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New genetic diagnostic measures and possible future treatment options for endometriosis

Introduction 

Endometriosis is characterized as the abnormal growth of endometrial tissue growing outside of the uterus. One in ten women of reproductive age have been diagnosed with endometriosis, some with symptoms starting as early as age twelve [1, 2]. Symptoms vary greatly among patients with chronic pelvic pain and dysmenorrhea, painful periods being the most common. Some women are hospitalized for their pain and require surgery to remove the lesions causing their pelvic pain; others are asymptomatic [2]. Although endometriosis affects women worldwide, there are few effective treatment options, leaving women to suffer from severe pelvic pain and fertility issues [1, 3]. Subsequently, about half of women suffer from infertility because of this disorder [3]. 

Along with a lack of treatment availability, there is also a lack of reliable diagnostic procedures. However, as genetic testing grows in popularity, researchers have begun identifying specific alleles in the human genome related to a heritable aspect of endometriosis [1, 4]. Researchers are working to identify specific genetic biomarkers to more accurately diagnose and eventually treat endometriosis [5, 6, 7, 8, 9]. This review will focus on new genetic biomarkers and their role in potential non-invasive diagnostic and possible treatment options. Furthermore, probable causes, heritable aspects, and current issues with diagnostic technology used for endometriosis will also be discussed. 

Endometriosis 

Possible Causes
Figure 1
Figure 1: Retrograde menstration contributes to endometrial tissue growth outside the uterus.

Identifying the cause of any disorder is the first step to recovery. With a chronic disorder like endometriosis, a diagnosis could reduce the mental burden of chronic symptoms and significantly increase the quality of life. Over the years, many theories regarding the cause of endometriosis have appeared, most of which remain inconclusive. The most promising theory is retrograde menstruation [10]. Retrograde menstruation is characterized as the backflow of menstrual debris from the uterus through the fallopian tubes and into the abdominal cavity [10, 11]. With this phenomenon occurring in over 76% of women, it is theorized that the amount and severity of retrograde menstruation are directly correlated with endometriosis [10]. 

Furthermore, a compromised immune system and the inability to regulate apoptosis and cell proliferation are linked to endometriosis [10]. An endometriosis diagnosis tends to be coupled with other coexisting, immunological conditions such as irritable bowel syndrome, chronic inflammation, and infertility [11, 12]. One study discovered a high correlation between autoimmune disorders and endometriosis, most likely due to suppressed hormone expression [12]. The correlation between autoimmune disorders and endometriosis has resulted in a delay in diagnosis for endometriosis, likely due to the crossover of the disorders, with the focus primarily being placed on the autoimmune disorder instead of endometriosis. However, the co-occurrence of these conditions can be used diagnostically to help identify endometriosis quicker if specific autoimmune disorders are found in direct correlation with endometriosis. 

In an analysis conducted by Kvaskoff and their colleagues, studies showed a strong positive correlation between endometriosis and autoimmune disorders such as scleroderma, multiple sclerosis, and rheumatoid arthritis [12]. The correlation between these autoimmune disorders and endometriosis is thought to be caused by a suppressed immune system and the specific variable expression of female hormones such as estrogen and prolactin [4].

Genetic Biomarkers of Endometriosis 

Heritable Aspects 

Although a definitive cause for endometriosis has not been concluded, correlations between lifestyle and genetics have been found. Approximately 47% of endometriosis is considered to be genetic, with a strong correlation between sisters (11.6%), and mothers and daughters (8%) [1, 4]. Given the statistical relevance of genetic predisposition to endometriosis, the scientific community has begun researching the genetic aspects that may increase susceptibility to endometriosis via genetic testing. Genetic testing allows physicians to conclude a patient's susceptibility to disease through non-invasive saliva samples and, occasionally, blood samples [13]. Considering the invasiveness of laparoscopic surgery, non-invasive options should be prioritized to prevent unnecessary complications. 

