Hormonal and clinical responses to prednisone treatment in adolescents with congenital adrenal hyperplasia

The effects of prednisone therapy and the withdrawal of prednisone for 3 days on hormonal relationships was investigated in 6 adolescent patients, age 10--19 years with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. Prednisone continuously suppressed adrenal release of 17 alpha-hydroxyprogesterone (17-OHP) in 4 patients and adequately controlled 17-oxosteroid (17-OS) excretion in 5. Serum dehydroepiandrosterone sulfate (DS) concentrations were not elevated during or 3 days after withdrawal of medication. Growth hormone (GH) secretion was not suppressed by prednisone. Withdrawal of treatment was associated with a decrease in the follicle-stimulating hormone (FSH) to luteinizing hormone (LH) ratio in 5 patients and a rise in serum testosterone in 4. The clinical courses of these patients emphasize the difficulty in achieving optimum control.     

Abnormalities of various serum enzyme activities in patients with congenital adrenal hyperplasia

Recently, attentions are being aroused as to the enzymatic network abnormalities lying behind congenital enzyme deficiency syndromes. We investigated abnormalities in activities of various hydrolytic enzymes in serum of patients with congenital adrenal hyperplasia (CAH, 21-hydroxylase deficiency). Several enzyme activities including trypsin-like enzyme, cathepsin C and esterase were significantly decreased in patients' serum. Especially the esterase activity in patients' serum was reduced to one third of controls and this may have some relations to the abnormal steroid metabolism of these patients. A multivariate analysis showed unexpectedly extensive abnormalities in enzyme interrelationships. These results suggest that wide variety of abnormal metabolism may be related to an apparent enzyme deficiency.     

Mineralocorticoids in congenital adrenal hyperplasia

While hypertension is observed in only two of the three major subtypes of congenital adrenal hyperplasia (CAH), 11β- and 17-hydroxylase deficiencies, deoxycorticosterone ( (DOC) production is increased in all. The elevated zona fasciculata (ZF) DOC produces mineralocorticoid hypertension with suppressed renin and reduced potassium concentrations. The DOC levels in 21-hydroxylase deficiency are in part produced by renin stimulation of the Zona glomerulosa (ZG) along with aldosterone. Assessment of the mineralocorticoid hormones of the ZF and ZF (17-deoxy steroids) provides additional unique characteristics of each subtype. Dissociation of DOC from cortisol is not unique to CAH. This dissociation is seen in other disorders and contrived conditions. There is a strong suggestion of a non-ACTH regulator of 17-deoxy steroids (DOC) that may contribute significantly to DOC production in general and effect DOC levels in CAH.     

Plasma levels of androgens and 17 alpha-OH-progesterone as an index of the adequacy of treatment in congenital adrenal hyperplasia

Plasma levels of dehydroepiandrosterone-sulfate (DHEA-S), dehydroepiandrosterone (DHEA), delta 4-androstenedione (delta 4), testosterone and 17 alpha-OH-progesterone (17-OH-P) were studied in 58 samples collected in 18 patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency, during long-term ambulatory treatment with hydrocortisone. At each visit the patients were classified as being either in good control (GC) or in poor control (PC), based on well-defined clinical, auxological and biochemical criteria. The results were analyzed in relation to the degree of control and to chronological age (CA), bone age (BA), body surface (BS) and pubertal development. The most clear distinction between the children with GC and those with PC is found for DHEA-S (p less than 0.001 for BA). The majority of the DHEA-S values in the children with GC are closely grouped and significantly below the normal limits for CA, BA, BS and pubertal stage (p less than 0.001). In contrast, the PC children have wide-spread values, most of them being within or above the normal limits. The difference between GC and PC is also significant for testosterone (p less than 0.01) and delta 4 (p less than 0.05), but not for DHEA. Of the five steroids studied, DHEA-S is the most specific, whereas testosterone is the most sensitive and especially useful in girls and in prepubertal boys. delta 4 and 17-OH-P are almost as sensitive as DHEA-S, but they are less specific. DHEA is the less valid criterium.     

Pitfalls in the etiological diagnosis of congenital adrenal hyperplasia in the early neonatal period

The plasma levels of 8 steroid hormones were studied longitudinally in 20 newborns affected with either 21-hydroxylase (21-OH), 11-hydroxylase (11-OH) or 3 beta-hydroxysteroid deshydrogenase (3 beta-ol) deficiencies during the first month of life. Comparison was also made between the patterns observed according to age at first examination (n = 13 before 8 days of age) and the type of the enzymatic block. The most striking findings were the variability in hormone levels and/or evolution with age and the difficulties in making a definite positive or etiological diagnosis at first examination. In some newborns with untreated 21-OH deficiency, 17 alpha-hydroxyprogesterone levels may start off within the normal range or not so far above it. Also, levels of unconjugated dehydroepiandrosterone and other delta 5 steroids may be so high during the first week of life in all 3 forms that an erroneous diagnosis of 3 beta-ol deficiency could easily be considered. In several cases the etiological diagnosis was only ascertained by multiple steroid determination and/or dynamic tests. These discrepancies were not found in infants studied later on in life. It thus appears that a peculiar steroid pattern is observed in the immediate postnatal period in babies with various enzyme defects, which might be related to the morphological changes occurring in the adrenal cortex at this age.     

