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Molecular biology and physiology of estrogen action

Authors
Sylvia Curtis Hewitt, MS
Kenneth S Korach, PhD
Section Editors
Peter J Snyder, MD
William F Crowley, Jr, MD
Deputy Editor
Kathryn A Martin, MD

INTRODUCTION

Estrogens act most importantly on the reproductive organs, but they also act on other organ systems such as cardiovascular, skeletal, immune, gastrointestinal, and neural sites [1-4]. Examples of the sites of responses to estrogen and the clinical consequences for the activity of estrogen in both females and males are summarized in the figure (figure 1). Their major actions are genomic, mediated by nuclear estrogen receptors (ERs), but they also have non-genomic actions.

The molecular mechanisms of estrogen action will be reviewed here; the physiological actions of estrogens and estrogen analogues (selective estrogen receptor modulators [SERMs]) are discussed separately. (See "Physiology of the normal menstrual cycle" and "Mechanisms of action of selective estrogen receptor modulators and down-regulators" and "Estrogen and cognitive function".)

ESTROGEN RECEPTORS

The genomic actions of estrogens are mediated via estrogen receptors (ERs), which are proteins that bind estrogens with high affinity and specificity. These receptors are members of a family of nuclear hormone receptors that include receptors that bind other steroids, thyroid hormone, and retinoids, and receptors such as peroxisome proliferator-activated receptor (PPAR), farnesoid X receptor (FXR), and liver X receptor (LXR) that mediate metabolic processes [5], as well as many “orphan” receptors for which no ligands have been identified. All these receptors function as ligand-modulated nuclear transcription factors [6-9].

Two ER molecules have been identified: the original ER-alpha, and the ER-beta [10,11]. Their structures are similar to those of the other members of this family of receptors [12,13]. The key components are the C or DNA-binding domain, which binds with high affinity and specificity to DNA sequences (estrogen response elements [EREs]) to regulate transcription rates of target genes, and the E or ligand-binding domain, which binds estrogens and estrogen analogues. (See "Mechanisms of action of selective estrogen receptor modulators and down-regulators".)

The consensus ERE is a 13-base-pair inverted-repeat DNA sequence (GGTCAnnnTGACC), to which dimers of ER complexes bind with high affinity and specificity [14,15], with one receptor molecule in contact with each five-base-pair segment of the response element [16]. Dimerization of ER complexes is facilitated by receptor binding to a response element. Additional sequences located in the ligand-binding domain of the receptor also are involved in dimerization [11,14], as demonstrated by the formation of homodimers by truncated receptors containing only a ligand-binding domain [17].

              

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References
Top
  1. Deroo BJ, Korach KS. Estrogen receptors and human disease. J Clin Invest 2006; 116:561.
  2. Mauvais-Jarvis F, Clegg DJ, Hevener AL. The role of estrogens in control of energy balance and glucose homeostasis. Endocr Rev 2013; 34:309.
  3. Cui J, Shen Y, Li R. Estrogen synthesis and signaling pathways during aging: from periphery to brain. Trends Mol Med 2013; 19:197.
  4. Nelson ER, Wardell SE, McDonnell DP. The molecular mechanisms underlying the pharmacological actions of estrogens, SERMs and oxysterols: implications for the treatment and prevention of osteoporosis. Bone 2013; 53:42.
  5. Huang P, Chandra V, Rastinejad F. Structural overview of the nuclear receptor superfamily: insights into physiology and therapeutics. Annu Rev Physiol 2010; 72:247.
  6. Mangelsdorf DJ, Thummel C, Beato M, et al. The nuclear receptor superfamily: the second decade. Cell 1995; 83:835.
  7. Acevedo ML, Kraus WL. Transcriptional activation by nuclear receptors. Essays Biochem 2004; 40:73.
  8. McEwan IJ. Sex, drugs and gene expression: signalling by members of the nuclear receptor superfamily. Essays Biochem 2004; 40:1.
  9. Brélivet Y, Rochel N, Moras D. Structural analysis of nuclear receptors: from isolated domains to integral proteins. Mol Cell Endocrinol 2012; 348:466.
  10. Gibson DA, Saunders PT. Estrogen dependent signaling in reproductive tissues - a role for estrogen receptors and estrogen related receptors. Mol Cell Endocrinol 2012; 348:361.
  11. Kumar R, Zakharov MN, Khan SH, et al. The dynamic structure of the estrogen receptor. J Amino Acids 2011; 2011:812540.