Researchers have recently attempted to identify the genes responsible for a patient's susceptibility to endometriosis through various genomic analysis tests. In a study conducted in 2018, Christofolini et al. analyzed three possible, unique, variant DNA sequences that differentiate individuals associated with endometriosis. These single nucleotide polymorphisms (SNPs) were chosen from a previous study that first discovered the possible correlation. Christofolini et al. analyzed the genome of 394 infertile women with endometriosis with a control of 650 fertile women to determine the association between endometriosis and SNPs in the genes KAZN rs10928050, LAMA5 rs242784, and TAC3 rs733629. Two of the three polymorphisms held statistical significance compared to the control group. One SNP in KAZN rs10928050 was found more frequently in stages one and two of endometrial tissue. In contrast, the SNP in LAMA5 rs242784 was found more frequently in stages three and four, a gene responsible for encoding laminin, a protein responsible for promoting cell adhesion [6]. The increased presence of laminin could increase abnormal cell adhesions outside of the uterus, exacerbating the severity of endometriosis [6]. Furthermore, the KAZN gene could be associated with the beginning of abnormal menstrual cell adhesion outside of the uterine cavity. Given this study focused on a Brazilian population, more research needs to be conducted on a broader gene pool.

Figure 2
Figure 2: Possible genetic correlation to endometriosis

In another study conducted in Taiwan in 2021, researchers found a second upregulated gene after a genome-wide association study. Two single nucleotide polymorphisms affected protein tyrosine phosphatase, receptor type D (PTPRD) [7]. Mutations to PTPRD are associated with increased cell migrations, proliferation, and elevated signal transducer and activator transcription 3 (STAT3) [7]. Signal transduction is the process of an extracellular signal ligand binding to a transmembrane protein, causing an intracellular effect. Signal transducer and activator transcription (STAT) mechanisms alter gene expression in the cell relating to cell differentiation and regulation. Elevated STAT3 levels have been linked to varying types of cancer as they promote a reduction in cell apoptosis [14]. Subsequently, elevated STAT3 expression can also result in unregulated endometrial tissue growing outside of the uterus, as seen in endometriosis. However, given geographical variations, different genes could be more common in the Taiwanese population than in Western or European populations. 

Another genomic study analyzed the role miRNAs play in endometriosis. MicroRNAs (miRNAs) regulate gene expression by binding to messenger RNAs (mRNAs).  In this study, the response of two miRNAs, (miR-16 & miR-20a) to stimuli was identified to be suppressed or downregulated in endometrial individuals, while three other miRNAs, (miR-99b, miR-125a, miR-143), were upregulated and fully expressed [8]. Given the downregulation of miR-16, a gene responsible for cell proliferation and apoptosis, its inhibition may be responsible for the body's inability to remove endometrial tissue growing outside the uterine cavity. Other studies have also identified and supported a correlation between endometriosis and miR-99b [8, 9, 15].

Figure 3
Figure 3: Genetically mediated protein growth in endometrial tissue

Multiple genetic factors contribute to the abnormal adhesion formation found in endometriosis patients. However, most factors are related to cell proliferation and cell apoptosis. Identifying specific contributors is essential in creating possible treatments to help reduce the effects of endometriosis. 

Current Diagnostic Procedures: The Problem 

Current standard diagnostic procedures include transvaginal ultrasounds, laparoscopic surgery, and magnetic resonance imaging (MRI) [2, 11]. Laparoscopic surgery has been the standard course of treatment for endometriosis since the 1900s [11, 16]. The success of laparoscopic surgery has risen over the years due to increased resources and specialized surgeons. It is considered the most accurate method of diagnosis due to inconsistencies in transvaginal ultrasounds and MRIs [16]. However, the accuracy of laparoscopic surgery depends on a physician's ability to identify lesions, which is difficult in the early stages of endometriosis [10, 17]. 

The absence of a reliable diagnostic measure for endometriosis has caused numerous women to go without treatment [16, 17, 18]. On average, women wait anywhere from five to eleven years from when symptoms initially begin to initial diagnosis [2]. Although new, non-invasive diagnostic procedures are emerging, the path to diagnosis is long and grueling for most. In a descriptive research study conducted by Lamvu et al., a surgeon specializing in gynecology at Orlando VA Center, a self-reported, online questionnaire was given to 317 women in the United States and 134 women outside the United States [2]. Lamvu et al.’s study focused on the patient experience and their path to a diagnosis. Similarly, a qualitative study conducted by Moradi et al. examined how the healthcare system affected the patient’s diagnostic journey in Australia [18]. Both studies concluded insufficient support or diligence in health care worldwide [2, 18]. Each study mentioned how painful and grueling endometriosis is and how the difficulties of navigating the healthcare system amplified the discomfort [2, 18].

