Elsevier

Contraception

Volume 95, Issue 2, February 2017, Pages 198-204
Contraception

Original research article
Tamoxifen for the treatment of breakthrough bleeding with the etonogestrel implant: a randomized controlled trial,☆☆

https://doi.org/10.1016/j.contraception.2016.10.001Get rights and content

Abstract

Objective

The etonogestrel (ENG) subdermal implant can cause frequent breakthrough bleeding in some users. The objective of this study was to evaluate whether a short course of tamoxifen reduces bleeding/spotting days compared to placebo in ENG implant users.

Study design

In this double-blind trial, we randomized ENG implant users with frequent or prolonged bleeding or spotting to tamoxifen 10 mg or placebo twice daily for 7 days, to be started after 3 consecutive days of bleeding/spotting. Treatment was repeated as needed up to three times in 180 days. Subjects completed a daily text message bleeding diary. A sample size of 56 provided 80% power to detect a difference of 6 days of bleeding/spotting per 30 days by two-sample t test. Ovulation was monitored by urinary metabolites of progesterone.

Results

From March 2014 to February 2015, 56 women enrolled. Fifty-one completed at least 30 days of follow up, and 34 completed 180 days. Compared to women randomized to placebo, women randomized to tamoxifen reported 5 fewer days of bleeding/spotting over 30 days (95% confidence interval [CI] −9.9 to −0.05, p=.05), and 15.2 more continuous bleeding-free days (95% CI 2.8–27.5 days, p=.02) after first use of study drug. Conclusions could not be drawn after 30 days due to higher-than-expected dropout. No ovulation was detected.

Conclusion

First use of tamoxifen by ENG implant users reduces bleeding/spotting days and provides a longer cessation of bleeding/spotting than placebo, without compromising ovulation suppression. Further study is needed to determine whether this effect is maintained with repeat use.

Implications

Women with frequent ENG implant-related breakthrough bleeding may experience a reduction in bleeding/spotting days and an increase in continuous bleeding-free days in the month following first use of tamoxifen. This short course of tamoxifen was well tolerated with bleeding cessation noted within a median of 5 days.

Introduction

The etonogestrel (ENG) contraceptive implant is a highly effective method of reversible contraception, but it can cause frequent breakthrough bleeding (BTB) in some users [1], [2]. Bleeding pattern changes, particularly increased frequency of bleeding, are the most commonly cited reasons for implant discontinuation [3]. A reliable treatment for BTB should increase acceptability and continuation of this highly effective contraceptive.

No pharmacologic therapy has demonstrated a prolonged reduction in BTB with the ENG implant [4]. Though combined oral contraceptive pills (COCs) are usually effective in terminating an episode of bleeding with the ENG implant, bleeding returns rapidly upon discontinuation, potentially requiring long-term cotherapy to maintain an acceptable bleeding profile [5]. Mifepristone may reduce BTB with ENG implants, but it has limited availability and could theoretically impair the contraceptive properties of the implant through antagonism of the progesterone receptor [4]. By contrast, a 10-day course of the selective estrogen receptor modulator tamoxifen provided a sustained reduction in BTB in users of levonorgestrel (LNG) implants [6]. Women who received tamoxifen reported fewer days of bleeding and spotting than women taking placebo during the 2 months after treatment (6.2 vs. 12.3 days in month one, p=.0003; 6.8 vs. 11.9 days in month two, p=.0008). This bleeding reduction after tamoxifen was associated with higher satisfaction and less implant discontinuation than placebo [4], [6].

The objective of this study was to determine whether tamoxifen reduces BTB in users of the ENG implant. We hypothesized that tamoxifen would reduce BTB and increase satisfaction without compromising ovulation suppression.

Section snippets

Study participants

This randomized, double blind, placebo-controlled trial was conducted at Oregon Health & Science University (OHSU) in Portland, OR, USA, from March 2014 to August 2015. The Institutional Review Board at OHSU approved the study protocol. All participants completed written informed consent prior to any study procedures.

