Growth hormone deficiency
Encyclopedia
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 (see HGH controversies).
Growth hormone deficiency has different effects at different ages. In newborn infants the primary manifestations may be hypoglycemia
or micropenis
, while in later infancy and childhood, growth failure is more likely. Deficiency in adults is rare, but may feature diminished lean body mass
, poor bone density
, and a number of physical and psychological symptoms. Psychological symptoms include poor memory
, social withdrawal, and depression
, while physical symptoms may include loss of strength, stamina, and musculature. Other hormonal or glandular disorders frequently coincide with diminished growth hormone production.
GH deficiency can be treated by growth hormone replacement
or injections of growth hormone.
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.
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 maxilla
ry hypoplasia and forehead prominence (said to resemble a kewpie doll
).
Children have sparse hair growth and frontal recession, and pili torti
and trichorrhexis nodosa
are also sometimes present.
of genuine adult-onset GHD, normally due to pituitary tumours, is estimated at 10 per million.
Recognised effects include:
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. 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.
s. 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. GH does function in adulthood to maintain muscle
and bone
mass and strength, and has poorly-understood effects on cognition and mood.
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 in assessing GHD, including:
"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:
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.
. 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.
s, 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 USA.
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:
Where treatment is indicated, duration is dependent upon indication.
Cost of adult treatment in the UK is UKP 3000-4000 annually.
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 fracture
s have not been shown to improve.
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.
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.
One of the most well known people to have suffered from this deficiency is F.C. Barcelona
striker Lionel Messi
. Diagnosed at age eleven, his family couldn't afford the treatment, but that cost was covered by Barcelona in exchange for Messi joining the team's youth department.
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.
Growth hormone
Growth hormone is a peptide hormone that stimulates growth, cell reproduction and regeneration in humans and other animals. Growth hormone is a 191-amino acid, single-chain polypeptide that is synthesized, stored, and secreted by the somatotroph cells within the lateral wings of the anterior...
(GH). Growth hormone, also called somatotropin, is a polypeptide hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
which stimulates growth
Human development (biology)
Human development is the process of growing to maturity. In biological terms, this entails growth from a one-celled zygote to an adult human being.- Biological development:...
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 (see HGH controversies).
Growth hormone deficiency has different effects at different ages. In newborn infants the primary manifestations may be hypoglycemia
Hypoglycemia
Hypoglycemia or hypoglycæmia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood"...
or micropenis
Micropenis
Micropenis is an unusually small penis. A common criterion is a dorsal erect penile length of at least 2.5 standard deviations smaller than the mean human penis size. The condition is usually recognized shortly after birth...
, while in later infancy and childhood, growth failure is more likely. Deficiency in adults is rare, but may feature diminished lean body mass
Body composition
In physical fitness, body composition is used to describe the percentages of fat, bone and muscle in human bodies. Because muscular tissue takes up less space in our body than fat tissue, our body composition, as well as our weight, determines leanness...
, poor bone density
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
, and a number of physical and psychological symptoms. Psychological symptoms include poor memory
Memory
In psychology, memory is an organism's ability to store, retain, and recall information and experiences. Traditional studies of memory began in the fields of philosophy, including techniques of artificially enhancing memory....
, social withdrawal, and depression
Depression (mood)
Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behaviour, feelings and physical well-being. Depressed people may feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable, or restless...
, while physical symptoms may include loss of strength, stamina, and musculature. Other hormonal or glandular disorders frequently coincide with diminished growth hormone production.
GH deficiency can be treated by growth hormone replacement
Growth hormone treatment
Growth hormone treatment refers to the use of growth hormone in medical treatment. Growth hormone is a peptide hormone secreted by the pituitary gland that stimulates growth and cell reproduction. In the past, growth hormone was extracted from human pituitary glands. GH is now produced by...
or injections of growth hormone.
Classification
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.The term hypopituitarism
Hypopituitarism
Hypopituitarism is the decreased secretion of one or more of the eight hormones normally produced by the pituitary gland at the base of the brain...
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
Diabetes insipidus
Diabetes insipidus is a condition characterized by excessive thirst and excretion of large amounts of severely diluted urine, with reduction of fluid intake having no effect on the concentration of the urine. There are several different types of DI, each with a different cause...
