Endocrine Physiology-Offline information
Insulin Receptor:
Insulin receptor is a glycoprotein with a molecular weight of 340,000. It is present in almost all the cells of the body. Insulin receptor is a tetramer, formed by four glycoprotein subunits (two α-subunits and two β-subunits). Intracellular surfaces of insulin receptor have the enzyme activity tyrosine kinase activity. When insulin binds with the receptor, the tyrosine kinase is activated by means of autophosphorylation. Activated tyrosine kinase acts on many intracellular enzymes by phosphorylating or dephosphorylating them so that some of the enzymes are activated while others are inactivated. Thus, insulin action is exerted on the target cells by the activation of some intracellular enzymes and by the inactivation of other enzymes.
Biphasic action of blood glucose on insulin secretion:
i. Initially, when blood glucose level increases after a meal, the release of insulin into blood increases rapidly. Within few minutes, concentration of insulin in plasma increases up to 100 µU/mL from the basal level of 10 µU/mL. It is because of release of insulin that is stored in pancreas. Later, within 10 to 15 minutes, the insulin concentration in the blood reduces to half the value, i.e. up to 40 to 50 µU/mL of plasma.
ii. After 15 to 20 minutes, the insulin secretion rises once again. This time it rises slowly but steadily. It reaches the maximum between 2 and 2½ hours. The prolonged increase in insulin release is due to the formation of new insulin molecules continuously from pancreas (Figure).
Diabetes Mellitus:
The regulation of blood glucose is essential for normal tissue function. High blood sugar (hyperglycemia) can lead to diabetes mellitus. Low blood sugar (hypoglycemia) can be the result of diet; a symptom of another medical condition, such as sepsis; or the result of a medication. Diabetes mellitus is a worldwide health epidemic and affects 8.3% of the U.S. population. Complications of diabetes include cardiovascular (endothelial dysfunction, hypertension, heart disease, and stroke), renal, and ocular problems as well as peripheral neuropathy. Part of this widespread damage is because hyperglycemia can damage fundamental structures, such as basement membranes and endothelial tissue. These complications can also negatively combine, such as when peripheral vascular damage and peripheral neuropathy lead to foot ulcers. Hyperglycemia in diabetes is defi ned as fasting plasma glucose 126 mg/dL or 200 mg/dL after an oral glucose tolerance test (rapid ingestion of 75 g glucose in 300 mL water and glucose monitoring over the following 120 min). There are two broad classifi cations of the disease.
Type 1: Type 1 diabetes mellitus results from destruction of the islet cells, often due to a virus or an autoimmune response. The onset of symptoms is often quite rapid. Without adequate -cell function and insulin release, blood glucose levels, especially after a meal, will rise because glucose cannot move into cells. Patients also present with polyuria (increase in urinary volume), glucosuria (glucose in the urine, see 26·III·B), polydipsia (excessive thirst), and ketoacidosis (see 28·V·E) in addition to hyperglycemia. Glucosuria can be easily detected via a paper strip test, which has an enzyme-linked dye with color intensity dependent on the glucose concentration. Polydipsia is the neural and hormonal response to the volume contraction. The high glucose levels associated with diabetes can glycosylate hemoglobin A1c. Red blood cells’ 2-month half-life gives insight into long-term presence of hyperglycemia in a patient. Treatment for type 1 diabetes is often insulin injections either as a bolus of a short-acting form before a meal to account for impending glucose or routine injections of longer-acting forms.1 For some persons, insulin pumps can simplify diabetes management, which is critical insofar as well-managed blood glucose strongly correlates with positive long-term outcomes.
Type 2: Type 2 diabetes mellitus is associated with inadequate production of insulin or an insensitivity to glucose and insulin. The incidence of type 2 diabetes in the United States has grown to epidemic proportions in recent decades, mirroring the coincident rise in the number of obese individuals. Risk factors for type 2 diabetes also include age and ethnic background. Insulin secretion can be increased via sulfonylureas, which block adenosine triphosphate–sensitive K channels and cause Ca2 influx into the cell. The glucose insensitivity occurs in cells, blunting the secretion of insulin, and insulin insensitivity occurs in peripheral tissues, blunting the uptake of glucose. Both of these insensitivities result in elevated concentrations of plasma glucose. This insulin resistance can be related to adipose signaling molecules, such as leptin and adiponectin (more of these substances are released when a fat cell is fuller), and decreases with weight loss. Similar to type 1, patients with type 2 diabetes also present with dyslipidemia, including low levels of high-density lipoproteins and high levels of chylomicrons and very low–density lipoproteins in the blood, which can contribute to cardiovascular disease. This is likely due to excess blood-borne fats that are not moved into cells via insulin.
