Growth hormone as the name suggests is responsible for the growth of all the tissues of the body. It is produced in the anterior lobe of the pituitary gland, a small pea-shaped gland at the base of the skull. The pituitary gland is commonly referred to as the master gland because it secretes various hormones that have a wide range of effects, either directly on tissues or by acting on other endocrine glands. Normally the level of growth hormone in the body is regulated by the gonadotropin hypothalamic-releasing hormone (GNRH) from the hypothalamus and somastatin from various other organs like the pancreas. These hormones act on the pituitary gland to stimulate growth hormone production and secretion. Sometimes the regulation is disrupted or disease within the pituitary gland leads to excessive secretion of growth hormone. When there is an excess of growth hormone then it causes an ‘overgrowth’ of the body tissues. In adults this is known as acromegaly while in children it leads to gigantism.
What is acromegaly?
Acromegaly is a growth disorder caused by the secretion of excessive amounts of growth hormone (GH) from the pituitary gland. The characteristic features are an ‘overgrowth’ of the body tissues which presents slightly differently in adults and children. This is largely due to the fact that the epiphyseal plates of the bones are not as yet fused in children and tissue overgrowth leads to gigantism. The effects in adults are also pronounced by somewhat limited by the fusion of the epiphyseal plates that prevents the bones from growing any further in length. Acromegaly is not a common condition and most cases are diagnosed in the 40 to 45 year age group. Gigantism is even less common. Both these conditions do not have a predilection for any race or gender meaning that it occurs as frequently in males and females of all races.
As mentioned above, the anterior lobe of pituitary gland, sometimes just referred to as the anterior pituitary, is responsible for producing and secreting growth hormone (GH). The GH secretion by pituitary is in turn controlled by two major factors :
- Gonadotropin Hypothalamic-Releasing Hormone (GHRH) secreted by hypothalamus. The higher the levels of GHRH, the more growth hormone is secreted.
- Somatostatin which is secreted by many tissues like then pancreas and has a negative feedback on GH secretion. This means that the higher the levels of circulating growth hormone, the less somastatin is released and vice versa.
Growth hormone released into the bloodstream stimulates insulinlike growth factor-1 (IGF-1) which is also known as somatomedin. This IGF-1 production occurs in various tissues of the body but primarily in the liver. It is this IGF-1 that causes the growth promoting effects of growth hormone. Sometimes it is not the high levels of growth hormone that increases IGF-1 levels. Instead the high levels of IGF-1 are present without the associated increase of GH levels. This also is seen with endogenous production of IGF binding protein that prolongs the half life of IGF-1.
The increased blood levels of GH / IGF-1 causes increased acral growth (growth of the limbs/peripheral tissues) which leads to soft tissue swelling and abnormal enlargement of the jaw, facial bones, tongue, heart muscles and other organs, as well as the hands and feet. It is important to note that this enlargement is not the same as the abnormal lengthening of the bones as is seen in gigantism because the fusion of the epiphyseal plates in adults prevents further lengthening of these bones.
Causes and Types of Acromegaly
Acromegaly can be GHRH-dependent or GHRH-independent.
Excessive production of GHRH from the hypothalamus stimulates the somatotrophs (cells responsible for GH production) of anterior pituitary. Although this increases the GH production, it does not have a negative effect on GHRH. Therefore the GHRH levels remain high despite the elevated GH levels. The main causes of GHRH overproduction are hypothalamic tumors and ectopic production of GHRH from other tumors like those of the pancreas, kidney or lungs.
In these cases the increased GH production acts like a negative feedback for GHRH production and subsequently the GHRH production from the hypothalamus is suppressed. Despite the low levels of GHRH, the higher than normal levels of growth hormone persists. In more than 95 % of cases the cause of GNRH-independent acromegaly is a growth on the pituitary gland known as a pituitary adenoma. It may be a macroadenoma (>1 cm) or microadenoma (<1 cm). Macroadenomas account for 80 % of pituitary adenomas whereas microadenoma are present in the remaining 20% of cases. Rarely ectopic production of GH from other cancers like a malignancy in the pancreas or lung can also cause this type of acromegaly.
