Open access peer-reviewed chapter

Endometriosis: The Enigma That It Continues to Be

Written By

Shikha Sharma and Akanksha Tripathi

Submitted: 01 October 2022 Reviewed: 26 October 2022 Published: 02 December 2022

DOI: 10.5772/intechopen.108774

From the Edited Volume

The Female Pelvis - Anatomy, Function and Disorders

Edited by Ran Pang, Xinyao Zhou and Jianxin Lu

Chapter metrics overview

109 Chapter Downloads

View Full Metrics

Abstract

Endometriosis is an enigmatic disease and there continues to be controversy regarding its incidence, pathogenesis, history and management despite the extensive research world over. It is an estrogen-dependent, benign, inflammatory disease that affects females during their premenarcheal, reproductive, and postmenopausal hormonal stages. The prevalence in general population is not exactly known and can vary considerably depending on whether symptomatic or asymptomatic population was studied and whether clinical or surgical methods were used for diagnosis. This pathology involves presence of endometrial glands and stroma outside of the uterine cavity and the lesions additionally also, contain fibrous tissue, blood and cysts. The lesions are most commonly located in the pelvis where they can involve the ovaries, bowel as well as peritoneum and also, other sites including the diaphragm, pleural cavity, urinary system and scar sites. These lesions typically have the tendency to cause extreme anatomical distortions. Although, endometriosis is a benign pathology, ectopic endometrial tissue and resultant inflammation can cause dysmenorrhea, dyspareunia, chronic pain, and infertility. Symptoms can range from minimal to severely debilitating and may not necessarily corroborate to the degree of anatomical or architectural disarray.

Keywords

  • chronic pelvic pain
  • endometriosis
  • pathogenesis
  • medical management
  • surgical management

1. Introduction

Endometriosis is a chronic inflammatory condition that affects 6–10% of women of reproductive age group. It is defined by presence of endometrial like tissue outside the uterus, commonly involving the pelvic lining and structures in it including ovaries and also, sometimes sites like urinary tract, gastro-intestinal tract and even diaphgram as well as pleural cavity.

It is a benign, estrogen-dependant, inflammatory disease that has a peak prevalence in those between 25 and 35 years age group but has occasionally been reported in premenarcheal girls and postmenopausal women. Endometriosis is a common cause of subfertility and pain during periods, sexual intercourse as well as defecation.

Endometriotic lesions contain endometrial glands and stroma just as the eutopic endometrium but exist outside the uterus and often contain fibrous tissue, blood, and cysts [1]. These lesions derive pigmentation from pigmented histiocytes and hemosiderin-laden macrophages formed as a result of breakdown of red blood cells by inflammatory cells.

Endometriotic pelvic lesions can be of the following phenotypes [1, 2].

1.1 Superficial peritoneal

Although, superficial peritoneal lesions classically contain endometrial glands and stroma, either the glandular component may be absent, sparse, or transformed by hormonal, metaplastic changes and/or cellular atypia or the stromal component may be infiltrated by foamy and pigmented histiocytes, fibrosis, or other processes [3].

1.2 Ovarian endometrioma

An ovarian endometrioma occurs as a result of the ectopic endometrial tissue bleeding within the ovary and forming a hematoma surrounded by ovarian parenchyma with bilateral ovarian involvement seen in one third of cases. Unlike most haemorrhagic physiological ovarian cysts, endometriomas typically exhibit fibrotic walls with surface adhesions, contain syrup-like chocolate-colored material and lined by endometrial epithelium, stroma, and glands [2, 4]. The endometrial epithelium and stroma, more commonly, may be replaced by granulation tissue and fibrosis making histological diagnosis cumbersome.

1.3 Deep endometriosis

Deep endometriosis (DE) is when endometriotic lesion invade more than 5 mm deep to the peritoneum [5]. Most common sites are rectovaginal septum, rectum, rectosigmoid colon, bladder, ureter, and other pelvic fibromuscular structures such as the uterine ligaments and vagina.

Advertisement

2. Anatomy and staging

2.1 Common pelvic sites

In decreasing order of frequency are:

Ovary and ovarian fossa- 67 and 32 percent, anterior and posterior cul-de-sac, posterior broad ligaments, uterosacral ligaments- 46 percent, pouch of douglas- 30 percent, bladder- 21 percent, uterus, fallopian tubes, sigmoid colon, appendix, round ligaments, vagina, cervix, rectovaginal septum, cecum, ileum, inguinal canals, perineal scars, ureters, and umbilicus [6, 7, 8, 9].

2.2 Extra-pelvic sites

Occasionally, endometriotic lesions may be noted in the anterior abdominal wall, usually at surgical incisional sites or umbilicus. Rarely, they have also been reported in the breast, pancreas, liver, gallbladder, kidney, urethra, extremities, vertebrae, bone, peripheral nerves, spleen, diaphragm, central nervous system, hymen and lung [10, 11, 12, 13].

2.3 Surgical staging

Endometriosis is surgically staged according to the revised American Society for Reproductive Medicine scoring system (Figures 1 and 2) but other staging systems also exist [14, 15]. Surgical exploration in endometriosis is indicated for

  1. Evaluation of incapacitating pain or other symptoms

  2. Persistent pelvic not responding to medical therapy

  3. Treatment of anatomic abnormalities, such as symptomatic ovarian cysts, rectovaginal nodules, or bladder lesions.

Figure 1.

ASRM classification of the disease.

Figure 2.

Revised ASRM classification of endometriosis.

2.3.1 Tissue biopsy versus visualization

Endometriosis is diagnosed conclusively by histologic evaluation of a visible lesion biopsied during laparoscopy [16]. Diagnosis by visual inspection alone can be limited by the stage and location of endometriosis as well as surgeon’s expertise [17, 18, 19].

2.3.2 Visual appearance of lesions

The gross appearance and size of visible implants can vary from raised flame-like patches, whitish opacifications, yellow-brown discolorations, translucent blebs, or reddish or reddish-blue irregularly-shaped islands or even blue- brown lesions described as “powder burns” [3]. The peritoneal surface may be scarred or puckered or have defects known as Allen-Masters syndrome, or give rise to nodules and cysts. Rarely, endometriosis may mimic a polypoidal growth giving the appearance of a malignant tumor.

2.3.3 Accuracy of biopsy

In a study of 976 women who underwent laparoscopy and biopsy for pelvic pain and/or infertility, the laparoscopic biopsy had a sensitivity of 98 percent, specificity of 79 percent, positive predictive value of 72 percent, and negative predictive value of 98 percent in diagnosing endometriosis compared with histology alone [20].

2.4 Visual lesions but negative histology

Classic endometriotic lesions at laparoscopy but with negative histology are still an indication for endometriosis treatment because negative biopsies can result from inadequate sampling and do not conclusively exclude disease [17].

2.5 Absence of visual and histologic disease

Absence of visual or histologic disease on laparoscopy excludes endometriosis with reasonable reliability [21]. Therefore, it is not advised to take random biopsies during a negative laparoscopy, although, occult microscopic sub-mesothelial implants are known to be present in normal appearing endometrium.

