May 2009
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Joint Recommendations: Investigation, Treatment, and Monitoring of Late-Onset Hypogonadism in Men
A diagnosis of treatable hypogonadism requires the presence of symptoms and signs suggestive of testosterone deficiency.
Reviewed by Christina Wang, MD; Compiled By Conni Bergmann Koury, Editor-in-Chief
The latest joint recommendations from the International Society of Andrology, International Society for the Study of the Aging Male, European Association of Urology, European Academy of Andrology, and American Society of Andrology offer recommendations on the investigation, treatment, and monitoring of late-onset hypogonadism in men.
The recommendations indicate that due to the increasing percentage of the population in the older age group, androgen deficiency in the aging male has become a topic of increasing interest and debate. It is known that testosterone falls progressively with age, and a significant percentage of men aged >60 years have serum testosterone levels that below the lower limits of young men.1-4 This data has led to exploration of the questions, will older hypogonadal men benefit from testosterone treatment, and what will be the risks associated with such intervention?
Evidence over the past 10 years has revealed that androgen treatment in hypogonadal men has a beneficial effect on multiple target organs, and the beneficial effects seen in older men are similar to those in younger men. Long-term data on the effects of testosterone treatment in the older population, however, are limited mainly to its effects on body composition and bone mass.5-10 Questions regarding the effect of testosterone supplementation on patient-reported outcomes and functional benefits are not yet available, and specific risk data on the prostate and cardiovascular systems are lacking.
The following is a summary of the recommendations that appeared this year in the European Journal of Endocrinology, European Urology, International Journal of Andrology, International Journal of Impotence Research, Journal of Andrology, and The Aging Male.
DEFINITION AND DIAGNOSIS
Definition. Late-onset hypogonadism is a clinical and biochemical syndrome characterized by symptoms and a deficiency in serum testosterone levels.11-15 It can be associated with not only a reduction in quality of life, but also an adverse affect on the function of multiple organ systems.
Clinical diagnosis. A diagnosis of treatable hypogonadism requires the presence of symptoms and signs suggestive of testosterone deficiency.11-14,16 According to the recommendations, the symptom most associated with hypogonadism is low libido,17,18 and other manifestations: erectile dysfunction (ED), decreased muscle mass and strength, increased body fat, decreased bone mineral density and osteoporosis, decreased vitality, and depressed mood. Although none of these symptoms are specific to the low androgen state, they may raise suspicion of testosterone deficiency. The presence of one or more symptoms must be accompanied by a low serum testosterone level.1,19-21
Laboratory diagnosis. A physical and biochemical work-up must be performed in men suspected of hypogonadism. Risk factors for hypogonadism in older men may include chronic illnesses (diabetes, chronic obstructive lung disease, inflammatory arthritis, renal, and HIV-related diseases), obesity, metabolic syndrome, and hemachromatosis.16
Serum total testosterone is the most widely accepted measure to establish the presence of hypogonadism, however there is no generally accepted lower limit of normal. A total testosterone level of >350 ng/dL does not require substitution. Based on data from younger men, consensus is that those individuals with total testosterone levels
<230 ng/dL will likely benefit from treatment. The recommendations note that in men with serum total testosterone between 230 to 350 ng/dL., repeating the measurement of total testosterone with sex hormone-binding globulin (SHBG) to calculate free or bioavailable testosterone may be helpful. Serum luteinizing hormone measurements help the clinician differentiate between primary and secondary hypogonadism, and serum prolactin should be measured if serum testosterone is <150 ng/dL22-25 or when secondary hypogonadism is suspected.16,26,27
Particularly in obese men, the measurement of free or bioavailable testosterone should be considered when serum total testosterone concentration is not indicative of hypogonadism. A free testosterone level <6.48 ng/dL can provide supportive evidence for testosterone treatment.27-29
Equilibrium dialysis is the gold standard for free testosterone measurement, and alternatively, serum SHBG measure plus a reliable serum total testosterone measure provides the data necessary for calculating free testosterone levels.
ASSESSMENT OF TREATMENT, THERAPY CONTINUATION
Assessment of treatment outcome, decisions regarding therapy. Patients undergoing testosterone treatment should be evaluated by improvement in signs and symptoms of testosterone deficiency. If the patient does not experience an improvement in clinical manifestations within 3 to 6 months, treatment should be discontinued and further investigation should be performed.
Body composition. Administration of testosterone improves body composition by decreasing fat mass and increasing lean body mass.6,8,9,30 These benefits may also include increased strength and muscle function and decreased metabolic and cardiovascular dysfunction.
