ENDOCRINOLOGICAL IMPLICATIONS AND COMPLICATIONS OF TESTOSTERONE REPLACEMENT IN AGEING MEN Frederick C.W. Wu Professor of Medicine and Endocrinology Andrology Research Unit, Centre for Endocrinology and Diabetes Institute of Human Development Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, University of Manchester, U.K. Postgraduate International School of Men s Health (PRISM), Besins Healthcare Bruges,Belgium 26 th September 2014
Testosterone Replacement in Older Men Benefits Risks Monitoring
Potential Benefits of Testosterone in Older Men Sexual health Physical health Bone health Metabolic health
Baseline T <7 nmol/l Standardized mean difference (95% CI) T 7-12 nmol/l Meta-analysis of 17 intervention randomized, placebo-trials on T and sexual dysfunction in men (mean age 50 yr) T >12 nmol/l T improves sexual function only in hypogonadal men with pre-treatment T <12 nmol/l Isidori et al. Clin Endocrinol 2005
Effects of Testosterone Supplement on Lean Mass, Muscle Strength & Physical Function in Older Men in 17 RCTs Study n Mo Rx Type & Dose Lean mass Grip strength Leg strength Tenover 1992 13 3 TE 100mg/wk - - Sih 1997 17 12 TC 200mg/14-17d - - - Physical function Snyder 1999 54 36 TTS 6mg/d Kenny 2001 22 12 TTS 5mg/d - - Ly 2001 17 3 DHT 70mg/d - Liu 2002 20 3 hcg 250mcg/wk - Ferrando 2002 7 6 TE 200mg/2 wk - Blackman 2002 21 6.5 TE 100mg/2 wk VO 2 Wittert 2003 39 12 TU 160mg/d Page 2005 46 36 TE 200mg/2 wk + F Nair 2006 27 24 TTS 5mg/d - - Emmelot-Vonk 2008 113 6 Oral TU 160mg/d Sattler 2009 19 / 21 4 TTS 5 / 10mg/d? (10 mg) VO 2 Kenny 2010 69 12 TTS 5mg/d Srinivas-Shankar2010 130 6 TTS 5mg/d Travison 2011 82* 6 TTS 10mg/d* (10 mg) (10 mg) Sheffield-Moore 2011 8/8* 5 TE 100mg/wk -
Free T (pmol/l) 200 300 500 FSH (IU/L) Total T (nmol/l) 10 15 20 25 30 LH (IU/L) Hormone Levels During Treatment ---- Testosterone ---- Testogel ---- Placebo ---- Placebo Mean (SD) Total Testosterone 1 2 5 10 20 LH Free Testosterone FSH Srinivas- Shankar et al JCEM 95:639 2010 2 5 10 20
Lower Limb Muscle Strength **P=0.02 Srinivas- Shankar et al JCEM 95:639 2010 IME-PT Isometric extension peak torque IMF-PT Isometric flexion peak torque IKE-PT Isokinetic extension peak torque IKF-PT isokinetic flexion peak torque
Improvement in Physical Function at 6 Month in Older and Frailer Men * ** * * *p<0.05 **p<0.01 Srinivas- Shankar et al JCEM 95:639 2010 75 yr n = 106 2 Frailty Criteria n = 100 75 yr n = 106 2 Frailty Criteria n = 100
Effects of Testosterone on Muscle Strength and Physical Function in Older Men in the TOM Trial Travison et al 2011
Testosterone Effects on Bone Mineral Density (BMD) in Men: Meta-analyses of RCTs Standardised Mean Difference in Lumbar Spine BMD Standardised Mean Difference in Femoral Neck BMD Tracz et al 2006
Change in Fat Mass (kg) 1.0 0.0-1.0-2.0 Testosterone Treatment of Elderly Men Placebo -3.0 Testosterone -4.0 0 12 24 Time (months) 36 Snyder PJ, et al. J Clin Endocrinol Metab. 1999;84:2647-2653
