1. REVIEWMARJAN ATTARAN, MD TOMMASO FALCONE, MD JEFFREY GOLDBERG, MDSection of Reproductive Endocrinology and Chairman, Department of Gynecology and Head, Section of ReproductiveInfertility, Department of Gynecology and Obstetrics, The Cleveland Clinic Endocrinology and Infertility, Department ofObstetrics, The Cleveland Clinic Gynecology and Obstetrics, The Cleveland ClinicEndometriosis:Still tough to diagnose and treats A B S T R AC T D tough to diagnose,endometriosis is and , ESPITE ADVANCES tough to treat, still Endometriosis is a chronic disease that may have life- tough to live with. altering implications such as chronic pelvic pain and Defined as the presence of endometrial infertility. The following review will familiarize the practicing glands and stroma outside the uterine cavity, physician with available therapies to maintain and enhance endometriosis can only be diagnosed defini- reproductive potential and control pelvic pain in women tively by seeing the endometriotic lesions on with endometriosis. laparoscopy or laparotomy. Medical therapy is far from ideal. Despite surgical ablation, manys KEY POINTS patients experience recurring pelvic pain and infertility. Medical treatments for endometriosis include oral In this article we explore the management contraceptives, progesterone, testosterone derivatives, of chronic pelvic pain in adult women and ado- and gonadotropin-releasing hormone (GnRH) agonists. lescents and infertility due to endometriosis. The antiestrogenic side effects of GnRH agonists (eg, bone s PATHOGENESIS IS UNCLEAR loss, hot flushes, vaginal dryness) can be mitigated by Various theories have been proposed to giving back estrogen in replacement doses, making long- explain the pathogenesis of endometriosis. term GnRH therapy possible. In the 1920s, Sampson1 proposed that in endometriosis, the pelvic peritoneum is “seed- Laparoscopic surgical resection of endometriotic lesions is ed” by retrograde menstruation. However, as effective as open surgery, but recurrence is common with 90% of women have been shown to have ret- either method. rograde menstruation; therefore, some authors propose that women with endometriosis have Endometriosis is the most common cause of chronic pelvic an immune deficiency that leads to inappro- pain in adolescents. priate clearance of endometrial cells from the pelvic peritoneum. Medical and surgical treatments for endometriosis do not Endometriosis in distant sites has been explained by metastasis of endometrial cells restore normal fertility rates, although surgery can improve through lymphatic or blood vessels. In addi- the patient’s chances of fertility. tion, some believe in the existence of totipo- tential cells that can transform into endome- trial cells. s CHRONIC PELVIC PAIN The most common clinical manifestation of PATIENT INFORMATION endometriosis is chronic pelvic pain. (Pelvic Endometriosis: What it is and how it is treated, page 654 pain is usually deemed chronic if it persists for CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 69 • NUMBER 8 AUGUST 2002 647
2. ENDOMETRIOSIS ATTARAN AND COLLEAGUES TA B L E 1 Medical therapies for pelvic pain due to endometriosis MEDICATION DOSAGE SIDE EFFECTS Nonsteroidal anti-inflammatory Variable Gastrointestinal irritation drugs (NSAIDs) Oral contraceptives 20–35 µg ethinyl estradiol Breakthrough bleeding, nausea, (cyclic or noncyclic) fluid retention Progestational agents Breakthrough bleeding, fluid retention, Medroxyprogesterone acetate (oral) 30–50 mg/day acne, weight gain (depot injection) 150 mg/3 months Megestrol acetate 40 mg/day Testosterone derivatives Methyltestosterone 5–10 mg/day Masculinization, fluid retention, irregular menses Danazol 800 mg/day Weight gain, hirsutism, acne, irregular menses, abnormal lipid profile GnRH agonists Hot flushes, vaginal dryness, Leuprolide (depot suspension) 3.75 mg/4 weeks decreased bone density Nafarelin 1 puff twice daily GnRH agonist plus A GnRH agonist, as above Possible decreased bone density “add-back” therapy plus (a) conjugated equine estrogens 0.625 mg/day and medroxyprogesterone 2.5 mg/day or (b) an oral contraceptive more than 6 months.) Some patients with physicians simply assume that any pelvic pain endometriosis may suffer from a concomitant in a patient with endometriosis is related to pain syndrome, which is defined as pain that: the endometriosis itself and do not consider • Does not respond to over-the-counter alternative diagnoses, treating the patient analgesics such as nonsteroidal anti- with medication or surgery—with significant inflammatory drugs (NSAIDs) side effects and very little relief. • Disrupts the patient’s life, preventing