RU2255759C2 - Method for therapeutic treatment of extrauterine proliferation of endometrial tissue chronic pain in pelvis region caused by thereof and fallopian tubes impenetrability - Google Patents

Abstract

FIELD: medicine, gynecology.

SUBSTANCE: invention relates to treatment of endometriosis and state associated with it. Method involves administration of LHRH antagonist by courses for 4-12 weeks. Also, method involves additional simultaneous and successive administration of nonsteroid anti-inflammatory agents, analgesic agents, contraceptive preparations and androgens. Invention provides prophylaxis of relapses of endometriosis symptoms in the absence of symptoms of estrogenic insufficiency.

EFFECT: improved and valuable method for treatment.

17 cl, 2 dwg

Description

FIELD OF THE INVENTION

Endometriosis is one of the most common pathologies diagnosed in gynecological patients. For example, in the United Kingdom and the USA, between 10% and 25% of women with symptoms of gynecological diseases are affected by this disease. A clinical diagnosis is usually made with a laparoscopic examination of hemorrhagic or fibrotic sites on the pelvic organs. Ectopic (with unusual localization) endometrial tissue undergoes cyclic changes in response to ovarian hormones. Cyclical bleeding from endometrial deposits contributes to the local inflammatory response. Endometriosis usually affects women of childbearing age with a frequency of at least 1% (see Shaw R.W., Atlas of Endometriosis, The Parthenon Publishing Group, (1993)).

Endometriosis is usually classified as follows: internal genital endometriosis (adenomyosis), external genital endometriosis, and extragenital endometriosis.

Chronic pelvic pain can either be caused by endometriosis, or be an independent disease.

Fallopian tube obstruction (NFT) is a relatively common disease and can cause up to 20% of cases of tubal infertility (see Winfield AC et al., Apparent cornual occlusion in hysterosalpingography and its restoration using glucagon (Apparent cornual occlusion in hysterosalpingography: Reversal by glucagon), AJR Am. J. Roentgenol., 139: 525-527, (1982)).

State of the art

Sampson suggested that menstrual regurgitation and subsequent implantation of endometrial tissue on the surface of the peritoneum leads to endometriosis [see Sampson J.A., Peritoneal endometriosis due to menstrual dissemination of the endometrial tissue into the peritoneal cavitiy, Am. J. Obstet. Gynecol., 14: 422, (1927)]. A number of etiological factors may participate in the pathogenesis of endometriosis: Dmowski et al. have suggested that genetic and immunological factors lead to endometriosis [see article by Dmowski W. P., Steele R.W. and Baker G.F., Cellular Immunodeficiency in Endometriosis (Deficient cellular immunity in endometriosis), Am. J. Obstet. Gynecol., 141, 377, (1981)]. Embolization of blood vessels and the lymphatic network in distant areas has been demonstrated, and it explains the (rare) cases of endometriosis outside the peritoneal cavity, for example, cutaneous, pulmonary, renal endometriosis.

The cells lining the muller duct come from stem cells that differentiate into peritoneal cells and cells on the surface of the ovaries. It is believed that these mature cells undergo reverse de-differentiation to their stem nature, and then transform into endometrial cells [see Levander G. article, Bone formation by induction. Experimental study (Bone formation by induction. An experimental study), Arch. Klin. Chir., 202, 497, (1941)]. Dysmenorrhea, acute or chronic pelvic pain, dyspareunia and infertility are the most common of the described clinical symptoms.

NFT is a heterogeneous group of this pathology, which is based on internal occlusion or external compression due to estrogen-sensitive disorders, such as endometriosis, adenomyosis, endosalpingitis and myoma. In addition to laparoscopy, NFT is usually diagnosed using hysterosalpingography.

Treatment of the first choice involves laparoscopic removal of endometrial formations. This procedure may be followed by treatment with a danazole or LHRH agonist (for six months). During treatment with danazolum, women may experience gastrointestinal and liver disorders, as well as severe androgenic side effects.

From a theoretical point of view, it was also proposed to use direct suppression for the treatment of endometriosis and uterine fibroids by introducing an LHRH antagonist in order to reduce the duration of treatment and accelerate the improvement of subjective symptoms [see article Th. Reissmann et al., Human Reproduction, T. 10, No. 8, pp. 1974-1981, (1995)].