Exogenous steroids: Corticosteroids are used as drugs since long. Exogenous steroids are extracted from adrenal cortex of animals or prepared artificially. Commercially available synthetic drugs with corticosteroid effects are widely used. These drugs are either used as replacement of natural hormones (replacement therapy) in patients with defciency disorders such as Addison disease or to treat a variety of other conditions such as arthritis, allergic conditions, asthma, skin disorders, etc. Synthetic steroids: Synthetic steroids that are commonly used are: 1. Cortisone and hydrocortisone, which are used for replacement therapy have both glucocorticoid and mineralocorticoid effects 2. Prednisolone has more glucocorticoid activity than mineralocorticoid activity 3. Fludrocortisone (9-fluorocortisol) has more mineralocorticoid activity than glucocorticoid activity. It has most potent mineralocorticoid effect. 4. Dexamethasone has only glucocorticoid effect.
APPLIED PHYSIOLOGY – DISORDERS OF PARATHYROID GLANDS:
Disorders of parathyroid glands are of two types:
I. Hypoparathyroidism
II. Hyperparathyroidism.
HYPOPARATHYROIDISM – HYPOCALCEMIA: Hyposecretion of PTH is called hypoparathyroidism. It leads to hypocalcemia (decrease in blood calcium level).
Causes for Hypoparathyroidism
- Surgical removal of parathyroid glands (parathyroidectomy)
- Removal of parathyroid glands during surgical removal of thyroid gland (thyroidectomy)
- Autoimmune disease
- Defciency of receptors for PTH in the target cells. In this, the PTH secretion is normal or increased but the hormone cannot act on the target cells. This condition is called pseudohypoparathyroidism.
- Hyper-reflexia and convulsions Increase in neural excitability results in hyper-reflexia (overactive reflex actions) and convulsive muscular contractions.
- Carpopedal spasm Carpopedal spasm is the spasm in hand and feet that occurs in hypocalcemic tetany. During spasm, the hand shows a peculiar attitude.
- Laryngeal stridor Stridor means noisy breathing. Laryngeal stridor means a loud crowing sound during inspiration, which occurs mainly due to laryngospasm (involuntary contraction of laryngeal muscles). Laryngeal stridor is a common dangerous feature of hypocalcemic tetany.
- Cardiovascular changes: i. Dilatation of the heart. ii. Prolonged duration of ST segment and QT interval in ECG. iii. Arrhythmias (irregular heartbeat). iv. Hypotension. v. Heart failure.
- Other features
i.
Decreased permeability of the cell membrane ii. Dry skin
with brittle nails iii. Hair loss iv. Grand
mal, petit mal or other seizures. v. Signs of mental retardation in
children or dementia in adults.
Latent Tetany: Latent tetany, also known as subclinical tetany is the neuromuscular hyperexcitability due to hypocalcemia that develops before the onset of tetany. It is characterized by general weakness and cramps in feet and hand. Hyperexcitability in these patients is detected by some signs, which do not appear in normal persons. 1. Trousseau sign: Trousseau sign is the spasm of the hand that is developed after 3 minutes of arresting the blood flow to lower arm and hand. The blood flow to lower arm and hand is arrested by inflating the blood pressure cuff 20 mm Hg above the patient’s systolic pressure. 2. Chvostek sign: Chvostek sign is the twitch of the facial muscles, caused by a gentle tap over the facial nerve in front of the ear. It is due to the hyperirritability of facial nerve. 3. Erb sign: Hyperexcitability of the skeletal muscles even to a mild electrical stimulus is called Erb sign. It is also called Erb-Westphal sign.
