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Biomedical subjects

S Ulick

Publications and source records attributed to S Ulick.

At least 37 records · Page 2Linked to original sources
PubMed1991

Synthesis of a deuterium-labeled cortisol for the study of its rate of 11 beta-hydroxy dehydrogenation in man.

11 beta-Hydroxy dehydrogenation of cortisol to cortisone is specifically impaired in the syndrome of apparent mineralocorticoid excess. This defect bears on the pathogenesis of the disorder by unmasking the potential mineralocorticoid agonism of unmetabolized cortisol at or near mineralocorticoid target tissues. A specific index of this defect is provided by measurement of the formation of tritiated water following the administration of [3H]11 alpha-cortisol. We have explored the use of a non-radioactive tracer to follow this unidirectional dehydrogenation reaction but because of the relatively lower sensitivity of measurement of 2H2O compared to 3H2O in body fluids, use of the corresponding [2H]11 alpha-cortisol was not feasible. We have devised instead a method incorporating additional deuterium atoms into cortisol to measure unidirectional 11 beta-hydroxy dehydrogenation not by the formation of labeled water but by the determination of the dehydrogenated cortisol product from its residual deuterium content. Cortisol-d4 metabolized to cortisone-d3 is conveniently measured by the techniques of organic mass spectrometry. The synthesis of cortisol-9 alpha, 11 alpha, 12 alpha 12 beta-d4 and the validation of its isotopic distribution by mass spectrometry and nuclear magnetic resonance is described.

Cortisone↗
PubMed1991

Measurement of 4 urinary C-18 oxygenated corticosteroids by stable isotope dilution mass fragmentography.

The cortisol C-18 oxidation pathway leading to the production of 18-hydroxy- and 18-oxocortisol is expressed in adenomatous primary aldosteronism and glucocorticoid remediable aldosteronism. In order to better define the significance of the pathway and its usefulness in differential diagnosis, we have developed a stable isotope dilution mass fragmentographic method for the determination of the tetrahydro metabolites of aldosterone, 18-hydroxycorticosterone and 18-oxocortisol and of unmetabolized 18-hydroxycortisol in urine. Stereochemically correct tetrahydro steroids containing 3 deuterium atoms were synthesized from the available 3-keto-4-pregnenes in 2 steps and 1,2-deuterium-labeled 18-hydroxycortisol was prepared by selective deuteration of the 1,2-double bond of a dienone precursor. Simultaneous measurement of the 4 steroids permitted a comparison of the abnormal products of the C-18 oxidation of cortisol with the normal C-18 oxidation products of corticosterone, 18-hydroxycorticosterone and aldosterone. Application of the method to the definition of the normal range is described.

Adrenal Cortex Hormones↗
PubMed1991

Two uncommon causes of mineralocorticoid excess. Syndrome of apparent mineralocorticoid excess and glucocorticoid-remediable aldosteronism.

Glucocorticoid-remediable aldosteronism is an inherited form of mineralocorticoid excess associated with moderate overproduction of aldosterone, in which biochemical and clinical remission is dramatically induced by small amounts of glucocorticoids. The disorder is associated with characteristic overproduction of 18-hydroxycortisol and 18-oxocortisol, which must now be regarded as an essential diagnostic feature and also as an aid in the detection of the disorder in the face of partial clinical expression.

Glucocorticoids↗
PubMed1990

Pathogenesis of the type 2 variant of the syndrome of apparent mineralocorticoid excess.

The syndrome of apparent mineralocorticoid excess, which is not a primary disorder of the adrenal cortex, describes the association of an unexplained hypermineralocorticoid state with a decreased rate of peripheral 11 beta-hydroxydehydrogenation of cortisol to cortisone. Studies in this syndrome have led to the hypothesis that peripheral cortisol inactivation is the normal mechanism permitting specific mineralocorticoid recognition. This view reconciled developing evidence that the mineralocorticoid receptor itself could not distinguish between mineralocorticoids and glucocorticoids. The syndrome occurs in two forms. In both forms there is decreased turnover of a normal level of plasma cortisol, consistent with the view that delayed removal of the glucocorticoid from strategic receptor sites unmasks its potential mineralocorticoid agonism. In the type 1 variant, impaired 11 beta-hydroxydehydrogenation is reflected by an elevated cortisol/cortisone metabolite ratio. In three patients with the type 2 variant, this ratio was normal, suggesting that the rate of 11 beta-hydroxydehydrogenation was unimpaired. The hypertension and hypokalemic alkalosis of both forms are improved by spironolactone, but patients with the type 2 variant have responded somewhat better to the suppression of cortisol by dexamethasone.