We used provider referrals and radio advertisements to recruit 15–45-year-old women using the ENG 68-mg subdermal implant (Implanon/Nexplanon, Merck, Kenilworth, NJ, USA) for at

Results

Fig. 1 depicts subject flow according to CONSORT guidelines [14]. A total of 12 women were lost to follow-up and 10 withdrew early (Fig. 1). Baseline characteristics of the two groups were generally similar (Table 1). Women in the tamoxifen group reported more days of baseline bleeding than the placebo group (p<.05, two-sample t test) and a slightly shorter duration of implant use (p>.05). These differences were unexpected, so analyses were completed with and without adjustment for these

Discussion

Among ENG implant users with frequent or prolonged BTB, the first use of tamoxifen led to statistically significant and clinically important short-term improvements in bleeding, with a reduction in B/S days in the month following treatment, and a longer bleeding-free interval compared to placebo. Bleeding cessation was noted within a median of 5 days after starting tamoxifen. It was not possible to draw conclusions on the effects of repeat tamoxifen dosing due to attrition and limitations of

Funding

This work was supported by the Society of Family Planning grant SFPRF14–1. The Society of Family Planning had no role in the study design, data collection, analysis, interpretation, writing or decision for publication.

Acknowledgements

The authors thank the Women's Health Research Unit at OHSU, particularly Monica Dunn, for essential contributions in recruitment and study coordination. Thank you to the Endocrine Technologies Support Core staff at the Oregon National Primate Research Center for analysis of hormone samples. We thank the Oregon Clinical and Translational Research Institute for access to the REDCap online database (grant support from 1 UL1 RR024140 01).

References (23)

  • M. Guiahi et al.

    Short-term treatment of bothersome bleeding for etonogestrel implant users using a 14-day oral contraceptive pill regimen

    Obstet Gynecol

    (2015)
  • Cited by (13)

    • Tamoxifen for the Treatment of Etonogestrel Implant-Associated Bleeding in an Adolescent Gynecology Practice

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      Progestins and selective progesterone receptor modulators such as mifepristone have also been reported to decrease episodes of unscheduled bleeding by possible upregulation of endometrial estrogen receptors.8,9 There are few randomized controlled trials examining the use of tamoxifen to address bothersome bleeding secondary to the ENG implant.10–14 Tamoxifen is a selective estrogen receptor modulator nonsteroidal agent that is commonly utilized as an anticancer drug in breast cancer due to its antiestrogenic properties in breast tissue.

    • Long-acting reversible contraceptives effects in abnormal uterine bleeding, a review of the physiology and management

      2022, European Journal of Obstetrics and Gynecology and Reproductive Biology
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      The authors concluded that the first use and found that the first use of tamoxifen for bleeding can provide bleeding cessation, without compromising the efficacy of contraception [51]. Some limitations of this study reported by authors were: loss of follow-up, the use of retrospective baseline bleeding data, and the duration of implant use [51]. However, an earlier RCT with 100 women had found that tamoxifen use at 10 mg (twice daily for 10 days) had promising results in SCI users [54].

    • Tamoxifen for the prevention of unscheduled bleeding in new users of the levonorgestrel 52-mg intrauterine system: a randomized controlled trial

      2019, Contraception
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      We recently reported in a randomized controlled trial that tamoxifen reduced bleeding in etonogestrel implant users within 30 days after use [16], confirming previous observations in levonorgestrel implant users [17]. In both studies, tamoxifen treatment resulted in a sustained bleeding reduction lasting beyond the treatment period [16,17]. Tamoxifen could improve unscheduled bleeding through antagonism of endometrial estrogen receptor β (ERβ) cells, causing down-regulated endometrial angiogenesis [18–20].

    • Unscheduled vaginal bleeding with progestin-only contraceptive use

      2017, American Journal of Obstetrics and Gynecology
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    Clinical Trial Registration: Clinicaltrials.gov, https://clinicaltrials.gov/ct2/show/NCT02070692, NCT02070692.

    ☆☆

    Conflicts of interest: Dr. Simmons has no conflicts of interest to report. Dr. Edelman is a Nexplanon trainer and consultant for Merck. Dr. Fu has no conflicts of interest to report. Dr. Jensen reports grants and personal fees from Bayer Healthcare, Merck, Abbvie, Evofem and Agile Pharmaceuticals; personal fees from ContraMed, Teva, Population Council and Microchips; and grants from Medicines360, FHI360, Bill & Melinda Gates Foundation and the National Institute of Health (National Institute of Child Health and Human Development), outside the submitted work.

    1

    Present address: University of North Carolina, Department of Obstetrics and Gynecology, 3006 Old Clinic Building, CB 7570, Chapel Hill, NC 27599.

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