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Androgens and prostate cancer risk
Best Practice & Research Clinical Endocrinology & Metabolism Vol. 22, No. 4, pp. 601–613, 2008 doi:10.1016/j.beem.2008.06.002 available online at http://www.sciencedirect.com
5 Androgens and prostate cancer risk Sara Wire´n
MD
Junior Physician
Pa¨r Stattin *
MD, PhD
Consultant in Urology, Associate Professor Department of Surgical and Perioperative Sciences, Urology and Andrology, Umea˚ University, SE-901 85 Umea˚, Sweden
Androgens have been implicated in prostate tumourigenesis. However, no association between circulating levels of androgens and prostate cancer risk was found in a recent large pooled analysis of prospective studies. A decreased risk of prostate cancer among men treated with finasteride, a 5a-reductase inhibitor which reduces levels of dihydrotestosterone, was observed in the Prostate Cancer Prevention Trial (PCPT), a large clinical trial. In the PCPT, a higher number of high-grade tumours was found in the finasteride group than in the control group; the reason for this finding is still unclear. Treatment of symptoms of late-onset hypogonadism – such as decreased muscle and bone mass and decreased cognition and libido – has become more prevalent with the advent of new forms of administration of testosterone replacement therapy. One small placebo-controlled study showed no increase in incidence of prostate cancer after 6 months of testosterone therapy, but data on the safety of testosterone replacement therapy remain limited. Key words: prostatic neoplasms; androgens; finasteride; testosterone; late-onset hypogonadism; testosterone replacement therapy.
TESTOSTERONE METABOLISM Androgens have long been implicated in prostate carcinogenesis.1–3 In animal models, high doses of androgens promote and stimulate prostate tumours4–6; in men, however, the association between circulating and intraprostatic levels of androgens and prostate cancer is less clear.7
* Corresponding author. Tel.: þ46 90 785 22 91; Fax: þ46 90 12 53 96. E-mail address: [email protected] (P. Stattin). 1521-690X/$ - see front matter ª 2008 Elsevier Ltd. All rights reserved.
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Testosterone, the main androgen in the circulation, is mainly protein-bound, either strongly to sex hormone binding globulin (SHBG), or loosely to albumin. Only about 2% is unbound; this is called free testosterone and is considered to be the most biologically active form of testosterone. In the target tissue testosterone can either bind directly to the androgen receptor (AR) or, if the tissue expresses the enzyme 5a-reductase, be converted to dihydrotestosterone (DHT). The AR is a liganddependent nuclear transcription factor which binds to androgen-response elements in the DNA and regulates transcription in androgen-regulated genes.8,9 Due to its stronger affinity for the AR, DHT is two to ten times more potent as an androgen than testosterone, giving tissues expressing 5a-reductase a mechanism for local regulation of androgen activity.8,10,11 The enzyme 5a-reductase exists in two forms: type 1, present mainly in the skin and to a lesser extent in the liver, and type 2, present mainly in the prostate and the genital skin.12 Inhibitors of 5a-reductase can either inhibit type 2 selectively (e.g. finasteride), or both types 1 and 2 (e.g. dutasteride). Serum DHT is decreased more by dutasteride (94%) than by finasteride (73%).13 Androstanediol glucuronide (A-diol-g), a circulating end-product of DHT14, is used as a marker for intraprostatic androgenicity. Although levels of A-diol-g reflect the activity of both types of 5a-reductase, selective inhibition of 5a-reductase type 2 lowers circulating A-diol-g by 86%, suggesting that most of the circulating A-diol-g comes from the prostate.15 PROSPECTIVE STUDIES ON ANDROGENS AND PROSTATE CANCER To date, about 20 prospective studies have investigated the relationship between endogenous circulating levels of androgens and risk of prostate cancer.16–35 Most of these studies have been case–control studies nested in prospective cohort studies. In these studies pre-diagnostic levels of androgens in men who after the blood draw were diagnosed with prostate cancer were compared with circulating androgen levels among matched controls that stayed cancer-free. Overall, these studies have not shown a consistent association between circulating levels of androgens and risk of prostate cancer. Individually, these studies have had limited power due to a relatively modest number of study subjects. In 2008, a pooled analysis of 18 prospective studies on circulating levels of androgens and prostate cancer risk was published by the Endogenous Hormones and Prostate Cancer Collaborative Group.36 The analysis included 3886 cases of prostate cancer and 6438 matched controls for whom plasma levels of testosterone and other androgens were available from prospectively collected blood samples. This study, the largest to date, reported no significant associations between high levels of any of the androgens under investigation and risk of prostate cancer (Figure 1). However, high levels of SHBG were significantly associated with a 14% reduction in risk of prostate cancer. Similar results have been reported in two very recent studies that were not included in the pooled analyses.34,35 Some studies have also investigated androgens in subgroups according to tumour aggressiveness, usually defined as high-grade tumour, i.e., Gleason score 7 and/or advanced stage. One study reported a non-significant increase in the risk of low-grade tumours and a significant decrease in the risk of high-grade tumours30, while other studies have shown only weak, non-significant decreases in risk of aggressive tumours, with increasing levels of testosterone.28,32,33,35 In contrast, one study reported a significant, linear increase in the risk of aggressive disease for an increased
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Figure 1. Associations between risk of prostate cancer and increasing fifths of hormone concentrations in the Endogenous Sex Hormones and Prostate Cancer Collaborative Analysis of 18 prospective studies, including 3886 men with incident prostate cancer and 6438 control subjects.36 The position of each square indicates the magnitude of the relative risk, and the area of the square is proportional to the amount of statistical information available. The length of the horizontal line through the square indicates the 95% confidence interval (CI). RR, relative risk; DHT, dihydrotestosterone; DHEA-S, dehydroepiandrosterone sulphate; SHBG, sex hormone binding globulin. Reprinted from Roddam et al (2008, Journal of the National Cancer Institute 100: 170–183) with permission.
ratio of testosterone to SHBG in older men.34 However, in the large pooled analyses, there were no significant differences in associations between levels of androgens and risk of prostate cancer in subgroups according to tumour stage or grade.36 Total levels of serum testosterone are inversely correlated with obesity, insulin, and leptin37, but testosterone is positively correlated with SHBG. The associations
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between these factors and prostate cancer risk have been investigated, and in particular the association between obesity and prostate cancer has been extensively studied. These data may give some circumferential evidence on the association between androgens and prostate cancer. Obesity is associated with an increased risk of prostate cancer of about 5%38,39 and an increased risk of prostate cancer death of about 25%.39 This might in part be due to the effect of obesity on levels of endogenous sex hormones. Obesity leads to increased levels of insulin and bioavailable insulinlike growth factor 1 which reduce biosynthesis of SHBG in the liver. The decreased levels of SHBG in turn cause a reduction in testicular production of testosterone. Also, levels of oestrogens increase due to conversion of androgenic precursors to oestrogens by aromatases in the adipose tissue.40 Obese men – i.e. men with a body mass index (BMI) >30 kg/m2 – had 30% lower levels of testosterone, 45% lower levels of SHBG, and 5% lower levels of free testosterone.41 There is some evidence for a differential effect of obesity on the risk of high- versus low-grade tumours, with obesity decreasing the risk of localized/low-grade cancer and increasing the risk of aggressive/high-grade cancer.38,39 Speculatively, this might be in line with the observation of a differential effect on high- and low-grade tumours with high levels of testosterone.30 Furthermore, in some case–control studies, low levels of serum testosterone have been associated with an increased incidence of high-grade tumours.42,43 Some other circumferential data on the association between androgens and prostate cancer risk comes from studies on fatherhood status and prostate cancer risk. In two large population-based studies, childless men were reported to have a reduced risk of prostate cancer.44,45 Although this is a heterogenic group of men, fertility may be an indicator of androgenicity. Prospective studies are considered to be the best study design for observational studies on aetiological factors of disease, as the risk of reversed causation and different background populations for cases and controls are minimized in such a study design. However, control subjects may have an undetected prostate cancer which would dilute a true association between androgen levels and case–control status. Prostate cancer might also affect hormone levels; levels of testosterone increase after radical prostatectomy, particularly in patients with high-grade tumours.46,47 Ideally, in studies relating androgens to risk of prostate cancer, intraprostatic levels of androgens would be measured. Even though circulating levels of A-diol-g have been used as a marker for 5a-reductase type 2 activity, it is not clear to what extent this or other circulating androgens actually reflect intraprostatic androgenicity. Furthermore, in most studies, serum or plasma samples are only available from a single blood draw. Testosterone levels are known to fluctuate, both during the day – with a peak in the morning and a modest decline of 13% in the afternoon – and during life, with a steady decline of on average 0.11 nmol/L per year.48,49 Although measurements of one sample from one single time point has been reported to be quite representative of 1-year testosterone levels50, it is not clear at what age levels of androgens are important in prostate cancer development. Since measuring free testosterone in large epidemiological studies is timeconsuming and expensive, most such studies have estimated free testosterone using a mass action equation based on the affinity of albumin and SHBG for testosterone.51,52 This estimation was highly correlated to the levels measured by a reference assay (correlation coefficient R ¼ 0.99).52 However, the accuracy of this method has been questioned.53 Variability of hormone levels through life, and limitations in measurement of hormones, may obscure an association between high levels of androgens and risk of
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prostate cancer. However, prospective studies on circulating endogenous hormones and risk of breast cancer have similar limitations, but have still reported significant associations54, suggesting that these limitations might obscure a modest association such as in prostate cancer but not a stronger association such as in breast cancer. However, absence of evidence of an association between testosterone levels and prostate cancer is not evidence of absence. In conclusion, the combined evidence from large observational prospective studies does not support the hypothesis that high levels of circulating endogenous androgens increase risk of prostate cancer. GENETIC VARIANTS OF ANDROGEN METABOLISM In order to avoid bias and confounding that may occur in studies on phenotype associations, such as plasma levels and risk of prostate cancer, genes with variants known to affect function in e.g. hormone signalling can be used as proxies for hormonal levels. These variants are distributed randomly and should not be affected by bias and confounding.55 In a case–control study within the Cancer Prostate in Sweden (CAPS) study, of 1461 cases and 796 controls, the reproducibility of 46 polymorphisms previously reported to influence the risk of prostate cancer was tested.56 Six polymorphisms, of which three coded for key enzymes in the androgen biosynthesis and response pathway, showed significant associations; the CAG repeat length in the androgen receptor (AR), the CYP17 gene, and the SRD5A2 gene. The CAG repeat length in the AR gene affects AR activity, with short CAG repeat lengths increasing activity in the receptor.57 The CYP17 gene encodes cytochrome P450 17a-hydroxylase which is involved in the regulation of the biosynthesis of testosterone, and SRD5A2 encodes 5a-reductase (Figures 2 and 3). Furthermore, a single nucleotide polymorphism in the AR was borderline significantly associated with a 50% increased risk of prostate cancer death.58 Globally, the individual contributions of these genes to prostate carcinogenesis seems to be moderate according to a recent review.59
Figure 2. Biosynthesis and metabolism of androgens. DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulphate. Reprinted from Hsing et al (2002, Prostate 52: 213–235) with permission.
