Adrenal Gland Functional Histology

Two parts- 1)Adrenal Cortex 2) Adrenal medula- Aldosterone(mineralocorticoid)  the cortisol (glucocorticoids) and androgenic hormones (Dehydroepiandrosterone). Angiotensin II ACTH 2) Adrenal medula- secretes the catecholamine hormones, adrenaline (epinephrine) Noradrenaline (norepinephrine)

Adrenal Morphology Zona glomerulosa Zona fasciculata Aldosterone Glucocorticoids Zona reticularis Androgens

Blood supply of the adrenal glands.

connective tissue capsule (Cap) Outer zona glomerulosa (G) -mineralocor-ticoids. The middle zona fasciculata (F) has linearly arranged cells that secrete glucocorticoids. The inner zona retuclaris (R) cells form a cell network and secrete weak androgens. inner medulla (M).

cells of the adrenal cortex -abundance of mitochondria, lipid and smooth endoplasmic reticulum- steroid secreting cells. Zona glomerulosa cells -rounded in clusters zona glomer-ulosa –mineralocorticoids- aldosterone Na+ and K+ balance(RAA System)

CRH ACTH (minor) Aldosterone Hypothalamus CRH Anterior Pituitary ACTH (minor) Angiotensin II K+ Adrenal Cortex (Zona Glomerulosa) Diagram showing the minimal effect of the hypothalamic-pituitary-adrenal axis on aldosterone release by the adrenal gland. The cells of the Zona glomerulosa have ACTH receptors but the importance of ACTH on aldosterone synthesis is arguable. The important message here is that the major regulators of aldosterone synthesis are angiotensin II and potassium. These work directly on the cells of the Zona glomerulosa to stimulate aldosterone synthesis. Aldosterone

Hypersecretion Effects:- Increased extracellular fluid volume Tumor in the Zona glomerulosa/primary/conn`s syndrome or increased renin secretion/secondary hyperaldosteronism. Effects:- Increased extracellular fluid volume Hypertension Hypokalemia Muscle weakness, arrhythmias Hypersecretion This is usually caused by a tumor in the Zona glomerulosa or increased renin secretion. Elevation of aldosterone levels can lead to hypertension, slightly expanded extracellular fluid volume, hypokalemia and slight hypernatremia. It may be diagnosed by finding high levels of aldosterone in plasma and urine even after a Na+ load. (Note: If due to a tumor in the Zona glomerulosa you would observe a low renin concentration).  

Hyposecretion Primary/Addisons disease Hyperkalemia Hyponatremia Decreased extracellular fluid volume Shock addisonian crisis. Hyposecretion Addison’s Disease, complete destruction of adrenal cortex, is the major cause of hyposecretion of aldosterone. Decreased levels of aldosterone may lead to polyuria, dehydration, hypotension, hyperkalemia and hyponatremia. Not surprisingly it may be diagnosed by the patient having low levels of aldosterone in both the plasma and urine accompanied by high levels of renin and AII.

Zona fasciculata (B) cells -cords or plates usually one – two cell thick separated by sinusoidal capillaries. Secrete glucocorticoids, - cortisol, - carbohydrate metabolism. Rounded nuclei and a vacuolated cytoplasm.

CRH ACTH Cortisol / Androgens Hypothalamus CRH Anterior Pituitary ACTH Adrenal Cortex (Zona Fasciculata Zona Reticularis) The hypothalamic-pituitary-adrenal axis and how it regulates glucocorticoid and androgen secretion by the adrenal gland. The hypothalamus releases CRH into portal blood vessels where it then binds to the corticotrophic cells of the anterior pituitary. This increases the synthesis and causes the release of ACTH into the circulation. This ACTH then binds to receptors of cells of the adrenal cortex to initiate the synthesis of the glucocorticoids (eg cortisol) and androgens Cortisol / Androgens

glucose General cell Fatty acids glycerol glucose Amino Acids glycogen Action of Insulin ?? glucose Energy General cell Fatty acids glycerol glucose Amino Acids glycogen Liver This diagram shows the mechanisms by which cortisol effects metabolism in the body. In the liver cortisol stimulates the production of glucose. This seems contraindicated by the elevated glycogen but this requires the presence of insulin. In muscle cortisol breaks down proteins elevating blood amino acids, these are taken up into the liver to form more glucose and also stimulate glucagon release. Cortisol is believed to inhibit the action of insulin on most cells and hence decreases glucose uptake by these cells elevating blood glucose. These cells use the breakdown products of fat metabolism in the adipose tissue to provide them with energy. Protein breakdown lipolysis Muscle Adipose Cells

