{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T16:26:46Z","timestamp":1792081606149,"version":"4.4.0"},"reference-count":30,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T00:00:00Z","timestamp":1768348800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T00:00:00Z","timestamp":1768348800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100016003","name":"Istanbul University Cerrahpa\u015fa","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100016003","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Ann Hematol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    This study aims to explore the long-term endocrine and gonadal effects of chemotherapy and radiotherapy in female acute lymphoblastic leukemia (ALL) patients. A cohort study included girls diagnosed with ALL and treated between 2000 and 2020. Patients with at least 2 years elapsed since treatment completion were included. Endocrinological evaluations included anthropometric measures and pubertal status, as well as fasting insulin, glucose, lipid levels, and hormone assessments for adrenal, and thyroid functions. Reproductive functions were evaluated based on gonadotropin, estradiol, and anti-M\u00fcllerian hormone (AMH) levels. A total of 51 female patients were included. At the time of study participation, the mean age was 14.7 years, and the mean time since treatment completion was 9.4 years. At least one endocrine disorder was present in 39.2% of participants, with dyslipidemia, insulin resistance, and obesity being the most common. Low AMH levels (&lt;\u20091.1 ng\/dL) were found in 41.6%, particularly in those who underwent bone marrow transplantation. A significant positive correlation was found between the time elapsed since treatment and AMH levels (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001,\n                    <jats:italic>r<\/jats:italic>\n                    \u2009=\u20090.612), while age at diagnosis, risk group (standard, intermediate or high risk), and cranial radiotherapy showed no significant associations. A substantial proportion of ALL survivors developed endocrine complications, with ovarian reserve compromised in over 40% of cases. Notably, this is the first cohort study to demonstrate a significant positive correlation between AMH levels and the time elapsed since treatment, suggesting a potential for gonadal recovery except in those exposed to intensive chemotherapy or transplantation.\n                  <\/jats:p>","DOI":"10.1007\/s00277-026-06783-x","type":"journal-article","created":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T00:28:15Z","timestamp":1768350495000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Long-Term endocrine outcomes with special emphasis on the gonadal impact of acute lymphoblastic leukemia treatment in females"],"prefix":"10.1007","volume":"105","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2282-2606","authenticated-orcid":false,"given":"Hasan","family":"Karaka\u015f","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00fcrkan","family":"Tar\u00e7\u0131n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elvan","family":"Bayramo\u011flu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hande","family":"Turan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suheyla","family":"Ocak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Volkan","family":"Turan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olcay","family":"Evliyao\u011flu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiraje","family":"Tiraje","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilmi","family":"Apak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oya","family":"Ercan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,14]]},"reference":[{"key":"6783_CR1","doi-asserted-by":"publisher","first-page":"1981","DOI":"10.1016\/S0140-6736(13)62564-7","volume":"383","author":"S de Fine Licht","year":"2014","unstructured":"de Fine Licht S, Winther JF, Gudmundsdottir T et al (2014) Hospital contacts for endocrine disorders in adult life after childhood cancer in Scandinavia (ALiCCS): a population-based cohort study. Lancet 383:1981\u20131989. https:\/\/doi.org\/10.1016\/S0140-6736(13)62564-7","journal-title":"Lancet"},{"key":"6783_CR2","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1530\/EJE-12-1043","volume":"168","author":"E