Human Reproduction, Vol. 14, No. 6, 1418-1420,
June 1999
© 1999 European Society of Human Reproduction and Embryology
Debate |
Recombinant follicle stimulating hormone
Centre of Reproductive Medicine Sahlgrenska University Hospital, S-41345 Göteborg, Sweden
The lead debate (Meniru, 1999) on recombinant gonadotrophins points to an important clinical problem – how can clinicians evaluate and use the recently available recombinant gonadotrophins? The author also questions the marketing performed by the medical industry of these new preparations. Even though I agree with some of the critical remarks made by Dr Meniru, I think one has to admit that the recombinant gonadotrophins bear clear advantages in comparison with the older urinary preparations.
The manufacture of human follicle stimulating hormone (FSH) by recombinant DNA technology makes production independent of urine collection and guarantees a high availability of a biochemically pure FSH preparation free from urinary protein contaminants. The purification process yields FSH with a specific activity of >10.000 IU FSH/mg protein. The high purity and low immunogenicity allows s.c administration. In contrast, there are reports of local and systemic adverse reactions to urinary gonadotrophins (Redfearn et al., 1995
; Albano et al., 1996). As well as high purity and constant availability batch-to-batch consistency offers a major advance. Even if both urinary gonadotrophins and recombinant preparations use a bioassay technique (the Steelman–Pohley rat in-vivo bioassay; Steelman and Pohley, 1953) to assess potency, the urinary gonadotrophins are biological products with an inconstant variation in their composition. A certain variation in clinical response will, therefore, be expected. Another advantage with the recombinant gonadotrophins which should be mentioned is the possibility of further development. FSH is a 34 kDa glycoprotein hormone consisting of a non-covalently linked heterodimer of two polypeptide chains, an 
- and ß-chain. FSH exhibits a high degree of heterogeneity due to different glycoforms (Storring, 1992). In particular, differences in sialic acid residue content are thought to play an essential role. These glycoforms differ in charge, half-life in the circulation and metabolic clearance rate (Wilson et al., 1990). Whether a difference in clinical potency also exists between these isoforms is, as yet, unknown. However, both luteinizing hormone (LH) and FSH glycoforms vary in relation to sex (Wide, 1985), age (Reader et al., 1983) and stage of menstrual cycle (Wide and Bakos, 1993) with more basic forms found at mid-cycle than at the follicular and luteal phases. Recombinant technology may offer an opportunity of controlling the glycoform composition of the gonadotrophins and, hence, of designing a FSH with a composition which resembles that of the normal menstrual cycle. A more physiological stimulation of follicular development, particularly for ovulation induction in anovulatory women, would in the future be possible.
In the article by Meniru (1999), the potency of recombinant FSH is extensively discussed. A higher bioactivity of rFSH has been demonstrated (Mannaerts et al., 1996) and prospective, randomized trials have found both follitrophin (Out et al., 1995) and follitrophin ß (Bergh et al., 1997; Frydman et al., 1998) to be more effective than urinary FSH in inducing follicular development. In these studies, the number of oocytes retrieved, the number of stimulation days and the number of ampoules needed for stimulation were all in favour of the recombinant compounds. However, the degree of this higher potency is hard to evaluate. I am aware of the suggestion that the potency of 50 IU rFSH might be regarded as equal to 75 IU of urinary FSH. In my experience, this is not necessarily valid, nor am I aware of any scientific studies supporting such a claim. After a 3 year period of experience with rFSH, I think a 15–25% increase in potency in comparison with the urinary compounds might be more realistic. I totally agree with Meniru that dosing regimens of rFSH will follow patterns similar to those used for urinary preparations and that doses used for stimulation will depend on patient characteristics, e.g. age, body mass index, ovarian ultrasound (especially the presence of polycystic ovaries), menstrual pattern, previous ovarian surgery etc. However, it is a great advantage that rFSH is available in several different ampoule sizes (37.5, 50, 75, 100 IU etc), thus encouraging the use of smaller and more individualized doses. The report from Brussels (Devroey et al., 1998) that 100 IU of Puregon was sufficient for ovarian stimulation before in-vitro fertilization (IVF) in a certain population of women might not be unique but indeed has some value, showing excellent results after a low dose of FSH stimulation. In a similar study (C.Bergh et al., unpublished data), we found that for 49 women starting on a dose of 100 IU Puregon, this dose was sufficient in 26 women, while in 23 women the dose had to be increased. The number of oocytes retrieved as well as the pregnancy rate was satisfactory, particularly in the group of women who continued with 100 IU rFSH throughout the stimulation period (Table I). It is highly probable that these women with a starting dose of 100 IU rFSH were women who earlier used 112.5 IU urinary FSH as stimulating dose, thus indicating a moderate increase in potency for rFSH.
