To report the influence of transdermal oestradiol therapy on the vascular dynamics of men with advanced prostate cancer.
Twenty patients with newly diagnosed locally advanced or metastatic prostate cancer (10 each) were treated using transdermal oestradiol patches. The vascular flow was assessed 6-monthly before and during a year of therapy using arterial and venous Doppler and duplex ultrasonography, arterial and venous photoplethysmography and opto-electronic plethysmography.
Arterial flow, as measured by the mean and peak systolic velocities and photoplethysmography, significantly increased over time. Arterial compliance initially decreased but had normalized after 12 months. The venous variables were unaffected. As a result, the total limb blood flow and the capillary filtration rate were significantly increased.
Transdermal oestradiol therapy causes an increase in arterial but not venous flow, and an initial decrease in arterial compliance, which adapts to the physiological range with time. It is possible that these changes may account for the increase in cardiovascular toxicity seen in the early phase of oestrogen therapy, and the cardioprotective effect that accrues thereafter.
[Show abstract][Hide abstract] ABSTRACT: The hypothesis of this grant proposal is that androgen-ablative therapy paradoxically increases growth factor secretion from bone stromal cells and that this may stimulate the growth of prostate cancer metastases. Based on the presence of androgen receptor regulatory elements in the promoter regions of the Interleukin-6 (IL-6) and hepatocyte growth factor/scatter factor (HGF/SF) genes and the presence of nuclear factor IL-6 binding sites in the promoter of the HGF gene, it is the premise of this project that IL-6 and HGF genes may serve as paradigms of genes that are increased in expression under androgensuppressed conditions. However, initial experiments failed to reveal regulation of HGF and IL-6 by androgen suppression. An analysis of global gene regulation in castrated mice demonstrated that 159 genes were regulated and that Insulin growth Factor Binding Protein-5 demonstrated the most consistent increase in expression. The support provided by the grant fostered the PI's career development to an independent investigator in the field of prostate cancer metastasis to bone. There were several publications supported by the funds from this grant.
[Show abstract][Hide abstract] ABSTRACT: Oral estrogens were the treatment of choice for carcinoma of the prostate for over four decades, but were abandoned because of an excess of cardiovascular and thromboembolic toxicity. It is now recognized that most of this toxicity is related to the first pass portal circulation, which upregulates the hepatic metabolism of hormones, lipids and coagulation proteins. Most of this toxicity can be avoided by parenteral (intramuscular or transdermal) estrogen administration, which avoids hepatic enzyme induction. It also seems that a short-term but modest increase in cardiovascular morbidity (but not mortality) is compensated for by a long-term cardioprotective benefit, which accrues progressively as vascular remodeling develops over time. Parenteral estrogen therapy has the advantage of giving protection against the effects of andropause (similar to the female menopause), which are induced by conventional androgen suppression and include osteoporotic fracture, hot flashes, asthenia and cognitive dysfunction. In addition, parenteral estrogen therapy is significantly cheaper than contemporary endocrine therapy, with substantive economic implications for health providers.
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