testosterone and other therapy, testosterone levels, hypogonadism symptoms, digital rectal examination (DRE) and PSA findings, cancers detected, and conclusions were entered into a Microsoft Excel workbook for subsequent data extraction and analysis.

Results

The literature search uncovered 197 articles, of which 52 had possible relevance to this systematic review as indicated by their title or abstract. Upon review of the full text of these 52 articles, 8 were excluded from analysis because they did not involve testosterone administered as monotherapy (n=2), involved subjects who were neither hypogonadal nor in the low-eugonadal range (n=3), provided no data relevant to prostate cancer risk (n=2), or were found to be review articles (n=1). The remaining 44 studies of testosterone supplementation are included in this analysis.

Of the 44 studies of men who had not had prostate cancer, 11 are placebo-controlled and randomized (Table 1) and 29 are not placebo-controlled (Table 2). Among the 29 not placebo-controlled, 15 are prospective and 14 are retrospective studies, including a case series of 20 men in whom prostate cancer developed during testosterone therapy and 8 reports of 1 or 2 cases. Also included are four non-placebo-controlled reports of testosterone therapy in hypogonadal men who had previously been treated for prostate cancer (Table 3).

Table 1 - Placebo-controlled, randomized studies of testosterone supplementation in hypogonadal men.

Full table

Table 2 - Non-placebo-controlled studies of men with no history of prostate cancer.

Full table

Table 3 - Non-placebo-controlled case studies of testosterone use in hypogonadal men who have had prostate cancer.

Full table

Placebo-controlled studies

In the 11 placebo-controlled, randomized studies, prostate cancer was detected in 7 of the 542 men treated with testosterone as monotherapy (1.3%) and 5 of the 333 men who received placebo (1.5%; Table 1). Prostate cancer incidences across studies varied from 0% for both the testosterone and the placebo groups in seven studies^{14, 27, 28, 30, 31, 34, 35} to 9.5% for the testosterone group and 21% for the placebo group in the study by Marks et al.²⁹ Prostate cancer in testosterone-treated men was detected at as early as 3 months³³ and in placebo-treated men at as early as 6 months.²⁹ Gleason grades were reported for four testosterone-treated patients (two of grade 5, one of grade 6 and one of grade 7) and four placebo-treated subjects (all grade 6).^{26, 29}

The Amory et al.²⁶ study included prostate ultrasound examination of all men entering and completing the study. Prostate volume increased significantly in all groups over the 3-year study period, with the increase in the testosterone-only group similar to that seen in the placebo group (P=0.35).²⁶

In the Marks et al. study, there were no remarkable changes in prostate tissue (for example, histologic changes, tissue biomarkers for cell proliferation and angiogenesis) in men receiving testosterone therapy compared to men receiving placebo, or in individuals' baseline levels compared to 6-month levels. These results indicate that exogenous testosterone does not accumulate in the prostate or provoke major biological change in the prostate gland.²⁹

Non-placebo-controlled studies of men with no history of prostate cancer

Of the 21 non-placebo-controlled studies, 1 was a retrospective study of 20 cases of prostate cancer diagnosed in men receiving testosterone therapy for hypogonadism in six private practices³⁶ (Table 2). Eleven of these cancers were detected during the first 2 years of testosterone therapy, and 9 were detected 28 months to 8 years after the start of therapy.³⁶ Gleason scores were 6 in nine cancers, 7 in six cancers, 8 in three cancers and 9 in two cancers.³⁶

Among the other 20 non-placebo-controlled studies, 6 prostate cancers were detected in 4 retrospective studies (Table 2),^{52, 54, 55, 56} and 6 prostate cancers were detected in 3 prospective studies.^{39, 50, 51} In these seven studies, prostate cancer incidences ranged from 1.2 to 4.5%. One cancer developed within 3 months of the start of testosterone therapy⁵² (Table 2). In Rhoden and Morgentaler's 2003 1-year retrospective study, prostate cancer (Gleason score 7) developed in 1 of 20 men (5%) at high risk for prostate cancer because of prostate intraepithelial neoplasia (PIN) detected at baseline prostate biopsy. No cancers developed among 55 men in whom PIN was not found on baseline biopsy (Table 2).⁵⁴

Among the eight case reports of prostate cancer detected in hypogonadal men, one is of a man who received testosterone therapy for pituitary insufficiency for 15 years before prostate cancer was detected. Another describes two men with Klinefelter syndrome in whom the cancer was detected after 7 and 35 years of testosterone therapy, respectively.

