Handbook of Clinical Neurology, Vol. 124 (3rd series) Clinical Neuroendocrinology E. Fliers, M. Korbonits, and J.A. Romijn, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 20

Medical approach to pituitary tumors S.J.C.M.M. NEGGERS* AND A.J. VAN DER LELY Section of Endocrinology, Department of Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands

INTRODUCTION Medical and surgical treatment are the two cornerstones in the management of pituitary adenoma. However, the type of adenoma does influence the reported efficacy of the two approaches and therefore affects the choice between medical and surgical options. There are adenomas such as prolactinomas in which surgical treatment has been more or less replaced by medical treatment. However, in Cushing’s disease or nonfunctional adenoma surgery is still the first step in treatment. In this chapter the possible medical options for the different adenomas will be discussed according to type of adenoma.

NONFUNCTIONAL ADENOMA Gonadotroph adenomas constitute about 80% of the nonfunctional adenomas (NFA) as their secretory products usually do not cause recognizable clinical symptoms or a syndrome and therefore they are also considered nonfunctional adenomas. Patients with NFA usually first seek medical attention when the adenoma’s size results in pressure on surrounding tissues, such as, e.g., the optic nerve, causing symptoms such as headaches, visual field defects, diplopia, and symptoms related to hypopituitarism.

Medical treatment The main aim in the treatment of NFA is a decrease in tumor size, since the majority of these adenomas do not cause a clinical syndrome. To date, no medical treatment modality has been found that has demonstrated reliable reduction in tumor size of NFAs (Greenman, 2007). There were attempts to use dopamine agonists to address tumor size. However, the small nonrandomized studies carried out mainly found a stabilization of tumor

size after surgery (Pivonello et al., 2004; Greenman et al., 2005). The lack of tumor size response has been attributed to a low density of membrane-bound dopamine receptors (Bevan et al., 1992; Pivonello et al., 2004; Greenman, 2007). A trial, preferably large, randomized, double-blind, and placebo-controlled, could end the speculation on the efficacy of dopamine agonists in NFA. In our opinion there is a limited role, if any, for dopamine agonists in NFA. They are potentially useful only after surgery, and in those rare cases in whom radiotherapy and a second surgical intervention are less attractive.

Side-effects of medical treatment Dopamine agonists have side-effects which are described below, under Prolactinoma.

PROLACTINOMA Prolactinomas, or lactotroph adenomas, are the most common pituitary secreting adenomas. More than any other type of pituitary adenoma, prolactinomas are treated primarily medically. To date, dopamine agonists have been used as first-line treatment as they usually rapidly normalize prolactin levels and reverse galactorrhea, they restore fertility, and they also cause tumor shrinkage in most patients (Verhelst et al., 1999). In macroadenomas, treatment is a necessity, while in micradenomas it is not. However, when patients seek medical attention due to infertility, hypogonadism, gynecomastia, galactorrhea, or when there is growth of the (micro)adenoma, pharmacologic intervention is indicated. Other treatment approaches should only be considered in the minority of prolactinomas that do not respond to dopamine agonists. Resistant prolactinomas can be treated by surgery and/or radiotherapy. This definition of pharmacologic resistance is empirically

*Correspondence to: S.J.C.M.M. Neggers, Section of Endocrinology, Department of Medicine, Erasmus University, Erasmus MC, PO Box 2040, 3000 CA Rotterdam, The Netherlands. E-mail: [email protected]

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defined; the most commonly used version is a failure to reach normal prolactin serum levels and/or reduce tumor volume by at least 50% during dopamine agonist treatment (Molitch, 2005; Gillam et al., 2006).

Medical treatment Dopamine agonists reduce tumor size and decrease prolactin hypersecretion of the lactotroph adenoma in more than 90% of patients. Thereby they decrease signs and symptoms caused by the hyperprolactemia. The lactotroph adenoma cells express dopamine receptors (D1 and D2 subtypes of dopamine receptors). By binding these cell-surface D1/2 receptors, dopamine agonists reduce synthesis and secretion of prolactin and also adenoma cell size (Verhelst et al., 1999). Usually, a decrease in serum prolactin levels is accompanied by tumor size reduction. Decrease in prolactin levels can be expected within 2–3 weeks after initiation of pharmacologic treatment and normally it precedes the reduction in tumor size. Tumor reduction can be observed from well before 6 weeks to 6 months after the initiation of dopamine agonist treatment (Molitch et al., 1985). In general the magnitude of decrease in serum prolactin levels correlates well with the decrease in tumor size. Several dopamine agonists are used in prolactinoma patients. Depending on the patient’s characteristics, therapeutic expectation, and possible side-effects, the optimal dopamine agonist should be chosen to increase efficacy and patient compliance. Bromocriptine is one of the oldest ergot derivatives and has been used for approximately 30 years. To reach an optimal therapeutic effect a twice-daily dose is needed (Vance et al., 1984). Cabergoline is an ergot dopamine agonist that can be administered once or twice weekly and is more effective than bromocriptine (Verhelst et al., 1999). Cabergoline also seems to have a lower tendency to cause nausea than bromocriptine (Biller et al., 1996). Pergolide, another ergot derivative, was used primarily in high doses of > 3 mg/day for the treatment of Parkinson’s disease (Kleinberg et al., 1983). In prolactinoma patients typical doses range from 0.05 to 1.0 mg/day. In high doses, as used for the treatment of Parkinson’s disease, pergolide is associated with an increased risk of valvular heart disease (Zanettini et al., 2007). In 2007, pergolide was withdrawn from the US market due to this risk. Quinagolide is the only once daily administered nonergot dopamine; however, it is not available in some countries (van der Lely et al., 1991; Barlier and Jaquet, 2006).

