AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

The somatotroph cells of the anterior pituitary gland produce growth hormone. Its secretion is stimulated by growth hormone-releasing hormone and inhibited by somatostatin, both of which are produced by the hypothalamus.

The clinical manifestations of growth hormone deficiency (GHD) are variable, depending on the age of onset. Children usually present with short stature, while adults have reduced physical performance and impaired psychological well-being.

The goals of growth hormone therapy differ in children and adults. In children, therapy promotes linear growth and restores body composition; in adults, the goals are to improve conditioning and strength, to restore normal body composition, and to improve the quality of life.

Pathophysiology

Growth hormone promotes linear growth by regulating the endocrine and paracrine production of insulinlike growth factor-1 (IGF-1), which is produced by the liver and other target tissues, including the epiphyseal growth plate. In addition, diverse metabolic actions include anabolic, lipolytic, and diabetogenic effects.

GHD results in alterations in the physiology of different systems of the body, manifesting in increased subcutaneous visceral fat and decreased muscle mass, bone density, and exercise performance.

Frequency

United States

The incidence of short stature associated with severe childhood GHD has been estimated to range between 1 per 4,000 to 1 per 10,000 live children in several studies. About 20,000 children per year receive growth hormone therapy, and approximately 4,000 new children are diagnosed annually as candidates for growth hormone therapy.

The exact prevalence of adult-onset GHD is not known. Approximately 35,000 adults have GHD, and approximately 6,000 new adult patients are diagnosed annually.

International

No data are available.

Mortality/Morbidity

• Adult GHD is associated with the following problems:
  • Reduced bone mineral density

  • Increased risk of osteoporotic bone fractures, impaired cardiac function, and central obesity

  • Increased insulin sensitivity

  • Reduced exercise capacity

  • Emotional disturbances
• Epidemiological data suggest that adults with GHD have reduced life expectancy. This increased mortality is mostly attributed to premature cardiovascular disease.

Age

• In children, the age of presentation varies with respect to the time of onset and the degree of GHD. Children with complete absence of growth hormone secretion usually present before reaching the age of 3 years, whereas those with lesser degrees of deficiency present at older ages.
• In adults, the age of presentation often coincides with the discovery of pituitary tumors, usually between the fourth and fifth decades of life.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Children

• Growth failure after a period of normal growth is a characteristic feature of growth hormone deficiency (GHD) that presents during childhood. Children present with short stature and low growth velocity for age and pubertal stage.

• Consider the possibility of hypopituitarism in patients with neonatal hypoglycemia, prolonged jaundice, septooptic dysplasia, midline facial defects (eg, cleft palate, solitary central incisor), male micropenis (not necessarily related to gonadotropin deficiency), histiocytosis X, previous cranial irradiation, and symptoms of a mass lesion in the hypothalamic-pituitary region (eg, headaches, visual disturbances).

• Adults

• Adults with GHD usually have a history of pituitary tumors that may have been treated with surgery or radiation, or they may have a history of head trauma.

• The symptoms of GHD in adults are often nonspecific. Reported symptoms may include low energy level, decreased strength and exercise tolerance, increased weight or difficulty losing weight, emotional lability, anxiety, social isolation, decreased libido, and impaired sleep. Some persons with GHD are entirely asymptomatic.

Physical

• Children
• • The standing height standard deviation score is usually below -2.

  • Growth velocity is below the 10-25th percentile, which reflects growth deceleration.

  • Increased subcutaneous fat is present, especially around the trunk.

  • The face is immature, with a prominent forehead and depressed midfacial development.

  • Dentition is delayed.

  • The average age of pubertal onset is delayed in both boys and girls.

  • In males, the phallus may be small.

• Adults
• • Reduced lean body mass and increased weight, with body fat mass predominantly in the abdominal region

  • Thin and dry skin

  • Cool peripheries

  • Poor venous access

  • Reduced muscle mass and strength and reduced exercise performance

  • Depressed affect

  • Labile emotions

Causes

• Causes of GHD in children can be divided into 3 categories.

• Congenital conditions
  
  
  • Defective pituitary development that leads to pituitary aplasia
  
  
  
  • Empty sella
  
  
  
  • Encephalocele
  
  
  
  • Midline defects
  
  
  
  • Septooptic dysplasia
  
  
  
  • Panhypopituitarism
  
  
  
  • Genetic abnormalities, including autosomal-recessive, autosomal-dominant, or X-linked defects or a mutation or deletion in the growth hormone gene or in growth hormone–releasing hormone.

• Acquired conditions
  
  
  • Tumors of the hypothalamic-pituitary region (Craniopharyngioma is the most common tumor.)
  
  
  
  • Cranial irradiation
  
  
  
  • Infiltrative diseases, including sarcoidosis, tuberculosis, histiocytosis X, hemochromatosis, and lymphocytic hypophysitis
  
  
  
  • Trauma
  
  
  
  • Hypoxic insult

• Idiopathic: In some cases, no clear etiology can be identified.

