Prostate-specific antigen (PSA) concentrations in hypogonadal men during 6 years of transdermal testosterone treatment Jean-Pierre Raynaud, Jean Gardette*, Jacques Rollet† and Jean-Jacques Legros‡ Université Pierre et Marie Curie, 4 place Jussieu, 75252 Paris, *40 rue de Chezy 92200, Neuilly/seine, †Institut Rhône alpin, Médicentre Val Ouest 69130 Ecully, France, and ‡CHR Citadelle, Université de Liège, Belgium What’s known on the subject? and What does the study add? • Hypogonadism affects an estimated 2–4 million men in the USA, but only 5% receive treatment. Testosterone replacement therapy reduces the effects of testosterone deficiency on sexual function, mood and energy in hypogonadal patients. Long-term hypogonadism management requires testosterone treatment to restore serum concentrations of testosterone and its active metabolites, within physiological ranges; a testosterone preparation that achieves physiological plasma concentrations without supra-physiological escape is a preferred option. A previous 1-year study European clinical study showed the efficacy and safety of a transdermal testosterone patch (Testopatch®). • The present study shows the long-term (6-year) safety and efficacy of Testopatch in patients with primary or secondary hypogonadism. We show that, over the long-term, Testopatch was associated with no relevant changes in PSA concentration and PSA velocity, or any significant prostate risks (there were no cases of prostate cancer). Objective • To assess the change in prostate-specific antigen (PSA) concentrations in patients with primary or secondary hypogonadism, receiving transdermal testosterone. Patients and Methods • This was an interventional, 6-year study, conducted in Urology and Endocrinology centres in Belgium, France, Germany, the Netherlands and Spain. • Participants were primary (48%) or secondary (52%) hypogonadal patients who received two 60 cm2 testosterone patches (Testopatch®), delivering 4.8 mg of testosterone per day, applied every 2 days. • During treatment, total testosterone (TT), dihydrotestosterone, oestradiol and, PSA concentrations were measured in a centralised laboratory every 3 months during the first year, and every 6 months thereafter. Results • In all, 200 patients [mean (sd) age 41.0 (12.5) years, body weight 82.5 (13.7) kg, height 177.2 (9.3) cm, body mass index 26.2 (3.4) kg/m2] were treated with transdermal testosterone patches. • In all, 161 patients completed the 1-year study and 115 entered into a 5-year study extension; 51 patients completed the sixth year of the study. • The mean baseline concentrations of TT and PSA were 1.4 ng/mL and 0.47 ng/mL, respectively; TT serum concentrations >3 ng/mL were achieved in 85% of patients and fluctuated between 4.4 and 6.0 ng/mL. • At each successive 6-month time point, mean the PSA values were 0.60, 0.67, 0.76, 0.70, 0.61, 0.68, 0.64, 0.71, 0.75, 0.74, 1.01, 0.78, 0.80 ng/mL, respectively. The mean PSA velocity was negligible (0.00–0.03 ng/mL/year) from 30 months to the end of the trial, except for a value of 0.08 at 60 months. Seven patients had a PSA concentration of >4 ng/mL due to a sharp PSA increase. Six of these patients had prostatitis and PSA concentrations returned to previous levels with appropriate treatment. No prostate cancer was reported during the trial. Conclusion • These data support a strong safety profile for Testopatch, even at the highest registered dosage. Keywords testosterone, hypogonadism, treatment, transdermal © 2013 BJU International | doi:10.1111/j.1464-410X.2012.11514.x 1 Raynaud et al. Introduction Testosterone replacement therapy (TRT) is a key issue for the management of hypogonadism, attenuating the effects of testosterone deficiency on sexual function, energy and mood [1–5]. The aim of TRT in hypogonadal patients is to restore hormone concentrations (testosterone and its metabolites) to the normal range of healthy young men, and to select the lowest dose that gives positive effects on desired endpoints. Although the decline of testosterone concentrations with age is often very slow, a significant number of men aged >50 years have biological testosterone concentrations below the normal range. Hypogonadism affects an estimated 2–4 million men in the USA, but only 5% receive treatment [1]. Management guidelines have been issued by various associations and societies [6], with the consensus that ‘testosterone therapy for symptomatic men with androgen deficiency, who have low testosterone concentrations, induce and maintain secondary characteristics and improve their sexual function, sense of well-being, muscle mass