Hum. Reprod. Advance Access originally published online on April 5, 2007
Human Reproduction 2007 22(6):1797-1798; doi:10.1093/humrep/dem049
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Letters to the Editor |
Comparing highly purified hMG and rFSH in patients undergoing IVF
Consultant in Reproductive Medicine and Surgery, Hammersmith Hospital, London, UK
1 To whom correspondence should be addressd at: Consultant in Reproductive Medicine and Surgery, Hammersmith Hospital, London, UK. E-mail: g.trew{at}ic.ac.uk
I read with interest the recent article by Andersen et al., (2006)
on behalf of the MERIT group reporting clinical outcomes from the randomized, controlled, assessor-blind trial comparing highly purified hMG and recombinant FSH in patients undergoing IVF (Andersen et al., 2006). This was obviously a carefully designed trial, and because of the large number of patients studied, the results of the trial and the interpretations thereof will carry a great deal of weight within the assisted reproduction community. It is for this reason that I feel compelled to provide an alternative viewpoint regarding some of the key findings.
The current study was designed to show superiority of HP hMG over rFSH (Gonal F) based on the retrospective finding from a previous comparative study (The EISG study) (The European and Israeli Study Group, 2002, Platteau et al., 2004) that found HP hMG might be associated with improved outcomes in the IVF population. In the MERIT trial, all efforts were made to rigorously test the hypothesis from the EISG study while maintaining the design of the EISG study. Despite efforts to showcase the potential benefits of LH add-back, the MERIT trial failed to demonstrate any superiority of HP hMG over recFSH. Instead, it confirmed non-inferiority as pertaining to pregnancy outcome. Two particular choices in protocol design are worthy of comment.
In the MERIT trial (Andersen et al., 2006), all patients received a long GnRH agonist down-regulation protocol (0.1 mg triptorelin/day) prior to initiation of ovarian stimulation. Interestingly, in a Ferring-sponsored study published in 2000, Janssens et al. (2000), found that doses of triptorelin as low as 15 µg were sufficient to suppress the LH surge, whereas 50 µg of triptorelin was as effective as 100 µg of triptorelin. Furthermore, it has previously been shown that triptorelin is one of the more potent GnRH agonists (Devroey et al., 1994). Therefore, the choice of 100 µg/day triptorelin would be expected to accentuate any potential benefit of LH add-back during subsequent stimulation with HP hMG.
Despite focusing on IVF-patients only, the MERIT trial did not demonstrate outcomes significantly different from the EISG study (Andersen et al., 2006). Thus it appears that focusing on the IVF population does not indicate that LH add-back is mandatory and the question of which subgroup might benefit from LH add-back remains unanswered. Perhaps it would be more logical to prevent the iatrogenic depletion of LH-activity by simply reducing the daily GnRH agonist dose currently employed in routine IVF practice?
I would also like to address the choice of the starting dose of 225 IU for rFSH in standard patients. We speculate that for a large proportion of these women, who have relatively good prognoses, this dose could be considered inappropriately high. Yet the authors fail to explain the rationale for choosing such a high dose. Indeed, a substantial body of work has been published in which 150 IU/day was used as the standard dose for standard patients (Latin American Puregon IVF Study Group, 2001; Popovic-Todorovic et al., 2003). The link between higher starting doses of rFSH and higher progesterone levels on the day of hCG administration is well established (Out et al., 2001; Latin American Puregon IVF study Group, 2001). Thus the use of such a high starting dose is likely to lead to a protocol-driven outcome of more follicles, higher progesterone levels and a more advanced endometrium. Accordingly, it could be argued that some of the pharmacodynamic differences alluded to in this trial may be protocol-driven rather than LH-activity derived.
In addition, the total consumption of gonadotropin in this trial was significantly higher in the HP-hMG group, whereas the number of oocytes retrieved was higher in the rFSH group. Both findings suggest enhanced efficiency of rFSH compared with HP hMG.
