CA2200541C - Lhrh-antagonists in the treatment of fertility disorders - Google Patents
Lhrh-antagonists in the treatment of fertility disorders Download PDFInfo
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- CA2200541C CA2200541C CA2200541A CA2200541A CA2200541C CA 2200541 C CA2200541 C CA 2200541C CA 2200541 A CA2200541 A CA 2200541A CA 2200541 A CA2200541 A CA 2200541A CA 2200541 C CA2200541 C CA 2200541C
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Abstract
A method of treating infertility disorders by 1) administering an LH-RH antagonist, preferably Cetrorelix, in amounts to selectively suppress endogenous LH but not FSH secretion and 2) inducing follicle growth by administration of exogenous gonadotropin. The selective suppression OF LH allows FSH secretion to be at natural level S thereby not affecting individual estrogen development. The LH-RH antagonist can be given as a single or dual subcutaneous dose in the range of 1 mg to 10 mg, preferably 2 mg - 6 mg. In multiple dosing posology, LH-RH antagonist can be administered subcutaneously in an amount in the range of 0.1 to 0.5 mg of LH-RH antagonist/day. LH-RH antagonist is applied starting cycle day 1 to 10, preferably on day 4 to 8, and ovulation can be induced between day 9 and 20 of the menstruation cycle by administering rec. LH, native LH-RH, LH-RH agonist or by HCG. In addition rec. LH, native LH-RH or LH-RH agonist can be given to avoid hyperstimulation syndrome and native LH-RH or a LH-RH agonist can be administered to avoid luteal phase stimulation by neutralizing the negative effects of HCG.
Description
LHRH - ANTAGONISTS IN THE TREATMENT
OF FERTILITY DISORDERS
Field of the Invention The field of invention is directed to the use of LHRH-antagonists to treat male and female fertility disorders.
Background of the Invention The reasons for unsuccessful attempts to establish pregnancy can be 2 0 attributed equally to male and female fertility disorders. Today many different assisted reproduction techniques are available. These techniques are used to induce multiple and synchronous follicular growth and thereby obtain fertilizable oocytes.
The current standard treatment is to induce multiple follicular 2 5 development by administering high doses of HMG (Human Menopausal Gonadotropin). This results in ovarian hyperstimulation. Upon reaching a suitable degree of oocyte maturation using these techniques, ovulation is induced by the administration of HCG (Human Chorion-Gonadotropin) in order to obtain a sufficient number of oocytes. During this time, the clinic-30 infrastructure preparation can begin. Preparation includes recovery of oocytes by abdominal or transvaginal puncture, intracorporal or extracorporal fertilization of oocytes by different techniques and embryo replacement into the uterus. Routinely, beginning pregnancy is supported by additional administrations of HCG or progesterone. Today this treatment is applied to clinical conditions of male and female infertility.
Complications that are frequently observed during the hyperstimulation procedure are:
A: premature surges of luteinizing hormone (LH) at a premature maturation state with a rupture of the follicles that induced a subsequent cancellation of the treatment occurring in about 25% of the patients; and B:
ovarian hyperstimulation syndromes induced by exogenous gonadotropins which in severe cases require hospitalization and are life-threatening.
In order to avoid premature LH-surges, today LHRH-agonists are used as a comedication. By continued administration of these drugs, a complete suppression of endogenous gonadotropins is achieved by desensitization of pituitary cells and down-regulation of their receptors.
Subsequently, the gonadotropin levels can be controlled by exogenous injection and the pituitary is refractory to the stimulation of LH-release by increasing levels of estradiol. Disadvantages are 1) a long treatment period until the suppression and down-regulation occur; 2) estrogen withdrawal symptoms; 3) disturbance of the normal menstrual cycle; 4) the need for frequent hormone determinations in order to evaluate the time of onset of suppression; and 5) high dose HMG treatment is needed for ovarian 2 0 stimulation.
The pathogenesis of hyperstimulation syndrome is not completely understood, but is thought to be associated with the use of HCG for ovulation induction and luteal phase support.
One recent approach involves the use of the LHRH antagonist 2 5 Cetrorelix (INN). In first clinical trials, short term treatment with Cetrorelix resulted in a complete avoidance of premature LH surges during stimulated cycles and the need for HMG. Due to the immediate suppression of gonadotropins by this antagonist, the unwanted stimulatory phase and also the withdrawal of estrogen produced by the agonists was avoided. The duration of treatment was also significantly shortened. In addition, it was shown that a single injection of an antagonist, given in the mid-follicular phase, would adequately suppress premature LH surges.
