Genetics and Endometriosis

Is there a genetic component to endometriosis? Current research says yes, although there are other factors that come into play.

"Multifactorial or polygenic disorders, such as endometriosis, are determined by multiple genes with allelic variations. Early studies by the groups of Simpson and Lamb [2,3] suggested that endometriosis has a heritable component. Endometriosis is a common, chronic, inflammatory and estrogen-dependent gynecological disease that develops as a consequence of a combination of genetic predisposition and environmental factors." http://genomemedicine.com/content/2/10/75

"Endometriosis is a benign disease with high prevalence in women of reproductive age estimated between 10 and 15% and is associated with considerable morbidity. Its etiology and pathogenesis are controversial but it is believed to involve multiple genetic, environmental, immunological, angiogenic, and endocrine processes. Altered expressions of growth factors, cytokines, adhesion molecules, matrix metalloproteinases, and enzymes for estrogen synthesis and metabolism have been frequently observed in this condition. The possibility of genetic basis of endometriosis is demonstrated in studies of familial disease, in which the incidence of endometriosis is higher for first-degree relatives of probands as compared to controls....

"This condition is considered as benign disorder, but exhibits cellular proliferation, cellular invasion, and neo angiogenesis. The glandular epithelium occasionally exhibits cytological atypia and/or hyperplasia (3) as well as DNA aneuploidy (4). The malignant potential of the endometriotic epithelial cells has been suggested in some cases considering the monoclonal methylation pattern of the HUMARA alleles and their invasive and metastatic ability in vitro (5, 6). In this context, previous studies supported the hypothesis that progression of endometriotic lesions to frank malignancy can occur although with a very rare incidence (7–11). However, the significance of the so-called malignant potential of endometriotic cells is controversial since monoclonal cells growth pattern was described in various benign lesions (5).

"There is strong evidence that the endometrium of women with endometriosis has an increased capacity to proliferate, implant, and grow in the peritoneal cavity (2). Morphological studies of tissue sections have demonstrated that the endometriotic glands have a wide range of morphologic development presenting a pattern ranging from poorly to highly differentiated glandular structures. Such morphological variations occur from gland to gland even within cellular areas in the same gland (19). Adequate morphological changes of the endometriotic glands were found in implants only during the proliferative phase of the menstrual cycle, whereas secretory changes were completely missing during the luteal phase (19). These changes include histological differentiation and induction of secretory proteins such as prolactin (PRL) (20), insulin-like growth factor binding protein-1 (IGF-BP1) (21), and extracellular matrix proteins such as fibronectin (22). In addition, several markers are aberrantly expressed in endometriotic cells in comparison to the normal cell elements, including the gap junction connexins (Cx) (23), β-cadherins (24), metalloproteinases (25), and P450 aromatase (26). Altogether, these features indicate a high degree of dedifferentiation in comparison to the normal situation....

"From the collected molecular data, it is evident that one or several genes may be disrupted by mutations or loss of DNA sequences in this condition. Loss of some protein functions may effect the regulation of several emerging down stream pathways, including the EGFR-axis, E-cadherin dynamics, transcriptional regulation, cell cycle regulation (proliferation/apoptosis), and cell adhesion. Divergences from mature endometrial epithelium to endometriotic epithelium must involve abnormal gene expression, which may directly cause or reinforce the alterations caused by changes of one or several genes undergoing germinal alterations. Within this context, the treatment strategies of endometriosis centered mainly toward ovarian function suppression and indirect limitation of cell growth and activity of endometriosis remain insufficient (73, 74).

"Future studies should concentrate on modifying and extending the use of the molecular biology techniques. Cytogenetic analysis with improved culture techniques of endometriotic tissue, capable of simulating the normal endometriotic environment, may help to prevent selective in vitro growth pressures. CGH and cDNA microarray studies has only been used to date on a limited number of primary endometriotic samples, yet has given us important informations (41, 75). Gene expression profiling, allelotyping, and FISH studies need to investigate the various types of endometriotic samples and more regions of the genome. As techniques are improving and examination of archival material is now possible it should be easier to correlate clinical data with the phenotypical features and genotype of primary lesions. This will certainly yield informations important for the early diagnosis and prognosis of patients.

