These results have potential clinical relevance in two areas. First, as human adipose tissue contains both free hormonally active E2 and inactive E2 fatty acyl ester, as well as the enzymatic machineries to produce these forms, adipose tissue may in principle function as a source of free E2 or as a storage site for hydrophobic esterified E2. This is of theoretical importance in postmenopausal women whose ovarian E2 production has ceased and whose cardiovascular health might benefit from endogenous E2 stored in fat tissue. Based on our study in obese individuals, free E2 levels in adipose tissue did not correlate with serum E2 levels, but adipose tissue E2 fatty acyl ester levels correlated with those in serum. Future studies are necessary to clarify whether estrogen metabolites can enter the circulation from a subcutaneous fat depot. Treatment trials with exogenous formulations of estrogen have shown no cardiovascular benefit, whereas endogenous estrogen produced in the adipose tissue could, in theory, be cardioprotective in the same way as is ovarian estrogen before the menopause.
Second, although free E2 might have beneficial cardiovascular effects in postmenopausal women, the opposite may be true in the female breast. Free E2 is regarded as a risk factor for breast cancer. As both esterifying and de-esterifying enzymatic activities are present in adipose tissue, the balance between these two pathways is important. Locally dominant E2 esterification activity could be beneficial by inactivating E2, but dominant de-esterification could result in high local E2
concentrations which might enhance carcinogenesis. In theory, activation of E2
esterification or inhibition of E2 fatty acyl ester hydrolysis could reduce the risk of breast cancer. Future studies are crucial to test these hypotheses and to investigate whether this system has therapeutical value.
9 ACKNOWLEDGEMENTS
This study was carried out in the Department of Medicine, University of Helsinki during the years 2006-2013. First of all, I wish to thank my supervisor, Professor Matti J. Tikkanen, who made a tremendous effort to support and guide me during the preparation of all published papers and this thesis work. What I learn from him is not only how to do research, but also how to work with other people and how to solve difficulties. All these will still be valuable for me in the future. I would like to thank my other supervisor, Adjunct Professor Matti Jauhiainen, for his constructive comments and wise advice on my work, and for his careful revision of my thesis manuscript.
I would like to thank the reviewers, Adjunct Professor Heikki Koistinen and Adjunct Professor Olavi Ukkola, for their careful reviews of my thesis and their valuable comments that improved the thesis. I would like to warmly thank my thesis committee members, Professor Olli A. Jänne and Adjunct Professor Oskari Heikinheimo, for their monitoring and evaluating the thesis project. I would like to thank Carol Norris for her carefully revising the language of the thesis.
I wish to thank Professor Herman Adlercreutz, Adjunct Professor Tomi Mikkola, Professor Elina Ikonen, Professor Kristiina Wähälä, Professor Hannele Yki-Järvinen, Adjunct Professor Esa Hämäläinen, Ursula Turpeinen, Marjut Leidenius, and Adjunt Professor Kirsi H. Pietiläinen for their excellent collaboration. I warmly thank Veera Vihma for the great collaboration and especially, for her support in the preparation of publication III and IV. Maija Badeau, Hanna Savolainen-Peltonen, Anja Koskela, Wei Wang, Jarkko Soronen, and Jussi Naukkarinen are thanked for their nice collaboration.
Besides, I would like to thank many other researchers who have contributed to this work.
I would like to thank Päivi Ihamuotila and Päivi Ruha for their assistance in the experimental and practical work, and for being with me during many important moments. I would like to thank Adile Samaledtin, Kirsti Räsänen, and many others for their excellent technical assistance and their friendship.
I would like to thank all my colleagues at Helsinki University including Hanna Paatela, Päivi Söderholm, Robert Badeau, Anna Lahikainen, and many others. The scientific, open, and positive working atmosphere they created has made my work easier and more attractive. The warm friendship they shared has been so very valuable for me. I wish to thank Raija Selivuo and others for their great secretarial assistance.
