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Biomedical subjects

D Engelhardt

Publications and source records attributed to D Engelhardt.

At least 55 records · Page 3Linked to original sources
PubMed1994

Therapy of Cushing's syndrome with steroid biosynthesis inhibitors.

Several substances with different inhibitory effects on adrenal steroid biosynthesis were investigated in patients with Cushing's syndrome. It has been shown that trilostane, a 3 beta-hydroxysteroid-dehydrogenase inhibitor, is not potent enough to block cortisol biosynthesis in patients with hypercortisolism. Aminoglutethimide inhibits side chain cleavage of cortisol synthesis, but it has been demonstrated that the blocking effect on cortisol secretion is not strong enough to normalize urinary cortisol excretion in patients with Cushing's disease. For metyrapone, an inhibitor of adrenal 11 beta-hydroxylase, promising results were reported for the treatment of Cushing's syndrome. However, the drug has several side effects and depending on the definition of the desired reduction of cortisol secretion a true remission was only found in a minority of patients. The antifungal drug ketoconazole in vitro predominantly blocks 17,20-desmolase (IC50 1 microM) and to a lesser extent 17 alpha-hydroxylase (IC50 10 microM) and 11 beta-hydroxylase (IC50 15-40 microM). Therefore, ketoconazole in vivo most potently suppresses androgen secretion and only to a lesser extent cortisol biosynthesis. Several therapeutic trials with ketoconazole treatment in patients with pituitary Cushing's disease showed various remission rates between 30 and 90%. In contrast, in almost all patients with benign, primary adrenal Cushing's syndrome cortisol levels were normalized. In patients with ectopic ACTH syndrome ketoconazole was effective in about 50% of all reported cases, while cortisol hypersecretion due to adrenocortical carcinoma was only rarely inhibited by ketoconazole. The main side effect of ketoconazole treatment was liver toxicity which occurred in 12% of all treated patients. In contrast to ketoconazole, the narcotic drug etomidate shows a strong inhibitory effect on 11 beta-hydroxylase (IC50 0.03-0.15 microM) but only a weak inhibition of 17,20 desmolase (IC50 380 microM). This correlates with in vivo studies where even low, non-hypnotic doses of etomidate induced a pronounced fall in serum cortisol levels in normals and in patients with Cushing's syndrome. However, its clinical use is limited by its mandatory intravenous application and its sedative effects. In conclusion, ketoconazole remains the only available steroid-inhibitory drug for a therapeutic trial in patients with Cushing's syndrome who cannot be treated definitively by surgery.

3-Hydroxysteroid Dehydrogenases↗
PubMed1994

Identification and characterization of insulin-like growth factor I (IGF-I) and IGF-II/mannose-6-phosphate (IGF-II/M6P) receptors in bovine adrenal cells.

We have identified and characterized insulin-like growth factor I (IGF-I) and IGF-II/mannose-6-phosphate (IGF-II/M6P) receptors in bovine adrenal cells. Iodine-125-labeled IGF-I ([125I]IGF-I) binding was characteristic of the IGF-I receptor, and binding kinetics as well as receptor densities were similar in cortical and medullary membranes. Scatchard analysis of [125I]IGF-I binding to cultured adrenocortical cells showed a single class of high-affinity binding sites with a Kd of 1.4 nmol/l and an average of 150,000 binding sites/cell. Affinity cross-linking experiments displayed a band at an apparent molecular weight of 135 kD, corresponding to the size of the alpha-subunit of the IGF-I receptor. In analogy, the binding of [125I]IGF-II to bovine adrenal membranes was characteristic of the IGF-II/M6P receptor and no differences between cortical and medullary membrane fractions were found. Scatchard analysis revealed a single class of high-affinity binding sites in adrenocortical cells with a Kd of 1.1 nmol/l and an average of 280,000 binding sites/cell. The identity of the IGF-II/M6P receptor was confirmed by western blotting of adrenocortical membranes with an anti-IGF-II/M6P receptor antibody and by affinity cross-linking of adrenocortical cells with labeled IGF-II. In conclusion, we have identified and characterized IGF-I and IGF-II/M6P receptors in bovine adrenocortical as well as medullary cells. In both regions of the bovine adrenal gland the IGF-II/M6P receptor is much more abundant than the IGF-I receptor.

Adrenal Cortex↗
PubMed1994

Transform practice information into team action.

To keep a dental office moving in the direction desired by the dentist/owner requires the active participation of all members of the dental team. This article discusses methods of measuring effectiveness in achieving practice goals.

Efficiency, Organizational↗
PubMed1993

Different inhibitory effect of etomidate and ketoconazole on the human adrenal steroid biosynthesis.

