Extensive research and clinical observations in the past 20 years confirmed that the cessation of ovarian function at menopause does not stop the process of sex steroid hormone synthesis in females. Indeed, multiple extra-ovarian tissues contain the same enzymatic machinery the ovary uses which can maintain a significant rate of local hormonal synthesis sufficient to cause pathological outcomes. This is commonly termed “intracrine”. However, two obstacles face intracrinology. Firstly, wide clinical appreciation of this mechanism in causing disease and in targeting it with therapy does not currently exist. Secondly, blood hormonal assays are used in the clinic to diagnose and manage intracrine based disorders. This could be entirely misleading, since hormonal synthesis, action and metabolism occur within the tissue and, therefore, measuring blood levels is not reflective of the actual disease environment.
This thesis presents evidence of significant intracrine based disorders in menopausal women that could be effectively managed by tackling the core intracrine mechanism. Three protocols are investigated emphasizing the usefulness of menopausal intracrine estrogen inhibition. The first presents a joint objective of treating menopausal symptoms using estrogenic replacement therapy while reducing breast cancer risk using long-term aromatase inhibitors. Aromatase inhibition is used to suppress the local estrogen synthesis in the breast. The second protocol is a new method of acute inhibition of breast estrogens to improve the accuracy of breast imaging techniques. This method showed a benefit in reducing the benign parenchymal enhancement during breast MRI indicating a potential improvement in specificity. The third protocol involves using aromatase inhibitors in the treatment of severe endometriosis that did not respond to oophorectomy. The pathogenesis of breast cancer, endometriosis and fibroids are believed to involve intracrine estrogen activity.
Another significant contribution presented in this thesis is the development of a new technique that enables minimally invasive tissue assays of hormones in their genuine site of synthesis rather than indirectly in the blood. The new assay requires only microliter volumes of sample and employs a novel digital microfluidics technology. Estrogen and other sex steroids were extracted from droplet-scale breast tissue and blood samples.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/26214 |
| Date | 17 February 2011 |
| Creators | Mousa, Noha |
| Contributors | Casper, Robert |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
Page generated in 0.0019 seconds