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

Abstract

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.

Conflict of interest statement

Financial Disclosure

Dr. Teal has served on scientific advisory boards of Allergan and Bayer Healthcare, and serves on a Data Monitoring Board for a study funded by Merck and Co. 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, Agile Therapeutics, Merck and Co, and Medicines360. Dr. Guiahi’s time was supported by the Society of Family Planning Junior Investigator Career Grant SFPRF10-JI1. The other authors did not report any potential conflicts of interest.

Figures

Figure 1:

Flow diagram for recruitment, screening, and enrollment of all 350 participants. CYP3A4, cytochrome P-450 3A4.

Figure 2:

Box plot of serum etonogestrel concentrations for all 350 participants. The box represents the first and third quartiles (IQR=63.5 pg/mL) with the band inside the box representing the median (137.4 pg/mL). Whiskers represent the data within 1.5 interquartile range of the upper and lower quartile. Circles indicate outliers with values between 1.5 and 3 times the IQR and asterisks indicate outliers with values greater than 3 times the IQR.

Figure 3:

Box plot of serum etonogestrel concentrations for participants with the CYP3A7 wild-type genotype versus CYP3A7*1C variant carriers. The box represents the first and third quartiles with the band inside the box representing the median for each respective group of participants. The whiskers represent the data within 1.5 interquartile range of the upper and lower quartile. The red dotted line represents a serum etonogestrel concentration of 90 pg/mL. Circles indicate outliers with values between 1.5 and 3 times the IQR and asterisks indicate outliers with values greater than 3 times the IQR. The distribution of serum etonogestrel concentrations significantly differs between the groups (Mann-Whitney U Test, P=.003).

Figure 4:

Box plot of serum etonogestrel concentrations by rs2461817 genotype in the NR1I2 (PXR) gene. Participants are split by the number of rs2461817 alleles with homozygous WT having no variant alleles, heterozygous A/C having one variant allele, and homozygous C/C having two variant alleles. The boxes represent the first and third quartiles with the band inside the box representing the median for each respective group of participants. The whiskers represent the data within 1.5 IQR of the upper and lower quartile. Circles indicate outliers with values between 1.5 and 3 times the IQR and asterisks indicate outliers with values greater than 3 times the IQR.

Figure 5:

Box plot of serum etonogestrel concentrations for participants with the progesterone receptor rs537681 wild-type genotype compared with progesterone receptor rs537681 variant carriers. The box represents the first and third quartiles with the band inside the box representing the median for each respective group of participants. The whiskers represent the data within 1.5 IQR of the upper and lower quartile. The red dotted line represents a serum etonogestrel concentration of 90 pg/mL. Circles indicate outliers with values between 1.5 and 3 times the IQR and asterisks indicate outliers with values greater than 3 times the IQR. The distribution of serum etonogestrel concentrations significantly differs between the groups (Mann-Whitney U Test, P=.002).