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1.
Eur J Endocrinol ; 182(5): 489-498, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32187576

RESUMO

Objective: Cushing's disease (CD) may recur despite corticotropic insufficiency (COI) following pituitary surgery. The predictive value of the desmopressin test (DT) for recurrence in this setting remains controversial. We have evaluated whether the disappearance of the response to DT predicts a low probability recurrence in a large cohort of patients with post-operative COI. Design: Multicentre retrospective study. Methods: Ninety-five patients with CD (women 82%, age 41 ± 14 years), responding preoperatively to DT and with early post-operative COI (08 00 am cortisol: <138 nmol/L), underwent a DT within 3 months post-surgery. Association between DT findings and the prediction of recurrence was tested using regression and ROC analyses. Results: Recurrence occurred in 17/95 patients within 29 to 91 months. The cortisol peak (327, 95% CI (237-417) vs 121 (79-164) nmol/L, P = 0.0001) and absolute increment during DT (208 (136-280) vs 56 (22-90) nmol/L, P = 0.005) were greater in the recurrence vs remission group. Cortisol peak (AUC: 0.786 (0.670-0.902)) and increment (0.793 (0.672-0.914)) yielded a higher prognostic performance for recurrence than did the early post-operative 08 00 am cortisol (0.655 (0.505-0.804)). In the context of COI, cortisol peak >100 nmol/L and increment >30 nmol/L had a high negative predictive value (94, 95% CI (88-100) and 94, (88-100), respectively). Patients with a cortisol peak ≤100 nmol/L (vs >100) or an increment ≤30 nmol/L (vs >30) were less likely to have CD recurrence (odds ratios: 0.12, 95% CI (0.03-0.41) and 0.11 (0.02-0.36), respectively). Conclusion: The disappearance of the response to the post-operative DT was independently associated with a lower odds of CD recurrence and offers an incremental prognostic value, which may help to stratify patients with COI and refine their follow-up according to the risk of recurrence.


Assuntos
Desamino Arginina Vasopressina/uso terapêutico , Hidrocortisona/sangue , Hipersecreção Hipofisária de ACTH/sangue , Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Complicações Pós-Operatórias/sangue , Adulto , Antidiuréticos/uso terapêutico , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Hipersecreção Hipofisária de ACTH/diagnóstico , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/etiologia , Valor Preditivo dos Testes , Recidiva , Estudos Retrospectivos
2.
Eur J Endocrinol ; 182(2): 207-217, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31804965

RESUMO

Objective: Monitoring of patients with Cushing's disease on cortisol-lowering drugs is usually performed with urinary free cortisol (UFC). Late-night salivary cortisol (LNSC) has an established role in screening for hypercortisolism and can help to detect the loss of cortisol circadian rhythm. Less evidence exists regarding the usefulness of LNSC in monitoring pharmacological response in Cushing's disease. Design: Exploratory analysis evaluating LNSC during a Phase III study of long-acting pasireotide in Cushing's disease (clinicaltrials.gov: NCT01374906). Methods: Mean LNSC (mLNSC) was calculated from two samples, collected on the same days as the first two of three 24-h urine samples (used to calculate mean UFC [mUFC]). Clinical signs of hypercortisolism were evaluated over time. Results: At baseline, 137 patients had evaluable mLNSC measurements; 91.2% had mLNSC exceeding the upper limit of normal (ULN; 3.2 nmol/L). Of patients with evaluable assessments at month 12 (n = 92), 17.4% had both mLNSC ≤ULN and mUFC ≤ULN; 22.8% had mLNSC ≤ULN, and 45.7% had mUFC ≤ULN. There was high variability in LNSC (intra-patient coefficient of variation (CV): 49.4%) and UFC (intra-patient CV: 39.2%). mLNSC levels decreased over 12 months of treatment and paralleled changes in mUFC. Moderate correlation was seen between mLNSC and mUFC (Spearman's correlation: ρ = 0.50 [all time points pooled]). Greater improvements in systolic/diastolic blood pressure and weight were seen in patients with both mLNSC ≤ULN and mUFC ≤ULN. Conclusion: mUFC and mLNSC are complementary measurements for monitoring treatment response in Cushing's disease, with better clinical outcomes seen for patients in whom both mUFC and mLNSC are controlled.


