A combination of estrogen and progesterone given during the follicular phase of the menstrual cycle significantly reduced the level of hormones needed for effective contraception, based on data from a new mathematical model.
Progesterone and estrogen are often used for contraception by preventing ovulation, but the adverse effects associated with large doses of these hormones remain a concern, wrote Brenda Lyn A. Gavina, a PhD candidate at the University of the Philippines Diliman, Quezon City, and colleagues.
In a study published in PLoS Computational Biology, the researchers examined how the timing of hormone administration during a cycle might impact the amount of hormones needed for contraception. Previous research shown that combining hormones can reduce the dosage needed, but the impact of timing on further dose reduction has not been well studied, they said.
The researchers applied optimal control theory in a mathematical model to show the contraceptive effect of estrogen and/or progesterone at different times in the menstrual cycle. The model was based on a normal menstrual cycle with pituitary and ovarian phases. The model assumed that synthesis of luteinizing hormone and follicle-stimulating hormone occurs in the pituitary, that LH and FSH are held in reserve before release into the bloodstream, and that the follicular/luteal mass goes through nine ovarian stages of development. The model also included the activity of ovarian hormones estradiol (E2), progesterone (P4), and inhibin (Inh), in a normal cycle. In the model, LH, FSH, and E2 peaked in the late follicular phase, and P4 and Inh peaked in the luteal phase.
The pituitary model predicted the synthesis, release, and clearance of LH and FSH, and the response of the pituitary to E2, P4, and Inh. The ovarian model predicted the response of E2, P4, and Inh as functions of LH and FSH.
The researchers simulated a constant dose of exogenous progesterone monotherapy and combined exogenous estrogen/progesterone. They determined that a P4 peak of 4.99 ng/mL was taken as the optimum constant dosage for progesterone monotherapy, and for combination estrogen/progesterone.
The researchers then assessed the impact of time on dosage. They found that estrogen administration starting on the first day of a normal cycle preventing FHS from reaching maximum value, and that the low level of FHS in the follicular phase and additional P4 inhibition slowed follicular growth, and use of combination estrogen/progesterone caused similar inhibition at a later follicular stage.
"The combination therapy suggests that time-varying doses of estrogen and progesterone given simultaneously from the start to the end of the 28-day period, only requires a surge in estrogen dose around the 12th day of the cycle (a delayed administration compared to the estrogen monotherapy)," they noted.
With attention to timing, the maximum progesterone levels throughout a menstrual cycle were 4.43 ng/mL, 4.66 ng/mL, and 4.31 ng/mL for estrogen monotherapy, progesterone monotherapy, and combination therapy, respectively. Total doses of the optimal exogenous hormone were 77.76 pg/mL and 48.84 ng/mL for estrogen and progesterone monotherapy, respectively, and 35.58 pg/mL and 21.67 ng/mL for estrogen and progesterone in combination.
The findings were limited by the use of a standard model that does not account for variations in cycle length, the researchers noted. However, the results reflect other studies of hormonal activity, and the model can be used in future studies of the effect of hormones on cycle length, they said.
Overall, the researchers determined that timing dosage with estrogen monotherapy based on their model could provide effective contraception with about 92% of the minimum total constant dosage, while progesterone monotherapy would be effective with approximately 43% of the total constant dose.
Although more work is needed, the current study results may guide clinicians in experimenting with the optimal treatment regimen for anovulation, the researchers said.
"The results presented here give insights on construction of timed devices that give contraception at certain parts of the menstrual cycle," they concluded.
Model aims to improve women's control of contraception
"Aside from wanting to contribute to controlling population growth, we aim to empower women more by giving them more control on when to conceive and start motherhood," and be in control of contraception in a safer way, said lead author Ms. Gavina, in an interview. In addition, studies are showing the noncontraceptive benefits of suppressing ovulation for managing premenstrual syndromes such as breast tenderness and irritability, and for managing diseases such as endometriosis, she said. "Anovulation also lowers the risk of ACL injuries in female athletes," she added.
Ms. Gavina said that she was surprised primarily by the optimal control result for estrogen monotherapy. "It was surprising that, theoretically, our mathematical model, with the simplifying assumptions, showed that as low as 10% of the total dose in constant administration could achieve contraception as long as the administration of this dosage is perfectly timed, and the timing was also shown in our optimization result," she said.
"Our model does not capture all factors in contraception, since the reproductive function in women is a very complex multiscale dynamical system highly dependent on both endogenous and exogenous hormones," Ms. Gavina told this news organization. However, "with the emergence of more data, it can be refined to address other contraception issues. Further, although the results of this study are not directly translatable to the clinical setting, we hope that these results may aid clinicians in identifying the minimum dose and treatment schedule for contraception," she said.
Future research directions include examining within and between women's variabilities and adding a pharmacokinetics model to account for the effects of specific drugs, she said. "We also hope to expand or modify the current model to investigate reproductive health concerns in women, such as [polycystic ovary syndrome] and ovarian cysts," she added.
Ms. Gavina disclosed support from the University of the Philippines Office of International Linkages, a Continuous Operational and Outcomes-based Partnership for Excellence in Research and Academic Training Enhancement grant, and a Commission on Higher Education Faculty Development Program-II scholarship.
This article originally appeared on MDedge.com, part of the Medscape Professional Network.
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Cite this: Cycle Timing May Reduce Hormonal Dosage for Contraception - Medscape - Apr 26, 2023.
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