Acromegaly resident survival guide

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Tayyaba Ali, M.D.[2]

Synonyms and Keywords: Somatotroph adenoma; Growth hormone excess; Growth hormone secreting pituitary adenoma

Overview

Acromegaly is the clinical syndrome that results from excessive secretion of growth hormone (GH). Its annual incidence is six to eight per million people. The mean age at diagnosis is 40 to 45 years. The most common cause of acromegaly is a somatotroph (GH-secreting) adenoma of the anterior pituitary. Life-threatening causes include conditions that may result in death or permanent disability within 24 hours if left untreated. There is no life-threatening cause of acromegaly. However, if left untreated, 30% of patients with acromegaly may progress to develop cardiovascular manifestations, pulmonary dysfunction, and cerebral complications. These comorbidities will increase the mortality rate. IGF-1 should be measured in patients without the typical manifestations of acromegaly, but who have several of these associated conditions: sleep apnea syndrome, type 2 diabetes mellitus, debilitating arthritis, carpal tunnel syndrome, hyperhidrosis, and hypertension. Katznelson et al. recommends Transsphenoidal surgery as the primary therapy in most patients. Endocrine society clinical practice guideline on acromegaly also recommends Radiation therapy in the setting of residual tumor mass following surgery, and if medical treatment is unavailable, unsuccessful, or not tolerated.

Causes

Life Threatening Causes

Life-threatening causes include conditions that may result in death or permanent disability within 24 hours if left untreated. There is no life-threatening cause of acromegaly. However, if left untreated, 30% of patients with acromegaly may progress to develop cardiovascular manifestations, pulmonary dysfunction, and cerebral complications. These comorbidities will increase the mortality rate. [1]

Common Causes

Diagnosis

The approach to diagnosis of Acromegaly is based on a step-wise testing strategy. Below is an algorithm summarising the identification and laboratory diagnosis of Acromegaly.[9]

 
 
 
 
 
 
 
 
 
 
 
 
Characterize the symptoms:

Headaches
❑ Enlargement of the hands (change in ring or glove size) and feet (change in shoe size)
Lethargy
Hyperhidrosis (excessive sweating)
Paraesthesia [10]
Fatigue
Jaw pain
❑ Body odor
Blood in the stool
Sleep apnea
Weight gain [11]

❑ In males:
Sexual dysfunction
Loss of libido
Gynecomastia [12]

❑ In females:
Amenorrhea
Galactorrhea [12]
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Examine the patient:

❑ HEENT

❑ Musculoskeletal exam:

❑ Neurological exam:

❑ Cardiovascular exam:

❑ Skin exam:

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Measure Insulin like growth factor-1 (IGF-1) levels
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal
 
Equivocal
 
Elevated
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Active acromegaly ruled out
 
 
Acromegaly confirmed in a patient with typical clinical manifestations
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inadequate suppression
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Active acromegaly ruled out
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal
 
Mass or empty sella
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest and abdominal CT, Growth hormone-releasing hormone (GHRH) measurement
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Extra-pituitary acromegaly
 


This algorithm developed and modified according to Endocrine Society (ES): Clinical practice guideline on acromegaly.

Treatment

Shown below is an algorithm summarizing the treatment of Acromegaly according the the Endocrine Society (ES): Clinical practice guideline on acromegaly.

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Transphenoidal surgery
❑ Complete resection
❑ Tumors that are unresectable, a surgical debulking procedure may be performed followed by medical therapy
 
Yes
 
Patient is not a surgical candidate
❑ Patient preference
❑ High risk due to medical comorbidities
❑ Unresectable tumors
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Are the following criteria met postoperatively?
❑ Morning serum GH the day after surgery <1ng/ml
❑ 12 weeks postoperative:
  • Normal serum IGF-1 (for age and gender)
  • No evidence of residual tumor on pituitary MRI
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Yes
 
No
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Remission
❑ Monitor with annual IGF-1
 
Is there residual tumor that appears resectable and readily accessible (eg, not invading the cavernous sinus)?
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Perform MRI for clinical or biochemical evidence of recurrence
 
Medical therapy

Somatostatin analogs:

  • Preferred regimen (1): Octreotide 50 mcg q8hr subcutaneous as initial dose and 100 mcg q8hr as effective dose.
  • Preferred regimen (2): Lanreotide 90 mg q4week for 3 months every 4 weeks subcutaneous.
  • Preferred regimen (3): Pasireotide 40 mg q4wk intramuscular.

