Temporal changes in cervical mucus after insertion of the levonorgestrel-releasing intrauterine system

doi:10.1016/j.contraception.2012.09.034

Contraception

Volume 87, Issue 4, April 2013, Pages 426-431

https://doi.org/10.1016/j.contraception.2012.09.034 Get rights and content

Abstract

Background

The major contraceptive action of the levonorgestrel-releasing intrauterine system (LNG-IUS) is cervical mucus (CM) thickening, which prevents sperm penetration. No study to date has examined the temporal relationship between the insertion of the LNG-IUS and changes in CM quality and sperm penetration.

Study Design

Participants were enrolled in a clinically descriptive study to compare the quality of CM and three parameters of sperm penetration prior to insertion of the LNG-IUS and on Days 1, 3 and 5 after insertion. Measurements of estradiol, progesterone and levonorgestrel (LNG) in serum and LNG in CM were also carried out at these times. CM was analyzed using the World Health Organization CM grading criteria. Sperm penetration was determined using an in vitro sperm–CM penetration test.

Results

All 10 participants underwent LNG-IUS insertion during midcycle when CM quality was good and sperm penetration was excellent. On Day 1 after LNG-IUS insertion, the majority of participants demonstrated poor CM quality and poor sperm penetration. On Day 3, all participants had poor CM quality, and all but one subject had poor sperm penetration. By Day 5, all participants had poor CM quality and poor sperm penetration. LNG levels in CM peaked on the day after LNG-IUS insertion.

Conclusion

Significant changes in quality of CM and sperm penetration were observed shortly after LNG-IUS insertion; however, CM can remain penetrable for up to 5 days when the LNG-IUS is inserted midcycle.

Introduction

The levonorgestrel-releasing intrauterine system (LNG-IUS) is a Food and Drug Administration-approved highly effective long-acting reversible contraceptive method. The device contains 52 mg of levonorgestrel (LNG), which is released in the uterus at a rate of 20 mcg per day. The major contraceptive action of the LNG-IUS is induction of cervical mucus (CM) thickening to prevent sperm penetration [1].

Multiple investigations have evaluated the time period from initiation of a progestin-only contraceptive method to onset of effect upon CM. There is variability in the length of time following progestin administration for sufficient changes in CM quality and sperm penetrability to occur. CM changes sufficient to prevent sperm penetration have been established within 24 h of administration of progestin-only pills [2]. Barbosa et al. [3] observed alterations in CM sufficient to prevent sperm penetration within 48 h of inserting Uniplant, a subcutaneous device containing the progestin nomegestrol. Measurements of CM change in users of Norplant, a subcutaneous implant containing LNG, found changes in CM sufficient to prevent sperm penetration by 72 h following implant insertion [4]. Petta et al. [5] demonstrated poor CM quality 7 days or more following injection of 150-mg depot medroxyprogesterone acetate (DMPA). These results offer clinically relevant information to providers and patients initiating progestin-only contraceptive methods.

Current product labeling recommends insertion of the LNG-IUS to occur within 7 days following the onset of menses [6]. World Health Organization (WHO) guidelines recommend that the LNG-IUS may be inserted any time pregnancy can be reasonably excluded with the use of a backup method for 7 days postinsertion [7]. However, there is no data to support this time interval for the LNG-IUS.

No study has examined the temporal relationship between LNG-IUS insertion and changes in CM quality and sperm penetration. Based on previous research with other progestin-only contraceptive methods, we hypothesize that these changes occur shortly after insertion not by postinsertion Day 7.

Section snippets

Materials and methods

This was a single-center, clinically descriptive study. The primary objective was to compare the quality of CM and three parameters of sperm penetration in participants immediately prior to insertion of the LNG-IUS and on postinsertion Days 1, 3 and 5. The secondary objective was to determine the serum concentrations of estradiol (E2), progesterone (P4) and LNG and the CM concentration of LNG at each interval. The study was approved by the University of Southern California Health Science Campus

Results

A total of 28 women were screened, and 15 women were enrolled in the study (Fig. 1). There were 11 screen failures: 6 women did not ovulate, 2 had difficult anatomy that would preclude CM sampling and intrauterine device (IUD) insertion, 2 had untreated cervical dysplasia and 1 was pregnant. Two participants withdrew consent prior to enrollment. Five women (30%) were discontinued from the study: 2 did not make adequate CM to study, and 3 were lost to follow up. Ten participants completed the

Discussion

The aim of this study was to compare the quality of CM and sperm penetration scores at the time of LNG-IUS insertion to postinsertion Days 1, 3 and 5. The device was inserted during the midcycle, preovulatory phase of the menstrual cycle when CM quality was good in all participants and all participants had good or excellent sperm penetration at 2 h. Our results show that by postinsertion Day 1, 7 of 10 subjects had poor CM quality, and 8 of 10 subjects had poor SPS at 2 h. These changes are

Acknowledgments

We gratefully acknowledge the anonymous donor who supported this study and the Bayer HealthCare Pharmaceuticals Grant for Investigator-Sponsored Studies in Women's Health who provided the IUDs. I would like to thank Nicole Bender, MD, Penina Segall-Gutierrez, MD, Rebecca Sokol, MD, MPH, Rachel Steward, MD, and Angelica Mora for their work on this study.