RCT of Metabolic Effects of Testosterone (T) in Obese Men with T2D or MetS Study n Age (yr) T Rx Duration (Weeks) Waist (cm) HbA1C (%) HOMA-IR Others Kapoor 2006 24 64 TE 200mg/2w 12-1.6* -0.37* -1.7* (-39%) total Chol (-0.4 mmol/l), no change in other lipids Heufelder 2009 32 57 TTS T 50mg/d 52-6.0-0.8-0.9 (-59%) CRP Kalichenko 2010 184 52 TU 1000mg/12w 30-4.6 Not reported -1.7 (-31%) body weight 3.9 Kg, No change fasting sugar Aversa 2010 50 58 TU 1000mg/12w 52-8.0-1.1-2.6 (-60%) No change lipids Hct (+3.8%) Jones 2011 220 60 TTS T 60mg/d 26 N.S -0.7-0.8 (-15%) No change % body fat Solvay (Unpub) 180 NR TTS T 50mg/d 26 NR N.S. N.S. 2.0 Kg lean mass
Benefits of Testosterone Therapy Spitzer et al 2013
Features of Hypogonadism Benefits of Androgens Young hypogonadal Ageing male Sexual function, (if low baseline T) Lean body mass (~ 1.5kg) Muscle strength UL Muscle strength LL These relatively modest/equivocal, (3%), (only high T dose) Physical function effects of T Rx in? ageing men may not Fat mass reliably translate to (~ 2kg) clinically or patient Lumbar spine BMD important outcomes Hip BMD Fracture, (if low baseline T),? Mood? Cognition? Quality of life?
Adverse Effects of Testosterone Therapy Formulation specific Injections i. m. Pain at injection site Fluctuations in mood, energy and sexual desire Coughing immediately after injection (POME) Transdermal gels Potential risk of gel transfer to others in close contact Skin irritation Fluctuations in absorption Transdermal patches Frequent skin reactions at the application site Buccal adhesive Gum irritation Dislodgement Alteration of taste Subcutaneous pellets Infection Bleeding/bruising Scarring Spontaneous extrusion Oral 17- -alkylated Hepatotoxicity Cholestasis Peliosis hepatis Hepatic tumour Marked in HDL-chol
Adverse Effects of Testosterone Replacement Therapy Acne truncal Seborrhoea Gynaecomastia Priapism Higher libido Behavioural change Fluid retention sperm production and infertility Erythrocytosis Aggravates prostate diseases? Urinary obstruction Tumour growth Detection of subclinical prostate cancer Sleep apnoea? Aggravates cardiovascular diseases?
Testosterone Replacement and Erythrocytosis
Effects of Testosterone on Erythropoiesis are Greater in Older Men than Young Men (Coviello et al JCEM 2008)
Testosterone Induces Erythrocytosis via Increased Erythropoietin and Suppressed Hepcidin: Evidence for a New Erythropoietin/Hemoglobin Set Point Bachman et al 2013
Testosterone Stimulates Erythropoietin and Suppresses Hepcidin Testosterone administration is associated with increased iron incorporation into red blood cells Testosterone upregulates renal erythropoietin mrna expression, and increased erythropoietin levels. Testosterone downregulates hepatic hepcidin mrna expression and suppresses hepcidin level. Testosterone stimulates erythropoiesis by stimulating EPO and recalibrating the set point of EPO in relation to hemoglobin and by increasing iron utilization for erythropoiesis.
