Role of Estrogen Receptor-β in Endometriosis

Role of Estrogen Receptor-β in Endometriosis

Serdar E. Bulun, M.D., Diana Monsavais, B.S., [...], and Emily J. Su, M.D., M.S.

 

"Endometriosis-related pain has conventionally been treated with endocrine agents such as synthetic progestins, oral contraceptives, or gonadotropin-releasing hormone analogs.1 These treatments, which interrupt ovulation and ovarian estrogen production, are successful in only half of the patients treated, however.9–11 Treatment with aromatase inhibitors in combination with an ovulation suppressor has successfully been used in cases refractory to these conventional measures of pain management.12 Patients often develop resistance to repeated treatments with the same agent over a period of 6 months to 3 years....

 

"Endometriotic tissue in ectopic locations, such as the peritoneum or ovary, is fundamentally different from eutopic endometrium within the uterus in terms of the production of cytokines and prostaglandins, estrogen biosynthesis and metabolism, and clinical response to progestins.11,22,23 There are substantial molecular differences with regard to progesterone response between normal endometrium and eutopic and ectopic tissues from women with endometriosis.17,24,25... Circumstantial and laboratory evidence strongly support the notion that estradiol is a key hormone for the growth and persistence of endometriotic tissue as well as inflammation and pain associated with it. Estradiol, which reaches endometriosis by circulation or is produced locally in endometriotic tissue, acts as a steroid hormone to regulate growth of endometriotic tissue. Estradiol enters cells and binds to the ER in estrogen-responsive cells. ER subtypes α and β are proteins with high affinity for estradiol and are encoded by separate genes....

 

"Despite its sensitivity to estrogen, endometriosis appears to contain a unique complement of steroid hormone receptors compared with that of its normal tissue counterpart, the eutopic endometrium. For example, several investigators reported markedly higher levels of ERβ and lower levels of ERα in human endometriotic tissues and primary stromal cells compared with eutopic endometrial tissues and cells.31,32 The levels of both isoforms of PR, particularly PR-B, are significantly lower in endometriosis compared with eutopic endometrium.6,33 The estradiol-receptor complex acts as a transcription factor that becomes associated with the promoters of estradiol-responsive genes via direct DNA binding or binding to other docking transcription factors at basal promoter regions.34 This interaction brings about ER-specific initiation of gene transcription, which promotes the synthesis of specific mRNAs and proteins.34 PR is one of many estradiol-responsive genes, and estradiol acts in eutopic endometrial tissues and stromal cells to promote endometrial responsiveness to progesterone.35 In contrast, PR mRNA and protein levels are not elevated in biopsied endometriotic tissues exposed to high estradiol levels during late proliferative phase or in endometriotic cells treated with estradiol, indicating that estradiol-induction PR expression in endometriosis is markedly blunted.33

"In addition to ERα, ERβ, and PR, the orphan nuclear receptor SF1 is also differentially regulated in endometriosis versus eutopic endometrium (Fig. 2). SF1 is responsible for coordinately activating the full steroidogenic cascade of genes including aromatase. The protein products of this set of steroidogenic genes are capable of converting cholesterol to estradiol locally in endometriotic tissue.36 We recently used real-time polymerase chain reaction (RT-PCR) to compare tissue mRNA levels of these key nuclear receptors in endometriosis and eutopic endometrium (Fig. 2). Ovarian endometriotic tissue SF1 and ERβ mRNA levels were >12,000 times and 142 times higher than in endometrium, respectively. In contrast, ERα, PR, and PR-B levels were remarkably lower in endometriotic tissue (Fig. 2).... ERα mRNA and protein levels are several fold lower in endometriotic tissue and stromal cells compared with endometrial tissue and stromal cells. ERα deficiency in endometriosis may be responsible for the failure of estradiol to induce PR expression, thus contributing to secondary PR deficiency and progesterone resistance in women with this disease. In vivo observations strongly suggest that estradiol induces ERα expression in mouse uterine tissue.39 It is quite likely that estradiol also plays a key role in regulating ERα expression in human endometrial stromal cells. However, strikingly high quantities of estradiol produced via local aromatase activity in addition to high ERβ levels in stromal cells of endometriosis may perturb this regulation and may suppress ERα expression.26,38... 

