Endometriosis: treatment with gonadotropinreleasing hormone agonist Buserelin*t

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1 FERTILITY AND STERILITY Copyright 989 The American Fertility Society Printed in U.S.A. Endometriosis: treatment with gonadotropinreleasing hormone agonist Buserelin*t Anton M. H. W. Franssen, M.D.:j: Frank M. Kauer, M.D. Dev R. Chadha, M.D.II Jeanette A. Zijlstra, M.D. Rune Rolland, M.D., Ph.D.:j:~ University Hospital, Nijmegen, University Hospital, Groningen, and Hoechst Holland N. V., Amsterdam, The Netherlands Fifty-one women with pelvic endometriosis were treated with the gonadotropin-releasing hormone agonist (GnRHa) Buserelin (Hoechst Holland N.V., Amsterdam, The Netherlands) f.lg three times a day intranasally for 6 months. Forty-nine women completed treatment; were available for 6 months of follow-up following, treatment. Symptoms showed prompt and significant improvement. Follow-up after treatment revealed persistent relief from dysmenorrhea and dyspareunia in, respectively, 58.6% and 88.% of the women, whereas pelvic pain returned to pretreatment scores. Serum estradiol (E ) was suppressed to predominantly early follicular phase concentrations. Laparoscopy at the end of therapy showed significant reduction of scores for implants only. There was no relation between the degree of E suppression during therapy and the improvement of symptoms or the reduction of endometriosis. Statistical analysis in infertile patients, of whom 7 conceived during follow-up, revealed no differences in E levels during therapy, improvement of symptoms, or reduction of endometriosis. Buserelin appears to be safe, well tolerated, and effective in the management of endometriosis and associated complaints. Fertil Steril5:, 989 The medical management of endometriosis presents many problems, as there is still no uniformly successful treatment regimen, free from untoward side effects. During the last years, several treatment regimens have been advocated, including high doses of stilbestrol/ combined estrogen-progestogen, pro- Received July, 988; revised and accepted November, 988. *Supported in part by Hoechst Holland N.V., Amsterdam, The Netherlands. t Hoechst Holland N.V. :j: Division of Gynecological Endocrinology and Infertility, Department of Obstetrics and Gynecology, University Hospital, Nijmegen. Department of Obstetrics and Gynecology, University Hospital, Groningen. II Hoechst Holland N.V., Medical Department, Amsterdam. If Reprint requests: Professor Rune Rolland, Division of Gynecological Endocrinology and Infertility, Department of Obstetrics and Gynecology, Sint Radboud University Hospital, P.O.B. 9, 65 HB Nijmegen, The Netherlands. gestin only, and during the last decade, danazol.. However, paucity of efficacy or tolerance, and adverse effects 5 have encouraged research for more useful and safer drugs. More recently, the!?-nortestosterone derivative gestrinone has been applied as a therapeutic agent in endometriosis. 6 7 The established antifertility effect of the gonadotropin-releasing hormone agonists (GnRHa) has provided a possible new approach, as endometriosis is limited to the reproductive period and resolves after surgical oophorectomy. Administration of the GnRHa induces reversible hypoestrogenism as a result of down-regulation of the pituitary ovarian axis caused by the desensitizational effect on the pituitary gonadotropic cells. Recent publications have shown a beneficial effect on endometriosis during such treatment in several small studies. 8 - The present noncomparative study reports the effects of GnRHa therapy (Buserelin, Hoechst Holland N.V., Amsterdam, The Netherlands) in 5 Franssen et al. Buserelin therapy for endometriosis

2 women suffering from endometriosis during 6 months treatment, with a follow-up of another 6 months. The aim of this study includes an evaluation of the clinical, laparoscopic, and hormonal results, drug safety, and tolerance. MATERIALS AND METHODS Fifty-two healthy women with ovulatory cycles, suffering from pelvic endometriosis as diagnosed by laparoscopy within month before commencement of therapy, were included. The indication for the operative diagnostic procedure was infertility in women and symptoms compatible with endometriosis in the remaining 8 patients. All infertile women had undergone a routine infertility workup, including cycle monitoring, postcoital tests, and sperm analysis of their partners twice; the patency of the tubes was tested during the laparoscopy. Although the causal relation between milder stages of endometriosis and infertility is doubted by some authors, the probably unpredictable course of endometriosis 7 and the association with long-standing infertility in our series (range, to years; median, 5 years), made us decide to treat also the milder stages of the disease. None of the women had received sex steroids or danazol within months before treatment. The study protocol was approved by the ethical committees of both university hospitals. All subjects had given their informed consent. Treatment was started within the first days of the menstrual cycle and consisted of intranasal administration of buserelin (D-Ser[TBU] 6 -des-gly NHl)GnRH ethylamide by spray, p,g three times a day. The therapy lasted weeks and was followed by a second laparoscopy on the last day of the medication. The endometriosis was scored according to the classification system of The American Fertility Society (AFS). 