By Rebecca H. Allen, MD, MPH, Editor
SYNOPSIS: In this randomized controlled trial of 54 patients with frequent or prolonged bleeding or spotting on the etonogestrel contraceptive implant, curcumin (the active ingredient in turmeric) was no better than placebo at controlling the total number of bleeding or spotting days during the 30-day study period.
SOURCE: Edelman A, Boniface E, Schrote K, et al. Treatment of unfavorable bleeding patterns in contraceptive implant users: A randomized clinical trial of curcumin. Am J Obstet Gynecol 2023;229:145.e1-145.e9.
Curcumin, the active ingredient in turmeric, has anti-inflammatory, anti-proliferative, and anti-angiogenic properties. The authors of this study sought to determine whether curcumin could reduce unscheduled bleeding and spotting caused by the etonogestrel implant. This progestin-only contraceptive is theorized to cause unscheduled bleeding and spotting by causing impaired angiogenesis, fragile blood vessels, and inflammation at the level of the endometrium.1
This was a double-blind, randomized controlled trial conducted at Oregon Health & Science University between February 2021 and November 2022. Inclusion criteria were participants aged 15 to 45 years using the 68-mg etonogestrel contraceptive implant for at least 30 days who were experiencing frequent or prolonged bleeding or spotting the previous month. Frequent bleeding or spotting was defined as two or more independent bleeding or spotting episodes in a 30-day interval. Prolonged bleeding or spotting was defined as seven or more consecutive days of bleeding or spotting in a 30-day interval.
Exclusion criteria included less than six months after delivery, less than six weeks after abortion, currently breastfeeding, undiagnosed abnormal uterine bleeding present before implant use, bleeding disorder, anticoagulation use, history of venous thromboembolism, allergy to turmeric, use of a P450 pathway-inducing drug, active cervicitis, or current implant use longer than two years and eight months. Baseline bleeding patterns were collected, and a pelvic exam was performed, with gonorrhea and chlamydia testing and urine pregnancy test upon enrollment as well as cervical cytology if indicated. The study drug or placebo was initiated on day 3 of consecutive bleeding or spotting after enrolment. Participants were randomized to 600 mg of Theracurmin HP (a commercially available curcumin supplement) or placebo taken as an oral pill every day. Daily data on medication use and bleeding patterns were collected electronically. Bleeding was defined as a day that required the use of protection with a pad, tampon, or liner and spotting as a day with blood loss that did not require protection. The primary outcome was the total number of days without bleeding or spotting. The study was powered to detect a six-day difference.
The authors enrolled and randomized 58 participants, of which 54 completed 30 days of treatment. The mean age of the study population was 24 years (standard deviation [SD] 4.5) and the mean body mass index was 24 kg/m2 (SD 4.4). The duration of implant use was no different between the two groups. There was no difference in the primary outcome between the two groups (mean days without bleeding or spotting, 16.7 [SD 6.9] curcumin vs. 17.5 [SD 4.8] placebo; P = 0.63). There also were no differences in the number of bleeding episodes (curcumin 2.0 [SD 0.8] vs. placebo 2.1 [SD 0.8]; P = 0.63). Most patients reported they were planning on keeping their implant (72%).
COMMENTARY
The etonogestrel contraceptive implant is highly effective with few contraindications to its use. The most common side effect, however, is unscheduled bleeding and spotting.2 Although this side effect is not dangerous, it can be annoying and leads patients to request early implant removal. Current guidelines for the treatment of unscheduled bleeding and spotting with the contraceptive implant include only nonsteroidal anti-inflammatory drugs (NSAIDs) for five to seven days or hormonal treatment with low-dose combined oral contraceptives or estrogen treatment for 10 to 20 days.3 These interventions may temporarily relieve the bleeding. Other therapies that have been studied include doxycycline, mifepristone, tranexamic acid, and tamoxifen.
Tamoxifen 10 mg taken twice daily for seven days was found to be effective by this same group of investigators.4 However, they stated in this manuscript that patients and providers are reluctant to use tamoxifen because it is used to treat breast cancer and has a small increased risk of venous thromboembolism. Therefore, these investigators opted to study a new agent, curcumin, which had not previously been studied for abnormal uterine bleeding. Curcumin is an over-the-counter supplement that has been studied for a variety of other health conditions, such as cancer, cardiovascular disease, and autoimmune disorders. Unfortunately, no effect from curcumin was found in this study. One limitation, however, is that the appropriate dose to treat menstrual bleeding for curcumin is not known.
More research needs to be done to find a medical therapy that works to treat unscheduled bleeding and spotting with the etonogestrel implant. Nevertheless, the vast majority of users are satisfied with the implant despite this side effect. Continuation rates for the etonogestrel implant in one large clinical study were 56.2% at three years compared to 69.8% for the levonorgestrel intrauterine device and 69.7% for the copper intrauterine device.5 These rates are much higher than continuation rates for shorter-acting methods.
Ultimately, in clinical practice, most of us offer patients a trial of a combined oral contraceptive for one month to attempt to treat the unscheduled bleeding and spotting, since this is the treatment endorsed by national guidance. Whether other treatments, such as tamoxifen, will become part of national guidelines in the future remains to be seen.
REFERENCES
- Milling Smith OP, Critchley HOD. Progestogen only contraception and endometrial break through bleeding. Angiogenesis 2005;8:117-126.
- Peipert JF, Zhao Q, Allsworth JE, et al. Continuation and satisfaction of reversible contraception. Obstet Gynecol 2011;117:1105-1113.
- Curtis KM, Jatlaoui TC, Tepper NK, et al. U.S. Selected Practice Recommendations for Contraceptive Use, 2016. MMWR Recomm Rep 2016;65:1-66.
- 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.
- Diedrich JT, Zhao Q, Madden T, et al. Three-year continuation of reversible contraception. Am J Obstet Gynecol 2015;213:662.e1-8.
