RESUMEN
Evidence from animal and human research shows that established memories can undergo changes after reactivation through a process called reconsolidation. Alterations of the level of the stress hormone cortisol may provide a way to manipulate reconsolidation in humans. Here, in a double-blind, within-subject design, we reactivated a 3-d-old memory at 3:55 A.M. in sixteen men and four women, immediately followed by oral administration of metyrapone versus placebo, to examine whether metyrapone-induced suppression of the morning cortisol rise may influence reconsolidation processes during and after early morning sleep. Crucially, reactivation followed by cortisol suppression versus placebo resulted in enhanced memory for the reactivated episode tested 4 d after reactivation. This enhancement after cortisol suppression was specific for the reactivated episode versus a non-reactivated episode. These findings suggest that when reactivation of memories is immediately followed by suppression of cortisol levels during early morning sleep in humans, reconsolidation processes change in a way that leads to the strengthening of episodic memory traces.SIGNIFICANCE STATEMENT How can we change formed memories? Modulation of established memories has been long debated in cognitive neuroscience and remains a crucial question to address for basic and clinical research. Stress-hormone cortisol and sleep are strong candidates for changing consolidated memories. In this double-blind, placebo-controlled, within-subject pharmacological study, we investigate the role of cortisol on the modulation of reconsolidation of episodic memories in humans. Blocking cortisol synthesis (3 g metyrapone) during early morning sleep boosts memory for a reactivated but not for a non-reactivated story. This finding contributes to our understanding of the modulatory role of cortisol and its circadian variability on reconsolidation, and moreover can critically inform clinical interventions for the case of memory dysfunctions, and trauma and stress-related disorders.
Asunto(s)
Hidrocortisona/antagonistas & inhibidores , Consolidación de la Memoria/efectos de los fármacos , Memoria Episódica , Metirapona/farmacología , Adulto , Ritmo Circadiano , Estudios Cruzados , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Hidrocortisona/análisis , Hidrocortisona/biosíntesis , Hidrocortisona/fisiología , Masculino , Consolidación de la Memoria/fisiología , Metirapona/administración & dosificación , Polisomnografía , Reconocimiento en Psicología , Saliva/química , Fases del Sueño/fisiología , Esteroide 11-beta-Hidroxilasa/antagonistas & inhibidores , Adulto JovenRESUMEN
We provide the details of the successful management of a patient with active Cushing's disease complicated with coronavirus disease 2019 (COVID-19) pneumonia. The patient was a 27-year-old Japanese female healthcare worker who was scheduled to undergo pituitary surgery for Cushing's disease. She had been in close contact with an undiagnosed patient infected with COVID-19 and then developed COVID-19 pneumonia. Despite a lack of known risk factors associated with severe COVID-19 infection, the patient's dyspnea worsened and her respiratory condition deteriorated, as indicated by the need for 7 L/min oxygen supply by mask to maintain her oxygen saturation at >90%. Medical treatment was initiated to control hypercortisolism by the 'block and replace' regimen using steroidogenesis inhibitors and hydrocortisone. The COVID-19 pneumonia improved with multi-modal treatment including antiviral therapy. One month later, after a negative severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) test result and with appropriate protection against virus transmission to medical staff in the operating room and daily medical care nurses, trans-sphenoidal surgery was performed by our highly experienced pituitary surgeon. One month after the surgery, the patient's basal ACTH and cortisol levels and urinary free cortisol were all under the detection limit. Surgical remission was expected. Since hypercortisolism due to active Cushing's disease may worsen a COVID-19 infection, multi-disciplinary management that includes appropriate and prompt treatment strategies is mandatory in such cases.
Asunto(s)
Amidas/administración & dosificación , Benzamidinas/administración & dosificación , COVID-19/terapia , Guanidinas/administración & dosificación , Metirapona/administración & dosificación , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/terapia , Pregnenodionas/administración & dosificación , Pirazinas/administración & dosificación , Adenoma Hipofisario Secretor de ACTH/complicaciones , Adenoma Hipofisario Secretor de ACTH/tratamiento farmacológico , Adenoma/complicaciones , Adenoma/tratamiento farmacológico , Adulto , COVID-19/complicaciones , COVID-19/patología , Terapia Combinada , Dihidrotestosterona/administración & dosificación , Dihidrotestosterona/análogos & derivados , Progresión de la Enfermedad , Femenino , Personal de Salud , Heparina/administración & dosificación , Humanos , Japón , Procedimientos Neuroquirúrgicos , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/sangre , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/complicaciones , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/patología , SARS-CoV-2/fisiología , Resultado del Tratamiento , Combinación Trimetoprim y Sulfametoxazol/administración & dosificaciónRESUMEN
There is extensive evidence that glucocorticoid hormones enhance memory consolidation, helping to ensure that emotionally significant events are well remembered. Prior findings suggest that the anteroventral region of bed nuclei of the stria terminalis (avBST) regulates glucocorticoid release, suggesting the potential for avBST activity to influence memory consolidation following an emotionally arousing learning event. To investigate this issue, male Sprague-Dawley rats underwent inhibitory avoidance training and repeated measurement of stress hormones, immediately followed by optogenetic manipulations of either the avBST or its projections to downstream regions, and 48 h later were tested for retention. The results indicate that avBST inhibition augmented posttraining pituitary-adrenal output and enhanced the memory for inhibitory avoidance training. Pretreatment with a glucocorticoid synthesis inhibitor blocked the memory enhancement as well as the potentiated corticosterone response, indicating the dependence of the memory enhancement on glucocorticoid release during the immediate posttraining period. In contrast, posttraining avBST stimulation decreased retention yet had no effect on stress hormonal output. Subsequent experiments revealed that inhibition of avBST input to the paraventricular hypothalamus enhanced stress hormonal output and subsequent retention, whereas stimulation did not affect either. Conversely, stimulation-but not inhibition-of avBST input to the ventrolateral periaqueductal gray impaired consolidation, whereas neither manipulation affected glucocorticoid secretion. These findings indicate that divergent pathways from the avBST are responsible for the mnemonic effects of avBST inhibition versus stimulation and do so via glucocorticoid-dependent and -independent mechanisms, respectively.