) the condition is termed panhypopituitarism.
In childhood
The incidence of idiopathic GHD in infants is about 1 in every 3800 live births, 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.Severe prenatal deficiency of GH, as occurs in congenital hypopituitarism
Congenital hypopituitarism
Congenital hypopituitarism is hypopituitarism which one is born with.One sign may be [micropenis]....
, has little effect on fetal growth. However, prenatal and congenital deficiency can reduce the size of a male's penis
Penis
The penis is a biological feature of male animals including both vertebrates and invertebrates...
, especially when gonadotropins are also deficient. Besides micropenis
Micropenis
Micropenis is an unusually small penis. A common criterion is a dorsal erect penile length of at least 2.5 standard deviations smaller than the mean human penis size. The condition is usually recognized shortly after birth...
, additional consequences of severe deficiency in the first days of life can include hypoglycemia
Hypoglycemia
Hypoglycemia or hypoglycæmia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood"...
and exaggerated jaundice
Jaundice
Jaundice is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia . This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid...
(both direct and indirect hyperbilirubinemia). Female infants will lack the microphallus
Micropenis
Micropenis is an unusually small penis. A common criterion is a dorsal erect penile length of at least 2.5 standard deviations smaller than the mean human penis size. The condition is usually recognized shortly after birth...
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
Hypothyroidism
Hypothyroidism is a condition in which the thyroid gland does not make enough thyroid hormone.Iodine deficiency is the most common cause of hypothyroidism worldwide but it can be caused by other causes such as several conditions of the thyroid gland or, less commonly, the pituitary gland or...
, 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
Bone age
Bone age is a way of describing the degree of maturation of child's bones. As a person grows from fetal life through childhood, puberty, and finishes growth as a young adult, the bones of the skeleton change in size and shape. These changes can be seen by x-ray. The "bone age" of a child is the...
and puberty
Puberty
Puberty is the process of physical changes by which a child's body matures into an adult body capable of reproduction, as initiated by hormonal signals from the brain to the gonads; the ovaries in a girl, the testes in a boy...
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
Muscle
Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
development, so that gross motor milestones such as standing, walking, and jumping may be delayed. Body composition
Body composition
In physical fitness, body composition is used to describe the percentages of fat, bone and muscle in human bodies. Because muscular tissue takes up less space in our body than fat tissue, our body composition, as well as our weight, determines leanness...
(i.e., the relative amounts of bone
Bone
Bones are rigid organs that constitute part of the endoskeleton of vertebrates. They support, and protect the various organs of the body, produce red and white blood cells and store minerals. Bone tissue is a type of dense connective tissue...
, muscle, and fat
Adipose tissue
In histology, adipose tissue or body fat or fat depot or just fat is loose connective tissue composed of adipocytes. It is technically composed of roughly only 80% fat; fat in its solitary state exists in the liver and muscles. Adipose tissue is derived from lipoblasts...
) 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 maxilla
Maxilla
The maxilla is a fusion of two bones along the palatal fissure that form the upper jaw. This is similar to the mandible , which is also a fusion of two halves at the mental symphysis. Sometimes The maxilla (plural: maxillae) is a fusion of two bones along the palatal fissure that form the upper...
ry hypoplasia and forehead prominence (said to resemble a kewpie doll
Kewpie doll (toy)
Kewpie dolls and figurines are based on comical strip-like illustrations by Rose O'Neill that appeared in Ladies' Home Journal in 1909. The small dolls were extremely popular in the early 1900s. They were first produced in Ohrdruf, a small town in Germany, then famous for its toy-manufacturers....
).
Children have sparse hair growth and frontal recession, and pili torti
Pili torti
Pili torti is characterized by short and brittle hairs that appear flattened and twisted when viewed through a microscope.This phenotype is noted in Menkes disease....
and trichorrhexis nodosa
Trichorrhexis nodosa
Trichorrhexis nodosa is a defect in the hair shaft characterized by thickening or weak points that cause the hair to break off easily. This group of conditions contributes to the appearance of hair loss, lack of growth, and damaged-looking hair....
are also sometimes present.
