In my earlier years of prescribing testosterone replacement therapies, I encountered many patients who had concomitant prostate disease and androgen deficiency symptoms. A few patients in particular, chose against prostate interventions, yet began or continued androgen therapy. Contrary to my expectations, these patients’ prostate conditions collectively improved. Observing their cases turbulently challenged my beliefs about the influence androgens have on prostate disease. I believed at the time, as I was taught in medical school, that androgens worsen prostate disease. Since my observations did not harmonize with my mechanistic understanding of this condition, I sought a new understanding.
I researched this topic to a great extent and discovered that the historical and current medical data did not support the prevailing medical belief that health care providers have about androgens and prostate disease. The medical literature does not indicate that androgens worsen or cause prostate disease.The shocking paradox that I discovered has motivated me to dedicate myself to share this valuable information with as many people as possible. Furthermore, I found that treating patients with this different understanding provided me better results, in terms of patient quality of life and organic disease progression. I felt that liberating androgens from the culprit position of prostate disease has allowed me to focus on different and more meaningful treatment interventions. In December of 2008, I wrote and published a book on the topic entitled, Demystifying Steroids. After my personal shocking realization of the data, I challenge current health care providers to assess their treatments that they offer prostate cancer patients in a hierarchical format based on the medical literature. At the very least, I believe that other health care providers should be aware of the research that supports this divergent understanding of prostate disease and offer patients all of the options listed within this article, such as watchful waiting.
Recognizing that involving patients in the decision making process increases therapeutic compliance and satisfaction with the health outcomes, my purpose of this article is to educate the reader and stimulate discussion between those concerned about prostate cancer and their healthcare provider (Garraway, Collins et al. 1991).
The medical literature employs various jargons to represent therapies that reduce testosterone concentrations in patients’ bodies. To improve the simplicity of this article, the following terms that appear in the referenced medical literature are treated synonymously: androgen ablation therapy (AAT), androgen deprivation therapy (ADT), primary androgen ablation therapy (PADT). Androgen deprivation therapy (ADT) will be primarily used to communicate this type of treatment in this article. This treatment may be accomplished with either surgery or medications.
- Most men with prostate cancer harbor indolent disease.
- Physicians and patients have an inappropriate urgency in regard to prostate cancer diagnosis and treatment.
- Evidence suggests prostate cancer screening does not reduce the rate of death and there is significant burden from screening.
- Widespread prostate cancer screening and subsequent urgent treatment leads to significant over-treatment in men with prostate cancer.
- Androgen deprivation therapy, a commonly used medical treatment for prostate cancer, has known severe limitations to improve, treat, manage or cure prostate cancer.
- Androgen deprivation therapy is associated with harsh adverse effects that may cause more widespread illness than the disease of prostate cancer.
- Androgen ablation therapy is not a logical therapeutic option for the widespread use in prostate cancer in the context of current medical literature.
- Androgen ablation therapy is expensive.
- Low levels of testosterone are associated with more prevalent and severe prostate cancer disease.
- Testosterone therapy does not increase the risk of prostate cancer.
- Testosterone therapy may have the potential to reduce illness and improve the organic disease of prostate cancer.
- The opposite therapy of androgen ablation, testosterone therapy, seems to be the better, more sensible treatment direction for future research when all of the evidence is reviewed.
The evidence for the natural history of prostate cancer shows most men identified with prostate cancer harbor indolent prostate disease and relatively few men with well differentiated disease die from prostate cancer (Albertsen 2009). These facts are a sharp contrast to the prevalent impression that all prostate cancers are rapidly progressing diseases that cause pain and cachexia that lead to death (Albertsen 2009). Many men never show evidence of prostate cancer disease progression during their lifetime (van den Bergh, Roemeling et al. 2009).
“Although men with these cancers are likely to die as a result of other causes, the majority of them are currently treated” (Roemeling, Roobol et al. 2006).
