Discerning Endometriosis as a Multifaceted Entity: A Comprehensive Review

Background: Endometriosis is a hormone-dependent benign inflammatory disease of the female reproductive system characterized by the presence of endometrium in an abnormal or ectopic location causing pain & infertility and affects approximately 10% of reproductive-age women. A more in-depth insight into the complex mechanisms involved in the commencement, development, and advancement is required to accomplish the desired objectives of therapy effective against the symptomatic disease, associated infertility, and malignancies. Methods: management of the disease. Abbreviations: ASRM: American Society for Reproductive Medicine; EFI: Endometriosis Fertility Index; QoL: Quality of Life; MRI: Magnetic Resolution Image; TVUS: Transvaginal Ultrasonography; DIE: Deep Infiltrating Endometriosis; CT: Computerized Tomography; MDCT-e: Multidetector CT Enema; MRI-e: MRI Enema; BMI: Body Mass Index; EAOC: Endometriosis-Associated Ovarian Cancer; RTKs: Receptor Tyrosine Kinase; ART: Assisted Reproductive Technology; NSAIDs: Non-Steroidal Anti-Inflammatory Drugs; COX: Cyclooxygenase; ASA: Acetylsalicylic Acid; GnRH: Gonadotropin-Releasing Hormone; ADR: Adverse Drug Reaction; OCP: Oral Contraceptive Pill; COC: Combined Oral Contraceptives; CI: Confidence Interval; FDA: Food Drug Administration; CHC: Combined Hormonal Contraceptive; Ais: Aromatase Inhibitor; VEGF: Vascular Endothelial Growth Factor; Cell Proliferation

Introduction women accounting twice high as expenses of healthcare [24]. In defiance of advancements in the diagnosis and understanding of endometriosis, many women with endometriosis often associated with multiple side effects, and high recurrence rates are struggling due to inefficient non-invasive diagnostic methods and treatments [25,26]. The QoL of the patients is broadly affected with a negative impact on social and family life, and high health care costs due to endometriosis [27,28].

Risk Factors
There are several existing evidence of risk factors that may play a role in the etiopathogenesis of endometriosis including age, genetic factors, menstrual parameters, anthropometric measures, body habitus, lifestyle factors, and environmental exposures.
Endometriosis is one of the salient diseases seen in the reproductive age of women which may be explained by estrogenic atmosphere strongly implicated in its pathogenesis and considered an average age of diagnosis being 28 years [29]. The risk of endometriosis has been linked to ethnicity, and several studies have reported a nine-fold increase in Asian women's risk when compared to the European-American white female population. A manifold of education has been said the link with ethnicity as Asian women have nine times greater risk than the European-American white female [30]. Nonetheless, black women appear less likely to be diagnosed with endometriosis compared with white women [31].
Some reproductive problems such as early menarche (≤11 years of age), short menstrual cycles (≤27 days), heavy and long-lasting bleeding, reduced parity and reduced lifetime duration of lactation collaborate with the increased risk of endometriosis [2,15,32].
Endometriosis is inversely correlated with body weight, body mass index, and waist-to-hip ratio. Besides, it is more common in taller and thinner women due to consistently elevated levels of estradiol in follicular phase [33]. The altered endangerment of endometriosis has been reported in association with certain lifestyle factors such as smoking, exercise, and consumption of alcohol and caffeine [34].
The risk of endometriosis appears to be increased in women who are associated with the following pictures [2,30,35,36] (Table 2). Reduced or no parity 10 First-degree relatives (mother, sister, daughter) with endometriosis Note: Table 2 explains the relationship between endometriosis and several risk factors. The risk of endometriosis has been linked to ethnicity, race, age, body mass index, height and other diseases.

Role of Animal Model in Diagnosis
The Among various animal models of endometriosis, rodent models have a plethora of benefits such as; cheaper due to their small size, large litters, and short gestation. Additionally, these animal models play a significant role in the study of endometriosis because of the wide availability of genetic knock-out mice, antibodies against murine and rat proteins as well as knowledge of the murine genome.

