18 hormone course كورس الهرمونات

Endocrine Regulation

Cells Communicate by Chemical Signals

• Exocrine glands release their secretions into ducts – e.g., sebaceous glands

• Endocrine glands are ductless and secrete directly into the surrounding interstitial fluid or blood

• Hormones usually diffuse into capillaries

• Neuroendocrine cells provide a link between the nervous and endocrine systems

• A hormone that acts on the cells which produce it is classified as an autocrine regulator

• Other hormones act on cells both close in proximity and distant, and are known as paracrine regulators

• Local hormones act as paracrine regulators

• e.g., histamine

Hormones: Four Chemical Groups

• Fatty acid derived hormones include such compounds as prostaglandin and juvenile hormone

Steroid Hormones

• Steroid hormones are synthesized from cholesterol, and include testosterone, estradiol, and ecdysone

Amino Acid Derivatives

• Amino acid derivatives include the simplest peptide hormones

• Thyroid hormones, epinephrine, and norepinephrineare amines synthesized from tyrosine

Peptide Hormones

• Protein (peptide) hormones include short chains such as oxytocinand ADH and longer

chains such as growth hormone and TSH

Hormone Secretion Regulation: Negative Feedback Mechanisms

• Vertebrate endocrine glands constantly secrete at least a small amount of hormone product

• Hormones are constantly circulating free or bound to plasma proteins

• Hormones are removed from circulation by target tissues, the liver, and the kidneys

• Negative feedback mechanisms regulate secretion of most hormones

• High concentration of a hormone or some other substance – such as a metabolic derivative or product of hormone activity – inhibits further secretion

Negative Feedback: Parathyroid Hormone

Hormone Receptors

• Hormones receptors are proteins in target cells

• Hormones may bind to receptor proteins and thereby affect the metabolism of the target cell

• May up-regulate or down-regulate their receptors

• The receptor may act as a signal transducer; changing the signal of the hormone to an intracellular signal

• Hormones may work synergistically

Hormones May Interact With Genes

• Steroid hormones and amino acid derivatives are small and lipid-soluble, and therefore may pass through the plasma membrane of the target cell by simple diffusion

• Such hormones may bind with protein receptors on the nuclear membrane or in the nucleus, leading to the synthesis of RNA coding for particular proteins that cause the ultimate effect of the hormone

Gene Activation by Steroid Hormones1. Steroid is secreted

2. Passes into cell

3. Into nucleus

4. Binds receptor, DNA

5. Activates or represses transcription

6. Controls translation

7. Peptide alters cellular activity

Signal Transduction

• Some hormones work through second messengers

• This type of hormone does not enter the cell

• The receptor in thecell membrane of the target cell relays the message to a second messengerwithin the cytoplasm

Second Messengers: G Proteins

• Two main types of systems: enzyme-linked and G protein-linked

• G-protein linked receptors are transmembrane proteins that loop 7 times through the plasma membrane

• Receptor activates G protein, which binds GTP

• When inactive, G protein is bound to GDP (guanosinediphosphate)

• G proteins interact with adenylyl cyclase, which makes cAMP

• Gs stimulates adenylyl cyclase

• Gi inhibits adenylyl cyclase

• When the hormone binds to a stimulatory receptor, the G protein releases GDP and binds to GTP

• Binding of the G protein to GTP enables it to activate adenylyl cyclase

cAMP• Cyclic AMP is most common second

messenger in animal cells; identified by Earl Sutherland in the 1960s

• Hormones bind receptors, and membrane-bound adenylyl cyclase is activated via the G protein

• Adenylyl cyclase catalyzes the conversion of ATP to cAMP

• cAMP activates protein kinases

• Protein kinases catalyze the phosphorylation of a specific protein, which triggers a chain of reactions leading to the particular metabolic effect of the hormone

• Protein kinases are very specific in action

• cAMP is rapidly inactivated and converted to AMP

Action of cAMP Kinases on Cells

Protein Kinases

• Protein kinases phosphorylate proteins –i.e. they add one or more phosphates

• The change in charge at that site makes major changes in the conformation, affects activity

