Prospective randomized study comparing the GnRH ...

Gynecological Endocrinology

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Prospective randomized study comparing the GnRH-agonist leuprorelin acetate and the gestagen lynestrenol in the treatment of severe endometriosis P. A. Regidor, M. Regidor, M. Schmidt, B. Ruwe, G. Lübben, P. Förtig, E. Kienle & A. E. Schindler To cite this article: P. A. Regidor, M. Regidor, M. Schmidt, B. Ruwe, G. Lübben, P. Förtig, E. Kienle & A. E. Schindler (2001) Prospective randomized study comparing the GnRH-agonist leuprorelin acetate and the gestagen lynestrenol in the treatment of severe endometriosis, Gynecological Endocrinology, 15:3, 202-209 To link to this article: http://dx.doi.org/10.1080/gye.15.3.202.209

Published online: 28 Aug 2009.

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Gynecol Endocrinol 2001;15:202–209

Prospective randomized study comparing the GnRH-agonist leuprorelin acetate and the gestagen lynestrenol in the treatment of severe endometriosis P. A. Regidor, M. Regidor, M. Schmidt, B. Ruwe, G. Lübben*, P. Förtig*, E. Kienle* and A. E. Schindler Department of Gynecology, University of Essen, Germany; and *Takeda Pharma GmbH, Aachen, Germany Key words: ENDOMETRIOSIS, GNRH-AGONIST, LEUPRORELIN ACETATE, GESTAGEN, LYNESTRENOL

ABSTRACT Endometriosis is thought to be an ovarian-dependent benign disease that affects up to 12% of women during their reproductive life. For the past ten years the gonadotropin-releasing hormone (GnRH)-agonists have been proved effective and safe drugs in the treatment of endometriosis. Nevertheless, gestagens such as lynestrenol still remain the most often used hormonal drugs for the treatment of this disease. The primary objective of this study was to compare the efficacy of the GnRH-agonist leuprorelin acetate depot (LAD) (Enantone®-Gyn) 3.75 mg subcutaneously per month with that of the gestagen lynestrenol (LYN) (Orgametril®) 5 mg orally twice per day in women with severe endometriosis, in terms of postoperative revised American Fertility Society (r-AFS) scores I–IV at first-look laparoscopy (score after removal of endometriotic lesions or adhesions) to the r-AFS score after six months’ treatment. Secondary objectives were the improvement of clinical symptoms and the side-effect profile.

Forty-eight women with postoperative r-AFS scores I–IV were evaluated in an open prospective randomized study between 1996 and 1998. All the participants underwent a first-look laparoscopy with resection of endometriotic lesions and six months’ therapy with one of the above mentioned drugs, and a further second-look laparoscopy. The six months’ treatment with LAD or LYN led to a significant reduction of the r-AFS score points in both groups. The mean r-AFS score in points for the LAD group after the first-look laparoscopy was 21.8 and was 27.2 for the LYN group. After the medical treatment a mean value of 11.5 points was observed in the LAD group compared with a mean value of 25.5 in the LYN group. This difference was statistically significant (p = 0.000014, Wilcoxon test). The improvement in the symptoms of dysmenorrhea, chronic pelvic pain and dyspareunia was also more pronounced in the LAD-treated group. LAD was more effective than LYN in the suppression of circulating serum 17 -estradiol

Correspondence: Professor A. E. Schindler, Department of Gynecology, University of Essen, Hufelandstr. 55, 45122 Essen, Germany

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levels after 6 months of treatment (mean 27.7 ± 9.3 pg/ml versus 42.6 ± 59.3 pg/ml). All the observed side-effects were deemed tolerable by the women who participated in this study. As the reduction of the r-AFS score in points was much more pronounced in the LAD group than in the LYN group, GnRH-agonists should therefore be used as first-choice drugs in the treatment of endometriosis. Due to the limited treatment of 6 months’ duration of GnRHagonists, gestagens might be used as second-line drugs for long-term and continuous treatment in the management of endometriosis to maintain the primary beneficial effect of GnRH-agonist treatment in patients who have completed their families.