Asunto(s)
Reacción de Prevención/fisiología , Glucocorticoides/metabolismo , Consolidación de la Memoria/fisiología , Núcleos Septales/fisiología , Hormona Adrenocorticotrópica/análisis , Hormona Adrenocorticotrópica/metabolismo , Animales , Reacción de Prevención/efectos de los fármacos , Corticosterona/análisis , Corticosterona/metabolismo , Glucocorticoides/análisis , Glucocorticoides/antagonistas & inhibidores , Masculino , Consolidación de la Memoria/efectos de los fármacos , Metirapona/administración & dosificación , Modelos Animales , Vías Nerviosas/fisiología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Optogenética , Núcleo Hipotalámico Paraventricular/fisiología , Sustancia Gris Periacueductal/fisiología , Ratas , Ratas Sprague-Dawley , Receptores de Glucocorticoides/metabolismo , Núcleos Septales/citologíaRESUMEN
Following a stressful event, the hypothalamus-pituitary-adrenal axis mediates the release of the stress hormone cortisol (corticosterone in rodents; CORT). Elevated CORT binds to glucocorticoid receptors to mediate physiological responses including facilitating memory formation. Previous work from our laboratory demonstrated that male rats exposed to chronic stress demonstrate enhanced contextual fear memories and sensitized CORT responses to subsequent stress exposure; however, this is unknown in female rats. The experiments here tested whether chronic stress enhances fear memory formation in female rats and whether the sensitized CORT response in chronic stress rats contributes to their enhanced fear memory. Studies first examined CORT responses to contextual fear conditioning in male and female rats and examined whether chronic stress enhanced the formation of contextual fear memories 24â¯h later. Studies then used metyrapone, a CORT synthesis inhibitor, to investigate whether blockade of plasma CORT would eliminate the chronic stress-induced enhancement in contextual fear memory. Results show that female rats have greater CORT responses than males, and chronic stress sensitizes the CORT response to fear conditioning in both sexes. However, female rats do not show enhanced contextual fear memory following chronic stress. Chronically stressed male rats show greater memory acquisition and show greater contextual fear memory 24â¯h later following fear conditioning. Metyrapone dampens contextual fear memory in all rats but does not eliminate the enhancement in freezing behavior in chronic stress rats. Collectively, these studies indicate sensitized CORT responses in chronically stressed rats is likely not the mechanism by which chronic stress facilitates memory formation.
Asunto(s)
Corticosterona/metabolismo , Miedo/fisiología , Memoria/fisiología , Estrés Psicológico/metabolismo , Estrés Psicológico/psicología , Animales , Condicionamiento Clásico , Corticosterona/antagonistas & inhibidores , Femenino , Masculino , Metirapona/administración & dosificación , Ratas Endogámicas F344RESUMEN
Most animals constitute potential prey and must respond appropriately to predator-mediated stress in order to survive. Numerous prey also adaptively tailor their response to the prevailing level of risk and stress imposed by their natural enemies, i.e. they adopt an inducible defence strategy. Predator exposure may activate the stress axis, and drive the expression of anti-predator traits that facilitate survival in a high-risk environment (the predation-stress hypothesis). Here, we quantified two key morphological anti-predator traits, body morphology and coloration, in crucian carp reared in the presence or absence of a predator (pike) in addition to experimental manipulation of physiological stress via implants containing either cortisol or a cortisol inhibitor. We found that predator-exposed fish expressed a deeper-bodied phenotype and darker body coloration as compared with non-exposed individuals. Skin analyses revealed that an increase in the amount of melanophores caused the dramatic colour change in predator-exposed fish. Increased melanization is costly, and the darker body coloration may act as an inducible defence against predation, via a conspicuous signal of the morphological defence or by crypsis towards dark environments and a nocturnal lifestyle. By contrast, the phenotype of individuals carrying cortisol implants did not mirror the phenotype of predator-exposed fish but instead exhibited opposite trajectories of trait change: a shallow-bodied morphology with a lighter body coloration as compared with sham-treated fish. The cortisol inhibitor did not influence the phenotype of fish i.e. neither body depth nor body coloration differed between this group and predator-exposed fish with a sham implant. However, our results illuminate a potential link between stress physiology and morphological defence expression.