EFFICACY Cabergoline seems to be superior to bromocriptine in decreasing serum prolactin levels (Verhelst et al.,

1999). Normalization of prolactin levels with an efficacy rate of 80–90% can be expected. A higher efficacy rate > 95% was observed in patients treated with high doses of cabergoline, up to 12 mg weekly (Ono et al., 2008). Quinagolide has more or less the same efficacy as cabergoline although a few studies suggest superiority to cabergoline (Barlier and Jaquet, 2006). The great advantage is the nonergot nature of the drug. This would imply an absence of the increased reported risk of the development of valvular heart disease, which can be seen during high-dose ergot derivate treatment.

WITHDRAWAL OF DOPAMINE AGONISTS Remission rates after discontinuation of a dopamine agonist differ greatly between studies. For macroadenomas rates of 16–64% and for microadenomas rates of 21–69% are reported. In a recent meta-analysis, an average remission rate of 21% for microadenomas and 16% for macroadenomas was reported (Dekkers et al., 2010). Higher remission rates were seen in studies in which cabergoline was used, the duration of the treatment was longer, and when shrinkage of the adenoma was > 50%. The highest probability of remission can be expected when prolactin serum levels are normal for a longer period of time and no visible tumor can be seen on MRI for at least 2 years.

Adverse effects The most common side-effects of dopamine agonist drugs are nausea, orthostatic hypotension, and mental disturbances. The gastrointestinal and orthostatic hypotension can be minimized when dopamine agonists are initiated at a low dose and slowly increased. Generally, cabergoline should be started at 0.25 mg once or twice a week, taken with food and/or at bedtime. Bromocriptine more frequently causes nausea than cabergoline. The usual bromocriptine starting dose is 1.25 mg twice daily. Although low doses decrease side-effects, some patients seem to be intolerant of dopamine agonists. For women, intravaginal administration of bromocriptine is reported to decrease the incidence of nausea (Kletzky and Vermesh, 1989). Less frequent side-effects are depression, constipation, Raynaud’s phenomenon, and alcohol intolerance. When patients with macrolactrotroph adenomas that have infiltrated the base of the skull are treated with a dopamine agonist, cerebrospinal fluid (CSF) leakage as rhinorrhea may occur due to rapid tumor shrinkage (Leong et al., 2000). Early recognition of this complication is important as there is a potential risk of bacterial meningitis.

MEDICAL APPROACH TO PITUITARY TUMORS

Valvular heart disease Ergot derivatives such as cabergoline and pergolide, when given in high doses, are associated with valvular heart disease in, e.g., Parkinson’s patients (Zanettini et al., 2007). As mentioned above, this association appears to be a dose-dependent effect. In Parkinson’s disease doses usually exceed those used in endocrine disorders. After the initial reports on cardiac valvulopathy in Parkinson’s patients during cabergoline use, a number of studies used cardiac ultrasonography in patients taking cabergoline for hyperprolactinemia (Valassi et al., 2010) to detecet valvulopathy. One study reported a higher frequency of moderate tricuspid regurgitation than in age- and gender-matched subjects. This was an exception; no other studies found any valvular regurgitation during long-term cabergoline treatment (Valassi et al., 2010). The majority of prolactinoma patients in these studies used standard doses of cabergoline of 0.5–1.5 mg/week. However, if patients use higher doses for longer periods there might be a risk of them developing valvular disease. Therefore, cardiac ultrasonography approximately every 2 years in patients using cabergoline > 2 mg per week should be advocated. Also, dose adaptation to the lowest dose of cabergoline that is necessary to lower prolactin to the normal range is desirable.

ACROMEGALY Acromegaly is the second most common secreting pituitary adenoma and acromegalic patients have clinical signs and symptoms that are related to the pathologic growth hormone (GH) secretion. In more than 95% of the patients with acromegaly the condition is caused by a pituitary adenoma (Melmed, 2006). More than 75% of these pituitary adenomas are macroadenomas, which often extend dorsally of the suprasellar region or laterally into the cavernal sinus (Melmed, 2006). Clinically, acromegaly is characterized by soft tissue swelling, excessive skeletal growth, reduced life expectancy, and a reduced quality of life (QoL) (Melmed, 2006; Neggers and van der Lely, 2009). The cornerstone of the biochemical diagnosis of acromegaly consists of insufficient GH suppression after an oral glucose load and elevated insulin-like growth factor 1 (IGF-1) serum levels. Treatment should aim for a reduction in signs and symptoms, an improvement in life expectancy, and optimization of QoL. Treatment objectives of active acromegaly are therefore threefold: management of GH hypersecretion in order to control the hypersecretion of IGF-1, control of tumor size, and optimized QoL. Biochemical control is

