What are the seven endocrine glands?
7. Endocrine pancreas
(8. ovaries & testes)
What is the main structural difference between the endocrine system and exocrine systems that affects the ways in which their products are distributed around the body?
The endocrine system is comprised of DUCTLESS glands, made up of secretory cells that secrete hormones into the interstitial space, where they are rapidly absorbed into the bloodstream (vascular system).
Eg, In the pancreas, the different secretory cells of the Islets of Langerhans secrete hormones eg. insulin, glucagon, somatostatin & ghrelin into the blood stream.
The exocrine system, by contrast, is made up mainly of secretory cells that secrete their products, such as enzymes, into ducts, which enables them to secrete directly into the target area.
Eg. In pancreas, pancreatic acini secrete digestive enzumes eg. trypsinogen, chymotrypsinogen, carboxypeptidase, pancreatic amylase via pancreatic duct directly into duodenum.
What are the 11 tissues and organs that have endocrine functions?
What are the four main classes of hormones?
What is the structure of protein & peptide hormones?
- made from (>1) amino acids
- can be big or small
- water-soluble (unlike steroids)
- large hormones like insulin & GH can exhibit species differences
- linked by peptide bonds, with amino group at one end & carboxy at another
- ring structure linked by disulphide bridges present in some mature hormones
How are protein/peptide hormones transported in the bloodstream? Bound or unbound to plasma protein?
Unbound to plasma protein.
Is synthesis of peptide & protein hormones fast or slow?
Slow because they need to be transcribed, translated, modified then packaged.
What type of receptors do peptide hormones & protein hormones bind to?
Cell-surface, trans-membrane receptors
(N-terminus on cell surface, C-terminus inside cell):
1. G-protein coupled receptors (GPCR) - often interact with adenylate cyclase to produce cAMP from ATP
2. Receptor tyrosine kinase (RTK)
What are some protein/peptide hormones?
Thyroid-releasing hormone (TRH)
Vasopressin (aka AVP & ADH)
What is the basic structure of steroid hormones?
- three benzene rings + 1 five-membered ring
- common cholesterol precursor (27 carbons)
- lipid soluble
- large or small
Are steroid hormones typically transported bound or unbound to proteins?
Bound to binding proteins.
What distinguishes amine hormones from peptide hormones?
Amine hormones are made up of only ONE amino acid, while peptide hormones are made up of >1 amino acid.
Amine hormones are made up of either tryptophan (ideoleamines) or tyrosine (catecholamines, thyroid hormones).
Amine hormones are small. Peptide hormones can be large or small.
Amine hormones can be lipid insoluble (catecholeamines, idoleamines) OR lipid soluble (thyroid hormones). Peptide hormones are only LIPID INSOLUBLE/WATER SOLUBLE.
Amine hormones can bind to cell-membrane receptors (catecholeamines, idoleamines) OR intracellular receptors (thyroid hormones). Peptide hormones can ONLY bind to cell-membrane receptors.
What is the structure of catecholeamines?
Small - no species variation
One amino acid: tyrosine
Lipid insoluble - do not enter cells, thus bind to cell-membrane receptors such as GPCR
What are some examples of catecholamines?
What is the structure of idoleamines?
Small - no species variation
One amino acid: tryptophan
Lipid insoluble, so doesn't enter cells
Binds to cell-membrane receptors like GPCR
How do thyroid hormones differ from other amine hormones, such as catecholamines & idoleamines, and how are they similar?
Thyroid hormones, while categorised as amines because they are derived from tyrosine (like catecholamines), act very differently than the others in this class. In fact, they much more resemble steroid hormones in structure & function.
Thyroid hormones, like catecholeamines & idoleamines, are small, so there is no species variation. Nearly 100% travel bound to carrier proteins in the bloodstream.
But thyroid hormones are LIPID SOLUBLE, so they can enter cells, and bind to intracellular receptors, often inside the cell nucleus. Catecholeamines & idoleamines are lipid insoluble, so they can't enter the cell and thus bind to cell receptors in the plasma membrane.
What are some examples of idoleamines?
Seratonin (5-HT hydroxytryptophan)
What are some examples of thyroid hormones?
What are eicanosoid hormones made from?
Arachidonic acid (AA) in membrane phospholipids
How are eicanosoids synthesized from arachidonic acid (AA)?
membrane-bound enzyme phospholipase-A2 (PLA2), present in inactive form in lysosomes, releases AA → cyclooxygenase (COX) or 5-lipoxygenase (5-LOX) convert AA into prostaglandins (PG) or leukotrienes (LT), respectively → downstream enzymes change PG to different forms
Give some examples of eicanosoids.
