Growth Hormone
Kathy Clark
RN CS MSN Pediatric Nurse Practitioner  

Altered Pituitary Function
Disorders at either the hypothalaic or pituitary level result in pituitary dysfunction. Most problems are those of hypofunction. Isolated growth hormone deficiency (GHD) also called hypopituitarism, the most common pituitary problem, is distinguished from panhypopituitarism.....( I will discuss that later), in which all anterior pituitary hormones are absent. Decreased function of the posterior pituitary gland can occur in isolation from anterior gland function, or it may be part of panhypopituitarism.

Growth Hormone Deficiency Hypopituitarism: Definition and Incidence.
Growth hormone deficiency (GHD) is a rare condition affecting 1 in 10,000 children in the US. GHD exists in a classic as well as a nonclassic form. In the classic form, GHD is the failure of the pituitary to produce enough growth hormone to sustain a normal growth rate in childhood, resulting in a adult stature that is below normal. People affected with a severe form of this deficiency are commonly referred to as midgets, and medical literature may call them pituitary dwarfs. Both terms are outdated and should be avoided when discussing the condition with children and their parents.

In contrast to the classic hypopituitarism, there is much controversy about the definition and treatment of children with a nonclassical form of growth hormone insufficiency. These children are shorter than expected, given their genetic heritage, and do not have evidence of other medical conditions that affect growth. Most endocrinologists believe that short stature alone does not constitute an endocrine problem and that treatment with growth hormone is inappropriate.

Etiology and Pathophysiology
Growth hormone stimulates the growth of every tissue and organ in the body, but it has an especially powerful effect on the long bones. GH also stimulates the synthesis of insulin-like growth factor 1 (IGF-1) or somatomedin C in most tissues but primarily the liver. IGF-1 stimulates somatic growth,and its absence (such as liver failure) results in poor growth.

GH is secreted in a pulsitile fashion during the day and night. During the waking hours GH production is less active. Adequate nutrition and healthy hepatic and renal systems are needed for GH or IGF-1 productions. GHD may be attributed to several causes........

Idiopathic GHD
Approximately 80% of the children with GHD have no known cause for the disorder. In about two-thirds of these children, there is no other pituitary malfunction. The condition generally occurs sporadically, but familiar patterns sometimes are recognized.

The incidence of idiopathic GHD is highly associated with perinatal insult including prolonged or precipitous labor or births, breech presentation, and cesarean birth. Children with GHD typically are of normal size at birth, because fetal growth is governed by maternal factors.

Tumor
The most common tumor causing GHD is craniopharyngioma. This cystic tumor impinges on the hypothalamic-pituitary area. Although it is not a malignant tumor, the recurrence rate is high, and it may grow quickly and compress vital centers in the brain. Without surgical intervention, children live 3 to 4 years following the onset of symptoms. Successful diagnosis and surgery increase the survival rate to 40% after 8 years.

Septo-optic Dysplasia
Developmental anomalies of the pituitary gland are associated with several congenital defects, one of which is SOD, also known as de Morsier syndrome. This condition appears as a group of conditions, including optic nerve hypoplasia, which may cause blindness, absence of the septum pellucidum, and pituitary hormone deficiencies. The child with this disorder has disabilities ranging from minor visual impairments to blindness and panhypopituitarism.

Empty sella Radiographic imaging of the pituitary area can reveal an absent or small pituitary gland that does not fill the sella foramen. The small gland may have been caused by pressure of cerebrospinal fluid impinging on it, possibly as a result of an incompetent sellar diaphragm, a defect of embryonic development.

Radiation Treatment the treatment for brain tumors or leukemia may include radiation to the head. Not all cranial tumors impinge on the pituitary gland, but radiation treatment is sufficient dosage cause damage to the hypothalamic-releasing hormones and the pituitary function. GH is the most radiation-sensitive hormone. Children who receive a total of 2500 rads or more are particularly at riskier GHD. Trauma Severe head trauma from abuse or accidents can damage the pituitary gland or sever its stalk. The loss of venous supply and hypothalamic stimulation to the gland results in varying degrees of hypofunction.

Growth Hormone Deficiency=GHD

Clinical Manifestations.
GHD results in statural growth that is slower than is the normal velocity for the age of the child. Short stature is not the hallmark, it is the rate of growth that is the essential component, although slow growth over time eventually leads to short stature. Unlike people with achondroplasia, a genetic bone disorder, children with GHD have normal body proportions.

