Gigantism and Acromegaly
- Author: Alicia Diaz-Thomas, MD, MPH; Chief Editor: Stephen Kemp, MD, PhD more...
Gigantism refers to abnormally high linear growth (see the image below) due to excessive action of insulinlike growth factor I (IGF-I) while the epiphyseal growth plates are open during childhood. Acromegaly is the same disorder of IGF-I excess but occurs after the growth plate cartilage fuses in adulthood.
In acromegaly, a severe disease that is often diagnosed late, morbidity and mortality rates are high, particularly as a result of associated cardiovascular, cerebrovascular, and respiratory disorders and malignancies.
Essential update: Researchers identify new gene that may play a part in growth disorders
Researchers have identified a gene on the X chromosome, GPR101, which was overexpressed 1000-fold more than normal in a genetic study of 43 patients affected by sporadic or inherited gigantism that manifested during childhood or adolescence. This duplication was not evident in patients who began abnormal growth at age 9 or 10, but only in those who started to grow excessively before the age of 3. In a separate analysis of 248 patients with sporadic acromegaly, a mutation in the GPR101 gene was found in about 4% of cases.[2, 3]
The GPR101 gene may be a target for the treatment of growth disorders.
Signs and symptoms
The presentation of patients with gigantism is usually dramatic, unlike the insidious onset of acromegaly in adults. Manifestations include the following:
Mild to moderate obesity (common)
Macrocephaly (may precede linear growth)
Soft tissue hypertrophy
Exaggerated growth of the hands and feet, with thick fingers and toes
Coarse facial features
Osteoarthritis (a late feature of IGF-I excess)
Peripheral neuropathies (eg, carpel tunnel syndrome)
Signs and symptoms of acromegaly include the following:
Doughy-feeling skin over the face and extremities
Thick and hard nails
Deepening of creases on the forehead and nasolabial folds
Noticeably large pores
Thick and edematous eyelids
Enlargement of the lower lip and nose (the nose takes on a triangular configuration)
Wide spacing of the teeth and prognathism
Cutis verticis gyrata (ie, furrows resembling gyri of the scalp) 
Small sessile and pedunculated fibromas (ie, skin tags)
Oily skin (acne is not common)
Hyperpigmentation (40% of patients)
Acanthosis nigricans (a small percentage of patients)
Excessive eccrine and apocrine sweating
Breast tissue becoming atrophic; galactorrhea
High blood pressure
Mitral valvular regurgitation
Mild hirsutism (in women)
Laboratory studies used in the diagnosis of growth hormone (GH)/IGF-I excess include the following:
Oral glucose: To determine the extent to which the patient can suppress GH concentration after the consumption of oral glucose
GH: Clearly elevated GH levels (>10 ng/mL) after oral glucose, combined with the clinical picture, secure the diagnosis of acromegaly
IGF-I: Elevated IGF-I values in a patient whose symptoms prompt appropriate clinical suspicion almost always indicate GH excess
Imaging studies include the following:
Magnetic resonance imaging (MRI): To image pituitary adenomas
Computed tomography (CT) scanning: To evaluate the patient for pancreatic, adrenal, and ovarian tumors secreting GH/GHRH; use chest CT scans to evaluate for bronchogenic carcinoma secreting GH/GHRH
Radiography: To demonstrate skeletal manifestations of GH/IGF-I excess
No single treatment modality consistently achieves control of GH excess. For pituitary adenomas, transsphenoidal surgery is usually considered the first line of treatment, followed by medical therapy for residual disease. Radiation treatment usually is reserved for recalcitrant cases.
Somatostatin and dopamine analogues and GH receptor antagonists are the mainstays of medical treatment for GH excess and are generally used when primary surgery fails to induce complete remission.
Primary treatment with the somatostatin analogues depot octreotide and lanreotide has been found to induce tumor shrinkage in newly diagnosed acromegaly. Dopamine-receptor agonists are generally used as adjuvant medical treatments for GH excess, and their effectiveness may be added to that of octreotide.
Radiation therapy is also generally recommended if GH hypersecretion is not normalized with surgery.
Gigantism refers to abnormally high linear growth due to excessive action of insulinlike growth factor I (IGF-I) while the epiphyseal growth plates are open during childhood. Acromegaly is the same disorder of IGF-I excess but occurs after the growth plate cartilage fuses in adulthood. (See Pathophysiology and Etiology.)
