Endometriosis is the appearance of endometrial glands or mesenchyme outside the uterus. It is considered one of the difficult gynecological conditions due to its insidious onset, often causing pelvic pain and infertility, and its invasive nature.
Endometriosis is a chronic disease that affects at least 10% of women of childbearing age, accounts for approximately 40% of infertility cases, and presents with pelvic pain in 90% of women.
Risk factors include family history, low body mass index, alcohol consumption, smoking, especially in infertility, Caucasian ethnicity, prolonged estrogen exposure (e.g., early menarche or late menopause) and nutritional/environmental factors.
The most typical triad of endometriosis is dysmenorrhea, painful intercourse and difficulty in defecation. The diagnosis of endometriosis is difficult due to a number of other obstetric or non-obstetric conditions that can also cause pelvic pain and the limitations of the pelvic examination in detecting endometriosis.
In addition, many endometriosis do not present with appropriate symptoms, so the available staging systems are very limited in their application. Finally, endometriosis can be diagnosed surgically.
Little is known about the pathophysiology of endometriosis. Various theories have been proposed for its development, including retrograde flow of menstrual blood, epithelial metaplasia of the corpora cavernosa, and lymphovascular or hematologic dissemination.
More recently, the pathogenesis of endometriosis has involved stem cells, but to date there is still no single theory that can fully explain all clinical symptoms and disease features.
Different pathophysiological mechanisms have been proposed that may help explain the different endometriosis manifestations, including peritoneal endometriosis, deep infiltrative endometriosis (DIE), endometrioma and adenomyosis.
Although uncommon, endometriosis can also occur outside the pelvic cavity, such as pleural, nasal, intrahepatic, transverse septal and abdominal wall endometriosis.
With regard to abdominal wall endometriosis, the most common type of extra-pelvic endometriosis, this type of endometriosis does not necessarily produce cyclic pain, but a mass can develop on the abdominal wall, most often in the location of a past incision. Usually menstrual symptoms should be noted.
Pharmacological and surgical treatments are the mainstays of endometriosis treatment, with different methods used depending on the clinical manifestations of the disease and the characteristics of the patient. Because the intrinsic mechanism of action of drug therapy is the suppression of ovarian function, drug therapy is usually used less frequently in women with a strong desire to have children.
If surgical treatment is not preferred, then assisted reproductive techniques can help overcome the adverse effects of pharmacological treatment. This review focuses on current treatment strategies for endometriosis pain and infertility.
1. Endometriosis and pain
As mentioned above, most women with endometriosis have chronic and cyclic pelvic pain and therefore a differential diagnosis of pelvic pain needs to be considered.
Endometriosis has a variety of clinical manifestations, including endometrial adenomyoma, adenomyosis, clear vesicles, black or red nodular lesions, and “burning” lesions on the typical peritoneal or plasma surface, all of which can cause pain due to different mechanisms.
Pain may be due to periodic bleeding of ectopic endometrial tissue, inflammatory mediators such as cytokines and nerve irritation. The most severe pain is associated with deep peritoneal (>6 mm) invasion, as in DIE. in addition, inflammation from endometriosis leading to pelvic adhesions can also lead to pelvic pain.
2. Drug treatment of endometriosis
The mechanism of pharmacological treatment of endometriosis is to inhibit endometriosis by controlling the endogenous hormonal environment, because estrogen stimulation can lead to the development and progression of endometriosis, and both estrogen and progesterone receptors are found in ectopic endometrial tissue. Although pain and the progression of endometriosis can be controlled, side effects of drug therapy result.
Non-hormonal treatments, such as NSAIDs, can be helpful in the treatment of primary dysmenorrhea; however, they have little effect in improving the pain caused by endometriosis.
The use of narcotics for the treatment of pain caused by endometriosis has not been completely resolved, but it is worth noting that chronic pelvic pain caused by endometriosis requires a multidisciplinary approach, and sometimes narcotics are indicated only for long-term control of symptoms or temporary pain control in the perioperative period.
The effective hormonal therapy discussed later has similar efficacy. It should be noted, however, that the placebo effect of pelvic pain treatment accounts for approximately 40% and should be taken into account as a factor in evaluating the success of treatment. Effective pharmacologic treatments for pelvic pain in endometriosis are as follows.
① Combination hormonal contraceptives
Hormonal contraceptives including ethinyl estradiol (EE) and progesterone can be used in the treatment of cyclic or persistent endometriosis. Continued use appears to result in better pain control, and this regimen may bring combination hormonal contraceptives (CHCs) closer to gonadotropin-releasing hormone (GnRH) analogs, which may also lead to amenorrhea.
Although direct controlled studies on CHCs and GnRH analogs are lacking, cyclic CHC use is better than GnRH for intercourse pain and cyclic pelvic pain by comparison.
