In this term paper we will discuss about:- 1. Hormones of Adrenal Medulla 2. Adrenal Cortex Hormones 3. Disturbances of Hormonal Function.
Hormones of Adrenal Medulla:
In the medulla of the human adrenal glands, adrenalin and, to a lesser extent, noradrenalin are formed which are stored as secretory granules in the chromaffin cells. An increased adrenalin secretion occurs as the glucose concentration in blood becomes lowered, as well as in a state of the organism called stress (stress occurs when the physiologic activity of the organism increases faster than the adaptive responses).
Adrenalin exerts a dual effect on the metabolism of target tissues depending on the predominant occurrence in them of either α-, or β-adrenoreceptors to which the hormone becomes bound. The binding of adrenalin to β-adrenoreceptors stimulates adenylate cyclase and produces metabolic alterations characteristic of cAMP. The adrenalin binding with α-adrenoreceptors stimulates guanylate cyclase and produces metabolic alterations typical of cAMP.
On the whole, adrenalin, similar to glucagon, exerts a cAMP-dependent action on the fat tissue metabolism as well as on skeletal muscles and liver, which are targets for the hormone. The alterations that occur in carbohydrate and lipid metabolisms are very much the same as those produced by glucagon.
Moreover, adrenalin affects the function of cardiovascular system. It enhances the amplitude and frequency of systole, elevates blood pressure, and expands capillary arterioles. Adrenalin also relaxes the smooth muscles of intestine, bronchi, and uterus.
In practice, adrenalin is rarely used as a metabolic regulator (occasionally, to compensate for an insulin over dosage, adrenalin is applied simultaneously with glucose to increase the glucose level in blood). Most frequently, it is employed for stimulating systole and elevating blood pressure.
Adrenal Cortex Hormones:
In the adrenal cortex, steroid hormones, or corticosteroids, are formed from cholesterol. Corticosteroids, by the physiological effect they produce, are subdivided into three groups – glucocorticoids chiefly affecting carbohydrate metabolism, mineralocorticoids chiefly affecting mineral metabolism, and sex hormones (male hormones androgens, and female hormones estrogens). The sex hormones are secreted in small amounts.
Normally, the human adrenal glands secrete glucocorticoids (hydrocortisone and corticosterone) and a mineralocorticoid (aldosterone).
The secretion of glucocorticoids is controlled by corticotropin bound to the adrenocortical cell membrane; corticotropin stimulates production of cAMP and, through the intermediacy of the latter, triggers the delivery of cholesterol esters for the synthesis of glucocorticoids. The release of corticotropin from the pituitary gland is a typical response to stress. This entails the secretion of glucocorticoids into the blood to facilitate the release of adrenalin. Glucocorticoids inhibit corticotropin secretion by a negative feedback mechanism.
Aldosterone secretion is controlled by Na+ and K+ cations. At low Na+ and high K+ concentrations in blood, the synthesis and secretion of aldosterone become increased. As is commonly believed, the epiphysis produces a tropic hormone called adrenoglomerulotropin acting as a stimulator for aldosterone secretion. However, a reliable evidence for the existence of this hormone is lacking.
Mechanism of Glucocorticoid Action:
Glucocorticoids become bound to α1 – globulin of blood plasma, called transcortin, to be transported in the complexed state to peripheral tissues.
The targets for glucocorticoids are liver, kidney, lymphoid tissue (spleen, lymph nodes, lymphoid plaques of the intestine, lymphocytes, and thymus), connective tissues (bones, subcutaneous connective tissue, and adipose tissue), and skeletal muscles. These tissues contain cytosolic receptors for binding glucocorticoids.
A hormone-cytoreceptor complex may exert an entirely opposite effect on protein synthesis in different tissues. In the liver and kidneys, this complex enhances the transcription of specific genes and the synthesis of corresponding proteins; in other tissues, on the contrary, it inhibits protein synthesis, while in the lymphoid tissue, this complex elicits lymphocytosis (or degradation of lymphoid tissue).
The blocking of protein synthesis in the lymphoid tissue and the active proteolysis in it increase the fund of free amino acids that are supplied in large amounts to the blood. The amino acids are used in liver and kidneys for protein synthesis; they serve also as substrates for gluconeogenesis.
In the liver and kidneys, glucocorticoids favour the utilization of amino acids in gluconeogenesis, since they act as specific inducers of the synthesis of gluconeogenesis enzymes (pyruvate carboxylase, phosphor pyruvate carboxylase, glucose 6-phosphatase, and fructose bisphosphatase). The glucose produced by gluconeogenesis is consumed in the synthesis of hepatic glycogen (since glucocorticoids stimulate synthesis of the enzyme glycogen synthetase) as well as in the production of glycogen in muscles.
Since glucocorticoids enhance the secretion of adrenalin from the adrenal medulla, the action of glucocorticoids becomes “augmented” by the metabolic effect of adrenalin. Thus, glucocorticoids mobilize triacylglycerides from the adipose tissue at the expense of adenylate cyclase activation, although the membrane intracellular activity is not typical of them.
Apparently, the mobilization of fat from the fat depots is associated with adrenalin. As a result, glycerol and fatty acids are supplied to the blood; glycerol is used in gluconeogenesis, while fatty acids are consumed in the liver to produce ketone bodies which are excreted in the blood.
Glucosuria, aminoaciduria, and ketonuria set in, as the concentrations of glucose, amino acids, fatty acids, glycerol, and ketone bodies in the blood increase. On the whole, these metabolic changes resemble a picture of diabetes mellitus. To be noted, this diabetic state is of different nature and for this reason is referred to as “steroid” diabetes.
