The Role of Interleukin-1 in the Pathophysiology of Polycystic Ovary Syndrome and Regulation of Copeptin

BACKGROUND Polycystic Ovary Syndrome (PCOS) is a highly complex endocrine disorder in women of reproductive age. Its main traits are overactivity of male sexual hormones and ovulatory dysfunction, which result in serious symptoms, e.g., hirsutism and infertility. Despite the high prevalence of PCOS, its pathophysiology is not yet understood and no causal therapeutic options are available. Experimental and observational studies suggest a role for Interleukin-(IL)-1-driven chronic low-grade inflammation in the pathophysiology of PCOS. Besides, IL-1-driven chronic low-grade inflammation is associated with high levels of copeptin, a stress hormone and marker for arginine vasopressin (AVP). Since data show stimulatory effects of IL-1 on AVP, IL-1 might have a role in the regulation of AVP/copeptin.
OBJECTIVE To investigate the role of IL-1 in the pathophysiology of PCOS and regulation of AVP/copeptin in healthy volunteers as well as in patients with chronic metabolic stress.
METHODS The main project is a prospective, interventional trial with an IL-1 receptor blocking agent in patients with PCOS and chronic low-grade inflammation. The second project was a secondary analysis of a randomized, placebo-controlled, cross-over trial to compare the effects of IL-1 receptor antagonism on physical stress-induced copeptin levels. To investigate copeptin regulation during chronic stress, data on copeptin levels from two interventional studies, where obese individuals with metabolic syndrome were treated with an IL-1 receptor antagonist or placebo, were analyzed.
RESULTS IL-1 receptor antagonism reduced inflammatory markers in women with PCOS. Short-term IL-1 receptor antagonism slightly increased androgen and estradiol levels and induced menstruation in a subgroup of patients. After four weeks of treatment androgens were not different from baseline, and no other clinical effects were visible.
In healthy volunteers, IL-1 receptor antagonism did not induce any changes in copeptin levels during one hour of physical exercise.
Baseline copeptin levels were higher in patients with metabolic syndrome who had higher baseline inflammatory markers. There was no difference in copeptin levels between patients treated with the IL-1 receptor antagonist anakinra or placebo.
DISCUSSION Chronic low-grade inflammation is regulated by IL-1 in PCOS. IL-1 receptor antagonism possibly induced new ovulatory cycles. This was observed by the increase in androgen and estradiol levels which normally occurs during the transition from the early to late follicular phase. Further analyses are needed to investigate potential mechanisms explaining the observed effects and to plan further long-term trials which investigate the anti-inflammatory therapeutic approach in PCOS. Finally, IL-1 does not seem to contribute to the regulation of copeptin levels.