Gigantism is a nonspecific term that refers to any standing height more than 2 standard deviations above the mean for the person's sex, age, and Tanner stage (ie, height Z score >+2). These disorders are placed along a spectrum of IGF-I hypersecretion, wherein the developmental stage when such excess originates determines the principal manifestations. The onset of IGF-I hypersecretion in childhood or late adolescence results in tall stature (see the image below). (See Clinical Presentation and Workup.)
Scientific breakthroughs in the molecular, genetic, and hormonal basis of growth hormone (GH) excess have provided important insights into the pathogenesis, prognosis, and treatment of this exceedingly rare disease. (See Prognosis, Treatment, and Medication.)
Acromegaly is a rare, insidious, and potentially life-threatening condition for which there is good, albeit incomplete, treatment that can give the patient additional years of high-quality life. (See Prognosis, Treatment, and Medication.)
Symptoms develop insidiously, taking from years to decades to become apparent. The mean duration from symptom onset to diagnosis is 5-15 years, with a mean delay of 8.7 years. Excess GH produces a myriad of signs and symptoms and significantly increases morbidity and mortality rates. Additionally, the mass effect of the pituitary tumor itself can cause symptoms. Annual new patient incidence is estimated to be 3-4 cases per million population per year. The mean age at diagnosis is 40 years in males and 45 years in females. (See Presentation.)
Growth hormone and insulinlike growth factor
GH is necessary for normal linear growth. Its secretion from the pituitary gland is controlled by combined hypothalamic regulation, with secretion being stimulated by GHRH and inhibited by somatostatin (also called GH release–inhibiting hormone). Several tissues, including the endocrine pancreas, produce somatostatin in response to GH. (See Pathophysiology and Etiology.)
GH acts indirectly, by stimulating the formation of IGF hormones (also called somatomedins). IGF-I (somatomedin C), the most important IGF in postnatal growth, is produced in the liver, chondrocytes, kidneys, muscles, pituitary gland, and gastrointestinal tract.
Once released into the circulation, GH stimulates the production of IGF-I. The main source of circulating IGF-I is the liver, though it is produced in many other tissues. IGF-I is the primary mediator of the growth-promoting effects of GH.
It is characterized by increased and unregulated GH production, usually caused by a GH-secreting pituitary tumor (somatotroph tumor). Other causes of increased and unregulated GH production, all very rare, include increased GH-releasing hormone (GHRH) from hypothalamic tumors; ectopic GHRH from nonendocrine tumors; and ectopic GH secretion by nonendocrine tumors.
Pathophysiology and Etiology
Causes of excess IGF-I action can be divided into the following 3 categories:
Release of primary GH excess from the pituitary
Increased GHRH secretion or hypothalamic dysregulation
Hypothetically, the excessive production of IGF-binding protein, which prolongs the half-life of circulating IGF-I
By far, most people with gigantism or acromegaly have GH-secreting pituitary adenomas or hyperplasia. Other causes of increased and unregulated GH production, all very rare, include increased GHRH from hypothalamic tumors; ectopic GHRH from nonendocrine tumors; and ectopic GH secretion by nonendocrine tumors.
Although gigantism is typically an isolated disorder, rare cases occur as a feature of other conditions, such as the following:
Approximately 20% of patients with gigantism have McCune-Albright syndrome (the triad of precocious puberty, café au lait spots, fibrous dysplasia) and may have either pituitary hyperplasia or adenomas. (See the image below.)
More than 95% of acromegaly cases are caused by a pituitary adenoma that secretes excess amounts of GH. Histopathologically, tumors include acidophil adenomas, densely granulated GH adenomas, sparsely granulated GH adenomas, somatomammotropic adenomas, and plurihormonal adenomas.
Ectopic production of GH and GHRH by malignant tumors accounts for other causes of IGF-I excess. (Ectopic GHRH-producing tumors, usually seen in the lung or pancreas, may occasionally be evident elsewhere, such as in the duodenum as a neuroendocrine carcinoma.)[8, 9]
Of these tumors, up to 40% have a mutation involving the alpha subunit of the stimulatory guanosine triphosphate (GTP)–binding protein. In the presence of a mutation, persistent elevation of cyclic adenosine monophosphate (cAMP) in the somatotrophs results in excessive GH secretion.
