Estrogen Production and Metabolism in Endometriosis

Bulun, Serdar E.; Yang, Shiyong; Fang, Z Y; Gürateş, Bilgin; Tamura, Mitsutoshi; Sebastian, Siby

doi:10.1111/j.1749-6632.2002.tb02767.x

Cited by 141 publications

(125 citation statements)

References 32 publications

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“…Endometriosis is an oestrogen-dependent disorder and immunohistochemical studies have localized oestrogen receptor expression and increased expression of aromatase in epithelial and stromal cells of endometriotic tissues and peritoneum (Matsuzaki et al, 2001;Bulun et al, 2002b). Other factors including aberrant expression of cytokines, matrix metalloproteinases (MMPs) and reduction in progesterone concentrations are contributing factors important in the pathophysiology of the disease (Bulun et al, 2000a).…”

Section: Endometriosismentioning

confidence: 99%

Cyclooxygenase enzymes and prostaglandins in pathology of the endometrium

Sales¹

2003

Reproduction

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Prostaglandins are bioactive lipids produced from arachidonic acid by cyclooxygenase (COX) enzymes and specific terminal prostanoid synthase enzymes. After biosynthesis, prostaglandins exert an autocrine-paracrine function by coupling to specific prostanoid G protein-coupled receptors to activate intracellular signalling and gene transcription. For many years, prostaglandins have been recognized as key molecules in reproductive biology by regulating ovulation, endometrial physiology and proliferation of endometrial glands and menstruation. More recently, a role for COX enzymes and prostaglandins has been ascertained in reproductive tract pathology, including carcinomas, menorrhagia, dysmenorrhoea and endometriosis. Although the mechanism by which prostaglandins modulate these pathologies is still unclear, a large body of evidence supports a role for COX enzymes, prostaglandins and prostaglandin receptor signalling pathways in angiogenesis, apoptosis and proliferation, tissue invasion and metastases and immunosuppression. Here, an overview is provided of some of the findings from these studies with specific emphasis on the role of COX enzymes, prostaglandin E 2 and F 2α in disorders of endometrial proliferation and menstruation in non-pregnant women.The arachidonic acid cascade generates a family of bioactive lipids, including prostaglandins, thromboxanes and leukotrienes that modulate diverse physiological and pathophysiological responses in the reproductive tract. There has been a great deal of interest over the past few years in the involvement of arachidonic acid metabolites in pathology. However, there is still much uncertainty about the manner in which they contribute to specific phenotypic cellular changes that may precipitate pathophysiology. The focus of this review is to provide some insight into the role of cyclooxygenase (COX) enzymes, prostaglandin E 2 (PGE 2 ) and PGF 2α and their respective receptors in reproductive pathophysiology, with specific regard to disorders of endometrial proliferation and dysfunctional menstruation.The kinetics of the prostaglandin biosynthetic pathway is driven by the availability of free arachidonic acid. When released from plasma membrane phospholipids or dietary fatty acids, after activation of phospholipase A2 (PLA2) or PLC, arachidonic acid is cyclized and oxygenated by COX enzymes by addition of the 15-hydroperoxy group to form prostaglandin G 2 (PGG 2 ). The hydroperoxy group of PGG 2 is reduced to the hydroxy group of PGH 2 (Marnett, 1992) (Fig. 1). This intermediate serves as the substrate for terminal prostanoid synthase enzymes. These enzymes are named according to the prostaglandin they produce, such that prostaglandin D 2 is synthesized by prostaglandin-D-synthase (PGDS), prostaglandin E 2 (PGE 2 ) by prostaglandin-E-synthase (PGES); prostaglandin F 2α by

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Section: Endometriosismentioning

confidence: 99%

Cyclooxygenase enzymes and prostaglandins in pathology of the endometrium

Sales¹

2003

Reproduction

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“…Although estradiol has been shown to increase aromatase activity in ESC cultures [38], several distinct lines of evidence lead us to suggest that genistein is not acting through an estrogen receptor mediated pathway in our cultures to increase aromatase activity. Genistein is a preferential estrogen receptor (ER)-β agonist and has been shown to have estrogenic actions in a variety of tissues in the rat [39,40].…”

Section: Discussionmentioning

confidence: 99%

The effects of dietary phytoestrogens on aromatase activity in human endometrial stromal cells

Edmunds¹,

Holloway²,

Crankshaw³

et al. 2005

Reprod. Nutr. Dev.

