1.
Testosterone supplementation therapy in the treatment of patients with metabolic syndrome.
Kovac, JR, Pastuszak, AW, Lamb, DJ, Lipshultz, LI
Postgraduate medicine. 2014;(7):149-56
-
-
Free full text
-
Abstract
Metabolic syndrome (MetS) comprises a clinical complex of patient risk factors, including increased waist circumference, high triglyceride levels, low high-density lipoprotein cholesterol level, high blood pressure, and insulin resistance, the presence of which increases the likelihood of developing diabetes and cardiovascular disease. With a quarter of the American adult population affected, MetS and type 2 diabetes mellitus have been referred to as the most significant public health threats of the 21st century. Lifestyle modification and weight loss are recommended, however, no specific pharmacologic treatment is known. Given that low levels of testosterone have been implicated in the pathogenesis of MetS and an inverse relationship exists between circulating testosterone levels and the development of MetS, it is tempting to speculate that men with MetS may benefit from testosterone supplementation therapy. As such, our review examines the role of testosterone and the use of testosterone supplementation therapy as a treatment in men with MetS.
3.
"Getting from here to there"--mechanisms and limitations to the activation of the androgen receptor in castration-resistant prostate cancer.
Sharifi, N, McPhaul, MJ, Auchus, RJ
Journal of investigative medicine : the official publication of the American Federation for Clinical Research. 2010;(8):938-44
-
-
Free full text
-
Abstract
Despite the clinical regression that typifies the initial response of advanced prostate cancer to gonadal testosterone depletion, tumors eventually progress. However, evidence supports the concept that signaling via the androgen receptor (AR) is important in progression to castration-resistant prostate cancer (CRPC).Steroid hormones are synthesized from cholesterol in a series of tightly regulated steps involving the cleavage of carbon-carbon bonds, the introduction of functional groups derived from activated molecular oxygen, and the oxidation and reduction of carbon-carbon and carbon-oxygen bonds. In the adrenal cortex and gonads, steroidogenesis is tightly regulated, very efficient, and highly directional. In contrast, steroid metabolism in peripheral tissues is characterized by competing enzymes and pathways, low efficiency, and great variability. Many steps are mechanistically and functionally irreversible, but some are not, and the repertoire of specific enzymes, intracellular redox state, and access to hormone precursors all contribute to steroid flux and accumulation.The investigation of steroid metabolizing enzymes in CRPC often assumes that the pathways and the patterns of metabolism mirror those defined in the adrenals and the gonads and validated by human deficiency syndromes. Unfortunately, several potential pathways using different enzymes might contribute substantially to androgen synthesis in CRPC. Finally, a number of mechanisms have been reported by which the AR is activated independent of ligand. Recent observations have suggested that AR forms with constitutive activity occur in CRPC, stimulating transcription without a requirement for ligand. This overview outlines a broad view of how the mechanisms by which the AR may be activated, whether by alternate pathways of androgen synthesis or the production of alternate forms of the AR, with an emphasis on what aspects must be accounted for when using model systems to explore the biology of human prostate cancer.