Endometriosis

Practice Essentials

Endometriosis is defined as the presence of normal endometrial mucosa (glands and stroma) abnormally implanted in locations other than the uterine cavity (see the image below). Approximately 30-40% of women with endometriosis will be subfertile.

View Image

Endometriosis. Red lesions on various organs.

Signs and symptoms

About one third of women with endometriosis remain asymptomatic.^[1] When they do occur, symptoms, such as the following, typically reflect the area of involvement:

• Dysmenorrhea
• Heavy or irregular bleeding
• Pelvic pain
• Lower abdominal or back pain^[2]
• Dyspareunia
• Dyschezia (pain on defecation) - Often with cycles of diarrhea and constipation
• Bloating, nausea, and vomiting
• Inguinal pain
• Pain on micturition and/or urinary frequency
• Pain during exercise

Patients with endometriosis do not frequently have any physical examination findings beyond tenderness related to the site of involvement.^{[3, 4, 5]} The most common finding is nonspecific pelvic tenderness.

See Clinical Presentation for more detail.

Diagnosis

Laparoscopy

Laparoscopy is considered the primary diagnostic modality for endometriosis. This is an invasive procedure with an overall sensitivity of 97% but with a specificity of only 77%.

The following sites are, in descending order, the most common sites of involvement found during laparoscopy:

• Ovaries
• Posterior cul-de-sac
• Broad ligament
• Uterosacral ligament
• Rectosigmoid colon
• Bladder
• Distal ureter

Histology

Histologic demonstration of a combination of endometrial glands and stroma in biopsy specimens obtained from outside the uterine cavity is required to make the diagnosis of endometriosis.

Laboratory studies

• Complete blood count (CBC) with differential - May help to differentiate pelvic infection from endometriosis, as well as to assess the degree of blood loss
• Urinalysis and urine culture - If urinary tract infection (UTI) is in the differential diagnosis
• Cervical Gram stain and cultures - Because sexually transmitted diseases (STDs) can also cause pelvic pain and infertility

Imaging studies

• Ultrasonography - Endometriosis can be assessed by either transvaginal ultrasonography or endorectal ultrasonography
• Magnetic resonance imaging (MRI)

See Workup for more detail.

Management

The dependence of endometriosis on the cyclic production of menstrual cycle hormones provides the basis for medical therapy. Thus, the following drugs form the mainstay of pharmacologic care:

• Combination oral contraceptive pills (COCPs)
• Danazol
• Progestational agents
• Gonadotropin-releasing hormone (GnRH) analogues

Surgical care for endometriosis can be broadly classified as follows:

• Conservative - When reproductive potential is retained
• Semiconservative - When reproductive ability is eliminated but ovarian function is retained
• Radical - When the uterus and ovaries are removed

Conservative surgery

Conservative procedures used in the treatment of endometriosis include the following:

• Drainage and laparoscopic cystectomy - Both procedures can be used in the treatment of ovarian endometriosis
• Ablation
• Presacral neurectomy
• Laparoscopic uterine nerve ablation (LUNA)

Semiconservative surgery

Semiconservative surgery is indicated mainly for women who have completed childbearing, are too young to undergo surgical menopause, and are debilitated by the symptoms. Such surgery involves hysterectomy and cytoreduction of pelvic endometriosis.

Ovarian endometriosis can be removed surgically, because one tenth of functioning ovarian tissue is all that is needed for hormone production. (Patients who undergo hysterectomy with ovarian conservation have a 6-fold higher rate of recurrence compared to women who undergo oophorectomy.^[6] )

Radical surgery

Radical surgery involves total hysterectomy with bilateral oophorectomy (TAH-BSO) and cytoreduction of visible endometriosis. Adhesiolysis is performed to restore mobility and normal intrapelvic organ relationships.

See Treatment and Medication for more detail.

• References

Background

Endometriosis is defined as 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.^[23]

This condition is a common, poorly understood, and extremely debilitating benign gynecologic condition. The psychologic impact of the severe pain experienced by the patient is compounded by the negative impact of the disease on fertility.^[2]

In the typical patient, the ectopic implants are located in the pelvis (ovaries, fallopian tubes, vagina, cervix, or uterosacral ligaments or in the rectovaginal septum) and manifest as severe dysmenorrhea, chronic pelvic pain, or infertility. More unusual implantation sites (laparotomy scars, pleura, lung, diaphragm, kidney, spleen, gallbladder, nasal mucosa, spinal canal, stomach, breast^{[24, 25]} ) can be responsible for bizarre symptoms such as cyclic hemoptysis and catamenial seizures.

The etiology and pathophysiology of endometriosis is not well understood because of the lack of a suitable animal model on which to study the anatomic correlates and natural history of disease.^[26] No cure exists for the disease, although the hormonal responsiveness of the implants can be exploited and provides the rationale for current methods of medical therapy. Treatment is directed toward medical suppression, surgical excision, and symptom alleviation.

Adenomyosis is the invasion of the myometrium by endometrial tissue.

The following are some images of active endometriosis and old scarring.

View Image

Active endometriosis with red and powder-burn lesions and adhesions from old scarring.

View Image

Scarring due to old disease and active endometriosis.

See also Emergent Treatment of Endometriosis and Endometrial Ablation.

• References

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 (see the following images).

View Image

Typical appearance of minimal endometriosis on the uterosacral ligaments. Note that some are pigmented (contain hemosiderin), whereas others are not.

View Image

Peritoneal erosions and adhesions in the posterior cul-de-sac. These are typical of more severe endometriosis.

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 (IL)-6 production in women with this disease.

The associated pain, adhesion formation (see the image below), and anatomic distortion are responsible for the clinical consequences of this disease.

View Image

Adhesions due to endometriosis.

• References

Etiology

The exact cause and pathogenesis of endometriosis is unclear. Several theories exist that attempt to explain this disease, although none have been entirely proven.^[1] Leading theories include metaplastic conversion of coelomic epithelium and hematogenous or lymphatic dispersion of endometrial cells. It is likely a combination of various factors that cause and determine the severity of this disease.

Previous theories suggest that endometriosis results from the transport of viable endometrial cells through retrograde menstruation. Cells flow backward through the fallopian tubes and deposit on the pelvic organs, where they seed and grow. A population of cells resides in the endometrium, which retain stem cell properties. It may be these properties that allow these cells to survive in ectopic locations.