In adulthood
The incidenceIncidence
Incidence may refer to:* Incidence , a measure of the risk of developing some new condition within a specified period of time* Incidence , the binary relations describing how subsets meet...
of genuine adult-onset GHD, normally due to pituitary tumours, is estimated at 10 per million.
Recognised effects include:
- Increased 5-alpha-reductase
- Reduced sex hormone-binding globulin (SHBG)
- Reduced muscle mass and strength
- BaldnessBaldnessBaldness implies partial or complete lack of hair and can be understood as part of the wider topic of "hair thinning". The degree and pattern of baldness can vary greatly, but its most common cause is male and female pattern baldness, also known as androgenic alopecia, alopecia androgenetica or...
in men - Reduced bone massOsteopeniaOsteopenia is a condition where bone mineral density is lower than normal. It is considered by many doctors to be a precursor to osteoporosis. However, not every person diagnosed with osteopenia will develop osteoporosis...
and osteoporosisOsteoporosisOsteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered... - Reduced quality of lifeQuality of lifeThe term quality of life is used to evaluate the general well-being of individuals and societies. The term is used in a wide range of contexts, including the fields of international development, healthcare, and politics. Quality of life should not be confused with the concept of standard of...
, particularly energy levels - Impaired concentration and loss of memory
- Increased body fat, particularly around the waistline
- Lipid abnormalities, particularly raised LDL cholesterol
- Insulin resistanceInsulin resistanceInsulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...
- Increased levels of fibrinogenFibrinogenFibrinogen is a soluble plasma glycoprotein, synthesised by the liver, that is converted by thrombin into fibrin during blood coagulation. This is achieved through processes in the coagulation cascade that activate the zymogen prothrombin to the serine protease thrombin, which is responsible for...
and plasminogen activator inhibitor - Cardiac dysfunction, including a thickened intima mediaIntima-media thicknessIntima-media thickness , also called intimal medial thickness, is a measurement of the thickness of artery walls, usually by external ultrasound, occasionally by internal, invasive ultrasound catheters, see IVUS, to both detect the presence and to track the progression of atherosclerotic disease in...
Causes
Childhood GHD 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 full list of causes includes:- mutationMutationIn molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s of specific geneGeneA gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s (e.g., GHRHR, GH1) - congenital diseases such as Prader-Willi syndromePrader-Willi syndromePrader–Willi syndrome is a rare genetic disorder in which seven genes on chromosome 15 are deleted or unexpressed on the paternal chromosome...
, Turner syndromeTurner syndromeTurner syndrome or Ullrich-Turner syndrome encompasses several conditions in human females, of which monosomy X is most common. It is a chromosomal abnormality in which all or part of one of the sex chromosomes is absent...
, or short stature homeobox-containing gene (SHOX) deficiency - congenital malformations involving the pituitary (e.g., septo-optic dysplasiaSepto-optic dysplasiaSepto-optic dysplasia , also known as de Morsier syndrome is a congenital malformation syndrome made manifest by hypoplasia of the optic nerve and absence of the septum pellucidum...
, posterior pituitary ectopia) - chronic renal insufficiency
- some infants who are small for gestational ageSmall for gestational ageSmall for gestational age babies are those who are smaller in size than normal for the baby's sex and gestational age, most commonly defined as a weight below the 10th percentile for the gestational age.-Terminology:...
- intracranial tumorsBrain tumorA brain tumor is an intracranial solid neoplasm, a tumor within the brain or the central spinal canal.Brain tumors include all tumors inside the cranium or in the central spinal canal...
in or near the sella turcicaSella turcica-External links:*...
, especially craniopharyngiomaCraniopharyngiomaCraniopharyngioma is a type of brain tumor derived from pituitary gland embryonic tissue, that occurs most commonly in children but also in men and women in their 50s and 60s.... - damage to the pituitary from radiation therapyRadiation therapyRadiation therapy , radiation oncology, or radiotherapy , sometimes abbreviated to XRT or DXT, is the medical use of ionizing radiation, generally as part of cancer treatment to control malignant cells.Radiation therapy is commonly applied to the cancerous tumor because of its ability to control...
to the head (e.g. for leukemiaLeukemiaLeukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
or brain tumorBrain tumorA brain tumor is an intracranial solid neoplasm, a tumor within the brain or the central spinal canal.Brain tumors include all tumors inside the cranium or in the central spinal canal...
s), from surgery, from trauma, or from intracranial disease (e.g. hydrocephalusHydrocephalusHydrocephalus , also known as "water in the brain," is a medical condition in which there is an abnormal accumulation of cerebrospinal fluid in the ventricles, or cavities, of the brain. This may cause increased intracranial pressure inside the skull and progressive enlargement of the head,...
