madman
Super Moderator
Purpose of review
Testosterone replacement therapy for men with organic hypogonadism due to medical disease of the hypothalamic-pituitary-testicular (HPT) axis is uncontroversial. In these men, testosterone replacement replaces the deficient hormone and relieves the signs and symptoms of androgen deficiency. In contrast, the role of testosterone treatment in middle-aged or older men who have clinical features consistent with androgen deficiency accompanied by reductions in serum testosterone but lack identifiable HPT axis disease, a scenario sometimes referred to as ‘functional’ or ‘late onset’ hypogonadism, has been uncertain.
Recent findings
Three large randomized controlled clinical trials, discussed in this review, have reported new data regarding short-term to medium-term benefits and risks of testosterone therapy in such middle-aged and older men, including effects on sexual function, vitality, cognition and mood, glucose metabolism, physical function, hematologic parameters, as well as bone, cardiovascular and prostate health.
Summary
The findings of these trials allow for a more nuanced, personalized approach to testosterone therapy in such men. However, long-term benefits and risk of testosterone therapy (beyond 3–4 years) remain unknown.
BENEFITS AND RISKS OF TESTOSTERONE REPLACEMENT IN MEN WITH CLASSICAL HYPOGONADISM
These experimental studies illustrate the importance of maintaining physiologic serum testosterone concentrations to prevent clinical features of androgen deficiency and indirectly support the concept using testosterone replacement to restore physiology and to prevent clinical features of androgen deficiency. Of note, these studies [11] have also shown that some of the clinical features of male hypogonadism are not directly due to testosterone deficiency but rather due to the concomitant oestradiol deficiency. These findings support the use of testosterone replacement as the treatment of choice in classical hypogonadism as testosterone is aromatised to estradiol and hence not only normalizes serum testosterone but also estradiol. Finally, testosterone also provides dihydrotestosterone (DHT), which has important androgenic actions in the prostate and the hair follicle. Therefore, testosterone is also sometimes referred to as ‘three hormones in one’ [13].
BENEFITS AND RISKS OF TESTOSTERONE THERAPY IN OLDER MEN WITH AGE RELATED REDUCTIONS IN SERUM TESTOSTERONE
In this section, I will review the clinical evidence regarding benefits and risk of testosterone therapy in older men with age-related declines in their serum testosterone. I will focus on three recent pivotal trials, the T-Trials, T4DM and TRAVERSE .Men with classical hypogonadism due to recognizable organic HPT axis disease were generally excluded from these trials.
Sexual function
In summary, testosterone appears to have a clinically meaningful effects on sexual desire and modestly improves most aspects of sexual function. Effects on erectile function are more moderate and clinically relevant mostly for men with mild erectile dysfunction. Men with significant cardiovascular disease might have erectile dysfunction refractory to testosterone.
Vitality, mood and cognitive function
Overall, in men with serum testosterone concentrations (<10.4 nmol/l), testosterone treatment is associated with small but significant effects on vitality, and modest improvements in mood in men with mild depressive symptoms but has no effect on cognitive function.
Glucose metabolism
In summary, testosterone therapy might have modest benefits on glycaemic parameters, and may prevent T2Din high-risk men, at least in the context of a lifestyle programme, but not all of the data are consistent.
Muscle and physical function
Overall, testosterone therapy might improve muscle strength and some aspects of physical function.
Bone health
Of note, men in all these studies were not selected based on low bone density or osteoporosis. The effects of testosterone therapy on bone architecture, bone strength or incident fracture have not been systematically evaluated in men with low serum testosterone concentrations who are
at high fracture risk.
Haematologic parameters
Overall, while testosterone might resolve unexplained anaemia, erythrocytosis can be an adverse effect, with however few men having to stop treatment.
Cardiovascular health
Overall, except for a possible increase in atrial fibrillation and pulmonary embolism, the trials suggest that, in carefully selected men, testosterone therapy at least in the short to medium term is unlikely to confer significant cardiovascular risks (or benefits).