INTRODUCTION The benign condition which affects 10–12% of women during their reproductive life, endometriosis1,2, is still an enigma, as different therapeutic approaches3 have not been able to establish standards in the management of this disease. Hormonal, surgical and/or combined therapies have been postulated in recent years. Even before Dizerega et al.4 defined endometriosis as a progressive and probably estrogen-dependent disease, many different hormonal therapeutic regimens had been studied. In 1958 Kistner5 postulated that a high dosage of estrogens and progestins, to induce a so-called ‘pseudopregnancy status’, would be an effective therapy for endometriosis patients. Due to a decidualization of the endometriotic implants, symptoms improved considerably. Later, other hormonal therapeutic approaches were used, such as treatment with methyltestosterone6, progestins alone7,8 or danazol9. The identification of the structure of the natural gonadotropin-releasing hormone (GnRH) in 1971 by Amoss et al10, and the subsequent synthesis of GnRH-agonists11, opened new possibilities for the induction of hypoestrogenic and hypoprogestagenic hormonal states. Suppression of gonadotropin secretion with different GnRH-agonists, such as goserelin12, triptorelin13, buserelin14, leuprorelin15 or nafarelin 16, revealed good results in the treatment of this disease. As mentioned above, gestagens such as lynestrenol (LYN) were, and still are, often-used drugs in the treatment of this disease, and have been reported to be also very effective. Since the first therapeutic descriptions of the effectiveness of


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LYN in the treatment of endometriosis by Ferin in 196217, many researchers have used this drug for the sole or the combined surgical pre- or postoperative treatment18,19. The primary objective of our study was the comparison of the postoperative revised American Fertility Society (r-AFS) score after the first-look laparoscopy and the r-AFS score at the secondlook laparoscopy after 6 months’ treatment with the GnRH-agonist leuprorelin acetate (Enantone®-Gyn) and with the progestin LYN (Orgametril ®), because so far a head-to-head comparison in a prospective randomized study with the three-step approach is lacking. Secondary objectives were the comparison of subjective clinical symptoms according to Biberoglu and Behrman 20 and the evaluation of the safety profile. Both drugs are registered in Germany by the BfArM for the treatment of endometriosis.

METHOD Study design and medication This study was an open prospective 4-block randomized single center clinical trial comparing the GnRH-agonist leuprorelin acetate depot (LAD) in a dosage of 3.75 mg administered monthly subcutaneously with the gestagen LYN in a dosage of 5 mg twice a day in women with a postoperative r-AFS score (score after removal of endometriotic lesions or adhesions) between I and IV. All participants received six months’ LAD or LYN treatment and underwent a second-look laparoscopy. Pretreatment evaluation included medical and endometriosis history, physical examination, laparoscopy with staging according to the AFS classifications of 1985 and 199621,22 and clinical evaluation of signs and symptoms (dysmenorrhea, dyspareunia, pelvic pain) of endometriosis. The clinical evaluation of signs and symptoms was performed at baseline, and after 3 and 6 months of treatment, according to the scale established by Biberoglu and Behrman 20. The results after 6 months of treatment were compared to baseline. Laboratory tests included routine full blood cell count, blood chemistry, pregnancy test and serum 17b-estradiol, progesterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels.

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After confirmation of endometriosis by firstlook laparoscopy and surgical removal or coagulation of endometriotic implants and/or adhesions, participants were randomized to one of the treatment groups and started therapy for 6 months. At week 24 a second-look laparoscopy was performed. At both laparoscopies the r-AFS score in points was revealed before and after a possible surgical removal or coagulation of endometriotic implants and/or adhesions.

Table 1 Demographics and history of endometriosis

Selection of participants

LAD, leuprorelin acetate depot; LYN, lynestrenol; p.o., orally; s.c., subcutaneously

Women were admitted to this study only with histologically proven endometriosis r-AFS score I to IV. All participants were premenopausal, not pregnant, not lactating and at least 18 years old. None had had hormonal or surgical treatment for endometriosis within 3 months of starting the study, and the serum 17b-estradiol and FSH levels had to be within normal ranges of premenopausal women.

