{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T16:12:22Z","timestamp":1790611942294,"version":"4.1.0"},"reference-count":35,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2024,11,20]],"date-time":"2024-11-20T00:00:00Z","timestamp":1732060800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Male patients with congenital hypogonadotropic hypogonadism (CHH) have impaired postnatal activation of the hypothalamic\u2013pituitary\u2013gonadal axis that occurs during mini-puberty. The aim of this study was to report our experience using gonadotropin replacement therapy for mini-puberty in male infants with CHH and to establish treatment recommendations. Methods: The patients included in this retrospective case series (n = 9) were diagnosed in the postnatal period due to micropenis, with two being accompanied by cryptorchidism and four with other associated hormonal deficits. All patients started treatment with gonadotropins early after diagnosis, between 2 weeks and 5 months of age, with a schedule of discontinuous injections with subcutaneous human chorionic gonadotropin (62.5\u2013500 IU) two times per week and recombinant follicle-stimulating hormone-alpha (37.5\u201375 IU) three times per week. Results: The data from our study show an early response, ranging from almost undetectable levels of testosterone at diagnosis to elevated levels after starting treatment, as well as a positive clinical response with increases in testicular volume and penis size in all cases without requiring complementary treatment with testosterone esters and without adverse effects. Conclusions: Our results show that gonadotropin replacement therapy is a well-tolerated and effective treatment for testicular and penile problems in male patients with CHH.<\/jats:p>","DOI":"10.3390\/jcm13226983","type":"journal-article","created":{"date-parts":[[2024,11,20]],"date-time":"2024-11-20T09:14:38Z","timestamp":1732094078000},"page":"6983","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["A Therapeutic Proposal for Mini-Puberty in Male Infants with Hypogonadotropic Hypogonadism: A Retrospective Case Series"],"prefix":"10.3390","volume":"13","author":[{"given":"Mar\u00eda Aurora","family":"Mesas-Ar\u00f3stegui","sequence":"first","affiliation":[{"name":"Pediatric Endocrinology Department, Instituto Hispalense de Pediatr\u00eda, Hospital Quir\u00f3n Marbella, 29603 M\u00e1laga, Spain"},{"name":"Pediatrics Department, Hospital of Guadix, 18500 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7215-5456","authenticated-orcid":false,"given":"Fidel","family":"Hita-Contreras","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Faculty of Health Sciences, University of Ja\u00e9n, 23071 Ja\u00e9n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9282-9139","authenticated-orcid":false,"given":"Juan Pedro","family":"L\u00f3pez-Siguero","sequence":"additional","affiliation":[{"name":"Pediatric Endocrinology Department, Hospital Regional Universitario de M\u00e1laga, 29010 M\u00e1laga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"84","DOI":"10.6065\/apem.2040094.047","article-title":"Minipuberty of human infancy\u2014A window of opportunity to evaluate hypogonadism and differences of sex development?","volume":"25","author":"Renault","year":"2020","journal-title":"Ann. Pediatr. Endocrinol. Metab."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1159\/000508329","article-title":"Minipuberty: Why Does it Happen?","volume":"93","author":"Becker","year":"2020","journal-title":"Horm. Res. Paediatr."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Lucaccioni, L., Trevisani, V., Boncompagni, A., Marrozzini, L., Berardi, A., and Iughetti, L. (2021). Minipuberty: Looking Back to Understand Moving Forward. Front. Pediatr., 8.","DOI":"10.3389\/fped.2020.612235"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4020","DOI":"10.1210\/jc.2007-0974","article-title":"Insulin-like factor 3 levels in cord blood and serum from children: Effects of age, postnatal hypothalamic-pituitary-gonadal axis activation, and cryptorchidism","volume":"92","author":"Bay","year":"2007","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1530\/eje.1.02066","article-title":"Postnatal penile length and growth rate correlate to serum testosterone levels: A longitudinal study of 1962 normal boys","volume":"154","author":"Boas","year":"2006","journal-title":"Eur. J. Endocrinol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1016\/j.yhbeh.2012.02.013","article-title":"Testosterone measured in infancy predicts subsequent sex-typed behavior in boys and in girls","volume":"61","author":"Hines","year":"2012","journal-title":"Horm. Behav."