Endocrinology Flashcards
What types of hormones do exist?
Three:
- Proteins and polypeptides -> secreted by anterior and posterior pituitary gland, pancreas (insulin and glucagon), parathyroid and many others. Water soluble - enter easy in circulation.
- Steroids -> secreted by adrenal cortex (cortisol and aldosterone), the ovaries (estrogens and progesterone) the testes (testosterone) and the placenta (estrogen and progesterone).
- Derivates of the aa tyrosine -> secreted by the thyroid (thyroxine and triiodothyronine) and the adrenal medulla (epinephrine and norepinephrine).
Not known polysaccharides or nucleic acid hormones.
Describe the protein and peptide hormone synthesis, storage and release.
- Synthesized in the rough endoplasmic reticulum as large, nonactive proteins called prehormones.
- Prehormones cleaved to form smaller prohormones, that will be transferred to the Golgi apparatus.
- In the Golgi apparatus they will be packet into small vesicles, and enzymes in the vesicles will cleave the pro hormones to produce smaller, biologically active hormones and inactive fragments.
- Vesicles stored in cytoplasm until their secretion is needed -> via exocytosis.
- In many cases, the stimulus for exocytosis is increased cytosolic calcium concentrations caused by depolarization of the cell membrane.
- In other cases, the stimulus can be increases of cAMP that will activate protein kinases, initiation the secretion of the hormone.
Steroid hormones synthesis
- Chemical structure similar to cholesterol, in most cases they derive from it.
- Normally very little hormone storage -> large stores of cholesterol esters in cytoplasm vacuoles that can be rapidly mobilized for steroid synthesis after a stimulus.
- Most of the cholesterol comes from the plasma, but also de-novo synthesis in steroid-producing cells
- Highly lipid soluble -> once synthesized they can diffuse across the cell membrane, enter the interstitial fluid then blood.
Amine hormones synthesis
- Formed by the actions of enzymes in the cytoplasm of glandular cells.
- Thyroid hormones -> synthesized and stored in thyroid gland, and incorporated into macromolecules of the protein thyroglobulin -> stored in large follicles within the thyroid gland.
- Hormone secretion: when the amines are split from the thyroglobulin and free hormones released into the blood stream, they combine with plasma proteins, especially thyroxine-binding globulin (slowly releases the hormones to target tissues).
- Epinephrine and norepinephrine -> formed in the adrenal medulla (x4 more epi than norepinephrine). They are taken up into preformed vesicles and stored until secreted.
- Catecholamines vesicles released from adrenal medulla by exocytosis -> once in the circulation they can exist free in the plasma or in conjugation with other substances.
What is the most common mechanism to regulate hormonal secretion? Explain and give an example.
- Negative feedback.
- A hormone has biologic actions that, directly or indirectly, inhibit further secretion of the hormone.
- Parathyroid hormone is secreted by the chief cells of the parathyroid gland in response to a decrease in serum Ca2+ concentration. In turn, parathyroid hormone’s actions on bone, kidney, and intestine all act in concert to increase the serum Ca2+ concentration. The increased serum Ca2+ concentration then decreases further parathyroid hormone secretion.
Explain and give examples of positive feedback
- Rare. Explosive and self-reinforcing.
- A hormone has biologic actions that, directly or indirectly, cause more secretion of the hormone.
- The surge of luteinizing hormone (LH) that occurs just before ovulation is a result of positive feedback of estrogen on the anterior pituitary. LH then acts on the ovaries and causes more secretion of estrogen.
How do hormones regulate the sensitivity of the target tissue?
- By regulating the number or sensitivity of receptors.
a) Down-regulation of receptors: a hormone decreases the number or affinity of receptors for itself or for another hormone. For example, in the uterus, progesterone down-regulates its own receptor and the receptor for estrogen.
b) Up-regulation of receptors: a hormone increases the number or affinity of receptors for itself or for another hormone. For example, in the ovary, estrogen up-regulates its own receptor and the receptor for LH.
Where are the different type of hormone receptors generally located?
- In or on the surface of the cell membrane -> for protein/peptides and catecholamine hormones
- In the cell cytoplasm -> for steroid hormones
- In the cell nucleus -> for the thyroid hormones, believed to be located in direct association with one or more of the chromosomes.
G protein coupled receptors (GPCR)
1) Receptor structure
Receptor with seven transmembrane helices - passes through the membrane 7 times
Binding sites for ligands are found in extracellular regions or between helices -> has an intracellular binding site for the G protein.
2) The G protein is normally bound to GDP (‘Off’ state – inactive receptor -> the G protein is bound to GDP).
Binding of a peptide hormone (e.g., epinephrine or oxytocin) changes the overall three-dimensional structure of the inside portion of the receptor
- The receptor activates the G protein by removing the GDP and adding on GTP (‘On’ state – active receptor -> the G protein is bound to GTP).
- The activated G protein can move along the membrane
Explain Gs protein-coupled receptors
1) G stimulatory protein.
The activated Gs protein (bounded to GTP) goes to an EFFECTOR enzyme on the cell membrane -> adenylate cyclase -> it has a specific point of attachment for the activated Gs protein. The effector enzyme then becomes very active.
2) Adenylate cyclase -> has a specific enzyme – GTPase
o GTPase cuts the GTP and turns it into GDP (removes a phosphate) -> G protein is turned off
o Energy is produced when removing the phosphate and used to convert ATP to cAMP
o cAMP activates protein kinase A (pkA)
NOTE: a kinase, by definition, is an enzyme that phosphorylates.
What can an activated pkA do?
Can phosphorylate multiple proteins which leads to different effects:
o Regulation of membrane permeability for different ions -> will phosphorylate channel proteins on the cell membrane.
o Regulation of metabolic pathways (glycolysis) -> phosphorylation of enzymes.
o Increased production of new proteins (transcription) -> phosphorylation of transcription factors.
o Increased cell proliferation and DNA replication, etc.
Explain Gq protein-coupled receptors
1) The activated Gq protein goes to an effector enzyme on the cell membrane -> Phospholipase C
o Phospholipase C becomes very active
2) Phospholipase C has a specific enzyme – GTPase
o GTPase cuts the GTP and turns it into GDP -> G protein is turned off
o Energy is produced and used to cut a specific molecule that is found in the membrane -> phosphatidylinositol biphosphate (PIP2) into diacylglycerol (DAG) and inositol trisphosphate (IP3)
o DAG activates a specific enzyme – protein kinase C (pkC)
3) pkC has the same function as pkA -> phosphorylation of different proteins (activation or deactivation).
o IP3 affects the smooth endoplasmic reticulum in most cells or the sarcoplasmic reticulum in muscle cells. The reticulum has specific receptors for IP3 -> IP3 binds to the receptor to open a specific channel -> calcium leaves the reticulum and goes in the cytoplasm.
4) Calcium binds to Calmodulin which then activate different types of kinases. The activated kinases phosphorylate different proteins (e.g., myosin to initiate contractions).
Steroid hormone receptors
- Can be intra cytosolic or intranuclear.
- Normally are bound to heat shock protein (HSP) (“off” state)
- When a steroid hormone (testosterone) goes through the cell membrane and binds to the receptor it displaces the HSP and activates the receptor (“on” state).
- The activated receptor binds to a specific gene sequence – hormone response element (HRE)
- A plethora of effects is triggered:
o DNA replication -> stimulates cell proliferation (mitosis)
o Transcription followed by translation -> stimulates the synthesis of proteins that:
• Control metabolism
• Control ion permeability
• Control protein synthesis
• Control cell growth
Catalytic (or enzymatic-linked) receptor mechanisms
- Hormone binds to extracellular receptors that have, or are associated with, enzymatic activity on the intracellular side of the membrane.
- Guanylyl cyclase
a. Atrial natriuretic peptide -> receptor guanylyl cyclase -> the extracellular side of the receptor binds ANP and the intracellular side of the receptor has guanylyl cyclase activity. Activation of guanylyl cyclase converts GTP to cyclic GMP, which is the second messenger.
b. Nitric oxide -> cytosolic guanylyl cyclase. Activation of guanylyl cyclase converts GTP to cyclic GMP, which is the second messenger.
- Tyrosine kinases -> hormone binds to extracellular receptors that have, or are associated with, tyrosine kinase activity. When activated, tyrosine kinase phosphorylates tyrosine moieties on proteins, leading to the hormone’s physiologic actions.