Studies of testosterone therapy in men with a history of prostate cancer

One prospective and three retrospective case series examined 53 men who received testosterone therapy for hypogonadism and had been treated for prostate cancer (Table 3).^{65, 66, 67, 68} There was no evidence of prostate cancer recurrence in these men over periods of 0.5–12 years. The prospective case series included five men who had subcapsular orchiectomy to treat advanced prostatic carcinoma; these men had PSA increases while undergoing testosterone therapy for up to 2.5 years.⁶⁵ One retrospective series followed 31 men who had brachytherapy for early prostate cancer and were treated with testosterone for up to 8.5 years. PSA values were <1 ng ml^-1 following treatment; no baseline PSA levels were available.⁶⁶ The other two retrospective studies included a total of 17 men who had radical prostatectomy. PSA levels remained undetectable for up to 12 years, including 1 man whose prostate showed a positive surgical margin.^{67, 68}

Discussion

The 11 placebo-controlled, randomized studies included in this review provide direct comparisons of the incidence of new prostate cancer in hypogonadal men receiving testosterone therapy and hypogonadal men not receiving testosterone. The prostate cancer incidence was similar in groups receiving testosterone therapy and those receiving placebo, 1.3 and 1.5%, respectively, which is similar to detection rates in screening programs.²⁴

Of the placebo-controlled studies, the Marks et al.²⁹ study had the highest prostate cancer incidences, 9.5% in the testosterone group and 21% in the placebo group. This was the only placebo-controlled study in which end-of-study prostate biopsies were performed routinely, optimizing the chance of detecting cancers. Because only one of the study's subjects had a PSA level >4.0 ng ml^-1, the six cancers might not have been detected had the biopsies not been performed.²⁹ Marks et al.²⁹ believe that the prostate cancers detected at the end of the study were present at the study's start, even though all subjects randomized into the study had a negative enrollment biopsy, and concluded that testosterone therapy cannot be implicated as a prostate cancer stimulus. The prostate cancer incidence rates in the Marks et al. study agree with those in another 2006 study. Morgentaler and Rhoden⁶⁹ included routine prostate biopsy and found prostate cancer in 15.1% of 345 men with a PSA level of 4.0 ng ml^-1.

Amory et al.²⁶ found lower prostate cancer incidences than Marks et al.: 6.2% in men who received testosterone as monotherapy and 5.5% in men who received placebo. The combination therapy arm of this study was not evaluated; however, it should be noted that no incidences of prostate cancer were reported in men who received testosterone with finasteride. Routine end-of-study biopsy was not performed. In only one subject, prostate cancer was suspected because of an elevated PSA level. A second case was detected because of an abnormal DRE, and a third, though seemingly untraditional signs and symptoms suggestive of prostate cancer, because of asthenia and fever. In the Marks et al.²⁹ study, all the cancers, regardless of testosterone or placebo grouping, were detected at 6 months in men who had a negative DRE result at 3 months and a negative start-of-study biopsy. Reports of other placebo-controlled studies did not disclose why prostate cancers were suspected.

This review's 21 non-placebo-controlled studies provide information about the effect of testosterone therapy on PSA level and its relation to prostate cancer, though not about the relative risk of prostate cancer developing or progressing in testosterone-treated vs nontreated men. In Guay et al.'s⁵² transdermal testosterone undecanoate patch and intramuscular testosterone groups, PSA levels increased in men aged 61–80 years (P=0.018 and 0.005, respectively) but not to the same degree in men aged 40–60 years (P=0.055 and 0.214, respectively). Biopsies were triggered by suspicious PSA levels in nine cases and a nodule detected by DRE in one case, resulting in three cancers detected (3% of 90 men).⁵²

