Endocrine Physiology Flashcards
Aldesteronism
Hyperaldosteronism will increase sodium reabsorption and potassium secretion. This will increase the concentration of extracellular sodium. Fluids will flow from intracellular fluid to extracellular fluid due to the concentration gradient differences. Furthermore, sodium retention by the kidneys will increase bicarbonate reabsorption and acid excretion. Oedema is not found in hyperaldosteronism as may be expected.
Hyperaldosteronism mainly alters sodium and potassium balance. It will cause hypernatraemia due to the increase in reabsorption of sodium. Hypernatraemia symptoms include muscle spasms and twitches, confusion, fatigue, seizure, and coma. Hypokalaemia will also occur, characterised by muscle weakness, myalgia, tremor, muscle cramps, and constipation. The extracellular volume will also increase due to an increase in water reabsorption and high sodium concentration. Glucose tolerance also decreases, causing some diabetes mellitus-like symptoms such as fatigue, polydipsia and polyphagia.
Hyperaldosteronism with high renin levels is secondary hyperaldosteronism. The high levels of aldosterone arise due to excessive renin secretion. It is seen in disease states like congestive cardiac failure, liver cirrhosis and nephrotic syndrome.
In primary hyperaldosteronism, adrenal dysfunction leads to excessive secretion of aldosterone, and renin secretion is suppressed by negative feedback. Causes include adrenal adenoma (Conn’s syndrome), adrenal hyperplasia and adrenal carcinoma.
Symptoms of hyperaldosteronism include weakness, polyuria, tetany and hypertension. Biochemically, a hypokalaemic alkalosis is observed, due to loss of potassium and protons, and retention of sodium. Oedema is not usually a feature.
Thyroxine binding
Thyroxine and triiodothyronine mainly circulate in plasma bound to plasma proteins. These plasma proteins are synthesized by the liver. Thyroxine is mainly secreted from the thyroid gland (93%).
Thyroxine is bound in the greatest amount to thyroxine-binding globulin and in a relatively smaller amount to thyroxin-binding albumin and prealbumin. Within the thyroid gland, these hormones are stored bound to thyroglobulin. 99.98% of T4 is bound in the plasma - only tiny amounts exist as free T4.
Albumin actually has the greatest capacity to bind T4, however TBG has a greater affinity for it and so most T4 is bound to TBG.
Transthyretin is a transport protein that binds small amounts of thyroxin and retinol. Ferritin is an intracellular protein that stores iron.
Thyroxine and triiodothyronine mainly circulate in plasma bound to plasma proteins. These plasma proteins are synthesized by the liver. The primary secretion from the thyroid gland is thyroxine (80%). Thyroxine is bound in the greatest amount to thyroid-binding globulin and in a relatively smaller amount to thyroid-binding albumin and prealbumin. Within the thyroid gland, these hormones are stored bound to thyroglobulin.
Growth hormone
Growth hormone is synthesized by the anterior pituitary gland by cells called “somatotropes”. Growth hormone stimulates the production of somatomedins by hepatocytes which play their role in bone growth. Somatomedins are also called “insulin-like growth factors”. Its release is inhibited by somatostatin (or “growth hormone-inhibiting hormone”). It stimulates the process of lipolysis and causes the release of fatty acids from the adipocytes.
Growth hormone (GH) is a peptide hormone that stimulates growth, cell reproduction, and cell regeneration in humans and other animals. GH also stimulates the production of IGF-1 and increases the concentration of glucose and free fatty acids. GH is also a mitogen, which means that it promotes mitosis in certain cells. GH has various metabolic effects. Growth hormone increases amino acid uptake, increases protein synthesis and decreases oxidation of proteins, in order to increase protein anabolism in many tissues. In fat metabolism, growth hormone enhances the utilization of fat by stimulating triglyceride breakdown and oxidation in adipocytes. Growth hormone has anti-insulin activity because it suppresses the abilities of insulin to stimulate the uptake of glucose in peripheral tissues and enhance glucose synthesis in the liver. Somewhat paradoxically, the administration of growth hormone stimulates insulin secretion, leading to hyperinsulinemia.
