Endometriosis

Endometriosis is defined as the presence of endometrial tissue (glands and stroma) outside the uterus. The most frequent sites of implantation are the pelvic viscera and the peritoneum. Endometriosis varies in appearance from a few minimal lesions on otherwise intact pelvic organs to massive ovarian endometriotic cysts that distort tubo–ovarian anatomy and extensive adhesions often involving bowel, bladder, and ureter. It is estimated to occur in 7% of reproductive–age women in the United States and often is associated  with pelvic pain and infertility. Considerable progress has been made in understanding the pathogenesis, spontaneous evolution, diagnosis, and treatment of endometriosis.

Diagnosis

Clinical Presentation

Endometriosis should be suspected in women with subfertility, dysmenorrhea, dyspareunia, or chronic pelvic pain. However, these symptoms can also be associated with other diseases. Endometriosis may be asymptomatic, even in some women with more advanced disease (ovarian or deeply invasive rectovaginal endometriosis).
Risk factors for endometriosis include short cycle length, heavier menstruation, and longer flow duration, probably related to a higher incidence of retrograde menstruation. Patient height and weight are positively and negatively, respectively, associated with the risk of endometriosis .
Endometriosis can be associated with significant gastrointestinal symptoms (pain, nausea, vomiting, early satiety, bloating and distention, altered bowel habits). A characteristic motility change (ampulla of Vater–duodenal spasm, a seizure equivalent of the enteric nervous system), along with bacterial overgrowth, has been documented in most women with the disease . Women of reproductive age with endometriosis are not osteopenic .
The average delay between onset of pain symptoms and surgically confirmed endometriosis is quite long: ±8 years in the United Kingdom and ±9 to 12 years in the United States . Similar durations have been observed in Scandinavia and in Brazil. A delay in diagnosis of endometriosis of 6 and 3 years in women with pain and women with infertility, respectively, has been reported. Over the past two decades, there has been a steady decrease in the delay in diagnosis and a decline in the prevalence of advanced endometriosis at first diagnosis. Concurrently, patient awareness of endometriosis has increased. For many patients, quality of life is affected by pain, emotional impact of subfertility, anger about disease recurrence, and uncertainty about the future regarding repeated surgeries or long–term medical therapy and its side effects. Therefore, endometriosis should be perceived as a chronic disease, at least in a subset of highly symptomatic women, and quality–of–life issues should be evaluated using reliable and valid questionnaires.

Pain

In adult women, dysmenorrhea may be especially suggestive of endometriosis if it begins after years of pain–free menses. Dysmenorrhea often starts before the onset of menstrual bleeding and continues throughout the menstrual period. In adolescents, the pain may be present after menarche without an interval of pain–free menses. The distribution of pain is variable but most often is bilateral.
Local symptoms can arise from rectal, ureteral, and bladder involvement, and lower back pain can occur. Most studies have failed to detect a correlation between the degree of pelvic pain and the severity of endometriosis.Some women with extensive disease have no pain, whereas others with only minimal disease may experience severe pelvic pain. Severe pelvic pain and dyspareunia may be associated with deep infiltrating subperitoneal endometriosis. The character of pelvic pain is related to the anatomic location of deeply infiltrating endometriotic lesions.
Possible mechanisms causing pain in patients with endometriosis include local peritoneal inflammation, deep infiltration with tissue damage, adhesion formation, fibrotic thickening, and collection of shed menstrual blood in endometriotic implants, resulting in painful traction with the physiologic movement of tissues.
In rectovaginal endometriotic nodules, a close histologic relationship has been observed between nerves and endometriotic foci and between nerves and the fibrotic component of the nodule.

Subfertility

An association between endometriosis and subfertility is generally accepted, but most of the studies suggesting this link have been based on retrospective or cross–sectional analysis. When endometriosis is moderate or severe, involving the ovaries and causing adhesions that block tubo–ovarian motility and ovum pickup, it is associated with subfertility. This effect has also been shown in primates, including cynomolgus monkeys and baboons.Although numerous mechanisms (ovulatory dysfunction, luteal insufficiency, luteinized unruptured follicle syndrome, recurrent abortion, altered immunity, and intraperitoneal inflammation) have been proposed ,the association between fertility and minimal or mild endometriosis remains controversial.