SUMMARY OF THE INVENTION
Despite the improvements described above, these treatment modalities suffered the drawback of treating the patients with the highest possible dose of exogenous gonadotropins to hyperstimulate multiple follicular development which results in some severe adverse events.
The current invention reduces the severe adverse events, improves patient compliance and reduces costs. Recent data obtained with Cetrorelix also demonstrates additional surprising new advantages for the treatment of male and female infertility.
In animal experiments and clinical studies with Cetrorelix, it was possible to induce an arrest of the normal, unstimulated follicular growth by multiple or single injections. These effects were observed with extremely low dosage levels. These low dosage levels present new possibilities for manipulating the time of ovulation during a normal, not exogenous gonadotropin-stimulated cycle, without affecting the viability of the growing follicle. In case of inadequate follicular growth related to treatment with LHRH-antagonists, low dose and short term administration of gonadotrophin or other trophic compounds will compensate for these 2 5 effects. Subsequently, by stopping the LHRH-antagonist treatment, it is possible to let the normal ovulation occur or to induce ovulation by exogenous manipulation, if necessary. Ovulation induction was induced by the administration of standard HCG or by administration of LHRH and/or LHRH agonistic analogs, such as recombinant LH, native LHRH, and HCG.
These described treatment alternatives are a departure from existing protocols, since they are possible only if preceded by treatment for LH-surge-control with an LHRH-antagonist. In animal and clinical studies with Cetrorelix it was shown that the responsiveness of the pituitary to LHRH or agonistic analogs is preserved under these conditions of treatment. Without this treatment, the pituitary cannot respond after agonistic pretreatment for LH-surge control due to receptor down-regulation. In addition, the possible use of ovulation inducing agents other than HCG results in a reduced incidence of ovarian hyperstimulation syndrome.
On the basis of the described results, for the first time it is possible to use normal, non-gonadotropin-stimulated cycles for assisted reproduction techniques, including sperm injections, by determining the time of ovulation by the duration and dose of Cetrorelix given. Especially in conjunction with the method of ICSI (Intra-Cytoplasmatic-Sperm-Injection) this antagonist-dependent treatment modality facilitates the inclusion of in-(sub-)fertile males into this kind of fertility treatment. Due to the direct injection of male gametes capable for fertilization, this method has a high success rate and hence, allows the harvest of only one follicle for fertilization. In addition, the use of LHRH-antagonists like Cetrorelix in the described manner relieves the patient from severe ovarian hyperstimulation and significantly reduces the costs of a treatment cycle.
LHRH-antagonists of the invention can be used in combination with assisted reproduction techniques, especially the extracorporal fertilization, e.g. the in-vitro fertilization and the sperm injection techniques.
OF FERTILITY DISORDERS
Field of the Invention The field of invention is directed to the use of LHRH-antagonists to treat male and female fertility disorders.
Background of the Invention The reasons for unsuccessful attempts to establish pregnancy can be 2 0 attributed equally to male and female fertility disorders. Today many different assisted reproduction techniques are available. These techniques are used to induce multiple and synchronous follicular growth and thereby obtain fertilizable oocytes.
The current standard treatment is to induce multiple follicular 2 5 development by administering high doses of HMG (Human Menopausal Gonadotropin). This results in ovarian hyperstimulation. Upon reaching a suitable degree of oocyte maturation using these techniques, ovulation is induced by the administration of HCG (Human Chorion-Gonadotropin) in order to obtain a sufficient number of oocytes. During this time, the clinic-30 infrastructure preparation can begin. Preparation includes recovery of oocytes by abdominal or transvaginal puncture, intracorporal or extracorporal fertilization of oocytes by different techniques and embryo replacement into the uterus. Routinely, beginning pregnancy is supported by additional administrations of HCG or progesterone. Today this treatment is applied to clinical conditions of male and female infertility.
Complications that are frequently observed during the hyperstimulation procedure are:
A: premature surges of luteinizing hormone (LH) at a premature maturation state with a rupture of the follicles that induced a subsequent cancellation of the treatment occurring in about 25% of the patients; and B:
ovarian hyperstimulation syndromes induced by exogenous gonadotropins which in severe cases require hospitalization and are life-threatening.
In order to avoid premature LH-surges, today LHRH-agonists are used as a comedication. By continued administration of these drugs, a complete suppression of endogenous gonadotropins is achieved by desensitization of pituitary cells and down-regulation of their receptors.
