AU769482B2

AU769482B2 - Method for the therapeutic management of extrauterine proliferation of endometrial tissue, chronic pelvic pain and fallopian tube obstruction

Info

Publication number: AU769482B2
Application number: AU77792/00A
Authority: AU
Inventors: Klaus Diedrich; Jurgen Engel; Ricardo Felberbaum; Wolfgang Kupker; Hilde Riethmuller-Winzen
Original assignee: Zentaris AG
Current assignee: Aeterna Zentaris GmbH
Priority date: 1999-09-23
Filing date: 2000-09-20
Publication date: 2004-01-29
Anticipated expiration: 2020-09-20
Also published as: TWI267373B; KR100772852B1; SK3752002A3; CN101045155A; RU2255759C2; EP1214086A2; NZ534836A; JP2003509467A; HK1049117A1; BG106584A; ZA200201374B; NO20021430L; NO20021430D0; CA2383510A1; PL201898B1; MXPA02002436A; WO2001021194A3; KR20020035879A; CN1376070A; NO331198B1

Description

WO 01/21194 PCT/EP00/09212 -1- Method for the therapeutic management of extrauterine proliferation of endometrial tissue, chronic pelvic pain and fallopian tube obstruction Field of Invention Endometriosis is one of the most frequently encountered pathologies diagnosed amongst gynecological patients. For example, between 10% and 25% of women to presenting with gynecological symptoms in UK and in the USA are affected. Clinical diagnosis is made usually by laparoscopic observation of hemorrhagic or fibrotic foci on the pelvic organs. The ectopic endometrial tissue responds to ovarian hormones undergoing cyclic changes. The cyclical bleeding from the endometric deposit contributes to a local inflammatory reaction. Endometriosis commonly affects women during their childbearing years with an incidence of at least 1% (see Shaw, R.W.

(1993), An Atlas of Endometriosis. The Parthenon Publishing Group).

Endometriosis is usually classified into endometriosis (genitalis) intema (adenomyosis), endometriosis genitalis externa and endometriosis extragenitalis.

Chronic pelvic pain may occur either in relation to endometriosis or as an independent disease.

Fallopian tube obstruction (FTO) is a relatively common disease and may account to for up to 20 of cases of tubal infertility (see Winfield, A.C. et al., Apparent cornual occlusion in hysterosalpingography: Reversal by glucagon. AJR Am J Roentgenol 1982; 139: 525 527).

Background information and Prior Art Sampson suggested that menstrual regurgitation and subsequent implantation of endometrial tissue on the peritoneal face results in endometriosis [Sampson, J.A.

CONFIRMATION COPY i u T m A WO 01/21194 PCT/EPOO/09212 -2- (1927), Peritoneal endometriosis due to menstrual dissemination of the endometrial tissue into the peritoneal cavitiy. Am. J. Obstet. Gynecol., 14, 422.] Several aetiologic factors may be involved in the pathogenesis of endometriosis Dmowski et. al. suggested that genetic and immunological factors lead to endometriosis (Dmowski, Steele, R.W. and Baker, G.F. (1981). Deficient cellular immunity in endometriosis. Am. J. Obstet. Gynecol., 141, 377] Vascular and lymphatic embolization to distant sites has been demonstrated and explains the (rare) finding of endometriosis outside the peritoneal cavity, e.g. skin, to lung, kidney.

Cells lining the MOllerian duct arise from primitive cells which differentiate into peritoneal cells and the cells on the surface of the ovaries. It is proposed that these adult cells undergo de-differentiation back to their primitive origin and then transform into endometrial cells Levander, G. (1941), Bone formation by induction. An experimental study. Arch. Klin. Chir., 202, 497] Dysmenorrhea, acute or chronic pelvic pain, dyspareunia, and infertility perform the most frequent clinical symptoms reported.

FTO represents a heterogenous group of underlying pathology, preliminary intrinsic occlusion or extrinsic compression from estrogen-sensitive disorders, such as endometriosis, adenomyosis, endosalpingiosis, and myomata. FTO is frequently diagnosed by hysterosalpingography, besides laparascopy.

First choice of treatment comprises laparoscopic removal of endometric lesions.

This procedure may be followed by the treatment with Danazol or LHRH agonist (for a period of six months). Women being treated with Danazol might experience gastrointestinal and hepatic disorders as well as severe androgenic side effects.

It was also proposed from a theoretical viewpoint for treatment of endometriosis and uterine myoma to use the immediate suppression by administration of a LHRH antagonist to reducing the duration of treatment and faster improvement of subjective symtoms [Th. Reissmann et al. Human Reproduction vol. 10 No. 8 pp. 1974-1981,(1995)] owanuffmilm woo WO 01/21194 PCT/EP00/09212 -3- Further Hodgen teaches in the US Patent 5,658,884 a regime for therapeutic management of a gonadal dependent condition by reducing the estrogen supply by means of long-term administration of an GnRH antagonist for 6 months or longer in an amount effective to inhibit proliferation of endometrial tissue without substantially stopping the production of endogenous estrogen. For this purpose, Hodgen teaches such a regimen or dose of GnRH antagonist to achieve a 24 hour serum estradiol level in the range of about 25 to 50 and preferably about 35 to 45 pg/ml. However, Hodgen does not describe estradiol serum levels oscillating between 50 pg/ml and pg/ml. Moreover, Hodgen only teaches in the US Patent 5,658,884 a continuous 0o long-term treatment (on a daily or periodic basis, the latter meaning a weekly or monthly administration) but not a short-term induction treatment for only 4 to 12 weeks. Hodgen also does not describe any combination therapy comprising the GnRH antagonist in the treatment of endometrosis. The treatment is only described on monkeys and also includes the performance of a costly and repeated progesterone challenge test to provide an 24 hour average serum estradiol level of to 50 pg/ml.

As a consequence of the flare-up effect of LHRH-agonistic therapy an exacerbation of symptoms might occur during some days. Following prolonged treatment which is required to avoid the re-proliferation of endometric tissue hormonal withdrawal symptoms as well as demineralization of bones occur.

Therefore, effective drug therapy should immediately reduce the residual extrauterine endometrial tissue present after laparoscopic surgery. Duration of therapy should be only 4 to 12 weeks without the occurrence of any major hormonal withdrawal symptoms or ovarian cyst formation.

LHRH antagonists exert an immediate onset of hormonal suppression, and therefore benign gynecological tumors, such as uterine fibroids decrease within short time [Human Reproduction 1998, 13 Object of the Invention A0 The present invention relates to the improvement of the medical treatment of extrauterine proliferation of endometrial tissue, i.e. the administration of LHRH antagonists in patients with clinical symptoms of endometriosis, the improvement consisting of: immediate reduction of ectopic endometrial tissue immediate cessation of symptoms, e.g. severe pain, chronic pelvic pain and dysmenorrhea prevention of any progress of the disease avoidance of hormonal withdrawal symptoms 0t prevention of ovarian cyst formation, demineralization of bones as well as of gastrointestinal or hepatic disorders.