5 In case of insufficient resolution of endometriotic implants, continuation of therapy was allowed for an additional months. The patients were seen every weeks during the first month and once a month thereafter. Symptoms of dysmenorrhea, _dyspareunia, and pelvic pain were scored according to a severity profile (Table ); they were recorded at every visit, as were bleeding patterns and side effects. Serum samples were collected for determination of luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E ), and progesterone (P). Samples collected before and at the end of the treatment period were assessed on the presence of antibodies against buserelin. Physical examination, hematologic screening (hemoglobin, hematocrit, prothrombin time, red blood cell count, white blood cell count, differential cell count, and platelet count) and serum chemistry determination (glutamate-oxaloacetate transaminase [GOT], glutamate-pyruvate transaminase [GPT], alkaline phosphatase, total proteins, albumin, creatinine, sodium, potassium, calcium, inorganic phosphorus, and glucose) were performed every months. Patients were to be followed up for 6 months after discontinuation of the therapy, or until a pregnancy occurred within this period. During this follow-up after treatment, the schedule of the assessments was as during the treatment period, with the exception of an additional visit 6 weeks after the discontinuation of therapy. Serum LH and FSH concentrations were determined by. specific radioimmunoassays (RIAs). 6 Estradiol and P were measured using dextrancoated charcoal-specific RIAs. 7 The scores of symptoms at all visits were first analyzed by the Friedman's two-way analysis (ranking within patients, followed by analysis of variance on the ranks; Statistical Analysis System Procedures RANK and ANOVA). In case of significance, multiple comparisons between the scores at the different visits were made by using the Wilcoxon's matched pairs signed rank test. Changes in the AFS scores for implants only also were analyzed by the Wilcoxon's matched pairs signed rank test. Unpaired variables were evaluated by the Wilcoxon Mann-Whitney's two-sample test. For the determination of correlations between variables, the Spearman's rank correlation coefficient was calculated. RESULTS The age of the 5 selected patients ranged from to years (median, years). As summarized in Table, one patient dropped out before the therapy had commenced, and another two discontinued treatment after months; all three dropped out for social reasons not related to the therapy itself. Of the 9 women who completed the treatment period of 6 months, 7 dropped out immediately after the second laparoscopy; discarded their desires of pregnancy, and 5 underwent laparotomy. In of the 5 patients who underwent a laparotomy, unilateral or bilateral endometriotic cysts were re- Franssen et al. Buserelin therapy for endometriosis Fertility and Sterility

3 Table Severity Profile for Endometriosis-Associated Symptoms Symptom Degree Score Criterium Dysmenorrhea None Mild Some loss in work efficiency Moderate Severe In bed part of day, occasional loss of work efficiency In bed or more days, incapacitation Dyspareunia None Mild Tolerated discomfort Moderate Severe Intercourse painful to the point of causing interruption Avoids intercourse because of pain Pelvic pain None Mild Occasional pelvic discomfort Moderate Noticeable discomfort for most part of cycle Severe Requires strong analgesics; pain persists during cycle when not menstruating sected. Of the remaining patients, underwent a salpingostomy (hydrosalpinx), and in the other, the hypotrophic uterine horn was resected (hemiuterus with rudimentary horn). Thus, patients were available for post-treatment evaluation. Symptoms Before therapy, dysmenorrhea was present in (86.