acromegaly is serious endocrinological derangement which , left untreated , reduces life expectancy and results in physiological derangements and complications that may negatively affect a patient 's quality of life .
those patients with residual or recurrent disease are often treated with medication to decrease growth hormone secretion or block its action on peripheral tissues .
these treatments are not universally effective for patients and are sometimes contraindicated . as an adjunct treatment , and sometimes as an alternative treatment , radiosurgery has proven to be an attractive therapy .
it is noninvasive , has few side effects , and is available in many centers internationally [ 13 ] . in the current paper , we first describe the pathophysiology of acromegaly , the existing surgical and medical treatments , and then introduce radiosurgical methods . in particular , we will focus on gamma knife radiosurgery ( gks ) since it has a broader base of supporting literature than alternative forms of stereotactic radiosurgery .
finally , the overall efficacy of gks is described , along with its reported morbidities .
acromegaly is a syndrome caused by elevated levels of circulating growth hormone ( gh ) .
the most common cause of the disorder , accounting for about 98% of cases , is a gh - secreting pituitary adenoma .
rare nonpituitary causes of acromegaly include diverse entities such as hypothalamic hamartomas , small - cell lung cancers , pheochromocytomas , and bronchial carcinoids .
among gh - secreting pituitary adenomas , roughly 60% are pure gh - secreting somatotrope adenomas , while the remainder are mixed mammosomatotropes , which secrete both gh and prolactin ( prl ) and sometimes thyroid - stimulating hormone ( tsh ) .
the symptoms of increased gh are mediated by both the direct effects of gh binding to the gh receptor , activating the jak / stat pathway , and indirectly via insulin - like growth factor 1 ( igf-1 ) .
the combined effects of gh and igf-1 on target tissues lead to bony and soft tissue growth , noted by a characteristic constellation of signs including frontal bossing , prognathism , widely spaced teeth ( due to mandibular growth ) , increased shoe or ring sizes , skin tags , carpal tunnel syndrome , and coarse facial features .
these externally recognizable signs in themselves are not as important to overall morbidity as internal changes , including cardiomegaly and visceromegaly [ 4 , 5 ] .
diabetes mellitus occurs in roughly 25% of patients , and cardiomyopathy with arrhythmia , hypertension , and diastolic dysfunction occurs in 30% .
additionally , colonic polyps are more frequent , as is sleep apnea which occurs in 60% of patients , presumably secondary to soft tissue expansion and macroglossia .
multiple studies through the 1920s to 1990s agreed on a prevalence of roughly 60 per million , a mean age of onset of 44 years , symptoms lasting on average 8 years before diagnosis , and no difference in incidence between men and women .
however , more recent studies place the prevalence at 86 per million , 124 per million , and a remarkably high 1034 per million . however , in addition to being geographically and demographically restricted ( primary care patients in germany ) , this last study was based on a biochemical definition of acromegaly ( elevated igf-1 and gh ) rather than a syndrome definition , and therefore will include many patients who would otherwise not seek treatment .
such a more liberal definition might be one method of discovering at - risk patients earlier in the course of their disease and permitting more time to mitigate the accruing morbidity .
surgery is typically the first line of treatment for acromegaly due to pituitary adenomas provided there are no surgical contraindications .
residual disease is then managed medically with somatostatin analogues , dopamine agonists , or gh receptor antagonists .
most adenomas are resected via the transsphenoidal approach ( transsphenoidal adenomectomy , tsa ) . using either a microscope or endoscope
, the surgeon enters the sphenoid sinus transnasally , then penetrates the sella , and finally debulks and removes the tumor , sparing as much of the normal pituitary as possible . for microadenomas ( < 10  mm in diameter ) , tsas lead to correction of gh levels in ~70% of patients .
only 50% of patients with macroadenomas achieve normalization . for those patients who do not experience normalization of gh levels after surgery , or who are not surgical candidates ,
the lar ( long - acting release ) formulation of octreotide uses polymeric microspheres and is injected monthly .
lanreotide atg ( autogel ) is the only formulation of lanreotide currently available in the united states and is suspended in aqueous solution in microsyringes for subcutaneous delivery by the patient .
the two formulations appear to be equally efficacious and normalize igf - i levels in 5060% of patients [ 1316 ] .
somatostatin analogues appear to induce tumor shrinkage in approximately 42% of patients , when data are pooled across studies .
interestingly , however , tumor shrinkage appears more pronounced in primarily treated patients ( 52% ) as opposed to patients receiving adjunctive , postsurgical treatment ( 21% ) .
dopamine agonists appear to work best in patients whose tumors also secrete prolactin . among dopamine agonists , cabergoline appears to be the most efficacious , resulting in normalization of igf - i levels in 34% of patients .
however , no dopamine agonist alone is as effective as a somatostatin analogue , although there might be synergistic effects when used in conjunction with somatostatin analogues [ 2124 ] .
pegvisomant is a pegylated growth hormone analogue that is subcutaneously injected by patients . in one study , treatment for 12 months led to normalized igf-1 levels in 97% of patients , and treatment for 24 months led to normalization in 76.3% of patients in a different study .
however , the side effects of pegvisomant include transaminitis , lipodystrophy at injection sites , and , most worrisome , possible tumor progression , due to blocking of the normal inhibitory feedback of growth hormone levels of the adenoma [ 2729 ] .
simply put , resective surgery is a means of removing unwanted tissue from the body .
radiosurgery ( rs ) achieves the identical goal but , rather than directly removing cells , induces cell death instead .
this cell death can be induced either directly , via necrosis or apoptosis , or indirectly , by damaging the tissue blood supply .
