{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T01:04:27Z","timestamp":1783127067000,"version":"3.54.6"},"reference-count":96,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,12,20]],"date-time":"2024-12-20T00:00:00Z","timestamp":1734652800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Thalassemia is an autosomal recessive hereditary chronic hemolytic anemia characterized by a partial or complete deficiency in the synthesis of alpha- or beta-globin chains, which are essential components of adult hemoglobin. Mutations in the globin genes lead to the production of unstable globin chains that precipitate within cells, causing hemolysis. This shortens the lifespan of mature red blood cells (RBCs) and results in the premature destruction of RBC precursors in the bone marrow. Regular red blood cell transfusions are the standard treatment for thalassemia. However, these transfusions can lead to increased iron overload, which can impair vital systems such as the liver, heart, ovaries, and endocrine system. Focusing on female reproductive endocrinology, recurrent blood transfusions can cause iron accumulation in the pituitary and hypothalamus, leading to hypogonadotropic hypogonadism (HH), the most common endocrinopathy in these patients, affecting 40\u201391% of women. Recurrent transfusions and the resulting iron overload can also lead to oxidative stress and ovarian damage in patients with beta-thalassemia major (BTM). Despite advancements in iron chelation therapy, hypothalamic\u2013pituitary damage associated with HH contributes to subfertility and sexual dysfunction, often with little to no recovery. In women exposed to gonadotoxic drugs, particularly those with BTM, anti-Mullerian hormone (AMH)\u2014a marker of ovarian reserve\u2014is frequently used to assess ovarian damage. This review aims to explore the pathophysiology of \u03b2-thalassemia and its major clinical manifestations, with a focus on endocrine complications and their impact on ovarian reserve. It also investigates how metabolomics can provide insights into the disease\u2019s metabolic alterations and inform current and emerging therapeutic strategies to mitigate complications and optimize patient outcomes, potentially leading to more effective and personalized treatments.<\/jats:p>","DOI":"10.3390\/metabo14120717","type":"journal-article","created":{"date-parts":[[2024,12,20]],"date-time":"2024-12-20T07:42:18Z","timestamp":1734680538000},"page":"717","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Reproductive Health in Women with Major \u03b2-Thalassemia: Evaluating Ovarian Reserve and Endocrine Complications"],"prefix":"10.3390","volume":"14","author":[{"given":"Vasileios","family":"Tsilionis","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Faculty of Medicine, School of Health Sciences, University of Thessaly, 41110 Larissa, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3333-2620","authenticated-orcid":false,"given":"Efthalia","family":"Moustakli","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanos","family":"Dafopoulos","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, European University Cyprus, Nicosia 2404, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9553-6803","authenticated-orcid":false,"given":"Athanasios","family":"Zikopoulos","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynecology, Royal Devon and Exeter Hospital Barrack Rd., Exeter EX2 5DW, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sotirios","family":"Sotiriou","sequence":"additional","affiliation":[{"name":"Department of Embryology, Faculty of Medicine, School of Health Sciences, University of Thessaly, 41110 Larissa, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Athanasios","family":"Zachariou","sequence":"additional","affiliation":[{"name":"Department of Urology, School of Medicine, Ioannina University, 45110 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9991-8097","authenticated-orcid":false,"given":"Konstantinos","family":"Dafopoulos","sequence":"additional","affiliation":[{"name":"IVF Unit, Department of Obstetrics and Gynecology, Faculty of Medicine, School of Health Sciences, University of Thessaly, 41110 Larissa, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"102619","DOI":"10.1016\/j.eclinm.2024.102619","article-title":"Global, regional, and national burden of thalassemia, 1990\u20132021: A systematic analysis for the global burden of disease study 