Enhanced Inflammatory Transcriptome in the Granulosa Cells of Women With Polycystic Ovarian Syndrome

CONTEXT: Polycystic ovarian syndrome (PCOS), the most common endocrine disorder of reproductive-aged women, is associated with systemic low-grade inflammation. OBJECTIVE: We propose that increased or altered intrafollicular inflammatory reactions also occur in periovulatory follicles of PCOS patients. DESIGN: Gene profiling and quantitative PCR (qPCR) analyses in granulosa-lutein cells (GCs) collected from PCOS and non-PCOS women undergoing in vitro fertilization were compared with serum and follicular fluid (FF) levels of cytokines and chemokines. SETTING: This was a university-based study. PATIENTS: Twenty-one PCOS and 45 control patients were recruited: demographic, hormone, body mass index, and pregnancy outcomes were abstracted from patient data files. INTERVENTIONS: GC cytokine/chemokine mRNAs were identified and analyzed by gene-chip microarrays/qPCR before and after culture with human chorionic gonadotropin, DHT, IL-6, or IL-8; serum/FF cytokine levels were also analyzed. MAIN OUTCOME MEASURES: Relative serum/FF cytokine levels and GC cytokine expression before and after culture were compared and related to body mass index. RESULTS: The following results were found: 1) PCOS GCs express elevated transcripts encoding cytokines, chemokines, and immune cell markers, 2) based on gene profiling and qPCR analyses, obese PCOS patients define a distinct PCOS disease subtype with the most dramatic increases in proinflammatory and immune-related factors, and 3) human chorionic gonadotropin and DHT increased cytokine production in cultured GCs, whereas cytokines augmented cytokine and vascular genes, indicating that hyperandrogenism/elevated LH and obesity in PCOS women augment intrafollicular cytokine production. CONCLUSIONS: Intrafollicular androgens and cytokines likely comprise a local regulatory loop that impacts GC expression of cytokines and chemokines and the presence of immune cells; this loop is further enhanced in the obese PCOS subtype.