Steroid metabolism in utero and in the neo-natal period

1. Two steroids were identified for the first time as major steroid components of urine collected from infants and plasma obtained from the umbilical blood vessels. These compounds have the formula 3p,l6|3- dihydroxyandrost-5-en-17-one and 3(3,17a-dihydroxyandrost-5-ene, but their importance in the metabolism of steroids by the foeto-placental unit is not known. 2. A method was developed for measuring steroids in plasma obtained from the umbilical blood vessels and urine collected from infants. This depends upon the separation of steroids by thin-layer chromatography, and their assay on the thin-layer plates by developing colours with various spray reagents and subsequent densitometric scanning. The accuracy and specificity of the method is discussed. 3. This method was used to establish normal ranges for the excretion of several 3|3-hydroxy-A steroids found in urine specimens obtained from infants, and to determine the effects upon the excretion of steroids of administering corticotrophin and human chorionic gonadotrophin to newborn infants. 4. The enzyme defects present in three infants with abnormal adrenal glands were investigated by analysis of steroids in urine specimens obtained from these patients. 5. Several 3(3-hydroxy-A"* steroids were measured in plasma samples prepared from venous and arterial blood obtained from the umbilical cord. The concentrations present in arterial plasma were higher than in the umbilical vein, indicating a net uptake of these steroids by the placenta, where it is thought that they are converted into 3-oxo-A steroids and oestrogens. The relationship between the levels of 3(3-hydroxy-Asteroids in plasma obtained from the umbilical blood vessels and oestrogen excretion by the mother was also investigated

The broad phenotypic spectrum of 17α-hydroxylase/17,20-lyase (CYP17A1) deficiency : a case series

Context 17α-Hydroxylase/17,20-lyase deficiency (17OHD) caused by mutations in the CYP17A1 gene is a rare form of congenital adrenal hyperplasia typically characterised by cortisol deficiency, mineralocorticoid excess and sex steroid deficiency. Objective To examine the phenotypic spectrum of 17OHD by clinical and biochemical assessment and corresponding in silico and in vitro functional analysis. Design Case series. Patients and results We assessed eight patients with 17OHD, including four with extreme 17OHD phenotypes: two siblings presented with failure to thrive in early infancy and two with isolated sex steroid deficiency and normal cortisol reserve. Diagnosis was established by mass spectrometry-based urinary steroid profiling and confirmed by genetic CYP17A1 analysis, revealing homozygous and compound heterozygous sequence variants. We found novel (p.Gly111Val, p.Ala398Glu, p.Ile371Thr) and previously described sequence variants (p.Pro409Leu, p.Arg347His, p.Gly436Arg, p.Phe53/54del, p.Tyr60IlefsLys88X). In vitro functional studies employing an overexpression system in HEK293 cells showed that 17,20-lyase activity was invariably decreased while mutant 17α-hydroxylase activity retained up to 14% of WT activity in the two patients with intact cortisol reserve. A ratio of urinary corticosterone over cortisol metabolites reflective of 17α-hydroxylase activity correlated well with clinical phenotype severity. Conclusion Our findings illustrate the broad phenotypic spectrum of 17OHD. Isolated sex steroid deficiency with normal stimulated cortisol has not been reported before. Attenuation of 17α-hydroxylase activity is readily detected by urinary steroid profiling and predicts phenotype severity