Biomedical subjects
Publications and source records attributed to M I New.
This article surveys the congenital and late-onset forms of the common steroidogenic enzyme defects of the adrenal cortex--steroid 21-hydroxylase, steroid 11 beta-hydroxylase, and 3 beta-hydroxysteroid dehydrogenase deficiencies--in connection with the occurrence of polycystic ovarian disease.
The locus for 21-hydroxylase (CA21HB) has been mapped to the interval between the HLA-B and HLA-DR loci on chromosome 6. Several methods of estimating genetic distance were used to determine whether CA21HB is closer to HLA-B or HLA-DR based on data collected on 157 families ascertained through a proband with the classical form of 21-hydroxylase deficiency (CA12Hd). The results were inconclusive but serve to highlight the limitations of present methods of estimating genetic distance when recombination frequencies are of the order of .005.
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The segregation of classical and nonclassical 21-hydroxylase deficiency (21-OHD) and its linkage to HLA-B was investigated in 220 families. First, the surprisingly high frequency of the nonclassical 21-OHD gene estimated elsewhere was confirmed using a different methodology which avoided particular assumptions concerning the classification of an individual's genotype. In the present study the gene frequency was found to be .103 +/- .020 in an ethnically pooled sample and was as high as .223 +/- .062 among Ashkenazi Jews. Second, the segregation analysis of families ascertained through a nonclassical 21-OHD proband and those ascertained through a classical 21-OHD proband showed essentially identical results. A partial recessive model with no recombination between 21-OHD and HLA-B fitted the data better than did a complete recessive model with approximately 0.5% recombination between 21-OHD and HLA-B. The support for the partial over the complete recessive model depended on the assumed ascertainment probability, an unknown parameter in these data. Four families provided most of the evidence against the complete recessive model. All these included an unaffected sib who shared both HLA-B specificities in common with the affected proband. Possible explanations for the condition in these families include recombination, gene conversion, mutation in one of the parental gametes, or technical errors.
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We studied an 18-year-old woman with progressive hirsutism, secondary amenorrhea, and polycystic ovarian disease. Excess androstenedione was secreted by the ovaries, most likely because of a genetic deficiency of ovarian 17-ketosteroid reductase, the enzyme that converts androstenedione to testosterone. Markedly elevated basal plasma levels of androstenedione, estrone, and testosterone were regulated by gonadotropin but not by ACTH. The rate of androstenedione production in the patient's blood at base line and after administration of dexamethasone was very high (10.0 to 11.6 mg per day; value in control women with hirsutism, less than 4.1 mg per day), whereas her blood production of testosterone was 0.64 to 0.7 mg per day, similar to or higher than that in control women with hirsutism. The fractional blood conversion ratio of androstenedione to testosterone was normal (5.6 percent). Thus, 88 to 93 percent of the testosterone in the blood was derived from the peripheral conversion of androstenedione, and very little testosterone was secreted by the ovaries. These in vivo biochemical data suggest that the patient had a deficiency of ovarian 17-ketosteroid reductase activity but normal pubertal activity. The patient's two younger sisters with peripubertal symptoms of androgen excess also had elevated serum levels of androstenedione. We propose that the increased secretion of androstenedione in the three siblings in this family was probably due to a genetic deficiency of ovarian 17-ketosteroid reductase.
The aim of this study was to determine if a change in protein/carbohydrate ratio influences plasma steroid hormone concentrations. There is little information about the effects of specific dietary components on steroid hormone metabolism in humans. Testosterone concentrations in seven normal men were consistently higher after ten days on a high carbohydrate diet (468 +/- 34 ng/dl, mean +/- S.E.) than during a high protein diet (371 +/- 23 ng/dl, p less than 0.05) and were accompanied by parallel changes in sex hormone binding globulin (32.5 +/- 2.8 nmol/l vs. 23.4 +/- 1.6 nmol/l respectively, p less than 0.01). By contrast, cortisol concentrations were consistently lower during the high carbohydrate diet than during the high protein diet (7.74 +/- 0.71 micrograms/dl vs. 10.6 +/- 0.4 micrograms/dl respectively, p less than 0.05), and there were parallel changes in corticosteroid binding globulin concentrations (635 +/- 60 nmol/l vs. 754 +/- 31 nmol/l respectively, p less than 0.05). The diets were equal in total calories and fat. These consistent and reciprocal changes suggest that the ratio of protein to carbohydrate in the human diet is an important regulatory factor for steroid hormone plasma levels and for liver-derived hormone binding proteins.
A 16-year-old female patient with recurrent Cushing's disease (CD) underwent successful treatment with pituitary irradiation. Within one year after radiotherapy, cortisol levels had returned to normal (but with continued absence of diurnal variation), growth velocity improved, and puberty ensued. Five years after treatment, the patient developed clinical and biochemical evidence of recurrent CD. The high baseline evening corticotropin level (9 pmol/L [40 pg/mL]) was unresponsive (maximum level, 10 pmol/L [46 pg/mL]) to stimulation with ovine corticotropin-releasing hormone (CRF). In patients with CD treated with radiotherapy, the corticotropin response to CRF stimulation may not be reliably compared with that of normal control values. After pituitary adenomectomy, the corticotropin concentration was still unresponsive to CRF. We suggest that the pituitary tumor was secondary to abnormal hypothalamic CRF regulation not corrected by pituitary irradiation; therefore, CD may recur despite pituitary irradiation.
