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

• Published in: The journal of clinical endocrinology and metabolism Vol. 96; no. 6; pp. 1737 - 1746
• Main Authors: Savaris, Ricardo F, Groll, Jeremy M, Young, Steven L, DeMayo, Franco J, Jeong, Jae-Wook, Hamilton, Amy E, Giudice, Linda C, Lessey, Bruce A
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 01-06-2011
• Subjects: Analysis of Variance; Biological and medical sciences; Case-Control Studies; Clomiphene - pharmacology; Clomiphene - therapeutic use; Endocrine Research; Endocrinopathies; Endometrium - drug effects; Endometrium - metabolism; Feeding. Feeding behavior; Female; Fundamental and applied biological sciences. Psychology; Gene Expression - drug effects; Gene Expression - physiology; Humans; Immunohistochemistry; Medical sciences; Oligonucleotide Array Sequence Analysis; Polycystic Ovary Syndrome - drug therapy; Polycystic Ovary Syndrome - genetics; Polycystic Ovary Syndrome - metabolism; Principal Component Analysis; Progesterone - pharmacology; Progesterone - therapeutic use; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Vertebrates: endocrinology; Non steroidal estrogen; Obesity; Ovulation inducer; Menstrual cycle; Nutrition; Nutrition disorder; Metabolic diseases; Clomifene; Ovarian hormone; Progestagen; Resistance; Selective estrogen receptor modulator; Treatment; Uterus; Female genital system; Progesterone; Sex steroid hormone; Endocrinology; Endometrium; Nutritional status
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2010-2600

The endometrium of women with PCOS is dysfunctional, exhibiting signs of progesterone resistance, consistent with the elevated risk of endometrial cancer and poor reproductive performance.
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.