A fresh look at three chemical mediators in endometriosis

June 2007

Cytokines in the peritoneum, progesterone resistance, chemokines in the epithelium. What a cocktail. But each of these three chemical mediators may have a significant role to play in endometriosis.

Cytokines in the Peritoneum

Bedaiwy et al [1] recently investigated the concentrations of the interleukins IL-1 beta, IL-6, IL-8, IL-3 and tumor necrosis factor alpha (TNF-alpha). Interleukins and TNF-alpha are a class of biological signaling molecules called cytokines which are responsible for the mediation of the inflammatory response and calling for immune assistance from leukocytes, as well as various other intercellular messages.

Bedaiwy and his team sampled the peritoneal fluid of three categories of women. The first group consisted of 17 women with endometriosis with ovarian involvement, the second group was 33 women with endometriosis without ovarian involvement, and the third group consisted of 33 women non-patients.

Of all the compounds analysed, only IL-8 and TNF-alpha were significantly higher in both groups of endometriosis patients versus non-patients, but there was no significant difference between IL-8 and TNF-alpha levels between endometriosis patient groups.

Progesterone Resistance

Burney et al [2] compared the gene expression signatures through different phases of the menstrual cycle in women with moderate and severe endometriosis as well as women with no endometriosis.

The study conducted was to survey which mRNAs were being produced during which parts of the menstrual cycle. It was found that a woman with endometriosis had a slightly different profile of mRNAs than non-patients. Patients with endometriosis expressed mRNAs associated with genes that relate to cellular survival, DNA synthesis and mitosis. This occurred in the transition between the proliferative phase and the secretory phase of the uterus. The proliferative phase is the time when the endometrium is thickening, and the secretory phase is the time when the endometrium is prepared to receive an embryo.

This finding is an indicator that the cells of the endometrium of a woman with endomtriosis are still actively multiplying long after those of a non-patient. Progesterone is a signaler that causes the endometrium to leave the proliferative phase, so these findings indicate that progesterone is attenuated in endometriosis.

While many investigators have examined single molecules in endometrium of women with endometriosis, this microarray study on tissue from carefully selected subjects, confirms that there is incomplete transitioning in endometrial gene expression from the proliferative to the secretory phase in the eutopic endometrium of women with endometriosis, according to a review by Lois Salamonsen on F1000 for Medicine[3].

The authors also confirmed dysregulation of progesterone dependent gene expression with progesterone insensitivity in the eutopic endometrium being intrinsic to women with endometriosis. Hence, the association between endometriosis and infertility becomes clear: the endometrium is not adequately prepared for implantation in the mid-secretory phase. The study raises the question as to whether the existence of endometriosis causes these changes in the eutopic endometrium or whether endometriotic lesions occur when such dysregulated endometrium reaches ectopic sites.

Chemokines in the epithelium

Chand et al [4] analysed the chemokines found right in the layers of the endometrium to determine the profile of chemokines expressed in endometriosis.

Chemokines are another sort of intercellular signaller, belonging to the cytokine family. The study targeted the secretory glands in the epithelium (surface layers) of the endometrium.

Patients and non-patients submitted samples of eutopic endometrium (the endometrium found normally in the uterus) to be tested for comparison. Significant results include the discovery that two chemokines, CCL16 and CCL21 were produced in excess in the eutopic and ectopic (misplaced) endometrium in endometriosis as compared with non-patients. It was also found that CCL16 was produced more abundantly in the ectopic endometrium than in the eutopic endometrium in endometriosis. The roles of CCL16 and CCL21 in endometriosis are not known, so two novel molecules have been introduced into the potential factors regulating endometriosis.

Review by: Eddie Ma


1. Bedaiwy MA, El-Nashar SA, Sharma RK, Falcone T. Effect of ovarian involvement on peritoneal fluid cytokine concentrations in endometriosis patients. Reprod Biomed Online 2007;14(5):620-5.

2. Burney RO, Talbi S, Hamilton AE, Vo KC, Nyegaard M. Nezhat CR. Lessey BA. Giudice LC.
Gene Expression Analysis of Endometrium Reveals Progesterone Resistance and Candidate Susceptibility Genes in Women with Endometriosis. Endocrinology 2007 [epub ahead of publication].

3. Lois Salamonsen: Faculty of 1000 Medicine, 15 Jun 2007

4. Chand AL, Murray AS, Jones RL, Hannan NJ, Salamonsen LA, Rombauts L. Laser capture microdissection and cDNA array analysis of endometrium identify CCL16 and CCL21 as epithelial-derived inflammatory mediators associated with endometriosis. Reprod Biol Endocrinol 2007;5:18.


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