  12. Tsai MJ, O'Malley BW. Molecular mechanisms of action of steroid/thyroid receptor superfamily members. Annu Rev Biochem 1994; 63:451.
  13. Heldring N, Pike A, Andersson S, et al. Estrogen receptors: how do they signal and what are their targets. Physiol Rev 2007; 87:905.
  14. Glass CK. Differential recognition of target genes by nuclear receptor monomers, dimers, and heterodimers. Endocr Rev 1994; 15:391.
  15. Maggi A. Liganded and unliganded activation of estrogen receptor and hormone replacement therapies. Biochim Biophys Acta 2011; 1812:1054.
  16. Klinge CM. Estrogen receptor interaction with estrogen response elements. Nucleic Acids Res 2001; 29:2905.
  17. Pike AC, Brzozowski AM, Hubbard RE. A structural biologist's view of the oestrogen receptor. J Steroid Biochem Mol Biol 2000; 74:261.
  18. Hall JM, McDonnell DP. Coregulators in nuclear estrogen receptor action: from concept to therapeutic targeting. Mol Interv 2005; 5:343.
  19. Edwards DP. The role of coactivators and corepressors in the biology and mechanism of action of steroid hormone receptors. J Mammary Gland Biol Neoplasia 2000; 5:307.
  20. Parker MG. Transcriptional activation by oestrogen receptors. Biochem Soc Symp 1998; 63:45.
  21. McKenna NJ, Lanz RB, O'Malley BW. Nuclear receptor coregulators: cellular and molecular biology. Endocr Rev 1999; 20:321.
  22. Johnson AB, O'Malley BW. Steroid receptor coactivators 1, 2, and 3: critical regulators of nuclear receptor activity and steroid receptor modulator (SRM)-based cancer therapy. Mol Cell Endocrinol 2012; 348:430.
  23. Bulynko YA, O'Malley BW. Nuclear receptor coactivators: structural and functional biochemistry. Biochemistry 2011; 50:313.
  24. O'Malley BW, Malovannaya A, Qin J. Minireview: nuclear receptor and coregulator proteomics--2012 and beyond. Mol Endocrinol 2012; 26:1646.
  25. Biddie SC, John S. Minireview: Conversing with chromatin: the language of nuclear receptors. Mol Endocrinol 2014; 28:3.
  26. Thomas S, Munster PN. Histone deacetylase inhibitor induced modulation of anti-estrogen therapy. Cancer Lett 2009; 280:184.
  27. Hewitt SC, Harrell JC, Korach KS. Lessons in estrogen biology from knockout and transgenic animals. Annu Rev Physiol 2005; 67:285.
  28. Gao H, Dahlman-Wright K. The gene regulatory networks controlled by estrogens. Mol Cell Endocrinol 2011; 334:83.
  29. Welboren WJ, Stunnenberg HG, Sweep FC, Span PN. Identifying estrogen receptor target genes. Mol Oncol 2007; 1:138.
  30. Carroll JS, Brown M. Estrogen receptor target gene: an evolving concept. Mol Endocrinol 2006; 20:1707.
  31. Fu X, Huang C, Schiff R. More on FOX News: FOXA1 on the horizon of estrogen receptor function and endocrine response. Breast Cancer Res 2011; 13:307.
  32. Zaret KS, Carroll JS. Pioneer transcription factors: establishing competence for gene expression. Genes Dev 2011; 25:2227.
  33. Hewitt SC, Li L, Grimm SA, et al. Research resource: whole-genome estrogen receptor α binding in mouse uterine tissue revealed by ChIP-seq. Mol Endocrinol 2012; 26:887.
  34. Kushner PJ, Agard DA, Greene GL, et al. Estrogen receptor pathways to AP-1. J Steroid Biochem Mol Biol 2000; 74:311.
  35. Safe S, Kim K. Nuclear receptor-mediated transactivation through interaction with Sp proteins. Prog Nucleic Acid Res Mol Biol 2004; 77:1.
  36. Safe S. Transcriptional activation of genes by 17 beta-estradiol through estrogen receptor-Sp1 interactions. Vitam Horm 2001; 62:231.
  37. Safe S, Kim K. Non-classical genomic estrogen receptor (ER)/specificity protein and ER/activating protein-1 signaling pathways. J Mol Endocrinol 2008; 41:263.
