scholarly journals On the Assessment of the in Vitro Biopotency and Site(s) of Action of Drugs Affecting Adrenal Steroidogenesis

1986 ◽  
Vol 23 (3) ◽  
pp. 225-229 ◽  
Author(s):  
A Lambert ◽  
J Frost ◽  
R Mitchell ◽  
W R Robertson
Keyword(s):  
Guinea Pig ◽  
Cyproterone Acetate ◽  
Hydroxysteroid Dehydrogenase ◽  
Megestrol Acetate ◽  
Cortisol Secretion ◽  
Adrenal Cells ◽  
Adrenal Steroidogenesis ◽  
Biological Potency ◽  
Sites Of Action

Dispersed guinea-pig adrenal cells have been employed in the in vitro estimation of the biological potency and sites of action of drugs acting against the adrenal. The effect of 12 drugs on cortisol secretion from cells stimulated with adrenocorticotrophin (ACTH, 50 ng/L, a 95% saturating dose) has been tested. All the drugs depressed cortisol output in a dose-related fashion. The concentration of drug which inhibited secretion by 50% was (μmol/L, mean±SEM): etomidate 0·1±0·002; epostane 0·44±0·02: 17-ketotrilostane 0·55±0·04: trilostane 1·3±0·1: metyrapone 3·5±0·6: cyproterone acetate 4·6±0·2: megestrol acetate 11±2: danazol 22±2: aminoglutethimide 41±5: stanozolol 50±4: thiopentone 160±18: propofol 170±18. The sites of the anti-steroidogenic effect of seven of these drugs have also been established using a method based upon the sequential stimulation by the exogenous precursor steroids of the various steps leading to the biosynthesis of cortisol by adrenal cells. Propofol acts between ACTH binding and pregnenolone production, trilostane, megestrol acetate and cyproterone acetate are 3β-hydroxysteroid dehydrogenase inhibitors whereas metyrapone, etomidate and thiopentone act at 11β-hydroxylase.

EFFECTS OF HYDROXYSTEROID DEHYDROGENASE INHIBITORS ON IN-VITRO AND IN-VIVO STEROIDOGENESIS IN THE OVINE ADRENAL GLAND

1982 ◽  
Vol 92 (2) ◽  
pp. 205-212 ◽  
Author(s):  
P. SINGH-ASA ◽  
G. JENKIN ◽  
G. D. THORBURN
Keyword(s):  
Adrenal Gland ◽  
Incubation Medium ◽  
Bovine Serum ◽  
Hydroxysteroid Dehydrogenase ◽  
Inhibitory Effect ◽  
Bovine Serum Albu ◽  
Stimulatory Action ◽  
Adrenal Steroidogenesis

The effectiveness of trilostane and azastene as inhibitors of adrenal steroidogenesis was compared by in-vitro and in-vivo methods. A radioimmunoassay was developed for the measurement of cortisol in ovine plasma, incubation medium and tissue extract using a specific antiserum raised against cortisol 21-acetate,3-carboxymethyloxime : bovine serum albu Trilostane (20 μmol/l) decreased cortisol synthesis and release both in unstimulated and in ACTH-stimulated adrenal tissues in vitro. The same concentration of azastene had a lesser effect on unstimulated adrenals and was completely ineffective in blocking the stimulatory action of ACTH. In vivo, trilostane suppressed adrenal steroidogenesis in pregnant and cyclic ewes but the suppression in pregnant ewes was over a longer period, and after lower doses. It is concluded that trilostane had an inhibitory effect on ovine adrenal steroidogenesis both in vitro and in vivo.

Biopotency and site of action of drugs affecting testicular steroidogenesis

1987 ◽  
Vol 113 (3) ◽  
pp. 457-461 ◽  
Author(s):  
A. Lambert ◽  
R. Mitchell ◽  
W. R. Robertson
Keyword(s):  
Cyproterone Acetate ◽  
Leydig Cells ◽  
Hydroxysteroid Dehydrogenase ◽  
Hormone Stimulation ◽  
Testosterone Secretion ◽  
Testicular Cells ◽  
Adrenal Steroidogenesis ◽  
Site Of Action ◽  
Testicular Steroidogenesis

ABSTRACT The effect of etomidate (an anaesthetic), epostane (WIN 32729; an inhibitor of ovarian and adrenal steroidogenesis) and cyproterone acetate (an antiandrogen) on testosterone secretion from mouse Leydig cells stimulated with LH (5 i.u./l) was tested. The concentration of drug which inhibited testosterone secretion by 50% was 11·5±1·1 (s.e.m.) μmol/l for cyproterone acetate, 1·2 ± 0·2 μmol/l for etomidate and 0·23 ± 0·03 μmol/l for epostane. The effect of all three drugs on testicular steroidogenesis was completely reversible. Thus testicular cells which had been washed after exposure to a >95% inhibitory dose of drug responded in a similar manner to hormone stimulation as cells similarly washed and which had not been exposed to the drug. The sites of the antisteroidogenic effect of epostane, etomidate and cyproterone acetate were established using a method based on the sequential stimulation by the exogenous precursor steroids of the various steps leading to the biosynthesis of testosterone. It was concluded that etomidate acts at the sequence between LH binding and pregnenolone production, epostane acts at 3β-hydroxysteroid dehydrogenase and cyproterone acetate inhibits 3β-hydroxysteroid dehydrogenase and C17,20-lyase. J. Endocr. (1987) 113, 457–461

