Cyclooxygenase enzymes and prostaglandins in pathology of the endometrium

Abstract

Prostaglandins are bioactive lipids produced from arachidonic acid by cyclooxygenase (COX) enzymes and specific terminal prostanoid synthase enzymes. After biosynthesis, prostaglandins exert an autocrine-paracrine function by coupling to specific prostanoid G protein-coupled receptors to activate intracellular signalling and gene transcription. For many years, prostaglandins have been recognized as key molecules in reproductive biology by regulating ovulation, endometrial physiology and proliferation of endometrial glands and menstruation. More recently, a role for COX enzymes and prostaglandins has been ascertained in reproductive tract pathology, including carcinomas, menorrhagia, dysmenorrhoea and endometriosis. Although the mechanism by which prostaglandins modulate these pathologies is still unclear, a large body of evidence supports a role for COX enzymes, prostaglandins and prostaglandin receptor signalling pathways in angiogenesis, apoptosis and proliferation, tissue invasion and metastases and immunosuppression. Here, an overview is provided of some of the findings from these studies with specific emphasis on the role of COX enzymes, prostaglandin E(2) and F(2alpha) in disorders of endometrial proliferation and menstruation in non-pregnant women.

Fig. 1

Schematic representation of the cyclooxygenase–prostanoid biosynthetic and signalling pathway. Arachidonic acid (AA) is released from plasma membrane phospholipids by phospholipase A2 (PLA2) and utilized by cyclooxygenases (COX) and specific synthase enzymes to form prostaglandin (PG), PGD₂, PGE₂, PGF_2α, PGI₂ and thromboxane (TX) A₂. These products are actively transported out of the cell by a prostanoid transporter (PGT), on which they exert an autocrine–paracrine effect by coupling to heptahelical transmembrane receptors to activate intracellular signalling. Inhibitors of COX enzyme function such as non-steroidal anti-inflammatory drugs (NSAIDs) can block PG biosynthesis and subsequent downstream events. IP₃: inositol trisphosphate; MAPK: mitogen-associated protein kinase; PGDS: prostaglandin-D-synthase; PGES: prostaglandin-E-synthase; PGFS: prostaglandin-F-synthase; PGIS: prostaglandin-I-synthase; TXS: thromboxane synthase.

Fig. 2

Possible mechanisms involved in the autocrine–paracrine–intracrine regulation of cyclooxygenase (COX) enzyme expression in epithelial and endothelial cells. A positive feedback loop is formed by prostaglandins (PG) to promote intracellular signalling via the cAMP, inositol trisphosphate (IP₃), mitogen-associated protein kinase (MAPK) and phosphatidyl inositol 3 kinase–protein kinase B (PI3K/Akt) pathways, and induction of COX enzyme expression. This positive feedback loop, in turn, results in activation of transcription of target genes involved in angiogenesis, inhibition of apoptosis, proliferation and tissue invasion and metastasis. In addition, the COX–prostanoid biosynthetic and signalling pathway, especially in neoplastically transformed endocervical cells, may also be regulated by immune function, cytokines, chemokines and seminal plasma prostanoids.