and strength, and bone mineral density’. In clinical trials, TRT has been shown to have very little effect on the prostate gland [7]; indeed, a statistically non-significant increase in prostate androgen concentrations was observed with TRT [8]. Long-term management of hypogonadism requires testosterone treatment to restore serum concentrations of total testosterone (TT) and its active metabolites, dihydrotestosterone (DHT) and oestradiol (E2), within physiological ranges [1,9]. A testosterone preparation that achieves physiological plasma concentrations without supra-physiological escape is a preferred option. Transdermally administered testosterone, by avoiding the first pass effect in the liver, may be the best way of administration, if local tolerability is managed properly. The Institut de Recherche Pierre Fabre (IRPF) has developed a ‘drug in adhesive’ transdermal patch (Testopatch®). Initially, a 1-year European clinical study was conducted to treat men with primary or secondary hypogonadism and results have been published elsewhere [10]. During the course of that study, an additional extension was proposed to all patients who wanted to continue on Testopatch, renewable every year according to the willingness of the patient. The objective of the extension study was to obtain information on the long-term safety and efficacy of the highest Testopatch dosage. No dose adaptation was planned in this extension study. study. Patients were recruited from January 2002 to December 2008. Screening for prostate cancer using PSA monitoring and Digital Rectal Examination were performed before initiating therapy and throughout treatment, every 3 months for the first year and every 6 months thereafter, according to accepted recommendations [11]. At baseline and every 6 months over 6 years, TT, bioavailable testosterone (BT), DHT and E2 were assayed using time-resolved-fluoroimmunoassay in a centralized hormonal laboratory (reference central laboratory normal ranges are 2.69–7.77 ng/mL for TT and 0.75–2.75 ng/mL for BT [12–14]; routine biological analyses and PSA (Immulite 2000 PSA ref L2KPS6) were conducted by MDS Central Laboratory (95560 Baillet, France); vital signs and clinical symptoms, were assessed by the investigator according to the Aging Male’s Symptoms (AMS) rating scale [15] and adhesiveness and local tolerability according to the USA Food and Drug Administration (FDA) guidelines [16]; notification of any skin reaction was reported by the patient. Patients with treatment-emergent adverse events (TEAEs) were tabulated by group according to the MeDRA V6.1 coding system. Inclusion Criteria • Age >18 years. • Body mass index (BMI) !32 kg/m2 • Signed an informed consent at inclusion and every year thereafter • TT concentration of !2.5 ng/mL. Exclusion Criteria • PSA concentration of "2 ng/mL, haematocrit "52%, blood pressure >160/90 mmHg, glucose level of >7.1 mmol/L. • Diabetes, epilepsy, migraine, asthma, liver or renal failure, oedema, hirsutism, psoriasis, eczema. • History of allergy to patch, alcohol or drug abuse, history of cancer. • Treatment with barbiturates, anticoagulants, insulin, ketoconazole, spironolactone, finasteride, anti-androgens, LHRH analogues, sildenafil. At the end of each year, a 1-year extension was proposed to the patient and, for consenting patients, preventive measures were taken. The scientific committee agreed that the threshold concentration for study continuation was a PSA concentration of >3 ng/mL. Patients and Methods Treatment This was a European multicentre (Belgium, France, Germany, the Netherlands and Spain), open label, 6-year Testopatch is a matricial, ‘drug-in-adhesive’ transdermal delivery system, consisting of a transparent backing film, a 2 © 2013 BJU International PSA change during 6 years of transdermal testosterone release liner and, in-between, an adhesive matrix contains 0.5 mg/cm2 testosterone and each 60 cm2 Testopatch delivers 2.4 mg/24 h [17,18]. Two patches were applied for 2 days to the upper arm, lower back, upper buttock or thigh. Results Patient Demographics In all, 200 patients with primary (48%) or secondary (52%) hypogonadism [mean (sd) age 41.0 (12.5) years; median (range) 40 (18–68) years, mean (sd) bodyweight 82.5(13.7) kg, height 177.2 (9.3) cm, BMI 26.2 (3.4) kg/m2]. were treated with Testopatch; 161 patients completed the first year and 115 patients entered into the study extension: 97, 73, 59, 57 and 51 patients (26%) completed 2, 3, 4, 5 and 6 years, respectively. Over time, the ratio between primary and secondary hypogonadism did not change. At study end, 26 patients had primary