How To Cure Endometriosis
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According to Wikipedia: "Endometriosis is a gynecological medical condition in which cells from the lining of the uterus (endometrium) appear and flourish outside the uterine cavity, most commonly on the membrane which lines the abdominal cavity. The uterine cavity is lined with endometrial cells, which are under the influence of female hormones. Endometrial-like cells in areas outside the uterus (endometriosis) are influenced by hormonal changes and respond in a way that is similar to the cells found inside the uterus. Symptoms often worsen with the menstrual cycle."
Gonadtropic-releasing hormone agonists may be safer than previously thought for endometriosis patients, results from two studies indicate.
Previously, computed tomography scans of patients' spinal trabecular bone showed decreased bone mineral density after GnRH agonist treatments. That side effect has delayed FDA approval of intranasal versions of the potent drug for endometriosis treatment.
But no such bone-loss problems turned up in two new studies using two different bone-measuring techniques.
Researchers at Rush-Presbyterian-St. Luke's Medical Center in Chicago conducted a prospective, randomized study of 38 women. Source: http://cellspynews.com For six months, 25 patients took leuprolide (Lupron, Abbott) intranasally while 13 patients took danazol (Danocrine, Winthrop-Breon). The patients also took calcium supplements daily, Dr. Ian Tummon told the American Fertility Society meeting here.
Both drugs suppressed ovarian function equally, says Dr. Tummon, an assistant professor of ob-gyn at Rush. After six months of therapy, the pregnancy rate of these patients was 70% using leuprolide, compared with 54% using danazol.
Bone mineral density. Dual-photon absorptiometry 26 weeks after treatment, measuring cortical and trabecular bone mass, showed that bone mineral density decreased slightly in the danazol group and increased slightly in the leuprolide group.
Side effects--experienced by patients in both groups--included hot flashes, vaginal dryness, and decreased libido, he says.
Researchers who conducted a similar study at Yale gave high marks to nafarelin (Syntex), another intranasal GnRH agonist. The Yale team studied 11 endometriosis patients who had been infertile for an average of four years, reports Dr. Robert G. Brzyski, formerly an ob-gyn resident at Yale.
All 11 patients improved clinically, and their disease showed no significant increase in severity in up to 18 months of follow-up, says Dr. Brzyski, who is now a clinical fellow in ob-gyn at Eastern Virginia Medical School in Norfolk. Six of the 11 conceived within four months of initiating therapy, and a seventh patient conceived four months later. Six of the seven patients who conceived did so despite some residual disease, he notes.
The therapy was "well tolerated," Dr. Brzyski says. Hot flashes and vaginal dryness were the main side effects. CT scans of the wrist revealed no change in bone density, says Dr. Florence Comite, an assistant professor of ob-gyn, pediatrics, and medicine at Yale.
Endometriosis Treatment
Both the Chicago group and the Yale group agree that the intranasal forms of GnRH agonists would offer a convenient nonsurgical treatment for endometriosis if approved this year, as expected. In injectable form,the potent drug is approved for treating prostate cancer.
In addition to treating endometriosis, GnRH agonists show promise in inducing ovulation as well as in treating breast cancer, amenorrhea, premenstrual syndrome, uterine bleeding, uterine myomata, precocious puberty, and polycystic ovaries.
Best news. The best news is that "bone loss doesn't seem to be as great a problem as we thought it would be," notes Dr. John Rock, an associate professor and director of reproductive endocrinology at Johns Hopkins in Baltimore. Previously, researchers believed that patients were losing up to 1% of their calcium within six months, but "it doesn't seem to be that much," he says. "When patients go off the medication, they recover bone mass quite quickly."
If there were no controversy over calcium loss, advocates could make a strong argument to leave endometriosis patients on GnRH agonists indefinitely, says Dr. David Archer, director of the contraceptive research program and a professor of ob-gyn at Eastern Virginia. A woman with severe endometriosis who wanted to preserve her childbearing potential could postpone surgery and control the disease with the drug, he says.
But a likelier role for intranasal GnRH agonists will be to reduce the size of fibroids or the endometrium to simplify surgery, Dr. Archer believes.
How To Cure Endometriosis
Much remains to be learned about the pathogenesis of endometriosis. Most of us learned in medical school that this disorder is probably the result of transport of viable endometrial cells to extrauterine sites via retrograde menstruation. The endometrial tissue, which may become lodged in the pelvis or at distal sites, retains its cyclic hormonal responsiveness; this accounts for the nature and periodicity of symptoms. Women with ectopic foci may experience pain resulting from inflammation and subsequent fibrosis. (In general, the deeper the lesion, the worse the pain.)
The mechanism of retrograde menstruation, first proposed in the 1920s, is still accepted today. That this process actually operates has been demonstrated in humans as well as in rhesus monkeys.
Another theory holds that immunologic mechanisms are involved in the pathogenesis. Studies show that roughly half of women with endometriosis diagnosed by laparoscopy produce autoantibodies to endometrial and/or uterine tubal tissue. Peritoneal washing of highly symptomatic patients has revealed functionally altered natural killer cells, peripheral lymphocytes, and macrophages. However, such abnormalities are not present in all women with this condition.
Endometriosis tends to be a highly familial disease. Heterozygous and homozygous models of endometriosis have been proposed. Some investigators theorize that women with mild endometriosis - a few scattered lesions and perhaps a little pain - are genetic heterozygotes, whereas women with obliterative disease are homozygotes. A long-standing, yet unproven, theory suggests that metaplastic transformation of the secondary mullerian system may be involved in the pathogenesis of early lesions.
Recent articles in the obstetrics and gynecology literature have posed interesting questions about endometriosis. Does endometriosis occur intermittently in all women? Is it perhaps not a consistent disease state, but a spectrum of conditions that vary from benign to severe? Some authors propose a differentiation between "endometriosis," a benign condition, and "endometriotic disease," defined by deep rectovaginal infiltration or ovarian cysts. However, this model does not address symptomatology: most women seek medical attention because of pain or infertility - conditions that may correlate poorly with the extent of macroscopic disease.
Table 1 - Manifestations of endometriosis
Pulmonary
Chest or pleuritic pain Shoulder pain Hemoptysis Pneumothorax
Urinary tract
Frequency Urgency Ureteral obstruction Suprapubic pressure or pain Hematuria
Gastrointestinal
Change in bowel habits Tenesmus Rectal bleeding Bloating, flatulence of recent onset Nausea, vomiting Appendicitis Dyschezia
Other manifestations
Ascites Sciatica Low back pain (diffuse or focal) or pressure Periodic pain or bleeding from any site Umbilical lesions (visible and tender)
CLASSIFICATION
Many systems of classification have been proposed, most of which are based on the location, size, depth, and extension of disease. The number of classification systems and the frequency with which they change reflect a poor understanding of the true nature of endometriosis and the difficulty of developing one classification scheme that encompasses diverse clinical manifestations. Even the revised American Fertility Society Classification System is weakened by:
* An inability to correlate clinical symptomatology or infertility
* A growing appreciation for microscopic lesions
* Observational error (the lesions of endometriosis are multicolored or occasionally nonpigmented)
Thus, this system does not help us understand how severely endometriosis affects the individual patient.
Endometriosis Remedies
These shortcomings are important because some women with minimal or no lesions visible on laparoscopy have severe pelvic pain. Other women, who are found to have extensive endometriosis when surgery is performed for totally unrelated reasons, may have no symptoms whatsoever. Recent studies, however, give weight to the observations that infertility is frequently associated with superficial implants, whereas pain is found with deeper lesions.
Our present lack of understanding of the pathophysiology of endometriosis makes it reasonable to assume that future classification schemes will benefit from new knowledge of the role of immunity, genetics, and developmental anatomy.
CLINICAL PRESENTATION
As noted, manifestations of endometriosis vary greatly from woman to woman, and no one symptom is pathognomonic. Symptoms depend, in part, on the severity and location of disease (Table 1). Pelvic pain, dysmenorrhea, dyspareunia, infertility, back pain, and rectal discomfort are the most common presentations.
