Optimizing oral contraceptive timing: Morning intake reduces doses and enhances efficacy

PLOS Computational Biology

Dear Dr. Kim,

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PLOS Computational Biology

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Authors:

Please note that one of the reviews is uploaded as an attachment.

Reviewer #1: The authors introduce circadian rhythms into a previously published mathematical model of the female menstrual cycle to analyze the impact of daytime of oral contraceptive (OC) dosing on the required dose to suppress ovulation. Their model predicts that the required dose can be reduced significantly with morning intake compared to evening intake, and that further reduction is possible with non-constant dosing regimens including intake-free days.

The article is well written and nicely illustrates the potential use of mechanistic models for dose optimization. However, the manuscript ignores important aspects of OCs which need to be addressed to make this work practically relevant instead of a sole computational exercise.

1. The results seem to be highly model- and parameter-specific. While testing the predictions with other models might go beyond the scope of the manuscript, testing other parameter regimens is possible (please also see my 2nd comment below). How robust are the findings w.r.t. to changes in model parameters?

2. The menstrual cycle is characterized by a high within- and between-subject variability, which is not accounted for in the model. The results seem to be valid only for a regular 28-day cycle, which occurs rarely. The authors should test other parametrizations of the model that result in different cycle lengths or quasi-periodic cycles (e.g. as in Hendrix et al., Bull Math Biol (2014) 76:136–156

DOI 10.1007/s11538-013-9913-7).

3. There exists a wide variety of oral contraceptives that differ in the PK and PD profiles, but the authors selected only one, arguing that it is particularly susceptible to circadian variation. What about other OCs with longer half-lifes? Would the findings be different?

4. Is the maintenance of P4 periodicity under constant OC intake a model artifact or are there data showing this? I believe it is an artifact as there should not be such a pattern if no corpus luteum is formed.

5. The data by Welt have only a resolution on the level of days, but do not contain information about daytime, meaning that the simulated hormone curves without circadian rhythms could be shifted by +/- 12 hours. How does such shifting impact the results?

6. The fit to the exogenous hormone data looks rather poor. Have the authors considered using a two-compartment model?

Minor comments:

7. What was the stepsize for testing different doses in a certain range. Was it steps of 1 microgram?

8. S1 Table 1: The units need to be formatted properly.

Reviewer #2: Please see attached.

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Have the authors made all data and (if applicable) computational code underlying the findings in their manuscript fully available?

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Reviewer #1: Yes

Reviewer #2: No: One cannot replicate the figures with what is presented.

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Reviewer #1: No

Reviewer #2: No

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Attachments

Attachment

Submitted filename: review_D2500553.docx

PCOMPBIOL-D-25-00553R1

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

PLOS Computational Biology

Dear Dr. Kim,

Thank you for submitting your manuscript to PLOS Computational Biology. After careful consideration, we feel that it has merit but does not fully meet PLOS Computational Biology's publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript within 30 days Dec 29 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at ploscompbiol@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pcompbiol/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

* A rebuttal letter that responds to each point raised by the editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. This file does not need to include responses to formatting updates and technical items listed in the 'Journal Requirements' section below.

* A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

* An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, competing interests statement, or data availability statement, please make these updates within the submission form at the time of resubmission. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

We look forward to receiving your revised manuscript.

Kind regards,

Marc Birtwistle

Section Editor

PLOS Computational Biology

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Authors:

Please note here if the review is uploaded as an attachment.

Reviewer #1: The authors have done a huge effort in addressing all my comments and questions. They have substantiated their findings by performing extensive parameter studies and provided clarification on technical details. I have no further comments or suggestions for improvement of the manuscript, despite one last question. I wonder if the authors can provide an explanation for why the total required DNG dose (and partially also the EE dose) is lower in the +12h shift scenario (Fig. 4B in S1) compared to the -12h shift. Is it also lower compared to the original (no shift) scenario? They should briefly comment on this in the results section (page 7, line 171).

Reviewer #2: Thanks to the authors for nicely replying to my comments and questions. A few small points remain to be addressed as below.

-First of all, the code online looks much better and can replicate the figure panels. However, there are still quite a few hard-coded lines that are not well explained. For instance, lines 115-136 in Fig2C_iii.m are not at all intuitive on what is going on.

-The new two-compartment model needs to be explained a bit more. What are the compartments, the reaction formalisms, reasons, the math.

-Finally, I am still skeptic on the choice of 3 ng/mL progesterone as the criteria used to define anovulation. What if 5 was chosen here as well? It could be discussed and showed simulation-wise that it is okay to deviate as such from the base Gavina model used.

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Have the authors made all data and (if applicable) computational code underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data and code underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data and code should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data or code —e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: No

Reviewer #2: No

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PCOMPBIOL-D-25-00553R2

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

PLOS Computational Biology

Dear Dr. Kim,

Thank you for submitting your manuscript to PLOS Computational Biology. After careful consideration, we feel that it has merit but does not fully meet PLOS Computational Biology's publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Mar 16 2026 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at ploscompbiol@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pcompbiol/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

* A letter that responds to each point raised by the editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. This file does not need to include responses to formatting updates and technical items listed in the 'Journal Requirements' section below.

* A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

* An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, competing interests statement, or data availability statement, please make these updates within the submission form at the time of resubmission. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

We look forward to receiving your revised manuscript.

Kind regards,

Marc Birtwistle

Section Editor

PLOS Computational Biology

Additional Editor Comments:

Please do give careful consideration to the github repository and its ability to enable sharing and reuse of this work.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Authors:

Please note here if the review is uploaded as an attachment.

Reviewer #1: The authors have addressed all my comments and I recommend acceptance of the manuscript.

Reviewer #2: I thank the authors for the rebuttal. However, I feel that my comments are not satisfactorily answered. Mainly, the GitHub repository code still lacks enough comments and contains too many hard-coded numbers for plotting/simulating. The repo needs a thorough rework to comply with reproducibility. Secondly, the increase of anovulation threshold seemed to cause losing the DNG levels in the provided Fig.R. Why is that?

**********

Have the authors made all data and (if applicable) computational code underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data and code underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data and code should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data or code —e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

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Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

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Reproducibility:

To enhance the reproducibility of your results, we recommend that authors of applicable studies deposit laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Dear Professor Kim,

We are pleased to inform you that your manuscript 'Optimizing oral contraceptive timing: Daytime intake reduces doses and enhances efficacy' has been provisionally accepted for publication in PLOS Computational Biology.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests.

Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated.

IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript.

Should you, your institution's press office or the journal office choose to press release your paper, you will automatically be opted out of early publication. We ask that you notify us now if you or your institution is planning to press release the article. All press must be co-ordinated with PLOS.

Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Computational Biology.

Best regards,

Marc Birtwistle

Section Editor

PLOS Computational Biology

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Reviewer's Responses to Questions

Comments to the Authors:

Please note here if the review is uploaded as an attachment.

Reviewer #2: Thank you to the authors for enhancing the repository and for their answer.

**********

Have the authors made all data and (if applicable) computational code underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data and code underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data and code should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data or code —e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

**********

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Reviewer #2: No