Growth Disorders


One of the remarkable roles of the endocrine system is the regulation of growth and development throughout our bodies. This work is directed by the pituitary gland — perhaps the most important “master gland” of the endocrine system – the ‘conductor of the endocrine orchestra’. A small oval-shaped organ at the base of the brain, the pituitary gland releases many types of hormones into the blood stream. One of these is growth hormone (GH). Once in the blood, GH travels to bone, muscle, and other tissues where it has many effects. The hypothalamus, a small structure located at the base of the brain just above the pituitary, controls the release of growth hormone by the pituitary gland. The principal stimulator of growth hormone secretion is called growth hormone-releasing hormone.

In children, for example, GH stimulates linear growth, or height. It is also important for the development of muscle and bone, and the distribution of body fat throughout the body. In adults, GH affects energy, muscle strength, bone health, and psychological well being. Having either too much or too little GH can cause health problems.
In some cases, individuals may have too much GH, a condition called acromegaly in adults. Acromegaly is usually caused by a non-cancerous tumour of the pituitary gland. In the rare instances when it occurs, too much GH in children causes gigantism.
A more common growth disorder is growth hormone deficiency (GHD). This is the condition of having too little GH. There are several possible explanations for its occurrence:

  • A child can be born with GHD.
  • The condition also may arise because of damage to the hypothalamus or pituitary gland as a child or adult because of a tumour, trauma, an infection, or radiation to the brain — usually for the treatment of a tumour.
  • A deficiency in GH may also have an undefined cause. (In this case, it is said to be of idiopathic origin.)

Pituitary disorders, such as GH excess or GHD, are evaluated and treated by endocrinologists. Because the diagnosis and treatment of such disorders require special expertise, GPs and other medical practitioners who suspect patients have GH abnormalities should refer them to an endocrinologist.


Incidence and Prevalence

Growth Hormone Excess
Excess growth hormone (GH) in children (gigantism) is extremely rare, occurring in just a few children in the UK. Excess GH in adults (acromegaly) most commonly occurs in middle-aged men and women. Approximately 60 out of every million UK citizens have acromegaly. Very infrequently, GH excess may run in families, or be one manifestation of a number of rare syndromes.

Estimates for the number of growth hormone deficiency (GHD) cases vary. Some countries have reported one in 10,000 children with GHD while others have reported one in 3,500 children.
Some children are born with GHD, which is called congenital GHD. In others, GHD develops at some point during childhood or adolescence, which is termed acquired GHD. Sometimes the cause of the GHD is relatively obvious, such as in a child born with structural brain abnormalities, or a history of head trauma. However, in other cases the cause of the GHD is unknown, or idiopathic.

For adult-onset GHD, indirect estimates based on the incidence of pituitary gland tumours suggest an incidence of 10 cases per million people annually. In the UK, the exact prevalence of GHD is unknown but estimated to be approximately 3 per 10,000 equating to 15,000 adults.



Signs and Symptoms

Growth Hormone Excess: Signs and Symptoms

Adults with acromegaly will usually have large hands and feet, thick lips, coarse facial features, a protruding forehead and jaw, and widely spaced teeth. Often patients perspire excessively. Many of the signs and symptoms evolve slowly, so the diagnosis is often made years after the symptoms begin.
There are numerous symptoms that may be associated with acromegaly:

  • Headaches
  • Numbness or burning of the hands or feet; carpal tunnel syndrome
  • Glucose intolerance, or type 2 diabetes
  • Cardiac dysfunction (heart failure, or enlarged heart)
  • High blood pressure
  • Goitre (enlarged thyroid gland)
  • Sleep apnoea
  • Tiredness
  • Menstrual disorders (irregular bleeding; absence of periods)
  • Decreased libido (low sex drive)
  • Vision problems (tunnel vision; vision loss)
  • Psychological problems (depression; anxiety)
  • Osteoarthritis (joint pains)

In children with gigantism, the main symptom is increased linear growth (height) causing extremely tall stature.

Diagnostic Tests
GH stimulates the production of another chemical called insulin-like growth factor-1 (IGF-1) by the liver and by many body tissues. Because of the link between excess GH and excess IGF-1, measuring the level of IGF-1 in the blood is an effective screening test for GH excess. However, the definitive diagnostic test is measuring GH during an oral glucose tolerance test. Patients in whom acromegaly is suspected will also frequently undergo a magnetic resonance imaging (MRI) scan of the pituitary and hypothalamus. An MRI can determine whether a tumour is the cause of the excess hormone secretion.


