{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T07:43:28Z","timestamp":1765439008792,"version":"build-2065373602"},"reference-count":27,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2024,10,8]],"date-time":"2024-10-08T00:00:00Z","timestamp":1728345600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Pantarhei Oncology"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: The co-treatment of androgen deprivation therapy (ADT) for advanced prostate cancer (PCa) with the fetal estrogen estetrol (E4) may further inhibit endocrine PCa tumor stimulators. We previously reported the suppression of follicle-stimulating hormone (FSH), total and free testosterone, and prostate-specific antigen by ADT+E4. Here, we provide more detailed data on FSH suppression by E4 and present new findings on the effect of ADT+E4 on insulin-like growth factor-1 (IGF-1). Methods: A Phase II, double-blind, randomized, placebo-controlled study (the PCombi study) was conducted in advanced PCa patients treated with ADT. The study assessed the effect of E4 co-treatment with LHRH agonist ADT on tumor stimulators, including FSH and IGF-1. Patients starting ADT were randomized 2:1 to receive either 40 mg E4 (n = 41) or placebo (n = 21) for 24 weeks. Non-parametric analyses were performed on the per-protocol population (PP) and individual changes were visualized. Results: The PP included 57 patients (37 ADT+E4; 20 ADT+placebo). ADT+E4 almost completely suppressed FSH in all patients (98% versus 37%; p &lt; 0.0001). IGF-1 levels decreased by 41% with ADT+E4 versus an increase of 10% with ADT+placebo (p &lt; 0.0001). Conclusions: The almost complete suppression of the tumor stimulator FSH using ADT plus E4 observed in all individual patients in this study, along with the augmented suppression of IGF-1 versus an increase by ADT only, may be clinically relevant and suggest the enhanced anti-cancer treatment efficacy of E4 in addition to the previously reported additional suppression of total and free T and PSA.<\/jats:p>","DOI":"10.3390\/jcm13195996","type":"journal-article","created":{"date-parts":[[2024,10,8]],"date-time":"2024-10-08T12:01:54Z","timestamp":1728388914000},"page":"5996","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Estetrol Inhibits the Prostate Cancer Tumor Stimulators FSH and IGF-1"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1550-9400","authenticated-orcid":false,"given":"Herjan J. T.","family":"Coelingh Bennink","sequence":"first","affiliation":[{"name":"Pantarhei Oncology, 3700 AL Zeist, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erik P. M.","family":"Roos","sequence":"additional","affiliation":[{"name":"Department of Urology, Antonius Hospital, 8601 ZK Sneek, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R. Jeroen A.","family":"van Moorselaar","sequence":"additional","affiliation":[{"name":"Department of Urology, Amsterdam UMC, Free University, 1081 HV Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harm H. E.","family":"van Melick","sequence":"additional","affiliation":[{"name":"Department of Urology, St. Antonius Hospital, 3435 CM Nieuwegein, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5277-6586","authenticated-orcid":false,"given":"Diederik M.","family":"Somford","sequence":"additional","affiliation":[{"name":"Department of Urology, Canisius-Wilhelmina Hospital, 6532 SZ Nijmegen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ton A.","family":"Roeleveld","sequence":"additional","affiliation":[{"name":"Department of Urology, North-West Hospital, 1815 JD Alkmaar, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tjard D.","family":"de Haan","sequence":"additional","affiliation":[{"name":"Department of Urology, Isala Hospital, 8025 AB Zwolle, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1513-6360","authenticated-orcid":false,"given":"Yacov","family":"Reisman","sequence":"additional","affiliation":[{"name":"Flare-Health, 1012 DA Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7113-1188","authenticated-orcid":false,"given":"Iman J.","family":"Schultz","sequence":"additional","affiliation":[{"name":"Pantarhei Oncology, 3700 AL Zeist, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Krijgh","sequence":"additional","affiliation":[{"name":"Pantarhei Oncology, 3700 AL Zeist, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frans M. J.","family":"Debruyne","sequence":"additional","affiliation":[{"name":"Andros Clinics, 6803 AA Arnhem, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,8]]},"reference":[{"key":"ref_1","first-page":"S3","article-title":"Hormonal therapy in prostate cancer: Historical approaches","volume":"6","author":"Crawford","year":"2004","journal-title":"Rev. Urol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.ejca.2023.02.018","article-title":"Management of patients with advanced prostate cancer-metastatic and\/or castration-resistant prostate cancer: Report of the Advanced Prostate Cancer Consensus Conference (APCCC) 2022","volume":"185","author":"Gillessen","year":"2023","journal-title":"Eur. J. 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