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.
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........
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.
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.
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.
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.
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.
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.
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.
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.
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).
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.
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
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.
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
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
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
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.
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.
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.
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.
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.
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.
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 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
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
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.
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.
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.
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
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.