  38. Ahlbory-Dieker DL, Stride BD, Leder G, et al. DNA binding by estrogen receptor-alpha is essential for the transcriptional response to estrogen in the liver and the uterus. Mol Endocrinol 2009; 23:1544.
  39. Hewitt SC, Li L, Grimm SA, et al. Novel DNA motif binding activity observed in vivo with an estrogen receptor α mutant mouse. Mol Endocrinol 2014; 28:899.
  40. Curtis SW, Washburn T, Sewall C, et al. Physiological coupling of growth factor and steroid receptor signaling pathways: estrogen receptor knockout mice lack estrogen-like response to epidermal growth factor. Proc Natl Acad Sci U S A 1996; 93:12626.
  41. Yee D, Lee AV. Crosstalk between the insulin-like growth factors and estrogens in breast cancer. J Mammary Gland Biol Neoplasia 2000; 5:107.
  42. Cenni B, Picard D. Ligand-independent Activation of Steroid Receptors: New Roles for Old Players. Trends Endocrinol Metab 1999; 10:41.
  43. Kelly MJ, Levin ER. Rapid actions of plasma membrane estrogen receptors. Trends Endocrinol Metab 2001; 12:152.
  44. Levin ER. Nuclear receptor versus plasma membrane oestrogen receptor. Novartis Found Symp 2000; 230:41.
  45. Coleman KM, Smith CL. Intracellular signaling pathways: nongenomic actions of estrogens and ligand-independent activation of estrogen receptors. Front Biosci 2001; 6:D1379.
  46. Farhat MY, Abi-Younes S, Ramwell PW. Non-genomic effects of estrogen and the vessel wall. Biochem Pharmacol 1996; 51:571.
  47. Gray GA, Sharif I, Webb DJ, Seckl JR. Oestrogen and the cardiovascular system: the good, the bad and the puzzling. Trends Pharmacol Sci 2001; 22:152.
  48. Vasudevan N, Pfaff DW. Membrane-initiated actions of estrogens in neuroendocrinology: emerging principles. Endocr Rev 2007; 28:1.
  49. Hewitt SC, Deroo BJ, Korach KS. Signal transduction. A new mediator for an old hormone? Science 2005; 307:1572.
  50. Hammes SR, Levin ER. Minireview: Recent advances in extranuclear steroid receptor actions. Endocrinology 2011; 152:4489.
  51. Levin ER. Minireview: Extranuclear steroid receptors: roles in modulation of cell functions. Mol Endocrinol 2011; 25:377.
  52. Losel RM, Falkenstein E, Feuring M, et al. Nongenomic steroid action: controversies, questions, and answers. Physiol Rev 2003; 83:965.
  53. Levin ER, Pietras RJ. Estrogen receptors outside the nucleus in breast cancer. Breast Cancer Res Treat 2008; 108:351.
  54. Pietras RJ, Márquez-Garbán DC. Membrane-associated estrogen receptor signaling pathways in human cancers. Clin Cancer Res 2007; 13:4672.
  55. Thomas P, Pang Y, Filardo EJ, Dong J. Identity of an estrogen membrane receptor coupled to a G protein in human breast cancer cells. Endocrinology 2005; 146:624.
  56. Prossnitz ER, Barton M. The G-protein-coupled estrogen receptor GPER in health and disease. Nat Rev Endocrinol 2011; 7:715.
  57. Barton M. Position paper: The membrane estrogen receptor GPER--Clues and questions. Steroids 2012; 77:935.
  58. Ogawa S, Washburn TF, Taylor J, et al. Modifications of testosterone-dependent behaviors by estrogen receptor-alpha gene disruption in male mice. Endocrinology 1998; 139:5058.
  59. Hess RA, Bunick D, Lee KH, et al. A role for oestrogens in the male reproductive system. Nature 1997; 390:509.
  60. Couse JF, Korach KS. Estrogen receptor null mice: what have we learned and where will they lead us? Endocr Rev 1999; 20:358.
  61. Britt KL, Drummond AE, Cox VA, et al. An age-related ovarian phenotype in mice with targeted disruption of the Cyp 19 (aromatase) gene. Endocrinology 2000; 141:2614.
  62. Bulun SE. Aromatase deficiency and estrogen resistance: from molecular genetics to clinic. Semin Reprod Med 2000; 18:31.
  63. Carani C, Qin K, Simoni M, et al. Effect of testosterone and estradiol in a man with aromatase deficiency. N Engl J Med 1997; 337:91.
