LEADING ARTICLE Drugs & Aging 2000 Aug; 17 (2): 81-92

1170-229X/00/0008-0081/$20.00/0

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Pharmacotherapy or Surgery as
Primary Treatment for Acromegaly?
Diego Ferone,1,2 Annamaria Colao,2 Art-Jan van der Lely1 and Steven W. J. Lamberts1
1 Department of Internal Medicine III, Erasmus University, Rotterdam, The Netherlands
2 Department of Molecular and Clinical Endocrinology and Oncology, ‘Federico II’ University,
Naples, Italy

Abstract In recent years important progress has been made in the management of acro-
megaly due to the availability of effective and well tolerated drugs and to
improved surgical techniques, resulting in a broader choice of therapeutic inter-
ventions. Although surgery in the hands of an experienced surgeon still represents
the primary option for the majority of patients, the new formulations of som-
atostatin analogues and dopamine agonists have partially modified the primary
therapeutic approach to this severe and disabling chronic disease.
Therapy with somatostatin analogues has been shown to reduce morbidity and
the mortality rate in patients with acromegaly, and currently in some patients this
medical approach may be preferable to surgery. Although in selected patients
individualised pharmacotherapy might represent the primary therapy, trans-
sphenoidal surgery of microadenomas and noninvasive macroadenomas remains
the primary option, since the remission rate is very high and the costs are relatively
low in comparison with lifelong therapy with somatostatin analogues. However,
the treatment schedule in acromegaly should consider criteria additional to tu-
mour size and invasiveness, such as the age and the general clinical condition of
the patient. Presurgical treatment with somatostatin analogues has been reported
to reduce surgical complications and time of hospitalisation after the operation.
Moreover, a multidisciplinary team of well trained specialists is needed in order
to guarantee the most optimal quality of life and life expectancy for patients with
acromegaly.

Acromegaly is an insidious neuroendocrine tors, such as insulin-like growth factor 1 (IGF-I).

disorder resulting almost invariably from a growth
hormone (GH)-secreting pituitary adenoma, of
which about 40% are microadenomas (<10mm in
diameter).[1] In less than 2% of patients hypersecre-
tion of GH depends on a hypothalamic or ectopic
tumour, such as a gangliocytoma, or bronchial or
pancreatic carcinoid, that produces growth hormone-
releasing hormone (GHRH) or much more rarely
GH.[1] The elevated circulating GH level results in
an increased production of other tissue growth fac-
The condition is disabling and disfigurement of the
face and extremities occurs together with other
clinical features (table I) which develop slowly but
progressively, leading to a delay between the onset
of symptoms and diagnosis ranging from 4 to 10
years, and, in some cases, even longer.[2] This de-
bilitating disorder has an annual incidence of ap-
proximately 3 to 4 new cases/million, while the
prevalence in the current population is estimated
around 40 to 60 cases/million.[3] However, because
82 Ferone et al.

Table I. Symptoms and signs of acromegaly An increased incidence of gastrointestinal neo-