Further, Hodgen in US Pat. No. 5,658,884 describes a therapeutic regimen for treating a condition dependent on the gonads by reducing estrogen intake by prolonged administration of a GnRH antagonist (gonadotropin releasing hormone) for 6 months or more in an amount that effectively suppresses endometrial tissue proliferation, practically without blocking the formation of endogenous estrogen. To this end, Hodgen presents such a schedule or dose of a GnRH antagonist at which serum estradiol levels are achieved within 24 hours in the range of about 25 to 50, and preferably about 35 to 45 pg / ml. However, Hodgen does not describe serum estradiol levels ranging between 50 pg / ml and 75 pg / ml. Moreover, Hodgen presents in US Pat. No. 5,658,884 only continuous continuous treatment (based on daily or periodic administrations, the latter mean weekly or monthly administration), but not a short-term stimulating treatment for only 4-12 weeks. Hodgen also does not describe some combination therapy using a GnRH antagonist in the treatment of endometriosis. The treatment is described only on monkeys and also includes an expensive and repeated test for stimulating the administration of progesterone to obtain an average serum estradiol level of 24-50 pg / ml over 24 hours.

As a consequence of the short duration of the effect of therapy using the LHRH agonist, exacerbation of the symptoms of the disease could occur over several days. After prolonged treatment, which is required to avoid repeated proliferation of endometrial tissue, symptoms of hormone withdrawal appear, as well as bone demineralization.

Therefore, effective drug therapy should directly reduce the amount of residual ectopic endometrial tissue present after laparoscopic surgery.

The duration of therapy should be only 4-12 weeks without the appearance of any major symptoms of hormone withdrawal or the formation of an ovarian cyst.

LHRH antagonists cause rapid suppression of hormones and as a result, benign gynecological tumors, such as uterine fibroids, decrease after a short period of time [see Journal of Human Reproduction, 13, (1998)].

SUMMARY OF THE INVENTION

This invention relates to the improvement of drug therapy for ectopic proliferation of endometrial tissue, i.e. administering LHRH antagonists to patients with clinical symptoms of endometriosis, the improvement consisting of:

a direct reduction in the amount of ectopic endometrial tissue,

immediate cessation of symptoms, such as acute pain, chronic pelvic pain, and dysmenorrhea,

prevention of any development of the disease,

avoid the symptoms of hormone withdrawal,

prevention of ovarian cyst formation, bone demineralization, as well as disorders of the gastrointestinal tract and liver.

According to the invention, drug therapy can be started in the early to middle follicular phase, preferably on the first to third day of the menstrual cycle. During treatment, serum estradiol levels are maintained between 35 pg / ml and 80 pg / ml, preferably between about 45-75 pg / ml, more preferably between about 50-75 pg / ml. The LHRH antagonist is administered only for 4-12 weeks (short-term stimulant treatment) by either daily, weekly or monthly administration. According to this invention, after short-term stimulating treatment, a contraceptive, non-steroidal antirheumatic agent, analgesic, androgen other than 17-α-alkyl substituted testosterone, or any combination thereof, is administered.

When treating ectopic endometrial tissue with an LHRH antagonist, therapy is started on the first to third day of the menstrual cycle. Before starting therapy using an LHRH antagonist, a laparoscopy is made. In cases of severe pain, therapy with the LHRH antagonist should be started without prior laparoscopy.

Treatment will continue until the clinical symptoms disappear and until endometrial proliferation ceases. Further proliferation of the endometrium does not occur due to the immediate suppression of gonadotropins LH (luteinizing hormone) and FSH (follicle-stimulating hormone), as well as sex steroids estradiol and progesterone. Benign tumors or other sex steroid-dependent lesions, like endometriosis, are reduced within four to twelve weeks of therapy. Due to the long-term effect, ovarian cysts do not develop.

In addition, there are no symptoms of hormone withdrawal, since estradiol values are maintained in the corresponding early follicular phase in the range of 35-80 pg / ml, preferably between about 45-75 pg / ml, more preferably between about 50-75 pg / ml without further increase or decrease. Determination of the titer of the dose of the LHRH antagonist, for example by conducting an expensive test for the stimulating administration of progesterone, is not necessary.

