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GH secretion is controlled by complex hypothalamic and peripheral factors. GHRH is a 44-amino acid hypothalamic peptide that stimulates GH synthesis and release. Gherlin, or octonoylated gastric-derived peptide, as well as synthetic agonists of the GHRP receptor stimulate GHRH and also directly stimulate GH release. Somatostatin is synthesised in the medial preoptic area of the hypothalamus and inhibits GH secretion. GHRH is secreted as discrete spikes that elicit GH pulses, whereas SRIF sets basal GH tone.
GH secretion is pulsatile, with greatest levels at night, generally correlating with the onset of sleep. GH secretory rates decline markedly with age so that the hormone production in middle age is about 15% of production during puberty. The changes are paralleled by an age related decline in lean muscle mass. GH secretion is also reduced in obese individuals, though IGF-I levels are usually preserved, suggesting a change in the set point for feedback control. Elevated GH occurs within an hour of deep sleep onset as well as after exercise, stress, and trauma and during sepsis. Integrated 24-hour GH secretion is higher in women and is also enhanced by oestrogen replacement.
GH is stimulated by high protein meals and by L - arginine. GH secretion in induced by dopamine and apomorphine, as well as α-adrenergic pathways. Β-Adrenergic blockage induces basal GH and enhances GHRH- and insulin-evoked- GH release.
GH induces protein synthesis and nitrogen retention and impairs glucose tolerance by antagonising insulin action. GH also stimulates lipolysis, leading to increase circulating fatty acid levels, reduced omental fat mass, and enhanced lean body mass. GH promotes sodium, potassium, and water retention and elevates serum levels of inorganic phosphate. Linear bone growth occurs as a result of complex hormonal and growth factor actions, including those of IGF-I. GH stimulates epiphyseal prechondrocyte differentiation. These precursor cells produce IGF-I locally and are also responsive to the growth factor.
Insulin-like growth factors
Though GH exerts different effects in target tissues, many of its physiological effects are mediated indirectly through IGF-I, a potent growth and differentiation factor. Peripheral tissue IGF-I exerts local paracrine actions that appear to be both dependent and independent of GH. Therefore, GH administration induces circulating IGF-I as well as stimulating IGF-I expression in multiple tissues.
Both IGF-I and - II are bound to high affinity circulating IGF-binding proteins that regulate IGF bioactivity. Levels if IGFBP3 are GH dependent, and it serves as the major carrier protein for circulating IGF-I. GH deficiency and malnutrition are associated with low IGFBP-3 levels. IGFBP1 and -2 regulate local tissue IGF action but do not bind appreciable amounts of circulating IGF-I.
Serum IGF-I concentrations are profoundly affected by various physiologic factors. Levels increase during puberty, peak at 16 years, and subsequently decline by more than 80% during the ageing process, IGF-I concentrations are higher in females than in males. Because GH is the major determinant of hepatic IGF-I synthesis, abnormalities of GH synthesis or action reduce IGF-I levels. Hypocaloric states are associated with GH resistance; IGF-I levels are therefore low with cachexia, malnutrition, and sepsis. In acromegaly, IGF-I levels are invariably high and reflect a log-linear relationship with GH concentrations.
Injected IGF-I induces hypoglycaemia, and lower doses improve insulin sensitivity in patients with insulin resistance and diabetes. In cachectic subjects, IGF-I infusion enhance nitrogen retention and lowers cholesterol levels. Longer term subcutaneous IGF-I injections exert a marked anabolic effect with enhanced protein synthesis. Bone turnover may also be stimulated by IGF-I.
IGF-I side effects are dose dependent, and overdose may result in hypoglycaemia, hypotension, fluid retention, temporamanibular jaw pain, and increased intracranial pressure, all of which are irreversible. Chronic excess IGF-I would presumably result in features of acromegaly.
