Peri-operative management of Cushing’s disease

Abstract

Management of patients with ACTH producing pituitary adenoma remains to be challenging. Removal of the pituitary adenoma through transsphenoidal surgery is the main stay of treatment. Complete resection of the adenoma is followed by the development of ACTH deficiency since the normal corticotrophs are suppressed by the pre-existing hypercortisolemia. The concern for ACTH deficiency has led many centers to advocate the use glucocorticoids before, during and after surgery. We provide evidence that such coverage with glucocorticoids is unnecessary until clinical or biochemical documentation of need is established. Given that patients are closely monitored, they are immediately treated with glucocorticoids once they exhibit any clinical and/or biochemical evidence of adrenal insufficiency. Defining remission in the immediate postoperative period has been rather difficult despite using different biochemical markers. Serum cortisol continues to be the best determinant of disease activity after surgical adenomectomy. However it needs to be interpreted with caution as a biochemical marker of remission in patients given glucocorticoids during and after surgery. Other biochemical markers are also used in the peri-operative period to determine the possibility of remission. These include the dexamethasone suppression test, CRH stimulation without dexamethasone, urinary free cortisol measurements, desmopressin stimulation test, the determination of salivary cortisol and / or plasma ACTH concentrations. Each test has its own advantages and limitations. The simplest and most informative approach is to measure serum cortisol levels repeatedly after surgery without the administration of exogenous glucocorticoids. Low serum cortisol levels (less than 2 μg/dL) in the peri-operative period are highly indicative of surgical success and a high likelihood for clinical remission. Higher serum cortisol levels require careful interpretation and further planning and discussions between the patient and the management team.

The Treatment of Cushing's Disease

“…The adrenal insufficiency ultimately resolves because ACTH secretion from the tumor gradually increases as a consequence of growth and progression of the residual tumor (118,120,125,126,140,142). Moreover, the use of exogenous glucocorticoids to prevent adrenal insufficiency in the immediate postoperative period could interfere with endogenous cortisol secretion because it doi: 10.1210/er.2013-1048 press.endocrine.org/journal/edrv 395 may suppress any remaining tumor tissue and mask the presence of persistent disease (89,90,143). Regarding the absolute cortisol cutoff for establishing disease remission, studies are conflicting.…”

Detection of recurrent Cushing’s disease: proposal for standardized patient monitoring following transsphenoidal surgery

“…Variability occurs in the types of biochemical parameters used to evaluate success, the assays used, limitations of the assays, and the timing of measurements [8]. Furthermore, results can be confounded by other factors, such as peri-operative administration of glucocorticoids and pre-operative treatment with steroidogenesis inhibitors [4, 5]. …”

“…Surgical success rates are variable, ranging from 65 to 90 %, and depend on surgeon expertise [2, 3]. Furthermore, criteria and testing parameters for assessing immediate remission vary from center to center, making the interpretation of results challenging [4, 5]. Additionally, post-surgical recurrence of CD is not uncommon, with reported recurrence rates ranging from 3 to 47 % [6, 7], and an observed mean time to recurrence of 16–49 months [3].…”

Avaliação do eixo hipotálamo-hipófise adrenal no diagnóstico e na remissão da doença de Cushing

“…Contudo, por definição, os pacientes com DC possuem um eixo HHA altamente ativado e estudos de medida intraoperatória dos níveis de cortisol e ACTH observaram que tanto o ACTH quanto o cortisol elevados declinam gradualmente após a adenomectomia hipofisária completa (43). De fato, considerando a meia-vida do cortisol sérico e do ACTH, os valores de ambos ainda são detectáveis nas primeiras 12 a 14 horas de PO (59). Os glicocorticoides levam em torno de 15 minutos para inibir a transcrição do gene da POMC no corticotrofo normal (60).…”

“…Portanto, o protocolo ideal de avaliação no PO da CTE seria aquele que, além do controle para o uso de medicações que interfiram no eixo HHA no pré-operatório, realizasse avaliação clínica e laboratorial do paciente no PO, com coleta de cortisol sérico a cada 6 horas do PO e com a administração de corticoide exó-geno apenas no paciente que apresentasse sintomas de insuficiência adrenal como hipotensão arterial ou valor de cortisol sérico abaixo de 2-5 µg/dL, mesmo na ausência de sinais e sintomas clínicos de insuficiên-cia adrenal (36,59). Poucos grupos têm analisado o cortisol sérico no PO sem a reposição de glicocorticoides.…”