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Endometriosis: Current Management

      Objective

      To review the clinical features, theories of pathogenesis, and current treatment of endometriosis-associated pain and infertility.

      Design

      We review the manifestation of endometriosis and the possible mechanisms that lead to its symptoms, examine the efficacy of current therapeutic options for pelvic pain and infertility, and provide specific recommendations for treatment based on the current literature.

      Material and Methods

      Endometriosis is the presence of hormonally responsive endometrial tissue occurring outside the uterine cavity. This condition may be asymptomatic but is often found in association with pelvic pain or infertility (or both). The precise pathogenesis has not been clearly established but likely involves retrograde menstruation with subsequent seeding of endometrial glands at extrauterine sites. The definitive diagnosis and staging of endometriosis are performed by laparoscopy. Various strategies have been used to treat endometriosis including expectant, medical, surgical, and combination management.

      Results

      The efficacy of treatment varies for pelvic pain and infertility. Endometriosis-associated pain may respond to both medical and surgical management. The use of medical therapy for endometriosis-associated infertility is not supported by current studies. Surgical management of infertility may be efficacious when pelvic anatomy is distorted because of endometriosis. The use of superovulation strategies and in vitro fertilization has been shown to be effective in overcoming endometriosis-associated infertility.

      Conclusion

      Pelvic pain and infertility in the presence of endometriosis necessitate individualization of therapy to achieve treatment goals. Neither medical nor surgical management is efficacious in all circumstances. As a better understanding of the pathogenesis of endometriosis evolves, treatment of this perplexing condition will probably continue to improve.
      AFS (American Fertility Society), CA 125 (cancer antigen 125), ERT (estrogen replacement therapy), FSH (follicle-stimulating hormone), GnRH (gonadotropin-releasing hormone), IUI (intrauterine insemination), IVF (in vitro fertilization), LH (luteinizing hormone), SO (superovulation)
      Endometriosis is defined as the presence of functioning ectopic endometrial glands and stroma outside the uterine cavity. Since the original description of this disease during the mid-19th century and because of more awareness among clinicians, endometriosis is being diagnosed with increasing frequency and is one of the most common conditions encountered by gynecologists. Nonetheless, despite decades of research and experience with this disease, controversies about its cause and treatment remain.
      Endometriosis was originally described as two variants. Endometriosis intema, growth of benign endometrial tissue into the myometrium, is now referred to as adenomyosis. Currently, the term “endometriosis” refers to endometriosis extema, the presence of endometrial tissue implants in all other sites. Although a benign condition, endometriosis is characterized by its ability to invade tissue and spread by means of local extension, intraperitoneal seeding, and vascular routes. These two processes differ in both pathogenesis and symptoms and thus represent distinct clinical entities. The rest of this article focuses on endometriosis.

      Incidence

      The actual incidence of endometriosis is difficult to establish because definitive diagnosis must be made by either laparotomy or laparoscopy. Rates vary widely among studies and have been reported to be from 1 to 50%, depending on the population studied. A prospective study of 1,000 women who underwent laparotomy for benign disease at the Mayo Clinic reported a 50% incidence of endometriosis.
      • Williams TJ
      • Pratt JH
      Endometriosis in 1.000 consecutive celiotomies: incidence and management.
      Of importance, these data are from surgical patients at a tertiary referral center. Wheeler
      • Wheeler JM
      Epidemiology of endometriosisassociated infertility.
      found that the prevalence of endometriosis ranges from 0.7% in women who have undergone tubal reanastomosis to 30% in those who have undergone diagnostic-operative laparoscopy. When these and other data are considered, a prevalence rate of 5 to 10% in the general population is widely accepted.

      Pathogenesis

      Several theories exist that attempt to explain the pathogenesis of endometriosis. Sampson's
      • Sampson JA
      Perforating hemorrhagic (chocolate) cysts of the ovary: their importance and especially their relation to pelvic adenomas of cndomelrial type (“adenomyoma” of the uterus, reclovaginal septum, sigmoid, etc).
      original explanation for the origin of the disease stated that it results from transport of viable endometrial cells through retrograde menstruation. The ectopic foci of endometrial tissue retain their cyclic hormonal responsiveness, which contributes to the symptoms. Diagnostic laparoscopy during the perimenstrual pe­ riod has shown that up to 90% of women with patent fallopian tubes have bloody peritoneal fluid;
      • Halme J
      • Hammond MG
      • Hulka JF
      • Raj SG
      • Talben LM
      Retrograde menstruation in healthy women and in patients with endometriosis.
      however, endometriosis does not develop in all women with retrograde menstruation. Research during the past decade suggests that immunologic factors are also involved. Alterations in cellmediated and humoral immunity responses have been demonstrated in women with endometriosis and seem to have a role during both the initial stage and progression of the disease.
      • Halme J
      • Becker S
      • Haskill S
      Altered maturation and function of peritoneal macrophages: possible role in pathogenesis of endometriosis.
      • Oosterlynck DJ
      • Comitlie FJ
      • Waer M
      • Vandeputte M
      • Koninckx PR
      Women with endometriosis show a defect in natural killer activity resulting in a decreased cytotoxicity to autologous endomctrium.
      Presumably, the transport of endometrial cells through hematogenous, lymphatic, or iatrogenic (during an operation) routes also explains endometriosis at sites beyond the abdominal cavity (such as the lungs and incisional scars).
      The theory of coelomic metaplasia explains the histogenesis of endometriosis by postulating that peritoneal mesothelium may undergo metaplastic transformation to endometrial tissue. This theory is based on the fact that both the endometrium and the peritoneum are derivatives of coelomicwall epithelium. Metaplastic transformation may be induced by chronic irritants in retrograde menstrual fluid.
      A third theory suggests that remnant miillerian cells may remain in the pelvic tissues during development of the miillerian system. In certain situations, such as estrogen stimulation, these cell remnants may be induced to differentiate into functioning endometrial glands and stroma.
      • Cullen TS
      Adcnomyoma of the reclovaginal septum.
      This theory may explain the reports of endometriosis in male patients treated with high doses of estrogens.
      • Schrodt GR
      • Alcorn MO
      • Ibanez J
      Endometriosis of the male urinary system; a case report.
      The potential involvement of genetic factors in endometriosis has been suspected from the numerous reports of a familial tendency for the development of this condition. If a first-degree relative is affected, the risk of having endometriosis is approximately 7%.
      • Simpson JL
      • Elias S
      • Maiinak LR
      • Buttram Jr, VC
      Heritable aspects of endometriosis. I. Genetic studies.
      Kindred studies suggest a polygenic and multifactorial mode of inheritance. Further elucidation of the genetic link will likely result from molecular biologic studies of families with endometriosis.