and 25 secondary hypogonadism. The high non-completer rate seen at the end of the first year is due to administrative reasons; when the extension was administratively accepted, the study was already closed for a large number of patients and they could not enter into the extension (accounting for 11.5% of the overall discontinuation rate). Furthermore, one investigating centre in the Netherlands was closed due to a restructure of the hospital facilities (patients lost to follow-up) and, in a Belgian centre, the investigator decided to switch patients to a phase I study. Discontinuation due to a lack of effect was low (insufficient response 7.5%). Apart from the administrative reasons, described above, that account for the high non-completer rate, the main treatment-related reasons for study discontinuation included local tolerability (15.0%), patch adhesiveness (9.5%) and inconvenience (5.5%) [together accounting for 60.5% of non-completers and discontinuations]. Other reasons were serious AEs (1.5%), AEs (3.5%), laboratory eligibility criteria (2.5%), compliance (1%), sponsor decision (1.5%) and other (3.5%). Population Data Sets The intention-to-treat (ITT) safety data set comprised 200 patients who signed the informed consent and applied two patches at least once. The ‘ITT efficacy’ data set included patients with at least one available on-treatment testosterone assessment (the first assessment was after 3 months of treatment). The ‘completers’ data set consisted of patients who completed the 6-year study. Hormone Concentrations For each time point, TT concentrations are shown in Table 1 using Hodges-Lehmann estimates (95% CI) and Table 1 Testosterone concentrations (ng/mL) at baseline and at each time point. Time, months Patients, n Hodges-Lehmann estimate (95% CI), ng/mL 183 145 133 104 98 81 75 62 59 57 57 53 51 1.33 (1.18–1.47) 5.50 (5.26–6.65) 4.92 (4.38–5.48) 4.93 (4.38–5.48) 4.22 (3.77–4.74) 4.52 (3.96–5.07) 4.37 (3.93–4.86) 4.78 (4.26–5.23) 4.53 (4.03–4.95) 4.21 (3.82–4.66) 5.26 (4.50–5.91) 5.53 (4.86–6.25) 5.18 (4.48–6.02) Baseline 6 12 18 24 30 36 42 48 54 60 66 72 For each time point, testosterone concentrations are given using Hodges-Lehmann estimates (95% CI) and using mean values (minimum, median, maximum, 95% CI), depicted in Figure 1 with box plots. It should be noted that the usual mean, which relies on the assumption of symmetric distribution, was not adequate to assess hormone concentrations. It is the same for the median, which does not reflect the impact of skew on the distribution. Consequently, the Hodges-Lehmann estimator, which is less sensitive to outliers than the mean, was regarded as a more robust estimate of the central position of the distribution (i.e. the location parameter). using mean values (minimum, median, maximum, 95% CI), depicted in Fig. 1 with box plots. It should be noted that the usual mean, which relies on the assumption of symmetric distribution, was not adequate to assess hormone concentrations. The median also does not reflect the impact of skew on the distribution. Consequently, the Hodges-Lehman estimator, which is less sensitive to outliers than the mean, was regarded as a more robust estimate of the central position of the distribution (i.e. the location parameter). In the ‘ITT efficacy’ data set, TT concentrations were restored in the low–middle range, fluctuating around 4.5–5.5 ng/mL during the study. BT, DHT and E2 were also restored within the normal range and remained stable over time. At the end of the 6-year study, there were 51 ‘completers’. These ‘completers’ showed an identical response to the ITT group for all evaluated parameters (see Fig. 2 for testosterone). Biological Response In the ‘ITT efficacy’ data set, the total AMS score decreased from 37.83 (14.17) at baseline to 28.85 (10.76), and the psychological, somatic and sexual sub-scores from 9.81 (4.35) to 7.81 (2.82), from 15.92 (6.29) to 12.38 (4.94) and from 12.09 (5.48) to 8.29 (3.15), respectively, over the 6 years of the study. The somatic and sexual sub-scores appeared to be the most sensitive to testosterone treatment: both decreased rapidly during the first 6 months and © 2013 BJU International 3 Raynaud et al. Fig. 1 Total testosterone (TT) levels by visits in 4 Clipped Boxes the intention-to-treat (ITT) efficacy “All 15 available” samples. 