Membrane Estrogen Receptor (GPER) and Follicle-Stimulating Hormone Receptor (FSHR) Heteromeric Complexes Promote Human Ovarian Follicle Survival

Livio Casarini, Clara Lazzaretti, Elia Paradiso, Silvia Limoncella, Laura Riccetti, Samantha Sperduti, Beatrice Melli, Serena Marcozzi, Claudia Anzivino, Niamh S. Sayers, Jakub Czapinski, Giulia Brigante, Francesco Potì, Antonio La Marca, Francesco De Pascali, Eric Reiter, Angela Falbo, Jessica Daolio, Maria Teresa Villani, Monica LispiGiovanna Orlando, Francesca G. Klinger, Francesca Fanelli, Adolfo Rivero-Müller, Aylin C. Hanyaloglu, Manuela Simoni

Research output: Contribution to journalArticlepeer-review


Classically, follicle-stimulating hormone receptor (FSHR)-driven cAMP-mediated signaling boosts human ovarian follicle growth and oocyte maturation. However, contradicting in vitro data suggest a different view on physiological significance of FSHR-mediated cAMP signaling. We found that the G-protein-coupled estrogen receptor (GPER) heteromerizes with FSHR, reprogramming cAMP/death signals into proliferative stimuli fundamental for sustaining oocyte survival. In human granulosa cells, survival signals are missing at high FSHR:GPER ratio, which negatively impacts follicle maturation and strongly correlates with preferential Gαs protein/cAMP-pathway coupling and FSH responsiveness of patients undergoing controlled ovarian stimulation. In contrast, FSHR/GPER heteromers triggered anti-apoptotic/proliferative FSH signaling delivered via the Gβγ dimer, whereas impairment of heteromer formation or GPER knockdown enhanced the FSH-dependent cell death and steroidogenesis. Therefore, our findings indicate how oocyte maturation depends on the capability of GPER to shape FSHR selective signals, indicating hormone receptor heteromers may be a marker of cell proliferation.

Original languageEnglish
Article number101812
Issue number12
Publication statusPublished - Dec 18 2020
Externally publishedYes


  • Endocrine Regulation
  • Female Reproductive Endocrinology
  • Molecular Biology

ASJC Scopus subject areas

  • General


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