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Investigation of testosterone therapy for male hyopgonadism and it’s effect on metabolism

Investigation of testosterone therapy for male hyopgonadism and it’s effect on metabolism

Project leader: John Flanagan

In recent years, a growing body of evidence has established that hypogonadism/low testosterone in men is an independent risk factor for the development of metabolic syndrome, type 2 diabetes and cardiovascular disease. The therapeutic recommended approach is testosterone replacement therapy (TRT), however, clinical studies have been conflicting with some demonstrating beneficial effects of therapy on glycemic control, insulin resistance, serum lipid profile, body composition, and central adiposity, while others showing little to no benefit. Yet, it is estimated that 4-5 million men in the U.S. suffer from hypogonadism with only 5% receiving replacement therapy according to the American Endocrine Society. Moreover, the projected annual sales of testosterone replacement products is over 1.5 billion dollars in the U.S. alone. Based on our own clinical studies and experience at the Center of Andrology and Sexual Medicine, we have observed only about a third of hypogonadal males with type-2 diabetes and metabolic syndrome respond and benefit to TRT (refer to as ‘high’ anabolic responders).

Assessment of TRT in hypogonadal men with comorbidities lack relevant endpoints and simple surrogate predictors for such endpoints. The current repertoire of diagnostic predictors for TRT therapy is limited. Hence, there is a great need for identifying predictors for ‘high’ responders in order to improve the selection criteria for personalized TRT to improved therapy. The prevailing questions for this project are 1) can ‘high’ anabolic responders be define in TRT androgen-deficient with men comorbidities by clinical predictors and potential mediators of testosterone’s anabolic/metabolic effects and used to improve selection criteria for tailored TRT and 2) are candidate mediators of testosterone actions required for proper anabolic/metabolic effects in hypogonadal men and can the lack of response to TRT define the ‘non-responsive’ hypogonadal man to therapy. The aims of the project are: 1) to characterize TRT in ‘high-responders’ and ‘non-responders’ hypogonadal men with comorbidities; 2) to evaluate the efficacy of dose response relationship between testosterone treatment and predictors of testosterone’s anabolic effects in clinical experimental models of male hypogonadism; 3) explore the possibility that certain novel candidate mediators of testosterone actions are required for proper anabolic/metabolic effects in hypogonadal men.

The main objectives for this project utilizes concluded clinical trail data and samples from TRT hypogonadal men with diabetes and metabolic syndrome studies, recruitment of new patients for TRT for further studies, examine TRT in unique clinical experimental human and animal hypogonadal models, and explore novel androgen regulated metabolic mediators. Developing reliable predictors are crucial to limit therapy to those that have the best prerequisites for a beneficial response and avoid therapy to non-responders and those that are at risk for development of side effects. Developing and optimizing potential predictors may have dramatic effects on the quality of life of the individual and on health care spending by the society. Considering the average lifespan of males is 4-6 years (in some societies up to 15 years) shorter than women, which indicate that important information and benefits can be gained in studying and treating the males.