      Manifestation

      The mean age of women diagnosed with endometriosis has been reported to range from 25 to 30 years. Endometriosis is also a common finding in adolescents with chronic pelvic pain or dyspareunia. During the perimenarcheal years, endometriosis is often associated with menstrual outflow abnormalities that may intensify retrograde menstruation. This situation may occur in the presence of an imperforate hymen, transverse vaginal septum, or mtillerian anomaly.
      The symptoms associated with endometriosis are diverse, and no single symptom is pathognomonic for the disease. Dysmenorrhea, dyspareunia, chronic pelvic or back pain, and rectal discomfort are often reported. The pain may be cyclic or constant and may vary in character. These symptoms are presumed to be caused by the site of the endometriotic implants; however, the intensity of pain and discomfort do not often correlate with the severity of disease. Infertility is another common complaint of patients with endometriosis. Endometriosis is usually diagnosed during laparoscopy and is noted in up to 60% of infertile patients.
      • Houston DE
      • Nollcr KL
      • Melton III, LJ
      • Selwyn BJ
      • Hardy RJ
      Incidence of pelvic endometriosis in Rochester, Minnesota, 1970–1979.
      Less frequently, endometriosis may be associated with ob­ struction of the gastrointestinal or urinary tract (Fig. 1). Cyclic hemoptysis or catamenial pneumothorax may occur with dissemination to the lungs.
      • Foster DC
      • Stem JL
      • Buscema J
      • Rock JA
      • Woodruff JD
      Pleural and parenchymal pulmonary endometriosis.
      Figure thumbnail gr1
      Fig. 1Barium enema of 34-year-old woman with stage IV endometriosis based on revised American Fertility Society classification of endometriosis, showing mid-sigmoid colon constriction caused by 25-cm endometrioma. (Photograph courtesy of Dr. Daniel A. Dumesic, Section of Reproductive Endocrinology and Infertility, Mayo Clinic Rochester.)

      Diagnostic Evaluation

      The diagnosis of endometriosis should be suspected in all women who have pelvic pain or who are infertile. A complete history will often reveal symptoms suggestive of endometriosis and is crucial in identifying the involvement of potential nongynecologic causes of symptoms. An association between pelvic pain and other somatization disorders with past sexual victimization has been increasingly acknowledged.
      • Walker EA
      • Stenchever MA
      Sexual victimization and chronic pelvic pain.
      Thus, an inquiry about potential physical or emotional abuse should become a routine part of the screening interview. On physical examination, a hallmark feature is the presence of tender nodular masses along thickened uterosacral ligaments, posterior uterus, and posterior culde-sac. Obliteration of the cul-de-sac in conjunction with fixed uterine retroversion implies extensive disease. Ovarian involvement may be accompanied with adnexal tenderness and palpable enlargement if “chocolate cysts” are present. The definitive diagnosis, however, necessitates surgical investigation.
      Currently, laparoscopy is the procedure of choice for the diagnosis of endometriosis. It is performed on an outpatient basis and enables the surgeon to detect and evaluate the extent of disease. The most common sites of involvement tend to be the dependent portions of the pelvis, as listed in descending order: ovary, posterior cul-de-sac, broad ligament, uterosacral ligament, rectosigmoid colon, bladder, and distal ureter. Endometriotic implants vary in appearance, and the experience of the laparoscopist is a major factor in their identification. In addition to the classic bluish-blackish “powder bum” lesion, endometriosis may appear as white, red, or clear vesicular implants; white or yellow papular lesions; flame hemorrhagic lesions; nodular implants; and fibrotic (healed) lesions (Fig. 2).
      • Jansen RP
      • Russell P
      Nonpigmented endometriosis: clinical, laparoscopic, and pathologic definition.
      Figure thumbnail gr2
      Fig. 2A, Circumscribed and thickened patches of opacified white peritoneum above left uterosacral ligament, approximately 8 mm in diameter. B, Thickened white peritoneum in right ovarian fossa, approximately I cm in diameter. Adjacent, more medial lesions (left side of figure) have nodular, glistening appearance. C, Raised glandlike lesions on right ovarian ligament. Glassy, translucent tissue resembles normal endometrium in color and consistency. D, Raised, red, flamelike lesion in cul-de-sac, approximately 3 mm in diameter. E, Vesicular superficial excrescences in right ovarian fossa after oil-based hysterosalpingography. (From Jansen and Russell.
      • Jansen RP
      • Russell P
      Nonpigmented endometriosis: clinical, laparoscopic, and pathologic definition.
      By permission.)
      During the diagnostic procedure, accurate staging of the disease is important. The revised American Fertility Society (AFS) classification of endometriosis is the most commonly used system (Fig. 3).
      • American Fertility Society
      Revised American Fertility Society classification of endometriosis: 1985.
      Staging facilitates an objective serial assessment of response to therapy and allows comparison of results of various treatments as well as consistent exchange of information among clinicians. Appropriate staging also provides a rational approach to the choice of treatment and a. basis when offering a prognosis to patients. Of note, the stage of disease based on the AFS system does not necessarily correlate with the degree of infertility or the severity of symptoms. The current classification does not consider factors such as type of active lesion, primary versus recurrent disease, or duration of symptoms. Despite such limitations, consistent staging of endometriosis is necessary for eventual identification of factors that may lead to a more comprehensive and clinically relevant classification system.
      • Olive DL
      • Haney AF
      Endometriosis–associated infertility: a critical review of therapeutic approaches.
      Figure thumbnail gr3
      Fig. 3Revised American Fertility Society classification of endometriosis. (From The American Fertility Society.
      • American Fertility Society
      Revised American Fertility Society classification of endometriosis: 1985.
      By permission.)
      After appropriate staging, the choice of treatment can be individualized to achieve the therapeutic goals. In general, most patients can be classified into one of three groups: (1) those with endometriosis-associated infertility with or without pain, (2) those with pelvic pain (without infertility) who want to preserve their fertility potential, or (3) those with pelvic pain who have completed childbearing.
      • Malinak LR
      • Wheeler JM
      Conservative surgery for endometriosis.
      Such categorization is not intended to “label” patients but serves to prioritize and focus the goals of treatment.
      Other modalities available for the evaluation of suspected endometriosis include measurement of serum cancer antigen 125 (CA 125) and imaging studies. Increased levels of CA 125 were originally found in ovarian epithelial neoplasms and have been used as markers of disease progression after treatment; however, increased CA 125 levels are also found in benign pelvic conditions such as endometriosis, myomas, adenomyosis, acute pelvic inflammatory disease, and ovarian cysts.
      • O'Shaughnessy A
      • Check JH
      • Nowroozi K
      • Lurie D
      CA 125 levels measured in different phases of the menstrual cycle in screening for endometriosis.
      Thus far, measurement of CA 125 has not been shown to be useful in screening or in monitoring therapy for endometriosis.
      Ultrasound studies have been shown to be helpful in the investigation of suspected pelvic masses. The ultrasonographic appearance of endometriomas varies and may manifest as adnexal masses with cystic to mixed echogenic patterns. Ultrasonography is not useful for detecting focal endometriotic lesions nor can it reliably distinguish endometriomas from other benign or malignant ovarian pathologic conditions. Magnetic resonance imaging has also been used in the investigation of pelvic masses and is highly accurate in detecting endometriomas; however, like ultrasonography, it has limited sensitivity in identifying diffuse pelvic endometriosis. Currently, routine radiographic imaging studies are not recommended for diagnosing endometriosis; however, they may be useful when suspicious masses are investigated or when visceral involvement (such as bowel or bladder) is suspected.