Growth Hormone Deficiency: Signs and Symptoms

Children. Most children with GHD grow less than 5 cm per year, whereas children with normal GH usually grow at least 5 cm annually. Some children with congenital GHD may grow normally until age two or three, but then their growth rate slows. Others may have a slow growth starting soon after birth.
Some children with GHD have extra fat in the abdomen and face. Their blood sugar levels also may be low. They may experience emotional distress because of their appearance, which differs from that of other children their own age. As adolescents, they may be slow to show signs of sexual maturity.
A GP or paediatrician who suspects a child has GHD on the basis of a persistently below average growth rate with no other identifiable cause, should refer the patient to a paediatric endocrinologist for evaluation.

Adults. Adults with GHD fall into two general categories. Some individuals may have had GHD as a child and continue to have the deficiency. Other individuals may have acquired the deficiency after reaching maturity. The consequences of GHD in adults result from a lack of both GH and IGF-1.
The disorder has several possible symptoms in adults:

  • Increased body fat (particularly at the waist and in the face)
  • Decreased muscle and bone mass
  • Thinning skin with fine wrinkles
  • Poor sweating or impaired temperature regulation
  • Reduced strength and endurance
  • Low energy level
  • Decreased well-being (moodiness, mild depression)
  • Loss of interest in sex
  • Poor sleep
  • Higher cholesterol levels, especially LDL (“bad”) cholesterol
  • Overproduction of insulin (a hormone produced by the pancreas that regulates the levels of sugar in the blood), resulting from overweight

Diagnostic Tests
Although there is no gold standard for the diagnosis of GHD, GH stimulation tests are commonly used in patients who have symptoms, low IGF-1, and normal levels of other pituitary hormones. Because the pituitary gland secretes GH in bursts throughout the 24 hours, random measurements of levels in the blood are useless.
In applying a growth hormone stimulation test, if a patient’s GH levels in blood are outside the lower limits of a normal response, it is likely the patient has GHD. GH stimulation tests are not perfect, however, and some endocrinologists question their utility. Some children with putative GHD have stimulated GH concentrations in blood that are above the arbitrary cutoff values for the tests.
Although no stimulation test is perfect, the insulin tolerance test tends to be an excellent predictor of GHD. The test involves giving the patient insulin after an overnight fast to lower their blood sugar. Failure to respond to insulin-induced hypoglycemia is a strong indication of GHD. (This test is not appropriate for patients who have seizures or coronary artery disease, and must be performed in a specialist investigation unit.)

An alternative to the insulin tolerance test is a stimulation test that uses GH-releasing hormone together with arginine — an amino acid necessary for the release of GH. This test is inappropriate for patients with liver or kidney disease.



Growth Hormone Excess & Deficiency Treatment

Growth Hormone Excess: Treatment Options

Because excess GH — acting alone or together with excess IGF-1 — produces adverse health effects, eliminating the hormone imbalance and reducing the levels to normal is desirable. Surgery, medication and/or irradiation of the pituitary gland may be appropriate to achieve these goals.

Surgery. The most common cause of GH hypersecretion is a non-cancerous tumour of the pituitary gland, which produces GH. For these patients, surgery to remove the tumour is usually the treatment of choice and in experienced hands is curative in 50-90% of patients depending on the size of the tumour.
If surgery does not normalize the GH level, or if a patient is not a candidate for surgery, other therapies are used. Medication and irradiation of the pituitary gland are options as primary or supplemental therapy.

Medications. Three types of drugs are now available for the treatment of GH excess — somatostatin analogues, GH receptor antagonists, and dopamine agonists. These medications do not “cure” the disorder but work, instead, to reduce levels of GH or IGF-1. These medications must be taken for life if surgery or irradiation fails to eliminate the cause of GH excess.

Pituitary Irradiation. Radiation therapy is another therapeutic approach for patients with acromegaly, who have undergone pituitary surgery and still have excess GH. Although pituitary irradiation can ultimately achieve complete remission, its disadvantage is the time needed to reach that goal. Conventional radiation therapy may take 10 years or longer to be fully effective. Newer methods of focused delivery — such as gamma knife, proton beam, or linear accelerator — deliver a high dose of radiation to the tumour and often affect an earlier remission than the conventional method. Unfortunately, there still may be a significant delay.
Although it takes longer to attain remission with irradiation than with medications, once remission is reached, the effects of irradiation are permanent. Patients may need to take medication until the radiation therapy achieves its effect.
Unlike in adults, radiation is considered a last resort in children with GH excess, as there as concerns about its effects on the developing brain.

