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Growth Hormone Deficiency

Mohsen S Eledrisi, MD, FACP, FACE, Consultant, Department of Internal Medicine, Division of Endocrinology and Metabolism, King Abdulaziz National Guard Medical Center, Saudi Arabia

Updated: Jun 2, 2008

Introduction

Background

The somatotroph cells of the anterior pituitary gland produce growth hormone. The hormone's secretion is stimulated by growth hormone – releasing hormone (GHRH) and is 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.1 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.2,3

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. Growth hormone's diverse metabolic actions also include anabolic, lipolytic, and diabetogenic effects.4,5

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.4,5

Frequency

United States

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

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

International

No data are available.

Mortality/Morbidity

  • Adult GHD is associated with the following problems2,3 :
    • Reduced bone mineral density and increased risk of osteoporotic bone fractures
    • Impaired cardiac function
    • Central obesity
    • Increased insulin sensitivity
    • Reduced exercise capacity
    • Emotional disturbances
    • Decreased quality of life
  • Epidemiologic data suggest that adults with GHD have reduced life expectancy. This increased mortality is probably attributable to premature cardiovascular disease.6,7

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

History

  • Children
    • Growth failure after a period of normal growth is a characteristic feature of GHD that presents during childhood. Children present with short stature and low growth velocity for age and pubertal stage.8
    • Consider the possibility of hypopituitarism in patients with neonatal hypoglycemia, prolonged jaundice, septo-optic 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).
  • Adults9
    • Adults with GHD usually have a history of pituitary tumors that may have been treated with surgery or radiation, or they may have previously suffered a head trauma.
    • Some patients will also have manifestations of deficiency of other pituitary hormones, such as thyroid, adrenal, and gonadal hormones
    • 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.4

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 males and females.
    • 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
      • Septo-optic 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 the GHRH.
    • 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 many cases, no clear etiology can be identified.
  • Causes of GHD in adults
    • Pituitary disease - More than 90% of patients have pituitary disease, which is usually caused by a pituitary tumor, by surgery, or by radiation therapy for the tumor.
    • Other causes - These include trauma, tuberculosis, histiocytosis X, hemochromatosis, lymphocytic hypophysitis, and infiltrative diseases, such as sarcoidosis.
    • Idiopathic - In rare instances, no cause can be found.

Differential Diagnoses

Adrenal Insufficiency
Hypothyroidism

Other Problems to Be Considered

Idiopathic short stature in children
Nonendocrine causes of short stature, such as celiac disease and chronic liver disease