Symptoms Signs plasms, in particular colonic polyps, has been re-
Arthralgias Acral growth ported as well, and high post-treatment GH levels
Paraesthesias Soft tissue swelling
were found to be associated with an increased
Carpal tunnel syndrome Heel pad thickness
Weakness Coarse features
mortality due to colon cancer and malignant dis-
Decreased exercise capacity Hyperhidrosis and skin oiliness eases.[8-13] In general, the mortality rate of patients
Headaches Thickening of the lips with acromegaly is 2 to 3 times that of the general
Visual field impairment Macroglossia population, but early diagnosis and effective treat-
Sleep apnoea Prognathism ment can have a significant impact on the disease
Hypertension Glucose intolerance and
course and survival, which in many cases can be
diabetes mellitus
Malocclusion Skin tags
restored to the age-matched population.[14] There-
Decreased libido Colonic polyps fore, appropriate and modern diagnostic procedures
Impotence (males) Goitre are mandatory to secure the diagnosis, to find the
Oligomenorrhoea/amenorrhoea Cardiomyopathy source of GH excess, and to monitor therapy once
(female)
this source has been established.
Myopathies Hypogonadism/hypopituitarism
Neuropathies Hyperprolactinaemia
The problems of dealing with the diagnosis of
Mild hirsutism acromegaly lie beyond the scope of this paper.
Electrolyte abnormalities Briefly, the diagnosis of acromegaly is based on
Sellar enlargement clinical findings and biochemical assays. Since
the secretion of GH displays a pulsatile pattern, a
single measurement is not advisable. The meas-
the diagnosis of acromegaly is frequently delayed urement of the plasma IGF-I level in one sample
or even missed, it is likely that its true prevalence is more reliable, since it is a function of the inte-
is underestimated. grated 24-hour GH level. For accurate control
Recent observations suggest an increase in the comparisons, IGF-I levels must be age- and gender-
incidence of pituitary adenomas in the elderly, adjusted. The oral glucose tolerance test represents
probably due to the rising proportion of elderly the most specific dynamic test to diagnose and
individuals as well as to the higher incidence of monitor the successful ‘control’ or ‘cure’’ of acro-
elderly patients with medical conditions, such as megaly. A lack of suppression of circulating GH
cerebrovascular and neurological diseases, which levels below 1 µg/L or a paradoxical GH increase
require careful investigation by modern imaging after an oral glucose load distinguishes patients
techniques.[4] However, the prevalence of secreting with active acromegaly from non-acromegalic pa-
tumours, including GH-secreting adenomas, is rel- tients or ‘cured’ patients with acromegaly.
atively low compared with clinically nonfunction- The diagnosis and the criteria for cure do not
ing adenomas.[4] Acromegaly has long been recog- significantly differ between older and young pa-
nised as being associated with increased mortality tients. However, the diagnosis in the elderly may
due to cardiovascular, respiratory and neoplastic be delayed because of the ‘aspecificity’ of symp-
diseases.[5,6] A large number of studies has demon- toms like hypertension, altered glucose tolerance,
strated that specific cardiomyopathy, and central asthenia, depression and arthralgias which also
and/or obstructive sleep apnoea occur in acromeg- frequently occur in the non-acromegalic popu-
aly and represent important risk factors for morbid- lation.[15] A reliable and sensitive method of GH
ity and mortality. An adequate suppression of GH assay helps to demonstrate the persistent GH hyper-
and IGF-I excess may stop disease progression and secretion.[14,16] Finally, adequate imaging tech-
significantly improve both these severe complica- niques, such as computed tomography scans or
tions.[7-9] magnetic resonance imaging, are mandatory to