• Causes of GHD in adults

• More than 90% of patients have pituitary disease, which is usually caused by a pituitary tumor, surgery, or radiation therapy for the tumor.

• Other causes include trauma, infiltrative diseases such as sarcoidosis, tuberculosis, histiocytosis X, hemochromatosis, and lymphocytic hypophysitis.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Adrenal insufficiency
Idiopathic short stature in children
Nonendocrine causes of short stature: celiac disease, chronic liver disease, etc

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Be aware of the local laboratory assay and the cutoff for that assay. In newborns, a serum growth hormone level of less than 20 ng/mL is highly suggestive of growth hormone deficiency (GHD). After the newborn period, random serum growth hormone levels are of little value because they are not reliable indicators of GHD. Physiological assessment of growth hormone secretion remains principally in the field of clinical research investigation rather than in a routine diagnostic setting.

• Growth hormone stimulation (provocative) tests play a critical role in the diagnosis of GHD. The tests most frequently mentioned in the literature include insulin tolerance tests (ITTs), arginine, glucagon with or without a beta-blocker such as propranolol, growth hormone–releasing hormone with or without arginine, and clonidine.

• The Growth Hormone Research Society has recommended ITT as the standard test for the diagnosis of GHD in adults.

• In the ITT, insulin is administered intravenously to produce a nadir in the plasma glucose level of less than 40 mg/dL (2.2 mmol/L), after which the peak serum growth hormone level is measured (usually 20-30 min later).

• GHD is diagnosed when the peak growth hormone level is less than 10 mcg/mL in children and less than 3 mcg/mL in adults. Some clinicians require that these criteria occur on 2 provocative tests. When ITT is used, GHD is diagnosed when the growth hormone level is less than 5.1 ng/mL. When the arginine and growth hormone–releasing hormone test are used, GHD is diagnosed when the growth hormone level is less than 4.1 ng/mL.

• An experienced staff under the direct supervision of a physician should perform the ITT.



• ITT is contraindicated in patients with cardiovascular disease, cerebrovascular disease, seizure disorders, or a combination thereof and in patients older than 65 years. Alternatives to ITT include provocative tests using arginine, levodopa, glucagon, clonidine, or propranolol.

• Levels of IGF-1 or IGF-binding protein-3 (IGFBP-3) can provide presumptive evidence of reduced growth hormone secretion.

• Patients with GHD may have increased total cholesterol, low-density lipoprotein (LDL) cholesterol, apolipoprotein B, and triglyceride levels. The high-density lipoprotein (HDL) cholesterol level may be low.

• The diagnosis of GHD in childhood is a complicated issue that involves both clinical and laboratory aspects and also health and insurance policies. Uncertainty can arise when making the diagnosis of GHD when laboratory results are not obviously abnormal. Certain insurance policies require attaining certain laboratory values on growth hormone provocation tests before growth hormone therapy can be reimbursed. 

• Evaluation for GHD should be considered for children with a standing height >2 standard deviations below the mean for chronological age, sex, and ethnic background; for those who have hypothalamic-pituitary dysfunction (eg, microphallus, septo-optic dysplasia, intracranial tumor, history of cranial irradiation) with decelerating growth; or for those who have deficits in other hypothalamic-pituitary hormones (congenital or acquired).

• At least 2 tests are recommended to ascertain the diagnosis of GHD because of the high frequency of false-negative results for each single test.

Imaging Studies

• Perform MRI of the hypothalamic-pituitary region to define the anatomy of the hypothalamic-pituitary region and to identify tumors or congenital anomalies.

• Imaging reveals delayed bone age in children.

• Reduced bone mineral density indicates an increased risk of osteoporotic fractures.

• Echocardiograms may reveal reduced ejection fraction at rest and during exercise.

Other Tests

• Increased type-1 plasminogen activator inhibitor (PAI-1) activity

• Increased fibrinogen levels

Histologic Findings

Histologic findings vary by the etiologic factor that causes GHD, eg, a pituitary tumor in adults (usually an adenoma), congenital anomalies in children, or other causes (see Causes).

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Surgical Care

Pituitary tumors and some of the congenital anomalies in children may require surgical resection.

Consultations

• Consult with an endocrinologist as early as possible.
• Consult with a neurosurgeon for evaluation for pituitary tumors.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goals of pharmacotherapy are to restore normal growth hormone levels and to reduce morbidity. The main therapeutic goals of growth hormone treatment in children with growth hormone deficiency (GHD) are to enable short children to achieve normal height with early improvement of the psychosocial problems related to short stature.

Drug Category: Growth hormones

Treatment requires recombinant growth hormone replacement.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Close follow-up care with an endocrinologist is recommended.



• No consensus exists concerning when to cease growth hormone treatment. Growth hormone should be continued until growth ceases, at which point the growth hormone axis should be retested with stimulation tests. Some patients, particularly those with idiopathic growth hormone deficiency, may have normal response and may not require continuation of therapy. Children who have multiple pituitary hormone deficiencies rarely recover and require continuation of treatment into adulthood.

