2Hormones of the Adrenal Cortex All adrenocortical hormones are steroids (fat soluble). Three groups:Glucocorticoids (cortisol in humans)Mineralocorticoids (aldosterone)Adrenal sex hormones (most important is dehydroepiandrostenone = DHEA)Cortex has three layers.Zona glomerulosaZona fasciculateZona reticularis
3Mineralocorticoid (aldosterone) Promotes Na+ reabsorption and K+ secretion in distal convoluted tubule. This is how total body Na+ is regulated by the kidney.Since Na+ is the major cation in ECF, controlling Na+ content controls plasma volume and arterial pressure.In absence of aldosterone, Na+ depletion lowers plasma volume and arterial pressure to fatal levels in 7 to 10 days. Added dietary salt can prevent this in acute cases. Elevated plasma K+ can disrupt cardiac rhythm. Long term maintenance is by administration of mineralocorticoids.
4Control of aldosterone secretion Aldosterone secretion is stimulated by decreased plasma Na+, increased plasma K+, and decreased arterial pressure.ACTH has a very small influence on aldosterone secretion.
5Glucocorticoids (mostly cortisol) Metabolic effects:Stimulates protein degradation -> muscle wasting and increased levels of plasma amino acidsStimulates conversion of amino acids to glucose in the liverInhibits glucose uptake from plasma, except in brainIncreases plasma glucose levelsPromotes lipid breakdown, increasing plasma lipid levelsThis conserves glucose for the brain, other tissues burn fatPermissive effect: Sympathetic responses require presence of some cortisol.Anti-inflammatory and immunosuppressive effects: Well known, but unimportant physiologically. Pharmacologically important, usually cortisone or hydrocortisone rather than cortisol.
6Control of Cortisol Secretion Major stimulus to secretion is ACTH. ACTH secretion is inhibited by cortisol (negative feedback loop), as is CRH secretion.Stress increases cortisol secretion. Probably by neural stimulation of CRH output from hypothalamus via brain pathways.Cortisol secretion varies during each 24 hour cycle. Highest in morning. Also a result of brain influence on endocrine system.
7Hypersecretion of Cortisol (Cushing’s syndrome) Result from cortisol secreting tumor, excess ACTH and/or excess CRHCauses muscle wasting and elevated plasma glucose levels.Increased subcutaneous fat deposition, especially in the face.
8Adrenal Cortex Atrophy Addison’s disease = atrophy of the adrenal cortex. Results in hyposecretion of cortisol and aldosterone.Hyposecretion of cortisol reduces plasma glucose and amino acid levels, but we can compensate.Hyposecretion of aldosterone causes loss of Na+, can be fatal in fairly short time. Can be treated with oral NaCl, though.
9Adrenal Sex HormonesDehydroepiandrostenone (DHEA) is a male sex hormone. Effects are similar to those of testosterone, but has much less potency.The only masculinizing hormone in women. Hypersecretion masculinizes: male body hair distribution, facial hair (hirsutism), increased muscle definition, deepening of voice, etc. Also causes reduction in breast size, menstrual abnormalities.Irrelevant in men. Even men with low testosterone levels have so much testosterone in their plasma that DHEA levels are trivial.Pre-pubertal boys with elevated DHEA levels develop adult male secondary sex characteristics, called precocious puberty. They look like they’ve gone through puberty, but they don’t produce sperm. Testosterone levels in the testes aren’t nearly high enough to support sperm production.
10Adrenal MedullaRefresher on sympathetics: Preganglionic neurons in CNS synapse with postganglionic neurons in ganglia, releasing ACh from axon terminals. Postganglionic neurons project axons to target cells, releasing norepinephrine from axon terminals.Neurons from CNS project axons to adrenal medulla, releasing ACh from axon terminals. Adrenal medullary cells release epinephrine and norepinephrine (4:1 ratio) into circulation. Epinephrine and norepinephrine have similar, but not identical effects. Also known as adrenalin and noradrenalin, for historical reasons.Thus, adrenal medulla is essentially part of the sympathetic branch of the autonomic nervous system.
11It’s been known since the 19th century that cells of the adrenal medulla stain vividly with histological stains. For that reason, they are called chromaffin cells. The vivid staining is in hormone-containing granules, known as chromaffin granules.When you are startled, you have immediate responses (increased heart rate and stroke volume, for example), which gradually come back to normal within a minute or so. The immediate response is neural (sympathetic), the prolonged response is from adrenal medullary hormones.
12Adrenal Medullary Disorders Deficiency: No known deficiency disorders. Maybe they exist but are compensated by sympathetic nervous system.Excess: There are adrenal medullary tumors that secrete large amounts of epinephrine and norepinephrine. These are known as pheochromocytomas. Symptoms are what you might expect of sympathetic hyperactivity; irritability, elevated plasma glucose levels, hypertension, etc.
