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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 2 588-593
Copyright © 2003 by The Endocrine Society

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

Veera Vihma, Satu Vehkavaara, Hannele Yki-Järvinen, Hannele Hohtari and Matti J. Tikkanen

Department of Medicine (V.V., S.V., H.Y.-J., M.J.T.), University of Helsinki, 00140 Helsinki; and Jorvi Hospital (H.H.), 02740 Espoo, Finland

Address all correspondence and requests for reprints to: Matti J. Tikkanen, M.D., Department of Medicine, Helsinki University Central Hospital, PB 340, 00290 Helsinki, Finland. E-mail: matti.tikkanen{at}hus.fi.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
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 µg/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.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
IT HAS BEEN shown that 17ß-estradiol fatty acid esters are potent and long-acting estrogens (1) that circulate at low concentrations in human blood (2, 3). Estradiol fatty acid esters seem to be exclusively transported in lipoprotein particles (4). Recently, several in vitro studies have indicated that estradiol fatty acid esters can protect low-density lipoprotein (LDL) particles against oxidation (5, 6, 7). Estradiol esterification and incorporation in LDL particles may even be a prerequisite for the antioxidant efficacy of physiologic plasma concentrations of estradiol (6).

Only a few studies have analyzed concentrations of circulating estradiol fatty acid esters in humans. When determined by gas chromatography-mass spectrometry, serum concentrations of estradiol fatty acid esters were low, but detectable, in premenopausal women (n = 4) but undetectable in postmenopausal women (n = 10) (3). We have recently developed a method for determination of estradiol fatty acid esters in human body fluids using time-resolved fluoroimmunoassay (TR-FIA) (8). Although originally developed for measurement of estradiol fatty acid esters in serum from pregnant women, this method was found to be sensitive enough for use in nonpregnant women and in men. We set out to investigate whether estradiol replacement therapy, given either orally or transdermally, might increase the amount of circulating estradiol fatty acid esters in postmenopausal women. To our knowledge, there are no previous data addressing effects of estradiol replacement therapy on serum estradiol fatty acid ester concentrations. To study possible physiological functions, we also related the changes in serum estradiol fatty acid ester concentrations to the changes in measures of endothelium-dependent and -independent vasodilatation during treatment (9).


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
A detailed description of the study design has been published elsewhere (9). In short, women with natural amenorrhea for at least 12 months or age more than 52 yr, and FSH more than 30 U/liter, were included. The patients gave written informed consent, and the experimental protocol was approved by the ethics committee of the Helsinki University Central Hospital. Eligible patients were randomly assigned to one of three groups. The first group (n = 9) used an oral estradiol tablet of 2 mg (Estrofem; Novo Nordisk, Bagsværd, Denmark) daily and a placebo patch, the second group (n = 10) used 50 µg/d transdermal estradiol (Menorest; Noven Pharmaceuticals, Inc., Miami, FL) and a placebo tablet, and the third group (n = 7) used a placebo patch and a placebo tablet for 12 wk. Blood samples were collected at 0 and 12 wk. After centrifugation, the serum samples were stored at -20 C until analyzed. Measurements of circulating hormone and lipid concentrations were performed as described below.

To compare the estradiol fatty acid ester/estradiol ratios in menstruating and postmenopausal women, serum estradiol fatty acid ester concentrations were also measured in seven healthy 16-yr-old women. Blood was obtained in one subject during the follicular phase (d 2 of menstrual cycle) and in six subjects during the luteal phase (d 16–26 of menstrual cycle). To compare the results with those obtained in men, pooled sera (purchased from the Finnish Red Cross, Helsinki, Finland; complement inactivated at 56 C for 30 min, serum stored at -20 C) from 50–60 male donors were analyzed.