 Adis International Limited. All rights reserved. Drugs & Aging 2000 Aug; 17 (2)
Treatment Options in Acromegaly
visualise the pituitary tumour and its invasion into
contiguous structures. Further and more sophisti-
cated investigations are often required when there
is the suspicion of an ectopic source of hormone
production.[16]
1. Management of Acromegaly
Optimal therapy for patients with acromegaly
aims at removing the tumour with resolution of its
mass effects, preventing biochemical or local re-
currence and preserving, as much as possible, nor-
mal residual pituitary function. After achieving
normal IGF-I levels and restoration of normal and
stimulated GH secretion, most clinical manifesta-
tions of acromegaly may disappear and a signifi-
cant relief from many symptoms occurs. The main
aim of successful treatment is to prevent disabling
long term consequences, as well as to normalise
risk factors for cardiovascular complications and
for malignancies. Since an effective treatment
linked to an improved survival rate is strongly
correlated with the reduction in serum GH levels,
standardised criteria should be established to de-
fine biochemical ‘control’ and ‘cure’’.[17] A recent
consensus suggested that ‘cure’ is associated with
GH levels <1 µg/L, as a nadir after oral glucose
load.[15] However, taking into account the results
from studies that demonstrated a normalised sur-
vival in patients with GH levels less than 2.5 µg/L
(5/7.5 mU/L, depending on reference standard be-
fore or after January 1997, respectively),[18] as well
as the correlation between mortality in patients
with acromegaly and GH levels after therapy,[19] it
seems best to define values of GH and IGF-I which
reflect both the achieved clinical remission and the
decreased long term morbidity and mortality.[18]
Such ‘safe values’ represent a more realistic con-
cept, and these imply serum GH levels of less than
2.5 µg/L, together with a IGF-I level which is nor-
mal after correction for age and gender.[20]
Treatment options for acromegaly include sur-
gical removal of the adenoma, radiotherapy and
pharmacological reduction of hormonal hyper-
secretion by dopamine agonists and somatostatin
analogues. Among these therapeutic approaches,
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83
the best option to be considered as suitable as pri-
mary therapy for acromegaly remains controver-
sial.
Three decades ago only surgery and radiother-
apy were the only effective treatments for pituitary
tumours. The scene definitively changed with the
introduction of dopaminergic compounds, which
in patients with prolactinoma, very effectively lower
prolactin (PRL) levels, which in turn restores al-
tered endocrine functions and induces significant
tumour shrinkage. Already with the first genera-
tion of dopamine agonists (the most widely used
of which is bromocriptine), and more recently with
the availability of second generation dopaminergic
agents (such as quinagolide and cabergoline), med-
ical therapy has replaced surgery and radiotherapy
as the first line of treatment in the majority of pa-
tients with microadenomas and macroadenomas
producing PRL.[21] This success has prompted
many investigators to search for alternative simi-
larly effective medical therapies for other pituitary
tumours.
For many years it was generally accepted that
GH-secreting pituitary adenomas should be surgi-
cally removed. However, somatostatin analogues,
which have been used for more than 10 years, have
been proven to be an effective adjuvant therapy
for acromegaly.[22,23] Somatostatin analogues were
employed as primary treatment only in selected
cases, including presurgical treatment in patients
with large invasive macroadenomas, for relief of
symptoms in patients awaiting surgery, in cases of
recurrence of morbidity in elderly patients and in
contraindications to neurosurgery.[24] In addition,
medical therapy with somatostatin analogues and/
or dopamine agonists might be advisable when pre-
vious surgical management did not achieve clinical
and biochemical remission.[14]
Thus, should surgery still be considered as the
most effective and well tolerated primary treat-
ment for acromegaly? Furthermore, as far as radio-
therapy is concerned, what should be its role in the
treatment of GH-secreting pituitary adenomas, in
light of the promising data using modern stereo-
tactic radiation therapy, including gamma-knife ra-
Drugs & Aging 2000 Aug; 17 (2)
84
diosurgery. To address these and other questions
on treatment choices, it might be useful to review
recent data concerning the 3 different therapeutic
approaches in patients with acromegaly.
2. Surgery
Surgery is still considered the traditional first line
treatment for GH-secreting pituitary tumours.[6,23]
Trans-sphenoidal adenomectomy performed by
skilled neurosurgeons has been reported to produce
a cure rate of approximately 70 and 50% in micro-
adenomas and macroadenomas, respectively.[5,24-28]
Results of series on surgical outcomes of acromeg-
aly are difficult to compare because the criteria
used to define ‘cure’ have varied over the years and
between different studies. However, surgery alone
is successful in most patients with microadenomas
and noninvasive macroadenomas, while patients
with invasive tumours often require adjunctive
therapy. GH levels quickly return to the normal
range, and IGF-I levels normalise within a few
weeks after successful surgery.
Symptoms related to high circulating growth
factors rapidly improve as well as the preoperative
signs and symptoms of compression on adjacent
structures, such as the optic nerve and cerebral ven-
tricles. Complications are rare and in the hands of
experienced neurosurgeons, cerebral spinal fluid
leaks, meningitis and temporary or permanent dia-
betes insipidus are less likely to occur today after
trans-sphenoidal surgery.[29-31] Recently, an inno-
vative single-nostril endoscopic trans-sphenoidal
procedure has been proposed to further increase
safety and to improve the surgical management of
the sella.[32,33] Treatment with the somatostatin
analogue octreotide may induce tumour shrinkage,
and while a preoperative treatment has been pro-
posed to improve the surgical outcome,[34-37] con-
trolled studies did not confirm this hypothe-
sis.[38,39] However, it has been demonstrated that 3
to 6 months of treatment with octreotide before sur-
gery improved the clinical condition of patients
with acromegaly and reduced the time of hospital-
isation after the operation.[40] The costs of surgery
(around $US2000) when curative are lower com-
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Ferone et al.
pared with lifelong medical treatment with somat-
ostatin analogues (around $US10 000 per year).
Unfortunately, the cure rate of surgery remains
too low in patients with macroadenomas, which
represent the majority of GH-secreting tumours,
and many patients require additional therapy to
reduce GH and IGF-I levels to within the normal
range. This additional treatment significantly in-
creases the costs of therapy. Although residual
pituitary function may be preserved, pituitary fail-
ure has been reported in up to 20% of patients
with macroadenomas.[5,24,41] The lost pituitary hor-
mones must be reliably replaced, and lifelong re-
placement therapy needs a more strict follow-up,
increasing the costs of the general management.
Moreover, acromegaly may recur in 5 to 10% of
patients several years after surgery.[24,29-31]
3. Radiotherapy
Multiple methods of delivery of radiation are
currently employed (external radiation, proton
beam, α-particles and interstitial radiotherapy), but
all have a similar efficacy. Although more data are
required for the most recent techniques, irradiation
of the pituitary tumour in patients with acromegaly
should be reserved for patients with severe contra-
indications to surgery or in those cases where sur-
gery was ineffective and medical treatment failed
in controlling persistent active disease due to a
remnant tumour.[42] The greatest GH level fall
occurs within the first 2 years, followed by a grad-
ual, further decline until 10 years thereafter.[43,44]
Moreover, considering current ‘cure’ criteria, a
decrease of GH levels to less than 2.5 µg/L occurs
in a smaller proportion of patients compared with
previous studies, where GH was considered norm-
alised when it reached less than 5 µg/L.[45] Further-
more, in a retrospective study it was demonstrated
that pituitary irradiation is unable to normalise
IGF-I levels, although these authors evaluated a
large group of patients not receiving a uniform ra-
diotherapeutic approach.[46]
Other studies reported better results, although
the continued lowering effect of radiotherapy on
GH levels seldom controlled GH hypersecre-
Drugs & Aging 2000 Aug; 17 (2)
Treatment Options in Acromegaly 85

