15. introduction to endocrinology
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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