The effect of testosterone and methyltestosterone on guanidoacetic acid, creatine, and creatinine in plasma and urine.

Since the major route of creatine formation in the animal body appears to involve the intermediate formation of guanidoacetic acid, methylated steroids such as methyltestosterone could cause the repeatedly observed (1,2) increase in production of creatine by one of three possible mechanisms: (a) by transferring methyl groups to guanidoacetic acid, (b) by increasing production of guanidoacetic acid, or (c) by catalyzing some other system of creatine synthesis. Wilkins and Fleishmann (3) in 1945 were able to demonstrate that only the methylated derivatives of the C19 steroid nucleus were effective in producing creatinurea. Methyltestosterone, methylandrostanediol-3,17, and methylandrostene-5-diol-3,17 all caused creatinurea, while ethyltestosterone and a number of other non-methylated steroids were found to be inactive. As a result of this work the idea was proposed that methylated steroids may act as catalysts for the process of methylating guanidoacetic acid to creatine. The work of Borsook and Dubnoff (4, 5), du Vigneaud et al. (6), and Block and Schoenheimer (7) has established the probable mechanism of creatine formation as follows: (a) guanidoacetic acid is formed in the kidney from glycine and arginine and (b) the guanidoacetic acid is methylated by methionine, principally in the liver. Borsook et al. (8) demonstrated that administration of arginine and glycine to man led to a marked increase in guanidoacetic acid in the urine. Simmonds and du Vigneaud (9) furnished indisputable proof that the methyl group of methionine gives rise to creatinine in man. It therefore appears that this proposed mechanism applies to man. If the role of catalyst proposed by Wilkins and Fleishmann were correct, it would follow that the increase in creatine levels should bear certain relations to the levels of guanidoacetic acid. Two alternatives appear possible. In the first case methylation of guanidoacetic acid could be accelerated