Growth Hormone Deficiency

Introduction

Growth hormone deficiency (GHD) is a medical condition due to not enough growth hormone (GH). Generally, the most noticeable symptom is a short height. In newborns there may be low blood sugar or a small penis. In adults there may be decreased muscle mass, high cholesterol levels, or poor bone density. There are three types of GH deficiency: congenital, acquired, and idiopathic.

Associated Anatomy

In vertebrate anatomy, the pituitary gland, or hypophysis, is an endocrine gland about the size of a pea and weighing 0.5 grams (0.018 oz) in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain. The hypophysis rests upon the hypophysial fossa of the sphenoid bone in the center of the middle cranial fossa and is surrounded by a small bony cavity (sella turcica) covered by a dural fold (diaphragma sellae). The anterior pituitary (or adenohypophysis) is a lobe of the gland that regulates several physiological processes (including stress, growth, reproduction, and lactation). The intermediate lobe synthesizes and secretes melanocyte-stimulating hormone. The posterior pituitary (or neurohypophysis) is a lobe of the gland that is functionally connected to the hypothalamus by the median eminence via a small tube called the pituitary stalk (also called the infundibular stalk or the infundibulum).

Hormones secreted from the pituitary gland help to control growth, blood pressure, energy management, all functions of the sex organs, thyroid glands and metabolism as well as some aspects of pregnancy, childbirth, breastfeeding, water/salt concentration at the kidneys, temperature regulation and pain relief.

Causes

Causes of growth hormone deficiency could be congenital or acquired. Congenital causes include genetic mutations in POU1F1, PROP-1, and GH-1 genes. Structural causes can cause growth hormone deficiency such as optic nerve hypoplasia, agenesis of corpus callosum, septo-optic dysplasia, empty sella syndrome, and holoprosencephaly. Acquired causes can cause growth hormone deficiency such as GHD following brain surgery and radiation therapy for brain tumors, central nervous system infection, craniopharyngioma, and pituitary adenoma.

Differential Diagnosis

Growth hormone deficiency in children must be differentiated from different infections that cause short stature in kids, for example, achondroplasia, constitutional growth delay, familial short stature, growth hormone resistance, Noonan syndrome, panhypopituitarism, pediatric hypothyroidism, Short stature accompanying systemic disease, psychosocial short stature, Silver-Russell Syndrome, Turner syndrome, and idiopathic short stature.

Drugs

Somatropin (Genotropin, Humatrope, Norditropin, Nutropin, Omnitrope, Saizen, TevTropin)

Purified polypeptide hormone of recombinant DNA origin. In children whose epiphyses are not yet fused, GH replacement usually causes significant increase in growth velocity (averaging 10-11 cm/y during first y of therapy). Response wanes each y, but growth velocity continues at faster than pretreatment rates. A long-acting depot preparation designed for monthly or bimonthly SC injection was available but is not off the market. Other long-acting preparations are currently under investigation.

Epidemiology

Prevalence and incidence data of growth hormone deficiency vary widely due to the lack of standard diagnostic criteria. Diagnosis of growth hormone deficiency is made during 2 broad age peaks; the first age peak occurs at 5 years. The second age peak occurs in girls aged 10-13 years and boys aged 12-16 years. There is no apparent racial difference in the incidence of GHD. In seventy-three percent of patients with idiopathic GHD, due to societies that concern more about males short stature than the females. Patients with GHD from organic causes such as tumors and radiation, in which no gender bias should be present, there was still 62% male.

Pathophysiology

The somatotroph cells of the anterior pituitary organ create development hormone (GH). The most widely studied impact of growth hormone is increasing weight. GH causes epiphyseal plate broadening and ligament development. GH inadequacy brings about changes in the physiology of various frameworks of the body, showing as modified lipid digestion, expanded subcutaneous instinctive fat, diminished bulk. The hereditary premise of inborn development hormone insufficiency relies upon numerous qualities, for instance, POU1F1 quality transformations are the most widely recognized hereditary reason for the joined pituitary hormone lack. Quality erasures, frameshift transformations, and jabber changes of GH1 quality have been portrayed as reasons for familial GHD.

Possible Complications

If left untreated, patients with growth hormone deficiency can also development to develop delayed postnatal growth, delayed bone age, delayed puberty, infantile fat distribution, and infantile voice. common complications of growth hormone deficiency encompass osteopenia, dyslipidemia, delayed puberty, and higher mortality rates than regular subjects.

Possible Treatment

Growth hormone (GH) is indicated for children with GH deficiency whose epiphyses are open. The dose for children is between 0.16 and 0.24 mg/kg/week, divided into once daily injections. Serum levels of insulin-like growth factor I (IGF-I) should be measured several weeks after beginning GH treatment or making a dose adjustment. GH side effects include headaches, Idiopathic intracranial hypertension, Slipped capital femoral epiphysis, worsening of existing scoliosis, Pancreatitis, and Gynecomastia. There is a possible role for GH in cancer risk.

Surgical intervention is not recommended for the management of growth hormone deficiency.

Prognosis

Prognosis is usually desirable with treatment. GH treatment can improve GH-deficient adults signs and symptoms. since recombinant DNA–derived growth hormone have become to be had, most children with growth hormone deficiency attain normal adult stature.

Primary Prevention

There are no established measures for the primary prevention of growth hormone deficiency.

Risk factors

Genetic risk factors that may influence growth hormone deficiency are:

Growth hormone insensitivity

• Growth hormone insensitivity is an absence of the effects of growth hormone despite a normal production of GH.
• It is caused by mutations in the growth hormone receptor gene which affects the GH-binding of the receptor.
• Its severity correlates to IGF-I and insulin-like growth factor-binding protein 3 (IGFBP-3) levels.