Brignardello","year":"2013","unstructured":"Brignardello E, Felicetti F, Castiglione A et al (2013) Endocrine health conditions in adult survivors of childhood cancer: the need for specialized adult-focused follow-up clinics. Eur J Endocrinol 168:465\u2013472. https:\/\/doi.org\/10.1530\/EJE-12-1043","journal-title":"Eur J Endocrinol"},{"key":"6783_CR3","doi-asserted-by":"publisher","first-page":"2059","DOI":"10.1210\/jc.2011-3180","volume":"97","author":"MFH Brougham","year":"2012","unstructured":"Brougham MFH, Crofton PM, Johnson EJ et al (2012) Anti-M\u00fcllerian hormone is a marker of gonadotoxicity in pre- and postpubertal girls treated for cancer: a prospective study. J Clin Endocrinol Metab 97:2059\u20132067. https:\/\/doi.org\/10.1210\/jc.2011-3180","journal-title":"J Clin Endocrinol Metab"},{"key":"6783_CR4","doi-asserted-by":"publisher","DOI":"10.1097\/01.gme.0000232032.84788.8c","author":"L Tauchmanov\u00e0","year":"2007","unstructured":"Tauchmanov\u00e0 L, Selleri C, De Rosa G et al (2007) Estrogen-progestin therapy in women after stem cell transplant: our experience and literature review. Menopause. https:\/\/doi.org\/10.1097\/01.gme.0000232032.84788.8c","journal-title":"Menopause"},{"key":"6783_CR5","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1093\/humupd\/dmh021","volume":"10","author":"M Sonmezer","year":"2004","unstructured":"Sonmezer M, Oktay K (2004) Fertility preservation in female patients. Hum Reprod Update 10:251\u2013266. https:\/\/doi.org\/10.1093\/humupd\/dmh021","journal-title":"Hum Reprod Update"},{"key":"6783_CR6","doi-asserted-by":"publisher","first-page":"1307","DOI":"10.1634\/theoncologist.2013-0138","volume":"18","author":"R Di Paola","year":"2013","unstructured":"Di Paola R, Costantini C, Tecchio C et al (2013) Anti-M\u00fcllerian hormone and antral follicle count reveal a late impairment of ovarian reserve in patients undergoing low-gonadotoxic regimens for hematological malignancies. Oncologist 18:1307\u20131314. https:\/\/doi.org\/10.1634\/theoncologist.2013-0138","journal-title":"Oncologist"},{"key":"6783_CR7","first-page":"426","volume":"47","author":"L Yuksel-Soycan","year":"2007","unstructured":"Yuksel-Soycan L (2007) BFM-TR ALL 2000: first Turkish multicentric study in the treatment of pediatric acute lymphoblastic leukemia. Pediatr Blood Cancer 47:426","journal-title":"Pediatr Blood Cancer"},{"key":"6783_CR8","unstructured":"BFM Study Group (2009) ALL IC-BFM 2009: International Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia Treatment Protocol"},{"key":"6783_CR9","doi-asserted-by":"publisher","first-page":"280","DOI":"10.4274\/jcrpe.2183","volume":"7","author":"O Neyzi","year":"2015","unstructured":"Neyzi O, Bundak R, G\u00f6k\u00e7ay G et al (2015) Reference values for weight, height, head circumference, and body mass index in Turkish children. J Clin Res Pediatr Endocrinol 7:280\u201393. https:\/\/doi.org\/10.4274\/jcrpe.2183","journal-title":"J Clin Res Pediatr Endocrinol"},{"key":"6783_CR10","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1542\/pir.2016-0178","volume":"38","author":"LR Braun","year":"2017","unstructured":"Braun LR, Marino R (2017) Disorders of growth and stature. Pediatr Rev 38:293\u2013304. https:\/\/doi.org\/10.1542\/pir.2016-0178","journal-title":"Pediatr Rev"},{"key":"6783_CR11","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2022-060640","author":"SE Hampl","year":"2023","unstructured":"Hampl SE, Hassink SG, Skinner AC et al (2023) Clinical practice guideline for the evaluation and treatment of children and adolescents with obesity. Pediatrics. https:\/\/doi.org\/10.1542\/peds.2022-060640","journal-title":"Pediatrics"},{"key":"6783_CR12","doi-asserted-by":"publisher","first-page":"100","DOI":"10.4274\/jcrpe.v2i3.100","volume":"2","author":"S Kurto\u011flu","year":"2010","unstructured":"Kurto\u011flu S, Hatipo\u011flu N, Maz\u0131c\u0131o\u011flu M et al (2010) Insulin resistance in obese children and adolescents: HOMA-IR cut-off levels in the prepubertal and pubertal periods. J Clin Res Pediatr Endocrinol 2:100\u2013106. https:\/\/doi.org\/10.4274\/jcrpe.v2i3.100","journal-title":"J Clin Res Pediatr Endocrinol"},{"key":"6783_CR13","doi-asserted-by":"crossref","unstructured":"Carmina E, Stanczyk FZ, Lobo RA (2014) In: Strauss JF, Barbieri RLBT, -Y&, Seventh JRE E (eds) Chap. 34 - Laboratory assessment. W.B. Saunders, Philadelphia, pp 