CN1199642A - LHRH-antagonists in treatment of fertility disorders - Google Patents
LHRH-antagonists in treatment of fertility disorders Download PDFInfo
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Abstract
A methd of treating infertility disorders by 1) administering an LH-RH abtagonist, 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 levels 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.
Description
The application makes on the basis of 60/011, No. 282 provisional application of submission on February 7th, 1996, and the content of this provisional application is incorporated herein by reference.
The present invention relates to the purposes of LHRH-antagonist, this lhrh antagonist is used for the treatment of male and female infertility.
The reason of conceived failure is considered to the result of male and female infertility.Current, there has been multiple different auxiliary procreation technology.These technology can be induced multistage, the synchronous growth of follicle, obtain fertilizable oocyte.
The therapy of standard is the multistage growth of inducing follicle by the HMG (human menopausal gonadotropin) that gives heavy dose at present.This can cause ovary too drastic.Use these technology, reach on the appropriate sophisticated basis, by giving HCG (human chorionic gonadotropin) induced ovulation, to obtain the oocyte of capacity at oocyte.So can begin to carry out the preparation of clinical basic measures.Its preparation for by through the abdominal cavity or transvaginal puncture reclaim oocyte, with oocyte in vivo or external fertilization, then the embryo is resetted in the uterus again with different technologies.Usually, could begin pregnancy by extra HCG or Progesterone administration.Nowadays, this method is used for the treatment of male and female infertility clinically.
The frequent complication that occurs has in too drastic process:
A: patient's lutropin (LH) of about 25% is earliness, and precocious sudden change can take place, and follicular rupture simultaneously causes the treatment failure subsequently; B: exogenous promoting sexual gland hormone is brought out ovary and is crossed bowel syndrome, and weight person needs hospitalization and is in peril of one's life.
For avoiding precocious LH sudden change, use lhrh antagonist at present as public medicine.Give these medicines continuously,, can suppress the endogenous promoting sexual gland hormone fully by the desensitization of pituicyte and the downward modulation of endogenous gonadotropin receptor level.Secondly, by exogenous injection may command promoting sexual gland hormone level, hypophysis should not stimulated in the release of LH by improving the estradiol level.Disadvantage is 1) suppress and to reduce the required treatment phase long; 2) produce the estrogen withdrawal symptom; 3) normal menstrual cycle imbalance; 4) need often carry out hormone determination, to judge the zero-time that suppresses; 5) the excited HMG that needs heavy dose of ovary.
Too drastic syndromic pathogeny still imperfectly understands, but can think that its use with HCG is relevant, and HCG is used for induced ovulation and keep pmgravid.
A nearest research relates to the purposes (INN) of lhrh antagonist Cetrorelix.In the clinical trial of at first carrying out, short-term uses the therapy of Cetrorelix to avoid the middle early LH sudden change of excited cycle fully, and this method also need not to use HMG.This antagonist has also just been avoided the generation of exciting phase owing to suppress promoting sexual gland hormone immediately, and this just people do not wish to see, also avoided the estrogen withdrawal symptom that causes by agonist simultaneously.The persistent period of treatment also significantly shortens.In addition, studies show that,, will fully suppress precocious LH sudden change at follicle single injection antagonist in mid-term.
Although above therapeutic modality improves to some extent, still there is such defective, promptly when patient is treated, to use heavy dose of exogenous promoting sexual gland hormone probably, excessively to excite the multistage growth of follicle, this can cause some serious adverse consequences.
The present invention can reduce serious adverse consequences, improves compliance of patients, and reduces cost.Nearest Cetrorelix data also shows, is obtaining brand-new, wonderful progress aspect treatment male and the female infertility.
In the zoopery and clinical research of Cetrorelix, can cause that by multistage or single injection normal unactivated ovarian follicular growth stops.This effect observes in the very low dose level.Low dosage level is providing new possibility for controlling ovulation period in the inductive cycle normally rather than by exogenous promoting sexual gland hormone, and does not influence the viablity of ovarian follicular growth.Under relating to the inadequate situation of lhrh antagonist treatment ovarian follicular growth, the promoting sexual gland hormone of low dosage or short-term or other nutrient compounds administration meeting are carried out compensatory to these results.Secondly, stop the lhrh antagonist drug treatment after, can also normally ovulate.Perhaps, if necessary, with exogenous operating condition induced ovulation.Inducing of ovulation is the HCG by the standard of giving or gives LHRH and/or LHRH agonist analog carries out.
Unique condition that the various selections of described therapy deviate from existing protocol is that these methods are better than the sudden change with a kind of lhrh antagonist control LH.Animal and the clinical research of Cetrorelix show that hypophysis has been protected under these treatment conditions the responsiveness of LHRH or agonist analog.If do not carry out this treatment, after agonist carried out pretreatment to LH sudden change control, because the acceptor levels downward modulation, hypophysis just can not produce and reply.In addition, use the ovulation induction agent except that HCG can reduce the too drastic syndromic sickness rate of ovary.
