BASICS
DESCRIPTION
- Insufficient production of growth hormone (GH) in adults or children caused by problems arising in the pituitary gland
- GH is produced by somatotroph cells of the anterior pituitary gland, which is stimulated by growth hormone-releasing hormone (GHRH) and inhibited by somatostatin from the hypothalamus.
- GH, also called somatotropin, is a polypeptide hormone that stimulates growth and cell reproduction.
- Hypopituitarism is GH deficiency (GHD) plus a deficiency in at least one other anterior pituitary hormone.
- Panhypopituitarism is a deficiency in all the hormones produced in the pituitary gland.
- System(s) affected: endocrine, musculoskeletal, psychological
- Synonym(s) and keywords: hypopituitarism; familial short stature; short height; growth pattern; pituitary dwarfism; acquired GHD; isolated GHD; congenital GHD; panhypopituitarism
EPIDEMIOLOGY
Incidence
- Most common cause of GHD in children is idiopathic.
- Most common cause of GHD in adults is a pituitary adenoma or treatment of the adenoma with surgery or radiotherapy:
- 76% of patients with GHD had a pituitary tumor.
- 13% had an extrapituitary tumor.
- 8% idiopathic cause
- 1% had sarcoidosis.
- 0.5% had Sheehan syndrome.
Prevalence
- In children, isolated GHD is reported to affect 1 in 5,000.
- Adult-onset idiopathic GHD is extremely rare.
ETIOLOGY AND PATHOPHYSIOLOGY
- GHD is caused by a genetic or acquired absence or decline in production of GH.
- Hypothalamus secretes GHRH, which stimulates the pituitary to secrete GH.
- Somatostatin is secreted by the hypothalamus to inhibit GH secretion.
- When GH pulses are secreted into the blood, then insulin-like growth factor (IGF)-1 is released.
- GHD may result from disruption of the GH axis-in the higher brain, the hypothalamus, or the pituitary gland (1)[C].
- Congenital
- Genetic (see "Genetics")
- Structural brain defects
- Agenesis of corpus callosum
- Septo-optic dysplasia
- Empty sella syndrome
- Encephalocele
- Hydrocephalus
- Arachnoid cyst
- Associated midline facial defects
- Single central incisor
- Cleft lip/palate
- Acquired
- Trauma
- CNS infection
- Tumors of hypothalamus or pituitary
- Pituitary adenoma
- Craniopharyngioma
- Rathke cleft cyst
- Glioma/astrocytoma
- Germinoma
- Metastatic tumor
- Infiltrative/granulomatous disease
- Sarcoidosis
- Tuberculosis
- Langerhans cell histiocytosis
- Hypophysitis
- Cranial irradiation
- Idiopathic
- Pituitary infarction
- Surgical
- Hemochromatosis (rare)
Genetics
A variety of congenital genetic causes of GHD:
- Transcription factor defects (POU1F1/PIT-1, PROP-1, LHX3/4, HESX-1, and PITX-2)
- GHRH-receptor gene defects
- GH secretagogue receptor gene defects
- GH receptor/postreceptor defects
- Prader-Willi syndrome
- Deletion and mutation of GH-1
COMMONLY ASSOCIATED CONDITIONS
- Macroadenoma
- Sarcoidosis
- Sheehan syndrome
DIAGNOSIS
HISTORY
- Children
- Poor height velocity, slower muscular development, and delayed gross motor milestones, such as standing, walking, and jumping
- Clinical questions
- Birth weight and length
- Previous growth points
- Nutritional history
- General health of child
- Height of parents
- Timing of puberty in parents
- Adults: Always consider evaluation in patients with structural hypothalamic/pituitary disease, surgery or radiation to hypothalamic/pituitary region, head traumatic brain injury, or a subarachnoid hemorrhage and evidence of other pituitary disorders:
- Fatigue
- Muscle weakness
- Depression
- Social withdrawal
- Poor memory
- Loss of strength and/or stamina
- Reduced physical performance
PHYSICAL EXAM
- Children with GHD
- Most common presentation is short stature and drop off in height, then weight, then head circumference on the growth curve:
- Strong suspicion if >2.5 SD below mean (corresponds to <0.5 percentile) for height (for chronologic, age, sex, and background) and/or height velocity >2 SD below mean (corresponds to approximately <3rd percentile) (2)[C]
- Newborns may present with hypoglycemia, prolonged jaundice, or micropenis.