Demographics and participants’ history of endometriosis Forty-eight premenopausal women with regular cycles and who had not used any hormonal drugs for at least three months before inclusion in this study were recruited. Twenty-six were treated with LAD 3.75 mg per month subcutaneously, and 22 with LYN 5 mg orally twice a day. Mean age of the LAD group was 32.4 ± 6.5 and of the LYN group was 30.9 ± 5.7. Their history of endometriosis before inclusion in this study was 1.2 years in the LAD group and 1.5 years in the LYN group. The number of medical and surgical pretreatments of the LAD and LYN groups were 1.4 and 1.9 versus 1.0 and 1.5, respectively (see Table 1).

Hormone analyses Serum of all patients was evaluated for levels of 17b-estradiol, progesterone, FSH and LH shortly before the first-look laparoscopy, after three months of treatment and on the day of the second-look laparoscopy. 17b-estradiol and progesterone were measured using a commercially available radioimmunoassay (Sorin Biomedica,

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Patients treated Patients treated with LAD with LYN 3.75 mg/month 2 5 mg/day s.c. (n = 26) p.o. (n = 22)

Mean ± SD

Age (years) 32.4 ± 6.5 History of endometriosis 1.2 ± 2.03 before therapy (years) Number of medical 1.4 ± 0.7 pretreatments Number of surgical 1.9 ± 0.99 pretreatments

30.9 ± 5.7 1.5 ± 2.6 1.0 ± 0 1.5 ± 0.8

Saluggia, Verucelly, Italy). FSH and LH were determined by an EIA assay (Johnson & Johnson, Norderstedt, Germany).

Statistical analyses The Wilcoxon test and the U-test were used to compare the r-AFS scores, and development of dysmenorrhea, chronic pelvic pain and dyspareunia after six months, with those at baseline and for intergroup comparisons. Statistical significances were assumed at p values < 0.05.

RESULTS General data After histological confirmation of endometriosis, 60 women fulfilled the inclusion criteria. Between randomization and the start of treatment, four of the LAD and eight of the LYN group withdrew consent, mainly because of objections to the forthcoming second-look laparoscopy. Forty-eight participants were randomized (26 LAD group, 22 LYN group) and there was no withdrawal during the treatment phase. All 48 participants were eligible for statistical analyses.

Endocrine evaluation Twenty-six LAD and 22 LYN participants had eligible hormonal data. Baseline 17b-estradiol and progesterone levels were determined before drug administration, and at months 3 and 6 of medical treatment. Mean baseline 17b-estradiol




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laparoscopy, with 11.5 ± 14.99 for the LAD group and 25.5 ± 27.99 r-AFS score points for the LYN group. The same finding is reflected postoperatively after second-look laparoscopy with 4.1 ± 9.6 and 8.1 ± 18 r-AFS score points. The difference in the r-AFS score points after 6 months’ medical treatment was statistically significant for the LAD-treated group (p = 0.000014, Wilcoxon test) (Table 3). Over 90% of the women treated with LAD reduced their r-AFS score in points, and only one had a one-point r-AFS score progression in points. In contrast, only 40% of the women treated with LYN had an r-AFS score reduction, and nearly 30% suffered from an r-AFS score progression in points with a mean of 8.8 points and a range of 3 to 20 points. The following results were obtained for each r-AFS score classification group. In the LAD group three women had at first diagnosis a score of I, four had a score of II, 11 a score of III and eight a score of IV. Preoperatively at second-look laparoscopy five women had a score of 0, seven a score of I, nine had a score of II, four of I and one of IV. In the LYN group five women had, at first diagnosis, a score of II, ten of III and seven of IV. Preoperatively at second-look laparoscopy two women had a score of 0, three of I, four of II, eight of III and five of IV. After second-look laparoscopy the distribution was as follows: in the LAD group 18 women had a score of 0, three of I, three of II and two of III; in

