Pathogenesis of Endometriosis: Roles of Retinoids and Inflammatory Pathways

Abstract

Endometriosis is a nonmalignant, but potentially metastatic, gynecological condition manifested by the extrauterine growth of inflammatory endometrial implants. Ten percent of reproductive-age women are affected and commonly suffer pelvic pain and/or infertility. The theories of endometriosis histogenesis remain controversial, but retrograde menstruation and metaplasia each infer mechanisms that explain the immune cell responses observed around the ectopic lesions. Recent findings from our laboratories and others suggest that retinoic acid metabolism and action are fundamentally flawed in endometriotic tissues and even generically in women with endometriosis. The focus of our ongoing research is to develop medical therapies as adjuvants or alternatives to the surgical excision of these lesions. On the basis of concepts put forward in this review, we predict that the pharmacological actions and anticipated low side-effect profiles of retinoid supplementation might provide a new treatment option for the long-term management of this chronic and debilitating gynecological disease.

Fig. 1

Endometrial vitamin A (retinol) metabolism and retinoic acid (RA) signaling. Uptake of retinol (ROL) bound with circulating plasma “retinol binding protein 4” (RBP4) is controlled by the membrane receptor, “stimulated by retinoic acid 6” (STRA6). Intracellular chaperone “cellular ROL-binding protein type 1” (RBP1) physically interacts with STRA6 to pick up ROL, protect ROL from nonspecific metabolism, and deliver it to retinol dehydrogenase enzymes which reversibly catalyze conversion of ROL to retinal. RBP1 then chaperones retinal-to-retinal dehydrogenases (ALDH1A2) which irreversibly convert retinal to RA. RA is then chaperoned by a distinct set of RA-binding proteins (CRABP1, CRABP2, FABP5), which are known to be expressed in endometrial stromal cells (ESC).^, Once formed, RA can be: (1) transported to the nucleus of the RA biosynthesizing ESC where it binds to nuclear receptors (RAR) and initiates gene transcription; (2) transported to adjacent epithelial cells (EEC) or secreted into the microenvironment to affect gene transcription in other cells such as peritoneal fluid macrophages (PFM); or (3) degraded. Genes known to be affected in PFM include various proinflammatory cytokines (IL-6, MCP-1, TNFα), which are downregulated by RA and the CD36 type-B scavenger receptor which is upregulated by RA. The consequence of this activity in PFM is a reduction in the inflammatory and oxidative status of the peritoneal environment and increased clearance of ectopic endometrial cells.

Fig. 2

Endometriotic stromal cells effectively metabolize [³H]arachidonic acid to PGE2 and PGF2α in vitro. Metabolic labeling of endometriotic stromal cell prostanoid production was performed as described by de Groot et al. Briefly, the cultures were incubated with 3 nM [³H] arachidonic acid (AA) for 24 hours and the spent media were extracted with chloroform:methanol:acetic acid (180:20:1) and subjected to high-performance liquid chromatography using a 3.9 × 150 mm Nova-Pack C18 reverse phase column on a Waters Model 204 liquid chromatograph. Unlabeled PGE2 and PGF2α standards eluted at 32 and 38 minutes, respectively, under these conditions. Radioactive counts per minute (cpm) were detected with a Radiometer FLO/ONE-β Model A250 detector.