Candidate mechanisms underlying atypical progesterone profiles as deduced from parameter perturbations in a...

The complex interplay of physiological factors that underlies fertility in dairy cows was investigated using a mechanistic mathematical model of the dynamics of the bovine estrous cycle. The model simulates the processes of follicle and corpus luteum development and its relations with key hormones that interact to control these processes. Several factors may perturb the regular oscillatory behavior of a normal estrous cycle, and such perturbations are likely the effect of simultaneous changes in multiple parameters. The objective of this paper was to investigate how multiple parameter perturbation changes the behavior of the estrous cycle model, so as to identify biological mechanisms that could play a role in the development of cystic ovaries. Cystic ovaries are a common reason for reproductive failure in dairy cows, but much about the causes of this disorder remains unknown. We investigated in which region of the parameter space the model predicts a normal cycle, and when a progesterone pattern occurred with delayed ovulation (indicating a cystic follicle) or delayed luteolysis (indicating a persistent corpus luteum). Perturbation of the initial values for all parameters simultaneously showed 2 specific parameter configurations leading to delayed ovulation or delayed luteolysis immediately. The most important parameter changes in these 2 configurations involve the regulation of corpus luteum functioning, luteolytic signals, and GnRH synthesis, suggesting that these mechanisms are likely involved in the development of cystic ovaries. In the multidimensional parameter space, areas exist in which the parameter configurations resulted in normal cycles. These areas may be separated by areas in which irregular cycle patterns occurred. These irregular patterns thus mark the transition from one stable (normal) situation to another. Interestingly, within a series, there were some cycles with delayed ovulation and some with delayed luteolysis in these patterns. This could represent a situation of resumption of normal cyclicity (e.g., after parturition). In conclusion, the method of parameter perturbation used in the present study is an effective tool to find parameter configurations that lead to progesterone profiles associated with delayed ovulation and delayed luteolysis. Thereby, the model helps to generate hypotheses regarding the underlying cause of the development of cystic ovaries, which could be investigated in future experiments.