PGE2 - softens cervix, causes uterine contraction, effectively stimulates progesterone secretion
PGF2α - promotes luteolysis, ie. degradation of corpus luteum, effectively reducing progesterone secretion & ↑ FSH secretion
Thromboxane (Tx) - clotting factor
Do eicanosoid hormones diffuse out of cells after they've been synthesized, or are they actively secreted?
They diffuse out of cells.
There is NO ACTIVE SECRETION.
They are transported UNBOUND to proteins in the circulation.
Contrast the synthesis of peptide hormones & steroid hormones.
Synthesized via “classical pathway” of mRNA transcription & translation:
translated in cytoplasm as long polypeptide pre-prohormone → “processed” in ER into prohormone ie., cleavage of N-terminal signal and/or glycosylation, which protects it from metabolism → packaged & stored in vesicles
Synthesized mainly in adrenal cortex, gonads, placenta
Cleavage of cholesterol at C21 & C22 result in core structure of 3 benzenes + 1 five-membered ring.
Contrast the secretion of peptide hormones & steroid hormones.
EXOCYTOSIS (regulated or constitutive)- secreted via exocytosis (need ↑[Ca2+]) → endopeptidase cleaves end of prohormone to facilitate folding into mature hormone just before entry into blood stream
What is synthesized diffuses out of cells
ie., NO DISTINCTION BETWEEN SYNTHESIS & SECRETION.
Do steroid hormones have rapid or slow onset of activation?
Slow. They have to enter the cell then bind to receptors in the cell nucleus.
What are examples of steroid hormones?
What is the role of the circulation in regulating the activity of hormones?
Endocrine (eg., insulin, aldosterone) & neuroendocrine hormones (eg. vasopressin, oxytocin) travel through the circulation from their site of synthesis to reach target cells in distal parts of the body.
Both negative feedback and positive feedback loops in endocrine signalling use the bloodstream.
Paracrine, autocrine & neurocrine hormones do not use the blood stream.
Paracrine hormones act locally (eg., insulin-like growth factors IGFs produced by liver, on adjacent or nearby cells within the same gland, diffusing through the extracellular space)
Autocrine hormones at on themselves, binding to receptors on their own surfaces (eg. prostaglandins)
Neurocrine hormones diffuse from a neurone into the synaptic cleft to affect an adjacent target cell (eg., Ach, norepinephrine, dopamine).
Describe the development of the hypothalamus.
In the early embryo, neuroectoderm of the forebrain (prosenecephalon), the primary brain vesicle, divides to form two secondary brain vesicles, telencephalon (endbrain, cortex) and diencephalon. From the diencephalon ventro-lateral wall, intermediate-zone proliferation generates the primordial hypothalamus.
The developed hypothalamus is located in the middle of the base of the brain, and encapsulates the ventral portion of the third ventricle.
Describe the development of the pituitary gland, aka hypophysis.
The hypophysis is an amalgam of two tissues. Ultimately, the two tissues grow into one another and become tightly apposed, but their structure remains distinctly different.
1. Anterior - Adeno - Upward Ectoderm
Early in gestation a finger of ectoderm grows upward from the roof of the mouth. This protrusion is called Rathke's pouch and will develop into the anterior pituitary or adenohypophysis.
2. Posterior - Neuroectoderm - Not upward
At the same time that Rathke's pouch is developing, another finger of ectodermal tissue evaginates ventrally from the diencephalon of the developing brain. This extension of the ventral brain will become the posterior pituitary or neurohypophysis.
What are the two ways peptide hormones, after being packaged by the Golgi apparatus into vesicles, are secreted, and which is the more common secretory mechanism?
The cell stores hormone in secretory granules and releases them in "bursts" when stimulated. This is the most commonly used pathway and allows cells to secrete a large amount of hormone over a short period of time.
The cell does not store hormone, but secretes it from secretory vesicles as it is synthesized.
In general, what is the halflife of circulating peptide hormone?
A few minutes.
What is the first and rate-limiting step in the synthesis of all steroid hormones?
Conversion of cholesterol to pregnenolone.
Where does conversion of cholesterol to pregnenolone, the first & rate-limiting step in the synthesis of steroid hormones, take place in the cell?
Pregnenolone is formed on the inner membrane of mitochondria then shuttled back and forth between mitochondrion and the endoplasmic reticulum for further enzymatic transformations involved in synthesis of derivative steroid hormones.
Are steroid hormones stored in vesicles before secretion?
Newly synthesized steroid hormones are rapidly secreted from the cell, with little if any storage. Increases in secretion reflect accelerated rates of synthesis.
How are steroid hormones typically eliminated?
By inactivating metabolic transformations and excretion in urine or bile.
What is the difference in half-life between thyroid hormones & catecholamines?
The circulating halflife of thyroid hormones is on the order of a few days. They are inactivated primarily by intracellular de-iodinases.