Basic and clinical aspects of congenital adrenal hyperplasia

Defective steroid 21-hydroxylation is the most common of the biochemical defects causing hyperplasia of the adrenal cortex. The genetic mode of transmission of all enzyme abnormalities seen in cortisol biosynthesis is autosomal recessive. Steroid 21-hydroxylase deficiency has three currently accepted forms: the simple virilizing and salt-wasting variants of the classical deficiency, and the nonclassical (attenuated) form, which shows a wide clinical range of effects and whose characterization emerged from co-ordinated hormonal testing and family studies. More recent molecular genetic studies have started to identify specific mutations altering 21-hydroxylase activity. Defects in the other enzymes occur more rarely and are less well known, although initial work with abnormal 11 beta-hydroxylase and 3 beta-hydroxylase indicates that allelic gene defects may be correlated with different clinical phenotypes seen for these disorders also. The gene for the enzyme steroid 21-hydroxylase, a cytochrome P-450, is situated within the major histocompatibility complex on the p arm of human chromosome 6, proximal to the HLA-B antigen locus. Linkage disequilibria between certain B and DR alleles and classical and nonclassical 21-hydroxylase deficiency permit the use of HLA genotyping in conjunction with hormonal evaluation for diagnosis of this disorder and for identification of carrier haplotypes in population studies. Test programs have shown the feasibility of neonatal screening for 21-hydroxylase deficiency by blood-spot hormonal assay for elevated 17-hydroxyprogesterone. Prenatal detection of disease currently depends on HLA serotyping of cultured aminocytes jointly with measurement of amniotic 17-hydroxyprogesterone (13-18 week gestation); molecular genetic techniques with more specific nuclear probes will improve the specificity of this test and will in addition permit even earlier definitive fetal genotyping by chorionic villus biopsy (6-10 week gestation).     

Prenatal diagnosis and treatment of congenital adrenal hyperplasia

Congenital adrenal hyperplasia is a group of inherited disorders caused by an enzyme deficiency in steroid biosynthesis. The most common form of congenital adrenal hyperplasia is 21-hydroxylase deficiency, which in its severe form can cause genital ambiguity in females. Steroid 21-hydroxylase deficiency can be diagnosed in utero through molecular genetic analysis of fetal DNA. Prenatal treatment successfully reduces genital ambiguity, and the subsequent problems of sex misassignment and gender confusion. Data from current studies show that prenatal diagnosis and treatment are safe for the mother and the fetus. The evidence also suggests that it is safe over the long term, but all subjects exposed to dexamethasone treatment during embryonic and fetal life should have their physical, cognitive and emotional developments recorded.     

Amniotic fluid steroid levels and fetal adrenal weight in congenital adrenal hyperplasia

The concentration of 17-OH-progesterone was determined in second trimester amniotic fluid collected from 58 pregnancies at risk for fetal 21-hydroxylase deficiency. The prediction was incorrect in 1 male nonsalt-loser who had an increased plasma 17-OH-progesterone concentration at 3 months of age. All 11 infants predicted to be affected were salt-losers. The adrenals from 2 affected fetuses available for study were significantly enlarged in comparison with adrenal size in 84 normal fetuses from 15 to 26 weeks' gestation. Amniotic fluid steroid analysis reliably predicts the fetus with 21-hydroxylase deficiency most at risk in early infancy. There is no evidence from this study to indicate that ACTH is not the main trophic factor for fetal adrenal growth and steroidogenesis.     

Body positions and movement patterns in female patients with congenital adrenal hyperplasia

Female patients with congenital adrenal hyperplasia (CAH; N = 33; 11-41 years), simple-virilizing (SV) patients (N = 19), salt-wasting (SW) patients (N = 13), and sister controls (N = 14) were compared with regard to their body positions and movement patterns. Data collection comprised both self assessments and mothers' assessments using 20 sex-dimorphic items with corresponding "more masculine" and "more feminine" versions for each variable, represented in photographs (forced-choice approach). Primarily based on mothers' assessments, single-item results suggested slightly more masculine positions and patterns for female CAH patients compared to sisters, for SW patients more distinct than for SV patients. Results from an 11-item scale ("motor behavior", alpha = 0.59) revealed differences between SW (more masculine) and SV patients for self assessments (P, one-tailed, < 0.09); sisters were in an intermediate position closer to the SV patients. According to mothers' assessments, the CAH patient group as a whole differed (more masculine) from sisters (P < 0.06); this finding was mainly accounted for by the SW group (P < 0.04). Complex analyses on the relationship of motor behavior and intervening variables (e.g., postnatal androgenization, onset of puberty, menarche, height, weight, sexual orientation) revealed very few significant results. Findings rather suggested organizational hormonal effects on body positions and movements prenatally; they are in line with main results from the interview section of the Hamburg CAH study (e.g., "Gender-related behavior"). An approach of this kind seems to be justified for investigating motor behavior in future psychoendocrine studies.     