Relative Risks (RR) of Erythrocytosis in Testosterone Therapy in Older Men Overall RR 3.15 (1.56 6.35) RR Commonest adverse effect of testosterone treatment in older men (Fernandez-Balsells et al JCEM 2010)
Hemoglobin (g/dl) Hematocrit (%) Erythropoiesis during Testosterone Replacement 16 48 46 15 44 14 42 S 0 3 6 9 12 15 18 21 24 27 30 Weeks T-Enanthate S 0 3 6 9 12 15 18 21 24 27 30 Weeks T-Undecanoate (Jockenhövel F, unpublished)
Testosterone Replacement and Prostate diseases
Prevalence of Histological Prostate Cancer in Autopsy Cases with Increasing Age Stamey et al 1993
Targeted drugs Molecules Implicated in Prostate Cancer progression through the Initiation and Progression Androgens are potent mediators of prostate cancer growth and normal or aberrant activation of the androgen receptor (AR), interacting with multiple signaling molecules, such as growth/transcription factors, oncogenes, and tumuor suppressors Despite the dependence on androgens for normal prostate development, there is limited evidence to suggest that androgens autonomously promote prostate cancer initiation, which is associated with many dysregulated developmental, tumour suppressor & oncogene signalling pathways Schrecengost & Knudsen 2013
Endogenous Sex Hormones Were Not Associated with Increased Risk or Grades of Prostate Cancer in 3886 Cases and 6438 Controls A Collaborative Analysis of 18 Prospective Studies (Roddam et al 2008)
Serum Testosterone and Dihydrotestosterone and Prostate Cancer Detection/Grade in the Placebo Arm of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) Trial Baseline serum testosterone and DHT levels were unrelated to prostate cancer detection or grade Locally weighted scatterplot smoothing of baseline serum testosterone and dihydrotestosterone (DHT) and final cancer status after considering all biopsies during 4 yr of the REDUCE trial. Men detected with prostate cancer were coded as 1, whereas men with no prostate cancer detected were coded as 0. Muller et al 2012
Risks (Odds Ratio 95%CI) of (a) prostate cancer (b) prostate biopsy in 9 short-term (<12 months) testosterone treatment (by modalities) RCT studies from 1966 to 2013 in hypogondal men, median age 52 80 yr (Total n = 2351 In 22 studies) Cui et al 2014
Risks (Odds Ratio 95%CI) of (a) prostate cancer (b) prostate biopsy in 8 longer-term (12 36 months) testosterone treatment (by modalities) RCT studies from 1966 to 2013 in hypogondal men, median age 52 80 yr (Total n = 2351 in 22 studies) Cui et al 2014
Standardised Mean difference 95%CI) in PSA change in 7 short-term ( 6 months) testosterone treatment RCT studies in 2351 hypogondal men, median age 52 80 yr Cui et al 2014
Testosterone Treatment - Risks of Prostate Cancer Not Defined Occult histological prostate cancer increases with age - very common in elderly men Androgens promote pre-existing prostate cancer growth but long latency Relationship between endogenous & exogenous androgens and prostate cancer incidence not established Normal PSA <4ng/mL does not exclude occult cancer & increase in PSA is not specific for cancer (e.g. age, BPH, testosterone treatment) Large scale prospective trials of testosterone treatment required to assess prostate cancer risks Particular caution is required in use of testosterone in elderly men
Testosterone Replacement and Sleep Disorders
Testosterone Replacement Therapy and Obstructive Sleep Apnoea Is There a Real Concern? Hanafy 2007