Infants with GHD may have significant hypoglycemia and be cortisol-deficient as well; both hormones are required to maintain euglycemia. Growth hormone plays a counter regulatory role in glucose regulation. Hyperglycemia, micropenis, small testes, and prolonged hyperbilirubinemia may be present in the neonate with GHD. Poor growth may be apparent by 6 months, but may not be obvious until 2 to 4 years of age. Glucose regulation is rarely a problem for the older child after the first year or two of life. However, undetected long-term hypoglycemia causes permanent intellectual impairment that becomes more obvious during the school years. Chronic hypoglycemia is discussed later.

Infants with GHD have facial features that may be described as "cherubic" in appearance. The forehead is prominent (bossing) and the eyes appear large,. The nasal bridge is underdeveloped, and the nose is infantile. The cheeks are full and the chin petite. The abdomen is rounded from deposits of ripply fat (truncal adiposity). The hands and feet are small, and the skin is soft. Dental eruption is often delayed. Male infants may have small genitals, a characteristic related to additional pituitary hypofunction (GnRH deficiency).

Older children with GHD have qualities similar to affected infants; these children appear much younger than their chronological age. Because cognitive development is not affected, children with normal developmental skills may appear precocious. Dental eruption continues to be delayed, and many children have high-pitched voices, even after puberty.

Adolescents with GHD also may have a significant delay in the onset of puberty. A bone age of 10 years for girls and 12 to 13 years for boys coincides with the beginning of puberty in the normal child. A child with untreated GHD may have a bone age many years behind the chronological age.

Growth failure may be the presenting complaint in GHD, although headaches and visual impairments may occur. Severe manifestations of pituitary insufficiency do not occur until the pituitary gland is almost completely destroyed.

Diagnostic Studies.
Many children are small for their age; by definition, 5% of children in the United States are at or below the 5th percentile on the growth curve but most of these children rarely require a diagnostic evaluation. However, the diagnosis of idiopathic GHD is controversial, and some endocrinologists may treat children who do not fit the classic diagnostic criteria.

Children of any size who fail to grow at a normal rate, and children who are below the 5th percentile on growth charts for height, require an evaluation. Growth velocity over time is the most important diagnostic measure. Classic criteria for diagnosing GHD include short stature (height below the third percentile), failure to produce growth hormone in response to two provocative tests, delayed bone age, and slow growth velocity. Screening tests. Screening tests are used to distinguish GHD from other causes of growth failure and include thyroid studies, complete blood count with sedimentation rate, and electrolytes. Urinalysis is done along with renal and liver function studies. Serum for analysis of IGF-1 concentration is obtained as an indication of growth hormone activity; the level is below normal in children with GHD. Growth Hormone secretion often can be stimulated by exercise, such as running up stairs or riding an exercise bicycle. After 15 minutes of vigorous exercise, blood is drawn for GH analysis. Growth hormone is expected to rise above 7 ng/dl. This type of testing is a basic screening tool and has a high rate for false-negative results.

A bone age study is used to determine the degree of skeletal delay. A lateral skull x-ray with sellar views is obtained to view the pituitary sella for emptiness, calcification of the pituitary gland, or tumor-related abnormalities.

Diagnostic tests for growth hormone secretion.
Children who have a low IGF-1 concentration, or who fail to produce adequate growth hormone on screening, require more extensive diagnostic testing when GHD is suspected. Laboratory studies for growth hormone assessment are complicated by the pulsatile release of this hormone. Growth hormone release can be pharmacologically stimulated; however, not all pharmacologic agents are successful even in normal subjects. Therefore, children are assessed with two stimulation, tests, performed sequentially or simutalaneously.

Arginine, insulin, L-dopa, glucagon, and clonidine are medications that may be used to stimulate the release of growth hormone. An intravenous heparin lock is placed, and a baseline blood concentration of growth hormone is obtained. The stimulators may be administered together, and blood is withdrawn at 30-minute intervals for 1 to 2 hours. The classic combinded test (the arginine tolerance test-insulin tolerance test) requires a total of 3 hours. There is a danger of profound hypoglycemia during this procedure, and constant monitoring of the child is required. Children without GHD normally produce a GH peak of at least 10ng/dl of growth hormone in response to at least one of the two provocative stimuli. Growth hormone secretion also can be measured with an overnight study. A heparin lock is inserted, and blood is withdrawn every 10 to 20 minutes either by syringe or pump. Analysis of the samples in the normal child provides a pattern that should include several large pulses of growth hormone and overall secretion rate that is in the normal range. Because deep sleep initiates growth hormone release, a sound sleep is essential to the quality of the results. These tests are described as overnight, physiologic, or integrated growth hormone tests.

