2. Growth hormone

Growth hormone-releasing hormone (GHRH):

1.Increases growth hormone secretion.

Pituitary Adenomas Cause

Excess Growth Hormone to be Secreted from the Pituitary

Somatropes secreted

GH

Prader-Willi syndrome is an autosomal dominant genetic disease associated with growth failure, obesity, and carbohydrate intolerance. In children GH treatment decreases body fat and increases lean body mass, linear growth, and energy expenditure.

Growth hormone treatment has also been shown to have a strong beneficial effect on final height of girls with Turner syndrome (45 X karyotype and variants). In clinical trials, GH treatment has been shown to increase final height in girls with Turner syndrome by 10-15 cm (4-6 inches). Because girls with Turner syndrome also have either absent or rudimentary ovaries, GH must be judiciously combined with gonadal steroids to achieve maximal height. Other conditions of pediatric growth failure for which GH treatment is approved include chronic renal insufficiency pre-transplant and small-for-gestational-age at birth in which the child's height remains more than 2 standard deviations below normal at 2 years of age. A controversial but approved use of GH is for children with idiopathic short stature(ISS). This is a heterogeneous population that has in common no identifiable cause of the short stature. Some have arbitrarily defined ISS clinically as having a height at least 2.25 standard deviations below normal for children of the same age and a predicted adult height that is less than 2.25 standard deviations below normal. In this group of children, many years of GH therapy result in an average increase in adult height of 4-7 cm (1.57-2.76 inches) at a cost of $5000-$40,000 per year. The complex issues involved in the cost-risk-benefit relationship of this use of GH are important because an estimated 400,000 children in the United States fit the diagnostic criteria for ISS. Treatment of children with short stature should be carried out by specialists experienced in GH administration. Dose requirements vary with the condition being treated, with GH-deficient children typically being most responsive. Children must be observed closely for slowing of growth velocity, which could indicate a need to increase the dosage or the possibility of epiphyseal fusion or intercurrent problems such as hypothyroidism or malnutrition.

Somatostatin:

Inhibits growth hormone

Somatotrophs are Cells of the Anterior Pituitary that Secrete

Somatotropin (or Growth Hormone)

Hypersecretion of growth hormone in adults causes

acromegaly —thickening of the bones and soft tissues with especially noticeable effects on the hands, feet, and face. The main pharmacological use of growth hormone is replacement therapy in cases of suspected dwarfism. Purified recombinant growth hormone (rDNA) replaced pituitary-derived human growth hormone for therapeutic use in the United States. Somatotropin ( Humatrope, Genotropin, and Nutropin ) is identical in amino acid sequence to the hormone produced by the human pituitary.

GH is released from the pituitary in a pulsatile fashion, and overall secretion peaks during

adolescence. In the bone, GH stimulates epiphyseal growth and increases osteoclast and osteoblast activity, resulting in increased bone mass. GH also increases amino acid transport in muscles. Other functions of GH include lipolysis and enhancement of hepatic protein synthesis.

Lack of growth hormone in children results in

dwarfism, whereas an excess of growth hormone results in gigantism

Somatotropin Pharmacodynamics ◦GH binds cell surface receptors & activates

signaling cascades. GH effects on growth, body composition, and carbohydrate, protein, and lipid metabolism

The main pharmacological use of growth hormone is replacement therapy in cases of

suspected dwarfism. Neonates with isolated GH deficiency are typically of normal size at birth because prenatal growth is not GH-dependent. In contrast, IGF-I is essential for normal prenatal and postnatal growth. Through poorly understood mechanisms, IGF-I expression and postnatal growth become GH-dependent during the first year of life. In childhood, GH deficiency typically presents as short stature, often with mild adiposity. Another early sign of GH deficiency is hypoglycemia due to the loss of a counter-regulatory hormonal response to hypoglycemia; young children are at risk for this condition due to high sensitivity to insulin. Criteria for diagnosis of GH deficiency usually include (1) a subnormal height velocity for age and (2) a subnormal serum GH response following provocative testing with at least two GH secretagogues. Clonidine (α2-adrenergic agonist), levodopa (dopaminergic agonist), and exercise are factors that increase GHRH levels. Arginine and insulin-induced hypoglycemia cause diminished SST, which increases GH release. The prevalence of GH deficiency is approximately 1:5000. If therapy with rhGH is initiated at an early age, many children with short stature due to GH deficiency will achieve an adult height within their midparental target height range. In the past, it was believed that adults with GH deficiency do not exhibit a significant syndrome. However, more detailed studies suggest that adults with GH deficiency often have generalized obesity, reduced muscle mass, asthenia, diminished bone mineral density, dyslipidemia, and reduced cardiac output. Growth hormone-deficient adults who have been treated with GH experience reversal of many of these manifestations.

