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The gonadotrophin-releasing hormone antagonist Cetrorelix is in advanced clinical development for the control of endogenous gonadotrophin secretion during the course of a fertility programme. The aim of the present study was to investigate the pharmacokinetics and pharmacodynamics of Cetrorelix following single and multiple s.c. administration of different doses. Thirty-six healthy female volunteers received either 0.25, 0.50 or 1.00 mg Cetrorelix, in a first menstrual cycle as single dose and in a second cycle as multiple dose (daily between cycle days 3 and 16). Frequent blood samples were collected for determination of Cetrorelix, follicle stimulating hormone (FSH), luteinizing hormone (LH), oestradiol and progesterone concentrations. Follicular growth was measured by transvaginal ultrasonography. After single administration of each dose, maximum Cetrorelix concentrations (Cmax) were reached after 1 h, and Cmax and area under curve (AUC) increased linearly with the dose. The median terminal half-life ranged from 5 to 10 h in the three different dose groups. FSH, LH, oestradiol and progesterone concentrations were suppressed, with a nadir at 6-12 h after Cetrorelix administration. During multiple administration, Cmax and AUC also showed dose-linearity. The median terminal half-life of Cetrorelix varied between 20 and 80 h. A dose-dependent suppression of FSH, LH and oestradiol concentrations was observed during treatment. After multiple administration, ovulation was delayed for 5, 10 and 13 days in the 0.25, 0.50 and 1.00 mg dose groups, respectively. In conclusion, Cetrorelix showed linear pharmacokinetics, and effectively delayed the LH surge.

A randomized study was performed in nine healthy women, to investigate pharmacokinetic parameters and bioequivalence of two human menopausal gonadotrophin preparations after i.v. administration. Endogenous gonadotrophin activity was suppressed by triptorelin administration. Humegon and Pergonal (225 IU of each) were injected i.v. in a cross-over way with an interval of 1 week. Blood samples were collected frequently and serum concentrations of follicle stimulating hormone (FSH), luteinizing hormone (LH), specific LH, and human chorionic gonadotrophin (HCG) were determined by fluoroimmunoassays assays. Serum LH bioactivity was measured by an in-vitro bioassay. The area under curve (AUC) and half-life of FSH were respectively 431.5 IU h/l and 22.20 h for Humegon, and 402.6 IU h/l and 21.33 h for Pergonal. For both preparations, the (total) LH immunoactivity and in-vitro bioactivity of serum LH were very similar, and appeared to be a composite of specific LH and HCG activity. The AUC data of specific LH were 17.50 IU h/l for Humegon and 21.79 IU h/l for Pergonal respectively. The AUC and half-life of HCG were 153.7 IU h/l and 14.80 h for Humegon, and 134.1 IU h/l and 12.11 h for Pergonal. The two preparations were bioequivalent with respect to FSH and HCG immunoreactivity. Bioequivalence could not be proven for LH activity because of the small number of subjects.

The aim of the present study was to investigate whether reducing the amount of luteinizing hormone (LH) in gonadotrophic preparations impairs follicular growth in in-vitro fertilization (IVF) cycles during suppression of endogenous LH levels. A selected group of 20 IVF patients was randomly divided into two groups. One group was treated with Org 31338 [follicle stimulating hormone (FSH)/LH 3:1], the other group with Metrodin (purified FSH), both during pituitary down-regulation with buserelin. A fixed daily dose of 150 IU FSH i.m. was given. Serum concentrations of FSH, LH, oestradiol and progesterone were determined frequently and serial ultrasound examinations were performed. Multiple follicular growth with concomitant rise of oestradiol levels was observed in all cycles. The duration of the stimulation phase was shorter in the group treated with Org 31338 than in the group treated with Metrodin. The number of follicles and oocytes and the fertilization rate was larger and the mean embryo quality was higher in the Org 31338 group, but the differences did not reach statistical significance. No significant differences were found in hormonal values. In women with normal endocrine profiles, lowering of the LH activity in gonadotrophic preparations during gonadotrophin-releasing hormone agonist treatment results in adequate ovarian stimulation. However, a preparation with some LH needed a shorter stimulation than a purified FSH preparation. Whether the other beneficial effects of Org 31338 also occur in a larger population needs further investigation.

Recently, several new urinary gonadotrophin preparations have been developed, containing less luteinizing hormone (LH) activity than human menopausal gonadotrophin. Normegon is a gonadotrophin preparation with a follicle stimulating hormone (FSH)/LH ratio of 3:1; Follegon and Metrodin-HP are purified FSH preparations. The aim of the present randomized study was to compare pharmaco-dynamics, -kinetics and local tolerance of these preparations after repeated s.c. administration. Thirty-six healthy female subjects were treated with Lyndiol contraceptive pills for 5 weeks to suppress endogenous gonadotrophin concentrations. After 3 weeks of Lyndiol treatment, 150 IU of Normegon, Follegon or Metrodin HP were administered once daily, s.c. for 7 days. Blood samples were collected once daily during the fourth and fifth weeks of the study and assayed for FSH and oestradiol. After the last gonadotrophin injection, blood samples were collected more frequently to determine pharmacokinetic parameters of FSH. During the fourth and fifth study weeks, daily ultrasound measurements of follicular growth were performed. Endogenous FSH and LH values were extremely suppressed during Lyndiol treatment. Serum FSH values showed similar patterns in the three groups. The maximum FSH concentration was reached 9-11 h post-injection, the terminal half-life was 43-47 h. The preparations were bioequivalent with respect to FSH immunoreactivity. The number of follicles tended to be larger after Normegon than after Follegon and Metrodin HP treatment, though this was not statistically significant. Serum oestradiol concentrations were significantly higher after Normegon treatment. In general, s.c injections were well tolerated. In conclusion, the three preparations were bioequivalent with respect to FSH immunoreactivity. Nevertheless, the biological activity of Normegon tended to be higher than that of Follegon and Metrodin HP in Lyndiol-suppressed women.