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The First World Congress On: Controversies in Obstetrics, Gynecology & InfertilityPrague, Czech Republic - 1999
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The introduction of urinary and recombinant preparations of pure FSH for the induction of ovulation has sparked research to compare the two with each other and with hMG in treating anovulation. For women devoid of endogenous gonadotrophins and requiring ovulation induction, some LH is necessary for normal ovarian steroidogenesis, but otherwise, the LH content of hMG has little effect on clinical outcome. Any differences found in the clinical results of the various preparations have been insignificant in the doses used for ovulation induction, although recombinant FSH seems more potent.
With the advent of ‘pure’ preparations of FSH, urinary (uFSH), highly purified urinary (uFSH-HP) and recombinant (recFSH), several comparative trials have been undertaken to find differences in their effects, efficiency, results and complication rate between themselves and compared with human menopausal gonadotrophins (hMG) in the treatment of anovulation. These preparations have been examined in women with hypogonadotrophic hypogonadism (H-H, WHO group I) and those with hypothalamic-pituitary dysfunction and endogenous estrogen (WHO group II), most of whom have polycystic ovary syndrome (PCOS).
Hypogonadotrophic hypogonadism is a condition with no or unmeasurable concentrations of FSH and LH. It thus provides a unique backdrop for the examination of the possible differences effected by the varying concentrations of LH in these preparations. From a large trial1 utilizing recFSH and several, randomized doses of recLH for ovulation induction in women with H-H, it is now clear that the two cell-two gonadotrophin hypothesis is true. Follicular growth can be achieved with FSH alone but some LH (approximately 75IU/day) is necessary to achieve adequate steroidogenesis and efficient ovulation and luteinization in response to hCG.
There are several theoretical reasons for believing that pure FSH preparations may improve efficiency and results of treatment of patients with PCOS compared with hMG. Administration of FSH will hypothetically correct the relative FSH deficiency and redress the high LH:FSH ratio, both prevalent and important factors contributing to anovulation in PCOS. In addition, pure FSH, rather than the additional LH in hMG, was thought to be more likely to reduce the miscarriage rate and increase chances of conception, both influenced by already high LH concentrations. In practice, uFSH, given for ovulation induction in PCOS, has not influenced follicular recruitment and development or ovulation and pregnancy rates when compared with hMG2. Both FSH and hMG decrease endogenous LH levels, FSH more than hMG, but the exogenous LH in hMG has very little impact on endogenous levels in doses used for ovulation induction in PCOS3. As a result, uFSH and hMG are equally successful in inducing ovulation and no difference in pregnancy rates or miscarriage rates has been noted. Complication rates are also similar. The mode of administration appears to be much more important than the preparations used; low dose therapy, be it with FSH or hMG, proving more efficient than conventional dose therapy in preventing multiple follicular development, multiple pregnancies and ovarian hyperstimulation syndrome. Comparisons of uFSH with recFSH have, on the whole, shown a greater bioactivity of recFSH for which a lower dose and shorter duration of administration was needed4,5. No clinical advantage in pregnancy rates was obtained with recFSH in the dose regimens used for ovulation induction in PCOS6.
1. RECOMBINANT HUMAN LH STUDY GROUP. Recombinant human luteinizing hormone (r-hLH) to support recombinant human follicle stimulating hormone (r-hFSH) - induced follicular development in LH and FSH deficient anovulatory women: a dose finding study. J Clin Endocrinol Metab, 83, 1507-1514, 1998.
2. SAGLE M, HAMILTON-FAIRLEY D, KIDDY D, FRANKS S. A comparative, randomizd study of low dose human menopausal gonadotrophin and follicle stimulating hormone in women with polycystic ovary syndrome. Fertil Steril, 55, 56-60, 1991.
3. LARSEN T, LARSEN JF, SCHIOLER V, BOSTOFE E, FELDING C. comparison of urinary follicle stimulating hormon and human menopausal gonadotrophin for ovarian stimulation in polycystic ovary syndrome. Fertil Steril, 53, 426-431, 1990.
4. COELINGH BENNINCK HJT, FAUSER BCJM, OUT HJ. Recombinant follicle stimulating hormone (FSH;Puregon) is more efficient than urinary FSH (Metrodin) in women with clomiphene resistant, normogonadotrophic chronic ovulation: a prospective, multicenter, assessor blind, randomized, clinical trial. Fertil Steril, 69, 19-25, 1998.
5. BALASCH J, FABREGUES F, PENNARUBIA J, MONTSERRAT C, VIDAL R. Follicular development and hormonal levels following highly purified or recombinant follicle stimulating hormone administration in ovulatory women and WHO Group II anovulatory infertile patients. J Assist Reprod Genet, 15, 552-559, 1998.
6. ARES-SERONO. A phase III, open, randomized, multicentre study to compare the safety and efficacy of rcombinant human follicle stimulating hormone (Metrodin) given intramuscularly, to induce ovulation in WHO Group II anovulatory infertile women. Ares-Serono Internal Report, 1995.