The Endocrine SystemThe Endocrine System

Introduction to EndocrinologyIntroduction to Endocrinology

•Overview and functions of endocrine system

•Endocrine glands and types of secretion

•Hormones and their function - hormones receptors - types of hormones - mechanism of hormone action

•Regulation of endocrine system

•Endocrine and nervous systems

Homeostasis of Some Body Parameters is Necessary for Life

•Cells of the body require specific conditions to survive and function

•Maintenance of body conditions in a stable steady state is called homeostasis

•Some of the body parameters kept in a steady state: Body temperature: regulated close to 37 deg C Blood pH: kept at 7.4 Arterial blood pressure: maintained around 120/80 mm

Hg

•Failure of homeostasis causes diseases and sometimes death

The Major Control Systems in the Body are the Nervous and Endocrine Systems

The Nervous System Uses Electrical Transmission of Signals

The Endocrine System Uses Chemical Transmission of

Signals•Like a radio or TV: signal broadcast to whole body- to pick it up cells need specific receptors •Endocrine organs secrete hormones into the blood •Delivery time of chemical signal less than a minute (entire blood supply circulates about once every minute)•Hormones are broken down rapidly, but they set in motion effects that may persist after the hormones are gone: stimulate metabolism, turn on genes, etc.. •Much of the endocrine system is controlled by the nervous system: hypothalamus and pituitary control a wide range of hormones through trophic hormones

Adrenal glandsDivided into 2 regions; secrete hormones that

influence the body's metabolism, blood chemicals, and body characteristics, as well asinfluence the part of the nervous system that isinvolved in the response and defense against

stress.Hypothalamus

Activates and controls the part of the nervous system that controls involuntary body functions, the

hormonal system, and many body functions, such as regulating sleep and stimulating appetite.

Ovaries and testiclesSecrete hormones that influence female and male

characteristics, respectively.Pancreas

Secretes a hormone (insulin and glucagon) that controls the use of glucose by the body.

Parathyroid glandsSecrete a hormone that maintains the calcium level

in the blood.Pineal body

Involved with daily biological cycles.Pituitary gland

Produces a number of different hormones that influence various other endocrine glands.

Thymus glandPlays a role in the body's immune system.

Thyroid glandProduces hormones that stimulate body heat

production, bone growth, and the body's metabolism.

Evolution of Endocrine Systems

Most animals with well-developed nervous and circulatory systems have anendocrine system.

The vertebrate endocrine system consists of glands and diffuse cell groups scattered in epithelial tissues.

More than fifty different hormones are secreted. Endocrine glands arise during development for all three embryologic tissue

layers (endoderm, mesoderm, ectoderm). The type of endocrine product isdetermined by which tissue layer a gland originated in. Glands of ectodermal

and endodermal origin produce peptide and amine hormones;mesodermal-origin glands secrete hormones based on lipids.

Types of secretionEndocrine secretion – substance released by cell into blood stream

that affects distant cells

Exocrine secretion – substance released by cell into a duct that leads to epithelial surface (onto skin or into gut). Action doesn’t depend on

receptors in target tissue.

Endocrine and exocrine secretions are glandular secretions; they comefrom specialized secretory cells that are clumped together to form a

gland.

Secretion may have several sites of action simultaneously.

                     

           

           

                 

Distinguish different communication pathways

Paracrine:

Cell produces hormone thatstimulates or inhibits itself

Cell produces hormone thatstimulates or inhibits its neighbor

Cells sit side by side. One has hormone on surface, the other has the receptor.

Juxtacrine:

The term hormonehormone is derived from Greek verb which means to excite

First was used by William Bayliss and Ernest Starling in 1902 todescribe the action of secretin (hormone of duodenum)

Based more on physiological effects hormones aresignal molecules, products of glandular cells, which are secreted

into the the internal medium, mostly into the blood.

Acting target cells and in turn they respond with changing of functional and nutritional status

What do hormones do?

•Stimulate cell function (e.g. insulin stimulates glucose uptake)

•Inhibit cell function (e.g. somatostatin inhibits Growth hormone secretion)

•Maintain status quo (e.g. maintain blood calcium level)

•Stimulate or inhibit cell division (growth or renewal of tissues or

organs)

•Stimulate cell differentiation

•Stimulate “programmed cell death” or protect cells from this process (apoptosis)

HGland (secretory cell)

M

Metabolic organ

RTarget tissue(target cell) effects

Receptor

Our endocrine system is a collection of glands that produce hormones that

regulate our body's growth, metabolism, and sexual development and function. The hormones are released into the

bloodstream and transported to tissues and organs throughout your body.

