The role of TRT in the management of hypogonadism and TRT: Dispelling the myths. Dr Geoff Hackett

Transcription

1 The role of TRT in the management of hypogonadism and TRT: Dispelling the myths Dr Geoff Hackett

2 Safety concerns over testosterone replacement therapy (TRT) Concerns over the safety of testosterone may have contributed to underuse of TRT Cardiovascular (CV) risk Prostate cancer and other prostate disorders (e.g. BPH) Extensive evidence shows that neither of these safety issues now warrants the concerns raised

3 Cardiovascular

4 Incidence of CHD (%) Testosterone and cardiac risk incidence of coronary heart disease (CHD) higher in men 60 Age-related incidence of CHD in the general population through 26 years 50 Males 40 Females Age (years) N=5,127 Lerner DJ & Kannel WB. Am Heart J 1986;111:

5 Cumulative survival CV mortality: adjusted survival by quartile of total testosterone in men aged yrs in the EPIC-Norfolk Study ,1 1 Testosterone 4 highest lowest 0,9 0,8 0, Years of follow up N=2,314 Khaw KT et al. Circulation 2007;116:

6 The Norway Tromsø-Study: androgens and the prospective mortality risk Number of deaths from all causes by decentiles of free testosterone N=1,687 Vikan T et al. Eur J Endocrinol 2009;161:

7 Proportion free of MACE lethality Proportion free of MACE lethality as a function of baseline testosterone in a consecutive series of 1,687 ED subjects TT 10.4 nmol/l TT nmol/l TT < 8 nmol/l p=ns p<0.05 vs. TT 10.4 p< vs. TT 10.4 Corona G et al. J Sex Med 2010;7: Follow up (years) N=1,687

8 Testosterone and coronary artery disease (CAD) Bioavailable testosterone (BT) levels are significantly reduced in males with CAD Approximately 1 in 4 men (23.4%) with CAD have serum T levels within the clinically hypogonadal range (93.5% positive ADAM questionnaire) TRT improves anginal symptoms and cardiac ischaemia TRT improves functional capacity and NYHA class compared with placebo Malkin et al showed a significant correlation between the increase in BT with treatment and the increase in walking distance, with results sustained over 12 months English et al. Eur. Heart J 2000;21: ; English et al. Circulation. 2000;102: ; Pugh et al. Endocrine Society Abstract 2003:p225. Malkin et al. Eur Heart J 2006;27:57 64.

9 Time (sec) Studies in men with cardiovascular disease Physiologic testosterone therapy (5mg T patch/d/3 months) improves angina threshold in men with chronic stable angina double-blind, randomised, placebo-controlled, add-on trial p= NS Baseline Week 6 Week 14 Baseline Week 6 Week 14 Testosterone Placebo English KM et al. Circulation 2000;102:

10 Proportion of men (%) Hypogonadism is present in a high proportion of men with CAD tt < 7.5 nmol/l and/or bt < 2.5 nmol/l tt < 12 nmol/l and/or bt < 4 nmol/l N=891 South Yorkshire Study, Pugh et al., unpublished.

11 Effect of baseline BT on all-cause mortality in men with proven CHD mean follow up 6.9 years N=930 Malkin CJ et al. Heart 2010;96:

12 Serum levels of total testosterone in men with cardiac heart failure (CHF) by NYHA Class Jankowska EA et al. Circulation 2006;114:

13 Pooled odds ratios for adverse CV events of TRT Event Testosterone rate (per 1,000 patientyears) Placebo rate (per 1,000 patientyears) Pooled odd ratio (95% CI) Haematocrit >50% *(0.46,2.52) Chest pain ischaemia (0.40;2.44) Myocardial infarction (0.67; 2.09 Coronary procedure, CABG Atrial fibrillation/ arrhythmia Cerebrovascular events All cardiovascular events Death Calof et al. 2005, cited by Buvat J et al. J Sex Med 2010;7: *Odd ratio significantly different from placebo CABG = coronary artery bypass graft

14 Adverse events of testosterone therapy in adult men: a systematic review and meta-analysis Fernández-Balsells MM et al. J Clin Endocrinol Metab 2010;95:

15 Distance walked (m) Studies in men with CVD Testosterone treatment improves exercise capacity in men with chronic heart failure randomised, doubleblind, placebo-controlled trial p=0.001 p=0.122 Baseline 12 weeks Baseline 12 weeks Testosterone Placebo Pugh PJ et al. Heart 2004;90:

16 LDL cholesterol (mmol/l) HDL cholesterol (mmol/l) Lipids: LDL and HDL absolute changes Testosterone Placebo -1E-15 0,2-0,1-0,2 0,1-0,3 0-0,4-0,1-0,5-0,6 p= wk vs. baseline 30 wk vs. baseline -0,2 p= wk vs. baseline 30 wk vs. Baseline Time Time Kalinchenko S et al. Clin Endocrinol 2010;73(5):

17 C-reactive protein (mg/dl) Tumour necrosis factor α (pg/ml) Inflammation: CRP and TNFα 5 (normal range: 0 5) 1,3 (normal range: 0) p= , p<0.001 Baseline Time (weeks) 1,1 1 0,9 Testosterone Placebo Baseline Time (weeks) Kalinchenko S et al. Clin Endocrinol 2010;73(5):

18 Testosterone replacement could reduce deaths in men with type 2 diabetes N=587 Jones TH. Endocrine Abstracts 2011;25:163.

19 Testosterone treatment is associated with reduced mortality in men with low serum testosterone levels Design: An observational, retrospective cohort study using VA electronic medical records, from Jan 2001 through Dec 2005, of 1,031 male veterans, 40 years or older, with low tt levels ( 250 ng/dl), excluding those with a history of prostate cancer and baseline anti-androgen or TRT Results: The T-treated men comprised 36% of the cohort (n=372) and were treated for an average of (SD) months. In unadjusted analyses, treated men had a cumulative mortality of 10% compared with 21% in the untreated men (p<0.001). Effect modification was noted with age, diabetes and coronary heart disease (p<0.05 for all) with a greater mortality reduction in men aged 40 65, with diabetes, and without cardiac disease Conclusions: Our data suggest that testosterone treatment in men with low testosterone levels is associated with decreased mortality, particularly in men aged and in diabetic men Shores et al. Endocr Rev, Vol (MeetingAbstracts): P1 772.

20 Adverse events associated with testosterone administration In this study, the testosterone dose applied was not in accordance with the product labelling, clearly recommending a starting dose of 50 mg testosterone (5 g Testim ). In the study, the starting dose was 100 mg testosterone (10 g Testim ). The dose of 150 mg testosterone (15 g Testim ) per day is not at all mentioned in the product labelling The study included patients with a high CV risk profile The study design does not comply with guidelines and recommendations on testosterone therapy and monitoring for hypogonadism by the medical societies The study was not sufficiently powered to give significance for CV events as AEs or SAEs respectively were not endpoints The adverse events usually occurred in men with higher testosterone levels There was a total low number of poorly documented events (for instance, self-reported syncope, review of medical records). These events are a mixture of different types with no clear evidence that one particular type of event is significant. Basaria S et al. N Engl J Med 2010;363(2):

21 Basaria NEJM 2009: CV-related events Basaria et al. NEJM 2010;363:

22 Editorial by William Bremner Bremner W. N Engl J Med 2010;336(2):

23 Lower testosterone levels predict incident stroke and transient ischaemic attack in older men 3,443 men at least 70 years of age in the Health In Men Study in Western Australia: A total testosterone level in the lowest quartile (<11.7 nmol/l) predicted incident stroke or TIA with a hazard ratio (HR) of 1.99 Yeap B et al. J Clin Endocrinol Metab 2009;94(7):

24 Meta-analysis of placebo-controlled testosterone trials in middle-aged and older men: cardiovascular adverse event rates per 1,000 patient-years Placebo Testosterone , , , ,3 7, ,7 5, ,8 Haematocrit > 50% 2 0 Calof OM et al. J Gerontol 2005;60A(11):

25 Testosterone and CV risk It has long been believed that high levels of testosterone may increase CV risk Results from >40 cross-sectional studies found NO association between high testosterone and CVD In approximately half of the studies that assessed the relationship between T and CHD found lower T levels in CHD patients Buvat J et al. J Sex Med 2010;7:

26 Prostate

27 Testosterone and prostate cancer risk Inverse relationship between decreasing serum testosterone concentration and the increasing prevalence of prostate cancer with age Total Testosterone (ng/dl) Relative frequency of prostate cancer > Age (years) Comhaire FH. Eur Urol. 2000;38:

28 Prostate growth or PSA The saturation model a b T-dependent range T-indifferent range c Serum testosterone concentration Morgentaler A. J Urol 2009;181:

29 Testosterone (ng/dl) Pre-treatment testosterone levels predict pathological stage in men with prostate cancer before radical prostatectomy p= Massengill JC et al. J Urol 2003;169: pt1-t2 (organ confined) pt3-t4 (nonorgan confined) 30 N=879

30 Testosterone (ng/ml) Testosterone levels and Gleason Scores in men with prostate cancer before radical prostatectomy p< Gleason score 2 6 (n=32) Gleason score 7 10 (n=17) Madersbacher S et al. Urol 2002;60:

31 PSA (µg/l) Effects on the prostate of normalising testosterone levels in hypogonadal men PSA in untreated hypogonadal men (n=47), testosterone-treated hypogonadal men (n=78), and age-matched normal men (n=75) 4 upper normal limit Untreated hypogonadal men Testosteronetreated hypogonadal men Normal men Behre H et al. Clin Endocrinol 1994;40:

32 Serum ng/dl Do high doses of testosterone induce adverse effects in the prostate? Serum PSA and testosterone flare in prostate cancer patients treated with LHRH-analogue Testosterone PSA Days following injection Tomera K et al. J Urol 2001;16: , In: Morgentaler A & Traish AM. Eur Urol 2009;55:

33 Effects on the prostate of normalising testosterone levels in hypogonadal men Meta-analysis of placebo-controlled testosterone trials in 1,070 middle-aged and older men: prostate adverse event rates per 1,000 patient-years Testosterone 40 38,7 Placebo ,3 9,2 10 2,8 0 Prostate biopsies 0 Diagnosed prostate cancer Calof OM et al. J Gerontol 2005;60A(11):

34 IPASS Nebido safety data (1,123 men) No case of prostate cancer was observed (4 prostate biopsies documented) Prostate enlargement and urinary retention occurred in 1 patient PSA (ng/ml) n Mean SD Baseline Visit Visit Visit Visit Haematocrit (%) n Mean SD Baseline Visit Visit Visit Visit PSA = prostate-specific antigen; SD = standard deviation Zitzmann M et al. Men s Health World Congress 2010.

35 Safety parameters: prostate PSA total, ng/ml Prostate volume, ml 1,2 1 0, p= p= ,6 20 0,4 0, Nebido Placebo 0 Nebido Placebo Baseline N=184 Kalinchenko S et al. Clin Endocrinol 2010;73(5):

36 Serum T Do high doses of testosterone induce adverse effects in the prostate? 3500 Serum testosterone and PSA in older men treated with escalating doses of testosterone Testosterone PSA Weekly testosterone dose (mg) Serum PSA Week 20 Bhasin S et al. J Clin Endocrinol Metab 2005;90:

37 PSA (ng/dl) Prostate volume (ml) Do high doses of testosterone induce adverse effects in the prostate? 0,9 0,8 0,7 Effect of exogenous testosterone on prostate volume and PSA in healthy young men Before TT Week 16 Week 28 Week ,6 13 0,5 0,4 0,3 12 0,2 0, mg/wk (n=10) 250 mg/wk (n=10) 500 mg/wk (n=10) mg/wk (n=10) 250 mg/wk (n=10) 500 mg/wk (n=11) Cooper CS et al. J Urol1998;159(2):

38 Changes in PSA levels during 36 months of Testogel treatment Month Wang C et al. J Clin Endocrinol Metab 2004;89(5):

39 PSA concentration (µg/l) No significant changes in PSA with 1 year of IM TU therapy 4 PSA in men with hypogonadism (n=28) presenting with ED under treatment with TU (Nebido ) Baseline 3 months 6 months 9 months 12 months Saad F et al. Arch Androl 2007;53:1 5. Normal value: <4.0 µg/l Median age: 64 years, range: 54 76

40 No significant changes in PSA after 1 year of testosterone treatment* in men with hypogonadism 4.0 PSA (ng/ml) 2.0 Before After years >60 years Injection Transdermal *IM or transdermal N=58 Rhoden EL & Morgentaler A. Int J Imp Res 2006;18:

41 PSA (µg/l) Prostate volume (ml) PSA and prostate volume during treatment with TE/TU in men with hypogonadism* 1.0 T-Enanthate T-Undecanoate 25 (Transrectal ultrasonography) Time (Weeks) Time (Weeks) *n=40 Mean age 41, range: yrs Huebler D et al. Int J Impot Res 2002;4(Suppl. 4):Abstract P52.