  64. Fisher CR, Graves KH, Parlow AF, Simpson ER. Characterization of mice deficient in aromatase (ArKO) because of targeted disruption of the cyp19 gene. Proc Natl Acad Sci U S A 1998; 95:6965.
  65. Grumbach MM, Auchus RJ. Estrogen: consequences and implications of human mutations in synthesis and action. J Clin Endocrinol Metab 1999; 84:4677.
  66. Oz OK, Zerwekh JE, Fisher C, et al. Bone has a sexually dimorphic response to aromatase deficiency. J Bone Miner Res 2000; 15:507.
  67. Robertson KM, O'Donnell L, Jones ME, et al. Impairment of spermatogenesis in mice lacking a functional aromatase (cyp 19) gene. Proc Natl Acad Sci U S A 1999; 96:7986.
  68. Robertson KM, Simpson ER, Lacham-Kaplan O, Jones ME. Characterization of the fertility of male aromatase knockout mice. J Androl 2001; 22:825.
  69. Simpson ER. Genetic mutations resulting in loss of aromatase activity in humans and mice. J Soc Gynecol Investig 2000; 7:S18.
  70. Dupont S, Krust A, Gansmuller A, et al. Effect of single and compound knockouts of estrogen receptors alpha (ERalpha) and beta (ERbeta) on mouse reproductive phenotypes. Development 2000; 127:4277.
  71. Hewitt SC, Kissling GE, Fieselman KE, et al. Biological and biochemical consequences of global deletion of exon 3 from the ER alpha gene. FASEB J 2010; 24:4660.
  72. Goulding EH, Hewitt SC, Nakamura N, et al. Ex3αERKO male infertility phenotype recapitulates the αERKO male phenotype. J Endocrinol 2010; 207:281.
  73. Winuthayanon W, Hewitt SC, Orvis GD, et al. Uterine epithelial estrogen receptor α is dispensable for proliferation but essential for complete biological and biochemical responses. Proc Natl Acad Sci U S A 2010; 107:19272.
  74. Arao Y, Hamilton KJ, Ray MK, et al. Estrogen receptor α AF-2 mutation results in antagonist reversal and reveals tissue selective function of estrogen receptor modulators. Proc Natl Acad Sci U S A 2011; 108:14986.
  75. Arao Y, Hamilton KJ, Goulding EH, et al. Transactivating function (AF) 2-mediated AF-1 activity of estrogen receptor α is crucial to maintain male reproductive tract function. Proc Natl Acad Sci U S A 2012; 109:21140.
  76. Jakacka M, Ito M, Martinson F, et al. An estrogen receptor (ER)alpha deoxyribonucleic acid-binding domain knock-in mutation provides evidence for nonclassical ER pathway signaling in vivo. Mol Endocrinol 2002; 16:2188.
  77. Hewitt SC, O'Brien JE, Jameson JL, et al. Selective disruption of ER{alpha} DNA-binding activity alters uterine responsiveness to estradiol. Mol Endocrinol 2009; 23:2111.
  78. Arnal JF, Fontaine C, Abot A, et al. Lessons from the dissection of the activation functions (AF-1 and AF-2) of the estrogen receptor alpha in vivo. Steroids 2013; 78:576.
  79. Adlanmerini M, Solinhac R, Abot A, et al. Mutation of the palmitoylation site of estrogen receptor α in vivo reveals tissue-specific roles for membrane versus nuclear actions. Proc Natl Acad Sci U S A 2014; 111:E283.
  80. Smith EP, Boyd J, Frank GR, et al. Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med 1994; 331:1056.
  81. Sudhir K, Chou TM, Chatterjee K, et al. Premature coronary artery disease associated with a disruptive mutation in the estrogen receptor gene in a man. Circulation 1997; 96:3774.
  82. Sudhir K, Chou TM, Messina LM, et al. Endothelial dysfunction in a man with disruptive mutation in oestrogen-receptor gene. Lancet 1997; 349:1146.
  83. Quaynor SD, Stradtman EW Jr, Kim HG, et al. Delayed puberty and estrogen resistance in a woman with estrogen receptor α variant. N Engl J Med 2013; 369:164.
  84. Smith EP, Specker B, Bachrach BE, et al. Impact on bone of an estrogen receptor-alpha gene loss of function mutation. J Clin Endocrinol Metab 2008; 93:3088.
