Typical appearance of an endometrioma with “ground glass” echogenicity.
Transvaginal sonography for the diagnosis of rectal endometriosis
A recent systematic review related to use of transvaginal sonography (TVS) for the diagnosis of bowel endometriosis reported a positive predictive value of 98% and a negative predictive value of 95%. TVS therefore appears to be useful for identifying and ruling out rectal endometriosis, but should be performed by clinicians that are highly experienced in TVS.
Magnetic resonance imaging
MRI is a useful technology for the diagnostic workup of ovarian and deep endometriosis, especially when there is suspicion (based on history or physical examination) of ureter or bowel involvement.
Laparoscopy may have blind spots and this is where MRI can have a key role. MRI can help to visualize those areas that may have escaped the laparoscopic field of view. Such areas include the retroperitoneal space or lesions obscured by dense adhesions. MRI may also be helpful to assess response to treatment and the recurrence of disease.
A major limitation is the diagnosis of peritoneal implants. The usefulness of MRI for diagnosis of peritoneal endometriosis is not well established. A promising breakthrough for MRI technology could be the concomitant use of a specific contrast agent called gadofosveset-trisodium. Because this agent extravasates from hyperpermeable vessels more easily than from mature vessels, it can detect angiogenesis more efficiently. It has been demonstrated that endometriotic lesions show formation of new vessels on histologic examination. The signal from those angiogenic spots have proven to be enhanced at least in an animal model. Schreinemacher, et al. recently described this potential application.[12]
Imaging technologies: specific considerations in deep infiltrating disease
Bladder involvement can be suspected from patient history, and TVS is helpful for corroborating the diagnosis. The usefulness of 3D ultrasound for diagnosing rectovaginal endometriosis is not well established.[13] The accuracy of barium enema for diagnosing bowel wall involvement is impossible at present to confirm.
Biomarkers
Many studies have focused on identifying biomarkers on blood or urine samples. May, et al. in a comprehensive two article review cover many molecules that have been studied as potential biomarkers.[14, 15] It is not recommended at present to clinically use biomarkers for the diagnosis of endometriosis.
Table 25-2 presents a list of the most common types of peripheral biomarkers that have been studied and those biomarkers assessing endometrial alterations. By far the most studied potential marker has been CA-125. A relationship exists between this marker and the presence of endometriosis. It may not be accurate in early stages of disease to distinguish between presence and absence of disease, but it may have higher accuracy at later stages.[16, 17] It also appears to be more commonly elevated with the presence of an endometrioma, but it is still not currently used to diagnose endometriosis. One potential future use may be for treatment monitoring.
| Peripheral biomarkers | Endometrial biomarkers |
|---|---|
| Cytokines | Endometrial cytokines |
| Antibodies | Immunology |
| Cell populations | Hormones and steroids |
| Glycoproteins | Growth factors and cell adhesion molecules |
| Cell adhesion molecules | Tissue remodeling |
| Growth factors | Angiogenesis and apoptosis |
| Proteomics | Reactive oxygen species |
| Hormones | Genetic studies |
| Other factors | Proteomics: menstrual and endometrial fluid analysis |
| Histology |
Endometrial biomarkers
Because of the ease of obtaining samples in the office setting without the need for anesthesia, endometrial tissue differences in endometriosis have been considered as potential diagnostic tools.
Certain molecules, such as cell adhesion molecules and angiogenesis factors, have the potential for future use as markers for endometriosis. The current recommendation, however, is that endometrial samples are not a diagnostic tool for endometriosis.
Treatment of pain in endometriosis
Patients with chronic pelvic pain associated with endometriosis require long-term treatment that involves repeated courses of medical and/or surgical therapy. In many cases the pain recurs within 6–12 months after completion of the treatment.[18] There are no studies that directly compare the effectiveness of medication versus surgery, so it is not possible to draw conclusions about the superiority of one over the other. Medical treatment is usually the initial choice because of the lower costs and lower risks.
