Growth hormone deficiency

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Template:Infobox medical conditionTemplate:Redirect Growth hormone deficiency (GHD), or hyposomatotropism, is a medical condition resulting from not enough growth hormone (GH).<ref name=GHR2012>Template:Cite web</ref> Generally the most noticeable symptom is that an individual attains a short height.<ref name=GARD2016>Template:Cite web</ref> Newborns may also present low blood sugar or a small penis size.<ref name="NORD2016" /> In adults there may be decreased muscle mass, high cholesterol levels, or poor bone density.<ref name=GARD2016/>

GHD can be present at birth or develop later in life.<ref name=GARD2016/> Causes may include genetics, trauma, infections, tumors, or radiation therapy.<ref name=NORD2016/> Genes that may be involved include GH1, GHRHR, or BTK.<ref name=GHR2012/> In a third of cases no cause is apparent.<ref name=NORD2016/> The underlying mechanism generally involves problems with the pituitary gland.<ref name=NORD2016/> Some cases are associated with a lack of other pituitary hormones, in which case it is known as combined pituitary hormone deficiency.<ref>Template:Cite web</ref> Diagnosis involves blood tests to measure growth hormone levels.<ref name=NORD2016/>

Treatment is by growth hormone replacement using synthetic human growth hormone.<ref name=GARD2016/> The frequency of the condition is unclear.<ref name=NORD2016/> Most cases are initially noticed in children.<ref name=GARD2016/> The genetic forms of this disease are estimated to affect about 1 in 7,000 people.<ref name=GHR2012/> Most types occur equally in males and females though males are more often diagnosed.<ref name=NORD2016>Template:Cite web</ref>

Signs and symptoms

Child

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 in males, additional consequences of severe deficiency in the first days of life can include hypoglycemia and exaggerated jaundice (both direct and indirect [[Bilirubin#Hyperbilirubinemia|hyperTemplate:ShybiliTemplate:ShyrubiTemplate:Shynemia]]).<ref>Template:Cite journal</ref>

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 Template:Convert.Template:Citation needed

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.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>

Other side effects in children include sparse hair growth and frontal recession, and pili torti and trichorrhexis nodosa are also sometimes present.<ref name="Andrews">James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. Template:ISBN.</ref>Template:Rp

Adults

Recognised effects include:<ref>Template:Cite web</ref><ref name="Gupta 2011 p=197">Template:Cite journal</ref>

Causes

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.<ref name="NICE">Template:Cite web</ref><ref>Template:Cite journal</ref> A more complete list of causes includes:

There are a variety of rare diseases that resemble GH deficiency, including the childhood growth failure, facial appearance, delayed bone age, and low insulin-like growth factor-1 (IGF-1) 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. Insensitivity to GH is traditionally termed 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.<ref>Template:Cite book</ref>

Familial isolated growth hormone deficiency (IGHD) can be inherited as an autosomal recessive (type I), autosomal dominant (type II), or X-linked (type III) characteristic.<ref name="pmid12201208">Template:Cite journal</ref>

Pathophysiology

As an adult ages, it is normal for the pituitary to produce diminishing amounts of GH and many other hormones, particularly the sex steroids. Physicians, therefore, distinguish between the natural reduction in GH levels which comes with age, and the much lower levels of "true" deficiency. Such deficiency almost always has an identifiable cause, with adult-onset GHD without a definable cause ("idiopathic GH deficiency") extremely rare.<ref name="Molitch et al. 2006">Template:Cite journal</ref> GH does function in adulthood to maintain muscle and bone mass and strength, and has poorly understood effects on cognition and mood.<ref>Template:Cite book</ref>

Diagnosis

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:<ref name="Diagnosis of growth hormone deficie">Template:Cite journal</ref>

  • 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,<ref name="Aimaretti et al. 1998">Template:Cite journal</ref> 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,<ref name="Aimaretti et al. 1998"/> and so is the test of choice.

