Medical treatment of symptomatic endometriosis

Transcription

1 Medical treatment of symptomatic endometriosis Ulrich Cirkel Department of Obstetrics and Gynecology, University Hospital Muenster, AlbertSchweitzerStraBe 33, Muenster, Germany The concept of endometriosis and strategies for its treatment are reviewed. Treatment is mainly endocrinebased, using progestogens, danazol and luteinizing hormonereleasing hormone (LHRH) agonists. Such treatment is complex, and therapy strategies have to be tailored to the individual; the choice of treatment, therefore, depends on the metabolic and sideeffects of each compound. Key words: endometriosis/medical therapy/symptomatology Introduction The prevalence of endometriosis in the female population of reproductive age is estimated to be 644% (Vercellini and Crosignani, 1993). However, our understanding of this phenomenon is changing because the histological definition of endometriosis as being endometrial glands and stroma outside the uterine cavity does not fulfil the criterion of a disease. Endometriosis as a disease is defined as 'the presence of ectopic endometrium, in association with evidence of cellular activity in the lesions and of progression, such as the formation of adhesions, or by its interference with normal physiological processes' (Audebert et al, 1992). With respect to this definition, there is increasing evidence that subtle peritoneal lesions should no longer be considered as a disease which is present or not, but rather as an event occurring intermittently in most, if not all, women (Koninckx, 1994). Therefore, modern research needs to concentrate on those factors which discriminate between endometriosis as a physiological process and endometriosis as a disease in order to define those patients who should be treated surgically and/or medically. As there are a lot of unanswered questions in this field of interest, today's therapeutic concepts are based solely on the macroscopic and, if possible, on the histological verification of endometriosis. With regard to medical therapy, it seems to be likely that future endocrine strategies will vary depending on the aim of treatment, including elimination of endometriotic implants, relief of pain and induction of pregnancy. Recent studies are often heterogenous in the population treated and the length of medical treatment regimens. Recent investigations compare 3 months with of Human Reproduction Volume 11 Supplement European Society for Human Reproduction and Embryology 89

2 U.Cirkel endocrine therapy, but include patients in whom endometriosis was operatively confirmed within 24 months of admission into the study (Hornstein et al, 1995). Until now, however, the operative procedure with histological verification of the disease is the gold standard. Even with modern ultrasonographic approaches, histological diagnosis of endometriosis in ovarian cysts is found only in about 78% of the adnexal masses that are suspicious in ultrasound examinations (Mais et al, 1993). On the other hand, despite advances in imaging techniques, no correlation has been found between clinical symptomatology and the anatomical site of the disease (Fedele et al., 1990), nor is there any correlation between subjective symptomatology and the stage of endometriosis as defined in the current revised American Fertility Society (rafs) classification (Vercellini et al., 1996). It is questionable whether symptomatology is a sufficient parameter in evaluating efficacy of any medical treatment, especially as it has been demonstrated that pain which had been assumed to be caused by endometriosis was influenced by each personality type (Gomibuchi et al, 1993) and that placebo therapy can influence painful menstruation in 41% of cases (Kauppila and Ronnberg, 1985). With infertility, endometriosis becomes even more enigmatic. Until now, despite theoretical links, it has not been well established whether endometriosis causes infertility. Therefore, data in the current literature are controversial and sometimes misleading in understanding treatment necessity and modality. Endometriosis symptomatology score Although subjective, the cardinal symptoms reported by endometriosis patients