Testosterone Deficiency and Treatment - the FACTS
Resolutions |
Expert comments |
1. TD is a well-established, significant medical condition that negatively affects male sexuality, reproduction, general health, and quality of life.
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TD (low levels of testosterone):
- May predict increased risk of developing diabetes, metabolic syndrome.
- Contributes to decreased bone mineral density.
- Is associated with increased all-cause and cardiovascular mortality.
- Negatively impacts general health and quality of life.
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2. The symptoms and signs of TD occur as a result of low levels of T and may benefit from treatment regardless of whether there is an identified underlying cause.
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- Symptoms and signs of TD occur in healthy volunteers or patients who undergo androgen deprivation; these symptoms and signs resolve with T normalization.
- Historically recognized causes of TD are rare (eg, anorchia, craniopharyngioma, pituitary tumor), recently termed classical hypogonadism. These conditions account for only a tiny fraction of men with TD.
- TD occurs frequently with conditions other than “classical” causes.
- No evidence exists to support restriction of T therapy only to men with known underlying cause.
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3. TD is a global public health concern.
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- Prevalence rates in men range from 2% to 38% in studies from Asia, Europe, North America, and South America.
- Variation in prevalence rates can be explained by differences in the definition of TD and T thresholds.
- A US study estimates an additional $190-$525 billion in health care expenditures over 20 years due to TD.
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4. T therapy for men with TD is effective, rational, and evidence based.
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High-level evidence shows T therapy effectively:
- Increases sexual desire (libido) and erectile and orgasmic function. - Increases lean body mass. - Decreases fat mass. - Improves bone mineral density.
Strongly suggestive evidence for improvement in mood, energy
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5. There is no T level threshold that reliably distinguishes those who will respond to treatment from those who will not.
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No study has revealed a single testosterone threshold that reliably separates those who experience signs and symptoms of TD from those who do not, nor who will likely respond to treatment.
Interpretation of total T levels is confounded by:
- Interindividual variation.
- Variation in serum SHBG (binds tightly to T, removing it from the bioavailable pool).
- Genetic variation in androgen receptor sensitivity.
Free T can be a useful indicator of androgen status.
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6. There is no scientific basis for any age-specific recommendations against the use of T therapy in men.
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- The term age-related hypogonadism is of questionable validity since the decline in mean serum T level with age is minor and primarily attributable to comorbidities, especially obesity.
- Older men respond well to T therapy, as do younger men.
- Increased risk of erythrocytosis (increased red blood cell mass) in older men requires monitoring but does not merit withholding T therapy if indicated.
- It is illogical to single out TD as the one medical condition among many (e.g., diabetes, hypertension, heart disease, cancer, arthritis) that does not merit treatment because it becomes more prevalent with age.
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7. The evidence does not support increased risks of CV events with T therapy.
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- Two observational studies received intense media attention after reporting increased CV risks. Both had major flaws/limitations. One misreported results, the other had no control group.
- Low serum T is associated with increased atherosclerosis, coronary artery disease, obesity, diabetes, and mortality.
- Several RCTs in men with known heart disease (angina, heart failure) showed greater benefits with T vs placebo (greater time to ischemia, greater exercise capacity).
- The largest meta-analysis showed no increased risk with T therapy; reduced risk was noted in men with metabolic conditions.
- No increased risk of blood clots (VTE) with T therapy.
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8. The evidence does not support increased risk of PCa with T therapy.
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- Blood androgen levels are not associated with increased risk of PCa nor aggressive PCa.
- T therapy has no greater risk of PCa than placebo.
- Aggressive/high-grade PCa is associated with low serum T levels.
- Early data suggest no increased risk of recurrence/progression with T therapy in men previously treated for PCa.
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9. Evidence supports a major research initiative to explore possible benefits of T therapy for cardiometabolic disease, including diabetes.
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- A large body of evidence suggests lower serum T concentrations are associated with increased CV risk; higher levels are protective.
- T therapy reliably increases lean mass, decreases fat mass, and may improve glycemic control.
- Mortality rates are reduced by half in men with TD who received T therapy compared with untreated men in observational studies.
- Among men who received T therapy, those with normalized T levels had a reduced rate of CV events/mortality vs men with persistently low T.
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Abbreviations: CV; cardiovascular; PCa; prostate cancer; RCT; randomized controlled trial; SHBG; sex hormone binding globulin; T; testosterone; TD; testosterone deficiency; VTE; venothrombotic events.
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Criticism against testosterone therapy and expert responses
Concerns about TD and T therapy that have appeared in the scientific and lay media
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Expert responses
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- The condition of low-T does not exist.
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False. Low-T is an informal term used to describe TD, much as “heart attack” is used inplace of myocardial infarction. TD is a well-established medical condition described in allgeneral medical textbooks.
