Dataset Information

A pilot study on the effect of isotretinoin on serum etonogestrel concentrations in contraceptive implant users.

ABSTRACT:

Objective

To explore the pharmacokinetic interaction between isotretinoin, a cytochrome P-450 (CYP) inducer and potent teratogen, and the etonogestrel contraceptive implant.

Study design

We enrolled healthy reproductive-age women initiating isotretinoin and using an etonogestrel implant. We compared serum etonogestrel concentrations at baseline and after four and nine weeks of isotretinoin co-administration using a validated assay.

Results

Among eight implant users, all serum etonogestrel concentrations remained >90 pg/mL during isotretinoin co-administration with no significant changes from baseline (p = 0.25, Friedman's test).

Conclusion

In this exploratory study, we found that isotretinoin did not cause serum etonogestrel concentrations to fall below the threshold for ovulatory suppression (<90 pg/mL) among implant users.

Implications

Reproductive-age women treated with isotretinoin require reliable contraception to prevent pregnancies impacted by teratogenic-effects. This small study demonstrates that contraceptive implant users maintained serum etonogestrel concentrations above the threshold for consistent ovulatory suppression during isotretinoin co-administration. The contraceptive implant remains an appropriate option for patients considering isotretinoin therapy.

SUBMITTER: Lazorwitz A

PROVIDER: S-EPMC7272275 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveTo determine whether serum etonogestrel concentrations in contraceptive implant users are associated with certain individual patient characteristics.Study designWe enrolled reproductive-age women using etonogestrel contraceptive implants between 12-36 months duration and measured a single serum etonogestrel concentration. Participants also completed a questionnaire about demographics.ResultsWe enrolled 350 participants; median age was 22.5 years (range 18.0-39.1), median months of implant use was 26.0 (range 12.0-36.0), and median body mass index was 25.7 kg/m2 (range 18.5-52.0). Our study population was primarily white/Caucasian (46.6% [163/350]) and Hispanic/Latina ethnicity (51.4% [180/350]). The median serum etonogestrel concentration was 137.4 pg/ml and etonogestrel concentrations varied 12.4 fold in the population (range 55.8-695.1 pg/ml). Using forward stepwise linear regression, months of implant use (β=-1.74, p<.001) and body mass index (β=-3.10, p<.001) were both significantly associated with decreased serum etonogestrel concentration with Black/African American race as a positive effect modifier (β=18.24, p=.099); R-squared for the model=0.13.ConclusionsIndividuals demonstrated a wide variability in serum etonogestrel concentrations, which can potentially affect side-effect profiles and efficacy. Increasing body mass index and longer duration of implant use were associated with small decreases in serum etonogestrel concentrations, while self-reported Black/African American race was associated with a non-significant increase. Despite these findings, most of etonogestrel variability was unaccounted for, suggesting that other clinical, pharmacologic, and genetic factors contributing to variability in etonogestrel concentrations remain to be determined.ImplicationsAlthough increases in body mass index are associated with lower etonogestrel levels in contraceptive implant users, the majority of women will maintain serum concentrations that consistently suppress ovulation. Furthermore, certain patient characteristics can only explain a small portion (13%) of the variability in serum etonogestrel levels among contraceptive implant users.

Project description: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.

Project description:ObjectiveTo identify genetic variants that influence steady-state etonogestrel concentrations among contraceptive implant users.MethodsWe 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.ResultsWe 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.ConclusionOnly 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 registrationClinicalTrials.gov, NCT03092037.

Project description:ObjectiveTo identify genetic variants associated with weight gain related to etonogestrel contraceptive implant use.Study designWe 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.ResultsAmong 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).ConclusionGenetic 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.ImplicationsGenetic 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.

Project description:BackgroundUnintended pregnancies (UIP) have a significant impact on health of women and the health budget of countries. Contraception is an effective way to prevent UIPs. The study objective was to collate evidence on clinical effectiveness of etonogestrel subdermal implant (ESI), continuation rate and side effect profile among eligible women of reproductive age group, as compared to levonorgestrel intrauterine system (LNG-IUS), copper intrauterine device (Cu-IUD) and depot medroxy progesterone acetate injections; other types of contraceptive implants were excluded as comparators.MethodsThe protocol of the systematic review was registered in Prospero (registration number: CRD42018116580). MEDLINE via PubMed, Cochrane library and web of science were the electronic databases searched. A search strategy was formulated and studies from 1998 to 2019 were included. Clinical trial registries and grey literature search was done. Critical assessment of included studies was done using appropriate tools. A qualitative synthesis of included studies was done and a meta-analysis was conducted in RevMan software for continuation rates of ESI as compared to other long acting reversible contraceptives (LARC) e.g. LNG IUS and Cu-IUD.ResultsThe search yielded 23,545 studies. After excluding 467 duplicates, 23,078 titles were screened and 51 studies were included for the review. Eight of the 15 studies reporting clinical effectiveness reported 100% effectiveness and overall pearl index ranged from 0 to 1.4. One-year continuation rates ranged from 57-97%; 44-95% at the end of second year and 25-78% by 3 years of use. Abnormal menstruation was the most commonly reported side effect. There was no significant difference in bone mineral density at 1 year follow-up. The meta-analyses showed that odds ratio (OR) of 1-year continuation rate was 1.55 (1.36, 1.76) for LNG-IUS vs. ESI and 1.34 (1.13, 1.58) for copper-IUD vs. ESI; showing that continuation rates at the end of one-year were higher in LNG-IUS and copper-IUD as compared to ESI.ConclusionESI is clinically effective and safe contraceptive method to use, yet 1-year continuation rates are lower as compared to LNG-IUS and copper-IUD, mostly attributed to the disturbances in the menstruation.