 

"Finally, the anatomical and the immuno-histochemical features of the ectopic organic structures identified in fetal female reproductive tract suggest that endometriotic as well as neoplastic disease in adult women may develop on the basis of misplaced endometrial glands and/or embryonic cell remnants."

 

Above from Frontiers in Surgery: http://journal.frontiersin.org/Journal/10.3389/fsurg.2014.00016/full

 

"Endometriosis is a benign gynecological disease characterized by the presence and growth of endometrial cells outside the uterus. Genetic, endocrine, immunological, and environmental factors have been suggested in its pathogenesis. A great number of studies have related genetic polymorphisms as a factor that contributes to the development of endometriosis. This review presents a detailed description of the contribution of genetic polymorphisms in genes that regulate vascular function and tissue remodeling in endometriosis (alpha 2-HS glycoprotein [AHSG], epidermal growth factor receptor [EGFR], vascular endothelial growth factor [VEGF], endostatin, plasminogen activator inhibitor 1 [PAI-1], angiotensin I-converting enzyme [ACE], and matrix metalloproteinases [MMPs]). Some polymorphisms of the VEGF (-460 C/T, +405 G/C, +936 C/T), PAI, MMP-1, 2, and 3 genes were widely studied, while polymorphisms of the AHSG, EGF, endostatin, and VEGF (-1154 G/A, -2578 A/C) genes were not. In this latter case, additional studies are required to confirm the findings of the few studies that have analyzed these single nucleotide polymorphisms (SNPs). Additionally, studies that found a positive or negative association of SNP with endometriosis emphasize the relevance of studies with a large number of control cases to confirm their findings. The haplotype analysis was performed only for the VEGF (-460, +405, -1154 and -2578), ACE (-240/2350) and MMP-1, 2, 3, and 9 genes, and in most of them, there was no association with endometriosis. Of the eight works that analyzed haplotypes of the VEGF gene, five did not associate them with endometriosis. Haplotypes of ACE and MMP-2 genes were not associated with endometriosis, while those of MMP-1, 3, and 9 genes were related to a high risk for the disease." lots more details at http://www.scielo.br/scielo.php?pid=S0104-42302012000500022&script=sci_arttext&tlng=en

 

"They have identified two new genetic variants that increase the risk of developing the disease, particularly moderate-severe stages.... The first is a variant on chromosome 7 believed to be involved in regulating nearby genes, probably those involved in the development of the womb and its lining. The second variant was found on chromosome 1, close to the gene WNT4. This is important for hormone metabolism and the development of the female reproductive tract, especially the ovaries, making it an important biological candidate for involvement in endometriosis.

"Our study is a breakthrough because it provides the first strong evidence that variations in DNA make some women more likely to develop endometriosis," says Dr Zondervan. "We now need to understand the effect of these variations on cells and molecules in the body."" http://www.well.ox.ac.uk/dec-10-genetic-variants-in...

 

"We conducted a genome-wide association meta-analysis of 4,604 endometriosis cases and 9,393 controls of Japanese¹ and European² ancestry. We show that rs12700667 on chromosome 7p15.2, previously found to associate with disease in Europeans, replicates in Japanese (P = 3.6 × 10⁻³), and we confirm association of rs7521902 at 1p36.12 near WNT4. In addition, we establish an association of rs13394619 in GREB1 at 2p25.1 with endometriosis and identify a newly associated locus at 12q22 near VEZT (rs10859871). Excluding cases of European ancestry of minimal or unknown severity, we identified additional previously unknown loci at 2p14 (rs4141819), 6p22.3 (rs7739264) and 9p21.3 (rs1537377). All seven SNP effects were replicated in an independent cohort and associated at P <5 × 10⁻⁸ in a combined analysis. Finally, we found a significant overlap in polygenic risk for endometriosis between the genome-wide association cohorts of European and Japanese descent (P = 8.8 × 10⁻¹¹), indicating that many weakly associated SNPs represent true endometriosis risk loci and that risk prediction and future targeted disease therapy may be transferred across these populations." http://www.nature.com/ng/journal/v44/n12/full/ng.2445.html

