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Cited by 130Hormonal Regulation and HypertensionEstrogen and related hormone effectsAdrenal Hormones and Disorders

Agonistic and antagonistic properties of progesterone metabolites at the human mineralocorticoid receptor

Quinkler, M, Meyer, B, Bumke-Vogt, C, Grossmann, C, Gruber, U, Oelkers, W, Diederich, S, Bahr, V·2002·European Journal of Endocrinology
DOI 10.1530/eje.0.1460789
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Abstract

OBJECTIVE: Progesterone binds to the human mineralocorticoid receptor (hMR) with nearly the same affinity as do aldosterone and cortisol, but confers only low agonistic activity. It is still unclear how aldosterone can act as a mineralocorticoid in situations with high progesterone concentrations, e.g. pregnancy. One mechanism could be conversion of progesterone to inactive compounds in hMR target tissues. DESIGN: We analyzed the agonist and antagonist activities of 16 progesterone metabolites by their binding characteristics for hMR as well as functional studies assessing transactivation. METHODS: We studied binding affinity using hMR expressed in a T7-coupled rabbit reticulocyte lysate system. We used co-transfection of an hMR expression vector together with a luciferase reporter gene in CV-1 cells to investigate agonistic and antagonistic properties. RESULTS: Progesterone and 11beta-OH-progesterone (11beta-OH-P) showed a slightly higher binding affinity than cortisol, deoxycorticosterone and aldosterone. 20alpha-dihydro(DH)-P, 5alpha-DH-P and 17alpha-OH-P had a 3- to 10-fold lower binding potency. All other progesterone metabolites showed a weak affinity for hMR. 20alpha-DH-P exhibited the strongest agonistic potency among the metabolites tested, reaching 11.5% of aldosterone transactivation. The agonistic activity of 11beta-OH-P, 11alpha-OH-P and 17alpha-OH-P was 9, 5.1 and 4.1% respectively. At a concentration of 100 nmol/l, progesterone, 17alpha-OH-P and 20alpha-DH-P inhibit nearly 75, 40 and 35% of the transactivation by aldosterone respectively. All other progesterone metabolites tested demonstrate weaker affinity, and agonistic and antagonistic potency. CONCLUSIONS: The binding affinity for hMR and the agonistic and antagonistic activity diminish with increasing reduction of the progesterone molecule at C20, C17 and at ring A. We assume that progesterone metabolism to these compounds is a possible protective mechanism for hMR. 17alpha-OH-P is a strong hMR antagonist and could exacerbate mineralocorticoid deficiency in patients with congenital adrenal hyperplasia.

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Crossref · 10.1530/eje.0.1460789

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  • The transactivation activities of progesterone and 17OHP were only 0.2 to 0.8% of that for cortisol, whereas the transactivation activity of 21-deoxycortisol was 8.5% and 17% in two different assays.

    “However, the transactivation activities of progesterone and 17OHP were only 0.2 to 0.8% of that for cortisol, whereas the transactivation activity of 21-deoxycortisol was 8.5% and 17% in two different assays (137,138).”

    From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [138]

  • In vitro, 21-deoxycortisol, corticosterone, 17OHP, and progesterone bind the glucocorticoid receptor with 24-43% of the affinity of cortisol.

    “In vitro, 21-deoxycortisol, corticosterone, 17OHP, and progesterone bind the glucocorticoid receptor with 24-43% of the affinity of cortisol.”

    From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [138]

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Authors
Quinkler, M., Meyer, B., Bumke-Vogt, C., Grossmann, C., Gruber, U., Oelkers, W., Diederich, S., & Bahr, V
Affiliations
Freie Universität Berlin (DE)
Corresponding author
Quinkler, M
ORCID
Venue
European Journal of Endocrinology
Publisher
Oxford University Press (OUP)
Published
2002-06-01
Volume
146
Issue
6
Pages
789-799
ISSN
  • 0804-4643 (ISSN-L)
  • 1479-683X
DOI
10.1530/eje.0.1460789
OpenAlex
W2165755939
Cited by
130
References
59
Citations by year
2026: 4 · 2025: 3 · 2024: 8 · 2023: 8 · 2022: 6 · 2021: 7 · 2020: 8 · 2019: 7 · 2018: 3 · 2017: 7 · 2016: 8 · 2015: 5 · 2014: 10 · 2013: 3 · 2012: 3
FWCI
1.73
Type
journal article
Language
en
Open access
closed
Locations
  • European Journal of Endocrinology (publishedVersion)
  • PubMed (publishedVersion)
Funders
Deutsche Forschungsgemeinschaft
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
Keywords
progesterone metabolites, receptor binding affinity, agonist activity, antagonist activity, 17-hydroxyprogesterone, 20alpha-dihydroprogesterone, 11β-hydroxyprogesterone, aldosterone, mineralocorticoid deficiency, congenital adrenal hyperplasia, pregnancy, transcriptional activation
MeSH terms
Aldosterone, Mineralocorticoid Receptor Antagonists, Animals, Desoxycorticosterone, Humans, Hydrocortisone, Luciferases, Progesterone, Rabbits, Reticulocytes, Transcription, Genetic, Transfection, Protein Biosynthesis, Transcriptional Activation, Receptors, Mineralocorticoid

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