Advertisement
Mayo Clinic Proceedings Home

Diagnosis and Treatment of Acromegaly: An Update

  • Nazanin Ershadinia
    Affiliations
    Neuroendocrine Unit and Neuroendocrine and Pituitary Tumor Clinical Center, Massachusetts General Hospital, Boston
    Search for articles by this author
  • Nicholas A. Tritos
    Correspondence
    Correspondence: Address to Nicholas A. Tritos, MD, DSc, Massachusetts General Hospital, Neuroendocrine Unit and Neuroendocrine and Pituitary Tumor Clinical Center, 100 Blossom St, Cox 140, Boston, MA 02114.
    Affiliations
    Neuroendocrine Unit and Neuroendocrine and Pituitary Tumor Clinical Center, Massachusetts General Hospital, Boston

    Harvard Medical School, Boston, MA
    Search for articles by this author

      Abstract

      Acromegaly is typically caused by a growth hormone–secreting pituitary adenoma, driving excess secretion of insulin-like growth factor 1. Acromegaly may result in a variety of cardiovascular, respiratory, endocrine, metabolic, musculoskeletal, and neoplastic comorbidities. Early diagnosis and adequate treatment are essential to mitigate excess mortality associated with acromegaly.
      PubMed searches were conducted using the keywords growth hormone, acromegaly, pituitary adenoma, diagnosis, treatment, pituitary surgery, medical therapy, and radiation therapy (between 1981 and 2021).
      The diagnosis of acromegaly is confirmed on biochemical grounds, including elevated serum insulin-like growth factor 1 and lack of growth hormone suppression after glucose administration. Pituitary magnetic resonance imaging is advised in patients with acromegaly to identify an underlying pituitary adenoma.
      Transsphenoidal pituitary surgery is generally first-line therapy for patients with acromegaly. However, patients with larger and invasive tumors (macroadenomas) are often not in remission postoperatively. Medical therapies, including somatostatin receptor ligands, cabergoline, and pegvisomant, can be recommended to patients with persistent disease after surgery. Select patients may also be candidates for preoperative medical therapy. In addition, primary medical therapy has a role for patients without mass effect on the optic chiasm who are unlikely to be cured by surgery. Clinical, endocrine, imaging, histologic, and molecular markers may help predict the response to medical therapy; however, confirmation in prospective studies is needed. Radiation therapy is usually a third-line option and is increasingly administered by a variety of stereotactic techniques. An improved understanding of the pathogenesis of acromegaly may ultimately lead to the design of novel, efficacious therapies for this serious condition.

      Abbreviations and Acronyms:

      GH (growth hormone), GHR (growth hormone receptor), GHRH (growth hormone–releasing hormone), IGF-1 (insulin-like growth factor 1), LAR (long-acting release), SRL (somatostatin receptor ligand), SSTR (somatostatin receptor), STAT (signal transducer and activator of transcription)
      Article Highlights
      • Acromegaly is associated with increased morbidity and mortality that can be mitigated by appropriate management resulting in control of growth hormone excess.
      • The diagnosis of acromegaly is confirmed on the basis of elevated serum insulin-like growth factor 1 and lack of growth hormone suppression after glucose administration.
      • Transsphenoidal pituitary surgery represents the cornerstone of management for most patients with acromegaly.
      • Medical therapy, including first- and second-generation somatostatin receptor ligands, cabergoline, and pegvisomant, has an important role for patients who are not in remission postoperatively but may also have a role as preoperative or primary therapy.
      • Radiation therapy is generally a third-line option and is increasingly administered by a variety of stereotactic techniques that may minimize exposure of healthy brain structures to radiation.
      Acromegaly is generally caused by excessive growth hormone (GH) secretion from a pituitary adenoma and is associated with substantial morbidity and mortality.
      • Melmed S.
      Pituitary-tumor endocrinopathies.
      This article includes an overview of GH physiology and pathogenesis of acromegaly, followed by a discussion of current and evolving approaches to the diagnosis and management of acromegaly.
      • Fleseriu M.
      • Biller B.M.K.
      • Freda P.U.
      • et al.
      A Pituitary Society update to acromegaly management guidelines.
      ,
      • Katznelson L.
      • Laws Jr., E.R.
      • Melmed S.
      • et al.
      Acromegaly: an Endocrine Society clinical practice guideline.
      Factors that may predict the response to surgery or medical therapy are reviewed and future directions are discussed.
      To compile this review, the authors have conducted electronic literature (PubMed) searches using the keywords growth hormone, acromegaly, pituitary adenoma, diagnosis, treatment, pituitary surgery, medical therapy, and radiation therapy (between 1981 and 2021). Articles were cited at the authors’ discretion.

      Growth Hormone Physiology

      Pulsatile GH secretion by anterior pituitary somatotroph cells is normally under dual control exerted by hypothalamic peptides, including stimulation by growth hormone–releasing hormone (GHRH) and inhibition by somatostatin.
      • Giustina A.
      • Veldhuis J.D.
      Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human.
      Ghrelin, predominantly secreted by the gastric fundus but also expressed in the hypothalamus, provides an additional albeit poorly understood stimulus to GH secretion.
      • Giustina A.
      • Veldhuis J.D.
      Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human.
      ,
      • Nass R.M.
      • Gaylinn B.D.
      • Rogol A.D.
      • Thorner M.O.
      Ghrelin and growth hormone: story in reverse.
      In healthy individuals, GH is secreted episodically, predominantly during slow-wave sleep or during exercise.
      • Giustina A.
      • Veldhuis J.D.
      Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human.
      Growth hormone exerts a multitude of effects on metabolism and promotes tissue growth, either directly or indirectly; the indirect GH actions are mediated by GH-induced stimulation of insulin-like growth factor 1 (IGF-1) secretion from hepatocytes and muscle and bone cells, among others, acting in an endocrine or paracrine manner.
      • Melmed S.
      Pathogenesis and diagnosis of growth hormone deficiency in adults.
      In healthy individuals, GH secretion is under negative feedback control by circulating IGF-1, most of which is of hepatic origin. In contrast to circulating GH, serum IGF-1 levels are stable during the course of a 24-hour time interval and serve as an accurate measure of GH action.
      • Giustina A.
      • Veldhuis J.D.
      Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human.
      ,
      • Clemmons D.R.
      Clinical laboratory indices in the treatment of acromegaly.
      ,
      • Clemmons D.R.
      Consensus statement on the standardization and evaluation of growth hormone and insulin-like growth factor assays.
      Growth hormone exerts its actions by binding to its cognate receptor (GHR), a member of the cytokine receptor superfamily.
      • Brooks A.J.
      • Dai W.
      • O'Mara M.L.
      • et al.
      Mechanism of activation of protein kinase JAK2 by the growth hormone receptor.
      The GHR exists in a dimeric form before ligand binding. On GH binding, the GHR undergoes conformational changes that allow Janus kinase 2 (JAK2) activation to occur, leading to phosphorylation and activation of several signal transducers and activators of transcription (STATs), including STAT 1, 3, and 5, which mediate intracellular GH signaling.
      • Brooks A.J.
      • Dai W.
      • O'Mara M.L.
      • et al.
      Mechanism of activation of protein kinase JAK2 by the growth hormone receptor.
      Additional GH signaling pathways have been well recognized.
      • Carter-Su C.
      • Schwartz J.
      • Argetsinger L.S.
      Growth hormone signaling pathways.
      Insulin-like growth factor 1, secreted in response to GH action, mediates its effects by binding to the IGF-1 receptor located in the cell membrane of target cells.
      • Hakuno F.
      • Takahashi S.I.
      IGF1 receptor signaling pathways.
      On ligand binding, the IGF-1 receptor’s intrinsic tyrosine kinase becomes activated, leading to phosphorylation of several substrates (including insulin receptor substrates) and downstream activation of the phosphatidylinositol 3-kinase and Ras-mitogen–activated protein kinase pathways.
      • Hakuno F.
      • Takahashi S.I.
      IGF1 receptor signaling pathways.

      Pathogenesis of Acromegaly

      In most cases, acromegaly occurs as a consequence of chronic exposure to excess GH, secreted from a somatotroph pituitary adenoma in an unregulated manner.
      • Melmed S.
      Pituitary-tumor endocrinopathies.
      These are typically benign tumors and can be histologically classified as densely granulated, sparsely granulated, acidophil stem cell, and mixed somatolactotroph and mammosomatotroph adenomas.
      • Cuevas-Ramos D.
      • Carmichael J.D.
      • Cooper O.
      • et al.
      A structural and functional acromegaly classification.
      ,
      • Lopes M.B.S.
      The 2017 World Health Organization classification of tumors of the pituitary gland: a summary.
      Somatotroph adenomas are generally sporadic.
      • Hage M.
      • Viengchareun S.
      • Brunet E.
      • et al.
      Genomic alterations and complex subclonal architecture in sporadic GH-secreting pituitary adenomas.
      However, familial or syndromic acromegaly occurs in a small minority of patients (Table 1).
      • Boguslawska A.
      • Korbonits M.
      Genetics of acromegaly and gigantism.
      These include familial isolated pituitary adenoma, multiple endocrine neoplasia 1 and 4, X-linked acrogigantism, hereditary paraganglioma-pheochromocytoma syndrome, Carney complex, and neurofibromatosis 1.
      • Boguslawska A.
      • Korbonits M.
      Genetics of acromegaly and gigantism.
      Exogenous GH, administered in excess, will recapitulate the phenotype of patients with acromegaly.
      • Karges B.
      • Pfaffle R.
      • Boehm B.O.
      • Karges W.
      Acromegaly induced by growth hormone replacement therapy.
      Very uncommonly, GHRH secretion from an ectopic neuroendocrine tumor or sellar gangliocytoma may drive GH excess from pituitary somatotrophs.
      • Thorner M.O.
      • Perryman R.L.
      • Cronin M.J.
      • et al.
      Somatotroph hyperplasia. Successful treatment of acromegaly by removal of a pancreatic islet tumor secreting a growth hormone-releasing factor.
      Very rarely, ectopic GH secretion from an islet cell tumor or a lymphoma has been reported.
      • Beuschlein F.
      • Strasburger C.J.
      • Siegerstetter V.
      • et al.
      Acromegaly caused by secretion of growth hormone by a non-Hodgkin's lymphoma.
      ,
      • Melmed S.
      • Ezrin C.
      • Kovacs K.
      • Goodman R.S.
      • Frohman L.A.
      Acromegaly due to secretion of growth hormone by an ectopic pancreatic islet-cell tumor.
      Table 1Genetics of Acromegaly
      Condition or syndromeGeneMutation typeInheritanceCommon features
      Familial isolated pituitary adenomaAIPInactivatingAD (incomplete penetrance)AIP gene mutations are present in about 20%-30% of patients with familial isolated pituitary adenoma; most pituitary tumors are GH or prolactin secreting
      Multiple endocrine neoplasia 1MEN1InactivatingADCardinal manifestations include primary hyperparathyroidism, pituitary adenomas, and enteropancreatic neuroendocrine tumors
      Multiple endocrine neoplasia 4CDKN1BInactivatingADCardinal manifestations include primary hyperparathyroidism and pituitary adenomas
      X-linked acrogigantismGPR101Gene microduplicationX-linkedAcrogigantism of onset in early childhood
      Hereditary paraganglioma-pheochromocytoma syndromeSDHA-D, SDHAF2InactivatingADPheochromocytomas and paragangliomas, pituitary adenomas (very low penetrance)
      McCune-Albright syndromeGNASSomatic mosaicism; activatingNoneFibrous dysplasia, café-au-lait spots, endocrine hyperfunction (including GH/prolactin excess)
      Carney complexPRKAR1A, PRKACBInactivating (PRKAR1A); activating (PRKACB)ADSpotty skin pigmentation, myxomas, thyroid and testicular tumors, primary pigmented nodular adrenocortical disease, GH/prolactin excess
      Neurofibromatosis 1NF1InactivatingADCafé-au-lait spots, axillary freckling, neurofibromas, Lisch nodules, optic pathway gliomas, pituitary adenomas, pheochromocytomas
      Sporadic acromegalyGNAS (gsp)Somatic (tumor); activatingNoneMutation present in 40% of sporadic GH-secreting adenomas
      AD, autosomal dominant; AIP, aryl hydrocarbon receptor–interacting protein; CDKN1B, cyclin-dependent kinase inhibitor 1B; GH, growth hormone; GNAS, guanine nucleotide–binding protein, alpha stimulating; GPR101, G protein–coupled receptor 101; MEN1, multiple endocrine neoplasia 1; NF1, neurofibromatosis 1; PRKAR1A, protein kinase A, regulatory subunit 1A; PRKACB, protein kinase A, catalytic subunit B; SDHA-D, succinate dehydrogenase, subunit A-D; SDHAF2, succinate dehydrogenase complex assembly factor 2.
      Somatotroph pituitary adenomas generally secrete GH autonomously, leading to GH and IGF-1 excess. However, silent somatotroph adenomas are also well recognized and are not associated with a syndrome of hormone excess.
      • Langlois F.
      • Woltjer R.
      • Cetas J.S.
      • Fleseriu M.
      Silent somatotroph pituitary adenomas: an update.
      Patients whose disease onset precedes epiphyseal fusion develop increased linear growth, leading to gigantism. In contrast, patients whose tumors occur after epiphyseal maturation develop acromegaly, characterized by typical facial features (frontal bossing, prominent cheeks and nose, thickened lips, prognathism, widely spaced teeth, and macroglossia), acral enlargement, and organomegaly. In addition, a multitude of manifestations have been associated with chronic GH excess, including cardiovascular (hypertension, ventricular hypertrophy, heart failure, arrhythmias), pulmonary (obstructive sleep apnea), neoplastic (colon polyps, colon cancer, differentiated thyroid cancer), endocrine and metabolic (insulin resistance and diabetes mellitus, oligomenorrhea), and musculoskeletal (vertebral deformities, osteoarthropathy, carpal tunnel syndrome) comorbidities.
      • Giustina A.
      • Barkan A.
      • Beckers A.
      • et al.
      A consensus on the diagnosis and treatment of acromegaly comorbidities: an update.
      About 70% of somatotroph adenomas are macroadenomas, defined as tumors exceeding 1 cm in largest diameter. Pituitary macroadenomas may exert local mass effect on the normal pituitary gland or surrounding structures, leading to hypopituitarism, headache, or visual compromise.

