endocrinology

You should now be familiar with:

The major chemical classes and general mechanisms of hormones. The location and structure of the pituitary gland, and its structural and functional relationships with the hypothalamus. The location and structure of each of the endocrine glands. The hormones produced by each of the endocrine glands, and the functions of those hormones. The functions of the hormones produced by the kidneys, heart, thymus, testes, ovaries and adipose tissue. How hormones interact to produce coordinated physiological responses.

Endocrinology

Endocrine: glands or specialized cells release into the circulating blood hormones that influence the function of cells at another location in the body. Paracrine: in which cells secrete substances that diffuse into the extra cellular fluid & affect neighboring cells. Autocrine: in which a cell secrets substances that affect the function of the same cell by binding to the same surface receptor. There are three classes of hormones: Proteins& polypeptides including hormones secreted by the anterior & posterior piuitary gland,insulin&glucagon,the parathyroid hormone. Steroids as cortisol & aldosterone,estrogen, progesterone and testosterone. Derivatives of the amino acid tyrosine as thyroxine& triiodothyronine, epinephrine&norepinephrine.

Transport of hormones in the blood

Water-soluble hormones ( peptides & catecholamines ) are dissolved in the plasma & transported from their sites of synthesis to target tissues where they diffuse out of the capillaries into the interstitial fluid & then to target cells. Steroids & thyroid hormones , circulate in the blood bound to plasma proteins. These can not diffuse easily across the capillaries ,so they are inactive until they dissociate from plasma proteins,binding of hormones to plasma proteins greatly slows their clearance from the plasma.

Clearance of hormones from blood

Two factors can increase or decrease the concentration of a hormone in blood. One of these is the rate of hormone secretion in blood. The second is the rate of removal of the hormone in blood. which is called the (metabolic clearance rate= rate of disappearance of hormone from the plasma/ concentration of hormone in each milliliter of plasma. Hormones are cleared from the plasma in several ways, including: Metabolic destruction by the tissues. Excretion by the liver . Excretion by the kidneys.. Mechanism of action of hormones The first step of hormone action is to bind to specific receptors at the target cells. Receptor located : In or on the surface of cell membrane as for protein ,peptide &catecholamine hormones. In the cell cytoplasm as for steroid hormones. In the cell nucleus as for thyroid hormones. After binding with the receptor some change the membrane permeability for ions , some activate intracellular enzymes ,some activate gens.

Hypothalamus

It is the portion of the anterior end of the diencephalon, it is divided into a variety of nuclei & nuclear areas the principal afferent & efferent neural pathways to & from the hypothalamus are mostly unmyelinated . Paraventricular neurons secrete oxytocin& vasopressin . An intrahypothalamic system of dopamine secreting neurons have cell bodies in the arcuate nucleus & end on or near the capillaries that form the portal vessels in the median eminence . There are neural connections between the hypothalamus & the posterior lobe of the pituitary gland & vascular connections between the hypothalamus & the anterior lobe .

THE HYPOTHALAMUS CONTROLS PITUITARY SECRETION

The major hypothalamic releasing &inhibitory hormones are:Thyrotropin-releasing hormone (TRH) which causes release of TSH.Corticotropin-releasing hormone (CRH) which causes release of adrenocorticotropin.Growth hormone releasing hormone (GHRH) causes release of GH & growth hormone inhibitory hormone (GHIH) also called somatostatin which inhibits release of GH.Gonadotropin –releasing hormone (GNRH) causes release of FSH &LHProlactin inhibitory hormone (PIH) inhibits PRL secretion.All or most of hypothalamic hormones are secreted at nerve endings in the median eminence before being transported to the anterior pituitary gland.

Hypophyseal portal system

All blood entering the portal system will reach the intended target cells before returning to the general circulation

Figure 18.8a

Figure 18.8 Feedback control of Endocrine Secretion

Figure 18.8b

Figure 18.8 Feedback control of Endocrine Secretion

Hormones of the Pituitary

Somatotropin (GH)- growth hormone; helps fat be used for energy Thyrotropin (TSH)- stimulates growth of the thyroid glandAdrenocorticotropic (ACTH)- stimulates growth of the adrenal glandMelanocyte (MSH) production of melanin pigment in the skinFollicle stimulating (FSH) – growth of the ovarian follicles, production of estrogen in females; & production of sperm in malesLuteinizing (LH) – stimulates ovulation and produces progesterone in females Prolactin (LTH) – develops breast tissue & secretion of milk from mammary glandsOxytocin (pitocin) – released during childbirth; causes contraction of the uterus during childbirthVasopressin/antidiuretic (ADH) – promotes reabsorption of water in kidneys, constricts blood vessels

THE PITUITARY GLAND

The anterior pituitary secrets six hormones : growth hormone (GH), adrenocorticotropin (ACTH) , thyroid stimulating hormone (TSH) , luteinizing hormone (LH) , follicle stimulating hormone (FSH) , prolactin (PRL) ..There are five cell types in the anterior pituitary:Somatotropes---human growth hormone.Corticotropes----ACTH.Gonadotropes—FSH&LH.Thyrotropes------TSH.Lactotropes------PRL.

The Posterior Pituitary Gland

Its also called the neurohypophysis or pars nervosa, contains the axones of some hypothalamic neurons. Neurons within the supraoptic & paraventricular nuclei manufacture : Antidiuretic hormone (ADH) also called vasopressin - Oxytocin


The posterior pituitary is made up of the endings of the axons that arise from the cell bodies in the supraoptic & the paraventricular nuclei & pass to the posterior pituitary via the hypothalamo-hypophysial tract , the portal hypophysial vessels form a direct vascular link between the hypothalamus & the anterior pituitary. The hormones of the posterior pituitary gland , oxytocin & vasopressin are nonapeptides synthesized in the cell bodies of the magnocellular neurons in the supraoptic & paraventricular nuclei & transported down the axons of these neurons to their endings in the posterior lobe, where they are secreted in response to the electrical activity in the endings. Vasopressin secreting neurons are found in the suprachiasmatic nuclei , & vasopressin & oxytocin are also found in the endings of neurons that project from the paraventricular nuclei to the brain stem & the spinal cord . These neurons appears to be involved in the cardiovascular control.