As disclosed herein, the invention relates to medical therapy which can start in the early to mid follicular phase, preferably on cycle day one to three. During the treatment the estradiol serum concentration levels are kept between 35 pg/ml and 80 pg/ml, is referably between about 45-75 pg/ml, more preferably between about 50-75 pg/ml. The LHRH antagonist is administered only for 4 to 12 weeks (short-term induction treatment), either by daily, weekly or monthly administration. Following the short-term induction treatment, the administration of a contraceptive, a non-steroidal anti-rheumatic, an analgetic, an androgen other than 17-alpha-alkyl substituted testosterone, or any combinations thereof.

Summary of the Invention According to one embodiment of the invention there is provided in a method of therapeutic management of extrauterine proliferation of endometrial tissue, chronic pelvic pain and/or fallopian tube obstruction (FTO), the improvement consisting of administration on menstrual cycle day one to three of an LHRH antagonist in the form of a short-term induction treatment for a period of about 4 to 12 weeks to a patient in need of such treatment such that the estrogen serum concentration level is between about pg/ml and about 80 pg/ml, whereby subsequently the administration of the LHRH 30 antagonist is ceased.

According to another embodiment of the invention there is provided a pharmaceutical composition when used for treating extrauterine proliferation of endometrial tissue, chronic pelvic pain and/or fallopian tube obstruction (FTO) comprising an LHRH antagonist and optionally one or more agents selected from the group consisting of a contraceptive, a non-steroidal anti-rheumatic agent, an analgetic, an [I:\DayLib\LIBH]03104.doc:UG androgen other than a 17-alpha-alkyl substituted testosterone, or any combinations thereof, optionally together with pharmaceutically acceptable excipients, whereby the LHRH antagonist is administered to a patient in need thereof in a short term induction treatment starting on cycle day one to day three for a period of about 4 to 12 weeks such that the estrogen serum concentration level is between about 35 and about 80 pg/ml, then the administration of the LHRH antagonist is ceased and optionally the one or more agents selected from the group consisting of a contraceptive, a non-steroidal antirheumatic agent, an analgetic, an androgen other than a 17-alpha-alkyl substituted testosterone or any combinations thereof, are administered together or separately to the patient.

According to a further embodiment of the invention there is provided the use of an LHRH antagonist for the preparation of a medicament for the therapeutic management of extrauterine proliferation of endometrial tissue, chronic pelvic pain and/or fallopian tube obstruction (FTO), wherein the LHRH antagonist is administered starting on cycle day one to day three in the form of a short-term induction treatment for a period of about 4 to 12 weeks to a patient in need of such treatment such that the estrogen serum concentration level is between about 35 pg/ml and 80 pg/ml, and then the administration of the LHRH antagonist is ceased.

According to another embodiment of the invention there is provided the use of an LHRH antagonist and one or more active agents selected from the group consisting of a contraceptive, a non-steroidal anti-rheumatic agent, an analgetic, an androgen other than a 17-alpha-alkyl substituted testosterone, or any combinations thereof, for the preparation of a medicament for the therapeutic management of extrauterine proliferation of endometrial tissue, chronic pelvic pain and/or fallopian tube obstruction (FTO), wherein the LHRH antagonist is administered starting on cycle day one to day three in the form of a short-term induction treatment for a period of about 4 to 12 weeks to a patient in need of such treatment such that the estrogen serum concentration level is between about pg/ml and 80 pg/ml, then the administration of the LHRH antagonist is ceased and the one or more active agent selected from the group consisting of a contraceptive, a non- 30 steroidal anti-rheumatic agent, an analgetic, an androgen other than a 17-alpha-alkyl substituted testosterone, or any combinations thereof, are administered together or separately to the patient.

\DayLibLBH0304.doc: *0 [l:\DayLib\LIBH]03104.doc:UG According to a further embodiment of the invention there is provided in a method of therapeutic management of extrauterine proliferation of endometrial tissue, chronic pelvic pain and/or fallopian tube obstruction (FTO), the improvement consisting of administration on menstrual cycle day one to three of an LHRH antagonist and one or more active agents selected from the group consisting of a contraceptive, a non-steroidal anti-rheumatic agent, an analgetic, an androgen other than a 17-alpha-alkyl substituted testosterone, or any combinations thereof, in the form of a short-term induction treatment for a period of about 4 to 12 weeks to a patient in need of such treatment such that the estrogen serum concentration level is between about 35 pg/ml and about 80 pg/ml, whereby subsequently the administration of the LHRH antagonist is ceased, and wherein the one or more active agent selected from the group consisting of a contraceptive, a nonsteroidal anti-rheumatic agent, an analgetic, an androgen other than a 17-alpha-alkyl substituted testosterone, or any combinations thereof, are administered together or separately to the patient.

In the treatment of extrauterine endometrial tissue with an LHRH antagonist, therapy is started on menstrual cycle day one to three. Before starting LHRH-antagonist therapy the diagnosis is performed by laparoscopy.

In cases of severe pain, LHRH antagonist therapy might be initiated without prior laparoscopy.

Therapy will continue until clinical symptomatology has resolved and no proliferation of the endometrium is seen. Due to the immediate onset of suppression of the gonadotropins LH and FSH as well of sex steroids estradiol and progesterone no [l:\DayLib\LIBH]03104.doc:LIG II BII^ W W M W Y i t 'i ,N ;IN i O I, 5 ;a I* WO 01/21194 PCT/EP00/09212 further proliferation of the endometrium occurs. Benign tumors or other sex steroid dependent lesions, like endometriosis decrease within four to twelve weeks of therapy. Due to the lack of flare-up no ovarian cysts develop.

Furthermore, no hormonal withdrawal symptoms are seen as the estradiol values are kept in the range of the early follicular phase of 35 to 80 pg/ml, preferably between about 45-75 pg/ml, more preferably between about 50-75 pg/ml without further increase or decrease. No titering of the dosage of the LHRH antagonist e.g. by conducting a costly progesterone challenge test, is necessary.

The method of therapeutic management of extrauterine proliferation of endometrial tissue the improvement according to the invention therefore embraces: immediate reduction of ectopic endometrial tissue prevention of any progress of the disease avoidance of hormonal withdrawal symptoms prevention of ovarian cyst formation, demineralization of bones as well as of gastrointestinal or hepatic disorders start of medical therapy on cycle day one to three and maintenance of estradiol levels at values of the early follicular phase throughout the entire duration of treatment by means of administration of a LHRH antagonist wherein the antagonist is preferabely cetrorelix, teverelix, ganirelix, antide or abarelix. The antagonist can also be the LHRH antagonist D-63153 (Ac-D-Nal-D-pCI-Phe-D-Pal-Ser-N-Me-Tyr-D- Hci-Nle-Arg-Pro-D-Ala-NH2) as described in the German Patent Application No. 199 11 771.3 filed on March 11, 1999.