tion.[30,45] The occurrence of severe complications,
such as cranial nerve palsies, optic neuritis, im-
paired memory, lethargy and tissue necrosis has
decreased with modern techniques, however, the
damage of the normal hypothalamic-pituitary re-
gion results in hypopituitarism in more than half of
patients within 10 years.[42,43] An increased risk for
a second tumour of the central nervous system after
external radiation therapy is still debated.[47,48]
Gamma-knife radiosurgery has been employed as
adjuvant treatment for pituitary adenomas in se-
lected cases and very recently a review of gamma-
knife effects has been reported.[49,50] The results of
gamma-knife radiosurgery in patients with GH-se-
creting tumours are still scarce and longer term fol-
low-ups are required to evaluate the real efficacy
and adverse effects of this approach.
4. Pharmacotherapy
Medical therapy with dopamine agonists and
somatostatin analogues or a combination of drugs
from both classes of compounds has become an
important additional tool in the management of
acromegaly. More recently, preliminary results of
trials using GH receptor antagonists, which may
block the peripheral action of endogenous GH,
suggest that this novel approach might be an effec-
tive alternative to the conventional medical treat-
ments of acromegaly (see section 4.4). The choice
of medical treatment needs to take into account
several factors: route of administration, adverse
effects and patient compliance, costs and efficacy
of the therapy.
4.1 Dopamine Agonists
Dopamine agonists, which stimulate GH secre-
tion in healthy individuals, are administered orally
and may suppress GH hypersecretion in patients
with acromegaly, probably via the dopamine D2
receptor subtype.[51] Bromocriptine, a dopamine
D1 and D2 receptor agonist, was the first dopamin-
ergic agent employed as effective medical therapy
for acromegaly. A significantly higher dose and
more frequent daily administrations are required to
suppress the altered GH secretion compared with
those usually given to normalise PRL levels in pa-
tients with prolactinoma.[16]
The therapeutic efficacy of bromocriptine has
been reported to be lower than that of octreo-
tide.[51] However, more recently, 2 new dopamine
agonists, highly selective for the dopamine D2 re-
ceptor subtype, have been successfully employed
in the medical treatment of patients with hyper-
prolactinaemia. Quinagolide, the only non ergot-
derivate, and cabergoline are very potent dopamine
agonists with a prolonged duration of action.[52-59]
Although variable results are reported in the liter-
ature, these compounds seem to renew the role of
dopamine agonists in the medical treatment of ac-
romegaly, (table II). Both drugs displayed a signif-