Mean ±SEM of the change from baseline for:- (a) oxygen desaturation index (ODI), (b)% time of total sleep time (TST) that the arterial oxygen saturation was <90% (SpO2T90%), (c) apnoea hypopnoea index (AHI) (d) AHI during non rapid eye movement sleep (NREM AHI). 1000 mg Testosterone Undecanoate or placebo at 0, 6 and 12 weeks
Testosterone and Sleep Disorders OSA per se is not a cause of low testosterone, rather it is due to obesity, and testosterone is increased by weight loss. Treatment of moderate to severe OSA with continuous positive airway pressure (CPAP) does not reliably increase testosterone levels in most studies Apart from a very transient deleterious effect physiological testosterone treatment does not adversely affect OSA in obese men with low T Suprapysiological doses of exogenous testosterone and anabolic/androgenic steroid abuse are associated with abnormalities of sleep duration and architecture
Testosterone Treatment and Cardiovascular Diseases
Pooled Effects of 27 Placebo-controlled Randomized Trials Testosterone Therapy Associated with Increased Risks, OR 1.54 (1.09 2.18), of Cardiovascular-related Events Xu et al 2013
Two Testosterone RCTs of Frailty Comparison - Design Inclusion Criteria Number of participants Srinivas-Shankar (2010) Frailty: 1 frailty criteria (Fried 2001) Active: n = 132 Placebo: n = 130 Total T <346 ng/dl or free T <7.2 ng/dl Basaria et al (2010) Mobility Limitation: Difficulty walking 2 blocks or climbing 10 steps. SPPB Score 4-9 Active: n = 106 Placebo: n = 103 Total T 100 350 ng/dl or free T <5 ng/dl Interventions Transdermal T 5mg/day Transdermal T 10mg/day Duration 6 months 6 months
Serious Adverse Events Serious Adverse Event Placebo Testosterone Constrictive pericarditis (died) 0 1 Ruptured abdominal aneurysm (died) 1 0 Acute myocardial infarction 1 0 Ca oesophagus 0 1 Ca lung 0 1 Pulmonary embolism 0 1 Heart failure Abdominal aortic aneurysm 0 0 1 1 Data are n Srinivas-Shankar et al JCEM 95:639 2010
TOM TRIAL- ADVERSE CARDIOVASCULAR EVENTS ASSOCIATED WITH TESTOSTERONE ADMINISTRATION Study Population 209 men 65 yr of age or older with limitations in mobility and Low T (Total Serum T: 100 to 350 ng/dl; Free Serum T level <50 pg/ml) Effects of transdermal T at 10mg/day for 6 months on lower extremity strength and physical function compared with a placebo Results 23 men in the T treatment group (n=106) and 5 in the placebo group (n=103) had CV-related events. The divergence was maintained over the 6-month intervention period and did not diminish during the 3-month observation phase that followed the intervention period. This increased risk warranted early termination of the trial. Basaria S et al. NEJM 2010
In 1031 Male Veterans Aged >40 yr, with Low Total T 250 ng/dl (8.7 nmol/liter), T-treated Men had a Decreased Risk of Dying Than Untreated Men over 40.5 month follow-up (P<0.029). (Shores et al 2012)
Association of Testosterone Therapy with Mortality, Myocardial Infarction, and Stroke in Men with Low Testosterone Vigen R et al. 2013. JAMA A retrospective nation wide cohort study Male veterans (n = 8709) 60 yr old who underwent coronary angiography between 2005 and 2011 and who had a total testosterone level less than 300 ng/dl. Primary outcome was a composite of all-cause mortality, MI, and ischemic stroke. Use of testosterone therapy was associated with increased risk of adverse outcomes (hazard ratio, 1.29; 95%CI, 1.04 to 1.58) during 27.5 months follow-up. Conclusions Use of testosterone therapy in this cohort of veterans with significant medical comorbidities was associated with increased risk of mortality, MI, or ischemic stroke. These findings were not modified by the presence of CAD.
