Growth hormone deficiency

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Overview
Growth Hormone Deficiency is the medical condition of inadequate production of growth hormone (GH) and its effects on children and adults. Growth hormone, also called somatotropin, is a polypeptide hormone which stimulates growth and cell reproduction. See separate articles on GH physiology and GH treatment. Deficiency of GH produces significantly different problems at various ages. In newborn infants the primary manifestations may be hypoglycemia or micropenis. In later infancy and childhood, growth failure may be major effect. Adults with growth hormone deficiency may have diminished lean body mass and poor bone density and a number of physical and psychological symptoms, including poor memory, social withdrawal, and even depression. Abnormally low growth hormone levels in adults typically result in diminished quality of life and can even be disabling. Physical symptoms include loss of strength, stamina, and musculature. Adults suffering from these symptoms should seek laboratory testing by an endocrinologist. Other hormonal or glandular disorders frequently coincide with diminished growth hormone production. GH deficiency can be congenital or acquired in childhood or adult life. It can be partial or complete. It is usually permanent, but sometimes transient. It may be an isolated deficiency or occur in association with deficiencies of other pituitary hormones. GH deficiency is treated by growth hormone replacement.

Terminology
The term hypopituitarism is often used interchangeably with GH deficiency by endocrinologists but more often denotes GH deficiency plus deficiency of at least one other anterior pituitary hormone. When GH deficiency (usually with other anterior pituitary deficiencies) is associated with posterior pituitary hormone deficiency (usually diabetes insipidus) the condition is termed panhypopituitarism. HGH also refers to human growth hormone but this older abbreviation has begun to develop paradoxical connotations (see fuller discussion of HGH in GH treatment and HGH quackery).

Causes of GH deficiency
There are many causes of GH deficiency. Some examples include: Many cases of isolated growth hormone deficiency (IGHD) recognized in childhood are idiopathic. IGHD has been reported to affect about 1 in 4000 children, but IGHD is difficult to distinguish from other causes of shortness such as constitutional delay, and the true incidence is unsettled. Severe prenatal deficiency of GH, as occurs in congenital hypopituitarism, has little effect on fetal growth. However, prenatal and congenital deficiency can reduce the size of a male's penis, especially when gonadotropins are also deficient. Besides micropenis, additional consequences of severe deficiency in the first days of life can include hypoglycemia and exaggerated jaundice (both direct and indirect hyperbilirubinemia). Female infants will lack the microphallus of course but may suffer from hypoglycemia and jaundice. Even congenital GH deficiency does not usually impair length growth until after the first few months of life. From late in the first year until mid teens, poor growth and/or shortness is the hallmark of childhood GH deficiency. Growth is not as severely affected in GH deficiency as in untreated hypothyroidism, but growth at about half the usual velocity for age is typical. It tends to be accompanied by delayed physical maturation so that bone maturation and puberty may be several years delayed. When severe GH deficiency is present from birth and never treated, adult heights can be as short as 48-58 inches (122-147 cm). Severe GH deficiency in early childhood also results in slower muscular development, so that gross motor milestones such as standing, walking, and jumping may be delayed. Body composition (i.e., the relative amounts of bone, muscle, and fat) is affected in many children with severe deficiency, so that mild to moderate chubbiness is common (though GH deficiency alone rarely causes severe obesity). Some severely GH-deficient children have recognizable, cherubic facial features characterized by maxillary hypoplasia and forehead prominence (said to resemble a kewpie doll).
 * mutations of specific genes (e.g., GHRHR, GH1)
 * congenital malformations involving the pituitary (e.g., septo-optic dysplasia, posterior pituitary ectopia)
 * damage to the pituitary from incracranial disease (e.g., hydrocephalus),
 * intracranial tumors in or near the sella turcica, especially craniopharyngioma,
 * damage to the pituitary from radiation therapy to the head for leukemia or brain tumors,
 * surgery in the area of the pituitary,
 * autoimmune inflammation (hypophysitis),
 * severe head trauma,
 * ischemic or hemorrhagic infarction from low blood pressure (Sheehan syndrome) or hemorrhage pituitary apoplexy.

Adult GH deficiency
Though growth ends with sexual maturity, GH continues to be secreted throughout life. In adults, GH contributes to maintenance of muscle and bone mass and strength as well as quality and productivity in life. Understanding of the effects and benefits of GH in adults increased in the 1980's and the features of adult GH deficiency have not only been published, but can be said to have gained some notoriety. Reported effects of severe GH deficiency in adults have included: As an adult ages, diminishing amounts of GH are produced by the pituitary. This is characteristic of other hormones (especially the sex steroids) as well, and most physicians distinguish between the "naturally" reduced (age-related slowing) secretion of aging and the lower levels of real deficiency.
 * reduced muscle mass and strength
 * reduced bone mass and strength
 * reduced physical, mental, and social energy and resilience
 * impaired concentration and loss of memory
 * mild depression
 * neuralgic arthralgias
 * increased body fat, particularly around the waistline
 * increased cholesterol
 * increased mortality due to cardiovascular disease

Diagnosis of growth hormone deficiency
Pediatric endocrinologists are the physicians who specialize in diagnosis and treatment of growth hormone deficiency and growth problems in children. Internist endocrinologists are the physicians with the most expertise in assessment and treatment of adult GH 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.

