Typical Skull RX (Thickening of the Calvarium) of an Acromegalic patient
Pituitary Macroadenoma (MRI)
Acromegaly/Gigantism is a very rare disease (annual incidence: 3/1.000.000). The syndrome results from a chronic exposure to GH (Growth Hormone) leading to the classic clinical features that the diagnosis seems to be easy.
High exposure to GH produces gigantism in youths prior to epiphyseal fusion and acromegaly in adults.
The early diagnosis and intervention may prevent irreversible changes associated with chronic overproduction of GH (as well IGF-1) and may also normalize life expectancy. These patients have an increased mortality rate from systemic sequela of hypersomatotrophism in 2-4 times that of the healthy population.
Acromegaly/Gigantism is the second in frequency of Pituitary Adenomas, accounting for about 17% of them.
It is often caused by a pituitary adenoma GH secreting (99%), but other causes has been described such as:
A rare form caused by hypersecretion of GHRH from an ectopic source (pancreatic islet or carcinoid tumors) or from within the central nervous system such as ganglyoneuroma (called eutopic). Even more rare form is a nonpituitary GH secreting tumor documented in a few lung tumors and in those called Ectopic Pituitary Tumor (Esphenoidal)
GH secreting Pituitary adenomas are often over 1cm in diameter when the diagnosis is established. Arising from the lateral wings of the anterior pituitary. Rarely is due to a microadenoma.
About 15% of GH secreting tumors also hypersecrete Prl, explaining the clinical manifestation of hyperprolactinemia also seen in these patients.
By microscopy the pituitary adenomas are classified as:
| Incidence | Adenoma Type | A/B/C * | Hormone |
| 5% | Plurihormonal | C - A | GH – Prl |
| 5% | Acidophil Stem Cell | C | GH - Prl |
| 5% | Mammosomatotroph | A | GH - Prl |
| 15% | Mixed GH Cell – Prl Cell | A - C | GH - Prl |
| 10 – 20% | Somatotrophic - Densely Granulated Cell | A | GH |
| 20 – 30% | Somatotrophic - Sparsely Granulated Cells | C - A | GH |
The oversecretion of GH in acromegaly has an abnormal dynamic control. Secretion remains episodic, however the duration, amplitude and number of secretory episodes are elevated. The characteristic nocturnal surge is absent and there are abnormal responses to suppression and stimulation. TRH and GnRH may cause GH release whereas these substances do not stimulate normal secretion. (These factors are very helpful to make the diagnosis)
Most of the deleterious effects of GH hypersecretion are caused by its stimulation of excessive amounts of IGF-1 (also known as Sm-C). GH can directly regulate somatic function of body via GH receptor, as well indirectly, via stimulating hepatic and multiple extrahepatic tissue production of IGF-1.
IGF-1 is a somatomedine and its growth-promoting leads to proliferation of bone, cartilage, soft tissues and increase in size of other organs.
Distinctive features and pathologic findings associated with GH excess usually begin in the third or fourth decade and progress insidiously. The mean age at diagnosis is 42 years and equally in sex incidence. Typically the duration of symptoms is usually 5-10 years before the diagnosis.
Soft tissue proliferation is one of the early manifestations. Leading to the classic features: enlargement of the hands, feet and facial features, the most common complaint of the patients.
In adults, the syndrome is characterized by local overgrowth of bone (skull, mandible). Linear growth does not occur because of prior fusion of the epiphyses of long bones. Many younger may have hypogonadism associated which delays epiphyseal closure. The combination of elevated IGF-1 and hypogonadism leads to a striking acceleration of linear growth.
This bony and soft tissue changes are also associated by other systemic disorders of endocrine, cardiovascular and respiratory systems.
The major problem of the treatment is when the patients come to medical attention. The tumor is is typically in a very aggressive phase producing headache, visual field changes and/or hypopituitarism (Resulting from the mass effect).
Coarsening of features
Prognathism
Diastema (widely spaced teeth)
Acral enlargement
Increased ring and shoe sizes
Hands become enlarged, moist and soft.
Tufting of distal phalanges
Skin changes
Generalized Thickening
Increased sweating and oiliness – an important sign of activity of the
disease.
Hypertrichosis, Acanthosis nigricans, acne
Visceromegaly
Neuropathies and Arthropathy
Carpal Tunnel Syndrome
Peripheral neuropathy, paresthesias
Spinal Cord or nerve root compression from bony overgrowth
Enlargement of bone
Local Effects of Pituitary (mass effect)
Headache; visual impairment, hypopituitarism, rhinorrhea
Cardiovascular disease
Cardiomyopathy left ventricular diastolic function decreased; Left
ventricular mass increased; arrhythmia
Hypertension
Respiratory Disease
Upper Airway Obstruction (Caused by Soft Tissue Overgrowth)
Sleep Apnea
Malignancy
Colon, Esophagus, Stomach, Polyps
Melanoma
Lymphoma
Endocrinopathy (due either to GH excess or to mechanical effects
of the adenoma)
Hyperprolactinemia
Diabetes Mellitus/Carbohydrate intolerance
Hypogonadism; Hypothyroidism; Hypoadrenalism
Decreased libido or impotence
General Systemic Manifestations
Fatigue or lethargy
Weight Gain
Heat intolerance
Photophobias
Increased sleep requirement
The disease is characteristically disfigurating and many of the facial and acral distortions due to the excessive soft tissue are reversible. The muskuloskeletal abnormalities are generally not reversible but myalgias and arthralgias frequently decrease. Especially after 45 years of age, an increase of mortality rate from cardiovascular and cerebrovascular atherosclerosis (36-62%), respiratory diseases (0-25%) and malignancies (9-25%) occurs. Death rates tend to be higher when D. Mellitus or Hypertension is associated.