her Many disorders can cause chronic pelvic from functioning in the family or on the pain: irritable bowel syndrome, interstitial cys- job titis, musculoskeletal problems, and others. • Is accompanied by depression or other Think about consulting a gastroenterologist if psychologic disorder the symptoms are focused in the gastrointesti- • Is out of proportion to any identifiable nal system, or a urologist if the symptoms are abnormality found on examination or in the urinary system. imaging studies. s DIAGNOSIS Consider other causes of chronic pain Even if a patient has been diagnosed with Symptoms that suggest endometriosis are endometriosis, it is important to consider menstrual cycle-related pain (eg, midcycle other causes of chronic pain. Endometriosis is pain or dysmenorrhea) and deep dyspareunia a common finding on laparoscopy performed (pain during sexual intercourse). However, for indications other than pelvic pain. Often, women with endometriosis do not have a648 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 69 • NUMBER 8 AUGUST 2002
3. higher prevalence of menstrual dysfunction. ping treatment, pain scores did not differThe pain can be diffuse or localized. between the two groups. Areas of tenderness can be better identi- Patients who still have significant dys-fied by performing a physical examination menorrhea while on cyclic oral contraceptivesduring a menstrual period. Nodularity of the may take it continuously to prevent menstru-cul-de-sac can be felt in patients with deeply ation and its associated pain.infiltrating disease. Danazol is a derivative of 17-alpha Imaging studies, such as ultrasonography ethinyltestosterone that inhibits the midcycleor magnetic resonance imaging, will not show gonadotropin surge and ovarian steroidogene-peritoneal disease or adhesions unless there sis. The net effect is a hypoestrogenic, hyper-are large endometriomas.2 Serum markers androgenic environment. Danazol is as effec-such as cancer antigen (CA) 125 are not sen- tive as the GnRH agonists,6 but has sidesitive enough to be used for screening.3 The effects related to hypoestrogenemia anddefinitive diagnosis of endometriosis can only hyperandrogenemia. Irreversible hepatocellu-be made by laparoscopy or laparotomy. lar damage has been reported. Progestins. Medroxyprogesterone acetates FOUR STAGES OF ENDOMETRIOSIS was as effective as danazol in relieving pain symptoms in a placebo-controlled trial.7In the classification system developed by the Gonadotropin-releasing hormone (GnRH)American Society of Reproductive Medicine,4 agonists, after a brief stimulatory phase, suppressendometriosis has four stages, based on the estradiol levels to castrate levels. Subcutaneouslocation and extent of disease: stage 1 (mini- and inhalational forms may be taken on a dailymal), 2 (mild), 3 (moderate), and 4 (severe). basis; intramuscular preparations can be given Perception of pain is related to both once a month or once every 3 months.somatic and psychologic components. Patients Randomized clinical trials have shownwith deeply infiltrating disease of the cul-de- excellent short-term results. Leuprolide, asac often have significantly higher pain scores; GnRH agonist, was shown in a placebo-con-however, the stage of disease often does not trolled trial to be effective in treating Even if thecorrelate with the severity of the pain. endometriosis-associated pain.8 patient has The main side effects of GnRH agonistss MEDICAL TREATMENT OF ENDOMETRIOSIS are due to low estrogen levels. Patients lose endometriosis, ASSOCIATED WITH PELVIC PAIN trabecular bone density, which can take up to 2 years to restore after 6 months of treatment.9 consider otherA variety of medical therapies are available for In addition, they notice symptoms such as hot causes ofpatients with recurring pelvic pain due to flushes and vaginal dryness.endometriosis (TABLE 1). With recurrence of These side effects initially precluded long- chronic paindysmenorrhea, a trial of NSAIDs may be all term use of GnRH agonists, until “add-back”that is necessary to control the symptoms. therapy was developed in which the patient is Oral contraceptives are the most com- given enough estrogen to relieve the flushesmon form of medical treatment. No specific and prevent bone loss. A combination of con-formulation is superior. jugated estrogens 0.625 mg and medroxypro- In an open-label, randomized clinical gesterone 2.5 mg daily has been shown to betrial,5 a cyclic low-dose oral contraceptive was effective in preventing the hypoestrogenicinferior to the gonadotropin-releasing hor- side effects of GnRH agonists and maintainingmone (GnRH) agonist goserelin in relieving their efficacy. Other agents such as bisphos-deep dyspareunia but similar in relieving non- phonates have been used successfully to pre-menstrual pain. (The women in the goserelin vent bone loss.group had no menstrual pain because the drug These add-back regimens have introducedsuppressed the menses completely.) Pain the possibility of long-term therapy in somescores fell significantly from baseline in the patients. Long-term results of therapy withoral contraceptive group, but some patients GnRH agonists showed a 5-year recurrencestill had dysmenorrhea. Six months after stop- rate of 37% with minimal disease and 74% CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 69 • NUMBER 8 AUGUST 2002 649
