METHOD FOR THE TREATMENT OF FERTILITY DISORDERS

Abstract: In the method of therapeutic management of infertility by intrauterine insemination the improvement consisting of a) the dose-dependent suppression of endogenous gonadotropins, especially LH, with a LH-RH Antagonist allowing the maintenance of physiological oestrogen levels, b) exogeneous stimulation of the ovarian follicle growth, c) ovulation induction with HCG, native LHRH, LHRH-Agonists or recombinant LH, d) intrauterine insemination by sperm injection. The LHRH Antagonists may be preferably Cetrorelix or Antarelix. The stimulation is performed by administration of HMG or recombinant FSH with or without recombinant LH or with antiestrogens as for example Chlomiphen as well as with the combination of antiestrogens as for example Chlomiphen with gonadotropins.

Description: Method for the treatment of fertility disorders One of the ethical problems of more recent times is the increasing sterility and unwanted childlessness of many couples. With respect to the therapy of these fertility disorders, inter alia, the following treatment methods of artificial fertilization have been established: 1. Substitution therapy - applied in patients with hypogonadotropic amenorrhoea 2. Stimulation therapy - given to anovulatory patients with active, albeit deranged hypothalamic pituitary-ovarian axis 3. Regulation therapy - employed in women with POCD 4. Hyperstimulation therapy - used in IVF, gamete intrafallopian transfer (GIFT) , tubal embryo transfer (TET) , intracytoplas atic sperm injection (ICSI) and intrauterine insemination (IUI) . The present invention especially relates to the improvement of the method of artificial sperm cell transfer in the uterus, i.e. the fertilization by intrauterine insemination (IUI) mentioned under item 4. For the methods under items 2 and 4, it is necessary to stimulate follicle growth, which is achieved by the administration of gonadotropins, e.g. HMG, FSH and LH, with or without preliminary therapy with clomiphene. It has further proved that the risk of luteinization by a premature LH surge, which leads to unfavourable implantation conditions and relatively low pregnancy rates, can be decreased by complete suppression of the endogenous gonadotropins using GnRH agonists (Garcia et al., 1984; Navot et al . , 1991; Hoffmann et al . , 1993). For the control of ovarian stimulation with subsequent induction of ovulation, with the aim of obtaining fertilizable egg cells, both recombinant FSH and HMG and FSH and HMG obtained from urine are employed. - 2 - In connection with IUI, it is also desirable to control - follicle growth and to specifically trigger ovulation. The statements in the specialist literature about the therapeutic accompaniment of IUI, in particular using GnRH analogues, are mainly negative, such as, for example, the following: 1. IUI after ovarian stimulation with clomiphene may be important as the l Ξt choice of therapy, provided the male partner has a normal spermiogram (Hum. Reprod. 1997; July; 12 (7) : 1458-1463) . 2. GnRH agonists/HMG stimulation, however, may be ineffective in routine IUI. Treatment with GnRH agonists with maximum suppression of the endogenous gonadotropins requires a relatively long treatment period (about 3 weeks) and leads to an increased consumption of HMG and is associated with side effects. 3. Reports also exist which confirm that an increase in the pregnancy rate is not achieved by the use of GnRH agonists/HMG against HMG alone for IUI treatment in the case of unclarified infertility (Hum. Reprod. 1994 June 9(6) 1043-1047. 4. The cost differences of GnRH-a/HMG stimulation compared with clomiphene/HMG is indicated by Finnish authors in Eur . J. Obstet . Gynecol . Reprod. Biol . 1997 July 74: GnRH-a/HMG stimulation is not cost-effective in routine IUI therapy. In a study by Diedrich et al . from 1994 Hum. Reprod. 1994 May; 9(5), the suppression of the undesired, premature LH surge by cetrorelix during ovarian stimulation with HMG and the on-time induction of ovulation was described in the context of a COS-ART study. It was possible to shorten the length of the treatment period using this LHRH antagonist and the partial dose- dependent suppression of the endogenous gonadotropins additionally proved advantageous, since it was possible - 3 - to reduce the consumption in comparison to the use of agonists of HMG. The object of the invention is therefore to improve, i.e. to make inexpensive and more effective, the treatment method of intrauterine insemination known per se and thus in the end to fulfil the desire for children of many couples. It has now been found that the treatment method of IUI can be improved by carrying out a partial suppression of the endogenous gonadotropins, which can only be achieved by means of LHRH antagonists, preferably cetrorelix or antarelix. At the same time, follicle growth is stimulated by means of urinary or recombinant FSH, HMG or clomiphene, or a combination thereof. Subsequently, ovulation can be triggered at a desired time by means of HCG, native LHRH, LHRH agonists or recombinant LH. Surprisingly, this takes place when the dominant follicle has reached a diameter of about 16-18 mm. Intrauterine sperm injection then takes place with the aim of intracorporeal fertilization. It is possible in this way to carry out a stimulation treatment which is less stressful for the patient and guarantees a high degree of safety with respect to the ovulation time and leads to a saving in cost.

Claims: _ 4 _ Claims : 1. In the method of therapeutic management of infertility by intrauterine insemination, the improvement consisting of a) the dose-dependent suppression of endogenous gonadotropins, especially LH, with an LH-RH antagonist allowing the maintenance of physiological oestrogen levels b) exogenous stimulation of the ovarian follicle growth c) ovulation induction with HCG, native LHRH, LHRH agonists or recombinant LH. d) intrauterine insemination by sperm injection. 2. The method of therapeutic management of infertility by intrauterine insemination according to claim 1 in which the LHRH antagonist is cetrorelix. 3. The method of therapeutic management of infertility by intrauterine insemination according to claim 1 in which the LHRH antagonist is antarelix. 4. The method of therapeutic management of infertility by intrauterine insemination according to claim 1 in which the stimulation is performed by administration of urinary or recombinant FSH or HMG, with or without recombinant LH. 5. The method of therapeutic management of infertility by intrauterine insemination according to claim 1 in which the ovarian stimulation is achieved with antioestrogens as for example clomiphene . 6. The method of therapeutic management of infertility by intrauterine insemination according - 5 - to claim 1 in which the ovarian stimulation is achieved with the combination of antioestrogens as for example clomiphene with gonadotropins.

Inventors: ENGEL JUERGEN, REISSMANN THOMAS, RIETHMUELLER-WINZEN HILDE, ENGEL, JUERGEN, REISSMANN, THOMAS, RIETHMUELLER-WINZEN, HILDE
Applicants: ASTA MEDICA AG, ASTA MEDICA AKTIENGESELLSCHAFT
Application year: 1999
Main classification: A61K38
IPC codes: A61K31, A61K35, A61K38, A61K45, A61P15