Cannabinoids in Gynecological Diseases, Petra Luschnig et al., 2019

Cannabinoids in Gynecological Diseases

Petra Luschnig, Rudolf Schicho

Medical Cannabis & Cannabinoids, 2019, 2, 14-21

Doi : 10.1159/000499164



The endocannabinoid system (ECS) is a multifunctional homeostatic system involved in many physiological and pathological conditions. The ligands of the ECS are the endocannabinoids, whose actions are mimicked by exogenous cannabinoids, such as phytocannabinoids and synthetic
cannabinoids. Responses to the ligands of the ECS are mediated by numerous receptors like the classical cannabinoid receptors (CB1 and CB2) as well as ECS-related receptors, e.g., G protein-coupled receptors 18 and 55 (GPR18 and GPR55), transient receptor potential ion channels, and nuclear peroxisome
proliferator-activated receptors. The ECS regulatesalmost all levels of female reproduction, starting with oocyte production through to parturition. Dysregulation of the ECS is associated with the development of gynecological disorders from fertility disorders to cancer. Cannabinoids that act at the ECS as specific agonists or antagonists may potentially influence dysregulation and, therefore, represent new therapeutic options for the therapy of gynecological disorders.

Keywords : Endocannabinoid system · Cannabinoid receptors · Endometriosis · Cervical cancer · TRPV1

Cannabinoids and the Endocannabinoid System

Cannabinoids: Endo-, Phyto-, and Synthetic Cannabinoids

Since its first description as a multifunctional system 2 decades ago, the endocannabinoid system (ECS) has gained a lot of interest [1]. The ECS comprises enzymes, cannabinoid receptors and their related receptors, and ligands, i.e., the endocannabinoids (eCB), which are synthesized endogenously. Phytocannabinoids (pCB) that are isolated from Cannabis sativa and synthetic cannabinoids (sCB) affect the receptors of the ECS as exogenous cannabinoids.

The first eCB that were discovered were N-arachidonoyl- ethanolamine, better known as anandamide
(AEA), and 2-arachidonoylglycerol (2-AG) [2–4]. Further endogenous ligands of the ECS are 2-AG ether (noladin ether), N-arachidonoyl dopamine, and O-arachidonoyl ethanolamine (virodhamine) [5–7]. The best investigated eCB are AEA and 2-AG, which are produced “on demand”. They are triggered by a stimulus that leads to an increase in the intracellular Ca2+ concentration and cleavage of precursor molecules [6, 7]. Synthesis of eCB take place in several tissues and cell types where they are catalyzed by specific synthases, such as N-acylphosphatidylethanolamine- hydrolyzing phospholipase D (NAPEPLD)
and others [8]. After release, inactivation of AEA and 2-AG occurs promptly by enzymatic hydrolysis of the amide and ester bonds by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) [9–13].

More than a 100 pCB have been identified, of which the psychotropic (–)-trans-Δ9 tetrahydro-cannabidiol (THC) and the nonpsychotropic (–)-cannabidiol (CBD) are the best studied [14–16]. THC and CBD mediate a broad spectrum of biological actions including analgesic, antiemetic, and anti inflammatory effects [12–14].

Classical Cannabinoid Receptors

Responses to eCB, but also to pCB and sCB, are mediated by numerous receptors of which cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2) represent the classical cannabinoid receptors. CB1 and CB2 are G-protein-coupled receptors and they are involved in many (patho-) physiological processes such as pain, inflammation, cancer, and hypertension as well as neurodegenerative disorders [15]. The expression of the CB1 receptor in the brain is responsible for the psychotropic effects of THC and other synthetic CB1 agonists. CB1 expression has also been found in peripheral organs like the heart, spleen, and endocrine glands as well as in parts of the male and female reproductive systems and the urinary tract, including the ovaries, uterus, testis, prostate, and placenta [16–19]. The second classical cannabinoid receptor, CB2, is expressed only to a minor degree in the nervous system. It is mainly located in tissues of the immune system including the spleen, tonsils, thymus, and bone marrow as wells as in immune cells such as B cells, natural killer cells, monocytes, neutrophils, and CD8+ and CD4+ T cells [20–22].