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Biomedical subjects

P Vecsei

Publications and source records attributed to P Vecsei.

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

Interference of C17-spirosteroids with late steps of aldosterone biosynthesis. Structure-activity studies.

Structure-activity relationships concerning the steroidal skeleton as well as the C21,17-ring systems could be established while investigating the inhibitory effects of 27 different C17-spirosteroids on aldosterone synthesis in vitro. 18-hydroxylation appeared to be the crucial point of interference with all active compounds, whereas impairment of 11 beta- and 21-hydroxylase, respectively, was of minor importance, i.e. occurring to a smaller degree and only with a few test substances. Inhibition of 18-hydroxylation was associated with the following structural features: C21,17-spiro-gamma-lactone ring with 17 beta-O-atom; 3-oxo group in combination with delta 4,5-6,7-diene structure or, alternately, combination of 3-oxo group or even a bulky 3-O-function, if it protrudes out of ring plane in beta-position, and 7a-thioalkyl- or thioacyl- or thiol groups; combination of 17-spiro-gamma-lactone and a 3-O-function may result in an active compound even without 7a-substituents, provided there are no additional groups fixed on the steroidal skeleton. Elimination of an angular methyl group (----nor-compound), however, is acceptable. On the other hand, inhibitory potency is abolished or diminished by the following structural features: 7a-groups containing oxidized sulphur (e.g. suphoxy- or sulphonyl groups); bulky 3-substituents fixed in the ring plane via double bond; 18-alkyl groups; 6 beta-substituents; 2-substituents in absence of 7a-groups, depending on their configuration (e.g. cycle or chain); introduction of a heteroatom at C21, i.e. instead of the carbonyl-C-atom. Mespirenone (CAS 87952-98-5), the test substance of central concern, possesses favourable structural features finding its expression in a correspondingly enhanced inhibitory action.

17-alpha-Hydroxyprogesterone↗
PubMed1991

5 alpha-dihydrocortisol in human aqueous humor and metabolism of cortisol by human lenses in vitro.

Glucocorticoids have long been implicated in the etiology of primary open-angle glaucoma (POAG) and cataract. Cortisol metabolites have biologic activity and may affect aqueous humor dynamics. This study was done to determine whether these metabolites are found in human aqueous humor and can be produced by ocular tissues. Radioimmunoassays (RIA) were developed for 5 alpha-dihydrocortisol (5 alpha-DHF) and 5 beta-dihydrocortisol (5 beta-DHF). These assays, as well as a cortisol RIA, were used to quantify these three steroids in 20 surgically derived aqueous humor specimens from patients with and without POAG. The mean concentrations of cortisol and 5 alpha-DHF were 2.5 and 1.3 ng/ml, respectively. In the small group studied, there was no statistically significant difference between the aqueous humor steroid levels in patients with and without POAG. The amount of 5 beta-DHF was at the lower limits of detection of the assay system and could not be uniquivocally shown. Human lenses metabolized cortisol in vitro to 5 alpha-DHF and 3 alpha,5 alpha-tetrahydrocortisol (3 alpha,5 alpha-THF). There was no 5 beta-DHF or cortisone formed. The 5 alpha-DHF and 3 alpha,5 alpha-THF were identified by their positions on thin-layer chromatography, their retention times on high-performance liquid chromatography, and recrystallization with authentic standards to constant specific activity. The data suggest that the lens is the source of 5 alpha-DHF in aqueous humor.

Aged↗
PubMed1990

Synthesis of 19-nor-aldosterone, 18-hydroxy-19-nor-corticosterone and 18,19-dihydroxycorticosterone in the human aldosterone-producing adenoma.

The recently synthesized 18-C-steroid derivative, 19-nor-aldosterone(19-nor- aldo) and 18-hydroxy-19-nor-corticosterone(18-OH-19-nor-corticosterone) possess mineralocoroticoid and hypertensinogenic activity. They and an additional newly synthesized steriod, 18,19-dihydroxycorticosterone[18,19(OH)2-corticosterone], may play a role in the etiology and pathogenesis of disorders thought to be caused by steroids with mineralocorticoid and hypertensionogenic properties. In this study we provide evidence that 19-nor-aldo, 18-OH-19-nor-corticosterone and 18,19(OH)2-corticosterone are produced in vitro by aldosterone-producing adrenal adenomas and adenomas and adenoma of Cushing's syndrome. "silent" adrenal adenomas and the adjacent adrenal tissue. Measurable amounts of these steroids were found in the incubation fluids of adrenal tissues using specific RIAs performed after a sequence of HPLC systems. The rates of production of the three steroids were high in the aldosterone-producing adrenal adenomas and in adrenal hyperplasia compared with in either Cushing's adenoma or "silent" adenoma.