Adult↗
PubMed1990

Defective fasciculata zone function as the mechanism of glucocorticoid-remediable aldosteronism.

Glucocorticoid-remediable aldosteronism is characterized by unusual sensitivity of aldosterone secretion to ACTH. Suppressibility by glucocorticoid and continued stimulability by exogenous ACTH has provided the basis for diagnosis and treatment of the disorder. A qualitative biochemical abnormality consisting of marked overproduction of the products of the cortisol C-18 oxidation pathway, 18-hydroxycortisol and 18-oxocortisol, has been examined in 10 patients with the disorder and compared to the normal C-18 oxidation products of corticosterone, aldosterone, and 18-hydroxycorticosterone. The technique, based on stable isotope dilution mass fragmentography, measured the tetrahydro urinary metabolites of aldosterone, 18-hydroxycorticosterone, and 18-oxocortisol and unmetabolized 18-hydroxycortisol. All 4 C-18 oxygenated corticosteroids were markedly elevated in the untreated state and showed rapid parallel suppression with low doses of glucocorticoid. The proportional changes in C-18 oxygenated cortisols together with aldosterone and 18-hydroxycorticosterone suggested the mechanism of a common catalytic site of a cytochrome P450 methyl oxidase serving both cortisol and corticosterone substrates. The ACTH-dependent secretion of the C-18 oxidation products of both corticosterone and cortisol in the disorder is attributed to the acquisition of methyl oxidase activity by the fasciculata zone, where there are abundant pools of these precursors.

Adolescent↗
PubMed1989

Anomalous oxidative cleavage of the side chain of 18-oxocortisol and its tetrahydro metabolite.

The course of oxidative side chain cleavage of two recently isolated 17 alpha-hydroxy C-18 oxygenated naturally-occurring corticosteroids differed in that 18-hydroxycortisol yielded a 17-ketosteroid (Chu M. D., and Ulick S. (1982) J. biol. Chem. 257, 2218-2224) whereas 18-oxocortisol yielded a gamma-etiolactone (Ulick S., Chu M. D. and Land M. (1983) J. biol. Chem. 258, 5498-5502). In an analytic application of the periodic acid oxidative cleavage reaction to 18-oxocortisol, the finding of a second product of the reaction prompted a reinvestigation of its course. Both the delta 4,3-ketone secreted form of the steroid and its tetrahydro urinary metabolite were cleaved predominantly to 17-ketosteroids along with smaller amounts of gamma-etiolactones, whose proof of structure is herein reported. This anomalous course of oxidative cleavage was considered to reflect an equilibrium between C-20 ketone and cyclic-hemiketal forms in which the glycerol-type side chain structure of the later becomes the precursor of a 17-ketosteroid. Because of the similarities between in vitro oxidative side chain cleavage and in vivo corticosteroid metabolism, these findings suggest that C-18 oxygenated steroids may contribute to the 17-ketosteroid fraction of human urine.

Gas Chromatography-Mass Spectrometry↗
PubMed1989

A new form of the syndrome of apparent mineralocorticoid excess.

The syndrome of apparent mineralocorticoid excess combines the features of unexplained but spironolactone-correctable mineralocorticoid excess in association with a decreased rate of oxidation of cortisol to cortisone. No relationship was initially implied between the pathogenesis of the disorder and the metabolic disturbance as expressed by an elevated cortisol:cortisone metabolite ratio but the ratio itself has served as a biochemical marker for the disorder. Cortisol has been suggested as the mineralocorticoid in a setting of enhanced sensitivity to the steroid as a result of the incomplete oxidative metabolism of cortisol by the kidney. We present evidence that diminished conversion of cortisol to cortisone is not an obligatory mechanism in the syndrome of apparent mineralocorticoid excess. A form of the disorder is described, designated the Type 2 variant, in which all features are preserved except that the cortisol:cortisone metabolite ratio is normal. An essential feature of both variants, however, is a decrease in the cortisol metabolic clearance rate. These findings require a more generalized definition of the syndrome of apparent mineralocorticoid excess to include other deficient mechanisms of metabolic inactivation of cortisol.

