Clinical predictors of dopamine agonist resistance in macroprolactinoma, a single-arm pilot study

Zahra Davoudi¹Hamed Borhani²Mohammad Mirahmadi Eraghi³Guive Sharifi⁴Reza Naseri²Kaveh Ebrahimzadeh³Seyed Ali Mousavinejad³Mohammad Hallajnejad³Samar Heydari⁵Arezoo Chouhdari⁶Mohammad Samadian^4*

• ¹Department of Endocrinology, Loghman-Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
• ²Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
• ³Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran, Tehran, Iran
• ⁴Shahid Beheshti University of Medical Sciences, Tehran, Alborz, Iran
• ⁵Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
• ⁶Faculty of Medicine, Islamic Azad University of Medical Sciences, Tehran, Iran

Abstract Background: Prolactin-secreting tumors represent the predominant pituitary adenomas. Dopamine agonists (DAs) provide the primary therapeutic option; however, a large group of patients tend to be resistant to DAs. We sought to address the clinical predictors attributed to DA resistance in macroprolactinomas. Methods: We performed a single-arm, prospective pilot study including 48 patients with macroprolactinoma (size ≥ 1 cm). The clinical, hormonal, and radiological findings of eligible patients were analyzed from 2017 to 2023. Results: Thirty-five males and 13 females were included, and 31 and 17 patients were categorized as responsive and resistant groups. A significant difference was found among the groups in terms of age (p < 0.001), gender (p < 0.001), symptoms such as headaches (p = 0.02) and loss of libido (p < 0.001), baseline prolactin (PRL) levels (p = 0.001), and hypopituitarism (p < 0.001). 81.8% of patients in the resistance group had an initial PRL level greater than 1000 ng/mL. The resistant group had larger tumors. 88% and 45% of patients in the responsive and resistant groups, respectively, had cavernous sinus invasion, indicating a favorable response to medical treatment despite cavernous sinus extension. The most robust predictor for the responsive group was the administration of a low dose of cabergoline (< 1.5 mg/week). Patients experiencing remission with low-dose cabergoline were the only index responders. Conclusion: DA resistance macroprolactinomas are associated with younger age and higher baseline PRL. An adjusted dose of cabergoline represents a predictor of DA responsiveness. The cabergoline (<1.5 mg/week) not only demonstrated a positive response within the initial months but also represented the most robust predictor for the response group. Individualized therapeutic strategies and early identification of DA resistance should be attempted to optimize the outcomes.