Long-term Follow-up and Prognosis
Patients treated for acromegaly need to be monitored to make sure that GH excess does not return. Patients should also be monitored for medical problems that are associated with acromegaly, which include heart disease, high blood pressure, colon polyps and cancer, and high blood sugar. They also need to be watched for signs of hypopituitarism, caused by low levels of pituitary hormones.
Loss of other pituitary functions can result from the pituitary gland tumour mass. It also can be a complication of surgery or radiation therapy. Pituitary failure requires appropriate hormone replacement therapy.
Treating acromegaly to reduce excess GH is beneficial to patients. Persons with untreated acromegaly, for example, have a mortality rate that is two to three times higher than the general population. Mostly this is due to cardiovascular and respiratory complications, although increased rates of some cancers have also been reported. Decreased survival is more likely when the GH level is higher and when diabetes mellitus is present.
Reducing the hormone imbalance so the levels of GH and IGF-1 are normal is thought to be associated with a return to normal life expectancy.


Growth Hormone Deficiency : Treatment

GH is usually administered as a daily injection under the skin. Because adults tend to have more side effects than children, their treatment often begins at a low dose and then is raised gradually. 
The doses of GH used to treat children — especially adolescents — are often much higher than those in adults. Younger adult patients require higher doses than older ones, and women require more than men. Women taking estrogen by mouth may need a higher dose of GH.

Long-term Follow-up and Prognosis
Children. Children should be evaluated every three to six months to monitor their GH treatment. The best indicators are gains in height and rate of growth. Follow-up is important to assure compliance with the daily injections, to detect and manage possible side effects, monitor growth progress, and to adjust dosage periodically.
If patients have been compliant with their injections and their growth remains lower than desirable then the GH dose may be increased within the recommended guidelines. If the patient’s serum IGF-1 levels are well above the normal range at any time, then a decreased dose should be considered.
The children with the best chance of reaching their height potential are those who start GH therapy as soon as the diagnosis is made, and continue it through adolescence. With the current GH products, most children with GHD reach normal adult stature. When children with GHD reach late adolescence, tests should be done to see if they still need GH therapy into adulthood.

Adults. Monthly follow-up visits are usual for patients starting growth hormone replacement therapy. Continued monitoring for side effects, optimal replacement dosage, and long-term treatment results are needed. Some adults taking GH report joint pain and oedema, an abnormal build up of fluid in joints and tissues. Decreasing the dosage temporarily can relieve these problems.
Blood sugar levels may need to be monitored as well. There is great variability in changes in insulin sensitivity because of differences in body composition, age, and genetic predisposition. Patients with type II diabetes need special attention because growth hormone therapy hinders control of that disease until the patient loses excess abdominal fat. Follow-up visits, even for those on lifetime replacement therapy, should be scheduled at least twice a year.
Undesirable effects of growth hormone therapy in childhood are exceedingly rare. The most troubling side effects in children are increased intracranial pressure and a hip disorder called slipped capital femoral epiphysis. Intracranial pressure should be seen by a doctor who may “treat” it by stopping the dose for a few days and then slowly increasing it. This usually occurs only in the first month of therapy. Muscle and joint pain is quite uncommon in kids. Growth hormone is known to cause small alterations in insulin and glucose levels. While it may “unmask” underlying type II diabetes, there is no evidence that GH causes diabetes.



Growth Disorders Lifestyle and Prevention

For children:
Because growth hormone is taken for years, it is good for parents of children with GHD to be aware of some safety precautions:

  • Carefully follow the directions for taking GH
  • Tell all doctors who care for your child that he or she is undergoing growth hormone therapy
  • Make sure your child takes any other prescription drugs exactly as prescribed
  • Contact your child's doctor immediately if you have any questions about treatment or signs or symptoms which suggest a complication of GH treatment

In addition, encourage your child to have a healthy lifestyle. Eating a variety of healthy foods will help your child to grow and respond to growth hormone therapy. Be sure that your child gets regular exercise and plenty of sleep, too.

For adults:
Adults receiving GH treatment should also eat a balanced diet, get regular exercise, and plenty of sleep.
Some adults find their lives are much better after taking GH alone. Others may find they still need some help, particularly with the psychological symptoms of GHD. You may need medication to control anxiety or lift your mood.
Counselling may be helpful too. Some forms of therapy, such as cognitive-behavior therapy, can allow you to correct negative thoughts you may be having. You also may want to join a support group with other adults who have GHD. Talking to others who have been through the same thing can be healing.