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reserved for subjects in whom a normalized serum GH and IGF-1 level within the age-adjusted limits of healthy individuals have been reached by whatever treatment modality. Normalization of GH excess will result in a decrease in signs and symptoms, a decrease in morbidity, and a normal life expectancy (Neggers and van der Lely, 2011). With regard to long-term treatment, morbidity and especially mortality rates, both the biochemical parameters GH and IGF-1 seem to be important. The reported mortality rates are mainly assessed in acromegaly patients treated with pituitary surgery and sometimes with radiotherapy (RT). To date, there are hardly any data available on mortality rates during (primary) medical treatment. Medical treatment modalities have high reported efficacy rates and therefore it might be expected that future data will become available on a possible reduction in mortality and morbidity (Neggers et al., 2012). Important biochemical predictors of mortality in acromegaly are GH (Bates et al., 1993; Orme et al., 1998; Ayuk et al., 2004) and IGF-1 (Swearingen et al., 1998; Biermasz et al., 2004; Holdaway et al., 2004). The latest GH correlates better with an increased mortality risk than the latest IGF-1 (Ayuk and Sheppard, 2008; Dekkers et al., 2008). GH, and sex- and age-matched IGF-1 concentrations are not only important biochemical parameters for mortality but are also at present the most widely accepted parameters for monitoring treatment response. There is an ongoing discussion on normal values of GH and IGF-1 (Pokrajac et al., 2007; Neggers et al., 2012) but this is beyond the scope of this chapter.

Medical treatment To date, over 90% of acromegaly patients are initially treated by transsphenoidal surgery. However, reported remission rates vary from 80% (Giustina et al., 2000; Holdaway, 2004) to less than 40% for microadenomas (Bates et al., 2008). Remission can be achieved in less than 50% of patients with macroadenomas, even in highly experienced neurosurgical centers (Melmed, 2006). Reported remission rates for macroadenomas are between 20% and 30% (Bates et al., 2008). Furthermore, recurrence rates after initial curative surgery are reported to be between 3% and 10% (Abosch et al., 1998; Swearingen et al., 1998; Kreutzer et al., 2001; Barker et al., 2003; Dekkers et al., 2008). If we compare surgery with long-acting somatostatin analogs (LA-SRIFS), with an efficacy rate of 44–77% in normalizing IGF-1 levels, remission rates for surgery of 30–80% are within the same range. However, if we compare surgery with reported efficacy rates of medical treatment with the GH receptor antagonist pegvisomant (PEG-V), with or without LA-SRIFS co-treatment, surgical efficacy rates

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in acromegaly patients with macroadenomas are considerably lower. It is worth noting that successful surgery is followed by a rapid fall in GH and IGF-1 levels, and the costs relative to long-term drug therapy are probably much lower.

Somatostatin analogs Somatotroph adenomas predominately express somatostatin receptor subtypes 2 (SSTR2) and 5 (SSTR5) (Murray and Melmed, 2008). The two commercially available LA-SRIFS, octreotide LAR and lanreotide autosolution, predominantly bind to the SSTR2 receptor, with similar affinity (Murray and Melmed, 2008). LA-SRIFS suppress GH secretion by the pituitary adenoma but also inhibit tumor growth via stimulation of apoptosis and inhibition of angiogenesis (Feelders et al., 2009). For obvious reasons, there are more long-term efficacy and safety data available on LA-SRIFS than on PEG-V, since LA-SRIFS were introduced more than 20 years ago while PEG-V only became available around 2003. The studies that have been conducted on long-term treatment with LA-SRIFS were biased as they frequently included patients who were responsive to LA-SRIFS before the start of the study (Melmed, 2006). In one of the few available prospective studies, LA-SRIFS reduced signs and symptoms and induced tumor shrinkage in about 42% of the patients (Bevan, 2005; Feelders et al., 2009). In theory, preoperative tumor shrinkage might improve surgical efficacy rates. Recently, a randomized controlled trial indeed observed improved normalization rate of IGF-1, but not of GH, in patients with macroadenomas who were pretreated for 6 months with octreotide LAR (Carlsen et al., 2008).

