Mechanistic model of hormonal contraception
Open accessAbstract
Contraceptive drugs intended for family planning are used by the majority of married or in-union women in almost all regions of the world. The two most prevalent types of hormones associated with contraception are synthetic estrogens and progestins. Hormonal based contraceptives contain a dose of a synthetic progesterone (progestin) or a combination of a progestin and a synthetic estrogen. In this study we use mathematical modeling to understand better how these contraceptive paradigms prevent ovulation, special focus is on understanding how changes in dose impact hormonal cycling. To explain this phenomenon, we added two autocrine mechanisms essential to achieve contraception within our previous menstrual cycle models. This new model predicts mean daily blood concentrations of key hormones during a contraceptive state achieved by administering progestins, synthetic estrogens, or a combined treatment. Model outputs are compared with data from two clinical trials: one for a progestin only treatment and one for a combined hormonal treatment. Results show that contraception can be achieved with synthetic estrogen, with progestin, and by combining the two hormones. An advantage of the combined treatment is that a contraceptive state can be obtained at a lower dose of each hormone. The model studied here is qualitative in nature, but can be coupled with a pharmacokinetic/pharamacodynamic (PKPD) model providing the ability to fit exogenous inputs to specific bioavailability and affinity. A model of this type may allow insight into a specific drug's effects, which has potential to be useful in the pre-clinical trial stage identifying the lowest dose required to achieve contraception.
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Wright et al. concluded that a low dose of both treatments given together is most effective at achieving contraception.
“They concluded that a low dose of both treatments given together is most effective at achieving contraception.”
From A Survey of Mathematical Modeling of Hormonal Contraception and the Menstrual Cycle (2024) · cites this paper as [46]
The Results (Combined hormonal contraception, Fig. 8) report that two low doses achieved the model’s ‘total contraception’ when combined, though neither did so alone. The paper does not establish that this regimen is the most effective: high-dose single-hormone treatments also achieved total contraception, and the Discussion cautions that the model results cannot be directly translated to clinical use. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe model of Gavina et al. [47] was also created to explore the effects of hormonal contraception, although from a different perspective than [46].
“The model of Gavina et al. [47] was also created to explore the effects of hormonal contraception, although from a different perspective than [46].”
From A Survey of Mathematical Modeling of Hormonal Contraception and the Menstrual Cycle (2024) · cites this paper as [46]
The Discussion says this paper developed a model to predict the effects of contraceptive hormone treatments, supporting the stated purpose. But the cited paper is by Wright et al., not Gavina et al.; our copy does not establish the claimed identification or the comparison with [46]. (LLM, conf=0.87)
Experimental — accuracy not yet measuredMany other authors [43, 45-47] parameterized their models using the Welt et al. data set [12], but the ways they handled the inhibin data are slightly different.
“Many other authors [43, 45-47] parameterized their models using the Welt et al. data set [12], but the ways they handled the inhibin data are slightly different.”
From A Survey of Mathematical Modeling of Hormonal Contraception and the Menstrual Cycle (2024) · cites this paper as [46]
The Methods > Data section says the paper used Welt et al.’s hormone data, including inhibin A, and the Discussion says its model includes inhibin A but not inhibin B. However, Methods > Model summary describes comparisons with the Welt data, while Results says most parameter values were retained from Margolskee and Selgrade; our copy does not establish that this model was parameterized using the Welt dataset or compare its inhibin handling with the other cited models. No page numbers are available in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredBoth Gavina et al. [47] and Wright et al. [46] included only inhibin A in their model and used the data from the younger age group.
“Both Gavina et al. [47] and Wright et al. [46] included only inhibin A in their model and used the data from the younger age group”
From A Survey of Mathematical Modeling of Hormonal Contraception and the Menstrual Cycle (2024) · cites this paper as [46]
The Discussion states that FSH synthesis in Wright et al.’s model depends only on inhibin A and identifies inhibin B as a proposed addition. Methods > Data says the normal-cycle data came from 23 normally cycling women in Welt et al., but does not identify them as the younger age group. This verdict addresses Wright et al. only, not Gavina et al. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe Wright et al. model included a system of nonlinear delay differential equations with four auxiliary equations representing the ovarian hormones E2, P4, and inhibin A.
“This model also included a system of nonlinear delay differential equations with four auxiliary equations representing the ovarian hormones E . 2, P . 4, and inhibin A.”
From A Survey of Mathematical Modeling of Hormonal Contraception and the Menstrual Cycle (2024) · cites this paper as [46]
The models first developed by Selgrade, Schlosser, and Harris Clark stand out because they have been used as the foundation for a significant number of subsequent models.
“Of this collection of modeling efforts, the models first developed by Selgrade, Schlosser, and Harris Clark [7, 8, 41, 42] stand out because they have been used as the foundation for a significant number of subsequent models [43-47].”
From A Survey of Mathematical Modeling of Hormonal Contraception and the Menstrual Cycle (2024) · cites this paper as [46]
As with the previous works of Harris Clark et al. and Margolskee and Selgrade, the Wright et al. model only tracked inhibin A and did not incorporate inhibin B.
“As with the previous works of Harris Clark et al. [41] and Margolskee and Selgrade [45], this model only tracked inhibin A and did not incorporate inhibin B.”