If the disease involves the diaphragm, the initial complaint is often right-sided shoulder pain or abdominal pain. Pulmonary manifestations may include catamenial pneumothorax or hemoptysis. Urinary tract endometriosis may cause urgency, urinary frequency, suprapubic pressure or pain, and hematuria. Severe disease may completely obstruct the ureters, and frank renal failure may ensue. When symptoms of recurrent urinary tract infection persist despite therapy, endometriosis may be the underlying cause.
In the GI tract, signs that suggest endometriosis include diarrhea, constipation and, in general, any change in bowel habits, as well as tenesmus, rectal bleeding, and appendicitis. Appendicitis is actually one of the most common presentations of GI endometriosis, accounting for 20% of symptomatic cases.
Radicular symptoms may result from endometrial implants on nerves. This occurs most commonly on the sciatic and obturator nerves. Endometriosis can also involve the pancreas, omentum, and liver, and can sometimes produce palpable umbilical hernias. Endometriosis has even been found to cause recurrent nosebleeds.
The bottom line: endometrial implants can turn up almost anywhere. They can migrate by direct extension, by hematogenous routes, or by lymphatic channels. The greater a site's distance from the pelvis, the less likely is endometriosis to be found there.
MAKING THE DIAGNOSIS
Suspect endometriosis in any woman with pelvic pain or who is infertile. Cyclic or periodic symptoms in a premenopausal woman are other good clues (Table 2). Ask the patient about the origin of pain (it should not precede menarche). The frequency, severity, and location of pain are important clues, as is a history of pain with deep intercourse. If the patient has taken oral contraceptives, ask whether symptoms diminished while she was taking them.
Table: 2 - Clinical indications of endometriosis
Symptoms
Dysmenorrhea Dyspareunia Pelvic or back pain Infertility
Signs (abnormal findings on pelvic examination)
Tender or nodular posterior cul-de-sac and uterosacral ligaments Fixed, tender, retroverted uterus Palpable thickening or masses in the rectavaginal septum Ovarian enlargement Visible lesions in cervix or vagina
Natural Remedies For Endometriosis
Note that noncyclic or persistent symptoms do not absolutely rule out endometriosis. Indeed, undiagnosed endometriosis may be manifested by symptoms that persist for most of the month. Although these symptoms most commonly correlate with menses, they may occur before or after menstruation. Chronic pelvic pain, for example, may be present for all but a few days of the month.
CA-125 is under investigation for its role in monitoring therapy for patients with endometriosis. It is not used as a screening tool because of its low sensitivity and specificity. Antiendometrial antibodies and endometrial secretory protein PP14 are also currently being investigated as potential serum markers.
Most imaging techniques have limited use in the evaluation of endometriosis. Ultrasonography can help identify solid and cystic masses but offers no information about etiology. Although MRI is showing usefulness in the evaluation of adenomyosis, it does not offer significant information beyond ultrasonographic examination in women who have endometriosis. Laparoscopy is still required for tissue diagnosis.
If you suspect endometriosis from the patient's history, perform a pelvic examination. A diagnosis of endometriosis is made by laparoscopy in up to 90% of women who are found to have such abnormal physical findings as tenderness or nodularity along the uterosacral ligaments; a fixed, tender, retroverted uterus; palpable thickening or masses of the rectovaginal septum; or adnexal tenderness and ovarian enlargement.
In about 5% to 10% of cases, there may be a visible lesion on the vagina or cervix. A biopsy of this lesion can confirm the diagnosis, but laparoscopy is usually needed to define the extent of disease, to determine the best therapy, and to monitor the patient's response to therapy.
In short: consider endometriosis if your patient's complaints are cyclic or persistent despite therapy. Perform a pelvic examination to look for evidence of disease. If the history and physical examination both reveal suspicious fundings, there is a good chance that endometriosis may be the underlying cause.
The four stages of endometriosis
STAGE I
Minimal disease. A small volume of superficial brownish, reddish, blue-black, white, clear, or grainy implants.
STAGE II
Mild disease. The same as Stage I, except somewhat deeper, more numerous implants.
STAGE III
Moderate disease. Many deep implants, small endometriomas on one or both ovaries, and some filmy adhesions.
STAGE IV
Severe disease. Many deep implants and dense adhesions, and large endometriomas on one or both ovaries. The rectum may adhere to the back of the uterus.
The only way to diagnose endometriosis definitively is through laparoscopic visualization and tissue sampling with confirmation on histology. This method is 70-95% accurate. Imaging methods such as ultrasound, MRI, and CT aren't sensitive enough to detect endometriosis, although you may need to order them to rule out other disorders and justify laparoscopy. These other modalities can reveal ovarian masses that resemble endometriomas -- cysts containing blood and endometrial tissue.
Recent research has focused on measurement of the serum cancer antigen 125 (CA 125) level as a possible diagnostic test for endometriosis. In women with the disease, that level is usually elevated. The main problem, however, is that the level of CA 125 also rises with many other benign and malignant conditions. Because of the poor specificity of this test, measuring CA 125 levels is currently not considered useful when endometriosis is suspected.[1]
TREATMENT
There is no certain cure for endometriosis. Even with the various treatments available, the disease recurs in up to half of patients within 2-3 years.[1] The goal of treatment, then, is to keep the disease and its symptoms in check. Based on the disease stage, the severity of symptoms, and the patients age, desire to have children, and circumstances and preferences, the gynecologist typically recommends one of three approaches -- medical, surgical, or a combination. Many gynecologists prefer the latter approach, first surgically removing as much of the diseased tissue as possible and then placing the patient on medical therapy. For recurrent disease, follow-up surgery with continued medical therapy may be recommended.
Ways To Treat Endometriosis
Be aware that a few centers in this country provide immune therapy for endometriosis. This relatively new approach assumes that an immune system deficiency is at the root of the disease (see "A budding treatment for endometriosis").
Surgery
Because laparoscopy is required to definitively diagnose endometriosis, it is the most common initial treatment. After making the diagnosis, the surgeon usually excises as many endometrial implants and adhesions as possible or obliterates them through laser surgery or electrocautery. Endometriosis-related symptoms are temporarily relieved in most cases, preparing the way for medical therapy.
A total hysterectomy with bilateral oophorectomy is the most definitive treatment for endometriosis. It permanently relieves patients, pain 90% of the time and is rarely followed by disease recurrence.[1,4] However, most women with endometriosis want to preserve their fertility, so the prevailing practice is to use hysterectomy only as a last resort. Patients who do have the procedure are generally at the end of their reproductive years and already have children. At that point, their main desire is often to eliminate symptoms. Only in very rare cases is hysterectomy recommended for women still in their child bearing years -- usually when the other medical or surgical treatments available have not provided adequate pain control.
A few gynecologists are trained in an experimental procedure -- outpatient endometrial resection ablation (OPERA) -- that may be a less radical alternative to hysterectomy. As the name of the procedure suggests, only the endometrium and basement membrane are removed. The ovaries and outer surface of the uterus remain intact. The surgeon also resects any uterine fibroids that are present. (See "Uterine fibroids: Treat -- or ignore?" page 48.)
It's unclear from research whether the laparoscopic treatment of endometriosis enhances fertility. But many clinicians say it does, particularly in cases of moderate to severe disease where the patient undergoes excision of deep endometrial implants. These patients commonly become pregnant within six months of surgery after having tried and failed to conceive for many years.
Medical treatment
Medical therapy seeks to suppress ovarian function to the point that the patient doesn't menstruate. At such a high level of suppression, existing endometrial implants should no longer be stimulated by estrogen and the other hormones they need to grow and multiply, and symptoms should improve. What's more, the amenorrheic state minimizes retrograde menstruation. A variety of hormones are used to induce and maintain amenorrhea. Patients may take these for many years, either continually or cyclically in 3-9-month courses. Most clinicians agree that medical therapy doesn't enhance fertility.