      Management

      General Considerations.—The therapeutic options available for patients with endometriosis continue to increase, and, thus, clinicians may experience some confusion in choosing the optimal course of management. Treatment should be directed at achieving the patient's therapeutic goals and be based on established efficacy; however, before a treatment plan can be established, the extent of disease must be accurately assessed. As discussed earlier, laparoscopy is the “gold standard” for the diagnosis and staging of endometriosis. For infertile couples, a thorough examination to exclude accompanying factors is also indicated; combined male and female traits that contribute to infertility are found in up to 40% of couples.
      Expectant Treatment.— The traditional initial treatment of stage I (minimal) or stage II (mild) endometriosis-associated infertility is expectant management. Several studies have reported conception rates to be 55 to 75% in patients in whom laparoscopic diagnosis of minimal or mild endometriosis was treated expectantly.
      • Schenken RS
      • Maiinak LR
      Conservative surgery versus expectant management for the infertile patient with mild endometriosis.
      • Hull ME
      • Moghissi KS
      • Magyar DF
      • Hayes MF
      Comparison of different treatment modalities of endometriosis in infertile women.
      These results did not differ significantly from those obtained with medical or conservative surgical treatment and suggest that a period of observation (5 to 12 months) may be reasonable in patients with stage I and II infertility. The diagnostic procedure itself may have therapeutic effects such as alleviation of tubal obstruction from chromopertubation. Of note, expectant management does not imply no treatment, and additional factors such as ovulatory disorders should be treated.
      Expectant management is not justified for extensive disease (stage III or IV) in patients with infertility or severe pain (or both). Surgery appears to improve pregnancy rates in patients with moderate or severe disease in comparison with observation alone.
      • Olive DL
      • Ijec KL
      Analysis of sequential treatment protocols for endometriosisassociated infertility.
      Because endometriosis is a progressive condition, delaying treatment of symptomatic pelvic pain has no value, regardless of the stage. Patients whose prime motivation for obtaining medical care is eradication of severe symptomatic pain must clearly define their therapeutic goals relative to future reproductive potential.
      Surgical Treatment. Conservative.—Surgical management is one of the most common initial treatments of endometriosis. Conservative surgical treatment is directed at maintaining and, perhaps, enhancing fertility potential by removing or destroying endometriotic implants and endometriomas by excision, electrocautery, or laser; the organs necessary for procreation are preserved. It may be performed at the time of diagnostic laparoscopy or laparotomy. Various adjunctive procedures are often performed concurrently including adhesiolysis, uterine or ovarian suspension (or both), uterosacral plication, presacral neurectomy, and tuboplasty. The value of these ancillary procedures in decreasing symptoms or in improving fertility remains undetermined, however, and implants have been shown to recur in up to 28% of patients within 18 months after conservative surgical treatment
      • Gordts S
      • Boeckx W
      • Brosens I
      Microsurgery of endometriosis in infertile patients.
      and in 40% after 9 years of follow-up.
      • Wheeler JM
      • Maiinak LR
      Recurrent endometriosis: incidence, management, and prognosis.
      The value of adhesiolysis can also be limited because adhesions may re-form in up to 50% of patients.
      • Vancaillie T
      • Schenken RS
      Endoscopic surgery.
      The risk of adhesion recurrence is highest postoperatively in the presence of inflammation and exposed raw tissue surfaces. The use of dextran or physiologic saline may aid in preventing adhesion re-formation by means of an intraperitoneal hydroflotation effect.
      • Adhesion Study Group
      Reduction of postoperative pelvic adhesions with intraperitoneal 32% dextran 70: a prospective, randomized clinical trial.
      The duration of effectiveness of such adjuvants has not been established, however, and pelvic adhesion re-formation has been found within 3 months.
      • Diamond MP
      • Danicll JF
      • Martin DC
      • Festc J
      • Vaughn WK
      • Mclaughlin DS
      Tubal patency and pelvic adhesions at early second-look laparoscopy following intraabdominal use of the carbon dioxide laser: initial report of the intraabdominal laser study group.
      Laparoscopic adhesiolysis does not seem to decrease adhesion recurrence.
      • Operative Laparoscopy Study Group
      Postoperative adhesion development after operative laparoscopy: evaluation of early second look procedures.
      Despite a lack of conclusive efficacy, up to half of the patients experience some restoration of pelvic anatomy after adhesiolysis.
      Numerous uncontrolled studies have attempted to evaluate the efficacy of conservative surgical treatment to alleviate pelvic pain; although estimates vary, 61 to 100% of patients experience relief of symptoms.
      • Vancaillie T
      • Schenken RS
      Endoscopic surgery.
      Polan and Defherney
      • Polan ML
      • DeCherncy A
      Presacral neurectomy for pelvic pain in infertility.
      reported that 75% of infertile patients with endometriosis remained free of pain after presacral neurectomy for a mean of 2.3 years; however, these results may have limited value for the current discussion because none of the women in the control group had endometriosis.
      For the vast majority of patients, the primary appeal of conservative surgical management is that fertility may be retained. Although such treatment is widely used to enhance fertility, its efficacy for endometriosis-associated infertility has yet to be demonstrated. Early studies suggest cumulative pregnancy rates of approximately 52% after conservative surgical management of endometriosis.