include dysmenorrhoea, dyspareunia and pelvic discomfort/pain. Symptoms elicited upon gynaecological examination are pelvic tenderness and induration. In order to have a means of judging the therapeutic effectiveness and of comparing complaints, either during individual medical attendance or before and after any kind of medical treatment, a severity profile score of symptoms and findings has to be introduced. The scoring system established by Biberoglu and Behrman (1981) (Table I) is a subjective rating scale (+ = mild; ++ = moderate; = severe) based on the patients' selfassessment of pain and the gynaecological palpation of the attending physician. Dysmenorrhoea comprises a minor loss of work efficiency (mild) and a complete incapacitation for 1 or more days (severe). Dyspareunia is defined as a limitation of sexual activity ranging from tolerated discomfort (mild) to sexual abstinence (severe). Nonmenstrual pelvic pain is defined as occasional discomfort (mild) and permanent use of analgesics (severe). A physical examination is comprehensive in pelvic tenderness which means an inability of pelvic palpation in severe cases and genital induration (severe forms with frozen uterus and nodular adnexa). Objective parameters in this scoring system are clearly missing. Physical examination can be aggravated by the patients' operative history (one or more laparotomies, e.g. for endometriosis) and abdominal muscular defence. Organic and functional 90

3 Table I. Severity profile for symptoms and findings* Symptom Degree Criterion Medical treatment of symptomatic endometriosis Dysmenorrhea Dyspareunia Pelvic pain Pelvic tenderness Induration Severe Moderate Mild Severe Moderate Mild Severe Moderate Mild Severe Moderate Mild Severe Moderate Mild According to Biberoglu and Behrman, In bed 1 or more days, incapacitation In bed part of day, occasional loss of work Some loss of work efficiency Avoids intercourse because of pain Intercourse painful to the point of causing interdiction Tolerated discomfort Requires strong analgesics, persistent during cycle other than during menstruation Noticeable discomfort for most of cycle Occasional pelvic discomfort Unable to palpate because of tenderness Extensive tenderness on palpation Minima] tenderness on palpation Nodular adnexa and culdesac, uterus frequently frozen Thickened and indurated adnexa and culdesac, restricted uterine mobility Uterus freely mobile, induration in the culdesac causes for endometriosisassociated pain are multiple, and contributing factors including sexual dysfunction and conflict, affective disorders, a history of sexual abuse and other detrimental development experiences make the disease even more complex (Rock, 1993). Until now, more objective parameters have been missing, so the comparison of medical and/or surgical therapeutic attempts has to be based on the available scoring systems. Endometriosis and infertility In the general population, the monthly conception rate is ~2030% when counting only live births. There is a great variability between couples and, even when the assumption is made that there are no totally sterile patients, 24% of these will remain without conception after 2 years (Querleu et al, 1993). With regard to this background information, endometriosisassociated infertility remains one of the most difficult situations in reproductive medicine because the prevalence of endometriosis in the infertile population is estimated to be 2040% (Mahmmod and Templeton, 1991). There are various mechanisms which might explain how endometriosis lowers monthly fecundity rates (Table II). The most probable reason for inhibiting conception is the anatomical damage of pelvic organs including tuboovarian adhesions and tubal distortions. When there are normal Fallopian tubes and ovaries without any adhesions, the exact mechanism by which endometriosis impairs fertility remains speculative. To date, ovarian deficiency, altered peritoneal environment as well as implantation failure and early abortions have been considered as interesting hypotheses. There is a lack of sufficient data to establish a highly significant correlation between these non 91

