Expert Review of Endocrinology & Metabolism

ISSN: 1744-6651 (Print) 1744-8417 (Online) Journal homepage: http://www.tandfonline.com/loi/iere20

Medical versus surgical treatment of

prolactinomas: an analysis of treatment outcomes

Martin J. Rutkowski & Manish K. Aghi

To cite this article: Martin J. Rutkowski & Manish K. Aghi (2017): Medical versus surgical
treatment of prolactinomas: an analysis of treatment outcomes, Expert Review of Endocrinology &
Metabolism, DOI: 10.1080/17446651.2018.1411798

To link to this article: https://doi.org/10.1080/17446651.2018.1411798

Accepted author version posted online: 05

Dec 2017.

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Download by: [RMIT University Library] Date: 06 December 2017, At: 06:43
 Publisher: Taylor & Francis

Journal: Expert Review of Endocrinology & Metabolism

DOI: 10.1080/17446651.2018.1411798
Article type: review

Medical versus surgical treatment of prolactinomas: an analysis of treatment outcomes

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Martin J. Rutkowski1, Manish K. Aghi1
1
California Center for Pituitary Disorders, Department of Neurological Surgery, University of California,

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San Francisco, 505 Parnassus Avenue, M-779, San Francisco, CA, 94143

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Corresponding author
Martin J. Rutkowski
Department of Neurological Surgery
University of California, San Francisco
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505 Parnassus Avenue, M-779
San Francisco, CA, 94143
E-mail: Martin.Rutkowski@ucsf.edu
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 Abstract

Introduction: Prolactinomas are unique tumors in that they may go into both hormonal and

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radiographic remission with dopamine agonist therapy or transsphenoidal surgery. Regardless of
modality, the goals of therapy remain the same: (1) biochemical remission, including reduction of

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prolactin and normalization of sex hormones; (2) radiographic tumor control, with a range including
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prevention of tumor growth, tumor regression, or complete tumor resolution; (3) resolution of

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preoperative symptoms, including those that are hormonal or neurologic; and (4) prevention of new
hypopituitarism or new neurologic symptoms. an
Areas Covered: In the following review, we performed a search of the literature using keywords
“prolactinoma,” “dopamine agonist,” “surgery,” “cost-effectiveness,” “recurrence,” and “complication”
to compare the relative merits of medical versus surgical therapy for prolactinoma, including special
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circumstances such as cystic tumors, pregnant patients, and the cost-effectiveness of different
strategies.
Expert Commentary: Medical therapy can offer a cure, but surgery provides an important adjunct to
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patients with resistance or intolerance to dopamine agonists, and offers excellent outcomes, including
when combined with continued postoperative medical therapy. Further head to head comparisons will
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benefit patients and practitioners weighing the relative risks and benefits of medical and surgical
intervention, including the issue of their relative cost-effectiveness.
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Keywords: prolactinoma, pituitary, adenoma, dopamine agonist, surgery

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1. Introduction

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Pituitary adenoma represents an extremely common form of intracranial tumor, with some
autopsy studies citing a 15-20% prevalence within the general population,[1] while high resolution MRI

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has detected pituitary adenomas in up to 10% of healthy volunteers[2]. More specifically,

prolactinomas—functional pituitary adenomas that oversecrete prolactin—have been estimated to

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represent 40% of pituitary adenomas, making their accurate diagnosis and treatment an important
consideration for patients and practitioners.
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Prolactinomas are benign tumors and classified as Grade 1 by the World Health Organization
(WHO).[3] When oversecreted by prolactinomas, signs and symptoms of hyperprolactinemia include
amenorrhea, galactorrhea, gynecomastia, and decreased libido. The most important consideration in
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the differential diagnosis of prolactinomas is a true hypersecreting prolactinoma versus a nonfunctional
adenoma of sufficient size to cause stalk effect, compressing the release of inhibitory dopamine from
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the hypothalamus and leading to increased prolactin secretion. Algorithms to differentiate