CHEMICAL STRUCTURES ADH AND OXYTOCIN

Both oxytocin and ADH are polypeptides , each containing nine amino acids. These two hormones are almost identical except that in vasopressin, phenylalanine and arginine replace isolucine and leucine of the oxytocin molecule .

EJECTION OF MILK (FUNCTION OF OXYTOCIN)

When baby suckles the breast , nerve signals transmitted to the spinal cord & then to the hypothalamus cause oxytocin secretion which result in contraction of myoepithelial cells surrounding the alveoli & ejection of milk . Generalized sympathetic stimulation inhibit oxytocin secretion & milk ejection . Other actions: oxytocin causes contraction of smooth muscle of the uterus. The sensitivity of uterine musculature to oxytocin is enhanced by estrogen & inhibited by progesterone , the inhibitory effect of progesterone is through direct effect on oxytocin receptors in the uterus . Oxytocin may also act on non- pregnant uterus to facilitate sperm transport . Circulating oxytocin is increased at time of ejaculation in males & it is possible that this increase causes increased contraction of smooth muscle of the vas deferens , propelling the sperm toward the urethra. .

PHYSIOLOGIC FUNCTIONS OF ADH

ADH decrease the excretion of water by the kidneys. 1.In the absence of ADH , the collecting tubules and ducts become almost impermeable to water , which prevents significant reabsorption of water and therefore allows extreme loss of water into the urine and causes dilution of urine . 2.In the presence of ADH , the permeability of collecting ducts and tubules to water increases greatly and allows most of the water to be re absorbed as the tubular fluid passes through these ducts , thereby conserving water in the body and producing very concentrated urine. .

REGULATION OF ADH PRODUCTION

1. Osmotic regulation Somewhere in or near the hypothalamus are modified neuron receptors called osmoreceptors . When the extracellular fluid becomes too concentrated , fluid is pulled by osmosis out of the osmoreceptor cell , decreasing its size and initiating nerve signals in the hypothalamus to cause ADH secretion . Conversely , when the extra cellular fluid becomes too dilute , water moves by osmosis in the opposite direction into the cell & this decreases signal for ADH secretion.

So concentrated body fluid stimulate the supraoptic nuclei , whereas dilute body fluids inhibit them . Higher concentrations of ADH have a potent effect of vasoconstricting the arterioles throughout the body , therefore increasing the arterial pressure . For this reason it is also called vasopressin . 2. One of the stimuli for causing ADH secretion is decreased blood volume , this occurs especially when the blood volume decreases 15-25 % , the secretory rate then sometimes rises to as high as 50 times normal . 3. The atria especially the right atrium have stretch receptors that are excited by overfilling , they signals to the brain to inhibit ADH secretion . 4. Decreased stretch of baroreceptors of the carotid , aortic & pulmonary regions , increases ADH secretion .

Growth Hormone (Somatotropin)

Most abundant pituitary hormone (10 - 15%)21 kDa protein91 amino acidsStructurally similar to prolactinHalf life = 20 –25 min; binds specific plasma proteins; increase half life for transport


Growth Hormone: Physiologic Effects
Promotes GrowthIncreases cell number in organsSkeletal growthCartilage formationCollagen biosynthesis (epiphysal plates)Muscle cell growthPromotes Protein SynthesisPositive nitrogen balanceIncreases amino acid uptakeDecreases urea excretionCarbohydrate and Lipid MetabolismPromotes fat usageSwitches metabolism from carbohydrate to fat blood glucose (ketosis ??)Exercise & Hypoglycemia GHFatty acid release from adipose

Growth Hormone Action

Growth Hormone Action
Synthesized and stored in Anterior PituitarySomatatrophs (specialized cells in AP)Most functions via somatomedinsGroup of peptide hormones produced predominantly in liver: insulin-like growth factors (IGF)IGF–1: homologous to insulin; binds to specific IGF-1 receptor; widely distributed; IGF-1 also produced in bone (controlled by parathyroid hormone and pGE2)IGF-2: produced in fetal tissue; important in fetal development; in adults important in brain, liver and kidney function; converted to IGF-1; binds IGF-1 receptor

Growth Hormone Action

Exercise, stress, sleep, low glucose
(+)

HYPOTHALAMIC & PERIPHERAL CONTROL OF GH

The secretion of GH is not stable over time . Adolescents have the highest level of circulating GH , followed by children,& finally adults .levels decline in old age. There are also diurnal variations .GH is found at relatively low levels at day,. During sleep, large pulsatile bursts of GH secretion occur. The hypothalamus control GH by GHRH , somatomedin, a third regulator of GH secretion is ghrelin which is secreted by the stomach but it is also produced by the hypothalamus & has marked GH stimulating activity . GH inhibits GHRH release at hypothalamic level.GH also increases circulating IGF-I & this inturn exerts a direct inhibitory action on GH secretion of the pituitary. It also stimulates somatostatin secretion.


GH
GH is increased by L- Dopa which increases the secretion of dopamine & norepinephrine in the brain & also by dopamine receptor agonist apomorphine. Hormonal effects on growth Plasma GH elevated in newborns .so average resting levels fall but the spikes of GH secretion are larger especially during puberty so the mean plasma level over 24 hours is increased , it is 2-4ng/ml in normal adults , but 5-8ng/ml in children . The growth spurt that occurs at time of puberty is due in part to the protein anabolic effect of androgens, & the secretion of androgens increase at this time in both sexes , however it is due to the interaction of sex steroids , GH & IGF-I.


