The Human Endocrine System

ENDOCRINE SYSTEM

Endocrine glands: glands that lack ducts (ductless), secrete hormones directly into the blood that affect target cells.

Exocrine glands are the ones that their secretions go via ducts to the lumen of other organs (like salivary glands leading to oral cavity ) or outside the body (sweat glands).

Hormones are biologically active molecules, that affect metabolism of their target organs, help regulate total body metabolism, growth, reprodution.

Neurohormones are secreted into blood by specialized neurons.

Why hormones affect only the target organ?Hormones are regulatory chemicals that work at a distance between organs traveling through the bloodstream from the gland to the target cell. The hormone binds only to cells having its receptor. Signaling can also be paracrine or autocrine.

Neural and Endocrine Regulation

• Both use chemicals to communicate • Some are used both as hormone and neurotransmitters

(NTs).• Differences:

• NTs diffuse across a synaptic cleft• Hormones are transported in blood. They have more

diverse effects on their targets.• Physiological regulation:

• Targets for both NTs and hormones must have specific receptor proteins

• Binding must cause a specific sequence of changes in the target cells

• Must be a mechanism to turn off the action of the regulator. The endocrine system rely on negative feedback mechanisms.

Hormones classes based on their chemistry• Amines: are hormones derived from 2 amino acids

(tryptophan and tyrosine) they include hormones secreted from:

1- Thyroid gland : T3 and T4. 2- Pineal gland : melatonine. 3- Adrenal medulla: epinephrine and norepinephrine.

• polypeptides: less than 100 aminoacids e.g ADH • Proteins: more than 100 aminoacids e.g Growth hormones.

• Glycoproteins: consist of polypeptides with one or more carbohydrate groups e.g: follicle stimulating hormone (FSH), Luteinizing hormone (LH) and thyroid stimulating hormone (TST).

• Steroids are lipids derived from cholesterol e.g progesterone, testesterone, estradiol, cortisol, aldosterone.

Lipid-soluble (hydrophobic)Water-soluble (hydrophilic)

Polypeptides Steroids

0.8 nmInsulin Cortisol

Amines

Epinephrine Thyroxine

Polarity of the hormones• Polar hormones – water-soluble.

– Polypeptides, glycoproteins hormones– Exception: melatonin derived from nonpolar amino acid tryptophan

can pass through the plasma membrane

• Nonpolar or lipophilic hormones – insoluble in water and can pass through plasma membrane of their target cells – Steroid hormones– Thyroid hormones: composed of the amino acid tyrosine with

iodine atoms

• Steroid and thyroid hormones are active when taken orally e.g contraceptive pills. Melatonine is also taken orally.

• Polypeptide and protein hormones are not given orally e.g insulin injections.

Prohormones and Prehormones• Prohormones – precursors molecules

– e.g. proinsulin is cut and spliced together to form insulin

• Prehormones – precursors of hormones– e.g. preinsulin

• Some hormones are inactive until activated by target cells

• The term prehormone designates the molecules secreted by endocrine glands but are inactive until they are changed into active form in their target cell

• e.g. thyroxine (T4) is inactive until converted to T3 in target cells

• Prehormone = T4 (inactive) T3 (active)

• Prehormone = Vit D3 (2 hydroxylations) 1,25 dihydroxyvit D3 (active).

Hormone Interactions• Target tissue usually responds to a number of different

hormones

1. Synergistic – two hormones work together – Produce a larger effect together than the added effect– e.g. norepinephrine and epinephrine on heart rate

-FSH and testesterone each is important in specific step in spermatogenesis; complimentary action.

-Estrogen, cortisol, prolactin, have complimentary effect on mammary glands to produce and secret milk.

2. Permissive effect – one hormone enhances theresponsiveness of a target organ to a second hormone– e.g. estradiol induces formation of receptors for

progesterone.– Low calcium levels in blood stimulates the release of

parathyroid hormone (PTH) which has Permissive effect Permissive effect on Vit. D. on Vit. D. PTH induces induces Vit D hydroxylations in liver and kidney 1,25 dihydroxy vit D increases Ca2+ reabsorbtion by intestine thereby rises Ca2+ level in the blood.

3. Antagonistic – action of one inhibits the effect of the other– e.g. lactation during pregnancy (high prolactin) inhibited by

estrogen (inhibits secretion and action of prolactin). – pancreatic islets secrete Insulin and Glucagon which has

Antagonistic effects.Antagonistic effects.