Growth hormone is secreted by the anterior pituitary gland in a pulsatile manner. Its secretion is regulated by various stimuli. Starvation and protein deficiency, increased blood amino acids such as L-arginine, low concentration of fatty acids in the blood, hypoglycemia, exercise, trauma, and excitement, increase the release of growth hormone. Growth hormone-releasing hormone produced from the hypothalamus, testosterone, and estrogen also increase its levels. Growth hormone levels are also increased during the first two hours of deep sleep.
Growth hormone has many effects besides increasing height in children and adolescents. For example, it promotes liver gluconeogenesis, promotes lipolysis, increases protein synthesis, increases calcium retention, increases the mineralization of bone, increases muscle mass, stimulates the growth of all internal organs (excluding the brain), and increases deiodination of T4 to T3. Growth hormone also antagonizes insulin’s action on peripheral tissues, such as the skeletal muscle, liver, and adipose tissue, resulting in decreased use of glucose for energy.
The release of growth hormone is regulated by growth hormone-releasing hormone and growth hormone-inhibiting hormone (somatostatin). Consumption of a high-carbohydrate diet and increased free fatty acids decrease the release of growth hormone. Physiologically, exercise, sex, starvation with protein deficiency, early hours of a deep sleep, trauma, and excitement increase growth hormone release.
Growth hormone (GH) secretion is stimulated by many factors, such as peptide hormones (GHRH and ghrelin), sex hormones (androgen, testosterone, and estrogen), clonidine, L-DOPA, arginine, propranolol, insulin, glucagon, and niacin. It can also be stimulated by fasting, vigorous exercise, hypoglycemia, and deep sleep.
Insulin
Insulin exerts its effects by binding to and activating a membrane receptor protein. The end effect is increased permeability of the cell membrane to amino acids, potassium ions, and phosphate ions. Autophosphorylation of the beta subunit of the insulin receptor activates tyrosine kinase, which further phosphorylates insulin-receptor substrates. There is increased cellular uptake of glucose in most of the body cell membranes. There is a negative feedback mechanism by which there is decreased binding of additional insulin molecules and inhibition of synthesis of additional receptor molecules.
Insulin is an anabolic hormone that binds to a receptor with tyrosine kinase activity. Insulin’s primary function is to increase glucose uptake by the muscles and adipose tissues, resulting in increased glycogen and triglyceride synthesis and storage. Insulin stimulates protein synthesis in a range of tissues and is believed to act as a neuropeptide, involved in satiety and appetite regulation. Glucose uptake by the brain is not insulin-dependent.
In our body, insulin’s main function is to decrease blood glucose levels in various ways. Insulin increases cellular uptake of blood glucose, increases fatty acid formation in adipose tissue, increases glycogenesis, decreases glucagon release by the pancreas, decreases liver gluconeogenesis, etc.
Insulin release is stimulated by many substances, such as the amino acids arginine and leucine, the parasympathetic release of acetylcholine, sulfonylurea, cholecystokinin (CCK), and the gastrointestinally-derived incretins, such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). Atropine is an antimuscarinic (a type of anticholinergic) that works by inhibiting the parasympathetic nervous system. So atropine will inhibit insulin secretion by inhibiting acetylcholine in the parasympathetic nervous system.
Insulin deficiency causes lipolysis of stored fat and release of free fatty acids. In an insulin-deficient state, there is decreased cellular uptake of glucose and a decrease in the activity of alpha glycerophosphate in the liver and fat cells. All tissues except for brain tissue switch their metabolism to gain energy from substrates other than glucose. This is due to insulin deficiency and not due to increased fatty acids in the blood. Hormone-sensitive lipase causes an increase in fatty acid release from adipose tissue. Free fatty acids become the main energy substrate.