"Summary:
High estrogen production is a consistently observed endocrine feature of endometriosis. Expression of steroid receptors and other nuclear receptors are strikingly different between endometriotic and eutopic endometrial tissues. Among these nuclear receptors, ERβ expression is maybe >100 times higher in endometriotic tissue than in endometrium. Defective DNA methylation and other accompanying epigenetic mechanisms may be responsible for strikingly high ERβ expression in endometriosis. ERβ suppresses ERα expression and results in strikingly high ERβ-to-ERα ratios in endometriotic cells. We speculate that a strikingly lower ERα-to-ERβ ratio in endometriotic stromal cells may cause a shift from estradiol stimulation to inhibition of PR expression in endometriotic stromal cells under in vivo circumstances (Fig. 3). This proposed mechanism may explain severely deficient PR-B in endometriotic stromal cells, which contributes to progesterone resistance in women with endometriosis. ERβ overexpression in endometriosis possibly has other broad effects important in the pathology of endometriosis. It is likely that ERβ simulates prostaglandin production in endometriotic tissues and cells via inducing COX2 expression." 

 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4034571/...

Increased expression of antimüllerian hormone and its receptor in endometriosis.

Carrarelli P¹, Rocha AL², Belmonte G³, Zupi E¹, Abrão MS⁴, Arcuri F¹, Piomboni P¹, Petraglia F⁵.

Author information

• ¹Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy.
• ²Division of Human Reproduction, Department of Obstetrics and Gynecology, Federal University of Minas Gerais, Belo Horizonte, Brazil.
• ³Department of Biomedical Sciences, Applied Biology, University of Siena, Siena, Italy.
• ⁴Department of Obstetrics and Gynecology, São Paulo University, São Paulo, Brazil.
• ⁵Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy. Electronic address: felice.petraglia@unisi.it.

Abstract

OBJECTIVE:

To evaluate antimüllerian hormone (AMH) and AMH receptor II (AMHRII) mRNA and protein expression in endometrium and in ovarian or deep lesions of women with endometriosis.

DESIGN:

Prospective study.

SETTING:

University hospitals in Italy and Brazil.

PATIENTS:

Patients with endometriosis (n = 55) and healthy women (n = 45).

INTERVENTIONS:

Specimens of endometrium obtained by hysteroscopy from patients with endometriosis and from healthy control subjects; specimens of ovarian endometriosis (n = 29) or of deep endometriosis (n = 26) were collected by laparoscopy. Serum samples were collected in some endometriotic patients (n = 23) and healthy control subjects (n = 20).

MAIN OUTCOME MEASURE(S):

AMH and AMHRII mRNA levels were evaluated by quantitative reverse-transcription polymerase chain reaction and protein localization by immunohistochemistry. AMH levels in tissue homogenates and in serum were assessed by ELISA.

RESULT(S):

Endometrium from women with endometriosis showed higher AMH and AMHRII mRNA levels than control women, with no significant differences between proliferative and secretory phases. Specimens collected from ovarian or deep endometriosis showed the highest AMH and AMHRII mRNA expression. Immunolocalization study confirmed the high AMH and AMHRII protein expression in endometriotic lesions. No difference of serum AMH levels between the groups was found.

CONCLUSION(S):

The increased AMH and AMHRII mRNA and protein expression in endometrium and in endometriotic lesions suggests a possible involvement of AMH in endometriosis.

company looking at developing a blood test for endometriosis

"VolitionRx Enters Agreement with University of Oxford to Initiate Endometriosis Study

Study will assess VolitionRx's proprietary Nucleosomics® platform for non-invasive diagnosis of endometriosis

November 11, 2014: 08:00 AM ET


NAMUR, Belgium, Nov. 11, 2014/PRNewswire/ -- VolitionRx Limited(OTCQB: VNRX), a life sciences company focused on developing blood-based diagnostic tests, today announced that it has entered an agreement with the University of Oxford, United Kingdom, to initiate a clinical study that will assess VolitionRx's proprietary Nucleosomics® platform technology for the diagnosis of endometriosis through a simple blood test.  Under the agreement, The University of Oxford will provide VolitionRx with serum and plasma samples from approximately 350 patients with endometriosis and 150 control patients over a period of two years. The samples are donated by participating women through the biospecimen repository of the Oxford Endometriosis CaRe Centre.