As a consequence, an improvement in the method of therapeutic treatment of ectopic proliferation of endometrial tissue according to the invention covers:

direct reduction in the amount of ectopic endometrial tissue,

prevention of any development of the disease,

avoid the symptoms of hormone withdrawal,

prevention of ovarian cyst formation, bone demineralization, as well as disorders of the gastrointestinal tract and liver,

initiation of drug therapy on the first to third day of the cycle and maintenance of estradiol levels at values characteristic of the early follicular phase throughout the treatment period by administration of the LHRH antagonist, where the antagonist is preferably represented by cetrorelix, teverelix, ganrelix, antidum or abarelix. The antagonist may also be represented by the LHRH antagonist D-63153 (Ac-D-Nal-D-pCI-Phe-D-Pal-Ser-N-Me-Tyr-D-Hci-Nle-Arg-Pro-D-Ala-NHg ), as described in German Patent Application No. 19911771.3, filed March 11, 1999.

The LHRH antagonist can be used for 4-12 weeks with a weekly dose of 3-10 mg / week or for 4-12 weeks with a daily dose of 0.25 mg to 0.5 mg / day.

It is also possible to use an LHRH antagonist for 4-12 weeks in a monthly dose of 12-40 mg / month.

With repeated therapeutic treatment, the LHRH antagonist is used for 4-12 weeks and the treatment is repeated two or three times a year, while the repeated course of treatment is not carried out immediately after short-term stimulating treatment. Typically, the period of weeks or months during which the LHRH antagonist is not administered is between the end of the short-term stimulant treatment and the start of re-treatment.

To demonstrate the ability to maintain estradiol secretion at a low level with selected treatment with an LHRH antagonist that provides therapeutic suppression without withdrawal symptoms, nine patients with a confirmed diagnosis of endometriosis were injected subcutaneously with 3 mg of cetrorelix acetate with weekly administration for 8 weeks. Since the patients tolerated the treatment regimen in the absence of any flushing or other withdrawal symptoms and without any signs of the development of the disease, confirmed by repeated laparoscopic examination, the average serum estradiol concentrations ranged between 37 pg / ml and 64 pg / ml, preferably between 45 -75 pg / ml, more preferably between about 50-75 pg / ml. Histological biopsy specimens showed no endometrial proliferation at the end of treatment. The formation of ovarian cysts did not occur.

List of figures of drawings and other materials

The Figure 1 shows the continuous suppression of estradiol levels to values corresponding to the early follicular phase (in the range from 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 with weekly administration of Cetrorelix (LHRH antagonist) at a dose of 3 mg for 8 weeks. Immediate and continuous suppression of estradiol levels was obtained without any signs of estradiol withdrawal symptoms and without endometrial proliferation at the end of treatment.

The Figure 2 presents the levels of estradiol in serum after weekly administration of cetrorelix in a dose of 1 mg to 3 mg once / week. Serum estradiol levels are between about 35-80 pg / ml, preferably between about 45-75 pg / ml, more preferably between about 50-75 pg / ml. Information confirming the possibility of carrying out the invention

A patient with endometriosis with characteristic symptomatic pain suffers from a chronic disease. Surgical methods as a method of treatment, as well as drug therapy to suppress the secretion of sex steroids in a patient, often result in only temporary improvement. The rate of relapse of the ailments is very high and amounts to approximately 70% within 5 years after the end of treatment (see Schweppe, 1999).

At the same time, radical surgery and suppression of estrogen secretion lead to significant side effects. Radical surgery in the form of a hysterectomy (hysterectomy) with bilateral adnexectomy (bilateral removal of the appendages) is not an adequate treatment for young women in premenopause. Chronic estrogen deficiency leads to the following vegetative symptoms: hot flashes, sweating, dry vagina, depression, and also carries the risk of developing osteoporosis. Alternative therapy with the synthetic steroid compound danazol may cause symptoms of masculinization due to the androgenic effect.

The goal of drug therapy for patients with symptomatic pain with endometriosis is to develop a treatment without side effects, in particular to avoid the negative effects of estrogen suppression, which, in this case, acts for a long period after the end of treatment. The specific pharmacological mode of action of LHRH antagonists presents new possibilities for the treatment of endometriosis.

Weekly administration of an appropriate dose of an LHRH antagonist, for example, subcutaneous administration of 3 mg of cetrotide® / week for eight weeks, results in controlled suppression of estrogen secretion, resulting in serum concentrations between about 35 pg / ml and about 80 pg / ml, preferably between about 45 -75 pg / ml, more preferably between about 50-75 pg / ml. In this range of serum concentrations, no autonomic symptoms occur. Osteoporosis can also be avoided. Symptomatic pain can be effectively suppressed at all stages of the disease (rAFS I-IV, where AFS is the American Trauma Society). At the stages of rAFS I-II, clinical regression of the disease was noted in terms of reducing the area of implantation (see the work of Felberbaum et al., 2000).

