Chandras, Christina; (2002) Novel paracrine/autocrine roles of prostaglandins in the human ovary. Doctoral thesis (Ph.D.), University College London.

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Abstract

Prostaglandin (PG)E2 and PGF2α exert important roles in ovulation and luteinisation. The studies reported herein have used human granulosa-lutein cells to investigate: (1) the relationship between basal PG and progesterone production; (2) participation of PGs in the steroidogenic response to high-density-lipoproteins (HDL); (3) the role for PGs in controlling ovarian cortisol metabolism by 11β-hydroxysteroid dehydrogenase (11β- HSD); (4) the role of EP1 and EP2 receptors in mediating ovarian responses to PGE2. In culture, basal PG production decreased with a concomitant rise in progesterone synthesis. However, meclofenamic acid suppressed both PGE2 and PGF2α output without affecting progesterone production, and aminoglutethimide inhibited progesterone production without affecting either PG concentration. Both HDL and apolipoprotein A-I increased PGE2, cAMP and progesterone concentrations. Each of these effects was abolished by co-treatment with meclofenamic acid. Meclofenamic acid, indomethacin and niflumic acid each suppressed ovarian cortisol oxidation, whereas co-treatment with PGE2, PGD2 and PGF2α each increased 11β-HSD activities. Human follicular fluid was confirmed to contain intrinsic aqueous stimuli and hydrophobic inhibitors of NADP+-dependent 11β-HSD activity that eluted from C18 mini-columns at 0-10% and 65-90% (v/v) methanol, respectively. PGE2, PGp2α and 6-keto-PGF1α each eluted at 20-50% (v/v) methanol. The ability of PGE2 to stimulate progesterone production was inhibited by SC19220 and abolished by AH6809 (preferential EP1 and EP2 antagonists respectively). While SC19220 had no significant effect on the stimulation of cAMP accumulation and 11β-HSD activity by PGE2, these effects were abolished by co-treatment with AH6809. In conclusion, while changes in the ouput of PGs and progesterone in luteinizing human granulosa cells appeared to occur independently of each other, PGs were implicated in the steroidogenic actions of HDL and apolipoprotein A-I. Locally synthesised PGs appear to maintain ovarian 11β-HSD activity but do not contribute to the hydrophilic stimuli of 11β-HSD activity present in follicular fluid. Both EP1 and EP2 receptors appear to participate in the stimulation of progesterone synthesis, cAMP accumulation and 11β-HSD activity by PGE2.

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