Progesterone Resistance in PCOS Endometrium: A Microarray Analysis in Clomiphene Citrate-Treated and Artificial Menstrual Cycles

Ricardo Francalacci Savaris, Jeremy M. Groll, Steven L. Young, Francesco J. DeMayo, Franco J. DeMayo, Jae-Wook Jeong, Amy E. Hamilton, Linda C. Giudice, Bruce A. Lessey
In: The Journal of Clinical Endocrinology & Metabolism · 2011 · vol. 96(6) , pp. 1737–1746 · doi:10.1210/jc.2010-2600 · PMID:21411543 · PMC3100753 · W1985124071
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This study found significantly altered gene expression in PCOS endometrium, indicating progesterone resistance and increased cell proliferation compared to normal controls.

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Abstract

CONTEXT: Polycystic ovary syndrome (PCOS), the most common endocrinopathy of reproductive-aged women, is characterized by ovulatory dysfunction and hyperandrogenism. OBJECTIVE: The aim was to compare gene expression between endometrial samples of normal fertile controls and women with PCOS. DESIGN AND SETTING: We conducted a case control study at university teaching hospitals. PATIENTS: Normal fertile controls and women with PCOS participated in the study. INTERVENTIONS: Endometrial samples were obtained from normal fertile controls and from women with PCOS, either induced to ovulate with clomiphene citrate or from a modeled secretory phase using daily administration of progesterone. MAIN OUTCOME MEASURE: Total RNA was isolated from samples and processed for array hybridization with Affymetrix HG U133 Plus 2 arrays. Data were analyzed using GeneSpring GX11 and Ingenuity Pathways Analysis. Selected gene expression differences were validated using RT-PCR and/or immunohistochemistry in separately obtained PCOS and normal endometrium. RESULTS: ANOVA analysis revealed 5160 significantly different genes among the three conditions. Of these, 466 were differentially regulated between fertile controls and PCOS. Progesterone-regulated genes, including mitogen-inducible gene 6 (MIG6), leukemia inhibitory factor (LIF), GRB2-associated binding protein 1 (GAB1), S100P, and claudin-4 were significantly lower in PCOS endometrium; whereas cell proliferation genes, such as Anillin and cyclin B1, were up-regulated. CONCLUSIONS: Differences in gene expression provide evidence of progesterone resistance in midsecretory PCOS endometrium, independent of clomiphene citrate and corresponding to the observed phenotypes of hyperplasia, cancer, and poor reproductive outcomes in this group of women.

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