In the typical patient, the ectopic implants are located in the pelvis and manifest as severe dysmenorrhea, chronic pelvic pain, or infertility. More unusual implantation sites can be responsible for bizarre symptoms such as cyclic hemoptysis and catamenial seizures. The hormonal responsiveness of the implants can be exploited and offers the rationale for current methods of medical therapy.

Pathophysiology: Ectopic endometrial tissues most commonly are located in the dependent portions of the female pelvis (posterior and anterior cul-de-sac, uterosacral ligaments, tubes, ovaries), but any organ system is potentially at risk.

These ectopic foci respond to cyclic hormonal fluctuations in much the same way as intrauterine endometrium with proliferation, secretory activity, and cyclic sloughing of menstrual material. The products of this metabolic activity, including the concentrated and cyclic release of cytokines and prostaglandins, lead to an altered inflammatory response characterized by neovascularization and fibrosis formation. Some investigators have been able to demonstrate abnormal T-cell and B-cell function, abnormal complement deposition, and altered interleukin 6 production in women with this disease.

The associated pain, adhesion formation, and anatomic distortion are responsible for the clinical consequences of this disease.

Frequency:

• In the US: The exact incidence in the general population is unknown because the definitive diagnosis requires biopsy or visualization of the endometriotic implants at laparoscopy or laparotomy. The best estimates of incidence in the general female population are 5-10%, and they come from women with proven fertility undergoing tubal sterilization procedures.

  Incidence has been shown to be as high as 60% in women undergoing surgical evaluation for dysmenorrhea and 30% in women being evaluated for infertility. In a large series involving adolescent females with chronic pelvic pain, 45% were found to have endometriosis at laparoscopy. Of note, only 25% had a normal pelvis. In that series, the rate of endometriosis was found to increase with age from 12% in females aged 11-13 years to 45% in females aged 20-21 years.

• Internationally: A strong racial predilection does not appear to exist, and US rates should reflect those of the international community.

Mortality/Morbidity: Adolescent patients typically present with increasingly severe dysmenorrhea and/or chronic pelvic pain. Any persistent complaints that seem cyclic in nature should prompt the practitioner to consider a search for endometriosis.

• Symptoms do not correlate well with disease severity. Significant dysfunction can be present with minimal gross disease, while severe endometriosis is sometimes asymptomatic.

• The pain of endometriosis responds poorly to antiprostaglandins and oral contraceptive pills.

• Symptoms are related to the site of endometriotic implants and the organ system involved.

Race: Previous studies suggesting increased rates in certain ethnic groups have not been supported by well-designed investigations. Strong racial predilection to endometriosis does not appear to exist.

Sex: Obviously, this is a disease largely confined to the female population. Interestingly, scattered case reports exist of lesions, histologically indistinguishable from endometriosis, found in men exposed to high-dose exogenous estrogens.

Age: Endometriosis largely is confined to women of reproductive age with an active hypothalamic-pituitary-ovarian axis.

• Prepubertal girls do not seem to be at risk for this disease, although the number of reports of endometriosis in young women shortly after menarche is increasing.

• Menopause (whether spontaneous or induced through surgical or medical means) usually leads to resolution of symptoms. The disease seems to remain quiescent even in the face of hormone replacement therapy.

History: Symptoms of endometriosis can be variable, but typically reflect the area of involvement. Because the majority of endometriotic implants are found on the uterus, ovaries, and posterior peritoneum, the patient usually presents with a history of progressively increasing pelvic pain and/or secondary dysmenorrhea.

In contrast to primary dysmenorrhea, pain associated with endometriosis is minimally responsive to nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclic oral contraceptive pills.

• Common elements in the history include nulliparity and regular though short menstrual cycles with prolonged flow of 8 or more days. Onset of pain usually precedes flow by a few days and begins to resolve 1-2 days into the menses. Patients who are sexually active may report deep dyspareunia that is at its worst in the premenstrual phase of the cycle.

• Not uncommonly, women report painful bowel movements, diarrhea, or even hematochezia in association with their menses when endometriosis involves the rectosigmoid colon. Likewise, dysuria, flank pain, or hematuria may be present if the bladder or ureters are involved.

• Occasionally, patients present with a cyclically painful, expanding mass in a pelvic surgery scar. Excision reveals a focus of endometriosis.

• More uncommon cyclic symptoms include hemoptysis (pulmonary involvement), catamenial seizures (endometriotic lesions in the brain), and umbilical bleeding (implants in the umbilicus).

• Partial or complete bowel obstruction occasionally occurs due to either adhesion formation or a circumferential endometriosis lesion.

• When the products of cyclic sloughing of endometriotic implants become entrapped by cyst formation, the resulting mass is referred to as an endometrioma. These can occur in any location but are found most commonly involving one or both ovaries. These masses can become quite painful, and rupture presents as an acute surgical abdomen.

• A familial/genetic predisposition has been documented. A woman with a first-degree relative with endometriosis has a lifetime risk of the disease approximately 10 times that of a woman without an affected family member.

• In one large case series, the average onset of cyclic or noncyclic pain was 2.9 years after menarche.

Physical:

• Patients with endometriosis frequently do not have any physical findings beyond tenderness related to the site of involvement.