      • Olive DL
      Conservative surgery.
      Analysis of the literature relative to stage of disease allows a rationalized approach toward determining which patients would benefit from a conservative operation. For mild to moderate endometriosis, the effect of such treatment on fertility does not differ significantly from that with either expectant management or danazol therapy;
      • Olive DL
      • Ijec KL
      Analysis of sequential treatment protocols for endometriosisassociated infertility.
      • Guzick DS
      • Rock JA
      A comparison of danazol and conservative surgery for Ihe treatment of infertility due to mild or moderate endometriosis.
      however, for severe endometriosis, conservative surgical treatment has been shown to improve fertility substantially in comparison with expectant management or danazol therapy.
      As previously stated, diagnostic laparoscopy is the procedure of choice for evaluating endometriosis. The rapidly advancing technical developments and expertise among gynecologic surgeons continue to broaden the possibilities for operative laparoscopic procedures at the time of diagnosis. In one prospective study, the laparoscopic cauterization of early-stage endometriosis was shown to improve pregnancy rates in comparison with expectant management alone;
      • Nowroozi K
      • Chase JS
      • Check JH
      • Wu CH
      The importance of laparoscopic coagulation of mild endomelriosis in infertile women.
      however, no prospective studies have confirmed an advantage for either laparoscopically performed procedures or traditional laparotomy in the treatment of endometriosis-associated infertility.
      • Gant NF
      Infertility and endometriosis: comparison of pregnancy outcomes with laparotomy versus laparoscopic techniques.
      Currently, laparoscopic conservative surgical treatment does not seem to be detrimental and thus may be considered by appropriately trained surgeons.
      Definitive.—Total abdominal hysterectomy with bilateral salpingo-oophorectomy is the definitive treatment of endometriosis-associated pain. This therapeutic option may be considered for patients whose condition is refractory to medical or conservative surgical treatment (or both) who can accept loss of their fertility potential. This approach may also be appropriate primary therapy for women with severe symptoms who have completed childbearing and who desire a permanent cure. Total abdominal hysterectomy with bilateral salpingo-oophorectomy and complete excision or ablation of endometriosis are 90% effective in relieving symptoms of pain.
      • Olive DL
      • Schwartz LB
      Endometriosis.
      When the surgeon performs a definitive operation, thorough abdominal exploration is necessary to ensure complete removal of all disease. In addition, the surgeon must be prepared to manage possible gastrointestinal and urinary tract disease.
      In patients with no extensive ovarian disease or adhesions to the ovaries, a conservative approach may be indicated. The risk of recurrence of disease and reoperation when at least one ovary is preserved is approximately 8%.
      • Walters MD
      Definitive surgery.
      In stage III or IV disease, the risk of recurrence may be as high as 44% without oophorectomy.
      • Colic ML
      • Grecnblall RB
      Contraceptive properties of danazol.
      Thus, an ovary-sparing procedure seems reasonable for mild to moderate endometriosis in young women who are willing to accept the low but substantial risk of reoperation. When ovarian endometriosis is unresectable or when severe adhesive disease cannot be alleviated, oophorectomy should not be postponed.
      Estrogen replacement therapy (ERT) should be considered for all women after definitive surgical treatment of endometriosis. After ERT, recurrence rates range from 0 to 5% in women with disease confined to the pelvis but are 18% in women with bowel involvement.
      • Walters MD
      Definitive surgery.
      The known benefits of ERT outweigh the low risk of eliciting recurrent endometriosis; thus, ERT (conjugated estrogens, 0.625 mg/day or its equivalent) should be offered to most patients who have undergone oophorectomy. Adding a progestin to the regimen after hysterectomy does not seem to be beneficial. Patients who receive ERT should be closely monitored, and therapy should be discontinued if symptoms recur.
      Medical.—The belief that steroid hormones are the primary stimulus for growth and maintenance of ectopic endometrial tissue forms the basis for the medical management of endometriosis. Estrogen, progesterone, and androgen receptors are present in varying degrees in ectopic endometrial implants, and such heterogeneous receptor content may explain the range of clinical responses to manipulation of hormones. Both hypoestrogenism and hyperestrogenism have been noted to result in endometrial atrophy. Pharmacologic doses of either progestins or androgens can cause decidualization of endometrial tissue, which results in atrophy.
      • Colic ML
      • Grecnblall RB
      Contraceptive properties of danazol.
      These actions underlie the strategies used to alter the menstrual cycle by means of hormonal action to decrease or alleviate endometriosis.
      • Barbieri RL
      • Homstein MD
      Medical therapy for endometriosis.
      Current regimens attempt to create states of pseudopregnancy, pseudomenopause, or chronic anovulation. Even though these treatments have demonstrated efficacy in alleviating symptoms of endometriosis, medical therapy should be viewed as suppressive rather than curative because eventual recurrence is common after cessation.
      Estrogen-Progesterone.—The use of a combination preparation of estrogen and progesterone oral contraceptives in a continuous fashion was one of the first effective medical treatments of endometriosis and has been termed “pseudopregnancy.” Almost every combination oral contraceptive has been used with comparable success in promoting decidualization of endometriotic implants and relief of symptoms. Pseudopregnancy is efficacious in alleviating pain in 75 to 89% of patients.
