{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T08:25:22Z","timestamp":1774254322487,"version":"3.50.1"},"reference-count":47,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T00:00:00Z","timestamp":1671753600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T00:00:00Z","timestamp":1671753600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100007950","name":"Tanta University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100007950","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Eur J Clin Pharmacol"],"published-print":{"date-parts":[[2023,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Introduction<\/jats:title>\n                <jats:p>Metformin may provide a therapeutic benefit in different types of malignancy.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Purpose<\/jats:title>\n                <jats:p>We aimed at evaluating the effect of metformin as an adjuvant therapy to letrozole on estradiol and other biomarkers involved in the pathogenesis of breast cancer in overweight and obese postmenopausal women.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Seventy-five postmenopausal stages II\u2013III breast cancer female patients were assessed for eligibility in an open-labeled parallel pilot study. Forty-five patients met the inclusion criteria and were assigned into three arms: the lean arm (<jats:italic>n<\/jats:italic>\u2009=\u200915) women who received letrozole 2.5\u00a0mg\/day, the control arm (<jats:italic>n<\/jats:italic>\u2009=\u200915) overweight\/obese women who received letrozole 2.5\u00a0mg\/day, and the metformin arm (<jats:italic>n<\/jats:italic>\u2009=\u200915) overweight\/obese women who received letrozole 2.5\u00a0mg\/day plus metformin (2000\u2009\u00b1\u2009500\u00a0mg\/day). The intervention duration was 6\u00a0months. Blood samples were obtained at baseline and 6\u00a0months after intervention for the measurement of serum estradiol, leptin, osteocalcin levels, fasting blood glucose concentration, and serum insulin.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>After the intervention and as compared to the control arm, the metformin arm showed a significantly lower ratio to the baseline (significant reduction) for estradiol (<jats:italic>p<\/jats:italic>\u2009=\u20090.0433), leptin (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001), fasting blood glucose (<jats:italic>p<\/jats:italic>\u2009=\u20090.0128), insulin (<jats:italic>p<\/jats:italic>\u2009=\u20090.0360), osteocalcin serum levels (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001), and the homeostatic model assessment of insulin resistance \u201cHOMA-IR\u201d value (<jats:italic>p<\/jats:italic>\u2009=\u20090.0145). There was a non-significant variation in the lactate ratio to the baseline among the three study arms (<jats:italic>p<\/jats:italic>\u2009=\u20090.5298).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Metformin may exert anti-cancer activity by decreasing the circulating estradiol, leptin, and insulin. Metformin might represent a safe and promising adjuvant therapy to letrozole in overweight\/obese postmenopausal women with breast cancer.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Trial registration<\/jats:title>\n                <jats:p>ClinicalTrials.gov Identifier: NCT05053841\/Registered September 23, 2021 - Retrospectively.