Adolescent↗
PubMed1987

Identification of a mineralocorticoid receptor binding substance in the urine of patients with congenital adrenal hyperplasia.

Increased amounts of circulating mineralocorticoid receptor binding substances presumed to be natural antagonists were previously demonstrated in congenital adrenal hyperplasia. In this study the feasibility of using urinary extracts for the identification of such binding substances was investigated. Urinary extracts from patients with the 21-hydroxylase defect did contain greater than normal amounts of mineralocorticoid receptor binding material. When subjected to chromatographic separation using a radioreceptor assay to follow the course of fractionation, a major aldosterone binding competitor was identified. On the basis of its chromatographic mobility in comparison with the labeled steroid, radioimmunoassay, ultraviolet absorption and radio-receptor assay of the native and acetylated derivative, the component was identified as 11-deoxycorticosterone and its structure confirmed by mass spectrometry. Although the major mineralocorticoid receptor binding component proved not to be an antagonist but an agonist, the results are in keeping with other evidence for overproduction of 11-deoxycorticosterone in the simple virilizing form of the disorder. Our finding did not disprove the existence of a circulating mineralocorticoid antagonist in congenital adrenal hyperplasia, but demonstrate that the major receptor binding substance in urinary extracts in that disorder is the mineralocorticoid agonist, 11-deoxycorticosterone.

Adrenocortical Hyperfunction↗
PubMed1987

Isolation and identification of an endogenous metabolite of 18-oxocortisol from human urine.

The naturally occurring mineralocorticoid agonist, 18-oxocortisol, is secreted in increased amounts in two hypertensive syndromes. One is primary aldosteronism and the other a genetic disorder first described by Sutherland and co-workers in which aldosterone secretion is ACTH-dependent and the mode of inheritance is autosomal dominant. 18-Hydroxy and -oxocortisol are the components of the cortisol oxidation pathway which arise when cortisol becomes an alternate substrate for corticosterone methyl oxidase. This enzyme system normally resides in the glomerulosa zone of the mammalian adrenal cortex. In an effort to account for a larger fraction of 18-oxocortisol and provide a reliable index of its secretion and of the expression of the cortisol C-18 oxidation pathway, metabolites were sought in the urine of a patient with the ACTH-dependent autosomal dominant form of aldosteronism. Using a variant of the technique of reverse isotope dilution, a pool of [3H]-labeled urinary metabolites form a normal subject was mixed with the patient's urine and subjected to customary methods of hydrolysis for urinary steroids. The radiolabeled glucuronide fraction was the most abundant and was subjected to repeated HPLC fractionation to yield the predominant component. The evidence from gas chromatography-mass spectrometry indicated that this metabolite was a tetrahydro derivative. The structure of the isolated tetrahydro 18-oxocortisol was confirmed by a biosynthesis of a reference standard from 18-oxocortisol and a 5 beta-pregnane reductase preparation.

Biotransformation↗
PubMed1986

Evidence for the secretion of an antimineralocorticoid in congenital adrenal hyperplasia.

Plasma extracts from patients with congenital adrenal hyperplasia were found to contain substances that competed with aldosterone for mineralocorticoid receptor-binding sites in a rat kidney cytosol system. In normal subjects and patients with other disorders, the mineralocorticoid receptor-binding activity in such extracts could be entirely accounted for by the sum of the contributions of the steroids known to bind to the mineralocorticoid receptor. The secretion of these binding substances in patients with the C-21 hydroxylation defect was ACTH dependent. While these substances could be either mineralocorticoid agonists or antagonists, the latter is more likely. Production of mineralocorticoid antagonists would account for the compensatory hyperaldosteronism that occurs in the simple virilizing form, in which there is minimal impairment of aldosterone secretory reserve, and for the tendency to Addisonian crisis in patients with the salt-losing form, who have a more severe defect in aldosterone biosynthesis.