Workup

Laboratory Studies

  • Evaluation for GHD should be considered if the following conditions exist:
    • A child with a standing height of more than 3 standard deviation below the mean for chronological age, sex, and ethnic background
    • A child with a height velocity below the fifth to tenth percentile for age, with no clear etiology
    • A child with a standing height that is 2 SD to 3 SD below the mean for chronologic age, and with growth deceleration (growth velocity less than the twenty-fifth percentile) that cannot otherwise be explained
    • Hypothalamic-pituitary dysfunction (eg, microphallus, septo-optic dysplasia, intracranial tumor, history of cranial irradiation) with decelerating growth
    • Deficits in other hypothalamic-pituitary hormones, either congenital or acquired
    • Adults with manifestations suggestive of GHD
  • Local laboratory assays and their cutoffs should be kept in mind when performing tests for GHD.10
  • In newborns, a serum growth hormone level of less than 20 ng/mL is highly suggestive of GHD. After the newborn period, random serum growth hormone levels are of little value because of the pulsatile nature of growth hormone secretion. Measurement of growth hormone secretion through the night or for 24 hours is cumbersome, costly, and impractical.
  • Growth hormone stimulation (provocative) tests play a critical role in the diagnosis of GHD. The most frequently used tests include the insulin tolerance test (ITT); arginine; GHRH, with or without arginine; levodopa (L-dopa); glucagon, with or without a beta blocker, such as propranolol; and clonidine.11,12
  • Most endocrinologists use a cutoff serum growth hormone concentration of more than 10 mcg/L in children and of more than 3 mcg/L (some authorities use 5 mcg/L) in adults to define normal response on provocative tests.10
    • The Growth Hormone Research Society has recommended the ITT as the standard test for the diagnosis of GHD in adults.
    • In an ITT, insulin is administered intravenously to produce a nadir in the plasma glucose level of less than 40 mg/dL (2.2 mmol/L); serum (or blood) glucose and serum growth hormone levels are measured at times 0, 15, 30, 60, 90, and 120 minutes after administering insulin. An experienced staff under the direct supervision of a physician should perform the test. GHD is diagnosed when the growth hormone level is less than 5.1 mcg/L.11
    • An ITT is contraindicated in patients with cardiovascular disease, cerebrovascular disease, or seizure disorders, or in patients older than 65 years.
    • The GHRH-arginine test is used by many centers as an alternative to the ITT. When the GHRH-arginine test is employed, a GHD is diagnosed when the growth hormone level is less than 4.1 mcg/L.11,7
    • In patients with a GHD of hypothalamic origin (as a result, for example, of irradiation), GHRH can give falsely normal testing. In such patients, arginine without GHRH should be used
  • Some clinicians require that these criteria occur on 2 provocative tests because of the high frequency of false-negative results for each single test.
    • Levels of insulinlike growth factor 1 (IGF-1) or IGF–binding protein 3 (IGFBP-3) can provide presumptive evidence of reduced growth hormone secretion, but normal levels do not exclude the possibility of GHD.11
    • Patients who have a deficiency of 3 or more pituitary hormones and an IGF-1 level of <84 ng/ml  can be considered to have GHD and may not require provocative testing. However, some insurance bodies require the results of a growth hormone stimulation test before providing reimbursement for GH therapy.
  • Patients with GHD may have an increase in total cholesterol, low-density lipoprotein (LDL) cholesterol, and apolipoprotein B, as well as in triglyceride levels. The high-density lipoprotein (HDL) cholesterol level may be low.4

Imaging Studies

    • Magnetic resonance imaging (MRI) of the hypothalamic-pituitary region to define the anatomy of this region and to identify tumors or congenital anomalies
    • Bone age radiographs to assess chronologic age in children
    • Bone mineral densitometry to look for reduced bone mineral density
    • Cardiac echocardiogram to look for 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, such as a pituitary tumor in adults (usually an adenoma) or a congenital anomaly in children (see Causes).

Treatment

Surgical Care

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

Consultations

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

Medication

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

Growth hormones

Treatment requires recombinant growth hormone.


Human growth hormone (Humatrope, Genotropin, Nutropin)

Currently widely available in subcutaneous injection form. Adjust dose gradually based on clinical and biochemical responses assessed at monthly intervals, including body weight, waist circumference, serum IGF-1, IGFBP-3, serum glucose, lipids, thyroid function, and whole body dual-energy x-ray absorptiometry. In children, assess response based on height and growth velocity. Continue treatment until final height, epiphysial closure, or both have been recorded.

Dosing

Adult

2-5 mcg/kg/d SC, usual starting dose, or approximately 100-300 mcg/d; increase q1-2 mo by 100-200 mcg to achieve clinical response and an IGF-1 level in upper half of age-adjusted reference range and to avoid side effects

Pediatric

0.04-0.05 mg/kg/d SC initially, given qd or 6 times/wk

Interactions

May increase activity of cytochrome P-450 system and alter clearance of some medications known to be metabolized by this system; monitoring advised when such medications (ie, corticosteroids, anticonvulsants, sex steroids, cyclosporine) used concomitantly

Contraindications

Documented hypersensitivity; closed epiphyses; actively growing intracranial tumor; any underlying intracranial lesion