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It has also been claimed that stimulation with rFSH yields oocytes and embryos of higher quality than stimulation with urinary compounds. In the controlled studies cited above (Out et al., 1995; Bergh et al., 1997
; Frydman et al., 1998) neither implantation rate, nor clinical or ongoing pregnancy rate per attempt or per transfer did differ significantly between urinary and rFSH stimulation. In our study (Bergh et al., 1997) the clinical pregnancy rate per started cycle and per embryo transfer was 48 and 45% for Gonal F and 47 and 37% for Metrodin HP respectively. The miscarriage rate was 25% in the Gonal F group and 14% in the Metrodin HP group yielding a delivery rate per embryo transfer of 36 and 40%. In the same study, when analysing oocyte maturity in patients undergoing intracytoplasmic sperm injection (ICSI) no differences were found between the two groups. Taken together, the results from that controlled study gave no support for the hypothesis that rFSH should yield oocytes and embryos of better quality. In conclusion, I think the newly developed recombinant gonadotrophins have clear advantages, particularly in purity, availability and batch-consistency. Concerning the higher potency of rFSH it seems to be of a more moderate degree than was initially suggested. That rFSH yields oocytes and embryos of higher quality has not been supported in clinical studies and is still an open question. The higher costs associated with the recombinant preparations is definitely a problem, particularly in a society with decreasing health resources.
Notes
This debate was previously published on Webtrack 59, March 26, 1999
References
Albano, C., Smitz, J., Camus, M. et al. (1996) Pregnancy and birth in an in-vitro fertilization cycle after controlled ovarian stimulation in a woman with a history of allergic reaction to human menopausal gonadotrophin. Hum. Reprod., 11, 1632–1634.
Bergh, C., Howles, C., Borg, K. et al. (1997) Recombinant human follicle stimulating hormone (r-hFSH; Gonal-F) versus highly purified urinary FSH (Metrodin HP): results of a randomized comparative study in women undergoing assisted reproductive techniques. Hum. Reprod., 12, 2133–2139.
Devroey, P., Tournaye, H., Van Steirteghem, A. et al (1998) The use of a 100 IU starting dose of recombinant follicle stimulating hormone (Puregon) in in-vitro fertilization. Hum. Reprod., 13, 565–566.
Frydman, R., Avril, C., Camier, B. et al. (1998) A double-blind, randomized study comparing the efficacy of recombinant human follicle stimulating hormone (rhFSH/Gonal-F) and highly purified FSH (uhFSH/Metrodin HP) in inducing superovulation in women undergoing assisted reproductive techniques. Hum. Reprod., 13 (Abstr. Book), 94.
Mannaerts, B.M.L.L., Rombout, F., Out, H.J. and Coelingh Bennink, H. (1996) Clinical profiling of recombinant follicle stimulating hormone (rFSH;Puregon):relationship between serum FSH and efficacy. Hum. Reprod. Update, 2, 153–161.
Out, H.J., Mannaerts, B.M.J.L., Driessen, S.G.A.J. et al (1996) A prospective, randomized, assessor-blind, multicentre study comparing recombinant and urinary follicle stimulating hormone (Puregon versus Metrodin) in in-vitro fertilization. Hum. Reprod., 10, 2534–2540.
Reader, S.C.J., Robertson, W.R. and Diczfalusy, E. (1983) Microheterogeneity of luteinizing hormone in pituitary glands from women of pre and postmenopausal age. Clin. Endocrinol., 19, 355–363.
Redfearn, A., Hughes, E.G., O'Connor, M. et al. (1995) Delayed-type hypersensitivity to human gonadotropin:case report. Fertil. Steril., 64, 855–856.[Web of Science][Medline]
Steelman, S.L. and Pohley, F.M. (1953) Assay of the follicle stimulating hormone based on the agumentation with human chorionic gonadotropin. Endocrinology, 53, 604–616.
Storring, P.L. (1992) Assaying glycoprotein hormones-influence of glycosylation on immunoreactivity. Trends Biotechnol., 10, 427–431.[Web of Science][Medline]
Wide, L. (1985) Median charge and charge heterogeneity of human pituitary FSH, LH and TSH II. Relationship between sex and age. Acta Endocrinol., 109, 190–197.
Wide, L. and Bakos, O. (1993) More basic forms of both human follicle stimulating hormone and luteinizing hormone at mid-cycle compared with the follicular and luteal phase. J. Clin. Endocrinol. Metab., 76, 885–889.[Abstract]
Wilson, C.A., Leigh, A.J. and Chapman, A.J. (1990) Gonadotrophin glycosylation and function. J. Endocrinol., 125, 3–14.
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