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." http://www.ncbi.nlm.nih.gov/m/pubmed/17403431/?i=5&from=/9851796/related

"...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 cycle^27–29. 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 reduced^27–29. 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 phase^{12, 30–31}. 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 growth^{11, 32–33}....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. " http://europepmc.org/articles/PMC3718308

 "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." http://www.ncbi.nlm.nih.gov/pubmed/22085558 

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." http://www.ncbi.nlm.nih.gov/pubmed/16406281 

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." http://www.medscape.com/viewarticle/819586_9  

" 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." http://www.ncbi.nlm.nih.gov/m/pubmed/9851796/?i=3&from=/16406281/related

"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. " http://www.ncbi.nlm.nih.gov/m/pubmed/16595205/?i=2&from=/9851796/related

Prevalence of Depression in Endo Patients

Depression, whether an independent diagnosis and exacerbated by endo or as a by-product of endo, is prevalent in endo patients:

"This cross-sectional prospective study evaluated 100 women receiving care at the Outpatients' Clinic for Endometriosis, Department of Obstetrics and Gynecology, Universidade Estadual de Campinas (UNICAMP), Campinas, São Paulo, Brazil, equally divided into two groups: one suffering from chronic pelvic pain and the other pain-free. The Beck Depression Inventory was used in order to measure depression.

RESULTS:
Depression was detected in 86 and 38% of the women with and without chronic pelvic pain, respectively. Complaints of depression, such as somatic concerns, work inhibition, dissatisfaction, and sadness, were observed at a significantly higher rate in the group with pain. A sensation of failure was the only variable observed more frequently in the pain-free group.

CONCLUSIONS:
Depression is highly prevalent in women with endometriosis, especially those with pelvic pain. Careful evaluation can identify women with depression who may benefit from treatment." http://www.ncbi.nlm.nih.gov/pubmed/16521687 

 It an be further compounded by the use of hormones as treatment, as some hormonal suppressants can cause depression: "The brain in women has been shown to be an estrogen target organ. Common symptoms are shared by women complaining of PMS, postpartum blues, the perimenopausal transition and menopause: depression, sleep disturbance, irritability, anxiety and panic, memory and cognitive dysfunction and a decreased sense of well-being. The antiestrogens progesterone, progestin and tamoxifen may also elicit these same symptoms. It is proposed that whenever brain estrogen levels fall below the minimum brain estrogen requirement, for whatever reason and at whatever age, brain center dysfunction may ensue." http://europepmc.org/abstract/MED/8887186 

 Also it is well shown that endometriosis can cause chronic inflammation: "In response to a peripheral infection, innate immune cells produce pro-inflammatory cytokines that act on the brain to cause sickness behaviour. When activation of the peripheral immune system continues unabated, such as during systemic infections, cancer or autoimmune diseases, the ensuing immune signalling to the brain can lead to an exacerbation of sickness and the development of symptoms of depression in vulnerable individuals. These phenomena might account for the increased prevalence of clinical depression in physically ill people. Inflammation is therefore an important biological event that might increase the risk of major depressive episodes, much like the more traditional psychosocial factors." http://www.nature.com/nrn/journal/v9/n1/abs/nrn2297.html

25% of Atypical Specimens Proved to be endo study

"All areas of viscera and peritoneum either with typical appearance suggestive of endometriosis or atypical appearance were completely excised and examined histologically. At laparoscopy, all excised lesions were documented in a diagram by the primary surgeon according to anatomic site and visual description and were labeled as either suggestive of endometriosis or otherwise atypical in appearance. The hospital pathology department received entire lesions fixed in formalin and evaluated specimens for presence or absence of endometriosis. Pathologists, who were blinded to the surgeon's suspicion of endometriosis, were provided only the anatomic site of excised tissue. By definition, diagnosis of endometriosis was made when histologic evidence existed of both endometrial glands and stroma.

MEASUREMENTS AND MAIN RESULTS:

Diagrams detailing appearance, anatomic site, and surgeon's suspicion of endometriosis versus atypical lesions were compared with final histologic diagnosis. The greatest number of patient lesions were excised from cul-de-sac (n = 309). For this site, using visual criteria for diagnosis of endometriosis, positive predictive value was 93.9%, sensitivity was 69.3%, negative predictive value was 41.9%, and specificity was 83.1%. Prevalence was noted to be 79.0% and accuracy was 72.2%. In addition, atypical-appearing tissue not presumed to be endometriosis was confirmed to be endometriosis histologically in 24.3%. In examining tissue specimens from multiple anatomic sites, laparoscopic visual diagnosis of typical endometriosis generally had high positive predictive value. However, both sensitivity and negative predictive value were lower than expected because of atypical lesions subsequently diagnosed as endometriosis.

CONCLUSIONS:

These data suggest that when the surgical objective is complete eradication of endometriosis, the surgeon must be prepared to excise all lesions suggestive of endometriosis and tissue atypical in appearance as in most anatomic sites approximately 25% of atypical specimens proved to be endometriosis."

Endometriosis and Associated Disorders Survey

If you have been surgically diagnosed with endometriosis, here is a survey being collected on the disorders associated with endo:  https://www.surveymonkey.com/s/KYGL8GF

Histology (what the path report shows) and Endometriosis

When your doctor sends specimens from your surgery to the pathologist for confirmation, the pathologist will be looking for glands and/or stroma ("Histologic demonstration of a combination of endometrial glands and stroma in biopsy specimens obtained from outside the uterine cavity is required to make the diagnosis of endometriosis." http://emedicine.medscape.com/article/271899-overview).