Physicians and patients have an inappropriate urgency in regard to prostate cancer diagnosis and treatment. Evidence suggests that urgent intense treatment does not produce superior outcomes for patients with newly diagnosed prostate cancer. Multiple randomized trials show that simple active surveillance is comparable or better than any studied medical intervention at all. One study compared radical prostatectomy, a widely used treatment of early prostate cancer, and watchful waiting in 695 patients with newly diagnosed prostate cancer. Although radical prostatectomy reduced disease specific mortality (16 deaths due to prostate cancer in surgery group versus 31 in watchful waiting group), there was no significant difference in overall patient survival (53 versus 62 deaths respectively) between surgery and watchful waiting (Holmberg, Bill-Axelson et al. 2002). Another study involving 293 patients compared two different interventions with watchful waiting, radical prostatectomy and radiotherapy. After eight years of observation, prostate cancer-specific survival 99.2% and the overall survival was 85.4%. “Only three men died of prostate cancer, none of whom were on watchful waiting” (Roemeling, Roobol et al. 2006). A third study retrospectively analyzed 50 men with Gleason score 7 prostate cancer who were initially managed expectantly. “The 6-year cancer-specific survival was 100%, which sharply contrasted with the 68% overall survival” (van den Bergh, Roemeling et al. 2009). The authors concluded that patients with screen-detected Gleason 7 prostate cancer, active surveillance “might be an option, especially those with comorbidity and/or a short life-expectancy” (van den Bergh, Roemeling et al. 2009).
Why are doctors rushing their patients into radical treatments from early screen detected prostate cancer?
Prostate specific antigen (PSA) testing and digital rectal exam (DRE) screening has not significantly reduced the rate of death from prostate cancer in research (Andriole, Crawford et al. 2009). In addition, PSA and DRE screening creates a significant screening burden. The risk of a false-positive finding for PSA and DRE are 10.4% and 15% respectively by the 4th year. Employing the PSA test and DRE results in 4.6% and 3.9% of men that receive a significant moderately invasive surgical procedure due to a false positive finding (Croswell, Kramer et al. 2009). Physicians should educate patients about the likelihood of false positives and resulting diagnostic interventions when counseling about cancer screening (Croswell, Kramer et al. 2009).
Widespread prostate cancer screening and subsequent urgent treatments are resulting in significant over-treatment of men with prostate cancer. A recent study found “For every one patient who was cured of clinically significant disease, there were 47 patients with either indolent disease or clinically significant disease who received no benefit from treatment” (Albertsen 2009). The remaining men not only received no benefit from treatment but were also exposed to the potential harms of intervention.
Although androgen ablation therapy is growing in popularity for localized prostate cancer, it lacks data to prove its efficacy (Lu-Yao, Albertsen et al. 2008). The results from a 1999 to 2001 survey indicate androgen ablation had risen at that time to the second most common treatment approach (Cooperberg, Grossfeld et al. 2003; Lu-Yao, Albertsen et al. 2008). “Chemical and surgical castration are the two preferred modalities used to suppress testosterone production in men with prostate cancer. GnRH (gonadotropin-releasing hormone) analogues alone or in combination with an antiandrogen are the most commonly used agents in the contemporary era” (Schwandt and Garcia 2009). Despite this progressive rise in popularity, data has not shown a benefit to androgen ablation in all types of prostate cancer (van der Poel 2009).
Androgen ablation therapy in the form medical or surgical castration may induce temporary subsidence of manifestations of prostate cancer, nevertheless “the development of castration-resistant disease is inevitable” with this treatment (Chi, Bjartell et al. 2009).
The researchers of a monumental ten year study comparing treatments in 19,271 men concluded that, “Primary androgen deprivation therapy is not associated with improved survival among the majority of elderly men with localized prostate cancer when compared with conservative management” (Lu-Yao, Albertsen et al. 2008).
Even more recent, androgen deprivation therapy was compared to observation in 16,535 men with organ-confined prostate cancer in the Surveillance, Epidemiology, and End Results (SEER) Medicare data and concluded that androgen ablation therapy did not improve survival (Wong, Freedland et al. 2009).
Not only does androgen deprivation therapy compromise overall survival, “use of ADT in men with prostate cancer is associated with numerous side effects that reduce quality of life” (Schwandt and Garcia 2009).
Androgen deprivation therapy causes more widespread illness than the disease of prostate cancer, which it aims to treat. The previously mentioned large, population-based SEER study suggests that primary androgen deprivation therapy results in worse outcomes for patients with prostate cancer compared to patients only under observation (Wong, Freedland et al. 2009).
Other studies support this finding by demonstrating that androgen deprivation therapy is associated with a high risk of experiencing harsh adverse effects.
“…a growing body of literature now demonstrates that chronic ADT use has been associated with ~10–50% increases in the risks of fracture, diabetes, coronary heart disease, myocardial infarction and sudden cardiac death, in addition to adverse effects on fat mass, cholesterol, and quality of life. There were 500% increases in the risk of gynecomastia and hot flashes in the Prostate Cancer Outcomes Study (PCOS), and a 267% increase in impotence was observed after one year of treatment” (Lu-Yao, Albertsen et al. 2008).