Adolescent↗
PubMed1983

Biosynthesis of 18-oxocortisol by aldosterone-producing adrenal tissue.

Aldosterone-biosynthesizing adrenal tissue contains an angular methyl oxidase which converts corticosterone to 18-hydroxycorticosterone and aldosterone. Cortisol, when incubated with an active source of this oxidase, the bullfrog interrenal gland, was converted to 18-hydroxycortisol and a new C-18-oxygenated steroid identified as 11 beta, 17 alpha,21-trihydroxy-3,20-diketo-4-pregnene-18-al, or 18-oxocortisol. Proof of structure was based on the evidence that it was an alpha, beta-unsaturated ketone biosynthesized from cortisol with an empirical formula of C21H28O6. Low resolution gas chromatography-mass spectrometry of its fully derivatized methoxime trimethylsilyl ether confirmed a trioxopregnenetriol structure in which one aldehyde group was partially masked as an internal hemiacetal. That the oxo group had replaced the C-18 angular methyl was shown by oxidative degradation of the side chain with either periodic acid or sodium bismuthate to yield an hydroxy gamma-lactone rather than an etioacid. It is suggested that the corticosterone methyl oxidase system of aldosterone-producing cells has diminished substrate specificity enabling it to accept cortisol as a suboptimal substrate. Angular methyl oxidation of cortisol to its 18-hydroxy and 18-oxoderivative in two hypertensive disorders is attributed to a derangement in adrenocortical functional zonation permitting access of glucocorticoid products into the mineralocorticoid-biosynthesizing system.

Adrenal Glands↗
PubMed1983

18-oxocortisol, a naturally occurring mineralocorticoid agonist.

Two C-18-oxygenated corticosteroids, 18-hydroxy- and 18-oxocortisol, have recently been isolated from the urine of patients with primary and genetic (dexamethasone-suppressible) aldosteronism and from adrenal tissue. The relevance of these steroids to the manifestations of mineralocorticoid excess in these disorders was investigated by measuring their affinity to rat renal corticosteroid receptors. 18-Oxocortisol showed greater affinity than the 18-hydroxy derivative for both mineralocorticoid and the glucocorticoid receptors and was accordingly assayed in vivo for mineralocorticoid activity. The 18-oxo derivative was found to be an agonist with a sodium-retaining and kaliuretic action qualitatively similar to that of aldosterone. Although 18-oxocortisol was one-third as active as 11-deoxycorticosterone in this assay, it was a more potent mineralocorticoid at the same total plasma concentration because of its lower affinity for corticosteroid-binding globulin.

Adrenalectomy↗
PubMed1983

Metabolic and blood pressure responses to hydrocortisone in the syndrome of apparent mineralocorticoid excess.

A syndrome of low renin hypertension in childhood with apparent mineralocorticoid excess associated with a defect in the peripheral metabolism of cortisol has been described previously in 2 patients. In these patients, decreased secretion rates of glucocorticoids, mineralocorticoids, and sex steroids have been demonstrated. In a 10(10/12)-yr-old girl with this disorder, continuous iv administration of hydrocortisone in doses of 5, 10, 15, and 20 mg/day resulted in an increase in blood pressure and a decrease in serum potassium concentration. The addition of spironolactone during the continued administration of 20 mg/day hydrocortisone did not result in a decrease in blood pressure. Withdrawal of hydrocortisone and continued administration of spironolactone alone resulted in a decrease in blood pressure, a rise in serum potassium concentration, and a fall in serum sodium concentrations. These studies suggest that an abnormality in cortisol action or metabolism causing cortisol to behave as a potent mineralocorticoid may account for this syndrome of apparent mineralocorticoid excess.

Adrenocorticotropic Hormone↗
PubMed1982

A proton magnetic resonance study of the 18-hydroxy derivatives of cortisol and corticosterone.