* Gonadotropin-releasing hormone (GnRH) agonists GnRH agonists produce symptom improvement within three months. The most common choices are leuprolide acetate, 3.75 mg IM once a month, goserelin acetate, 3.6 mg SC once a month, or nafarelin acetate, 200[Micro]g bid taken as a nasal spray. All of these regimens are followed for 3-6 months. A major advantage of GnRH agonists is that they produce fewer side effects than the other hormonal treatments. The risks may include hot flashes, vaginal dryness, headaches, and depression. A reversible 3-5% loss of bone mineral density is a common side effect that is of greatest concern when a course of drug treatment is expected to six months. To help prevent bone loss, all prolonged courses should include low-dose add-back estrogen and/or progestin therapy.
* Oral contraceptives Oral contraceptives are used mainly to continue the hormonal suppression and symptom improvement initially achieved with GnRH agonists. Treatment is typically continuous, with patients taking an active pill every day until they want children or reach menopause. Side effects, which can be minimized by using low-progestin oral contraceptives, may include breakthrough bleeding, weight gain, breast tenderness, nausea, depression, irritability, hypertension, and hypercholesterolemia.
* Progestins Medroxyprogesterone acetate(*) is the progestin most frequently used in this country to treat endometriosis. Patients commonly take 10-50 mg/d po or receive 100-mg IM injections every two weeks for the first four doses, followed by 200 mg IM per month for four months. Megestrol acetate, 10-40 mg/d po for 6-9 months,(*) and norethindrone acetate, 2.5-10 mg/d po, are two other common choices. Progestins have also been used in conjunction with GnRH agonists to reduce hot flashes and prevent bone loss.
Although they are effective for reducing endometriosis symptoms, progestins are best used in women who have already had children because ovarian function can take up to a year or even longer to return to normal after a course of therapy. Side effects of progestins may include breast tenderness, breakthrough bleeding, depression, edema, irritability, and weight gain.
* Danazol Widely used for the treatment of endometriosis after being introduced two decades ago, the anabolic steroid danazol has become steadily less popular because of its severe androgenic side effects. These include decreased breast size, hirsutism, oily skin, acne, increased muscle mass, and deepening of the voice. Many women taking danazol develop mood swings, and nearly all will gain weight -- at least 8-10 pounds. The typical dosage, 400-800 mg po bid for 3-6 months, is extremely effective for reducing endometriosis symptoms, however.
* Nononsteroidal anti-inflammatory drugs NSAIDs such as naproxen sodium are appropriate for patients who have severe symptoms only one or two days a month and want to avoid the strict regimens and side effects of the more potent medical therapies. These patients typically get adequate symptom relief by taking NSAIDs as directed by the manufacturer, starting three days before menstruation and continuing until their period stops. Investigational drugs Although considered experimental in the United States, oral contraceptives containing the progestin gestrinone are used in Europe to treat endometriosis without the cholesterol-raising effect typical of most of the oral contraceptives available here. Overseas studies suggest these agents may raise the risk of thromboembolism in the lower extremities, however. Research has also identified mifepristone as a possible treatment for endometriosis. This drug may soon be approved by the FDA as an abortifacient.
When treatment is controversial
Endometriosis experts disagree about whether to treat minimal asymptomatic disease, which is commonly discovered during diagnostic laparoscopy for infertility or other conditions. Opponents of treatment in these cases say there's no need because the patient isn't in pain. They also note that research hasn't been able to prove conclusively that there is a subsequent improvement in fertility. Advocates argue that all cases of endometriosis should be treated or else they will progress.
Regardless of disease severity, treatment should always take the whole patient into account. For example, in cases of severe endometriosis affecting the bowel, the gynecologist needs to coordinate care with a surgeon. If a patient has allergies, which are more common in women with endometriosis, the gynecologist should work closely with an allergist. To help maximize the effect of treatment, patients must be counseled about the importance of healthy habits, including proper nutrition and regular exercise.
PROVIDING INFORMATION AND SUPPORT
Women with endometriosis want to know about their disease and how it's diagnosed and treated. Take the time to answer their questions, and give them a copy of "About endometriosis," the patient handout that follows this article (see page 47). Many women also need help with difficult emotional issues -- distress resulting from constant pain, multiple attempts at treatment, unpleasant drug side effects, and difficulties related to the frequent inability to have sex because of dyspareunia. Be available to listen to patients' concerns, and encourage them to ear the Endometriosis Association listed in the patient handout for referrals to nearby support groups. Gynecologists may know about support groups in local hospitals and women's centers.
How Can I Stop Endometriosis?
At some point, nearly all women with endometriosis express concern about their future fertility. Many have been told that if they want children they must try to conceive right away because it will be impossible later. That isn't necessarily true. Because hormonal treatment usually provides effective long-term disease control and a variety of methods are available to successfully enhance fertility, most patients have an excellent chance of becoming pregnant -- when they want to. Of course, their chances are best during the prime reproductive years, ages 20-35.
Because their reproductive organs are often severely distorted, patients with stage IV disease have the poorest prospects for pregnancy -- about 30% over 12 months without fertility-enhancing treatment. In comparison, the unassisted one-year pregnancy rate for the general population is about 85%. However, the likelihood of success increases sharply as disease severity decreases. Without assistance, women with stage Ill disease have about a 50% chance of becoming pregnant within a year, and those with stage I or Il endometriosis have a 60-70% chance. These reduced pregnancy rates can be increased significantly by fertility treatment.
______________________________________________________________________
A slender woman, age 29, comes for an office visit and says she stopped using oral contraception almost a year ago and hoped to be pregnant with her first child by now. She recently recalled that she had begun to have moderate pain around the time of her menstrual periods a few months before she stopped using contraception and wonders if the pain is related to her inability to conceive. The presenting problems of pain and infertility might point to endometriosis as a strong possibility, but you would also consider pelvic inflammatory disease (PID) and coincidental primary dysmenorrhea and infertility in the differential.
Although a definitive diagnosis of endometriosis can only be made by laparoscopic examination, you can test your suspicion first by pursuing a more detailed description of the dysmenorrhea:
* Has the patient had bouts of moderate or severe pain in the past, or is the pain in the last year unusual?
* Does the pain occur only during menstruation, or is it noticeable before the onset of bleeding or after the bleeding stops?
* Does she have pain at midcycle as well?
* Does she have deep dyspareunia?
* Does she have painful defecation before or during menses?
Affirmative answers to any of these questions increase your suspicion of endometriosis, particularly when the nature or quality of dysmenorrhea in the last year is different from what she experienced before. The degree of pain does not necessarily correlate with the severity of the disease (see "The staging of endometriosis," opposite).
Ways of Treating Endometriosis
Since the patient was taking an oral contraceptive when she first felt the pain, you'd increase your suspicion of endometriosis; these drugs tend to control primary dysmenorrhea. Primary dysmenorrhea also characteristically becomes milder as menstruation progresses, while pain remains steady when the dysmenorrhea is a secondary condition. Unlike the secondary dysmenorrhea caused by endometriosis, pelvic pain related to PID tends to be accompanied by fever. The pain associated with PID is not necessarily perimenstrual, nor does it recur predictably each month. Keep in mind as well that an irritable or spastic colon can flare during menstruation and produce pain that persists at a steady level.
Although endometriosis is most common in white women in their late 20s or early 30s who have delayed childbearing, recent evidence suggests that it's not uncommon in women of other races and in those who are in their teens or 40s. The incidence of endometriosis in women with unexplained infertility may be as high as 30-50%, regardless of the existence of pain.