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Figure 3. Metabolism of androgens within the prostate gland. DHT, dihydrotestosterone; 3a-androstanediol, 5a-androstane-3a,17b-diol; 3b-androstanediol, 5a-androstane-3b,17b-diol. The dotted line with arrow indicates inactivation of DHT to a less potent androgen. Reprinted from Hsing et al (2002, Prostate 52: 213–235) with permission.
THE PROSTATE CANCER PREVENTION TRIAL The Prostate Cancer Prevention Trial (PCPT) is the largest randomized and placebocontrolled clinical trial in urology. It was a 7-year intervention trial which initially enrolled 24 482 men over 55 years of age; of these men, 18 882 had a serum prostate-specific antigen (PSA) level <3.0 ng/mL and a normal digital rectal examination (DRE), and subsequently underwent randomization. The men were assigned to 5 mg of finasteride, a selective inhibitor of 5a-reductase type 2, or placebo. There was annual screening for prostate cancer with DRE and measurement of serum PSA. If the DRE was abnormal, or if the PSA level was >4 ng/mL, a prostate biopsy was recommended. Finasteride decreases PSA levels by approximately 50%, so the PSA levels in the finasteride group was initially multiplied by 2 and later by 2.3, and an end-ofstudy biopsy was offered to all men who had not been diagnosed with prostate cancer during the study. The percentage of men that underwent prostate biopsy, either for cause or at the end of the study, was 60% in the finasteride group and 63% in the placebo group, resulting in 9060 men included in the final analysis. Men in the finasteride arm had a 25% decrease in the prevalence of prostate cancer on biopsy; cancer was detected in 18% of the men in the finasteride-treated group versus 24% of the men in the placebo group.60 Finasteride increased the sensitivity of serum PSA testing; the percentage of prostate cancer detected in biopsy for cause was 54% in the finasteride group and 50% in the control group, and the area under the curve in receiver operating characteristics for the finasteride group was larger for detecting prostate cancer (P < 0.001) and high-grade cancer (P ¼ 0.03) in comparison to the placebo group.61 Finasteride also significantly decreased the risk of high-grade prostatic intraepithelial neoplasia (PIN) by 15%.62 As a result of the inclusion criterion of a serum PSA <3 nmol/L and a normal DRE, the PCP trial included men at low risk of prostate cancer. In contrast to the overall decrease in incidence of prostate cancer and PIN, there was a higher number of high-grade tumours on biopsy in the finasteride-treated
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arm: n ¼ 280 (6%) compared to n ¼ 237 (5%) in the placebo arm. There are two putative interpretations of this result: finasteride may have induced high-grade tumours, or affected only low-grade tumours. However, the increase in high-grade tumours was seen already in the first year of the trial, and this fraction of tumours did not increase during the course of the study.63 Finasteride reduced prostate volume; the median gland volume in the finasteridetreated group was 25 cm3 compared to a median volume of 34 cm3 in the placebo group, a relative difference of 24%.60 A logistic model developed from the placebo group of the PCPT showed that the likelihood of detecting high-grade cancer on biopsy decreased as the volume increased, and when the original PCPT data were adjusted for gland volume and number of biopsy cores, the risk for high-grade cancer in the finasteride versus placebo groups was no longer significant.64 Also, for men in the PCPT who underwent radical prostatectomy, there were no significant differences between the groups in the prevalence of high-grade tumours in the prostatectomy specimens.65 The rate of upgrading from low-grade cancer on biopsy to high-grade cancer at prostatectomy was similar between the groups. One recent study reported significantly increased immunoreactivity for 5a-reductase type 1 and type 2 in high-grade tumours compared to low-grade tumours.66 Speculatively, this might mean that high-grade tumours, but not low-grade tumours, can produce enough DHT to grow even when 5a-reductase type 2 is inhibited. However, whether or not increased immunoreactivity truly reflects increased enzymatic activity is unclear. In conclusion, the prevalence of prostate cancer in the PCPT decreased by 25% in the finasteride-treated arm, but the number of high-grade tumours increased. The reason for this has not been fully elucidated, and the interpretation of these data is still hotly debated. Currently, a double-blind, placebo-controlled chemoprevention study designed to determine whether dutasteride, a combined inhibitor of 5a-reductase types 1 and 2, decreases the risk of biopsy-detectable prostate cancer in men at high risk of prostate cancer is ongoing. In the REDUCE trial (Reduction by Dutasteride of Prostate Cancer Events), a total of over 8000 men aged 50–75 years with a serum PSA of 3–10 ng/mL and with a negative prostate biopsy have been randomized to receive dutasteride or placebo for 4 years.67 No results are yet available from this study. ANDROGEN REPLACEMENT THERAPY Testosterone levels decline in aging men.49 This can lead to late-onset hypogonadism, with symptoms such as a decrease in muscle and bone mass, decreased cognition and libido, and increased fat mass.68 With the advent of new administration forms for testosterone, such as transdermal patches and gels instead of intramuscular injections, treatment has become more convenient. However, studies on the effect of testosterone replacement therapy (TRT) on the symptoms associated with late-onset hypogonadism have reported divergent results.69 To the best of our knowledge, the largest placebo-controlled study on the efficacy of TRT to date included 207 healthy hypogonadal men aged between 60 and 80 that received 80 mg oral testosterone or placebo twice daily for 6 months.70 There were significant increases in lean body mass and decreases in body fat, but no significant increases in functional motility or muscle strength in the testosterone-treated arm. There were no significant changes in cognitive function or bone mineral density, and serum PSA levels did not change significantly.
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One concern about TRT is the fear of promoting an already existing prostate tumour. Many hypogonadal men have an undetected prostate cancer; in a study on 345 men that were candidates for TRT, 15% had prostate cancer on biopsy.71 Due to the possible risk of promoting tumours in this group of patients, present recommendations advise clinicians to exclude the presence of prostate cancer by performing a digital rectal exam and obtaining a serum PSA level prior to initiation of treatment, and to monitor patients at quarterly intervals for the first 12 months, then annually.68,72 TRT is contraindicated in men with prostate cancer.68 Whether TRT increases the risk of prostate cancer is not established. There are case reports of prostate cancer in men receiving TRT for symptoms of Klinefelter syndrome73,74, a condition normally associated with a low incidence of prostate cancer.75 However, it is not clear whether TRT actually increases the risk of prostate cancer in these men or just exposes them to the same risk as normal men. In a compilation of prospective studies on TRT for up to 36 months, the incidence of prostate cancer was 1.1%, similar to that in the general population.76 In a recent review of 16 articles on TRT, no increased risk of prostate cancer was reported. However, only four of the studies were placebo-controlled, and most studies included less than 100 patients.77 One retrospective study has examined TRT and risk of prostate cancer in men with PIN, presumably at high risk of prostate cancer.78 The study included 20 men with PIN, and 50 men without PIN.79 After 1 year of TRT, only one of the 20 men with PIN developed prostate cancer, suggesting that TRT does not significantly promote prostate cancer growth even in a high-risk population. However, this was a small study and should thus be interpreted with caution. TRT can cause a small initial increase in serum PSA levels of 0.30–0.43 ng/mL76,80, i.e., to a level comparable to that in age-matched controls.81 An increase of more than 0.5 ng/mL during the first 3–6 months after initiation of treatment is considered to be an indication for biopsy.77 In a double-blinded, randomized, placebo-controlled trial in which 150 mg of testosterone enanthate or placebo were injected intramuscularly every 2 weeks for 6 months in 40 hypogonadal and symptomatic men aged 44–78, changes in serum as well as prostate tissue levels of testosterone were measured.82 Serum levels of testosterone increased to the mid-normal range in the testosterone-treated group, but no significant changes in tissue levels of testosterone or DHT were found. Thus, exogenous testosterone may not affect intraprostatic levels of androgens. In conclusion, short-term TRT has not been shown to increase the risk of prostate cancer; however, data are limited. SUMMARY Many moderately sized prospective studies have examined the relationship between circulating levels of androgens and risk of prostate cancer, with inconsistent results. A pooled analysis of these studies – including 3886 cases of prostate cancer and 6438 matched controls – reported no association of circulating androgens and risk of prostate cancer, either overall or for subgroups according to tumour stage or grade. However, SHGB levels were associated with a decreased risk. In the PCPT, finasteride decreased the risk of prostate cancer overall by 25% but increased the risk of highgrade tumours. The increase in risk may be due to a detection bias where the chance of detecting high-grade tumours increases with the finasteride-induced decrease in gland size, together with selective inhibition of low-grade tumours; alternatively, low levels of dihydrotestosterone may induce high-grade tumours.