Endometriosis is a common and painful condition in which endometrial tissue, which normally lines the cavity of the uterus, grows in other parts of the body[1]. It is a benign condition with a strong inflammatory component, which makes the disease a good candidate for Volition's NuQ® assays. The condition mostly affects women during their reproductive life span, and is a leading cause of difficulty conceiving. Unfortunately, there are currently no clinically useful biomarkers available for this condition, meaning diagnosis is only possible by performing minimally invasive surgery (laparoscopy). Across the world, this typically results in a delay in diagnosis of nearly 7 years[2].

The prospective study will focus on the development of a simple blood test to help clinicians diagnose endometriosis at an earlier stage. The 350-patient sample collection, supplemented with approximately 150 retrospectively-collected samples, will comprise healthy and endometriosis-positive individuals confirmed by laparoscopy. Differences in circulating nucleosomes will be evaluated across the menstrual cycle using VolitionRx's Nucleosomics® technology platform.

Collection of the samples will be led by Prof Christian Becker and Prof Krina Zondervan, of the Nuffield Department of Obstetrics & Gynaecology, University of Oxford, who are co-Directors of the Endometriosis CaRe Centre, Oxford. The Centre is a world leader in endometriosis research and clinical care and is dedicated to improve the life of women affected by the disease. The study will assess the samples collected from patients undergoing laparoscopic surgery for endometriosis-related symptoms or patients undergoing laparoscopic tubal sterilisation. Sample collection is anticipated to end in 2016 as part of an ongoing biospecimen collection and biobanking program.

"We are excited to sign this agreement with the University of Oxford," commented Dr. Mark Eccleston, VolitionRx's Collaborations Manager. "We look forward to assessing the potential of our test in the diagnosis of endometriosis and to build on our ongoing work in cancer screening by exploring applications of our NuQ® assays in diseases beyond cancer."

Prof Becker said: "We are looking forward to the results of this study. It compliments our ongoing efforts in the Endometriosis CaRe Centre of identifying non-invasive biomarkers for endometriosis which will be an essential step towards improved patient care."

In addition to this study, other clinical trials assessing the effectiveness of VolitionRx's assays include:

A 4,800 patient retrospective study and an 14,000 patient prospective study in colorectal cancer at Hvidovre Hospital,University of Copenhagen, DenmarkA 4,000 patient prospective study that involves patients with the 20 most prevalent cancers at University Hospital in Bonn,GermanyA 250 patient study in colorectal cancer at CHU-UCL Mont Godinne Hospital, BelgiumA study with MD Anderson, Texas, to establish the efficacy of VolitionRx's NuQ® tests to distinguish anaplastic prostate cancer, a particularly aggressive form of the disease, from typical castration resistant prostate cancer (CRPC), the less aggressive form.

[1]

Office of Women's Health. Endometriosis Fact Sheet. Available at: http://www.womenshealth.gov/publications/our-publications/fact-sheet/endometriosis.html

[2]

Nnoaham, K.E. et al. Impact of endometriosis on quality of life and work productivity: a multicenter study across ten countries. Fertil Steril. 2011;96(2):366-373.

-End-

About VolitionRx

VolitionRx is a life sciences company focused on developing blood-based diagnostic tests. The tests are based on the science of Nucleosomics which is the practice of identifying and measuring nucleosomes in the bloodstream – an indication that cancer is present.

VolitionRx's goal is to make the tests as common and simple to use, for both patients and doctors, as existing diabetic and cholesterol blood tests. VolitionRx's research and development activities are currently centred in Belgium as the company focuses on bringing its diagnostic products to market first inEurope, then in the US and ultimately, worldwide.

Visit VolitionRx's website (www.volitionrx.com) or connect with us via Twitter, LinkedIn or Facebook.

Media Contacts

Charlotte Reynolds, VolitionRx
Charlotte.Reynolds@volitionrx.com   
Telephone: +44 (0) 795 217 7498

Kirsten Thomas, The Ruth Group
kthomas@theruthgroup.com  
Telephone: +1 (646) 536-7014

Investor Contacts

Scott Powell, Investor Relations 
S.Powell@volitionrx.com
Telephone: +1 (646) 650-1351

Lee Roth, The Ruth Group
lroth@theruthgroup.com             
Telephone: +1 (646) 536-7012" http://money.cnn.com/news/newsfeeds/articles/prnewswire/CN62698.htm

Chronic Inflammation causes unwell feeling and depression

We have seen in several previous posts the numerous inflammatory markers seen in endometriosis.
This inflammation often gives rise to a general unwell feeling:

"Cytokines mediate and control immune and inflammatory responses. Complex interactions exist between cytokines, inflammation and the adaptive responses in maintaining homeostasis , health, and well-being. Like the stress response, the inflammatory reaction is crucial for survival and is meant to be tailored to the stimulus and time. A full-fledged systemic inflammatory reaction results in stimulation of four major programs: the acute phase reaction, the sickness syndrome, the pain program, and the stress response, mediated by the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. Common human diseases such as atopy/allergy, autoimmunity, chronic infections and sepsis are characterized by a dysregulation of the pro- versus anti-inflammatory and T helper (Th)1versus Th2 cytokine balance. Recent evidence also indicates the involvement of pro-inflammatory cytokines in the pathogenesis of atherosclerosis and major depression, and conditions such as visceral-type obesity, metabolic syndrome and sleep disturbances. During inflammation, the activation of the stress system, through induction of a Th2 shift, protects the organism from systemic ‘overshooting’ with Th1/pro-inflammatory cytokines. Under certain conditions, however, stress hormones may actually facilitate inflammation through induction of interleukin (IL)-1, IL-6, IL-8, IL-18, tumor necrosis factor- and C-reactive protein production and through activation of the corticotropin releasing hormone/substance P-histamine axis. Thus, a dysfunctional neuroendocrine-immune interface associate with abnormalities of the systemic anti-inflammatory feedback’ and/or ‘hyperactivity’ of the local pro-inflammatory factors may play a role in the pathogenesis of atopic/allergic and autoimmune diseases, obesity, depression, and atherosclerosis. These abnormalities and the failure of the adaptive systems to resolve inflammation affect the well-being of the individual, including behavioral parameters, quality of life and sleep, as well as indices of metabolic and cardiovascular health. These hypotheses require further investigation, but the answers should provide critical insights into mechanisms underlying a variety of common human immune-related diseases." http://www.depts.ttu.edu/animalwelfare/classes/ANSC%205318/Topics%20Stress%20&%20Immunity/Elenkovcytokineswellbeing2005.pdf

"Cytokine dysregulation, inflammation and well-being.

Elenkov IJ¹, Iezzoni DG, Daly A, Harris AG, Chrousos GP.

Author information

• ¹Division of Rheumatology, Immunology and Allergy, Georgetown University Medical Center, Washington, D.C., USA.

Abstract

Cytokines mediate and control immune and inflammatory responses. Complex interactions exist between cytokines, inflammation and the adaptive responses in maintaining homeostasis, health, and well-being. Like the stress response, the inflammatory reaction is crucial for survival and is meant to be tailored to the stimulus and time. A full-fledged systemic inflammatory reaction results in stimulation of four major programs: the acute-phase reaction, the sickness syndrome, the pain program, and the stress response, mediated by the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. Common human diseases such as atopy/allergy, autoimmunity, chronic infections and sepsis are characterized by a dysregulation of the pro- versus anti-inflammatory and T helper (Th)1 versus Th2 cytokine balance. Recent evidence also indicates the involvement of pro-inflammatory cytokines in the pathogenesis of atherosclerosis and major depression, and conditions such as visceral-type obesity, metabolic syndrome and sleep disturbances. During inflammation, the activation of the stress system, through induction of a Th2 shift, protects the organism from systemic 'overshooting' with Th1/pro-inflammatory cytokines. Under certain conditions, however, stress hormones may actually facilitate inflammation through induction of interleukin (IL)-1, IL-6, IL-8, IL-18, tumor necrosis factor-alpha and C-reactive protein production and through activation of the corticotropin-releasing hormone/substance P-histamine axis. Thus, a dysfunctional neuroendocrine-immune interface associated with abnormalities of the 'systemic anti-inflammatory feedback' and/or 'hyperactivity' of the local pro-inflammatory factors may play a role in the pathogenesis of atopic/allergic and autoimmune diseases, obesity, depression, and atherosclerosis. These abnormalities and the failure of the adaptive systems to resolve inflammation affect the well-being of the individual, including behavioral parameters, quality of life and sleep, as well as indices of metabolic and cardiovascular health. These hypotheses require further investigation, but the answers should provide critical insights into mechanisms underlying a variety of common human immune-related diseases." http://www.ncbi.nlm.nih.gov/pubmed/16166805

 

Research is also demonstrating the role of inflammation in depression. Could the reason behind the depression often seen with chronic illnesses not just be the crippling effect of pain, but actually physically caused by the inflammation associated with those illnesses? Sounds a lot like it!