      Diagnosis of Acromegaly

      Young patients with excessive linear growth during childhood or adolescence should be evaluated for the presence of GH excess. In adults, the diagnosis of acromegaly should be considered in patients presenting with acral enlargement or suggestive facial features as well as in those presenting with a constellation of symptoms, signs, or conditions associated with acromegaly, including frequent headache, excessive perspiration, hypertension, sleep apnea, oligomenorrhea, arthralgias, carpal tunnel syndrome, and type 2 diabetes mellitus.
      • Caron P.
      • Brue T.
      • Raverot G.
      • et al.
      Signs and symptoms of acromegaly at diagnosis: the physician's and the patient's perspectives in the ACRO-POLIS study [erratum appears in Endocrine. 2019;63(1):130].
      A high index of suspicion is needed to consider the diagnosis, particularly in patients presenting earlier in the course of the disease. An interval of several years between symptom onset and diagnosis is common.
      • Reid T.J.
      • Post K.D.
      • Bruce J.N.
      • Nabi Kanibir M.
      • Reyes-Vidal C.M.
      • Freda P.U.
      Features at diagnosis of 324 patients with acromegaly did not change from 1981 to 2006: acromegaly remains under-recognized and under-diagnosed.
      A longer interval between disease onset and diagnosis has been associated with higher all-cause mortality and a higher number of comorbidities, affirming the importance of early detection and prompt management.
      • Esposito D.
      • Ragnarsson O.
      • Johannsson G.
      • Olsson D.S.
      Prolonged diagnostic delay in acromegaly is associated with increased morbidity and mortality.
      Analysis of facial features on patients’ photographs has been reported to be helpful in detecting acromegaly in patients with subtle features.
      • Schneider H.J.
      • Kosilek R.P.
      • Gunther M.
      • et al.
      A novel approach to the detection of acromegaly: accuracy of diagnosis by automatic face classification.
      Machine learning approaches are being studied and may allow earlier identification of patients with this disease.
      • Kong X.
      • Gong S.
      • Su L.
      • Howard N.
      • Kong Y.
      Automatic detection of acromegaly from facial photographs using machine learning methods.
      In one study, machine learning methodology could detect acromegaly, based on analysis of facial photographs, with a sensitivity of 96%, a specificity of 96%, a positive predictive value of 96%, and a negative predictive value of 95%.
      • Kong X.
      • Gong S.
      • Su L.
      • Howard N.
      • Kong Y.
      Automatic detection of acromegaly from facial photographs using machine learning methods.
      Serum IGF-1, measured by immunoassay or liquid chromatography/tandem mass spectrometry, exhibits no significant diurnal variation and is the diagnostic test of choice when GH excess is suspected.
      • Bonert V.
      • Carmichael J.
      • Wu Z.
      • et al.
      Discordance between mass spectrometry and immunometric IGF-1 assay in pituitary disease: a prospective study.
      • Bystrom C.
      • Sheng S.
      • Zhang K.
      • Caulfield M.
      • Clarke N.J.
      • Reitz R.
      Clinical utility of insulin-like growth factor 1 and 2; determination by high resolution mass spectrometry.
      • Johannsson G.
      • Bidlingmaier M.
      • Biller B.M.K.
      • et al.
      Growth Hormone Research Society perspective on biomarkers of GH action in children and adults.
      The test is generally accurate when it is performed in a reliable assay; however, repeating this test is recommended, particularly when the result is borderline or does not fit with the clinical picture. Considering that serum IGF-1 levels decline with advancing age during adulthood, it is critical that reference intervals be carefully established for patients of different age groups.
      • Melmed S.
      Pathogenesis and diagnosis of growth hormone deficiency in adults.
      Serum IGF-1 levels normally rise during adolescence as well as in pregnancy, thereby potentially confounding test interpretation in these groups. On the other hand, serum IGF-1 levels can be blunted in patients with acromegaly exhibiting resistance to GH action, including those with advanced liver or kidney disease, severe hypothyroidism, malnutrition, anorexia, and poorly controlled diabetes mellitus, or in women receiving oral estrogen.
      • Schilbach K.
      • Strasburger C.J.
      • Bidlingmaier M.
      Biochemical investigations in diagnosis and follow up of acromegaly.
      Estrogen induces suppressor of cytokine signaling 2 (SOC2) in hepatocytes, thereby blunting GH-mediated signaling and IGF-1 secretion.
      • Leung K.C.
      • Doyle N.
      • Ballesteros M.
      • et al.
      Estrogen inhibits GH signaling by suppressing GH-induced JAK2 phosphorylation, an effect mediated by SOCS-2.
      Randomly sampled serum GH levels, measured by immunoassays, are generally not recommended for the diagnosis of acromegaly but have been associated with biochemical outcomes of both surgical and medical treatments. Serum GH levels, measured every 30 minutes for 2 hours after the administration of an oral glucose load (75 g), can be helpful in establishing the diagnosis of acromegaly. In most healthy individuals, GH levels decrease to a nadir below 0.4 μg/L after glucose administration (using sensitive immunoassays).
      • Schilbach K.
      • Gar C.
      • Lechner A.
      • et al.
      Determinants of the growth hormone nadir during oral glucose tolerance test in adults.
      In contrast, patients with acromegaly fail to suppress serum GH levels after oral administration of glucose. However, the optimal diagnostic cut point of this test has been a matter of debate.
      • Katznelson L.
      • Laws Jr., E.R.
      • Melmed S.
      • et al.
      Acromegaly: an Endocrine Society clinical practice guideline.
      ,
      • Ribeiro-Oliveira Jr., A.
      • Faje A.T.
      • Barkan A.L.
      Limited utility of oral glucose tolerance test in biochemically active acromegaly.
      A somewhat higher diagnostic cut point (1 μg/L) for nadir GH levels has been suggested for routine clinical use in the diagnosis of acromegaly, taking into consideration the more limited accuracy of some GH immunoassays currently in use.
      • Katznelson L.
      • Laws Jr., E.R.
      • Melmed S.
      • et al.
      Acromegaly: an Endocrine Society clinical practice guideline.
      Once the diagnosis of acromegaly has been confirmed on the basis of the results of endocrine testing, a pituitary magnetic resonance imaging (MRI) examination should be obtained to detect a pituitary adenoma, which is the cause of acromegaly in most cases. A computed tomography examination of the brain (with special attention to the sella) can be obtained in patients with contraindications to MRI. In one study, 3.2% of patients (6 of 190) with acromegaly had no evident pituitary tumor on standard MRI.
      • Lonser R.R.
      • Kindzelski B.A.
      • Mehta G.U.
      • Jane Jr., J.A.
      • Oldfield E.H.
      Acromegaly without imaging evidence of pituitary adenoma.
      Among the rare patients with acromegaly who have no evident tumor on pituitary MRI, serum GHRH levels and cross-sectional imaging of the chest and abdomen can be helpful in detecting an ectopic source.
      • Thorner M.O.
      • Perryman R.L.
      • Cronin M.J.
      • et al.
      Somatotroph hyperplasia. Successful treatment of acromegaly by removal of a pancreatic islet tumor secreting a growth hormone-releasing factor.
      ,
      • Melmed S.
      • Ezrin C.
      • Kovacs K.
      • Goodman R.S.
      • Frohman L.A.
      Acromegaly due to secretion of growth hormone by an ectopic pancreatic islet-cell tumor.

