Download PDF
Exp Clin Endocrinol Diabetes 2020; 128(04): 270-277
DOI: 10.1055/a-0885-1677
Review
© Georg Thieme Verlag KG Stuttgart · New York

The Case for an Estrogen-iron Axis in Health and Disease

Mawieh Hamad
1   Sharjah Institute for Medical Research, University of Sharjah, United Arab Emirates
2   Department of Medical Laboratory Sciences, College of Health Sciences, University of Sharjah, UAE
,
Khuloud Bajbouj
1   Sharjah Institute for Medical Research, University of Sharjah, United Arab Emirates
3   Department of Basic Medical Sciences, College of Medicine, University of Sharjah, UAE
,
Jalal Taneera
1   Sharjah Institute for Medical Research, University of Sharjah, United Arab Emirates
3   Department of Basic Medical Sciences, College of Medicine, University of Sharjah, UAE
› Author Affiliations Funding This work was supported by research grants 15010501005-P and 1701050126-P, University of Sharjah, UAE and grant AJF201664, Al-Jalila Foundation, Dubai, UAE.
Further Information

Publication History

received 17 October 2018
revised 24 March 2019

accepted 27 March 2019

Publication Date:
12 April 2019 (online)

Also available at
    Permissions and Reprints

Abstract

Clinical and experimental evidence suggest that estrogen manipulates intracellular iron metabolism and that elevated levels of estrogen associate with increased systemic iron availability. This has been attributed to the ability of estrogen to suppress hepcidin synthesis, maintain ferroportin integrity and enhance iron release from iron-absorbing duodenal enterocytes and iron-storing macrophages and hepatocytes. These observations speak of a potential “estrogen-iron” axis that manipulates iron metabolism in response to hematologic (erythropoiesis) and non-hematologic (uterine growth, pregnancy, lactation) needs for iron. Such an axis could contribute to minimizing iron deficiency in premenopausal women and iron overload in postmenopausal women. It could also exacerbate iron overload and related clinical consequences including cancer, osteoporosis, cardiovascular complications and neurodegenerative symptoms, especially in postmenopausal women on hormonal replacement therapy. Understanding the role of estrogen in iron metabolism may shed some light on the pleotropic, but often paradoxical, roles of estrogen in human health and disease.

Key words

hepcidin - ferritin - ferroportin - hormonal replacement therapy - iron - menopause
 

