Treatment of acromegaly aims to correct (or prevent) tumor compression of surrounding tissues by excising the disease-causing lesion and reduce growth hormone (GH) and IGF-1 levels to normal values. When surgery (the usual first-line treatment) fails to correct GH/IGF-1 hypersecretion, medical treatment with dopamine agonists (DAs; particularly cabergoline) or somatostatin analogs (SAs) can be used. The GH receptor antagonist pegvisomant is helpful in patients who are totally or partially resistant to SAs and can be given in association with both SAs and/or DAs. Thanks to this multistep therapeutic strategy, adequate hormonal disease control is achieved in most patients, giving them normal life expectancy. Comorbidities associated with acromegaly generally improve after treatment, but persistent sequelae may nonetheless impair quality of life.

Acromegaly is a rare disease characterized by progressive somatic modifications, mainly involving the face and extremities, together with systemic manifestations related to organ overgrowth and fluid retention. Acromegaly is associated with severe comorbidity and premature death if not adequately treated. It is due to excessive secretion of growth hormone (GH), originating from a pituitary adenoma in the vast majority of cases. Management of acromegaly is now rather consensual [1,2,3,4,5,6,7]. Although surgical removal of the pituitary GH-secreting adenoma is usually the first-line therapy, it is able to cure the disease only in microadenomas or small noninvasive macroadenomas. Persistent postoperative GH/IGF-1 hypersecretion needs to be treated with medical therapy, which is now generally preferred to radiation therapy for second-line treatment.

The clinical aims are to relieve symptoms, reduce the volume of the pituitary tumor, avoid tumor relapse, and improve long-term morbidity and mortality [8]. Recent epidemiological studies have helped to refine the definitions of ‘cure' and ‘good disease control', which are now far more precise: the GH concentration (in a random sample) must return to <1 µg/l in the new sensitive assays which are now used worldwide (if the oral glucose tolerance test is used, the nadir needs to be <0.4 µg/l), and the IGF-1 level must return to normal [4]. A stepwise therapeutic strategy based on surgery and/or radiotherapy and/or medical treatment allows these goals to be achieved.

Tumor excision, usually by the transsphenoidal route, is the most rapid way of reducing GH and IGF-1 concentrations in patients with acromegaly. Nevertheless, these levels normalize in only 40-70% of cases [9,10,11,12,13,14], depending on the size of the tumor (microadenomas are more amenable to cure), the preoperative GH concentration (the success rate is higher when GH concentrations are low, i.e. <10 µg/l or 30 mIU/l), and the surgeon's experience. When surgery fails to achieve good disease control, or when surgery is impossible or contraindicated, patients are now generally offered pharmacological treatments [6,7].

Bromocriptine moderately attenuates the symptoms of acromegaly and reduces GH concentrations, but it normalizes IGF-1 levels in only 10% of patients.

Cabergoline appears to be more effective [15,16]. In a meta-analysis of all published studies that we performed, GH levels below 2.5 ng/ml and IGF-1 normalization were achieved in 48 and 34% of cases, respectively [17]. Multivariate analysis showed that efficacy depended on the initial IGF-1 concentration, the treatment duration, and the basal concentration of prolactin (and, to a lesser degree, the dose of cabergoline) [17]. This treatment is thus more often recommended in patients with borderline or moderately increased IGF-1 levels [6,7]. However, it must be underlined that the treatment may be effective, even if this is rarer, in some patients with high levels of IGF-1 (fig. 1) and in patients with normal prolactin levels. This meta-analysis also showed that tumor shrinkage is observed in about one third of the patients treated with cabergoline and that, contrary to the secretory response for which the mixed (prolactin-GH) nature of the adenoma was not predictive, tumor response improved as the prolactin level increased [17].

Fig. 1

Individual IGF-1 levels expressed as a percentage of the upper limit of the age-adjusted normal range (ULN) before and after treatment with cabergoline in patients with acromegaly. Reproduced from a meta-analysis by Sandret et al. [17].

Fig. 1

Individual IGF-1 levels expressed as a percentage of the upper limit of the age-adjusted normal range (ULN) before and after treatment with cabergoline in patients with acromegaly. Reproduced from a meta-analysis by Sandret et al. [17].

