final Flashcards
3 types of muscle
- development of skeletal muscle
- Skeletal muscle – makes up muscular system
a. Includes diaphragm
b. Multinucleated – more than one nucleus per cell
- During development – many muscle cells fuse; contain multiple nuclei as a result
c. Striated – due to proteins/filaments
d. Long, stacked in parallel
- each individual muscle cell/fibre is long and skinny
- many are stacked together – go from one end to the other end of the muscle - Cardiac muscle – found only in the heart
a. Uninucleated
b. Striated – dark and light bands
c. Don’t only lay parallel – also stacked end to end
- joined via intercalated disk – region where one cardiac muscle cell contacts other at end - Smooth muscle – appears throughout the body systems as components of hollow organs and tubes
a. Key component of blood vessels – allows them to contract
b. Uninucleated
c. Not striated
d. Sheets or tubes – often spindle shaped; not as long as skeletal muscle cells
Muscle contraction allows
Classifications
Muscle contraction allows
- Locomotion – movement of joints, limbs and whole body
- Propulsion of contents through various hollow internal organs – movement of blood through the circulatory system; food through digestive system
- Emptying of contents of certain organs to external environment – sphincters act as valves; allows defecation and urination
Classified as either
- Striated or unstriated (better)
- Voluntary or involuntary
2 neuron chain of NMJ
Upper Motor Neurons – cell body in the motor cortex; synapse on LMN in the spinal cord
• Approx. 90% desiccate in the medulla – primary neurons on right side control left body
Lower Motor neurons – cell body in ventral root spinal cord; axons synapse on muscle cells
a. Activation of lower motor neuron causes contraction of muscle cells
• Neuromuscular junction
b. Motor unit – the group of muscle cells controlled by one LMN
i. Mammals – each muscle cell receives only one synapse
• Always excitatory – Ach
• LMN – can innervate one (more rare) or many muscle cells (more common)
ii. Other vertebrates – can have 2 synapses
NMJ differences
- summation
Very large
• NMJ – 1000 μm2
• Central synapse – 0.05 μm2
Highly folded – increases surface area
a. Crests – high density of nicotinic AChR (hundreds of thousands)
• High density causes large EPSP
b. Troughs – lots of voltage gated Na+ channels
Causes large EPSP – approx. 30-50mV (central synapse is approx. 0.5-1mV)
• always enough to stimulate opening of Na+ channels & fire AP
A single AP of LMN is always enough to cause AP in muscle cell
• No summation of EPSP – excitation will always result in contraction
• High safety factor
Structure of muscle
Consists a number of muscle fibers (cells) lying parallel to one another and held together by connective tissue
- Tendon – end of muscle; tough CT
- Muscle fascicle – bundle of cells/fibres within muscle; surrounded by CT
- Single skeletal muscle cell is known as a muscle fiber
a. Large, elongated, and cylindrically shaped
b. Fibers usually extend entire length of muscle
Structure of muscle cells
a. Multinucleated
b. Myofibrils – bundles of contractile proteins within cell
c. Sarcoplasmic reticulum – specialized endoplasmic reticulum; surrounds myofibril
• Always sits with middle in the middle of the sarcomere (middle of H zone)
• Stores Ca2+ ions
d. Sarcolemma – membrane of muscle cell
e. T-tubules – form a mesh of canals through muscles
• Have openings through sarcolemma
• Lie adjacent to & sits between sections of SR
Structure of myofibril
- proteins of M line!
- Sarcomere – z line to z line
• M line – middle of H zone
• Only thick filaments at rest
• A band – length of thick filaments - Thick filaments
a. Mainly myosin – protein molecule; 2 identical subunits shaped like golf club
i. Tail ends – intertwined around each other
• Oriented towards center of filament
ii. Myosin heads – globular ends project out from hinge at regular intervals
• Form cross bridges between thick and thin filaments
iii. 2 binding sites – critical to contraction
• Actin binding site
• Myosin ATPase
iv. A motor protein – hydrolyses ATP to convert chemical energy to carry out mechanical work - Thin filaments
a. Actin – primary structural component of thin filaments
• G-actin monomers are spherical – assemble into long chains
• Each actin molecule has a special binding site for attachment with myosin head
b. Tropomyosin – threadlike molecules; interact with actin along its spinal grove
• Covers myosin binding site
c. Troponin
i. 3 polypeptide units
• One binds to tropomyosin
• One binds actin
• One binds with Ca2+
ii. Unbound – troponin stabilizes tropomyosin ni blocking position
iii. Bound – tropomyosin uncovers binding site; allows formation of cross bridges & contraction
d. Nebulin – runs along the middle of actin ball chains & aligns actin filaments - Titin – giant elastic protein
a. Joins M-lines to Z lines at opposite ends of sarcomere – the whole length of sarcomere
b. Two important roles:
• Helps stabilize position of thick filaments in relation to thin filaments – keeps the thick filaments in the middle of thin filaments
• Improves muscle’s elasticity – sarcomere can get longer and shorter - Myomesin – main protein of M line
• Structural element – keeps thick filaments at regular intervals
Excitation Contration coupling
- sliding filament hypothesis
- process
- what bands are t-tubule and SR on
- do actin and myosin contract
- what happens to Ach
- calsequesterin!!
Sliding filament hypothesis – muscle shortens when actin and myosin slide past each other
Process
1. AP from LMN – causes release of Ach into synaptic cleft of NMJ
- ACh binds to the receptor – nicotinic AChR
a. Allows entry of Na+ through voltage gated channels
b. Causes EPSP large enough to trigger an AP – AP travels across membrane of cell - AP invades the T-tubule system – continuous with sarcoplasm
a. T-tubule – run perpendicular from surface of muscle cell into central portions of fibres
i. Aligned on edges of A band – directly adjacent to thick myofilaments/myosin
b. Causes voltage gated dihydropyridine (DHP) receptors to open – channel within t-tubule; blocked by dihydropyridine drug
i. Allows for small amount of Ca2+ to enter into cell
c. DHP is connected to RyR channel via RyR foot – piece of globular protein
i. Ryanodine receptor – channel within SR; blocked by ryanodine drug
- Physically pulled open
- Opening causes a massive release of Ca2+, and increase in intercellular Ca2+ concentration - Ca2+ binds troponin
a. At rest – myosin head is cocked in the absence of Ca2+
i. Tropomyosin is blocking the binding of myosin to actin – only weakly bound to actin
b. Binding of Ca2+ to troponin molecules – pulls tropomyosin away from binding sites on actin
i. Allows myosin to bind to actin
ii. Power stroke – cross bridges bend
- Myosin heads move thin filaments towards M line – releases Pi
- End of power stroke – releases ADP; tightly bound in rigor state
iii. Cross bridges release when ATP binds
- Hydrolyzation of ATP to ADP + Pi – energy allows cocking of myosin head
- Weakly bound to myosin at this stage
- Can binds to more distal actin site as long as Ca2+ is available to bind tropomyosin
- Repeating cycle shortens sarcomere – actin filaments slide closer to M line
c. Causes contraction of sarcomere – actin and myosin DO NOT contract - When AP stops arriving at NMJ
a. Ach dissociates from receptor & is degraded by AChE
i. Choline is recycled back into synaptic terminal
b. Free Ca2+ pumped back into SR from cytosol via ATPase – powerful ATPase transporter
i. Calsequestrin protein – binds Ca2+ and helps sequester
ii. Ca2+ dissociates from troponin – pumped into SR
c. Tropomyosin moves back in front of binding sites
i. Muscle is unable to maintain tension
d. Actin and myosin slip past each other
i. Pulled apart by titin & antagonistic muscle (ex. triceps contracting will cause stretching of bicep sarcomeres)
Rigor Mortis
Rigor state – myosin head is tightly bound to actin site; release via binding of ATP to myosin
a. ATP -> ADP + Pi causes reactivation of myosin head into cocked position – ready to bind again
- Will continue to bind as long as Ca2+ is available and will continue to shorten the muscle
~3-4 hours after death, peak at ~12 hours – muscle becomes very stiff
a. SR becomes leaky – intracellular Ca++ rises
b. Ca++ allows troponin-tropomyosin complex to move aside and allow myosin cross bridges to bind to actin.
• Release of ADP and Pi results in rigor state binding
c. Dead cells do not produce ATP – cross bridges cannot detach
Rigor mortis subsides when enzymes start to break down myosin heads
– Muscle is starting to break down
Energy use in muscles
- Splitting of ATP by myosin ATPase for power stroke
- Active transport of Ca2+ back into sarcoplasmic reticulum
a. Ca2+ ATPase pumps - Na+/K+ ATPase
a. Neurons and muscle cells need to maintain RMP in order to generate AP
Main energy sources for muscle contraction
- bloodflow requirements
- enzyme requirements
- what type of exercise
- Stored ATP (very little stored) – only have enough stored for a few seconds worth of activity; up to a minute
- Creatine phosphate – first energy storehouse tapped at onset of contractile activity
a. Creatine kinase – enzyme catabolizes bidirectional transfer between ATP and creatine
b. At rest – ATP demand is low
i. Creatine kinase transfers Pi from ATP to creatine
- Creatine phosphate = phosphorylated creatine
ii. Allows storage of energy as creatine phosphate
c. When energy is needed
i. Creatine kinase phosphorylates ADP from Pi on creatine
- ATP is used for contraction
- Provides 4-5 times the energy of stored ATP
- Limited supply (only a few minutes)
Most energy for long term sustained contraction comes from oxidative phosphorylation and anaerobic glycolysis
- Oxidative phosphorylation – takes place within muscle mitochondria if sufficient O2 is present
a. Provides energy during light to moderate exercise
b. Uses stores of glycogen in muscle (30 min) – depolymerizes to glucose
i. Good yield of ATP – 38 per glucose molecule
c. Aerobic exercise – requires adequate supply of oxygen
i. Increased blood flow via
- Increase ventilation
- Increase heart rate and force of contraction
- Dilate skeletal blood vessels - Anaerobic Glycolysis – primary source of ATP when o2 is low
a. Supports anaerobic & high-intensity exercise – oxygen supply is limited
b. Rapid supply of ATP
- Only a few enzymes involved – fewer enzymes than in oxidative phosphorylation
c. Very low ATP yield – only 2 ATP per glucose molecule
- Lactic acid – acidifies muscle and contributes to fatigue
- Duration of anaerobic glycolysis is limited
Causes of muscle fatigue
Central fatigue
a. Psychological
• “I just can’t” – differs person to person
• Plays larger role for elite athletes
Peripheral – plays larger role in majority of population; physiologists are unsure which is most important
a. Decrease in release of ACh from LMN with sustained activity
b. Receptor desensitization – when receptors are repeatedly exposed, they can lower affinity for ligand
c. Changes in of muscle RMP
• If muscle is very active – firing a lot of AP
• Eventually – you will see slight changes in ECF K+
• Causes depolarization of cells – can lead to inefficiency
d. Impaired Ca2+ release by SR – RyR may not be as effective at allowing Ca2+ into cell
e. Intracellular pH of muscle – due to lactic acid from anaerobic activity
f. Others….
