Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Metabolic Messengers
  • Published:

Metabolic Messengers: oestradiol

Nature Metabolism volume 7, pages 1114–1122 (2025)Cite this article

Subjects

Abstract

Oestradiol (E2), a steroid hormone derived from cholesterol, has long been recognized for its central role in female reproduction and pathobiology of menopause. However, accumulating evidence underscores a critical role for E2 in the regulation of systemic metabolism in both women and men. The metabolic actions of E2 are predominantly mediated by oestrogen receptor α (encoded by ESR1), a nuclear receptor with heritable expression patterns and tissue-specific transcript levels highly correlated with indices of metabolic health in both sexes. Here we provide an overview of the cell-specific actions of E2 and its receptors (α and β) in modulating key metabolic pathways. We contextualize these mechanistic preclinical studies with epidemiological data linking the menopausal transition to a marked rise of metabolic disease risk and provide evidence that E2 replacement mitigates this risk by preserving metabolic health.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Timeline of important discoveries in oestrogen research from discovery to clinical application.
Fig. 2: Oestrogen receptor-mediated action on metabolism.
Fig. 3: Tissue-specific regulation of metabolism by oestradiol/ERα.

Similar content being viewed by others

References

  1. Finkelstein, J. S. et al. Gonadal steroids and body composition, strength, and sexual function in men. N. Engl. J. Med. 369, 1011–1022 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Eriksson, A. L. et al. Genetic variations in sex steroid-related genes as predictors of serum estrogen levels in men. J. Clin. Endocrinol. Metab. 94, 1033–1041 (2009).

    Article  CAS  PubMed  Google Scholar 

  3. Jones, M. E. et al. Aromatase-deficient (ArKO) mice have a phenotype of increased adiposity. Proc. Natl Acad. Sci. USA 97, 12735–12740 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Simpson, E. R. Sources of estrogen and their importance. J. Steroid Biochem. Mol. Biol. 86, 225–230 (2003).

    Article  CAS  PubMed  Google Scholar 

  5. Simpson, E. & Santen, R. J. Celebrating 75 years of oestradiol. J. Mol. Endocrinol. 55, T1–T20 (2015).

    Article  CAS  PubMed  Google Scholar 

  6. Tabatadze, N., Sato, S. M. & Woolley, C. S. Quantitative analysis of long-form aromatase mRNA in the male and female rat brain. PLoS ONE 9, e100628 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Cornil, C. A. On the role of brain aromatase in females: why are estrogens produced locally when they are available systemically? J. Comp. Physiol. A Neuroethol. Sens Neural Behav. Physiol. 204, 31–49 (2018).

    Article  CAS  PubMed  Google Scholar 

  8. Sondern, C. W. & Sealey, J. L. The comparative estrogenic potency of diethyl stilbestrol, estrone, estradiol and estriol. Endocrinology 27, 670–672 (1940).

    Article  CAS  Google Scholar 

  9. Punnonen, R. & Lukola, A. High-affinity binding of estrone, estradiol and estriol in human cervical myometrium and cervical and vaginal epithelium. J. Endocrinol. Invest. 5, 203–207 (1982).

    Article  CAS  PubMed  Google Scholar 

  10. Shadyab, A. H. et al. Ages at menarche and menopause and reproductive lifespan as predictors of exceptional longevity in women: the Women’s Health Initiative. Menopause 24, 35–44 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Cui, R. et al. Relationships of age at menarche and menopause, and reproductive year with mortality from cardiovascular disease in Japanese postmenopausal women: the JACC study. J. Epidemiol. 16, 177–184 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Carr, M. C. The emergence of the metabolic syndrome with menopause. J. Clin. Endocrinol. Metab. 88, 2404–2411 (2003).

    Article  CAS  PubMed  Google Scholar 

  13. Jeong, H. G. & Park, H. Metabolic disorders in menopause. Metabolites.https://doi.org/10.3390/metabo12100954 (2022).

  14. Gurka, M. J., Vishnu, A., Santen, R. J. & DeBoer, M. D. Progression of metabolic syndrome severity during the menopausal transition. J. Am. Heart Assoc. https://doi.org/10.1161/JAHA.116.003609 (2016).