serum levels in the LAD group were 129.5 ± 177.9 pg/ml and in the LYN group 96.6 ± 74.9 pg/ml. After initiation of the medical treatment, both groups had a profound suppression of 17b-estradiol serum levels. 17b-estradiol serum levels at month 6 were lower in the LAD group (mean value 27.7 ± 9.3 pg/ml) than in the LYN group (mean value 42.6 ± 59.3 pg/ml). The differences between the LAD and the LYN group were statistically not significant as the Wilcoxon test values were p = 0.0000167 for the LAD group and p = 0.000692 for the LYN group. Standard deviations of the LAD and LYN groups were 9.3 pg/ml and 59.3 pg/ml respectively (see Table 2).

Changes of the r-AFS score in points after 6 months of medical treatment To judge efficacy of the medical treatment the r-AFS scores in points for adhesions and endometriotic lesions were compared at specified times for both treatment groups. At baseline and diagnosis the treatment groups were comparable, with 31.4 ± 22.9 r-AFS score points in the LAD group and 34.9 ± 28.7 r-AFS score points in the LYN group. This was also so after first-look laparoscopy postoperatively with 21.8 ± 20.2 and 27.2 ± 27.1 r-AFS score points respectively, but there was a pronounced difference after 6 months’ treatment from preoperatively, at second-look

Table 2 17b-Estradiol serum levels (pg/ml) during therapy Baseline LAD 129.5 177.6

Mean ± SD

After 3 months LYN 96.6 74.9

LAD 26.5 9.1

After 6 months

LYN 27.6 17.3

LAD 27.7 9.3

LYN 42.6 59.3

LAD, leuprorelin acetate depot; LYN, lynestrenol Table 3 Alteration of the revised American Fertility Society (r-AFS) score in points First-look laparoscopy At diagnosis Mean ± SD

LAD 31.4 22.9

LYN 34.9 28.7

Second-look laparoscopy

Postoperative LAD 21.8 20.2

LYN 27.2 27.1

After 6 months’ medical treatment preoperatively LAD 11.5 14.99

LYN 25.5 27.99

Postoperative LAD 4.1 9.6

LYN 8.1 18

LAD, leuprorelin acetate depot; LYN, lynestrenol


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the LYN group thirteen women had a score of 0, three of I, two of II, two of III and two of IV.


Change in dsymenorrhea, chronic pelvic pain and dyspareunia after 6 months of medical treatment Using the score of Biberoglu and Behrman20, clinical symptoms were allocated to the three categories mild, moderate and severe. Eighty-five per cent (22/26) of the LAD-treated group had reduced dysmenorrhea, whereas 15% (4/26) had no change. In the LYN-treated group only 50% (11/22) had reduced dysmenorrhea and the other 50% experienced no benefit (11/22). When analyzing the progress of chronic pelvic pain in relation to the therapy the following results were obtained: 18 (69%) of the LAD group reported no pelvic pain after the treatment, while 59% of the LYN group reported reduced pain. Similarly, better results were observed for the LAD group when analyzing the development of dyspareunia. Thirteen out of the 26 women (50%) treated with LAD experienced an improvement of dyspareunia, while in the LYN-treated group five out of 22 (23%) experienced some relief from dyspareunia. These results are shown in Table 4.

Number of participants with mid-cycle bleeding during the 6 months’ therapy After 1 month of medical treatment only one patient (3.8%) showed mid-cycle bleeding in the LAD group. Two bleedings that occured in month 1 can be interpreted as a hormonal-deprivation bleeding due to hypoestrogenism under GnRHagonist therapy. The high rate of amenorrhea thereafter corresponds to the low 17b-estradiol serum levels. In the LYN-treated group two

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women each showed bleeding after the first month in months 2, 3 and 4, five showed bleeding in month 5 and three in month 6. Thus, after month 1 there were still six women (27%) showing mid-cycle bleeding in the LYN-treated group.