Additionally, it seems to be a common perception that these severe adverse effects may only occur after a prolonged period of androgen ablation therapy, but that is not the case. For example, the “increased risk for serious cardiovascular disease becomes evident within months of beginning ADT” (Kintzel, Chase et al. 2008). Therefore, the risks of adverse effects begin relatively quickly with androgen ablation therapy.
Considering the lack of clinical effect and harsh adverse effects associated with androgen ablation therapy, it is not that surprising that the SEER study found patients who underwent this therapy experienced worse outcomes compared to observation. Androgen ablation therapy potentially results in the summation of adverse effects of ablation therapy and the symptoms of prostate cancer, because androgen ablation therapy does not cure prostate cancer, it only delays it.
The combination of harsh adverse effects from androgen ablation therapy, significant over-treatment of men with indolent prostate disease and no beneficial results of androgen ablation therapy for 80% of men with significant prostate cancer disease (Albertsen 2009) is disturbing. In the light of unproven benefit and excessive risk of serious adverse effects, there is no justification for continuing to expose a large asymptomatic patient population to androgen ablation treatments. Likewise, the theory that supports this type of treatment for prostate cancer should be abandoned. “This historical perspective reveals that there is not now-nor has there ever been-a scientific basis for the belief that T causes pCA to grow. Discarding this modern myth will allow exploration of alternative hypotheses regarding the relationship of T and pCA that may be clinically and scientifically rewarding” (Morgentaler 2006).
In addition, androgen ablation therapy is costly. “The costs associated with ADT medication use in the US exceeded 1 billion dollars in 2001 and ADT drugs represented the second highest Medicare Part B drug expenditure” (Lu-Yao, Albertsen et al. 2008). The considerable cost of androgen ablation therapy, adverse effects that must be endured and further managed and lack of beneficial results do not make this therapy cost effective for prostate cancer.
After careful review of the medical data, it has been hypothesized that declining levels rather than high levels of anabolic steroids are major contributors to prostate cancer (Prehn 1999). The data previously presented on low levels of testosterone and medical research specifically comparing high and low testosterone levels supports this new hypothesis of anabolic steroids and prostate cancer.
Low testosterone levels are associated with more severe prostate disease rather than high serum testosterone levels (Isbarn, Pinthus et al. 2009). A higher prevalence of occult prostate cancer has been identified in men with low anabolic steroid levels (Morgentaler, Bruning et al. 1996). In a study involving 238 patients, prostate cancer patients were compared with controls and found to have lower serum anabolic steroids (Hulka, Hammond et al. 1987). A study involving 345 hypogonadal men demonstrated more severe reductions in serum steroids are associated with an increased risk of prostate cancer (Morgentaler and Rhoden 2006). In another study of 117 men, low testosterone was found to be correlated with more extensive and progressive disease (Hoffman, DeWolf et al. 2000). In men with newly diagnosed prostate cancer, low serum anabolic steroid levels are associated with higher tumor microvessel and Gleason score signifying enhanced malignant potential (Schatzl, Madersbacher et al. 2003). A review study of 879 patients treated by radical prostectomy demonstrated low pretreatment testosterone levels increased the likelihood of extraprostatic disease in patients with localized prostate cancer (Massengill, Sun et al. 2003). In 144 patients with advanced prostate cancer, low serum steroid levels resulted in more aggressive disease and a poorer prognosis with a significant influence on overall survival (Ribeiro, Ruff et al. 1997). A different study involving radical prostectomy procedures showed low testosterone levels predict failure of prostate cancer treatment (Yamamoto, Yonese et al. 2007). “Worrisome features of prostate cancer such as high Gleason score, extracapsular disease and biochemical recurrence after surgery have been reported in association with low but not high testosterone” (Morgentaler 2009).
Furthermore, research shows that sex hormone binding globulin (SHBG) is significantly higher in prostate cancer patients and a “highly accurate predictor of lymph node metastasis”(Isbarn, Pinthus et al. 2009). Since high levels of SHBG are associated with low levels of testosterone, this research seem to support the idea that low androgen levels are related to poor prostate cancer outcomes (Isbarn, Pinthus et al. 2009).
Even in the context of androgen deprivation therapy, men with lower testosterone level experience worse health related quality of life (Dacal, Sereika et al. 2006).
Testosterone therapy does not increase the risk of prostate cancer. Evidence suggests that testosterone therapy does not increase the risk of developing prostate cancer nor that it converts indolent prostate disease into clinically significant disease (Isbarn, Pinthus et al. 2009). “This historical perspective reveals that there is not now–nor has there ever been–a scientific basis for the belief that testosterone causes prostate cancer to grow” (Morgentaler 2006). “There is no clinical evidence that the risk of either prostate cancer or benign prostate hyperplasia increases with testosterone replacement therapy”(Morley 2000). “No evidence exists that appropriate androgen administration with knowledgeable monitoring carries significant or potentially serious adverse effects on the prostate gland” (Morales 2005). These medical journal research reviews unanimously agree that testosterone does not cause prostate cancer.