Generation of tension
- timing of AP in neuron vs muscle cell
Electrode in motor neuron & in muscle cell – allows us to see timing of events
AP arrives from LMN
a. AP in muscle cell approx. 2 ms after neuronal AP
Tension generated in muscle – experiences lag
a. Latent period – due to:
• AP propagating in muscle
• Opening of DHR and RyR receptors – flooding of Ca2+
• Interaction of Ca2+ with myosin heads – pulling of tropomyosin away
b. Contraction phase
c. Relaxation phase
Types of stimulation
- Simulation at low frequency – muscle cell generates tension and relaxes
- Stimulation at higher frequency – stimulating muscle cell before it’s relaxes
a. Analogous to GP summation – can generate tension before single twitch has been allowed to relax - Summation leading to unfused tetanus
a. Stimulating repeatedly before relaxation – stimulated to maximum tension
b. Max tension – point of tetanus
- Unfused – still getting to relax slightly from one pulse to the next - Summation leading to complete tetanus – stimulated too quickly to get opportunities to start to relax
a. This is the most amount of tension that a muscle cell can generate
- Maximum tension is usually higher than unfused tetanus
Maximum tension
- 2 theories
requires several AP to occur; 2 theories (both likely contribute)
- Some think it takes several APs to increase intracellular Ca++ enough to saturate actin’s myosin binding sites
a. The concentration of Ca2+ doesn’t get high enough with single AP - Some think intracellular Ca++ reaches its maximum (saturates) after first action potential.
a. Summation and Tetanus develop because sustained elevation of increased Ca++ allows greater exposure of actin binding sites and therefore maximizes interaction with myosin (effect is time dependent)
b. More time dependent than concentration dependent
Length tension
the amount of tension a muscle can generate depends on initial resting state
Optimal resting length – we can generate the most tension from fibre when thin filaments only overall until the end of the myosin heads (medium amount of overlap)
Stretching – less overlap; muscle cell can’t generate as much tension because there’s not as many myosin heads able to interact with actin
Compressed – pushing thin filaments towards m line; can’t generate as much tension because contracted sarcomere has many proteins within cell
o All the other molecules start to push against each other – work against the generation of tension
Types of skeletal muscle fibres
- chickens vs mammels
- 3 types & features!
- In chickens and turkey – fibres are grouped together
o White meat – white muscle
o Dark meat – red muscle - Mammals – fibres are interspersed
o Different fibre types may coexist side by side
3 types of motor fibres/units – all muscle fibres within the same unit are the same type
- Slow twitch oxidative – slow & fatigue resistant
a. Small amounts of tension, slowly
i. Capable generating tension for long periods of time without running down energy stores
- Single twitch – approx. 2 grams tension
- Approx. 25 ms to generate full tension
- Unfused tetanic force – generates max force after approx. 1 second
ii. Tension can be sustained over long period of time – stays consistent up to an hour
b. Features
i. Large numbers of mitochondria
ii. Small fibres
iii. Well vascularized – myoglobin to facilitate oxygen transfer from blood
- Blood – makes them red; supplies with o2 - Fast oxidative-glycolytic – fast & fatigue resistant
a. Can do both oxidative and glycolytic – o2 or no o2
i. Generate a lot of tension, moderately fast
- Single twitch – approx. 10 grams tension
- Unfused tetanic – takes a few stimulations to reach peak
ii. Somewhat resistant to fatigue – can maintain tension with gradual decrease approx. 15 min
b. Features
i. Moderate # of mitochondria – fewer than slow twitch
ii. Fibres are larger than slow twitch - Fast twitch glycolytic – fast fatigable & only anaerobic
a. White muscle – no o2; does not require o2 to be transported here
i. Generate the most tension
- Single twitch – approx. 50 grams
- Approx. 10 ms to generate full tension
- Unfused tetanic – very few stimulations required to reach peak; faster than others
ii. Fatigue rapidly – can only generate max tension approx. 1 min
b. Features
i. Few mitochondria – breakdown glucose via anaerobic catabolism
ii. Fibres are larger than slow twitch – these are the largest & most tension
Recruitment of motor units
- size of motor units
Slow twitch fatigue resistant – first Motor units recruited; red & oxidative
a. Ex. these will be activated if lifting a light weight
b. Smallest motor neurons
- Each MU has only a few fibres
Fast fatigue resistant – second recruited
a. Motor neurons are slightly larger
Fast twitch glycolytic (fatigable; white muscle) – last recruited
a. Ex. lifting a very heavy weight
b. Largest motor units – most fibres
- Motor unit has many fibres
Size principle – size matters
Homeostatic control mechanisms
Organs that have endocrine functions
Set point range (examples) & integration
Homeostatic control mechanisms – allows coordination between body systems
Many not classically endocrine organs have endocrine functions
Maintain set point range – metabolism, salt and water, reproduction, growth
Requires integration
• Positive input – stimulation
• Negative input – inhibition
Origins of endocrinology
Early 20th century – William Bayliss and Ernest Starling
Identifying cause and effect functions
• Anatomy (form) and physio (function)
Hypothesized control of secretion of alkaline juice from the pancreas into the duodenum – nervous of chemical control?
a. Began with Pavlov’s dog experiment – is there endocrinology associated with it
b. Anatomically
o Stomach goes into duodenum & pancreas opens into duodenum
c. Physio
o The stomach produces acidic chyme – too acidic for duodenum to digest properly
o Pancreas secretes alkaline juices
Experiment
a. Severed neurons that connected pancreas in dogs – found there was still entry of alkaline fluids into duodenum
b. Concluded a blood borne agent
o Stimulus of endocrine agents – promotes pancreas to release endocrine juices & alkaline juices
c. Secretin – later was identified as the hormone that promotes secretion of alkaline fluid from pancreas
Presented these findings in 1905 in the royal college of physicians of London
a. Pharmacopoeias – a legally binding collection of standards and quality specifications for medicines used in a country or region
b. Hormone – Greek for “I excite or arouse”; carried from the organ where they are produced to the organ which they affect by means of the blood stream and the continually recurring physiological needs of the organism must determine their repeated production and orientation through the body
- Released from an endocrine gland into circulation and acts at far site
- This is not entirely true – there are many types of hormones
Variability in hormone effects and production (7)
- tropic vs nontropic
- rhythms
- One endocrine gland can produce many hormones
a. Ex. pituitary gland - The same hormone can be secreted by many tissue types
a. Every cell in the body has the mechanisms to transcribe genes and produce hormones
i. Ex. the brain – not a traditional endocrine gland but has endocrine functions
b. Estrogens and androgens are often sex specific (secreted by sex organs)
i. Also released in other areas – ex. release of estrogen in the brain for neuromodulation - There is more than one target cell for a single hormone
a. Ex. a hormone released to control blood pressure may affect:
i. Endothelial cells of blood vessels
ii. Kidney – controls blood volume
b. Integrates function of different organs - A target cell can be influenced by many hormones
a. Non-tropic hormones – hormones that directly stimulate target cells to induce effects
b. Tropic hormones – act on another endocrine gland to initiate release of other hormones - Secretion varies over time and will be affected by changes in the environment
a. Rhythms – release of hormones is entrained to environmental cycles which vary in interval length and duration
i. Growth hormones – peaks at night
ii. Cortisol – usually peaks in the morning
iii. Melatonin – peaks as night - Hormones can be blood borne or neuronally derived
a. Found in the brain – can regulate neuron function - Hormones can be excreted from tissues that have other functions
Chemical classifications of hormones
- solubility
- type of secretion
- transport
- location
- Peptides – chains of amino acids (3 to 500+)
a. Solubility – hydrophilic
b. Secretion – exocytosis
c. Transport – free active peptide or precursor (inactive form that may be activated via post translational modification)
d. Source – pituitary, pancreas, GI tract etc
i. Occurs everywhere – every cell has mechanisms to secrete proteins - Amino acid derivatives
a. Catecholamines (ex. norepinephrine and epinephrine)
i. Solubility – hydrophilic
ii. Secretion – exocytosis
iii. Transport – 50% to carrier protein
iv. Main source – adrenal medulla
- Not the only site
b. Thyroid hormone (T3 and T4)
i. Solubility – hydrophobic
ii. Secretion – endo & exocytosis
iii. Transport – most bound to carrier
- Hydrophobic relies more heavily on carrier proteins
iv. Source – thyroid gland
- The most specific in terms of cite of synthesis – chemical conditions to synthesize are very harsh
c. Melatonin
i. Solubility – hydrophilic
ii. Secretion – exocytosis
iii. Transport – 50% to carrier protein
iv. Source – pineal gland - Steroids – cholesterol derivatives
a. Solubility – hydrophobic
b. Secretion – diffusion (non polar and small)
c. Transport – most bound to carrier protein
i. Hydrophobic relies more heavily on carrier proteins
d. Source – adrenal cortex and sex steroids
i. Adrenal cortex – cortisol and aldosterone
Synthesis and most translational modification of peptide hormones
examples
- thyrotropin releasing hormone
- adrenocorticotrophic hormone
- Hormone is synthesized via transcription and translation
- Modifications in golgi – may be required in order to become bioactive
a. Undergoes peptide cleavage
b. Addition of functional groups
i. Glycosylation – addition of sugar
ii. Phosphorylation – addition of phosphate group
iii. Sulfation – addition of sulfide group
iv. Amidation – addition of amide group
v. Acetylation – addition of acetyl group
c. Subunit aggregation (ex. insulin receptors)
Examples:
Thyrotropin releasing hormone
- PreproTRH – precursor peptide has 6 copies of 3 AA TRH hormone
a. Must undergo proteolytic activation in order to release the TRH hormone
b. Protein segments in between may be protective – play a role in regulation but understanding of their role is limited - Adrenocorticotrophic hormone – produced in the pituitary
a. Pro-opiomelanocortin – prohormone for ACTH
i. May contain several peptide sequences with biological activity
ii. ACTH – regulates cortisol synthesis and release
secretion of hormones
- negative and positive feedback (and examples)
Feedback control is mainly negative – output counteracts input
a. Common in tropic hormones
- ex. release of TSH (thyroid stimulating hormone) from anterior pituitary -> promotes thyroid hormone synthesis -> releases TH (thyroid hormone) -> TH inhibits production of thyrotropin releasing hormone (TRH) in hypothalamus -> inhibits production of TSH in the pit gland
Can be positive
a. Ovarian cycles
i. Increasing maturation of follicles during ovulation causes increase in estrogen -> estrogen stimulates hypothalamus and causes release of gonadotrophin releasing hormone (GnRH) -> causes further increase in estrogen
b. Letdown reflex in nursing mothers
c. Oxytocin release in contraction of endometrium during birth/patriation
Carrier proteins
- where do hydrophobic vs phillic hormones illicit responses
- dictated by what
Release requires changes in environment – stimulus triggers synthesis and release of hormone
Free hormones bind to proteins and form complexes – very few free hormones within the blood stream
Carrier proteins
1. Often required for both hydrophobic and hydrophilic hormones