Asunto(s)
Adaptación Fisiológica , Carpas/anatomía & histología , Carpas/fisiología , Conducta Predatoria , Estrés Fisiológico/fisiología , Animales , Color , Esocidae , Hidrocortisona/administración & dosificación , Hidrocortisona/antagonistas & inhibidores , Melanóforos/efectos de los fármacos , Melanóforos/fisiología , Metirapona/administración & dosificaciónRESUMEN
Glucocorticoid hormones (GCs) play a pivotal role in many stress-related biological processes. In the hippocampus, GCs act through mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) to modify gene transcription. The involvement of GCs in biological processes has been investigated using the corticosterone (CORT)-synthesis blocker metyrapone. How metyrapone affects the action of GC at the genomic level still remains unclear. Therefore, we investigated the effects of this enzyme blocker on plasma CORT levels and hippocampal MR and GR binding to GC responsive elements (GREs) within the GC target genes Fkbp5 (FK506-binding protein 5), Per1 (Period 1) and Sgk1 (Serum- and glucocorticoid-activated kinase 1), as well as the transcriptional responses of these genes under control and acute stress conditions in rats. For comparison, we also investigated these endpoints in rats that had undergone adrenalectomy (ADX). Although metyrapone had no effect on baseline levels of CORT, the drug increased MR and GR to GRE binding within the GC target genes and the transcriptional activity of these genes. As expected, acute forced swim (FS) stress strongly increased plasma CORT levels, hippocampal MR and GR to GRE binding within Fkbp5, Per1 and Sgk1, and the transcriptional activity (mainly hnRNA levels) of these genes. Metyrapone attenuated, but did not abolish, these effects of stress on plasma CORT and MR and GR to GRE binding. The drug effects on FS-induced transcriptional activity were gene-dependent with a reduction seen in Fkbp5 hnRNA (but not Fkbp5 mRNA), an enhancement in Per1 hnRNA (but not Per1 mRNA), and no effect on both Sgk1 hnRNA and mRNA levels. ADX however completely abrogated the effects of FS on plasma CORT, as well as hippocampal MR and GR to GRE binding and transcriptional responses. Thus, in contrast to ADX, metyrapone produced inconsistent effects on GC-sensitive genomic endpoints that question its suitability as a tool in neuroendocrine and other research.
Asunto(s)
Inhibidores Enzimáticos/administración & dosificación , Genoma/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Metirapona/administración & dosificación , Receptores de Glucocorticoides/metabolismo , Receptores de Mineralocorticoides/metabolismo , Transcripción Genética/efectos de los fármacos , Animales , Corticosterona/sangre , Proteínas Inmediatas-Precoces/metabolismo , Masculino , Proteínas Circadianas Period/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Ratas Wistar , Estrés Psicológico/metabolismo , Proteínas de Unión a Tacrolimus/metabolismoRESUMEN
Two years after diagnosis of a metastatic neuroendocrine gastrin-secreting tumour and after several cycles of chemotherapy and peptide receptor radionuclide therapy, a 56-year-old woman presented with hypokalaemic metabolic alkalosis, hypertension, leg oedema and new-onset diabetes mellitus. Further investigations revealed renal potassium loss confirmed by a transtubular potassium gradient of 16, fully suppressed serum aldosterone, but instead highly elevated blood levels of morning cortisol and adrenocorticotropic hormone as well as increased urinary excretion of glucocorticoid and mineralocorticoid metabolites. Ruling out other causes, paraneoplastic hypercortisolism was diagnosed. Pharmacological inhibition of the steroid 11ß-hydroxylase with metyrapone resulted in complete resolution of metabolic alkalosis, hypokalaemia, hypertension, hyperglycaemia and leg oedema within 1 week.
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Síndrome de Cushing/diagnóstico , Síndrome de Cushing/tratamiento farmacológico , Metirapona/administración & dosificación , Alcalosis , Síndrome de Cushing/enzimología , Diabetes Mellitus/enzimología , Diabetes Mellitus/etiología , Femenino , Humanos , Hipertensión/enzimología , Hipertensión/etiología , Hipopotasemia/enzimología , Hipopotasemia/etiología , Metirapona/uso terapéutico , Persona de Mediana Edad , Esteroide 11-beta-Hidroxilasa/antagonistas & inhibidores , Resultado del TratamientoRESUMEN
Sex differentiation in many lower vertebrates (e.g. reptiles, amphibians, and fishes) can be influenced by environmental factors experienced during sensitive developmental periods. Environmental stressors, acting through cortisol, masculinize some teleost fishes during development by limiting gonadal cytochrome P450 aromatase (cyp19a1a), the enzyme that irreversibly converts testosterone to 17ß-estradiol. In this study, we examined the influence of cortisol, cortisol inhibitors and a repeated, acute stressor (net-chasing) on sex differentiation in black sea bass (BSB; Centropristis striata), a protogynous hermaphroditic teleost. Wild-caught, sexually-undifferentiated, BSB juveniles (~90â¯mm) were collected from Rhode Island waters, raised in recirculating systems and fed diets supplemented with cortisol, a cortisol receptor antagonist (mifepristone), a cortisol synthesis inhibitor (metyrapone), or net-chased twice a week for two min until gonads were differentiated (77-89â¯days). Long term cortisol administration partially masculinized all female fish, but repeated net-chasing did not alter sex differentiation relative to the control group. Blocking cortisol receptor binding delayed sex differentiation in some individuals, but overall led to increased masculinization compared to control fish. The proportion of treatment fish that developed as males suggests a functionally, diandric protogynous reproductive strategy in this species. We also identified a glucocorticoid response element in the gonadal aromatase (cyp19a1a) promoter, indicating a possible relationship between cortisol and cyp19a1a gene expression.