In a preferred embodiment of the invention, after this period of eight to twelve weeks, the patient could take a contraceptive, preferably an oral contraceptive, preferably with gestagenic components, until the desire to become pregnant appears. In this regard, mention should be made of combinations containing 2 mg of linestrenol and 0.04 mg of ethinyl estradiol or 2.5 mg of linestrenol and 0.05 mg of ethinyl estradiol (e.g. Yermonil® Lyn-ratiopharm-Sequenz®).

Combination therapy using androgens other than 17-α-alkyl substituted testosterones, such as danazole, can also be used after a short-term stimulation regimen with the LHRH antagonist, either as monotherapy or in combination with non-steroidal antirheumatic agents and / or analgesics. An example of a suitable androgen is halotestin ™ (fluoxymesterone).

Treatment using a contraceptive, preferably a contraceptive for oral administration, preferably containing progestogens, should be continued in individual cases until there is a pain sensation. At this stage, the patient will have relatively weak menstrual bleeding as a result of the action of the progestogen component of this contraceptive, preferably a contraceptive for oral administration. In order to also cover the most critical premenstrual and menstrual days in terms of pain, in this phase, concomitant drug therapy with appropriate non-steroidal anti-rheumatic drugs, for example diclofenac, ibuprofen, indomethacin, derivatives of oxycam or acetylsalicylic acid, can be prescribed. It is also possible to use an analgesic such as flupirtine maleate (Katadolon®).

If further pain symptoms persist during combination therapy with gestagen contraceptives, preferably oral contraceptives, daily, weekly or monthly treatment with appropriate doses of the LHRH antagonist, as described above, can be repeated. Detailed information on the respective treatment conditions is given below. If the patient has absolutely no pain, the treatment can be replaced with a progestogen contraceptive, preferably a contraceptive for oral use, in combination with concomitant medication with appropriate non-steroidal antirheumatic drugs or analgesics.

This method of therapy using the introduction of the LHRH antagonist with interruptions leads to the creation of a new and more rational treatment that has no limitations in the absence of side effects and significantly reduces the drug load in the patient.

Pharmaceutical preparations suitable for treatment.

Pharmaceutical preparations of the LHRH antagonist suitable for the therapeutic treatment of ectopic proliferation of endometrial tissue, chronic pelvic pain and obstruction of the fallopian tubes can be presented, for example:

a) acetates of preparations at a concentration of 1 mg / 1 ml or lower, in which the powder can be dissolved in water for injection (v / i) or gluconic acid (HA);

b) acetates of preparations in a concentration of from 1.5 mg / 1 ml to 5.0 mg / 1 ml, preferably 2.5 mg / 1 ml, in which the powder can be dissolved in water for injection (v / i) or gluconic acid (GK);

c) preparation pamoates in a concentration of from 10 mg / ml to 30 mg / ml, preferably 15 mg / ml, in which the lyophilisate powder can be dissolved in gluconic acid (HA) or water for injection (v / v).

According to one aspect of the present invention, there is provided a method for the therapeutic treatment of ectopic proliferation of endometrial tissue, chronic pelvic pain and / or fallopian tube obstruction (NFT), the improvement of which consists in administering an LHRH antagonist to a patient in need of this treatment in the form of a short-term stimulating treatment during approximately 4-12 weeks, followed by cessation of administration of the LHRH antagonist.

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

According to another aspect of the present invention, the aforementioned method provides an improvement in which the LHRH antagonist is administered such that the serum estrogen concentration level is between about 35 pg / ml and about 80 pg / ml, preferably between about 45-75 pg / ml, more preferably between about 50-75 pg / ml.

According to another aspect of the present invention, the aforementioned method provides an improvement characterized in that after a short stimulating treatment with an LHRH antagonist, a contraceptive preparation, preferably a contraceptive preparation for oral administration, is administered.

According to another aspect of the present invention, the aforementioned method provides an improvement characterized in that after a short-term stimulant treatment with an LHRH antagonist, administration of a non-steroidal antirheumatic agent follows.

According to another aspect of the present invention, an improvement is provided in the aforementioned method, characterized in that after a short stimulant treatment with an LHRH antagonist, an analgesic is administered.

