Endometriosis results from implantation of endometrial tissue outside the uterine cavity. Endometriosis might remain asymptomatic and discovered accidentally. However, it may cause symptoms, which include chronic pelvic pain, bleeding, infertility, and increases susceptibility to development of adenocarcinoma. The most prevailing hypothesis is that endometriosis results from implantation of endometrial tissue that gains access to peritoneal cavity by retrograde flow during menstruation. The factors contributing to the establishment and persistence of the endometriotic lesions (plaques) most probably include abnormalities of the genital tract, genetic predisposition, hormonal imbalance, altered immune surveillance, inflammatory response and abnormal regulation of the endometrial cells. The mediators that contribute to survival and progression of endometriosis are likely involved in the development of the symptoms of this process. Genomic studies have started to delineate the wide array of mediators involved and the complex genetic background required in the development of endometriosis. This review summarizes our current knowledge regarding the pathogenesis of endometriosis, including progress made with transgenic animals, and a clinical perspective on the diagnosis and management of this common process.

To characterize the signaling pathway by which the neurotransmitter dopamine modulates progesterone receptor (PR) activation, the steroid-dependent behavior lordosis was used in estrogen-primed ovariectomized Sprague-Dawley rats with stereotaxic implanted third ventricle cannulas. Lordosis was observed in response to solicitous males in females after central administration of the D1-like agonist SKF38393 and three of its analogs (SKF77434, SKF75640, and SKF85174). In contrast, D1-like antagonist SCH23390 and D1-like/D2 repopulation inhibitor EEDQ blocked behavior inducible by the D1-like agonists. Further, antisense oligonucleotides to D5, but not D1, dopamine receptor mRNA suppressed reproductive behavior associated with D1-like stimulation. This finding provides strong evidence that dopaminergic modulation of lordosis is mediated by the novel D5 dopamine receptor. Although D1, but not D5, dopamine receptor mRNAs were detected in the ventromedial nucleus (VMN) by in situ hybridization, agonists microinjected into the VMN, but not into the arcuate nucleus or preoptic area, induced lordosis, suggesting the functional presence of D5 dopamine receptors in the VMN. Also in support, D5 receptor mRNA antisense microinjected into the VMN blocked the subsequent induction of lordosis by D1-like agonists. Finally, facilitation of sex behavior by D1-like agonists was blocked by the antiprogestin RU38486 and PR antisense oligonucleotide. Collectively, the data provide strong evidence for dopaminergic modulation of reproductive behavior through D5 dopamine receptor-mediated modulation of PR-dependent behavior in rat CNS. Key words: steroid receptors; D5 dopamine receptors; lordosis; antisense oligonucleotides; progesterone; estrogenIn the female rat, the ovarian steroid hormone estrogen modulates the reproductive behavior lordosis (Pfaff and SchwartzGiblin, 1988). Estrogen effect on lordosis is mediated in part by steroid receptors in the estrogen-concentrating neurons located in the ventrolateral region of the hypothalamic ventromedial nucleus (VMN). The major effect of estrogen on lordosis is thought to be mediated by progesterone receptors (PR), because (1) estrogen induces PR in the VMN, and (2) RU38486 and PR antisense oligonucleotide block the induction of lordosis by progesterone (P) (Pfaff and Schwartz-Giblin, 1988;McCarthy et al., 1993). Thus, the dependence of lordosis on estrogen and progestins can be used in vivo to probe cellular and molecular mechanisms for mammalian behavior.As ligand-dependent nuclear transcription factors, steroid receptors alter the expression of specific genes or gene networks (Evans, 1988). However, the PR can be activated in vitro in a ligand-independent manner by the neurotransmitter dopamine (Tsai and O'Malley, 1994). Dopamine is thought to act selectively through D1-like and D2 receptors (Grierson et al., 1988). Centrally administered dopamine (Mani et al., 1994) and the D1-like agonist SKF38393 (Foreman and Moss, 1979) induce lordosis in rats primed with low doses (5-10 g) of estroge...

