The clinical benefits of recombinant gonadotrophins

E.R. Hernandez

Clinica de Reproduccion Asitida FIV-Madrid, C/ Alvarez de Baena 4, 28006 Madrid. Instituto de Bioquimica, CSIC, 28040 Madrid, Spain

Dear Sir,

As my father once remarked when he got back from a trip abroad: `If you have seen one Sistine Chapel, you have seen them all' (Friedman, 1986Go). In my opinion, that is particularly true for recombinant follicle stimulating hormone (FSH), introduced by pharmaceutical companies, as something unique with which we can fulfil all of our expectations for ovulation induction.

However, it seems to me that, with respect to the clinical benefits of recombinant rather than urinary FSH, we are moving into a desert surrounded by scientific business to the north and in a clinical limbo to the south. Nevertheless, it is very gratifying to know that the pharmaceutical industry is sharing the distress that the price of recombinant FSH will have on the patient's budget and on the final cost of assisted reproductive technology (ART) procedures (Out et al., 1999Go). I agree with these authors that the pharmaceutical companies have to spend thousands of dollars on clinical studies before they are able to obtain revenue, but what I cannot agree with is the concept that `The price of the recombinant FSH is a reflection of >10 years of research and development', as a means to vindicate the final price of recombinant FSH. To the best of my knowledge, the technology used to obtain recombinant FSH has been used for >10 years and is a common tool in any molecular laboratory. For example, human FSH was cloned and sequenced in 1987 (Watkins et al., 1987Go), plasmid pBR322 and Chinese hamster ovarian cells are available from the ATCC (Rockville, MD, USA) for US$60, while subcloning, transfection and related techniques were described in the first edition of Maniatis in 1982 (Sambrook et al., 1982Go), etc. In any event, it is not my intention to undervalue the excellent work done by the scientists who have developed recombinant FSH, but it is clear to me that the technology on which recombinant FSH was based, was already there and should not be used as a justification for the price of recombinant FSH. Furthermore, this is not the first molecule to be produced by recombinant technology. For example, recombinant insulin has been available for >10 years and is a good example of a hormone born by recombinant technology, living in a very competitive market, but selling at an affordable price for the patients.

Putting aside finances and moving on to the scientific arena where the discussion with regard to the differences between recombinant and urinary FSH in ovulation induction brings us into a scientific limbo. Overall, this debate takes us back to the 1930s, when endocrinologists were discussing the physiological role of a hormone without the notion of the receptor. To the best of my knowledge, to date, several kinds of receptor have been described: native receptors (well-characterized with a known ligand), hybrid receptors [e.g. the one described for insulin/insulin-like growth factor (IGF)-I], orphan receptors (with an unknown ligand) and the forgotten receptor, the FSH receptor (FSHR), which has been well characterized but has been totally ignored. However, in order to understand the clinical benefits of recombinant rather than urinary FSH, one must keep in mind how FSH works at the cellular level. Briefly, in the granulosa cells, when FSH binds to the FSH receptor, it triggers an intracellular cascade of events that involve G-proteins and adenyl cyclase activation, increase in cAMP, interaction of cAMP response element binding protein (CREB) protein with cAMP response element (CRE) consensus sequences in the 5' region of any given gene and finally gene transcription (Richards, 1980Go; Findlay et al., 1999). By definition, all these steps and the subsequent biological response to FSH (e.g. oestrogen production) in the granulosa cell, are correlated with the number of FSH receptors in the cell surface and the affinity of FSH for its receptor (Richards, 1980Go). So far, the research done to determine the affinity, binding capacity and bioactivity of recombinant and urinary FSH for the FSH receptor was the same (Mannaerts et al., 1991Go; Matikainen et al., 1994Go). Furthermore, no differences in the in-vitro production of oestrogen or cAMP were found between these two gonadotrophins (Mason et al., 1993Go). These results should not surprise anyone because there is 99.99% amino acid homology between recombinant, urinary and native FSH and may explain the small differences found in ovulation induction between gonadotrophins of diverse origin (Hoomans et al., 1999Go) With all these arguments it seems as if I were against recombinant FSH. Not at all. I would like to say that recombinant FSH in its present molecular structure does not add much more than urinary FSH in ovulation induction. To me, recombinant FSH is in an interlude between what is today and what will be in the future, when in-vitro mutagenesis would be at play. By then, recombinant FSH the `coming of wonders' will be a `super drug' (Out et al., 1999Go). Although considerable substitution in in-vitro mutagenesis would be required to fully understand the mechanism by which mutated FSH may effect the basis of the FSH–FSHR complex (Dias et al., 1998Go). Finally, I would like to acknowledge all the scientists that have made the synthesis of recombinant FSH possible, because they have realised a dream – a dream that started 30 years ago when the first urinary FSH was obtained in a laboratory in Italy. Thanks to molecular biology techniques, these scientists have accomplished what the Italian researchers have already in their mind, i.e. to recreate in the laboratory a FSH as pure as the natural one. A scientific dream – a dream that has became unreachable for many infertile couples.

References

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