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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-1372
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 11 4327-4331
Copyright © 2007 by The Endocrine Society

Estradiol Fatty Acid Esters in Adipose Tissue and Serum of Pregnant and Pre- and Postmenopausal Women

Maija Badeau, Veera Vihma, Tomi S. Mikkola, Aila Tiitinen and Matti J. Tikkanen

Departments of Medicine (M.B., V.V., M.J.T.) and Obstetrics and Gynecology (T.S.M., A.T.), Helsinki University Central Hospital, Haartmaninkatu 2, 00029 HUCH, Helsinki, Finland

Address all correspondence and requests for reprints to: Matti J. Tikkanen, M.D., Department of Medicine, Helsinki University Central Hospital, Haartmaninkatu 4, 00290 Helsinki, Finland. E-mail: matti.tikkanen{at}hus.fi.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Context: The 17ß-estradiol fatty acid esters are hormone derivatives with long-lasting estrogenic effect. They are transported in serum lipoproteins and thought to be sequestered in adipose tissue.

Objective: Our objective was to determine the 17ß-estradiol fatty acid ester concentrations in serum and adipose tissue in women of various hormonal states.

Design: After several chromatographic steps separating esterified from free estradiol, time-resolved fluoroimmunoassay was used as a quantifying tool.

Participants: Samples were obtained from pregnant women undergoing cesarean section (n = 13), or premenopausal (n = 8) and postmenopausal women (n = 6) during gynecological surgery.

Main Outcome Measures: 17ß-Estradiol and 17ß-estradiol fatty acid ester concentrations in serum, and visceral and sc adipose tissue were examined.

Results: The ratio of esterified to free estradiol in plasma increased with decreasing estradiol level from 0.5% in pregnant, to 15% in premenopausal and 110% in postmenopausal women. Estradiol esters constituted about 10% of the free estradiol present in adipose tissue in pregnancy. In nonpregnant women, most of the adipose tissue estradiol was in esterified form, the median ester to free ratio being elevated to 150–490%. After menopause, the overwhelming majority of estradiol in both free and esterified form was present in adipose tissue.

Conclusions: The overall higher ester to free estradiol ratio in adipose tissue than in serum indicates active esterification capacity in adipose tissue. The predominance of esterified and free estradiol in postmenopausal adipose tissue compared with serum suggests in situ production and storage. Whether the estradiol esters have an independent physiological role in adipose tissue remains to be clarified.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
ESTRADIOL FATTY ACID esters are naturally occurring steroid hormone derivatives present in the tissues of humans, other vertebrates, and also invertebrates (1, 2, 3). Animal and cell culture studies have shown that estradiol esters are formed in different tissues at varying efficiency (1, 4). The lipophilic estradiol esters as well as other known steroid fatty acid esters are not excreted in the urine in contrast to the hydrophilic sulfate and glucuronide conjugates but seem to be sequestered in fatty tissues (5). Estradiol esters are metabolically protected, long lasting, and potent hormone derivatives that release the active hormone after the cleavage of the ester bond by esterase (1, 6, 7, 8, 9, 10). It is likely that long-chain fatty acid esters of estradiol do not bind to estrogen receptors (ERs) (11). It has been suggested that the estradiol esters form a reservoir of functional steroid hormones when the circulating free estradiol levels are depleted (1), but their exact role is not known.

The endogenously synthesized fatty acid esters of estradiol accumulate and are transported in lipoprotein particles in the circulation (12). In human plasma, high-density lipoprotein 3 (HDL3) associated lecithin-cholesterol acyltransferase (LCAT) esterifies estradiol with different long-chain fatty acids, and transport of these esters to low-density lipoprotein (LDL) is enhanced by cholesterol ester transfer protein (13, 14). LCAT is also responsible for estradiol esterification in ovarian follicular fluid (15). However, in other tissues, the mechanisms of estradiol ester formation are not as well established, but the enzyme systems responsible differ from that in the blood and are not identical with the one for cholesterol esterification (1, 16, 17).