Table II. Effects of quinagolide and cabergoline treatment on growth hormone (GH), insulin-like growth factor (IGF)-I levels and tumour size
in patients with acromegaly
Study No. of Dopamine No. of patients No. of patients No. of patients Cure
patients agonist achieving normal achieving normal displaying tumour criteria for
GH levels IGF-I levels size reduction GH (µg/L)
Ferrari et al.,[57] 1988 6 Cabergoline 3 3 1 <5
Chiodini et al.,[58] 1993 17 Quinagolide 2 2 0 <5
Lombardi et al.,[56] 1995 12 Quinagolide 5 5 1 <5
Muratori et al.,[59] 1997 3 Cabergoline 3 3 0 <2
Colao et al.,[52] 1997 16 Quinagolide 8 7 2 <5
Colao et al.,[52] 1997 11 Cabergoline 0 0 0 <5
Jackson et al.,[53] 1997 10 Cabergoline 2 2 ND <5 mU/L
Abs et al.,[54] 1998 64 Cabergoline 30 25 13/21 <2
Cozzi et al.,[55] 1998 18 Cabergoline 5 5 3 <2
ND = not determined.

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86
icant effect in lowering GH and IGF-I levels and
produced tumour shrinkage in selected (therapy-
resistant) and unselected groups of patients with
acromegaly, at a lower dose compared with bromo-
criptine.[52-61] Although a marked reduction of GH
and IGF-I levels has been shown in more than 65%
of unselected patients with acromegaly treated
with individualised cabergoline doses,[54] further
studies are needed to confirm this finding. Dopa-
mine agonists seem to be much more effective in
GH-producing adenomas that co-secrete PRL or
display significant PRL immunoreactivity.[52,62]
The occurrence of adverse effects (table III), which
may represent an important limiting factor for the
treatment, can be prevented by starting the therapy
at lower doses.
4.2 Somatostatin Analogues
Somatostatin inhibits the secretion of a variety
of hormones, such as GH, thyroid-stimulating hor-
mone (TSH), PRL and gastrointestinal hormones.
In vivo, somatostatin has a biological half-life of
only 1 to 3 minutes and its clinical application is
therefore restricted to intravenous continuous infu-
sion.[63] Over the last 15 years many long-acting
somatostatin analogues have been developed and
whereas octreotide and lanreotide have become
available for clinical application in the treatment
of acromegaly, rapreotide is in late stage clinical
trials. The synthetic somatostatin analogues cur-
rently used in clinical practice are octapeptides
with specific receptor binding characteristics (table
IV).[64-66] The first, octreotide, was introduced as
an effective therapy for acromegaly more than 10
years ago.[67] The potency of this analogue, admin-
istered subcutaneously, is 40-fold greater than that
of somatostatin in suppressing GH. This effect is
exerted through somatostatin receptor subtypes 2
and 5, which are the subtypes mainly expressed
on GH-secreting tumours.[68,69] In a recent paper,
Colao and Lombardi reviewed the data from sev-
eral trials with up to 50 patients, and in a total of
466 patients, octreotide suppressed GH levels to
less than 2.5 µg/L in 29.2%, normalised IGF-I lev-
els in 39.9% of patients, and achieved a significant
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Ferone et al.
Table III. Prevalence of adverse effects during treatment with
dopamine agonists
Adverse effects Prevalence (%)
Hypotension ≈50
Nausea ≈50
Vomiting ≈35
Headache ≈30
Vertigo ≈25
Nasal congestion ≈7
Depression <5
Rare central adverse effects
Psychosis <1
Hallucinations <1
Nightmares <1
Insomnia <1
tumour shrinkage in 38.6%.[16] Signs and symp-
toms of acromegaly were quickly relieved in up to
75% of patients, and despite the lack of biochemi-
cal remission, symptom improvement was reported
in up to 95% of patients.[16] Moreover, prolonged
therapy with this analogue (more than 10 years)
was not associated with tachyphylaxis and desen-
sitisation.[23] Octreotide is generally well tolerated
and adverse effects (table V), which occur in one-
third of patients, disappear within a few days after
the start of treatment. Gallbladder abnormalities
(echogenic sludge, microlithiasis, cholesterol gall-
stones) may disappear spontaneously or after treat-
ment with ursodeoxycholic acid (table V). How-
ever, the treatment should be withdrawn in patients
with symptomatic cholelithiasis.
Since octreotide treatment requires multiple daily
injections, long-acting depot preparations of somat-
ostatin analogues have been developed. These new
