Control of gonadal function by the pituitary gonadotropins is firmly established. However, the role of luteinizing hormone (LH) heterogeneity and its clinical ramifications are poorly understood. The overall objective of the proposed research is to investigate WHAT CAUSES LH HETEROGENEITY, the QUANTITATION AND REGULATION OF LH HETEROGENEITY and the BIOLOGICAL FUNCTIONS OF LH HETEROGENEITY. At present, the molecular basis for LH heterogeneity is not fully understood. Our preliminary studies suggest that the multiple charge isomers of both human (h) and ovine (o) LH are associated with their oligosaccharides. Thus, we propose to examine the fine structures of the various sugar units attached to LH and relate oligosaccharide structures to the distinct molecular forms of LH observed in pituitary extracts. Previous studies suggested a critical role for oligosaccharides in the expression of LH biological activity (LH deglycosylated with hydrogen fluoride). Our preliminary data using a less radical method (endoglycosidase F) suggest otherwise. To address this disparity and to carefully dissect the role of carbohydrate in LH action we propose to examine circulatory survival and the abilities of each naturally occurring oLH and hLH isohormone to bind to receptors and to stimulate the production of cAMP and testosterone. LH in which specific components of the oligosaccharides have been removed will be similarly examined. We propose to continue identifying and quantitating the molecular forms of LH """"""""isohormones"""""""") in the pituitary using sheep subjected to various endocrine manipulations and to establish their relationship with forms which are secreted. These experiments will illustrate changes in LH heterogeneity under various endocrine conditions and possibly reveal the factors which modulate the LH isohormone profile. In order to identify and characterize molecular forms of LH which are immunoreactive but possess little biological activity we propose examining LH isohormones found in serum and urine of humans with normal and abnormal reproductive function as well as changes associated with the onset and quiescence of gonadal function. These studies should clarify the role of specific molecular forms of LH in the regulation of gonadal function.
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