Hormone Interactions

Body cellstake up moreglucose.

Insulin

Beta cells ofpancreasrelease insulininto the blood.

Liver takesup glucose and stores itas glycogen.

Blood glucoselevel declines.

Blood glucoselevel rises.

Homeostasis:Blood glucose level

(70–110 mg/m100mL)

STIMULUS:Blood glucose level rises

(for instance, after eating acarbohydrate-rich meal).

Liver breaksdown glycogenand releasesglucose intothe blood.

Alpha cells of pancreasrelease glucagon intothe blood.

Glucagon

STIMULUS:Blood glucose level

falls (for instance, afterskipping a meal).

Hormone Levels and Tissue Responses

• Half-life – time required for plasma concentration of a hormone to be reduced by half– Ranges from minutes to hours for most (days for thyroid

hormones)

• Normal tissue responses produced only when hormones are within normal physiological range

• High (pharmacological) doses – cause side effects– Probably by binding to receptors of different but closely

related hormones

Hormone Levels and Tissue Responses

• Priming effect (upregulation)– a hormone induces more of its own receptors in target

cells– Results in greater response in target cell– e.g. GnRH secreted by the hypothalamus increases

sensitivity of anterior pituitary cells to further stimulation (upregulation of receptors)

• Desensitization (downregulation) – occurs after long exposure to high levels of polypeptide

hormone (e.g. adipose cells to insulin)– Subsequent exposure to this hormone produces a lesser

response (downregulation of receptors)– Most peptide hormones have pulsatile secretion

(spurts) which prevents downregulation

Mechanisms of Hormone Action

• Target cell receptors show– specificity, high affinity (strength of binding), and low capacity

(saturation) for a hormone• Lipophilic hormones

– have receptors in target's cytoplasm and/or nucleus – diffuse through plasma membrane – target is the nucleus where they affect transcription

• Called genomic action and takes at least 30 minutes

• Receptors for hydrophilic hormones – are on surface of target cell– These act through 2nd messengers; effects are quick– Some steroids also act on cell surface receptors

• Called nongenomic action

Mechanism of Steroid Hormones

• Lipid hormones travel in blood attached to carrier proteins– dissociate from carriers– pass through plasma

membrane to target cell

• Bind to receptors in the cytoplasm – nuclear hormone receptor

• Hormone-receptor complex translocates to nucleus binds DNA

• Genetic transcription and translation produce proteins

Nuclear Hormone Receptors

• Serve as transcription factors when bound to hormone ligands to activate transcription

• “Superfamily" – steroid family and thyroid hormone family – Also Vitamin D and

retinoic acid

Hormones That Use Second Messengers

• Water soluble hormones use cell surface receptors

• Actions are mediated by 2nd messengers – Hormone is the extracellular signal– 2nd messenger carries signal from receptor to inside of cell

• Adenylate Cyclase-cAMP 2nd Messenger System • cAMP mediates effects of many polypeptide and glycoprotein

hormones• Hormone binds to receptor causing dissociation of a G-protein

subunit that binds to and activates adenylate cyclase• Inhibitory subunit dissociates, activating protein kinase• Phosphorylates enzymes that produce hormone’s effects• cAMP gets inactivated by phosphodiesteras

Adenylate Cyclase-cAMP• Binding converts ATP into cAMP – attaches to inhibitory subunit of

protein kinase

Table 11.4

Phospholipase-C-Ca2+

2nd Messenger System• Serves as 2nd messenger system for some hormones• Hormone binds to surface receptor activates G-protein

activates phospholipase C

Phospholipase-C-Ca2+

• Phospholipase C splits a membrane phospholipid into 2nd messengers IP3 and DAG• IP3 diffuses through cytoplasm to ER causing Ca2+ channels to open

• Ca2+ diffuses into cytoplasm and binds to and activates calmodulin• Ca2+-Calmodulin activates protein kinases

– phosphorylate enzymes that produce hormone's effects

Endocrine Glands

Many endocrine glands are organs whose primary function is hormone secretion.

Some are mixed glands: e.g the pancreas is an endocrine and exocrine gland.

Steroids are secreted by only the adrenal cortex and the gonads (testis & ovary).