To further evaluate the possibility of endometriosis, perform a rectovaginal examination, preferably shortly before the anticipated start of menstruation; endometrial implants are larger and more tender at that time. Palpate the cul-de-sac, the most common location for the implants. Rarely, you'll identify implants when you raise the cervix with the speculum and examine the vaginal epithelium. Nodules in the cul-de-sac are usually under 1 cm; they are palpable in about one third of women who have the disorder. Since fecal material can confuse your impression during palpation, keep in mind that true nodules in the cul-de-sac tend to be exquisitely tender. Nodularity merits referral for laparoscopy to rule out other causes of cul-de-sac or adnexal masses and to confirm the diagnosis of endometriosis.
Other findings during the rectovaginal examination that help confirm endometriosis include a fixed, retroverted uterus, some general pelvic fixation, and nodularity of the uterosacral ligaments. About one third of all women with endometriosis and half of those who have severe disease have retroversion of the uterus.
Having completed an initial evaluation of the history and physical findings, you are still not likely to be sure whether the patient has endometriosis, pelvic inflammatory disease (PID), or coincidental primary dysmenorrhea and infertility. Your management options at this point include:
* A standard workup for PID If your workup reveals negative cultures but you suspect deep infection, treat the patient with an appropriate antibiotic regimen. Insufficient relief of symptoms after a trial of antibiotics is an indication for diagnostic laparoscopy.
* Antiprostaglandin treatment Women with minimal or mild endometriosis whose only complaint is perimenstrual pain may get adequate relief with ibuprofen (Motrin, Rufen), naproxen (Naprosyn), or naproxen sodium (Anaprox) until the disease worsens. This is the first conservative therapy of choice.
* Diagnostic laparoscopy Refer the patient who has multiple or severe signs and symptoms for diagnostic laparoscopy. Laparoscopy rather than sonography is the procedure of choice because it is the only means for obtaining a definitive diagnosis (see "Endometriosis through the laparoscope," page 79).
When a diagnosis of endometriosis is reasonably certain, you may try to ease the pain with an antiprostaglandin or refer the patient first for diagnostic laparoscopy. Either way, make sure the patient's expectations are realistic. To become knowledgeable in her decision making along the way, she has to understand that this is a progressive disease that is responsive to several treatments. Explain that the goals of therapy are either to suppress the growth of the endometrial implants, usually by suppressing ovarian function, or to remove them by laparotomy or more extensive surgery. Tell her that the ultimate "cure" is menopause or a complete hysterectomy and bilateral salpingo-oophorectomy, but reassure her that other means often are effective for many years. In other words, she needs to know that your immediate objectives are to ease her discomfort and, if appropriate, to maintain her ability to have children.
Once laparoscopic study confirms minimal or mild endometriosis, consider prescribing a low-dose oral contraceptive (OC), one that contains 35[mu]g of ethinyl estradiol, for the patient under age 35 when there are no contraindications to its use (see "The staging of endometriosis," page 71). A regimen in which OCs are taken continuously, rather than with one week of interruption each cycle, does not seem to cause any special problems, and it may possibly contain the growth rate of the endometrial implants.
Danazol (Danocrine) is an alternative for laparoscopically confirmed minimal or mild endometriosis, but it is ineffective for endometrioma of the ovary. Whether any drug therapy currently available for endometriosis ultimately increases the odds for conception is questionable. In addition, six months to one year of ovarian suppression with danazol may also involve side effects such as weight gain, hirsutism, hot flashes, a decrease in breast size, and irregular or prolonged bleeding.
Some 8% of patients develop a rash while taking danazol, but this may occur as an allergic response to a dye in the capsule. Anecdotal reports suggest that patients who had this side effect lost the rash when they began taking the drug after emptying the capsule's contents into a spoon.
Despite the potential side effects, danazol might be your best choice when diagnostic laparoscopy reveals obliteration of the posterior cull-de-sac annd an absence of ovarian or retrouterine endometrima and adnexalll pathology. Using danazol as single-drug therapy for one year in this circumstance allows you to avoid recommending surgery that would entail the risk of bowel injury or the need to remove part of the vagina or bowel.
Before prescribing the drug, which should be started no later than day 5 of the menstrual cycle, make sure the patient isn't pregnant. If the patient wants to use a contraceptive while taking danazol, the barrier methods are the ones to select. Plan to do a pelvic examination every 2-3 months to monitor progress while the patient is taking danazol. In addition, plan to order liver function studies every six months for the patient who will be taking danazol longer than that. Prolonged use has been associated with a substantialll lowering of high-density lipoprotein cholesterol levels. At the typical starting dosage of 200 mg qid, the cost of danazol therapy is about $135/mo.
Endometriosis Bible Review
Consider prescribing oral medroxyprogesterone acetate (Amen, Curretab, Provera), 30 mg/d, for the patient who could take danazol but can't afford the cost of treatment. Although only relatively small studies have been done on the efficacy of medroxyprogesterone for endometriosis, its abillity to suppress ovarian function makes it a viable choice. The patient with sickle cell disease who may be sensitive to estrogen compounds is a particularly likely candidate for the drug. Like all ovarian suppressants that prevent periodic endometrial shedding, medroxyprogesterone is associated with spotting and irregular bleeding. This problem could be resolved by adding estrogen to the regimen, but that would be counterproductive in this setting. Llike danazol, medroxyprogesterone may not increase the odds of conception.
Investigational studies of luteinizing hormone releasing hormone agonists, such as buserelin and naferalin, are showing promising results. These drugs appear to cause regression of endometrial implants as effectively as danazoll, but they do not seem to cause as many androgenic side effects.
The patient who doesn't want to conceive will do welll to remain on an OC, taken in the usual cyclic manner. On the other hand, the patient who has been taking a drug for hormonal suppression for six months or a year can then stop the drug if she wants to become pregnant. If she is unsuccessfull after a year, she needs a repeat laparoscopy to identify recurrent disease and is a likely candidate for surgery. Surgical treatment for endometriosis is indicated when the patient has moderate or severe disease, when drug therapy provides inadequate relief of symptoms, or when the infertile patient is quite eager to become pregnant. The advantage of the more invasive approaches over hormonal treatment alone is that they provide more immediate and longer lasting regression of disease. Preliminary findings of studies under way to evaluate the effect of laser or electrocautery treatment on the ability to conceive are promising.
The first option for minimal and most cases of mild disese is to cauterize or vaporize those implants that are easily accessible during the initial laparoscopy procedure. Repeat laparoscopy as indicated for recurrent pain.
When diagnostic laparoscopy reveals an ovarian or retrouterine endometrioma, a sign of moderate or severe disease, conservative surgery--laparoscopy--is the most realistic treatment, particularly for the patient who wants to become pregnant. Danazol (Danocrine), 200 mg qid, is given for at least two months before surgery to improve the pelvic environment. This may allow less extensive surgery and thereby reduce the risk of postperative adhesions. Surgery may involve the excision of deeply invaded uterosacral ligaments and even a presacral neurectomy if the patient has been having severe pain. The insertion of a 32% solution of dextran 70 in 10% dextrose (Hyskon) into the pelvic cavity prior to closing may help prevent adhesions.
The fertility rate is about 50-60% of women with endometriosis following conservative surgery. Reduced pain is reported in about 85% of those who undergo presacral neurectomy. Laparoscopy may be followed by treament for 6-9 months with danazol, 200 mg qid, if the surgeon was unable to excise most of the disease.
Clearly the management of endometriosis demands flexibility on the part of the physician and the patient. Over the years, medical therapy, therapeutic laparoscopy, or laparoscopy may be indicated to contain the disease and preserve the ovaries and uterus. Openness and emotional support will help maintain the patient's trust when coping with this difficult, prgressive disorder.
If the condition becomes unbearable prior to menopause and it is unresponsive to more conservative measurers, hysterectomy usually with bilateral salpingo-oophorectomy is the final option. In some cases the distribution of implants allows the surgeon to spare the ovaries. The argument against sparing them is that estrogens fuel the endometriosis, which raises the specter of postsurgical recurrence, perhaps of severe disease. On the other hand, the dosage required for estrogen supplementation following a hysterectomy and bilateral salpingo-oophorectomy--usually up to 0.625 mg/d of conjugated estrogens (Estrocon, Premarin) or esterified estrogens (Estratab, Menest)--is unlikely to cause a resurgence of the disease
Gonadtropic-releasing hormone agonists may be safer than previously thought for endometriosis patients, results from two studies indicate.