Endorphins
Endorphins are produced by the central nervous system and pituitary gland. They are synthesized as part of a larger molecule that includes the sequence of ACTH. Their main function is to inhibit the transmission of pain signals. They increase the pain threshold and have an analgesic effect. This effect is mediated by peptide neurotransmitters at different sites in the central nervous system. They also affect the gastrointestinal system and predominantly cause constipation. Stress stimulates the pituitary release of endorphins.
Cushing’s
Cushing’s syndrome arises due to an excess of glucocorticoids. It may be independent of, or dependent on, ACTH levels.
ACTH-dependent cases are due to an excess of ACTH, provoked by pituitary tumours or other tumours that secrete ACTH or CRH (corticotrophin-releasing hormone), eg small cell lung cancer.
ACTH-independent causes include adrenal hyperplasia, adrenal adenomas or carcinomas and, most commonly, exogenous glucocorticoids.
Cortisol causes mobilisation of protein, lipid and carbohydrate stores, and immunosuppression. Excess levels cause muscle wasting, a characteristic fat deposition around the abdomen and between the scapulae, thin skin and striae, psychiatric disorders, hyperglycaemia and diabetes mellitus, poor healing, osteoporosis, oedema and fluid retention.
Oedema and fluid retention are caused by the mineralocorticoid effect of glucocorticoids. Glucocorticoids can act on aldosterone receptors and cause the picture of hyperaldosteronism, with sodium and water retention, and potassium and acid loss.
Alpha adrenergic receptors
Alpha-adrenergic receptors are found in the radial muscle of the iris in the eye, skeletal muscle, arterioles and pilomotor muscles in the skin, splanchnic vessels, systemic veins, gastrointestinal smooth muscle, urinary bladder sphincter, uterus, liver, pancreas, and salivary glands. In contrast, cardiac muscle and bronchial smooth muscles exclusively possess beta-adrenergic receptors.
AcH
Acetylcholine (ACh) is a primary parasympathetic neurotransmitter and is released by all preganglionic neurons, all parasympathetic postganglionic neurons, sympathetic postganglionic neurons innervating sweat glands, as well as those supplying some blood vessels in skeletal muscles (sympathetic vasodilator nerves). Neurons of the adrenal medulla are sympathetic and secrete epinephrine, norepinephrine, and other peptides (not acetylcholine) directly into the bloodstream.
Noradrenaline
Norepinephrine, also known as “noradrenaline”, is continuously released into blood circulation at low levels. It is the most common transmitter of the sympathetic nervous system and acts on alpha- and beta-adrenergic receptors. Noradrenaline has a greater affinity for alpha-adrenoceptors, whereas epinephrine (adrenaline) has a higher affinity for beta-adrenoceptors. Muscarinic and nicotinic are types of cholinergic receptors and are acted upon by acetylcholine.
Calcitonin
Calcitonin is secreted by the parafollicular C cells in the thyroid when calcium levels are raised. It lowers serum calcium levels by decreasing osteoclastic resorption of bone and increasing excretion at the kidney. Levels may be increased by dopamine, oestrogens, beta-agonists, glucagon and gastrin.
Thyroid hormones
Thyroid hormones decrease the reaction time of stretch reflexes. This property is used in detection of hypothyroidism by elicitation of an ankle jerk/knee jerk reflex. Thyroid hormones lead to increased metabolism, resulting in increased nitrogen excretion, weight loss, increased urate excretion, and precipitation of vitamin deficiency. Increased protein breakdown takes place in muscles due to the action of thyroid hormone.
Thyroxine and triiodothyronine predominantly circulate in plasma bound to plasma proteins. Thyroxine is bound in the greatest amount to thyroid-binding globulin and in smaller amounts to thyroid-binding albumin and prealbumin. Thyroid hormones increase glucose absorption from the small bowel. They also increase oxygen dissociation from haemoglobin. Thyroid hormones stimulate erythrocyte production by causing maturation of erythrocyte progenitors.