prolactinoma from nonfunctional adenomas with stalk effect have been developed.[4] An additional
consideration in patients whose serum prolactin elevation may not be consistent with adenoma size is
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macroprolactinemia, which occurs with the formation of a large molecular mass of prolactin called
macroprolactin, representing a complex of prolactin with anti-prolactin autoantibodies.[5]
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Prolactinomas are more evident in female patients, and the prevalence of microprolactinoma
remains higher in women.[6] Approximately 90% of premenopausal women exhibit abnormal or absent
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menses, and galactorrhea can be seen in up to 80% of women.[7] Prolactinomas are also unique in that
the degree of hyperprolactinemia correlates with the size of the tumor at presentation; thus,
macroprolactinomas are more often associated with symptoms like galactorrhea than
microprolactinomas. Prolactin is also known to have effects on gonadal function by interrupting
production of gonadotrophin releasing hormone, decreasing levels of follicle stimulating hormone and
luteinizing hormone, which may cause infertility.[7]
 Prolactinomas may also present with signs and symptoms of visual compromise when tumors
extend laterally into the cavernous sinus and place mass effect on cranial nerves responsible for
extraocular eye movements, or when they extend into the suprasellar space and place mass effect on
one or both optic nerves or the optic chiasm, causing blurred vision and/or field cuts.
While somatotrophs and corticotrophs sometimes achieve remission with dopamine agonist
medical therapy, the biochemical and radiographic remission rates for prolactinomas in response to

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dopamine agonist therapy are so high that medical management with dopamine agonists has come to

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be regarded as standard of care for prolactinomas, by many providers while transsphenoidal surgery is
still universally regarded as first treatment for somatotrophs and corticotrophs. The responsiveness of

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prolactinomas to dopamine agonist therapy relies on the physiologic response of lactotrophic cells
within the adenohypophysis to dopamine by decreasing secretion of prolactin[8]. Surgery can also

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represent an attractive option, as gross total resection provides a cytoreductive strategy that can
eliminate the need for lifelong medical therapy with dopamine agonist medications. And while beyond
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the scope of this current review, radiation-based treatments including radiosurgery with Gamma Knife
may also be useful for refractory prolactinomas, such as those unresponsive to medical therapy and
surgically inaccessible.
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2. Goals of Therapy
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Given the multiple options for treatment, the recent literature has increasingly focused on the
endocrinological, visual, and socioeconomic effects of treating patients with medical versus surgical
therapy. Regardless of modality, the goals of therapy remain the same: (1) biochemical remission,
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including reduction of prolactin and normalization of sex hormones restoring libido and fertility; (2)
radiographic tumor control, with a range including prevention of tumor growth, tumor regression, or
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complete tumor resolution;, (3) resolution of preoperative symptoms, including those that are hormonal
(e.g. galactorrhea or loss of libido) or neurologic (e.g. headaches or vision loss); and (4) prevention of
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new hypopituitarism or new neurologic symptoms.

Medical therapy is now standard of care, including patients who present with visual
compromise. In physiologic states, prolactin is responsible for milk production in lactating females, with
no known function in males, and lactotrophic cells that secrete prolactin are normally inhibited by tonic
dopamine production from the hypothalamus. Dopamine agonist therapy replies on the ability of
medicines such as bromocriptine and cabergoline to bind dopamine D2-receptors on lactotroph cells,
leading to decreased synthesis and release of prolactin, and reduction in tumor size. When bound to
 dopamine agonists, lactotroph D2 receptors decrease cellular metabolism and prolactin synthesis, in
addition to decreasing cell size and inducing apoptosis[9].
Nevertheless, medical therapy may not be appropriate for all patients, including those with side
effects, patients with persistent signs and symptoms of mass effect, apoplectic patients, and patients
with dopamine agonist-resistant tumors[10,11],[8,12]. For these patients, surgical intervention may
provide a cure or the necessary debulking to allow medical therapy to be more effective. The risks and

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benefits of each modality, including a consideration of financial impact, will be discussed here, and are

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essential components of patient counseling and treatment strategy for prolactinoma.
3. Medical Therapy