  85. George FW, Wilson JD. Sex determination and differentiation. In: The Physiology of Reproduction, Knobil E, Neill J (Eds), Raven Press, New York 1988. p.3.
  86. Lubahn DB, Moyer JS, Golding TS, et al. Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene. Proc Natl Acad Sci U S A 1993; 90:11162.
  87. Krege JH, Hodgin JB, Couse JF, et al. Generation and reproductive phenotypes of mice lacking estrogen receptor beta. Proc Natl Acad Sci U S A 1998; 95:15677.
  88. Rumi MAK, Dhakal P, Kubota K, et al. Generation of Esr1 knockout rats using zinc finger nuclease-mediated genome editing. Endocrinology 2014; Epub ahead of print.
  89. Otto C, Fuchs I, Kauselmann G, et al. GPR30 does not mediate estrogenic responses in reproductive organs in mice. Biol Reprod 2009; 80:34.
  90. Toda K, Takeda K, Okada T, et al. Targeted disruption of the aromatase P450 gene (Cyp19) in mice and their ovarian and uterine responses to 17beta-oestradiol. J Endocrinol 2001; 170:99.
  91. Simpson ER, Jones ME. Of mice and men: the many guises of estrogens. Ernst Schering Found Symp Proc 2006; :45.
  92. Lindzey J, Jayes FL, Yates MM, et al. The bi-modal effects of estradiol on gonadotropin synthesis and secretion in female mice are dependent on estrogen receptor-alpha. J Endocrinol 2006; 191:309.
  93. Risma KA, Clay CM, Nett TM, et al. Targeted overexpression of luteinizing hormone in transgenic mice leads to infertility, polycystic ovaries, and ovarian tumors. Proc Natl Acad Sci U S A 1995; 92:1322.
  94. Couse JF, Bunch DO, Lindzey J, et al. Prevention of the polycystic ovarian phenotype and characterization of ovulatory capacity in the estrogen receptor-alpha knockout mouse. Endocrinology 1999; 140:5855.
  95. Emmen JM, Couse JF, Elmore SA, et al. In vitro growth and ovulation of follicles from ovaries of estrogen receptor (ER){alpha} and ER{beta} null mice indicate a role for ER{beta} in follicular maturation. Endocrinology 2005; 146:2817.
  96. Abot A, Fontaine C, Raymond-Letron I, et al. The AF-1 activation function of estrogen receptor α is necessary and sufficient for uterine epithelial cell proliferation in vivo. Endocrinology 2013; 154:2222.
  97. Hewitt SC, Li Y, Li L, Korach KS. Estrogen-mediated regulation of Igf1 transcription and uterine growth involves direct binding of estrogen receptor alpha to estrogen-responsive elements. J Biol Chem 2010; 285:2676.
  98. Billon-Galés A, Fontaine C, Filipe C, et al. The transactivating function 1 of estrogen receptor alpha is dispensable for the vasculoprotective actions of 17beta-estradiol. Proc Natl Acad Sci U S A 2009; 106:2053.
  99. Bocchinfuso WP, Lindzey JK, Hewitt SC, et al. Induction of mammary gland development in estrogen receptor-alpha knockout mice. Endocrinology 2000; 141:2982.
  100. Jordan VC. Chemoprevention of breast cancer with selective oestrogen-receptor modulators. Nat Rev Cancer 2007; 7:46.
  101. Ogawa S, Eng V, Taylor J, et al. Roles of estrogen receptor-alpha gene expression in reproduction-related behaviors in female mice. Endocrinology 1998; 139:5070.
  102. Ogawa S, Chan J, Chester AE, et al. Survival of reproductive behaviors in estrogen receptor beta gene-deficient (betaERKO) male and female mice. Proc Natl Acad Sci U S A 1999; 96:12887.
  103. Krezel W, Dupont S, Krust A, et al. Increased anxiety and synaptic plasticity in estrogen receptor beta -deficient mice. Proc Natl Acad Sci U S A 2001; 98:12278.
  104. Hess RA, Bunick D, Lubahn DB, et al. Morphologic changes in efferent ductules and epididymis in estrogen receptor-alpha knockout mice. J Androl 2000; 21:107.
  105. Eddy EM, Washburn TF, Bunch DO, et al. Targeted disruption of the estrogen receptor gene in male mice causes alteration of spermatogenesis and infertility. Endocrinology 1996; 137:4796.