822\u2013850e3","DOI":"10.1016\/B978-1-4557-2758-2.00034-2"},{"key":"6783_CR14","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1542\/peds.2008-1349","volume":"122","author":"SR Daniels","year":"2008","unstructured":"Daniels SR, Greer FR (2008) Lipid screening and cardiovascular health in childhood. Pediatrics 122:198\u2013208. https:\/\/doi.org\/10.1542\/peds.2008-1349","journal-title":"Pediatrics"},{"key":"6783_CR15","doi-asserted-by":"publisher","first-page":"3888","DOI":"10.1210\/jc.2016-2118","volume":"101","author":"M Fleseriu","year":"2016","unstructured":"Fleseriu M, Hashim IA, Karavitaki N et al (2016) Hormonal replacement in hypopituitarism in adults: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 101:3888\u20133921. https:\/\/doi.org\/10.1210\/jc.2016-2118","journal-title":"J Clin Endocrinol Metab"},{"key":"6783_CR16","doi-asserted-by":"publisher","first-page":"1616","DOI":"10.1093\/humrep\/der092","volume":"26","author":"AP Ferraretti","year":"2011","unstructured":"Ferraretti AP, La Marca A, Fauser BCJM et al (2011) ESHRE consensus on the definition of \u2018poor response\u2019\u2019 to ovarian stimulation for in vitro fertilization: the Bologna criteria\u2020.\u2019. Hum Reprod 26:1616\u20131624. https:\/\/doi.org\/10.1093\/humrep\/der092","journal-title":"Hum Reprod"},{"key":"6783_CR17","doi-asserted-by":"publisher","DOI":"10.1016\/j.rbmo.2023.05.013","volume":"47","author":"M G\u00e9nard-Walton","year":"2023","unstructured":"G\u00e9nard-Walton M, Warembourg C, Duros S et al (2023) Heavy metals and diminished ovarian reserve: single-exposure and mixture analyses amongst women consulting in French fertility centres. Reprod Biomed Online 47:103241. https:\/\/doi.org\/10.1016\/j.rbmo.2023.05.013","journal-title":"Reprod Biomed Online"},{"key":"6783_CR18","doi-asserted-by":"publisher","first-page":"4248","DOI":"10.1002\/cncr.31736","volume":"124","author":"EK Browne","year":"2018","unstructured":"Browne EK, Zhou Y, Chemaitilly W et al (2018) Changes in body mass index, height, and weight in children during and after therapy for acute lymphoblastic leukemia. Cancer 124:4248\u20134259. https:\/\/doi.org\/10.1002\/cncr.31736","journal-title":"Cancer"},{"key":"6783_CR19","doi-asserted-by":"publisher","first-page":"3698","DOI":"10.1200\/JCO.2008.19.7251","volume":"27","author":"KC Oeffinger","year":"2009","unstructured":"Oeffinger KC, Adams-Huet B, Victor RG et al (2009) Insulin resistance and risk factors for cardiovascular disease in young adult survivors of childhood acute lymphoblastic leukemia. J Clin Oncol 27:3698\u20133704. https:\/\/doi.org\/10.1200\/JCO.2008.19.7251","journal-title":"J Clin Oncol"},{"key":"6783_CR20","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1515\/jpem.2010.23.7.669","volume":"23","author":"S Karaman","year":"2010","unstructured":"Karaman S, Ercan O, Yildiz I et al (2010) Late effects of childhood ALL treatment on body mass index and serum leptin levels. J Pediatr Endocrinol Metab 23:669\u2013674. https:\/\/doi.org\/10.1515\/jpem.2010.23.7.669","journal-title":"J Pediatr Endocrinol Metab"},{"key":"6783_CR21","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1007\/s00520-014-2394-x","volume":"23","author":"J Cohen","year":"2015","unstructured":"Cohen J, Wakefield CE, Tapsell LC et al (2015) Exploring the views of parents regarding dietary habits of their young cancer-surviving children. Support Care Cancer 23:463\u2013471. https:\/\/doi.org\/10.1007\/s00520-014-2394-x","journal-title":"Support Care Cancer"},{"key":"6783_CR22","unstructured":"Republic of Turkey Ministry of Health General Director of Public Health (2019) Turkey Nutrition and Health Survey 2017 (TNHS 2017)"},{"key":"6783_CR23","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1111\/j.1365-2141.2005.05740.x","volume":"131","author":"MFH Brougham","year":"2005","unstructured":"Brougham MFH, Wallace WHB (2005) Subfertility in children and young people treated for solid and haematological malignancies. Br J Haematol 131:143\u2013155. https:\/\/doi.org\/10.1111\/j.1365-2141.2005.05740.x","journal-title":"Br J Haematol"},{"key":"6783_CR24","doi-asserted-by":"publisher","DOI":"10.1177\/1179558119870163","volume":"13","author":"Z Blumenfeld","year":"2019","unstructured":"Blumenfeld Z (2019) Fertility preservation using GnRH agonists: rationale, possible mechanisms, and explanation of controversy. Clin Med