EFFECTS OF ESTROGEN ON PROGESTERONE SYNTHESIS AND ARACHIDONIC-ACID METABOLISM IN HUMAN LUTEAL CELLS

OBJECTIVE Locally produced oestrogens and prostaglandins (PGs) are imp licated in the regulation of luteal lifespan in the hu man ovary. This study (1) assesses direct effects of these factors on progesterone sy nthesis in isolated luteal cells, and (2) explores interactions betwee n luteal age and treatment with gonadotrophin or oestrogen on the meta bolism of arachidonic acid (prostaglandin precursor) by steroidogenic luteal cells in vitro. DESIGN Primary monolayer cultures of human lute al cells obtained at different stages of the luteal phase were used to investigate the effect of oestradiol, catechol oestrogens (2- and 4-h ydroxyoestradiol), diethylstilboestrol, PGE(2) and PGF(2x) on basal an d human chorionic gonadotrophin (hCG) stimulated progesterone producti on in vitro. The role of PGs as modulators of luteal cell function was further investigated by studying the metabolic fate of radioactively labelled arachidonic acid in hormone treated (oestradiol and hCG) and control cultures, assessed by high performance liquid chromatography. PATIENTS Corpora lutea were enucleated from nine women with regular ov ulatory cycles undergoing microsurgical reversal of tubal sterilizatio n. Granulosa cell aspirates were obtained from three patients undergoi ng in-vitro fertilization treatment. RESULTS PGE(2) and PGF(2x) at var ious concentrations did not have a consistent effect, whereas oestradi ol, diethylstilboestrol (and 2-hydroxyoestradiol in early luteal cell cultures) significantly inhibited basal and hCG stimulated progesteron e biosynthesis. Evidence for direct inhibition of 3 beta-hydroxysteroi d dehydrogenase enzymic activity by oestradiol was obtained. Both majo r metabolic pathways of arachidonic acid (lipoxygenase and cyclo-oxyge nase) were operative in steroidogenic luteal cells recovered throughou t the luteal phase. The ratio of PGE(2) to PGF(2x) synthesis in vitro by human luteal cells from endogenously incorporated arachidonic acid did not change significantly with corpus luteum age, with PGE(2) tendi ng to predominate. Oestradiol treatment shifted arachidonic acid metab olism from the lipoxygenase towards the cyclooxygenase pathway in cell s isolated from ageing corpora lutea. CONCLUSIONS Oestradiol, at relat ively high concentrations, is a potent inhibitor of basal and hCG indu ced luteal cell steroidogenesis in vitro. No support is provided for t he concept that luteolysis is mediated by local production of PGF(2x). The putative luteolytic effect of oestradiol may entail reduced metab olism of arachidonic acid to lipoxygenase derived products by luteal c ells rather than direct stimulation of prostaglandin production by its elf.