CHAPTER 5 Endometriosis
Endometriosis is a condition in which endometrial tissue implants in sites outside the uterus, most commonly in the ovaries, fallopian tubes, and peritoneum. It is estimated to affect as many as 15% of all women.1 Endometriosis is the third leading cause of hospitalization for gynecologic problems in the United States and a major reason for hysterectomy.
The implants of endometrial tissue in endometriosis are derived from the glandular and stromal tissues of the endometrium, the lining of the uterus. These hormone-responsive tissues maintain their response to hormonal stimulation even outside the uterus. During the normal shedding of the endometrial lining at the end of each menstrual cycle, the endometriotic tissue bleeds into the surrounding tissue, causing local inflammation. This peritoneal inflammation leads to the formation of adhesions and ovarian cysts, resulting in pain2 and sometimes infertility.3 Symptoms typically include dysmenorrhea, dyspareunia, and abdominal pain. The risk of ectopic (tubal) pregnancy is increased if the fallopian tube becomes narrowed as a result of the formation of adhesions. Infertility occurs in many women with endometriosis.
The origin of endometriosis is not completely understood, but retrograde menstruation, which occurs in roughly 90% of women may play a role.4 When a woman menstruates, some menstrual blood, containing endometrial tissue, flows into the fallopian tubes instead of through the cervix and into the vagina. This tissue can then implant and grow on surrounding organs. But if so many women experience retrograde flow, why does endometriosis develop in so few? Researchers hypothesize that the immune system fails to seek out and eliminate this aberrant tissue. It is thought that these endometrial cells implant in women with deficient cell-mediated immunity.5
Endometriosis also appears to involve the humoral immune system; the formation of autoantibodies to endometrial tissue has been noted.6
Environmental factors may play a role in the development of endometriosis. A team of investigators has linked the environmental toxin dioxin (2,7,8-tetra-chloro-dibenzo-p-dioxin) to endometriosis in primates.7 It is speculated that endometriosis develops after excessive dietary exposure to dioxin and related pesticides. Chemotoxins such as dioxin are known to disrupt the reproductive and immune systems8 and have also been found to increase the risk of breast and prostate cancer.
Genetics may be a contributing factor in endometriosis; first-degree relatives of women with the condition are at approximately 10 times greater risk of having it themselves.9 The reality is that the cause of endometriosis is likely multifactorial and that it comprises a combination of physiologic, immunologic, genetic, and environmental factors.
TREATMENT
Nonsteroidal Antiinflammatory Drugs
For mild to moderate pain associated with endometriosis, nonsteroidal antiinflammatory agents can offer effective, temporary relief. Ibuprofen, naproxen, and mefenamic acid, among others, are effective and safe when used appropriately for short periods. As many as 80% of all women experience some relief with these agents; however, complete alleviation of pain does not always occur. Something more than just prostaglandins is probably responsible for the pain associated with the disorder. Acetaminophen has not been as effective, probably because of its lack of antiinflammatory activity.10 Women with a history of peptic ulcer disease or renal failure should check with a health care provider before using nonsteroidal antiinflammatory drugs.
Hormonal Therapies
Oral contraceptives.
For women who are not attempting pregnancy, oral contraceptives (OCs) can be used to control pelvic pain. Cyclic therapy (3 weeks on, 1 week off) may be used; however, continuous therapy is most often recommended. Combination OCs that contain both estrogen and progesterone are taken every day. This places the woman in a state of “pseudopregnancy” and prevents the endometrial implants from enlarging, bleeding, and causing pain. In clinical trials, as many as 90% of women with endometriosis have achieved improvement with this therapy.11 Symptoms often recur when treatment is discontinued; thus use of OCs offers a long-term treatment strategy. Common adverse effects associated with OCs include nausea, breakthrough bleeding, breast tenderness, headache, and weight gain. This therapy works best for women who do not currently desire pregnancy, who do not smoke, and who do not have a history of blood clots. Some practitioners recommend OCs for patients at high risk for endometriosis.
Progestins.
Prolonged administration of progestin induces endometrial atrophy, which limits the growth of endometrial implants. The progestin medroxyprogesterone acetate (MPA), administered orally or as a long-acting depot injection, is commonly prescribed for endometriosis, although it is no longer approved by the U.S. Food and Drug Administration (FDA) for this indication. When given by injection, MPA suppresses ovulation and provides pain relief for many women.12 The most common adverse effects of MPA are weight gain, depression, breast tenderness, and reduced libido.
Gonadotropin-releasing hormone agonists.
When continuous therapy with OCs does not effectively control endometriosis-related pain, gonadotropin-releasing hormone (GnRH) agonists are usually tried. Initially these agents increase circulating levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), resulting in a worsening of symptoms during the first month of therapy. However, long-term administration leads to a decline in LH and FSH secretion, followed by inhibition of ovulation and menstruation. These drugs place the body in a state of “pseudomenopause.” The pituitary gland decreases production of LH and FSH, which in turn causes a reduction in ovarian secretion of estrogen. Menstrual cycles become irregular or cease, and implants of endometrial tissue shrink as hormone levels decrease.13 At the time of this writing, three GnRH agonists have been approved by the FDA for the treatment of endometriosis: goserelin, leuprolide, and nafarelin.