Hormones are active at low concentration, so the glandular production is usually small.

Endocrine system includes system of hormone distribution andelimination:

•a few hormones circulate simply dissolved in the blood, but most are carried in the blood bound to plasma proteins

•elimination takes place through liver and kidneys

Cell secret hormones into the blood stream•Vascular system is a conduit for hormone

•May have a widespread effect•Endocrine cells may in turn be regulated by other hormones (sometimes from distant

part from the body)

The endocrine system is made up of subsystems; each has a regulatorycircuitry

The endocrine system establishes as adequate hormoneconcentration at the level of receptors on target cells.

Hormone Structure Functions

Pituitary Hormones

Oxytocin polypeptide of 9 amino acids CYIQNCPLG (C's are disulfide bonded)

uterine contraction, causes milk ejection in lactating females, responds to suckling reflex and estradiol, lowers steroid synthesis in testes

Vasopressin polypeptide of 9 amino acids CYFQNCPRG (C's are disulfide bonded)

responds to osmoreceptor which senses extracellular [Na+], blood pressure regulation, increases H2O readsorption from

distal tubules in kidney

Melanocyte-stimu-

lating hormone (MSH)

polypeptide = 13 amino acids polypeptide = 18 amino acids polypeptide = 12 amino acids

pigmentation

Corticotropin (ACTH) polypeptide = 39 amino acids stimulates cells of adrenal gland to increase steroid synthesis and secretion

Thyrotropin (TSH) 2 proteins: is 96 amino acids; is 112

acts on thyroid follicle cells to stimulate throid hormone synthesis

Growth hormone (GH) protein of 191 amino acids general anabolic stimulant, increases release of insulin-like growth factor-I (IGF-I), cell growth and bone sulfation

Prolactin protein of 197 amino acids protein of 197 amino acids

Luteinizing hormone

(LH)

2 proteins: is 96 amino acids; is 121

increases ovarian progesterone synthesis, luteinization; acts on Leydig cells of testes to increase testosterone synthesis and release and increases interstitial cell development

Follicle-stimulating

Hormone (FSH)

2 proteins: is 96 amino acids; is 120

ovarian follicle development and ovulation, increases estrogen production; acts on Sertoli cells of semiferous tubule to increase spermatogenesis

Hypothalamic Hormones

Corticotropin-releasing factor (CRF)

protein of 41 amino acids acts on corticotrope to release ACTH and -endorphin (lipotropin)

Gonadotropin-releasing factor (GnRF)

polypeptide of 10 amino acids acts on gonadotrope to release LH and FSH

Prolactin-releasing factor (PRF)

this may be TRH acts on lactotrope to release prolactin

Prolactin-releasing inhibiting factor (PIF)

may be derived from GnRH precursor, 56 amino acids

acts on lactotrope to inhibit prolactin release

Growth hormone releasing factor (GRF)

protein of 40 and 44 amino acids

stimulates GH secretion

Somatostatin polypeptide of 14 and 28 amino acids

inhibits GH and TSH secretion

Thyrotropin-releasing factor (TRF)

polypeptide of 3 amino acids stimulates TSH and prolactin secretion

Thyroid Hormones

Thyroxine and triiodothyronine

iodinated dityrosin derivatives responds to TSH and stimulates oxidations in many cells

Calcitonin protein of 32 amino acids produced in parafollicular C cells of the thyroid, regulation of Ca2+ and Pi

metabolism

Calcitonin gene-related peptide (CGRP)

protein of 37 amino acids, product of the calcitonin gene derived by alternative splicing of the precursor mRNA in the brain

acts as a vasodilator

Parathyroid Hormone

Parathyroid hormone (PTH)

protein of 84 amino acids regulation of Ca2+ and Pi metabolism,

stimulates bone resorption thus increasing serum [Ca2+], stimulates Pi secretion by

kidneys

Hormones and Peptides of the Gut

Glucagon-like peptide 1(GLP-1)formerly called enteroglucagon

Two forms: 31 amino acids, GLP-1(7-37) and 30 amino acids, GLP-1(7-36)amide

potentiates glucose-dependent insulin secretion, inhibits glucagon secretion, inhibits gastric emptying

Glucose-dependent insulinotropic polypeptide(GIP)originally called gastric inhibitory polypeptide

polypeptide of 42 amino acids inhibits secretion of gastric acid, enhances insulin secretion