a. Hydrophobic – more reliant; more protein complexes than free hormones
o Genomic response – crosses membrane and binds to cytoplasmic or nuclear receptors; leads to transcription of new proteins
- Slow acting – seconds to minutes
b. Hydrophilic – may be bound more loosely
o Highly water soluble – more free hormones than bound
o Nongenomic response – binds to membrane receptors
- Fast acting – minutes to hours
2. Dictated by binding affinity – affinity of hormone to carrier will affect total amount of free hormone in circulation
Types of carriers – can be general or specific to hormone
1. Specific carriers
• Corticosteroid binding globulin (CBG) – carry corticosteroids
• Thyroid hormone binding globulin, thyroid binding globulin, & transthyretin – carry thyroid hormones
2. General carrier
• Albumin – many hydrophilic hormones bind; typically low affinity
Activation and inactivation of hormones
- half lives
- ex. of deg enz
Activation – metabolism of the precursor or release from carrier protein activation
1. Prohormone – inactive form of hormone often present in the blood
a. Common with peptide hormones – must undergo proteolytic activation
2. Released hormone has a half life in the blood – effects efficacy
a. Affinity to carriers will be influenced by energy required to synthesize hormones
• Steroids require lots of energy – will bind more tightly to carriers to prevent release and degradation in the blood
• AA derived – require less energy & won’t bind to carriers as tightly
b. General half lives
• Singe AA derivatives – 1 minute
• Peptide hormones – minutes to hours
• Steroid hormones – hours
3. Free hormones bind to receptors of cells – either membrane bound or within cytosol or nucleus response
a. Response generally resets balance in response to change – often negative feedback
Inactivation
1. Enzymatic degradation
a. Endopeptidases – enzyme that degrades peptide bonds in the interior of an AA chain
• Ex. trypsin – general endopeptidase
b. Exopeptidases – enzymes that release single AA from peptides chains by removing from the ends
2. Hormone receptor complex endocytosis – complex is taken into cell and inactivated
3. Conjugation – chemical group is attached
a. Sulfation – common for steroids
• Improves water solubility – will be present in solution, filtered by the kidney, and excreted
4. Inactive proteins can be excreted when no longer required by the body
Reflex pathways
- Neuroendocrine responses – combine neuronal and hormonal processes
a. Activation of neuron causes release of neurotransmitters from axon terminal -> acts directly on target cells (does not enter bloodstream) -> endocrine response
i. Ex. knee jerk response
ii. Uses neurotransmitters – still a neuroendocrine response
b. Activation of neuron causes release of neurohormones from axon terminal -> enters into bloodstream -> acts on target cells -> endocrine response - Hormone release with stimulation from neuron
a. Neurotransmitter is released from axon terminal onto endocrine gland -> causes release of hormone -> enters bloodstream - Complex neuroendocrine
a. Neurohormone released from axon terminal -> travels through bloodstream and stimulates endocrine gland -> causes release of hormone
Neuromodulation
nt in systems
effects
Not the same as neuroendocrine
Estrogen functions in neuromodulation
- Diffuse modulatory systems – neurons diffused throughout the brain that regulate many physiological functions and behaviour
a. Norepinephrine, Ach, serotonin, dopamine - Estrogens – reset the balance and receptivity of diffuse modulation systems
a. Can govern mood, appetite, and are involved in mood disorders (ex. depression and bipolar and anxiety)
Endocrine dysfunction
- levels of dysfunction (example)
- types of dysfunction
Levels of dysfunction
o Primary dysfunction – site of lesion for the active non tropic hormone (ex. adrenal gland, thyroid gland)
o Secondary dysfunction – dysfunction elsewhere in endocrine pathway
o Tertiary dysfunction – dysfunction at site of action of the hormone (ex. end organ resistance)
Ex. exogenous cortisol
a. CRH is released from hypothalamus -> stimulates ACTH release from ant pit -> stimulates release of cortisol from adrenal cortex
b. Primary dysfunction – occurs at adrenal cortex in release of cortisol
• This is the hormone that actually causes the response
Types of dysfunction
- Hyposecretion – can be primary or secondary; too little hormones or response
a. Usually the result of atrophy of the endocrine gland
i. Normally treated through replacement therapy – supply of substance lacking in body
b. Target cells may lack receptors or biochemical machinery at the target cell
i. Ex. hyperinsulinemia – type II diabetes
- There lots of insulin but response is malfunctioning - Hypersecretion – primary or secondary; too much hormone or response
a. Usually the result of a benign tumor (adenoma)
i. Normally treated through inhibition (antagonists)
b. Target cell responsiveness is altered naturally (decreased response due to decreased hormones present)
Effects of hormones at target cell
- 4 types
- binding kinetics
- law of mass action
- Up and down regulation – receptors at the target cell are regulated in response to hormone levels which influence abundance and affinity of hormone
a. Binding kinetics – how fast a compound binds to target and dissociates from it
i. Types and effects
- Competitive and allosteric
- Agonistic and antagonistic
ii. Reliant on abundance and affinity
b. Law of mass action (pg 47-48) – determines concentration of [hormone] and [receptor] vs [hormone receptor complexes]
- Equilibrium – association constant (Ka) drives the reaction both ways depending on the concentration of each
- At equilibrium: [hormone] x [receptors] x Ka = [hormone receptor complex] x Kd
i. Ka = association constant
- High Ka = high binding affinity or high [hormone]
ii. Kd = dissociation constant
- High Kd = low binding affinity or low [hormone]
c. Not all hormones complexes follow the law of mass action
i. Non cooperative law of mass action is upheld
ii. Positively cooperative ligand binding increases receptor affinity of vacant receptors
iii. Negatively cooperative ligand binding decreases receptor affinity of vacant receptors
- Permissiveness – hormone cannot have full effect without another hormone being present
a. Ex. T3 - Synergism – the combined effect of multiple hormones is greater than the sum of the parts
a. Ex. blood glucose levels are increased by the presence of cortisol and epinephrine - Antagonism – one hormone reduces the effectiveness of another hormone; can be direct or indirect
a. Pharmaceutical applications – drugs able to bind to receptors to inhibit the actions of an endogenous hormone/signaling molecule
b. Also occurs naturally
Types of hormone receptors
- what hydrophobic hormones
- Membrane bound
a. ligand gated; enzyme linked; guanylyl cyclase and GPCR
i. most common is GPCR
- 7 trans membrane domains (7 MSR)
ii. enzyme linked
- normally 1 MSR (single pass)
- ex. insulin receptors
iii. important in the NS and other excitable cells
b. Second messenger systems
i. Adenylate cyclase
- Linked GPCR
ii. Guanylate cyclase
- Linked to guanylyl cyclase receptors (1 MSR)
iii. Inositol phosphate and diacyl glycerol
- Linked to GPCR - Nuclear receptors – most lipophilic hormones act through; often a genomic response
a. Steroid hormone
i. Bind in cytoplasm or nucleus – will form a ligand transcription factor
- Affects transcription of genes and mRNA -> proteins
ii. Initially thought that all steroid acted through nuclear receptors
- More rapid response discovery in recent years indicates membrane bound receptors activation
- There are membrane bound receptors for progesterone, estrogen, thyroid hormones (all lipophilic)
The pituitary gland and hypothalamus
- structures
- 3 portions of pituitary - origins and nomenclature
- Infundibulum – stalk that connects the pituitary to the brain/hypothalamus
- Sphenoid bone – surrounds the pituitary gland
Posterior pituitary – nervous tissue
a. Extension of the neural tissue
- Directly connected to hypothalamus
- Neural embryonic origin
b. Nomenclature
- Pars nervosa
- Neurohypophysis
Anterior pituitary – glandular origin
a. True endocrine gland of epithelial origin
- Trophic hormones typically stimulate production of hormones within ant pit
b. Nomenclature
- Pars distalis
- Adenohypophysis
Intermediate pituitary – pars intermedia
a. Disappear in humans by the time were born
- Play a larger role in nonhuman animals
- Mainly produces alpha melanocyte stimulating hormone (MSH)
Posterior pituitary anatomy
- what kind of release
Neuroendocrine system between the hypothalamus and posterior pituitary
Cell bodies originate in the hypothalamus -> axons extend through infundibulum and terminate in post pit
a. Hypothalamus synthesizes posterior pituitary hormones in 2 major nuclei
• Paraventricular nucleus – mainly oxytocin
• Supraoptic nucleus – mainly vasopressin
b. Both nuclei can synthesis vasopressin and oxytocin incase of dysfunction in one
Posterior pituitary releases hormones on demand – regulated
- Regulated release – most hormones; only released when required
- Constitutive release – more rare; constant release
Neurophysins
Neurohypophysial peptides
Structure of AVP and OT
- Brattleboro rats
Neurophysins – carrier proteins of OT and AVP synthesized in hypothalamus
a. Neurophysins and proteolytic enzymes are packaged into vesicles and transported down through the axons of nuclei
- Stored in secretory granules within axon terminals until stimulated to release
Neurohypophysial peptides are released from post pit
a. 2 types of nonapeptides (9 AA) – oxytocin (OT) and vasopressin (AVP)
i. Similar structures
• Ile and Phe differ
• Leu and Arg differ
ii. Different functions & release mechanisms
OT and AVP are closely related but one can function without the other
Ex. Brattleboro rats – genetically diabetic insipidus
- Diabetes – “running through”
a. Diabetes mellitus - glucose in urine causes increases in urine production due to osmotic mvmt of water
- Mellitus – “honey”; sweet to the taste due to glucose
b. Diabetes insipidus - lack of vasopressin (same as antidiuretic hormone)
- AVP/ADH – allows the uptake of water back into the body in the kidney
- Insipidus – sour to the taste
Vasopressin
- nomenclature
- release sources
- action
- dieresis vs anti-dieresis
Nomenclature
o Arginine vasopressin
o Antidiuretic hormone (ADH)
Release is stimulated by decrease in ECF volume – 2 sources
1. Due to water loss
a. Reduced ECFV -> increased plasma osmolarity (more salts) -> fluid moves into ICF and triggers osmoreceptor activity (detect changes in osmotic pressure) -> increased AVP release from post pit
• Ex. sweating – loss of water volume causes increase in plasma osmolarity -> water moves into cells to maintain concentration and triggers osmoreceptors
2. Due to blood loss
a. Decreased left arterial volume in cardiac cycle -> decreased arterial BP -> trigger baroreceptors -> increased AVP release from post pit
Action - targets kidney
- Increases water resorption in renal tubules
- Diaresis – increase in urine flow rate
- Anti diaresis – reduction in urine flow rate (hence antidiuretic); retention of water in body - Causes vasoconstriction in vascular smooth muscle
- Maintains blood pressure if there is blood loss
Oxytocin
- release
- action
Release is stimulated by
o Birth canal distension - increased OT
o Infant suckling - increased OT
Action - positive feedback
o Increased uterine/myometrium contraction during birth
o Increased milk ejection from mammary gland
Behavioural aspects of OT and AVP
Oxytocin
1. Rats
a. Increases maternal behaviour – estrogens need to be present
2. Humans
a. Plasma OT levels increase during sexual arousal in both sexes
• May be linked in transport of sperm through reproductive tract due to increased levels in males and females
3. Acts as a strong neuromodulators in the brain – influence social recognition, memory and affiliative behaviours such as “pair bonding” (rodent research)