Infertility

Based on the number of asymptomatic women who are found to have endometriosis during tubal ligation, it would appear that the prevalence of endometriosis is not necessarily higher in infertile than in fertile women with endometriosis (5). In fertile women, endometriosis has been reported to be minimal or mild in 80% and moderate or severe in 20% .
In women with mild disease, some studies have reported a lower spontaneous monthly fecundity rate (MFR), which is the total number of pregnancies divided by the number of months of pregnancy exposure (i.e., 5%–11% compared with 25% in a normally fertile population). Other studies using artificial insemination with donor semen have reported that the MFR in women with minimal and mild endometriosis is either reduced (4%) or normal (20%). Fertility is not reduced in baboons with spontaneous minimal endometriosis. In one study, the fecundity rate (probability of becoming pregnant in the first 36 weeks after laparoscopy and carrying the pregnancy to 20 weeks or more) was 18% in infertile women with minimal to mild endometriosis and 23.7% in women with unexplained infertility (no significant difference). None of these women had been surgically treated for endometriosis during the diagnostic laparoscopy. However, 10% of women in each group had been treated with intrauterine insemination, in vitro fertilization (IVF), or cystectomy–myomectomy. It remains unclear whether the mere presence of peritoneal endometriosis directly correlates with infertility.
Spontaneous Abortion
A possible association between endometriosis and spontaneous abortion has been suggested in mostly uncontrolled or retrospective studies. Some controlled studies evaluating the association between endometriosis and spontaneous abortion have important methodologic shortcomings: heterogeneity between cases and controls, analysis of the abortion rate before the diagnosis of endometriosis, and selection bias of study and control groups. Based on controlled prospective studies, there is no evidence that endometriosis is associated with (recurrent) pregnancy loss, or that medical or surgical treatment of endometriosis reduces the spontaneous abortion rate.

Endocrinologic Abnormalities

Endometriosis has been associated with anovulation, abnormal follicular development with impaired follicle growth, reduced circulating E2 levels during the preovulatory phase, disturbed luteinizing hormone (LH) surge patterns, premenstrual spotting, the luteinized unruptured follicle syndrome, and galactorrhea and hyperprolactinemia. Increased incidence and recurrence of the luteinized unruptured follicle syndrome has been reported in baboons with mild endometriosis, but not in primates with minimal endometriosis or a normal pelvis (147). Luteal insufficiency with reduced circulating E2 and progesterone levels, out–of–phase endometrial biopsies, and aberrant integrin expression has been reported in the endometrium of women with endometriosis by some researchers (146,148), but these findings have not been confirmed by other investigators (149). Therefore, no convincing data exist to conclude that the incidence of these endocrinologic abnormalities is increased in women who have endometriosis.

Extrapelvic Endometriosis

Extrapelvic endometriosis, although often asymptomatic, should be suspected when symptoms of pain or a palpable mass occur outside the pelvis in a cyclic pattern. Endometriosis involving the intestinal tract (especially colon and rectum) is the most common site of extrapelvic disease and may cause abdominal and back pain, abdominal distention, cyclic rectal bleeding, constipation, and obstruction. Ureteral involvement can  lead to obstruction and result in cyclic pain, dysuria, and hematuria. Pulmonary endometriosis can manifest as pneumothorax, hemothorax, or hemoptysis during menses. Umbilical endometriosis should be suspected when a patient has a palpable mass and cyclic pain in the umbilical area.

Clinical Examination

In many women with endometriosis, no abnormality is detected during the clinical examination. The vulva, vagina, and cervix should be inspected for any signs of endometriosis, although the occurrence of endometriosis in these areas is rare (e.g., episiotomy scar). Other possible signs of endometriosis include uterosacral or cul–de–sac nodularity, lateral or cervical displacement caused by uterosacral scarring (150), painful swelling of the rectovaginal septum, and unilateral ovarian (cystic) enlargement. In more advanced disease, the uterus is often in fixed retroversion, and the mobility of the ovaries and fallopian tubes is reduced. Evidence of deeply infiltrative endometriosis (deeper than 5 mm under the peritoneum) in the rectovaginal septum with cul–de–sac obliteration or cystic ovarian endometriosis should be suspected by clinical documentation of uterosacral nodularities during menses, especially if CA125 serum levels are higher than 35 IU/mL .
The clinical examination may have false–negative results. Therefore, the diagnosis of endometriosis should be confirmed by biopsy of suspicious lesions that are obtained laparoscopically.

