Impact of sex hormones on pheochromocytomas, paragangliomas, and gastroenteropancreatic neuroendocrine tumors.
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Wang Katharina, Fischer Alessa, Maccio Umberto, Zitzmann Kathrin, Robledo Mercedes, Lauseker Michael, Bauer Jana, Bechmann Nicole, Gahr Simon, Maurer Julian, Peischer Lea, Reul Astrid, Nieß Hanno, Zimmermann Petra, Ilmer Matthias, Schilbach Katharina, Knösel Thomas, Kroiss Matthias, Fassnacht Martin, Müller Simon A, Morand Gregoire B, Huber Alexander, Vetter Diana, Lehmann Kuno, Kulcsar Zsolt, Mohr Hermine, Pellegata Natalia S, Hantel Constanze, Reincke Martin, Beuschlein Felix, Pacak Karel, Grossman Ashley B, Auernhammer Christoph J, Nölting Svenja
Аннотация
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.