Dopamine agonists:

  • Preferred regimen (1): Cabergoline 0.25 mg 2x/week orally.
  • Preferred regimen (2): Bromocriptine 1.25-2.5 mg qDay orally.

GH receptor antagonist:

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Failure of medical therapy
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Radiation therapy
❑ Stereotactic radiotherapy is most common method
 
 
 
 
 


This algorithm developed and modified according to Endocrine Society (ES): Clinical practice guideline on acromegaly.

Do's

  • Endocrine society clinical practice guideline recommends measuring IGF-1 in patients without acromegaly's typical manifestations, but who have several of these associated conditions: sleep apnea syndrome, type 2 diabetes mellitus, debilitating arthritis, carpal tunnel syndrome, hyperhidrosis, and hypertension.
  • Serum IGF-1 should be measured to rule out acromegaly in a patient with a pituitary mass.
  • When serum IGF-1 levels are elevated or equivocal in patients, confirmation of the diagnosis is recommended by finding a lack of GH suppression to < 1 μg/L following documented hyperglycemia during an oral glucose load.
  • Following a biochemical diagnosis of acromegaly, we recommend performing an imaging study to visualize tumor size and appearance, as well as parasellar extent. Magnetic resonance imaging (MRI) is recommended as the imaging modality of choice, followed by computed tomography (CT) scan when MRI is contraindicated or unavailable.
  • It is recommended to perform a formal visual field testing when the tumor is found to abut the optic chiasm on an imaging study.
  • When the diagnosis of acromegaly is made, screening is recommended for colon neoplasia with colonoscopy.
  • Thyroid ultrasound is recommended if there is palpable thyroid nodularity.
  • It is recommended to assess for hypopituitarism and replacing hormone deficits.
  • Recommendations from Endocrine society clinical practice guideline also includes evaluation of all patients that present with acromegaly for associated comorbidities, including hypertension, diabetes mellitus, cardiovascular disease, osteoarthritis, and sleep apnea. These comorbidities are longitudinally monitored and rigorously managed.
  • Katznelson et al. recommends Transsphenoidal surgery as the primary therapy in most patients.
  • Repeat surgery should be considered in a patient with the residual intrasellar disease following initial surgery.
  • Following surgery, it is recommended to measure an IGF-1 level and a random GH at 12 weeks or later. GH level should be measured after a glucose load in a patient with a GH greater than 1 μg/L.
  • Imaging study should be performed at least 12 weeks after surgery to visualize the residual tumor and adjacent structures. MRI is the imaging modality of choice followed by a CT scan when MRI is contraindicated or unavailable.
  • In a patient with significant disease (ie, with moderate-to-severe signs and symptoms of GH excess and without local mass effects), we suggest the use of either a Somatostatin receptor ligand (SRL) or pegvisomant as the initial adjuvant medical therapy.
  • In a patient with only modest elevations of serum IGF-1 and mild signs and symptoms of GH excess, dopamine agonist trial is suggested, usually cabergoline, as the initial adjuvant medical therapy.
  • Serial imaging with MRI scan is recommended to evaluate tumor size in a patient receiving pegvisomant.
  • The guideline recommends Liver function tests to be monitored monthly for the first six months and then every six months in a patient receiving pegvisomant, considering discontinuation of pegvisomant if the transaminases are more remarkable than 3-fold elevated.
  • Pegvisomant or cabergoline should be added in a patient with inadequate response to a Somatostatin receptor analog (SRL).
  • In a patient who cannot be cured by surgery, has extensive cavernous sinus invasion, does not have chiasmal compression, or is a poor surgical candidate, Somatostatin receptor analog (SRL) should be used as primary therapy.
  • During pregnancy, serial visual field testing is recommended in patients with macroadenomas.
  • Endocrine society clinical practice guideline on acromegaly recommends Radiation therapy in the setting of residual tumor mass following surgery, and if medical treatment is unavailable, unsuccessful, or not tolerated.
  • The guideline suggests using Stereotactic radiotherapy (SRT) over conventional radiation therapy (RT) in patients with acromegaly. The guideline recommends RT if the SRT is not available, in case of a significant residual tumor burden, or the tumor abuts the optic chiasm resulting in exposure of more than 8 Gy.
  • The guideline suggests annual GH/IGF-1 reassessment following medication withdrawal to monitor the efficacy of radiation therapy.
  • Annual hormonal testing of patients is recommended following RT for hypopituitarism and other delayed radiation effects. [9]

