An exploratory analysis on the influence of genetic variants on weight gain among etonogestrel contraceptive implant users

Abstract

Objective: To identify genetic variants associated with weight gain related to etonogestrel contraceptive implant use.

Study design: We conducted a retrospective analysis from a parent pharmacogenomic study of healthy, reproductive-aged women using etonogestrel implants. We reviewed medical records to calculate objective weight changes from implant insertion to study enrollment and asked participants about subjective weight gain (yes/no) during contraceptive implant use. We used genotyping data (99 genetic variants) from the parent study to conduct backward-stepwise generalized linear modeling to identify genetic variants associated with objective weight changes.

Results: Among 276 ethnically diverse participants, median body-mass index (BMI) was 25.8 kg/m² (range 18.5-48.1). We found a median weight change of +3.2 kg (range -27.6 to +26.5) from implant insertion to study enrollment. Report of subjective weight gain had minimal agreement with measured weight gain during implant use (Cohen's kappa = 0.21). Our final generalized linear model contained two variables associated with objective weight change that met conservative statistical significance (p < 5.0 × 10^-4). Participants with two copies (homozygous) of the ESR1 rs9340799 variant on average gained 14.1 kg more than all other participants (p = 1.4 × 10^-4). Higher enrollment BMI was also associated with objective weight gain (β = 0.54, p = 9.4 × 10^-12).

Conclusion: Genetic variants in the estrogen receptor 1 (ESR1) do not have known associations with obesity or metabolic syndrome, but there is physiologic plausibility for a progestin-mediated genetic association between ESR1 and weight gain. Additional genetic research is needed to substantiate our findings and elucidate further advances in individualized counseling on the risk of weight gain with exogenous steroid hormones.

Implications: Genetic variation in the estrogen receptor 1 gene may account for variability in weight gain among etonogestrel contraceptive implant users. If these findings can be replicated with other progestin-containing medications, we may be able to better individualize contraceptive counseling.

Keywords: Contraception; Estrogen receptor; Etonogestrel; Obesity; Pharmacogenomics; Weight gain.

Figure 1 Legend:

Histogram of weight change from implant insertion to study enrollment for all 276 participants with available medical records.

Figure 2 Legend:

Box plots of weight change from implant insertion to study enrollment among participants with the CYP2C19 rs7088784 wild-type genotype (n=248) compared with CYP2C19 rs7088784 variant carriers (n=48), excluding those with unknown genotype for this single nucleotide polymorphism (n=54). The box represents the first and third quartiles with the band inside the box representing the median for each respective group. The whiskers represent the data within 1.5 interquartile range of the upper and lower quartile. Circles indicate outliers with values between 1.5 times and 3 times the IQR and asterisks indicate outliers with values greater than 3 times the IQR.

Figure 3 Legend:

Box plots of weight change from implant insertion to study enrollment among participants homozygous for the ESR1 rs9340799 variant allele (n=7) versus carriers of at least one wild-type allele (n=324), excluding those with unknown genotype for this single nucleotide polymorphism (n=19). The box represents the first and third quartiles with the band inside the box representing the median for each respective group. The whiskers represent the data within 1.5 interquartile range of the upper and lower quartile. Circles indicate outliers with values between 1.5 times and 3 times the IQR and asterisks indicate outliers with values greater than 3 times the IQR.