In the Gerstenbluth et al.⁵⁶ study, a rise in PSA level above 4.0 ng ml^-1 led to biopsy in 6 of the 54 men (11.1%) and to 1 prostate cancer (1.9%). All of the men met inclusion criteria, with a PSA level <4.0 ng ml^-1 before treatment, normal results on DRE, or a pretreatment prostate biopsy negative for cancer for men with an abnormal DRE or an elevated PSA level. PSA levels increased, but no cancers were detected in the El-Sakka et al.⁴¹ 1-year study of patients with hypogonadism associated with erectile dysfunction. Douglas et al.⁴⁰ found a rise in PSA level of about 40% and a doubling of average serum testosterone level for 10 men receiving therapy with testosterone patch, but no cancer cases; neither PSA nor prostate-specific membrane antigen were testosterone dependent. In this study, PSA was found to be less sensitive than DRE in detecting prostate cancer in the series of 20 cases collected retrospectively by Gaylis et al.³⁶ In the Rhoden and Morgentaler⁵⁵ study, testosterone therapy caused only a mild increase in PSA levels in most men and did not appear to be influenced by age or baseline PSA or serum testosterone levels.

High-grade PIN is associated with a higher risk of developing prostate cancer⁷⁰; prostate cancer develops in 25.8% of men with high-grade PIN within 3 years of the PIN finding.⁷¹ Upon biopsy before testosterone therapy in the Rhoden and Morgentaler⁵⁴ study, 20 prostates were positive for high-grade PIN and 55 were negative. The PIN-positive and PIN-negative groups had similar mean levels of testosterone (P=0.88) and PSA (P>0.05) at baseline and at the end of the 1-year study. The single prostate cancer detected in the study group was in a man whose prostate was PIN positive (5%). The prostate cancer incidence rate was 1.3% for the entire group.⁵⁴ In a subsequent report, Morgentaler²⁴ concluded that testosterone therapy did not cause precipitous progression of prostate cancer in these men.

Data in the studies covered by this review are insufficient to determine whether more severe grades of prostate cancer are found with testosterone treatment vs without, but they seem to indicate the cancer grades are not necessarily more severe with treatment. The Gleason grades of 6 and 7 in the cancers detected by Marks et al.²⁹; the scores of 6, 7 and 8–10 in the Gaylis et al.³⁶ study; and the score of 7 in the Rhoden and Morgentaler⁵⁴ study suggest that these cancers are all of clinical significance, regardless whether in testosterone-treated or nontreated subjects. Further, data from the four studies of men who received testosterone therapy over periods of up to 12 years after treatment for prostate cancer provide no evidence that testosterone therapy increased the risk of cancer recurrence or metastasis.^{65, 66, 67, 68}

This review was designed to provide information to help answer the specific question about whether prostate cancer risks are increased by testosterone therapy for hypogonadism. The review included studies of adult men of any age with hypogonadism of any etiology, regardless whether the studies were placebo-controlled and randomized or involved men with previous prostate cancer.

The extensive variation of the 44 study designs and objectives, inclusion and exclusion criteria, patient populations, testosterone formulations and dosages, baseline testosterone levels, and other features, however, limit the conclusions that can be drawn relating testosterone therapy to the risk of new prostate cancer or recurrence of prostate cancer. The small number of placebo-controlled studies, intrinsic weaknesses of noncontrolled or retrospective trials, short duration and small numbers of subjects in some studies, and varied response of serum testosterone levels to testosterone administration are among other limitations of this review. Further, none of the studies was planned or powered to answer this review's single, salient question of whether testosterone therapy increases the risk of prostate cancer. Despite these limitations, this review discloses data that permit relevant observations.

First, there is no evidence that US Food and Drug Administration (FDA)-approved formulations of testosterone therapy increase the risk of prostate cancer in hypogonadal men. As shown by the overall similar incidence of prostate cancer in testosterone- and placebo-treated subjects in the 11 placebo-controlled studies, a higher incidence of prostate cancer was detectable within 6 months in placebo-treated subjects.^{14, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35} In addition, the higher number of prostate cancers detected at 6 months in the placebo group than in the testosterone group may indicate that testosterone plays a protective role in hypogonadism.

There were no cancer recurrences or metastases in patients treated with FDA-approved testosterone formulations who had a history of prostate cancer.^{65, 66, 67, 68} Further, men with high-grade PIN treated with testosterone did not have a greater increase in PSA or a significantly elevated risk of prostate cancer than testosterone-treated men without PIN.⁵⁴ Testosterone therapy did not cause a sudden progression to prostate cancer in men with PIN.⁵⁴ There are no data suggesting that testosterone therapy favors the development of more severe grades of prostate cancer compared to placebo or no treatment with testosterone, as evidenced by Gleason scores.

