2 182 D Kim and others PRL cut-offs and tumor size 182:2 177–183 Clinical Study reduction Prolactin ≤1 ng/mL predicts macroprolactinoma reduction after cabergoline therapy Correspondence Daham Kim, Cheol Ryong Ku, Kyungwon Kim, Hyein Jung and Eun Jig Lee should be addressed Department of Internal Medicine, Institute of Endocrine Research, Yonsei University College of Medicine, to C R Ku Seoul, Korea Email [email protected] Abstract Objective: The association between prolactin level variation and prolactinoma size reduction remains unclear. This study aimed to determine the prolactin level cut-off predictive of a tumor size reduction. Design: Retrospective cohort study. Methods: We reviewed medical records of patients with prolactinoma who received primary cabergoline therapy and for whom complete data on pituitary hormone assays and sellar MRI at baseline and 3 months post treatment were available. We tested whether the certain prolactin level after 3 months post treatment predicted better response. Results: Prolactin levels normalized in 109 (88.6%) of 123 included macroprolactinoma patients. The mean tumor size reduction was 22.9%, and patients in the lowest prolactin tertile (≤0.7) had the highest frequency of tumor size reductions of ≥20% (73.7 vs 52.9% and 45.9% in tertiles 2 (>0.7 to 2.6) and 3 (>2.6 to 20), P = 0.015). Patients with prolactin levels ≤1 ng/mL exhibited larger tumor size reductions vs those with prolactin levels of 1–20 (27.2 ± 18.3% vs 19.5 ± 13.9%, P = 0.014), 1–10 (19.3 ± 13.7%, P = 0.017) and 1–5 ng/mL (19.2 ± 14.3%, P = 0.039). A multivariable logistic regression analysis revealed that a prolactin level ≤1 ng/mL at 3 months and high-dose cabergoline therapy were significantly associated with tumor size reductions of≥ 20% (odds ratio (OR): 2.8, 95% confidence interval (CI): 1.2–6.7, P = 0.017; OR: 2.0, 95% CI: 1.0–3.9, P = 0.043). European Journal of Endocrinology Conclusions: A prolactin level ≤1 ng/mL at 3 months after cabergoline treatment was correlated with a significant tumor size reduction in patients with macroprolactinoma. This finding may help clinical decision making when treating macroprolactinoma patients. European Journal of Endocrinology (2020) 182, 177–183 Introduction Prolactinomas are the most commonly occurring pituitary The first line of therapy involves medical management adenomas, accounting for approximately 40% of all with dopamine agonists such as bromocriptine and pituitary tumors and 50–60% of all functional pituitary cabergoline. Surgical resection is generally reserved for tumors (1). These tumors cause headaches, visual patients who are unresponsive or intolerant to medical dysfunction, hypopituitarism, and hyperprolactinemia therapy. Cabergoline, a specific D2 receptor agonist, is the (2). Patients with prolactinoma typically exhibit the first choice of treatment because of its superior efficacy clinical features of hyperprolactinemia, including gonadal and better tolerability (3). The recommended cabergoline dysfunction, amenorrhea, and galactorrhea. dosage for initiation is 0.25–0.5 mg twice a week, whereas Serum prolactin level normalization and tumor the usual weekly maintenance doses range from 0.25 to shrinkage are the major goals of prolactinoma treatment. 3.0 mg (4). https://eje.bioscientifica.com © 2020 European Society of Endocrinology Published by Bioscientifica Ltd. https://doi.org/10.1530/EJE-19-0753 Printed in Great Britain Downloaded from Bioscientifica.com at 09/26/2021 11:48:25AM via free access -19-0753 Clinical Study D Kim and others PRL cut-offs and tumor size 182:2 178 reduction In a previous study, treatment with 0.125–1.0 mg cabergoline twice weekly for 12–24 months resulted in the normalization of prolactin levels in 95% of patients with microprolactinoma (5). In another study of macroprolactinoma, normoprolactinemia was achieved in 81% of patients receiving 0.25–2 mg cabergoline weekly (6). Cabergoline treatment is very effective, and response assessments based on the tumor volume reduction and prolactin normalization after 3 months of treatment are useful for predicting long-term responses and resistance to cabergoline (7). However, prolactin levels may decrease below the normal range even after normalization following 3 months of cabergoline treatment. Figure 1 Differences in tumor size reduction within the Flow chart of the study. CAB, cabergoline; MRI, magnetic prolactin normalization cut-off values have not yet been resonance imaging; PRL, prolactin; TSA, transsphenoidal determined. Therefore, this study aimed to evaluate the adenomectomy; 3m f/u, 3-month follow-up. potential use of prolactin cut-off values to predict tumor size reductions in patients with macroprolactinoma. Treatment and response assessment In all cases, oral