Measurement of plasma renin activity (PRA) and aldosterone with a knowledge of dietary sodium balance is critical to the diagnostic evaluation of childhood hypertension. Disturbances of steroid production, regulation, metabolism and sensitivity have been implicated in the pathogenesis of low-renin hypertension in childhood. Prompt initiation of treatment is essential because the hemodynamic changes caused by long-standing hypertension may become irreversible. The clinical features and hormonal findings of the most important adrenocortical disorders associated with low-renin hypertension in childhood are summarized.
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).
This article reviews the processes of normal adrenal function, including the three main classes of hormones. From there it describes reduced or absent enzyme activity in the stages of steroid synthesis, and proceeds to outline the enzyme deficiency responsible for the clinical effects that manifest themselves in characteristic metabolic disturbances.
Nonclassic adrenal hyperplasia due to 21-hydroxylase deficiency (21-OHD) is an autosomal recessive disorder distinguished from classic 21-OHD by clinical and hormonal criteria. It is most often described as a disorder of adrenal steroidogenesis with onset of virilization in late childhood, peripubertally or postpubertally. An overview of adrenal steroidogenesis is presented elsewhere in this publication. It is the aim of this article to focus on the clinical and hormonal manifestations of the disorder, with discussion of the current methods of diagnosis and management. Recent advances in classic and molecular genetics will follow.
We report two female siblings (ages 4 and 9 years) and one 8-year-old male with the syndrome of apparent mineralocorticoid excess (AME) presenting with low renin hypertension and hypoaldosteronism. The deficiency of 11 beta-hydroxysteroid dehydrogenase results in a defect of the peripheral metabolism of cortisol (F) to cortisone (E). As a result, the serum cortisol half-life (T1/2) is prolonged, ACTH is suppressed, and serum F is normal. The specific diagnosis of the disorder was made by the decreased ratio of the urinary metabolites of E (tetrahydrocortisone, THE) and F (tetrahydrocortisol, THF). Continuous i.v. hydrocortisone administration caused an increase in blood pressure and decrease in serum potassium demonstrating the abnormal mineralocorticoid activity of cortisol in these patients. Addition of spironolactone resulted in a decrease in blood pressure, rise in serum potassium and a gradual increase in plasma renin activity. These studies suggest that an abnormality in cortisol action or metabolism results in cortisol behaving as a potent mineralocorticoid and causing the syndrome of AME.
In nonclassical steroid 21-hydroxylase deficiency, the genotype may be represented as a homozygous mild (nonclassical) form of the 21-hydroxylase defect or as a compound heterozygote, with one severe (classical) and one mild (nonclassical) 21-hydroxylase deficiency allele. We examined hormone levels in patients with nonclassical 21-hydroxylase deficiency in whom pedigree analysis and/or HLA linkage disequilibrium allowed unequivocal identification of the respective haplotypes as either classical or nonclassical. The results indicated that compound heterozygotes (21-OH defsevere/21-OH defmild) have an ACTH-stimulated 17-hydroxyprogesterone (17-OHP) response significantly greater than that of mild homozygotes (21-OH defmild/21-OH defmild): at 60 min, 8,131 +/- 4,205 (+/-SD) (n = 17) vs. 4,468 +/- 2,123 ng/dl (n = 31) for the respective groups (P less than or equal to 0.01); at 360 min, 11,067 +/- 5,582 (n = 17) vs. 5746 +/- 1565 (n = 8, P less than or equal to 0.01). Since serum cortisol levels were the same in both groups, the ratio of 17-OHP to cortisol was higher in the former group. Sixty minute ACTH-stimulated serum delta 4-androstenedione levels also were significantly higher in compound heterozygotes than in mild homozygotes. Serum dehydroepiandrosterone and its sulfate were not significantly different between the two groups. Notably, compound heterozygotes were no more likely to have signs of androgen excess than were homozygotes for the mild gene defect. Stimulated levels of serum 17-OHP, 17-OHP/cortisol, delta 4-androstenedione and dehydroepiandrosterone and its sulfate did not differ significantly between heterozygotes for the classical (21-OH defsevere/21-OHnormal) and nonclassical (21-OH defmild/21-OHnormal) 21-hydroxylase deficiency alleles. Thus, the presence of a single normal 21-hydroxylase allele is sufficient to obscure the difference between a severe and a mild 21-hydroxylase deficiency allele on the opposite haplotype. We conclude that the compound heterozygous patients as a group have a significantly higher response of 21-hydroxylase precursors to ACTH stimulation than do patients with the homozygous mild 21-hydroxylase deficiency state.
