This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.In recent years there has been an explosion of interest in issues related to the function and the abnormalities of the reproductive axis in general and infertility in particular. Moreover, there has been considerable focus on abnormalities of the hypothalamic gonadotropin releasing hormone (GnRH) pulse generator and of the cells within the anterior pituitary, which secrete the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Less attention has been paid to the feedback effects of LH and FSH on ovarian function and the feedback effect of the ovarian hormones on hypothalamic and pituitary function. Indeed, in the past, the reproductive system has been considered as a group of individual components and the investigation of the relationships between these components have been thwarted by the complexity of the system. In this regard, biomathematical methods have been shown to contribute successfully to the study of various complex physiological systems but these techniques have been used only to assess the function of individual components of the reproductive system without taking into account the temporal relationships between the components. Consequently, this approach has limited ability to understand the functional mechanisms and the specific changes that underlie a particular system abnormality. We suggest that it is now time to consider the GnRH pulse generator/pituitary/ovarian axis as a dynamic network of feedforward/feedback interactions which govern the system temporal behavior. In this regard, we have recently developed quantitative methods that can be applied to the investigation of the reproductive axis. The approach allows physiological system properties to be detected from hormone concentration time-series specifics and can link abnormalities of the axis to detectable changes in the pulsatility characteristics. One well-validated method to detect these changes is deconvolution analysis. However, the successful application of such analysis depends on the correct choice of sampling paradigms. In particular, we must have blood samples collected at a frequency that would allow for the precise determination of the hormone half-life. The current pilot protocol will use a frequent sampling paradigm and deconvoluton analytical technique to determine:(i) the half-lives of endogenously released LH, FSH, estradiol, and progesterone during the mid-luteal and LH, FSH, 17-OH progesterone, and androstenedione during the follicular phase of the reproductive cycle, and (ii) optimal frequent sampling paradigms for analytical determination of reproductive hormone half-lives. A long-term objective is to collect preliminary data of simultaneously sampled pituitary and ovarian hormones to develop markers of the ovarian function based on a dynamic network approximation of the reproductive axis. We believe that the current pilot protocol will initiate broader interdisciplinary studies of the GnRH pulse generator/pituitary/ovarian axis and will be of interest for future steps in the investigation of the reproductive ensemble endocrine control.
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