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i. Bromocriptine
Bromocriptine is an ergoline derivative that binds both the D1 and D2 dopamine receptors. In

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one of the first studies of its efficacy for macroadenomas, a 1985 multicenter prospective trial showed
efficacy in hormonal normalization and tumor involution: 67% of patients showed normal prolactin
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levels following bromocriptine therapy, 64% showed a reduction in tumor size of at least 50%, and 9 of
10 patients presenting with visual deficits showed improvements in vision[13]. Importantly, tumor
involution occurred early during treatment, with most tumors shrinking within 6 weeks of bromocriptine
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initiation[13]. Nevertheless, side effects such as dyspepsia, nausea, vomiting, headaches, dizziness,
dyskinesias, hypotension, and syncope can limit patient tolerance; escalating doses are known to
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worsen side effects[14]. Nevertheless, it remains an effective medication for patients who can tolerate
it: 80-90% of microprolactinomas and 70% of macroprolactinomas show normalized prolactin, tumor
involution, and restoration of gonadal function following therapy[15,16]. Results with bromocriptine
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resemble those seen with surgical intervention[17,18], as a meta-analysis established that 74% of
microadenomas and 32% of macroadenomas experienced prolactin normalization within 12 weeks of
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surgery[19].
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ii. Cabergoline
Cabergoline is an ergoline agonist that specifically targets the D2 dopamine receptor; due to a
longer half-life, administration is just twice a week versus daily bromocriptine. Cabergoline is currently
the standard of care initial therapy for newly diagnosed prolactinomas due to better tolerance and
superior efficacy in normalization of prolactin levels and a higher incidence of tumor involution[20–23].
Both micro- and macroadenomas have shown good response to cabergoline therapy, as 95% of
 microprolactinomas and 80% of macroprolactinomas show normalized prolactin, tumor involution, and
restoration of gonadal function following therapy[15,16].

iii. Bromocriptine versus Cabergoline

The superior efficacy of cabergoline in normalizing prolactin, inducing tumor involution, and
lower side effect profile have made it a preferred initial therapy when compared to

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bromocriptine[21,24]. Randomized comparisons of the two therapies have also shown an improved

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side effect profile with cabergoline[24].
Webster et al.[21] performed a randomized multicenter trial involving 459 women that showed

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normalized prolactin levels in 59% of women treated with bromocriptine and 83% in women treated
with cabergoline. Furthermore, they found that abnormal menses persisted for just 7% of women on

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cabergoline versus 16% of women on bromocriptine, with 3% of women stopping cabergoline for side
effects versus 12% of women on bromocriptine. Another multicenter, randomized study of 120 women
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with prolactinomas showed prolactin normalization in 93% of women on cabergoline versus just 48% of
women on bromocriptine, further corroborating the superiority of cabergoline monotherapy in
prolactinoma treatment[22].
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Notably, cabergoline is highly effective for patients who are intolerant of, or resistant to
bromocriptine[23]. A study from 2008 demonstrated that higher doses of cabergoline are efficacious in
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normalizing prolactin regardless of previous treatment with other dopamine agonist drugs, including
patients previously resistant to other drugs[25].
Nevertheless, when counseling patients on the use of medical therapy, any conversation should
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include a discussion of the risks of valvular heart disease with prolonged use. A number of studies have
looked at long term outcomes, including head to head comparisons of cabergoline and bromocriptine.
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Boguszewski et al. 2012 showed that subclinical mitral and tricuspid regurgitation were seen for both
medications, but no patients suffered appreciable symptoms.[26] Echocardiography may detect silent
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abnormalities, but it appears that clinically significant effects have only been documented at higher
doses in patients with other conditions such as Parkinson’s disease.[27,28] In fact, it is debatable
whether the prevalence of cardiac abnormalities is higher than the general population, as two studies
found similar rates among patients treated with cabergoline over 24[29] and 60 months of use[30].
Ultimately, standard medical therapy dosing for prolactinoma likely does not require close cardiac
follow-up, but prolonged dosing at higher levels may warrant screening.[20]
 iv. Cessation of medical therapy
Endocrinologists who start their prolactinoma patients on dopamine agonist therapy will
eventually face a dilemma of whether these patients can be tried off of medical therapy or if they must
remain on medical therapy for life. The efficacy of medical therapy cessation is quite variable as
reported in the literature. In one large meta-analysis of 19 studies, stable and normal prolactin levels
were seen in 21% of patients with microprolactinomas and 16% of macroprolactinomas following