Close modal

The use of very high doses of dopamine agonists (DAs) in patients with Parkinson's disease has been associated with an increase in the risk of cardiac valve disease [18,19]. This has not been confirmed in hyperprolactinemic patients [20,21] or in acromegalic patients treated with cabergoline in our cross-sectional and longitudinal studies [22].

The cabergoline-pegvisomant combination therapy has been proposed in some patients when cabergoline was unable to adequately control GH/IGF-1 levels. Indeed, pegvisomant (Somavert®) is a GH-receptor antagonist [23] which does not act at the level of the pituitary somatotroph adenoma but directly at the level of the GH peripheral receptors. It is used alone or in combination with other drugs [DAs or somatostatin analogs (SAs)]. In a multicenter, open-label, prospective clinical trial [24], the combination of cabergoline and low-dose pegvisomant (10 mg/day) was associated with a significant decrease in IGF-1 levels compared with cabergoline alone, and 68% of patients achieved normalization. Then, when cabergoline was withdrawn and pegvisomant continued as monotherapy, only 26% of the patients maintained normal IGF-1 levels. The adjunction of cabergoline may be interesting when pegvisomant alone achieved minimally increased IGF-1 levels [25].

Somatostatin Receptor Subtypes

SAs suppress GH secretion by binding to somatostatin receptors. There are five somatostatin receptor subtypes (sst) on somatotroph adenoma cells. First-generation SAs such as octreotide or lanreotide exert their antisecretory and antitumoral effects by acting on sst2 and 5.

Antisecretory Effects

Octreotide (Sandostatin®) can be injected subcutaneously, generally by the patient him/herself, at a dose of 100-200 µg two or three times a day. This was the first such analog to be marketed in the 1980s and represented a real therapeutic advance [26]. Sustained-release lanreotide (Somatuline® LP 30 mg) was the first slow-release preparation to be marketed. It was injected intramuscularly every 10-14 days (the frequency of injections depended on the impact on the GH concentration). Lanreotide is now available for deep subcutaneous injection every 28 days at doses of 60, 90, and 120 mg (Somatuline® Autogel® 60, 90, or 120 mg). Octreotide long-acting release (LAR; Sandostatin® LAR 10-20 or 30 mg), the sustained-release version of octreotide, is administered intramuscularly once a month. Treatment is usually started at the median dose and is then adjusted (decreased or increased) according to the GH concentration. Alternatively, it is possible to increase or decrease the frequency of injections.

The two SAs have very similar efficacy [27,28]. They allow to achieve GH concentrations below 2 µg/l (5 mUI/l) in 60-70% of patients and normalize IGF-1 levels in 50-80% of patients [29,30,31]. The wide range of SAs' efficacy from one study to the other was analyzed in a recent study looking at clinical trial methodology impact on reported biochemical effects [28]. This meta-analysis showed that overall achieved control rates were 56% for mean GH and 55% for IGF-1 normalization. If treatment duration, prior SA therapy, and year of study publication were related to biochemical control, no significant differences in GH or IGF-1 response rates were observed for multicenter versus single center, retrospective versus prospective, study drug, preselection for SA responsiveness, dosing scheme, GH response criterion, or switch study design [28]. However, when studies reported a composite endpoint (GH + IGF-1), this lowered the remission rate: the mean difference between the composite and individual GH and IGF-1 efficacy rates were 13 ± 14.5% and 8 ± 9.3%, respectively (thus, around 43-47%) [28]. This lower efficacy rate (compared to what was claimed previously) was confirmed by another recent meta-analysis of the effects of SAs in an unbiased group, that of treatment-naive patients: using strict combined cutoff criteria (normal serum IGF-1 levels and serum GH <1 µg/l), remission was observed in only 45% of these patients [14]. It must be noted that 35-40% of treated acromegalic patients exhibit discordant GH and IGF-1 concentrations [32,33,34], with a higher proportion of patients considered as in remission who have normal IGF-1 and in whom increased GH levels persist. This may be related to the GH assays which are now more sensitive or to the effect of sex (female patients have increased GH levels compared with males) or younger age [32].