Risk factors for endometriosis include the following:

• Family history of endometriosis
• Early age of menarche
• Short menstrual cycles (< 27 d)
• Long duration of menstrual flow (>7 d)
• Heavy bleeding during menses
• Inverse relationship to parity
• Delayed childbearing
• Defects in the uterus or fallopian tubes
• Hypoxia and iron deficiency may contribute to the early onset of endometriosis

Retrograde menstruation

Early in the 20th century (1927), Samson proposed his theory of retrograde menstruation through the fallopian tubes into the peritoneal cavity as a cause of endometriosis. Subsequent studies have shown that retrograde menstruation is a quite common physiologic event and cannot adequately explain the extrauterine implantation of endometrial tissue. Diagnostic laparoscopy during the perimenstrual period has shown that as many as 90% of women with patent fallopian tubes have bloody peritoneal fluid. Nonetheless, conditions that increase the rate of retrograde menstruation, such as congenital outflow tract obstructions, do increase the risk of endometriosis. Various animal experiments and clinical observations support this theory.^{[7, 8, 9, 10]}

Because most women do not have endometriosis, perhaps immunologic or hormonal dysfunction leaves some women predisposed.

Immunologic dysfunction

Relatively recent research has suggested involvement of the immune system in the pathogenesis of endometriosis. An altered immune response to the displaced endometrial tissue has been shown to play an important role as well. Women with this disorder appear to exhibit increased humoral immune responsiveness and macrophage activation while showing diminished cell-mediated immunity with decreased T-cell and natural killer cell responsiveness. Humoral antibodies to endometrial tissue have also been found in sera of women with endometriosis.^[11]

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. However, epidemiologic investigations have not been able to confirm this association in humans.

Studies in recent years have focused on assessing the differences between eutopic endometrium and endometriosis. In endometriosis, an aberrantly expressed factor SF-1 activates the expression of the enzyme aromatase, which converts C19 steroids to estrogens. Consequently, estrogen increases the synthesis of prostaglandin E2, which exerts a positive feedback effect, resulting in increased aromatase activity. Additionally, endometriotic tissue is deficient in the enzyme 17-beta hydroxy steroid dehydrogenase type 2, which converts E2 in eutopic endometrium to the less potent E1 under the direction of progestins.

One study found a higher number of endometriomas, more bilateral disease, and a higher incidence of significant pain in women with aromatase positive disease.^[12] However, other studies have shown increased cyclooxygenase-2 (COX-2) expression in the stromal cells^[13] and aberrant aromatase expression^[14] in eutopic endometrium of women with endometriosis.

Although successful treatment has been described with the aromatase inhibitor anastrozole in women with severe postmenopausal endometriosis,^[15] more recent studies have also shown it to be effective in cases of severe endometriosis in premenopausal women.^{[16, 17]} Additional data are needed before recommending this as primary treatment.

Metaplasia

Metaplasia, or the changing from one normal type of tissue to another normal type of tissue, is another theory. The endometrium and the peritoneum are derivatives of the same coelomic wall epithelium. Transformation of coelomic epithelium into endometrial-type glands in response to as yet unknown stimuli could explain endometriosis in unusual sites.^[18] Coelomic metaplasia is also believed to explain the occurrence of endometriosis in women who have undergone total hysterectomy and are not taking estrogen replacement.^[19] Peritoneal mesothelium has been postulated to retain its embryologic ability to transform into reproductive tissue. Such transformation may occur spontaneously, or it may be facilitated by exposure to chronic irritation by retrograde menstrual fluid.

Endometriosis may also occur in men on high-dose estrogen therapy.^[20]

Remnant Mullerian cells

Another theory states that remnant Mullerian cells may remain in the pelvic tissues during development of the Mullerian system. Under situations of estrogen stimulation, they may be induced to differentiate into functioning endometrial glands and stroma.

Genetics

Some women may have a genetic predisposition to endometriosis. Studies have shown that first-degree relatives of women with this disease are more likely to develop it as well. The search for an endometriosis gene is currently under way.

Anatomic spread, dissemination and deposition

Transtubal dissemination is the most common route, although other routes, such as lymphatic and vascular channels, have been observed. This may explain how endometrial tissue can be found at distant, noncontiguous locations in the body.

Iatrogenic deposition of endometrial tissue has been found in some cases following gynecologic procedures and cesarean sections.

The ovary is the most common site for endometriosis. Spread to the ovary is believed to be lymphatic,^[21] although superficial implants may be due to retrograde menstrual flow, because the ovaries are in a dependent part of the pelvis. Lesions can vary in size from spots to large endometriomas. The classic lesion is a chocolate cyst of the ovary that contains old blood that has undergone hemolysis (see the first image below). Once intracystic pressure rises, the cyst perforates, spilling its contents within the peritoneal cavity. This can cause the severe abdominal pain typically associated with endometriosis exacerbations. The inflammatory response causes adhesions that further increase the morbidity of the disease (see the second image below).

View Image

Endometriosis. Chocolate cyst of the ovary.

View Image

Adhesions due to endometriosis.

Uterine serosa can be affected. Vesicular lesions may provoke an inflammatory response and scarring that cause the bladder to adhere anteriorly. Posteriorly, the disease may cause obliteration of the cul-de-sac and form dense adhesions between the posterior vaginal wall or cervix and the anterior rectum. Severe dyspareunia, dyschezia, and alteration of bowel habits are the clinical sequelae of this common spread.

Deep peritoneal disease is caused by infiltration of the uterosacral ligaments and rectovaginal septum by endometriotic nodules. Tethering of the uterus can lead to fixed retroversion. Dyspareunia is an important feature.

Through contiguous spreading, endometriosis may invade the rectovaginal septum and the anterior rectal wall. It may also involve the upper rectum and sigmoid colon, infiltrating the muscularis. Cyclical rectal bleeding (hematochezia) is pathognomonic of endometriosis. However, transmural bowel involvement by endometriosis remains a rarity. The ileum, appendix, and cecum may also be involved, leading to intestinal obstruction. Cicatrization as a consequence of endometriosis may lead to symptoms of obstruction even in postmenopausal women.

Although uncommon, interference in the genitourinary tract by endometriosis can affect the bladder, ureters, and kidneys by invasion, compression, or scarring. Medical therapy has less than satisfactory results, and surgical intervention is often required.

Uncommon sites include incisional scars, the umbilicus, and the thoracic cavity. Catamenial or cyclic pneumothorax can cause hemoptysis. Remember that ectopic endometrial tissue theoretically can undergo malignant transformation; histologic evaluation may be necessary. Significant predictive factors for the presence of malignant transformation of endometriosis appear to include age older than 49 years and cysts that are multilocular and have solid components.^[22] Although elevated, levels of serum cancer antigen 125 (CA-125) do not appear to be a significant predictor of malignant transformation of endometriosis.

