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Selective Androgen Receptor Modulator (SARM) Action: Androgen Therapy Revisited

Coss, Christopher C.
http://rave.ohiolink.edu/etdc/view?acc_num=osu1227282252

Abstract Details

2008, Doctor of Philosophy, Ohio State University, Pharmacy.
Despite continuing advances in the clinical development of selective androgen receptor modulators (SARMs) for male hypogonadism, osteoporosis, muscle wasting and myriad diseases of the prostate, mechanism remains controversial. To date, mechanistic work in the selective hormone receptor modulator (SRM) field has been dominated by selective estrogen receptor modulators (SERMs) where a full understanding of SERM action contributed to the development of second generation molecules with better selectivity and reduced side effects. It follows that a better understanding of SARM action could lead to improvements in rationale SARM design and even molecules tailor made for specific patient populations or disease states. The studies described herein were carried out to shed light on the molecular mechanism of aryl propionamide SARM action resulting in full efficacy in anabolic tissues (muscle and bone), while sparing androgenic tissues (prostate and skin). To this end genome wide androgen receptor (AR) promoter binding and transcriptional profiling in LNCaP prostate cancer cells was performed. In these experiments, the primary prostatic androgen 5α-dihydrostestosterone (DHT) was compared to aryl propionamide SARMs, revealing largely overlapping but distinct modes of action. These works support the existence of qualitative differences, not solely due to potency, underlying SARM mechanism. A renewed therapeutic interest in androgens has created an opportunity to re-evaluate side effects that have prevented wide scale androgen therapy. Seemingly pro-athrogenic lipid profiles result from androgen treatment though links to cardiovascular disease are largely observational and conflicting. Also studies showing androgens to be hepatotoxic are confounded by existing disease states and a heavy focus on anabolic steroid abusers. Nevertheless, the dogma surrounding dangers of androgen administration contribute to clinicians’ apprehensions in using anabolic agents to treat a cadre of human ailments. The studies described herein characterize these effects for aryl propionamide SARMs arguing that elevations of serum ALT, thought to reflect liver toxicity, are actually the result of androgen mediated gene expression. Reductions in serum HDL-C were found to be tightly linked with anabolic efficacy in short term studies, but flexibility in the aryl propionamide pharmacophore coupled with high amenability to varied formulations offer hope toward future SARM therapies.
James Dalton, PhD (Advisor)
Rober Brueggemeier, PhD (Committee Member)
Thomas Schmittgen, PhD (Committee Member)
Mamuka Kvaratskhelia, PhD (Committee Member)
243 p.
Pharmacology
SARM; androgen; HDL-C; LNCaP; androgen pharmacology; prostate cancer; cholesterol; selective androgen receptor modulator

Recommended Citations

Citations

  • Coss, C. C. (2008). Selective Androgen Receptor Modulator (SARM) Action: Androgen Therapy Revisited [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1227282252

    APA Style (7th edition)

  • Coss, Christopher. Selective Androgen Receptor Modulator (SARM) Action: Androgen Therapy Revisited. 2008. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1227282252.

    MLA Style (8th edition)

  • Coss, Christopher. "Selective Androgen Receptor Modulator (SARM) Action: Androgen Therapy Revisited." Doctoral dissertation, Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=osu1227282252

    Chicago Manual of Style (17th edition)

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© 2008, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.