Assuntos
Ritmo Circadiano , Hidrocortisona/metabolismo , Hipersecreção Hipofisária de ACTH/metabolismo , Adenoma Hipofisário Secretor de ACT/complicações , Adenoma Hipofisário Secretor de ACT/cirurgia , Adulto , Feminino , Hormônios/uso terapêutico , Humanos , Hidrocortisona/urina , Masculino , Pessoa de Meia-Idade , Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Hipersecreção Hipofisária de ACTH/etiologia , Hipersecreção Hipofisária de ACTH/urina , Neoplasias Hipofisárias/complicações , Neoplasias Hipofisárias/cirurgia , Saliva/química , Somatostatina/análogos & derivados , Somatostatina/uso terapêutico , Resultado do Tratamento
3.
Neurosurg Clin N Am ; 30(4): 499-508, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31471057

RESUMO

Medical therapy for Cushing disease is primarily used to control hypercortisolism in patients whose disease persists or with recurrent disease after pituitary surgery, including those awaiting the salutary effects of radiation therapy. In can also be used to control hypercortisolism preoperatively, and in patients who decline surgery or whose tumor location is unknown. Steroidogenesis inhibitors, centrally acting agents, and glucocorticoid receptor antagonists are currently available to treat hypercortisolism, and several novel agents are in development. Given the absence of head-to-head clinical trials, choice between treatments has to be individualized based on careful consideration of patient, tumor, and disease characteristics.


Assuntos
Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Cabergolina/uso terapêutico , Etomidato/uso terapêutico , Humanos , Cetoconazol/uso terapêutico , Metirapona/uso terapêutico , Mitotano/uso terapêutico , Hipersecreção Hipofisária de ACTH/complicações , Somatostatina/análogos & derivados , Somatostatina/uso terapêutico , Temozolomida/uso terapêutico , Resultado do Tratamento
4.
J Pediatr Endocrinol Metab ; 32(8): 911-914, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31256066

RESUMO

Nonbullous congenital ichthyosis erythroderma (CIE) is an autosomal recessive disorder of ineffective keratinization. We present a unique case of a 16-year-old female with CIE who developed Cushing disease (CD) at age 13 with concomitant worsening of her skin disease. After transsphenoidal resection of her pituitary adenoma, she had both resolution of her Cushing symptoms and significantly milder skin manifestations of her CIE. To the best of our knowledge, this is the first reported case of a patient with both CD and CIE, one that is important in demonstrating the role of glucocorticoids in this disorder.


Assuntos
Glucocorticoides/farmacologia , Eritrodermia Ictiosiforme Congênita/prevenção & controle , Hipersecreção Hipofisária de ACTH/prevenção & controle , Adolescente , Feminino , Humanos , Hidrocortisona/sangue , Eritrodermia Ictiosiforme Congênita/complicações , Eritrodermia Ictiosiforme Congênita/tratamento farmacológico , Hipersecreção Hipofisária de ACTH/complicações , Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Prognóstico , Suspensão de Tratamento
5.
BMJ Case Rep ; 12(2)2019 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-30765454

RESUMO

A 47-year-old Caucasian man was referred to our clinic with a severe clinical and biochemical phenotype of endogenous hypercortisolism for further evaluation and treatment. In addition to confirming adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome, we found left temporal hemianopsia, massively increased prolactin, increased growth hormone/insulin-like growth factor 1 values, hypogonadotropic hypogonadism and central hypothyroidism. As the cause of these abnormalities we revealed an invasive macroadenoma of the pituitary secreting ACTH, prolactin and growth hormone, resulting not only in a clinically predominant picture of Cushing's syndrome but also causing hypogonadotropic hypogonadism and central hypothyroidism. The patient responded surprisingly well to dopamine agonist treatment leading not only to normalisation of prolactin levels but also to clinical and biochemical remission of Cushing's syndrome. Tumour size decreased successively in follow-up MRI scans. Despite lacking immunohistochemical analysis of tumour tissue, we assume plurihormonal secretion of ACTH, prolactin and growth hormone from pituitary macroadenoma, which fortunately responded well to dopamine agonist treatment.


Assuntos
Agonistas de Dopamina/uso terapêutico , Hipersecreção Hipofisária de ACTH/diagnóstico , Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Neoplasias Hipofisárias/tratamento farmacológico , Adenoma , Adulto , Humanos , Masculino , Hipersecreção Hipofisária de ACTH/metabolismo , Prolactina/metabolismo , Resultado do Tratamento
6.
J Endocrinol Invest ; 42(7): 757-768, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30443856