4 U.Cirkel Table II. Contributions of endometriosis to infertility Cause of infertility tuboovarian adhesion tubal distortion ovarian dysfunction ovarian endometrioma disturbance of follicular maturation luteinized unruptured follicle syndrome luteal deficiency altered peritoneal environment (immunological changings) implantation failure and early abortions none (chance association) Table III. Progestogens in the treatment of endometriosis Author Donnez (1990) Korte (1970) Lembke (1986) n Luciano (1988) 21 Moghissi (1976) 35 Willemsen (1985)H 9 Progestogen Lynestrenol Lynestrenol Chlormadinon acetate MPA MPA MPA MPA *By secondlook operation. MPA = medroxyprogesterone acetate. Dosage (mg/day) Duration (months) Improvement objective* (%) subjective _ Pregnancy rate (%) anatomical alterations and reproductive failure in humans with endometriosis. In the absence of objectivelyconfirmed mechanisms, endometriosis may simply be a cofactor of infertility. So far, many of the studies dealing with the subject are retrospective analyses of the data with a doubtful value. A clearlydefined control group is often missing and the results are seldom balanced with regard to the amount of time spent undergoing medical therapy during which conception was impossible. Therefore, pregnancy rates after a specific treatment for endometriosis, surgical and/or medical, should be evaluated critically. Progestogens in endometriosis Continuous application of progestogens will lead to a hypooestrogenic, hypergestagenic endocrine environment causing initial decidualization of endometrial tissue with eventual atrophy. Progestational agents are administered in a variety of protocols with different dosages and duration of therapy (Table HI). The divergent results may be explained by the lack of an obligatory pretreatment, histological verification of the disease and the nonhomogeneous treatment modalities. Donnez et al. (1990) investigated the effect of lynestrenol on ovarian 92

5 Medical treatment of symptomatic endometriosis endometriosis using a secondlook microsurgical procedure by laparotomy. There were only minor changes in the objective AFS score which were comparable to those of another progestogenic compound used in the study (2.5 mg gestrinone, three times a week). The pregnancy rate of 52% was achieved after the microsurgical removal of residual implants, so that a direct effect of lynestrenol on the pregnancy rate in endometriosis patients cannot be stated. Moghissi and Boyce (1976) observed an excellent subjective improvement of symptoms (100%) after 30 mg of medroxyprogesterone acetate (MPA), but the pregnancy rate varied according to the male factor (fertile husbands: 90%, deficient male factor: 20%) and the anatomical situation of the genital organs (one pregnancy out of 26 women with severe endometriosis). Therefore, a sole effect of the progestogenic compound could not be proven. As a secondlook operation was not obligatory in the same study, the effect on the objective improvement of endometriotic implants could not be reported. Different dosages of MPA (20 mg versus 250 mg) were investigated by Willemsen et al. (1985). They found a higher cure rate with the higher dosage of MPA. On the other hand, higher dosages of MPA and derivatives of nortestosterone such as lynestrenol are known to be linked to metabolic side effects, e.g. on lipid metabolism. As well as an often observed poor cycle control with lower dosages of progestogens (breakthrough bleeding), it was shown that, after the end of endocrine treatment with the higher dosages of these compounds, cycle recovery is delayed with signs of amenorrhoea and anovulation. This is a major disadvantage, especially in women in whom the induction of pregnancy is the aim of the treatment. According to these observations, therapy with progestogens may be favoured in those patients in whom painrelief is to be achieved. On the other hand, data so far available do not exclude any positive effects of progestogens on endometriotic implants themselves. Therefore, randomized placebocontrolled clinical trials are necessary in order to better evaluate the potential benefits of these compounds. Luteinizing hormonereleasing hormone agonist and danazol in endometriosis The