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Impact of drug loading on release from levonorgestrel intrauterine systems
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Burst release of drug may lead to toxicity, limited drug utilization, frequent dosing and shortened release profiles (Huang and Brazel, 2001). LNG-IUSs have been reported (Natavio et al., 2013; Wildemeersch and Andrade, 2010) to have an initial burst effect in clinical studies. However, this effect may not be reflected in all accelerated and real-time release profiles when plotting the release percentage against time.
Levonorgestrel intrauterine systems (LNG-IUSs) are polydimethylsiloxane (PDMS) based non-biodegradable complex drug-device combination products providing efficacy for up to several years based on the strength. A large amount of LNG (e.g., 52 mg in Mirena and Liletta) must be loaded in the LNG-IUS products to maintain the long-acting effect even though LNG is a potent hormone. However, the high amount of LNG not only poses the potential risk of dose dumping, but also leads to drug waste due to incomplete drug utilization close to the end of usage. It has been unclear whether the duration of usage of these products should be extended for full drug utilization or products with lower drug loading should be developed. Therefore, it is critical to understand the impact of strength (or drug loading) on drug release from LNG-IUSs. In the current study, drug reservoirs with a broad range of drug loading (from 0.5% w/w to 50% w/w) were prepared and assembled into LNG-IUSs. Different accelerated release conditions were used to perform release testing of LNG-IUSs with different drug loading. 5% to 10% variation in excipient of the LNG-IUSs did not significantly alter the drug release profiles of the LNG-IUSs. The release rate of LNG-IUSs is inversely proportional to their drug loading at high drug loading (10% w/w, 25% w/w and 50% w/w). Drug release was incomplete for LNG-IUS with low drug loading (2.5% w/w and 1% w/w) and no drug release could be detected for the LNG-IUS with 0.5% w/w drug loading. In addition, the burst effect of the LNG-IUSs with different drug loading was investigated. This is the first research report covering ultra-long duration (more than four years) of real-time drug release from LNG-IUSs with different drug loading (0.5%-50% w/w). The amount of excipient (PDMS) used in the reservoir of LNG-IUSs was determined to be not a critical quality parameter in the formulation design since LNG-IUSs (50% w/w drug loading) with up to 10% variation in excipient did not show significant differences in their release profiles. The drug release kinetics/mechanism remained the same for LNG-IUSs with drug loading ranging from 1% to 50%. In addition, the accelerated release testing methods were confirmed to be representative of the real-time release profiles and this can give confidence in extending the duration of usage for these products provided that the device remains physically intact (no tearing or damage in the outer membrane) and the release rate is within the therapeutic window. It is recommended to perform both real-time and accelerated release testing simultaneously for LNG-IUSs to understand the burst effect as well as the complete release characteristics. Lastly, drug/polymer interaction may play a role when designing LNG-IUS formulations with low drug loading (<5% w/w) since drug/polymer interaction is significant when only a small amount of drug present.
Rates of pregnancy among levonorgestrel and copper intrauterine emergency contraception initiators: Implications for backup contraception recommendations
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Cervical mucus may become impenetrable to sperm as soon as 2 to 4 hours from ingestion of progestin-only pills [18]. Data suggest prompt changes in cervical mucus, and subsequent blockage of sperm penetration, following levonorgestrel IUS placement, as well [19]. Levonorgestrel IUS's immediate efficacy may also derive benefit from a foreign body effect similar to that seen with inert IUDs [8, 20-23].
This study assessed the timing, frequency, use of backup method and 1-month pregnancy rates among individuals who had an intrauterine device (IUD) placed as emergency contraception and reported intercourse within 7 days post-placement.
In this secondary analysis of a randomized control trial of IUDs for emergency contraception, 518 individuals reporting unprotected intercourse in the preceding 5 days had a 52 mg levonorgestrel intrauterine system (IUS) or 380 mm² copper IUD placed outside the first week of their menstrual cycle. All participants were advised to use backup contraception for 7 days. We assessed pregnancy status 1 month after placement by urine testing or, when not available, by survey responses and electronic health record review. Participants reported whether their first sexual activity after device placement occurred within 7 days of their placement, the frequency of intercourse and whether they used backup contraception.