HYPERPARATHYROIDISM – HYPERCALCEMIA
Hypersecretion of PTH is called hyperparathyroidism. It results in hypercalcemia. Hypercalcemia is the increase in plasma calcium level. It occurs in hyperparathyroidism because of increased resorption of calcium from bones. Hyperparathyroidism is of three types:
1. Primary hyperparathyroidism Primary hyperparathyroidism is due to the development of tumor in one or more parathyroid glands. Sometimes, tumor may develop in all the four glands.
2. Secondary hyperparathyroidism Secondary hyperparathyroidism is due to the physiological compensatory hypertrophy of parathyroid glands, in response to hypocalcemia which occurs due to other pathological conditions such as: i. Chronic renal failure ii. Vitamin D defciency iii. Rickets.
3. Tertiary hyperparathyroidism Tertiary hyperparathyroidism is due to hyperplasia (abnormal increase in the number of cells) of all the parathyroid glands that develops due to chronic secondary hyperparathyroidism.
Signs and symptoms of hypercalcemia i. Depression of the nervous system ii. Sluggishness of reflex activities iii. Reduced ST segment and QT interval in ECG iv. Lack of appetite v. Constipation. Depressive effects of hypercalcemia are noticed when the blood calcium level increases to 12 mg/dL. The condition becomes severe with 15 mg/dL and it becomes lethal when blood calcium level reaches 17 mg/dL.
Other effects of hypercalcemia: i. Development of bone diseases such as osteitis fbrosa cystica ii. Development of parathyroid poisoning. It is the condition characterized by severe manifestations that occur when blood calcium level rises above 15 mg/dL. In hyperparathyroidism, the concentration of both calcium and phosphate increases leading to formation of calciumphosphate crystals. Concentration of phosphate also increases because, kidney cannot excrete the excess amount of phosphate resorbed from the bone iii. Deposition ofcalcium-phosphate crystalsin renal tubules, thyroid gland, alveoli of lungs, gastric mucosa and in the wall of the arteries, resulting in dysfunction of these organs. Renal stones are formed when it is deposited in kidney.
Physiology of bone:
Bone or osseous tissue is a specialized rigid connective tissue that forms the skeleton. It consists of special type of cells and tough intercellular matrix of ground substance. The matrix is formed by organic substances like collagen (These collagen fibers form about 90% of the bone) and it is strengthened by the deposition of mineral salts like calcium phosphate and calcium carbonate (called hydroxyapatites). Throughout the life, bone is renewed by the process of bone formation and bone resorption.
Functions of bone: 1. Protective function: Protects soft tissues and vital organs of the body 2. Mechanical function: Supports the body and brings out various movements of the body by their attachment to the muscles and tendons 3. Metabolic function: Plays an important role in the metabolism homeostasis of calcium and phosphate in the body. 4. Hemopoietic function: Red bone marrow in the bones is the site of production of blood cells.
Classification of bone Depending upon the size and shape, the bones are classifed into fve types: 1. Long bones: Bones of the limbs 2. Short bones: Bones in the wrist and ankle 3. Flat bones: Skull bones, mandible, scapula, etc. 4. Irregular bones: Vertebra 5. Sesamoid bones: Patella.
Parts
of bone Long bones are formed by a
cylindrical tube of bone tissue, which has three portions:
- Diaphysis:
Midportion or midshaft
- Epiphysis: Wider extremity or the head on either end
- Metaphysis: Portion between the diaphysis and the epiphysis (Figure).
In growing age, a layer of cartilage called epiphyseal cartilage or epiphyseal plate or growth plate is present in between epiphysis and metaphysis. Epiphyseal plate is responsible for the longitudinal growth of the bones.
Bone remodeling: Bone remodeling is a dynamic lifelong process in which old bone is resorbed and new bone is formed. Usually, it takes place in groups of bone cells called the basic multicellular units (BMU). The entire process of remodeling extends for about 100 days in compact bone and about 200 days in spongy bone.
Processes
of bone remodeling:
- Bone
resorption: Destruction of bone matrix and removal of calcium (osteoclastic
activity).
- Bone formation: Development and mineralization of new matrix (osteoblastic activity).