      Management of Acromegaly

      Overview

      Patients with uncontrolled acromegaly experience diminished survival, which has been attributed to increased risks of cardiovascular, cerebrovascular, respiratory, and neoplastic disease.
      • Ritvonen E.
      • Loyttyniemi E.
      • Jaatinen P.
      • et al.
      Mortality in acromegaly: a 20-year follow-up study.
      ,
      • Dal J.
      • Leisner M.Z.
      • Hermansen K.
      • et al.
      Cancer incidence in patients with acromegaly: a cohort study and meta-analysis of the literature.
      Patients whose disease is controlled, including those with normal serum IGF-1 and low serum GH levels (random GH level <2.5 μg/L in older polyclonal immunoassays or GH level <1.0 μg/L in newer monoclonal immunoassays), have mortality rates that are indistinguishable from those in the general population.
      • Holdaway I.M.
      • Bolland M.J.
      • Gamble G.D.
      A meta-analysis of the effect of lowering serum levels of GH and IGF-I on mortality in acromegaly.
      Broadly, the goals of treatment in patients with acromegaly include normalization of GH secretion or (at least) GH action as indicated by a normal IGF-1 level as well as by resolution of tumor-induced mass effects, acromegaly-related symptoms, and associated comorbidities, all aiming at mitigating excess mortality while preserving normal pituitary function.
      • Giustina A.
      • Barkhoudarian G.
      • Beckers A.
      • et al.
      Multidisciplinary management of acromegaly: a consensus.
      Management options for patients with acromegaly include pituitary surgery, medical therapy, and radiation therapy (Table 2).
      • Giustina A.
      • Barkhoudarian G.
      • Beckers A.
      • et al.
      Multidisciplinary management of acromegaly: a consensus.
      Pituitary surgery is the cornerstone of treatment for most patients.
      • Katznelson L.
      • Laws Jr., E.R.
      • Melmed S.
      • et al.
      Acromegaly: an Endocrine Society clinical practice guideline.
      Medical therapy and radiation therapy generally represent second-line and third-line options, respectively, and are typically advised for patients who are not in remission postoperatively (Figure). In addition, preoperative medical therapy may have a role in the management of patients with sleep apnea or heart failure to reduce perioperative risk.
      • Katznelson L.
      • Laws Jr., E.R.
      • Melmed S.
      • et al.
      Acromegaly: an Endocrine Society clinical practice guideline.
      Some studies have reported that preoperative medical therapy with somatostatin receptor ligands (SRLs) may improve surgical remission rates.
      • Katznelson L.
      • Laws Jr., E.R.
      • Melmed S.
      • et al.
      Acromegaly: an Endocrine Society clinical practice guideline.
      ,
      • Bollerslev J.
      • Heck A.
      • Olarescu N.C.
      Management of endocrine disease: individualised management of acromegaly.
      ,
      • Yao S.
      • Chen W.L.
      • Tavakol S.
      • et al.
      Predictors of postoperative biochemical remission in acromegaly.
      However, methodologic concerns and low remission rates among the groups of patients who underwent surgery without preoperative medical therapy have raised concerns about the generalizability of some of these studies.
      • Fougner S.L.
      • Bollerslev J.
      • Svartberg J.
      • Oksnes M.
      • Cooper J.
      • Carlsen S.M.
      Preoperative octreotide treatment of acromegaly: long-term results of a randomised controlled trial.
      ,
      • Shen M.
      • Shou X.
      • Wang Y.
      • et al.
      Effect of presurgical long-acting octreotide treatment in acromegaly patients with invasive pituitary macroadenomas: a prospective randomized study.
      Select patients may also be candidates for primary medical therapy with SRLs, including those whose tumors do not compress the optic apparatus and are unlikely to be cured by surgery (because of tumor extension into the cavernous sinuses or clivus) and those who decline surgery.
      • Katznelson L.
      • Laws Jr., E.R.
      • Melmed S.
      • et al.
      Acromegaly: an Endocrine Society clinical practice guideline.
      Deep learning and other artificial intelligence technologies may be helpful in accurately predicting the response to therapy.
      • Wildemberg L.E.
      • da Silva Camacho A.H.
      • Miranda R.L.
      • et al.
      Machine learning–based prediction model for treatment of acromegaly with first-generation somatostatin receptor ligands.
      In addition to treatment directed at the underlying tumor and control of GH excess, careful attention is needed to identify and to manage acromegaly-associated comorbidities, which may lead to impaired quality of life (even in patients in remission) and excess mortality.
      • Giustina A.
      • Barkan A.
      • Beckers A.
      • et al.
      A consensus on the diagnosis and treatment of acromegaly comorbidities: an update.
      To detect such comorbidities, several assessments have been recommended, including blood pressure measurements, electrocardiography, echocardiography, testing for sleep apnea (sleep study), evaluation of glycemia and anterior pituitary function, bone mineral density and vertebral morphometry (by X rays), screening colonoscopy, and assessments of quality of life.
      • Giustina A.
      • Barkan A.
      • Beckers A.
      • et al.
      A consensus on the diagnosis and treatment of acromegaly comorbidities: an update.
      Table 2Management Options for Acromegaly
      CSF, cerebrospinal fluid; D2, dopamine receptor 2; GH, growth hormone; GHR, growth hormone receptor; IGF-1, insulin-like growth factor 1; SSTR, somatostatin receptor.
      Treatment modalityMechanism of actionAdvantagesLimitations
      Transsphenoidal surgeryNot applicableRapid control of GH excess in most patients with microadenomas

      Decompression of the optic chiasm in patients with macroadenomas

      Tumor control
      Less effective in achieving biochemical control in patients with macroadenomas

      Recurrence risk (low probability)

      Complications (low risk in experienced hands): epistaxis, bleeding, CSF leak, meningitis, stroke, hypopituitarism, hyponatremia
      Medical therapy
       Somatostatin receptor ligandsSSTR agonists
      First-generation somatostatin receptor ligands (octreotide acetate, octreotide LAR, lanreotide depot, oral octreotide) activate SSTR2 and, to a lesser extent, SSTR5; second-generation somatostatin receptor ligands (pasireotide LAR) activate SSTR1, 2, 3, and 5 (activation of SSTR2 and SSTR5 is considered to be central to drug effectiveness).
      Can be effective in achieving both biochemical and tumor controlAdverse effects: diarrhea, dyspepsia, cholelithiasis, hair loss, sinus bradycardia, diabetes mellitus, hyperglycemia
       CabergolineD2 receptor agonistMore effective in patients with lower baseline IGF-1 levels; orally activeAdverse effects: nausea, orthostasis, headache, nasal congestion, constipation, digital vasospasm, (possibly) cardiac valvulopathy, impulse control disorders
       PegvisomantGHR antagonistRapid control of IGF-1 levels in most patientsNo tumor control

      Adverse effects: injection site reactions, rash, transaminitis
      Radiation therapyNot applicableTumor control is achieved in most patientsBiochemical control is slowly achieved in some patients in the absence of medical therapy

      Risks of anterior hypopituitarism (high probability), cranial neuropathies (low probability); possible risks of secondary tumors or stroke (low probability)
      a CSF, cerebrospinal fluid; D2, dopamine receptor 2; GH, growth hormone; GHR, growth hormone receptor; IGF-1, insulin-like growth factor 1; SSTR, somatostatin receptor.
      b First-generation somatostatin receptor ligands (octreotide acetate, octreotide LAR, lanreotide depot, oral octreotide) activate SSTR2 and, to a lesser extent, SSTR5; second-generation somatostatin receptor ligands (pasireotide LAR) activate SSTR1, 2, 3, and 5 (activation of SSTR2 and SSTR5 is considered to be central to drug effectiveness).
      Figure thumbnail gr1
      FigureSuggested management of patients with acromegaly caused by a somatotroph pituitary adenoma. Factors that are predictive of the response to medical therapy may be considered in making decisions about choice of medical therapy. GH, growth hormone; IGF-I, insulin-like growth factor 1; MRI, magnetic resonance imaging; OGTT, oral glucose tolerance test (growth hormone suppression test); SRL, somatostatin receptor ligand.

      Pituitary Surgery

      Pituitary surgery is generally carried out transsphenoidally using an endoscope in most cases, although some surgeons may still use an operating microscope. Use of the endoscope may be associated with a higher rate of gross total resection but not a difference in endocrine remission.
      • Chen C.J.
      • Ironside N.
      • Pomeraniec I.J.
      • et al.
      Microsurgical versus endoscopic transsphenoidal resection for acromegaly: a systematic review of outcomes and complications.
      ,
      • Fathalla H.
      • Cusimano M.D.
      • Di Ieva A.
      • et al.
      Endoscopic versus microscopic approach for surgical treatment of acromegaly.
      Pituitary surgery requires substantial expertise to achieve optimal outcomes with regard to endocrine remission and tumor resection while minimizing perioperative complications, including epistaxis, cerebrospinal fluid leak, tumor bed hemorrhage, meningitis, stroke, diabetes insipidus, hyponatremia, and anterior hypopituitarism.
      • Buchfelder M.
      • Schlaffer S.M.
      The surgical treatment of acromegaly.
      Perioperative mortality rates are below 1% in expert hands.
      When transsphenoidal surgery is performed by experienced surgeons, endocrine remission can be achieved in up to 90% of patients with acromegaly who have tumors smaller than 1 cm in maximal diameter (microadenomas).
      • Swearingen B.
      • Barker 2nd, F.G.
      • Katznelson L.
      • et al.
      Long-term mortality after transsphenoidal surgery and adjunctive therapy for acromegaly.
      In contrast, patients with larger tumors (macroadenomas) achieve endocrine remission in 50% to 60% of cases after transsphenoidal surgery.
      • Buchfelder M.
      • Schlaffer S.M.
      The surgical treatment of acromegaly.
      • Swearingen B.
      • Barker 2nd, F.G.
      • Katznelson L.
      • et al.
      Long-term mortality after transsphenoidal surgery and adjunctive therapy for acromegaly.
      • Babu H.
      • Ortega A.
      • Nuno M.
      • et al.
      Long-term endocrine outcomes following endoscopic endonasal transsphenoidal surgery for acromegaly and associated prognostic factors.
      In addition to surgical expertise and tumor size, tumor invasiveness and serum GH levels predict the likelihood of postoperative remission.
      • Buchfelder M.
      • Schlaffer S.M.
      The surgical treatment of acromegaly.
      • Swearingen B.
      • Barker 2nd, F.G.
      • Katznelson L.
      • et al.
      Long-term mortality after transsphenoidal surgery and adjunctive therapy for acromegaly.
      • Babu H.
      • Ortega A.
      • Nuno M.
      • et al.
      Long-term endocrine outcomes following endoscopic endonasal transsphenoidal surgery for acromegaly and associated prognostic factors.
      • Coopmans E.C.
      • Postma M.R.
      • Wolters T.L.C.
      • et al.
      Predictors for remission after transsphenoidal surgery in acromegaly: a Dutch multicenter study.
      • Anthony J.R.
      • Alwahab U.A.
      • Kanakiya N.K.
      • et al.
      Significant elevation of growth hormone level impacts surgical outcomes in acromegaly.
      Immediate postoperative GH levels represent a strong predictor of long-term remission.
      • Kim E.H.
      • Oh M.C.
      • Lee E.J.
      • Kim S.H.
      Predicting long-term remission by measuring immediate postoperative growth hormone levels and oral glucose tolerance test in acromegaly.
      Patients with pituitary adenomas that extend into the cavernous sinuses, clivus, or dura are significantly less likely to achieve endocrine remission after transsphenoidal surgery and will generally require additional therapy.
      • Coopmans E.C.
      • Postma M.R.
      • Wolters T.L.C.
      • et al.
      Predictors for remission after transsphenoidal surgery in acromegaly: a Dutch multicenter study.
      ,
      • Agrawal N.
      • Ioachimescu A.G.
      Prognostic factors of biochemical remission after transsphenoidal surgery for acromegaly: a structured review.
      However, subtotal tumor resection (debulking) improves tumor response to SRL therapy.
      • Fahlbusch R.
      • Kleinberg D.
      • Biller B.
      • et al.
      Surgical debulking of pituitary adenomas improves responsiveness to octreotide lar in the treatment of acromegaly.
      Transsphenoidal surgery is generally effective in decompressing the optic chiasm, thereby improving vision in most patients who present with visual compromise as a result of mass effect exerted by a pituitary adenoma. Several symptoms and comorbidities associated with acromegaly also improve in patients who are in biochemical remission postoperatively, and organomegaly regresses.
      • Giustina A.
      • Barkan A.
      • Beckers A.
      • et al.
      A consensus on the diagnosis and treatment of acromegaly comorbidities: an update.
      ,
      • Zhang Z.
      • Li Q.
      • He W.
      • et al.
      The comprehensive impact on human body induced by resolution of growth hormone excess.
      However, some comorbidities may persist (hypertension) or even progress (osteoarthropathy) despite achievement of biochemical control of GH excess and require additional treatment.
      • Giustina A.
      • Barkan A.
      • Beckers A.
      • et al.
      A consensus on the diagnosis and treatment of acromegaly comorbidities: an update.

