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Exploring the effects of estrogen deficiency and aging on organismal homeostasis during menopause

Nature Aging volume 4, pages 1731–1744 (2024)Cite this article

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Abstract

Sex hormone signaling declines during aging, from early midlife through menopause, as a consequence of reduced circulating estrogens and decreased receptiveness to these hormones in target tissues. Estrogens preserve energy homeostasis and promote metabolic health via coordinated and simultaneous effects throughout the brain and body. Age-associated loss of estrogen production during menopause has been implicated in a higher risk for metabolic diseases and increased mortality. However, it remains unclear whether age-associated changes in homeostasis are dependent on reduced estrogen signaling during menopause. Although menopausal hormone therapies containing estrogens can alleviate symptoms, concerns about the risks involved have contributed to a broad decline in the use of these approaches. Non-hormonal therapies have emerged that target tissues or pathways with varying levels of selectivity, reducing risk. We summarize here the broad effects of estrogen loss on homeostasis during menopause, current and emerging therapies and opportunities for understanding homeostatic disruptions associated with menopause.

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Fig. 1: Overview of estrogen signaling and physiological effects.

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References

  1. Dillin, A., Gottschling, D. E. & Nyström, T. The good and the bad of being connected: the integrons of aging. Curr. Opin. Cell Biol. 26, 107–112 (2014).

    Article  CAS  PubMed  Google Scholar 

  2. Pataky, M. W., Young, W. F. & Nair, K. S. Hormonal and metabolic changes of aging and the influence of lifestyle modifications. Mayo Clin. Proc. 96, 788–814 (2021).

    CAS  Google Scholar 

  3. Roh, E., Song, D. K. & Kim, M. S. Emerging role of the brain in the homeostatic regulation of energy and glucose metabolism. Exp. Mol. Med. 48, e216 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Marsh, M. L., Oliveira, M. N. & Vieira-Potter, V. J. Adipocyte metabolism and health after the menopause: the role of exercise. Nutrients 15, 444 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Burger, H. G., Hale, G. E., Dennerstein, L. & Robertson, D. M. Cycle and hormone changes during perimenopause: the key role of ovarian function. Menopause 15, 603–612 (2008).

    PubMed  Google Scholar 

  6. Wang, X., Wang, L. & Xiang, W. Mechanisms of ovarian aging in women: a review. J. Ovarian Res. 16, 67 (2023).

    Google Scholar 

  7. Reyes, F. I., Winter, J. S. & Faiman, C. Pituitary–ovarian relationships preceding the menopause. I. A cross-sectional study of serum follice-stimulating hormone, luteinizing hormone, prolactin, estradiol, and progesterone levels. Am. J. Obstet. Gynecol. 129, 557–564 (1977).

    CAS  PubMed  Google Scholar 

  8. Longcope, C., Franz, C., Morello, C., Baker, R. & Johnston, C. C. Steroid and gonadotropin levels in women during the peri-menopausal years. Maturitas 8, 189–196 (1986).

    Article  CAS  PubMed  Google Scholar 

  9. Al-Azzawi, F. & Palacios, S. Hormonal changes during menopause. Maturitas 63, 135–137 (2009).

    Article  CAS  PubMed  Google Scholar 

  10. Ambikairajah, A., Walsh, E., Tabatabaei-Jafari, H. & Cherbuin, N. Fat mass changes during menopause: a metaanalysis. Am. J. Obstet. Gynecol. 221, 393–409 (2019).

    Article  PubMed  Google Scholar 

  11. Greendale, G. A. et al. Changes in body composition and weight during the menopause transition. JCI Insight 4, e124865 (2019).

  12. Gordon, T., Kannel, W. B., Hjortland, M. C. & McNamara, P. M. Menopause and coronary heart disease. The Framingham Study. Ann. Intern. Med. 89, 157–161 (1978).

    Article  CAS  PubMed  Google Scholar 

  13. Mendelsohn, M. E. Protective effects of estrogen on the cardiovascular system. Am. J. Cardiol. 89, 12–17 (2002).

    Article  Google Scholar 

  14. Recker, R., Lappe, J., Davies, K. & Heaney, R. Characterization of perimenopausal bone loss: a prospective study. J. Bone Miner. Res. 15, 1965–1973 (2000).

    Article  CAS  PubMed  Google Scholar 

  15. Finkelstein, J. S. et al. Bone mineral density changes during the menopause transition in a multiethnic cohort of women. J. Clin. Endocrinol. Metab. 93, 861–868 (2008).

    Article  CAS  PubMed  Google Scholar 

  16. Anagnostis, P. et al. Association between age at menopause and fracture risk: a systematic review and meta-analysis. Endocrine 63, 213–224 (2019).

    Article  CAS  PubMed  Google Scholar 

  17. Dobbs, M. B., Buckwalter, J. & Saltzman, C. Osteoporosis. Iowa Orthop. J. 19, 43–52 (1999).

  18. Sun, L. et al. FSH directly regulates bone mass. Cell 125, 247–260 (2006).

    Article  CAS  PubMed  Google Scholar 

  19. Rocca, W. A., Grossardt, B. R., de Andrade, M., Malkasian, G. D. & Melton, L. J. Survival patterns after oophorectomy in premenopausal women: a population-based cohort study. Lancet Oncol. 7, 821–828 (2006).

    Article  PubMed  Google Scholar 

  20. Parker, W. H. et al. Long-term mortality associated with oophorectomy compared with ovarian conservation in the Nurses’ Health Study. Obstet. Gynecol. 121, 709–716 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Gottschau, M. et al. Long-term health consequences after ovarian removal at benign hysterectomy: a nationwide cohort study. Ann. Intern. Med. 176, 596–604 (2023).

    Article  PubMed  Google Scholar 

  22. Melton, L. J., Crowson, C. S., Malkasian, G. D. & O’Fallon, W. M. Fracture risk following bilateral oophorectomy. J. Clin. Epidemiol. 49, 1111–1115 (1996).

    Article  PubMed  Google Scholar 

  23. Rocca, W. A. et al. Long-term effects of bilateral oophorectomy on brain aging: unanswered questions from the Mayo Clinic Cohort Study of Oophorectomy and Aging. Womens Health 5, 39–48 (2009).

