Endometriosis is the appearance of endometrial glands or mesenchyme outside the uterus. It is often considered one of the difficult gynecological conditions because of its insidious onset, 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, 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. However, the diagnosis of endometriosis is difficult due to a number of other obstetric or non-obstetric conditions that can also cause pelvic pain, in addition to the limitations of the pelvic examination in detecting endometriosis. In addition, many endometriosis do not present with appropriate symptoms, so the usefulness of available staging systems is very limited. Finally, endometriosis can be diagnosed surgically.
Little is known about the pathophysiology of endometriosis. Various theories have been proposed for its development, including menstrual blood reflux, epithelial metaplasia of the corpora cavernosa, and lymphovascular or hematologic dissemination. More recently, the pathogenesis of endometriosis has involved stem cells; however, no single theory has so far been able to fully explain all clinical symptoms and disease features.
Different pathophysiologic mechanisms have been proposed that may help explain the different endometriosis phenotypes, 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 previous incision. Usually menstrual symptoms should be noticed.
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 technologies can help overcome the adverse effects of pharmacological treatment. This review focuses on current treatment strategies for endometriosis pain and infertility.
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 produced by endometriosis leads to pelvic adhesions, which can also lead to pelvic pain.
Pharmacological treatment of endometriosis The mechanism of pharmacological treatment of endometriosis is to suppress endometriosis by controlling the endogenous hormonal environment, as estrogen stimulation can lead to the development and progression of endometriosis, with both estrogen and progesterone receptors present in the 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 endometriosis pelvic pain 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 make combination hormonal contraceptives (CHCs) more closely resemble gonadotropin-releasing hormone (GnRH) analogs, which may also lead to amenorrhea. Although direct controlled studies of 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 the treatment of 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 antiproliferative effect of progesterone by reducing progesterone receptor expression.
The progesterone component of CHC exerts an anti-endometrial effect by causing methylation 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. The anti-endometrial effect.
2. Progesterone contraceptives, long-acting or short-acting, are effective in the treatment of endometriosis. Long- and short-acting progestins include daily or long-acting medroxyprogesterone acetate (MPA), etoprogesterone 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%, so patients are satisfied and compliance is good. Continued use primarily increases the incidence of amenorrhea and may result in pain control.
Data from several recent trials suggest that LNG-IUS can be used as first-line therapy in the pharmacological management of endometriosis and can control postoperative recurrence. In particular, a randomized controlled trial of LNG-IUS and a GnRH analogue found similar efficacy in the control of pain associated with endometriosis.LNG-IUS also has beneficial effects on lipid metabolism, with reduced total and LDL levels and unchanged HDL levels.
LNG-IUS is also used in rectovaginal endometriosis and adenomyosis, with significant improvement in painful intercourse, bleeding and pain. Although LNG-IUS inhibits only 25%-50% of first trimester ovulation, it may 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.
Etonogestrel studies are limited, but some data suggest the use of etonogestrel implants for the treatment of dysmenorrhea, a pain associated with endometriosis, is more effective. A recent randomized controlled trial showed a significant 68% reduction in pain after six months with etopregnant implants compared to the MPA group (54% in the MPA group). Patient satisfaction was 60 percent in both groups. Although similar to MPA, a common side effect of etoprogesterone is penetrating bleeding.
Multiple studies of other progestins and antiprogestins have shown that progesterone denogestrel improves pelvic pain due to endometriosis and remains persistently effective after 6 months of discontinuation. In addition, late in life denogestrel is a norethindrone derivative, but without the common side effects of androgens. Unfortunately, while 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.
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 about 60-100%. gnRHa can be used empirically for 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 has only approved the addition of ethinyl acetate to reverse add-on therapy, low-dose estrogen or low-dose estrogen and progesterone combinations can be used at the lowest threshold of stimulation for endometriosis.
In contrast 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.
4. Aromatase inhibitorsAromatase 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 combination of CHCs and aromatase inhibitors may eliminate bone loss in premenopausal women.
5. Danazol Danazol impedes ovarian steroid production, but has 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.
Surgical treatment of endometriosis Although surgical evaluation is often used to confirm the diagnosis of endometriosis, it can also be used to treat refractory pelvic pain and infertility where medication has failed, as detailed below. Laparoscopy is the standard of care for the surgical treatment of endometriosis, and the goals of this procedure include optimal treatment of visible and deep disease, restoration of normal anatomy, and prevention of adhesions.
Large meta-analyses have shown that laparoscopic surgery improves mild, moderate, and severe pain from endometriosis by 100%, 70%, and 40%, respectively, with recurrence rates of 20%-40% at the start and later in the procedure. Repeat procedures 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 no clear advantage to surgical excision, it appears superficially that histological examination can be performed after excision, sparing deeper damage. For these reasons, many advocate resection of endometriosis lesions whenever possible.
Preoperative imaging Given the very limited findings of physical examination for endometriosis, impacted studies become 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 with an enema prior to TVUS. Compared to MRI, the modified TVUS technique increases the sensitivity and specificity of the diagnosis.
The optimal surgical treatment of rectal DIE with deep infiltrative endometriosis requires careful surgical planning, including preoperative bowel preparation. If DIE involves the rectum, rectal resection, including superficial circular excision or partial bowel resection anastomosis, is required. Although incomplete resection can be followed by GnRHa therapy, 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 symptoms of endometriosis remain. 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 involves partial resection of the presacral nerve. It is considered as one of the treatments for pelvic pain, endometriosis or adenomyosis, especially for women who strongly wish to preserve their uterus. Although laparoscopic uterosacral nerve excision does not appear to have any benefit, PSN has excellent results for long-term pain control compared to conventional laparoscopy.
Hysterectomy Hysterectomy with bilateral tubal and ovarian resection (BSO) is the definitive surgical procedure 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 younger women, unilateral or bilateral ovaries need to be considered at the time of hysterectomy, but the risk of reoperation in these women is 6 times higher than in women who have undergone BSO.
For women who undergo hysterectomy/BSO after having children, 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 is only 3.5%.
In conclusion endometriosis is a common condition in women of childbearing age and seriously jeopardizes the quality of life of patients due to pain and impact on pregnancy. Medication is the first-line treatment for endometriosis-associated pain, while surgery is used in cases where the initial diagnosis is made and medication is 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. Surgery to improve fertility may be considered in early and late stages if infertility is the main symptom; however this must also take into account the patient’s age, ovarian reserve function, duration of infertility and other infertility factors.