4. ENDOMETRIOSIS ATTARAN AND COLLEAGUES with severe disease.10 In another retrospective completeness of resection, patients may be review,11 the median time to recurrence of started on medical therapy immediately after symptoms after medical therapy (danazol or a surgery. GnRH agonist) was 6 months. GnRH agonist therapy has also been used s ENDOMETRIOSIS IN ADOLESCENTS to prevent postoperative recurrence of symp- toms, although the results have been contra- Endometriosis is the most common cause of dictory. Hornstein et al,12 in a placebo-con- chronic pelvic pain in adolescents,18 account- trolled trial, found that a GnRH agonist ing for up to 70% of cases.19 The likelihood of increased the median time to initiation of finding endometriosis in an adolescent with alternative treatment (24 months with the pelvic pain increases with age.20 Unlike in GnRH agonist nafarelin vs 11 months with adult women, definitive therapy (removal of placebo). However, at 6 months, the two all reproductive organs) to manage endo- groups did not differ in their pain scores. metriosis pain is not an option for adolescents. s SURGICAL TREATMENT OF ENDOMETRIOSIS Endometriotic lesions are different ASSOCIATED WITH PELVIC PAIN in adolescents Endometriotic lesions in adolescents do not Conservative surgical treatment of endo- have the typical “powder-burn” appearance metriosis entails removing or destroying the found in adults. Therefore, the surgeon must lesions. maintain a high level of suspicion when perus- Laparoscopic surgery. Several observa- ing the pelvis. Lesions may be clear, vesicular, tional studies found laparoscopy to be just as white, or hemorrhagic. With time, they are effective as laparotomy in treating endometrio- believed to progress to the typical powder- sis, regardless of severity.13 burn lesions seen in adults.20 Redwine21 Sutton et al14 performed one of the few showed that black lesions are usually noted 10 randomized double-blind clinical trials to years later than red and clear lesions.The stage of evaluate the results of surgery for endometrio- Most adolescents with endometriosis pre- sis. Patients were randomized to undergo sent with stage 1 disease.18 Indeed, in mostdisease often either diagnostic laparoscopy or laparoscopy series, none of the adolescent patients haddoes not with treatment. Pain scores improved in 22% stage 3 or 4 disease. of the patients in the control group (owing to The degree of pain and discomfort incorrelate with a placebo effect), compared with 63% of the these patients does not correlate with thethe severity of treated women, of whom 90% continued to amount or location of endometriosis.22 One report pain relief 1 year later.15 study23 showed that a higher amount ofthe pain Nerve ablation. If pain persists, other sur- prostaglandin F2-alpha is released from hem- gical options include denervation procedures orrhagic lesions, possibly explaining the such as uterosacral nerve ablation (“LUNA” if increased dysmenorrhea in adolescents. performed laparoscopically) or presacral neurectomy. Müllerian anomalies The LUNA procedure involves transect- Patients with obstructive müllerian anom- ing nerves near the cervix. A recent review by alies such as imperforate hymen, transverse the International Cochrane Collaboration vaginal septum, cervical agenesis, or a non- concluded there is no evidence that the communicating uterine horn have a higher LUNA procedure adds benefit to surgery for incidence of endometriosis. An obstruction endometriosis ablation.16 in the outflow tract will lead to increased Presacral neurectomy involves transecting backflow of blood into the peritoneal cavity, nerves below the bifurcation of the aorta. A which is likely to increase the probability of randomized clinical trial found that this pro- endometriosis.24 cedure did show some benefit in relieving These adolescents are more likely to pre- midline pelvic pain.17 sent with stage 3 or 4 endometriosis as com- Depending on the extent of disease and pared with adolescents without müllerian 650 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 69 • NUMBER 8 AUGUST 2002