Effects of Cyproterone Acetate on Adrenal Steroidogenesis in vitro

1984 ◽  
Vol 20 (2) ◽  
pp. 108-115 ◽  
Author(s):  
M.T. Pham-Huu-Trung ◽  
N. de Smitter ◽  
A. Bogyo ◽  
F. Girard
Keyword(s):  
Cyproterone Acetate ◽  
Adrenal Steroidogenesis

scholarly journals Autoantibodies reactive to adrenocorticotropic hormone can alter cortisol secretion in both aggressive and nonaggressive humans

2018 ◽  
Vol 115 (28) ◽  
pp. E6576-E6584 ◽  
Author(s):  
Henning Værøy ◽  
Csaba Adori ◽  
Romain Legrand ◽  
Nicolas Lucas ◽  
Jonathan Breton ◽  
...  
Keyword(s):  
Amino Acids ◽  
Adrenocorticotropic Hormone ◽  
Cortisol Secretion ◽  
Adrenal Cells ◽  
Igg Binding ◽  
History Of ◽  
Response To Stress ◽  
Underlying Mechanisms ◽  
Epitope Binding

Violent aggression in humans may involve a modified response to stress, but the underlying mechanisms are not well understood. Here we show that naturally present autoantibodies reactive to adrenocorticotropic hormone (ACTH) exhibit distinct epitope-binding profiles to ACTH peptide in subjects with a history of violent aggression compared with controls. Namely, while nonaggressive male controls displayed a preferential IgG binding to the ACTH central part (amino acids 11–24), subjects who had committed violent acts of aggression had IgG with increased affinity to ACTH, preferentially binding to its N terminus (amino acids 1–13). Purified IgGs from approximately half of the examined sera were able to block ACTH-induced cortisol secretion of human adrenal cells in vitro, irrespective of the source of sample (from a control subject or a violent aggressor). Nevertheless, in the resident–intruder test in mice, i.p. injection of residents with ACTH and IgG from aggressive subjects, but not from control subjects, shortened latency for the first attack against intruders. Immunohistochemical screening of violent aggressors’ sera on rat brain and pituitary sections did not show IgG binding to ACTH-producing cells, but 4 of 16 sera revealed selective binding to a nonidentified antigen in vasopressinergic neurons of the hypothalamic paraventricular and supraoptic nuclei. Thus, the data show that ACTH-reactive plasmatic IgGs exhibit differential epitope preference in control and violently aggressive subjects. These IgGs can modulate ACTH-induced cortisol secretion and, hence, are involved in the regulation of the stress response. However, the possible role of ACTH-reactive autoantibodies in aggressive behavior needs further investigation.

scholarly journals Food-Dependent Cushing’s Syndrome: Possible Involvement of Leptin in Cortisol Hypersecretion*

1999 ◽  
Vol 84 (10) ◽  
pp. 3817-3822 ◽  
Author(s):  
François P. Pralong ◽  
Fulgencio Gomez ◽  
Louis Guillou ◽  
François Mosimann ◽  
Sebastiano Franscella ◽  
...  
Keyword(s):  
Food Intake ◽  
Cushing’S Syndrome ◽  
Adrenal Adenoma ◽  
Cushing's Syndrome ◽  
Cortisol Secretion ◽  
Adrenal Hyperplasia ◽  
Adrenal Cells ◽  
Patient Reported ◽  
Stimulation Of

Abstract Stimulation of cortisol secretion by food intake has been implicated in the pathogenesis of some cases of ACTH-independent Cushing’s syndrome, via an aberrant response of the adrenal glands to gastric inhibitory polypeptide (GIP). We report here a novel case of food-dependent Cushing’s syndrome in a patient with bilateral macronodular adrenal hyperplasia. In this patient we were able to confirm a paradoxical stimulation of cortisol secretion by GIP in vivo as well as in vitro on dispersed tumor adrenal cells obtained at surgery. In addition to GIP, in vitro stimulation of these cultured tumor adrenal cells with leptin, the secreted product of the adipocyte, induced cortisol secretion. By comparison, no such stimulation was observed in vitro in adrenal cells obtained from another patient with bilateral macronodular adrenal hyperplasia and Cushing’s syndrome that did not depend on food intake, in tumor cells obtained from a solitary cortisol-secreting adrenal adenoma, and in normal human adrenocortical cells. These results demonstrate that as in previously described cases of food-dependent Cushing’s syndrome, GIP stimulated cortisol secretion from the adrenals of the patient reported here. Therefore, they indicate that such a paradoxical response probably represents the hallmark of this rare condition. In addition, they suggest that leptin, which normally inhibits stimulated cortisol secretion in humans, participated in cortisol hypersecretion in this case. Further studies in other cases of food-dependent Cushing’s syndrome, however, will be necessary to better ascertain the pathophysiological significance of this finding.

