Dopamine Receptor Expression and Function in Corticotroph Pituitary Tumors

Abstract

The role of dopamine agonist treatment in corticotroph pituitary tumors is controversial. The aim of this study was to evaluate D(2) receptor expression in 20 corticotroph pituitary tumors and to correlate it to the in vitro effect of dopamine agonists on ACTH secretion and the in vivo effect of short-term cabergoline treatment on cortisol secretion. D(2) expression was evaluated by receptor-ligand binding, immunohistochemistry, and RT-PCR. A 50% or more decrease in daily urinary cortisol levels was considered a significant clinical response. At receptor-ligand binding, specific binding of [(125)I]epidepride was found in 80% of cases. At immunohistochemistry, specific D(2) immunostaining was found in 75% of cases. D(2) expression was found in 83.3% of cases (D(2long) in 40%, D(2short) in 20%, and both in 40%) by RT-PCR. Significant in vitro inhibition of ACTH secretion was found in 100% of D(2)-positive cases, but not in 100% of D(2)-negative cases by either bromocriptine or cabergoline. A significant in vivo inhibition of cortisol secretion after 3-month cabergoline treatment was found in 60%, although a normalization of cortisol secretion was found in 40% of cases. All cabergoline-responsive cases were associated with D(2) expression, whereas all noncabergoline-responsive cases but one were not associated with D(2) expression. In conclusion, functional D(2) receptors were expressed in approximately 80% of corticotroph pituitary tumors. The effectiveness of cabergoline in normalizing cortisol secretion in 40% of cases supports its therapeutic use in the management of Cushing's disease.

The potential role of D2 dopamine receptors as a target in the management of neuroendocrine tumors

“…17,18 It is also noteworthy that dopamine receptors are expressed in corticotroph pituitary tumors, in tumors derived from the adrenal medulla, in phaeochromocytomas and have been recently found in tumors derived from the adrenal cortex, mainly aldosterone-secreting and cortisol-secreting tumors. [19][20][21] In corticotroph pituitary tumors, D 2 receptors may play an important role in mediating the inhibitory effects of dopaminergic drugs on ACTH and consequently, cortisol secretion, such that treatment with cabergoline has been shown to induce remission in one third of patients with Cushing's disease. On the other hand, a possible role for dopaminergic drugs in the treatment of adrenal tumors is yet to be shown.…”

Análise da expressão da filamina A nos tumores hipofisários e suas implicações clínicas e terapêuticas

“…Quanto ao grupo de corticotropinomas, a taxa de resposta hormonal com CAB e a expressão de DRD2 moderada ou intensa também foram compatíveis com os dados de literatura (124)(125)(126)(127)(128)(129)(130) . Em nosso estudo, não encontramos correlação entre expressão de DRD2 e resposta hormonal à CAB, o que foi descrito em apenas um estudo, ainda que sem significância estatística (125) .…”

“…No mesmo ano, Pivonello et al demonstraram a expressão proteica do DRD2 em 75% de 15 corticotropinomas avaliados e uma tendência na associação entre a expressão do DRD2 e a resposta clínica à CAB (P = 0,067), sendo que todos os pacientes responsivos a CAB expressavam DRD2 e, entre os não-responsivos, havia expressão em apenas um deles (124) .…”

“…Há sete séries de casos de pacientes com Doença de Cushing, sem remissão após o tratamento cirúrgico, submetidos ao tratamento com CAB (124)(125)(126)(127)(128)(129)(130) . (128) .…”

“…Na Tabela 4, a seguir, resume-se a freqüência de resistência às drogas utilizadas para cada subtipo tumoral. Redução tumoral 55-60% (75) AD 65% (72) ACNF Cirúrgico AD Redução tumoral 44-62% (153,155) Corticotropinoma Cirúrgico AD Fu normal 60-70% (124) LRS de nova geração Fu normal 74% (136) AD: agonista dopaminérgico; Fu: cortisol urinário; LRS: ligante de receptor de somatostatina; GH:…”