Aromatase and endo study

"Endometriosis is an estrogen-dependent inflammatory disease defined by the growth of endometrial stroma and glands outside of the uterus. Epidemiological and clinical studies show that estrogen is essential for the growth of endometriosis. There are several molecular links between estrogen production and inflammation in endometriosis. The enzyme aromatase P450 is expressed aberrantly in endometriosis and is stimulated by prostaglandin E2 , resulting in production of estrogen that induces prostaglandin E2 expression within endometriotic lesions. Furthermore, estrogen promotes the secretion of several inflammatory cytokines and growth factors, which contribute to the progression of endometriosis and stimulate estrogen production. On the basis of the local estrogen biosynthesis in endometriotic implants, nonsteroidal aromatase inhibitors have been successfully used to treat pain symptoms caused by endometriosis. These agents do not cause the disappearance of endometriosis; they cannot be considered routine treatment and should only be administered in adequately controlled clinical studies."  http://www.ncbi.nlm.nih.gov/pubmed/24738993

Pelvic Floor Spasm: The missing link in chronic pelvic pain

This has been posted here before but is worth a second look:

Pelvic Floor Spasm: The missing link in chronic pelvic pain

Publish date: OCT 01, 2012

 

By: Patrice M. Weiss, MD and Jennifer Rich, MS, PT and Eric Swisher, MD

"Acute or chronic pelvic pain is often due to musculoskeletal disorders, which may go unrecognized during a traditional pelvic examination. Proper evaluation facilitates the diagnosis of spasm or trigger points, and physical therapy often achieves a major improvement in quality of life for these women....

The pelvic floor consists of striated muscles, ligaments, and connective tissues that support the pelvic organs against gravity and intraabdominal pressure. The pelvic diaphragm is composed of the coccygeus muscle posteriorly and the levator ani anterolaterally. Although they are not fully distinct, the components of the levator ani consist of the iliococcygeus, the pubococcygeus, and the puborectalis muscle group. The pelvic floor must allow relaxation of this support at the urogenital hiatus during voiding and parturition while maintaining the anatomic position of pelvic structures. The complex mechanics of its bimodal function and frequent insults to the integrity of the pelvic diaphragm from gravity, daily activities, and vaginal birth contribute to the pelvic musculature’s vulnerability to damage and injury. Lying within the pelvic cavity are the piriformis, and obturator muscles, which are not elements of the pelvic diaphragm but may contribute to pelvic pain when injured.⁵

 Pelvic floor hypertonus may be the primary cause of pelvic pain in some patients; in others it may simply be a response to the underlying pelvic disorder.⁶ Several mechanisms of injury may lead to spasm of the pelvic floor. These include, but are not limited to, traumatic vaginal delivery, pelvic surgery, positional insults such as prolonged driving or occupations that require prolonged sitting, gait disturbances, traumatic injury to the back or pelvis, and sexual abuse. Malalignment of the pelvis, especially in the sacroiliac joint, due to trauma, poor posture, pelvic floor deconditioning, muscular asymmetry, or excessive athletics also may contribute to muscular dysfunction of the pelvis.

Injury leading to myofascial pain begins with an acute phase, characterized by inflammatory and immune responses. The injury may perpetuate itself with spasm promoting further inflammation, neurotransmitter release, and central nervous system sensitization. As the injury evolves, the second stage is the musculodystrophic stage, during which fibrosis develops and the process favors a chronic syndrome.