Other effects Modulates behaviour and mood Maturation of the fetus Role in parturition????? Modifies and controls both inflammatory and immune responses Important in stress response The following is a list of the actions of glucocorticoids in the body.   Growth/Development accelerates the development of many fetal systems (unknown mechanism) Cardiovascular System increases contractility of the heart increases vascular reactivity to catecholamines and angiotensin II Mammary gland must be present for lactation to occur Lung stimulates surfactant production (important for fetal lung development) Immune System inhibits many steps of the immune response including production of interleukin-1 (hence  fever), interleukin-2 and 6 as well as inhibiting T-cell proliferation. OVERALL inhibits !!! Inflammatory response - inhibits many steps of the inflammatory response (NO and platelet activating factor production; inhibits phospholipase, cyclooxygenase   pg and AA production. CNS effects maintains emotional balance increases appetite

Inflammation Anti-inflammatory Helps repair after the event Stabilizes lysosomes  capillary permeability  WBC migration & phagocytosis  decreases fever Helps repair after the event

Hypothalamus CRH Anterior Pituitary ACTH Adrenal Cortex Cortisol (Zona Fasciculata Zona Reticularis) Flow diagram showing the negative feedback control of cortisol secretion. The major controller of cortisol secretion is negative feedback directly on the hypothalamus by cortisol decreasing CRH release. Cortisol

Cortisol Hypersecretion Cushing’s Disease – cortisol excess due to hypersecretion of pituitary ACTH Cushing’s Syndrome - a myriad of problems associated with cortisol excess Cortisol Hypersecretion Causes Long-term corticosteroid medication Pituitary adenoma Ectopic ACTH syndrome (eg lung tumors) Adrenal tumors-Primary

Metabolic effects-  liver glucose output (+ insulin) fat deposition in trunk, face and upper back Muscle wasting and weakness Impaired glucose tolerance, insulin-resistant DM,  glucose uptake by tissues As the glucocorticoids have many effects throughout the body there are many symptoms associated with hypersecretion. These include a moon-face, truncal obesity, buffalo hump. This goes against the grain as you know from above that glucocorticoids promote lipolysis. So why the preferential fat deposition in these areas??? We just don’t know why … but we know it happens. You also observe muscle wasting and weakness, the formation of stretch marks on the skin, poor wound healing and easy bruising, menstrual irregularities (maybe due to elevated androgens), glucose intolerance and hypertension (due to the mineralocorticoid action of glucocorticoids).   The diagnosis of hypercortisolism and the underlying cause involves numerous tests. Initially you should observe elevated plasma/urinary cortisol levels and if it is secondary hypercortisolism you should observe elevated plasma/urinary ACTH levels. In primary hypercortisolism ACTH levels will be decreased due to negative feedback Elevated cortisol levels also lead to specific effects in the body. These effects may be used to diagnose hypercortisolism. In connective tissue you have loss of collagen and connective tissue, and the inhibition of fibroblasts, you observe easy bruising, thin skin and poor wound healing. In bone you have inhibition of the formation of bone and the promotion of resorption, you observe ease in the breaking of bones. It also causes negative calcium balance (see bone resorption above) due to a reduced intestinal calcium reabsorption and increased calcium urinary excretion.

Others Suppression of immune system Hypertension Mineralocorticoid activity Hypokalemia  ECF Skin/connective tissue Easy to bruise Striae formation Poor wound healing

Hyposecretion-Addison’s Disease Metabolism  liver glucose output and glycogen storage  lipolysis Muscle weakness  glycogen stores Hypoglycemia Modified insulin response

Pigmentation in Addison's disease

ACTH 39 amino acids Synthesized in corticotrophs of AP Half-life of ~ 10 minutes pro-opiomelanocorticotrophin (POMC) Beta- lipotropin(β –LPH) ACTH is processed from a large precursor molecule POMC. CRH activating its receptor on the corticotrophic cell stimulates both the production and cleaving of POMC. This of course increases ACTH production.   -MSH acts in lower vertebrates to produce temporary changes in skin color by causing the dispersion of melanin granules in pigment cells. As noted earlier, the adult human has only a vestigial intermediate lobe and does not produce and secrete significant amounts of a-MSH or other hormones derived from POMC. However, because ACTH contains the a-MSH amino acid sequence at its N-terminal end, it has melanocyte-stimulating activity when present in the blood at high concentrations. Humans who have high blood levels of ACTH, as a result of Addison disease or an ACTH-secreting tumor, are often hyperpigmented a-melanocyte-stimulating hormone (a-MSH)

zona reticularis -smallest of the secretory cells of the adrenal cortex irregular network of branching cellular cords surrounded by blood vessels and connective tissue. Zona reticularis -weak androgens- dehydroepiandrosterone.