Medical treatment
Because endometriosis is an estrogen-mediated condition, all medical treatments block ovarian function, but they do so in different ways. The hormonal medications used for treating endometriosis include gonadotropin-releasing hormone (GnRH) agonists, oral contraceptives, danazol, progestogens, and anti-progestogens. Pain relief is also a part of the medical treatment. These medications are effective for alleviating pain and also reduce the risk of recurrence after surgery. Because medical treatments block ovarian function, these medications are not indicated for treating infertile patients who also have endometriosis.
A brief description of the different kinds of medications used for treating pain in endometriosis is provided in the following sections.
Nonsteroidal anti-inflammatory drugs
Nonsteroidal anti-inflammatory drugs (NSAIDs) are usually the first line of treatment for pain. They seem to be effective for the treatment of primary dysmenorrhea, but a recent Cochrane analysis did not find enough evidence to show that they significantly reduce pain in endometriosis.[19]
Combined hormonal contraceptives
Combined hormonal contraceptives have been used in a continuous or cyclic manner to treat endometriosis symptoms. The proposed mechanism of action is that of decidualization followed by atrophy of the endometrium. Oral contraceptives (OC) appear to be more effective at alleviating symptoms after surgical treatment if used in a continuous fashion compared to cyclic administration. OC with desogestrel are equally effective as the traditional ones containing the more androgenic progestagens, such as 19-nortestosterone derivatives.
Progestagens
Progestagens are also commonly used and seem to be effective in reducing pain. The mechanism of action is similar to OC, with the addition of suppression of matrix metalloproteinases (important for the growth and implantation of ectopic endometrium) and inhibition of angiogenesis. The most common types include medroxyprogesterone acetate (MPA) and 19-nortestosterone derivatives. The levonorgestrel-releasing intrauterine device also appears to improve the symptoms of dysmenorrhea.
GnRH agonists
GnRH agonists bind to GnRH receptors in the pituitary resulting in a down-regulation of the pituitary-ovarian axis. Their mode of action is also related to the induction of amenorrhea and endometrial atrophy. Commonly used GnRH agonists are leuprolide, goserelin, buserelin, and triptorelin. They are usually administered in a depot formulation by injection every one to three months, but there is also short-acting presentations. Another option is a nasal spray presentation (nafarelin).
GnRH agonists are effective in alleviating symptoms in women with endometriosis, and no route of administration appears superior to another, according to a recent systematic review.[20]
Important side effects include the hypoestrogenic symptoms (hot flushes, vaginal dryness, decreased libido, headache, mood swings, and bone loss). They are usually not administered for more than six months because of these side effects, including the risk of osteopenia. To reduce the side effects and to allow longer treatment periods, an “add-back“ therapy has been advocated. This treatment consists of norethindrone or a combination of estrogens and progestogens. It should be started at the same time of agonist administration. It has been show that this approach can decrease bone loss and reduces the severity of the side effects.[21]
Danazol
Danazol is a derivative of 17 alpha-ethinyl testosterone. Its mode of action is related to the inhibition of the luteinizing hormone (LH) surge and by increasing free testosterone levels. It is generally administered orally although there are different presentations. Danazol appears to relieve symptoms of endometriosis, but hyperandrogenic effects are common (acne, weight gain, hirsutism, and deepening of the voice). These significant side effects limit its clinical usefulness.
Aromatase inhibitors
Because of the increased activity of aromatase in the endometriotic tissue, aromatase inhibitors (AI) have been used as therapy. They seem to be an effective option for the treatment of pelvic pain in endometriosis, although they have not been approved for this indication specifically.
It must be mentioned that AI can increase follicle-stimulating hormone (FSH) levels in premenopausal women, leading to multifollicular development. They should therefore be used in combination with other agents such as OC, GnRH-a, or progestogens.