Previously, computed tomography scans of patients' spinal trabecular bone showed decreased bone mineral density after GnRH agonist treatments. That side effect has delayed FDA approval of intranasal versions of the potent drug for endometriosis treatment.
But no such bone-loss problems turned up in two new studies using two different bone-measuring techniques.
Researchers at Rush-Presbyterian-St. Luke's Medical Center in Chicago conducted a prospective, randomized study of 38 women. Source: http://cellspynews.com For six months, 25 patients took leuprolide (Lupron, Abbott) intranasally while 13 patients took danazol (Danocrine, Winthrop-Breon). The patients also took calcium supplements daily, Dr. Ian Tummon told the American Fertility Society meeting here.
Both drugs suppressed ovarian function equally, says Dr. Tummon, an assistant professor of ob-gyn at Rush. After six months of therapy, the pregnancy rate of these patients was 70% using leuprolide, compared with 54% using danazol.
Bone mineral density. Dual-photon absorptiometry 26 weeks after treatment, measuring cortical and trabecular bone mass, showed that bone mineral density decreased slightly in the danazol group and increased slightly in the leuprolide group.
Side effects--experienced by patients in both groups--included hot flashes, vaginal dryness, and decreased libido, he says.
Researchers who conducted a similar study at Yale gave high marks to nafarelin (Syntex), another intranasal GnRH agonist. The Yale team studied 11 endometriosis patients who had been infertile for an average of four years, reports Dr. Robert G. Brzyski, formerly an ob-gyn resident at Yale.
All 11 patients improved clinically, and their disease showed no significant increase in severity in up to 18 months of follow-up, says Dr. Brzyski, who is now a clinical fellow in ob-gyn at Eastern Virginia Medical School in Norfolk. Six of the 11 conceived within four months of initiating therapy, and a seventh patient conceived four months later. Six of the seven patients who conceived did so despite some residual disease, he notes.
The therapy was "well tolerated," Dr. Brzyski says. Hot flashes and vaginal dryness were the main side effects. CT scans of the wrist revealed no change in bone density, says Dr. Florence Comite, an assistant professor of ob-gyn, pediatrics, and medicine at Yale.
Endometriosis Treatment
Both the Chicago group and the Yale group agree that the intranasal forms of GnRH agonists would offer a convenient nonsurgical treatment for endometriosis if approved this year, as expected. In injectable form,the potent drug is approved for treating prostate cancer.
In addition to treating endometriosis, GnRH agonists show promise in inducing ovulation as well as in treating breast cancer, amenorrhea, premenstrual syndrome, uterine bleeding, uterine myomata, precocious puberty, and polycystic ovaries.
Best news. The best news is that "bone loss doesn't seem to be as great a problem as we thought it would be," notes Dr. John Rock, an associate professor and director of reproductive endocrinology at Johns Hopkins in Baltimore. Previously, researchers believed that patients were losing up to 1% of their calcium within six months, but "it doesn't seem to be that much," he says. "When patients go off the medication, they recover bone mass quite quickly."
If there were no controversy over calcium loss, advocates could make a strong argument to leave endometriosis patients on GnRH agonists indefinitely, says Dr. David Archer, director of the contraceptive research program and a professor of ob-gyn at Eastern Virginia. A woman with severe endometriosis who wanted to preserve her childbearing potential could postpone surgery and control the disease with the drug, he says.
But a likelier role for intranasal GnRH agonists will be to reduce the size of fibroids or the endometrium to simplify surgery, Dr. Archer believes.
How To Cure Endometriosis
Much remains to be learned about the pathogenesis of endometriosis. Most of us learned in medical school that this disorder is probably the result of transport of viable endometrial cells to extrauterine sites via retrograde menstruation. The endometrial tissue, which may become lodged in the pelvis or at distal sites, retains its cyclic hormonal responsiveness; this accounts for the nature and periodicity of symptoms. Women with ectopic foci may experience pain resulting from inflammation and subsequent fibrosis. (In general, the deeper the lesion, the worse the pain.)
The mechanism of retrograde menstruation, first proposed in the 1920s, is still accepted today. That this process actually operates has been demonstrated in humans as well as in rhesus monkeys.
Another theory holds that immunologic mechanisms are involved in the pathogenesis. Studies show that roughly half of women with endometriosis diagnosed by laparoscopy produce autoantibodies to endometrial and/or uterine tubal tissue. Peritoneal washing of highly symptomatic patients has revealed functionally altered natural killer cells, peripheral lymphocytes, and macrophages. However, such abnormalities are not present in all women with this condition.
Endometriosis tends to be a highly familial disease. Heterozygous and homozygous models of endometriosis have been proposed. Some investigators theorize that women with mild endometriosis - a few scattered lesions and perhaps a little pain - are genetic heterozygotes, whereas women with obliterative disease are homozygotes. A long-standing, yet unproven, theory suggests that metaplastic transformation of the secondary mullerian system may be involved in the pathogenesis of early lesions.
Recent articles in the obstetrics and gynecology literature have posed interesting questions about endometriosis. Does endometriosis occur intermittently in all women? Is it perhaps not a consistent disease state, but a spectrum of conditions that vary from benign to severe? Some authors propose a differentiation between "endometriosis," a benign condition, and "endometriotic disease," defined by deep rectovaginal infiltration or ovarian cysts. However, this model does not address symptomatology: most women seek medical attention because of pain or infertility - conditions that may correlate poorly with the extent of macroscopic disease.
Table 1 - Manifestations of endometriosis
Pulmonary
Chest or pleuritic pain Shoulder pain Hemoptysis Pneumothorax
Urinary tract
Frequency Urgency Ureteral obstruction Suprapubic pressure or pain Hematuria
Gastrointestinal
Change in bowel habits Tenesmus Rectal bleeding Bloating, flatulence of recent onset Nausea, vomiting Appendicitis Dyschezia
Other manifestations
Ascites Sciatica Low back pain (diffuse or focal) or pressure Periodic pain or bleeding from any site Umbilical lesions (visible and tender)
CLASSIFICATION
Many systems of classification have been proposed, most of which are based on the location, size, depth, and extension of disease. The number of classification systems and the frequency with which they change reflect a poor understanding of the true nature of endometriosis and the difficulty of developing one classification scheme that encompasses diverse clinical manifestations. Even the revised American Fertility Society Classification System is weakened by:
* An inability to correlate clinical symptomatology or infertility
* A growing appreciation for microscopic lesions
* Observational error (the lesions of endometriosis are multicolored or occasionally nonpigmented)
Thus, this system does not help us understand how severely endometriosis affects the individual patient.
Endometriosis Remedies
These shortcomings are important because some women with minimal or no lesions visible on laparoscopy have severe pelvic pain. Other women, who are found to have extensive endometriosis when surgery is performed for totally unrelated reasons, may have no symptoms whatsoever. Recent studies, however, give weight to the observations that infertility is frequently associated with superficial implants, whereas pain is found with deeper lesions.
Our present lack of understanding of the pathophysiology of endometriosis makes it reasonable to assume that future classification schemes will benefit from new knowledge of the role of immunity, genetics, and developmental anatomy.
CLINICAL PRESENTATION
As noted, manifestations of endometriosis vary greatly from woman to woman, and no one symptom is pathognomonic. Symptoms depend, in part, on the severity and location of disease (Table 1). Pelvic pain, dysmenorrhea, dyspareunia, infertility, back pain, and rectal discomfort are the most common presentations.