when inducing cell death , rs uses ionizing radiation , wherein charged particles or photons strip electrons from atoms and molecules , thereby damaging dna , proteins , and other molecules within cells and in the extracellular matrix . when this damage can not be repaired , cells undergo either apoptosis or necrosis [ 30 , 31 ] .
various types of radiosurgery are available , but each works by emitting charged particles or photons .
proton beams , for example , generated by particle accelerators and can be used to target structures deep within the cranium .
this is due , in part , to the characteristic peak and subsequent drop - off of radiation intensity in proton beams  the bragg peak .
the depth of this peak can be modulated and is used to focus the effects of the radiation on particular structures , sparing healthy ones .
the drawback to proton therapy , however , is the high cost and relative scarcity of facilities capable of providing therapeutic proton beams .
the two major techniques are linear accelerators and radioactive isotopes . linear accelerators , like the cyberknife ( accuray inc . ,
sunnyvale , ca ) , produce photons which are then aimed toward deep structures within the brain or spine . to limit damage along the path of the beam
thus , the target of the beam is constant , always receiving radiation , but the intervening structures are exposed only briefly [ 3032 ] . the gamma knife ( elekta ab , stockholm , sweden ) , developed by lars leksell in 1968 ,
each source generates a beam of photons as the cobalt decays , and these beams are focused on a central target within the brain through the use of collimators .
because each individual beam is weak , intervening tissue is exposed to far less radiation than the central target , which is the common focus of all 201 beams .
the gamma knife has been around longer than most linear accelerator radiosurgical devices and is therefore a better - studied tool for use by neurosurgeons , though direct comparisons between the gamma knife and linear accelerators will undoubtedly change the prevailing practices in the future .
a large number of small case series have been carried out to evaluate the effects of gamma knife surgery ( gks ) on acromegaly ( table 1 ) .
most use remission criterion of a normal igf-1 level and many add the criterion gh < 1 to 2  ng / ml , but it should be noted that remission criteria vary across studies .
these criteria are roughly in line with the criteria set forth by the acromegaly consensus group on 2010 ( normal igf-1 and gh < 1  ng / ml ) .
also variable between studies is the follow - up time , along with radiation dose , targeting protocol , and , most critically , pre - gks therapy .
this last note is particularly important since most series include patients who have already received transsphenoidal surgical resection as an inadequate treatment .
unfortunately , the data are not presented in the reviewed papers in such a way as to separate out response rates in patients receiving prior treatment versus those who were treated primarily with gks .
overall , however , the results from these studies suggest that gks is an effective treatment for acromegaly . across the 29 studies and 964 cases examined , 43% of patients achieved remission . the time to remission is not
reliably reported , but most studies agree that the further out from rs patients are examined , the more likely they are to achieve a cure .
for example , vik - mo et al .   showed an increase from 58% of patients with normal igh-1 levels to 86% of patients over the time span of 5 to 10 years after rs .
how exactly the effects of rs continue to evolve over such a protracted time is unknown , but consistent with how rs affects other diseases , like epilepsy   and vestibular schwannoma .
interestingly , there is some ( still debated ) evidence that the use of antiacromegalic medicines prior to irradiation attenuates the effects of gks
. that is , using somatostatin analogues or gh receptor antagonists has been shown in select studies to decrease a patient 's chances of remission [ 3739 ] .
though this has not been thoroughly examined , the mechanism is believed to be suppression of tumor cell cycle , thereby making the cells less prone to radiation - induced damage .
there does not appear to be a correlation between radiation dose and rates of remission ( figure 1 ) .
however , the heterogeneity in study design , follow - up , and definition of remission makes such conclusions fraught .
the most common complication of gks for acromegaly is hypopituitarism , presumably from damage to the normal gland during irradiation , ranging from 0 to 43%   ( table 2 ) .
however , the degree to which such damage is a pure result of gks versus prior surgery , if done , is unclear .
moreover , there is no discernible relationship between radiation dose and the incidence of this complication ( figure 2 ) , though these are very heterogeneous studies and it is possible that better - controlled or larger studies would uncover such relationships if they exist .
other complications are inadequately documented but include headache , epilepsy , carotid artery stenosis , and , more frequently , cranial nerve palsies or neuropathies ( including trigeminal neuralgia and visual decline )   ( table 2 ) .
the rate of visual disturbances seems to be , in the worst case , 11% [ 40 , 41 ] , though most trials either do not report these adverse events or show them to be on the order of 06% ( table 2 ) .
nevertheless , these complications should be viewed in light of the complications inherent to uncontrolled acromegaly or , if being used as an alternative to surgery , the morbidity of an endonasal neurosurgical procedure .
while surgical resection remains the first line of treatment , stereotactic radiosurgery is proving itself a feasible alternative therapy ( when surgery might be contraindicated ) and adjunct ( when surgical resection is unsuccessful in leading to complete disease remission ) .
ultimately , further studies are needed to delineate which patients are most likely to receive benefit from gks , along with ways to improve gks outcomes .
 acromegaly is debilitating disease occasionally refractory to surgical and medical treatment . 
 stereotactic radiosurgery , and in particular gamma knife surgery ( gks ) , has proven to be an effective noninvasive adjunct to traditional treatments , leading to disease remission in a substantial proportion of patients . 
 such remission holds the promise of eliminating the need for expensive medications , along with side effects , as well as sparing patients the damaging sequelae of uncontrolled acromegaly . 
 numerous studies of radiosurgical treatments for acromegaly have been carried out . 
 these illustrate an overall remission rate over 40% . 
 morbidity from radiosurgery is infrequent but can include cranial nerve palsies and hypopituitarism . 
 overall , stereotactic radiosurgery is a promising therapy for patients with acromegaly and deserves further study to refine its role in the treatment of affected patients . 