Subsequently, the gonadotropin levels can be controlled by exogenous injection and the pituitary is refractory to the stimulation of LH-release by increasing levels of estradiol. Disadvantages are 1) a long treatment period until the suppression and down-regulation occur; 2) estrogen withdrawal symptoms; 3) disturbance of the normal menstrual cycle; 4) the need for frequent hormone determinations in order to evaluate the time of onset of suppression; and 5) high dose HMG treatment is needed for ovarian 2 0 stimulation.
The pathogenesis of hyperstimulation syndrome is not completely understood, but is thought to be associated with the use of HCG for ovulation induction and luteal phase support.
One recent approach involves the use of the LHRH antagonist 2 5 Cetrorelix (INN). In first clinical trials, short term treatment with Cetrorelix resulted in a complete avoidance of premature LH surges during stimulated cycles and the need for HMG. Due to the immediate suppression of gonadotropins by this antagonist, the unwanted stimulatory phase and also the withdrawal of estrogen produced by the agonists was avoided. The duration of treatment was also significantly shortened. In addition, it was shown that a single injection of an antagonist, given in the mid-follicular phase, would adequately suppress premature LH surges.
SUMMARY OF THE INVENTION
Despite the improvements described above, these treatment modalities suffered the drawback of treating the patients with the highest possible dose of exogenous gonadotropins to hyperstimulate multiple follicular development which results in some severe adverse events.
The current invention reduces the severe adverse events, improves patient compliance and reduces costs. Recent data obtained with Cetrorelix also demonstrates additional surprising new advantages for the treatment of male and female infertility.
In animal experiments and clinical studies with Cetrorelix, it was possible to induce an arrest of the normal, unstimulated follicular growth by multiple or single injections. These effects were observed with extremely low dosage levels. These low dosage levels present new possibilities for manipulating the time of ovulation during a normal, not exogenous gonadotropin-stimulated cycle, without affecting the viability of the growing follicle. In case of inadequate follicular growth related to treatment with LHRH-antagonists, low dose and short term administration of gonadotrophin or other trophic compounds will compensate for these 2 5 effects. Subsequently, by stopping the LHRH-antagonist treatment, it is possible to let the normal ovulation occur or to induce ovulation by exogenous manipulation, if necessary. Ovulation induction was induced by the administration of standard HCG or by administration of LHRH and/or LHRH agonistic analogs, such as recombinant LH, native LHRH, and HCG.
These described treatment alternatives are a departure from existing protocols, since they are possible only if preceded by treatment for LH-surge-control with an LHRH-antagonist. In animal and clinical studies with Cetrorelix it was shown that the responsiveness of the pituitary to LHRH or agonistic analogs is preserved under these conditions of treatment. Without this treatment, the pituitary cannot respond after agonistic pretreatment for LH-surge control due to receptor down-regulation. In addition, the possible use of ovulation inducing agents other than HCG results in a reduced incidence of ovarian hyperstimulation syndrome.
On the basis of the described results, for the first time it is possible to use normal, non-gonadotropin-stimulated cycles for assisted reproduction techniques, including sperm injections, by determining the time of ovulation by the duration and dose of Cetrorelix given. Especially in conjunction with the method of ICSI (Intra-Cytoplasmatic-Sperm-Injection) this antagonist-dependent treatment modality facilitates the inclusion of in-(sub-)fertile males into this kind of fertility treatment. Due to the direct injection of male gametes capable for fertilization, this method has a high success rate and hence, allows the harvest of only one follicle for fertilization. In addition, the use of LHRH-antagonists like Cetrorelix in the described manner relieves the patient from severe ovarian hyperstimulation and significantly reduces the costs of a treatment cycle.
LHRH-antagonists of the invention can be used in combination with assisted reproduction techniques, especially the extracorporal fertilization, e.g. the in-vitro fertilization and the sperm injection techniques.
Compounds with the desired LHRH-antagonistic activity include a TM
LHRH-analog such as Ganirelix, Antarelix, Amide, Azaline B, Ramorelix, A-761 54, Nal-Glu, 88-88, in particular -Cetrorelix or a structure-truncated peptide with LHRH-antagonistic activity or a peptideomimetic with LHRH-antagonistic activity, for example D-23980 and D-24824, or a bicyclic (1-4.4-10) LHRH analog with antagonistic activity.
