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Cancer and Prostatic Diseases (2006) 9, 14–18 & 2006 Nature Publishing Group All rights reserved 1365-7852/06 $30.00 www.nature.com/pcan REVIEW replacement therapy for late onset : what is the risk of inducing ?

DC Gould and RS Kirby The Prostate Centre, Wimpole Street, London, UK

Prescription sales of testosterone have risen considerably over the last decade and are likely to continue to grow as further preparations become available. Testosterone promotes existing prostate cancer; however, concern does exist as to whether or not testosterone therapy induces prostate cancer. The aim of this article is to review the evidence for such a link. Prostate Cancer and Prostatic Diseases (2006) 9, 14–18. doi:10.1038/sj.pcan.4500839; published online 1 November 2005

Keywords: testosterone; ; dihydrotestosterone; hypogonadism

Late onset hypogonadism Many new formulations of testosterone utilising a variety of routes of administration from Testosterone replacement therapy (TRT) is indicated in to buccal tablets have entered the market over the past 5 hypogonadal symptomatic men, where contraindications years and testosterone prescription sales in the USA have to treatment do not exist. The International Society for grown by five-fold since 1993. the Study of the Aging Male recommends a threshold An ongoing concern is whether TRT initiates prostate level for consideration for treatment of 11 nmol/l for total cancer, influences carcinogenesis in microscopic precan- testosterone, 0.255 nmol/l for calculated free testosterone cerous foci or transforms clinically insignificant ‘latent’ and 3.8 nmol/l for bioavailable testosterone.1 prostate cancer into clinically significant cancer. The Late onset hypogonadism (the andropause, question remains unanswered even though testosterone deficiency in the adult male) which occurs mainly in therapies have been available for over 60 years and the latter half of life and identified by a spectrum of widespread use and scientific study have failed to illicit a symptoms associated with low plasma levels of andro- carcinogenic signal. gens is becoming an increasingly discussed area of men’s health and the largest potential market for TRT. Total and freely circulating plasma levels of testosterone Prostate cancer decline by 1 and 2% per annum, respectively, with some men experiencing greater declines than others due to a Prostate cancer has the highest prevalence of any non- variety of factors. Using total testosterone data, it has cancer in the human body with approximately been estimated that 21% men aged between 60 and 80 230 000 new cases and 30 000 deaths in the USA increasing to 35% of men over the age of 80 are 5,6 2 predicted for 2004. The incidence of clinically signifi- hypogonadal. This figure increases to 50% of men over cant prostate cancers has increased in the last 50 years in the age of 50 if one uses cutoff values for bioavailable 3 part due to an ageing population and greater diagnostic testosterone. testing. The aim of TRT is to normalise plasma testosterone Microscopic foci of cancer (‘latent’ cancer) are present levels. Supraphysiological levels should be avoided and in 30% men in their 50s and 70% men over the age of 80 a testosterone preparation that allows dosing and years. Essentially all men with circulating androgens will titration to within physiological plasma concentration 1,4 develop microscopic latent cancer if they live long parameters should be used. enough, but not all will progress to clinically significant cancer which develops in about 10% men. The chance of dying because of prostate cancer is about 3%. Correspondence: Dr Duncan C Gould, The Prostate Centre, 32, The incidence of ‘latent’ prostate cancer is similar in all Wimpole Street, London W1G 8GT. E-mail: [email protected] populations studied throughout the world, being inde- Received 1 July 2005; revised 22 August 2005; accepted 23 August pendent of ethnicity, androgen levels, 5 alpha-reductase 7 2005; published online 1 November 2005 activity, diet and environmental factors. TRT for late onset hypogonadism DC Gould and RS Kirby