Control of Growth Hormone Release
Hypothalamus Growth Hormone Releasing Hormone (GHRH): Stimulates GH releaseRelease is pulsatileCan be used in diagnosis of GH deficiencyBinds to specific receptors on somatotrophs in anterior pituitarySomatostatin (GHRIH): Blocks GH release from somatotrophsWidely distributed outside hypothalamusInhibits a variety endocrine and exocrine glandsinsulin levelsAffects other axes

GH Insensitivity (Laron dwarfism)

Somatomedin (IGF-1)
GH
Ghrelin GHRH Somatostatin

Diseases of Pituitary

Diabetes insipidus Decreased secretion of antidiuretic hormone (posterior lobe) that prevents water from being absorbed in kidneys leading to an excessive amount of water and electrolyte loss

Gigantism

Over-secretion of growth hormone prior to puberty. Excessive growth of long bones Treatment: drug therapy to inhibit GH release

Acromegaly

Over-secretion of growth hormone during adulthood usually from tumor Enlargement of the extremities and/or face Treatment: drug therapy to inhibit GH release

Dwarfism

Under-production of growth hormone during childhood Long bone growth is decreased Body is proportioned and intelligence is normal Treatment: early diagnosis & injections of GH for 5 or more yrs.

Prolactin

-Structure similar to GH-Glycoprotein hormone -Synthesized and stored in lactotrophs-Principally responsible for lactation-Effects on gonads- species specific-Concentration increases 20 –40x during pregnancy-Mechanism of action- binds to cell surface receptors

Physiological Effects of Prolactin

-Growth and development of breasts during pregnancy -Maintains lactation (in presence of estrogens, progesterone, insulin and corticosteroids) -Blocks effects of FSH and LSH; initially prevents lactation

Lies near the thyroid cartilage of the larynx Two lobes connected by an isthmus

The Thyroid Gland

The thyroid gland

Formation & secretion of thyroid hormones : The main hormones secreted by the thyroid are thyroxine(T4) &triiodothronine(T3) T3 is also formed in the peripheral tissues by deiodination of T4.both hormones are iodine containing amino acids.T3 is more active than T4. Iodied pump : The first stage in the formation of thyroid hormones is transport of iodieds from the blood into the thyroid glandular cells & follicles this is called iodied trapping , in normal gland the iodied pump concentrates the iodied to about 30 times its concentration in blood. the rate of iodide trapping is influenced by several factors , the most important is the concentration of TSH.

Thyroglobulin & chemistry of thyroxin & triiodothyronin formation

Thyroglobulin is a large glycoprotein molecule has a molecular weight of about 335,000.the molecule of thyroglobulin contains 70 tyrosine amino acids &they are the major substrates that combine with iodine to form thyroid hormones .thus thyroid hormones form within the thyroglobulin molecule . Thyroglobulin is synthesized in the thyroid cells & secreted into the colloid . the first step in the formation of thyroid hormones is conversion of iodide ions to an oxidized form of iodine , this oxidation of iodine is promoted by the enzyme peroxidase . tyrosine is first iodized to monoiodotyrosine (MIT) this is next iodinated to form diiodotyrosin (DIT).

Figure 18.12 The Thyroid Follicles

Figure 18.12a

Physiologic functions of thyroid hormones

Thyroid hormones increase cellular metabolic activity the BMR increase to 60-100% above normal when large quantities of hormone are released .the rate of utilization of foods for energy is accelerated ,the rate of protein synthesis is increased . thyroid hormones increase the number& activity of the mitochondria . thyroid hormones increase active transport of ions through cell membranes. 1.Effect of thyroid hormones on growth: The effect of thyroid hormones on growth manifest in growing children.

In those who are hypothyroid the rate of growth is retarded. In those who are hyperthyroid excessive skeletal growth occur causing the child to become taller at an earlier age. An important effect is to promote growth & development of the brain during fetal life &for first few years of postnatal life. 2.effects of thyroid hormones on specific bodily mechanisms: Stimulation of carbohydrate metabolism , it causes rapid uptake of glucose by cells , increased glycolysis , enhanced gluconeogenesis , increased insulin secretion. Stimulation of fat metabolism. Increased requirement for vitamins. Increased BMR. Decreased body weight.

3.Effect of thyroid hormones on cardiovascular system

Increased blood flow and cardiac output . Increased metabolism in the tissues causes more utilization of oxygen than normal & releases greater than normal metabolic end products from the tissues , these effects cause vasodilation so it increase blood flow & as a consequence cardiac output is increased . Increased heart rate . Increased heart strength when only slight excess of thyroid hormones is secreted , but when increased markedly the strength of heart muscle decrease . Normal arterial pressure :

4. Increased respiration : the increase in utilization of oxygen & formation of co2 increases the rate & depth of respiration . 5. Increased G.I.T motility : thyroid hormone increases both the rate of secretion of digestive juices & the motility of G.I.T . Diarrhea often result from hyperthyroidism while constipation from hypothyroidism . 6. Excitatory effects on the C.N.S : the hyperthyroid subject have extreme nervousness , anxiety . 7. Effect on the function of the muscles : increased thyroid hormone weakens the muscles because of protein catabolism , while hypothyroidism causes the muscle to become relax slowly after contraction .

8. Effect on sleep : the hyperthyroid subject often feels of constant tiredness and because of the excitable effect of thyroid hormone on the synapses its difficult to sleep . 9. Effect on other endocrine glands : increased thyroid hormones increase the rate of secretions of most endocrine glands . 10. Effect of thyroid hormones on sexual function : in men , lack of thyroid hormone cause loss of libido . In women , lack of thyroid hormone cause irregular perioids and even amenorrhea .

Regulation of thyroid hormone secretion

The anterior pituitary secretion of TSH is controlled by TRH which secreted by nerve endings in the median emninence of the hypothalamus , then TRH is transported to the anterior pituitary by way of hypothalamic – hypophysial portal blood . TRH is a tripeptide amide , it stimulates the anterior pituitary to secrete TSH .TSH also called thyrotropin , is a glycoprotein with a molecular weight of about 28000 , this hormone increases the secretion of thyroxin e& tri-iodothyronine by the thyroid gland .increased thyroid hormone in body fluids , decreases secretion of TSH by the anterior pituitary .

