Testosterone deficiency and treatment - international expert consensus resolutions
August 2016
Fundamental Concepts Regarding Testosterone Deficiency and Treatment: International Expert Consensus Resolutions. Morgentaler A, Zitzmann M, Traish AM, et al. Mayo Clin. Proc. 2016;91(7):881-896.
Testosterone deficiency and treatment is a very misunderstood and controversial topic among scientists, regulatory agencies (such as the FDA and EMA) and doctors, as well as the popular media.
On October 1, 2015, an international expert consensus conference about testosterone deficiency and its treatment was held in Prague, sponsored by King’s College London and the International Society for the Study of the Aging Male (ISSAM).1 The impetus for this meeting was to address the widespread misinformation and confusion about testosterone deficiency and testosterone therapy.2
The ultimate goal of this consensus conference was to document what is true or untrue about testosterone deficiency and testosterone therapy, to the best degree possible based on existing scientific and clinical evidence.1
There were 18 experts from 11 countries on 4 continents. Specialties included urology, endocrinology, internal medicine, diabetology, and basic science research. Experts were invited on the basis of extensive clinical experience with testosterone deficiency and its treatment and/or research experience.
KEY POINTS
- Testosterone deficiency is a well-established, significant medical condition that negatively affects male sexuality, reproduction, general health, and quality of life.
- Symptoms and signs of testosterone deficiency occur as a result of low levels of testosterone and may benefit from treatment regardless of whether there is an identified underlying cause.
- Symptoms and signs of testosterone deficiency should get more attention because of the limitations of measuring and interpreting testosterone levels in men.
- Testosterone deficiency is a global public health concern.
- Testosterone therapy for men with testosterone deficiency is effective, rational, and evidence based.
- There is no scientific basis for any age-specific recommendations against the use of testosterone therapy in men.
- The evidence does not support increased risks of either cardiovascular events or prostate cancer with testosterone therapy.
- Evidence supports a major research initiative to explore possible benefits of testosterone therapy for cardiometabolic disease, including diabetes.
Resolutions about testosterone deficiency/ therapy and expert comments
The final consensus on several key issues related to testosterone therapy was published in the form of 9 resolutions (i.e. firm decisions), coupled with expert comments1, which we summarize here.
Table 1: Resolutions of the International Expert Consensus Conference on Testosterone Deficiency and Its Treatment.1
| Resolutions | Expert comments |
|---|---|
| 1. TD is a well-established, significant medical condition that negatively affects male sexuality, reproduction, general health, and quality of life. |
TD (low levels of testosterone):
|
| 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. |
|
| 3. TD is a global public health concern. |
|
| 4. T therapy for men with TD is effective, rational, and evidence based. |
High-level evidence shows T therapy effectively:
Strongly suggestive evidence for improvement in mood, energy |
| 5. There is no T level threshold that reliably distinguishes those who will respond to treatment from those who will not. | 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: Free T can be a useful indicator of androgen status.
|
| 6. There is no scientific basis for any age-specific recommendations against the use of T therapy in men. |
|
| 7. The evidence does not support increased risks of CV events with T therapy. |
|
| >8. The evidence does not support increased risk of PCa with T therapy. |
|
| 9. Evidence supports a major research initiative to explore possible benefits of T therapy for cardiometabolic disease, including diabetes. |
|
Abbreviations: CV; cardiovascular; PCa; prostate cancer; RCT; randomized controlled trial; SHBG; sex hormone binding globulin; T; testosterone; TD; testosterone deficiency; VTE; venothrombotic events.
Criticism against testosterone therapy and expert responses
In Nov 2014 and Jan 2015, intense myopic attention was given to 2 flawed studies purporting increased CV risk, leading to criticism in both medical and lay press against the use of testosterone therapy, and issuance of warnings by regulatory agencies. Public criticisms of testosterone therapy has trivialized the symptoms of testosterone deficiency, questioned the very existence of testosterone deficiency as a medical condition, asserted that the benefits of testosterone therapy are unproven and exaggerated the cardiovascular and prostate cancer risks associated with treatment.1 These and other criticisms, together with responses by the expert panel, are summarized in table 2.