If the disease involves the diaphragm, the initial complaint is often right-sided shoulder pain or abdominal pain. Pulmonary manifestations may include catamenial pneumothorax or hemoptysis. Urinary tract endometriosis may cause urgency, urinary frequency, suprapubic pressure or pain, and hematuria. Severe disease may completely obstruct the ureters, and frank renal failure may ensue. When symptoms of recurrent urinary tract infection persist despite therapy, endometriosis may be the underlying cause.
In the GI tract, signs that suggest endometriosis include diarrhea, constipation and, in general, any change in bowel habits, as well as tenesmus, rectal bleeding, and appendicitis. Appendicitis is actually one of the most common presentations of GI endometriosis, accounting for 20% of symptomatic cases.
Radicular symptoms may result from endometrial implants on nerves. This occurs most commonly on the sciatic and obturator nerves. Endometriosis can also involve the pancreas, omentum, and liver, and can sometimes produce palpable umbilical hernias. Endometriosis has even been found to cause recurrent nosebleeds.
The bottom line: endometrial implants can turn up almost anywhere. They can migrate by direct extension, by hematogenous routes, or by lymphatic channels. The greater a site's distance from the pelvis, the less likely is endometriosis to be found there.
MAKING THE DIAGNOSIS
Suspect endometriosis in any woman with pelvic pain or who is infertile. Cyclic or periodic symptoms in a premenopausal woman are other good clues (Table 2). Ask the patient about the origin of pain (it should not precede menarche). The frequency, severity, and location of pain are important clues, as is a history of pain with deep intercourse. If the patient has taken oral contraceptives, ask whether symptoms diminished while she was taking them.
Table: 2 - Clinical indications of endometriosis
Symptoms
Dysmenorrhea Dyspareunia Pelvic or back pain Infertility
Signs (abnormal findings on pelvic examination)
Tender or nodular posterior cul-de-sac and uterosacral ligaments Fixed, tender, retroverted uterus Palpable thickening or masses in the rectavaginal septum Ovarian enlargement Visible lesions in cervix or vagina
Natural Remedies For Endometriosis
Note that noncyclic or persistent symptoms do not absolutely rule out endometriosis. Indeed, undiagnosed endometriosis may be manifested by symptoms that persist for most of the month. Although these symptoms most commonly correlate with menses, they may occur before or after menstruation. Chronic pelvic pain, for example, may be present for all but a few days of the month.
CA-125 is under investigation for its role in monitoring therapy for patients with endometriosis. It is not used as a screening tool because of its low sensitivity and specificity. Antiendometrial antibodies and endometrial secretory protein PP14 are also currently being investigated as potential serum markers.
Most imaging techniques have limited use in the evaluation of endometriosis. Ultrasonography can help identify solid and cystic masses but offers no information about etiology. Although MRI is showing usefulness in the evaluation of adenomyosis, it does not offer significant information beyond ultrasonographic examination in women who have endometriosis. Laparoscopy is still required for tissue diagnosis.
If you suspect endometriosis from the patient's history, perform a pelvic examination. A diagnosis of endometriosis is made by laparoscopy in up to 90% of women who are found to have such abnormal physical findings as tenderness or nodularity along the uterosacral ligaments; a fixed, tender, retroverted uterus; palpable thickening or masses of the rectovaginal septum; or adnexal tenderness and ovarian enlargement.
In about 5% to 10% of cases, there may be a visible lesion on the vagina or cervix. A biopsy of this lesion can confirm the diagnosis, but laparoscopy is usually needed to define the extent of disease, to determine the best therapy, and to monitor the patient's response to therapy.
In short: consider endometriosis if your patient's complaints are cyclic or persistent despite therapy. Perform a pelvic examination to look for evidence of disease. If the history and physical examination both reveal suspicious fundings, there is a good chance that endometriosis may be the underlying cause.
The four stages of endometriosis
STAGE I
Minimal disease. A small volume of superficial brownish, reddish, blue-black, white, clear, or grainy implants.
STAGE II
Mild disease. The same as Stage I, except somewhat deeper, more numerous implants.
STAGE III
Moderate disease. Many deep implants, small endometriomas on one or both ovaries, and some filmy adhesions.
STAGE IV
Severe disease. Many deep implants and dense adhesions, and large endometriomas on one or both ovaries. The rectum may adhere to the back of the uterus.
The only way to diagnose endometriosis definitively is through laparoscopic visualization and tissue sampling with confirmation on histology. This method is 70-95% accurate. Imaging methods such as ultrasound, MRI, and CT aren't sensitive enough to detect endometriosis, although you may need to order them to rule out other disorders and justify laparoscopy. These other modalities can reveal ovarian masses that resemble endometriomas -- cysts containing blood and endometrial tissue.
Recent research has focused on measurement of the serum cancer antigen 125 (CA 125) level as a possible diagnostic test for endometriosis. In women with the disease, that level is usually elevated. The main problem, however, is that the level of CA 125 also rises with many other benign and malignant conditions. Because of the poor specificity of this test, measuring CA 125 levels is currently not considered useful when endometriosis is suspected.[1]
TREATMENT
There is no certain cure for endometriosis. Even with the various treatments available, the disease recurs in up to half of patients within 2-3 years.[1] The goal of treatment, then, is to keep the disease and its symptoms in check. Based on the disease stage, the severity of symptoms, and the patients age, desire to have children, and circumstances and preferences, the gynecologist typically recommends one of three approaches -- medical, surgical, or a combination. Many gynecologists prefer the latter approach, first surgically removing as much of the diseased tissue as possible and then placing the patient on medical therapy. For recurrent disease, follow-up surgery with continued medical therapy may be recommended.
Ways To Treat Endometriosis
Be aware that a few centers in this country provide immune therapy for endometriosis. This relatively new approach assumes that an immune system deficiency is at the root of the disease (see "A budding treatment for endometriosis").
Surgery
Because laparoscopy is required to definitively diagnose endometriosis, it is the most common initial treatment. After making the diagnosis, the surgeon usually excises as many endometrial implants and adhesions as possible or obliterates them through laser surgery or electrocautery. Endometriosis-related symptoms are temporarily relieved in most cases, preparing the way for medical therapy.
A total hysterectomy with bilateral oophorectomy is the most definitive treatment for endometriosis. It permanently relieves patients, pain 90% of the time and is rarely followed by disease recurrence.[1,4] However, most women with endometriosis want to preserve their fertility, so the prevailing practice is to use hysterectomy only as a last resort. Patients who do have the procedure are generally at the end of their reproductive years and already have children. At that point, their main desire is often to eliminate symptoms. Only in very rare cases is hysterectomy recommended for women still in their child bearing years -- usually when the other medical or surgical treatments available have not provided adequate pain control.
A few gynecologists are trained in an experimental procedure -- outpatient endometrial resection ablation (OPERA) -- that may be a less radical alternative to hysterectomy. As the name of the procedure suggests, only the endometrium and basement membrane are removed. The ovaries and outer surface of the uterus remain intact. The surgeon also resects any uterine fibroids that are present. (See "Uterine fibroids: Treat -- or ignore?" page 48.)
It's unclear from research whether the laparoscopic treatment of endometriosis enhances fertility. But many clinicians say it does, particularly in cases of moderate to severe disease where the patient undergoes excision of deep endometrial implants. These patients commonly become pregnant within six months of surgery after having tried and failed to conceive for many years.
Medical treatment
Medical therapy seeks to suppress ovarian function to the point that the patient doesn't menstruate. At such a high level of suppression, existing endometrial implants should no longer be stimulated by estrogen and the other hormones they need to grow and multiply, and symptoms should improve. What's more, the amenorrheic state minimizes retrograde menstruation. A variety of hormones are used to induce and maintain amenorrhea. Patients may take these for many years, either continually or cyclically in 3-9-month courses. Most clinicians agree that medical therapy doesn't enhance fertility.
