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

Summary

Patient-derived PPGL models show that estradiol and progesterone exert antitumor effects, particularly in NF1-mutant tumors, and that ERα-positive tumors are sensitive to estradiol. The GPER agonist G-1 exhibited strong antitumor activity with sex-related differences, nominating hormone/GPER signaling as a therapeutic avenue without growth-promoting effects in GEP-NETs.

Key Findings

• Estradiol and progesterone (1 µM) reduced PPGL cell viability, with strongest effects in NF1 (cluster 2) tumors.
• ERα positivity in 11/36 PPGLs (including 4/4 HNPGLs); ERα-positive tumors responded significantly to estradiol.
• GPER agonist G-1 showed strong antitumor activity, with greater responsiveness in tumors from male patients and in NF1-mutant tumors.
• High-dose testosterone (10 µM) exerted antitumor effects in select AR-positive tumors; DHEAS/testosterone at 1 µM had no effect.
• Sex hormones did not promote growth in GEP-NETs.

Clinical Implications

Consider hormone receptor profiling (ERα/AR/GPER) in PPGLs, especially HNPGLs and NF1-mutant tumors, and exercise caution with exogenous hormones. GPER agonists such as G-1 warrant translational development and sex-informed trial designs.

Limitations

• Predominantly ex vivo/in vitro data without clinical outcome trials
• Sample sizes are modest and external generalizability is uncertain

Future Directions

Conduct biomarker-driven early-phase trials of GPER agonists (e.g., G-1) stratified by NF1 status and sex; clarify endocrine therapy risks in PPGL during pregnancy or hormone replacement.