Prolactinomas Resistant to Treatment With Dopamine Agonists: Long-Term Follow-Up of Six Cases

Abstract

Introduction: Prolactinomas are preferentially treated with dopamine agonists. However, a few adenomas are resistant to this treatment.Objective: To evaluate the characteristics of patients with resistance to dopamine agonists in the long-term.Method: A retrospective study of six cases was made. Patients who did not achieve normalized prolactin blood concentrations and a reduction of more than 50% of the tumor volume with the minimum dose of 3.5 mg per week of cabergoline for 3 months or the maximum supported dose of bromocriptine for 6 months were considered resistant to dopamine agonists. Patients were followed up at the Clinic of Neurology and Endocrinology or the University Hospital of Brasilia.Results: Six patients were selected. Three patients were initially treated with bromocriptine prior to treatment with cabergoline. Four patients were men, and two were women. At the time of diagnosis, ages ranged from 9 to 62 years. Initial prolactin concentrations ranged from 430 to 14,992 ng/mL and in the last assessment ranged from 29.6 to 2,169 ng/mL. The tumor volume ranged from 0.77 to 24.0 mm3. Tumor regression occurred in all patients, ranging from 20 to 100%, but total disappearance of the adenoma with an empty sella occurred in one patient. The maximum weekly doses of cabergoline ranged from 3.0 to 4.5 mg. Follow-up time ranged from seven to 17 years. Normalization of prolactin concentrations occurred only in one woman after 17 years of treatment. Three patients also underwent surgery, but only one woman was cured of the disease.Conclusion: This study confirms that tumors resistant to dopamine agonists are more aggressive, since we did not have any microadenoma; treatment with high dose of cabergoline may reduce the size of the tumor without its disappearance, and that normalization of prolactin concentration rarely occurs. To our knowledge, this is the longest follow-up of a series of cases with resistance to dopamine agonists.

Dopamine Agonist-Resistant Microprolactinoma—Mechanisms, Predictors and Management: A Case Report and Literature Review

“…The Ki-67 antigen is a protein used as a proliferation marker for human tumour cells. Refractory prolactinomas often show aggressive features and tend to exert higher angiogenesis, cell proliferation, and atypia [ 10 , 20 , 23 , 25 ]. Moreover, the presence of genetic predisposition indicates a poorer prognosis [ 19 , 20 , 23 ].…”

“…Refractory prolactinomas often show aggressive features and tend to exert higher angiogenesis, cell proliferation, and atypia [ 10 , 20 , 23 , 25 ]. Moreover, the presence of genetic predisposition indicates a poorer prognosis [ 19 , 20 , 23 ]. Prolactinomas may occur as a part of multiple neoplasia type 1 (MEN1) or familial isolated pituitary adenoma (FIPA) [ 11 ].…”

“…One of the possibilities is to switch to another, more potent DA [ 20 , 22 ]. In most cases, a substitution with CAB is recommended based on its greater efficacy and better tolerability compared to other DAs [ 5 , 9 ].…”

“…At present, there is no universal consensus on the definition of DA resistance [ 12 , 16 ]. It is most often described as a failure to achieve normoprolactinaemia and a less than 50% decrease in maximal tumour diameter on maximally tolerated doses of DA administered for at least 3–6 months [ 16 , 17 , 18 , 19 , 20 ]. Those doses vary amongst patients but are usually defined as ≥15 mg of BRC per day, ≥2.0 mg of CAB per week, and ≥225 ug of QUI per day [ 16 ].…”

Multiple Endocrine Neoplasia in Childhood: An Update on Diagnosis, Screening, Management and Treatment

“…Resistance to medical therapy is defined as persistent hyperprolactinemia after three months of maximal treatment dosing and less than 50% tumor shrinkage. In these resistant cases, the prolactinoma can be considered more aggressive [62]. Surgical intervention is thus indicated.…”