RESUMO

PURPOSE: To investigate the glucocorticoid-induced impairments of muscle mass and structure in patients presenting different stages of steroid myopathy progression. METHODS: Thirty-three patients (28 women) affected by active (N = 20) and remitted (N = 13) Cushing's disease were recruited and the following variables were assessed: walking speed, handgrip strength, total body and appendicular muscle mass by bioelectrical impedance analysis (BIA), thickness and echo intensity of lower limb muscles by ultrasonography. RESULTS: The two groups of patients showed comparable values of both handgrip strength [median (interquartile range) values: active disease: 27.4 (7.5) kg vs. remitted disease: 26.4 (9.4) kg; P = 0.58] and walking speed [active disease: 1.0 (0.2) m/s vs. remitted disease: 1.1 (0.3) m/s; P = 0.43]. Also, the thickness of the four muscles and all BIA-derived sarcopenic indices were comparable (P > 0.05 for all comparisons) between the two groups. On the contrary, the echo intensity of vastus lateralis, tibialis anterior (lower portion), and medial gastrocnemius was significantly (P < 0.05 for all comparisons) higher in patients with active disease compared to patients with remitted disease. Finally, significant negative correlations were found in the whole group of patients between muscle echo intensity and muscle function assessments. CONCLUSIONS: We provided preliminary evidence that the ultrasound-derived measurements of muscle thickness and echo intensity can be useful to detect and track the changes of muscle mass and structure in patients with steroid myopathy and we suggest that the combined assessment of muscle mass, strength, and performance should be systematically applied in the routine examination of steroid myopathy patients.


Assuntos
Glucocorticoides/efeitos adversos , Força da Mão , Força Muscular/efeitos dos fármacos , Doenças Musculares/patologia , Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Ultrassonografia/métodos , Índice de Massa Corporal , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Musculares/induzido quimicamente , Doenças Musculares/diagnóstico por imagem , Prognóstico
7.
J Clin Endocrinol Metab ; 104(3): 925-933, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30535260

RESUMO

Context: The most frequent cause of endogenous hypercortisolism is Cushing disease (CD), a devastating condition associated with severe comorbidities and high mortality. Effective tumor-targeting therapeutics are limited. Design: Search in PubMed with key words "corticotroph" and "Cushing's disease" plus the name of the mentioned therapeutic agent and in associated references of the obtained papers. Additionally, potential therapeutics were obtained from ClinicalTrials.gov with a search for "Cushing disease." Results: At present, the tumor-targeted pharmacological therapy of CD is concentrated on dopamine agonists (cabergoline) and somatostatin analogs (pasireotide) with varying efficacy, escape from response, and considerable side effects. Preclinical studies on corticotroph pathophysiology have brought forward potential drugs such as retinoic acid, silibinin, and roscovitine, whose efficacy and safety remain to be determined. Conclusions: For many patients with CD, effective tumor-targeted pharmacological therapy is still lacking. Coordinated efforts are pivotal in establishing efficacy and safety of novel therapeutics in this rare but devastating disease.


Assuntos
Adenoma Hipofisário Secretor de ACT/tratamento farmacológico , Adenoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Corticotrofos/efeitos dos fármacos , Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Adenoma Hipofisário Secretor de ACT/complicações , Adenoma Hipofisário Secretor de ACT/patologia , Adenoma/complicações , Adenoma/patologia , Antineoplásicos/farmacologia , Cabergolina/farmacologia , Cabergolina/uso terapêutico , Ensaios Clínicos como Assunto , Corticotrofos/patologia , Humanos , Hipersecreção Hipofisária de ACTH/etiologia , Hipersecreção Hipofisária de ACTH/patologia , Roscovitina/farmacologia , Roscovitina/uso terapêutico , Silibina/farmacologia , Silibina/uso terapêutico , Somatostatina/análogos & derivados , Somatostatina/farmacologia , Somatostatina/uso terapêutico , Resultado do Tratamento , Tretinoína/farmacologia , Tretinoína/uso terapêutico
8.
Exp Clin Endocrinol Diabetes ; 127(2-03): 147-155, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30130808

RESUMO

BACKGROUND: Despite advances in diagnostic and therapeutic approach, Cushing's disease (CD) presents a challenging situation for the treating physician. AIMS: To elucidate current challenges, present strengths and pitfalls of existing diagnostic tests, enlighten the need for new diagnostic approaches, appraise the effects of surgery and available pharmacological agents and identify future perspectives regarding CD. MATERIALS AND METHODS: Systematic search to PubMed and Medline databases for publications mainly over the last five years. RESULTS: Mutations in the ubiquitin specific peptidase 8 gene have been recently identified in functional sporadic corticotroph adenomas causing CD. Since the prevalence of obesity and metabolic syndrome is rapidly increasing, new diagnostic tests are necessary to differentiate these conditions. Next to the traditional tests, a cutoff of preoperative ACTH/cortisol ratio, an ultrasensitive late night salivary cortisol assay and the desmopressin test have been suggested as valid tools for the diagnosis and differential diagnosis of CD. Transsphenoidal surgery with variable remission and recurrence rates presents the treatment of choice for CD. Medical therapy consists of adrenal-targeted drugs e. g. ketoconazole, metyrapone, etomidate and mitotane and pituitary-targeted drugs e. g. pasireotide, cabergoline and retinoic acid. CONCLUSIONS: CD is associated to a significant clinical burden, since numerous comorbidities persist after long-term biochemical control. These chronically ill patients show an increased mortality despite disease remission. Clinicians should treat comorbidities aggressively and seek for appropriate consultations. Structured consultation hours and expert excellence networks are needed in order to allow optimal, individualized care for affected patients, reverse increased morbidity and mortality and identify tumor recurrence early.