Side-effects during the 6 months’ treatment with LAD or LYN After 6 months of treatment with LAD, 23 women (89%) complained of side-effects such as hot flashes in 21 cases or sweating in 14 cases. In the LYN group 18 women (82%) also developed side-effects such as hot flashes in 13 cases or sweating in 9 cases, demonstrating therapeutically induced hypoestrogenism. In the LYN group, side-effects such as acne or seborrhea were reported by five, whereas none of the LAD group experienced such side-effects. No differences concerning weight gain (two patients of the LAD and three of the LYN group) were observed. It is important to mention that (with the exception of acne and seborrhea) the participants described the experienced side-effects as tolerable and not influencing quality of life. No participant discontinued the treatment due to side-effects (Table 5).

DISCUSSION Many studies have confirmed the efficacy and safety of leuprorelin acetate in the treatment of women with endometriosis. As well as relief from or improvement of dysmenorrhea and pelvic pain, the stage of disease in general, verified by laparoscopy, improved significantly15,23,24. Comparative studies of the effect of GnRH-agonists and danazol in the treatment of endometriosis have shown that GnRH-agonists are at least as effective as danazol measured by the r-AFS score, but compare more

Table 4 Change of dysmenorrhea, chronic pelvic pain and dyspareunia after 6 months of treatment Dysmenorrhea

Chronic pelvic pain

Dyspareunia

Improved No change Deterioration



18 7 (69.2 %) (27.0 %) 13 9 (59.1 %) (40.9 %)

13 13 (50.0 %) (50.0 %) 5 17 (22.7 %) (87.3 %)

Patients treated 22 4 with LAD (84.6 %) (15.4 %) Patients treated 11 11 with LYN (50.0 %) (50.0 %)

0 0

1 (3.9 %) 0

0 0

LAD, leuprorelin acetate depot; LYN, lynestrenol

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Table 5 Side-effects during the 6 months of treatment with LAD or LYN


LAD group (n = 26)

No side-effects Hot flashes Sweating Nausea Body weight gain Headache Psychological alterations Allergic reactions Tiredness Acne

LYN group (n = 22)

After 3 months’ treatment n %




3 21 13 2 2 2 3 1 1 0

3 21 14 2 2 2 3 1 1 0

5 11 7 0 3 0 2 0 0 5

4 13 9 0 3 0 1 0 0 5

11.5 80.8 50 7.7 7.7 7.7 11.5 3.8 3.8 0

11.5 80.8 53.8 7.7 7.7 7.7 11.5 3.8 3.8 0

22.7 50 31.8 0 13.6 0 9.1 0 0 22.7

18.2 59.1 40.9 0 13.6 0 4.5 0 0 22.7

LAD, leuprorelin acetate; LYN, lynestrenol

favorably in their side-effect profile25–28. In these investigations the ovarian suppression by leuprorelin acetate was more drastic as judged by serum 17b-estradiol levels, and associated with a greater proportion of rapid onset of amenorrhea without irregular bleeding. Neither hepatic adverse effects nor weight gain or myalgia, which were observed among danazol recipients, could be observed among the leuprorelin acetate recipients because of its lack of androgenic and anabolic properties. Similarly, in our study, a more pronounced pain relief was observed in the GnRH-agonist group compared with the gestagen group. Although the gestagen LYN has been used in the management of endometriosis for more than 35 years17 and several reports have demonstrated the efficacy of this drug, limited data are available about comparing GnRH-agonists with the gestagen LYN29. Korte et al.18 reported in 1970 encouraging results in combined surgical and long-term hormonal treatment with LYN in women with endometriosis. They demonstrated that the addition of LYN to the surgical treatment resulted in a significant improvement in the subjective findings of women with endometriosis. Nevertheless this study reported that the most common side-effects were break-through or mid-cycle bleeding. The first report of long-term follow-up evaluations of patients treated with combined surgical/hormonal treatment revealed high recurrence rates of endometriosis, and surgical