The pathologic effects of GH excess include acral overgrowth, insulin antagonism, nitrogen retention, increased risk of colon polyps/tumors, and acral overgrowth (ie, macrognathia; enlargement of the facial bone structure, as well as of the hands and feet; and visceral overgrowth, including macroglossia and enlargement of the heart muscle, thyroid, liver, and kidney).
Pathologic studies on acromegalic hearts have shown extensive interstitial fibrosis, suggesting the existence of a specific acromegalic cardiomyopathy.
Despite diverse pathophysiologic mechanisms, the final common abnormality in gigantism and acromegaly is IGF-I excess. Elevated tissue levels of free IGF-I, which is produced primarily in hepatocytes in response to excess GH, mediate most, if not all, growth-related outcomes in gigantism. Transgenic mice that overexpressed GH, GHRH, or IGF-I were found to have dramatically accelerated somatic growth compared with control litter mates.
One acromegalic patient had low serum GH levels and elevated serum total IGF-I levels; this finding implicates IGF-I as the key pathologic factor in this disease. Serum levels of IGF-I are consistently elevated in patients with acromegaly and, therefore, are used to monitor treatment success. The conditions described below can cause IGF-I oversecretion.
Primary pituitary GH excess
In most individuals with GH excess, the underlying anomaly is a benign pituitary tumor composed of somatotrophs (GH-secreting cells) or mammosomatotrophs (GH-secreting and prolactin-secreting cells) in the form of a pituitary microadenoma (< 1 cm) or macroadenoma (>1 cm). The adenomas are most characteristically well-demarcated and confined to the anterior lobe of the pituitary gland. In some people with GH excess, the tumor spreads outside the sella, invading the sphenoid bone, optic nerves, and brain. GH-secreting tumors are more likely to be locally invasive or aggressive in pediatric patients than in adults.
Gs-alpha (Gsa) mutation
G proteins play an integral role in postligand signal transduction in many endocrine cells by stimulating adenyl cyclase, resulting in an accumulation of cyclic adenosine monophosphate (cAMP) and subsequent gene transcription. About 20% of patients with gigantism have McCune-Albright syndrome and pituitary hyperplasia or adenomas.
Activating mutations of the stimulatory Gsa protein have been found in the pituitary lesions in McCune-Albright syndrome and are believed to cause the other glandular adenomas observed. Point mutations found in several tissues affected in McCune-Albright syndrome involve a single amino-acid substitution in codon 201 (exon 8) or 227 (exon 9) of the gene for Gsa. Somatic point mutations have been identified in the somatotrophs of less than 40% of sporadic GH-secreting pituitary adenomas. The resulting oncogene (gsp) is thought to induce tumorigenesis by persistently activating adenyl cyclase, with subsequent GH hypersecretion.
Loss of band 11q13 heterozygosity
Loss of heterozygosity at the site of a putative tumor-suppressor gene on band 11q13 was first identified in tumors from patients with MEN type I and GH excess. Loss of heterozygosity at band 11q13 has also been observed in all types of sporadically occurring pituitary adenomas. It is associated with an increased propensity for tumoral invasiveness and biologic activity.
Isolated familial somatotropinoma, a rare disease, refers to the occurrence of 2 or more cases of acromegaly or gigantism in a family in whom the features of Carney complex or MEN type 1 are absent. It appears to be inherited as an autosomal dominant disease with incomplete penetrance. Although an association exists between isolated familial somatotropinoma and loss of heterozygosity on 11q13, the responsible gene remains unknown.
Abnormality at Carney loci on chromosomes 2 and 17
The Carney complex, which is characterized by myxomas, endocrine tumors, and spotty pigmentation, is transmitted as an autosomal dominant trait. About 8% of affected individuals have GH-producing pituitary adenomas. The causative gene for this disease was mapped to bands 2p16 and 17q22-24. Germline mutations in PRKAR1A (which encodes for the protein kinase A type I-alpha regulatory subunit, an apparent tumor-suppressor gene on chromosome arm 17q) were detected in several families with Carney complex.