Postmenopausal endometriosis may be encountered in women who are on estrogen replacement therapy (ERT). Occasionally, if ERT is administered after total abdominal hysterectomy, endometriosis can be stimulated in an ovarian remnant. Extrapelvic endometriosis is believed to be hormone-resistant when it occurs after surgical castration. Transplantation of endometrial implants during the original surgery is believed to explain this occurrence. Another possible explanation is coelomic metaplasia.

• References

Epidemiology

Endometriosis occurs in 6-10% of US women in the general population,^[26] and approximately 4 per 1000 women are hospitalized with this condition each year. 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. Most prevalence studies are based on a surgical population in which the likelihood of disease is greater, with the best estimates of incidence in the general female coming from women with proven fertility undergoing tubal sterilization procedures.

Endometriosis is an estrogen-dependent disease and, thus, usually affects reproductive-aged women. This condition has a prevalence rate of 20-50% in infertile women,^{[26, 28, 29, 30]} but it can be as high as 71-87% in women with chronic pelvic pain.^{[26, 31]} 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.^[32] In an earlier study, evidence of endometriosis was found during laparoscopy in 20-50% of asymptomatic women.^[33] A familial association exists, with a 10-fold increased incidence in women with an affected first-degree relative.^[34] Monozygotic twins are markedly concordant for endometriosis.^[35]

Race-, sex-, and age-related differences in incidence

Most research and case studies have been performed in white populations; however, no difference appears to exist among ethnic or social groups.^[36] Although endometriosis is obviously 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.

Endometriosis is largely confined to women of reproductive age with an active hypothalamic-pituitary-ovarian axis. Pelvic endometriosis typically occurs in women aged 25-30 years. Extrapelvic manifestations of this disorder occur in woman aged 35-40 years. Women younger than 20 years with this disease often have anomalies of the reproductive system. 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.

• References

Prognosis

Endometriosis has been found to resolve spontaneously in one third of women who are not actively treated.^[37] However, it is generally a progressive disease, with an unpredictable extent of progression and subsequent morbidity. Although most patients (up to 95% in some studies) respond to medical therapy (suppression of ovulation) for decreasing pelvic pain, such therapy is ineffective for treatment of endometriosis-associated infertility but does preserve the potential for conception. Nonetheless, as many as 50% of women have a return of symptoms within 5 years with medical management.

Combination estrogens/progestins relieve pain in as many as 80-85% of patients with endometriosis-related pelvic pain. After 6 months of danazol therapy, as many as 90% of patients with moderate endometriosis experience adequate pain relief.

Findings from the prospective Australian Longitudinal Study on Women's Health of 9,585 women (age at trial onset, 18-23 y) indicated that, regardless of fertility status, previous exposure to oral contraceptive pills (OCPs) reduced the risk of a subsequent diagnosis of endometriosis among parous women but increased the risk among nulliparous women.^[38]

Relative to women who never used OCPs, the hazard ratio (HR) for endometriosis among women with up to 5 years of OCP use before diagnosis was 1.8 in nulliparous women compared with 0.41 in parous women. In those with a history of OCP use for 5 years or longer, the HR was 2.3 in nulliparous women and 0.45 in parous women.^[38] The investigators suggested a possible reason for the twofold increased risk of endometriosis among the nulliparous women may have been early noncontraceptive use of OCPs.

Minimally invasive surgical therapy affords better fertility rates, but this treatment is not as effective at eliminating pain. Definitive surgical therapy (total hysterectomy with bilateral salpingo-oophorectomy [TAH-BSO] and peritoneal stripping) offers the best chance for long-term resolution of pain (up to 90%). However, reserve this option as a last resort in patients with completely incapacitating disability or those who have no desire for future childbearing.

In general, pregnancy is possible but depends on the severity of the disease. Endometriosis signs and symptoms generally regress with the onset of menopause and during pregnancy.

Mortality/morbidity

Acute or chronic pelvic pain is common in patients with endometriosis. Infertility is also common. Approximately 30-40% of women with endometriosis will be subfertile.

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, whereas severe endometriosis is sometimes asymptomatic. The pain of endometriosis responds poorly to antiprostaglandins and OCPs. Symptoms are related to the site of endometriotic implants and the organ system involved.

Cases have been reported of extrapelvic involvement in virtually every other organ system including the central nervous system (CNS), lungs, pleura, kidney, and bladder.^{[24, 25]} The gastrointestinal (GI) tract is the most common extrapelvic site of endometriosis, and symptoms include bowel obstruction, rectal bleeding, and constipation. Symptoms in other locations are related to the site and size of endometrial implants.

Mortality is negligible.

Complications

Complications of endometriosis may include or fall into the following 3 categories:

• Infertility/subfertility
• Chronic pelvic pain and subsequent disability
• Anatomic disruption of involved organ systems (eg, adhesions, ruptured cysts)

• References

Patient Education

Stress to patients 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. Educate patients with severe disease about the symptoms of bowel and ureteral obstruction.

For patient education information, see Pregnancy Center and Women's Health Center, as well as Endometriosis, Female Sexual Problems, Birth Control Overview, and Birth Control Methods.

For patients interested in more information or support groups, Endometriosis Research at the National Institutes of Health (NIH), The Endometriosis Association, and Endometriosis.org are valuable resources.

• References

History

Common elements in the history include nulliparity and regular 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. Symptoms also usually improve during pregnancy and after menopause; they can recur postpartum or with postmenopausal hormone replacement therapy.

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.

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.

Symptoms

Although a significant number of women with endometriosis remain asymptomatic (approximately one third),^[1] the most important point to remember is that the degree of visible endometriosis has no correlation with the degree of pain or other symptomatic impairment, because the location and depth of endometrial implants affect the symptomatology.^[39] However, pain does correlate with the depth of tissue infiltration, as pain is thought to be related to the degree of peritoneal inflammation rather than the volume of implants.^{[40, 41]} Associated intrapelvic/intra-abdominal adhesions are also important determinants of the degree of pain experienced. Midline disease is generally believed to be more painful than lateral disease. In addition to pain, patients present with nonspecific symptoms of fatigue, generalized malaise, and sleep disturbances.