Diseases of the thyroid gland

Hyperthyroidism : The thyroid gland is increased 2 – 3 times normal size and increase thyroid secretion . Symptoms :Excitability .Intolerance to heat .Increase sweating . Weight loss .Diarrhea .Muscle weakness .Nervousness .Fatigue .Tremor of hands .


Hypothyroidism : Decreased thyroid hormone secretion . symptoms : Fatigue and sleep up to 12 -14 h / day . Slow heart rate and decreased cardiac output , decreased blood volume . Increased body weight . Constipation . Mental sluggishness . Husky voice . Decreased hair growth .

Thyroid Disorders

Figure 18.13

Diseases of Thyroid Gland

Hyperthyroidism Over-activity of thyroxin leading to enlargement of the gland Tx: total or partial removal of thyroid gland or radiation to suppress the activity Consume large quantities of food, but loss of body fat and weight


Grave’s disease Severe form of hyperthyroidism More common in women Symptoms: strained and tense facial expression, exophthalmia, goiter, nervous irritability
goiter
exophthalmos

Hypothyroidism

Under-secretion of thyroxin; due to los T3 & T4 levels or high TSH levels Adult hypothyroidism may be due to iodine deficiency Major cause due to inflammation of the thyroid which destroys the ability of the gland to make thyroxine Dry/itchy skin, dry/brittle hair, constipation, muscle cramps

Problems with the Thyroid Gland

Hypothyroidism in infant(cretinism) hyperthyroidism

Myxedema

Face becomes swollen, weight increases and memory begins to fail Treatment is daily thyroid hormone Follow-up tests to measure TSH blood levels are important
Cretinism
Develops early in infancy or childhood Lack of mental/physical growth resulting in mental retardation and malformation Sexual development and physical growth does not reach beyond 7-8 year old children Normal development cannot be completely restored w/ tx.

parathyroid glandcalcium & phosphate regulation in the extra cellular fluid & plasma

ECF calcium normal value 9.4 mg / dl (2.7 nmol / L ) .Calcium plays a key role in many physiological processes including : Contraction of skeletal ,cardiac and smooth muscle .Blood clotting .Transmission of nerve impulses .Only 0.1% of total body Ca is in the ECF , 17% is in the cells and the rest is stored in the bones .About 85% of the body s phosphate is stored in bones , 14 – 15 %is in the cells and less than 1% is in the ECF.

The calcium in the plasma is present in three forms :

1. About 41%( 1nmol / L) of calcium is combined with the plasma proteins . 2. About 9% ( 0.2 nmol / L) is combined with an ionic substances ( citrate & phosphate ) . 3. 50 % is ionized . Plasma Ca ion concentration is 2.4meq/ L

Figure 18.15

The Homeostatic Regulation of Calcium Ion Concentrations

Inorganic phosphate in extra cellular fluid

Inorganic phosphate in the plasma is mainly in two forms : HpO4 and H2PO4 . When the pH of ECF becomes more acidic , there is a relative increase in H2PO4 and decrease in HPO4 , the opposite occur when the ECF becomes alkaline . The average total quantity of Inorganic phosphate is about 4 mg / dlL.

Non –bone physiologic effect of altered Ca & phosphate concentrations in the body fluids. Hypocalcemia causes nervous system excitement & tetany . Hypercalcemia decreases nervous system & muscle activity . When ECF concentration of Ca ions falls below normal the nervous system becomes more excitable , because this causes increased neural membrane permeability to Na ions allowing easy initiation of action potential . At plasma Ca 50% below normal , the peripheral nerve fibers become so excitable that they discharge spontaneously initiating nerve impulses that pass to the peripheral skeletal muscles to cause tetanic muscle contraction . It also causes seizures because of its action of increasing excitability of the brain .


this pic. Shows carpopedal spasm .

Tetany occurs when the blood concentration of Ca falls from 9.4 mg / dl to about 6 mg / dl , which is only 35% below normal & is usually lethal at about 4 mg / dl .

When calcium level in the body fluids rises above normal , the nervous system becomes depressed & reflex activities of the nervous system are sluggish , also decrease the QT interval of the heart , constipation and lack of appetite .

These effects occur when the level of calcium rises above 12 mg / dl . when the level of calcium rises above 17mg /dl in blood , calcium , phosphate crystals precipitate throughout the body .

Absorption & excretion of calcium and phosphate

Intestinal absorption & fecal excretion . the usual rates of intake are about 1000 mg / day for calcium & phosphate , Ca are poorly absorbed from the intestine , vitamin D promotes its absorption by the intestine. about 35%( 350 mg / day ) of ingested calcium is usually absorbed , the remaining is excreted in the feces . an additional 250 mg of calcium enters the intestine via secreted G.I.T. juices thus90% ( 900 mg / day ) of daily intake of calcium is excreted in feces .

Intestinal absorption of phosphate occurs easily except from the portion of phosphate that is excreted in the feces in combination with non absorbed calcium , almost all the dietary phosphate is absorbed into the blood from the gut and later excreted in the feces .

Renal excretion of calcium & phosphate

About 10% ( 100 mg / day ) of ingested calcium is excreted in urine . About 41%of plasma calcium is bound to plasma proteins and therefore not filtered by the glomerular capillaries . The rest is combined with anions such as phosphate ( 9% ) or ionized 50% and is filtered through the glomeruli into the renal tubules . Normally renal tubules absorb 99% of the filtered calcium & about 100mg / day is excreted in urine . About 90%of calcium in the glomerular filtrate is reabsorbed in the proximal tubules , loop of Henle and early distal tubules , then in the late distal tubular and early collecting ducts ,reabsorption of remaining 10% is very selective , depending on calcium ion concentration in blood . When concentration is low , this reabsorption is great , so that almost , no calcium is lost in urine . Conversely , even a minute increase in blood calcium ion concentration above normal increases excretion markedly.