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Most frequent adverse effects related to injection-site reactions such as swelling, pain, erythema, itching, bruising and lipoatrophy; because growth hormone may reduce insulin sensitivity, monitor patients for hyperglycemia; patients with diabetes mellitus may need adjustment of insulin during growth hormone therapy; intracranial hypertension with headache, nausea, vomiting, visual changes due to macular edema and proliferative retinopathy usually during the first 8 wk of growth hormone therapy; funduscopic examination recommended at initiation and periodically during the course of therapy; growth hormone therapy not recommended during pregnancy because studies have not been conducted and placental growth hormone is secreted from the end of the first trimester until term

Follow-up

Further Outpatient Care

    • Close follow-up care with an endocrinologist is recommended.
    • In children, the response to treatment is evaluated by assessing height, weight, and growth velocity.
    • In adults, change in body composition, exercise capacity, skeletal integrity, lipids, and quality of life are monitored.2,3 The suggested favorable effect of growth hormone treatment on vascular mortality in patients with hypopituitarism remains to be proven.
    • There is no consensus on the duration of growth hormone treatment. Growth hormone should be continued until growth ceases, after which it is recommended to retest the growth hormone axis by stimulation tests.13,14 Some patients, particularly those with idiopathic growth hormone deficiency, may have a normal response and not require a continuation of therapy. Children who have multiple pituitary hormone deficiencies rarely recover and require continuation of treatment into adulthood.
    • Growth hormone therapy can be continued for adults if benefits are observed. If no objective benefits are seen after 1 year of treatment, discontinuation of growth hormone therapy should be considered.

Complications

  • Premature cardiovascular disease6
  • 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 be expected only to make short children grow at a normal 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

Medicolegal 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 who have undergone treatment for such tumors.
  • Failure to provide appropriate therapy could be life threatening.

References

  1. Attanasio AF, Lamberts SW, Matranga AM, et al. 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):82-8. [Medline]. [Full Text].

  2. Molitch ME, Clemmons DR, Malozowski S, et al. Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. May 2006;91(5):1621-34. [Medline]. [Full Text].

  3. 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):309-17. [Medline]. [Full Text].

  4. 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):382-95. [Medline]. [Full Text].

  5. 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]. [Full Text].

  6. Bates AS, Van't Hoff W, Jones PJ. The effect of hypopituitarism on life expectancy. J Clin Endocrinol Metab. 1996;81(3):1169-72. [Medline]. [Full Text].

  7. Utz AL, Yamamoto A, Hemphill L, et al. Growth hormone deficiency by GHRH/arginine testing criteria predicts increased cardiovascular risk markers in normal young overweight and obese women. J Clin Endocrinol Metab. Apr 29 2008;[Medline]. [Full Text].

  8. 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]. [Full Text].

  9. Johannsson G. Management of adult growth hormone deficiency. Endocrinol Metab Clin North Am. Mar 2007;36(1):203-20. [Medline].

  10. Bidlingmaier M, Strasburger CJ. What endocrinologists should know about growth hormone measurements. Endocrinol Metab Clin North Am. Mar 2007;36(1):101-8. [Medline].

  11. Biller BM, Samuels MH, Zagar A, et al. Sensitivity and specificity of six tests for the diagnosis of adult GH deficiency. J Clin Endocrinol Metab. May 2002;87(5):2067-79. [Medline]. [Full Text].

  12. Kageyama K, Nigawara T, Sakihara S, et al. Diagnostic usefulness of the growth hormone-releasing peptide-2 test as a substitute for the insulin tolerance test in hypopituitarism. Endocr J. May 21 2008;[Medline]. [Full Text].

  13. Attanasio AF, Shalet SM. Growth hormone and the transition from puberty into adulthood. Endocrinol Metab Clin North Am. Mar 2007;36(1):187-201. [Medline].