  • References

  • 1 Cui J, Yong S, Li R. Estrogen synthesis and signaling pathways during ageing: From periphery to brain. Trends Mol Med 2013; 19: 197-209
    CrossrefPubMedGoogle Scholar
  • 2 Prossnitz ER, Arterburn JB, Sklar LA. GPR30: A G protein-coupled receptor for estrogen. Mol Cell Endocrinol 2007; 265-266: 138-142
    CrossrefPubMedGoogle Scholar
  • 3 Marin R, Diaz M. Estrogen interactions with lipid rafts related to neuroprotection. Impact of brain ageing and menopause. Front Neurosci 2018; DOI: org/10.3389/fnins.2018.00128.
    CrossrefPubMedGoogle Scholar
  • 4 Björnström L, Sjöberg M. Mechanisms of estrogen receptor signaling: Convergence of genomic and nongenomic actions on target genes. Mol Endocrinol 2005; 19: 833-842
    CrossrefPubMedGoogle Scholar
  • 5 Ganz T, Nemeth E. Hepcidin and disorders of iron metabolism. Annual Reviews of Medicine 2011; 62: 347-360
    CrossrefPubMedGoogle Scholar
  • 6 Anderson GJ, Wang F. Essential but toxic: Controlling the flux of iron in the body. Clin Exp Pharmacol Physiol 2012; 39: 719-724
    CrossrefPubMedGoogle Scholar
  • 7 Nemeth E, Tuttle MS, Powelson J. et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 2004; 306: 2090-2093
    CrossrefPubMedGoogle Scholar
  • 8 Peyssonnaux C, Zinkernagel AS, Schuepbach RA. et al. Regulation of iron homeostasis by the hypoxia-inducible transcription factors [HIFs]. J Clin Invest 2007; 117: 1926-1932
    CrossrefPubMedGoogle Scholar
  • 9 Tanno T, Bhanu NV, Oneal PA. et al. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med 2007; 3: 1096-1101
    PubMedGoogle Scholar
  • 10 Silvestri L, Pagani A, Nai A. et al. The serine protease matriptase-2 [TMPRSS6] inhibits hepcidin activation by cleaving membrane hemojuvelin. Cell Metab 2008; 8: 502-511
    CrossrefPubMedGoogle Scholar
  • 11 Schmidt PJ, Toran PT, Giannetti AM. et al. The transferrin receptor modulates Hfe-dependent regulation of hepcidin expression. Cell Metab 2008; 7: 205-214
    CrossrefPubMedGoogle Scholar
  • 12 Lee P, Peng H, Gelbart T. et al. Regulation of hepcidin transcription by interleukin-1 and interleukin-6. PNAS 2005; 102: 1906-1910
    CrossrefPubMedGoogle Scholar
  • 13 Nemeth E, Rivera S, Gabayan V. et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone. J Clin Invest 2004; 113: 1271-1276
    CrossrefPubMedGoogle Scholar
  • 14 Meynard D, Kautz L, Darnaud V. et al. Lack of the bone morphogenetic protein BMP6 induces massive iron overload. Nat Genet 2009; 41: 478-481
    CrossrefPubMedGoogle Scholar
  • 15 Andriopoulos Jr B, Corradini E, Xia Y. et al. BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nat Genet 2009; 41: 482-487
    CrossrefPubMedGoogle Scholar
  • 16 Wang RH, Li C, Xu X. et al. A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell Metab 2005; 2: 399-409
    CrossrefPubMedGoogle Scholar
  • 17 Raso GM, Irace C, Esposito E. et al. Ovariectomy and estrogen treatment modulate iron metabolism in rat adipose tissue. Biochem Pharmacol 2009; 78: 1001-1007
    CrossrefPubMedGoogle Scholar
  • 18 Horiguchi H, Oguma E, Kayama F. The effects of iron deficiency on estradiol-induced suppression of erythropoietin induction in rats: Implications of pregnancy-related anemia. Blood 2005; 106: 67-74
    PubMedGoogle Scholar
  • 19 Pentecost BT, Teng CT. Lactotransferrin is the major estrogen inducible protein of mouse uterine secretions. J Biol Chem 1987; 262: 10134-10139
    CrossrefPubMedGoogle Scholar
  • 20 Stuckey R, Aldridge T, Lima FL. et al. Induction of iron homeostasis genes during estrogen-induced uterine growth and differentiation. Mol Cell Endocrinol 2006; 253: 22-29