EFFICACY Octreotide LAR and lanreotide autosolution both inhibit GH secretion of the pituitary adenoma. Octreotide is available in depot preparations of 10, 20, and 30 mg, while lanreotide preparations include 60, 90, and 120 mg (Feelders et al., 2009). Both formulations are usually administrated once every 4 weeks and have more or less the same efficacy rates (Murray and Melmed, 2008; Feelders et al., 2009). Normalization of IGF-1 and GH ( 90% (van der Lely rate PEG-V in all stratification arms are more or less et al., 2001a). The mean weekly doses of the observameaningless, since any observed efficacy less than close tional registries are 106 mg in patients with a normal to 100%, in whatever treatment arm, simply indicates IGF-1, and 113 mg in those with an elevated IGF-1 that the dose of PEG-V was suboptimal, and not that (van der Lely et al., 2012). The lower efficacy of 62% the medication used in that specific treatment arm was might be explained by the relatively low dose of PEG-V less effective. administered in the registries. To achieve efficacy rates The reason why the PEG-V dose can be reduced durof above 90% by PEG-V monotherapy, the average ing combination treatment with LA-SRIF might be parexpected weekly dose will rise, probably above tially explained by the 20% increase in PEG-V serum 120–130 mg. levels compared to monotherapy with an equal dose (van der Lely et al., 2001b; Jorgensen et al., 2005). Since Combination therapy with pegvisomant and PEG-V is a competitive blocker of GH, competing somatostatin analogs endogenous GH concentrations are very relevant. GH Efficacy rates of PEG-V as single agent and in combinalevels increase during PEG-V treatment (van der Lely tion therapy of LA-SRIFS and PEG-V are comparable. et al., 2001b), but when PEG-V is combined with However, the necessary weekly PEG-V dose during comLA-SRIF, lower GH serum concentrations are observed bined treatment with LA-SRIFS appears to be much (van der Lely et al., 2001b; Jorgensen et al., 2005). PEG-V lower (around 50%) and can still be accompanied by effimeets less competition of endogenous GH around the cacy rates of over 90% (Neggers et al., 2009a; Neggers GHR, resulting in a lower necessary dose of PEG-V to and van der Lely, 2011; van der Lely et al., 2011). The block all GHRs, during combination therapy (Feenstra mean cumulative weekly dose was 77 mg PEG-V during et al., 2005; Neggers et al., 2007, 2009b; Hodish and combined treatment of LA-SRIF and PEG-V (Neggers Barkan, 2008; Neggers and van der Lely, 2009, 2011; et al., 2009a; Neggers and van der Lely, 2011). In another van der Lely et al., 2011). Additionally, LA-SRIF in report, two patients who were controlled with high-dose rodent studies showed that the number of GHRs PEG-V monotherapy were converted to lanreotide autoexpressed in the liver is reduced as a result of decreased gel 120 mg monthly and PEG-V weekly (Neggers et al., portal insulin concentration (Wurzburger et al., 1993; 2011a). After conversion, a weekly dose reduction of Shishko et al., 1994; Leung et al., 2000). Therefore,

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PEG-V (being a competitive GHR blocker) has less GH to compete with and less GHRs to block. In addition, LA-SRIFS may directly inhibit the production of IGF-1 by hepatocytes (Murray et al., 2004). These mechanisms together are the basis for the observed dose reduction during combined use of LA-SRIF and PEG-V (Feenstra et al., 2005; Neggers et al., 2007; Hodish and Barkan, 2008; Neggers et al., 2009a; Neggers and van der Lely, 2009, 2011; van der Lely et al., 2011). The PEG-V dose required to normalize IGF-1 was positively correlated with baseline IGF-1 levels, corrected for age and gender (r ¼ 0.48; p ¼ 0.006) (Neggers et al., 2007). A similar result was observed during coadministration of lanreotide autogel and PEG-V (van der Lely et al., 2011). However, gross debulking of the pituitary ademoma or RT did not reduce the necessary dose of PEG-V to normalize IGF-1 levels during combined treatment (Neggers et al., 2007).

Quality of life aspects of combination therapy From a patient’s perspective, QoL is an important parameter of disease control (Neggers et al., 2008a). From a clinician’s perspective the main parameter seems to be normalization of both IGF-1 and GH, which has been shown to correlate with normalization of the elevated long-term mortality rates of patients with acromegaly (Swearingen et al., 1998; Beauregard et al., 2003; Holdaway et al., 2003, 2004, 2008). As mentioned above, biochemical normalization does not guarantee complete relief from acromegalic symptoms (Hua et al., 2006; Neggers et al., 2008a). These residual symptoms appear to result in a measurable impairment in QoL in patients with acromegaly (Biermasz et al., 2004, 2005; Bonapart et al., 2005). QoL can be quantified by the Acromegaly Quality of Life Questionnaire (AcroQoL™) (Webb et al., 2002) and symptoms by questionnaires such as the Patient-assessed Acromegaly Symptom Questionnaire (PASQ™) (van der Lely et al., 2001a). In a prospective double-blind, placebo-controlled crossover study, QoL was assessed by AcroQoL and symptoms by PASQ, with or without the addition of PEG-V to LA-SRIF. All patients in that study had IGF-1 levels within the age- and sex-adjusted normal limits and GH levels of less than 2.5 mg/L (Neggers et al., 2008a). During the period of 16 weeks with 40 mg PEG-V weekly, QoL improved in these so-called controlled acromegalic subjects, as indicated by an increase in AcroQoL total score and especially AcroQoL physical dimension. This was accompanied by a reduction in total PASQ score and the single PASQ questions, perspiration, soft tissue swelling, and overall health status. The observation of the improvement in QoL and