CHCs estrogen progesterone is the preferred regimen for endometriosis, but newer generation progesterone has also shown better efficacy. Low-dose EE pill therapy is advocated because of the known proliferative effects of estrogen in endometriosis. However, EE enhances the anti-proliferative effect of progesterone by reducing progesterone receptor expression.
The optimal EE therapeutic dose in CHC is not yet determined, therefore the choice of CHC should be based on its side effects and the patient’s own characteristics, such as age, physical condition, whether he/she smokes and family history.
The progesterone component of CHC exerts an anti-endometrial effect by causing metaplasia and thus atrophy of endometrial tissue, and there may be other mechanisms of action, including inhibition of metalloproteinases that promote invasion of ectopic endometrial tissue and anti-angiogenic effects.
②Progesterone contraceptives
Either long-acting or short-acting progesterone is effective in the treatment of endometriosis. Long- and short-acting progestins include daily or long-acting medroxyprogesterone acetate (MPA), etogestrel implants and other norethindrone derivatives such as norethindrone and levonorgestrel.
As for the latter, the levonorgestrel intrauterine extended-release system (LNG-IUS) represents the creation of a new type of therapy for endometriosis, which minimizes systemic side effects due to its usually its local action.
Typical side effects of progesterone contraceptives include abnormal bleeding, weight gain and mood disorders. However, pain is reduced by 70-100% and, as a result, patients are satisfied and have better compliance. Continued use mainly increases the incidence of amenorrhea and may allow pain to be controlled.
LNG-IUS
Data from several recent trials suggest that LNG-IUS may be used as first-line therapy for the pharmacological treatment of endometriosis and may control postoperative recurrence.
In particular, a randomized controlled trial of LNG-IUS and a GnRH analogue found similar efficacy in the control of endometriosis-induced pain. lNG-IUS also has beneficial effects on lipid metabolism, with reduced total and LDL levels and unchanged HDL levels.
LNG-IUS was also used in rectovaginal endometriosis and adenomyosis, with significant improvement in painful intercourse, bleeding and pain. Although LNG-IUS only inhibits ovulation in the first trimester by 25-50%, it can however prevent recurrence of endometriosis after surgical treatment.
The underlying mechanisms are atrophy of the in situ endometrium, reduction of menstrual blood reflux, and higher local concentrations of levonorgestrel in the peritoneal cavity, which acts as a direct inhibitor of endometrioma.
Studies are limited, but some data suggest the use of etonogestrel implants for the treatment of dysmenorrhea, a painful condition associated with endometriosis, is more effective.
A recent randomized controlled trial showed a significant 68% reduction in pain after six months with etogestrel implants compared to the MPA group (54% in the MPA group). Patient satisfaction was 60% in both groups. Although similar to MPA, a common side effect of etoprogesterone was penetrating bleeding.
Other progestins and antiprogestins
Multiple studies have shown that progesterone denogestrel improves pelvic pain due to endometriosis, with lasting effectiveness after 6 months of discontinuation of the drug. In addition, late in life denogestrel is a norethindrone derivative, but without the common side effects of androgens.
Unfortunately, although denogestrel is widely used in Europe, Australia and Japan, it is not available in the United States. Similarly, antiprogestins and mifepristone are not approved for use, but this represents a potential pharmacological treatment.
(iii) Gonadotropin-releasing hormone agonists
Despite the significant side effects of low estrogen symptoms, gonadotropin-releasing hormone agonist (GnRHa) therapy (vascular injection or nasal spray) remains the mainstay of treatment for endometriosis.
Large meta-analyses have shown that GnRHa improves endometriosis-associated pain by approximately 60-100%. GnRHa can be used empirically in the treatment of suspected endometriosis or to delay postoperative recurrence of the disease.
Reverse addition therapy is used to minimize bone loss and to help control other side effects due to low estrogen, such as hot flashes and vaginal dryness, and can be added after GnRHa therapy is started. Without reverse addition therapy, bone loss is about 13% after 6 months of GnRHa treatment.
Although the FDA only approved the addition of ethinyl acetate to reverse addition therapy, low-dose estrogen or low-dose estrogen and progesterone combinations can be used at the lowest threshold of stimulation for endometriosis.
Compared to GnRHa, injectable GnRH antagonists can act rapidly on the hypothalamic pituitary ovarian axis for the treatment of endometriosis; however, data are limited and the drugs used for long-term ovarian suppression are realistically cost prohibitive.
Although not yet in clinical use, oral GnRH antagonists may hold promise as a treatment for endometriosis-associated pain with minimal bone loss side effects.
④Aromatase inhibitors
Aromatase inhibitors are rate-limiting enzymes for estrogen biosynthesis and therefore may be effective in the treatment of pelvic pain due to endometriosis. Aromatase inhibitors are as effective as GnRH in the treatment of endometriosis.