Symptoms of endometriosis can be variable but typically reflect the area of involvement. Such symptoms may include the following:

• Dysmenorrhea
• Heavy or irregular bleeding
• Pelvic pain
• Lower abdominal or back pain^[2]
• Dyspareunia
• Dyschezia (pain on defecation) often with cycles of diarrhea and constipation
• Bloating, nausea, and vomiting
• Inguinal pain
• Pain on micturition and/or urinary frequency
• Pain during exercise

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. 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.

Cyclic pain is pain that accompanies bleeding at the time of menstruation. This could involve the bladder (hematuria), bowel (hematochezia and painful defecation), or, rarely, bleeding at uncommon sites such as the umbilicus, abdominal wall, or perineum. Occasionally, patients present with a cyclically painful expanding mass in a pelvic surgery scar; excision reveals a focus of endometriosis. In one large case series, the average onset of cyclic or noncyclic pain was 2.9 years after menarche.

Acute exacerbations are believed to be caused by chemical peritonitis due to leakage of old blood from an endometriotic cyst. With conscious laparoscopic pain mapping, painful lesions were found to involve peripheral spinal nerves rather than autonomic nerves.^[39]

Secondary dysmenorrhea occurs twice as often in women with endometriosis as in controls.^[33] Pain frequently commences before menses. Endometriosis should be considered in a patient presenting with significant dysmenorrhea, and the patient should be started on empiric therapy.

Patients who are sexually active may report deep dyspareunia that is worst in the premenstrual phase of the cycle. Deep dyspareunia may be due to scarring of the uterosacral ligaments, nodularity of the rectovaginal septum, cul-de-sac obliteration, and/or uterine retroversion, all of which may also lead to chronic backache. These symptoms are exaggerated during menses. Women with deep infiltration of the uterosacral ligaments were shown to have the most severe impairment of sexual function.^[42]

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. Ureteral obstruction and hydronephrosis can result from endometrial implants on the ureter or mass effect from an endometrioma.

• References

Physical Examination

Patients with endometriosis do not frequently have any physical findings beyond tenderness related to the site of involvement.^{[3, 4, 5]} The most common finding is nonspecific pelvic tenderness. In one study, 22% of adolescents had abnormal physical findings consistent with anatomic lesions found during surgery.

On pelvic evaluation, tenderness upon examination is best detected at the time of menses. The hallmark finding on examination is the presence of tender nodular masses along thickened uterosacral ligaments, the posterior uterus, or the posterior cul-de-sac. Obliteration of the cul-de-sac in conjunction with fixed uterine retroversion implies extensive disease. Occasionally, a bluish nodule may be seen in the vagina due to infiltration from the posterior vaginal wall.

Rupture of an ovarian endometrioma may present as an acute abdomen.

Extensive involvement of the rectum and other areas of the gastrointestinal (GI) tract may cause adhesions and obstruction.

Examination should also include evaluation for cervicitis, abnormal discharge, and sexually transmitted diseases (STDs).

• References

Staging

The American Society for Reproductive Medicine classification of endometriosis is currently the most widely used staging system.^[43] Point scores are assigned based on the number of lesions and their bilaterality as well as associated adhesion formation noted at the time of surgery. Lesion size is also a scoring factor. This classification is a fairly accurate method of recording laparoscopic findings. However, high intraobserver and interobserver variability precludes its use in comparing the outcomes of therapeutic studies.^[44] Furthermore, this staging system does not correlate well with pain and dyspareunia,^[45] and fecundity rates cannot be predicted accurately.

However, 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; a discussion of its details is beyond the scope of this article.

• References

Approach Considerations

Few laboratory tests prove to be valuable in the diagnosis of endometriosis, although some tests may be helpful in ruling out specific conditions in the differential diagnosis.

Routine radiographs are not recommended unless other disease entities requiring these studies are in the differential diagnosis.

Pelvic ultrasonography, computed tomography (CT) scanning, and magnetic resonance imaging (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.

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.

Hysterosalpingography may reveal tubal occlusion or periadnexal adhesions.

Conscious pain mapping (ie, with the patient awake) has been used to locate the specific areas that cause pain.^[39] Subsequently, the patient is placed under anesthesia and the deposits are ablated.

• References

Laboratory Studies

A complete blood cell (CBC) count with differential may help differentiate pelvic infection from endometriosis as well as assess the degree of blood loss.

Urinalysis and urine culture should be sent if urinary tract infection (UTI) is in the differential diagnosis. In addition, cervical Gram stain and cultures should be considered, because sexually transmitted diseases (STDs) can also cause pelvic pain and infertility.

With a serum cancer antigen 125 (CA-125) test, serial measurements have a low sensitivity in detecting endometriosis,^[46] although levels may be elevated in advanced cases, but the results are useful as prognosticators of treatment outcome.^[47] However, normal posttreatment values do not mean that endometriosis is absent. Thus, the test lacks adequate sensitivity or specificity to be of clinical value.

Outpatient tests

A diagnostic test based on the detection of autoantibodies against Thomsen-Friedenreich (T) antigen (Gal beta1-3GalNAc) bearing proteins appears promising. The sensitivity and specificity of the test are 80%. This test may prove useful in the outpatient setting.^[48]

Another office test is the marker CCR1. The expression of the blood-borne marker CCR1 mRNA in peripheral blood leukocytes is significantly higher in women with endometriosis compared with unaffected women.^[49]

• References

Ultrasonography

Endometriosis can be assessed by either transvaginal ultrasonography or endorectal ultrasonography. The ultrasonographic features of endometriomas vary from simple cysts to complex cysts with internal echoes to solid masses, usually devoid of vascularity.^[50]

Transvaginal ultrasonography is a useful method of identifying the classic chocolate cyst of the ovary. The typical appearance is that of a cyst containing low-level homogenous internal echoes consistent with old blood.

• References

MRI and CT Scanning

Magnetic resonance imaging (MRI) offers a superior combination of 3-dimensional (3-D) imaging with high-resolution special and temporal resolution, low observer dependency, no radiation exposure, and none of the risks associated with iodinated contrast agents.

With dynamic contrast-enhanced MRI, dynamic changes in MR signal intensity in selected tissues can be detected. Some of the newer generation contrast agents can be loaded with specific antibodies that allow for targeted imaging.

MRI is helpful in detecting rectal involvement^[51] and has been shown to accurately detect rectovaginal endometriosis and cul-de-sac obliteration in more than 90% of cases when ultrasonographic gel was inserted in the vagina and rectum.^[52] MRI has a higher sensitivity for detecting pelvic masses than ultrasonography but is limited in identifying diffuse pelvic endometriosis.

However, the cost-effectiveness of this MRI for endometriosis has yet to be justified for use as a routine tool.

