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). The impetus for this meeting was to address the widespread misinformation and confusion about testosterone deficiency and testosterone therapy. 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.
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. 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 comments. These are summarized in table 1.
Table 1: Resolutions of the International Expert Consensus Conference on Testosterone Deficiency (TD) and Its Treatment.
CRITICISM AGAINST TESTOSTERONE THERAPY & 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. These and other criticisms, together with responses by the expert panel, are summarized in table 2.
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 group-think. 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 showed up…
Several of these resolutions contradict recent positions taken by the FDA. For example, FDA states that the available evidence does not support an indication for testosterone therapy for “age-related hypogonadism.”  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.
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. 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. 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.” In other words, experts in medical practice and science feel that the FDA has no medical expertise!
Evidence from the recently published Testosterone Trials  – 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) 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. 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.
Monica Mollica holds a Master Degree in Nutrition from the University of Stockholm and Karolinska Institue, Sweden. She has also done PhD level course work at renowned Baylor University, TX.
Monica is a medical writer and clinical website developer. Being a fitness athlete herself, she is also sharing her hands-on experience by offering nutrition & health consultations, and body transformation coaching.
Having lost her father in a lifestyle-induced sudden heart attack at an age of 48, she is very passionate about health promotion and specializes in preventive medicine.
Monica is currently in the process of writing a book on testosterone, covering health related issues for both men and women. You can visit her website at www.Lean.Fitness.
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).