Human adipose tissue is known to be an important source of estrogens in the postmenopausal physiological state characterized by low estrogen levels. The adipose tissue levels of estrogen precursor hormones (e.g. testosterone and androstenedione) exceed their concentrations in other tissues, and adipose tissue with its active aromatase and 17ß-hydroxysteroid dehydrogenase enzymes probably is an important site for estrogen formation at all ages (18). The adipose tissue is also regulated by estrogens, and the human adipose tissue has contained ERs {alpha} and ß, as well as different isoforms of the latter subtype (19, 20), the expression of which proposedly could influence hormonal effects on adipose tissue deposition (20).

The estradiol fatty acid esters present in adipose tissue may exert independent functions or simply serve as a hormone reservoir. Using mass spectrometric methods, estradiol fatty acid ester concentrations exceeding those in serum have been measured in human and bovine adipose tissue (5, 21). Animal studies suggest that more estradiol fatty acid esters are formed when high concentrations of estrogens are present in the organism (22). In line with this, we have reported elevated serum concentrations of estradiol esters in pregnancy (23). The aims of this study were to quantify the serum and adipose tissue estradiol esters in pregnant and nonpregnant fertile-aged women as well as in postmenopausal women.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Instrumentation and chemicals

Instruments and related reagents for time-resolved fluoroimmunoassay (TR-FIA) were purchased from Wallac Oy, Turku, Finland (PerkinElmer). Fluorescence was measured with the VICTOR 1420 multilabel counter with software 1.0. White goat antirabbit IgG-coated microtitration strips, DELFIA Platewash, DELFIA Plateshake, and DELFIA wash solution were used for immunoassay procedures, and dissociation-enhanced lanthanide fluoroimmunoassay (DELFIA) enhancement solution to develop the fluorescence. Radioactivity was determined with the Rackbeta liquid scintillation counter.

Methanol, hexane, ethyl acetate (HPLC grade), and diethyl ether (glass distilled grade) were from Rathburn Chemicals Ltd. (Walkerburn, Scotland, UK), and chloroform (Uvasol) was from Merck KgaA (Darmstadt, Germany). The assay buffer, Tris-HCl (pH 7.8), consisted of Tris 50 mmol/liter, 8.78 g NaCl, 0.5 g sodium azide, 5 g BSA (Sigma Chemical Co., St. Louis, MO), and 100 µg/liter Tween 40 up to 1000 ml of sterilized water. OptiPhase ‘HiSafe’2 scintillation fluid was from Wallac Oy.

Control samples and internal standard

3H-labeled estradiol-3,17ß-dioleate was used as an internal standard in each sample for determining the recovery. It was synthesized from 3H-labeled 17ß-estradiol (New England Nuclear Life Science Products, Inc., Waltham, MA) as described previously (23). Before each assay, the standard was purified by Sephadex LH-20 chromatography on the same or previous day. Estradiol-17ß-stearate (Steraloids, Inc., Newport, RI) added to a male serum pool (Finnish Red Cross) was used to prepare control samples. In each assay, two different concentrations of control estradiol-17ß-stearate in serum as well as distilled water were processed identically to the samples. The calibrators for TR-FIA were prepared from nonradioactive 17ß-estradiol (Steraloids, Inc.) by serial dilutions of stock solution (in methanol) in the assay buffer [11.5–1836 pmol/liter (3.13–500 ng/liter)].

Tissue samples

The visceral and sc adipose tissue, and blood were obtained from pregnant women undergoing cesarean section (n = 13), or nonpregnant, premenopausal women (n = 8) as well as postmenopausal women (n = 6) undergoing gynecological surgery for nonmalignant conditions. Subjects receiving any hormonal therapy were excluded from the study. Blood was centrifuged within 1 h. The serum and tissues were stored in –20 C or –80 C until analyzed. The study was approved by the Ethics Committee of the Department of Gynecology and Obstetrics in Helsinki University. All volunteering subjects gave their informed signed consent.

