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.