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Section General Endocrinology Heading Section sub Benefits and Consequences of Testosterone Replacement Therapy: A Review Polackwich AS 1 , Tadros NN 1 , Ostrowski KA 1 , Hedges JC 2 1. Urology Resident, 2. Assistant Professor, Department of Urology, Oregon Health & Science University, Portland, OR, USA. Abstract Late onset hypogonadism (LOH) is an issue of increasing concern. Studies have shown the importance of testosterone in the maintenance of homeostasis, especially with respect to bone health, sexual function, diabetes, cardiovascular risk, mental health and cognition. Much of the dysfunction in hypogonadism can be reversed or improved with testosterone replacement therapy (TRT). Physicians worry about the possible consequences of TRT, especially regarding the prostate. By reviewing the literature, we have found there are significant benefits to TRT, and fears of adverse effects on the prostate are largely unfounded, though there is a great need for larger studies with longer periods of follow-up, especially to evaluate adverse events. Keywords Late onset hypogonadism (LOH), testosterone replacement, hormone replacement, testosterone, aging Disclosure: The authors have no conflicts of interest to declare. Received: 25 December 2012 Accepted: 21 January 2013 Citation: European Endocrinology, 2013;9(1):59–64 Correspondence: A Scott Polackwich Jr., MD, Department of Urology, Oregon Health & Science University, 3303 SW Bond Ave, CH10U, Portland, OR 97223, US. E: polackwi@ohsu.edu Introduction In our increasingly aged population, late-onset hypogonadism (LOH) is an important public health issue with an incidence estimated at 12.3 cases per 1000 person years. 1 There is an increased public knowledge of this condition and more patients are approaching their physicians about diagnosis and treatment. Late-onset hypogonadism is an important clinical entity that should not be ignored by practitioners. It is associated with osteoporosis, 2 frailty, 3 loss of libido and erectile dysfunction, 4 depression, 5 cognitive dysfunction, 6 even cardiovascular disease 7 and metabolic syndrome. 8 Many patients and practitioners have lingering questions about the risks and benefits of this therapy as well as its use in certain populations, such as patients who have had prostate cancer or voiding dysfunction. While the use of testosterone in patients with a history of prostate cancer is currently contraindicated and considered off label use, many studies have started to evaluate it. Here we provide a review of testosterone replacement therapy (TRT); the benefits of this treatment and the risks it may pose. Testosterone and Erectile Dysfunction The incidence of erectile dysfunction (ED) is increasing 9 along with the incidence of hypogonadism. 10 Links between the two have been found on epidemiologic and basic science levels. After controlling for cofounders such as diabetes and vascular disease that typically occur in this population, the Massachusetts Male Aging Study found an increase in ED with decreasing testosterone among 625 patients, especially with luteinizing hormone (LH) levels >8 IU/l. 11 Overall sexual dysfunction, especially ED has been associated with testosterone levels up to 8 nmol/L in a study of 2838 men. 12 The effect of testosterone on ED is even more important in those with metabolic syndrome. 13 Endothelial dysfunction appears to be the main mechanism by which testosterone deficiency increases the incidence of ED. 14 Studies in © To u ch MEd ica l MEdia 2013 rats have shown decreased cavernosal tissue apoptosis in diabetic rats when treated with testosterone. 15 Similar effects are seen in humans and studies have found testosterone is important in tissue remodeling and maintenance of smooth muscle in erectile tissue. Late- onset hypogonadism alters this hormonal support and may increase progenitor cell differentiation into adipocytes. 16 This translates into an increase in arterial stiffness and arteriogenic ED in patients with late- onset hypogonadism. 17,18 In addition to LOH being a risk factor for development of ED, multiple studies have found improvement in ED with TRT. Animal studies have found improvement in nitric oxide (NO) synthase and erections after TRT therapy. 19 In human studies, improvement in IIEF scores can be seen after as little as 3–6 months of testosterone replacement therapy (TRT) alone. 20,21 This improvement in erectile function, along with multiple other indices of sexual function (libido, ejaculatory function and bother), have been found to improve quickly with TRT, and continue to improve for 12 months in an evaluation of 849 patients in a large multicenter registry. 4 One study that evaluated patients’ response to TRT after maximal titration of phosphodiesterase type 5 inhibitors (PDE5I) found no additional improvement, though patients were not significantly hypogonadal, and these patients had good initial response to PDE5Is. 22 In patients with LOH who have previously failed oral PDE5I therapy however, TRT has been found to improve responsiveness to PDE5Is. 23 Penile doppler studies have shown this is likely by improvement of vasodilatory response to PDE5Is. 24 This may save patients from being advanced to more invasive ED management such as intracavernosal injections and penile prosthesis placement. Evidence also suggests that early TRT may help in post prostatectomy ED 25 (use in this population is currently contraindicated). With this evidence, patients with refractory ED should be evaluated for hypogonadism as evidence suggests there is a clinical benefit to concurrent treatment. 59