Effects of interleukin-1 receptor antagonism in women with polycystic ovary syndrome-the FertIL trial

Front Endocrinol (Lausanne). 2024 Sep 11:15:1435698. doi: 10.3389/fendo.2024.1435698. eCollection 2024.

Abstract

Introduction: Chronic low-grade inflammation might contribute to hyperandrogenemia and metabolic complications in polycystic ovary syndrome (PCOS). The proinflammatory cytokine interleukin (IL)-1 stimulates androgen production from ovarian cells, whereas blockade of the IL-1 pathway improves cardiometabolic health. We aimed to investigate whether blocking the IL-1 pathway ameliorates hyperandrogenemia in patients with PCOS.

Methods: This is a prospective, interventional, single-arm, proof-of-concept trial performed at a tertiary hospital in Switzerland (August 2018 to July 2020) in 18 premenopausal women with a diagnosis of PCOS according to the Rotterdam criteria, total testosterone levels ≥ 1.7 nmol/L, and C-reactive protein (CRP) ≥ 1.0 mg/L. Patients received 100 mg/day of the IL-1-receptor antagonist anakinra for 28 days and underwent weekly blood sampling until 1 week after the end of treatment. The primary endpoint was the change in serum androstenedione levels on day 7 of treatment, assessed with liquid chromatography-tandem mass spectrometry. Seven of these women participated in a subsequent observational sub-study (May 2021 to December 2021).

Results: Median [interquartile range (IQR)] androstenedione increased by 0.5 [-0.1, 1.6] nmol/L (p = 0.048) with anakinra and by 1.3 [0.08, 2.4] nmol/L [p = 0.38] without anakinra between baseline and day 7. Anakinra reduced CRP levels on days 7, 21, and 28 (p < 0.001) but did not lead to an absolute reduction in androgens. However, four of six patients (67%) had smaller areas under the curves for androstenedione and/or testosterone during the 28-day intervention with anakinra as compared to 28 days without treatment.

Discussion: Our findings suggest that anakinra suppresses IL-1-mediated chronic low-grade inflammation in PCOS and might attenuate biochemical hyperandrogenemia.

Keywords: PCOS; anakinra; hyperandrogenemia; inflammation; interleukin-1; polycystic ovary syndrome.

Publication types

  • Clinical Trial

MeSH terms

  • Adult
  • Androstenedione / blood
  • Female
  • Humans
  • Hyperandrogenism / blood
  • Hyperandrogenism / drug therapy
  • Hyperandrogenism / metabolism
  • Interleukin 1 Receptor Antagonist Protein* / blood
  • Polycystic Ovary Syndrome* / blood
  • Polycystic Ovary Syndrome* / drug therapy
  • Polycystic Ovary Syndrome* / metabolism
  • Proof of Concept Study
  • Prospective Studies
  • Receptors, Interleukin-1 / antagonists & inhibitors
  • Receptors, Interleukin-1 / metabolism
  • Testosterone / blood
  • Young Adult

Substances

  • Interleukin 1 Receptor Antagonist Protein
  • Testosterone
  • Androstenedione
  • Receptors, Interleukin-1

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by grants awarded to MC-C, MW-P, and SM by the Swiss National Science Foundation (MCC: SNF-162608, MP: SNF-177578, and SM: SNF-199391). WA is supported by the Wellcome Trust (Investigator Award WT209492/Z/17/Z).