Rapid return to sexual activity was common and use of backup contraception was rare, regardless of type of IUD placed. Of participants who resumed penile-vaginal intercourse in the first month, most (286/446, 64.1%) participants reported intercourse within 7 days of IUD placement; only 16.4% (74/446) used condoms or withdrawal. No pregnancies occurred among users of the levonorgestrel IUS who reported intercourse within 7 days of placement (0/138, 0.0%, 95% CI 0.0%, 2.6%) nor among users of the 380mm² copper IUD (0/148, 0.0%, 95% CI 0.0%, 2.5%).
Pregnancy rates are low after placement of an IUD for emergency contraception, even among the many who resume intercourse within days following IUD placement without use of backup contraception.
Clinical guidelines should facilitate access to contraception, including elimination of unnecessary recommendations for backup contraception or abstinence in the 7 days following 52 mg levonorgestrel intrauterine system.
Long-acting reversible contraceptive (LARCs) methods
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In fact, it is now known that the main mechanism of action of copper-IUDs is spermicidal action through the development of a local sterile inflammatory process induced by the presence of a foreign body in the uterus [13,14]. However, the mechanism of action of the existing models of the LNG IUS, independently of the daily release of LNG, is primarily the thickening of cervical mucus and impaired sperm penetration [15,16]. Ovulation is suppressed but at different rates according to the daily LNG release rate.
Unplanned pregnancy (UP) is a public health problem, which affects millions of women worldwide. Providing long-acting reversible contraceptive (LARC) methods is an excellent strategy to avoid or at least reduce UP, because the effectiveness of these methods is higher than other methods, and is indeed comparable to that of permanent contraception. As the initial introduction of the inert plastic intrauterine device (IUD) and of the six-rod implant, pharmaceutical companies have introduced a copper IUD (Cu-IUD), different models of levonorgestrel-releasing intrauterine system (LNG IUS), and one and two-rod implants, which certainly improved women's LARC options. The main characteristic of LARCs is that they provide high contraceptive effectiveness with a single intervention, and that they can be used for a long time. Emerging evidence from the last few years has demonstrated that it is possible to extend the use of the 52 mg LNG IUS and of the etonogestrel-implant beyond five- and three years, respectively, which adds new value to these LARCs.
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They found that the frequency of “favorable” mucus (69% control vs. 14% IUS) and sperm penetration (79% vs. 0% for SCMPT) scores was significantly different. Natavio et al. evaluated the onset of this effect by following 10 women with serial exams until a mucus score of ≥10 was obtained, at which time an LNG-IUS was inserted, followed by additional mucus exams on days 1, 3 and 5 following insertion [109]. One day following insertion, 3/10 women had mucus scores ≥10, and none by day 3.
Cervical mucus varies in response to both natural and artificial hormonal changes. It is commonly believed that cervical mucus thinning is associated with normal fertility and that progestogen-induced thickening is an essential contraceptive mechanism. This review aims to broadly summarize our current knowledge about cervical mucus from both a clinical and basic research perspective.
We reviewed published literature pertinent to cervical mucus and contraception across scientific disciplines. We first present the most current understanding of the composition of cervical mucus, how it is hormonally regulated, and examine the role of mucus as an immune barrier. We then critically assess the current clinical tests used as surrogate markers for a contraceptive effect. Finally, we review contraceptive studies that have specifically focused on cervical mucus changes.
Existing research suggests that cervical mucus has potential to be a contraceptive target with unique, multipurpose characteristics. However, methodologic limitations associated with clinical assessments of cervical mucus complicate our understanding of contraceptive treatment effects. Key pathways involved in cervical mucus production with potential as novel nonhormonal contraceptive targets have been identified.
More research is needed to clarify the role of cervical mucus in current hormonal contraceptives and to support the development of novel nonhormonal cervix-based methods.
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^☆: The study was funded through an educational grant from an anonymous donor. The intrauterine devices were provided through the Bayer HealthCare Pharmaceuticals Grant for Investigator-Sponsored Studies in Women's Health. The sponsors had no role in study design, data collection, analysis or interpretation or report writing.

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Original research articleTemporal changes in cervical mucus after insertion of the levonorgestrel-releasing intrauterine system☆

Abstract

Background

Study Design

Results

Conclusion

Introduction

Section snippets

Materials and methods

Results

Discussion

Acknowledgments

Contraception

Contraception

Contraception

Fertil Steril

Fertil Steril

Fertil Steril

Contraception

Fertil Steril

Original research article
Temporal changes in cervical mucus after insertion of the levonorgestrel-releasing intrauterine system☆