{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T15:57:08Z","timestamp":1791561428991,"version":"4.3.4"},"reference-count":26,"publisher":"American Medical Association (AMA)","issue":"10","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"\n Importance<\/jats:title>\n Childhood cancer treatment can result in male infertility. Understanding which patients are at risk of future infertility would facilitate early fertility counseling.<\/jats:p>\n <\/jats:sec>\n \n Objectives<\/jats:title>\n To investigate associations between pubertal reproductive hormone levels and adult gonadal outcomes and cancer treatment exposures.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n This cohort study was conducted at Helsinki Children\u2019s Hospital among male childhood cancer survivors who received a diagnosis under the age of 17 years between 1964 and 2000, for whom at least 1 reproductive hormone concentration (measured 1982-2017) was available. Data were analyzed from May to December 2025.<\/jats:p>\n <\/jats:sec>\n \n Exposure<\/jats:title>\n Alkylating chemotherapy, quantified using cyclophosphamide equivalent dose (CED), and testicular radiotherapy.<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n \n Serum hormone levels (follicle-stimulating hormone [FSH], luteinizing hormone [LH], or testosterone) were collected at 2-year intervals between ages 12 and 18 years and at age 20 or older; hormone concentrations were converted to age-specific\n z<\/jats:italic>\n scores. Data on gonadal outcomes were obtained in adulthood.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n The study included 221 childhood cancer survivors (median age at diagnosis, 6.0 years [IQR, 3.2-11.7 years]). FSH showed a dose-dependent pattern with testicular radiotherapy, with elevated FSH\n z<\/jats:italic>\n scores seen from age 12 years among patients who received more than 1 Gy of testicular radiotherapy. Compared with the group that received less than 4 g\/m\n 2<\/jats:sup>\n CED (median FSH\n z<\/jats:italic>\n score, 0.1; IQR, \u22121.2 to 1.2) at age 18 years, higher FSH\n z<\/jats:italic>\n scores occurred among patients who received 4 to less than 12 g\/m\n 2<\/jats:sup>\n CED (median FSH\n z<\/jats:italic>\n score, 1.4; IQR, 0.5-2.6;\n P<\/jats:italic>\n \u2009=\u2009.04) or received 12 g\/m\n 2<\/jats:sup>\n or more CED (median FSH\n z<\/jats:italic>\n score, 1.6; IQR, 0.7-2.5;\n P<\/jats:italic>\n \u2009=\u2009.007). There was evidence of normalization at age 20 years or older for patients who received 4 to less than 12 g\/m\n 2<\/jats:sup>\n CED (median FSH\n z<\/jats:italic>\n score, 0.7; IQR, \u22120.6 to 1.7) but not those who received 12 g\/m\n 2<\/jats:sup>\n or more CED (median FSH\n z<\/jats:italic>\n score, 1.7; IQR, 0.9-2.5). The highest FSH\n z<\/jats:italic>\n score at age 14 to 16 years was associated with azoospermia in adulthood, with an optimal cutoff corresponding to 11.2 IU\/L at age 14 years and 12.5 IU\/L at age 16 years (area under the curve, 0.87). Elevated LH\n z<\/jats:italic>\n scores occurred from age 12 years onward among patients receiving more than 14 Gy of radiotherapy, but exposure to high CED was not associated with impaired Leydig cell function.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n In this cohort study of male patients treated for childhood cancer, gonadotrophin levels during puberty were associated with future testicular function. Impairment of testicular function after radiotherapy persisted into adulthood, while there was evidence of recovery after alkylating chemotherapy. The results suggest increased sensitivity of the Sertoli cell\u2013germ cell compartment compared with Leydig cells. These findings can be used to guide reproductive counseling for male survivors of childhood cancer.<\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2026.38294","type":"journal-article","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T15:30:26Z","timestamp":1791559826000},"page":"e2638294","source":"Crossref","is-referenced-by-count":0,"title":["Pubertal Testicular Function in Childhood Cancer Survivors and Future Fertility"],"prefix":"10.1001","volume":"9","author":[{"given":"Mikael","family":"Koskela","sequence":"first","affiliation":[{"name":"Children\u2019s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland"},{"name":"Department of Women\u2019s and Children\u2019s Health, Karolinska Institute and University Hospital, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen","family":"Duffin","sequence":"additional","affiliation":[{"name":"Centre for Reproductive Health, Institute of Regeneration and Repair, University of Edinburgh, Edinburgh, United Kingdom"},{"name":"Royal Hospital for Children and Young People, Edinburgh, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Korhonen","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikko","family":"Anttonen","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry, University of Helsinki and Helsinki University Hospital, Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanne","family":"Frederiksen","sequence":"additional","affiliation":[{"name":"Department of Growth and Reproduction, Copenhagen University