18-Hydroxycorticosterone↗
PubMed1990

Secondary biosynthetic defects in women with late-onset congenital adrenal hyperplasia.

BACKGROUND AND METHODS: Late-onset (non-classic) congenital adrenal hyperplasia is a cause of hirsutism, menstrual disorders, and infertility, but its frequency and the patterns of abnormalities in adrenal hormone secretion are not well understood. We investigated the frequency and ethnic distribution of nonclassic congenital adrenal hyperplasia due to deficiencies of 3 beta-hydroxy-delta 5-steroid dehydrogenase, 21-hydroxylase, or 11 beta-hydroxylase among 170 Israeli Jewish women with these clinical problems. All enzyme defects were identified by comparing the patients' hormonal responses to a 0.25-mg intravenous bolus dose of alpha 1-24-ACTH with those of 26 age-matched normal women. RESULTS: Twenty women (12 percent) had 3 beta-hydroxy-delta 5-steroid dehydrogenase deficiency, 18 (10 percent) 21-hydroxylase deficiency (14 homozygous), and 14 (8 percent) 11 beta-hydroxylase deficiency. All the homozygous women with 21-hydroxylase deficiency also had evidence of a partial deficiency in 11 beta-hydroxylase activity. Similarly, most of the women with 11 beta-hydroxylase deficiency also had evidence of a deficiency in 3 beta-hydroxy-delta 5-steroid dehydrogenase. Among the 118 women with no adrenal biosynthetic defect, 38 had high plasma androgen concentrations, and 80 had normal concentrations. CONCLUSIONS: About one third of Israeli Jewish women with hirsutism, menstrual disorders, or unexplained infertility had nonclassic congenital adrenal hyperplasia. Secondary adrenal biosynthetic defects were frequent in these women and were probably caused by intra-adrenal androgen excess rather than by dual inherited enzymatic deficiencies.

3-Hydroxysteroid Dehydrogenases↗
PubMed1990

[Therapy of hirsutism in females with adrenal enzyme defects of steroid hormone biosynthesis: comparison of dexamethasone with cyproterone acetate].

In patients with adrenal hirsutism or enzyme deficiencies in steroidogenesis, elevated adrenal androgens could be normalized by dexamethasone. We were interested to see if dexamethasone would be as effective as cyproterone acetate in treating hirsutism in selected patients with adrenal pathogenesis. Therefore 28 patients with hirsutism of adrenal origin or enzyme deficiency were treated cyclically either with cyproterone acetate and ethinylestradiol (2 mg cyproterone acetate + 0.035 mg ethinyl-estradiol days 1-21, +10 mg cyproterone acetate days 1-15) (n = 15) or with 0.25-0.5 mg dexamethasone daily at 10 pm (n = 13). In the dexamethasone group there was a significant drop in dehydroepiandrosterone and dehydroepiandrosterone sulfate levels within 9 months, but there was a diminution in hirsutism in only four women (31%); in four out of seven menstrual irregularities decreased. In the cyproterone acetate group hirsutism diminished significantly in 66% (n = 10) without suppression of adrenal androgens. Weight gain occurred in a few cases in both groups; other side effects developed in 33% in the cyproterone acetate group. Preselection of patients with hirsutism is useful with respect to diagnosis; adrenal pathogenesis should not generally indicate dexamethasone treatment of hirsutism unless there is a desire for pregnancy, because cyproterone acetate is a more powerful agent in reducing hair growth.

3-Hydroxysteroid Dehydrogenases↗
PubMed1990

Synthesis of 4,19-disubstituted derivatives of DOC. Radioreceptor assay of some corticosteroid derivatives in human mononuclear leukocytes.