Medical studies involving anabolic steroids have failed to show prostate conditions or even prostate markers worsen with anabolic steroid treatment. Elevated anabolic steroid levels induced in men younger than 40 years of age have not shown a significant increase in prostate problems, prostate size or prostate-specific antigen (PSA) in multiple studies, even at supraphysiological doses (Cooper, MacIndoe et al. 1996; Cooper, Perry et al. 1998; Bhasin, Woodhouse et al. 2001). In fact, Cooper et al. concluded in their study that “Serum PSA is not responsive to elevated serum testosterone levels in healthy young men” (Cooper, MacIndoe et al. 1996). 187 hypogonadal male subjects above 45 years of age treated with anabolic steroids experienced no significant change in PSA or prostate disease after one year of therapy (El-Sakka, Hassoba et al. 2005). In a randomized, double-blind, placebo-controlled trial, 44 hypogonadal men aged 44 to 78 years received anabolic steroids or matching placebo for 6 months. Prostate biopsies performed before and after therapy showed no treatment-related change in prostate histology, tissue biomarkers, gene expression, or cancer incidence or severity (Marks, Mazer et al. 2006). Eleven hypogonadal men with a median age of 36 years were treated with anabolic steroid trans-scrotal patches for 7 to 10 years. No relevant changes occurred in clinical chemistry, hemoglobin and erythrocyte counts, prostate volume or prostate disease, and bone density increased slightly during the observation period. Prostate-specific antigen levels were constantly low in all patients, and the authors concluded long-term anabolic steroid therapy for male hypogonadism is safe (Behre, von Eckardstein et al. 1999). A placebo-controlled study in 13 hypogonadal men aged 57 to 76 years old demonstrated three months of anabolic steroid treatments resulted in an increase in lean body mass, no increase in prostate disease and possibly a decline in bone resorption. The authors also observed some effect on serum lipoproteins, hematological parameters, and only a slight sustained increase in serum PSA levels (Tenover 1992). A short- term study on men over 70 years of age showed no ill effects on prostate size, symptoms or PSA levels with either transdermal or intramuscular anabolic steroid treatment (Kenny, Prestwood et al. 2000). The longer-follow up investigation of the previously mentioned study showed no significant increase of PSA levels after one year of transdermal anabolic steroid use and resulted in no change in signs or symptoms of prostate hyperplasia (Kenny, Prestwood et al. 2001). One year of anabolic steroid treatments in 48 hypogonadal men resulted in a mild increase in most of the hypogonadal men’s PSA values without observation of increased prostate disease (Rhoden and Morgentaler 2006).
Another study monitored 81 hypogonadal men for a mean of 34 months taking testosterone therapy and showed normalized testosterone levels, improved cardiovascular effect, improved sexual function and better overall quality of life. The incidence of prostate cancer among men with hypogonadism receiving testosterone treatment “is no greater than that of the general population” (Coward, Simhan et al. 2009).
Since testosterone trials have failed to show any significant increase in prostate cancer rates, testosterone therapy “may not even be harmful in men undergoing surveillance for low-risk PCa” (Isbarn, Pinthus et al. 2009)
In men at high risk for developing prostate cancer (with and without a history of high grade prostatic intraepithelial neoplasia), anabolic steroid treatments were provided for 12 months. Of the 75 men, prostate cancer was identified with biopsy in one man and represents a 1.3% prostate cancer risk overall, which is not beyond the population background prevalence. The results do not suggest an abrupt increase of prostate cancer growth or development in patients administered anabolic steroid therapy. Thus, anabolic steroid treatments are not contraindicated in men with this type of high risk for developing prostate cancer (Rhoden and Morgentaler 2003).
Testosterone therapy in men with previous prostate cancer did not produce increased disease recurrence. No ill effects from anabolic steroid administration in hypogonadal men previously treated for prostate cancer were observed for periods up to 12 years in 17 men, including prostate cancer recurrence (Kaufman and Graydon 2004). Patients with organ-confined prostate cancer after radical prostatectomy experienced no PSA recurrences or increases after a median of 19 months of anabolic steroid therapy (Agarwal and Oefelein 2005). 31 hypogonadal men received anabolic steroid treatments after prostate brachytherapy for a median of 4.5 years without cancer recurrence or documented cancer progression (Sarosdy 2007).