The value of PSA level as an indicator of possible prostate cancer makes its relationship to FDA-approved testosterone therapy a matter of some importance. In the studies covered in this review, there was no consistent effect of testosterone therapy on PSA level; PSA levels were increased in men aged 61–80 years but not in younger men,⁵² or increased in the first 6 months of testosterone therapy but not during the next 3 years.⁵⁰ However, other PSA isoforms that impact the risk of a positive biopsy, such as a low or falling percent free PSA, have not been adequately studied in this population of men. Gore et al. demonstrated that optimizing the distribution and number of cores sampled during prostate biopsy increases the prostate cancer detection rate. An improved sampling regimen detected a 25% risk of cancer developing in men with PSA between 2.5 and 4.0 ng ml^-1 and a 50% risk of cancer developing in men with PSA between 4.0 and 10 ng ml^-1.⁷² It remains prudent to perform a biopsy before the initiation of testosterone therapy for men with higher PSA levels.

Although non-FDA-approved testosterone supplementation was not the focus of this review, a study by Shariat et al.⁷³ reported two highly unusual cases of aggressive prostate cancer after initiation of a non-FDA-approved oral supplement that contained a proprietary combination of substances that included testosterone, estradiol, chrysin and elk velvet antler. Furthermore, androgen-independent disease developed quickly in these patients within months of beginning combined androgen blockade. Laboratory analysis of the product demonstrated that it was a more potent stimulator of prostate cancer cell growth compared to testosterone alone in both hormone-refractory (DU-145) and hormone-sensitive (LNCaP) human prostate cancer cell lines. These cases suggest that standard formulations of testosterone therapy, tested in FDA trials before approval, can be used safely, but there may be a significant risk when combining androgens and estrogens with other bioactive substances. This merits further study and caution.⁷³

Because of its restricted focus on the risk of prostate cancer, this review has not considered to any great extent other negative and positive effects of testosterone therapy, including effects on prostate size, symptoms of prostatism, signs and symptoms of hypogonadism, lipids and the cardiovascular system, hematocrit increase, sleep apnea and fluid retention. The review published recently by Seftel⁴ covers pharmacologic and clinical profiles of available and potential testosterone preparations and monitoring and safety issues associated with testosterone therapy.

In addition, an important study from the Endogenous Hormones and Prostate Cancer Collaborative Group was recently published. This study investigated 18 prospective longitudinal studies that analyzed whether differences in circulating levels of sex hormones were related to risk of prostate cancer. This collaborative analysis definitively found no association between serum testosterone concentrations and the risk of prostate cancer.⁷⁴

The studies in this review demonstrate that FDA-approved testosterone therapy is well tolerated, safe and efficacious in the treatment of hypogonadal men.

Conclusion

There is no evidence that testosterone therapy increases the risk of prostate cancer in hypogonadal men. Selected studies in this systematic review demonstrated that the incidence rates for developing prostate cancer did not increase and did not cause high-grade PIN to progress to frank prostate cancer in hypogonadal men treated with testosterone therapy. Further, endogenous concentrations of serum testosterone have not been directly linked to abnormal changes in PSA, and testosterone therapy appears to be safe in men treated with curative therapy for prostate cancer. FDA-approved formulations of testosterone therapy may be administered to symptomatic hypogonadal men who have either normal PSA and DRE results or higher/rising PSA levels or abnormal DRE results but a prostate biopsy that is negative for cancer. Testosterone therapy requires regular monitoring of PSA and DRE. Urologic referral is recommended for prostate biopsy if there is a rise in PSA levels or an abnormality detected by DRE. An important finding demonstrates that testosterone therapy can be safely administered with monitoring to men who have had curative therapy for prostate cancer and have symptoms of hypogonadism.

Author contributions

Dr Shabsigh, Dr Crawford, Dr Nehra and Dr Slawin had full access to all of the data in the review and take responsibility for the integrity of the data and the accuracy of the data analysis.

