cortodoxone and pregnanetriolone

The classic androgen synthesis pathway proceeds via dehydroepiandrosterone, androstenedione, and testosterone to 5α-dihydrotestosterone. However, 5α-dihydrotestosterone synthesis can also be achieved by an alternative pathway originating from 17α-hydroxyprogesterone (17OHP), which accumulates in congenital adrenal hyperplasia (CAH). Similarly, recent work has highlighted androstenedione-derived 11-oxygenated 19-carbon steroids as active androgens, and in CAH, androstenedione is generated directly from 17OHP. The exact contribution of alternative pathway activity to androgen excess in CAH and its response to glucocorticoid (GC) therapy is unknown.. We sought to quantify classic and alternative pathway-mediated androgen synthesis in CAH, their diurnal variation, and their response to conventional GC therapy and modified-release hydrocortisone.. We used urinary steroid metabolome profiling by gas chromatography-mass spectrometry for 24-hour steroid excretion analysis, studying the impact of conventional GCs (hydrocortisone, prednisolone, and dexamethasone) in 55 adults with CAH and 60 controls. We studied diurnal variation in steroid excretion by comparing 8-hourly collections (23:00-7:00, 7:00-15:00, and 15:00-23:00) in 16 patients with CAH taking conventional GCs and during 6 months of treatment with modified-release hydrocortisone, Chronocort.. Patients with CAH taking conventional GCs showed low excretion of classic pathway androgen metabolites but excess excretion of the alternative pathway signature metabolites 3α,5α-17-hydroxypregnanolone and 11β-hydroxyandrosterone. Chronocort reduced 17OHP and alternative pathway metabolite excretion to near-normal levels more consistently than other GC preparations.. Alternative pathway-mediated androgen synthesis significantly contributes to androgen excess in CAH. Chronocort therapy appears superior to conventional GC therapy in controlling androgen synthesis via alternative pathways through attenuation of their major substrate, 17OHP.

Topics: 17-alpha-Hydroxypregnenolone; Adolescent; Adrenal Hyperplasia, Congenital; Adult; Androgens; Androsterone; Circadian Rhythm; Cortodoxone; Delayed-Action Preparations; Dexamethasone; Female; Gas Chromatography-Mass Spectrometry; Glucocorticoids; Humans; Hydrocortisone; Male; Middle Aged; Prednisolone; Pregnanetriol; Young Adult

To characterize the urinary steroid metabolome of neonates and infants born either at term or preterm.. We retrospectively analyzed urinary steroid hormone metabolites determined by gas chromatography-mass spectrometry of 78 neonates and infants born at term and 83 neonates and infants born preterm (median 34 weeks of gestational age). The subjects' 11β-hydroxylase and 21-hydroxylase activities were assessed on the basis of urinary metabolite substrate-to-product ratios.. Preterm neonates and infants had elevated urinary concentrations of 17α-hydroxyprogesterone (17OHP) metabolites (P<.001) but lower urinary concentrations of the 21-deoxycortisol metabolite pregnanetriolone (PTO) (P<.01). One reason was lower 11β-hydroxylase activity in preterms. We could demonstrate a correlation between low 11β-hydroxylase activity and high urinary concentrations of 17OHP metabolites (r=0.51, P<.001) but low urinary concentrations of the 21-deoxycortisol metabolite PTO (r=-0.24, P=.03) in preterms.. Low 11β-hydroxylase activity may explain increased 17OHP but decreased 21-deoxycortisol metabolite excretion in preterms. Our analysis clarifies, first, why preterms have higher 17OHP levels and thus higher rates of false-positive screening results for congenital adrenal hyperplasia than do term infants, and, second, why 21-deoxycortisol or its urinary metabolite PTO is more specific than 17OHP for the diagnosis of 21-hydroxylase deficiency.