Bone density and fracture rate. Hypogonadal men experience higher rates of osteopenia, osteoporosis, and fracture prevalence.31 Bone density in these men increases with testosterone substitution,7,10,32 however, fracture data are not yet available and the long-term benefit of testosterone requires further investigation, according to the guidelines. Clinicians should measure bone density at 2-year intervals in hypogonadal men, and all men with osteopenia should have their serum testosterone measured.33,34
TESTOSTERONE, SEXUAL FUNCTION
Testosterone and sexual function. The guidelines state that the initial assessment of all men with ED and/or diminished libido should include determination of serum testosterone, as these dysfunctions (with or without testosterone deficiency) might be related to comorbidities (eg, diabetes, hyperprolactinemia, metabolic syndrome, bladder outlet obstruction, peripheral vascular disease), or medications.35
If men have ED and/or a diminished libido with documented testosterone deficiency, they are candidates for testosterone therapy. For men who have clinical symptoms or signs of testosterone deficiency and borderline serum testosterone levels, a 3-month therapeutic trial of treatment may be justified.
Combination treatment with testosterone and phosphodiesterase-5 inhibitors should be considered in hypogonadal men with ED who fail to respond to either treatment alone.
Testosterone and obesity, metabolic syndrome, and type 2 diabetes. It is well known that many of the components of the metabolic syndrome (eg, obesity, hypertension, dyslipidemia, impaired glucose regulation, insulin resistance) are present in hypogonadal men. Furthermore, epidemiological studies have established a link between obesity and low serum testosterone levels in healthy men,36 and 20% to 64% of obese men have a low serum total or free testosterone levels.37 Metabolic syndrome and type 2 diabetes are associated with low plasma testosterone,21,36,38-43 therefore, serum testosterone should be measured in men with type 2 diabetes and symptoms suggestive of testosterone deficiency. It is not clear whether testosterone treatment will have beneficial effects on metabolic syndrome or type 2 diabetes when the patients do not have low serum testosterone.
Prostate cancer and benign prostatic hyperplasia. There is currently no conclusive evidence that testosterone therapy increases the risk of prostate cancer or benign prostatic hyperplasia.44,45 There is also no evidence that testosterone treatment will convert subclinical prostate cancer to clinically detectable prostate cancer. Testosterone, however, can stimulate growth and aggravate symptoms in men with locally advanced and metastatic prostate cancer.46,47 Adequately powered and optimally designed long-term prostate disease data are not available to determine whether there is any additional risk from testosterone replacement.
Patients receiving testosterone therapy should be monitored for prostate disease at 3 to 6 months, 12 months, and annually thereafter. Men who have been successfully treated for prostate cancer and who have confirmed symptomatic hypogonadism are potential candidates for testosterone substitution.48-51 Clinicians must exercise good judgment together with adequate knowledge of the advantages and drawbacks of testosterone therapy in this situation, according to the recommendations.
TREATMENT, DELIVERY, FOLLOW-UP
Treatment and delivery. Natural testosterone preparations should be used for substitution therapy. Intramuscular, subdermal, transdermal, oral, and buccal preparations currently on the market are safe and effective. The possible development of an adverse event during treatment requires rapid discontinuation of testosterone substitution, therefore, short-acting preparations may be preferred in older men. Obese men are more likely to develop adverse effects.54,55
Adverse effects, monitoring. Testosterone treatment is contraindicated in men with prostate or breast cancer, and is relatively contraindicated in men at high risk of developing prostate cancer.54,56,57 Additionally, men with significant erythrocytosis, untreated obstructive sleep apnea, and untreated severe congestive heart failure should not be started on treatment with testosterone without resolution of the condition. Age is not a contraindication to initiation of testosterone treatment, however, assessment of comorbidities and potential risks versus benefits of treatment is particularly important in elderly men.
CONCLUSION
"The diagnosis of late-onset testosterone deficiency is based on the presence of symptoms or signs and persistent low serum testosterone levels," according to the joint recommendations. "The benefits and risks of testosterone therapy must be clearly discussed with the patient and assessment of prostate and other risk factors considered before commencing testosterone treatment. Response to testosterone treatment should be assessed. If there is no improvement of symptoms and signs, treatment should be withdrawn and the patient investigated for other possible causes of the clinical presentations."
Christina Wang, MD, is Program Director, General Clinical Research Center, Harbor-UCLA Medical Center and Professor of Medicine, UCLA School of Medicine. Dr. Wang disclosed that she has served as a temporary consultant for Indevus, and has received research support from Acrux, Indevus, M et P, Clarus Therapeutics, and Besins Healthcare. Dr. Wang may be reached at wang@labiomed.org; or fax: 310-533-6972.
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