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cessation of dopamine agonist therapy, indicating the majority of patients suffer from rebound

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hyperprolactinemia while off medical therapy[31]. It is thought that medical therapy cessation is most
efficacious in patients with normalized prolactin levels, no tumor on MRI or 50% tumor involution, and

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no local invasion for at least 2 years[32]; furthermore, some have suggested that medical therapy may
be weaned and discontinued after 4-6 years of therapy[33,34]. It remains unclear if length of treatment

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or use of cabergoline is associated with greater remission rates after cessation of medical
therapy[8,31,35,36].
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4. Surgical Treatment and Primary Outcomes
Surgical removal of prolactinomas through a transsphenoidal approach is an important part of
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patient counseling when deciding on initial treatment options. Unfortunately, many patients are not
presented with this option due to the feeling in the endocrinology community that dopamine agonists
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are the unquestioned standard of care for prolactinoma treatment because of the efficacy of these
agents combined with concerns in the medical community that any morbidity associated with
transsphenoidal surgery is enough to justify only offering patients medical treatment. Given the low
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morbidity and durability of transsphenoidal surgery when performed by an experienced

neurosurgeon,[37] newly diagnosed prolactinoma patients should be evaluated by an endocrinologist
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and neurosurgeon and transsphenoidal surgery can be offered for patients whom the neurosurgeon
deems potentially curable with surgery. For these patients, risks and benefits should be discussed with
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either approach, including the likely need for lifelong medical therapy, side effect profile, and cost
associated with sustained medication use, versus the risks of surgical intervention, anesthesia, and the
likelihood of gross total resection and a durable surgical cure[38,39]. For patients who fail medical
therapy or are intolerant of its side effects, transsphenoidal surgery is an important option. Surgery may
also be indicated in 1) lack of prolactin normalization on medical therapy, 2) apoplectic tumors, 3) visual
loss despite medical therapy, 4) development of CSF leak following medical therapy, 5) patients
dependent on antipsychotic medications, and/or 6) patient preference to undergo surgical resection.
 Transsphenoidal surgery provides excellent results for prolactinomas. Prolactin normalization
exceeds 90% long-term for resected microprolactinomas, with a strong correlation between
postoperative day 1 levels and long term durability[40,41]. In one study, Amar and colleagues found
that a prolactin level less than 10 ng/ml on postoperative day 1 was associated with cure rates
approaching 100%.[40] Furthermore, transsphenoidal surgery has an acceptable complication risk
profile (less than 1%), and is a potentially curative intervention for patients with prolactinomas when

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performed by neurosurgeons experienced in the surgical treatment of pituitary disease[11,14,17,42–

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44]. In general, multidisciplinary centers that have expertise in pituitary disease have been shown to
give patient’s better outcomes, including morbidity, mortality, and length of hospitalization[37,45], and

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endocrinologists would be well advised to refer patients only to neurosurgeons with extensive
experience in surgical management of prolactinoma.

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While cure rates are predictably lower for macroadenomas, success is generally correlated with
preoperative tumor size, parasellar invasion into the cavernous sinus(es) or suprasellar cistern, and
an
degree of hyperprolactinemia, with one study demonstrating that tumor recurrence reaches 70% when
preoperative prolactin levels measure greater than 250 ng/ml[40]. Even when a gross total resection is
impossible, cytoreduction can results in increased responsiveness to de-escalating doses of
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cabergoline[46]. Furthermore, it appears that many tumors that show dopamine agonist resistance may
in fact have favorable outcomes following surgical intervention; in one study[47], 84% of patients with
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microadenomas showed prolactin normalization following transsphenoidal surgery, and 36% of patients
with macroprolactinomas, demonstrating that transsphenoidal surgery can be effective for patients who
have failed medical therapy.
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In general, microprolactinomas have favorable remission rates approaching 90% long

term[38,48–50]. Studies of male and female patients with prolactinomas similarly found comparable
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rates of prolactin normalization following transsphenoidal surgery or medical therapy[51,52]. Finally,

there may be an important role in resolving headache symptoms associated with pituitary
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microadenomas, as up to 58% of patients showed complete resolution of preoperative headaches

following transsphenoidal resection[53].

