Open access peer-reviewed chapter - ONLINE FIRST
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
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.
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
Evaluation of incapacitating pain or other symptoms
Persistent pelvic not responding to medical therapy
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.
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].
3.3 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.
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.
4.5 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].
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].
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
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.
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
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.
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].
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].
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
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
Pelvic endometriosis can be categorized as superficial peritoneal, ovarian and deep depending upon the size and depth of the lesions.
Globally, ten percent of reproductive age group women have endometriosis but the prevalence may vary as per clinical population.
The pathogenesis appears to be multifactorial including ectopic endometrial tissue, altered immunity, imbalanced cell proliferation and apoptosis, aberrant endocrine signaling, and genetic factors.
Endometriosis is staged at the time of surgery and most commonly the American Society for Reproductive Medicine scoring is used.
It is associated with reduced fertility, poor obstetrical outcomes, epithelial ovarian cancer especially clear cell carcinoma and endometroid ovarian cancer and also, atherosclerosis.
In general, the management of endometriosis depends upon patients’ symptomatology and their expectation of the same.
Surgical treatment is only preserved for cases of failed medical management and those requiring repair of tubo-ovarian architecture.
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