Table 2: Common Concerns Regarding Testosterone Deficiency and Testosterone Therapy and Consensus Conference Expert Responses.1
| Concerns about TD and T therapy that have appeared in the scientific and lay media | Expert responses |
|---|---|
|
False. Low-T is an informal term used to describe TD, much as “heart attack” is used in place of myocardial infarction. TD is a well-established medical condition described in all general medical textbooks. |
|
The symptoms of TD are of considerable importance to many affected men. However, decisions regarding treatment must be individualized. |
|
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 evidence fails to support assertions that T therapy is associated with increased CV risk or PCa. |
|
Available evidence reveals no increased risk of VTE with T therapy.3 |
|
Two flawed studies reporting increased CV risk with T therapy received enormous media attention. One misreported primary results4 and the other5 had no control/comparison group. In contrast, several dozen studies provide high-level evidence that reduced T levels are associated with atherosclerosis and increased CV events, whereas T therapy appears to reduce CV risk or improve known CV risk factors.6 |
|
Not supported by evidence. Longitudinal data reveal no relationship between higher serum T level and PCa risk.7 Meta-analyses found no greater risk of PCa in men who received T therapy compared with placebo.8 High-grade disease and poor prognostic PCa features are associated with low serum T levels.9 |
|
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 |
|
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 heart disease (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. |
Abbreviations: T; testosterone; TD; testosterone deficiency; PCa; prostate cancer; CAD; coronary artery disease
Video Summary
One of the international consensus meeting panelist was Dr. Abraham Morgentaler, Associate Clinical Professor at Harvard Medical School and Beth Israel Deaconess Medical Center in Boston, MA. In this video Dr. Morgentaler summarizes the unanimous approval - based on available scientific evidence - of the 9 fundamental resolutions regarding testosterone deficiency and testosterone therapy.
Comments
The resolutions, comments and responses summarized in the tables represent the conclusive agreement reached by a broad range of medical and scientific experts from around the whole world, and are thus not biased by regional or specialty-based biases and groupthink.
Because of the involvement of regulatory agencies in the public debates regarding testosterone, invitations to participate were extended to the FDA and to the EMA (European Medicines Agency); one representative from the EMA did attend in a nonvoting capacity. No representative from the FDA was present.
Several of these resolutions contradict recent positions taken by the FDA.12 For example, FDA states that the available evidence does not support an indication for testosterone therapy for “age-related hypogonadism.”12 The consensus experts found no scientific justification for this statement, and reasserted that the symptoms and manifestations of testosterone deficiency are due to inadequate testosterone levels, regardless of the underlying cause, known or unknown.2
Over the past 20 years, a number of new causes of testosterone deficiency have been identified, especially the contribution of comorbidities - such as diabetes and obesity – to the development of testosterone deficiency, which the FDA and other regulatory agencies have so far failed to recognize. The expert consensus fiercely oppose restricting testosterone treatment only to men with identified causes (i.e. classical hypogonadism, caused by pituitary tumors, granulomatous invasion of the pituitary gland, craniopharyngioma, Kallmann syndrome, prolactinomas or primary testicular damage due to mumps orchitis, Klinefelter syndrome, chemotherapy, or radiation) because most symptomatic men benefit from testosterone therapy even if their testosterone deficiency has no known cause.2 They draw a parallel with high blood pressure; 80% of individuals with high blood pressure have no known underlying cause. An analogous recommendation would be to restrict antihypertensive treatment to only the 20% of patients with known causes of hypertension. Thus, the FDA recommendation to restrict testosterone treatment only to men with classical hypogonadism is illogical and unscientific.2 The consensus experts state “It is worth recognizing that although the FDA plays a critical role in the regulation of medications, it does not regulate the practice of medicine. Concepts regarding medical issues require medical expertise, which we have attempted to provide in this consensus document.”1
Evidence from the recently published Testosterone Trials10 – funded by the NIH (National Institute of Health) counters several FDA recommendations and provides support for the conclusions reached by the expert consensus. The Testosterone Trials demonstrated major benefits with testosterone therapy; improvement in various testosterone deficiency-related symptoms, rejection of age-based restrictions (men in the Testosterone Trials are all aged 65 years and older). Notably, with the Testosterone Trials we now have level 1 evidence contradicting the assertion by FDA that the benefits of testosterone therapy have been adequately confirmed only in men with an identified underlying cause (classical hypogonadism).10,12
It should be underscored that the expert consensus fully endorses the importance of symptoms and signs of testosterone deficiency, which is promoted in the latest medical guidelines 13-15 but not embraced so far by regulatory agencies. Symptoms and signs of testosterone deficiency should get more attention because of the limitations of measuring and interpreting testosterone levels in men:1
(1) Various testosterone deficiency symptoms and signs manifest at different intra-individual thresholds.
