dinoprost and 2-hydroxyestradiol

The mechanisms underlying the pathogenesis of estrogen-induced breast carcinogenesis remain unclear. The present study investigated the roles of estrogen metabolism and oxidative stress in estrogen-mediated mammary carcinogenesis in vivo. Female August Copenhagen Irish (ACI) rats were treated with 17beta-estradiol (E(2)), the antioxidant vitamin C, the estrogen metabolic inhibitor alpha-naphthoflavone (ANF), or cotreated with E(2) + vitamin C or E(2) + ANF for up to 8 months. E(2) (3 mg) was administered as an subcutaneous implant, ANF was given via diet (0.2%) and vitamin C (1%) was added to drinking water. At necropsy, breast tumor incidence in the E(2), E(2) + vitamin C and E(2) + ANF groups was 82, 29 and 0%, respectively. Vitamin C and ANF attenuated E(2)-induced alterations in oxidative stress markers in breast tissue, including 8-iso-prostane F(2alpha) formation and changes in the activities of antioxidant enzymes superoxide dismutase and glutathione peroxidase. Quantification of 2-hydroxyestradiol (2-OHE(2)) and 4-hydroxyestradiol (4-OHE(2)) formation in breast tissue confirmed that ANF inhibited 4-hydroxylation of E(2) and decreased formation of the highly carcinogenic 4-OHE(2). These results demonstrate that antioxidant vitamin C reduces the incidence of estrogen-induced mammary tumors, increases tumor latency and decreases oxidative stress in vivo. Further, our data indicate that ANF completely abrogates breast cancer development in ACI rats. The present study is the first to demonstrate the inhibition of breast carcinogenesis by antioxidant vitamin C or the estrogen metabolic inhibitor ANF in an animal model of estrogen-induced mammary carcinogenesis. Taken together, these results suggest that E(2) metabolism and oxidant stress are critically involved in estrogen-induced breast carcinogenesis.

Topics: Animals; Antioxidants; Ascorbic Acid; Benzoflavones; Cell Transformation, Neoplastic; Dinoprost; Estradiol; Estrogens, Catechol; Female; Mammary Neoplasms, Experimental; Neoplasms, Hormone-Dependent; Oxidative Stress; Rats; Rats, Inbred ACI

Locally produced oestrogens and prostaglandins (PGs) are implicated in the regulation of luteal lifespan in the human ovary. This study (1) assesses direct effects of these factors on progesterone synthesis in isolated luteal cells, and (2) explores interactions between luteal age and treatment with gonadotrophin or oestrogen on the metabolism of arachidonic acid (prostaglandin precursor) by steroidogenic luteal cells in vitro.. Primary monolayer cultures of human luteal cells obtained at different stages of the luteal phase were used to investigate the effect of oestradiol, catechol oestrogens (2- and 4-hydroxyoestradiol), diethylstilboestrol, PGE2 and PGF2 alpha on basal and human chorionic gonadotrophin (hCG) stimulated progesterone production 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.. Corpora lutea were enucleated from nine women with regular ovulatory cycles undergoing microsurgical reversal of tubal sterilization. Granulosa cell aspirates were obtained from three patients undergoing in-vitro fertilization treatment.. PGE2 and PGF2 alpha at various concentrations did not have a consistent effect, whereas oestradiol, diethylstilboestrol (and 2-hydroxyoestradiol in early luteal cell cultures) significantly inhibited basal and hCG stimulated progesterone biosynthesis. Evidence for direct inhibition of 3 beta-hydroxysteroid dehydrogenase enzymic activity by oestradiol was obtained. Both major metabolic pathways of arachidonic acid (lipoxygenase and cyclo-oxygenase) were operative in steroidogenic luteal cells recovered throughout the luteal phase. The ratio of PGE2 to PGF2 alpha synthesis in vitro by human luteal cells from endogenously incorporated arachidonic acid did not change significantly with corpus luteum age, with PGE2 tending to predominate. Oestradiol treatment shifted arachidonic acid metabolism from the lipoxygenase towards the cyclooxygenase pathway in cells isolated from ageing corpora lutea.. Oestradiol, at relatively high concentrations, is a potent inhibitor of basal and hCG induced luteal cell steroidogenesis in vitro. No support is provided for the concept that luteolysis is mediated by local production of PGF2 alpha. The putative luteolytic effect of oestradiol may entail reduced metabolism of arachidonic acid to lipoxygenase derived products by luteal cells rather than direct stimulation of prostaglandin production by itself.

Topics: Arachidonic Acids; Cells, Cultured; Chorionic Gonadotropin; Chromatography, High Pressure Liquid; Corpus Luteum; Depression, Chemical; Diethylstilbestrol; Dinoprost; Dinoprostone; Estradiol; Estrogens; Female; Humans; Luteal Phase; Progesterone

Prostaglandin (PG) and thromboxane (TX) synthesis by homogenates of the hypothalamus of rats has been measured in relation to the preovulatory surge of LH. Prostaglandin and TX production by the median eminence (ME) was five to ten times higher than that by the anterior hypothalamus/preoptic area (AH-POA). Prostaglandin E2 and PGF2 alpha were the major prostaglandins synthesized by the ME and AH-POA respectively. During the 4-day oestrous cycle, the PG- and TX-synthesizing capacity of the ME showed daily changes, being high at 06.00 and 22.00 h and, with the exception of pro-oestrus, low at 18.00 h. There was an additional peak of PGE2 production by the ME at 18.00 h on pro-oestrus coincident with the preovulatory LH surge. Progesterone treatment stimulated PGE2 synthesis by the ME of long-term ovariectomized, oestradiol-primed rats but not by the ME of acutely ovariectomized, oestradiol-primed rats. 2-Hydroxyoestradiol had no effect on PG and TX production by the ME at 18.00 h on dioestrus or 18.00 h on pro-oestrus. Noradrenaline stimulated PG and TX synthesis by the ME at the former time but not at the latter time. Prostaglandin F2 alpha-synthesizing capacity of the AH-POA peaked at 22.00 h on each day of the 4-day cycle. There was also an additional peak at 14.00 h on each day except dioestrus. Similar peaks occurred in the production of PGE2 and TXB2, except on pro-oestrus when the production of each compound remained low. There was no association between increased PGE2 production by the AH-POA and the preovulatory surge of LH. Noradrenaline, but not 2-hydroxyoestradiol, stimulated PG and TX production by the AH-POA at 18.00 h on both dioestrus and pro-oestrus. Progesterone stimulated PGE2, PGF2 alpha and 6-oxo-PGF1 alpha production by the AH-POA of acute, ovariectomized, oestradiol-primed rats but not of long-term ovariectomized, oestradiol-primed rats. Flurbiprofen, a cyclo-oxygenase inhibitor, prevented the preovulatory LH surge in two rats and delayed the LH surge by 2 h in four rats. It also reduced PG and TX production by the ME and AH-POA. Overall, the present studies show that there is an increase in PGE2-synthesizing capacity of the ME at the time of the preovulatory LH surge in the rat, and that the administration of an inhibitor of prostaglandin synthesis interferes with the timing of the LH surge.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Castration; Circadian Rhythm; Dinoprost; Dinoprostone; Estradiol; Estrus; Female; Flurbiprofen; Hypothalamus; Luteinizing Hormone; Median Eminence; Norepinephrine; Pregnancy; Preoptic Area; Progesterone; Prostaglandins; Prostaglandins E; Prostaglandins F; Radioimmunoassay; Rats; Rats, Inbred Strains; Thromboxane B2