    Google Scholar 

  24. Rocca, W. A. et al. Long-term risk of depressive and anxiety symptoms after early bilateral oophorectomy. Menopause 15, 1050–1059 (2008).

    Article  PubMed  Google Scholar 

  25. Jacoby, V. L. et al. Oophorectomy vs ovarian conservation with hysterectomy: cardiovascular disease, hip fracture, and cancer in the Women’s Health Initiative Observational Study. Arch. Intern. Med. 171, 760–768 (2011).

    Article  PubMed  Google Scholar 

  26. Finch, A. et al. The impact of prophylactic salpingo-oophorectomy on menopausal symptoms and sexual function in women who carry a BRCA mutation. Gynecol. Oncol. 121, 163–168 (2011).

  27. Atsma, F., Bartelink, M. L. E. L., Grobbee, D. E. & van der Schouw, Y. T. Postmenopausal status and early menopause as independent risk factors for cardiovascular disease: a meta-analysis. Menopause 13, 265–279 (2006).

    Article  PubMed  Google Scholar 

  28. Mueller, K. & Hsiao, S. Estrus- and ovariectomy-induced body weight changes: evidence for two estrogenic mechanisms. J. Comp. Physiol. Psychol. 94, 1126–1134 (1980).

    Article  CAS  PubMed  Google Scholar 

  29. Rogers, N. H., Perfield, J. W. I. I., Strissel, K. J., Obin, M. S. & Greenberg, A. S. 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 

  30. Stubbins, R. E., Holcomb, V. B., Hong, J. & Núñez, N. P. Estrogen modulates abdominal adiposity and protects female mice from obesity and impaired glucose tolerance. Eur. J. Nutr. 51, 861–870 (2012).

    Article  CAS  PubMed  Google Scholar 

  31. Wang, Y. et al. Administration of 17β-estradiol to ovariectomized obese female mice reverses obesity-hypertension through an ACE2-dependent mechanism. Am. J. Physiol. Endocrinol. Metab. 308, E1066–E1075 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Cintron, D. et al. Plasma orexin A levels in recently menopausal women during and 3 years following use of hormone therapy. Maturitas 99, 59–65 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Slonaker, J. R. The effect of the excision of different sexual organs on the development, growth and longevity of the albino rat. Am. J. Physiol. 93, 307–317 (1930).

    Article  Google Scholar 

  34. Benedusi, V. et al. Ovariectomy shortens the life span of female mice. Oncotarget 6, 10801–10811 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Asdell, S. A. & Joshi, S. R. Reproduction and longevity in the hamster and rat. Biol. Reprod. 14, 478–480 (1976).

    Article  CAS  PubMed  Google Scholar 

  36. Phelan, J. P. Reproductive Costs and Longevity in the House Mouse. Ph.D. thesis, Harvard Univ. (1995).

  37. Mühlbock, O. Factors influencing the life-span of inbred mice. Gerontologia 3, 177–183 (2009).

    Article  Google Scholar 

  38. Arriola Apelo, S. I. et al. Ovariectomy uncouples lifespan from metabolic health and reveals a sex-hormone-dependent role of hepatic mTORC2 in aging. eLife 9, e56177 (2020).

  39. Strong, R. et al. Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α-glucosidase inhibitor or a Nrf2-inducer. Aging Cell 15, 872–884 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Harrison, D. E. et al. 17-α-estradiol late in life extends lifespan in aging UM-HET3 male mice; nicotinamide riboside and three other drugs do not affect lifespan in either sex. Aging Cell 20, e13328 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Garratt, M., Bower, B., Garcia, G. G. & Miller, R. A. Sex differences in lifespan extension with acarbose and 17-α estradiol: gonadal hormones underlie male-specific improvements in glucose tolerance and mTORC2 signaling. Aging Cell 16, 1256–1266 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Stout, M. B. et al. 17α-estradiol alleviates age-related metabolic and inflammatory dysfunction in male mice without inducing feminization. J. Gerontol. A Biol. Sci. Med. Sci. 72, 3–15 (2017).

    Article  CAS  PubMed  Google Scholar 

  43. Camon, C. et al. Systemic metabolic benefits of 17α-estradiol are not exclusively mediated by ERα in glutamatergic or GABAergic neurons. Geroscience 46, 6127–6140 (2024).

  44. Garratt, M. et al. 17-α estradiol ameliorates age-associated sarcopenia and improves late-life physical function in male mice but not in females or castrated males. Aging Cell 18, e12920 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Mann, S. N. et al. Health benefits attributed to 17α-estradiol, a lifespan-extending compound, are mediated through estrogen receptor α. eLife 9, e59616 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Steyn, F. J. et al. 17α‐estradiol acts through hypothalamic pro‐opiomelanocortin expressing neurons to reduce feeding behavior. Aging Cell 17, e12703 (2018).

    Article  PubMed  Google Scholar 

  47. Regan, J. C. & Partridge, L. Gender and longevity: why do men die earlier than women? Comparative and experimental evidence. Best Pract. Res. Clin. Endocrinol. Metab. 27, 467–479 (2013).

    Article  PubMed  Google Scholar 

  48. Austad, S. N. & Fischer, K. E. Sex differences in lifespan. Cell Metab. 23, 1022–1033 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Miller, R. A. et al. Lifespan effects in male UM-HET3 mice treated with sodium thiosulfate, 16-hydroxyestriol, and late-start canagliflozin. Geroscience 46, 4657–4670 (2024).

  50. Cargill, S. L., Carey, J. R., Müller, H. G. & Anderson, G. Age of ovary determines remaining life expectancy in old ovariectomized mice. Aging Cell 2, 185–190 (2003).

    Article  CAS  PubMed  Google Scholar 

  51. Mason, J. B., Cargill, S. L., Anderson, G. B. & Carey, J. R. Transplantation of young ovaries to old mice increased life span in transplant recipients. J. Gerontol. A Biol. Sci. Med. Sci. 64A, 1207–1211 (2009).

    Article  PubMed Central  Google Scholar 

  52. Mason, J. B. et al. Transplantation of young ovaries restored cardioprotective influence in postreproductive-aged mice. Aging Cell 10, 448–456 (2011).

    Article  CAS  PubMed  Google Scholar 

  53. Habermehl, T. L. et al. Extension of longevity and reduction of inflammation is ovarian-dependent, but germ cell-independent in post-reproductive female mice. Geroscience 41, 25–38 (2019).

