• Reduced strength and exercise capacity

• Defective sweating

• Psychological problems

• Depression

• Fatigue/listlessness

• Sleep disturbance

• Social isolation

• Emotional lability and impaired self-control

• Poor marital and socioeconomic performance Signs

• Increased fat mass (especially abdominal obesity)

• Reduced lean body mass

• Reduced muscle strength

• Reduced exercise performance

• Thin, dry skin; cool peripheries; poor venous access

• Depressed affect, labile emotions

• Impaired cardiac function Laboratory Tests

• Patients will exhibit a peak GH level of less than 5 ng/mL (5 mcg/L) following a GH stimulation test.

• Low or low-normal IGF-I level also may be present.

• Increased low-density lipoprotein cholesterol, total cholesterol, triglycerides; decreased high-density lipoprotein cholesterol.

• Reduced bone mineral density associated with an increased risk of fracture.

• Increased insulin resistance and increased prevalence of impaired glucose tolerance.

• GH deficiency may be accompanied by the loss of other pituitary hormones.

Begin GH therapy as soon as possible to optimize long-term growth, especially for

young children in whom GH deficiency is complicated by fasting hypoglycemia. Selection of the optimal GH replacement dose will need to be individualized depending on response, financial resources, and product availability. Although the appropriate time to discontinue therapy remains controversial in childhood GH deficiency, it is reasonable to continue GH replacement until either the child has reached satisfactory adult height, achieved documented epiphyseal closure, or failed to respond to ther-

apy. Management of the transition between pediatric and adult GH replacement remains a challenge because there are no current data to indicate the correct approach. Starting GH therapy at a low dose and gradually titrating upward may decrease the potential for adverse effects. The need for GH replacement therapy may be lifelong.

Children treated with GH replacement therapy rarely experience significant adverse effects, whereas adults are more susceptible to dose-related adverse effects. Treatment with GH may mask underlying central hypothyroidism and adrenal insufficiency. GH-induced symptoms, such as edema, arthralgia, myalgia, and carpal tunnel syndrome, are common and necessitate dose reductions in up to 40% of adults. Benign increases in intracranial pressure may occur with GH therapy and generally are reversible with discontinuation of treatment. Often, GH therapy can be restarted with smaller doses without symptom recurrence.

In rapidly growing children, a slipped capital femoral epiphysis may occur when

the head of the femur shifts in a backward direction. There is no evidence that this problem is caused by GH therapy, but any child who experiences a change in gait

during treatment should be evaluated by an orthopedic surgeon. Treatment with GH may induce insulin resistance and lead to the development of glucose intolerance in patients with pre-existing risk factors. Presently, there is no compelling evidence that

GH replacement therapy is associated with an increased risk of leukemia, solid tu-


mor, or tumor recurrence. However, in children with a history of malignancies, it would be prudent to wait for a 1-year tumor-free period (5 years for adults) before initiating GH therapy. Any patients treated for a prior malignancy may be at risk

for a second malignancy and should be monitored carefully for tumor recurrence. Other rare findings associated with GH replacement therapy include breast development, pancreatitis, juvenile osteochondritis (inflammation of a bone and its cartilage),

worsening of scoliosis, and increased pigmentation. Because deaths have been reported with use of GH in children with Prader-Willi syndrome who are severely obese or suffer from respiratory impairments, use of GH is contraindicated in these individuals.

Insulin-Like Growth Factor I Therapy

Mecasermin (Increlex) is the only recombinant IGF-I replacement therapy for the treatment of growth failure in children with severe primary IGF-I deficiency or with GH gene deletions who have developed neutralizing antibodies to GH. This product has not been evaluated in patients with GH deficiency aside from the genetic abnormalities.

Outcome Evaluation

• Children with GH deficiency should be evaluated by a pediatric endocrinologist every 3 to 6 months. Monitor for an increase in height and change in height velocity to assess response to GH therapy30'38 Every effort should be made to maximize height before the onset of puberty. Once final adult height is reached and GH is discontinued for at least 1 month, retest and reevaluate the patient using the adult GH-

deficiency diagnostic criteria.

• Assess patients with scoliosis for further curvature of the spine.

• Although GH and IGF-I levels do not always correlate with growth response, measure IGF-I levels yearly to assess adherence to therapy and patient response. If the

IGF-I levels are substantially above the normal range 2 years after GH replacement

therapy, the dose should be reduced. IGF-I level may be used as a guide to gradually reduce replacement dose after epiphyseal closure.

• Routine monitoring of fasting lipid profile, bone mineral density, and body composition in children is not typically required during GH replacement but should be done

30 38

before and after discontinuation of therapy.

• In adults, measurement of serum IGF-I, along with careful clinical evaluation, appears to be the most reliable way to assess the appropriateness of the GH dose. Measure IGF-I serum concentrations annually and 6 weeks following dosage adjust-


• Continuously monitor for dose-related adverse effects such as edema, arthralgia, myalgia, and carpal tunnel syndrome.

• Evaluate psychological well-being. Assess patient's bone mineral density every 2

years. Measure body composition, metabolic status, and cardiac risks (e.g., fasting

lipid profile) yearly.

• Patients with a history of cancer or those at risk for malignancy should be monitored closely.

• Measure a free thyroxine serum concentration at baseline and at 6- to 12-month intervals thereafter. 0

• Measure fasting blood glucose levels at baseline and annually to assess for glucose intolerance.35

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