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00228-022-03444-6","type":"journal-article","created":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T13:04:58Z","timestamp":1671800698000},"page":"299-309","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Effect of metformin as an adjuvant therapy to letrozole on estradiol and other biomarkers involved in the pathogenesis of breast cancer in overweight and obese postmenopausal women: a pilot study"],"prefix":"10.1007","volume":"79","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2274-4030","authenticated-orcid":false,"given":"Aya Ahmed","family":"El-attar","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2775-350X","authenticated-orcid":false,"given":"Osama Mohamed","family":"Ibrahim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suzan Ahmed","family":"Alhassanin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5749-3289","authenticated-orcid":false,"given":"Enas Said","family":"Essa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1071-5416","authenticated-orcid":false,"given":"Tarek Mohamed","family":"Mostafa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2022,12,23]]},"reference":[{"key":"3444_CR1","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1038\/s41572-019-0111-2","volume":"5","author":"N Harbeck","year":"2019","unstructured":"Harbeck N, Penault-Llorca F, Cortes J et al (2019) Breast cancer Nat Rev Dis Primers 5:66. https:\/\/doi.org\/10.1038\/s41572-019-0111-2","journal-title":"Breast cancer Nat Rev Dis Primers"},{"key":"3444_CR2","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1007\/s12609-016-0229-0","volume":"8","author":"CC O\u2019Sullivan","year":"2016","unstructured":"O\u2019Sullivan CC, Ruddy KJ (2016) Management of potential long-term toxicities in breast cancer patients. Curr Breast Cancer Rep 8:183\u2013192. https:\/\/doi.org\/10.1007\/s12609-016-0229-0","journal-title":"Curr Breast Cancer Rep"},{"key":"3444_CR3","doi-asserted-by":"publisher","first-page":"R19","DOI":"10.1530\/JME-15-0310","volume":"57","author":"H Zhao","year":"2016","unstructured":"Zhao H, Zhou L, Shangguan AJ, Bulun SE (2016) Aromatase expression and regulation in breast and endometrial cancer. J Mol Endocrinol 57:R19\u2013R33. https:\/\/doi.org\/10.1530\/JME-15-0310","journal-title":"J Mol Endocrinol"},{"key":"3444_CR4","doi-asserted-by":"publisher","first-page":"E2661","DOI":"10.1210\/jc.2014-2550","volume":"99","author":"H Savolainen-Peltonen","year":"2014","unstructured":"Savolainen-Peltonen H, Vihma V, Leidenius M et al (2014) Breast adipose tissue estrogen metabolism in postmenopausal women with or without breast cancer. J Clin Endocrinol Metab 99:E2661\u2013E2667. https:\/\/doi.org\/10.1210\/jc.2014-2550","journal-title":"J Clin Endocrinol Metab"},{"key":"3444_CR5","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2017\/9574874","volume":"2017","author":"J Cuello-L\u00f3pez","year":"2017","unstructured":"Cuello-L\u00f3pez J, Fidalgo-Zapata A, V\u00e1squez-Trespalacios E (2017) Obesity and prognostic variables in Colombian breast cancer patients: a cross-sectional study. Int J Breast Cancer 2017:1\u20137. https:\/\/doi.org\/10.1155\/2017\/9574874","journal-title":"Int J Breast Cancer"},{"key":"3444_CR6","doi-asserted-by":"publisher","first-page":"1055","DOI":"10.1016\/j.ejca.2014.01.007","volume":"50","author":"PE L\u00f8nning","year":"2014","unstructured":"L\u00f8nning PE, Haynes BP, Dowsett M (2014) Relationship of body mass index with aromatisation and plasma and tissue oestrogen levels in postmenopausal breast cancer patients treated with aromatase inhibitors. Eur J Cancer 50:1055\u20131064. https:\/\/doi.org\/10.1016\/j.ejca.2014.01.007","journal-title":"Eur J Cancer"},{"key":"3444_CR7","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.mce.2017.09.014","volume":"466","author":"C G\u00e9rard","year":"2018","unstructured":"G\u00e9rard C, Brown KA (2018) Obesity and breast cancer \u2013 role of estrogens and the molecular underpinnings of aromatase