Modeling endocrine control of the pituitary-ovarian axis: androgenic influence and chaotic dynamics.

Hendrix, Angelean O

Hughes, Claude L

Selgrade, James F

2018-06-04T14:27:10Z

2018-06-04T14:27:10Z

2014-01

2018-06-04T14:27:00Z

Mathematical models of the hypothalamus-pituitary-ovarian axis in women were first developed by Schlosser and Selgrade in 1999, with subsequent models of Harris-Clark et al. (Bull. Math. Biol. 65(1):157-173, 2003) and Pasteur and Selgrade (Understanding the dynamics of biological systems: lessons learned from integrative systems biology, Springer, London, pp. 38-58, 2011). These models produce periodic in-silico representation of luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol (E2), progesterone (P4), inhibin A (InhA), and inhibin B (InhB). Polycystic ovarian syndrome (PCOS), a leading cause of cycle irregularities, is seen as primarily a hyper-androgenic disorder. Therefore, including androgens into the model is necessary to produce simulations relevant to women with PCOS. Because testosterone (T) is the dominant female androgen, we focus our efforts on modeling pituitary feedback and inter-ovarian follicular growth properties as functions of circulating total T levels. Optimized parameters simultaneously simulate LH, FSH, E2, P4, InhA, and InhB levels of Welt et al. (J. Clin. Endocrinol. Metab. 84(1):105-111, 1999) and total T levels of Sinha-Hikim et al. (J. Clin. Endocrinol. Metab. 83(4):1312-1318, 1998). The resulting model is a system of 16 ordinary differential equations, with at least one stable periodic solution. Maciel et al. (J. Clin. Endocrinol. Metab. 89(11):5321-5327, 2004) hypothesized that retarded early follicle growth resulting in "stockpiling" of preantral follicles contributes to PCOS etiology. We present our investigations of this hypothesis and show that varying a follicular growth parameter produces preantral stockpiling and a period-doubling cascade resulting in apparent chaotic menstrual cycle behavior. The new model may allow investigators to study possible interventions returning acyclic patients to regular cycles and guide developments of individualized treatments for PCOS patients.

0092-8240

1522-9602

https://hdl.handle.net/10161/17105

eng

Springer Science and Business Media LLC

Bulletin of mathematical biology

10.1007/s11538-013-9913-7

Ovary

Ovarian Follicle

Hypothalamo-Hypophyseal System

Humans

Polycystic Ovary Syndrome

Follicle Stimulating Hormone

Luteinizing Hormone

Androgens

Systems Biology

Menstrual Cycle

Nonlinear Dynamics

Models, Biological

Computer Simulation

Female

Mathematical Concepts

Feedback, Physiological

Modeling endocrine control of the pituitary-ovarian axis: androgenic influence and chaotic dynamics.

Journal article

Hughes, Claude L|0000-0001-5178-2258

1

School of Medicine

Duke

Obstetrics and Gynecology

Clinical Science Departments

Published

76