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¹ Department of Biochemistry and Molecular Biology, Royal Free and University College Medical School, University College London, Rowland Hill Street, London NW3 2PF, UK
² Department of Veterinary Basic Science, Royal Veterinary College, Royal College Street, London NW1 0TU, UK
³ Department of Clinical Science at South Bristol (Obstetrics and Gynaecology), University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol BS1 3NY, UK
⁴ Division of Clinical Developmental Sciences, Academic Section of Obstetrics and Gynaecology, Centre for Developmental and Endocrine Signalling, St George’s University of London, Cranmer Terrace, Tooting, London SW17 0RE UK

(Requests for offprints should be addressed to A E Michael; Email: tony.michael{at}sgul.ac.uk)

(C Chandras is now at Developmental Biology, Foundation for Biomedical Research of the Academy of Athens, 11527 Athens, Greece)

In luteinizing granulosa cells, prostaglandin E₂ (PGE₂) can exert luteotrophic actions, apparently via the cAMP signalling pathway. In addition to stimulating progesterone synthesis, PGE₂ can also stimulate oxidation of the physiological glucocorticoid, cortisol, to its inactive metabolite, cortisone, by the type 1 11ß-hydroxysteroid dehydrogenase (11ßHSD1) enzyme in human granulosa–lutein cells. Having previously shown these human ovarian cells to express functional G-protein coupled, E-series prostaglandin (PTGER)1, PTGER2 and PTGER4 receptors, the aim of this study was to delineate the roles of PTGER1 and PTGER2 receptors in mediating the effects of PGE₂ on steroidogenesis and cortisol metabolism in human granulosa–lutein cells. PGE₂-stimulated concentration-dependent increases in both progesterone production and cAMP accumulation (by 1.9 ± 0.1- and 18.7 ± 6.8-fold respectively at 3000 nM PGE₂). While a selective PTGER1 antagonist, SC19220, could partially inhibit the steroidogenic response to PGE₂ (by 55.9 ± 4.1% at 1000 nM PGE₂), co-treatment with AH6809, a mixed PTGER1/PTGER2 receptor antagonist, completely abolished the stimulation of progesterone synthesis at all tested concentrations of PGE₂ and suppressed the stimulation of cAMP accumulation. Both PGE₂ and butaprost (a preferential PTGER2 receptor agonist) stimulated concentration-dependent increases in cortisol oxidation by 11ßHSD1 (by 42.5 ± 3.1 and 40.0 ± 3.0% respectively, at PGE₂ and butaprost concentrations of 1000 nM). Co-treatment with SC19220 enhanced the ability of both PGE₂ and butaprost to stimulate 11ßHSD1 activity (by 30.2 ± 0.2 and 30.5 ± 0.6% respectively), whereas co-treatment with AH6809 completely abolished the 11ßHSD1 responses to PGE₂ and butaprost. These findings implicate the PTGER2 receptor–cAMP signalling pathway in the stimulation of progesterone production and 11ßHSD1 activity by PGE₂ in human granulosa–lutein cells.

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