The LHRH antagonist may be given for 4 to 12 weeks in a weekly dose of 3 to 10 mg per week or for 4 to 12 weeks in a daily dose of 0.25 mg to 0.5 mg/day.

It is also possible to give the LHRH antagonist 4 to 12 weeks in a monthly dose of 12 to 40 mg per month.

In a repeat therapeutic treatment the LHRH antagonist is given for 4 to 12 weeks and the treatment is repeated two or three times a year, whereby a repeated YOMP -RAY WO 01/21194 PCT/EP00/09212 -6treatment does not following directly after a short-term induction treatment. Usually a period of time of weeks or months, where no LHRH antagonist is administered, is between the end of the short-term induction treatment and the start of the repeat treatment.

To demonstrate the feasibility to maintain a low estradiol secretion under adjusted LHRH- antagonist treatment so that a therapeutic suppression occurs without withdrawal symtoms nine patients with confirmed endometriosis were treated with 3 mg of Cetrorelix acetate s.c. by weekly administration for 8 weeks. While patients to compliance was excellent avoiding any hot flushes or other withdrawal symptoms and without any progress of the disease confimed by 2 nd look laparascopy the mean estradiol serum concentrations oscillated between 37 pg/ml and 64 pg/ml, preferably between 45-75 pg/ml, more preferably between about 50-75 pg/mI. Histological biopsies showed no proliferation of the endometrium at the end of treatment. No ovarian cyst formation occurred.

The figure 1 shows the continuous estradiol suppression to values of the early follicular phase (range of 35 pg/ml to 80 pg/ml, preferably between 45-75 pg/ml, more preferably between about 50-75 pg/ml) obtained in patients with endometriosis by a weekly dose of 3 mg of Cetrorelix (LHRH antagonist) for 8 weeks. Immediate and continuous suppression of estradiol levels is obtained without any signs of estradiol withdrawal symptoms and without proliferation of the endometrium at the end of treatment.

Fig. 2 shows estradiol serum levels after administration of cetrorelix at a weekly dose of 1 mg resp. 3 mg once per week. The estradiol serum levels are between about pg/ml, preferably between about 45-75 pg/ml, more preferably between about pg/ml.

The endometriosis patient with distinctive symptomatic pain is suffering from a chronic disease. Surgical methods in sense of curative therapy as well as medicinal treatment to suppress the sexual steroid secretion of the patient often result only in a i F %WVIRVIM WO O1/21104 PCT/EP00/09212 -7temporary improvement. The relapse rate of the discomforts is very high and about within 5 years after finishing therapy (Schweppe, 1999).

At the same time the radical surgical therapy and the suppression of the estrogen secretion leads to considerable side effects. The radical surgical therapy in sense of hysterectomy with bilateral adnexectomy is no adequate therapy for the younger, premenopausal woman. The chronical lack of estrogen leads to the following vegetative symptoms: hot flashes, sweating, dryness of the vagina, depressive feelings and also holds the risk of osteoporosis. The alternative therapy with the synthetic steroidal compound Danazol may cause virilizing symptoms because of the androgenic effect.

Aim of the medicinal therapy of patients with endometriosis with symptomatic pain is to obtain a treatment without side effects, especially avoiding the negative effects of estrogen suppression and which is long-lasting after finishing therapy. The specific pharmacological mode of action of LHRH antagonists allows new possibilities for treatment of endometriosis.

The weekly administration of an adequate dose of an LHRH antagonist, e.g. 3 mg Cetrotide® per week over a period of eight weeks leads to a controlled suppression of estrogen secretion so that serum concentrations between about pg/ml and about 80 pg/ml, preferably between about 45-75 pg/ml, more preferably between about 50-75 pg/ml are obtained. In this serum concentration range no vegetative symptoms arise. Also the development of osteoporosis can be avoided.

The symptomatic pain will be effectively suppressed in all stages of the disease (rAFS I IV). In the stages rAFS I II a clinical regression of the disease in sense of decrease of the implantation area is noticed (Felberbaum et. al., 2000).

In a preferred embodiment of this invention, after this treatment period of eight to twelve weeks the patient could take a contraceptive, preferably an oral contraceptive, preferably with gestagen components, unless there is a wish for pregnancy. In this connection combinations with Lynestronol 2 mg with 0,04 mg WO 01/2119q4 PCT/EP00/09212 -8- Ethinylestradiol or 2,5 mg Lynestrenol with 0,05 mg of Ethinylestradiol (e.g.

Yermonil®, Lyn-ratiopharm-Sequenz') have to be mentioned.

A combination therapy with androgens other than 17-alpha-alkyl substituted testosterones such as danazol may also be applied subsequently to the short-term induction regimen with the LHRH antagonist either alone or in combination with nonsteroidal anti-rheumatics and/or analgetics. An example for a suitable androgene is halotestinTM (fluoximesterone).

The treatment with a contraceptive, preferably an oral contraceptive, preferably containing gestagens, should be individually continued until typical pain sensation occurs. In this stage the patient will have relatively small menstrual bleeding as an effect of the gestagen component of this contraceptive, preferably oral contraceptive.

For covering also the especially critical pre-menstrual and menstrual days with regard to pain sensation in this phase a concomitant medication with appropriate non-steroidal anti-rheumatic drugs, e.g. diclophenac, ibuprofen, indometeacin, oxicam derivates or acetylsalicylic acid may be given. Also an analgetic such as flupirtinmaleat (Katadolon") can be administered.

If further pain symptoms occur during this combination therapy with gestagenic contraceptives, preferably oral contraceptives, a daily, weekly or monthly therapy with the adequate dose of an LHRH antagonist as described above may be repeated. Detailed information on the respective treatment options are given below.

If the patient is absolutely free of pain treatment can be changed to gestagenic contraceptive, preferably oral contraceptive,s in combination with concomitant medication of appropriate non-steroid anti-rheumatic drugs or analgetics.

This therapy using the intermittent administration of an LHRH antagonist leads to a new and innovative unlimited treatment without side effects and lowers treatment burden for the patient significantly.

WO 01/21194 PCTIEPO0/09212 -9- Pharmaceutical Formulations Suitable for Treatment Pharmaceutical formulations of the LHRH antagonist suitable for the therapeutic management of extrauterine proliferation of endometrial tissue, chronic pelvic pain and fallopian tube obstruction may be for example a) acetate salt formulations in the concentration of 1 mg/1 ml or lower where the powder may be dissolved in Water for Injection (Wfl) or in Gluconic Acid (GA); b) acetate salt formulations in the concentration of 1.5 mg/1 ml to 5.0 mg /1 ml, preferably 2.5 mg/1 ml where the powder may be dissolved in Water for Injection (Wfl) or in Gluconic Acid (GA); c) pamoate salt formulations in the concentration of 10 mg/1 ml to 30 mg/1 ml, preferably 15 mg/1 ml where the lyophylisate powder may be dissolved in Gluconic Acid (GA) or in Water for Injection (Wfl.