      • Olive DL
      Medical treatment: alternatives to danazol.
      The actual effect of pseudopregnancy on the regression of endometriotic implants is undetermined. No large studies have assessed the effect of pseudopregnancy on fertility, although pregnancy rates of about 40% have been reported in several small series.
      • Andrews WC
      • Larsen GD
      Endometriosis: treatment with hormonal pseudopregnancy and/or operation.
      • Noble AD
      • Letchworth AT
      Medical treatment of endometriosis: a comparative trial.
      A state of pseudopregnancy is achieved by administering oral contraceptives continuously for 6 to 12 months. Breakthrough bleeding is treated by increasing the dose of these agents or by administering conjugated estrogens, 1.25 mg/day for 2 weeks. Side effects and contraindications to therapy are similar to those associated with cyclic oral contracepti therapy.
      Estrogen.— The use of estrogen alone for the treatment of endometriosis is no longer acceptable. Such therapy was initiated during the 1940s, and its lack of efficacy has been proved in primate studies.
      • Olive DL
      Medical treatment: alternatives to danazol.
      The extensive side-effect profile includes endometrial hyperplasia, thromboemboli, dysfunctional uterine bleeding, hypertension, and severe nausea and vomiting. Currently, estrogen alone cannot be clinically justified in the treatment of endometriosis.
      Danazol.—Danazol, an isoxazol derivative of 17 α-ethynyl I testosterone, has been used in the treatment of endometriosis-associated pain and infertility since 1971.
      • Grcenblatt RB
      • Dmowski WP
      • Mahesh VB
      • Scholer HFL
      Clinical studies with an antigonadotropin-danazol.
      It is well absorbed after oral administration, and its half-life is 4.5 hours. Secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) is inhibited, an outcome that decreases estrogen and progesterone secretion from the ovary and thereby removes hormonal support of endometriotic implants. Danazol also displaces testosterone from sex hormone binding globulin, a phenomenon that leads to increased free testosterone levels, which promote its androgenic effects.
      The hormonal milieu created by danazol is responsible for the therapeutic effect against endometriosis-associated pain. After 6 months of danazol therapy, up to 90% of patients with mild to moderate endometriosis experience alleviation of pelvic pain.
      • Bayer SR
      • Seibel MM
      • Saffan DS
      • Berger MJ
      • Taymor ML
      Efficacy of danazol treatment for minimal endometriosis in infertile women: a prospective, randomized study.
      Danazol is less effective in decreasing dyspareunia or chronic pelvic pain due to pelvic adhesions. Studies that used second-look laparoscopy indicate that danazol is effective in eliminating mild to moderate endometriosis but is less effective in decreasing lesions larger than 1 cm in diameter; no effect has been noted for pelvic adhesions. Therapy for at least 6 months leads to diminishment of severe disease and is significantly better than placebo for up to 6 months after treatment.
      • Telimaa S
      • Puolakka J
      • Ronnberg L
      • Kauppila A
      Placebo-controlled comparison of danazol and high-dose medroxyprogeslerone acetate in the treatment of endometriosis.
      The effectiveness of danazol in treating infertility is less clear. For minimal to mild disease, danazol is as effective as observation alone. In severe endometriosis, pelvic adhesions and anatomic distortion, neither of which is alleviated with medical therapy, have a substantial role in infertility. Because of the proven effectiveness of danazol in decreasing the extent of endometriotic implants, some surgeons advocate preoperative danazol therapy to make an operation technically easier, but prospective outcome analysis has not been performed.
      • Barbieri RL
      • Evans S
      • Kistner RW
      Danazol in Ihe treatment of endometriosis: analysis of 100 cases with a 4-year follow-up.
      Danazol is ineffective therapy for infertility associated with minimal and mild endometriosis and should not be used.
      Traditionally, danazol has been administered orally in two dosages of 400 mg/day. Because of its half-life, some investigators have advocated dividing the daily dose into four equal administrations. Evidence shows that lower daily dosages may also be effective for less severe disease.
      • Bayer SR
      • Seihel MM
      Medical treatment: danazol.
      Thus, the trend is toward initiation of danazol therapy at 400 mg/day. Treatment is commenced after menses in order to avoid fetal exposure associated with an early pregnancy, and patients should use barrier contraception during the first few months of therapy. If no improvement occurs within 6 weeks, the dosage may be increased to 600 or 800 mg/day. Therapy is generally continued for 6 months, although briefer regimens may be effective.
      Up to 80% of patients taking danazol will experience some side effects, including weight gain, fluid retention, acne, decreased breast size, atrophic vaginitis, hot flushes, muscle cramps, and emotional lability. Additionally, danazol has been associated with decreased high-density lipoprotein levels. Thus, avoiding its use in patients with hyperlipidemia or a strong family history of heart disease may be prudent.
      • Dlugi AM
      • Rufo S
      • D'Amico JF
      • Seibel MM
      A comparison of the effects of buserclin versus danazol on plasma lipoprotcins during treatment of pelvic endometriosis.
      Progestins.—The progestin most commonly used to treat endometriosis is orally administered medroxyprogesterone acetate. Progestin therapy has been shown to be as effective as danazol in the regression of endometriosis. The usual dosage is 10 to 30 mg/day orally and occasionally up to 100 mg/day. An intramuscular preparation has also been administered—100 mg intramuscularly every 2 weeks for four doses, followed by 200 mg monthly for 4 months.
