To overcome this problem, female partners of infertile couples undergo ovarian stimulation with gonadotropins like HMG (human menopausal gonadotropin), FSH (follicle stimulating hormone) or by the antioestrogen clomiphene and gonadotropins.

This therapy stimulates the growth of a cohort of 6-12 follicles and oocytes to guarantee the fertilisation of sufficient oocytes by highly specified laboratory technologies. During this procedure a premature ovulation indicated by an LH and progesterone surge is prevented by the administration of LHRH-analogues, either by LHRH-antagonists or by LHRH-agonists.

Background Information and Prior Art According to the known treatment protocols HMG is given on day 2 of the menstruation cycle. A single or multiple dose of 0,25mg to 5mg of LHRH antagonist Cetrorelix was administered to prevent LH surges on day 5 until and including the day of ovulation induction with HCG. (Hum. Reprod. 1994 May ; 9 (5) : 788-91, Hum. Reprod.

1995 Jun ; 10 (6) : 1382-6, Fertil. Steril. 1997 ; 67 : 917-22, Hum. Reprod. 1998 Sep ; 13 (9) 2411-4) In the PCT application WO 98/58657 the LHRH antagonist ganirelix in an amount of 0,125-1 mg is administered in the method to prevent premature LH surges in women undergoing controlled ovarian hyperstimulation in combination with exogeneous FSH.

The EP 161 063 also teaches the use of a gonadotropin releasing hormone antagonist to prepare a pharmaceutical composition comprising a gonadotropin selected from HMG and FSH in the treatment of female infertility to suppress estrogen variability, in which treatment the antagonist composition is administered in an effective amount cojointly with the gonadotropin composition.

Usually for controlled induction of ovulation and final follicle maturation HCG (human chorionic gonadotropin) is given. 36 hours thereafter oocytes are picked up (OPU) by transvaginal or laparoscopic follicle puncture.

For the fertilisation of multiple oocytes by the sperms of the male partner assisted reproductive techniques (ART) are applied like IVF (in-vitro-fertilisation), ICSI (intracytoplasmic sperm injection), GIFT (gamete intra-Fallopian transfer) or ZIFT (zygote intra-Fallopian transfer) in highly specialized laboratories on the day of OPU.

Normally, two to four days after extracorporeal fertilization embryo transfer is performed by the replacement of several embryos into the cavum uteri to obtain pregnancy.

As many follicles develop following controlled ovarian stimulation therapy (COS) ovarian enlargement occurs and many oocytes are picked up. Therefore, oocyte pick up procedures have to be done in the operating theatre and with the application of general or regional anesthesia.

Assisted reproductive techniques are carried out in highly specialized laboratories by qualified personnel thereafter.

Preferably, these procedures have to be included into the routine operating theatre plans from Mondays to Fridays. The performance of oocyte pick up as well as of embryo transfer on weekends or holidays is avoided due to lack of enough qualified personnel on duty in most clinics. Furthermore, some hospitals undertake these

procedures only on a few days each month in order to have the oocyte pick up and fertilization procedures performed by a highly specialized serviceteam to increase the number of oocytes obtained as well as the fertilization rates and the number of good quality embryos. Therefore, programmed ovarian stimulation protocols are applied.

Object of the Invention The present invention especially relates to the improvement of the method of programming of ovarian stimulation procedures, i. e. the administration of LHRH- antagonists in controlled ovarian stimulation where the start of menstrual cycle and ovarian stimulation was programmed.

Summary of the Invention In a controlled ovarian stimulation procedure conducted with an LHRH-antagonist for the prevention of premature ovulation, gonadotropin injection is started at cycle day one to three of a menstrual cycle and is continued until the day of HCG when enough big follicles have developed.

The LHRH-antagonist is given at the days of risk of premature ovulation. The duration of ovarian stimulation takes normally ten days in these treatment cycles.

In order to perform oocyte pick up and fertilization procedures during Mondays to Fridays the start of a menstrual cycle and of COS are programmed.

For the programming of the start of the menstrual cycle and of controlled ovarian stimulation procedures oral contraceptives or progestogen-only containing preparations are given in the follicular phase, preferably starting at menstrual cycle day 1 or 2, or in the late luteal phase of the previous menstrual cycle.