Catecholamines, on the other hand, are rapidly degraded, with circulating half-lives of only a few minutes.
Both types of hormones are amine hormones, derived from tyrosine.
How are eicanosoids, fatty-acid-derived hormones, inactivated & how long are their half-lives?
Eicanosoids like prostaglandins, prostacyclins, leukotrienes and thromboxanes, are rapidly inactivated by being metabolized, and are typically active for only a few seconds.
Describe how the production of thyroid hormones is an example of a negative feedback loop.
Neurons in the hypothalamus secrete thyroid releasing hormone (TRH), which stimulates cells in the anterior pituitary to secrete thyroid-stimulating hormone (TSH).
TSH binds to receptors on epithelial cells in the thyroid gland, stimulating synthesis and secretion of thyroid hormones, which affect probably all cells in the body.
** When blood concentrations of thyroid hormones increase above a certain threshold, TRH-secreting neurons in the hypothalamus are inhibited and stop secreting TRH. **
What are the three main sources of cholesterol precursor needed for steroidogenesis?
1. Cholesterol synthesized within the cell from acetate
2. Cholesterol ester stores in intracellular lipid droplets
3. Uptake of cholesterol-containing low density lipoproteins from plasma (blood following digestion)
Describe the process of steroidogenesis beginning with free cholesterol in cell cytoplasm.
Free cholesterol is transported from the cell cytoplasm into mitochondria, across the mitochondrial membrane.
Within mitochondria, cholesterol is converted to pregnenolone by a cleaving enzyme called CYP11A1 in the inner mitochondrial membrane.
Pregnenolone itself is not a hormone, but is the immediate precursor for the synthesis of all of the steroid hormones.
What are the five types of steroid hormones, classified by their receptors? What are prominent examples of each type?
1. Corticosteroids - eg. Cortisol
2. Mineralcorticoids - eg. Aldosterone
3. Androgens - eg. Testosterone
4. Oestrogens - eg. Oestradiol, Oestrone
5. Progestogens aka Progestins - eg. Progesterone
What are the four types of second messengers triggered inside a cell when first messengers -- peptide/protein hormones, catecholamines & idoleamines, and eicanosoid hormones -- bind to integral receptors on the cell plasma membrane?
1. Cyclic AMP
2. Protein kinase
3. Calcium and/or phosphoinositides
4. Cyclic GMP
How does the cAMP (cyclic AMP) second messenger change the state of a target cell?
Cyclic adenosine monophosphate (cAMP) is a nucleotide generated from ATP through the action of the enzyme adenylate cyclase.
The intracellular concentration of cAMP is increased or decreased by a variety of hormones and such fluctuations affect a variety of cellular processes.
One prominent and important effect of elevated concentrations of cAMP is activation of a cAMP-dependent protein kinase called protein kinase A (PKA).
PKA becomes active when it binds cAMP. Upon activation, PKA phosphorylates a number of other proteins, many of which are themselves enzymes that are either activated or suppressed by being phosphorylated. Such changes in enzymatic activity within the cell clearly alter its state.
Give an example of a hormone that triggers the cAMP second-messenger system.
Glucagon, as first messenger, uses the cAMP second-messenger system in conjunction with Protein Kinase A.
1. Glucagon is a peptide hormone that binds its G-protein-coupled receptor in the plasma membrane of target cells (e.g. hepatocytes).
2. Bound receptor interacts with and, through a set of G proteins, turns on adenylate cyclase, which is also an integral membrane protein.
3. Activated adenylate cyclase converts ATP to cAMP, resulting in an elevated intracellular concentration of cAMP.
4. High levels of cAMP in the cytosol bind to & activate PKA.
5. Active PKA "runs around the cell" adding phosphates to other enzymes, thereby changing their conformation and modulating their catalytic activity - - - the cell has been changed!
6. Levels of cAMP decrease due to destruction by cAMP-phosphodiesterase and the inactivation of adenylate cyclase.
How is protein kinase used as a second messenger when triggered by a first-messenger hormone such as peptide hormones insulin, growth hormone, prolactin & oxytocin?
The receptors for several protein hormones such as insulin, GH, prolactin & oxytocin are themselves protein kinases that are switched on by binding of hormone.
The kinase activity associated with such receptors results in phosphorylation of tyrosine residues on other proteins:
1. The hormone binds to receptor domains exposed on the cell's surface, resulting in a conformational change that activates kinase domains located in the cytoplasmic regions of the receptor.
2. In many cases, the receptor phosphorylates itself as part of the kinase activation process.
3. The activated receptor phosphorylates a variety of intracellular targets, many of which are enzymes that become activated or are inactivated upon phosphorylation.
