Human Reproduction Update Advance Access originally published online on January 28, 2008
Human Reproduction Update 2008 14(2):194-195; doi:10.1093/humupd/dmm046
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Comment on: 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. By Venetis et al (2007)
Instituto Valenciano de Infertilidad,
Plaza Policía Local, 3, 46015,
Valencia, Spain
* Corresponding address. Tel: +34-96-305-09-00;Fax: +34-96-305-09-99; E-mail: ebosch{at}ivi.es
I have read with great interest the systematic review and meta-analysis published in your journal by Venetis et al. (2007)
in which the association between serum progesterone (P) elevation on the day of human chorionic gonadotrophin (hCG) administration with the probability of pregnancy in IVF is evaluated in depth.
First of all, I would like to complement the tremendous job the authors have done, with an initial screening of 1114 studies, and the final inclusion of 12 studies for the systematic review and of five studies for the meta-analysis, all of which meet appropriate strict and rigorous criteria for properly analysing such association. Nevertheless, there are some interesting data that merit further evaluation and comments.
In regard to the main and final conclusion of the study, the authors conclude that the available data do not support an association between P elevation on the day of hCG and the probability of clinical pregnancy. However, data obtained from the five selected studies for meta-analysis, which include a total of 700 cycles, show an OR = 0.75 (95% CI: 0.53–1.06), (P = 0.10), and a mean difference of –0.10 (95% CI: –0.22–0.2) (P = 0.11) between patients with P elevation versus those without it. Despite the fact that the different studies chose different serum P threshold levels to define premature luteinization, and that the variation coefficients of the hormonal assays obviously differ among the studies, these data reflect a trend to a negative association between P elevation and pregnancy rate. Although differences do not reach statistical significance, they are of a clear clinical relevance. Moreover, if analysis of crude data from the two GnRH antagonist cycles is performed (Ubaldi et al., 1996; Bosch et al., 2003), a statistically significant difference between patients with and without serum P elevation is observed (OR = 0.41; 95% CI: 0.17–0.97); P = 0.04, even considering the different P threshold level employed in each of the studies.
In this context, I completely agree with the authors comment that the use of the term ‘premature luteinization’ might not be appropriate, as serum P elevation is occurring despite the use of GnRH analogues, and therefore, under normal serum LH concentrations. Luteinization is the process, by which the mature ovarian follicle transforms into a corpus luteum, and it is mainly induced by LH (Murphy, 2000); thus, these two events are not related.
On the other hand, defining a single threshold for a detrimental serum P level seems imprecise: most of the studies failing to demonstrate an association employed a threshold level of 0.9 ng/ml. Probably, a trend analysis relating both variables would be of greater interest.
The second issue that needs to be clarified is the analysis of the factors related to serum P elevation. The authors performed a single variable analysis to study the different relationships of FSH requirements, duration of FSH stimulation, serum estradiol (E2) levels on the day of hCG administration and the number of oocytes retrieved with the presence of P elevation. Only E2 levels showed a significant relationship with P elevation. This simple approach provides a preliminary conclusion, but cannot be definitive. The most correct way of analysing the influence of diverse risk factors on a particular condition is a multivariate analysis, as co-linearity among the different variables could be present, and any of them might be a confounding variable, or could act by modifying the effect of one or the rest of them. In our study (Bosch et al., 2003), we performed a multivariate analysis with logistic regression in which all potentially related variables were included. As a result, the total dose of FSH employed and the serum E2 levels on the day of hCG showed a statistically significant relationship with the occurrence of P elevation. This finding is in consistency with others' in which serum P levels correlated positively with the dose of FSH administered (Filicori et al., 2002) and with circulating FSH concentrations (Adonakis et al., 1998). Altogether, these data suggest that increased serum P is related to high circulating FSH concentrations that provide the development of more follicles augmenting total granulose cells' activity. As a consequence, P elevation appears associated to high serum E2 levels on the day of hCG.
In conclusion, the available evidence suggests that the elevation of circulating P concentrations at the end of the follicular phase has a negative impact on GnRH antagonist cycles. On the other hand, this negative effect remains to be demonstrated in GnRH agonist cycles; the evaluation of larger series with an appropriate (higher) threshold P value may lead to a similar outcome. The total FSH dose employed for ovarian stimulation seems to be the factor most related to circulating P, through the increase of total granulosa cells' activity.
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Adonakis G, Deshpande N, Yates RW, Fleming R. Luteinizing hormone increases estradiol secretion but has no effect on progesterone concentrations in the late follicular phase of in vitro fertilization cycles in women treated with gonadotropin-releasing hormone agonist and follicle-stimulating hormone. Fertil Steril (1998) 69:450–453.[CrossRef][Web of Science][Medline]
Bosch E, Valencia I, Escudero E, Crespo J, Simon C, Remohi J, Pellicer A. Premature luteinization during gonadotropin-releasing hormone antagonist cycles and its relationship with in vitro fertilization outcome. Fertil Steril (2003) 80:1444–1449.[CrossRef][Web of Science][Medline]
Filicori M, Cognigni GE, Pocognoli P, Tabarelli C, Spettoli D, Taraborrelli S, Ciampaglia W. Modulation of folliculogenesis and steroidogenesis in women by graded menotrophin administration. Hum Reprod (2002) 17:2009–2015.
Murphy BD. Models of luteinization. Biol Reprod (2000) 63:2–11.
Ubaldi F, Albano C, Peukert M, Riethmuller-Winzen H, Camus M, Smitz J, Van Steirteghem A, Devroey P. Subtle progesterone rise after the administration of the gonadotrophin-releasing hormone antagonist cetrorelix in intracytoplasmic sperm injection cycles. Hum Reprod (1996) 11:1405–1407.
Venetis CA, Kolibianakis EM, Papanikolaou E, Bontis J, Devroey P, Tralatzis 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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