The molecular connections between the cannabinoid system and endometriosis.

The endocannabinoid system consists of an array of endogenously produced bioactive lipids that activate cannabinoid 1 (CB1) and 2 (CB2) receptors. Alterations of this system have been described in almost every category of disease. These changes can be protective or maladaptive, making the endocannabinoid network an attractive therapeutic target. Little is known about the potential role of endocannabinoids in endometriosis development although this is a topic worthy of further investigation since endocannabinoid modulators have recently been shown to affect specific mechanisms critical to endometriosis establishment and maintenance. A literature review was herein performed with the aim of defining the regulation and function of the endocannabinoid signaling in in vitro and animal models of endometriosis. The components of the endocannabinoid system, CB1 and CB2 receptors and the enzymes N-acylphosphatidylethanolamine-phospholipase D and fatty acid amide hydrolase are differentially regulated throughout the menstrual cycle in the endometrium and are expressed in deep endometriotic nodules and in sensory and sympathetic neurons innervating the lesions. Selective cannabinoid receptor agonists, such as WIN 55212-2, appear to have a favorable action in limiting cell proliferation and in controlling pain symptoms. Conversely, endometrial cell migration tends to be stimulated by receptor agonists. The phosphatidylinositol 3-kinase/Akt and extracellular signal-regulated kinase 1/2 pathways seem to be involved in these processes. However, the underlying mechanisms of action are only just beginning to unfold. Given the complexity of the system, further studies are needed to clarify whether the endocannabinoid system might represent a promising target for endometriosis.