To the Editor:
I read the paper by Elgindy (1) on the detrimental role of progesterone levels on the day of hCG administration in pregnancy rates.
The detrimental effect of the high steroid levels on endometrial receptivity is a matter of debate. The advances in the study of endometrial receptivity are providing us with deeper knowledge of the possible mechanisms (2). The advances in cryopreservation are helping to propose new strategies to make up for the endometrium-embryo desynchronization (3).
However, Elgindy’s article raises two points:
Firstly, the authors find through ROC analysis that the levels of P > 1.5 ng/mL and the rate of P/E > 0.55 on the day of hCG administration had a detrimental effect on the pregnancy rates in the cleave-stage embryo transfer compared with blastocyst-stage embryo transfer. However, in an earlier study (4), using the same kind of analysis and with a population of similar characteristics (normal response and long protocol) we did not identify a cut-off level that had prognostic value, for which reason we disagree with their conclusions.
A closer look at Elgindy’s data shows that the AUC for the levels of P> 1.5 ng/mL is 0.67 (0.58-0.77) and for P/E > 0.55 it is 0.66(56-0.76). In order to indicate that a parameter might have prognostic value it should have to present an AUC > 0.80 (5). The estradiol levels and the number of oocytes differ significantly between the two groups. The differences observed in the pregnancy rates could be attributed to the negative impact on oocytes, embryos and/or endometrium of this kind of response, or to there being two different types of patient who respond differently to the same stimulation. To attribute the lower pregnancy rate to the higher level of progesterone on the day of hCG a population should have been selected with similar basal characteristics and number of oocytes as response to stimulation, and then the ROC curve analysis should have been done.
The author proposes transfer at blastocyst stage as a strategy for reducing the hypothetical endometrium-embryo desynchronization in cases of high P and P/E levels, suggesting that the embryos transferred on day + 3 would probably implant in the endometrium before reaching expanded blastocyst stage, which is rather hard to understand. Another explanation would be that the embryos selected to be transferred on day + 3 probably have less potential for implantation than the embryos selected for transfer in blastocyst stage, or that the presence of embryos in the uterus between day 3 and the day of hypothetical implantation could interfere with a possible self-correction effect of the endometrial desynchronization.
To summarize, while the advanced endometrium is not favorable to implantation, the author’s findings are different from what was observed elsewhere, and they do not sufficiently clarify the significance of modestly raised P and P/E levels in the pregnancy rates, so that the author’s enthusiasm for the proposed strategy should be tempered. Nevertheless, the idea that transfer in blastocyst presents a better implantation rate when there are a sufficient number of available embryos is strengthened.
Francisca Martínez, Ph.D.
Department of Obstetrics and Gynecology
Institut Universitari Dexeus
1. Elgindy EA: Progesterone level and progesterone/estradiol ratio on the day of hCG administration: detrimental cutoff levels and new treatment strategy. Fertil Steril, 2011; 95:1639-1644.
2. Cakmak H, Taylor HS: Implantation failure: molecular mechanisms and clinical treatment. Hum Reprod, 2011; 17:242-253
3. Zhu D, Zhan J, Cao S, Zhang J, Heng BC, Huang M, Ling X, Duan T, Tong GQ: Vitrified-warmed blastocyst transfer cycles yield higher pregnancy and implantation rates compared with fresh blastocyst transfer cycles- Time for a new embryo transfer strategy. Fertil Steril, 2011; 95:1691-5
4. Martinez F, Coroleu B, Clua E, Tur R, Buxaderas R, Parera N, Barri PN, Balasch J: Serum progesterone concentrations on the day of HCG administration cannot predict pregnancy in assisted reproduction cycles. RBM On line, 2004; 8:183-190
5. Swets JA. Measuring the accuracy of diagnostic systems. Science 1988; 240: 1.285-1.293.
Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2011.04.013
The Author Responds:
We thank Dr Francisca Martínez for interest in our article (1).
Regarding patients in our study, they had more strict inclusion criteria (age ≤ 35 years, day 3 serum FSH 6. All participants should have endometrial thickness ≥ 8 mm on hCG day and at least four grade-one embryos available for transfer on day 3 after retrieval). Further, while AUC for the levels of P > 1.5 ng/mL was 0.67 (0.58-0.77) and for P/E > 0.55 was 0.66 (56-0.76), still, when day 3 ET patients were classified according to the defined cutoff values, women with P ≤ 1.5 ng/mL or P/E2 ≤ 0.55 had significantly higher CPR than those with higher values (57.8% vs. 24.3% [P=0.001] and 57.3% vs. 26.3% [P=0.002], respectively.
Grade-one embryo was comparable between women with high P and P/E2 ratio and those with lower values. Moreover, fertilized oocytes were even higher among women with higher values. So, the results do not support the suggestion that the differences observed in the pregnancy rates could be attributed to the negative impact on oocytes or embryos.
Further, basal characteristics (age, duration and cause of infertility, basal FSH, AFC) were comparable between participants with P >1.5 ng/mL and P/E2 ratio > 0.55 and those with lower values. This does not support the assumption that lower CPR could be attributed to different populations.
Importantly, we did not suggest that the embryos transferred on day + 3 would probably implant in the endometrium before reaching expanded blastocyst stage. It is that, in cases of extreme advancement of the luteal endometrium, a transferred cleavage-stage embryo has the disadvantage of interacting with out-of-phase factors that might hinder its development to the blastocyst stage and thus its implantation. Alternatively, blastocysts have the advantage of interacting with a less out-of-phase endometrium, resulting in a better interaction with the implantation molecular milieu.
Eman Elgindy, M.D.
Zagazig University School of Medicine
Al-Banoon Fertility Center
1. Elgindy EA: Progesterone level and progesterone/estradiol ratio on the day of hCG
administration: detrimental cutoff levels and new treatment strategy. Fertil Steril, 2011;
Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2011.04.014