Gestrinone
Gestrinone is an antiprogestational steroid that inhibits ovarian steroidogenesis. It is administered orally. Anti-estrogenic and androgenic side effects have been described. It has been shown to be as effective as danazol and GnRH agonists. It is not currently available in the United States but is in use in Europe.
Other molecules
Several other options are under investigation. These include mifepristone, selective PR and ER modulators, GnRH antagonists, agents that inhibit angiogenesis and the effects of TNF-alpha, matrix metalloproteinases, and pentoxifylline.
Adjuvant therapy
Acupuncture and Chinese herbal remedies have been studied, and both seem to significantly relieve pain.
Since chronic pelvic pain may cause musculoskeletal pain derived from muscle contractures, referral to a physiotherapist may prove to be beneficial in relieving part of the pain. A mental health professional may add benefit because of the psychological stress and depression that come with chronic pelvic pain. Additionally, a pain management specialist may help to guide the analgesic treatment.
Surgical treatment
Surgical treatment consists of eliminating endometriotic lesions, division of adhesions (to restore pelvic anatomy), and interruption of nerve pathways (with the intention of improving pain control). Surgical treatment may be recommended to treat endometriotic lesions at the time of the diagnostic laparoscopy. It has been observed that treatment with laparoscopic surgery in endometriosis appears to alleviate symptoms and promote disease improvement. Practically, the presence of pain strongly weighs in favor of surgery at the time of diagnostic laparoscopy.
Pain recurrence after primary surgery ranges between 20% and 40%; this is similar after repeat surgery because of recurrent disease.
Laparoscopic uterosacral nerve ablation, presacral neurectomy, and hysterectomy
Currently, laparoscopic uterosacral nerve ablation does not seem to offer any added benefits to conservative surgery. Rare complications have been described such as uterine prolapse and transection of the ureter.
Presacral neurectomy is a technically challenging procedure associated with significant risk of bleeding. Although it has been proposed to treat midline pain associated with menstruation, its effects on other types of pain are inconsistent.
Hysterectomy with bilateral salpingo-oophorectomy (BSO) is usually the procedure of last resort. It is reserved for women with incapacitating symptoms related to endometriosis that have completed childbearing and in whom other therapies have failed. Hysterectomy without BSO is commonly less effective as recurrence rates are higher. Combined hormonal therapy (estrogen-progesterone) is the usual regimen for treating women after hysterectomy and BSO. Although hormonal therapy always carries the risk of disease recurrence, unopposed estrogens might be more likely to promote it. Hormonal therapy should always be used with caution due to therapeutic risks.
Adjuvant medical treatment after surgery
In women with advanced disease, moderate-to-severe dysmenorrhea and noncyclic pelvic pain, postoperative medical therapy may improve pain management. It appears that the return of symptoms is a significantly longer time interval with adjuvant medical therapy after surgery.
Medical treatment of ovarian endometriosis
Endometriomas do not usually respond well to medical treatment, and surgical resection is a very common procedure around the world either to overcome infertility or to relieve pain. Resection of such an endometrioma, however, is not based on solid clinical evidence.
Medical therapy may cause a temporary reduction in size of the cyst, but not complete resolution. The simple drainage of endometriomas is associated with a high recurrence rate within 6 months; it is therefore not recommended as definitive therapy.
Endometriosis and infertility
There is good correlation between the amount, type, and location of endometriotic lesions and the pain encountered.[22] On the other hand, the relationship between endometriosis and infertility is less clear, although the association is clinically recognized.[23] The current vision today is that infertility in endometriosis is multifactorial.[24] Of course when infertility is present, both the female and male partner should undergo a full evaluation.
Treatment of infertility
Before contemplating surgery, certain factors must be considered. If the ovarian reserve is altered, or the patient is older than 38 years of age or if infertility is longstanding, ART procedures should be offered initially. If tubal or sperm status is altered, then the option also is to go straight to ART. Another factor to consider is the availability of time, for many women desire to achieve pregnancy as soon as possible.