Endometriosis in Association with Fertility
Fertility is affected by many pathways in the case of endometriosis such as peritoneal inflammation and endocrine imbalance, which interfere with ovarian function and ultimately reduce oocyte's competence, but minimal and mild endometriosis has been shown to improve fertility modestly after removal of superficial foci. The chance of fertility after resection of endometriomas and deep infiltrating lesions has remained undocumented [17].

Endometriosis in Association with Infertility
The routine intricacy that is seen in women with moderate to severe endometriosis is infertility [5]. A large cohort study revealed an increased risk of subsequent infertility by 2-fold in women age of fewer than 35 years with a prior history of laparoscopically confirmed endometriosis [15]. During endometriosis, the inflammatory environment of Pelvic anatomy becomes distorted and results in the reduced monthly fecundity rate via mechanical interruption like pelvic adhesions. These disruption imbalances the process of oocyte release or pickup alters sperm motility, interferes with the myometrium contraction ability, impairs fertilization, and embryo transport. Also, gamete transport and embryo implantation are affected due to escalation in cytokine production, which reduces the tubal function and decline in the tubal motility and contractility.  (Figure 1).

Figure 1: Endometriosis in association with infertility.
Note: Endometriosis has been associated with infertility. However, this figure tries to explain the mechanisms by which endometriosis affects gametes and embryos, the fallopian tubes and embryo transport, implantation and the eutopic endometrium; these abnormalities begins from altered pituitary ovarian axis leading to infertility.

Endometriosis in Association with Sub-Fertility
Endometriotic lesions may vary from just a few implants to extensive adhesions and organ infiltration and even outside the pelvic cavity, validated by ASRM classification into four classes:

Endometriosis and Pregnancy
Endometriosis is a disease of women's reproductive period.
The individual with a previous diagnosis of the disease had adverse consequences such as an increased risk of pregnancy and neonatal complications, and this risk remained significant after adjusting for maternal age. The risk of multiple pregnancies, breech presentation, and placenta previa was more than two-fold higher in women with endometriosis than in the control group. Besides, the estimated risk of stillbirth was more than 1.5-fold higher in the affected group. Endometriosis does not influence fetal well-being because the pregnant mothers with endometriosis are at higher risk of obstetric complications like miscarriages, threatened miscarriages, preterm labor, preterm birth, and a higher cesarean section rate [60]. Women with endometriosis are more vulnerable to serious and important adverse maternal, fetal and neonatal outcomes [61]. with different pathogenesis [66]. Also, the multislice computerized tomography (CT) enteroclysis and multidetector CT enema (MDCT-e) and MRI enema (MRI-e) are useful in the evaluation of bowel endometriosis and their sensitivity and specificity are 98.7% and 100%, respectively [67,68].

Biomarkers of Endometriosis
Researchers are exploring the utility of biomarkers for early diagnosis as a noninvasive approach, but more investment in this area is required for it to be fruitful.