Asunto(s)
Lubina/fisiología , Hidrocortisona/administración & dosificación , Diferenciación Sexual , Estrés Fisiológico , Animales , Femenino , Masculino , Metirapona/administración & dosificación , Mifepristona/administración & dosificaciónRESUMEN
Ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is a condition of endogenous hypercortisolism sustained by an extrapituitary ACTH-secreting tumor. Olfactory neuroblastoma (ONB) is a rare malignant neoplasm of the sinonasal tract and is derived from the olfactory epithelium. Because the paranasal sinus is not a common site of EAS, the development of ONB in patients with EAS is rare. We herein report the first known case of ONB with acquirement of ACTH production during the clinical course as proven by immunohistochemistry. A 50-year-old man diagnosed with ONB was referred to our department in July 2015 because of hypokalemia, hyperglycemia, decreased eosinophil and granulocyte counts, and elevated serum levels of ACTH and cortisol. Although two previous ONB biopsy specimens (2011 and 2014) showed no ACTH immunoreactivity, a newly obtained specimen in August 2015 clearly showed ACTH immunoreactivity. This is the first case of ectopic ACTH syndrome associated with an ONB that acquired the ability to express ACTH during its clinical course as shown by serial immunohistochemical examinations.
Asunto(s)
Hormona Adrenocorticotrópica/metabolismo , Progresión de la Enfermedad , Estesioneuroblastoma Olfatorio/patología , Hormona Adrenocorticotrópica/sangre , Glucemia/metabolismo , Eosinófilos/patología , Estesioneuroblastoma Olfatorio/sangre , Estesioneuroblastoma Olfatorio/tratamiento farmacológico , Fluorodesoxiglucosa F18/química , Humanos , Hidrocortisona/sangre , Inmunohistoquímica , Recuento de Leucocitos , Masculino , Metirapona/administración & dosificación , Metirapona/uso terapéutico , Persona de Mediana Edad , Octreótido/análogos & derivados , Octreótido/química , Tomografía de Emisión de Positrones , Potasio/sangre , SíndromeRESUMEN
In the rat experimental model of posttraumatic stress disorder (PTSD), the level of blood corticosterone was at least eight-fold increased (an overrelease). The use of hypobaric hypoxic preconditioning or short-term inhibition of glucocorticoid synthesis by metyrapone injection prevented development of the experimental PTSD.
Asunto(s)
Glucocorticoides/sangre , Trastornos por Estrés Postraumático/sangre , Animales , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/uso terapéutico , Precondicionamiento Isquémico/métodos , Masculino , Metirapona/administración & dosificación , Metirapona/uso terapéutico , Ratas , Ratas Wistar , Trastornos por Estrés Postraumático/prevención & controlRESUMEN
Context: Adrenal incidentalomas (AIs) are found commonly on axial imaging. Around 30% exhibit autonomous cortisol secretion (ACS) associated with increased cardiovascular events and death. Objective: We hypothesized that AI/ACS patients have an abnormal cortisol rhythm that could be reversed by use of carefully timed short-acting cortisol synthesis blockade, with improvement in cardiovascular disease markers. Design, Setting, and Participants: In a phase 1/2a, prospective study (Eudract no. 2012-002586-35), we recruited six patients with AI/ACS and two control groups of six sex-, age-, and body mass index-matched individuals: (1) patients with AI and no ACS (AI/NoACS) and (2) healthy volunteers with no AI [healthy controls (HC)]. Twenty-four-hour circadian cortisol analysis was performed to determine any differences between groups and timing of intervention for cortisol lowering using the 11ß-hydroxylase inhibitor metyrapone. Circadian profiles of serum interleukin-6 (IL-6) were assessed. Results: Serum cortisol levels in group AI/ACS were significantly higher than both group AI/NoACS and group HC from 6 pm to 10 pm [area under the curve (AUC) difference: 0.81 nmol/L/h; P = 0.01] and from 10 pm to 2 am (AUC difference: 0.86 nmol/L/h; P < 0.001). In light of these findings, patients with ACS received metyrapone 500 mg at 6 pm and 250 mg at 10 pm, and cortisol rhythms were reassessed. Postintervention evening serum cortisol was lowered, similar to controls [6 pm to 10 pm (AUC difference: -0.06 nmol/L/h; P = 0.85); 10 pm to 2 am (AUC difference: 0.10 nmol/L/h; P = 0.76)]. Salivary cortisone showed analogous changes. IL-6 levels were elevated before treatment [10 pm to 2 pm (AUC difference: 0.42 pg/mL/h; P = 0.01)] and normalized post treatment. Conclusions: In AI/ACS, the evening and nocturnal cortisol exposure is increased. Use of timed evening doses of metyrapone resets the cortisol rhythm to normal. This unique treatment paradigm is associated with a reduction in the cardiovascular risk marker IL-6.