42 Prostate Volume (ml) Changes in prostate volume with long term TU treatment (Nebido ) Time (Weeks) Highest value in total observation period Von Eckardstein S et al. Andrologia 2004;36(4):65(Abstract).

43 Changes in PSA levels in hypogonadal men undergoing long-term treatment with TU (Nebido ) Zitzmann M et al. Endo Abstract 306. Time (weeks) N=22

44 PSA (ng/dl) Testosterone in patients at high risk of PCa Conclusions After 1 year of TRT: No increase in PSA in men with PIN is observed No significantly increased risk of cancer is observed in men without PIN Therefore, TRT is not contraindicated in men with a history of PIN Results of 1 year of testosterone treatment in hypogonadal men with prostatic intraepithelial neoplasia (PIN) 2 1,5 1 0,5 0 no PIN (n=55) Before TT After TT Change Rhoden EL & Morgentaler A. J Urol 2003;170:

45 Testosterone in patients at high risk of PCa Study Agarwal and Oefelein Kaufman and Graydon No of patients Follow-up (months) Pre-TRT PSA (ng/dl) Post-TRT PSA (ng/dl) Pre-T (ng/dl) Post-T (ng/dl) <0.1 < <0.1 < Khera et al <0.1 < Total 74 Conclusion: TRT is effective in improving testosterone levels, without increasing PSA values, in men with hypogonadism who have undergone radical prostatectomy (RP) Khera M et al. J Sex Med 2009;6:

46 Maximal urine flow (ml/s) Testosterone and lower urinary tract symptoms (LUTS) Urine flow in untreated hypogonadal men (n=47), testosterone-treated hypogonadal men (n=78), and age-matched normal men (n=75) Untreated hypogonadal men T-treated hypogonadal men Normal men Behre et al. Clin Endocrinol 1994;40:

47 Prostate volume (ml) Effects on the prostate of normalising testosterone levels in hypogonadal men Prostate volume measured by transrectal ultrasonography Hypog. pat. without therapy Hypog. pat. with therapy Normal men Age (years) Behre H et al. Clin Endocrinol 1994;40:

48 Testosterone and LUTS Effect of treatment with IM testosterone undecanoate (Nebido ) for 26 weeks on IPSS and PSA in 20 men with late-onset hypogonadism (LOH) Baseline 16 weeks 26 weeks p< NS p< , IPSS Total T 0 PSA Kalinchenko SY et al. Aging Male 2008;11(2):57 61.

49 IPSS score Bladder capacity (ml) Testosterone and LUTS Effect of treatment with testosterone gel mg/d (Testogel ) for 6 months in 24 men with LOH and ED on urinary function Baseline 6 months N S p= p= IPSS Average flow (ml/s) 500 Maximal bladder capacity (ml) Karazindiyanoğlu S & Çayan S. Aging Male 2008;11(3):

50 Testosterone and LUTS Effect of treatment with testosterone gel mg/d (Testogel ) for 6 months in 24 men with LOH and ED on urinary function p=0.037 Bladder compliance (ml/cm H2O) Baseline 6 months p=0.016 P detrusor at Qmax (cm H2O) Karazindiyanoğlu S & Çayan S. Aging Male 2008;11(3):

51 What the guidelines say about TRT and the prostate Wang C et al. Eur Urol 2009;55:

52 EAU guidelines on erectile dysfunction Treatment of erectile dysfunction Hatzimouratidis, Amar, Eardley et al. Eur Urol 2010;57(5):

53 Fact from fiction the prostate There is no evidence that endogenous testosterone is associated with prostatic diseases Treating testosterone deficiency normalises prostate development so an initial increase in prostate volume and PSA is physiologic and could be expected Based on the current scientific and medical evidence, treating hypogonadism with physiologic testosterone doses after proper diagnosis and under proper monitoring according to the guidelines can be considered acceptably safe

54 Separating the facts from the myths Fear of testosterone treatment being associated with an increased risk of prostate cancer Current literature does not provide any evidence for a cause-effect relationship between endogenous T or T treatment and prostate cancer development