14 13 Total Testosterone, ng/mL 12 11 10 9 8 7 6 5 4 3 2 1 0 M0 M6 M12 M18 M24 M30 M36 M42 M48 M54 M60 M66 M72 Visits, Months Max at M6 = 27.5, at M12 = 47.9, at M24 = 15.4, at M72 = 18.3 (Patients with TT levels > 15 ng/mL: At M6: Patient # 1301, TT = 18.68; Patient # 2438: TT = 18.19; Patient # 4107: TT = 27.54; Patient # 5014: TT = 24.55; At M12: Patient # 1208: TT = 47.94; Patient 4211: TT = 23.01; At M24: Patient # 1301, TT = 15.43; At M72: Patient # 2447: TT = 18.3) remained stable thereafter. At study end, the total AMS score was at the same level as that seen in a normal population of healthy volunteers, as described by Raynaud et al. [19]. The low impact on the psychological sub-score suggests that the response was not associated with a placebo effect. Biochemical Analysis Over the 6 years of the study, erythrocyte levels increased <2%, haemoglobin <5% and the mean haematocrit increased from 44% to 46%. Triglyceride levels remained stable. Cholesterol levels decreased by 10% during the first 2 years and remained stable thereafter. Low-density lipoprotein decreased during the first 3 years, and then increased slightly. High-density lipoprotein levels fluctuated at ª1.35 mmol/L. None of these changes were of clinical significance. There were no changes in creatinine, sodium, potassium, chloride, calcium and glucose levels. There were no clinically relevant mean changes in blood pressure and heart rate. The mean change in patient weight remained <3 kg. 4 © 2013 BJU International Prostate Safety Mean PSA concentration and mean changes In the ‘ITT safety’ data set (n = 200), the mean PSA concentration increased from 0.47 ng/mL at baseline to 0.60 ng/mL at 3 months and then steadily increased at each time point, up to 0.80 ng/mL after 6 years (Table 2, Fig. 3). In the ‘completers’ data set (n = 51), mean PSA concentrations and the change in mean PSA over the 6 years of the study had the same profile of distribution as those observed in the ‘ITT safety’ data set (Table 2). In the ‘ITT safety’ data set, >90.0% of patients had PSA concentrations of <2 ng/mL over the 6 years of the study. Less than 5% of patients had a PSA concentration of 2–4 ng/mL between 3 and 42 months and, 3–10% between 48 and 72 months. One patient (number 1103) who had a PSA concentration of 3.1 ng/mL at 12 months was withdrawn by the sponsor because this value did not meet the inclusion criteria (PSA threshold concentration >3 ng/mL) for entry into the first year of the extension. One month after being withdrawn, PSA change during 6 years of transdermal testosterone Fig. 2 Total testosterone (TT) levels by visits in 4 Clipped Boxes the Completers “All available samples”. 15 14 13 Total Testosterone, ng/mL 12 11 10 9 8 7 6 5 4 3 2 1 0 M0 M6 M12 M18 M24 M30 M36 M42 M48 M54 M60 M66 M72 Visits , Months Max at M6 = 18.7, at M12 = 47.9, at M24 = 15.4, at M72 = 18.3 (At M6: patient #1301, TT = 18.7; patient #2438, TT = 18.19; At M12: patient # 1208, TT = 47.9; At M72: patient # 2447, TT = 18.3) the patient had prostatitis with a PSA concentration of 43.75 ng/mL. PSA concentrations decreased to 6.4 ng/mL and to 2.0 ng/mL, 3 and 6 months later, respectively. The patient received oral testosterone undecanoate (Pantestone®) and PSA concentrations were 3.3 and 3.5 ng/mL, at 3 and 6 years, respectively. During a short period, seven patients had a PSA concentration of >4 ng/mL. Among these patients, five had an episode of prostatitis and PSA concentrations returned to <4 ng/mL within 3–6 months following adequate treatment (Table 3). The sixth patient (number 2102), aged 49 years, had a PSA concentration of 6.8 ng/mL at 60 months that remained >4 ng/mL (5.88 ng/mL) 1 month later, at which point the patient discontinued. A DRE and an echography revealed no prostatic hypertrophy but a hypoechogenic mass. A suspect biopsy led to a tomodensitometry analysis. Results were negative and antibiotic treatment induced a PSA decrease to 2.39 ng/mL 1 month later. The seventh patient (number 4213), aged 59 years, with a history of TURP 6 years before entering the study, showed the following PSA evolution: a concentration of 1.60 ng/mL at baseline, 3.80 ng/mL at 12 months, with a re-test indicating a concentration of 4.70 ng/mL. Subsequently, the PSA concentration increased to 5.4 ng/mL at 18 months and the patient was withdrawn from the study. No biopsy was taken. Among the 200 patients, 193 patients (96.5%) had no PSA concentrations >4 ng/mL and 188 patients (94.0%) had no increase >1.4 ng/mL within any 12-month period of treatment. DRE was normal at each examination. No prostate cancer was reported during the study. The change in mean PSA increased by 0.14 ng/mL at 3 months and then progressively increased up to 0.30 ng/mL until the end of the trial. As shown in Table 2, the lower 95% CI indicates that the increase was already statistically significant at 3 months and significance