    Article  CAS  PubMed  Google Scholar 

  54. Buffenstein, R., Poppitt, S. D., McDevitt, R. M. & Prentice, A. M. Food intake and the menstrual cycle: a retrospective analysis, with implications for appetite research. Physiol. Behav. 58, 1067–1077 (1995).

    Article  CAS  PubMed  Google Scholar 

  55. Fessler, D. M. T. No time to eat: an adaptationist account of periovulatory behavioral changes. Q. Rev. Biol. 78, 3–21 (2003).

    Article  PubMed  Google Scholar 

  56. Slonaker, J. R. The effect of pubescence, oestruation and menopause on the voluntary activity in the albino rat. Am. J. Physiol. 68, 294–315 (1924).

    Article  Google Scholar 

  57. Brobeck, J. R., Wheatland, M. & Strominger, J. L. Variations in regulation of energy exchange associated with estrus, diestrus and pseudopregnancy in rats. Endocrinology 40, 65–72 (1947).

    Article  CAS  PubMed  Google Scholar 

  58. Kopp, C., Ressel, V., Wigger, E. & Tobler, I. Influence of estrus cycle and ageing on activity patterns in two inbred mouse strains. Behav. Brain Res. 167, 165–174 (2006).

    CAS  Google Scholar 

  59. Olofsson, L. E., Pierce, A. A. & Xu, A. W. Functional requirement of AgRP and NPY neurons in ovarian cycle-dependent regulation of food intake. Proc. Natl Acad. Sci. USA 106, 15932–15937 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Sanchez-Alavez, M., Alboni, S. & Conti, B. Sex- and age-specific differences in core body temperature of C57Bl/6 mice. Age 33, 89–99 (2011).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Park, S. et al. Repressor of estrogen receptor activity (REA) is essential for mammary gland morphogenesis and functional activities: studies in conditional knockout mice. Endocrinology 152, 4336–4349 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. 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 

  64. Geary, N., Asarian, L., Korach, K. S., Pfaff, D. W. & Ogawa, S. Deficits in E2-dependent control of feeding, weight gain, and cholecystokinin satiation in ER-α null mice. Endocrinology 142, 4751–4757 (2001).

    Article  CAS  PubMed  Google Scholar 

  65. Roepke, T. A. et al. Genes associated with membrane-initiated signaling of estrogen and energy homeostasis. Endocrinology 149, 6113–6124 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  67. Correa, S. M. et al. An estrogen-responsive module in the ventromedial hypothalamus selectively drives sex-specific activity in females. Cell Rep. 10, 62–74 (2015).

    Article  CAS  PubMed  Google Scholar 

  68. 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 

  69. Krause, W. C. et al. Estrogen drives brain melanocortin to increase physical activity in females. Nature 599, 131–135 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Spiteri, T., Ogawa, S., Musatov, S., Pfaff, D. W. & Agmo, A. The role of the estrogen receptor α in the medial preoptic area in sexual incentive motivation, proceptivity and receptivity, anxiety, and wheel running in female rats. Behav. Brain Res. 230, 11–20 (2012).

    CAS  Google Scholar 

  71. Santollo, J. & Daniels, D. Anorexigenic effects of estradiol in the medial preoptic area occur through membrane-associated estrogen receptors and metabotropic glutamate receptors. Horm. Behav. 107, 20–25 (2019).

    Article  CAS  PubMed  Google Scholar 

  72. Puelles, L. Survey of midbrain, diencephalon, and hypothalamus neuroanatomic terms whose prosomeric definition conflicts with columnar tradition. Front. Neuroanat. 13, 20 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Xu, P. et al. Estrogen receptor-α in medial amygdala neurons regulates body weight. J. Clin. Invest. 125, 2861–2876 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Wilson, M. E. et al. Age differentially influences estrogen receptor-α (ERα) and estrogen receptor-β (ERβ) gene expression in specific regions of the rat brain. Mech. Ageing Dev. 123, 593–601 (2002).

    Article  CAS  PubMed  Google Scholar 

  75. Thakur, M. K. & Sharma, P. K. Aging of brain: role of estrogen. Neurochem. Res. 31, 1389–1398 (2006).

    Article  CAS  PubMed  Google Scholar 

  76. Foster, T. C., Sharrow, K. M., Kumar, A. & Masse, J. Interaction of age and chronic estradiol replacement on memory and markers of brain aging. Neurobiol. Aging 24, 839–852 (2003).

    Article  CAS  PubMed  Google Scholar 

  77. Hajdarovic, K. H. et al. Single-cell analysis of the aging female mouse hypothalamus. Nat. Aging 2, 662–678 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Sharma, G. & Prossnitz, E. R. Targeting the G protein-coupled estrogen receptor (GPER) in obesity and diabetes. Endocr. Metab. Sci. 2, 100080 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Davis, K. E. et al. Sexually dimorphic role of G protein-coupled estrogen receptor (GPER) in modulating energy homeostasis. Horm. Behav. 66, 196–207 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Della Torre, S. et al. Amino acid-dependent activation of liver estrogen receptor α integrates metabolic and reproductive functions via IGF-1. Cell Metab. 13, 205–214 (2011).

    Article  PubMed  Google Scholar 

  81. Mondal, S. A. et al. Metabolic benefits of 17α-estradiol in liver are partially mediated by ERβ in male mice. Sci. Rep. 13, 9841 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. 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 

  83. Dahlman, I. et al. Estrogen receptor α gene variants associate with type 2 diabetes and fasting plasma glucose. Pharmacogenet. Genomics 18, 967–975 (2008).

    Article  PubMed  Google Scholar 

  84. Chow, J. D. Y., Jones, M. E. E., Prelle, K., Simpson, E. R. & Boon, W. C. A selective estrogen receptor α agonist ameliorates hepatic steatosis in the male aromatase knockout mouse. J. Endocrinol. 210, 323–334 (2011).

    Article  CAS  PubMed  Google Scholar 

  85. Della Torre, S. et al. An essential role for liver ERα in coupling hepatic metabolism to the reproductive cycle. Cell Rep. 15, 360–371 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Francavilla, A. et al. Regenerating rat liver: correlations between estrogen receptor localization and deoxyribonucleic acid synthesis. Gastroenterology 86, 552–557 (1984).

