In 1937 Butler and Marrian found large amounts of the
steroid pregnanetriol in urine from a patient with the
adrenogenital syndrome, a virilizing condition known to be caused by compromised adrenal secretion even in this pre-
cortisol era. This introduced the concept of the study of altered excretion of metabolites as an in vivo tool for understanding
sterol and
steroid biosynthesis. This approach is still viable and has experienced renewed significance as the field of metabolomics. From the first cyclized
sterol lanosterol to the most downstream product
estradiol, there are probably greater than 30 steps. Based on a distinctive metabolome clinical disorders have now been attributed to about seven post-
squalene cholesterol (C) biosynthetic steps and around 15 en-route to
steroid hormones or needed for further metabolism of such
hormones. Forty years ago it was widely perceived that the principal
steroid biosynthetic defects were known but interest rekindled as novel metabolomes were documented. In his career this investigator has been involved in the study of many
steroid disorders, the two most recent being P450
oxidoreductase deficiency and apparent
cortisone reductase deficiency. These are of interest as they are due not to mutations in the primary catalytic
enzymes of steroidogenesis but in ancillary
enzymes needed for co-factor oxido-reduction A third focus of this researcher is
Smith-Lemli-Opitz syndrome (SLOS), a
cholesterol synthesis disorder caused by
7-dehydrocholesterol reductase mutations. The late George Schroepfer, in whose honor this article has been written, contributed greatly to defining the
sterol metabolome of this condition. Defining the cause of clinically severe disorders can lead to improved treatment options. We are now involved in murine gene therapy studies for SLOS which, if successful could in the future offer an alternative
therapy for this severe condition.