A role for androgen reduction treatment in kennedy disease?

Abstract

Over the past 4 years, there have been 3 published reports of randomized, placebo-controlled trials of androgen reduction therapy in patients with spinal and bulbar muscular atrophy (SBMA, Kennedy disease). 1–3 Despite clear evidence of efficacy of androgen reduction in transgenic mouse models, 4,5 the clinical trials, which studied 2 different drugs, leuprorelin and dutasteride, and included 50–200 subjects followed for up to 2 years, did not show significant benefits compared with placebo in the primary outcome measures [the amyotrophic lateral sclerosis (ALS) functional rating scale, barium swallow, and quantitative muscle assessment, respectively]. There was evidence for efficacy in secondary outcome measures in an open-label extension and with post hoc subgroup analysis of patients symptomatic for less than 10 years; this left open the possibility of unproven benefit that might emerge with longer treatment. Now, a small, open-label study reported in this issue indicates that androgen reduction with leuprorelin does not prevent disease progression over a longer period (3.5 years).6 The primary outcome measure in this study was leg strength. There are shortcomings of such a small-scale, uncontrolled study: Would patients on placebo have fared worse? Would a different, perhaps more sensitive and clinically meaningful outcome measure have shown benefit? Would patients closer to disease onset, or even before the onset of weakness, have done better? Here again, a subset analysis indicates that patients early in the disease course, with higher baseline testosterone levels, may do better with the treatment. Secondary outcome measures such as the 10 m timed walk and ALS Functional Rating Scale did not show a significant decline, and serum creatine kinase levels decreased with treatment. It is still possible that androgen reduction has some benefit in SBMA, particularly in younger patients with higher testosterone levels before treatment. However, based on the results of these studies, it is unlikely that such a benefit, if present, amounts to much for the typical patient. It is clear that this is not the treatment that patients and clinicians would like, one that improves muscle function or stops the disease progression over time. One problem may be that androgen reduction, while perhaps preventing the toxicity of the mutant androgen receptor protein, exacerbates the loss of androgen receptor function that also occurs in SBMA, and deprives patients of the anabolic benefits of endogenous androgens on muscle. The positive correlation of testosterone levels with muscle strength found in this and previous studies supports this conjecture.6,7 Other therapeutic approaches, currently under investigation and also beneficial in mouse models, may do better in patients.8 Further well-designed clinical trials are needed to address this possibility.