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Departments of Obstetrics and Gynecology (S.Ta., A.E.H., K.C.V., S.Tu., M.T.O., C.D., N.L.S., C.N.N., N.R.N., L.C.G.) and Pathology (R.K.), Stanford University, Stanford, California 94305; and Department of Obstetrics and Gynecology (B.A.L.), Greenville Hospital System, Greenville, South Carolina 29605
Address all correspondence and requests for reprints to: Linda C. Giudice, M.D., Ph.D., Professor and Chair, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, Parnassus, M1495, Box 0132, San Francisco, California 94143-0132. E-mail: giudice{at}obgyn.ucsf.edu.
Histological evaluation of endometrium has been the gold standard for clinical diagnosis and management of women with endometrial disorders. However, several recent studies have questioned the accuracy and utility of such evaluation, mainly because of significant intra- and interobserver variations in histological interpretation. To examine the possibility that biochemical or molecular signatures of endometrium may prove to be more useful, we have investigated whole-genome molecular phenotyping (54,600 genes and expressed sequence tags) of this tissue sampled across the cycle in 28 normo-ovulatory women, using high-density oligonucleotide microarrays. Unsupervised principal component analysis of all samples revealed that samples self-cluster into four groups consistent with histological phenotypes of proliferative (PE), early-secretory (ESE), mid-secretory (MSE), and late-secretory (LSE) endometrium. Independent hierarchical clustering analysis revealed equivalent results, with two major dendrogram branches corresponding to PE/ESE and MSE/LSE and sub-branching into the four respective phases with heterogeneity among samples within each sub-branch. K-means clustering of genes revealed four major patterns of gene expression (high in PE, high in ESE, high in MSE, and high in LSE), and gene ontology analysis of these clusters demonstrated cycle-phase-specific biological processes and molecular functions. Six samples with ambiguous histology were identically assignable to a cycle phase by both principal component analysis and hierarchical clustering. Additionally, pairwise comparisons of relative gene expression across the cycle revealed genes/families that clearly distinguish the transitions of PE
ESE, ESEMSE, and MSELSE, including receptomes and signaling pathways. Select genes were validated by quantitative RT-PCR. Overall, the results demonstrate that endometrial samples obtained by two different sampling techniques (biopsy and curetting hysterectomy specimens) from subjects who are as normal as possible in a human study and including those with unknown histology, can be classified by their molecular signatures and correspond to known phases of the menstrual cycle with identical results using two independent analytical methods. Also, the results enable global identification of biological processes and molecular mechanisms that occur dynamically in the endometrium in the changing steroid hormone milieu across the menstrual cycle in normo-ovulatory women. The results underscore the potential of gene expression profiling for developing molecular diagnostics of endometrial normalcy and abnormalities and identifying molecular targets for therapeutic purposes in endometrial disorders.
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A. Hever, R.B. Roth, P.A. Hevezi, J. Lee, D. Willhite, E.C. White, E.M. Marin, R. Herrera, H.M. Acosta, A.J. Acosta, et al. Molecular characterization of human adenomyosis Mol. Hum. Reprod., December 1, 2006; 12(12): 737 - 748. [Abstract] [Full Text] [PDF]
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J. Francis, R. Rai, N. J. Sebire, S. El-Gaddal, M. S. Fernandes, P. Jindal, A. Lokugamage, L. Regan, and J. J. Brosens Impaired expression of endometrial differentiation markers and complement regulatory proteins in patients with recurrent pregnancy loss associated with antiphospholipid syndrome Mol. Hum. Reprod., July 1, 2006; 12(7): 435 - 442. [Abstract] [Full Text] [PDF]
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S. Tulac, M. T. Overgaard, A. E. Hamilton, N. L. Jumbe, E. Suchanek, and L. C. Giudice Dickkopf-1, an Inhibitor of Wnt Signaling, Is Regulated by Progesterone in Human Endometrial Stromal Cells J. Clin. Endocrinol. Metab., April 1, 2006; 91(4): 1453 - 1461. [Abstract] [Full Text] [PDF]
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