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Background: Emergency contraception with levonorgestrel (LNG) is a viable option to prevent unintended pregnancies. Although the efficacy of LNG as an anovulatory agent decreases as treatment approaches ovulation, it still provides some contraceptive benefits., Aim: To better understand the contraceptive mechanisms of LNG in ovulatory subjects., Methods: We conducted a study on Wistar rats that received a single dose of LNG (0.01 or 0.05 mg/kg) on the morning of proestrus before ovulation and evaluated its effects on ovarian gene expression, ovulation, and implantation., Results: Our findings showed changes in the expression of genes involved in follicular development and oocyte quality. Pregnancy rates - as an indicator of ovulation - and embryo implantation were significantly lower than those in the control group., Conclusions: This study suggests that LNG alters regulatory factors in the ovary that are essential for the development of competent fertilizable oocytes, highlighting the non-anovulatory mechanisms by which levonorgestrel may regulate fertility and suggesting that it could be a novel observation that contributes to the understanding of emergency contraception in humans., Competing Interests: Conflict of Interest The authors declare no competing interests in this work., (Copyright © 2023 Instituto Mexicano del Seguro Social (IMSS). Published by Elsevier Inc. All rights reserved.)

Background: Levonorgestrel (LNG) is a progesterone receptor agonist used in both regular and emergency hormonal contraception; however, its effects on the endometrium as a contraceptive remain widely unknown and under public debate., Objective: To analyze the effects of LNG or mifepristone (MFP), a progesterone receptor antagonist and also known as RU-486, administered at the time of follicle rupture (FR) on endometrial transcriptome during the receptive period of the menstrual cycle., Methods: Ten volunteers ovulatory women were studied during two menstrual cycles, a control cycle and a consecutively treated cycle; in this last case, women were randomly allocated to two groups of 5 women each, receiving one dose of LNG (1.5 mg) or MFP (50 mg) the day of the FR by ultrasound. Endometrial biopsies were taken 6 days after drug administration and prepared for microarray analysis., Results: Genomic functional analysis in the LNG-treated group showed as activated the bio-functions embryo implantation and decidualization, while these bio-functions in the T-MFP group were predicted as inhibited., Conclusions: The administration of LNG as a hormonal emergency contraceptive resulted in an endometrial gene expression profile associated with receptivity. These results agree on the concept that LNG does not affect endometrial receptivity and/or embryo implantation when used as an emergency contraceptive.

When levonorgestrel (LNG) is given for emergency contraception during the follicular phase, it not only inhibits or delays ovulation, but also induces changes in endometrial secretions that modulate sperm functionality. In order to characterize the female reproductive tract secreted molecules that may affect human spermatozoa, we analyzed changes in the protein content of uterine flushings obtained from women during the periovulatory phase of a control and a LNG-treated menstrual cycle. Lectin affinity analysis and 2D gel electrophoresis of uterine samples showed changes in protein glycosylation patterns and the presence of 31 differentially expressed proteins (8 upregulated and 23 downregulated). Mass spectrometry and Western blot analyses of the differential expressed proteins showed lactotransferrin (LTF) as one of the upregulated molecules by LNG. In this study, LTF exhibited significant dose-related effects on sperm functionality, particularly a decrease of calcium ionophore-induced acrosome reaction and protein tyrosine phosphorylation. Overall, the results indicated that LNG promoted changes in the proteome of uterine secretions that might compromise human sperm capacitation. These data further support the participation of other mechanisms of action of LNG as emergency contraceptive, in addition to those on ovulation.

Levonorgestrel (LNG), a synthetic 19 nor-testosterone derivative, is widely used for emergency contraception. It is well known that LNG prevents ovulation only when given prior to the surge of serum luteinizing hormone (LH) during the periovulatory phase of the menstrual cycle. This observation suggests that LNG, given its contraceptive efficacy, has additional effects other than those affecting ovulation. In this study, we have evaluated the effects on human sperm functionality of uterine flushings (UF) obtained from women at day LH + 1 of a control cycle (CTR-LH + 1) and after receiving LNG (LNG-LH + 1) two days before the surge of LH. Human sperm from normozoospermic donors were incubated with UF and protein tyrosine phosphorylation, sperm motility, acrosome reaction as well as zona pellucida (ZP) binding capacity were assessed. A significant decrease in total motility and tyrosine phosphorylation accompanied by an increase on spontaneous acrosome reaction was observed when sperm were incubated in the presence of LNG-LH + 1. None of these effects were mimicked by purified glycodelin A (GdA). Moreover, the addition of UF obtained during the periovulatory phase from LNG-treated women or the presence of purified GdA significantly decreased sperm-ZP binding. The data were compatible with changes affecting sperm capacitation, motility and interaction with the ZP. These results may offer evidence on additional mechanisms of action of LNG as an emergency contraceptive., (© 2017 Society for Reproduction and Fertility.)

