PubMed · 8753284
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Y Shimizu, K Okubo, T Yanaihara. 1995. [17 alpha-hydroxypregnenolone].. https://pubmed.ncbi.nlm.nih.gov/8753284/
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Pregnenolone (PREG) and dehydroepiandrosterone (DHEA) have been reported to improve memory in aged rodents. In brain, these neurosteroids are transformed predominantly into 7alpha-hydroxylated metabolites by the cytochrome P450-7B1 (CYP7B). The biological role of steroid B-ring hydroxylation is unclear. It has been proposed to generate bioactive derivatives that enhance cognition, immune, and other physiological processes. In support, 7alpha-hydroxylated DHEA increases the immune response in mice with greater potency than the parent steroid. Whether the memory-enhancing effects of PREG in rats is mediated via its 7alpha-hydroxylated metabolite 7alpha-hydroxyPREG is not known. We investigated this by treating memory-impaired aged rats (identified by their spatial memory performances in the Morris water maze task compared with young controls) with 7alpha-hydroxyPREG or PREG administered intracerebroventricularly using osmotic minipumps and then tested the rats during week 2 of steroid treatment in the eight-arm radial-arm version of the water maze (RAWM) that allows repeated assessment of learning. CYP7B bioactivity in hippocampal tissue (percentage conversion of [14C]DHEA to [14C]7alpha-hydroxyDHEA) was decreased selectively in memory-impaired aged rats compared with both young and memory-intact aged rats. 7alpha-hydroxyPREG (100 ng/h) but not PREG (100 ng/h) administration to memory-impaired aged rats for 11 d enhanced spatial memory retention (after a 30 min delay between an exposure trial 1 and test trial 2) in the RAWM. These data provide evidence for a biologically active enzyme product 7alpha-hydroxyPREG and suggests that reduced CYP7B function in the hippocampus of memory-impaired aged rats may, in part, be overcome by administration of 7alpha-hydroxyPREG.
BACKGROUND: Congenital adrenal hyperplasia is a group of autosomal recessive disorders caused by a deficiency of 1 of 4 enzymes required for the synthesis of glucocorticoids, mineralocorticoids, and sex hormones. Analysis of 11-deoxycortisol (11DC), 17-hydroxyprogesterone (17OHP), 17-hydroxypregnenolone (17OHPr), and pregnenolone (Pr) in blood allows detection of these enzyme defects. METHODS: The steroids were extracted from 200 microL of serum or plasma by solid-phase extraction, derivatized to form oximes, and extracted again with methyl t-butyl ether. Instrumental analysis was performed on an API 4000 tandem mass spectrometer with electrospray ionization in positive mode and multiple reaction-monitoring acquisition. RESULTS: The limits of detection were 0.025 microg/L for 11DC, 17OHP, and Pr and 0.10 microg/L for 17OHPr. The method was linear to 100 microg/L for 11DC, 17OHP, and Pr, respectively, and to 40 microg/L for 17OHPr. Within- and between-run (total) imprecision (CVs) were <7.1% and 11%, respectively. Reference intervals for children in Tanner stages 1 through 5 and adult males and females for 17OHP, 11DC, Pr, and 17OHPr were established. Prepared samples were stable for >72 h. CONCLUSIONS: The detection limit and selectivity of this method and its small sample volume requirement allow analysis of endogenous concentrations of adrenal steroids in serum or plasma from children and adults. The method thus has an important potential role in the evaluation of the status of 4 of the enzymes involved in adrenal steroid biosynthesis.
OBJECTIVE: This study was conducted in order to evaluate the effect of glucose-insulin homeostasis on adrenal steroids and was designed to separate the effects of hyperglycaemia from those of insulin. DESIGN: Eight healthy men aged 22.6 +/- 3.4 (SD) underwent an 80 mU/m2/min hyperinsulinaemic euglycaemic 100-min clamp, a 200-min graded glucose infusion at 2-16 mg/kg/min and a measurement of fat mass. MEASUREMENTS: Circulating glucose, insulin and adrenal steroid levels including dehydroepiandrosterone (DHEA) were determined before and during both infusion tests. Steroid variations in relation to insulinaemia and glycaemia were analysed using univariate, multivariate tests and nonlinear mixed models. RESULTS: Hyperinsulinaemia induced no significant modification of adrenal steroid levels. By contrast, hyperglycaemia decreased all adrenal steroids except DHEA-sulphate by 47-66%. The drop occurred early, averaging 51% for 17OH pregnenolone and 57% for DHEA at the 80th minute of glucose infusion, whereas blood glucose was 7.1 +/- 1.2 mmol/1. This effect was independent of insulinaemia, fat mass and waist circumference. Thus, we estimated models that could best predict steroid variations according to blood glucose. At thresholds defining impaired fasting glycaemia and diabetes, the estimated decrease in DHEA was 40% and 45%, respectively, culminating at 60% at 9.3 mmol/1 glycaemia, with no detectable further decrease. CONCLUSIONS: Our data suggest that hyperglycaemia dramatically decreases adrenal androgen levels in men, possibly by acting at early steps of synthesis, independently of insulinaemia and fat mass.