Topics: 17-alpha-Hydroxyprogesterone; Adrenal Hyperplasia, Congenital; Chromatography, Gas; Cortodoxone; Female; Gas Chromatography-Mass Spectrometry; Humans; Infant; Infant, Newborn; Infant, Premature; Male; Mass Spectrometry; Metabolome; Pregnanetriol; Retrospective Studies; Steroid 11-beta-Hydroxylase; Steroid 17-alpha-Hydroxylase

To establish a detailed reevaluation system for infants who were recalled by a neonatal mass screening for congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, pregnanetriol (PT) and pregnanetriolone (PTL) in a single urine specimen combined with plasma 17 alpha-hydroxyprogesterone (17-OHP) and 21-deoxycortisol (21-DOF) were determined by a simple method using glass capillary gas chromatography. A pilot study of neonatal mass screening for CAH with a determination of "disc 17-OHP" value in dried blood on filter paper was carried out in Western Shizuoka Prefecture. During the study period (32 months), 37472 neonates were determined by mass screening, and 362 neonates proved to be abnormal candidates who needed further evaluations. From out of these candidates, 262 neonates responded with recall and were studied. Amongst these 262 neonates, 241 neonates visited directly our outpatient clinic at Hamamatsu University Hospital. The reevaluation conducted at our clinic included a physical examination, detailed family history, measurement of serum electrolytes, disc 17-OHP, plasma 17-OHP and 21-DOF values, and PT and PTL in a single urine specimen. Consequently, 3 neonates appeared to be patients with CAH. Two of them were the salt-losing type and the other was the simple virilizing type. The rest of the candidates who received reevaluation were finally decided to be healthy neonates, indicating false positivity by mass screening. Compared to the candidates who showed false positivity in the mass screening, the CAH patients had an apparently high urinary PT and PTL titer of ten or one hundred fold. Additionally, despite corticosteroid treatment in one case, significantly elevated levels of PT and PTL were detected. To assay PTL was a more reliable parameter for the detection of CAH and for following up the candidates because PTL was not detectable in 63.3% of the false positive cases, suggesting that PTL was less likely to indicate false positive cases. PTL was detected at more than 0.01 microgram/ml urine in 19.4% of false positive cases, however, no case showed further elevation of PTL during the follow up period. In all false positive cases, PTL was not detectable until the age of six months. Despite problems to be resolved, determination of urinary PTL titer is valuable for the detection of CAH patients. In addition, urinary PTL could be a good parameter for the further follow up of false positive cases in neonatal mass screening.

Topics: 17-alpha-Hydroxyprogesterone; Adrenal Hyperplasia, Congenital; Chromatography, Gas; Cortodoxone; Female; Follow-Up Studies; Humans; Hydroxyprogesterones; Male; Mass Screening; Pregnancy; Pregnanetriol; Steroid Hydroxylases

Twenty five patients (10 males and 15 females) aged 0-23 yr with congenital adrenal hyperplasis due to 11 beta-hydroxylase deficiency were studied. They were divided into 13 classic (group A), and 12 mild (group B) patients. The patients of group A were diagnosed at a younger age and had more severe clinical symptoms (ambiguous genitalia in girls, pseudoprecocious puberty in boys). Two had neonatal salt wasting before treatment, and one gynecomastia. Seven had moderate to severe hypertension. Their mean 3 alpha,17,21-trihydroxy-5 beta-pregnan-20-one (THS) and 3 alpha, 21-dihydroxy-5 beta-pregnane-11,20-dione (THDOC) excretion was 14.2 +/- 4.1 and 7.2 +/- 4.2 mg/m2 . day, respectively. The patients of group B had mostly late onset of symptoms (hirsutism, amenorrhea in girls, pseudoprecocious puberty in boys, tall stature, and advanced bone age in both sexes). One boy had bilateral cryptorchidism. Four had moderate hypertension. In seven patients, THS (5.3 +/- 2.3 mg/m2 . day) and THDOC (3.9 +/- 0.5 mg/m2 . day) responded to ACTH. In five, only THS (4.3 +/- 1.1 mg/m2 . day) responded, but THDOC remained undetectable. It is concluded that the clinical and biochemical expression of 11 beta-hydroxylase deficiency is variable, that hypertension in not directly related to deoxycorticosterone, and that, regardless of the intensity of the defect, there are patients in whom the 11 beta-hydroxylation of 17 alpha-hydroxylated steroids only is impaired, and others in whom both the conversion of 17,20-dihydroxy-4-pregnene-3,20-dione and deoxycorticosterone are reduced.

Topics: 17-Ketosteroids; Adolescent; Adrenal Hyperplasia, Congenital; Adrenocorticotropic Hormone; Adult; Child; Child, Preschool; Cortodoxone; Female; Humans; Hydrocortisone; Infant, Newborn; Male; Pregnanediones; Pregnanetriol; Steroid Hydroxylases