A 52-year-old man after radical prostatectomy was given adjuvant external beam radiation and LH-RH agonist therapy for PSA level recurrence. The treatment and disease progression resulted in sustained loss of libido, hot flashes and depression. After 16 months of no PSA recurrence, he was treated with anabolic steroids, which produced significant relief of symptoms and no increase in PSA. Sustained anabolic steroids were required to alleviate the patient’s symptoms (Brawer 2004).
“In another case, a 63-year-old man with prostate cancer and PSA 5.0 ng/ml underwent radical prostatectomy with findings of Gleason 7/10 and one seminal vesicle involved with cancer. He then received three successive 3-month gosereline injections and adjuvant radiotherapy. One year after surgery he complained of poor libido and hot flushes; PSA was undetectable but serum testosterone was in the castrate range at 28ng/dl. At 3 months, when PSA remained undetectable and testosterone still measured only 45ng/dl, he was started on 1% testosterone gel 5 g/day. Hypogonadal symptoms improved rapidly, and at follow-up, 26 months after surgery and 20 months after his last LH-RH agonist administration, he still remains hypogonadal (testosterone 194 ng/dl) and uses testosterone gel every 2 days” (Kaufman 2006).
“Despite the wide spread of contraindication of testosterone replacement in men with known or suspected PCa, there is no convincing evidence that the normalization of testosterone serum levels in men with low but no castrate levels is deleterious” (Rhoden, Averbeck et al. 2008). “The available literature suggests that testosterone therapy is reasonable for patients who have received curative therapy for prostate cancer and that testosterone therapy does not jeopardize cancer control in patients suffering from symptomatic hypogonadism” (Isbarn, Pinthus et al. 2009). One hundred and eleven men were monitored in six uncontrolled studies with testosterone therapy after surgical or radiation treatment for prostate cancer and only two experienced disease recurrence (Morgentaler 2009). “Anecdotal evidence suggests that testosterone therapy does not necessarily cause increased prostate specific antigen even in men with untreated prostate cancer” (Morgentaler 2009).
“The effectiveness of PADT in LAPC, in particular, is worthy of attention. There is a possibility that therapeutic strategies for LPC and LAPC may change dramatically in the near future” (Akaza 2006). This radical shift in therapy has been anticipated.
Higher levels of testosterone may instead be beneficial for reducing the risk of prostate cancer development. A nested case-control study involving 300 cases and 300 controls discovered men with upper quartile levels of testosterone had lower prostate cancer risk than those with lower testosterone levels (Chen, Weiss et al. 2003). A larger study involving 2,950 men found modest but significant decreases in prostate cancer risks for increasing levels of total testosterone (Stattin, Lumme et al. 2004). Accordingly, the possibility has been recognized that anabolic steroid therapy could prevent prostate cancer occurrence and reduce the growth of androgen-independent prostate cancers (Prehn 1999; Algarte-Genin, Cussenot et al. 2004). Along these same lines, in a reply to a letter to the editor, a hypothesis stating that testosterone therapy may eradicate prostate cancer in early stages of the disease was mentioned. The idea to treat prostate cancer with testosterone therapy was also recognized as quite intriguing because this approach was deemed erroneous in the recent past (Isbarn 2009). Testosterone treatment could theoretically help prostate cancer because it could increase patients’ low testosterone levels that are associated with worse prostate disease.
Testosterone therapy has the potential to improve many of the recognized symptoms and signs of prostate cancer, especially ones that overlap with testosterone deficiency. Testosterone therapy is associated with many beneficial concomitant effects as opposed to other treatments for prostate cancer like androgen deprivation therapy that can cause and exacerbate the opposite effect of testosterone therapy. “Body composition changes, hyperlipidemia, insulin resistance, metabolic syndrome, and acute coronary syndrome are all reported adverse effects of ADT, which are consequences of reduced levels of circulating testosterone” (Kintzel, Chase et al. 2008). Studies that administered testosterone to men with prostate cancer are limited, but demonstrate no cancer progression in non-castrated men while improving sense of well-being, pain, appetite, fatigue and weight gain (Brendler, Chase et al. 1950; Trunnell and Duffy 1950; Prout and Brewer 1967). Although 67 patients with metastatic adenocarcinoma of the prostate were administered anabolic steroids and analyzed in this next study, only four patients had not had additional therapies such as castration or estrogen treatment. However, these four men experienced no negative effects from the anabolic steroid treatments, and some experienced symptomatic benefits. These four men continued to receive daily testosterone injections for as long as 310 days (Fowler and Whitmore 1981). More recently, a single case report of two years of testosterone treatment resulted in a reduction of serum prostate specific antigen (PSA) in a man with untreated prostate cancer. The case makes available support for the concept that prostate cancer growth may not necessarily be propagated by testosterone therapy outside of castrate or near castrate serum testosterone values (Morgentaler 2009). Data regarding these issues are limited and based on a relatively small number of subjects. Thus guidelines that dictate testosterone therapy’s restricted use in prostate cancer should be re-examined and large prospective studies addressing the long-term effect of testosterone therapy are overdue and needed to accurately construct meaningful guidelines (Isbarn, Pinthus et al. 2009).