regulation in breast adipose tissue. Mol Cell Endocrinol 466:15\u201330. https:\/\/doi.org\/10.1016\/j.mce.2017.09.014","journal-title":"Mol Cell Endocrinol"},{"key":"3444_CR8","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.ctrv.2017.06.004","volume":"59","author":"AM Brufsky","year":"2017","unstructured":"Brufsky AM (2017) Long-term management of patients with hormone receptor-positive metastatic breast cancer: concepts for sequential and combination endocrine-based therapies. Cancer Treat Rev 59:22\u201332. https:\/\/doi.org\/10.1016\/j.ctrv.2017.06.004","journal-title":"Cancer Treat Rev"},{"key":"3444_CR9","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1007\/s10549-014-3091-7","volume":"147","author":"SJ Ioannides","year":"2014","unstructured":"Ioannides SJ, Barlow PL, Elwood JM, Porter D (2014) Effect of obesity on aromatase inhibitor efficacy in postmenopausal, hormone receptor-positive breast cancer: a systematic review. Breast Cancer Res Treat 147:237\u2013248. https:\/\/doi.org\/10.1007\/s10549-014-3091-7","journal-title":"Breast Cancer Res Treat"},{"key":"3444_CR10","doi-asserted-by":"publisher","first-page":"4203","DOI":"10.1200\/JCO.2016.68.4480","volume":"34","author":"S Jiralerspong","year":"2016","unstructured":"Jiralerspong S, Goodwin PJ (2016) Obesity and breast cancer prognosis: evidence, challenges, and opportunities. J Clin Oncol 34:4203\u20134216","journal-title":"J Clin Oncol"},{"key":"3444_CR11","doi-asserted-by":"publisher","first-page":"6","DOI":"10.3389\/FENDO.2017.00006\/BIBTEX","volume":"8","author":"A Chaudhury","year":"2017","unstructured":"Chaudhury A, Duvoor C, Reddy Dendi VS et al (2017) Clinical review of antidiabetic drugs: implications for type 2 diabetes mellitus management. Front Endocrinol (Lausanne) 8:6. https:\/\/doi.org\/10.3389\/FENDO.2017.00006\/BIBTEX","journal-title":"Front Endocrinol (Lausanne)"},{"key":"3444_CR12","doi-asserted-by":"publisher","first-page":"2421","DOI":"10.2147\/DDDT.S141675","volume":"11","author":"Y-W Wang","year":"2017","unstructured":"Wang Y-W, He S-J, Feng X et al (2017) Metformin: a review of its potential indications. Drug Des Devel Ther 11:2421\u20132429. https:\/\/doi.org\/10.2147\/DDDT.S141675","journal-title":"Drug Des Devel Ther"},{"key":"3444_CR13","doi-asserted-by":"publisher","first-page":"1675","DOI":"10.1007\/s00384-018-3104-9","volume":"33","author":"BM El-fatatry","year":"2018","unstructured":"El-fatatry BM, Ibrahim OM, Hussien FZ, Mostafa TM (2018) Role of metformin in oxaliplatin-induced peripheral neuropathy in patients with stage III colorectal cancer: randomized, controlled study. Int J Colorectal Dis 33:1675\u20131683. https:\/\/doi.org\/10.1007\/s00384-018-3104-9","journal-title":"Int J Colorectal Dis"},{"key":"3444_CR14","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1159\/000381643","volume":"24","author":"M Kinaan","year":"2015","unstructured":"Kinaan M, Ding H, Triggle CR (2015) Metformin: an old drug for the treatment of diabetes but a new drug for the protection of the endothelium. Med Princ Pract 24:401\u2013415. https:\/\/doi.org\/10.1159\/000381643","journal-title":"Med Princ Pract"},{"key":"3444_CR15","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1055\/s-0032-1327734","volume":"121","author":"C Seifarth","year":"2013","unstructured":"Seifarth C, Schehler B, Schneider HJ (2013) Effectiveness of metformin on weight loss in non-diabetic individuals with obesity. Exp Clin Endocrinol Diabetes 121:27\u201331. https:\/\/doi.org\/10.1055\/s-0032-1327734","journal-title":"Exp Clin Endocrinol Diabetes"},{"key":"3444_CR16","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1007\/s10549-012-2278-z","volume":"136","author":"C