Addressing the role of 11β-hydroxysteroid dehydrogenase type 1 in the development of polycystic ovary syndrome and the putative therapeutic effects of its selective inhibition in a preclinical model
Abstract
Background Polycystic ovary syndrome (PCOS) is the most common metabolic and endocrine disorder among reproductive-age women, and the leading cause of anovulatory infertility. 11β-hydroxysteroid dehydrogenases-1 (11β-HSD1) catalysing the conversion of inactive cortisone to active cortisol plays a crucial role in various metabolic diseases. However, whether 11β-HSD1 is associated with the pathogenesis of PCOS and whether 11β-HSD1 can be a treating target of PCOS remain unknown.Methods This study was first designed to explore the role of 11β-HSD1 in PCOS development and the effect of selective 11β-HSD1 inhibitor administration on PCOS treatment. Follicular fluid and granulosa cells (GCs) were collected from 32 non-PCOS patients and 37 patients with PCOS to measure cortisol and 11β-HSDs levels. Female Sprague-Dawley rats (3-week-old) were injected with dehydroepiandrosterone (DHEA) to induce PCOS and their ovaries were collected to measure the abundance of corticosterone (CORT) and 11β-HSDs. To determine the role of 11β-HSD1 in PCOS development, we overexpressed 11β-HSD1 in the ovaries of female rats (5-week-old) or knocked down the expression of 11β-HSD1 in the ovaries from PCOS rats via lentivirus injection. After lentivirus infection, the body weights, ovarian weights, estrous cycles, reproductive hormones and morphology of the ovary were analysed in rats from different experimental groups. Then to figure out the translational potential of the selective 11β-HSD1 inhibitor in treating PCOS, PCOS rats were treated with BVT.2733, a selective 11β-HSD1 inhibitor and a cluster of PCOS-like traits were analysed, including insulin sensitivity, ovulatory function and fertility of rats from the Control, PCOS and PCOS+BVT groups. Rat ovarian explants and human GCs were used to explore the effect of CORT or cortisol on ovarian extracellular matrix remodelling.Results The elevated expression of 11β-HSD1 contributed to the increased cortisol and corticosterone (CORT) concentrations observed in the ovaries of PCOS patients and PCOS rats respectively. Our results showed that ovarian overexpression of 11β-HSD1 induced a cluster of PCOS phenotypes in rats including irregular estrous cycles, reproductive hormone dysfunction and polycystic ovaries. While knockdown of ovarian 11β-HSD1 of PCOS rats reversed these PCOS-like changes. Additionally, the selective 11β-HSD1 inhibitor BVT.2733 alleviated PCOS symptoms such as insulin resistance (IR), irregular estrous cycles, reproductive hormone dysfunction, polycystic ovaries, ovulatory dysfunction and subfertility. Moreover, we showed that cortisol target ovarian insulin signalling pathway and ovarian extracellular matrix (ECM) remodelling in vivo, in ovarian explants and in GCs.Conclusion Elevated 11β-HSD1 abundance in ovarian is involved in the pathogenesis of PCOS by impairing insulin signalling pathway and ECM remodelling. Selective inhibition of 11β-HSD1 ameliorates a cluster of PCOS phenotypes. Our study demonstrates the selective 11β-HSD1 inhibitor as a novel and promising strategy for the treatment of PCOS.
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Hydroxysteroid dehydrogenase (HSD) genes were observed only in Lm. fermentum strains.
“hydroxysteroid dehydrogenase (HSD) genes [46], involved in steroid degradation, were observed only in Lm. fermentum strains.”
From Women's health is a team effort: probiogenomics supports the development of a multi-species vaginal probiotic (2026) · cites this paper as [46]
These strains may be potentially involved in hormonal disorders.
“these strains may be potentially involved in hormonal disorders [46].”
From Women's health is a team effort: probiogenomics supports the development of a multi-species vaginal probiotic (2026) · cites this paper as [46]
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- Authors
- Li, X., Hu, S., Zhu, Q., Yao, G., Yao, J., Li, J., Wang, Y., Ding, Y., Qi, J., Xu, R., Zhao, H., Zhu, Z., Du, Y., Sun, K., & Sun, Y.
- Affiliations
- Shanghai Jiao Tong University (CN)
- Corresponding author
- Sun, Yun
- ORCID
- Venue
- Metabolism
- Publisher
- Elsevier BV
- Published
- 2021-06
- Volume
- 119
- Pages
- 154749
- ISSN
- 0026-0495 (ISSN-L)
- OpenAlex
- W3136994764
- Cited by
- 26
- References
- 53
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 6 · 2023: 4 · 2022: 5
- FWCI
- 3.45
- Type
- journal article
- Language
- en
- Update notices
- erratum (2026-02-01)
- Open access
- closed
- Licence
- Locations
- Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Shanghai Municipal Education Commission (20161413)
- National Natural Science Foundation of China (81771648)
- National Key Research and Development Program of China (2017YFC1001403, 2019YFA0802604)
- Science and Technology Commission of Shanghai Municipality (17DZ2271100)
- Innovative Research Team of High-level Local University in Shanghai
- Program of Shanghai Academic Research Leader (2017BR015)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- polycystic ovary syndrome, 11β-hydroxysteroid dehydrogenase type 1, 11β-HSD1 inhibition, cortisol, corticosterone, granulosa cells, follicular fluid, DHEA-induced PCOS, insulin sensitivity, ovulation, fertility
- MeSH terms
- Benzenesulfonamides, Animals, Cells, Cultured, Disease Models, Animal, Drug Evaluation, Preclinical, Enzyme Inhibitors, Female, Humans, Infertility, Female, Insulin Resistance, Ovary, Piperazines, Polycystic Ovary Syndrome, Sulfonamides, Thiazoles, Rats, Sprague-Dawley, 11-beta-Hydroxysteroid Dehydrogenase Type 1, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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