    Article  CAS  PubMed  Google Scholar 

  87. Srisowanna, N. et al. The effect of estrogen on hepatic fat accumulation during early phase of liver regeneration after partial hepatectomy in rats. Acta Histochem. Cytochem. 52, 67–75 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Kim, S. E., Min, J. S., Lee, S., Lee, D. Y. & Choi, D. Different effects of menopausal hormone therapy on non-alcoholic fatty liver disease based on the route of estrogen administration. Sci. Rep. 13, 15461 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Mattsson, L. A. et al. Efficacy and tolerability of continuous combined hormone replacement therapy in early postmenopausal women. Menopause Int. 13, 124–131 (2007).

    Article  CAS  PubMed  Google Scholar 

  90. Wang, Y., Wang, Y., Liu, L. & Cui, H. Ovariectomy induces abdominal fat accumulation by improving gonadotropin-releasing hormone secretion in mouse. Biochem. Biophys. Res. Commun. 588, 111–117 (2022).

    Article  CAS  PubMed  Google Scholar 

  91. Nishio, E. et al. Lack of association of ovariectomy-induced obesity with overeating and the reduction of physical activities. Biochem. Biophys. Rep. 20, 100671 (2019).

    PubMed  PubMed Central  Google Scholar 

  92. Camara, C. et al. Effect of ovariectomy on serum adiponectin levels and visceral fat in rats. J. Huazhong Univ. Sci. Technolog. Med. Sci. 34, 825–829 (2014).

    CAS  Google Scholar 

  93. 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 

  94. Richard, A. J., White, U., Elks, C. M. & Stephens, J. M. Adipose tissue: physiology to metabolic dysfunction. In Endotext (eds Feingold, K. R. et al.) (MDText.com, 2000).

  95. Trayhurn, P. & Beattie, J. H. Physiological role of adipose tissue: white adipose tissue as an endocrine and secretory organ. Proc. Nutr. Soc. 60, 329–339 (2001).

    Article  CAS  PubMed  Google Scholar 

  96. Cannon, B. & Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004).

    Article  CAS  PubMed  Google Scholar 

  97. Carpentier, A. C. et al. Brown adipose tissue energy metabolism in humans. Front. Endocrinol. 9, 447 (2018).

    Article  Google Scholar 

  98. Heilbronn, L. K. et al. Effect of 6-mo. calorie restriction on biomarkers of longevity, metabolic adaptation and oxidative stress in overweight subjects. JAMA 295, 1539–1548 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Neff, L. M. et al. Core body temperature is lower in postmenopausal women than premenopausal women: potential implications for energy metabolism and midlife weight gain. Cardiovasc. Endocrinol. 5, 151–154 (2016).

    Article  CAS  PubMed  Google Scholar 

  100. Torres Irizarry, V. C., Jiang, Y., He, Y. & Xu, P. Hypothalamic estrogen signaling and adipose tissue metabolism in energy homeostasis. Front. Endocrinol. 13, 898139 (2022).

    Article  Google Scholar 

  101. Santos, R. S. et al. Activation of estrogen receptor α induces beiging of adipocytes. Mol. Metab. 18, 51–59 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Koźniewski, K. et al. Epigenetic regulation of estrogen receptor genes’ expressions in adipose tissue in the course of obesity. Int. J. Mol. Sci. 23, 5989 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Lapid, K., Lim, A., Clegg, D. J., Zeve, D. & Graff, J. M. Oestrogen signalling in white adipose progenitor cells inhibits differentiation into brown adipose and smooth muscle cells. Nat. Commun. 5, 5196 (2014).

    Article  CAS  PubMed  Google Scholar 

  104. Schaffler, M. B. & Kennedy, O. D. Osteocyte signaling in bone. Curr. Osteoporos. Rep. 10, 118–125 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Matsuoka, K., Park, K., Ito, M., Ikeda, K. & Takeshita, S. Osteoclast-derived complement component 3a stimulates osteoblast differentiation. J. Bone Miner. Res. 29, 1522–1530 (2014).

    Article  CAS  PubMed  Google Scholar 

  106. Bonewald, L. F. & Mundy, G. R. Role of transforming growth factor β in bone remodeling: a review. Connect. Tissue Res. 23, 201–208 (1989).

    Article  CAS  PubMed  Google Scholar 

  107. Cauley, J. A. Estrogen and bone health in men and women. Steroids 99, 11–15 (2015).

    Article  CAS  PubMed  Google Scholar 

  108. Ji, M. X. & Yu, Q. Primary osteoporosis in postmenopausal women. Chronic Dis. Transl. Med. 1, 9–13 (2015).

    PubMed  PubMed Central  Google Scholar 

  109. Cheng, C. H., Chen, L. R. & Chen, K. H. Osteoporosis due to hormone imbalance: an overview of the effects of estrogen deficiency and glucocorticoid overuse on bone turnover. Int. J. Mol. Sci. 23, 1376 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Sioka, C. et al. Age at menarche, age at menopause and duration of fertility as risk factors for osteoporosis. Climacteric 13, 63–71 (2010).

    Article  CAS  PubMed  Google Scholar 

  111. Couse, J. F., Lindzey, J., Grandien, K., Gustafsson, J. Å. & Korach, K. S. Tissue distribution and quantitative analysis of estrogen receptor-α (ERα) and estrogen receptor-β (ERβ) messenger ribonucleic acid in the wild-type and ERα-knockout mouse. Endocrinology 138, 4613–4621 (1997).

    Article  CAS  PubMed  Google Scholar 

  112. Wiik, A., Ekman, M., Johansson, O., Jansson, E. & Esbjörnsson, M. Expression of both oestrogen receptor α and β in human skeletal muscle tissue. Histochem. Cell Biol. 131, 181–189 (2009).

    Article  CAS  PubMed  Google Scholar 

  113. Hevener, A. L., Ribas, V., Moore, T. M. & Zhou, Z. The impact of skeletal muscle ERα on mitochondrial function and metabolic health. Endocrinology 161, bqz017 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  114. 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 

  115. Torres, M. J. et al. 17β-estradiol directly lowers mitochondrial membrane microviscosity and improves bioenergetic function in skeletal muscle. Cell Metab. 27, 167–179 (2018).

