Reframing the Paradigm: A Nuanced Approach to Prolactinoma Management
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Prolactinomas are the most prevalent type of functioning pituitary tumor. Population-based studies estimate the prevalence of prolactinoma to be about 500 cases per million, although this figure is substantially lower, at 82.5 cases per million, in Korea [1,2]. Women are three times more likely than men to develop prolactinomas and present with a higher ratio of microprolactinomas to macroprolactinomas [1]. The standardized incidence rate for women is triple that of men. Additionally, the ratio of macroprolactinomas to microprolactinomas is approximately 1:8 in women, compared to 4:1 in men.
Petersenn et al. [3] present an international consensus statement on the diagnosis and management of prolactinomas, providing evidence-based guidance for clinicians who care for patients with these tumors. Developed by experts from the Pituitary Society, this comprehensive statement offers important updates on several key areas of prolactinoma management (Fig. 1).
Reframing the treatment algorithm for prolactinoma. HRT, hormone replacement therapy; PRL, prolactin; MRI, magnetic resonance imaging.
The most notable part of this statement is that surgery can now be considered a first-line treatment for patients with microprolactinoma and well-circumscribed macroprolactinoma (Knosp grade 0 and 1). Previously, guidelines recommended surgery only for cases resistant to medical management, those intolerable to dopamine agonists, and women planning pregnancy [4]. However, advances in surgical techniques, such as extra-pseudocapsular resection, along with a low complication rate, now support the consideration of surgery as a primary treatment option for prolactinoma [5,6]. Additionally, the preference for surgical treatment is sometimes due to the prolonged duration and low overall remission rate (only 21%) associated with medical treatment [7]. Therefore, it is important for doctors to discuss with patients who have microprolactinomas and well-circumscribed macroprolactinomas the benefits and side effects of both treatment options: surgery and dopamine agonists. This discussion underscores the importance of shared decision-making, taking into account the patients’ personal values and preferences.
Notably, this consensus statement advocates for a less stringent approach to cardiac valvulopathy surveillance, which represents a slight departure from the guidelines previously issued [8]. Baseline echocardiography is recommended only for patients requiring more than 2.0 mg/week of long-term cabergoline treatment, and it should be repeated every 2 to 3 years [3]. In patients receiving cabergoline at doses of ≤2.0 mg/week for over 5 to 6 years, echocardiography is recommended, although the supporting evidence is weak.
Based on a meta-analysis primarily consisting of observational studies, preoperative medical therapy has been shown to reduce the surgical remission rate [9]. Patients who undergo preoperative medical treatment often present with more aggressive or resistant prolactinomas. This may be due to tumor fibrosis induced by the use of dopamine agonists, such as bromocriptine, which could impact the surgical remission rate [10]. However, the relationship between cabergoline use and tumor fibrosis remains unclear. Therefore, before drawing any conclusions, it is necessary to await the results from an ongoing randomized study comparing primary surgery to surgery following dopamine agonist treatment in patients with non-invasive prolactinomas [11].
Dopamine agonist withdrawal criteria have not been universally recognized. Instead, favorable predictors such as low maintenance doses of cabergoline (0.25 to 0.5 mg/week), treatment duration exceeding 2 years, and significant adenoma size reduction have been suggested. However, these predictors alone are insufficient to determine the appropriate timing for withdrawal. The criteria have been slightly relaxed regarding tumor size reduction, contrasting with previous guidelines that recommended no visible tumor remnants on magnetic resonance imaging [4]. Although not discussed in this paper, factors such as the percent change in prolactin levels 3 months after starting dopamine agonists, the lowest prolactin level achieved during treatment, and the degree of cavernous sinus invasiveness should also be considered as predictive factors for treatment response and recurrence [12-15].
In this statement, it is recommended that patients who have successfully withdrawn from cabergoline undergo annual lifelong follow-up due to the high rate of recurrence [3]. However, for patients who show no visible tumors at the time of drug withdrawal, follow-up may be discontinued after approximately 6 years, as the longest reported time to recurrence is between 5 and 6 years [7,13]. Future studies are needed to determine the optimal follow-up period after dopamine agonist withdrawal in patients who are in remission, in order to reduce the burden.
This international consensus statement highlights key advancements in the management of prolactinomas, recommending surgery as the primary treatment in specific cases. It stresses the importance of shared decision-making and updates the guidelines for cardiac valvulopathy monitoring. The effectiveness of preoperative medical therapy on surgical outcomes is still being studied. The guidelines for withdrawing dopamine agonists underscore the necessity for tailored treatment approaches, although more research is needed to refine these guidelines and improve predictions of patient responses and recurrence rates. Furthermore, the advice to conduct annual lifelong follow-ups after discontinuing dopamine agonists underscores the need for ongoing monitoring, calling for additional research to establish the best follow-up protocols.
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CONFLICTS OF INTEREST
Jung Hee Kim is a deputy editor of the journal. But she was not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.