Relation of Testosterone, Dihydrotestosterone, and Estradiol With Changes in Outcomes Measures in the Testosterone Trials

Abstract

Context: Many effects of testosterone are mediated through dihydrotestosterone (DHT) and estradiol.

Objective: To determine the relative contributions of each hormone to the observed effects of testosterone treatment in older men with hypogonadism.

Methods: Using data from the Testosterone Trials, we assessed the association of changes in total testosterone, estradiol, and DHT levels over 12 months of testosterone treatment with hemoglobin, high-density lipoprotein (HDL) cholesterol, volumetric bone mineral density (vBMD) of lumbar spine, sexual desire, and prostate-specific antigen (PSA). We used random forests to model the associations of predicted mean changes in outcomes with change in each hormone at low, mean, or high change in the other 2 hormones. Stepwise regression models were run to confirm the findings of random forests.

Result: Predicted increases in hemoglobin and sexual desire were greater with larger increases in estradiol and were larger with high change in DHT compared with low change in DHT. Greater increases in estradiol were associated with larger decreases in HDL cholesterol; this association did not vary according to changes in DHT or testosterone. Change in vBMD was most robustly associated with change in estradiol and was greater with high change in testosterone and DHT. There was no consistent relation between change in PSA and change in any hormone.

Conclusion: Change in estradiol level was the best predictor not only of the change in vBMD and sexual desire but also of the changes in hemoglobin and HDL cholesterol. Consideration of testosterone, estradiol, and DHT together offers a superior prediction of treatment response in older hypogonadal men than testosterone alone.

Trial registration: ClinicalTrials.gov NCT00799617.

Keywords: dihydrotestosterone and bone mineral density; dihydrotestosterone and sexual desire; estradiol and HDL cholesterol; estradiol and hemoglobin; relation of sex hormones with outcomes; testosterone and bone mineral density; the testosterone trials.

© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Figures

Figure 1.

Random forest prediction of mean change in hemoglobin by average change in estradiol (A,B), DHT (C,D), and total testosterone (E,F), fixing changes in other hormones at the mean level in all men (left) and stratifying by high (75th percentile) or low (25th percentile) changes in other hormones (right). (B) Circles, high change in DHT; asterisks, low change in DHT; blue, high change in total testosterone; orange, low change in total testosterone. (D) Circles, high change in estradiol; asterisks, low change in estradiol; blue, high change in total testosterone; orange, low change in total testosterone. (F) Circles, high change in estradiol; asterisks, low change in estradiol; blue, high change in estradiol; orange, low change estradiol.

Figure 2.

Random forest prediction of mean change in HDL cholesterol by average change in estradiol (A,B), DHT (C,D), and total testosterone (E,F), fixing changes in other hormones at the mean level in all men (left) and stratified by high (75th percentile) or low (25th percentile) changes in other hormones (right). (B) Circles, high change in DHT; asterisks, low change in DHT; blue, high change in total testosterone; orange, low change in total testosterone. (D) Circles, high change in estradiol; asterisks, low change in estradiol; blue, high change in total testosterone; orange, low change in total testosterone. (F) Circles, high change in estradiol; asterisks, low change in estradiol; blue, high change in estradiol; orange, low change in estradiol.

Figure 3.

Random forest prediction of mean change in volumetric bone mineral density (vBMD) by average change in estradiol (A,B), DHT (C,D), and total testosterone (E,F), fixing changes in other hormones at the mean level in all men (left) and stratified by high (75th percentile) or low (25th percentile) changes in other hormones (right). (B) Circles, high change in DHT; asterisks, low change in DHT; blue, high change in total testosterone; orange, low change in total testosterone. (D) Circles, high change in estradiol; asterisks, low change in estradiol; blue, high change in total testosterone; orange, low change in total testosterone. (F) Circles, high change in estradiol; asterisks, low change in estradiol;; blue, high change in estradiol; orange, low change estradiol.

Figure 4.

Random forest prediction of mean change in sexual desire (vBMD) by average change in estradiol (A,B), DHT (C,D), and total testosterone (E,F), fixing changes in other hormones at the mean level in all men (left) and stratified by high (75th percentile) or low (25th percentile) changes in other hormones (right). (B) Circles, high change in DHT; asterisks, low change in DHT; blue, high change in total testosterone; orange, low change in total testosterone. (D) Circles, high change in estradiol; asterisks, low change in estradiol; blue, high change in total testosterone; orange, low change in total testosterone. (F) Circles, high change in estradiol; asterisks, low change in estradiol; blue, high change in estradiol; orange, low change estradiol.

Figure 5.

Random forest prediction of mean change in serum PSA by average change in estradiol (A,B), DHT (C,D), and total testosterone (E,F), fixing changes in other hormones at the mean level in all men (left) and stratified by high (75th percentile) or low (25th percentile) changes in other hormones (right). (B) Circles, high change in DHT; asterisks, low change in DHT; blue, high change in total testosterone; orange, low change in total testosterone. (D) Circles, high change in estradiol; asterisks, low change in estradiol; blue, high change in total testosterone; orange, low change in total testosterone. (F) Circles, high change in estradiol; asterisks, low change in estradiol; blue, high change in estradiol; orange, low change estradiol.