Assuntos
Comorbidade , Hipersecreção Hipofisária de ACTH/diagnóstico , Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Hipersecreção Hipofisária de ACTH/cirurgia , Humanos
9.
Vet Res Commun ; 42(4): 283-288, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30187173

RESUMO

Canine hypercortisolism is most often caused by an ACTH-secreting pituitary adenoma (pituitary-dependent hypercortisolism; PDH). An interesting target for a selective medical treatment of PDH would be the receptor for ACTH: the melanocortin 2 receptor (MC2R). In this study we investigated whether two peptide compounds, BIM-22776 (#776) and BIM-22A299 (#299), are effective MC2R antagonists in vitro. Their effects on cortisol production and mRNA expression of steroidogenic enzymes, MC2R and melanocortin 2 receptor accessory protein (MRAP) were evaluated in primary adrenocortical cell cultures (n = 8) of normal canine adrenal glands. Cortisol production stimulated by 50 nM ACTH was dose-dependently inhibited by #299 (inhibition 90.7 ± 2.3% at 5 µM) and by #776 (inhibition 38.0 ± 5.2% at 5 µM). The ACTH-stimulated mRNA expression of steroidogenic enzymes, MC2R and MRAP was significantly inhibited by both compounds, but most potently by #299. These results indicate that canine primary cell culture is a valuable in vitro system to test MC2R antagonists, and that these compounds, but especially #299, are effective MC2R antagonists in vitro. To determine its efficacy in vivo, further studies are warranted. Antagonism of the MC2R is a promising potential treatment approach in canine PDH.


Assuntos
Doenças do Cão/tratamento farmacológico , Hipersecreção Hipofisária de ACTH/veterinária , Receptor Tipo 2 de Melanocortina/antagonistas & inibidores , Córtex Suprarrenal/citologia , Córtex Suprarrenal/efeitos dos fármacos , Animais , Células Cultivadas , Cães , Feminino , Hidrocortisona/metabolismo , Técnicas In Vitro , Masculino , Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Reação em Cadeia da Polimerase em Tempo Real/veterinária
10.
J Endocrinol Invest ; 41(12): 1445-1455, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30097903

RESUMO

CONTEXT: The primary treatment of choice for Cushing's disease (CD) is the removal of the pituitary adenoma by transsphenoidal surgery (TSS). The surgical failure is seen in up to 75% of cases depending on the experience of the surgeon in different studies. Medical therapy is one of the options for the treatment of recurrent or persistent CD. METHODOLOGY: The primary outcome of this meta-analysis was to find the proportion of patients achieving normalisation of 24-h urinary free cortisol (remission of CD) following cabergoline monotherapy. Literature search was conducted in January 2018 in PubMed/MEDLINE database from its date of inception to 31st December 2017. The search strategy used was "[(cushing) OR Cushing's] AND cabergoline". Individual participant data were extracted from the included studies and risk of bias was analysed by review checklist proposed by MOOSE. RESULTS: The individual participant data of 124 patients from six observational studies were included in this meta-analysis. 92 patients (74.2%) had past pituitary surgery. The proportion of patients achieving remission of CD with cabergoline monotherapy was 39.4% (95% confidence interval 0.31-0.49; P = 0.026). The previous surgery [odds ratio (OR) 28.4], duration of cabergoline monotherapy (OR 1.31) and maximum cabergoline dose (OR 0.19) were predictors for remission of CD. Mild and severe side effects were reported in 37.3% and 5.6% of patients, respectively, during cabergoline monotherapy. CONCLUSIONS: This meta-analysis shows that cabergoline monotherapy is a reasonable alternative for subjects with persistent or recurrent CD after TSS. It can also be used in CD patients either as a bridge therapy while waiting for surgery or in those unwilling for surgery or have contraindication to it.


