Endocrine DOI 10.1007/s12020-014-0281-3


Surgical treatment of microprolactinomas: pros Roberto Salvatori

Received: 18 March 2014 / Accepted: 25 April 2014 Ó Springer Science+Business Media New York 2014

Abstract Medical therapy with dopaminergic agonists (DAs) has been used for several decades for the treatment of both micro- and macroprolactinomas, without much differentiation between the two conditions. While most cases respond well to DAs in terms of prolactin normalization and control of tumor growth, DAs are often needed for many years, or even for lifetime. Concerns have been raised recently about the possible side effects of long-term use of these medications on the anatomy and function of the heart valves. While macroprolactinomas are rarely surgically curable, pituitary surgery in expert hands is a safe and effective method to permanently cure microprolactinomas, with long-term cure rates around 70 %. In this article, I will review the data on safety of DAs an on the effectiveness and safety of surgery, and I will make an argument that surgery should be offered as a possible therapy to microprolactinoma patients, provided that an experienced pituitary neurosurgeon is available. Keywords Surgery

Prolactin  Adenoma  Dopaminergic therapy 

Introduction Prolactinomas represent the majority of hormone-secreting pituitary adenomas [1]. Even when they are small and therefore not causing any mass effect, the elevated serum

R. Salvatori (&) Division of Endocrinology, Diabetes and Metabolism, and Pituitary Center, Department of Medicine, The Johns Hopkins University School of Medicine, 1830 East Monument Street #333, Baltimore, MD 21287, USA e-mail: [email protected]

prolactin causes menstrual irregularities, amenorrhea, galactorrhea and infertility in females, and hypogonadism, and erectile dysfunction in males. Medical treatment by dopaminergic agents (DAs) results in prolactin normalization in about 90 % of cases and tumor shrinkage in approximately 2/3 [2]. These good results have led most physicians and medical societies to recommend the use of these medications in most situations (independently from the size and location of the adenoma and the degree of hyperprolactinemia), reserving surgical therapy for patients who do not respond or cannot tolerate DAs, have persistent chiasmal compression, have medically unresponsive cystic prolactinomas, or when DAs are contraindicated for psychiatric conditions [3–6]. The Pituitary Society guidelines do mention that ‘‘in centers with experienced neurosurgeons the possibility of cure by surgery versus long-term dopamine agonist therapy should be discussed with the patient, and patient preference is also an indication for surgery’’ [4]. I agree with the Endocrine and Pituitary Societies’ recommendation that DA therapy should be the first line of treatment for patients who have large macroprolactinomas. These tumors are unlikely to be completely cured by surgery, and most patients would continue to need medical therapy after the surgical intervention [7]. In fact, in my opinion the larger the tumor, the more DA therapy is the preferred route. The situation is, however, less obvious for microprolactinomas (or small intra-sellar macros), particularly the ones that occur in surgically favorable sellar locations. In this paper, I will challenge the opinion of ‘‘DA therapy fits all,’’ and outline why surgery should at least be considered in the treatment of microprolactinomas. Let us first analyze the DAs routinely used to treat hyperprolactinemia. Cabergoline (CAB) is generally