Signs and Symptoms
Symptoms due to excessive IGF-1 and/or GH levels include :
- Enlarged extremities
- Enlarged and protruding jaw (macrognathia and prognathism)
- Enlarged tongue (macroglossia)
- Soft tissue swelling
- Hyperhidrosis – excessive sweating
- Coarse facial features, thickening of nasal bone and frontal bossing.
|The picture below illustrates the facial features characteristic of acromegaly. Take note of the coarse facial features discussed above.|
Picture from Wikimedia Commons.
|The hand of a male acromegaly patient (right) compared to a normal male (left). Take note of the thickening and swelling of the tissue despite the similarity in length.|
Picture from Wikimedia Commons.
Other conditions may arise with acromegaly including :
- Obstructive sleep apnea due to enlarged laryngeal and pharyngeal tissues.
- Increased risk of diabetes mellitus, hypertension and cardiovascular events.
- Increased blood levels of phosphate, calcium and cholesterol.
- Cardiomyopathy due to enlargement of the heart muscle which can lead to heart failure.
- Increased risk of developing colonic polyps and adenocarcinoma of the colon.
Additional symptoms may be seen due to the local mass effects of pituitary tumors. These symptoms depend on the size of the tumor and can vary but may include :
- Mild headaches
- Visual field defects like bitemporal hemianopsia which is caused by pressure on optic chaism.
- Hyperprolactinemia (high prolactin levels) may occur as the tumor damages the pituitary gland.
- Deficiencies of other hormones like adrenal hormones, sex hormones and thyroid hormone.
Blood Growth Hormone Levels
Random values of growth hormone will not provide a diagnostic confirmation of of acromegaly. After testing baseline growth hormone levels, glucose is administered in doses of 75mg or 100 mg following which growth hormone level measurements are taken at 30, 60, 90 and 120 minutes. Patients with acromegaly are not able to suppress growth hormone concentration less than 2 ng/dl after a 75 mg glucose-loading dose.
Blood IGF-1 Levels
Estimation of IGF-1 levels are useful for screening acromegaly cases in a large population group and also to estimate the efficacy of the treatment. Blood levels of IGF-binding protein-3 (IGFBP-3) are elevated in acromegaly and can help with a diagnosis.
Other Hormone Levels
Measuring the levels of adrenal, thyroidal and gonadal hormones will also help with the evaluation but on its own are not conclusive of acromegaly.
These investigations are indicated only after the biochemical confirmation has been done. An MRI is more sensitive than a CT scan in these instances. MRI shows the details of surrounding structures such as the cavernous sinus and optic chiasma. A CT scan of other parts of body help in diagnosing ectopic GH / IGF-1 production such as from the pancreatic, adrenal, ovarian tumors and bronchogenic carcinoma.
The goal of treatment is to maintain normal GH and IGF-1 levels. The condition is managed by maintaining GH levels at less than 2ng/dl by radioimmunoassay method and the levels of IGF-1 within a normal range. Since most cases of acromegaly are associated with a pituitary adenoma or other tumors, there is a multi-modality approach to treatment.
Surgery is the first line treatment followed by medical treatment (use of medication) and radiotherapy in refractory cases.
This is the first line treatment in majority of cases. Transsphenoidal hypophysectomy is the procedure of choice. It has the dual advantage of rapidly improving symptoms caused by mass effect of the tumor and reducing GH/IGF-I concentrations significantly. Remission depends on factors such as the initial size of the tumor and initial GH level.
Somatostatin and dopamine analogues and GH receptor antagonists (blockers) are indicated after failure of surgery to yield the desired results.
- Bromocriptine is a dopamine analogue and can reduce IGF-1 levels to less than 5 ng/dl in about 20% of cases.
- Cabergoline is also a dopamine agonist which is effective when compared to bromocryptine.
- Octreotide is a somatostatin analogue which reduces GH levels to less than 5ng/dl in 65 % of patients and less than 2ng/dl in 40 % of patients.
- Pegvisomant is a GH receptor antagonist which can normalize IGF-I levels in most acromegaly patients.
Article reviewed by Dr. Greg. Last updated on December 3, 2011