Pelvic floor dysfunction can also arise in response to other common chronic pain syndromes, such as endometriosis, irritable bowel disease, vulvodynia, and interstitial cystitis. A prospective evaluation of patients with chronic pelvic pain of various etiologies found abnormal musculoskeletal findings in 37%, versus 5% of controls.⁷ For this reason, the pelvic floor should be included in any evaluation regardless of the suspected source of pelvic pain....

The treatment of symptomatic pelvic floor hypertonus begins with rehabilitation of the neuromuscular unit or neuromuscular reeducation using biofeedback, muscle relaxation techniques, and soft-tissue manipulation. During the therapist’s manipulation of the affected pelvic floor musculature, the patient is asked to contract and relax. Verbal and tactile cues are used to help the patient recognize when she has appropriately controlled the pelvic floor. External or intravaginal electrodes may be used to monitor the electrical activity of the pelvis and provide visual or auditory biofeedback as the patient attempts to contract or relax. A key objective of neuromuscular reeducation is to improve the patient’s proprioceptive awareness of the pelvic floor. Once a woman is able to recognize contracted versus relaxed pelvic musculature, she is better able to control the pelvic floor.

Physical therapy modalities for chronic pelvic pain also include massage, ultrasound, and myofascial release. Therapists may perform intravaginal soft tissue work as well as manual stretching, although these techniques are most beneficial in the presence of trigger points, banding, or contractures. Massage tools allow self-treatment at home on a more frequent basis. A crystal wand is one of the most commonly used devices for independent therapy of the pelvic floor. In some cases, therapeutic exercise may address musculoskeletal imbalances, and neuromuscular stimulation is used to relieve persistent spasm.

No single modality for pelvic floor therapy has proved to be superior, perhaps because most physical therapists take a multifaceted approach to this complex disorder. Although most treatment options can be applied to almost any patient, our experience suggests that generalized hypertonus usually responds best to generalized therapy (such as strengthening, stretching, biofeedback, ultrasound), whereas trigger points and other focal anomalies more often require manual therapy (such as myofascial release, crystal wand manipulation, trigger point injection). Substantial overlap exists, and a multimodal approach is therefore typical. Some therapy options, such as intravaginal manual therapy, may not be acceptable to all patients.

Physical therapy is relatively successful for patients with chronic pelvic pain related to pelvic floor dysfunction, especially considering the typical outcome and persistence of symptoms for this patient population as a whole. Only a few prospective randomized trials have been conducted, but FitzGerald et al demonstrated a 57% response rate to myofascial physical therapy for urologic pelvic pain syndrome among patients presenting with pelvic floor tenderness.¹⁰ The same multicenter collaborative group later confirmed these results with a 59% response rate in women treated with myofascial physical therapy for interstitial cystitis and painful bladder syndrome.¹¹ In a study by Glazer et al, patients with vulvar vestibulitis and pelvic hypertonus also demonstrated a 50% response rate to physical therapy and biofeedback.¹² Finding a physical therapist with the skill and interest to address pelvic floor dysfunction may pose a challenge in some geographic areas. Therapists familiar with women’s health issues and chronic pelvic pain are listed at the American Physical Therapy Association Web site (http://www.apta.org) under the “Find a PT” link.  The Herman & Wallace Pelvic Rehabilitation Institute (http://hermanwallace.com) specializes in pelvic floor rehabilitation training for physical therapists and maintains a database of practitioners.