In all subjects >65 (n yr = (n 55,593), = 7054), the the post/pre prescription myocardial infarction rate (per 100 persons.yr) ratio (RR) for testosterone prescription was 1.36 2.19 (95% CI 1.03, 1.27, 1.81) 7.27) after 90 days Heart Disease History No Heart Disease History Testosterone PDE5I Testosterone PDE5I Age <65 yr N= 4,006 N= 10,681 N= 44,533 N= 130,831 Rate Ratio (CI) 2.9 (1.49, 5.62) 1.4 (0.91, 2.14) 0.90 (0.61, 1.34) 0.99 (0.84, 1.17) Ratio of RR (CI) 2.07 (1.05, 4.11) 0.91 (0.60, 1.37) Age 65 yr N= 2,047 N= 5,492 N= 5,057 N= 20,275 Rate Ratio (CI) 2.16 (0.92, 5.10) 1.13 (0.68, 1.88) 2.21 (1.09, 4,46) 0.92 (0.60, 1.39) Ratio of RR (CI) 1.90 (0.66, 5.50) 2.41 (1.12, 5.17)
Cardiovascular risk associated with testosterone-boosting medications: a systematic review and meta-analysis Source MH-OR LL UL p 0,00 0,01 Odds ratio for MACE 0,10 1,00 10,00 100,00 0.01 0.1 1 10 100 1000,00 TS #Events # Patients Placebo #Events # Patients Copenaghen SG 1986 (27) 1,97 0,08 48,82 0,68 Hall et al., 1996 (30) 0,32 0,01 8,23 0,49 Sih et al., 1997 (32) 0,88 0,05 15,33 0,93 Snyder et al., 1999 (36) 2,04 0,18 23,17 0,57 English et al., 2000 (38) 3,12 0,12 80,39 0,49 Seidman et al., 2001 (43) 0,41 0,02 10,83 0,59 Steidle et al., 2003 (48) 2,83 0,11 70,27 0,53 Armory et al., 2004 (50) 3,13 0,12 80,68 0,49 Kenny et al., 2004 (52) 0,23 0,01 7,05 0,40 Svartberg et al., 2004 (56) 0,29 0,01 7,74 0,46 Brockenbrough et al., 2006 (59) 3,75 0,36 39,59 0,27 Malkin et al., 2006 (65) 2,17 0,19 25,01 0,53 Nair et al., 2006 (68) 5,70 0,26 123,78 0,27 Svartberg et al., 2008 (77) 3,16 0,12 82,64 0,49 Chapman et al., 2009 (80) 1,00 0,05 20,83 1,00 Legros et al., 2009 (81) 1,01 0,04 25,01 1,00 Aversa et al., 2010 (85) 0,08 0,00 2,07 0,13 Aversa et al., 2010 (86) 0,07 0,00 1,97 0,12 Basaria et al., 2010 (10) 13,39 0,74 240,78 0,08 Kalinchenko et al., 2010 (88) 0,21 0,01 5,15 0,34 Srinivas-Shankar et al., 2010 (89) 1,01 0,14 7,31 0,99 Ho et al., 2011 (91) 1,00 0,06 16,37 1,00 Jones et al., 2011 (92) 0,51 0,05 5,75 0,59 Kaufman et al., 2011 (93) 0,87 0,04 18,48 0,93 Behere et al., 2012 (95) 2,95 0,12 72,91 0,51 Hildreth et al., 2013 (97) 0,15 0,02 1,53 0,11 Overall 1,01 0,57 1,77 0,98 1 134 0 87 0 35 1 35 1 17 1 15 2 54 1 54 1 25 0 25 0 13 1 17 1 106 0 99 1 24 0 24 0 6 1 5 0 15 1 14 3 19 1 21 2 37 1 39 2 30 0 32 1 19 0 19 1 6 1 6 1 237 0 79 0 40 1 10 0 42 1 10 6 106 0 103 0 113 1 71 2 136 2 138 1 60 1 60 1 108 2 112 2 234 0 40 1 183 0 179 1 96 3 47 31 1895 20 1341 Placebo TS Corona et al., 2014
FDA adding general warning to testosterone products about potential for venous blood clots [06/19/2014] The U.S. Food and Drug Administration (FDA) is requiring manufacturers to include a general warning in the drug labeling of all approved testosterone products about the risk of blood clots in the veins. Blood clots in the veins, also known as venous thromboembolism (VTE), include deep vein thrombosis (DVT) and pulmonary embolism (PE). The risk of venous blood clots is already included in the labeling of testosterone products as a possible consequence of polycythemia, an abnormal increase in the number of red blood cells that sometimes occurs with testosterone treatment. Because there have been postmarket reports of venous blood clots unrelated to polycythemia, FDA is requiring a change to drug labeling of all testosterone products to provide a more general warning regarding venous blood clots and to ensure this risk is described consistently in the labeling of all approved testosterone products.
In conclusion, these studies do not provide conclusive evidence of increased cardiovascular risk associated with the use of testosterone therapy or causality.