According to another aspect of the present invention, the aforementioned method provides an improvement characterized in that after a short stimulant treatment with an LHRH antagonist, an androgen other than 17-α-alkyl substituted testosterone is administered.

According to another aspect of the present invention, the aforementioned method provides an improvement characterized in that, after a short stimulant treatment with an LHRH antagonist, there should be a combined or separate administration of at least one active agent selected from the group consisting of a contraceptive preparation, preferably a contraceptive preparation for oral administration, a non-steroidal antirheumatic agent, analgesic, androgen, other than 17-α-alkyl-substituted testosterone a, or any combination thereof.

According to another aspect of the present invention, an improvement is provided in the aforementioned method, characterized in that the LHRH antagonist is administered starting from the early to middle follicular phase, preferably on the first to third days of the cycle.

According to another aspect of the present invention, the above method provides an improvement 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, the aforementioned method provides an improvement characterized in that the LHRH antagonist is administered during a short-term stimulant treatment for 4-12 weeks at a weekly dose of 3-10 mg / week.

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

According to another aspect of the invention, the aforementioned method provides an improvement characterized in that the LHRH antagonist is administered during a short-term stimulant treatment for about 4-12 weeks at a monthly dose of about 12-40 mg / month.

According to another aspect of the present invention, the aforementioned method provides an improvement characterized in that the LHRH antagonist is used for stimulant treatment for about 4-12 weeks and the treatment is repeated two or three times a year.

According to a further aspect of the present invention, there is provided a pharmaceutical composition for treating ectopic proliferation of endometrial tissue, chronic pelvic pain and / or fallopian tube obstruction (NFT), comprising an LHRH antagonist and optionally at least one agent selected from the group consisting of a contraceptive preparation preferably a contraceptive for oral administration, a non-steroidal antirheumatic agent, an analgesic, androgen other than 17-α-alkyl substituted t stosterone or any combination thereof, optionally with pharmaceutically acceptable excipients, wherein the LHRH antagonist is administered to a patient in need of a short-term stimulant treatment for about 4-12 weeks, then the administration of the LHRH antagonist is discontinued and optionally the patient is administered together or separately at least one an agent selected from the group consisting of a contraceptive, preferably a contraceptive for oral administration, a non-steroidal anti-rheumatic agent a, analgetic, an androgen other than a 17-α-alkyl substituted testosterone or any combinations thereof.

Suitable excipients or dosage forms are described, for example, in the monograph of K.N. Bauer, K.-H. Frömming and C. Führer, Pharmaceutical Technology Handbook (Lehrbuch der Pharmazeutischen Technologie), 6th ed., Stuttgart, pp. 163-186 (excipients) and pp. 227-386 (dosage forms), (1999), including references cited in this context.

For example, an LHRH antagonist can be administered subcutaneously (s.c.), intramuscularly (i.m.), or inhaled. Agents selected from the group consisting of a contraceptive, preferably a contraceptive for oral administration, a non-steroidal antirheumatic agent, analgesic, androgen other than 17-α-alkyl substituted testosterone, or any combination thereof, may be administered as is known in the art ( see, for example, German and European Pharmacopoeia or US Pharmacopoeia), preferably orally or by inhalation.

According to another aspect of the present invention, the aforementioned pharmaceutical composition is provided wherein the LHRH antagonist is administered in such a way that the serum estrogen concentration 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, there is provided the aforementioned pharmaceutical composition, the use of which, after a short stimulant treatment with an LHRH antagonist, is followed by the administration of a contraceptive preparation, preferably a contraceptive preparation for oral administration.

According to another aspect of the present invention, the aforementioned pharmaceutical composition is provided, the use of which, after a short stimulant treatment with an LHRH antagonist, is followed by the administration of a non-steroidal anti-rheumatic agent.

According to another aspect of the present invention, there is provided the aforementioned pharmaceutical composition, the use of which, after a short stimulating treatment with an LHRH antagonist, is followed by administration of an analgesic.

According to another aspect of the present invention, the aforementioned pharmaceutical composition is provided, the use of which, after a short stimulating treatment with an LHRH antagonist, is followed by the administration of an androgen other than 17-α-alkyl substituted testosterone.

