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

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

TLDR

  • The study investigates the effects of sex hormones on PPGLs and GEP-NETs, demonstrating antitumor effects of estradiol, progesterone, and G-1, and sex-related differences in responsiveness to G-1.
  • The findings suggest that G-1 might be a potential therapeutic option for some PPGLs depending on patient's sex and the individual tumor's genetic/molecular background.

Abstract

The effects of sex hormones remain largely unexplored in pheochromocytomas and paragangliomas (PPGLs) and gastroenteropancreatic neuroendocrine tumors (GEP-NETs). 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). 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. 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.

Overview

  • The study investigates the effects of sex hormones on pheochromocytomas and paragangliomas (PPGLs) and gastroenteropancreatic neuroendocrine tumors (GEP-NETs).
  • The study evaluates the effects of estradiol, progesterone, Dehydroepiandrosterone sulfate (DHEAS), and testosterone on human patient-derived PPGL/GEP-NET primary culture cell viability and tumor tissues.
  • The primary objective of the study is to explore the impact of sex hormones on PPGL and GEP-NET tumor growth, potentially providing novel insights into the development of targeted therapies.

Comparative Analysis & Findings

  • Estradiol and progesterone (1 μm) demonstrated significant antitumor effects in PPGLs, with the strongest efficacy in PPGLs with NF1 pathogenic variants.
  • Testosterone (1 μm) demonstrated no effects, but higher doses (10 μm) showed significant antitumor effects, including a pheochromocytoma lung metastasis with strong androgen receptor positivity (30%).
  • The G-protein-coupled estrogen receptor (GPER) agonist G-1 showed strong significant antitumor potential, with the strongest efficacy in tumors with NF1 pathogenic variants, and sex-related differences, with tumors from male patients showing stronger responsivity to G-1 compared with tumors from female patients.

Implications and Future Directions

  • The study provides novel data on the effects of elevated sex hormone levels on PPGL and GEP-NET tumor growth, potentially seen during pregnancy or hormone replacement therapy.
  • G-1 might offer a novel therapeutic approach for some PPGLs depending on patient's sex and the individual tumor's genetic/molecular background.
  • Further research is needed to fully understand the mechanisms underlying the antitumor effects of sex hormones and to explore their potential applications in the treatment of PPGLs and GEP-NETs.
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