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.yhbeh.2015.01.002","article-title":"Postnatal penile growth concurrent with mini-puberty predicts later sex-typed play behavior: Evidence for neurobehavioral effects of the postnatal androgen surge in typically developing boys","volume":"69","author":"Pasterski","year":"2015","journal-title":"Horm. Behav."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1560","DOI":"10.1210\/clinem\/dgac115","article-title":"Dynamic Changes of Reproductive Hormones in Male Minipuberty: Temporal Dissociation of Leydig and Sertoli Cell Activity","volume":"107","author":"Busch","year":"2022","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"O\u2019Shaughnessy, P.J., Antignac, J.P., Le Bizec, B., Morvan, M.L., Svechnikov, K., S\u00f6der, O., Savchuk, I., Monteiro, A., Soffientini, U., and Johnston, Z.C. (2019). Alternative (backdoor) androgen production and masculinization in the human fetus. PLoS Biol., 17.","DOI":"10.1371\/journal.pbio.3000002"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1530\/EC-17-0095","article-title":"Beyond hormone replacement: Quality of life in women with congenital hypogonadotropic hypogonadism","volume":"6","author":"Dzemaili","year":"2017","journal-title":"Endocr. Connect."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"160","DOI":"10.4274\/jcrpe.galenos.2023.2022-10-14","article-title":"Clinical Characteristics and Genetic Analyses of Patients with Idiopathic Hypogonadotropic Hypogonadism","volume":"15","author":"Akbulut","year":"2023","journal-title":"J. Clin. Res. Pediatr. Endocrinol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"97","DOI":"10.3389\/fendo.2019.00097","article-title":"Congenital Hypogonadotrophic Hypogonadism: Minipuberty and the Case for Neonatal Diagnosis","volume":"10","author":"Swee","year":"2019","journal-title":"Front. Endocrinol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/1750-1172-6-41","article-title":"Incidence, phenotypic features and molecular genetics of Kallmann syndrome in Finland","volume":"6","author":"Laitinen","year":"2011","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"176","DOI":"10.6065\/apem.2244208.104","article-title":"Treatment of congenital hypogonadotropic hypogonadism in male patients","volume":"27","author":"Lee","year":"2022","journal-title":"Ann. Pediatr. Endocrinol. Metab."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1080\/17446651.2022.2023008","article-title":"Current concepts surrounding neonatal hormone therapy for boys with congenital hypogonadotropic hypogonadism","volume":"17","author":"Swee","year":"2022","journal-title":"Expert. Rev. Endocrinol. Metab."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1210\/er.2018-00116","article-title":"Clinical Management of Congenital Hypogonadotropic Hypogonadism","volume":"40","author":"Young","year":"2019","journal-title":"Endocr. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1038\/nrendo.2011.164","article-title":"Neonatal gonadotropin therapy in male congenital hypogonadotropic hypogonadism","volume":"8","author":"Bouvattier","year":"2011","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_18","first-page":"217","article-title":"Micropenis: Etiology, diagnosis and treatment approaches","volume":"55","year":"2013","journal-title":"J. Clin. Res. Pediatr. Endocrinol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1159\/000439332","article-title":"Different Medications for Hypogonadotropic Hypogonadism","volume":"30","author":"Rastrelli","year":"2016","journal-title":"Endocr. Dev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1111\/ppe.12777","article-title":"Cohort profile: The COPENHAGEN Minipuberty Study\u2014A longitudinal prospective cohort of healthy full-term infants and their parents","volume":"35","author":"Busch","year":"2021","journal-title":"Paediatr. Perinat. Epidemiol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Lanciotti, L., Cofini, M., Leonardi, A., Penta, L., and Esposito, S. (2018). Up-To-Date Review About Minipuberty and Overview on Hypothalamic-Pituitary-Gonadal Axis Activation in Fetal and Neonatal Life. Front. Endocrinol., 