Don'ts

  • Physicians should not rely on the use of random GH levels to diagnose acromegaly.
  • Preoperative medical therapy should not continue to improve biochemical control after surgery.
  • In a patient with parasellar disease making total surgical resection is not recommended, surgical debulking should be done to improve subsequent response to medical therapy.
  • Monitoring of GH and/or IGF-1 levels during pregnancy.
  • Acromegaly medical therapy should be withheld and administered only for tumor and headache control.
  • Long-acting somatostatin receptor ligands (SRL) formulations and pegvisomant should be discontinued approximately two months before conceiving, with the use of short-acting octreotide as necessary until conception.
  • A routine abdominal ultrasound should not be performed to detect gallstone disease in a patient receiving a Somatostatin receptor ligand (SRL) [9]

References

  1. Melmed S (2009). "Acromegaly pathogenesis and treatment". J Clin Invest. 119 (11): 3189–202. doi:10.1172/JCI39375. PMC 2769196. PMID 19884662.
  2. Landis CA, Masters SB, Spada A, Pace AM, Bourne HR, Vallar L (1989). "GTPase inhibiting mutations activate the alpha chain of Gs and stimulate adenylyl cyclase in human pituitary tumours". Nature. 340 (6236): 692–6. doi:10.1038/340692a0. PMID 2549426.
  3. Vallar L, Spada A, Giannattasio G (1987). "Altered Gs and adenylate cyclase activity in human GH-secreting pituitary adenomas". Nature. 330 (6148): 566–8. doi:10.1038/330566a0. PMID 2825031.
  4. Hayward BE, Barlier A, Korbonits M, Grossman AB, Jacquet P, Enjalbert A; et al. (2001). "Imprinting of the G(s)alpha gene GNAS1 in the pathogenesis of acromegaly". J Clin Invest. 107 (6): R31–6. doi:10.1172/JCI11887. PMC 208949. PMID 11254676.
  5. Melmed S, Ezrin C, Kovacs K, Goodman RS, Frohman LA (1985). "Acromegaly due to secretion of growth hormone by an ectopic pancreatic islet-cell tumor". N Engl J Med. 312 (1): 9–17. doi:10.1056/NEJM198501033120103. PMID 2981107.
  6. Altstadt TJ, Azzarelli B, Bevering C, Edmondson J, Nelson PB (2002). "Acromegaly caused by a growth hormone-releasing hormone-secreting carcinoid tumor: case report". Neurosurgery. 50 (6): 1356–9, discussion 1360. doi:10.1097/00006123-200206000-00029. PMID 12015856.
  7. Beuschlein F, Strasburger CJ, Siegerstetter V, Moradpour D, Lichter P, Bidlingmaier M; et al. (2000). "Acromegaly caused by secretion of growth hormone by a non-Hodgkin's lymphoma". N Engl J Med. 342 (25): 1871–6. doi:10.1056/NEJM200006223422504. PMID 10861322.
  8. "Correction to Lancet Infectious Diseases 2020; published online April 29. https://doi.org/10.1016/ S1473-3099(20)30064-5". Lancet Infect Dis. 20 (7): e148. 2020. doi:10.1016/S1473-3099(20)30370-4. PMID 32595044 Check |pmid= value (help). External link in |title= (help)
  9. 9.0 9.1 9.2 9.3 Katznelson L, Laws ER, Melmed S, Molitch ME, Murad MH, Utz A; et al. (2014). "Acromegaly: an endocrine society clinical practice guideline". J Clin Endocrinol Metab. 99 (11): 3933–51. doi:10.1210/jc.2014-2700. PMID 25356808.
  10. 10.0 10.1 10.2 Molitch ME (1992). "Clinical manifestations of acromegaly". Endocrinol Metab Clin North Am. 21 (3): 597–614. PMID 1521514.
  11. 11.0 11.1 11.2 "Acromegaly: MedlinePlus Medical Encyclopedia".
  12. 12.0 12.1 Iuliano SL, Laws ER (2014). "Recognizing the clinical manifestations of acromegaly: case studies". J Am Assoc Nurse Pract. 26 (3): 136–42. doi:10.1002/2327-6924.12076. PMID 24170330.
  13. Ben-Shlomo A, Melmed S (2006). "Skin manifestations in acromegaly". Clin Dermatol. 24 (4): 256–9. doi:10.1016/j.clindermatol.2006.04.011. PMID 16828406.


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