5. anomalies who have endometriosis. Müllerian to detect any psychologic issues that may beanomalies are likely to be first detected in contributing to lack of pain control, but alsoadolescence, when, at menarche, the patient to teach methods of pain control.is likely to begin experiencing symptoms. It is imperative to spend additional timeInitially she may complain of cyclic pain, with adolescents to explain endometriosis andwhich gradually progresses to pain throughout its possible clinical implications. Multiple vis-the cycle. its should be scheduled to answer questions The physician’s index of suspicion must and concerns that arise as the adolescentbe very high to diagnose these patients appro- attempts to understand her disease.priately. An adolescent presenting with pelvicpain or amenorrhea or menstrual irregularities s ENDOMETRIOSIS AND INFERTILITYshould have an evaluation of her reproductiveorgans. Early diagnosis is mandatory, since From 25% to 40% of women undergoing diag-relief of the müllerian obstruction leads to res- nostic laparoscopy because of infertility areolution of endometriosis and pain.24 In addi- found to have endometriosis, compared withtion, the earlier the abnormality is detected, 2% to 5% of women undergoing laparoscopicthe greater the chance that damage to repro- tubal ligation.25 In addition, the disease isductive organs can be minimized and fertility more severe in the infertile group.potential maintained. How does endometriosis impair fertility?Therapy for adolescent endometriosis In advanced endometriosis, large endometri-A combination of medical and surgical thera- omas and extensive pelvic adhesions can dis-py is used to manage adolescent endometrio- rupt the normal anatomic relationshipsis. The goal is to control pain, minimize the between the fallopian tubes and the ovaries,number of surgical procedures, and preserve creating an obvious impediment to concep-all reproductive organs. tion. However, in minimal or mild disease it is Surgery. At the time of diagnosis during unclear how a few superficial lesions canlaparoscopy, all endometriotic lesions should reduce the monthly fecundity rate from a nor- Withoutbe destroyed through excision, endocoagula- mal of about 20% down to 2% to 3%. estrogention, or laser vaporization. Women managed A possible mechanism of infertility is thatwith laser laparoscopy vs expectant manage- endometriosis generates a local peritoneal replacement,ment have significant relief of pain.14 inflammatory response, leading to immune patients loseHowever, results are poorest for stage 1 dysfunction and altered levels of pros-patients.14 taglandins, growth factors, and cytokines.26 bone density Since adolescents are more likely to have Increased numbers of peritoneal macrophageslow-stage endometriosis, they are less likely to may phagocytose sperm and reduce their fer- and have hotexperience complete resolution of symptoms tility potential. flushes on GnRHwith surgical destruction of lesions. Con- Other possible mechanisms:comitant diagnoses such as irritable bowel • Endometriosis may interfere with ovula- agonistssyndrome and lactose intolerance must be tion and oocyte pickup by its association withconsidered. Also, a thorough sexual history the luteinized unruptured follicle syndromemust be obtained, since girls with a history of and a factor that inhibits capture of the ovu-sexual abuse are more likely to have pelvic lated oocyte by the fimbria of the fallopianpain. tube, although the evidence for this is very Medical treatment of pelvic pain due to weak.26endometriosis in adolescents is similar to its • Endometriosis may impair fertilizationmanagement in adults (TABLE 1). However, and embryo quality.danazol and methyltestosterone are rarely • It may also reduce implantation of theused in adolescents, owing to their unaccept- embryo by reducing endometrial alpha-v-able side effects. beta-3 integrin (an adhesion molecule neces- Education. Some adolescents may need sary for implantation of the fertilized egg) andto be seen by a pediatric psychologist, not only leukemia inhibitory factor.27 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 69 • NUMBER 8 AUGUST 2002 651
