Endometriosis Awareness Month

Endometriosis is a debilitating gynecologic disease characterized by the presence of uterine epithelial and stromal tissues outside of the uterine cavity. with variable phenotypic and symptomatic presentation (1). Epidemiologic data show that in Canada, the inability of women to contribute to society because of disease amounts to the economic burden of $1.8 billion, which is increased to $18–22 billion in the United States (2). In 2014, the World Endometriosis Research Foundation published a series of guidelines (3). In 2016, standardized methods of sample collection and analysis of data were highlighted as research priorities for endometriosis. Apart from estrogen dependence, immune dysfunction and inflammation also play a role in its pathobiology. Genome-wide assessment studies have started to elucidate the genetic variants associated with endometriosis. Epigenetic mapping is also being carried out by identifying aberrantly methylated genes (e.g., TNFRSF1B, IGSF21, and TP73 involved in the pathogenesis of endometriosis Elevated levels of proinflammatory cytokines in the peritoneal fluid, eutopic endometrium, and ectopic lesion samples, and blood in women with endometriosis is documented. Though it is now well established that endometriosis thrives in an inflammatory environment however, it remains unclear whether inflammation contributes to the pathogenesis or is a by-product of the process. Very few people have heard of the disease, even though an estimated 176 million women worldwide suffer from endometriosis. Endometriosis Awareness is observed in March, sponsored by the Endometriosis Association. An entire month patients, charities, and organizations share information on the disease to raise much-needed awareness.

Cullen in the 19th century described 10 different sites in the pelvis where he found the presence of ‘‘uterine mucosa.’’. Decades of research into the pathogenesis of endometriosis have led to insightful elucidations into the hormonal and nonhormonal mechanisms involved in disease development and persistence. However, the therapeutic regimens to treat endometriosis and the methods for early diagnosis of endometriosis are still lacking. Laparoscopic surgery remains the current criterion-standard diagnostic tool. But, it is invasive surgery so women of reproductive age opt to temporarily diminish pain symptoms by other therapeutic mechanisms. Nonsteroidal anti-inflammatory drugs, GnRH agonists, progestins, and oral contraceptive pills are mainstream therapeutic options to diminish the disease burden and minimize symptoms of pain. Most of the established therapeutics are targeted to create a hypoestrogenic state offering temporary relief as estrogen is the primary driver of endometriosis lesion development. One of the major disadvantages of the present drug treatments available for endometriosis is women are forced to decide between the quality of life by diminishing pelvic pain and chances of pregnancy.

Pelvic pain is the primary symptom of endometriosis often associated with the menstrual period. Endometriosis patients typically describe menstrual pain that’s far worse than usual and also report that the pain increases over time. Some common signs and symptoms of endometriosis are dysmenorrhea – painful periods, pain with intercourse, pain with bowel movements or urination, menorrhagia (heavy periods) or menometrorrhagia (bleeding between periods) and infertility. Few possible explanations for endometriosis are: Retrograde menstruation – where menstrual blood containing endometrial cells flows back through the fallopian tubes and into the pelvic cavity where endometrial cells stick, grow and continue to thicken and bleed over the course of each menstrual cycle, peritoneal cells transformation – It is proposed that hormones or immune factors promote transformation of peritoneal cells into endometrial cells, estrogen may transform embryonic cells into endometrial cell implants during puberty, post-surgery such as a hysterectomy or C-section, endometrial cells may attach to a surgical incision, the immune system may be unable to recognize and destroy endometrial tissue that’s growing outside the uterus.

The search for a noninvasive biomarker for endometriosis is challenging and its ongoing issue. Noninvasive diagnostic markers have been investigated in blood, tissue, and urine from endometriosis patients. Fassbender et al. in 2015 published the most up-to-date review of the biomarkers for endometriosis (4). Later a Cochrane Database Systematic Review was published focused on noninvasive biomarkers of endometriosis from urine, blood, endometrial samples, and imaging tests. A list of noninvasive biomarkers of endometriosis has been published recently by identifying elevated levels of certain metabolites—fucose and branched-chain amino acid—in the urine and plasma of endometriosis patients with the use of 1 H-nuclear magnetic resonance spectroscopy. Another study demonstrated the effectiveness of plasma brain-derived neurotrophic factor as a noninvasive biomarker for detecting patients with stage I–II endometriosis with 91.7% sensitivity and 69.4% specificity. In addition, elevated levels of synuclein-gamma (SNCG) was also documented in human endometriotic lesions. SNCG is a member of the synuclein family of neuronal proteins that are involved in cellular proliferation by means of interacting with the mitotic checkpoint kinase BubR1. By a mouse model, the potential role of SNCG in disease pathogenesis has been established. It was found that treatment with the peptide inhibitor of SNCG SP012 led to decreased growth and vascularization of endometriotic lesions. Endometrial sample obtaining method i.e. by using either pipelle or curette is minimally invasive. Also, a biopsy can prove to be useful also as a diagnostic tool for endometriosis in an outpatient setting. The widely accepted theory of retrograde menstruation says that the menstrual endometrium is the source of ectopic endometriotic foci. Hence, it has been stated to use the direct source of the disease to identify biomarkers for endometriosis. It has been documented that the endometrium of women with endometriosis responds differently to ovarian hormones, and this fact is being utilized to discover new potential biomarkers. This is critical to elucidate why only 10% of women develop endometriosis although the phenomenon of retrograde menstruation occurs in 76%–90% of reproductive-age women.

Using nonhuman primate models of endometriosis, it has been demonstrated that the menstrual fragments in the peritoneal cavity directly influence gene expression pattern of the eutopic endometrium. A possibility of ‘‘cross-talk’’ between the ectopic endometriotic foci and the eutopic endometrium is proposed. The presence of endometriosis likely programs hyperestrogenic responsiveness and progesterone resistance into the eutopic endometrium as the disease progresses. Epigenetic modification of the genome is a reversible and dynamic process which may get influenced by the level of hormones and inflammatory factors in the extracellular environment. Multiple genome-wide association studies (GWASs) identified single-nucleotide polymorphisms (SNPs) associated with the disease risk. A meta-analysis of eight GWASs published demonstrated SNPs in six genetic loci across European, American, and Japanese women with stage III-IV endometriosis. An increase in the incidence of early menarche in young girls displaying endometriosis-related symptoms makes a reliable diagnostic marker imperative. It is more likely that instead of a single biomarker, a group of biomarkers will provide improved diagnostic performance. It might be useful to minimize false positives and negatives during differential diagnosis. With the advent of GWAS, an improved understanding between SNPs and genetic variants it may be feasible to identify a panel of diagnostic biomarkers composed of endometrial methylome and expression patterns of circulating noncoding RNA (i.e., miRNA and lncRNA).

Intriguingly, the only aspect of its pathogenesis targeted for therapeutic approach focus on the dependence of endometriosis on estrogen for growth, the suppression of which remains perhaps the single scientifically and clinically proven therapy with some success.

References

1. Giudice LC. Endometriosis. N Engl J M 2010;2389–98
2. Guo SW. Epigenetics of endometriosis. Mol Hum Reprod 2009;15:587– 607.
3. Becker CM, Laufer MR, Stratton P, Hummelshoj L, Missmer SA, Zondervan KT, et al. World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonisation Project: I. Surgical phenotype data collection in endometriosis research. Fertil Steril 2014;102: 1213–22.
4. Fassbender A, Burney RO, O DF, d’Hooghe T, Giudice L. Update on biomarkers for the detection of endometriosis. Biomed Res Int 2015; 2015:1–14