Several long-term studies have shown that the cure rate tends to improve over time [35,36,37]. SA therapy must be continued indefinitely because, theoretically, it only suspends GH hypersecretion. In fact, it seems possible, in a handful of very good responders, to lengthen the interval between injections, or even to stop the treatment permanently with no subsequent increase in GH/IGF-1 concentrations [38,39].

An oral formulation of octreotide is currently in development. Absorption to the circulation is apparent within 1 h after dose administration, and escalating doses resulted in dose-dependent increased plasma octreotide concentrations, with an observed rate of plasma decay similar to parenteral administration; both 20 mg oral octreotide and injection of 0.1 mg s.c. octreotide resulted in equivalent pharmacokinetic parameters, supporting oral octreotide as an alternative to parenteral octreotide treatment for patients with acromegaly [40].

Antitumoral Effects of SAs

SAs also have effects on tumor volume, which decreases in 20-70% of patients [30,41]. A recent meta-analysis showed that this was achieved in 53% of patients treated with octreotide [42] and in 66% of patients treated with octreotide LAR. The overall weighted mean percentage reduction in tumor size was 37.4%, rising to 50.6% with octreotide LAR [42]. The reduction in tumor volume is larger when an SA is the first-line treatment [43]. Even when SA therapy does not lead to a reduction in tumor volume, it controls at least tumor volume in the vast majority of cases [30]. The antitumoral effects of SAs vary from one study to another, probably due to methodological reasons. In a recent multicenter study, where the primary endpoint was the proportion of patients with clinically significant (≥20%) tumor volume reduction under lanreotide administered at a dose of 120 mg every 4 weeks, in treatment-naive patients, it was shown that 62% of patients reached this criterion after 1 year of treatment [44]. The main antitumoral effect is generally achieved within the first 3 months and slowly progresses thereafter: mean reductions of tumor volume from baseline were 20% by week 12, 25% by week 24, and 27% by week 48 in that study.

SA Therapy as First-Line Therapy

SA therapy is indicated after surgical failure, but it can sometimes be used for first-line treatment, especially when severe comorbidities create a risk of perioperative complications. Thus, when heart failure or respiratory problems are associated with acromegaly [45,46], it is preferable to prepare the patient for surgery by administering an SA for a few months first. This has been introduced in the new recommendations for the treatment of acromegaly [6,7]. In some cases, when the tumor is very large and extends outside the sella and is not completely extractable by surgery (which would justify postoperative SA therapy), an SA can be administered first in the hope of controlling GH hypersecretion and tumor growth, thus avoiding the need for surgery [6,7]. Indeed, it has long been considered that the effectiveness of first-line medical therapy (in treatment-naive patients) is equivalent to that of second-line treatment after surgery or radiotherapy [43,47,48,49,50]. In fact, according to the meta-analysis published by Freda et al. [29], IGF-1 is more likely to normalize after second-line treatment than after first-line drug therapy. In this setting, it is interesting to know how primary medical or surgical therapy compares in terms of efficacy regarding both secretion (GH/IGF-1) and tumor control. Retrospective data from the German Registry indicate that SA treatment is less effective than surgical treatment [51]. This has not been confirmed by the only prospective study, which did not find significant differences in terms of efficacy and adverse events [52]. In a systematic review and meta-analysis to synthesize the existing evidence comparing these two approaches in treatment-naive patients, surgery was associated with a higher remission rate (67 vs. 45%), particularly when follow-up periods were long (≥24 months) and when performed by a single operator [14].

Strategy in Case of SAs Partial Resistance

When SA therapy fails to achieve remission, some authors report that an increase in the SA dose or a shorter interval between injections can rescue some patients [53].

When SA therapy is inadequate, another possibility is debulking surgery aimed at lowering hormone levels, in which case retreatment with an SA often provides disease control [54,55].