(2) Substantial inter-individual variability in testosterone thresholds for the same symptom or sign, depending in part on variations in androgen receptor sensitivity.
(3) Variability in SHBG levels among individuals influences the levels of free testosterone for any given total testosterone level. Free testosterone measurement can be an important biochemical test in the assessment of men with symptoms indicative of testosterone deficiency.
Therefore, diagnosis of testosterone deficiency should include assessment of the entire clinical picture, combined with blood testing. Rigid application of a uniform total testosterone level threshold for all individuals as the primary instrument to diagnose testosterone deficiency lacks a scientific foundation and is discouraged.1
Importantly, the expert consensus found no high-quality evidence to support FDA’s concerns regarding cardiovascular risk with testosterone therapy. To the contrary, substantial evidence was found linking low testosterone levels to cardiovascular disease and mortality, with suggestive evidence of reduced cardiovascular risk with testosterone therapy.
Recommendations
References
- Morgentaler A, Zitzmann M, Traish AM, et al. Fundamental Concepts Regarding Testosterone Deficiency and Treatment: International Expert Consensus Resolutions. Mayo Clin. Proc.2016;91(7):881-896. Return to content
- Morgentaler A, Zitzmann M, Traish AM, Fox A. International expert consensus conference on testosterone deficiency and its treatment held in Prague, Czech Republic. The aging male : the official journal of the International Society for the Study of the Aging Male.2015;18(4):205-206. Return to content
- Baillargeon J, Urban RJ, Morgentaler A, et al. Risk of Venous Thromboembolism in Men Receiving Testosterone Therapy. Mayo Clin. Proc. 2015;90(8):1038-1045. Return to content
- Vigen R, ODonnell CI, Baron AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013;310(17):1829-1836. Return to content
- Finkle WD, Greenland S, Ridgeway GK, et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PloS one. 2014;9(1):e85805. Return to content
- Morgentaler A, Miner MM, Caliber M, Guay AT, Khera M, Traish AM. Testosterone therapy and cardiovascular risk: advances and controversies. Mayo Clin. Proc. 2015;90(2):224-251. Return to content
- Endogenous H, Prostate Cancer Collaborative G, Roddam AW, Allen NE, Appleby P, Key TJ. Endogenous sex hormones and prostate cancer: a collaborative analysis of 18 prospective studies. J. Natl. Cancer Inst. 2008;100(3):170-183. Return to content
- Cui Y, Zong H, Yan H, Zhang Y. The effect of testosterone therapy on prostate cancer: a systematic review and meta-analysis. Prostate cancer and prostatic diseases.2014;17(2):132-143. Return to content
- Khera M, Crawford D, Morales A, Salonia A, Morgentaler A. A new era of testosterone and prostate cancer: from physiology to clinical implications. Eur. Urol. 2014;65(1):115-123. Return to content
- Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of Testosterone Treatment in Older Men. N. Engl. J. Med. 2016;374(7):611-624. Return to content
- Wu FC, Tajar A, Pye SR, 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):2737-2745. Return to content
- Nguyen CP, Hirsch MS, Moeny D, Kaul S, Mohamoud M, Joffe HV. Testosterone and Age-Related Hypogonadism--FDA Concerns. N. Engl. J. Med. 2015;373(8):689-691. Return to content
- Morales A, Bebb RA, Manjoo P, 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):1369-1377. Return to content
- Dean JD, McMahon CG, Guay AT, et al. The International Society for Sexual Medicines Process of Care for the Assessment and Management of Testosterone Deficiency in Adult Men. The journal of sexual medicine. 2015;12(8):1660-1686. Return to content
- Dohle GR, Arver S, Bettocchi C, Jones TH, Kliesch S, Punab M. 2015 EAU Guidelines on Male Hypogonadism, available at http://uroweb.org/wp-content/uploads/EAU-Guidelines-Male-Hypogonadism-2016.pdf (accessed July 26, 2016). Return to content