Advertisement

3. Pathogenesis

3.1 Pathogenesis and etiology

Endometriosis has a multifactorial pathogenesis, including altered immunity, imbalanced cell proliferation and apoptosis, aberrant endocrine signaling and genetic factors. Genetic studies, have identified genomic regions and mutations in cancer driver genes (PIK3CA, KRAS, ARID1A) associated with endometriosis which may partly explain the aggressive nature of deeply invasive lesions compared with superficial peritoneal lesions [22, 23, 24].

3.2 Theories of endometriosis development

Multiple existent theories for endometriosis development are,

3.2.1 Sampson’s theory of retrograde menstruation

Says that endometrial cells flow backwards through the fallopian tubes and into the peritoneal cavity during menses as is evident by the increased incidence of endometriosis in girls with genital tract obstruction and increased tubal reflex. However, it is also to be noted that although, up to 90 percent of females have retrograde menstruation, most do not develop endometriosis indicating the involvement of additional factors [25, 26, 27].

3.2.2 Alternate mechanisms

Some theories suggest that the source of ectopic endometrial cells include mesothelium, stem cells, müllerian rests, bone marrow stem cells and embryonic vestiges as well as lymphatic or vascular dissemination and coelomic metaplasia [28, 29, 30].

3.2.3 Premenarcheal endometriosis

Is possibly due to the existence of müllerian embryonic rests caused by neonatal uterine bleeding resulting from maternal hormone exposure [31, 32, 33].

3.3 Mechanism of pain

The pelvic pain of endometriosis is caused by increased production of inflammatory and pain mediators as well as the associated neurological dysfunction [34]. There is a subsequent increase in nerve fibers and imbalance of sympathetic and sensory nerve fibers. The symptoms of pain may be due to the neuro-modulating effect of estrogen selectively repulsing the sympathetic axons while preserving sensory innervation, peripheral nerve sensitization, and chronic changes in the central nervous system [34, 35, 36, 37, 38, 39].

3.4 Mechanism of subfertility

Endometriosis is known to affect all aspects of fertility by means of anatomic distortion from pelvic adhesions and endometriomas and/or production of substances (eg, prostanoids, cytokines, growth factors) that are “hostile” to normal ovarian function/ovulation, ova quality, sperm mobility, fertilization, and implantation.

Advertisement

4. Epidemiology

4.1 Prevalence

Determining the prevalence of endometriosis in general population is challenging because individuals may be asymptomatic, or have varied and non-specific presentations besides also, the fact that definitive diagnosis typically requires surgery [40].

Reported prevalence ranges for different populations are [41, 42]:

  • Asymptomatic individuals- 1 to 7 percent

  • Individuals undergoing hysterectomy for benign indications- 15 percent

  • Adolescents with genital tract anomalies- 40 percent

  • Females presenting with infertility- up to 50 percent

  • Adolescent and adult females presenting for evaluation of chronic pelvic pain- up to 70 percent

4.2 Risk factors

Factors associated with an increased risk of endometriosis are positive family history, nulliparity, early menarche and late menopause, shorter menstrual cycles (defined as ≤21 days), heavy menstrual bleeding, obstruction of menstrual outflow (eg, cervical stenosis, müllerian anomalies), taller height and lower body mass index [43, 44, 45, 46, 47, 48, 49, 50, 51].

Factors known to reduce the risk include multiple births, extended intervals of lactation and late menarche (after age 14 years) [48, 52, 53].

4.3 Presenting symptoms

4.3.1 Common symptoms

Include chronic abdominal/pelvic pain and/or pressure, severe dysmenorrhea, dyspareunia, heavy menstrual bleeding, and infertility. The chronic pelvic pain is typically dull, throbbing, sharp, and/or burning. Additionally bowel and bladder dysfunction (eg, pain, urgency, frequency), abnormal uterine bleeding, low back pain, and chronic fatigue have also been noted [2].

4.3.2 Symptom constellation

The seven visceral symptoms associated with endometriosis include abdominal pain with no relation to menstruation, pain during urination, pain during defecation, constipation or diarrhea, irregular bleeding, nausea or vomiting, and feeling tired or lacking energy.

4.3.3 Asymptomatic individuals

Individuals with endometriosis can sometimes be asymptomatic and are often diagnosed at the time of surgery for another indication [5].

4.4 Predictive symptomatology

The type and site of endometriosis can be suggested by the leading symptom as below:

4.4.1 Dyspareunia

Dyspareunia can suggest presence of peritoneal or deep endometriosis lesions.

4.4.2 Deep dyspareunia

Deeply infiltrating endometriosis lesions can occur on the uterosacral and cardinal ligaments, pouch of Douglas, posterior vaginal fornix, and anterior rectal wall and contribute to deep sexual pain.

4.4.3 Superficial dyspareunia

Distal or superficial dyspareunia can result from lesions of the cervix, hymen, perineum, and episiotomy scars [6, 7, 8, 9, 10].

4.5 Urinary frequency, urgency, and/or painful micturition

Typically seen with bladder endometriosis and may worsen with menstruation. Ureteral endometriosis can be asymptomatic or associated with colicky flank pain or gross haematuria [11].

4.6 Diarrhea, constipation, and/or abdominal cramping

Typically seen with bowel endometriosis [12, 13]. Deeply infiltrating endometriosis of the posterior cul-de-sac and rectovaginal septum typically causes dyspareunia and painful defecation. Rectal bleeding may occur but is rare.

4.7 Abdominal wall pain

Cyclical or continuous abdominal wall pain is typically seen with endometriotic lesions of the abdominal wall.

4.8 Chest pain, hemoptysis, and/or pneumothorax

Individuals with thoracic endometriosis may present with chest pain, pneumothorax, haemothorax, hemoptysis, scapular or cervical pain which is mostly catamenial [15].

Advertisement

5. Natural history

The number of peritoneal areas affected by endometriosis appears to increase during adolescence until the early 20s [22]. Factors that cause endometriosis to either progress, regress, or remain stable are not yet fully understood.

In studies where second-look laparoscopy was performed 6 to 12 months after a diagnostic laparoscopy confirmed endometriosis, disease progressed in 29 to 45 percent of untreated women, regressed in 22 to 29 percent, and remained stable in 33 to 42 percent [23, 24, 25].

In a prospective study that followed 88 asymptomatic women with rectovaginal disease for one to nine years, fewer than 10 percent of the women had disease progression, defined as development of symptoms or increase in lesion size [26].

Advertisement

6. Clinical impact

6.1 Fertility

30–50% of endometriosis cases are estimated to be suffering from subfertility and 25–50% infertility cases are estimated to have endometriosis [2, 3]. It is hypothesized that minimal/mild endometriosis incites an inflammatory response involving overproduction of prostaglandins, metalloproteinases, cytokines, and chemokines as well as macrophages and natural killer cells. This inflammatory process is known to impair ovarian, peritoneal, tubal, and endometrial function leading, subsequently, to defective folliculogenesis, fertilization as well as implantation.