Mechanisms of hormone action
“These type of hormones are water soluble and work through the ____________ systems after binding to cell membrane receptors. Some examples are:
These type of hormones can pass through the bilipid bilayer and act in receptors inside the cell. Some examples are: “
- Peptide hormones, second messenger (Gs, Gi),
ex: oxytocin, FSH, LH, glucagon, PTH, calcitonin, TRH… - Steroid hormones/lipid soluble (derived from colesterol). Examples: testosterone, estrogen, progesterone, aldosterone, cortisol, vitamin D, thyroid hormone
How does thyroid hormones contribute to an increase cardiac output
Upregulate expression of B1 receptors (increases HR and inotrophy)
T/F Thyroid hormone increases the synthesis of Na+, K+-ATPase and consequently increases 02 consumption related to Na/K pump activity
TRUE
Mention two molecules that act through the Guanylyl cyclase pathway having GMP as the second messenger
Atrial natriuretic peptide
Nitric oxide
List the hormones that act via the tyrosine kinase pathway
Insulin
Insulin-like growth factor
Growth hormone
Prolactin
The anterior lobe of the pituitary gland is linked to the hypothalamus by the _________________________
Hypothalamic- hypophyseal portal system.
Blood from the hypothalamus that contains high concentrations of hypothalamic hormones is delivered directly to the anterior pituitary. Hypothalamic hormones then stimulate or inhibit the release of anterior pituitary hormones.
Connection between hypothalamus and hypophysis
- Tract – neural connection - between the hypothalamus and the neurohypophysis (hypothalamic hypophyseal tract)
- Portal system – connection of two capillary beds by a portal vein -> between the hypothalamus and the adenohypophysis (hypothalamic hypophyseal portal system)
Anatomy of hypothalamus / hypophysis
1) Hypothalamus
- Several gray matter nuclei – supraoptic nucleus (SON), paraventricular nucleus (PVN), arcuate nucleus (AN), preoptic nucleus (PON), etc
- Situated anterior and a little bit inferior to the thalamus
2) Infundibulum -> connection between the hypothalamus and the hypophysis
3) Pituitary gland (Hypophysis)
Anterior pituitary gland (Adenohypophysis)
o Made of glandular cuboidal epithelial tissue
o Originates form pharyngeal mucosa - Rathke’spouch
Posterior pituitary gland (Neurohypophysis)
o Made of neural tissue - pituicytes (glial cells)
o Considered a part of the brain and not a separate type of endocrine gland.
REMINDER:
- Nucleus - a group of cell bodies in the central nervous system collectively joined together in a specific area which is unmyelinated and forming gray matter.
- Tract – a bundle of axons grouped together in the central nervous system.
The posterior lobe of the pituitary gland is derived from where?
From neural tissue. The nerve cell bodies are located in hypothalamic nuclei. Posterior pituitary hormones are synthesized in the nerve cell bodies, packaged in secretory granules, and transported down the axons to the posterior pituitary for release into the circulation.
Supraoptical nucleus -> ADH
Paraventricular nucleus -> oxytocin
Neurohypophysis -> supraoptic nucleus (SON)
Secretes antidiuretic hormone (ADH, aka vasopressin)
After it’s created it is transported down the axons, in synaptic vesicles by specific motor proteins.
The vesicles need certain stimuli to release the ADH
o ↓ blood volume → ↓ blood pressure
o ↑ plasma osmolality
o Pain
Inhibitors of the ADH secretion
o ↑ blood volume
o ↓ plasma osmolality
o Alcohol
REMINDER:
Osmolality refers to the concentration solutes and water inside the plasma
o High plasma osmolality - ↓ water, ↑ solutes -> hypertonic plasma
o Low plasma osmolality - ↑ water, ↓solutes -> hypotonic plasma
o Osmoreceptors - register the plasma osmolality -> high osmolality stimulates the receptors
Mention the 4 main actions of ADH
1) Increases H20 permeability (aquaporin 2, AQP2) of the principal cells of the late distal tubule and collecting duct (via a V2 receptor and an adenylate cyclase-cAMP mechanism).
2) Constriction of vascular smooth muscle (via a V1 receptor and an IP3 /Ca2+ mechanism).
3) Increased Na+-2CI–K+ cotransport in thick ascending limb, leading to increased countercurrent multiplication and osmotic gradient.
4) Increase urea recycling in inner medullary collecting ducts, leading to increased osmotic gradient.
Regulators of ADH secretion
Where is oxytocin produced?
In the paraventricular nucleus in the hypothalamus
Regulation of oxytocin secretion
1) Suckling is the major stimulus for oxytocin secretion.
Afferent fibers carry impulses from the nipple to the spinal cord. Relays in the hypothalamus trigger the release of oxytocin from the posterior pituitary.
The sight or sound of the infant may stimulate the hypothalamic neurons to secrete oxytocin, even in the absence of suckling.
2) Dilation of the cervix and orgasm increases the secretion of oxytocin.
Actions of oxytocin
1) Contraction of myoepithelial cells in the breast
Milk is forced from the mammary alveoli into the ducts and ejected.
2) Contraction of the uterus - during pregnancy, oxytocin receptors in the uterus are up-regulated as parturition approaches, although the role of oxytocin in normal labor is uncertain. Oxytocin can be used to induce labor and reduce postpartum bleeding
What controls the secretion of the anterior pituitary hormones?
The hypothalamic releasing and inhibitory hormones.
What are the different cells present in the anterior pituitary, and what do they synthesize?
- Usually, there is one cell type for each major hormone formed in the anterior pituitary gland.
- Somatotropes - growth hormone (GH) - 30-40% of the cells
- Corticotropes - adrenocorticotropic hormone (ACTH) - about 20% of the cells
- Thyrotropes - thyroid stimulating hormone (TSH) - 3-5% of the cells
- Gonadotropes - gonadotropic hormones - Luteinizing hormone (LH and follicle stimulating hormone (FSH) - 3-5% of the cells
- Lactotropes - prolactin (PRL) - 3-5% of the cells.
What type of hormones are the hypothalamic releasing and inhibitory hormones?
Peptides, polypeptides or derivatives of tyrosine.
Hypothalamic release and inhibitory hormones
Regulation of growth hormone secretion
- Growth hormone is released in pulsatile fashion.
- Secretion is increased by sleep, stress, hormones related to puberty, starvation, exercise, and hypoglycemia.
- Secretion is decreased by somatostatin (aka growth hormone inhibitory hormone), somatomedins, obesity, hyperglycemia, and pregnancy.
1) Hypothalamic control -> GHRH and somatostatin
- GHRH stimulates the synthesis and secretion of growth hormone.
- Somatostatin inhibits secretion of growth hormone by blocking the response of the anterior pituitary to GHRH.
2) Negative feedback control by somatomedins
- Somatomedins are produced when growth hormone acts on target tissues. Somatomedins inhibit the secretion of growth hormone by acting directly on the anterior pituitary and by stimulating the secretion of somatostatin from the hypothalamus.
3) Negative feedback control by GHRH and growth hormone
- GHRH inhibits its own secretion from the hypothalamus.
- Growth hormone also inhibits its own secretion by stimulating the secretion of somatostatin from the hypothalamus.
Actions of growth hormone
- In the liver, growth hormone generates the production of somatomedins (IGFs),which serve as the intermediaries of several physiologic actions.
- The IGF receptor has tyrosine kinase activity, similar to the insulin receptor
1) Direct actions of growth hormone
- Decreases glucose uptake into cells (diabetogenic).
- Increases lipolysis.
- Increases protein synthesis in muscle and increases lean body mass.
- Increases production of IGF.
2) Actions of growth hormone via IGF
- Increases protein synthesis in chondrocytes and increases linear growth (pubertal growth spurt).
- Increases protein synthesis in muscle and increases lean body mass.
- Increases protein synthesis in most organs and increases organ size.
_______________ inhibits secretion of growth hormone by blocking the response of the anterior pituitary to GHRH
Somatostatin (aka growth hormone inhibitory hormone)
Growth hormone deficiency
In children causes dwarfism, failure to grow, short stature, mild obesity, and delayed puberty.
Can be caused by:
(a) Hypothalamic dysfunction (decreases in GHRH).
(b) Lack of anterior pituitary growth hormone.
(c) Failure to generate IGF in the liver.
(d) Growth hormone receptor deficiency.
Growth hormone excess
Hypersecretion of growth hormone causes acromegaly.
(a) Before puberty, excess growth hormone causes increased linear growth (gigantism).
(b) After puberty, excess growth hormone causes increased periosteal bone growth, increased organ size, and glucose intolerance Can be treated with somatostatin analogues (e.g., octreotide), which inhibit growth hormone secretion.
Prolactin
- Is the major hormone responsible for lactogenesis.
- Participates, with estrogen, in breast development.
- Is structurally homologous to growth hormone.
Regulation of prolactin secretion
1) Hypothalamic control by dopamine and thyrotropin-releasing hormone (TRH)
- Prolactin secretion is inhibited by dopamine (prolactin-inhibiting factor [PIF]) secreted by the hypothalamus. Thus, interruption of the hypothalamic-pituitary tract causes increased secretion of prolactin and sustained lactation.