Analytical procedures (Fig. 1Go)

The protocol followed was a modification from the validated quantitative method for 17ß-estradiol fatty acid esters (23) summarized as follows.


Figure 1
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  		FIG. 1. Analytical procedures.

 
Extraction

The thawed adipose tissue samples were weighed (100–300 mg) and rinsed with 1 ml sterile saline. The samples were then transferred into disposable glass tubes and homogenized (Ultra Turrax T8 Ika-Werke) in 1 ml distilled water. Internal standard, 3H-labeled estradiol-17ß-dioleate (3000–4000 dpm in 5 µl methanol per sample), was pipetted into disposable glass tubes (Fig. 1Go) with 1000 µl serum (patient samples), 500 µl control serum samples, or homogenized adipose tissue samples. The serum samples were extracted four times with 2.5 volumes and tissue homogenates 3.5 volumes of diethyl ether-ethyl acetate (1:1, vol/vol) by mixing for 3 min. The organic phase was collected and evaporated under nitrogen until dry.

Isolation of esterified estradiol

Sephadex LH-20 chromatography was performed using 5-cm columns in disposable Pasteur pipettes (Pharmacia Biotech, Uppsala, Sweden) using hexane-chloroform (1:1, vol/vol). The samples were dissolved in 300 µl hexane-chloroform (1:1, vol/vol) and applied to the columns. The sample tubes were further washed twice with 300 µl hexane-chloroform, which was added to the columns. The estradiol esters were eluted with 6 ml hexane-chloroform. The nonesterified estradiol was then eluted with 5 ml methanol. The estradiol ester-containing fraction was evaporated to dryness under nitrogen. The nonesterified estradiol was stored at 4 C until analysis.

Hydrolysis and purification of the esters

The estradiol ester-containing fraction was hydrolyzed at 60 C for 2 h in 1 ml (adipose tissue) or 500 µl (serum) 1-mol/liter potassium hydroxide in methanol. To neutralize the samples, 1 ml (500 µl) distilled water and 280 µl (140 µl) 4 mol/liter HCl were added. The organic phase was removed by evaporation, and samples were then extracted twice with 3 ml diethyl ether, after which the organic phase was evaporated to dryness under nitrogen. The samples were dissolved in 300 µl hexane-chloroform (1:1, vol/vol) and subjected to another chromatography on Sephadex LH-20. After the addition of the samples to the columns, the sample tubes were further washed twice with 300 µl hexane-chloroform, which was added to the columns. Lipophilic impurities were eluted with 6 ml hexane-chloroform. The free estradiol produced by alkaline hydrolysis was eluted with 5 ml methanol and evaporated to dryness under nitrogen.

TR-FIA

Samples were dissolved in the assay buffer (0.5% BSA Tris). At low concentrations the samples were concentrated 3- to 2-fold to give better precision, i.e. values located on the linear part of the standard curve. At high concentrations the ester fractions were diluted 2-fold and the free estradiol fractions up to 200-fold. The recovery was determined by liquid scintillation counting. The protocol for the commercial TR-FIA reagent set was followed in our assay except that the estradiol antiserum and europium tracer were 50% more diluted.

The results were corrected for the recovery based on the internal standard, and for the dilution factor, if appropriate. The mean recovery for all serum samples was 64%, and for the adipose tissue 66%.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The median serum concentrations of estradiol fatty acid esters and nonesterified, free estradiol in late pregnancy, in nonpregnant premenopausal and postmenopausal women are shown in Table 1Go. As expected, serum free estradiol levels were high in pregnancy, intermediate in premenopausal women, and very low in the postmenopause. Conversely, the estradiol ester to free ratio was lowest in pregnancy (0.5%) but increased to 15% in premenopausal women and 110% in postmenopausal women. The estradiol ester as well as free estradiol concentrations in pregnancy serum and their ratio were in agreement with previously published results (12, 23).


