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Controlled Ovarian Stimulation Induces a Functional Genomic Delay of the Endometrium with Potential Clinical Implications

Fundación IVI-Instituto Universitario IVI-Universidad de Valencia (J.A.H., F.D., A.P., C.S.), Valencia 46015, Spain; Obstetric and Gynecology and Reproductive Sciences (J.A.H., L.C.G.), University of California, San Francisco, California 94143; Bioinformatics Department and Functional Genomics Node (P.M., J.D.), Centro de Investigación Príncipe Felipe, Valencia 46013, Spain; and Department of Experimental Biology (C.S., F.J.E.), University of Jaén, 23071 Jaén, Spain

Address all correspondence and requests for reprints to: C. Simón. c/ Guadassuar, 1 Bajo, Valencia 46015, Spain. E-mail: csimon{at}ivi.es.

Context: Controlled ovarian stimulation induces morphological, biochemical, and functional genomic modifications of the human endometrium during the window of implantation.

Objective: Our objective was to compare the gene expression profile of the human endometrium in natural vs. controlled ovarian stimulation cycles throughout the early-mid secretory transition using microarray technology.

Method: Microarray data from 49 endometrial biopsies obtained from LH+1 to LH+9 (n = 25) in natural cycles and from human chorionic gonadotropin (hCG) +1 to hCG+9 in controlled ovarian stimulation cycles (n = 24) were analyzed using different methods, such as clustering, profiling of biological processes, and selection of differentially expressed genes, as implemented in Gene Expression Pattern Analysis Suite and Babelomics programs.

Results: Endometria from natural cycles followed different genomic patterns compared with controlled ovarian stimulation cycles in the transition from the pre-receptive (days LH/hCG+1 until LH/hCG+5) to the receptive phase (day LH+7/hCG+7). Specifically, we have demonstrated the existence of a 2-d delay in the activation/repression of two clusters composed by 218 and 133 genes, respectively, on day hCG+7 vs. LH+7. Many of these delayed genes belong to the class window of implantation genes affecting basic biological processes in the receptive endometrium.

Conclusions: These results demonstrate that gene expression profiling of the endometrium is different between natural and controlled ovarian stimulation cycles in the receptive phase. Identification of these differentially regulated genes can be used to understand the different developmental profiles of receptive endometrium during controlled ovarian stimulation and to search for the best controlled ovarian stimulation treatment in terms of minimal endometrial impact.

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