Measurement of serum estradiol fatty acid ester and estradiol concentrations

Serum estradiol fatty acid ester and estradiol concentrations were determined as described previously (8). In short, after adding [3H]estradiol-3,17ß-dioleate (2600–3500 dpm) as an internal standard to each sample for determination of recovery, serum samples (1 ml) and low-, medium-, and high-control samples (1 ml; estradiol-17ß-stearate added to pooled male serum, corresponding to estradiol concentrations of 110 pM, 257 pM, and 598 pM, respectively) were extracted with diethylether:ethyl acetate. Sephadex LH-20 column chromatography was then performed to separate estradiol fatty acid esters from nonesterified estradiol. After saponification of the estradiol ester fraction in methanolic KOH (potassium hydroxide) and washing in Sep-Pak C18 column, cholesterol and other lipid impurities were eliminated by Lipidex 5000 reversed-phase and Sephadex LH-20 column chromatography. The dry residues of the hydrolyzed estradiol ester fraction and the nonesterified estradiol fraction (the latter obtained from the first Sephadex LH-20 separation step) were concentrated 2-fold by dissolving in 0.5 ml buffer (control samples were dissolved in 1.0 ml buffer). To determine recovery, radioactivity in the estradiol ester fraction of each sample was measured by liquid scintillation counting. The concentration of estradiol in both fractions was analyzed by TR-FIA as previously described (8). In postmenopausal women, samples obtained at 0 and 12 wk were analyzed in the same assay. Serum estradiol concentrations in postmenopausal women were also measured by RIA (9).

Estradiol-17ß-stearate-containing control samples were analyzed in every assay. According to the coefficients of variation of these low-, medium-, and high-control samples, the interassay imprecision of the quantitative estradiol ester method in seven assays was 5.5%, 8.5%, and 13%, respectively. A male serum sample (pooled human male sera) was also analyzed in every assay as a control. The measured concentrations of hydrolyzed estradiol esters in the 2-fold concentrated male serum sample were within the working range of estradiol TR-FIA (working range, 38–1840 pM). The interassay imprecision of the 2-fold concentrated male serum sample in seven assays was 12%, and the intraassay imprecision was 6% (n = 5). The concentration of serum estradiol fatty acid esters in postmenopausal women, young women, and men was calculated by correcting for recovery of the tritiated internal standard and then normalizing to volume. The mean recovery of the tritiated internal standard in seven assays was 72% (95% confidence interval, 70.9–73.2%). No correction for blank was made. The measured concentration of estradiol esters in a 2-fold concentrated H2O sample (reagent blank) was repeatedly less than 11.5 pM (<3.13 pg/ml), the lowest calibrator in TR-FIA.

Other measurements

Serum and lipoprotein cholesterol, triglyceride, apolipoprotein B, and serum SHBG concentrations were measured as previously described (9, 10). Because oral (but not transdermal) estradiol treatment increases serum SHBG concentrations, the concentrations of free (nonprotein-bound) estradiol were calculated (11). In vivo endothelial function was assessed from blood flow responses to intrabrachial infusions of endothelium-dependent (7.5 and 15 µg/min acetylcholine) and endothelium-independent (3 and 10 µg/min sodium nitroprusside) vasodilators at 0 and 12 wk, as has been reported previously (9).

Statistical analyses

Data are expressed as mean (SEM), except for the estrogen concentrations, which are expressed as median (range). Wilcoxon signed ranks test (two tailed) was performed to compare data at baseline and after 12 wk of treatment within the groups. Mann-Whitney test was used to compare estradiol ester concentrations between the groups. Correlation analyses were performed using Spearman’s nonparametric correlation coefficient.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Serum lipid, estradiol fatty acid ester, and nonesterified estradiol concentrations in postmenopausal women before and after estradiol replacement therapy

Serum total, LDL, and high-density lipoprotein (HDL) cholesterol; serum triglyceride; and apolipoprotein B concentrations at 0 and 12 wk are shown in Table 1Go. The concentrations of serum estradiol fatty acid esters, serum nonesterified estradiol, and free (nonprotein-bound) estradiol are shown in Table 2Go; and individual serum estradiol fatty acid ester concentrations at baseline and at 12 wk, in Fig. 1Go. The concentration of serum estradiol fatty acid esters increased significantly after 12 wk of treatment in the oral estradiol group (P = 0.028) but remained unchanged in the transdermal estradiol and placebo groups (Table 2Go). The serum estradiol fatty acid ester concentrations were significantly higher in the oral estradiol group, at 12 wk, than in the transdermal estradiol (P = 0.022) or placebo groups (P = 0.030). When serum estradiol ester concentration was expressed relative to total serum cholesterol, LDL cholesterol, or apolipoprotein B concentration, these ratios increased significantly (by 33%, 47%, and 40%, respectively) after oral but not transdermal estradiol or placebo treatment (Table 2Go). In all three treatment groups, the median baseline concentration of estradiol fatty acid esters was higher than the median nonesterified estradiol concentration. At 12 wk, there was a positive correlation between serum total nonesterified estradiol and estradiol ester concentrations in the transdermal and oral estradiol treatment groups (n = 19, r = 0.53, P = 0.019). Serum SHBG concentrations increased significantly in the oral (P = 0.008), but not in the transdermal estradiol or placebo groups (Table 2Go). The calculated median concentrations of free (nonprotein-bound) estradiol were similar in the oral and transdermal groups at 12 wk. Serum total nonesterified estradiol concentrations measured in the present study by TR-FIA correlated well (Spearman’s correlation coefficient, 0.92, P < 0.001) with those previously measured by RIA (9).