"Anyone who has experienced a viral or bacterial infection knows what it means to feel sick. The behaviour of sick people changes dramatically; they often feel feverish and nauseated, ignore food and beverages, and lose interest in their physical and social environments. They tire easily and their sleep is often fragmented. In addition, they feel depressed and irritable, and can experience mild cognitive disorders ranging from impaired attention to difficulties in remembering recent events. Despite their negative impact on well-being, these symptoms of sickness are usually ignored. They are viewed as uncomfortable but banal components of infections¹.

Sickness is a normal response to infection, just as fear is normal in the face of a predator. It is characterized by endocrine, autonomic and behavioural changes and is triggered by soluble mediators that are produced at the site of infection by activated accessory immune cells. These mediators are known as pro-inflammatory cytokines, and include interleukin-1α and β (IL-1α and IL-1β), tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6). They coordinate the local and systemic inflammatory response to microbial pathogens. However, these peripherally produced cytokines also act on the brain to cause the aforementioned behavioural symptoms of sickness. Recently, it has been suggested that ‘sickness behaviour’^2,3, a term used to describe the drastic changes in subjective experience and behaviour that occur in physically ill patients and animals, is an expression of a previously unrecognized motivational state. It is responsible for re-organizing perceptions and actions to enable ill individuals to cope better with an infection⁴. During the last five years, it has been established that pro-inflammatory cytokines induce not only symptoms of sickness, but also true major depressive disorders in physically ill patients with no previous history of mental disorders. Some of the mechanisms that might be responsible for inflammation-mediated sickness and depression have now been elucidated. These findings suggest that the brain–cytokine system, which is in essence a diffuse system, is the unsuspected conductor of the ensemble of neuronal circuits and neurotransmitters that organize physiological and pathological behavior...." Please read the full article at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2919277/ From inflammation to sickness and depression: when the immune system subjugates the brain: Robert Dantzer, Jason C. O’Connor, [...], and Keith W. Kelley

 

Endometriosis and cancer risk

"Related to a number of hereditary, environmental, epigenetic, and menstrual characteristics and alterations, some sharing certain common processes with cancer,28 endometriosis remains the third leading cause of gynecologic hospitalization in United States29 and is considered a leading cause of female primary and secondary infertility, prevalent in 0.5% to 5.0% in fertile and 25% to 40% of infertile women.30 ...

Endometriosis, more than simply "killer cramps" as it is so often trivialized, may be related to a number of hereditary, environmental, epigenetic, and menstrual characteristics, some sharing certain common processes with cancer.28 Indeed, it is important to note that endometriosis is not cancer. The disease does, however, correspond to a variety of co-morbid conditions, ranging from autoimmune disease to food and environmental allergies to malignant concerns. Multiple prior studies have indicated an association between endometriosis and a number of autoimmune diseases, multiple chemical sensitivities, inflammatory bowel disease, food intolerances, allergies, and chronic fatigue.3,63,64

Less clear is the potential link between endometriosis and certain cancers. Much debate continues to surround the cancer-endometriosis link, with researchers calling the "histogenesis of endometriosis and endometriosis-associated ovarian cancer [one of the] most mysterious aspects of pathology."65 Current evidence is insufficient to draw any definitive conclusions whether this association represents causality or the sharing of similar risk factors and/or antecedent mechanisms.66 Nonetheless, it has been well established that the disease is indeed associated with an increased risk for non-Hodgkin lymphoma and certain malignant tumors, notably ovarian, with 15% to 40% of endometrioid ovarian carcinoma cases being associated with endometriosis. Based on this frequent association, many reports implicate endometriosis as a precursor lesion to ovarian cancer.