The incidence of clinically significant disease varies terone in the prostate, induce cell division and apoptosis 15 markedly according to geography and ethnicity. Migra- and over a lifetime the large number of cell divisions tion studies have shown that men from countries of low may result in accumulation of spontaneous in incidence assume the incidence of the adopted country prostate cells. after about 25 years especially after exposure to a Once malignant transformation has become estab- western lifestyle, thus inferring an environmental causal lished, androgens play a role in stimulating malignant component in transformation of latent into clinically cell activity and division and suppression of testosterone significant cancer. Therefore, certain racial groups may levels by medical or surgical castration causes regression have a genetic predisposition to the disease, while of the cancer, at least initially. As such, treatment of environmental factors may influence the aggressiveness. hypogonadal men with testosterone in the presence of Prostate cancer is characteristically a slowly progres- suspected or confirmed prostate cancer is contraindi- sing tumour with a doubling time of 4–5 years cated. commencing possibly as foci of proliferative inflamma- tory atrophy (PIA), progressing through precancerous lesions to latent or clinically significant cancer and then beyond (Figure 1). Each stage may be dependent upon Androgen levels and prostate cancer further exogenous insult resulting in genetic mutations There is no direct correlation between serum testosterone that allow for acceleration of the malignant snowball. levels in men and the risk of developing prostate cancer. With present knowledge genetic predisposition through Indeed, high grade prostate cancer has been associated the presence of susceptibility seems to account for 12 8 with low plasma levels of testosterone however, this nearly 50% of the risk of developing cancer. may be due to a testosterone lowering effect by In addition to inherited susceptibility, others factors the presence of prostatic carcinoma.13,14 At present there including environmental, dietary, infectious and lifestyle appears to be no compelling evidence that testosterone issues have been implicated in risk and may have an 15–19 6 has a causative role in prostate cancer. Studies using accumulative effect with age. Whether cancer can arise frozen plasma showed no difference in testosterone in men without genetic susceptibility is not known. levels in men who did and did not develop prostate Epidemiological data have implicated local infection cancer 7–25 years later17–19 and it is interesting to (prostatitis and sexually transmitted disease) with note that prostate cancer becomes more prevalent exactly increased prostate cancer risk and recently it has been at the time of a man’s life when testosterone levels proposed that infection and inflammation may play a 9–11 decline. Testosterone exists in bound and unbound part in triggering carcinogenesis. states, the former as weakly and strongly bound to albumin and binding globulin (SHBG) respectively. SHBG bound testosterone is not bioavailble. The role of androgens in prostate cancer SHBG levels are inversely related to plasma testosterone levels and are affected by other factors such as obesity The precise role of androgens in terms of carcinogenesis and insulin, thyroid hormone, oestrogen and insulin-like is unclear. Androgens, primarily through dihydrotestos- growth factor levels. As higher levels of testosterone are

Normal prostate RNASEL or MRS1 germline epithelium defects or variants: MnSOD or hOGG1 variants

Infection ? TRT influence? Proliferative inflammatory atrophy

GSTP1 CpG island hypermethylation Prostatic Localised prostate cancer intraepithelial ‘latent’ neoplasia

Localised prostate cancer clinically Oxidative stress significant

Metastatic prostate cancer

Figure 1 A model of prostrate cancer pathogenesis.9

Prostate Cancer and Prostatic Diseases TRT for late onset hypogonadism DC Gould and RS Kirby