Diorio","year":"2012","unstructured":"Diorio C, Lemieux J, Provencher L et al (2012) Aromatase inhibitors in obese breast cancer patients are not associated with increased plasma estradiol levels. Breast Cancer Res Treat 136:573\u2013579. https:\/\/doi.org\/10.1007\/s10549-012-2278-z","journal-title":"Breast Cancer Res Treat"},{"key":"3444_CR17","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1055\/s-0032-1327734","volume":"121","author":"C Seifarth","year":"2012","unstructured":"Seifarth C, Schehler B, Schneider H (2012) Effectiveness of metformin on weight loss in non-diabetic individuals with obesity. Exp Clin Endocrinol Diabetes 121:27\u201331. https:\/\/doi.org\/10.1055\/s-0032-1327734","journal-title":"Exp Clin Endocrinol Diabetes"},{"key":"3444_CR18","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1093\/jnci\/djaa082","volume":"113","author":"I Pimentel","year":"2021","unstructured":"Pimentel I, Chen BE, Lohmann AE et al (2021) The effect of metformin vs placebo on sex hormones in Canadian cancer trials group MA.32. J Natl Cancer Inst 113:192\u2013198. https:\/\/doi.org\/10.1093\/jnci\/djaa082","journal-title":"J Natl Cancer Inst"},{"key":"3444_CR19","doi-asserted-by":"publisher","first-page":"444","DOI":"10.1200\/JCO.19.01455","volume":"38","author":"L Fehrenbacher","year":"2020","unstructured":"Fehrenbacher L, Cecchini RS, Geyer CE et al (2020) NSABP B-47\/NRG oncology phase III randomized trial comparing adjuvant chemotherapy with or without trastuzumab in high-risk invasive breast cancer negative for HER2 by FISH and with IHC 1+ or 2+. J Clin Oncol 38:444\u2013453. https:\/\/doi.org\/10.1200\/JCO.19.01455","journal-title":"J Clin Oncol"},{"key":"3444_CR20","doi-asserted-by":"publisher","first-page":"2105","DOI":"10.1200\/JCO.2018.77.8738","volume":"36","author":"AC Wolff","year":"2018","unstructured":"Wolff AC, Elizabeth Hale Hammond M, Allison KH et al (2018) Human epidermal growth factor receptor 2 testing in breast cancer: American society of clinical oncology\/ college of American pathologists clinical practice guideline focused update. J Clin Oncol 36:2105\u20132122. https:\/\/doi.org\/10.1200\/JCO.2018.77.8738","journal-title":"J Clin Oncol"},{"key":"3444_CR21","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1007\/BF00280883","volume":"28","author":"DR Matthews","year":"1985","unstructured":"Matthews DR, Hosker JP, Rudenski AS et al (1985) Homeostasis model assessment: insulin resistance and \u03b2-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412\u2013419. https:\/\/doi.org\/10.1007\/BF00280883","journal-title":"Diabetologia"},{"key":"3444_CR22","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1002\/pst.185","volume":"4","author":"SA Julious","year":"2005","unstructured":"Julious SA (2005) Sample size of 12 per group rule of thumb for a pilot study. Pharm Stat 4:287\u2013291. https:\/\/doi.org\/10.1002\/pst.185","journal-title":"Pharm Stat"},{"key":"3444_CR23","doi-asserted-by":"publisher","first-page":"2553","DOI":"10.3892\/or.2016.4675","volume":"35","author":"J Kim","year":"2016","unstructured":"Kim J, Lee J, JANG SY, et al (2016) Anticancer effect of metformin on estrogen receptor-positive and tamoxifen-resistant breast cancer cell lines. Oncol Rep 35:2553\u20132560. https:\/\/doi.org\/10.3892\/or.2016.4675","journal-title":"Oncol Rep"},{"key":"3444_CR24","doi-asserted-by":"publisher","unstructured":"Kr\u00e1sensk\u00e1 M (2016) Treatment with aromatase inhibitors in postmenopausal women with breast cancer and the possibility of influencing side effects.