Head Scans
Children who have GHD of no known cause will have radiologic or nuclear medicine studies to rule out lesions, such as tumors or empty sella. CT scans do not readily detect small tumors in the pituitary hypothalamic region, and an MRI may be necessary. Children with congenital GHD may have the diagnosis of septo-optic dysplaisa or optic nerve hyoplasia. A head scan can determine the extent of brain structure anomalies, such as absence of the corpus callosum or septum pellucidum.

Growth Hormone Replacement
GHD is usually treated by replacing the missing growth hormone with a synthetic preparation given as a daily subcutaneous injection. Growth hormone is a complex molecule that is available only as injectable medication, but has been in use for more than 30 years. Initial limited supplies were obtained from human pituitary tissue, but biosynthetic growth hormone is now available in unlimited supply due to recombinant DNA technology. Growth hormone is an expensive drug, with an average wholesale cost of about $20,000per year for a school-age child. Insurance companies and state Medicaid or other payment programs recognize the diagnosis of GHD when the evaluation has been thorough and the child fulfills the classic criteria.

Growth hormone injections are given subcutaneously and are not painful. The growth hormone powder is packaged with diluent and administered with an insulin syringe. Parents or children need instruction in diluting the hormone, preparing the dose, and injecting the medication. Written instructions as well as practice in mixing and administering the injections are required.

Infants with hypoglycemia require oral cortisol and injections of growth hormone. Daily injection are associated with the best growth response, but some children may be placed on a schedule requiring injection every other day or three times a week. Current replacement is up to 0.3 mg/kg/week, and the dose is adjusted over time as the child grows. Administration of growth hormone can be individualized for each family. Growth hormone replacement promotes growth at an accelerated velocity within 6 months of beginning treatment. Children who had been growing at 4 cm per year may grow 8 to 12 cm during the first year of treatment. Even with accelerated growth, it may be several years before the child catches up to the peer group. This pace can be a disappointment if the family and child are not prepared for the lengthy course of treatment. Treatment goals and expectations must be clearly communicated before beginning growth hormone replacement.

Growth hormone injections continue until the child ceases to respond to treatment, the family and adolescent indicate that an acceptable height has been achieved, or maximum growth potential is attained (epiphyseal fusion). Even with optimal response to treatment it is unusual for children with idiopathic GHD to achieve a normal height early in their treatment course and few of these children reach their genetic potential for height.

Side effects
Side effects of growth hormone replacement therapy include diabetes mellitus, the development of antibodies for synthetic growth hormone, and the risk of growth hormone excess problems. In 1985, human-derivded growth hormone was associated with several cases of a fatal viral condition known as Creutzfeldt-Jakob disease, and it was subsequently withdrawn from the world market. Additionally, an association with increased risk of leukemia has been reported in Japan, but studies of the US population receiving growth hormone do not substantiate this observation. Some conditions that lead to GHD, such as tumors, are associated with an increased risk of secondary tumors or leukemia, but treatment with growth hormone does not appear to increase these risks. In addition to the physical side effects, psychological side effects should be considered. The child and parents may have unrealistic growth expectations and face disappointment or depression when treatment ends.

Resistance to the injections is generally short lived, and age appropriate defenses are seen in toddlers and preschoolers. Older children who resist the injections may be afraid to lose the special status of being small.

Children receiving growth hormone are followed closely in the ambulatory setting, and visits are scheduled every 3 to 4 months. This routine provides the opportunity for monitoring growth velocity and dosage needs and permits emotional support during the long treatment course.

Children with GHD often appear to be cognitively precocious. Relatives and strangers may reinforce this impression by their comments---- "My , she talks so well for being so small!! She must be very bright." In fact the 6 year old child (who appears to only be 3 years old) may have developmental delays.

Some investigators have found that children with GHD have a high incidence of academic underachievement, learning disabilities or slightly depressed IQ scores. Therefore, all children with this diagnosis benefit from comprehensive psychometric testing before entering kindergarten or as soon as possible after diagnosis. Older children with GHD who are having any school problems should have psychometric testing. Some children with GHD do well in school, but their performance should continue to be assessed over time.

Complications
Children who are treated with growth hormone should grow at faster than normal speed for 2 to 4 years. If growth is not improved, the cause must be discovered. Possible problems include compliance with the prescribed routine of injections, adequacy of the growth hormone dose, or medication mixing technique. Other reasons for inadequate growth, such as other hormone deficiencies, poor nutrition, and emotional distress, may be identified.

Long term care
Children with hypopituitarism who have been diagnosed and treated early have an excellent prognosis for achieving height within normal range. Clinical research trials have begun to assess the need for growth hormone replacement into adulthood. Although growth hormone normally is produced throughout life, no current evidence supports the need to continue treatment when growth has ended.