Resistance to Dopamine Agonists in Pituitary Tumors: Molecular Mechanisms

Pivonello, Claudia; Patalano, Roberta; Negri, Mariarosaria; Pirchio, Rosa; Colao, Annamaria; Pivonello, Rosario; Auriemma, Renata S.

doi:10.3389/fendo.2021.791633

Cited by 8 publications

(4 citation statements)

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“…Prolactinomas that are resistant or refractory to these DA doses are rarer, and some can have aggressive clinical characteristics ( 22 , 23 ). The pathophysiology of DA resistance in prolactinomas is largely unknown, but factors like altered expression of dopamine D2 receptor levels have been suggested ( 24 ). Although AIP has been implicated in resistance to somatostatin analogs in AIPvar somatotropinomas ( 16 , 25 ), this has not been explored in details in AIPvar prolactinomas.…”

Section: Discussionmentioning

confidence: 99%

“…Most present as microadenomas in fertile women that are responsive to labelled doses of cabergoline (2). Prolactinomas that are resistant or refractory to these DA doses are rarer, and some can have aggressive clinical characteristics (22,23). The pathophysiology of DA resistance in prolactinomas is largely unknown, but factors like altered expression of dopamine D2 receptor levels have been suggested (24).…”

Section: Discussionmentioning

confidence: 99%

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The clinical and therapeutic profiles of prolactinomas associated with germline pathogenic variants in the aryl hydrocarbon receptor interacting protein (AIP) gene

Vroonen,

Beckers,

Camby

et al. 2023

Front. Endocrinol.

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IntroductionProlactinomas are the most frequent type of pituitary adenoma encountered in clinical practice. Dopamine agonists (DA) like cabergoline typically provide sign/ symptom control, normalize prolactin levels and decrease tumor size in most patients. DA-resistant prolactinomas are infrequent and can occur in association with some genetic causes like MEN1 and pathogenic germline variants in the AIP gene (AIPvar).MethodsWe compared the clinical, radiological, and therapeutic characteristics of AIPvar-related prolactinomas (n=13) with unselected hospital-treated prolactinomas (“unselected”, n=41) and genetically-negative, DA-resistant prolactinomas (DA-resistant, n=39).ResultsAIPvar-related prolactinomas occurred at a significantly younger age than the unselected or DA-resistant prolactinomas (p<0.01). Males were more common in the AIPvar (75.0%) and DA- resistant (49.7%) versus unselected prolactinomas (9.8%; p<0.001). AIPvar prolactinomas exhibited significantly more frequent invasion than the other groups (p<0.001) and exhibited a trend to larger tumor diameter. The DA-resistant group had significantly higher prolactin levels at diagnosis than the AIPvar group (p<0.001). Maximum DA doses were significantly higher in the AIPvar and DA-resistant groups versus unselected. DA-induced macroadenoma shrinkage (>50%) occurred in 58.3% in the AIPvar group versus 4.2% in the DA-resistant group (p<0.01). Surgery was more frequent in the AIPvar and DA- resistant groups (43.8% and 61.5%, respectively) versus unselected (19.5%: p<0.01). Radiotherapy was used only in AIPvar (18.8%) and DA-resistant (25.6%) groups.DiscussionAIPvar confer an aggressive phenotype in prolactinomas, with invasive tumors occurring at a younger age. These characteristics can help differentiate rare AIPvar related prolactinomas from DA-resistant, genetically-negative tumors.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The clinical and therapeutic profiles of prolactinomas associated with germline pathogenic variants in the aryl hydrocarbon receptor interacting protein (AIP) gene

Vroonen,

Beckers,

Camby

et al. 2023

Front. Endocrinol.

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“…However, in any case of DAs resistance, the problem of its overcoming and prescribing effective treatment arises. [ 23 - 24 ].…”