ethisterone derivative danazol, which has been in general use for this common gynaecological disorder since 1973, is considered as the 'gold standard' of endometriosis therapy. The mode of action of danazol is complex and involves the inhibition of steroidogenesis (gonads, adrenal gland), the interaction with the androgen, progesterone, glucocorticoid receptor and the binding proteins sex hormonebinding globulin and corticosteroidbinding globulin (Barbieri, 1990). These effects lead to a hypooestrogenic, hyperandrogenic environment which is unfavourable for the growth of endometriotic implants. Unfortunately, danazol therapy is accompanied by many general, metabolic, hypooestrogenic and hyperandrogenic sideeffects. Therefore, the search for alternatives in the endocrine therapy of endometriosis was accelerated. In 1981, luteinizing hormonereleasing hormone (LHRH) analogues (agonists) were first used in clinical trials 93

6 U.Cirkel Table IV. Luteinizing hormonereleasing hormone (LHRH) agonists and danazol in the treatment of endometriosis Author n Therapy Duration Improvement (%) objectivei* subjective** Pregnancy rate (%) Recurrence rate (%) Burry (1989) Claesson (1989) Dmowski (1989) Fedele (1989) Henzl (1988) Kennedy (1990) NEET (1992) Rolland (1990) Shaw (1992) Tummon (1989) Wheeler (1992) mg/d Danazol 600 mg/d Danazol 800 ug/d Naf. i. n. 400 Xg/d Naf. i. n. 600 mg/d Danazol 400 ug/d Naf. i. n. 800 mg/d Danazol 200 ug/d Bus. s. c Jig/d Bus. i. n. 600 mg/d Danazol 1200 ng/d Bus. i. n. 800 mg/d Danazol 400 ug/d Naf. i. n. 800 ug/d Naf i. n. 600 mg/d Danazol 400 p.g/d Naf. i. n. 600 mg/d Danazol 400 ug/d Naf. i. n. 400 mg/d Danazol 400 Mg/d Naf. i. n. 600 mg/d Danazol 3.6 mg/4 weeks Gos. s. c. 800 mg/d Danazol 1600 ug/d Leupr. i. n. 800 mg/d Danazol 3.75 mg/4 weeks Leupr. l. m. 26 weeks 24 weeks _ ^ ^ _ 100" loo" l a 84" 85.8 a 4V 87 b 94 b 89" 83 b 60" 76.9 s 58.8" 86.7" 78 b 77 b s *Regression of endometriosis assured during II 0 look operation (total rafs score). "Subjective improvement: * reduction of symptoms, b percentage of patients with amelioration of symptoms. s :Subjective recurrence. h :Histologicallyproven recurrence. Naf. = nafarelin; Bus. = buserelin; Gos. = goserelin; Leupr. = Leuprorelin. _ 37.5 s 26.7 s 56.3 s 15.6 h 56.7 s 13.3 h 22 s s as a medical treatment for endometriosis. These substances have a significantly longer halflife than the natural decapeptide LHRH and show a high affinity for gonadotrophinreleasing hormone receptors. During treatment with these compounds, the initial phase of release of luteinizing hormone (LH) and follicle stimulating hormone (FSH) is followed by a decrease in gonadotrophin secretion. These pituitary sideeffects lead to a hypogonadal state with a marked suppression of ovarian oestrogen and progesterone production (Barbieri, 1990). In order to prove the efficacy of LHRH agonists in endometriosis therapy, they have to be compared with danazol in clinical trials. Today there are several studies available investigating the clinical results of danazol and LHRH analogues in comparative multicentre trials (Table IV). A placebo arm in these studies is missing, but it is 94

7 Medical treatment of symptomatic endometriosis ethically questionable whether a stage III or IV disease, e.g. with an involvement of both ovaries, should be treated expectantly. On the other hand, in these comparative trials quite a high number of patients were included with stage I endometriosis (American Fertility Society, 1985), which implies an overtreatment and a delay for women in whom pregnancy is the only aim of therapy. Interestingly, Henzl etal. (1988) as well as the Nafarelin European Endometriosis Trial Group (NEET, 1992) found a progression of endometriosis (5.6 and 8% respectively) despite treatment. However, as for the decrease in the adhesion score under endocrine therapy reported by the same study groups, it has to be questioned whether these findings are the result of an error inherent in the clinical scoring procedure induced by the number of participating study centres. So far, clinical results for LHRH agonists and danazol are comparable and with no significant differences between substances. Based on the