Current knowledge on testosterone deficiency with practical recommendations for diagnosis and treatment

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Testosterone deficiency. Traish AM, Miner MM, Morgentaler A, et al. Am J Med 2011;124(7):578-587.

This article aimed to provide practical recommendations for the diagnosis of testosterone deficiency (TD) and information on the benefits and risks of testosterone replacement in middle-aged and older men through a comprehensive review of epidemiological and clinical studies. The review addressed the potential role of testosterone in general men’s health concerns, including the sexual realm, metabolic effects, body composition and mortality, and included an analysis of treatment modalities and examination of current areas of concern and uncertainty.1

Key Points

Overview1

  • Testosterone (T) deficiency (TD; hypogonadism) is associated with aging and affects approximately 30% of men aged 40–79 years, ranging from 9% in men in their 50's to 91% of those in their 80’s

    • Levels of free T decrease by approximately 1.4% per year in men aged 39 to 70 years
    • T levels are lower in men with one or more comorbidities
    • Significantly increased risk of TD associated with obesity, type 2 diabetes mellitus (T2DM) and hypertension
    • Strong association between TD and metabolic syndrome (MetS)
  • The clinical signs and symptoms of TD include:

    • Decreased libido, erectile dysfunction (ED), fatigue (3 most common symptoms)
    • Negative mood states, impaired cognition and memory, diminished energy, sense of vitality or well-being
    • Changes in body composition (decreased lean body mass, increased fat mass, decrease bone mineral density), frailty

Relationship between TD and MetS and T2DM1

  • Complex bidirectional relationship between TD and MetS that involves multiple pathophysiological pathways:

    • Increased insulin resistance, hyperglycaemia, visceral fat accumulation, dyslipidaemia, increased inflammatory cytokines and endothelial dysfunction, leading to vascular disease
    • Emerging evidence links TD to multiple cardiovascular (CV) risk factors, including obesity, diabetes, hypertension and altered lipid profiles, suggesting that TD has a significant role in the regulation of metabolic homeostasis and is an independent determinant of endothelial dysfunction
    • T replacement therapy (TRT) significantly improves lipid profiles, reduces body fat and increases lean muscle mass and decreases fasting glucose levels in men with TD

TD and all-cause mortality and CV disease risk1

  • Significant associations between T levels and all-cause and CV death in men ≥40 years
  • In men aged 40–79 years, every 173 ng/dL (6.0 nmol/L) increase in serum T was associated with a 21% lower risk of all-cause death
  • Total and bioavailable T have also been shown to be inversely related to risk of death and low total T predicts increased risk of CV and respiratory disease death
  • There are data supporting the benefits of long-acting intramuscular (IM) T supplementation in combination with optimal therapy in improving functional exercise capacity, muscle strength, insulin levels and baroreflex sensitivity in elderly men with chronic heart failure

Effect of testosterone replacement therapy on MetS or early T2DM1

  • The level of evidence supporting TRT in the treatment of MetS, T2DM and CV disease (CVD) is variable. However:

    • There is rigorous evidence supporting TRT in reducing fat mass, a key component in treating individuals with MetS or T2DM
    • Clinical trials have shown that TRT is associated with a significant reduction in fasting plasma glucose, homeostasis model assessment index of insulin resistance (HOMA-IR), triglycerides and waist circumference, and an increase in high-density lipoprotein cholesterol in patients with TD and MetS
    • TRT in men with TD and newly diagnosed T2DM significantly improved glycemic control, insulin levels and sensitivity, and C-reactive protein levels

Use of TRT in patients with TD and erectile dysfunction and low libido1

  • Overall, there is consistent support for the benefits of TRT in improving sexual desire, erectile function and performance