Several new 4,19-substituted steroids and previously synthesized corticosteroids were assayed for affinity to type 1 receptors in human mononuclear leukocytes. 11 beta,19-epoxy-4,21-dihydroxypregn-4-ene-3,20-dione (2) was hydrogenated with Pd-C to yield a mixture of all four dihydro derivatives 5, accompanied by 4,21-diacetoxy-11 beta,19-epoxy-3-hydroxypregnan-20-one (6) and 21-acetoxy-11 beta,19-epoxy-4-hydroxypregnane-3,20-dione (7). With hot acetic + p-toluenesulfonic acid 5 underwent rearrangement to 21-acetoxy-11 beta,19-epoxypregn-5-ene-4,20-dione (8) Pd-C hydrogenation of 3,21-diacetoxy-5 beta,19-cyclopregna-2,9(11)-diene-4,20-dione (10) gave 3,21-diacetoxy-5 beta,19-cyclopregn-5-ene-4,20-dione (11) and the 9,11-dihydro derivative of the latter. Treatment of 10 with warm HCl furnished 19-chloro-4,21-dihydroxypregna-4,9(11)-diene-3,20-dione (13). Pd-C hydrogenation of its diacetate 14 afforded the 4,5-dihydro derivative 18, 19-chloro-21-acetoxypregn-9(11)-en-20-one (15), its 4-acetoxy derivative 16 and the 3,4-diacetoxy derivative 17. When tested in a radioreceptor assay in human mononuclear leukocytes the synthesized compounds showed only low relative binding affinities (RBA) to type 1 receptor, the highest being 0.72% for 13 (aldosterone = 100%). For comparison, other RBA in this system were: 19-noraldosterone, 20%; 18-deoxyaldosterone, 5.8%; 18-deoxy-19-noraldosterone, 4.7%; 18,21-anhydroaldosterone, 0.37%; 17-isoaldosterone, 7.6% and apoaldosterone, 4.3%

Aldosterone↗
PubMed1990

Production of 21-deoxyaldosterone by rat adrenal tissue in vitro: evidence for an alternative biosynthetic pathway of aldosterone.

Quartered rat adrenal glands transformed labelled 21-deoxyaldosterone into aldosterone in vitro. 21-deoxyaldosterone was released from the quartered rat adrenals in vitro in amounts 10 times lower than those of aldosterone and 18-hydroxycorticosterone. The production of all three steroids was qualitatively dependent on the same regulatory elements (electrolytes, ACTH, exogenous precursors, zonal specificity). However, quantitative differences could be observed. The results support a role for 21-deoxyaldosterone as a facultative precursor of aldosterone and indicate that the regulation of its production shows similarities to that of aldosterone.

18-Hydroxycorticosterone↗
PubMed1990

Normal values for a short-time ACTH intravenous and intramuscular stimulation test in women in the reproductive age.

Normal values in endocrine testing are the most important precondition for the recognition of disorders of the endocrine system. To establish a reference range for adrenocorticotropic hormone (ACTH) stimulation tests, an intravenous and intramuscular ACTH stimulation test was conducted in 29 female volunteers without hyperandrogenism. A total of 25 IU of ACTH were administered intravenously or intramuscularly and blood sampling was performed before, 1 h and 2 h after ACTH injection. The test was performed on days 3-5 of the menstrual cycle. The following steroid hormones were assessed in the serum: 17 alpha-hydroxyprogesterone, 17 alpha-hydroxypregnenolone, dehydroepiandrosterone, testosterone, free testosterone and 5 alpha-dihydrotestosterone. The normal range was defined by the interval between the 5th and 95th percentiles; additionally the 1st, 25th, 50th, 75th and 99th percentiles are reported. A significant increase of serum hormone levels after ACTH administration could be observed for the following hormones: cortisol, 17 alpha-hydroxyprogesterone, 17 alpha-hydroxypregnenolone and dehydroepiandrosterone. There was no rise after ACTH application for testosterone, 5 alpha-dihydrotestosterone and free testosterone. It could be shown for all hormones that there was no significant difference between the serum levels that were reached after intravenous and intramuscular ACTH injection. Neither could we find a significant difference in the relative increase of the serum hormones when stimulation values were related to basal values. Since in most studies with ACTH stimulation tests, only the serum values 1 h after ACTH application are measured, we investigated whether the measurement of steroid hormones 2 h after ACTH application gave further information. We could demonstrate that for most measured serum hormones the majority of the volunteers had the maximal response 2 h after ACTH application, no matter whether ACTH was injected intramuscularly or intravenously. As a conclusion, we recommend the measurement of the respective hormones not only 1 h but also 2 h after ACTH stimulation. Since there is no increase after ACTH stimulation for total testosterone, free testosterone and 5 alpha-dihydrotestosterone, it is sufficient to assess the basal values of these hormones. Excessive adrenal response is reflected by dehydroepiandrosterone, 17 alpha-hydroxyprogesterone, 17 alpha-hydroxypregnenolone and cortisol.

