Diagnosis and treatment guidelinesConsensus RecommendationsFundamental Concepts Regarding Testosterone Deficiency and Treatment: International Expert Consensus Resolutions
Section snippets
Terminology
It was agreed that we would use the following terminology, consistent with an effort to use language that promotes accuracy and clarity: testosterone therapy (T therapy) rather than the older term testosterone replacement therapy; and testosterone deficiency (TD) rather than the older term hypogonadism. We note that the term low T is an informal, non-technical term for TD, analogous to the use of “heart attack” in place of MI.
Participants
Broad geographic and specialty distribution of the expert panel was achieved. There were 18 participants 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 TD and its treatment, research experience, or both. Our goal in achieving such broad geographic and specialty representation was to provide assurance that resolutions that met broad
Methods
A set of 9 statements, termed resolutions, were prepared by a working group and circulated to the participants before the conference. At the conference, the relevant science and literature were presented by one expert (presenter), followed by comments by a second expert (discussant). The resolution then underwent vigorous discussion by the entire consensus panel, including debate regarding final wording of the resolution. As a consensus conference, there was no requirement for unanimity:
RESOLUTION 1. TD is a Well-established, Significant Medical Condition That Negatively Affects Male Sexuality, Reproduction, General Health, and Quality of Life
Testosterone has a broad range of physiologic functions affecting multiple organ systems, including the brain, peripheral nerves, muscle, fat, bone, CV system, and male genital and reproductive systems. It regulates the metabolism of carbohydrates, lipids, and proteins and influences muscle growth and adipogenesis. Recognized as an important medical condition since at least 1940,4 TD is a well-established, major medical condition that negatively impacts male sexuality, reproduction, general
RESOLUTION 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 Etiology
The clinical manifestations of TD arise as a direct result of low circulating androgen concentrations. Diminished T concentrations may occur in the presence of known underlying conditions or in association with comorbidities such as diabetes and obesity, or the cause may be unknown. A state indistinguishable from TD can be reproduced in healthy volunteers by pharmacologically lowering serum T levels and in men with advanced PCa who undergo androgen deprivation. Resolution of signs and symptoms
RESOLUTION 3. TD is a Global Public Health Concern
Epidemiological data suggest that TD is common worldwide, albeit with widely varying reported frequencies among studies and countries.22 This variability is attributable to the studied populations, instruments used to identify TD/hypogonadism, and differences in applied biochemical thresholds for T. In the United States, 4 studies reported prevalence rates ranging from 6% to 30%.23, 24, 25, 26 The European Male Ageing Study reported an overall prevalence of TD of 2.1% in men based on
RESOLUTION 4. T Therapy for Men With TD is Effective, Rational, and Evidence Based
Population studies suggest that sexual symptoms are the most consistent symptoms associated with TD.11 A recent meta-analysis of available RCTs (29 studies, 1930 patients) indicates that T therapy significantly improves erectile function, sexual-related erections, and sexual desire.29 Of importance, these improvements were observed in men with TD but not in eugonadal or mixed populations. Orgasmic function was improved as well. The severity of TD at baseline was positively associated with a
RESOLUTION 5. There is No T Concentration Threshold That Reliably Distinguishes Those Who Will Respond to Treatment From Those Who Will Not
There is no clear-cut T threshold that reliably distinguishes men who will respond to treatment from those who will not, a fact acknowledged by the Endocrine Society in the United States, among others.35 Rather, TD symptoms and signs become more likely with decreasing T levels. Testosterone-related loss of libido or vigor increases below T concentrations of 15 nmol/L, increased visceral fat is observed below concentrations of 12 nmol/L, and depression and type 2 diabetes mellitus become more
RESOLUTION 6. There is No Scientific Basis for Any Age-specific Recommendations Against the Use of T Therapy in Men
Although it is commonly asserted that T levels decline with age, data from the European Male Ageing Study and other sources reveal that age alone is associated with little decline in mean total T levels in men aged 40 years to more than 75 years, with much of the observed decline attributable to comorbidities, including increased BMI.17 Free and bioavailable T concentrations decline more rapidly than total T levels, in large part due to age-related increase in SHBG. Age is not a specific risk
