AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Endometriosis is the presence of normal endometrial mucosa (glands and stroma) abnormally implanted in locations other than the uterine cavity. This tissue, possessing the same steroid receptors as normal endometrium, is capable of responding to the normal cyclic hormonal milieu. Microscopic internal bleeding, with the subsequent inflammatory response, neovascularization, and fibrosis formation, is responsible for the clinical consequences of this disease.

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 provides the rationale for current methods of medical therapy.

Pathophysiology

Ectopic endometrial tissues are most commonly located in the dependent portions of the female pelvis (eg, 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- 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

United States

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.

International

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 symptoms 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 racial 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 that are histologically indistinguishable from endometriosis found in men exposed to high-dose exogenous estrogens.

Age

Endometriosis is largely 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.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

Symptoms of endometriosis can be variable but typically reflect the area of involvement. Because most 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 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 because of 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 most commonly found involving one or both ovaries. These masses can become quite painful, and patients with rupture present with 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 do not frequently 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 of 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 nonhuman 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.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Dysmenorrhea
Pelvic adhesions
Serositis
Functional or neoplastic ovarian cyst
Ovarian Cysts
Pelvic Inflammatory Disease
Uterine malformation

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• No laboratory 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 are rarely elevated in mild-to-moderate disease. The test lacks adequate sensitivity or specificity to be of clinical value.

Imaging Studies

• Pelvic ultrasonography, CT scanning, and MRI are only useful in the case of advanced disease with endometrial cyst formation or severe anatomic distortion.
• Intravenous pyelography 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 is usually 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 for 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 patient's stage (ie, 1-4, or minimal, mild, moderate, and severe) may be useful in determining her prognosis for subsequent reproduction. The staging system can also be used to monitor a patient's response to therapeutic efforts. Surgical exploration is required for this staging system, both initially and for subsequent follow-up, and a discussion of its details is beyond the scope of this article.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

• The dependence of endometriosis on the woman's cyclic production of menstrual cycle hormones provides the basis for medical therapy.
• Medications currently recommended include gonadotropin-releasing hormone (GnRH) agonists, progestins, oral contraceptive pills, and androgens. Each of these interrupts the normal cyclic production of reproductive hormones. There is some data supporting the use of aromatase inhibitors for refractory or recurrent endometriosis.

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 is generally 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 is generally 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.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medications for the treatment of endometriosis fall into 1 of 5 categories: GnRH agonists (GnRH analogs), progestins, oral contraceptive pills, androgens, and aromatase inhibitors. Evidence for the use of aromatase inhibitors is currently very limited.

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 follicle-stimulating hormone (FSH) and luteinizing hormone (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 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. GnRH agonists should be used with caution in adolescents younger than 16 years because of adverse effects on bone density.

Drug Name	Nafarelin (Synarel)
Description	Analog of GnRH that is approximately 200 times more potent than natural endogenous GnRH. Upon long-term administration, suppresses gonadotrope responsiveness to endogenous GnRH, thereby reducing secretion of LH and FSH, which in turn reduces ovarian and testicular steroid production. Available as nasal solution (2 mg/mL). Administration is delivered via a nasal spray, which requires bid dosing; otherwise similar to the other drugs in this category.
Adult Dose	200 mcg (1 spray) in 1 nostril in the am and 1 spray in the alternate nostril in the pm
Pediatric Dose	Adolescents: Administer as in adults
Contraindications	Documented hypersensitivity; pernicious anemia; prepubertal patients
Interactions	None reported
Pregnancy	X - Contraindicated in pregnancy
Precautions	Resulting hypoestrogenic state can lead to serious medical consequences if of a prolonged duration; significant bone mineral loss commonly occurs with even a 6-mo course but quickly recovers after discontinuation of the drug; bone density surveillance is usually not indicated for therapy of normal duration