 

When they find those glands and/or stroma, then endometriosis is confirmed. If they do not find them, then it is inconclusive (meaning it may be endo but they could not positively identify in the specimen sent). It can be inconclusive for several reasons:

"Although the histologic diagnosis of endometriosis is usually straightforward, many diagnostic problems can arise as a result of alterations or absence of its glandular or stromal components. The diagnostic difficulty in such cases can be compounded by tissue that is limited to a small biopsy specimen. The appearance of the glandular component can be altered by hormonal and metaplastic changes, as well as cytologic atypia and hyperplasia... In some cases, the endometriotic glands are sparse or even absent (stromal endometriosis). The stromal component can be obscured or effaced by infiltrates of foamy and pigmented histiocytes, fibrosis, elastosis, smooth muscle metaplasia, myxoid change, and decidual change....Inflammatory and reactive changes within, adjacent to, or at a distance from foci of endometriosis can complicate the histologic findings...The histologic diagnosis of endometriosis can also be challenging when it involves an unusual or unexpected site. Five such site-specific problematic areas considered are endometriosis on or near the ovarian surface, superficial cervical endometriosis, vaginal endometriosis, tubal endometriosis, and intestinal endometriosis... Finally, endometriotic foci can occasionally be intimately admixed with another process, such as peritoneal leiomyomatosis or gliomatosis, resulting in a potentially confusing histologic appearance." http://www.ncbi.nlm.nih.gov/pubmed/17592255

"Positive histology for endometriosis was confirmed in 75% of cases, the histology was negative in 18.7% and in 6.3% was non-diagnostic. The study confirmed that correlation between laparoscopic findings and positive histology was dependant on the site of lesion and the stage of endometriosis. As more information was provided to the laboratory and as the pathologists became accustomed to looking for the disease, there was a higher detection of endometriosis." http://informahealthcare.com/.../10.1080/01443610802217918

"Positive histology confirms the diagnosis of endometriosis; negative histology does not exclude it. Whether histology should be obtained if peritoneal disease alone is present is controversial: visual inspection is usually adequate but histological confirmation of at least one lesion is ideal. In cases of ovarian endometrioma (> 4 cms in diameter), and in deeply infiltrating disease, histology should be obtained to identify endometriosis and to exclude rare instances of malignancy." http://guidelines.endometriosis.org/diagnosis.html

"Stromal endometriosis, characterised histologically by small microscopic nodules or plaques of endometrioid-type stroma, sometimes with a whorled pattern and prominent vascularity and erythrocyte extravasation, was identified in 44.9% of the biopsies. In 6.6% of the biopsies, stromal endometriosis occurred without typical endometriosis. The foci of stromal endometriosis usually had a superficial location just beneath the mesothelial surface or protruding above this. Associated histological features present in some cases included reactive mesothelial proliferation, inflammation, giant cell or granuloma formation, haemosiderin pigment deposition, microcalcification and decidualisation and myxoid change.

CONCLUSIONS:

Stromal endometriosis, usually in the form of superficial nodules or plaques, is a relatively common form of endometriosis which typically occurs in association with typical endometriosis but occasionally on its own. Pathologists should be aware of the existence of this form of endometriosis, the morphological features of which may be subtle. The typical location, intimately associated with surface mesothelium, may suggest that stromal endometriosis derives from mesothelial or submesothelial cells via a metaplastic process." http://www.ncbi.nlm.nih.gov/pubmed/19155237

More details (and pictures!) if you are curious: http://www.slideshare.net/.../the-pathology-of-endometriosis

“Although the histological diagnosis of endometriosis is usually easy to make, there are diagnostic problems in relation to certain aspects such as the atypias and neoplastic alterations of the endometriotic glandular and stromal components and in cases of endometriosis in unusual places the small size of specimens available for histological examination does not aid the correct diagnosis….

Usually both, glands and stroma are observed but occasionally the diagnosis can be

made when only one component is present. Endometriosis is distinct from adenomyosis or

endometriosis interna which is defined by the presence of endometrial components in the

myometrium. These two entities were linked in the past by common terminology but

present different clinical presentation, epidemiologic and etiologic patterns….

The location and the age of the endometriotic lesion and the patients’ age affect the

morphological appearance of endometriosis and may lead to diagnostic difficulties….

Typically endometriosis in women of reproductive age presents histologically as one or

more endometrioid glands surrounded by stromal cells, resembling the endometrial stromal

cells of the proliferative phase. The glandular epithelium is one layer thick with cuboidal or

tall cells and eosinophilic cytoplasm. Nuclei are ovoid with vertical orientation and very

rare mitoses. The whole picture is usually consistent with inactive or irregular proliferative

endometrium, although typical proliferative or secretory changes may be observed. Cilia

may be observed as well. Stromal cells are supported by a delicate reticulin network in

which hyperemic small vessels may be observed. In the case of exogenous administration of

progestins, cyclically functionic endometriosis or pregnancy, a stromal decidual reaction

may be observed. A diffuse infiltration of histiocytes is usually observed. The histiocytes

convert the red blood cells into glucolipid and brown pigment (pseudoxanthoma cells) .The

pigment is usual a ceroid such as lipofuscin and to a lesser extend hemosiderin .The amount

of the pigment increases with the age of the lesion. Inflammatory cells may be present and a

small component of smooth muscle cells especially in the wall of endometrioid cysts may be

observed. Not all the above described elements are easily identified in endometriosis.” http://cdn.intechopen.com/pdfs-wm/36756.pdf