  15. Greendale, G. A. et al. Changes in body composition and weight during the menopause transition. JCI Insight. https://doi.org/10.1172/jci.insight.124865 (2019).

  16. Hulley, S. et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 280, 605–613 (1998).

    Article  CAS  PubMed  Google Scholar 

  17. Rossouw, J. E. et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA 288, 321–333 (2002).

    Article  CAS  PubMed  Google Scholar 

  18. Anderson, G. L. et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 291, 1701–1712 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Lobo, R. A. Hormone-replacement therapy: current thinking. Nat. Rev. Endocrinol. 13, 220–231 (2017).

    Article  CAS  PubMed  Google Scholar 

  20. Bluming, A. Z., Hodis, H. N. & Langer, R. D. Tis but a scratch: a critical review of the Women’s Health Initiative evidence associating menopausal hormone therapy with the risk of breast cancer. Menopause 30, 1241–1245 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Lacey, J. V. Jr. The WHI ten year’s later: an epidemiologist’s view. J. Steroid Biochem. Mol. Biol. 142, 12–15 (2014).

    Article  CAS  PubMed  Google Scholar 

  22. Hodis, H. N., Collins, P., Mack, W. J. & Schierbeck, L. L. The timing hypothesis for coronary heart disease prevention with hormone therapy: past, present and future in perspective. Climacteric: J. Int. Menopause Soc. 15, 217–228 (2012).

    Article  CAS  Google Scholar 

  23. Bhupathiraju, S. N. & Stampfer, M. J. Menopausal Hormone therapy and cardiovascular disease: unraveling the role of age and time since menopause onset. Clin. Chem. 64, 861–862 (2018).

    Article  CAS  PubMed  Google Scholar 

  24. Allen, E. & Doisy, E. A. Landmark article Sept 8, 1923. An ovarian hormone. Preliminary report on its localization, extraction and partial purification, and action in test animals. JAMA 250, 2681–2683 (1983).

    Article  CAS  PubMed  Google Scholar 

  25. Doisy, E. A. The crystals of the follicular ovarian homrone. Exp. Biol. Med. 27, 417–419 (1930).

    Article  Google Scholar 

  26. Corbin, C. J. et al. Isolation of a full-length cDNA insert encoding human aromatase system cytochrome P-450 and its expression in nonsteroidogenic cells. Proc. Natl Acad. Sci. USA 85, 8948–8952 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Sanghera, M. K. et al. Immunocytochemical distribution of aromatase cytochrome P450 in the rat brain using peptide-generated polyclonal antibodies. Endocrinology 129, 2834–2844 (1991).

    Article  CAS  PubMed  Google Scholar 

  28. Kilgore, M. W., Means, G. D., Mendelson, C. R. & Simpson, E. R. Alternative promotion of aromatase P-450 expression in the human placenta. Mol. Cell. Endocrinol. 83, R9–R16 (1992).

    Article  CAS  PubMed  Google Scholar 

  29. Simpson, E. R. et al. Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis. Endocr. Rev. 15, 342–355 (1994).

    CAS  PubMed  Google Scholar 

  30. Brodie, A. M. & Santen, R. J. Aromatase in breast cancer and the role of aminoglutethimide and other aromatase inhibitors. Crit. Rev. Oncol. Hematol. 5, 361–396 (1986).

    Article  CAS  PubMed  Google Scholar 

  31. Santen, R. J., Brodie, H., Simpson, E. R., Siiteri, P. K. & Brodie, A. History of aromatase: saga of an important biological mediator and therapeutic target. Endocr. Rev. 30, 343–375 (2009).

    Article  CAS  PubMed  Google Scholar 

  32. Yi, M., Negishi, M. & Lee, S. J. Estrogen sulfotransferase (SULT1E1): its molecular regulation, polymorphisms, and clinical perspectives. J. Pers. Med. https://doi.org/10.3390/jpm11030194 (2021).

  33. Qian, Y., Deng, C. & Song, W. C. Expression of estrogen sulfotransferase in MCF-7 cells by cDNA transfection suppresses the estrogen response: potential role of the enzyme in regulating estrogen-dependent growth of breast epithelial cells. J. Pharmacol. Exp. Ther. 286, 555–560 (1998).