Drug Name	Goserelin (Zoladex)
Description	Administered monthly as an SC implant in the upper abdominal wall; otherwise similar to the drugs in this class.
Adult Dose	Implant: 3.6 mg SC q28d
Pediatric Dose	Adolescents: Administer as in adults
Contraindications	Documented hypersensitivity; pernicious anemia; prepubertal patients
Interactions	None reported
Pregnancy	X - Contraindicated in pregnancy
Precautions	Resulting hypoestrogenic state can lead to serious medical consequences if of a prolonged duration; significant bone mineral loss commonly occurs with even a 6 mo course, but quickly recovers after discontinuation of the drug; bone density surveillance is usually is not indicated for therapy of normal duration

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 provide pain relief equivalent to the GnRH analogs and seem to have a slightly lower recurrence rate.

Drug Name	Medroxyprogesterone acetate (Amen, Cycrin, Provera, Depo-Provera)
Description	Common progestin available in both a PO and a depo form; efficacy and adverse effects are similar to norethindrone.
Adult Dose	10-30 mg PO qd for a 6-mo treatment period 150-400 mg IM q1-3mo for a 6-mo treatment period Note: 150 mg/mo IM (contraceptive dose) can sometimes be used for prolonged periods as maintenance after the 6-mo therapeutic dose
Pediatric Dose	Adolescents: Administer as in adults
Contraindications	Documented hypersensitivity; known progestin-dependent tumors; undiagnosed vaginal bleeding; thrombophlebitis; liver dysfunction
Interactions	Aminoglutethimide and rifampin may increase hepatic clearance, thus decreasing efficacy
Pregnancy	X - Contraindicated in pregnancy
Precautions	Caution in impaired liver function, CHF, and HTN; patients may notice weight gain (usually lean body mass), worsening of acne, and depressed mood; while these drugs are frequently listed as increasing the risk of thromboembolic disease because of their associated use in PO contraceptive pills, currently no available evidence suggests that progestins not in combination with estrogens increase the occurrence of these events

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 suppress both the hypothalamic-ovarian axis and endometriosis at a local level.

Drug Category: Aromatase Inhibitors

These medications work by blocking the aromatase activity in extraovarian sites that suppress the conversion of androstenedione and testosterone to estrogen. This action may result in suppression of endometriosis at a local level.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Management of this disease is largely outpatient.
• In patients who underwent surgery for endometriosis (or had endometriosis discovered during surgery for another indication), consider adjuvant medical treatment (see Medical Care). At a minimum, place these patients on oral contraceptive pills until they are ready to conceive.

Further Outpatient Care

• Start patients with classic symptoms of endometriosis and no reason to suspect another cause on medical therapy.
• Surgical diagnosis is not always required.
• Lack of rapid response (within 1-2 cycles) to medical therapy should prompt a search for other causes of the patient's symptoms.
• Consider diagnostic laparoscopy if it has not been performed previously.

Transfer

• Treat these patients in consultation with a physician experienced in the diagnosis and management of endometriosis and its complications.

Deterrence/Prevention

• No current methods of prevention are known.
• Some evidence suggests that rapid and aggressive medical or surgical therapy can arrest progression, especially when the disease is caught in the early (minimal-to-mild) stages.
• Early and prolonged use of oral contraceptive pills, pregnancy, and breast-feeding seem to afford some degree of protection against this disease.

Complications

• Complications of this disease fall into the following 3 categories:
• • Pain and subsequent disability
  • Anatomic disruption of involved organ systems
  • Infertility or subfertility

Prognosis

• Endometriosis is generally a progressive disease.
• The extent of progression and subsequent morbidity is unpredictable.
• While most patients (up to 95% in some studies) respond to medical therapy, as many as 50% have a return of symptoms within 5 years.
• Minimally invasive surgical therapy affords better fertility rates but is not as effective at eliminating pain.
• Definitive surgical therapy (total hysterectomy with bilateral salpingo-oophorectomy and peritoneal stripping) offers the best chance for long-term resolution of pain. Obviously, reserve this option as a last resort in patients with completely incapacitating disability or no desire for future childbearing.