Endometriosis-Associated Cancer
The association between endometriosis and gynecological cancer on a molecular basis is obscure. Formation of endometriallike tissue and lesion on the surface of the uterus and fallopian tubes cause pelvic inflammation, severe pain, and infertility [71,72].
The relationship between endometriosis and ovarian cancer was first published in 1927 [73]. No epidemiological evidence was published until the end of the 20th century. After that, the first large epidemiological study popped in from Sweden along with two big studies (20,686 and 64,492 participants respectively).
The studies revealed that there was an increased risk of ovarian cancer for those women who were suffering from endometriosis [74,75]. Also, there are many pathological factors involved to cause endometriosis, which includes; early menarche, abnormal uterine bleeding, abnormal estrogen level, low body mass index (BMI), cell adhesion factors, angiogenic factors, elevated gonadotropins, and chronic inflammation. According to the previous pieces of evidence of endometriosis, the parents, siblings, children as well as twins of those who have the disease, the likelihood of cancer may be up to ten folds higher than the healthy population.
Moreover, single nucleotide polymorphism may increase the risk of endometriosis and its associated cancer [76]. The overall risk of Endometriosis-associated carcinoma remains low despite it is a common medical issue. According to a huge epidemiological study, the all-inclusive prevalence of ovarian cancer in a patient diagnosed with endometriosis was 0.3-0.8 percent, which was 2-3 times perilous than the controls [77]. Endometriosis is somatically taught genetic change similar to those found in cancer, leading to clonal expansion and genetically abnormal cells. Endometriotic Hepatocyte nuclear factor -1β (HNF-1β) is a transcription factor that has significantly been expressed in ovarian cancer and seldom expressed in non-clear cell carcinoma [83]. The data collected antecedent research suggested that endometriosis is a monoclonal neoplastic disease and also a precursor of EAOC notwithstanding menopause. On one hand various types of molecular events like alteration of p53 gene, PTEN silencing, K-ras mutations have been discovered in EAOC. While activation of HNF-1 on the other hand, appears to be distinctive to clear cell carcinoma in becoming apparent in Endometriosis [84].
According to contemporary studies of whole -genome or biphosphate (PIP2) lead to produce phosphatidylinositol [3][4][5] triphosphate (PIP3), for the activation of 2 nd messenger PIP3, thus triggering AKT in the plasma membrane. The blockade of this pathway leads to independent cell growth due to a lack of a negative regulator of PIP3K/AKT/ [93,94]. Endometriosis is a benign inflammatory disease however, the molecular and cellular features work in a similar manner like; malignancy occurs, including increased cell proliferation, re-expression of the pluripotent transcription factor OCT4 [95], epithelial-tomesenchymal transition [96] acquisition of migratory phenotype [95,97] development of distant foci, cell adhesion, invasion [98] angiogenesis, and at times, treatment resistance [99]. It is not fully declined but there is a strong association between endometriosis and ovarian cancer. Genetic mutation is the major factor of ovarian cancer thus many protein markers are used for advanced diagnosis, prognosis, and treatment. All genomic and proteomic markers facilitate the development of the best diagnostic tool for endometriosis -associated ovarian cancer.

Management
Endometriosis is a chronic inflammatory disease that requires long term or lifelong treatment. Three major therapeutic management types exist for endometriosis, including Medical treatment, surgery, and assisted reproductive technology (ART) [100]. Accurate diagnosis is imperative because it provides outright information regarding severity of the disease. Many societies such as American College of Obstetricians and Gynecologists and American Societies of Reproductive Medicine approved medical treatment before definitive diagnosis [101,102]. The medical treatment provides only short term pain relief but when combined with surgical intervention, divulges long term relief. The main concern is how endometriosis-associated pain can be managed.
Physicians believe in optimal management for this condition. All these treatments are suppressive and do not possess curative effect.
1) Egg preservation in young patients affected by endometriosis.
2) Preoperative surgical management to inhibit evolution and to avoid removal of cyst that might look like endometriosis.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Non-steroidal anti-inflammatory drugs (NSAIDs) are used to reduce pain associated with dysmenorrhea in 80% of women. It inhibits cyclooxygenase (COX), a key enzyme in the biosynthesis of prostaglandin in endometriosis-associated pain and inflammation.

Hormonal Therapy
Gonadotropin-releasing hormone (GnRH) agonists are useful to deplete further synthesis of endogenous gonadotropins from the pituitary gland, interrupting the menstrual cycle, eventually resulting to cause endometrial atrophy and amenorrhea [107].
Progestin is an acceptable alternative drug for first-line therapy of endometriosis and has been used for over 30 years. Endometrial carcinoma has been treated with a more diverse method than the other malignant tumors that affect intra pelvic organs in untreatable cases. Radiotherapy, chemotherapy, and hormonal therapy are used in cases of endometrial malignancy. Here in hormonal treatment is better for those who wish to remain fertile after the early development of pre-menopausal endometrial cancer [108,109]. Progestin is effective in suppressing endometrial tumor growth in comparison to GnRH and Danazol. The cost-effectiveness and lower incidence of estrogen deficiency associated with adverse drug reaction (ADR) are lower than GnRH and danazol in the treatment of endometriosis. Thus, investigators have considered progestin as more effective and useful than GnRH and Danazol.
Progestin with hormonal contraceptives can be provided either alone or in combination with estrogen to prevent development endometriosis hyperplasia. It decreases glandular cellularity by including apoptosis and inhibits angiogenesis in the myometrium [109][110][111].