Assuntos
Cabergolina/uso terapêutico , Agonistas de Dopamina/uso terapêutico , Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Humanos , Resultado do Tratamento
11.
Endocr Pract ; 24(10): 875-881, 2018 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-29975580

RESUMO

OBJECTIVE: Pituitary patients with different etiologies of hypopituitarism exhibit differing phenotypes, despite similar replacement therapy strategies. We hypothesized that differential regulation of the isoenzyme 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1), which mediates the net autocrine conversion of cortisone to cortisol in adipose tissues and liver, may play a role. METHODS: We studied 11ß-HSD1 activity (using urine cortisol/cortisone metabolites ratio) in 36 hypopituitary patients with treated craniopharyngiomas, treated remitted Cushing disease, and treated nonfunctioning pituitary adenomas + prolactinomas on and off growth hormone (GH) replacement. RESULTS: 11ß-HSD1 activity was higher in subjects with craniopharyngioma both on and off GH, as evidenced by increased tetrahydrocortisol to tetrahydrocortisone metabolite ratios compared to other diagnostic groups, but there was no difference in body mass index, insulin levels, serum hormone measurements, or hydrocortisone dose between groups. CONCLUSION: Craniopharyngiomas are associated with enhanced 11ß-HSD1 activity compared to other diagnostic hypopituitary groups, and this may contribute to the adverse phenotypic and metabolic features seen in this condition. ABBREVIATIONS: BMI = body mass index; Em = cortisone metabolites; Fm = cortisol metabolites; GH = growth hormone; 11ß-HSD1 = 11ß-hydroxysteroid dehydrogenase type 1; IGF-1 = insulin-like growth factor 1; NFPA = nonfunctioning pituitary adenoma; THE = tetrahydrocortisone; THF = tetrahydrocortisol.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Hipopituitarismo/etiologia , Hipopituitarismo/metabolismo , Adulto , Estudos de Casos e Controles , Cortisona/metabolismo , Cortisona/urina , Craniofaringioma/complicações , Craniofaringioma/tratamento farmacológico , Craniofaringioma/metabolismo , Feminino , Transtornos do Crescimento/complicações , Transtornos do Crescimento/tratamento farmacológico , Transtornos do Crescimento/metabolismo , Terapia de Reposição Hormonal , Hormônio do Crescimento Humano/deficiência , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Hidrocortisona/metabolismo , Hidrocortisona/urina , Hipopituitarismo/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Hipersecreção Hipofisária de ACTH/complicações , Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Hipersecreção Hipofisária de ACTH/metabolismo , Neoplasias Hipofisárias/complicações , Neoplasias Hipofisárias/tratamento farmacológico , Neoplasias Hipofisárias/metabolismo , Prolactinoma/complicações , Prolactinoma/tratamento farmacológico , Prolactinoma/metabolismo
12.
Endocrine ; 62(1): 207-214, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29980915

RESUMO

INTRODUCTION: Cushing's disease (CD) is characterized by procoagulative profile. Treatment with cortisol-reducing medications might normalize the coagulation impairment potentially eliminating the risk of thromboembolic complications. AIM: The aim of this prospective study is to evaluate the effectiveness of 6-12 months of treatment with pasireotide (Signifor®, Novartis) 600 µg twice daily on coagulative factors in 21 patients (16 females, mean age 46 ± 12.2 years) with CD. Biochemical, hormonal (urinary free cortisol, UFC; late night salivary cortisol, LNSC; ACTH) and coagulative parameters as Protrombin time (PT), aPTT, factors VIII, IX and XI, antithrombin III, protein C, protein S, fibrinogen, were evaluated at baseline and during therapy. RESULTS: UFC showed a significant reduction from baseline (3.2 ± 1.8 vs. 1.0 ± 0.8, p < 0.0001) with normalization in 13/21 (61.9%) and in 7/16 (43.8%) at 6 and 12 months, respectively. On the same way LNSC returned to normal in 5/11 at 6 months, showing a trend to reduction (8.6 ± 5 vs. 4.1 ± 2.9), even though without statistical significance (p = 0.07). Throughout the treatment period there was an increase in serum glycaemia (5.5 ± 2.3 vs. 6.8 ± 2.3 mmol/L, p = 0.09), with a concomitant significant increase in HbA1c after 6 months (40.7 ± 8.4 vs. 50.7 ± 12.3 mmol/mol, p = 0.006). Regarding coagulative parameters, no differences were found neither in clotting nor in anticoagulant factors during therapy. No patients developed thrombotic complication during treatment. CONCLUSIONS: Pasireotide resulted an effective treatment in controlling hypercortisolism in more than half of CD patients with partial restoration also of circadian cortisol secretion. No significant improvements were observed on clotting factors; this fact might depend on persistence of typical alteration of CD, such as obesity and hypertension, and reflects also on the worsening in glucide metabolism induced by the drug. Clinical implications of persistent procoagulative impairment while on medical therapy should be considered.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Hipersecreção Hipofisária de ACTH/sangue , Somatostatina/análogos & derivados , Adulto , Testes de Coagulação Sanguínea , Glicemia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Estudos Prospectivos , Somatostatina/farmacologia , Somatostatina/uso terapêutico , Resultado do Tratamento
13.
Pituitary ; 21(5): 490-498, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30039432