Sex steroids exert profound influence on neural development and function through activation of intranuclear receptors. However, during sexual differentiation and at onset of puberty, intracerebral estrogen (E) availability is subsequent to these effects. The potent mitogen epidermal growth factor (EGF) activates estrogen receptor (ER)-dependent transcription in cultured cells in the absence of exogenous E. Since reproductive behavior in female rodents is the result of E-dependent transcriptional activity and protein synthesis, lordosis serves as a well established in vivo model for probing cellular and molecular mechanisms of steroid receptor-dependent behavior. Here we demonstrate that EGF can signal through the classical E receptor (ERalpha) to alter in vivo function in rodent central nervous system. EGF and EGF receptor ligands induced lordosis in a dose- and time-dependent manner in the absence of steroid treatment in ovariectomized rats and mice. Using antisense oligonucleotides, pharmacological and antibody blockade, and mutant mice, we also report that this behavioral responsiveness is mediated through ERalpha by specific stimulation of membrane-bound EGF receptors and EGF receptor-specific tyrosine kinase rather than by direct ligand activation of the ERalpha. Of biological significance, delayed onset of puberty and the absence of synchronization between reproductive behavior and ovulation was detected in intact mutant Wa-2 mice that express a naturally occurring point mutation in the EGF receptor. To our surprise, EGF-mediated behavior was independent of progesterone (P) and progesterone receptor (PR) since antiprogestins, PR antisense oligonucleotides, and targeted disruption of PR in ovariectomized transgenic mice failed to impede the display of lordosis after EGF. Finally, we also found that another growth factor, insulin-like growth factor-1, which provokes ER-dependent transcription in vitro, activates mating behavior in a similar E-independent manner. Thus, growth factor mediation of ER-targeted function may be a universal feature in the rodent central nervous system, raising critical questions about the role of growth factors in mediating ER-dependent processes in development and reproduction.

Herbivorous and omnivorous vertebrates have evolved in the presence of a variety of phytoestrogens, i.e., plant-derived compounds that can mimic, modulate or disrupt the actions of endogenous estrogens. Since the discovery of the estrus-inducing effects of some plant products in 1926, considerable effort has been devoted to the isolation and structural and pharmacological characterization of phytoestrogens. Recently, agricultural and industrial pollution has added anthropogenic estrogenic compounds to the list of environmental estrogens. Unlike phytoestrogens, these xenoestrogens tend to accumulate and persist in adipose tissue for decades and may cause long-lasting, adverse endocrine effects. Here we review the endocrine effects of known phytoestrogens and xenoestrogens with special emphasis on molecular structure-activity relationships. Phytoestrogens include flavonoids, isoflavonoids, chalcons, coumestans, stilbenes, lignans, ginsenosides and other saponins, as well as the recently discovered tetrahydrofurandiols. Fungal estrogenic compounds may enter the food chain via infested crops. Since some phytoestrogens have been shown to display organ-specific actions, pharmaceutical estrogen analogues with similar properties (selective estrogen receptor modulators, SERMs) are also discussed. Xenoestrogens include dichlorodiphenyltrichloroethane (DDT) and its metabolites, bisphenols, alkylphenols, dichlorophenols, methoxychlor, chlordecone, polychlorinated benzol derivatives (PCBs), and dioxins. While most of these compounds act through estrogen receptors alpha and beta, some of their effects may be mediated by other nuclear or membrane-bound receptors or receptor-independent mechanisms. Some might also interfere with the production and metabolism of ovarian estrogens. Better understanding of the molecular pharmacology of phyto- and xenoestrogens may result in the development of novel compounds with therapeutic utility and improved environmental protection.