Medroxyprogestrone Acetate (MPA)
MPA is a synthetic and one of the most studied progestin that is typically used to cure irregular menstruation and abnormal uterine bleeding. It has been a greater effect on pain and improving quality life in placebo therapy, but the MPA and GnRH agonist dose 15-50 mg daily administration the efficacy has been found equivalent [110,112] The result was useful as there was a significant reduction in the severity of blood loss in all women after 2 months of treatment [116].

Hormonal Contraceptives
Limited studies said that oral contraceptives are useful in the treatment of endometriosis-associated with chronic pain. GnRH is the principal regulatory hormone of FSH) and LH. All these hormones are involved in the synthesis and regulation of estrogen for ovulation and follicular development. Oral Contraceptive Pill (OCP) inhibits the synthesis of LH and FSH to prevent estrogen and progesterone synthesis by suppressing the activation of GnRH, resulting in the prevention of endometrial proliferation and produces scanty cervical mucus [109]. Estrogen -progestin combination or alone progestin is one of the most common contraceptives used as the first-hand treatment for chronic pain the in case of endometriosis and ovarian function. These can be prescribed through oral contraceptive pills, transdermal patches, vaginal ringsEstrogen -progestin combination or alone progestin is one of the most common contraceptives used as the first-line treatment of endometriosis-associated with chronic pain and ovarian function. These can be prescribed through oral contraceptive pills, transdermal patches, vaginal rings [118]. According to the degree of success in women who were affected by endometriosis or its associated pain, the cost, ease of administration, and tolerance effect are the key factor of these drugs to make them common.

Continuous therapy of combined oral contraceptives (COC) is
better to control chronic pain as compared to cyclic administration [111]. A systemic review by Vercellini P, et al. 2011 [119]. A study undergone by Sullivan H, et al. 1999 to rule out whether the dose of COC was effective in endometriosis or ovarian activities revealed that COC had positive impacts on endometriosis.
A total of 30 healthy women were included, who were administered 60 mcg of Gestodene and 15 mcg of Ethinyl Estradiol on 21 st and 24 th day in every 28 days menstrual cycle and were monitored over 5 months. The outcome was that such a regimen is an active treatment for endometriosis as compared to an alone ultra-low dose of estrogen treatment [120]. Medroxyprogesterone acetate 10-100 mg of norethindrone acetate 5 mg daily is commonly prescribed to treat endometriosis; this progesterone is completely suppressing hypothalamic-pituitary axis for preventing ovulation [121].

Gonadotropin Releasing Hormone (GnRH) Agonist
GnRH agonists are one of the most common drugs used for the treatment of endometriosis. These drugs are down-regulating GnRH receptors from the hypothalamic-pituitary gland, which decreases gonadotropin secretion to inhibit ovulation and reduce serum estrogen level [122]. It is prescribed only after consultation with a physician. Leuprolide is a GnRH agonist that is effective in endometriosis as approved by the Food Drug Administration (FDA) [123]. Initially, the administration of Leuprolide stimulates LH and FSH which leads to increment in steroidogenesis thus, it elevates estrogen level in females and testosterone along with dihydrotestosterone (DHT) in males. Moreover, long term administration of Leuprolide can decrease the hormonal level, which may ultimately inhibit gonadotropin release by inhibiting the secretion of LH and FSH in both males and females [124].
In comparison with combined hormonal contraceptive (CHC) treatment, GnRH agonists have better efficacy in endometriosis and its associated chronic pain [125]. Various research have been conducted to improve novel treatment with GnRH agonists for endometriosis and its associated symptoms, to conclude how currently existing therapies work, which type of biochemical abnormalities are seen and how can they be minimized. All these studies concluded a similar effect of GnRH agonists found effective in preventing endometriosis and chronic pain [126][127][128][129][130].

Anta.)
GnRH antagonists have an advantage over the agonists about initial flare and hypoestrogenism through a direct mechanism that completely inhibits the GnRH receptors resulting in immediate suppression of LH and FSH secretion [131]. With the aid of cloning and high throughput peptide screening of oral human GnRH receptors, antagonist Elagolix was developed. It has a high affinity to bind GnRH receptors and reduces the interaction with CYP450 in inhibiting LH and FSH [132,133]. In the clinical trial, 40 mg Linzagolix is used in combination with Ethyl estradiol 0.1 mg or 0.5 mg NETA (clinical trial registration No. NCT03204318, NCT03204331, and NCT02778919) [135].

