Pharmacological management of Cushing's syndrome: an update

Abstract

The treatment of choice for Cushing's syndrome remains surgical. The role for medical therapy is twofold. Firstly it is used to control hypercortisolaemia prior to surgery to optimize patient's preoperative state and secondly, it is used where surgery has failed and radiotherapy has not taken effect. The main drugs used inhibit steroidogenesis and include metyrapone, ketoconazole, and mitotane. RESUMOManejo Farmacológico da Síndrome de Cushing: Uma Atualização. O tratamento de escolha para a síndrome de Cushing ainda é a cirurgia. O papel da terapia medicamentosa é duplo: ele é usado para controlar o hipercortisolismo antes da cirurgia e otimizar o estado pré-operatório do paciente e, adicionalmente, quando ocorre falha cirúrgica e a radioterapia ainda não se mostrou efetiva. Os principais medicamentos são empregados para inibir a esteroidogênese e incluem: metirapona, cetoconazol e mitotano. Medicamentos visando o eixo hipotálamo-hipofisário têm sido investigados, mas seu papel na prática clínica permanece limitado, embora o agonista PPAR-γ e análogo de somatostatina, som-230 (pasireotídeo), requeira estudos adicionais. A única droga que age perifericamente no receptor glicocorticóide é a mifepristona (RU486). O manejo da síndrome de Cushing deve envolver uma combinação terapêutica atuando em diferentes vias da hipercortisolemia, mas o monitoramento dessa terapia ainda permanece um desafio. (Arq Bras Endocrinol Metab

Effectiveness of cabergoline in monotherapy and combined with ketoconazole in the management of Cushing’s disease

“…Some patients undergoing longterm cabergoline or ketoconazole monotherapy may show relapse after having been in full remission [8,10,14,29]. A treatment escape was observed in two of the seven (28.6%) full responders and three of the eight (37.5%) partial responders to cabergoline from the series by Pivonello et al [14] after 12-18 months of treatment but in none of our patients that were given cabergoline alone or in combination.…”

“…Some neuromodulatory drugs were used in the past, however, due to their limited efficacy, they never reached a widespread clinical use for the treatment of CD [4,8,10]. The most effective was the DA bromocriptine that was reported to induce a significant inhibition or normalization of cortisol secretion in up 40% of patients after short-term treatment [11,[19][20][21], but normalization of cortisol secretion was rarely maintained and tumor shrinkage was only sporadically found after long-term treatment [19,22,23].…”

“…Indeed, while the main action of cabergoline is inhibiting ACTH secretion by the corticotroph adenoma, ketoconazole blocks many steps of adrenal steroidogenesis, including the enzymes 17,20-lyase, 11b-hydroxylase and 17a-hydroxylase [8,35]. The potential advantages of the combination of cabergoline with ketoconazole compared with either monotherapy would include a higher probability of longterm control of the hypercortisolism at lower doses, a lower incidence of side-effects and, possibly, a lower rate of treatment escapes.…”

“…Pharmacotherapy, particularly ketoconazole (an adrenal blocking drug), is rather used before surgery or as a transient palliative treatment before definitive cure in patients submitted to pituitary radiotherapy [4,8]. There are also few reports of successful primary therapy with ketoconazole in patients that refused or had contraindications to surgery [9,10].…”

Cushing’s disease: current trends in treatment

“…The usual starting dose is 250 mg three-times daily, which may be increased if needed to a maximal dose of 6 g/day in divided doses, aiming for a mean cortisol of 150-300 nmol/l (5.4-10.8 µg/dl) [39] on a five-point cortisol day curve. However, as 11-dexycortisol may cross-react in conventional cortisol assays, possibly a slightly lower level may need to be targeted if using newer mass spectrometry-based assays [9].…”