    CrossrefPubMedGoogle Scholar
  • 21 Harrison-Findik DD. Gender-related variations in iron metabolism and liver diseases. World J Hepatol 2010; 2: 302-310
    CrossrefPubMedGoogle Scholar
  • 22 Qian Y, Zhang S, Guo W. et al. Polychlorinated Biphenyls (PCBs) Inhibit hepcidin expression through an estrogen-like effect associated with disordered systemic iron homeostasis. Chem Res Toxicol 2015; 28: 629-640
    CrossrefPubMedGoogle Scholar
  • 23 Bajbouj K, Shafarin J, Allam H. et al. Elevated levels of estrogen suppress hepcidin synthesis and enhance serum iron availability in premenopausal women. Exp Clin Endocrinol Diabetes 2018; DOI: 10.1055/s-0043-124077.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 24 Ulas M, Cay M. Effects of 17b-estradiol and vitamin E treatments on blood trace element and antioxidant enzyme levels in ovariectomized rats. Biol Trace Elem Res 2011; 139: 347-355
    CrossrefPubMedGoogle Scholar
  • 25 Huang X, Xu Y, Partridge NC. Dancing with sex hormones, could iron contribute to the gender difference in osteoporosis?. Bone 2013; 55: 458-460
    CrossrefPubMedGoogle Scholar
  • 26 Akinloye O, Adebayo TO, Oguntibeju OO. et al. Effects of contraceptives on serum trace elements, calcium and phosphorus levels. West Indian Med J 2011; 60: 308-315
    PubMedGoogle Scholar
  • 27 Milman N, Kirchhoff M, Jørgensen T. Iron status markers, serum ferritin and hemoglobin in 1359 Danish women in relation to menstruation, hormonal contraception, parity, and postmenopausal hormone treatment. Ann Hematol 1992; 65: 96-102
    CrossrefPubMedGoogle Scholar
  • 28 Lehtihet M, Bonde Y, Beckman L. et al. Circulating Hepcidin-25 is reduced by endogenous estrogen in humans. PLoS ONE 2016; 11: e0148802
    CrossrefPubMedGoogle Scholar
  • 29 Bajbouj K, Shafarin J, Abdalla MY. et al. Estrogen-induced disruption of intracellular iron metabolism leads to oxidative stress, membrane damage, and cell cycle arrest in MCF-7 cells. Tumour Biol 2017; 39: 1010428317726184
    CrossrefPubMedGoogle Scholar
  • 30 Shafarin J, Bajbouj K, El-Serafy A. et al. Estrogen-dependent downregulation of hepcidin synthesis induces intracellular iron efflux in cancer cells in vitro. Biology and Medicine 2016; 8: 356. doi:10.4172/0974-8369.1000356
    PubMedGoogle Scholar
  • 31 Yang Q, Jian J, Katz S. et al. 17β-estradiol inhibits iron hormone hepcidin through an estrogen responsive element half-site. Endocrinol 2012; 153: 3170-3178
    CrossrefPubMedGoogle Scholar
  • 32 Hou Y, Zhang S, Wang L. et al. Estrogen regulates iron homeostasis through governing hepatic hepcidin expression via an estrogen response element. Genetics 2012; 11: 398-403
    PubMedGoogle Scholar
  • 33 Hua K, Din J, Cao Q. et al. Estrogen and progestin regulate HIF-1alpha expression in ovarian cancer cell lines via the activation of Akt signaling transduction pathway. Oncol Rep 2009; 21: 893-898
    PubMedGoogle Scholar
  • 34 Kazi AA, Molitoris KH, Koos RD. Estrogen rapidly activates the PI3K/AKT pathway and hypoxia-inducible factor 1 and induces vascular endothelial growth factor A expression in luminal epithelial cells of the rat uterus. Biol Reprod 2009; 81: 378-378
    PubMedGoogle Scholar
  • 35 Ikeda Y, Tajima S, Izawa-Ishizawa Y. et al. Estrogen Regulates Hepcidin Expression via GPR30-BMP6-Dependent Signaling in Hepatocytes. PLoS ONE 2012; 7: e40465
    CrossrefPubMedGoogle Scholar
  • 36 Zhen AW, Nguyen NH, Gibert Y. et al. The small molecule, genistein, increases hepcidin expression in human hepatocytes. Hepatology 2013; 58: 1315-1325
