Diagnosis and management of testosterone deficiency syndrome in adult men: clinical practice guideline (CMAJ)

Transcription

1 Diagnosis and management of testosterone deficiency syndrome in adult men: clinical practice guideline (CMAJ) Alvaro Morales CM MD, Richard A. Bebb MD, Priya Manjoo MD MSc, Peter Assimakopoulos MD, John Axler MD, Christine Collier PhD, Stacy Elliott MD, Larry Goldenberg CM OBC MD, Irv Gottesman MD, Ethan D. Grober MD MEd, Gordon H. Guyatt MD MSc, Daniel T. Holmes MD, Jay C. Lee MD; Canadian Men s Health Foundation Multidisciplinary Guidelines Task Force on Testosterone Deficiency

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3 Diagnosis 1. We recommend a thorough history and physical examination, instead of the exclusive reliance on standard questionnaires, to identify patients requiring biochemical testing Strong Recommendation; Moderate-quality evidence

4 ADAM Questionnaire A positive answer represents Yes to questions 1 or 7 or any 3 other questions: YES NO 1. Do you have a decrease in libido (sex drive)? 2. Do you have a lack of energy? 3. Do you have a decrease in strength and/or endurance? 4. Have you lost height? 5. Have you noticed a decreased enjoyment of life? 6. Are you sad and/or grumpy? 7. Are your erections less strong? 8. Have you noticed a recent deterioration in your ability to play sports? 9. Are you falling asleep after dinner? 10. Has there been a recent deterioration in your work performance? 1. Morley JE, et al. Metabolism. 2000;49:

5 Evaluation of ADAM Questionnaire Validity Criteria of ADAM Test 1 Free Testosterone Cutoff Point (ng/l) Sensitivity (%) Specificity (%) High sensitivity ~ 80% Marginal specificity ~ 21% 1. Tancredi A, et al. Eur J Endocrinol. 2004;151:

6 Prevalence of Positive Answers for Each of the 10 Questions Prevalence (%) of Positive Answers Question s topic Total <70 ng/l 70 ng/l P value (n=5028) (n=1939) (n=3088) (<70 vs. 70) Q1. Libido < Q2. Energy Q3. Strength endurance Q4. Height Q5. Enjoyment of life Q6. Sad/grumpy Q7. Erection Q8. Playing sport Q0. Sleeping after dinner Q10. Work performance Tancredi A, et al. Eur J Endocrinol. 2004;151:

7 Diagnosis 2. The initial biochemical test should be total testosterone level measure in a blood sample taken in the am; determination of bioavailable T or free T should be restricted to patients with equivocal low total T levels Strong recommendation; high-quality evidence

8 Forms of T Bioavailable (BT; 40%) Albumin-bound (38%) Total (TT; 100%) Free (FT; 2%) SHBG-bound (60%)

9 Calculated Bioavailable T Albumin, total T (am), sex hormone-binding globulin n > 4.0

10 Calculated Free and Bioavailable T More accurate reflection of bioactive T T and DHT circulate in plasma unbound (free approximately 2 3%), bound to SHBG and weakly bound to albumin SHBG-bound fraction is biologically inactive because of high binding affinity for T Free T = free fraction Bioavailable T = free T plus T weakly bound to albumin

11 Diagnosis 3. We recommend that sample collection for T measurement occur between 7 am and 11 am, or within 3 hours after waking in the case of shift workers Strong recommendation; Moderate-Quality Evidence

12 Diagnosis 4. T levels should be measured with the use of T assays traceable to internationally recognized standardized reference material; commercial assays should be certified by the T standardization program of the US Centers for Disease Control and Prevention Strong Recommendation; High-Quality Evidence

13 Diagnosis 5. Measurement of SHBG, calculated free T, calculated bioavailable T, or bioavailable T should be restricted to men with symptoms of TDS and equivocally low T levels Strong Recommendation; Moderate-Quality Evidence

