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  • Review Article
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The G protein-coupled oestrogen receptor GPER in health and disease: an update

Nature Reviews Endocrinology volume 19, pages 407–424 (2023)Cite this article

Subjects

Abstract

Oestrogens and their receptors contribute broadly to physiology and diseases. In premenopausal women, endogenous oestrogens protect against cardiovascular, metabolic and neurological diseases and are involved in hormone-sensitive cancers such as breast cancer. Oestrogens and oestrogen mimetics mediate their effects via the cytosolic and nuclear receptors oestrogen receptor-α (ERα) and oestrogen receptor-β (ERβ) and membrane subpopulations as well as the 7-transmembrane G protein-coupled oestrogen receptor (GPER). GPER, which dates back more than 450 million years in evolution, mediates both rapid signalling and transcriptional regulation. Oestrogen mimetics (such as phytooestrogens and xenooestrogens including endocrine disruptors) and licensed drugs such as selective oestrogen receptor modulators (SERMs) and downregulators (SERDs) also modulate oestrogen receptor activity in both health and disease. Following up on our previous Review of 2011, we herein summarize the progress made in the field of GPER research over the past decade. We will review molecular, cellular and pharmacological aspects of GPER signalling and function, its contribution to physiology, health and disease, and the potential of GPER to serve as a therapeutic target and prognostic indicator of numerous diseases. We also discuss the first clinical trial evaluating a GPER-selective drug and the opportunity of repurposing licensed drugs for the targeting of GPER in clinical medicine.

Key points

  • Oestrogens exert multiple activities in physiology, including reproduction, immunity, cardiovascular and endocrine functions, and ageing, as well as in diseases such as hormone-sensitive cancers, arterial hypertension, atherosclerosis and osteoporosis.

  • Oestrogen signalling mediates both acute (non-genomic) and chronic (transcriptional) effects through cytosolic or nuclear oestrogen receptors ERα and ERβ and membrane subpopulations and the G protein‐coupled oestrogen receptor (GPER), which is a 7-transmembrane protein.

  • Molecules that activate oestrogen receptors include natural oestrogens, phytooestrogens, mycooestrogens and synthetic compounds, such as selective oestrogen receptor modulators and downregulators and xenooestrogens (also known as endocrine disruptors), activate oestrogen receptors and/or GPER.

  • Research using Gper-deficient animals, GPER‐selective agonists and antagonists, and non-selective compounds has revealed multiple roles of GPER in physiology and disease, including as a constitutive activator of the reactive oxygen species-producing enzyme NOX1.

  • GPER holds potential to become a diagnostic, prognostic and therapeutic target in clinical medicine, including the repurposing of licensed drugs targeting GPER and the ongoing first-in-human clinical trial of the GPER-selective agonist G-1.

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Fig. 1: Cellular signalling pathways activated by ERα, ERβ and GPER.
Fig. 2: Chemical structures of compounds that act as ligands for ERα, ERβ and/or GPER.
Fig. 3: GPER in health and disease.

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Acknowledgements

E.R.P. is supported by grants from the US National Institutes of Health (R01 CA163890 and R01 CA194496), from Dialysis Clinic, Inc., and by the UNM Comprehensive Cancer Center (NIH P30 CA118100) and the Autophagy, Inflammation and Metabolism (AIM) Center of Biomedical Research Excellence (CoBRE, NIH P20 GM121176). M.B. is supported by grants 108 258 and 122 504 from the Swiss National Science Foundation (SNSF).

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Authors and Affiliations

  1. Department of Internal Medicine, Division of Molecular Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, USA

    Eric R. Prossnitz

  2. Center of Biomedical Research Excellence in Autophagy, Inflammation and Metabolism, University of New Mexico Health Sciences Center, Albuquerque, NM, USA

    Eric R. Prossnitz

  3. University of New Mexico Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, NM, USA

    Eric R. Prossnitz

  4. Molecular Internal Medicine, University of Zürich, Zürich, Switzerland

    Matthias Barton

  5. Andreas Grüntzig Foundation, Zürich, Switzerland

    Matthias Barton

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Competing interests

M.B. and E.R.P. are inventors on U.S. patent Nos. 10,251,870, 10,682,341 and 10,980,785, and E.R.P. is an inventor on U.S. Patent Nos. 10,471,047 and 10,561,648, all for the therapeutic use of compounds targeting GPER (“Method for treating obesity, diabetes, cardiovascular and kidney diseases by regulating GPR30/GPER”). E.R.P. is an inventor on U.S. Patent Nos. 7,875,721 and 8,487,100 for GPER-selective ligands and imaging agents (“Compounds for binding to ERα/β and GPR30, methods of treating disease states and conditions mediated through these receptors and identification thereof”). M.B. has served or serves as a consultant to Abbott, Inc., Abbvie, Inc., Travere, Inc. and Pharmazz, Inc.

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Abstracts of all articles published on GPR30 or GPER, published between January 1996 and February 2023, were retrieved from the U.S. National Library of Medicine (PubMed.gov). Articles were assessed for relevance, importance and scientific rigour, with a focus on publication in the past 10 years. The authors apologize to their colleagues whose work could not be included due to space and reference restrictions.

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Prossnitz, E.R., Barton, M. The G protein-coupled oestrogen receptor GPER in health and disease: an update. Nat Rev Endocrinol 19, 407–424 (2023). https://doi.org/10.1038/s41574-023-00822-7

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