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Testosterone replacement therapy to relieve symptoms of late-onset hypogonadism has become simpler with new modes of testosterone administration. Whether or not this treatment affects the risk of prostate cancer has not been firmly established. The relatively small, short-term studies that exist to date do not report an increased risk of prostate cancer with testosterone therapy. Practice points high levels of circulating endogenous testosterone have not been associated with an increased risk of prostate cancer inhibition of 5a-reductase by finasteride decreases the risk of prostate cancer. The increased risk of high-grade cancer may be a detection bias caused by a smaller gland and increased sensitivity of serum PSA as a screening tool in the finasteride-treated group; alternatively, low levels of dihydrotestosterone may induce high-grade tumours there is no evidence to support an increased risk of prostate cancer with short-term testosterone replacement therapy for late-onset hypogonadism; however, it seems prudent to exclude the presence of prostate cancer by a digital rectal exam and a measurement of serum PSA before initiating therapy
Research agenda studies relating intra-prostatic levels and serum levels of testosterone and other androgens to prostate cancer risk are needed we await the results from the REDUCE trial in which men at high risk of prostate cancer are treated with the 5a-reductase inhibitor dutasteride larger studies are needed to determine the efficacy and safety of testosterone replacement therapy
ACKNOWLEDGEMENTS Swedish cancer foundation, Lions 2008-03-06. REFERENCES *1. Bosland MC. The role of steroid hormones in prostate carcinogenesis. Journal of the National Cancer Institute. Monographs 2000; (27): 39–66. 2. Hsing AW, Reichardt JK & Stanczyk FZ. Hormones and prostate cancer: current perspectives and future directions. Prostate 2002 Aug 1; 52(3): 213–235. *3. Platz EA & Giovannucci E. The epidemiology of sex steroid hormones and their signaling and metabolic pathways in the etiology of prostate cancer. The Journal of Steroid Biochemistry and Molecular Biology 2004 Nov; 92(4): 237–253. 4. Bladou F, Vessella RL, Buhler KR et al. Cell proliferation and apoptosis during prostatic tumor xenograft involution and regrowth after castration. International Journal of Cancer 1996 Sep 17; 67(6): 785–790. 5. Lucia MS, Bostwick DG, Bosland M et al. Workgroup I: rodent models of prostate cancer. Prostate 1998 Jun 15; 36(1): 49–55.
610 S. Wire´n and P. Stattin 6. Noble RL. The development of prostatic adenocarcinoma in Nb rats following prolonged sex hormone administration. Cancer Research 1977 Jun; 37(6): 1929–1933. 7. Bostwick DG, Burke HB, Djakiew D et al. Human prostate cancer risk factors. Cancer 2004 Nov 15; 101(Suppl. 10): 2371–2490. 8. Keller ET, Ershler WB & Chang C. The androgen receptor: a mediator of diverse responses. Frontiers in Bioscience: A Journal and Virtual Library 1996 Mar 1; 1: d59–d71. 9. Kaarbo M, Klokk TI & Saatcioglu F. Androgen signaling and its interactions with other signaling pathways in prostate cancer. BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology 2007 Dec; 29(12): 1227–1238. 10. Zhou ZX, Lane MV, Kemppainen JA et al. Specificity of ligand-dependent androgen receptor stabilization: receptor domain interactions influence ligand dissociation and receptor stability. Molecular Endocrinology 1995 Feb; 9(2): 208–218. 11. Gao W, Bohl CE & Dalton JT. Chemistry and structural biology of androgen receptor. Chemical Reviews 2005 Sep; 105(9): 3352–3370. 12. Russell DW & Wilson JD. Steroid 5 alpha-reductase: two genes/two enzymes. Annual Review of Biochemistry 1994; 63: 25–61. 13. Amory JK, Wang C, Swerdloff RS et al. The effect of 5alpha-reductase inhibition with dutasteride and finasteride on semen parameters and serum hormones in healthy men. The Journal of Clinical Endocrinology and Metabolism 2007 May; 92(5): 1659–1665. 14. Rittmaster RS, Zwicker H, Thompson DL et al. Androstanediol glucuronide production in human liver, prostate, and skin. Evidence for the importance of the liver in 5 alpha-reduced androgen metabolism. The Journal of Clinical Endocrinology and Metabolism 1993 Apr; 76(4): 977–982. 15. Norman RW, Coakes KE, Wright AS et al. Androgen metabolism in men receiving finasteride before prostatectomy. The Journal of Urology 1993 Nov; 150(5 Pt 2): 1736–1739. 16. Nomura A, Heilbrun LK, Stemmermann GN et al. Prediagnostic serum hormones and the risk of prostate cancer. Cancer Research 1988 Jun 15; 48(12): 3515–3517. 17. Nomura AM, Stemmermann GN, Chyou PH et al. Serum androgens and prostate cancer. Cancer Epidemiology, Biomarkers & Prevention 1996 Aug; 5(8): 621–625. 18. Barrett-Connor E, Garland C, McPhillips JB et al. A prospective, population-based study of androstenedione, estrogens, and prostatic cancer. Cancer Research 1990 Jan 1; 50(1): 169–173. 19. Hsing AW & Comstock GW. Serological precursors of cancer: serum hormones and risk of subsequent prostate cancer. Cancer Epidemiology, Biomarkers & Prevention 1993 Jan–Feb; 2(1): 27–32. 20. Carter HB, Pearson JD, Metter EJ et al. Longitudinal evaluation of serum androgen levels in men with and without prostate cancer. Prostate 1995 Jul; 27(1): 25–31. 21. Gann PH, Hennekens CH, Ma J et al. Prospective study of sex hormone levels and risk of prostate cancer. Journal of the National Cancer Institute 1996 Aug 21; 88(16): 1118–1126. 22. Guess HA, Friedman GD, Sadler MC et al. 5 alpha-reductase activity and prostate cancer: a casecontrol study using stored sera. Cancer Epidemiology, Biomarkers & Prevention 1997 Jan; 6(1): 21–24. 23. Vatten LJ, Ursin G, Ross RK et al. Androgens in serum and the risk of prostate cancer: a nested casecontrol study from the Janus serum bank in Norway. Cancer Epidemiology, Biomarkers & Prevention 1997 Nov; 6(11): 967–969. 24. Dorgan JF, Albanes D, Virtamo J et al. Relationships of serum androgens and estrogens to prostate cancer risk: results from a prospective study in Finland. Cancer Epidemiology, Biomarkers & Prevention 1998 Dec; 7(12): 1069–1074. 25. Heikkila R, Aho K, Heliovaara M et al. Serum testosterone and sex hormone-binding globulin concentrations and the risk of prostate carcinoma: a longitudinal study. Cancer 1999 Jul 15; 86(2): 312–315. 26. Mohr BA, Feldman HA, Kalish LA et al. Are serum hormones associated with the risk of prostate cancer? Prospective results from the Massachusetts Male Aging Study. Urology 2001 May; 57(5): 930–935. 27. Stattin P, Lumme S, Tenkanen L et al. High levels of circulating testosterone are not associated with increased prostate cancer risk: a pooled prospective study. International Journal of Cancer 2004 Jan 20; 108(3): 418–424. 28. Chen C, Weiss NS, Stanczyk FZ et al. Endogenous sex hormones and prostate cancer risk: a casecontrol study nested within the Carotene and Retinol Efficacy Trial. Cancer Epidemiology, Biomarkers & Prevention 2003 Dec; 12(12): 1410–1416.