\u00a0Klin Onkol\u00a029:3S39\u20133S49. https:\/\/doi.org\/10.14735\/amko20163S39","DOI":"10.14735\/amko20163S39"},{"key":"3444_CR25","doi-asserted-by":"publisher","first-page":"821","DOI":"10.3332\/ecancer.2018.821","volume":"12","author":"J Zekri","year":"2018","unstructured":"Zekri J, Farag K, Allithy A (2018) Obesity and outcome of post-menopausal women receiving adjuvant letrozole for breast cancer. Ecancermedicalscience 12:821. https:\/\/doi.org\/10.3332\/ecancer.2018.821","journal-title":"Ecancermedicalscience"},{"key":"3444_CR26","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2020.117717","volume":"254","author":"B Zhao","year":"2020","unstructured":"Zhao B, Luo J, Yu T et al (2020) Anticancer mechanisms of metformin: a review of the current evidence. Life Sci 254:117717. https:\/\/doi.org\/10.1016\/j.lfs.2020.117717","journal-title":"Life Sci"},{"key":"3444_CR27","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/S13058-018-1026-7\/FIGURES\/2","volume":"20","author":"S Borgquist","year":"2018","unstructured":"Borgquist S, Rosendahl AH, Czene K et al (2018) Long-term exposure to insulin and volumetric mammographic density: observational and genetic associations in the Karma study. Breast Cancer Res 20:1\u201313. https:\/\/doi.org\/10.1186\/S13058-018-1026-7\/FIGURES\/2","journal-title":"Breast Cancer Res"},{"key":"3444_CR28","doi-asserted-by":"publisher","first-page":"58","DOI":"10.3389\/fendo.2020.00058","volume":"11","author":"LD Yee","year":"2020","unstructured":"Yee LD, Mortimer JE, Natarajan R et al (2020) Metabolic health, insulin, and breast cancer: why oncologists should care about insulin. Front Endocrinol (Lausanne) 11:58. https:\/\/doi.org\/10.3389\/fendo.2020.00058","journal-title":"Front Endocrinol (Lausanne)"},{"key":"3444_CR29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/jncics\/pkz096","volume":"4","author":"JA Meyerhardt","year":"2020","unstructured":"Meyerhardt JA, Irwin ML, Jones LW et al (2020) Randomized phase II trial of exercise, metformin, or both on metabolic biomarkers in colorectal and breast cancer survivors. JNCI Cancer Spectr 4:1\u20138. https:\/\/doi.org\/10.1093\/jncics\/pkz096","journal-title":"JNCI Cancer Spectr"},{"key":"3444_CR30","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1080\/13102818.2019.1711184","volume":"34","author":"P Kamenova","year":"2020","unstructured":"Kamenova P (2020) Therapeutic potential of metformin in normal glucose tolerant persons with metabolic syndrome. Biotechnol Biotechnol Equip 34:30\u201337. https:\/\/doi.org\/10.1080\/13102818.2019.1711184","journal-title":"Biotechnol Biotechnol Equip"},{"key":"3444_CR31","doi-asserted-by":"publisher","first-page":"1642","DOI":"10.1126\/science.1120781","volume":"310","author":"RJ Shaw","year":"2005","unstructured":"Shaw RJ, Lamia KA, Vasquez D et al (2005) The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310:1642\u20131646. https:\/\/doi.org\/10.1126\/science.1120781","journal-title":"Science"},{"key":"3444_CR32","doi-asserted-by":"publisher","first-page":"6156","DOI":"10.1038\/s41598-019-42531-0","volume":"9","author":"O Horakova","year":"2019","unstructured":"Horakova O, Kroupova P, Bardova K et al (2019) Metformin acutely lowers blood glucose levels by inhibition of intestinal glucose transport. Sci Rep 9:6156. https:\/\/doi.org\/10.1038\/s41598-019-42531-0","journal-title":"Sci Rep"},{"key":"3444_CR33","doi-asserted-by":"publisher","first-page":"8191","DOI":"10.3390\/ijms21218191","volume":"21","author":"X Qu","year":"2020","unstructured":"Qu X, Donnelly R (2020) Sex hormone-binding globulin (SHBG) as an early biomarker and therapeutic target in polycystic ovary syndrome. Int J Mol Sci 21:8191. https:\/\/doi.org\/10.3390\/ijms21218191","journal-title":"Int J Mol