Differential Effects of Oral and Transdermal Estradiol Treatment on Circulating Estradiol Fatty Acid Ester Concentrations in Postmenopausal Women

Abstract

Estradiol fatty acid esters are potent lipophilic estrogens with antioxidant properties, transported by lipoproteins in blood. We investigated effects of oral and transdermal estradiol replacement therapy on concentrations of estradiol fatty acid esters in serum in postmenopausal women in a double-blind, randomized fashion. The first group (n = 9) received oral (2 mg/d); the second (n = 10), transdermal estradiol (patch delivering 50 microg/d); and the third group (n = 7), placebo treatment for 12 wk. After extraction of serum and separation of esterified estradiol from nonesterified estradiol, the concentration of saponified estradiol esters was measured by time-resolved fluoroimmunoassay. In the oral estradiol group, the median serum estradiol fatty acid ester concentration rose by 27%, from 77 to 98 pM (P = 0.028) but remained unchanged in the transdermal estradiol and placebo groups. The median concentrations of serum nonprotein-bound estradiol increased similarly in the oral and transdermal estradiol groups. The change in serum estradiol ester concentrations during treatment, but not that of nonesterified estradiol, correlated positively with enhanced forearm blood flow responses in vivo. These data raise the possibility that an increase in serum estradiol fatty acid esters may contribute to beneficial effects of oral estradiol treatment, compared with an equipotent dose of transdermal estradiol.

Fatty acid esters of steroids: Synthesis and metabolism in lipoproteins and adipose tissue

“…By estradiol time-resolved fluoroimmunoassay [42], Vihma et al more recently measured serum concentrations of estradiol fatty acid esters in different groups of women as well as in pooled male serum. The concentration of serum estradiol esters was in the same range in postmenopausal women [70] and in men but slightly higher in premenopausal women [43] (Table 1). In men, the greater proportion of serum esterified estradiol compared to premenopausal women could be attributed to their greater proportion of free, nonproteinbound estradiol in serum [71].…”

“…A history of intrahepatic cholestasis of pregnancy appeared to have no effect on the esterification of serum estradiol. Similarly to the first study on estrogen therapy [43], four weeks of oral estrogen therapy increased the median serum estradiol fatty acid ester concentration by 29% (P = 0.002) ( Table 1), which correlated positively with increases in serum estradiol, estrone and sex hormone-binding globulin (SHBG) concentrations. The median serum estradiol ester concentration returned to pretreatment levels during the four-week wash-out period.…”

“…These results clearly indicated that the formation of estradiol esters by active LCAT in HDL is associated with increased resistance of HDL to oxidation in vitro. It was, however, estimated that these in vitro experiments produced one thousand times higher concentrations of HDL-associated fatty acylated estradiol compared to the concentrations previously reported in pregnant women [42], not to mention women taking oral or transdermal estrogen therapy who have even lower levels [43]. In summary, the studies mentioned above [40,41] suggest that incorporation of esterified estradiol in lipoproteins can enhance the oxidation resistance of these particles in vitro but this can be achieved only at very high supraphysiological concentrations.…”

“…We hypothesized that serum estradiol and thereby also estradiol fatty acid ester concentrations might increase during estrogen therapy. The effect of 12 weeks of oral micronized estradiol (2 mg/d) and transdermal estradiol (patch delivering 50 g/d) and placebo treatment on serum estradiol ester concentrations was investigated in 26 postmenopausal women [43]. In the oral estradiol group, the median concentration of estradiol esters in serum increased by 27% (P = 0.028), in association with serum concentration of estradiol which increased approximately nine-fold.…”

Traitement hormonal chez les femmes ménopausées: tous les traitements sont-ils équivalents?

“…De plus, elle a l'inconvénient d'augmenter les taux des triglycérides et la résistance à l'insuline. Au plan des marqueurs inflammatoires [40][41][42][43][44][45][46][47][48][49], l'estradiol donné par voie cutanée ou nasale n'entraîne pas de variation significative des taux de la protéine C-Reactive (CRP), de l'homocystéine ou d'autres paramètres associés au risque cardiovasculaire, telles les métallopro-téinases (MMPs) ou différentes protéines d'adhésion (VCAM, ICAM, E-Selectin). De plus, la voie cutanée entraîne moins ou pas de perturbations de l'hémostase [33][34][35]43,44,46,47], contrairement à la voie orale qui a tendance à augmenter la fibrinolyse et la coagulation.…”