{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T15:52:15Z","timestamp":1753890735379,"version":"3.41.2"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,8,10]],"date-time":"2021-08-10T00:00:00Z","timestamp":1628553600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Insulin-like factor 3 (INSL3) is produced in the testes and has been proposed as a circulating biomarker of Leydig cell capacity, but remains undescribed in 45,X\/46,XY mosaicism. The aim was to examine serum concentrations and gonadal expression of INSL3 in 45,X\/46,XY mosaicism.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Retrospectively collected data from medical records, gonadal tissue samples, and prospectively analyzed serum samples from eighteen male patients with 45,X\/46,XY mosaicism (one prepubertal, four testosterone-treated, 13 untreated) were included. Biochemical, clinical, and histological outcomes were evaluated according to serum INSL3 concentrations, quantified by LC-MS\/MS methodology, and gonadal INSL3 immunohistochemical expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Serum INSL3 concentrations spanned from below to above the reference range. In untreated patients, the median serum INSL3 SD score was -0.80 (IQR: -1.65 to 0.55) and no significant difference was observed between INSL3 and testosterone. There was no clear association between serum INSL3 and External Genitalia Score at diagnosis, spontaneous puberty, or sperm concentration. INSL3 and CYP11A1 expression overlapped, except for less pronounced INSL3 expression in areas with severe Leydig cell hyperplasia. No other apparent links between INSL3 expression and histological outcomes were observed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>In this pilot study, serum INSL3 concentrations ranged and seemed independent of other reproductive hormones and clinical features in males with 45,X\/46,XY mosaicism. Discordant expression of INSL3 and CYP11A1 may explain low INSL3 and normal testosterone concentrations in some patients. Further studies are needed to elucidate the divergence between serum INSL3 and testosterone and the potential clinical use of INSL3.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2021.709954","type":"journal-article","created":{"date-parts":[[2021,8,10]],"date-time":"2021-08-10T05:23:55Z","timestamp":1628573035000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Serum Concentrations and Gonadal Expression of INSL3 in Eighteen Males With 45,X\/46,XY Mosaicism"],"prefix":"10.3389","volume":"12","author":[{"given":"Marie Lindhardt","family":"Ljubicic","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne","family":"J\u00f8rgensen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lise","family":"Aksglaede","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John Erik","family":"Nielsen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jakob","family":"Albrethsen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anders","family":"Juul","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Trine Holm","family":"Johannsen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,8,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2013-2288","article-title":"Insulin-Like Peptide 3 (INSL3) in Men With Congenital Hypogonadotropic Hypogonadism\/Kallmann Syndrome and Effects of Different Modalities of Hormonal Treatment: A Single-Center Study of 281 Patients","volume":"99","author":"Trabado","year":"2014","journal-title":"J Clin Endocrinol Metab"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1097\/MED.0b013e3283398ee2","article-title":"Androgens and Obesity","volume":"17","author":"Allan","year":"2010","journal-title":"Curr Opin Endocrinol Diabetes Obes"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgaa145","article-title":"Evaluation of Serum Insulin-Like Factor 3 Quantification by LC-MS\/MS as a Biomarker of Leydig Cell Function","volume":"105","author":"Albrethsen","year":"2020","journal-title":"J Clin Endocrinol Metab"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0307061101","article-title":"Paracrine Regulation of Mammalian Oocyte Maturation and Male Germ Cell Survival","volume":"101","author":"Kawamura","year":"2004","journal-title":"Proc Natl Acad Sci"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M600472200","article-title":"Analogs of Insulin-Like Peptide 3 (INSL3) B-Chain Are LGR8 Antagonists In Vitro and In Vivo","volume":"281","author":"Del Borgo","year":"2006","journal-title":"J Biol