    Article  CAS  PubMed  Google Scholar 

  116. Hansen, R. D., Raja, C., Baber, R. J., Lieberman, D. & Allen, B. J. Effects of 20-mg oestradiol implant therapy on bone mineral density, fat distribution and muscle mass in postmenopausal women. Acta Diabetol. 40, s191–s195 (2003).

    Article  CAS  PubMed  Google Scholar 

  117. Ronkainen, P. H. A. et al. Postmenopausal hormone replacement therapy modifies skeletal muscle composition and function: a study with monozygotic twin pairs. J. Appl. Physiol. 107, 25–33 (2009).

    Article  CAS  PubMed  Google Scholar 

  118. Erkkola, R. et al. Transdermal oestrogen replacement therapy in a Finnish population. Maturitas 13, 275–281 (1991).

    Article  CAS  PubMed  Google Scholar 

  119. Scharf, M. B., McDannold, M. D., Stover, R., Zaretsky, N. & Berkowitz, D. V. Effects of estrogen replacement therapy on rates of cyclic alternating patterns and hot-flush events during sleep in postmenopausal women: a pilot study. Clin. Ther. 19, 304–311 (1997).

    Article  CAS  PubMed  Google Scholar 

  120. Banks, E., Beral, V., Reeves, G., Balkwill, A., Barnes, I. & Million Women Study Collaborators. Fracture incidence in relation to the pattern of use of hormone therapy in postmenopausal women. JAMA 291, 2212–2220 (2004).

    Article  CAS  PubMed  Google Scholar 

  121. Cameron, C. R., Cohen, S., Sewell, K. & Lee, M. The art of hormone replacement therapy (HRT) in menopause management. J. Pharm. Pract. 37, 736–740 (2023).

  122. Notelovitz, M. et al. Initial 17β-estradiol dose for treating vasomotor symptoms. Obstet. Gynecol. 95, 726–731 (2000).

    CAS  PubMed  Google Scholar 

  123. MacLennan, A., Lester, S. & Moore, V. Oral oestrogen replacement therapy versus placebo for hot flushes. Cochrane Database Syst. Rev. https://doi.org/10.1002/14651858.CD002978 (2001).

  124. Goldstein, I. Recognizing and treating urogenital atrophy in postmenopausal women. J. Womens Health 19, 425–432 (2010).

    Article  Google Scholar 

  125. de Novaes Soares, C., Almeida, O. P., Joffe, H. & Cohen, L. S. Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women: a double-blind, randomized, placebo-controlled trial. Arch. Gen. Psychiatry 58, 529–534 (2001).

    Article  Google Scholar 

  126. Costa, G. B. C., Carneiro, G., Umeda, L., Pardini, D. & Zanella, M. T. Influence of menopausal hormone therapy on body composition and metabolic parameters. Biores. Open Access. 9, 80–85 (2020).

    CAS  Google Scholar 

  127. Cappelletti, M. & Wallen, K. Increasing women’s sexual desire: the comparative effectiveness of estrogens and androgens. Horm. Behav. 78, 178–193 (2016).

    Article  CAS  PubMed  Google Scholar 

  128. Cheng, Y. S. et al. Pharmacologic and hormonal treatments for menopausal sleep disturbances: a network meta-analysis of 43 randomized controlled trials and 32,271 menopausal women. Sleep Med. Rev. 57, 101469 (2021).

    Article  CAS  PubMed  Google Scholar 

  129. Pan, Z. et al. Different regimens of menopausal hormone therapy for improving sleep quality: a systematic review and meta-analysis. Menopause 29, 627–635 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  130. Lufkin, E. G. et al. Treatment of postmenopausal osteoporosis with transdermal estrogen. Ann. Intern. Med. 117, 1–9 (1992).

    Article  CAS  PubMed  Google Scholar 

  131. Lees, B. & Stevenson, J. C. The prevention of osteoporosis using sequential low-dose hormone replacement therapy with estradiol-17β and dydrogesterone. Osteoporos. Int. 12, 251–258 (2001).

    Article  CAS  PubMed  Google Scholar 

  132. Cagnacci, A. & Venier, M. The controversial history of hormone replacement therapy. Medicina 55, 602 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Buist, D. S. M. et al. Hormone therapy prescribing patterns in the United States. Obstet. Gynecol. 104, 1042–1050 (2004).

    Article  PubMed  Google Scholar 

  134. Clanget, C. et al. Patterns of hormone replacement therapy in a population-based cohort of postmenopausal German women. Changes after HERS II and WHI. Exp. Clin. Endocrinol. Diabetes 113, 529–533 (2005).

    Article  CAS  PubMed  Google Scholar 

  135. Guay, M. P., Dragomir, A., Pilon, D., Moride, Y. & Perreault, S. Changes in pattern of use, clinical characteristics and persistence rate of hormone replacement therapy among postmenopausal women after the WHI publication. Pharmacoepidemiol. Drug Saf. 16, 17–27 (2007).

    Article  PubMed  Google Scholar 

  136. Menon, U. et al. Decline in use of hormone therapy among postmenopausal women in the United Kingdom. Menopause 14, 462–467 (2007).

    Article  PubMed  Google Scholar 

  137. Ettinger, B. et al. Evolution of postmenopausal hormone therapy between 2002 and 2009. Menopause 19, 610–615 (2012).

    PubMed  Google Scholar 

  138. Mikkola, T. S. et al. Increased cardiovascular mortality risk in women discontinuing postmenopausal hormone therapy. J. Clin. Endocrinol. Metab. 100, 4588–4594 (2015).

    Article  CAS  PubMed  Google Scholar 

  139. Park, C. Y., Lim, J. Y., Kim, W. H., Kim, S. Y. & Park, H. Y. Evaluation of menopausal hormone therapy use in Korea (2002–2013): a nationwide cohort study. Maturitas 146, 57–62 (2021).

    Article  CAS  PubMed  Google Scholar 

  140. Clarkson, T. B., Meléndez, G. C. & Appt, S. E. Timing hypothesis for postmenopausal hormone therapy: its origin, current status, and future. Menopause 20, 342–353 (2013).

    Article  PubMed  Google Scholar 

  141. El Khoudary, S. R. et al. Menopause transition and cardiovascular disease risk: implications for timing of early prevention: a scientific statement from the American Heart Association. Circulation 142, e506–e532 (2020).