formulations usually need 1 or 2 intramuscular
injections every month and significantly improve
patient compliance. Lanreotide is a slow release
cyclic octapeptide preparation able to control hor-
monal hypersecretion, signs, symptoms and com-
plications in one third of patients with an efficacy
similar to that of octreotide.[70-75] Tumour shrink-
age was observed in about 15% of patients.[70,71,75]
However, patient compliance was much better,
considering the longer interval between injec-
tions.[71,75] One study in 22 patients treated for 3
Drugs & Aging 2000 Aug; 17 (2)
Treatment Options in Acromegaly
years showed that, in order to achieve normal GH
and IGF-I levels, an increase in frequency of ad-
ministration to 3 doses per month was necessary in
13 cases.[71] The occurrence and the variety of ad-
verse effects reflected the spectrum observed in pa-
tients treated with octreotide.
Recently, a long-acting depot preparation of oc-
treotide incorporated in microspheres has become
available for clinical use. This formulation pro-
duces sustained elevated blood concentrations of
the drug. Gillis et al.[76] reviewed the data on hor-
mone secretion suppressive activity of this prepa-
ration, and from the records of a total of 175 cases,
the authors observed that GH levels were sup-
pressed to less than 5 µg/L in 86 to 100% of pa-
tients, to less than 2 µg/L in 39 to 75%, and to less
than 1 µg/L in 24 to 40%. IGF-I levels decreased
in parallel and were often normalised, while a
tumour shrinkage greater than 20% was detected
in 71.8% of patients.[76] The majority of studies
using long-acting depot preparations of somato-
statin analogues have been performed in patients
already known to be sensitive to octreotide, which
may increase the efficacy rate of these new formu-
lations.
An additional important observation from this
study was the higher rate of gallbladder abnor-
malities recorded in patients who were previously
treated with subcutaneous octreotide compared with
those treated primarily with the slow release oc-
treotide formulation.[76] The tolerability was sig-
nificantly better and patients experienced only mild
to moderate adverse effects which disappeared
within a few weeks.
Table IV. Somatostatin analogues and somatostatin receptor subtypes: pharmacological binding characteristics of somatostatin and its
octapeptide analoguesa
sst1 sst2
Somatostatin-14 1.1 1.3
Somatostatin-28 2.2 4.1
Octreotide >1000 2.1
Lanreotide >1000 1.8
Vapreotide >1000 5.4
a Affinity constant (Ki) in nmol/L.[64-66]
sst1-5 = somatostatin receptor subtypes 1-5.
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87
Finally, from comparative studies it has been
observed that the 2 depot preparations of somat-
ostatin analogues are both effective in patients with
acromegaly. However, the slow release octreotide
preparation seems more effective than lanreotide
in lowering mean GH levels.[77,78]
4.3 Combined Treatment With Dopamine
Agonists and Somatostatin Analogues
Somatostatin analogues are more effective than
dopamine agonists. However, the combination of
octreotide and bromocriptine was found to in-
duce an additive suppressive effect on GH and
IGF-I levels than the administration of either drug
alone.[79-81] This additive effect suggests that this
treatment schedule might be useful in patients re-
sponsive to but intolerant of high doses, as well as
in patients partially resistant to both compounds
when administered alone. Indeed, the combination
of octreotide and quinagolide lowered GH and
IGF-I levels to a greater degree in a subset (2 out
of 7) of octreotide-resistant patients with acromeg-
aly than single-drug treatment.[56] This effect
might be due to the increased bioavailability of
dopamine agonists when administered in combina-
tion with octreotide, as has been shown in a phar-
macokinetics study, and the effect is more pro-
nounced in patients with GH-secreting adenomas
displaying a co-secretion of PRL.[79-81]
The combination of lanreotide and cabergoline
in therapy-resistant patients also seems to be a
promising new approach.[82] In fact, among 10 pa-
tients that underwent the combined therapy, norm-
alisation of GH and IGF-I levels occurred in 4 and
sst3 sst4 sst5
1.6 0.5 0.9
6.1 1.1 0.1
4.4-35 >1000 5.6
43 66 0.6
30.9 45 0.7
Drugs & Aging 2000 Aug; 17 (2)
88 Ferone et al.