Several studies have reported that the increased numbers of macrophages and cytokines in the peritoneal fluid of women with endometriosis inhibits both sperm and fallopian tube ciliary function in vitro. In addition, the eutopic endometrium also, may not function with endometriosis as a consequence of which, implantation is impaired [5, 6].

In a study involving monkeys with experimentally induced endometriosis, the pregnancy rate was approximately 40 percent in normal controls, but only 12 percent in animals with advanced endometriosis and 0 percent if ovarian adhesions were present [8].

Advanced endometriosis is also reported to adversely impact the quality of ovarian follicles leading to abnormal folliculogenesis and reduced fertilization potential of oocytes [9, 10].

6.2 Pregnancy

Often causes decidualization of the endometriotic lesions leading to reduction or disappearance in the endometriosis related pain. However, complications have been reported in even the decidualized spots such as intestinal perforation, hemoperitoneum, uroperitoneum, acute appendicitis, and ruptured or infected ovarian endometrioma. Since these events are a rarity, it is not warranted to do any additional monitoring for pregnant individuals. Possible explanations could be traction by the growing uterus on adhesions, increased friability of inflamed tissues, and alteration of vessel walls by decidualized lesions [54, 55, 56, 57, 58, 59, 60, 61, 62, 63].

6.3 Obstetric outcomes

Evidence suggests an increased risk of preterm birth, preeclampsia, and cesarean birth when compared with individuals without endometriosis (adjusted odds ratio [aOR] 1.67, 95% CI 1.37–2.05; aOR 1.37, 95% CI 1.06–1.77; aOR 1.83, 95% CI 1.60–2.09, respectively). A meta-analysis of 33 studies on over 3 million pregnant women reported that, amongst those who conceived spontaneously, endometriosis was associated with placenta previa, cesarean delivery, preterm birth, and low birth weight. However, additional surveillance for pregnant individuals with endometriosis is not advised [63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73].

6.4 Postmenopause

Although, endometriosis may remain active after menopause with approximately 2 percent of all initial surgical diagnosis seen amongst postmenopausal women, severe symptomatic endometriosis is not usually seen in that age group. Symptomatic postmenopausal endometriosis has been seen amongst those both on and off hormone therapy. This could possibly be due to extra-ovarian estrogen production (eg, skin, fat tissue) and or lesion-specific production [74, 75].

6.5 Ovarian cancer risk

6.5.1 Summary

It has been reported that ovarian endometriosis, whether superficial lesions or endometriomas or both, could have an increased risk of ovarian cancer, particularly endometrioid and clear cell types. Some ovarian lesions harbor genetic changes that are common to ovarian cancer such as mutations in ARID1A, PTEN, HNF1B and k-ras. While there is a raised relative risk, the absolute risk of ovarian cancer remains low. The risk of malignant transformation in endometriosis is estimated at 1 percent and 1–2.5 percent for premenopausal and post-menopausal women respectively. In a meta-analysis of 13 case-control studies including nearly 8000 women with epithelial ovarian cancer (EOC), those with a history of endometriosis had three times the risk of clear cell EOC and two times the risk of endometrioid and low-grade serous EOC but no change in risk of high-grade serous or mucinous EOC. Ovarian cancer developing in endometriotic lesions is seen in younger women (49 versus 59 years old) and with a better medial overall survival (196 versus 34 months) than patients without endometriosis. Activation of oncogenic KRAS and PI3K pathways and inactivation of tumor suppressor genes PTEN and ARID1A have been suggested as mechanisms for the transformation of endometriosis, particularly ovarian endometriomas, to malignancy [76, 77, 78, 79, 80, 81].

6.5.2 Ovarian cancer surveillance not advised

Endometriosis is not considered a premalignant lesion and surveillance for ovarian cancer is not recommended. Also, there is no evidence to suggest prophylactic removal of endometriosis lesions. However, oral contraceptive pills lower the risk of ovarian cancer in all users.

6.5.3 Cardiovascular disease

Two studies reported an increased risk of cardiovascular disease, myocardial infarction, composite cardiovascular disease, and all-cause mortality in those harboring endometriosis [82, 83]. However, more data is needed to validate this fact.

Advertisement

7. Medical treatment options

Include nonsteroidal analgesics, hormonal contraceptives, gonadotropin-releasing hormone (GnRH) analogues, and aromatase inhibitors (AI). Medical interventions do not improve fertility, diminish endometriomas, or treat those features of deep endometriosis that require targeted definitive management strategies.

7.1 Nonsteroidal anti-inflammatory drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs), e.g. Propionic acids such as ibuprofen, naproxen or Fenamates such as mefenamic acid, acetic acids such as Indomethacin, diclofenac, etodolac, Oxicams such as piroxicam are considered the first-line treatment for pelvic pain, including endometriosis-related pain as they are affordable, readily available, carry an acceptable side-effect profile, and have consistently demonstrated effective reduction of primary dysmenorrhea. For women attempting conception, we avoid selective Cyclo-oxygenase-2 (COX-2) inhibitors (celecoxib, refecoxib, and valdecoxib) as some studies indicate these drugs can prevent or delay ovulation [2].

7.2 Estrogen-progestin contraceptives

Combined contraceptives are an excellent option as they can be used long-term, are affordable, well-tolerated, easy to use, as well as provide additional benefits of contraception and ovarian and endometrial cancer risk reduction [84]. Estrogen-progestin contraceptives suppress ovarian function causing decidualization and subsequent atrophy of endometrial tissue.

Although, both cyclic and continuous-dose hormonal regimens can be used, two systematic reviews reported that continuous combined oral contraceptive (COC) regimens were more effective at pain reduction than cyclical COC regimens [12, 13, 84].

7.3 Progestins

For women with contra-indications to estrogens, progestin-only therapy is a valid treatment option. The available options are:

  • Norethindrone acetate- Commonly used as 5 mg daily, but can be increased to 15 mg daily depending on side effects including breakthrough bleeding [15].

  • Medroxy-progesterone acetate- Depot MPA can be given as 150 mg intramuscular injection every three months or as a 104 mg subcutaneous injection every three months [23].

  • Dienogest- Prescribed commonly as a 2 mg oral daily pill or combined with estradiol valerate as a multiphasic oral contraceptive pill [24]. Also, available in 1 mg and 4 mg doses.

Progestins act by causing decidualization and atrophy of endometrial tissue and additionally, also, cause suppression of matrix metalloproteinases and inhibition of angiogenesis.

Progestin-only treatment avoids the estrogen-related thromboembolic risk as seen with estrogen-containing contraceptives and also, avoids bone loss seen with GnRH analogues. When compared with danazol, progestins are better tolerated with less impact on lipids and no androgenic side effects. However, progestins have earned a little disrepute as they are known to cause irregular uterine bleeding/spotting, amenorrhea, weight gain, mood changes, and bone loss specifically with long-term use of depot MPA as well as 4 mg dose of dienogest. Additionally, long-term use of norethindrone acetate causes significant reduction in high-density lipoprotein with subsequent increase in low-density lipoprotein, cholesterol and triglycerides necessitating monitoring of lipid levels in patients on long-term therapy [1, 26, 27].

