PMC:3724972 / 14962-21317
Annnotations
{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/3724972","sourcedb":"PMC","sourceid":"3724972","source_url":"https://www.ncbi.nlm.nih.gov/pmc/3724972","text":"Dopamine receptors and dopamine receptor agonists\nLike somatostatin receptors, dopamine receptors are widely expressed in normal neuro-endocrine tissues and pituitary adenomas, including approximately 80 % of corticotroph adenomas [48, 49]. Five dopamine receptor subtypes have been characterized, usually classified as D1-like or D2-like, with most D2-like receptors associated with inhibitory actions [50]. The dopamine agonists bromocriptine and cabergoline have both been used to treat pituitary adenomas; however, cabergoline is more selective at D2 receptors and has been found to be more effective and better tolerated than bromocriptine in women receiving treatment for hyperprolactinemia [51].\nIn clinical studies, bromocriptine has had small and variable effects on ACTH secretion in patients with CD [50]. In contrast, a 2004 study demonstrated significant in vitro inhibition of ACTH secretion with cabergoline in 100 % of cases with confirmed D2 receptor expression, and significant in vivo reduction of cortisol levels in 60 % of cases—with 40 % normalization of cortisol secretion [48]. Altogether, 3 small, non-randomized studies (one with a long-term follow-up publication) have found evidence have found evidence for efficacy of cabergoline in this setting [48, 52, 53].\nIn a study of 10 patients, 6 achieved UFC normalization after 3 months’ treatment with cabergoline, and 2 additional patients achieved significant UFC reductions [48]. In a follow-up to this investigation, 20 patients were enrolled who had CD unsuccessfully treated by surgery [53]. After 3 months of cabergoline (1 mg/week with dose adjusted to a maximum of 7 mg/week), 7 patients (35 %) achieved eucortisolism and an additional 8 (40 %) experienced ≥25 % decline in UFC. The 8 partial responders all had dose increases, and 6 of these had normal UFC after 6–12 months. However, 5 patients who achieved normal UFC levels either initially or after dose increase escaped from treatment control. Thus, at 12 months, 10 patients (50 %) had normal UFC levels. However, 2 of these patients subsequently discontinued treatment because of severe asthenia, resulting in a long-term control rate of 40 %. Most responders exhibited improvements in signs and symptoms of CD, including significant mean declines in blood pressure, waist/hip ratio, serum glucose, and tumor volume, and significant improvements in β-cell function.\nSimilar supportive results were found in a retrospective, non-randomized analysis of 30 patients with CD in Buenos Ares and Montreal who received cabergoline (initially 0.5–1.0 mg/week adjusted to a maximum of 6 mg/week) for up to 5 years [54]. Within 3–6 months, 11 patients (37 %) achieved sustained normalization of UFC (≥2 normal values measured at 1–3 months apart; complete response). Nine of these patients achieved long-term UFC normalization after a mean of 37 months (range, 12–60) on a mean cabergoline dose of 2.1 mg/week. Four patients (13 %) achieved UFC \u003c125 % ULN (partial response) within 3–6 months of cabergoline initiation, but none of these patients experienced long-term response. Escape from response was observed in 2 patients with long-term complete response after 2 and 5 years of treatment, although one patient transiently renormalized after cabergoline dose increase. Long-term tolerability was positive; no serious adverse events were reported during treatment. No symptoms of cardiovascular dysfunction were reported and no patients presented symptomatic adrenal insufficiency.\nAlthough the results of these small studies have shown promise for the use of cabergoline as medical therapy for CD, no large-scale, double-blind trials have been conducted. Thus, it is difficult to draw conclusions about the overall efficacy and safety of this approach.\nOne potential concern regarding the use of DA agonists for CD has been the association of long-term ergot derivatives with increased risk of valvular heart disease [55–57]. However, this risk was identified in studies performed in patients using DA agonists for Parkinson’s disease at doses considerably higher (often \u003e3 mg/day) than those used in CD (generally \u003c7 mg/week). Schade et al. [56] reported that the relative risk of valvular heart disease was 50.3 (95 % CI 6.6–381.4) in patients receiving \u003e3 mg/day compared to 2.6 (95 % CI 0.5–12.8) in patients receiving \u003c3 mg/day. Furthermore, a study of 78 patients receiving DA agonists (including 47 who were using cabergoline) for an average of 8 years for prolactinoma found an increased risk of aortic valve calcification and mild tricuspid regurgitation, but no increase in the risk of clinically relevant valvular heart disease compared to control patients [58]. Among patients receiving cabergoline, the mean duration of therapy was 5.2 ± 0.4 years and the mean cumulative dose was 363 ± 55 mg. There was no relation between cumulative dose of cabergoline and the presence of mild, moderate or severe valve regurgitation. Thus, the evidence suggests that valvular heart disease associated with long-term use of DA agonists is much less of a concern for patients using the doses typical of treatment regimens for CD. A summary of current prospective studies with pituitary targeted medical therapy is provided in Table 2 [40, 43, 48, 52, 53, 59].\nTable 2 Medical treatments for Cushing’s disease evaluated in prospective clinical studies\nCompound Trial Patients (N) Treatment duration Outcome\nPasireotide Boscaro et al. [40] 29 15 days 5/29 patients (17 %) achieved UFC ≤ ULN; 22/29 patients (76 %) experienced reduction in mean UFC\nColao et al. [43] 162 12 months 33/162 patients (20 %) achieved UFC ≤ ULN within 6 months without increase from randomized dose; the majority of patients experienced reduction in UFC at month 6, sustained through month 12\nCabergoline Lila et al. [52] 18 5 months 5 patients (28 %) achieved MNSC \u003c5 μg/dL or low-dose dexamethasone-suppressed serum cortisol \u003c1.8 μg/dL\nPivonello et al. [48, 53] 20 3–24 months After 3 months, 15 patients (75 %) achieved UFC ≤ ULN or ≥25 % reduction from baseline; 8 patients (40 %) maintained UFC ≤ ULN at 24 months\nRetinoic acid Pecori Girald et al. [59] 7 6–12 months 3/7 patients (43 %) achieved UFC ≤ ULN; 5/7 patients (71 %) experienced reduction in UFC\nMNSC midnight salivary cortisol, UFC urinary free cortisol, ULN upper limit of 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