5. Recurrence Following Initial Remission

Despite favorable rates of tumor control in prolactinoma, a notable minority of patients will
suffer recurrence despite achieving initial hormonal remission. One large meta-analysis of patients who
suffered recurrence following initial remission reported a pooled mean remission rate of almost 69% for
 prolactinoma among the 13 studies they included.[54] Follow-up time averaged 4.9 years, with a
recurrence rate following initial remission of around 20%. Interestingly, the recurrence rate of
prolactinomas appeared to be significantly higher when compared to that of patients with acromegaly
or Cushing’s disease. The meta-analysis spanned 3 decades of publications and found no difference in
the incidence of prolactinoma recurrence, just a slight improvement with time.[54] In particular, for
prolactinomas, the recurrence rate appeared to be highest between 1 and 5 years following

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documentation of initial remission.

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Attempts to delineate factors associated with recurrence after remission found no significance
for patient age[18,55–58] or gender[18,56,57,59], nor for tumor size[18,55–57,60] or

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invasiveness[17,40,55,58,61–63]. However, there may be an association between subnormal immediate

postoperative prolactin serum concentration (< 10ug/L) and re-normalization of thyrotropin-releasing

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hormone (TRH) with long term cure.[17,18,40,55,56,58,59,62–64] Data are too limited to draw
conclusions regarding remission rates for microscopic versus endoscopic techniques.[65–67]
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6. Surgical Risk Profile
Preoperative counseling of patients considering surgical resection of prolactinoma necessitates
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a judicious discussion of complications that may occur from operative intervention. The rates of
complications appear to be similar regardless of microscopic versus endoscopic approach.[67,68]Based
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on numerous surgical case series and analyses, the most common complication following surgical
resection appears to be cerebrospinal fluid (CSF) leak, with rates reported between 2 and 16%.[68–71]
Mortality, life-threatening hemorrhage, and meningitis remain rare in most series, typically less than 1%,
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while postoperative hypopituitarism is uncommon, around 1-14%.[68,72] While there is limited

evidence that endoscopic approaches may decrease the rates of nasal complications, such as sinusitis
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and altered olfaction, this has not been rigorously studied.[71,72]

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7. Special Considerations
i. Pregnancy
Women with prolactinomas who become pregnant should be watched closely for tumor growth.
The increase in serum estrogen levels associated with pregnancy is a known stimulus for prolactinoma
growth, with rates of 2-3% for microprolactinomas and 21% of macroprolactinomas,[73] though one
group noted that up to 68% of pregnant women with prolactinomas actually experienced resolution of
their hyperprolactinemia upon becoming pregnant, without any treatment.[74] Given the increased risk
 of fetal loss when operating on a pregnant patient[73], medical therapy is an attractive option and has
been shown to be safe and effective in multiple studies. Bromocriptine and cabergoline have not been
associated with an increase in spontaneous abortion, ectopic pregnancy, trophoblastic disease,
congenital malformations, or premature birth; in both short and long term follow-up studies on the
health of newborns and children, cabergoline and bromocriptine have proven to be safe.[73–83] In
general, surgical intervention should be performed only in very select circumstances, including women

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intolerant of medical therapy due to side effects, those who require larger than conventional doses

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deemed safe in previous research studies, or those with documented loss of vision. Interestingly, a
recent study demonstrated that pregnancy can actually resolve hyperprolactinemia, contradicting the

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commonly held principle that increased estrogens have a stimulatory and proliferative effect on
lactotrophic adenomas cells.