RESOLUTION 7. The Evidence Does Not Support Increased Risks of CV Events With T Therapy
Two recent observational studies reporting increased CV risks with T therapy received intense media attention.1, 2 However, neither provided credible evidence of increased risk. The first underwent 2 official corrections: one for misreporting its results, which actually showed an approximately 50% lower absolute rate of adverse CV events in men who received a T prescription compared with untreated men, and the second for large data errors, including that nearly 10% of its all-male database was
RESOLUTION 8. The Evidence Does Not Support Increased Risk of PCa With T Therapy
Despite a long-standing concern that higher androgen concentrations lead to development of de novo PCa or rapid growth of aggressive PCa, this belief is not supported by the evidence.6, 63 Large prospective longitudinal studies have found no association between endogenous androgen concentrations and PCa risk.64 Meta-analyses of placebo-controlled T therapy trials have documented no increased risk of PCa in men receiving T therapy.65 In men who received T therapy, there was no increased risk of
RESOLUTION 9. The Evidence Supports a Major Research Initiative to Explore Possible Benefits of T Therapy for Cardiometabolic Disease, Including Diabetes
Type 2 diabetes, as well as obesity and the metabolic syndrome, are highly prevalent conditions associated with high rates of morbidity and mortality, including CV mortality.75 Independent of these conditions, CV events account for approximately 40% of male deaths in industrialized countries. There is a high prevalence of low T levels in men with type 2 diabetes, metabolic syndrome, obesity, and CV disease,21, 76, 77, 78, 79 and TD is associated with an adverse CV risk profile and increased
Discussion
In the face of considerable public and scientific confusion regarding TD and its treatment, an international expert consensus conference was held to assert, or reassert, fundamental concepts based on the best available evidence and to thereby provide an accurate scientific framework for ongoing and future discussions.
The expert panel vigorously debated 9 resolutions regarding TD and T therapy. These resolutions address key areas, several of which represent foundational concepts that have been
Conclusion
An international group of experts has reached the following conclusions: TD is an important medical condition affecting the health and well-being of men; the symptoms of TD result from low levels of T regardless of whether an underlying condition is identified; the impact of TD is global; T therapy is effective, rational, and evidence based; caution must be used in the rigid application of T thresholds in determining who is a candidate for T therapy; there is no basis for restricting T therapy
References (88)
Testosterone and prostate cancer: an historical perspective on a modern myth
Eur Urol
(2006)- et al.
High serum testosterone is associated with reduced risk of cardiovascular events in elderly men: the MrOS (Osteoporotic Fractures in Men) study in Sweden
J Am Coll Cardiol
(2011) - et al.
Testosterone therapy and cardiovascular risk: advances and controversies
Mayo Clin Proc
(2015) - et al.
Perspective: regulatory agencies' changes to testosterone product labeling
J Sex Med
(2015) - et al.
Testosterone deficiency
Am J Med
(2011) - et al.
The 20-year public health impact and direct cost of testosterone deficiency in U.S. men
J Sex Med
(2013) - et al.
Testosterone supplementation and sexual function: a meta-analysis study
J Sex Med
(2014) - et al.
Obesity and late-onset hypogonadism
Mol Cell Endocrinol
(2015) - et al.
Aging males' symptoms in relation to the genetically determined androgen receptor CAG polymorphism, sex hormone levels and sample membership
Psychoneuroendocrinology
(2010) - et al.
CAG repeat testing of androgen receptor polymorphism: is this necessary for the best clinical management of hypogonadism?
J Sex Med
(2013)
Outcomes of testosterone therapy in men with testosterone deficiency (TD): part II
Steroids
Impact of testosterone replacement therapy on myocardial infarction, stroke, and death in men with low testosterone concentrations in an integrated health care system
Am J Cardiol
Risk of venous thromboembolism in men receiving testosterone therapy
Mayo Clin Proc
A new era of testosterone and prostate cancer: from physiology to clinical implications
Eur Urol
Long-term exposure to testosterone therapy and the risk of high grade prostate cancer
J Urol
Use of testosterone replacement therapy in the United States and its effect on subsequent prostate cancer outcomes
Urology
Effect of exogenous testosterone on prostate volume, serum and semen prostate specific antigen levels in healthy young men
J Urol
Goodbye androgen hypothesis, hello saturation model
Eur Urol
Testosterone deficiency: a risk factor for cardiovascular disease?
