Endometriosis, the presence of endometriumlike glands and stroma outside the uterus, is a common, poorly understood, and extremely debilitating benign gynecological condition. The psychological impact of the severe pain experienced by the patient is compounded by the negative impact of the disease on fertility. 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 (ACOG Committee on Practice Bulletins, 1999). No cure exists for the disease, and treatment is directed toward medical suppression, surgical excision, and symptom alleviation.

Adenomyosis is the invasion of the myometrium by endometrial tissue.

History:

A significant number of women with endometriosis remain asymptomatic.

• Cyclic pain: 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.

• Chronic pain: 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 . However, pain does correlate with the depth of tissue infiltration. Midline disease is generally believed to be more painful than lateral disease.

• Acute exacerbations: These are believed to be caused by chemical peritonitis due to leakage of old blood from an endometriotic cyst. Recently, with conscious laparoscopic pain mapping, painful lesions were found to involve peripheral spinal nerves rather than autonomic nerves.

• Dysmenorrhea: Secondary dysmenorrhea occurs twice as often in women with endometriosis as in controls. Pain frequently commences prior to menses. Endometriosis should be considered in a patient presenting with significant dysmenorrhea, and the patient should be started on empiric therapy.

• Dyspareunia: 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 these may also lead to chronic backache. These symptoms are exaggerated during menses.

Physical Examination:

• Pelvic examination: Tenderness upon examination is best detected at the time of menses. Nodularity of the uterosacral ligaments and the cul-de-sac may be found. The uterus may be fixed in retroversion, owing to adhesions. Occasionally, a bluish nodule may be seen in the vagina due to infiltration from the posterior vaginal wall.

Causes:

Theories of causation include the following:

• Retrograde menstruation

• Sampson described this theory in his classic paper published in 1927. Retrograde flow of endometrial tissue through the fallopian tubes into the peritoneal cavity is believed to cause endometriosis.

• Various animal experiments and clinical observations support this theory .

• Lymphatic and vascular spread

• These pathways may explain the occurrence of endometriosis at distant, noncontiguous sites.

• Ovarian endometriosis is also believed to be caused by lymphatic spread , although superficial ovarian endometriosis may also be due to implantation via retrograde menstruation.

• Coelomic metaplasia

• Transformation of coelomic epithelium into endometrial-type glands in response to as yet unknown stimuli could explain endometriosis in unusual sites .

• Coelomic metaplasia is also believed to explain the occurrence of endometriosis in women who have undergone total hysterectomy and are not taking estrogen replacement.

• Endometriosis may also occur in men on high-dose estrogen therapy.

• Immunogenetic defects

• These are believed to increase the susceptibility of a woman to endometriosis. Humoral antibodies to endometrial tissue have also been found in sera of women with endometriosis .

• Recent work has focused on studying 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.

• A case report has been published describing treatment with the aromatase inhibitor anastrozole in a women with severe postmenopausal endometriosis, resulting in dramatic symptom resolution. Additional data are needed before recommending this as treatment.

• Anatomic spread

• The ovary is the most common site for endometriosis. Spread to the ovary is believed to be lymphatic, 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. 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.

• 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.
• 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.

• Serum cancer antigen 125 test: Serial measurements have a low sensitivity in detecting endometriosis , but the results are useful as prognosticators of treatment outcome. However, normal posttreatment values do not mean that endometriosis is absent.

Imaging Studies:

• Ultrasonography: Transvaginal sonography 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.

• MRI: MRI has a low sensitivity in detecting rectal involvement  but may help detect deeply infiltrating endometriosis that involves the uterosacral ligaments and cul-de-sac. The cost-effectiveness of this imaging modality for endometriosis has yet to be justified in view of the low diagnostic yield.

Other Tests:

• Laparoscopy: Laparoscopy is considered the primary diagnostic modality for endometriosis. Endometriosis has been described as protean in appearance. The classic lesions are blue-black or have a powder-burned appearance. However, the lesions can be red, white, or nonpigmented. Peritoneal defects and adhesions are also indicative. Bear in mind that microscopic evidence of endometriosis may be found in normal-appearing peritoneum.

• Conscious pain mapping: Recently, conscious pain mapping (ie, with the patient awake) has been used to locate the specific areas that cause pain . Subsequently, the patient is placed under anesthesia and the deposits are ablated.
  

Staging:

The American Society for Reproductive Medicine classification is currently the most widely used staging system (American Society for Reproductive Medicine, 1997). Point scores are assigned based on the number of lesions and their bilaterality. 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 . Further, this staging system does not correlate well with pain and dyspareunia and fecundity rates cannot be predicted accurately.

Medical Care:

• 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. Results from studies on the role of prostaglandins are inconclusive.
• Medical treatment of minimal or mild endometriosis has not been shown to increase pregnancy rates. Moderate-to-severe endometriosis should be treated surgically .
• 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 . Further, other analyses have shown improvement in 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.
• Surgical ablation of asymptomatic endometriosis has also been shown to improve fecundity rates on a 3-year follow-up .