Prostate health
Overall, in low-risk men receiving short to medium-term therapy, testosterone therapy does not appear to increase the risk of de-novo prostate cancer or to promote BPH with LUTS.
CONCLUSION: CLINICAL SYNTHESIS AND OUTLOOK
In men with classical hypogonadism due to organic HPT axis disease, testosterone replacement intended to restore physiologic concentrations of testosterone (and its downstream products estradiol and DHT) relieves the clinical features of androgen deficiency, although it can impair fertility. Although evidence from placebo-controlled, randomized clinical trials is (due to ethical reasons) lacking, testosterone replacement is generally accepted as the treatment of choice for men with classical hypogonadism. This notion is supported by physiologic principles, by parallels to other endocrine deficiency states, by experimental clinical trials combining suppression of endogenous gonadal steroid production with testosterone add-back, and by the marked benefits of testosterone replacement reported in open-label clinical trials. The benefits of testosterone replacement in men with classical hypogonadism are summarized in Table 1.
Consistent with the widespread expression of the androgen receptor, the T-Trials, T4DM and TRAVERSE recruiting men with age-related reductions in serum testosterone have shown that testosterone treatment has pleiotropic actions in many tissues and organ systems. These effects are summarized in Table 2. It is evident that for some deficits in isolated domains, there is better evidence for targeted therapies (e.g. phosphodiesterase 5-inhibitor treatment for severe erectile dysfunction due to neurovascular disease, osteoporotic drug therapy with proven antifracture benefit for men at high risk of fracture). Moreover, in the absence of longer-term, larger studies that inform about long term benefits and risks of testosterone therapy, it is difficult to formulate precise indications for testosterone therapy. Decisions about testosterone therapy not only require balancing the benefits and potential risks, but also involve cost and potential inconvenience of testosterone therapy (e.g. daily gel application or regular injections, periodic blood test to measure serum testosterone, haematocrit and in some men, PSA). It also has been postulated that prolonged testosterone treatment might create androgen dependence in some men [34], although this is less of a problem with shorter (6–12 month) courses of therapy [2&].
Nevertheless, the data from the T-Trials, T4DM and TRAVERSE allow first steps towards applying‘precision medicine’ to testosterone therapy for middle-aged and older men with clinical and biochemical features of possible hypogonadism but no identifiable HPT axis therapy. The results from these RCTs enable a more nuanced approach to counselling such men about the short to medium term benefits (up to 3–4 years), and risks of testosterone treatment. It is intuitive that the more testosterone responsive domains a patient has disease burden in (Table 2), the more attractive testosterone treatment would be for this individual. Thus, an older man with confirmed low serum testosterone measured by a reliable assay who has low libido, mildly reduced erectile dysfunction, mildly reduced mood and energy and otherwise unexplained anaemia and who is at high risk of diabetes could be counselled that testosterone treatment might improve his symptoms, increase his haemoglobin and, in conjunction with a lifestyle programme, could reduce his risk of developing type 2 diabetes. Risks of cardiovascular disease and adverse effects on prostate health in the short to medium term would be expected to be low, provided he is not at high risk for prostate cancer and does not have significant BPH. However, there might be small excess risk of arrythmias (especially atrial fibrillation) and of VTE (especially pulmonary embolism). The patient should also be advised about the lack of data on long term (>3–4 years) effects of testosterone treatment, and of the possible risk of HPT axis suppression with prolonged treatment. Overall, before testosterone treatment can routinely be recommended to older men with clinical and biochemical features consistent with hypogonadism, but who do not have identifiable HPT disease, larger longer term trials of testosterone therapy to better define health benefits and risks are still required. In the interim, the clinical consultation with a patient concerned about his low testosterone offers an opportunity to provide holistic patient centred care, with the emphasis on implementing healthy lifestyle measures and assiduous care of comorbidities.