Evaluation of neonatal screening for congenital adrenal hyperplasia

Neonatal screening for congenital hypothyroidism has been effective in early detection and treatment of the condition. The position with respect to neonatal screening for congenital adrenal hyperplasia has been debated for many years. Some countries have performed congenital adrenal hyperplasia screening for many years, others have conducted pilot studies that were then not adopted. This article endeavours to summarize the complex issues behind decisions whether to screen or not and summarizes the findings of neonatal congenital adrenal hyperplasia screening programmes.     

Precursor-to-product ratios reflect biochemical phenotype in congenital adrenal hyperplasia

Precursor-to-product ratios in steroid hormone metabolism may accurately reflect enzymatic activity and production of metabolites relative to their disappearance. The purpose of this study was to explore the use of direct precursor-to-product steroid ratios to discriminate between infants with congenital adrenal hyperplasia (CAH) due to 21-α-hydroxylase deficiency and infants with no disorder, thus characterizing the biochemical phenotype in CAH. Deidentified dried blood spot samples from confirmed CAH cases identified by newborn screen (CAH-positive, N = 8) and from cases with no disorder (CAH-negative, N = 10) were obtained from the California State Newborn Screening Program. Samples (~6.25 mm circular spots) underwent methanol and water extraction (9:1 ratio). Deuterated steroids served as isotope internal standards. 17-α-hydroxyprogesterone (17-OHP), 11-deoxycortisol (S), androstenedione (A4) and cortisol (F) concentrations were determined by liquid chromatography–tandem mass spectrometry (LC–MS/MS), and the 17-OHP/S, 17-OHP/A4, and S/F ratios were calculated. The mean 17-OHP and A4 concentrations in samples from CAH cases were significantly increased when compared to cases with no disorder (p = 0.003 for both). 17-OHP/S and 17-OHP/A4 ratios were also significantly elevated in CAH cases (p = 0.007 and p < 0.001, respectively). In contrast, S and F concentrations and the S/F ratio were similar between the two groups. In CAH, the elevated 17-OHP/S ratio is a biomarker of diminished 21-α-hydroxylase activity, and the elevated 17-OHP/A4 ratio is a biomarker of adrenal androgen excess via increased 17,20-lyase activity. The similar S/F ratio indicates that the rate of production via 11-β-hydroxylase and disappearance of F is maintained in CAH.     

Masculinized finger length patterns in human males and females with congenital adrenal hyperplasia

The ratio of the length of the second digit (2D) to the length of the fourth digit (4D) is greater in women than in men. Since androgens are involved in most somatic sex differences and since the sexual dimorphism in 2D:4D is stable from 2 years of age in humans, it was hypothesized that finger length pattern development might be affected by early androgen exposure. Human females with congenital adrenal hyperplasia (CAH) are exposed prenatally to higher than normal levels of adrenal androgens, providing an opportunity to test the effects of early androgen exposure on digit ratios. The 2D:4D was calculated for females with CAH, females without CAH, males with CAH, and males without CAH. Females with CAH had a significantly smaller 2D:4D on the right hand than did females without CAH. Males with CAH had a significantly smaller 2D:4D on the left hand than did males without CAH. A subset of six males with CAH had a significantly smaller 2D:4D on both hands compared with their male relatives without CAH. These results are consistent with the idea that prenatal androgen exposure reduces the 2D:4D and plays a role in the establishment of the sex difference in human finger length patterns. Finger lengths may therefore offer a retrospective marker of perinatal androgen exposure in humans.     

Increased salt appetite in patients with congenital adrenal hyperplasia 21-hydroxylase deficiency

Salt appetite was investigated in 14 patients with congenital adrenal hyperplasia of the salt-wasting form (SW group), 12 patients with the simple virilized form who are not salt losing, and 18 healthy siblings. Salt appetite was evaluated by questionnaire, preference tests, and dietary analyses. The findings showed that SW who were not therapeutically normalized showed increased salt appetite but no change in sweet preference. Their salt appetite correlated with symptoms of salt wasting, namely, plasma renin activity, plasma K(+), and urine Na(+) and (inversely) with blood pressure. Sensitivity to the taste of NaCl was not altered. Factor analyses of a larger group confirmed the distinction between salt appetite and sweet preference, but intake of dietary Na(+) and sweet carbohydrates and intake of salty and sweet snacks did not reflect distinct salt or sweet preferences. We confirm that putative perinatal dehydration, due to maternal nausea and vomiting during pregnancy, childhood vomiting, and diarrhea with occasional saline infusion, was related to increased salt appetite in adolescence. The findings suggest that salt appetite in humans is determined by interdependent, innate, physiological, and acquired attributes. Salt appetite in SW patients is an adaptive response mediated by the renin-angiotensin system, an innate predisposition to acquire salt preference (in anticipation of both sodium loss and its consequence), and imprinting by perinatal hyponatremic occurrences. Our findings contribute to understanding human salt intake, provide insight into the motivation for salt in patients with congenital adrenal hyperplasia 21-OH deficiency, and may point the way to improvements in therapeutic compliance in these patients.