16 associated with lower levels of SHBG, the latter is However, those men treated with who did thought to be inversely correlated with prostate cancer develop prostate cancer had a greater chance of devel- risk as reported in one study using multivariate oping more aggressive cancers than those given placebo. analysis.20 The reasons for this have not as yet been fully elucidated. One study revealed that 14% of 77 hypogonadal men A placebo-controlled trial of , a dual with a mean age of 64, normal PSA values and digital inhibitor of 5 alpha-reductase (the REDUCE study) is rectal examination had prostate cancer on prostate now underway in men at increased risk of prostate biopsy prior to planned treatment with testosterone.21 cancer.23 Dutasteride inhibits both the type 1 and type 2 This figure rose to 29% when data for men over 60 were iso- of 5 alpha-reductase and reduces the analysed. Gleason scores for all cancers were 6–7. It conversion of testosterone to DHT to a greater extent seems clear therefore that a sizeable group of men being than finasteride.24 Adverse event data from three large treated for hypogonadism, who have normal PSA levels placebo-controlled studies in men with BPH reported a and rectal examination findings will have occult prostate reduction in risk of prostate cancer detection after 27 cancer. If latent cancer is present, it is therefore possible months of 51%.25 that administering testosterone may increase the chances 5 alpha-reductase inhibitors significantly reduce ser- that a proportion of these cancers progress to become um and intraprostatic DHT however plasma levels of clinically evident. testosterone increase. The reduction in prostate cancer events with these agents would indicate that DHT and not testosterone is more important in prostate cancer development at least in the early stages of the disease. To Androgen and androgen support this, ethnic differences in 5 alpha-reductase signalling activity have been reported. The activity is lower in Japanese men than in African–American men who have Inheritable differences in androgen metabolism and a higher risk of prostate cancer, inferring a higher activity androgen signalling mechanisms play a part in prostate and therefore a greater conversion of testosterone to cancer risk. DHT in the prostate is associated with an increased risk Prostate cancer and BPH never develop in men of cancer. castrated before or in men deficient in 5 alpha- reductase type II iso-, which converts testoster- one in the prostate into the more potent androgen DHT. Such men have raised plasma testosterone levels. The Indeed, the recent large placebo-controlled Prostate Cancer Prevention Trial involving over 18 000 men at low Nucleotide polymorphisms of CAG regions on exon 1 of risk of prostate cancer treated for a 7 year period has the androgen receptor are common. The number of shown that blocking the conversion of testosterone to repeat CAG sequences has been shown to correlate with DHT with the selective type two 5 alpha-reductase variability in cancer risk. African–American males have inhibitor, finasteride, reduces the detection of biopsy- shorter CAG repeats than Asian men and greater cancer proven prostate cancer by 25% indicating that reductions risk, while white men have repeat lengths in between. in DHT reduce the development of emerging cancer.22 The greater the number of CAG repeats the greater the

Table 1 Studies of testosterone therapy in which the identification of prostate cancer was reported [— indicates not placebo controlled] Study Author Duration months Increase in PSA ng/ml/no. pts Prostate cancer no. ca/no. pts Route of Administration

Placebo Testosterone Placebo Testosterone

Tenover28 3 — 0.6/13 — 0/13 i.m. Hajjar et al.29 24 0.25/15 0.5/26 0/27 0/45 i.m. Dobs et al.30 24 — 0/33 — 2/33 i.m. 24 — 0.5 — 1/33 Patch Sih et al.31 12 0.5/15 0.9/17 0/15 0/17 i.m. Guay et al.32 3 — 0.2/16 — Patch — 0.63/25 — 3 overall i.m. — 1.0/49 — clomiphene Svetec et al.33 12.8 — 0.29/49 — 0/48 i.m. Kenny et al.34 12 0.3/33 0.6/34 0/33 0/34 Patch Wang et al.35 6 — 0/76 — 0/76 Patch — 1.1/73 — 0/73 (50 mg) — 1.2/78 — 1/78 Gel (100 mg) Gooren36 120 — NA — 0/33 Oral Gerstenbluth et al.37 58 (all436) — 0.65/23 — 0/23 i.m. Snyder et al.38 36 NA 0/54 1/54 Patch Snyder et al.39 36 — NA — 0/18 Scr. patch Wang et al.40 42 — 0.26/123 — 3/123 Gel Schubert et al.41 37.5 — NA — 0/40 Nebido Feneley et al.42 p15 years — NA — 10/1500 Oral implants Rhoden et al.43 12 — 0.25(PINÀ) — 1/20(PIN+) i.m. — 0.33(PIN+) 0/55(PINÀ) Gel

