Multiple follicular development and ovarian steroidogenesis following subcutaneous administration of a highly purified urinary FSH preparation in pituitary desensitized women undergoing IVF: a multicentre European phase III study

A multicentre, multinational study was carried out between November1990 and February 1992 to assess the safety and efficacy ofa new highly purified urinary human follicle stimulating hormone(FSH; Metrodin HP®) which is practically devoid of luteinizinghormone (LH) activity. Metrodin HP was administered s.c. tostimulate multiple follicular development in women undergoingin-vitro fertilization (IVF) and embryo transfer. A total of139 women were recruited from 10 participatin centres. Of these,135 underwent pituitary desensitization with a long gonadotrophin-releasinghormone (GnRH) agonist protocol and following deter-minationof ovarlan inactivity (mean± SD of 12.9 ± 3.2days), Metrodin Hp s.c. stimulation was started; 122 patientswere fully eligible for efficacy analysios and 118 of these(97%) received up to 10 000 IU human chrionic gonadotrophin(HCG) to induce final folicular maturation and timed oocyterecovey. Mean plasma LH concentrations at the beginning of Metro-dinHP treaement were 1.6 ± 0.8 mIU/ml and by the day ofHCG administration were significantly (p<0.001) reduced (1.2±0.8mIU/ml). The mean plasma oestradiol and inhibin concentrationson the day of HCG were 6173±3567 pmol/l and 8.2 ±4.4IU/ml respectively. There was a positive correlation (r= 0.49,p<0.001) between individual oestradiol and inhibin concentrationson the day of HCG. In the 118 patients who received HCG, themean number of oocytes recovered was 8.4 ± 4.7 followingstimulation with 36 ± 10, 75 IU ampoules of MetrodinHP over 12.2±2.1 days. One-hundred-and-eight patients(89% of 122 eligible) ahd 5.3±3.3 oocyted fertilized,and 105 (86%) had 2.8±1.0 embryos transferred; 28 patients(23% perinitiated cycle) had a clinical pregnancy and subsequently18 of these (15% per initiated cycle) had a live birth. A totalof 135 patients who reveiced Metrodin HP were eligible for safetyanalysis. One patient did not receive HCG because of the riskof developing ovarian hyperstimulation syndrome (OHSS). Sevenpatients (5% of those who received HCG) developed OHSS, onesevere, five moderate and one mild case. Three OHSS patientswere pregnant and hospitalized. The patient with severe OHSSwas found to have an ectopic pregnancy. Local side effects werereported by 24 (18%) patients at the site of s.c injection.The most common compliant was brusing (48.5%). There was nodevelopment of antobodies to FSH. In conclusion Metrodln HP,a urinary gonadotrophin preparation in which>95% of the proteincontent is FSH, was effective in stimulating multiple folliculardevelopment and oestradol synthesis to a similar degree reportedfor other gonadotrophin preparations, even when endogenous LHsecretion was significantly reduced by a GnRH agonist. Thesedata support the concept that only very low concentrations ofLH are required in conjunction with FSH for the stimulationof follicular development and ovarian steroidogenesis. MetrodinHp was well tolerated locvally thus enabling convenient self-adminstrationwithout compromising safety or efficacy