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ii. Cystic Tumors
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Long considered a contraindication to medical therapy, cystic prolactinomas may in fact be
responsive and demonstrate lasting and meaningful reduction in cyst and tumor size. One recent study
by Faje and colleagues[84] showed that in a cohort of 30 patients with cystic prolactinomas treated with
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dopamine agonists, cysts reduced a mean of 84% within a 6 month window, with 4 of 5 patients
showing resolution of chiasmatic compression and improvement in pre-treatment hypopituitarism seen
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in 5 of 6 patients. Though transsphenoidal surgery was performed in half the cohort ultimately, the
preliminary results challenge the assumption that medical therapy is obviated in cystic prolactinomas,
and may be worth a trial in select patients.
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8. Socioeconomic Considerations
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Given comparable efficacy rates in treating prolactinoma, newer studies have focused on the
economic implications of medical therapy versus transsphenoidal surgery and their relative cost. For
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example, Turner et al. found that the economic cost of surgical resection is comparable to medical
therapy over a 10 year period in the UK), indicating that beyond 10 years patients may be better served
by primary surgery[43]. Another study corroborated these findings, noting that either endoscopic or
microscopic transsphenoidal surgical intervention carried lower overall cost among patients followed 10
years from either primary surgery or prolonged medical therapy.[85] Zygourakis and colleagues came to
a similar conclusion, noting that within their cohort, a patient diagnosed with prolactinoma at age 40
incurs the lowest lifetime cost for treatment by undergoing surgical resection, followed by
 bromocriptine, and then cabergoline[86]. This value may apply be healthcare system dependent,
however, as a Chinese group found significant savings associated with medical therapy rather than
surgical intervention[87]. Furthermore, patient specific factors such as expected length of life, quality-
adjusted life years, and tolerance of morbidity of hyperprolactinemia (galactorrhea, amenorrhea,
decreased libido) versus potential medical or surgical side effects should be considered given that
beneficial outcomes for surgery are seen in a delayed fashion. Furthermore, patient anxiety over

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various interventions may not be quantifiable, but is nevertheless an important factor in counseling.

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The knowledge that an adenoma can be immediately and definitively removed or suppressed medically
may alleviate patient concerns over disease chronicity and risks of surgery, respectively, and influence

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patients differently about their best course of action.

Interestingly, the US study by Zygourakis reported significantly higher surgical and medical costs

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than the UK and Chinese studies. This likely reflects the greater privatization of health care in the US
compared to these other countries, as well as temporal trends specific to the UK study, which included
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patients treated between 1976 and 1997, while Zygourakis and the Chinese group studied patients
treated between October 2008 and November 2009[87]. The Zygourakis study also calculated actual
hospital costs, as compared to cost estimates (as used in the U.K. study[88]) or hospital charges (i.e.,
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what the hospital bills the insurance company). Several recent studies show that hospital charges (or
billing) bear little resemblance to economic cost[89], and use of hospital charges as a proxy for cost may
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lead researchers to draw unwarranted conclusions[90]. The best cost measure is actual resource
utilization[90] which may be very challenging to calculate. Furthermore, it is very difficult to account for
the cost of surgical morbidity when developing surgical cost estimates, or to account for changes in the
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cost of surgery versus continued dopamine agonist therapy over time.

While slightly different in focus, a study by King and colleagues[91] focused on the cost
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effectiveness of different management strategies (watchful waiting, serum prolactin testing, full
hormone testing, MRI follow-up) for incidentally discovered microadenomas and found that
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straightforward serum prolactin level monitoring may be the most cost-effective strategy. While the
lesions studied included only asymptomatic tumors, they found a modest improvement in quality-
adjusted life years based on an incremental cost of $34 for prolactin screening versus MRI follow-up at
$1549. Importantly, few patients will ultimately undergo surgery for asymptomatic microadenomas,
making the effect of variability in surgical outcomes totally negligible on cost-effectiveness of initial
management strategies[91]. Notably, the lead author performed similar studies on the cost-
effectiveness of elective surgery for unruptured , asymptomatic intracranial aneurysms[92] and for
 medically refractory epilepsy[93], and found a benefit for prompt surgical intervention for both disease
processes, arguing that considerations of cost, quality of life, and disease course figure heavily into
decision making on treatment modality.
If studies continue to support the hypothesis that curative transsphenoidal surgery of
prolactinomas is more cost-efficient than lifelong medical management, then these findings would be
similar to what has been shown for laryngeal cancer where surgery is more cost effective than organ