According to another aspect of the present invention, there is provided the aforementioned pharmaceutical composition, the use of which, after a short stimulating treatment with an LHRH antagonist, should be combined or separate administration of at least one active agent selected from the group consisting of a contraceptive preparation, preferably a contraceptive preparation for oral administration, a non-steroidal antirheumatic agent , analgesic, androgen, other than 17-α-alkyl-substituted testostero on, or any combination thereof.

According to another aspect of the present invention, the aforementioned pharmaceutical composition is provided wherein the LHRH antagonist is administered from the early to middle follicular phase, preferably on the first to third days of the cycle.

According to another aspect of the present invention, the aforementioned pharmaceutical composition 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 aforementioned pharmaceutical composition is provided wherein the LHRH antagonist is administered during a short-term stimulant treatment for 4-12 weeks at a weekly dose of 3-10 mg / week.

According to another aspect of the invention, the aforementioned pharmaceutical composition is provided, wherein the LHRH antagonist is administered during a short-term stimulant treatment for 4-12 weeks at a daily dose of 0.25 mg to 0.5 mg / day.

According to another aspect of the invention, the aforementioned pharmaceutical composition is provided, wherein the LHRH antagonist is administered during a short-term stimulant treatment for about 4-12 weeks at a monthly dose of about 12-40 mg / month.

According to another aspect of the invention, the aforementioned pharmaceutical composition is provided in which the LHRH antagonist is used for stimulant treatment for about 4-12 weeks and the treatment is repeated two or three times a year.

According to another aspect of the present invention, there is provided the aforementioned pharmaceutical composition in which at least one active agent selected from the group consisting of a contraceptive, preferably a contraceptive for oral administration, a non-steroidal anti-rheumatic agent, an analgesic, an androgen other than 17-α-alkyl -substituted testosterone, or any combination thereof, are in the same or separate dosage forms.

According to another aspect of the present invention, there is provided the use of an LHRH antagonist for the manufacture of a medicament for the therapeutic treatment of ectopic proliferation of endometrial tissue, chronic pelvic pain and / or fallopian tube obstruction (NFT), in which an LHRH antagonist is administered to a patient in need of this treatment in the form short-term stimulant treatment for approximately 4-12 weeks, followed by cessation of administration of the LHRH antagonist.

According to another aspect of the present invention, there is provided the use of the aforementioned LHRH antagonist, wherein the LHRH antagonist is administered such that the serum estrogen concentration is between about 35 pg / ml and about 80 pg / ml, preferably between about 45-75 pg / ml, more preferably between about 50-75 pg / ml.

According to another aspect of the present invention, there is provided the use of the aforementioned LHRH antagonist, wherein, after a short stimulant treatment with the LHRH antagonist, a contraceptive preparation, preferably a contraceptive preparation for oral administration, is administered.

According to another aspect of the present invention, there is provided the use of the aforementioned LHRH antagonist, wherein, after a short stimulant treatment with the LHRH antagonist, administration of a non-steroidal antirheumatic agent follows.

According to another aspect of the present invention, there is provided the use of the aforementioned LHRH antagonist, wherein, after a short stimulant treatment with the LHRH antagonist, an analgesic is administered.

According to another aspect of the present invention, there is provided the use of the aforementioned LHRH antagonist, wherein, after a short stimulant treatment with the LHRH antagonist, administration of an androgen other than 17-α-alkyl substituted testosterone follows.

According to another aspect of the present invention, there is provided the use of the aforementioned LHRH antagonist, wherein, after a short stimulant treatment with the LHRH antagonist, there should be a combined or separate administration of at least one active agent selected from the group consisting of a contraceptive preparation, preferably a contraceptive preparation for oral administration, a non-steroidal anti-rheumatic agent , analgesic, androgen other than 17-α-alkyl substituted testosterone, or any of their bination.

According to another aspect of the present invention, there is provided the use of the aforementioned LHRH antagonist, wherein the LHRH antagonist is administered from the early to middle follicular phase, preferably on the first to third days of the cycle.

According to another aspect of the present invention, there is provided the use of the aforementioned LHRH antagonist, 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, there is provided the use of the aforementioned LHRH antagonist, wherein the LHRH antagonist is administered during a short-term stimulant treatment for about 4-12 weeks at a weekly dose of 3 to 10 mg / week.

According to another aspect of the present invention, there is provided the use of the aforementioned LHRH antagonist, wherein the LHRH antagonist is administered during a short-term stimulant treatment for about 4-12 weeks at a daily dose of 0.25 mg to 0.5 mg / day.