Although these drugs are often effective, their side effects must be considered. The patient who takes such an agent is placed in a menopausal state (reversible with discontinuation of the drug) and may accordingly experience hot flashes, vaginal dryness, depression, weight gain, insomnia, and bone loss. Because of the loss of bone density and because long-term effects of therapy are uncertain, treatment with GnRH agonists has been limited to 6 months. However, this practice may change; newer research has shown that “add-back” hormone replacement therapy (HRT) can maintain bone mineral density (BMD) and reduce both the incidence and severity of hot flashes.14 The authors of one prospective, randomized, placebo-controlled trial found that goserelin plus HRT is as effective as goserelin alone in alleviating the pain and symptoms of endometriosis while reducing the loss of BMD and the physiologic side effects of hot flashes and vaginal dryness.15 When a GnRH agonist is the treatment of choice, HRT should be used in combination.16
Danazol.
The first drug approved for the treatment of endometriosis was danazol, a synthetic male hormone. The antiestrogenic activity of danazol causes regression and shrinkage of both the uterine lining (endometrium) and endometrial implants. Evidence also suggests that it helps reduce the extent of endometriosis associated with autoimmune abnormalities.17 Relief of pain is obtained while the drug is being used but returns once the woman stops taking it. Practitioners should note that this drug is pregnancy category X and advise patients to use appropriate barrier methods, even though danazol inhibits ovulation. Side effects include hot flashes, weight gain, acne, male pattern hair growth, muscle cramps, reduction of breast size, and increased cholesterol levels. The androgenic effects may be irreversible, so patients must be instructed to watch closely for signs of virilization.
Surgery
Laparotomy may be necessary if scar tissue is excessive or if the endometrial implants are very large (endometriomas). This surgery is more extensive and the recovery time is longer, but laparotomy is often necessary for those with extensive implants and adhesions. The results of surgical treatment are not permanent in all women. Recurrence rates range from 5% to 20% per year, with a rate of 40% after 5 years.18 The rate of recurrence depends on the severity and extent of endometriosis, the surgical method used, and the skill of the surgeon.19 Some practitioners recommend hormone therapy to prevent the reappearance of endometriotic implants in women who do not desire pregnancy.
Integrative Approaches
Many of the measures taken in the past to relieve pelvic pain and menstrual cramps are still used by herbalists. Most contemporary practitioners of these systems of medicine rely on a holistic approach to treatment. The following is a review of some of the dietary approaches and botanical remedies that are either being recommended for the treatment endometriosis or show some promise of efficacy. Few randomized studies have been conducted to support the use of these recommendations, although many are well founded in a biologically plausible approach.
Dietary considerations.
Common sense indicates that a woman living with endometriosis should focus on a diet rich in vegetables and fiber, as this type of diet has been shown to reduce the level of active estrogens in the bloodstream.20 A high-fiber diet can reduce the amount of estrogen that is reabsorbed and increase the amount that is excreted in the feces. Because estrogen has been shown to support the growth of endometriotic implants, a decrease in the circulating level of this hormone might be beneficial.
Some women choose to eat organically grown foods, when possible, to reduce their dietary intake of chemotoxins. The Environmental Protection Agency estimates that 90% of human dioxin exposure comes through food, and dioxin levels are highest in sources such as meat and dairy products.21 Increased consumption of plant-based foods and fish paired with a reduced intake of other animal products may be beneficial to health in general and specifically helpful for women with endometriosis and those at high risk for the condition because of the presence of established risk factors (discussed previously). In many traditional systems of medicine, reduced intake of animal products is recommended for patients with inflammatory conditions. Such recommendations are biochemically plausible. For example, arachidonic acid (AA) is found preformed in animal fats and dairy products. When AA is liberated from the cell membrane, it is converted to the inflammatory prostaglandin-2 series and thromboxanes by the enzyme cyclooxygenase or to the inflammatory leukotrienes by way of the lipoxygenase pathway. All roads lead to inflammation.
Essential fatty acids.
Several articles addressing the association of low omega-3 intake and dysmenorrhea have been published. Danish researchers found that a higher intake of marine omega-3 fatty acids was associated with less menstrual pain.22 In one small randomized crossover study of 42 adolescent girls with primary dysmenorrhea, participants took fish oil (1,080 mg of eicosapentaenoic acid and 720 mg of docosahexaenoic acid) and 1.5 mg of vitamin E each day for 2 months and then took placebo or took placebo for 2 months and followed it with the active treatment. On a 7-point scale (4 representing “moderately effective”), 73% of the girls rated the treatment a 4 or higher.23 Although this study focused on primary dysmenorrhea in adolescents, not endometriosis, the biochemical rationale remains the same. The purpose of reducing AA and increasing omega-3 fatty acids in the diet is to increase the levels of the antiinflammatory prostaglandin-1 and -3 series while decreasing the presence of the proinflammatory prostaglandin-2 series.
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