POU1F1 gene mutations

• It is the most common known genetic cause of the combined pituitary hormone deficiency.
• It is responsible for pituitary-specific transcription of genes for GH, prolactin, thyrotropin, and the growth hormone-releasing hormone (GHRH) receptor.
• PROP1 mutations result in failure to activate POU1F1/Pit1 gene expression and probably cause pituitary hypoplasia.

GH1 gene mutations

• It is GH1 is the gene encoding GH, located on chromosome 17.
• Gene deletions, frameshift mutations, and nonsense mutations of GH1 have been described as causes of familial GHD.

Syndrome of bioinactive GH

Bioinactive GH has the main symptoms and signs of isolated GHD with normal basal GH levels and low insulin-like growth factor I concentrations.

GH receptor signal transduction

It is essential for normal signaling of the GH receptor. Mutations in the gene encoding signal transducer decrease the response of receptors to GH.

IGF-I gene mutations

Mutations in the gene encoding IGF-I cause a unique syndrome of GHD.

Patients with IGF-I gene mutations have prenatal growth failure, microcephaly, significant neurocognitive deficits, and sensorineural hearing loss.

Defective stabilization of circulating IGF-I

Acid-labile subunit is important for the stabilization of the IGF-I.

Mutations in the gene coding for it causes less stable and subsequently less effect.

Secondary prevention

Patients who are receiving growth hormone therapy should be followed up 2-4 times per year. Growth rate usually increases during the first year of treatment, with an average increase of 8-10 cm/y. A slow growth rate more than expected should be investigated to exclude other causes such as hypothyroidism or inflammatory bowel disease.

Signs or 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 hyperbilirubinemia).

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 48-65 inches (122–165 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.

Other side effects in children include sparse hair growth and frontal recession, and pili torti and trichorrhexis nodosa are also sometimes present.

Adults

Recognised effects include:

• Increased 5-alpha-reductase
• Reduced sex hormone-binding globulin (SHBG)
• Reduced muscle mass and strength
• Baldness in men
• Reduced bone mass and osteoporosis
• Reduced energy
• Impaired concentration and memory loss
• Increased body fat, particularly around the waistline
• Lipid abnormalities, particularly raised LDL cholesterol
• Increased levels of fibrinogen and plasminogen activator inhibitor
• Cardiac dysfunction, including a thickened intima media

Studies

Active Not Recruiting

Number of studies: 5

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Completed

Number of studies: 168

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Enrolling by Invitation

Number of studies: 1

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Not Yet Recruiting

Number of studies: 4

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Recruiting

Number of studies: 21

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Results Available

Number of studies: 44

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Results Not available

Number of studies: 209

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Suspended

Number of studies: 0

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Terminated

Number of studies: 31

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Withdrawn

Number of studies: 4

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Types

Growth hormone deficiency can be classified by cause into congenital type in which infants show symptoms such as hypoglycemia, neonatal growth failure, neonatal jaundice, and asphyxia or acquired type presents with severe growth failure, delayed bone age, delayed puberty, or Idiopathic growth hormone deficiency which defined as having a height significantly shorter than the normal population with no detectable cause for short stature.

Typical Test

History and Symptoms

The hallmark of growth hormone deficiency is growth failure. The most common symptoms of GHD in infants are delayed Bone age, perinatal asphyxia, hypoglycemia, and jaundice. Adults symptoms include increased lean body mass, fractures of the lumbar spine, and osteopenia.

Physical Examination

Patients with growth hormone deficiency usually look tired and less energetic than normal subjects. Extremities show Clubbing, muscle atrophy, neonatal jaundice, neonatal cyanosis. Head may show infantile facies, delayed dentition, and brittle hair. Children may show hyporeflexia and delayed puberty.

Laboratory Findings

An immediate investigation should be started in severe short stature defined as a short child more than 3 standard deviations below the mean of children at the same age. Measurement of a random serum GH level alone is not helpful. Measurement of Insulin-like growth factor I (IGF-I) and Insulin-like growth factor binding protein-3 (IGFBP-3) is more helpful than GH level alone. GH stimulation tests are indicated for most patients suspected to have GHD. If the clinical and other laboratory criteria are sufficient to make the diagnosis of GHD, there is no need to perform the test. Pharmacologic stimuli include clonidine, glucagon, arginine, and insulin-induced hypoglycemia. Administration of sex steroids for a few days prior to the provocative GH testing reduces the chance of a false-positive result.

X-ray

An x-ray may be helpful in the diagnosis of delayed bone age associated with growth hormone deficiency.

CT scan

Pituitary CT scan may be helpful in the diagnosis of growth hormone deficiency if an MRI is not available. Brain CT of pituitary apoplexy is insensitive to the diagnosis of apoplexy unless intracranial hemorrhage is present. Brain CT of adrenal adenoma shows typically has attenuation similar to the brain and calcification is rarely found.

MRI

Brain MRI may be helpful in the diagnosis of growth hormone deficiency. On T1-weighted imaging, a clear demarcation can be made between the adenohypophysis and the neurohypophysis, which appears as hyperintense. Other pituitary abnormalities such as anterior pituitary hypoplasia, pituitary stalk agenesis, and posterior pituitary ectopia can be diagnosed using MRI.

References:

https://www.wikidoc.org/index.php/Growth_hormone_deficiency
https://emedicine.medscape.com/article/923688-overview
https://emedicine.medscape.com/article/120767-overview
https://www.ncbi.nlm.nih.gov/pubmed/23435439