- TRH increases prolactin secretion.
2) Negative feedback control -> prolactin inhibits its own secretion by stimulating the hypothalamic release of dopamine.
Actions of prolactin
1) Stimulates milk production in the breast.
2) Stimulates breast development (in a supportive role with estrogen).
3) Inhibits ovulation by decreasing synthesis and release of gonadotropin-releasing hormone (GnRH).
4) Inhibits spermatogenesis (by decreasing GnRH).
Pathophysiology of prolactin
1) Prolactin deficiency (destruction of the anterior pituitary) -> results in the failure to lactate.
2) Prolactin excess
- Results from hypothalamic destruction (due to loss of the tonic “inhibitory” control by dopamine) or from prolactin-secreting tumors (prolactinomas).
- Causes galactorrhea and decreased libido.
- Causes failure to ovulate and amenorrhea (absence of menstruation) because it inhibits GnRH secretion.
- Can be treated with bromocriptine, which reduces prolactin secretion by acting as a dopamine agonist.
Thyroid gland
- Located in the anterior neck - just below the larynx of the voice box
- Butterfly shaped
- Consists of thyroid follicles -> structural and functional unit of the thyroid gland. They are made up of simple cuboidal epithelial cells called follicular cells.
What hormones are mainly secreted by the thyroid
Thyroxine - T4 (about 93%)
Triiodothyronine - T3 (about 7%)
Hypothalamic - pituitary - thyroid axis (HPT)
1) The synthesis begins in the paraventricular nuclei (PVN) inside the hypothalamus, secreting thyrotropin-releasing hormone (TRH).
2) TRH goes in the hypophyseal portal system to the anterior pituitary and stimulates specific cells -> the thyrotropes, to secrete thyroid stimulating hormone (TSH) into the bloodstream.
3) TSH (it is a peptide hormone) goes to the follicles of the thyroid gland and binds to receptors present on the cell membrane -> it activates a G stimulatory protein (2nd messenger is adenylate cyclase) -> will convert ATP into cAMP and activate protein kinase A (pkA).
4) Activated pkA goes into the cell nucleus and stimulates genes to start producing thyroglobulin colloid
Why is iodine needed?
- To produce thyroid hormone - it is ingested with different nutrients (iodized salt).
- It circulates in the bloodstream in ion form (called iodide, has a negative charge)
Iodide transport
- It has be to be transported from area with low concentration (blood) to area with high concentration (follicular cells)
- Sodium uses passive transport to go from an area with high concentration (blood) to area with low concentration (follicular cells) -> iodide cotransports with it (secondary active transport - an indirect use of ATP).
- A specific protein called pendrin transports iodide from the follicular cells into the luminal space.
What happens in the luminal space of the thyroid follicles once iodide has been moved in by pendrin?
There is an enzyme called thyroid peroxidase that has three functions:
1) Iodine oxidation
o Converts iodide into iodine -> iodide loses an electron (loses its negative charge, oxydation) -> becomes neutral
2) Iodination
o Attaches 1 or 2 iodine molecules to the tyrosine amino acids in the thyroglobulin colloid
- 1 molecule creates monoiodotyrosine (MIT)
- 2 molecules create diiodotyrosine (DIT)
3) Coupling
o Couples the iodinated tyrosine amino acids into thyroxine (T4) and triiodothyronine (T3)
- Diiodotyrosine and diiodotyrosine (DIT+DIT) creates T4
- Diiodotyrosine and monoiodotyrosine (DIT+MIT) creates T3
o Apart from thyroid peroxidase there are other enzymes that help the coupling reaction with cleavage processes and rearrangements
T3 and T4 collectively are the thyroid hormone (TH)
Isolation of T3 and T4
1) The iodinated thyroglobulin goes inside the follicular cells via endocytosis
o Ends up inside vesicles - then the vesicles fuse with lysosomes
o The lysosomal enzymes cut the thyroglobulin to isolate the T3 and T4
Then the vesicles containing the T3 and T4 fuse with the cell membrane to release the thyroid hormones into the bloodstream.
2) The tyrosine amino acid contains a benzene ring inside its molecule, therefore, T3 and T4 are not water soluble
o In the blood T3 and T4 bind to a transporting protein -> thyroxine binding globulin (TBG, synthesized by the liver).
Recap of thyroid synthesis steps
What happens in the peripheral tissues with T3 and T4?
- T4 is converted to T3 by 5’-iodinase (or to rT3).
- T3 is more biologically active than T4.
- rT3 is inactive.
Control of thyroid hormone secretion
Which are the target organs of thyroid hormones?
- Cells
- Liver
- Heart
- CNS
- Bones
- Adipose tissue
- Muscle
- Integumentary system
- GI
Effects of thyroid hormones on cells
1) Thyroid hormone (T3 and T4) circulates the bloodstream bound to thyroxine binding globulin (T4 is major component) -> passes through the lipid bilayer of the cellular membrane.
2) Inside the cell the enzyme 5’-deiodinase removes an iodine form thyroxine, converting T4 into T3 (the active form of the thyroid hormone).
3) T3 binds to a transcription factor -> to exert its effects, it needs retinoic acid (RXR) to
bind to the transcription factor as well. When both substances bind to the transcription factor o It is activated
o Moves inside the nucleus
o Stimulates a specific gene sequence
4) The gene sequence undergoes transcription, translation and modifications
o The end result is the synthesis of a protein -> sodium-potassium ATPase -> merges with the cell membrane pumps 3Na+ out - 2K+ inside, ATP dependent process -> will deplete ATP.
5) This ATP depletion will force the cells to start “burning more fuel” to increase the ATP -> more consumption of carbohydrates, lipids and proteins to produce ATP.
- Increased O2 consumption
- Increase metabolic rate
- Increase heat production
- Increase number of mitochondria
- Hyperthrophy of the mitochondria
Effects of thyroid hormones on the liver
Produces proteins that stimulate
- Glycogenolysis (conversion of glycogen into glucose) -> BG goes into the blood, increasing its levels.
- Gluconeogenesis -> conversion of non-carbohydrates into glucose (glycerol, amino acids and lactate located in the liver).
- The expression of LDL receptors (LDL-R) -> increases numbers of LDL receptors, increases LDL uptake and decreases LDL levels in blood (LDL - low-density lipoproteins - bad cholesterol).
Effects of thyroid hormones on the heart
1) On the cardiomyocytes -> stimulates the expression of B1-adrenergic receptors -> they bind epinephrine and norepinephrine: increases contractility, stroke volume -> cardiac output -> increases in BP.
2) TH also affects the non-contractile muscle cells of the SA node and the AV node
Stimulates the expression of B1-adrenergic receptors -> they bind epinephrine and norepinephrine: increases action potentials -> increases heart rate -> increases BP.
Effects of thyroid hormones on the CNS
↑ dendrite formation -> increase number of neural connections
↑ myelination -> faster action potentials
↑ number of synapses -> increases number of chemical reactions between neurons.
As a result of all this hyperthyroidism can lead to anxiety and irritability
Effects of thyroid hormones on the bone
1) In the bones there are two types of important cells
o Osteoblasts -> responsible for bone deposition
o Osteoclasts -> responsible for bone resorption
2) TH regulates and maintains the balance between the two
o Prevents excessive osteoblastic or osteoclastic activity
o The process is called bone remodeling
3) TH affects the chondrocytes in the epiphyseal plates
o The chondrocytes undergo proliferation, hypertrophy and eventually ossification
o This causes the bones to grow in length -> interstitial growth
4) TH stimulates endochondral ossification (turning cartilage into bone).
Effects of thyroid hormones on the adipose tissue
TH stimulates lipolysis:
- The process of of breakdown of triglycerides (main component of the adipose tissue) into fatty acids and glycerol by activating specific enzymes
- The produced glycerol goes to the liver and is converted into glucose via gluconeogenesis
Effects of thyroid hormones on the muscle
1) The protein metabolism is the sum total of catabolism (conversion of proteins to amino acids) and anabolism (conversion of amino acids into proteins).
2) TH regulates the activity of both keeping them balanced
3) Hyperthyroidism causes the balance shifts to catabolism -> weak, atrophied muscles, weak muscle movements (not to be mistaken with lethargy).
Effects of thyroid hormones on the integumentary system
1) Skin
- Epidermis
- Dermis - contains the blood vessels that provide nutrition
2) TH increases the metabolic rate -> increases internal body temperature.
- The body tries to regulate it. Blood vessels dilate and increase the blood flow -> the skin to look soft and flushed and radiates heat.
- The apocrine and merocrine sweat glands start producing sweat -> TH ↑ the sweat glands sensitivity to catecholamines (epi and norepinephrine) -> increases sweat production -> when sweat is on the skin -> evaporative cooling.