treatment alone was reported to be superior to the combined therapy30. The use of gestagens and especially the gestagen LYN still remains a therapeutic option in the treatment of endometriosis, even if several data concerning the efficacy and tolerability of different GnRH-agonists in the treatment of endometriosis have been published in recent years12–16. It is clear that hormonal therapies, even when they improve subjective conditions, probably have only modulatory effects on endometriosis, as new data suggest that endometriotic lesions are dedifferentiated tissues that exist independently of the hormonal milieu31,32. Therefore, combined surgical/hormonal treatment has to aim at the objective and subjective benefits of the drug administration and on the side-effects. In our investigation we not only demonstrated the statistically significant superiority of the GnRH-agonist leuprorelin acetate over the gestagen LYN by means of the reduction of the r-AFS score in points, but also the better results concerning the endometriosis-associated pain symptomatology. Nevertheless, the gestagens still play a role in endometriosis as they are useful drugs for a long-term maintenance treatment to avoid early recurrence of symptoms. Whether the gestagen LYN is a reliable option has to be discussed, as LYN has estrogenic and androgenic activity and causes a reduction in high-density lipoprotein cholesterol and a rise in low-density lipoprotein

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cholesterol33. Gestagens such as medrogestone should therefore be favored in the maintenance therapy of endometriosis because of their lack of such side-effects33. Whether progestins alone or with the use of GnRH-agonists in ‘add-back’ treatment may be useful or comparable tools for long-term management of endometriosis still remains controversial, and has also to be evaluated from the point of view of estimated costs. In conclusion, our data indicate that GnRH-agonists such as leuprorelin acetate

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(EnantoneÒ-Gyn) should be used as first-choice drugs in the treatment of endometriosis, if a three-step therapy is used, as they are superior to gestagens in terms of symptom relief and reduction of endometriosis score after six months.

ACKNOWLEDGEMENT This study was sponsored by a grant from Takeda Pharma GmbH, Viktoriaalle 3–5, 52066 Aachen, Germany

REFERENCES 1. Barbieri RL. New therapy for endometriosis. New Engl J Med 1988;318:512–14 2. Schindler AE. Endometriose und Fertilitätsstörungen. Der Frauenarzt 1995;2:211–14 3. Wingfield M, Healy DL. Endometriosis: medical therapy. Baillière’s Clin Obstet Gynecol 1993; 7:813–37 4. Dizerega GS, Barber DL, Hodgen GD. Endometriosis: role of ovarian steroids in initiation, maintenance, and suppression. Fertil Steril 1980;33:649–53 5. Kistner RW. The use of newer progestins in the treatment of endometriosis. Am J Obstet Gynecol 1958;75:264–77 6. Preston SN, Campbell HB. Pelvic endometriosis: treatment with methyltestosterone. Obstet Gynecol 1953;2:152–7 7. Kouridis A, Kistner RW. Three synthetic progestins in the treatment of endometriosis. Obstet Gynecol 1968;31:821 8. Moghissi KS. Management of endometriosis with oral medroxyprogesterone acetate. Obstet Gynecol 1976;47:265–7 9. Schweppe KW. Therapieerfolge und Rezidivrate nach Endometriose-behandlung mit Danazol. Endometriose 1987;5:4–12 10. Amoss M, Burgos R, Blackwell P, et al. Purification, amino acid composition and Nterminus of the hypothalamic luteinizing hormone releasing factor (LRF) of ovine origin. Biochem Biophys Res Commun 1971;44:205–10 11. Geiger R, König W, Wissmann H, et al. Synthesis and characterization of a decapeptide having LH-RH-FSH-RH activity. Biochem Biophys Res Commun 1971;45:767–73 12. Mettler L, Steinmüller H, SchachnerWünschmann E. Experience with a depot GnRH-agonist (Zoladex) in the treatment of genital endometriosis. Hum Reprod 1991;6:694–8