Pharmacologic management options for pelvic floor dysfunction begin with nonsteroidal anti-inflammatory drugs, cyclobenzaprine, amitriptyline, or baclofen. Narcotics are tempting for patients in extreme discomfort but are a poor long-term solution. Gabapentin and pregabalin have shown promise in patients with pelvic floor myalgia.^8,13 Injection of persistent trigger points with lidocaine, with or without cortisone, is also a successful approach to the myofascial component of pelvic pain.⁸ More recently, purified botulinum toxin (Botox) has been used to treat pelvic floor muscle spasm, with proven success.^8,13 Sacral nerve, pudendal nerve, and posterior tibial nerve stimulation are all developing modalities with therapeutic promise.^8...
 Attention to the pelvic floor musculature during pelvic examinations is an effective and inexpensive diagnostic strategy that can be life-changing for patients with pelvic pain, yet requires minimal time and effort. These patients may have to undergo the usual chronic pelvic pain algorithm without the option of physical therapy if hypertonus goes unrecognized.Physical therapy with or without pharmacologic management offers many patients significant relief or even resolution. Educating patients and using physical therapy to make them active partners in their own care give women with chronic pelvic pain a sense of empowerment and benefit them physically and psychologically."

http://contemporaryobgyn.modernmedicine.com/contemporary-obgyn/news/modernmedicine/modern-medicine-feature-articles/pelvic-floor-spasm-missing-l

Macrophages

There have been several studies on macrophages involved in endometriosis. Let's look first at what, exactly, do macrophages do:

"Macrophages function as control switches of the immune system, providing a balance between pro- and anti-inflammatory responses. To accomplish this, they develop into different subsets: classically (M1) or alternatively (M2) activated macrophages. Whereas M1 macrophages display a cytotoxic, proinflammatory phenotype, much like the soldiers of The Dark Side of The Force in the Star Wars movies, M2 macrophages, like Jedi fighters, suppress immune and inflammatory responses and participate in wound repair and angiogenesis. Critical to the actions of these divergent or polarized macrophage subpopulations is the regulated release of inflammatory mediators. When properly controlled, M1 macrophages effectively destroy invading pathogens, tumor cells, and foreign materials. However, when M1 activation becomes excessive or uncontrolled, these cells can succumb to The Dark Side, releasing copious amounts of cytotoxic mediators that contribute to disease pathogenesis. The activity of M1 macrophages is countered by The Force of alternatively activated M2 macrophages, which release anti-inflammatory cytokines, growth factors, and mediators involved in extracellular matrix turnover and tissue repair. It is the balance in the production of mediators by these two macrophage subpopulations that ultimately determines the outcome of the tissue response to chemical toxicants." http://www.drthrasher.org/page167.html

 

"Macrophages are recruited at sites of hypoxia and tissue stress, where they clear cell debris and heme-iron and generate pro-life and pro-angiogenesis signals. Macrophages are abundant in endometriotic lesions, where are recruited and undergo alternative activation. In rodents macrophages are required for lesions to establish and to grow; bone marrow-derived Tie-2 expressing macrophages specifically contribute to lesions neovasculature, possibly because they concur to the recruitment of circulating endothelial progenitors, and sustain their survival and the integrity of the vessel wall. Macrophages sense cues (hypoxia, cell death, iron overload) in the lesions and react delivering signals to restore the local homeostasis: their action represents a necessary, non-redundant step in the natural history of the disease. Endometriosis may be due to a misperception of macrophages about ectopic endometrial tissue. They perceive it as a wound, they activate programs leading to ectopic cell survival and tissue vascularization. Clearing this misperception is a critical area for the development of novel medical treatments of endometriosis, an urgent and unmet medical need." http://www.ncbi.nlm.nih.gov/pubmed/23372570

"The expression of CD68, NCL-MACRO, HAM56, TNFα, IL-6, and IL-1β was significantly higher in PF macrophages obtained from women with endometriosis than in controls. The ERα and ERβ had significantly higher expression in macrophages of women with endometriosis than in controls. A positive correlation was observed between the expression of ERα and ERβ both in women with and without endometriosis. The ERα expression was positively correlated with the expression of inflammatory cytokines in women with endometriosis but not in controls; ERβ expression was correlated to the expression of inflammatory cytokines in the both groups. There is a correlation between the expression of ERβ and proinflammatory cytokines both in women with and without endometriosis. The expression of ERα correlates with cytokine production selectively in women with endometriosis but not in controls.” http://www.fertstert.org/article/S0015-0282(07)00095-7/abstract