4. Some of the targets of receptor kinases are protein phosphatases which, upon activation by receptor tyrosine kinase, remove phosphates from other proteins and alter their activity.
In general, after steroid hormones or thyroid hormones enter cell cytoplasm or nucleus and bind to intracellular receptors, what does this hormone-receptor complex do next?
The hormone-receptor complex binds to promoter regions of responsive genes and stimulate or sometimes inhibit transcription from those genes.
Thus, steroid hormones & thyroid hormones are also known as transcription factors, or ligand-dependent transcription factors.
What are the three core domains of the intracellular receptor that bind steroids and thyroid hormones?
1. amino terminus
2. DNA-binding domain
3. carboxy terminus aka ligand-binding domain
In the intracellular receptor for steroid & thyroid hormones, what happens at the amino-terminus domain?
In most cases, this region is involved in activating or stimulating transcription by interacting with other components of the transcriptional machinery, such as other transcription factors. The sequence is highly variable among different receptors.
In the intracellular receptor for steroid & thyroid hormones, what happens at the DNA-binding domain?
Amino acids in this region are responsible for binding of the receptor to specific sequences of DNA.
In the intracellular receptor for steroids & thyroid hormones, what happens at the carboxy terminus, aka the ligand-binding domain?
This is the region that binds hormone.
What is the difference between the way steroid hormones enter target cells and the way thyroid hormones enter target cells?
Both are lipid soluble, so they bind with intracellular receptors.
Steroid hormones enter by simple diffusion across the plasma membrane.
Thyroid hormones enter by facilitated diffusion.
Where are intracellular hormone receptors located in the cell?
Cytoplasm or nucleus.
What is the sequence of events that occur after a hormone binds to an intracellular receptor?
1. Receptor activation - conformational changes in the receptor are induced by binding hormone. The major consequence of activation is that the receptor becomes competent to bind DNA.
2. Binding - activated receptors bind to "hormone response elements", which are short specific sequences of DNA which are located in promoters of hormone-responsive genes. In most cases, hormone-receptor complexes bind DNA in pairs.
3. Transcription - Most commonly, receptor binding stimulates transcription. The hormone-receptor complex thus functions as a transcription factor.
Explain why Vitamin D, or calcitriol, is classified as a steroid hormone.
Aka 1,25-dihydroxycholecalciferol (1-25-DHC)
Vitamin D, as either D3 or D2 is metabolized within the body to the hormonally-active 1,25-DHC.
Each of the forms of vitamin D is lipid soluble/hydrophobic, like other steroid hormones, and is transported in blood bound to carrier proteins. The major carrier is called, appropriately, vitamin D-binding protein. The halflife of 1,25-dihydroxycholecalciferol is only a few hours.
1-25-DHC binds to intracellular receptors that then function as transcription factors to modulate gene expression. The vitamin D receptor forms a complex with another intracellular receptor, the retinoid-X receptor, and that heterodimer is what binds to DNA.
What is the main physiological effect of active Vitamin D, 1-25 dihydroxycholecalciferol (DHC)?
Its most dramatic effect is to facilitate intestinal absorption of calcium, although it also stimulates absorption of phosphate and magnesium ions.
In the absence of vitamin D, dietary calcium is not absorbed at all efficiently. Vitamin D stimulates the expression of a number of proteins involved in transporting calcium from the lumen of the intestine, across the epithelial cells and into blood.
What are the different forms of Vitamin D?
Vit. D3 aka cholecalciferol:
Generated in the skin of animals when light energy is absorbed by a precursor molecule 7-dehydrocholesterol
Vit. D2 aka egosterol:
Plant form (dietary) of Vit. D
1-25 DHCC aka 1-25-dihydroxycholecalciferol:
Hormonally-active form, generated by:
1. hydroxylation in liver, where D3 is hydroxylated into 25-hydroxycholecalciferol by 25-hydroxylase
2. hydroxylation in kidney, where 25-DHC is hydroxylated into 1,25 DHC by by 1-alpha-hydroxlase
What are the major controls behind conversion of inactive forms of Vit. D into the biologically active hormone, 1,25-dihydroxycholecalciferol in the liver & kidneys?
Liver synthesis of 25-hydroxycholecalciferol (HCC) is only loosely regulated, and blood levels of this molecule largely reflect the amount of amount of vitamin D produced in the skin or ingested.
In contrast, the activity of 1-alpha-hydroxylase in the kidney is tightly regulated and serves as the major control point in production of the active hormone, DHCC.
The major stimulant of 1-alpha-hydroxylase in the kidney is parathyroid hormone (PTH); it is also induced by low blood levels of phosphate. Increase in PTH leads to more DHCC, and a decrease in plasma phosphate also leads to an increase in DHCC. These conditions result in more absorption of calcium from the GIT.