Growth hormone (somatotropin), or GH, is referred to as a general hormone that regulates

the growth and maintenance of all body tissues, especially cartilage, bone muscle, and fat. ◦Unique in that it acts a general hormone for all tissues.

Growth hormone ◦Is controlled by two hormones from

the hypothalamus. Growth hormone-releasing hormone (GHRH): Somatostatin: ◦Is essential to normal tissue growth and maturation. ◦Affects aging, sleep, nutritional status, stress, and reproductive hormones.

Many of the anabolic functions of GH are mediated, at least in part, by

the insulin-like growth factors (IGFs), also known as the somatomedins. There are two primary forms of IGF: IGF-1 and IGF-2, of which IGF-1 is the most biologically active. They both circulate bound to a group of binding proteins (IGFBP). IGF-1 binds to both insulin receptors, providing an insulin-like effect on skeletal muscle, and with the IGF-1 receptor, which mediates the anabolic effects of GH. IGF-2 causes a negative effect on tissue growth, thus balancing the activity of the IGF-1. Because of the anabolic effects of GH and IGF, they can be used to treat growth disorders and increase muscle mass but their use also has been linked to increased rates of cancer.19 Interestingly, deficiencies in the growth hormone receptor have been linked to decreased risk of cancer and diabetes.20

Recombinant GH Has a Long Half-life ◦Absorption, Metabolism and Clearance

◦Circulating endogenous GH has a half-life of approximately 20 minutes and is predominantly cleared by the liver. ◦Recombinant human GH (rhGH) is administered subcutaneously 6-7 times per week. Peak levels occur in 2-4 hours and active blood levels persist for approximately 36 hours.

Lack of Growth Hormone Results in Dwarfism

◦General Tom Thumb was the stage name of Charles Sherwood Stratton (1838-1883) ◦Born 9lbs developed normally for 6 months ◦Pituitary Dwarfism; limbs with normal proportions

Growth Hormone Deficiency: Causes

◦Genetic basis ◦Associated with midline developmental defect syndromes (eg, septo-optic dysplasia) ◦Acquired as a result of damage to the pituitary or hypothalamus by a traumatic event (including breech or traumatic delivery), intracranial tumors, infection, infiltrative or hemorrhagic processes, or irradiation. ◦ ◦Adults with GH deficiency often have generalized obesity, reduced muscle mass, asthenia, diminished bone mineral density, dyslipidemia, and reduced cardiac output. ◦Growth hormone-deficient adults who have been treated with GH experience reversal of many of these manifestations.

The growth-promoting effects are mediated principally, but not solely, through an increase in the production of

◦IGF-1. ◦Stimulates longitudinal bone growth until the epiphyses close—near the end of puberty. ◦Anabolic effects in muscle and catabolic effects in adipose cells that shift the balance of body mass to an increase in muscle mass and a reduction in adiposity.

Somatotropin Indications in Children

◦Inadequate endogenous GH secretion ◦Growth failure caused by disorder other than GH deficiency ◦Chronic renal insufficiency Small babies that fail to catch up by age 2

treatment for deficient GH Anterior Pituitary Growth Hormone (Somatotropin)

◦Initially obtained from human cadavers (process stopped when there was a suggested linked to Creutzfeldt-Jakob's disease outbreak) ◦Purified recombinant growth hormone has replaced pituitary derived human growth hormone. ◦Identical in amino acid sequence to the hormone produced by the pituitary.

◦GH induces liver and other tissues to produce growth stimulants (direct) ◦ GH also induces the liver to produce growth stimulants (indirect).

◦Insulin-like growth factors (IGF-1 and IGF-2) or somatomedins. ◦Induces bone growth and epiphyseal plates during childhood. ◦GH increases plasma glucose, fatty acids, and glycerol by inhibiting glucose uptake in the cell providing the energy needed for growth.

Somatotropin Indications in Syndromes

◦Prader-Willi syndrome (1 in 10-25,000 births) ◦Growth failure, obesity, and carbohydrate intolerance. ◦Most common genetic cause of morbid obesity in children ◦ ◦ ◦Turner syndrome (1 in 2,500 births) ◦Females missing the X chromosome ◦Growth hormone increases height

GH directly stimulates tissues such as

◦bone, cartilage, muscle, and fat. ◦It induces liver and other tissues to produce growth stimulants called insulin-like growth factors (IGF-1, IGF-2), or somatomedins, which go on to stimulate target cells.

Excess growth hormone in children results in

◦gigantism (because bone growth plates have not fused) ◦Tallest man known to have lived the "Giant of Illinois" ◦Robert Wadlow (1918-1940) (8 ft, 11 inches with his father, Harold (6 ft, 0 inches) ◦Weighed 439lb at his death at age 22 when he was still growing