[Truncated abstract] The activity of the reproductive endocrine axis is the result of interactions among many organs and tissues, particularly the hypothalamus, pituitary gland and gonad. However, it depends on more than the communication between anatomical structures because it is also affected by genotype, internal factors (e.g., metabolic inputs) and external factors (e.g., photoperiod, socio-sexual cues, stress, nutrition). This multifactorial complexity makes it difficult to use animal experimentation to investigate the pathways and mechanisms involved. Therefore, in this study, I have turned to mathematical modelling. The general hypothesis was that, by modelling the hormonal feedback loop that links the hypothalamus, pituitary gland and gonad, I would be able to discover the critical control points in this homeostatic system. This would allow me to inform and direct research into the processes that control reproduction, including inputs from environmental factors. My studies began with the development of a model of the negative feedback loop through which testosterone controls the secretion of pulses of gonadotrophin-releasing hormone (GnRH) by the hypothalamus. The model incorporated two critical factors: testosterone concentration and a time delay in the inhibition of the activity of the GnRH 'pulse generator' by testosterone. The general assumptions were: i) there are two positive feedforward processes (GnRH pulses stimulate LH pulses, and, in turn, LH pulses stimulate testosterone secretion); ii) testosterone exerts negative feedback that reduces the frequency of GnRH pulses. The model incorporated a group of equations that represent the GnRH pulse generator, through which the inhibitory effect of testosterone acted to reduce GnRH pulse frequency. Simulations were run with various values for the time delay in feedback and, as model development progressed, the simulations were extended to include combinations of time delays and levels of sensitivity of the GnRH pulse generator to inhibition by testosterone. The output of the simulations showed clearly that a time delay in negative feedback, as well as the concentration of testosterone, can greatly affect the frequency of GnRH pulses and the shape of the GnRH secretory profile. Importantly, the effect of the time delay depends on the sensitivity of the pulse generator to testosterone. In addition, the simulations suggested two additional components that might be involved in the control of the GnRH pulse generator: i) a delay in the rate of adaptation to a change in steroid feedback; and ii) a minimum pulse interval (maximum frequency). These studies iii therefore suggest that the regulation of the activity of the GnRH pulse generator, and thus the frequency and profile of GnRH and LH pulses, requires interactions among these four components. These interactions should be tested in animal experimentation. In the next stage, I extended the model so I could test whether the feedback delay might involve the process of aromatization in which testosterone is converted to oestradiol at brain level. ... This information can be used to direct future experimental studies that will help us to understand the factors that underlie the dynamic behaviour of the hypothalamic and pituitary systems that control reproduction.
| Identifer | oai:union.ndltd.org:ADTP/194771 |
| Date | January 2008 |
| Creators | Ferasyi, Teuku Reza |
| Publisher | University of Western Australia. School of Animal Biology, University of Western Australia. Faculty of Natural and Agricultural Sciences |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | Copyright Teuku Reza Ferasyi, http://www.itpo.uwa.edu.au/UWA-Computer-And-Software-Use-Regulations.html |
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