According to one aspect of the present invention in the method of therapeutic management of extrauterine proliferation of endometrial tissue, chronic pelvic pain and/or fallopian tube obstruction (FTO), the improvement consisting of administration of an LHRH antagonist in the form of a short-term induction treatment for a period of about 4 to 12 weeks to a patient in need of such treatment, whereby subsequently the administration of the LHRH antagonist is ceased, is provided.

The duration of the short term induction treatment is about 4 to about 12 weeks, that means that the treatment can be between about 28 to about 84 days or from about one to about three months.

According to another aspect of the present invention in a method as mentioned above the improvement is provided, wherein the LHRH antagonist is administered such that the estrogen serum concentration level is between about 35 pg/ml and WO 01/21194 PCT/EP00/09212 about 80 pg/ml, preferably between about 45-75 pg/ml, more preferably about 50-75 pg/ml.

According to another aspect of the present invention in a method as mentioned above the improvement is provided, characterized in that the short-term induction treatment with the LHRH antagonist is followed by administration of a contraceptive, preferably an oral contraceptive.

According to another aspect of the present invention in a method as mentioned above the improvement is provided, characterized in that the short-term induction treatment with the LHRH antagonist is followed by administration of a non-steroidal anti-rheumatic agent.

According to another aspect of the present invention in a method as mentioned above the improvement is provided, characterized in that the short-term induction treatment with the LHRH antagonist is followed by administration of an analgetic.

According to another aspect of the present invention in a method as mentioned above the improvement is provided, characterized in that the short-term induction treatment with the LHRH antagonist is followed by administration of an androgen other than a 17-alpha-alkyl substituted testosterone.

According to another aspect of the present invention in a method as mentioned above the improvement is provided, characterized in that the short-term induction treatment with the LHRH antagonist is followed by the combined or separate administration of one or more active agents selected from the group consisting of a contraceptive, preferably an oral contraceptive, a non-steroidal anti-rheumatic agent, an analgetic, an androgen other than a 17-alpha-alkyl substituted testosterone or any combinations thereof.

According to another aspect of the present invention in a method as mentioned above the improvement is provided, characterized in that the LHRH antagonist is -tF ."Wr WO 01/21194 PCT/EP00/09212 WO 01/21194 PTEO/91 -11administered starting in the early to mid follicular phase, preferably on cycle day one to three.

According to another aspect of the present invention in a method as mentioned s above the improvement is provided, characterized in that the LHRH antagonist is selected from the group consisting of cetrorelix, teverelix, ganirelix, antide, abarelix and D-63153.

According to another aspect of the present invention in a method as mentioned above the improvement is provided, characterized in that the LHRH antagonist is administered during the short-term induction treatment for 4 to 12 weeks at a weekly dose of 3 to 10 mg per week.

According to another aspect of the present invention in a method as mentioned above the improvement is provided, characterized in that the LHRH antagonist is administered during the short-term induction treatment for 4 to 12 weeks at a daily dose of 0.25 mg to 0.5 mg/day.

According to another aspect of the present invention in a method as mentioned above the improvement is provided, characterized in that the LHRH antagonist is administered during the short-term induction treatment for 4 to 12 weeks at a monthly dose of 12 to 40 mg per month.

According to another aspect of the present invention in a method as mentioned above the improvement is provided, characterized in that the LHRH antagonist is given for the induction treatment during 4 to 12 weeks and the treatment is repeated two or three times a year.

According to a further aspect of the present invention a pharmaceutical composition for treating extrauterine proliferation of endometrial tissue, chronic pelvic pain and/or fallopian tube obstruction (FTO) comprising an LHRH antagonist and optionally one or more agents selected from the group consisting of a contraceptive, preferably an oral contraceptive, a non-steroidal anti-rheumatic agent, an analgetic agent, an ~i i~i#Lr(Tw~ j~~NMWVQAM"'" OR'~fq wn n1/'n114 PCT/EP00/09212 -12androgen agent other than a 17-alpha-alkyl substituted testosterone or any combinations thereof, optionally together with pharmaceutically acceptable excipients, whereby the LH-RH antagonist is administered to a patient in need thereof in a short term induction treatment for a period of about 4 to 12 weeks, then the administration of the LH-RH antagonist is ceased and optionally the one or more agents selected from the group consisting of a contraceptive, preferably an oral contraceptive, a non-steroidal anti-rheumatic agent, an analgetic, an androgen other than a 17-alpha-alkyl substituted testosterone or any combinations thereof, are administered together or separately to the patient is provided.

Suitable excipients and dosage forms are for example described by K.H. Bauer, K.- H. Fromming and C. Fuhrer, Lehrbuch der Pharmazeutischen Technologie, 6 th edition, Stuttgart 1999, pages 163-186 (excipients) and pages 227-386 (dosage forms), including the references as cited therein.

The LH-RH antagonist can be administered for example sucutaneous intramuscular or inhalative. The agents selected from the group consisting of a contraceptive, preferably an oral contraceptive, a non-steroidal anti-rheumatic agent, an analgetic, an androgen other than a 17-alpha-alkyl substituted testosterone or any combinations thereof can be administered as known in the art (see for example the German, European or U.S. pharmacopoeia), preferably oral or inhalative.

According to another aspect of the present invention, a pharmaceutical composition as mentioned above is provided wherein the LHRH antagonist is administered such that the estrogen serum concentration level is between about 35 pg/ml and about pg/ml, preferably between about 45-75 pg/ml, more preferably about 50-75 pg/ml.

According to another aspect of the present invention, a pharmaceutical composition as mentioned above is provided wherein the short-term induction treatment with the LHRH antagonist is followed by administration of a contraceptive, preferably an oral contraceptive.

MYTAWAVOM 9,1MARIPC w i C"in~r riawesew~~wi a~r~i~ nir WO 01/21194 PCT/EP00/09212 -13- According to another aspect of the present invention, a pharmaceutical composition as mentioned above is provided wherein the short-term induction treatment with the LHRH antagonist is followed by administration of a non-steroidal anti-rheumatic agent.

According to another aspect of the present invention, a pharmaceutical composition as mentioned above is provided wherein the short-term induction treatment with the LHRH antagonist is followed by administration of an analgetic.

According to another aspect of the present invention, a pharmaceutical composition as mentioned above is provided wherein the short-term induction treatment with the LHRH antagonist is followed by administration of an androgen other than a 17alpha-alkyl substituted testosterone.

According to another aspect of the present invention, a pharmaceutical composition as mentioned above is provided wherein the short-term induction treatment with the LHRH antagonist is followed by the combined or separate administration of one or more active agents selected from the group consisting of a contraceptive, preferably an oral contraceptive, a non-steroidal anti-rheumatic agent, an analgetic, an androgen other than a 17-alpha-alkyl substituted testosterone or any combinations thereof.