The narcotic agent etomidate and the antimycotic drug ketoconazole are known to block steroid biosynthesis in man. To study the different effects of these imidazole derivatives on human adrenal steroid biosynthesis we incubated slices of human adrenal glands with 3H-labeled precursors and increasing concentrations of etomidate or ketoconazole (0-2000 microM). After extraction the labeled metabolites were separated by thin-layer chromatography and quantified by scintillation counting. Etomidate inhibited most potently 11 beta-hydroxylase activity by suppressing the formation of corticosterone from 11-deoxycorticosterone to 1% of control [50% inhibitory concentration (IC50) 0.03 microM] while ketoconazole suppressed 11 beta-hydroxylase to only 39% of control activity (IC50 15 microM). Ketoconazole however, most potently blocked the conversion of 17 alpha-hydroxy-progesterone to androstenedione by C17,20-desmolase to about 15% of control activity (IC50 1 microM) while etomidate showed a much weaker effect on this enzyme with a suppression to 50% of C17,20-desmolase control activity at a concentration of 380 microM. Both imidazole drugs showed a similar strong inhibitory effect on the activity of 17 alpha-hydroxylase (IC50 6-18 microM) and 16 alpha-hydroxylase (IC50 4-8 microM) and did not affect 21-hydroxylase. These in vitro data indicate a predominant inhibitory effect of etomidate on corticosteroid biosynthesis by relative selective inhibition of 11 beta-hydroxylase and of ketoconazole on the adrenal androgen biosynthesis by a predominant inhibition of C17,20-desmolase. This differential inhibitory effect of etomidate and ketoconazole on human steroid biosynthesis may be of clinical importance for a possible therapeutic use of these imidazole derivatives in endocrine disorders.

Adrenal Glands↗
PubMed1991

[The spontaneous course of compensated autonomous thyroid gland adenomas].

The spontaneous course of 58 patients with compensated autonomous adenoma of the thyroid was followed. Scintigraphic appearance (compensated (CAA) or decompensated (DAA)) was documented and the serum levels of thyroxine (T4), triiodothyronine (T3) and thyroid-stimulating hormone after TSH-stimulating hormone were measured at the beginning of observation and 3.8 years (median) later. During follow-up period, 13 patients (22%) with CAA developed DAA. 9/13 patients (15%) had overt hyperthyroidism with elevated T4 and/or T3 levels, 4/13 patients (7%) had normal thyroid hormone levels. Life table analysis showed a risk for developing hyperthyroidism of 19% at five years. The size of all adenomata measured scintigraphically was increasing during follow-up, and there was no discrimination of CAA from DAA using this technique. Eight CAA patients received iodinated contrast medium but none develop DAA. In conclusion from these results as well as from the literature, there is no indication for surgery or radioiodine therapy of patients with a CAA, even if there are plans to administer iodinated contrast medium.

Adenoma↗
PubMed1991

Effect of ketoconazole on human ovarian C17,20-desmolase and aromatase.

Ketoconazole, an imidazole antimycotic drug, inhibits steroid biosynthesis in adrenal and testicular tissue by blocking cytochrome P-450 dependent enzymes. To study the effect of ketoconazole on steroid biosynthesis in the human ovary we incubated human ovarian tissue (mainly theca cells) or granulosa cells with radiolabeled precursors and increasing concentrations of ketoconazole. After incubation, steroids were extracted and separated by thin layer chromatography (TLC). Activity of C17,20-desmolase and aromatase was estimated by measuring the amount of their radioactive products with liquid scintillation counting. After incubation of ovarian tissue with [3H]17-hydroxyprogesterone the production of [3H]androstenedione was reduced by increasing concentrations of ketoconazole (0-200 microM) to a minimum of 31% of basal production. This indicates a strong inhibition of ovarian C17,20-desmolase by ketoconazole with a 50% inhibiting concentration (IC50) of 23 microM. After incubation of human granulosa cells with ketoconazole (0-2000 microM) and [3H]androstenedione the production of [3H]estrone and [3H]estradiol was suppressed to minimally 37 and 35% of basal values, indicating a significant inhibition of ovarian aromatase. IC50-values were 105 microM ketoconazole for estradiol and 130 microM for estrone. In conclusion, ketoconazole was shown to inhibit human ovarian C17,20-desmolase and aromatase in vitro. As in human adrenals and testes ovarian C17,20-desmolase seems to be most sensitive to the inhibitory effect of ketoconazole.

17-alpha-Hydroxyprogesterone↗
PubMed1991

The influence of ketoconazole on human adrenal steroidogenesis: incubation studies with tissue slices.

