title: Novel contraceptive targets to inhibit ovulation: the prostaglandin E2 pathway.
abstract: BACKGROUND
  Prostaglandin E2 (PGE2) is an essential intrafollicular regulator of ovulation. In contrast with the one-gene, one-protein concept for synthesis of peptide signaling molecules, production and metabolism of bioactive PGE2 requires controlled expression of many proteins, correct subcellular localization of enzymes, coordinated PGE2 synthesis and metabolism, and prostaglandin transport in and out of cells to facilitate PGE2 action and degradation. Elevated intrafollicular PGE2 is required for successful ovulation, so disruption of PGE2 synthesis, metabolism or transport may yield effective contraceptive strategies.
  
  
  METHODS
  This review summarizes case reports and studies on ovulation inhibition in women and macaques treated with cyclooxygenase inhibitors published from 1987 to 2014. These findings are discussed in the context of studies describing levels of mRNA, protein, and activity of prostaglandin synthesis and metabolic enzymes as well as prostaglandin transporters in ovarian cells.
  
  
  RESULTS
  The ovulatory surge of LH regulates the expression of each component of the PGE2 synthesis-metabolism-transport pathway within the ovulatory follicle. Data from primary ovarian cells and cancer cell lines suggest that enzymes and transporters can cooperate to optimize bioactive PGE2 levels. Elevated intrafollicular PGE2 mediates key ovulatory events including cumulus expansion, follicle rupture and oocyte release. Inhibitors of the prostaglandin-endoperoxide synthase 2 (PTGS2) enzyme (also known as cyclooxygenase-2 or COX2) reduce ovulation rates in women. Studies in macaques show that PTGS2 inhibitors can reduce the rates of cumulus expansion, oocyte release, follicle rupture, oocyte nuclear maturation and fertilization. A PTGS2 inhibitor reduced pregnancy rates in breeding macaques when administered to simulate emergency contraception. However, PTGS2 inhibition did not prevent pregnancy in monkeys when administered to simulate monthly contraceptive use.
  
  
  CONCLUSIONS
  PTGS2 inhibitors alone may be suitable for use as emergency contraceptives. However, drugs of this class are unlikely to be effective as monthly contraceptives. Inhibitors of additional PGE2 synthesis enzymes or modulation of PGE2 metabolism or transport also hold potential for reducing follicular PGE2 and preventing ovulation. Approaches which target multiple components of the PGE2 synthesis-metabolism-transport pathway may be required to effectively block ovulation and lead to the development of novel contraceptive options for women. Therapies which target PGE2 may also impact disorders of the uterus and could also have benefits for women's health in addition to contraception.
authors.affiliation: Department of Physiological Sciences, Eastern Virginia Medical School, 700 Olney Road, Lewis Hall, Norfolk, VA 23507, USA duffydm@evms.edu.
authors.forename: Diane M
authors.initials: DM
authors.lastname: Duffy
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000502:physiology; D003267:Contraception / Q000379:methods; D003270:Contraceptive Agents / Q000494:pharmacology*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D005260:Female; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000502:physiology; D008251:Macaca; D009865:Oocytes / Q000502:physiology; D006080:Ovarian Follicle / Q000502:physiology; D010060:Ovulation / Q000187:drug effects*; D054467:Phospholipases A2 / Q000502:physiology; D011247:Pregnancy; D018873:Pregnancy Rate; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D003270:Contraceptive Agents; D052246:Cyclooxygenase 2 Inhibitors; D012333:RNA, Messenger; D006911:Hydroxyprostaglandin Dehydrogenases; D011451:Prostaglandin-Endoperoxide Synthases; D054467:Phospholipases A2; D015232:Dinoprostone
keywords: contraception; follicle; ovary; prostaglandin E2, cyclooxygenase-2