considered more effective and better tolerated than bromocriptine (BRC), allowing for once or twice per week administration [2]. It is therefore the preferred therapy by most physicians. Even CAB is not tolerated by about 4 % of patients [8]. Until recently, DAs were generally considered safe, with the exception of gastrointestinal side effects or dizziness (more likely with BRC) [9]. Among patients on DAs therapy, however, I often encounter subtle complains of tiredness, stuffy nose, and fatigue (particularly evident the day after CAB administration), which— because mild—may be under-reported. Rare descriptions of worsening psychosis and behavioral changes, including compulsive gambling, have also been reported [10, 11]. In 2007, two simultaneous reports described an increased risk of heart valve damage in CAB-(and pergolide—no longer available in the US market) treated Parkinson’s disease patient. These patients were arguably taking CAB dosages (average 3 mg per day) that vast exceed the doses used in most prolactinoma patients [12, 13]. The mechanism of this side effect is thought to be activation of 5-hydroxytryptamine 2B (5-HT2B) receptor, in a fashion similar to the mechanism of racemic fenfluramine and dexfenfluramineinduced valvular disease [14]. This observation led an opinion leader in an accompanying article in the New England Journal of Medicine to recommend (arguably quite extremely) that ‘‘practitioners should avoid prescribing drugs that are potent 5-HT2B–receptor agonists’’ [14]. Several (but relatively small) subsequent studies have reported no or minimal effects on heart valve anatomy and function in prolactinoma patients treated with DAs [15]. A very recent large (747 patients) cross-sectional echocardiography study of patients receiving DA therapy for hyperprolactinemia found no obvious evidence of valvular damage [16]. Despite this, some worry remains on whether very long-term use of small amounts of CAB (i.e., large cumulative doses) could cause valvular problems. Indeed, even BRC, thought to be safer from this point of view, is not completely free of subclinical valvular side effects [17, 18]. These observations have generated the recommendation to use lowest possible DA dose, and to address the question of echocardiographic monitoring on an individual basis [15]. Some authors recommend an echocardiographic examination at the beginning of therapy and periodically during therapy with DAs that act as full or partial agonists of 5-HT2B. I usually obtain echocardiograms in patients who are taking 3.5 mg of CAB per week or more, although this cutoff is not based on solid data. An important issue to consider is the length of DA medical therapy. The initial report that a majority (69 %) of microprolactinoma patients who had good response to CAB (and fit specific clinical, radiological, and biochemical criteria) did not recur after the medication was discontinued [19] was not fully confirmed by other studies,


suggesting that more patients (52 % in our study, and 79 % in a meta-analysis) end up relapsing than remaining cured [20–22]. Furthermore, patients who recur seem unlikely to be cured by additional 2 (or more) years of therapy [23]. Therefore, one has to consider the possibility that DA therapy, once started, must be continued for many years (or at least until the indication for treatment remains). A second issue is cost. Regrettably, no study is available at present that analyzed the different costs of a single potentially curative (but also potentially harmful) surgical procedure versus long-term medical therapy. Such study would be helpful in formulating future guidelines. Surgery has been used to treat pituitary adenomas for longer than 100 years. During this time, tremendous technical and imaging advances have been made, resulting in a decrease in morbidity and mortality once associated with pituitary surgery. Equally importantly, the cure rates for secretory tumors have increased with time [24]. In patients with microadenomas causing acromegaly, for instance, nobody argues that curative surgery is the first choice of treatment, because cure rates are very high, independently whether the endoscopic or microscopic approach is used [25, 26]. Yet, several medical therapies are available for acromegaly (including CAB) [27–29]. Similar is the case of Cushing disease (although the medical therapies are less tolerable and efficacious). Why, then, not to consider surgery for microprolactinomas? Nine papers in the English language have been published from different continents during the last 6 years (2008–2013) looking at the outcome of surgery in microprolactinomas [7, 30–37]. The total number of microprolactinomas included in these papers is 627 (although the majority-400-came from a single paper [36]). The cumulative postoperative cure rate (defined in most papers as normal prolactin level in the immediate postoperative period) was 83.2 % (522/627) (Table 1). Not all the studies reported long-term recurrence but from those that did the weighted average recurrence rate was 10.3 % of apparently cured subjects (8.8 % of the initial number), bringing the long-term cure rate to a still respectable 74.4 % (similar to the one of GH-secreting microadenomas [26]). These cure and recurrence rates are very similar to ones reported by Tyrrel et al. in 1999 (91 and 11 %, respectively) on a large series of prolactinomas operated by Dr. Wilson at UCSF [38]. It is true that older studies by other outstanding neurosurgeons have reported recurrence rates to be as high as 17 % of apparently cured subjects with microprolactinomas [39, 40], but even applying this recurrence rate, the permanent cure rate of the papers listed in the table would still be 69 %. Furthermore, some subjects who seem to recur after surgery become normoprolactinemic after 6 or 7 years, suggesting that the recurrence of mild hyperprolactinemia after surgery is not necessarily a permanent