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/metabolismo , Ritmo Circadiano , Hidrocortisona/metabolismo , Metirapona/administración & dosificación , Neoplasias de las Glándulas Suprarrenales/tratamiento farmacológico , Neoplasias de las Glándulas Suprarrenales/patología , Anciano , Área Bajo la Curva , Índice de Masa Corporal , Estudios de Casos y Controles , Cortisona/sangre , Cortisona/metabolismo , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Hidrocortisona/sangre , Interleucina-6/metabolismo , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Estadísticas no ParamétricasRESUMEN
OBJECTIVE: To determine whether an overnight metyrapone test (OMT) within the first week postpituitary surgery can definitively assess the hypothalamic-pituitary-adrenal (HPA) axis, compared with subsequent dynamic tests and glucocorticoid requirement at 6 months. DESIGN: Prospective study measuring morning cortisol levels on days 3 and 4 post-operatively, OMT day 5-7 and week 6, week 6 250 µg short Synacthen test (SST) and week 7 insulin tolerance test (ITT). PATIENTS AND MEASUREMENTS: Forty participants who underwent pituitary surgery at a single centre (Cushing's disease excluded) were followed for at least 6 months. 46% had pre-operative adrenal insufficiency. PRIMARY OUTCOME: week 1 OMT compared to glucocorticoid requirement at 6 months. SECONDARY OUTCOMES: the performance of ITT as a "definitive" test and all tests compared to glucocorticoid requirement at 6 months. RESULTS: Week 1 OMT showed concordance with ITT at week 7 of 78% and glucocorticoid requirement at 6 months of 81% respectively which was not significantly different from post-operative morning cortisol levels; 37% of participants with an abnormal OMT on day 6 had a normal OMT at week 6. All HPA axis tests showed similar concordance with glucocorticoid requirement at 6 months of 80%-85%. CONCLUSIONS: Overnight metyrapone test within the first week after pituitary surgery was no better than an early morning cortisol level at predicting glucocorticoid requirement at 6 months. OMT at week 6 demonstrated recovery of HPA axis in a substantial proportion of participants who failed earlier assessments; thus, definitive testing should be delayed until 6 weeks post-operatively.
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Sistema Hipotálamo-Hipofisario/fisiología , Metirapona/farmacología , Hipófisis/cirugía , Sistema Hipófiso-Suprarrenal/fisiología , Recuperación de la Función/fisiología , Insuficiencia Suprarrenal/cirugía , Adulto , Femenino , Glucocorticoides/uso terapéutico , Humanos , Hidrocortisona/sangre , Masculino , Metirapona/administración & dosificación , Persona de Mediana Edad , Periodo Posoperatorio , Valor Predictivo de las Pruebas , Estudios Prospectivos , Esteroide 11-beta-Hidroxilasa/antagonistas & inhibidores , Factores de TiempoRESUMEN
Cushing's syndrome (CS) is a rare disease caused by a chronic excess of cortisol. Hypercortisolaemia may affect reproductive system leading to infertility in women. However, some of the patients remain fertile, although pregnancy is uncommon. In our report, we describe the case of a 31-years old woman suffering from hypertension, oligomenorrhea, easy bruising, muscle weakness and elevated levels of cortisol. During hospitalization, high level of serum cortisol with stiff diurnal rhythm and undetectable plasma ACTH concentration were found. The overnight 1 mg dexamethasone (DEX) suppression test and the test with 8 mg of DEX were performed - plasma cortisol levels after both doses of DEX were over expected values. Thus, the diagnosis of ACTH independent hypercortisolaemia was established. After three weeks of ketoconazole treatment, high level of ß-HCG was found corresponding to the third week of pregnancy. The ketoconazole was shift to metyrapone but afterwards ketoconazole was added again. The treatment was well tolerated and pregnancy proceeded without complications. US scan revealed a 2 cm adenoma of the left adrenal gland, confirmed by CT. An adrenalectomy was performed. Concluding, we think that medical treatment of CS in pregnant women is well tolerated and safe both for the mother and fetus.