RESUMO

PURPOSE: The present study evaluates the usefulness of an ACTH suppression test shortly after surgery, and to determine optimal cut-off values of included laboratory analyses, in predicting short- and long-term remission after surgery of Cushing's disease. METHODS: A 48 h suppression test with betamethasone 2 mg/day applied after 45 transphenoidal adenomectomies in 28 patients was evaluated. Receiver operating characteristic (ROC)-curves were created for the included assays: plasma cortisol, plasma adrenocorticotropic hormone (ACTH) and urinary free cortisol (UFC). Plasma levels of cortisol and ACTH were measured both at 24 and 48 h. Youden's index was used to determine cut-off with the highest sensitivity and specificity in predicting short- (3 months) and long-term (5 years or longer) remission. The area under curve (AUC) illustrated the clinical accuracy of the different assays. RESULTS: Plasma cortisol after 24 h with betamethasone was most accurate in predicting both short- and long-term remission. 3 months remission with cut-off 107 nmol/L: sensitivity 0.85, specificity 0.94, positive predictive value (PPV) 0.96 and AUC 0.92 (95% CI 0.85-1). 5 years remission with cut-off 49 nmol/L: sensitivity: 0.94, specificity 0.93, PPV 0.88, AUC 0.98 (95% CI 0.95-1). Analyses of ACTH or UFC did not improve diagnostic accuracy. CONCLUSIONS: A 48 h, 2 mg/day betamethasone suppression test after transphenoidal surgery of Cushing's disease could predict short- and long-term remission with a high accuracy. Suppression of plasma cortisol after 24 h with betamethasone to values excluding Cushings disease in the diagnostic setting yielded the highest accuracy in predicting long-term remission.


Assuntos
Hormônio Adrenocorticotrópico/sangue , Hipersecreção Hipofisária de ACTH/sangue , Adulto , Idoso , Betametasona/uso terapêutico , Feminino , Humanos , Hidrocortisona/sangue , Masculino , Pessoa de Meia-Idade , Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Hipersecreção Hipofisária de ACTH/patologia , Período Pós-Operatório , Curva ROC , Resultado do Tratamento , Adulto Jovem
14.
J Zoo Wildl Med ; 49(2): 404-411, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29900762

RESUMO

Pituitary pars intermedia dysfunction (PPID), also known as equine Cushing's disease, is widely reported in middle-aged to older domestic equids but to date reported in only one nondomestic equid, the onager ( Equus hemionus onager). This case series reports clinical, hematological, and pathological findings consistent with PPID in two further equid species: one Chapman's zebra ( Equus quagga chapmani) and five Przewalski's horses ( Equus ferus przewalskii). The case series reports basal adrenocorticotropic hormone (ACTH) testing as a method to diagnose and monitor PPID in zoological equids and the use of pergolide mesylate to reduce basal ACTH concentration and reduce clinical signs associated with PPID. Gross and histopathological examinations of the pituitary gland in four of these cases revealed either pars intermedia adenomas or adenomatous hyperplasia, similar to pathological findings in domestic equids affected by PPID. These findings suggest that clinicians working with nondomestic equids should be aware of this condition and consider screening for it routinely, particularly given that improvements in management and veterinary care for exotic animals are resulting in a more aged captive population. Early diagnosis and treatment of PPID may prevent the development of painful clinical sequelae and therefore improve the welfare of zoo equids.


Assuntos
Equidae , Doenças dos Cavalos/diagnóstico , Hipersecreção Hipofisária de ACTH/veterinária , Adeno-Hipófise Parte Intermédia/patologia , Animais , Animais de Zoológico , Inglaterra , Feminino , Doenças dos Cavalos/tratamento farmacológico , Doenças dos Cavalos/patologia , Cavalos , Masculino , Hipersecreção Hipofisária de ACTH/diagnóstico , Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Hipersecreção Hipofisária de ACTH/patologia , Adeno-Hipófise Parte Intermédia/diagnóstico por imagem , Adeno-Hipófise Parte Intermédia/fisiopatologia
15.
Endocr Rev ; 39(5): 519-548, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-29905835

RESUMO

Osteoporosis associated with long-term glucocorticoid therapy remains a common and serious bone disease. Additionally, in recent years it has become clear that more subtle states of endogenous glucocorticoid excess may have a major impact on bone health. Adverse effects can be seen with mild systemic glucocorticoid excess, but there is also evidence of tissue-specific regulation of glucocorticoid action within bone as a mechanism of disease. This review article examines (1) the role of endogenous glucocorticoids in normal bone physiology, (2) the skeletal effects of endogenous glucocorticoid excess in the context of endocrine conditions such as Cushing disease/syndrome and autonomous cortisol secretion (subclinical Cushing syndrome), and (3) the actions of therapeutic (exogenous) glucocorticoids on bone. We review the extent to which the effect of glucocorticoids on bone is influenced by variations in tissue metabolizing enzymes and glucocorticoid receptor expression and sensitivity. We consider how the effects of therapeutic glucocorticoids on bone are complicated by the effects of the underlying inflammatory disease being treated. We also examine the impact that glucocorticoid replacement regimens have on bone in the context of primary and secondary adrenal insufficiency. We conclude that even subtle excess of endogenous or moderate doses of therapeutic glucocorticoids are detrimental to bone. However, in patients with inflammatory disorders there is a complex interplay between glucocorticoid treatment and underlying inflammation, with the underlying condition frequently representing the major component underpinning bone damage.