Gastrin 17 amino acids produced by stomach antrum, stimulates acid and pepsin secretion, also stimulates pancreatic secretions

Secretin 27 amino acids secreted from duodenum at pH values below 4.5, stimulates pancreatic acinar cells to release bicarbonate and H2O

Cholecystokinin, CCK 33 amino acids stimulates gallbladder contraction and bile flow, increases secretion of digestive enzymes from pancreas

Motilin 22 amino acids controls gastrointestinal muscles

Vasoactive intestinal peptide (VIP)

28 amino acids produced by hypothalamus and GI tract, relaxes the GI, inhibits acid and pepsin secretion, acts as a neurotransmitter in peripheral autonomic nervous system, increases secretion of H2O and electrolytes

from pancreas and gut

Somatostatin 14 amino acid version inhibits release and action of numerous gut peptides, e.g. CKK, gastrin, secretin, motilin, GIP; also inhibits insulin and glucagon secretion from pancreas

Substance Pa member of the tachykinin family that includes neurokinin A (NKA) and neurokinin B (NKB)

11 amino acids CNS function in pain (nociception), involved in vomit reflex, stimulates salivary secretions, induces vasodilationantagonists have anti-depressant properties

Pancreatic Polypeptide, PP

36 amino acids suppresses glucose-induced insulin secretion, inhibits bicarbonate and protein secretion from pancreas

Peptide Tyrosine Tyrosine, PYY

36 amino acids inhibits gastric motility by inhibiting cholinergic neurotransmission, inhibits gastric acid secretion

Neuropeptide Tyrosine, NPY

36 amino acids6 receptors

effects on hypothalamic function in appetite, controls feeding behavior and energy homeostasis, levels increase during starvation to induce food intake

Amphiregulin 2 peptides: 78 amino acid truncated form and 84 amino acid form with 6 additional N-terminal amino acids

homology to EGF and binds to the EGF receptor (EGFR)

Pancreatic Hormones

Insulin disulfide bonded dipeptide of 21 and 30 amino acids

produced by -cells of the pancreas, increases glucose uptake and utilization, increases lipogenesis, general anabolic effects

Glucagon polypeptide of 29 amino acids produced by -cells of the pancreas, increases lipid mobilization and glycogenolysis in order to increase blood glucose levels

Pancreatic polypeptide polypeptide of 36 amino acids increases glycogenolysis, regulation of gastrointestinal activity

Somatostatin 14 amino acid version inhibition of glucagon and somatotropin release

Placental Hormones

Estrogens steroids maintenance of pregnancy

Progestins steroids mimic action of progesterone

Chorionic gonadotropin 2 proteins: is 96 amino acids; is 147

activity similar to LH

Placental lactogen protein of 191 amino acids acts like prolactin and GH

Relaxin 2 proteins of 22 and 32 amino acids

produced in ovarian corpus luteum, inhibits myometrial contractions, secretion increases during gestation

Gonad Hormones

Estrogens (ovarian) steroids; estradiol and estrone maturation and function of female secondary sex organs

Progestins (ovarian) steroid; progesterone implantation of ovum and maintenance of pregnancy

Androgens (testicular) steroid; testosterone maturation and function of male secondary sex organs

Inhibins A and B 1 protein ( is 134 amino acids; is 115 and 116 amino acids

inhibition of FSH secretion

Adrenal Cortical Hormones

Glucocorticoids steroids; cortisol and corticosterone

diverse effects on inflammation and protein synthesis

Mineralocorticoids steroids; aldosterone maintenance of salt balance

Adrenal Medullary Hormones

Epinephrine (adrenalin)

derived from tyrosine glycogenolysis, lipid mobilization, smooth muscle contraction, cardiac function

Norepinephrine (noradrenalin)

tyrosine derivative lipid mobilization, arteriole contraction

Liver Hormones

Angiotensin II polypeptide of 8 amino acids derived from angiotensinogen (present in the 2-globin fraction of

plasma) which is cleaved by the kidney enzyme renin to give the decapeptide, angiotensin I, the C-terminal 2 amino acids are then released (by action of angiotensin-converting enzyme, ACE) to yield angiotensin II

responsible for essential hypertension through stimulated synthesis and release of aldosterone from adrenal cells

Kidney Hormones

Calcitriol

[1,25-(OH)2-vitamin D3]

derived from 7-dehydrocholesterol

responsible for maintenance of calcium and phosphorous hoemostasis, increases intestinal Ca2+ uptake, regulates bone mineralization