GH deficiency in children
GH Deficiency, isolated GH deficiency is characterised by short stature, micropenis, increased fat, high pitched voice, and a propensity to hypoglycaemia. Familial modes of inheritance are seen in one-third of these individuals and may be autosomal dominant, recessive, or X linked. About 10% of children with GH deficiency have mutations in the GH-N gene, including gene deletions and a wide range of point mutations. Mutations in transcription factors Pit-1 and Prop-1, which control somatotrope development, cause GH deficiency in combination with other pituitary hormone deficiencies, which may only manifest in adulthood.
GHRH Receptor Mutations, Recessive mutations of the GHRH receptor gene in subject with severe proportionate dwarfism are associated with low basal GH levels that cannot be stimulated by exogenous GHRH, GHRP, or insulin- induced hypoglycaemia. The syndrome exemplifies the importance of the GHRH receptor for somatotrope cell proliferation and hormonal responsiveness.
Growth Hormone Insensitivity, this is caused by defect of GH structure and signalling. Homozygous and heterozygous mutations of the GH receptor are associated with partial or complete GH insensitivity and growth failure (Laron syndrome). This diagnosis is based on normal or high GH levels, which decreased circulating GHBP and low IGF-I levels, very rarely, defective IGF-I, IGF-I RECEPTOR, or IGF-I signalling defects are also encountered.
Presentation and Diagnosis. Short stature is commonly encountered in clinical practice, and the decision to evaluate these children requires clinical judgment in association with auxologic data and family history. Short stature should be comprehensively evaluated if a patient's height is more than 3 SD below the mean for age or growth rate has decelerated. Skeletal maturation is best evaluated by measuring a radiologic bone age, which is based mainly on the degree of growth plate fusion. Final height can be predicted using standardised scales.
Laboratory Investigation. Because GH secretion is pulsatile, GH deficiency is best assumed by examining the response to provocative stimuli including exercise, insulin-induced hypoglycaemia, and other pharmacologic tests which normally increase GH to more than 7µg/L in children. Random GH measurements do not distinguish normal children from those with true GH deficiency. Adequate adrenal and thyroid hormone replacement should be assured before testing. Age and gender matched IGF-I levels are not sufficiently sensitive or specific to make the diagnosis but can be useful to confirm GH deficiency. Pituitary MRI may reveal pituitary mass lesions or structural defects.
Treatment for GH disorders
Replacement therapy with recombinant GH restored growth velocity in GH deficient children to about 10 cm/year. If pituitary insufficiency is documented, other associated hormone deficits should be corrected- especially adrenal steroids. GH treatment is also moderately affected against accelerating growth rates in children with Turner syndrome and chronic renal failure.
In patients with GH insensitivity and growth retardation due to mutations of the GH receptor, treatment with IGF-I bypass the dysfunctional GH receptor. Growth rates have been maintained for several years, and this therapy now portends improved final adult stature in this group of patients.
Adult GH DEFICIENCY (AGHD)
This disorder is usually caused by hypothalamic or pituitary somatotrope damage. Acquired pituitary hormone deficiency follows a typical sequential pattern whereby loss of adequate GH reserve foreshadows subsequent hormone deficits. The sequential order of hormone loss is usually GHƒ FSH/LH ƒ TSH ƒ ACTH.
The clinical cages in AGHD include changes in the body composition, lipid metabolism, and the quality of life and cardiovascular dysfunction. Body compositions changes are common, and include reduced lean body mass, increased fat mass with selective deposition of intraabdominal visceral fat, and increased waist-to-hip ratio. Hyperlipidemia, left ventricular dysfunction, hypertension, and increased plasma fibrinogen levels may also be present. Bone mineral content is reduced, with resultant increased fracture rates. Patients may experience social isolation, depression and difficultly in maintaining gainful employment. Adult hypopituitarism is associated with 3 fold increase cardiovascular mortality rate in comparison to age and sex matched controls, and this may be due to GH deficiency.
Acromegaly is a hormonal disorder that results from too much growth hormone (GH) in the body. The pituitary, a small gland in the brain, makes GH. In acromegaly, the pituitary produces excessive amounts of GH. Usually the excess GH comes from benign, or noncancerous, tumours on the pituitary. These benign tumours are called adenomas.