Several types of evidence are used to ascertain GH sufficiency or deficiency.
 * 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)
 * 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.

Severe GH deficiency in childhood has the following measurable characteristics:
 * Proportional stature well below that expected for family heights
 * Below-normal velocity of growth
 * Delayed physical maturation
 * Delayed bone age
 * Low levels of IGF1, IGF2, IGF binding protein 3
 * 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
 * Increased growth velocity after a few months of GH treatment

Severe GH deficiency in adults has the following measurable characteristics:
 * Body composition has higher amount of body fat
 * Subnormal bone density
 * Diminished muscle strength
 * Higher cholesterol levels
 * Low IGF1 level
 * Subnormal frequency and amplitude of GH secretory peaks when tracked over several hours
 * Subnormal GH secretion in response to at least two provocative stimuli
 * Increased IGF1 levels after a few days of GH treatment

When these features are accompanied by corroboratory evidence of hypopituitarism such as deficiency of other pituitary hormones, a structurally abnormal pituitary, or a history of damage to the pituitary, the diagnosis is confirmed and presumed to be lifelong. When these corroborative features are not present, further testing is needed to establish the diagnosis.

For GH deficiency, as for many other diseases, the practical purpose and effect of these diagnostic criteria is to determine who is to be treated with it. GH deficiency accounts for only a minority of short stature among children. GH deficiency accounts for an even smaller proportion of fatigability, excessive fat, osteopenic bones, and underdeveloped muscles in adults. An ideal diagnostic test cleanly separates people who would benefit from a treatment from those who would not. Unfortunately, none of the criteria listed above do so, not even in various combinations.

The common clinical problem is that many children and adults being evaluated meet some, but not all, of the above criteria. Since many children and adults who do not meet all of the diagnostic criteria may receive some of the benefits of treatment, small differences in the diagnostic criteria make large differences in the number of short or tired people diagnosed with deficiency.

Because of uncertainties and complexities of diagnosis and the high costs of treatment, diagnosis of growth hormone deficiency has been a more persistent subject of debate and controversy in clinical endocrinology than any other aspect of endocrine diagnosis. It has become a major type of internet fraud {HGH quackery}.

Treatment of GH deficiency
GH deficiency is treated by replacing GH. Until 1985, growth hormone for treatment was obtained by extraction from human pituitary glands collected at autopsy. Since 1985 GH is a synthetic copy of human GH, manufactured by recombinant DNA technology.

Treatment of GH deficiency in 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. Parents often notice increased strength, appetite, and energy. Increased muscle strength may allow young children to overcome delays of motor development. Excess adipose tissue may be reduced.

There are almost no significant side effects of this type of physiologic replacement. Rare risks and unsettled issues are discussed in the article on GH treatment, but GH deficient children receiving replacement doses are at the lowest risk for problems and receive the greatest benefit.

Nevertheless, costs of treatment in terms of money, effort, and perhaps quality of life, are substantial. Treatment usually involves daily injections of growth hormone for children. 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. Nearly painless insulin syringes and pen injectors reduce the discomfort. Most children and families are enthusiastic once the benefits begin to be seen. Treatment is expensive - as much as $US 10,000 to 30,000 a year is common.

Little except the cost of treating severely deficient children is controversial, and it is likely that the majority of children with severe growth hormone deficiency in North America, Japan, and much of Europe and the rest of the developed world are offered treatment, and most accept. The story is very different for adult deficiency.

It has been shown repeatedly in research studies that 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. Blood lipid levels improve, but long term mortality benefit has not yet been demonstrated.

GH for severe adult deficiency is usually prescribed as three injections per week at a weekly dose about 25% of children's doses and comparably lower cost. Despite the demonstrated benefits, most adults with GH deficiency are not being treated due to a combination of factors such as unwillingness of young adults to seek medical care, unacceptability of injections, inadequate insurance coverage, and significantly lower rates of diagnosis and treatment offer by internist endocrinologists.

History
Perhaps the most famous person who exemplified the appearance of untreated congenital growth hormone deficiency was Charles Sherwood Stratton (1838-1883), who was exhibited by P.T. Barnum as General Tom Thumb, and married Lavinia Warren. Pictures of the couple appear to show the typical adult features of untreated severe growth hormone deficiency. Despite the severe shortness, limbs and trunk are proportional.

Like many other 19th century medical terms which lost precise meaning as they gained wider currency, “midget” as a term for someone with severe proportional shortness acquired pejorative connotations and is no longer used in a medical context.

GH resistance
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. However, GH testing elicits normal or high levels of GH in the blood, demonstrating that the problem is not due to a deficiency of GH but rather to a reduced sensitivity to its action. GH treatment does not increase IGF levels or improve growth very much.

The traditional term for this condition is Laron dwarfism, but over the last 15 years many different types of GH resistance have been identified, primarily involving mutations of the GH binding protein or receptors. Trials of treatment with IGF1 were not successful enough to warrant adoption as standard use.