Cardiac Hormones

Atrial natriuretic peptide

(ANP)

several active peptides cleaved from a 126 amino acid precursor

released from heart atria in response to hypovolemia, acts on outer adrenal cells to decrease aldosterone production; smooth muscle relaxation

Pineal Hormones

Melatonin N-acetyl-5-methoxytryptamine regulation of circadian rhythms

•True hormones are secreted into the blood by endocrine glands. E.g. thyroxine, epinephrine (adrenaline), testosterone, estradiol, insulin

•Neurohormones are secreted by nerve cells, Antidiuretic Hormone (ADH) and oxytocin

•Pheromones are air-borne signals secreted by exocrine glands and stimulate target cells in another animal, usually of the opposite sex. Sex pheromones have been found in insects, mammals, reptiles. Mammals that "mark their territory" with urine, feces, and scent glands do so through the action of pheromones. Androstenone (in pigs) of a male pheromone that elicits a pattern of behavior in females.

•Interferons are proteins released by cells in response to viral infection. They stimulate the release of antiviral proteins (enzymes) that act to destroy the virus. Interferons also activate the immune system to attack cancer cells.

•Prostaglandins are fatty acid-based chemicals that are made in most of the tissues of the body. They have a diverse range of actions, including inflammation, fever, and development of pain. Many of their actions are associated with control of smooth muscle cells in blood vessels. Medication that reduces swelling and inflammation, and reduces fever work by counter acting prostaglandins.

Hormones are grouped into three classes based on their structure:

SteroidsPeptides

Amines

SteroidsSteroids are lipids derived from cholesterol.

Steroid hormones are secreted by the gonads, adrenal cortex, and placenta.

Structure of some steroid hormones and their pathways of formation

Peptides and AminesPeptides are short chains of amino acids; most hormones are peptides. They are secreted

by the pituitary, parathyroid, heart, stomach, liver, and kidneys. Amines are derived fromthe amino acid tyrosine and are secreted from the thyroid and the adrenal medulla.

Solubility of the various hormone classes varies.

Mechanisms of Hormone ActionMechanisms of Hormone Action

The endocrine system acts by releasing hormones that in turn trigger actions

in specific target cells. Receptors on target cell membranes bind only to onetype of hormone. More than fifty human hormones have been identified; all

act by binding to receptor molecules. The binding hormone changes the shapeof the receptor causing the response to the hormone. There are two

mechanisms of hormone action on all target cells.

Nonsteroid Hormones or

Hormones with Cell Surface Receptors

Steroid Hormonesor

Hormones with IntracellularReceptors

Nonsteroid Hormones (water-soluble) or

Hormones with Cell Surface Receptors

Protein and peptide hormones, catecholaminesand prostaglandins find their receptors

decorating the plasma membrane of target cells.

Binding of hormone to receptor initiates a series of events whichleads to generation of so-called second messengerssecond messengers within

the cell (the hormone is the first messenger). The secondmessengers then trigger a series of molecular interactions that

alter the physiologic state of the cell.

Synonym signal transduction.

Structure of Cell Surface Receptors

Cell surface receptors are integral membrane proteins and, as such,have regions that contribute to three basic domains:

•Extracellular domains: Some of the residues exposed to the outside of the cell interact with and bind the hormone - another term for these regions is

the ligand-binding domain.

•Transmembrane domains: Hydrophobic stretches of amino acids are "comfortable" in the lipid bilayer and serve to anchor the receptor in the membrane.

•Cytoplasmic or intracellular domains: Tails or loops of the receptor that are within the cytoplasm react to hormone binding by interacting in some way with other molecules, leading to generation of second messengers.

Cytoplasmic residues of the receptor are thus the effector region of the molecule

Several distinctive variations in receptor structure

Second Messenger SystemsSecond Messenger SystemsConsider what would happen if, late at night, you noticed a building on fire…

Second messenger Examples of hormones which utilize this system

Cyclic AMP Epinephrine and norepinephrine, luteinizing hormone, follicle stimulating hormone, thyroid – stimulating hormone, calcitonin, parathyroid hormone, antidiuretic hormone

Protein kinase activity Insulin, growth hormone, prolactin, oxytocin, erythropoietin, several growth factors

Calcium and/orphosphoinositides Epinephrine and norepinephrine, angiotensin II, antidiuretic hormone, gonadotropin-releasing hormone, thyroid-releasing hormone

Cyclic GMP Atrial naturetic hormone, nitric oxide.