Financial disclosures

Dr Shabsigh was a consultant for American Medical Systems, Auxilium, Bayer Schering Pharma, Boehringer Ingelheim, Indevus Pharmaceuticals, Johnson & Johnson, Lilly, and Pfizer. He was a lecturer for American Medical Systems, Bayer Schering Pharma, Lilly, and Pfizer. Dr Crawford was a lecturer for Auxilium, Endocare, GlaxoSmithKline, Oncura and Sanofi-Aventis. He was on a scientific trial for Oncura. He was a consultant for the National Institutes of Health and the University of Colorado Cancer Center. Dr Nehra was a consultant for GlaxoSmithKline, Indevus and Pfizer. Dr Slawin was a board member and consultant for Bellicum Pharmaceuticals, Inc. He was an investor, owner of Indevus Pharmaceuticals. He was a meeting participant for Boehringer Ingelheim. He was on a scientific trial and a meeting participant for Novacea.

References

1. Nieschlag E. Testosterone treatment comes of age: new options for hypogonadal men. Clin Endocrinol 2006; 65: 275–281. | Article | ChemPort |
2. Swyer GI. Male hypogonadism with unexpected response to testosterone therapy. Proc R Soc Med 1951; 44: 157–158. | PubMed | ChemPort |
3. Hirschhauser C, Hopkinson CR, Sturm G, Coert A. Testosterone undecanoate: a new orally active androgen. Acta Endocrinol (Copenh) 1975; 80: 179–187. | PubMed | ChemPort |
4. Seftel A. Testosterone replacement therapy for male hypogonadism, part III: pharmacologic and clinical profiles, monitoring, safety issues, and potential future agents [review]. Int J Impot Res 2007; 19: 2–24. | Article | PubMed | ChemPort |
5. Tan RS, Salazar JA. Risks of testosterone replacement therapy in ageing men [review]. Expert Opin Drug Saf 2004; 3: 599–606. | Article | PubMed | ChemPort |
6. Mulligan T, Frick MF, Zuraw QC, Stemhagen A, McWhirter C. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract 2006; 60: 762–769. | Article | PubMed | ISI | ChemPort |
7. Seftel AD. Male hypogonadism, part I: epidemiology of hypogonadism [review]. Int J Impot Res 2006; 18: 115–120. | Article | PubMed | ISI | ChemPort |
8. Feldman HA, Longcope C, Derby CA, Johannes CB, Araujo AB, Coviello AD et al. Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. J Clin Endocrinol Metab 2002; 87: 589–598. | Article | PubMed | ISI | ChemPort |
9. Araujo AB, O'Donnell AB, Brambilla DJ, Simpson WB, Longcope C, Matsumoto AM et al. Prevalence and incidence of androgen deficiency in middle-aged and older men: estimates from the Massachusetts Male Aging Study. J Clin Endocrinol Metab 2004; 89: 5920–5926. | Article | PubMed | ISI | ChemPort |
10. Cunningham GR. Testosterone replacement therapy for late-onset hypogonadism [review]. Nat Clin Pract Urol 2006; 3: 260–267. | Article | PubMed | ChemPort |
11. Handelsman DJ. Testosterone: use, misuse and abuse. MJA 2006; 185: 436–439. | PubMed |
12. Seftel A. Male hypogonadism, part II: etiology, pathophysiology, and diagnosis [review]. Int J Impot Res 2006; 18: 223–228. | Article | PubMed | ChemPort |
13. 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 [reprint of Int J Androl 2005; 28: 125–127]. J Androl 2006; 27: 135–137. | Article | PubMed | ChemPort |
14. Tenover JS. Effects of testosterone supplementation in the aging male. J Clin Endocrinol Metab 1992; 75: 1092–1098. | Article | PubMed | ISI | ChemPort |
15. Rhoden EL, Morgentaler A. Risks of testosterone-replacement therapy and recommendations for monitoring [review]. N Engl J Med 2004; 350: 482–492. | Article | PubMed | ISI | ChemPort |
16. Huggins C, Hodges CV. Studies on prostatic cancer, I: the effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate [reprinted by: J Urol 2002; 167: 948–951]. Cancer Res 1941; 1: 293–297. | ISI | ChemPort |
17. Barqawi A, Crawford ED. Testosterone replacement therapy and the risk of prostate cancer: is there a link [review]? Int J Impot Res 2006; 18: 323–328. | Article | PubMed | ChemPort |