    CrossrefPubMedGoogle Scholar
  • 37 Scott DE. Anemia in pregnancy. Obstetrics & Gynecology Annual 1972; 1: 219-244
    PubMedGoogle Scholar
  • 38 Bothwell TH. Iron requirements in pregnancy and strategies to meet them. Am J Clin Nutr 2000; 72: 257S-264S
    CrossrefPubMedGoogle Scholar
  • 39 Gao G, Liu SY, Wang HJ. et al. Effects of Pregnancy and Lactation on Iron Metabolism in Rats. Biomed Res Int 2015; ID 105325
    PubMedGoogle Scholar
  • 40 Millard KN, Frazer DM, Wilkins SJ. et al. Changes in the expression of intestinal iron transport and hepatic regulatory molecules explain the enhanced iron absorption associated with pregnancy in the rat. Gut 2004; 53: 655-660
    CrossrefPubMedGoogle Scholar
  • 41 Koenig MD, Tussing-Humphreys L, Day J. et al. Hepcidin and Iron Homeostasis during Pregnancy. Nutrients 2014; 6: 3062-3083
    CrossrefPubMedGoogle Scholar
  • 42 Buster JE, Carson SA. Placental endocrinology and diagnosis of pregnancy. In Gabbe SG, Niebyl JR, Simpson JL. eds Obstetrics: Normal and Problem Pregnancies. 2nd ed New York: Churchill Livingstone; 1991: 59-91
    Google Scholar
  • 43 Nakada D, Oguro H, Levi BP. et al. Estrogen increases haematopoietic stem cell self-renewal in females and during pregnancy. Nature 2014; 505: 555-558
    PubMedGoogle Scholar
  • 44 Bothwell TH, Charlton RW. A general approach of the problems of iron deficiency and iron overload in the population at large. Semin Hematol 1982; 19: 54-67
    PubMedGoogle Scholar
  • 45 Fairbanks VF. Iron in medicine and nutrition. In Shils ME, Shike M, Ross AC. et al. eds Modern Nutrition in Health and Disease. 10th ed Baltimore: Lippincott Williams & Wilkins; 1999: 193-221
    Google Scholar
  • 46 Zittermann A, Schwarz I, Scheld K. et al. Physiologic fluctuations of serum estradiol levels influence biochemical markers of bone resorption in young women A. J Clin Endocrinol Metab 2000; 85: 95-101
    CrossrefPubMedGoogle Scholar
  • 47 Finch CA, Bellotti V, Stray S. et al. Plasma ferritin determination as a diagnostic tool. West Journal of Medicine 1986; 145: 657-663
    PubMedGoogle Scholar
  • 48 Jian J, Pelle E, Huang X. Iron and menopause: does increased iron affect the health of postmenopausal women?. Antioxid Redox Signal 2009; 11: 2939-2943
    CrossrefPubMedGoogle Scholar
  • 49 Liu JM, Hankinson SE, Stampfer MJ. et al. Body iron stores and their determinants in healthy postmenopausal US women. Am J Clin Nutr 2003; 78: 1160-1167
    CrossrefPubMedGoogle Scholar
  • 50 Hickey M, Davis SR, Sturdee DW. Treatment of menopausal symptoms: what shall we do now?. Lancet 2005; 366: 409-421
    CrossrefPubMedGoogle Scholar
  • 51 Murday HK, Rusli FD, Blandy C. et al. Night sweats: it may be hemochromatosis. Climacteric 2016; 19: 406-408
    CrossrefPubMedGoogle Scholar
  • 52 Kim BJ, Ahn SH, Bae SJ. et al. Iron overload accelerates bone loss in healthy postmenopausal women and middle-aged men: A 3-year retrospective longitudinal study. JBMR 2012; 27: 2279-2290
    CrossrefPubMedGoogle Scholar
  • 53 Cho GJ, Shin JH, Yi KW. et al. Serum ferritin levels are associated with metabolic syndrome in postmenopausal women but not in premenopausal women. Menopause 2011; 18: 1120-1124
    CrossrefPubMedGoogle Scholar
  • 54 Sukumaran A, Chang JO, Han M. et al. Iron overload exacerbates age-associated cardiac hypertrophy in a mouse model of hemochromatosis. Sci Rep 2017; 7: 5756
    CrossrefPubMedGoogle Scholar