Pituitary Gland• Located beneath hypothalamus at base of forebrain• Also called hypophysis

Pituitary Gland

• Structurally & functionally divided into anterior and posterior lobes

• Hangs below hypothalamus by infundibulum

• Anterior produces own hormones– Controlled by

hypothalamus

• Posterior stores and releases hormones made in hypothalamus

Posterior Pituitary Gland• Stores and releases

vasopressin also called antidiuretic hormone (AVP or ADH) and oxytocin – Hormones are made in

the hypothalamus

• Supraoptic nuclei of hypothalamus produce ADH

• Paraventricular nuclei produce oxytocin

• Both are transported along hypothalamo-hypophyseal tract to posterior pituitary

Hypothalamic Control of Posterior Pituitary

Neurons in the hypothalamus called neurosecretory cells produce Antidiuretic hormone (ADH) that promotes reabsorption of water from the collecting ducts in the kidneys.

ADH is released upon stimulation of osmoreceptors in the hypothalamus in response to rise in blood osmolality. An increased osmotic pressure increases the frequency of action potentials in the neurons that produce ADH this causes the opening of voltage-gated Ca+ channels which causes the release of ADH by exocytosis.

ADH secretion is inhibited by sensory input from stretch receptors in the left atrium which are stimulated by a rise in blood volume. As the blood becomes dilute, ADH is no longer released; this is a case of negative feedback.

Oxytocin stimulates uterine muscle contraction during parturition

It also stimulates the release of milk from mammary glands.

The mechanical stimulus of suckling acts via sensory nerve impulses to the hypothalamus to stimulate the reflex secretion of oxytocin.

The Oxytocin causes contraction of myoepithelial cells in mammary glands and milk begins to flow.

This mechanism is called milk letdown or milk ejection

Oxytocin

Anterior Pituitary Gland

• Secretes 6 trophic hormones

• Maintain size of target organs:

1. High blood levels cause target to hypertrophy

2. Low levels cause atrophy

Anterior Pituitary

• Releasing and inhibiting hormones from hypothalamus– released from axon

endings into capillary bed in median eminence

– Carried by hypothalamo-hypophyseal portal system to another capillary bed

– Diffuse into and regulate secretion of anterior pituitary hormones

Anterior Pituitary

• 1. Stimulation by the hypothalamus controls the release of anterior pituitary hormones through a portal system consisting of two capillary systems connected by a vein.

• 2. The hypothalamus produces hypothalamic-releasing and hypothalamic-inhibiting hormones which pass to the anterior pituitary by this portal system.

E.G• Thyroid-releasing hormones (TRH) released from the

hypothalamus act on cells in the anterior pituitary to stimulate the production and secretion of a specific hormone TSH.

• Prolactin – inhibiting hormone ( PIH) it inhibits secretion of prolactin hormone by anterior pituitary gland.

Anterior Pituitary1. Growth hormone (GH) promotes growth, protein synthesis,

and movement of amino acids into cells

2. Thyroid stimulating hormone (TSH) stimulates thyroid to produce and secrete T4 and T3

3. Adrenocorticotrophic hormone (ACTH) stimulates adrenal cortex to secrete cortisol, aldosterone

4. Follicle stimulating hormone (FSH) stimulates growth of ovarian follicles and sperm production

5. Luteinizing hormone (LH) causes ovulation and secretion of testosterone in testes

6. Prolactin (PRL) stimulates milk production by mammary glands

The anterior pituitary produces six different hormones.a. Four of these anterior pituitary hormones affect other glands.

• 1) The thyroid-stimulating hormone (TSH) stimulates the thyroid gland to produce and secrete thyroxin (T4).

• 2) Adrenocorticotropic hormone (ACTH) stimulates the adrenal cortex to release cortisol.

• 3) Gonadotropic hormones (follicle-stimulating hormone [FSH] and luteinizing hormone

• [LH]) act on the gonads (ovaries and testes) to secrete sex hormones.

• b. The other two hormones do not affect other glands.• 1) Prolactin (PRL) causes the mammary glands to

produce milk.• b) It also plays a role in carbohydrate and fat

metabolism.

• 2) Growth hormone (GH or somatotropic hormone)• a) GH promotes skeletal and muscular growth.• b) GH acts to stimulate the transport of amino acids into

cells and to increase the activity of ribosomes.