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Síndrome de Cushing/tratamiento farmacológico , Síndrome de Cushing/patología , Cetoconazol/administración & dosificación , Metirapona/administración & dosificación , Complicaciones del Embarazo/tratamiento farmacológico , Complicaciones del Embarazo/patología , Adulto , Quimioterapia Combinada , Femenino , Humanos , Embarazo , Resultado del TratamientoRESUMEN
Purpose: To investigate the kinetics of adrenocorticotropin (ACTH) following oral metyrapone administration and describe differences between ACTH-deficient and non-ACTH-deficient subjects. Methods: Patients from a tertiary endocrine center at a University Hospital in Munich, Germany, were tested for secondary adrenal insufficiency in a regular patient care setting. Metyrapone (Metopirone, HRA Pharma, France) was administered with a dosage of 40 mg/kg bodyweight at 8 a.m. Consecutive levels of ACTH were determined at 0, 60, 120, 180, and 240 min. Patients were categorized according to their need of glucocorticoid substitution in the follow-up phase. Results: A significant rise in ACTH concentration compared to basal values was found at 60 and 120 min following oral metyrapone administration. ACTH concentrations at 60 and 120 min predicted patients without need for glucocorticoid substitution. ACTH concentrations determined later had no additional benefit. Conclusion: In contrast to previous reports, we found a significant rise in ACTH concentration as soon as one hour after oral metyrapone administration. ACTH values seem to estimate the pituitary corticotrophic function when correlating results to the further clinical course of subjects. Further studies are needed to investigate this finding as a potential basis for a ACTH-based metyrapone short test protocol.
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Hormona Adrenocorticotrópica/sangre , Hipopituitarismo , Metirapona/administración & dosificación , Metirapona/farmacocinética , Administración Oral , Adulto , Anciano , Femenino , Estudios de Seguimiento , Alemania , Humanos , Hipopituitarismo/sangre , Hipopituitarismo/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Centros de Atención TerciariaRESUMEN
The objectives of this study were to determine the role of glucocorticoids in the regulation of prolactin (PRL) release induced by mammary gland stimulation and to investigate whether the milk depression induced by glucocorticoids in dairy cows is due to a decrease in PRL release. In experiment 1, 8 dairy cows were used in a 4 × 4 Latin square design. Four hours after the morning milking, the cows received 1 of the following treatments: (1) a 5-min manual stimulation of the mammary gland; (2) an i.v. injection of 1 mg of dexamethasone; (3) 2 infusions of 2.5 g of metyrapone (an inhibitor of cortisol biosynthesis) in the omasum 4 and 2 h before a 5-min stimulation of the mammary gland; or (4) no treatment. Sixty minutes later, the mammary gland of each cow was stimulated for 5 min. Blood samples were collected from 20 min before to 120 min after the start of the treatment. When the mammary gland was stimulated twice in 60 min, less PRL and cortisol were released during the second stimulation. Metyrapone did not affect PRL or cortisol release. Dexamethasone decreased serum cortisol concentration but did not affect PRL concentration. In experiment 2, 16 cows were used in a crossover experimental design consisting of 2 experimental weeks separated by 1 resting week. During the first week, cows were treated as follows: (1) 4 cows were injected with 0.5 g of domperidone (a PRL secretagogue) in canola oil on d 1 and 2 and 20 mg of dexamethasone on d 1; (2) 4 cows were injected with 0.5 g of domperidone on d 1 and 2; (3) 4 cows were injected with canola oil on d 1 and 2 and with 20 mg of dexamethasone on d 1; and (4) 4 cows were injected with canola oil on d 1 and 2. During the second experimental week, the same 4 treatments were repeated, except the cows that did not receive dexamethasone in the first week received it on d 1 of the second week, and cows that did receive it in the first week did not receive it in the second week. On d 1 and 2 of each week, blood samples were collected during morning milking for PRL determination. Dexamethasone reduced milk production and decreased both basal and milking-induced PRL release. It also increased milk fat and protein percentages and decreased milk lactose content. Domperidone increased basal PRL levels in serum and milk but did not affect milk yield. Although we cannot rule out the possibility that inhibition of PRL secretion or reduction of mammary gland PRL responsiveness play a role in the inhibition of milk production by glucocorticoids, the fact that enhancement of PRL secretion by domperidone could not prevent the depression of milk yield suggests that other mechanisms are involved.