3) Hypothyroidism causes brittle nails and thin hair
4) Hyperthyroidism causes thick hair
Effects of thyroid hormones on the GI tract
1) TH stimulates the secretions of the entire GI tract
o Alkaline fluid
o Intestinal fluid, etc.
2) TH enhances the motility of the entire GI tract -> stimulates the contractions of the smooth muscle cells.
Hyperthyroidism causes diarrhea
Hypothyroidism causes constipation
Anatomy of parathyroid gland
The parathyroid glands are located in the posterior aspect of the thyroid gland
There are generally 4 parathyroid glands
Parathyroid glands consist of two types of cells:
(i) Oxyphilcells -> believed to play a role in stimulating the other cells to produce parathyroid hormone and to play a role in producing parathyroid hormone-related protein and vitamin D
(ii) Chief cells -> primarily responsible for secreting parathyroid hormone (PTH)
Parathyroid hormone synthesis
There are specific genes expressed in the nucleus -> will be translated it into a protein -> a preform of parathyroid hormone
The protein undergoes specific modifications and cleavage processes within the rough ER and Golgi apparatus -> turns into parathyroid hormone packaged into vesicles.
The vesicles remain in the cell, ready to be released until the appropriate stimulus triggers them.
Primary stimulus for RELEASE of PTH
Hypocalcemia
On the chief cells there are 7 pass transmembrane receptors, very sensitive to Ca++
When Ca++ levels are high -> calcium binds to these receptors -> triggers different intercellular processes and the overall effect of it is the inhibition of PTH release.
If the Ca++ levels are low, there is less inhibitory input -> the vesicles containing PTH merge with the cell membrane -> PTH is released into the bloodstream.
Primary stimulus for PRODUCTION of PTH
Is stimulate by humoral stimuli, that could be:
o Ions -> Ca++ in the case of PTH
o Nutrients
o Chemicals, etc.
There are two other types of stimuli
o Hormonal
o Neural
Parafollicular cells of the thyroid
The main structural unit of the thyroid gland -> follicular cells
In between the follicles there is another type of cells -> parafollicular cells (aka C-cells)
- Regulate calcium
- Stimulated by high calcium blood levels
- They work through calcium sensitive receptors (or also though calcium channels) -> the overall stimulus is hypercalcemia.
Hypercalcemia -> stimulates the production of calcitonin packaged in vesicles -> The vesicles remain in the cell, ready to be released until the appropriate stimulus triggers them.
High blood calcium levels stimulate the vesicles to fuse with the cell membrane and calcitonin is released into the bloodstream
Between PTH and calcitonin, which one is the primary to regulate calcium levels?
PTH
On which organs is the PTH going to work?
Bone
Kidneys
Effect of PTH on the bones
Two types of cells in the bones that regulate bone remodeling:
o Osteoclasts -> responsible for bone resorption (breakdown the bone and the release the
breakdown products in the blood.
o Osteoblasts -> responsible for bone deposition (taking the required substance from the blood and depositing them into the bones).
2) On the osteoblasts there are receptors for PTH -> PTH binds to them -> the cell is stimulated to start secreting a specific chemical: RANK ligand
3) On the osteoclasts there are RANK-receptors. When RANK ligand binds to RANK receptors. The osteoclast becomes very active -> start secreting chemicals that will start breaking down some of components of the bones (collagen type 1, hydroxyapatite, calcium phosphate…)
4) A lot of Ca++ and PO43- are accumulated and released into the blood, increasing calcium and phosphate levels.
Effect of PTH on the kidneys (direct effect)
1) PTH affects the cells of the distal convoluted tubule (DCT) in the nephron
2) It activates a G stimulatory protein -> converts ATP to cAMP and cAMP activates protein kinase A
3) The activated pKA goes to the cell nucleus and stimulates specific genes -> produce specific proteins (packed into vesicles) -> calcium transport proteins
4) These proteins will be embed into the cellular membrane -> allow the Ca++ in the lumen of the DCT to flow into the cell, when normally the DCT is impermeable to ions (Na, Cl, Ca) and water. But Ca2+ cannot go out into the circulation as it would go against concentration gradient -> needs help.
5) There are sodium-potassium ATPases embedded in the membrane that pump 3Na+ outside and 2K+ inside the cells (primary active transport, requires ATP).
6) When there is a buildup of Na+ in the extracellular space, it goes into the cell down the concentration gradient (without using energy) -> this process helps Ca++ get out to the blood against its concentration gradient (secondary active transport) -> This leads to an increase in calcium concentration in the blood.
At the same time phosphates are excreted in the form of PO43- or HPO42- -> they are part of the phosphate buffer system.
Effect of PTH on the kidneys (indirect effect)
1) In the skin there is a specific chemical – INACTIVE precursor of vitamin D -> it is converted into cholecalciferol (CCF) when exposed to UV light, then it is released into the bloodstream and goes to the liver.
2) In the liver 25-hydroxylase will convert the CCF into 25-hydroxycholecalciferol and is released back into the blood. Then it goes to the kidneys.
3) In the kidneys, PTH affects specific tubular cells, increasing the expression of a specific enzyme -> 1-alpha-hydroxylase.
- 25-hydroxycholecalciferol interacts with 1-alpha- hydroxylase -> produces 1,25-hydroxycholecalciferol (calcitriol, it is the ACTIVE form of vitamin D).
- The produced calcitriol is released into the bloodstream and goes to the the duodenum (small intestine)
4) In the duodenum Vitamin D goes to the enterocytes and acts a steroid hormone -> asses through the cell membrane, binds to the intracellular receptor and stimulates a specific gene sequence -> produce specific proteins -> called calcium channel proteins. They help absorb more calcium from the gut lumen, and it is then released into the blood
Effects of calcitonin
1) Calcitonin is stimulated by high blood calcium levels -> its purpose is to lower them. It only affects the bones (changes the balance between osteoblastic and osteoclastic activity).
2) There are receptors for calcitonin directly onto the osteoclasts -> when calcitonin binds it sends signals to inhibit the osteoclast -> tips the balance towards osteoblastic activity (taking calcium from the blood and depositing it into the bone).
3) The osteoblasts also secrete other substances to complete bone deposition and make the bones thicker.
Adrenal gland anatomy
1) The adrenal glands sit on top of the kidneys -> also called suprarenal glands
2) Have a roughly pyramid shape
3) Parts of the adrenal gland
Cortex - has three layers (all layers are mostly glandular cuboidal epithelial tissue)
- Zona glomerulosa - most superficial
- Zona fasciculata - in the middle, the thickest
- Zona reticularis - the deepest
Medulla -> has only one layer and is made up of neural tissue -> chromatin cells (cell bodies of the postganglionic neurons of the SNS.
Stimuli / inhibition for aldosterone production / secretion
1) Low blood pressure
- The strongest STIMULUS of zona glomerulosa
- Low blood pressure causes the juxtaglomerular cells in the kidneys produce renin.
- The liver produces angiotensinogen -> renin acts on the angiotensinogen and converts it into angiotensin I.
- In the lungs, angiotensin converting enzyme (ACE) converts angiotensin I into angiotensin II.
- ATII goes to zona glomerulosa of the adrenal cortex and it activates a G stimulatory protein (adenylate cyclase 2nd messenger) -> converts ATP to cAMP o cAMP activates protein kinase A (pkA).
2) Hyponatremia / hyperkalemia - the second strongest STIMULUS of zona glomerulosa
- Zona glomerulosa cells are very sensitive to hyponatremia and hyperkalemia.
- ↓ Na+ levels and ↑ K+ levels exert a specific type of stimulus to synthesize aldosterone
3) ACTH - the weakest STIMULUS of zona glomerulosa.
- The paraventricular nucleus in the hypothalamus secrete corticotropin-releasing hormone (CRH) -> goes to the anterior pituitary and stimulates the corticotrope cells in the adenohypophysis to secrete adrenocorticotropic hormone (ACTH) into the bloodstream.
- ACTH goes to the adrenal cortex, binds to a g-protein coupled receptor, it activates a G stimulatory protein (adenylate cyclase) - converts ATP to cAMP that will activate protein kinase A.
4) Atrial natriuretic peptide (ANP) -> an INHIBITOR for the synthesis of aldosterone. Secreted when the blood pressure is high. Binds to specific receptors and activates a G inhibitory pathway. Results in potassium efflux out of the cell -> hyperpolarization of the cell -> alters enzymatic activity within the cholesterol pathway, resulting in inhibition of aldosterone production.
Synthesis and release of aldosterone
1) In the adrenal cortex steroid hormones are synthesized from cholesterol. Cholesterol is converted to corticosterone, and this to aldosterone -> each step in this pathway is regulated by specific enzymes.
