ABSTRACT
Background: Familial hyperaldosteronism type I is caused by the generation of a chimeric aldosterone synthase enzyme (ASCE) which is regulated by ACTH instead of angiotensin II. We have reported that in vitro, the wild-type (ASWT) and chimeric aldosterone synthase (ASCE) enzymes are inhibited by progesterone and estradiol does not affect their activity. Aim: To explore the direct action of testosterone on ASWT and ASCE enzymes. Material and Methods: HEK-293 cells were transiently transfected with vectors containing the full ASWT or ASCE cDNAs. The effect of testosterone on AS enzyme activities was evaluated incubating HEK-cells transfected with enzyme vectors and adding deoxycorticosterone (DOC) alone or DOC plus increasing doses of testosterone. Aldosterone production was measured by HPLC-MS/MS. Docking of testosterone within the active sites of both enzymes was performed by modelling in silico. Results: In this system, testosterone inhibited ASWT (90% inhibition at five pM, 50% inhibitory concentration (IC50) =1.690 pM) with higher efficacy andpotency than ASCE (80% inhibition at five pM, IC50=3.176 pM). Molecular modelling studies showed different orientation of testosterone in ASWT and ASCE crystal structures. Conclusions: The inhibitory effect of testosterone on ASWT or ASCE enzymes is a novel non-genomic testosterone action, suggesting that further clinical studies are needed to assess the role of testosterone in the screening and diagnosis of primary aldosteronism.
ABSTRACT
Background: Melatonin receptors are widely distributed in human tissues but they have not been reported in human adrenal gland. Aim: To assess if the human adrenal gland expresses melatonin receptors and if melatonin affeets cortisol response to ACTH in dexamethasone suppressed volunteers. Material and methods: Adrenal glands were obtained from 4 patients undergoing unilateral nephrectomy-adrenalectomy for renal cáncer. Expression of mRNA MT1 and MT2 melatonin receptors was measured by Reverse Transcriptase Polymerase Chain Reaction (RT-PCR). The effect of melatonin on the response to intravenous (i.v.) ACTH was tested (randomized cross-over, double-blind, placebo-controlled tríal) in eight young healthy males pretreated with dexamethasone (1 mg) at 23:00 h. On the next day at 08:00 h, an i.v. Une was inserted, at 08:30 h, and after a blood sample, subjeets ingested 6 mg melatonin or placebo. At 09:00 h, 1-24 ACTH (Cortrosyn, 1µg/1.73 m² body surface área) was injected, drawing samples at 0, 15, 30, 45 and 60 minutes after. Melatonin, cortisol, cortisone, progesterone, aldosterone, DHEA-S, testosterone and prolactin were measured by immunoassay. Results: The four adrenal glands expressed only MT1 receptor mRNA. Melatonin ingestión reduced the cortisol response to ACTH from 14.6+1.45µg/dl at 60 min in the placebo group to 10.8+1.2µg/dl in the melatonin group (p <0.01 mixed model test). It did not affect other steroid hormone levels and abolished the morningphysiological decline of prolactin. Conclusions: The expression ofMTl melatonin receptor in the human adrenal, and the melatonin reduction of ACTH-stimulated cortisol production suggest a direct melatonin action on the adrenal gland .
Subject(s)
Adult , Humans , Male , Young Adult , Adrenal Glands/drug effects , Adrenocorticotropic Hormone/pharmacology , Hydrocortisone/biosynthesis , Melatonin/pharmacology , Receptor, Melatonin, MT1/analysis , /analysis , Adrenal Glands , Adrenocorticotropic Hormone/administration & dosage , Cross-Over Studies , Dexamethasone/pharmacology , Double-Blind Method , Glucocorticoids/pharmacology , Immunoassay , Melatonin/administration & dosage , RNA, Messenger/analysis , Receptor, Melatonin, MT1/drug effects , /drug effects , Reverse Transcriptase Polymerase Chain Reaction , Time Factors , Young AdultABSTRACT
The circadian time-keeping system ensures predictive adaptation of individuals to the reproducible 24-h day/night alternations of our planet by generating the 24-h (circadian) rhythms found in hormone release and cardiovascular, biophysical and behavioral functions, and others. In mammals, the master clock resides in the suprachiasmatic nucleus (SCN) of the hypothalamus. The molecular events determining the functional oscillation of the SCN neurons with a period of 24-h involve recurrent expression of several clock proteins that interact in complex transcription/translation feedback loops. In mammals, a glutamatergic monosynaptic pathway originating from the retina regulaltes the clock gene expression pattern in the SCN neurons, synchronizing them to the light:dark cycle. The emerging concept is that neural/humoral output signals from the SCN impinge upon peripheral clocks located in other areas of the brain, heart, lung, gastrointestinal tract, liver, kidney, fibroblasts, and most of the cell phenotypes, resulting in overt circadian rhythms in integrated physiological functions. Here we review the impact of day/night alternation on integrated physiology; the molecular mechanisms and input/output signaling pathways involved in SCN circadian function; the current concept of peripheral clocks; and the potential role of melatonin as a circadian neuroendocrine transducer.
Subject(s)
Animals , Circadian Rhythm , Gene Expression , Melatonin , Suprachiasmatic Nucleus , Circadian RhythmSubject(s)
Infant , Adult , Middle Aged , Humans , Male , Female , Hypoparathyroidism/complications , Retrospective Studies , Hypoparathyroidism/physiopathology , SyndromeSubject(s)
Adult , Middle Aged , Humans , Male , Female , Parathyroid Neoplasms/diagnosis , Radionuclide Imaging , Adenoma/diagnosis , HyperplasiaABSTRACT
Diferentes pruebas inespecíficas de estimulación se emplean para estudiar la capacidad de la hipófisis para secretar hormona del crecimiento, pero ninguno es totalmente confiable. Los autores emplearon factor liberador de hormona del crecimiento (1microng x kg de peso corporal endovenoso) en 6 niños de talla baja pero sin afecciones endocrinas y en 4 pacientes con deficiencia comprobada de hormona del crecimiento. La concentración plasmática máxima de la hormona en los niños normales, durante la prueba, fue de 47,4 + ou - 15,4 ng x ml. Tres de los cuatro pacientes no mostraron respuesta a la provocación y en el cuatro la concentración plasmática máxima alcanzada fue de 5,3 ng x ml sugiriendo un origen hipotalámico para su deficiencia hormonal. El empleo de factor liberador sería de utilidad en el futuro para el diagnóstico y tratamiento de la deficiencia de hormona del crecimiento
Subject(s)
Child , Adolescent , Adult , Middle Aged , Humans , Male , Female , Growth Disorders/blood , Growth Hormone-Releasing Hormone/pharmacology , Growth Hormone/metabolism , ChileABSTRACT
Las formas de deficiencia aislada de hormona de crecimiento son poco frecuentes. Se presentan 2 casos de deficiencia aislada de somatotrofina, un hombre adulto y su hija. El probando, hija única a la edad de 2 a 7 edad de 2 2 a 7 meses medía 69,0 y tenía las características clínicas descritas en el hipopituitarismo infantil. Sus niveles séricos de hormona de crecimiento fueron subnormales y no respondió a la hipoglicemia inducida ni a GRF. El padre tiene una talla de 139,0 cm, también con las características clínicas de deficiencia de hormona de crecimiento. En ambos pacientes el resto de la función hipofisiaria fue normal. Las diferentes formas genéticas de enanismo hipofisiario corresponde a una forma autosómica dominante y esta familia representa la primera que se publica en Chile