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Wang, K.* ; Fischer, A.* ; Maccio, U.* ; Zitzmann, K.* ; Robledo, M.* ; Lauseker, M.* ; Bauer, J.* ; Bechmann, N.* ; Gahr, S.* ; Maurer, J.* ; Peischer, L.* ; Reul, A.* ; Nieß, H.* ; Zimmermann, P.* ; Ilmer, M.* ; Schilbach, K.* ; Knösel, T.* ; Kroiss, M.* ; Fassnacht, M.* ; Müller, S.A.* ; Morand, G.B.* ; Huber, A.* ; Vetter, D.* ; Lehmann, K.* ; Kulcsar, Z.* ; Mohr, H. ; Pellegata, N.S. ; Hantel, C.* ; Reincke, M.* ; Beuschlein, F.* ; Pacak, K.* ; Grossman, A.B.* ; Auernhammer, C.J.* ; Nölting, S.*

Impact of sex hormones on pheochromocytomas, paragangliomas, and gastroenteropancreatic neuroendocrine tumors.

Eur. J. Endocrinol. 192, 46-60 (2025)
DOI PMC
OBJECTIVE: The effects of sex hormones remain largely unexplored in pheochromocytomas and paragangliomas (PPGLs) and gastroenteropancreatic neuroendocrine tumors (GEP-NETs). METHODS: We evaluated the effects of estradiol, progesterone, Dehydroepiandrosterone sulfate (DHEAS), and testosterone on human patient-derived PPGL/GEP-NET primary culture cell viability (n = 38/n = 12), performed next-generation sequencing and immunohistochemical hormone receptor analysis in patient-derived PPGL tumor tissues (n = 36). RESULTS: In PPGLs, estradiol and progesterone (1 µm) demonstrated overall significant antitumor effects with the strongest efficacy in PPGLs with NF1 (cluster 2) pathogenic variants. Estrogen receptor alpha (ERα) positivity was detected in 11/36 PPGLs, including 4/4 head-and-neck paragangliomas (HNPGLs). ERα-positive tumors responded with a significant cell viability decrease to estradiol. DHEAS and testosterone (1 µm) displayed no effects, but higher doses of testosterone (10 µm) demonstrated significant antitumor effects, including a pheochromocytoma lung metastasis with strong androgen receptor positivity (30%). Driven by the antitumor effects of estrogen, we evaluated G-protein-coupled estrogen receptor (GPER) agonist G-1 as a potential therapeutic option for PPGLs and found strong significant antitumor potential, with the strongest efficacy in tumors with NF1 pathogenic variants. Moreover, we detected sex-related differences-tumors from male patients showed significantly stronger responsivity to G-1 compared with tumors from female patients. In GEP-NETs, sex hormones showed overall no effects, especially no tumor growth-promoting effects. CONCLUSION: We provide novel data on the effects of elevated sex hormone levels, potentially seen during pregnancy or hormone replacement therapy, on PPGL/GEP-NET tumor growth. G-1 might offer a novel therapeutic approach for some PPGLs depending on patient's sex and the individual tumor's genetic/molecular background. All HNPGLs showed ERα positivity.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Estrogen ; Hormone Receptor ; Neuroendocrine Tumor ; Pheochromocytoma ; Progesterone; Estrogen; Receptor; Expression; Management; Benign; Serum; Estradiol; Outcomes
ISSN (print) / ISBN 0804-4643
e-ISSN 1479-683X
Zeitschrift European Journal of Endocrinology
Quellenangaben Band: 192, Heft: 1, Seiten: 46-60 Artikelnummer: , Supplement: ,
Verlag BioScientifica
Verlagsort Great Clarendon St, Oxford Ox2 6dp, England
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Cancer (IDC)
Förderungen German Research Foundation (Deutsche Forschungsgemeinschaft