Original research articleTamoxifen for the treatment of breakthrough bleeding with the etonogestrel implant: a randomized controlled trial☆,☆☆
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)
- et al.
Tamoxifen treatment of bleeding irregularities associated with Norplant use
Contraception
(2005) - et al.
Effect of intermittent treatment with mifepristone on bleeding patterns in Norplant® implant users
Contraception
(2004) - et al.
Recommendations for standardization of data collection and analysis of bleeding in combined hormone contraceptive trials
Contraception
(2007) - et al.
Generation of allocation sequences in randomised trials: chance, not choice
Lancet
(2002) - et al.
Mifepristone for the prevention of breakthrough bleeding in new starters of depo-medroxyprogesterone acetate
Steroids
(2003) - et al.
Ovarian function during the use of a single contraceptive implant: Implanon compared with Norplant
Fertil Steril
(1998) - et al.
The effects of Implanon® on menstrual bleeding patterns
Eur J Contracept Reprod Health Care
(2008) - et al.
The contraceptive efficacy of Implanon®: a review of clinical trials and marketing experience
Eur J Contracept Reprod Health Care
(2009) - et al.
A 12-month multicenter, randomized study comparing the levonorgestrel intrauterine system with the etonogestrel subdermal implant
Fertil Steril
(2016) - et al.
Treatment of vaginal bleeding irregularities induced by progestin only contraceptives
Cochrane Database Syst Rev
(2013)
Short-term treatment of bothersome bleeding for etonogestrel implant users using a 14-day oral contraceptive pill regimen
Obstet Gynecol
Cited by (13)
Treatment of unfavorable bleeding patterns in contraceptive implant users: a randomized clinical trial of curcumin
2023, American Journal of Obstetrics and GynecologyTamoxifen for the Treatment of Etonogestrel Implant-Associated Bleeding in an Adolescent Gynecology Practice
2022, Journal of Pediatric and Adolescent GynecologyCitation Excerpt :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 BiologyCitation Excerpt :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, ContraceptionCitation Excerpt :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
- ☆
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.