%) of the 5 treated patients (Fig. ). The patients were classified according to the severity profile (Table ). Of the 9 sexually active women, (.9%) reported deep dyspareunia. Pelvic pain not related to vaginal blood loss was presented by ( 7. %) of the 5 patients. The frequency of dysmenorrhea declined sharply after institution of the therapy. Persistent amenorrhea occurred in about half of the women; incidental blood loss in the remaining half was predominantly painless. Dyspareunia and pelvic pain showed a statistically significant reduction from, Table Numbers of Patients Participating in the Different Periods of the Trial a Selected for treatment Drop-outs (social reasons) Before treatment During treatment Treatment period completed Drop-outs after second laparoscopy Social reasons Laparotomy Entering follow-up period Pregnancies No. of patients a For indications of the laparotomies, see text. b One woman who conceived desired pregnancy only after completion of treatment respectively, the second and fourth week oftherapy onward (P <.). At the end of the 6 months of treatment, only (.5%) patients reported dyspareunia; pelvic pain was presented by (8.6%) women. At the end of the follow-up period, 8 (5.5%) of patients who had had a menstruation in the preceding month, reported dysmenorrhea. Seventeen (58.6%) of the 9 women who noted this complaint at admission appeared improved. In patients with mild dysmenorrhea in all but one, the symptom was unaltered. In women, a deterioration had occurred ( patient from nil to mild complaints, patient from mild to moderate complaints). Dyspareunia was still present in 5 of women. In 5 (88.%) of 7 women who reported this complaint at admission, the symptom appeared improved. In the remaining patients with mild dyspareunia, the symptom did not change. One woman without dyspareunia at admission mentioned mild pain at the end of the follow-up period. Statistical analysis revealed a significant improvement of both symptoms after and 6 months of post-treatment follow-up in comparison with the pretreatment scores (P <.). Pelvic pain showed a gradual deterioration, nearly reaching pretreatment scores after and 6 months. Endometriosis According to the AFS scoring system/ 5 patients were classified as having mild, moderate, and severe endometriosis. Of the patients who dropped out during therapy, had mild and had moderate disease. Table shows the individual AFS scores for implants only at admission in rela- Franssen et al. Buserelin therapy for endometriosis

4 number of patients 5 ~ r- 5 5 r- Dysmenorrhea months. The scores of symptoms in these 6 patients remained unchanged during this period, and were comparable to those seen at the end of the preceding 6 months of therapy. Worsening of endometriosis was observed in 5 women. Superficial ovarian endometriotic implants were present in seven women; they resolved in five patients and were markedly reduced in number and size in the other two women. Of the ten endometriornata present in eight women, three cysts, ranging in diameter from.5 to em, appeared to be resolved at the repeat laparoscopy, while of one endometrioma of em diameter, only a small spot was left. The remaining six endometriomas present in four women and ranging in diameter from to 7 em, remained unaltered or had increased in size. Three of these latter four patients underwent a resection of the endometriotic cysts and dropped out. No statistically significant difference could be demonstrated in the improvement of symptoms during therapy or follow-up, comparing the patients who showed a reduction of at least 5% in the score for implants only with the patients who did not months +--trealmen,.~ post-treatment Figure Frequency of dysmenorrhea, dyspareunia, and pelvic pain during 6 months buserelin therapy and 6 months follow-up, classified according to the severity profile (Table ; severe,~ moderate, Q mild, none, D not applicable). tion to the scores at the end of the study for the 9 patients who completed the treatment of 6 months. Statistical analysis of these scores for implants only revealed a highly significant improvement (P <.). In 9 patients, the endometriosis had disappeared completely. In patients, there were only a few "pin-prick" brown spots left, mostly surrounded by slight scarification at the place of the previously observed implants. In 6 patients, infertile, a favorable but incomplete regression of the endometriotic implants was observed; as some of the endometriotic areas were judged as residual active disease, the additional therapy was given for Hormonal Findings After an initial slight increase, the mean LH concentration stabilized at weeks' treatment around values compatible with the early to midfollicular phase of the menstrual cycle (Fig. ). The mean FSH level remained in the low range of the early follicular phase. As illustrated in Figure, the E levels also showed an initial increase at weeks treatment. From the second month onwards, 9.% of the monthly E determinations were at or below castrate level (75 pmolfl), whereas 7.% were well within the range of the early follicular phase (76 to 8 pmol/l). Of the determinations,.% were above this range. In the six women who received the additional months' therapy, the E levels during this period were comparable or slightly lower than the concentrations determined during the second half of the 6 months treatment period. In five patients, a slightly elevated P concentration was measured at weeks of treatment (5 to 5 nmol/l). Three women showed levels just above this range. Subsequently, 96.9% of all monthly P determinations were below 5 nmol/l, compatible with a definite anovulatory state. In eight (. 7%) of the measurements, there was a slightly elevated P level. One patient showed a P concentration of Franssen et al. Buserelin therapy for endometriosis Fertility and Sterility