Aromatase Inhibitor
The Aromatase enzyme comprised two types of polypeptides.
The first one belongs to the superfamily of the cytochrome P450 (CYP450arom), which is the product of single gene CYP19, and second is flavoprotein (flavoprotein NADPH-CYP450 reductase). It is expressed on different body sites like ovarian granulosa cells, adipose tissue, placental syncytiotrophoblast, osteoblasts, and brain. Aromatase's main source is ovarian cells in premenopausal women, while adipose tissues in postmenopausal women [136,137]. Aromatase converts approximately 2% of Androstenedione to E1. Further, it turned to E2 in postmenopausal women by 17ß-Hydroxysteroid dehydrogenase type 1 in peripheral tissue resulting to high level of E2 circulating in the blood to cause endometrial hyperplasia and carcinoma [138]. The agent Aromatase inhibitor (AIs) was first employed to manage estrogen receptor activating breast carcinoma.
AIs represent the new promising treatment of endometriosis.
It has the capability to reduce estrogen production by inhibiting the enzyme cytochrome P450 [139]. AIs are classified into three generations. The first generation is Glutehimide, which has many adverse effects like lethargy, hypersensitivity, nausea, etc. The second generation is, Fadrozole and Formestancel have more selective and higher efficacy over the first generation and have less adverse effects. The third generation Aromatase inhibitors, namely; Letrozole, Anastrazole, and Examestande, are triazole derivatives that are selective, reversible as well as more potent, making them ideal for using clinically. These agents are prescribed in premenopausal women to decrease the estrogen level and increase FSH secretion from pituitary glands. Treatment with Aromatase inhibitors must be combined with other potent drugs to downregulate [137].

Letrozole
Letrozole is a non-steroidal aromatase inhibitor that has been commonly used for the management of endometriosis-associated pelvic pain and breast carcinoma. It was first reported in 2004 for the management of endometriosis. Letrozole has been used alone or in combination with other steroidal or non-steroidal analogs for the treatment of [140]. In the preclinical study, the animals were selected and made develop endometriosis by Vernon and Wilson's method. After the 14th day of model development, the animals underwent laparoscopy to measure heterotrophic. After that, they were provided 0.5 mg/kg AIs (Letrozole) daily for 3 weeks. Upon completion of treatment, the animals were re-examined, and the size of heterotrophy was determined. Besides, the histopathology study was carried out in both groups (control and AIs treated group).
The result suggested that 0.5 mg/kg for 21 days of treatment with Letrozole decreases the size of heterotopies. The total percentage of reduction of 79.92% ± 7.89% was observed [141]. A Prospective non-randomized study was carried out, including 20 patients with endometriosis and its associated chronic pelvic pain. Both Letrozole and norethindrone were prescribed in combined form as 2.5mg/kg for 6 months starting from the 3 rd day of the menstrual cycle. Besides, the pain score was recorded 30 days before starting the treatment. The result showed that following the procedure, and all the patients showed significant improvement in pain and [142].

Role of Micro-RNAs in Endometriosis Treatment
Micro-RNAs (miRNAs) are the highly conserved 9-22 nucleotide long non-coding RNAs that play a crucial role in cellular functions such as; cell proliferation, angiogenesis, apoptosis, and gene expression. miRNAs are directly bound to the 3 untranslated regions of messenger RNA (mRNA [143]. miRNAs have been found in most body fluids and the expression of miRNAs differs between healthy and diseased people however its physiological roles are obscure [144]. Endometriosis is a multifactorial disease characterized by the presence of endometrial tissue surrounding the womb. miRNAs are expressed in different gynecological disorders like; malignancies, leiomyoma, endometriosis, etc. Ovarian carcinoma is a rampant lethal malignancy in developed countries [145]. As angiogenesis is a key factor in endometriosis, several studies have reported that increment in VEGF level causes endometriosis [146][147][148]. miRNAs are involved in apoptosis disease progression as a result of which, in endometriosis, they are used as a diagnosing tool for detecting the progress of the disease and cell proliferation. Also, miRNAs are potential and efficient in the early detection of [143].