According to another aspect of the present invention, a pharmaceutical composition as mentioned above is provided wherein the LHRH antagonist is administered starting in the early to mid follicular phase, preferably on cycle day one to three.

According to another aspect of the present invention, a pharmaceutical composition as mentioned above is provided wherein the LHRH antagonist is selected from the group consisting of cetrorelix, teverelix, ganirelix, antide, abarelix and D-63153.

According to another aspect of the present invention, a pharmaceutical composition as mentioned above is provided wherein the LHRH antagonist is administered during i 0 11 %W OW N UJIM, WO 01/21194 PCT/EP00/09212 -14the short-term induction treatment for 4 to 12 weeks at a weekly dose of 3 to 10 mg per week.

According to another aspect of the present invention, a pharmaceutical composition as mentioned above is provided wherein the LHRH antagonist is administered during the short-term induction treatment for 4 to 12 weeks at a daily dose of 0.25 mg to mg/day.

According to another aspect of the present invention, a pharmaceutical composition 0o as mentioned above is provided wherein the LHRH antagonist is administered during the short-term induction treatment for 4 to 12 weeks at a monthly dose of 12 to mg per month.

According to another aspect of the present invention, a pharmaceutical composition as mentioned above is provided wherein the LHRH antagonist is given for the induction treatment during 4 to 12 weeks and the treatment is repeated two or three times a year.

According to another aspect of the present invention, a pharmaceutical composition as mentioned above is provided, wherein the the one or more active agents selected from the group consisting of a contraceptive, preferably an oral contraceptive, a nonsteroidal anti-rheumatic agent, an analgetic, an androgen other than a 17-alpha-alkyl substituted testosterone or any combinations thereof, are in the same or separate dosage forms.

According to another aspect of the present invention, a use of an LH-RH antagonist for the preparation of a medicament for the therapeutic management of extrauterine proliferation of endometrial tissue, chronic pelvic pain and/or fallopian tube obstruction (FTO), whereby the LHRH antagonist is administered in the form of a short-term induction treatment for a period of about 4 to 12 weeks to a patient in need of such treatment and then the administration of the LHRH antagonist is ceased, is provided.

:k7W MA- WE W n i i ia iA' WNWWW. MW A. ftv W~MMM~' i WO 01/21194 PCT/EP00/09212 According to another aspect of the present invention, a use of an LH-RH antagonist as mentioned above is provided wherein the LHRH antagonist is administered such that the estrogen serum concentration level is between about 35 pg/ml and about pg/ml, preferably between about 45-75 pg/ml, more preferably about 50-75 pg/ml.

According to another aspect of the present invention, a use of an LH-RH antagonist as mentioned above is provided, wherein the short-term induction treatment with the LHRH antagonist is followed by administration of a contraceptive, preferably an oral contraceptive.

According to another aspect of the present invention, a use of an LH-RH antagonist as mentioned above is provided, wherein the short-term induction treatment with the LHRH antagonist is followed by administration of a non-steroidal anti-rheumatic agent.

According to another aspect of the present invention, a use of an LH-RH antagonist as mentioned above is provided, wherein the short-term induction treatment with the LHRH antagonist is followed by administration of an analgetic.

According to another aspect of the present invention, a use of an LH-RH antagonist as mentioned above is provided, wherein the short-term induction treatment with the LHRH antagonist is followed by administration of an androgen other than a 17alpha-alkyl substituted testosterone.

According to another aspect of the present invention, a use of an LH-RH antagonist as mentioned above is provided, wherein the short-term induction treatment with the LHRH antagonist is followed by the combined or separate administration of one or more active agents selected from the group consisting of a contraceptive, preferably an oral contraceptive,, a non-steroidal anti-rheumatic agent, an analgetic, an androgen other than a 17-alpha-alkyl substituted testosterone or any combinations thereof.

I j~A~,-4Wk ~4 ff~~iL ~L1~.A L~ ,-AIV WO 01/21194 PCT/EP00/09212 -16- According to another aspect of the present invention, a use of an LH-RH antagonist as mentioned above is provided, wherein the LHRH antagonist is administered starting in the early to mid follicular phase, preferably on cycle day one to three.

According to another aspect of the present invention, a use of an LH-RH antagonist as mentioned above is provided, wherein the LHRH antagonist is selected from the group consisting of cetrorelix, teverelix, ganirelix, antide, abarelix and D-63153.

According to another aspect of the present invention, a use of an LH-RH antagonist as mentioned above is provided, wherein the LHRH antagonist is administered during the short-term induction treatment for 4 to 12 weeks at a weekly dose of 3 to mg per week.

According to another aspect of the present invention, a use of an LH-RH antagonist as mentioned above is provided, wherein the LHRH antagonist is administered during the short-term induction treatment for 4 to 12 weeks at a daily dose of 0.25 mg to 0.5 mg/day.

According to another aspect of the present invention, a use of an LH-RH antagonist as mentioned above is provided, wherein the LHRH antagonist is administered during the short-term induction treatment for 4 to 12 weeks at a monthly dose of 12 to 40 mg per month.

According to another aspect of the present invention, a use of an LH-RH antagonist as mentioned above is provided, wherein the LHRH antagonist is given for the induction treatment during 4 to 12 weeks and the treatment is repeated two or three times a year.

According to another aspect of the present invention, a use of an LH-RH antagonist and one or more active agents selected from the group consisting of a contraceptive, preferably an oral contraceptive, a non-steroidal anti-rheumatic agent, an analgetic, an androgen other than a 17-alpha-alkyl substituted testosterone, or any combinations thereof, for the preparation of a medicament for the therapeutic A fl K tt'±M ,T oA.AA"iA A "AAAK A AAAA. AA~ WO 01/21194 PCT/EP00/09212 -17management of extrauterine proliferation of endometrial tissue, chronic pelvic pain and/or fallopian tube obstruction (FTO), whereby the LHRH antagonist is administered in the form of a short-term induction treatment for a period of about 4 to 12 weeks to a patient in need of such treatment, then the administration of the LHRH antagonist is ceased and the one or more active agent selected from the group consisting of a contraceptive, preferably an oral contraceptive, a non-steroidal antirheumatic agent, an analgetic, an androgen other than a 17-alpha-alkyl substituted testosterone, or any combinations thereof, are administered together or separately to the patient, is provided.

According to another aspect of the present invention the use of an LH-RH antagonist and one or more active agents as mentioned above is provided, wherein the LHRH antagonist is administered such that the estrogen serum concentration level is between about 35 pg/ml and about 80 pg/ml, preferably between about 45-75 pg/ml, more preferably about 50-75 pg/ml.

According to another aspect of the present invention the use of an LH-RH antagonist and one or more active agents as mentioned above is provided, wherein the shortterm induction treatment with the LHRH antagonist is followed by administration of a contraceptive, preferably an oral contraceptive.