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-Dietary phytoestrogens have been reported to inhibit aromatase activity in placental microsomes, but the effects in the human endometrium are unknown. Aromatase, the rate-limiting enzyme in the conversion of androgens to estrogens, has recently been shown to be expressed in the endometrium of women with endometriosis and is thought to play a role in the pathophysiology of this disease. Therefore, the objective of this study was to screen dietary phytoestrogens for their ability to inhibit aromatase activity in human endometrial stromal cells (ESC) and identify potential novel therapeutic agents for the treatment of endometriosis. The inhibition of aromatase activity by direct interaction with the dietary phytoestrogens genistein, daidzein, chrysin, and naringenin was tested in a cell free assay. Furthermore, test compound effects on aromatase activity in ESC cultures were also examined. Genistein and daidzein were inactive in the human recombinant aromatase assay whereas naringenin and chrysin inhibited aromatase activity. However, genistein (1 nM to 1 mM) stimulated aromatase activity in ESC whereas other phytoestrogens had no effect. Immunopositive aromatase cells were demonstrated in genistein-treated ESC but not in untreated control cultures. Taken together, our data suggest that genistein can increase aromatase activity in ESC likely via increased enzyme expression.phytoestrogens / endometriosis / aromatase / genistein / endometrium

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“…The extensive metabolism by peripheral organs such as liver is likely responsible for the greater number of EM and higher abundance of less potent estrogen E 1 observed in urine and serum samples. On the other hand, the aberrant expression of aromatase (enzyme responsible for synthesis of E 2 ) and deficiency of 17β-hydroxysteroid dehydrogenase type 2 (enzyme responsible for converting E 2 to E 1 ) due to endometriosis itself may contribute to the higher biologically active and total E 2 observed in human peritoneal fluid [6]. Given these differences in observed EM profiles among urine, serum, and peritoneal fluid samples, the ability to directly and quantitatively measure both biologically active and total EM in human peritoneal fluid has a number of potential applications in the study of diseases such as endometriosis.…”

Section: Resultsmentioning

confidence: 99%

“…In addition, peritoneal fluid allows direct secretion of ovarian hormones into peritoneal and endometrial cavities, influencing the endometrial cycle [1][2][3][4][5]. Peritoneal fluid represents a suitable medium for studying estrogen metabolism in endometriosis, a disorder associated with pelvic pain and infertility which affects 2-10% of child-bearing age women [6]. It is believed that the parent estrogens (17β-estradiol and estrone) as well as some hydroxylated estrogen metabolites (EM), such as catechol estrogens, may contribute to the proliferative and inflammatory characteristics of endometriosis [6,7].…”

Section: Introductionmentioning

confidence: 99%

“…Peritoneal fluid represents a suitable medium for studying estrogen metabolism in endometriosis, a disorder associated with pelvic pain and infertility which affects 2-10% of child-bearing age women [6]. It is believed that the parent estrogens (17β-estradiol and estrone) as well as some hydroxylated estrogen metabolites (EM), such as catechol estrogens, may contribute to the proliferative and inflammatory characteristics of endometriosis [6,7]. In contrast, methylated catechol estrogens, such as 2-methoxy-17β-estradiol, a 2-O-methyl conjugate of 2-hydroxy-17β-estradiol formed via the action of catechol-O-methyl transferase (COMT), exhibit potent apoptotic, antiangiogenic, and antiproliferative activities [8].…”

Section: Introductionmentioning

confidence: 99%

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Multiplexed quantitation of endogenous estrogens and estrogen metabolites in human peritoneal fluid

Othman

Issaq

et al. 2008

Electrophoresis

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Endogenous estrogens and estrogen metabolites (EM) in human peritoneal fluid may play an important role in health and disease, yet little is known regarding their types and levels present in human peritoneal fluid, primarily due to the lack of an analytical method that is capable of directly quantifying their absolute abundances. In this report, we describe the application of a capillary LC-MS/MS method for identifying and quantifying biologically active and total endogenous EM in human peritoneal fluid. The method requires only 50 μL of peritoneal fluid, yet can quantify 13 distinct EM. Calibration curves for each EM were linear over a 10 3 -fold concentration range and the lower LOQ was 50 fg on-column. For a charcoal stripped human peritoneal fluid sample containing 10 pg/mL of each EM, accuracy ranged from 83 to 118%, and intrabatch precision ranged from 0.2 to 4.4% RSD and interbatch precision ranged from 5.5 to 15.5% RSD. The analyses of human female perito-neal fluid shows that at least 10 biologically active and 11 total endogenous EM can be positively identified and quantitatively measured. Many of the biologically active forms are present in high abundance and possess distinct biological activities which warrant further study. Although micellar EKC gave baseline separation of a standard mixture of 10 EM, the LOQs using UV detection were not suitable for the assay of the low level estrogens in biological samples.

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Estrogen Production and Metabolism in Endometriosis

Cited by 141 publications

References 32 publications

Cyclooxygenase enzymes and prostaglandins in pathology of the endometrium

Cyclooxygenase enzymes and prostaglandins in pathology of the endometrium

The effects of dietary phytoestrogens on aromatase activity in human endometrial stromal cells

Multiplexed quantitation of endogenous estrogens and estrogen metabolites in human peritoneal fluid

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