"On the basis of the common occurrence of high concentration of estrogen and activated macrophages in patients with endometriosis, we postulate that interaction between 17beta-estradiol and macrophage may be an important affair in endometriosis. So our study was focused on the effect of 17beta-estradiol on macrophage. First morphology of macrophages was examined with environmental scanning electron microscopy. Increased size, extension of more microvilli, expression of retraction fibers and elaboration of membrane ruffles were detected in 17beta-estradiol treated macrophages. Then Nitrate and nitrite level in the supernatant was measured by the method of Griess and iNOS expression was analyzed using immunohistochemical staining. It showed that 17beta-estradiol could induce NO release from peritoneal macrophages and expression of iNOS was increased. Also more TNF-alpha in supernatant that was measured by MTT via L929 cell was produced by macrophages under the inducing of 17beta-estradiol. Furthermore, [Ca2+]i, which was viewed by microscope in a laser scanning confocal unit, elevated 39.8% in peritoneal macrophages after 17beta-estradiol 100 nmol/L treated. The results above demonstrated that peritoneal macrophage had been activated in both morphology and cytokine line when interaction with 17beta-estradiol, which indicated that macrophage activated by 17beta-estradiol might play a permission role in development of endometriosis." http://www.ncbi.nlm.nih.gov/pubmed/15088640

"Macrophages particularly play important roles in facilitating development, growth, and repair of nerve fibers...Thus the evidence which suggests that the immune cell population, particularly macrophages, are likely to play crucial roles in growth and survival of nerve fibers in endometriosis is compelling, and indicates that certain inflammatory mechanisms may substantially contribute to the generation of pain in endometriosis." Endometriosis: Science and Practice edited by Linda C. Giudice, MD, Johannes L. H. Evers, MD, David L. Healy, MD http://books.google.com/books?id=kxzaBqmglrMC&pg=PA221...

Could this switching of macrophages also be used to help with the inflammation of endometriosis then?

"Macrophages are critical effector cells in the inflammatory response. Classically activated macrophages initiate the innate immune response and direct the activity of the acquired immune response. Upon resolution of inflammation, macrophages convert to an anti-inflammatory phenotype called alternatively activated. Alternatively activated macrophages promote debris scavenging, tissue remodeling and wound healing. Intriguingly, macrophages can be manipulated to move back and forth between these two phenotypes. During inflammatory disorders, like inflammatory bowel disease, switching macrophages to an alternatively activated phenotype, could dampen down inflammation and reduce disease. We are currently assessing the macrophage phenotype present during inflammatory bowel disease and mechanisms that we could use to switch macrophages to an anti-inflammatory phenotype during disease."  http://www.vangopro.ca/Sly-Lab/overview.html

 

It still appears that complete removal of endometriosis lesions is the best therapy.

Stress and Pain

"A new study investigating the relationship between stress and the painful symptoms of the disease is currently underway. It offers, for the first time, evidence of the negative consequences of stress in the progression of endometriosis, most likely through an effect on the immune system....the endo-control rats had higher colonic damage scores than sham-stressed animals, which was increased further by stress. The endo-stress rats had the shortest colon length, the highest levels of MPO, the greatest number of colonic mast cells, and an increase in peritoneal fluid immune cell infiltration, all indicative of  activation of inflammatory mechanisms.
Conclusion
According to the senior researcher for the study, Dr. Appleyard, “These findings contribute to our understanding of how stress may affect the severity of endometriosis. We think there is likely a connection with the immune system because of the observed levels of mast cells in the colon and the increased levels of inflammatory cells in the peritoneum of the affected rats, since this has also been observed in patients with endometriosis.”  Appleyard continued, “The results offer a jumping off point to help identify stress-management interventions that will help those women who are affected by the disease.”" http://www.sciencedaily.com/releases/2008/04/080407114627.htm

"A research team at Carnegie Mellon University in Pittsburgh found that chronic psychological stress is associated with the body losing its ability to regulate the inflammatory response.