• cAMP is inactivated by phosphodiesterases, which quickly act to downregulate its activity

Calcium Ions

• Calcium ions can act as second messengers

• The non-stimulated cytoplasmic calcium concentration is very low; some stimulation events cause transient elevation of intracellular calcium

• Calcium can bind proteins and regulate cellular function as a result

• One example of such calcium – protein binding is the calcium-calmodulin (CaM) complex

Ca++ Based Regulation

• Calcium entry can occur in response to a G-protein stimulated event

• The calcium may bind CaM and activate a protein kinase that may go on to regulate other cellular events

IP3 and DAG• Phospholipid products

can act as second messengers

• Phosphatidyl inositol 4,5 bisphosphate is split into inositol trisphosphate (IP3) and diacylglycerol(DAG)

• IP3 causes the release of Ca++ from the ER

• DAG goes on to activate protein kinase C (PKC) along with the Ca++ -CaM complex

• PKC in turn phosphorylates protein that go on to generate various cellular effects

Hormone Signal Amplification

• Hormone signals can be amplified

• A single hormone-receptor complex can induce the production of many cAMP molecules; this amplifies the strength of the response

The Hypothalamus

• Links the vertebrate nervous and endocrine systems

• Vertebrate hormones regulate growth, development, fluid balance, metabolism, and reproduction

• Homeostasis depends on normal concentrations of hormones

• Endocrine disorders may involve too little or too much hormone, or receptor

• Hypersecretion may cause over-stimulation of target cells, or paradoxically, under-stimulation due to down-regulation of receptors

• Hyposecretion may cause under-stimulation of target cells

• Disruption of normal function endangers homeostatic systems

Human Endocrine

Glands

• In the brain:

• Hypothalamus

• Pituitary gland

• Pineal gland

• Adrenal gland

• Pancreas

• Ovary

• Testis

Hypothalamus and Pituitary

• The hypothalamus regulates the pituitary gland (also called the hypophysis), a small, pea-size gland on a thin stalk located under the brain in a depression in the sphenoid bone under the brain

• The hypothalamus links the nervous and endocrine systems

• Neurons of the hypothalamus secrete neurohormones whichtarget the release of hormones by the pituitary gland

• The pituitary secretes at least 7 distinct hormones that have a wide variety of target cells and effects

• The pituitary of humans consists of an anterior and posterior

lobe

The Posterior Pituitary

• The posterior lobe of the pituitary gland releases hormones produced by the hypothalamus

• Oxytocin and antidiuretic hormone ADH (vasopressin) are peptide hormones released by the posterior lobe

• These hormones are produced by neurons in the hypothalamus, and travel to the posterior lobe via the axons of the neurons

• Vasopressin regulates water reabsorption in the kidneys

• Oxytocin stimulates uterine contractions during labor

• Oxytocin also stimulates contraction of muscle cells in the breast while nursing, resulting in expulsion of milk

Activity of the Posterior Pituitary

• Releases ADH

• Increases kidney tubule permeability

• Increases water reabsorption

• Releases oxytocin

• Causes uterine contractions,

• Causes milk release

The Pituitary Anterior Lobe • Anterior lobe of the pituitary gland regulates growth and other

endocrine glands

• Tropic hormones stimulate other endocrine glands

• Releasing hormones and inhibiting hormones produced by the hypothalamus affect the production of hormones produced by the anterior pituitary

• These hormones reach the pituitary by a portal system

• Growth hormone (GH, also called somatotropin) stimulates protein synthesis and therefore growth – is anabolic

• GH stimulates liver cells to produce somatomedins,

• Stimulate skeletal growth and elongation

• Stimulates the growth of cartilage at the epiphyseal plates

• Stimulates general growth of tissues

• GH promotes mobilization of fat and carbohydrate metabolism

The Anterior Lobe

Hormones Released by the Pituitary

TRH

(+)

Hypothalamus

PIF

(-)

GnRH

(+)

CRH

(+)

Somatostatin

(-)

