Effect of single post-ovulatory administration of levonorgestrel on gene expression profile during the receptive period of the human endometrium

Abstract

The hypothesis that levonorgestrel (LNG) used as an emergency contraceptive interferes with endometrial receptivity remains unproven. We compared the endometrial gene expression profile during the receptive period after administering a single dose of LNG 1 . 5 mg or placebo on day 1 of the luteal phase. An endometrial biopsy was done on day LHC7 or LHC8 and samples were taken from seven volunteers, each one contributing with one cycle treated with placebo and another with LNG. The expression of 20 383 genes was determined using cDNA microarrays. Real-time RT-PCR was used 1) to confirm the differences found in DNA microarray analysis and 2) to determine the effect of LNG on transcript levels of C3, C4BPa, COX2, MAOA, S100A4, and SERPINB9, known to be upregulated during receptivity, and on cPLA2a, JAK1, JNK1, CTSL1, and GSTP1, known to respond to mifepristone. Additional endometrial biopsies were done during the pre-receptive (LHC3) and receptive (LHC7) period and samples were taken from eight untreated volunteers in order to determine the changes associated with acquisition of receptivity of 14 genes. Mean levels of PAEP, TGM2, CLU, IGF2, and IL6ST mRNAs increased after administering LNG while those of HGD, SAT1, EVA1, LOC90133, ANXA1, SLC25A29, CYB5A, CRIP1, and SLC39A14 decreased. Except for the level of ANXA1 transcript, all changes remained within the range observed in untreated controls, and none of the transcripts responding to mifepristone changed in response to LNG. Post-ovulatory administration of LNG caused minimal changes in gene expression profiling during the receptive period. Neither the magnitude nor the nature or direction of the changes endorses the hypothesis that LNG interferes with endometrial receptivity.

Analysis of the Endometrial Transcriptome at the Time of Implantation in Women Receiving a Single Post-Ovulatory Dose of Levonorgestrel or Mifepristone

“…In the present study, administration of MFP led to inhibition of genes involved in the processes of decidualization and implantation of the embryo, particularly of STAT3, in which the canonical signaling pathways ERK/MAPK, JAK/Stat, IL-15, and the acute phase signaling are shown to be associated with endometrial receptivity 20 . These observations agree with three previously published studies, in which the post-ovulatory administration of LNG did not change the expected pregnancy rate, nor the expression of genes involved in implantation 2,33,34 .…”

Metformin Ameliorates Uterine Defects in a Rat Model of Polycystic Ovary Syndrome

“…Although our study was not designed to determine whether aberrant regulation of Maoa , Ednrb , and Hbegf gene expression reduces endometrial receptivity and blood flow in PCOS-like rats, our results combined with a clinical study indicating the beneficial effect of metformin on endometrial receptivity and blood flow in PCOS patients (Palomba et al, 2006) led us to speculate that metformin improves uterine receptivity and blood flow through the correction of aberrant Maoa , Ednrb , and Hbegf gene expression under hyperandrogenism and insulin resistance conditions and that this is important for the establishment of implantation and subsequent fertility. Indeed, several clinical studies have reported that endometrial MAOA and HBEGF expression is decreased in infertile women (Leach et al, 2012, Vargas et al, 2012). …”

Effects of low doses of mifepristone on human embryo implantation process in a three-dimensional human endometrial in vitro co-culture system

“…Low doses of mifepristone administered daily or weekly in humans do not affect ovulation and fail to prevent pregnancy sufficiently although endometrial morphology and some of studied receptivity markers are affected [75,79,217]. Further, even well studied compounds such as LNG alter the gene expression in endometrium, although LNG does not adversely affect implantation [56,57,222,223].…”