The normal level of serum GH is 3 to 5 ng/mL. More than 10 ng/mL is found in 90% of patients with acromegaly. Although children and younger can have normal levels of GH even up to 50ng/ml.
However, a single measurement is not entirely reliable, though GH is secreted by pituitary in spurts and its concentration can vary widely. At a given moment, an acromegalic may has normal GH levels, whereas a GH level in a health person may be 5 times higher specially in conditions as: stress, sleeping time, exercise.
Because of these problems, more accurate diagnosis can be done when GH is measured under conditions in which GH secretion is normally suppressed. So, physicians often use:
Oral Glucose Tolerance Test (OGTT)
This is the best test to confirm the disease. Since its simplest and
most specific dynamic test.
100g of Glucose is administered after an overnight fast.
Results can be:
Normal – GH < 2 ng/ml
<
>Acromegalia – in 70 –80% shows any alteration of the response
such as:
Low levels of GH (but not at normal levels)
Without alteration on GH
High levels of GH (called "paradoxal increase")
IGF-1 Measurement (normal ranges vary in different laboratories) is an indirect measurement of GH. Since IGF-1 levels are much more stable over a day, they are often more particle and reliable of the measurements of GH levels. An other advantage of this exam is showing activity of the disease.
TRH & GnRH Tests
After 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.
After GH or IGF-1 has diagnosed acromegaly, other exams can be done:
Tumor Localization
In all patients, MRI (90% have more than 1cm in diameter) can show tumor
localization and size.
The finding of a normal MRI is very rare. In this case, the next
procedure
is considering an extrapituitary ectopic source of GHRH or GH. If the scans
suggest diffuse pituitary enlargement or hyperplasia, ectopic GRH should
be suspect.
Pituitary Macroadenoma (MRI)
Heel Pad Measurement
Usually more than 22mm and must be measured with lateral RX
1. Surgical therapy
This is the gold standard of GH-secreting tumors because of its aggressive behavior. And must be done as the primary choice in all patients who are otherwise acceptable surgical risks. The surgical modality can be transsphenoidal (the better) or craniotomy (in case of extrasellar enlargement of the adenoma)
The effectiveness of this therapy by using a value of 10ng/ml or less was 73%. And it is more successful when the tumor is restricted to sella.
2. Radiation therapy
The main disadvantage of this therapy is the long-term duration to reach the ‘goals of therapy’. About 5 years are required for reduction of GH levels to normal in 50% of the patients.
Side effects of this therapy are the development of panhipopituitarism in 15-15% of the patients with a lag time from less than 1 to 10 years. This percentage is very higher than the surgical therapy. And it is indicated to 1- Patients whom surgery failed to achieve normal GH levels. 2- Patients with high risk of surgery.
3. Clinical Therapy
Two medications are currently used: (Medical therapy is sometimes used to shrink large tumors before surgery)
These medications are derived from ergoline family: bromocriptine,
pergolide.
In at least 50% of acromegalic, dopamine action is presumably through
a dopamine D2 receptor mediated mechanism, thus suppressing GH secretion.
This is the major limitation of this treatment and 15% have the coexistence of Prl Hypersecretion. Since D2 are not so dense as in the prolactinomas. Thus, the goal on reducing the size of the tumor when using these drugs is just 10-15% in contrast to 70-80% of the Prolactinomas.
Furthermore, this kind of treatment is the 3rd choice.
Bromocriptine is divided in 2-3 doses of about 15-60mg daily and reduces GH secretion from some pituitary tumors. Side effects include GH upset, nausea, vomiting, light headedness when standing and nasal congestion. These effects can be reduced or eliminated if medication is started at a very low dose at bedtime, taken with food, and gradually increased to the full therapeutic dose.
As explained below with the use of dopaminergic analogues, the use of octreotide also depends on the presence of somatostatine receptors in the adenoma. But 10-30% of acromegalic has low density of these receptors.
This drug must be injected under the skin every 8 hours about 300µg/daily for effective treatment. In 50% a reduction of GH levels < 5ng/ml occurs. And those patients who initially had GH < 20ng/ml, the levels of GH and IGF-1 become normalized in 95%.
In many patients, GH levels fall within one hour and headaches improve within minutes after the injection. Several studies have shown that octreotide is effective for long-term treatment. Also has been successfully to treat patients with acromegaly caused by non-pituitary tumors.
Because it inhibits gastrointestinal and pancreatic function, long term use causes digestive problems such as decreased gastrointestinal motility, nausea, gas, abdominal pain, fat malabsortion, acholic stools, colelitiasis in one third of patients. And 25% develop gallstones. May also causes Glucose Intolerance, although scientists have found that in some acromegalic with Diabetes, the drug improves blood sugar control.
The levels of GH and also improved clinical and metabolic parameters.
At the present time the treatment of choice is surgery. Pharmacotherapy is not yet an acceptable alternative to surgery. It's indicated when neither surgery nor radiotherapy was successful and/or there were contra-indications for the patient.
Goals of therapy can be best defined when:
GH < 2,5ng/ml
GH after OGTT < 1ng/ml
IGF-1 at normal levels
Improvement in Clinical and metabolic parameters. Besides that, acromegalic must have annual physical examination, chest RX, MRI of sella, mammography (women) and at least sigmoidoscopy. As discussed, the risk of development of colon polyps and cancer is very high even normalized the GH levels, so a full colonoscopy should be done every 3-5 years. And every 6 months biochemical tests.
| I express special gratitude to Estela Wajcberg,M.D.,
resident of the 3rd year of Endocrinology at
Federal University of Rio de Janeiro, in her invaluable assistance in preparing and reviewing this article. |
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