Twenty three patients (19 girls, 4 boys) presented with typical features of premature pubarche between the ages of 2-7 yr. The patients were studied for the presence of an adrenal steroidogenic defect by ACTH stimulation testing (Cortrosyn, 0.25 mg iv bolus dose). Based on published nomogram standards for serum 17-hydroxyprogesterone (17-OHP), seven patients (30%) were diagnosed as having the nonclassical symptomatic form of 21-hydroxylase deficiency [mean post ACTH 4244 +/- 1113 (SD) ng/dl]. Three patients (13%) were diagnosed to have a mild form of 3 beta-hydroxysteroid dehydrogenase deficiency based upon the response of serum delta 5-17-hydroxypregnenolone (delta 5-17P) and dehydroepiandrosterone, and the ratio of delta 5-17P/17-OHP to ACTH stimulation (delta 5-17P: 1543 +/- 272 ng/dl vs. Tanner stage I control subjects, 350 +/- 197 ng/dl; dehydroepiandrosterone: 675 +/- 190 ng/dl vs. Tanner stage I control subjects, 82 +/- 79 ng/dl; delta 5-17P/17-OHP: 8.1 +/- 2.6 vs. Tanner stage I control subjects, 1.4 +/- 0.6). No enzyme defect could be identified in the remaining 13 patients (57%). Eleven patients with premature pubarche, with and without an adrenal enzymatic defect, underwent dexamethasone suppression. In all patients the measured steroid levels were suppressed. Thus, the dexamethasone suppression test alone did not distinguish the pathogenesis of premature pubarche. In conclusion, premature pubarche is more commonly due to a partial enzyme defect in adrenal steroidogenesis than has been previously recognized.
A screening test for nonclassical 21-hydroxylase deficiency (NC 21-OHD) has been established based on early morning salivary 17-hydroxyprogesterone (17-OHP) measurements. Saliva and serum samples were collected simultaneously between 0700 and 1100 h from 57 normal subjects (37 women and 20 men) and from 15 untreated patients (6 women and 9 men) with NC 21-OHD. The salivary (mean +/- SD, 524 +/- 508 pg/mL) and serum (10,548 +/- 5,998 pg/mL) 17-OHP concentrations in all 15 patients were unequivocally higher than the levels in normal subjects (saliva, 51 +/- 24 pg/mL; serum, 1,564 +/- 787 pg/mL). Salivary 17-OHP levels in patients with NC 21-OHD were significantly higher at 0700-0900 h (828 +/- 653 pg/mL) than at 0900-1100 h (314 +/- 227 pg/mL), while no such change was found in normal subjects. The salivary 17-OHP concentration was 1.3-6.9% of its serum concentration, and there was an excellent correlation (r = 0.93) between salivary and serum concentration in both normal subjects and patients with NC 21-OHD. In conclusion, early morning salivary 17-OHP measurement is an excellent screening test for the diagnosis of NC 21-OHD, since it accurately reflects serum 17-OHP levels, and sample collection is easy and noninvasive. We propose that salivary 17-OHP determination be used in population screening programs for NC 21-OHD to establish the true frequency of this disease.
We determined the adrenal steroid responses to metyrapone, ACTH, and CRH in 12 ACTH-intact and 5 ACTH-deficient hypopituitary children to determine the mechanisms that control adrenal androgen secretion. Serum adrenal androgen concentrations [dehydroepiandrosterone (DHEA) and delta 4-androstenedione (delta 4-A)] rose in response to oral administration of metyrapone (450 mg/m2 X dose, every h for 7 doses) in ACTH-intact hypopituitary children with multiple or isolated pituitary hormone deficiencies [mean postmaryrapone level: DHEA, 225 ng/dL (range, 27-566); delta 4-A, 313 ng/dL (range, 105-651)], except in 2 young children in whom DHEA did not rise. These adrenal androgens did not rise in all ACTH-deficient hypopituitary children [mean postmetyrapone level: DHEA, 11.0 ng/dL (range, 3-16); delta 4-A, 6.2 ng/dL (range, 3-10)]. The increases in both serum cortisol and adrenal androgens, including DHEA sulfate, in response to short term ACTH infusion (40 U in 6 h) in ACTH-intact hypopituitary children were normal or above normal, while these steroid responses were significantly (P less than 0.05-0.01) lower in ACTH-deficient hypopituitary children compared to normal values. However, prolonged administration of ACTH (40 U/day, or im) for 6 days to 2 ACTH-deficient hypopituitary children resulted in normal DHEA responses to the 6-h ACTH stimulation test (DHEA levels after the first test, 14 and 30 ng/dL, after priming, 80 and 50 ng/dL). Furthermore, CRH administration to 4 ACTH-deficient patients caused a rise in serum DHEA and cortisol in patients with a normal ACTH response, while those with a poor ACTH response had a lesser rise in DHEA and cortisol. These data suggest that ACTH is the major tropic hormone for adrenal androgen secretion.