Intraprostatic testosterone and dihydrotestosterone. Part II: concentrations after androgen hormonal manipulation in men with benign prostatic hyperplasia and prostate cancer BJUIBJU INTERNATIONAL Tim M. van der Sluis , Eric J.H. Meuleman , R. Jeroen A. van Moorselaar , Hong N. Bui * , Marinus A. Blankenstein * , Annemieke C. Heijboer * and Andr é N. Vis Departments of Urology and * Clinical Chemistry, VU University Medical Centre, Amsterdam, The Netherlands Accepted for publication 26 July 2011 Androgen deprivation therapy (ADT) and What ’ s known on the subject? and What does the study add? 5- α -reductase (5AR) inhibition are used in The male steroid hormone metabolism is an important target in the treatment of the treatment of men with advanced or prostatic diseases. However, present literature is inconsistent about intraprostatic metastatic prostate cancer and benign concentrations of steroid hormones and the role of intraprostatic steroid hormones in prostatic hyperplasia (BPH), respectively. the arise and the course of prostatic diseases is yet to be determined. These drugs exert their effect by lowering androgen levels in the serum and allegedly, Part II of this two-piece mini-review reviews the effect of medication that alters the the prostate gland. It is, however, unknown male steroid hormone metabolism (i.e. 5-alpha reductase inhibitors, androgen whether (increased) intraprostatic androgen deprivation therapy) on intraprostatic steroid hormone concentrations. Better levels are associated with the pathogenesis knowledge of the intraprostatic steroid hormone concentrations might lead to more of BPH and with the initiation and individualized treatment and even to new medical targets. progression of prostate cancer. Also, it is unclear whether intraprostatic treated with ADT for hormone-naive treatment that is tailored to the needs of dihydrotestosterone (DHT) levels correlate prostate cancer, and of those with the individual patient, and probably to new with a response to initial hormonal therapy castration-resistant prostate cancer are all therapeutic targets as well. or with patient outcome. These altered in an equivalent manner because of uncertainties have resulted from the hormonal manipulation. Increased KEYWORDS fi nding that serum testosterone levels do knowledge of the mechanisms of the not necessarily refl ect those in the prostate androgenic steroid pathways in prostatic prostate , prostate cancer , fi nasteride , gland. Intraprostatic DHT levels of men diseases, with a special focus on dutasteride , testosterone , being treated with 5AR inhibition, of those intraprostatic androgen levels, may lead to dihydrotestosterone , androgen treatment INTRODUCTION DHT, 5-alpha-reductase (5AR). Multiple men who receive treatment that is known to randomized studies initiated in the 1980s on interfere with the hypothalamic-pitituary- It has long been recognized that androgenic 5AR inhibition in men with BPH showed a gonadal axis, e.g. ADT and 5AR-inhibition. activity is a major mediator of biological reduction of prostate volume, improvement Knowledge of the levels of intraprostatic processes in the prostate. Early studies from in symptoms and peak urinary fl ow, and a androgens before and after hormonal the 1940s onwards reported that androgen reduction of the risk of acute urinary manipulation might give more insight into deprivation therapy (ADT), by oestrogens retention and BPH-related surgery. In these the bio-availability of intraprostatic (diethylstilbestrol [ DES ] ) or by surgical men, clinical benefi ts were obtained without androgens, and into the cellular mechanisms castration, was able to lower serum lowering testosterone levels in the systemic that lead to the success of or the resistance testosterone levels resulting in a marked circulation. to drug-initiated treatments. biochemical and clinical response in men with metastasized prostate cancer. Currently, In Part I of the present review on ADT by LHRH-agonist treatment or by intraprostatic testosterone and DHT 5AR INHIBITION bilateral orchidectomy is the standard assessment, the levels of the most powerful treatment in those with advanced or biologically active androgens are outlined in ANDROGEN LEVELS AND 5AR INHIBITION disseminated disease [ 1,2 ] . The fi nding that the normal adult prostate, in untreated BPH, IN BPH dihydrotestosterone (DHT) is the major and in prostate cancer. androgen in the prostate led to the McConnell et al . [ 3 ] reported on 69 men development of drugs that block the enzyme Part II of the present review gives an with BPH, who were scheduled for TURP, to that is known to convert testosterone to overview of intraprostatic androgen levels in determine the effect of fi nasteride, a © 2011 THE AUTHORS BJU INTERNATIONAL © 2011 BJU INTERNATIONAL | 109, 183–188 | doi:10.1111/j.1464-410X.2011.10652.x 183 VAN DER SLUIS ET AL. TABLE 1 Testosterone and DHT concentrations after 5AR inhibition Tissue, Method of Tissue DHT, testosterone, Authors n Year Pathology determination 5AR inhibition ng/g tissue ng/g tissue McConnell et al . [ 3 ] 69 1992 BPH RIA Placebo 2.97 0.2 Finasteride 1 mg 0.4 § 1.25 § Finasteride 100 mg 0.14 § 1.69 § Norman et al . [ 4 ] 10 1993 BPH RIA Placebo 5.39 0.32 9 Finasteride 1 mg 1.1 § 2.2 § 8 Finasteride 5 mg 0.49 § 2.4 § Span et al . [ 5 ] 7 1999 BPH RIA Placebo 4.38 0.53 13 Finasteride 5 mg 1.39 § 2.81 § Geller et al . [ 6 ] 10 1990 BPH RIA Baseline 4.5 0.17 Finasteride 5 mg 0.30 § 1.18 § Hill et al . [ 7 ] 15 1996 BPH RIA Placebo 3.54 0.92 6 Finasteride 5 mg 0.68 § 1.96 § Marks et al . [ 8 ] 15 2001 BPH RIA Placebo 4.9 1.5 7 Finasteride 1.0 § 3.6 § Habib et al . * [ 9 ] 9 1997 BPH RIA Placebo 26.6 30.8 19 Finasteride 5 mg 22.9 58.5 § Andriole et al . † [ 10 ] 18 2004 BPH GC-MS Placebo 6.18 0.12 16 Dutasteride 0.17 § 0.25 § 5/10 mg Wurzel et al . † [ 12 ] 21 2007 BPH LC-MS Placebo 3.23 0.092 22 Dutasteride 0.5 mg 0.21 § 2.54 § Rittmaster et al . † [ 11 ] 21 2008 BPH + Prostate GC-MS/LC-MS Placebo 3.37 ‡ 0.17 cancer ‡ Dutasteride 0.5 mg – – 72 2 weeks 0.55 § 1.72 § 71 1 month 0.33 § 1.91 § 22 3 months 0.26 § 2.80 § 25 4 months 0.23 § 3.40 § Gleave et al . † [ 13 ] 14 2006 Prostate cancer GC-MS Placebo 3.3 0.07 14 Dutasteride 0.5 mg 0.23 § 3.4 § 13 Dutasteride 3.5 mg 0.039 § 2.8 § * Measurement in dry weight. † Similar study group. ‡ Pooled data of BPH and prostate cancer patients. § Statistically signifi cant difference against baseline. Placebo = placebo tablet or ‘ no therapy ’ . Testosterone: 1 nmol/L = 28.8 ng/dL; 1 ng = 0.00347 nmol. DHT: 1 nmol/L = 29.0 ng/dL; 1 ng = 0.00344 nmol. 5ARI, 5AR inhibitor; RIA, radioimmunoassay; LC, liquid-chromatography mass spectrometry; GC, gas-chromatography mass spectrometry. 5AR-type-2 inhibitor, on clinical outcome, Norman et al . [ 4 ] studied 27 men who were Similar decreases in intraprostatic DHT side-effects and (intraprostatic) androgen scheduled for TURP for BPH and who were levels, and reciprocal rises of prostatic levels. Patients were treated with placebo or randomized between placebo ( n = 10), and testosterone levels after fi nasteride 1, 5, 10, 50 or 100 mg fi nasteride for 7 days 6 – 8 weeks pretreatment with 1 mg treatment up to 100 mg/day have been before surgery. In the placebo group, the fi nasteride ( n = 9), or 5 mg fi nasteride ( n = reported by other study groups [ 5 – 8 ] ; mean prostatic DHT level was 2.97 ng/g 8). Tissue DHT levels in the placebo group however, Habib et al . [ 9 ] , in their randomized tissue, and the mean tissue testosterone were 5.39 ng/g tissue, and decreased to study on intraprostatic androgen levels on level was 0.2 ng/g tissue ( Table 1 [ 3 – 13 ] ). 1.1 ng/g tissue for 1 mg fi nasteride, and 5AR treatment, were unable to show a There was an incremental increase of 0.49 ng/g tissue for 5 mg fi nasteride ( P = signifi cant difference in testosterone and intraprostatic testosterone level and a 0.049 between doses). Intraprostatic DHT levels between the fi nasteride and reciprocal decrease of intraprostatic DHT testosterone levels in the placebo group placebo-treated group. level with higher dosages of fi nasteride. All increased from 0.32 ng/g tissue to 2.2 ng/g treatment groups were signifi cantly different tissue with 1 mg fi nasteride and 2.4 ng/g Rittmaster et al . [ 10 ] published a study on from the placebo group, but not different tissue with 5 mg fi nasteride ( P = intraprostatic androgen levels in men with from each other. nonsignifi cant between doses). BPH who were scheduled for TURP [ 10 – 12 ] . © 2011 THE AUTHORS 184 BJU INTERNATIONAL © 2011 BJU INTERNATIONAL INTRAPROSTATIC ANDROGEN LEVELS AFTER ANDROGEN HORMONAL MANIPULATION Patients were randomized between surgery palmetto. Similar observations were made by by 80% after 1 month of LHRH antagonist alone and placebo or neoadjuvant Di Silverio et al . [ 14 ] . treatment and that intraprostatic androgen dutasteride, a dual 5AR-type-1 and -2 levels were not suppressed to the same inhibitor, 0.5 mg or 3.5 mg. After 4 months degree as serum androgen levels. of drug treatment, the mean intraprostatic ADT DHT level was suppressed by 93.1% for 0.5 mg dutasteride and by 98.9% for 3.5 mg ANDROGEN LEVELS AND ADT IN BPH ANDROGEN LEVELS AND ADT IN PROSTATE dutasteride (both P < 0.001 versus placebo). CANCER For testosterone, intraprostatic values were Various types of ADT, alone or in signifi cantly greater in subjects who combination, were compared for their effect Multiple studies have shown that relatively received dutasteride 0.5 mg or 3.5 mg on intraprostatic DHT concentration in large amounts of DHT exist in prostate versus the surgery-alone group ( P < 0.001).