Growth hormone deficiency

Growth hormone deficiency is a rare condition in which the body does not make enough growth hormone. Growth hormone is made by the anterior pituitary gland, a small organ at the base of the brain. In children, growth hormone is essential for normal growth, muscle and bone strength, and distribution of body fat. Growth hormone also helps control glucose (sugar) and lipid (fat) levels in the body. Without enough growth hormone, a child is likely to grow slowly and be much shorter than other children of the same age and gender. The incidence of growth hormone deficiency is estimated to be 1 in 4,000 to 10,000 individuals worldwide. An estimated 6,000 adults are diagnosed with growth hormone deficiency every year in the United States ¹. Adult growth hormone deficiency has been estimated to affect 1 in 100,000 people annually ². In adults, growth hormone plays a role in regulating bone density, muscle mass, and glucose and lipid metabolism. It can also affect heart and kidney function. Deficiencies may have begun in childhood or develop in adulthood. A deficiency can develop, for example, because of damage to the pituitary gland caused by a head injury, brain tumor, or surgery or radiation treatment. This can result in a decrease in pituitary hormones (hypopituitarism). The deficiency in growth hormone can lead to decreased bone density, less muscle mass, and altered lipid levels. However, testing for growth hormone deficiency is not routine in adults who have decreased bone density and/or muscle strength or increased lipids. growth hormone deficiency is a very rare cause of these disorders.

It’s important for parents to know that there are many reasons for slow growth and below-average height in children. At times, slow growth is normal and temporary, such as right before puberty starts. A pediatric endocrinologist (children’s hormone specialist) or primary care doctor can help find out why a child is growing slowly. Most children with growth hormone deficiency grow less than two inches (5 centimeters) each year.

There are four types of isolated growth hormone deficiency differentiated by the severity of the condition, the gene involved, and the inheritance pattern.

Isolated growth hormone deficiency type 1A is caused by an absence of growth hormone and is the most severe of all the types. In people with type 1A, growth failure is evident in infancy as affected babies are shorter than normal at birth.

People with isolated growth hormone deficiency type 1B produce very low levels of growth hormone. As a result, type 1B is characterized by short stature, but this growth failure is typically not as severe as in type 1A. Growth failure in people with type 1B is usually apparent in early to mid-childhood.

Individuals with isolated growth hormone deficiency type 2 have very low levels of growth hormone and short stature that varies in severity. Growth failure in these individuals is usually evident in early to mid-childhood. It is estimated that nearly half of the individuals with type II have underdevelopment of the pituitary gland (pituitary hypoplasia). The pituitary gland is located at the base of the brain and produces many hormones, including growth hormone.

Isolated growth hormone deficiency type 3 is similar to type 2 in that affected individuals have very low levels of growth hormone and short stature that varies in severity. Growth failure in type 3 is usually evident in early to mid-childhood. People with type 3 may also have a weakened immune system and are prone to frequent infections. They produce very few B cells, which are specialized white blood cells that help protect the body against infection (agammaglobulinemia).

Growth hormone deficiency in children treatment involves growth hormone shots (injections) given at home. The shots are most often given once a day. Older children can often learn how to give themselves the shot.

Treatment with growth hormone is long-term, often lasting for several years. During this time, the child needs to be seen regularly by the pediatrician to ensure the treatment is working. If needed, your child’s endocrinologist will change the dosage of the medicine.

Serious side effects of growth hormone treatment are rare. Common side effects include:

• Headache
• Fluid retention
• Muscle and joint aches
• Slippage of the hip bones

Growth hormone deficiency causes

Growth hormone deficiency may result from disruption of the growth hormone axis in the higher brain, hypothalamus, or pituitary. Most instances of growth hormone deficiency are idiopathic (doctors can find no cause). Some children are born with growth hormone deficiency (congenital growth hormone deficiency). Others develop it after birth due to a brain injury, a tumor, or radiation treatment to the head (acquired growth hormone deficiency).

Isolated growth hormone deficiency is caused by mutations in one of at least three genes. Isolated growth hormone deficiency types 1A and 2 are caused by mutations in the GH1 gene. Type 1B is caused by mutations in either the GH1 or GHRHR gene. Type 3 is caused by mutations in the BTK gene.

The GH1 gene provides instructions for making the growth hormone protein. Growth hormone is produced in the pituitary gland and plays a major role in promoting the body’s growth. Growth hormone also plays a role in various chemical reactions (metabolic processes) in the body. Mutations in the GH1 gene prevent or impair the production of growth hormone. Without sufficient growth hormone, the body fails to grow at its normal rate, resulting in slow growth and short stature as seen in isolated growth hormone deficiency types 1A, 1B, and 2.

