cortodoxone and trilostane

Trilostane is thought to be a competitive inhibitor of the 3beta-hydroxysteroid dehydrogenase (3beta-HSD), an essential enzyme system for the synthesis of cortisol, aldosterone and androstenedione. Due to its reliable clinical efficacy, trilostane is increasingly used to treat dogs with pituitary-dependant hyperadrenocorticism (PDH). The objective of our study was to investigate the effect of trilostane on precursor concentrations located before (17alpha-OH-pregnenolone, dehydroepiandrostenedione) and after (17alpha-OH-progesterone, androstenedione, 11-deoxycortisol, 21-deoxycortisol) the proposed enzyme inhibition, on end products of steroid biosynthesis (cortisol and aldosterone) and on endogenous adrenocorticotrophic hormone (ACTH) concentrations in dogs with PDH. Hormones of the steroid biosynthesis pathway were evaluated in 15 dogs before and 1h after injection of synthetic ACTH prior to (t(0)), in weeks 1-2 (t(1)) and in weeks 3-7 (t(2)) of trilostane treatment. Endogenous ACTH concentrations were measured at the same time points before performing the ACTH stimulation test. During trilostane treatment baseline and post-stimulation cortisol concentrations decreased significantly. Baseline serum aldosterone levels showed a significant increase; post-stimulation values decreased. Baseline and post-stimulation 17alpha-OH-pregnenolone and dehydroepiandrostenedione concentrations increased significantly. 17alpha-OH-progesterone and androstenedione levels did not change. Post-stimulation 21-deoxycortisol concentrations decreased significantly, baseline 11-deoxycortisol concentrations increased significantly. Endogenous ACTH levels showed a significant increase. The significant increase in 17alpha-OH-pregnenolone and dehydroepiandrostenedione concentrations confirms an inhibitory effect of trilostane on the 3beta-HSD. Since 17alpha-OH-progesterone concentrations did not change, but cortisol concentrations markedly decreased, trilostane seems to influence additional enzymes of the hormone cascade, like the 11beta-hydroxylase and possibly the 11beta-hydroxysteroid dehydrogenase.

Topics: 17-alpha-Hydroxypregnenolone; 3-Hydroxysteroid Dehydrogenases; Adrenocortical Hyperfunction; Adrenocorticotropic Hormone; Aldosterone; Androstenedione; Animals; Cortodoxone; Dehydroepiandrosterone; Dihydrotestosterone; Dog Diseases; Dogs; Enzyme Inhibitors; Female; Hydrocortisone; Male; Prospective Studies; Statistics, Nonparametric

Recombinant human (rh) insulin-like growth factor-I (IGF-I) was more potent than rhIGF-II at inducing in vitro germinal vesicle breakdown (GVBD), a marker for resumption of meiosis, in oocytes of striped bass. Treatment of ovarian fragments containing oocytes in intact follicles with rhIGF-I increased concentrations of estradiol-17beta and maturation-inducing steroid (MIS) 17,20beta, 21-trihydoxy-4-pregnen-3-one (20beta-S) in the culture medium and decreased testosterone levels. The follicles were too immature for oocytes to complete GVBD in response to 20beta-S (MIS incompetent) or hCG. Addition of 20beta-S to cultures did not increase the percentage of oocytes completing GVBD in response to rhIGF-I or rhIGF-II. Bovine insulin was without effect on GVBD or steroid production. Incubation of MIS-competent follicles with actinomycin D, cyanoketone, trilostane, 1-heptanol, or 1-octanol had no effect on rhIGF-I-induced GVBD, but attenuated hCG-induced GVBD and 20beta-S production. Cycloheximide inhibited rhIGF-I-induced GVBD. Collectively, these observations indicate that IGF-I can induce GVBD via MIS- and transcription-independent pathways without coupled gap junctions between oocytes and granulosa cells or among granulosa cells, but requires protein synthesis to do so. An rhIGF-I analogue that does not bind IGF-binding proteins, des(1,3)IGF-I, was more potent than rhIGF-I in inducing GVBD, suggesting ovarian IGF-binding proteins may inhibit IGF-I action.

Topics: 1-Octanol; Animals; Bass; Cattle; Chorionic Gonadotropin; Cortodoxone; Cyanoketone; Cycloheximide; Dactinomycin; Dihydrotestosterone; Female; Heptanol; Humans; Hydroxysteroid Dehydrogenases; In Vitro Techniques; Insulin; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Oocytes; Ovary; Peptide Fragments; Recombinant Proteins; Steroids; Transport Vesicles; Uncoupling Agents

The effect of trilostane and aminoglutethimide on steroidogenesis was studied on isolated guinea pig adrenocortical cells in order to verify whether, in addition to the inhibitory influence of trilostane on 3beta-hydroxysteroid dehydrogenase and isomerase and the inhibition by aminoglutethimide of pregnenolone formation, these inhibitors may also affect other enzymatic steps of cortisol synthesis. While trilostane completely abolished cortisol production in response to ACTH with concomitant enhancement in pregnenolone and 17-hydroxypregnenolone formation, the conversion of progesterone, 17-hydroxyprogesterone and 11-deoxycortisol into cortisol was not affected by the presence of the inhibitor. Contrasting with this specific inhibitory effect of trilostane, aminoglutethimide inhibited not only pregnenolone formation but also several other enzymatic steps involved in the conversion of this precursor of steroidogenesis into cortisol. Among these additional effects of aminoglutethimide on steroidogenesis, the inhibition of 11 beta-hydroxylation was clearly demonstrated.

Topics: 17-alpha-Hydroxypregnenolone; 17-alpha-Hydroxyprogesterone; Adrenal Cortex; Adrenocorticotropic Hormone; Aminoglutethimide; Animals; Cortodoxone; Dihydrotestosterone; Guinea Pigs; Hydrocortisone; Hydroxyprogesterones; Male; Pregnenolone; Progesterone