Abstract
Many enzymes in one-carbon metabolism (OCM) are up- or down-regulated by the sex hormones which vary diurnally and throughout the menstrual cycle. During pregnancy, estradiol and progesterone levels increase tremendously to modulate physiological changes in the reproductive system. In this work, we extend and improve an existing mathematical model of hepatic OCM to understand the dynamic metabolic changes that happen during the menstrual cycle and pregnancy due to estradiol variation. In particular, we add the polyamine drain on S-adenosyl methionine and the direct effects of estradiol on the enzymes cystathionine β-synthase (CBS), thymidylate synthase (TS), and dihydrofolate reductase (DHFR). We show that the homocysteine concentration varies inversely with estradiol concentration, discuss the fluctuations in 14 other one-carbon metabolites and velocities throughout the menstrual cycle, and draw comparisons with the literature. We then use the model to study the effects of vitamin B12, vitamin B6, and folate deficiencies and explain why homocysteine is not a good biomarker for vitamin deficiencies. Additionally, we compute homocysteine throughout pregnancy, and compare the results with experimental data. Our mathematical model explains how numerous homeostatic mechanisms in OCM function and provides new insights into how homocysteine and its deleterious effects are influenced by estradiol. The mathematical model can be used by others for further in silico experiments on changes in one-carbon metabolism during the menstrual cycle and pregnancy.
Highlights
Physiological changes during the menstrual cycle and pregnancy have important health consequences, and understanding these changes is essential for holistic medical care
The complete mathematical model is described in S1 Text
We begin with homocysteine (Hcy), a type of amino acid formed from methionine that has many deleterious effects
Summary
Physiological changes during the menstrual cycle and pregnancy have important health consequences, and understanding these changes is essential for holistic medical care. 5–8% of women suffer from moderate to severe premenstrual syndrome (PMS), with psychological and physical symptoms such as depressed mood, fatigue, and irritability [1]. Those experiencing premenstrual dysphoric disorder (PMDD) have symptoms that interfere with work, school, or relationships [1]. Our goal in this paper is to study changes in an important aspect of metabolism during the menstrual cycle and pregnancy. Many of the enzymes in one-carbon metabolism (OCM) are influenced by sex hormones, estrogen and testosterone. We study the effects of estradiol (E2) on hepatic one-carbon metabolism. E2 varies significantly throughout the menstrual cycle [7, 8, 10] and increases by about 100-fold during pregnancy [11]
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