  • 55 Harvey RE, Coffman KE, Miller VM. Women-specific factors to consider in risk, diagnosis and treatment of cardiovascular disease. Women’s Health [Lond] 2015; 11: 239-257
    PubMedGoogle Scholar
  • 56 Dye RV, Miller KJ, Singer EJ. et al. Hormone replacement therapy and risk for neurodegenerative diseases. J Alzheimers Dis Rep 2012; 258454
    PubMedGoogle Scholar
  • 57 Brigham D, Beard J. Iron and thermoregulation: A review. Crit Rev Food Sci Nutr 1996; 36: 747-763
    CrossrefPubMedGoogle Scholar
  • 58 Zacharski LR, Ornstein DL, Woloshin S. et al. Association of age, sex, and race with body iron stores in adults: Analysis of NHANES III data. Am Heart J 2000; 140: 98-104
    CrossrefPubMedGoogle Scholar
  • 59 Fonseca-Nunes A, Jakszyn P, Agudo A. Iron and Cancer Risk – A Systematic Review and Meta-analysis of the Epidemiological Evidence. Cancer Epidemiol Biomarkers Prev 2014; 23: 12-32
    CrossrefPubMedGoogle Scholar
  • 60 Pinnix ZK, Miller LD, Wang W. et al. Ferroportin and iron regulation in breast cancer progression and prognosis. Sci Transl Med 2010; 2: 43ra56
    PubMedGoogle Scholar
  • 61 Shpyleva SI, Tryndyak VP, Kovalchuk O. et al. Role of ferritin alterations in human breast cancer cells. Breast Cancer Res Treat 2011; 126: 63-71
    CrossrefPubMedGoogle Scholar
  • 62 Yang J, Bielenberg DR, Rodig SJ. et al. Lipocalin 2 promotes breast cancer progression. PNAS 2009; 106: 3913-3918
    CrossrefPubMedGoogle Scholar
  • 63 Yang J, McNeish B, Butterfield C. et al. Lipocalin 2 is a novel regulator of angiogenesis in human breast cancer. FASEB Journal 2013; 27: 45-50
    CrossrefPubMedGoogle Scholar
  • 64 Yager JD, Davidson NE. Estrogen carcinogenesis in breast cancer. N Engl J Med 2006; 354: 27082
    PubMedGoogle Scholar
  • 65 Levenson AS, Jordan VC. MCF-7: the first hormone-responsive breast cancer cell line. Cancer Res 1997; 57: 3071-3078
    PubMedGoogle Scholar
  • 66 Jordan VC. A century of deciphering the control mechanisms of sex steroid action in breast and prostate cancer: The origins of targeted therapy and chemoprevention. Cancer Res 2009; 69: 1243-1254
    CrossrefPubMedGoogle Scholar
  • 67 Wang K, Li F, Chen L. et al. Change in risk of breast cancer after receiving hormone replacement therapy by considering effect-modifiers: a systematic review and dose-response meta-analysis of prospective studies. Oncotarget 2017; 8: 81109-81124
    CrossrefPubMedGoogle Scholar
  • 68 Kim S, Ko Y, Lee HJ. et al. Menopausal hormone therapy and the risk of breast cancer by histological type and race: a meta-analysis of randomized controlled trials and cohort studies. Breast Cancer Res Treat 2018; DOI: 10.1007/s10549-018-4782-2.
    CrossrefPubMedGoogle Scholar
  • 69 Bajbouj K, Shafarin J, Hamad M. High-Dose Deferoxamine Treatment Disrupts Intracellular Iron Homeostasis, Reduces Growth, and Induces Apoptosis in Metastatic and Nonmetastatic Breast Cancer Cell Lines. Technol Cancer Res Treat 2018; 17: 1533033818764470
    Google Scholar
  • 70 Haddow A, Watkinson JM, Paterson E. et al. Influence of synthetic oestrogens on advanced malignant disease. Br Med J 1944; 2: 393-398
    CrossrefPubMedGoogle Scholar
  • 71 Ingle JN, Ahmann DL, Green SJ. et al. Randomized clinical trial of diethylstilbestrol versus tamoxifen in postmenopausal women with advanced breast cancer. N Engl J Med 1981; 304: 16-21
    CrossrefPubMedGoogle Scholar
  • 72 Peethambaram PP, Ingle JN, Suman VJ. et al. Randomized trial of diethylstilbestrol vs. tamoxifen in postmenopausal women with metastatic breast cancer. An updated analysis. Breast Cancer Res Treat 1999; 54: 117-122
    CrossrefPubMedGoogle Scholar
