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Relationship Between Etonogestrel Concentrations and Bleeding Patterns in Contraceptive Implant Users

Lazorwitz, Aaron MD, MSCS; Aquilante, Christina L. PharmD; Dindinger, Eva MPH; Harrison, Margaret BA; Sheeder, Jeanelle PhD; Teal, Stephanie MD, MPH

doi: 10.1097/AOG.0000000000003452
Contents: Contraception: Original Research

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.

Higher levels of circulating progestin are associated with higher rates of abnormal bleeding and increased need for interventions for bothersome bleeding among contraceptive implant users.

Department of Obstetrics and Gynecology, Division of Family Planning, and the Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado.

Corresponding author: Aaron Lazorwitz, MD, MSCS, Department of Obstetrics and Gynecology, Division of Family Planning, University of Colorado Anschutz Medical Campus, Aurora, CO; email:

Supported by the Society of Family Planning Research Fund [grant number SFPRF17-3]. This work was also supported by NIH/NCATS Colorado CTSA Grant Number UL1 TR001082. Dr. Lazorwitz's time is also supported by the NICHD K12 Women's Reproductive Health Research Scholar Program (grant number 5K12HD001271-18). The contents are the authors' sole responsibility and do not necessarily represent official NIH views.

Financial Disclosure Dr. Teal has served on the scientific advisory boards of Allergan and Bayer Healthcare, and has received honoraria from Merck and Co. for serving on a Data Monitoring Board for an FDA-mandated Phase 4 study. Dr. Teal has also received honoraria in her role as Society of Family Planning Board President. Dr. Teal and Dr. Lazorwitz receive research funding from Merck and Co. for an investigator-initiated study on drug–drug interactions with the etonogestrel contraceptive implant. The University of Colorado Department of Obstetrics and Gynecology has received research funding from Bayer Healthcare, Agile Therapeutics, Sebela, Merck and Co, and Medicines360. The other authors did not report any potential conflicts of interest.

The authors thank Dr. Serge Cremers and Dr. Renu Nandakumar at the Biomarkers Core Laboratory at Columbia University for assisting with the etonogestrel analysis.

Each author has confirmed compliance with the journal's requirements for authorship.

Peer reviews and author correspondence are available at

© 2019 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.