• 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 .
• Medical therapy: Combination oral contraceptive pills (COCPs), danazol, progestational agents, and GnRH analogs form the mainstay of medical therapy. All these therapies have similar clinical efficacy in terms of reduction in pain-related symptoms and duration of relief.

• COCPs act by ovarian suppression and continuous progestin administration.
• Initially, a trial of continuous or cyclic COCPs should be administered for 3 months. If pain is relieved, this treatment is continued for 6-12 months. Subsequent pregnancy rates upon 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.
• 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 . 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.
• GnRH analogs produce a hypogonadotrophic-hypogonadic state by down-regulation of the pituitary gland. Currently, goserelin and leuprolide acetate are the commonly used agonists.
• Once again, efficacy is limited to pain suppression and fertility rates may show no improvement.
• 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. Other prominent adverse effects include hot flashes and vaginal dryness.
• Much interest has been shown in whether 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. 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 .
• A clinical trial has shown that a 3-month empiric course of GnRH, based on a diagnostic algorithm without definitive laparoscopic diagnosis, is efficacious . However, long-term effects of GnRH analogs 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. 
• GnRH therapy has also been proven to relieve the pain and bleeding associated with extrapelvic distant endometriosis .
• 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.
• Because of the possibility of virilizing changes in a female fetus, additional barrier contraception must be used while on danazol therapy.

Surgical Care:

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.

• 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 . Ablation can be performed with laser or electrodiathermy. Overall, the recurrence rate is 19% and is similar for all techniques . Ovarian endometriomas can be treated by drainage or cystectomy. Laparoscopic cystectomy was found to yield better pain relief and pregnancy rates than drainage. Medical therapy with GnRH agonists reduces the size of the cyst but does not influence pain relief.

• 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 . However, when combined with laparoscopic ablation, LUNA significantly reduced pain attributed to endometriosis . In patients with subfertility, tissue ablation significantly increased the cumulative pregnancy rate.

• For patients with mild disease, postoperative adjunctive hormonal treatment has been shown effective in reducing pain but has no impact on fertility. GnRH analogs, danazol, and medroxyprogesterone have all been found to be useful for this indication . However, for severe endometriosis, the efficacy of preoperative or postoperative hormonal treatment has not yet been established.

• Semiconservative surgery

• The indication for this type of surgery is mainly in women who have completed their childbearing, are too young to undergo premature 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.
• Medical therapy in women who have completed childbearing is equally efficacious for symptom suppression.

• Radical surgery

• This involves total hysterectomy with bilateral oophorectomy 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 ERT is given postoperatively . ERT can be instituted safely immediately after surgery, especially in younger women who face the prospect of accelerated bone loss and vasomotor symptoms . No trials have reported the use of estrogen plus progestin therapy compared to estrogen therapy alone postoperatively. However, theoretically, the addition of a continuous progestin could decrease the regrowth of endometriosis.

• Comparison of medical and 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.

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Oral contraceptives -- COCPs act by ovarian suppression and continuous progestin administration. Initially, a trial of continuous or cyclic COCPs should be given for 3 mo. If pain is relieved, this treatment is continued for 6-12 mo. 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.

ETHINYL ESTRADIOL & NORGESTIMATE:

Schedule 1 (Sunday starter)
Begin dose on first Sunday after onset of menstruation; start that Sunday if menstrual period starts on Sunday
21-tab package: 1 tab qd for 21 d followed by 7 d off medication; new course begins on day 8 after taking last tab
28-tab package: 1 tab qd without interruption

Schedule 2 (day 1 starter)
Start dose on d 1 of menstrual cycle
21-tab package: 1 tab qd for 21 d followed by 7 d off medication; begin new course on day 8 after taking last tab
Continue dosing cycle if one period missed; pregnancy test required if 2 periods missed.

Drug Category: Progestational agents -- All act by decidualization and atrophy of the endometrium.

MEDROXYPROGESTERONE:10-20 mg PO qd continuously.

MEGESTROL ACETATE:40 mg PO qd

Drug Category: Gonadotropin-releasing hormone analogs -- Produce a hypogonadotrophic-hypogonadic state by down-regulation of the pituitary gland. Currently, goserelin and leuprolide acetate are the commonly used agonists.

GOSERELIN:3.6 mg SC q28d or 10.8 mg SC q12wk for 6 mo.

LEUPROLIDE:3.5-7.5 mg/mo IM; not to exceed 6 mo without adding low-dose estrogen and progestin therapy.

Drug Category: Antigonadotropic agents -- Act by inhibiting the midcycle FSH and LH surge and preventing steroidogenesis in the corpus luteum. Most extensively studied agents for endometriosis. Danazol has been shown to be as effective as any of the newer agents, but with a higher incidence of adverse effects.

DANAZOL:600-800 mg/d PO 

Prognosis:

• Endometriosis was found to resolve spontaneously in one third of women who were not actively treated.