a. Neuromodulators – oxytocin resets balance (similar to estrogen)
b. Pair bonding may be related to OT release during let down reflex of mammary glands – pair bonding occurs during this process
Vasopressin
1. Stimulates release of ACTH (adrenocorticotropic hormones) -> synergistic with CRH -> increases cortisol (due to stress)
2. Rodent research – seems to play a greater role in males than females in social recognition and consolidation of social memory (rodent research)
a. Involved in aggression, courtship, scent marking, and learning
• Research is done on tetrapods – related to link between AVP and fluid balance (water)
o you need to protect your water resource as a land animals – links to aggression in rodents
Anterior pituitary
- anatomy
- cell types
Neurosecretory neurons release tropic hormones into median eminence – releases into hypophyseal portal blood supply
1. hypophysiotropic hormones – tropic hormones released from the hypothalamus into capillary bed that regulate the ant pit
2. portal capillary bed - capillary bed flows directly into another capillary bed
a. first capillary bed at median eminence
b. second capillary bed at anterior pit
• blood vessels are surrounded by different cell types within ant pit that synthesize and release different hormones depending on trophic hormone in capillary bed
3. non portal supply: arteriole -> capillary -> venule
adenohypophysial cells – cells surrounding blood vessels; release hormones into the capillary bed and blood stream
1. histological and cytological methods have provided definitive evidence on the cellular source for each hormone released from the adenohypophysis
a. types of staining
• basophil – basic staining
• acidophil – acidic staining
cell types and staining characteristics
1. Corticotroph cells - adrenocorticotropic hormone (ACTH)
• Basophil
2. Thyrotroph cells - thyroid stimulating hormone (TSH)
• Basophil
3. Gonadotroph cells - FSH & LH
• There are cell types that release both and some that release only one or the other
• Basophil
4. Lactotroph cells - prolactin (PRL)
• Acidophil
5. Somatotroph cells - growth hormone (GH)
• Acidophil
Anterior pituitary axis
- axis’s from anterior pituitary
- what axis are under stimulatory and inhibitory control
Hypothalamus
o Release hypophysiotropic hormones into hypophyseal portal blood supply can be stimulatory or inhibitory
Endocrine axis – connects the hypophysiotropic hormones anterior pit hormones final hormone (often stimulates synthesis and release of other hormones)
1. Cortisol release axis
a. High CNS has stressor
b. Hypothalamus synthesizes and releases CRH -> released into medial eminence and hypophyseal blood supply -> stimulates ant pit
c. Anterior pit releases ACTH -> released into bloodstream -> stimulates adrenal cortex
d. Adrenal cortex releases cortisol
i. Cortisol regulates its own release
o Long loop -> cortisol inhibit release in hypothalamus, ant pit, and higher CNS
o Short loop -> ACTH inhibits release from ant pit and hypothalamus
- Thyroid hormone axis
a. Hypophysiotropic hormone -> thyrotropin releasing hormone (TRH)
b. Ant pit hormone -> thyroid stimulation hormone (TSH)
c. Thyroid gland -> releases thyroid hormones (T3 and T4) - Androgen and estrogen axis
a. Hypophysiotropic hormone -> gonadotropin releasing hormone (GnRH)
b. Ant pit hormone -> FSH and LH
c. Gonads (ovaries and testes) - androgens and estrogens - Growth hormone/IGF axis
a. Hypophysiotropic hormone -> growth hormone releasing hormone (GHRH)
b. Ant pit hormone -> growth hormone (GH)
c. Target cells -> IGF’s
• Liver and other tissues are targeted
All axis have inhibitory and stimulatory factors – generally under control of one or the other
1. 4 main axis under stimulatory hypophysiotropic hormones – typically require stimulatory factors
a. GnRH - stimulates release of LH and FSH in ant pit
b. CRH - stimulates release of ACTH in ant pit
c. TRH - stimulates release of TSH in ant pit
2. 2 main axis under inhibitory – dominant signal that regulates release is inhibitory -> require lack of inhibition in order to activate stimulatory regulators and release hormone
a. Growth hormone
• Somatostatin – prevents production of GHRH
o Lack of somatostatin -> allows release of GHRH -> allows release of GH
b. Prolactin
• Dopamine – inhibits production of prolactin releasing hormone
o Lack of dopamine -> allows production of prolactin
Many hormones have metabolic actions in final effects -> regulation of energy
Adenohypophysial hormones
- 10 hormones secreted by anterior pituitary (type of hormone)
- structural characteristics of each family
The anterior pituitary produces 10 polypeptide hormones (FLAT PG)
o FSH, LH, ACTH, TSH, PRL, GnRH
2 families
1. GH and prolactin – similar structure family
a. Growth hormone – well conserved in vertebrates
• Any mutations throughout evolution have not been tolerated
• AA sequence in humans will be similar to that of fish
b. Prolactin – lots of variability
• Same gene expresses different variants – normal (mammalian), cleaved, spliced
- Glycoprotein family – similar structure
a. Named due to the large % of carbohydrate moieties – up to 33% by weight are carbs
b. Types
• Follicle stimulating hormone (FSH)
• Luteinizing hormone (LH)
• Thyroid stimulating hormone (TSH)
• Human chorionic gonadotropin hormone (hCG)
c. Each has alpha and beta subunit
i. Alpha unit - AA sequence is similar between hormones
- Mutations have not been tolerated in evolution
ii. Beta unit – varies between hormones
- Functionally differentiates the types of hormones
Ex. hCG – spikes early in pregnancy; pregnancy tests target these levels
• Pregnancy tests would give pos tests to everyone if it targeted alpha subunit
Pars intermedia
- regulation of POMC
Many animals have an anatomically separate pars intermedia
- By the time humans are born – has disappeared
a. During embryonic development - aMSH is produced by pars intermedia
b. As adults - cells are not anatomically distinct but still synthesize and secrete aMSH (often considered part of anterior pituitary)
Predominant endocrine product is αMSH – humans produce this in the ant pit
1. Precursor peptide -> pro-opiomelanocortin (POMC)
a. POMC is also involved in regulating food intake
b. POMC -> ACTH -> aMSH
• aMSH is derived from AA sequence of ACTH which is an AA sequence of POMC
• one POMC can’t synthesize and release ACTH and aMSH simultaneously
2. aMSH functions – pleotropic hormone (many functions)
a. melanin synthesis
• melanocytes regulation (skin pigmentation) – this is how it was first identified and named for
b. anorexigenic – inhibit food intake; regulates energy balance
c. immune responses
3. All occurs intracellularly in ant pit
a. Different cell types will express proconvertase enzyme
i. PC enzymes 1, 2, & 3 -> responsible for chopping up POMC depending on signal received
o requiring reduction in food intake – will release aMSH
o stress response – ACTH
ii. higher signal dictate activity of proconvertase enzymes
Normal growth types
- growth is influenced by
Normal growth types
- Anabolic processes – protein, fat and cartilage synthesis
- Cell proliferation
a. Hyperplasia – increase in numbers
b. Hypertrophy – increase in size - Bone lengthening
a. Increased extracellular matrix
b. Occurs a lot during puberty to reach genetically resolved height - height achieved assuming adequate nutrients
Normal growth is influenced by
- Genetic resolve
a. Reliant on proper nutrients – especially in fetal development and early life history (1-4yr old) - Diet and nutrient transfer
a. If malnourished children increase nutrient intake as they grow – can correct; creates opportunity to address possible impacts on growth and reach genetic resolve - Disease and stress
a. If it occurs in early life – will often result in not reaching genetic resolve - Multiple layers of hormonal control -> dictates individual tissue growth and whole body growth
a. Ex. brain (individual), height (whole body)
Growth rate throughout life
- what increases during puberty and what are the sources
Neonatal growth occurs under the influence of placental hormones
After birth
o Brain – fairly developed by age 10
o Height – a lot in early life and again in puberty
Pubertal growth – GH levels increase dramatically
- Associated with gonad development in males and female
a. Androgen production
i. Males – testicular androgens are very important and increase dramatically during puberty
ii. Females – adrenal androgens increase
- Adrenal gland is important for female development – lack testes
- Adrenal androgens - dehydroepiandrosterone (DHEA)
- Play large role in development of secondary sex characteristics in females
b. Testosterone and estrogen both ultimately “put the brakes on” once genetic resolve has been achieved
Hypothalamic pituitary hepatic axis
- terms
- hormones released by each structure
- GH size and abundance
- when does it secrete
- triggers for release of hormones
- how is GH transported
Terms
o Somatostatin GHIH
o Somatotrophin GH
o Somatomedins IGF’s (insulin like growth factors)
Hypophysiotropic hormones (hypothalamus/higher neural centers)
a. Growth hormones releasing hormone (GHRH) -> stimulates production of GH
b. Somatostatin (growth hormone inhibiting hormone) -> inhibits production of GH
- Dominant regulatory hormone
Anterior pituitary - secretes somatotrophin (GH)
1. GH is produced in somatotrophs (adenohypophysial cell)
a. GH is a 191 amino acid long polypeptide (large)
b. It is the most abundant adenohypophysial hormone
• 4-10% of the wet weight of the gland (~ 5-10mg)
2. Functions in
a. General anabolism
b. Height and growth
3. Spontaneous secretion over a 24 h period
a. Usually peaks in the first 90 minutes of sleep – many repair mechanisms regulated by GH while we sleep
Triggers for release of GHRH and GHIH
1. GHIH - Exercise, stress and decrease in blood glucose
a. GHIH (somatostatin) - Inhibits GH release from ant pit & downstream affects
2. GHRH - Increase blood AA or fatty acids
a. GH (somatotropin) affects
i. Liver – promotes somatomedins (IGF’s)
o IGF’s - facilitates many actions of GH
- Implicated in increased cell division, protein synthesis, and bone growth
ii. Metabolic activities not related to growth
- Energy balance - Increased fat breakdown and decreases glucose uptake by muscle cells
- Increases concentration of glucose and FA in circulation to maintain homeostasis
- Mobilizes energy resources
GH is transported in plasma attached to one or more binding proteins
o Hydrophilic – still requires and binds to proteins
The somatomedin hypothesis
- types of somatomedins
- when were IGFs identified and how
- affects of IGFs
- insulin and IGF similarities - what are dimers attached by
“Growth hormone does not have a direct effect on growth of any given tissue but rather acts indirectly through somatomedins”
- Doesn’t mean GH doesn’t influence growth - it does influence growth directly but is often facilitated by somatomedins
Types of somatomedins (IGF’s)
1. 2 main somatomedins – both share many similarities with insulin
a. IGF I -> 70 AA
• Largely influenced by levels of GH
b. IGF II -> 67 AA
• Influenced less by GH
2. Mainly secreted and synthesized in the liver
IGF’s were identified in early experiments – Influencing bone growth from blood samples
3 treatments in experiment
1 – serum from a hypex mouse
a. Hypex = hypophysectomy -> connection between hypothalamus and pituitary is severed
o No signals from HPH axis -> no GH or IGF hormones
b. Saw no growth
2 – added GH + serum from hypex mouse
a. Saw no growth with only GH
3 – injected hypex mouse with GH then added serum from mouse
a. Saw growth
o Indicated that GH stimulated something else that stimulated growth IGF’s
Affects of IGF’s
1. IGF I is associated with long bone growth
a. Massive increase during puberty
• GH levels increase much less by comparison
• IGF I is primary driver of growth during puberty
b. Tissue specific regulation of IGF I synthesis is evident in terms of bone growth
2. IGF II is important during fetal development