Primary adrenocortical micronodular adenomatosis causing Cushing's syndrome. Effects of ketoconazole on steroid production and in vitro performance of adrenal cells

1986 ◽  
Vol 113 (3) ◽  
pp. 370-377 ◽  
Author(s):  
W. Oelkers ◽  
V. Bähr ◽  
J. Hensen ◽  
H. Pickartz ◽  
P. Exner ◽  
...  
Keyword(s):  
Cushing’S Syndrome ◽  
Plasma Cortisol ◽  
Venous Blood ◽  
Clinical Signs ◽  
Cushing's Syndrome ◽  
Cortisol Secretion ◽  
Urinary Cortisol ◽  
Adrenal Cells

Abstract. Mild Cushing's syndrome was diagnosed in a 35 year old woman. Elevated plasma and urinary cortisol levels were unsuppressible with up to 32 mg dexamethasone per day. Aldosterone, 18-OH-corticosterone and testosterone in plasma were normal and dehydroepiandrosterone-sulphate was low. No adrenal tumour was found by CT or adrenal venography, and bilateral cortisol secretion was demonstrated by steroid measurements in adrenal venous blood. A circadian rhythm of plasma cortisol was absent. Plasma ACTH was suppressed, even after injection of CRH, during insulininduced hypoglycaemia and after metyrapone administration, which led to a large fall in plasma cortisol but to a subnormal rise of plasma 11-deoxy-cortisol. The clinical diagnosis of primary micronodular adenomatosis of the adrenal gland was histologically confirmed, when the patient finally underwent bilateral adrenalectomy. In vitro, the adrenal cells did not produce more cortisol and aldosterone than adrenal cells from cadaver kidney donors. In vivo and in vitro, cortisol was slightly less than normally responsive to ACTH. Intermittent treatment of the patient with 800 mg/day of ketoconazole led to a rapid fall of cortisol secretion and clinical signs of adrenocortical insufficiency. Treatment for 7 weeks with 200–400 mg ketoconazole per day reduced plasma and urinary cortisol less dramatically into the normal range. This case unequivocally documents autonomous dysfunction of the adrenal cortex in this rare form of Cushing's syndrome and the efficacy of ketoconazole in the treatment of ACTH-independent hypercortisolism.

The cellular mechanism of the antiandrogenic action of nomegestrol acetate, a new 19-nor progestagen, on the rat prostate

1987 ◽  
Vol 115 (4) ◽  
pp. 544-550 ◽  
Author(s):  
Jacqueline Botella ◽  
Jacques Paris ◽  
Brahim Lahlou
Keyword(s):  
Androgen Receptor ◽  
Cyproterone Acetate ◽  
Megestrol Acetate ◽  
Ventral Prostate ◽  
Chlormadinone Acetate ◽  
Rat Ventral Prostate ◽  
Nomegestrol Acetate ◽  
Nuclear Location ◽  
Rat Prostate

Abstract. Nomegestrol acetate, like other synthetic progestins such as medroxyprogesterone acetate (MPA), chlormadinone acetate, megestrol acetate and cyproterone acetate, is able to modify the physiological actions of androgens. In the present study, the effects of nomegestrol acetate and other antiandrogens on the binding of androgen to the androgen receptor (AR) and on the 'activation' of this receptor were investigated, using rat ventral prostate as target model. Relative binding affinities (RBA) for AR were first estimated in vitro with respect to [3H]testosterone for a series of structurally-related compounds. The values obtained ranged as follows: dihydrotestosterone (DHT) » megestrol acetate ≥ testosterone (T) > nomegestrol acetate > 19-nor progesterone (19NP) > progesterone (P). An assay was established, using two different incubation times (3 h and 24 h) to further investigate relationships between binding affinity and androgenic, or antiandrogenic, activity. The following order (as %) was obtained for progestins as against [3H]mibolerone (DMNT): 1) DMNT (100) » acetate (42) > megestrol acetate (29) > chlormadinone acetate (9) > MPA (8) > cyproterone acetate (6) after 3 h and 2) DMNT (100) » MPA (53) » nomegestrol acetate (19) > megestrol acetate (12) > chlormadinone acetate (14) and cyproterone acetate (8) after 24 h. Since the RBA of nomegestrol acetate declined with time, these results indicate that this substance may act like an antiandrogen rather than an androgen, while the contrary prevails concerning MPA. The effects of these progestins, administered either alone or in combination with DHT to the animals, on the location (nuclear or cytosolic) of AR were also analyzed. DHT (0.05 or 4 mg/kg) produced maximal nuclear location of AR. Of the progestins tested, only MPA and norethisterone acetate reproduced this effect, while other steroids were ineffective. Furthermore, cyproterone acetate, megestrol acetate and nomegestrol acetate were able to inhibit to a large extent the DHT-elicited effect. The evidence from these studies suggests that the new compound nomegestrol acetate may oppose the actions of androgens on ventral prostate by directly interacting with the androgen receptor.

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