Hospital\u2013Rigshospitalet, Copenhagen, Denmark"},{"name":"International Research Centre for Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital\u2013Rigshospitalet, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anders","family":"Juul","sequence":"additional","affiliation":[{"name":"Department of Growth and Reproduction, Copenhagen University Hospital\u2013Rigshospitalet, Copenhagen, Denmark"},{"name":"International Research Centre for Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital\u2013Rigshospitalet, Copenhagen, Denmark"},{"name":"Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rod T.","family":"Mitchell","sequence":"additional","affiliation":[{"name":"Centre for Reproductive Health, Institute of Regeneration and Repair, University of Edinburgh, Edinburgh, United Kingdom"},{"name":"Royal Hospital for Children and Young People, Edinburgh, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsi","family":"Jahnukainen","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland"},{"name":"Department of Women\u2019s and Children\u2019s Health, Karolinska Institute and University Hospital, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","published-online":{"date-parts":[[2026,10,9]]},"reference":[{"issue":"2","key":"zoi261031r1","doi-asserted-by":"publisher","first-page":"R69","DOI":"10.1530\/EC-17-0382","article-title":"Cancer treatment in childhood and testicular function: the importance of the somatic environment.","volume":"7","author":"Stukenborg","year":"2018","journal-title":"Endocr Connect"},{"issue":"12","key":"zoi261031r2","doi-asserted-by":"publisher","first-page":"1525","DOI":"10.1016\/S1470-2045(22)00637-4","article-title":"Long-term survival and cure fraction estimates for childhood cancer in Europe (EUROCARE-6): results from a population-based study.","volume":"23","author":"Botta","year":"2022","journal-title":"Lancet Oncol"},{"issue":"3","key":"zoi261031r3","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1007\/s10654-018-0370-3","article-title":"The PanCareSurFup cohort of 83,333 five-year survivors of childhood cancer: a cohort from 12 European countries.","volume":"33","author":"Grabow","year":"2018","journal-title":"Eur J Epidemiol"},{"issue":"2","key":"zoi261031r4","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1016\/S0022-3476(97)70345-7","article-title":"Gonadal function after bone marrow transplantation for acute leukemia during childhood.","volume":"130","author":"Sarafoglou","year":"1997","journal-title":"J Pediatr"},{"key":"zoi261031r5","doi-asserted-by":"publisher","DOI":"10.1016\/j.mam.2024.101308","article-title":"Impacts of cancer therapy on male fertility: past and present.","volume":"100","author":"Duffin","year":"2024","journal-title":"Mol Aspects Med"},{"issue":"2","key":"zoi261031r6","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1007\/s00520-014-2366-1","article-title":"Fertility as a priority among at-risk adolescent males newly diagnosed with cancer and their parents.","volume":"23","author":"Klosky","year":"2015","journal-title":"Support Care Cancer"},{"issue":"2","key":"zoi261031r7","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1089\/jayao.2014.0007","article-title":"Fertility preservation preferences and perspectives among adult male survivors of pediatric cancer and their parents.","volume":"3","author":"Stein","year":"2014","journal-title":"J Adolesc Young Adult Oncol"},{"issue":"2","key":"zoi261031r8","doi-asserted-by":"publisher","first-page":"e57","DOI":"10.1016\/S1470-2045(20)30582-9","article-title":"Fertility preservation for male patients with childhood, adolescent, and young adult cancer: recommendations from the PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group.","volume":"22","author":"Mulder","year":"2021","journal-title":"Lancet Oncol"},{"issue":"2","key":"zoi261031r9","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1016\/j.beem.2010.09.007","article-title":"Testicular function and fertility preservation in male cancer patients.","volume":"25","author":"Jahnukainen","year":"2011","journal-title":"Best Pract Res Clin Endocrinol Metab"},{"issue":"7","key":"zoi261031r10","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0181377","article-title":"Follicle stimulating hormone is an accurate predictor of azoospermia in childhood cancer survivors.","volume":"12","author":"Kelsey","year":"2017","journal-title":"PLoS One"},{"issue":"2","key":"zoi261031r11","doi-asserted-by":"publisher","DOI":"10.1093\/hropen\/hoae010","article-title":"A 20-year overview of fertility preservation in boys: new insights gained through a comprehensive international survey.","volume":"2024","author":"Duffin","year":"2024","journal-title":"Hum Reprod Open"},{"issue":"22","key":"zoi261031r12","doi-asserted-by":"publisher","first-page":"3633","DOI":"10.1002\/cncr.34971","article-title":"Therapeutic exposures and pubertal testicular dysfunction are associated with adulthood milestones and paternity after childhood cancer.","volume":"129","author":"Korhonen","year":"2023","journal-title":"Cancer"},{"issue":"1","key":"zoi261031r13","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.35623","article-title":"Longitudinal trends in testicular volume z scores from puberty to adulthood, sperm