) - autoimmuneAutoimmunityAutoimmunity is the failure of an organism to recognize its own constituent parts as self, which allows an immune response against its own cells and tissues. Any disease that results from such an aberrant immune response is termed an autoimmune disease...
inflammationInflammationInflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
(hypophysitis) - ischemic or hemorrhagic infarction from low blood pressure (Sheehan syndrome) or hemorrhage pituitary apoplexyPituitary apoplexyPituitary apoplexy or pituitary tumor apoplexy is bleeding into or impaired blood supply of the pituitary gland at the base of the brain. This usually occurs in the presence of a tumor of the pituitary, although in 80% of cases this has not been diagnosed previously...
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. 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.
Pathophysiology
As an adult ages, it is normal for the pituitary to produce diminishing amounts of GH and many other hormones, particularly the sex steroidSex steroid
Sex steroids, also known as gonadal steroids, are steroid hormones that interact with vertebrate androgen or estrogen receptors. Their effects are mediated by slow genomic mechanisms through nuclear receptors as well as by fast nongenomic mechanisms through membrane-associated receptors and...
s. 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. GH does function in adulthood to maintain muscle
Muscle
Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
and bone
Bone
Bones are rigid organs that constitute part of the endoskeleton of vertebrates. They support, and protect the various organs of the body, produce red and white blood cells and store minerals. Bone tissue is a type of dense connective tissue...
mass and strength, and has poorly-understood effects on cognition and mood.
Diagnosis
Pediatric endocrinologists are the physicians who specialize in diagnosis and treatment of growth hormone deficiency and growth problems in children. InternistInternal medicine
Internal medicine is the medical specialty dealing with the prevention, diagnosis, and treatment of adult diseases. Physicians specializing in internal medicine are called internists. They are especially skilled in the management of patients who have undifferentiated or multi-system disease processes...
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 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
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
, levodopa
Levodopa
L-DOPA is a chemical that is made and used as part of the normal biology of some animals and plants. Some animals including humans make it via biosynthesis from the amino acid L-tyrosine. L-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine , and epinephrine collectively...
, clonidine
Clonidine
Clonidine is a sympatholytic medication used to treat medical conditions, such as high blood pressure, some pain conditions, ADHD and anxiety/panic disorder...
, epinephrine
Epinephrine
Epinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...
and propranolol, glucagon
Glucagon
Glucagon, a hormone secreted by the pancreas, raises blood glucose levels. Its effect is opposite that of insulin, which lowers blood glucose levels. The pancreas releases glucagon when blood sugar levels fall too low. Glucagon causes the liver to convert stored glycogen into glucose, which is...
and insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
. 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
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.
Treatment
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 autopsyAutopsy
An autopsy—also known as a post-mortem examination, necropsy , autopsia cadaverum, or obduction—is a highly specialized surgical procedure that consists of a thorough examination of a corpse to determine the cause and manner of death and to evaluate any disease or injury that may be present...
. Since 1985, recombinant human growth hormone (rHGH) is a recombinant
Recombinant DNA
Recombinant DNA molecules are DNA sequences that result from the use of laboratory methods to bring together genetic material from multiple sources, creating sequences that would not otherwise be found in biological organisms...
form of human GH produced by genetically engineered bacteria
Genetic engineering
Genetic engineering, also called genetic modification, is the direct human manipulation of an organism's genome using modern DNA technology. It involves the introduction of foreign DNA or synthetic genes into the organism of interest...
, 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.
Treatment in 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 3–6 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 syringeSyringe
A syringe is a simple pump consisting of a plunger that fits tightly in a tube. The plunger can be pulled and pushed along inside a cylindrical tube , allowing the syringe to take in and expel a liquid or gas through an orifice at the open end of the tube...
s, 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 USA.