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  		TABLE 1. Serum estradiol fatty acid ester and free estradiol concentrations in late pregnancy, and in nonpregnant premenopausal (premenop) and postmenopausal (postmenop) women

 
The corresponding results of determinations in adipose tissues are shown in Tables 2Go and 3Go. The concentrations of estradiol fatty acid esters in visceral adipose tissue (Table 2Go) and those in sc adipose tissue (Table 3Go) were highest in pregnant women and lower in premenopausal and postmenopausal women. In visceral adipose tissue, the median estradiol ester to free ratio increased from 9.6% in pregnant women to 147% in premenopausal and 390% in postmenopausal women (Table 2Go). As shown in Table 3Go, a similar trend was observed in sc adipose tissue, with estradiol ester to free ratio increasing from 10.7% in pregnancy to 259% in premenopausal and 490% in postmenopausal women. The visceral and sc adipose tissue concentrations of esterified or free estradiol did not differ significantly from each other in pregnant, premenopausal, or postmenopausal women. In all postmenopausal subjects, there was more esterified than nonesterified estradiol in the adipose tissue (Tables 2Go and 3Go).


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  		TABLE 2. Visceral adipose tissue estradiol fatty acid ester and free estradiol concentrations in late pregnancy, and in nonpregnant premenopausal (premenop) and postmenopausal (postmenop) women

 

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  		TABLE 3. Subcutaneous adipose tissue estradiol fatty acid ester and free estradiol concentrations in late pregnancy, and in nonpregnant premenopausal (premenop) and postmenopausal (postmenop) women

 
Interestingly, median estradiol fatty acid concentrations in adipose tissue were in all three groups of women at least 10 times higher than in serum (pmol/g compared with pmol/ml). In addition, the concentration of free estradiol was higher in adipose tissue than in serum in all postmenopausal women and in six of eight nonpregnant, premenopausal women (pmol/g compared with pmol/ml) (no individual values shown). In all nonpregnant women, the estradiol ester to free ratio was much higher compared with pregnant women, both in serum and in adipose tissue.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this study the endogenous estradiol fatty acid ester and the free estradiol concentrations were determined for the first time in the adipose tissue of pregnant women. Both esterified and nonesterified estradiol were abundant in adipose tissue during late pregnancy. In the serum of pregnant women, the amount of esterified estradiol averaged about 0.5% the free estradiol concentration, but in adipose tissue the median ester to free estradiol ratio was 20 times higher. The results in the nonpregnant premenopausal and postmenopausal women showed that the proportion of esters increased with decreasing serum free estradiol levels, in line with our previous study (24). In the adipose tissue of these women, there was more esterified than free estradiol. In postmenopausal women the median estradiol ester concentration also exceeded that of serum free estradiol. The very low serum levels of free and esterified estradiol in postmenopausal women compared with adipose tissue levels suggest that the vast majority of estradiol is produced and stored in adipose tissue in these women. This also indicates that the estradiol originating in adipose tissue is not effectively transported elsewhere. The estradiol ester to free estradiol ratio was higher in adipose tissue than in serum in all pregnant and postmenopausal women, and in all but one nonpregnant, obese premenopausal woman, indicating active esterification capacity in fat tissue.

Clearly, the estradiol fatty acid esters are more abundant than free estradiol in the adipose tissue of nonpregnant women. The pathways for fatty acid esterification of estradiol as well as other steroid hormones have been observed in different organisms ranging from invertebrates, including insects, to vertebrates. Therefore, it is intriguing that the physiological role for endogenous steroid fatty acid esters is not clear. Based on the potent and long-lasting hormonal activity of these derivatives, it has been hypothesized that they form a reservoir of estrogen to be released for use in the target tissues, in situations characterized by estrogen depletion (1). This theory is supported by the relative abundance of esterified estradiol in comparison to levels of free estradiol in postmenopausal women’s adipose tissue, as shown by our results.