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- The symptoms of TD do not merit treatment, particularly decreased libido and fatigue.
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The symptoms of TD are of considerable importance to many affected men. However, decisions regarding treatment must be individualized.
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- T therapy is risky.
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All medical treatments entail some degree of risk. Known risks of T therapy include acne, gynecomastia, peripheral edema, infertility, decreased testicular volume, and erythrocytosis. These are reversible with discontinuation of treatment. The evidencefails to support assertions that T therapy is associated with increased CV risk or PCa.
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- T therapy increases risks of VTE, such as deep venous thrombosis or pulmonary emboli.
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Available evidence reveals no increased risk of VTE with T therapy.[3]
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- T therapy increases the risk of myocardial infarction, stroke, and death.
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Two flawed studies reporting increased CV risk with T therapy received enormous media attention. One misreported primary results [4]and the other [5]had no control/comparison group.
In contrast, several dozen studies provide high-level evidence that reduced T levelsare associated withatherosclerosisand increased CV events, whereas T therapy appears to reduce CV risk orimprove known CV risk factors.[6]
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- T therapy causes PCa to develop or become aggressive.
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Not supported by evidence. Longitudinal data reveal no relationship between higherserum T level and PCa risk.[7]
Meta-analyses found no greater risk of PCa in men whoreceived T therapy compared with placebo.[8]
High-grade disease and poor prognosticPCa features are associated with low serum T levels.[9]
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- T therapy is experimental/investigational.
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False. T therapy has been a standard form of medical treatment for men with TD for more than 70 years, with numerous studies documenting benefits and a reasonable safety profile.[6, 10]
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- The decline in T is due to normal aging and does not merit treatment.
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Age alone has little impact on serum T concentrations. Most of the age-associated decline in serum T levels is associated with development of comorbidities, especially obesity.[11]
Many important medical conditions are age related, including heartdisease(CAD), diabetes, arthritis, cataracts, and most adult cancers.
We find no justification to single out TD as a condition that does not merit treatment because it becomes more prevalent with age.
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Comments
References:
1. Morgentaler, A., et al., International expert consensus conference on testosterone deficiency and its treatment held in Prague, Czech Republic. Aging Male, 2015. 18(4): p. 205-6.
2. Morgentaler, A., et al., Fundamental Concepts Regarding Testosterone Deficiency and Treatment: International Expert Consensus Resolutions. Mayo Clin Proc, 2016.
3. Baillargeon, J., et al., Risk of Venous Thromboembolism in Men Receiving Testosterone Therapy. Mayo Clin Proc, 2015. 90(8): p. 1038-45.
4. Vigen, R., et al., Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA, 2013. 310(17): p. 1829-36.
5. Finkle, W.D., et al., Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS One, 2014. 9(1): p. e85805.
6. Morgentaler, A., et al., Testosterone therapy and cardiovascular risk: advances and controversies. Mayo Clin Proc, 2015. 90(2): p. 224-51.
7. Endogenous, H., et al., Endogenous sex hormones and prostate cancer: a collaborative analysis of 18 prospective studies. J Natl Cancer Inst, 2008. 100(3): p. 170-83.
8. Cui, Y., et al., The effect of testosterone replacement therapy on prostate cancer: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis, 2014. 17(2): p. 132-43.
9. Khera, M., et al., A new era of testosterone and prostate cancer: from physiology to clinical implications. Eur Urol, 2014. 65(1): p. 115-23.
10. Snyder, P.J., et al., Effects of Testosterone Treatment in Older Men. N Engl J Med, 2016. 374(7): p. 611-24.
11. Wu, F.C., et al., Hypothalamic-pituitary-testicular axis disruptions in older men are differentially linked to age and modifiable risk factors: the European Male Aging Study. J Clin Endocrinol Metab, 2008. 93(7): p. 2737-45.
12. Nguyen, C.P., et al., Testosterone and "Age-Related Hypogonadism"--FDA Concerns. N Engl J Med, 2015. 373(8): p. 689-91.
13. Morales, A., et al., Diagnosis and management of testosterone deficiency syndrome in men: clinical practice guideline. Appendix available at: http://www.cmaj.ca/content/suppl/2015/10/26/cmaj.150033.DC1/15-0033-1-at.pdf (accessed Jan 10, 2016). CMAJ, 2015. 187(18): p. 1369-77.
14. Dean, J.D., et al., The International Society for Sexual Medicine's Process of Care for the Assessment and Management of Testosterone Deficiency in Adult Men. J Sex Med, 2015. 12(8): p. 1660-86.
15. Dohle, G.R., et al. 2015 EAU Guidelines on Male Hypogonadism, available at http://uroweb.org/wp-content/uploads/EAU-Guidelines-Male-Hypogonadism-2015.pdf (accessed Jan 10, 2016).