When semen parameters and tubal status are not an issue, the usefulness of middle-ground treatment (such as intrauterine insemination) is of questionable value in patients with endometriosis. They do not seem to be better than a wait-and-see approach with natural conception. Until more data is available, it is not recommended to use this middle-ground approach in women with endometriosis, either before or after surgery.[25]
Although success rates of ART procedures such as in vitro fertilization (IVF) appear to be diminished in women with endometriosis (compared to women with tubal factor infertility), IVF can maximize cycle fecundity.
If a patient goes through surgery then it is advisable to wait at least one year for natural conception to happen. If this is not achieved, then ART procedures should be offered.
It should be emphasized that the patient needs to have all the pertinent information, with advantages and disadvantages of surgery and the availability of ART. A valid option is to go directly to ART procedures if the couple being treated for infertility decides to avoid surgery.
In certain cases the main reason for choosing surgery or ART procedures comes from the primary activity of the health professional that is being initially consulted; the best interests of the patient would be a better approach.
In principle, surgery performed immediately before ART is of little help.[24] The exception could be pelvic pain, hydrosalpinges, and large endometriomas. Hydrosalpinges are important to consider, for they reduce the outcome of ART almost by 50%; surgery should also be envisioned in patients with severe pain, because pain by itself can be associated with infertility.
Information about the value of surgery improving the chances of natural conception is complex. Confusion exists because there are different forms of endometriosis (superficial, deep infiltrating, and endometriomas), different types of surgery, and different modes of assessing fertility (natural or in vitro). There is some evidence weighing in favor of surgery for superficial lesions to improve fertility.[26] At least one year is needed as sufficient time to maximize the chances of a natural pregnancy. Women treated surgically for any stage of endometriosis have an approximately 50% chance of spontaneous conception one to two years after the procedure.[24] This increase is seen irrespective of disease stage. On the other hand, surgery for deep infiltrating disease is usually for alleviating pain and data in relation to improving fertility after surgery is still unclear.
Surgical removal of endometriomas in infertility
Surgery should be approached with caution in women with endometriomas. Regardless of the type of surgical procedure used for removal of the endometrioma, it seems to cause some damage to healthy ovarian tissue with consequences on the ovarian reserve. This has an even more deleterious effect for bilateral endometriomas; a potential risk of premature ovarian failure exists after the procedure.
When infertility is present, sparing the surgical procedure and proceeding directly to ART reduces the time to achieve a pregnancy. Surgery should be performed only during specific circumstances, such as pelvic pain, difficult access to the follicles during oocyte retrieval and risk of malignancy. It has also been seen that excision of an endometrioma does not appear to have any additional benefits on ART outcomes. Garcia-Velasco, et al. in a case-control study of surgery for ovarian endometriosis showed no outcome improvement for ART versus expectant management.[27] Some authors have argued that keeping endometriomas in place could increase the risk of infection during oocyte retrieval, but this has not been confirmed.
Medical pretreatment before ART
Ovarian suppression with GnRH agonists appears to have favorable effects on ART outcome in women with endometriosis.[28] The optimal duration of this pretreatment is still unknown, but a meta-analysis confirmed the benefit of a three- to six-month period of GnRH agonists before commencing ART.[29] The mechanism by which this pretreatment improves ART outcome is uncertain, but it could be related to correcting endometrial alterations and because of this possibly amplifying receptivity for embryo implantation.
Concluding remarks
Endometriosis is a chronic disease that causes significant morbidity in women’s lives. A lifelong management plan is beneficial. Medical therapy is usually the initial approach and surgical support may eventually be required. Assisted reproductive technologies are an option for overcoming infertility. Endometriosis continues to be a challenging disease not only to diagnose but also to treat. In order to obtain more specific diagnostic tools and treatment options, research must continue to improve our understanding of the pathogenesis of endometriosis.