Published in the Proceedings of the National Academy of Sciences today, the research shows for the first time that the effects of psychological stress on the body's ability to regulate inflammation can lead to the development and progression of disease.

Sheldon Cohen, professor of psychology at the university's Dietrich College of Humanities and Social Sciences, said prolonged stress alters the effectiveness of cortisol to regulate the inflammatory response because it decreases tissue sensitivity to the hormone.

Specifically, immune cells become insensitive to cortisol's regulatory effect and in turn runaway inflammation is thought to promote the development and progression of many diseases.

He said: "Inflammation is partly regulated by the hormone cortisol and when cortisol is not allowed to serve this function, inflammation can get out of control." "When under stress, cells of the immune system are unable to respond to hormonal control, and consequently, produce levels of inflammation that promote disease. Because inflammation plays a role in many diseases such as cardiovascular, asthma and autoimmune disorders, this model suggests why stress impacts them as well.

"Knowing this is important for identifying which diseases may be influenced by stress and for preventing disease in chronically stressed people."  http://www.huffingtonpost.co.uk/.../pain-stress-link...
"'Cortisol, a hormone produced by the adrenal glands, is sometimes called the 'stress hormone' as it is activated in reaction to stress. Our study shows that a small hippocampal volume is associated with higher cortisol levels, which lead to increased vulnerability to pain and could increase the risk of developing pain chronicity," explained Étienne Vachon-Presseau.

As Dr. Pierre Rainville described, "Our research sheds more light on the neurobiological mechanisms of this important relationship between stress and pain. Whether the result of an accident, illness or surgery, pain is often associated with high levels of stress Our findings are useful in that they open up avenues for people who suffer from pain to find treatments that may decrease its impact and perhaps even prevent chronicity. To complement their medical treatment, pain sufferers can also work on their stress management and fear of pain by getting help from a psychologist and trying relaxation or meditation techniques.'" http://www.sciencedaily.com/rele.../2013/02/130225092038.htm

Findings from Vanderbilt research

Vanderbilt University is partnered with the Endometriosis Association for research in endometriosis. Here are some findings from that research so far:

 

  "KEY FINDINGS FROM VANDERBILT ENDOMETRIOSIS ASSOCIATION RESEARCH
•Studies on the action of progesterone which have shown the critical role of this hormone in the development of endometriosis
•Discovered that dioxin exposure leads to this alteration in progesterone function
•Showed that just one exposure to dioxin during pregnancy led to damage for five generations-whether exposure was paternal or maternal
•Demonstrated that exposure during pregnancy can lead to pre-term birth
•Showed that dioxin exposure leads to damage to the immune system
•Demonstrated that nutritional anti-inflammatory agents such as fish oil can provide some protection against the disruptive impact of dioxin
•Developed a unique model of surgical adhesions that allows the role of inflammation to be examined during the earliest stages of endometriosis-mediated adhesions development" from http://www.endometriosisassn.org


