Non-steroidal anti-inflammatory drugs (NSAIDs) and ovulation: lessons from morphology.
Ovulation constitutes the central event in ovarian physiology, and ovulatory disfunction is a relevant cause of female infertility. Non-steroidal anti-inflammatory drugs (NSAIDs), widely used due to their analgesic and anti-inflammatory properties, consistently inhibit ovulation in all mammalian species investigated so far, likely due to the inhibition of cyclooxygenase 2 (COX-2), the inducible isoform of COX, that is the rate-limiting enzyme in prostaglandin (PG) synthesis. COX-2 inhibition has major effects on ovulation, fertilization and implantation, and NSAID therapy is likely implicated in human infertility and could be an important, frequently overlooked, cause of ovulatory disfunction in women. Although there is compelling evidence for a role of PGs in ovulation, the molecular targets and the precise role of these compounds in the ovulatory process are not fully understood. Morphological studies from rats treated with indomethacin (INDO), a potent inhibitor of PG synthesis, provide evidence on the actions of NSAIDs in ovulation, as well as on the possible roles of PGs in the ovulatory process. Cycling rats treated with INDO during the preovulatory period show abnormal ovulation, due to disruption of the spatial targeting of follicle rupture at the apex. Noticeably, gonadotropin-primed immature rats (widely used as a model for the study of ovulation) show age-dependent ovulatory defects similar to those of cycling rats treated with INDO. These data suggest that NSAID treatment disrupts physiological mechanisms underlying spatial targeting of follicle rupture at the apex, which are not fully established in very young rats. We summarize herein the ovulatory defects after pharmacologic COX-2 inhibition, and discuss the possible mechanisms underlying the anti-ovulatory actions of NSAIDs.
Department of Cell Biology, Physiology and Immunology, School of Medicine, University of Córdoba, Spain.
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M
Gaytán
C
C
Morales
C
C
Bellido
J E
JE
Sánchez-Criado
F
F
Gaytán
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000502:physiology; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D005260:Female; D006062:Gonadotropins / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007247:Infertility, Female / Q000503:physiopathology; D006080:Ovarian Follicle / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D010060:Ovulation / Q000187:drug effects* / Q000502:physiology*; D011453:Prostaglandins / Q000096:biosynthesis / Q000502:physiology; D051381:Rats
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D006062:Gonadotropins; D011453:Prostaglandins; D051546:Cyclooxygenase 2; D007213:Indomethacin