2021","volume":"72","author":"Tuo","year":"2024","journal-title":"eClinicalMedicine"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"a011726","DOI":"10.1101\/cshperspect.a011726","article-title":"Pathophysiology and Clinical Manifestations of the \u03b2-Thalassemias","volume":"2","author":"Nienhuis","year":"2012","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1182\/hematology.2019000036","article-title":"Iron overload in transfusion-dependent patients","volume":"2019","author":"Coates","year":"2019","journal-title":"Hematol. Am. Soc. Hematol. Educ. Program"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/j.transci.2019.04.023","article-title":"Biological mechanisms implicated in adverse outcomes of sex mismatched transfusions","volume":"58","author":"Alshalani","year":"2019","journal-title":"Transfus. Apher. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Juan, C.A., P\u00e9rez De La Lastra, J.M., Plou, F.J., and P\u00e9rez-Lebe\u00f1a, E. (2021). The Chemistry of Reactive Oxygen Species (ROS) Revisited: Outlining Their Role in Biological Macromolecules (DNA, Lipids and Proteins) and Induced Pathologies. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22094642"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1111\/j.1365-2265.2012.04495.x","article-title":"Endocrinopathies in transfusion-associated iron overload","volume":"78","author":"Kim","year":"2013","journal-title":"Clin. Endocrinol."},{"key":"ref_7","first-page":"42","article-title":"Hypogonadism in thalassemia major patients","volume":"5","author":"Srisukh","year":"2016","journal-title":"J. Clin. Transl. Endocrinol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3361","DOI":"10.1210\/clinem\/dgaa513","article-title":"Anti-M\u00fcllerian Hormone and Ovarian Reserve: Update on Assessing Ovarian Function","volume":"105","author":"Moolhuijsen","year":"2020","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"AL-Zwaini, I. (2018). Hypogonadism in Female Patients with Beta Thalassemia Major. Thalassemia and Other Hemolytic Anemias [Internet], InTech. Available online: http:\/\/www.intechopen.com\/books\/thalassemia-and-other-hemolytic-anemias\/hypogonadism-in-female-patients-with-beta-thalassemia-major.","DOI":"10.5772\/intechopen.68657"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4871","DOI":"10.4081\/thal.2014.4871","article-title":"Review of Endocrine Complications in Adult Patients with \u03b2-Thalassaemia Major","volume":"4","author":"Tzoulis","year":"2014","journal-title":"Thalass. Rep."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Carsote, M., Vasiliu, C., Trandafir, A.I., Albu, S.E., Dumitrascu, M.C., Popa, A., Mehedintu, C., Petca, R.-C., Petca, A., and Sandru, F. (2022). New Entity\u2014Thalassemic Endocrine Disease: Major Beta-Thalassemia and Endocrine Involvement. Diagnostics, 12.","DOI":"10.3390\/diagnostics12081921"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3034","DOI":"10.3390\/nu5083034","article-title":"Out of balance\u2014Systemic iron homeostasis in iron-related disorders","volume":"5","author":"Steinbicker","year":"2013","journal-title":"Nutrients"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"P55","DOI":"10.1186\/1687-9856-2013-S1-P55","article-title":"Endocrine complications in patients with thalassaemia major","volume":"2013","author":"Meng","year":"2013","journal-title":"Int. J. Pediatr. Endocrinol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"8","DOI":"10.4103\/2230-8210.107808","article-title":"Growth and endocrine disorders in thalassemia: The international network on endocrine complications in thalassemia (I-CET) position statement and guidelines","volume":"17","author":"Soliman","year":"2013","journal-title":"Indian J. Endocrinol. Metab."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Barbero, U., Ajassa, M., Gaglioti, C.M., Piga, A., Ferrero, G.B., and Longo, F. (2021). The Influence of Cardiovascular Risk Factors and Hypogonadism on Cardiac Outcomes in an Aging Population of Beta-Thalassemia Patients. J. Cardiovasc. Dev. Dis., 9.","DOI":"10.3390\/jcdd9010003"},{"key":"ref_16","first-page":"6","article-title":"Hypogonadism in male thalassemia major patients: Pathophysiology, diagnosis and treatment","volume":"89","author":"Soliman","year":"2018","journal-title":"Acta Bio-Medica Atenei Parm."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1186\/s13052-021-01116-2","article-title":"Detection of endocrine disorders in young children with multi-transfused thalassemia major","volume":"47","author":"Mahmoud","year":"2021","journal-title":"Ital. J. Pediatr."