The thyroid gland secretes thyroxine (T4) and, in lesser quantities, triiodothyronine (T3). Iodine is the raw material for thyroid hormone synthesis and a minimum daily intake of 150 micrograms of iodine is essential to maintain normal thyroid function in adults. During thyroid hormone synthesis, oxidation and reaction of iodide with a glycoprotein known as “thyroglobulin” is mediated by thyroid peroxidase. T3 has a higher biological activity than T4 and is formed in peripheral tissue by deiodination of T4. Both T4 and T3 are found in plasma in the biologically-active free form in much lower quantities than the bound fraction.
Tyrosine is iodized to monoiodotyrosine and then to diiodotyrosine. Monoiodotyrosine combines with diiodotyrosine to form triiodothyronine (T3). Monoiodotyrosine does not circulate in the blood and has no physiological activity of its own. Iodinated tyrosine in the form of mono- and diiodotyrosine are bound to thyroglobulin in the thyroid gland. When thyroglobulin is digested to release thyroid hormones, these iodinated tyrosines are not released into the blood; rather, iodine is recycled by the deiodinase enzyme.
Thyrotropin-releasing hormone (TRH) is secreted from the hypothalamus and, in turn, stimulates the release of thyroid-stimulating hormone (TSH) from the pituitary gland. TSH is secreted by the anterior pituitary and regulates thyroid hormone synthesis and release from the thyroid gland. Dopamine, somatostatin and glucocorticoids inhibit TRH action, thus inhibiting TSH secretion. Additionally, high levels of iodine inhibit the release of thyroid hormones; low levels are required for their synthesis.
Thyroid hormones (T4 and T3) are exclusively produced in the follicular cells of the thyroid gland and are regulated by thyroid-stimulating hormone (TSH). T3 is three to five times more active than T4. Thyroxine is produced by attaching iodine atoms to the ring structures of this protein’s tyrosine residues. This process is called “iodination”. Thyroxine (T4) contains four iodine atoms, while triiodothyronine (T3) contains three iodine atoms.
An increased concentration of thyroid hormones in the plasma increases the basal metabolic rate and oxygen consumption of all metabolically-active tissues of the body. Oxygen consumption in the liver, kidneys, gastric mucosa, skeletal muscles, skin, and heart are increased. The exceptions to this are the spleen, testes, adult brain, uterus, lymph nodes, and anterior pituitary gland.
Also increase milk secretion
Parathyroid hormone
Parathyroid hormone is made by the chief cells of the four parathyroid glands found embedded in the posterior thyroid gland in the neck. It begins life as a preprohormone, and is converted to a prohormone and then active hormone within the parathyroid glands before being secreted.
Its action is primarily to increase serum calcium levels. It does this by directly increasing resorption of bone, mobilising bony calcium stores. It increases phosphate excretion in the distal convoluted tubules and increases calcium reabsorption in the kidney and intestine. It also catalyses the conversion of vitamin D to its active form, 1,25-dihydroxycholecalciferol. In the long term it is stimulatory to both osteoblasts and osteoclasts.
Adrenaline
The predominant substance secreted by the adrenal medulla is epinephrine. It also secretes small amounts of norepinephrine. The zona fasciculata of the adrenal cortex secretes glucocorticoids (mainly cortisol and corticosterone). Dopamine is a neurohormone that is released from the hypothalamus and dopaminergic nerve endings. The zona glomerulosa of the adrenal cortex contains the enzyme aldosterone synthase and secretes the hormone aldosterone.
Epinephrine has a weak vasoconstrictive effect on the blood vessels in muscles, as compared to the stronger constriction caused by norepinephrine. Norepinephrine excites mainly alpha receptors. It also excites the beta receptors, albeit to a lesser extent. Norepinephrine thus greatly increases the total peripheral resistance and elevates arterial pressure. It decreases the pulse pressure.
In the heart, adrenaline increases heart rate, contractility and conduction. In the lungs, it promotes faster respiratory rate and bronchodilation. It also increases blood glucose by promoting glycogenolysis in liver and muscle. Adrenaline also increases metabolic rate and promotes vasoconstriction in most of the systemic vascular circuit.