Imaging and Endometriosis

The presence of filling defects (presence of hypertrophic or polypoid endometrium) detected by hysterosalpingography has a significant positive correlation with endometriosis. The positive predictive value of this finding is 84% and negative predictive value is 75%.
Gynecologic transvaginal or transrectal ultrasonography is an important diagnostic tool in the assessment of ovarian endometriotic cysts (differentiation from other adnexal masses) and of rectovaginal endometriosis (sensitivity, 97%; specificity, 96%).
Other imaging techniques, including computed tomography (CT) and MRI, can be used to provide additional and confirmatory information, but they cannot be used for primary diagnosis. These techniques are more costly than ultrasonography, and their added value is not clear.
 
Medical Treatment
Empirical Treatment

If the patient desires treatment of pain symptoms suggestive of endometriosis in the absence of a definitive diagnosis, a therapeutic trial of a hormonal medication to reduce menstrual flow is appropriate. Empirical treatment for pain presumed to be due to endometriosis in the absence of a definitive diagnosis includes counseling, analgesia, nutritional therapy, progestins, or combined oral contraceptives. It is unclear whether combined oral contraceptives should be taken in a conventional, continuous, or tricycle regimen. A GnRH agonist may be taken, but this class of drug is more expensive and associated with more side effects and concerns about bone density than oral contraceptives.

Dysmenorrhea

Generally, women suffering from dysmenorrhea are treated with analgesics; many women treat themselves with over–the–counter oral analgesics. In a recent systematic Cochrane review evaluating the use of nonsteroidal anti–inflammatory drugs (NSAIDs) for primary dysmenorrhea, primary dysmenorrhea was described as menstrual pain without organic pathology. Exclusion of pelvic pathology was based on physical examination alone. It can be argued that some of these women with so–called primary dysmenorrhea probably in fact had endometriosis. It was concluded that NSAIDs, except niflumic acid, were more effective than placebo for pain relief , but there was insufficient evidence to suggest whether any individual NSAID was more effective than another. In another review, selective cyclo–oxygenase–2 inhibitors rofecoxib and valdecoxib were found to be as effective as naproxen and more effective than placebo for the treatment of primary dysmenorrheal. However, concerns have been raised about the safety of these medications, and its manufacturers have recently withdrawn rofecoxib from the market.
According to a systematic review based on two relatively small randomized controlled trials comparing paracetamol and co–proxamol with placebo, respectively, co–proxamol (paracetamol 650 mg and dextropropoxyphen 65 mg) but not paracetamol (500 mg 4 times daily) was more effective than placebo in reducing pain. This observation can possibly be explained by the suboptimal dosage of paracetamol used.

Pain

Considering that endometriosis is a chronic inflammatory disease, anti–inflammatory drugs would appear to be effective for treatment (see Chapter 15). Nonsteroidal anti–inflammatory drugs may be effective in reducing endometriosis associated pain. Although NSAIDs have been used extensively and have often been the first line therapy for reduction of endometriosis–related pain, the analgesic effect of NSAIDs has not been studied extensively. Only one small, double–blind, placebo–controlled, four–period, crossover clinical study has been published. This study showed complete or substantial pain relief of endometriosis–related dysmenorrhea in 83% of cases treated with naproxen compared with 41% in cases treated with placebo. Women who received naproxen needed significantly fewer supplemental analgesics compared to women taking placebo.
Endometriosis–related pain is nociceptive , but persistent nociceptive input from endometriotic lesions leads to central sensitization manifested by somatic hyperalgesia and increased referred pain. The effectiveness of NSAIDs in the reduction of endometriosis–related pain may be explained by both a local antinociceptive effect and a reduced central sensitization in addition to the anti–inflammatory effect. However, NSAIDs have significant side effects, including gastric ulceration and possible inhibition of ovulation. Prostaglandins also are involved in the follicle rupture mechanism at ovulation, which is why women who wish to become pregnant should not take NSAIDs at the time of ovulation.