Since androgen receptors have been shown to upregulate in tumors, continued efforts targeting and inhibiting androgen synthesis has been identified as a valuable strategy in prostate cancer research (Bellmunt, Rosenberg et al. 2009). However, I propose that androgen receptor upregulation could also be viewed as the body’s intelligent attempt to restore homeostasis of the involved prostate cells that function best with androgen stimulation. Depriving prostate cells of anabolic steroids, even cancerous cells, may be opposite to an action that produces an optimal outcome. It should be recognized that anabolic steroids also stimulate growth and propagation of other cells responsible for fighting, containing and eliminating all types of cancer cells. For cancer to propagate, it seems that a breakdown of these defensive and immune cells is required and that anabolic steroid deficiency may contribute to the process. On the other hand, anabolic steroid treatments restore and optimize both intracellular and extracellular communication in the human body. With all of the data presented in this article and testosterone’s inability to stimulate of prostate cancer, research continuing to focus on the androgen receptor seems discouraging.
The improved outcomes associated with intermittent hormone therapy (IHT) (Calais da Silva, Bono et al. 2009) could provide limited evidence for the hypothesis that testosterone levels directly influence treatment efficacy and quality of life outcomes . The improvement of IHT compared to ADT be explained by a large continuum that ranges from complete ADT to elevated levels of testosterone, with the best outcomes associated with the latter. Time and future research will tell.
Performing a large, long-term anabolic steroid trial designed to monitor for prostate cancer is necessary to answer these questions about the potential preventive and treatment benefits of anabolic steroids, but most available evidence suggests that possibility.
Previously, the predominate mindset of health care practitioners has been that widespread screening, early diagnosis of prostate cancer, subsequent prompt aggressive medical treatments and androgen reduction treatments were wise. These practices were never originally established with appropriate data. The realization of the world prevalence of such inappropriate medical practices may serve as a powerful lesson in the importance of evidence based medicine. The irony is that recent evidence has not only proven against these practices, but supported medical practices in their opposition, such as increasing testosterone in men with prostate cancer.
Agarwal, P. K. and M. G. Oefelein (2005). “Testosterone replacement therapy after primary treatment for prostate cancer.” J Urol 173(2): 533-6.
Akaza, H. (2006). “Trends in primary androgen depletion therapy for patients with localized and locally advanced prostate cancer: Japanese perspective.” Cancer Sci 97(4): 243-7.
Albertsen, P. (2009). “Lies, Damn Lies, and Cancer Statistics.” Eur Urol.
Algarte-Genin, M., O. Cussenot, et al. (2004). “Prevention of prostate cancer by androgens: experimental paradox or clinical reality.” Eur Urol 46(3): 285-94; discussion 294-5.
Andriole, G. L., E. D. Crawford, et al. (2009). “Mortality results from a randomized prostate-cancer screening trial.” N Engl J Med 360(13): 1310-9.
Behre, H. M., S. von Eckardstein, et al. (1999). “Long-term substitution therapy of hypogonadal men with transscrotal testosterone over 7-10 years.” Clin Endocrinol (Oxf) 50(5): 629-35.
Bellmunt, J., J. E. Rosenberg, et al. (2009). “Recent Progress and Pitfalls in Testing Novel Agents in Castration-Resistant Prostate Cancer.” Eur Urol.
Bhasin, S., L. Woodhouse, et al. (2001). “Testosterone dose-response relationships in healthy young men.” Am J Physiol Endocrinol Metab 281(6): E1172-81.
Brawer, M. K. (2004). “Testosterone replacement therapy for a man with prostate cancer.” Rev Urol 6 Suppl 6: S35-7.
Brendler, H., W. E. Chase, et al. (1950). “Prostatic cancer: further investigations of hormonal relationships.” Arch Surg 61: 433-440.
Calais da Silva, F. E., A. V. Bono, et al. (2009). “Intermittent androgen deprivation for locally advanced and metastatic prostate cancer: results from a randomised phase 3 study of the South European Uroncological Group.” Eur Urol 55(6): 1269-77.
