Menstrual Disorders: Endometriosis, Dysmenorrhea, and Premenstrual Dysphoric Disorder
Irene Woo
Melissa Yates
ENDOMETRIOSIS
Endometriosis is defined as the extrauterine presence of functioning endometrial glands and stroma. It is most commonly found in the ovaries but also located in the pouch of Douglas, vesicouterine space, uterosacral ligaments, and surrounding pelvic peritoneum. It is less commonly seen in laparotomy and episiotomy scars; appendix, pleural, and pericardial cavities; and the cervix.
Theories of the Pathogenesis of Endometriosis
The etiology of endometriosis is unknown. Several theories involving anatomic, immunologic, hormonal, and genetic factors have been postulated.
Retrograde menstruation: Sampson’s original theory suggests that endometriosis is related to retrograde menstruation of endometrial tissue via the fallopian tubes into the peritoneal cavity. Support for this theory is as follows:
Blood flow from the fimbriated ends of fallopian tubes has been visualized during laparoscopy (seen in 90% of women with patent fallopian tubes).
Endometriosis is most often found in the dependent portions of the pelvis.
Incidence of endometriosis is higher in women with obstruction to normal outward menstrual flow (e.g., cervical stenosis).
Endometriosis is more common in women with shorter menstrual cycles or longer duration of flow, providing more opportunity for endometrial implantation.
Immunologic factors: Increasing data suggest that specific immunologic factors at the site of endometrial implants play a major role in determining whether and to what extent a patient will develop the disease. These factors are thought to explain the attachment and proliferation of the endometriotic cells.
Inflammatory factors: Elevated levels of interleukin-6 and tumor necrosis factor-α have been noted in the peritoneal fluid of endometriosis patients. Interleukin-8 may help in the attachment of endometrial implants in the peritoneum and is also an angiogenic agent.
Hormonal factors: Unlike normal endometrial tissue, endometriotic implants can produce aromatase, leading to extraovarian estrogen production. This may explain why endometriosis can recur in women who have undergone hysterectomy and bilateral salpingo-oophorectomy. Prostaglandin E2, a proinflammatory compound, has been shown to be a powerful inducer of aromatase activity in endometriotic implants.
Coelomic metaplasia: This theory postulates that totipotential cells of the ovary and peritoneum are transformed into endometriotic lesions by repeated hormonal or infectious stimuli. This may explain the finding of endometriosis in mature teratomas and extraperitoneal sites.
Lymphatic spread: One study showed that 29% of women with endometriosis at autopsy had positive pelvic lymph nodes for the disease. Thus, lymphatic spread may be another mechanism to explain why endometriotic implants can be found in remote anatomic areas, such as the lung.
Genetic factors: Women who have a first-degree relative with endometriosis have a sevenfold greater risk of developing endometriosis. The mode of inheritance is most likely multifactorial.
Patient Characteristics
Mean age at diagnosis is 25 to 30 years. The greatest incidence has been observed in nulliparous women with early age at menarche and shorter menstrual cycles. Increased parity and greater cumulative lactation have been shown to be protective factors in development of endometriosis.
Although some women with endometriosis are asymptomatic, the most common symptoms are infertility and pelvic pain.
Infertility: Incidence of endometriosis is believed to be 20% to 40% among infertile couples, with some studies showing endometriosis to be 7 to 10 times more likely in this patient group. Often, asymptomatic patients undergoing laparoscopy for infertility often will be diagnosed with mild endometriosis.
Pelvic pain: Seventy-one percent to 87% of women with chronic pelvic pain have endometriosis. Endometrial lesions can lead to chronic inflammation with increase in inflammatory cytokines and subsequent overproduction of prostaglandins, both of which can be a source of pain. Furthermore, endometriotic lesions may harbor high levels of nerve growth factors. However, the severity of pelvic pain does not correlate with the amount of endometriosis present. The pain typically associated with endometriosis is central, deep, and often in the rectal area. Unilateral pain may be compatible with lesions in the ovary or pelvic sidewall. Dysuria or dyschezia can result from urinary or intestinal tract involvement, respectively, and oftentimes predict deeply infiltrating endometriosis. Forty percent to 50% of patients with deep dyspareunia have been found to have endometriosis.
Incidence of endometriosis in patients with dysmenorrhea is believed to be 40% to 60%. One study found endometriotic implants in approximately 70% of teenagers who underwent laparoscopy for chronic pelvic pain. Dysmenorrhea often starts before the onset of menstrual bleeding and continues until bleeding abates.
Abnormal Clinical Findings Associated with Endometriosis
Nodularity of the uterosacral ligaments, which are often tender and enlarged
Painful swelling of the rectovaginal septum
Pain with motion of the uterus and adnexa
Fixed retroverted uterus and large immobile adnexa are indicative of severe pelvic disease.