Secondary GH excess
Causes of secondary GH excess include increased secretion of GHRH due to an intracranial or ectopic source and dysregulation of the hypothalamic-pituitary-GH axis.
Hypothalamic GHRH excess is postulated as a cause for gigantism, possibly secondary to an activating mutation in hypothalamic GHRH neurons. Excess GHRH secretion may be due to an intracranial or ectopic tumor. Several well-documented incidents of hypothalamic GHRH excess demonstrated intracranial gangliocytomas associated with gigantism or acromegaly.
Ectopic GHRH-secreting tumors have included carcinoid, pancreatic islet-cell, and bronchial neoplasms. Prolonged tumoral secretion of GHRH leads to pituitary hyperplasia, with or without adenomatous transformation, that increases levels of GH and other adenohypophyseal peptides.
Disruption of somatostatin tone
Tumoral infiltration into somatostatinergic pathways are hypothesized to be the basis for GH excess in rare incidents of gigantism associated with neurofibromatosis and optic glioma or astrocytomas.
Occurrence in the United States
Gigantism is extremely rare, with approximately 100 reported cases to date. Acromegaly is more common than gigantism, with an incidence of 3-4 cases per million people per year and a prevalence of 40-70 cases per million population.
Gigantism may begin at any age before epiphyseal fusion. The mean age for onset of acromegaly is in the third decade of life; the delay from the insidious onset of symptoms to diagnosis is 5-15 years, with a mean delay of 8.7 years. The mean age at diagnosis for acromegaly is 40 years in males and 45 years in females.
Because of the small number of people with gigantism, mortality and morbidity rates for this disease during childhood are unknown.
In acromegaly, a severe disease that is often diagnosed late, morbidity and mortality rates are high, particularly as a result of associated cardiovascular, cerebrovascular, and respiratory disorders and malignancies.
Because IGF-I is a general growth factor, somatic hypertrophy in acromegaly occurs across all organ systems. Associated complications include the following :
Increased muscle and soft tissue mass
Increased kidney size
Articular overgrowth of synovial tissue and hypertrophic arthropathy
Joint symptoms, back pain, and kyphosis: Common presenting features
Hyperhidrosis (often malodorous)
Carpal tunnel syndrome and other entrapment syndromes
Macroglossia: May result in sleep apnea
Cerebral aneurysm and increased risk of cerebrovascular accident: Less common 
Early diagnosis of acromegaly, however, results in early transsphenoidal pituitary microsurgery, and currently, patients are more likely to be cured than in the past.
Reversal of excessive GH produces the following:
Decreased soft tissue swelling
Restoration of normal glucose tolerance
No studies have established, however, that the treatment of acromegaly leads to a reduction in morbidity and mortality rates, although successful treatment, with normalization of IGF-I levels, may be associated with a return to normal life expectancy.
Remission depends on the initial size of the tumor, the patient’s GH level, and the skill of the neurosurgeon. Remission rates of 80-85% and 50-65% can be expected for microadenomas and macroadenomas, respectively.
The postoperative GH concentration may predict remission rates. According to the results of one study, a postoperative GH concentration of less than 3 ng/dL was associated with a 90% remission rate, which declined to 5% in patients with a postoperative GH concentration of greater than 5 ng/dL.
Metabolic and endocrine complications
Diabetes mellitus occurs in 10-20% of patients with acromegaly. A 2009 study suggests that in patients with acromegaly, insulin resistance and hyperinsulinemia are positively correlated with the level of disease activity. Hypertriglyceridemia is found in 19-44% of patients. Multinodular goiter also is often present in acromegaly.
Hypopituitarism may develop in patients with acromegaly, as a result of the pituitary mass or as a complication of surgery or radiation therapy. Treat pituitary failure with appropriate hormone-replacement therapy.