- Children with severe GHD have maxillary hypoplasia and forehead prominence.
- Accurately measure height and weight.
- Assess pubertal status using Tanner staging system.
- Adults
- Decreased lean body mass
- Increased fat mass, particularly in the abdominal region
- Poor bone density
- Reduced physical performance: loss of strength, stamina, and muscle
- Reduced quality of life: poor memory, social withdrawal, and depression
- Abnormal labs
- Dyslipidemia
- Increased insulin resistance
- Glucose intolerance
DIFFERENTIAL DIAGNOSIS
- Adrenal insufficiency
- Hypothyroidism
- Turner syndrome
- Renal failure
- Small size for gestational age in newborns
- Prader-Willi syndrome
- Idiopathic short stature
- Noonan syndrome
- Russell-Silver syndrome
- Down syndrome
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
- Thyroid-stimulating hormone (TSH): Hypothyroidism should be excluded, and thyroxine should be adequately replaced prior to testing for GHD.
- Serum electrolytes (low bicarbonate levels may indicate renal tubular acidosis)
- CBC
- ESR
- Karyotype (in females to rule out Turner syndrome)
- Radiograph of hand and wrist to determine skeletal age in children
- GHD is effectively excluded in children with normal bone age and height velocity.
Follow-Up Tests & Special Considerations
- If labs above are normal and growth curve shows short stature and drop off in height, then weight, then head circumference, consider IGF-1 and insulin-like growth factor-binding protein (IGFBP-3) (both decreased in GHD).
- IGF-1 is a good screening test for GHD in younger, lean patients (<40 years; BMI <25 kg/m2) with evidence of hypopituitarism; however, a normal IGF-1 does not rule out GHD at any age.
- Multiple blood sample testing for GH levels: Testing for GHD by random measurement of GH in a single blood sample is not beneficial because GH is nearly undetectable for most of the day.
- Brain MRI to evaluate for a pituitary tumor
Diagnostic Procedures/Other
Stimulatory tests should be done after abnormal levels of IGF-1 or IGFBP-3 are obtained and if they are not explainable by malnutrition:
- Insulin tolerance test (ITT) is considered the gold standard in adults by American Association of Clinical Endocrinologists. It is recommended to perform ITT under careful medical management in an experienced endocrine unit and is contraindicated for several clinical conditions including history of seizures or ischemic heart disease (3)[C].
- GHRH-arginine and GHRH + GH-releasing peptide-2 (GHRP-2) are most common, although not widely available.
- Alternative provocative tests: Give a dose of an agent that in a normal person causes a surge in the release of GH: Common agents used include arginine, clonidine, glucagons, insulin, levodopa, and propranolol (3)[C].
- After agent is given, GH serum levels are drawn q15min for a total of 60 minutes.
TREATMENT
MEDICATION
- GHD is treated with GH replacement.
- The goal of replacement therapy is to correct the metabolic, functional, and psychological abnormalities associated with GHD.
- Recombinant human growth hormone (rhGH) was first approved for childhood GHD in 1985.
- The recommended rhGH dose for children in the United States is 0.175 to 0.350 mg/kg/wk, with 0.3 mg/kg/wk being most commonly used. Stepwise increase during pubertal stages has been shown to improve growth velocity. It has also been shown that pulsatile administration is more effective than three times weekly.
- The rhGH therapy for adults with GHD offers significant clinical benefits in body composition, including skeletal integrity, lipids, quality of life, and exercise capacity. The dosing plans have evolved from weight-based to individualized dose-titration strategies based on age, gender, estrogen status, IGF-1 levels, appropriate clinical response, and avoidance of side effects (4)[C].