Glucocorticoids produce changes in the water-salt metabolism: they increase the Na+ ion reabsorption and renal excretion of K+; they retain sodium and water in the extracellular space of the organism tissues (which may lead to oedemas). This action is similar to the effect due to mineralocorticoids, only less pronounced. Inhibition of the bone tissue protein synthesis leads to local deossification of the bones. Calcium and phosphorus are eliminated from the affected bone tissue into the blood and then are excreted in the urine.
Glucocorticoids and their analogues are widely applied in clinics. It stands to reason that this is not solely because of their ability to produce a diabetes-like state (metabolic diabetes-like disturbances are in fact side effects in therapy with glucocorticoid preparations). The medicinal effect of glucocorticoids is based on their ability to affect lymphoid and connective tissues.
The lymphoid tissue is involved in the generation of antibodies and in the defence of the organism from extraneous agents. In response to an infection or invasion of foreign substances, antibodies are produced in the organism that specify a state of hypersensitivity, or sensitization, to a given extraneous agent. On repeated contact of the organism with the same invader, the antibodies interact with the invading agent, which is manifested by a vigorous reaction called allergic response, or simply allergy.
Allergy leads to an inflammation accompanied by local disorders of vascular permeability and by tissue damage. The destroyed portions of tissue are replaced by connective tissue, and a connective cicatrix is formed which deforms the affected organ.
Glucocorticoids inhibit the formation of antibodies in the lymphoid tissue to reduce the state of sensitization towards invaders, and thus prevent further development of allergic response and inflammation. The glucocorticoid inhibition of collagen formation by connective tissue fibro-plasts prevents an excessive growth of connective fibres at the sites of tissue damaged by inflammation. Thus the hormones retard the development of vicious cicatrices or cicatricial adhesions that lead to a deformity of organs and impair their normal function.
Mechanism of Mineralocorticoid Action:
Aldosterone controls the balance of Na+, K+, CI– ions and water in the organism; for this reason, the normal function of this hormone is of utmost importance for the vital activity of the organism.
Aldosterone is transported in the blood to tissues by using plasma albumins as carrier adsorbents. The targets for aldosterone are epithelial cells of distal tubules of the kidney, which contain a large number of cytoreceptors for binding this hormone. The aldosterone-cytoreceptor complex penetrates the nuclei of the renal tubule cells and activates the transcription of chromosomal genes that carry information on the proteins involved in the transport of Na+ ions across the membranes of tubular epithelium.
Owing to this, the reabsorption of Na+ and its counterion CI– from the urine into intercellular fluid and further into blood becomes increased. Simultaneously, K+ ions are excreted (in exchange for Na+) in the urine from the epithelium of renal tubules. On the whole, the aldosterone effect is manifested by a retention of Na+, CI–, and water in the tissues and by urinary loss of K+ ions.
Disturbances of Hormonal Function of the Adrenal Glands:
Hyper function of the adrenal cortex, or hypercorticoidism, can manifest itself as an enhanced secretion of all the corticosteroids, or as a prevalent secretion of a group of hormones. For example, in such forms of hypercorticoidism as Cushing’s disease (which occurs due to the impaired hypothalamohypophyseal system conducive to corticotropin hyper secretion) and corticosteroma (a tumor active chiefly in the synthesis of hydrocortisone), a hyper production of glucocorticoids is observed, which explains the symptoms of these disturbances in the organism – atrophy of subcutaneous connective tissue, development of steroid diabetes, osteoporosis (abnormal rarefication of bone), and hypertension (because of the secondary enhancement of adrenalin and noradrenalin secretion by substantia medullaris).
There occurs hypercorticoidism attended by excessive secretion of aldosterone (hyperaldosteronism, or Konn’s disease). In this disease, the symptoms of influence of aldosterone excess on the water-salt balance are observed, viz. oedemas, high blood pressure, and myocardial hyper excitability. An excessive dietary intake of salt may lead to the so-called “salt” hypertension.
Hypocorticoidism, also called Addison’s disease, or bronze disease, is manifested by a deficiency in all the corticosteroids and attended by manifold alterations in metabolism and functions of the organism. Glucocorticoid deficiency causes a reduced resistance of the organism to emotional stress and damage factors (infectious, chemical, and mechanical) and leads to the development of pronounced hypoglycemia.
This symptomatology is aggravated by water-salt metabolism disturbances produced by aldosterone deficiency. The organism loses sodium and water and accumulates potassium, with the ensuing development of hypotension (relaxation of the smooth muscles of vascular wall), acute myasthenia, and progressive fatiguability leading to a total impotence.
These symptoms are associated with a disturbed myoblast membrane potassium-sodium gradient (hyperpolarization), with the ensuing low muscular excitability. In hypocorticoidism, the fatal outcome is due to the disturbed water-salt balance.
Practical Applications of Corticosteroids:
Glucocorticoids and their numerous analogues are widely used in treatment of allergic and autoimmune diseases (rheumatism, collagenases, nonspecific arthritis’s, bronchial asthma, dermatoses, etc.) as desensitizing, anti-inflammatory, and immunodepressive agents. Their immunodepressive action (inhibition of antibody synthesis by lymphoid cells) is used in the prophylaxy of transplanted organ rejection.
In clinical practice, a synthetic analogue of natural mineralocorticoids. Deoxycorticosterone, is applied in the substitution therapy of hypocorticoidism and, occasionally, in treatment of hypotension.