In acromegaly, respiratory complications occur as follows:
Increased lung capacity: 81% of men and 56% of women
Small airway narrowing: 36% of patients
Upper airway narrowing: 26% of patients
Acute dyspnea and stridor
Sleep apnea: As a significant cause of morbidity, sleep apnea may be both obstructive and central; curing acromegaly does not necessarily correct the disorder
A study by Berg et al found an increased prevalence of cardiovascular risk factors in patients with acromegaly compared with controls. Cardiovascular complications include the following:
Acromegalic cardiomyopathy (with dysfunction and arrhythmias)
Left ventricular hypertrophy
Increased left ventricular mass
Disorders of calcium and bone metabolism
The following calcium and bone metabolism disorders can be found in acromegaly:
In acromegaly, these include the following:
Weakness (although with muscular appearance)
Nerve root compression
Carpal tunnel syndrome
Patients with acromegaly may be at increased risk for colorectal cancer and premalignant adenomatous polyps. Most studies suggest that as many as 30% of patients may have a premalignant colon polyp at diagnosis and that as many as 5% may have a colonic malignancy. In studies, polyps were generally multiple and proximal to the splenic flexure, making them less likely to be discovered during sigmoidoscopy. However, the long-term effect of colonic lesions on morbidity and mortality has not been established.
Patients with acromegaly may also have an increased risk of developing breast and prostate tumors, although no clear evidence supports this; the risk of thyroid cancer is increased in males. However, the prevalence of cancers in patients with acromegaly remains controversial, although patients might be advised to undergo screening colonoscopy and thyroid ultrasonography.[16, 17, 15]
For individuals with acromegaly, the mortality rate is 2-3 times that of the general population, with cardiovascular and respiratory complications being the most frequent causes of death. Transgenic mouse models of acromegaly demonstrate cardiac and vascular hypertrophy but normal function, raising the concern that hypertrophic cardiomyopathy may contribute to the increased mortality.
A study by Bates et al suggested that the extent of a patient’s GH excess impacts mortality. The investigators found that acromegaly patients with a GH concentration of greater than 10 ng/mL had double the expected mortality rate, whereas patients with a GH concentration of less than 5 ng/mL approached normal mortality. These results underscore the necessity to reduce GH and IGF-I concentration in patients with acromegaly.
Researchers disagree on whether malignancy is a significant cause of increased mortality in acromegaly. Although benign tumors (including uterine myomas, prostatic hypertrophy, and skin tags) are frequently encountered in acromegaly, documentation for overall prevalence of malignancies in patients with acromegaly remains controversial.
Berg C, Petersenn S, Lahner H, Herrmann BL, Buchfelder M, Droste M, et al. Cardiovascular risk factors in patients with uncontrolled and long-term acromegaly: comparison with matched data from the general population and the effect of disease control. J Clin Endocrinol Metab. 2010 Aug. 95(8):3648-56. [Medline].
Nainggolan L. Gene Discovery in Giants Could Shed Light on Human Growth. Medscape Medical News. Available at http://www.medscape.com/viewarticle/836216.. Accessed: December 12, 2014.
Trivellin G, Daly AF, Faucz FR, Yuan B, Rostomyan L, Larco DO, et al. Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation. N Engl J Med. 2014 Dec 18. 371(25):2363-74. [Medline].
Al-Bedaia M, Al-Khenaizan AS. Acromegaly presenting as cutis verticis gyrata. Int J Dermatol. 2008 Feb. 47(2):164. [Medline].
Bush ZM, Vance ML. Management of acromegaly: is there a role for primary medical therapy?. Rev Endocr Metab Disord. 2008 Mar. 9(1):83-94. [Medline].
Colao A, Pivonello R, Auriemma RS, Briganti F, Galdiero M, Tortora F, et al. Predictors of tumor shrinkage after primary therapy with somatostatin analogs in acromegaly: a prospective study in 99 patients. J Clin Endocrinol Metab. 2006 Jun. 91(6):2112-8. [Medline].
Giustina A, Chanson P, Bronstein MD, Klibanski A, Lamberts S, Casanueva FF, et al. A consensus on criteria for cure of acromegaly. J Clin Endocrinol Metab. 2010 Jul. 95(7):3141-8. [Medline].
Colak Ozbey N, Kapran Y, Bozbora A, Erbil Y, Tascioglu C, Asa SL. Ectopic growth hormone-releasing hormone secretion by a neuroendocrine tumor causing acromegaly: long-term follow-up results. Endocr Pathol. 2009 Summer. 20(2):127-32. [Medline].
Uchoa HB, Lima GA, Corrêa LL, Vidal AP, Cavallieri SA, Vaisman M, et al. Prevalence of thyroid diseases in patients with acromegaly: experience of a Brazilian center. Arq Bras Endocrinol Metabol. 2013 Dec. 57(9):685-90. [Medline].