7.4 Levonorgestrel intrauterine device (LNG- IUS)

A review of three trials concluded that the recurrence of dysmenorrhoea in women with surgically confirmed endometriosis reduced with the postoperative use of LNG-IUS significantly [28, 29]. However, irregular menstrual bleeding and amenorrhea were common side effects, with no effect on bone mineral density or lipid levels [30, 31].

7.5 Gonadotropin-releasing hormone agonists/antagonists

7.5.1 Agonist analogues

GnRH agonists include nafarelin, leuprolide, buserelin, goserelin, and triptorelin. A meta-analysis reported that GnRH analogs were more effective than placebo and as effective as other medical therapies (danazol, levonorgestrel, COC) for relieving pain [85]. A trial comparing GnRH agonists treatment, laparoscopy, and combined medical/surgical treatment concluded an equal cure rate of ≥50 percent for all three groups.

Commonly used regimens of GnRH agonists include leuprolide acetate 3.75 mg intramuscular monthly, leuprolide acetate 11.25 mg intramuscular every three months, and intranasal nafarelin acetate 200 mcg given twice daily with the choice being driven by availability and cost [86].

GnRH agonists bind to receptors in the pituitary gland leading to down-regulation of the pituitary-ovarian axis which causes hypoestrogenism, amenorrhea and progressive endometrial atrophy. The hypoestrogenic state is what causes the pain relief but on the flip side also, causes adverse effects, including hot flushes, vaginal dryness, decreased libido, mood swings, headache, and loss of bone density. Add-back therapy, typically with oral norethindrone acetate or a combination of estrogen and progestin (COC pill) diminishes the hypoestrogenic side effects to a great extent [1, 87, 88, 89].

7.5.2 Antagonist

GnRH antagonists suppress the pituitary gonadotropin hormone production causing a hypoestrogenic stat. As antagonists do not cause an initial surge in LH and FSH, unlike agonists, they do not require 7 to 14 days for GnRH suppression. The antagonists elagolix and relugolix are available in oral form [34]. The GnRH antagonists induce a dose-dependent hypoestrogenic state to inhibit endometriotic cell proliferation. Symptom relief and adverse events such as vasomotor phenomena, vaginal atrophy, and bone loss are all dose-dependent.

7.5.3 Elagolix

Available in doses of 150 mg to be taken once daily for up to 24 months (low dose) or 200 mg twice daily for up to six months (high dose). Although, the lower effective dose is preferred, higher dose works better in cases of severe deep dyspareunia. The medication is started within seven days of menses. It is to be noted that low-dose elagolix seemed less effective as compared to GnRH agonist.

Significant reduction in dysmenorrhoea was reported by 44, 74 and 21 percent of women in the high-dose, low dose and placebo groups respectively while non-menstrual pelvic pain was decreased in 50, 56, and 36 percent of women in the low-dose, high-dose and placebo groups respectively.

7.5.4 Adverse events and side effects

Hepatic dysfunction is an absolute contra-indication while the reported side effects include hot flushes or night sweats. Hot flushes were the most common adverse event.

Mean deviation from baseline in lumbar spine bone density, at 6 month interval, were approximately −0.5, −2.6, and + 0.5 percent in the low-dose, high-dose, and placebo groups, respectively.

7.5.5 Relugolix

Can be used as combination therapy (relugolix 40 mg, estradiol 1 mg, and norethisterone acetate 0.5 mg) or as monotherapy (40 mg dose for 12 weeks) followed by combination therapy for 12 weeks.

7.5.6 Relugolix phase-three trial data

Two phase-three, multicenter trials, performed across six continents, compared placebo with relugolix combination therapy (relugolix 40 mg, estradiol 1 mg, and norethisterone acetate 0.5 mg) or delayed relugolix combination therapy (relugolix monotherapy, 40 mg dose for 12 weeks, followed by combination therapy for 12 weeks) in individuals with moderate-to-severe endometriosis-related pain. Across the two trials, compared with the placebo group, more patients receiving relugolix reported reductions in dysmenorrhea (75 percent versus 27 to 30 percent) and less non-menstrual pelvic pain (58 to 66 percent versus 40 to 43 percent) at six months of follow-up. The most common adverse events were headache, nasopharyngitis, and hot flushes. Both treatment groups do cause some loss of bone mineral density but it is insignificant. Data comparing relugolix with established treatments for endometriosis-related pain are lacking.

7.6 Newer GnRH antagonists

7.6.1 Linzagolix

It is a new oral, non-peptide GnRH antagonist under investigation currently. The pharmacokinetics, pharmacodynamic impact on estradiol and safety of this drug have already been studied in a previous trial on healthy female volunteers [90]. In order to study the effect of Linzagolix on endometriosis associated pain (EAP), a multinational, parallel group, randomized, placebo-controlled, double blind was carried out on women aged 18–45 years with surgically proven endometriosis. The interventions examined were 50, 75, 100 or 200 mg linzagolix administered daily for a period of 24 weeks.

Estimated percentages of women with a 30% reduction in overall pelvic pain (OPP) at week 12 were 34.5%, 49.4%, 61.5%, 56.4%, and 56.3% in the placebo, 50 mg, 75 mg, 100 mg, and 200 mg groups, respectively. The differences, as compared with placebo, were significant in the 75 mg (p = .003), 100 mg (P = .039), and 200 mg (P = .034) dose groups but not in the 50 mg dose group (P = .155). There was a significant reduction in dyschezia scores in the 75 mg (P = .002), 100 mg (P = .004), and 200 mg (P = .022) dose groups at 12 weeks. Dyspareunia scores at week 12 decreased significantly compared with placebo in the 200 mg dose group (P=. 023) [91].

7.6.2 ASPI707

ASPI707 is an oral GnRH antagonist currently being investigated for endometriosis- related pain, which it is known to ameliorate by supressing the pituitary-gonadal axis. Phase I studies on healthy young women suggest that it effectively suppresses E2 levels, thereby, reducing endometriosis- related pain. The phase II TERRA study evaluated the efficacy, safety and dose-response relationship of this drug in subjects with endometriosis- associated pelvic pain. This trial was a multinational, multicentre, double-blind, randomized, parallel group, placebo- controlled study conducted in Europe and Japan wherein the eligible subjects were randomized in a ratio of 1:1:1:1:1:1 to placebo, one of four doses of ASPI707 (3,5,10 or 15 mg) or leuprolide acetate (subcutaneous injection 3.75 mg/month) observed over a 24 week treatment period. Compared with placebo, statistically significant differences in the absolute change from baseline in mean NRS were observed for OPP (10 mg, P = 0.011) and dysmenorrhea (3 mg, P = 0.003; 5 mg, P < 0.001; 10 mg, P < 0.001; 15 mg, P < 0.001).

Although, Leuprorelin and all ASP1707 dose groups showed statistically significant reductions in bone marrow density (BMD) from baseline at 24 weeks compared with baseline, the percentage reduction across all ASP1707 dose groups was significantly lower than leuprorelin for total hip (P ≤ 0.017) and spine (P ≤ 0.001). The effect of ASP1707 on the BMD of the spine was lower for the 10-mg dose group compared with the 15-mg dose group [92].