According to another aspect of the present invention, there is provided the use of the aforementioned LHRH antagonist, wherein the LHRH antagonist is administered for a short-term stimulant treatment for about 4-12 weeks at a monthly dose of 12 to 40 mg / month.

According to another aspect of the present invention, there is provided the use of the aforementioned LHRH antagonist, wherein the LHRH antagonist is used for stimulant treatment for about 4-12 weeks and the treatment is repeated two or three times a year.

According to another aspect of the present invention, there is provided the use of an LHRH antagonist and at least one active agent selected from the group consisting of a contraceptive, preferably a contraceptive for oral administration, a non-steroidal antirheumatic agent, an analgesic, androgen other than 17-α-alkyl-substituted testosterone, or any combination thereof for the preparation of a medicament for the therapeutic treatment of ectopic proliferation of endometrial tissue, chronic pelvic pain and / or obstruction of the fallopian tubes (NFT), in which the LHRH antagonist is administered to a patient in need of this treatment in the form of a short-term stimulant treatment for about 4-12 weeks, then the administration of the LHRH antagonist is stopped and the patient is administered together or separately at least one active agent selected from the group consisting of a contraceptive, preferably a contraceptive for oral administration, a non-steroidal antirheumatic agent, an analgesic , An androgen other than a 17-α-alkyl substituted testosterone or any combinations thereof.

According to another aspect of the present invention, there is provided the use of an LHRH antagonist and at least one of the aforementioned active agent, wherein the LHRH antagonist is administered such that the serum estrogen concentration level is between about 35 pg / ml and about 80 pg / ml, preferably between about 45 -75 pg / ml, more preferably between about 50-75 pg / ml.

According to another aspect of the present invention, there is provided the use of an LHRH antagonist and at least one of the aforementioned active agent, wherein a short-term stimulant treatment with an LHRH antagonist is followed by the administration of a contraceptive preparation, preferably a contraceptive preparation for oral administration.

According to another aspect of the present invention, there is provided the use of an LHRH antagonist and at least one of the aforementioned active agent, wherein, after a short stimulant treatment with an LHRH antagonist, administration of a non-steroidal antirheumatic agent follows.

According to another aspect of the present invention, there is provided the use of an LHRH antagonist and at least one of the aforementioned active agent, wherein, after a short stimulant treatment with an LHRH antagonist, an analgesic is administered.

According to another aspect of the present invention, there is provided the use of an LHRH antagonist and at least one of the aforementioned active agent, wherein administration of an androgen other than 17-α-alkyl substituted testosterone follows a short stimulant treatment with an LHRH antagonist.

According to another aspect of the present invention, there is provided the use of an LHRH antagonist and at least one of the aforementioned active agent, and after a short stimulant treatment with an LHRH antagonist, a combined or separate administration of at least one active agent selected from the group consisting of a contraceptive preparation, preferably a contraceptive preparation for oral administration, non-steroidal antirheumatic agent, analgesic, androgen, other than 17-α-alkylzame ennogo testosterone, or any combinations thereof.

According to another aspect of the present invention, there is provided the use of an LHRH antagonist and at least one of the aforementioned active agent, wherein the LHRH antagonist is administered starting from the early to middle follicular phase, preferably on the first to third days of the cycle.

According to another aspect of the present invention, there is provided the use of an LHRH antagonist and at least one of the aforementioned active agent, 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, there is provided the use of an LHRH antagonist and at least one of the aforementioned active agent, wherein the LHRH antagonist is administered for a short-term stimulant treatment for 4-12 weeks at a weekly dose of 3 to 10 mg / week.

According to another aspect of the present invention, there is provided the use of an LHRH antagonist and at least one of the aforementioned active agent, wherein the LHRH antagonist is administered for a short-term stimulant treatment for about 4-12 weeks at a daily dose of 0.25 mg to 0.5 mg / day .

According to another aspect of the present invention, there is provided the use of an LHRH antagonist and at least one of the aforementioned active agent, wherein the LHRH antagonist is administered for a short-term stimulant treatment for about 4-12 weeks at a monthly dose of 12 to 40 mg / month.

According to another aspect of the present invention, there is provided the use of an LHRH antagonist and at least one of the aforementioned active agent, wherein the LHRH antagonist is used for stimulant treatment for 4 to 12 weeks and the treatment is repeated two or three times a year.