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  		Table 1. Serum and lipoprotein cholesterol, serum triglyceride, and apolipoprotein B concentrations during 12 wk of oral and transdermal estradiol and placebo treatment

 

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  		Table 2. Effect of 12 wk of oral and transdermal estradiol and placebo treatment on serum estradiol fatty acid ester and estradiol concentrations

 


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  		Figure 1. Individual serum estradiol fatty acid ester concentrations at baseline and after 12 wk of treatment. The serum estradiol fatty acid ester concentration rose significantly in the oral estradiol group (P = 0.028) and remained unchanged in the transdermal estradiol and placebo groups (Wilcoxon signed ranks test).

 
Changes in serum estradiol fatty acid ester concentration and forearm blood flow responses during treatment in postmenopausal women

The change in serum estradiol fatty acid ester concentration in all postmenopausal women (n = 26) at 12 wk vs. 0 wk was positively correlated to the changes in forearm blood flow responses: both to the changes in endothelium-dependent (7.5 and 15 µg/min acetylcholine; r = 0.41 and r = 0.43; P = 0.038 and P = 0.028, respectively) and endothelium-independent (10 µg/min sodium nitroprusside; r = 0.44; P = 0.024) vasodilatation. The correlation between the change in serum estradiol fatty acid ester concentration and the percent change (flow above basal compared with 0 wk) in sodium nitroprusside-induced (10 µg/min) vasodilatation during treatment (n = 26, r = 0.47, P = 0.015) is shown in Fig. 2Go. In contrast, no significant correlations were observed between the change in serum nonesterified estradiol concentration and the changes in blood flow responses during treatment (9).



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  		Figure 2. The correlation between the change in serum estradiol fatty acid ester concentration and the percent change in forearm blood flow response in postmenopausal women (n = 26) at 12 vs. 0 wk. The change in serum estradiol ester concentration (pM) correlated positively (r = 0.47; P = 0.015) with the change in sodium nitroprusside-induced increase in blood flow (%; flow above basal compared with 0 wk).

 
Estradiol fatty acid ester and nonesterified estradiol concentrations in young women and in men

Serum estradiol fatty acid ester concentrations in 16-yr-old menstruating women (n = 7), pooled human male sera (obtained from 50–60 donors), and all postmenopausal women at baseline (n = 26) are shown in Table 3Go. The median serum estradiol fatty acid ester concentrations were in the same range in young menstruating and postmenopausal women, between 75–80 pM (20–22 pg/ml) (P = not significant). In men, despite a higher serum concentration of nonesterified estradiol than in postmenopausal women, the serum estradiol fatty acid ester concentration was lower than in postmenopausal women (P = 0.001) (Table 3Go).


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  		Table 3. Plasma estradiol fatty acid ester and estradiol concentrations in postmenopausal women, 16-yr-old women, and pooled human male serum

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We investigated the effect of oral and transdermal estradiol replacement therapy on serum estradiol fatty acid ester concentrations in a placebo-controlled 12-wk trial in 26 postmenopausal women. We found that the median serum estradiol fatty acid ester concentration increased significantly, by 27%, during oral estradiol treatment but remained unchanged in the transdermal estradiol and placebo groups. The difference in serum estradiol ester concentrations between the oral and transdermal estradiol groups was significant after 12 wk of treatment. In contrast to changes in median serum free estradiol concentrations, which were similar between the oral and transdermal estradiol groups, the change in serum estradiol fatty acid ester concentrations correlated positively with changes in blood flow responses to both endothelium-dependent and -independent vasodilators.