      Medical Therapy

      Current options for medical treatment of patients with acromegaly include SRLs, cabergoline, and pegvisomant (Table 2). Several SRLs and pegvisomant are Food and Drug Administration approved for treatment of patients with acromegaly. Cabergoline has been used off-label in this population of patients.
      First-generation SRLs (octreotide acetate, octreotide long-acting release [LAR], lanreotide depot, oral octreotide) and a second-generation SRL (pasireotide LAR) activate distinct subsets of somatostatin receptors (SSTRs), thereby inhibiting GH secretion while promoting apoptosis and exerting antiproliferative effects.
      • Gunther T.
      • Tulipano G.
      • Dournaud P.
      • et al.
      International Union of Basic and Clinical Pharmacology. CV. Somatostatin receptors: structure, function, ligands, and new nomenclature.
      These agents signal through both canonical and noncanonical pathways. They engage Gi proteins to inhibit adenylate cyclase and calcium channels while activating potassium channels, leading to membrane hyperpolarization.
      • Gunther T.
      • Tulipano G.
      • Dournaud P.
      • et al.
      International Union of Basic and Clinical Pharmacology. CV. Somatostatin receptors: structure, function, ligands, and new nomenclature.
      These events culminate in decreased GH secretion. In addition, SRLs activate pertussis toxin–independent G proteins, leading to phospholipase C activation and inositol 1,4,5-triphosphate generation.
      • Gunther T.
      • Tulipano G.
      • Dournaud P.
      • et al.
      International Union of Basic and Clinical Pharmacology. CV. Somatostatin receptors: structure, function, ligands, and new nomenclature.
      Furthermore, the tyrosine phosphatases SHP-1 and SHP-2 are activated in response to SSTR activation, as is the tyrosine kinase Src.
      • Gunther T.
      • Tulipano G.
      • Dournaud P.
      • et al.
      International Union of Basic and Clinical Pharmacology. CV. Somatostatin receptors: structure, function, ligands, and new nomenclature.
      These pathways culminate in the up-regulation of antiproliferative and proapoptotic pathways that result in antitumor effects.
      First-generation SRLs engage SSTR-2 primarily and SSTR-5 secondarily to exert their salutary effects in acromegaly.
      • Melmed S.
      Pituitary-tumor endocrinopathies.
      In a meta-analysis of 90 studies, administration of first-generation SRLs resulted in IGF-1 normalization and GH control in 54% and 55% of 3787 patients with acromegaly, respectively.
      • Carmichael J.D.
      • Bonert V.S.
      • Nuno M.
      • Ly D.
      • Melmed S.
      Acromegaly clinical trial methodology impact on reported biochemical efficacy rates of somatostatin receptor ligand treatments: a meta-analysis.
      There was no difference in efficacy between octreotide LAR and lanreotide depot. Studies of first-generation SRLs in unselected patients have reported somewhat lower efficacy with regard to biochemical control (achieved in about 30% to 40% of patients).
      • Caron P.J.
      • Bevan J.S.
      • Petersenn S.
      • et al.
      Tumor shrinkage with lanreotide Autogel 120 mg as primary therapy in acromegaly: results of a prospective multicenter clinical trial.
      Approximately 60% of patients with acromegaly controlled on parenteral first-generation SRL therapy maintain biochemical control after being switched to oral octreotide.
      • Samson S.L.
      • Nachtigall L.B.
      • Fleseriu M.
      • et al.
      Maintenance of acromegaly control in patients switching from injectable somatostatin receptor ligands to oral octreotide.
      Some degree of tumor shrinkage has been reported in 53% of 1685 patients in another meta-analysis of 41 studies involving first-generation SRL therapy.
      • Giustina A.
      • Mazziotti G.
      • Torri V.
      • Spinello M.
      • Floriani I.
      • Melmed S.
      Meta-analysis on the effects of octreotide on tumor mass in acromegaly.
      Several symptoms and comorbidities associated with acromegaly improve in response to SRL therapy, including headache, soft tissue swelling, ventricular function, and sleep apnea.
      • Giustina A.
      • Barkhoudarian G.
      • Beckers A.
      • et al.
      Multidisciplinary management of acromegaly: a consensus.
      Several factors have been reported as possible predictors of biochemical response to first-generation SRL therapy, including age and sex of the patient, baseline GH and IGF-1 levels, genetic abnormalities, histopathologic features, and imaging characteristics of the underlying tumor (Table 3).
      • Bollerslev J.
      • Heck A.
      • Olarescu N.C.
      Management of endocrine disease: individualised management of acromegaly.
      ,
      • Petersenn S.
      • Houchard A.
      • Sert C.
      • Caron P.J.
      PRIMARYS Study Group
      Predictive factors for responses to primary medical treatment with lanreotide autogel 120 mg in acromegaly: post hoc analyses from the PRIMARYS study.
      • Brzana J.
      • Yedinak C.G.
      • Gultekin S.H.
      • Delashaw J.B.
      • Fleseriu M.
      Growth hormone granulation pattern and somatostatin receptor subtype 2A correlate with postoperative somatostatin receptor ligand response in acromegaly: a large single center experience.
      • Galm B.P.
      • Buckless C.
      • Swearingen B.
      • et al.
      MRI texture analysis in acromegaly and its role in predicting response to somatostatin receptor ligands.
      Table 3Possible Predictors of Biochemical Response to Medical Therapy for Acromegaly
      Drug class (agents)Factors associated with higher responseFactors associated with lower response
      First-generation SRLs (octreotide acetate, octreotide LAR, lanreotide depot, oral octreotide)Clinical: older age, female sex

      Genetic: somatic gsp mutation

      Histologic/molecular markers: densely granulated tumors, higher SSTR2 expression, lower Ki-67 index, higher E-cadherin expression, higher ZAC1 expression, lower β-arrestin expression, higher RKIP expression

      Imaging characteristics: T2-hypointense tumors, higher maximal pixel intensity on image texture analysis
      Endocrine: higher GH or IGF-1 levels at baseline

      Genetic: AIP gene mutation, GPR101 gene amplification, McCune-Albright syndrome

      Histologic/molecular markers: higher SSTR5 expression, lower AIP expression
      Second-generation SRL (pasireotide LAR)Higher SSTR2 or SSTR5 expression

      Imaging characteristics: T2 signal intensity
      CabergolineLower baseline serum IGF-1