Severe GH deficiency in childhood additionally has the following measurable characteristics:<ref name="Diagnosis of growth hormone deficie"/>

  • 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

In childhood and adulthood, the diagnosing doctor will look for these features 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. This would confirm the diagnosis; in the absence of pituitary pathology, further testing would be required.<ref>Template:Cite journal</ref>

Classification

Growth hormone 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.<ref>Template:Cite book</ref>

The term hypopituitarism is often used interchangeably with GH deficiency 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.<ref>Template:Cite web</ref>

Treatment

Template:Main 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 at autopsy. Since 1985, recombinant human growth hormone (rHGH) is a recombinant form of human GH produced by genetically engineered bacteria, manufactured by recombinant DNA technology. In both children and adults, costs of treatment in terms of money, effort, and the impact on day-to-day life, are substantial.<ref>Template:Cite journal</ref>

Child

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.<ref name="NICE kids2">Template:Cite web</ref> Children requiring treatment usually receive daily injections of growth hormone. Most pediatric endocrinologists monitor growth and adjust dose every 3–6 months and many of these visits involve blood tests and x-rays. 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, pen injectors, or a needle-free delivery system reduce the discomfort. Injection sites include the biceps, thigh, buttocks, and stomach. Injection sites should be rotated daily to avoid lipoatrophy. Treatment is expensive, costing as much as US$10,000 to $40,000 a year in the US.Template:Citation needed

Adults

GH supplementation is not recommended medically for the physiologic age-related decline in GH/IGF secretion.<ref name="NICE"/><ref name="Molitch et al. 2006"/> It may be appropriate in diagnosed adult-onset deficiency, where a weekly dose of 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.<ref name="urlConsensus Guidelines for Adult Growth Hormone Deficiency 2007">Template:Cite web</ref>

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,<ref name="SocietyEndo"/> 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

Where treatment is indicated, duration is dependent upon indication.

Cost of adult treatment in the UK is 3000-4000 GBP annually.<ref name="SocietyEndo"/>

Side effects

Prognosis

Child

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 their height may grow into the normal height range. Excess adipose tissue may be reduced.<ref>Template:Cite journal</ref>

Adults

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 of more than double controls,<ref name="SocietyEndo"/> treatment has not been shown to improve mortality, although blood lipid levels do improve. Similarly, although measurements of bone density improve with treatment, rates of fractures have not been shown to improve.<ref name="SocietyEndo"/>

Effects on quality of life are unproven, with a number of studies finding that adults with GHD had near-normal indicators of QoL at baseline (giving little scope for improvement), and many using outdated dosing strategies. However, it may be that those adults with poor QoL at the start of treatment do benefit.<ref name="NICE"/>

Epidemiology

The incidence of idiopathic GHD in infants is about 1 in every 3800 live births,<ref>Template:Cite web</ref> and rates in older children are rising as more children survive childhood cancers which are treated with radiotherapy, although exact rates are hard to obtain.<ref name="NICE kids">Template:Cite web</ref> The incidence of genuine adult-onset GHD, normally due to pituitary tumours, is estimated at 10 per million.<ref name="SocietyEndo">Template:Cite web</ref>

History

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.<ref>Template:Cite journal</ref>

Notable modern pop cultural figures with growth hormone deficiency include actor and comedian Andy Milonakis, who has the appearance and voice of an adolescent boy despite being in his 40s.<ref>Template:Cite web</ref><ref>Template:Cite web</ref> Argentine footballer Lionel Messi was diagnosed at age 10 with growth hormone deficiency and was subsequently treated.<ref name="The Legend of El Enano">Template:Cite news</ref> TLC reality star Shauna Rae was affected by a medically-caused growth hormone deficiency resulting from childhood glioblastoma cancer treatment.<ref>Template:Cite web</ref> Oscar winning actress Linda Hunt was diagnosed as having this condition when a teenager.

See also

References

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