Effect of one month ketoconazole treatment on GH, cortisol and ACTH release after ghrelin, GHRP-6 and GHRH administration in patients with cushing’s disease

Abstract

GH responses to ghrelin, GHRP-6, and GHRH in Cushing's disease (CD) are markedly blunted. There is no data about the effect of reduction of cortisol levels with steroidogenesis inhibitors, like ketoconazole, on GH secretion in CD. ACTH levels during ketoconazole treatment are controversial. The aims of this study were to compare the GH response to ghrelin, GHRP-6, and GHRH, and the ACTH and cortisol responses to ghrelin and GHRP-6 before and after one month of ketoconazole treatment in 6 untreated patients with CD. Before treatment peak GH (µg/L; mean ± SEM) after ghrelin, GHRP-6, and GHRH administration was 10.0 ± 4.5; 3.8 ± 1.6, and 0.6 ± 0.2, respectively. After one month of ketoconazole there was a significant decrease in urinary cortisol values (mean reduction: 75%), but GH responses did not change (7.0 ± 2.0; 3.1 ± 0.8; 0.9 ± 0.2, respectively). After treatment, there was a significant reduction in cortisol (µg/dL) responses to ghrelin (before: 30.6 ± 5.2; after: 24.2 ± 5.1). No significant changes in ACTH (pg/mL) responses before (ghrelin: 210.9 ± 69.9; GHRP-6: 199.8 ± 88.8) and after treatment (ghrelin: 159.7 ± 40.3; GHRP-6: 227 ± 127.2) were observed. In conclusion, after short-term ketoconazole treatment there are no changes in GH or ACTH responses, despite a major decrease of cortisol levels. A longer period of treatment might be necessary for the recovery of pituitary function. RESUMO Efeito do Tratamento com Ketoconazole por um Mês na Liberação de GH, Cortisol e ACHT Após Administração de GHrelin, GHRP-6 e GHRH em Pacientes com Síndrome de Cushing.Na doença de Cushing (DC), as respostas do GH à ghrelina, ao GHRP-6 e ao GHRH estão diminuídas. Não existem dados sobre o efeito da redução dos níveis de cortisol, após cetoconazol, na secreção de GH na DC. Nessa situação, os níveis de ACTH são variáveis. Os objetivos do estudo são comparar as respostas do GH à administração de ghrelina, GHRP-6 e GHRH, e de ACTH e cortisol à ghrelina e ao GHRP-6 antes e após um mês de tratamento com cetoconazol em 6 pacientes com DC não tratados. Antes do tratamento, o pico de GH (µg/L; média ± EPM) após a administração de ghrelina, GHRP-6 e GHRH foi de 10,0 ± 4,5; 3,8 ± 1,6 e 0,6 ± 0,2, respectivamente. Após um mês de cetoconazol, ocorreu diminuição significante do cortisol urinário (redução média: 75%), mas as respostas de GH permaneceram inalteradas (7,0 ± 2,0; 3,1 ± 0,8; 0,9 ± 0,2, respectivamente). Após o tratamento, houve redução da resposta de cortisol (µg/dL) à ghrelina (antes: 30,6 ± 5,2; após: 24,2 ± 5,1), mas não ocorreram mudanças nas respostas de ACTH (pg/mL) (ghrelina antes: 210,9 ± 69,9; após: 159,7 ± 40,3;8 ± 88,8; após: 227 ± 127,2). Assim, o tratamento a curto prazo com cetoconazol não modificou as respostas de GH ou ACTH, apesar da redução do cortisol. Para a recuperação da função hipofisária deve ser necessário um período de tratamento maior.

Partial restoration of GH responsiveness to ghrelin in Cushing's disease after 6 months of ketoconazole treatment: comparison with GHRP-6 and GHRH

“…It has been previously shown that acute clinical interventions such as inhibition of free fatty acids and short-term dietary restriction (14,15) were able to increase GH secretion in CD. However, we did not observe significant changes in GH responses to ghrelin, GHRP-6, and GHRH after a short period (1 month) of ketoconazole use in patients with CD, although UFC values had a considerable fall (26).…”

Levoketoconazole: a novel treatment for endogenous Cushing's syndrome

“…The modest rise in ACTH in patients with CD receiving levoketoconazole [57], and the preclinical findings of inhibitory effects on ACTH secretion and corticotroph cell growth [36], suggest the possibility of direct antisecretory effects on ACTH and/or a direct effect of tumor inhibition in the pituitary gland, similar to what has been reported with ketoconazole [42,62]. In addition, there is no evidence that short-or long-term treatment with ketoconazole has adverse effects on pituitary function in patients with CD or in healthy individuals or patients with other endocrine disorders [88][89][90][91][92][93][94][95].…”

Adrenocorticotrophic hormone (ACTH) responsiveness to ghrelin increases after 6 months of ketoconazole use in patients with Cushing’s disease: comparison with GH‐releasing peptide‐6 (GHRP‐6)

“…6 Heterogeneous ACTH responses have been reported with ketoconazole use. [20][21][22][23][24]27 In short-term studies, a marked ACTH increase after CRH 23 and no changes in ACTH responsiveness to GHS 27 were observed, but higher doses of ketoconazole were used in the former study. In addition, no changes after CRH have been demonstrated after 3-13 months of ketoconazole use.…”

“…21,23 Unchanged ACTH responsiveness to CRH was observed after 3-13 months of ketoconazole use, 21 while a marked rise in ACTH responses after 4 to 6 weeks of treatment has also been demonstrated. 23 Recently, we have shown that GHS-stimulated ACTH levels do not change after 1 month of ketoconazole use in CD, 27 but these responses have not been studied after prolonged utilization of this compound.…”