Using computed tomography (CT) scanning, endometriomas may appear as cystic masses, but their appearance is nonspecific and this imaging modality should not be relied on for diagnosis. Complications of endometriosis, including bowel obstruction and hydronephrosis, may be seen on CT scans.

• References

Laparoscopy and Biopsy

Laparoscopy is considered the primary diagnostic modality for endometriosis. This is an invasive procedure with an overall sensitivity of 97% and a specificity of only 77%.

Endometriosis has been described as protean in appearance. The classic lesions are blue-black or have a powder-burned appearance (see the first 2 images). However, the lesions can be red, white, or nonpigmented. Peritoneal defects and adhesions are also indicative (see the second 2 images). Bear in mind that microscopic evidence of endometriosis may be found in normal-appearing peritoneum.

View Image

Powder-burn lesions of endometriosis.

View Image

Active endometriosis with red and powder-burn lesions and adhesions from old scarring.

View Image

Peritoneal erosions and adhesions in the posterior cul-de-sac. These are typical of more severe endometriosis.

View Image

Adhesions due to endometriosis.

The most common sites of involvement found during laparoscopy are the following, in descending order (see the following images):

• Ovaries
• Posterior cul-de-sac
• Broad ligament
• Uterosacral ligament
• Rectosigmoid colon
• Bladder
• Distal ureter

The following images are from various sites of endometriosis involvement.

View Image

Endometriosis. Red lesions on various organs.

View Image

Endometriosis. Red lesions on the sigmoid colon and cul-de-sac.

View Image

Peritoneal erosions and adhesions in the posterior cul-de-sac. These are typical of more severe endometriosis.

View Image

Typical appearance of minimal endometriosis on the uterosacral ligaments. Note that some are pigmented (contain hemosiderin), whereas others are not.

In a study of low-grade ovarian endometrial adenocarcinomas, KRAS mutations were identified in 29% of endometriosis-associated tumors but only 3% in which endometriosis was not identified. This may be relevant to future targeted therapies.^[53]

Histologic features

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.

• References

Approach Considerations

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 are some data supporting the use of aromatase inhibitors for refractory or recurrent endometriosis.

Medical vs surgical therapy

In women who wish to preserve their reproductive potential, the rates of recurrent pain symptoms are 44% with surgical management and 53% with medical management.^{[54, 55]}

Endometriosis and subfertility

Peritubal and periovarian adhesions can interfere mechanically with ovum transport and contribute to subfertility. Peritoneal endometriosis has been postulated to contribute to subfertility by interfering with tubal motility, folliculogenesis, and corpus luteum function. Aromatase is believed to increase the prostaglandin E levels via increase in the cyclooxygenase-2 (COX-2) expression. Endometriosis may also cause subfertility by causing more sperm binding to the ampullary epithelium, thereby affecting sperm-endosalpingeal interactions.^[56]

Medical treatment of minimal or mild endometriosis has not been shown to increase pregnancy rates.^[57] Moderate to severe endometriosis should be treated surgically.^[58]

Other options for achieving pregnancy include intrauterine insemination, superovulation, and in vitro fertilization. In a case-controlled study, pregnancy rates with intracytoplasmic sperm injection were not affected by the presence or extent of endometriosis.^[59] Furthermore, other analyses have shown improvement with in vitro fertilization pregnancy rates with pretreatment of stage 3 and 4 endometriosis with gonadotropin-releasing hormone (GnRH) agonists.

Interval treatment

Some authorities believe that endometriosis should be suppressed prophylactically by continuous combined oral contraceptives, GnRH analogs, medroxyprogesterone, or danazol in order to cause regression of asymptomatic disease and enhance subsequent fertility. However, according to a Cochrane review, no benefit is derived from ovulation suppression in subfertile women with endometriosis who wish to conceive.^[60]

A Cochrane review of interventions in women with endometriomata (cysts of endometriosis in the ovaries) before the use of assisted reproductive technology (ART) identified 4 trials with 312 participants could reach no conclusions regarding interventions for the management of endometriomata in women undergoing ART.^[61]

In a 2015 systematic review and meta-analysis of the influence of endometriosis on ART outcomes from 36 studies (of 1346 articles), investigators found similar outcomes for live births between women with endometriosis who underwent in vitro fertilization and intracytoplasmic sperm injection and women without endometriosis.^[62] However, women with severe endometriosis had lower live birth rates, clinical pregnancy rates, and mean number of retrieved oocyte relative to those without endometriosis. The investigators noted there remains not enough evidence to support recommending surgery routinely before women undergo ART.^[62]

Surgical ablation of asymptomatic endometriosis has also been shown to improve fecundity rates on a 3-year follow-up.^[58]

Recurrent pregnancy loss

Based on results from controlled prospective studies, no evidence indicates that endometriosis is associated with recurrent pregnancy loss, and no evidence indicates that medical or surgical treatment of endometriosis reduces the spontaneous abortion rate.^[63]

• References

Hormonal Therapy

The dependence of endometriosis on the woman's cyclic production of menstrual cycle hormones provides the basis for medical therapy. Thus, combination oral contraceptive pills (COCPs), danazol, progestational agents, and gonadotropin-releasing hormone (GnRH) analogues form the mainstay of medical therapy. All these treatments have similar clinical efficacy in terms of reduction in pain-related symptoms and duration of relief. See Medications.

Nonsteroidal anti-inflammatory agents (NSAIDS) have not been shown to have any benefit in placebo-controlled trials.^[64] In a systematic review, aromatase inhibitors were shown to have promising results for pain relief when combined with either progestins, COCPs , or GnRH analogues.^[65] However, the authors concluded that the strength of this inference was limited due to lack of sizeable trials.^[65]

Combination oral contraceptive pills

COCPs act by ovarian suppression and continuous progestin administration. Initially, a trial of continuous or cyclic COCPs should be administered for 3 months. With pain relief, this treatment is continued for 6-12 months. Pregnancy rates following discontinuation of the pill are 40-50%. This applies to a population unselected for stage and fertility status of the disease. Although few choices are available among individual formulations, note that the long-term efficacy of multiphasic preparations remains unproven.

Continuous noncyclical administration of COCPs, omitting the placebo menstrual tablets, for 3-4 months helps avoid any menstruation and associated pain. A study by Guzick et al examined a head-head-to-head comparison of Lupron and continuous oral contraceptives for the treatment of endometriotic pelvic pain; both were found to be equally effective.^[66]

Women with endometriosis are at increased risk of epithelial ovarian cancer, and COCPs are believed to protect against this.^[67]

Progestational agents

All progestational agents act by decidualization and atrophy of the endometrium.

