Levonorgestrel as emergency contraceptive (LNG-EC) is world widely used with clinical success. For maximal effectiveness it should be administered within the 72 hrs after the unprotected intercourse. Single dose (1.5 mg) of Levonorgestrel or divided (0.75 mg) 12 hrs apart effectively prevents the undesired pregnancy [Citation1]. Investigations on the mechanism of action clearly revealed that LNG-EC administration during early-mid proliferative phase inhibits or delays the ovulation process whereas any endometrial morphological alterations are observed if the drug is administered during the periovulatory or early luteal phase [Citation2,Citation3].
Since the maximal fertility range encompasses a narrow period including the five days before ovulation and the day of ovulation itself, it is interesting to elucidate whether the administration of LNG-EC during the LH surge is capable to inhibit the ovulation, the corpus luteum production of steroids or whether it alters the endometrial maturation and molecular features of the receptive endometrium.
The endometrium is receptive to embryo attachment during the implantation window, a defined period of the luteal phase that encompasses the days 20–24 of the menstrual cycle. In preparation for the maternal–embryo dialogue and further successful implantation the endometrium undergoes morphological, biochemical and molecular changes driven by ovarian steroids and local factors [Citation4].
Progesterone, the main hormone produced by the corpus luteum regulates the expression of endometrial genes and their proteins associated to endometrial receptivity including cytokines, growth factors and cell attachment molecules [Citation5].
It is thought that progesterone has effect on the endometrium mainly through its cognate receptor (A and B) acting directly on epithelial surface or indirectly from stromal compartment through cytokines and growth factors [Citation6].
The expression of endometrial progesterone receptor (PR) is regulated by estradiol and progesterone. The downregulation of epithelial endometrial progesterone receptor and its persistence in the stroma compartment is a characteristic of all mammalian endometrium during the implantation period and appears to be critical for endometrial receptivity [Citation7].
Levonorgestrel is a synthetic progestin commonly administered in gynecologic clinical practice by way of contraceptive pills, IUD-delivering Levonorgestrel and long acting subdermal implants. A common side effect reported is the unscheduled vaginal bleeding that is associated with atrophic endometrium and disruption of progesterone receptor expression [Citation8].
To test the hypothesis that LNGEC administered the day of LH surge may alter the expression of endometrial PR and endometrial receptivity biomarkers we conducted a randomized prospective trial to compare the effect of LNGEC in treated and non-treated subjects previously sterilized by tubal ligation.
Our study demonstrated that neither ovulation nor progesterone production by the corpus luteum and endometrial PR expression were effected by LNGEC. Moreover, the critical epithelial endometrial PR downregulation as well as the expression of selected endometrial receptivity biomarkers including Glycodelin-A, avb3 integrin and L-selectin ligand were not different between control subjects than those treated with LNGEC [Citation9].
The effect of Levonorgestrel on endometrial PR appears to be related to the pharmacokinetics of the different modes of administration. For example, we demonstrated that tissue concentration of Levonorgestrel in LNGEC is 100 times lower than in IUD-delivering LNG [Citation10].
It is thought that LNG-EC fails in preventing pregnancy primarily when the unprotected intercourse takes place during the peri-ovulatory period. Thus, the contraceptive mechanism of LNGEC during the peri-ovulatory period, if any, remains unclear. However, our recent in-vivo investigation demonstrates that it does not include alteration of the corpus luteum function or alteration of PR or endometrial receptivity biomarkers indicating that the molecules involved in embryo implantation are not impaired.
Declaration of interest: Supported by Chilean research council CONICYT-FONDAP Grant #15010006.
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