Human Reproduction Update Advance Access originally published online on July 4, 2008
Human Reproduction Update 2008 14(5):538; doi:10.1093/humupd/dmn027
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Progesterone elevation and probability of pregnancy after IVF: facts and fiction
Unit for Human Reproduction, 1st Department of Obstetrics and
Gynaecology, Medical School, Aristotle University of Thessaloniki,
M. Kallidou 65 Street, Thessaloniki 55131, Greece
1 Correspondence address. Tel: +30-699-699-699-2; Fax: +30-231-0414-089; E-mail: venetis{at}gmail.com
We are truly delighted that the publication of our meta-analysis (Venetis et al., 2007
) initiated a very constructive debate with two recently published letters to the Editor by Fleming (2008) and de Ziegler et al. (2008). The focus of this debate is the association between progesterone elevation on the day of human chorionic gonadotrophin (hCG) administration and the probability of pregnancy after in vitro fertilization (IVF).
In his letter (Fleming, 2008), Dr Fleming suggests that measurements of progesterone during the follicular phase using commercial assays are unreliable and this might explain the lack of association between progesterone elevation and probability of pregnancy in the meta-analysis by Venetis et al. (2007). Although such a possibility cannot be excluded, it is imperative that researchers in this field undertake a clear approach.
If measurements of progesterone during the follicular phase, using commercially available assays, are indeed invalid, as Dr Fleming suggests, then all currently existing studies have apparently been performed in vain. In this case, unless more reliable methods of progesterone determination are widely available, further research on this issue is probably not worth undertaking.
On the contrary, if commercially available kits for progesterone measurement produce results with acceptable consistency, then relevant published research is of value and further appropriately designed studies should be performed.
Considering the above, the approach adopted by de Ziegler et al. in order to support their theory regarding the modifying effect of ovarian response on the association between progesterone elevation and the probability of pregnancy (de Ziegler et al., 2008) is at least confusing. Although, de Ziegler et al. (2008) share the methodological concerns raised by Fleming (2008), regarding the lack of reliability of progesterone measurements, they seem to ignore that these are also applicable to their own retrospective study (Fanchin et al., 1997). In that study, a progesterone kit, similar to the ones used in the studies included in the meta-analysis by Venetis et al. (2007), was used. Therefore, if de Ziegler et al. (2008) accept that measurements of progesterone during the follicular phase are unreliable, then the conclusions of their own retrospective study, although interesting, are probably invalid.
However, even if de Ziegler et al. (2008) believed that measurements of progesterone during the follicular phase are reliable, the conclusions of their study and the proposed theory (Fanchin et al., 1997) would still be of questionable validity due to several methodological flaws. Besides including patients contributing more than one cycles (1182 cycles, 1012 patients), an approach known to inflate P-values (Kruskal, 1988), the serum cut-off used to classify patients as having or not progesterone elevation was arbitrarily chosen, as were the criteria used for classifying patients as ‘weak’, ‘adequate’ or ‘strong’ responders. These retrospective data might have been more useful if the association of progesterone elevation on the day of hCG administration with the probability of pregnancy had been examined by a multivariate regression analysis. In this way, the potential interaction effects of the various measures of ovarian response used by Fanchin et al. (1997) to classify patients as ‘weak’, ‘adequate’ or ‘strong’ responders (total dose of gonadotrophins required, number of oocytes retrieved, estradiol levels on the day of hCG) could have also been evaluated.
Finally, it is interesting to note that neither the authors of the study by Fanchin et al. (1997) nor any other investigator tested this theory in a subsequently properly designed prospective study. In scientific literature, numerous theories are presented constantly. The fact that the vast majority of these theories are not subsequently challenged cannot be interpreted as evidence of their own validity.
It should be stressed that in the systematic review and meta-analysis by Venetis et al. (2007), it was clearly stated that there is an evident need for further well-designed trials that could provide more reliable answers regarding the association of progesterone on the day of hCG with the probability of pregnancy. In the context of these studies, the questions raised in this debate might be worth examining. Until, such evidence is available and the various hypotheses are properly tested, we choose not to succumb to speculation.
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de Ziegler D, Bijaoui G, Chapron C. Pre-hCG elevation of plasma progesterone: good, bad or otherwise. Hum Reprod pdate (2008) 14:393.
Fanchin R, Righini C, Olivennes F, Ferreira AL, de iegler D, Frydman R. Consequences of premature progesterone levation n the outcome of in vitro fertilization: insights into a controversy. Fertil teril (1997) 68:799–805.[CrossRef]
Fleming R. Progesterone elevation on the day of hCG: methodological issues. Hum Reprod Update (2008) 14:391–392.
Kruskal W. Miracles and statistics: the casual assumption of independence. J Am Stat Assoc (1988) 83:929–937.[CrossRef][Web of Science]
Venetis CA, Kolibianakis EM, Papanikolaou E, Bontis J, Devroey P, Tarlatzis BC. Is progesterone elevation on the day of human chorionic gonadotrophin administration associated with the probability of pregnancy in in vitro fertilization? A systematic review and meta-analysis. Hum Reprod Update (2007) 13:343–355.
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