Hypothalamic- Pituitary-Adrenal cortex System

this system is essential for regulating mineral and carbohydrate metabolism. The hypothalamus secretes corticotrophin- releasing hormone, a 41-amino acid polypeptide, into the portal blood system, which binds to receptors on specialized anterior pituitary cells, resulting in the release of corticotrophin or adrenocorticotropic hormone(ACTH) into the circulation. ACTH binds to receptors on cells in the adrenal cortex, which are stimulated to secrete the steroid hormones, cortisol and aldosterone.

ACTH acts as a short-loop feedback control on the hypothalamus, while cortisol and aldosterone are long-loop regulators. Aldosterone functions in the kidneys to regulate salt and water homeostasis. Cortisol interacts in many peripheral tissues and has many metabolic functions involving the regulation of carbohydrates, protein, lipid, and overall energy metabolism. Cortisol also acts as antiinflammatory agent

Diseases result from hyperfunction or hypofunction of the hypothalamic-pituitary-adrenal pathway. Diseases may be primary, resulting from end organ dysfunction, or secondary, resulting from pituitary or hypothalamic disease. Congenital Pediatric diseases associated with primary disorders of the adrenal cortex include 21-hydroxylase deficiency resulting in elevated levels of 17- hydroxyprogesterone and low levels of cortisol. Deficiency of 17-α-hydroxylase resulting in low levels of testosterone, while deficiency in 18- hydroxylase resulting in low levels of aldosterone and elevated levels of renin.

Steroid21-hydroxylase deficiency is common,about 1of 5000 births, in most developed countries, a blood spot is used for measurement of 17-hydroxyprogesterone levels. Aldosterone deficiency results in renal salt-losing crises and patients in the newborn period can be profoundly hyponatremic and hyperkalemic. Failure to synthesize cortisol results in stress- induced hypoglycemia.

Intermediates of steroid metabolism, which build up as a result of the metabolic block, cause androgenization. Girls born with this disorder frequently have ambiguous genitalia and may be first classed as boys. Boys may still develop electrolyte crises but they do not have abnormalities at birth as do girls. Defects of the other enzymes in the steroid pathway result in a variety of clinical signs including salt loss, androgenization, hypertension, and hypoglycemia and diagnosis frequently requires steroid profiling.

Growth Factors The hypothalamus secretes two regulatory hormones that affect growth: *GH-releasing hormone is a 40-amino acid polypeptide that stimulates release of GH from the anterior pituitary. *GH-inhibiting factor(somatostatin), inhibits GH secretion. *Additional factors from higher cerebral centers(cerebral cortex), including catecholamines, serotonin, ghrelin, and endorphins have a positive effect on GH secretion.

GH is a 191-amino acids, with the liver as its primary site of action. GH receptors on the liver that are occupied by a GH molecule cause the liver to secrete a group of related polypeptide hormones, called insulin growth factors(IGFs), and their binding proteins, called IGF-binding proteins. IGF-1 and IGF-BP3 are the most significant products of GH activity on the liver. IGF-1 has a molecular structure similar to insulin. It is a potent stimulator of growth and increased metabolism in infants. This pathway is responsible for normal childhood growth, its deficiency results in short statured adults.

There are difficulties in measuring GH in serum Which results from diurnal variation of secretion and stress-related effectors including catecholamines. A single, low level of GH is not sufficient to confirm GH deficiency. It is important to determine true organic deficiency caused by hypothalamic or pituitary disease, from emotional deficiency because only organic deficiency responds to GH replacement therapy, while nonorganic GH deficiency will respond to emotional lifestyle changes.

Laboratory Investigations Several stimulation tests have been devised to Test the absolute capacity of the pituitary to secrete GH. These stimulation tests include inducement of hypoglycemia with insulin, arginine, or clonidine. These tests require five blood samples to be collected in the 2 hours poststimulation and the peak level of GH secretion determined. If this is less than 7ng/ml(7ug/L), the patient has organic GH deficiency and is likely to respond to GH therapy.

Cont. Investigations Testing for serum IGF-1 and IGF-BP3 levels is available and shows great promise in the identification of GH deficiency because these compounds are not secreted by the liver in GH deficiency and their basal levels do not seem to have the large variation that occurs for GH. In addition, defects of both IGF and IGF-BP synthesis and secretion have been recognized as a cause of growth failure in certain infants. Individuals with these defects are unlikely to respond to GH replacement.

Endocrine Control Of Sexual Maturation The hypothalamus secretes a 10-amino acid peptide called gonadotrophin-releasing hormone(GnRH) into the portal blood system. GnRH binds to a specific receptor and causes the release of two larger polypeptide hormones, called FSH and LH, from the anterior pituitary in both males and females. Baseline levels of the gonadotrophins FSH and LH are very low in infants and young children as a result of GnRH suppression.

FSH and LH have different effects in males and females before and during puberty. In males, the target hormonal activity is directed to the testis and causes the release of androgens, primarily the steroid hormones testosterone and androstenedione which are released into the circulation. In females, the primary site of action is the ovary and results in the secretion of estrogens, primarily estradiol into the circulation.

Laboratory Investigations Prior to puberty, the circulating levels of androgens and estrogens are very low. Testosterone is particularly difficult to measure in prepubertal children as many commercial immunoassays detect an interferring compounds. Measurement by mass spectrometry overcomes these interferences.

Secondary Sexual Characteristics During puberty, the GnRH suppression is removed and there is gradual increase in FSH and LH secretion, with concomitant increase in androgen levels in males and estrogen and progesterone levels in females. These changes result in the development of secondary sexual characteristics and onset of menarche in females. This period of childhood is also associated with a major surge in linear and bone mass growth until adult proportions are achieved.

Disorders Disorders of this endocrine pathway are associated with either premature or precocious puberty or delayed onset of puberty. The measurement of serum FSH, LH, testosterone, and estradiol levels is useful in evaluating disordered puberty. Often, disorders of other endocrine system effect puberty. Congenital adrenal hyperplasia results in excess secretion of androgen-like steroids that can effect puberty. Disorders of the hypothalamus and pituitary can effect secretion of FSH and LH, which if reduced will result in delayed puberty.