Assisted Reproduction and Endometriosis

The treatment of endometriosis–related infertility is dependent on the age of the woman, the duration of infertility, the stage of endometriosis, the involvement of ovaries, tubes, or both in the endometriosis process, previous therapy, associated pain symptoms, and the priorities of the patient, taking into account her attitude toward the disease, the cost of treatment, her financial means, and the expected results. Assisted reproduction—including controlled ovarian hyperstimulation with intrauterine insemination, IVF, and gamete intrafallopian transfer—may be options for infertility treatment in addition to surgical reconstruction and expectant management. IVF is the method of choice when distortion of the tubo–ovarian anatomy contraindicates the use of superovulation with intrauterine insemination or gamete intrafallopian transfer.

In Vitro Fertilization

Based on several retrospective studies, investigators have suggested that the pregnancy rate after IVF may be lower in women with endometriosis than in women without the disease. In earlier studies, this finding had been attributed to lower oocyte quality and decreased fertilization rate in women with endometriosis. However, these findings were not confirmed in more recent studies that reported a normal fertilization rate but a reduced implantation rate per embryo transferred in women obtaining oocytes from donors with endometriosis. This reduced implantation rate could be related to increased interleukin–6 levels in follicular fluid of women with endometriosis when compared with controls. A more recent case–control study in an IVF egg–donation program compared oocyte receptors in patients with endometriosis stage III or IV (cases) with oocyte receptors in patients without endometriosis (controls). Similar rates of implantation, miscarriage, and pregnancy were observed in cases and controls, suggesting that there is no endometrial implantation problem in women with endometriosis stage III or IV treated with IVF. In another case–control study, the cumulative pregnancy rate and live–birth rates were comparable after five cycles of IVF in women with ovarian endometriosis and those with tubal infertility. The cumulative pregnancy rates were 63% and 63%, respectively, and the cumulative live–birth rates were 47% and 51%, respectively, but women with ovarian endometriosis had poorer responses and needed higher doses of gonadotropin therapy.
When endometriosis was assigned a stage, the pregnancy rate after IVF was decreased in patients with stage IV endometriosis but normal in women with less advanced disease. However, some studies have been unable to demonstrate a significant negative correlation between either the presence or stage of endometriosis and the pregnancy rate per cycle. The best evidence probably is provided by a recently published meta–analysis   showing that IVF pregnancy rates are lower in patients with endometriosis than in those with tubal infertility, even when women with minimal to mild endometriosis were analyzed separately. The use of danazol, gestrinone, or GnRH agonists in women with endometriosis before IVF has been reported to improve the pregnancy rate by some (396,400,401) but not all investigators. Prolonged treatment with a GnRH agonist before IVF in moderate to severe endometriosis can be considered and discussed with patients; although improved pregnancy rates have been reported,  the long duration of treatment may limit the practical application of this treatment.
Laparoscopic ovarian cystectomy is recommended if an ovarian endometrioma 4 cm or more in diameter is present to confirm the diagnosis histologically. This procedure may reduce the risk of infection, improve access to follicles, and possibly improve ovarian response. The woman should be counseled regarding the risks of reduced ovarian function after surgery and the loss of the ovary.

Coping with Disease

Coping with endometriosis as a chronic disease is an important component of management. According to guidelines for the management of endometriosis (159), evidence from two systematic reviews suggests that high frequency transcutaneous electrical nerve stimulation (TENS), acupuncture, vitamin B1, and magnesium may help to relieve dysmenorrheal. Whether such treatments are effective in endometriosis–associated dysmenorrhea is unknown. Many women with endometriosis report that nutritional and complementary therapies such as reflexology, traditional Chinese medicine, herbal treatments, and homeopathy improve pain symptoms. Although there is no evidence from randomized controlled trials to support the effectiveness of these treatments in endometriosis, they should not be ruled out if the woman feels they work in conjunction with more traditional therapies or that they could be beneficial to her overall pain management and quality of life. Patient self–help groups can provide invaluable counseling, support, and advice.

The Web site http://www.endometriosis.org/support.html provides a comprehensive list of all the self–help groups in the world.

Complete text in Berek & Novak's Gynecology, 14th Edition, Thomas M. D'Hooghe
Joseph A. Hill III