Note: Descriptions are shown in the official language in which they were submitted.
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Method for the therapeutic management of extrauterine proliferation of
endometrial tissue, chronic pelvic pain and fallopian tube obstruction
s
Field of Invention
Endometriosis is one of the most frequently encountered pathologies diagnosed
amongst gynecological patients. For example, between 10% and 25% of women
io 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
is 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) interns
(adenomyosis), endometriosis genitalis externs 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
2s 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
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(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
s Dmowski et. al. suggested that genetic and immunological factors lead to
endometriosis [Dmowski, W.P., 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 Mullerian 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
~s 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
20 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.
2s 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
3o 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)]
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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
s 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
75 pg/ml. Moreover, Hodgen only teaches in the US Patent 5,658,884 a
continuous
io 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
is progesterone challenge test to provide an 24 hour average serum estradiol
level of
30 to 50 pglml.
As a consequence of the flare-up effect of LHRH-agonistic therapy an
exacerbation of symptoms might occur during some days. Following prolonged
2o 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
2s 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
30 [Human Reproduction 1998, 13 ]
Object of the Invention
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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
s 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
Io prevention of ovarian cyst formation, demineralization of bones as well as
of
gastrointestinal or hepatic disorders.
The inventive medical therapy 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, preferably
between
is 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
2o combinations thereof is provided according to the present invention.
Summary of the Invention
2s 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
laparascopy.
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
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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.
s 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 pglml, 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.
to
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
is 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
2o 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-pCl-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
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treatment 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.
s
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 "d look laparascopy the
mean
estradiol serum concentrations oscillated between 37 pg/ml and 64 pg/ml,
preferably
between 45-75 pglml, more preferably between about 50-75 pg/ml. Histological
biopsies showed no proliferation of the endometrium at the end of treatment.
No
is ovarian cyst formation occurred.
The figure 1 shows the continuous estradiol suppression to values of the early
follicular phase (range of 35 pglml to 80 pg/ml, preferably between 45-75
pg/ml,
more preferably between about 50-75 pg/ml) obtained in patients with
endometriosis
2o 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.
2s 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
35-
80 pg/ml, preferably between about 45-75 pglml, more preferably between about
50-
75 pg/ml.
3o 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
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temporary improvement. The relapse rate of the discomforts is very high and
about
70% within 5 years after finishing therapy (Schweppe, 1999).
At the same time the radical surgical therapy and the suppression of the
estrogen
s 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
to 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
is 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
2o Cetrotide~ s.c./ per week over a period of eight weeks leads to a
controlled
suppression of estrogen secretion so that serum concentrations between about
35
pg/ml and about 80 pglml, preferably between about 45-75 pglml, 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.
2s 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
3o 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
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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
s 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
non-
steroidal anti-rheumatics andlor analgetics. An example for a suitable
androgene is
halotestinTM (fluoximesterone).
to 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
is 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.
2o 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
2s contraceptive, preferably oral contraceptives 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
3o burden for the patient significantly.
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Pharmaceutical Formulations Suitable for Treatment
Pharmaceutical formulations of the LHRH antagonist suitable for the
therapeutic
s 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 mgl1 ml or lower where
the
powder may be dissolved in Water for Injection (Wfl) or in Gluconic Acid (GA);
to
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);
is c) pamoate salt formulations in the concentration of 10 mg/1 ml to 30 mg/1
ml,
preferably 15 mgl1 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
2o 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.
2s
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.
so 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
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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
s 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
to 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
is 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
2o 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
2s 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
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administered 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
io 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
is 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
2o 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
2s 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
3o for treating extrauterine proliferation of endometrial tissue, chronic
pelvic pain andlor
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
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androgen 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
s 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.
io
Suitable excipients and dosage forms are for example described by K.H. Bauer,
K.-
H. Fromming and C. Fuhrer, Lehrbuch der Pharmazeutischen Technologie, gtn
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 (s.c.),
intramuscular (i.m.) 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
2o 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
2s 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, a pharmaceutical
composition
as mentioned above is provided wherein the short-term induction treatment with
the
3o LHRH antagonist is followed by administration of a contraceptive,
preferably an oral
contraceptive.
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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.
s
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.
io 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 17-
alpha-alkyl substituted testosterone.
is 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
2o 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
2s 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
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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, a pharmaceutical
composition
s 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 pharmaceutical
composition
to 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 pharmaceutical
composition
is 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
2o 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 non-
steroidal 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
3o 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.
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s
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 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, 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
to
is
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.
2o 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 17-
alpha-alkyl substituted testosterone.
is 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
3o androgen other than a 17-alpha-alkyl substituted testosterone or any
combinations
thereof.
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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.
s 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
to 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
is 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
2o 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
2s 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
3o 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
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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, then the administration of
the LHRH
s 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 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.
io
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 pglml, preferably between about 45-75
pg/ml,
is 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
short
term induction treatment with the LHRH antagonist is followed by
administration of a
2o 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
short
term induction treatment with the LHRH antagonist is followed by
administration of a
2s 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
short
term induction treatment with the LHRH antagonist is followed by
administration of
3o 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-
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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 the use of an LH-RH
antagonist
s and one or more active agents 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
to 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
is 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,
2o 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
2s 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
3o weeks at a daily dose of 0.25 mg to 0.5 mglday.
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
L_HRH
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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 the use of an LH-RH
antagonist
s and one or more active agents as mentioned above is provided, wherein the
t_HRH
antagonist is given for the induction treatment during 4 to 12 weeks and the
treatment is repeated two or three times a year.