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sparing non-surgical strategies.[94] One crucial difference between prolactinomas versus laryngeal

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cancer is that the cost-benefits of transsphenoidal surgery are not accumulated for many years and
given the transitory nature of commercial insurance in the US, unlike government run health care in

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countries like the UK, the payors are obligated to ensure short term, not long-term, cost reduction.

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9. Conclusions
Prolactinomas most often present with symptoms of hyperprolactinemia, including amenorrhea,
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hypogonadism, and galactorrhea, or from symptoms of mass effect on adjacent structures such as
hypopituitarism or visual field deficits and/or compromise. Treatment strategies may be developed and
tailored for individual patients, but should always include a conversation regarding the use of dopamine
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agonist medical therapy versus surgical intervention. While rates of prolactin normalization and tumor
involution are comparable, side effects, comorbidities, chronicity of treatment, and lifelong costs all
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factor in to individual decision making. Medical therapy can offer a cure, but surgery provides an
important adjunct to patients with resistance or intolerance to dopamine agonists, and offers excellent
outcomes, including when combined with continued postoperative medical therapy. Further head to
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head comparisons will benefit patients and practitioners weighing the relative risks and benefits of
medical and surgical intervention.
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10. Expert Commentary

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Because of the multifocal presentation of prolactinomas, which can comprise myriad

endocrinological and neurological signs and symptoms, definitions of therapeutic success can vary.
While endocrinologists might consider hormonal remission and tumor control a measure of success,
neurosurgeons might place more emphasis on rates of recurrence, technical nuances for invasive
disease, and biochemical response to transsphenoidal surgery or stereotactic radiosurgery. The
literature is similarly biased toward outcomes that favor the target audience. Few if any studies
comprehensively examine long term durability of either dopamine agonist or surgical intervention in all
 spheres, including radiological (tumor resolution, control, recurrence), endocrinologic (remission,
normalization, resolution of secondary stigmata e.g. amenorrhea, decreased libido), and neurological
(visual fields, cranial neuropathy, hydrocephalus). Furthermore, long held tenets regarding treatment
of pregnant patients, those with cystic tumors, and the relative dangers and costs of medical therapy are
changing as clinical studies continue, drug data are generated, and cost analyses reveal the shifting
landscape of healthcare and access to different treatment modalities. Long term data are still seriously

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lacking, as are any randomized controlled trials on the best upfront treatment for newly diagnosed

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micro- and macro-prolactinomas. The field can and must continue to focus on direct comparisons of
the two therapies, but specifically for similar indications, e.g. similarly sized tumors with similar

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presenting signs and symptoms. As it stands now, choice of therapy is too dependent on treating
practitioner (endocrinologist versus neurosurgeon) and on possibly outdated contraindications such as