OBJECTIVE: The influence of ketoconazole on the various enzymes of human adrenal steroid biosynthesis was examined in vitro. MEASUREMENTS: After incubation of human adrenal tissue slices with labelled precursors and ketoconazole (0-2000 microM), radioactive metabolites were separated by thin-layer chromatography and quantified by liquid scintillation counting. Enzyme activity was assessed by measuring conversion of tritium-labelled precursors to products. RESULTS: In vitro, ketoconazole showed a significant inhibition on the following adrenal enzyme systems (with decreasing activity): C17,20-desmolase (IC50 2 microM), 16 alpha-hydroxylase (IC50 9 microM), 17 alpha-hydroxylase (IC50 18 microM), 18-hydroxylase (IC50 28 microM), and 11 beta-hydroxylase (IC50 35 microM). In the tested concentrations ketoconazole had no inhibitory effect on the 21-hydroxylase, the 3 beta-hydroxysteroid dehydrogenase and the 20-hydroxysteroid dehydrogenase component of the C17,20-desmolase enzyme system. CONCLUSIONS: The data are in accordance with clinical findings where a strong suppression of serum androgen levels by relatively selective inhibition of C17, 20-desmolase has been assumed. The predominant blocking effect of ketoconazole on adrenal as well as on gonadal androgen biosynthesis might be of clinical benefit in the management of hyperandrogenic states.

Adrenal Glands↗
PubMed1991

Serum androgens in intensive-care patients: correlations with clinical findings.

Serum androgen levels were studied in 100 patients (50 male) with varying degrees of severe illness, determined by Acute Physiological and Chronic Health Evaluation (APACHE). Comparison with normal subjects revealed the following changes: (1) Basal dehydroepiandrosterone sulphate (DHEAS) values were decreased in the ill female patients (P less than 0.001) as well as in the ill males (two groups, P less than 0.01; P less than 0.05). Androstenedione values did not differ from the controls in patients of either sex. Basal testosterone levels were decreased in ill male patients (P less than 0.001), but not in females. (2) The low testosterone concentrations in the severely ill male patients correlated inversely with the APACHE score; additionally, a dependence on diagnostic categories could be demonstrated in men, since the lowest values were found in patients suffering from sepsis or liver cirrhosis. Acutely ill males had a moderately decreased testosterone, whereas chronically ill males showed a marked reduction of testosterone compared to the controls. Lowered DHEAS and androstenedione levels could be measured in chronically ill males but not in ill females. (3) 17 alpha-OH-progesterone and 17 alpha-OH-pregnenolone levels in subgroups of the patients suggested a probable enzymatic block in the delta 5-pathway of androgen biosynthesis in severe illness. The ratio of 17 alpha-OH-pregnenolone to DHEAS was significantly higher in male patients and tended to be high in ill females, whereas the ratio of 17 alpha-OH-progesterone to androstenedione showed no difference between healthy and ill subjects.

17-alpha-Hydroxypregnenolone↗
PubMed1989

Inhibition of human adrenal androgen secretion by ketoconazole.

The effect of ketoconazole on adrenal androgen secretion was examined in 15 patients with elevated serum androgens. In a dose of 600 mg per day orally ketoconazole inhibited the biosynthesis of all measured androgens. The mean reduction in serum levels of dehydroepiandrosterone sulfate was 32%, of dehydroepiandrosterone 54%, of androstenedione 52%, and of testosterone 43%; mean serum levels of cortisol only fell by 19%. The reduction in serum androgen levels was first significant 24 h after beginning of treatment and persisted as long as the drug was administered. We conclude that ketoconazole inhibits adrenal androgen biosynthesis more pronouncedly than cortisol biosynthesis more pronouncedly than cortisol biosynthesis. This might be of clinical benefit in the treatment of hirsutism and other states of androgen hypersecretion.

ACTH Syndrome, Ectopic↗
PubMed1989

Different therapeutic efficacy of ketoconazole in patients with Cushing's syndrome.

The property of ketoconazole to inhibit adrenal biosynthesis of cortisol was used in a clinical study of 14 patients with Cushing's syndrome (pituitary-dependent Cushing's disease, n = 10; adrenocortical adenoma, n = 2; adrenocortical carcinoma, n = 1; ectopic ACTH syndrome, n = 1). Five patients were treated in a short-term manner (1000 mg over 24 h) and nine patients for a longer period (600 mg/die from 1 week up to 12 months). After short-term administration of ketoconazole, serum cortisol levels fell distinctly only in the patient with adrenocortical adenoma, but not at all or only slightly in the other patients, whereas serum levels of progesterone and 11-deoxy-compounds increased markedly in all patients, with the exception of the patient with adrenocortical carcinoma. Plasma ACTH levels increased in the patients with Cushing's disease but not in the patients with tumor. After long-term treatment of three patients with Cushing's disease over 3, 10, and 12 months, the clinical signs of hypercortisolism persisted or were only slightly ameliorated. In these three patients as well as in three other patients with Cushing's disease treated for a shorter period of 1 to 4 weeks, serum and urinary cortisol levels decreased, but were not normalized, whereas plasma ACTH levels increased variably. Only in one patient with Cushing's disease, in the second patient with adrenocortical adenoma, and in the patient with ectopic ACTH syndrome, serum and urinary cortisol levels returned to normal. We conclude from our data, that the antimycotic drug inhibits biosynthesis of cortisol by blocking adrenal 11 beta- and 17 alpha-hydroxylase activity.(ABSTRACT TRUNCATED AT 250 WORDS)

ACTH Syndrome, Ectopic↗