2) The activated pkA (coming from all the stimuli previously mentioned) activates by phosphorylation the enzymes catalyzing this pathway on multiple steps.
3) Aldosterone is released into the bloodstream. It is a steroid hormone, therefore needs to bind to specific proteins for transportation -> mostly it binds to corticosteroid binding globulin (CBG, aka transcortin. Sometimes it binds to albumin).
Effects of aldosterone
Aldosterone goes to the the cells of the distal convoluted tubule of the nephron
As a steroid hormone, aldosterone passes through the lipid bilayer of the cell membrane and binds to an intracytosolic receptor.
The activated receptor activates 3 specific gene sequences, producing three different proteins:
1) Sodium-potassium ATPase -> pumps 3Na+ out and 2K+ into the cell. Utilizes ATP
2) Protein channels for Na+ into the luminal membrane -> bring Na+ from the filtrate into the cell and from the cell it goes into the blood -> water follows sodium -> increases blood volume, increases BP.
3) Protein channels for K into the luminal membrane -> move potassium that comes from the blood from the cell into the filtrate, to be lost in the urine (in response to the hyperkaliemia stimulus).
Cortisol synthesis
1) The paraventricular nucleus in the hypothalamus secrete corticotropin-releasing hormone (CRH). CRH goes to the anterior pituitary and stimulates the corticotropes cells in the adenohypophysis to secrete adrenocorticotropic hormone (ACTH) into the bloodstream.
2) ACTH (STRONG STIMULUS) goes to the adrenal cortex and binds to a g-protein coupled receptor, triggering an intracellular cascade -> G stimulatory protein -> cAMP -> pkA.
3) In the adrenal cortex steroid hormones are synthesized from cholesterol. Cholesterol is converted to progesterone, then to cortisol -> each step in this pathway is regulated by specific enzymes.
4) The activated pkA (produced after ACTH stimulation) activates by phosphorylation the enzymes catalyzing this pathway on multiple steps, leading to the formation of cortisol.
5) Cortisol it is a steroid hormone (lipid soluble), therefore needs to bind to specific proteins for transportation
- Approx. ~75% binds to corticosteroid binding globulin (CBG, aka transcortin)
- Approx. ~25% of it binds to albumin
Stimuli for the release of cortisol
1) Hypoglycemia is one of the main stimuli of cortisol. In response to it, cortisol will:
o Indirectly stimulates glycogenolysis (by increasing the sensitivity of adrenergic receptors to norepinephrine).
o Directly stimulates gluconeogenesis (the production of glucose from non-carbohydrate sources).
o Directly stimulates glycogenesis (the conversion of glucose into glycogen).
2) Long term (chronic) stress is another stimulus -> causes a direct release of CRH -> excessive ACTH -> increased production of cortisol. In response cortisol will:
o ↑ the sensitivity of adrenergic receptors for NE in the smooth muscle cells of the vessels -> vasoconstriction -> increased BP -> allows cells to get more nutrients.
o ↑ muscle catabolism -> provides nutrients
o Depresses the immune system
Cortisol feedback
↑ levels of cortisol in the blood
- Exert a negative feedback on the hypothalamus.
- Inhibit the adenohypophysis production of ACTH.
↓ levels of cortisol in the blood
- Not enough is going to the hypothalamus and the adenohypophysis to cause inhibition.
- The hypothalamic nuclei are stimulated to produce more CRH -> the pituitary is stimulated to produce more ACTH -> synthesis of cortisol is stimulated.
Cortisol effects on the muscles
As a steroid hormone cortisol passes through the lipid bilayer of the cell membrane, binds to an intracytosolic receptor and activates it.
The activated receptor activates specific genes expressed in the nucleus -> translate it into proteins - PROTEASES.
The proteases break the peptide bonds inside the muscle proteins -> produce amino acids that will be released into the bloodstream and go to the liver.
The process is called protein CATABOLISM and it is stimulated by cortisol.
Cortisol also stimulates catabolism within the bones.
Cortisol effects on the adipose tissue
Main component of the adipocytes -> triglycerides
Cortisol passes through the lipid bilayer of the cell membrane and binds to an intracytosolic receptor, activating it.
The activated receptor activates specific genes expressed in the nucleus and will be translate it into proteins.
These proteins break down the triglycerides into fatty acids (utilized by the muscles or redistributed and relocated to different parts of the body) and glycerol (goes to the liver).
This is called LIPOLYSIS.
Cortisol effects on the liver
Cortisol passes through the lipid bilayer of the cell membrane, binds to an intracytosolic receptor and activates it.
The activated receptor activates specific genes expressed in the nucleus and will be translate it into proteins
These proteins stimulate the processes of gluconeogenesis and glycogenesis.
GLUCONEOGENESIS is a process where glucose is produced from non- carbohydrate sources (amino acids and lactic acid from the muscle, or glycerol / fatty acids coming from the adipose tissue).
GLYCOGENESIS is a process where glucose is converted into glycogen (a storage molecule for glucose)
Cortisol enhances the sympathetic nervous system -> acts on many different tissues sensitive to norepinephrine -> there are adrenergic receptors on the liver and they bind to NE, cortisol enhances the sensitivity of the G proteins to E/NE.
The overall effect of norepinephrine on the vessels is glycogenolysis (conversion of glycogen into glucose).
Therefore cortisol, directly stimulates glycogenesis (the conversion of glucose into glycogen), and indirectly stimulates glycogenolysis (the conversion of glycogen into glucose) by increasing the sensitivity of the adrenergic receptors for norepinephrine.
Cortisol effects on the blood vessels
Cortisol enhances the sympathetic nervous system
Acts on many different tissues sensitive to norepinephrine -> there are adrenergic receptors in the smooth muscle cells within the tunica media of the vessels (they bind norepinephrine).
As a steroid hormone cortisol passes through the lipid bilayer of the cell membrane, binds to an intracytosolic receptor and activates it.
The activated receptor activates specific genes expressed in the nucleus and will be translate it into proteins
These proteins increase the sensitivity of the G protein-coupled adrenergic receptors of the cell -> the overall effect of norepinephrine on the vessels is vasoconstriction
Cortisol amplifies the VASOCONSTRICTION.
Cortisol effects on the immune system
Cortisol can inhibit specific processes inside the immune cells:
o Basophils are responsible for secreting histamines, leukotrienes and prostaglandins
o Lymphocytes and monocytes are responsible for secreting interleukins (IL1, IL2, IL4, etc.) and cytokines
Cortisol inhibits the inflammatory immune response by preventing the immune cells from producing all those chemicals.
What is the thoracolumbar outflow?
T1-L2, sympathetic outlflow
What is the primary stimulus for the SNS?
Short term stress (fight or flight)
Who activates the sympathetic nervous system and where do the fibers go?
The hypothalamus activates the SNS (very strong regulator)
Has a sympathetic and a parasympathetic component and it sends presynaptic potential down through descending fibers to the lateral gray horn (LGH) of the spinal cord, between T1 to L2.
In the LGH are located the bodies of the preganglionic motor neurons of the SNS- -> their axons come out through the ventral ramus and move through sympathetic chain ganglia, all the way to the adrenal medulla.
REMEMBER:
In most cases, SNS preganglionic neurons -short -> go to the chain ganglia -> postganglionic neurons are long (they begin from the chain ganglia).
The ADRENAL MEDULLA is an EXCEPTION -> preganglionic motor neurons are long -> reach the postganglionic cell bodies -> postganglionic cell neurons are very short -> cell bodies located inside the actual organ (adrenal medulla) -> called an intramural ganglion.
Synthesis of catecholamines
- SNS preganglionic motor neurons are cholinergic -> they release acetylcholine, that binds to nicotinic receptors on the chromaffin cells.
- Cations (e.g. Na+) flow in and activate specific action potentials, stimulating certain processes within the cell.
- The depolarization of the cell activates certain enzymes (a specific biochemical pathway is triggered)
- Tyrosine is the building block of this pathway -> will be converted to dopamine
- Dopamine is converted to norepinephrine (by dopamine betahydroxylase)
- Norepinephrine is converted to epinephrine.
Release of catecholamines
The synapse of the axon of the postganglionic motor neurons secretes 80% epinephrine and 20% norepinephrine.
Normally epinephrine and norepinephrine are presynthesized, put into vesicles and located in the terminal bulb of the axon.
When Na+ enters the cell -> action potential -> travel down the axon and when they reach the terminal bulb -> Ca++ channels located there, open -> Ca++ starts flowing in and acts as a bridge. Causes the vesicles to merge with the cell membrane and epinephrine and norepinephrine are released into the bloodstream.
On which organs do catecholamine produce effects? (main ones)
Liver
Adipose tissue
Heart
Respiratory system
Blood vessels going to GI tract, kidneys and skin.