Medroxyprogesterone acetate has proven efficacy in pain suppression in both the oral and injectable depot preparations.^{[68, 69]} Oral doses of 10-20 mg/d can be administered continuously. The time to resumption of ovulation is longer and variable with depot preparations. Adverse effects include weight gain, fluid retention, depression, and breakthrough bleeding.

Megestrol acetate has been used in doses of 40 mg with similarly good results.^[70]

The levonorgestrel intrauterine system (LNG-IUS) has been shown to reduce endometriosis-associated pain.^[71] When inserted at the time of laparoscopic surgery, it has been found to reduce the recurrence of dysmenorrhea by 35%.^[72]

Gonadotropin-releasing hormone therapies

Gonadotropin-releasing hormone analogues

GnRH analogues produce a hypogonadotrophic-hypogonadic state by downregulation of the pituitary gland. Goserelin and leuprolide acetate are the commonly used agonists. Efficacy is limited to pain suppression, and fertility rates may show no improvement.^[73]

Winkel et al have claimed that GnRH therapy may lead to improvement in pain associated with endometriosis in 85-100% of women.^[74] Furthermore, the pain relief is believed to persist for 6-12 months after cessation of treatment.

Treatment is usually restricted to monthly injections for 6 months. Loss of trabecular bone density caused by GnRH is restored by 2 years after cessation of therapy.^[75] Other prominent adverse effects include hot flashes and vaginal dryness.

Gonadotropin-releasing hormone antagonists

Elagolix is an oral GnRH receptor antagonist that inhibits endogenous GnRH signaling by binding competitively to GnRH receptors in the pituitary gland. It was approved by the FDA in July 2018 for management of moderate-to-severe pain associated with endometriosis. Administration results in dose-dependent suppression of LH and FSH, leading to decreased blood concentrations of the ovarian sex hormones, estradiol and progesterone.

Approval of elagolix was based on 2 replicate Phase 3 clinical trials (n=872). Improvement of dysmenorrhea was reported in 43.4-46.4% of women in the lower-dose elagolix groups and 72.4-75.8% in the higher-dose elagolix groups, compared with 19.6-22.7% in the placebo groups (P < 0.001 for all comparisons). Nonmenstrual pelvic pain improvement was reported by 49.8-50.4% of women in the lower-dose elagolix groups and 54.5-57.8% in the higher dose groups, compared with 36.5% in the placebo groups (P = 0.003 and P < 0.001, respectively).^[111]

Both elagolix doses are associated with hypoestrogenic adverse effects including hot flushes, elevated serum lipids, and greater decreases from baseline in bone mineral density compared with women who received placebo. Because of this, treatment duration recommendations are specified for each dosage regimen.

Add-back therapy and empiric therapy

Much interest has been shown in whether estrogen/progestin "add-back" therapy should be instituted to prevent osteoporosis and hypoestrogenic symptoms. Hormone replacement therapy preparations, progestins, tibolone maleate, and bisphosphonates have all been shown to be effective.^{[76, 77, 78, 79]} Add-back therapy has been shown to prevent loss in bone density and to relieve vasomotor symptoms without reducing the efficacy of GnRH regimens. GnRH agonists have been used for 12 months with norethindrone add-back therapy with good results.^[80]

A clinical trial has shown that a 3-month empiric course of GnRH, based on a diagnostic algorithm without definitive laparoscopic diagnosis, is efficacious.^[81] However, long-term effects of GnRH analogues on bone density in this population remain unproven. Therefore, add-back therapy remains the standard of care while the patient is on GnRH treatment. Also, empiric treatment without a firm diagnosis could result in unnecessary treatment in patients with chronic pelvic pain, whose condition could be due to other causes. In Ling's study, 13% of subjects were shown to not have endometriosis.^[81]

GnRH therapy has also been proven to relieve the pain and bleeding associated with extrapelvic distant endometriosis.^[82]

GnRH analogues vs danazol

A Cochrane review comparing GnRH analogues with danazol treatment showed no difference in improvement of dysmenorrhea, dyspareunia, pelvic pain, or pelvic tenderness.^[83] Likewise, no difference in retrospective American Fertility Society (rRAFS) score was found at approximately 24 weeks' follow-up. In contrast, studies that evaluated total pain resolution showed greater benefit from GnRH analogues compared with danazol. Side-effect profiles differed, with greater frequency of hot flushes and vaginal dryness with GnRH analogues, whereas danazol treatment resulted in a greater frequency of weight gain, acne, and headaches.

Danazol

Danazol acts by inhibiting the midcycle follicle-stimulating hormone (FSH) and luteinizing hormone (LH) surges and preventing steroidogenesis in the corpus luteum. It is the most extensively studied agent for endometriosis.

Danazol has been shown to be as effective as any of the newer agents, but with a higher incidence of adverse effects. Its androgenic manifestations include oily skin, acne, weight gain, deepening of the voice, and facial hirsutism. Hypoestrogenic features due to danazol include emotional lability, hot flashes, vaginal dryness, and reversible breast atrophy.

The recommended dose is 600-800 mg/d. However, smaller doses have been used with success.^{[84, 85]} In a small study of 21 patients, vaginal danazol (200 mg/d) was successful in relieving endometriosis-associated pain.^[86]

Barrier contraception and ERT

Because of the possibility of virilizing changes in a female fetus, additional barrier contraception must be used while on danazol therapy.

The evidence for estrogen replacement therapy (ERT) in women with postsurgical menopause for treatment of endometriosis is unclear at the present time.^[87]

• References

Surgical Intervention

Surgical care can be broadly classified as conservative when reproductive potential is retained, semiconservative when reproductive ability is eliminated but ovarian function is retained, and radical when the uterus and ovaries are removed. Age, desire for future childbearing, and deterioration of quality of life are the main considerations when deciding on the extent of surgery.

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 (TAH-BSO). This is generally reserved for women who have completed their family or for women with severely disabling pain that is unresponsive to more conservative approaches.