My master’s degree supervisor, Adjunct Professor Guiying Zheng in Jilin University, and my doctoral study supervisor, Professor Juan Du in China Medicine University, are warmly thanked for their support and encouragement. All my friends are thanked for their interest in my work. I wish to thank my parents Yaxuan Wang and Shuren Liu, my sister Ye, and my mother-in-law Weiqin Zhang, for their love, understanding, and support. I thank my beloved son and daughter, Chunyang and Chunxiao, for their company, especially during the last phase of the thesis preparation. Finally, I want to thank my beloved husband, Guangyu, who has encouraged me and provided support to me to complete the thesis during these years.
This study was financially supported by Folkhälsan, the Sigrid Jusélius Foundation, Erityisvaltionosuus (EVO) TYH Grants, the Finska Läkaresällskapet, Päivikki and Sakari Sohlberg Foundation, Finnish Heart Foundation, the Finnish Medical Foundation, and Helsinki University Chancellor’s Travel Grant, and Biomedicum Helsinki Foundation. All these foundations are gratefully acknowledged for the financial support for me to complete the thesis. The Women’s Clinical Hospital personnel are thanked for their help with sample collection. I would like to thank all the subjects who voluntarily participated in these studies.
Helsinki, December, 2013
10 REFERENCES
[1] Abraham GE. Solid-phase radioimmunoassay of estradiol-17 beta. J Clin Endocrinol Metab 1969; 29: 6: 866-870.
[2] Abul-Hajj YJ. Formation of estradiol-17ß fatty acyl 17-esters in mammary tumors.
Steroids 1982; 40:2: 149-155.
[3] Adams JB, Martyn P, Smith DL and Nott S. Formation and turnover of long-chain fatty acid esters of 5-androstene-3 beta, 17 beta-diol in estrogen receptor positive and negative human mammary cancer cell lines in culture. Steroids 1988; 51: 3-4: 251-267.
[4] Adams JB, Vrahimis R and Young CE. Metabolism of lipoidal derivatives of estradiol-17-beta in human mammary cancer tissue and cell lines. J Steroid Biochem Molec 1991; 39: 5A: 751-758.
[5] Alsted TJ, Nybo L, Schweiger M, Fledelius C, Jacobsen P, Zimmermann R, Zechner R and Kiens B. Adipose triglyceride lipase in human skeletal muscle is upregulated by exercise training. Am J Physiol Endocrinol Metab 2009; 296: 3: E445-53.
[6] Ameis D, Merkel M, Eckerskorn C and Greten H. Purification, characterization and molecular cloning of human hepatic lysosomal acid lipase. Eur J Biochem 1994;
219: 3: 905-914.
[7] Anwar A, McTernan P.G., Anderson L.A., Askaa J., Moody C.G., Barnett A.H., Eggo M.C., kumar S. Site-specific regulation of oestrogen receptor-alpha and –beta by oestradiol in human adipose tissue. Diabetes Obes Metab 2001; 3: 5: 338-49.
[8] Armellini F, Zamboni M and Bosello O. Hormones and body composition in humans: clinical studies. Int J Obes Relat Metab Disord 2000; 24: Suppl 2: S18-21.
[9] Assmann G and Seedorf U. Acid lipase deficiency: Wolman disease and cholesteryl ester storage disease. In: The Metabolic and Molecular Bases of Inherited Disease, edited by Scriver CR, Beaudet AL, Sly WS and Valle D. New York.: McGraw-Hill, Inc. 2001; p. 3551-3572.
[10] Badeau M, Vihma V, Mikkola TS, Tiitinen A and Tikkanen MJ. Estradiol Fatty Acid Esters in Adipose Tissue and Serum of Pregnant and Pre- and Postmenopausal Women. J Clin Endocrinol Metab 2007; 92: 11: 4327-4331.
[11] Badeau M, Badeau R, Jauhiainen M and Tikkanen MJ. Steroid hormone-fatty acid esters and bone. J Bone Miner Res 2008; 23: 11: 1866-1867.