Hypersecretion Females (adrenogenital syndrome) Males lack of 21- or 11-hydroxylase activity in the adrenal cortex leads to the preferential formation of adrenal androgens- Congenital adrenal hyperplasia. Females (adrenogenital syndrome) ADULTS-Masculine characteristics (hair, voice, enlarged clitoris, muscles)  virilization INFANTS- Female Pseudohermaphroditism. Males Will induce pubertal effects Hypersecretion There are two major instances that lead to hypersecretion of adrenal androgens. Firstly a lack of 21- or 11-hydroxylase activity in the adrenal cortex leads to the preferential formation of adrenal androgens. The lack of cortisol production means ACTH levels rise (due to lack of negative feedback). Secondly adrenal hyperplasia (will also observe elevated cortisol levels) will cause androgen hypersecrtion.   In females hypersecretion of adrenal androgens will lead to masculinization of the fetus in utero and in adults loss of menses, regression of breast tissue, body hair, acne, deepening of voice, enlargement of clitoris and the formation of more muscle.

Adrenal Medulla

Autonomic Nervous System Pre-ganglionic neuron Adrenal Medulla The adrenal medulla is an important source of circulating catecholamines. It is considered part of the sympathetic nervous system and its function is controlled to some extent by a pre-ganglionic neuron secreting ACh. The adrenal medulla has an important role in metabolism and the flight/fright response. It also coordinates with the adrenal cortex in the body’s response to stress Diagram showing the relationship of the adrenal medulla with the Autonomic Nervous System. As you can see the adrenal medulla receives input from the preganglionic neuron of the autonomic nervous system. It is the neurotransmitter acetylcholine released from this neuron that stimulates both the synthesis and release of the catecholamines (epinephrine/norepinephrine) from the adrenal medulla Chromaffin cell Epinephrine/Norepinephrine

Synthesis of the two major adrenal medulla hormones :- Tyrosine Epinephrine(80-90%) Tyrosine hydroxylase Cortisol Dopa ACTH PNMT Dopamine β-hydroxylase Dopamine Norepinephrine(10-20%) Diagram showing the various steps of the synthesis of the two major adrenal medulla hormones norepinephrine and epinephrine. As you can see the synthesis of both follow the same pathway starting with tyrosine conversion into dopa. ACh stimulates the activity of tyrosine hydroxylase which sets the pathway in motion. Dopamine is moved from the cytosol of the medullary cell into the secretory granule where the enzyme dopamine β-hydroxylase is present to convert it into norepinephrine. This norepinephrine is either stored ready for release or may be converted in epinephrine. The conversion into epinephrine requires the norepinephrine to leave the secretory granule to the cytoplasm where phenylethanolamine-N-methyltransferase is found. This epinephrine is then taken back up in the granule waiting for release.   Modulators of Synthesis ACh released from preganglionic sympathetic nervous system is a major controller of catecholamine synthesis by the adrenal medulla by increasing the activity of tyrosine hydroxylase and long term stimulation upregulates transcription and translation of tyrosine hydroxylase and dopamine -hydroxylase. Cortisol increases the synthesis and activity of phenylethanolamine-N-methyltransferase (PMNT). This increases the epinephrine:norepinephrine ratio Catecholamines in general negatively feedback on the activity of tyrosine hydroxylase Epinephrine Secretory granule Chromaffin cell PNMT- phenylethanolamine-N-methyltransferase

Chromaffin Cell ACh Na+ Vm N Vesicles containing Epinephrine and Norepinephrine N Release of Epi and Norepi via exocytosis Ca2+ Transport and Circulation of Medullary Hormones ~ 50% travel loosely bound to albumin Half-life of between 10-100 seconds, very short

The adrenal medulla- pheochromocytes, and large venous structures. Two distinct classes of medullary cells Distinguished from each other - secretory granules.

Medullary cells -larger and large caliber veins are located in the medulla. The pheochromocytes -stained with chromic salts. The cells take on a yellow brown color and are called chromafin cells.

Chromaffin cells modified post-ganglionic sympathetic neurons that lack dendrites and axons secreted in response to intense emotional reactions and stresses placed on the individual.

Sympathetic ganglion cells round or polygonal with prominent nuclei

Pheochromocytoma Hypersecretion of medullary hormones Usually due to tumor  unregulated burst of c/a release Get sudden symptoms associated with excess catecholamines Esp. on stress or postural changes

STRESS Hypothalamus ANS/ Adrenal Medulla Pituitary-Adrenal Cortex cortisol Release of catecholamines glucocorticoids mineralocorticoids HR & BP Blood glucose Metabolic rate Bronchodilation BP Protein b/down Fat b/down Immune supression Long-term response Short-term response