Updated guidance on the diagnosis and treatment of hypogonadism: focus on the European Association of Urology (EAU) guidelines 2012
September 2013
Guidelines on male hypogonadism. Dohle GR, Arver S, Bettocchi C, et al. European Association of Urology 2012. Feb:1−28.
ISA, ISSAM, EAU, EAA and ASA recommendations: Investigation, treatment and monitoring of late-onset hypogonadism in males. The Aging Male 2009;12:5−12.
Testosterone therapy in men with androgen deficiency syndromes: An Endocrine Society Clinical Practice Guideline. Bahsin S, Cunningham GR, Hayes FJ, et al. J Clin Endocrinol Metab 2010;95:2536– 2559.
This editorial focuses on the conclusions and recommendations of the Guidelines on Male Hypogonadism recently published by the European Association of Urology (EAU) in 2012.1 Conclusions and recommendations in these guidelines are compared to those presented in earlier guidelines published by the International Society for the Study of the Aging Male (ISSAM, 2009) and Endocrine Society (2010).2,3
KEY POINTS
- Late-onset hypogonadism (LOH) is defined as hypogonadism in a person who has had normal pubertal development that resulted in the development of normal male secondary sex characteristics1
- The decline in gonadal function may be gradual, and resulting symptoms and signs may be obscured by the variation in physiological phenotype1
- Previous guidelines define LOH as a clinical and biochemical syndrome associated with advancing age and characterized by low serum testosterone levels below the reference range for young, healthy adult males (aged 20–30 years)2
- Additional clinical symptoms and signs suggestive of hypogonadism now include metabolic syndrome, insulin resistance and type 2 diabetes mellitus.1These additional symptoms expand on typical symptoms (e.g. decrease in lean body mass, hot flushes, reduced sexual desire) published in earlier guidelines2,3
- Confirmation of hypogonadism by measurement of levels of serum testosterone is required
- The lower (normal) level of total serum testosterone to distinguish between normal levels and levels possibly associated with deficiency is now recommended as 12.1 nmol/L.1 This cut-off is a revision of the lower limit (10.4 nmol/L) published in 2010 guidelines3
- Levels of serum testosterone below this new limit are associated with a greater likelihood of presenting symptoms3
- Treatment with testosterone provides several benefits in metabolic control and body composition1
- Studies in hypogonadal men with impaired glucose tolerance and lipid profiles have demonstrated the positive effects of testosterone therapy on glycemic and lipid profiles, insulin resistance and visceral adiposity1
- Several studies demonstrate 3-months treatment with testosterone is associated with an improvement in body weight, body mass index and lipid profile; a significant reduction in trunk and waist fat; and a decrease in waist size1
- Testosterone therapy is recommended in patients with a decline in muscle mass and strength1
- Testosterone treatment has been associated with favorable benefits in body composition, with a decrease of fat mass and increase of lean body mass1,2
- Similar results are reported in guidelines from 2010, which show a significantly greater increase in lean body mass (2.7 kg; 95% Confidence Interval [CI] 1.6, 3.7) and a greater reduction in fat mass (-2.0 kg; 95% CI -3.1, -0.8) with testosterone treatment vs. placebo3
- Testosterone therapy is not related to the development of de novo cardiovascular events1
- Caution is advised when using testosterone treatment in males with existing cardiovascular diseases, as an increase in red blood cells is a common side effect. Thus, hematocrit and hemoglobin measurements are recommended prior to and periodically after treatment 1
- In patients undergoing surgery for localized prostate cancer, testosterone therapy for treatment of hypogonadism should not be initiated before 1 year of follow-up without prostate-specific antigen (PSA) recurrence1
- Treatment should be restricted to patients with a low risk for recurrent prostate cancer (pre-surgery Gleason <8; pT1-2; PSA <10 ng/ml)1
- Guidelines published in 2010 previously preclude a general recommendation due to a lack of data from randomized trials, but acknowledge that clinicians begin testosterone treatment in such patients who have been disease-free for 2 years or more3
What is known
The incidence of androgen deficiency in middle-aged men has been reported as 6%.4 The association between advancing age and declining levels of testosterone is well known5,6 and is an area of active research. In light of this, guidelines from several societies have been published over the past decade that offer recommendations and gand present in men with normal levels of testosteroneuidance for the treatment and diagnosis of male hypogonadism.1-3 The recommendations within guidelines are commonly categorized according to the strength of scientific evidence; providing transparency between the supporting evidence and recommendation given. In the absence of trials data, guidelines are able to provide suggestions based on clinical experience of respected authorities. With the continued publication of trial data in male hypogonadism, guidelines are updated regularly.