Endocrine Table 1 Immediate cure and recurrence rates in microprolactinomas Study

Year of publication

No. of patients

Initial remission (%)

Recurrence rate (%)a

Kreutzer et al. [30]



38 (86.3)


Raverot et al. [34]



58 (95)


Sinha et al. [7]



14 (87.5)


Babey et al. [31]



32 (94)


Qu et al. [32]



15 (83.3)


Tamasauskas et al. [33]



9 (90)


Primeau et al. [35]



17 (63)


Berkmann et al. [37]



6 (55)

Loyo-Varela et al. [36]



328 (82)



522 (83.2)

Weighted average 10.3

Total a


% of patients considered in remission who recurred

feature and does not inevitably indicate operative failure [41]. Cure rates are not available for small intra-sellar macroprolactinomas, but in the acromegaly literature the cure rates for these tumors are similar to the ones for microadenomas [26]. Hence, surgery seems a reasonable way to ‘‘cure’’ a majority of patient permanently. Female patients with only transient remission could take advantage of the remission phase to become pregnant without having to resort to DAs. Some important caveats need to be highlighted. As somebody once said, ‘‘no surgeon reports bad outcomes.’’ Arguably, the published data were mostly generated by surgeons who have an interest in pituitary disease, and therefore are more likely to have a large experience and high pituitary surgical volumes. Furthermore, they are more likely to work in large academic center, where they collaborate with specialized endocrinologists, radiologists, and anesthesiologist. This is important, as there are abundant data showing that the outcome (cure rate) of pituitary surgery for acromegaly relates to the surgeon’s experience, which has led to the proposal that pituitary surgery should be concentrated in 1 or 2 surgeons in any given center [42– 44]. Therefore, the cure rates mentioned above do not necessarily apply to less expert neurosurgeons that only occasionally operate on pituitary adenomas. Similarly, the risk of surgical complications decreases with the surgeon’s experience, reaching its lowest number for surgeons who have performed 500 or more pituitary surgeries [45]. Indeed, complication rates for overall trans-sphenoidal surgeries in the US (including tumor of all sizes) vary greatly depending on whether this is done in low volume or high volume centers [46]. In centers that perform more than 25 procedures per year mortality is low (0.2 %). While fluid end electrolyte abnormalities and peri-operative diabetes insipidus are reported relatively commonly, in

series reported by very experienced neurosurgeons, permanent DI is quite rare (\5 %) [47, 48]. Based on the above data, I think that when an endocrinologist is presented with a patient who has a microprolactinoma, provided that an experienced pituitary neurosurgeon is available, the surgical options should at least be discussed. This discussion should be done at first encounter, before DA therapy is instituted, as there is some evidence that surgical cure rate is lower in patients who are pre-treated with these drugs, possibly due to DAs-induced tumor fibrosis [35]. Fibrosis seems more likely after BRC than CAB therapy [49]. Patients should be explained that, while medical therapy may need to be continued for many years, surgery has *70 % chance of solving the problem permanently. This is particularly important for young patients who may not want decades of medical therapy and are otherwise healthy, and therefore have very low surgical risk. As no surgery has zero risk, general anesthesia and specific surgery risks should be discussed as well. It is the endocrinologist’s responsibility to know the performance of her/his neurosurgeon and to determine whether the published statistics apply to that physician. Traveling to a Pituitary Center of excellence [50] should also be discussed with the patient if an experienced pituitary neurosurgeon is not available in the local area. In summary, surgery for microprolactinomas is an underutilized treatment modality that—in light of modern surgical advances—should be included in the armamentarium of treating these patients, provided that a specialized pituitary neurosurgeon is available to perform the procedure.

Conflict of interest

The author has no conflict of interest to declare.



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Surgical treatment of microprolactinomas: pros.

Medical therapy with dopaminergic agonists (DAs) has been used for several decades for the treatment of both micro- and macroprolactinomas, without mu...
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