Effects of catecholamines on liver
Epinephrine goes to the liver and binds to a G protein-coupled receptor -> activates a G stimulatory protein (adenylate cyclase -> convert ATP to cAMP, cAMP activates pkA).
Glycogenolysis -> there is about 300g of glycogen in the liver -> enzymes (glycogen phosphorylase, debranching enzymes, etc.) cut up the glycogen into individual monomers (glucose). The process is stimulated by catecholamines (cortisol increases the sensitivity of the adrenergic receptors to catecholamines).
Gluconeogenesis -> a process where non-carbohydrate sources are turned into glucose (amino acids and lactic acid form the muscles, glycerol and odd chain fatty acids from the adipose tissue)
The overall result of both glycogenolysis and gluconeogenesis is increased blood glucose
The glucose can be utilized by the muscles for contraction
Effects of catecholamines on adipose tissue
Catecholamines bind to a G protein-coupled receptor and activated the enzyme hormone sensitive lipase (HSL) -> breaks down triglycerides into fatty acids and glycerol.
The glycerol then goes to the liver and gets converted to glucose
The fatty acids go to the muscles and undergo beta oxidation and produce ATP (helps with contraction).
Effects of catecholamines on the heart
On the cardiomyocytes:
Stimulates the expression of B1-adrenergic receptors -> they bind catecholamines -> increase contractility -> increased stroke volume -> increased CO -> increased BP.
Non-contractile muscle cells of the SA node and the AV node:
Stimulates the expression of B1-adrenergic receptors, that bind catecholamines -> increased action potentials -> increased HR -> increased CO -> increased BP.
Catecholamines also bind to alpha-1-adrenergic receptors on some blood vessels -> cause vasoconstriction -> decreases lumen diameter -> increased vascular resistance -> increased BP. Increases in blood pressure will get more nutrients to the vital tissues and faster.
Effects of catecholamines on the respiratory system
Smooth muscle surrounds the bronchi -> catecholamines act on those smooth muscle cells by binding to B-2-adrenergic receptors -> cause the bronchioles to dilate.
If they dilate -> more air into respiratory system -> increases oxygen going into the lungs and amount of CO2 being exhaled.
Effects of catecholamines on GI, kidneys and skin
The vessels going to the GI tract constrict and divert the blood to skeletal muscles, brain, heart, etc. Therefore catecholamines ↓ GI tract activity.
The blood vessels going to the kidneys constrict and divert the blood.
The blood vessels in the skin constrict and divert the blood.
Describe the 2 functions of the pancreas and where are they generated
- Endocrine function -> from Islets of Langherans (alpha, beta, delta, pp and epsilon cells)
- Exocrine (digestive) functions -> from pancreatic acini
Which cells produce insulin? And glucagon?
B cells
Alpha cells
Which cells produce amylin? And somatostatin?
Beta cells
Delta cells
Where is the pancreatic polypeptide secreted from?
PP cells
What are stimulus for insulin secretion?
Secreted in response to increased energy-giving foods in the diet:
- Glucose
- Amino acids
- Gastrin, secretin, CCK, glucose-dependent insulinotrophic peptide
- Glucagon, growth hormone, and cortisol (prolonged excessive increased cortisol leads to beta cell exhaustion -> leads to diabetes mellitus)
This pump actively transports iodide into the thyroid follicular cells for subsequent incorporation into thyroid hormones
The iodide (i-) pump, or Na+-I- cotransport
In the peripheral tissues, T4 is converted to T3 by
5’-iodinase
This molecule activates a Gi receptor in the zona glomerulosa of the adrenal gland inhibiting aldosterone secretion
Atrial Natriuretic peptide
ACTH increases steroid hormone synthesis in all zones of the adrenal cortex by stimulating the enzyme______________ and increasing the conversion of cholesterol to _______________
cholesterol desmolase
pregnenolone
How can you differentiate a patient with a low dose dexamethasone test from normal, having an ACTH secreting tumor or having an adrenal cortical tumor?
In normal persons, low-dose dexamethasone inhibits or “suppresses” ACTH secretion and, consequently, cortisol secretion. In persons with ACTH-secreting tumors, low-dose dexamethasone does not inhibit cortisol secretion but high-dose dexamethasone does. In persons with adrenal cortical tumors, neither low- nor high-dose dexamethasone inhibits cortisol secretion.
Glucocorticoids induce the synthesis of __________ which is an inhibitor of phospholipase A
Lipocortin
What are the anti-inflammatory effects of glucocorticoids?
- induce the synthesis of lipocortin, an inhibitor of phospholipase A,
- inhibit the production of IL-2
- inhibit the proliferation of T lymphocytes.
- Inhibit the release of histamine from mast cells
- inhibit the release of serotonin from platelets.
How do glucocorticoids supress the immune system?
Glucocorticoids inhibit the production of IL-2 and T lymphocytes
21-carbon steroids include: ______________,____________,__________and _____________
Hydroxylation at ______leads to the production of deoxycorticosterone, which has mineralocorticoid (but not glucocorticoid) activity. Hydroxylation at _____ leads to the production of glucocorticoids (cortisol).
progesterone, deoxycorticosterone, aldosterone, and cortisol.
C-21
C-17
Comparison of insulin and glucagon: stimulus for secretion, major actions and overall effects on blood levels
Cells of the Islets of Langherans
Mechanism of insulin secretion
* Glucose, the stimulant for insulin secretion, binds to the _________receptor on the beta cells.
* Inside the beta cells, glucose is oxidized to ATP, which closes _____channels in the cell membrane and leads to depolarization of the beta cells.
* Depolarization opens ____ channels, which leads to an increase in _________and then to secretion of insulin
Glut 2
Potassium
Calcium
intracellular [Ca2+]
How is the composition of the insulin receptor
Is a tetramer, with two alpha subunits and two beta subunits.
a. The alpha subunits are located on the extracellular side of the cell membrane.
b. The beta subunits span the cell membrane and have intrinsic tyrosine kinase activity.
This hormone is secreted by the delta cells of the pancreas. inhibits the secretion of insulin, glucagon, and gastrin
Somatostatin
Which of the following hormones originates in the anterior pituitary?
(A) Dopamine
(B) Growth hormone-releasing hormone (GHRH)
(C) Somatostatin
(D) Gonadotropin-releasing hormone (GnRH)
(E) Thyroid -stimulating hormone (TSH)
(F) Oxytocin
(G) Testosterone
E. Thyroid-stimulating hormone (TSH) is secreted by the anterior pituitary.
Dopamine, growth hormone-releasing hormone (GHRH), somatostatin, and gonadotropin-releasing hormone (GnRH) all are secreted by the hypothalamus. Oxytocin is secreted by the posterior pituitary. Testosterone is secreted by the testes.
Which of the following hormones acts on its target tissues by a steroid hormone mechanism of action?
(A) Thyroid hormone
(B) Parathyroid hormone (PTH)
(C) Antidiuretic hormone {ADH) on the collecting duct
(D) beta 1-adrenergic agonists
(E) Glucagon
A)Thyroid hormone, an amine, acts on its target tissues by a steroid hormone mechanism, inducing the synthesis of new proteins.
The action of antidiuretic hormone (ADH) on the collecting duct (V2 receptors) is mediated by cyclic adenosine monophosphate (cAMP), although the other action of ADH (vascular smooth muscle, V1 receptors) is mediated by inositol1,4,5-triphosphate (IP3). Parathyroid hormone (PTH), beta 1 -agonists, and glucagon all act through cAMP mechanisms of action.
Which of the following inhibits the secretion of growth hormone by the anterior pituitary?
(A) Sleep
(B) Stress
(C) Puberty
(D) Somatomedins
(E) Starvation
(F) Hypoglycemia
The answer is D. Growth hormone is secreted in pulsatile fashion, with a large burst occurring during deep sleep. Growth hormone secretion is increased by sleep, stress, puberty, starvation, and hypoglycemia. Somatomedins are generated when growth hormone acts on its target tissues; they inhibit growth hormone secretion by the anterior pituitary, both directly and indirectly (by stimulating somatostatin release).
Selective destruction of the zona glomerulosa of the adrenal cortex would produce a deficiency of which hormone?
(A) Aldosterone
(B) Androstenedione
(C) Cortisol
(D) Dehydroepiandrosterone
(E) Testosterone
The answer is A. Aldosterone is produced in the zona glomerulosa of the adrenal cortex because that layer contains the enzyme for conversion of corticoste- rone to aldosterone (aldosterone synthase). Cortisol is produced in the zona fasciculata. Androstenedione and dehydroepiandrosterone are produced in the zona reticularis. Testosterone is produced in the testes, not in the adrenal cortex.
Which step in steroid hormone biosynthesis, if inhibited, blocks the production of all androgenic compounds but does not block the production of glucocorticoids’?