    Article  CAS  PubMed  Google Scholar 

  34. Falany, C. N., Wheeler, J., Oh, T. S. & Falany, J. L. Steroid sulfation by expressed human cytosolic sulfotransferases. J. Steroid Biochem. Mol. Biol. 48, 369–375 (1994).

    Article  CAS  PubMed  Google Scholar 

  35. Fashe, M., Yi, M., Sueyoshi, T. & Negishi, M. Sex-specific expression mechanism of hepatic estrogen inactivating enzyme and transporters in diabetic women. Biochem. Pharmacol. 190, 114662 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Green, S. et al. Cloning of the human oestrogen receptor cDNA. J. Steroid Biochem. 24, 77–83 (1986).

    Article  CAS  PubMed  Google Scholar 

  37. Kuiper, G. G., Enmark, E., Pelto-Huikko, M., Nilsson, S. & Gustafsson, J. A. Cloning of a novel receptor expressed in rat prostate and ovary. Proc. Natl Acad. Sci. USA 93, 5925–5930 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hewitt, S. C. & Korach, K. S. Estrogen receptors: new directions in the new millennium. Endocr. Rev. 39, 664–675 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Green, S., Kumar, V., Krust, A., Walter, P. & Chambon, P. Structural and functional domains of the estrogen receptor. Cold Spring Harb. Symp. Quant. Biol. 51, 751–758 (1986).

    Article  CAS  PubMed  Google Scholar 

  40. Helsen, C. et al. Structural basis for nuclear hormone receptor DNA binding. Mol. Cell. Endocrinol. 348, 411–417 (2012).

    Article  CAS  PubMed  Google Scholar 

  41. Ponglikitmongkol, M., Green, S. & Chambon, P. Genomic organization of the human oestrogen receptor gene. EMBO J. 7, 3385–3388 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Zhou, Z. et al. Estrogen receptor α controls metabolism in white and brown adipocytes by regulating Polg1 and mitochondrial remodeling. Sci. Transl. Med. https://doi.org/10.1126/scitranslmed.aax8096 (2020).

  43. Nilsson, M. et al. Oestrogen receptor α gene expression levels are reduced in obese compared to normal weight females. Int J. Obes. 31, 900–907 (2007).

    Article  CAS  Google Scholar 

  44. Kozniewski, K. et al. Epigenetic regulation of estrogen receptor genes’ expressions in adipose tissue in the course of obesity. Int. J. Mol. Sci. https://doi.org/10.3390/ijms23115989 (2022).

  45. Danielian, P. S., White, R., Lees, J. A. & Parker, M. G. Identification of a conserved region required for hormone dependent transcriptional activation by steroid hormone receptors. EMBO J. 11, 1025–1033 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Shang, Y., Hu, X., DiRenzo, J., Lazar, M. A. & Brown, M. Cofactor dynamics and sufficiency in estrogen receptor-regulated transcription. Cell 103, 843–852 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. McKenna, N. J., Lanz, R. B. & O’Malley, B. W. Nuclear receptor coregulators: cellular and molecular biology. Endocr. Rev. 20, 321–344 (1999).

    CAS  PubMed  Google Scholar 

  48. Arao, Y. & Korach, K. S. The physiological role of estrogen receptor functional domains. Essays Biochem. 65, 867–875 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Torres, M. J. et al. 17β-estradiol directly lowers mitochondrial membrane microviscosity and improves bioenergetic function in skeletal muscle. Cell Metab. 27, 167–79 e7 (2018).

    Article  CAS  PubMed  Google Scholar 

  50. Scheidt, H. A., Badeau, R. M. & Huster, D. Investigating the membrane orientation and transversal distribution of 17β-estradiol in lipid membranes by solid-state NMR. Chem. Phys. Lipids 163, 356–361 (2010).

    Article  CAS  PubMed  Google Scholar 

  51. Ribas, V. et al. Impaired oxidative metabolism and inflammation are associated with insulin resistance in ERα-deficient mice. Am. J. Physiol. Endocrinol. Metab. 298, E304–E319 (2010).