      Previous radiation therapy to the sella
      PegvisomantLower BMI

      Lower baseline serum IGF-1
      Diabetes mellitus
      BMI, body mass index; GH, growth hormone; IGF-1, insulin-like growth factor 1; LAR, long-acting release; RKIP, Raf kinase inhibitory protein; SRL, somatostatin receptor ligand; SSTR, somatostatin receptor.
      In a study of 88 patients who were treated with lanreotide depot at maximal doses for 48 weeks, older age (odds ratio [OR], 2.2 per higher decade of life) and female sex (OR, 2.9) were associated with biochemical control of GH excess (normal serum IGF-1 and GH level below 2.5 μg/L).
      • Petersenn S.
      • Houchard A.
      • Sert C.
      • Caron P.J.
      PRIMARYS Study Group
      Predictive factors for responses to primary medical treatment with lanreotide autogel 120 mg in acromegaly: post hoc analyses from the PRIMARYS study.
      In the same study, lower serum IGF-1 levels at baseline were associated with a higher likelihood of achieving biochemical control.
      • Petersenn S.
      • Houchard A.
      • Sert C.
      • Caron P.J.
      PRIMARYS Study Group
      Predictive factors for responses to primary medical treatment with lanreotide autogel 120 mg in acromegaly: post hoc analyses from the PRIMARYS study.
      Lower serum GH levels at baseline have also been reported as being predictive of IGF-1 normalization in response to SRL therapy in some but not other studies.
      • Petersenn S.
      • Houchard A.
      • Sert C.
      • Caron P.J.
      PRIMARYS Study Group
      Predictive factors for responses to primary medical treatment with lanreotide autogel 120 mg in acromegaly: post hoc analyses from the PRIMARYS study.
      ,
      • Newman C.B.
      • Melmed S.
      • Snyder P.J.
      • et al.
      Safety and efficacy of long-term octreotide therapy of acromegaly: results of a multicenter trial in 103 patients—a clinical research center study [erratum appears in J Clin Endocrinol Metab. 1995;80(11):3238].
      Germline genetic abnormalities are present in a minority of patients with acromegaly and may influence the response to first-generation SRL therapy.
      • Boguslawska A.
      • Korbonits M.
      Genetics of acromegaly and gigantism.
      Patients with inactivating mutations in the aryl hydrocarbon receptor–interacting protein (AIP) gene who develop acromegaly have been reported to exhibit lower GH and IGF-1 decrements after SRL administration and are less likely to show tumor shrinkage on such therapy.
      • Daly A.F.
      • Tichomirowa M.A.
      • Petrossians P.
      • et al.
      Clinical characteristics and therapeutic responses in patients with germ-line AIP mutations and pituitary adenomas: an international collaborative study.
      In patients with AIP-mutated somatotroph adenomas, miR-34a is up-regulated and appears to promote resistance to SRL therapy.
      • Bogner E.M.
      • Daly A.F.
      • Gulde S.
      • et al.
      miR-34a is upregulated in AIP-mutated somatotropinomas and promotes octreotide resistance.
      Patients with GPR101 gene amplification develop acrogigantism of early onset.
      • Beckers A.
      • Lodish M.B.
      • Trivellin G.
      • et al.
      X-linked acrogigantism syndrome: clinical profile and therapeutic responses.
      These patients are unlikely to show IGF-1 normalization in response to SRL therapy.
      • Beckers A.
      • Lodish M.B.
      • Trivellin G.
      • et al.
      X-linked acrogigantism syndrome: clinical profile and therapeutic responses.
      Patients with the McCune-Albright syndrome may also show a poor biochemical response to SRL therapy.
      • Salenave S.
      • Boyce A.M.
      • Collins M.T.
      • Chanson P.
      Acromegaly and McCune-Albright syndrome.
      Somatic (tumor) mutations in the GNAS gene (gsp) are present in 40% of somatotroph adenomas and may predict a more favorable GH response to SRL therapy in some but not all studies.
      • Efstathiadou Z.A.
      • Bargiota A.
      • Chrisoulidou A.
      • et al.
      Impact of gsp mutations in somatotroph pituitary adenomas on growth hormone response to somatostatin analogs: a meta-analysis.
      ,
      • Larkin S.
      • Reddy R.
      • Karavitaki N.
      • Cudlip S.
      • Wass J.
      • Ansorge O.
      Granulation pattern, but not GSP or GHR mutation, is associated with clinical characteristics in somatostatin-naive patients with somatotroph adenomas.
      In a meta-analysis, the presence of the gsp mutation was associated with a greater decrease in GH levels during the acute octreotide test (which predicts the response to long-term SRL therapy).
      • Efstathiadou Z.A.
      • Bargiota A.
      • Chrisoulidou A.
      • et al.
      Impact of gsp mutations in somatotroph pituitary adenomas on growth hormone response to somatostatin analogs: a meta-analysis.
      Densely granulated adenomas account for 30% to 50% of somatotroph tumors and show perinuclear keratin immunoreactivity.
      • Asa S.L.
      • Ezzat S.
      An update on pituitary neuroendocrine tumors leading to acromegaly and gigantism.
      These tumors are generally seen in older patients and are typically hypointense on T2-weighted MRI sequences.
      • Asa S.L.
      • Ezzat S.
      An update on pituitary neuroendocrine tumors leading to acromegaly and gigantism.
      Patients with densely granulated adenomas are more likely to respond to first-generation SRL therapy.
      • Brzana J.
      • Yedinak C.G.
      • Gultekin S.H.
      • Delashaw J.B.
      • Fleseriu M.
      Growth hormone granulation pattern and somatostatin receptor subtype 2A correlate with postoperative somatostatin receptor ligand response in acromegaly: a large single center experience.
      ,
      • Larkin S.
      • Reddy R.
      • Karavitaki N.
      • Cudlip S.
      • Wass J.
      • Ansorge O.
      Granulation pattern, but not GSP or GHR mutation, is associated with clinical characteristics in somatostatin-naive patients with somatotroph adenomas.
      ,
      • Bhayana S.
      • Booth G.L.
      • Asa S.L.
      • Kovacs K.
      • Ezzat S.
      The implication of somatotroph adenoma phenotype to somatostatin analog responsiveness in acromegaly.
      In a study of 40 patients who were treated with octreotide LAR for a mean of 28 months, those with densely granulated tumors were significantly more likely to normalize serum IGF-1 and GH levels (GH level <1 μg/L) in response to SRL administration (OR, 58.4) compared with those with sparsely granulated tumors.
      • Bhayana S.
      • Booth G.L.
      • Asa S.L.
      • Kovacs K.
      • Ezzat S.
      The implication of somatotroph adenoma phenotype to somatostatin analog responsiveness in acromegaly.
      Several other histopathologic characteristics and molecular tumor markers have been proposed as possible predictors of response to SRL. Ki-67 is a nuclear protein expressed in cells that are not in resting phase (G0).
      • Asa S.L.
      • Ezzat S.
      An update on pituitary neuroendocrine tumors leading to acromegaly and gigantism.
      A lower Ki-67 index (Ki-67 <2.3%) may predict a higher response to first-generation SRL therapy.
      • Kasuki L.
      • Wildemberg L.E.
      • Neto L.V.
      • Marcondes J.
      • Takiya C.M.
      • Gadelha M.R.
      Ki-67 is a predictor of acromegaly control with octreotide LAR independent of SSTR2 status and relates to cytokeratin pattern.
      In addition, a higher SSTR-2 expression has been associated with a greater likelihood of achieving biochemical control in patients with acromegaly in response to SRL therapy.
      • Brzana J.
      • Yedinak C.G.
      • Gultekin S.H.
      • Delashaw J.B.
      • Fleseriu M.
      Growth hormone granulation pattern and somatostatin receptor subtype 2A correlate with postoperative somatostatin receptor ligand response in acromegaly: a large single center experience.
      ,
      • Kasuki L.
      • Wildemberg L.E.
      • Neto L.V.
      • Marcondes J.
      • Takiya C.M.
      • Gadelha M.R.
      Ki-67 is a predictor of acromegaly control with octreotide LAR independent of SSTR2 status and relates to cytokeratin pattern.
      A higher ratio between SSTR-2 and SSTR-5 expression has been associated with better biochemical response to first-generation SRL therapy.
      • Taboada G.F.
      • Luque R.M.
      • Neto L.V.
      • et al.
      Quantitative analysis of somatostatin receptor subtypes (1-5) gene expression levels in somatotropinomas and correlation to in vivo hormonal and tumor volume responses to treatment with octreotide LAR.
      Among patients without germline AIP mutations, a higher AIP expression in somatotroph tumor cells has been associated with a higher likelihood of achieving biochemical control on first-generation SRL therapy.
      • Kasuki L.
      • Vieira Neto L.
      • Wildemberg L.E.
      • et al.
      AIP expression in sporadic somatotropinomas is a predictor of the response to octreotide LAR therapy independent of SSTR2 expression.
      It has been suggested that SSTR-2 expression, AIP expression, and the Ki-67 index may independently predict the biochemical response to SRL therapy.
      • Kasuki L.
      • Wildemberg L.E.
      • Neto L.V.
      • Marcondes J.
      • Takiya C.M.
      • Gadelha M.R.
      Ki-67 is a predictor of acromegaly control with octreotide LAR independent of SSTR2 status and relates to cytokeratin pattern.
      ,
      • Kasuki L.
      • Vieira Neto L.
      • Wildemberg L.E.
      • et al.
      AIP expression in sporadic somatotropinomas is a predictor of the response to octreotide LAR therapy independent of SSTR2 expression.
      A lower β-arrestin expression, a protein that downregulates SSTR-2–mediated signaling, has been associated with a higher response rate to SRL therapy.
      • Gatto F.
      • Biermasz N.R.
      • Feelders R.A.
      • et al.
      Low beta-arrestin expression correlates with the responsiveness to long-term somatostatin analog treatment in acromegaly.
      In addition, a higher expression of E-cadherin, a cell adhesion protein, has been associated with a greater likelihood of achieving biochemical control on SRL therapy.
      • Venegas-Moreno E.
      • Flores-Martinez A.
      • Dios E.
      • et al.
      E-cadherin expression is associated with somatostatin analogue response in acromegaly.
      Similarly, a higher expression of ZAC1, a zinc finger transcription factor that appears to be one of the intracellular signaling mediators of octreotide action, has been associated with higher biochemical response to first-generation SRL therapy.
      • Theodoropoulou M.
      • Stalla G.K.
      • Spengler D.
      ZAC1 target genes and pituitary tumorigenesis.
      • Theodoropoulou M.
      • Tichomirowa M.A.
      • Sievers C.
      • et al.
      Tumor ZAC1 expression is associated with the response to somatostatin analog therapy in patients with acromegaly.
      • Theodoropoulou M.
      • Zhang J.
      • Laupheimer S.
      • et al.
      Octreotide, a somatostatin analogue, mediates its antiproliferative action in pituitary tumor cells by altering phosphatidylinositol 3-kinase signaling and inducing Zac1 expression.
      A higher expression of Raf kinase inhibitory protein, which is involved in SSTR-mediated signaling, has been associated with a better response to SRL therapy in acromegaly.
      • Fougner S.L.
      • Bollerslev J.
      • Latif F.
      • et al.
      Low levels of raf kinase inhibitory protein in growth hormone–secreting pituitary adenomas correlate with poor response to octreotide treatment.
      Image characteristics on MRI may also predict the response to first-generation SRL therapy. T2-hypointense adenomas account for about 40% of somatotroph adenomas and are generally densely granulated.
      • Heck A.
      • Emblem K.E.
      • Casar-Borota O.
      • Bollerslev J.
      • Ringstad G.
      Quantitative analyses of T2-weighted MRI as a potential marker for response to somatostatin analogs in newly diagnosed acromegaly.
      ,
      • Heck A.
      • Ringstad G.
      • Fougner S.L.
      • et al.
      Intensity of pituitary adenoma on T2-weighted magnetic resonance imaging predicts the response to octreotide treatment in newly diagnosed acromegaly.
      Tumors that are T2 hypointense are more likely to show a good biochemical response to SRL therapy.
      • Heck A.
      • Emblem K.E.
      • Casar-Borota O.
      • Bollerslev J.
      • Ringstad G.
      Quantitative analyses of T2-weighted MRI as a potential marker for response to somatostatin analogs in newly diagnosed acromegaly.
      • Heck A.
      • Ringstad G.
      • Fougner S.L.
      • et al.
      Intensity of pituitary adenoma on T2-weighted magnetic resonance imaging predicts the response to octreotide treatment in newly diagnosed acromegaly.
      • Puig-Domingo M.
      • Resmini E.
      • Gomez-Anson B.
      • et al.
      Magnetic resonance imaging as a predictor of response to somatostatin analogs in acromegaly after surgical failure.
      Image texture analysis refers to quantification of image gray-level pixel distribution on MRI.
      • Tourassi G.D.
      Journey toward computer-aided diagnosis: role of image texture analysis.
      In a recent study, maximum pixel intensity was predictive of serum IGF-1 normalization on first-generation SRL therapy.
      • Galm B.P.
      • Buckless C.
      • Swearingen B.
      • et al.
      MRI texture analysis in acromegaly and its role in predicting response to somatostatin receptor ligands.
      Pasireotide LAR is a second-generation SRL with expanded SSTR specificity (engaging SSTR-1, 2, 3, and 5).
      • Colao A.
      • Bronstein M.D.
      • Freda P.
      • et al.
      Pasireotide versus octreotide in acromegaly: a head-to-head superiority study.
      Pasireotide LAR is likely to be more effective than first-generation SRLs in effecting control of GH secretion.
      • Colao A.
      • Bronstein M.D.
      • Freda P.
      • et al.
      Pasireotide versus octreotide in acromegaly: a head-to-head superiority study.
      Approximately 20% of patients with acromegaly who are not controlled on first-generation SRLs can achieve biochemical control on pasireotide LAR therapy.
      • Gadelha M.R.
      • Bronstein M.D.
      • Brue T.
      • et al.
      Pasireotide versus continued treatment with octreotide or lanreotide in patients with inadequately controlled acromegaly (PAOLA): a randomised, phase 3 trial.
      Whether SSTR-5 or SSTR-2 expression predicts response to pasireotide LAR therapy is debatable.
      • Iacovazzo D.
      • Carlsen E.
      • Lugli F.
      • et al.
      Factors predicting pasireotide responsiveness in somatotroph pituitary adenomas resistant to first-generation somatostatin analogues: an immunohistochemical study.
      ,
      • Muhammad A.
      • Coopmans E.C.
      • Gatto F.
      • et al.
      Pasireotide responsiveness in acromegaly is mainly driven by somatostatin receptor subtype 2 expression.
      In addition, T2 signal intensity on MRI may predict the response to pasireotide LAR.
      • Coopmans E.C.
      • Schneiders J.J.
      • El-Sayed N.
      • et al.
      T2-signal intensity, SSTR expression, and somatostatin analogs efficacy predict response to pasireotide in acromegaly.
      All SRLs share similar potential for gastrointestinal adverse effects (diarrhea, abdominal pain, cholelithiasis), alopecia, and sinus bradycardia.
      • Giustina A.
      • Barkhoudarian G.
      • Beckers A.
      • et al.
      Multidisciplinary management of acromegaly: a consensus.
      However, pasireotide LAR is more likely than first-generation SRLs to induce hyperglycemia or diabetes mellitus, probably as a consequence of SSTR-5 activation that results in blunted insulin and incretin secretion.
      • Colao A.
      • Bronstein M.D.
      • Freda P.
      • et al.
      Pasireotide versus octreotide in acromegaly: a head-to-head superiority study.
      ,
      • Gadelha M.R.
      • Bronstein M.D.
      • Brue T.
      • et al.
      Pasireotide versus continued treatment with octreotide or lanreotide in patients with inadequately controlled acromegaly (PAOLA): a randomised, phase 3 trial.
      Cabergoline is a D2-selective agonist at dopamine receptors that is Food and Drug Administration approved for treatment of patients with hyperprolactinemia. It is used off-label in patients with acromegaly. A meta-analysis of 9 studies reported that cabergoline therapy (dose range, 0.3 to 7.0 mg/wk) resulted in IGF-1 normalization and GH control in, respectively, 34% and 48% of 149 patients.
      • Sandret L.
      • Maison P.
      • Chanson P.
      Place of cabergoline in acromegaly: a meta-analysis.
      Lower baseline serum IGF-1 levels and previous radiation therapy to the sella predicted a good biochemical response to cabergoline therapy.
      • Sandret L.
      • Maison P.
      • Chanson P.
      Place of cabergoline in acromegaly: a meta-analysis.
      In the same meta-analysis (5 studies) of data on patients inadequately controlled on SRLs, add-on cabergoline therapy resulted in IGF-1 normalization in 52% of 77 patients.
      • Sandret L.
      • Maison P.
      • Chanson P.
      Place of cabergoline in acromegaly: a meta-analysis.
      Lower baseline serum IGF-1 levels predicted a higher likelihood of biochemical response to cabergoline.
      • Sandret L.
      • Maison P.
      • Chanson P.
      Place of cabergoline in acromegaly: a meta-analysis.
      Adverse effects associated with cabergoline therapy include nausea, vomiting, orthostatic dizziness, headache, nasal congestion, constipation, and digital vasospasm.
      • Sandret L.
      • Maison P.
      • Chanson P.
      Place of cabergoline in acromegaly: a meta-analysis.
      In patients with Parkinson disease, cabergoline therapy in high doses (3 to 7 mg/d) has been associated with cardiac valvulopathy, probably as a result of activation of 5-hydroxytryptamine subtype 2B receptors by cabergoline.
      • Zanettini R.
      • Antonini A.
      • Gatto G.
      • Gentile R.
      • Tesei S.
      • Pezzoli G.
      Valvular heart disease and the use of dopamine agonists for Parkinson's disease.
      Cabergoline doses administered to patients with acromegaly are often above the usual dose range advised in hyperprolactinemic patients (0.5 to 2.0 mg/wk) but lower than typical doses used in Parkinson disease (3 to 7 mg/d). The risk of cardiac valvulopathy in patients with hyperprolactinemia appears to be low.
      • Stiles C.E.
      • Lloyd G.
      • Bhattacharyya S.
      • et al.
      Incidence of cabergoline-associated valvulopathy in primary care patients with prolactinoma using hard cardiac endpoints.
      However, the risk of valvulopathy in patients with acromegaly receiving cabergoline remains unclear. Periodic echocardiography appears prudent in patients receiving more than 2 mg/wk of cabergoline. Nonetheless, the cost-effectiveness of this strategy has not been established. Impulse control disorders have been reported in hyperprolactinemic patients receiving cabergoline therapy, presumably as a consequence of D2 receptor activation in the mesolimbic dopamine pathway.
      • De Sousa S.M.C.
      • Baranoff J.
      • Rushworth R.L.
      • et al.
      Impulse control disorders in dopamine agonist-treated hyperprolactinemia: prevalence and risk factors.
      Pegvisomant is a GH analogue that carries several amino acid substitutions and functions as a GHR antagonist.
      • Kopchick J.J.
      Discovery and mechanism of action of pegvisomant.
      Several polyethylene glycol moieties have been covalently attached to pegvisomant to prolong its half-life in the systemic circulation.
      • Kopchick J.J.
      Discovery and mechanism of action of pegvisomant.
      Pegvisomant binds to the GHR with high affinity but does not activate downstream signaling through the JAK/STAT pathway.
      • Kopchick J.J.
      Discovery and mechanism of action of pegvisomant.
      Pegvisomant is effective in inhibiting GH action, resulting in IGF-1 normalization in 89% to 97% of patients with acromegaly in pivotal clinical trials.
      • Trainer P.J.
      • Drake W.M.
      • Katznelson L.
      • et al.
      Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant.
      ,
      • van der Lely A.J.
      • Hutson R.K.
      • Trainer P.J.
      • et al.
      Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist.
      In postmarketing studies, pegvisomant therapy led to IGF-1 normalization in up to 75% of patients.
      • Fleseriu M.
      • Fuhrer-Sakel D.
      • van der Lely A.J.
      • et al.
      More than a decade of real-world experience of pegvisomant for acromegaly: ACROSTUDY.
      It is possible that inadequate dose titration or adherence to therapy may have resulted in lower effectiveness of pegvisomant in real-world settings. Glycemia may improve in patients switching from SRL therapy to pegvisomant as a consequence of inhibition of GH action and lack of suppression of insulin or incretin secretion.
      • Barkan A.L.
      • Burman P.
      • Clemmons D.R.
      • et al.
      Glucose homeostasis and safety in patients with acromegaly converted from long-acting octreotide to pegvisomant.
      Patients with lower body mass index or lower serum IGF-1 levels at baseline appear to be more likely to achieve IGF-1 normalization with pegvisomant monotherapy.
      • Sievers C.
      • Baur D.M.
      • Schwanke A.
      • et al.
      Prediction of therapy response in acromegalic patients under pegvisomant therapy within the German ACROSTUDY cohort.
      Patients with diabetes mellitus may be less likely to achieve IGF-1 normalization with pegvisomant, presumably reflecting the effects of insulin on GHR expression in hepatocytes.
      • Droste M.
      • Domberg J.
      • Buchfelder M.
      • et al.
      Therapy of acromegalic patients exacerbated by concomitant type 2 diabetes requires higher pegvisomant doses to normalise IGF1 levels [erratum appears in Eur J Endocrinol. 2014;171(6):X5].
      Pegvisomant has been administered as add-on therapy to patients who have a partial response to SRLs and is an effective treatment option in this population.
      • Neggers S.J.
      • van Aken M.O.
      • Janssen J.A.
      • Feelders R.A.
      • de Herder W.W.
      • van der Lely A.J.
      Long-term efficacy and safety of combined treatment of somatostatin analogs and pegvisomant in acromegaly.
      ,
      • Qiao N.
      • He M.
      • Shen M.
      • et al.
      Comparative efficacy of medical treatment for acromegaly: a systematic review and network meta-analysis of integrated randomized trials and observational studies.
      Patients with lower body mass index or lower serum IGF-1 levels at baseline may require a lower pegvisomant dose to normalize serum IGF-1 with combination therapy.
      • Franck S.E.
      • Korevaar T.I.M.
      • Petrossians P.
      • et al.
      A multivariable prediction model for pegvisomant dosing: monotherapy and in combination with long-acting somatostatin analogues.
      Adverse effects associated with pegvisomant administration include transaminitis, rash, and injection site reactions (including lipohypertrophy).
      • Trainer P.J.
      • Drake W.M.
      • Katznelson L.
      • et al.
      Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant.
      ,
      • Buchfelder M.
      • van der Lely A.J.
      • Biller B.M.K.
      • et al.
      Long-term treatment with pegvisomant: observations from 2090 acromegaly patients in ACROSTUDY.
      Transaminitis is reversible with dose reduction or drug discontinuation and has not been reported to result in hepatic failure. A verified increase in size of somatotroph adenomas has been reported in 3.2% of 936 patients receiving pegvisomant therapy.
      • Buchfelder M.
      • van der Lely A.J.
      • Biller B.M.K.
      • et al.
      Long-term treatment with pegvisomant: observations from 2090 acromegaly patients in ACROSTUDY.
      In some cases, this increase in tumor size may have been a consequence of withdrawal from SRL therapy or may have simply reflected the natural history of more aggressive pituitary adenomas. Periodic pituitary imaging is advisable in patients who receive pegvisomant therapy to detect a possible increase in tumor size.
      Several investigational therapies are currently in development, including paltusotine (an orally active, nonpeptide SRL), somatoprim (an SRL engaging SSTR-2, 4, and 5), CAM2029 (liquid crystal formulation of octreotide depot), and an antisense oligonucleotide targeting the mRNA encoding the GHR.
      • Melmed S.
      New therapeutic agents for acromegaly.
      ,
      • Antunes X.
      • Kasuki L.
      • Gadelha M.R.
      New and emerging pharmacological treatment options for acromegaly.

