We appreciate Drs. Contreras and Vigil’s interest in our work (1). The objective of our study was to evaluate the long-term effects of testosterone replacement on insulin sensitivity (using the octreotide suppression test) in older men with low to low-normal testosterone levels. The important findings recently reported by Contreras et al. (2) correlating endogenous testosterone with insulin sensitivity in a relatively younger cohort of mostly insulin-resistant men (mean age, 42.9 years; range, 18 to 80 years) suggest that insulin resistance (measured using a pancreatic suppression test, just as in our trial) was a stronger predictor of hypogonadism. However, hypogonadism only modestly predicted for insulin resistance (2), suggesting a potential bidirectional relationship. Epidemiological studies can only suggest an association but cannot establish causality. Similar to the estrogen replacement studies in women, it is important to acknowledge the differences in the relation of endogenous testosterone with outcomes in a cohort study vs the effects of exogenous testosterone in a randomized controlled trial. Differences in the effects of endogenous hormones vs exogenous hormonal treatment and the variable at-risk time periods could have contributed to the apparent differences between epidemiologic and clinical trial results. To the best of our knowledge, our study is the longest trial to date to examine the effect of testosterone treatment on insulin sensitivity for a 3-year period in older men with age-related declines in testosterone levels. Drs. Contreras and Vigil are correct in pointing out that the men in our study with low-normal or mildly low testosterone levels were nondiabetic and hence likely relatively insulin sensitive, potentially explaining our null findings. However, we believe our population is representative of most middle-age and older men prescribed testosterone therapy in the United States (3). It is also the case that the findings in the population we studied were similar to those from several trials showing no substantial effect of testosterone treatment on glucose metabolism in men with metabolic syndrome or diabetes, also with normal or mildly low testosterone levels (4, 5). However, we agree that the long-term effects of testosterone on insulin sensitivity need further study in individuals with unequivocally low testosterone levels who are also at high risk of insulin resistance and diabetes.
Acknowledgments
Disclosure Summary: S. Basaria has received grant support from Abbott Pharmaceuticals for investigator-initiated studies unrelated to this study and has previously consulted for Eli Lilly, Inc. S. Bhasin has received research grant support from AbbVie Pharmaceuticals, Transition Therapeutics, and Metro International Biotechnology, LLC, for investigator-initiated research unrelated to this study. S. Bhasin has served as a consultant to AbbVie and Novartis. S. Bhasin has a financial interest in Function Promoting Therapies, LLC, a company aiming to develop innovative solutions that enhance precision and accuracy in clinical decision making and facilitate personalized therapeutic choices in reproductive health. S. Bhasin’s interests were reviewed and are managed by Brigham and Women’s Hospital and Partners HealthCare in accordance with their conflict of interest policies. The remaining authors have nothing to disclose.
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