Relationship Between Etonogestrel Concentrations and Bleeding Patterns in Contraceptive Implant Users

Abstract

OBJECTIVE: To estimate whether serum etonogestrel concentrations influence bleeding patterns and related side effects in contraceptive implant users. METHODS: We conducted a prospective cross-sectional study with healthy, reproductive-aged women using etonogestrel implants for 12–36 months. Participants completed a brief questionnaire to assess their current bleeding pattern and any experience of abnormal bleeding with the implant. We then measured serum etonogestrel concentrations. We also reviewed the charts of participants to determine whether a prescription for oral contraceptive pills was ever given for treatment of implant-related bothersome bleeding. We performed multivariable logistic regression to test for associations between serum etonogestrel concentrations and both bleeding patterns and related side effects. RESULTS: We enrolled 350 women, and 59.4% reported having experienced abnormal bleeding with the contraceptive implant. Only 14.9% of participants reported amenorrhea and 37.7% reported monthly periods. Among participants with reviewable medical records (n=253), roughly 20% had received a prescription for oral contraceptive pills during implant use. Increasing serum etonogestrel concentrations were significantly associated with increasing odds of reporting abnormal bleeding (adjusted odds ratio [aOR] 1.005, P=.015) and increasing odds of having received an oral contraceptive pill prescription (aOR 1.008, P=.002). For every 100 pg/mL increase in serum etonogestrel concentration, contraceptive implant users in this study had 1.6 times the odds of reporting abnormal bleeding and 2.3 times the odds of having received a prescription as treatment for bothersome bleeding. CONCLUSION: We found both objective and subjective evidence that higher levels of progestin from the contraceptive implant were associated with bleeding side effects experienced by women in this study. Pharmacologic variation may influence the side effects women experience with a variety of hormonal contraceptive methods, in turn affecting patient satisfaction and discontinuation rates.

Safety and Benefits of Contraceptives Implants: A Systematic Review

“…Mifepristone combined with either E2 or doxycycline was significantly more effective than placebo in stopping bleeding in women with prolonged and/or frequent bleeding during Implanon use [67,68]. In a prospective cross-sectional study, Lazorwitz et al [66] studied 350 healthy, reproductive-aged women using ENG implants for 12-36 months, showing that 20% received a prescription for OCs [69]. In a prospective randomized study [70], 84 Implanon users with prolonged or frequent bleeding were assigned to receive OCs containing Ethinlestradiol (EE2) 20 mcg/150 mg DSG for two cycles.…”

Applicability of ancestral genotyping in pharmacogenomic research with hormonal contraception

“…This was a secondary analysis of a parent pharmacogenomic association study 13 . The methodology for study enrollment has been previously published, including all inclusion and exclusion criteria, assessment of bleeding side effect profiles and subjective weight gain, and measurement of etonogestrel concentrations 4,6,13 . All participants in the parent study were users of the etonogestrel contraceptive implant and had used their implant between 12 and 36 months at the time of enrollment 13 .…”

“…These progestin‐related side effects are the most commonly reported reasons for early contraceptive method discontinuation, which places patients at increased risk of unintended pregnancies and related adverse health and social outcomes 1 . From our own work, we found that participants who self‐reported their race as Black or African American were more likely to report a monthly period during contraceptive implant use (adjusted odds ratio [aOR] 2.22, 95% confidence interval [CI] 1.14–4.32) and that women of self‐reported Asian or Pacific Islander race were more likely to report amenorrhea (aOR 3.25, 95% CI 1.15–9.22) as compared with all other participants 4 . These associations are not solely found with bleeding side effects, as we also found that self‐reported Hispanic or Latina participants had almost three times the odds of reporting subjective weight gain during contraceptive implant use 6 …”

“… 1 , 2 , 3 The demographics of patients, reported in the form of race and ethnicity, have demonstrated associations with progestin‐related side effects, such as abnormal bleeding, amenorrhea (i.e., absence of menses), and weight gain. 4 , 5 These progestin‐related side effects are the most commonly reported reasons for early contraceptive method discontinuation, which places patients at increased risk of unintended pregnancies and related adverse health and social outcomes. 1 From our own work, we found that participants who self‐reported their race as Black or African American were more likely to report a monthly period during contraceptive implant use (adjusted odds ratio [aOR] 2.22, 95% confidence interval [CI] 1.14–4.32) and that women of self‐reported Asian or Pacific Islander race were more likely to report amenorrhea (aOR 3.25, 95% CI 1.15–9.22) as compared with all other participants.…”

“…Additionally, in our previous work, we found that differences in contraceptive pharmacokinetics (i.e., increased serum etonogestrel concentrations) were associated with key pharmacodynamic outcomes among contraceptive implant users, such as increased odds of abnormal bleeding and increased odds of having received medical treatment for bothersome bleeding. 4 Etonogestrel shares a common metabolic pathway to all steroid hormones that is primarily mediated by cytochrome P‐450 (CYP) 3A enzymes, specifically CYP3A4 and CYP3A5. 1 The gene encoding CYP3A5 is known to have functional variants with differing prevalence by genetic ancestry.…”