      Radiation Therapy

      Radiation therapy is another treatment option for patients with acromegaly and is typically advised for those who are not in remission postoperatively and do not show a good response or tolerance to medical therapy.
      • Giustina A.
      • Barkhoudarian G.
      • Beckers A.
      • et al.
      Multidisciplinary management of acromegaly: a consensus.
      Radiation therapy may also be administered to control tumor growth in patients with pituitary adenomas that do not respond adequately to surgery and medical therapy. Radiation therapy can be administered either as conventional fractionated radiation therapy or, increasingly, as stereotactic radiation therapy (Gamma knife, linear accelerator/CyberKnife, and proton beam).
      • Lee C.C.
      • Vance M.L.
      • Xu Z.
      • et al.
      Stereotactic radiosurgery for acromegaly.
      ,
      • Gheorghiu M.L.
      Updates in outcomes of stereotactic radiation therapy in acromegaly.
      Stereotactic radiation therapy can be delivered in a single session (“radiosurgery”) in patients with smaller tumors that are distant from the optic apparatus.
      • Lee C.C.
      • Vance M.L.
      • Xu Z.
      • et al.
      Stereotactic radiosurgery for acromegaly.
      ,
      • Gheorghiu M.L.
      Updates in outcomes of stereotactic radiation therapy in acromegaly.
      Biochemical control can be achieved in up to 60% of patients with acromegaly after a period of several years, thus necessitating the institution of interim medical therapy until the salutary effects of radiation therapy occur.
      • Lee C.C.
      • Vance M.L.
      • Xu Z.
      • et al.
      Stereotactic radiosurgery for acromegaly.
      ,
      • Gheorghiu M.L.
      Updates in outcomes of stereotactic radiation therapy in acromegaly.
      In a recent retrospective analysis of 352 patients from the German Acromegaly Registry, endocrine remission was achieved sooner among patients who received stereotactic radiosurgery in comparison with those who received fractionated radiotherapy (mean interval of 2 years vs 3 years).
      • Knappe U.J.
      • Petroff D.
      • Quinkler M.
      • et al.
      Fractionated radiotherapy and radiosurgery in acromegaly: analysis of 352 patients from the German Acromegaly Registry.
      However, the proportion of patients who achieved endocrine remission at 10 years after radiation therapy was not different between the groups. Tumor control is achieved in more than 90% of patients with acromegaly receiving radiation therapy.
      • Shih H.A.
      • Loeffler J.S.
      Radiation therapy in acromegaly.
      Adverse effects associated with radiation therapy include anterior hypopituitarism (affecting 40% to 50% of patients at 5 years) and optic or other cranial neuropathies (in 1% to 2% of patients). The development of anterior pituitary hormone deficiencies may be less frequent after the administration of stereotactic radiosurgery in comparison with fractionated techniques.
      • Knappe U.J.
      • Petroff D.
      • Quinkler M.
      • et al.
      Fractionated radiotherapy and radiosurgery in acromegaly: analysis of 352 patients from the German Acromegaly Registry.
      Temporal lobe necrosis, stroke, and secondary tumors have been uncommonly reported in association with conventional radiation therapy. However, long-term data are needed to determine whether these uncommon, long-term adverse effects may also occur after stereotactic radiation therapy because newer radiotherapy techniques minimize the exposure of healthy brain structures to radiation.
      • Shih H.A.
      • Loeffler J.S.
      Radiation therapy in acromegaly.

      Conclusion

      A high index of suspicion is needed to minimize delays in diagnosis of acromegaly. Early diagnosis and adequate treatment of acromegaly are needed to mitigate excess mortality associated with this condition. Pituitary surgery is currently the cornerstone of management, with medical therapies and radiation therapy typically representing second- and third-line options, respectively.
      Further advances in our understanding of the pathogenesis of somatotroph adenomas are needed and may eventually lead to the development of novel, rationally designed medical therapies. Prospective studies that use robust criteria to assess potential predictors of response to medical therapy will be helpful to refine our ability to reliably predict therapeutic responses. In the not too distant future, a robust, targeted approach to medical therapy in patients with acromegaly may become a reality.