Sci"},{"key":"3444_CR34","doi-asserted-by":"publisher","first-page":"446","DOI":"10.1161\/HYPERTENSIONAHA.116.07353","volume":"68","author":"A Dean","year":"2016","unstructured":"Dean A, Nilsen M, Loughlin L et al (2016) Metformin reverses development of pulmonary hypertension via aromatase inhibition. Hypertension 68:446\u2013454. https:\/\/doi.org\/10.1161\/HYPERTENSIONAHA.116.07353","journal-title":"Hypertension"},{"key":"3444_CR35","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1007\/s10549-010-0834-y","volume":"123","author":"KA Brown","year":"2010","unstructured":"Brown KA, Hunger NI, Docanto M, Simpson ER (2010) Metformin inhibits aromatase expression in human breast adipose stromal cells via stimulation of AMP-activated protein kinase. Breast Cancer Res Treat 123:591\u2013596. https:\/\/doi.org\/10.1007\/s10549-010-0834-y","journal-title":"Breast Cancer Res Treat"},{"key":"3444_CR36","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1016\/j.clbc.2013.08.012","volume":"13","author":"C Campagnoli","year":"2013","unstructured":"Campagnoli C, Berrino F, Venturelli E et al (2013) Metformin decreases circulating androgen and estrogen levels in nondiabetic women with breast cancer. Clin Breast Cancer 13:433\u2013438. https:\/\/doi.org\/10.1016\/j.clbc.2013.08.012","journal-title":"Clin Breast Cancer"},{"key":"3444_CR37","doi-asserted-by":"publisher","first-page":"1544","DOI":"10.5958\/0976-5506.2019.00935.5","volume":"10","author":"AB Roomi","year":"2019","unstructured":"Roomi AB, AL-Salih RMH, Ali SaherA, (2019) The effect insulin therapy and metformin on osteoporosis in diabetic post-menopausal Iraqi women. Indian J Public Health Res Dev 10:1544. https:\/\/doi.org\/10.5958\/0976-5506.2019.00935.5","journal-title":"Indian J Public Health Res Dev"},{"key":"3444_CR38","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1007\/S00774-014-0581-Y","volume":"33","author":"SK Hegazy","year":"2015","unstructured":"Hegazy SK (2015) Evaluation of the anti-osteoporotic effects of metformin and sitagliptin in postmenopausal diabetic women. J Bone Miner Metab 33:207\u2013212. https:\/\/doi.org\/10.1007\/S00774-014-0581-Y","journal-title":"J Bone Miner Metab"},{"key":"3444_CR39","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1359\/jbmr.090732","volume":"25","author":"MS Molinuevo","year":"2010","unstructured":"Molinuevo MS, Schurman L, McCarthy AD et al (2010) Effect of metformin on bone marrow progenitor cell differentiation: in vivo and in vitro studies. J Bone Miner Res 25:211\u2013221. https:\/\/doi.org\/10.1359\/jbmr.090732","journal-title":"J Bone Miner Res"},{"key":"3444_CR40","doi-asserted-by":"publisher","unstructured":"Guo S, Liu M, Wang G et al (2012) Oncogenic role and therapeutic target of leptin signaling in breast cancer and cancer stem cells.\u00a0Biochim Biophys Acta\u00a01825:207\u2013222. https:\/\/doi.org\/10.1016\/j.bbcan.2012.01.002","DOI":"10.1016\/j.bbcan.2012.01.002"},{"key":"3444_CR41","doi-asserted-by":"publisher","first-page":"596","DOI":"10.3389\/fonc.2019.00596","volume":"9","author":"F S\u00e1nchez-Jim\u00e9nez","year":"2019","unstructured":"S\u00e1nchez-Jim\u00e9nez F, P\u00e9rez-P\u00e9rez A, de la Cruz-Merino L, S\u00e1nchez-Margalet V (2019) Obesity and breast cancer: role of leptin. Front Oncol 9:596. https:\/\/doi.org\/10.3389\/fonc.2019.00596","journal-title":"Front Oncol"},{"key":"3444_CR42","doi-asserted-by":"publisher","first-page":"620","DOI":"10.1002\/MRD.23342\/FORMAT\/PDF","volume":"87","author":"L Annie","year":"2020","unstructured":"Annie L, Jeremy M, Gurusubramanian G et al (2020) Effect of metformin on testicular expression and localization of leptin receptor and levels of leptin in the diabetic mice. Mol