According to another aspect of the present invention the use of an LH-RH antagonist and one or more active agents as mentioned above is provided, wherein the shortterm induction treatment with the LHRH antagonist is followed by administration of a non-steroidal anti-rheumatic agent.

According to another aspect of the present invention the use of an LH-RH antagonist and one or more active agents as mentioned above is provided, wherein the shortterm induction treatment with the LHRH antagonist is followed by administration of an analgetic.

According to another aspect of the present invention the use of an LH-RH antagonist and one or more active agents as mentioned above is provided, wherein the short- WO 01/21194 PCT/EP00/09212 -18term induction treatment with the LHRH antagonist is followed by administration of an androgen other than a 17-alpha-alkyl substituted testosterone.

According to another aspect of the present invention the use of an LH-RH antagonist and one or more active agents as mentioned above is provided, wherein the shortterm induction treatment with the LHRH antagonist is followed by the combined or separate administration of one or more active agents selected from the group consisting of a contraceptive, preferably an oral contraceptive, a non-steroidal antirheumatic agent, an analgetic, an androgen other than a 17-alpha-alkyl substituted o0 testosterone or any combinations thereof.

According to another aspect of the present invention the use of an LH-RH antagonist and one or more active agents as mentioned above is provided, wherein the LHRH antagonist is administered starting in the early to mid follicular phase, preferably on cycle day one to three.

According to another aspect of the present invention the use of an LH-RH antagonist and one or more active agents as mentioned above is provided, wherein the LHRH antagonist is selected from the group consisting of cetrorelix, teverelix, ganirelix, antide, abarelix and D-63153.

According to another aspect of the present invention the use of an LH-RH antagonist and one or more active agents as mentioned above is provided, wherein the LHRH antagonist is administered during the short-term induction treatment for 4 to 12 weeks at a weekly dose of 3 to 10 mg per week.

According to another aspect of the present invention the use of an LH-RH antagonist and one or more active agents as mentioned above is provided, wherein the LHRH antagonist is administered during the short-term induction treatment for 4 to 12 weeks at a daily dose of 0.25 mg to 0.5 mg/day.

According to another aspect of the present invention the use of an LH-RH antagonist and one or more active agents as mentioned above is provided, wherein the LHRH a i u u n m 4 uu mi 1ML2 WO 01/21194 PCTEP00/09212 -19antagonist is administered during the short-term induction treatment for 4 to 12 weeks at a monthly dose of 12 to 40 mg per month.

According to another aspect of the present invention the use of an LH-RH antagonist and one or more active agents as mentioned above is provided, wherein the LHRH antagonist is given for the induction treatment during 4 to 12 weeks and the treatment is repeated two or three times a year.

t 7 7M~

Claims

1. In a method of therapeutic management of extrauterine proliferation of endometrial tissue, chronic pelvic pain arid/or fallopian tube obstruction (FTO), the improvement consisting of administration on menstrual cycle day one to three of an LHRH antagonist in the form of a short-term induction treatment for a period of about 4 to 12 weeks to a patient in need of such treatment such that the estrogen serum concentration level is between about 35 pg/ml and about 80 pg/ml, whereby subsequently the administration of the LHRH antagonist is ceased.

2. The method according to claim 1, wherein the LHRH antagonist is administered such that the estrogen serum concentration level is between about 45 pg/ml and about 75 pg/ml.

3. The method according to claim 2, wherein the LHRH antagonist is administered such that the estrogen serum concentration level is between about 50 and about 75 pg/ml.

4. The method according to any one of claims 1 to 3 wherein the short-term induction treatment with the LHRH antagonist is followed by administration of a contraceptive. The method according to claim 4, wherein said contraceptive is an oral contraceptive.

6. The method according to any one of claims 1 to 3 wherein the short-term induction treatment with the LHRH antagonist is followed by administration of a non- steroidal anti-rheumatic agent.

7. The method according to any one of claims 1 to 3 wherein the short-term 0 induction treatment with the LHRH antagonist is followed by administration of an analgetic.

8. The method according to any one of claims 1 to 3 wherein the short-term induction treatment with the LHRH antagonist is followed by administration of an androgen other than a 17-alpha-alkyl substituted testosterone.

9. The method according to any one of claims 1 to 3 wherein the short-term 30 induction treatment with the LHRH antagonist is followed by the combined or separate administration of one or more active agents selected from the group consisting of a °contraceptive, a non-steroidal anti-rheumatic agent, an analgetic, an androgen other than a

17-alpha-alkyl substituted testosterone, or any combinations thereof. The method according to claim 9 wherein said contraceptive is an oral contraceptive. [I:\DayLib\LIBH]03104.doc:LUG 11. The method according to any one of claims 1 to 10 wherein the LHRH antagonist is selected from the group consisting of cetrorelix, teverelix, ganirelix, antide, abarelix and D-63153. 12. The method according to any one of claims 1 to 11 wherein the LHRH antagonist is administered during the short-term induction treatment for about 4 to 12 weeks at a weekly dose of about 3 to 10 mg per week. 13. The method according to any one of claims 1 to 12 wherein the LHRH antagonist is administered during the short-term induction treatment for about 4 to 12 weeks at a daily dose of about 0.25 mg to 0.5 mg/day. 14. The method according to any one of claims 1 to 12 wherein the LHRH antagonist is administered during the short-term induction treatment for about 4 to 12 weeks at a monthly dose of about 12 to 40 mg per month. The method according to any one of claims 1 to 12 wherein the LHRH antagonist is given for the induction treatment during about 4 to 12 weeks and the treatment is repeated two or three times a year. 16. A pharmaceutical composition when used for treating extrauterine proliferation of endometrial tissue, chronic pelvic pain and/or fallopian tube obstruction (FTO) comprising an LHRH antagonist and optionally one or more agents selected from the group consisting of a contraceptive, a non-steroidal anti-rheumatic agent, an analgetic, an androgen other than a 17-alpha-alkyl substituted testosterone, or any combinations thereof, optionally together with pharmaceutically acceptable excipients, whereby the LHRH antagonist is administered to a patient in need thereof in a short term induction treatment starting on cycle day one to day three for a period of about 4 to 12 weeks such that the estrogen serum concentration level is between about 35 and about 80 pg/ml, then 25 the administration of the LHRH antagonist is ceased and optionally the one or more agents selected from the group consisting of a contraceptive, a non-steroidal anti- rheumatic agent, an analgetic, an androgen other than a 17-alpha-alkyl substituted testosterone or any combinations thereof, are administered together or separately to the •patient. 17. The pharmaceutical composition when used according to claim 16, wherein said contraceptive is an oral contraceptive.

18. The pharmaceutical composition when used according to claim 16 or 17, wherein the LHRH antagonist is administered such that the estrogen serum concentration level is between about 45 and about 75 pg/ml. [I:\DayLib\LIBH]03104.doc: UG

19. The pharmaceutical composition when used according to claim 18, wherein the LHRH antagonist is administered such that the estrogen serum concentration level is between about 50 pg/ml to The pharmaceutical composition when used according to any one of claims 16 to 19 wherein the short-term induction treatment with the LHRH antagonist is followed by administration of a contraceptive.