[12] Badeau RM, Metso J, Tikkanen MJ and Jauhiainen M. High-density lipoprotein-associated 17beta-estradiol fatty acyl ester uptake by Fu5AH hepatoma cells:
implications of the roles of scavenger receptor class B, type I and the low-density lipoprotein receptor. Biochim Biophys Acta 2007; 1771: 10: 1329-1334.
[13] Baglietto L, English DR, Hopper JL, MacInnis RJ, Morris HA, Tilley WD, Krishnan K and Giles GG. Circulating steroid hormone concentrations in postmenopausal women in relation to body size and composition. Breast Cancer Res Treat 2009; 115: 1: 171-179.
[14] Banerjee S, Katz J, Levitz M and Finlay TH. Identification of a Novel Esterase in Human Breast Cyst Fluida. Ann N Y Acad Sci 1990; 586: 1: 204-212.
[15] Banerjee S, Katz J, Levitz M and Finlay TH. Purification and Properties of an Esterase from Human Breast Cyst Fluid. Cancer Res 1991; 51: 4: 1092-1098.
[16] Bélanger A, Candas B, Dupont A, Cusan L, Diamond P, Gomez JL and Labrie F.
Changes in serum concentrations of conjugated and unconjugated steroids in 40- to 80-year-old men. J Clin Endocrinol Metab 1994; 79: 4: 1086-1090.
[17] Bélanger B, Caron S, Bélanger A and Dupont A. Steroid fatty acid esters in adrenals and plasma: effects of ACTH. J Endocrinol 1990; 127: 3: 505-511.
[18] Bélanger B, Roy R and Bélanger A. Administration of pregnenolone and dehydroepiandrosterone to guinea pigs and rats causes the accumulation of fatty acid esters of pregnenolone and dehydroepiandrosterone in plasma lipoproteins. Steroids 1992; 57: 9: 430-436.
[19] Bélanger C, Hould F, Lebel S, Biron S, Brochu G and Tchernof A. Omental and subcutaneous adipose tissue steroid levels in obese men. Steroids 2006; 71: 8: 674-682.
[20] Bellemare V, Laberge P, Noël S, Tchernof A and Luu-The V. Differential estrogenic 17-hydroxysteroid dehydrogenase activity and type 12 17-hydroxysteroid dehydrogenase expression levels in preadipocytes and differentiated adipocytes. J Steroid Biochem Mol Biol 2009; 114: 3–5: 129-134.
[21] Bjorntorp P. The regulation of adipose tissue distribution in humans. Int J Obes Relat Metab Disord 1996; 20: 4: 291-302.
[22] Blankenstein MA, Szymczak J, Daroszewski J, Milewicz A and Thijssen JH.
Estrogens in plasma and fatty tissue from breast cancer patients and women undergoing surgery for non-oncological reasons. Gynecol Endocrinol 1992; 6: 1: 13-17.
[23] Blankenstein MA, van de Ven J, Maitimu-Smeele I, Donker GH, de Jong PC, Daroszewski J, Szymczak J, Milewicz A and Thijssen JH. Intratumoral levels of estrogens in breast cancer. J Steroid Biochem Mol Biol 1999; 69: 1-6: 293-297.
[24] Bligh EG and Dyer WJ. A rapid method of total lipid extaction and purification.
Can J Biochem Physiol 1959; 37: 8: 911-917.
[25] Blouin K, Richard C, Brochu G, Hould FS, Lebel S, Marceau S, Biron S, Luu-The V and Tchernof A. Androgen inactivation and steroid-converting enzyme expression in abdominal adipose tissue in men. J Endocrinol 2006; 191: 3: 637-649.
[26] Blouin K, Nadeau M, Mailloux J, Daris M, Lebel S, Luu-The V and Tchernof A.
Pathways of adipose tissue androgen metabolism in women: depot differences and modulation by adipogenesis. Am J Physiol Endocrinol.Metab. 2009; 296: 2: E244-E255.
[27] Bolca S, Urpi-Sarda M, Blondeel P, Roche N, Vanhaecke L, Possemiers S, Al-Maharik N, Botting N, De Keukeleire D, Bracke M, Heyerick A, Manach C and Depypere H. Disposition of soy isoflavones in normal human breast tissue. Am J Clin Nutr 2010; 91: 4: 976-984.