operative findings from a secondlook operation, the reduction in total rafs score ranges from %. With the subjective complaints, treatment efficacy seems to be even more pronounced (maximally 100% amelioration of symptoms, Claesson and Bergquist, 1989). In order to find out whether methodological problems of multicentre trials, such as different investigators and laboratory evaluations, nonhomogeneity of dosages and treatment periods, have any influence on the results of a comparative study between danazol and an LHRH analogue, 55 premenopausal women with histologicallyproven endometriosis were treated at a single centre (Department of Obstetrics and Gynaecology, University of Muenster, Germany; Cirkel et al, 1995). Stage I endometriosis (rafs) was excluded from the protocol. During 24 weeks, 30 women were treated with the LHRH analogue depot triptorelin (Decapeptyl ; Ferring, Kiel, Germany; 3.75 mg every 4 weeks i.m.), and 25 patients were prescribed danazol (Winobanin ; Sanofi Winthrop, Munich, Germany; three times 200 mg orally). Due to the pharmacological properties of both substances, there were distinct differences in their endocrine effects. With regard to the gonadotrophins LH and FSH, which were measured by commercially available radioimmunoassays, the LHRH analogue led to a significant decrease in both pituitary hormones compared with the steroid danazol (Figure 1). A sharp decrease of FSH after 4 weeks of treatment with the analogue was remarkable; this was followed by a slight, but steady increase in this gonadotrophin throughout the remaining treatment period. In comparison, FSH remained elevated after an initial rise during treatment with danazol. The effects on gonadotrophins were accompanied by characteristic alterations in ovarian function. The LHRH analogue, triptorelin, led to a sharp fall in mean serum oestradiol concentrations to the postmenopausal range (<80 pmol/1), which was significantly lower than changes induced by danazol (Figure 2). At the same time, progesterone concentrations were deeply suppressed, which is indicative of a lack of luteinization. As far as the suppression of oestradiol is concerned, it was suggested by Homstein et al. (1995) that patients with lower oestradiol values (<40 pg/ml) generally would have better symptom relief than less hypooestrogenic patients. This is in accordance with Barbieri (1992) who 95

8 U.Cirkel LH ttl/0. triptorelln depot danazol FSH 9 (U/B I treatment weeks I treatment 1 48 weeks Figure 1. Concentrations of the gonadotrophins luteinizing hormone (LH) and follicle stimulating hormone (FSH) during and after 24 weeks of treatment with triptorelin depot or danazol. E, 600 (pmol/1) 300 triptorelln depot o danazol treatment Prog (nmol/d 20 p<0.05 "p < treatment Figure 2. Ostradiol (E 2 ) and progesterone (Prog) concentrations during and after 24 weeks of treatment with triptorelin depot or danazol postulated a hierarchy of responsiveness of various organs to oestradiol. Oestradiol concentrations in the range of 30 pg/ml seem to reliably produce regression in endometriotic lesions. However, until now the question has been unsolved as to what precise concentration of oestradiol is necessary to induce atrophy of endometriotic lesions. The answer would allow the individualization of treatment regimens by introducing sufficient add back therapy in order to avoid unnecessary 96

9 PELVIC TENDERNESS TRIPTORELIN DEPOT GROUP Medical treatment of symptomatic endometriosis J DANAZOL GROUP baseline 24 week PELVIC INDURATION baseline 24 week PELVIC PAIN DYSMENORRHEA I fuswru baseline 24 week baseline 24 week DYSPAREUN1A H 1 baseline 24 week PERCENTAGE OF PATIENTS DEGREE OF SYMPTOMS WMH%M light WHHWM moderate ^ severe Figure 3. Improvement of subjective complaints after 24 weeks of treatment with triptorelin depot or danazol. pronounced hypooestrogenic side effects. Concerning the androgenic parameters, the influence of the LHRH analogue was negligible in comparison with danazol, where a marked hyperandrogenic environment could be confirmed. Although these differences in the endocrine effects of the LHRH analogue triptorelin and danazol could be shown, both drugs are equally effective in achieving