Hormone Doses in Contraceptives Could Be Reduced by As Much As 92%

A new study has used computer modeling to explore how exogenous hormones – such as those included in hormonal contraceptives – impact the body’s own hormone levels and menstrual cycle. Using this model, the research team behind the study suggests that the dose of exogenous hormones used in contraceptives could be reduced by up to 92% in some cases.

The menstrual cycle and reproductive lifespan

The female reproductive lifespan is regulated by the menstrual cycle. Defined as the interval between the first menstrual bleed and menopause, it is approximately 35 years in length on average. Based on current average human life expectancy figures, and excluding fertility issues, this means that the female body can bear children for almost half of its lifetime. For many individuals, contraception – via artificial or natural means – will likely be a point of consideration at some point in their reproductive life. A wide variety of contraceptive methods are now available, which are broadly classified into hormonal and non-hormonal approaches.

A normal menstrual cycle is controlled by a delicate interplay of hormones, including estrogen, progesterone, follicle-stimulating hormone (FSH) and luteinising hormone (LH), among others. These molecules are produced by the various glands in the body that make up the endocrine system. Hormonal contraceptives – including the contraceptive pill, some intrauterine devices (IUDs) and hormonal implants – utilize exogenous (or synthetic) hormones to block or suppress ovulation, the phase of the menstrual cycle where an egg is released into the uterus.

Suppressing ovulation to treat premenstrual syndromes

Beyond their use as methods to prevent pregnancy, hormonal contraceptives are also being increasingly used to suppress ovulation as a method for treating premenstrual syndromes. Scientists including Brenda Lyn A. Gavina, PhD student at the University of the Philippines Diliman, and Professor Johnny T. Ottesen from the Centre for Mathematical Modeling – Human Health and Disease at Roskilde University, are exploring methods to optimize the dosage of exogenous hormones in such contraceptives. Their overall aim is the creation of patient-specific minimizing dosing schemes, to prevent adverse side effects that can be associated with hormonal contraceptive use and empower individuals in their contraceptive journey.

Gavina and colleagues have published a new computational method that analyzes the interactions between various hormones during different phases of the menstrual cycle, and how these are impacted by exogenous hormone administration. The model, outlined in PLOS Computational Biology, was developed using hormone data from 23 women aged 20–34 years with normal menstrual cycles, published in an earlier study by the endocrinologist Dr. Corrine Welt and colleagues.

Taken from Technology Networks.

Using the data generated by the model, Gavina and team share evidence that the doses of exogenous hormones in certain contraceptive methods could be reduced, while still ensuring ovulation is suppressed. Reducing the total exogenous hormone dose by 92% in estrogen-only contraceptives, or the total dose by 43% in progesterone-only contraceptives, for example, prevented ovulation according to the model. In contraceptives combining estrogen and progesterone, the doses could be reduced further still.

To learn more about how Gavina and colleagues built their model, the key findings from their data and its potential application, Technology Networks interviewed the research team.

Q: Can you talk to us about the inspiration behind this study?

A: Aside from wanting to contribute to controlling population growth, we aim to empower women by giving them more control over when they conceive and start motherhood.

Moreover, studies are showing the non-contraceptive benefits of suppressing ovulation, for instance, in managing premenstrual syndromes like breast tenderness, irritability or diseases like endometriosis. Anovulation (the lack or absence of ovulation) also lowers the risk of anterior cruciate ligament injuries in female athletes. We aim to empower women and see them have a better quality of life.

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Q: You used a computational model to depict the interactions between hormone levels and the impact of exogenous hormone levels. Can you describe how your model functions, and how it was built on pre-existing work?

A: Our menstrual cycle model predicts the daily levels of the hormones LH, FSH, estradiol (E₂), progesterone (P₄), and inhibin A (Inh A) for 28 days, averaged from 23 normally cycling women. It also reflects the decrease in maximum pituitary and ovarian hormone levels caused by addition of exogenous estrogen and/or progesterone.

To obtain our current model, we modified the mathematical model by Margolskee and Selgrade (by introducing new expressions) to include mechanisms depicting the contraceptive effect of exogenous progesterone on the menstrual cycle. Parameter estimation is then employed to calibrate our model to the patient data extracted from Welt et al. Then optimal control theory is applied to simulate contraception using the current model.

Q: You used data from a sample of 23 women aged 20–34 years with normal menstrual cycles. Why was this your sample of choice?

A: To our knowledge, publicly available human/female menstrual cycle data are limited. The dataset used in the study is fairly recent and robust.

Q: Can you summarize your key findings, and how you validated these findings?

A: Repeated numerical simulations show that, compared to the administration of constant dosage (which is how most contraceptive pills are administered), a continuous infusion with varying doses, the total dose of which is significantly lower than that of constant administration, may still effectively suppress ovulation.

It was surprising that, theoretically, our mathematical model (with the simplifying assumptions) showed that a dose as low as 10% of the total exogenous estrogen dose in constant administration could achieve contraception, if this dosage is perfectly timed.

Q: What do you view as being the biggest implications of this research?

A: Lower exogenous estrogen and/or progesterone doses could reduce the risk of adverse side effects such as thrombosis and myocardial infarction that are associated with large doses. Now, the results of this study are not directly translatable to actual patients, but the principles proposed in our study could easily be translated. We hope these results aid clinicians in identifying the most favorable dose and treatment schedule for contraception.

Q:  Are there any limitations to the study that you wish to highlight? What are your next steps in this research space?

A: The current mathematical model does not capture all factors in contraception since the reproductive function in women is a very complex multiscale dynamical system.

However, with the emergence of more data, the model can be refined to address other contraception issues. For instance, the current model can be coupled with a pharmacokinetics model to consider the exact nature and metabolism of administered hormones to investigate the effects of specific drugs. We also hope to build on this model to investigate reproductive health concerns in women like polycystic ovarian syndrome and ovarian cysts.

Brenda Gavina and colleagues were speaking to Molly Campbell, Senior Science Writer for Technology Networks.  

Reference: Gavina BLA, de los Reyes V AA, Olufsen MS, Lenhart S, Otteson JT. Toward an optimal contraception dosing strategy. PLoS Comput Biol. 2023.e1010073. doi: 10.1371/journal.pcbi.1010073