      • Glass RH
      Infertility.
      Common side effects are breakthrough bleeding, nausea, fluid retention, depression, and breast tenderness, all of which resolve after therapy. Breakthrough bleeding is common and may be treated with ethynyl estradiol (20 μg/day) or conjugated estrogens (1.25 mg/day) for 1 to 2 weeks. Pain relief with progestin therapy is comparable to that with danazol, and both are substantially better than expectant management. Neither treatment is effective for pain from pelvic adhesions. Progestin therapy is not effective for endometriosis-associated infertility. In light of the decreased cost, comparable efficacy, and more tolerable sideeffect profile of progestins in comparison with danazol, many investigators advocate the use of progestins as the first-line drug for medical treatment of endometriosis.
      Gonadotropin-Releasing Hormone Analogues.—The most recent advance in the medical management of endometriosis was heralded by the advent of gonatropin-releasing hormone (GnRH) analogues, which allow the achievement of a reversible “medical oophorectomy.” These synthetic decapeptides differ from the native GnRH molecule by one or more amino acid substitutions and act to down-regulate the pituitary gland and decrease the secretion of FSH and LH by means of an agonist mechanism. These preparations may be administered subcutaneously (leuprolide acetate and goserelin) or intranasally (nafarelin acetate) with varying dosage schedules. Administration leads to a decrease in FSH and LH levels, which profoundly diminishes ovarian steroid levels to the “castrate range” within 6 weeks. Hormonal support of the endometriotic implants is withdrawn, an outcome that results in regression and relief of symptoms. After 24 weeks of depot leuprorelin acetate therapy, significantly decreased AFS scores have been demonstrated by second-look laparoscopy.
      • Gerhard I
      • Schindler AE
      • Biihler K
      • Winkler U
      • Meincn K
      • Mancarella D
      • et al.
      Treatment of endometriosis with leuprorelin acetate depot: a German multiccntrc study.
      Side effects of GnRH therapy are attributable to the hypoestrogenic state and include hot flushes, vaginal dryness, transient vagi­ nal bleeding, insomnia, irritability, depression, breast tenderness, fatigue, headache, and joint stiffness. With GnRH therapy, in comparison with danazol, hot flushes are more severe, whereas weight gain, nervousness, and edema are decreased. The main concern with GnRH therapy is osteoporosis, and in light of the measurable (but reversible) loss of trabecular bone after 6 months of treatment, its use has been limited to 6 months.
      • Whitehouse RW
      • Adams JE
      • Bancroft K
      • Vaughan-Williams CA
      • Elstcin M
      The effects of nafarelin and danazol on vertebral trabecu-lar bone mass in patients with endometriosis.
      GnRH is as effective as danazol for the relief of endometriosis-associated pelvic pain.
      • Nafarelin European Endomelriosis Trial Group (NEET)
      Nafarelin for endometriosis: a large-scale, danazol-controllcd trial of efficacy and safety, with 1-year follow-up.
      • Kauppila A
      Changing concepts of medical treatment of endometriosis.
      • Rock JA
      • Truglia JA
      • Caplan RJ
      • Zoladex Endometriosis Study Group
      Zoladex (goserelin acetate implant) in the treatment of endometriosis: a randomized comparison with danazol.
      In up to 50% of patients with minimal and mild disease, symptoms may recur in varying degrees within a year after therapy, and treatment has not been shown to enhance fertility in patients with endometriosis.
      • Fedele L
      • Parazzini F
      • Radici E
      • Bocciolonc L
      • Bianchi S
      • Bianchi C
      • et al.
      Buscrelin acetate versus expectant management in the treatment of infertility associated with minimal or mild endometriosis: a randomized clinical trial.
      In order to avoid the long-term hypoestrogenic effects of GnRH therapy, various types of so-called add-back therapy have been investigated. Such regimens combine administration of GnRH analogues with steroid hormone replacement therapy on the basis that different thresholds of estrogen levels exist for hot flushes, bone maintenance, and estrogendependent processes such as endometriosis.
      • Barbieri RL
      Gonadotropin-releasing hormone agonists and estro-gen-progestogen replacement therapy.
      An early report showed that the addition of medroxyprogesterone (30 mg/day) to GnRH therapy decreased the associated occurrence of bone loss and hot flushes; however, this regimen also compromised the efficacy of GnRH treatment of endometriosis.
      • Cedars MI
      • Lu JK
      • Meldrum DR
      • Judd HL
      Treatment of endometriosis with a long-acting gonadotropin-releasing hormone agonist plus medroxyprogeslerone acetate.
      Surrey and associates
      • Surrey ES
      • Gambone JC
      • Lu JK
      • Judd HL
      The effects of combining norcthindrone with a gonadotropin-releasing hormone agonist in the treatment of symptomatic endometriosis.
      reported effective relief of pain that was associated with endometriosis when norethindrone was combined with a GnRH agonist. Currently, the role of add-back therapy for endometriosis remains to be determined.
      • Hurst BS
      • Schlaff WD
      Treatment options for endometriosis: medical therapies.
      Gestrinone.—Gestrinone (ethylnorgestrienone, RU 2323, Roussel-UCLAF, Paris) is an antiprogestational 19-nortestosterone derivative widely used in Europe for the treatment of endometriosis. Several mechanisms of action contribute to its therapeutic effect. An agonist effect at androgen receptors and an agonist-antagonist effect at progesterone combine to induce atrophy of endometrial tissue. The long half-life allows oral administration two or three times a week (5 to 10 mg/week) for 6 to 8 months. Gestrinone seems to be effective in the relief of endometriosis-associated pain. For endometriosis-associated infertility, results seem to be similar to those obtained with other types of medical therapy.