14 Diagnosis 6. We recommend investigation for secondary or reversible causes of hypogonadism in all men with TDS Strong Recommendation; Moderate-Quality Evidence

15 Primary VS. Secondary causes Low serum testosterone Primary causes Testicular origin Results in: Low testosterone levels Impairment of spermatogenesis Elevated gonadotropin levels Exclude: Klinefelter syndrome Secondary causes Pituitary/hypothalamic origin Results in: Low testosterone levels Impairment of spermatogenesis Low/low-normal gonadotropin levels Exclude: Pituitary neoplasia Hyperprolactinemia Hemochromatosis Obstructive sleep apnea Genetic disorders associated with gonadotropin deficiency 1. Bhasin et al. J Clin Endocrinol Metab. 2010;95:

16 Diagnosis 7a. We recommend investigation for TDS and treatment with T in men with anemia or sarcopenia of undetermined origin (Strong Recommendation; Moderate-Quality Evidence) 7b. We suggest investigation and T treatment for men with depression refractory to standard treatment, as well as for men taking glucocorticoid or opioid therapy and men with HIV if they have experienced weight loss (Weak Recommendation; Low-Quality Evidence)

17 Diagnosis 8. In men with ED and no other manifestations of TDS, we suggest investigation only after a trial of PDE5i has failed Weak Recommendation; Low-Quality Evidence

18 Treatment 9. We recommend that men with documented TDS and no contraindications should receive treatment with T Strong Recommendation; High-Quality Evidence

19 Treatment 10. Men with TDS and stable CV disease are candidates for T treatment Weak Recommendation; Low-Quality Evidence

20 Two Controversial Studies The only two studies to suggest any increase CV risk with testosterone therapy i) TOM Study ii) Vigen Study All others suggest no effect or decreased risk with testosterone therapy

21 Objective Determine the effects of testosterone administration on lower extremity strength & physical function in older men with limitations in mobility & low levels of free & total T Primary Outcome Efficacy Men receiving TRT had significantly greater in strength. Leg-press Chest-press Stair climbing Adverse Events application of testosterone gel was associated with an increase in adverse cardiovascular events

22 Cumulative probability of event CV-related Events 209 men with hypogonadism and mobility limitations 1 Included patients with a high CV risk Used higher than recommended T dose Not sufficiently powered for significance of CV events Should not prevent clinicians from prescribing TRT for well established, late-onset hypogonadism, but use caution when prescribing TRT in older men with extensive history of CV disease and limited mobility p < Testosterone Placebo Months since randomization 1. Basaria S, et al. N Engl J Med 2010;363: Bremner WJ. N Engl J Med 2010;363:189-91

23 NEJM July 2010 Adverse Events Associated with Testosterone Administration (n=209, limited mobility, age 74yrs, TOM Study ) New York Times: Testosterone Gel Trial Ends After Heart Issue Wall Street Journal: Testosterone Trial Was Halted Over Cardiovascular Events Washington Post: Testosterone supplement may have cardiovascular risks for older men

24 Adverse Effects Associated with Testosterone Administration (TOM) NEJM July 8, 2010 HOWEVER: Analysis for cardiovascular events was atypical. MedDRA Events occurred in only 10 T treated patients, not the other 13 of those reported (n=23). 2 Undocumented tachycardia 5 ankle edema 3 self reported syncope 4 increase BP 2 patients ectopy on ECG Only one death

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26 Adverse Effects Associated with Testosterone Administration (TOM) NEJM July 8, 2010 Recruitment bias of more men in T group with: - treated hypertension - dyslipidemia

27 Study Limitations: 1. CV events not a planned 1 or 2 outcome 2. Randomization Failure in regards to CV risk factors

28 Vigen R et al. J Am Med Assoc 310(17): (2013)

29 Wall Street Journal: Testosterone Therapy Tied to Heart Risks Veterans With History of Heart Disease Had Higher Risk of Death, Heart Attack and Stroke, According to JAMA Study ABC News: Testosterone Supplements Tied to Heart Attacks, Strokes, Early Death Dr. Steven Nissen, chairman of cardiovascular medicine at the Cleveland Clinic said the finding underscores concerns that he already had about testosterone supplementation. The Associated Press (Canada) Heavily marketed testosterone products linked with heart risks, strokes, deaths in older men

