Acquired resistance to cabergoline: progression from initially responsive micro to macroprolactinoma

Abstract

In a recent issue of this Journal, Behan et al.[1] published a case of secondary resistance to cabergoline in a patient with prolactinoma. We communicate another case of this exceptional circumstance.A 40-year old woman was submitted to us for study of hyperprolactinemia, spontaneous galacthorrea and secondary amenorrhea, all of which had started one year earlier. She had previous diagnoses of rheumatoid arthritis and idiopathic thrombocytopenic purpurae, which had not required treatment. The initial study showed high serum prolactin (PRL) levels of 171 ng/ml (reference values [RV]: 6-29.9 ng/ml), and suppressed levels of LH (\1 mUI/ml; [RV]: 1.2-12.9 mUI/ml). All others pituitary hormones were within normal ranges. Platelet count was 30,000/ll.The magnetic resonance imaging (MRI) of the pituitary gland showed a lesion consistent with a microadenoma of 8 9 9 mm in the right lobe ( Fig. 1). The patient was started on cabergoline, 0.5 mg/week, switching to 0.25 mg/week after 6 months and to 0.75 mg/week 18 months later, in order to maintain normal levels of PRL, which oscillated between 9 and 25 ng/ml during follow-up. Menses returned and galactorrhea resolved since the first month of therapy.Three and half years after presentation, while the patient was still under cabergoline treatment, she complained of reappearance of spontaneous galacthorrea and amenorrhea, along with headache and decreased visual acuity. A new endocrine assessment revealed PRL levels of 128 ng/ml, without changes in other pituitary hormones. Pregnancy, treatment with estrogens and non-compliance were excluded. Strict surveillance of treatment fulfilment was performed in each visit from that time on. A new MRI demonstrated growth of the prolactinoma (15 9 12 mm, Fig. 2a), which presented poorly defined margins and a suprasellar extension that contacted with the inferior surface of the optic chiasm. Physical examination and visual field testing did not show optical damage and cabergoline dose was increased to 2 mg per week. Two months later the patient referred worsening of headache and blurry vision. Magnetic resonance imaging showed a 3 mm increase of the craneocaudal diameter of the adenoma and signs of intratumoral bleeding (Fig. 2b). Platelet count was 40,000/ ll. With the diagnosis of mild symptomatic pituitary apoplexy, the patient was admitted to the hospital and conservative treatment with 12 mg/day dexametasone was administered for a week, resulting in improvement of headache and visual acuity. Three weeks after inpatient treatment with 2 mg per week of cabergoline, serum levels of PRL had risen to 290 ng/ml, but dose was not increased since it could have acted as a precipitating factor for pituitary apoplexy. A MRI performed 2 months later did not show substantial changes. Cabergoline dose was then increased to 3 mg/week, leading to a reduction of PRL levels to 97 ng/ml. One month later, the patient presented sustained headache and bitemporal hemianopsia. Prolactin levels were 313.7 ng/ml and platelet count 43,000/ll. The patient und...

Resistance to dopamine agonists in prolactinoma is correlated with reduction of dopamine D2 receptor long isoform mRNA levels

“…Only six such patients have been reported in the literature (excluding malignant transformation) (3,4,5,6,7). The possible explanations for acquired non-responsiveness include non-compliance, onset of gonadal steroid replacement that causes dopamine resistance in the lactotrophs, and, rarely, transformation to carcinoma (37,41).…”

“…There have been very few reported cases of prolactinoma exhibiting secondary resistance, i.e. cases that show an initial response to dopamine agonists, but then become refractory with prolonged treatment (3,4,5,6,7).…”

Resistance to Dopamine Agonists in Pituitary Tumors: Molecular Mechanisms

“…Only a small subset of patients with prolactinomas does not respond to DAs treatment (primary resistance), as approximately 20-30% is resistant to BRC and around 10-20% to CAB (24,45), due to modification of DRs expression or to intracellular molecular mechanisms. Very infrequently patients with prolactinomas experience a delayed resistance becoming refractory to DAs prolonged treatment (secondary resistance) (46)(47)(48)(49)(50)(51). This condition is generally considered an expression of a negative prognosis as it might indicate a malignant transformation of the prolactinoma (46).…”

The role of MAPK11/12/13/14 (p38 MAPK) protein in dopamine agonist-resistant prolactinomas

“…As a result, a decrease in D2 receptor expression levels will cause the failure of DAs to inhibit prolactin and further lead to DA resistance in prolactinoma [ 5 ]. Studies have shown that the reduction of dopamine D2 receptor expression is considered to be the main cause of DA resistance in prolactinoma [ 6 – 8 ], but DRD2-mediated resistance cannot explain all the issues. Therefore, it is urgent to explore the mechanism of drug resistance in prolactinoma.…”