18. Bhasin S, Buckwalter JG. Testosterone supplementation in older men: a rational idea whose time has not yet come. J Androl 2001; 22: 718–731. | PubMed | ISI | ChemPort |
19. Gould DC, Kirby RS. Testosterone replacement therapy for late onset hypogonadism: what is the risk of inducing prostate cancer [review]? Prostate Cancer Prostatic Dis 2006; 9: 14–18. | Article | PubMed | ChemPort |
20. Gruenewald DA, Matsumoto AM. Testosterone supplementation therapy for older men: potential benefits and risks. J Am Geriatr Soc 2003; 51: 101–115. | Article | PubMed | ISI |
21. Kaufman J. A rational approach to androgen therapy for hypogonadal men with prostate cancer [review]. Int J Impot Res 2006; 18: 26–31. | Article | PubMed | ChemPort |
22. Slater S, Oliver RTD. Testosterone: its role in development of prostate cancer and potential risk from use as hormone replacement therapy. Drugs Aging 2000; 17: 431–439. | Article | PubMed | ISI | ChemPort |
23. Miner MM, Seftel AD. Testosterone and ageing: what have we learned since the institute of medicine report and what lies ahead? Int J Clin Pract 2007; 61: 622–632. | Article | PubMed | ChemPort |
24. Morgentaler A. Testosterone therapy for men at risk for or with history of prostate cancer. Curr Treat Options Oncol 2006; 7: 363–369. | Article | PubMed |
25. Liverman CT, Blazer DG eds. Testosterone and Aging: Clinical Research Directions. National Academies Press: Washington, DC, 2004.
26. 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. | Article | PubMed | ISI | ChemPort |
27. Bhasin S, Storer TW, Asbel-Sethi N, Kilbourne A, Hays R, Sinha-Hikim I et al. Effects of testosterone replacement with a nongenital, transdermal system, Androderm, in human immunodeficiency virus-infected men with low testosterone levels. J Clin Endocrinol Metab 1998; 83: 3155–3162. | Article | PubMed | ISI | ChemPort |
28. 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; 56A: M266–M272.
29. 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: a randomized controlled trial. JAMA 2006; 296: 2351–2361. | Article | PubMed | ChemPort |
30. Okun MS, Fernandez HH, Rodriguez RL, Romrell J, Suelter M, Munson S et al. Testosterone therapy in men with Parkinson disease: results of the TEST-PD Study. Arch Neurol 2006; 63: 729–735. | Article | PubMed |
31. Sih R, Morley JE, Kaiser FE, Perry III HM, Patrick P, Ross C. Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. J Clin Endocrinol Metab 1997; 82: 1661–1667. | Article | PubMed | ISI | ChemPort |
32. 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. | Article | PubMed | ISI | ChemPort |
33. Steidle C, Schwartz S, Jacoby K, Sebree T, Smith T, Bachand R, the North American AA2500T Gel Study Group. AA2500 testosterone gel normalizes androgen levels in aging males with improvements in body composition and sexual function. J Clin Endocrinol Metab 2003; 8: 2673–2681. | Article | ChemPort |
34. Tan RS, Pu SJ. A pilot study on the effects of testosterone in hypogonadal aging male patients with Alzheimer's disease. Aging Male 2003; 6: 13–17. | Article | PubMed | ChemPort |
35. Wittert GA, Chapman IM, Haren MT, Mackintosh S, 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; 58A: 618–625.
36. Gaylis FD, Lin DW, Ignatoff JM, Amling CL, Tutrone RF, Cosgrove DJ. Prostate cancer in men using testosterone supplementation. J Urol 2005; 174: 534–538. | Article | PubMed | ISI | ChemPort |
37. Arver S, Dobs AS, Meikle AW, Caramelli KE, Rajaram L, Sanders SW et al. Long-term efficacy and safety of a permeation-enhanced testosterone transdermal system in hypogonadal men. Clin Endocrinol 1997; 47: 727–737. | Article | ISI | ChemPort |
38. Behre HM, Nieschlag E. Testosterone buciclate (20 Aet-1) in hypogonadal men: pharmacokinetics and pharmacodynamics of the new long-acting androgen ester. J Clin Endocrinol Metab 1992; 75: 1204–1210. | Article | PubMed | ISI | ChemPort |