    Article  CAS  PubMed  Google Scholar 

  52. Ribas, V. et al. Skeletal muscle action of estrogen receptor α is critical for the maintenance of mitochondrial function and metabolic homeostasis in females. Sci. Transl. Med. 8, 334ra54 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Drew, B. G. et al. Estrogen receptor (ER)α-regulated lipocalin 2 expression in adipose tissue links obesity with breast cancer progression. J. Biol. Chem. 290, 5566–5581 (2015).

    Article  CAS  PubMed  Google Scholar 

  54. Zhou, Z. et al. Estrogen receptor alpha protects pancreatic beta-cells from apoptosis by preserving mitochondrial function and suppressing endoplasmic reticulum stress. J. Biol. Chem. 293, 4735–4751 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Ribas, V. et al. Myeloid-specific estrogen receptor alpha deficiency impairs metabolic homeostasis and accelerates atherosclerotic lesion development. Proc. Natl Acad. Sci. USA 108, 16457–16462 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Couse, J. F., Yates, M. M., Walker, V. R. & Korach, K. S. Characterization of the hypothalamic-pituitary-gonadal axis in estrogen receptor (ER) Null mice reveals hypergonadism and endocrine sex reversal in females lacking ERα but not ERβ. Mol. Endocrinol. 17, 1039–1053 (2003).

    Article  CAS  PubMed  Google Scholar 

  57. Chen, J. Q., Delannoy, M., Cooke, C. & Yager, J. D. Mitochondrial localization of ERα and ERβ in human MCF7 cells. Am. J. Physiol. Endocrinol. Metab. 286, E1011–E1022 (2004).

    Article  CAS  PubMed  Google Scholar 

  58. Chen, J. Q., Yager, J. D. & Russo, J. Regulation of mitochondrial respiratory chain structure and function by estrogens/estrogen receptors and potential physiological/pathophysiological implications. Biochim. Biophys. Acta 1746, 1–17 (2005).

    Article  CAS  PubMed  Google Scholar 

  59. Karakas, B. et al. Mitochondrial estrogen receptors alter mitochondrial priming and response to endocrine therapy in breast cancer cells. Cell Death Discov. 7, 189 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Monje, P. & Boland, R. Subcellular distribution of native estrogen receptor α and β isoforms in rabbit uterus and ovary. J. Cell. Biochem. 82, 467–479 (2001).

    Article  CAS  PubMed  Google Scholar 

  61. Melanson, E. L. et al. Regulation of energy expenditure by estradiol in premenopausal women. J. Appl Physiol. 119, 975–981 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Moorman, P. G. et al. A prospective study of weight gain after premenopausal hysterectomy. J. Women’s Health (Larchmt.). 18, 699–708 (2009).

    Article  PubMed Central  Google Scholar 

  63. Rogers, N. H. et al. Reduced energy expenditure and increased inflammation are early events in the development of ovariectomy-induced obesity. Endocrinology 150, 2161–2168 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Moran, A. L., Nelson, S. A., Landisch, R. M., Warren, G. L. & Lowe, D. A. Estradiol replacement reverses ovariectomy-induced muscle contractile and myosin dysfunction in mature female mice. J. Appl Physiol. 102, 1387–1393 (2007).

    Article  CAS  PubMed  Google Scholar 

  65. Hamilton, D. J. et al. Estrogen receptor α activation enhances mitochondrial function and systemic metabolism in high-fat-fed ovariectomized mice. Physiol Rep. https://doi.org/10.14814/phy2.12913 (2016).

  66. Said, S. A. et al. Effects of long-term dietary administration of estrogen receptor-β agonist diarylpropionitrile on ovariectomized female ICR (CD-1) mice. Geroscience 40, 393–403 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Cooke, P. S., Heine, P. A., Taylor, J. A. & Lubahn, D. B. The role of estrogen and estrogen receptor-α in male adipose tissue. Mol. Cell. Endocrinol. 178, 147–154 (2001).

    Article  CAS  PubMed  Google Scholar 

  68. Heine, P. A., Taylor, J. A., Iwamoto, G. A., Lubahn, D. B. & Cooke, P. S. Increased adipose tissue in male and female estrogen receptor-alpha knockout mice. Proc. Natl Acad. Sci. USA 97, 12729–12734 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Ohlsson, C. et al. Obesity and disturbed lipoprotein profile in estrogen receptor-α-deficient male mice. Biochem. Biophys. Res. Commun. 278, 640–645 (2000).

