Hormones

ENDOCRINE SYSTEM

DR.AMJAD H. ABID LECTURE (6)

HORMONES OF ADRENAL MEDULLA

The adrenal medulla (A.M.) is considered as a part of the sympathetic nervous system whereby the splanchic preganglionic nerve fibers terminate in the adrenal medulla where they innervate the chromaffin cells that produce the catecholamines: Dopamine, Nor-epinephrine, Epinephrine.The A.M is thus a specialized ganglion without axonal extensions, with its chromaffin cells synthesize, store, and release products that act on distant sites, so that it also functions as an endocrine organ. *so, the “sympathoadrenal system” consists of the following:

Parasympathetic NS with cholinergic pre- and postganglionic nerves.
The sympathetic NS with cholinergic pre – ganglionic and adrenergic post ganglionic nerves.
The A.M.

The hormones of the sympathoadrenal system are required for adaptation to acute and chronic stress. They are the major elements in the response to severe stress. This response involves an acute integrated adjustment of many complex processes in the organs vital to the response (brain, muscles, cardiopulmonary system, liver) at the expense of other organs that are less immediately involved (skin, GIT, lymphoid tissue).

Biosynthesis of CatecholaminesThese amines are synthesized in the chromaffin cells of the adrenal medulla, they are so named because they contain granules that develop a red – brown color when exposed to potassium dichromate stain. Collections of these cells are also found in (heart, liver, kidney, gonads, adrenergic neurons of the postganglionic sympathetic system, and CNS).

Catecholamines are 3,4 dihydroxyderivatives of phenylethylamine. The major product of adrenal medulla is epinephrine-which constitutes about 80% of the catecholamines in the medulla and it's not made in the extra medullary tissue. However, most of the nor-epinephrine present in organs innervated by sympathetic nerves is made insitu and most of the rest is made in other nerve endings and reaches the target tissue via the circulation.
In other wards; in the extra-adrenal chromaffin cell catecholamines synthesis ends up with the formation of NEP, while cells of adrenal medulla can convert NEP to EP which is the major catecholamine product by the adrenal medulla. In addition, the chromaffin cells of extra-adrenal tissues have the property of the synthesis, storage and re-uptake of the discharged catecholamine, while the adrenal medullary cells can synthesize, store, and secrete but not uptake the discharged catecholamine.


Catecholamine are usually derived from TYROSINE, the conversion of tyrosine to EPN. requires 4- sequential steps :
1. Ring hydroxylation., 2. Decarboxylation., 3. Side-chain hydroxylation.4. N- methylation.

1- Ring hydroxylation:

Tyrosine is the immediate precursor of catecholamines, and “tyrosine hydroxylase” is the rate-limiting enzyme in catecholamines biosynthesis. This enzyme is found in both soluble and particle- bound forms only in tissues that synthesize catecholamines. It functions as an oxidoreductase with tetrahydropteridine as a co-factor to convert L-tyrosine to L- dihydroxyphenyl alanine (L-dopa). This step is regulated in variety of ways. The most important mechanism involves feedback inhibition by the catecholamine.
It's also inhibited by a series of tyrosine derivatives including a-methyltyrosine (this compound is occasionally used to treat catecholamine excess in pheochromocytoma). A third group that inhibits this enzyme is those compounds that act by chelating iron and thus removing the co-factor.

2-DOPA decarboxylation:

This soluble enzyme is present in all tissues of the body and requires pyridoxal phosphate for conversion of L- dopa to 3, 4 dihydroxyphenylethylamine (dopamine). Compounds that resemble L-dopa are competitive inhibitors of this reaction as * α-Methyldopa, *3- hydroxytyramine, metaraminol, *α-methyl -tyrosine. These compounds are thus usually used in treatment of hypertension.

3-Side chain hydroxylation:

This step is catalyzed by DBH (dopamine β- hydroxylase) and needs ascorbate as an electron donor, copper at the active side and fumarate as modulator. This enzyme is present in the particulate fraction of the medullary cells probably in the secretion granules, thus the conversion of dopamine to nor- epinephrine occurs in these organelles.

4-N-METHYLATION:

It’s the addition of methyl group to nitrogen, it is catalyzed by (PNMT) phenyl ethanol amine N- methyl transferase and so converts NEP to EP in the epinephrine forming cells of adrenal medulla. Since PNMT is soluble; it's assumed that the conversion occurs in the cytoplasm.
The synthesis of PNMT is induced by glucocorticoid hormones that reach the medulla via the intra- adrenal portal system.The intra- adrenal portal system provides a 100 fold steroid concentration gradient over systemic arterial blood, and this high intra- adrenal concentration appears to be necessary for induction of PNMT. Following the formation of NE in the secretory granules, it will leave the secretion granules to the cytoplasm where its conversion to Ep will take place, however the newly formed EP. and NE. can be retaken by a new population of secretion granules.


STORAGE AND SECRETION OF CATECHOLAMINES

The secretory chromaffin granules are capable of biosynthesis, uptake, storage and secretion of CA. These granules contain a number of substances in addition to the CA. including ATP, Mg+2,Ca+2 ,DBH and the protein chromagranin A.

The Neural stimulation of the adrenal medulla results in the fusion of the membrane of the storage granules with the plasma membrane and this leads to the exocytosic release of NEP and EP. This process is calcium dependent and is stimulated by cholinergic and b-adrenergic agents. CA and ATP are released in proportion to their intra-granular ratio as the other contents including DBH, Ca+2, chromagranin A. (the ratio is 4\1; this means that the CA is 4 and the ATP is 1).



The secretory granules

Neural reuptake of CA is an important mechanism for conserving these hormones and for quickly terminating their hormonal or neurotransmitter activities. The adrenal epinephrine goes to the liver and skeletal muscles, but then rapidly metabolized (half life is very short; 10-30 seconds.)

METABOLISM OF CATECHOLAMINES:

Less than 5% of CAs. can be excreted unchanged in the urine, however 95% of CA. usually undergoes conversions to metabolites that are excreted mainly as conjugated derivatives (with glucoronide or sulfate) in urine. Two enzymes are involved in the metabolism of CA:

1. COMT (catechol O- methyl transferase):

Is a cytosolic enzyme found in many tissues; it catalyzes the addition of a methyl group usually at 3- position on the benzene ring. The result of this reaction -depending on the substrate- is the production of (homovanillic acid, no-r metanephrine, and metanephrine.

2.MAO (mono amino oxidase)

Is an oxidoreductase that deaminates mono- amines, it is located in many tissues, but mainly in liver, stomach, kidneys and intestine. It is of two subtypes:
*MAO-A: is found in neural tissue and deaminates serotonin, epinephrine, and nor-epinephrine.*MAO-B: is found in the extra-neural tissues and is mostly active against 2- phenylethylamine and benzylamine. Both forms metabolize dopamine and tyramine as well.

VMA is the end product of the metabolism of NE and EP. and usually increases if there is a tumor of the adrenal medulla (pheochromocytoma.)