The risk of ovarian cancer among those patients with endometriosis is higher than those without the disease by 30% to 40%. One analysis of benign ovarian endometrioid tumors found frequent coexistence of endometriosis and endometrioid neoplasms, supporting a genetic link between the two. In an estimated 60% of endometriosis-associated ovarian cancers, the cancer is adjacent to or directly arising from the endometriotic tissue, lending credence to the fact that malignant transformation can and does occur.19

Animal studies suggest that common molecular genetic pathways, specifically K-RAS/MAPK and PTEN/PI13, are involved in the pathogenesis of both endometriosis and endometrioid ovarian carcinoma. Separate studies have identified upregulation of multiple genes within the RAS/RAF/MAPK and P13K pathways in endometriosis patients, as compared to controls. Of note, PTEN and K-RAS mutations were found to play a role in the development of low-grade ovarian endometrioid carcinomas; synchronous mutations were also identified in uterine and ovarian endometrioid carcinomas associated specifically with endometriosis. Moreover, loss of the PTEN tumor suppressor gene has been implicated in progression from endometriosis to endometrioid ovarian cancer.19

Endometriosis does present serious risk factors that can accelerate the development
of ovarian cancer by 5.5 years.19 Still, epidemiological findings on the association between endometriosis and cancer remain elusive, with modifications to the standard treatment regimens for the disease unjustified at this time.67 Nonetheless, providers from all disciplines should be aware of this increased risk profile and strive for early detection." https://www.apgo.org/elearn/endo/endomonon2.pdf <<<<<< A lot of good pearls from this so check it out!

How Endo Tissue Is Influenced

We've looked at several articles on the research behind the Mullerian/organogenesis theory to endometriosis. (http://www.hindawi.com/journals/ogi/2013/527041/, http://www.ncbi.nlm.nih.gov/pubmed/23314961, http://webcache.googleusercontent.com/search...)

Here's a little explanation of how that misplaced tissue is influenced:

So you have this misplaced tissue sittin' there, just waiting around. Many things influence how it behaves. Estrogen makes it become like the Hulk- it doesn't replicate, just gets bigger and angrier.

Through complicated processes, the increased estrogen B receptors can make the tissue less responsive to progesterone (which would calm it down a bit- this may be why some women don't respond to progesterone driven drugs). So more estrogen=more tissue activation=more symptoms. The tissue can also have its own nerves (unmylenated sensory C nerves) and blood vessels- after all it needs some nourishment! Endo is a chronic , INFLAMMATORY disease, so all these immune cells come to party (remember the MIT study ID'd 13 macrophages in endo patients), they bring along the cytokines and they just party on down (causing pain, scarring, overall unwell feelings). As the cycle of inflammation, pain, endocrine alterations continues, you may see more far reaching consequences, like pelvic floor muscle spasms, bowel symptoms, bladder irritation, etc. Then you add in that when we don't feel well we may not eat as well, be as active, then everything continues to feel worse. The longer chronic pain continues then the more speedy and strong the pain nerve signals get (central sensitization), and the harder it is to control. Some will try to treat endo by lowering the estrogen in the body; however estrogen protects the heart, brain, bones, and metabolism, so lowering it in the long term can be detrimental to our overall health. (They've even shown how removing endo can result in lowered heart risk! "Surgical treatment of endometriosis leads to endothelial function improvement, resulting in reduction of cardiovascular risk." http://m.humrep.oxfordjournals.org/content/29/6/1205) This is why excision of all the endometriosis is being strongly advocated these days. http://endocomprehensive.blogspot.com/2014/07/why-excision-is-recommended.html

Your bacteria and endometriosis

Better bacteria=better estrogen clearance.

"Since the 1970s, it has been known that in addition to supporting digestion, the intestinal bacteria that make up the gut microbiome influence how women's bodies process estrogen, the primary female sex hormone. The colonies of bacteria determine whether estrogen and the fragments left behind after the hormone is processed continue circulating through the body or are expelled through urine and feces..." http://www.sciencedaily.com/rele.../2014/09/140911135316.htm "In the blood, estrogens circulate either bound to proteins or free. The liver inactivates estrogens by conjugation...; conjugated estrogens are then finally excreted with bile acids and are transported into the intestinal lumen [71]. Once in the intestinal lumen, the fate of these conjugated estrogens depends on the composition of the intestinal microbiota present in the host. Individuals with an intestinal microbiome capable of deconjugating estrogens will reabsorb the free estrogen via the enterohepatic circulation, increasing the estrogenic potency in the host. Those with an intestinal microbiome less favorable to deconjugation will promote estrogen excretion in feces [72]." http://www.hindawi.com/journals/isrn/2013/693920/ 

 Also, could the inflammation from endo also alter the microbiome? "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....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. " http://www.medscape.com/viewarticle/819586_9