By Katherine Rivlin, MD, MSc
Assistant Professor, Obstetrics and Gynecology, The Ohio State University Wexner Medical Center, Columbus, OH
Dr. Rivlin reports no financial relationships relevant to this field of study.
In this double-blind, randomized controlled trial, etonogestrel implant users with prolonged or frequent menses who took 10 mg of tamoxifen twice daily for seven days as needed for irregular bleeding had an average of 9.8 (95% confidence interval, 4.6-15.0) more consecutive days of amenorrhea over a 90-day period compared to those who took a placebo.
SOURCE: Edelman AB, Kaneshiro B, Simmons KB, et al. Treatment of unfavorable bleeding patterns in contraceptive implant users: A randomized controlled trial. Obstet Gynecol 2020;136:323-332.
The etonogestrel-containing implant is a highly effective method of contraception that has been associated with unpredictable bleeding patterns, including amenorrhea and infrequent, frequent, and/or prolonged bleeding.1 Some implant users find these bleeding patterns unacceptable, which can lead to discontinuation of the contraceptive method.2 Breakthrough bleeding from this progestin-only implant likely results from abnormal blood vessel development in the endometrium in the absence of estrogen. Currently, options for management of bleeding irregularities are limited. Tamoxifen, a selective estrogen receptor modulator, may inhibit endometrial angiogenesis, and therefore could provide a sustained effect after treatment completion.
This double-blind, randomized, placebo-controlled trial enrolled 112 implant users (ages 15 to 45 years) experiencing frequent bleeding (two or more independent bleeding episodes in 30 days) or prolonged bleeding (seven or more consecutive days of bleeding in 30 days). Exclusion criteria included having any of the following: other etiologies of irregular bleeding patterns (e.g., breastfeeding, postpartum, bleeding dyscrasias); a contraindication to tamoxifen use (e.g., history of a venous thromboembolism); or a three-year implant that would expire during the study time period.
Participants were randomized to take either 10 mg of tamoxifen twice daily for seven days after experiencing three consecutive days of bleeding, or an identical placebo. Participants then repeated these treatments as needed over a 90-day period with a maximum of three treatments, and recorded daily bleeding patterns by text message. Research staff and participants were blinded to treatment assignments. In the second half of the study, all participants entered a 90-day open-label phase in which both study arms received tamoxifen as needed.
Research subjects, recruited from Portland, OR, and Honolulu, were predominantly white with an average body mass index of 27. Both study arms were demographically similar. The tamoxifen group reported 9.8 more consecutive days of amenorrhea after the first treatment than the placebo group in the first 90 days (95% confidence interval [CI], 4.6-15.0; no P value provided). The placebo group experienced a similar benefit after the first tamoxifen treatment in the open-label phase.
At the end of the first 90 days of the study, median bleeding satisfaction (range, 0-100 mm) was higher in the tamoxifen group (62 mm) than in the placebo group (46 mm, P = 0.023). However, median implant satisfaction (range, 0-100 mm) was similar for both groups at the end of both the 90-day time period (83 mm vs. 80.5 mm, P = 0.369) and at the end of the 180-day time period (81 mm vs. 81.57 mm, P = 0.767). Although few adverse events occurred in the study, participants taking tamoxifen were more likely to report fluid retention, headache, and mood changes.
COMMENTARY
As the use of long-acting, reversible methods of contraception increases, clinicians more commonly encounter etonogestrel implant users experiencing irregular bleeding patterns.3 Although such bleeding is unlikely to cause harm, it can be irritating to patients, and is a commonly cited reason for method discontinuation.4 Unfortunately, few options exist to manage this bleeding in a sustained way. Combined hormonal oral contraceptives can improve bleeding irregularities during therapy, but they provide no long-lasting effect after pill discontinuation.5
Edelman and colleagues showed a more sustained effect of tamoxifen after treatment discontinuation — with 9.8 more days of amenorrhea among tamoxifen users compared to placebo. Notably, the authors powered their study to find a 15-day difference between the two groups — which, ultimately, they did not find. They achieved statistical significance because of a higher participant retention rate than anticipated, since a higher sample size increases the power of a study.
However, statistical significance does not always indicate clinical significance. Do nine additional days of amenorrhea over a three-month time period make a difference to patients? Patient satisfaction may be a more important clinical indicator than amenorrhea days. The tamoxifen group had higher bleeding satisfaction over the first 90 days of the study compared to the placebo group, but implant satisfaction was the same between the two groups at both 90 days and at the end of the study.
In addition, one should consider the implications of taking tamoxifen to manage bleeding irregularities. Although few adverse events occurred in the study, any side effects may be more bothersome to a patient than irregular bleeding, depending on that patient’s preferences. The authors describe challenges in study recruitment among both patients and clinicians because of concerns about taking a “cancer drug” to manage implant bleeding. Only implant users willing to take tamoxifen enrolled in the study, which introduces selection bias into a study population with already limited demographic generalizability.
The acceptability of tamoxifen to manage bleeding irregularities to a broader patient population is unclear. Presumably, many users choose the implant precisely because of its nondaily dosing. A question left unanswered by this study is just how acceptable do patients find periodically taking any medication to manage irregular bleeding.
As the authors note, although tamoxifen improved bleeding patterns for many implant users, for some it made no difference. Irregular bleeding patterns among progestin-only contraceptive users are multifactorial, resulting from more than just angiogenesis. Inflammatory and coagulation components likely also play a role and will not be affected by tamoxifen. Therefore, finding a one-size-fits-all treatment is challenging.
Overall, this study adds to an evolving toolbox of management options for irregular bleeding with the etonogestrel implant but does not solve the problem. The authors note that tamoxifen provides a treatment but not a cure. As with all contraceptive counseling and management, patient-centered care is key. In practice, one should avoid automatically recommending tamoxifen to all implant users experiencing bothersome bleeding patterns. Rather, a clinician should explore patient concerns and preferences using shared decision-making. The patient and clinician ultimately could decide on a course of tamoxifen if the patient should express interest and find the dosing, cost, potential side effects, and unpredictable outcomes acceptable.
REFERENCES
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- Blumenthal PD, Gemzell-Danielsson K, Marintcheva-Petrova M. Tolerability and clinical safety of Implanon. Eur J Contracept Reprod Health Care 2008;13(Suppl 1):29-36.
- Daniels K, Abma JC. Current contraceptive status among women aged 15-49: United States, 2015-2017. NCHS Data Brief No. 327. National Center for Health Statistics. December 2018. https://www.cdc.gov/nchs/products/databriefs/db327.htm
- Apter D, Briggs P, Tuppurainen M, et al. A 12-month multicenter, randomized study comparing the levonorgestrel intrauterine system with the etonogestrel subdermal implant. Fertil Steril 2016;106:151-157.e5.
- Guiahi M, McBride M, Sheeder J, Teal S. Short-term treatment of bothersome bleeding for etonogestrel implant users using a 14-day oral contraceptive pill regimen: A randomized controlled trial. Obstet Gynecol 2015;126:508-513.
