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Testosterone Treatment in Middle-Aged and Older Men with Hypogonadism
Authors: Shalender Bhasin, M.B., B.S., and Peter J. Snyder, M.D
In men, marked hypogonadism due to pituitary or testicular disease generally has readily recognizable clinical manifestations, such as decreases in libido and sexual activity, loss of secondary sex characteristics and muscle mass, hot flushes, and anemia. Testosterone preparations have been approved by regulatory agencies to treat hypogonadism and are effective in correcting the clinical abnormalities associated with this condition in many men. Most men currently treated with testosterone preparations, however, are middle-aged or older and have only moderately decreased testosterone levels, a high burden of chronic diseases, and nonspecific symptoms that overlap with age-related symptoms. The benefits and risks of testosterone treatment in this population are less clear and are associated with controversy. In this review, we consider available information about the benefits and risks of testosterone treatment in middle-aged and older men with moderate degrees of hypogonadism.
Mechanisms of Action of Testosterone
Many of the benefits and some of the risks of testosterone treatment are mediated by the mechanisms through which testosterone acts (Fig. 1). Testosterone has anabolic effects on muscle (Fig. 2A)3,4 and bone (Fig. 2B)21 and stimulates erythropoiesis (Fig. 2C)5 through androgen receptor–mediated mechanisms. Nongenomic mechanisms of action increase penile blood flow22 and improve erectile function (Fig. 2D). The effects of testosterone on sexual desire6,7 and bone8,9 are mediated largely through its conversion to 17β-estradiol.10 Testosterone is also converted todihydrotestosterone (DHT), which stimulates prostate growth23 and has additional anabolic effects on muscle and bone.23 Testosterone and DHT increase penile blood flow and erections through a rapid increase in the production of nitric oxide, which is endothelium-dependent, as well as through inhibition of voltage-operated l-type calcium channels, activation of potassium channels on smooth muscle, or both mechanisms, which are endothelium-independent (Fig. 2D).20,24 A metabolite of DHT, 5α-androstane-3α,17β-diol, which is a ligand for the γ-aminobutyric acid receptor, has been linked to mood and affect.25
Studies of Testosterone Treatment
* Studies of Benefits and Risks
* Clinical Outcomes That Testosterone Treatment May Improve
* Outcomes with No Evidence of Benefit fromTestosterone Treatment
Established Risks of Testosterone Treatment
* Cardiovascular Risks
- Major Adverse Cardiovascular Events
- Venous Thromboembolism
- Atrial Fibrillation
* Erythrocytosis
Erythrocytosis, a well-recognized adverse effect o ftestosterone treatment, appears to be associated with testosterone levels that are at the high end of the normal range or higher during treatment.55 The incidence of erythrocytosis was substantially higher in trials in which injectable testosterone esters were used44 than in those in which transdermal formulations were used, probably because of higher testosterone levels in trials with testosterone esters.56,57 For example, in the T4DM trial, in which injectable testosterone undecanoate was used, the incidence of erythrocytosis was 22%.44 The incidence of erythrocytosis in the TTrials and the TRAVERSE trial was low (1.8% and 0.2%, respectively), most likely because the testosterone dose in each trial was adjusted to keep the testosterone and hemoglobin levels within the normal range.56,57 These results indicate that a physiologic dose of testosterone is an uncommon cause oferythrocytosis.
Prostate Events
* Prostate Cancer
- Other Prostate Risks
* Fracture
* Other Risks
Balancing Benefits and Risks of Testosterone
Testosterone treatment in middle-aged and older men with hypogonadism has been reported to improve libido, sexual activity, and erectile function. It has also been associated with the correction of anemia, slight decreases in depressive symptoms, and slight improvements in mood, energy, and walking ability. However, testosterone treatment has been found to increase the risk of pulmonary embolism and clinical fractures,and it may increase the risk of atrial fibrillation. Testosterone treatment has not been reported to increase the risk of MACE, lower urinary tract symptoms, or prostate cancer
On the basis of these findings, the decision of whether to recommend testosterone treatment should be made with an approach that balances the benefits and risks of treatment (Fig. S1 in theSupplementary Appendix, available with the fulltext of this article at NEJM.org). Benefits can be expected only in men with unequivocal hypogonadism based on two or more measurements of fasting, early-morning testosterone levels with values below the lower limit of the normal range. The lower the testosterone level (e.g., <200 ng perdeciliter [6.9 nmol per liter]), the greater the likelihood of a benefit. A benefit is less likely in men whose testosterone levels are only slightly below the lower limit of the normal range, especially men with obesity and metabolic disorders. Testosterone treatment consistently improves libido but may not be effective if the main symptom is erectile dysfunction. In men with anemia, testosterone treatment may be corrective and may improve energy.
If testosterone treatment is considered to be warranted on the basis of the expected benefit, the expected risk should be minimized. In our view, older men for whom testosterone treatmentis being considered should undergo a baseline evaluation for the risk of prostate cancer and for lower urinary tract symptoms. Prostate cancer screening and monitoring also carry risks. Although trials have not shown that testosterone treatment increases the risk of prostate cancer or lower urinary tract symptoms, men at high risk for those conditions were excluded from the trials. The absolute risk of thromboembolism during testosterone treatment is low; however, prophylactic anticoagulant therapy should be considered before testosterone treatment is initiated in men with a previous thromboembolic event. In the TRAVERSE trial, testosterone treatment was associated with an increased risk of fracture, so men at high risk for fracture should be treated with a medication for osteoporosis. The risk of erythrocytosis can be minimized by monitoring the hematocrit and adjusting the testosterone dose to maintain the testosterone level in the physiologic range.
The decision to prescribe testosterone for a middle-aged or older man with hypogonadism should be guided by the degree of hypogonadism, the type and severity of symptoms, and the patient’s willingness to accept the risks of treatment and monitoring.