The GHRHR gene provides instructions for making a protein called the growth hormone releasing hormone receptor. This receptor attaches (binds) to a molecule called growth hormone releasing hormone. The binding of growth hormone releasing hormone to the receptor triggers the production of growth hormone and its release from the pituitary gland. Mutations in the GHRHR gene impair the production or release of growth hormone. The resulting shortage of growth hormone prevents the body from growing at the expected rate. Decreased growth hormone activity due to GHRHR gene mutations is responsible for many cases of isolated growth hormone deficiency type 1B.

The BTK gene provides instructions for making a protein called Bruton tyrosine kinase (BTK), which is essential for the development and maturation of immune system cells called B cells. The BTK protein transmits important chemical signals that instruct B cells to mature and produce special proteins called antibodies. Antibodies attach to specific foreign particles and germs, marking them for destruction. It is unknown how mutations in the BTK gene contribute to short stature in people with isolated growth hormone deficiency type 3.

Some people with isolated growth hormone deficiency do not have mutations in the GH1, GHRHR, or BTK genes. In these individuals, the cause of the condition is unknown. When this condition does not have an identified genetic cause, it is known as idiopathic isolated growth hormone deficiency.

A mutation in a transcription factor (POUF-1, also known as PIT-1) is known to result in familial growth hormone deficiency ³. As many as 14 different mutations have been described. In addition to growth hormone deficiency, affected individuals have had prolactin deficiencies and variable thyroid-stimulating hormone (TSH) deficiencies. Imaging of the pituitary gland usually reveals a hypoplastic or ectopic posterior pituitary.

Growth hormone deficiency with other hypopituitarism associated with inactivating mutations of the PROP1 (Prophet of PIT-1) transcription factor gene have been documented in reports. Patients with this mutation usually do not produce luteinizing hormone (LH) or follicle-stimulating hormone (FSH), and thus, do not spontaneously progress into puberty. They may also have TSH (thyroid-stimulating hormone) deficiency. Imaging of the pituitary gland of patients with PROP1 mutations may show either a small anterior pituitary or an intrapituitary mass.

Congenital growth hormone deficiency may be associated with an abnormal pituitary gland (seen on MRI) or may be part of a syndrome such as septooptic dysplasia (de Morsier syndrome), which may include other pituitary deficiencies, optic nerve hypoplasia, and absence of the septum pellucidum; it occurs with an incidence of about 1 in 50,000 births. Septooptic dysplasia (de Morsier syndrome) may be associated with a mutation in the gene for another transcription factor, HESX1.

Acquired growth hormone deficiency may result from trauma, infections (eg, encephalitis, meningitis), cranial irradiation (somatotrophs appear to be the most radiation-sensitive cells in the pituitary), and other systemic diseases (particularly histiocytosis). Although most instances of isolated growth hormone deficiency are idiopathic, specific etiologies cause most growth hormone deficiency associated with other pituitary deficiencies. A reported 12-86% of children with apparent isolated growth hormone deficiency have sellar developmental defects.

Of more than 20,000 children receiving growth hormone in the National Cooperative Growth Study (a database of patients receiving growth hormone therapy), approximately 25% of the patients with growth hormone deficiency had a acquired growth hormone deficiency. These causes included the following ⁴:

• Central nervous system (CNS) tumor, including craniopharyngioma – 47%
• Central nervous system (CNS) malformation – 15%
• Septooptic dysplasia (de Morsier syndrome) – 14%
• Leukemia – 9%
• Central nervous system (CNS) radiation – 9%
• Central nervous system (CNS) trauma – 3%
• Histiocytosis – 2%
• Central nervous system (CNS) infection – 1%

Multiple Pituitary Hormone Deficiency is a condition caused by a shortage of several hormones produced by the pituitary gland. It has similar characteristics to growth hormone deficiency but has additional complications caused by the absence of other hormones including:

• Thyroid-simulating hormone (TSH) and cortisol, the hormone associated with the body’s fright and flight response.
• The gonadotrophins – follicle stimulating hormone (FSH) and lutenising hormone (LH)
• Adrenal-stimulating hormone (ACTH) is much less frequently involved, but the deficiency of this hormone is extremely important to detect.

Growth hormone deficiency symptoms

Slow growth may first be noticed in infancy and continue through childhood. The pediatrician will most often draw the child’s growth curve on a growth chart. Children with growth hormone deficiency have a slow or flat rate of growth. The slow growth may not show up until a child is 2 or 3 years old.