Releasing factorsfrom hypothalamus

Anterior. Pituitaryhormones

LH

&

FSH

Growth

• Growth is affected by many factors

• GH is secreted in pulses during the day in both adults and children

• The hypothalamus secretes GHRH (growth hormone-releasing hormone) and GHIH (growth hormone-inhibiting hormone, also called somatostatin) which signals the pituitary

• Secretion of GH increases during exercise and during sleep

• Emotional support is necessary for production of GH; lack results in psychosocial dwarfism

• Thyroid hormones and sex hormones also interact in the growth process

GH: Improper Release

• Inappropriate amounts of growth hormone secretion result in abnormal growth

• Pituitary dwarfs are a result of hyposecretion

• Recombinant GH may now be used to treat this condition

• Gigantism results from juvenile hypersecretion

• Acromegaly results from adult hypersecretion of GH

• Bones of the face, hands, feet thicken and become much heavier

Thyroid Hormones• Thyroid hormones increase metabolic rate

• The thyroid produces thyroxine (T4) and triiodothyronine (T3) by combining iodine and the amino acid tyrosine

• Collectively known as thyroid hormones

• Increase the metabolic rate

• Regulated by negative feedback mechanisms

• When thyroid hormone concentration drops, the pituitaryproduces thyroid stimulating hormone (TSH), which stimulates the thyroid to produce thyroid hormones

• When too high, thyroid hormones stimulate the hypothalamus to inhibit its production of TSH-releasing hormone

• Very cold weather stimulates the hypothalamus to increase production of TSH-releasing hormone

• Raises body temperature, limits secretion of thyroid hormone

• TSH acts by way of cAMP to promote production and release of thyroid hormones

Thyroid Hormone Regulation

• Stimulatory pathways are in green; negative feedback pathways are in red

• T3 and T4 feed back on the hypothalamus and the anterior pituitary, thereby limiting their own production

Effects of Thyroid Malfunction• Juvenile hypothyroidism may lead to cretinism, which is

characterized by retarded mental and physical development

• Adult hypothyroidism is characterized by a sluggish metabolic rate

• Extreme adult hypothyroidism causes myxedema (slowing down of mental and physical activity), and may be treated by thyroid hormone administration

• Hyperthyroidism increases metabolism, but not growth

• The most common cause of hyperthyroidism is Grave’s disease, which is an autoimmune disorder

• An enlarged thyroid is a goiter and can be associated with either hypersecretion or hyposecretion

• Iodine deficiency in the diet is a common cause of goiter

• The goiter is a greatly enlarged thyroid gland, the result of over-secretion of TSH by the anterior pituitary due to the lack of thyroid hormone

The Parathyroid Glands

• The parathyroid glands regulate calcium concentration

• The parathyroid glands are embedded in tissue surrounding the thyroid gland

• Produces parathyroid hormone (PTH) acts to increase blood calcium concentrations

• Stimulates calcium release from the bones

• Stimulates calcium reabsorption from the kidney tubules

• Increases intestinal calcium absorption from food

• Calcitonin produced by the thyroid acts in opposition to PTH

• Inhibits osteoclast-based release of Ca++ from bone

• Decreases reabsorption of Ca++ from kidney tubules

Activity Of The Parathyroid Glands

Pancreatic Regulation of Blood Glucose

• The islets of Langerhans are the endocrine tissues of the pancreas

• ~ 1,000,000 in the pancreas

• Beta cells secrete insulin and alpha cells secrete glucagon

• Insulin lowers the concentration of glucose in the blood

• Stimulates cells to take up glucose, to be used immediately or stored as glycogen

• Stimulates the storage of fats and promotes protein synthesis

• Glucagon raises the concentration of glucose in the blood

• Acts in opposition to insulin; mobilizing fatty acids, glucose and amino acids

Hormonal Regulation of Blood Glucose

• The beta cells and alpha cells work in opposition to each other;

• Beta cells’ secretion of insulin decreases glucose

• Alpha cells’ secretion of glucagon increases:

• Glycogenolysis – the production of glucose from liver glycogen

• Gluconeogenesis –the production of glucose from sources other than glycogen

Diabetes mellitus

• A serious disorder of carbohydrate metabolism

• Is the most common endocrine disorder, serious cases may cause blindness, and complications which may lead to death

• Most diabetics have type 2 diabetes (non-insulin dependentdiabetics; NIDD)

• Type 2 diabetics lack functional receptors on target cells

• Most common in adults who are overweight

• Has a slow onset

• Insulin-dependent diabetes (type 1 diabetes, or IDD) typicallydevelops before age 30, and is due to a decline in the number of beta cells

• Daily insulin injections may be necessary for correction

• Type 1 diabetes is an autoimmune disorder

Effects of Diabetes

• Diabetes results in hyperglycemia

• High glucose may exceed the Tm for glucose, which is then excreted into the urine

• Thus, high sugar level will fall after kidney clearance of the glucose

• Fat stores are mobilized, and may lead to atherosclerosis

• Increased fat metabolism results in formation of ketone bodies, which can build up and cause ketoacidosis; blood and body fluids become acidic

• Can lead to coma and death

• Protein stores are depleted

• Electrolyte imbalance

• Excretion of ketone bodies and glucose is accompanied by additional water loss to the urine by osmosis

• Ketones also carry Na+ and K+ with them

• In addition excessive drinking because of thirst causes electrolyte imbalance

Hypoglycemia

• In hypoglycemia the glucose concentration is too low

• Excessive insulin secretion leads to low blood sugar

• Insulin shock may result

• Patient appears drunk due to lack of nutrient to the brain cells

• May become unconscious, experience convulsions, or die

Adrenal Glands

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Two glands

Cortex – outer glandular region in three layers

Medulla – inner neural tissue region

Sits on top of the kidneys

Adrenal Glands

• Are located above the kidneys

• The adrenal medulla secretes epinephrine and norepinephrine in response to Ach stimulation

The Adrenal Glands• The adrenal glands help the body cope with stress

• Paired adrenal glands are located above the kidneys

• Stress causes the innervation from the sympathetic nerves to release acetylcholine (Ach)

• This stimulates the centrally located adrenal medulla to initiate an alarm reaction in which it secretes epinephrine and norepinephrine in response to Ach stimulation

• Epinephrine and norepinephrine are catecholamines – same as those released by the sympathetic neurons, and the effect is the same: they affect mood

• The effect of hormonal stimulation is much more lengthy than neural stimulation; in the alarm reaction,

• Metabolic rate increases

• Blood is rerouted to the brain, muscles and heart by dilation of the blood vessels supplying those organs

• Skin and kidney blood vessels are constricted – face/skin pales with rage

Adrenal Cortex• The outermost layer of the adrenal gland is the adrenal cortex

• Helps the body deal with chronic stress

• Cortical hormones are steroids made from cholesterol

• The three classes of cortical hormones include androgens, mineralocorticoids, and glucocorticoids

• The androgen DHEA (dehydroepiandrosterone) is secreted by both sexes and converted to testosterone by the tissues

• Additional testosterone is produced by the testes

• DHEA accounts for the majority of the androgen infemales

• Mineralocorticoids include aldosterone, which regulates fluid balance

• Cortisol (hydrocortisone) is the primary glucocorticoid which stimulates gluconeogenesis, as well as mobilization of fats and transportation of amino acids to liver cells

Hormones of the Adrenal Cortex

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Mineralocorticoids (mainly aldosterone)

Produced in outer adrenal cortex

Regulate mineral content in blood, water, and electrolyte balance

Target organ is the kidney

Hormones of the Adrenal Cortex

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Glucocorticoids (including cortisone and cortisol)

Produced in the middle layer of the adrenal cortex

Promote normal cell metabolism

Help resist long-term stressors

Released in response to increased blood levels of ACTH

Hormones of the Adrenal Cortex

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Sex hormones

Produced in the inner layer of the adrenal cortex

Androgens (male) and some estrogen (female)

Hormones of the Adrenal Medulla

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Produces two similar hormones (catecholamines)