Macrophage migration inhibitory factor (MIF), the pro-inflammatory cytokine, first described in 1966, plays an essential role in both, innate and adaptive immune response. It has been implicated in tumour growth and angiogenesis and it exerts an antagonistic action against glucocorticoid immunosuppressive effect. Its perplexing enzymatic tautomerase activity has attracted considerable interest in the last decade. It has been suggested, that a multitude of autoimmune/inflammatory/neoplastic disease states might benefit from therapeutic measures, targeting MIF. Hence, small molecule inhibitors of MIF are relentlessly sought as potential anti-inflammatory (antitumour) agents, while a true in vivo substrate for MIF still remains unidentified. One of the first studied MIF inhibitor group was the D-dopachrome family, and its carboxyderivatives have shown good inhibitory effect, as well as the fluorosubstituted phenylpyruvic acid class. The substance ISO-1 of isoxazoline skeleton was the first small molecular inhibitor of MIF, not related to its known substrates. N-acetyl-p-benzoquinone, an acetaminophen metabolite and its synthetic derivatives exerted submicromolar IC(50) values. An acetylenic compound, the 2-oxo-4-phenyl-3-butynoate is a potent active-site-directed irreversible inhibitor of the phenyl pyruvate tautomerase activity of MIF. Some oxygen heterocycles, coumarines and chromenes, have also drawn attention as MIF inhibitors. The alpha,beta-unsaturated carbonyl compounds constitute a large novel class of MIF inhibitors. Several potent inhibitors were found among the cinnamic acid derivatives, thealpha,beta-unsaturated cyclic ketones, and the natural curcuminoids. Some other plant derived compounds were also studied. One of the latest developments in the field is the synthesis of AVP-13546, an exceptionally potent inhibitor. The structural pattern of MIF enzyme inhibitors exhibits wide variety; compounds having quite different molecular backbones belong to the MIF inhibitor family. In this paper, the separate classes of MIF inhibitors are discussed.

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Transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) receptors expressed predominantly in sensory nerves are activated by inflammatory stimuli and mediate inflammation and pain. Although they have been shown in the human endometrium, their regulation and function are unknown. Therefore, we investigated their estrogen-and progesterone-dependent alterations in the rat endometrium in comparison with the estrogenregulated inflammatory cytokine macrophage migration inhibitory factor (MIF). Four-week-old (sexually immature) and four-month-old (sexually mature) female rats were treated with the non-selective estrogen receptor (ER) agonist diethylstilboestrol (DES), progesterone and their combination, or ovariectomized. RT-PCR and immunohistochemistry were performed to determine mRNA and protein expression levels respectively. Channel function was investigated with ratiometric [Ca 2C ] i measurement in cultured primary rat endometrial cells. Both TRP receptors and MIF were detected in the endometrium at mRNA and protein levels, and their localizations were similar. Immunostaining was observed in the immature epithelium, while stromal, glandular and epithelial positivity were observed in adults. Functionally active TRP receptor proteins were shown in endometrial cells by activation-induced calcium influx. In adults, Trpa1 and Trpv1 mRNA levels were significantly up-regulated after DES treatment. TRPA1 increased after every treatment, but TRPV1 remained unchanged following the combined treatment and ovariectomy. In immature rats, DES treatment resulted in increased mRNA expression of both channels and elevated TRPV1 immunopositivity. MIF expression changed in parallel with TRPA1/TRPV1 in most cases. DES up-regulated Trpa1, Trpv1 and Mif mRNA levels in endometrial cell cultures, but 17b-oestradiol having ERa-selective potency increased only the expression of Trpv1. We provide the first evidence for TRPA1/TRPV1 expression and their estrogen-induced up-regulation in the rat endometrium in correlation with the MIF. Journal of Molecular EndocrinologyResearch K POHÓ CZKY and others TRPV1 and TRPA1 in the rat endometrium 56:2 135-149

The protective effects of plant polyphenol intake on cardiovascular morbidity and mortality are widely acknowledged. Caffeine‐free chicory coffee is a rich source of plant phenolics, including caffeic acid, which inhibits in vitro platelet aggregation, and also phenylpyruvate tautomerase enzymatic activity of the proinflammatory cytokine, macrophage migration inhibitory factor (MIF). To assess whether chicory coffee consumption might confer cardiovascular benefits a clinical intervention study was performed with 27 healthy volunteers, who consumed 300 mL chicory coffee every day for 1 week. The dietary intervention produced variable effects on platelet aggregation, depending on the inducer used for the aggregation test. Whole blood and plasma viscosity were both significantly decreased, along with serum MIF levels, after 1 week of chicory coffee consumption. Moreover, significant improvements were seen in red blood cell deformability. No changes in hematocrit, fibrinogen level or red blood cell counts were detected. The full spectrum of these effects is unlikely to be attributable to a single compound present in chicory coffee, nevertheless, the phenolics, including caffeic acid, are expected to play a substantial role. In conclusion, our study offers an encouraging starting‐point to delineate the antithrombotic and antiinflammatory effects of phenolic compounds found in chicory coffee. Copyright © 2011 John Wiley & Sons, Ltd.