symptomatic relief of endometriosis. Gynaecological complaints reported by all patients before endocrine therapy included dysmenorrhoea (triptorelin depot: 82.7%; danazol: 83.4%), pelvic pain (48.3 and 50% respectively) and dyspareunia (34.5 and 33.4% respectively). Symptoms elicited upon gynaecological examination were pelvic induration (51.7 and 70.8% respectively) and tenderness (13.8 and 8.3% respectively). After 24 weeks of treatment, the percentage of patients showing a reduction of symptoms with triptorelin depot was: dysmenorrhoea down 82.7%, pelvic pain down 24.2%, dyspareunia down 24.2%; compatible figures with danazol were: dysmenorrhoea down 83.4%, pelvic pain down 25%, dyspareunia down 33.4%, as well as of pelvic induration (down 6.9% and 14.3% respectively) and tenderness (down 13.8% and 8.3% respectively) could be ascertained for both substances. There were some changes, however, in the severity profile after 24 weeks of endocrine treatment for both danazol and triptorelin (Figure 3). Concerning symptomatic relief and a reduction of objective rafs score, there were no significant differences between the steroid danazol and the LHRH analogue triptorelin (Cirkel et al, 1995). This is in accordance with the other comparative trials (Table IV), although multicentre studies have the disadvantage of multiinvestigator heterogeneity and noncomparability of laboratory investigations. The choice of treatment for endometriosis patients is therefore dependent on the side effect profile and the metabolic alterations of danazol and the prescribed LHRH analogue. 60

10 U.Cirkel As far as pregnancy rates after specific therapy are concerned, data are even more confusing. Results vary from 0% (Burrey et al, 1989) to 70% (Tummon et al, 1989) (Table IV). This nonhomogeneity is mainly due to the different AFS stages being treated (including stage I disease; is it really a disease?), a different observation period after the end of treatment and concomitant therapy of infertility factors other than endometriosis, if present. On the other hand, prolonged LHRH analogue suppression of ovarian function before ovarian stimulation in endometriosis patients undergoing assisted reproduction techniques may overcome some causes of infertility in these women. Nakamura et al. (1992) reported a significant increase in the clinical pregnancy rate/transfer in patients after the ultralong compared with the long protocol (67 versus 27%, P <0.05). Similar results were found by Oehninger et al. (1989). They reported a pregnancy rate of 41.6% after LHRH agonist pretreatment (control cycle without LHRH analogue: 16.6%). With respect to the stage of the disease, patients suffering from stage III or IV endometriosis had a more dramatic improvement with LHRH agonists than those with minimal or mild disease. In a retrospective study by Olivennes et al. (1995), patients with endometriosis as the sole factor for infertility and invitro fertilization (IVF) treatment had a delivery rate of 38.9% per cycle (41.9% per retrieval, 43.2% per transfer). They suggested that pituitary suppression before gonadotrophin stimulation for IVF may be beneficial for all endometriosis patients. Another problem which remained unsolved until now is the determination of the longterm recurrence rate of endometriosis after medical treatment. Available data refer mainly to the patients' subjective complaints (Table IV). Fedele et al. (1989) found a discrepancy between these subjective results (recurrence rate %) and the histologicallyproven relapse of the disease ( %). According to Waller and Shaw (1993), particularly those patients with severe forms of endometriosis at the outset are more likely to suffer from a recurrence of the disease (overall recurrence rate: 43.8%). With these investigations in mind, it becomes even clearer that today's available medical therapy does not cure endometriosis. Appropriate means to detect and to prevent (postpone?) a relapse of the disease are thought to be necessary. Conclusions and perspectives Medical management of women with endometriosis is complex, and therapy strategies have to be individualized with respect to the patients' age and complaints. To date, medical therapy is mainly based upon endocrine treatment modalities including progestogens, danazol and LHRH agonists. These substances are obviously equally effective in terms of reduction in implant scores proven upon operation and relief of subjective symptoms. Therefore the choice of treatment should depend on the metabolic and general sideeffects of each compound. On the other hand, the disease and its symptoms may recur following the different endocrine treatment modalities, indicating that available hormonal 98