5 Table Cross-Tabulation of AFS Scores for Endometriotic Implants Only in 9 Patients at Admission (Vertical) and at the End of 6 Months Buserelin Therapy (Horizontal) Admission End of therapy AFS score No. of patients 9" " " 6b b " " " " " 9 No. of patients a One patient out of the respective group became pregnant. b One patient out of the respective group dropped out for surgical reasons. nmol/ after month of treatment, indicating ovulation with adequate corpus luteum function. Statistical analysis revealed no significant correlation between the mean E concentrations from month to month 6 of therapy, and the improvement of symptoms after 6 months of therapy or after and 6 months of follow-up. Furthermore, the mean E concentration from month to month 6 of therapy in the group of patients who showed a reduction in the AFS score for implants only of at least 5%, did not differ from the mean concentration in the group of women who had a less favorable reduction of the endometriotic deposits or who even had an increase of disease. Blood Loss During Therapy Apart from the menstruation at the start of the trial, 7 patients reported blood loss within the first 8 FSH (miu/) Estradiol (pmol/) '---'----''---'----'--'----"-..._ LH (miu/) Progesterone (nmol/) months Figure Serum LH and FSH levels (mean and SEM) during 6 months buserelin therapy. 5 6 months Figure Serum E and P levels (mean and SEM) during 6 months buserelin therapy. Franssen et al. Buserelin therapy for endometriosis 5

6 month during to days (median, 5 days). During the remaining period of the therapy, 7 periods of mainly mild blood loss were reported by 8 women during to days (median, 6 days). Around 6% occurred during the second and third month of therapy. As treatment progressed, the number of periods of blood loss decreased, as did the intensity of bleeding. Side Effects Forty-five women reported hot flushes at half of all visits. In the majority of patients, the flushes were not distressing. In women, administration of clonidine was necessary, but relieved symptoms in only. Penetration dyspareunia caused by a "dry vagina" was several times reported by 5 patients during the second half of the treatment period. Transient breast engorgement and weight gain were mentioned by 5 patients each during the first month of therapy. Further complaints included headache (65% of the 6 mentions were recorded within the first months), nausea, and dizziness ( and 7 mentions, respectively, distributed over the whole treatment period), and tiredness and a "dry skin" ( and 9 mentions, respectively, predominantly during the second half of the treatment period). Safety Parameters Hematologic and biochemical evaluation revealed no pathologic alterations; all values measured remained within the normal range. Serum samples collected at baseline and after 6 months of treatment were all negative for antibodies to Buserelin. Restoration of Cycle After discontinuation of the buserelin administration, 77.% of the patients had their first period within 7, and 9.% within 9 weeks. The menstrual cycle was restored within weeks in all but one patient, who showed resumption of periods after weeks. Pregnancies Seven (.8%) out of patients with infertility only attributed to endometriosis, conceived during the 6-month period after treatment. One of these pregnancies occurred in of the infertile women in whom the additional therapy was administered. Thus, 6 out of 9 infertile women who received 6 months of therapy became pregnant. Comparison between these pregnant and nonpregnant groups regarding the mean E levels from month to month 6 of therapy, the improvement of AFS scores for implants only, and relief of dyspareunia and pelvic pain during therapy revealed no differences. An additional patient desiring pregnancy only after completion of therapy, also became pregnant. As depicted in Table, all but one patient became pregnant in the presence of residual endometriosis. Five women gave birth to healthy infants and did not have ongoing pregnancies; aborted spontaneously, and had an ectopic pregnancy. DISCUSSION Our study establishes a good efficacy of buserelin, JLg three times a day intranasally, in the management of endometriosis-associated complaints. Dyspareunia and pelvic pain showed a prompt, statistically significant improvement. Six months after treatment, follow-up revealed a lasting and significant amelioration of both dysmenorrhea and dyspareunia. However, pelvic pain showed a gradual deterioration, nearly reaching pretreatment scores. Despite the reported good compliance,.9% of the P determinations during 6 months treatment revealed a concentration above the upper limit of definite anovulation (5 nmol/). Nine of these elevated values were found at and weeks of treatment, including the only four values above 5 nmolfl, which is compatible with ovulation and adequate corpus luteum function. E showed an initial, transient elevation caused by the commencement of the agonist therapy during the early follicular phase. From the second month onwards, 7.