Adrenaline increases cardiac output by increasing the force of both cardiac contraction and heart rate. It causes vasodilation in skeletal muscles and hepatic vessels. Blood vessels of the abdominal viscera and cutaneous vessels of the limbs are constricted by sympathetic stimulation. It stimulates glycogenolysis in the liver via beta-receptors. Beta-2 agonists also stimulate the intracellular shift of potassium, which can cause a decrease in plasma potassium.
Calcium homeostasis
Glucocorticoids decrease serum calcium levels by decreasing intestinal absorption and increasing renal excretion of calcium. Growth hormone causes increased calcium absorption from the gastrointestinal tract, calcium resorption from bones and increased renal excretion of calcium. Hypercalcemia is seen in acromegalic patients. Thyroid hormone release leads to increased serum levels of calcium while calcitonin causes a decrease in serum calcium levels.
Androgens
Testosterone is the primary sex hormone in males. Dihydrotestosterone is formed from testosterone, catalysed by 5-alpha-reductase. Dihydrotestosterone is a far more potent androgen than testosterone. Androgen synthesis and secretion is controlled by the complex interaction between the hypothalamic–pituitary–testicular axis. The secretion of adrenal androgens is regulated by ACTH. Level of secretion of DHEA peaks in young adulthood and it declines by up to 80% in old age. Androgens are required for normal spermatogenesis.
Testes
Luteinizing hormone, secreted by the anterior pituitary gland, stimulates the Leydig cells to secrete testosterone. Testosterone is secreted by the Leydig cells located in the interstitium of the testis. About 97 percent of the testosterone becomes either loosely bound with plasma albumin or more tightly bound with a beta globulin called “sex hormone-binding globulin”. Follicle-stimulating hormone, also secreted by the anterior pituitary gland, stimulates the Sertoli cells for conversion of spermatids to sperm.
Renin
Renin secretion is increased by increased sympathetic stimulation, catecholamines, and prostaglandins. Other stimuli include sodium depletion, haemorrhage, standing upright, cardiac failure, diuretics, cirrhosis, dehydration, renal artery stenosis, and hypotension.
It is decreased by increased sodium and chloride reabsorption in the macula densa, vasopressin, angiotensin II, and increased afferent arteriolar pressure.
Glucocorticoids
Glucocorticoids act as promoters to enhance the effect of noradrenaline on vascular smooth muscles. An increased cortisol response leads to an increase in arterial contractile sensitivity to norepinephrine and increased vascular resistance via glucocorticoid receptors. They also enhance the process of gluconeogenesis. Cortisol increases the conversion of amino acids into glucose in the liver cells. They decrease the protein stores in the body (except in the liver). They also suppress the T-lymphocytes, thereby suppressing the immune response of the body. Hepatic lipogenesis is reduced and fatty acids are mobilized from the adipose tissue.
Humoral hypercalcemia
Humoral hypercalcemia of malignancy is commonly associated with solid tumors of the lung, breast, and kidney. In contrast, it is rarely associated with colon tumors. Humoral hypercalcemia of malignancy is secondary to overproduction of parathyroid hormone-related protein (PTHrP). This is described as a paraneoplastic syndrome.
Vitamin D
25-hydroxyvitamin D (or 25-hydroxycholecalciferol) is formed in the liver. It is the storage form of vitamin D. The hormone 1,25-dihydroxy vitamin D (D hormone) is formed in a second hydroxylation step in the kidney from 25-hydroxycholecalciferol. The kidneys have the enzyme one-alpha hydroxylase which carries out this conversion, which is regulated by parathyroid hormone.
Progesterone
Progesterone is secreted by the corpus luteum, ovary and placenta. It acts on the uterus, breast and brain.
In the uterus it reduces myometrial excitability and increases production of a thick, cellular mucus. It also inhibits the effects of oestrogens on the uterus.