(A) Cholesterol -> pregnenolone
(B) Progesterone–> 11-deoxycorticosterone
C) 17-Hydroxypregnenolone –> dehydroepiandrosterone
(D) Testosterone –> estradiol
(E) Testosterone –> dihydrotestosterone
The answer is C. The conversion of 17-hydroxypregnenolone to dehydroepiandrosterone (as well as the conversion of 17-hydroxyprogesterone to androstenedione) is catalyzed by 17,20-lyase. If this process is inhibited, synthesis of androgens is stopped.
Which of the following decreases the conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol?
A) A diet low in Ca2+
B) Hypocalcemia
C) Hyperparathyroidism
D) Hypophosphatemia
E) Chronic renal failure
The answer is E deficiency (low caz.. diet or hypocalcemia) activates !a-hydroxylase, which catalyzes the conversion of vitamin D to its active form, 1,25-dihy- droxycholecalciferol. Increased parathyroid hormone (PTH) and hypophosphatemia also stimulate the enzyme. Chronic renal failure is associated with a constellation of bone diseases, including osteomalacia caused by failure of the diseased renal tissue to produce the active form of vitamin D.
Increased adrenocorticotropic hormone (ACTH) secretion would be expected in patients
a. with chronic adrenocortical insufficiency (Addison disease)
b. with primary adrenocortical hyperplasia
c. who are receiving glucocorticoid for immunosuppression after a renal transplant
d. with elevated levels of angiotensin II
The answer is A, Addison disease is caused by primary adrenocortical insufficiency. The resulting decrease in cortisol production causes a decrease in negative feedback inhibition on the hypothalamus and the anterior pituitary. Both of these conditions will result in increased adrenocorticotropic hormone (ACTH) secretion. Patients who have adrenocortical hyperplasia or who are receiving exogenous glucocorticoid will have an increase in the negative feedback inhibition of ACTH secretion.
Which of the following hormones acts by an inositol1,4,5-triphosphate (IP3)-Ca2+ mechanism of action?
A) 1,25-Dihydroxycholecalciferol
B) Progesterone
C) Insulin
D) Parathyroid hormone (PTH)
E) Gonadotropin-releasing hormone (GnRH)
E) Gonadotropin-releasing hormone (GnRH)
Which step in steroid hormone biosynthesis is stimulated by adrenocorticotropic hormone (ACTH)?
A) Cholesterol ~pregnenolone
B) Progesterone~ 11-deoxycorticosterone
C) 17-Hydroxypregnenolone ~ dehydroepiandrosterone
D) Testosterone ~ estradiol
E) Testosterone ~ dihydrotestosterone
The answer is A. The conversion of cholesterol to pregnenolone is catalyzed by cholesterol desmolase. This step in the biosynthetic pathway for steroid hormones is stimulated by adrenocorticotropic hormone (ACTH).
Which of the following causes increased aldosterone secretion?
A) Decreased blood volume
B) Administration of an inhibitor of angiotensin-converting enzyme (ACE)
C) Hyperosmolarity
D) Hypokalemia
The answer is A. Decreased blood volume stimulates the secretion of renin (because of decreased renal perfusion pressure) and initiates the renin-angiotensin-aldo- sterone cascade. Angiotensin-converting enzyme (ACE) inhibitors block the cascade by decreasing the production of angiotensin II. Hyperosmolarity stimulates antidiuretic hormone (ADH) (not aldosterone) secretion. Hyperkalemia, not hypokalemia, directly stimulates aldosterone secretion by the adrenal cortex.
Which of the following results from the action of parathyroid hormone (PTH) on the renal tubule?
(A) Inhibition of 1a-hydroxylase
(B) Stimulation of Ca2+ reabsorption in the distal tubule
(C) Stimulation of phosphate reabsorption in the proximal tubule
(D) Interaction with receptors on the luminal membrane of the proximal tubular cells
(E) Decreased urinary excretion of cyclic adenosine monophosphate (cAMP)
The answer is B. Parathyroid hormone (PTH) stimulates both renal Ca2+ reabsorption in the renal distal tubule and the 1a-hydroxylase enzyme. PTH inhibits (not stimulates) phosphate reabsorption in the proximal tubule, which is associated with an increase in urinary cyclic adenosine monophosphate (cAMP). The receptors for PTH are located on the basolateral membranes, not the luminal membranes.
Which of the following pancreatic secretions has a receptor with four subunits, two of which have tyrosine kinase activity?
(A) Insulin
(B) Glucagon
(C) Somatostatin
(D) Pancreatic lipase
The answer is A. The insulin receptor in target tissues is a tetramer. The two J3 subunits have tyrosine kinase activity and autophosphorylate the receptor when stimu- lated by insulin.
List common causes of secondary nephrogenic diabetes insipidus
T/F Glucocorticoid administration is thought to decrease vasopressin release in dogs and therefore can be included in the causes of canine acquired CDI.
TRUE
Medullary washout occurs in small animal patients for two common reasons
- Severe PU/PD (ex. Cushings, aggressive IV fluid therapy)
- The solutes necessary to produce the medullary hypertonicity gradient are lacking, such as insufficient urea in dogs and cats with hepatic insufficiency or insufficient sodium in dogs with hypoadrenocorticism.
Chronic kidney disease as a cause of polyuria and polydipsia is unlikely if the urine specific gravity is _____________
Hyposthenuric
What would be your differentials in the following patient:
older dog with severe polyuria, polydipsia, and hyposthenuric urine and no abnormal findings on physical examination, complete blood count, serum biochemistry profile, urinalysis (except the hyposthenuria), urine culture, and abdominal radiographs or ultrasonography.
Which additional diagnostics would you recommend to rule out your differential diagnoses?
The most likely remaining causes of the severe polyuria and polydipsia in this dog are hyperadrenocorticism, CDI or NDI, and primary or psychogenic polydipsia.
Additional diagnostics:
- low dose dex. Suppresion test for cushing’s (or urine cortisol/creat ratio)
- Serum osmolality (if <280mOsm/L –> suspect psycogenic polydipsia / if 280 or more –> grey zone)
- Modified water deprivation test
- Desmopressin acetate trial
How can a serum osmolality help you distinguish between psycogenic polydipsia vs conditions that cause polyuria (Cushings, DI)?
Theoretically the dogs with primary or psychogenic polydipsia should always be slightly overhydrated (with a low serum sodium concentration and low serum osmolality), and dogs with other causes of polyuria and polydipsia including diabetes insipidus should be slightly dehydrated (with a relatively high serum sodium concentration and serum osmolality)
why? because in primary polydipsia dogs drink excessively and as a consecuence of the polydipsia they become polyuric. In other causes (Cushings, DI), patient urinates excessively and as a consecuence becomes polydipsic
On a random serum osmolality assay a result of less than 280 mOsm/L would be most consistent with psychogenic polydipsia.
Explain the water deprivation test (indications, interpretation)
Is based on the premise that a dog that truly suffers from diabetes insipidus will not be able to concen- trate its urine even under conditions of moderate dehydration. This is because of either a lack of vasopressin (CDI) or lack of an appropriate renal response to vasopressin (NDI). An appropriate rise in urine specific gravity while dehydrated would be suggestive of psychogenic polydipsia.
If not appropiate rise in USG after dehydration –> CDI vs NDI? –> Desmopressin given IM:
marked increase in USG –> CDI
Complete lack of response –> suggestive of NDI
The modified water deprivation test was created in an attempt to eliminate this problem ____________________
Medullary washout
If the medullary interstitium has been “washed out” of solutes because of chronic severe polyuria and polydipsia for any reason, no urine concentration will occur despite the presence of endogenous vasopressin, desmopressin, and intact renal V2 receptors. These dogs are then mistakenly diagnosed as suffering from NDI. The modified water deprivation test protocol attempts to eliminate this problem by recommending mild water restriction for a number of days before the test.
Explain the mechanism of SIADH secondary to pulmonary disease
Pulmonary tumors that ectopically produce ADH
Diseases that interrupt the inhibitory impulses in vagal afferents from stretch receptors in the atria and great veins.
This findings are consistent with __________________
Serum osmolality is less than 280 mOsm/kg, whereas urine osmolality is more than 150 mOsm/kg and urine sodium usually more than 20 mEq/L
SIADH
T/F An increased BUN concentration typically excludes a diagnosis of SIADH
TRUE
T/F Plasma ADH determination is the gold standard for the diagnosis of SIADH
FALSE - Most cases of hyponatremia, hyposmolality, and hypovolemia are associated with an elevated ADH concentration, regardless of the cause.