a. Plays a role in adult growth – not as much as IGF I
Insulin and IGF receptor similarities
- Both single pass (1 MSR)
a. linked to tyrosine kinase domains – enzyme of ICF triggered by binding of ligand to ECF side - Both dimers
a. Monomers are attached by sulfate bridges
Bone tissue and cell types
- anatomy of bone
- spongy vs compact
- bone modelling
Bone is living tissue – surrounded by an extracellular organic matrix; have cell types with specific roles
- Cells – important in the modulation and shaping of bone and in calcium balance
a. Osteoblasts – bone builders
b. Osteoclasts – bone breakers (crushers)
Anatomy of bone
1. Diaphysis – the mature bone shaft
2. Epiphysis – at either end
a. Epiphyseal plate – separates the epiphysis from the diaphysis during growth
• Plate is Important in growth
b. Epiphyseal line – separates epiphysis from diaphysis after maturation
Compact vs spongy bone
o Compact – outer surface of bone; dense and used for support
o Spongy/trabecular – forms calcified lattice within compact bone
Bone modelling requires constant formation (adding cells) and breaking down (removing cells)
Bone growth
- width
- length
Bone growth width – occurs throughout life
- Osteoblasts – deposit new bone matrix on the outer edges of old bond to increase width
a. Produce osteoid that provide a framework for hydroxyapatite crystals
- Osteoid – mixture of collagen, enzymes and proteins
- Hydroxyapatite crystal – inorganic components of bone tissue composed of calcium and phosphate
- Within collagen matrix - Bone width formation is a dynamic process
a. Osteoblasts - turn into mature bone cells (osteocytes)
b. Osteoclasts - model the formation as bone grows
- Bone degradation will slightly outpace construction throughout life
- Bones become more brittle as we age
Bone growth length – occurs during puberty
1. Largely governed by IGF’s
o Growing pains – painful as bones lengthen
2. Process
a. Chondrocytes – cartilage cells located in the epiphyseal plates
- Lengthen bond by dividing and multiplying – proliferative cell layer
- Older cartilage cells enlarging at the border of the diaphysis – hypertrophic layer
b. Aspects of growth
i. Hyperplasia - lots of cell division
• Causes epiphysis to move apart from each other
• Direction of growth is towards the epiphysis
ii. Hypertrophia - increase in cell size
• Occurs near diaphysis
c. Ossification – chondrocytes disintegrate and osteoblasts lay bone on top of cartilage
- Provides matric for hydroxyapatite crystals to aggregate on
Dual effector theory
- what kind of local communication with IGFs
GH and IGF I both direct proliferation and hypertrophia
GH targets cells within germinal cell layer
1. Affects
a. Increase in transcription and translation of IGF I – local production of IGF hormone
• IGF production also occurs largely in the liver
b. Increase in the development of IGF I responsiveness
• increases receptor sensitivity and affinity – more efficient
IGF I functions in proliferative cell layer and hypertrophic layer
a. Functions as autocrine and paracrine factor
b. Affects
- Promotes cell division within proliferative layer – pushes epiphysis apart
- Promotes cytoplasmic maturation and cell size increase in hypertrophic layer
Abnormal growth
influenced by the HPH axis
Normal
o GH targets liver cells - promote synthesis and release of IGF’s
o IGF’s target somatic cells - stimulates growth
Primary dysfunction - dysfunction in anterior pituitary
1. Hyperactivity – increase in activity and release of GH
a. 2 phenotypes can result – dependent on when there is an increase
• During infantry - results in gigantism
• During puberty and adulthood - acromegaly
b. People who suffer from:
• Robert Wadlow – gigantism
• Andre the giant – suffered from both gigantism and acromegaly; Very hyperactive pit gland throughout infant and lifetime
2. Hypoactivity – decrease in activity and release of GH
a. Results in dwarfism – less GH being released less action of GH targeting the liver less IGF’s
• Won’t grow to genetic resolve due to mutation
Secondary dysfunction – dysfunction between pituitary gland and liver
1. Laron dwarfism - genetic mutation
a. Village in Mexico (Loja) – everyone within that village is short in height
• Due to genetic mutation
• Doesn’t seem to affect men as much
2. Many forms - all affect IGF I
a. Lack of GH receptors on liver - not as responsive
• Leads to lack of IGF I production
b. Reduced carrying capacity due to lack of binding proteins
• Reduced affinity/abundance of GH binding protein
• Reduced affinity/abundance of IGF binding protein
Tertiary dysfunction – end organ resistance
- IGF’s may not be able to impact the actions in long bone growth
- Can be influenced directly by GH
- If communication between GH and germinal cell layer is impacted - end organ resistance
Other hormones involved in growth
- hypothyroidism
- cross reactivity
- what family do they belong to
- Thyroid hormones – involved in energy homeostasis (balance and allocation)
a. Hypothyroidism – reduced growth; due to inability to produce sufficient TH
i. TH is largely permissive
- Permissive – presence of TH is necessary for another hormone to have its affects
- Critical for neuronal development - Insulin – involved in carbohydrate metabolism (glucose)
a. Deficiency can block growth and excess can promote growth, potential cross reactivity with IGF receptors
i. Deficient insulin – can block growth
ii. Excess – can promotes - Androgens & estrogens – arrest “long-bone” length growth through ossification of the epiphyseal plate after puberty
a. Different levels of hormones will cause different mechanisms
i. Prepubescent boy - low levels of androgens
ii. Puberty - increase in testosterone
- Androgens can promote muscle growth - no one hormone acts alone; different combinations
iii. Post puberty - causes ossification
- It reaches a certain concentration at a certain age that triggers we need to stop growing - Prolactin – belongs to the GH family; influences mammary gland growth as well as aspects of the immune system (lymphocyte growth)
a. Similar structure as GH - Placental lactogen – belongs to the GH family; influences neonatal development, maternal glucose and amino acid supply
a. Peaks around mid pregnancy until full term
b. Can play a role in gestational diabetes - there is a conflict between mother and fetus for nutrients
i. The mother presents as type II diabetic – creates conflict between mother and fetus for glucose
- Child is trying to rob mother of glucose
ii. 90% of women – once the baby is born they’re fine
Growth factors involved in growth
- Neurotropic factors – nerve growth factors (NGF’s)
a. Important for development and survival of neurons
b. Often used in early treatment of neurodegenerative disorders
i. Ex. Alzheimer’s - Erythropoietin – red blood cell growth factor
a. Promotes growth of RBC
b. Epo doping – athletes inject to promote RBC
i. Have blood drawn and store blood
ii. Use blood stores during training to promote o2 transfer and aerobic capacity
iii. Banned - Platelet derived growth factors – vascular injury repair; also involved in the development of atherosclerosis (hardening of arteries caused by buildup of plaque in the inner lining of an artery)
- Epidermal growth factors – enhanced proliferation of epidermis, gut lining, pulmonary lining
a. Evolutionary connection in EGFs
i. When herbivores graze leave saliva on plant
- There has been research that saliva promotes regrowth of plant
- Epidermal GF within saliva is deposited on plant and plant uses for growth - Tumour derived growth factors – angiogenesis (growth of blood vessels)
a. Tumors won’t grow without blood supply
i. Research – understanding how cancer cells direct and promote angiogenesis
b. Fibroblast growth factors
c. Transforming growth factors
i. Have different processes they target
Critical role of calcium regulation
- concentrations in ICF, ECF
- role in second messenger signalling and excitability
Linked to bone remodeling & Ca2+ in body
Regulation is critical
Highly regulated ion
1. 99% of Ca2+ is locked in bone within hydroxyapatite crystals
2. 0.9% in intracellular stores (vesicles and SER)
a. Overall concentration is higher than ECF but majority is sequestered within cells
• [free Ca2+] ~0.001 mM
o Requires active transport to move ICF to ECF (even through overall concentration is higher) Ca2+ ATPase
3. 0.1% in ECF
a. 0.05% is bound to proteins or negatively charged ions
b. 0.05% is free floating Ca2+
• [free Ca2+] ~2.5 mM
Plays a role in excitability of cells and second messenger signaling
a. Neuromuscular excitability – reduced calcium leads to tetanic muscle contraction and high levels lead to reduced muscular contraction
- High levels would lead to reduced contraction
- Reduced leads to tetanic muscle contraction
b. Stimulus secretion coupling – many cells will require calcium to allow substance to enter the cell to stimulate the secretion of a given substance
c. Cell to cell structure of tight junctions
d. Cofactor for clotting blood
e. Required for structural form of bone and teeth
Sources of Calcium
- how can ca2+ be excreted
- balance and homeostasis
- hormone effects (not super specific)
Balance – input and output regulated by diet
1. Dietary ca2+
a. Must maintain balance - dietary intake should equal loss in urine and feces
2. Loss through urine
a. if it is in the free form - passively filters into nephron (functional unit of kidney)
i. may be voided or taken back up by cells
o PTH - promotes reabsorption
o Calcitonin - inhibits ca2+ reabsorption from urine
b. if Ca2+ is bound to carrier - not freely filtered; benefit
Homeostasis – internal regulation that feeds into balance
1. Hormones functions
a. promote uptake of Ca2+ from small intestine calcitriol (PTH and prolactin)
b. promote deposition of ca2+ in the bone calcitonin
c. promote release of ca2+ from the bond into the ECF enviro
• small amount of ca2+ is present here; half is bound to carrier proteins
Calcium and phosphate
very closely linked; make up hydroxyapatite crystals of bony tissue
Bone – living tissue; hydroxyapatite crystals are between a collagen matrix
o Hydroxyapatite crystals – composed of calcium & phosphate; regulation of calcium always impacts phosphate concentrations
Precipitation of hydroxyapatite crystals – reversible reaction; calcium salts have low solubility
- If concentration of ca2+ and phosphate exceed solubility product - precipitation
a. Precipitation within bone - ca2+ and phosphate are shuttled toward spaces in bone; crystals precipitate out and provide strength of bond
b. If this occurs in the wrong place - kidney stones - Below solubility product constant - ions stay in solution
a. This is the goal in the ECF
Bone remodelling
- 2 sources of Ca2+
- cell function in bone remodelling
- what are cells derived from
2 sources of Ca2+ in bone – slow and fast component
- Fast – taking Ca2+ phosphate from bone fluid space; fast homeostatic regulation (ATM)
- Slow – taking from bony matrix; functions in balancing total body Ca2+ (teller)
a. Bony matrix - ca2+ and phosphate have exceeded coefficient & hydroxyapatite crystals are formed
b. In order to utilize requires 3 main cells
Remodeling (slow process) requires 3 cells that function deposition (formation of bone) and resorption (breakdown of bone)
1. Osteocytes – mature bone cells
a. Derived from osteoblasts – will differentiate into mature bone cells
• Osteoblasts – on peripheral bone; are actively building bone
• Osteocytes – more inner; star shaped
- Osteoblasts – bone builders; responsible for depositing the collagen matrix
a. Derived from stromal cells – connective tissue
b. Opposite function of osteoclasts - Osteoclasts – bone breakers; dissolve the hydroxyapatite crystals within bony matrix
a. Derived from hematopoietic cells/macrophages in bone marrow – stem cell derivation
• Stem cells also give rise to macrophages & blood cells (ex. platelets)
b. Key characteristics – make them beneficial as bone breakers