13Endocrine Control of Circulating Fuels We absorb fatty acids and glycerol, amino acids, and sugars from the gut; store them as fats, proteins and glycogen.Most of stored protein is muscle; increased by increasing muscle mass, only mobilized under starvation conditions. Sugars are stored in muscle and liver as glycogen, amount we can store is very limited. Lipid is stored as fat, virtually unlimited amount.When we have more sugar and/or amino acid than can be stored, they’re converted into and stored as fat.
14Brain can only use glucose as fuel Brain can only use glucose as fuel. Probably for this reason, plasma glucose levels are closely regulated. Normal level is about1 mg/ml = 100 mg/100 ml = 100 mg/dL = 100 mg% = 3 mMRegulation is by having other tissues burn fatty acids when glycogen stores are depleted, and converting other compounds to glucose (gluconeogenesis).We eat periodically, rather than continuously. Therefore, there are two metabolic states: (1) Fed or absorptive state, when nutrients are being absorbed from the gut. (2) Fasting or postabsorptive state, when not much is being absorbed from the gut.During fed state, glucose is used as fuel, and is converted into glycogen and fat for storage. During fasting state, glycogen and fat are converted to glucose, and most cells use fats as fuel. This conserves glucose for the brain. The state we are in is under endocrine control.
15Epinephrine, norepinephrine, cortisol and GH affect plasma glucose levels. But the major influences come from two polypeptide hormones secreted by the endocrine pancreas (islets of Langerhans).1. Insulin, produced by beta cells2. Glucagon, produced by alpha cells.Insulin’s most important effects:Promotes glucose uptake by liver and muscle, decreasing plasma glucose levels.Promotes increased glycogen in liver and muscle by stimulating glycogen synthesis and inhibiting glycogen breakdown.Promotes uptake of fatty acids and amino acids and their conversion into fat and protein.
16Significance of Splanchnic Circulation Venous drainage of pancreas goes straight to liver. Thus, insulin reaches liver before dilution in circulation.Venous drainage of small intestine goes straight to liver. Thus, absorbed nutrients reach liver before dilution in circulation.Liver is one of the two major sites of insulin action.
17Control of Insulin Secretion Plasma glucose concentration. As plasma glucose levels increase, insulin secretion increases.Neural control. Sympathetic stimulation inhibits insulin release (that’s why sympathetic stimulation increases plasma glucose levels), parasympathetic stimulation promotes insulin release (parasympathetic output increases while meals are being digested).
18Diabetes Mellitus Diabetes = high volume of urine Mellitus = honey-likeUrine of victim is sometimes very sweet, attracts flies and dogs. This has been known for at least 500 years. The sweetness comes from a high glucose content (normal urine has none).Plasma glucose levels can exceed transport maximum in kidneys, increasing volume osmotically. Plasma glucose is elevated because insulin’s effects aren’t happening.This is the most common of all endocrine disorders, although it’s actually two very different disorders with the same name and symptoms.
19Types of Diabetes Mellitus Type I: Insufficient insulin secretion by beta cellsType II: Reduced sensitivity of cells to insulinEffects are the same either way – insulin’s effects are blunted or absent. Sometimes described as starvation in the midst of plenty, because cells are bathed in a nutrient-rich environment but can’t transport the nutrients into cells where they can be used.
20What happens in diabetes mellitus? Glucose output from liver increases, glucose uptake into liver, muscle and other cells decreases. Therefore, plasma glucose levels rise (hyperglycemia)Protein is broken down and resulting amino acids are converted into glucose. This leads to muscle wasting.When plasma glucose levels get above 3 mg/ml, glucose enters urine (glucosuria) and urine volume expands osmotically.
21Effects of high rate of loss of water Person drinks lots of water (thirst is a compensatory mechanism when plasma volume falls). Despite this, dehydration occurs; the water intake doesn’t quite compensate for the water loss.Dehydration reduces arterial pressure, reducing tissue perfusion. This can cause renal failure, poor wound healing, neuropathies.Reduced intracellular glucose levels cause hunger and increased food intake. Despite this, cells continue to starve, and fats are used for energy by most cells.Fat metabolism results in some ketones as end products, giving a characteristic sweet odor to breath (acetone is a commonly used ketone). It also reduces plasma pH because some end products are organic acids, less volatile than CO2. Acidosis can progress to cause coma or death.
22Treatment of Diabetes Mellitus Type I – Treated with insulinType II – Treated with drugs that stimulate insulin secretion. Since person can produce insulin, it’s often possible to overcome the reduced sensitivity to it this way. Mild cases can often be controlled by diet and exercise.Exercise is valuable for any diabetic, because glucose uptake by muscle rises during exercise independently of insulin.If a Type I diabetic overdoses on insulin, hypoglycemia can result. Depriving the brain of a glucose supply can cause loss of consciousness.
23GlucagonIf you understand insulin, glucagon is easy. Everything is simply opposite to what’s true for insulin.Glucagon increases gluconeogenesis and decreases glycogen synthesis in liver, thus increasing plasma glucose levels.Glucagon promotes fat breakdown, inhibits protein synthesis and promotes protein breakdown.Glucagon secretion is also controlled by plasma glucose levels, but increased levels of glucose reduce glucagon secretion.