Chen, C., N. S. Weiss, et al. (2003). “Endogenous sex hormones and prostate cancer risk: a case-control study nested within the Carotene and Retinol Efficacy Trial.” Cancer Epidemiol Biomarkers Prev 12(12): 1410-6.
Chi, K. N., A. Bjartell, et al. (2009). “Castration-resistant Prostate Cancer: From New Pathophysiology to New Treatment Targets.” Eur Urol.
Cooper, C. S., J. H. MacIndoe, et al. (1996). “The effect of exogenous testosterone on total and free prostate specific antigen levels in healthy young men.” J Urol 156(2 Pt 1): 438-41; discussion 441-2.
Cooper, C. S., P. J. Perry, et al. (1998). “Effect of exogenous testosterone on prostate volume, serum and semen prostate specific antigen levels in healthy young men.” J Urol 159(2): 441-3.
Cooperberg, M. R., G. D. Grossfeld, et al. (2003). “National practice patterns and time trends in androgen ablation for localized prostate cancer.” J Natl Cancer Inst 95(13): 981-9.
Coward, R. M., J. Simhan, et al. (2009). “Prostate-specific antigen changes and prostate cancer in hypogonadal men treated with testosterone replacement therapy.” BJU Int 103(9): 1179-83.
Croswell, J. M., B. S. Kramer, et al. (2009). “Cumulative incidence of false-positive results in repeated, multimodal cancer screening.” Ann Fam Med 7(3): 212-22.
Dacal, K., S. M. Sereika, et al. (2006). “Quality of life in prostate cancer patients taking androgen deprivation therapy.” J Am Geriatr Soc 54(1): 85-90.
El-Sakka, A. I., H. M. Hassoba, et al. (2005). “Prostatic specific antigen in patients with hypogonadism: effect of testosterone replacement.” J Sex Med 2(2): 235-40.
Fowler, J. E., Jr. and W. F. Whitmore, Jr. (1981). “The response of metastatic adenocarcinoma of the prostate to exogenous testosterone.” J Urol 126(3): 372-5.
Garraway, W. M., G. N. Collins, et al. (1991). “High prevalence of benign prostatic hypertrophy in the community.” Lancet 338(8765): 469-71.
Hoffman, M. A., W. C. DeWolf, et al. (2000). “Is low serum free testosterone a marker for high grade prostate cancer?” J Urol 163(3): 824-7.
Holmberg, L., A. Bill-Axelson, et al. (2002). “A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer.” N Engl J Med 347(11): 781-9.
Hulka, B. S., J. E. Hammond, et al. (1987). “Serum hormone levels among patients with prostatic carcinoma or benign prostatic hyperplasia and clinic controls.” Prostate 11(2): 171-82.
Isbarn, H. (2009). “Reply to A. Edward Friedman’s Letter to the Editor re: Hendrik Isbarn, Jehonathan H. Pinthus, Leonard S. Marks, et al. Testosterone and Prostate Cancer: Revisiting Old Paradigms. Eur Urol 2009; 56: 48-56.” European Urology In Press, Uncorrected Proof.
Isbarn, H., J. H. Pinthus, et al. (2009). “Testosterone and Prostate Cancer: Revisiting Old Paradigms.” Eur Urol.
Kaufman, J. (2006). “A rational approach to androgen therapy for hypogonadal men with prostate cancer.” Int J Impot Res 18(1): 26-31.
Kaufman, J. M. and R. J. Graydon (2004). “Androgen replacement after curative radical prostatectomy for prostate cancer in hypogonadal men.” J Urol 172(3): 920-2.
Kenny, A. M., K. M. Prestwood, et al. (2001). “Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels.” J Gerontol A Biol Sci Med Sci 56(5): M266-72.
Kenny, A. M., K. M. Prestwood, et al. (2000). “Short-term effects of intramuscular and transdermal testosterone on bone turnover, prostate symptoms, cholesterol, and hematocrit in men over age 70 with low testosterone levels.” Endocr Res 26(2): 153-68.
Kintzel, P. E., S. L. Chase, et al. (2008). “Increased risk of metabolic syndrome, diabetes mellitus, and cardiovascular disease in men receiving androgen deprivation therapy for prostate cancer.” Pharmacotherapy 28(12): 1511-22.
Lu-Yao, G. L., P. C. Albertsen, et al. (2008). “Survival following primary androgen deprivation therapy among men with localized prostate cancer.” JAMA 300(2): 173-81.