Soares BS, Eguchi K, Frohman LA. Tumor deletion mapping on chromosome 11q13 in eight families with isolated familial somatotropinoma and in 15 sporadic somatotropinomas. J Clin Endocrinol Metab. 2005 Dec. 90(12):6580-7. [Medline].
Melmed S, Casanueva FF, Klibanski A, Bronstein MD, Chanson P, Lamberts SW, et al. A consensus on the diagnosis and treatment of acromegaly complications. Pituitary. 2013 Sep. 16(3):294-302. [Medline]. [Full Text].
Oshino S, Nishino A, Suzuki T, et al. Prevalence of cerebral aneurysm in patients with acromegaly. Pituitary. 2013 Jun. 16(2):195-201. [Medline].
Stelmachowska-Banas M, Zdunowski P, Zgliczynski W. Abnormalities in glucose homeostasis in acromegaly. Does the prevalence of glucose intolerance depend on the level of activity of the disease and the duration of the symptoms?. Endokrynol Pol. 2009 Jan-Feb. 60(1):20-4. [Medline].
Dworakowska D, Gueorguiev M, Kelly P, Monson JP, Besser GM, Chew SL, et al. Repeated colonoscopic screening of patients with acromegaly: 15-year experience identifies those at risk of new colonic neoplasia and allows for effective screening guidelines. Eur J Endocrinol. 2010 Jul. 163(1):21-8. [Medline].
Loeper S, Ezzat S. Acromegaly: re-thinking the cancer risk. Rev Endocr Metab Disord. 2008 Mar. 9(1):41-58. [Medline].
Kurimoto M, Fukuda I, Hizuka N, Takano K. The prevalence of benign and malignant tumors in patients with acromegaly at a single institute. Endocr J. 2008 Mar. 55(1):67-71. [Medline].
Izzard AS, Emerson M, Prehar S, Neyses L, Trainer P, List EO, et al. The cardiovascular phenotype of a mouse model of acromegaly. Growth Horm IGF Res. 2009 Oct. 19(5):413-9. [Medline].
[Guideline] Katznelson L, Atkinson JL, Cook DM, Ezzat SZ, Hamrahian AH, Miller KK. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Diagnosis and Treatment of Acromegaly--2011 update: executive summary. Endocr Pract. 2011 Jul-Aug. 17(4):636-46. [Medline].
Wang M, Mou C, Jiang M, Han L, Fan S, Huan C, et al. The characteristics of acromegalic patients with hyperprolactinemia and the differences in patients with merely GH-secreting adenomas: clinical analysis of 279 cases. Eur J Endocrinol. 2012 May. 166(5):797-802. [Medline].
Almalki MH, Chesover AD, Johnson MD, Wilkins GE, Maguire JA, Ur E. Characterization of management and outcomes of patients with acromegaly in Vancouver over 30 years. Clin Invest Med. 2012 Feb 1. 35(1):E27-33. [Medline].
Sata A, Ho KK. Growth hormone measurements in the diagnosis and monitoring of acromegaly. Pituitary. 2007. 10(2):165-72. [Medline].
Daroszewski J, Bolanowski M, Kaluzny M, Siewinski M. The imbalance of cathepsin B-like activity in acromegalic patients--preliminary report. Neuro Endocrinol Lett. 2010. 31(2):256-60. [Medline].
Roelfsema F, Biermasz NR, Romijn JA, Pereira AM. Treatment strategies for acromegaly. Expert Opin Emerg Drugs. 2005 Nov. 10(4):875-90. [Medline].
[Guideline] Katznelson L, Laws ER Jr, Melmed S, et al. Acromegaly: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2014 Nov. 99(11):3933-51. [Medline].
[Guideline] Nainggolan L. New Guidelines for Acromegaly Include Advice on Pregnancy. Medscape Medical News. Nov 10 2014. [Full Text].
Azkur D, Yoldas T, Toyran M, Kocabas CN. A pediatric case of anaphylaxis due to octreotide. Asian Pac J Allergy Immunol. 2011 Dec. 29(4):361-3. [Medline].
