# Optimizing oral contraceptive timing: Daytime intake reduces doses and enhances efficacy

## TL;DR

Taking oral contraceptives during the day instead of the evening can reduce hormone doses and improve effectiveness by aligning with the body's natural hormone cycles.

## Contribution

A mathematical model integrating circadian rhythms with contraceptive pharmacokinetics to optimize dosing timing and regimen.

## Key findings

- Daytime OC dosing reduces ethinyl estradiol and dienogest doses by aligning with luteinizing hormone production peaks.
- An optimal nonconstant regimen lowers ethinyl estradiol doses by 67% and reduces intake days from 21 to 8 per cycle.
- Incorporating circadian rhythms in OC timing enhances safety and efficacy while reducing adverse event risks.

## Abstract

Contraception is essential for reproductive health and women’s empowerment because it allows informed choices about pregnancy prevention. Oral contraceptives (OCs) are a popular method due to their accessibility and high level of effectiveness in attaining contraception through the suppression of ovulation. However, current OC regimens do not consider circadian hormonal rhythms, which significantly influence hormone secretion and drug metabolism. Accounting for circadian rhythms may further reduce the dosage of current formulations, which pose risks, including an increased likelihood of venous thromboembolism. We addressed this gap by developing a mathematical model that integrates circadian rhythms with contraceptive pharmacokinetics. Our results show that daytime OC dosing reduces the required ethinyl estradiol (EE) dose by about 6% and the required dienogest (DNG) dose by about 52% compared to evening dosing, due to the alignment of EE and DNG concentrations with luteinizing hormone production peaks. We further lowered the EE dose by about 67% using an optimal nonconstant regimen and decreased the number of intake days from 21 to 8. This dual-timescale optimization demonstrates how incorporating circadian rhythms can significantly enhance contraceptive regimens, enabling safer and more effective dosing strategies with broader implications for chronopharmacological interventions.

Oral contraceptives (OCs) are widely used to prevent pregnancy and manage reproductive health conditions like endometriosis and polycystic ovary syndrome. However, current OCs often use higher hormone doses than necessary, increasing the risk of side effects such as blood clots (venous thromboembolism). Although previous studies have tried reducing doses to make these OCs safer, most have overlooked the natural daily hormonal cycles (circadian rhythms) that influence how our bodies interact with exogenous hormones. In this study, we used mathematical modeling to explore whether the timing of taking OCs could reduce hormone doses while maintaining efficacy to inhibit ovulation securely. We found that taking the OC in the daytime significantly lowers the necessary hormone dose compared to taking it in the evening because it better aligns with the body's natural hormone cycles. Further, by adjusting daily doses rather than using a constant dose each day, we dramatically reduced the total hormone dose and reduced the number of drug-taking days from 21 days to just 8 days per cycle. These findings suggest that considering circadian rhythms when planning contraceptive use can significantly reduce the risks of adverse events from exogenous hormones, without compromising the contraceptive’s efficacy, providing an exciting new approach to contraception.