Bone Resorption – Osteoclastic Activity: Osteoclastic activity is the process that involves destruction of bone matrix, followed by removal of calcium. Osteoclasts are responsible for bone resorption by their osteoclastic activity. Part of the bone to be resorbed is known as bone resorbing compartment. Resorption of that particular compartment occurs by some substances released from membranous extensions of osteoclasts such as: 1. Collagenase 2. Phosphatase 3. Lysosomal enzymes 4. Acids like citric acid and lactic acid.
Sequence of events during bone resorption: Citric acid and lactic acid cause acidifcation of the area and decrease pH to 4 2 → Lysosomal enzymes are activated at this pH → Activated enzymes digest or dissolve the collagen → Enzymes also dissolve the hydroxyapatite and form solution of bone salts → All the dissolved materials are now released into ECF → Some elements enter the blood → Remaining elements are cleaned up by the macrophages → A shallow cavity is formed in the bone resorbing compartment.
Bone Formation – Osteoblastic Activity: Osteoblastic activity is the process which involves the synthesis of collagen and formation of bone matrix that is mineralized. Osteoblasts are concerned with bone formation. Osteoblasts synthesize and release collagen into the shallow cavity formed after resorption in the bone resorbing compartment. The collagen fibers arrange themselves in regular units and form the organic matrix called osteoid.
Mineralization: Mineralization is the process by which the minerals are deposited on bone matrix. Mineralization starts about 10 to 12 days after the formation of osteoid. First, a large quantity of calcium phosphate is deposited. Afterwards, the hydroxide and bicarbonate ions are gradually added causing the formation of hydroxyapatite crystals. The process of mineralization is accelerated by the enzyme alkaline phosphatase, secreted by osteoblast. The process also requires the availability of adequate amount of calcium and phosphate in the ECF. The completely mineralized bone surrounds the osteoblast. Now, the synthetic activity of osteoblast is reduced slowly and the cell is converted into osteocytes. Later, the bone is arranged in concentric lamellae on the inner surface of the cavity. At the end of the formation of new bone, the cavity is reduced to form Haversian canal.
Signifcance of Bone Remodeling:
- In children: 1. Thickness of bone increases 2. Bone obtains strength in proportion to the growth 3. Shape of the bone is re-altered in relation to growth of the body.
- In adults: 1. Toughness of bone is maintained 2. Mechanical integrity of skeleton is ensured throughout life 3. Blood calcium level is maintained.
Regulation of Bone Remodeling: Bone remodeling occurs continuously throughout the life. So a balance is maintained always between the bone resorption and bone formation. However, in persons like athletes, soldiers and others, in whom the bone stress is more, the bone becomes heavy and strong. It is because of the stimulation of osteoblastic activity and mineralization of bone by repeated physical stress. Apart from the physical stress, a variety of hormonal substances and growth factors are involved in regulation of bone resorption and bone formation (Table).
Pineal gland
Pineal gland or epiphysis is located in the diencephalic area of brain above the hypothalamus. Pineal gland has two types of cells: 1. Large epithelial cells called parenchymal cells 2. Neuroglial cells. In adults, the pineal gland is calcifed. But, the epithelial cells exist and secrete the hormonal substance.
Pineal gland has two functions: 1. It controls the sexual activities in animals by regulating the seasonal fertility. However, the pineal gland plays little role in regulating the sexual functions in human being 2. It secretes the hormonal substance called melatonin. Melatonin is secreted by the parenchymal cells of pineal gland. Melatonin acts mainly on gonads. In humans, it inhibits the onset of puberty by inhibiting the gonads. Melatonin secretion is more in darkness than in daylight, i.e. circadian rhythm. Hypothalamus is responsible for the circadian fluctuations of melatonin secretion
Thymus
Thymus is small in newborn infants and gradually enlarges till puberty and then decreases in size. Thymus has lymphoid function and endocrine function. It plays an important role in development of immunity in the body. Thymus has two functions: 1. Processing the T lymphocytes 2. Endocrine function.
1. Processing the T Lymphocytes: Thymus plays an essential role in the development of immunity by processing the T lymphocytes. The lymphocytes which are produced in bone marrow are processed in thymus into T lymphocytes. It occurs during the period between 3 months before birth and 3 months after birth. So, the removal of thymus 3 months after birth, will not affect the cell-mediated immunity.
2. Endocrine Function of Thymus: Thymus secretes two hormones: i. Thymosin
ii. Thymin.