      References

        • Melmed S.
        Pituitary-tumor endocrinopathies.
        N Engl J Med. 2020; 382: 937-950
        • Fleseriu M.
        • Biller B.M.K.
        • Freda P.U.
        • et al.
        A Pituitary Society update to acromegaly management guidelines.
        Pituitary. 2021; 24: 1-13
        • Katznelson L.
        • Laws Jr., E.R.
        • Melmed S.
        • et al.
        Acromegaly: an Endocrine Society clinical practice guideline.
        J Clin Endocrinol Metab. 2014; 99: 3933-3951
        • Giustina A.
        • Veldhuis J.D.
        Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human.
        Endocr Rev. 1998; 19: 717-797
        • Nass R.M.
        • Gaylinn B.D.
        • Rogol A.D.
        • Thorner M.O.
        Ghrelin and growth hormone: story in reverse.
        Proc Natl Acad Sci U S A. 2010; 107: 8501-8502
        • Melmed S.
        Pathogenesis and diagnosis of growth hormone deficiency in adults.
        N Engl J Med. 2019; 380: 2551-2562
        • Clemmons D.R.
        Clinical laboratory indices in the treatment of acromegaly.
        Clin Chim Acta. 2011; 412: 403-409
        • Clemmons D.R.
        Consensus statement on the standardization and evaluation of growth hormone and insulin-like growth factor assays.
        Clin Chem. 2011; 57: 555-559
        • Brooks A.J.
        • Dai W.
        • O'Mara M.L.
        • et al.
        Mechanism of activation of protein kinase JAK2 by the growth hormone receptor.
        Science. 2014; 344: 1249783
        • Carter-Su C.
        • Schwartz J.
        • Argetsinger L.S.
        Growth hormone signaling pathways.
        Growth Horm IGF Res. 2016; 28: 11-15
        • Hakuno F.
        • Takahashi S.I.
        IGF1 receptor signaling pathways.
        J Mol Endocrinol. 2018; 61: T69-T86
        • Cuevas-Ramos D.
        • Carmichael J.D.
        • Cooper O.
        • et al.
        A structural and functional acromegaly classification.
        J Clin Endocrinol Metab. 2015; 100: 122-131
        • Lopes M.B.S.
        The 2017 World Health Organization classification of tumors of the pituitary gland: a summary.
        Acta Neuropathol. 2017; 134: 521-535
        • Hage M.
        • Viengchareun S.
        • Brunet E.
        • et al.
        Genomic alterations and complex subclonal architecture in sporadic GH-secreting pituitary adenomas.
        J Clin Endocrinol Metab. 2018; 103: 1929-1939
        • Boguslawska A.
        • Korbonits M.
        Genetics of acromegaly and gigantism.
        J Clin Med. 2021; 10: 1377
        • Karges B.
        • Pfaffle R.
        • Boehm B.O.
        • Karges W.
        Acromegaly induced by growth hormone replacement therapy.
        Horm Res. 2004; 61: 165-169
        • Thorner M.O.
        • Perryman R.L.
        • Cronin M.J.
        • et al.
        Somatotroph hyperplasia. Successful treatment of acromegaly by removal of a pancreatic islet tumor secreting a growth hormone-releasing factor.
        J Clin Invest. 1982; 70: 965-977
        • Beuschlein F.
        • Strasburger C.J.
        • Siegerstetter V.
        • et al.
        Acromegaly caused by secretion of growth hormone by a non-Hodgkin's lymphoma.
        N Engl J Med. 2000; 342: 1871-1876
        • Melmed S.
        • Ezrin C.
        • Kovacs K.
        • Goodman R.S.
        • Frohman L.A.
        Acromegaly due to secretion of growth hormone by an ectopic pancreatic islet-cell tumor.
        N Engl J Med. 1985; 312: 9-17
        • Langlois F.
        • Woltjer R.
        • Cetas J.S.
        • Fleseriu M.
        Silent somatotroph pituitary adenomas: an update.
        Pituitary. 2018; 21: 194-202
        • Giustina A.
        • Barkan A.
        • Beckers A.
        • et al.
        A consensus on the diagnosis and treatment of acromegaly comorbidities: an update.
        J Clin Endocrinol Metab. 2020; 105: dgz096
        • Caron P.
        • Brue T.
        • Raverot G.
        • et al.
        Signs and symptoms of acromegaly at diagnosis: the physician's and the patient's perspectives in the ACRO-POLIS study [erratum appears in Endocrine. 2019;63(1):130].
        Endocrine. 2019; 63: 120-129
        • Reid T.J.
        • Post K.D.
        • Bruce J.N.
        • Nabi Kanibir M.
        • Reyes-Vidal C.M.
        • Freda P.U.
        Features at diagnosis of 324 patients with acromegaly did not change from 1981 to 2006: acromegaly remains under-recognized and under-diagnosed.
        Clin Endocrinol (Oxf). 2010; 72: 203-208
        • Esposito D.
        • Ragnarsson O.
        • Johannsson G.
        • Olsson D.S.
        Prolonged diagnostic delay in acromegaly is associated with increased morbidity and mortality.
        Eur J Endocrinol. 2020; 182: 523-531
        • Schneider H.J.
        • Kosilek R.P.
        • Gunther M.
        • et al.
        A novel approach to the detection of acromegaly: accuracy of diagnosis by automatic face classification.
        J Clin Endocrinol Metab. 2011; 96: 2074-2080
        • Kong X.
        • Gong S.
        • Su L.
        • Howard N.
        • Kong Y.
        Automatic detection of acromegaly from facial photographs using machine learning methods.
        EBioMedicine. 2018; 27: 94-102
        • Bonert V.
        • Carmichael J.
        • Wu Z.
        • et al.
        Discordance between mass spectrometry and immunometric IGF-1 assay in pituitary disease: a prospective study.
        Pituitary. 2018; 21: 65-75
        • Bystrom C.
        • Sheng S.
        • Zhang K.
        • Caulfield M.
        • Clarke N.J.
        • Reitz R.
        Clinical utility of insulin-like growth factor 1 and 2; determination by high resolution mass spectrometry.
        PLoS One. 2012; 7e43457
        • Johannsson G.
        • Bidlingmaier M.
        • Biller B.M.K.
        • et al.
        Growth Hormone Research Society perspective on biomarkers of GH action in children and adults.
        Endocr Connect. 2018; 7: R126-R134
        • Schilbach K.
        • Strasburger C.J.
        • Bidlingmaier M.
        Biochemical investigations in diagnosis and follow up of acromegaly.
        Pituitary. 2017; 20: 33-45
        • Leung K.C.
        • Doyle N.
        • Ballesteros M.
        • et al.
        Estrogen inhibits GH signaling by suppressing GH-induced JAK2 phosphorylation, an effect mediated by SOCS-2.
        Proc Natl Acad Sci U S A. 2003; 100: 1016-1021
        • Schilbach K.
        • Gar C.
        • Lechner A.
        • et al.
        Determinants of the growth hormone nadir during oral glucose tolerance test in adults.
        Eur J Endocrinol. 2019; 181: 55-67
        • Ribeiro-Oliveira Jr., A.
        • Faje A.T.
        • Barkan A.L.
        Limited utility of oral glucose tolerance test in biochemically active acromegaly.
        Eur J Endocrinol. 2011; 164: 17-22
        • Lonser R.R.
        • Kindzelski B.A.
        • Mehta G.U.
        • Jane Jr., J.A.
        • Oldfield E.H.
        Acromegaly without imaging evidence of pituitary adenoma.
        J Clin Endocrinol Metab. 2010; 95: 4192-4196
        • Ritvonen E.
        • Loyttyniemi E.
        • Jaatinen P.
        • et al.
        Mortality in acromegaly: a 20-year follow-up study.
        Endocr Relat Cancer. 2016; 23: 469-480
        • Dal J.
        • Leisner M.Z.
        • Hermansen K.
        • et al.
        Cancer incidence in patients with acromegaly: a cohort study and meta-analysis of the literature.
        J Clin Endocrinol Metab. 2018; 103: 2182-2188
        • Holdaway I.M.
        • Bolland M.J.
        • Gamble G.D.
        A meta-analysis of the effect of lowering serum levels of GH and IGF-I on mortality in acromegaly.
        Eur J Endocrinol. 2008; 159: 89-95
        • Giustina A.
        • Barkhoudarian G.
        • Beckers A.
        • et al.
        Multidisciplinary management of acromegaly: a consensus.
        Rev Endocr Metab Disord. 2020; 21: 667-678
        • Bollerslev J.
        • Heck A.
        • Olarescu N.C.
        Management of endocrine disease: individualised management of acromegaly.
        Eur J Endocrinol. 2019; 181: R57-R71
        • Yao S.
        • Chen W.L.
        • Tavakol S.
        • et al.
        Predictors of postoperative biochemical remission in acromegaly.
        J Neurooncol. 2021; 151: 313-324
        • Fougner S.L.
        • Bollerslev J.
        • Svartberg J.
        • Oksnes M.
        • Cooper J.
        • Carlsen S.M.
        Preoperative octreotide treatment of acromegaly: long-term results of a randomised controlled trial.
        Eur J Endocrinol. 2014; 171: 229-235
        • Shen M.
        • Shou X.
        • Wang Y.
        • et al.
        Effect of presurgical long-acting octreotide treatment in acromegaly patients with invasive pituitary macroadenomas: a prospective randomized study.
        Endocr J. 2010; 57: 1035-1044
        • Wildemberg L.E.
        • da Silva Camacho A.H.
        • Miranda R.L.
        • et al.
        Machine learning–based prediction model for treatment of acromegaly with first-generation somatostatin receptor ligands.
        J Clin Endocrinol Metab. 2021; 106: 2047-2056
        • Chen C.J.
        • Ironside N.
        • Pomeraniec I.J.
        • et al.
        Microsurgical versus endoscopic transsphenoidal resection for acromegaly: a systematic review of outcomes and complications.
        Acta Neurochir (Wien). 2017; 159: 2193-2207
        • Fathalla H.
        • Cusimano M.D.
        • Di Ieva A.
        • et al.
        Endoscopic versus microscopic approach for surgical treatment of acromegaly.
        Neurosurg Rev. 2015; 38 (discussion 548-549): 541-548
        • Buchfelder M.
        • Schlaffer S.M.
        The surgical treatment of acromegaly.
        Pituitary. 2017; 20: 76-83
        • Swearingen B.
        • Barker 2nd, F.G.
        • Katznelson L.
        • et al.
        Long-term mortality after transsphenoidal surgery and adjunctive therapy for acromegaly.
        J Clin Endocrinol Metab. 1998; 83: 3419-3426
        • Babu H.
        • Ortega A.
        • Nuno M.
        • et al.
        Long-term endocrine outcomes following endoscopic endonasal transsphenoidal surgery for acromegaly and associated prognostic factors.
        Neurosurgery. 2017; 81: 357-366
        • Coopmans E.C.
        • Postma M.R.
        • Wolters T.L.C.
        • et al.
        Predictors for remission after transsphenoidal surgery in acromegaly: a Dutch multicenter study.
        J Clin Endocrinol Metab. 2021; 106: 1783-1792
        • Anthony J.R.
        • Alwahab U.A.
        • Kanakiya N.K.
        • et al.
        Significant elevation of growth hormone level impacts surgical outcomes in acromegaly.
        Endocr Pract. 2015; 21: 1001-1009
        • Kim E.H.
        • Oh M.C.
        • Lee E.J.
        • Kim S.H.
        Predicting long-term remission by measuring immediate postoperative growth hormone levels and oral glucose tolerance test in acromegaly.
        Neurosurgery. 2012; 70 (discussion 1113): 1106-1113
        • Agrawal N.
        • Ioachimescu A.G.
        Prognostic factors of biochemical remission after transsphenoidal surgery for acromegaly: a structured review.
        Pituitary. 2020; 23: 582-594
        • Fahlbusch R.
        • Kleinberg D.
        • Biller B.
        • et al.
        Surgical debulking of pituitary adenomas improves responsiveness to octreotide lar in the treatment of acromegaly.
        Pituitary. 2017; 20: 668-675
        • Zhang Z.
        • Li Q.
        • He W.
        • et al.
        The comprehensive impact on human body induced by resolution of growth hormone excess.
        Eur J Endocrinol. 2018; 178: 365-375
        • Gunther T.
        • Tulipano G.
        • Dournaud P.
        • et al.
        International Union of Basic and Clinical Pharmacology. CV. Somatostatin receptors: structure, function, ligands, and new nomenclature.
        Pharmacol Rev. 2018; 70: 763-835
        • Carmichael J.D.
        • Bonert V.S.
        • Nuno M.
        • Ly D.
        • Melmed S.
        Acromegaly clinical trial methodology impact on reported biochemical efficacy rates of somatostatin receptor ligand treatments: a meta-analysis.
        J Clin Endocrinol Metab. 2014; 99: 1825-1833
        • Caron P.J.
        • Bevan J.S.
        • Petersenn S.
        • et al.
        Tumor shrinkage with lanreotide Autogel 120 mg as primary therapy in acromegaly: results of a prospective multicenter clinical trial.
        J Clin Endocrinol Metab. 2014; 99: 1282-1290
        • Samson S.L.
        • Nachtigall L.B.
        • Fleseriu M.
        • et al.
        Maintenance of acromegaly control in patients switching from injectable somatostatin receptor ligands to oral octreotide.
        J Clin Endocrinol Metab. 2020; 105: e3785-e3797