GH is part of a cascade of hormones that, as the name implies, regulates the physical growth of the body. This cascade begins in a part of the brain called the hypothalamus. The hypothalamus makes hormones that regulate the pituitary. One of the hormones in the GH series is growth hormone-releasing hormone (GHRH), which stimulates the pituitary gland to produce GH.
Secretion of GH by the pituitary into the bloodstream stimulates the liver to produce another hormone called insulin-like growth factor I (IGF-I). IGF-I is what actually causes tissue growth in the body. High levels of IGF-I, in turn, signal the pituitary to reduce GH production.
The hypothalamus makes another hormone called somatostatin, which inhibits GH production and release. Normally, GHRH, somatostatin, GH, and IGF-I levels in the body are tightly regulated by each other and by sleep, exercise, stress, food intake, and blood sugar levels. If the pituitary continues to make GH independent of the normal regulatory mechanisms, the level of IGF-I continues to rise, leading to bone overgrowth and organ enlargement.
In more than 95 percent of people with acromegaly, a benign tumour of the pituitary gland, called an adenoma, produces excess GH. Pituitary tumours are labelled either micro- or macro-adenomas, depending on their size. Most GH-secreting tumours are macro-adenomas. Depending on their location, these larger tumours may compress surrounding brain structures. Some GH-secreting tumours may also secrete too much of other pituitary hormones.
Most pituitary tumours develop spontaneously and are not genetically inherited. They are the result of a genetic alteration in a single pituitary cell, which leads to increased cell division and tumour formation. This genetic change, or mutation, is not present at birth, but happens later in life. The mutation occurs in a gene that regulates the transmission of chemical signals within pituitary cells. It permanently switches on the signal that tells the cell to divide and secrete GH. The events within the cell that cause disordered pituitary cell growth and GH over secretion currently are the subject of intensive research.
Surgical treatment of GH-secreting adenomas is the initial treatment for most patients. Somatostatin analogues are used as adjuvant treatment for preoperative shrinkage of large invasive macroadenomas, immediate relief of debilitating symptoms, and reduction of GH hypersecretion, in elderly patients experiencing morbidity, in patients who decline surgery, or, when surgery fails to achieve biochemical control. Irradiation or repeat surgery may be required for patients who cannot tolerate or do not respond to adjunctive medical therapy. Irradiation is relatively ineffective in normalising IGF-I levels. Stereotactic ablation of GH secreting adenomas by gamma-knife radiotherapy is promising, but long term results are not available and the side effects have not been clearly delineated. Somatostatin analogues may be given while awaiting the full affect of radiotherapy.
Transphenoidal surgical resection by an experienced surgeon is preferred primary treatment for both microadenomas and macroadenomas. Soft tissue swelling improves immediately after tumour resection. GH levels return to normal within an hour, and IGF-I are normalised within 3-4 days. In about 10% of patients acromegaly may recur 7 years after apparently successful surgery.
Somatostatin analogues exert their therapeutic affects through SSTR2 and -5 receptors, both of which are expressed by GH-secreting tumours. Octreotide acetate is an 8 amino acid synthetic somatostatin analogue. In contrast to naïve somatostatin, the analogue is relatively resistant to plasma degradation. Octreotide is administered by subcutaneous injection. Fewer than 10% of patients do not respond to the analogue. Octreotide suppresses integrated GH levels to less than 5µg/l in about 70% of patients and less than 2µg/l in up to 60% of patients. It normalizes IGF-I levels in about 75% of treated patients. Rapid headache relief and soft tissue swelling occurs in about 75% of patients within days to week of treatment initiation.
Bromocriptine may suppress GH secretion in some acromegaly patients, particularly those with cosecretion of PRL. High doses, administered as 3 -4 daily doses are usually required to reduce GH, and therapeutic efficacy is modest. GH levels are suppressed to less than 5µg/l in about 20% of patients, and IGF-I levels are normalized in only 10% of patients.
GH analogues antagonize endogenous GH action by blocking peripheral GH binding to its receptor. Consequently, serum levels are suppressed, potentially reducing the deleterious effects of excess endogenous GH.