From A Survey of Mathematical Modeling of Hormonal Contraception and the Menstrual Cycle (2024) · cites this paper as [46]
Wright et al. provided numerical experiments illustrating that the combined contraceptive treatment pushes the system into a nonovulatory menstrual cycle fairly quickly.
“They provided numerical experiments that illustrate how the combined contraceptive treatment pushes the system into a nonovulatory menstrual cycle fairly quickly and that the cycle also returns to normal in short order after the treatment ends.”
From A Survey of Mathematical Modeling of Hormonal Contraception and the Menstrual Cycle (2024) · cites this paper as [46]
The Wright et al. model extended the Margolskee and Selgrade and Harris Clark et al. models by adding autocrine mechanisms to describe how exogenous estrogen and progesterone could push a normal cycle into a contraceptive state.
“The model extended the Margolskee and Selgrade [45] and Harris Clark et al. [41] models by adding autocrine mechanisms to describe how exogenous estrogen and progesterone could push a normal cycle into a contraceptive state.”
From A Survey of Mathematical Modeling of Hormonal Contraception and the Menstrual Cycle (2024) · cites this paper as [46]
Wright et al. provided numerical experiments illustrating that the cycle returns to normal in short order after the treatment ends.
“They provided numerical experiments that illustrate how the combined contraceptive treatment pushes the system into a nonovulatory menstrual cycle fairly quickly and that the cycle also returns to normal in short order after the treatment ends.”
From A Survey of Mathematical Modeling of Hormonal Contraception and the Menstrual Cycle (2024) · cites this paper as [46]
Hormonal contraceptive treatments via oral administration of ethinyl estradiol and progestin were modeled by modifying state variables for blood concentrations of E2 and P4 in the Wright et al. model.
“Hormonal contraceptive treatments via oral administration of ethinyl estradiol and progestin were modeled by modifying state variables for blood concentrations of E . 2 and P . 4 .”
From A Survey of Mathematical Modeling of Hormonal Contraception and the Menstrual Cycle (2024) · cites this paper as [46]
Wright et al. showed that the administration of synthetic progesterone, synthetic estrogen, or a combination of these can have a contraceptive effect by preventing ovulation.
“Wright et al. showed that the administration of synthetic progesterone, synthetic estrogen, or a combination of these can have a contraceptive effect by preventing ovulation.”
From A Survey of Mathematical Modeling of Hormonal Contraception and the Menstrual Cycle (2024) · cites this paper as [46]
The focus of the Wright et al. model was to explore the effects of oral contraceptive drugs in hormonal control of the menstrual cycle of adult women.
“The focus of the Wright et al. [46] model was to explore the effects of oral contraceptive drugs in hormonal control of the menstrual cycle of adult women.”
From A Survey of Mathematical Modeling of Hormonal Contraception and the Menstrual Cycle (2024) · cites this paper as [46]
The modifications made in the Gavina et al. model introduce different qualitative dynamics with constant exogenous hormonal contraception than for the Wright et al. [46] model.
“We notice that the modifications made in this model introduce different qualitative dynamics with constant exogenous hormonal contraception (Fig. 10D and H) than for the Wright et al. [46] model.”
From A Survey of Mathematical Modeling of Hormonal Contraception and the Menstrual Cycle (2024) · cites this paper as [46]
The models of [8, 41, 45-47] incorporate explicit time delays in strategic parts of the models.
“The models of [8, 41, 45-47] incorporate explicit time delays in strategic parts of the models”
From A Survey of Mathematical Modeling of Hormonal Contraception and the Menstrual Cycle (2024) · cites this paper as [46]
Wright et al. [46] developed their model with the intention of including hormonal contraception.
“In contrast to previous models, Wright et al. [46] developed their model with the intention of including hormonal contraception.”
From A Survey of Mathematical Modeling of Hormonal Contraception and the Menstrual Cycle (2024) · cites this paper as [46]
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- Authors
- Wright, A. A., Fayad, G. N., Selgrade, J. F., & Olufsen, M. S.
- Affiliations
- North Carolina State University (US)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Corresponding author
- Olufsen, Mette S.
- Venue
- PLOS Computational Biology
- Publisher
- Public Library of Science (PLoS)
- Published
- 2020-06-29
- Volume
- 16
- Issue
- 6
- Pages
- e1007848
- ISSN
- 1553-734X (ISSN-L)
- 1553-7358
- PMC
- PMC7365466
- OpenAlex
- W3037606745
- Cited by
- 26
- References
- 39
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 5 · 2023: 2 · 2022: 3 · 2021: 1
- FWCI
- 1.12
- Type
- journal article
- Language
- en
- Update notices
- new_version (2020-07-16)
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Computational Biology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Directorate for Mathematical and Physical Sciences (1225607)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Health and Contraception
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
- Keywords
- hormonal contraception, ovulation inhibition, progestins, synthetic estrogens, combined hormonal contraceptives, dose optimization, pharmacokinetic-pharmacodynamic modeling
- MeSH terms
- Hormonal Contraception, Adult, Contraceptive Agents, Estrogens, Female, Follicle Stimulating Hormone, Humans, Hypothalamus, Luteinizing Hormone, Menstrual Cycle, Models, Biological, Ovary, Pituitary Gland, Progestins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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