      Treatment of Endometriosis-Associated Infertility

      Endometriosis-associated infertility is often diagnosed during the course of the fertility investigation, especially in patients without associated pelvic pain. In the absence of anatomic distortion, however, the contribution of endometriosis to infertility is unclear. Successful fertilization may occur even in the presence of severe disease, but many patients with mild disease have decreased fecundity. Ovulation suppression (danazol, progestins, gestrinone, and GnRH) is an ineffective strategy for the treatment of endometriosis-associated infertility.
      • Hughes EG
      • Fcdorkow DM
      • Collins JA
      A quantitative overview of controlled trials in endometriosis-associated infertility.
      The benefit of conservative surgical treatment of infertility associated with minimal and mild disease has not yet been established. Therefore, many physicians who have been confronted with such cases have used advanced reproductive techniques to bypass or overwhelm the unknown mechanism (or mechanisms).
      Superovulation (SO) with clomiphene citrate or with human menopausal gonadotropins has been used successfully to treat endometriosis-associated infertility (Table 1). A prospecti ve study of patients with endometriosis found that the likelihood of achieving pregnancy with clomiphene citrate was 3 times greater than that with either danazol or expectant management.
      • Simpson CW
      • Taylor PJ
      • Collins JA
      A comparison of ovulaiion suppression and ovulation stimulation in the treatment of endometriosis associated infertility.
      A prospective study of a series of patients with minimal to mild endometriosis showed SO to result in a significantly higher cycle fecundity rate than that with expectant management alone (0.148 versus 0.045, re­ spectively).
      • Fedele L
      • Bianchi S
      • Marchini M
      • Villa I
      • Brioschi D
      • Parazzini F
      Superovulation with human menopausal gonadotropins in the treatment of infertility associated with minimal or mild endometriosis: a controlled randomized study.
      The addition of intrauterine insemination with SO (SO-lUI) has been reported to improve cycle fecundity rates further. In an early retrospective noncontrolled analysis of women with endometriosis, Dodson and associates
      • Dodson WC
      • Whitesidcs DB
      • Hughes Jr, CL
      • Easley III, HA
      • Hancy AF
      Supcrovulalion with intrauterinc insemination in the treatment of infertility: a possible alternative to gamete intrafallopian transfer and in vitro fertilization.
      reported a 17% cycle fecundity rate with SO-lUI. Chaffkin and colleagues
      • Chaffkin LM
      • Nulsen JC
      • Luciano AA
      • Metzgcr DA
      A comparative analysis of the cycle fecundity rates associated with combined human menopausal gonadotropin (hMG) and inlrautcrine insemination (1U1) versus either hMG or IUI alone.
      found a cycle fecundity rate of 12.8% in 109 patients with endometriosis who underwent SO-IUI versus 6.6% in those receiving SO only.
      Table 1Reported Pregnancy Rates for Superovulation Cycles in Women With and Without Endometriosis
      CC = clomiphcne citrate; HMG = human menopausal gonadotropins; lUI = intrauterine insemination,
      EndometriosisPatients
      ReferenceTreatmentMinimal (.%)Mild (%)Moderate (%)SevereWith endometriosis (%)Without endometriosis (%)
      Dodson et al,
      • Dodson WC
      • Whitesidcs DB
      • Hughes Jr, CL
      • Easley III, HA
      • Hancy AF
      Supcrovulalion with intrauterinc insemination in the treatment of infertility: a possible alternative to gamete intrafallopian transfer and in vitro fertilization.
      1987
      HMG-iUI4012171716
      Chaffkin et al, 1991HMG6.66.2
      HMG-IUI….12.822.5
      Fedele et al, “1992HMG14.8
      Includes patients with minimal endometriosis.
      4.5
      Kemmann et al,
      • Kemmann E
      • Ghazi D
      • Corsan G
      • Bohrer MK
      Does ovulation stimulation improve fertility in women with minimal/mild endometriosis after laser laparoscopy?.
      1993
      Expectant2.8
      CC6.6
      CC-HMG11.4
      HMG-IUI7.3
      * CC = clomiphcne citrate; HMG = human menopausal gonadotropins; lUI = intrauterine insemination,
      Includes patients with minimal endometriosis.
      In patients in whom SO therapy fails, in vitro fertilization (IVF) may be considered as the next step for treatment of endometriosis-associated infertility (Table 2). A recent prospective study suggests improved pregnancy rates for patients with endometriosis who undergo IVF in comparison with control subjects treated expectantly (33% versus 0%).
      • Soliman S
      • Daya S
      • Collins J
      • Jarrell J
      A randomized trial of in vitro fertilization versus conventional treatment for infertility.
      The concerns of potential detrimental effects of endometriosis on success rates of IVF have not been proved in recent studies. Cycle fecundity rates have been shown to be comparable to those attained in patients without endometriosis who undergo IVF.
      • Inoue M
      • Kobayashi Y
      • Honda I
      • Awaji H
      • Fujii A
      The impact of endometriosis on the reproductive outcome of infertile patients.
      • Soliman S
      • Daya S
      • Collins J
      • Jarrell J
      A randomized trial of in vitro fertilization versus conventional treatment for infertility.
      • Curtis P
      • Jackson A
      • Bernard A
      • Shaw RW
      Pretreatment with gonadotrophin releasing hormone (GnRH) analogue prior to in vitro fertilisation for patients with endometriosis.
      Thus, the presence of endometriosis does not negatively influence the results of IVF; however, long durations of endometriosis-associated infertility probably correlate with poor IVF outcome.
      • Tumraon IS
      • Colwcll KA
      • Mackinnon CJ
      • Nisker JA
      • Yuzpe AA
      Abbreviated endometriosis-associated infertility correlates with in vitro fertilization success.
      Sev­ eral studies have investigated the efficacy of a course of GnRH agonist therapy before IVF and have suggested that this approach may further improve IVF success rates.
      • Chaffkin LM
      • Nulsen JC
      • Luciano AA
      • Metzgcr DA
      A comparative analysis of the cycle fecundity rates associated with combined human menopausal gonadotropin (hMG) and inlrautcrine insemination (1U1) versus either hMG or IUI alone.
      • Nakamura K
      • Oosawa M
      • Kondou I
      • Inagaki S
      • Shibala H
      • Narita O
      • et al.
      Menotropin stimulation after prolonged gonadotropin releasing hormone agonist prctrcatment for in vitro fertilization in patients with endometriosis.
      Table 2Reported Pregnancy Rates per Embryo Transfer for In Vitro Fertilization in Women With and Without Endometriosis
      GnRH = gonadotropin'Teleasing hormone; IVF = in vitro fertilization,
      EndometriosisPatients
      ReferenceTreatmentMinimal (%)Mild (%)Moderate (%)Severe (%)With endometriosis (.%)Without endometriosis (%)
      Dicker ct al
      • Dicker D
      • Goldman JA
      • Levy T
      • Fcldberg D
      • Ashkcnazi J
      The impact of long-term gonadotropin-releasing hormone analogue treatment on prcclinical abortions in patients with severe endometriosis undergoing in vitro fertilization embryo transfer.
      1992
      IVF5.3
      GnRH-IVF33.3
      Inoue et al,
      • Inoue M
      • Kobayashi Y
      • Honda I
      • Awaji H
      • Fujii A
      The impact of endometriosis on the reproductive outcome of infertile patients.
      1992
      Danazol (6 mo)-lVF30.431.731.630.230.927.0
      Nakamuraet al
      • Nakamura K
      • Oosawa M
      • Kondou I
      • Inagaki S
      • Shibala H
      • Narita O
      • et al.
      Menotropin stimulation after prolonged gonadotropin releasing hormone agonist prctrcatment for in vitro fertilization in patients with endometriosis.
      1992
      IVF27
      GnRH-IVF67
      Soliman et al,
      • Soliman S
      • Daya S
      • Collins J
      • Jarrell J
      A randomized trial of in vitro fertilization versus conventional treatment for infertility.
      1993
      IVF33.310.1
      Curtis et al,
      • Curtis P
      • Jackson A
      • Bernard A
      • Shaw RW
      Pretreatment with gonadotrophin releasing hormone (GnRH) analogue prior to in vitro fertilisation for patients with endometriosis.
      1993
      GnRH-IVF17.2
      Includes patients with minimal endometriosis.
      18.6
      Includes patients with moderate endometriosis.
      17.7
      Kemmann et al,
      • Kemmann E
      • Ghazi D
      • Corsan G
      • Bohrer MK
      Does ovulation stimulation improve fertility in women with minimal/mild endometriosis after laser laparoscopy?.
      1993
      IVF22.2
      Includes patients with minimal endometriosis.
      * GnRH = gonadotropin'Teleasing hormone; IVF = in vitro fertilization,
      Includes patients with minimal endometriosis.
      Includes patients with moderate endometriosis.