signs and symptoms was not accompanied by a significant decrease in IGF-1. No correlation between change in IGF-1 and improvement in QoL was observed, but body weight correlated with the improvement in AcroQoL physical, although the absolute decrease in body weight was not significant (Neggers et al., 2008a). Noteworthy is that this improvement in QoL after the addition of PEG-V in controlled acromegaly patients was not reconfirmed by Madsen et al. (2011). Madsen’s study design, however, was different from the design of Neggers’s study. In the Danish study the dose of LA-SRIF was changed when PEG-V was added and the AcroQoL was not used. Furthermore, patients were not used as their own control, which decreased the power of their study. These differences in study design might explain the contradictory results. The mode of action of LA-SRIFS might also explain why the addition of PEG-V might improve QoL (Neggers et al., 2008b; Neggers and van der Lely, 2011). As already mentioned above, LA-SRIF treatment reduces portal insulin concentrations and therefore the number of available GHRs in the liver (Leung et al., 2000; Neggers et al., 2011b). LA-SRIFS can also directly inhibit IGF-1 production by hepatocytes (Murray et al., 2004). These mechanisms suggest that whereas the liver becomes relatively resistant to GH during LA-SRIF treatment, GH activity in other organs and tissues of the body is still too high (Neggers et al., 2008b, 2011b; Rubeck et al., 2010). Recently, in a Danish study, acromegaly patients with a normalized IGF-1 during LA-SRIF treatment still had higher nadir GH levels as compared with patients with a normal IGF-1 after surgery and had a reduced disease-specific health status (Rubeck et al., 2010). In line with this, we recently introduced the concept of “extrahepatic acromegaly” (Neggers et al., 2011b) (Fig. 20.1). One might expect that treatment of this “extrahepatic acromegaly” with lowdose, weekly PEG-V would improve the GH-dependent signs and symptoms and the patient’s QoL (Neggers et al., 2008a).

New developments As stated before, the SSTR pattern of GH-producing pituitary adenomas is characterized by predominant expression of SSTR2 and SSTR5 (Thodou et al., 2006; Murray and Melmed, 2008). In vitro studies suggest a synergistic effect between SSTR2 and SSTR5 activation in the control of GH secretion (Ren et al., 2003). Pasireotide (SOM230) is a so-called universal LA-SRIF that binds with high affinity to all SSTR except for SSTR4 (Schmid, 2008). Pasireotide has a particularly high affinity for SSTR5 and could thus be a potent GH inhibitor in octreotide-resistant adenomas. Pasireotide potently

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Fig. 20.1. (A) Effects of somatostatin analogs (SMSA) in SMSA-sensitive acromegalic subjects. Red arrows indicate inhibitory effects; green arrows indicate stimulatory effects; while thickness of arrow indicates level of inhibition. (B) Effects of pegvisomant in acromegalic subjects. Red arrows indicate inhibitory effects; green arrows indicate stimulatory effects; while thickness of arrow indicates level of inhibition. WAT, white adipose tissue; GH, growth hormone; IGF-1, insulin-like growth factor 1. (Reproduced from Neggers et al., 2011b, with permission from Bioscientifica.)

suppressed IGF-1 levels in rats (Weckbecker et al., 2002). In a single-dose proof-of-concept study in acromegalic patients, pasireotide (100 and 250 mg) and octreotide (100 mg) were equipotent in GH suppression in 8/12 patients, but in 3/12 patients pasireotide was more efficacious than octreotide. Adenomatous tissue from one of these octreotide-resistant patients could be assessed for SSTR expression and showed a relatively high SSTR5 expression (van der Hoek et al., 2004). In a phase II study, pasireotide at dose between 200 and 600 mg induced a complete biochemical response, i.e., normalization of GH and IGF-1 levels after 3 months in 27% of

patients (Petersenn et al., 2010). Studies evaluating the efficacy and safety of long-acting pasireotide are ongoing. The majority of GH-producing adenomas simultaneously express SSTR2 and dopamine receptor subtype 2 (Da2) and a functional interaction between SSTR2 and Da2 via heterodimerization has been shown in vitro (Rocheville et al., 2000). This may in part explain the synergistic effects of combined treatment with a somatostatin analog and dopamine agonist in acromegaly (Flogstad et al., 1994). Based on these observations, chimeric compounds have been developed that target both