The child will be much shorter than most children of the same age and gender. The child will still have normal body proportions, but may be chubby. The child’s face often looks younger than other children of the same age. The child will have normal intelligence in most cases.

In older children, puberty may come late or may not come at all, depending on the cause.

Signs of growth hormone deficiency:

• Slowed growth in height in infants, children, or adolescents (teenagers)
• A young-looking face compared with other children of the same age
• A chubby body, small hands and feet, and poorly developed muscles
• Low blood glucose levels (in infants and toddlers with severe growth hormone deficiency)
• A very small penis (in male newborns with severe growth hormone deficiency)
• Delayed puberty

Growth hormone deficiency diagnosis

Your doctor will review your child’s medical history and growth charts, and look for signs of growth hormone deficiency and other conditions that affect growth. Your doctor may do tests to help find the cause of slow growth. These include:

• An X-ray of the hand to check bone growth (bone age) and assess growth potential
• Blood tests and other laboratory tests to rule out other conditions that affect growth
• Specific tests for growth hormone deficiency include
• Insulin-like growth factor (IGF-1). A blood test checks levels of IGF-1, a hormone that reflects growth hormone levels.
• Growth hormone stimulation test. The child is given medicines that stimulate the pituitary to release growth hormone. Then, if growth hormone levels in the blood don’t rise to a certain level, it can mean the pituitary is not making enough growth hormone.
• Magnetic resonance image (MRI). An MRI (imaging test) of the head will look for a problem with the pituitary or the brain, and can rule out a brain tumor.

Growth hormone deficiency test

Testing is most often done after the pediatrician has looked into other causes of poor growth. Tests that may be done include:

Growth hormone testing

Growth hormone testing is primarily used to identify growth hormone deficiency and to help evaluate pituitary gland function, usually as a follow-up to other abnormal pituitary hormone test results.

Because growth hormone is released in pulses, a single measurement of the blood level is not normally clinically useful. Therefore, testing for the suppression or stimulation of growth hormone release from the pituitary is usually done.

• Growth hormone stimulation tests help to diagnose growth hormone deficiency and hypopituitarism. For a stimulation test, a sample of blood is drawn after 10-12 hours of fasting. Then, under close medical supervision, a person is given an intravenous solution of a substance that normally stimulates the release of growth hormone from the pituitary. Blood samples are then drawn at timed intervals and growth hormone levels are tested in each to see if the pituitary gland was stimulated to produce the expected levels of growth hormone. The most commonly used stimulant is arginine, but others include clonidine and glucagon. Since exercise normally causes an increase in growth hormone, vigorous exercise may also be used as the stimulant for growth hormone release.
• Growth hormone stimulates the production of insulin-like growth factor-1 (IGF-1). IGF-1 is a hormone that mediates the effects of growth hormone and helps promote normal bone and tissue growth and development. However, unlike growth hormone, its level is stable in the blood throughout the day. This makes IGF-1 a useful indicator of average growth hormone levels and the IGF-1 test is often used to help evaluate growth hormone deficiency or growth hormone excess.
• Other blood tests that may be used to evaluate pituitary gland function include prolactin, free T4, TSH, cortisol, FSH, LH, and testosterone. These tests are usually performed prior to growth hormone testing to make sure that they are normal and/or controlled with medication before growth hormone testing is done. For example, hypothryoidism must be treated prior to testing for growth hormone deficiency in children; otherwise, a falsely low growth hormone result may be seen.

If they pituitary gland is failing to produce sufficient qunatities of all the hormones it produces the condition is known as Panhypopituitarism.

• MRI of the head can show the hypothalamus and pituitary glands.
• Tests to measure other hormone levels may be done, because a lack of growth hormone may not be the only problem.

Growth hormone deficiency treatment

Children with growth hormone deficiency receive treatment with daily injections of synthetic (manufactured) human growth hormone, a prescription medicine. The growth hormone, given at home, is injected under the skin. Growth is usually monitored every 3 to 6 months by a pediatric endocrinologist, who will adjust the dose as needed.

The best results occur when growth hormone deficiency is diagnosed and treated early. In some children, growth hormone can lead to four inches (10 centimeters) of growth during the first year of treatment. Others grow less, but usually faster than without treatment. Some children need treatment until adolescence; others need it into adulthood.

