Progesterone elevation on the day of human chorionic gonadotropin administration adversely affects the outcome of IVF with transferred embryos at different developmental stages

Huang et al. Reproductive Biology and Endocrinology (2015) 13:82 DOI 10.1186/s12958-015-0075-3 RESEARCH Open Access Progesterone elevation on the day of human chorionic gonadotropin administration adversely affects the outcome of IVF with transferred embryos at different developmental stages Yan Huang, En-yin Wang, Qing-yun Du, Yu-jing Xiong, Xiao-yi Guo, Yi-ping Yu and Ying-pu Sun* Abstract Background: The effect of progesterone elevation (PE) on the day of human chorionic gonadotropin (hCG) administration on the pregnancy outcomes of in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles is a matter of ongoing debate. The replacement of cleavage-stage embryos with blastocyst-stage embryos for transfer was proposed to avoid the possible impairment of PE in fresh cycles. This study aimed to assess the association between PE on the day of human chorionic gonadotropin (hCG) administration and clinical pregnancy rates (CPRs) in IVF/ICSI cycles with embryos transferred at different developmental stages (cleavage and blastocyst). Moreover, a secondary aim was to determine the thresholds at which PE has a detrimental effect on CPRs. Methods: This single-center retrospective cohort study included more than 10,000 patients undergoing day 3 cleavage-stage embryo transfer (ET) and 1146 patients undergoing day 5 blastocyst-stage embryo transfer (ET) using gonadotropin and GnRH agonist for controlled ovarian stimulation. Results: Serum PE was inversely associated with CPRs in both cleavage- and blastocyst-stage ET cycles. In the day 3 ET cycles, CPRs (progesterone levels < 0.5 ng/ml, 49.2 %) significantly declined when the progesterone concentration reached 1.0 ng/ml (45.5 %) and decreased further when the progesterone concentration increased to 1.5 ng/ml (36.2 %). In the day 5 blastocyst-stage ET cycles, patients with serum progesterone levels ≥1.75 ng/ml had significantly lower CPRs (31.3 % VS. 41.4 %, p < 0.001) compared to patients with serum progesterone levels <1.75 ng/ml. The negative association of PE with CPRs was noted in both ET groups, even after adjusting for confounders. Furthermore, the developmental stage of the transferred embryos was not linked to the effect of PE on CPRs because the interaction between the developmental stage of the transferred embryos and PE was not significant. Conclusions: PE on the day of hCG administration is associated with decreased CPRs in GnRH agonist IVF/ intracytoplasmic sperm injection (ICSI) cycles regardless of the developmental stage of the transferred embryos (cleavage versus blastocyst stage). Keywords: IVF, Progesterone, Pregnancy rate, GnRH agonist, Blastocyst * Correspondence: Department of Reproductive Medical Center, First Affiliated Hospital of Zhengzhou University, Jianshe Dong Road, Erqi District, Zhengzhou City, Henan Province, People’s Republic of China © 2015 Huang et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Huang et al. Reproductive Biology and Endocrinology (2015) 13:82 Background Despite the widespread use of gonadotropin-releasing hormone (GnRH) analogues for pituitary down-regulation, progesterone elevation (PE), which refers to an increase in serum progesterone concentrations, still occurs at different frequencies on the day of human chorionic gonadotropin (hCG) administration for final oocyte maturation in fresh in vitro fertilization (IVF) cycles [1]. Moreover, the question of whether PE on the day of hCG administration affects the outcomes of IVF is still being debated [2–12]. Some studies have indicated that PE does not affect the probability of pregnancy in IVF [2–4, 12]; however, other studies have concluded that PE resulted in a decreased probability of pregnancy [5–11]. The use of simple bivariate analyses and arbitrary cut-off levels in most of these studies may explain these varying results. Recently, a large-sample meta-analysis confirmed the adverse effect of PE on IVF pregnancy outcomes [1]. The precise endocrinological mechanism underlying the adverse effects of PE is still unclear; however, oocyte quality [13] and endometrial receptivity [14, 15] may play roles in this process. The hypothesis regarding endometrial receptivity is seemingly more convincing because of the results of gene expression studies on the endometrium [16, 17] and studies showing that the live birth rates of women implanted with frozen-thawed embryos or donor oocytes from fresh cycles did not significantly differ between those with PE and those without PE [1, 18]. Several strategies have been proposed to avoid the possible detrimental effects of PE in fresh IVF cycles [19, 20]. One strategy is to replace cleavage-stage embryos with blastocyst-stage embryos prior to transfer because evidence suggests that PE does not decrease pregnancy rates in day 5 single blastocyst transfer cycles [7, 21]. However, the reliability of these results has not been confirmed, and some researchers have found that PE can still impair IVF outcomes, even in blastocyst transfers [8, 13, 22]. Hence, the aim of this study was to assess the association between PE on the day of hCG administration and the clinical pregnancy rates (CPRs) of GnRH agonist IVF/intracytoplasmic sperm injection (ICSI) cycles with the transfer of embryos at different developmental stages. Moreover, a secondary aim was to determine the thresholds at which PE has a detrimental effect on CPRs. Material and methods Study population This was a single-center retrospective cohort study. Patients who were undergoing IVF with gonadotropin and a GnRH agonist for controlled ovarian stimulation were enrolled from January 2010 to October 2014. A total of 10,864 patients were assigned to the day 3 embryo Page 2 of 10 transfer (ET) group undergoing cleavage-stage ET, and 1146 patients were assigned to the day 5 ET group undergoing blastocyst-stage ET. The Ethics Committee of the First Hospital of Zhengzhou University approved the research protocol for this study. The exclusion criteria were as follows: (i) individuals in the first or second oocyte or sperm donation cycles and (ii) couples in which either member had chromosomal abnormalities. Each patient was included in the study only once, during either the first or second IVF/ ICSI cycle. The following patient characteristics were evaluated: age, basal follicle-stimulating hormone (bFSH) level, body mass index (BMI), cause of infertility, duration of infertility and type (...truncated)