* Gonadotropin-releasing hormone (GnRH) agonists GnRH agonists produce symptom improvement within three months. The most common choices are leuprolide acetate, 3.75 mg IM once a month, goserelin acetate, 3.6 mg SC once a month, or nafarelin acetate, 200[Micro]g bid taken as a nasal spray. All of these regimens are followed for 3-6 months. A major advantage of GnRH agonists is that they produce fewer side effects than the other hormonal treatments. The risks may include hot flashes, vaginal dryness, headaches, and depression. A reversible 3-5% loss of bone mineral density is a common side effect that is of greatest concern when a course of drug treatment is expected to six months. To help prevent bone loss, all prolonged courses should include low-dose add-back estrogen and/or progestin therapy.
* Oral contraceptives Oral contraceptives are used mainly to continue the hormonal suppression and symptom improvement initially achieved with GnRH agonists. Treatment is typically continuous, with patients taking an active pill every day until they want children or reach menopause. Side effects, which can be minimized by using low-progestin oral contraceptives, may include breakthrough bleeding, weight gain, breast tenderness, nausea, depression, irritability, hypertension, and hypercholesterolemia.
* Progestins Medroxyprogesterone acetate(*) is the progestin most frequently used in this country to treat endometriosis. Patients commonly take 10-50 mg/d po or receive 100-mg IM injections every two weeks for the first four doses, followed by 200 mg IM per month for four months. Megestrol acetate, 10-40 mg/d po for 6-9 months,(*) and norethindrone acetate, 2.5-10 mg/d po, are two other common choices. Progestins have also been used in conjunction with GnRH agonists to reduce hot flashes and prevent bone loss.
Although they are effective for reducing endometriosis symptoms, progestins are best used in women who have already had children because ovarian function can take up to a year or even longer to return to normal after a course of therapy. Side effects of progestins may include breast tenderness, breakthrough bleeding, depression, edema, irritability, and weight gain.
* Danazol Widely used for the treatment of endometriosis after being introduced two decades ago, the anabolic steroid danazol has become steadily less popular because of its severe androgenic side effects. These include decreased breast size, hirsutism, oily skin, acne, increased muscle mass, and deepening of the voice. Many women taking danazol develop mood swings, and nearly all will gain weight -- at least 8-10 pounds. The typical dosage, 400-800 mg po bid for 3-6 months, is extremely effective for reducing endometriosis symptoms, however.
* Nononsteroidal anti-inflammatory drugs NSAIDs such as naproxen sodium are appropriate for patients who have severe symptoms only one or two days a month and want to avoid the strict regimens and side effects of the more potent medical therapies. These patients typically get adequate symptom relief by taking NSAIDs as directed by the manufacturer, starting three days before menstruation and continuing until their period stops. Investigational drugs Although considered experimental in the United States, oral contraceptives containing the progestin gestrinone are used in Europe to treat endometriosis without the cholesterol-raising effect typical of most of the oral contraceptives available here. Overseas studies suggest these agents may raise the risk of thromboembolism in the lower extremities, however. Research has also identified mifepristone as a possible treatment for endometriosis. This drug may soon be approved by the FDA as an abortifacient.
When treatment is controversial
Endometriosis experts disagree about whether to treat minimal asymptomatic disease, which is commonly discovered during diagnostic laparoscopy for infertility or other conditions. Opponents of treatment in these cases say there's no need because the patient isn't in pain. They also note that research hasn't been able to prove conclusively that there is a subsequent improvement in fertility. Advocates argue that all cases of endometriosis should be treated or else they will progress.
Regardless of disease severity, treatment should always take the whole patient into account. For example, in cases of severe endometriosis affecting the bowel, the gynecologist needs to coordinate care with a surgeon. If a patient has allergies, which are more common in women with endometriosis, the gynecologist should work closely with an allergist. To help maximize the effect of treatment, patients must be counseled about the importance of healthy habits, including proper nutrition and regular exercise.
PROVIDING INFORMATION AND SUPPORT
Women with endometriosis want to know about their disease and how it's diagnosed and treated. Take the time to answer their questions, and give them a copy of "About endometriosis," the patient handout that follows this article (see page 47). Many women also need help with difficult emotional issues -- distress resulting from constant pain, multiple attempts at treatment, unpleasant drug side effects, and difficulties related to the frequent inability to have sex because of dyspareunia. Be available to listen to patients' concerns, and encourage them to ear the Endometriosis Association listed in the patient handout for referrals to nearby support groups. Gynecologists may know about support groups in local hospitals and women's centers.
How Can I Stop Endometriosis?
At some point, nearly all women with endometriosis express concern about their future fertility. Many have been told that if they want children they must try to conceive right away because it will be impossible later. That isn't necessarily true. Because hormonal treatment usually provides effective long-term disease control and a variety of methods are available to successfully enhance fertility, most patients have an excellent chance of becoming pregnant -- when they want to. Of course, their chances are best during the prime reproductive years, ages 20-35.
Because their reproductive organs are often severely distorted, patients with stage IV disease have the poorest prospects for pregnancy -- about 30% over 12 months without fertility-enhancing treatment. In comparison, the unassisted one-year pregnancy rate for the general population is about 85%. However, the likelihood of success increases sharply as disease severity decreases. Without assistance, women with stage Ill disease have about a 50% chance of becoming pregnant within a year, and those with stage I or Il endometriosis have a 60-70% chance. These reduced pregnancy rates can be increased significantly by fertility treatment.
______________________________________________________________________
A slender woman, age 29, comes for an office visit and says she stopped using oral contraception almost a year ago and hoped to be pregnant with her first child by now. She recently recalled that she had begun to have moderate pain around the time of her menstrual periods a few months before she stopped using contraception and wonders if the pain is related to her inability to conceive. The presenting problems of pain and infertility might point to endometriosis as a strong possibility, but you would also consider pelvic inflammatory disease (PID) and coincidental primary dysmenorrhea and infertility in the differential.
Although a definitive diagnosis of endometriosis can only be made by laparoscopic examination, you can test your suspicion first by pursuing a more detailed description of the dysmenorrhea:
* Has the patient had bouts of moderate or severe pain in the past, or is the pain in the last year unusual?
* Does the pain occur only during menstruation, or is it noticeable before the onset of bleeding or after the bleeding stops?
* Does she have pain at midcycle as well?
* Does she have deep dyspareunia?
* Does she have painful defecation before or during menses?
Affirmative answers to any of these questions increase your suspicion of endometriosis, particularly when the nature or quality of dysmenorrhea in the last year is different from what she experienced before. The degree of pain does not necessarily correlate with the severity of the disease (see "The staging of endometriosis," opposite).
Ways of Treating Endometriosis
Since the patient was taking an oral contraceptive when she first felt the pain, you'd increase your suspicion of endometriosis; these drugs tend to control primary dysmenorrhea. Primary dysmenorrhea also characteristically becomes milder as menstruation progresses, while pain remains steady when the dysmenorrhea is a secondary condition. Unlike the secondary dysmenorrhea caused by endometriosis, pelvic pain related to PID tends to be accompanied by fever. The pain associated with PID is not necessarily perimenstrual, nor does it recur predictably each month. Keep in mind as well that an irritable or spastic colon can flare during menstruation and produce pain that persists at a steady level.
Although endometriosis is most common in white women in their late 20s or early 30s who have delayed childbearing, recent evidence suggests that it's not uncommon in women of other races and in those who are in their teens or 40s. The incidence of endometriosis in women with unexplained infertility may be as high as 30-50%, regardless of the existence of pain.
To further evaluate the possibility of endometriosis, perform a rectovaginal examination, preferably shortly before the anticipated start of menstruation; endometrial implants are larger and more tender at that time. Palpate the cul-de-sac, the most common location for the implants. Rarely, you'll identify implants when you raise the cervix with the speculum and examine the vaginal epithelium. Nodules in the cul-de-sac are usually under 1 cm; they are palpable in about one third of women who have the disorder. Since fecal material can confuse your impression during palpation, keep in mind that true nodules in the cul-de-sac tend to be exquisitely tender. Nodularity merits referral for laparoscopy to rule out other causes of cul-de-sac or adnexal masses and to confirm the diagnosis of endometriosis.