[28] Brodeur MR, Brissette L, Falstrault L, Luangrath V and Moreau R. Scavenger receptor of class B expressed by osteoblastic cells are implicated in the uptake of cholesteryl ester and estradiol from LDL and HDL3. J Bone Miner Res 2008; 23: 3:
326-337.
[29] Calle EE and Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer 2004; 4: 8: 579-591.
[30] Chang TY, Li BL, Chang CC and Urano Y. Acyl-coenzyme A:cholesterol acyltransferases. Am J Physiol Endocrinol Metab 2009; 297: 1: E1-9.
[31] Chung S, Sawyer JK, Gebre AK, Maeda N and Parks JS. Adipose tissue ATP binding cassette transporter A1 contributes to high-density lipoprotein biogenesis in vivo. Circulation 2011; 124: 15: 1663-1672.
[32] Cooke PS and Naaz A. Role of estrogens in adipocyte development and function.
Exp Biol Med 2004; 229: 11: 1127-1135.
[33] Couillard C, Gagnon J, Bergeron J, Leon AS, Rao DC, Skinner JS, Wilmore JH, Després J and Bouchard C. Contribution of Body Fatness and Adipose Tissue Distribution to the Age Variation in Plasma Steroid Hormone Concentrations in Men:
The HERITAGE Family Study. J Clin Endocrinol Metab 2000; 85: 3: 1026-1031.
[34] D'Eon TM, Souza SC, Aronovitz M, Obin MS, Fried SK and Greenberg AS.
Estrogen regulation of adiposity and fuel partitioning. Evidence of genomic and non-genomic regulation of lipogenic and oxidative pathways. J Biol Chem 2005; 280: 43:
35983-35991.
[35] Dos Santos EG, Dieudonne MN, Pecquery R, Le Moal V, Giudicelli Y and Lacasa D. Rapid nongenomic E2 effects on p42/p44 MAPK, activator protein-1, and cAMP response element binding protein in rat white adipocytes. Endocrinology 2002; 143: 3:
930-940.
[36] Dunn JF, Nisula BC and Rodbard D. 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 1981; 53: 1: 58-68.
[37] Edman CD and MacDonald PC. Effect of obesity on conversion of plasma androstenedione to estrone in ovulatory and anovulator young women. Am J Obstet Gynecol 1978; 130: 4: 456-461.
[38] Elbashir S.M., Harborth J., Lendeckel W., Yalcin A., Weber K. and Tuschl T.
Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 2001; 411: 6836: 494-498.
[39] Findlay JW, Smith WC, Lee JW, Nordblom GD, Das I, DeSilva BS, Khan MN and Bowsher RR. Validation of immunoassays for bioanalysis: a pharmaceutical industry perspective. J Pharm Biomed Anal 2000; 21: 6: 1249-1273.
[40] Forney JP, Milewich L, Chen GT, Garlock JL, Schwarz BE, Edman CD and MacDonald PC. Aromatization of androstenedione to estrone by human adipose tissue in vitro. Correlation with adipose tissue mass, age, and endometrial neoplasia. J Clin Endocrinol Metab 1981; 53: 1: 192-199.
[41] Friedman JM and Halaas JL. Leptin and the regulation of body weight in mammals. Nature 1998; 395: 6704: 763-770.
[42] Gent J and Braakman I. Low-density lipoprotein receptor structure and folding.
Cell Mol Life Sci 2004; 61: 19-20: 2461-2470.
[43] Goldberg IJ and Merkel M. Lipoprotein lipase: physiology, biochemistry, and molecular biology. Front Biosci 2001; 6: D388-405.
[44] Goldstein JL, Dana SE, Faust JR, Beaudet AL and Brown MS. Role of lysosomal acid lipase in the metabolism of plasma low density lipoprotein. Observations in cultured fibroblasts from a patient with cholesteryl ester storage disease. J Biol Chem 1975; 250: 21: 8487-8495.