      Conclusion

      Endometriosis is a condition of uncertain pathogenesis in which afflicted persons may have pelvic pain, infertility, or both. Often, a presumptive diagnosis can be made on the basis of the history and physical examination along with a high index of suspicion. Magnetic resonance imaging and ultrasonography are of limited usefulness in the investigation of endometriosis but are most helpful in the evaluation of an adnexal mass. Laparoscopic examination and staging of disease based on the revised AFS classification of endometriosis remain the gold standard in the diagnostic evaluation of endometriosis. After the diagnosis of endometriosis has been confirmed, many surgeons proceed with conservative surgical treatment of accessible endometriotic lesions. Although recurrence of disease is frequent, most patients with pain will experience some degree of relief after such procedures. The benefits of fulguration of endometriotic lesions for improving infertility are less clear. For infertile patients with stage III or IV disease, lysis of extensive adhesions may be beneficial because pelvic anatomy can be restored. Currently, no single available therapy is effective for all symptoms of endometriosis; therefore, the clinician must educate the patient about her condition and prioritize therapeutic goals.
      Medical management of endometriosis maintains fertility potential and has proven efficacy in decreasing endometriosis-associated pelvic pain. This therapeutic option should be pursued as initial therapy for most patients with pain. As previously stated, conservative surgical treatment at the time of diagnostic laparoscopy often diminishes symptoms of pain; however, such relief is often short lived without postoperative medical therapy. For patients with mild symptoms, continuous administration of oral contraceptives should be considered. Progestin, danazol, or GnRH agonist therapy can be considered for patients with stage III or IV disease or when symptoms are severe. For patients in whom initial medical therapy fails and who desire to maintain fertility potential, a repeated operation for fulguration of recurrent lesions may be necessary, with the understanding that expected results are less favorable. In patients with midline dysmenorrhea, presacral neurectomy may prove beneficial
      • Tjaden B
      • Schlaff WD
      • Kimball A
      • Rock JA
      The efficacy of presacral neurectomy for the relief of midline dysmenorrhea.
      Patients with unresponsive, lifestyle-limiting pain should be advised to complete childbearing because the definitive care for their condition is hysterectomy with oophorectomy.
      Medical therapy should also be considered initially for patients with mild to moderate pain who have completed childbearing. The advantages of a conservative operation at the time of diagnosis have previously been stated; however, hysterectomy with oophorectomy might be considered sooner for patients with pain resistant to medical therapy than for those in the previously discussed group. In patients who are not contemplating future childbearing and who have severe debilitating pain, definitive surgical treatment may be the appropriate initial option. Such an operation might also be considered for the few women in the perimenopausal agegroup who have severe symptoms of pain. In this lastmentioned group, however, the pain will often resolve spon­ taneously during menopause.
      In contrast to the management of pelvic pain, no role seems to exist for ovulation-suppression strategies in the treatment of endometriosis-associated infertility. The benefit of conservative surgical treatment of infertility associated with stage I and II disease has not been clearly established. Conservative surgical management seems to be most beneficial for patients with stage III or IV disease in whom anatomic distortion of the reproductive organs may have a substantial role in infertility. The exclusion of other infertility-related factors is necessary in couples who are infertile. SO with ovulation induction and IUI seems to benefit patients with endometriosis-associated infertility, and after 3 to 6 months of expectant management, such therapy should be considered. In patients who are unable to achieve pregnancy with these measures, IVF has been shown to be efficacious.
      Endometriosis is an enigmatic disease that poses unique challenges for clinicians. No simple algorithm exists to guide one through the broad range of available therapies. Until a greater understanding of the pathogenesis is attained, selection of treatment will continue to be primarily empiric and based on clinical judgment. Because of the many poten­ tial management strategies, optimal individualization of therapy necessitates a clear line of communication between the patient and physician.

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