Trends Endocrinol Metab
Effect of long-acting testosterone treatment on functional exercise capacity, skeletal muscle performance, insulin resistance, and baroreflex sensitivity in elderly patients with chronic heart failure: a double-blind, placebo-controlled, randomized study
J Am Coll Cardiol
Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials
BMC Med
American Association of Clinical Endocrinologists and American College of Endocrinology position statement on the association of testosterone and cardiovascular risk
Endocr Pract
Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels
JAMA
Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men
PLoS One
International expert consensus conference on testosterone deficiency and its treatment held in Prague, Czech Republic
Aging Male
Endocrines: the use of testosterone
N Engl J Med
Trends in androgen prescribing in the United States, 2001 to 2011
JAMA Intern Med
Testosterone and “age-related hypogonadism”—FDA concerns
N Engl J Med
Identification of late-onset hypogonadism in middle-aged and elderly men
N Engl J Med
Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men
Diabetes Care
Associations between sex steroids and the development of metabolic syndrome: a longitudinal study in European men
J Clin Endocrinol Metab
A randomized, double-blind, placebo-controlled trial of testosterone gel on body composition and health-related quality-of-life in men with hypogonadal to low-normal levels of serum testosterone and symptoms of androgen deficiency over 6 months with 12 months open-label follow-up
Aging Male
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
Low testosterone in men with type 2 diabetes: significance and treatment
J Clin Endocrinol Metab
Effects of testosterone treatment in older men
N Engl J Med
Systematic literature review of the epidemiology of nongenetic forms of hypogonadism in adult males
J Hormones
Prevalence of hypogonadism in males aged at least 45 years: the HIM study
Int J Clin Pract
Prevalence and incidence of androgen deficiency in middle-aged and older men: estimates from the Massachusetts Male Aging Study
J Clin Endocrinol Metab
Prevalence of symptomatic androgen deficiency in men
J Clin Endocrinol Metab
Longitudinal effects of aging on serum total and free testosterone levels in healthy men
J Clin Endocrinol Metab
Treatment of symptomatic androgen deficiency: results from the Boston Area Community Health Survey
Arch Intern Med
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Potential Competing Interests: Dr Morgentaler was a paid consultant for AbbVie, Auxilium, Antares, Clarus, Endo, and TesoRx, received honoraria from Bayer, Merck, and Pfizer, and received research grants from Eli Lilly. Dr Jones was a paid consultant for Bayer, Eli Lilly, Merck, and Mereo BioPharma, received honoraria from Bayer, Besins, Clarus, Merck, ProStrakan, and Eli Lilly, and received research grants from Bayer, Besins, ProStrakan. Dr Maggi was a paid consultant for Intercept, Menarini, and ProStrakan, received honoraria from Bayer, and received research grant from Intercept. Dr Aversa received honoraria from Bayer, Eli Lilly, and Menarini. Dr Dobs is on the speaker's bureau for AbbVie, was a paid consultant for AbbVie and Advance Medical, and received research grants from Covance, Clarus, and the National Institutes of Health. Dr Hellstrom was a paid consultant for AbbVie, Allergan, American Medical Systems, Astellas, Coloplast, Endo, Lipocine, Pfizer, and Repros, received research grants from Coloplast, Endo, New England Research Institutes, received honoraria from Endo, and Menarini, and was a board member, officer, and trustee for Theralogix, and served on the data monitoring committee for the NIH-funded Testosterone Trials. Dr Lim was a paid consultant for Bayer and Besins. Dr Mskhalaya was a paid consultant and received honoraria from Bayer and Besins. Dr Torres was a paid consultant for Pfizer, Besins, and Eli Lilly, and received honoraria from Pfizer, Lilly, Bayer, Besins, GSK, and Astellas. Dr Chan has been a paid consultant for Bayer, Pfizer and Besins Healthcare; has received research grants from Bayer and Pfizer (to the Chinese University of Hong Kong), received honoraria from Bayer, Pfizer and Besins Healthcare (donated to the Chinese University of Hong Kong), and is on the speaker bureau for Bayer, Pfizer and Besins. She does not own any stocks in these companies. Dr Arver was a paid consultant for Pfizer, and received honoraria from Bayer and Eli Lilly.