    Article  PubMed  Google Scholar 

  142. Hodis, H. N. et al. Vascular effects of early versus late postmenopausal treatment with estradiol. N. Engl. J. Med. 374, 1221–1231 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Ali, N. et al. The role of estrogen therapy as a protective factor for Alzheimer’s disease and dementia in postmenopausal women: a comprehensive review of the literature. Cureus 15, e43053 (2023).

    PubMed  PubMed Central  Google Scholar 

  144. Chlebowski, R. T. et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative Randomized Trial. JAMA 289, 3243–3253 (2003).

    Article  CAS  PubMed  Google Scholar 

  145. Gold, E. B. et al. Longitudinal analysis of the association between vasomotor symptoms and race/ethnicity across the menopausal transition: Study of Women’s Health Across the Nation. Am. J. Public Health 96, 1226–1235 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  146. Appling, S., Paez, K. & Allen, J. Ethnicity and vasomotor symptoms in postmenopausal women. J. Womens Health 16, 1130–1138 (2007).

    Article  Google Scholar 

  147. DeBono, N. L. et al. Race, menopausal hormone therapy, and invasive breast cancer in the Carolina Breast Cancer Study. J. Womens Health 27, 377–386 (2018).

    Article  Google Scholar 

  148. Cui, J., Shen, Y. & Li, R. Estrogen synthesis and signaling pathways during ageing: from periphery to brain. Trends Mol. Med. 19, 197–209 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Hou, N. et al. Hormone replacement therapy and breast cancer: heterogeneous risks by race, weight, and breast density. J. Natl Cancer Inst. 105, 1365–1372 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Chlebowski, R. T. et al. Estrogen alone and health outcomes in Black women by African ancestry: a secondary analyses of a randomized controlled trial. Menopause 24, 133–141 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  151. Graham, S., Archer, D. F., Simon, J. A., Ohleth, K. M. & Bernick, B. Review of menopausal hormone therapy with estradiol and progesterone versus other estrogens and progestins. Gynecol. Endocrinol. 38, 891–910 (2022).

    Article  CAS  PubMed  Google Scholar 

  152. Gompel, A. & Stuenkel, C. A. Neurokinin 3 receptor antagonists for menopausal vasomotor symptoms, an appraisal. Cell Rep. Med. 4, 101076 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Navarro, V. M. et al. Regulation of gonadotropin-releasing hormone secretion by kisspeptin/dynorphin/neurokinin B neurons in the arcuate nucleus of the mouse. J. Neurosci. 29, 11859–11866 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Clarkson, J. et al. Definition of the hypothalamic GnRH pulse generator in mice. Proc. Natl Acad. Sci. USA 114, E10216–E10223 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Rance, N. E., Dacks, P. A., Mittelman-Smith, M. A., Romanovsky, A. A. & Krajewski-Hall, S. J. Modulation of body temperature and LH secretion by hypothalamic KNDy (kisspeptin, neurokinin B and dynorphin) neurons: a novel hypothesis on the mechanism of hot flushes. Front. Neuroendocrinol. 34, 211–227 (2013).

  156. David, P. S., Smith, T. L., Nordhues, H. C. & Kling, J. M. A clinical review on paroxetine and emerging therapies for the treatment of vasomotor symptoms. Int. J. Womens Health 14, 353–361 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Chen, M. N., Lin, C. C. & Liu, C. F. Efficacy of phytoestrogens for menopausal symptoms: a meta-analysis and systematic review. Climacteric 18, 260–269 (2015).

    Article  CAS  PubMed  Google Scholar 

  158. Patisaul, H. B. & Jefferson, W. The pros and cons of phytoestrogens. Front. Neuroendocrinol. 31, 400–419 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Martinkovich, S., Shah, D., Planey, S. L. & Arnott, J. A. Selective estrogen receptor modulators: tissue specificity and clinical utility. Clin. Interv. Aging 9, 1437–1452 (2014).

    PubMed  PubMed Central  Google Scholar 

  160. Júnior, J. K., Kulak, C. A. M. & Taylor, H. S. SERMs in the prevention and treatment of postmenopausal osteoporosis: an update. Arq. Bras. Endocrinol. Metabol. 54, 200–205 (2010).

    Article  PubMed Central  Google Scholar 

  161. Emons, G., Mustea, A. & Tempfer, C. Tamoxifen and endometrial cancer: a Janus-headed drug. Cancers 12, 2535 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Mortimer, J. E. et al. Tamoxifen, hot flashes and recurrence in breast cancer. Breast Cancer Res. Treat. 108, 421–426 (2008).

    Article  CAS  PubMed  Google Scholar 

  163. Balfour, J. A. & Goa, K. L. Raloxifene. Drugs Aging 12, 335–341 (1998).

    Article  CAS  PubMed  Google Scholar 

  164. Mosca, L. et al. Effect of raloxifene on stroke and venous thromboembolism according to subgroups in postmenopausal women at increased risk of coronary heart disease. Stroke 40, 147–155 (2009).

    Article  CAS  PubMed  Google Scholar 

  165. Palacios, S. et al. Raloxifene is not associated with biologically relevant changes in hot flushes in postmenopausal women for whom therapy is appropriate. Am. J. Obstet. Gynecol. 191, 121–131 (2004).

    Article  CAS  PubMed  Google Scholar 

  166. Lello, S., Capozzi, A. & Scambia, G. The tissue-selective estrogen complex (bazedoxifene/conjugated estrogens) for the treatment of menopause. Int. J. Endocrinol. 2017, 5064725 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  167. Pinkerton, J. V., Pickar, J. H., Racketa, J. & Mirkin, S. Bazedoxifene/conjugated estrogens for menopausal symptom treatment and osteoporosis prevention. Climacteric 15, 411–418 (2012).

    Article  CAS  PubMed  Google Scholar 

  168. Shin, J. J., Kim, S. K., Lee, J. R. & Suh, C. S. Ospemifene: a novel option for the treatment of vulvovaginal atrophy. J. Menopausal Med. 23, 79–84 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  169. Goldstein, S. R. et al. A 12-month comparative study of raloxifene, estrogen, and placebo on the postmenopausal endometrium. Obstet. Gynecol. 95, 95–103 (2000).