11 Medical treatment of symptomatic endometriosis therapy strategies for endometriosis do not eradicate the disease. We have to reevaluate the conception of endometriosis as a microcosm of endometrial tissue. Only ~60% of endometriotic implants are in phase with the cyclicity of the uterine endometrium (Bergquist et al, 1984). The socalled 'ectopic endometrial implant' often seems to be independent of those factors regulating the eutopic endometrium. Therefore efforts have to be strengthened to understand the local factors involved in the development and progression of the implants and to discriminate between those lesions representing a disease and physiological alterations. These mechanisms include local inflammatory reactions with altered immune response as well as auto and paracrine regulatory principles of the endometriotic tissue. The possible role of immunomodulatory substances such as glucocorticoids (Simon et al, 1992) and pentoxifylline (Steinleitner et al, 1991) as well as direct inhibitory effects of danazol and LHRH agonists on the cell growth of endometriotic implants have to be elucidated in the future research and therapy of endometriosis. References Audebert, A., Backstrom, T., Barlow, D.H. et al. (1992) Endometriosis, 1991: a discussion document. Hum. Reprod., 7, 432^435. Barbieri, R.L. (1990) Comparison of the pharmacology of nafarelin and danazol. Am. J. Obstet. Gynecol, 162, Barbieri, R.L. (1992) Hormone treatment of endometriosis: the estrogen threshold hypothesis. Am. J. Obstet. Gynecol, 166, Bergquist, A., Ljungberg, O. and Myhre, E. (1984) Comparison of the histological appearance of human endometrium and endometriotic tissue obtained simultaneously. Acta Obstet. Gynecol. Scand., 123 (Suppl.), Biberoglu, K.O. and Behrman, S.J. (1981) Dosage aspects of danazol therapy in endometriosis: Shortterm and longterm effectiveness. Am. J. Obstet. Gynecol, 139, Burrey, K.A., Patton, P.E. and Mingworth, D.R. (1989) Metabolic changes during medical treatment of endometriosis: nafarelin acetate versus danazol. Am. J. Obstet. Gynecol, 160, Cirkel, U., Ochs, H. and Schneider, H.P.G. (1995) A randomized, comparative trial of triptorelin depot (DTrp 6 LHRH) and danazol in the treatment of endometriosis. Eur. J. Obstet. Gyn. Reprod. Biol., 59, Claesson, B. and Bergquist, C. (1989) Clinical experience treating endometriosis with nafarelin. J. Reprod. Med., 34, Dmowski, W.P., Radwanska, E., Binor, Z. et al. (1989) Ovarian suppression induced with buserelin or danazol in the management of endometriosis: a randomized, comparative study. Fertil. Steril, 51, 395^00. Donnez, A., Nisolle, M, Clerckx, F. et al. (1990) Evaluation of preoperative use of danazol, gestrinone, lynestrenol, buserelin spray and buserelin implant, in the treatment of endometriosis associated infertility. In Chadha, D.R., and Buttram, V.C. (eds), Current Concepts in Endometriosis. Alan R.Liss, New York, pp Fedele, L., Bianchi, S., Arcaini, L. et al. (1989) Buserelin versus danazol in the treatment of endometriosisassociated infertility. Am. J. Obstet. Gynecol, 161, Fedele, L., Parazzini, F., Bianchi, St. et al. (1990) Stage and localization of pelvic endometriosis and pain. Fertil. Steril, 53, Gomibuchi, H., Taketani, Y, Doi, M. et al. (1993) Is personality involved in the expression of dysmenorrhea in patients with endometriosis? Am. J. Obstet. Gynecol, 169,