Asunto(s)
Bovinos , Glucocorticoides/farmacología , Glándulas Mamarias Animales/fisiología , Prolactina/metabolismo , Aminoquinolinas/farmacología , Animales , Dexametasona/administración & dosificación , Domperidona/administración & dosificación , Antagonistas de Dopamina , Femenino , Glucocorticoides/fisiología , Humanos , Hidrocortisona/antagonistas & inhibidores , Hidrocortisona/sangre , Lactancia/efectos de los fármacos , Lactancia/fisiología , Metirapona/administración & dosificación , Leche/química , Omaso/efectos de los fármacos , Estimulación Física , Prolactina/análisis , Prolactina/sangreRESUMEN
BACKGROUND: Cushing's syndrome (CS) is a severe condition with excess mortality and significant morbidity necessitating control of hypercortisolemia. There are few data documenting use of the steroidogenesis inhibitor metyrapone for this purpose. OBJECTIVE: The objective was to assess the effectiveness of metyrapone in controlling cortisol excess in a contemporary series of patients with CS. DESIGN: This was designed as a retrospective, multicenter study. SETTING: Thirteen University hospitals were studied. PATIENTS: We studied a total of 195 patients with proven CS: 115 Cushing's disease, 37 ectopic ACTH syndrome, 43 ACTH-independent disease (adrenocortical carcinoma 10, adrenal adenoma 30, and ACTH-independent adrenal hyperplasia 3). MEASUREMENTS: Measurements included biochemical parameters of activity of CS: mean serum cortisol "day-curve" (CDC) (target 150-300 nmol/L); 9 am serum cortisol; 24-hour urinary free cortisol (UFC). RESULTS: A total of 164/195 received metyrapone monotherapy. Mean age was 49.6 ± 15.7 years; mean duration of therapy 8 months (median 3 mo, range 3 d to 11.6 y). There were significant improvements on metyrapone, first evaluation to last review: CDC (91 patients, 722.9 nmol/L [26.2 µg/dL] vs 348.6 nmol/L [12.6 µg/dL]; P < .0001); 9 am cortisol (123 patients, 882.9 nmol/L [32.0 µg/dL] vs 491.1 nmol/L [17.8 µg/dL]; P < .0001); and UFC (37 patients, 1483 nmol/24 h [537 µg/24 h] vs 452.6 nmol/24 h [164 µg/24 h]; P = .003). Overall, control at last review: 55%, 43%, 46%, and 76% of patients who had CDCs, UFCs, 9 am cortisol less than 331 nmol/L (12.0 µg/dL), and 9 am cortisol less than upper limit of normal/600 nmol/L (21.7 µg/dL). Median final dose: Cushing's disease 1375 mg; ectopic ACTH syndrome 1500 mg; benign adrenal disease 750 mg; and adrenocortical carcinoma 1250 mg. Adverse events occurred in 25% of patients, mostly mild gastrointestinal upset and dizziness, usually within 2 weeks of initiation or dose increase, all reversible. CONCLUSIONS: Metyrapone is effective therapy for short- and long-term control of hypercortisolemia in CS.
Asunto(s)
Síndrome de Cushing/tratamiento farmacológico , Inhibidores Enzimáticos/uso terapéutico , Metirapona/uso terapéutico , Adenoma Hipofisario Secretor de ACTH/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/efectos adversos , Humanos , Hidrocortisona/sangre , Hidrocortisona/orina , Lactante , Masculino , Metirapona/administración & dosificación , Metirapona/efectos adversos , Persona de Mediana Edad , Neoplasias Hipofisarias/tratamiento farmacológico , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
Steroidogenesis enzyme inhibitors are the mainstay of medical therapy in Cushing's syndrome (CS). Ketoconazole (KTZ) and metyrapone are the most commonly used agents. Although there is considerable experience of their use in individual specialist centres, these drugs have not been rigorously tested in prospective clinical trials. Clinicians face uncertainties and concerns with respect to the safety profile of these agents, and best means to monitor effect. We review steroidogenesis inhibitors in the management of CS, including older agents (KTZ, metyrapone, etomidate and mitotane) and those currently under development (LCI699, non-racemic KTZ), and offer a practical approach for their use in clinical practice.
Asunto(s)
Síndrome de Cushing/tratamiento farmacológico , Etomidato , Imidazoles , Cetoconazol , Metirapona , Mitotano , Piridinas , Inhibidores de la Síntesis de Esteroides , Etomidato/administración & dosificación , Etomidato/efectos adversos , Etomidato/farmacología , Humanos , Imidazoles/administración & dosificación , Imidazoles/efectos adversos , Imidazoles/farmacología , Cetoconazol/administración & dosificación , Cetoconazol/efectos adversos , Cetoconazol/farmacología , Metirapona/administración & dosificación , Metirapona/efectos adversos , Metirapona/farmacología , Mitotano/administración & dosificación , Mitotano/efectos adversos , Mitotano/farmacología , Piridinas/administración & dosificación , Piridinas/efectos adversos , Piridinas/farmacología , Inhibidores de la Síntesis de Esteroides/administración & dosificación , Inhibidores de la Síntesis de Esteroides/efectos adversos , Inhibidores de la Síntesis de Esteroides/farmacologíaRESUMEN
Cortisol's effects on memory follow an inverted U-shaped function such that memory retrieval is impaired with very low concentrations, presumably due to insufficient activation of high-affine mineralocorticoid receptors (MR), or with very high concentrations, due to predominant low-affine glucocorticoid receptor (GR) activation. Through corresponding changes in re-encoding, the retrieval effect of cortisol might translate into a persistent change of the retrieved memory. We tested whether partial suppression of morning cortisol synthesis by metyrapone, leading to intermediate, circadian nadir-like levels with presumed predominant MR activation, improves retrieval, particularly of emotional memory, and persistently changes the memory. In a randomized, placebo-controlled, double-blind, within-subject cross-over design, 18 men were orally administered metyrapone (1g) vs. placebo at 4:00 AM to suppress the morning cortisol rise. Retrieval of emotional and neutral texts and pictures (learned 3 days earlier) was assessed 4h after substance administration and a second time one week later. Metyrapone suppressed endogenous cortisol release to circadian nadir-equivalent levels at the time of retrieval testing. Contrary to our expectations, metyrapone significantly impaired free recall of emotional texts (p<.05), whereas retrieval of neutral texts or pictures remained unaffected. One week later, participants still showed lower memory for emotional texts in the metyrapone than placebo condition (p<.05). Our finding that suppressing morning cortisol to nadir-like concentrations not only impairs acute retrieval, but also persistently weakens emotional memories corroborates the concept that retrieval effects of cortisol produce persistent memory changes, possibly by affecting re-encoding.