Table V. Adverse effects of somatostatin analogues and their might expect that in the near future pharmacother-
management
apy will become the primary approach to this dis-
Early adverse effects Management
ease. Today, however, it remains unclear whether
Pain at injection site Local alcohol
Abdominal discomfort Pancreatic enzymes
the current formulations of somatostatin analogues
Nausea Pancreatic enzymes and dopamine agonists should be considered as suit-
Flatulence Pancreatic enzymes able primary therapy for acromegaly. In a recent
Diarrhoea Pancreatic enzymes multicentre study in the US, investigators com-
Fat malabsorption Pancreatic enzymes pared the efficacy of octreotide therapy in 2 groups
Late adverse effects of patients with acromegaly.[86] The first group
Biliary sediment Ursodeoxycholic acid received octreotide as primary treatment, while in
Biliary sludge Ursodeoxycholic acid
the second group it was given as secondary treat-
Microlithiasis Ursodeoxycholic acid
Cholesterol gallstones Ursodeoxycholic acid
ment after unsuccessful surgery and/or radiother-
Gastritis (very rare) Treatment withdrawal, apy. The authors demonstrated a comparable low-
somatostatin analogues, proton ering effect in serum IGF-I levels with octreotide,
pump inhibitors or antacids as well as an equivalent improvement in the clini-
Pancreatitis (very rare) Treatment withdrawal,
somatostatin analogues
cal symptoms in both groups. Although this retro-
spective study was not specifically performed to
analyse the differences between primary or second-
ary therapy with somatostatin analogues, these re-
5 patients, respectively after 3 months of treatment.
sults prompted the authors to conclude that in cases
Conversely, lanreotide alone normalised GH levels
after 6 months in only 1 patient.[82] where the possibility of surgical cure is low, be-
cause a large tumour is unlikely to be completely
4.4 Growth Hormone Antagonists resected, octreotide can be considered as primary
therapy for acromegaly.[86] Moreover, not only the
Recently, a novel potential treatment option ap- somatostatin analogues, but also the new formu-
peared for the management of acromegaly. A syn- lations of dopamine agonists are progressively
thetic GH analogue (B-2036-PEG, pegvisomant) emerging and assuming a renewed role in the med-
that antagonises endogenous GH binding to its re- ical treatment of acromegaly.[52-55]
ceptor-binding sites, and a GHRH antagonist that However, most authors agree that transsphen-
blocks the effect of this releasing factor on the oidal adenomectomy is the most cost-effective and
hypothalamus and pituitary are under investiga- rapid initial treatment of acromegaly. Although the
tion.[83,84] A preliminary 12-week, randomised, results of surgery over the last 20 years are difficult
double-blind study has demonstrated the effective- to compare, many recent studies have reported on
ness of the GH receptor antagonist in reducing surgical outcomes using restrictive criteria to de-
IGF-I levels and improving clinical signs and fine ‘cure’ in acromegaly.[25-27,29-31,87] These au-
symptoms in patients with acromegaly.[85] Only thors have reported concordant results of a high
mild adverse effects and no significant antibody success rate of surgery in microadenomas and non-
formation have been observed in this first trial.[85] invasive macroadenomas. Moreover, they have
also documented low recurrence rates, as well as a
5. Pharmacotherapy or Surgery as
high safety of the transsphenoidal approach with
Primary Treatment for Acromegaly?
low complication rates. The majority of these au-
Considering the impact of medical therapy on thors commented on the importance of an experi-
the management of acromegaly in recent years, as enced neurosurgeon, and particularly in the United
well as the progressive development of new com- Kingdom, it has been emphasised that a single sur-
pounds and easier administration schemes, one geon is advisable for all potential patients in a de-

