Toward an optimal contraception dosing strategy
Open accessPublished version of a preprint
Abstract
Anovulation refers to a menstrual cycle characterized by the absence of ovulation. Exogenous hormones such as synthetic progesterone and estrogen have been used to attain this state to achieve contraception. However, large doses are associated with adverse effects such as increased risk for thrombosis and myocardial infarction. This study utilizes optimal control theory on a modified menstrual cycle model to determine the minimum total exogenous estrogen/progesterone dose, and timing of administration to induce anovulation. The mathematical model correctly predicts the mean daily levels of pituitary hormones LH and FSH , and ovarian hormones E 2 , P 4 , and Inh throughout a normal menstrual cycle and reflects the reduction in these hormone levels caused by exogenous estrogen and/or progesterone. Results show that it is possible to reduce the total dose by 92% in estrogen monotherapy, 43% in progesterone monotherapy, and that it is most effective to deliver the estrogen contraceptive in the mid follicular phase. Finally, we show that by combining estrogen and progesterone the dose can be lowered even more. These results may give clinicians insights into optimal formulations and schedule of therapy that can suppress ovulation.
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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.
“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 [47]
The Introduction says Margolskee et al. fitted a model to the Welt data, and Parameter estimation says this paper also used those data. The Data section specifies that this paper used only inhibin A. Our copy does not establish that all the other cited authors used the Welt dataset or compare how they handled its inhibin data. (LLM, conf=0.83)
Experimental — accuracy not yet measuredThe 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 [47]
A 25% reduction in VFSH results in a loss of periodicity in our simulations of the Gavina et al. [47], Margolskee and Selgrade [45], and Harris Clark et al. [41] models.
“A 25% reduction in . VFSH results in a loss of periodicity in our simulations of the Gavina et al. [47], Margolskee and Selgrade [45], and Harris Clark et al. [41] models.”
From A Survey of Mathematical Modeling of Hormonal Contraception and the Menstrual Cycle (2024) · cites this paper as [47]
The 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 [47]
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 [47]
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.
“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 [47]
Of the models discussed in Sect. 4.4, only [47] explores time-varying exogenous hormones.
“of these, only [47] explores time-varying exogenous hormones.”
From A Survey of Mathematical Modeling of Hormonal Contraception and the Menstrual Cycle (2024) · cites this paper as [47]
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References 62 · Cited by 9
Research works printed but not linked: 4
- [7]Harris L. Differential equation models for the hormonal regulation of the menstrual cycle [Ph.D. thesis]. North Carolina State University; 2002.
- [18]Reinecke I. Mathematical modeling and simulation of the female menstrual cycle [Ph.D. thesis]. Freie Universität Berlin, Germany; 2009.
- [33]Shirin A. Optimal control strategies for complex biological systems [Ph.D. thesis]. University of New Mexico; 2019.
- [51]Digirolamo C. Applications of GPOPS-II to optimal control problems with delays [Ph.D. thesis]. North Carolina State University; 2020.
- Authors
- Gavina, B. L. A., de los Reyes V, A. A., Olufsen, M. S., Lenhart, S., & Ottesen, J. T.
- Affiliations
- Maritime Academy of Asia and the Pacific (PH)
- North Carolina State University (US)
- University of Tennessee at Knoxville (US)
- Roskilde University (DK)
- Corresponding author
- Gavina, Brenda Lyn A.
- Olufsen, Mette S.
- Lenhart, Suzanne
- Ottesen, Johnny T.
- ORCID
- Venue
- PLOS Computational Biology
- Publisher
- Public Library of Science (PLoS)
- Published
- 2023-04-13
- Volume
- 19
- Issue
- 4
- Pages
- e1010073
- ISSN
- 1553-734X (ISSN-L)
- 1553-7358
- PMC
- PMC10101497
- OpenAlex
- W4365443999
- Cited by
- 9
- References
- 62
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 4
- FWCI
- 2.29
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Computational Biology (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- RUCforsk (Roskilde University) (submittedVersion, cc-by)
- Funders
- University of the Philippines (UP-OIL-COOPERATE)
- Commission on Higher Education (Faculty Development Program - II (CHED-FDP-II))
- Institute for Basic Science (IBS-R029-C3)
- 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 › Mathematical and Theoretical Epidemiology and Ecology Models
- Keywords
- contraception, anovulation, ovulation inhibition, exogenous estrogen, exogenous progesterone, optimal control, dose minimization, luteinizing hormone, follicle-stimulating hormone, estradiol, progesterone, inhibin, follicular phase
- MeSH terms
- Anovulation, Contraception, Estradiol, Estrogens, Female, Humans, Luteinizing Hormone, Progesterone
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