Confirmation of Diagnosis
Definitive diagnosis can be made only through histology and examination of lesions removed at the time of surgery. Histology reveals both endometrial glands and stroma. Hemosiderin-laden macrophages have been identified in 77% of endometriosis biopsy specimens. Pelvic ultrasonography can be useful in differentiating the presence of endometriomas from other adnexal masses.
Experienced clinicians often presumptively diagnose endometriosis based on clinical history and timing of symptoms. First-line therapy with oral contraceptive pills can be initiated without a surgical diagnosis; however, when this fails, a thorough survey of the pelvis via diagnostic laparoscopy is recommended. Endometriotic lesions classically appear as blue-black powder-burn visual appearance; however, studies have reported a marked discrepancy in appearance of the lesions and the histology. Nonclassic lesions may appear vesicular, red, white, tan, or nonpigmented. The presence of defects in the peritoneum (usually scarring overlying endometrial implants) is known as Allen-Masters syndrome. Endometriomas, “chocolate cysts,” appear filled with dark brown blood.
Medical Treatment
Estrogen stimulates the growth of endometriotic implants similar to its effect on normal endometrial tissue. Medical therapy is aimed at suppressing ovarian estrogen stimulation by interrupting the hypothalamic-pituitary-ovarian axis. Inhibition of ovulation by gonadotropin suppression removes the stimulation of endometriosis by cycling sex steroids.
Oral contraceptive pills (OCPs): These pills cause anovulation and decidualization, which results in atrophy of endometrial tissue. Symptomatic relief of pelvic pain and dysmenorrhea is reported in 60% to 95% of patients. However, the
estrogenic component may potentially stimulate growth and increase pain during the first few weeks of treatment. The recommended dose is a 20- to 30-mg ethinyl estradiol pill. Continuous combined OCPs can provide significant pain relief in patients suffering mainly from dysmenorrhea.
Gonadotropin-releasing hormone (GnRH) agonists: when given over the longterm suppress pituitary function by downregulating pituitary GnRH receptors. This interruption of the hypothalamic-pituitary-ovarian axis produces a “medical oophorectomy” or “pseudomenopause.” Three available agents are leuprolide acetate (Lupron Depot), 3.75 mg by intramuscular injection every month for 6 months; nafarelin acetate nasal spray, 200 mg twice daily for 6 months; and goserelin acetate (Zoladex), 3.6 mg subcutaneous implants at 28-day intervals for 6 months. Side effects are related to the hypoestrogenic state. The U.S. Food and Drug Administration (FDA) has approved the use of a 12-month course to avoid the long-term consequences of the hypoestrogenic state on bone metabolism and lipid profile changes.
Add-back therapy: largely used for minimization of side effects. Numerous studies have demonstrated the efficacy of adding back combined estrogen/progesterone to patients on GnRH agonist therapy. Patients receiving add-back therapy have significantly less vasomotor side effects and bone mineral density loss over a 6-month period while still benefiting from pain improvement from their endometriosis. Vaginal bleeding is a side effect of add-back therapy and is dose dependent. A postmenopausal estrogen-progesterone add-back regimen can be used, such as daily conjugated estrogen 0.625 mg together with medroxyprogesterone acetate 2.5 mg. An alternate regimen is 2.5 mg norethindrone acetate daily.
Progestins: Progestins inhibit ovulation by luteinizing hormone (LH) suppression and, eventually, may induce amenorrhea (Table 38-1). They also suppress endometriosis through decidualization and atrophy of endometrial tissue. Progesterone therapy can be continued for suppression of endometriosis symptomatology; however, health care providers should be aware of the potential for bone demineralization with long-term progesterone use.
Danazol (Danocrine): a derivative of the synthetic steroid 17α-ethinyl testosterone. It suppresses the midcycle LH surge, inhibits steroidogenesis in the human corpus luteum, and produces a high-androgen and low-estrogen environment that does not support the growth of endometriosis. Approximately 80% of patients experience relief or improvement in symptoms within 2 months of beginning danazol treatment. Androgenic side effects greatly reduce compliance. Recurrence of symptoms is almost 50% within 4 to 12 months after discontinuation of therapy. Adverse side effects occur in approximately 15% of women taking danazol.
Aromatase inhibitors: Recent studies have evaluated the third-generation aromatase inhibitors, letrozole and anastrozole, for treatment of endometriosis refractory to other modalities. They are used alone or combined with GnRH agonists. These medications have been shown to decrease circulating estrogen levels by 50%. The most significant side effect is decreased bone density, which is not necessarily ameliorated with the use of calcium and vitamin D; however, evidence at this point is conflicting with regard to the overall decrease in bone density, requiring further study.
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