Item – Theses Canada

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OCLC number
54206218
Link(s) to full text
LAC copy
LAC copy
Author
Hodgert Jury, Heather Lynne,1970-
Title
Human sex hormone-binding globulin modulates the biological activity of its ligands in vitro and in vivo.
Degree
Ph. D. -- University of Western Ontario, 2001
Publisher
Ottawa : National Library of Canada = Bibliothèque nationale du Canada, [2003]
Description
3 microfiches.
Notes
Includes bibliographical references.
Abstract
The regulation of sex steroid bioavailability at the target tissue level is a result of the interaction of these hormones with plasma proteins. In particular, the interaction of sex steroids with human sex hormone-binding globulin (SHBG), a protein with high affinity and low capacity for steroids, is important in determining the bioavailability of sex steroids at the tissue level. Previous studies have shown that certain nonsteroidal compounds interact with the SHBG steroid-binding site, and I have therefore developed a screening assay to identify natural and synthetic compounds that bind SHBG. This assay uses undiluted human serum and therefore has the advantage of identifying possible interactions with other serum proteins by comparing results in this assay versus conventional assays, therefore providing insight into the factors that contribute to the bioavailability of endocrine active compounds within the body. A limited number of 'in vitro' studies have shown that it is the non protein-bound steroid fraction that is biologically active, consistent with the free hormone hypothesis, but these studies cannot model tissue blood flow and transit time. Additionally, there is evidence that SHBG may have a direct influence on the actions of its ligands as a result of targeted delivery. Rodents are often used as 'in vivo' models for estrogen action, however they lack SHBG in the blood as adults. I have therefore made use of transgenic mice that express human SHBG transgenes and have various levels of human SHBG in their blood to assess the effects of SHBG on estrogen action by measuring uterine hypertrophy following administration of pharmacologically relevant estrogens, and by monitoring the incidence of chemically-induced mammary tumours that are known to be estrogen-dependent. Immunohistochernical analysis of uteri harvested from these mice revealed an estrogen-dependent accumulation of SHBG in the endometrial stroma. The extracellular matrix protein fibulin-2, which is known to interact with SHBG 'in vitro' was found to have a similar localization pattern in the mouse uterus following estrogen stimulation. These data indicate that fibulin-2 is involved in the extravascular sequestration of SHBG in the mouse uterus and that this interaction can be regulated in an SHBG ligand-dependent manner.
ISBN
0612680428
9780612680425