7.6.3 Danazol

Danazol is a 17 alpha-ethinyl testosterone derivative that inhibits steroidogenesis, luteinizing hormone surge and increases free testosterone levels. It primarily acts by inhibiting pituitary gonadotropin secretion, directly inhibiting ovarian enzymes secretion and thereby, curbing growth of endometriotic implants.

It is highly effective at treating endometriosis-related pain, with various studies validating that six months of danazol treatment was more effective than placebo in relieving endometriosis-related pain and that the effect persisted even six months after discontinuation of therapy. However, the unwelcome side effects, including acne, muscle cramps, oedema, weight gain of up to 5 percent of body weight, spotting, hirsutism, and voice deepening have limited the use of danazol. Danazol is typically given orally in divided doses ranging from 400 to 800 mg daily, generally for six months. One systematic review reported symptom relief with vaginal danazol, particularly for cases with rectovaginal endometriosis [38, 39, 40, 41, 42].

7.6.4 Aromatase inhibitors

Endometriosis treatment is an off-label use of these medications. It is usually reserved for women with severe, refractory, endometriosis-related pain. AIs are often used in combination with progestins. Typical treatments include oral anastrozole 1 mg once daily or oral letrozole 2.5 mg once daily, usually in combination with progestins. These act by regulating local estrogen formation within the endometriotic lesions, in addition to inhibiting estrogen production in the ovary, brain, and peripheral tissues (eg, adipose tissue) [40].

A systematic review concluded that AI treatment, with or without progestin, COC, or GnRH analogue, significantly reduced pain compared with GnRH analogue alone. An RCT comparing six months of post-operative goserelin plus anastrozole with goserelin alone in severe endometriosis cases reported longer time to symptom recurrence with combination therapy but equal quality-of-life and bone mass outcomes between the groups [44].

Side effects of prolonged AIs use include bone loss and ovarian follicular cyst development. It is therefore, prescribed in combination with a GnRH analogue or an oral estrogen-progestin contraceptive or oral norethindrone acetate 5 mg alone to suppress follicular development.

Advertisement

8. Surgical treatment

Surgical treatment is reserved for cases wherein the medical treatment has either failed or the symptoms have re-surfaced. Surgical resection, besides pain relief, provides tissue for histological diagnosis [1]. However, endometriosis surgery involves substantial risk of injury to the bowel and bladder, possible reduction of ovarian reserve in case of endometriomas and post-operative adhesion formation, in addition to the common surgical risks.

8.1 Surgical resection

Surgical resection may either be conservative involving targeted ablation or resection of visible lesions, or definitive involving hysterectomy with or without oophorectomy in addition to resection of endometriosis or radical that involves removal of all visible implants.

8.2 Nerve transection

Includes laparoscopic uterosacral nerve ablation (LUNA) and presacral neurectomy (PSN). The available data suggests that LUNA is ineffective. Although, PSN may be effective for midline pain, but the success of this procedure depends largely on the experience of the surgeon, and it’s long-term efficacy remains questionable [1].

Advertisement

9. Special populations

9.1 Infertility

The treatment of infertility associated with endometriosis involves a combination of surgery and assisted reproduction technology. Hormonal therapies, alone, are not offered as they prevent pregnancy and do not improve fertility.

9.2 Endometrioma

Endometriomas are managed to relieve pain, exclude malignancy, improve subfertility, and preserve ovarian function. Symptomatic or expanding endometriomas are removed laparoscopically, which is known to diminish ovarian reserve [45, 46]. It is a wise clinical practice to not operate on asymptomatic and small endometriomas ≤5 cm.

9.3 Deep endometriosis

The management of rectovaginal or bowel endometriosis is guided by the symptomatology, location of lesions, and patient expectation of the treatment. For women with bothersome urinary or bowel symptoms such as urinary urgency or frequency, dyspareunia, dysmenorrhea, or dyschezia, hormonal suppression is appropriate [49]. Surgery is better preserved for women with ureteral or bowel obstruction or women whose symptoms do not improve with medical management [3].

9.4 Lesions of nonreproductive organs

Endometriosis has been reported at distant locations like upper abdomen, diaphragm, abdominal wall (umbilicus, surgical scar), perineum (episiotomy or obstetric scar), and thorax [3]. Complications such as pneumothorax are treated as indicated.

Typically, ovarian suppression with gonadotropin-releasing hormone (GnRH) analogues is the first line of treatment since, they effectively suppress ovarian hormone production and also, inhibit the growth of endometrial tissue [50, 51, 52, 53, 54, 55, 56, 57, 58].

Advertisement

10. Complementary therapies

10.1 Acupuncture

Acupuncture may serve as a complement or alternative to the treatment modalities mentioned. Acupuncture is believed to alleviate pain by means of various physiological and psychological processes, such as activation of endogenous descending pain inhibitory systems, deactivation of brain areas that transmit pain-related signals, interaction between nociceptive impulses and somato-visceral reflexes, and the expectation of symptom relief [93, 94].

Various studies have demonstrated that acupuncture can reduce the level of serum CA-125, thereby, relieving the pelvic pain associated with endometriosis [95, 96, 97, 98]. In a trial on 67 participants, auricular acupuncture was found to be significantly more effective than Chinese herbal medicine for treating dysmenorrhea in women with endometriosis [59, 60]. Current literature consistently finds that acupuncture yields better reductions in pain and serum CA-125 levels than do control treatments, regardless of the control intervention used. To confirm this finding, additional studies with proper controls, blinding methods, and adequate sample sizes are needed.

10.2 Diet

Endometriosis, as we all know, is a multifactorial pathology with a concomitant inflammatory pattern. Although, high level evidence and well-designed randomized studies on the impact of modifiable risk factors on endometriosis are lacking, certain studies have suggested that fish oil may have a positive effect on reducing endometriosis related pain. This may be due the anti-inflammatory prostaglandins PGE3 and PGE3 which are derivatives of omega-3 fatty acids. Similarly, antioxidants vitamins C, D and E are also, seen to alleviate endometriosis symptoms of pain [99].

One study reported that higher intake of green vegetables and fruit reduced the risk of developing endometriosis while higher intake of beef or other red meat increased the endometriosis risk [61]. Several studies have addressed the correlation of diet and dysmenorrhea, but not exclusively in patients with endometriosis. There is also evidence that the adaptation of individualized dietary changes yields statistically significant improvements in endometriosis-related symptoms [100]. Thus, there may be great benefit to including a dietician in the management of these patients, especially at younger ages and in early stages.

11. Conclusion

Endometriosis is a pathology that is known to affect women of all age groups including pre-menarcheal as well as post-menopausal. It can have an array of presentations from asymptomatic to subfertility to incapacitating symptoms. The management of endometriosis includes mainly medical treatment while surgical management is preserved for those who fail to respond to medical management or require correction of tubo-ovarian disarray.

12. Summary and recommendations

  1. Pelvic endometriosis can be categorized as superficial peritoneal, ovarian and deep depending upon the size and depth of the lesions.