Other findings during the rectovaginal examination that help confirm endometriosis include a fixed, retroverted uterus, some general pelvic fixation, and nodularity of the uterosacral ligaments. About one third of all women with endometriosis and half of those who have severe disease have retroversion of the uterus.
Having completed an initial evaluation of the history and physical findings, you are still not likely to be sure whether the patient has endometriosis, pelvic inflammatory disease (PID), or coincidental primary dysmenorrhea and infertility. Your management options at this point include:
* A standard workup for PID If your workup reveals negative cultures but you suspect deep infection, treat the patient with an appropriate antibiotic regimen. Insufficient relief of symptoms after a trial of antibiotics is an indication for diagnostic laparoscopy.
* Antiprostaglandin treatment Women with minimal or mild endometriosis whose only complaint is perimenstrual pain may get adequate relief with ibuprofen (Motrin, Rufen), naproxen (Naprosyn), or naproxen sodium (Anaprox) until the disease worsens. This is the first conservative therapy of choice.
* Diagnostic laparoscopy Refer the patient who has multiple or severe signs and symptoms for diagnostic laparoscopy. Laparoscopy rather than sonography is the procedure of choice because it is the only means for obtaining a definitive diagnosis (see "Endometriosis through the laparoscope," page 79).
When a diagnosis of endometriosis is reasonably certain, you may try to ease the pain with an antiprostaglandin or refer the patient first for diagnostic laparoscopy. Either way, make sure the patient's expectations are realistic. To become knowledgeable in her decision making along the way, she has to understand that this is a progressive disease that is responsive to several treatments. Explain that the goals of therapy are either to suppress the growth of the endometrial implants, usually by suppressing ovarian function, or to remove them by laparotomy or more extensive surgery. Tell her that the ultimate "cure" is menopause or a complete hysterectomy and bilateral salpingo-oophorectomy, but reassure her that other means often are effective for many years. In other words, she needs to know that your immediate objectives are to ease her discomfort and, if appropriate, to maintain her ability to have children.
Once laparoscopic study confirms minimal or mild endometriosis, consider prescribing a low-dose oral contraceptive (OC), one that contains 35[mu]g of ethinyl estradiol, for the patient under age 35 when there are no contraindications to its use (see "The staging of endometriosis," page 71). A regimen in which OCs are taken continuously, rather than with one week of interruption each cycle, does not seem to cause any special problems, and it may possibly contain the growth rate of the endometrial implants.
Danazol (Danocrine) is an alternative for laparoscopically confirmed minimal or mild endometriosis, but it is ineffective for endometrioma of the ovary. Whether any drug therapy currently available for endometriosis ultimately increases the odds for conception is questionable. In addition, six months to one year of ovarian suppression with danazol may also involve side effects such as weight gain, hirsutism, hot flashes, a decrease in breast size, and irregular or prolonged bleeding.
Some 8% of patients develop a rash while taking danazol, but this may occur as an allergic response to a dye in the capsule. Anecdotal reports suggest that patients who had this side effect lost the rash when they began taking the drug after emptying the capsule's contents into a spoon.
Despite the potential side effects, danazol might be your best choice when diagnostic laparoscopy reveals obliteration of the posterior cull-de-sac annd an absence of ovarian or retrouterine endometrima and adnexalll pathology. Using danazol as single-drug therapy for one year in this circumstance allows you to avoid recommending surgery that would entail the risk of bowel injury or the need to remove part of the vagina or bowel.
Before prescribing the drug, which should be started no later than day 5 of the menstrual cycle, make sure the patient isn't pregnant. If the patient wants to use a contraceptive while taking danazol, the barrier methods are the ones to select. Plan to do a pelvic examination every 2-3 months to monitor progress while the patient is taking danazol. In addition, plan to order liver function studies every six months for the patient who will be taking danazol longer than that. Prolonged use has been associated with a substantialll lowering of high-density lipoprotein cholesterol levels. At the typical starting dosage of 200 mg qid, the cost of danazol therapy is about $135/mo.
Endometriosis Bible Review
Consider prescribing oral medroxyprogesterone acetate (Amen, Curretab, Provera), 30 mg/d, for the patient who could take danazol but can't afford the cost of treatment. Although only relatively small studies have been done on the efficacy of medroxyprogesterone for endometriosis, its abillity to suppress ovarian function makes it a viable choice. The patient with sickle cell disease who may be sensitive to estrogen compounds is a particularly likely candidate for the drug. Like all ovarian suppressants that prevent periodic endometrial shedding, medroxyprogesterone is associated with spotting and irregular bleeding. This problem could be resolved by adding estrogen to the regimen, but that would be counterproductive in this setting. Llike danazol, medroxyprogesterone may not increase the odds of conception.
Investigational studies of luteinizing hormone releasing hormone agonists, such as buserelin and naferalin, are showing promising results. These drugs appear to cause regression of endometrial implants as effectively as danazoll, but they do not seem to cause as many androgenic side effects.
The patient who doesn't want to conceive will do welll to remain on an OC, taken in the usual cyclic manner. On the other hand, the patient who has been taking a drug for hormonal suppression for six months or a year can then stop the drug if she wants to become pregnant. If she is unsuccessfull after a year, she needs a repeat laparoscopy to identify recurrent disease and is a likely candidate for surgery. Surgical treatment for endometriosis is indicated when the patient has moderate or severe disease, when drug therapy provides inadequate relief of symptoms, or when the infertile patient is quite eager to become pregnant. The advantage of the more invasive approaches over hormonal treatment alone is that they provide more immediate and longer lasting regression of disease. Preliminary findings of studies under way to evaluate the effect of laser or electrocautery treatment on the ability to conceive are promising.
The first option for minimal and most cases of mild disese is to cauterize or vaporize those implants that are easily accessible during the initial laparoscopy procedure. Repeat laparoscopy as indicated for recurrent pain.
When diagnostic laparoscopy reveals an ovarian or retrouterine endometrioma, a sign of moderate or severe disease, conservative surgery--laparoscopy--is the most realistic treatment, particularly for the patient who wants to become pregnant. Danazol (Danocrine), 200 mg qid, is given for at least two months before surgery to improve the pelvic environment. This may allow less extensive surgery and thereby reduce the risk of postperative adhesions. Surgery may involve the excision of deeply invaded uterosacral ligaments and even a presacral neurectomy if the patient has been having severe pain. The insertion of a 32% solution of dextran 70 in 10% dextrose (Hyskon) into the pelvic cavity prior to closing may help prevent adhesions.
The fertility rate is about 50-60% of women with endometriosis following conservative surgery. Reduced pain is reported in about 85% of those who undergo presacral neurectomy. Laparoscopy may be followed by treament for 6-9 months with danazol, 200 mg qid, if the surgeon was unable to excise most of the disease.
Clearly the management of endometriosis demands flexibility on the part of the physician and the patient. Over the years, medical therapy, therapeutic laparoscopy, or laparoscopy may be indicated to contain the disease and preserve the ovaries and uterus. Openness and emotional support will help maintain the patient's trust when coping with this difficult, prgressive disorder.
If the condition becomes unbearable prior to menopause and it is unresponsive to more conservative measurers, hysterectomy usually with bilateral salpingo-oophorectomy is the final option. In some cases the distribution of implants allows the surgeon to spare the ovaries. The argument against sparing them is that estrogens fuel the endometriosis, which raises the specter of postsurgical recurrence, perhaps of severe disease. On the other hand, the dosage required for estrogen supplementation following a hysterectomy and bilateral salpingo-oophorectomy--usually up to 0.625 mg/d of conjugated estrogens (Estrocon, Premarin) or esterified estrogens (Estratab, Menest)--is unlikely to cause a resurgence of the disease