Section: Dopamine Agonist Resistancementioning

confidence: 99%

Current and Perspective Approaches to the Treatment of Prolactinomas

Barabash,

Tykhonova,

Kanishcheva

2023

AML

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Background: Along with the presence of the 2011 Endocrine Society Clinical Practice Guidelines and numerous large-scale studies on the treatment of hyperprolactinemia of different origin, there are some unresolved questions, ambiguous and sometimes contradictory points of view regarding the management of patients with prolactinomas. This overview is devoted to the analysis of the results of modern clinical studies and the approaches towards the management of hyperprolactinemia caused by prolactinoma.Materials and methods: A systematic research of the literature for the appropriate keywords published mainly for the last 10 years was done; also, a reference list of each selected article was analysed. We included to our review the articles reporting controversial issues or new data on the treatment of hyperprolactinemia.Results: The review describes various problems arising during the treatment of prolactinoma. The presence of primary and secondary dopamine agonist resistance in each case requires an individual approach, and sometimes may include the use of the antineoplastic agent temozolomide. The side effects of dopamine agonists are discussed, with quite rare ones, including valvulopathy, pathological psychological conditions and cerebrospinal rhinorrhea. The controversial issue of the duration and doses of the drug used to achieve a lasting effect in the treatment of prolactinomas is considered. There are some points connected with the frequency of relapses. Thus, recurrence is correlated to the duration of treatment with dopamine agonists, prolactin levels at diagnosis, and the initial tumor size. Metformin, somatostatin analogues, selective estrogen receptor modulators, tyrosine kinase inhibitors, inhibitors of the mammalian target of rapamycin, epidermal growth factor receptor antagonists are investigated nowadays as potential alternative methods of drug treatment of prolactinomas. Conclusion: Drug therapy with dopamine agonists makes it possible to achieve the desired results in the vast majority of patients. However, despite the proven safety of this group of medicines, the risk of side effects should still be taken into account. The therapy regimen should be determined by the clinical course of prolactinoma and the patient’s response to treatment. Other options of treatment should be considered in patients intolerant to medical therapy, with contraindication or resistance to dopamine agonists, in the case of a malignant tumor. The presence of refractory to any of the applied methods of treatment and aggressive prolactinomas leads to the search for new drugs.

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“…In the clinic, lactotroph PitNETs are usually effectively controlled with dopamine D2 receptor agonists, including bromocriptine and cabergoline, or transsphenoidal surgery (Zhang et al, 2022). However, some lactotroph PitNET patients are resistant to dopamine agonists or suffer from cerebrospinal rhinorrhea or hypopituitarism after surgery (Pivonello et al, 2021). Therefore, there is a need to better understand the pathogenesis and to develop novel therapeutic strategies for lactotroph PitNETs.…”

Section: Introductionmentioning

confidence: 99%

Intranasal 15d-PGJ2 inhibits the growth of rat lactotroph pituitary neuroendocrine tumors by inducing PPARγ-dependent apoptotic and autophagic cell death

Chen

Zhang

et al. 2023

Front. Neurosci.

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PPARγ agonists have been reported to induce cell death in pituitary neuroendocrine tumor (PitNET) cell cultures. However, the therapeutic effects of PPARγ agonists in vivo remain unclear. In the present study, we found that intranasal 15d-PGJ2, an endogenous PPARγ agonist, resulted in growth suppression of Fischer 344 rat lactotroph PitNETs induced by subcutaneous implantation with a mini-osmotic pump containing estradiol. Intranasal 15d-PGJ2 reduced the volume and weight of the pituitary gland and the level of serum prolactin (PRL) in rat lactotroph PitNETs. 15d-PGJ2 treatment attenuated pathological changes and significantly decreased the ratio of PRL/pituitary-specific transcription factor 1 (Pit-1) and estrogen receptor α (ERα)/Pit-1 double-positive cells. Moreover, 15d-PGJ2 treatment induced apoptosis in the pituitary gland characterized by an increased ratio of TUNEL-positive cells, cleavage of caspase-3, and elevated activity of caspase-3. 15d-PGJ2 treatment decreased the levels of cytokines, including TNF-α, IL-1β, and IL-6. Furthermore, 15d-PGJ2 treatment markedly increased the protein expression of PPARγ and blocked autophagic flux, as evidenced by the accumulation of LC3-II and SQSTM1/p62 and the decrease in LAMP-1 expression. Importantly, all these effects mediated by 15d-PGJ2 were abolished by cotreatment with the PPARγ antagonist GW9662. In conclusion, intranasal 15d-PGJ2 suppressed the growth of rat lactotroph PitNETs by inducing PPARγ-dependent apoptotic and autophagic cell death. Therefore, 15d-PGJ2 may be a potential new drug for lactotroph PitNETs.

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Resistance to Dopamine Agonists in Pituitary Tumors: Molecular Mechanisms

Cited by 8 publications

References 107 publications

The clinical and therapeutic profiles of prolactinomas associated with germline pathogenic variants in the aryl hydrocarbon receptor interacting protein (AIP) gene

The clinical and therapeutic profiles of prolactinomas associated with germline pathogenic variants in the aryl hydrocarbon receptor interacting protein (AIP) gene

Current and Perspective Approaches to the Treatment of Prolactinomas

Intranasal 15d-PGJ2 inhibits the growth of rat lactotroph pituitary neuroendocrine tumors by inducing PPARγ-dependent apoptotic and autophagic cell death

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