was maintained at all future time points, until the end of the study, in both the ITT safety population and the ‘completers’. Considering that this initial increase in mean PSA concentration could be due to replenishment of the androgen binding sites after androgen depletion during the wash-out period, the increase between PSA concentrations at 3 months and all subsequent time points was analysed. Increases in PSA concentrations between 3 months and 6, 12, 18, 24, 30, 36, 42, 48 and 54 months were not statistically significant. However, the slow but constant increase became significant at the fifth and sixth year. Similar results were seen when the value of reference for PSA concentration was taken at 6 and 12 months. © 2013 BJU International 5 Raynaud et al. Table 2 Mean and change in PSA concentrations (ng/mL) in the ITT safety and completers population. ITT safety 3 months Baseline Value Change 6 months Baseline Value Change 12 months Baseline Value Change 18 months Baseline Value Change 24 months Baseline Value Change 30 months Baseline Value Change 36 months Baseline Value Change 42 months Baseline Value Change 48 months Baseline Value Change 54 months Baseline Value Change 60 months Baseline Value Change 66 months Baseline Value Change 72 months Baseline Value Change Completers Mean (sd) Min/median/max 95% CI Mean (sd) Min/median/max 95% CI N = 185 0.46 (0.42) 0.60 (0.50) 0.14 (0.35) N = 157 0.45 (0.41) 0.67 (0.86) 0.22 (0.72) N = 145 0.47 (0.41) 0.76 (1.38) 0.29 (1.31) N = 105 0.49 (0.41) 0.70 (0.65) 0.21 (0.48) N = 98 0.48 (0.39) 0.61 (0.48) 0.13 (0.35) N = 80 0.47 (0.37) 0.68 (0.62) 0.21 (0.56) N = 75 0.48 (0.38) 0.64 (0.47) 0.16 (0.35) N = 62 0.49 (0.40) 0.71 (0.59) 0.22 (0.38) N = 59 0.50 (0.41) 0.75 (0.65) 0.25 (0.52) N = 57 0.50 (0.41) 0.74 (0.53) 0.24 (0.41) N = 57 0.50 (0.41) 1.01 (1.35) 0.51 (1.21) N = 54 0.50 (0.42) 0.78 (0.63) 0.28 (0.42) N = 51 0.50 (0.43) 0.80 (0.59) 0.30 (0.38) N = 185 0.05/0.4/2.5 0.05/0.5/4.2 -1.0/0.1/2.6 N = 157 0.05/0.4/1.9 0.05/0.5/9.3 -1.2/0.1/8.1 N = 145 0.05/0.4/1.9 0.05/0.5/15.7 -1.1/0.1/15.2 N = 105 0.05/0.4/1.9 0.05/0.5/5.4 -1.1/0.1/3.8 N = 98 0.05/0.4/1.9 0.05/0.5/3.0 -1.1/0.1/1.5 N = 80 0.05/0.4/1.9 0.1/0.5/4.5 -1.0/0.1/4.5 N = 75 0.05/0.4/1.9 0.1/0.5/2.2 -1.2/0.15/1.5 N = 62 0.05/0.4/1.9 0.05/0.5/3.0 -1.0/0.2/1.7 N = 59 0.05/0.4/1.9 0.1/0.6/3.1 -1.0/0.1/2.4 N = 57 0.05/0.4/1.9 0.1/0.6/2.6 -0.8/0.2/1.5 N = 57 0.05/0.4/1.9 0.05/0.7/6.8 -1.2/0.2/6.0 N = 54 0.05/0.4/1.9 0.1/0.6/3.0 -0.9/0.2/1.5 N = 51 0.05/0.4/1.9 0.1/0.7/2.5 -0.80/0.3/1.5 N = 185 N = 52 0.50 (0.43) 0.64 (0.44) 0.14 (0.36) N = 52 0.50 (0.43) 0.67 (0.48) 0.17 (0.32) N = 52 0.50 (0.43) 0.66 (0.46) 0.16 (0.33) N = 52 0.50 (0.43) 0.67 (0.45) 0.17 (0.34) N = 52 0.50 (0.42) 0.66 (0.48) 0.16 (0.35) N = 52 0.50 (0.42) 0.76 (0.73 0.26 (0.68) N = 52 0.50 (0.43) 0.68 (0.52) 0.18 (0.39) N = 52 0.50 (0.43) 0.75 (0.57) 0.25 (0.41) N = 52 0.50 (0.43) 0.74 (0.59) 0.23 (0.48) N = 52 0.50 (0.43) 0.75 (0.54) 0.25 (0.42) N = 52 0.50 (0.43) 0.95 (1.15) 0.45 (0.99) N = 52 0.50 (0.43) 0.79 (0.64) 0.29 (0.42) N = 51 0.50 (0.43) 0.80 (0.59) 0.30 (0.38) N = 52 0.05/0.4/1.9 0.10/0.5/1.9 -1.0/0.1/1.6 N = 52 0.05/0.4/1.9 0.1/0.6/2.2 -1.2/0.2/0.9 N = 52 0.05/0.4/1.9 0.1/0.5/2.5 -1.1/0.1/1.2 N = 52 0.05/0.4/1.9 0.1/0.6/2.3 -1.1/0.15/1.2 N = 52 0.05/0.4/1.9 0.1/0.6/2.4 -1.1/0.2/1.2 N = 52 0.05/0.4/1.9 0.1/0.6/4.5 -1.0/0.2/4.5 N = 52 0.05/0.4/1.9 0.1/0.5/2.2 -1.2/0.2/1.5 N = 52 0.05/0.4/1.9 0.05/0.6/3.0 -1.0/0.2/1.7 N = 52 0.05/0.4/1.9 0.1/0.6/2.7 -1.0/0.15/2.4 N = 52 0.05/0.4/1.9 0.1/0.65/2.6 -0.8/0.2/1.5 N = 52 0.05/0.4/1.9 0.05/0.7/6.3 -1.2/0.2/5.7 N = 52 0.05/0.4/1.9 0.1/0.6/3.0 -0.9/0.2/1.5 N = 51 0.05/0.4/1.9 0.1/0.7/2.5 -0.80/0.3/1.5 N = 52 0.53–0.68 0.09–0.19 N = 157 0.54–0.81 0.10–0.33 N = 145 0.53–0.98 0.07–0.50 N = 105 0.58–0.83 0.11–0.30 N = 98 0.51–0.70 0.06–0.20 N = 80 0.54–0.82 0.08–0.33 N = 75 0.53–0.75 0.08–0.24 N = 62 0.57–0.85 0.13–0.32 N = 59 0.58–0.92 0.12–0.39 N = 57 0.60–0.88 0.13–0.35 N = 57 0.65–1.37 0.19–0.83 N = 54 0.61–0.95 0.17–0.40 N = 51 0.64–0.97 0.19–0.41 PSA velocity PSA velocity (ng/mL/year) remained stable over the 6 years of the study, ranging from 0.00 to 0.02 ng/mL/year, except at 60 months, when PSA velocity increased up to 0.08 ng/mL/year due to an outlier value corresponding to a patient with prostatitis. In all, 10 patients had at least one PSA velocity value >0.4 ng/mL/year. 6 © 2013 BJU International 0.51–0.76 0.04–0.24 N = 52 0.53–0.80 0.08–0.26 N = 52 0.53–0.79 0.07–0.25 N = 52 0.55–0.80 0.08–0.27 N = 52 0.53–0.80 0.07–0.26 N = 52 0.56–0.97 0.07–0.45 N = 52 0.54–0.83 0.07–0.29 N = 52 0.59–0.91 0.14–0.36 N = 52 0.57–0.90 0.10–0.37 N = 52 0.60–0.90 0.13–0.37 N = 52 0.63–1.26 0.17–0.72 N = 52 0.61–0.97 0.18–0.41 N = 51 0.64–0.97 0.19–0.41 Considering all 200 patients, only four had PSA concentrations >4 ng/mL, a PSA increase >1.4 ng/mL and a PSA velocity >0.4 ng/mL/year AEs For the 36 serious AEs reported by 25 patients, a causal relationship with the study drug was excluded, except for PSA change during 6 years of transdermal testosterone Fig. 3 Prostate Specific Antigen (PSA) 5 Clipped Boxes concentrations by visits [Intention-to-treat 4.0 (ITT) – Safety]. 