- Thymosin is a peptide. It accelerates
lymphopoiesis and proliferation of T lymphocytes.
- Thymin is also called thymopoietin. It suppresses the neuromuscular activity by inhibiting acetylcholine release. Hyperactivity of thymus causes myasthenia gravis.
Kidneys
Kidneys secrete five hormonal substances:
1. Erythropoietin
2. Thrombopoietin
3. Renin
4. 1,25-dihydroxycholecalciferol (calcitriol)
5. Prostaglandins
Effects of extirpation of testes: Extirpation (removal) of testes is called castration. Effects of castration depend upon the age when testes are removed.
1. Effects of Extirpation of Testes before Puberty – Eunuchism: If a boy loses the testes before puberty, he continues to have infantile sexual characters throughout his life and this condition is called eunuchism. Height of the person is slightly more but the bones are weak and thin. Muscles become weak and shoulder remains narrow. Sex organs do not increase in size and the male secondary sexual characters do not develop. The voice remains like that of a child. There is abnormal deposition of fat on buttocks, hip, pubis and breast, resembling the feminine distribution.
2. Effects of Extirpation of Testes Immediately after Puberty: If testes are removed after puberty, some of the male secondary sexual characters revert to those of a child and other masculine characters are retained. Sex organs are depressed. Seminal vesicles and prostate undergo atrophy. Penis remains smaller. Voice remains mostly masculine but other secondary sexual characters like masculine hair distribution, musculature and thickness of bones are lost. There may be loss of sexual desire and sexual activities.
3. Effect of Extirpation of Testes in Adults: Removal of testes in adults does not cause loss of secondary sexual characters. But, accessory sex organs start degenerating. The sexual desire is not totally lost. Erection occurs but ejaculation is rare because of degeneration of accessory sex organs and lack of sperms
IGF-1
Because of the pulsatile nature and short half-life of GH, measurement of the more stable IGF-1 in the plasma can provide a better way of assessing hypothalamic–pituitary–liver axis status.Insulin-like growth factor 1 (IGF-1) deficiencies are seen in high prevalence in certain ethnic groups such as the Bayaka (see figure) of central Africa (one of the traditional pygmy peoples). In this ethnic group, many persons are proportioned normally but have very short stature. Adult men are often 5 ft (150 cm) tall. In these individuals, growth hormone levels are normal to high, whereas IGF-1 concentration is very low.
The heart
The endocrine cells in the heart are cardiac muscle cells in the walls of the atria (chambers that receive blood from the veins) and the ventricles (chambers that pump blood to the rest of the body). If blood volume becomes too great, these cells are stretched excessively, to the point at which they begin to secrete natriuretic peptides. In general, the effects of natriuretic peptides oppose those of angiotensin II: Natriuretic peptides promote the loss of Na+ and water by the kidneys, and inhibit renin release and the secretion of ADH and aldosterone. They also suppress thirst and prevent angiotensin II and norepinephrine from elevating blood pressure. The net result is a reduction in both blood volume and blood pressure, thereby reducing the stretching of the cardiac muscle cells in the heart walls.
Adipose tissue
Adipose tissue is a type of loose connective tissue. Adipose tissue produces a peptide hormone called leptin, which has several functions. Its best known function is feedback control of appetite. When we eat, adipose tissue absorbs glucose and lipids and synthesizes triglycerides for storage. At the same time, it releases leptin into the bloodstream. leptin binds to hypothalamic neurons involved with emotion and appetite control. The result is a sense of fullness (satiation) and the suppression of appetite. leptin was first discovered in a strain of obese mice that had a defective leptin gene. When treated with leptin, these overweight mice quickly turned into slim, athletic animals. The initial hope that leptin could be used to treat human obesity was soon dashed, however. Most obese people appear to have defective leptin receptors (or leptin pathways) in the appetite centers of the CNS. Their circulating leptin levels are already several times higher than those in individuals of normal body weight. Additional leptin would have no effect. Researchers are now investigating the structure of the receptor protein and the biochemistry of the pathway triggered by leptin binding. leptin must be present for normal levels of GnRH and gonadotropin synthesis to take place. This explains why (1) thin girls commonly enter puberty relatively late, (2) an increase in body fat can improve fertility, and (3) women stop menstruating when their body fat content becomes very low.