  2. Globally, ten percent of reproductive age group women have endometriosis but the prevalence may vary as per clinical population.

  3. The pathogenesis appears to be multifactorial including ectopic endometrial tissue, altered immunity, imbalanced cell proliferation and apoptosis, aberrant endocrine signaling, and genetic factors.

  4. Endometriosis is staged at the time of surgery and most commonly the American Society for Reproductive Medicine scoring is used.

  5. It is associated with reduced fertility, poor obstetrical outcomes, epithelial ovarian cancer especially clear cell carcinoma and endometroid ovarian cancer and also, atherosclerosis.

  6. In general, the management of endometriosis depends upon patients’ symptomatology and their expectation of the same.

  7. Surgical treatment is only preserved for cases of failed medical management and those requiring repair of tubo-ovarian architecture.

References

  1. 1. International working group of AAGL, ESGE, ESHRE and WES, Tomassetti C, Johnson NP, et al. An international terminology for endometriosis, 2021. Journal of Minimally Invasive Gynecology. 2021;28:1849
  2. 2. Vercellini P, Viganò P, Somigliana E, Fedele L. Endometriosis: Pathogenesis and treatment. Nature Reviews. Endocrinology. 2014;10:261
  3. 3. Clement PB. The pathology of endometriosis: A survey of the many faces of a common disease emphasizing diagnostic pitfalls and unusual and newly appreciated aspects. Advances in Anatomic Pathology. 2007;14:241
  4. 4. Muzii L, Bianchi A, Bellati F, et al. Histologic analysis of endometriomas: What the surgeon needs to know. Fertility and Sterility. 2007;87:362
  5. 5. De Cicco C, Corona R, Schonman R, et al. Bowel resection for deep endometriosis: A systematic review. BJOG. 2011;118:285
  6. 6. Audebert A, Petousis S, Margioula-Siarkou C, et al. Anatomic distribution of endometriosis: A reappraisal based on series of 1101 patients. European Journal of Obstetrics, Gynecology, and Reproductive Biology. 2018;230:36
  7. 7. Victory R, Diamond MP, Johns DA. Villar’s nodule: A case report and systematic literature review of endometriosis externa of the umbilicus. Journal of Minimally Invasive Gynecology. 2007;14:23
  8. 8. Jaime TJ, Jaime TJ, Ormiga P, et al. Umbilical endometriosis: Report of a case and its dermoscopic features. Anais Brasileiros de Dermatologia. 2013;88:121
  9. 9. Lee HJ, Park YM, Jee BC, et al. Various anatomic locations of surgically proven endometriosis: A single-center experience. Obstetrics & Gynecology Science. 2015;58:53
  10. 10. Minaglia S, Mishell DR Jr, Ballard CA. Incisional endometriomas after cesarean section: A case series. The Journal of Reproductive Medicine. 2007;52:630
  11. 11. Horton JD, Dezee KJ, Ahnfeldt EP, Wagner M. Abdominal wall endometriosis: A surgeon’s perspective and review of 445 cases. American Journal of Surgery. 2008;196:207
  12. 12. Morales Martínez C, Tejuca SS. Abdominal wall endometriosis. American Journal of Obstetrics and Gynecology. 2017;217:701
  13. 13. Canlorbe G, Laas E, Cortez A, Daraï E. Spontaneous hymeneal endometriosis: A rare cause of dyspareunia. BMJ Case Reports. 2014:1-2. DOI: 10.1136/bcr-2013-202299
  14. 14. Abrao MS, Andres MP, Miller CE, et al. AAGL 2021 endometriosis classification: An anatomy-based surgical complexity score. Journal of Minimally Invasive Gynecology. 2021;28:1941
  15. 15. Keckstein J, Saridogan E, Ulrich UA, et al. The #Enzian classification: A comprehensive non-invasive and surgical description system for endometriosis. Acta Obstetricia et Gynecologica Scandinavica. 2021;100:1165
  16. 16. Duffy JM, Arambage K, Correa FJ, et al. Laparoscopic surgery for endometriosis. Cochrane Database of Systematic Reviews. 2014;4:CD011031
  17. 17. Dunselman GAJ et al. ESHRE guideline: Management of women with endometriosis. 29(3):400-412. Available from: https://www.eshre.eu/Guidelines-and-Legal/Guidelines/Endometriosis-guideline
  18. 18. Stegmann BJ, Sinaii N, Liu S, et al. Using location, color, size, and depth to characterize and identify endometriosis lesions in a cohort of 133 women. Fertility and Sterility. 2008;89:1632
  19. 19. Fernando S, Soh PQ, Cooper M, et al. Reliability of visual diagnosis of endometriosis. Journal of Minimally Invasive Gynecology. 2013;20:783
  20. 20. Almeida Filho DP, Oliveira LJ, Amaral VF. Accuracy of laparoscopy for assessing patients with endometriosis. São Paulo Medical Journal. 2008;126:305
  21. 21. Wykes CB, Clark TJ, Khan KS. Accuracy of laparoscopy in the diagnosis of endometriosis: A systematic quantitative review. BJOG. 2004;111:1204
  22. 22. Rahmioglu N, Nyholt DR, Morris AP, et al. Genetic variants underlying risk of endometriosis: Insights from meta-analysis of eight genome-wide association and replication datasets. Human Reproduction Update. 2014;20:702
  23. 23. Anglesio MS, Papadopoulos N, Ayhan A, et al. Cancer-associated mutations in endometriosis without cancer. The New England Journal of Medicine. 2017;376:1835
  24. 24. Bulun SE, Wan Y, Matei D. Epithelial mutations in endometriosis: Link to ovarian cancer. Endocrinology. 2019;160:626
  25. 25. Sampson JA. Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue into the peritoneal cavity. American Journal of Obstetrics and Gynecology. 1927;14:422
  26. 26. Olive DL, Henderson DY. Endometriosis and mullerian anomalies. Obstetrics and Gynecology. 1987;69:412
  27. 27. Dovey S, Sanfilippo J. Endometriosis and the adolescent. Clinical Obstetrics and Gynecology. 2010;53:420
  28. 28. Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertility and Sterility. 2012;98:511
  29. 29. Du H, Taylor HS. Contribution of bone marrow-derived stem cells to endometrium and endometriosis. Stem Cells. 2007;25:2082
  30. 30. Gruenwald P. Origin of endometriosis from the mesenchyme of the celomic walls. American Journal of Obstetrics and Gynecology. 1942;44:470
  31. 31. Marsh EE, Laufer MR. Endometriosis in premenarcheal girls who do not have an associated obstructive anomaly. Fertility and Sterility. 2005;83:758
  32. 32. Oliveira FR, Dela Cruz C, Del Puerto HL, et al. Stem cells: Are they the answer to the puzzling etiology of endometriosis? Histology and Histopathology. 2012;27:23