310 S.J.C.M.M. NEGGERS AND A.J. VAN DER LELY somatostatin and dopamine receptors. For instance dependency (Biering et al., 2006; Neggers et al., 2007, BIM-23A760, which binds to SSTR2, SSTR5, and Da2, 2009b; Hodish and Barken, 2008; Trainer, 2009; Trainer strongly suppresses GH production in vitro ( Jaquet et al., 2009; Neggers and van der Lely, 2011). The et al., 2005). This compound was, however, not potent incidence of elevated transaminases of more than three enough during use in early studies in humans. times the upper limit of normal (ULN), is higher during combined treatment (15%) (Neggers and van der Lely, 2009, 2011; Madsen et al., 2011) than during PEG-V monoAdverse effects therapy (5.2%) (Biering et al., 2006; van der Lely et al., Somatostatin analogs have relatively few side-effects. 2012). A recent combination study observed a 10% prevTransient complaints of loose stools, abdominal discomalence of elevated transaminases of more than 2 ULN fort, nausea, flatulence, and fat malabsorption during (van der Lely et al., 2011). The difference in follow up the first weeks of treatment have been reported in about of the patients in various studies could explain the two-thirds of patients. Most of these side-effects resolve differences in the prevalence of elevated transaminases, within 10 weeks (Lamberts et al., 1996). In the first because the GPOS (Biering et al., 2006; Schreiber et al., 18 months of treatment, the development of asymptom2007) resembles everyday practice, whereas the comatic gallstones or sludge in about 25% of the patients has bined studies from Rotterdam have a more systematic been reported, most likely due to the reduced postpranfollow-up (Feenstra et al., 2005, 2006; Neggers et al., dial gallbladder contractility and emptying (Freda, 2002). 2007, 2008a, 2009b; Neggers and van der Lely, 2009, There are three important side-effects of PEG-V. Usu2011; van der Lely et al., 2011). When the intervals between ally these side-effects are quite mild, transient, and selfoutpatient visits are long enough, many episodes of tranlimiting. Lipohypertrophy has been described in several sient elevated transaminases will occur unnoticed. It reports during PEG-V monotherapy and in combination seems that a specific group of acromegaly patients might treatment with LA-SRIF, with a low prevalence have an increased risk of developing these elevated (Maffei et al., 2006; Bonert et al., 2008; Neggers and transaminases with a common polymorphism associated van der Lely, 2009; van der Lely et al., 2012). When lipowith Gilbert’s syndrome, UGT1A1*28 and male sex hypertrophy does occur, frequent rotation of the injec(Bernabeu et al., 2010). The incidence of homozygous tion site can reverse local lipohypertrophy, although it and heterozygous genotypes of UGT1A1*28 in acromegcan remain detectable for more than 8 months aly patients was 54% (Bernabeu et al., 2010). In some stud(Neggers et al., 2009b). In some cases it remains present ies it has been reported that diabetic acromegaly patients so that PEG-V therapy needs to be discontinued. It is have a 2.3 times higher risk (Neggers et al., 2007, 2009b). probably caused by a severe local GH deficiency due to However, the impact of diabetes mellitus on elevated very high PEG-V tissue levels at the injection site in the transaminases over 3 ULN seems to be less visible in presence of insulin. This disbalance may lead to accumularger follow-up studies in cohorts of patients (Neggers lation of adipose tissue around the injection sites (Hodish and van der Lely, 2009; Neggers et al., 2009b). In and Barkan, 2008; Neggers and van der Lely, 2009). other studies, no relationship between diabetes and eleThe second side-effect involves hepatocellular liver vated transaminases was reported (Biering et al., 2006; enzyme disturbances. Elevations in liver enzyme levels Schreiber et al., 2007; van der Lely et al., 2011). Nor does are mainly transient and self-limiting and occur both (cumulative) PEG-V dose or concomitant medication during PEG-V monotherapy and when used in combinaseem to be related to the occurrence of these hepatoceltion with LA-SRIF. There are two types of hepatic lular liver enzyme disturbances (Neggers et al., 2007; enzyme disturbance: hepatocellular and cholestatic. Neggers and van der Lely, 2009). Cholestatic disturbances are most often related to curIn the recent past, some concerns were raised that rent or previous treatment with LA-SRIFS (Shi et al., PEG-V might induce pituitary tumor growth. However, 1993; Biering et al., 2006; Neggers et al., 2007; despite a few reports of an increase in tumor size during Neggers and van der Lely, 2009). A significant proporPEG-V therapy, there is no unequivocal evidence that tion of these patients had asymptomatic bile stones and PEG-V directly promotes tumor growth (Buchfelder active biliary disease is rare during LA-SRIF treatment et al., 2009; van der Lely et al., 2011, 2012). It might be (Shi et al., 1993). When LA-SRIFS are discontinued, conmore correct to conclude that PEG-V is unable to prevent tractility of the biliary gland normalizes and when sludge tumor growth. Tumor growth can also occur during or stones are present, symptoms of biliary obstruction or long-term LA-SRIF, in which it seems to be present in active biliary disease can occur. Hepatocellular liver 2.6% of the treated patients (Bevan, 2005). In the GPOS enzyme disturbances are probably directly related to database, tumor size increase was carefully and systemthe use of PEG-V. They seem to occur almost exclusively atically reviewed in over 300 patients. In this systematic within the first year of treatment and there is no dose review, only three of the eight patients with an initially