39. Dobs AS, Meikle AW, Arver S, Sanders SW, Caramelli KE, Mazer NA. 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 1999; 84: 3469–3478. | Article | PubMed | ISI | ChemPort |
40. Douglas TH, Connelly RR, McLeod DG, Erickson SJ, Barren III R, Murphy GP. Effect of exogenous testosterone replacement on prostate-specific antigen and prostate-specific membrane antigen levels in hypogonadal men. J Surg Oncol 1995; 59: 246–250. | Article | PubMed | ISI | ChemPort |
41. El-Sakka AI, Hassoba HM, Elbakry AM, Hassan HA. Prostatic specific antigen in patients with hypogonadism: effect of testosterone replacement. J Sex Med 2005; 2: 235–240. | Article | PubMed | ChemPort |
42. Gooren LJG. A ten-year safety study of the oral androgen testosterone undecanoate. J Androl 1994; 15: 212–215. | PubMed | ISI | ChemPort |
43. Katznelson L, Finkelstein JS, Schoenfeld DA, Rosenthal DI, Anderson EJ, Klibanski A. Increase in bone density and lean body mass during testosterone administration in men with acquired hypogonadism. J Clin Endocrinol Metab 1996; 81: 4358–4365. | Article | PubMed | ISI | ChemPort |
44. McNicholas TA, Dean JD, Mulder H, Carnegie C, Jones NA. A novel testosterone gel formulation normalizes androgen levels in hypogonadal men, with improvements in body composition and sexual function. BJU Int 2003; 91: 69–74. | Article | PubMed | ISI | ChemPort |
45. Meikle AW, Arver S, Dobs AS, Adolfsson J, Sanders SW, Middleton RG et al. Prostate size in hypogonadal men treated with a nonscrotal permeation-enhanced testosterone transdermal system. Urology 1997; 49: 191–196. | Article | PubMed | ChemPort |
46. Pechersky AV, Mazurov VI, Semiglazov VF, Karpischenko AI, Mikhailichenko VV, Udintsev AV. Androgen administration in middle-aged and ageing men: effects of oral testosterone undecanoate on dihydrotestosterone, oestradiol and prostate volume. Int J Androl 2002; 25: 119–125. | Article | PubMed | ChemPort |
47. Snyder PJ, Peachey H, Berlin JA, Hannoush P, Haddad G, Dlewati A et al. Effects of testosterone replacement in hypogonadal men. J Clin Endocrinol Metab 2000; 85: 2670–2677. | Article | PubMed | ISI | ChemPort |
48. Von Eckardstein S, Nieschlag E. Treatment of male hypogonadism with testosterone undecanoate injected at extended intervals of 12 weeks: a phase II study. J Androl 2002; 23: 419–425. | PubMed | ISI | ChemPort |
49. Wang C, Swerdloff RS, Iranmanesh A, Dobs A, Snyder PJ, Cunningham G et al. Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. J Clin Endocrinol Metab 2000; 85: 2839–2853. | Article | PubMed | ISI | ChemPort |
50. 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 mineral density in hypogonadal men. J Clin Endocrinol Metab 2004; 89: 2085–2098. | Article | PubMed | ISI | ChemPort |
51. Swerdloff RS, Wang C. Three-year follow-up of androgen treatment in hypogonadal men: preliminary report with testosterone gel. Aging Male 2003; 6: 207–211. | Article | PubMed | ChemPort |
52. Guay AT, Perez JB, Fitaihi WA, Vereb M. Testosterone treatment in hypogonadal men: prostate-specific antigen level and risk of prostate cancer. Endocr Pract 2000; 6: 132–138. | PubMed | ChemPort |
53. Hajjar RR, Kaiser FE, Morley JE. Outcomes of long-term testosterone replacement in older hypogonadal males: a retrospective analysis. J Clin Endocrinol Metab 1997; 82: 3793–3796. | Article | PubMed | ISI | ChemPort |
54. Rhoden EL, Morgentaler A. Testosterone replacement therapy in hypogonadal men at high risk for prostate cancer: results of 1 year of treatment in men with prostatic intraepithelial neoplasia. J Urol 2003; 170: 2348–2351. | Article | PubMed | ISI | ChemPort |