  33. 33. Figueira PG, Abrão MS, Krikun G, Taylor HS. Stem cells in endometrium and their role in the pathogenesis of endometriosis. Annals of the New York Academy of Sciences. 2011;1221:10
  34. 34. McKinnon BD, Bertschi D, Bersinger NA, Mueller MD. Inflammation and nerve fiber interaction in endometriotic pain. Trends in Endocrinology and Metabolism. 2015;26:1
  35. 35. Arnold J, Barcena de Arellano ML, Rüster C, et al. Imbalance between sympathetic and sensory innervation in peritoneal endometriosis. Brain, Behavior, and Immunity. 2012;26:132
  36. 36. Arnold J, Vercellino GF, Chiantera V, et al. Neuroimmunomodulatory alterations in non-lesional peritoneum close to peritoneal endometriosis. Neuroimmunomodulation. 2013;20:9
  37. 37. Liang Y, Yao S. Potential role of estrogen in maintaining the imbalanced sympathetic and sensory innervation in endometriosis. Molecular and Cellular Endocrinology. 2016;424:42
  38. 38. Wheeler MA, Heffner DL, Kim S, et al. TNF-α/TNFR1 signaling is required for the development and function of primary nociceptors. Neuron. 2014;82:587
  39. 39. As-Sanie S, Harris RE, Napadow V, et al. Changes in regional gray matter volume in women with chronic pelvic pain: A voxel-based morphometry study. Pain. 2012;153:1006
  40. 40. Hickey M, Ballard K, Farquhar C. Endometriosis. BMJ. 2014;348:g1752
  41. 41. old Shafrir AL, Farland LV, Shah DK, et al. Risk for and consequences of endometriosis: A critical epidemiologic review. Best Practice & Research. Clinical Obstetrics & Gynaecology. 2018;51:1
  42. 42. Soliman AM, Surrey E, Bonafede M, et al. Real-world evaluation of direct and indirect economic burden among endometriosis patients in the United States. Advances in Therapy. 2018;35:408
  43. 43. Falcone T, Flyckt R. Clinical Management of Endometriosis. Obstetrics and Gynecology. 2018;131:557
  44. 44. Ballard KD, Seaman HE, de Vries CS, Wright JT. Can symptomatology help in the diagnosis of endometriosis? Findings from a national case-control study--part 1. BJOG. 2008;115:1382
  45. 45. Hediger ML, Hartnett HJ, Louis GM. Association of endometriosis with body size and figure. Fertility and Sterility. 2005;84:1366
  46. 46. Sinaii N, Plumb K, Cotton L, et al. Differences in characteristics among 1,000 women with endometriosis based on extent of disease. Fertility and Sterility. 2008;89:538
  47. 47. Giudice LC. Clinical practice. Endometriosis. The New England Journal of Medicine. 2010;362:2389
  48. 48. Treloar SA, Bell TA, Nagle CM, et al. Early menstrual characteristics associated with subsequent diagnosis of endometriosis. American Journal of Obstetrics and Gynecology. 2010;202:534.e1
  49. 49. Nnoaham KE, Webster P, Kumbang J, et al. Is early age at menarche a risk factor for endometriosis? A systematic review and meta-analysis of case-control studies. Fertility and Sterility. 2012;98:702
  50. 50. Benagiano G, Brosens I. In utero exposure and endometriosis. The Journal of Maternal-Fetal & Neonatal Medicine. 2014;27:303
  51. 51. Farland LV, Missmer SA, Bijon A, et al. Associations among body size across the life course, adult height and endometriosis. Human Reproduction. 2017;32:1732
  52. 52. Parazzini F, Cipriani S, Bianchi S, et al. Risk factors for deep endometriosis: A comparison with pelvic and ovarian endometriosis. Fertility and Sterility. 2008;90:174
  53. 53. Farland LV, Eliassen AH, Tamimi RM, et al. History of breast feeding and risk of incident endometriosis: Prospective cohort study. BMJ. 2017;358:j3778
  54. 54. Pisanu A, Deplano D, Angioni S, et al. Rectal perforation from endometriosis in pregnancy: Case report and literature review. World Journal of Gastroenterology. 2010;16:648
  55. 55. Brosens IA, Fusi L, Brosens JJ. Endometriosis is a risk factor for spontaneous hemoperitoneum during pregnancy. Fertility and Sterility. 2009;92:1243
  56. 56. Brosens IA, Lier MC, Mijatovic V, et al. Severe spontaneous hemoperitoneum in pregnancy may be linked to in vitro fertilization in patients with endometriosis: A systematic review. Fertility and Sterility. 2016;106:692
  57. 57. Lier M, Malik RF, van Waesberghe J, et al. Spontaneous haemoperitoneum in pregnancy and endometriosis: A case series. BJOG. 2017;124:306
  58. 58. Lier MCI, Malik RF, Ket JCF, et al. Spontaneous hemoperitoneum in pregnancy (SHiP) and endometriosis - a systematic review of the recent literature. European Journal of Obstetrics, Gynecology, and Reproductive Biology. 2017;219:57
  59. 59. Chiodo I, Somigliana E, Dousset B, Chapron C. Urohemoperitoneum during pregnancy with consequent fetal death in a patient with deep endometriosis. Journal of Minimally Invasive Gynecology. 2008;15:202
  60. 60. Leone Roberti Maggiore U, Remorgida V, Sala P, et al. Spontaneous Uroperitoneum and preterm delivery in a patient with bladder endometriosis. Journal of Minimally Invasive Gynecology. 2015;22:923
  61. 61. Faucheron JL, Pasquier D, Voirin D. Endometriosis of the vermiform appendix as an exceptional cause of acute perforated appendicitis during pregnancy. Colorectal Disease. 2008;10:518
  62. 62. Murphy SJ, Kaur A, Wullschleger ME. Endometrial decidualization: A rare cause of acute appendicitis during pregnancy. Journal of Surgery Case Reports. 2016;2016(4):1-3
  63. 63. Leone Roberti Maggiore U, Ferrero S, Mangili G, et al. A systematic review on endometriosis during pregnancy: Diagnosis, misdiagnosis, complications and outcomes. Human Reproduction Update. 2016;22:70
  64. 64. Glavind MT, Forman A, Arendt LH, et al. Endometriosis and pregnancy complications: A Danish cohort study. Fertility and Sterility. 2017;107:160
  65. 65. Saraswat L, Ayansina DT, Cooper KG, et al. Pregnancy outcomes in women with endometriosis: A national record linkage study. BJOG. 2017;124:444
  66. 66. Stephansson O, Kieler H, Granath F, Falconer H. Endometriosis, assisted reproduction technology, and risk of adverse pregnancy outcome. Human Reproduction. 2009;24:2341
  67. 67. Fernando S, Breheny S, Jaques AM, et al. Preterm birth, ovarian endometriomata, and assisted reproduction technologies. Fertility and Sterility. 2009;91:325
  68. 68. Santulli P, Marcellin L, Menard S, et al. Increased rate of spontaneous miscarriages in endometriosis-affected women. Human Reproduction. 2016;31:1014