Renal phosphate excretion is controlled by an overflow mechanism that is when phosphate concentration in the plasma is below the critical value of about 1 mmol / L, all the phosphate in the glomerular filtrate is reabsorbed & no phosphate is lost in the urine . But above this critical concentration , the rate of phosphate loss is directly proportional to the additional increase .

Vitamin D

Vitamin D3 ( cholecalciferol ) is found in the skin . This is activated &converted to 25-hydroxycholecalciferol in the liver & this has a negative feedback effect on the conversion reactions .


25-hydroxycholecalciferol in the proximal tubules of the kidneys is converted to 1, 25-dihydroxycholecalciferol .this is the most active form of vitamin D .this conversion requires PTH .

This demonstrates that plasma concentration of 1, 25-dihydroxycholecalciferol is inversely affected by the concentration of calcium in the plasma.

There are 2 reasons for this :First : the calcium ion itself has a slight effect in preventing the conversion of 25-hydroxycholecalciferol to 1, 25-dihydroxycholecalciferol . Second : the rate of secretion of PTH is greatly decreased when plasma calcium ion concentration rises above 9 – 10 mg / 100ML , therefore , at calcium concentration below this level ,PTH promotes the conversion of 25-hydroxycholecalciferol to 1, 25-dihydroxycholecalciferol in the kidneys .At higher plasma calcium concentration when PTH is decreased , the 25-hydroxycholecalciferol is converted to 24, 25-dihydroxycholecalciferol that has no vitamin D effect .

Actions of vitamin D It promotes intestinal calcium absorption . It promotes phosphate absorption by the intestines . It decreases renal calcium and phosphate excretion . It plays an important role in both bone absorption & bone deposition .

Embedded in the posterior surface of the thyroid gland Chief cells produce parathyroid hormone (PTH) in response to lower than normal calcium concentrations Parathyroid hormones plus calcitriol are primary regulators of calcium levels in healthy adults
Four parathyroid glands
The Parathyroid Glands

Figure 18.14 The Parathyroid Glands

Figure 18.14

Parathyroid hormone

Normally there are 4 parathyroid glands in humans , they are located immediately behind the thyroid gland and behind each of the upper &each of the lower poles of the thyroid.

The parathyroid gland contains mainly chief cells which secret PTH .PTH is a polypeptide with 84 amino acids .

Effect of PTH on calcium & phosphate concentration in ECF

1. PTH increases calcium &phosphate absorption from the bone . 2. It decrease the excretion of the calcium by the kidney . 3. It increases renal phosphate excretion .

Effect of PTH on bone . PTH has 2 effects on bone in causing absorption of calcium & phosphate ; One Is rapid phase that begins in minutes & increasing progressively for several hours , this phase results from activation of the already existing bone cells to promote calcium and phosphate absorption . The second phase is a much slower one requiring several days or even weeks , it result from proliferation of the osteoclasts followed by increased osteoclastic reabsorption . Effect of PTH on renal tubules . PTH increases renal tubular reabsorption of calcium , at the same time it decreases phosphate reabsorption . The increase of calcium absorption occurs mainly in the late distal tubules , the collecting tubules & the ascending loop of Henle to a lesser extent.

Effect of PTH on intestine . PTH increases intestinal absorption of calcium & phosphate by increasing the formation of 1, 25-dihydroxycholecalciferol in the kidneys for vitamin D .

Control of PTH secretion by calcium ion concentration

Even the slightest decrease in calcium ion concentration in ECF causes the parathyroid glands to increase their rate of secretion within minutes , if the decreased calcium continue , the glands will hypertrophy , sometimes five folds . The parathyroid glands enlarge in rickets , in pregnancy and in lactation . Conversely conditions that increase Ca ion concentration above normal cause decreased activity & reduced size of parathyroid gland such condititions include : Excess calcium in the diet . Increased vit.D in the diet . Bone absorption caused by disuse of bones .

calcitonin

It is a peptide hormone secreted by the thyroid gland , it decreases plasma calcium concentration &has effects opposite to those of PTH . synthesis & secretion of calcitonin occur in the Para follicular cells or C cells , lying in the interstitial fluid between the follicles of the thyroid gland . The primary stimulus for calcitonin secretion is increased calcium ion concentration in plasma . The reduction of Ca ions concentration caused by calcitonin leads within hours to a powerful stimulation of PTH secretion which over rides the calcitonin effect .

Disease of Parathyroid

Hyperparathyroidism Over-activity of parathyroid resulting in increased calcium in the blood Leads of kidney stones, GI disturbances Bones become weak, deformed and fracture easily because calcium is drawn from the bone
Hypoparathyroidism Under-activity of parathyroid gland causing a low level of calcium in blood Tetany, hyperirritability of nervous system, twitching Death can occur if the larynx and respiratory muscles are involved.

Adrenal Gland

The two adrenal glands , each of which weighs 4 gm , lie at the superior poles of the kidneys


Each gland is composed of 2 parts , the adrenal medulla and adrenal cortex. The adrenal medulla ,central 20% of the gland , is functionally related to the sympathetic nervous system , it secrets the hormones epinephrine & norepinephrine in response to sympathetic stimulation . In turn these hormones cause almost the same effect as direct stimulation of the sympathetic nerves in all parts of the body . The adrenal cortex secretes corticoids . These hormones synthesized from the steroid cholesterol ,and they all have the similar chemical formulas .

The corticoids , mineralocorticoids ,glucocorticoids and androgens

Two major types of adrenocortical hormones , the mineralocorticoids & the glucocorticoids, are secreted by the adrenal cortex . In addition small amount of hormones are secreted , especially androgenic hormones which have the same effect of testosterone ( male sex hormone ) . Mineralocorticoids affect the electrolytes ( minerals ) of the ECF , sodium & potassium . Glucocorticoids they increase blood glucose concentration . The steroids include aldosterone & cortisols which are the principal glucocorticoids .

The Adrenal Gland

Figure 18.16

Synthesis and secretion of the adrenocortical hormones

The adrenal cortex has 3 distinct layers .