        • Giustina A.
        • Mazziotti G.
        • Torri V.
        • Spinello M.
        • Floriani I.
        • Melmed S.
        Meta-analysis on the effects of octreotide on tumor mass in acromegaly.
        PLoS One. 2012; 7e36411
        • Petersenn S.
        • Houchard A.
        • Sert C.
        • Caron P.J.
        • PRIMARYS Study Group
        Predictive factors for responses to primary medical treatment with lanreotide autogel 120 mg in acromegaly: post hoc analyses from the PRIMARYS study.
        Pituitary. 2020; 23: 171-181
        • Brzana J.
        • Yedinak C.G.
        • Gultekin S.H.
        • Delashaw J.B.
        • Fleseriu M.
        Growth hormone granulation pattern and somatostatin receptor subtype 2A correlate with postoperative somatostatin receptor ligand response in acromegaly: a large single center experience.
        Pituitary. 2013; 16: 490-498
        • Galm B.P.
        • Buckless C.
        • Swearingen B.
        • et al.
        MRI texture analysis in acromegaly and its role in predicting response to somatostatin receptor ligands.
        Pituitary. 2020; 23: 212-222
        • Newman C.B.
        • Melmed S.
        • Snyder P.J.
        • et al.
        Safety and efficacy of long-term octreotide therapy of acromegaly: results of a multicenter trial in 103 patients—a clinical research center study [erratum appears in J Clin Endocrinol Metab. 1995;80(11):3238].
        J Clin Endocrinol Metab. 1995; 80: 2768-2775
        • Daly A.F.
        • Tichomirowa M.A.
        • Petrossians P.
        • et al.
        Clinical characteristics and therapeutic responses in patients with germ-line AIP mutations and pituitary adenomas: an international collaborative study.
        J Clin Endocrinol Metab. 2010; 95: E373-E383
        • Bogner E.M.
        • Daly A.F.
        • Gulde S.
        • et al.
        miR-34a is upregulated in AIP-mutated somatotropinomas and promotes octreotide resistance.
        Int J Cancer. 2020; 147: 3523-3538
        • Beckers A.
        • Lodish M.B.
        • Trivellin G.
        • et al.
        X-linked acrogigantism syndrome: clinical profile and therapeutic responses.
        Endocr Relat Cancer. 2015; 22: 353-367
        • Salenave S.
        • Boyce A.M.
        • Collins M.T.
        • Chanson P.
        Acromegaly and McCune-Albright syndrome.
        J Clin Endocrinol Metab. 2014; 99: 1955-1969
        • Efstathiadou Z.A.
        • Bargiota A.
        • Chrisoulidou A.
        • et al.
        Impact of gsp mutations in somatotroph pituitary adenomas on growth hormone response to somatostatin analogs: a meta-analysis.
        Pituitary. 2015; 18: 861-867
        • Larkin S.
        • Reddy R.
        • Karavitaki N.
        • Cudlip S.
        • Wass J.
        • Ansorge O.
        Granulation pattern, but not GSP or GHR mutation, is associated with clinical characteristics in somatostatin-naive patients with somatotroph adenomas.
        Eur J Endocrinol. 2013; 168: 491-499
        • Asa S.L.
        • Ezzat S.
        An update on pituitary neuroendocrine tumors leading to acromegaly and gigantism.
        J Clin Med. 2021; 10: 2254
        • Bhayana S.
        • Booth G.L.
        • Asa S.L.
        • Kovacs K.
        • Ezzat S.
        The implication of somatotroph adenoma phenotype to somatostatin analog responsiveness in acromegaly.
        J Clin Endocrinol Metab. 2005; 90: 6290-6295
        • Kasuki L.
        • Wildemberg L.E.
        • Neto L.V.
        • Marcondes J.
        • Takiya C.M.
        • Gadelha M.R.
        Ki-67 is a predictor of acromegaly control with octreotide LAR independent of SSTR2 status and relates to cytokeratin pattern.
        Eur J Endocrinol. 2013; 169: 217-223
        • Taboada G.F.
        • Luque R.M.
        • Neto L.V.
        • et al.
        Quantitative analysis of somatostatin receptor subtypes (1-5) gene expression levels in somatotropinomas and correlation to in vivo hormonal and tumor volume responses to treatment with octreotide LAR.
        Eur J Endocrinol. 2008; 158: 295-303
        • Kasuki L.
        • Vieira Neto L.
        • Wildemberg L.E.
        • et al.
        AIP expression in sporadic somatotropinomas is a predictor of the response to octreotide LAR therapy independent of SSTR2 expression.
        Endocr Relat Cancer. 2012; 19: L25-L29
        • Gatto F.
        • Biermasz N.R.
        • Feelders R.A.
        • et al.
        Low beta-arrestin expression correlates with the responsiveness to long-term somatostatin analog treatment in acromegaly.
        Eur J Endocrinol. 2016; 174: 651-662
        • Venegas-Moreno E.
        • Flores-Martinez A.
        • Dios E.
        • et al.
        E-cadherin expression is associated with somatostatin analogue response in acromegaly.
        J Cell Mol Med. 2019; 23: 3088-3096
        • Theodoropoulou M.
        • Stalla G.K.
        • Spengler D.
        ZAC1 target genes and pituitary tumorigenesis.
        Mol Cell Endocrinol. 2010; 326: 60-65
        • Theodoropoulou M.
        • Tichomirowa M.A.
        • Sievers C.
        • et al.
        Tumor ZAC1 expression is associated with the response to somatostatin analog therapy in patients with acromegaly.
        Int J Cancer. 2009; 125: 2122-2126
        • Theodoropoulou M.
        • Zhang J.
        • Laupheimer S.
        • et al.
        Octreotide, a somatostatin analogue, mediates its antiproliferative action in pituitary tumor cells by altering phosphatidylinositol 3-kinase signaling and inducing Zac1 expression.
        Cancer Res. 2006; 66: 1576-1582
        • Fougner S.L.
        • Bollerslev J.
        • Latif F.
        • et al.
        Low levels of raf kinase inhibitory protein in growth hormone–secreting pituitary adenomas correlate with poor response to octreotide treatment.
        J Clin Endocrinol Metab. 2008; 93: 1211-1216
        • Heck A.
        • Emblem K.E.
        • Casar-Borota O.
        • Bollerslev J.
        • Ringstad G.
        Quantitative analyses of T2-weighted MRI as a potential marker for response to somatostatin analogs in newly diagnosed acromegaly.
        Endocrine. 2016; 52: 333-343
        • Heck A.
        • Ringstad G.
        • Fougner S.L.
        • et al.
        Intensity of pituitary adenoma on T2-weighted magnetic resonance imaging predicts the response to octreotide treatment in newly diagnosed acromegaly.
        Clin Endocrinol (Oxf). 2012; 77: 72-78
        • Puig-Domingo M.
        • Resmini E.
        • Gomez-Anson B.
        • et al.
        Magnetic resonance imaging as a predictor of response to somatostatin analogs in acromegaly after surgical failure.
        J Clin Endocrinol Metab. 2010; 95: 4973-4978
        • Tourassi G.D.
        Journey toward computer-aided diagnosis: role of image texture analysis.
        Radiology. 1999; 213: 317-320
        • Colao A.
        • Bronstein M.D.
        • Freda P.
        • et al.
        Pasireotide versus octreotide in acromegaly: a head-to-head superiority study.
        J Clin Endocrinol Metab. 2014; 99: 791-799
        • Gadelha M.R.
        • Bronstein M.D.
        • Brue T.
        • et al.
        Pasireotide versus continued treatment with octreotide or lanreotide in patients with inadequately controlled acromegaly (PAOLA): a randomised, phase 3 trial.
        Lancet Diabetes Endocrinol. 2014; 2: 875-884
        • Iacovazzo D.
        • Carlsen E.
        • Lugli F.
        • et al.
        Factors predicting pasireotide responsiveness in somatotroph pituitary adenomas resistant to first-generation somatostatin analogues: an immunohistochemical study.
        Eur J Endocrinol. 2016; 174: 241-250
        • Muhammad A.
        • Coopmans E.C.
        • Gatto F.
        • et al.
        Pasireotide responsiveness in acromegaly is mainly driven by somatostatin receptor subtype 2 expression.
        J Clin Endocrinol Metab. 2019; 104: 915-924
        • Coopmans E.C.
        • Schneiders J.J.
        • El-Sayed N.
        • et al.
        T2-signal intensity, SSTR expression, and somatostatin analogs efficacy predict response to pasireotide in acromegaly.
        Eur J Endocrinol. 2020; 182: 595-605
        • Sandret L.
        • Maison P.
        • Chanson P.
        Place of cabergoline in acromegaly: a meta-analysis.
        J Clin Endocrinol Metab. 2011; 96: 1327-1335
        • Zanettini R.
        • Antonini A.
        • Gatto G.
        • Gentile R.
        • Tesei S.
        • Pezzoli G.
        Valvular heart disease and the use of dopamine agonists for Parkinson's disease.
        N Engl J Med. 2007; 356: 39-46
        • Stiles C.E.
        • Lloyd G.
        • Bhattacharyya S.
        • et al.
        Incidence of cabergoline-associated valvulopathy in primary care patients with prolactinoma using hard cardiac endpoints.
        J Clin Endocrinol Metab. 2021; 106: e711-e720
        • De Sousa S.M.C.
        • Baranoff J.
        • Rushworth R.L.
        • et al.
        Impulse control disorders in dopamine agonist-treated hyperprolactinemia: prevalence and risk factors.
        J Clin Endocrinol Metab. 2020; 105: dgz076
        • Kopchick J.J.
        Discovery and mechanism of action of pegvisomant.
        Eur J Endocrinol. 2003; 148: S21-S25
        • Trainer P.J.
        • Drake W.M.
        • Katznelson L.
        • et al.
        Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant.
        N Engl J Med. 2000; 342: 1171-1177
        • van der Lely A.J.
        • Hutson R.K.
        • Trainer P.J.
        • et al.
        Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist.
        Lancet. 2001; 358: 1754-1759
        • Fleseriu M.
        • Fuhrer-Sakel D.
        • van der Lely A.J.
        • et al.
        More than a decade of real-world experience of pegvisomant for acromegaly: ACROSTUDY.
        Eur J Endocrinol. 2021; 185: 525-538
        • Barkan A.L.
        • Burman P.
        • Clemmons D.R.
        • et al.
        Glucose homeostasis and safety in patients with acromegaly converted from long-acting octreotide to pegvisomant.
        J Clin Endocrinol Metab. 2005; 90: 5684-5691
        • Sievers C.
        • Baur D.M.
        • Schwanke A.
        • et al.
        Prediction of therapy response in acromegalic patients under pegvisomant therapy within the German ACROSTUDY cohort.
        Pituitary. 2015; 18: 916-923
        • Droste M.
        • Domberg J.
        • Buchfelder M.
        • et al.
        Therapy of acromegalic patients exacerbated by concomitant type 2 diabetes requires higher pegvisomant doses to normalise IGF1 levels [erratum appears in Eur J Endocrinol. 2014;171(6):X5].
        Eur J Endocrinol. 2014; 171: 59-68
        • Neggers S.J.
        • van Aken M.O.
        • Janssen J.A.
        • Feelders R.A.
        • de Herder W.W.
        • van der Lely A.J.
        Long-term efficacy and safety of combined treatment of somatostatin analogs and pegvisomant in acromegaly.
        J Clin Endocrinol Metab. 2007; 92: 4598-4601
        • Qiao N.
        • He M.
        • Shen M.
        • et al.
        Comparative efficacy of medical treatment for acromegaly: a systematic review and network meta-analysis of integrated randomized trials and observational studies.
        Endocr Pract. 2020; 26: 454-462
        • Franck S.E.
        • Korevaar T.I.M.
        • Petrossians P.
        • et al.
        A multivariable prediction model for pegvisomant dosing: monotherapy and in combination with long-acting somatostatin analogues.
        Eur J Endocrinol. 2017; 176: 421-431
        • Buchfelder M.
        • van der Lely A.J.
        • Biller B.M.K.
        • et al.
        Long-term treatment with pegvisomant: observations from 2090 acromegaly patients in ACROSTUDY.
        Eur J Endocrinol. 2018; 179: 419-427
        • Melmed S.
        New therapeutic agents for acromegaly.
        Nat Rev Endocrinol. 2016; 12: 90-98
        • Antunes X.
        • Kasuki L.
        • Gadelha M.R.
        New and emerging pharmacological treatment options for acromegaly.
        Expert Opin Pharmacother. 2021; 22: 1615-1623
        • Lee C.C.
        • Vance M.L.
        • Xu Z.
        • et al.
        Stereotactic radiosurgery for acromegaly.
        J Clin Endocrinol Metab. 2014; 99: 1273-1281
        • Gheorghiu M.L.
        Updates in outcomes of stereotactic radiation therapy in acromegaly.
        Pituitary. 2017; 20: 154-168
        • Knappe U.J.
        • Petroff D.
        • Quinkler M.
        • et al.
        Fractionated radiotherapy and radiosurgery in acromegaly: analysis of 352 patients from the German Acromegaly Registry.
        Eur J Endocrinol. 2020; 182: 275-284
        • Shih H.A.
        • Loeffler J.S.
        Radiation therapy in acromegaly.
        Rev Endocr Metab Disord. 2008; 9: 59-65