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cystic tumors requiring surgery and pregnant patients avoiding medical therapy. Only a randomized
controlled trial including patients with tumors that truly lend themselves equally well to either
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therapeutic option will shed light on the ideal upfront strategy.
As with most controversies in medicine, the truth likely likes somewhere in between. While
clinical equipoise may truly exist for certain tumors, most lend themselves better to one treatment
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modality versus the other. Thus, in addition to randomized controlled trials comparing cabergoline with
transsphenoidal surgery, further data on the nuances of either treatment modality likely present the
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most exciting arenas for future research, and could potentially revolutionize the field of prolactinoma
treatment. Expanded endoscopic approaches may yield improved tumor control rates for
macroadenomas and those with local invasion, as may new radiosurgery based strategies such as Cyber
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Knife. The potential for newer dopamine agonists with improved tropism for lactotrophic adenoma cells
may render medical therapy an even better and more targeted approach, and perhaps diminish
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troublesome side effects and long term cardiac risk. The fact that recurrence rates do not appear to
have significantly changed over the last 3 decades of surgical practice likely indicates that newer surgical
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techniques are unlikely to be a panacea, but the prevalence of dopamine agonist resistance or
intolerance of side effects similarly prevents medical therapy from truly being superior. Newer medical
agents and supplementary focused radiation techniques are more likely to alter outcomes data, and
offer an exciting avenue for potential future research.
Finally, while the debate continues regarding optimal clinical strategy, socioeconomic data are
increasingly relevant in the choice of therapeutic modality. Systems of healthcare and associated costs
vary greatly between countries, but this has not stopped several researchers from attempting to
 compare dopamine agonist medical therapy and transsphenoidal resection. Insurance status, likelihood
of gross total resection, initial hormonal response, and patient preference are all potential confounders
in any comparison of their cost, but should be used for patient counseling and to aid decision making
about choice of initial therapy. The limited literature does make clear, however, that long-term data
are the only way to delineate any significant difference between medical and surgical therapy. Despite
preliminary indications that long term disease remission via surgical approaches may be more cost

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effective than lifelong medical therapy, these arguments also rely on potentially outdated data, such as

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the idea that medical therapy cannot be stopped once started, or that a gross total resection equates to
long term disease control. Thus, while socioeconomic analyses represent one of the most exciting and

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imminent areas of research in prolactinoma, the field must continue to progress as a whole for this head
to head analysis to remain meaningful. With newer drugs, longer outcomes data, and more data on

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cost, the debate on deal prolactinoma treatment may become clearer.

11. Five-Year View

an
Modern data from contemporaneous case series and prolactinoma patient cohorts will make it
more apparent to providers which treatment strategy is best for individual patients. Drug development
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to decrease rates of medical resistance and side effect profiles may ultimately change the nature of
dopamine agonist therapy, but more advanced, modern surgical techniques such as use of the
ed

endoscope may also decrease surgical morbidity. Thus, head to head comparisons of cost will provide
some of the most compelling data for prolactinoma treatment in the next five years. We also anticipate
that the roles for surgery and medical therapy will become more patient customized. More invasive
pt

tumors will be more frequently treated with more targeted medical therapies to access disease that is
surgically inaccessible, while transsphenoidal approaches may yield better long-term data as the
ce

endoscope becomes more widespread and technical mastery improves.

Ac

12. Key Issues

• While somatotrophs and corticotrophs sometimes achieve remission with dopamine agonist
medical therapy, the biochemical and radiographic remission rates for prolactinomas in
response to dopamine agonist therapy are so high that medical management with dopamine
agonists has come to be regarded as standard of care for prolactinomas, by many providers
while transsphenoidal surgery is still universally regarded as first treatment for somatotrophs
 and corticotrophs. Dopamine agonist therapy for prolactinomas capitalizes on the physiologic
response of lactotrophic cells within the adenohypophysis to dopamine by decreasing secretion
of prolactin.

• Cabergoline is currently the standard of care initial therapy for newly diagnosed prolactinomas
due to better tolerance and superior efficacy in normalization of prolactin levels and a higher

t
incidence of tumor involution when compared to bromocriptine.

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• Surgery may be indicated for lack of prolactin normalization on medical therapy, apoplectic

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tumors, visual loss despite medical therapy, development of CSF leak following medical therapy,
patients dependent on antipsychotic medications, and/or patient preference to undergo surgical

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resection.
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• Tumors resistant to dopamine agonist therapy have excellent results following surgical
resection.
M

• Despite the need for more head to head comparisons of dopamine agonist medical therapy
versus surgical treatment, the financial burden of continued medical therapy appears to favor
ed

surgical resection as a cost-effective primary option, assuming long term follow-up.

pt

Funding
This manuscript was not funded.
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Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a
Ac

financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.
This includes employment, consultancies, honoraria, stock ownership or options, expert testimony,
grants or patents received or pending, or royalties.
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