Bifurcation analysis of a menstrual cycle model reveals multiple mechanisms linking testosterone and classical PCOS

A system of 16 differential equations is described which models hormonal regulation of the menstrual cycle focusing on the effects of the androgen testosterone (T) on follicular development and on the synthesis of luteinizing hormone (LH) in the pituitary. Model simulations indicate two stable menstrual cycles - one cycle fitting data in the literature for normal women and the other cycle being anovulatory because of no LH surge. Bifurcations with respect to sensitive model parameters illustrate various characteristics of polycystic ovarian syndrome (PCOS), a leading cause of female infertility. For example, varying one parameter retards the growth of preantral follicles and produces a "stockpiling" of these small follicles as observed in the literature for some PCOS women. Modifying another parameter increases the stimulatory effect of T on LH synthesis resulting in reduced follicular development and anovulation. In addition, the model illustrates how anovulatory and hyperandrogenic cycles which are characteristic of PCOS can be reproduced by perturbing both pituitary sensitivity to T and the follicular production of T. Thus, this model suggests that for some women androgenic activity at the levels of both the pituitary and the ovaries may contribute to the etiology of PCOS.