What these studies add
Guidelines published by EAU in 20121 expand on existing suggestions and recommendations given in guidelines published by ISSAM (2009)2 and Endocrine Society (2010).3 The recent EAU guidelines provide an updated definition for LOH, and include additional clinical symptoms and signs suggestive of hypogonadism in patients with low levels of testosterone.4,7 Many of these symptoms are associated with normal aging and present in men with normal levels of testosterone.5 It is suggested that clinicians measure serum testosterone levels in patients with one or more clinical symptoms. Following evaluation of data from three large community-based samples, Bhasin et al. suggest a cut-off value of 12.1 nmol/L for the lower normal level of testosterone.8 Although a consensus on a specific value has not been reached, the EAU 2012 guidelines highlight a range of 8–12 nmol/L for the lower normal range.1 Patients with levels of testosterone below this value have an increased risk of symptoms of androgen deficiency and adverse health outcomes. Hypogonadism may not always present as low testosterone levels, such as in men with primary testicular damage. As a result, levels of luteinizing hormone should also be considered.
Low levels of testosterone are associated with a number of chronic diseases, and patients may benefit from testosterone treatment. The conclusions drawn from EAU 2012 guidelines are supported by evidence obtained from well-designed controlled studies without randomization. The positive effect of testosterone treatment on body composition in hypogonadal men are presented in EAU guidelines, with an increase in lean body mass and decrease in fat mass.9 The beneficial effects of 3-months treatment with testosterone on trunk and waist fat, body weight, body mass index and lipid profile are also reported.10,11 Testosterone treatment has also demonstrated a positive effect on glycemic and lipid profiles, and a consequent decrease in cardiovascular risk.12
Evidence of potential risks of testosterone treatment in various diseases are presented in EAU guidelines, and recommendations are suggested to clinicians. The EAU guidelines conclude that testosterone therapy is not related to the development of cardiovascular events. This decrease in risk is supported by meta-analysis of randomized trials.13,14,15 For patients at low-risk of recurrent prostate cancer (and with no evidence of active disease) testosterone therapy can be cautiously considered not before 1 year of follow-up.16-18 However, this treatment remains off-label.16,17
Recommendations
References
- Dohle G, Arver S, Betocchi C, et al. Guidelines on Male Hypogonadism. 2012:28. Return to content
- Wang C, Nieschlag E, Swerdloff RS, et al. ISA, ISSAM, EAU, EAA and ASA recommendations: investigation, treatment and monitoring of late-onset hypogonadism in males. The Aging Male 2009;12(1):5-12. Return to content
- 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. Return to content
- Hall S, Esche G, Araujo A. Correlates of low testosterone and symptomatic androgen deficiency in a population-based sample. J Clin Endocrinol Metab 2008;93(10):3870- 3877. Return to content
- Kaufman J, Vermeulen A. The decline of androgen levels in elderly men and its clinical and therapeutic implications. Endocr Rev 2005;26(6):933-876. Return to content
- Wu F, Tajar A, Pye S, 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 Endocrinol Metab 2008;93(7):2737- 2745. Return to content
- 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. Return to content
- Bhasin S, Pencina M, Jasuja GK, et al. Reference ranges for testosterone in men generated using liquid chromatography tandem mass spectrometry in a community-based sample of healthy nonobese young men in the Framingham Heart Study and applied to three geographically distinct cohorts. J Clin Endocrinol Metab 2011;96(8):2430- 2439. Return to content
- Saad F, Aversa A, Isidori AM, et al. Onset of effects of testosterone treatment and time span until maximum effects are achieved. Eur J Endocrinol 2011;165(5):675-685. Return to content
- Saad F, Gooren L, Haider A, et al. An exploratory study of the effects of 12 month administration of the novel long-acting testosterone undecanoate on measures of sexual function and the metabolic syndrome. Arch Androl 2007;53(6):353-357. Return to content
- Haider A, Gooren L, Padungtod P, et al. Improvement of the metabolic syndrome and of non-alcoholic liver steatosis upon treatment of hypogonadal elderly men with parenteral testosterone undecanoate. Exp Clin Endocrinol Diabetes 2010;118(3):167-171. Return to content
- Kapoor D, Aldred H, Clark S, et al. Clinical and biochemical assessment of hypogonadism in men with type 2 diabetes: correlations with bioavailable testosterone and visceral adiposity. Diabetes Care 2007;30(4):911-917. Return to content
- Haddad RM, Kennedy CC, Caples SM, et al. Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clin Proc 2007;82(1):29-39. Return to content
- Shabsigh R, Katz M, Yan G, et al. Cardiovascular issues in hypogonadism and testosterone therapy. Am J Cardiol 2005;96(12B):67-72. Return to content
- Carson C, Rosano G. Exogenous testosterone, cardiovascular events, and cardiovascular risk factors in elderly men: a review of trial data. J Sex Med 2012;9(1):54-67. Return to content
- Morgentaler A, Morales A. Should hypogonadal men with prostate cancer receive testosterone? J Urol 2010;184(4):1257-1260. Return to content
- Morgentaler A. Testosterone therapy in men with prostate cancer: scientific and ethical considerations. J Urol 2009;181(3):972-979. Return to content
- Kaufman J, Graydon R. Androgen replacement after curative radical prostatectomy for prostate cancer in hypogonadal men. J Urol 2004;172(3):920-922. Return to content