In the Lamvu et al. study, 61.5% of US participants claimed their practitioners were dismissive and did not acknowledge the full extent of the symptoms they were experiencing [2]. In the same study, approximately three-quarters of participants reported having more than five discussions with a physician before reaching a diagnosis [2]. The period between each discussion is variable, but the severity and quantity of symptoms the patient was experiencing prolonged the experience. 

Symptoms of endometriosis lie on a spectrum, leaving some with a multitude of symptoms and others asymptomatic [2, 10, 11]. The wide variety of symptoms a patient can present with leads to a prolonged diagnostic experience or a misdiagnosis. Lamvu et al. found a positive correlation between patients with a multitude of symptoms and reaching a diagnosis later in life compared to those who only have a few, more apparent symptoms [2]. Participants in the Harris et al. study who experienced a wider variety of symptoms were diagnosed with other disorders, such as irritable bowel syndrome, depression, or anxiety, before endometriosis was considered a possibility [12]. The dismissiveness of physicians combined with the variation of symptoms from case to case results in a significant decrease in the patient's quality of life. Receiving an early diagnosis would allow patients to begin the search for possible treatment options or seek emotional support. A diagnosis could also help patients get referrals to a specialist early on, preventing more debilitating symptoms down the line.

Possible Advances in Treatment Options 

Identifying the origin of a physiological disorder can help identify the root of the problem, allowing for more accurate treatment options. Since endometriosis has some heritable aspects due to genetic mutations, there is a possibility of formulating medication directed toward identified genetic pathways. In a recent study, researchers identified a mutation in miRNA 196b on the HOX10 factor. This mutation, in turn, affected miRNAs c-myc and Bcl-2 expression, which play a crucial role in cell proliferation and apoptosis [5]. Researchers identified the cause of HOX10 inhibition–hypermethylation. Researchers attempted to treat patients with demethylation agents during the study and demonstrated significant improvement in symptoms and fertility [5]. This study provides a foundation for future research into the long-term efficacy of demethylating agents. Further research on medicated treatment options targeting biochemical pathways caused by genetic polymorphisms should be explored. 

Hormone treatment for endometriosis is an already established treatment option, utilizing specific birth control options to help regulate menstruation and related pain. However, for some women, birth control is ineffective, and hormone contraceptives are not an option for those who wish to become pregnant. A recent study conducted in Boston identified a statistically significant difference in pain levels after six months of vitamin D supplements [19]. However, most study participants were diagnosed with Stage One endometriosis, resulting in an inaccurate representation of every stage. Vitamin D supplements can assist in the regulation of estrogen, with the potential to benefit some patients. Vitamin D supplements are a possible homeopathic treatment for some, showing improvement in stage one endometriosis patients [19]. 

A recent study in 2023 discovered a possible correlation between Fusobacterium and endometriosis. In this translational study, Ayako et al. found the presence of Fusobacterium more than half of their sample [20]. Aykayo et al. theorizes that the presence of Fusobacterium and retrograde menstruation are responsible for endometrial lesions in the abdominal cavity. It is not certain that Fusobacterium is the primary cause of endometriosis, but targeted antibiotic treatments like metronidazole and chloramphenicol may improve the quality of life for many patients, especially those with aggressive stages of endometriosis. This is a promising treatment option that should be explored more to help manage the debilitating symptoms of endometriosis.

Conclusion 

Studies focusing on drug trials targeting gene expression and regulation concerning endometriosis are the frontier of reproductive research. With more genetic mutations identified in recent studies, the promise of specified regulatory drugs and supplements holds the potential for new, non-invasive treatment options. Women want to be heard and for action to be taken against this crippling disease that affects every aspect of their lives. Research can only go so far when it is also a physician’s responsibility to advocate for their patients when they cannot do it themselves. The progression towards a comprehensive treatment and diagnostic plan is a group effort in numerous specialties, starting with primary care physicians. 

Author's Note

The idea for this Literature Review originated from personal experience. I have always struggled to understand my own body and why such a common occurrence for almost half of the population was never really talked about. Taking UWP 102B with Professor Amy Goodman-Bide allowed me to grow as a writer, helping me narrow my topic to something I am truly passionate about. I am forever grateful for everything she has taught me through UWP 102B. This Literature Review is for everyone to take from, especially those who suffer from endometriosis but don’t fully understand their disorder. If you are anything like me, getting to the root cause of an issue brings comfort. I hope this does just that. 

References

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