Chem"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod.113.108969","article-title":"INSL3 as a Biomarker of Leydig Cell Functionality","volume":"88","author":"Ivell","year":"2013","journal-title":"Biol Reprod"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2004-2257","article-title":"Andersson a-M. Insulin-Like Factor 3 Serum Levels in 135 Normal Men and 85 Men With Testicular Disorders: Relationship to the Luteinizing Hormone-Testosterone Axis","volume":"90","author":"Bay","year":"2005","journal-title":"J Clin Endocrinol Metab"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgaa603","article-title":"Insulin-Like Factor 3 Emerges From the Shadow of Testosterone as a Leydig Cell Biomarker","volume":"106","author":"Toppari","year":"2021","journal-title":"J Clin Endocrinol Metab"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/deu124","article-title":"Expression Patterns of DLK1 and INSL3 Identify Stages of Leydig Cell Differentiation During Normal Development and in Testicular Pathologies, Including Testicular Cancer and Klinefelter Syndrome","volume":"29","author":"Lottrup","year":"2014","journal-title":"Hum Reprod"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/deaa271","article-title":"Age-Related Changes in Human Leydig Cell Status","volume":"35","author":"Mularoni","year":"2020","journal-title":"Hum Reprod"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20225717","article-title":"Blood Testis Barrier and Somatic Cells Impairment in a Series of 35 Adult Klinefelter Syndrome Patients","volume":"20","author":"Giudice","year":"2019","journal-title":"Int J Mol Sci"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2018-02752","article-title":"Clinical But Not Histological Outcomes in Males With 45,X\/46,XY Mosaicism Vary Depending on Reason for Diagnosis","volume":"104","author":"Ljubicic","year":"2019","journal-title":"J Clin Endocrinol Metab"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2012-1388","article-title":"45,X\/46,XY Mosaicism: Phenotypic Characteristics, Growth, and Reproductive Function\u2013a Retrospective Longitudinal Study","volume":"97","author":"Lindhardt Johansen","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-11-0756","article-title":"Impaired Puberty, Fertility, and Final Stature in 45,X\/46,XY Mixed Gonadal Dysgenetic Patients Raised as Boys","volume":"166","author":"Martinerie","year":"2012","journal-title":"Eur J Endocrinol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1159\/000281468","article-title":"Children With 45,X\/46,XY Karyotype From Birth to Adult Height","volume":"74","author":"Tosson","year":"2010","journal-title":"Horm Res Paediatr"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2011-0232","article-title":"Gonadal Pathology and Tumor Risk in Relation to Clinical Characteristics in Patients With 45,X\/46,XY Mosaicism","volume":"96","author":"Cools","year":"2011","journal-title":"J Clin Endocrinol Metab"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-18-0309","article-title":"Should 45,X\/46,XY Boys With No or Mild Anomaly of External Genitalia be Investigated and Followed Up","volume":"179","author":"Dumeige","year":"2018","journal-title":"Eur J Endocrinol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1007\/s00431-011-1600-9","article-title":"Description of Children With 45,X\/46,XY Karyotype","volume":"171","author":"Tosson","year":"2012","journal-title":"Eur J Pediatr"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1159\/000329477","article-title":"Gonadal Development and Tumor Formation at the Crossroads of Male and Female Sex Determination","volume":"5","author":"Cools","year":"2011","journal-title":"Sex Dev"},{"key":"B20","doi-asserted-by":"publisher","first-page":"899","DOI":"10.1515\/jpem-2017-0039","article-title":"45,X\/46,XY Ovotesticular Disorder of Sex Development Revisited: Undifferentiated Gonadal Tissue may be Mistaken as Ovarian Tissue","volume":"30","author":"De Andrade","year":"2017","journal-title":"J Pediatr Endocrinol Metab"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpag.2014.09.016","article-title":"Occurrence of Gonadoblastoma in Patients With 45,X\/46,XY Mosaicism","volume":"28","author":"Dendrinos","year":"2015","journal-title":"J Pediatr Adolesc Gynecol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2265.2007.02859.x","article-title":"Impact of the Y-Containing Cell Line on Histological Differentiation Patterns in Dysgenetic Gonads","volume":"67","author":"Cools","year":"2007","journal-title":"Clin Endocrinol (Oxf)"},{"key":"B23","doi-asserted-by":"publisher","first-page":"e13009","DOI":"10.1111\/and.13009","article-title":"Clinical Aspects of 49 Infertile Males With 45,X\/46,XY Mosaicism Karyotype: A Case Series","volume":"50","author":"Mohammadpour Lashkari","year":"2018","journal-title":"Andrologia"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1159\/000455260","article-title":"The Clinical Manifestation and Genetic Evaluation in Patients With 45,X\/46,XY Mosaicism","volume":"11","author":"Wu","year":"2017","journal-title":"Sex Dev"},{"key":"B25","doi-asserted-by":"publisher","first-page":"108","DOI":"10.5489\/cuaj.1574","article-title":"45,X\/46,XY Mixed Gonadal Dysgenesis: A Case of Successful Sperm Extraction","volume":"8","author":"Flannigan","year":"2014","journal-title":"Can Urol Assoc J"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgz142","article-title":"The External Genitalia Score (Egs): A European Multicenter Validation Study","volume":"105","author":"van der Straaten","year":"2020","journal-title":"J Clin Endocrinol Metab"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1111\/andr.12508","article-title":"Quantification of the Leydig Cell Compartment in Testicular Biopsies and Association With Biochemical Leydig Cell Dysfunction in Testicular Cancer Survivors","volume":"6","author":"Tarsitano","year":"2018","journal-title":"Andrology"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1515\/cclm-2018-0171","article-title":"Development and Validation of a Mass Spectrometry-Based Assay for Quantification of Insulin-Like Factor 3 in Human Serum","volume":"56","author":"Albrethsen","year":"2018","journal-title":"Clin Chem Lab Med"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2017.03.002","article-title":"Isotope-Dilution Turboflow-LC-MS\/MS Method for Simultaneous Quantification of Ten Steroid Metabolites in Serum","volume":"468","author":"S\u00f8eborg","year":"2017","journal-title":"Clin Chim Acta"},{"key":"B30","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1016\/j.cca.2014.06.018","article-title":"Sex, Age, Pubertal Development and Use of Oral Contraceptives in Relation to Serum Concentrations of DHEA, DHEAS, 17\u03b1-Hydroxyprogesterone, \u03944-Androstenedione, Testosterone and Their Ratios in Children, Adolescents and Young Adults","volume":"437","author":"S\u00f8eborg","year":"2014","journal-title":"Clin Chim Acta"},{"key":"B31","doi-asserted-by":"publisher","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":"B32","doi-asserted-by":"publisher","DOI":"10.1111\/j.2047-2927.2014.00204.x","article-title":"Low INSL3 in Klinefelter Syndrome Is Related to Osteocalcin, Testosterone Treatment and Body Composition, as Well as Measures of the Hypothalamic-Pituitary-Gonadal Axis","volume":"2","author":"Overvad","year":"2014","journal-title":"Andrology"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2006-0669","article-title":"Serum Insulin-Like Factor 3 Levels During Puberty in Healthy Boys and Boys With Klinefelter Syndrome","volume":"91","author":"Wikstr\u00f6m","year":"2006","journal-title":"J Clin Endocrinol Metab"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1111\/andr.12851","article-title":"Effects of Acute hCG Stimulation on Serum INSL3 and 25-OH Vitamin D in Klinefelter Syndrome","volume":"8","author":"Santi","year":"2020","journal-title":"Andrology"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2350-14-115","article-title":"The Phenotype of 45,X\/46,XY Mosaicism: An Analysis of 92 Prenatally Diagnosed Cases","volume":"46","author":"Chang","year":"1990","journal-title":"Am J Hum Genet"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1007\/s12020-021-02609-0","article-title":"Serum Insulin-Like Factor 3 Quantification by LC\u2013MS\/MS in Male Patients With Hypogonadotropic Hypogonadism and Klinefelter Syndrome","volume":"71","author":"Johannsen","year":"2021","journal-title":"Endocrine"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2021.709954\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,8,10]],"date-time":"2021-08-10T05:23:58Z","timestamp":1628573038000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2021.709954\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,10]]},"references-count":36,"alternative-id":["10.3389\/fendo.2021.709954"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2021.709954","relation":{},"ISSN":["1664-2392"],"issn-type":[{"type":"electronic","value":"1664-2392"}],"subject":[],"published":{"date-parts":[[2021,8,10]]},"article-number":"709954"}}