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1007\/s12325-008-0085-z","article-title":"Iron chelation therapy: Clinical effectiveness, economic burden and quality of life in patients with iron overload","volume":"25","author":"Payne","year":"2008","journal-title":"Adv. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1111\/cen.15097","article-title":"Society for endocrinology guideline for understanding, diagnosing and treating female hypogonadism","volume":"101","author":"Jayasena","year":"2024","journal-title":"Clin. Endocrinol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1007\/s12098-021-03883-6","article-title":"Endocrinal Complications in Children and Adolescents with Thalassemia Major in Central India: An Observational Study","volume":"89","author":"Dixit","year":"2022","journal-title":"Indian J. Pediatr."},{"key":"ref_21","first-page":"e15572","article-title":"Investigating the Role of Ferritin in Determining Sexual Underdevelopment in Beta-Thalassemia Major Patients: A Cross-Sectional Analysis From Pakistan","volume":"13","author":"Shahid","year":"2021","journal-title":"Cureus"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"R109","DOI":"10.1530\/JOE-17-0023","article-title":"Exposure to endocrine disruptors during adulthood: Consequences for female fertility","volume":"233","author":"Rattan","year":"2017","journal-title":"J. Endocrinol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1510","DOI":"10.1210\/clinem\/dgac039","article-title":"Evaluation of Female Fertility\u2014AMH and Ovarian Reserve Testing","volume":"107","author":"Cedars","year":"2022","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e2019029","DOI":"10.4084\/mjhid.2019.029","article-title":"Thyroid Disorders in Homozygous \u03b2-Thalassemia: Current Knowledge, Emerging Issues and Open Problems","volume":"11","author":"Soliman","year":"2019","journal-title":"Mediterr. J. Hematol. Infect. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Evangelidis, P., Venou, T.M., Fani, B., Vlachaki, E., and Gavriilaki, E. (2023). Endocrinopathies in Hemoglobinopathies: What Is the Role of Iron?. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242216263"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.ijgo.2005.03.024","article-title":"Hypothalamic-pituitary-gonadal function in adolescent females with beta-thalassemia major","volume":"90","author":"Jallad","year":"2005","journal-title":"Int. J. Gynecol. Obstet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"617204","DOI":"10.1155\/2013\/617204","article-title":"Beta-Thalassemia Major and Female Fertility: The Role of Iron and Iron-Induced Oxidative Stress","volume":"2013","author":"Roussou","year":"2013","journal-title":"Anemia"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"G53","DOI":"10.1093\/ejendo\/lvae050","article-title":"Clinical practice guidelines for the care of girls and women with Turner syndrome","volume":"190","author":"Gravholt","year":"2024","journal-title":"Eur. J. Endocrinol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Pinto, V.M., and Forni, G.L. (2020). Management of Iron Overload in Beta-Thalassemia Patients: Clinical Practice Update Based on Case Series. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21228771"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Rochette, L., Dogon, G., Rigal, E., Zeller, M., Cottin, Y., and Vergely, C. (2022). Lipid Peroxidation and Iron Metabolism: Two Corner Stones in the Homeostasis Control of Ferroptosis. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24010449"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"761","DOI":"10.4103\/0377-4929.91489","article-title":"Antioxidant status in beta thalassemia major: A single-center study","volume":"54","author":"Waseem","year":"2011","journal-title":"Indian J. Pathol. Microbiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"694","DOI":"10.3389\/fphys.2020.00694","article-title":"Lifestyle, Oxidative Stress, and Antioxidants: Back and Forth in the Pathophysiology of Chronic Diseases","volume":"11","author":"Zucca","year":"2020","journal-title":"Front. Physiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"8416763","DOI":"10.1155\/2017\/8416763","article-title":"Oxidative Stress: Harms and Benefits for Human Health","volume":"2017","author":"Pizzino","year":"2017","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1111\/j.1582-4934.2009.00897.x","article-title":"Chemical and molecular mechanisms of antioxidants: Experimental approaches and model systems","volume":"14","author":"Lin","year":"2010","journal-title":"J. Cell. Mol. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"67","DOI":"10.3109\/03630269.2010.544624","article-title":"Increased Oxidative Stress and Iron Overload in Jordanian \u03b2-Thalassemic Children","volume":"35","author":"Abdalla","year":"2011","journal-title":"Hemoglobin"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1007\/s12291-008-0074-7","article-title":"Oxidative stress and disturbance in antioxidant balance in beta thalassemia major","volume":"23","author":"Ghone","year":"2008","journal-title":"Indian J. Clin. Biochem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3608","DOI":"10.1182\/blood.V88.9.3608.bloodjournal8893608","article-title":"Oxidative stress and antioxidant status in beta-thalassemia major: Iron overload and depletion of lipid-soluble antioxidants","volume":"88","author":"Livrea","year":"1996","journal-title":"Blood"},{"key":"ref_38","first-page":"1226","article-title":"Lipid Peroxidation and Antioxidative Status in \u03b2-Thalassemia Major Patients with or Without Hepatitis C Virus Infection","volume":"44","author":"Chiou","year":"2006","journal-title":"Clin. Chem. Lab. Med. CCLM"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1016\/S1472-6483(10)62151-7","article-title":"Role of free radicals in female reproductive diseases and assisted reproduction","volume":"9","author":"Agarwal","year":"2004","journal-title":"Reprod. Biomed. Online"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/1477-7827-3-28","article-title":"Role of oxidative stress in female reproduction","volume":"3","author":"Agarwal","year":"2005","journal-title":"Reprod. Biol. Endocrinol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1093\/humupd\/dmn011","article-title":"Oxidative stress and antioxidants: Exposure and impact on female fertility","volume":"14","author":"Ruder","year":"2008","journal-title":"Hum. Reprod. Update"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1089\/ars.2007.1964","article-title":"Redox Considerations in Female Reproductive Function and Assisted Reproduction: From Molecular Mechanisms to Health Implications","volume":"10","author":"Agarwal","year":"2008","journal-title":"Antioxid. Redox Signal."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1095\/biolreprod.111.095224","article-title":"Roles of reactive oxygen species and antioxidants in ovarian toxicity","volume":"86","author":"Devine","year":"2012","journal-title":"Biol. Reprod."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1016\/j.rbmo.2012.08.004","article-title":"Roles of antioxidant enzymes in corpus luteum rescue from reactive oxygen species-induced oxidative stress","volume":"25","author":"Garrel","year":"2012","journal-title":"Reprod. Biomed. Online"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1186\/1477-7827-10-49","article-title":"The effects of oxidative stress on female reproduction: A review","volume":"10","author":"Agarwal","year":"2012","journal-title":"Reprod. Biol. Endocrinol."},{"key":"ref_46","first-page":"1083","article-title":"Insights into iron and nuclear factor-kappa B (NF-\u03baB) involvement in chronic inflammatory processes in peritoneal endometriosis","volume":"26","author":"Lousse","year":"2011","journal-title":"Histol. Histopathol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/S0015-0282(02)02959-X","article-title":"Oxidative stress and peritoneal endometriosis","volume":"77","author":"Donnez","year":"2002","journal-title":"Fertil. Steril."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1016\/j.fertnstert.2007.04.034","article-title":"Evaluation of the relationship between follicular fluid oxidative stress, ovarian hormones, and response to gonadotropin stimulation","volume":"89","author":"Appasamy","year":"2008","journal-title":"Fertil. Steril."