21. The pharmaceutical composition according to claim 20 wherein said contraceptive is an oral contraceptive.

22. The pharmaceutical composition when used according to any one of claims 16 0o to 21 wherein the short-term induction treatment with the LHRH antagonist is followed by administration of a non-steroidal anti-rheumatic agent.

23. The pharmaceutical composition when used according to any one of claims 16 to 21 wherein the short-term induction treatment with the LHRH antagonist is followed by administration of an analgetic.

24. The pharmaceutical composition when used according to any one of claims 16 to 21 wherein the short-term induction treatment with the LHRH antagonist is followed by administration of an androgen other than a 17-alpha-alkyl substituted testosterone. The pharmaceutical composition when used according to any one of claims 16 to 21 wherein the short-term induction treatment with the LHRH antagonist is followed by the combined or separate administration of one or more active agents selected from the group consisting of a contraceptive, a non-steroidal anti-rheumatic agent, an analgetic, an androgen other than a 17-alpha-alkyl substituted testosterone or any combinations thereof.

26. The pharmaceutical composition when used according to claim 25 wherein said contraceptive is an oral contraceptive. 25 27. The pharmaceutical composition when used according to any one of claims 16 to 26 wherein the LHRH antagonist is selected from the group consisting of cetrorelix, teverelix, ganirelix, antide, abarelix and D-63153.

28. The pharmaceutical composition when used according to any one of claims 16 to 27, wherein the LHRH antagonist is administered during the short-term induction treatment for about 4 to 12 weeks at a weekly dose of about 3 to about 10 mg per week.

29. The pharmaceutical composition when used according to any one of claims 16 to 27, wherein the LHRH antagonist is administered during the short-term induction treatment for about 4 to 12 weeks at a daily dose of about 0.25 mg to about 0.5 mg/day. [I:\DayLib\LIBH]03104.doc:LUG The pharmaceutical composition when used according to any one of claims 16 to 27, wherein the LHRH antagonist is administered during the short-term induction treatment for about 4 to 12 weeks at a monthly dose of about 12 to 40 mg per month. 3 1. The pharmaceutical composition when used according to any one of claims 16 to 27, wherein the LHRH antagonist is given for the induction treatment during about 4 to 12 weeks and the treatment is repeated two or three times a year.

32. The pharmaceutical composition when used according to any one of claims 16 to 31, wherein the one or more active agents selected from the group- consisting of a contraceptive, a non-steroidal anti-rheumatic agent, an analgetic, an androgen other than a 1 7-alpha-alkyl substituted testosterone or any combinations thereof, are in the same or separate dosage fors.

33. The pharmaceutical composition when used according to claim 32 wherein said contraceptive is an oral contraceptive.

34. Use of an LHRI{ antagonist for the preparation of a medicament for the therapeutic management of extrauterine proliferation of endometrial tissue, chronic pelvic pain and/or fallopian tube obstruction (FTO), wherein the LHRH antagonist is administered starting on cycle day one to day three in the form of a short-term induction treatment for a period of about 4 to 12 weeks to a patient in need of such treatment such that the estrogen serum concentration level is between about 35 pglml and 80 pg/ml, and then the administration of the LHRH antagonist is ceased. Use of an LHR}I antagonist according to claim 34 wherein the LHRH antagonist is administered such that the estrogen serum concentration level is between about 45 and about 75 pg/ml.

36. Use of an LHRH antagonist according to claim 35 wherein the LHRH 25 antagonist is administered such that the estrogen serum concentration level is between about 50 and about 75 pg/ml.

37. Use of an LHRH antagonist according to any one of claims 34 to 36 wherein the short-term induction treatment with the LHRH antagonist is followed by *00000administration of a contraceptive.

38. Use of an LHRH antagonist according to claim 37, wherein said contraceptive is an oral contraceptive. :*039. Use of an LHR.H antagonist according to any one of claims 34 to 36 wherein the short-term induction treatment with the LHRH antagonist is followed by administration of a non-steroidal anti-rheumatic agent. [I:\DayLib\LIBH]03 104.docUG Use of an LHRH antagonist according to any one of claims 34 to 36 wherein the short-term induction treatment with the LHRH antagonist is followed by administration of an analgetic.

41. Use of an LHRH antagonist according to any one of claims 34 to 36 wherein the short-term induction treatment with the LHRH antagonist is followed by administration of an androgen other than a 17-alpha-alkyl substituted testosterone.

42. Use of an LHRH antagonist according to any one of claims 34 to 36 wherein the short-term induction treatment with the LHRH antagonist is followed by the combined or separate administration of one or more active agents selected from the group consisting of a contraceptive, a non-steroidal anti-rheumatic agent, an analgetic, an androgen other than a 17-alpha-alkyl substituted testosterone, or any combinations thereof

43. Use of an LHRH antagonist according to claim 42, wherein said contraceptive is an oral contraceptive.

44. Use of an LHRH antagonist according to any one of claims 34 to 43 wherein the LHRH antagonist is selected from the group consisting of cetrorelix, teverelix, ganirelix, antide, abarelix and D-63153. Use of an LHRH antagonist according to any one of claims 34 to 44 wherein the LHRH antagonist is administered during the short-term induction treatment for about 4 to 12 weeks at a weekly dose of about 3 to about 10 mg per week.

46. Use of an LHRH antagonist according to any one of claims 34 to 44 wherein S"the LHRH antagonist is administered during the short-term induction treatment for about 4 to 12 weeks at a daily dose of about 0.25 mg to about 0.5 mg/day.

47. Use of an LHRH antagonist according to any one of claims 34 to 44 wherein 25 the LHRH antagonist is administered during the short-term induction treatment for about 4 to 12 weeks at a monthly dose of about 12 to about 40 mg per month.

48. Use of an LHRH antagonist according to any one of claims 34 to 44 wherein the LHRH antagonist is given for the induction treatment during about 4 to 12 weeks and the treatment is repeated two or three times a year.

49. Use of an LHRH antagonist and one or more active agents selected from the group consisting of a contraceptive, a non-steroidal anti-rheumatic agent, an analgetic, an androgen other than a 17-alpha-alkyl substituted testosterone, or any combinations thereof, for the preparation of a medicament for the therapeutic management of extrauterine proliferation of endometrial tissue, chronic pelvic pain and/or fallopian tube obstruction (FTO), wherein the LHRH antagonist is administered starting on cycle day [I:\DayLib\LIBH03 104.doc:UG one to day three in the formn of a short-term induction treatment for a period of about 4 to 12 weeks to a patient in need of such treatment such that the estrogen serum concentration level is between about 35 pg/mi and 80 pg/mi, then the' administration of the LHRH antagonist is ceased, and wherein the one or more active agent selected from the group consisting of a contraceptive, a non-steroidal anti-rheumatic agent, an analgetic, an androgen other than a 1 7-alpha-alkyl substituted testosterone, or any combinations thereof, are administered together or separately to the patient. Use of an LHRH antagonist and one or more active agents according to claim 49, wherein said contraceptive is an oral contraceptive.