The hypothalamic-pituitary-gonad axis

• The hypothalamic-pituitary-gonad axis (control system)

• Involves negative feedback by target gland hormones

Higher Brain Function and Anterior Pituitary Secretion

Hypothalamus receives input from higher brain centers – can affect anterior pituitary secretion– e.g. emotional states and psychological stress can

affect circadian rhythms, menstrual cycle, and adrenal hormones

Adrenal Glands

• Suprarenal glands – sit on top of kidneys

• Each consists of outer cortex and inner medulla– arise differently during

development

Adrenal Glands• Medulla synthesizes and secretes 80% epinephrine and 20%

norepinephrine– Controlled by sympathetic division of autonomic nervous

system

• Cortex is controlled by ACTH and secretes:– Cortisol which inhibits glucose utilization and stimulates

gluconeogenesis (generation of glucose from non-carbohydrate carbon substrates hence helps elevate blood glucose levels)

– Aldosterone which stimulate kidneys to reabsorb Na+ and secrete K+ regulate the levels of minerals in the blood

– And some supplementary sex steroids (the adrenal cortex also secretes a small amount of both male and female sex hormones in both sexes).

Adrenal Cortex

Glucocorticoids

Cortisol promotes the breakdown of muscle protein into amino acids taken up by the liver from the blood.

Cortisol breaks down fatty acids rather than carbohydrates; cortisol therefore raises blood glucose levels.

Cortisol counteracts the inflammatory response

The primary target organ of Aldosterone is the kidney where it promotes the reabsorption of Na+ and the excretion of K +.

Atrial natriuretic hormone (ANH) causes the excretion of sodium.

1) When the atria of the heart are stretched due to increased blood volume, cardiac cells release ANH.

2) ANH inhibits the secretion of aldosterone from the adrenal cortex.

3) When sodium is excreted, so is water; the blood volume and pressure then return to normal.

Mineralocorticoids

Regulation ofBlood Pressure and Volume

Adrenal Medulla

• Hormonal effects of epinephrine last 10X longer than norepinephrine

• Innervated by preganglionic Sympathetic fibers

• Activated during "fight or flight" response– Increased respiratory rate – Increased heart rate and cardiac output– General vasoconstriction which increases venous return– Glycogenolysis and lipolysis

Stress and the Adrenal Gland

• Stress induces a non-specific response: general adaptation syndrome (GAS)

• Causes release of ACTH and cortisol

CRH : corticotropin releasing hormone

Stress and the Adrenal Gland

• Chronic stress can induce high levels of cortisol that cause a number of negative effects:– atrophy of hippocampus (involved in memory)– reduced sensitivity of tissues to insulin (insulin resistance)– inhibition of vagus nerve activity– suppression of growth hormone, thyroid hormone, and

gonadotropins

• Exogenous glucocorticoids used to supress the immune response and inhibit inflammation such as in asthma & rheumatoid arthritis. They have side effects like hyperglycemia and osteoporosis.

(b) Long-term stress response and the adrenal cortex

Stress

Releasinghormone

Hypothalamus

Anterior pituitary

Blood vessel

ACTH

Adrenal cortexsecretes mineralo-corticoids andglucocorticoids.

Effects of mineralocorticoids:

Effects of glucocorticoids:

• Retention of sodium ions and water by kidneys

• Increased blood volume and blood pressure

• Proteins and fats broken down and converted to glucose, leading to increased blood glucose

• Partial suppression of immune system

Adrenalgland

Kidney

Spinal cord(cross section)

(a) Short-term stress response and the adrenal medulla

Stress

Nervesignals

Nervecell

Nerve cellAdrenal medullasecretes epinephrineand norepinephrine.

Adrenalgland

Kidney

Effects of epinephrine and norepinephrine:

• Glycogen broken down to glucose;increased blood glucose

• Increased blood pressure• Increased breathing rate• Increased metabolic rate• Change in blood flow patterns, leading to

increased alertness and decreased digestive,excretory, and reproductive system activity

Hypo-thalamus

Thyroid Gland• Located just below the larynx• Secretes T4 and T3 which set

basal metabolic rate (increase the metabolic rate; there is no one target organ—all organs respond)– needed for growth, development

– Secrete also calcitonin that lowers the calcium level in the blood and increases deposits of calcium in the bone

• Consists of microscopic thyroid follicles– Outer layer follicle cells

synthesize T4

– Interior filled with colloid, a protein-rich fluid

A scan of the thyroid 24 hrs. after intake of radioactive iodine

Figure 11.22

Parathyroid Glands

• 4 glands embedded in lateral lobes of posterior side of thyroid gland

• Secrete Parathyroid hormone (PTH) – Most important hormone for

control of blood Ca2+ levels

11-62

Parathyroid Hormone

• Release is stimulated by decreased blood Ca2+

• Acts on bones, kidney, and intestines to increase blood Ca2+ levels

Under the influence of PTH, the calcium level in blood increases and the phosphate level decreases.