List Potential Precipitating Events for Feline Thyroid Storm
MOA of Methimazole
Methimazole inhibits iodine incorporation into thyroglobulin and thus prevents the synthesis of active thyroid hormone
it does not prevent the secretion of already formed thyroid hormones
Methimazole will block the formation of new, active thyroid hormone, but other measures must be instituted to prevent further secretion of formed hormone, which is stored in high concentrations in the thyroid gland. This can be done with
stable iodine compounds such as potassium iodide
T/F Dexamethasone at a dose of 0.1 to 0.2 mg/kg PO or IV may be used to inhibit the release of thyroid hormone from the thyroid gland and to block the peripheral conversion of T4 to T3
TRUE
The most rapid relief of signs caused by thyroid storm is accomplished with medications that block _______________, such as _______________
The β-adrenergic receptors
Propranolol and atenolol
What is the advantage of using Propanolol vs atenolol in thyroid storm?
Propranolol inhibits the peripheral conversion of T4 to T3
This breed is at increased risk of hypothyroid crisis
Rottweiler
T/F Oral prednisone at a dosage of 0.55 mg/kg q12h lowers the concentration of thyroid hormones in dogs.
TRUE
This is a possible finding on the CBC of a dog with hypothyroid crisis_____________
Non-regenerative anemia
Thyroid hormones bind thyroid hormone receptors on erythroid progenitors and act directly to increase erythroid proliferation. Thyroid hormones also increase expression of the erythropoietin gene, further contributing to red blood cell formation
This enzyme converts tyrosine to Dopa, leading to synthesis of NE
Tyrosine hydroxylase
Approximately ____% of dogs with pheochromocytomas have neoplastic invasion of the caudal vena cava
15-38%
T/F In patients with pheochromocytoma, clinical signs are not reliably associated with the extent or presence of vena caval invasion
TRUE
T/F A very low percentage of patients with pheochromocytoma are diagnosed via abdominal ultrasound, limiting it’s use as a first line imaging modality
FALSE - In dogs 65% to 83% of pheochromocytomas are detected via abdominal ultrasonography, making it a useful first-line imaging modality.
This adrenal tumors seem to have a higher likelihood for vena caval invasion ____________
Pheochromocytomas seem to have a higher likelihood for vena caval invasion than do adrenocortical tumors (ultrasonographically both can look very similar).
From the tests that measure urinary and plasma cathecholamines and its metabolites for diagnosis of pheochromocytoma, which one has proven to be superior?
Urinary normetanephrine to creatinine ratio
Which one would be your first choice for treatment of hypertensive crisis in a patient with pheochromocytoma?
A. alpha-adrenergic antagonists
b. beta-blockers
a. alpha-blockers –> phenoxybenzamine 0.6mg/kg PO q12h for 20 days before surgical removal decreased mortality by 48 to 13% of patient undergoing adrenalectomy
Use of beta-blockers is not reported in veterinary pheochromocytoma patients and should be initiated only after alpha-blockade is achieved.
_____% of patients with acute hemoabdomen secondary to a pheochromocytoma can die in the perioperative period, and ___% of patient in general going for adrenalectomy for pheochormocytoma do not survive the perioperative period.
50%
18-31%
Secondary hyperaldosteronism can result from:
Renal hypoperfusion, JG cells hypoperfusion
Renin secreting tumors
*rare –> primary hyperaldosteronism is more common (cats)
T/F Most patient with hyperaldosteronism are hypernatremic
FALSE –> despite an absolute increase in total body sodium, these patients appear normonatremic due to water retention
- most cats with PHA will have a normal sodium but are typically hypokalemic.
Which recommendations would you give for medical management of a cat with PHA before adrenalectomy?
Amlodipine besylate 0.625mg/kg PO q24h
Potassium supplementation (K gluconate 2mEq/cat q12h)
Spironolactone 2mg/kg q12h
Hyperglycemia and insulin release
1) Beta cells respond to hyperglycemia -> in the cell membrane there are Glucose transporters type 2 (GLUT2), that are insulin independent.
2) Glucose enters the cell and undergoes glycolysis, producing ATP.
3) There are K+ channels on the cell membrane that bind that ATP -> this closes them and K+ ions are accumulated as they cannot leave the cell.
4) These are positively charged ions -> increases the positive membrane potential, stimulating Ca++ channels -> influx of Ca++
6) Influx of Ca++ causes the vesicles and the membrane to fuse and insulin, c-peptide and amylin go into the blood.
Effects of insulin on liver
1) Insulin binds to a tyrosine kinase receptor
- This way it stimulates phosphorylation of tyrosine residues -> an intracellular messenger is activated (PI3K / AKT).
- In the liver there are GLUT-2 receptors -> same as the beta cells (insulin independent) -> glucose moves in at a constant rate
2) Insulin takes effect once glucose is in the liver (via GLUT2 transporters)
Glycogenesis (glucose is polymerized to glycogen)
Glycolysis -> convert glucose into pyruvate, blablabla) -> ATP is produced
Effects of insulin on the muscle
1) Insulin binds to a tyrosine kinase receptor -> stimulates phosphorylation of tyrosine residues -> the intracellular messenger – PI3K/AKT is activated
2) PI3K/AKT activates GLUT- 4 receptors (insulin dependent) and increases glucose intake.
3) Inside the cell
- Glycolysis -> ATP is produced
- PI3K/AKT increases amino acid intake -> stimulates the amino acid channels (during the ‘fed’/absorptive state the blood levels of amino acids are high).
- PI3K/AKT stimulates the protein synthesis from amino acids.
- PI3K/AKT converts glucose into glycogen in the muscles.
Effects of insulin on the adipose tissue
1) Insulin binds to a tyrosine kinase receptor - PI3K/AKT is activated -> activates GLUT-4 receptors (insulin dependent) -> increased glucose intake
2) Lipogenesis
Inside the cell, glucose splits into
o Glyceraldehyde 3-phosphate (G3P) (eventually forms pyruvate and acetyl CoA)
o Dihydroxyacetone phosphate (DHAP)
Insulin stimulates
o Conversion of DHAP into glycerol
o Conversion of acetyl CoA into fatty acids -> glycerol and fatty acids are combined into
triacylglycerol (TAG, aka tryglycerides) – lipogenesis
Insulin also stimulates the intake of fatty acids
Effects of glucagon on the liver
- Glucagon activates a G stimulatory protein (adenylate cyclase 2nd messenger -pkA activation)
- Glycogenolysis -> the activated pkA stimulates the enzyme glycogen phosphorylase to convert glycogen into glucose.
- Gluconeogenesis -> activated pkA phosphorylates enzymes that converts glycerol, amino acids and fatty acids into glucose
- Glucose is released into the blood and elevates the glucose blood levels.
Effects of glucagon on adipose tissue
Glucagon activates a G stimulatory protein (adenylate cyclase 2nd messenger) -> activates protein kinase A.
The activated pKA phosphorylates different enzymes, like the hormone sensitive lipase (HSL) -> breaks the ester bonds that hold triacylglycerol (TAG) together -> two products glycerol (goes to the liver to undergo gluconeogenesis) and fatty acids -> LIPOLYSIS.
Effects of glucagon on the heart
Glucagon activates a G stimulatory protein -> adenylate cyclase 2nd messenger -> activates pkA.
- The activated pKA activates and opens up specific Ca++ channels.
- The elevated Ca++ levels increase the contractility of the heart -> ↑ stroke volume -> ↑ cardiac output -> ↑ blood pressure
Glucagon is a POSITIVE INOTROPIC agent
In patients with DKA, how fast should the K be substituted (based on serum K level?)
What are possible protocols for insulin treatment of HHS patients?
Regular insulin at the lower dose: 1 IU/kg into 250 ml of NaCl instead of 2.2
Regular insulin IM: 0.05-0.1 IU/kg q 2-4h
What are the current recommendations on the Sepsis Guidelines 2021 for the use of corticosteroids?
Normal adult calcium distribution
What happens when the kidneys age/CKD and the calcium/phosphorus handling?
There will be increases in postprandial phosphorus that will bind to calcium, forming the CPP (calciprotein particles), actively participating in inflammation and damage to the kidneys.
What is renal 2ary hyperparathyroidism
Secondary hyperparathyroidism occurs when the parathyroid glands become enlarged and release too much PTH, causing a high blood level of PTH, normally secondary to kidney disease.
Phosphorus retention
Kidneys cannot make active vitamin D -> needed to absorb calcium -> lower blood calcium levels -> increased PTH production.
What is the acute Ca2+ complexing?
When due to different conditions (for example ethylene glycol intoxication), calcium binds to other than proteins (citrate, lactate, bicarbonate, phosphate), and can decrease the ionized calcium. Normally the fraction of ca2+ complexed is low.
Uncommon / rare causes of hypocalcemia
Severity of ionized hypercalcemia and hypocalcemia is associated with etiology in dogs and cats - Frontiers, 2019 - summary of findings
How can we manage persistent hypocalcemia?
