Endocrine Abstracts

Background

Polycystic Ovary Syndrome (PCOS) is the most prevalent endocrine disorder in women of reproductive age. The main components are hyperandrogenemia and oligo-/amenorrhea. The pathophysiology of PCOS is not fully understood which is why no causal treatment options are available. A multitude of observational studies demonstrated elevated C-reactive protein (CRP) levels in patients with PCOS compared with weight-matched controls. CRP is a sensitive marker for the proinflammatory cytokine Interleukin-(IL)-1. IL1 stimulated ovarian androgen production and impaired gonadotropin signaling and fertility in experimental studies. In clinical studies, therapeutic IL1 blockade had beneficial effects on cardiometabolic health. The aim of this study was to investigate whether IL1 blockade ameliorates hyperandrogenemia in patients with PCOS.

Methods

This is a prospective, interventional, single-arm, proof-of-concept trial. Seventeen patients with PCOS and C-reactive protein (CRP) levels ≥1 mg/l were treated with 100 mg of the IL1 receptor antagonist anakinra daily for 28 days. The primary endpoint was change in serum androstenedione levels on day 7 of treatment, assessed with liquid chromatography-tandem mass spectrometry. Secondary endpoints included changes in serum androgen concentrations, pituitary-gonadal axis hormones, and clinical parameters on treatment days 7, 14, 21, 28, and one week after end of treatment.

Results

Treatment with anakinra reduced CRP levels on days 7, 21, and 28 (P < 0.001). It increased serum androstenedione levels by a median (IQR) of 0.6 (0.2, 1.7) nmol/l to day 7 (P = 0.008). Serum testosterone as well as dihydrotestosterone levels increased from baseline to day 7 (both: P = 0.03). Estradiol levels were increased during the first three weeks of treatment (P = 0.02), which was followed by a menstrual bleeding in five patients of which three were previously oligo-/amenorrheic. There was no overall change in gonadotropins or other clinical parameters.

Discussion

We conclude that chronic low-grade inflammation is regulated by IL1 in PCOS as evidenced by a reduction of circulating CRP levels upon anakinra. Short-term IL1 blockade increased steroidogenesis likely by enabling gonadotropin action. Additionally, this increase might reflect the onset of a new anakinra-induced ovulatory cycle, since androgens as well as estradiol levels rise during the transition from the early to late follicular/ovulatory phase. Three patients experienced an unexpected menstrual bleeding by the end of the study. This data is reassuring to conduct a next randomized placebo-controlled long-term trial with menstrual cyclicity as primary endpoint.