Abnormal Dopamine Sensitivity in Some Human Prolactinomas

Pellegrini, Isabelle; Costa, Rafael; Grisoli, F; Jaquet, P

doi:10.1159/000181081

Cited by 13 publications

(11 citation statements)

References 21 publications

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“…It has been reported that the suppression of GH/PRL by D2R agonists was correlated to D2R gene expression in lactotroph and somatotroph tumors in vitro [20,21]. In the present study, however, no significant differences were detected in responsiveness to bromocriptin between the two subtypes, despite the greater expression of D2R in SG type than DG-type adenomas.…”

Section: Discussioncontrasting

confidence: 76%

Differential expression of genes related to drug responsiveness between sparsely and densely granulated somatotroph adenomas

et al. 2012

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Section: Discussioncontrasting

confidence: 76%

Differential expression of genes related to drug responsiveness between sparsely and densely granulated somatotroph adenomas

et al. 2012

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“…However, 8-15% of them are unsuccessfully treated by high doses of bromocriptine (15 mg daily); maximal doses are unable to normalize the blood PRL levels and, in some patients, a further tumor growth occurs despite therapy [34,35], These tumors are refered to as bromocriptineresistant tumors. The variations in sensitivity to the dopa mine agonists correlate neither with the circulating bromo criptine levels obtained after oral or parenteral administra tion.…”

Section: Abnormal Transduction Mechanisms In Pituitary Adenomasmentioning

confidence: 99%

Abnormal Transduction Mechanisms in Pituitary Adenomas

et al. 1997

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Pituitary adenomas are differentiated tumors expressing their appropriate mature hormone. Tumoral cells sometimes present with a defective physiological inhibitory or stimulatory control, resulting in paradoxical responses or nonresponsiveness to regulatory neurohormones. These abnormalities can be explained by defects at the intracellular transduction mechanism level. Knowledge of these defective pathways has made progress in the understanding of the pathogenesis of pituitary adenomas possible. The discovery of mutations of Gsα named gsp oncogenes in 40% of human somatotropinomas represents one of the most important advances in this field. Other molecular alterations were identified but are rare and sporadic and the pathogenesis of pituitary adenomas remains largely unknown.Abnormal transduction mechanisms may also result in a variable sensitivity of tumors to pharmacological therapy. The dopamine agonist, bromocriptine, is able to normalize blood PRL levels and to reduce tumor size in the majority of patients with prolactinoma, but is ineffective in 8-15% of them. Under physiological conditions, PRL secretion is under the tonic inhibitory control of dopamine which binds D2 receptors negatively coupled to adenylyl cyclase. Several defects in the dopaminergic transduction pathways participate in this bromocriptine resistance. The mean D2-binding site density is decreased to 50% as compared to responsive tumors. This loss of D2 receptors can account for a lower transcription level of its gene and is accompanied by modifications in the messenger alternative splicing; the D2 short isoform receptor expression decreases preferentially. A reduction in Gi2α protein expression is also observed and is correlated to that of the D2 receptor. Finally, the pituitary-specific transcription factor Pit-1 expression is affected. A highly significant correlation was seen between the D2 receptor mRNA and Pit-1 mRNA levels. These defects observed on many levels of the dopaminergic transduction cascade may be the first steps in the loss of the functional features of differentiated tumors toward more proliferative tumors.

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“…Duranteau et al [11 ]classified as resistant those patients who did not normalize PRL or who did not show tumor shrinkage, or both, within the same treatment schedule. Based on these criteria, these authors concluded that bromocriptine resistance is present in between 5 and 18% of patients [10, 12, 13]. However, some authors [14, 15] define resistance on a clinical basis, also taking into account drug intolerance.…”

Section: Introductionmentioning

confidence: 99%

“…There is a spectrum of DA resistance in prolactinomas, ranging from the most responsive ones (those that achieve PRL normalization) to the most resistant ones (those that present PRL and tumor growth during treatment) [13]. The mechanisms involved in prolactinoma resistance to DA are not completely understood.…”

Section: Introductionmentioning

confidence: 99%

Genes Differentially Expressed in Prolactinomas Responsive and Resistant to Dopamine Agonists

Passos¹,

Fortes

Giannella-Neto

et al. 2008

Neuroendocrinology

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Background/Aims: Prolactin (PRL) secretion and its gene expression are inhibited by dopamine. Prolactinomas are the most common secreting pituitary adenomas, and dopamine agonists (DA) are the first choice for their treatment. However, a subset of patients is resistant to DA. As the mechanisms involved in DA resistance are not fully understood, the aim of this study was to obtain new insights regarding the molecular differences between the prolactinomas that are responsive to DA and those that are resistant. Methods: Tumor tissue samples were collected from 17 patients who harbored prolactinomas, which were classified as responsive or resistant according to their clinical and laboratorial reaction to DA. The expression of 6 genes was evaluated by real-time polymerase chain reaction: dopamine receptor type 2 (DRD₂), nerve growth factor-β (NGFB) and its receptor (NGFR), estrogen receptor-α (ERA), estrogen receptor-β (ERB) and the pituitary tumor transforming gene (PTTG). Results: Median DRD₂ and NGFR expression in responsive patients was significantly higher than in resistant ones (p = 0.029 and p = 0.020, respectively). Moreover, the expressions of DRD₂ and NGFR were positively correlated with PRL decrease during treatment (r = 0.66, p = 0.005 and r = 0.57, p = 0.044, respectively). Furthermore, ERB expression was positively correlated to PTTG expression (r = 0.68, p = 0.032) and negatively correlated to NGFB expression (r = –0.75, p = 0.02). Conclusions: DRD₂ and NGFR expressions are related to the responsiveness of prolactinoma to DA. However, PTTG, ERB and ERA expressions are not. Also ERB, ERA and PTTG expressions did not present a clear correlation to tumor aggressiveness. Furthermore, the response of prolactinomas to DA should be viewed as a spectrum ranging from the most responsive to the most resistant ones.

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Abnormal Dopamine Sensitivity in Some Human Prolactinomas

Cited by 13 publications

References 21 publications

Differential expression of genes related to drug responsiveness between sparsely and densely granulated somatotroph adenomas

Differential expression of genes related to drug responsiveness between sparsely and densely granulated somatotroph adenomas

Abnormal Transduction Mechanisms in Pituitary Adenomas

Genes Differentially Expressed in Prolactinomas Responsive and Resistant to Dopamine Agonists

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