Anti-Angiogenesis Factor
Presently available medical treatment is effective to suppress hormonal synthesis. Oral contraceptives, androgenic agents, progestin analogs, GnRH agonists and GnRH antagonists have been successfully used for the treatment of endometriosis.
However, these agents are not effective in eradicating the disease in some cases. Long term use of these agents exhibits major adverse effects. Interleukins-8, vascular endothelial growth factor (VGEF) receptor-2, Endoglin, Urokinase-type plasminogen activator, matrix metalloproteinase-2, and 9, as well as a placental growth factor, is found in an activated endometrial cell in tumors [111,[149][150][151]. Previous studies showed that soluble truncated fms like tyrosine kinase-1 receptor and affinity-purified VEGF antibody are significantly useful to inhibit the angiogenesis factor in endometriosis. The blockade of VEGF signaling prevents endometrial lesions and associated carcinoma. Bevacizumab is a recombinant humanized anti-VEGF monoclonal antibody that prevents vascular density and also leads increment in apoptotic cell demise in case of surgically induced endometriosis.
Bevacizumab is in phase II clinical trial 15 mg/kg intravenous route of administration every 3 weeks until the disease progression is effective in endometrial carcinoma [152,153]. Thalidomide is also used as an anti-angiogenic agent in endometriosis. The mechanism of action of thalidomide is suppression of phosphoinositide 3 kinases (P13K)/protein kinase B (AKT) signaling to inhibit the formation of angiogenesis-related effect [154]. Antônio LG, et al. investigated the effect of thalidomide in the progression of endometrial lesions. 1 and 10 mg/kg thalidomide was administered in Wistar rats daily for 10 days. After 10 days of treatment, the tissue was isolated, and the cell proliferation index (CPI) was identified. The result proved that thalidomide had significantly reduced the lesion area and CPI [155]. Women who had relapsing endometriosis after surgical treatment of ovarian and peritoneal endometriosis were made discontinue GnRH agonist treatment, meanwhile, 300 mg/kg of thalidomide was prescribed for 6 months. Eventually, following the anti-angiogenic treatment with thalidomide, the relapse of endometriosis was completely suppressed [156].

Surgical Treatment
Surgical management of endometriosis requires extensive knowledge of the disease that should be managed by a multidisciplinary team to lead professional gynecologists.
Laparoscopy is a useful tool for the diagnosis of disease and determining the severity of disease before starting the surgical treatment [157]. It is effective in suppressing symptoms and chronic pain and can increase the fertility of women. Approximately, 50% of cases will re-develop symptoms within a few years of surgery.
The severity of the disease determines the successful surgical treatment of Endometriosis [122]. Patients who have chronic pelvic pain or ovarian endometrium and do not respond to medical management need surgical treatment. There are some approaches for considering surgical management viz; 1) Egg preservation in young patients affected by endometriosis.
2) Preoperative surgical management to inhibit evolution and to avoid removal of cyst that might look like endometriosis.

Conclusion
It is mandatory to understand that endometriosis is a complex, debilitating disease comprising multiple factors in its origin and development. Researchers are comprehending the distinct clinical features, including chronic pelvic pain and infertility, to discover the significant markers or therapeutic strategies to battle the mysterious disease. It is significant to gain cognizance into the complex etiology of endometriosis due to different causes viz; the unavailability of non-invasive diagnostic markers, delay in diagnosis, high risk of recurrence of the disease following surgical removal of the tissue, and lack of a definitive cure for the disease.
This article will furnish the readers with up-to-date knowledge regarding the pathogenesis, biomarkers, association of infertility, pregnancy, and carcinoma with the ailment and also shed light on the management of the disease.

Future Prospective
Still, endometriosis research is lacking the exact mechanism for etiology, biomarkers, and effective treatment modalities to generate convincing data with high sensitivity and specificity.
Besides, limitations derive from small sample size and suboptimal characterization of specimens.