Introduction
Prolactinomas are the most common pituitary neuroendocrine tumors (PitNETs) with a prevalence ranging from 6–10 to 60 per 100,000 patients [
1‐
3]. Most of them arise from monoclonal expansion of lactotroph cells. Less than 5% of the cases are related to a hereditary syndrome, such as Multiple Endocrine Neoplasia 1 and 4 (MEN1 and MEN4, respectively), familial isolated pituitary adenoma (FIPA) or Carney complex [
4‐
6].
The clinical manifestations of prolactinomas relate to mass-effects (most frequently visual field defects, headaches and hypopituitarism) and/or to hyperprolactinemia-related consequences (hypogonadism and its sequelae and galactorrhea). Primary goals of treatment are reduction in tumor size, achievement of normal prolactin and restoration of gonadal function [
7,
8]. The treatment of prolactinomas is unique amongst the PitNETs, since they are the only type of pituitary tumor in which first-line approach is medical therapy [with dopamine agonists (DA)] rather than surgery. Consensus guidelines recommend cabergoline in preference to other DAs, such as bromocriptine and quinagolide [
7]. This is based on studies showing more optimal tolerability profile and higher efficacy in achieving normoprolactinemia and tumor shrinkage with this agent [
9‐
12], attributed to higher affinity to D2 receptor and more potent cytocidal effect in tumor cells (compared with bromocriptine) [
13]. In addition, a meta-analysis has underlined that DAs, in this case bromocriptine, can successfully manage various clinical manifestations seen in patients with prolactinoma, including 86% of those with galactorrhea, 78% with amenorrhea, 67% with sexual dysfunction, 67% with visual field defects and 53% of patients with infertility [
14].
A small subset of patients does not respond to DAs (primary resistance). It should be noted, however, that definitions of resistance are highly variable throughout the literature, rendering the comparison of response rates and relevant predictors rather challenging. Practice guidelines for hyperprolactinemia suggest that a failure to achieve normal prolactin on maximally tolerated doses of DAs and a failure to achieve 50% reduction in tumor size should be regarded as DA-resistance [
7]. This definition has also been acknowledged by the other publications [
15,
16]. The maximally tolerated doses vary amongst patients and can be up to 12 mg weekly for cabergoline and 30 mg daily for bromocriptine [
15‐
17]. In common clinical practice, the mean maximum dose of cabergoline (the most frequently used DA) is around 4 mg per week [
18]. There is no agreement on the minimum duration of treatment and it would seem reasonable to suggest at least 6 months on the highest tolerated DA dose [
17]. It is also worth mentioning that the relative importance of tumor shrinkage as a criterion for resistance needs to be challenged in adenomas in which, although reduction in size has not been achieved, they are not causing pressure effects. Consensus recommendations recognize that failure to restore fertility may also reflect treatment resistance, and that some patients might have a discordant biochemical and tumoral response, further complicating the establishment of a standard definition [
7]. It should be further underlined that previous studies have used different cut-offs, such as 50% decrease in prolactin levels or 30% reduction in craniocaudal diameter of the tumor [
19,
20]. Irrespective of the criteria adopted for defining DA resistance, decisions on continuing treatment with these agents should also rely on the clinical benefit (e.g. restoration of gonadal function, resolution of mass effects and particularly visual disturbances, absence of tumor growth) achieved for each individual patient.
Primary DA-resistance has been reported in approximately 20–30% of the patients on bromocriptine, and in around 10% of those on cabergoline [
15,
17,
21]. Yet, when focusing on macroprolactinomas only, cabergoline fails to lead to normoprolactinemia in 17% of the cases and to tumor shrinkage in 29% of them [
15]. Further studies have suggested that tumor size and invasiveness (namely cavernous sinus extension), younger age at diagnosis and male gender are predictors of lower response [
18,
22‐
24]. Decreased expression of D2 dopamine receptors in tumor cells, alterations in other receptors modulating dopamine receptors [e.g. nerve growth factor receptor (NGFR)], changes in downstream cascades (e.g. in G protein subunit), increased angiogenic markers, and increased fibrosis through disruptions in the transforming growth factor (TGF)-β1 pathway have all been suggested as possible mechanisms playing a role in DA-resistance [
25‐
29]. However, an extensive audit of these mechanisms is outside the scope of this review.
Secondary (or acquired) resistance to DAs is very rare and describes patients that initially responded to DA but later showed increasing prolactin levels and/or tumor enlargement. It should be pointed out that some patients who initially responded to bromocriptine but then acquired some degree of resistance have benefited from a switch to cabergoline, and, therefore, they should not be regarded as truly DA-resistant [
30]. To the best of our knowledge, only six cases in the literature have reported true secondary DA-resistance, in some of them 10 years after an initial response [
31‐
35]. The histologic characteristics of these tumors were heterogenous, ranging from adenomas without worrisome features to atypical adenomas with a high cell proliferation index. It is unknown if the mechanisms underlying secondary DA-resistance differ from those associated with primary resistance.
Current practice guidelines recommend several possible approaches for patients with DA-resistant prolactinomas [
7]. In cases resistant to bromocriptine, a switch to cabergoline is recommended, based on the superior results of this agent when compared to other DAs, as previously discussed, and on studies reporting prolactin normalization in 80–85% of the patients after this change [
11,
36]. Switch to quinagolide can not be excluded, although a meta-analysis found no differences when bromocriptine and quinagolide were compared for various clinical and biochemical outcomes [
37]. Surgical removal is a further approach with remission rates of 63–72% and 32–60% for micro- and for non-invasive macroprolactinomas, respectively; these rates also include patients offered surgery due to DA intolerance [
38,
39]. Radiotherapy is an alternative option with studies reporting normoprolactinemia rates of 15–50% that can be further increased when DA therapy is added (40–100%) [
40]. Malignant and aggressive prolactinomas represent a rare and difficult setting of DA-resistance posing significant therapeutic challenges [
41,
42].
The above described options to overcome DA-resistance may not always be successful and in this setting, the value of alternative medical agents has been investigated. In the following sections, we have reviewed the available literature on different pharmacological options in DA-resistant prolactinomas.
Conclusions and future perspectives
Primary or secondary resistance to DAs represent challenging clinical scenarios. This is particularly true for aggressive prolactinomas in which surgery and radiotherapy may not achieve tumor control. In these settings, alternative medical treatments have been considered but data on their efficacy should be interpreted within the constraints of publication bias and of lack of relevant clinical trials. The limited reports on SSAs have shown conflicting results, but, nonetheless, cases with optimal outcomes have been documented. Data on estrogen modulators and metformin are scarce and their usefulness remains to be evaluated. In aggressive lactotroph PitNETs, temozolomide has demonstrated optimal outcomes, whereas for other cytotoxic agents, TKIs and for mTOR inhibitors, higher quality evidence is needed. Finally, promising preliminary results from in vitro and animal reports need to be validated and translated in human studies.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.