Thursday, May 8, 2014

Progesterone Resistence 2

"CONCLUSION: A stromal cell defect in endometriosis blocks formation of progesterone-dependent production of factors leading to 17beta-hydroxysteroid dehydrogenase type 2 deficiency and defective conversion of estradiol to estrone in epithelium."

"...initial studies comparing endometrial tissues from women with and without endometriosis examined circulating progesterone levels relative to expected histological responses across the secretory phase of the menstrual cycle2729. These investigations revealed that while women with endometriosis exhibit normal circulating ovarian progesterone levels, the endometrium's ability to respond appropriately to this steroid appeared to be reduced2729. Subsequent studies confirmed that endometrial tissues from women with endometriosis did not exhibit the changes in specific gene and protein expression normally expected during the progesterone-dominated secretory phase12, 3031. Perhaps not surprisingly, altered expression of genes and proteins in endometriosis patients was reported to be associated with changes in the expression pattern of progesterone receptor (PR) isotypes (PR-A and PR-B), at both eutopic and ectopic sites of endometrial growth11, 3233....At present, the biological origin of reduced endometrial progesterone responsiveness among women with endometriosis remains to be fully elucidated; however, a number of research groups have begun to examine whether chronic inflammatory processes may promote the development of endometrial resistance to this steroid. Within the reproductive tract, an important component of steroidal regulation of inflammation involves cellular signaling by members of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) family. This signaling network has been suggested to play a critical role in triggering, or enhancing, the inflammatory processes...Although the studies noted above support the concept that inflammatory processes may represent a potential trigger for the loss of progesterone sensitivity related to endometriosis, the precise cellular and molecular mechanisms leading to this disease phenotype remain elusive. In this regard, a number of recent observations suggest that epigenetic modification, mediated by chronic inflammation, could explain the progesterone resistant endometrial phenotype observed in women with endometriosis. "

 "Throughout the reproductive years, the rise and fall in ovarian hormones elicit in the endometrium waves of cell proliferation, differentiation, recruitment of inflammatory cells, apoptosis, tissue breakdown and regeneration. The activated progesterone receptor, a member of the superfamily of ligand-dependent transcription factors, is the master regulator of this intense tissue remodelling process in the uterus. Its activity is tightly regulated by interaction with cell-specific transcription factors and coregulators as well as by specific posttranslational modifications that respond dynamically to a variety of environmental and inflammatory signals. Endometriosis, a chronic inflammatory disorder, disrupts coordinated progesterone responses throughout the reproductive tract, including in the endometrium. This phenomenon is increasingly referred to as 'progesterone resistance'. Emerging evidence suggests that progesterone resistance in endometriosis is not just a consequence of perturbed progesterone signal transduction caused by chronic inflammation but associated with epigenetic chromatin changes that determine the intrinsic responsiveness of endometrial cells to differentiation cues." 

So we see progesterone resistance in patients with endo and then we see that progesterone helps in the process of metabolizing estrogen: 

"The biologically active estrogen estradiol (E2) is the best-defined mitogen for the growth and inflammation processes in the ectopic endometriotic tissue that commonly resides on the pelvic organs. Progesterone and progestins may relieve pain by limiting growth and inflammation in endometriosis but a portion of patients with endometriosis and pelvic pain do not respond to treatment with progestins. Moreover, progesterone-induced molecular changes in the eutopic (intrauterine) endometrial tissue of women with endometriosis are either blunted or undetectable.  The molecular basis of progesterone resistance in endometriosis may be related to an overall reduction in the levels of progesterone receptors (PRs) and the lack of the PR isoform named progesterone receptor B (PR-B). In normal endometrium, progesterone acts on stromal cells to induce secretion of paracrine factor(s). These unknown factor(s) act on neighboring epithelial cells to induce the expression of the enzyme 17beta-hydroxysteroid dehydrogenase type 2 (17beta-HSD-2), which metabolizes the biologically active estrogen E2 to estrone (E1). In endometriotic tissue, progesterone does not induce epithelial 17beta-HSD-2 expression due to a defect in stromal cells. The inability of endometriotic stromal cells to produce progesterone-induced paracrine factors that stimulate 17beta-HSD-2 may be due to the lack of PR-B and very low levels of progesterone receptor A (PR-A) observed in vivo in endometriotic tissue.  The end result is deficient metabolism of E2 in endometriosis giving rise to high local concentrations of this local mitogen." 

Furthermore (part of this is particular for those with infertility): "On the basis of the role of inflammation in the induction of a progesterone-resistant endometrium, we hypothesize that failure of implantation might be explained, perhaps in part, by alteration in the uterine microbiome in response to inflammation...This hypothesis finds support in the ability of environmental factors to alter progesterone sensitivity...A very important finding derived from this study demonstrated that TCDD-mediated P4 resistance might increase sensitivity to inflammation, even in subsequent generations not exposed to the toxicants, resulting in PTB.[98] By means of extrapolation, these data support the hypothesis that a combination of environmental factors, taken together, are a risk for recurrent pregnancy loss and PTB in humans; the mechanism being creation of a P4-resistant endometrium and the presence of inflammation. Therefore, we conclude that the association between the microbiome of the reproductive tract and circulating serum E2 concentrations may reflect the environment and availability of glycogen. However, progesterone resistance, albeit an unproven relationship to the microbiome, might contribute to implantation failure and infertility. This putative role of undetected endometrial colonization and progesterone resistance requires further investigation."  

" In conclusion, inactivation of 17beta-estradiol is impaired in endometriotic tissues due to deficient expression of 17betaHSD-2, which is normally expressed in eutopic endometrium in response to progesterone. The lack of 17betaHSD-2 expression in endometriosis is not due to alterations in the levels of immunoreactive progesterone or estrogen receptors in this tissue and may be related to an inhibitory aberration in the signaling pathway that regulates 17betaHSD-2 expression."

"PATIENT(S): Patients with deep endometriosis and fertile women with macroscopically normal pelvic cavities.
INTERVENTION(S): During surgery, 30 endometrial and 16 endometriotic samples were obtained from 30 patients with deep endometriosis. Control endometrial samples were obtained from 24 fertile women with macroscopically normal pelvic cavities who underwent laparoscopic tubal ligation or reversal of tubal sterilization. Epithelial cells and stromal cells from endometrial or endometriotic tissues were microdissected using laser capture microdissection.
MAIN OUTCOME MEASURE(S): Expression levels of aromatase and 17betaHSD2 mRNA in microdissected epithelial and stromal cells were determined using quantitative real-time reverse transcriptase polymerase chain reaction.
RESULT(S): Aromatase mRNA expression was significantly higher in epithelial cells than in stromal cells in both eutopic and ectopic endometrium obtained from endometriosis patients. In the ectopic endometrium of 8 patients (8/16, 50%), 17betaHSD2 expression was not detected in either epithelial or stromal cells. In eutopic endometrium from endometriosis patients, 17betaHSD2 expression in epithelial cells was significantly increased during the early, middle, and late secretory phases compared with the late proliferative phase, whereas no significant cyclical difference was detected in control endometrium.
CONCLUSION(S): Local estrogen concentration may be much higher in epithelial cells than in stromal cells in deep endometriotic tissue. "