Androgens and prostate cancer risk 611 29. Ozasa K, Nakao M, Watanabe Y et al. Serum phytoestrogens and prostate cancer risk in a nested case-control study among Japanese men. Cancer Science 2004 Jan; 95(1): 65–71. 30. Platz EA, Leitzmann MF, Rifai N et al. Sex steroid hormones and the androgen receptor gene CAG repeat and subsequent risk of prostate cancer in the prostate-specific antigen era. Cancer Epidemiology, Biomarkers & Prevention 2005 May; 14(5): 1262–1269. 31. Parsons JK, Carter HB, Platz EA et al. Serum testosterone and the risk of prostate cancer: potential implications for testosterone therapy. Cancer Epidemiology, Biomarkers & Prevention 2005 Sep; 14(9): 2257–2260. 32. Severi G, Morris HA, MacInnis RJ et al. Circulating steroid hormones and the risk of prostate cancer. Cancer Epidemiology, Biomarkers & Prevention 2006 Jan; 15(1): 86–91. 33. Travis RC, Key TJ, Allen NE et al. Serum androgens and prostate cancer among 643 cases and 643 controls in the European Prospective Investigation into Cancer and Nutrition. International Journal of Cancer 2007 Sep 15; 121(6): 1331–1338. 34. Weiss JM, Huang WY, Rinaldi S, et al. Endogenous sex hormones and the risk of prostate cancer: a prospective study. International Journal of Cancer, in press. 35. Wiren S, Stocks T, Rinaldi S et al. Androgens and prostate cancer risk: a prospective study. Prostate 2007 Aug 1; 67(11): 1230–1237. *36. Roddam AW, Allen NE, Appleby P et al. Endogenous sex hormones and prostate cancer: a collaborative analysis of 18 prospective studies. Journal of the National Cancer Institute 2008 Feb 6; 100(3): 170–183. *37. Kaaks R, Lukanova A, Rinaldi S et al. Interrelationships between plasma testosterone, SHBG, IGF-I, insulin and leptin in prostate cancer cases and controls. European Journal of Cancer Prevention 2003 Aug; 12(4): 309–315. 38. MacInnis RJ & English DR. Body size and composition and prostate cancer risk: systematic review and meta-regression analysis. Cancer Causes Control 2006 Oct; 17(8): 989–1003. 39. Hsing AW, Sakoda LC & Chua Jr. S. Obesity, metabolic syndrome, and prostate cancer. The American Journal of Clinical Nutrition 2007 Sep; 86(3): s843–s857. 40. Calle EE & Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nature Reviews. Cancer 2004 Aug; 4(8): 579–591. 41. Allen NE, Appleby PN, Davey GK et al. Lifestyle and nutritional determinants of bioavailable androgens and related hormones in British men. Cancer Causes Control 2002 May; 13(4): 353–363. 42. Hoffman MA, DeWolf WC & Morgentaler A. Is low serum free testosterone a marker for high grade prostate cancer? Journal of Urology 2000 Mar; 163(3): 824–827. 43. Schatzl G, Madersbacher S, Thurridl T et al. High-grade prostate cancer is associated with low serum testosterone levels. Prostate 2001 Apr; 47(1): 52–58. 44. Giwercman A, Richiardi L, Kaijser M et al. Reduced risk of prostate cancer in men who are childless as compared to those who have fathered a child: a population based case-control study. International Journal of Cancer 2005 Jul 20; 115(6): 994–997. 45. Jorgensen KT, Pedersen BV, Johansen C et al. Fatherhood status and prostate cancer risk. Cancer 2008 Feb 15; 112(4): 919–923. 46. Miller LR, Partin AW, Chan DW et al. Influence of radical prostatectomy on serum hormone levels. Journal of Urology 1998 Aug; 160(2): 449–453. 47. Madersbacher S, Schatzl G, Bieglmayer C et al. Impact of radical prostatectomy and TURP on the hypothalamic-pituitary-gonadal hormone axis. Urology 2002 Nov; 60(5): 869–874. 48. Crawford ED, Barqawi AB, O’Donnell C et al. The association of time of day and serum testosterone concentration in a large screening population. BJU International 2007 Sep; 100(3): 509–513. 49. Harman SM, Metter EJ, Tobin JD et al. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. The Journal of Clinical Endocrinology and Metabolism 2001 Feb; 86(2): 724–731. 50. Vermeulen A & Verdonck G. Representativeness of a single point plasma testosterone level for the long term hormonal milieu in men. The Journal of Clinical Endocrinology and Metabolism 1992 Apr; 74(4): 939–942. 51. Anderson PH, Fukushima K & Schiller HS. Radioimmunoassay of plasma testosterone, with use of polyethylene glycol to separate antibody-bound and free hormone. Clinical Chemistry 1975 May; 21(6): 708–714. 52. Vermeulen A, Verdonck L & Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. The Journal of Clinical Endocrinology and Metabolism 1999 Oct; 84(10): 3666–3672.
612 S. Wire´n and P. Stattin 53. Giton F, Fiet J, Guechot J et al. Serum bioavailable testosterone: assayed or calculated? Clinical Chemistry 2006 Mar; 52(3): 474–481. 54. Key TJ, Appleby PN, Reeves GK et al. Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. Journal of the National Cancer Institute 2003 Aug 20; 95(16): 1218–1226. 55. Ebrahim S & Davey Smith G. Mendelian randomization: can genetic epidemiology help redress the failures of observational epidemiology? Human Genetics 2008 Feb; 123(1): 15–33. 56. Lindstrom S, Zheng SL, Wiklund F et al. Systematic replication study of reported genetic associations in prostate cancer: Strong support for genetic variation in the androgen pathway. Prostate 2006 Dec 1; 66(16): 1729–1743. 57. Chamberlain NL, Driver ED & Miesfeld RL. The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Research 1994 Aug 11; 22(15): 3181–3186. 58. Lindstrom S, Adami HO, Balter KA et al. Inherited variation in hormone-regulating genes and prostate cancer survival. Clinical Cancer Research 2007 Sep 1; 13(17): 5156–5161. *59. Chokkalingam AP, Stanczyk FZ, Reichardt JK et al. Molecular epidemiology of prostate cancer: hormone-related genetic loci. Frontiers in Bioscience: A Journal and Virtual Library 2007; 12: 3436–3460. *60. Thompson IM, Goodman PJ, Tangen CM et al. The influence of finasteride on the development of prostate cancer. The New England Journal of Medicine 2003 Jul 17; 349(3): 215–224. 61. Thompson IM, Chi C, Ankerst DP et al. Effect of finasteride on the sensitivity of PSA for detecting prostate cancer. Journal of the National Cancer Institute 2006 Aug 16; 98(16): 1128–1133. 62. Thompson IM, Lucia MS, Redman MW et al. Finasteride decreases the risk of prostatic intraepithelial neoplasia. Journal of Urology 2007 Jul; 178(1): 107–109. discussion 10. 63. Thompson IM, Klein EA, Lippman SM et al. Prevention of prostate cancer with finasteride: US/European perspective. European Urology 2003 Dec; 44(6): 650–655. 64. Cohen YC, Liu KS, Heyden NL et al. Detection bias due to the effect of finasteride on prostate volume: a modeling approach for analysis of the Prostate Cancer Prevention Trial. Journal of the National Cancer Institute 2007 Sep 19; 99(18): 1366–1374. 65. Lucia MS, Epstein JI, Goodman PJ et al. Finasteride and high-grade prostate cancer in the Prostate Cancer Prevention Trial. Journal of the National Cancer Institute 2007 Sep 19; 99(18): 1375–1383. 66. Thomas LN, Douglas RC, Lazier CB et al. Levels of 5alpha-reductase type 1 and type 2 are increased in localized high grade compared to low grade prostate cancer. Journal of Urology 2008 Jan; 179(1): 147–151. 67. Andriole G, Bostwick D, Brawley O et al. Chemoprevention of prostate cancer in men at high risk: rationale and design of the reduction by dutasteride of prostate cancer events (REDUCE) trial. Journal of Urology 2004 Oct; 172(4 Pt 1): 1314–1317. *68. Nieschlag E, Swerdloff R, Behre HM et al. Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, and EAU recommendations. Journal of Andrology 2006 Mar–Apr; 27(2): 135–137. 69. Miner MM & Seftel AD. Testosterone and ageing: what have we learned since the Institute of Medicine report and what lies ahead? International Journal of Clinical Practice 2007 Apr; 61(4): 622–632. *70. Emmelot-Vonk MH, Verhaar HJ, Nakhai Pour HR et al. Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men: a randomized controlled trial. JAMA 2008 Jan 2; 299(1): 39–52. 71. Morgentaler A & Rhoden EL. Prevalence of prostate cancer among hypogonadal men with prostatespecific antigen levels of 4.0 ng/mL or less. Urology 2006 Dec; 68(6): 1263–1267. 72. Brand TC, Canby-Hagino E & Thompson IM. Testosterone replacement therapy and prostate cancer: a word of caution. Current Urology Reports 2007 May; 8(3): 185–189. 73. Hwang JJ, Dharmawardana PG, Uchio EM et al. Prostate cancer in Klinefelter syndrome during hormonal replacement therapy. Urology 2003 Nov; 62(5): 941. 74. Bydder SA, Joseph DJ, Weinstein S et al. Prostate cancer following testosterone replacement in Klinefelter syndrome. ANZ Journal of Surgery 2007 Jan–Feb; 77(1–2): 93–94. 75. Swerdlow AJ, Schoemaker MJ, Higgins CD et al. Cancer incidence and mortality in men with Klinefelter syndrome: a cohort study. Journal of the National Cancer Institute 2005 Aug 17; 97(16): 1204–1210. 76. Rhoden EL & Morgentaler A. Risks of testosterone-replacement therapy and recommendations for monitoring. The New England Journal of Medicine 2004 Jan 29; 350(5): 482–492.
Androgens and prostate cancer risk 613 77. Gould DC, Feneley MR & Kirby RS. Prostate-specific antigen testing in hypogonadism: implications for the safety of testosterone-replacement therapy. BJU International 2006 Jul; 98(1): 1–4. 78. Bostwick DG, Pacelli A & Lopez-Beltran A. Molecular biology of prostatic intraepithelial neoplasia. Prostate 1996 Aug; 29(2): 117–134. 79. 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. Journal of Urology 2003 Dec; 170(6 Pt 1): 2348–2351. 80. Raynaud JP, Legros JJ, Rollet J et al. Efficacy and safety of a new testosterone-in-adhesive matrix patch applied every 2 days for 1 year to hypogonadal men. The Journal of Steroid Biochemistry and Molecular Biology 2008; 109(1–2): 168–176. 81. Behre HM, Bohmeyer J & Nieschlag E. Prostate volume in testosterone-treated and untreated hypogonadal men in comparison to age-matched normal controls. Clinical Endocrinology 1994 Mar; 40(3): 341–349. *82. Marks LS, Mazer NA, Mostaghel E et al. Effect of testosterone replacement therapy on prostate tissue in men with late-onset hypogonadism: a randomized controlled trial. JAMA 2006 Nov 15; 296(19): 2351–2361.