55. Rhoden EL, Morgentaler A. Influence of demographic factors and biochemical characteristics on the prostate-specific antigen (PSA) response to testosterone replacement therapy. Int J Impot Res 2006; 18: 201–205. | Article | PubMed | ChemPort |
56. Gerstenbluth RE, Maniam PN, Corty EW, Seftel AD. Prostate-specific antigen changes in hypogonadal men treated with testosterone replacement. J Androl 2002; 23: 922–926. | PubMed | ISI |
57. Bydder SA, Joseph DJ, Weinstein S, Stuckey BGA. Prostate cancer following testosterone replacement in Klinefelter syndrome [case report]. ANZ J Surg 2007; 77: 93–94. | Article | PubMed |
58. Hwang JJ, Dharmawardana PG, Uchio EM, Wynberg J, Phillips JL. Prostate cancer in Klinefelter syndrome during hormonal replacement therapy. Urology 2003; 62: 941iv–941vi. | Article |
59. Curran MJ, Bihrle III W. Dramatic rise in prostate-specific antigen after androgen replacement in a hypogonadal man with occult adenocarcinoma of the prostate. Urology 1999; 53: 423–424. | Article | PubMed | ISI | ChemPort |
60. Ferri M, Norman RW. Prostate cancer in a hypogonadal male receiving androgen supplementation [case report]. Can J Urol 2000; 7: 1055–1056. | PubMed | ChemPort |
61. Halland A, Jønler M, Pedersen KV. Prostate cancer after exogenous testosterone replacement therapy in a patient with pituitary insufficiency [case report]. Scand J Urol Nephrol 2005; 39: 87–88. | Article | PubMed |
62. Jackson JA, Waxman J, Spiekerman AM. Prostatic complications of testosterone replacement therapy. Arch Intern Med 1989; 149: 2365–2366. | Article | PubMed | ISI | ChemPort |
63. Loughlin KR, Richie JP. Prostate cancer after exogenous testosterone treatment for impotence. J Urol 1997; 157: 1845. | Article | PubMed | ISI | ChemPort |
64. Sandeman TF. Impotence, androgens and prostate cancer [letter]. Med J Aust 1998; 169: 400. | PubMed | ChemPort |
65. Ferreira U, Leitao VA, Denardi F, Matheus WE, Stopiglia RM, Netto Jr NR. Intermittent androgen replacement for intense hypogonadism symptoms in castrated patients. Prostate Cancer Prostatic Dis 2006; 9: 39–41. | Article | PubMed | ChemPort |
66. Sarosdy MF. Testosterone replacement for hypogonadism after treatment of early prostate cancer with brachytherapy. Cancer 2007; 109: 536–541. | Article | PubMed | ChemPort |
67. Agarwal PK, Oefelein MG. Testosterone replacement therapy after primary treatment for prostate cancer. J Urol 2005; 173: 533–536. | Article | PubMed | ISI | ChemPort |
68. Kaufman JM, Graydon RJ. Androgen replacement after curative radical prostatectomy for prostate cancer in hypogonadal men. J Urol 2004; 172: 920–922. | Article | PubMed | ISI | ChemPort |
69. Morgentaler A, Rhoden EL. Prevalence of prostate cancer among hypogonadal men with prostate-specific antigen levels of 4.0 ng/mL or less. Urology 2006; 68: 1263–1267. | Article | PubMed |
70. Pacelli A, Bostwick DG. Clinical significance of high-grade prostatic intraepithelial neoplasia in transurethral resection specimens. Urology 1997; 50: 355–359. | Article | PubMed | ISI | ChemPort |
71. Lefkowitz GK, Taneja SS, Brown J, Melamed J, 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 2002; 168: 1415–1418. | Article | PubMed | ISI |
72. Gore JL, Shariat SF, Miles BJ, Kadmon D, Jiang N, Wheeler TM et al. Optimal combinations of systematic sextant and laterally directed biopsies for the detection of prostate cancer. J Urol 2001; 165: 1554–1559. | Article | PubMed | ISI | ChemPort |
73. Shariat SF, Lamb DJ, Iyengar RG, Roehrborn CG, Slawin KM. A herbal/hormonal dietary supplement: an association with prostate cancer progression? Clin Cancer Res 2008; 14: 607–611. | Article | PubMed | ChemPort |
74. Endogenous Hormones and Prostate Cancer Collaborative Group. Endogenous sex hormones and prostate cancer: a collaborative analysis of 18 prospective studies. J Natl Cancer Inst 2008; 100: 170–183. | Article | PubMed | ChemPort |