    Article  CAS  PubMed  Google Scholar 

  70. Osterlund, M., Kuiper, G. G., Gustafsson, J. A. & Hurd, Y. L. Differential distribution and regulation of estrogen receptor-alpha and -beta mRNA within the female rat brain. Brain Res. Mol. Brain Res. 54, 175–180 (1998).

    Article  CAS  PubMed  Google Scholar 

  71. Xu, Y. et al. Distinct hypothalamic neurons mediate estrogenic effects on energy homeostasis and reproduction. Cell Metab. 14, 453–465 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Martinez de Morentin, P. B. et al. Estradiol regulates brown adipose tissue thermogenesis via hypothalamic AMPK. Cell Metab. 20, 41–53 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Musatov, S. et al. Silencing of estrogen receptor α in the ventromedial nucleus of hypothalamus leads to metabolic syndrome. Proc. Natl Acad. Sci. USA 104, 2501–2506 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Velickovic, K. et al. Expression and subcellular localization of estrogen receptors α and β in human fetal brown adipose tissue. J. Clin. Endocrinol. Metab. 99, 151–159 (2014).

    Article  CAS  PubMed  Google Scholar 

  75. van Veen, J. E. et al. Hypothalamic estrogen receptor α establishes a sexually dimorphic regulatory node of energy expenditure. Nat. Metab. 2, 351–363 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  76. Krause, W. C. et al. Oestrogen engages brain MC4R signalling to drive physical activity in female mice. Nature 599, 131–135 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Mosca, L., Barrett-Connor, E. & Wenger, N. K. Sex/gender differences in cardiovascular disease prevention: what a difference a decade makes. Circulation 124, 2145–2154 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Allard, M. F., Schonekess, B. O., Henning, S. L., English, D. R. & Lopaschuk, G. D. Contribution of oxidative metabolism and glycolysis to ATP production in hypertrophied hearts. Am. J. Physiol. 267, H742–H750 (1994).

    CAS  PubMed  Google Scholar 

  79. Lopaschuk, G. D. & Jaswal, J. S. Energy metabolic phenotype of the cardiomyocyte during development, differentiation, and postnatal maturation. J. Cardiovasc. Pharmacol. 56, 130–140 (2010).

    Article  CAS  PubMed  Google Scholar 

  80. Herrero, P. et al. Impact of hormone replacement on myocardial fatty acid metabolism: potential role of estrogen. J. Nucl. Cardiol. 12, 574–581 (2005).

    Article  PubMed  Google Scholar 

  81. Tham, Y. K. et al. Estrogen receptor α deficiency in cardiomyocytes reprograms the heart-derived extracellular vesicle proteome and induces obesity in female mice. Nat. Cardiovasc Res. 2, 268–289 (2023).

    Article  CAS  PubMed  Google Scholar 

  82. Baskin, K. K. et al. MED13-dependent signaling from the heart confers leanness by enhancing metabolism in adipose tissue and liver. EMBO Mol. Med. 6, 1610–1621 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Dewey C. M., Spitler, K. M., Ponce, J. M., Hall, D. D. & Grueter, C. E. Cardiac-secreted factors as peripheral metabolic regulators and potential disease biomarkers. J. Am. Heart Assoc. https://doi.org/10.1161/JAHA.115.003101 (2016).

  84. Yang, W. et al. An estrogen receptor α-derived peptide improves glucose homeostasis during obesity. Nat. Commun. 15, 3410 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Qiu, S. et al. Hepatic estrogen receptor α is critical for regulation of gluconeogenesis and lipid metabolism in males. Sci. Rep. 7, 1661 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Gao, H. et al. Long-term administration of estradiol decreases expression of hepatic lipogenic genes and improves insulin sensitivity in ob/ob mice: a possible mechanism is through direct regulation of signal transducer and activator of transcription 3. Mol. Endocrinol. 20, 1287–1299 (2006).

    Article  CAS  PubMed  Google Scholar 

  87. Meda, C. et al. Hepatic ERα accounts for sex differences in the ability to cope with an excess of dietary lipids. Mol. Metab. 32, 97–108 (2020).