Insights Reprod Health 13:1179558119870163. https:\/\/doi.org\/10.1177\/1179558119870163","journal-title":"Clin Med Insights Reprod Health"},{"key":"6783_CR25","doi-asserted-by":"publisher","first-page":"828","DOI":"10.1089\/jayao.2022.0128","volume":"12","author":"A Hoyos-Martinez","year":"2023","unstructured":"Hoyos-Martinez A, Scheurer ME, Allen-Rhoades W et al (2023) Leuprolide protects ovarian reserve in adolescents undergoing gonadotoxic therapy. J Adolesc Young Adult Oncol 12:828\u2013834. https:\/\/doi.org\/10.1089\/jayao.2022.0128","journal-title":"J Adolesc Young Adult Oncol"},{"key":"6783_CR26","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1093\/humupd\/dmn022","volume":"14","author":"Z Blumenfeld","year":"2008","unstructured":"Blumenfeld Z, von Wolff M (2008) GnRH-analogues and oral contraceptives for fertility preservation in women during chemotherapy. Hum Reprod Update 14:543\u2013552. https:\/\/doi.org\/10.1093\/humupd\/dmn022","journal-title":"Hum Reprod Update"},{"key":"6783_CR27","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1016\/j.fertnstert.2010.04.006","volume":"95","author":"KR Hansen","year":"2011","unstructured":"Hansen KR, Hodnett GM, Knowlton N, Craig LB (2011) Correlation of ovarian reserve tests with histologically determined primordial follicle number. Fertil Steril 95:170\u2013175. https:\/\/doi.org\/10.1016\/j.fertnstert.2010.04.006","journal-title":"Fertil Steril"},{"key":"6783_CR28","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1002\/hon.2681","volume":"37","author":"M Krawczuk-Rybak","year":"2019","unstructured":"Krawczuk-Rybak M, P\u0142onowski M, Leszczy\u0144ska E et al (2019) The influence of different intensity of treatment on hormonal markers of gonadal function in acute lymphoblastic leukemia survivors. Hematol Oncol 37:609\u2013616. https:\/\/doi.org\/10.1002\/hon.2681","journal-title":"Hematol Oncol"},{"key":"6783_CR29","doi-asserted-by":"publisher","first-page":"1922","DOI":"10.1016\/j.fertnstert.2011.02.002","volume":"95","author":"DM Green","year":"2011","unstructured":"Green DM, Nolan VG, Kawashima T et al (2011) Decreased fertility among female childhood cancer survivors who received 22\u201327 Gy hypothalamic\/pituitary irradiation: a report from the childhood cancer survivor study. Fertil Steril 95:1922\u20131927 1927.e1. https:\/\/doi.org\/10.1016\/j.fertnstert.2011.02.002","journal-title":"Fertil Steril"},{"key":"6783_CR30","doi-asserted-by":"publisher","DOI":"10.1007\/s11864-016-0426-0","volume":"17","author":"C Follin","year":"2016","unstructured":"Follin C, Erfurth EM (2016) Long-term effect of cranial radiotherapy on pituitary-hypothalamus area in childhood acute lymphoblastic leukemia survivors. Curr Treat Options Oncol 17:50. https:\/\/doi.org\/10.1007\/s11864-016-0426-0","journal-title":"Curr Treat Options Oncol"}],"container-title":["Annals of Hematology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00277-026-06783-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00277-026-06783-x","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00277-026-06783-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T03:33:54Z","timestamp":1770262434000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00277-026-06783-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,14]]},"references-count":30,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["6783"],"URL":"https:\/\/doi.org\/10.1007\/s00277-026-06783-x","relation":{},"ISSN":["1432-0584"],"issn-type":[{"value":"1432-0584","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,14]]},"assertion":[{"value":"30 June 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 November 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 January 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study protocol was approved by the local ethics committee (Approval number: 743862). Informed consent was obtained from all parents and also from the patients over 18 years of age.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"Consent for publication was obtained from all participants or their legal guardians.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to publish"}},{"value":"This study was reported in accordance with the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) statement.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Reporting guideline"}}],"article-number":"7"}}