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13. Regidor P-A, Imberg C, Bühler K, et al. Behandlung der Endometriose mit dem GnRHAnalogon Triptorelin unter besonderer Berücksichtigung der Entwicklung der Knochendichte. Zentralbl Gynäkol 1993;115:473–7 14. Schindler AE, Bühler K, Mettler L, et al. Treatment of endometriosis with the GnRH agonist buserelin (Suprecur ®): a multicenter study. Geburtsh Frauenheilk 1994;54:569–73 15. Schindler AE, Bühler K, Gerhard I, et al. Behandlung der Endometriose mit dem GnRHAgonisten Leuprorelinacetat Depot (EnantoneÒGyn Monats-Depot): Eine multizentrische Studie. Zentralbl Gynäkol 1994; 116:679–86 16. Regidor P-A, Regidor M, Heck M, et al. Behandlung der Endometriose mit dem GnRHAnalogon Nafarelin. Wirksamkeit und Verträglichkeit von Synarela. Gynäkol Prax 1995;19: 669–72 17. Ferin J. Artificial induction of hypoestrogenic amenorrhea with methylestrenolone, or with lynestrenol. Acta Endocr 1962;39:47 18. Korte W, Beck KJ, Scherholz KP. Surgical treatment of endometriosis and long-term therapy with lynestrenol. Geburtsh Frauenheilk 1970;30: 122–32 19. Donnez J, Lemaire-Rubbers M, Karaman Y, et al. Combined (hormonal and microsurgical) therapy in infertile women with endometriosis. Fertil Steril 1987;48:239–42 20. Biberoglu KO, Behrman SJ. Dosage aspects of danazol therapy in endometriosis: short-term and long-term effectiveness. Am J Obstet Gynecol 1981; 139:645–54 21. Revised American Fertility Society classification of endometriosis. Fertil Steril 1985;43:351–2 22. Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril 1997;67:817–21



Leuprorelin acetate compared with lynestrenol in endometriosis 23. Dlugi AM, Miller ID, Knittle J. Lupron depot (leuprolide acetate for depot suspension) in the treatment of endometriosis: a randomized, placebo-controlled, double-blind study. Lupron Study Group. Fertil Steril 1990;54:419–27 24. Gerhard I, Schindler AE, Bühler K, et al. Treatment of endometriosis with leuprorelin acetate depot: a German multicentre study. Clin Ther 1992; 14:(Suppl. A):3–16 25. Wheeler JM, Knittle JD, Miller JD. Depot leuprolide versus danazol in treatment of women with symptomatic endometriosis. I. Efficacy results. Am J Obstet Gynecol 1992;167:1367–71 26. Wheeler JM, Knittle JD, Miller JD. Depot leuprolide acetate versus danazol in the treatment of women with symptomatic endometriosis: a multicenter, double-blind randomized clinical trial. II: Assessment of safety. The Lupron Endometriosis Study Group. Am J Obstet Gynecol 1993;169:26–33 27. Shaw RW. An open randomized comparative study of the effect of goserelin depot and danazol in the treatment of endometriosis. Zoladex Endometriosis Study Group. Fertil Steril 1992; 58:265–72


Regidor et al. 28. The Nafarelin European Endometriosis Trial Group. Nafarelin for endometriosis: a large-scale, danazol-controlled trial of efficacy and safety, with 1-year follow-up. Fertil Steril 1992;57:514–22 29. Wenzl R, Schurz B, Freude G, et al. GnRH analogs versus gestagens in therapy of endometriosis. Gynaecol Geburt Rund 1993;33:269–70 30. Richter K. Investigations on 324 patients with histologically proved external endometriosis followed up for as long as 17 years. 3. Therapy. Geburtsh Frauenheilk 1974;34:501–14 31. Sillem M, Hahn U, Coddington CC, et al. Ectopic growth of endometrium depends on its structural integrity and proteolytic activity in the cynomolgus monkey (Macaca fascicularis) model of endometriosis. Fertil Steril 1996;66:468–73 32. Scotti S, Regidor P-A, Schindler AE, et al. Proliferation and cell adhesion is altered in endometriosis. Mol Hum Reprod 2000;6:610–17 33. Rößner P. Die Gestagene- Übersicht der Grundlagen und der Wirkungen. Menopause Praxis 1999;1:3–10

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