Project description:OBJECTIVE:To evaluate whether ulipristal acetate reduces the number of bleeding days in etonogestrel implant users in a 30-day period as compared with placebo. METHODS:We performed a single-center, randomized, double-blind, placebo-controlled trial. Eligible participants were women aged 18-45 years with an etonogestrel implant in place for greater than 90 days and less than 3 years who reported greater than one bleeding episode in a 24-day period. Enrolled participants were randomized to receive 15 mg ulipristal acetate compared with an identical-appearing placebo daily for 7 days. Participants completed daily bleeding diaries using automated text messaging to evaluate whether ulipristal acetate reduces the number of bleeding days as compared with placebo. Secondary outcomes included participant satisfaction with bleeding and the effect of ulipristal acetate on ovulation status. A sample size of 52 per group (n=104) was planned, calculated with an effect size of a 30% reduction in bleeding days, SD of 10 days, and dropout of 15%. Our study was terminated early (N=65) as a result of a U.S. Food and Drug Administration hold, but power was sufficient for analysis. The effect of ulipristal acetate on ovulatory potential was evaluated in a subset with weekly serum progesterone. RESULTS:From May 2017 to January 2018, 65 women were allocated to receive 15 mg ulipristal acetate (n=32) or placebo (n=33) daily for 7 days. Demographic characteristics were similar between groups. Women randomized to ulipristal acetate reported 5 fewer days of bleeding over a 30-day reference period after treatment (P=.002). At the conclusion of the 30-day follow-up period, women in the ulipristal acetate group were more satisfied with their bleeding profile than the placebo group (87.5% vs 60%, respectively; P<.001). Serum progesterone levels were nonovulatory in a subset of each group (placebo group range: less than 0.2-1.3 ng/mL; ulipristal acetate group range: less than 0.2-4.4 ng/mL). CONCLUSION:Ulipristal acetate is well-tolerated and reduced the number of bleeding days in etonogestrel implant users in our study. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov, NCT03118297.

Project description:Introduction: This study explored implant user and healthcare provider experiences of accessing and providing contraceptive implant removal services in Gaborone, Botswana, following introduction of the implant in the public sector in 2016. We sought to understand reasons for satisfaction and dissatisfaction with services and their potential impact on wider perceptions of the implant, including influence on future uptake. Methods: Qualitative data were collected through in-depth interviews. Participants comprised ten women who had previously undergone implant removal, and ten providers whose work included provision of implant insertion and removal. Data were analyzed using thematic content analysis. Results: Seven of the ten users in this study had experienced a delay between initial request and undergoing implant removal. This interval ranged from <1 week to 3 months. Users identified the principal barriers to accessing implant removal services as lack of access to trained removal providers, inconvenient appointment times, and provider resistance to performing removal. Nine of the ten providers in this study had experienced barriers to providing implant removal, including insufficient training, lack of equipment, lack of time, and lack of a referral pathway for difficult removals. Despite experiencing barriers in accessing removal, users' perceptions of the implant remained generally positive. Providers were concerned that ongoing negative user experiences of removal services would damage wider perceptions of the implant. Conclusion: Introduction of the contraceptive implant in Botswana has been an important strategy in increasing contraceptive choice. Following an initial focus on provision of insertion services, the development of comparable, accessible removal services is critical to ensuring that the implant remains a desirable contraceptive option and is vital to upholding women's reproductive health rights. The experiences of users and providers in this study can inform the ongoing development of services for implant insertion and removal in Botswana and other lower-resource settings.

Project description:ObjectiveTo evaluate whether a short course of tamoxifen decreases bothersome bleeding in etonogestrel contraceptive implant users.MethodsIn a 90-day, double-blind randomized control trial, we enrolled etonogestrel implant users with frequent or prolonged bleeding or spotting. A sample size of 40 per group (N=80) was planned to compare 10 mg tamoxifen or placebo twice daily for 7 days after 3 consecutive days of bleeding or spotting no more than once per 30 days (maximum three treatments). Participants then entered a 90-day open-label study where all received tamoxifen if needed every 30 days (maximum three treatments). Participants used text messages to record daily bleeding patterns. Our primary outcome was the total number of consecutive amenorrhea days after the first treatment. Secondary outcomes included time to bleeding or spotting cessation and restart after first treatment, overall bleeding patterns, and satisfaction.ResultsFrom January 2017 to November 2018, 112 women enrolled in the study; 88 (79%) completed 90 days, and 79 (71%) completed 180 days. Participant characteristics did not differ between groups; mean age 24, majority identified as white not Hispanic with at least some college education. After the first treatment, the tamoxifen group reported an average of 9.8 (95% CI 4.6-15.0) more consecutive days of amenorrhea and more total days of no bleeding (amenorrhea or spotting) in the first 90 days (median 73.5 [range 24-89] vs 68 [range 11-81], P=.001). The placebo group showed a similar treatment benefit after first active use of tamoxifen in the open-label phase. At the end of the randomized study (first 90 days), women who received tamoxifen reported higher satisfaction (median 62 mm [range 16-100]) than those treated with placebo (46 mm [range 0-100]; P=.023).ConclusionA short course of tamoxifen reduces problematic bleeding and improves satisfaction in users of etonogestrel implants.Clinical trial registrationClinicalTrials.gov, NCT02903121.