A lifelong model for the female reproductive cycle with an antimüllerian hormone treatment to delay menopause

Abstract

A system of 16 non-linear, delay differential equations with 66 parameters is developed to model hormonal regulation of the menstrual cycle of a woman from age 20 to 51. This mechanistic model predicts changes in follicle numbers and reproductive hormones that naturally occur over that time span. In particular, the model illustrates the decline in the pool of primordial follicles from age 20 to menopause as reported in the biological literature. Also, model simulations exhibit a decrease in antimüllerian hormone (AMH) and inhibin B and an increase in FSH with age corresponding to the experimental data. Model simulations using the administration of exogenous AMH show that the transfer of non-growing primordial follicles to the active state can be slowed enough to provide more follicles for development later in life and to cause a delay in the onset of menopause as measured by the number of primordial follicles remaining in the ovaries. Other effects of AMH agonists and antagonists are investigated in the setting of this model.

Anti-Müllerian hormone overexpression restricts preantral ovarian follicle survival

“…Alternatively, the collapse of the primordial follicle population may be indirect and subsequent to the profound effects on the developing follicle population. However, the possibility that prolonged elevation in AMH is toxic to dormant primordial follicles requires urgent investigation because AMH treatment has been proposed as a reversible contraceptive and a therapeutic inhibitor of ovarian reserve depletion (Margolskee & Selgrade 2013, Hayes et al 2016, Kong et al 2016, Kano et al 2017. The loss of primordial follicles is thought to be irreversible and the 5-month-old Thy1.2-AMH Tg phenotype indicates that more research is needed to determine the safety of longterm AMH treatment.…”

Modeling endocrine regulation of the menstrual cycle using delay differential equations

“…Welt et al [50] collected data for two types of inhibin, InhA and InhB. Both inhibit FSH synthesis but InhB is a good indicator of ovarian aging and is useful for extending the model to older reproductive women in the age range 35-45 years (see [23]). Another refinement would be to separate the functions of the pituitary and hypothalamus in order to describe the role of gonadotropin releasing hormone (GnRH), because many cycle abnormalities involve irregular GnRH pulsing.…”

“…Over the last 10-15 years, we have developed and analyzed mechanistic, deterministic, mathematical models [14,15,17,23,32,39,[41][42][43][44] which predict average serum concentrations of reproductive hormones that agree with data in the biological literature for normally cycling adult women [27,50]. This article reviews the procedure which we and other modelers, e.g., Boer et al [3], Bogumil et al [4,5], Chen and Ward [7], Reinecke and Deuflhard [34], Röblitz et al [35], and Zeeman et al [55], have found effective for modeling hormonal regulation of the female reproductive system.…”

Advances in computational modeling approaches of pituitary gonadotropin signaling

“…The model can be refined by embedding additional variables to include more detailed biological knowledge. In particular, the distinction between two types of inhibin (inhibin A and inhibin B), which affect differentially the synthesis of FSH, and the role of Anti-Müllerian Hormone (AMH) on the developing follicles was included in [25]. These refinements allowed the authors to broaden the timescale of the model up to a lifelong model, and to investigate the impact of a putative AMH treatment on the onset of menopause.…”