i. Jagged edges of the border – facing interface of cell/bone space
o Increases the surface area – allows for more interaction of any chemicals released from osteoclasts onto the bone
ii. Secrete - Hydrogen ions – decrease pH (more acidic)
- increases the solubility coefficient – causes faster dissolution of crystals; frees ca2+ and P
• H+ + PO43— HPO42—
• Decrease in PO43— causes increased dissolution of hydroxyapatite crystals - Cathepsin – enzyme that degrades collagen and other proteins
- Breaks down structure to free hydroxyapatite crystals - Osteoblasts and osteocytes – move free ca2+ and phosphate into the blood
a. Requires specific Ca2+ ATPase transporters
• Ca2+ ATPase are on surface of osteocytes and blasts – allows uptake of ca2+ into cell (active) from bone fluid space to release into blood
o Influences the solubility coefficient within bone fluid space -> decreased concentration of ca2+ within space
Hormones in osteoblast and osteoclast communication
- which cells secrete hormones
- also regulates Ca2+
Communication between osteoblasts and osteoclasts:
Osteoblasts & its precursor cells produce two main messengers
1. RANKL (receptor activator of NFκB ligand) – allows communication from osteoblasts to osteoclasts
a. RANKL binds to osteoclasts and macrophages
b. 2 effects
- Promotes differentiation of immature osteoclasts from macrophages
- Suppresses degradation of osteoclasts
c. Promotes osteoclast action -> reduces bone mass
2. Osteoprotegerin – inhibits RANKL by decreasing RANKL concentration within ECF space
• Causes decrease in osteoclast action - maintains bone mass
• Estradiol - stimulates the production of Osteoprotegerin
Bone resorption and deposition often balance
a. Bone resorption tends to slightly outpace bond deposition – brittle bones as you age
b. Most menopausal women – brittle bones are higher risk
• Estradiol decreases – lack signal to stop clast activation and activity & bone resorption outpaces bone deposition
Osteoporosis
- onset and loss thereafter
- therapy
- men vs women
Reduced bone mineral density & hydroxyapatite crystals
Onset of osteoporosis results ~1% of bone mass is lost every year after
o Therapy efficacy depend on reason for osteoporosis presence in the first place
Therapy includes:
a. Exercise
b. Ca2+supplements
c. HRT
d. Calcitonin
e. SERMS and ANGELS
- Serms – selective estrogen receptor modulator
- Angels – activators of nongenomic estrogen like signaling
Prevalence in men and women
a. Lower prevalence in men – primary sex steroid is androgens; lower levels of estrogens
- Testosterone is converted by aromatase to estrogens
- Aromatase is expressed is cells that surround bone matrix and hydroxyapatite crystals -> convert androgens to estrogens so estrogen levels are more constant
b. Prevalent in pre and post-menopausal women – due to decrease in estradiol concentrations
3 main hormones in regulating Ca2+
- Parathyroid hormone
- Vitamin D/calcitriol/cholicalciferol
- Calcitonin
Parathyroid hormone
Strong negative relationship between plasma [PTH] concentration and plasma [Ca2+]
Extremely sensitive
1. Ca2+ sensing receptors on parathyroid gland
a. Decrease in [Ca2+] causes increase in PTH secretion
o PTH is hypercalcemic causes increase in ca2+ concentration in blood
Function of PTH
1. Stimulates osteoclast activity - promotes the dissolution of crystals within mineralized bone area (slow regulation of Ca2+)
2. Kidney - 2 effects (mass balance)
a. Increases ca2+ resorption – more reuptake into body in renal tubes
b. Decreases phosphate resorption
• Ca2+ and P are regulated together - decrease in phosphate causes increase in dissolution of hydroxyapatite crystals to free both ca2+ and P
3. Intestine - Important in absorbing ca2+ from diet (mass balance)
a. Actions are indirect through simulation of vitamin D3 production
Vitamin D3
- effects
- what occurs in a hypocalcaemic event
- target sites of vitamin D (in gut)
- WHAT CAN OCCUR IN CELLS
- lack of vitamin D
calcitriol (cholecalciferol)
Often considered a hormone - can be produced in the skin from 7-dehydrocholesterol
1. Needs to be converted to 1,25-dihydroxyvitamin D3
a. Cholesterol is one of the substrates
2. Structure
a. 1,25 – (OH2) – vitamin D3 (calcitriol)
3. OH group addition -> steroid hormone becomes vitamin D3
a. Vitamin D is a seco steroid – similar structure to normal steroids that we synthesize (4 carbon rings)
• Seco – one aromatic rings is broken
4. Two important enzymatic steps in sequential addition of hydroxyl groups to structure
a. Activation of 1α hydroxylase -> enzyme is regulated by PTH; activating step
• PTH promotes the activity of 1a hyd to promote the synthesis of vitamin D
Regulation of vitamin D with PTH (make diagram**)
1. Vitamin D3 is hypercalcemic - causes increase in plasma Ca2+
2. In hypocalcaemic event (low calcium)
a. Vitamin D production
i. Sunlight UV radiation assists in conversion of cholesterol derivative to vitamin D in the skin
o Moves to liver – additional OH group is added to position 25
o Moves to kidney – another OH group is attached in position 1
- Catalyzed by 1α hydroxylase -> stimulated by PTH (+)
- Converts precursor to active vitamin D3 hormone
ii. Active vitamin D3 targets
o Gut – promote ca2+ uptake
o Bone – promote ca2+ dissolution
o Kidney – ca2+ reabsorption
iii. Increased vitamin D3 -> increase in ca2+ in circulation -> decrease in PTH release from parathyroid gland
o Reduction of PTH stops to promotion of vitamin D
Target sites of NB vitamin D (make diagram**)
1. Steroids are hydrophobic – has a genomic effect (slow intracellular affect)
a. Also has a rapid response – indicates binding to membrane receptors to illicit response
2. The gut – probably the best documented area of vitamin D3 action
a. Vitamin D influences all components in enterocytes
i. Rapid and slow components
o Rapid – mainly facilitated by binding to cell membrane receptor
o Slow – binding to nuclear receptors
ii. Initiates transcription and translation of
o TRPV-5 channels – allows influx of Ca2+ down gradient
o Calbindin & calmodulin – sequestering of Ca2+ within cell
o NCX pump and Ca2+ ATPase – active transport from ICF to ECF
b. Many transport proteins involved in moving ca2+
i. Lumen = ~1mM ca2+
ii. ICF = ~100nm ca2+ (much smaller than ECF)
o Apical membrane – passive movement of ca2+
- TRPV-5 – epithelial ca2+ channels (ECaC) allows passive movement from lumen to ICF
o Sequestering of Ca2+
- Calbindin and calmodulin – bind ca2+ within cell to maintain low concentration
- Ca2+ can also be taken up by organelles
iii. ECF = ~1.2 mM ca2+
o Basolateral membrane – active transport
- NCX pump – secondary active transport; Na+ Ca2+ exchanger
• Relies on Na+ gradient initially established by Na+ K+ ATPase
- Plasma membrane Ca+ ATPase – primary active transport
Lack of vitamin D -> lack ability to bring Ca2+ into the blood
- Ricket’s disease – brittle bones
Calcitonin
- where is it synthesized
Effects
- Hypocalcaemic hormone – reduces plasma Ca2+
- The only hypocalcaemic hormone - Hypophosphatemic – reduces plasma phosphate
Synthesis and secretion within the thyroid gland
o Parafollicular cells – clear cells (c cells); between thyroid hormone follicles
PTH and calcitonin – antagonistic effects
- Increase in plasma ca2+
a. Reduces PTH
b. Increases calcitonin - Decrease in plasma ca2+
a. Reduces calcitonin
b. Increases PTH
Not involved in constant regulation - may be involved during the absorptive state & pregnancy
1. Absorptive – post meal
a. High influx of ca2+ will reduce if too much ca2+ is present in circulation
2. Pregnancy – milk is rich in ca2+
b. Newborn requires ca2+ prevent ca2+ levels getting too high
• Satiety hormone – triggers stopping of feeding when infant is suckling
Thyroid gland
- anatomy and vascularization
produces thyroid hormones
- Well vascularized tissue – important in thyroid hormones, PTH, and calcitonin release
o Carotid artery – running down either side
o Sinusoidal capillaries – go through follicles - Parathyroid gland functions independently of thyroid gland but is right on top of the tissue
Thyroid hormones
- 2 main types & main function
- synthesis and structure of TH
- goiter
2 main hormones – tetraiodothyronine (T4) and triiodothyronine (T3)
1. Both are involved in the regulation of metabolic rate and are key during development
2. Both derived from thyroglobulin – precursor molecule
a. Inefficient synthesis
• Thyroglobulin is a very large precursor molecule (over 200 AA) – very few thyroid hormones (only 1 AA) are synthesized from these
3. Synthesized in follicles – fairly inefficient
a. Follicular cells – surround colloid space
b. Colloid – glycoproteins
Synthesis of T3 and T4
1. Precursor is tyrosine – nonessential AA (can be made by the body)
a. 2 tyrosine are linked together by ether link – oxygen bond
i. Position of tyrosine carbon rings are important in function
o Inner tyrosyl ring
o Outer phenyl ring
2. Iodine/iodide (ion) – essential component of our diet
a. Goiter – abnormally functioning thyroid gland; very prevalent 100 years ago
i. Main causes – a lack of dietary iodine
o Today – most table salt is supplemented with iodine
ii. Main demographic – young to middle aged women
o Not entirely understood
Differentiation of hormones
1. T4 -> 4 iodine’s attached
2. T3 -> 3 iodine
a. Most functionally relevant – primary biologically active component in pathway
b. 2 types – dependent on placement of iodine
i. Triiodothyronine T3 -> 2 iodine on inner tyrosyl ring
• Loss of iodine on outer phenyl ring
ii. Reverse T3 -> 2 iodine on outer phenyl ring
• Loss of iodine on inner tyrosyl ring
• Some function -> not as prevalent as T3
3. T2 -> 2 iodine’s attached to the backbone
4. T1 -> 1 iodine attached to the backbone
Hypothalamic pituitary thyroid axis
- detailed synthesis of TH
Hypothalamus – secretes TRH -> stimulates anterior pituitary
Pituitary gland – secretes TSH -> stimulates follicular cells of thyroid gland
a. TSH binds to GPCR -> initiates adenylyl cyclase pathway
- TSH stimulates many varieties of factors within thyroid follicular cell
Within follicles of thyroid gland -> TH are synthesized (make diagram**)
1. Iodide must enter the follicular cell from ECF
a. Iodine concentration is typically higher in ICF
- Na+ I- symporter – secondary active transport
- Iodine moves into cell up concentration gradient
- Na+ moves into cell down concentration gradient
- Initially established by Na+ K+ ATPase
b. Iodide is moved from basolateral to apical membrane
• Pendrin – ionic transporter; moves iodine from ICF to lumen of follicle
2. Peroxide generating system – within follicular lumen
a. Thyroid peroxidase converts I- to free radical iodide – high energy emitting; causes damage to neighboring molecules
• Must be created within follicular lumen/colloid space in ECF – could otherwise damage cell
b. Free radical is required to couple to ring structures of tyrosine molecule via oxidative coupling – binds tyrosine residue on thyroglobulin molecule
3. Thyroglobulin – synthesized in follicular cells and secreted into colloid/lumen
a. Precursor to TH
i. Very large molecule
o Has 2 identical subunits – both 330 kilodaltons
ii. Only about 4-6 tyrosine residues per thyroglobulin
o Iodine radicals must bind to tyrosine residues – limits the number of TH synthesized
b. Thyroid peroxidase – catalyzes oxidative coupling of iodine free radicals to tyrosine residues on thyroglobulin
i. MIT and DIT
o monoiodotyrosine – 1 iodine
o diiodotyrosine – 2 iodine
ii. MIT and DIT -> further oxidative coupling to T3 or T4
o Still attached to thyroglobulin molecule at this stage
o MIT + DIT = T3
o DIT + DIT = T4
4. Endocytosis of colloid droplet into follicle – thyroglobulin with T3 and T4 attached
a. Fuses with secondary lysosome
• Releases T3 and T4 enter into circulation
5. Deiodination
a. Thyroglobulin’s iodotyrosines are recycled – iodine is expensive
• Shuttled back to processing area for TH synthesis
• Deiodinase – enzyme recycles iodotyrosines to iodine & Also converts T4 to T3 or reverse T3 – will be located in tissues that T3 and T4 are moved to