[45] Goldstein JL, Basu SK and Brown MS. Receptor-mediated endocytosis of low-density lipoprotein in cultured cells. Methods Enzymol 1983; 98: 241-260.
[46] Gong M, Wilson M, Kelly T, Su W, Dressman J, Kincer J, Matveev SV, Guo L, Guerin T, Li XA, Zhu W, Uittenbogaard A and Smart EJ. HDL-associated estradiol stimulates endothelial NO synthase and vasodilation in an SR-BI-dependent manner. J Clin Invest 2003; 111: 10: 1579-1587.
[47] Havel RJ, Eder HJ, Bragdon JH. The distribution and chemical composition of centrifugally separated lipoprotein in human serum. Eur J Clin Inves 1955; 34: 1345-1353.
[48] Heine PA, Taylor JA, Iwamoto GA, Lubahn DB and Cooke PS. Increased adipose tissue in male and female estrogen receptor-alpha knockout mice. Proc Natl Acad Sci USA 2000; 97: 23: 12729-12734.
[49] Helisten H, Höckerstedt A, Wähälä K, Tiitinen A, Adlercreutz H, Jauhiainen M and Tikkanen MJ. Accumulation of High-Density Lipoprotein-Derived Estradiol-17{beta} Fatty Acid Esters in Low-Density Lipoprotein Particles. J Clin Endocrinol Metab 2001; 86: 3: 1294-1300.
[50] Hershcopf RJ, Bradlow HL, Fishman J, Swaneck GE, Larner JM and Hochberg RB. Metabolism of estradiol fatty acid esters in man. J Clin Endocrinol Metab 1985; 61:
6: 1071-1075.
[51] Hochberg RB. Biological Esterification of Steroids. Endocr Rev 1998; 19: 3: 331-348.
[52] Höckerstedt A, Tikkanen MJ and Jauhiainen M. LCAT facilitates transacylation of 17{beta}-estradiol in the presence of HDL3 subfraction. J Lipid Res 2002; 43: 3:
392-397.
[53] Höckerstedt A, Jauhiainen M and Tikkanen MJ. Lecithin/Cholesterol Acyltransferase Induces Estradiol Esterification in High-Density Lipoprotein, Increasing Its Antioxidant Potential. J Clin Endocrinol Metab 2004; 89: 10: 5088-5093.
[54] Holm C. Molecular mechanisms regulating hormone-sensitive lipase and lipolysis. Biochem Soc Trans 2003; 31: Pt 6: 1120-1124.
[55] Hsing AW, Stanczyk FZ, Bélanger A, Schroeder P, Chang L, Falk RT and Fears TR. Reproducibility of Serum Sex Steroid Assays in Men by RIA and Mass Spectrometry. Cancer Epidemiol Biomarkers Prev 2007; 16: 5: 1004-1008.
[56] Huhtaniemi IT, Tajar A, Lee DM, O'Neill TW, Finn JD, Bartfai G, Boonen S, Casanueva FF, Giwercman A, Han TS, Kula K, Labrie F, Lean MEJ, Pendleton N, Punab M, Silman AJ, Vanderschueren D, Forti G, Wu FCW and the EMAS Group. Comparison of serum testosterone and estradiol measurements in 3174 European men using platform immunoassay and mass spectrometry; relevance for the diagnostics in aging men. Eur J Endocrinol 2012; 166: 6: 983-991.
[57] Hussain MM, Strickland DK and Bakillah A. The mammalian low-density lipoprotein receptor family. Annu Rev Nutr 1999; 19: 1: 141-172.
[58] Janocko L and Hochberg RB. Estradiol fatty acid esters occur naturally in human blood. Science 1983; 222: 4630: 1334-1336.
[59] Janocko L and Hochberg RB. Radiochemical evidence for estradiol-17-fatty acid esters in human blood. J Steroid Biochem 1986; 24: 5: 1049-1052.
[60] Janocko L, Larner JM and Hochberg RB. The interaction of C-17 esters of estradiol with the estrogen receptor. Endocrinology 1984; 114: 4: 1180-1186.