Epinephrine

Norepinephrine

These hormones prepare the body to deal with short-term stress

Hormones of the Adrenal Cortex

Slide 9.28bCopyright © 2003 Pearson Education, Inc. publishing as Benjamin Cummings

Figure 9.10

Roles of the Hypothalamus and Adrenal

Glands in the Stress Response

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Figure 9.12

Stress

• Stress causes the hypothalamus to secrete corticotropin-releasing factor (CRF), which stimulates the anterior lobe of the pituitary to secrete adrenocorticotropic hormone (ACTH)

• ACTH regulates glucocorticoid and aldosterone secretion

• Can stimulate a 20-fold increase in blood cortisol in minutes

• High cortisol inhibits hypothalamic CRF secretion and pituitary ACTH secretion when stress has passed

Stress Pathways

Stress Pathways of the Adrenal Medulla

Stress Pathways of the Adrenal

Cortex

Lecture 6

• abnormalities of adrenal cortex function

excess secretion of glucocorticoids

- Cushing’s syndrome:

redistribution of fat

Hypertention

increased susceptibility to infection

osteoporosis

adrenal insufficiency

- Addison’s disease:

low plasma Na+, high plasma K+

low blood pressure

muscle weakness

vomiting, dehydration

low blood sugar

excess pigmentation of skin

Adrenal Hormones Have Other Effects

• Hyposecretion of adrenal cortical hormones causes Addison’sdisease

• Reduced cortisol results in poor blood glucose regulation

• Patient cannot cope with stress

• Mild infections can lead to death

• Glucocorticoids are used to alleviate inflammation

• Inhibit production of prostaglandins (mediate inflammation)

• This occurs via stimulation of an inhibitor of phospholipase A, which is needed for PG synthesis

• Decrease the inflammation reaction by decreasing permeability of capillary membranes, reducing swilling

• They also reduce effects of histamine

High Glucocorticoids

• Hyposecretion or continued administration of glucocorticoids cause Cushing’s Disease

• Continued high doses of glucocorticoids has serious side effects

• Stabilizes lysosomes so that they do not destroy tissues

• However, they also reduce lysosomes’ ability to destroy foreign particles

• Also reduces secretion of interleukin-1

• Blocks cell-mediated immunity

• Reduces ability to fight infections

Cushing’s Disease

• Cushing’s Disease results from continued high glucocorticoid levels

• Fat is deposited in the body trunk

• Edema makes the face look moon-like

• Blood-glucose levels rises chronically, causing adrenal diabetes

• May cause beta cells to die

• Reduced ability to respond to infection may result in death

Pineal Gland

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Found on the third ventricle of the brain

Secretes melatonin

Helps establish the body’s wake and sleep

cycles

May have other as-yet-unsubstantiated

functions

Thymus

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Located posterior to the sternum

Largest in infants and children

Produces thymosin

Matures some types of white blood cells

Important in developing the immune system

Hormones of the Ovaries

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Estrogens

Produced by Graafian follicles or the placenta

Stimulates the development of secondary female characteristics

Matures female reproductive organs

Helps prepare the uterus to receive a fertilized egg

Helps maintain pregnancy

Prepares the breasts to produce milk

Hormones of the Ovaries

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Progesterone

Produced by the corpus luteum

Acts with estrogen to bring about the menstrual cycle

Helps in the implantation of an embryo in the uterus

Hormones of the Testes

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Interstitial cells of testes are hormone-producing

Produce several androgens

Testosterone is the most important androgen

Responsible for adult male secondary sex characteristics

Promotes growth and maturation of male reproductive system

Required for sperm cell production

Other Hormones

• The pineal gland produces melatonin

• Involved in biological rhythms and onset of sexual maturity

• The thymus gland produces thymosin

• Regulates immune responses

• Atrial natriuretic factor (ANF) is produced by the heart

• Regulates sodium excretion

• Lowers blood pressure

• Adipose tissue

• Secretes leptin, which signals the brain, changing feeding habits and leading to decreased fat deposition

• Also secretes resistin, a small peptide hormone that causes cells to be less sensitive to insulin – causing insulin resistance much as is seen in Type 2 diabetes