 Adis International Limited. All rights reserved. Drugs & Aging 2000 Aug; 17 (2)
Treatment Options in Acromegaly 89

fined geographic territory.[27,28] This may lead to a

Acromegaly
cure rate higher than 80%.[27]
An important adjunctive topic is the treatment
of elderly patients with acromegaly. Acromeg-
Enclosed Macroadenoma,
aly in elderly patients seems to be milder than in macroadenoma or large invasive
young patients and associated with lower GH lev- microadenoma tumour
els as well as smaller tumours at presentation.[88,89]
These characteristics have raised the question of Pre-operative
somatostatin
whether specific treatment should be given at all analogues
in selected cases.[90] However, considering the in-
crease in life expectancy of the population at large,
with the lowered quality of life of patients with Surgery

acromegaly, as well as the availability of effective Cure

therapy, it is not acceptable to withhold treatment
Persistent GH hypersecretion
only on the basis of age. Moreover, both surgery
and medical therapy have demonstrated a proven Follow-up

efficacy in elderly patients with acromegaly.[88,91] Somatostatin analogues

The lack of a prospective and randomised study
with a large series of patients using the slow-
release formulations of somatostatin analogues in Positive prolactin
immunochemistry
comparison with surgery does not allow definite
conclusions to be drawn concerning the role of
pharmacotherapy as primary treatment for acromeg- Persistent GH hypersecretion
aly. Another important point is the considerable
heterogeneity in the presentation of this disease
which still requires an individualised treatment Change scheme of
schedule by a team of specialists, that should in- somatostatin analogues

clude an endocrinologist with a knowledge of pi-

tuitary diseases, an experienced neurosurgeon, a
neuroradiologist and a neuropathologist. Addi-
tional suggestions might come from a cardiologist,
a rheumatologist, and, lastly but not less impor-
tantly, a trained psychologist. Such close collabo-
ration is helpful in the choice of the most appro-
priate treatment, as well as in making all other
decisions during the follow-up period.
6. Conclusion
In conclusion, a potential algorithm for the man-
agement of acromegaly should include different
options (fig. 1). However, before making a deci-
sion on the treatment schedule in an individual pa-
tient with acromegaly, the criteria that need to be
taken into consideration include the size and inva-
siveness of the pituitary tumour, the general clini-
Add or replace with
dopamine agonists
Persistent GH hypersecretion
Radiotherapy or GH antagonist (?)
Fig. 1. Proposed algorithm for the management of patients with
growth hormone (GH)-secreting pituitary adenomas. The gen-
eral guidelines should be adjusted by evaluating the different
characteristics of individual patients. The final choice should
take into consideration the risk-benefit ratio, costs, age of the
patient and other variables potentially present in every individ-
ual patient. An elderly patient with a macroadenoma might be
primarily treated with somatostatin analogues; however, the pa-
tient might also be pre-treated and then undergo surgery for
tumour debulking. High positivity for prolactin (30%) at immuno-
histochemistry might be a positive predictor for the efficacy of
treatment with dopamine agonists alone or in combination with
somatostatin analogues. The dashed lines indicate alternative
options to evaluate on the basis of individual patient needs.

 Adis International Limited. All rights reserved. Drugs & Aging 2000 Aug; 17 (2)
90
cal conditions as well as the wishes of the patient.
The protocol of therapy chosen for an individual
patient should result in the best life condition and
life expectancy possible.
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Correspondence: Professor Steven W.J. Lamberts, Depart-
ment of Internal Medicine III, University Hospital Dijkzigt,
Dr. Molewaterplein, 40, 3015 GD Rotterdam, The Nether-
lands.
E-mail:lamberts@inw3.azr.nl
Offprints: Dr Diego Ferone, Department of Molecular and
Clinical Endocrinology and Oncology, ‘Federico II’ Univer-
sity, via S. Pansini, 5, 80131, Naples, Italy.
E-mail: dferone@hotmail.com
Drugs & Aging 2000 Aug; 17 (2)