Monitoring Estradiol and DHT to Predict Outcomes in Male Hypogonadism

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madman

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Join us for our 2-year anniversary episode! Host Chase Hendrickson, MD, from Vanderbilt University Medical Center; regular contributor Rich Comi, MD, from Dartmouth Hitchcock Medical Center; and male reproduction expert Mathis Grossman, MD, PhD, FRACP, from the University of Melbourne and Austin Health discuss an article from the January 2022 edition of The Journal of Clinical Endocrinology & Metabolism:Relation of Testosterone, Dihydrotestosterone, and Estradiol with Changes in Outcomes Measures in the Testosterone Trials.”
 
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*Circulating testosterone is converted in many peripheral tissues to its two active metabolites, 5α dihydrotestosterone (DHT) and 17β estradiol (E2)

*In many androgen-responsive tissues, a family of steroid 5α reductase enzymes converts testosterone to DHT, and the aromatase enzyme, a product of the CYP19A1 gene, converts it to E2

*Many tissue-specific biologic effects of testosterone are mediated through DHT and E2

*The rates of conversion of testosterone to DHT and E2 vary among people due to polymorphisms of genes that encode the steroid 5α reductases and the aromatase enzyme as well as other host-specific factors that affect the activity of these enzymes

*It is not known how the circulating concentrations of testosterone’s metabolites – DHT and E2 – modulate the effects of testosterone on various outcomes and how their circulating levels rank in their contribution to the observed effects of testosterone treatment on physiologic outcomes
 
*The data from the present analyses suggest that the interaction of the three sex hormones with their cognate binding proteins is highly complex and dynamic and influenced by their relative circulating concentrations. Therefore, models of testosterones binding to SHBG, based on the assumption of fixed apparent binding affinity of sex hormones with SHBG, that do not consider the influence of estradiol and dihydrotestosterone on the free testosterone fraction are unlikely to provide accurate estimates of free testosterone fraction.






*Our finding that the estradiol, DHT, and testosterone interact to alter free testosterone fraction non-linearly suggests that in men with hypogonadism who are receiving TRT, free testosterone levels should be measured using a reliable method to guide the dose titration. The models that do not consider changes in estradiol and DHT concentrations are susceptible to error in estimating free testosterone concentrations.

*These data suggest that changes in estradiol and dihydrotestosterone concentrations should be considered in evaluating response to testosterone treatment because of their differential influence on free testosterone concentrations in addition to their ability to exert other independent biologic effects. Because of these complex interactions between various sex hormones as well as other ligands with sex hormone binding globulin, direct measurements of free testosterone using a reliable assay, such as the equilibrium dialysis method, may be a superior marker of testosterone’s treatment effect.
 
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