A. Introduction

1. Acromegaly is due to overproduction of growth hormone (GH)
   1. Pituitary tumors represent ~15% of primary brain tumors
   2. Incidence of acromegaly is ~3 cases per million per year
2. Benign hyperplasia of anterior pituitary somatotroph cells cause 90% of cases
   1. Monoclonal expansion of GH producing cells in anterior pituitary
   2. GH stimulates production of somatomedins which stimulate soft tissue growth
   3. Benign tumor subtypes include "sparsely" and "densely" granulated adenomas
   4. About 40% of these tumors have activating mutations in G-protein alpha [9]
   5. These mutations lead to excessive signalling, cAMP increases, and cell proliferation
   6. Both endocrine effects and space-expanding symptoms occur
3. Other Causes of GH Excess
   1. Hypothalamic tumors - overproduction of GH releasing hormone (GHRH)
   2. Ectopic production of GH
4. Most cases diagnosed between ages 20-40
5. Prevalence of GH secreting adenomas is 50-80 cases per million

B. Biology of Growth Hormone (GH) [1]

1. GH is mainly a 191 amino acid polypeptide hormone, coded on chromosome 17q
2. Less abundant 176 amino acid form also produced
3. GH is synthesized by cells in the anterior pituitary gland called somatotrophs
4. Normal Regulation of GH Secretion by Somatotrophs
   1. Stimulated by GHRH released from hypothalamus
   2. GHRH is GH releasing hormone induces synthesis and secretion of GH
   3. Somatostatin, produced in hypothalamus, suppresses secretion of GH
   4. Also regulated by ghrelin, a GH secretagogue-receptor ligand
   5. Ghrelin is made primarily in gastrointestinal tract in response to nutrients
   6. Ghrelin acts through hypothalamus to stimulate GH secretion
5. GH Action
   1. GH binds to GH receptor, which is a G protein coupled receptor (GPCR)
   2. GH binding to GH-R causes production of Somatomedins in target tissues
6. Somatomedins stimulate growth of soft tissue structures
   1. Major somatomedin is Insulin-like growth factor 1 (IGF-1)
   2. IGF-1 was previously called somatomedin C
   3. IGF-1 circulates in complex with IGF-I binding protein 3 (IGF-BP3)

C. Symptoms

1. Due to Mass Effects
   1. Pituitary enlargement
   2. Visual field defects
   3. Cranial nerve palsy
   4. Headache
2. Acral Anlargement
   1. Growth of hands, feet, and head
   2. Increased head size is called acromegaly
   3. Overall body increase size is called gigantism
   4. Thickening of soft tissue of hands and feet
3. Coarsened facial features and frontal bossing (increased spacing between teeth)
4. Fatigue, weight gain
5. Cardiovascular
   1. Left ventricular hypertrophy
   2. Asymmetric septal hypertrophy
   3. Cardiomyopathy
   4. Hypertension
   5. Congestive Heart Failure
6. Endocrine Dysfunction
   1. Deceased libido, erectile dysfunction
   2. Oligomenorrhea
   3. Galactorrhea
   4. Low levels of sex-hormone binding globulin
   5. Hyperglycemia, possible diabetes mellitus
   6. Hypertriglyceridemia
   7. Hypercalciuria
   8. Goiter
   9. Multiple endocrine neoplasia type 1: hyperparathyroidism, pancreatic iselt-cell tumors
7. Weakness, proximal myopathy
8. Carpal tunnel syndrome - due to increased edema of median nerve [11]
9. Seizures
10. Skin
    1. Skin tags
    2. Hyperhidrosis / Diaphoresis / Heat intolerance
    3. Oily texture
11. Sleep Abnormalities
    1. Sleep apnea - central and obstructive
    2. Narcolepsy

D. Complications of Acromegaly and Gigantism

1. Congestive Heart Failure (CHF) [13]
   1. Often high output heart failure
   2. Dilated ventricle and increased left ventricular mass
   3. Occurs in ~10% at presentation
2. Nephrolithiasis and Nephromegaly [8]
3. Pituitary Apoplexy
4. Diabetes mellitus
5. Cholelithiasis - ~70% of patients
6. Osteoarthritis
7. Disfigurement

E. Diagnosis

1. Acromegaly and gigantism are usually obvious and confirmed with GH level >10µg/L
2. Measurement of IGF-1 (Somatomedin C) is most reliable single test [3]
   1. Occasionally, IGF-1 level will be normal in acromegaly
   2. A high total IGF-1 level is generally diagnostic of the disease
   3. In setting of nephrotic syndrome, IGF-1 measurements are unreliable [8]
3. If acromegaly is suspected with a normal IGF-1 level, then glucose suppression is done
   1. 75gm of oral glucose is given to the patient
   2. GH and IGF-1 levels will be suppressed to <2ng/mL in normal persons
4. Measurement of Growth Hormone Releasing Hormone (GHRH)
   1. Useful in evaluation of acromegaly
   2. Suppressed in acromegaly cases due to pituitary tumors or ectopic hormone
   3. Small cell lung carcinoma occasionally produces ectopic GH
   4. Highly elevated in hpothalamic tumors which produce GHRH
5. Radiographic Studies
   1. MRI study of the pituitary region is gold standard
   2. Skull films may show metastatic or invasive disease
   3. Chest radiography (or CT scan) may show lung tumor

