Elsevier

Contraception

Volume 71, Issue 6, June 2005, Pages 451-457
Contraception

Original research article
Late 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

https://doi.org/10.1016/j.contraception.2005.01.003Get rights and content

Abstract

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.

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.

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