Response to Letter to the Editor

We enjoyed reading the letter to the editor by Lin et al. (1) and appreciate their interest in our study (2). We agree that the relationship between skeletal muscle and lower urinary tract symptoms (LUTS) in older men is complex and potentially bidirectional. Our goal was to evaluate the association of skeletal muscle measures with changes in LUTS severity, although a relationship in the opposite direction is certainly possible and worth evaluating given the public health importance of identifying modifiable risk factors for poor skeletal muscle health and mobility disability in older adults. We also agree that LUTS and poor sleep frequently co-occur and that poor sleep may accelerate biological aging mechanisms and exacerbate the functional impact of LUTS.

Lin et al. have proposed a conceptual model suggesting that benign prostatic hyperplasia (BPH) causes decreased lower extremity skeletal muscle mass and strength, both directly and indirectly via disrupted sleep leading to decreased testosterone. Although components of this conceptual model are supported by data, we remain skeptical that testosterone plays a major role for several reasons. First, as the authors point out, serum testosterone levels are not consistently associated with LUTS severity in large population-based studies, particularly those with appropriate confounder adjustment (3). Second, the idea of a “detrimental cycle difficult to break without intervention” is not supported by several longitudinal studies demonstrating that low serum testosterone levels do not predict more severe or worsening LUTS and placebo-controlled, randomized clinical trials demonstrating that increasing testosterone via supplementation does not decrease LUTS severity in older hypogonadal men (4–6). Lastly, the relationship between poor sleep and low testosterone in older men is not well established in high-quality prospective cohort studies (7–9). Given weak or nonexistent associations of multiple sequential mediators, we believe more plausible explanations may exist for a direct relationship between LUTS and decline in skeletal muscle function, such as decreased mobility, life space, and physical activity (10–12).

Fortunately, the proposed hypotheses can be evaluated using data from existing longitudinal data sets, many of which are now publicly available or accept analysis proposals from external investigators (including the Baltimore Longitudinal Study of Aging: https://www.blsa.nih.gov/), and applying causal mediation methods that can formally decompose indirect and direct effects. In the meantime, we prefer to remain diligent and avoid suggesting that medical and/or surgical therapies for BPH could improve skeletal muscle function, mobility, or other geriatric syndromes in older men. We aim to continue our work to identify and test the most plausible data-informed conceptual models to explain why older men with LUTS disproportionately experience mobility disability. Our hope is that this research will lead to the development and adoption of novel interventions, such as structured physical activity programs, that simultaneously improve symptom burden and preserve functional status in older men with LUTS.

Funding

This work was supported by the Intramural Research Program of the National Institutes of Health and National Institute on Aging as well as grants to M.E.L. from the National Institute of Diabetes and Digestive and Kidney Diseases (grant number K01DK129405), to S.R.B. from the National Institute on Aging (grant numbers 1R03AG067937 and 1K76AG074903) and the UCSF Claude D. Pepper Older Americans Independence Center funded by National Institute on Aging (grant number P30 AG044281).

Conflict of Interest

None.

Author Contributions

S.R.B.: conception and design, drafting and revising the article, final approval of the version to be published. M.E.L.: conception and design, revising the article for important intellectual content, final approval of the version to be published. L.F.: conception and design, revising the article for important intellectual content, final approval of the version to be published. E.M.S.: conception and design, revising the article for important intellectual content, final approval of the version to be published.