LHRH-antagonists of the invention can be subcutaneously administered in dosage amounts of about 0.001-0.2 mg/kg-Both dosing schedules demonstrate the prevention of any premature LH surge. After both posologies good fertilization rates have been obtained with good follicle and oocytes quality. Pregnancy rates are good after both treatments. To date, a total of 44 healthy babies are born following both treatments.
The single dose regimen requires only one single injection of 3 ml.
This has to be regarded as being convenient for the patient. So far, duration of effect to prevent a premature LH surge is up to 6.5 days. After 3 days, monitoring of hormones is advisable in order to apply a second injection in case of a low responder to HMG with prolonged administration of HMO, and if an increase of LH values is seen.
The multiple dose schedule requires daily injections of 1 ml for 3 to 7 days, sometimes up to 10 or 14 days. This is not as convenient as a single or dual injection. On the other hand, regular monitoring of the hormones is not required and the application of HCG could even be extended if required in rare cases.
It is an embodiment that the LH-RH antagonist in the single or dual dosage regimen is started on cycle day 1 to 10, cycle day 4 to 8 or cycle day 6 to 10.
In summary, from a medical point of view, both treatments comparable efficacy, safety and practicability, therefore each gynecologist should have the possibility to decide upon the dosing schedule with respect to the situation observed in each single patient.
The results of a phase II clinical trial are shown in Table I.
A total of 235 patients were treated.
No premature LH surge was seen in any patient undergoing COS/ART treated with either multiple doses of 0.25 mg or higher or a single dose of 3 mg or higher. During multiple dosing, the mean days of Cetrorelix application is 6 days. 25 babies were born by the end of May 1996 (7 following multiple doses; 18 following single/dual doses).
LHRH-analog such as Ganirelix, Antarelix, Amide, Azaline B, Ramorelix, A-761 54, Nal-Glu, 88-88, in particular -Cetrorelix or a structure-truncated peptide with LHRH-antagonistic activity or a peptideomimetic with LHRH-antagonistic activity, for example D-23980 and D-24824, or a bicyclic (1-4.4-10) LHRH analog with antagonistic activity.
LHRH-antagonists of the invention can be subcutaneously administered in dosage amounts of about 0.001-0.2 mg/kg-Both dosing schedules demonstrate the prevention of any premature LH surge. After both posologies good fertilization rates have been obtained with good follicle and oocytes quality. Pregnancy rates are good after both treatments. To date, a total of 44 healthy babies are born following both treatments.
The single dose regimen requires only one single injection of 3 ml.
This has to be regarded as being convenient for the patient. So far, duration of effect to prevent a premature LH surge is up to 6.5 days. After 3 days, monitoring of hormones is advisable in order to apply a second injection in case of a low responder to HMG with prolonged administration of HMO, and if an increase of LH values is seen.
The multiple dose schedule requires daily injections of 1 ml for 3 to 7 days, sometimes up to 10 or 14 days. This is not as convenient as a single or dual injection. On the other hand, regular monitoring of the hormones is not required and the application of HCG could even be extended if required in rare cases.
It is an embodiment that the LH-RH antagonist in the single or dual dosage regimen is started on cycle day 1 to 10, cycle day 4 to 8 or cycle day 6 to 10.
In summary, from a medical point of view, both treatments comparable efficacy, safety and practicability, therefore each gynecologist should have the possibility to decide upon the dosing schedule with respect to the situation observed in each single patient.
The results of a phase II clinical trial are shown in Table I.
A total of 235 patients were treated.
No premature LH surge was seen in any patient undergoing COS/ART treated with either multiple doses of 0.25 mg or higher or a single dose of 3 mg or higher. During multiple dosing, the mean days of Cetrorelix application is 6 days. 25 babies were born by the end of May 1996 (7 following multiple doses; 18 following single/dual doses).