12 U.Cirkel Henzl, M.R., Corson, S.L., Moghissi, K. et al. (1988) Administration of nasal nafarelin as compared with oral danazol for endometriosis. N. Engl. J. Med., 318, Homstein, M.D., Yuzpe, A.A., Burrey, K.A. et al. (1995) Prospective randomized doubleblind trial of 3 versus of nafarelin therapy for endometriosis associated pelvic pain. Fertil. Sterii, 63, Kauppila, A. and Ronnberg, L. (1985) Naproxen sodium in dysmenorrhea secondary to endometriosis. Obstet. Gynecol, 65, Kennedy, S.H., Williams, I.A., Brodribb, J. et al. (1990) A comparison of nafarelin acetate and danazol in the treatment of endometriosis. Fertil. Sterii, 53, Koninckx, P.R. (1994) Is mild endometriosis a disease? Is mild endometriosis a condition occurring intermittently in all women? Hum. Reprod., 9, Korte, W., Beck, K. J. and Scherholz, K.P. (1970) Operative Behandlung der Endometriose und LangzeitTherapie mit Lynoestrenol. Geburtsh. u. Frauenheilk., 2, Lembke, J. and Lembke, S. (1986) Die Effektivitat der Therapie der Endometriose mit Danazol und Chlormadinonazetat sowie deren EinfluP auf paraklinische Parameter. Zent.bl. Gynakoi, 108, Luciano, A.A., Turksoy, R.N. and Carleo, J. (1988) Evaluation of oral medroxyprogesterone acetate in the treatment of endometriosis. Obstet. Gynecol., 72, Mahmmod, T.A. and Templeton, A. (1991) Prevalence and genesis of endometriosis. Hum. Reprod., 6, Mais, V., Guerriero, St., Ajossa, S. et al. (1993) The efficiency of transvaginal ultrasonography in the diagnosis of endometrioma. Fertil. Sterii, 60, Moghissi, K.S. and Boyce, C.R. (1976) Management of endometriosis with oral medroxyprogesterone acetate. Obstet. Gynecol., 47, Nakamura, K., Oosa Wa, M., Kondou, I. et al. (1992) Menotropin stimulation after prolonged gonadotropin releasing hormone agonist pretreatment for in vitro fertilization in patients with endometriosis. /. Assist. Reprod. Genet., 9, Nafarelin European Endometriosis Trial Group/NEET (1992) Nafarelin for endometriosis: a largescale, danazolcontrolled trial of efficacy and safety, with 1year followup. Fertil. Sterii, 57, Oehninger, S., Brzyski, R.G., Muasher, S.J. et al. (1989) Invitro fertilization and embryo transfer in patients with endometriosis: impact of a gonadotropin releasing hormone agonist. Hum. Reprod., 4, Olivennes, R, Feldberg, D., Lin, H.Chr. el al. (1995) Endometriosis: a stage by stage analysisthe role of in vitro fertilization. Fertil. Sterii, 64, Querleu, D., Lecuru, F. and Subtil, D. (1993) Endometriosisassociated infertility: an epidemiological approach. In Brosens, I., and Donnez, J. (eds), The Current Status of Endometriosis. Parthenon Publishing, Carnforth, UK, pp Rock, J.A. (1993) Endometriosis and pelvic pain. Fertil. Sterii, 60, Rolland, R. and van der Heijden, P.F.M. (1990) Nafarelin versus danazol in the treatment of endometriosis. Am. J. Obstet. Gynecol., 162, Shaw, R.W./Zoladex Endometriosis Study Team (1992) An open randomized comparative study of the effect of goserelin depot and danazol in the treatment of endometriosis. Fertil. Sterii, 58, Simon, C, Gomez, E., Mir, A. et al. (1992) Glucocorticoid treatment decreases sera embryotoxicity in endometriosis patients. Fertil. Sterii, 58, Steinleitner, A., Lambert, H. and Roy, S. (1991) Immunomodulation with pentoxifylline abrogates macrophagemediated infertility in an in vivo model: a paradigm for a novel approach to the treatment of endometriosisassociated subfertility. Fertil. Sterii, 55, Tummon, I.S., Pepping, M.E., Binor, Z. et al. (1989) A randomized, prospective comparison of endocrine changes induced with intranasal leuprolide or danazol for treatment of endometriosis. Fertil. Sterii, 51, Vercellini.P. and Crosignani, P.G. (1993) Epidemiology of endometriosis. In Brosens, I. and Donnez, J. (eds), The Current Status of Endometriosis. Parthenon Publishing, Carnforth, UK, pp

13 Medical treatment of symptomatic endometriosis Vercellini, P., Trespidi, L., De Giorgi, O. et al. (1996) Endometriosis and pelvic pain: relation to disease stage and localization. Fertil. Steril., 65, Waller, K.G. and Shaw, R.W. (1993) Gonadotropinreleasing hormone analogues for the treatment of endometriosis: longterm followup. Fertil. Steril., 59, Wheeler, J.M., Knittle, J.D. and Miller, J.D. (1992) Depot leuprolide versus danazol in treatment of women with symptomatic endometriosis. Am. J. Obstet. Gynecol., 167, Willemsen, W.H.P., Rolland, R., Vemer, H.M. et al. (1985) Low versus highdose medroxyprogesterone acetate in the treatment of endometriosis. Arch. Gynecol., 237,