17-alpha-Hydroxypregnenolone↗
PubMed1990

[18-Hydroxycorticosterone, 18-hydroxydesoxycorticosterone. Why, when, how to determine plasma levels in some adrenal pathologies].

The authors review some current ideas concerning the role of 18-hydroxylated corticosteroids as mineralocorticoids themselves and as possible precursors of the principal mineralocorticoid, aldosterone. In particular, the physiological and pharmacological agents affecting their secretion are discussed together with a description of the methods used for their analysis in plasma in the department of Clinical Biochemistry Pitié-Salpétrière. Finally, the value of these assays in the differential diagnosis of mineralocorticoid hypertension and inborn errors of corticosteroid biosynthesis is assessed and the constraints on sampling technique listed.

18-Hydroxycorticosterone↗
PubMed1990

[Treatment of radiogenic colitis with a rectal foam containing cortisol. Clinical and pharmacologic data].

20 patients with highly dosed irradiation of the small pelvis had been treated with Colifoam (hydrocortisone) in order to prove the therapeutic effect of radiation-induced proctitis. Over a period of three to six weeks starting in the third week of irradiation all patients received one applicator filling of rectal foam after bowel movement daily. The findings were verified by proctoscopy, histology and subjective personal well being. In ten patients we determined the daily cortisol profiles. Six months post irradiation ten patients underwent barium enema of the colon. During therapy no major complaints were recorded. The proctoscopic findings showed little changes concerning the submucous vascular walls. In none of the patients any kind of late lesion could be observed. The daily cortisol profile did not show any aberration of the physiological patterns. In conclusion the local therapy of Colifoam can be considered an additional treatment of radiation-induced colitis (proctitis).

Abdominal Neoplasms↗
PubMed1989

[Primary hyperaldosteronism without arterial hypertension].

Treatment-resistant hypokalaemia (2.27 mmol/l) developed in a 43-year-old woman. Plasma renin activity was depressed (0.24 ng/ml.h), aldosterone and hydroxycorticosterone concentrations were elevated (123 ng/dl and 688 ng/dl, respectively). Mean blood pressure value (30 readings) was 133/88 mm Hg. An adrenal adenoma was diagnosed by ultrasound, computed tomography and subtraction angiography and then removed. Postoperatively the signs of hyperaldosteronism (Conn's syndrome) regressed and the average blood pressure was 112/76 mm Hg. Blood-gas analysis, which preoperatively had shown a minimal metabolic alkalosis, now revealed a mild metabolic acidosis. Preoperatively present bilateral renal calcifications in the region of the papillary tips were confirmed by computed tomography. An acid loading test revealed diminished renal acid secretion, making the diagnosis of distal renal-tubular acidosis. The latter, in combination with the primary hyperaldosteronism, may have been the cause of the low blood pressure, unusual in Conn's syndrome.

18-Hydroxycorticosterone↗
PubMed1989

[3 beta-hydroxysteroid dehydrogenase deficiency and 21-hydroxylase deficiency in hirsutism].

Of 218 women with hirsutism 16 (7%) were found to have partial 21-hydroxylase deficiency, while 38 (17%) had partial 3 beta-hydroxysteroid dehydrogenase deficiency. Six women (3%) had a steroid constellation which resembled that of an augmented adrenarche. In the women with enzyme deficiency over-weight and abnormal menstruations were more frequent (50%) than in those without such deficiency (33%). The degree of hirsutism and age at diagnosis were similar in those with and those without partial enzyme deficiency. Furthermore, the diagnosis of partial enzyme deficiency could only be made with certainty by the ACTH stimulation test, because with sole measurement of basal levels (17-hydroxyprogesterone and 21-desoxycortisol in 21-hydroxylase deficiency, and 17-hydroxypregnenolone and dehydroepiandrosterone in 3 beta-hydroxysteroid dehydrogenase deficiency) the enzyme defects are in most instances not revealed.

3-Hydroxysteroid Dehydrogenases↗
PubMed1989

Primary glucocorticoid receptor defect with likely familial involvement.

A 29-year-old woman with moderately elevated blood pressure and signs of hyperandrogenism (hirsutism and acne) but without typical Cushing's syndrome symptoms has been followed for almost 6 years. Steroid and glucocorticoid receptor studies indicated a primary glucocorticoid receptor defect. Elevated androgen values were of special interest. Clinical manifestation of hyperandrogenism seemed not to be proportional to the biochemical findings. Therefore, the possibility of a partial androgen receptor defect should also be considered.