FDA Advisory Panel Urges Restrictions on Testosterone Use September 18, 2014 Change in labeling for testosterone-replacement products recommended A combined US Food and Drug Administration (FDA) advisory panel has voted nearly unanimously to change the labeling for testosterone-replacement products, with the aim of clamping down on their current widespread use for "age-related" hypogonadism. "Benefit is unclear in men diagnosed with hypogonadism due to no apparent cause other than older age. Yet testosterone is being predominantly prescribed to men 40 to 64 years of age. This has prompted the FDA to question whether labeling accurately reflects the appropriate indicated population," Hylton V. Joffe, MD, director of the Division of Bone, Reproductive, and Urologic Products at the FDA, told the panel in his introductory remarks. Given the magnitude of off-label use "and lack of strong data on effectiveness in this population, I think it's important to include something about cardiovascular safety in the label. Maybe not to the level of black box, but certainly that there are serious concerns that have not yet been adequately addressed," he added. Trials Required for Cardiovascular Safety The panel also indicated that large studies are needed to demonstrate both clinical benefit and safety of the products. Several panelists said that a large, randomized clinical trial would be needed to determine whether or not the cardiovascular signal was real, noting that men with low testosterone are already at increased cardiovascular risk. Others felt that an observational trial
Recommendations for Monitoring Testosterone Replacement in Older Men
Absolute Contraindications for Testosterone Treatment Untreated prostate cancer High-grade PIN History of breast cancer Myocardial infarct, acute coronary event, unstable angina or coronary re-vascularisation in past 6 months
Relative Contraindications for Testosterone Treatment Prostate specific antigen (PSA) >4 ng/ml* Unevaluated prostate nodule/induration Successfully treated localised low-grade prostate cancer Severe urinary obstructive symptoms (IPSS symptom score >19) Polycythaemia Hct >50% Severe uncontrolled heart, renal or liver failure fluid retention Untreated severe sleep apnoea *PSA >3ng/mL in men with high risk of prostate cancer e.g. Afro-Caribbean or first degree relative
Special Precautions in Starting Testosterone Replacement Therapy in Older Men (>40 Yr) - Do Not Start Without Urological Evaluation Prostate abnormal on DRE PSA concentration >4 ng/ml PSA concentration >3 ng/ml First degree relatives with prostate cancer Afro-american or Afro-caribbean Severe urinary obstructive symptoms (IPSS symptom score >19) due to BPH Haematocrit >50% Bhasin et al; JCEM 95:2536-2559 2010
Monitoring of Continuing Testosterone Replacement Therapy in Older Men (>40 Yr) DRE prostate and PSA at 3-6 and 12 month after starting treatment, and thereafter annually Urological consultation if Abnormal DRE at any time PSA >4.0 ng/ml at any time Increase in PSA >1.4 ng/ml in first 3 or 6 month, or any subsequent 1 year interval Check haematocrit at 3, 6 and 12 month after starting treatment, and thereafter annually Haematocrit >54%, stop or reduce dose of T therapy Evaluate for hypoxia and sleep apnea Consider venesection Bhasin et al; JCEM 95:2536-2559 2010
Testosterone level during TRT Aim to maintain mid-normal testosterone levels 15-20 nmol/l (no circadian rhythm) Testosterone gel Assess any time after application Transdermal testosterone delivery systems (patches) Assess T levels 3 to 10 hours after application of the patch. Injectable testosterone Monitor nadir testosterone levels, prior to the next injection. If T >15nmol/L or <8 nmol/l, adjust frequency or dose or both Testosterone implants Monitor nadir testosterone levels before next implant. If T >15nmol/L or <8 nmol/l, adjust frequency or dose or both
Monitoring of Testosterone Replacement - Efficacy Matsumoto 2013
Conclusions Best practice guidelines based on opinions rather than strong evidence still evolving Erythrocytosis is common, dose-dependent and avoidable Sleep apnoea risk may be over-estimated Long term risks (CVD & prostate) of T treatment in older men are unknown shapes careful monitoring of AEs Careful assessment/explanation of overall benefits/risks with individual patients Re-assess diagnosis and review clinical response regularly to determine need for continuing treatment
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Research Agenda Population-based reference ranges for testosterone are needed to rationally partition men into those with normal Harmonize testosterone and low levels. assays across Population laboratories cohort to ensure studies are indicated to determine the physicians can interpret natural history (e.g. wellbeing, frailty, mortality) of men with and compare hormone different levels of testosterone levels obtained from different laboratories. Long-term, adequately-powered, randomized studies should placebocontrolled trials are needed to determine the the efficacy health and benefits and risks the long-term risks of testosterone therapy associated in with symptomatic older men with low testosterone levels. various thresholds of testosterone levels. New therapeutic strategies, e.g. development of selective androgen receptor modulators (SARMs), are needed to dissociate beneficial anabolic effects of testosterone from potential adverse effects on the prostate and cardiovascular events