PTH stimulates • the retention of Ca2+ (& excretion

of phosphate) by the kidney.• demineralization of bone by

promoting the activity of osteoclasts.

• Vit D promotes the intestinal absorption of Ca2+.

Regulation of Blood Calcium Level

Activevitamin D

Increases Ca2

uptake inintestines

Stimulates Ca2

uptake in kidneys

Stimulates Ca2 releasefrom bones

Parathyroidgland (behindthyroid)

PTH

Blood Ca2

level rises.

Homeostasis:Blood Ca2 level

(about 10 mg/100 mL)

STIMULUS:Falling blood

Ca2 level

Islets of Langerhans• Scattered clusters of endocrine cells in pancreas• Contain alpha and beta cells• Diabetes mellitus is a fairly common disease

Islets of Langerhans – Alpha Cells

• Alpha cells secrete glucagon in response to low blood glucose– Stimulates glycogenolysis and lipolysis – Increases blood glucose

Islets of Langerhans – Beta Cells

• Beta cells secrete insulin in response to high blood glucose– Promotes entry of glucose

into cells– And conversion of glucose

into glycogen and fat– Decreases blood glucose

level

11-67

Regulation of Blood Glucose Level

Pineal Gland

• Located in basal forebrain near thalamus

• Secretes melatonin in response to activity of suprachiasmatic nucleus (SCN) of hypothalamus

Pineal Gland

• SCN – primary timing center for circadian rhythms– Reset by daily light/dark changes

• Melatonin – is involved in sleep/awake cycle

– Secreted at night and inhibited by light– Implicated in jet-lag

The pineal gland may also be involved in human sexual development; children in whom a brain tumor has destroyed the pineal gland experience puberty earlier.

Thymus Gland1. The thymus gland is a lobular gland that lies

just beneath the sternum in the upper thoracic cavity.

2. It reaches its largest size and is most active during childhood; with age, it shrinks and becomes fatty.

3. Some lymphocytes that originate in the bone marrow pass through the thymus and change into T lymphocytes.

4. The thymus produces thymosins, which aid in the differentiation of T cells and may stimulate immune cells.

The ovaries, located in the pelvic cavity, produce the female sex hormones estrogens and progesterone.

a. Estrogens secreted at puberty stimulate the maturation of ovaries and other sexual organs.

b. Estrogen is necessary for oocyte development.c. It is responsible for the development of female

secondary sex characteristics: a layer of fat beneath the skin, a larger pelvic girdle, etc.

d. Estrogen and progesterone are required for breast development and the regulation of the uterine cycle.

Sex Hormones

• Testosterone normally is the reason men have larger muscles than women.

• It is responsible for the development of male secondary sex characteristics.

• Anabolic Steroids: are synthetic drugs very similar in structure and action to male hormone testosterone.

The Effects of Anabolic Steroid Use

Local regulators such as prostaglandins (PG) are produced by certain cells and act on neighboring cells.

PG functions• They cause the contraction of uterine muscle• They mediate the effects of pyrogens (chemicals believed to

affect the temperature regulatory center of the brain).• Certain prostaglandins reduce gastric secretions, others

lower blood pressure.d. Aspirin reduces temperature and controls pain because of

its effect on prostaglandins (inhibits cyclooxygenase, the enzyme that synthesizes PGs).

Paracrine & Autocrine regulation

Endocrine gland

Major hormone

Target tissue

Effect

Adipose tissue

leptin Hypo- thalamus

Suppresses appetite

heart Atrial natriuretic hormone

kidneys Promotes secretion of Na+ in urine

Small intestine

Secretin, CKK Stomach, liver & pancreas

Inhibits gastric motility, stimulates secretion of bile & pancreatic juice

kidneys Erythro- poietin

Bone marrow

Stimulates RBC production

skin 1,25 dihydroxyvit D3

Small intestine

Stimulates absorption of Ca 2+

stomach gastrin stomach Stimulates acid secretion

Thymus thymopoietin Lymph nodes

Stimulates WBC production ( Lymphocyte )