  106. Weiss J, Bernhardt ML, Laronda MM, et al. Estrogen actions in the male reproductive system involve estrogen response element-independent pathways. Endocrinology 2008; 149:6198.
  107. Mahato D, Goulding EH, Korach KS, Eddy EM. Spermatogenic cells do not require estrogen receptor-alpha for development or function. Endocrinology 2000; 141:1273.
  108. Mahato D, Goulding EH, Korach KS, Eddy EM. Estrogen receptor-alpha is required by the supporting somatic cells for spermatogenesis. Mol Cell Endocrinol 2001; 178:57.
  109. Robertson KM, O'Donnell L, Simpson ER, Jones ME. The phenotype of the aromatase knockout mouse reveals dietary phytoestrogens impact significantly on testis function. Endocrinology 2002; 143:2913.
  110. Ogawa S, Chester AE, Hewitt SC, et al. Abolition of male sexual behaviors in mice lacking estrogen receptors alpha and beta (alpha beta ERKO). Proc Natl Acad Sci U S A 2000; 97:14737.
  111. Couse JF, Hewitt SC, Bunch DO, et al. Postnatal sex reversal of the ovaries in mice lacking estrogen receptors alpha and beta. Science 1999; 286:2328.
  112. Vidal O, Lindberg MK, Hollberg K, et al. Estrogen receptor specificity in the regulation of skeletal growth and maturation in male mice. Proc Natl Acad Sci U S A 2000; 97:5474.
  113. Windahl SH, Hollberg K, Vidal O, et al. Female estrogen receptor beta-/- mice are partially protected against age-related trabecular bone loss. J Bone Miner Res 2001; 16:1388.
  114. Karas RH, Hodgin JB, Kwoun M, et al. Estrogen inhibits the vascular injury response in estrogen receptor beta-deficient female mice. Proc Natl Acad Sci U S A 1999; 96:15133.
  115. Karas RH, Schulten H, Pare G, et al. Effects of estrogen on the vascular injury response in estrogen receptor alpha, beta (double) knockout mice. Circ Res 2001; 89:534.
  116. Pare G, Krust A, Karas RH, et al. Estrogen receptor-alpha mediates the protective effects of estrogen against vascular injury. Circ Res 2002; 90:1087.
  117. Hodgin JB, Krege JH, Reddick RL, et al. Estrogen receptor alpha is a major mediator of 17beta-estradiol's atheroprotective effects on lesion size in Apoe-/- mice. J Clin Invest 2001; 107:333.
  118. Nelson RL, Dollear T, Freels S, Persky V. The relation of age, race, and gender to the subsite location of colorectal carcinoma. Cancer 1997; 80:193.
  119. Grodstein F, Newcomb PA, Stampfer MJ. Postmenopausal hormone therapy and the risk of colorectal cancer: a review and meta-analysis. Am J Med 1999; 106:574.
  120. Weyant MJ, Carothers AM, Mahmoud NN, et al. Reciprocal expression of ERalpha and ERbeta is associated with estrogen-mediated modulation of intestinal tumorigenesis. Cancer Res 2001; 61:2547.
  121. Cho NL, Javid SH, Carothers AM, et al. Estrogen receptors alpha and beta are inhibitory modifiers of Apc-dependent tumorigenesis in the proximal colon of Min/+ mice. Cancer Res 2007; 67:2366.
  122. Wild S, Roglic G, Green A, et al. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 2004; 27:1047.
  123. Louet JF, LeMay C, Mauvais-Jarvis F. Antidiabetic actions of estrogen: insight from human and genetic mouse models. Curr Atheroscler Rep 2004; 6:180.
  124. Xu Y, Nedungadi TP, Zhu L, et al. Distinct hypothalamic neurons mediate estrogenic effects on energy homeostasis and reproduction. Cell Metab 2011; 14:453.
  125. Hart-Unger S, Korach KS. Estrogens and obesity: is it all in our heads? Cell Metab 2011; 14:435.
  126. Ribas V, Drew BG, Le JA, et al. Myeloid-specific estrogen receptor alpha deficiency impairs metabolic homeostasis and accelerates atherosclerotic lesion development. Proc Natl Acad Sci U S A 2011; 108:16457.
  127. Le May C, Chu K, Hu M, et al. Estrogens protect pancreatic beta-cells from apoptosis and prevent insulin-deficient diabetes mellitus in mice. Proc Natl Acad Sci U S A 2006; 103:9232.