    CAS  PubMed  Google Scholar 

  170. Prokai, L. et al. The prodrug DHED selectively delivers 17β-estradiol to the brain for treating estrogen-responsive disorders. Sci. Transl. Med. 7, 297ra113 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  171. Salinero, A. E. et al. Treatment with brain specific estrogen prodrug ameliorates cognitive effects of surgical menopause in mice. Hormones Behav. 164, 105594 (2024).

    Article  CAS  Google Scholar 

  172. Madak-Erdogan, Z. et al. Design of pathway-preferential estrogens that provide beneficial metabolic and vascular effects without stimulating reproductive tissues. Sci. Signal. 9, ra53 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  173. Zuo, Q. et al. Pathway preferential estrogens prevent hepatosteatosis due to ovariectomy and high-fat diets. Nutrients 13, 3334 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Gérard, C. & Foidart, J. M. Estetrol: from preclinical to clinical pharmacology and advances in the understanding of the molecular mechanism of action. Drugs R. D. 23, 77–92 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  175. Holinka, C. F., Brincat, M. & Coelingh Bennink, H. J. T. Preventive effect of oral estetrol in a menopausal hot flush model. Climacteric 11, 15–21 (2008).

    Article  CAS  PubMed  Google Scholar 

  176. Gaspard, U. et al. A multicenter, randomized study to select the minimum effective dose of estetrol (E4) in postmenopausal women (E4Relief): part 1. Vasomotor symptoms and overall safety. Menopause 27, 848–857 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  177. Takahashi, K. et al. Efficacy and safety of oral estriol for managing postmenopausal symptoms. Maturitas 34, 169–177 (2000).

    Article  CAS  PubMed  Google Scholar 

  178. Griesser, H., Skonietzki, S., Fischer, T., Fielder, K. & Suesskind, M. Low dose estriol pessaries for the treatment of vaginal atrophy: a double-blind placebo-controlled trial investigating the efficacy of pessaries containing 0.2 mg and 0.03 mg estriol. Maturitas 71, 360–368 (2012).

    Article  CAS  PubMed  Google Scholar 

  179. Sánchez-Rovira, P., Hirschberg, A. L., Gil-Gil, M., Bermejo-De Las Heras, B. & Nieto-Magro, C. A phase II prospective, randomized, double-blind, placebo-controlled and multicenter clinical trial to assess the safety of 0.005% estriol vaginal gel in hormone receptor-positive postmenopausal women with early stage breast cancer in treatment with aromatase inhibitor in the adjuvant setting. Oncologist 25, e1846–e1854 (2020).

    Article  PubMed  Google Scholar 

  180. Abdi, F., Mobedi, H., Mosaffa, N., Dolatian, M. & Ramezani Tehrani, F. Hormone therapy for relieving postmenopausal vasomotor symptoms: a systematic review. Arch. Iran. Med. 19, 141–146 (2016).

    PubMed  Google Scholar 

  181. Lovre, D., Lindsey, S. H. & Mauvais-Jarvis, F. Effect of menopausal hormone therapy on components of the metabolic syndrome. Ther. Adv. Cardiovasc. Dis. 11, 33–43 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  182. Raz, L. et al. Differential effects of hormone therapy on serotonin, vascular function and mood in the KEEPS. Climacteric 19, 49–59 (2016).

    Article  CAS  PubMed  Google Scholar 

  183. Fait, T. Menopause hormone therapy: latest developments and clinical practice. Drugs Context 8, 212551 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  184. Gosset, A., Pouillès, J. M. & Trémollieres, F. Menopausal hormone therapy for the management of osteoporosis. Best Pract. Res. Clin. Endocrinol. Metab. 35, 101551 (2021).

    Article  CAS  PubMed  Google Scholar 

  185. Meziou, N., Scholfield, C., Taylor, C. A. & Armstrong, H. L. Hormone therapy for sexual function in perimenopausal and postmenopausal women: a systematic review and meta-analysis update. Menopause 30, 659–671 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  186. Wright, A. C. et al. The effectiveness and value of fezolinetant for moderate-to-severe vasomotor symptoms associated with menopause: a summary from the Institute for Clinical and Economic Review’s Midwest Public Advisory Council. J. Manag. Care Spec. Pharm. 29, 692–698 (2023).

  187. Writing Group for the Women’s Health Initiative Investigators. 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).

  188. Clark, J. H. A critique of Women’s Health Initiative studies (2002-2006). Nucl. Recept. Signal. 4, e023 (2006).

    PubMed  PubMed Central  Google Scholar 

  189. Manson, J. E. et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the women’s health initiative randomized trials. JAMA 310, 1353–1368 (2013).

    Article  CAS  PubMed  Google Scholar 

  190. Grady, D. et al. Heart and Estrogen/progestin Replacement Study (HERS): design, methods, and baseline characteristics. Control. Clin. Trials. 19, 314–335 (1998).

    Article  CAS  PubMed  Google Scholar 

  191. Herrington, D. M. The HERS trial results: paradigms lost? Heart and Estrogen/progestin Replacement Study. Ann. Intern. Med. 131, 463–466 (1999).

    Article  CAS  PubMed  Google Scholar 

  192. El Khoudary, S. R. et al. The menopause transition and women’s health at midlife: a progress report from the Study of Women’s Health Across the Nation (SWAN). Menopause 26, 1213–1227 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  193. Kravitz, H. M. et al. Sleep difficulty in women at midlife: a community survey of sleep and the menopausal transition. Menopause 10, 19–28 (2003).

    PubMed  Google Scholar 

  194. Matthews, K. A. et al. Associations between depressive symptoms and inflammatory/hemostatic markers in women during the menopausal transition. Psychosom. Med. 69, 124–130 (2007).

    Article  PubMed  Google Scholar 

  195. Hodis, H. N. et al. Methods and baseline cardiovascular data from the Early versus Late Intervention Trial with Estradiol testing the menopausal hormone timing hypothesis. Menopause 22, 391–401 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  196. Miller, V. M. et al. The Kronos Early Estrogen Prevention Study (KEEPS): what have we learned? Menopause 26, 1071–1084 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  197. Mosekilde, L. et al. The Danish Osteoporosis Prevention Study (DOPS): project design and inclusion of 2000 normal perimenopausal women. Maturitas 31, 207–219 (1999).

