Effects of Obesity on Estradiol Metabolism: Decreased Formation of Nonuterotropic Metabolites

Obesity is associated with an increased incidence of reproductive dysfunction and estrogen-linked diseases. In the present study, we have examined the principal oxidative biotransformations of estradiol in 13 obese premenopausal females and 10 obese males compared to those in 9 premenopausal female and 15 male controls. These studies were carried out using a recently devised, sensitive radiometric method which permits the assessment of the total in vivo oxidative metabolism of estradiol at specific sites (i.e. 17λ, 16λ, or C-2) on the steroid molecule. Our results indicate that obesity (>60% above ideal body weight) is associated with significant decreases in hydroxylation at C-2 in both sexes (P < 0.001 for females and P < 0.02 for males) and in oxidation at 17λ in premenopausal females (P < 0.05) compared to that in age-matched, normal weight controls. Analysis of the plasma ³H₂O specific activity curves suggested a slight decrease in the rate of 17-oxidation in obese subjects. The extent of hydroxylation at 16λ was not significantly affected by obesity. These metabolic alterations documented in obesity could result in a relative hyperestrogenic state, since, unlike the other estrogen metabolites, the 2-hydroxyestrogen compounds display relatively little peripheral estrogenic activity. This metabolic alteration on a prolonged basis might be contributory to the prevalence of certain hormonally related diseases in obese individuals.