5 Androgens and prostate cancer risk Sara Wire´n
MD
Junior Physician
Pa¨r Stattin *
MD, PhD
Consultant in Urology, Associate Professor Department of Surgical and Perioperative Sciences, Urology and Andrology, Umea˚ University, SE-901 85 Umea˚, Sweden
Androgens have been implicated in prostate tumourigenesis. However, no association between circulating levels of androgens and prostate cancer risk was found in a recent large pooled analysis of prospective studies. A decreased risk of prostate cancer among men treated with finasteride, a 5a-reductase inhibitor which reduces levels of dihydrotestosterone, was observed in the Prostate Cancer Prevention Trial (PCPT), a large clinical trial. In the PCPT, a higher number of high-grade tumours was found in the finasteride group than in the control group; the reason for this finding is still unclear. Treatment of symptoms of late-onset hypogonadism – such as decreased muscle and bone mass and decreased cognition and libido – has become more prevalent with the advent of new forms of administration of testosterone replacement therapy. One small placebo-controlled study showed no increase in incidence of prostate cancer after 6 months of testosterone therapy, but data on the safety of testosterone replacement therapy remain limited. Key words: prostatic neoplasms; androgens; finasteride; testosterone; late-onset hypogonadism; testosterone replacement therapy.
TESTOSTERONE METABOLISM Androgens have long been implicated in prostate carcinogenesis.1–3 In animal models, high doses of androgens promote and stimulate prostate tumours4–6; in men, however, the association between circulating and intraprostatic levels of androgens and prostate cancer is less clear.7
* Corresponding author. Tel.: þ46 90 785 22 91; Fax: þ46 90 12 53 96. E-mail address: [email protected] (P. Stattin). 1521-690X/$ - see front matter ª 2008 Elsevier Ltd. All rights reserved.
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Testosterone, the main androgen in the circulation, is mainly protein-bound, either strongly to sex hormone binding globulin (SHBG), or loosely to albumin. Only about 2% is unbound; this is called free testosterone and is considered to be the most biologically active form of testosterone. In the target tissue testosterone can either bind directly to the androgen receptor (AR) or, if the tissue expresses the enzyme 5a-reductase, be converted to dihydrotestosterone (DHT). The AR is a liganddependent nuclear transcription factor which binds to androgen-response elements in the DNA and regulates transcription in androgen-regulated genes.8,9 Due to its stronger affinity for the AR, DHT is two to ten times more potent as an androgen than testosterone, giving tissues expressing 5a-reductase a mechanism for local regulation of androgen activity.8,10,11 The enzyme 5a-reductase exists in two forms: type 1, present mainly in the skin and to a lesser extent in the liver, and type 2, present mainly in the prostate and the genital skin.12 Inhibitors of 5a-reductase can either inhibit type 2 selectively (e.g. finasteride), or both types 1 and 2 (e.g. dutasteride). Serum DHT is decreased more by dutasteride (94%) than by finasteride (73%).13 Androstanediol glucuronide (A-diol-g), a circulating end-product of DHT14, is used as a marker for intraprostatic androgenicity. Although levels of A-diol-g reflect the activity of both types of 5a-reductase, selective inhibition of 5a-reductase type 2 lowers circulating A-diol-g by 86%, suggesting that most of the circulating A-diol-g comes from the prostate.15 PROSPECTIVE STUDIES ON ANDROGENS AND PROSTATE CANCER To date, about 20 prospective studies have investigated the relationship between endogenous circulating levels of androgens and risk of prostate cancer.16–35 Most of these studies have been case–control studies nested in prospective cohort studies. In these studies pre-diagnostic levels of androgens in men who after the blood draw were diagnosed with prostate cancer were compared with circulating androgen levels among matched controls that stayed cancer-free. Overall, these studies have not shown a consistent association between circulating levels of androgens and risk of prostate cancer. Individually, these studies have had limited power due to a relatively modest number of study subjects. In 2008, a pooled analysis of 18 prospective studies on circulating levels of androgens and prostate cancer risk was published by the Endogenous Hormones and Prostate Cancer Collaborative Group.36 The analysis included 3886 cases of prostate cancer and 6438 matched controls for whom plasma levels of testosterone and other androgens were available from prospectively collected blood samples. This study, the largest to date, reported no significant associations between high levels of any of the androgens under investigation and risk of prostate cancer (Figure 1). However, high levels of SHBG were significantly associated with a 14% reduction in risk of prostate cancer. Similar results have been reported in two very recent studies that were not included in the pooled analyses.34,35 Some studies have also investigated androgens in subgroups according to tumour aggressiveness, usually defined as high-grade tumour, i.e., Gleason score 7 and/or advanced stage. One study reported a non-significant increase in the risk of low-grade tumours and a significant decrease in the risk of high-grade tumours30, while other studies have shown only weak, non-significant decreases in risk of aggressive tumours, with increasing levels of testosterone.28,32,33,35 In contrast, one study reported a significant, linear increase in the risk of aggressive disease for an increased
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Figure 1. Associations between risk of prostate cancer and increasing fifths of hormone concentrations in the Endogenous Sex Hormones and Prostate Cancer Collaborative Analysis of 18 prospective studies, including 3886 men with incident prostate cancer and 6438 control subjects.36 The position of each square indicates the magnitude of the relative risk, and the area of the square is proportional to the amount of statistical information available. The length of the horizontal line through the square indicates the 95% confidence interval (CI). RR, relative risk; DHT, dihydrotestosterone; DHEA-S, dehydroepiandrosterone sulphate; SHBG, sex hormone binding globulin. Reprinted from Roddam et al (2008, Journal of the National Cancer Institute 100: 170–183) with permission.
ratio of testosterone to SHBG in older men.34 However, in the large pooled analyses, there were no significant differences in associations between levels of androgens and risk of prostate cancer in subgroups according to tumour stage or grade.36 Total levels of serum testosterone are inversely correlated with obesity, insulin, and leptin37, but testosterone is positively correlated with SHBG. The associations
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between these factors and prostate cancer risk have been investigated, and in particular the association between obesity and prostate cancer has been extensively studied. These data may give some circumferential evidence on the association between androgens and prostate cancer. Obesity is associated with an increased risk of prostate cancer of about 5%38,39 and an increased risk of prostate cancer death of about 25%.39 This might in part be due to the effect of obesity on levels of endogenous sex hormones. Obesity leads to increased levels of insulin and bioavailable insulinlike growth factor 1 which reduce biosynthesis of SHBG in the liver. The decreased levels of SHBG in turn cause a reduction in testicular production of testosterone. Also, levels of oestrogens increase due to conversion of androgenic precursors to oestrogens by aromatases in the adipose tissue.40 Obese men – i.e. men with a body mass index (BMI) >30 kg/m2 – had 30% lower levels of testosterone, 45% lower levels of SHBG, and 5% lower levels of free testosterone.41 There is some evidence for a differential effect of obesity on the risk of high- versus low-grade tumours, with obesity decreasing the risk of localized/low-grade cancer and increasing the risk of aggressive/high-grade cancer.38,39 Speculatively, this might be in line with the observation of a differential effect on high- and low-grade tumours with high levels of testosterone.30 Furthermore, in some case–control studies, low levels of serum testosterone have been associated with an increased incidence of high-grade tumours.42,43 Some other circumferential data on the association between androgens and prostate cancer risk comes from studies on fatherhood status and prostate cancer risk. In two large population-based studies, childless men were reported to have a reduced risk of prostate cancer.44,45 Although this is a heterogenic group of men, fertility may be an indicator of androgenicity. Prospective studies are considered to be the best study design for observational studies on aetiological factors of disease, as the risk of reversed causation and different background populations for cases and controls are minimized in such a study design. However, control subjects may have an undetected prostate cancer which would dilute a true association between androgen levels and case–control status. Prostate cancer might also affect hormone levels; levels of testosterone increase after radical prostatectomy, particularly in patients with high-grade tumours.46,47 Ideally, in studies relating androgens to risk of prostate cancer, intraprostatic levels of androgens would be measured. Even though circulating levels of A-diol-g have been used as a marker for 5a-reductase type 2 activity, it is not clear to what extent this or other circulating androgens actually reflect intraprostatic androgenicity. Furthermore, in most studies, serum or plasma samples are only available from a single blood draw. Testosterone levels are known to fluctuate, both during the day – with a peak in the morning and a modest decline of 13% in the afternoon – and during life, with a steady decline of on average 0.11 nmol/L per year.48,49 Although measurements of one sample from one single time point has been reported to be quite representative of 1-year testosterone levels50, it is not clear at what age levels of androgens are important in prostate cancer development. Since measuring free testosterone in large epidemiological studies is timeconsuming and expensive, most such studies have estimated free testosterone using a mass action equation based on the affinity of albumin and SHBG for testosterone.51,52 This estimation was highly correlated to the levels measured by a reference assay (correlation coefficient R ¼ 0.99).52 However, the accuracy of this method has been questioned.53 Variability of hormone levels through life, and limitations in measurement of hormones, may obscure an association between high levels of androgens and risk of
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prostate cancer. However, prospective studies on circulating endogenous hormones and risk of breast cancer have similar limitations, but have still reported significant associations54, suggesting that these limitations might obscure a modest association such as in prostate cancer but not a stronger association such as in breast cancer. However, absence of evidence of an association between testosterone levels and prostate cancer is not evidence of absence. In conclusion, the combined evidence from large observational prospective studies does not support the hypothesis that high levels of circulating endogenous androgens increase risk of prostate cancer. GENETIC VARIANTS OF ANDROGEN METABOLISM In order to avoid bias and confounding that may occur in studies on phenotype associations, such as plasma levels and risk of prostate cancer, genes with variants known to affect function in e.g. hormone signalling can be used as proxies for hormonal levels. These variants are distributed randomly and should not be affected by bias and confounding.55 In a case–control study within the Cancer Prostate in Sweden (CAPS) study, of 1461 cases and 796 controls, the reproducibility of 46 polymorphisms previously reported to influence the risk of prostate cancer was tested.56 Six polymorphisms, of which three coded for key enzymes in the androgen biosynthesis and response pathway, showed significant associations; the CAG repeat length in the androgen receptor (AR), the CYP17 gene, and the SRD5A2 gene. The CAG repeat length in the AR gene affects AR activity, with short CAG repeat lengths increasing activity in the receptor.57 The CYP17 gene encodes cytochrome P450 17a-hydroxylase which is involved in the regulation of the biosynthesis of testosterone, and SRD5A2 encodes 5a-reductase (Figures 2 and 3). Furthermore, a single nucleotide polymorphism in the AR was borderline significantly associated with a 50% increased risk of prostate cancer death.58 Globally, the individual contributions of these genes to prostate carcinogenesis seems to be moderate according to a recent review.59
Figure 2. Biosynthesis and metabolism of androgens. DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulphate. Reprinted from Hsing et al (2002, Prostate 52: 213–235) with permission.