• Findings suggestive of endometriosis include uterosacral ligament nodularity and tenderness, adnexal tenderness, and/or a tender adnexal mass.

Causes:

• Early in the 20th century, Samson proposed his theory of retrograde menstruation as a cause of endometriosis. Subsequent studies have shown that retrograde menstruation is quite common and cannot adequately explain the extrauterine implantation of endometrial tissue. Nonetheless, conditions that increase the rate retrograde menstruation, such as congenital outflow tract obstructions, do increase the risk of endometriosis.

• Other leading theories include metaplastic conversion of coelomic epithelium and hematogenous or lymphatic dispersion of endometrial cells. A combination of these explanations is required to explain all of the many clinical presentations of the disease.

• An altered immune response to the displaced endometrial tissue has been shown to play an important role as well.

• Intriguing primate studies have demonstrated a strong association between dioxane exposure and the development of endometriosis, implying further that dysfunction of the immune system may contribute to this disease. Epidemiologic investigations have not been able to confirm this association in humans.

Lab Studies:

• No lab studies have been shown to be useful in the diagnosis of endometriosis.

• Cancer antigen 125 (CA-125) levels may be elevated in advanced cases, but rarely are elevated in mild-to-moderate disease. The test lacks adequate sensitivity or specificity to be of clinical value.

Imaging Studies:

• Pelvic ultrasound, CT scan, and MRI are only useful in the case of advanced disease with endometrial cyst formation or severe anatomic distortion.

• Intravenous pyelograms and colonic studies are indicated if the clinical presentation suggests extragenital involvement of these organ systems.

Procedures:

• Gross visualization of endometrial implants remains the definitive method of diagnosis.

• In this era of minimally invasive surgery, laparoscopy is the procedure of choice.

• Laparotomy can be another method of diagnosis. This usually is performed when another cause of patient pain is suspected.

Histologic Findings: Histologic demonstration of both endometrial glands and stroma in biopsy specimens obtained from outside the uterine cavity is required to make the diagnosis of endometriosis. Occasionally, the finding of fibrosis in combination with hemosiderin-laden macrophages is sufficient for a presumptive diagnosis.

Staging: The American Society of Reproductive Medicine has a staging scheme based on the size, number, and location of endometrial implants, and associated adhesion formation, noted at the time of surgery.

• The dependence of endometriosis on the woman's cyclic production of menstrual cycle hormones provides the basis for medical therapy.

• Medications currently in vogue include gonadotropin-releasing hormone (GnRH) agonists, progestins, oral contraceptive pills, and androgens. Each of these interrupts the normal cyclic production of reproductive hormones.

Surgical Care: Surgical efforts are aimed at removal of the endometrial implants and correction of anatomic distortions.

• Implants can be ablated using either laser energy or electrosurgical techniques.

• Resection of the implants and adjacent peritoneum is considered the treatment of choice by some authors.

• A radical surgical approach involves total hysterectomy and bilateral salpingo-oophorectomy. This generally is reserved for women who have completed their reproductive career or for women with severely disabling pain that is unresponsive to more conservative approaches.

Consultations:

• Consultation with an obstetrician/gynecologist generally is recommended when this diagnosis is suggested.

• If extensive disease is present, specialists in reproductive endocrinology, urology, colorectal surgery, and even gynecologic oncology may be required.

Medications for the treatment of endometriosis fall into 1 of 4 categories: GnRH agonists (GnRH analogs), progestins, oral contraceptive pills, and androgens.
 

Drug Category: Gonadotropin-releasing hormone analogs -- Normal menstrual cycles rely on pulsatile delivery of GnRH to the pituitary. The GnRH analogs (agonists) supply constant stimulation of the pituitary receptors leading to down-regulation and eventual suspension of FSH and LH secretion. This suspension results in a profound hypoestrogenic state, similar to menopause. Because endometrial implants are dependent on estrogen stimulation, they subsequently regress. Because of hypoestrogenic adverse effects, the use of these drugs is limited to 6 months duration. The use of so-called add-back therapy, addition of low-dose dose estrogen with or without a progestin, for prolonged therapy has been investigated. The results are mixed, and, currently, a sound recommendation cannot be made. The expense of GnRH analogs is a significant limitation to their long-term use.

Drug Category: Progestins -- Use of this category of drugs relies on high-dose hormones to suppress the hypothalamus through negative feedback. This results in a hypoestrogenic state. Evidence for direct inhibition of endometrial implants by progestins also exists. These medications give equivalent pain relief to the GnRH analogs and seem to have a slightly lower recurrence rate.

Drug Category: Oral contraceptive pills -- OCPs are generally progestin dominant and work to suppress the hypothalamic ovarian axis and, thus, endometriosis implants. Clinically, they probably work better for suppression of the disease rather than actual therapy. Some patients gain significant pain relief with this class of medication, especially when the pills are taken continuously (ie, the patient skips the placebo week of each 28-day pack, going directly to the next pack's first active pill).

Drug Category: Androgens -- These medications work to both suppress the hypothalamic ovarian axis and to suppress endometriosis at a local level.

Further Inpatient Care:

• Management of this disease is largely outpatient.