Proton magnetic resonance spectroscopy played a crucial role in the identification of a new corticosteroid, 18-hydroxycortisol, recently isolated from the urine of a patient with an aldosterone-producing adenoma. Mass spectrometric analysis and chemical degradative studies demonstrated an empirical formula of C21 H30 O6 corresponding to a diketopregnenetetrol and placed three of the four hydroxyl groups at the 11 beta, 18 and 21 positions. The first suggestion that the locus of the fourth hydroxyl was 17 alpha came from the n.m.r. spectrum in the form of negative evidence for proton linked to the carbon atom bearing this fourth hydroxyl. The n.m.r. spectral features of the 18-hydroxy derivatives of cortisol and corticosterone are compared. Both were found to exist in the 20, 18 cyclic hemiketal form.

18-Hydroxycorticosterone↗
PubMed1982

Hypersecretion of a new corticosteroid, 18-hydroxycortisol in two types of adrenocortical hypertension.

The most abundant substance in the urinary free steroid fraction of patients with primary aldosteronism has been identified as 18-hydroxycortisol. 18-hydroxycortisol is very likely an adrenocortical secretory product rather than a peripheral metabolite, since it is abundantly synthesized by aldosteronoma tissue slices. The biogenesis of 18-hydroxycortisol takes place from cortisol rather than from 18-hydroxycorticosterone; that is, 17 alpha-precedes 18-hydroxylation. Cortisol 18-hydroxylation appears to be unrelated to the two other types of adrenocortical hydroxylation at this position. The pathway is present to a small extent in the normal human adrenal cortex and is only moderately stimulated by ACTH. Cortisol 18-hydroxylation is markedly accentuated in two circumstances: in the aldosteronoma cell where its presence may serve to distinguish tumor from bilateral hyperplasia and in ACTH-stimulatable hyperaldosteronism where it represents the first qualitative steroid biochemical abnormality to be demonstrated and as such may be useful in diagnosis and genetic studies. The possible contribution of 18-hydroxycortisol to the severity of the clinical manifestations of mineralocorticoid excess in these two types of aldosteronism remains to be explored.

Adenoma↗
PubMed1981

Orally active mineralocorticoid agonists and antagonists: delta 1-derivatives of aldosterone and 18-deoxyaldosterone.

The effect of delta 1 unsaturation on the oral effectiveness of a representative mineralocorticoid agonist and antagonist was investigated in an adrenalectomized rat bioassay. Dehydrogenation at the 1.2 position did not alter the qualitative nature of the mineralocorticoid activity of the parent compound. Thus delta 1-aldosterone (21,18-dihydroxy-11 beta, 18-oxido-1,4-pregnadiene-3,20-dione) retained pure mineralocorticoid agonism, and delta 1-18-deoxyaldosterone (21-hydroxy-11 beta, 18-oxido-1,4-pregnadiene-3,20-dione)demonstrated the same relative degree of predominant antagonism as 18-deoxyaldosterone (21-hydroxy-11 beta, 18-oxido-4-=pregnene-3,20-dione) itself. In each instance, receptor affinity was diminished by 1,2 unsaturation, but this effect was offset by the greater bioavailability of the delta 1 derivatives on oral administration. (Endocrinology 108: 517, 1981)

Administration, Oral↗
PubMed1980

Mineralocorticoid unresponsiveness with severe neonatal hyponatremia and hyperkalemia.

An infant with severe neonatal hyponatremia and hyperkalemia is described. Although marked elevations of urinary 17-hydroxycorticosteroids suggested an 18-dehydrogenase aldosterone biosynthetic defect, the infant proved to have mineralocorticoid unresponsiveness, or pseudohypoaldosteronism. Dietary sodium supplementation and ion exchange resin administration resulted in normalization of serum electrolytes and urinary 17-hydroxycorticosteroids. ACTH infusion produced natriuresis, suggesting the need for additional sodium supplementation during the stress of illness, with a resultant increase in ACTH secretion. Determinations of the relative amounts of urinary 18-hydroxy and aldosterone metabolites appear necessary for early definitive diagnosis of the disorder.

17-Hydroxycorticosteroids↗