The serum estradiol fatty acid ester concentrations were determined as equivalents of estradiol by immunoassay after complete chromatographic separation and hydrolysis of the nonpolar ester fraction. In contrast to our previous study that analyzed pregnancy serum (8), the serum samples of the present study obtained from men and nonpregnant women were concentrated 2-fold before measurement. As judged from reproducibility of determinations of low estradiol ester concentrations in men, and specificity of the antiserum, the estradiol ester concentrations presented for men and postmenopausal women are accurate. A limitation of the study was that it was not possible to get and analyze serum samples containing no estradiol esters; and thus, the possible confounding effects of serum matrix components on the measured estradiol ester levels could not be completely ruled out. Because the number of subjects was relatively small in this study, the results should be reproduced in a larger cohort.

When the ratios of serum estradiol fatty acid esters to serum nonesterified estradiol were compared, the ratio was 0.29 in young women, 0.75 in men, but 2.2 in postmenopausal women at baseline before any replacement therapy (Table 3Go). These proportions are much higher than those we previously found during pregnancy (8). Thus, the estradiol fatty acid ester/estradiol ratio in blood seems to increase, rather than fall, with physiological decreases in serum estradiol concentrations. Because estradiol esters are synthesized in blood by HDL-associated lecithin:cholesterol acyltransferase (LCAT) (12, 13, 14), their substrate in men and postmenopausal women is presumably estradiol produced by peripheral aromatization of gonadal and adrenal androgens. The higher proportion of esterified estradiol in men, compared with young women (Table 3Go), could be partly explained by the higher proportion of nonprotein-bound estradiol in men, compared with young women (15). The unexpectedly high proportion of estradiol ester in postmenopausal women could, in theory, represent a storage mechanism for estrogen during postmenopausal hormone deficiency (3). Also, some in vivo and in vitro studies have provided data of enhanced steroid fatty acid esterification associated with aging (16, 17). In a previous study using different methodology, serum estradiol ester concentrations in men and postmenopausal women were considered to be below the detection limit, as determined by mass spectrometry after saponification of the esters (3). In that same study, however, omental and sc adipose tissue of women menopausal for less than 12 yr contained substantial amounts of estradiol fatty acid esters (670 fmol/g), about two thirds of the amount determined in adipose tissue of premenopausal women (3). Even 15–20 yr after menopause, there seemed to be relatively large amounts of estradiol esters in fat (3). The accumulation of esterified estradiol in adipose tissue after menopause suggests an important physiological function for estrogen esters (3).

Supraphysiological (micromolar) concentrations of 17ß-estradiol have been shown to inhibit both cellular and copper-mediated oxidation of LDL in vitro (18, 19). Physiological estradiol concentrations (nano- to picomolar) may also inhibit LDL oxidation in vitro in the presence of ascorbic acid (20). Estradiol concentrations of 1–100 nM have been shown to inhibit LDL oxidation in vitro but only after estradiol had been transformed to estradiol fatty acid esters in plasma (6). Sack et al. (21) reported that administration of 17ß-estradiol intraarterially or transdermally to postmenopausal women was associated with an increased resistance of LDL to oxidation ex vivo. Other studies have either supported (22, 23, 24) or not supported (25, 26, 27) protection of LDL against oxidation by estrogen replacement therapy. These data thus raise the possibility that estradiol, especially in its esterified form, may, at physiological concentrations in plasma, protect lipoproteins from oxidation. In our study, the significant increase, by 47%, in the estradiol fatty acid ester/LDL cholesterol ratio during oral estradiol treatment suggests that the number of estradiol fatty acid ester molecules per LDL particle may have been increased (Table 2Go). The increased estradiol fatty acid ester/LDL cholesterol ratio could, in theory, provide an explanation for the reported antioxidant protection of LDL during estrogen administration (21, 28).