Zona glomerulosa: a thin layer of cells that lies just underneath the capsule , constitutes about 15% of the adrenal cortex . These cells secrete aldosterone because they contain the enzyme aldosterone synthase . The secretion of these cells is controlled by the ECF concentration of angiotensin II & potassium , both of which stimulates aldosterone secretion . Zona fasiculata : the middle and widest layer , constitutes about 75% of the adrenal cortex and secretes the glucocorticoids , cortisole and corticosterone as well as small amounts of androgens and estrogens . The secretion of these cells is controlled by the hypothalamic – pituitary axis via ACTH .

Zona reticularis : the deep layer of the cortex , secretes the adrenal androgens dehydroepiandrosterone (DHEA) and androstenedione , as well as small amounts of estrogens and some glucocorticoids. ACTH also regulates secretion of these cells .


Mineralocorticoids include :Aldosterone (very potent account for 90 % of all mineralocorticoids activity).Deoxycorticosterone (1 / 30 as a potent as aldosterone , but very small quantities secreted).Corticosterone ( slight mineralocorticoid activity ) 9 - Fluocorisol ( Synthetic, slightly more potent than aldosterone ) .Cortisol ( very slight mineralocorticoid activity, but large quantity secreted ).Cortisone ( Synthetic, slight mineralocorticoid activity ) .

Glucocorticoids : Cortisol ( very potent, account for about 95% of all glucocorticoids activity ). Corticosterone ( provides about 4% of total glucocorticoids activity, but much less potent than cortisol ). Cortisone ( synthetic, almost as potent as cortisol ). Prednisone (synthetic, four times as potent as cortisol). Methyl prednisone ( synthetic, five times as potent as cortisol) Dexamethasone ( synthetic, 30 times as potent as cortisol ). Approximately 90-95% of cortisol in the plasma binds to plasma proteins , especially globulin called cortisol-binding globulin or transcortin & to a lesser extent to albumin . Cortisol has half life of 60-90 minutes . Only about 60% of the circulating aldosterone combinds with the plasma proteins, so about 40% in the free form . Aldosterone has short half life of about 20 minutes .


The concentration of aldosterone in blood is about 6 nanograms/100 ml .The concentration of cortisol in the blood averages 12 mg /100 ml.Functions of the mineralocorticoids – aldosteroneRenal & circulatory effects of aldosterone :Aldosterone increases absorption of sodium and secretion of potassium by the renal tubular epithelial cells especially in the principal cells of the collecting tubule and to a lesser extent in the distal tubules and the collecting ducts. Therefore, aldosterone causes sodium to be conserved in the ECF while increasing potassium excretion in the urine .Excess aldosterone increases ECF volume and arterial pressure but has only small effect on the plasma sodium concentration, although, has a potent effect in decreasing the rate of sodium excretion by the kidneys, the concentration of sodium in the extra cellular fluids often rises only a few milli equivalents .

The reason for this is that when sodium is reabsorbed , there is simultaneous osmotic absorption of almost equivalent amount of water also small increase in ECF sodium concentration stimulate thirst and increased water intake .Therefore the ECF volume , increases almost as much as the retained sodium , but without much change in sodium concentration .An aldosterone – mediated increase in ECF volume last for 1-2 days also leads to an increase in arterial pressure , this increases kidney excretion of both salt and water called pressure natriuresis and pressure diuresis . This return to normal of salt and water excretion by the kidneys as a result of pressure diuresis and natriuresis is called aldosterone escape . Conversely , when aldosterone secretion becomes zero , large amounts of salt are lost in the urine , decreasing the ECF volume , the result is circulatory shock .

3. Excess aldosterone causes hypokalemia and muscle weakness . Too little aldosterone causes hyperkalemia and cardiac toxicity .Excess secretion of aldosterone causes serious decrease in plasma potassium concentration , sometimes from the normal value of 4.5 mg / L to as low as 2 mg / L this condition is called hypokalemia . When potassium ion concentration falls below about Ѕ normal severe muscle weakness often develops .Conversely , when aldosterone is deficient , the ECF potassium ion concentration can rise above normal , when it rises 60 – 100 % above normal cardiac toxicity occur , causes weakness of heart contraction and development of arrhythmia .

4. Excess aldosterone increases tubular hydrogen ion secretion , with resultant mild alkalosis . Aldosterone causes secretion of hydrogen ions in exchange for sodium in the intercalated cells of the cortical collecting tubules , this decrease the hydrogen ion concentration in the ECF . This effect usually causes a mild degree of alkalosis .


Aldosterone stimulates sodium and potassium transport in sweat glands , salivary glands & intestinal epithelial cells
Aldosterone has almost the same effects on sweat glands and salivary glands as it has on the renal tubules . Both these glands form a primary secretion that contains large quantities of sodium chloride , but much of this is reabsorbed by excretory ducts ,whereas potassium and bicarbonate ions are secreted . The effect on the sweat glands is important to conserve body salt in hot environment and the effect on salivary glands is necessary to conserve salt when excessive quantities of saliva are lost . Aldosterone also greatly enhances sodium absorption by the intestines especially in the colon which prevents lose of sodium in the stools . The absence of aldosterone leads to diarrhea , with loss of salt from the body .

Regulation of aldosterone secretion

Four factors play essential roles in the regulation ;Increased potassium ion concentration in the ECF greatly increases aldosterone secretion .Increase activity of the rennin – angiotensin system greatly increases aldosterone secretion .Increased sodium ion concentration in the ECF may slightly decrease aldosterone secretion .ACTH from the anterior pituitary gland is necessary for aldosterone secretion , but has little effect in controlling the rate of secretion .

Of these factors , K + concentration & the rennin – angiotensin system are the most potent in regulating aldosterone secretion .Activation of rennin – angiotensin system cause several fold increase in aldosterone secretion . In turn , the aldosterone acts on the kidneys ;To help the excrete the excess potassium ions .To increase blood volume & arterial pressure thus returning rennin – angiotensin system toward normal , these feedback control mechanisms are essential for maintaining life .