[61] Jo D, Abdallah MA, Young J, Baulieu E and Robel P. Pregnenolone, dehydroepiandrosterone, and their sulfate and fatty acid esters in the rat brain.
Steroids 1989; 54: 3: 287-297.
[62] Jones ME, Thorburn AW, Britt KL, Hewitt KN, Misso ML, Wreford NG, Proietto J, Oz OK, Leury BJ, Robertson KM, Yao S and Simpson ER. Aromatase-deficient (ArKO) mice accumulate excess adipose tissue. J Steroid Biochem Mol Biol 2001; 79: 1-5: 3-9.
[63] Kanji SS, Kuohung W, Labaree DC and Hochberg RB. Regiospecific esterification of estrogens by lecithin:cholesterol acyltransferase. J Clin Endocrinol Metab 1999; 84:
7: 2481-2488.
[64] Karastergiou K, Smith SR, Greenberg AS and Fried SK. Sex differences in human adipose tissues - the biology of pear shape. Biol Sex Differ 2012; 3: 13.
[65] Katz J, Finlay TH, Banerjee S and Levitz M. An estrogen-dependent esterase activity in MCF-7 cells. J Steroid Biochem 1987; 26: 6: 687-692.
[66] Kelly MJ and Levin ER. Rapid actions of plasma membrane estrogen receptors.
Trends Endocrinol Metab 2001; 12: 4: 152-156.
[67] Kolehmainen M, Vidal H, Ohisalo JJ, Pirinen E, Alhava E and Uusitupa MI.
Hormone sensitive lipase expression and adipose tissue metabolism show gender difference in obese subjects after weight loss. Int J Obes Relat Metab Disord 2001; 26:
1: 6-16.
[68] Kovanen PT and Nikkila EA. Cholesterol exchange between fat cells, chylomicrons and plasma lipoproteins. Biochim Biophys Acta 1976; 441: 3: 357-369.
[69] Kraemer FB and Shen WJ. Hormone-sensitive lipase: control of intracellular tri-(di-) acylglycerol and cholesteryl ester hydrolysis. J Lipid Res 2002; 43: 10: 1585-1594.
[70] Kraemer FB, Shen WJ, Natu V, Patel S, Osuga J, Ishibashi S and Azhar S. Adrenal neutral cholesteryl ester hydrolase: identification, subcellular distribution, and sex differences. Endocrinology 2002; 143: 3: 801-806.
[71] Krause BR and Hartman AD. Adipose tissue and cholesterol metabolism. J Lipid Res 1984; 25: 2: 97-110.
[72] Krone N, Hughes BA, Lavery GG, Stewart PM, Arlt W and Shackleton CHL. Gas chromatography/mass spectrometry (GC/MS) remains a pre-eminent discovery tool in clinical steroid investigations even in the era of fast liquid chromatography tandem mass spectrometry (LC/MS/MS). J Steroid Biochem Mol Biol 2010; 121: 3-5: 496-504.
[73] Kuohung W, Shwaery GT and Keaney JF,Jr. Tamoxifen, esterified estradiol, and physiologic concentrations of estradiol inhibit oxidation of low-density lipoprotein by endothelial cells. Am J Obstet Gynecol 2001; 184: 6: 1060-1063.
[74] Labrie F, Bélanger A, Cusan L and Candas B. Physiological Changes in Dehydroepiandrosterone Are Not Reflected by Serum Levels of Active Androgens and Estrogens But of Their Metabolites: Intracrinology. J Clin Endocrinol Metab 1997a; 82:
8: 2403-2409.
[75] Labrie F, Bélanger A, Cusan L, Gomez J and Candas B. Marked Decline in Serum Concentrations of Adrenal C19 Sex Steroid Precursors and Conjugated Androgen Metabolites During Aging. J Clin Endocrinol Metab 1997b; 82: 8: 2396-2402.
[76] Labrie F, Luu-The V, Bélanger A, Lin S, Simard J, Pelletier G and Labrie C. Is dehydroepiandrosterone a hormone? J Endocrinol 2005; 187: 2: 169-196.
