Human gonadotrophins for ovarian stimulation in infertility treatment

Infertility problems are present in 10 to 15 % of couples of fertile age. Ovulatory dysfunction, as a single cause, can be successfully treated and in-vitro fertilisation (IVF) can help a considerable number of couples, also when male problems are present. Gonadotrophins, consisting of mixed hormones of variable molecular composition, are used in different ways in this connection for ovarian stimulation.

The aims of the thesis were to i) evaluate whether the composition of available drugs could explain varying ovarian response, ii) compare pharmaco-kinetic and -dynamic properties of the drugs used, iii) study the ovarian response to highly purified follicle stimulating hormone (FSH) in the absence of luteinizing hormone (LH), iv) compare the efficacy of purified urinary FSH (FSH-HP) and urinary menopausal gonadotrophin (hMG) preparation and v-vi) to compare two recombinant FSH preparations, in terms of ovarian stimulatory effects, pregnancy and delivery rates.

Marketed urinary preparations were analysed by isoelectric focusing, and by bio- and immuno-assays for FSH and LE Stimulatory effects and elimination rates were compared in crossover studies. Recombinant FSH (rhFSH) stimulatory effects were studied in gonadotrophin-deficient women. In a clinical comparative crossover study the stimulatory effects of FSH-HP and hMG were assessed. Two rhFSH preparations were compared clinically, with regard to their efficiency in ovarian stimulation as well as to pregnancy rates. This study was further extended to a comparison of delivery rates after IVF.

Conclusions: The urinary gonadotrophin preparations examined are dissimilar in terms of heterogeneity of their FSH and LH molecular constituents and FSH- and LH-potencies. Different methods of preparation might be responsible for these differences. However, the pharmacokinetic and pharmacodynamic properties are not influenced by the heterogeneities observed. Repeated injections result in an accumulation of FSH in plasma, due to its long circulating half-life. The concept of an optimal FSH/LH ratio is not supported by the results obtained.

Recombinant FSH exhibits no LH-effect. It can stimulate normal inhibin production, normal granulosa cell function, and growth of ovarian follicles in the absence of estrogens. FSH-HP is as effective as hMG for use in IVF; however lower estradiol levels can be expected in treatment cycles, when highly purified FSH preparations are used; this should be taken into consideration when the day of ovum retrieval is based on circulating oestrogen levels. Available rhFSH preparations are equally suitable and effective, when used in IVF.

List of scientific papers

I. Harlin J, Khan SA, Diczfalusy E (1986). "Molecular composition of luteinizing hormone and follicle-stimulating hormone in commercial gonadotropin preparations. " Fertil Steril 46(6): 1055-61
https://pubmed.ncbi.nlm.nih.gov/3096793

II. Diczfalusy E, Harlin J (1988). "Clinical-pharmacological studies on human menopausal gonadotrophin. " Hum Reprod 3(1): 21-7
https://pubmed.ncbi.nlm.nih.gov/3127421

III. Schoot DC, Harlin J, Shoham Z, Mannaerts BM, Lahlou N, Bouchard P, Bennink HJ, Fauser BC (1994). "Recombinant human follicle-stimulating hormone and ovarian response in gonadotrophin-deficient women. " Hum Reprod 9(7): 1237-42
https://pubmed.ncbi.nlm.nih.gov/7962424

IV. Fried G, Harlin J, Csemiczky G, Wramsby H (1996). "Controlled ovarian stimulation using highly purified FSH results in a lower serum oestradiol profile in the follicular phase as compared with H" Hum Reprod 11(3): 474-7
https://pubmed.ncbi.nlm.nih.gov/8731179

V. Harlin J, Csemiczky G, Wramsby H, Fried G (2000). "Recombinant follicle stimulating hormone in in-vitro fertilization treatment-clinical experience with follitropin alpha and follitropin beta. " Hum Reprod 15(2): 239-44
https://pubmed.ncbi.nlm.nih.gov/10655291

VI. Harlin J, Aanesen A, Csemiczky G, Wramsby H, Fried G (2001). "Delivery rates following IVF treatment, using two recombinant FSH-preparations for ovarian stimulation." Hum Reprod (In Print)