• References

Conservative Surgery

With conservative surgery, the aim is to destroy visible endometriotic implants and lyse peritubal and periovarian adhesions that are a source of pain and may interfere with ovum transport. The laparoscopic approach is the method of choice for treating endometriosis conservatively.^{[88, 89]}

Ablation can be performed with laser or electrodiathermy. Overall, the recurrence rate is 19% and is similar for all techniques.^[90] Laparoscopic ablative surgery with bipolar diathermy or laser for endometriomas was shown to be effective for relieving pelvic pain in 87% of patients.^[91]

Drainage vs laparoscopic cystectomy

Ovarian endometriomas can be treated by drainage or cystectomy. Laparoscopic cystectomy was found to yield better pain relief and pregnancy rates than drainage.^{[92, 93]} Medical therapy with gonadotropin-releasing hormone (GnRH) agonists reduces the size of the cyst but does not influence pain relief.^[94]

Ablation vs diagnostic laparoscopy

In the short term, the absolute benefit for women undergoing surgical ablation of endometriosis is 30-40% over women having only diagnostic laparoscopy. This benefit is reduced over time, and the reoperation rate is as high as 50%.^[95] In cases of rectovaginal endometriosis, significant short-term pain relief was reported by up to 80%, but at 1-year follow-up, 50% required analgesics or hormones for pain relief. During postoperative treatment, GnRH analogues resulted in significantly reduced pain scores in women who received treatment for 6 months.

Tubal flushing with oil-soluble media has been shown to improve pregnancy rates in women with endometriosis-associated infertility.^[96]

Presacral neurectomy and laparoscopic uterine nerve ablation

Presacral neurectomy is used to relieve severe dysmenorrhea. The nerve bundles are transected at the level of the third sacral vertebra, and the distal ends are ligated. Vascular injury to the middle sacral artery and vein is a potential complication, and some authors advocate prophylactic ligation. Also, constipation is a long-term adverse effect (94%) of this procedure and should be considered while deciding whether to perform this procedure.

Nodularity of the uterosacral ligaments may contribute to dyspareunia and low back pain. The transmission of neural pathways is via the Lee-Frankenhäuser plexus. Laparoscopic uterine nerve ablation (LUNA) is performed to interrupt the pain fibers. Potential complications of this procedure include uterine prolapse and pelvic denervation. A systematic review of trials of LUNA found no advantage in terms of pain relief when compared to placebo.^[97] However, when combined with laparoscopic ablation, LUNA significantly reduced pain attributed to endometriosis.^[54] In patients with subfertility, tissue ablation significantly increased the cumulative pregnancy rate.^[58] A Cochrane review failed to show any benefit from either LUNA or presacral neurectomy.^[98]

Postoperative adjunctive hormone therapy

For patients with mild disease, postoperative adjunctive hormonal treatment has been shown effective in reducing pain but has no impact on fertility. GnRH analogues, danazol, and medroxyprogesterone have all been found to be useful for this indication.^{[99, 100, 101, 102]} However, for severe endometriosis, the efficacy of preoperative or postoperative hormonal treatment has not yet been established.

• References

Semiconservative Surgery

The indication for this semiconservative surgery is mainly in women who have completed their childbearing, are too young to undergo surgical menopause, and are debilitated by the symptoms. Such surgery involves hysterectomy and cytoreduction of pelvic endometriosis.

Ovarian endometriosis can be removed surgically, because one tenth of functioning ovarian tissue is all that is needed for hormone production. Patients who undergo hysterectomy with ovarian conservation have a 6-fold higher rate of recurrence compared to women who undergo oophorectomy.^[6]

Medical therapy in women who have completed childbearing is equally efficacious for symptom suppression.^{[55, 103, 104]}

• References

Radical Surgery

Radical surgery involves total hysterectomy with bilateral oophorectomy (TAH-BSO) and cytoreduction of visible endometriosis. Adhesiolysis is performed to restore mobility and normal intrapelvic organ relationships.

Ureteric obstruction may warrant surgical release or excision of a damaged segment. Bowel obstruction may require a resection anastomosis or a wedge resection if the obstruction is confined to the anterior rectosigmoid.

Endometriosis may recur in 15% of women after extirpative surgery, irrespective of whether estrogen-replacement therapy (ERT) is given postoperatively.^[105] ERT can be instituted safely immediately after surgery, especially in younger women who face the prospect of accelerated bone loss and vasomotor symptoms.^{[105, 106]} No trials have reported the use of estrogen plus progestin therapy with respect to estrogen therapy alone postoperatively. However, theoretically, the addition of a continuous progestin could decrease the regrowth of endometriosis.

• References

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 breastfeeding seem to afford some degree of protection against this disease.

A prospective cohort study by Farland et al that included 72,394 women who have had a pregnancy in the last 6 months, of which, 3,296 had endometriosis at follow-up, reported a 40% reduced risk of endometriosis for women who breastfed for 36 months or more throughout their reproductive lifetime compared with women who never breastfed (0.60, 0.50 to 0.72). The study also reported an 8% lower risk of endometriosis for every additional three months of total breastfeeding per pregnancy (hazard ratio 0.92, 95% confidence interval 0.90 to 0.94; P< 0.001 for trend).^[107]

• References

Consultations

Treat patients with endometriosis in consultation with a physician experienced in the diagnosis and management of this condition and its complications, such as an obstetrician/gynecologist. If extensive disease is present, specialists in reproductive endocrinology, urology, colorectal surgery, and even gynecologic oncology may be required.

Any postpubertal patient going to the operating room for acute or chronic pelvic/abdominal pain could have endometriosis, therefore, 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.

A study by Mu et al examined the prospective association between laparoscopically confirmed endometriosis and subsequent coronary heart disease among 116,430 women in the Nurses' Health Study II from 1989-2009. The study found that laparoscopically confirmed endometriosis was associated with increased risk of coronary heart disease. Women with endometriosis were 1.52 times more likely to have a myocardial infarction, 1.91 times more likely to develop angiographically confirmed angina, and 1.35 times more likely to need coronary artery bypass graft surgery, a coronary angioplasty procedure, or a stent.^{[108, 109]}

• References

Long-Term Monitoring

If the presumptive diagnosis is endometriosis and follow up is arranged, pain management can include the use of nonsteroidal anti-inflammatory drugs (NSAIDs) or narcotic analgesics. 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.

In patients who underwent surgery for endometriosis (or had endometriosis discovered during surgery for another indication), consider adjuvant medical treatment. At a minimum, place these patients on oral contraceptive pills until they are ready to conceive.

Endometriosis is progressive and can result in chronic pain and infertility. Gynecologic follow-up is advised.

Pediatric patients

Although 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.^[110] Investigate moderate to severe dysmenorrhea that is unresponsive to NSAIDs and pelvic pain persisting longer than 3 months.