    Article  CAS  PubMed  Google Scholar 

  198. Schierbeck, L. L. et al. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial. BMJ 345, e6409 (2012).

    Article  PubMed  Google Scholar 

  199. Shufelt, C. L. & Manson, J. E. Menopausal hormone therapy and cardiovascular disease: the role of formulation, dose, and route of delivery. J. Clin. Endocrinol. Metab. 106, 1245–1254 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  200. Rejnmark, L. et al. Response rates to oestrogen treatment in perimenopausal women: 5-year data from the Danish Osteoporosis Prevention Study (DOPS). Maturitas 48, 307–320 (2004).

    Article  CAS  PubMed  Google Scholar 

  201. Karim, R. et al. Determinants of the effect of estrogen on the progression of subclinical atherosclerosis: Estrogen in the Prevention of Atherosclerosis Trial. Menopause 12, 366–373 (2005).

    Article  PubMed  Google Scholar 

  202. Straczek, C. et al. Prothrombotic mutations, hormone therapy, and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration. Circulation 112, 3495–3500 (2005).

    Article  CAS  PubMed  Google Scholar 

  203. Hodis, H. N. et al. Estrogen in the prevention of atherosclerosis. a randomized, double-blind, placebo-controlled trial. Ann. Intern. Med. 135, 939–953 (2001).

    Article  CAS  PubMed  Google Scholar 

  204. Mosca, L. et al. Hormone replacement therapy and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation 104, 499–503 (2001).

    Article  CAS  PubMed  Google Scholar 

  205. Kelemen, M. et al. Hormone therapy and antioxidant vitamins do not improve endothelial vasodilator function in postmenopausal women with established coronary artery disease: a substudy of the Women’s Angiographic Vitamin and Estrogen (WAVE) trial. Atherosclerosis 179, 193–200 (2005).

    Article  CAS  PubMed  Google Scholar 

  206. Waters, D. D. et al. Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women: a randomized controlled trial. JAMA 288, 2432–2440 (2002).

    Article  CAS  PubMed  Google Scholar 

  207. Veerus, P. et al. Results from the Estonian postmenopausal hormone therapy trial [ISRCTN35338757]. Maturitas 55, 162–173 (2006).

    Article  CAS  PubMed  Google Scholar 

  208. Hovi, S. L., Veerus, P., Rahu, M. & Hemminki, E. Experiences of a long-term randomized controlled prevention trial in a maiden environment: Estonian Postmenopausal Hormone Therapy trial. BMC Med. Res. Methodol. 8, 51 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  209. Yang, D., Li, J., Yuan, Z. & Liu, X. Effect of hormone replacement therapy on cardiovascular outcomes: a meta-analysis of randomized controlled trials. PLoS ONE 8, e62329 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Stepniak, J. & Karbownik-Lewinska, M. 17β-estradiol prevents experimentally-induced oxidative damage to membrane lipids and nuclear DNA in porcine ovary. Syst. Biol. Reprod. Med. 62, 17–21 (2016).

    Article  CAS  PubMed  Google Scholar 

  211. Malespin, M. & Nassri, A. Endocrine diseases and the liver: an update. Clin. Liver Dis. 23, 233–246 (2019).

    Google Scholar 

  212. Hess, R. A. Estrogen in the adult male reproductive tract: a review. Reprod. Biol. Endocrinol. 1, 52 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  213. Lee, H. R., Kim, T. H. & Choi, K. C. Functions and physiological roles of two types of estrogen receptors, ERα and ERβ, identified by estrogen receptor knockout mouse. Lab Anim. Res. 28, 71–76 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  214. Hewitt, S. C., Winuthayanon, W. & Korach, K. S. What’s new in estrogen receptor action in the female reproductive tract. J. Mol. Endocrinol. 56, R55–R71 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  215. Tang, Z. R., Zhang, R., Lian, Z. X., Deng, S. L. & Yu, K. Estrogen-receptor expression and function in female reproductive disease. Cells 8, 1123 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Osterlund, M. K., Keller, E. & Hurd, Y. L. The human forebrain has discrete estrogen receptor α messenger RNA expression: high levels in the amygdaloid complex. Neuroscience 95, 333–342 (2000).

    Article  CAS  PubMed  Google Scholar 

  217. Wilson, M. E., Westberry, J. M. & Prewitt, A. K. Dynamic regulation of estrogen receptor-α gene expression in the brain: a role for promoter methylation? Front. Neuroendocrinol. 29, 375–385 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Liu, X. & Shi, H. Regulation of estrogen receptor α expression in the hypothalamus by sex steroids: implication in the regulation of energy homeostasis. Int. J. Endocrinol. 2015, 949085 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  219. Shughrue, P. J., Komm, B. & Merchenthaler, I. The distribution of estrogen receptor-β mRNA in the rat hypothalamus. Steroids 61, 678–681 (1996).

    Article  CAS  PubMed  Google Scholar 

  220. Björnström, L. & Sjöberg, M. Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes. Mol. Endocrinol. 19, 833–842 (2005).

    Article  PubMed  Google Scholar 

  221. Fuentes, N. & Silveyra, P. Estrogen receptor signaling mechanisms. Adv. Protein Chem. Struct. Biol. 116, 135–170 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Marino, M., Galluzzo, P. & Ascenzi, P. Estrogen signaling multiple pathways to impact gene transcription. Curr. Genomics 7, 497–508 (2006).

    CAS  Google Scholar 

  223. Méndez-Reséndiz, K. A. et al. Steroids and TRP channels: a close relationship. Int. J. Mol. Sci. 21, 3819 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We are grateful for scholarships to C.C. from the Elman Poole Trust, the Hope Foundation for Research on Ageing, the Collaboration of Ageing Research Excellence at the University of Otago and the Australasian Menopause Society. S.M.C. was supported by NIH grants AG066821 and DK136073.

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  1. Centre for Neuroendocrinology, Department of Anatomy, University of Otago, Dunedin, New Zealand

    Celine Camon & Michael Garratt

  2. Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA

    Celine Camon & Stephanie M. Correa

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  1. Celine Camon
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C.C. led the conceptualization and drafting of the manuscript. C.C., M.G. and S.M.C. drafted and edited the manuscript.

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Camon, C., Garratt, M. & Correa, S.M. Exploring the effects of estrogen deficiency and aging on organismal homeostasis during menopause. Nat Aging 4, 1731–1744 (2024). https://doi.org/10.1038/s43587-024-00767-0

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