Table I
Cetrorelix Development Controlled Ovarian Stimulation (COS/ART) Subj. Nos. Phase Dose/Day Posology (mg) (days) 14 II/proof concept 3 3-10 19 11/proof concept 1 3-10 11 II/proof concept 0.5 3-10 32 lU 0.5 3-7/14 30 dose finding/ 0.25 min. effect. dose (28) minimal effective dose 0.10 no effect. dose 21 11/proof concept 5 1 or 2 18 II/proof concept 3 1 or 2 32 11/dose finding/ 3 min. effective dose 1 30 minimal effective dose 2 no effect. Dose 1 SUM 235 71 pregnancies (30%) 44 healthy Phase 11 finished 16 pregnancies (ongoing) children The main advantages in controlled ovarian stimulation (COS/ART) with Cetrorelix are:
1. New therapeutic principle a) Prevention of premature LH-surges b) Uniform and continuous follicular synchronization c) Uniform and continuous estradiol development d) Very low LH-values for optimal follicular development 2. Short term treatment of 3 to 7 days to max 14 days a) Short-term exposure during follicular development b) Low medication exposure during follicular development 3. No flare-up but immediate hormonal response 4. No pretreatment for 14 to 21 days before start of HMG needed 5. Fits well into normal menstrual cycle with a) No modification of physiological menstrual cycle pattern or b) No hormonal withdrawal syndromes before stimulation 6. No or only ultrashort-term residual effects after ovulation induction 7. No residual effects during and following embryo transfer 8. No ovarian cyst formation before start of stimulation 9. Reduction of HMG.
Table II (flow chart) shows an example on a typical treatment start and duration of HMG and Cetrorelix in patients to undergo controlled ovarian superovulation for ART.
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C.2 ~i U) L) L.. co U. 40 /r L it u m m W : ' r _ J x X x X X X X 7 Example 238 patients were treated with Cetrorelix by subcutaneous injection of Cetrorelix Acetat-Lyophilisat.
134 patients were treated with multiple doses and 104 patients with single or dual doses. The multiple doses are 0.25 mg/day or higher. The single dose was 3 mg or higher. No premature LH surge was seen in any patient undergoing controlled ovarian superovulation for assisted reproduction technology (COS/ART) treated with these dosages. Multiple doses were applied for 3 to a maximum of 10 days dependent on follicular development.
As a result 71 pregnancies were obtained = 30.0%
38 of 134 following the multiple does regimen = 28.4%
33 of 104 following the single/dual dosage regimen = 31.7%
Following treatment 44 babies were born that means 15 following multiple does and 29 following single/dual does. 16 pregnancies are still ongoing. Figure 1 shows this in particular Figure 1 shows an absolute prevention of any premature LH surge.
Furthermore, FSH secretion is maintained at a natural level and therefore the individual estrogen development is not affected.
Cetrorelix Development Controlled Ovarian Stimulation (COS/ART) Subj. Nos. Phase Dose/Day Posology (mg) (days) 14 II/proof concept 3 3-10 19 11/proof concept 1 3-10 11 II/proof concept 0.5 3-10 32 lU 0.5 3-7/14 30 dose finding/ 0.25 min. effect. dose (28) minimal effective dose 0.10 no effect. dose 21 11/proof concept 5 1 or 2 18 II/proof concept 3 1 or 2 32 11/dose finding/ 3 min. effective dose 1 30 minimal effective dose 2 no effect. Dose 1 SUM 235 71 pregnancies (30%) 44 healthy Phase 11 finished 16 pregnancies (ongoing) children The main advantages in controlled ovarian stimulation (COS/ART) with Cetrorelix are:
1. New therapeutic principle a) Prevention of premature LH-surges b) Uniform and continuous follicular synchronization c) Uniform and continuous estradiol development d) Very low LH-values for optimal follicular development 2. Short term treatment of 3 to 7 days to max 14 days a) Short-term exposure during follicular development b) Low medication exposure during follicular development 3. No flare-up but immediate hormonal response 4. No pretreatment for 14 to 21 days before start of HMG needed 5. Fits well into normal menstrual cycle with a) No modification of physiological menstrual cycle pattern or b) No hormonal withdrawal syndromes before stimulation 6. No or only ultrashort-term residual effects after ovulation induction 7. No residual effects during and following embryo transfer 8. No ovarian cyst formation before start of stimulation 9. Reduction of HMG.
Table II (flow chart) shows an example on a typical treatment start and duration of HMG and Cetrorelix in patients to undergo controlled ovarian superovulation for ART.
2200541, L 3 _ `
G
ar O ~` cc 0 o Q
m Ee chi c N x Z
o o W
o p h. X X x o O N
LL 0 E _ W co o (L LL' co co W CL o g d o tO X X X E c u -7 .c Y
~
F- W m u o X X d o 9 T A
p o d a AI " N N C
N C O
c X o~ - 0 1 ai m O X x c o C O
r^ `ol y A .a A2 I
V E rte..' +` f ~' tT Q . O
CL
V - ai E _ 'n C 4) rn d y CL E o AI y +~. 9' E a$ > 2 n ~.