Claims (17)

1. A method for the therapeutic treatment of ectopic proliferation of endometrial tissue, in particular endometriosis, or the therapeutic treatment of chronic pelvic pain and / or fallopian tube obstruction due to ectopic proliferation of endometrial tissue, comprising administering an LHRH antagonist to a patient in need of this treatment, in that the LHRH antagonist is administered for about 4-12 weeks, after which, after a period of several weeks or months, it is not necessary to re-administer e LHRH antagonist for approximately 4-12 weeks. 2. The method according to claim 1, characterized in that the LHRH antagonist is administered at such doses that the serum estrogen concentration is between about 35 pg / ml and about 80 pg / ml, preferably between about 45-75 pg / ml, more preferably between about 50-75 pg / ml. 3. The method according to claim 1, characterized in that after the short-term treatment with an LHRH antagonist, a contraceptive is administered, preferably a contraceptive for oral administration. 4. The method according to claim 1, characterized in that after the aforementioned short-term treatment with an LHRH antagonist, a non-steroidal antirheumatic agent is administered. 5. The method according to claim 1, characterized in that after the short-term treatment with an LHRH antagonist, an analgesic is administered. 6. The method according to claim 1, characterized in that after the aforementioned short-term treatment with an LHRH antagonist, an androgen other than 17α-alkyl substituted testosterone is administered. 7. The method according to claim 1, characterized in that after said short-term treatment with an LHRH antagonist, at least one active agent selected from the group consisting of a contraceptive preparation, preferably a contraceptive preparation for oral administration, a non-steroidal anti-rheumatic agent, an analgesic is administered in combination or separately , androgen other than 17α-alkyl substituted testosterone, or any combination thereof. 8. The method according to claim 1, characterized in that the LHRH antagonist is administered starting from the early to middle follicular phase, preferably on the first to third days of the cycle. 9. The method according to claim 1, characterized in that the LHRH antagonist is selected from the group consisting of cetrorelix, teverelix, ganirelix, antide, abarelix and D-63153. 10. The method according to claim 1, characterized in that the LHRH antagonist is administered in a weekly dose of approximately 3-10 mg / week. 11. The method according to claim 1, characterized in that the LHRH antagonist is administered in a daily dose of about 0.25-0.5 mg / day. 12. The method according to claim 1, characterized in that the LHRH antagonist is administered in a monthly dose of approximately 12-40 mg / month. 13. The method according to claim 1, characterized in that the said short-term treatment with an LHRH antagonist is repeated two or three times a year. 14. The use of a pharmaceutical composition comprising an LHRH antagonist and optionally at least one agent selected from the group consisting of a contraceptive, preferably a contraceptive for oral administration, a non-steroidal antirheumatic agent, an analgesic, androgen other than 17α-alkyl substituted testosterone, or any combinations thereof, optionally with pharmaceutically acceptable excipients, as a medicine in a form containing an amount of an LHRH antagonist, current for therapeutic treatment lasting from 4 to 12 weeks extrauterine proliferation of endometrial tissue, in particular endometriosis or chronic pelvic pain and / or fallopian tube obstruction (NFT) due to an ectopic endometrial tissue proliferation. 15. The use according to 14 as a medicine in a form that provides in one or different dosage forms at least one agent selected from the group comprising a contraceptive, preferably a contraceptive for oral administration, a non-steroidal antirheumatic agent, analgesic and androgen different from 17α-alkyl substituted testosterone. 16. The use of an LHRH antagonist as an active ingredient in the preparation of a medicament in a form providing an amount of LHRH antagonist sufficient for therapeutic treatment lasting from 4 to 12 weeks for ectopic proliferation of endometrial tissue, in particular endometriosis, or chronic pelvic pain, and / or obstruction of the fallopian tubes (NFT) due to ectopic proliferation of endometrial tissue. 17. The use of the LHRH antagonist as an active ingredient in combination with at least one active ingredient selected from the group consisting of a contraceptive, preferably a contraceptive for oral administration, a non-steroidal antirheumatic agent, an analgesic, androgen other than 17α-alkyl substituted testosterone and any of them combination, in the preparation of a medicinal product in a form providing therapeutic treatment lasting from 4 to 12 weeks of ectopic proliferation endometrial tissue, in particular endometriosis, or chronic pelvic pain, and / or fallopian tube obstruction (NFT) due to ectopic proliferation of endometrial tissue.

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