It is also possible to combine cabergoline with an SA: according to a recent meta-analysis of studies in which cabergoline was added to an SA that had failed to produce remission, IGF-1 levels normalized in half of the patients [17]. The synergistic effect of DAs and SAs has led to the development of chimeric agonists binding both DA and SRIF receptors (particularly sst2 and sst5) [56]. One of these compounds, BIM 23A760 [57], with an in vitro synergistic effect on GH secretion, showed promising results in studies on monkeys and in humans after a single dose. Unfortunately, the multicenter trial in patients with acromegaly which was initiated in 2008 was prematurely interrupted due to insufficient efficacy.

In case of inadequate control of acromegaly with first-generation SAs, it is also possible to use pegvisomant (Somavert®), a GH receptor antagonist [23], which can either replace SAs or be given in combination with them. The SA-pegvisomant combination therapy has been developed [58]. IGF-1 normalization was obtained in all the patients with a median weekly pegvisomant dose of 60 mg [59]. This decreased dose requirement during combined therapy might be partially explained by an increase of about 20% in serum levels of pegvisomant [60]. Biochemical hepatic anomalies were quite frequent (although always transient) with this combination [61,62].

The availability of new SAs such pasireotide may also be helpful for controlling some patients resistant to octreotide or lanreotide (see below).

Effects of Preoperative SA Treatment on Surgical Outcome

There is some controversy surrounding the ability of preoperative SA therapy to improve surgical outcome [63]: some studies [64,65,66,67,68,69,70,71] indicate that, in some patients with isolated somatotroph macroadenomas, surgery provides better control of acromegaly when patients are pretreated with an SA compared with those operated immediately, without SA preparation, while other studies showed no difference [72,73,74]. A recent meta-analysis of all controlled trials showed a borderline short-term effect of SA treatment on biochemical cure with a pooled odds ratio (OR) of 1.62 (95% CI, 0.93-2.82); an analysis of the three prospective controlled trials showed a statistically significant effect (OR 3.62, 95% CI, 1.88-6.96) [75]. However, after a longer follow-up, even the studies which were initially in favor of preoperative SA treatment did not confirm any differences in terms of acromegaly control after surgery between patients treated and not treated preoperatively with SAs [71,76]. In any case, patients with minimally invasive macroadenomas (e.g. minor cavernous sinus invasion) represent the subgroup most likely to benefit from improved remission rates after preoperative SA therapy [63].

Side Effects of First-Generation SAs

SAs have mild adverse effects, consisting mainly of transient gastrointestinal disorders (abdominal bloating, nausea, diarrhea) and gallstones in 10-20% of cases (ursodeoxycholic acid has no proven effectiveness in this setting) [77]. Gallstone complications are rare, and the guidelines for their monitoring have been much relaxed in recent years [78]. Changes in glucose metabolism are sometimes observed, including impaired glucose tolerance or even diabetes in patients who are overweight. In other cases, however, glucose tolerance improves following the reduction in insulin resistance due to lowering of GH concentrations. Overall, according to a recent meta-analysis, the consequences are very minor in terms of fasting glucose and HbA1c levels [79]. Regular metabolic monitoring is nevertheless justified.

Second-Generation SAs: Pasireotide

SAs bind with high affinity to sst2 and 5. As a significant proportion of somatotroph adenomas appear partially or totally resistant to octreotide or lanreotide, possibly owing to variable expression or a reduced density of receptor subtypes [80], it was logical to develop new, more potent SAs able to bind with greater affinity to certain sst. Pasireotide (Signifor®) is a new SA that binds with high affinity to sst1, 2, 3, and 5 [81] and that potently inhibits GH and IGF1 in different animal models [82]. According to published studies, pasireotide appears more effective than octreotide in terms of the GH/IGF-1 levels achieved [83]. It is now available in a long-acting preparation which (pasireotide LAR) is administered every 28 days at a dose of 40-60 mg. In a head-to-head prospective, randomized, double-blind trial with treatment-naive patients, biochemical control was achieved by significantly more pasireotide LAR patients than octreotide LAR patients (31.3 vs. 19.2% and 35.8 vs. 20.9% when including patients with IGF-1 below the lower normal limit) [84]; gastrointestinal adverse events occurred at a similar frequency, but glucose metabolism was more strongly altered on pasireotide (57.3 vs. 21.7% in the head-to-head comparison study) [84]. This drug may be particularly interesting in patients with partial resistance to first-generation SAs such as octreotide or lanreotide. This has been recently studied in a large multicenter randomized trial performed in patients inadequately controlled with maximal doses of octreotide LAR or lanreotide LAR: 15% of patients in the 40 mg pasireotide group and 20% of patients in the 60 mg pasireotide group achieved biochemical control compared with no patients in the active control group (who pursued their previous SA treatment) [85]. The most common adverse events were hyperglycemia (33% under 40 mg pasireotide and 31% under 60 mg pasireotide vs. 14% with active control), and diabetes (21% under 60 mg and 26% under 40 mg pasireotide vs. 8% in active controls). Diarrhea was also more frequent during pasireotide in this trial [85].