The hormonal Responses to Stress
Any condition—physical or emotional—that threatens homeostasis is a form of stress. Specific homeostatic adjustments oppose many stresses. For example, a decrease in body temperature leads to shivering or changes in the pattern of blood flow, which can restore normal body temperature. In addition, the body has a general response to stress that can occur while other, more specific responses are under way. A wide variety of stress-causing factors produce the same general pattern of hormonal and physiological adjustments. These responses are part of the general adaptation syndrome (GAS), also known as the stress response. It has three phases:
Hormones and Athletic Performance:
The use of hormones to improve athletic performance is widely banned. The International Olympic Committee, the U.S. Olympic Committee, the National Collegiate Athletic Association, Major League Baseball, and the National Football League all ban it. The American Medical Association and the American College of Sports Medicine condemn the practice. Yet a significant number of amateur and professional athletes persist in this dangerous practice. Athletes most often use synthetic forms of testosterone. They might also use any combination of testosterone, GH, EPO, and a variety of synthetic hormones.
Androgen Abuse: The use of anabolic steroids, or androgens, has become popular with many amateur and professional athletes. The goal of steroid use is to increase muscle mass, endurance, and “competitive spirit.” A steroid, such as androstenedione, is converted to testosterone in the body. One supposed justification for this steroid use is the unfounded opinion that compounds made in the body are not only safe, but good for you. In reality, the administration of natural or synthetic androgens in abnormal amounts carries unacceptable health risks. Androgens are known to produce several complications. These problems include (1) premature closure of epiphyseal cartilages, (2) various liver dysfunctions (such as jaundice and liver tumors), (3) prostate gland enlargement and urinary tract obstruction, and (4) testicular atrophy and infertility. Links to heart attacks, impaired cardiac function, and strokes have also been suggested. The normal regulation of androgen production involves a feedback mechanism comparable to that described for adrenal steroids earlier in this chapter. GnRH stimulates the production of LH, and LH stimulates the secretion of testosterone and other androgens by the interstitial cells of the testes. Circulating androgens, in turn, inhibit the production of both GnRH and LH. For this reason, high doses of synthetic androgens can suppress the normal production of testosterone and depress the manufacture of GnRH by the hypothalamus. This suppression of GnRH release can be permanent. The use of androgens as “bulking agents” by female bodybuilders may add muscle mass, but it can also alter muscular proportions and secondary sex characteristics. For example, women taking steroids can develop irregular menstrual periods and changes in body hair distribution (such as baldness). Finally, androgen abuse can depress the immune system.
Erythropoietin Abuse: Erythropoietin (EPO) is readily available because it is now synthesized by recombinant DNA techniques. Endurance athletes, such as cyclists and marathon runners, sometimes use it to boost the number of oxygen-carrying red blood cells in the bloodstream. This effect increases the oxygen content of blood, but it also makes blood more viscous. For this reason, the heart must work harder to push the “thick” blood through the blood vessels. This effort can result in death due to heart failure or stroke in young and otherwise healthy individuals. The Tour de France bicycle races have been tainted by competitors testing positive for banned substances. These include testosterone, erythropoietin, and an illegal blood transfusion. Androgens and EPO are hormones with reasonably well-understood effects. Drug testing is now widespread in amateur and professional sports, but athletes interested in “getting an edge” are experimenting with drugs not easily detected by standard tests. The long-term and short-term effects of these drugs are difficult to predict.
Gamma-hydroxybutyrate Use: Another drug used by amateur athletes is gammahydroxybutyrate (GHb). It was tested for use as an anesthetic in the 1960s but rejected, in part because it was linked to seizures. In 1990, the drug appeared in health-food stores. It was sold as an anabolic agent and diet aid. It has also been used as a “date rape” drug. According to the FDA, GHB and related compounds—sold or distributed under the names Renewtrient, Revivarant, Blue Nitro, Firewater, and Serenity— have recently been responsible for serious illnesses and even deaths. Signs and symptoms include reduced heart rate, lowered body temperature, confusion, hallucinations, seizures, and coma at doses from 0.25 teaspoon to 4 tablespoons.