  69. 69. Exacoustos C, Lauriola I, Lazzeri L, et al. Complications during pregnancy and delivery in women with untreated rectovaginal deep infiltrating endometriosis. Fertility and Sterility. 2016;106:1129
  70. 70. Bruun MR, Arendt LH, Forman A, Ramlau-Hansen CH. Endometriosis and adenomyosis are associated with increased risk of preterm delivery and a small-for-gestational-age child: A systematic review and meta-analysis. Acta Obstetricia et Gynecologica Scandinavica. 2018;97:1073
  71. 71. Farland LV, Stern JE, Liu CL, et al. Pregnancy outcomes among women with endometriosis and fibroids: Registry linkage study in Massachusetts. American Journal of Obstetrics and Gynecology. 2022;226:829.e1
  72. 72. Marcellin L, Goffinet F, Azria E, et al. Association between endometriosis phenotype and preterm birth in France. JAMA Network Open. 2022;5:e2147788
  73. 73. Lalani S, Choudhry AJ, Firth B, et al. Endometriosis and adverse maternal, fetal and neonatal outcomes, a systematic review and meta-analysis. Human Reproduction. 2018;33:1854
  74. 74. ESHRE Guideline Endometriosis. European Society of Human Reproduction and Embryology. 2022. https://www.eshre.eu/Guidelines-and-Legal/Guidelines/Endometriosis-guideline [Accessed: February 18, 2022]
  75. 75. Attar E, Bulun SE. Aromatase and other steroidogenic genes in endometriosis: Translational aspects. Human Reproduction Update. 2006;12:49
  76. 76. Saavalainen L, Lassus H, But A, et al. Risk of gynecologic cancer according to the type of endometriosis. Obstetrics and Gynecology. 2018;131:1095
  77. 77. Oxholm D, Knudsen UB, Kryger-Baggesen N, Ravn P. Postmenopausal endometriosis. Acta Obstetricia et Gynecologica Scandinavica. 2007;86:1158
  78. 78. Van Gorp T, Amant F, Neven P, et al. Endometriosis and the development of malignant tumours of the pelvis. A review of literature. Best Practice & Research. Clinical Obstetrics & Gynaecology. 2004;18:349
  79. 79. Pearce CL, Templeman C, Rossing MA, et al. Association between endometriosis and risk of histological subtypes of ovarian cancer: A pooled analysis of case-control studies. The Lancet Oncology. 2012;13:385
  80. 80. Orezzoli JP, Russell AH, Oliva E, et al. Prognostic implication of endometriosis in clear cell carcinoma of the ovary. Gynecologic Oncology. 2008;110:336
  81. 81. Grandi G, Toss A, Cortesi L, et al. The association between Endometriomas and ovarian cancer: Preventive effect of inhibiting ovulation and menstruation during reproductive life. BioMed Research International. 2015;2015:751571
  82. 82. Mu F, Rich-Edwards J, Rimm EB, et al. Endometriosis and risk of coronary heart disease. Circulation. Cardiovascular Quality and Outcomes. 2016;9:257
  83. 83. Okoth K, Wang J, Zemedikun D, et al. Risk of cardiovascular outcomes among women with endometriosis in the United Kingdom: A retrospective matched cohort study. BJOG. 2021;128:1598
  84. 84. Gustofson RL, Kim N, Liu S, Stratton P. Endometriosis and the appendix: A case series and comprehensive review of the literature. Fertility and Sterility. 2006;86:298
  85. 85. Brosens I, Puttemans P, Benagiano G. Endometriosis: A life cycle approach? American Journal of Obstetrics and Gynecology. 2013;209:307
  86. 86. Wang G, Tokushige N, Markham R, Fraser IS. Rich innervation of deep infiltrating endometriosis. Human Reproduction. 2009;24:827
  87. 87. Tran LV, Tokushige N, Berbic M, et al. Macrophages and nerve fibres in peritoneal endometriosis. Human Reproduction. 2009;24:835
  88. 88. Matsuzaki S, Darcha C. Involvement of the Wnt/β-catenin signaling pathway in the cellular and molecular mechanisms of fibrosis in endometriosis. PLoS One. 2013;8:e76808
  89. 89. Adamson GD, Kennedy S, Hummelshoj L. Creating solutions in endometriosis: Global collaboration through the world endometriosis research foundation. Journal of Endometriosis. 2010;2:3-6
  90. 90. Pohl O, Marchand L, Fawkes N, Gotteland JP, Loumaye E. Gonadotropinreleasing hormone receptor antagonist mono- and combination therapy with estradiol/norethindrone acetate add-back: Pharmacodynamics and safety of OBE2109. The Journal of Clinical Endocrinology and Metabolism. 2018;103:497-504
  91. 91. Donnez J, Taylor HS, Taylor RN, et al. Treatment of endometriosis-associated pain with linzagolix, an oral gonadotropin-releasing hormone-antagonist: A randomized clinical trial. Fertility and Sterility. 2020;114(1):44-55
  92. 92. D’Hooghe T, Fukaya T, Osuga Y, et al. Efficacy and safety of ASP1707 for endometriosis-associated pelvic pain: The phase II randomized controlled TERRA study. Human Reproduction. 2019;34(5):813-823
  93. 93. Hui KK, Liu J, Marina O, Napadow V, Haselgrove C, Kwong KK, et al. The integrated response of the human cerebro-cerebellar and limbic systems to acupuncture stimulation at ST 36 as evidenced by fMRI. NeuroImage. 2005;27(3):479-496. DOI: 10.1016/j.neuroimage.2005.04.037
  94. 94. Chen S, Wang S, Rong P, Wang J, Qiao L, Feng X, et al. Acupuncture for visceral pain: Neural substrates and potential mechanisms. Evidence-based Complementary and Alternative Medicine. 2014;2014:609594. DOI: 10.1155/2014/609594
  95. 95. Sun YZ, Chen HL. Controlled study on Shu-Mu point combination for treatment of endometriosis. Zhongguo Zhen Jiu. 2006;26(12):863-865 Chinese
  96. 96. Xiang DF, Sun QZ, Liang XF. Effect of abdominal acupuncture on pain of pelvic cavity in patients with endometriosis. Zhongguo Zhen Jiu. 2011;31(2):113-116 Chinese
  97. 97. Xu Y, Zhao W, Li T, Zhao Y, Bu H, Song S. Effects of acupuncture for the treatment of endometriosis-related pain: A systematic review and meta-analysis. PLoS ONE. 2017;12(10):e0186616. DOI: 10.1371/journal.pone.0186616
  98. 98. Zhang XX, Li W. Efficacy on endometriosis treated with electroacupuncture. Zhongguo Zhen Jiu. 2015;35(4):323-326 Chinese
  99. 99. Habib N, Buzzaccarini G, Centini G, Moawad GN, Ceccaldi PF, Gitas G, et al. Impact of lifestyle and diet on endometriosis: A freshlook to a busy corner. Menopause Review/Przegląd Menopauzalny. 2022;21(2):124-132
  100. 100. Karlsson JV, Patel H, Premberg A. Experiences of health after dietary changes in endometriosis: A qualitative review study. BMJ Open. 2020;10:e032321

Written By

Shikha Sharma and Akanksha Tripathi

Submitted: 01 October 2022 Reviewed: 26 October 2022 Published: 02 December 2022