    Article  CAS  PubMed  Google Scholar 

  88. Zhu, L., Martinez, M. N., Emfinger, C. H., Palmisano, B. T. & Stafford, J. M. Estrogen signaling prevents diet-induced hepatic insulin resistance in male mice with obesity. Am. J. Physiol. Endocrinol. Metab. 306, E1188–E1197 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Goodman, M. P. Are all estrogens created equal? A review of oral vs. transdermal therapy. J. Women’s Health (Larchmt.). 21, 161–169 (2012).

    Article  Google Scholar 

  90. Larson, A. A., Baumann, C. W., Kyba, M. & Lowe, D. A. Oestradiol affects skeletal muscle mass, strength and satellite cells following repeated injuries. Exp. Physiol. 105, 1700–1707 (2020).

    Article  CAS  PubMed  Google Scholar 

  91. Zhou, Z. et al. Enhanced metabolic resilience and exercise adaptation of skeletal muscle in males by Esr1-induced remodeling of mitochondrial cristae-nucleoid architecture. Cell Rep. Med. 6, 102116 (2025).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Heinonen, S. et al. Mitochondria-related transcriptional signature is downregulated in adipocytes in obesity: a study of young healthy MZ twins. Diabetologia 60, 169–181 (2017).

    Article  CAS  PubMed  Google Scholar 

  93. Gannon, M., Kulkarni, R. N., Tse, H. M. & Mauvais-Jarvis, F. Sex differences underlying pancreatic islet biology and its dysfunction. Mol. Metab. 15, 82–91 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Marchese, E. et al. Enumerating β-cells in whole human islets: sex differences and associations with clinical outcomes after islet transplantation. Diabetes Care 38, e176–e177 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Mauvais-Jarvis, F., Manson, J. E., Stevenson, J. C. & Fonseca, V. A. Menopausal hormone therapy and type 2 diabetes prevention: evidence, mechanisms, and clinical implications. Endocr. Rev. 38, 173–188 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Contreras, J. L. et al. 17β-Estradiol protects isolated human pancreatic islets against proinflammatory cytokine-induced cell death: molecular mechanisms and islet functionality. Transplantation 74, 1252–1259 (2002).

    Article  CAS  PubMed  Google Scholar 

  97. Herz, C. T. et al. Sex differences in brown adipose tissue activity and cold-induced thermogenesis. Mol. Cell. Endocrinol. 534, 111365 (2021).

    Article  CAS  PubMed  Google Scholar 

  98. Cypess, A. M. et al. Identification and importance of brown adipose tissue in adult humans. N. Engl. J. Med. 360, 1509–1517 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Chella Krishnan, K. et al. Sex-specific genetic regulation of adipose mitochondria and metabolic syndrome by Ndufv2. Nat. Metab. 3, 1552–1568 (2021).

    Article  CAS  PubMed  Google Scholar 

  100. Kautzky-Willer, A., Harreiter, J. & Pacini, G. Sex and gender differences in risk, pathophysiology and complications of type 2 diabetes mellitus. Endocr. Rev. 37, 278–316 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Ahmed, F. et al. Altered expression of aromatase and estrogen receptors in adipose tissue from men with obesity or type 2 diabetes. J. Clin. Endocrinol. Metab. https://doi.org/10.1210/clinem/dgaf038 (2025).

    Article  PubMed  Google Scholar 

  102. Yin, X. et al. Adipocyte mitochondrial function is reduced in human obesity independent of fat cell size. J. Clin. Endocrinol. Metab. 99, E209–E216 (2014).

    Article  CAS  PubMed  Google Scholar 

  103. Norheim, F. et al. Gene-by-sex interactions in mitochondrial functions and cardio-metabolic traits. Cell Metab. 29, 932–49 e4 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Davis, K. E. et al. The sexually dimorphic role of adipose and adipocyte estrogen receptors in modulating adipose tissue expansion, inflammation, and fibrosis. Mol. Metab. 2, 227–242 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Saavedra-Pena, R. D. M., Taylor, N. & Rodeheffer, M. S. Insights of the role of estrogen in obesity from two models of ERα deletion. J. Mol. Endocrinol. 68, 179–194 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Cioffi, M. et al. Cytokine pattern in postmenopause. Maturitas 41, 187–192 (2002).