3.5 3.0 PSA, ng/mL 2.5 2.0 1.5 1.0 0.5 0 M0 M6 M12 M18 M24 M30 M36 M42 M48 M54 M60 M66 M72 Visits, Months Max at M6 = 9.3, at M12 = 15.7, at M18 = 5.4, at M30 = 4.5, at M60 = 6.8 Table 3 Patients with a PSA concentration increase of >4 ng/mL. Patient number. 2408* 2001* 2423* 2528* 2418* 2102 4213 Age, years PSA, ng/mL baseline PSA, ng/mL (month) PSA, ng/mL (month) Follow-up 26 30 46 36 61 49 59 0.2 0.6 1.4 0.5 1.2 0.8 1.6 4.5 (30) 6.3 (66) 4.5 (60) 15.7 (12) 9.3 (6) 6.8 (60) 4.2 (3) 0.8 (36) 1.2 (66) 2.5 (62) 0.5 (18) 2.9 (12) 5.9 (61) 5.4 (18) Remained in the trial until study end; PSA 0.35 ng/mL Remained in the trial until study end; PSA 1.0 ng/mL Remained in the trial until study end; PSA 0.35 ng/mL Discontinued (month 24) due to inconvenience; PSA 0.5 ng/mL Discontinued (month 12) due to local tolerability; PSA 2.9 ng/mL Withdrawn (month 61); antibiotics (month 64): PSA 2.4 ng/mL Patient was withdrawn (month 18); PSA 5.4 ng/mL *All five patients had prostatitis, which was resolved !6 months by antibiotic treatment. two patients. One patient presented an exacerbation of chronic fatigue syndrome and low back pain, and the second patient presented a transient ischaemic attack at 46 months (causal relationship was deemed to be doubtful). One patient (aged 39 years) died after the first 6 months of treatment: he had McCune-Albright syndrome and used a wheelchair due to hip dysplasia for a period of 5 years. The patient, hospitalised due to a fall leading to a non-displaced fracture of the right humerus, slipped 1 week later, suffering from quadriplegia (C1–C2 dislocation with compression) and died from a pulmonary embolism. These events were considered as not related to the study drug by the investigators and by the sponsor. In all, 155 patients reported a total of 1136 TEAEs; a relationship with treatment was not excluded for 380 TEAEs. Administration site reactions were one of the most frequent TEAEs. According to the investigators, during the study, 44.3–62.6% of patients had no evidence of skin irritation, 32.2–50.7% of patients had minimal erythema, barely perceptible; definite erythema, readily visible appeared in <6.3% of patients and erythema and papules in two patients only. Local corrective treatment (topical corticosteroids), which is frequently needed during © 2013 BJU International 7 Raynaud et al. Androderm® application [20,21], was only required for two patients. Discussion The present interventional study was conducted to assess the long-term safety of a treatment, Testopatch, which restores testosterone concentrations within the physiological range. In the present study, every year each patient had the choice to continue and the sponsor or investigator had the opportunity to exclude a patient if the PSA concentration was >3 ng/mL and/or if the testosterone concentration was <2.5 ng/mL. Based on these laboratory eligibility criteria, only five of 200 patients withdrew from the study. There were no significant safety events at the highest dosage of Testopatch. Unfortunately, it was very difficult to follow patients once they stopped treatment, either after discontinuation or at study closure. However, it was of interest to verify whether, with ageing during the study, patients were exposed to a potential prostate safety problem. This appears not to be the case and, furthermore, strongly indicates that any sharp increase in PSA concentration is due to prostatitis and not due to an exacerbation of a latent cancer. In the seven patients with an increase of PSA concentration of >4 ng/mL, for six of them the increase in PSA was retested to eliminate laboratory errors, and antibiotics were administered, resulting in an immediate decrease in PSA concentrations and a return to initial values within 6 months. Thus, when a sharp increase in PSA concentration is seen in a hypogonadal treated patient, it is essential to verify the presence of prostatitis and initiate antibiotic treatment, if necessary, before stopping TRT and embarking on an invasive search for prostate cancer. The small PSA concentration increase in the present study is indicative of the physiological stimulation of the prostate by testosterone and its metabolites [22]. It has been postulated in the Saturation Model [23] that ‘physiologic concentrations of testosterone provide an excess of testosterone and DHT for optimal prostatic growth requirements. However, reducing testosterone concentration below a critical concentration threshold (the saturation point) creates an intracellular milieu in which the availability of androgen becomes the rate-limiting step governing prostate growth’. This model is based on evidence that binding of androgen to the androgen receptor follows a similar saturation curve [24]. That the hypogonadal patients had been deprived of treatment by a wash-out period could explain that the secretion of PSA became sensitive to the re-introduction of exogenous testosterone and increased until reaching a plateau within 3 months. This has been reported previously by Arver et al. [4] who showed that PSA concentrations 8 © 2013 BJU International decreased from 1.0 ng/mL during i.m. testosterone enanthate treatment to 0.5 ng/mL after a 3–4 week wash-out period and increased to 0.66 ng/mL during permeation-enhanced transdermal testosterone treatment. In a small group of 25 consecutive men who received testosterone gel for 1 year, Rhoden and Morgentaler [25] reported a mean increase in baseline PSA concentrations after 1 year of treatment (0.18 ng/mL) that was similar to concentrations seen in the present study (0.21 ng/mL), despite the fact that baseline PSA concentrations [mean (sd) 1.8 (1.9) ng/mL) were higher than those in the present study [0.46 (0.42) ng/mL]. Furthermore, in the study by Rhoden and Morgentaler, although a proportion (21%) of all patients had decreased PSA concentrations after 1 year of treatment with i.m. testosterone (n = 33) or testosterone gel (n = 25), PSA concentrations in almost 80% of patients were either unchanged or increased [25]; the authors concluded that TRT caused only a mild increase in PSA concentrations in most hypogonadal men and did not appear to be influenced by the mode of TRT, age, or baseline PSA or testosterone concentrations [25]. In a multicentre, randomised, cross-over study [26], 44 men aged >18 years and with a TT concentration of !2.5 ng/mL after a wash-out period, received either two patches (Testopatch) every other day in the morning or two capsules (Pantestone; 40 mg twice daily), each treatment for a 22-day period. PSA concentrations were slightly increased, by 0.18 and 0.15 ng/mL, at the end of the first treatment period [from a mean (sd) 0.78 (0.66) to 0.96 (0.76) ng/mL, and from 0.81 (0.75) to 0.96 (0.86) ng/mL for Testopatch and Pantestone, respectively). Thus, the small increase in PSA concentration after testosterone administration is very rapid. Only three patients in each group had a PSA concentration of >2 ng/mL after the first treatment period. Of these six patients, three already had elevated PSA concentrations at screening. The maximum PSA concentration recorded was 3.23 ng/mL, after Pantestone treatment. In a 6-month cross-sectional study, in which hypogonadal patients were treated with testosterone preparations, the prostate volume increased to a level that can be expected in normal men of comparable age [7]. It has been reported that there was little change in the PSA concentrations in patients continuing on TRT >2 years, despite increases in mean TT or BT concentrations [27]. Patient numbers were very different between the start and the end of the present study and, at study end, the population was 6 years older. Furthermore, all patients had been hypogonadal for many years and were undergoing TRT. Depending on the formulation, patients had to stop treatment from 1 to 3 weeks before entering into the trial. We do not know the PSA concentration when the patient PSA change during 6 years of transdermal testosterone was on TRT, thus baseline values were somewhat underestimated and we cannot appreciate how worrisome the rise in PSA concentration is over time with TRT. In the present study, 15% of patients treated with Testopatch withdrew due to local tolerability concerns. As expected for a transdermal product, skin irritation was the most commonly reported AE. However, this must be placed in perspective by comparison with other marketed patches [4,20,21]. For example, Arver et al. [4] reported that, in a 1-year long-term efficacy and safety study of a permeation-enhanced testosterone transdermal system in hypogonadal men, while 56% of patients had transient erythema or itching at some time during the