21-Hydroxylase deficiency in the neonate – trends in steroid anabolism and catabolism during the first weeks of life
Deficiency of 21-hydroxylase provides an in vivo model of intrauterine induction of enzymes participating in steroid anabolism and catabolism. Quantitative data for 93 steroid metabolites in urine from 111 patients and 7 controls (25 samples) were compared over the first six weeks of life. Net flux through the key anabolic enzymes was examined by comparison of the totals of steroids derived from the intermediates prior to and following each enzymatic step. Metabolic relationships were established on structural grounds and by Pearson correlation. The relative importance of each catabolic route was evaluated after summing metabolites classified according to their structure as fetal, neonatal, and classical (adult) type.
Hierarchical cluster analysis identified the structure at C3–C5 as a key distinguishing feature of the major catabolic streams and demonstrated a split point in metabolic pattern in patients at 7 days. Changes with time in steroid metabolism, larger in patients than in controls, could be interpreted as reflecting increased cortisol demand post partum, the clinical onset of salt-wasting and a transition in catabolism from fetal to postnatal life. Faster involution of the fetal zone and pronounced enhancement of steroid production in zona fasciculata and zona glomerulosa were indicated in patients. Predominant at birth were ‘planar’ fetal-type 5α-reduced metabolites, adapted to placental excretion, which gave way to additionally hydroxylated neonatal-type metabolites, facilitating renal excretion. Classical metabolism made gains over the study period. Overproduction of steroids in utero in 21-hydroxylase deficiency would have induced fetal catabolic pathways dependent on 5α-reduction. A progressive increase of steroids likely to arise from 5α-reductase type 2 activity, again more distinct in disease, was observed.
We demonstrate that the key intermediates in the hypothetical ‘backdoor’ pathway of androgen synthesis are part of a broader catabolic network and should not be examined in isolation.
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Published: 2013 Nov;138:334-47. doi: 10.1016/j.jsbmb.2013.07.013. Epub 2013 Jul 31