    Article  CAS  PubMed  Google Scholar 

  107. Ghisletti, S., Meda, C., Maggi, A. & Vegeto, E. 17β-Estradiol inhibits inflammatory gene expression by controlling NF-κB intracellular localization. Mol. Cell. Biol. 25, 2957–2968 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Hodgin, J. B. et al. Estrogen receptor α is a major mediator of 17β-estradiol’s atheroprotective effects on lesion size in Apoe-/- mice. J. Clin. Invest. 107, 333–340 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Yu, Y. et al. Systematic analysis of adverse event reports for sex differences in adverse drug events. Sci. Rep. 6, 24955 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Rushovich, T. et al. Adverse drug events by sex after adjusting for baseline rates of drug use. JAMA Netw. Open. 6, e2329074 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  111. Lee, K. M. N. et al. A gender hypothesis of sex disparities in adverse drug events. Soc. Sci. Med. 339, 116385 (2023).

    Article  PubMed  Google Scholar 

  112. Shih, Y. H., Yang, C. Y., Wang, S. J. & Lung, C. C. Menopausal hormone therapy decreases the likelihood of diabetes development in peri‑menopausal individuals with prediabetes. Diabetes Metab. 50, 101546 (2024).

    Article  CAS  PubMed  Google Scholar 

  113. Margolis, K. L. et al. Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: results from the Women’s Health Initiative Hormone Trial. Diabetologia 47, 1175–1187 (2004).

    Article  CAS  PubMed  Google Scholar 

  114. Flores, V. A., Pal, L. & Manson, J. E. Hormone therapy in menopause: concepts, controversies, and approach to treatment. Endocr. Rev. 42, 720–752 (2021).

    Article  PubMed  Google Scholar 

  115. Amar, D. et al. Temporal dynamics of the multi-omic response to endurance exercise training. Nature 629, 174–183 (2024).

    Article  Google Scholar 

  116. Wang, J. et al. Exploring the mechanisms of genome-wide long-range interactions: interpreting chromosome organization. Brief. Funct. Genomics 15, 385–395 (2016).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

A.L.H. holds the Sidney Roberts and Clara Szego Roberts Chair in Molecular and Cellular Endocrinology and her work is funded by the Iris Cantor-UCLA Women’s Health Center, UCLA Jonsson Comprehensive Cancer Center and the NIH (R01 DK128957, U54 HL170326, R01 DK060484, P30DK063491 and previously NURSA NDSP U24DK097748). S.M.C. is supported by the NIH (R01 AG066821, NIH R01 DK136073 and R21 CA249338), Iris Cantor-UCLA Women’s Health Center and Allen Distinguished Investigator Award in Sex Hormones grant no. 202211-13640.

Author information

Authors and Affiliations

  1. David Geffen School of Medicine, Department of Medicine, Division of Endocrinology and Metabolism, University of California, Los Angeles, Los Angeles, CA, USA

    Andrea L. Hevener

  2. GRECC, Greater Los Angeles VA Medical Center, Los Angeles, CA, USA

    Andrea L. Hevener

  3. Iris Cantor-UCLA Women’s Health Research Center, University of California, Los Angeles, Los Angeles, CA, USA

    Andrea L. Hevener & Stephanie M. Correa

  4. Life Sciences, Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA

    Stephanie M. Correa

Authors
  1. Andrea L. Hevener
    View author publications

    Search author on:PubMed Google Scholar

  2. Stephanie M. Correa
    View author publications

    Search author on:PubMed Google Scholar

Contributions

A.L.H. and S.M.C. jointly wrote this article.

Corresponding author

Correspondence to Andrea L. Hevener.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Metabolism thanks Sylvia Hewitt, Manuel Tena-Sempere and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editors: Jean Nakhle and Ashley Castellanos-Jankiewicz, in collaboration with the Nature Metabolism team.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hevener, A.L., Correa, S.M. Metabolic Messengers: oestradiol. Nat Metab 7, 1114–1122 (2025). https://doi.org/10.1038/s42255-025-01317-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s42255-025-01317-7

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing