Bromocriptine-Responsive Cushing's Disease; Clinical and Biochemical Remission Accompanied by Amelioration of Impaired Ocular Movement

Kawamura, Mitsunobu; Nakano, Takahito; Miki, Hirofumi; Tamura, Yuriko; Miyazaki, Shigeru; Hirata, Yukio

doi:10.2169/internalmedicine.46.6436

Cited by 7 publications

(6 citation statements)

References 20 publications

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“…It directly stimulates ERK/MAPK activity on the corticotropic hormone gene transcription in the paraventricular nucleus and exerts indirect inhibitory actions through modulation of neural pathways to the paraventricular nucleus to modulate plasticity of the neuroendocrine system during lactation (37). Whether PRL acts directly on pituitary ACTH production is controversial because (i) bromocriptine-responsive Cushing disease is rare (38,39), (ii) hyperprolactinemia and bromocriptine-induced hypoprolactinemia do not influence plasma ACTH levels (40,41) even though the presence of PRLR on corticotroph cells has been established (42). Furthermore, it is not clear whether the stabilization of ACTH levels by bromocriptine or cabergoline in Nelson syndrome is rather ascribed to an indirect effect of dopaminergic-induced hypoprolactinemia or a direct dopaminergic effect through the abnormal expression of the D2 receptor in some corticotroph tumor cells (43).…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Control of Adrenal Steroidogenesis

Lefrançois‐Martinez

Blondet-Trichard

Binart

et al. 2011

Journal of Biological Chemistry

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In the adrenal gland, adrenocorticotropin (ACTH) acting through the cAMP protein kinase (PKA) transduction pathway is the main regulator of genes involved in glucocorticoid synthesis. The prolactin (PRL) receptor is expressed in the adrenal cortex of most mammals, but experimental proof that PRL ensures direct control on glucocorticoid synthesis in rodents remains elusive. To unravel the physiological importance of PRL in adrenocortical functions, we measured steroidogenic capacity of Prlr-deficient mice (Prlr ؊/؊ ) and explored the influence of JAK/STAT signaling, the major PRL transduction pathway, on the steroidogenic activity of adrenocortical cell cultures. We demonstrate that lack of Prlr does not affect basal (nor stress-induced) corticosterone levels in mice. PRL triggers JAK2/STAT5-dependent transcription in adrenal cells, but this does not influence corticosterone release. In contrast, pharmacological or siRNA-mediated inhibition of JAK2 reveals its essential role in both basal and ACTH/cAMP-induced steroidogenesis. We demonstrate that nuclear JAK2 regulates the amount of active transcription factor CREB (cAMP response element-binding protein) through tyrosine phosphorylation and prevention of proteasomal degradation, which in turn leads to transcriptional activation of the rate-limiting steroidogenic Star gene. Hence, we describe a novel link between PKA and JAK2 by which nuclear JAK2 signaling controls adrenal steroidogenesis by increasing the stability of CREB.Acute and chronic adrenal cortex steroidogenesis is regulated mainly through the adrenocorticotropin (ACTH) activation of the cAMP-dependent protein kinase A (PKA) signaling pathway. Chronic response to ACTH results in increased transcription of genes encoding steroidogenic enzymes and the proteins responsible for cholesterol mobilization and transport, such as the steroidogenic acute regulatory protein (STAR), 4 which mediates the rate-limiting and regulated step in steroidogenesis. cAMP-induced PKA activations result at least in the phosphorylation of the transcription factors GATA-4-binding protein, steroidogenic factor 1 (SF1), CAAT enhancerbinding protein (C/EBP) and cAMP response element-binding protein (CREB). These in turn stimulate transcription of genes involved in steroidogenesis (1, 2). The cAMP-responsive unit of the mouse Star proximal promoter (Ϫ110 and Ϫ67 bp) is a prototypical sequence that involves multiple DNA binding motifs for these transcription factors including three CRE halfsites that can bind CREB (2-4).Although cAMP is an essential inducer of steroidogenesis, other mechanisms triggered by paracrine and endocrine signals have been involved in the regulation of steroid synthesis in basal or stress-induced conditions. They can either act independently or in synergy with the PKA signaling (5). Prolactin (PRL) is a stress-related protein that has been reported to enhance aldosterone and glucocorticoid production in various mammalian species including rat, guinea pig, mouse, pig, and human (6 -12). A direct action of PRL o...

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Section: Discussionmentioning

confidence: 99%

Transcriptional Control of Adrenal Steroidogenesis

Lefrançois‐Martinez

Blondet-Trichard

Binart

et al. 2011

Journal of Biological Chemistry

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“…However, in prospective studies, only 3 of 13 patients with Cushing's disease achieved a biochemical response when treated acutely with 2.5 mg bromocriptine, 91 and data showing clinical benefits with longer term bromocriptine therapy at doses ranging from 5 to 15 mg/day are limited to very small studies and case reports. 92,93 Due to its more favourable pharmacological profile, characterized by a longer half-life and increased binding capacity and specificity for D2, 1 would anticipate greater efficacy with cabergoline. However, its utility in the treatment of Cushing's disease remains controversial.…”

Section: Dopamine Agonists For the Treatment Of Cushing's Diseasementioning

confidence: 99%

Dopamine agonists for the treatment of pituitary tumours: From ergot extracts to next generation therapies

Wexler

Page-Wilson

2023

Brit J Clinical Pharma

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They are the established first-line treatment for prolactinomas which express high levels of D2 receptors. Growing data support their use as an adjuvant treatment option for other pituitary tumours including growth hormone, adrenocorticotrophic hormones, thyroid hormone secreting adenomas and nonfunctional pituitary tumours, all of which have been shown to express D2 receptors as well, albeit to varying extents. For those pituitary tumours inadequately treated by dopamine agonist alone, combined agonism of D2 and somatostatin receptors represent a new frontier in clinical development. Here we review the development and role of dopamine agonist for the treatment of prolactinomas, the literature supporting their adjuvant use for the treatment of all other pituitary tumours, and recent progress in the development of the next generation of chimeric compounds that target D2 and other receptor subtypes highly expressed on pituitary tumour cells.

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“…The use of 2.5 to 5 mg/day bromocriptine has been reported to suppress ACTH and cortisol levels in patients of Cushing's disease and Nelson's syndrome, bearing increased plasma level of ACTH and cortisol, by directly inhibiting the ACTH production by corticotrophs or/and by dopaminergic modulation of ACTH secretion via hypothalamic corticotropin releasing hormone release in such patients. 281,[345][346][347][348] Excess ACTH is characterized to be released by ACTH releasing pituitary adenomas and the bromocriptine by binding to DRD2, expressed in $80% of patients with adenomas, has been found to not only decrease the ACTH level, but also decreases the size of tumour. 349 However, some researchers found it less effective or effective in only mild cases of such syndromes.…”

Section: Bromocriptine In Cushing's Disease and Nelson's Syndromementioning

confidence: 99%

Bromocriptine therapy: Review of mechanism of action, safety and tolerability

Naz

Malik

Riaz

et al. 2022

Clin Exp Pharma Physio

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Bromocriptine is a sympatholytic dopamine D2 receptor agonist with remarkable bioactivities. It has been used clinically as a prescription drug for more than 30 years to treat hyperprolactinemia associated conditions, Parkinson's disease, acromegaly, prolactinomas and other pituitary hormone dependent adenomas and recently, diabetes mellitus as well as various other disorders. Long‐term treatment with bromocriptine has minimal or no harmful effects on renal, hepatic, cardiac or hematologic functions. This review article was planned to study the hypothetical and proposed mechanism of action as well as provide a brief discussion about its safety issues and tolerability. Bromocriptine represents an attractive option with high efficacy and safety profile for hyperprolactinemia‐associated conditions, acromegaly, parkinsonism, type 2 diabetes mellitus and various other diseases in a variety of dosage forms for best possible beneficial effects. It appeared to be an effective and safe addition to the pharmacopoeia of drugs for the treatment of a vast variety of diseases as monotherapy or in combination with other drugs.

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Bromocriptine-Responsive Cushing's Disease; Clinical and Biochemical Remission Accompanied by Amelioration of Impaired Ocular Movement

Abstract: Abstract

Cited by 7 publications

References 20 publications

Transcriptional Control of Adrenal Steroidogenesis

Transcriptional Control of Adrenal Steroidogenesis

Dopamine agonists for the treatment of pituitary tumours: From ergot extracts to next generation therapies

Bromocriptine therapy: Review of mechanism of action, safety and tolerability

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