Levonorgestrel (LNG), a synthetic progestin, is used in emergency contraception (EC). The mechanism is preventing or delaying ovulation at the level of the hypothalamic pituitary unit; however, little knowledge exists on LNG effects at the ovary. The aim of this study was to identify the effects of LNG on FSH-induced 17β-estradiol (E 2 ) production, including LNG-mediated changes on global gene expression in rat granulosa cells (GC). Isolated GC from female Wistar rats were incubated in vitro in the presence or absence of human FSH and progestins. At the end of incubations, culture media and cells were collected for E 2 and mRNA quantitation. The results showed the ability of LNG to inhibit both hFSH-induced E 2 production and aromatase gene expression. Microarray analysis revealed that LNG treatment affects GC functionality particularly that related to folliculogenesis and steroid metabolism. These results may offer additional evidence for the mechanisms of action of LNG as EC., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: The study was conducted to assess the effects of levonorgestrel (LNG) on hormonal behavior and on the secretory pattern of intrauterine glycodelin at the midcycle of ovulatory women., Study Design: Thirty healthy sterilized women with normal ovarian function were studied during one control untreated cycle and one LNG-treated cycle. In the treated cycle, each woman received two doses of 0.75 mg of LNG 12 h apart during the preovulatory phase approximately 2 days before the LH surge. Daily follicle development recordings were performed until follicle rupture was observed, and serum glycodelin, LH, estradiol, estrone and progesterone were measured as well. In addition, glycodelin concentrations were assayed in uterine flushing obtained on Days LH+1 and LH+12., Results: LNG did not modify follicle rupture in 20 of 30 women. In spite of ovulatory progesterone and the occurrence of follicle rupture in these women, luteal phase length was significantly decreased, as well as the serum concentrations of LH, estradiol and estrone in the periovulatory phase. Glycodelin in serum and uterine flushings was significantly elevated in the periovulatory phase when compared to control cycles., Conclusions: LNG taken at the dose used in emergency contraception before the LH surge increased prematurely serum and intrauterine concentrations of glycodelin at the time of ovulation. Since there are well established glycodelin inhibitory effects upon fertilization, these results may represent an additional action of LNG in situations where the intervention did not interfere with ovulation., (Copyright © 2010 Elsevier Inc. All rights reserved.)

This study examined serum glycodelin concentrations and endometrial expression during the luteal phase following oral administration of levonorgestrel (LNG) at different stages of the ovarian cycle. Thirty women were recruited and allocated into three groups. All groups were studied during two consecutive cycles, a control cycle and the treatment cycle. In the treatment cycle, each woman received two doses of 0.75 mg LNG taken 12 h apart on days 3-4 before the luteinizing hormone (LH) surge (Group 1), at the time of LH rise (Group 2) and 48 h after the rise in LH was detected (Group 3). Serum progesterone (P) and glycodelin were measured daily during the luteal phase, and an endometrial biopsy was taken at day LH +9 for immunohistochemical glycodelin-A staining. In Group 1, serum P levels were significantly lower, serum glycodelin levels rose earlier and endometrial glycodelin-A expression was weaker than in Groups 2 and 3, in which no differences were found between control and treatment cycles. Levonorgestrel taken for emergency contraception (EC) prior to the LH surge alters the luteal phase secretory pattern of glycodelin in serum and endometrium. Based on the potent gamete adhesion inhibitory activity of glycodelin-A, the results may account for the action of LNG in EC in those women who take LNG before the LH surge.

