The good, the bad and the ugly

E.R. Hernández

Centro de Reproduccion Asistida FIV-Madrid, Alvarez de Baena 4, Madrid, Spain and Instituto de Bioquimica, CSIC, Madrid, Spain

After recently spending 2 days listening to a group of very distinguished professors and scientists with many years of experience in ovulation induction, and having read the recent debate on Puregon (Meniru, 1999Go), it seems to me that the ovulation induction market resembles a spaghetti western; the film `The Good, the Bad and the Ugly' comes particularly to mind, with the characters in our version being recombinant follicle stimulating hormone (FSH) as the good guy, urinary FSH as the ugly one and clomiphene citrate as the bad guy. Just as in the original movie, the good guy and the ugly guy join forces to fight the bad guy in their quest for the hidden gold (the market, in our movie).

This analogy came to mind because, during presentations and discussions throughout the congress, gonadotrophins and clomiphene citrate were held up as good alternatives for ovulation induction. In my opinion, the two main reasons behind this renewed interest and the revival of clomiphene citrate for ovulation induction are: (i) the arrival of gonadotrophin-releasing hormone (GnRH) antagonists and (ii) the price of the new gonadotrophins (mostly recombinant ones). Preliminary data on the use of GnRH antagonists in ovulation induction protocols suggest that their two main adverse effects, i.e. the need to increase the amount of gonadotrophins to overcome the ovarian resistance stage and exaggerated follicle recruitment (hence the risk of hyperstimulation), can be avoided.

Translated into daily clinical practice, this means a significant reduction in the number of follicles recruited and in the number of ampoules of gonadotrophins used; both factors which contribute to lowering the cost of ovulation induction protocols. Furthermore, if we take into account the current trend to transfer fewer and fewer embryos (two or three), everyone is looking for less and less aggressive protocols.

In the light of this scenario, many professionals (as was abundantly clear throughout the symposium) are looking again at clomiphene citrate as a means of lowering the cost of in-vitro fertilization (IVF); and when it comes to efficacy and price, clomiphene citrate is number one. I could not agree more that we need to reduce the cost of assisted reproduction techniques in order to treat the broadest patient base possible, and extend these therapeutic measures to the third world (where clomiphene citrate can play a major role). However, what I find hard to swallow is that we seem to be forgetting (or perhaps ignoring), the enormous amount of scientific work that went into identifying the efficacy of each product and clarifying what each one does in the ovulation induction process. As I see things, when it comes to deciding which drugs to prescribe in order to initiate ovulation induction, we should not be swayed by what one group of experts opine, since their modus operandi may be limited by the conditions in their countries of origin, working centres, etc. Our decisions should be based not only on scientific evidence, but on the access the patients have to the gonadotrophins and the health care conditions present in each of our countries.

In an effort to be brief, suffice it to refer the reader to the scientific literature on the subject to see what scientific conclusions have been reached concerning ovulation induction (Sharom et al., 1989Go; Doyle et al., 1991Go; Karlstrom et al., 1993Go; Zosmer and Tan, 1994Go; Ransom et al., 1996Go; Ganirelix Dose-Finding Study Group, 1998Go; Guzick et al., 1998Go; Tarlatzis and Grimbizis, 1998Go). These studies clearly show that the gonadotrophins are better than clomiphene citrate, as they lead to more and better-quality follicles, which translate into higher pregnancy rates.

These are facts that almost everyone working in the field of assisted reproduction are aware of. So, if everything is so clear, why have these questions been raised anew, and where does the conflict reside? The conflict crops up when scientific evidence and the patients' budgets are projected together in a philosophy that calls for saving money, without compromising (in these circumstances) results and efficacy. However, the truth of the matter is that this cannot be done, and what is more, this way of thinking only breeds confusion. As a result, the worldwide market for ovulation induction is in upheaval and people do not know which way to turn.

Just as on the stock market, where everything revolves around the price of the shares, in our market, it is the cost of gonadotrophins that has triggered this commotion and, hence, has made clomiphene citrate look particularly attractive. In light of this, the health care systems operating in each of our countries, and the access that the patient has to drugs, hold the key to the conundrum. For example, in countries with socialized medicine (most European countries) where the government covers the costs, it should not be very hard for patients to be given. In these countries, infertile couples are highly informed (through associations, books, the press, etc); they are familiar with the drugs available in the market and are aware of which are the most efficient, when it come to achieving pregnancy.

Furthermore, for the last 5 years we have ourselves been preaching the benefits of the gonadotrophins from every imaginable pulpit, so when it comes to prescribing treatment, many of these patients already know what they want. In countries where the couple must pay for the drugs used in treatment, the specialist's advice and a consensus reached between the specialist and the patient set the guidelines for ovulation induction and for what can be expected from treatment.

In conclusion, I think that what we are witnessing now is a little score settling until the market offers what (in my opinion) will significantly reduce the cost of IVF in the near future: improvements in culture media techniques and the possibility of transferring embryos (one or two) with proven survival capacity (without losing quality in ovulation induction).

Finally, returning to our movie, it was never the scriptwriter's intention to wipe the bad guy completely out of the picture, but simply to confine him to the limits that nature and science had already written for him.

Notes

This debate was previously published on Webtrack 57, March 22, 1999

References

Doyle, M.B., Thornton, K.L., Seifer, D.B. and De Cherney, A.H. (1991) Induction of ovulation for IVF and its effect on the luteal phase. Ann. N.Y. Acad. Sci., 217–227.

Ganirelix Dose-Finding Study Group (1998) A double-blind randomized dose-finding study to assess the efficacy of the gonadotrophin-releasing hormone antagonist ganirelix (Org 37462) to prevent premature luteinizing hormone surges in women undergoing ovarian stimulation with recombinant follicle stimulating hormone (Puregon®). Hum. Reprod., 13, 3023–3031.[Abstract]

Guzick, D.D., Sullivan, M.W., Adamson, G.D. et al. (1998) Efficacy of treatment for unexplained infertility. Fertil. Steril., 70, 207–213.[ISI][Medline]

Karlstrom, B.O., Bergh, T. and Lundkvist, O. (1993) A prospective randomised trial of artificial insemination versus intercourse in cycles stimulated with human menopausal gonadotropin or clomiphene citrate. Fertil. Steril., 59, 554–559.[ISI][Medline]

Meniru, G. (1999) What are the clinical benefits of recombinant gonadotrophins? Is Purgon a `good' or `super' drug? Hum. Reprod., 14, 1409–1411.[Free Full Text]

Ransom, M.X., Dougham, N.C. and Garcia, A.J. (1996) Menotropins alone are superior to a clomiphene citrate and menotropin combination for superovulation induction among clomiphene citrate patients. Fertil. Steril., 65, 1169–1174.[ISI][Medline]

Sharom, Z., Lidor, A. and Lunenfeld, B. (1989) The assessment of a cycle with clomiphene citrate as an indicator for further treatment. J. Endocrinol. Invest., 12, 9–12.[ISI]

Tarlatzis, B.C. and Grimbizis, G. (1998) Future use of clomiphene in ovarian stimulation. Will clomiphene persist in the 21st century?. Hum. Reprod., 13, 2356–2365.[Free Full Text]

Zosmer, A. and Tan, S.-L. (1994) Infertility and spontaneous abortion – the role of LH. In Filicori, M. and Flamigni, C. (eds), Ovulation Induction. Elsevier Scientific, Amsterdam, The Netherlands, pp. 347–352.





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