30 REPORTED ACTUAL EVENTS IN T-GROUP AND NO-T GROUPS Data from: Vigen R et al. J Am Med Assoc 310(17): (2013)

31 Retrospective, non-randomized, observational study of 8,709 men, 61 to 64 yrs, who had undergone coronary angiography with a low serum total testosterone. Study Group Testosterone Rx Number of Subjects Deaths MI CVA Total Events/gr oup Event Rate before stats Event Rate after stats % 25.7% Control Group % 19.9%

32 Issues with the Study stabilized inverse probability of treatment weighting The group that did not receive testosterone had twice the absolute rate (~ 20% vs 10%) of events compared to the group that received testosterone. It was only with their complicated weighting system that they were able to conclude that CV events were higher than expected in the group receiving testosterone versus the untreated group. One has to question the validity of such a weighting system that completely reverses the observed rates!

33 Treatment 11. We suggest that men with TDS and localized prostate cancer and no evidence of active disease receive T therapy Weak Recommendation; Low-Quality Evidence

34 Testosterone therapy and prostate cancer Testosterone therapy is contraindicated in men with prostate cancer 1,2 Fear of accelerating tumour growth Huggins and Hodges (1941): castration caused a decline in serum marker acid phosphatase 3 Testosterone caused an enhanced rate of growth of prostate cancer Fowler et al. (1981): testosterone administration resulted in an unfavourable response in 45 of 52 men with metastatic prostate cancer 4 1. Morales et al. CUAJ. 2010;4:269-75; 2. Bhasin et al. J Clin Endocrinol Metab. 2010;95: ; 3. Huggins et al. Cancer Res. 1941;1:293-7; 4. Fowler et al. J Urol. 1981;126:372-5.

35 Emerging view of testosterone Levels and prostate cancer Prostate cancer is largely unaffected by variations in serum testosterone levels within the naturally occurring ranges 1 TESTOSTERONE DEFICIENCY may be associated with: 1,2 Greater risk of prostate cancer High Gleason scores Worse stage at presentation Worse survival No recurrence of prostate cancer upon testosterone therapy 3,4 1. Morgentaler. Urol Clin N Am. 2011;38:119-24; 2. Morgentaler.Eur Urol. 2006;50:935-9; 3. Kaufman et al. J Urol. 2004;172:920-2; 4. Khera et al. J Sex Med. 2009;6:

36 Revisiting the original evidence Increase in serum testosterone after androgen deprivation results in an increase in PSA, even in men without cancer 1 Huggins and Hodges: only 1 patient without prior androgen deprivation 1,2 Fowler et al: 4/52 men did not have prior androgen deprivation 3 1 patient had an unfavourable result 3 patients continued to receive testosterone with no apparent negative effect PSA: prostate specific antigen. 1. Morgentaler et al. Urol Clin N Am. 2011;38:119-24; 2. Huggins et al. Cancer Res. 1941;1:293-7; 3. Fowler et al. J Urol. 1981;126:372-5.

37 Testosterone Therapy in Prostate Cancer Survivors Q How should a patient who has been successfully treated for prostate cancer be managed for testosterone deficiency? Testosterone therapy may be considered on an individualized basis, in patients who have undergone radial prostatectomy and: 1,2 Have been disease free for >2 years * Have undetectable PSA levels No general recommendation due to lack of randomized-controlled trials 1 *Individualized approach for patients disease free for <2 years, with severe symptoms (i.e. suicidal). PSA: prostate specific antigen. 1. Bhasin et al. J Clin Endocrinol Metab. 2010;95: ; 2. Bebb et al. BCMJ. 2011; 53:

38 Treatment 12. We suggest T treatment for men with TDS and mild-to-moderate symptoms due to BPH Weak Recommendation; Very-Low Quality Evidence

39 Testosterone Therapy in Patients with BPH-LUTS Testosterone is contraindicated in men with severe BPH-LUTS (IPSS >19) 1 Original consensus: testosterone therapy may worsen symptoms of BPH 1,2 Current view: testosterone therapy improves LUTS in men with low testosterone and mild BPH 3 No compelling data to suggest that testosterone therapy contributes to worsening of LUTS or promotion of urinary retention 3 BPH: benign prostatic hyperplasia; IPSS: International Prostate Symptom Score; LUTS: lower urinary tract symptoms. 1. Bhasin et al. J Clin Endocrinol Metab. 2010;95: ; 2. Bassil et al. Ther Clin Risk Manag. 2009;5:427-48; 3. Shigehara et al. Aging Male Mar;14:53-8.

40 Treatment 13. We recommend AGAINST TRT in men with metastatic prostate cancer Strong Recommendation; Moderate- to High- Quality Evidence

41 Treatment 14. Men with a history of breast cancer are not candidates for TRT Weak Recommendation; Moderate-Level Evidence

42 Treatment 15. We recommend AGAINST TRT in men more interested in maintaining fertility over symptomatic improvement Strong Recommendation; High-Quality Evidence

43 Treatment 16. We recommend treatment with a PDE5i in men with TDS and persistent ED that is adequately treated with T Strong Recommendation; High-Quality Evidence

44 Treatment 17. In men with a clinical picture strongly suggestive of TDS but T levels in the lownormal range, we suggest a therapeutic trial with T Weak Recommendation; Very-Low Quality Evidence

45 Monitoring 18. We recommend assessment of response and adverse effects at three and 6 months after onset of therapy Strong Recommendation; High-Quality Evidence

46 Monitoring 19. We suggest that T levels should be assessed at three and six months after onset of therapy and then annually thereafter if stable Weak Recommendation; Low-Quality Evidence

47 Monitoring 20. We recommend assessment of hematocrit at baseline, at three and six months and then annually Strong Recommendation; High-Quality Evidence

48 Monitoring 21. We recommend determinations of PSA at baseline, at three and six months and then annually Strong Recommendation; Moderate- to Low- Quality Evidence

49 Monitoring 22. A DRE should be performed at baseline, at six months and then annually following onset of treatment Weak Recommendation; Very-Low Quality Evidence

50 Monitoring 23. We suggest that TRT should be discontinued in men with TDS if contraindications to therapy arise or if there is no improvement after an adequate therapeutic trial Weak Recommendation; Moderate-Quality Evidence

51 Potential Benefits and Harms of TRT in Men with TDS Organ System Benefits Harms ED/Libido Improvement None Depression/Mood/Fatigue Improvement Aggressive Behaviour Erythropoiesis Increase in HCT Increased risk of polycythemia, embolism Skeletal Muscle Increase in fat-free mass None Bone Metabolism Prevention of osteoporosis None CV Prostate Improvement in CHF, exercise capacity Increased risk of thromboembolic CV event BPH None Marginal increase in vol and PSA Cancer (Metastatic) Absolute contraindication Reucrrence and rapid progression Cancer (Localized/Treated) None None Testicles None Atrophy, impaired spermatogenesis

52 Key Points 1. Asymptomatic men should NOT be screened for TDS; these guidelines are for symptomatic men. 2. There are limitations to the traditional T assays which contributes to the variability in levels between sites, but the initial test should be am total T. 3. Treatment of adult onset secondary hypogonadism is mainly for symptomatic improvement and improvement of QoL. It should not be used to promote weight loss, or improve metabolic parameters as there are better established treatments. 4. Careful appraisal of the literature does not support a causal association between TRT and CV safety and Prostate Cancer 5. Hypogonadism (and ED) is associated with a higher prevalence of CVD and identification of these patients presents an opportunity to address these issues.