Based on The above results, in comprising the auxiliary procreation technology of sperm injection, utilizing the inductive treatment cycle of normal, non-promoting sexual gland hormone by the mensuration ovulation period may still be for the first time, and the mensuration of ovulation period is to be determined by the persistent period of Cetrorelix administration and dosage.Especially with ICSC (sperm injection in the Cytoplasm) when method is used jointly, the therapeutic modality that antagonist relies on has been simplified the treatment of the raising fertility that sterile (subfertile) male is carried out.Owing to be direct injection male's the gamete with fertility, the success rate of this method is higher, therefore can only obtain a fertilization follicle.In addition, use lhrh antagonist can make patient avoid the serious too drastic hardship of ovary in this way, and significantly reduce the cost of treatment cycle such as Cetrorelix.
Lhrh antagonist of the present invention can use in conjunction with auxiliary procreation technology, especially the technology of external fertilization, for example fertilization and sperm injection technology in teat glass.
Chemical compound with required LHRH antagonistic activity comprises the LHRH analog, such as Ganirelix, and Antarelix, Azaline B, Ramorelix, A-76154, Nal-Glu, 88-88, especially Cetrorelix, or have the peptide of the amputated structure of LHRH antagonistic activity, or have the peptide mimics of LHRH antagonistic activity, for example D-23980 and D-24824, or a kind of bicyclo-(1-4,4-10) LHRH analog with antagonistic activity.
Lhrh antagonist of the present invention can be through subcutaneous administration, and dosage range is the 0.001-0.2 mg/kg.
There are two kinds of dosages can both prevent any precocious LH sudden change.By after these two kinds of dosiology administrations, high-quality follicle and oocyte have brought high rate of fertilization, so pregnancy rate is also higher.Up to now, by following these two kinds of therapies, the baby due of existing 44 health.
Single dose system only needs 3 milliliters of injections.This is very easily to patient.At present, prevent that the persistent period that precocious LH suddenlys change from can reach 6.5 days.Hormonal readiness monitoring is carried out in suggestion after 3 days because just in case HMG is replied when prolonging the HMG administration lower, and if the LH level raise, all to carry out second time and inject.
Multistage dosage requires inject 1 milliliter every day, injects 3 to 7 days, sometimes until 10 or 14 days.This is so convenient not as single or dual injection.But from another point of view, do not need hormonal readiness is monitored regularly, under rare occasion, if necessary, even may prolong the HCG administration.
In a word, on the medical science viewpoint, two kinds of therapies have similar effect, safety and feasibility, and therefore, each gynecologist should be able to select a kind of dosage after the concrete condition of having considered each patient.
The II clinical trial phase the results are shown in Table I.Altogether 235 patients are treated.
Do not find precocious LH sudden change in the patient who accepts the treatment of COS/ART method, this therapy adopts 0.25 milligram or higher multistage dosage, perhaps 3 milligrams or higher single dose.In multistage dosage, the average administration time of Cetrorelix is 6 days.Existing in by the end of May, 1,996 25 baby dues (7 multistage dosimetries by name; 18 are called single/dual dosimetry).
Table I
Use the major advantage of the controlled short ovary maturity method (COS/ART) of Cetrorelix to be:
| The controlled short ovary maturity method of Cetrorelix (COS/ART) process |
| The curer number | Stage | Dosage/sky (milligram) | Dosiology (natural law) | |
| ????14 | II phase/preliminary identification | ????3 | ????3-10 | |
| ????19 | II phase/preliminary identification | ????1 | ????3-10 | |
| ????11 | II phase/preliminary identification | ????0.5 | ????3-10 | |
| ????32 ????30 ????(28) | II phase/dosage is groped/least effective dose (LED) | 0.5 0.25 least effective dose (LED), 0.10 ineffective dose | ??3-7/14 | |
| ????21 | II phase/preliminary identification | ????5 | 1 or 2 | |
| ????18 | II phase/preliminary identification | ????3 | 1 or 2 | |
| ????32 ????30 | II phase/dosage is groped/least effective dose (LED) | 3 least effective dose (LED)s, 2 ineffective doses | ????1 ????1 | |
| Amount to the II phase | 235 have finished | 71 people's pregnancies (30%) 16 people is conceived | 44 healthy childrens |
1. Xin Ying treatment principle
A) prevent precocious LH sudden change
B) homogeneous, successive follicle synchronous growth
C) homogeneous, successive estradiol generate
D) the required LH level of best follicular development is very low
2. short treating period, 3 to 7 days, maximum 14 days
A) open-assembly time is short in the follicular development process
B) effect of follicular development process Chinese medicine is little
3, immediately but not the burst hormone response
4, before the HMG administration, need not pretreatment in 14 to 21 days
5, coincide good with normal menstrual cycle
A) do not change physiological menstrual cycle mode
B) there is not the hormone withdrawal symptom before inducing
6, after the induced ovulation, there is not or only has extremely short residual effect
7, in the embryo shifts and after shifting, there is not residual effect
8, before inducing beginning, there is not ovarian cyst to form
9, the reduction of HMG consumption
Table II (flow chart) has shown the initial and process of using the typical course of treatment of HMG and Cetrorelix, in this course of treatment patient is adopted the superovulated method of controlled ovary by ART.