[77] Labrie F, Bélanger A, Bélanger P, Bérubé R, Martel C, Cusan L, Gomez J, Candas B, Castiel I, Chaussade V, Deloche C and Leclaire J. Androgen glucuronides, instead of testosterone, as the new markers of androgenic activity in women. J Steroid Biochem Mol Biol 2006; 99: 4-5: 182-188.
[78] Labrie F, Bélanger A, Bélanger P, Bérubé R, Martel C, Cusan L, Gomez J, Candas B, Chaussade V, Castiel I, Deloche C and Leclaire J. Metabolism of DHEA in postmenopausal women following percutaneous administration. J Steroid Biochem Mol Biol 2007; 103: 2: 178-188.
[79] Labrie F, Martel C and Balser J. Wide distribution of the serum dehydroepiandrosterone and sex steroid levels in postmenopausal women: role of the ovary? Menopause 2011; 18: 1: 30-43.
[80] Larner JM and Hochberg RB. The clearance and metabolism of estradiol and estradiol-17-esters in the rat. Endocrinology 1985; 117: 3: 1209-1214.
[81] Larner JM, MacLusky NJ and Hochberg RB. The naturally occurring C-17 fatty acid esters of estradiol are long-acting estrogens. J Steroid Biochem 1985; 22: 3: 407-413.
[82] Larner JM, Rosner W and Hochberg RB. Binding of estradiol-17-fatty acid esters to plasma proteins. Endocrinology 1987; 121: 2: 738-744.
[83] Larner JM, Shackleton CHL, Roitman E, Schwartz PE and Hochberg RB.
Measurement of estradiol-17-fatty acid esters in human tissues. J Clin Endocrinol Metab 1992; 75: 1: 195-200.
[84] Larner JM, Pahuja SL, Shackleton CH, McMurray WJ, Giordano G and Hochberg RB. The isolation and characterization of estradiol-fatty acid esters in human ovarian follicular fluid. Identification of an endogenous long-lived and potent family of estrogens. J Biol Chem 1993; 268: 19: 13893-13899.
[85] Lavallée B, Provost PR, Roy R, Gauthier MC and Bélanger A.
Dehydroepiandrosterone-fatty acid esters in human plasma: formation, transport and delivery to steroid target tissues. J Endocrinol 1996a; 150: Suppl: S119-124.
[86] Lavallée B, Provost PR and Bélanger A. Formation of pregnenolone- and dehydroepiandrosterone-fatty acid esters by lecithin-cholesterol acyltransferase in human plasma high density lipoproteins. Biochim Biophys Acta 1996b; 1299: 3: 306-312.
[87] Lavallée B, Provost PR, Kahwash Z, Nestler JE and Bélanger A. Effect of insulin on serum levels of dehydroepiandrosterone metabolites in men. Clin Endocrinol (Oxf) 1997; 46: 1: 93-100.
[88] Lee FT and Adams JB. Solubilisation and reconstitution of acylcoenzyme A:estradiol-17 beta acyltransferase. Biochem Biophys Res Commun 1987; 144: 2: 569-575.
[89] Lee F, Adams JB, Garton AJ and Yeaman SJ. Hormone-sensitive lipase is involved in the hydrolysis of lipoidal derivatives of estrogens and other steroid hormones. Biochim Biophys Acta 1988; 963: 2: 258-264.
[90] Lee JS, Ettinger B, Stanczyk FZ, Vittinghoff E, Hanes V, Cauley JA, Chandler W, Settlage J, Beattie MS, Folkerd E, Dowsett M, Grady D and Cummings SR. Comparison of methods to measure low serum estradiol levels in postmenopausal women. J Clin Endocrinol Metab 2006; 91: 10: 3791-3797.
[91] Levin ER. Cellular Functions of the Plasma Membrane Estrogen Receptor. Trends Endocrinol Metab 1999; 10: 9: 374-377.
[91] Levin ER. Cellular Functions of the Plasma Membrane Estrogen Receptor. Trends Endocrinol Metab 1999; 10: 9: 374-377.