Interestingly, the change in serum estradiol fatty acid ester concentration in all postmenopausal women during treatment was positively correlated with the changes in blood flow responses to endothelium-dependent and -independent vasoactive drugs in forearm resistance vessels. The significance of these correlations is unclear, because such a relationship between serum estradiol ester concentration and vascular function does not prove causality. As reported previously in the same group of women (9), oral estradiol treatment markedly improved endothelium-dependent and -independent blood flow responses, but there was no correlation between serum estradiol concentrations and measures of vascular responses, apparently because both transdermal and oral estradiol increased free (nonprotein-bound) estradiol concentrations similarly. As shown in the present study, only oral estradiol increased serum estradiol fatty acid ester concentrations. These data add another potential candidate to the list of putative mechanisms whereby oral (but not transdermal) estradiol increase blood flow. However, apart from the increase in serum estradiol esters, increases in HDL cholesterol and serum estrone concentrations and decreases in LDL cholesterol, lipoprotein (a), and serum free testosterone concentrations are other possible causes for beneficial effects of oral estradiol treatment on endothelial function (9).

One possible explanation for the increase in median serum estradiol fatty acid ester concentration in the oral estradiol group only could be that orally, but not transdermally, administered estradiol undergoes hepatic first-pass metabolism. The liver is capable of synthesizing estradiol fatty acid esters upon incubation with estradiol (12, 29), but the role of the liver in metabolism of estradiol fatty acid esters in humans remains unknown. Another possible explanation could be that the higher estradiol ester concentration during oral, compared with transdermal, treatment might have resulted from the greater estrogen dose administered orally. Although serum nonprotein-bound estradiol levels were the same in both treatment groups, serum total estradiol and estrone concentrations (and presumably several other metabolites) were much higher during oral treatment. Consequently, the exposure of the liver to estrogen was greater, as demonstrated by the elevated HDL3 level during oral therapy, which could have facilitated estradiol fatty acid ester formation. Several experimental studies indicate that serum estradiol fatty acid esters, as well as the fatty acid esters of some other steroids, are synthesized in HDL particles (30, 31, 32), particularly in the HDL3 subfraction (14, 32), in an enzymatic reaction mediated by LCAT (13, 14). Estradiol fatty acid esters may be further transferred from HDL particles to LDL (30, 31). LDL particles are potent modulators of vascular function. LDL, especially oxidized LDL, blunts endothelium-dependent vasodilatation in vitro (33), but lowering of LDL cholesterol with statins has been shown, in multiple studies, to enhance endothelium-dependent vasodilatation (34, 35). The possibility that the ability of LDL particles to modulate vascular function depends on their content of estradiol fatty acid esters warrants further study based on the present data.

In conclusion, the results of this study suggest that serum estradiol fatty acid ester concentration may be increased by oral estradiol therapy. The data also raise the possibility that estradiol fatty acid esters, perhaps when incorporated in LDL particles, contribute to enhanced vascular function during oral estradiol treatment.


   Acknowledgments
 
Terhi Hakala and Katja Tuominen are acknowledged for technical assistance.


   Footnotes
 
This work was supported by grants from the Sigrid Juselius Foundation (to M.J.T. and H.Y.-J.) and Academy of Finland (to H.Y.-J. and S.V.) and by Erityisvaltionosuus (EVO) Grants TYH 0017, TYH 0337, and TYH 1241 (to M.J.T.).

Abbreviations: HDL, High-density lipoprotein; LCAT, lecithin:cholesterol acyltransferase; LDL, low-density lipoprotein; TR-FIA, time-resolved fluoroimmunoassay.

Received June 7, 2002.