  • 73 Jordan VC. The 38th David A. Karnofsky Lecture: The paradoxical actions of estrogen in breast cancer—survival or death?. J Clin Oncol 2008; 26: 3073-3082
    CrossrefPubMedGoogle Scholar
  • 74 Barrett-Connor E, Bush TL. Estrogen and coronary heart disease in women. JAMA 1991; 265: 1861-1867
    CrossrefPubMedGoogle Scholar
  • 75 Grady D, Rubin SM, Petitti DB. et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 1992; 117: 1016-1037
    PubMedGoogle Scholar
  • 76 Barrett-Connor E, Grady D. Hormone replacement therapy, heart disease, and other considerations. Annu Rev Public Health 1998; 19: 55-72
    CrossrefPubMedGoogle Scholar
  • 77 Hulley S, Grady D, Bush T. et al. Heart and Estrogen/progestin Replacement Study [HERS] Research Group Randomized Trial of Estrogen Plus Progestin for Secondary Prevention of Coronary Heart Disease in Postmenopausal Women. JAMA 1998; 280: 605-613
    CrossrefPubMedGoogle Scholar
  • 78 Rossouw JE, Anderson GL, Prentice RL. et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results From the Women’s Health Initiative randomized controlled trial. Writing Group for the Women’s Health Initiative Investigators. JAMA 2002; 288: 321-333
    CrossrefPubMedGoogle Scholar
  • 79 Tuomainen TP, Punnonen K, Nyyssönen K. et al. Association between body iron stores and the risk of acute myocardial infarction in men. Circulation 1998; 97: 1461-1466
    CrossrefPubMedGoogle Scholar
  • 80 Witztum JL, Steinberg D. Role of oxidized low density lipoprotein in atherogenesis. J Clin Invest 1991; 88: 1785-1792
    CrossrefPubMedGoogle Scholar
  • 81 Meroño T, Gómez L, Sorroche P. et al. High risk of cardiovascular disease in iron overload patients. Eur J Clin Invest 2011; 41: 479-486
    CrossrefPubMedGoogle Scholar
  • 82 Basuli D, Stevens RG, Torti FM. et al. Epidemiological associations between iron and cardiovascular disease and diabetes. Front Pharmacol 2014; 5: 117. doi:10.3389/fphar.2014.00117
    PubMedGoogle Scholar
  • 83 van der A DL, Grobbee DE, Roest M. et al. Serum ferritin is a risk factor for stroke in postmenopausal women. Stroke 2005; 36: 1637-1641
    CrossrefPubMedGoogle Scholar
  • 84 Jamshed N, Ozair FF, Aggarwal P. et al. Alzheimer disease in post-menopausal women: Intervene in the critical window period. J Medwife Health 2014; 5: 38-40
    PubMedGoogle Scholar
  • 85 Imtiaz B, Tuppurainen M, Rikkonen T. et al. Postmenopausal hormone therapy and Alzheimer disease: A prospective cohort study. Neurology 2017; 88: 1062-1068
    CrossrefPubMedGoogle Scholar
  • 86 Petitti D, Buckwalter JG, Crooks VC. et al. Prevalence of dementia in users of hormone replacement therapy as defined by prescription data. J. Gerontol A [Biological Sciences and Medical Sciences] 2002; 57: M532-M538
    CrossrefPubMedGoogle Scholar
  • 87 Lei P, Ayton S, Finkelstein DI. et al. Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export. Nat Med 2012; 18: 291-295
    CrossrefPubMedGoogle Scholar
  • 88 Popat RA, Van Den Eeden SK, Tanner CM. et al. Effect of reproductive factors and postmenopausal hormone use on the risk of Parkinson disease. Neurology 2005; 65: 383-390
    CrossrefPubMedGoogle Scholar
  • 89 Guggenbuhl P, Deugnier Y, Boisdet JF. et al. Bone mineral density in men with genetic hemochromatosis and HFE gene mutation. Osteoporos Int 2005; 16: 1809-1814
    CrossrefPubMedGoogle Scholar
  • 90 Valenti L, Varenna M, Fracanzani AL. et al. Association between iron overload and osteoporosis in patients with hereditary hemochromatosis. Osteoporos Int 2009; 20: 549-555
    CrossrefPubMedGoogle Scholar