The LHRH antagonist Cetrorelix was also used successfully for this purpose previously when 1mg were given in the luteal phase and luteal regression was obtained and menses started 2 to 4 days later.

The duration of oral contraceptive or progestogen administration will be a minimum of

ten up to a maximum of 25 days. Intake of the last tablet will preferably be on a Monday to Thursday to obtain start of menstrual bleeding and of ovarian stimulation therapy on Fridays to Mondays. Thereafter, oocyte pick up and further ART procedures can be schduled and undertaken on Mondays to Thursdays.

The in a controlled ovarian stimulation procedure applied LHRH-antagonist for the prevention of premature ovulation can be for instance cetrorelix, teverelix, ganirelix antide or abarelix.

It is further in scope of the invention that the programming of COS and ART procedures is performed by oral administration of progestogen preparations, ethinylestradiol and progestogen, combined mono-bi-and triphasic contraceptive preparations containing contraceptive preparations, mestranol and progestogen, as well as by subcutaneous injection of LHRH antagonists.

The LHRH antagonists may be cetrorelix, teverelix, ganirelix, antide or abarelix and should be administered during the luteal phase in a dosage of 0,5 mg to 10 mg.

The ovarian stimulation is performed by administration of urinary or recombinant FSH or HMG, with or without recombinant LH and with antioestrogens as for example clomiphene also with a combination of antioestrogens as for example clomiphene with gonadotropins.

Example Material and methods A total of 30 patients, 15 from each German study center was enrolled for one treatment cycle. In the pre-treatment cycle, each patient received monophasic oral contraceptive (OC) pills containing 30 Klg Estradiol in combination with levonogastrel.

Gonal-F @ administration starting at dose 150 IU or 225 IU began on the first day of withdrawal bleeding after OC treatment. Cetrotide 0 0, 25 mg was given daily from the evening of stimulation day (s-day) 5/morning of s-day 6 until the day before hCG administration. On the basis of the ultrasound scans performed on s-day9/10 (s-day 9/10), and a calculation of follicular growth of 2mm per day, hCG was administered to trigger ovulation (when >2 follicle's > 18 mm) were visualized.

Efficacy endpoint assessed included number of follicles 2 18 mm on s-day 9/10, total number of vials of Cetrotide @ and ampoules of Gonal-F used, duration of Cetrotide @and Gona !-F @ treatments, number of patients receiving hCG, patients undergoing oocyte retrieval, number of oocytes retrieved, reliability of prediction of day of oocyte retrieval, and pregnancy rate. Safety end-points were indicated and severity of adverse events.

Results Preliminary results from 17 patents show that the mean number of follicles 2 18 mm on s-day 9/10 was 2,2. On the last day of Cetrotide° administration the mean number of follicles with diameters of < 14 mm, 15-17 mm and 218 mm were 2,7,4,9 and 2,7 respectively. A median number of 24 ampoules of Goal-fie equivalent to 75 IU were administered for 10, 0 days, and daily injections of Cetrotideo 0,25 mg were administered for 5,7 days on average, respectively. All 17 women who received hCG had ovum pick up and embryo transfer. Overall, a mean number of 8,8 oocytes were retrieved and a mean of 2 embryos was transferred.

The pregnancy rate per attempt/cycle was 41 %. The difference between predicted and actual day of OPU was 2 day on average. There as no cases of OHSS nor adverse events.

Conclusions This is the first result of the use of Cetrotidee in COS cycles programmed by OCs.

Overall, the stimulation results are similar to those observed in non-programmed cycles. Cetrotidee appears to be effective in OC programmed cycles, is well tolerated and allows reliable prediction of the day of oocyte retrieval. Thus use of Cetrotide @ in programmed stimulation cycles represents another step towards well-tolerated, effective and convenient procedures in ART.

Cetrotide @ is the registered Trade Mark for the LHRH Antagonist cetrorelix.

The various embodiments which have been described herein intended to be representative and not limiting, as various changes and modifications can be made in the present invention without departing from the spirit and scope thereof.