Accepted October 18, 2002.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Hochberg RB 1998 Biological esterification of steroids. Endocr Rev 19:331–348[Abstract/Free Full Text]
  2. Janocko L, Hochberg RB 1983 Estradiol fatty acid esters occur naturally in human blood. Science 222:1334–1336[Abstract/Free Full Text]
  3. Larner JM, Shackleton CHL, Roitman E, Schwartz PE, Hochberg RB 1992 Measurement of estradiol-17-fatty acid esters in human tissues. J Clin Endocrinol Metab 75:195–200[Abstract]
  4. Larner JM, Rosner W, Hochberg RB 1987 Binding of estradiol-17-fatty acid esters to plasma proteins. Endocrinology 121:738–744[Abstract/Free Full Text]
  5. Kuohung W, Shwaery GT, Keaney Jr JF 2001 Tamoxifen, esterified estradiol, and physiologic concentrations of estradiol inhibit oxidation of low-density lipoprotein by endothelial cells. Am J Obstet Gynecol 184:1060–1063[CrossRef][Medline]
  6. Shwaery GT, Vita JA, Keaney Jr JF 1997 Antioxidant protection of LDL by physiological concentrations of 17ß-estradiol: requirement for estradiol modification. Circulation 95:1378–1385[Abstract/Free Full Text]
  7. Shwaery GT, Vita JA, Keaney Jr JF 1998 Antioxidant protection of LDL by physiologic concentrations of estrogens is specific for 17-beta-estradiol. Atherosclerosis 138:255–262[CrossRef][Medline]
  8. Vihma V, Adlercreutz H, Tiitinen A, Kiuru P, Wähälä K, Tikkanen MJ 2001 Quantitative determination of estradiol fatty acid esters in human pregnancy serum and ovarian follicular fluid. Clin Chem 47:1256–1262[Abstract/Free Full Text]
  9. Vehkavaara S, Hakala-Ala-Pietilä T, Virkamäki A, Bergholm R, Ehnholm C, Hovatta O, Taskinen M-R, Yki-Järvinen H 2000 Differential effects of oral and transdermal estrogen replacement therapy on endothelial function in postmenopausal women. Circulation 102:2687–2693[Abstract/Free Full Text]
  10. Vehkavaara S, Silveira A, Hakala-Ala-Pietilä T, Virkamäki A, Hovatta O, Hamsten A, Taskinen M-R, Yki-Järvinen H 2001 Effects of oral and transdermal estrogen replacement therapy on markers of coagulation, fibrinolysis, inflammation and serum lipids and lipoproteins in postmenopausal women. Thromb Haemost 85:619–625[Medline]
  11. Moore JW, Clark GMG, Bulbrook RD, Hayward JL, Murai JT, Hammond GL, Siiteri PK 1982 Serum concentrations of total and non-protein-bound oestradiol in patients with breast cancer and in normal controls. Int J Cancer 29:17–21[Medline]
  12. Pahuja SL, Hochberg RB 1995 A comparison of the esterification of steroids by rat lecithin:cholesterol acyltransferase and acyl coenzyme A:cholesterol acyltransferase. Endocrinology 136:180–186[Abstract]
  13. Kanji SS, Kuohung W, Labaree DC, Hochberg RB 1999 Regiospecific esterification of estrogens by lecithin:cholesterol acyltransferase. J Clin Endocrinol Metab 84:2481–2488[Abstract/Free Full Text]
  14. Höckerstedt A, Tikkanen MJ, Jauhiainen M 2002 LCAT facilitates transacylation of 17ß-estradiol in the presence of HDL3 subfraction. J Lipid Res 43:392–397[Abstract/Free Full Text]
  15. Dunn JF, Nisula BC, Rodbard D 1981 Transport of steroid hormones: binding of 21 endogenous steroids to both testosterone-binding globulin and corticosteroid-binding globulin in human plasma. J Clin Endocrinol Metab 53:58–68[Abstract/Free Full Text]
  16. Bélanger A, Candas B, Dupont A, Cusan L, Diamond P, Gomez JL, Labrie F 1994 Changes in serum concentrations of conjugated and unconjugated steroids in 40- to 80-year-old men. J Clin Endocrinol Metab 79:1086–1090[Abstract]
  17. Vallet-Strouve C, Fresinsky E, Mowszowicz I 1986 Changes in the metabolic pattern of estrogens as a function of age in cultured myometrial cells: synthesis of a lipoidal derivative of estradiol. Mech Ageing Dev 35:233–243[CrossRef][Medline]
  18. Mazière C, Auclair M, Ronveaux M-F, Salmon S, Santus R, Mazière J-C 1991 Estrogens inhibit copper and cell-mediated modification of low density lipoprotein. Atherosclerosis 89:175–182[CrossRef][Medline]
  19. Rifici VA, Khachadurian AK 1992 The inhibition of low-density lipoprotein oxidation by 17-ß estradiol. Metabolism 41:1110–1114[CrossRef][Medline]
