Diagnosis and treatment guidelines
Consensus Recommendations
Fundamental Concepts Regarding Testosterone Deficiency and Treatment: International Expert Consensus Resolutions

https://doi.org/10.1016/j.mayocp.2016.04.007Get rights and content

Abstract

To address widespread concerns regarding the medical condition of testosterone (T) deficiency (TD) (male hypogonadism) and its treatment with T therapy, an international expert consensus conference was convened in Prague, Czech Republic, on October 1, 2015. Experts included a broad range of medical specialties including urology, endocrinology, diabetology, internal medicine, and basic science research. A representative from the European Medicines Agency participated in a nonvoting capacity. Nine resolutions were debated, with unanimous approval: (1) TD is a well-established, clinically significant medical condition that negatively affects male sexuality, reproduction, general health, and quality of life; (2) 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; (3) TD is a global public health concern; (4) T therapy for men with TD is effective, rational, and evidence based; (5) there is no T concentration threshold that reliably distinguishes those who will respond to treatment from those who will not; (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 cardiovascular events with T therapy; (8) the evidence does not support increased risk of prostate cancer with T therapy; and (9) the evidence supports a major research initiative to explore possible benefits of T therapy for cardiometabolic disease, including diabetes. These resolutions may be considered points of agreement by a broad range of experts based on the best available scientific evidence.

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

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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.

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