study, only 9% discontinued transdermal TRT due to skin irritation and that mild skin irritation was ameliorated by applying topical hydrotestosterone or diphenhydramine. Furthermore, the present study was of 1-year duration in only 36 patients, compared with the overall study duration (6 years) including 200 patients, thus amplifying the reasons for discontinuation due to local tolerability. No prostate cancer was reported during the present study and there was no correlation between testosterone concentrations and an increase in PSA concentration. The mean age of patients (41 years) and the limited number of patients (200) included in the present study population, preclude the ability to draw definite conclusions relating to an increased risk of prostate cancer. This study population, with a median age lower than the common age for prostate cancer, is representative of men with primary or secondary hypogonadism already receiving conventional TRT. Results cannot be extrapolated to the ageing male testosterone-deficient population, but they add evidence with regard to the safety of TRT in ageing males. In a very elegant study, Morgentaler et al. [28] have shown that TRT in men with untreated prostate cancer (Gleason score 6) and elected to active surveillance, the PSA concentration did not increase after a median of 2.5 years and patients had an improvement in quality of life (libido, sexual performance, mood and energy). The reluctance to treat patients is essentially based upon a risk assessment. Should we treat symptomatic patients when we do not know to what extent TRT increases prostate cancer risk and promotes prostate cancer growth? Suppression of testicular androgen secretion by castration (surgical or medical) causes prostate cancer regression but it has never been either observed or demonstrated that raising testosterone concentrations in hypogonadal intact men leads to enhanced prostate cancer growth. Currently, the absolute contraindication for TRT is prostate cancer, even if there is no solid evidence that exogenous androgens promote the development of prostate cancer [29,30]. According to Morgentaler [31], ‘the withholding of TRT in men because of the fear of prostate cancer risk or progression is no longer tenable in an age of evidence-based medicine, because neither evidence nor theory supports this position. It is time for a more sophisticated rethinking of the relation between testosterone and prostate cancer, one that is still internally consistent, scientifically based, and accounts for all the risk and various set of clinical and research data regarding prostate cancer and hormones’. The results of the present study support the concept that TRT is not associated with significant prostate risks. Only a minor change in PSA concentration was noted over 5 years of study, and no cancers were detected. In conclusion, for prostate safety, as evidenced by no relevant changes in PSA concentrations and PSA velocity, Testopatch (2 ¥ 60 cm2) applied every 2 days is safe. Acknowledgements The authors gratefully acknowledge the other members of the Testopatch Study Group: L. Bassas, Fundación Puigvert, Barcelona, Spain; A. Beckers, CHU Liège, Liège, Belgium; M. Berse, Urologische Praxis, Duisburg, Germany; P. Bondil, Centre Hospitalier de Chambéry, Chambéry, France; A. Charro, Hospital Clínico San Carlos, Madrid, Spain; D. Chevallier, Hôpital Pasteur, Nice, France; F. Comhaire, UZ Gent, Gent, Belgium; P. Coremans, UZA, Dienst Fertiliteit, Edegem, Belgium; B. Cuzin, Hôpital Edouard Herriot, Lyon, France; B. Delemer, Hôpital de Maison Blanche, Reims, France; J. Duarte, Hop.12 de Octubre, Madrid, Spain; E. Hellmis, Urologische Gemeinschaftspraxis, Duisburg, Germany; J. Hermabessière, Centre République, Clermont-Ferrand, France; A. Hermus, Universitair Medisch Centrum St Radboud, Nijmegen, the Netherlands; H. Koppeschaar, Universitair Medisch Centrum Utrecht, Utrecht, the Netherlands; J-M. Kuhn, CHU de Rouen, Bois Guillaume, France; A. Leriche, Hôpital Henry Gabrielle, St Genis Laval, France; J-P. Louvet, CHU Rangueil-Larrey, Toulouse, France; J.M. Miralles, Hospital Clínico Universitario de Salamanca, Salamanca, Spain; M. Pugeat, Hôpital Neuro Unité 34, Bron, France; W. Ricart, Hospital Universitari Josep Trueta; Girona, Spain; A. Sanmarti, Hospital Germans Trias i Pujol, Badalona, Spain; J. Soler, Ciutat Sanitaria i Universitaria de Bellvitge, L’ Hospitalet de Llobregat, Spain; W. Spiegelhalder, Urologische Praxis, Mettman, Germany; C. Stief, Ludwigs-Maximilians-Universität, München, Germany; A. 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