Commercial formulations for the treatment of TD1

  • Short-acting IM injections achieve physiological serum concentrations of T within 2–3 days but require an injection schedule of at least every 2–3 weeks
  • Topical gels or patches provide a more stable serum T concentration over time than short-acting injections, but patches are associated with a high rate of skin reactions. There is a transfer potential when using T gels
  • Subcutaneous T pellets provide 3–6 months of normal T levels, but pellets may extrude after implantation
  • A long-acting injectable formulation of T undecanoate maintains physiological levels of serum T with a 10–12-week dosing schedule
  • Current treatment modalities appear relatively safe, and adverse events definitively associated with treatment (acne, gynecomastia, erythrocytosis, and oedema) reversible on withdrawal of treatment
  • The relationship of other risks such as sleep apnea, worsening of urinary voiding symptoms, and prostate cancer to T therapy is less well established
  • Oral alkylated T preparations (e.g. methyltestoserone) are associated with liver toxicity and should be avoidedStandard forms of TRT do not appear to adversely affect renal function

Other issues in the diagnosis and treatment of TD1

  • A lack of a clearly-defined serum threshold for distinguishing T deficiency remains an area of controversy in the biochemical determination of TD:

    • Published consensus guidelines recommend arbitrary thresholds, generally ranging from 200 to 350 ng/dL (6.94–12.15 nmol/L)
    • Although there is general agreement that free or bioavailable T provides a better estimation of T status than serum T, uncertainty remains about the reliability of those assays
    • Furthermore, patient responsiveness to T may be influenced by androgen receptor polymorphisms
    • Consequently, symptoms of TD can play an important role in the diagnosis of TD
  • Physicians managing patients with TD should take these considerations into account together with their clinical judgment and experience in determining which patients require diagnosis and treatment
  • A recent international, random population sample study by the European Male Aging Study (EMAS) group provided evidence-based criteria demonstrating that the presence of a cluster of three sexual symptoms (decreased frequency of morning erection, decreased frequency of sexual thoughts, and erectile dysfunction) in combination with low T levels (total T of <317 ng/dL [11 nmol/L] and a free T of <220 pmol/L [6.35 pg/mL]) can be regarded as necessary to establish a diagnosis of late-onset hypogonadism, although other non-sexual symptoms may also be present.2 (see June 2011 Research News article)

    • This highlights the importance of using stringently defined, symptom-based criteria in addition to biochemical measures for accurate diagnosis of late-onset hypogonadism
  • Emerging data suggest the potential of T to ameliorate comorbidities such as MetS and early T2DM, which take T beyond the sexual domain into the metabolic realm and as an overall marker of good health
  • Current clinical evidence does not demonstrate a significant association between serum androgen concentrations and prostate cancer

Guidelines

  • A range of consensus guidelines on the investigation, treatment and monitoring of TD in men have been published3-6
  • The recent Endocrine Society guidelines5 included revised recommendations for the treatment of older men, advising against a general policy of offering TRT to all older men with low T levels in the absence of clinically significant symptoms of androgen deficiency

Conclusions and recommendations1

  • The identification of low serum T levels in conjunction with signs or symptoms suggestive of TD provides the opportunity not only to return T levels to the normal physiological range and to treat the presenting symptoms, but also has the potential to improve or reverse associated metabolic and general male health status.

What this study adds

This comprehensive review was based on the examination of the relevant published medical literature on TD and provides practical recommendations for the diagnosis of TD and the use of TRT in men with low testosterone. The practical algorithm for the work-up and management of TD developed by the authors (Traish AM, et al.) is presented in the Figure.

Figure: Practical algorithm for work-up and management of testosterone deficiency. Developed by Traish, AM et al. Reproduced with permission.
Reproduced with permission from Elsevier

References

1. Traish AM, Miner MM, Morgentaler A, et al. Testosterone deficiency. Am J Med 2011;124(7):578-587.
2. Wu FC, Tajar A, Beynon JM, et al. Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med 2010;363(2):123-135.
3. Nieschlag E, Swerdloff R, Behre HM, et al. Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, and EAU recommendations. J Androl 2006;27(2):135-137.
4. Wang C, Nieschlag E, Swerdloff R, et al. Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA, and ASA recommendations. Eur Urol 2009;55(1):121-130.
5. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010;95(6):2536-2559.
6. Buvat J, Maggi M, Gooren L, et al. Endocrine aspects of male sexual dysfunctions. J Sex Med 2010;7(4 Pt 2):1627-1656.

The original article is recommended for additional detail and supporting references for the statements summarised in this Research News article, which are too numerous to cite in full.

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Last updated: 2018
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