Assessment method guide look Table II (flow chart)
X
1First day (d1) of=injection hMG: confirm in the period, do not have pregnancy (carry out morning) afterwards: hCG → ignore (≤10 ius/liter); P≤1 nanograms/milliliter (≤3.81 nanomoles/liter); FSH≤10 ius/liter; (〉=2 centimetres of φ cause E not have ovarian cyst
2〉=50 slight grams per milliliters (〉=185 pmols/liter)).The the 2nd or 3 day of the first day=menstrual cycle of hMG! X
2(see X=the previous day of depending on the hMG administration of follicle maturity
3).X
310,000 iu hMG days of=injection: the average diameter that has a follicle at least is measured by ultrasound wave (USS) and is reached 20 millimeters or observe E
2〉=1,200 slight grams per milliliters (〉=4,405 pmols/liter) with regard to start injection.X
4=note: in case 12 more than the follicle 〉=15 millimeters φ or E are arranged in induction period
2〉=4,000 slight grams per milliliter (〉=14,684 pmols/liter) → forbid injection A cancellation of → cycle! X
5=keep luteal phase according to central dogma: give Progesterone (as 3 * 200 mg/day) by central dogma injection hCG or by the central dogma transvaginal! X
6=any relevant precocious research stops all having data to prove (as situation about coming off).X
7=in hospital or in addition, extracted 2 blood samples (after morning and the hCG administration) for hormone determination the same day at injection hCG.A ultrasound wave (USS): (X) carried out between the same day to injecting hCG in injection the 6th day behind the hMG by central dogma! USS should carry out at injection hCG the same day.Embodiment
| Stage: | ?????????????????hMG 2Stage d1 → until hCG day | Use hCG 4If: | HMG is after the stage | ||||||||
| Treatment/research | ? ????Cclrorclix | Leading follicle: 〉=20 millimeters φ or E 1〉=1,200 slight grams per milliliters | |||||||||
| Parameter: | ? ? ? | HMG day | 1 1The the 2nd or 3 day of cycle | HMG natural law d2-d5 | HMG day is d6 | Second day of hMG, be d7 until hCG, day | Cancellation, if: 12 follicles are above 〉=15 millimeters φ or E 2〉=4,000 slight grams per milliliter (〉=14,684 pmols/liter) | ? ? ??OPU | ? ? ??ET | Behind the ET 6-8 days | Record at last: behind the ET 20-25 days |
| Garbled data | ?X | Pregnancy and baby's follow-up study follow-up study: reset cycle | |||||||||
| The test card tail | ????X 6 | ||||||||||
| Ccirorelix 0.25mg s.c. every day | ????X | ????X | ????X | ||||||||
| HMG injects (2/3/4+) | ??X 12Amp | ??X?2?Amp | ???? | ?? | ?? | ||||||
| → hCG10,000 iu intravenous injection | ??X 3 | ||||||||||
| Ultrasound wave (USS) | ?X | ??X | (X) optional | (X) optional | ??X | ??X | ????X | ||||
| Hormone: (hCG) LH, FSH, E 2，P | ?X | ??X 1 | ????X | X every day | ?? | ??X | ???X | ????X | ????X | ||
| Laboratory (Htemal clinical chemistry) | ?X | ????X | ??X | ????X | |||||||
| Keep luteal phase → hCG or Progesterone | ???X 5 | ????X 5 | |||||||||
| Toleration/AE ' s | ?X | Ask and visit each patient | |||||||||
To 238 patient's subcutaneous injection Cetrorelix Acetat-Lyophilisat.
134 patients are by the administration of multistage dosage mode, and 104 patients are by the administration of single or dual dosage mode.Multistage dosage is 0.25 mg/day or higher.Single dose is 3 milligrams or higher.By above-mentioned dosage, in the patient that the method for the controlled ovary superovulation (COS/ART) of accepting the employing auxiliary procreation technology is treated, do not find precocious LH sudden change.According to the difference of follicular development, the multistage dosed administration time is 3 to maximum 10 days.