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Figure 3. Metabolism of androgens within the prostate gland. DHT, dihydrotestosterone; 3a-androstanediol, 5a-androstane-3a,17b-diol; 3b-androstanediol, 5a-androstane-3b,17b-diol. The dotted line with arrow indicates inactivation of DHT to a less potent androgen. Reprinted from Hsing et al (2002, Prostate 52: 213–235) with permission.
THE PROSTATE CANCER PREVENTION TRIAL The Prostate Cancer Prevention Trial (PCPT) is the largest randomized and placebocontrolled clinical trial in urology. It was a 7-year intervention trial which initially enrolled 24 482 men over 55 years of age; of these men, 18 882 had a serum prostate-specific antigen (PSA) level <3.0 ng/mL and a normal digital rectal examination (DRE), and subsequently underwent randomization. The men were assigned to 5 mg of finasteride, a selective inhibitor of 5a-reductase type 2, or placebo. There was annual screening for prostate cancer with DRE and measurement of serum PSA. If the DRE was abnormal, or if the PSA level was >4 ng/mL, a prostate biopsy was recommended. Finasteride decreases PSA levels by approximately 50%, so the PSA levels in the finasteride group was initially multiplied by 2 and later by 2.3, and an end-ofstudy biopsy was offered to all men who had not been diagnosed with prostate cancer during the study. The percentage of men that underwent prostate biopsy, either for cause or at the end of the study, was 60% in the finasteride group and 63% in the placebo group, resulting in 9060 men included in the final analysis. Men in the finasteride arm had a 25% decrease in the prevalence of prostate cancer on biopsy; cancer was detected in 18% of the men in the finasteride-treated group versus 24% of the men in the placebo group.60 Finasteride increased the sensitivity of serum PSA testing; the percentage of prostate cancer detected in biopsy for cause was 54% in the finasteride group and 50% in the control group, and the area under the curve in receiver operating characteristics for the finasteride group was larger for detecting prostate cancer (P < 0.001) and high-grade cancer (P ¼ 0.03) in comparison to the placebo group.61 Finasteride also significantly decreased the risk of high-grade prostatic intraepithelial neoplasia (PIN) by 15%.62 As a result of the inclusion criterion of a serum PSA <3 nmol/L and a normal DRE, the PCP trial included men at low risk of prostate cancer. In contrast to the overall decrease in incidence of prostate cancer and PIN, there was a higher number of high-grade tumours on biopsy in the finasteride-treated
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arm: n ¼ 280 (6%) compared to n ¼ 237 (5%) in the placebo arm. There are two putative interpretations of this result: finasteride may have induced high-grade tumours, or affected only low-grade tumours. However, the increase in high-grade tumours was seen already in the first year of the trial, and this fraction of tumours did not increase during the course of the study.63 Finasteride reduced prostate volume; the median gland volume in the finasteridetreated group was 25 cm3 compared to a median volume of 34 cm3 in the placebo group, a relative difference of 24%.60 A logistic model developed from the placebo group of the PCPT showed that the likelihood of detecting high-grade cancer on biopsy decreased as the volume increased, and when the original PCPT data were adjusted for gland volume and number of biopsy cores, the risk for high-grade cancer in the finasteride versus placebo groups was no longer significant.64 Also, for men in the PCPT who underwent radical prostatectomy, there were no significant differences between the groups in the prevalence of high-grade tumours in the prostatectomy specimens.65 The rate of upgrading from low-grade cancer on biopsy to high-grade cancer at prostatectomy was similar between the groups. One recent study reported significantly increased immunoreactivity for 5a-reductase type 1 and type 2 in high-grade tumours compared to low-grade tumours.66 Speculatively, this might mean that high-grade tumours, but not low-grade tumours, can produce enough DHT to grow even when 5a-reductase type 2 is inhibited. However, whether or not increased immunoreactivity truly reflects increased enzymatic activity is unclear. In conclusion, the prevalence of prostate cancer in the PCPT decreased by 25% in the finasteride-treated arm, but the number of high-grade tumours increased. The reason for this has not been fully elucidated, and the interpretation of these data is still hotly debated. Currently, a double-blind, placebo-controlled chemoprevention study designed to determine whether dutasteride, a combined inhibitor of 5a-reductase types 1 and 2, decreases the risk of biopsy-detectable prostate cancer in men at high risk of prostate cancer is ongoing. In the REDUCE trial (Reduction by Dutasteride of Prostate Cancer Events), a total of over 8000 men aged 50–75 years with a serum PSA of 3–10 ng/mL and with a negative prostate biopsy have been randomized to receive dutasteride or placebo for 4 years.67 No results are yet available from this study. ANDROGEN REPLACEMENT THERAPY Testosterone levels decline in aging men.49 This can lead to late-onset hypogonadism, with symptoms such as a decrease in muscle and bone mass, decreased cognition and libido, and increased fat mass.68 With the advent of new administration forms for testosterone, such as transdermal patches and gels instead of intramuscular injections, treatment has become more convenient. However, studies on the effect of testosterone replacement therapy (TRT) on the symptoms associated with late-onset hypogonadism have reported divergent results.69 To the best of our knowledge, the largest placebo-controlled study on the efficacy of TRT to date included 207 healthy hypogonadal men aged between 60 and 80 that received 80 mg oral testosterone or placebo twice daily for 6 months.70 There were significant increases in lean body mass and decreases in body fat, but no significant increases in functional motility or muscle strength in the testosterone-treated arm. There were no significant changes in cognitive function or bone mineral density, and serum PSA levels did not change significantly.
608 S. Wire´n and P. Stattin
One concern about TRT is the fear of promoting an already existing prostate tumour. Many hypogonadal men have an undetected prostate cancer; in a study on 345 men that were candidates for TRT, 15% had prostate cancer on biopsy.71 Due to the possible risk of promoting tumours in this group of patients, present recommendations advise clinicians to exclude the presence of prostate cancer by performing a digital rectal exam and obtaining a serum PSA level prior to initiation of treatment, and to monitor patients at quarterly intervals for the first 12 months, then annually.68,72 TRT is contraindicated in men with prostate cancer.68 Whether TRT increases the risk of prostate cancer is not established. There are case reports of prostate cancer in men receiving TRT for symptoms of Klinefelter syndrome73,74, a condition normally associated with a low incidence of prostate cancer.75 However, it is not clear whether TRT actually increases the risk of prostate cancer in these men or just exposes them to the same risk as normal men. In a compilation of prospective studies on TRT for up to 36 months, the incidence of prostate cancer was 1.1%, similar to that in the general population.76 In a recent review of 16 articles on TRT, no increased risk of prostate cancer was reported. However, only four of the studies were placebo-controlled, and most studies included less than 100 patients.77 One retrospective study has examined TRT and risk of prostate cancer in men with PIN, presumably at high risk of prostate cancer.78 The study included 20 men with PIN, and 50 men without PIN.79 After 1 year of TRT, only one of the 20 men with PIN developed prostate cancer, suggesting that TRT does not significantly promote prostate cancer growth even in a high-risk population. However, this was a small study and should thus be interpreted with caution. TRT can cause a small initial increase in serum PSA levels of 0.30–0.43 ng/mL76,80, i.e., to a level comparable to that in age-matched controls.81 An increase of more than 0.5 ng/mL during the first 3–6 months after initiation of treatment is considered to be an indication for biopsy.77 In a double-blinded, randomized, placebo-controlled trial in which 150 mg of testosterone enanthate or placebo were injected intramuscularly every 2 weeks for 6 months in 40 hypogonadal and symptomatic men aged 44–78, changes in serum as well as prostate tissue levels of testosterone were measured.82 Serum levels of testosterone increased to the mid-normal range in the testosterone-treated group, but no significant changes in tissue levels of testosterone or DHT were found. Thus, exogenous testosterone may not affect intraprostatic levels of androgens. In conclusion, short-term TRT has not been shown to increase the risk of prostate cancer; however, data are limited. SUMMARY Many moderately sized prospective studies have examined the relationship between circulating levels of androgens and risk of prostate cancer, with inconsistent results. A pooled analysis of these studies – including 3886 cases of prostate cancer and 6438 matched controls – reported no association of circulating androgens and risk of prostate cancer, either overall or for subgroups according to tumour stage or grade. However, SHGB levels were associated with a decreased risk. In the PCPT, finasteride decreased the risk of prostate cancer overall by 25% but increased the risk of highgrade tumours. The increase in risk may be due to a detection bias where the chance of detecting high-grade tumours increases with the finasteride-induced decrease in gland size, together with selective inhibition of low-grade tumours; alternatively, low levels of dihydrotestosterone may induce high-grade tumours.
