We appreciate the insightful comments on our recent paper, "Toward an optimal contraception dosing strategy." The detailed analysis and practical concerns raised regarding applying our findings in clinical setting are commendable.

From a clinical point of view, the concerns addressed in the Formal Comment, about applying theoretical models to real-world scenarios are entirely valid. However, as researchers, we know that any mathematical model inherently simplifies reality. Like any other field, our work serves as a step in a continuum of scientific inquiry—to gain quantitative insights into complex systems. The human body interacts with countless variables, many interconnected in ways that current science cannot fully quantify. As such, our study contributes to a broader understanding of contraception that may, over time, inform more personalized and effective treatments.

Regarding (4), we recognize that the objectives of modeling studies are limited, just as those of clinical studies and experimental findings are. Our study considers the administration of exogenous hormones, and for simplicity, it does not account for pharmacokinetics. An obvious way to expand our findings is to couple the presented model with a PKPD model linking hormonal to a specific drug with known compounds and use parameter estimation to adapt the model to specific patients.

In response to their concerns about estrogen-only preparations, we agree that such regimens pose significant risks, particularly in terms of endometrial health. The historical data referenced regarding the rise in endometrial cancer rates with certain cyclical combined contraceptives serves as a reminder of the importance of including progestin in contraceptive regimens. Our model does not advocate for the use of estrogen-only contraception without careful consideration of these risks. Instead, it suggests that there may be opportunities to optimize the timing and dosage of estrogen and progestin to reduce overall hormone exposure while maintaining efficacy and safety. Our study shows how a continuous infusion of exogenous hormone following a non-constant profile could significantly lower the drug dose. Furthermore, we have shown that the best dosing scheme involves estrogen and progesterone, which reduces the levels of both hormone components.

As they correctly pointed out in (5) and (6), the clinical acceptability of any contraceptive method depends not only on its efficacy in preventing ovulation but also on its ability to control the menstrual cycle and minimize side effects. The history of oral contraceptives has shown that even minor adjustments in hormone levels can have significant impacts on patient outcomes, both positive and negative. This is why any proposed dosing strategy is carefully tested in diverse populations before being recommended for widespread use.

We are pleased that our paper has sparked reflections on practical clinical issues, such as the variability in patients’ responses and the potential side effects of hormonal contraception. These are the considerations as we move from theoretical models to practical applications.