Acne Vulgaris↗
PubMed1989

[Clinical features and diagnosis of mild 3-beta-hydroxysteroid dehydrogenase deficiency in men].

3 beta-hydroxysteroid dehydrogenase (HSD) deficiency was demonstrated in six males, aged between 18 and 24 years, who had gynaecomastia, hypogonadism or infertility. The predominant laboratory finding was a striking elevation of dehydroepiandrosterone sulphate (DHEAS) levels. The diagnosis of HSD deficiency was confirmed by finding a marked rise in dehydroepiandrosterone (DHEA) and 17-hydroxypregnenolone levels. In contrast to these findings in late-onset enzyme deficiency, in four males with the classical form of 21-hydroxylase deficiency the only sign was a reduction in adult height. The prevalence of late-onset HSD deficiency in men is not known and may be more relevant in patients with gynaecomastia or abnormal gonadal function than has hitherto been realized.

17-alpha-Hydroxypregnenolone↗
PubMed1989

The pathogenesis of pseudohyperaldosteronism from carbenoxolone.

Carbenoxolone is a derivative of glycyrrhetinic acid used for the treatment of peptic ulcer and gastritis, with salt and water retention a very common side-effect. To investigate this drug-induced pseudohyperaldosteronism we have studied 6 male volunteers before, during and after treatment with carbenoxolone for 7 days. Serum, urinary and sweat electrolytes values were consistent with a mineralocorticoid-like effect of drug administration. PRA was suppressed, and plasma cortisol and aldosterone progressively decreased over treatment. We have also determined by radioreceptor assay the plasma levels of factors which bind to mineralocorticoid receptors in rat kidney cytosol. The levels of these factors were decreased significantly at day 3 of treatment, suggesting a local renal effect of carbenoxolone to amplify endogenous steroid action. At day 7 the radioreceptor assay values were still decreased but significantly higher than at day 3, suggesting in addition a direct mineralocorticoid effect of the drug. We conclude that the drug is initially effective by amplifying the effect of endogenous steroids, and then when the plasma concentrations of the drug or its metabolites reach a higher plasma concentration, there may also be in addition a direct mineralocorticoid-like effect.

Adult↗
PubMed1989

Congenital adrenal hyperplasia due to combined 21- and 11 beta-hydroxylase deficiency.

A 26-day-old male was evaluated because on routine follow-up visit his weight was noted to be 3292 g which was not a significant weight gain over his birth weight of 3178 g. His serum electrolytes (NA 107 meq/1, K 8.0 meq/1, Cl 82 meq/1, and HCO2 12 meq/1) were abnormal, urine Na concentration (68 meq/1) was high, and his serum concentrations of 21-deoxycortisol 10, 113 ng/dl (normal 1.2-13), 11-deoxycortisol 15,000 ng/dl (normal 50-250), and 11-deoxycorticosterone 148 ng/dl (normal 2-13) were markedly elevated. Patients having increased levels of the three indicated steroids are diagnosed as having combined 21- and 11 beta-hydroxylase deficiency. On glucocorticoid and mineralocorticoid replacement therapy his electrolytes returned to normal and his weight increased 428 g by the 10th day post initiation of therapy. We hypothesize that the elevated steroid pattern designated as combined 21- and 11 beta-hydroxylase deficiency could result from extraadrenal conversion of 17-hydroprogesterone to 11-deoxycortisol and progesterone to 11-deoxycorticosterone in subjects with adrenal 21-hydroxylase deficiency.

Adrenal Hyperplasia, Congenital↗
PubMed1989

Glucocorticoid receptors and dissociation constant (Kd) are decreased in mononuclear leukocytes of spontaneously hypertensive rats (SHR-SP) as compared to normotensive Wistar-Kyoto rats (WKY).

We were able to show that spontaneously hypertensive stroke-prone rats (SHR-SP) have a lower number of glucocorticoid receptors (P-value is of borderline significance, 0.01 greater than P less than 0.05) with a highly significant lower Kd (P less than 0.0005), i.e higher affinity in their mononuclear leukocytes, compared to normotensive Wistar-Kyoto rats (WKY). The plasma levels of corticosterone, aldosterone and 18-hydroxycorticosterone of the two strains do not differ.

18-Hydroxycorticosterone↗