MEDICAL APPROACH TO PITUITARY TUMORS 311 reported increase in tumor size had a real, but minor approach, persistent disease can be treated either by a secincrease after PEG-V treatment was initiated ond transsphenoidal surgery or with medical therapy, (Buchfelder et al., 2009). In another three of the eight radiotherapy, or bilateral adrenalectomy in very selected subjects, the initially reported increase had already cases. The medical therapy of CD can be used as a bridgstarted before the initiation of PEG-V treatment. In ing, preoperative, or primary medical treatment when two subjects a detectable rebound of tumor size was surgery is contraindicated. Unlike prolactinoma and encountered after cessation of LA-SRIF therapy acromegaly patients, primary medical treatment in CD (Buchfelder et al., 2009). In 75 patients in a Spanish suris a rare exception. Clearly there is an unmet need for vey, five (6.7%) acromegaly patients were identified highly efficacious and safe pharmacologic treatment with an increase in pituitary tumor size (Marazuela in CD. et al., 2011). All of these patients were pretreated with LA-SRIF analogs and then switched to PEG-V monotherMedical treatment apy. The reference MRI was made just after LA-SRIF was discontinued. The patients with tumor size increase The main aim in the treatment of CD is to reduce the clinwere pretreated with LA-SRIFS for a shorter period of ical syndrome. There are several types of medical treatment modalities. The first type of pharmacologic agents time and had not been treated before with radiotherapy target the adrenal cortisol production. They inhibit the (Marazuela et al., 2011). Therefore the tumor size increase in this study could again be due to the rebound steroidogenesis by steroid enzyme inhibition or by both phenomenon after cessation of the LA-SRIF treatment. inhibition and cytotoxic effects on the adrenocortical When LA-SRIFS are continued and PEG-V added, no cells (adrenolytic medication). increase in tumor size was observed in about 99 patients Steroid enzyme inhibitors are aminoglutethimide, eto(Neggers and van der Lely, 2009). Only in the study by midate, fluconazole, ketoconazole, metyrapone, and triJorgensen and co-workers was an increase in tumor size lostane. They block one or more enzymes involved in the synthesis of cortisol (Tritos et al., 2011). Ketoconazole observed in one of the 11 patients studied (Jorgensen and metyrapone are the most commonly used. Ketoconaet al., 2005). Some of the patients in this study, however, received a high dose of octreotide LAR (30 mg every zole inhibits several steroidogenic enzymes and thereby 2 weeks) prior to study entry. There were no data on decreases cortisol production in about 70–80% of the the tumor size increase prior to study entry and the study patients (Tritos et al., 2011). The doses necessary to achieve also included a period with PEG-V monotherapy. Therethis efficacy range from 200 to 1200 mg daily, divided into fore, it is impossible to determine whether the increase in two administrations and starting with a twice or thrice tumor size was caused by a rebound effect after discondaily dose of 200 mg. Metyrapone inhibits 11b hydrolase and is used as a monotherapy. It results in a similar effitinuation or decrease in frequency of the LA-SRIFS or cacy to ketoconazole with a decrease in cortisol synthesis was continued growth of the adenoma that had already started prior to study entry. Moreover, during combinain 75–80% of patients (Tritos et al., 2011). The daily dose tion treatment, in about 19% of the subjects a decrease in ranges from 750 to 6000 mg, divided over two to three tumor size was observed, suggesting that LA-SRIF treatdaily administrations, starting with a twice or thrice daily ment can still control tumor size, even in the presence of dose of 250 mg. The combination of metyrapone with PEG-V (Neggers and van der Lely, 2009; Neggers other steroid inhibitors may increase efficacy and limit et al., 2009a). the side-effects. Metyrapone is the most frequently used inhibitor during pregnancy, although there are some safety concerns (Tritos et al., 2011). Unlike metyrapone and ketoCUSHING’S DISEASE conazole, etomidate is not an oral formulation. It is priCushing’s disease (CD) is caused by an adenoma that marily used as a parenteral anesthetic drug. Etomidate secrets corticotropin (ACTH), which results in a glucoadministration results in a rapid control of cortisol excess corticoid excess. This excess gives rise to the clinical signs but also leads to unwanted sedation. Doses used to control and symptoms of Cushing’s syndrome. This results in cortisol excess are < 0.1 mg/kg/h. many signs and symptoms that can be seen as part of Mitotane is an adrenocorticolytic drug in high doses, the metabolic syndrome, such as central obesity, hyperbut in low doses inhibits steriodogenesis. It is not the tension, dyslipidemia, and diabetes mellitus, as well as preferred first-line medication for CD, since it has a others such as hirsutism, proximal muscle weakness, slow onset and an accumulation in fat that results in easy bruising, and osteoporosis. CD has the highest mordetectable plasma levels long after the treatment has tality rate of all pituitary adenomas (Dekkers et al., 2007). been terminated (Hogan et al., 1978). Mitotane should Primary treatment is transsphenoidal surgery and, if be primarily reserved for the treatment of adrenal necessary, additional pituitary radiation. After this first carcinoma.