Patient Education

• Stress the importance of continuing medical therapy for the full 6-month course.
• Medical therapy often relieves pain but induces uncomfortable adverse effects, and the patient needs encouragement to complete the course of treatment.
• Recurrence of symptoms after therapy should prompt the patient to return for further evaluation.
• Teach patients with severe disease about the symptoms of bowel and ureteral obstruction.
• The National Institutes of Health (NIH) is currently conducting a clinical trial to research new treatments for endometriosis. Patients who are interested in participating in this study may visit http://endometriosis.nichd.nih.gov/ for more information.
• For excellent patient education resources, visit eMedicine's Women's Health Center. Also, see eMedicine's patient education articles Female Sexual Problems, and Endometriosis.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Any postpubertal patient going to the operating room for acute or chronic pelvic/abdominal pain could have endometriosis. Consultation with a physician having the experience to recognize, diagnose, and treat this disease is prudent. Conservation of future fertility may be dependent on the conservative and meticulous surgical approach of an expert reproductive surgeon.
• Consider performing a pregnancy screening test.

Special Concerns

• While most pediatric patients are not currently interested in becoming pregnant, subsequent fertility is likely a major concern. Evidence is mounting that early and aggressive therapy may alter the course of this disease. Investigate moderate-to-severe dysmenorrhea that is unresponsive to NSAIDs and pelvic pain persisting longer than 3 months.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Typical appearance of minimal endometriosis on the uterosacral ligaments. Note that some are pigmented (contain hemosiderin) while others are not.
	View Full Size Image
Media type:  Photo

Media file 2:  Peritoneal erosions and adhesions in the posterior cul-de-sac. These are typical of more severe endometriosis.
	View Full Size Image
Media type:  Photo

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

• Ailawadi RK, Jobanputra S, Kataria M, et al. Treatment of endometriosis and chronic pelvic pain with letrozole and norethindrone acetate: a pilot study. Fertil Steril. Feb 2004;81(2):290-6. [Medline].
• American College of Obstetricians and Gynecologists. Endometriosis. Technical Bulletin. 1993;Number 184:1-6.
• American College of Obstetricians and Gynecologists. Endometriosis in Adolescents. Committee Opinion. April 2005;Number 310:1-7.
• Cook AS, Rock JA. The role of laparoscopy in the treatment of endometriosis. Fertil Steril. Apr 1991;55(4):663-80. [Medline].
• Creatsas G, Hassan E, Koumantakis E. Adolescent laparoscopy. Clin Exp Obstet Gynecol. 1997;24(3):147-8. [Medline].
• Eskenazi B, Warner ML. Epidemiology of endometriosis. Obstet Gynecol Clin North Am. Jun 1997;24(2):235-58. [Medline].
• Ferrero S, Abbamonte LH, Anserini P, et al. Future perspectives in the medical treatment of endometriosis. Obstet Gynecol Surv. Dec 2005;60(12):817-26. [Medline].
• Goldstein DP. Acute and chronic pelvic pain. Pediatr Clin North Am. Jun 1989;36(3):573-80. [Medline].
• Goldstein DP, De Cholnoky C, Emans SJ. Adolescent endometriosis. J Adolesc Health Care. Sep 1980;1(1):37-41. [Medline].
• Kontoravdis A, Hassan E, Hassiakos D, et al. Laparoscopic evaluation and management of chronic pelvic pain during adolescence. Clin Exp Obstet Gynecol. 1999;26(2):76-7. [Medline].
• Olive DL, Schwartz LB. Endometriosis. N Engl J Med. Jun 17 1993;328(24):1759-69. [Medline].
• Ryan IP, Taylor RN. Endometriosis and infertility: new concepts. Obstet Gynecol Surv. Jun 1997;52(6):365-71. [Medline].
• Scialli AR. Evaluating chronic pelvic pain. A consensus recommendation. Pelvic Pain Expert Working Group. J Reprod Med. Nov 1999;44(11):945-52. [Medline].

Article Last Updated: May 15, 2006