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1369\/0022155411431734","article-title":"Age-related Accumulation of Non-heme Ferric and Ferrous Iron in Mouse Ovarian Stroma Visualized by Sensitive Non-heme Iron Histochemistry","volume":"60","author":"Asano","year":"2012","journal-title":"J. Histochem. Cytochem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1016\/j.rbmo.2009.05.005","article-title":"Factors contributing to gender differences in serum retinol and \u03b1-tocopherol in infertile couples","volume":"19","author":"Omu","year":"2009","journal-title":"Reprod. Biomed. Online"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"159","DOI":"10.4274\/jtgga.galenos.2023.2022-12-2","article-title":"Assessment of the ovarian reserve in patients with beta-thalassemia major: A prospective longitudinal study","volume":"24","author":"Toz","year":"2023","journal-title":"J. Turk. Ger. Gynecol. Assoc."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1080\/01443615.2019.1692802","article-title":"Reproductive health issues in female patients with beta-thalassaemia major: A narrative literature review","volume":"40","author":"Cassinerio","year":"2020","journal-title":"J. Obstet. Gynaecol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"BMI.S537","DOI":"10.4137\/BMI.S537","article-title":"Biomarkers of Ovarian Reserve","volume":"3","author":"Roudebush","year":"2008","journal-title":"Biomark. Insights"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1186\/s13048-023-01296-x","article-title":"Potential factors result in diminished ovarian reserve: A comprehensive review","volume":"16","author":"Zhu","year":"2023","journal-title":"J. Ovarian Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1097\/GRF.0000000000000445","article-title":"Ovarian Reserve Testing: A Review of the Options, Their Applications, and Their Limitations","volume":"62","author":"Ulrich","year":"2019","journal-title":"Clin. Obstet. Gynecol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1016\/j.fertnstert.2006.11.006","article-title":"Ultrasonography as a tool for the prediction of outcome in IVF patients: A comparative meta-analysis of ovarian volume and antral follicle count","volume":"87","author":"Hendriks","year":"2007","journal-title":"Fertil. Steril."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/s43066-024-00330-x","article-title":"Role of magnetic resonance imaging (MRI) in liver iron quantification in thalassemic (thalassemia major) patients","volume":"14","author":"Seema","year":"2024","journal-title":"Egypt. Liver J."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Haering, C., Coyne, K., Daunov, K., Anim, S., Christianson, M.S., and Flyckt, R. (2024). Ovarian Tissue Cryopreservation for Fertility Preservation in Patients with Hemoglobin Disorders: A Comprehensive Review. J. Clin. Med., 13.","DOI":"10.3390\/jcm13133631"},{"key":"ref_59","unstructured":"Feingold, K.R., Anawalt, B., Blackman, M.R., Boyce, A., Chrousos, G., Corpas, E., de Herder, W.W., Dhatariya, K., Dungan, K., and Hofland, J. (2000). Evaluation of Amenorrhea, Anovulation, and Abnormal Bleeding. Endotext [Internet], MDText.com, Inc.. Available online: http:\/\/www.ncbi.nlm.nih.gov\/books\/NBK279144\/."},{"key":"ref_60","first-page":"e30326","article-title":"Fertility with Early Reduction of Ovarian Reserve","volume":"14","author":"Kesharwani","year":"2022","journal-title":"Cureus"},{"key":"ref_61","unstructured":"Feingold, K.R., Anawalt, B., Blackman, M.R., Boyce, A., Chrousos, G., Corpas, E., de Herder, W.W., Dhatariya, K., Dungan, K., and Hofland, J. (2000). Ovarian Reserve Testing. Endotext [Internet], MDText.com, Inc.. Available online: http:\/\/www.ncbi.nlm.nih.gov\/books\/NBK279058\/."},{"key":"ref_62","first-page":"239","article-title":"A Review on Iron Chelators in Treatment of Iron Overload Syndromes","volume":"10","author":"Mobarra","year":"2016","journal-title":"Int. J. Hematol.-Oncol. Stem Cell Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1093\/humupd\/dmt037","article-title":"Individualization of controlled ovarian stimulation in IVF using ovarian reserve markers: From theory to practice","volume":"20","author":"Sunkara","year":"2014","journal-title":"Hum. Reprod. Update"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1093\/humupd\/dmu020","article-title":"Anti-M\u00fcllerian hormone: Ovarian reserve testing and its potential clinical implications. Hum","volume":"20","author":"Broer","year":"2014","journal-title":"Reprod. Update"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1210\/edrv-17-2-121","article-title":"Regulation of Ovarian Follicular Development in Primates: Facts and Hypotheses","volume":"17","author":"Gougeon","year":"1996","journal-title":"Endocr. Rev."