Reprod Dev 87:620\u2013629. https:\/\/doi.org\/10.1002\/MRD.23342\/FORMAT\/PDF","journal-title":"Mol Reprod Dev"},{"key":"3444_CR43","first-page":"3868","volume":"20","author":"A Kargulewicz","year":"2016","unstructured":"Kargulewicz A, Szuli\u0144ska M, Kujawska-\u0141uczak M et al (2016) Improvement of serum adiponectin and leptin concentrations: effects of a low-calorie or isocaloric diet combined with metformin or orlistat - a prospective randomized open-label trial. Eur Rev Med Pharmacol Sci 20:3868\u20133876","journal-title":"Eur Rev Med Pharmacol Sci"},{"key":"3444_CR44","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1053\/META.2002.31332","volume":"51","author":"B Fruehwald-Schultes","year":"2002","unstructured":"Fruehwald-Schultes B, Oltmanns KM, Toschek B et al (2002) Short-term treatment with metformin decreases serum leptin concentration without affecting body weight and body fat content in normal-weight healthy men. Metabolism 51:531\u2013536. https:\/\/doi.org\/10.1053\/META.2002.31332","journal-title":"Metabolism"},{"key":"3444_CR45","doi-asserted-by":"publisher","unstructured":"Upadhyaya P, Rehan HS, Seth V (2011) Serum leptin changes with metformin treatment in polycystic ovarian syndrome: correlation with ovulation, insulin and testosterone levels. EXCLI J 10:9\u201315. https:\/\/doi.org\/10.17877\/DE290R-1136","DOI":"10.17877\/DE290R-1136"},{"key":"3444_CR46","doi-asserted-by":"publisher","first-page":"S532","DOI":"10.4103\/2230-8210.105569","volume":"16","author":"MP Baruah","year":"2012","unstructured":"Baruah MP, Kalra S, Ranabir S (2012) Metformin; a character actor in the leptin story! Indian J Endocrinol Metab 16:S532\u2013S533. https:\/\/doi.org\/10.4103\/2230-8210.105569","journal-title":"Indian J Endocrinol Metab"},{"key":"3444_CR47","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1016\/j.metabol.2015.10.014","volume":"65","author":"R DeFronzo","year":"2016","unstructured":"DeFronzo R, Fleming GA, Chen K, Bicsak TA (2016) Metformin-associated lactic acidosis: current perspectives on causes and risk. Metabolism 65:20\u201329. https:\/\/doi.org\/10.1016\/j.metabol.2015.10.014","journal-title":"Metabolism"}],"container-title":["European Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00228-022-03444-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00228-022-03444-6\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00228-022-03444-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,26]],"date-time":"2023-01-26T08:05:33Z","timestamp":1674720333000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00228-022-03444-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,23]]},"references-count":47,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2023,2]]}},"alternative-id":["3444"],"URL":"https:\/\/doi.org\/10.1007\/s00228-022-03444-6","relation":{},"ISSN":["0031-6970","1432-1041"],"issn-type":[{"value":"0031-6970","type":"print"},{"value":"1432-1041","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,23]]},"assertion":[{"value":"21 July 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 December 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 December 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Tanta University\u2019s National Research Ethics Committee gave its approval to this study (approval code: 34653\/4\/2). The study was consistent with the Helsinki Declaration\u2019s ethical principles in 1964 and its later amendments.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"All the study participants provided their informed consent since there is no personal data, publication consent is not requested.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}