- Several GHRPs or nonpeptide analogs are to be evaluated in children and adults. It is too early to evaluate their long-term safety and efficacy.
- Treatment is expensive, costing as much as $10,000 to $40,000 per year.
ISSUES FOR REFERRAL
Patients with GHD would benefit from a referral to an endocrinologist.
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
- Children: Follow-up with a pediatric endocrinologist. Most endocrinologist will monitor growth and adjust dose every 3 to 6 months.
- Childhood onset GHD, the need for continuation of GH replacement should be evaluated following completion of statural growth (usually <20 years).
- Adults: Follow-up with an endocrinologist is recommended. Consider monitoring every 1 to 2 months during dose titration, then every 6 months. Assess clinical status, side effects, IGF-1 levels. Check fasting lipids and glucose annually. Consider dual-energy x-ray absorptiometry scan for prolonged treatments (>2 years) to quantify changes in body composition and assess bone density (5)[C].
DIET
No restrictions
PROGNOSIS
- Determined by response to GH replacement therapy; is generally favorable
- GH treatment is meant for replacement therapy with expectations of growth at a normal rate.
- Five independent predictors of pubertal growth:
- Gender
- Age at onset of puberty
- Age at end of growth
- Dose of GH at onset of puberty
- Deviation of target height from height at onset of puberty
COMPLICATIONS
- In children:
- Slipped capital femoral epiphysis
- Scoliosis
- In adults and children:
- Premature cardiovascular disease
- Osteoporosis
- Psychiatric disturbances
- Insulin resistance
- Metabolic effects (monitor thyroid and adrenal functions)
- Antibodies to GH
- Cancer: lymphoma, colon, tumor recurrence
- Fluid retention: pseudotumor cerebri, carpal tunnel syndrome, pancreatitis, and edema
REFERENCES
11 Fukuda I, Hizuka N, Muraoka T, et al. Adult growth hormone deficiency: current concepts. Neurol Med Chir (Tokyo). 2014;54(8):599-605.22 Miller BS. rhGH safety and efficacy update. Adv Pediatr. 2011;58(1):207-241.33 Molich 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. 2006;91(5):1621-1634.44 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. 2011;96(6):1587-1609.55 Ho KK, 2007 GH Deficiency Consensus Workshop Participants. Consensus guidelines for the diagnosis and treatment of adults with GH deficiency II: a statement of the GH Research Society in association with the European Society for Pediatric Endocrinology, Lawson Wilkins Society, European Society of Endocrinology, Japan Endocrine Society, and Endocrine Society of Australia. Eur J Endocrinol. 2007;157(6):695-700.
ADDITIONAL READING
- Binder G. Growth hormone deficiency: new approaches to the diagnosis. Pediatr Endocrinol Rev. 2011;9(Suppl 1):535-537.
- Cook DM, Yuen KC, Biller BM, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for growth hormone use in growth hormone-deficient adults and transition patients-2009 update. Endocr Pract. 2009;15(Suppl 2):1-29.
- Kirk J. Indications for growth hormone therapy in children. Arch Dis Child. 2012;97(1):63-68.
- Richmond EJ, Rogol AD. Growth hormone deficiency in children. Pituitary. 2008;11(2):115-120.
SEE ALSO
Pituitary Adenoma
CODES
ICD10
E23.0 Hypopituitarism
ICD9
- 253.3 Pituitary dwarfism
- 253.2 Panhypopituitarism
SNOMED
- Growth hormone deficiency (disorder)
- Panhypopituitarism (disorder)
- Pituitary dwarfism
CLINICAL PEARLS
- Most common cause of GHD in children is idiopathic.
- Most common cause of GHD in adults is pituitary adenoma.
- Most common presentation of childhood GHD is short stature and poor growth velocity.
- Patients taking replacement GH therapy should have regular monitoring for both adverse effects and physiologic benefits in addition to IGF-1 levels.