As a result, have 71 people's pregnancy=30.0%
134 philtrums by multistage dosage mode have 38 people's pregnancy=28.4%
104 philtrums by single/dual dosimetric system have 33 people's pregnancy=31.7%
By this therapy, existing 44 baby dues that is to say, by have 15 of multistage dosage, by 29 births that have of single/dual dosage.Other has 16 people conceived.See Fig. 1 for details.
Fig. 1 shows that precocious LH sudden change has been prevented fully.And FSH secretions maintains the nature level, therefore can not have influence on individual estrogenic generation.
Claims (14)
1. a LH-RH antagonist is used for the treatment of purposes in the medicine of method of infertility in preparation, this method is to give a kind of LH-RH antagonist, and induce ovarian follicular growth by giving exogenous promoting sexual gland hormone, contain a certain amount of LH-RH antagonist in this exogenous promoting sexual gland hormone, the content of this LH-RH antagonist is low to moderate can only suppress endogenous LH, make FSH maintain the nature level, and individual estrogenic generation can not be affected.
2. according to the preparation in the method that is used for the treatment of infertility of claim 1, this method is to give a kind of LH-RH antagonist, and induces ovarian follicular growth by giving exogenous promoting sexual gland hormone, and described antagonist is Cetrorelix.
3. according to the preparation of claim 2, the growth of described follicle is to excite with the material except that exogenous promoting sexual gland hormone.
4. according to the preparation of claim 2, at described LH-RH antagonist, be preferably Cetrorelix and act on natural LH and produce inhibitory action after, the growth of follicle is not to excite (for example adding promoting sexual gland hormone) by external factor, but is kept by the endogenous promoting sexual gland hormone.
5. according to the preparation of claim 2, the subcutaneous administration weight range of described Cetrorelix in multistage dosage is learned is 0,1 to 5 mg/day.
6. a LH-RH antagonist is used for the purposes of the medicine of controlled short ovary maturity method in preparation, in this method Cetrorelix the 1st to 10 day of menstrual cycle, be preferably administration in the 4th to 8 day, ovulation can be induced between the 8th to 18 day of menstrual cycle.
7. according to the medicine of claim 1, described LH-RH antagonist is through single or dual subcutaneous administration, and dosage range is 1 milligram to 10 milligrams, is preferably 2 milligrams to 6 milligrams.
8. the medicine that is used for controlled short ovary maturity method, in this method preferred LH-RH antagonist Cetrorelix as described in the claim 7 in administration in the 6th to 10 day of menstrual cycle, ovulation can be induced between the 9th to 16 day of menstrual cycle.
9. according to the medicine of claim 6, described ovulation is induced by rec.LH.
10. according to the medicine of claim 6, described ovulation is induced by natural LHRH.
11. according to the medicine of claim 6, described ovulation is by the LHRH agonist induction.
12. according to the medicine of claim 6, described ovulation is induced by HCG.
13. medicine according to Claim 8, described natural LHRH or LHRH agonist produce negative effect to avoid excitement luteal phase by giving in luteal phase with preventing HCG.
14. medicine according to Claim 8, described rec.LH, natural LHRH or LHRH agonist are used for avoiding too drastic syndromic generation.
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| Application Number | Priority Date | Filing Date | Title |
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| CN 97111580 CN1199642A (en) | 1997-05-16 | 1997-05-16 | LHRH-antagonists in treatment of fertility disorders |
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| CN 97111580 CN1199642A (en) | 1997-05-16 | 1997-05-16 | LHRH-antagonists in treatment of fertility disorders |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003103770A2 (en) * | 2002-06-07 | 2003-12-18 | Pantarhei Bioscience B.V. | Method of controlled ovarian hyperstimulation and pharmaceutical kit for use in such method |
| CN101397339B (en) * | 2008-09-24 | 2012-07-25 | 上海天伟生物制药有限公司 | Method for removing/inactivating virus in glucoprotein |
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1997
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003103770A2 (en) * | 2002-06-07 | 2003-12-18 | Pantarhei Bioscience B.V. | Method of controlled ovarian hyperstimulation and pharmaceutical kit for use in such method |
| WO2003103770A3 (en) * | 2002-06-07 | 2004-04-22 | Ares Trading Sa | Method of controlled ovarian hyperstimulation and pharmaceutical kit for use in such method |
| EA009371B1 (en) * | 2002-06-07 | 2007-12-28 | Арес Трейдинг С.А. | Method of controlled ovarian hyperstimulation pharmaceutical kit for use in such method |
| CN101397339B (en) * | 2008-09-24 | 2012-07-25 | 上海天伟生物制药有限公司 | Method for removing/inactivating virus in glucoprotein |
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