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

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.

Figure 1

Study flowchart. CRP, C-reactive protein; PCOS, polycystic ovary syndrome.

Figure 2

Change in androstenedione, testosterone, and CRP with and without anakinra. Only patients who participated in both the interventional and the observational studies are displayed (n = 7). Absolute changes were computed by subtracting the baseline concentration from the corresponding follow-up value. Values above the dashed line represent an increase and values below the dashed line represent a decrease as compared to baseline. Androgens were measured with tandem-mass spectrometry (LC-MS/MS), and CRP was measured with an immunoturbidimetric assay (Tina-quant C-Reactive Protein IV; Roche Diagnostics GmbH). CRP, C-reactive protein.

Figure 3

Absolute changes in androgens with anakinra based on the predominant androgen pathway. The predominant androgen pathway was computed by dividing baseline androstenedione (A4) levels (classic androgen pathway) by baseline 11β-hydroxyandrostenedione (11OHA4) levels (11-oxygenated C19 steroid pathway) (42). A quotient above the median (0.872 nmol/nmol) was considered as a predominance toward the classic androgen pathway and a quotient below the median was considered as a predominance toward the 11-oxygenated C19 steroid pathway. The boxplots represent relative changes in androgens from baseline. Values above the dashed line represent an increase and values below the dashed line represent a decrease in androgens as compared to baseline. Androgen levels were measured with tandem-mass spectrometry (LC-MS/MS).