• References

Medication Summary

Medical therapy for treating endometriosis involves hormonal therapy. Progestins, combination estrogens/progestins, danazol, gonadotropin-releasing hormone (GnRH) antagonists (eg, elagolix), or GnRH agonists with or without hormone replacement therapy are some of the medications used. Patients should not begin a regimen of danazol or GnRH agonists unless they are monitored by a gynecologist and have a laparoscopically confirmed diagnosis of endometriosis. Evidence for the use of aromatase inhibitors is currently limited.

Suppression of ovulation and menses often occurs with medical management.

• References

Desogestrel and ethinyl estradiol (Desogen, Ortho-Cept, Velivet, Azurette, Cyclessa)

• Dosing, Interactions, etc.

Clinical Context:  The combination of desogestrel and ethinyl estradiol reduces the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary by decreasing the amount of gonadotropin-releasing hormones (GnRHs). This is one example of an oral contraceptive pill (OCP). All the modern formulations are equally efficacious, although some of the newer (so-called third-generation) pills have a larger progestin effect and may offer greater efficacy.

• References

Norgestimate/ethinyl estradiol (Ortho-Cyclen, Tri-Sprintec, Ortho Tri-Cyclen)

• Dosing, Interactions, etc.

Clinical Context:  The combination of norgestimate and ethinyl estradiol reduces the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary by decreasing the amount of gonadotropin-releasing hormones (GnRHs).

• References

Class Summary

Combination oral contraceptive pills (COCPs) act by ovarian suppression and continuous progestin administration. Initially, a trial of continuous or cyclic COCPs should be given for 3 months. If the patient pain is relieved, this treatment is continued for 6-12 months. Subsequent pregnancy rates are 40-50% upon discontinuation of the contraceptive pill.

Although individual formulations offer few variations, note that the long-term efficacy of multiphasic preparations remains unproven. In addition, continuous noncyclical administration of COCPs, omitting the placebo menstrual tablets, for 3-4 months helps avoid any menstruation and associated pain.

These agents 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-d pack, going directly to the next pack's first active pill).

• References

Norethindrone acetate (Aygestin, Camila, Errin)

• Dosing, Interactions, etc.

Clinical Context:  Norethindrone is a common progestin used in many of the oral (PO) contraceptive pills currently available; the dose administered for endometriosis is significantly higher.

• References

Medroxyprogesterone (Provera, Depo-Provera)

• Dosing, Interactions, etc.

Clinical Context:  Progestins stop endometrial cell proliferation, allowing organized sloughing of cells after withdrawal. These agents typically do not stop acute bleeding episode, but they produce normal bleeding episodes following withdrawal.

Medroxyprogesterone is a common progestin available in both an oral (PO) and an intramuscular (IM) depo form. The efficacy and adverse effects of this drug are similar to those of norethindrone.

• References

Megestrol (Megace)

• Dosing, Interactions, etc.

Clinical Context:  Megestrol produces results similar to those of medroxyprogesterone.

• References

Class Summary

All progestational agents act by decidualization and atrophy of the endometrium. 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 gonadotropin-releasing hormone (GnRH) analogues and seem to have a slightly lower recurrence rate.

• References

Goserelin (Zoladex)

• Dosing, Interactions, etc.

Clinical Context:  Goserelin suppresses ovarian and testicular steroidogenesis by decreasing luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels. This agent is administered monthly as a subcutaneous (SC) implant in the upper abdominal wall; it is otherwise similar to the drugs in this class.

• References

Leuprolide (Lupron Depot, Eligard)

• Dosing, Interactions, etc.

Clinical Context:  Leuprolide suppresses ovarian and testicular steroidogenesis by decreasing luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels. This agent is available in a daily subcutaneous (SC) dosing regimen and the much more convenient monthly intramuscular (IM) depo formulation. A 3-month depo dosing formulation is also available, but experience with its use is limited for endometriosis.

• References

Nafarelin (Synarel)

• Dosing, Interactions, etc.

Clinical Context:  Nafarelin is an analogue of gonadotropin-releasing hormone (GnRH) that is approximately 200 times more potent than natural endogenous GnRH. Upon long-term administration, this agent suppresses gonadotrope responsiveness to endogenous GnRH, thereby reducing secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which in turn reduces ovarian and testicular steroid production.

Nafarelin is available as a nasal solution (2 mg/mL). Administration of this agent is delivered via a nasal spray, which requires twice daily (bid) dosing; it is otherwise similar to the other drugs in this category.

• References

Class Summary

Gonadotropin-releasing hormone (GnRH) analogues produce a hypogonadotrophic-hypogonadic state by downregulation of the pituitary gland. Goserelin and leuprolide acetate are commonly used agonists.

Normal menstrual cycles rely on pulsatile delivery of GnRH to the pituitary. The GnRH analogues (agonists) supply constant stimulation of the pituitary receptors, leading to downregulation 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. Owing to 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, thus, a sound recommendation cannot be made currently.

The expense of GnRH analogues 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.

• References

Elagolix (Orilissa)

• Dosing, Interactions, etc.

Clinical Context:  Indicated for management of moderate-to-severe pain associated with endometriosis.

• References

Class Summary

Inhibits endogenous GnRH signaling by binding competitively to GnRH receptors in the pituitary gland.

• References

Danazol

• Dosing, Interactions, etc.

Clinical Context:  Danazol is a synthetic steroid analogue with strong antigonadotropic activity (inhibits luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) and weak androgenic action.

However, although efficacious, androgens have fallen out of favor because of their unpleasant adverse effects, and because newer medications work as well or better. These drugs may represent a less expensive alternative, or better choice, for certain patients and remain part of the armamentarium. Danazol requires at least 3-6 months to determine its effectiveness.

• References

Class Summary

Antigonadotropic agents work to suppress both the hypothalamic-ovarian axis and endometriosis at a local level and act by inhibiting the midcycle follicle-stimulating hormone (FSH) and luteinizing hormone (LH) surge and preventing steroidogenesis in the corpus luteum. These are the most extensively studied agents for endometriosis. Danazol has been shown to be as effective as any of the newer agents, but it has a higher incidence of adverse effects.

• References

Letrozole (Femara)

• Dosing, Interactions, etc.

Clinical Context:  Letrozole is a competitive inhibitor of the aromatase enzyme system that leads to a reduction in plasma estrogen levels in postmenopausal women. Although this agent has been used extensively in breast cancer treatment, experience to date in endometriosis management is limited. Letrozole may decrease pain in patients whose conditions have previously failed other treatments. Although initial results appear promising, further studies are required to establish the role of aromatase inhibitors in the management of endometriosis.

• References

Class Summary

Aromatase inhibitors 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.

• References