Growth Hormone (GH)

GROWTH HORMONE (GH)

It is a 191 amino acid, single chain peptide of MW 22000.

Physiological Functions

GH promotes growth of all organs by inducing hyperplasia. In general, there is a proportionate increase in the size and mass of all parts, but in the absence of gonadotropins, sexual maturation does not take place. The growth of brain and eye is independent of GH. It promotes retention of nitrogen and other tissue constituents: more protoplasm is formed. The positive nitrogen balance results from increased uptake of amino acids by tissues and their synthesis into proteins. GH promotes utilization of fat and spares carbohydrates: uptake of glucose by muscles is reduced while its output from liver is enhanced; fat is broken down.

GH acts on cell surface JAKSTAT protein kinase receptors (present on practically all cells). Binding of one GH molecule to the extracellular domain of two GH receptor molecules induces their dimerization and activates the intracellular domain to associate with cytoplasmic JAKSTAT tyrosineprotein kinase resulting in metabolic effects as well as regulation of gene expression.

The growth promoting, nitrogen retaining and certain metabolic actions of GH are exerted indirectly through the elaboration of peptides called Somatomedins or Insulinlike growth factors (mainly IGF1, also IGF2) which are extracellular mediators of GH response. Liver is the major source of circulating IGF1, while IGF1 produced by other target cells acts locally in a paracrine manner. Like insulin, IGF1 promotes lipogenesis and glucose uptake by muscles. The IGF1 receptor also is structurally and functionally analogous to the insulin receptor.

GH acts directly as well to induce lipolysis in adipose tissue, glycogenolysis in liver and decreased glucose utilization by muscles. These effects are opposite to those of IGF1 and insulin. As such, GH accentuates the metabolic derangement in diabetes.

Regulation Of Secretion

The hypothalamus produces GH releasing (GHRH) as well as release inhibitory (somatostatin) hormones. Both are peptides. Somatostatin is also produced by D cells of islets of Langerhans in the pancreas and by few other tissues. Receptors for GHRH and somatostatin are G protein coupled receptors which enhance or inhibit GH secretion by increasing or decreasing cAMP formation respectively in pituitary somatotropes. Somatostatin has also been shown to inhibit Ca2+ channels and open K+ channels.

Stimuli that cause GH release are—fasting, hypoglycaemia, exercise, stress and i.v. infusion of arginine. GH secretion is inhibited by increase in plasma free fatty acid levels and by high doses of glucocorticoids. Dopaminergic agents cause a brief increase in GH release in normal subjects but paradoxically depress it in acromegalics. IGF1 causes feedback inhibition of GH secretion. Short loop feedback inhibition of secretion by GH itself has also been described.

Pathological Involvements

Excess production of GH is responsible for gigantism in childhood and acromegaly in adults. Hyposecretion of GH in children results in pituitary dwarfism. Adult GH deficiency is rare.

Preparations And Use

The primary indication for GH is pituitary dwarfism—0.03–0.07 mg/kg (0.06–0.16 Units/ kg) i.m. or s.c. 3 times a week upto the age of 20–25 years. Two forms of human GH produced by recombinant DNA technique (rhGH) somatropin (191AA) and somatrem (192AA) are available for clinical use. rhGH causes IGF1 to appear in plasma after a delay of several hours. IGF1 then remains detectable for upto 48 hours. Early diagnosis and institution of GH therapy restores stature to near normal. rhGH can also be used in Turner’s syndrome and in children with renal failure.

rhGH has been tried in children with constitutional short stature (only if epiphyses are open) with encouraging results. Commercial interests are promoting it for accelerating growth in children without GH deficiency, but medical, ethical, cost benefit and social objections have been raised. In adult GH deficient patients, it increases lean body mass, decreases body fat, improves energy and mentation and may reudce excess morbidity and mortality, but stature is unaffected. Unlimited availability of recombinant GH has provided opportunity for its trial in catabolic states like severe burns, bedridden patients, chronic renal failure, osteoporosis, etc. It is now approved for AIDS related wasting: higher dose (0.05–0.1 mg/kg/day) is needed. However, it should not be given to postoperative, trauma, cancer and other critically ill patients. Its abuse by athletes is banned, and it is one of the drugs included in ‘dope testing’.

Somatropin: GENOTROPIN, NORDITROPIN 4 iu, 12 iu, 16 iu, 36 iu, SAIZEN 10 iu vials for inj (12 iu=5 mg).

Adverse Effects

Somatrem has an additional methionine residue and is more immunogenic than somatropin, but allergic reactions or resistance to treatment are not a problem. Pain at injection site and lipodystrophy can occur. Glucose intolerance, hypothyroidism (due to unmasking of TSH deficiency), salt and water retention, hand stiffness, myalgia, headache are the possible adverse effects. Rise in intracranial tension occurs in few cases.

GH Inhibitors

Somatostatin

This 14 amino acid peptide inhibits the secretion of GH, TSH and prolactin by pituitary; insulin and glucagon by pancreas and of almost all gastrointestinal secretions including that of gastrin and HCl. The g.i. action produces steatorrhoea, diarrhoea, hypochlorhydria, dyspepsia and nausea as side effect. Somatostatin constricts splanchnic, hepatic and renal blood vessels. The decreased g.i. mucosal blood flow can be utilized for controlling bleeding esophageal varices and bleeding peptic ulcer, but octreotide is preffered now due to longer duration of action. Its antisecretory action is beneficial in pancreatic, biliary or intestinal fistulae; can also be used to reduce complications after pancreatic surgery. It also has adjuvant value in diabetic ketoacidosis (by inhibiting glucagon and GH secretion).

Use of somatostatin in acromegaly is limited by its short duration of action (t½ 2–3 min), lack of specificity for inhibiting only GH secretion and GH rebound on discontinuation.

Dose: (for upper g.i.bleeding) 250 μg slow i.v. injection over 3 min followed by 3 mg i.v. infusion over 12 hours.

STILMEN, SOMATOSAN 250 μg and 3 mg amps.

Octreotide This synthetic octapeptide surrogate of somatostatin is 40 times more potent in suppressing GH secretion and longer acting (t½ ~90 min), but only a weak inhibitor of insulin secretion. It is being preferred over somatostatin for acromegaly and seretory diarrhoeas associated with carcinoid, AIDS, cancer chemotherapy or diabetes. Control of diarrhoea is due to suppression of hormones which enhance intestinal mucosal secretion.

Dose: Initially 50–100 μg s.c. twice daily, increased upto 500 μg TDS.

Adverse effects are abdominal pain, nausea, steatorrhoea, diarrhoea, and gall stones (due to biliary stasis).

Octreotide injected i.v. (100 μg followed by 25–50 μg/hr) reduces hepatic blood flow and helps stop esophageal variceal bleeding.

SANDOSTATIN, OCTRIDE 50 μg, 100 μg in 1 ml amps.

Pegvisomant: This polyethylene glycol complexed mutant GH binds to the GH receptor but does not trigger signal transduction: acts as a GH antagonist. It is indicated in acromegaly due to small pituitary adenomas.