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1093\/humrep\/deg042","article-title":"Serum anti-M\u00fcllerian hormone is more strongly related to ovarian follicular status than serum inhibin B, estradiol, FSH and LH on day 3","volume":"18","author":"Fanchin","year":"2003","journal-title":"Hum. Reprod. Oxf. Engl."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1093\/humupd\/dmt062","article-title":"The physiology and clinical utility of anti-Mullerian hormone in women","volume":"20","author":"Dewailly","year":"2014","journal-title":"Hum. Reprod. Update"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"285","DOI":"10.3349\/ymj.2019.60.3.285","article-title":"Correlation between Ovarian Reserve and Incidence of Ectopic Pregnancy after In Vitro Fertilization and Embryo Transfer","volume":"60","author":"Kim","year":"2019","journal-title":"Yonsei Med. J."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1161\/CIR.0b013e31829b2be6","article-title":"Cardiovascular function and treatment in \u03b2-thalassemia major: A consensus statement from the American Heart Association","volume":"128","author":"Pennell","year":"2013","journal-title":"Circulation"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.freeradbiomed.2015.07.019","article-title":"Iron and oxidative stress in cardiomyopathy in thalassemia","volume":"88","author":"Berdoukas","year":"2015","journal-title":"Free Radic. Biol. Med."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"e2015047","DOI":"10.4084\/mjhid.2015.047","article-title":"Late-onset Male Hypogonadism and Fertility Potential in Thalassemia Major Patients: Two Emerging Issues","volume":"7","author":"Soliman","year":"2015","journal-title":"Mediterr. J. Hematol. Infect. Dis."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Michalczyk, K., and Cymbaluk-P\u0142oska, A. (2021). Fertility Preservation and Long-Term Monitoring of Gonadotoxicity in Girls, Adolescents and Young Adults Undergoing Cancer Treatment. Cancers, 13.","DOI":"10.3390\/cancers13020202"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"e192","DOI":"10.1016\/j.bbmt.2020.03.025","article-title":"Fertility Concerns and Access to Care for Stem Cell Transplantation Candidates with Sickle Cell Disease","volume":"26","author":"Mishkin","year":"2020","journal-title":"Biol. Blood Marrow Transplant."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Dolmans, M.M., Hossay, C., Nguyen, T.Y.T., and Poirot, C. (2021). Fertility Preservation: How to Preserve Ovarian Function in Children, Adolescents and Adults. J. Clin. Med., 10.","DOI":"10.3390\/jcm10225247"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1146476","DOI":"10.3389\/fendo.2023.1146476","article-title":"Ovarian stimulation and oocyte cryopreservation in females and transgender males aged 18 years or less: A systematic review","volume":"14","author":"Slonim","year":"2023","journal-title":"Front. Endocrinol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1147898","DOI":"10.3389\/fendo.2023.1147898","article-title":"Fertility preservation in pediatric healthcare: A review","volume":"14","author":"Chen","year":"2023","journal-title":"Front. Endocrinol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1186\/s12884-023-06112-4","article-title":"Analysis of controlled ovarian hyperstimulation protocols in women over 35 years old with poor ovarian response: A real-world study","volume":"23","author":"Duan","year":"2023","journal-title":"BMC Pregnancy Childbirth"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"ESHRE Working Group on Ultrasound in ART, D\u2019Angelo, A., Panayotidis, C., Amso, N., Marci, R., Matorras, R., Onofriescu, M., Turp, A.B., Vandekerckhove, F., and Veleva, Z. (2019). Recommendations for good practice in ultrasound: Oocyte pick up\u2020. Hum. Reprod. Open, 2019, hoz025.","DOI":"10.1093\/hropen\/hoz025"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.tjog.2011.01.014","article-title":"Update on management of ovarian hyperstimulation syndrome","volume":"50","author":"Chen","year":"2011","journal-title":"Taiwan J. Obstet. Gynecol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/s10815-010-9387-6","article-title":"Ovarian hyperstimulation syndrome: Pathophysiology and prevention","volume":"27","author":"Nastri","year":"2010","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1002\/ajh.25821","article-title":"Vaso-occlusive crisis and acute chest syndrome in sickle cell disease due to 2019 novel coronavirus disease (COVID-19)","volume":"95","author":"Nur","year":"2020","journal-title":"Am. J. Hematol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"985525","DOI":"10.3389\/fendo.2022.985525","article-title":"Fertility