The DOI matches its Crossref record; 59 of the 59 references it cites were found in a registry or an index.
Agonistic and antagonistic properties of progesterone metabolites at the human mineralocorticoid receptor
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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“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 the citing paper
“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]
Citations
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Congenital adrenal hyperplasia due to 21-hydroxylase deficiency*
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Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy
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Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management
Claahsen - van der Grinten, H. L., Speiser, P. W., Ahmed, S. F., Arlt, W., Auchus, R. J., Falhammar, H., Flück, C. E., Guasti, L., Huebner, A., Kortmann, B. B. M., et al. (2022) · Endocrine Reviews · doi:10.1210/endrev/bnab016 · Cited by 556
Stanczyk, F. Z., Hapgood, J. P., Winer, S., & Mishell, D. R. (2013) · Endocrine Reviews · doi:10.1210/er.2012-1008 · Cited by 429
“However, the anti-MR effects of progesterone may be relevant only when endogenous progesterone concentrations are high, such as during the luteal phase of the menstrual cycle and pregnancy, because progesterone has a short half-life and is rapidly converted to metabolites without anti-MR activity (199).”
BackgroundThe Mineralocorticoid Receptor: Insights into its Molecular and (Patho)Physiological Biology
Viengchareun, S., Menuet, D. L., Martinerie, L., Munier, M., Tallec, L. P.-L., & Lombès, M. (2007) · Nuclear Receptor Signaling · doi:10.1621/nrs.05012 · Cited by 342
“It is now clear that progesterone and androgens and their derivatives could also bind MR and exert partial agonist and antagonist effects depending on the cellular context [Marissal-Arvy et al., 2004; Quinkler et al., 2002; Quinkler et al., 2003; Takeda et al., 2007].”
Africander, D., Verhoog, N. J. D., & Hapgood, J. P. (2011) · Steroids · doi:10.1016/j.steroids.2011.03.001 · Cited by 244
Hahner, S., Ross, R. J., Arlt, W., Bancos, I., Burger-Stritt, S., Torpy, D. J., Husebye, E. S., & Quinkler, M. (2021) · Nature Reviews Disease Primers · doi:10.1038/s41572-021-00252-7 · Cited by 223
Metadata
- 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
- 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
- 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 › Endocrinology › 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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