Functions of the Glucocorticoids

95% of the glucocorticoid activity of the adrenocortical secretion results from the secretion of cortisol , known also as hydrocortisone , in addition small but significant amount of glucocorticoid activity is provided by corticosterone .


Effect of cortisone on carbohydrate metabolism
Stimulation of gluconeogenesis . that is formation of carbohydrate from proteins & other substances by the liver this result mainly from two effects of cortisol : a. Cortisol increases the enzymes required to convert amino acids into glucose in the liver cells . b. cortisol causes mobilization of amino acids from the extra hepatic tissues mainly from muscle . 2. Decreased glucose utilization by the cells . 3. Elevated blood glucose concentration & adrenal diabetes .

Effect of cortisol on fat metabolism

Mobilization of fatty acids , this helps shift the metabolic system of the cells in times of starvation or other stresses from utilization of glucose for energy to utilization of fatty acids .Many people with excess cortisol secretion develop type of obesity , with excess deposition of fat in the chest & head regions of the body giving a buffalo like tor so and a rounded “ moon face “ this obesity result from excess food intake .

Cortisol is important in resisting stress & inflammation

Almost any type of stress causes an immediate & marked increase in ACTH secretion by the anterior pituitary followed by increased adrenocortical secretion of cortisol . Some different types of stress that increase cortisol release are the following ; Trauma , infection , intense heat or cold , injection of norepinephrine ,surgery , injection of necrotizing substances beneath the skin , any debilitating disease . Glucocorticoids cause rapid mobilization of amino acids & fats from their cellular stores making them immediately available both for energy & for synthesis of other compounds including glucose needed by different tissues of the body .

Anti-inflammatory effect of high levels of cortisol

When tissues are damaged by trauma ,by infection with bacteria , they almost become inflamed , the administration of cortisol can usually block this inflammation by ; 1. It can block the early stages of inflammation process . 2. If inflammation has already begun , it causes rapid resolution of the inflammation & increased rapidity of healing . Cortisol prevents shock or death in anaphylaxis .

Regulation of cortisol secretion by ACTH from the anterior pituitary

ACTH is a large polypeptide , has 39 amino acids .it is controlled by Corticotropin –releasing factor ( CRF) from the hypothalamus .

ACTH act on adrenocortical cells to produce steroids , Stress stimuli activate the entire control system to cause rapid release of cortisol & the cortisol in turn initiates a series of metabolic effects .there is direct feedback of the cortisol to both the hypothalamus & the anterior pituitary to decrease the concentration of cortisol in plasma . The secretory rate of CRF, ACTH & cortisol are high in early morning but low in the late evening .

Adrenal Androgens

The most important male sex hormone is dehydroepiandrosterone secreted by the adrenal cortex , also female sex hormones are secreted in small quantities as estrogen & progesterone some of the adrenal androgens are converted to testosterone in the extra-adrenal tissues. Abnormalities of adrenocortical secretion 1. Hypoadrenalism __ Addison s disease is failure of adrenal cortex to produce adrenocortical hormones . 2. Hyperadrenalism __ cushing s syndrome . 3. Primary aldosteronism __ conn s syndrome , tumor of zona granulosa.

Disease of Adrenal glands

Addison’s diseaseDecreased function of adrenal cortexExcessive pigmentation, low blood pressure when standing, muscular weakness/fatigue, diarrhea, wt. loss, vomitingTx. Replace hormone Cushing’s syndromeHypersecretion of glucocorticoidsCauses hyperglycemia, hypertension, poor wound healing, bruising, “moon” face and obesity

Pancreas

The pancreas is a nodular organ occupying a space between the stomach & small intestine. It contains both exocrine & endocrine cells. The exocrine pancreas secretes an enzyme-rich fluid into the lumen of the digestive tract. Cells of the endocrine pancreas form clusters called pancreatic islets (islets of Langerhans).Each islet contains 4 cell types: alpha cells produce glucagon;beta cells secrete insulin; &delta cells secrete somatostatin (growth hormone-inhibiting factor).F- cells secrete pancreatic polypeptide.(10% of the cells).Β- cells account for 60-75% of the cells in the islet.Α- cells account for 20% of cells of islet.

Insulin and its metabolic effects

Insulin was first isolated from the pancreas in 1922 . It is a small protein , has a molecular weight of 5808 . It is composed of two amino acid chains connected to each other by disulfide linkages . Insulin is synthesized in the beta cells , when insulin is secreted in the blood , it circulates in an unbound form , it has a plasma half life about 6 minutes , so that it is cleared from the circulation within 10-15 minutes . Insulin is degraded by the enzyme insulinase mainly in the liver & to a lessor extent in the kidneys & muscles , except that portion of insulin that combines with receptors in the target cells.

Effects of insulin

The effects are divided into rapid, intermediate & delayed actions. the rapid effect(seconds), is increased transport of glucose, A.A ,& K ion in insulin sensitive cells. Intermediate effect(minutes) are: Stimulation of protein synthesis. Inhibition of protein degradation. Activation of glycolytic enzymes & glycogen synthase. Inhibition of phosphorylase & gluconeogenic enzymes. Delayed effect(hours) increase in mRNAs for lipogenic & other enzymes.

muscle

Increase glucose entry. Increase glycogen synthesis. Increase amino acid uptake. Increase protein synthesis in ribosomes. Decreased protein catabolism. Decreased release of gluconeogenic amino acids. Increased ketone uptake. Increased K ion uptake ( insulin increase the sensitivity of Na-K ATPase in cell membrane.

Regulation of insulin secretion

Summary of Blood Glucose Regulation
In normal person , the blood glucose concentration between 80 -90 mg / dl in the fasting person . This concentration increases to 120-140 mg / dl during the first hour after meal , but the feedback system of glucose return the glucose concentration rapidly to the control level . Conversely , in starvation , the gluconeogenesis function of the liver provides glucose to F.B.S.