Shimatsu A, Teramoto A, Hizuka N, Kitai K, Ramis J, Chihara K. Efficacy, safety, and pharmacokinetics of sustained-release lanreotide (lanreotide Autogel) in Japanese patients with acromegaly or pituitary gigantism. Endocr J. 2013. 60(5):651-63. [Medline].
Sheppard M, Bronstein MD, Freda P, Serri O, De Marinis L, Naves L, et al. Pasireotide LAR maintains inhibition of GH and IGF-1 in patients with acromegaly for up to 25 months: results from the blinded extension phase of a randomized, double-blind, multicenter, Phase III study. Pituitary. 2014 Aug 8. [Medline].
Gadelha MR, Bronstein MD, Brue T, Coculescu M, Fleseriu M, Guitelman M, 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 Nov. 2(11):875-84. [Medline].
Sandret L, Maison P, Chanson P. Place of cabergoline in acromegaly: a meta-analysis. J Clin Endocrinol Metab. 2011 May. 96(5):1327-35. [Medline].
van der Lely AJ, Biller BM, Brue T, Buchfelder M, Ghigo E, Gomez R, et al. Long-term safety of pegvisomant in patients with acromegaly: comprehensive review of 1288 subjects in ACROSTUDY. J Clin Endocrinol Metab. 2012 May. 97(5):1589-97. [Medline].
Higham CE, Atkinson AB, Aylwin S, Bidlingmaier M, Drake WM, Lewis A, et al. Effective combination treatment with cabergoline and low-dose pegvisomant in active acromegaly: a prospective clinical trial. J Clin Endocrinol Metab. 2012 Apr. 97(4):1187-93. [Medline].
Rix M, Laurberg P, Hoejberg AS, Brock-Jacobsen B. Pegvisomant therapy in pituitary gigantism: successful treatment in a 12-year-old girl. Eur J Endocrinol. 2005 Aug. 153(2):195-201. [Medline].
Castinetti F, Morange I, Dufour H, Regis J, Brue T. Radiotherapy and radiosurgery in acromegaly. Pituitary. 2009. 12(1):3-10. [Medline].
Weber DC, Momjian S, Pralong FP, Meyer P, Villemure JG, Pica A. Adjuvant or radical fractionated stereotactic radiotherapy for patients with pituitary functional and nonfunctional macroadenoma. Radiat Oncol. 2011 Dec 8. 6:169. [Medline]. [Full Text].
Jagannathan J, Yen CP, Pouratian N, Laws ER, Sheehan JP. Stereotactic radiosurgery for pituitary adenomas: a comprehensive review of indications, techniques and long-term results using the Gamma Knife. J Neurooncol. 2009 May. 92(3):345-56. [Medline].
Espinosa-de-Los-Monteros AL, Sosa E, Cheng S, Ochoa R, Sandoval C, Guinto G, et al. Biochemical evaluation of disease activity after pituitary surgery in acromegaly: a critical analysis of patients who spontaneously change disease status. Clin Endocrinol (Oxf). 2006 Mar. 64(3):245-9. [Medline].
Abe T, Tara LA, Lüdecke DK. Growth hormone-secreting pituitary adenomas in childhood and adolescence: features and results of transnasal surgery. Neurosurgery. 1999 Jul. 45(1):1-10. [Medline].
Ronchi CL, Giavoli C, Ferrante E, Verrua E, Bergamaschi S, Ferrari DI, et al. Prevalence of GH deficiency in cured acromegalic patients: impact of different previous treatments. Eur J Endocrinol. 2009 Jul. 161(1):37-42. [Medline].
van der Klaauw AA, Bax JJ, Roelfsema F, Bleeker GB, Holman ER, Corssmit EP, et al. Uncontrolled acromegaly is associated with progressive mitral valvular regurgitation. Growth Horm IGF Res. 2006 Apr. 16(2):101-7. [Medline].
Chahal HS, Stals K, Unterländer M, Balding DJ, Thomas MG, Kumar AV, et al. AIP mutation in pituitary adenomas in the 18th century and today. N Engl J Med. 2011 Jan 6. 364(1):43-50. [Medline].
Kannan S, Kennedy L. Diagnosis of acromegaly: state of the art. Expert Opin Med Diagn. 2013 Sep. 7(5):443-53. [Medline].