b. Deiodinases can have a strong preference for specific TH’s
i. Type I -> preference for reverse T3
ii. Type II -> deiodinates only the outer ring
o coverts T4 to T3
iii. Type III -> deiodinates only the inner ring
o converts T4 to reverse T3
c. Can be tissue specific
i. Type II is highly expressed in the liver
o Outer ring deiodination coverts T4 to T3
IRD – inner ring deiodination
ORD – outer ring deiodination
Actions of thyroid hormone
Calorigenic – TH is the most important regulator of basal metabolic rate
1. Balancing energy input and output
a. Input – allows storage of energy as lipids or use immediately
i. Internal and external work
o Internal – general cell function
o External – movement
b. Output – all generate thermal energy
2. Promotes the consumption of energy generates processes withing cell
a. Futile cycles – important in generating heat
• Ex. promotes the insertion of Na K ATPase into cell membranes – forces change in membrane potential
- Energy used by ATPase – heat is a byproduct
b. Brown adipose tissue – generates heat through futile cycles stimulated by thyroid hormone production
• Common in infants
o Initially thought we could not produce heat through adipose tissue past infancy – we’ve learned that we can through similar mechanisms
Sympathomimetic effect – action similar to the sympathetic nervous system
1. Ex. in cardiovascular regulation
a. Promotes increases in catecholamine receptors and their effects
b. In heart – epinephrine and NE can increase
• heart rate – chronotropic effect (time/rate)
• stroke volume – inotropic effect (increasing force of contraction of the ventricle in a single cardiac cycle)
Cardiovascular – largely a result of the increase in catecholamine receptors and calorigenic effects
Growth – synergistic actions with both GH and IGF’s. TH is essential for normal growth and neural development
o Critical role of TH during development – neural development
Thyroid hormone abnormalities
- 2 types - common effects
- primary vs secondary
- medicating
- removal
common endocrine disorder (close to type II diabetes); prevalent in young women
2 types – hypothyroidism & hyperthyroidism
1. Both are characterized by Goiter – enlargement of the thyroid gland due to overstimulation
a. Overstimulation of thyroid gland is not necessarily related to the capacity of the gland to synthesize and release TH
• Can be linked to autoimmune disorders
2. Exophthalmos – bulging eyes
a. Common feature of Graves disease – an autoimmune disease
• Link between overactive thyroid gland is not well understood
b. Caused by buildup of fluid and carbohydrates behind the eye – forces the eyeball outwards
Hypothalamic pituitary thyroid axis
a. TRH -> TSH -> T3 and T4
- Components can negatively feedback and stop stimulus from previous steps
b. Primary dysfunction – at thyroid gland
c. Secondary dysfunction – at anterior pituitary or hypothalamus
When medicating – can overshoot and cause symptoms of both when trying to balance medication
Removal of thyroid gland – it can be much easier to maintain medicated levels
Hypothyroidism
- causes
- symtoms
lacking TH
Causes 1. Primary dysfunction – dysfunction in the thyroid gland; not making enough T3 and T4 a. ↓T3& T4, ↑TSH i. TSH wants to increase T3 and T4 o Hypothalamus – produces more TRH o Pituitary – produces more TSH ii. TSH target thyroid and promotes hypoplasia and hypertropia of follicular cells o Causes goiter b. Goiter present
- Secondary dysfunction – hypothalamic or anterior pituitary failure; unable to produce sufficient TRH or TSH
a. ↓T3& T4, ↓TRH and/or ↓TSH
• Reduced signaling mechanism – doesn’t promote thyroid synthesis
b. No goiter - Lack of dietary iodine – similar to primary failure; can’t make enough T3 and t4 (not enough iodine)
a. ↓T3& T4, ↑TSH
b. Goiter present
Symptoms o Low BMR o Decreased perspiration o Slow pulse o Lowered body temperature o Cold intolerance o Lethargy, tiredness o Weight gain o Loss of hair o Edema of face and eyelids o Menstrual irregularities o Goiter (may or may not be present)
Hyperthyroidism
- causes
- symptoms
increase in T3 and t4 production
Causes
1. Abnormal presence of long acting thyroid stimulator (LATS) – Grave’s disease
a. Signaling mechanisms from hypothalamus and pituitary is still working
b. Antibody (part of autoimmune disorder) – acts in place of TSH and promotes thyroid hormone synthesis and release and enlargement of glands
i. ↑T3& T4, ↓TSH
o Presence of T3 and T4 inhibits TSH
c. Goiter present
- Secondary dysfunction – excess hypothalamic or anterior pituitary secretion
a. ↑T3& T4, ↑TRH and/or ↑TSH
• Overstimulation of thyroid gland and increase in T3 and T4
b. Goiter present - Hypersecreting thyroid tumour – increasing T3 and T4 production (primary dysfunction?**)
a. ↑T3& T4, ↓TSH
• Inhibits TSH production
b. Goiter is often not present
• You would expect there would be due to presence of tumour -> not often the case
Symptoms o Elevated BMR o Increased perspiration o Rapid pulse o Increased body temp o Heat intolerance o Nervousness and anxiety o Weight loss o Muscle wasting o Increase appetite o Exophthalmos (sometimes) o Goiter (primary or secondary in origin)
Melatonin
- synthesized from what AA
- rhythms - universality and resetting
- effects
- regulation of effects
Released from the pineal gland
Synthesized from the amino acid tryptophan
Synthesized and released rhythmically 1. Closely related to circadian rhythms a. Regulated by light • Scotophase (dark) – stimulates synthesis and release • Photophase (light) – inhibits release b. Universal for humans • Polar regions can be light or dark for 24 hours a day – rhythm of melatonin synthesis is still maintained through optic tract o it fluctuates in different seasons c. Peaks in the middle of the night
Enzymes involved in synthesis of melatonin also follow a daily rhythm
Reproduction follows cycles – there is a link between melatonin-sex hormones and reproduction
1. Hypothalamic pituitary gonadotropin axis (HPG)
2. Research on the antigonadotrophic actions of melatonin in long day breeders – animals that breed in spring after winter
• Longer days - total amount of melatonin released becomes less because the nights shorten
• Longer night - less breeding
Pleotropic effects – many processes (similar to TH)
o Aids in sleep
o Antigonadotrophic actions (lessen reproductive hormones) – affects humans as well
Rhythm is regulated by the link between suprachiasmatic nucleus and pineal gland
- Suprachiasmatic Nucleus (SCN) – major biological clock
a. PER genes are expressed into CLOCK proteins – cycles at a constant rate that shifts depending on light cues
i. 3 families of PER genes
- PER I – expression is continuous in darkness
ii. Expression of genes and translation to clock proteins runs at 24 hours + 11 min (+ or – 16 min)
- Slightly offset from 24 hour clock - Resets daily to 24 hour cycle based on the earths rotation
a. Lower light levels in nocturnal species and humans that are exposed to longer nighttime – still allows clock to reset
- Linked between optic tract and pineal gland – important in regulating daily rhythms
2 pathways
1. Inferior accessory optic tract
2. Retino hypothalamic pathway
a. Sunlight in daytime – retina receives photo info
i. Melanopsin – released from the back of eyeball -> activates retino-hypothalamic pathway
- Stimulation of SCN -> brainstem -> spinal cord -> preganglionic fibres -> synapse onto superior cervical ganglions (post ganglionic fibres) -> synapse onto pineal gland -> decreased secretion of NE
ii. Sunlight = less NE
b. Nighttime – no stimulus of retino pathway
o NE increases -> acts as nt to promote pineal gland activity -> promotes melatonin synthesis and release
Adrenal gland
- anatomy - what does each hormone balance
- axis
- Adrenal medulla – release catecholamines
a. Often considered an extension of the sympathetic NS
i. Preganglionic neurons release Ach onto adrenal medulla – acts as a modified post ganglionic neuron
b. Primary products
i. Epinephrine ~ 80%
ii. Norepinephrine ~ 20% - Adrenal cortex – there are primary steroid hormones released from each (adrenal steroids)
a. Zona glomerulosa – aldosterone
i. Mineralocorticoids – balances minerals
b. Zona fasciculata – cortisol
i. Glucocorticoids – balance glucose and energy
c. Zona reticularis – DHEA (adrenal androgens & some estrogens)
i. Adrenal sex steroids play larger role in females and development of secondary sex characteristics – lack other types of androgen synthesis
ii. Sex hormones
- Dehydroepiandrosterone & androstenedione – androgens
- Estrogens
Hypothalamic pituitary adrenal axis (HPA axis)
- Hypothalamus CRH
- Anterior pituitary ACTH
- Adrenal cortex
a. Cortisol
b. Aldosterone – life essential hormone
- Proximity to kidney – hormones are involved in adrenal function
- Not many hormones are absolutely life essential – there are usually backup systems that will maintain function
Adrenal cortex
- hormones
- synthesis of hormones (precursors)
Precursors for hormones – most reactions are reversible (steroids are expensive to make and you want to be able to utilize that energy if you need it)
1. Adrenocorticosteroids
a. Corticosterone – precursor for
• Cortisol – major glucocorticoid in humans
• Aldosterone – major mineralocorticoid in humans
2. Sex steroids
a. Androgens
i. DHEA -> androstenedione -> testosterone -> DHT (terminal steroid)
ii. DHEA - dehydroepiandrosterone
iii. DHT - dihydrotestosterone
- Terminal steroid – cannot be reversed (many other can be reversed)
b. Estrogens
i. DHEA -> androstenedione -> aromatase -> estrone
ii. Aromatase – key enzyme in conversion of androgens to estrone; creates an aromatic ring structure in the first ring that forms androgens
- Allows conversion of androgens to estriols within the bony tissue
iii. Testosterone -> aromatase -> estradiol -> estriol
o ex. within bony tissue – makes men less prone to osteoporosis
Synthesis of adrenal hormones
1. Cholesterol is a precursor to hormones of adrenal gland – required for steroid synthesis
a. Side chain (after 20 carbon) – important in steroid synthesis
i. P450 sidechain cleavage enzyme (P450SCC) – key enzyme required to synthesize steroids (steroidogenesis)
- Removes sidechain carbon – different amounts depending on parent molecule being synthesized
- First step in steroidogenesis
2. 3 main parent molecules
a. C = number of carbon atoms in a molecule
b. Functionally
• Pregnane – pregnenolone (C21)
• Androstane – androgens (C19)
• Estrange – estrogens (C18)
Mineralcorticoid function
Aldosterone
- secretion
- effects & where does it act
- levels of dysfunction (name)
- hyperaldosteronism
- Secretion of aldosterone
a. Largely independent of pituitary gland
b. Regulated by
i. Renin angiotensin system
- Angiotensin II especially
ii. Circulating K+ concentrations – direct affects - Aldosterone – acts on the distal and collecting tubules of the nephron in the kidney; promotes Na+ resorption and K+ excretion in kidney
a. Regulates body fluid volume -> implications on the renal and cardiovascular systems
i. Increased Na+ uptake = increased volume within body
ii. Increased K+ secretion = decreased volume within body
b. The steroid is essential for life -> cells cannot number if concentrations of K+ and Na+ are affected
i. All vertebrates have – cells cannot function without correct concentrations of Na+ and K+
ii. Body has evolved to have “backup systems” – aldosterone does not have a backup system - Hyperaldosteronism
a. Levels of dysfunction
i. Primary -> Conn’s syndrome
- At adrenal gland
ii. Secondary
b. Symptoms
i. Hypernatremia – too much Na+
ii. Hypokalemia – too little K+
iii. Usually hypertension
- Especially common with hypernatremia – increased Na+ in ECF will cause movement of water out of cells -> increased volume in vessels and increased pressure
Dehydroepiandrosterone (DHEA) function
- products
- sex differences
- adrenogenital syndrome
- adrenarche
- Adrenal gland produces small amounts of androgens and estrogens from DHEA
