Adrenal Glands
PKGhatak, MD
A pair of endocrine glands, one sitting on the top of each kidney, separate but closed in by the same kidney capsule and are essential for health and life. Adrenals are also called Suprarenal glands. In adults the adrenals are small in size, but very vascular, getting the most blood supply per gram of tissue. Like the pituitary gland, the adrenal gland consists of two different endocrine glands - one mesodermal origin endocrine gland, the other neuroectodermal origin endocrine gland. In the developing fetus and newborn adrenal, sizes are large in comparison to the whole body. Adrenals are larger than the kidneys at birth and weigh 5 gm. In childhood, the glands start to regress in size but the glands start to grow again at age 4-5 yr., then after the end of the growth period, the size began to shrink to a mere 4 grams each in adults.
Adrenals lie behind the parietal peritoneum, attached firmly at the back to the pillars of the diaphragm. The right adrenal gland is taller and shaped like a pyramid, and the left one has a wider base and looks like a Napoleon hat; each gland measures about 3 cm x 5 cm x 0.1 cm in height, width and thickness respectively.
The growth and development of adrenal glands are quite distinct in humans and not matched in other mammals except perhaps that of chimpanzees. The fetal adrenals function differently than adult adrenals and in association with the placenta provide estrogen for fetal growth.
Fetal adrenal glands.
Some of the neuroectodermal cells of the neural crest migrate near the dorsal aorta at 6 weeks of gestation and by 9 weeks come close together to form the fetal medulla of the adrenal gland, one on each side of the dorsal aorta, close to the site of developing fetal Adrenal cortex and genitourinary ridge. A layer of cells from the fetal adrenal cortex surrounds the fetal medulla at 8 weeks of gestation and is called the Definitive zone. The neuronal derived cells take up chromium stain and are so named chromaffin cells and these cells remain scattered in small groups in the fetal cortex. The outer layer of cortical cells is in the proliferative stage whereas the inner cells develop organelles in order to produce cortisone. It is still debated whether the production of cortisol in the early fetal stage is truly independent of adrenal action or under the influence of pituitary ACTH (adrenocorticotropic). At 12 weeks, a new cell layer called the Transitional zone develops in between the layers. Definitive zone cells reduce the production of cortisol and the cells of the transitional zone begin producing Dehydroepiandrosterone (DHEA) and Dehydroepiandrosterone sulfate (DHEA-S). DHEA and DHEA-S are converted to Estrogen in the placenta. Estrogen is needed for fetal growth. At 24 weeks the size of the fetal cortex is reduced in size and the transitional zone is now called zona fasciculata and the outer definitive zone is called the Granulosa zone. The granulosa zone keeps producing cortisone under the influence of ACTH. At birth, the medulla of the adrenal gland is still rudimentary and does not secrete hormone and the cortex has only two zones – a larger granulosa zone and a smaller fasciculata zone.
In newborns the medulla remains inactive, growth starts at 8 months of age and reaches the maximum at 12 to 18 months.
Hormones of the adult adrenal glands.
The adrenal cortex hormones are called Steroid hormones, majority of adrenal hormones have one hydroxyl group (-OH) bound to the carbon atom in the side chain and are therefore also called Sterols.
Cholesterol is the prime chemical from which all steroids are produced. Cholesterol is obtained from the LDH cholesterol of the blood. If the blood level of LDL is low, LDL cholesterol is synthesized in the adrenal cortex. The first step in steroid synthesis is to cleave the side chain of cholesterol and oxidation to generate Pregnenolone. ACTH influences this initial step. This conversion takes place in mitochondria and is then transported to the endoplasmic reticulum of the cell. The endoplasmic reticulum contains specific enzymes for the production of a specific hormone, specific for a zone of the adrenal cortex.
Zona Glomerulosa.
Pregnenolone is converted to Progesterone then oxidized to 11- Deoxycorticosterone. The next step is 18- Hydroxycorticosterone then the final product is Aldosterone. Aldosterone exists in two forms namely 18-aldehyde form and 11-helical form.
Zona Fasciculata.
Pregnenolone is converted to 17 alfa-Hydoxypregnenolone. The next step is 11-Deoxycortisol by hydroxylation then to 11-Deoxycortisol and the final step is Hydrocortisone and Cortisone.
Zona Reticulosa.
The cells of this zone work differently from other zones. Gonadotropin Releasing Hormone of the Anterior pituitary regulates the production of these sex hormones. There are two releasing hormones - Luteinizing releasing hormone (LHRH)and follicular stimulating releasing hormone (FSRH).
Pregnenolone is converted to 17-alfa-Hydoxypregnenolone; then the next step is Dehydroepiandrosterone. The next product is Androstenedione .and the final product is Testosterone. The primary adrenal androgens are dehydroepiandrosterone and androstenedione and a tiny amount of testosterone. The gonads of individuals produce most of the sex hormones, stimulated by the pituitary hormones and reproductive cycle and growth period by way of negative feedback.
Adrenal Medulla.
Hormones produced by the adrenal medulla are important but not essential for life. The medulla is in fact a special structure of the sympathetic nerve ganglion. The hormone is known by the generic name Catecholamines, it can be gotten from other sympathetic nerve ganglions. Catecholamines are Nor-adrenaline and Adrenaline, as the Britishers call them, the universal names are Norepinephrine and Epinephrine. About 80 % of catecholamines are epinephrine and 20 % of the rest are norepinephrine.
The catecholamines are derived from the amino acids - Phenylamine and Tyrosine. Tyrosine is converted to L-Dopa (Levo- dihydroxyphenylalanine) and the next stage is Dopamine. Then to Norepinephrine to Epinephrine. Epinephrine is stored in the chromaffin cells as granules till it is time to release into the circulation.