Treatment in 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-I.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
NICE
NICE may refer to:* National Independent Cadres and Elites in Iraq* National Institute for Coordinated Experiments, a fictional organisation in C.S...
suggest three criteria which all need to be met for treatment to be indicated:
- Severe GH deficiency, defined as a peak GH response of <9mU/litre during an insulin tolerance test
- Perceived impairment of quality of life, as assessed by questionnaire
- 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 UKP 3000-4000 annually.
Side-effects
- Headache
- Joint painArthralgiaArthralgia literally means joint pain; it is a symptom of injury, infection, illnesses or an allergic reaction to medication....
and muscle painMyalgiaMyalgia means "muscle pain" and is a symptom of many diseases and disorders. The most common causes are the overuse or over-stretching of a muscle or group of muscles. Myalgia without a traumatic history is often due to viral infections... - Fluid retention, and carpal tunnel syndromeCarpal tunnel syndromeCarpal Tunnel Syndrome is an entrapment idiopathic median neuropathy, causing paresthesia, pain, and other symptoms in the distribution of the median nerve due to its compression at the wrist in the carpal tunnel. The pathophysiology is not completely understood but can be considered compression...
- Mild hypertensionHypertensionHypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
- Visual problems
- Nausea and vomiting
- Paraesthesiae
- Antibody formation
- Reactions at the injection site
- Rarely, benign intracranial hypertension.
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. Excess adipose tissue may be reduced.In adulthood
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 hypopituitarismHypopituitarism
Hypopituitarism is the decreased secretion of one or more of the eight hormones normally produced by the pituitary gland at the base of the brain...
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 fracture
Fracture
A fracture is the separation of an object or material into two, or more, pieces under the action of stress.The word fracture is often applied to bones of living creatures , or to crystals or crystalline materials, such as gemstones or metal...
s have not been shown to improve.
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.
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. BarnumP. T. Barnum
Phineas Taylor Barnum was an American showman, businessman, scam artist and entertainer, remembered for promoting celebrated hoaxes and for founding the circus that became the Ringling Bros. and Barnum & Bailey Circus....
as General Tom Thumb
General Tom Thumb
General Tom Thumb was the stage name of Charles Sherwood Stratton , a dwarf who achieved great fame under circus pioneer P.T. Barnum.-Early life:...
, and married Lavinia Warren
Lavinia Warren
Lavinia Warren was an American proportionate dwarf and the wife of General Tom Thumb.-Early life:Warren was born at Middleborough, Massachusetts as Mercy Lavinia Warren Bump, a descendant of a French Catholic family named Bonpasse, of Governor Thomas Mayhew, and five Mayflower passengers: John...
. 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.
One of the most well known people to have suffered from this deficiency is F.C. Barcelona
FC Barcelona
Futbol Club Barcelona , also known as Barcelona and familiarly as Barça, is a professional football club, based in Barcelona, Catalonia, Spain....
striker Lionel Messi
Lionel Messi
Lionel Andrés "Leo" Messi is an Argentine footballer who plays for FC Barcelona and captains the Argentina national team, mainly as a striker. Messi received several Ballon d'Or and FIFA World Player of the Year nominations by the age of 21, and won in 2009 and 2010...
. Diagnosed at age eleven, his family couldn't afford the treatment, but that cost was covered by Barcelona in exchange for Messi joining the team's youth department.
Like many other 19th century medical terms which lost precise meaning as they gained wider currency, "midget
Midget
A midget is a short person with relatively average bodily proportions in comparison with other human beings. The term is often improperly used to describe a person with the medical condition dwarfism. The two terms are often used synonymously because both terms originate as words defining small...
" as a term for someone with severe proportional shortness acquired pejorative connotations and is no longer used in a medical context.
External links
- NIH Medline Plus
- Am Assoc Clinical Endocrinologists - practice guidelines and recommendations for diagnosis and treatment of GH deficiency, reflecting standard practice among U.S. endocrinologists
- Growth, Genetics, & Hormones - online journal primarily written for pediatric endocrinologists that has been publishing reviews and research synopses related to growth hormone and growth issues for many years
- National Organization of Short Statured Adults - non-profit advocacy group for adults of short stature