6. ENDOMETRIOSIS ATTARAN AND COLLEAGUES Treatments to enhance fertility tion or no treatment. The live birth rate per Infertile patients have three options short of cycle was significantly better with treatment: in vitro fertilization: medical, surgical, and 11% vs 2%. superovulation with intrauterine insemina- A similar study35 compared three cycles of tion. superovulation with intrauterine insemina- Medical and surgical treatment. Although tion to six cycles of expectant management minimal and mild endometriosis reduces and found that the monthly fecundity rate was monthly fecundity rates, medical and surgical significantly higher with treatment (15% vs treatments have not been shown to restore 4.5%), but the cumulative pregnancy rate was normal fertility. In fact, placebo-controlled tri- not (37.5% vs 24%). als have not shown suppressive therapy with GnRH agonists, danazol, or progestins to Does endometriosis affect enhance fertility for any stage of endometrio- in vitro fertilization success rates? sis.28,29 Studies comparing pregnancy rates with in A meta-analysis of pregnancy rates with vitro fertilization between patients with endometriosis treatment found that surgical endometriosis vs tubal infertility yielded treatment with laparotomy or laparoscopy inconsistent results. Several noted reduced resulted in significantly higher pregnancy pregnancy and implantation rates in women rates than medical treatment or expectant with endometriosis,36–38 while others showed management.30,31 However, the improvement no difference.39,40 The stage of disease does was limited to patients with moderate to not seem to affect pregnancy rates.40,41 The severe disease. presence of endometriomas also did not impair Two randomized studies—one from Italy pregnancy rates. and the other from Canada—compared surgi- Lower fertilization rates were reported in cal treatment with no treatment at the time of some studies.38 One study36 also observed that diagnostic laparoscopy for minimal to mild embryos from women with endometriosis con- endometriosis. The Canadian study32 followed tained fewer blastomeres and that moreMedical patients for 36 weeks postoperatively. The embryos arrested in culture. control group had a monthly fecundity rate of The same study also noted no difference intreatment of 2.4% compared with 4.7% for the treatment pregnancy rates between women with or with-endometriosis group. Although this difference was statistical- out endometriosis who received oocytes donat- ly significant, 4.7% is still a long way from the ed from women without endometriosis. On thedoes not normal 20%. other hand, oocytes donated from women withimprove The pregnancy rates at 1 year in the endometriosis yielded lower pregnancy rates Italian study were 24% in the control group vs than oocytes from donors without the dis-fertility 29% in the treatment group; the difference ease.36 Another study confirmed that oocyte was not statistically significant.33 recipients with and without endometriosis had Superovulation with intrauterine insem- the same pregnancy rates.41 ination. Tummon et al34 randomized patients These findings suggest that endometriosis with minimal to mild endometriosis to under- impairs oocyte and subsequent embryo quality go superovulation with intrauterine insemina- but not endometrial receptivity. s REFERENCES sification of endometriosis. Fertil Steril 1985; 43:351–352. 1. Sampson JA. Benign and malignant endometrial implants in the peri- 5. Vercellini P, Trespidi L, Colombo A, et al. A gonadotropin-releasing toneal cavity and their relationship to certain ovarian tumors. Surg hormone agonist versus a low dose oral contraceptive for pelvic pain Gynecol Obstet 1924; 38:287–311. associated with endometriosis. Fertil Steril 1993; 60:75–79. 2. Alcazar JL, Laparte C, Jurado M, Lopez-Garzia G. The role of trans- 6. Henzl MR, Corson SL, Moghissi K, Buttram VC, Berqvist C, Jacobson J. vaginal ultrasonography combined with color velocity imaging and Administration of nasal nafarelin as compared with oral danazol for pulsed Doppler in the diagnosis of endometrioma. Fertil Steril 1997; endometriosis. A multicenter double-blind comparative clinical trial. N 67:487–491. Engl J Med 1998; 318:485–489. 3. Franssen AMHW, van der Heijden PFM, Thomas CMG, et al. On the 7. Telimaa S, Puolakka J, Ronnberg L, Kaupilla A. Placebo controlled origin and significance of serum CA-125 concentrations in 97 patients comparison of danazol and high-dose medroxyprogesterone acetate with endometriosis before, during, and after buserelin acetate, in the treatment of endometriosis. Gynecol Endocrinol 1987; 1:13–25. nafarelin, or danazol. Fertil Steril 1992; 57:974–979. 8. Dlugi AM, Miller JD, Knittle J. Lupron depot in the treatment of 4. The American Fertility Society. Revised American Fertility Society clas- endometriosis: a randomized, placebo-controlled, double blind study. 652 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 69 • NUMBER 8 AUGUST 2002
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