Levonorgestrel (LNG), a 19-nor-testosterone derivative, is widely used in contraceptive formulations. This compound does not bind to the estrogen receptor (ER), but it shows estrogen-like effects under in vivo and in vitro conditions. The estrogenicity of LNG may be attributed to its bio-transformation into non-phenolic metabolites. In this study, the ability of A-ring reduced LNG metabolites to activate transcription via an estrogenic mechanism of action, including differences between ER alpha and ER beta subtypes, were investigated. Transactivation assays were performed in HeLa cells transfected with expression vectors for ER alpha and ER beta and an estrogen-responsive reporter gene. Cells were also transfected with expression vectors for both progesterone receptor (PR) isoforms (A or B). As expected, the tetrahydro derivatives of LNG (3 alpha,5 alpha- and 3 beta,5 alpha-LNG) showed significantly lower PR-mediated transcriptional activities through both isoforms when compared with progesterone (P(4)) and LNG. In contrast, the 3 beta,5 alpha-tetrahydro derivative resulted in a significant activation of estrogen-dependent gene transcription. This effect was selectively confined to the ER alpha, since little if any activity could be observed with the ER beta and no antagonistic activities were demonstrated. This study provides structural and molecular clues for the well documented in vitro and in vivo intrinsic estrogenicity of 19-nor-testosterone-derived progestins and ligand requirements for ER alpha recognition.

There is still controversy regarding the mechanism of action of levonorgestrel (LNG) for emergency contraception (EC). For those who state that pregnancy starts prior to implantation, any compound able to interfere with post-fertilization and pre-implantation stages, should be considered as abortifacient. Previous research suggests that EC in humans acts predominantly after fertilization. Current evidence with LNG-only EC supports a pre-fertilization mechanisms to explain its action. There are many potential mechanisms of action, which could vary pending on the day during the fertilization window of the ovarian cycle at which the contraceptive is given. This paper reviews the evidence for each potential mechanism of action. According to the most recently statements, it is concluded that the primary and possible the only mechanism of action of LNG-only EC is preventing or delaying ovulation. [ABSTRACT FROM AUTHOR]

The aim of this study was to analyze the effects of mid-cycle administration of Ulipristal acetate (UPA) on gene expression in endometrial biopsies taken during the receptive phase of the cycle. Fourteen healthy menstruating women were studied during 14 control non-treated and 12 treated cycles with a single dose of 30 mg UPA when follicle diameter reached 20 mm. Ovulation in both treated and control cycles was confirmed by serial determinations of serum LH, progesterone and vaginal ultrasound. An endometrial biopsy at day LH+7, in each cycle, was taken for RNA microarray and qPCR analysis or prepared for histological and immunohistochemistry studies. Functional analysis of differentially expressed genes showed the presence of changes compatible with a non-receptive endometrial phenotype, further confirmed by qPCR and immunohistochemistry. This study suggests the effects of UPA on endometrial receptivity, offering a plausible explanation for the higher contraceptive efficacy of this method compared to that of levonorgestrel. [ABSTRACT FROM AUTHOR]

Levonorgestrel (LNG), a 19-nor-testosterone derivative, is widely used in contraceptive formulations. This compound does not bind to the estrogen receptor (ER), but it shows estrogen-like effects under in vivo and in vitro conditions. The estrogenicity of LNG may be attributed to its bio-transformation into non-phenolic metabolites. In this study, the ability of A-ring reduced LNG metabolites to activate transcription via an estrogenic mechanism of action, including differences between ERα and ERβ subtypes, were investigated. Transactivation assays were performed in HeLa cells transfected with expression vectors for ERα and ERβ and an estrogen-responsive reporter gene. Cells were also transfected with expression vectors for both progesterone receptor (PR) isoforms (A or B). As expected, the tetrahydro derivatives of LNG (3α,5α- and 3β,5α-LNG) showed significantly lower PR-mediated transcriptional activities through both isoforms when compared with progesterone (P4) and LNG. In contrast, the 3β,5α-tetrahydro derivative resulted in a significant activation of estrogen-dependent gene transcription. This effect was selectively confined to the ERα, since little if any activity could be observed with the ERβ and no antagonistic activities were demonstrated. This study provides structural and molecular clues for the well documented in vitro and in vivo intrinsic estrogenicity of 19-nor-testosterone-derived progestins and ligand requirements for ERα recognition. [Copyright &y& Elsevier]