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Growth hormone deficiency

GHD, Growth hormone receptor deficiency

Overview

Growth Hormone Deficiency (GHD) is a medical condition in which the body does not produce enough growth hormone (GH). Growth hormone, also called somatotropin, is a polypeptide hormone which stimulates growth and cell reproduction. HGH also refers to human growth hormone but this older abbreviation has begun to develop paradoxical connotations, particularly in relation to the peddling of medically unnecessary GH supplementation (so-called HGH quackery).
There are a variety of rare diseases which resemble GH deficiency, including the childhood growth failure, facial appearance, delayed bone age, and low IGF levels.

Symptoms - Growth hormone deficiency

Signs and symptoms associated with the condition vary but may include:

  • Short stature
  • Reduced muscle strength and endurance
  • Hypoglycemia in infancy
  • Delayed puberty
  • Small genitals
  • Thin, fragile hair
  • Dental abnormalities
  • Short limbs (arms and legs)
  • Obesity
  • Distinctive facial features (protruding forehead, a sunken bridge of the nose, and blue sclera.

Causes - Growth hormone deficiency

Growth hormone deficiency in childhood commonly has no identifiable cause (idiopathic), and adult-onset GHD is commonly due to pituitary tumours and their treatment or to cranial irradiation. A more complete list of causes includes:

  • mutations of specific genes (e.g., GHRHR, GH1)
  • congenital diseases such as Prader-Willi syndrome, Turner syndrome, or short stature homeobox gene (SHOX) deficiency
  • congenital malformations involving the pituitary (e.g., septo-optic dysplasia, posterior pituitary ectopia)
  • chronic renal insufficiency
  • some infants who are small for gestational age
  • intracranial tumors in or near the sella turcica, especially craniopharyngioma
  • damage to the pituitary from radiation therapy to the head (e.g. for leukemia or brain tumors), from surgery, from trauma, or from intracranial disease (e.g. hydrocephalus)
  • autoimmune inflammation (hypophysitis)
  • ischemic or hemorrhagic infarction from low blood pressure (Sheehan syndrome) or hemorrhage pituitary apoplexy

Prevention - Growth hormone deficiency

Most cases are not preventable.

Review your child's growth chart with the pediatrician at each checkup. If there is concern about your child's growth rate, evaluation by a specialist is recommended.

Diagnosis - Growth hormone deficiency

Although GH can be readily measured in a blood sample, testing for GH deficiency is constrained by the fact that levels are nearly undetectable for most of the day. This makes simple measurement of GH in a single blood sample useless for detecting deficiency. Physicians therefore use a combination of indirect and direct criteria in assessing GHD, including:

  • Auxologic criteria (defined by body measurements)
  • Indirect hormonal criteria (IGF levels from a single blood sample)
  • Direct hormonal criteria (measurement of GH in multiple blood samples to determine secretory patterns or responses to provocative testing), in particular:
    • Subnormal frequency and amplitude of GH secretory peaks when sampled over several hours
    • Subnormal GH secretion in response to at least two provocative stimuli
    • Increased IGF1 levels after a few days of GH treatment
  • Response to GH treatment
  • Corroborative evidence of pituitary dysfunction

"Provocative tests" involve giving a dose of an agent that will normally provoke a pituitary to release a burst of growth hormone. An intravenous line is established, the agent is given, and small amounts of blood are drawn at 15 minute intervals over the next hour to determine if a rise of GH was provoked. Agents which have been used clinically to stimulate and assess GH secretion are arginine, levodopa, clonidine,epinephrine and propranolol, glucagon and insulin. An insulin tolerance test has been shown to be reproducible, age-independent, and able to distinguish between GHD and normal adults, and so is the test of choice.

Severe GH deficiency in childhood additionally has the following measurable characteristics:

  • Proportional stature well below that expected for family heights, although this characteristic may not be present in the case of familial-linked GH deficiency
  • Below-normal velocity of growth
  • Delayed physical maturation
  • Delayed bone age
  • Low levels of IGF1, IGF2, IGF binding protein 3
  • Increased growth velocity after a few months of GH treatment

Prognosis - Growth hormone deficiency

Childhood:

When treated with GH, a severely deficient child will begin to grow faster within months. In the first year of treatment, the rate of growth may increase from half as fast as other children are growing to twice as fast (e.g., from 1 inch a year to 4 inches, or 2.5 cm to 10). Growth typically slows in subsequent years, but usually remains above normal so that over several years a child who had fallen far behind in his height may grow into the normal height range. Excess adipose tissue may be reduced.

Aulthood:

GH treatment can confer a number of measurable benefits to severely GH-deficient adults, such as enhanced energy and strength, and improved bone density. Muscle mass may increase at the expense of adipose tissue. Although adults with hypopituitarism have been shown to have a reduced life expectancy, and a cardiovascular mortality rate more than double controls, treatment has not been shown to improve mortality, although blood lipid levels do improve. Similarly, although measurements of bone density improve with treatment, no rates of fractures have not been shown to improve.

Treatment - Growth hormone deficiency

GH deficiency is treated by replacing GH with daily injections under the skin or into muscle. Until 1985, growth hormone for treatment was obtained by extraction from human pituitary glands collected atautopsy. Since 1985, recombinant human growth hormone (rHGH) is a recombinant form of human GH produced by genetically engineered bacteria, manufactured by recombinant DNA technology. 

Childhood:

GH treatment is not recommended for children who are not growing despite having normal levels of growth hormone, and in the UK it is not licensed for this use. Children requiring treatment usually receive daily injections of growth hormone. Most pediatric endocrinologists monitor growth and adjust dose every 3-4 months and many of these visits involve blood tests. Treatment is usually extended as long as the child is growing, and lifelong continuation may be recommended for those most severely deficient. 

Adulthood:

GH supplementation is not recommended medically for the physiologic age-related decline in GH/IGF secretion. It may be appropriate in diagnosed adult-onset deficiency, where a weekly dose approximately 25% of that given to children is given. Lower doses again are called for in the elderly to reduce the incidence of side effects and maintain age-dependent normal levels of IGF-1.

In many countries, including the UK, the majority view among endocrinologists is that the failure of treatment to provide any demonstrable, measurable benefits in terms of outcomes means treatment is not recommended for all adults with severe GHD, and national guidelines in the UK as set out by NICE suggest three criteria which all need to be met for treatment to be indicated:

  1. Severe GH deficiency, defined as a peak GH response of <9mU/litre during an insulin tolerance test
  2. Perceived impairment of quality of life, as assessed by questionnaire
  3. They are already treated for other pituitary hormone disorders

Resources - Growth hormone deficiency

Refer to Research Publications.

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Research Publications