Asunto(s)
Emociones/fisiología , Hidrocortisona/fisiología , Memoria/fisiología , Recuerdo Mental/fisiología , Adulto , Estudios Cruzados , Método Doble Ciego , Emociones/efectos de los fármacos , Humanos , Masculino , Memoria/efectos de los fármacos , Recuerdo Mental/efectos de los fármacos , Metirapona/administración & dosificación , Adulto JovenRESUMEN
CONTEXT: Severe Cushing's syndrome elicited by ectopic ACTH syndrome (EAS) or adrenal carcinoma (ACC) can threaten life in the short term. The effectiveness of oral administration of the inhibitors of steroidogenesis ketoconazole and metyrapone in this situation is poorly described. OBJECTIVE: To report the short-term effectiveness and tolerability of metyrapone and ketoconazole elicited either by EAS or by ACC in patients exhibiting severe hypercortisolism. DESIGN: Retrospective analysis of data obtained for patients with urinary free cortisol (UFC) level estimated to be fivefold the upper limit of the normal range (ULN). PATIENTS AND SETTINGS: A total of 14 patients with EAS and eight with ACC treated in two tertiary-care university hospitals. INTERVENTION: Metyrapone and ketoconazole treatment in combination (along with symptomatic treatments for co-morbidities). MAIN OUTCOME: Evolution of clinically relevant endpoints (blood pressure, kalaemia and glycaemia) and biological intensity of hypercortisolism 1 week and 1 month after starting steroidogenesis inhibition. RESULTS: After 1 week of treatment, median UFC fell from 40.0 to 3.2 ULN and from 16.0 to 1.0 ULN in patients with EAS and ACC respectively. Median UFC after 1 month of treatment was 0.5 and 1.0 ULN in patients with EAS and ACC respectively and UFC values were normal in 73 and 86% of patients respectively. Clinical status improved dramatically along with kalaemia, glycaemia and blood pressure, allowing a decrease in the relevant treatments.Side effects were minimal and only two patients (one EAS and one ACC) experienced plasma transaminase elevations necessitating ketoconazole withdrawal. CONCLUSION: Metyrapone-ketoconazole combination therapy is well tolerated and provides rapid control of endocrine cancer-related life-threatening hypercortisolism.
Asunto(s)
Síndrome de ACTH Ectópico/tratamiento farmacológico , Neoplasias de las Glándulas Suprarrenales/tratamiento farmacológico , Carcinoma Corticosuprarrenal/tratamiento farmacológico , Síndrome de Cushing/tratamiento farmacológico , Cetoconazol/administración & dosificación , Metirapona/administración & dosificación , Neoplasias de las Glándulas Suprarrenales/metabolismo , Carcinoma Corticosuprarrenal/metabolismo , Adulto , Anciano , Síndrome de Cushing/etiología , Quimioterapia Combinada , Femenino , Humanos , Cetoconazol/efectos adversos , Masculino , Metirapona/efectos adversos , Persona de Mediana Edad , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
This article is part of a Special Issue "Energy Balance". Seasonal modulation of glucocorticoids plays an important role in supporting critical life-history events, and probably facilitates transitions between different life-history stages. In a well-studied population of red-sided garter snakes (Thamnophis sirtalis parietalis), glucocorticoids are elevated during the mating season, but males dispersing to summer feeding grounds have significantly lower baseline glucocorticoids than courting males at the den. We tested the hypothesis that decreased plasma glucocorticoids mediate the behavioral switch between reproduction and foraging in this species. Using a two-choice Y-maze paradigm, we demonstrate that males treated with the glucocorticoid synthesis inhibitor metyrapone (1 and 3mg implants) prefer feeding cues (worm trail) over reproductive cues (female pheromone trail) significantly earlier than control-treated snakes. The metyrapone-induced changes in appetitive feeding behavior were independent of changes in plasma androgens and body mass loss. Metyrapone-treated males continued to court females at levels similar to those of control-treated snakes, suggesting that appetitive reproductive and ingestive behaviors are not mutually exclusive during this life-history transition. Consistent with this hypothesis, metyrapone treatment did not alter the number of arginine vasotocin-immunoreactive cells in any brain region, while it significantly increased neuropeptide Y-immunoreactive cell number in both the cortex and nucleus sphericus (homologues of the mammalian hippocampus and amygdala, respectively). Our results suggest that male red-sided garter snakes have the potential to maximize reproductive opportunities by continuing to court females they encounter even as they disperse from the den in search of food. Taken together, these data have important implications for understanding the neuroecology of seasonal life-history transitions.