During testosterone replacement therapy of men with hypogonadism, changes in testosterone, dihydrotestosterone, and estradiol concentrations each altered percent free testosterone non-linearly, with small changes in estradiol concentrations exerting much larger effects on free testosterone fraction than testosterone and dihydrotestosterone.
Key Findings
Results
Testosterone replacement therapy increased not only total testosterone, dihydrotestosterone, estradiol, and free testosterone concentrations, but also the percent free testosterone fraction.
This increase in percent free testosterone occurred even though sex hormone binding globulin levels did not change during testosterone replacement therapy.
Data were drawn from the Testosterone Trials over 12 months of testosterone replacement therapy in men with hypogonadism.
Free testosterone fraction was measured using equilibrium dialysis.
Results
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.
Random forests were used to evaluate the associations of predicted mean changes in free testosterone fraction with changes in circulating concentrations of each hormone.
The non-linear relationships were assessed at low, mean, or high change in the other two hormones.
Greater increases in testosterone, dihydrotestosterone, and estradiol levels during testosterone replacement therapy were each independently associated with higher model-predicted percent free testosterone.
Results
Substantially smaller changes in molar concentrations of estradiol and dihydrotestosterone had a greater effect on percent free testosterone than equivalent changes in testosterone concentrations.
This finding suggests complex interactions of the three hormones with sex hormone binding globulin and albumin binding proteins.
Testosterone, estradiol, and dihydrotestosterone share common ligand binding sites on sex hormone binding globulin and albumin.
The disproportionate effect of estradiol and dihydrotestosterone on free testosterone fraction was observed despite their lower molar concentrations relative to testosterone.
Conclusions
Assessment of changes in free testosterone during testosterone replacement therapy should include consideration of changes in all three hormones — testosterone, dihydrotestosterone, and estradiol.
All three hormones independently modulated the free testosterone fraction during testosterone replacement therapy.
The interactions among the three hormones and binding proteins are complex and non-linear.
The authors conclude that standard assessments focusing only on total testosterone may be insufficient to characterize the free testosterone fraction during testosterone replacement therapy.