% of the monthly E determinations were within the range of the early follicular phase, whereas.% showed values above this range. Of the estimations, 9.% were at or below castrate level. No correlation existed between the improvement of symptoms during therapy and the degree of suppression of the ovarian estrogen production. Commencement of the agonist therapy in the early or midluteal phase would solve the problem of the unwanted initial stimulation of the pituitary ovarian axis and also reduce the risk of luteinization or ovulation during the first month of therapy. Although others observed anovulation with even 6 Franssen et al. Buserelin therapy for endometriosis Fertility and Sterility

7 lower doses than we applied,8 the determination of eight slightly elevated P concentrations beyond month suggests that the daily dose is borderline to guarantee persistent anovulation. The second laparoscopy at the end of treatment, revealed a highly significant reduction of the AFS scores for implants only. There is general agreement, confirmed by Dickey et al., 8 that the degree of improvement of endometriosis during therapy depends on the completeness of the suppression of the ovarian estrogen production; however, our data do not support this concept. The mean E level from month to month 6 in the group of women who showed at least a 5% reduction of the AFS score for implants only appeared even slightly higher than the mean E concentration in the remaining patients who showed a less favorable response or who even had an increase of disease. The results of other investigators also are not conclusive in this respect.8 Apart from a possibly heterogeneous response of endometriotic cells to hormones, 9 no clear explanation exists for these rather conflicting observations. However, laparoscopic determination of the efficacy of treatment on the reduction of endometriosis has its limitations. In our series, 9 patients showed no more visible disease, whereas in women only some "pin-prick" brown spots were left, mostly surrounded by slight scarification. In some of these patients, biopsies were taken from these areas; several still showed the presence of endometrial glands, indicating the necessity of histologic examination of biopsies from suspect areas or from previous areas of involvement. After recovery of the ovulatory cycle, reactivation of implants may occur, which can only be detected by a third laparoscopy or postponement of the second laparoscopy. Additional therapy of reactivated lesions (electrocoagulation or laser-vaporization) then can also be performed. This therapeutic approach needs further evaluation. Although it is suggested that endometriosis is the expression of an inherited immunological defect and can therefore be suppressed only temporarily, it is beyond discussion that many symptomatic patients have experienced a lasting beneficial effect of temporary ovarian suppression, whereas conception occurred in many previously infertile women. In our series, around one-third of the subgroup of patients with long-standing infertility only attributed to endometriosis, conceived during the 6 months post-treatment follow-up. The remarkable lack of difference regarding mean E levels, reduction of endometriosis, and relief of symptoms, between the groups of patients who conceived and who did not, probably could be due to the small numbers of patients. On the basis of our findings and regarding the above-mentioned considerations, it can be concluded that buserelin, f.lg three times a day intranasally, is safe according to the parameters evaluated, well tolerated, and very effective in the medical management of endometriosis-related complaints. An increase of the daily dose and commencement of therapy in the luteal phase of the menstrual cycle possibly will solve the initial unwanted stimulation of the pituitary ovarian axis and will also reduce the number of elevated progesterone levels and periods of blood loss during therapy. Raising the daily dose may increase the number and severity of side effects due to the estrogen deprivation. Until now, potentially serious side effects of temporary ovarian suppression consist only of transient negative effects on bone metabolism. At present, this is under further investigation. 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