9.","DOI":"10.3389\/fendo.2018.00410"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1111\/andr.262","article-title":"Factors affecting spermatogenesis upon gonadotropin-replacement therapy: A meta-analytic study","volume":"2","author":"Rastrelli","year":"2014","journal-title":"Andrology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1530\/eje.0.1460075","article-title":"Early postnatal treatment of hypogonadotropic hypogonadism with recombinant human FSH and LH","volume":"146","author":"Main","year":"2002","journal-title":"Eur. J. Endocrinol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2202","DOI":"10.1210\/jc.2008-0121","article-title":"Effects of an early postnatal treatment of hypogonadotropic hypogonadism with a continuous subcutaneous infusion of recombinant follicle-stimulating hormone and luteinizing hormone","volume":"93","author":"Pantalone","year":"2008","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1186\/s13023-015-0287-9","article-title":"Kallmann syndrome with FGFR1 and KAL1 mutations detected during fetal life","volume":"10","author":"Sarfati","year":"2015","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/s13633-016-0031-9","article-title":"Growth and descent of the testes in infants with hypogonadotropic hypogonadism receiving subcutaneous gonadotropin infusion","volume":"2016","author":"Lambert","year":"2016","journal-title":"Int. J. Pediatr. Endocrinol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1159\/000454861","article-title":"Efficacy and Safety of Continuous Subcutaneous Infusion of Recombinant Human Gonadotropins for Congenital Micropenis during Early Infancy","volume":"87","author":"Stoupa","year":"2017","journal-title":"Horm. Res. Paediatr."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1210\/js.2019-00083","article-title":"Replacement of Male Mini-Puberty","volume":"3","author":"Papadimitriou","year":"2019","journal-title":"J. Endocr. Soc."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1093\/humrep\/dez040","article-title":"Treatment of gonadotropin deficiency during the first year of life: Long-term observation and outcome in five boys","volume":"34","author":"Kohva","year":"2019","journal-title":"Hum. Reprod."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.anpedi.2018.02.021","article-title":"Monitorizaci\u00f3n del tratamiento del hipogonadismo hipogonadotropo en el lactante [Monitoring of the treatment of hypogonadotropic hypogonadism in the infant]","volume":"90","year":"2019","journal-title":"An. Pediatr."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e220252","DOI":"10.1530\/EC-22-0252","article-title":"Gonadotropin administration to mimic mini-puberty in hypogonadotropic males: Pump or injections?","volume":"12","author":"Avril","year":"2023","journal-title":"Endocr. Connect."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1210\/er.2018-00065","article-title":"Two Hormones for One Receptor: Evolution, Biochemistry, Actions, and Pathophysiology of LH and hCG","volume":"39","author":"Casarini","year":"2018","journal-title":"Endocr. Rev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e2867","DOI":"10.1097\/MD.0000000000002867","article-title":"Efficacy and Outcome Predictors of Gonadotropin Treatment for Male Congenital Hypogonadotropic Hypogonadism: A Retrospective Study of 223 Patients","volume":"95","author":"Liu","year":"2016","journal-title":"Medicine"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1111\/nyas.15177","article-title":"Combined gonadotropin therapy to replace mini-puberty in male infants with congenital hypogonadotropic hypogonadism","volume":"1537","author":"Howard","year":"2024","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_35","first-page":"23","article-title":"Congenital hypogonadotrophic hypogonadism, induction of minipuberty, and future fertility","volume":"2023","author":"Stuckey","year":"2023","journal-title":"Endocrinol. Diabetes Metab. Case. Rep."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/13\/22\/6983\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:35:43Z","timestamp":1760114143000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/13\/22\/6983"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,20]]},"references-count":35,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2024,11]]}},"alternative-id":["jcm13226983"],"URL":"https:\/\/doi.org\/10.3390\/jcm13226983","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,20]]}}}