  20. Hwang J, Peterson H, Hodis HN, Choi B, Sevanian A 2000 Ascorbic acid enhances 17 ß-estradiol-mediated inhibition of oxidized low density lipoprotein formation. Atherosclerosis 150:275–284[CrossRef][Medline]
  21. Sack MN, Rader DJ, Cannon III RO 1994 Oestrogen and inhibition of oxidation of low-density lipoproteins in postmenopausal women. Lancet 343:269–270[CrossRef][Medline]
  22. Wilcox JG, Hwang J, Hodis HN, Sevanian A, Stanczyk FZ, Lobo RA 1997 Cardioprotective effects of individual conjugated equine estrogens through their possible modulation of insulin resistance and oxidation of low-density lipoprotein. Fertil Steril 67:57–62[CrossRef][Medline]
  23. Wakatsuki A, Ikenoue N, Sagara Y 1998 Effects of estrogen on susceptibility to oxidation of low-density and high-density lipoprotein in postmenopausal women. Maturitas 28:229–234[CrossRef][Medline]
  24. Koh KK, Bui MN, Mincemoyer R, Cannon III RO 1997 Effects of hormone therapy on inflammatory cell adhesion molecules in postmenopausal healthy women. Am J Cardiol 80:1505–1507[CrossRef][Medline]
  25. Mc Manus J, Mc Eneny J, Thompson W, Young IS 1997 The effect of hormone replacement therapy on the oxidation of low density lipoprotein in postmenopausal women. Atherosclerosis 135:73–81[CrossRef][Medline]
  26. Nenseter MS, Volden V, Berg T, Drevon CA, Ose L, Tonstad S 1996 Effect of hormone replacement therapy on the susceptibility of low-density lipoprotein to oxidation among postmenopausal hypercholesterolaemic women. Eur J Clin Invest 26:1062–1068[CrossRef][Medline]
  27. Brussaard HE, Gevers Leuven JA, Kluft C, Krans HMJ, van Duyvenvoorde W, Buytenhek R, van der Laarse A, Princen HMG 1997 Effect of 17ß-estradiol on plasma lipids and LDL oxidation in postmenopausal women with type II diabetes mellitus. Arterioscler Thromb Vasc Biol 17:324–330[Abstract/Free Full Text]
  28. Keaney Jr JF, Shwaery GT, Xu A, Nicolosi RJ, Loscalzo J, Foxall TL, Vita JA 1994 17ß-estradiol preserves endothelial vasodilator function and limits low-density lipoprotein oxidation in hypercholesterolemic swine. Circulation 89:2251–2259[Abstract/Free Full Text]
  29. Schatz F, Hochberg RB 1981 Lipoidal derivative of estradiol: the biosynthesis of a nonpolar estrogen metabolite. Endocrinology 109:697–703[Abstract/Free Full Text]
  30. Helisten H, Höckerstedt A, Wähälä K, Tiitinen A, Adlercreutz H, Jauhiainen M, Tikkanen MJ 2001 Accumulation of high-density lipoprotein-derived estradiol-17ß fatty acid esters in low-density lipoprotein particles. J Clin Endocrinol Metab 86:1294–1300[Abstract/Free Full Text]
  31. Abplanalp W, Scheiber MD, Moon K, Kessel B, Liu JH, Subbiah MTR 2000 Evidence for the role of high density lipoproteins in mediating the antioxidant effect of estrogens. Eur J Endocrinol 142:79–83[Abstract]
  32. Leszczynski DE, Schafer RM 1991 Metabolic conversion of six steroid hormones by human plasma high-density lipoprotein. Biochim Biophys Acta 1083:18–28[Medline]
  33. Chin JH, Azhar S, Hoffman BB 1992 Inactivation of endothelial derived relaxing factor by oxidized lipoproteins. J Clin Invest 89:10–18
  34. Dupuis J, Tardif J-C, Cernacek P, Théroux P 1999 Cholesterol reduction rapidly improves endothelial function after acute coronary syndromes: the RECIFE (reduction of cholesterol in ischemia and function of the endothelium) trial. Circulation 99:3227–3233[Abstract/Free Full Text]
  35. 1Anderson TJ, Meredith IT, Yeung AC, Frei B, Selwyn AP, Ganz P 1995 The effect of cholesterol-lowering and antioxidant therapy on endotheliumdependent coronary vasomotion. N Engl J Med 332:488–493[Abstract/Free Full Text]



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J. Clin. Endocrinol. Metab., November 1, 2007; 92(11): 4327 - 4331.
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V. Vihma, A. Tiitinen, O. Ylikorkala, and M. J. Tikkanen
Quantitative Determination of Estradiol Fatty Acid Esters in Lipoprotein Fractions in Human Blood
J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2552 - 2555.
[Abstract] [Full Text] [PDF]

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