  • 91 Valenti L, Varenna M, Fracanzani AL. et al. Association between iron overload and osteoporosis in patients with hereditary hemochromatosis. Osteoporos Int 2009; 20: 549-555
    CrossrefPubMedGoogle Scholar
  • 92 Doyard M, Chappard D, Leroyer P. et al. Decreased Bone Formation Explains Osteoporosis in a Genetic Mouse Model of Hemochromatosiss. PLoS ONE 2016; 11: e0148292
    CrossrefPubMedGoogle Scholar
  • 93 Yamasaki K, Hagiwara H. Excess iron inhibits osteoblast metabolism. Toxicol. Lett 2009; 191: 211-215
    CrossrefPubMedGoogle Scholar
  • 94 Yang Q, Jian J, Abramson SB. et al. Inhibitory effects of iron on bone morphogenetic protein 2-induced steoblastogenesis. J Bone Miner Res 2011; 26: 1188-1196
    CrossrefPubMedGoogle Scholar
  • 95 Ishii KA, Fumoto T, Iwai K. et al. Coordination of PGC-1beta and iron uptake in mitochondrial biogenesis and osteoclast activation. Nat Med 2009; 15: 259-266
    CrossrefPubMedGoogle Scholar
  • 96 Tsay J, Yang Z, Ross FP. et al. Bone loss caused by iron overload in a murine model: Importance of oxidative stress. Blood 2010; 116: 2582-2589
    PubMedGoogle Scholar
  • 97 Zarjou A, Jeney V, Arosio P. et al. Ferritin ferroxidase activity: A potent inhibitor of osteogenesis. J Bone Miner Res 2010; 25: 164-172
    CrossrefPubMedGoogle Scholar
  • 98 Nelson HD. Hormone Replacement Therapy and Osteoporosis. Rockville [MD], Agency for Healthcare Research and Quality [US], Preventive Services Task Force Evidence Syntheses 2002 [accessed May 4th, 2018]
    PubMed
  • 99 The Writing Group for the PEPI. Effects of hormone therapy on bone mineral density: Results from the postmenopausal estrogen/progestin interventions [PEPI] trial. JAMA 1996; 276: 1389-1396
    CrossrefPubMedGoogle Scholar
  • 100 Ten Bolscher M, Netelenbos JC, Barto R. et al. Estrogen regulation of intestinal calcium absorption in the intact and ovariectomized adult rat. J Bone Miner Res 1999; 14: 1197-1202
    CrossrefPubMedGoogle Scholar
  • 101 Prince RL, Dick I. Oestrogen effects on calcium membrane transport: A new view of the inter-relationship between oestrogen deficiency and age-related osteoporosis. Osteoporos Intl 1997; 7 [Supplement 3] SlSG-S1S4
    PubMedGoogle Scholar
  • 102 Prince RL, Smith M, Dick IM. et al. Prevention of postmenopausal osteoporosis. A comparative study of exercise, calcium supplementation, and hormone-replacement therapy. NEJM 1991; 325: 1189-1195
    CrossrefPubMedGoogle Scholar
  • 103 Reid IR, Ames RW, Evans MC. et al. Effect of calcium supplementation on bone loss in postmenopausal women. NEJM 1993; 328: 460-464
    CrossrefPubMedGoogle Scholar
  • 104 Yin X, Wang X, Hu X. et al. ERβ induces the differentiation of cultured osteoblasts by both Wnt/β-catenin signaling pathway and estrogen signaling pathways. Exp Cell Res 2015; 5: 107-114
    PubMedGoogle Scholar
  • 105 Qiu X, Jin X, Shao Z. et al. 17β estradiol induces the proliferation of hematopoietic stem cells by promoting the osteogenic differentiation of mesenchymal stem cells. Tohoku J Exp Med 2014; 233: 141-148
    CrossrefPubMedGoogle Scholar
  • 106 Mishra S, Tai Q, Gu X. et al. Estrogen and estrogen receptor alpha promotes malignancy and osteoblastic tumorigenesis in prostate cancer. Oncotarget 2015; 6: 44388-44402
    CrossrefPubMedGoogle Scholar
  • 107 Song L, Zhao J, Zhang X. et al. Icariin induces osteoblast proliferation, differentiation and mineralization through estrogen receptor-mediated ERK and JNK signal activation. Eur J Pharmacol 2013; 714 [1-3] 15-22
    CrossrefPubMedGoogle Scholar