cabergoline was initiated at a low dose (0.5–1 mg/week), and the dosage was gradually increased Patients and methods to a maintenance dose within 2–4 weeks (7). The latter dose was maintained for 3 months after treatment Patients initiation to ensure a sufficient period of drug exposure. We reviewed the medical records of patients with A response evaluation was conducted after 3 prolactinoma who were treated with cabergoline as a months. The serum prolactin levels were measured using primary drug therapy at Severance Hospital between chemiluminescence immunoassay using commercial November 2011 and June 2017. A diagnosis of prolactinoma kits (Beckman Coulter, Brea, CA, USA). The lower limit was made if a patient presented with a serum prolactin of detection for the prolactin assay was 0.25 ng/mL, and if the prolactin values were not as high as expected, the European Journal of Endocrinology level above the normal range and pituitary adenomas on sellar MRI (8). Before confirming a prolactinoma diagnosis, assay was repeated after a 1:100 serum sample dilution to secondary causes of hyperprolactinemia were ruled overcome a potential hook effect. The within-run and total out by assessing the clinical history, including current coefficients of variation for prolactin concentrations were medications, physical examination findings, pregnancy 3.66 and 3.77%, respectively. Prolactin normalization was tests, routine biochemical analysis with thyroid function defined as the achievement of a concentration <20 ng/ tests, and neuroimaging. mL. The lower limit of normal prolactin level was 5 ng/ To evaluate the relationships among parameters, we mL, and the lower limit of detectable prolactin level was included patients for whom the following information 1 ng/mL. These criteria were used to classify patients (8). was available: complete pituitary hormone assay data Although our assay kit is more sensitive, we used generally and sellar MRI findings at baseline, follow-up prolactin accepted criteria. assay data, and sellar MRI findings at 3 months after Sellar MRI was performed using a 1.5-Tesla (Signa; cabergoline treatment. We excluded patients who General Electric, Minneapolis, MN, USA) or 3.0-Tesla underwent transsphenoidal adenomectomy before the system (Achieva; Philips, Best, The Netherlands). The third month of cabergoline treatment. Accordingly, 217 maximum tumor diameter was measured and used to of 221 identified patients were enrolled Fig.( 1). This study classify prolactinomas as microprolactinoma (<10 mm) or was conducted in accordance with the 1964 Declaration macroprolactinoma (≥10 mm) (8). A tumor size reduction of Helsinki and was approved by the Institutional Review was calculated as the (initial tumor size − tumor size after Board of Severance Hospital (No. 4-2019-0400). The 3 months of cabergoline treatment)/initial tumor size. We requirement for informed consent was waived because of set the tumor size reduction cut-off value according to the retrospective nature of this study. the mean size reduction of macroprolactinoma patients https://eje.bioscientifica.com Downloaded from Bioscientifica.com at 09/26/2021 11:48:25AM via free access Clinical Study D Kim and others PRL cut-offs and tumor size 182:2 179 reduction who achieved prolactin normalization after 3 months of 96.8% of patients in the microprolactinoma group and cabergoline treatment. 88.6% of those in the macroprolactinoma group achieved prolactin normalization. However, the percentage of size reduction was greater in the macroprolactinoma group than Statistical analysis in the microprolactinoma group. As it is difficult to measure SPSS Statistics version 23 (IBM Corp.) was used for all exact size changes in small tumors, our further evaluations statistical analyses. Categorical variables are presented included only patients with macroprolactinoma patients as numbers and percentages. Continuous variables are who achieved prolactin normalization. expressed as means ± S.D. Statistical comparisons of the mean values were performed using Student’s t-test, and Tumor size reduction according to prolactin level group comparisons were performed using the χ2 test or linear-by-linear association, as appropriate. A multivariable Next, we compared tumor size reductions within the logistic regression analysis was used to determine variables prolactin normalization cut-off value after 3 months independently associated with tumor size reductions of cabergoline treatment. Macroprolactinoma patients (≥20%) based on observed characteristics of patients (age who achieved prolactin normalization had a mean size (years), sex (female), initial tumor size (mm), cabergoline reduction of 22.9%. Simple linear regression analysis dose (mg/week), and prolactin ≤1 ng/mL). was performed