Effects of oral and transdermal estradiol administration on levels of sex hormone-binding globulin in postmenopausal women with and without a history of intrahepatic cholestasis of pregnancy.

SHBG, the most important transport protein for sex steroids, is produced in the liver under the control of estrogen action. In a randomized, double-blind, prospective crossover study we compared basal levels of serum SHBG and their responses to increasing doses of oral and transdermal estradiol (E2), followed by E2 plus oral progestin (medroxyprogesterone acetate [MPA]), in 40 postmenopausal women with or without a history of intrahepatic cholestasis of pregnancy (ICP), which could affect the synthesis of SHBG. Serum samples collected at baseline, on the last day of each E2 period, and on the last day of the E2 plus MPA combination were assayed for SHBG and E2. Basal levels of SHBG showed no difference between the study groups. Oral but not transdermal E2 increased SHBG concentrations by 67-171% in the control group, but the response was smaller (42-121%) in the ICP group. Addition of MPA decreased SHBG levels by 14-18% in both groups during both treatments. In conclusion, a history of ICP is associated with blunted responses of SHBG to oral estrogen.

Lipophilic oestrogen derivatives contained in lipoprotein particles.

Steroid fatty acid esters constitute a unique family of lipophilic hormones carried exclusively in circulating lipoproteins. Our studies have focused on the formation of 17beta fatty acid esters of labelled oestradiol in in vitro incubations with human ovarian follicular fluid and plasma and demonstrated the accumulation of these labelled derivatives in lipoprotein particles. The oestradiol esters are formed in a reaction catalysed by lecithin : cholesterol acyltransferase in association with high-density lipoprotein particles and they can be transferred to low-density lipoprotein particles in a process mediated by cholesteryl ester transfer protein. Using a novel quantitative method for the determination of oestradiol esters their endogenous concentrations in follicular fluid and in early and late pregnancy plasma have been determined. In addition, using labelled genistein and its chemically synthesized fatty acid esters, we also demonstrated that phytoestrogen derivatives could be incorporated in lipoprotein particles. Both oestradiol and genistein contain aromatic hydroxyl groups which cause them to exert powerful antioxidant activity in lipid-aqueous systems in vitro. The physiological role of the steroidal fatty acid esters remains to be elucidated. In theory, the hormonal esters might form a reservoir constituted by esterified hormones stored in lipoprotein particles and perhaps in fat tissue, or they might use lipoproteins as vehicles for endocrine transport, or they could act as antioxidant protection of the lipoprotein particles. Enzyme systems necessary for the formation of lipophilic oestrogen and phytoestrogen derivatives as well as for their incorporation in lipoprotein particles are present in human body fluids. Because of their water-insolubility, steroid fatty acid esters are carried exclusively by circulating lipoproteins. These esters can provide antioxidant protection for lipoprotein particles.

Quantitative determination of estradiol fatty acid esters in human pregnancy serum and ovarian follicular fluid.

BACKGROUND: Lipophilic estradiol derivatives carried by lipoprotein particles in blood may mediate antioxidant or endocrine effects. We developed a new quantitative method to determine the concentration of circulating lipophilic estradiol fatty acid esters in human early- and late-pregnancy serum and in ovarian follicular fluid. METHODS: After extraction from serum or follicular fluid, estradiol fatty acid esters were separated from nonesterified estradiol by Sephadex LH-20 column chromatography. The estradiol ester fraction was hydrolyzed by saponification and further purified by several chromatographic steps. The hydrolyzed estradiol esters were measured by time-resolved fluoroimmunoassay. RESULTS: The average estradiol fatty acid ester concentration in serum increased 10-fold during pregnancy, from 40.4 pmol/L (expressed as pmol/L estradiol; range, 25.0-64.2 pmol/L) in early pregnancy (n = 8) to 404 pmol/L (196-731 pmol/L) in late pregnancy (n = 10). The ratio of estradiol ester to nonesterified estradiol remained relatively constant during pregnancy, at 0.4-0.6%. In 10 follicular fluid samples, the mean estradiol ester concentration was 106 nmol/L (56.9-262 nmol/L). Compared with serum, a greater proportion of estradiol in follicular fluid (3.0-10%) was in the esterified form. CONCLUSION: The new method provides a means to measure circulating estradiol fatty acid ester concentrations in human pregnancy serum.

Effect of soybean phytoestrogen intake on low density lipoprotein oxidation resistance.

The oxidation of low density lipoproteins (LDLs) is thought to take place in the arterial intima when the particles have become isolated from circulating water-soluble antioxidants. We hypothesized that isoflavonoid antioxidants derived from soy could be incorporated into lipoproteins and possibly could protect them against oxidation, which is regarded as atherogenic. Six healthy volunteers received 3 soy bars [containing the isoflavonoid antioxidants genistein (12 mg) and daidzein (7 mg)] daily for 2 weeks. LDLs were isolated from blood drawn at the the end of a 2-week dietary baseline period, after 2 weeks on soy, and after discontinuation of soy. Large increases in plasma isoflavonoid levels occurred during soy feeding, but only minute amounts were stably associated with lipoproteins (less than 1% of plasma isoflavonoids in the LDL fraction). The LDLs were subjected to copper-mediated oxidation in vitro. Compared with off soy values, lag phases of LDL oxidation curves were prolonged by a mean of 20 min (P < 0.02) during soy intake, indicating a reduced susceptibility to oxidation. The results suggest that intake of soy-derived antioxidants, such as genistein and daidzein, may provide protection against oxidative modification of LDL. As only very small amounts of these substances were detected in purified LDL, modified LDL particles may have been produced in vivo by circulating isoflavonoids promoting resistance to oxidation ex vivo.