R a 11 X x o ,' u N AI rv ..,y i,. K 7 n 7 ^ U
4 W Al W r Cr X C Q m' OG O
E O A ~, 70 -a t:
k tom- V-) y d++ o N n R g' o >, L C O a v H > E d^ o 3 ~ : y 5 c E C7 0 CL 'D 0 LL (~ ea a c T- c m Ct a m >
V
O L N
lU N E Al ii E a c CL C a C A d W N
c J t m Cv7 N 3 N vl :. C L F
C1 .~ Iv ~.. o w E V
t a~ A l gyy m a r V d c ~'K X x.. r W U,' Al I C m m 2) N U 7E m y t % o ? 3 N
6- t:
`~- CL X x x x X 0 E 11 E A
C.2 ~i U) L) L.. co U. 40 /r L it u m m W : ' r _ J x X x X X X X 7 Example 238 patients were treated with Cetrorelix by subcutaneous injection of Cetrorelix Acetat-Lyophilisat.
134 patients were treated with multiple doses and 104 patients with single or dual doses. The multiple doses are 0.25 mg/day or higher. The single dose was 3 mg or higher. No premature LH surge was seen in any patient undergoing controlled ovarian superovulation for assisted reproduction technology (COS/ART) treated with these dosages. Multiple doses were applied for 3 to a maximum of 10 days dependent on follicular development.
As a result 71 pregnancies were obtained = 30.0%
38 of 134 following the multiple does regimen = 28.4%
33 of 104 following the single/dual dosage regimen = 31.7%
Following treatment 44 babies were born that means 15 following multiple does and 29 following single/dual does. 16 pregnancies are still ongoing. Figure 1 shows this in particular Figure 1 shows an absolute prevention of any premature LH surge.
Furthermore, FSH secretion is maintained at a natural level and therefore the individual estrogen development is not affected.
Claims (6)
1. A use of a luteinizing hormone releasing hormone (LHRH) antagonist for the manufacture of a medicament for the production of a fertilizable oocyte within a program of controlled ovarian stimulation for assisted reproduction techniques (COS/ART), wherein the medicament is adapted as a unit dosage form comprising 0.25 mg of the LHRH
antagonist to be used in the absence of follicular growth stimulation by an exogenous gonadotropin, and wherein the LHRH antagonist is selected from the group consisting of Cetrorelix, Ganirelix, Antarelix, Antide, Azaline B, Ramorelix, A-76154, NalGLu, D-23980 and D-24824.
antagonist to be used in the absence of follicular growth stimulation by an exogenous gonadotropin, and wherein the LHRH antagonist is selected from the group consisting of Cetrorelix, Ganirelix, Antarelix, Antide, Azaline B, Ramorelix, A-76154, NalGLu, D-23980 and D-24824.
2. The use of claim 1, wherein the medicament is adapted for subcutaneous injection.
3. The use of claim 1 or 2, wherein the LHRH antagonist is Cetrorelix.
4. A pharmaceutical composition comprising a luteinizing hormone releasing hormone (LHRH) antagonist and a pharmaceutically acceptable carrier for the production of a fertilizable oocyte within a program of controlled ovarian stimulation for assisted reproduction techniques (COS/ART), wherein the composition is adapted as a unit dosage form comprising 0.25 mg of the LHRH antagonist to be used in the absence of follicular growth stimulation by an exogenous gonadotropin, and wherein the LHRH antagonist is selected from the group consisting of Cetrorelix, Ganirelix, Antarelix, Antide, Azaline B, Ramorelix, A-76154, NalGLu, D-23980 and D-24824.
5. The composition of claim 4, wherein the medicament is adapted for subcutaneous injection.
6. The composition of claim 4 or 5, wherein the LHRH antagonist is Cetrorelix.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US78693797A | 1997-01-22 | 1997-01-22 | |
| US08/786,937 | 1997-01-22 |
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| Publication Number | Publication Date |
|---|---|
| CA2200541A1 CA2200541A1 (en) | 1998-07-22 |
| CA2200541C true CA2200541C (en) | 2013-02-19 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2200541A Expired - Lifetime CA2200541C (en) | 1997-01-22 | 1997-03-20 | Lhrh-antagonists in the treatment of fertility disorders |
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| CA (1) | CA2200541C (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US8173592B1 (en) * | 1999-03-31 | 2012-05-08 | Zentaris Ivf Gmbh | Method for a programmed controlled ovarian stimulation protocol |
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