  14. Geffner ME. Transition to the adult endocrine clinic: testing pituitary function - what tests and when?. Growth Horm IGF Res. Aug 2003;13 Suppl A:S117-21. [Medline].

  15. American Association of Clinical Endocrinologists medical guidelines for clinical practice for growth hormone use in adults and children--2003 update. Endocr Pract. Jan-Feb 2003;9(1):64-76. [Medline].

  16. Bulow B, Hagmar L, Mikoczy Z. Increased cerebrovascular mortality in patients with hypopituitarism. Clin Endocrinol (Oxf). 1997;46(1):75-81. [Medline].

  17. 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].

  18. 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].

  19. 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]. [Full Text].

  20. 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].

  21. Shalet SM. Growth hormone outgrows growth. Clin Endocrinol (Oxf). Jul 2004;61(1):1-9. [Medline].

  22. Stavrou S, Kleinberg DL. Diagnosis and management of growth hormone deficiency in adults. Endocrinol Metab Clin North Am. Sep 2001;30(3):545-63. [Medline].

  23. Tanaka T, Cohen P, Clayton PE, et al. 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. Oct 2002;12(5):323-41. [Medline].

  24. 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].

Keywords

growth hormone deficiency, GHD, GH deficiency, adult GHD, hypopituitarism, somatotroph cells, pituitary gland, pituitary tumors, growth hormone–releasing hormone, GHRH, somatostatin, hypothalamus, short stature, hypoglycemia, failure to thrive, growth hormone therapy, growth hormone replacement therapy, GHRT, pituitary aplasia, empty sella, encephalocele, midline defects, septo-optic dysplasia, septooptic dysplasia, panhypopituitarism, craniopharyngiomas, cranial irradiation, sarcoidosis, tuberculosis, histiocytosis X, hemochromatosis, lymphocytic hypophysitis, hypoxic insult, pituitary disease

Contributor Information and Disclosures

Author

Mohsen S Eledrisi, MD, FACP, FACE, Consultant, Department of Internal Medicine, Division of Endocrinology and Metabolism, King Abdulaziz National Guard Medical Center, Saudi Arabia
Mohsen S Eledrisi, MD, FACP, FACE is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians-American Society of Internal Medicine, American Diabetes Association, American Medical Association, and Endocrine Society
Disclosure: Nothing to disclose.

Medical Editor

Steven R Gambert, MD, MACP, Chairman, Department of Medicine, Physician-in-Chief, Sinai Hospital of Baltimore; Professor of Medicine, Program Director, Internal Medicine Program, Johns Hopkins University School of Medicine
Steven R Gambert, MD, MACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physician Executives, American College of Physicians, American Geriatrics Society, Association of Professors of Medicine, Endocrine Society, and Gerontological Society of America
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Don S Schalch, MD, Professor Emeritus, Department of Internal Medicine, Division of Endocrinology, University of Wisconsin Hospitals and Clinics
Don S Schalch, MD is a member of the following medical societies: American Diabetes Association, American Federation for Medical Research, Central Society for Clinical Research, and Endocrine Society
Disclosure: Nothing to disclose.

CME Editor

Mark Cooper, MBBS, PhD, FRACP, Head, Diabetes & Metabolism Division, Baker Heart Research Institute, Professor of Medicine, Monash University
Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD, Professor of Medicine, St Louis University School of Medicine
George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, Endocrine Society, International Society for Clinical Densitometry, and Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.

Acknowledgments

Ali A Al-Qarni, MD, Consulting Endocrinologist, King Abdulaziz National Guard Hospital, Saudi Arabia, contributed to this article.

Further Reading

Related eMedicine topics:
 Growth Failure
Growth Hormone Deficiency [Pediatrics: General Medicine]
Growth Hormone Replacement in Older Men
Hypopituitarism [Emergency Medicine]
Hypopituitarism [Pediatrics: General Medicine]
Hypopituitarism (Panhypopituitarism)
Pituitary Tumors
Short Stature

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