{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T14:26:54Z","timestamp":1790864814510,"version":"4.1.0"},"reference-count":55,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T00:00:00Z","timestamp":1768262400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Conselho Nacional de Pesquisa","award":["307576\/2022-1"],"award-info":[{"award-number":["307576\/2022-1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,2,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The Itabaianinha cohort in Brazil carries a homozygous growth hormone-releasing hormone (GHRH) receptor (GHRH-R) gene mutation, causing congenital isolated GH deficiency (GHD). Affected individuals present with severe short stature, central obesity, hypercholesterolemia, and marked reductions in serum GH, IGF-I, and IGFBP 3 concentrations yet show no premature atherosclerosis and maintain a normal lifespan. IGF-I mostly circulates bound to IGFBPs and requires proteolytic cleavage for IGF-I receptor activation. Pregnancy-associated plasma protein A (PAPP-A) is an important IGF-dependent cleavage enzyme, binding to IGFBP 4 and releasing IGF-I. PAPP-A activity is inhibited by stanniocalcin-2 (STC2). The IGFBP 4-STC2-PAPP-A axis (ISPa) has emerged as a key regulator of IGF-I bioactivity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We evaluated the ISPa in: (1) GHD subjects with homozygous GHRH-R c.57 + 1G\u2192A mutation, (2) heterozygotes (HTZ), and (3) homozygous wild-type controls (HMZ). Parameters from the ISPa were measured at LMU Klinikum, Munich. Additional biochemical parameters were analyzed at the Federal University of Sergipe, Brazil.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>As expected, GHD subjects had markedly low GH, IGF-I, IGF-II, free IGF-I, and IGFBP 3 (P &amp;lt; .001), while HTZ resembled HMZ subjects. STC2, PAPP-A, and PAPP-A-STC2 complex concentrations did not differ between groups. However, PAPP-A2 and intact IGFBP 4 were higher in the GHD subjects (P &amp;lt; .05 and P &amp;lt; .01). Notably, IGF-I and IGFBP 3 positively correlated with IGF-II, whereas intact IGFBP 4 and PAPP-A2 showed inverse correlations with IGF-I and IGF-II.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings suggest altered IGF-I bioavailability regulation via the ISPa in congenital lifetime GHD, leading to increased PAPP-A2 proteolytic activity, reduced PAPP-A enzymatic activity, and reduced sequestration of PAPP-A2 by STC2.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/ejendo\/lvag007","type":"journal-article","created":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T12:34:19Z","timestamp":1768048459000},"page":"136-145","source":"Crossref","is-referenced-by-count":3,"title":["IGF-I bioavailability in congenital isolated growth hormone deficiency"],"prefix":"10.1093","volume":"194","author":[{"given":"Viviane C","family":"Campos","sequence":"first","affiliation":[{"name":"Health Sciences Graduate Program, Federal University of Sergipe , Aracaju ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9979-9881","authenticated-orcid":false,"given":"Manuel H","family":"Aguiar Oliveira","sequence":"additional","affiliation":[{"name":"Health Sciences Graduate Program, Federal University of Sergipe , Aracaju ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4681-6668","authenticated-orcid":false,"given":"Martin","family":"Bidlingmaier","sequence":"additional","affiliation":[{"name":"Medizinische Klinik und Poliklinik IV, LMU Klinikum, Ludwig-Maximilians-Universit\u00e4t , Munich ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin C J","family":"Yuen","sequence":"additional","affiliation":[{"name":"University of Arizona College of Medicine and Creighton University School of Medicine , Phoenix, AZ ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6495-2244","authenticated-orcid":false,"given":"Roberto","family":"Salvatori","sequence":"additional","affiliation":[{"name":"Johns Hopkins University , Baltimore, MD ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla R P","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Health Sciences Graduate Program, Federal University of Sergipe , Aracaju ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Leal","sequence":"additional","affiliation":[{"name":"Health Sciences Graduate Program, Federal University of Sergipe , Aracaju ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enaldo","family":"Melo","sequence":"additional","affiliation":[{"name":"Health Sciences Graduate Program, Federal University of Sergipe , Aracaju ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8667-0296","authenticated-orcid":false,"given":"Katharina","family":"Schilbach","sequence":"additional","affiliation":[{"name":"Medizinische Klinik und Poliklinik IV, LMU Klinikum, Ludwig-Maximilians-Universit\u00e4t , Munich ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5379-0961","authenticated-orcid":false,"given":"Jan","family":"Frystyk","sequence":"additional","affiliation":[{"name":"University of Southern Denmark , Odense ,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8050-9127","authenticated-orcid":false,"given":"J\u00fania R O L","family":"Schweizer","sequence":"additional","affiliation":[{"name":"Medizinische Klinik und Poliklinik IV, LMU Klinikum, 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