Complications

• Premature cardiovascular disease
• Osteoporosis
• Psychiatric disturbances
• Insulin resistance
• Obesity and its hazards

Prognosis

• Prognosis is determined by response to growth hormone replacement therapy and is generally favorable.



• Growth hormone treatment is meant to be a replacement therapy and can only be expected to make short children grow at a normal growth rate.

Patient Education

• Educating adults and parents of affected children about the disease is crucial.
• Patients must learn the technique of growth hormone subcutaneous injection.
• For excellent patient education resources, visit eMedicine's Growth Hormone Deficiency Center. Also, see eMedicine's patient education articles Growth Hormone Deficiency, Growth Hormone Deficiency in Children, Growth Failure in Children, Understanding Growth Hormone Deficiency Medications, and Growth Hormone Deficiency FAQs.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• The diagnosis of GHD should be considered in children with conditions such as hypoglycemia, failure to thrive, and hypopituitarism. GHD should also be considered in adults with pituitary tumors or as a consequence of treatment of the tumor.
• Failure to provide appropriate therapy could be life threatening.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• American Association of Clinical Endocrinologists. Medical guidelines for clinical practice for growth hormone use in adults and children. Endocrine Practice. 2003;9(1):64-76.
• Attanasio AF, Lamberts SW, Matranga AM. Adult growth hormone (GH)-deficient patients demonstrate heterogeneity between childhood onset and adult onset before and during human GH treatment. Adult Growth Hormone Deficiency Study Group. J Clin Endocrinol Metab. Jan 1997;82(1):82-88. [Medline].
• Bates AS, Van't Hoff W, Jones PJ. The effect of hypopituitarism on life expectancy. J Clin Endocrinol Metab. 1996;81(3):1169-1172. [Medline].
• Bengtsson BA, Eden S, Lonn L. Treatment of adults with growth hormone (GH) deficiency with recombinant human GH. J Clin Endocrinol Metab. 1993;76(2):309-317. [Medline].
• Biller BM, Samuels MH, Zagar A. Sensitivity and specificity of six tests for the diagnosis of adult GH deficiency. J Clin Endocrinol Metab. May 2002;87(5):2067-79.
• Bulow B, Hagmar L, Mikoczy Z. Increased cerebrovascular mortality in patients with hypopituitarism. Clin Endocrinol (Oxf). 1997;46(1):75-81. [Medline].
• Carroll PV, Christ ER, Bengtsson BA. Growth hormone deficiency in adulthood and the effects of growth hormone replacement: a review. Growth Hormone Research Society Scientific Committee. J Clin Endocrinol Metab. 1998;83(2):382-395. [Medline].
• Chipman JJ, Attanasio AF, Birkett MA. The safety profile of GH replacement therapy in adults. Clin Endocrinol (Oxf). Apr 1997;46(4):473-81. [Medline].
• Fowelin J, Attvall S, Lager I. Effects of treatment with recombinant human growth hormone on insulin sensitivity and glucose metabolism in adults with growth hormone deficiency. Metabolism. Nov 1993;42(11):1443-7. [Medline].
• Geffner ME. Transition to the adult endocrine clinic: testing pituitary function - what tests and when?. Growth Horm IGF Res. 2003;13 Suppl A:S117-21.
• Koller EA, Green L, Gertner JM. Retinal changes mimicking diabetic retinopathy in two nondiabetic, growth hormone-treated patients. J Clin Endocrinol Metab. Jul 1998;83(7):2380-3. [Medline].
• Saggese G, Ranke MB, Saenger P. Diagnosis and treatment of growth hormone deficiency in children and adolescents: towards a consensus. Ten years after the Availability of Recombinant Human Growth Hormone Workshop held in Pisa, Italy, 27-28 March 1998. Horm Res. 1998;50(6):320-40. [Medline].
• Shalet SM, Toogood A, Rahim A. The diagnosis of growth hormone deficiency in children and adults. Endocr Rev. Apr 1998;19(2):203-23. [Medline].
• Shalet SM. Growth hormone outgrows growth. Clin Endocrinol (Oxf). 2004;61(1):1-9.
• Stavrou S, Kleinberg DL. Diagnosis and management of growth hormone deficiency in adults. Endocrinol Metab Clin North Am. Sep 2001;30(3):545-63.
• Tanaka T, Cohen P, Clayton PE. Diagnosis and management of growth hormone deficiency in childhood and adolescence-part 2: growth hormone treatment in growth hormone deficient children. Growth Horm IGF Res. 2002;12(5):323-41.
• Vance ML, Mauras N. Growth hormone therapy in adults and children [see comments]. N Engl J Med. Oct 14 1999;341(16):1206-16. [Medline].
• de Boer H, Blok GJ, Van der Veen EA. Clinical aspects of growth hormone deficiency in adults. Endocr Rev. Feb 1995;16(1):63-86. [Medline].

Article Last Updated: May 12, 2006