Assuntos
Densidade Óssea/efeitos dos fármacos , Síndrome de Cushing/tratamento farmacológico , Glucocorticoides/efeitos adversos , Terapia de Reposição Hormonal/efeitos adversos , Osteoporose/induzido quimicamente , Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Glucocorticoides/farmacologia , Glucocorticoides/uso terapêutico , Humanos
16.
Endocrinol Metab Clin North Am ; 47(2): 367-373, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29754637

RESUMO

Despite the best outcomes from trans-sphenoidal surgery, approximately one-third of patients with Cushing's disease will need medical therapy. Current treatments have drawbacks and there is a clear clinical need for new therapies. Recent understanding of molecular pathways leading to excess ACTH secretion has identified key components that may be targeted with the aim to provide novel effective treatment for this devastating disease. These include testicular orphan nuclear receptor 4, heat shock protein 90, and epidermal growth factor receptor. Based on data from preclinical studies, clinical trials are seeking to assess whether targeting these novel pathways can translate into patient benefit.


Assuntos
Endopeptidases/metabolismo , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Hipersecreção Hipofisária de ACTH/metabolismo , Pró-Opiomelanocortina/metabolismo , Receptores de Esteroides/metabolismo , Receptores dos Hormônios Tireóideos/metabolismo , Ubiquitina Tiolesterase/metabolismo , Receptores ErbB/metabolismo , Humanos
17.
J Am Vet Med Assoc ; 252(11): 1403-1408, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29772978

RESUMO

OBJECTIVE To evaluate clinical signs, endocrine test results, and pituitary tumor size for dogs with medically managed pituitary-dependent hyperadrenocorticism (PDH) and macroadenoma following 6 months of concurrent treatment with pasireotide. DESIGN Prospective case series. ANIMALS 9 client-owned dogs with PDH and macroadenoma in which PDH had been successfully managed with adrenal-directed treatment (trilostane or mitotane). PROCEDURES Dogs were given pasireotide (0.03 mg/kg [0.014 mg/lb], SC, q 12 h) for 6 months, while adrenal-directed treatment was continued. Physical examination, basic clinicopathologic testing, ACTH stimulation testing, and plasma ACTH concentration measurement were performed before (baseline) and 3 and 6 months after treatment began. Measurements of pituitary gland volume and pituitary gland-to-brain ratio were performed via MRI at baseline and 6 months after treatment began. RESULTS No dog developed neurologic abnormalities or signs of adverse effects during the study period. No differences from baseline were identified in clinicopathologic values, ACTH stimulation test results, or plasma ACTH concentration at the 3- or 6-month assessment points. After 6 months of pasireotide treatment, 6 dogs had decreases in MRI-measured values, and 3 had increases. CONCLUSIONS AND CLINICAL RELEVANCE Pasireotide as administered in this study had no noted adverse effects on dogs with PDH and macroadenoma successfully managed with standard treatment. Placebo-controlled, randomized studies are needed to determine whether pasireotide protects from the development of neurologic signs or improves outcome in dogs with pituitary macroadenomas.


Assuntos
Adenoma/veterinária , Hiperfunção Adrenocortical/veterinária , Doenças do Cão/tratamento farmacológico , Hormônios/uso terapêutico , Hipersecreção Hipofisária de ACTH/veterinária , Somatostatina/análogos & derivados , Adenoma/classificação , Adenoma/tratamento farmacológico , Hiperfunção Adrenocortical/tratamento farmacológico , Animais , Cães , Feminino , Masculino , Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Neoplasias Hipofisárias/veterinária , Estudos Prospectivos , Somatostatina/uso terapêutico
18.
Can Vet J ; 59(4): 397-407, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29606727

RESUMO

Many articles published in the past few years have contributed to a better understanding of the use of trilostane in dogs. Trilostane is a competitive inhibitor of 3ß-hydroxysteroid dehydrogenase, the enzyme essential for synthesis of cortisol and all other steroids. Trilostane is reported to be safe and effective in the treatment of pituitary-dependent hyperadrenocorticism (HAC), adrenal-dependent HAC, and alopecia X. While trilostane controls most of the clinical signs associated with HAC, abnormalities such as hypertension, hypercoagulability, and proteinuria may persist despite therapy. Because the duration of cortisol suppression after a dose of trilostane is often less than 12 hours, many dogs with HAC could benefit from low dose trilostane treatment every 12 hours. Many controversies regarding trilostane still exist. This review provides a comprehensive commentary on trilostane's indications, mode of action, dose, monitoring, efficacy, and adverse effects.


Assuntos
Di-Hidrotestosterona/análogos & derivados , Doenças do Cão/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Hiperfunção Adrenocortical/tratamento farmacológico , Hiperfunção Adrenocortical/veterinária , Alopecia/tratamento farmacológico , Alopecia/veterinária , Animais , Di-Hidrotestosterona/administração & dosagem , Di-Hidrotestosterona/efeitos adversos , Di-Hidrotestosterona/uso terapêutico , Cães , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Hipersecreção Hipofisária de ACTH/veterinária
19.
Curr Drug Metab ; 19(10): 876-882, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29595102

RESUMO

BACKGROUND: Pasireotide (SOM230) is a multi-receptor ligand somatostatin analogue (SSA) developed as the successor of the first-generation SSAs. Currently, pasireotide is recommended for the treatment of patients with Cushing's disease in whom surgery was unsuccessful, and patients with acromegaly who either remain uncontrolled after surgical therapy or in whom tumor resection is not possible. METHODS AND RESULTS: Phase II and III clinical trials have shown pasireotide efficacy in these diseases, with a similar rate of adverse events when compared with first-line SSA, although higher incidence of hyperglycemia has been observed. CONCLUSION: Pasireotide therapy provides biochemical control, tumor volume reduction, and improves the quality of life in patients with those disorders. Furthermore, pasireotide might be considered as second-line therapy in patients with metastatic neuroendocrine tumors, and it also might be effective in other neoplasms with a high expression of somatostatin receptors. In addition, therapy with this novel agent has been effective in prevention of postoperative complications after pancreatectomy. However, considering the diversified responsiveness to this drug in vivo, future studies should identify factors predicting better clinical response to pasireotide.


Assuntos
Somatostatina/análogos & derivados , Acromegalia/tratamento farmacológico , Animais , Neoplasias Gastrointestinais/tratamento farmacológico , Humanos , Tumores Neuroendócrinos/tratamento farmacológico , Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Somatostatina/efeitos adversos , Somatostatina/farmacocinética , Somatostatina/farmacologia , Somatostatina/uso terapêutico
20.
Clin Endocrinol (Oxf) ; 88(6): 787-798, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29574994

RESUMO

OBJECTIVE: Hypercortisolism in Cushing's syndrome (CS) is associated with impaired health-related quality of life (HRQoL), which may persist despite remission. We used the data entered into the European Registry on Cushing's syndrome (ERCUSYN) to evaluate if patients with CS of pituitary origin (PIT-CS) have worse HRQoL, both before and after treatment than patients with adrenal causes (ADR-CS). METHODS: Data from 595 patients (492 women; 83%) who completed the CushingQoL and/or EQ-5D questionnaires at baseline and/or following treatment were analysed. RESULTS: At baseline, HRQoL did not differ between PIT-CS (n = 293) and ADR-CS (n = 120) on both EuroQoL and CushingQoL. Total CushingQoL score in PIT-CS and ADR-CS was 41 ± 18 and 44 ± 20, respectively (P = .7). At long-time follow-up (>1 year after treatment) total CushingQoL score was however lower in PIT-CS than ADR-CS (56 ± 20 vs 62 ± 23; P = .045). In a regression analysis, after adjustment for baseline age, gender, remission status, duration of active CS, glucocorticoid dependency and follow-up time, no association was observed between aetiology and HRQoL. Remission was associated with better total CushingQoL score (P < .001), and older age at diagnosis with worse total score (P = .01). Depression at diagnosis was associated with worse total CushingQoL score at the last follow-up (P < .001). CONCLUSION: PIT-CS patients had poorer HRQoL than ADR-CS at long-term follow-up, despite similar baseline scoring. After adjusting for remission status, no interaetiology differences in HRQoL scoring were found. Age and presence of depression at diagnosis of CS may be potential predictors of worse HRQoL regardless of CS aetiology.


Assuntos
Adenoma/fisiopatologia , Hidrocortisona/metabolismo , Hipersecreção Hipofisária de ACTH/metabolismo , Hipersecreção Hipofisária de ACTH/fisiopatologia , Adenoma/tratamento farmacológico , Adenoma/metabolismo , Adulto , Feminino , Glucocorticoides/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Estudos Prospectivos , Qualidade de Vida , Inquéritos e Questionários
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