51. Use of an LHRH antagonist and one or more active agents according to claim 49 or 50, wherein the LHRH antagonist is administered such that the estrogen serum concentration level is between about 45 and about 75 pg/mi.

52. Use of an LHRH antagonist and one or more active agents according to claim 51, wherein the LHRLH antagonist is administered such that the estrogen serum concentration level is between about 50 and about 75 pg/ml.

53. Use of an LHRH antagonist and one or more active agents according to any one of claims 49 to 52, wherein the short-term induction treatment with the LHRH antagonist is followed by administration of a contraceptive.

54. Use of an LHRH antagonist and one or more active agents according to claim 53, wherein said contraceptive is an oral contraceptive. Use of an LHRH antagonist and one or more active agents according to any o: one of claims 49 to 52, wherein the short-term induction treatment with the LHRH antagonist is followed by administration of a non-steroidal anti-rheumatic agent.

56. Use of an LHRH antagonist and one or more active agents according to any 25~ one of claims 49 to 52, wherein the short-termn induction treatment with the LHRH 000 antagonist is followed by administration of an analgetic.

57. Use of an LHRH antagonist and one or more active agents according to any one of claims 49 to 52, wherein the short-term induction treatment with the LHRH antagonist is followed by administration of an androgen other than a 17-aipha-alkyl substituted testosterone.

58. Use of an LHRH anaoitand one or more active agnsacrigto any one of claims 49 to 52, wherein the short-term induction treatment with the LHRH 0:0. :antagonist is followed by the combined or separate administration of one or more active agents selected from the group consisting of a contraceptive, a non-steroidal anti- [i:\DayLib\LIBH]O3 104.doc:UG rheumatic agent, an analgetic, an androgen other than a 17-alpha-alkyl substituted testosterone or any combinations thereof.

59. Use of an LHRH antagonist and one or more active agents according to claim 58, wherein said contraceptive is an oral contraceptive.

60. Use of an LHRH antagonist and one or more active agents according to any one of claims 49 to 59 wherein the LHRH antagonist is selected from the group consisting of cetrorelix, teverelix, ganirelix, antide, abarelix and D-63153.

61. Use of an LHRH antagonist and one or more active agents according to any one of claims 49 to 60 wherein the LHRH antagonist is administered during the short- term induction treatment for about 4 to 12 weeks at a weekly dose of about 3 to 10 mg per week.

62. Use of an LHRH antagonist and one or more active agents according to any one of claims 49 to 60 wherein the LHRH antagonist is administered during the short- term induction treatment for about 4 to 12 weeks at a daily dose of about 0.25 mg to mg/day.

63. Use of an LHRH antagonist and one or more active agents according to any one of claims 49 to 60 wherein the LHRH antagonist is administered during the short- term induction treatment for about 4 to 12 weeks at a monthly dose of about 12 to 40 mg per month.

64. Use of an LHRH antagonist and one or more active agents according to any one of claims 41 to 60 wherein the LHRH antagonist is given for the induction treatment during about 4 to 12 weeks and the treatment is repeated two or three times a year.

65. In a method of therapeutic management of extrauterine proliferation of endometrial tissue, chronic pelvic pain and/or fallopian tube obstruction (FTO), the 25 improvement consisting of administration on menstrual cycle day one to three of an S• LHRH antagonist and one or more active agents selected from the group consisting of a contraceptive, a non-steroidal anti-rheumatic agent, an analgetic, an androgen other than a 17-alpha-alkyl substituted testosterone, or any combinations thereof, in the form of a short-term induction treatment for a period of about 4 to 12 weeks to a patient in need of such treatment such that the estrogen serum concentration level is between about pg/ml and about 80 pg/ml, whereby subsequently the administration of the LHRH antagonist is ceased, and wherein the one or more active agent selected from the group consisting of a contraceptive, a non-steroidal anti-rheumatic agent, an analgetic, an androgen other than a 17-alpha-alkyl substituted testosterone, or any combinations thereof, are administered together or separately to the patient. [I:\DayLib\LIBH]03104.doc:LUG

66. The method according to claim 65, wherein said contraceptive is an oral contraceptive.

67. The method according to claim 65 or 66, wherein the LHRH antagonist is administered such that the estrogen serum concentration level is between about 45 and about 75 pg/ml.

68. The method according to claim 67, wherein the LHRH antagonist is administered such that the estrogen serum concentration level is between about 50 and about 75 pg/ml.

69. The method according to any one of claims 65 to 68, wherein the short-term induction treatment with the LHRH antagonist is followed by administration of a contraceptive. The method according to claim 69, wherein said contraceptive is an oral contraceptive.

71. The method according to any one of claims 65 to 68, wherein the short-term induction treatment with the LHRH antagonist is followed by administration of a non- steroidal anti-rheumatic agent.

72. The method according to any one of claims 65 to 68, wherein the short-term induction treatment with the LHRH antagonist is followed by administration of an analgetic.

73. The method according to any one of claims 65 to 68, wherein the short-term induction treatment with the LHRH antagonist is followed by administration of an o .androgen other than a 17-alpha-alkyl substituted testosterone.

74. The method according to any one of claims 65 to 68, wherein the short-term induction treatment with the LHRH antagonist is followed by the combined or separate administration of one or more active agents selected from the group consisting of a contraceptive, a non-steroidal anti-rheumatic agent, an analgetic, an androgen other than a 17-alpha-alkyl substituted testosterone or any combinations thereof. The method according to claim 74, wherein said contraceptive is an oral contraceptive.

76. The method according to any one of claims 65 to 75, wherein the LHRH antagonist is selected from the group consisting of cetrorelix, teverelix, ganirelix, antide, abarelix and D-63153.

77. The method according to any one of claims 65 to 76, wherein the LHRH antagonist is administered during the short-term induction treatment for about 4 to 12 weeks at a weekly dose of about 3 to 10 mg per week. [I:\DayLib\LIBH]03104.doc:UG sifw, swK^^

78. The method according to any one of claims 65 to 76, wherein the LHRH antagonist is administered during the short-term induction treatment for about 4 to 12 weeks at a daily dose of about 0.25 mg to 0.5 mg/day.

79. The method according to any one of claims 65 to 76, wherein the LHRH antagonist is administered during the short-term induction treatment for about 4 to 12 weeks at a monthly dose of about 12 to 40 mg per month. The method according to any one of claims 65 to 76, wherein the LHRH antagonist is given for the induction treatment during about 4 to 12- weeks and the treatment is repeated two or three times a year. Dated 26 November, 2003 Zentaris AG Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON 0* 0**0 S 0 00 0 [1\DayLb\LBH]03 04.doc: UG