The advantages, disadvantages, and costs of the different treatment options must be taken into account.

A therapeutic strategy is proposed by the author of this review [86] in figure 2. Currently, if surgical treatment fails to cure acromegaly, medical treatment with SAs is preferred to radiotherapy. In some selected patients (those with moderately increased IGF-1), cabergoline may be tried first. If SA therapy fails, repeat surgery may be proposed in order to remove a large tumor remnant before trying a SA again. Combination with cabergoline may also be interesting if an SSA is only partially effective. If this does not allow good control of GH/IGF-1 levels, pegvisomant is generally proposed, generally in combination with SAs if they are partially effective, in particular against tumor. The recent introduction of second-generation SAs such as pasireotide might change these strategies in the future if their superiority to first-generation SAs is confirmed. However, the choice of a second-generation SA will be guided by its side effects, particularly on glucose metabolism. Finally, the cost of these medical treatments, which may be required indefinitely (except if a radiotherapy susceptible to progressively decrease the GH production is proposed and presumably leads to a decrease in the requirement for medical treatment), also needs to be considered in the therapeutic decision. If surgery is contraindicated, first-line somatostatin therapy may be proposed.

Fig. 2

A strategy proposed by the author for the current management of acromegaly. CAB = Cabergoline; GHRA = GH receptor antagonist (pegvisomant). Adapted from Chanson et al. [86].

Fig. 2

A strategy proposed by the author for the current management of acromegaly. CAB = Cabergoline; GHRA = GH receptor antagonist (pegvisomant). Adapted from Chanson et al. [86].

Close modal

All these treatments must be reassessed on a yearly basis if the treatment is effective but as requested if the treatment is ineffective or in case of titration. After radiotherapy, if a medical treatment is necessary while waiting for the effects of irradiation, its regular withdrawal is necessary for assessing the persistence of the active disease.

Acromegaly is a rare disease usually due to GH hypersecretion by a pituitary adenoma. In addition to this dysmorphic syndrome, acromegaly has cardiovascular, respiratory, rheumatological, and metabolic consequences and is associated with a risk of neoplasia. Treatment is aimed at correcting (or preventing) tumor compression of neighboring tissues by excising the culprit lesion, and at reducing GH and IGF-1 levels to normal values. When surgery fails to correct GH/IGF-1 hypersecretion, medical treatment with SAs and/or cabergoline can be used. The GH receptor antagonist pegvisomant is used to treat patients who are resistant to or intolerant of SAs. Pasireotide, the second-generation SA with an improved somatostatin receptor binding profile may also be interesting in this setting, but it increases the risk of hyperglycemic events. Radiotherapy is nowadays proposed as third-line treatment, but medical treatment will be necessary while waiting for the benefits of radiotherapy to emerge. The prognosis of acromegaly has improved in recent years: adequate hormonal control is achieved in most cases, providing a life expectancy similar to that of the general population.

For further reading on acromegaly in this issue, see [87,88,89,90,91,92,93,94,95,96].

P.C. is a consultant for Novartis, Ipsen, and Pfizer. Honoraria and lecture fees from Novartis, Ipsen, and Pfizer were paid to his institution. The Service d'Endocrinologie et des Maladies de la Reproduction, Hôpital de Bicêtre, received educational and research grants from Novartis, Ipsen, and Pfizer.

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