Termed acromegaly, the disease occurs equally in men and women but is diagnosed more frequently in women. It may occur at any age, but is mostly diagnosed in the 40-50 year age group. It is estimated that three new cases per million are diagnosed annually. If the disease occurs before puberty, gigantism is the result. Gigantism affects less than 5% of patients.

Although 99% of acromegalic cases are caused by a pituitary tumor, excessive production of growth hormone can also be caused by peripheral tumors (ectopic). Examples are pancreatic tumors, medullary thyroid cancer, small cell lung cancer , and some adrenal tumors.

Acromegaly is a debilitating disorder.  It is disfiguring and debilitating, and left untreated, it reduces life expectancy by 2-3 times the general population.  Patients with active acromegaly die prematurely by an average of a decade, predominately due to cardiovascular reasons. The symptoms of Acromegaly progress slowly. Diagnosis can be delayed as many as 10 to 20 years.

Symptoms

Symptoms of Acromegaly include:

	Headaches Visual field disturbances Excessive Sweating Diabetes Acanthosis nigricans Sleep Apnea Soft Tissue Skin Thickening – palms of hands, soles of  feet, scalp Psoriasis Hypertension Thyroid gland enlargement New skin tags – stretchy moles Skeletal: Joint pain Carpal Tunnel Syndrome Osteoarthritis Backache Muscle weakness
	Enlargement of : Hands Feet Head size Forehead Lips Tongue Nose breadth Check bones Mandible (elongate which can cause widened spaces between the teeth) Chest (barrel chest)

Specific to women, symptoms of Acromgegaly include:

• Menstrual disorders:
• Amenorrhea – no menstrual periods
• Oligomenorrhea – light or infrequent menstrual periods
• Menorrhagia – heavy menstrual periods
• Irregularities of cycle length
• Hyperprolactinemia
• Galactorrhea – breast milk when not nursing a baby
• Masculinized facial features
• Lowered voice pitch
• Mild Hirsutism

Specific to men, symptoms of acromegaly include:

• Decreased libido
• Impotence
• Enlarged testes

Complications

There are serious and sometimes life-threatening complications related to Acromegaly.

 1. Macroadenomas that extend beyond the sella: 

• Headache 
• Visual abnormalities - Compression of optic chiasm
• Bitemporal hemianopsia from superior extension
• Homonymous visual field defect from posterior extension
• Homonymous visual field defect also if chiasm prefixed
• Lateral extension into cavernous sinus can cause impaired oculomotor function Involving cranial nerves III, II, VI, and V1 and V2 divisions of Cranial Nerve V
• Extensions into the temporal lobe can cause seizures
• Hypopituitarism caused by compression of normal pituitary tissue.

2. Insulin Resistance

3. Hypertriglyceridemia – increased tyiglycerides

4. Pulmonary complications

• Upper airway narrowing
• Sleep Apnea – Apneic episodes, snoring, and daytime sleepiness

5. Cardiovascular

• Hypertension
• Cardiomyopathy

6. Neuromuscular

• Weakness because of myopathy.
• Nerve root compression in the spine
• Spinal stenosis and amyotrophic lateral sclerosis
• Carpal Tunnel
• Colon Polyps – increased risk for colon cancer.

Acromeglic patients are at risk for early death, usually from cardiovascular and pulmonary causes.

Diagnosis

 The clinical diagnosis of acromegaly is confirmed by laboratorial testing.

Blood Tests – Screening for Acromegaly

A single growth hormone (GH) measurement is not helpful for diagnosing or excluding acromegaly.

Frequent blood sampling every 5 to 20 minutes over 24 hours can chart GH release. Acromegalic patients may have a 10 to 15 times increase in their 24 hour mean GH concentrations. The number of GH pulses is 2 to 3 times higher than normal individuals, and basal GH levels are typically increased 16 to 20 times above normal. Uncommonly, it is possible for a clinical acromeglic to have a 24 hour mean GH level that is normal, and an abnormal GH secretion pattern.