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Testosterone replacement therapy to relieve symptoms of late-onset hypogonadism has become simpler with new modes of testosterone administration. Whether or not this treatment affects the risk of prostate cancer has not been firmly established. The relatively small, short-term studies that exist to date do not report an increased risk of prostate cancer with testosterone therapy. Practice points high levels of circulating endogenous testosterone have not been associated with an increased risk of prostate cancer inhibition of 5a-reductase by finasteride decreases the risk of prostate cancer. The increased risk of high-grade cancer may be a detection bias caused by a smaller gland and increased sensitivity of serum PSA as a screening tool in the finasteride-treated group; alternatively, low levels of dihydrotestosterone may induce high-grade tumours there is no evidence to support an increased risk of prostate cancer with short-term testosterone replacement therapy for late-onset hypogonadism; however, it seems prudent to exclude the presence of prostate cancer by a digital rectal exam and a measurement of serum PSA before initiating therapy
Research agenda studies relating intra-prostatic levels and serum levels of testosterone and other androgens to prostate cancer risk are needed we await the results from the REDUCE trial in which men at high risk of prostate cancer are treated with the 5a-reductase inhibitor dutasteride larger studies are needed to determine the efficacy and safety of testosterone replacement therapy
ACKNOWLEDGEMENTS Swedish cancer foundation, Lions 2008-03-06. REFERENCES *1. Bosland MC. The role of steroid hormones in prostate carcinogenesis. Journal of the National Cancer Institute. Monographs 2000; (27): 39–66. 2. Hsing AW, Reichardt JK & Stanczyk FZ. Hormones and prostate cancer: current perspectives and future directions. Prostate 2002 Aug 1; 52(3): 213–235. *3. Platz EA & Giovannucci E. The epidemiology of sex steroid hormones and their signaling and metabolic pathways in the etiology of prostate cancer. The Journal of Steroid Biochemistry and Molecular Biology 2004 Nov; 92(4): 237–253. 4. Bladou F, Vessella RL, Buhler KR et al. Cell proliferation and apoptosis during prostatic tumor xenograft involution and regrowth after castration. International Journal of Cancer 1996 Sep 17; 67(6): 785–790. 5. Lucia MS, Bostwick DG, Bosland M et al. Workgroup I: rodent models of prostate cancer. Prostate 1998 Jun 15; 36(1): 49–55.
610 S. Wire´n and P. Stattin 6. Noble RL. The development of prostatic adenocarcinoma in Nb rats following prolonged sex hormone administration. Cancer Research 1977 Jun; 37(6): 1929–1933. 7. Bostwick DG, Burke HB, Djakiew D et al. Human prostate cancer risk factors. Cancer 2004 Nov 15; 101(Suppl. 10): 2371–2490. 8. Keller ET, Ershler WB & Chang C. The androgen receptor: a mediator of diverse responses. Frontiers in Bioscience: A Journal and Virtual Library 1996 Mar 1; 1: d59–d71. 9. Kaarbo M, Klokk TI & Saatcioglu F. Androgen signaling and its interactions with other signaling pathways in prostate cancer. BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology 2007 Dec; 29(12): 1227–1238. 10. Zhou ZX, Lane MV, Kemppainen JA et al. Specificity of ligand-dependent androgen receptor stabilization: receptor domain interactions influence ligand dissociation and receptor stability. Molecular Endocrinology 1995 Feb; 9(2): 208–218. 11. Gao W, Bohl CE & Dalton JT. Chemistry and structural biology of androgen receptor. Chemical Reviews 2005 Sep; 105(9): 3352–3370. 12. Russell DW & Wilson JD. Steroid 5 alpha-reductase: two genes/two enzymes. Annual Review of Biochemistry 1994; 63: 25–61. 13. Amory JK, Wang C, Swerdloff RS et al. The effect of 5alpha-reductase inhibition with dutasteride and finasteride on semen parameters and serum hormones in healthy men. The Journal of Clinical Endocrinology and Metabolism 2007 May; 92(5): 1659–1665. 14. Rittmaster RS, Zwicker H, Thompson DL et al. Androstanediol glucuronide production in human liver, prostate, and skin. Evidence for the importance of the liver in 5 alpha-reduced androgen metabolism. The Journal of Clinical Endocrinology and Metabolism 1993 Apr; 76(4): 977–982. 15. Norman RW, Coakes KE, Wright AS et al. Androgen metabolism in men receiving finasteride before prostatectomy. The Journal of Urology 1993 Nov; 150(5 Pt 2): 1736–1739. 16. Nomura A, Heilbrun LK, Stemmermann GN et al. Prediagnostic serum hormones and the risk of prostate cancer. Cancer Research 1988 Jun 15; 48(12): 3515–3517. 17. Nomura AM, Stemmermann GN, Chyou PH et al. Serum androgens and prostate cancer. Cancer Epidemiology, Biomarkers & Prevention 1996 Aug; 5(8): 621–625. 18. Barrett-Connor E, Garland C, McPhillips JB et al. A prospective, population-based study of androstenedione, estrogens, and prostatic cancer. Cancer Research 1990 Jan 1; 50(1): 169–173. 19. Hsing AW & Comstock GW. Serological precursors of cancer: serum hormones and risk of subsequent prostate cancer. Cancer Epidemiology, Biomarkers & Prevention 1993 Jan–Feb; 2(1): 27–32. 20. Carter HB, Pearson JD, Metter EJ et al. Longitudinal evaluation of serum androgen levels in men with and without prostate cancer. Prostate 1995 Jul; 27(1): 25–31. 21. Gann PH, Hennekens CH, Ma J et al. Prospective study of sex hormone levels and risk of prostate cancer. Journal of the National Cancer Institute 1996 Aug 21; 88(16): 1118–1126. 22. Guess HA, Friedman GD, Sadler MC et al. 5 alpha-reductase activity and prostate cancer: a casecontrol study using stored sera. Cancer Epidemiology, Biomarkers & Prevention 1997 Jan; 6(1): 21–24. 23. Vatten LJ, Ursin G, Ross RK et al. Androgens in serum and the risk of prostate cancer: a nested casecontrol study from the Janus serum bank in Norway. Cancer Epidemiology, Biomarkers & Prevention 1997 Nov; 6(11): 967–969. 24. Dorgan JF, Albanes D, Virtamo J et al. Relationships of serum androgens and estrogens to prostate cancer risk: results from a prospective study in Finland. Cancer Epidemiology, Biomarkers & Prevention 1998 Dec; 7(12): 1069–1074. 25. Heikkila R, Aho K, Heliovaara M et al. Serum testosterone and sex hormone-binding globulin concentrations and the risk of prostate carcinoma: a longitudinal study. Cancer 1999 Jul 15; 86(2): 312–315. 26. Mohr BA, Feldman HA, Kalish LA et al. Are serum hormones associated with the risk of prostate cancer? Prospective results from the Massachusetts Male Aging Study. Urology 2001 May; 57(5): 930–935. 27. Stattin P, Lumme S, Tenkanen L et al. High levels of circulating testosterone are not associated with increased prostate cancer risk: a pooled prospective study. International Journal of Cancer 2004 Jan 20; 108(3): 418–424. 28. Chen C, Weiss NS, Stanczyk FZ et al. Endogenous sex hormones and prostate cancer risk: a casecontrol study nested within the Carotene and Retinol Efficacy Trial. Cancer Epidemiology, Biomarkers & Prevention 2003 Dec; 12(12): 1410–1416.