They must be used along with ovarian suppression in premenopausal women, as it is uncertain whether ovulation induction is a side effect. Aromatase inhibitors can be used to treat endometriosis in menopausal women.
Limitations of aromatase inhibitors include negative effects on bone, out-of-indication applications, and unknown long-term effects. the combined use of CHCs and aromatase inhibitors may eliminate bone loss in premenopausal women.
⑤ Danazol
Danazol impedes ovarian steroidogenesis, but has very limited use due to androgenic side effects such as acne, hirsutism, and voice coarsening. However, because danazol can also reduce pain, it is worth considering when other treatments are not available.
3. Surgical treatment of endometriosis
Laparoscopy is the standard of care for surgical treatment of endometriosis. The goals of this procedure include optimal treatment of visible and deep disease, restoration of normal anatomy, and prevention of adhesions.
A large meta-analysis showed that laparoscopic surgery resulted in 100%, 70% and 40% improvement in mild, moderate and severe pain caused by endometriosis, respectively, with a recurrence rate of 20%-40% at the beginning and later in the procedure.
Repeat surgery should be avoided whenever possible because of the risks of surgery, including postoperative adhesions and reduced ovarian reserve function due to medically induced ovarian destruction.
Based on recent meta-analyses, although there is not yet a clear advantage to resection by surgery, it appears superficially that histological examination can be performed after resection, sparing deeper damage. For these reasons, many advocate resection of endometriosis lesions whenever possible.
Preoperative imaging
Given that physical examination findings are very limited in the detection of endometriosis, impacted imaging becomes particularly important, especially for preoperative surgical planning. Transvaginal ultrasonography (TVUS) is the first-line imaging modality for endometriosis because it allows visualization of the female reproductive system, is inexpensive compared to MRI, and is widely used.
Although basic TVUS is indicated for the evaluation of endometriomas and endometriosis, it has limitations for the examination of intestinal endometriosis.
This limitation can be addressed by adding adjunctive measures, including bowel preparation using an enema prior to TVUS. Compared to MRI, the modified TVUS technique increases the sensitivity and specificity of the diagnosis.
Surgical treatment of deep infiltrative endometriosis
Optimal surgery for rectal DIE requires careful surgical planning, including bowel preparation prior to surgery. If DIE involves the rectum, rectal resection, including superficial circular excision or partial bowel resection anastomosis, is required. Although incomplete resection can be supplemented with GnRHa therapy after surgery, incomplete resection should be avoided if possible, as it may lead to early recurrence and the need for reoperation.
Surgical treatment of endometrioma
Medication for endometriosis may leave the cyst unchanged in size or temporarily reduce it, but definitive surgical treatment is also needed when endometriosis symptoms persist.
Even when asymptomatic, endometriomas larger than 4 cm require surgical treatment for histopathologic diagnosis and differentiation from ovarian cancer.
Although cystectomy for endometrioma reduces ovarian reserve, it does not impair the ovulation-inducing response, and resection of endometriomas larger than 4 cm can improve fertility outcomes. The use of complex surgical treatment includes removal of most of the endometrioma with minimal ovarian tissue damage and protection of ovarian angiogenesis.
Presacral neurectomy (PSN)
PSN is a very difficult procedure that includes partial resection of the anterior sacral nerve. It is considered as one of the treatments for pelvic pain, endometriosis or adenomyosis, especially for women who strongly wish to preserve the uterus.
Although laparoscopic removal of the uterosacral nerve does not appear to have any benefit over conventional laparoscopic surgery, PSN has excellent results for long-term pain control.
Hysterectomy
Hysterectomy with bilateral salpingo-oophorectomy (BSO) is the definitive surgical approach for the treatment of endometriosis with a very low risk of recurrence. However, the risk of persistent pain is 10-15%, and 3-5% of patients are at risk of worsening pain.
In young women, preservation of one or both ovaries needs to be considered at the time of hysterectomy, but the risk of reoperation in these women is 6 times higher than in women undergoing BSO.
For women undergoing hysterectomy/BSO after childbirth, surgical menopausal risks need to be taken into account, including risks to the cardiovascular system and bone health. Younger women need to undergo hormone therapy (HT). Based on an RCT, the risk of recurrence in combination with HT therapy was only 3.5%.
4. Summary
Endometriosis is a common disease in women of reproductive age and seriously jeopardizes the quality of life of patients due to pain and impact on pregnancy.
Drug therapy is the first-line treatment for endometriosis-associated pain, while surgery is used in cases where the initial diagnosis and drug therapy are ineffective. Although it is possible that repeat surgery may be necessary due to the high recurrence rate of the disease and symptoms.
However, the medical risks of surgical treatment, including the formation of adhesions and damage to ovarian tissue, which in turn can affect fertility, should be minimized.
If infertility is the main symptom, surgery may be considered in early and late stages to improve fertility; however this must also take into account the patient’s age, ovarian reserve function, duration of infertility and other infertility factors.