preservation for pediatric patients with hemoglobinopathies: Multidisciplinary counseling needed to optimize outcomes","volume":"13","author":"Bedrick","year":"2022","journal-title":"Front. Endocrinol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1007\/s10815-019-01639-y","article-title":"Ovarian stimulation is a safe and effective fertility preservation option in the adolescent and young adult population","volume":"37","author":"Manuel","year":"2020","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1093\/humrep\/dew084","article-title":"The medical and ethical challenges of fertility preservation in teenage girls: A case series of sickle cell anaemia patients prior to bone marrow transplant","volume":"31","author":"Lavery","year":"2016","journal-title":"Hum. Reprod."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"S131","DOI":"10.3109\/03630260903365023","article-title":"Current Perspectives of Fertility and Pregnancy in Thalassemia","volume":"33","author":"Bajoria","year":"2009","journal-title":"Hemoglobin"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"636","DOI":"10.3109\/03630269.2011.623809","article-title":"Hypogonadotrophic Hypogonadism and Diminished Gonadal Reserve Accounts for Dysfunctional Gametogenesis in Thalassaemia Patients with Iron Overload Presenting with Infertility","volume":"35","author":"Bajoria","year":"2011","journal-title":"Hemoglobin"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1657","DOI":"10.1056\/NEJMra1614676","article-title":"Fertility Preservation in Women","volume":"377","author":"Donnez","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1016\/j.clinthera.2019.12.003","article-title":"Systematic Literature Review of the Burden of Disease and Treatment for Transfusion-dependent \u03b2-Thalassemia","volume":"42","author":"Betts","year":"2020","journal-title":"Clin. Ther."},{"key":"ref_89","first-page":"501","article-title":"Analysis of ovarian reserve markers (AMH, FSH, AFC) in different age strata in IVF\/ICSI patients","volume":"14","author":"Mehrabi","year":"2016","journal-title":"Int. J. Reprod. Biomed."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3892\/br.2020.1355","article-title":"Novel genetic therapeutic approaches for modulating the severity of \u03b2-thalassemia (Review)","volume":"13","author":"Amjad","year":"2020","journal-title":"Biomed. Rep."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1038\/nrn3475","article-title":"Power failure: Why small sample size undermines the reliability of neuroscience","volume":"14","author":"Button","year":"2013","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Paw\u0142owski, P., Zi\u0119tara, K.J., Michalczyk, J., Fryze, M., Buchacz, A., Zaucha-Pra\u017cmo, A., Zawitkowska, J., Torres, A., and Samardakiewicz, M. (2023). Fertility Preservation in Children and Adolescents during Oncological Treatment\u2014A Review of Healthcare System Factors and Attitudes of Patients and Their Caregivers. Cancers, 15.","DOI":"10.3390\/cancers15174393"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"103767","DOI":"10.1016\/j.rbmo.2023.103767","article-title":"Fertility preservation in patients undergoing gonadotoxic treatments: A Canadian Fertility and Andrology Society clinical practice guideline","volume":"48","author":"Roberts","year":"2024","journal-title":"Reprod. Biomed. Online"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1177\/1933719117702251","article-title":"Current Success and Efficiency of Autologous Ovarian Transplantation: A Meta-Analysis","volume":"24","author":"Pacheco","year":"2017","journal-title":"Reprod. Sci."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1093\/humrep\/dei268","article-title":"Restoration of ovarian function after orthotopic (intraovarian and periovarian) transplantation of cryopreserved ovarian tissue in a woman treated by bone marrow transplantation for sickle cell anaemia: Case report","volume":"21","author":"Donnez","year":"2006","journal-title":"Hum. Reprod."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"593718","DOI":"10.3389\/fendo.2020.593718","article-title":"Consequences of \u03b2-Thalassemia or Sickle Cell Disease for Ovarian Follicle Number and Morphology in Girls Who Had Ovarian Tissue Cryopreserved","volume":"11","author":"Mamsen","year":"2021","journal-title":"Front. 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