Original research articleLate follicular phase administration of levonorgestrel as an emergency contraceptive changes the secretory pattern of glycodelin in serum and endometrium during the luteal phase of the menstrual cycle
Introduction
Progestins are widely used for contraception in various modes of administration, such as injectables, subdermal implants, intrauterine systems, and peroral tablets [1], including hormonal emergency contraception (EC). Hormonal EC is an effective means to prevent unwanted pregnancies [2]. As a contraceptive, this method does not disrupt an established pregnancy and, among several modalities, the use of steroid hormones has become the method of choice. The two widely used hormonal EC methods are the combined estrogen–progestin and the progestin-only regimens [3], [4]. In both, two doses of the contraceptive formulation taken 12 h apart are administered after unprotected intercourse. The contraceptive mechanisms of action of these methods remain largely unknown. It is likely that multiple mechanisms operate, depending on the timing of drug intake with respect to ovulation. In previous studies, treatment around the ovulatory phase of the cycle has affected the luteinizing hormone (LH) surge and ovulation in some, but not in the majority of cases, suggesting that mechanisms other than anovulation are often involved. Additional possible mechanisms include thickening of the cervical mucus, alterations in sperm penetration or transport, fertilization, and/or interference with fertilization, follicular growth, corpus luteum development and/or implantation [5], [6], [7], [8], [9], [10], [11].
Glycodelin-A is a major secretory progesterone (P)-regulated glycoprotein of the human endometrium [12]. During the normal periovulatory phase, glycodelin-A is absent from the endometrium, and it becomes highly expressed during the last week of the luteal phase only [13], [14]. The temporal expression is significant because glycodelin-A is a potent inhibitor of sperm–zona binding [15]. Through its inhibitory activity on the immune cells, glycodelin-A is also believed to play a role in feto-maternal defense mechanisms [16], [17], [18].
In a previous study [5], we reported a high frequency of anovulation when levonorgestrel (LNG) was taken before the LH surge, whereas ovulation was more frequent among those women who took the drug at the time of or after the LH surge. This too indicated that mechanisms other than anovulation must play a part. Interestingly, no difference was found in endometrial histology in ovulatory cycles of women who took LNG during midcyle. We hypothesized that progestin-only EC may interfere with the normal cyclical pattern of glycodelin expression. To this effect, we used the same material as in the study by Durand et al. [5] to investigate whether periovulatory intake of LNG may alter the expression pattern of glycodelin-A in the endometrium and/or the glycodelin levels in serum.
Section snippets
Subjects and study design
The study was approved by the institutional review board of the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, and the subjects signed an informed consent form. The anthropometric and clinical characteristics of all subjects included in this study have been previously described [5]. The material from our previous study was used for this study in a retrospective fashion [5], excluding those women in whom drug intake fell outside the three defined categories (see below).
Results
The secretion profile of glycodelin in serum from subjects belonging to Groups 1 and 2 is shown in Fig. 1. Treatment with LNG before the LH surge shortened by 4 days the lag period before appearance of glycodelin in serum during the luteal phase (p<.05). In these subjects, serum glycodelin levels steadily rose from day LH +2 to days LH +7–8 of the luteal phase after which they declined (panel A, closed circles). Daily serum P concentrations during this time of the luteal phase remained
Discussion
Anovulation explains only a part of the mechanisms of action of hormonal EC. This appears to be the case particularly when medication is taken during the mid to the late follicular phase, before the LH surge [5], [8], [9], [28]. In ovulatory cycles, hostile cervical mucus brought about by progestin only is likely to contribute to contraceptive activity of the regimen, and a short luteal phase is not uncommon [5], [7]. However, normal ovulation and even normal corpus luteum function may occur if
Acknowledgments
Technical assistance of Mrs. Annikki Löfhjelm and Mr. Ora Julkunen is gratefully acknowledged. This work was supported by grants from Family Health International (North Carolina, USA), the Consejo Nacional de Ciencia y Tecnología (CONACyT, Mexico City, Mexico), the University of Helsinki, the Academy of Finland, the Helsinki University Central Hospital Research Funds, the Finnish Federation of Life and Pension Insurance Companies, and the Finnish Cancer Foundation.
References (39)
- et al.
On the mechanism of action of short-term levonorgestrel administration in emergency contraception
Contraception
(2001) - et al.
Statistical evidence about the mechanism of action of the Yuzpe regimen of emergency contraception
Obstet Gynecol
(1999) - et al.
The effects of peri-ovulatory administration of levonorgestrel on the menstrual cycle
Contraception
(2001) - et al.
Emergency contraception with mifepristone and levonorgestrel: mechanism of action
Obstet Gynecol
(2002) - et al.
