Affiliation:
1. Research Program in Men's Health: Aging and Metabolism, Boston Claude D. Pepper Older Americans Independence Center Brigham and Women's Hospital, Harvard Medical School Boston Massachusetts USA
2. Department of Biostatistics Harvard T.H. Chan School of Public Health Boston Massachusetts USA
3. Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania USA
4. Division of Endocrinology, Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania USA
Abstract
AbstractBackgroundTestosterone, estradiol, and dihydrotestosterone share common ligand binding sites on sex hormone binding globulin and albumin. It is unknown whether and how changes in testosterone, dihydrotestosterone, and estradiol concentrations during testosterone replacement therapy affect free testosterone fraction.ObjectiveTo determine the effect of changes in testosterone, dihydrotestosterone, and estradiol concentrations on free testosterone fraction during testosterone replacement therapy of men with hypogonadism.MethodsUsing data from the Testosterone Trials, we assessed the association of changes in total testosterone, estradiol, and dihydrotestosterone concentrations over 12 months of testosterone replacement therapy with changes in free testosterone fraction, measured using equilibrium dialysis. We used random forests to evaluate the associations of predicted mean changes in free testosterone fraction with changes in circulating concentrations of each hormone at low, mean, or high change in the other two hormones.ResultsTestosterone replacement therapy not only increased total testosterone, dihydrotestosterone, estradiol, and free testosterone concentrations, but also the percent free testosterone, even though sex hormone binding globulin levels did not change. The predicted changes in free testosterone fraction during testosterone replacement therapy exhibited a non‐linear relationship with changes in each of total testosterone, dihydrotestosterone, and estradiol concentrations. Greater increases in testosterone, dihydrotestosterone, and estradiol levels during testosterone replacement therapy were each associated with higher model‐predicted percent free testosterone. Substantially smaller changes in molar concentrations of estradiol and dihydrotestosterone had a greater effect on percent free testosterone than those in testosterone.ConclusionDuring testosterone replacement therapy of men with hypogonadism, changes in testosterone, dihydrotestosterone, and estradiol concentrations each altered percent free testosterone non‐linearly. Small changes in estradiol concentrations exerted much larger effect on the free testosterone fraction than testosterone and dihydrotestosterone, suggesting complex interactions of the three hormones with the binding proteins. Assessment of changes in free testosterone during testosterone replacement therapy should include consideration of changes in all three hormones.
Funder
National Institutes of Health
National Institute of Child Health and Human Development