In the breast, progesterone stimulates lobular growth. In the brain it stimulates an increase in body temperature and respiration.
Hypothyroidism
Physiological creatinuria is decreased in hypothyroidism. Hypothyroidism causes cold, dry, and coarse skin, whereas hyperthyroidism causes warm and moist skin. Hair is brittle, coarse, and breaks easily in hypothyroidism. Hypothyroidism also decreases the motility of the digestive tract and causes constipation.
Prolactin
Prolactin has a negative feedback effect on gonadotrophins, reducing their secretion. Their action on the ovaries is also inhibited, resulting in absent ovulation and reduced secretion of oestrogens and progesterones. Fertility is thus reduced.
Prolactin is produced by the anterior pituitary. Its secretion is routinely inhibited by the hypothalamus, therefore dividing the pituitary stalk and removing this control will result in increased prolactin secretion. Exercise, stress, and nipple stimulation increase secretion, as do TRH and TSH.
Dopamine and chlorpromazine decrease prolactin secretion.
Prolactin has multiple effects. It stimulates milk production in the breast, and has a negative feedback effect on gonadotrophins, reducing their secretion. Their action on the ovaries is also inhibited, and the result is absent ovulation and reduced secretion of oestrogens and progesterones. Fertility is thus reduced in the postpartum period.
Oestrogen
Oestrogens stimulate duct proliferation primarily; progesterones mainly stimulate lobular growth. Prolactin is responsible for milk production. Oxytocin is responsible for milk let-down or ejection.
Oestrogens are C18 steroids, and include estriol, estrone and 17-beta estradiol. They are produced by the ovarian granulosa cells, placenta and corpus luteum. Oestrogen production is stimulated by LH and FSH. Oestrogens are derived from androgens such as testosterone and androstenedione, by a process called “aromatisation” (facilitated by the enzyme aromatase), in the granulosa cells of the ovary. The androgens are supplied by the theca interna cells.
98% of circulating oestrogens are bound to albumin and sex hormone-binding globulin (SHBG). They are excreted by conversion to glucuronides and sulfate conjugates in the liver, and then secreted into bile to enter the gut.
Effects of oestrogens include:
- Protein anabolism
- Increased uterine blood flow and myometrial excitability
- Ovarian follicle growth
- Increased fallopian tube motility
- Increased libido
- Breast duct and alveolar growth
- Reduction of plasma cholesterol
Aldosterone
Aldosterone is a mineralocorticoid hormone, produced by the zona glomerulosa of the adrenal gland. Aldosterone secretion in a healthy person is increased by a low-salt diet (<2 gm/day), a high-potassium diet, stress, upright posture, and diuretic therapy, and is decreased by a high-sodium diet and supine position.
Aldosterone is a mineralocorticoid hormone, produced by the zona glomerulosa of the adrenal gland. Aldosterone is an essential hormone for sodium absorption in many organs, such as the kidneys, salivary glands, sweat glands, and intestines.
t mainly acts on the distal convoluted tubules and collecting ducts of the kidneys, where it acts on nuclear mineralocorticoid receptors to increase the number of basolateral sodium/potassium channels. More sodium is pumped out of the cells in exchange for potassium in the extracellular fluid, and this sets up a concentration gradient which causes the movement of sodium out of the tubular lumen and into the tubule cells across the apical membrane. Thus, sodium is retained. Aldosterone also increases the number of epithelial sodium channels (ENaCs) in the collecting ducts and the colon, increasing the permeability of the apical membrane to sodium. Other effects include secretion of potassium and protons (H+) into the tubular fluid, increasing loss of these two ions, and retention of sodium in exchange for potassium in the sweat glands and salivary glands.
Aldosterone secretion is stimulated by hyperkalaemia, a rise in angiotensin II or ACTH, increased discharge of renal nerves, or decreased blood pressure (detected by atrial stretch receptors). Increased secretion is seen in pregnancy, trauma, burns and blood loss. Reduction of dietary sodium will increase aldosterone secretion.
