The potential value of mid-follicular phase LH

Marco Filicori, Prof.

Reproductive Endocrinology Center, University of Bologna, Via Massarenti, 13, 40138 Bologna, Italy

Correspondence: E-mail: filicori{at}med.unibo.it

Dear Sir,

I read with interest the article by Balasch et al. on the potential value of mid-follicular phase (MFP) measurements of LH to determine the outcome of gonadotrophin ovulation induction and assisted reproduction technology (ART) (Balasch et al., 2001Go). Previous studies had found that low MFP LH concentrations were associated with a longer duration of stimulation, lower rates of oocyte and embryo yields, and a higher incidence of poor response in highly purified FSH-treated patients (Fleming et al., 2000Go) and with increased pregnancy wastage in recombinant FSH-treated patients (Westergaard et al., 2000Go). Conversely, Balasch et al. could not identify any significant difference in treatment outcome based on various day 7 LH level thresholds and concluded that their results, `Do not support the need for additional exogenous LH supplementation'.

Balasch et al. retrospectively examined patients who had become pregnant on ART and matched them with the non-conception ART cycles that immediately followed, while Fleming et al. analysed cohorts of patients without selectivity bias (Fleming et al. 2000Go) and Westergaard et al. studied 200 consecutive cycles of patients who simply fulfilled pretreatment inclusion criteria (Westergaard et al., 2000Go); thus, case selection criteria were markedly different. More importantly, Balasch et al. failed to detect any significant difference in serum estradiol concentrations on day 7 and on the day of HCG administration in the groups of patients who showed significantly lower day 7 LH levels (Balasch et al., 2001Go). Conversely, Fleming and Westergaard found significantly higher estradiol concentrations in patients with normal LH levels both at stimulation day 7–8 and on the day of HCG administration (Fleming et al., 2000Go; Westergaard et al., 2000Go). This discrepancy suggests that, although Balasch et al. found that MFP LH concentrations were reduced in some of their patients, these decrements were not large enough to exert biologically significant actions on ovarian steroidogenesis. Low follicular phase estradiol levels is one of the potential mechanisms by which inadequate LH input may exert untoward effects on oocyte and embryo quality (Filicori, 1999Go), and lack of this feature may explain the negative findings of Balasch. Thus, it is conceivable that, possibly because of the less intense GnRH agonist regimen employed, the great majority of the patients studied by Balasch et al. may not have been as depleted in endogenous LH activity as was found in previous studies. This interpretation is supported by the finding that on day 7, only 7 and 15% of the patients in this study had LH <0.5 IU/l and <=0.7 IU/l respectively, as compared with 23–32% in Fleming's and 49% in Westergaard's reports (Fleming et al., 2000Go; Westergaard et al., 2000Go). The different hormone assays methods used to measure serum LH may also account for lack of consistency among these studies.

Finally, I found entirely unwarranted the conclusion of Balasch et al. that the findings of this article do not support the need for LH supplementation in ART ovulation induction. Even if no relationship existed between MFP LH concentrations and ART outcome, this would not necessarily mean that patients do not profit from LH activity supplementation during FSH ovulation induction. Prospective studies from our and other groups (that Balasch et al. entirely failed to reference), where different types and levels of LH activity were added to FSH, unequivocally showed that LH can optimise, reduce costs and potentially enhance safety of FSH ovulation induction. LH activity stimulated large antral follicle development independently of FSH (The European Recombinant Human LH Study Group, 1998Go; Filicori et al., 1999bGo), lowered the duration of gonadotrophin stimulation and the FSH dose needed per treatment cycle (Filicori et al., 1999aGo,bGo, 2001Go), reduced small preovulatory antral follicle number (Filicori et al., 2001Go), a parameter linked to the ovarian hyperstimulation syndrome (Navot et al., 1988Go), and improved embryo implantation (Gordon et al., 2001Go). Thus, although detailed retrospective analyses can provide interesting results that hint at favourable outcomes of specific treatment regimens, the necessity of LH activity supplementation in ovulation induction can only be proven or disproven through careful prospective studies that test different regimens of gonadotrophin administration in a controlled manner.

Acknowledgements

Prof. Marco Filicori is a scientific advisor to Ferring Pharmaceuticals S.p.A.

References

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