The indications for androgen therapy has expanded such that today, androgens are used in both men and women, and in addition to their use in treating primary (or secondary) hypogonadism the potential benefit of increasing bone mineral density, inducing greater muscle mass and strength, enhancing sexual function, and improving mood. Androgens are also being considered as a treatment for rheumatoid arthritis, wound healing, and male contraception. More than 1.7 million prescriptions for testosterone were written in the United States in 2002, representing a 30% increase over that prescribed in 2001 and a 170% increase from that prescribed in 1999. Further, Frost & Sullivan report that that the market for androgens is growing at a 25% compound annual growth rate (CAGR). Of specific relevance to this proposal, it should be noted that though the aging population is clearly an important demographic for which androgen therapy may be indicated, this same population is also at a higher risk for stroke or developing such neurodegenerative diseases as Alzheimer's disease. Given the discrepancy between reports in the literature as to whether androgens are beneficial or detrimental, there is a critical need to devise an effective screening tool to better define the population most likely to benefit from androgen therapy. Currently there is no known diagnostic available to define risk in a patient who is considered for androgen therapy. As such, this Phase I application outlines a strategy, based on our preliminary data, to develop a diagnostic tool for the relative assessment of two pharmacologically distinct androgen receptors, each of which appear to mediate different effects on cell survival. One receptor (the classical, intracellular/nuclear androgen receptor), subserves a beneficial (cell survival promoting) effect, while the other, a membrane androgen receptor (mAR), promotes cell death. Such potentially """"""""competing"""""""" mechanisms could explain the discrepancy in the literature as to whether androgens are protective or promote cell dysfunction and death. Importantly, these data serve as the basis for our hypothesis, which states that the relative abundance (or ratio) of these two competing receptor mechanisms predicts whether individuals will respond favorably to androgens or are more prone to the negative consequences of androgens. This hypothesis will be tested within the confines of two specific aims. The first will develop and validate a methodology to simultaneously assess the levels of the classical AR and the mAR from both brain tissue and blood (white blood cells). The latter will address whether simple blood measurements of these receptors may reliably predict the mAR:AR ratio in androgen's target tissue.
The second aim will test the predictability of the mAR:AR ratio on the therapeutic outcome of androgens by assessing if the negative outcome associated with androgens in an animal model of stroke is correlated with a relatively higher abundance of mAR in both the affected brain regions and in white blood cells (the latter serving as a surrogate marker for the brain). Successful completion of this project will provide the necessary foundation for a Phase II STTR application and the development of a diagnostic tool to define those individuals for whom androgen therapy is not only indicated, but also effective and safe. ? ? ?
