Toward an optimal contraception dosing strategy

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 E2, P4, 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. Author summary Hormonal contraceptives composed of exogenous estrogen and/or progesterone are commonly administered artificial means of birth control. Despite many benefits, adverse side effects associated with high doses such as thrombosis and myocardial infarction, cause hesitation to usage. Our study presents an improved mathematical model for hormonal control of the menstrual cycle and applies optimal control theory to minimize total exogenous estrogen and/or progesterone dose, and determine timing of administration that lead to contraception. We observe a reduction in dosage of about 92% in estrogen monotherapy and 43% in progesterone monotherapy. Our simulations show that it is most effective to deliver the estrogen contraceptive in the mid follicular phase. In addition, we illustrate that combination therapy significantly lower doses further. Our findings may give clinicians insights into optimal dosing scheme for contraception.