Androgens and prostate cancer risk 611 29. Ozasa K, Nakao M, Watanabe Y et al. Serum phytoestrogens and prostate cancer risk in a nested case-control study among Japanese men. Cancer Science 2004 Jan; 95(1): 65–71. 30. Platz EA, Leitzmann MF, Rifai N et al. Sex steroid hormones and the androgen receptor gene CAG repeat and subsequent risk of prostate cancer in the prostate-specific antigen era. Cancer Epidemiology, Biomarkers & Prevention 2005 May; 14(5): 1262–1269. 31. Parsons JK, Carter HB, Platz EA et al. Serum testosterone and the risk of prostate cancer: potential implications for testosterone therapy. Cancer Epidemiology, Biomarkers & Prevention 2005 Sep; 14(9): 2257–2260. 32. Severi G, Morris HA, MacInnis RJ et al. Circulating steroid hormones and the risk of prostate cancer. Cancer Epidemiology, Biomarkers & Prevention 2006 Jan; 15(1): 86–91. 33. Travis RC, Key TJ, Allen NE et al. Serum androgens and prostate cancer among 643 cases and 643 controls in the European Prospective Investigation into Cancer and Nutrition. International Journal of Cancer 2007 Sep 15; 121(6): 1331–1338. 34. Weiss JM, Huang WY, Rinaldi S, et al. Endogenous sex hormones and the risk of prostate cancer: a prospective study. International Journal of Cancer, in press. 35. Wiren S, Stocks T, Rinaldi S et al. Androgens and prostate cancer risk: a prospective study. Prostate 2007 Aug 1; 67(11): 1230–1237. *36. Roddam AW, Allen NE, Appleby P et al. Endogenous sex hormones and prostate cancer: a collaborative analysis of 18 prospective studies. Journal of the National Cancer Institute 2008 Feb 6; 100(3): 170–183. *37. Kaaks R, Lukanova A, Rinaldi S et al. Interrelationships between plasma testosterone, SHBG, IGF-I, insulin and leptin in prostate cancer cases and controls. European Journal of Cancer Prevention 2003 Aug; 12(4): 309–315. 38. MacInnis RJ & English DR. Body size and composition and prostate cancer risk: systematic review and meta-regression analysis. Cancer Causes Control 2006 Oct; 17(8): 989–1003. 39. Hsing AW, Sakoda LC & Chua Jr. S. Obesity, metabolic syndrome, and prostate cancer. The American Journal of Clinical Nutrition 2007 Sep; 86(3): s843–s857. 40. Calle EE & Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nature Reviews. Cancer 2004 Aug; 4(8): 579–591. 41. Allen NE, Appleby PN, Davey GK et al. Lifestyle and nutritional determinants of bioavailable androgens and related hormones in British men. Cancer Causes Control 2002 May; 13(4): 353–363. 42. Hoffman MA, DeWolf WC & Morgentaler A. Is low serum free testosterone a marker for high grade prostate cancer? Journal of Urology 2000 Mar; 163(3): 824–827. 43. Schatzl G, Madersbacher S, Thurridl T et al. High-grade prostate cancer is associated with low serum testosterone levels. Prostate 2001 Apr; 47(1): 52–58. 44. Giwercman A, Richiardi L, Kaijser M et al. Reduced risk of prostate cancer in men who are childless as compared to those who have fathered a child: a population based case-control study. International Journal of Cancer 2005 Jul 20; 115(6): 994–997. 45. Jorgensen KT, Pedersen BV, Johansen C et al. Fatherhood status and prostate cancer risk. Cancer 2008 Feb 15; 112(4): 919–923. 46. Miller LR, Partin AW, Chan DW et al. Influence of radical prostatectomy on serum hormone levels. Journal of Urology 1998 Aug; 160(2): 449–453. 47. Madersbacher S, Schatzl G, Bieglmayer C et al. Impact of radical prostatectomy and TURP on the hypothalamic-pituitary-gonadal hormone axis. Urology 2002 Nov; 60(5): 869–874. 48. Crawford ED, Barqawi AB, O’Donnell C et al. The association of time of day and serum testosterone concentration in a large screening population. BJU International 2007 Sep; 100(3): 509–513. 49. Harman SM, Metter EJ, Tobin JD et al. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. The Journal of Clinical Endocrinology and Metabolism 2001 Feb; 86(2): 724–731. 50. Vermeulen A & Verdonck G. Representativeness of a single point plasma testosterone level for the long term hormonal milieu in men. The Journal of Clinical Endocrinology and Metabolism 1992 Apr; 74(4): 939–942. 51. Anderson PH, Fukushima K & Schiller HS. Radioimmunoassay of plasma testosterone, with use of polyethylene glycol to separate antibody-bound and free hormone. Clinical Chemistry 1975 May; 21(6): 708–714. 52. Vermeulen A, Verdonck L & Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. The Journal of Clinical Endocrinology and Metabolism 1999 Oct; 84(10): 3666–3672.
612 S. Wire´n and P. Stattin 53. Giton F, Fiet J, Guechot J et al. Serum bioavailable testosterone: assayed or calculated? Clinical Chemistry 2006 Mar; 52(3): 474–481. 54. Key TJ, Appleby PN, Reeves GK et al. Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. Journal of the National Cancer Institute 2003 Aug 20; 95(16): 1218–1226. 55. Ebrahim S & Davey Smith G. Mendelian randomization: can genetic epidemiology help redress the failures of observational epidemiology? Human Genetics 2008 Feb; 123(1): 15–33. 56. Lindstrom S, Zheng SL, Wiklund F et al. Systematic replication study of reported genetic associations in prostate cancer: Strong support for genetic variation in the androgen pathway. Prostate 2006 Dec 1; 66(16): 1729–1743. 57. Chamberlain NL, Driver ED & Miesfeld RL. The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Research 1994 Aug 11; 22(15): 3181–3186. 58. Lindstrom S, Adami HO, Balter KA et al. Inherited variation in hormone-regulating genes and prostate cancer survival. Clinical Cancer Research 2007 Sep 1; 13(17): 5156–5161. *59. Chokkalingam AP, Stanczyk FZ, Reichardt JK et al. Molecular epidemiology of prostate cancer: hormone-related genetic loci. Frontiers in Bioscience: A Journal and Virtual Library 2007; 12: 3436–3460. *60. Thompson IM, Goodman PJ, Tangen CM et al. The influence of finasteride on the development of prostate cancer. The New England Journal of Medicine 2003 Jul 17; 349(3): 215–224. 61. Thompson IM, Chi C, Ankerst DP et al. Effect of finasteride on the sensitivity of PSA for detecting prostate cancer. Journal of the National Cancer Institute 2006 Aug 16; 98(16): 1128–1133. 62. Thompson IM, Lucia MS, Redman MW et al. Finasteride decreases the risk of prostatic intraepithelial neoplasia. Journal of Urology 2007 Jul; 178(1): 107–109. discussion 10. 63. Thompson IM, Klein EA, Lippman SM et al. Prevention of prostate cancer with finasteride: US/European perspective. European Urology 2003 Dec; 44(6): 650–655. 64. Cohen YC, Liu KS, Heyden NL et al. Detection bias due to the effect of finasteride on prostate volume: a modeling approach for analysis of the Prostate Cancer Prevention Trial. Journal of the National Cancer Institute 2007 Sep 19; 99(18): 1366–1374. 65. Lucia MS, Epstein JI, Goodman PJ et al. Finasteride and high-grade prostate cancer in the Prostate Cancer Prevention Trial. Journal of the National Cancer Institute 2007 Sep 19; 99(18): 1375–1383. 66. Thomas LN, Douglas RC, Lazier CB et al. Levels of 5alpha-reductase type 1 and type 2 are increased in localized high grade compared to low grade prostate cancer. Journal of Urology 2008 Jan; 179(1): 147–151. 67. Andriole G, Bostwick D, Brawley O et al. Chemoprevention of prostate cancer in men at high risk: rationale and design of the reduction by dutasteride of prostate cancer events (REDUCE) trial. Journal of Urology 2004 Oct; 172(4 Pt 1): 1314–1317. *68. Nieschlag E, Swerdloff R, Behre HM et al. Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, and EAU recommendations. Journal of Andrology 2006 Mar–Apr; 27(2): 135–137. 69. Miner MM & Seftel AD. Testosterone and ageing: what have we learned since the Institute of Medicine report and what lies ahead? International Journal of Clinical Practice 2007 Apr; 61(4): 622–632. *70. Emmelot-Vonk MH, Verhaar HJ, Nakhai Pour HR et al. Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men: a randomized controlled trial. JAMA 2008 Jan 2; 299(1): 39–52. 71. Morgentaler A & Rhoden EL. Prevalence of prostate cancer among hypogonadal men with prostatespecific antigen levels of 4.0 ng/mL or less. Urology 2006 Dec; 68(6): 1263–1267. 72. Brand TC, Canby-Hagino E & Thompson IM. Testosterone replacement therapy and prostate cancer: a word of caution. Current Urology Reports 2007 May; 8(3): 185–189. 73. Hwang JJ, Dharmawardana PG, Uchio EM et al. Prostate cancer in Klinefelter syndrome during hormonal replacement therapy. Urology 2003 Nov; 62(5): 941. 74. Bydder SA, Joseph DJ, Weinstein S et al. Prostate cancer following testosterone replacement in Klinefelter syndrome. ANZ Journal of Surgery 2007 Jan–Feb; 77(1–2): 93–94. 75. Swerdlow AJ, Schoemaker MJ, Higgins CD et al. Cancer incidence and mortality in men with Klinefelter syndrome: a cohort study. Journal of the National Cancer Institute 2005 Aug 17; 97(16): 1204–1210. 76. Rhoden EL & Morgentaler A. Risks of testosterone-replacement therapy and recommendations for monitoring. The New England Journal of Medicine 2004 Jan 29; 350(5): 482–492.
Androgens and prostate cancer risk 613 77. Gould DC, Feneley MR & Kirby RS. Prostate-specific antigen testing in hypogonadism: implications for the safety of testosterone-replacement therapy. BJU International 2006 Jul; 98(1): 1–4. 78. Bostwick DG, Pacelli A & Lopez-Beltran A. Molecular biology of prostatic intraepithelial neoplasia. Prostate 1996 Aug; 29(2): 117–134. 79. 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. Journal of Urology 2003 Dec; 170(6 Pt 1): 2348–2351. 80. Raynaud JP, Legros JJ, Rollet J et al. Efficacy and safety of a new testosterone-in-adhesive matrix patch applied every 2 days for 1 year to hypogonadal men. The Journal of Steroid Biochemistry and Molecular Biology 2008; 109(1–2): 168–176. 81. Behre HM, Bohmeyer J & Nieschlag E. Prostate volume in testosterone-treated and untreated hypogonadal men in comparison to age-matched normal controls. Clinical Endocrinology 1994 Mar; 40(3): 341–349. *82. Marks LS, Mazer NA, Mostaghel E et al. Effect of testosterone replacement therapy on prostate tissue in men with late-onset hypogonadism: a randomized controlled trial. JAMA 2006 Nov 15; 296(19): 2351–2361.