quality, and paternity outcomes after childhood cancer.","volume":"131","author":"Korhonen","year":"2025","journal-title":"Cancer"},{"issue":"6","key":"zoi261031r14","doi-asserted-by":"publisher","first-page":"1236","DOI":"10.1002\/ijc.35247","article-title":"Influence of therapy exposures on specific late morbidities, prescription drug purchases, and mortality in aging male survivors of childhood cancer: a registry-based study.","volume":"156","author":"Koskela","year":"2025","journal-title":"Int J Cancer"},{"issue":"2","key":"zoi261031r15","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1080\/08880018.2025.2609234","article-title":"Long-term health outcomes in male survivors of childhood cancer after hematopoietic stem cell transplantation: a registry-based study.","volume":"43","author":"Koskela","year":"2026","journal-title":"Pediatr Hematol Oncol"},{"issue":"1","key":"zoi261031r16","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1002\/pbc.24679","article-title":"The cyclophosphamide equivalent dose as an approach for quantifying alkylating agent exposure: a report from the Childhood Cancer Survivor Study.","volume":"61","author":"Green","year":"2014","journal-title":"Pediatr Blood Cancer"},{"issue":"2","key":"zoi261031r17","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1667\/RR15201.1","article-title":"Adaptations to a generalized radiation dose reconstruction methodology for use in epidemiologic studies: an update from the MD Anderson Late Effect Group.","volume":"192","author":"Howell","year":"2019","journal-title":"Radiat Res"},{"issue":"1","key":"zoi261031r18","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1080\/00365510701496496","article-title":"Determination of testosterone in serum by liquid chromatography\u2013tandem mass spectrometry.","volume":"68","author":"Turpeinen","year":"2008","journal-title":"Scand J Clin Lab Invest"},{"issue":"10","key":"zoi261031r19","doi-asserted-by":"publisher","first-page":"2323","DOI":"10.1093\/humrep\/deaa182","article-title":"The LH\/FSH ratio is not a sex-dimorphic marker after infancy: data from 6417 healthy individuals and 125 patients with differences of sex development.","volume":"35","author":"Ljubicic","year":"2020","journal-title":"Hum Reprod"},{"key":"zoi261031r20","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2024.119852","article-title":"Sex- and age-specific reference intervals of 16 steroid metabolites quantified simultaneously by LC-MS\/MS in sera from 2458 healthy subjects aged 0 to 77 years.","volume":"562","author":"Frederiksen","year":"2024","journal-title":"Clin Chim Acta"},{"issue":"7","key":"zoi261031r21","doi-asserted-by":"publisher","first-page":"2004","DOI":"10.1210\/clinem\/dgac155","article-title":"Reference curves for pediatric endocrinology: leveraging biomarker z-scores for clinical classifications.","volume":"107","author":"Madsen","year":"2022","journal-title":"J Clin Endocrinol Metab"},{"issue":"8","key":"zoi261031r22","doi-asserted-by":"publisher","first-page":"1771","DOI":"10.1111\/andr.13629","article-title":"Pubertal testicular volume references for ruler, orchidometer, and ultrasonography measurements based on a longitudinal follow-up.","volume":"12","author":"Koskela","year":"2024","journal-title":"Andrology"},{"issue":"10","key":"zoi261031r23","doi-asserted-by":"publisher","first-page":"1352","DOI":"10.1530\/EC-21-0154","article-title":"Childhood reproductive hormone levels after pediatric hematopoietic stem cell transplantation in relation to adult testicular function.","volume":"10","author":"Mathiesen","year":"2021","journal-title":"Endocr Connect"},{"issue":"11","key":"zoi261031r24","doi-asserted-by":"publisher","first-page":"1215","DOI":"10.1016\/S1470-2045(14)70408-5","article-title":"Cumulative alkylating agent exposure and semen parameters in adult survivors of childhood cancer: a report from the St Jude Lifetime Cohort Study.","volume":"15","author":"Green","year":"2014","journal-title":"Lancet Oncol"},{"issue":"8","key":"zoi261031r25","first-page":"1391","article-title":"ESHRE good practice recommendations on fertility preservation involving testicular tissue cryopreservation in children receiving gonadotoxic therapies.","volume":"40","author":"Mitchell","year":"2025","journal-title":"Hum Reprod"},{"issue":"1","key":"zoi261031r26","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1111\/andr.12550","article-title":"An update on semen quality among young Finnish men and comparison with Danish data.","volume":"7","author":"Rodprasert","year":"2019","journal-title":"Andrology"}],"container-title":["JAMA Network Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/articlepdf\/2855119\/koskela_2026_oi_261031_1790955531.40612.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T15:30:27Z","timestamp":1791559827000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/fullarticle\/2855119"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,9]]},"references-count":26,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2026,10,1]]}},"URL":"https:\/\/doi.org\/10.1001\/jamanetworkopen.2026.38294","relation":{},"ISSN":["2574-3805"],"issn-type":[{"value":"2574-3805","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,9]]}}}