Inhibition of oxytocin receptor function by direct binding of progesterone
Abstract
The steroid hormone progesterone (P4) is essential for establishing and maintaining pregnancy in mammals. One of its functions includes maintenance of uterine quiescence by decreasing uterine sensitivity to the uterotonic peptide hormone oxytocin. Although it is generally held that steroid hormones such as P4 act at a genomic level by binding to nuclear receptors and modulating the expression of specific target genes, we show here that the effect of P4 on uterine sensitivity to oxytocin involves direct, non-genomic action of P4 on the uterine oxytocin receptor (OTR), a member of the G-protein-coupled receptor family. P4 inhibits oxytocin binding to OTR-containing membranes in vitro, binds with high affinity to recombinant rat OTR expressed in CHO cells, and suppresses oxytocin-induced inositol phosphate production and calcium mobilization. These effects are highly steroid- and receptor-specific, because binding and signalling functions of the closely related human OTR are not affected by P4 itself but by the P4 metabolite 5beta-dihydroprogesterone. Our findings provide the first evidence for a direct interaction between a steroid hormone and a G-protein-coupled receptor and define a new level of crosstalk between the peptide- and steroid-hormone signalling pathways.
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OXT effects in women may vary as a function of steroid hormones.
“Clearly, OXT effects in women may vary as a function of steroid hormones, which influence plasma levels of the peptide (Chiodera et al., 1991), regulate the expression of the OXTR gene (Quinones-Jenab et al., 1997) and affect OXTR function through a non-genomic mechanism (Grazzini et al., 1998).”
From Hormonal contraceptives suppress oxytocin-induced brain reward responses to the partner’s face (2016) · cites this paper as Grazzini et al., 1998
Direct binding of progesterone to OXTRs inhibits OXTR functioning.
“a potential mechanism could be related to the direct binding of progesterone to OXTRs, thereby inhibiting OXTR functioning (Grazzini et al., 1998).”
From Hormonal contraceptives suppress oxytocin-induced brain reward responses to the partner’s face (2016) · cites this paper as Grazzini et al., 1998
Androgens and progesterone modulate oxytocin and oxytocin receptor expression, while estrogens seem to have the greatest impact on the oxytocin system.
“While androgens and progesterone modulate Oxt and Oxtr expression (72–75), it is the estrogens that seem to have the greatest impact on the Oxt system (68, 70, 74, 76–78).”
From Oxytocin during Development: Possible Organizational Effects on Behavior (2015) · cites this paper as [75]
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“Peripheral estradiol and progesterone levels were found to be altered in women using HC and therefore a potential mechanism could be related to the direct binding of progesterone to OXTRs, thereby inhibiting OXTR functioning (Grazzini et al., 1998).”
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- Authors
- Grazzini, E., Guillon, G., Mouillac, B., & Zingg, H. H.
- Affiliations
- Royal Victoria Hospital (CA)
- Inserm (FR)
- Corresponding author
- Zingg, Hans H.
- ORCID
- Mouillac, Bernard
- Venue
- Nature
- Published
- 1998-04
- Volume
- 392
- Issue
- 6675
- Pages
- 509-512
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1541228389
- Cited by
- 466
- References
- 28
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 4 · 2023: 6 · 2022: 2 · 2021: 12 · 2020: 10 · 2019: 10 · 2018: 11 · 2017: 11 · 2016: 10 · 2015: 18 · 2014: 11 · 2013: 18 · 2012: 15
- FWCI
- 13.56
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Keywords
- progesterone, oxytocin receptor, non-genomic steroid action, G protein-coupled receptors, uterine quiescence, inositol phosphate formation, calcium mobilization, pregnancy
- MeSH terms
- Animals, Arginine Vasopressin, Female, Cricetinae, Hormone Antagonists, Inositol Phosphates, Ligands, Oxytocin, Pregnancy, Progesterone, Protein Binding, Recombinant Proteins, Uterus, Signal Transduction, CHO Cells, Rats, Sprague-Dawley, Receptors, Oxytocin, GTP-Binding Proteins, Rats
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