The Serum Insulin-Like Growth Factor 1 (IGF-1) concentration is the best screening test for acromegaly. Serum IGF-1 levels reflect overall GH levels from the previous 24 hours.  This measurement typically correlates with the 24 hr GH blood sampling. IGF-1 levels decline with age; therefore, normal ranges vary with age and sex. Reference ranges for age and sex must be provided by the laboratory.

False results: Chronic and critical illness, including liver disease, renal failure, diabetes mellitus, and thyroid disease, may alter serum IGF-I levels. An increased IGF-I is almost always specific for acromegaly, but in pregnancy and adolescence, IGF-I may be increased without acromegaly.

Oral Glucose Tolerance Test (OGTT) – Diagnosing Acromegaly

Acromegly is diagnosed when the serum GH level does not decrease to less than 1.0 [mu]g/L  after an oral glucose tolerance test. The oral glucose tolerance test. should be done after fasting. A blood sample is taken 30 minutes before the test if an IV with heparin lock is inserted. A blood sample is then taken right before injestiong a flavored iced-drink that has 75g of glucose. Blood samples are taken of GH and glucose 30, 60,90 and 120 minutes later. In some cases, serum insulin is tested too. The suppression of  serum GH  to less than 1.0 [mu]g/L may help exclude acromegaly. A fall of GH to less than 1.0 [mu]g/L during an OGTT does not necessarily exclude acromegaly.

The elevated IGF-1 level and an elevated OGTT results in the biochemical diagnosis of acromegaly.

Other tests

Other tests that may be used, but not routinely, are TRH, GHRH, levodopa, and other dopamine agonists.

• TRH/GNRH test: 500µg I.V. of TRH or 100µg I.V. of GnRH, GH will increase in most patients with acromegaly. TRH can release GH in 70-80% of acromegalic patients. Its major advantage is when the OGTT shows a boderline response. Its response require a TRH receptor presence in the tumor.
• Levodopa  test: Growth hormone (GH) release is stimulated by levodopa (500 mg) in normal subjects but inhibited in acromegaly. In acromegaly, the mean decrease is 52% of basal GH levels. 

Treatment:

Treatment for GH secreting tumors includes surgery, radiation, and medication.

Surgical

Surgery is indicated as primary therapy for Acromegaly.  Surgical control of disease varies depending on the expertise of the pituitary surgeon. Published studies show that disease remission rates double when care is sought from a dedicated pituitary neurosurgeon. The goal is to completely resect the GH-secreting adenoma and to preserve the remaining pituitary function. Several studies show that in the hands of an experienced neurosurgeon,  the disease remission rate for microadenomas (tumors less than 1cm) are 70% and for macroadenomas 50%. In macroadenomas, surgery may reduce tumor mass and improve clinical symptoms. Recurrence can occur several years after surgery in 5 to 10% of patients who were initially in post-surgical disease remission.

The treatment goals are to return GH secretion to normal, correct the clinical symptoms, and preserve pituitary function. Absolute biochemical remission is defined when GH secretion patterns normalize, basal GH and IGF-1 levels normalize to age and sex matched normal ranges, and the GH response to the OGTT is normal. The post op GH concentration <10 [mu]g/L is considered a biochemical remission.  Currently, the post-treatment value of GH <5 [mu]g/L has been shown to have the same mortality as the general population.

Radiotherapy

Radiotherapy is used for patients that have residual disease after surgery to prevent tumor regrowth and reduce GH hypersecretion. Radiotherapy leads to a predictable lowering of GH in the majority of patients with the majority of patients showing improvement within 2 years. Plasma GH declines below 5 [mu]g/L in up to 80% of patients 10–15 yrs after radiotherapy.  Current radiotherapies include:

• Conventional high-dose therapy
• Radioisotope implantation
• Stereotactic radiosurgery such as:
  
• Gamma Knife
• Linear Acceleration
• Proton Beam

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