Influence of Genetic Variants on Steady-State Etonogestrel Concentrations Among Contraceptive Implant Users

Objective: To identify genetic variants that influence steady-state etonogestrel concentrations among contraceptive implant users.

Methods: We enrolled healthy, reproductive-age women in our pharmacogenomic study using etonogestrel implants for 12-36 months without concomitant use of hepatic enzyme inducers or inhibitors. We collected participant characteristics, measured serum etonogestrel concentrations, and genotyped each participant for 120 single nucleotide variants in 14 genes encoding proteins involved in steroid hormone (ie, estrogens, progestins) metabolism, regulation, or function. We performed generalized linear modeling to identify genetic variants associated with steady-state etonogestrel concentrations.

Results: We enrolled 350 women, who had a median serum etonogestrel concentration of 137.4 pg/mL (range 55.8-695.1). Our final generalized linear model contained three genetic variants associated with serum etonogestrel concentrations: NR1I2(PXR) rs2461817 (β=13.36, P=.005), PGR rs537681 (β=-29.77, P=.007), and CYP3A7*1C (β=-35.06, P=.025). Variant allele frequencies were 69.4%, 84.9%, and 5.1%, respectively. Our linear model also contained two nongenetic factors associated with etonogestrel concentrations: body mass index (BMI) (β=-3.08, P=7.0×10) and duration of implant use (β=-1.60, P=5.8×10); R for the model =0.17.

Conclusion: Only BMI and duration of implant use remained significantly associated with steady-state etonogestrel concentrations. Of the three novel genetic associations found, one variant associated with increased etonogestrel metabolism (CYP3A7*1C) causes adult expression of fetal CYP3A7 proteins and can consequently alter steroid hormone metabolism. Women with this variant may potentially have increased metabolism of all steroid hormones, as 27.8% (5/18) of CYP3A7*1C carriers had serum etonogestrel concentrations that fell below the threshold for consistent ovulatory suppression (less than 90 pg/mL). More pharmacogenomic investigations are needed to advance our understanding of how genetic variation can influence the effectiveness and safety of hormonal contraception, and lay the groundwork for personalized medicine approaches in women's health.

Clinical Trial Registration: ClinicalTrials.gov, NCT03092037.