F. Treatment

1. Objectives [2]
   1. Removal of tumor with resolution of mass effects
   2. Preservation of normal residual pituitary function
   3. Prevention of recurrences
   4. Relief of symptoms due to GH excess
   5. Prevention of long-term complications
   6. Multimodality treatment is usually used
2. Surgery
   1. Microsurgical techniques for removal of microadenomas have ~60% cure rates
   2. Transsphenoidal surgery for microadenomas and GH levels <40µg/L
   3. Macroadenomas treated with resection have ~30-40% cure rates
   4. Invasion of cavernous sinus prevents complete resection
   5. These cure rates are based on normalization of serum hormone levels
   6. However, a "safe" level of GH after removal is probably 1.7-2.5µg/L [2]
   7. Tumors tend to recur in ~10% of surgically treated cases
3. Radiotherapy
   1. As primary therapy, reduction in GH levels only occur over years
   2. Electron beam radiation usually used over 5-6 week period
   3. Concern for side effects including panhypopituitarism
   4. Probably best as adjunct to surgery or in patients where surgery cannot be used
   5. Serum GH levels fall after radiation to <5µg/L in 40-80% of patients
4. Dopamine Agonists
   1. Dopamine is known to suppress GH levels in patients with acromegaly
   2. Dopamine agonists stimulate GH in normal persons, however
   3. Dopamine agonists inhibit GH secreting tumors which also produce prolactin
   4. Bromocriptine (Parlodel®) is commonly used
   5. Bromocriptine starting dose is 1.25mg per day
   6. Reduces GH to <10µg/L in ~50% of cases, to <5µg/L in ~15% of cases
5. Long-Acting Somatostatin Analogs
   1. Octreotide (Sandostatin®) is a long-acting somatostatin analog given 100µg sc tid
   2. Somatostatin blocks GH release from somatotrophs
   3. Octreotide therapy reduces GH levels in ~70% of patients [4]
   4. Octreotide reduced GH to <2.5µg/L in ~30% of patients [2]
   5. Octreotide has little effect on total tumor size although it inhibits cell growth [6]
   6. Octreotide is generally reserved for patients who fail surgery, or during radiotherapy
   7. Side effects include gallbladder problems in ~20% of persons
   8. Lanreotide is a cyclic octapeptide; similar activity and better tolerance than octreotide
6. GH Receptor Antagonist [10,14]
   1. Pegvisomant (Somavert®) is genetically engineered analogue of hGH
   2. This analog has 9 amino acid substitutions which cause antagonist actions
   3. Conjugated to polyethylaene glycol (PEG) to reduce renal clearance and immunogenicity
   4. Doses 10-20mg per day for >12 months reduced serum IGF-1 levels ~50%
   5. Serum insulin and glucose concentrations significantly reduced
   6. Reduced soft tissue swelling, degree of perspiration and fatigue with 15-20mg/day
   7. Mean pituitary tumor volume decreased slightly
   8. Well tolerated with mild injection site reactions, some nausea, vomiting, chest pain
   9. Anti-GH Abs formed in 17% of patients
   10. Cost is $50,000-$100,000 annually, but may be most effective medication to date
7. Combination Somatostatin Analogs with Pegvisomant [5]
   1. Pegvisomant once daily is very costly
   2. Long-acting somatostatin analogs (above) once monthly+weekly pegvisomant very effective
   3. Combination leads to normalization of IGF-1 concentrations in 95% of patients
   4. Mild increases in liver enzymes in 38%
   5. Considerably reduced costs and potential for improved compliance
8. Aggressive therapy of complications of disease

References

1. Melmed S. 2006. NEJM. 355(24):2558
2. Colao A and Lombardi G. 1998. Lancet. 352(9138):1455
3. Le Roith D. 1997. NEJM. 336(9):633
4. Lamberts SWJ, van der Lely AJ, de Herder WW, Hofland LJ. 1996. NEJM. 334(4):246
5. Feenstra J, de Herder WW, ten Have SMTH, et al. 2005. Lancet. 365:1645
6. Thapar K, Kovacs KT, Stefaneanu L, et al. 1997. May Clin Proc. 72(10):893
7. Colao A and Lombardi G. 1998. Lancet. 352(9139):1455
8. Hammerman MR and Hill DA. 1995. Am J Med. 99(5):563 (Case Report CPC)
9. Farfel Z, Bourne HR, Iiri T. 1999. NEJM. 340(13):1012
10. Trainer PJ, Drake WM, Katznelson L, et al. 2000. NEJM. 342(16):1171
11. Jenkins PJ, Sohaib SA, Akker S, et al. 2000. Ann Intern Med. 133(3):197
12. Van der Lely AJ, Hutson RK, Trainer PJ, et al. 2001. Lancet. 358(9295):1754
13. Damjanovic SS, Neskovic AN, Petakov MS, et al. 2002. Am J Med. 112(8):610
14. Pegvisomant. 2003. Med Let. 45(1160):54