There is some in vitro evidence that estradiol fatty acid esters protect LDL particles from oxidation at physiologically relevant concentrations (25), and LDL associated estradiol fatty acid esters can be delivered in human macrophages, protecting them against oxidation (26). However, it is not clear how important the antioxidative effects are in vivo, and whether the reduced serum esterified and nonesterified estradiol concentrations contribute to cardiovascular or other diseases on postmenopausal women. Furthermore, some data from rat studies seem to show that estrogen esters are important in stimulating cell growth in the fat-rich mammary tissue, whereas in uterus the endometrial free estradiol is more effective in this respect (22). Studies in invertebrates under conditions of excess estradiol suggest that esterification with fatty acids by activated estradiol acyltransferase could serve as a homeostatic mechanism to maintain stable endogenous free estradiol levels (27).

The exact mechanisms of the endogenous formation of estradiol fatty acid esters are not fully known. In blood, estradiol fatty acid esters synthesized by LCAT circulate associated with lipoprotein particles, especially with high-density lipoprotein (12). It has been proposed that estradiol esters are formed in situ in various tissues by specific acyltransferases (1, 16, 17). In rats, one microsomal enzyme may be responsible for estradiol, as well as testosterone and {Delta}5–3ß-hydroxy steroid (pregnenolone and dehydroepiandrosterone) fatty acid esterification (4). An acylcoenzyme A-estradiol-17ß acyltransferase has been implicated in studies in a variety of animal species (3, 16, 28, 29), but the enzymatic systems operating in humans remain to be characterized.

In adipose tissue, estrogen has direct effects on lipogenesis by decreasing the activity of lipoprotein lipase, and also has indirect effects on lipolysis, like inducing the hormone-sensitive lipase (HSL) (30). Interestingly, steroid fatty acid ester hydrolysis is regulated by HSL (31), which also regulates triglyceride hydrolysis in adipose tissue. The lipolytic activity of HSL is inhibited by insulin, and diminished HSL activity has been reported in various conditions characterized by insulin resistance and elevated serum levels of insulin (32). Accordingly, the regeneration of biologically active estradiol and other steroids by de-esterification may be linked to various metabolic states that regulate adipose tissue lipolysis. Estrogens, as well as other steroid hormones, also control the adipose tissue distribution, most likely via specific differences in the expression of steroid hormone receptors in various tissue deposits (20, 30). Human adipocytes from males and females express both ERs {alpha} and ß, and estrogen effects may be mediated by ER {alpha} in adipose tissue (30). Esterified estradiol does not bind to ERs (11), and variation in esterification capacity could, in theory, have effects on the adipose tissue deposition.

In conclusion, estradiol esterification with fatty acids is relatively low during estrogen excess associated with pregnancy but increases with lower levels of circulating estradiol. In the postmenopause the overwhelming majority of estradiol is present in adipose tissue, mostly in the form of fatty acid esters. In contrast, serum esterified and free estradiol concentrations are low, suggesting that the effects of estradiol produced in adipose tissue are not systemic but local.


   Acknowledgments
 
We thank Robert Badeau, Päivi Ihamuotila, Kirsti Räsänen, and Inga Wiik for technical assistance, as well as the Helsinki University Central Hospital Naistenklinikka personnel involved with the collecting of the tissue samples. Terhi Hakala and Adile Samaledtin are acknowledged for technical advice, and Kristiina Wähälä’s Laboratory of Organic Chemistry in Helsinki University for the synthesis of 3H-labeled estradiol-3, 17ß-dioleate.


   Footnotes
 
The study was financially supported by the Erityisvaltionosuus Grant, Sigrid Juselius Foundation, and Päivikki and Sakari Sohlberg Foundation.

Disclosure Statement: M.B., V.V., and A.T. have nothing to declare. T.S.M. reports consulting fees or paid advisory board and lecture fees from a commercial sponsor. M.J.T. reports consulting fees or advisory board (Merck, Pfizer) and lecture fees (Pfizer).

First Published Online August 28, 2007

Abbreviations: ER, Estrogen receptor; HSL, hormone-sensitive lipase; LCAT, lecithin-cholesterol acyltransferase; LDL, low-density lipoprotein; TR-FIA, time-resolved fluoroimmunoassay.

Received June 20, 2007.

Accepted August 20, 2007.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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