Marks, L. S., N. A. Mazer, et al. (2006). “Effect of testosterone replacement therapy on prostate tissue in men with late-onset hypogonadism: a randomized controlled trial.” Jama 296(19): 2351-61.
Massengill, J. C., L. Sun, et al. (2003). “Pretreatment total testosterone level predicts pathological stage in patients with localized prostate cancer treated with radical prostatectomy.” J Urol 169(5): 1670-5.
Morales, A. (2005). “Monitoring androgen replacement therapy: testosterone and prostate safety.” J Endocrinol Invest 28(3 Suppl): 122-7.
Morgentaler, A. (2006). “Testosterone and prostate cancer: an historical perspective on a modern myth.” Eur Urol 50(5): 935-9.
Morgentaler, A. (2009). “Testosterone therapy in men with prostate cancer: scientific and ethical considerations.” J Urol 181(3): 972-9.
Morgentaler, A. (2009). “Two years of testosterone therapy associated with decline in prostate-specific antigen in a man with untreated prostate cancer.” J Sex Med 6(2): 574-7.
Morgentaler, A., C. O. Bruning, 3rd, et al. (1996). “Occult prostate cancer in men with low serum testosterone levels.” Jama 276(23): 1904-6.
Morgentaler, A. and E. L. Rhoden (2006). “Prevalence of prostate cancer among hypogonadal men with prostate-specific antigen levels of 4.0 ng/mL or less.” Urology 68(6): 1263-7.
Morley, J. E. (2000). “Testosterone replacement and the physiologic aspects of aging in men.” Mayo Clin Proc 75 Suppl: S83-7.
Prehn, R. T. (1999). “On the prevention and therapy of prostate cancer by androgen administration.” Cancer Res 59(17): 4161-4.
Prout, G. R., Jr. and W. R. Brewer (1967). “Response of men with advanced prostatic carcinoma to exogenous administration of testosterone.” Cancer 20(11): 1871-8.
Rhoden, E. L., M. A. Averbeck, et al. (2008). “Androgen replacement in men undergoing treatment for prostate cancer.” J Sex Med 5(9): 2202-8.
Rhoden, E. L. and A. Morgentaler (2003). “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 170(6 Pt 1): 2348-51.
Rhoden, E. L. and A. Morgentaler (2006). “Influence of demographic factors and biochemical characteristics on the prostate-specific antigen (PSA) response to testosterone replacement therapy.” Int J Impot Res 18(2): 201-5.
Ribeiro, M., P. Ruff, et al. (1997). “Low serum testosterone and a younger age predict for a poor outcome in metastatic prostate cancer.” Am J Clin Oncol 20(6): 605-8.
Roemeling, S., M. J. Roobol, et al. (2006). “Management and survival of screen-detected prostate cancer patients who might have been suitable for active surveillance.” Eur Urol 50(3): 475-82.
Sarosdy, M. F. (2007). “Testosterone replacement for hypogonadism after treatment of early prostate cancer with brachytherapy.” Cancer 109(3): 536-41.
Schatzl, G., S. Madersbacher, et al. (2003). “Associations of serum testosterone with microvessel density, androgen receptor density and androgen receptor gene polymorphism in prostate cancer.” J Urol 169(4): 1312-5.
Schwandt, A. and J. A. Garcia (2009). “Complications of androgen deprivation therapy in prostate cancer.” Curr Opin Urol 19(3): 322-6.
Stattin, P., S. Lumme, et al. (2004). “High levels of circulating testosterone are not associated with increased prostate cancer risk: a pooled prospective study.” Int J Cancer 108(3): 418-24.
Tenover, J. S. (1992). “Effects of testosterone supplementation in the aging male.” J Clin Endocrinol Metab 75(4): 1092-8.
Trunnell, J. B. and B. J. Duffy, Jr. (1950). “The influence of certain steroids on the behavior of human prostatic cancer.” Trans N Y Acad Sci 12: 238.
van den Bergh, R. C., S. Roemeling, et al. (2009). “Gleason score 7 screen-detected prostate cancers initially managed expectantly: outcomes in 50 men.” BJU Int 103(11): 1472-7.
van der Poel, H. G. (2009). “Chemical Castration and Survival in Low-risk Prostate Cancer.” Eur Urol.
Wong, Y. N., S. J. Freedland, et al. (2009). “The Role of Primary Androgen Deprivation Therapy in Localized Prostate Cancer.” Eur Urol.
Yamamoto, S., J. Yonese, et al. (2007). “Preoperative serum testosterone level as an independent predictor of treatment failure following radical prostatectomy.” Eur Urol 52(3): 696-701.