"KEY FINDINGS FROM VANDERBILT ENDOMETRIOSIS ASSOCIATION RESEARCH

• Demonstrated a critical role of retinoic acid, the bioactive form of Vitamin A, in controlling normal endometrial expression of matrix degrading enzymes
• Found that a loss of progesterone sensitivity is a central component of the pathophysiology of endometriosis
• Identified that in utero and developmental dioxin exposure in mice creates the same endometrial phenotype observed in women with endometriosis
• Discovered an epigenetic link between dioxin action and the loss of progesterone response observed in women with endometriosis
• Presented evidence that dioxin exposure leads to an altered path-way of cell-cell communication in the endometrium that mimics an inflammatory like event
• Discovered developmental exposure of mice to dioxin leads to disruption of endometrial function for multiple generations, suggesting this toxicant can impact endometrial biology thru the germline
• Demonstrated that nutritional anti-inflammatory agents such as  fish oil can provide some protection against the disruptive impact of dioxin on endometrial function
• Developed a novel model system in which the role of immune cells can be examined in the development, progression, and therapeutic treatment of endometriosis
• Developed a unique model of surgical adhesion that allows the role of inflammation to be examined during the earliest stages of endometriosis-mediated adhesion development
• In collaboration with multiple pharmaceutical companies and other NIH -funded investigators, continue to screen new compounds for potential use as therapeutics for women with endometriosis"

"Our data has pointed to the influence of local inflammation in the loss of progesterone sensitivity observed in the uteruses of women with endometriosis."

"We have recently demonstrated adult endometrial dysfunction in mice following exposure to TCDD (dioxin). Endometrial changes were markedly similar to alterations observed in the endometrium of women with endometriosis, and it resulted in reduced progesterone responsiveness and infertility..."
For More Information, See: http://www.endometriosisassn.org/pdfs/vanderbilt.pdf

 

Yeast infections and estrogen

Yeast Infections- ever feel like you get more than your fair share? Estrogen may have something to do with it:

"In summary, the results of this study show that estrogen is

the dominant reproductive hormone that supports and sustains

an experimental vaginal C. albicans infection and reduces the

inhibitory activity of epithelial cells against Candida. Progesterone,

on the other hand, has no demonstrable effect on the

vaginal infection or on systemic and/or local immune responsiveness

associated with the infection. Taken together, these

results suggest that estrogen, but not progesterone, is important

in the reproductive-hormone-associated susceptibility to

 vaginal C. albicans infection."  
 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC97188/ 

  "Yeast infections appear to occur more frequently in women with increased estrogen levels — for instance, in women who are pregnant, those taking high-dose estrogen birth control pills or those taking estrogen hormone therapy." http://www.mayoclinic.org/.../risk-factors/con-20035129 

  "In a normal menstrual cycle, estrogen deposits glycogen (a form of sugar) in the cells that are found in the lining of the vagina. The release of progesterone causes the cells to shed into the vagina, so the sugar becomes available for yeast to feed on, multiply and grow. Estrogen and sugar production peak at the midpoint between periods, and then progesterone begins to build and sugar is released. Yeast infection symptoms can follow the hormonal pattern of this cycle. Usually, the most severe symptoms occur before the onset of a woman's period when more sugar is available. During and after the flow, symptoms are likely to subside. Additionally, changes in the vaginal pH can disrupt the immune system or destroy the so-called friendly bacteria that populate the vaginal canal and keep the yeast fungus in check." http://health.howstuffworks.com/.../the-basics-of-yeast...   

See here about estrogen and endometriosis: http://endocomprehensive.blogspot.com/2013/11/estrogen-receptors-importance-in.html
 "Aberrant estrogen synthesis and metabolism have been suggested to increase local estradiol (E2) concentration in endometriosis and thus to promote the growth of the lesions. However, tissue estrogen concentrations within the endometrium and different types of endometriosis lesions have not been described....Endometrial or endometriotic intratissue E2 concentrations did not reflect the corresponding serum levels. In the proliferative phase, endometrial E2 concentration was five to eight times higher than in the serum, whereas in the secretory phase the E2 concentration was about half of that in the serum. Accordingly, a markedly higher E2/E1 ratio was observed in the endometrium at the proliferative phase compared with the secretory phase. In the endometriosis lesions, E2 levels were predominating over those of E1 throughout the menstrual cycle. Among the hydroxysteroid (17β) dehydrogenase (HSD17B) enzymes analyzed, HSD17B2 negatively correlated with the E2 concentration in the endometrium, and HSD17B6 was strongly expressed, especially in the deep lesions."  http://www.ncbi.nlm.nih.gov/pubmed/22969138