Mechanism of action of hormonal preparations used for emergency contraception: a review of the literature
Contraception
(2001) - et al.
Endometrial glycodelin-A expression in the luteal phase of stimulated ovarian cycles
Fertil Steril
(2000) - et al.
Factors affecting fertilization: endometrial placental protein 14 reduces the capacity of human spermatozoa to bind to the human zona pellucida
Fertil Steril
(1995) - et al.
Identification of placental protein 14 as an immunosuppressive factor in human reproduction
Lancet
(1987) - et al.
Time resolved immunofluorometric assay for placental protein PP14
Clin Chim Acta
(1989) - et al.
Dating the endometrial biopsy
Fertil Steril
(1950)
Use of integrins to date the endometrium
Fertil Steril
Effects of the Yuzpe regimen, given during the follicular phase, on ovarian function
Contraception
The effects of levonorgestrel administered in large doses at different stages of the cycle on ovarian function and endometrial morphology
Contraception
Endometrial expression of glycodelin in women with levonorgestrel-releasing subdermal implants
Fertil Steril
Gender-specific glycosylation of human glycodelin affects its contraceptive activity
J Biol Chem
Serum levels of placental protein 14 reflect ovulation in nonconceptional menstrual cycles
Fertil Steril
The variation of endometrial protein PP14 in different parts of the human endometrium
Int J Gynaecol Obstet
Fertility regulation technology: status and prospects
Popul Bull
Task Force on Postovulatory Methods of Fertility Regulation. Randomized controlled trial of levonorgestrel versus the Yuzpe regimen of combined oral contraceptives for emergency contraception
Lancet
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Effect of levonorgestrel emergency contraception on implantation and fertility: A review
2022, ContraceptionCitation Excerpt :Five in vivo biomedical studies showed that Levonorgestrel EC administered either before, on the day of, or after LH surge resulted in no change in endometrial receptivity markers compared to controls [24,32–35] and the authors concluded that levonorgestrel did not affect implantation. Two in vivo biomedical studies showed that Levonorgestrel EC taken before the LH surge induced premature rise in serum and intrauterine concentrations of glycodelin-A in the peri-ovulatory phase compared to controls, which might inhibit sperm-oocyte interaction if ovulation were to occur [36], but a weaker expression of glycodelin-A on day 9 following the LH surge (LH +9) or no significant change when taken on or after the day of LH surge, indicating lack of effect on implantation [37]. Another in vivo study showed that vaginal Levonorgestrel EC exposure after the LH surge had no effect on 14 endometrial receptivity markers, but that oral exposure affected the expression of three biomarkers: a reduction in expression of progesterone receptors (PR-A and PR-B) in the glandular epithelium, and increased expression of leukemia inhibitory factor (LIF) [38].
Results from pooled Phase III studies of ulipristal acetate for emergency contraception
2012, ContraceptionCitation Excerpt :UPA, when taken after ovulation, has been found to decrease endometrium thickness and alter l-selectin ligands, but whether this change would inhibit implantation is unknown [8]. LNG EC taken before the luteinizing hormone surge has also been reported in one study to alter the luteal phase secretory pattern of glycodelin in serum and the endometrium [9], although two later studies explicitly designed to assess endometrial glycodelin expression did not confirm these findings [10,11]. Pooling the data increases statistical power and allows a more in-depth analysis of factors associated with UPA failures, generalizable to the population living in Europe and North America.
Hormonal evaluation and midcycle detection of intrauterine glycodelin in women treated with levonorgestrel as in emergency contraception
2010, ContraceptionCitation Excerpt :In addition, Durand et al. [7] demonstrated that when LNG is taken within this window, a premature appearance of glycodelin in serum is observed at the time of ovulation. Although this observation is important, because of the well-known inhibitory effects of intrauterine glycodelin-A on sperm binding to the zona pellucida [8], the glycodelin concentration in serum was far below [7] that required for sperm-egg binding inhibition [8]. In this context, the purpose of the present study was to assess the presence of glycodelin-A in uterine flushing at the midcycle of ovulatory women treated with LNG during the preovulatory phase of their menstrual cycles.
A single midcycle dose of levonorgestrel similar to emergency contraceptive does not alter the expression of the L-selectin ligand or molecular markers of endometrial receptivity
2010, Fertility and SterilityCitation Excerpt :Endometrial expression of Gly-A, other than during the secretory phase, was also reported in women using IUD-releasing LNG, suggesting another contraceptive mechanism (22). An interesting investigation also demonstrated that late follicular administration of LNG, but not at the time of the LH surge, produces an early rise in serum Gly-A (23). In this study, very little if any Gly-A protein expression was detected in biopsies 48 hours after LNG-EC administration, a finding that is in agreement with another recent report (24).
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