Bye-bye urinary gonadotrophins? Reply to Debate

Cees Jansen

Reinier de Graafgroep, loc Diaconessenhuis, Fonteynenburghlaan 5, 2275 CX Voorburg, The Netherlands e-mail: keesj@rdgg.nl

Dear Sir,

Drs Matorras and Crosignani have recently published a debate on urinary gonadotrophins: ‘Bye-bye gonadotrophins,’ (Matorras et al., 2002Go; Crosignani, 2002Go) in which both authors suggested a potential risk of prion infectivity to which I would like to respond. Discouraging the use of urinary gonadotrophins solely on the grounds of potential risks associated with prion infectivity is a deliberate oversimplification of the truth. In order to meet the objective of a serious debate, we should consider the available evidence for both recombinant and urinary-derived gonadotrophins.

In the literature, several references are made to two meta-analyses (Daya and Gunby 1999Go; Daya, 2002Go), which suggest that recombinant products are superior to urinary gonadotrophins. However, these meta-analyses have been criticised for including studies which are not statistically comparable and consequently lack clinical relevance. A major drawback of these meta-analyses is that different types of recombinant gonadotrophins were compared with different urinary products, i.e. unpurified and highly purified urinary (u)FSH. In the first meta-analysis, in 97% of all cycles in the alpha recombinant arm the comparison was made with highly purified uFSH, whilst this was only 13% of all cycles in the {beta} recombinant FSH; the latter product was mainly compared with the unpurified urinary product. It is implied that both uFSH products are totally equivalent, however, there is not a single randomized controlled trial that shows an equal bio-potency of unpurified versus highly purified FSH. Furthermore, there was no discrimination between studies using different pituitary desensitization protocols. Apart from this, the analysis excluded any comparison between recombinant gonadotrophin and human menopausal gonadotrophin. Several clinical trials have compared recombinant with urinary-derived gonadotrophins, but the wealth of evidence-based medicine available has failed to demonstrate any difference between either preparation in terms of clinical efficacy and safety.

To date, there has not been a single reported case of prion infection from the urinary gonadotrophins since their introduction more than 40 years ago. Likewise, the production process of recombinant products should be scrutinized. This process utilizes foetal calf serum and monoclonal antibodies, and furthermore, the collection of foetal calf serum may be crude and prone to contamination. Indeed, the risk associated with blood-based products is reflected in the approach adopted by regulatory authorities, whereby plasma and blood donations undergo the strictest screening procedures to minimise prion infectivity, amongst other infectious agents. However, Matorras and co-authors overlook these facts and instead focus on the study by Shaked et al. (2001Go), which demonstrated excretion of some form of a prion in urine, although it was stated to be a non-infectious isoform. Even so, the presence of the urinary isoform has been questioned as a possible artefact, generated by the dialysis technique used. (Reichl et al., 2002Go),

On the subject of multiple pregnancies, the Crosignani article chooses to ignore the fact that the rate of multiple pregnancies in assisted reproductive technology (ART) is similar regardless of whether urinary or recombinant gonadotrophins are used. In this article the author refers to the study of Gleicher et al. (2000Go), which makes no comparison between urinary and recombinant products, but instead questions whether ovulation induction in general should be replaced by IVF as a means of reducing the risk of higher order multiple pregnancy.

To conclude, I feel that if we are to make progress in terms of how best to manage patients undergoing ART then we need to adopt an objective approach. Until evidence-based medicine can demonstrate differences between recombinant and urinary gonadotrophins, any attempt to promote recombinant and denigrate urinary gonadotrophins is as yet unsubstantiated.

References

Matorras, R. and Rodriguez-Escudero, F.J. (2002) Bye-bye urinary gonadotrophins? The use of urinary gonadotrophins should be discouraged. Hum. Reprod., 17, 1675–1683.[Abstract/Free Full Text]

Crosignani, P.G. (2002) Risk of infection is not the main problem. Hum. Reprod., 17, 1675–1683.[Abstract/Free Full Text]

Daya, S. (2002) Updated meta-analysis of recombinant follicle-stimulating hormone (FSH) versus urinary FSH for ovarian stimulation in assisted reproduction. Fertil. Steril., 77, 711–714.[CrossRef][ISI][Medline]

Daya, S. and Gunby, J. (1999) Recombinant versus urinary follicle stimulating hormone for ovarian stimulation in assisted reproduction. Hum. Reprod., 14, 2207–15.[Abstract/Free Full Text]

Shaked, G.M., Shaked, Y., Kariv-Inbal, Z., Halimi, M., Avraham, I. and Gabizon, R. (2001) A protease-resistant prion protein isoform is present in urine of animals and humans affected with prion diseases. J. Biol. Chem., 276, 31479–31482[Abstract/Free Full Text]

Reichl, H., Balen, A. and Jansen, C.A.M. (2002) Prion transmission in blood and urine: what are the implications for recombinant and urinary derived gonadotrophins? Hum. Reprod., 17, 2501-2508.

Gleicher, N., Oleske, D.M., Tur-kaspa, I., Vidali, A. and Karande, V. (2000) Reducing the risk of high order multiple pregnancy after ovarian stimulation with gonadotrophins. N. Engl. J. Med., 343, 2–7.[Abstract/Free Full Text]