Side effects of growth hormone therapy

Mild to moderate side effects are uncommon. They include:

• Headaches
• Muscle or joint pain
• Mildly under active thyroid gland
• Swelling of hands and feet
• Curvature of the spine (scoliosis)
• Development of breast tissue in boys

Rare but serious side effects include:

• Severe headache with vision problems
• A hip problem, when the top of the thigh bone slips out of place
• Inflamed pancreas (pancreatitis)

For most children, the benefits of taking growth hormone outweigh the risks.

Overall, growth hormone has been shown to be a safe hormone when used at recommended doses. There are excellent large databases for evaluation of possible safety signals that occur during treatment with growth hormone. Growth hormone adverse events have been carefully documented in a review by Krysiak R et al. ⁵. Most adverse events have been local injection site reactions, which rarely lead to discontinuation. Headache, nausea, and fever have been generally self-limiting and are well tolerated. Adverse events such as edema or carpal tunnel syndrome are seen more often in adults than children, and they may be the result of fluid retention caused by growth hormone. Adverse events seen particularly in children have included transient idiopathic intracranial hypertension (also known as pseudotumor cerebri), gynecomastia, and slipped capital femoral epiphysis. The idiopathic intracranial hypertension resolved after discontinuation of growth hormone and restarting at a low dose.

There have been concerns about cancer associated with growth hormone administration, and these concerns have stemmed from several observations. First, acromegaly (a condition of growth hormone excess) is known to increase the risk of colorectal cancer. Second, epidemiological studies have shown a relationship between tall statue and cancer risk, between insulin like growth factor I (IGF-I) levels and the risk of prostate cancer, and an increase in breast cancer associated with levels of free IGF-I. One study has suggested that there may be reason for concern because of cases of Hodgkin disease and colorectal cancer found in long-term follow up of patients who had received human-derived growth hormone. Although the incidence of these diseases was greater than the population at large, it was not outside the confidence ranges.

Further, follow up of patients receiving human-derived growth hormone in the United States has not shown such a correlation. There has been recent concern from analysis of data in French children who were treated with growth hormone between 1985 and 1996, and then followed until 1996 (the SAGhE study) ⁶. A retrospective analysis of mortality in this population suggests the possibility of increased cardiovascular disease and bone tumors in adults who received growth hormone as children. The cardiovascular disease was primarily attributed to subarachnoid or intracerebral hemorrhages. Overall cancer mortality rates were not higher than the general population, but bone tumor–related deaths were 5 times higher than expected. There appeared to be a dose relationship (risk was highest in patients receiving doses >50 mcg/d).

The study is flawed by not having a control group (data from those who took growth hormone as children were compared to the population at large, which may not be an appropriate comparison). In addition, there was no apparent relationship with duration of growth hormone therapy, which one would expect if the increase in mortality was actually related growth hormone therapy, suggesting that the increase in mortality in this group could be more likely related to the reason they were short and taking growth hormone, rather than an effect of the growth hormone itself.

Similar data from Sweden, The Netherlands, and Belgium ⁷ have shown no increase in mortality rates, and all of the deaths were attributable to accidents or suicide, further suggesting that the French data could be misleading. Clearly, what is most needed is long-term adult follow up of those patients who received growth hormone as children

Growth hormone deficiency prognosis

The earlier growth hormone deficiency is treated, the better the chance that a child will grow to near-normal adult height. Many children gain 4 or more inches (about 10 centimeters) during the first year and 3 or more inches (about 7.6 centimeters) during the next 2 years. The rate of growth then slowly decreases.

Growth hormone therapy does not work for all children.

Left untreated, growth hormone deficiency may lead to short stature and delayed puberty. Average adult height for untreated patients with severe isolated growth hormone deficiency is 143 cm in men and 130 cm in women. Approximately 5% of children with growth hormone deficiency also have episodes of hypoglycemia, particularly in infancy, which resolve with growth hormone therapy.

Adults with untreated growth hormone deficiency have altered body composition (eg, excess body fat, lower lean body mass), decreased bone mineralization, cardiovascular risk factors (in particular, altered blood lipids), and decreased exercise tolerance. In addition, these patients may be socially isolated.

Growth hormone deficiency can occur with deficiencies of other hormones such as those that control:

• Production of thyroid hormones
• Water balance in the body
• Production of male and female sex hormones
• The adrenal glands and their production of cortisol, DHEA, and other hormones

Mortality in children with growth hormone deficiency is due almost entirely to other pituitary hormone deficiencies ⁸. These children have an increased relative risk of death in adulthood from cardiovascular causes resulting from altered body composition and dyslipidemia.

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