The mechanism of control as follows

The liver functions as an important blood glucose buffer system , that when blood glucose increases after meal 2/3 of glucose absorbed from the gut immediately stored in the liver in the form of glycogen. Then during the succeeding hours when both the blood glucose concentration &the rate of insulin secretion fall , the liver releases glucose back into the blood. 2. Both insulin & glucagon function as important feedback control systems for maintaining a normal blood glucose concentration , that when glucose concentration rises , insulin is secreted , the insulin decreases blood glucose concentration toward normal .

Conversely , decrease in blood glucose stimulates glucagon secretion , the glucagon increase the glucose toward normal . 3. In sever hypoglycemia , a direct effect of low blood glucose on the hypothalamus stimulates the sympathetic N.S. in turn epinephrine secreted by adrenal glands causes further release of glucose from the liver . 4. Over a period of hours & days both GH& cortisol are secreted in response to prolonged hypoglycemia , they both decrease the rate of glucose utilization by most cells of the body . Glucose is the only nutrient that normally can be used by the brain , retina &germinal epithelium of the gonads.

Factors that stimulate & inhibit insulin secretion

stimulators
GlucoseGastrin,secretin,CCKβ-ketoacidsAcetylcholineβ-adrenergic stimulatorsTheophyllinesulfonylureas inhibitors
Somatostatin Epinephrine& nor-epinephrine Propra nolol K ion depletion phenytoin

Diabetes mellitus

Diabetes mellitus is a syndrome of impaired carbohydrate, fat & protein metabolism caused by either lack of insulin secretion or decreased sensitivity of the tissues to insulin .ther are two types of diabetes mellitus: Type1 (IDDM) caused by lack of insulin secretion . Type 2(NIDDM) caused by decreased sensitivity of target tissues to the metabolic effect of insulin. In both types of diabetes , metabolism of all the foodstuffs is altered . The basic effect of insulin lack or insulin resistance on glucose metabolism is to prevent the efficient uptake & utilization of glucose by most cells of the body except those of the brain .

Glucagon and its function

Is a hormone secreted by the alpha cells of the islet of langerhans when the blood glucose concentration falls , has several functions that opposed to those of insulin . Most important of these functions is to increase the blood glucose concentration . Glucagon is a large polypeptide , it has a molecular weight of 3485 and is composed of 29 amino acids .

Effect of glucagon on glucose metabolism

The major effects of glucagon on glucose metabolism are:- Breakdown of liver glycogen ( glycogenolysis ). Increased gluconeogenesis in the liver . Both of these effects enhance the availability of glucose to the other organs of the body . Other effects of glucagon occur only when its concentration rises well above the maximum normally found in blood. The most important effect is that glucagon activates adipose cell lipase , making increased quantities of fatty acids .



Glucagon in very high concentration also :- Enhance the strength of the heart . Increase blood flow in some tissues . Enhances bile secretion . Inhibit gastric acid secretion .

Regulation of glucagon secretion

Increase blood glucose inhibits glucagon secretion : the blood glucose concentration is the most potent factor that controls glucagon secretion . That the effect of blood glucose concentration on glucagon secretion is exactly the apposite direction from the effect of glucose on insulin secretion

The decrease in the blood glucose concentration to hypoglycemic levels can increase the plasma concentration of glucagon several fold , conversely the blood glucose to hyperglycemic levels decreases plasma glucagon. 2. Increased blood amino acids stimulate glucagon secretion , it is the same effect on insulin secretion . glucagon promotes rapid conversion of amino acids to glucose . 3. Exercise stimulates glucagon secretion , in exhaustive exercise , the blood concentration of glucagon increase four fold to five fold .

Somatostatin inhibits glucagon & insulin secretion

The delta cells of the islet of Langerhans secrete somatstatin , which is a polypeptide containing 14 amino acids , it has short half life of 3 minutes . Almost all factors related to the ingestion of food stimulate somatostatin secretion . They include : Increased blood glucose . increased amino acids . Increased fatty acids . Increased concentrations of several of G.I.T. hormones.

In turn , somatostatin has multiple inhibitory effects : 1. somatostatin acts locally within the islets of Langerhans themselves to decrease the secretion of both insulin & glucagon . 2. somatostatin decreases the motility of the stomach , dudenum & gallbladder . 3. it decreases both secretion & absorption in the G.I.T.

Thymus

Mass of tissue found under the sternumActive in early life activating cells in the immune systemAtrophies during pubertyProduces only one hormone – thymosin which stimulates production of antibodies in early years

Small structure attached to the third ventricle in the brainLittle known about the glandSecreted 3 main hormones Melatonin – regulates sleep/wake cycle; may delay puberty by inhibiting sex hormonesAdrenoglomerulotropin – stimulates adrenal cortexSeratonin – prevent vasoconstriction of blood vessels in the brain Temporary endocrine gland produced only during childbirthEstrogen – stimulates growth of reproductive organsChorionic gonadotropin – causes ovaries to continue secretionsProgesterone – maintains lining of uterus to provide fetal nutritionPromotes milk production in breastsExpelled after birth of child“afterbirth” Pineal Body
Placenta

Pineal Gland

Secrets one hormone only : Melatonin Involved in your circadian rhythm (your recognition of day and night ) -- Melatonin secretion decreases in the day -- Melatonin secretion increases in the night Melatonin is thought to be involved in the female monthly cycle and may be in the onset of puberty

Ghrelin

So-called “hunger hormone” discovered in 1999Produced in fundus of stomach and arcuate nucleus of hypothalamusStimulates GH release in anterior pituitary via separate mechanism to GHRH, utilizes the Growth Hormone Secretagogue ReceptorImportant in hippocampus neurotrophy (learning effects)Increases food intake and fat mass-part of reward circuit (comfort food)Sleep increases levels (while lowering leptin levels)

Ghrelin

Disrupted ghrelin circadian rythmn in obese Promotes lung growth and development in the fetus Prader-Willi Syndrome characterized by high fasting levels Can be severely affected by gastric bypass surgery Obestatin is a converse hormone generated by differential splicing of ghrelin precursor Anti-obesity vaccine?