One additional consequence of using an inappropriately high starting dose of rFSH is also worth addressing. The authors report that the increased number of oocytes retrieved in the recFSH group was not accompanied by a higher proportion of top-quality embryos (TQE). The authors then speculate that the higher proportion of TQEs in the HP hMG group may be due to the LH-activity present in HP hMG. This could be misleading, as proportions are dependent on both the numerator and the denominator. As noted, more oocytes were retrieved from women receiving rFSH. If only 2–3 TQEs are generated per cohort/retrieval, the proportion will be lower when more oocytes are retrieved. It seems reasonable to speculate, then, that above a certain threshold no additional TQEs will be obtained. This alternate speculation is consistent with the findings of this study and again reflects the choice of a higher-than-necessary dose of rFSH rather than the consequence of the added LH.
I think the following quote from Mark Twain seems particularly apt; ‘There is something fascinating about science - one gets such wholesale returns of conjecture out of such a trifling investment of fact’.
I believe that it is more interesting to explore how protocols can be optimized and individualized rather than indiscriminately adding LH (i.e. hMG to all IVF patients) without evidence of significant benefit. It has been demonstrated that such an individualized approach to gonadotropin stimulation, based on predictive factors, increased the proportion of appropriate ovarian responses, decreased the need for dose adjustments, and was associated with improved outcomes (Popovoric-Todorovic et al., 2003).
Finally, I believe that an optimized treatment protocol should also consider other important factors such as tolerability, convenience, compliance and patient preference. Unfortunately, tolerability is not discussed in this article despite a sufficiently large sample size to identify important differences. Obviously this topic deserves further scrutiny. There is clearly a need for further well-designed clinical trials that will allow the collection of additional data that can be used to evaluate this complex clinical question.
References
Andersen AN, Devroey P, Arce JC. (2006) Clinical outcome following stimulation with highly purified hMG or recombinant FSH in patients undergoing IVF: a randomized assessor-blind controlled trial. Hum Reprod 21:3217–27.
Devroey P, Mannaerts B, Smitz J, et al. (1994) Clinical outcome of a pilot efficacy study on recombinant human FSH (Org 32489) combined with various GnRH agonist regimens. Hum Reprod 9:1064–9.
Janssens RMJ, Lambalk CB, Vermeiden JPW, et al. (2000) Dose-finding study of triptorelin acetate for prevention of a premature LH surge in IVF: a prospective, randomized, double-blind, placebo-controlled study. Hum Reprod 15:2333–40.
Latin American Puregon IVF Study Group. (2001) A double-blind clinical trial comparing a fixed daily dose of 150 and 250 IU of recombinant follicle stimulating hormone in women undergoing in vitro fertilization. Fertil Steril 76:950–6.[CrossRef][ISI][Medline]
Out HJ, David I, Ron-El R, et al. (2001) A randomized, double-blind clinical trial using fixed daily doses of 100 or 200 IU of recombinant FSH in ICSI cycles. Hum Reprod 16:1104–10.
Platteau P, Smitz J, Albano C, et al. (2004) Exogenous luteinizing hormone activity may influence the treatment outcome in in vitro fertilization but not in intracytoplasmic sperm injection cycles. Fertil Steril 81:1401–4.[CrossRef][ISI][Medline]
Popovic-Todorovic B, Loft a., Bredkjaeer HE, Bangsboll S, et al. (2003) A prospective randomized clinical trial comparing an individual dose of recombinant FSH based on predictive factors versus a "standard" dose of 150 IU/day in "standard" patients undergoing IVF/ICSI treatment. Hum Reprod 18:2275–82.
The European and Israeli Study Group, on highly purified hMG versus rFSH. (2002) Efficacy and safety of highly purified menotropin versus recombinant follicle-stimulating hormone in in vitro fertilization/intracytoplasmic sperm injection cycles: a randomized, comparative trial. Fertil Steril 78:520–8.[CrossRef][ISI][Medline]
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