Prostate Cancer and Prostatic Diseases TRT for late onset hypogonadism DC Gould and RS Kirby length of an amino-acid sequence in the androgen carcinogenesis. Dihydrotestosterone in men at risk 17 receptor protein and consequent androgen binding appears to play a part, as studies of 5-alpha reductase capacity. Shorter CAG repeat lengths confer greater inhibitors have been shown to prevent or delay prostate activity of the AR and have been associated with an cancer. increased risk and earlier onset on cancer.26,27 This may If TRT does have a carcinogenic role in early stage suggest that early tumorigenesis depends upon a more disease, then progression is likely to be very slow as active androgen receptor.10 Androgen receptor expres- prostate cancer has a doubling time of 4–5 years and cell sion is increased in the intermediate proliferating cells in death is not as outpaced by cellular proliferation as in the prostatic inflammatory atrophy (PIA) and further in later stages of prostate cancer when further genetic prostatic intraepithelial neoplasia (PIN) cells. Such mutations allow for cancer acceleration. increased expression may enable enhanced androgenic The Institute of Medicine Committee on Assessing the signalling in these early stages in cancer development. Need for Clinical Trials of Testosterone Replacement Therapy in the US recently concluded that insufficient evidence exists to justify embarking on a long-term study to determine the risks associated risks associated with Testosterone replacement therapy and testosterone replacement therapy.45 It has been estimated prostate cancer that a study would need to include 6000 elderly hypogonadal men randomly assigned to testosterone or A number of studies, some placebo-controlled, using placebo for 6 years in order to determine whether various testosterone formulations over periods ranging testosterone treatment increases the risk of prostate from several months to 15 years, have not revealed an cancer by 30%.45 Instead, the committee recommended increased risk of prostate cancer over the background 28–43 first performing short-term controlled studies of the prevalence (see Table 1). effect of testosterone on several outcomes in elderly men A recent prospective audit of hypogonadal men whose testosterone levels were below 300 ng/dl and then screened for prostate cancer prior to and during TRT 42 only if short-term studies demonstrated efficacy, per- supports this. Over a period of 15 years, 2200 men with forming a long-term study to evaluate the risk. It is, symptoms of androgen deficiency were screened for therefore, very doubtful that a definitive answer will be prostate cancer and investigated for hypogonadism. Of forthcoming within the next 10–20 years, if ever. these, 12 (0.5%) were diagnosed as having prostate In the meantime, hypogonadal symptomatic men cancer through digital rectal examination and PSA should be considered for testosterone replacement assessment. In all, 1500 of the original 2200 men had a therapy in line with published guidelines. It is important biochemical diagnosis of hypogonadism and were to exclude prostate cancer before initiation of treatment treated and followed up with digital rectal examinations and to follow-up the patient with regular prostate and PSA measurements on a 3–6 monthly basis for up to monitoring and patients should be informed that to 15 years. In all, 10 cases of cancer, all clinically localised, date definitive placebo-controlled data relating to testos- were detected over this time frame of 2100 man years of terone treatment and prostate safety do not exist. A testosterone treatment (0.48% cases per annum). testosterone preparation that achieves physiological plas- The European Randomised Study of Screening for ma levels without supraphysiological escape is preferred. Prostate cancer (ERSSPC) has been running since the mid 1990s. The Finnish component of the study is the largest with 80 000 men enrolled. Men were randomised to a prostate screening arm with PSA analyses at baseline and at 4 years, or a control arm. Analysis of a cohort of References men studied revealed that over the 4-year-period the overall prostate cancer detection rate was 2.2% (0.55% 1 Morales A, Lunenfeld B. Investigation, treatment and monitor- 44 ing of late-onset hypogonadism. The Aging Male 2002; 5: 74–86. per annum). 2 Vermeulen A, Kaufman JM. 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