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Mifepristone is mainly an antiprogestin. However, at higher doses it acts as a glucocorticoid receptor antagonist. Some of the CD symptoms decrease rapidly and in some patients it may even cause symptoms of hypocortisolism. Monitoring this potential hypocortisolism is cumbersome, since the levels of cortisol no longer reflect cortisol action when the glucocorticoid receptor is blocked. Doses needed to control cortisol excess range between 300 and 1200 mg daily (Fleseriu et al., 2012). Starting doses of mifepristone are usually 200–400 mg daily. The other type of medical intervention in CD targets the pathologic ACTH hypersecretion of the pituitary adenoma. Centrally acting agents are the dopamine agonist cabergoline and the somatostatin analog pasireotide (SOM230). Currently available dopamine agonists and somatostatin analogs that have been tested in Cushing’s disease have not been very effective. Chronic use of cabergoline can decrease urinary free cortisol (UFC) up to 125% of the ULN in about 29% of patients with CD (Godbout et al., 2010; Vilar et al., 2010). The dose required ranged from 1 to 7 mg weekly. Pasireotide is a multiligand somatostatin analog. It is an agonist of SSTR subtypes 1, 2, 3, and 5. Subtype 5 is frequently expressed in pituitary adenomas of CD patients, and when serum levels of cortisol normalize, subtype 2 receptor expression increases (de Bruin et al., 2009). Pasireotide can normalize UFC levels in 16% of CD patients. However, in a stepwise combination with cabergoline and ketoconazole its efficacy can reach 66–88% (Feelders et al., 2010; Tritos et al., 2011). At present only pasireotide has been registered for the treatment of Cushing’s disease.

Side-effects of medical treatment Ketoconazole can cause transaminitis, and even severe hepatotoxity, for which dose adjustment or discontinuation is necessary. Transient transaminitis can be observed in 10% of treated patients and serious liver injury in < 0.01% of patients (Tritos et al., 2011). Ketoconazole can decrease sex-steroid levels in both men and women. In men it causes gynecomastia and testosterone replacement may be required. In females, low estrogens do not cause clinical symptoms, since most female Cushing’s patients already have oligomenorrhea or amenorrhea. The inhibition of steroidogenesis by metyrapone causes an increase in androgens that can lead to hirsutism. The increase in deoxycorticosterone can lead to hypertension and salt retention. Combinations of other steroid-inhibiting agents with metyrapone may decrease the side-effects caused by the accumulation of the precursors.

Gastrointestinal side-effects are possible during treatment with steroid-inhibiting agents and pasireotide. Pasireotide has the typical gastrointestinal side-effects seen during treatment with the well-known and presently available somatostatin analogs octreotide and lanreotide (see side-effects of acromegaly). The main side-effect of pasireotide is hyperglycemia; this can be observed in 73% of patients, with 63% requiring additional glucoselowering medication (Colao et al., 2012). In about 70% of patients an IGF-1 level below the lower limit of normal was observed. Cabergoline’s side-effects are discussed above in the section on prolactinoma, although doses in CD are sometimes significantly higher. Mitotane can cause dyslipidemia and because of its accumulation in fatty tissue, women should not become pregnant within 5 years after discontinuation of this medication. Most of this medication can be titrated until cortisol levels are within the normal range, although a so-called “block and replace” treatment can be another solution. We recommend that medical treatment in CD is reserved for specific groups of patients, mainly as a possible presurgical intervention or as bridging treatment, or as a last resort.

THYROTROPIN-SECRECTING ADENOMA Thyrotropin-secrecting adenomas are very rare and account for < 1% of all functional pituitary adenomas. The excess in thyrotropin-releasing hormone (TSH) gives rise to the clinical signs and symptoms of a classic hyperthyroidism. Surgical resection has a poor reported result. Remission can be achieved in less than a third of patients, and in another third it leads to an improved biochemical profile (Beck-Peccoz et al., 1996). Medical treatment, therefore, is required in the majority of patients.

Medical treatment DOPAMINE AGONISTS Bromocriptine and cabergoline can be efficacious in these patients, usually in those that present with co-secretion of prolactin (Beck-Peccoz et al., 1996). Bromocriptine doses of 10–20 mg are required, and for cabergoline doses of 0.25–0.5 mg twice weekly are necessary.

SOMATOSTATIN ANALOGS Octreotide and lanreotide have more or less the same efficacy in the treatment of acromegaly. It can be expected that the same is true in the treatment of thyrotropin-secrecting adenomas. However, there are

MEDICAL APPROACH TO PITUITARY TUMORS more data available on the efficacy of lanreotide than octreotide. In 13 of 16 patients, TSH and thyroid hormones normalized (Kuhn et al., 2000).

ANTITHYROID TREATMENT Any type of antithyroid treatment primarily targeting the thyroid should be avoided. The decrease in thyroid hormone levels could lead to a further increase in TSH secretion and therefore further stimulate the growth of the pituitary adenoma. Hyperthyroidism symptoms can be controlled with b-blockers such as propranolol or atenolol.

SIDE-EFFECTS The side-effects of dopamine agonists are presented above, in the section on prolactinomas. The side-effects of somatostatin analogs are presented in the section on acromegaly.

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Medical approach to pituitary tumors.

Transsphenoidal surgery and medical treatment are the cornerstones of the management of pituitary adenomas. However, the optimal therapy should be cho...
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