Regulatory control of Steroid hormones.
Negative feedback is the common control system for all endocrine glands. Both the hypothalamus and pituitary gland monitor blood levels of adrenal hormones. When the blood level falls, say aldosterone, the hypothalamus releases ACTH Releasing Hormone (ACTHRH) and that results in the production of more aldosterone. As the aldosterone level rises the ACTHRH from the pituitary is turned off. Several other paths for steroid hormone production exist.
Aldosterone.
By the Glomerular Apparatus of the Kidney.
In each kidney, there are about 1 million glomeruli– a tuft of capillaries enclosed by a funnel like structure known as the Bowen capsule. A branch of the renal arteriole feeds the glomerulus with blood and is called the afferent arteriole, and blood exits after filtration by the efferent arteriole. A loop of distal convoluted tubule of a nephron at this site and a group of juxtaglomerular mesangial cells of Lacis (Lacis cells) form the Glomerular apparatus. Special muscle cells of afferent and fewer muscle cells of efferent glomerular arterioles lie in layers like a cuff. The modified epithelial cells of the distal convoluted tubule are tall and have a prominent nucleus known as Macula Densa. Extraglomerular mesangial cells are loose networks of connective tissue cells located around the afferent and efferent arterioles. Macula densa monitor sodium and potassium concentration of the urine. The receptor of BP in afferent arteriole communicates directly with the juxtaglomerular cells(JG cells), and the JG cells release Renin. Renin converts the angiotensinogen of blood to angiotensin I, which is converted to angiotensin II by ACE (angiotensin converting enzyme). ACE is produced by pulmonary endothelium and endothelium kidneys and also by the epithelium of renal proximal tubules. Angiotensin II acts on the adrenal cortex to increase aldosterone production and release. The Lacis cells produce selective vasoconstriction or vasodilatation of the arterioles based on the nature of the input. Angiotensin I and angiotensin II are broken down by an enzyme angiotensinase to angiotensin III & IV.
The second path is the sympathetic nervous system. In any stressful situation, the hypothalamus discharges neuronal signals by sympathetic preganglionic fibers to sympathetic ganglions. The postganglionic Beta 1 and Beta 2 nerve fibers carry that signal to the adrenal cortex directly to the chromaffin cells without forming synapses and aldosterone is released in blood in response.
Glucocorticoids.
Similar systems of sensors for glucocorticoids are present in tissues, and information is relayed to the hypothalamic-pituitary-adrenal axis (H-P-A axis). Release of glucocorticoid hormone results. Cortisol breaks down hepatic glycogen to glucose. Glucose generation from amino acids and fatty acids- commonly called glucogenesis happens. Glucose levels are normalized.
The 2nd pathway is through the sympathetic nervous system via the hypothalamus and via the close relationship with epinephrine and norepinephrine.
Regulation of Sex Hormones of Adrenal Cortex.
Gonadal hormones are the main source of sex hormones. Pituitary FSHRH and LHRH, Growth hormone and adrenocortical DHEA, DHEA-S and Testosterone are integrated by the Hypothalamic-Pituitary axis. Adrenal sex hormones are taken up by gonads and use as the raw materteral for gonadal sex hormones production. Gonads also produce DHEA and DHEA-S, the initial steps of LH and FSH production.
This scheme of regulation of hormone production is a simplified version. There are much more intricate relationships between hormones, tissue cytokines, chemokines and the production of hormone carrier proteins by the liver. The role of cytochrome P 450, Cyclic AMP, and other enzymes is too complex for this simple presentation. The cytoskeleton of mitochondria and endoplasmic reticulum, the protein messengers for communication between organelle have a special role also. Aromatase CYP 19 is essential in the conversion of androgen to estrogen.
Physiological functions of Adrenal hormones.
Steroid hormones are regulators of the whole body homeostasis. Metabolism of carbohydrates, protein and fatty acids is under control by glucocorticoids for the purpose of maintaining an adequate supply of glucose to the tissues. The new sugar is made from protein and fat (glucogenesis), and sugar is freed from glycogen stores called glycogenolysis. Under the prolonged influence of glucocorticoids, the matrix of bone (made of protein) is thinned out and calcium moves out of bone and bones become brittle (osteoporosis). Excess calcium, magnesium and uric acid are excreted in the urine. Renal calcification and urinary stones are common complications. Aldosterone maintains extracellular volume by controlling Sodium loss by the kidney, excreting potassium and hydrogen ions in the exchange for sodium. Corticosteroids have profound effects on the cardiovascular system, musculoskeletal system, and central nervous system. Corticoids are suppressors of acute inflammation/infection. The immune cell and lymphocyte functions are downregulated. The production of antibodies is delayed and downregulated. Fetal growth by steroid hormone and maturation of various systems, specially lungs in pre and postnatal stages is provided by corticosteroids.
A detailed description can be found elsewhere.
Regulation of Catecholamines of the adrenal medulla.
In any stressful situation, the hypothalamus discharges neuronal signals by sympathetic preganglionic fibers to sympathetic ganglions. The postganglionic Beta 1 and Beta 2 nerve fibers carry that signal directly to the chromaffin cells of the adrenal medulla. Regulation and release depend on local tissue negative feedback in addition to nerve hypothalamic control. Noradrenaline increases vasoconstriction, and BP, acceleration of conduction of cardiac impulses, tachycardia.
Epinephrine dilates blood vessels of muscles, increases blood sugar, and dilates bronchial wall and cardiac output.
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