Second messengers activate other intracellular chemicals to produce

the target cell response

•Glucagon binds its receptor in the plasma membrane of target cells (e.g. hepatocytes).

•Bound receptor interacts with and, through a set of G proteins,

turns on adenylate cyclase, which is also an integral membrane protein.

•Activated adenylate cyclase begins to convert ATP to cyclic AMP, resulting in an elevated intracellular concentration of cAMP.

•High levels of cAMP in the cytosol make it probable that protein kinase A will be bound by cAMP and therefore catalytically active.

•Active protein kinase A "runs around the cell" adding phosphates to other enzymes, thereby changing their conformation and modulating their catalytic activity…

•Levels of cAMP decrease due to destruction by

cAMP-phosphodiesterase and the inactivation of adenylate cyclase.

Steroid Hormones or Hormones with Intracellular Receptors

Receptors for steroid and thyroid hormones are located inside target cells, in

the cytoplasm or nucleus, and function as ligand-dependent transcription factors.

The hormone-receptor complex binds to promoter regions of responsive

genes and stimulate or inhibit transcription from those genes.

The mechanism of action of steroid hormones is

to modulate gene expression in target cells

Structure of Intracellular ReceptorsSteroid and thyroid hormone receptors are members of a largegroup ("superfamily") of transcription factors. These receptors

are composed of a single polypeptide chain that has three distinct domains:

•The amino-terminus: this region is involved in activating or stimulating transcription by interacting with other components of

the transcriptional machinery. The sequence is highly variable among different receptors.

•DNA binding domain: Amino acids in this region are responsible

for binding of the receptor to specific sequences of DNA.

•The carboxy-terminus or ligand-binding domain: the region that binds hormone.

Hormone-Receptor Binding and Interactions with DNA

Being lipids, steroid hormones enter the cell by simple diffusion.Thyroid hormones enter the cell by facilitated diffusion.

The receptors exist either in the cytoplasm or nucleus, whichis where they meet the hormone. When hormone binds to receptor, a

series of events occurs:

•Receptor activation. Induced by binding hormone. The major consequence of activation is that the receptor becomes competent to bind DNA.

•Activated receptors bind to "hormone response elements", which are short specific sequences of DNA which are located in promoters of

hormone-responsive genes.

•Transcription from those genes to which the receptor is bound is affected. Receptor binding stimulates transcription.

The hormone-receptor complex thus functions as a transcription factor.

Steroid hormones bind,once inside the cell, to the

nuclear membrane receptors,producing an activated

hormone-receptor complex.The activated

hormone-receptor complexbinds to DNA and activates

specific genes, increasingproduction of proteins.

Endocrine Systems and Feedback Cycles

The endocrine system uses cycles, negative feedback and antagonistic pairs of hormones

to regulate physiological functions.

Negative feedback regulates the secretion of almost every hormone.

Cycles of secretion maintain physiological and homeostatic control.

These cycles can range from hours to months in duration.

Negative feedback in the thyroxine release reflex

Antagonistic pairs of hormones

• Insulin causes the level of blood sugar (glucose) to drop when it has risen.Glucagon causes it to rise when it has fallen.

Endocrine-related Problems

1. Overproduction of a hormone

2. Underproduction of a hormone

3. Nonfunctional receptors that cause target cells to become insensitive to hormones

Biological Cycles

Cycles involve hibernation, mating behavior, body temperature and many other physiological processes.

Rhythms or cycles that show cyclic changes on a daily (or even a few hours) basis are known as circadian rhythms. Many hormones, such as ACTH-cortisol, TSH, and GH

show circadian rhythms.

The menstrual cycle is controlled by a number of hormones secreted in a cyclical fashion.

Thyroid secretion is usually higher in winter than in summer.

Childbirth is hormonally controlled, and is highest between 2 and 7 AM.

Internal cycles of hormone production are controlled by the hypothalamus, specifically the suprachiasmic nucleus (SCN).

According to one model, the SCN is signaled by messages from the light-detecting retina of the eyes. The SCN signals the pineal gland in the brain to signal the hypothalamus, etc.

The Nervous and Endocrine Systems

There is a stalk links the pituitary to the hypothalamus, which controls release of pituitary hormones.

The hypothalamus contains neurons that control releases from the anterior pituitary.Seven hypothalamic hormones are released into a portal system connecting the

hypothalamus and pituitary, and cause targets in the pituitary to release eight hormones.

The location and roles of thehypothalamus and pituitary glands