a. DHEA – an adrenal androgen -> can be converted by aromatase - Sex differences
a. Males -> testosterone overpowers the actions of DHEA
i. Gonads produce androgens
b. Females -> lack other sources of androgens; DHEA plays a role in the pubertal growth spurt, hair growth and the female sex drive
i. Gonads produce estrogen - Adrenogenital syndrome – too much DHEA; symptoms are dependent on sex and age of hyperactivity onset
a. Adult females – masculinization, facial hair, deepening of voice etc
b. Newborn females – psuedohermaphrodism born with male genitalia phenotype
i. Can reverse during puberty – does not always
c. Adult males – no effect (testosterone overpowers anyway)
d. Pubertal males – precocious pseudopuberty adult male phenotype (secondary sex characteristics) is expressed but they are infertile - Adrenarche – unique to humans and old world monkeys
a. In females
i. Stead increase in fetal development of DHEA – peaks at birth
- May be related to triggering parturition
ii. Post birth
- Declines & stays low in early years
- Increase during onset of puberty -> increase in sexual development
- Peaks and declines slowly throughout life
Glucocorticoids
- what kind of release
- direct actions
- permissive actions
- anti inflammatory and immunosuppressive
Release
a. HPA axis (hypo pit adrenal)
i. CRH/CRF (f = factor) stimulates ACTH cortisol in adrenal cortex
- ACTH precursor is POMC = pro-opiomelanocortin
- POMC produces multiple complexes -> ACTH, endorphins and MSH
- Cortisol has a steroid base
ii. Cortisol release is continuous – normally peaks in the morning and decreases at night
Direct actions
a. Catabolic effects – breakdown of macromolecules to be used for energy
b. Increases blood glucose (hyperglycemic) – linked to stress response (mobilizing energy reserves)
i. Stimulates gluconeogenesis – generation of glucose from non-carbohydrate substrates (amino acids, pyruvates, glycerol)
ii. Inhibits glucose uptake by many peripheral tissues (ex. muscle cells)
- Makes more available to nervous system to maintain brain function
c. Increase in blood amino acids
i. Stimulates protein degradation in muscle
d. Increase in blood fatty acids
i. Stimulates lipolysis – alternative energy source
Permissive actions
a. Enables glucagon activity – also hyperglycemic
b. Enables catecholamine activity – modifies within synaptic clefts through the regulation of enzymes involved in degradation of NE and E
i. Vascular collapse can occur during stressful events if glucocorticoids are absent
- Very rare – speaks to how important presence of cortisol is in a stressful event
- NE and E regulate blood vessels – especially required during acute stressful events
Anti-inflammatory and immunosuppressive
a. Prevention of leucocyte infiltration into the wound site
b. Atrophy of lymphatic system
i. More chronic stress – inhibit ability to fight infection
- Ex. during exams – getting colds
c. Anti-inflammatory effects are seen in supra physiologic (far above physiological levels) or pharmacologically induced states
i. Cortisol injection in site of inflammation – injection site is critical to have proper effects
ii. NSAIDS – nonsteroidal anti-inflammatory agents
- Ex. ibuprofen & advil & Tylenol
Dysfunction of cortisol release
Causes and symptoms:
- Cushings
- Addisons
Cushings syndrome – hypersecretion
a. Causes
i. Increased CRH or ACTH
- Excessive activity in hypothalamus or anterior pituitary – secondary or tertiary
ii. Adrenal tumours at adrenal gland – primary
iii. Ectopic ACTH release – atypical tissue releasing ACTH
- Many reasons this occurs
b. Symptoms include:
i. Excess glucose – cortisol promotes energy liberation
- Adrenal diabetes – elevated levels of glucose in blood
ii. Fat deposition in the face and abdomen, thin legs and arms
iii. Facial hair excess
Addisons disease – hyposecretion
a. General name for bilateral damage to the adrenals – there are many forms of addisons disease with varying severity
b. Can also be primary or secondary in nature
i. Damage to adrenal – primary
ii. Pituitary or hypothalamus – secondary or tertiary
c. Symptoms include:
i. Increased integument pigmentation
- HPA axis – CRH release in hypothal -> ACTH in pit -> cortisol from adrenal gland
a. Reduction in cortisol due to bilateral damage negatively feeds back and increases CRH and ACTH
i. Increase in ACTH -> requires increase in POMC
- POMC – precursor to multiple hormones
- MSH - promotes skin pigmentation
ii. Weakness, weight loss, hypotension, salt craving and hypoglycemia
- Hypotension & salt craving – linked to lack of aldosterone (losing too much Na+)
- Hypoglycemia – lack of cortisol
- Weakness and weight loss – burning more energy to try and promote glucose production
a. Linked to lack of cortisol and epinephrine
i. Lessened ability to access glucose -> leads to weakness and lethargy
ii. You still have energy but it’s not as efficient
General adaption to stress
- origins
- 3 stages
Developed from Canon’s ideas on “Fight or flight” and Hans Seyle’s “General adaptation syndrome”
o General adaption syndrome – general alarm response they would display regardless of stimuli they were faced with
3 stages
- Primary alarm response – during acute response
a. catecholamine surge into the system – lots of NE and E
b. ↑ in basal metabolic rate (BMR) – mobilize energy reserves
c. ↑in blood flow to required organs – the brain and muscles
i. Away from intestine
d. hepatic glycogenolysis – breakdown of glycogen into glucose - Secondary resistance response
a. Effects of cortisol -> increases blood glucose, FA, AA
i. mobilization of glucose for central organs – the brain
ii. breakdown of alternative energy stores – lipids and proteins
- gluconeogenesis – forming glucose from other sources - Tertiary exhaustion response – maladaptive
a. muscle wasting, hyperglycemia (diabetes mellitus)
b. atrophy of the immune system, gastric ulcers
c. vascular derangements
d. impacts on cardiac functions
i. chronic stress -> prone to heart attacks
Adrenal medulla
- extension of
- effects on catecholamines - where are they stored
- receptor promiscuity
- ephinephrine effects
Extension of sympathetic NS – preganglionic fibres synapse onto medulla and release Ach
Acts in primary alarm response
Catecholamine release is largely under the control of the SNS
o Chromaffin granules – stores NE and E
o 80% epinephrine and 20% nor-epinephrine
NE and E are active ligands in the adrenergic system – bind to adrenergic receptors: α1, α2, β1, β2, β3
- Large area of research
a. Effects of ligands on different isoforms of receptors - Receptors are promiscuous?? (double check)
a. Both NE and E bind to all isoforms – there are isoforms of the 5 listed (ex. alpha 1A and B)
b. Will have different effects depending on receptor bound – receptor that is expressed at target site is just as important as what hormone is released
Epinephrine effects
1. Rapid mobilization of the bodies energy reserves
2. Increase cardiac output and total peripheral resistance
a. Increase in cardiac output – caused by both chronotropic and inotropic effects
• Chronotropic – increased HR
• Inotropic – increased contraction force
3. Increase coronary and skeletal muscle arteriolar dilation – powers fight or flight
4. Reduce gut motility – non essential
5. Increases glycogenolysis in liver and muscle
6. Increased CNS alertness
7. Dilates pupils and flattens the lens
8. Increases sweating
Adrenoreceptors
- pharmacological development
Opposing effects of ligand depending on what receptor the ligand is bound to
α1 - Most sympathetic target cells
a. Not all sympathetic target cells
i. ex. B2 is expressed in some
b. ligand affinity -> NE > E
c. 2nd messenger -> activates PLC
d. Generalized arteriolar vasoconstriction
α2 - Digestive system
a. ligand affinity -> NE > E
b. 2 mess -> ↓ cAMP
c. Decreased motility in digestive tract during acute stressful event
β1 - Heart & kidney
a. ligand affinity -> NE = E (equivalent)
b. 2nd mess -> ↑ cAMP
c. Inotropic and chronotropic actions
i. Betablockers – targets this receptors within the heart
- Pharmacological treatment to reduce impacts of NE and E
β2 - Skeletal and smooth muscle in some blood vessels and organs
a. ligand affinity -> E > NE
b. 2nd mess -> ↑ cAMP
c. Glycogen breakdown in skeletal muscle, bronchiolar dilation, and smooth muscle dilation in blood vessels in the heart
i. Heart blood vessel dilation – facilitate blood flow
ii. Bronchiolar – increased oxygen uptake
β3 - Adipose tissue
a. ligand affinity -> NE > E
b. 2nd mess -> ↑ cAMP
c. Mobilizes lipids for subsequent catabolism – energy reserves are mobilized
Ephinephrine reversal
- pharma
Antagonistic effects due to the differing effects depending on which receptor is activated
a. Multiple receptors with different responses – can reverse the response
o Both can be expressed in blood vessels – regulation of vascular tone where E can dilate and constrict the same blood vessel
b. Numerous agonists/antagonists for adrenoreceptors have been developed
o Betablockers
o Phenylephrine is an antagonist specific for α adrenoceptors – used to regulate hypertensive effects
Integrated stress response
Hypothalamus activates SNS -> release of E from adrenal medulla
a. E stimulates pancreas & arteriolar smooth muscle
i. Pancreas - Increase in glucagon and decrease insulin
• Insulin is hypoglycemic – will remove glucose from circulation
• Glucagon is hyperglycemic – will increase glucose in circulation
ii. Vasoconstriction in blood vessels - decreases renal blood flow
• Increase in renin -> increases angiotensin -> increases aldosterone
Hypothalamus releases CRH -> releases ACTH -> releases cortisol
Exocrine vs endocrine
Exocrine – acinar cells; secrete juice into duodenum
a. In response to acidic chyme entering from the stomach
- Entering of chyme causes release of secretin from the endothelial cells lining the duodenum
- Stimulates the acinar cells of the pancreas to release enzymes and alkaline juice to neutralize and digest
Endocrine – islets of Langerhans; secrete into blood vessels
o Release many hormones
Islets of Langerhans
- cells
- hormones released
- effects
All hormones are involved in regulating fuel metabolism and all act at multiple levels
Insulin & amylin - released from B or β cells
a. 10:1 ratio of insulin to amylin
b. Insulin – hypoglycemic hormone
c. Amylin – released with insulin following a meal
i. Slows down the absorbance of glucose in intestine to prevent dramatic spike in blood glucose
- Assists insulin to prevent hyperglycemia
Glucagon - released from α cells
a. Acts antagonistically to insulin
b. Hyperglycemic
Somatostatin - released from D or δ cells
a. Released in response to increased glucose and amino acid levels
i. Acts as paracrine and autocrine signal to regulate release of hormones from alpha, beta cells and F cells
- D cells are always close to a and B cells – local regulation of insulin and glucagon
ii. Inhibits digestion, absorption, and mobilization of energy reserves – your blood levels are already high
b. Plays a role in inhibiting GH
i. In the pancreas – largely independent of GH axis
Pancreatic polypeptide (PP) - released from PP or F cells
a. Increase in plasma PP postprandial (after meal)
b. Antagonistic to somatostatin
i. PP levels suppress SST levels and vice versa
Complex integration and regulation between 4 cells types
a. D and F cells may be regulating each other (as well as αand βcells)
Insulin secretion activation
Increase in blood glucose -> glucose enters b cells -> converted through glycolysis to produce ATP -> increase in ICF ATP -> inhibit ATP gated K+ channels -> changes RMP -> allows L type Ca2+ to open -> ca2+ moves into cell -> increase in ICF Ca2+ causes release of insulin into circulation -> insulin secretion from B cells into circulation
Metabolism
- energy sources
- metabolism
- balance between anabolism and catabolism
Energy sources – Carbohydrates, Fats and Proteins
o Carbs – primary (glucose)
Metabolism – a generalist term for the chemical reactions that occur in the body
a. Anabolism – energy requiring (ATP); synthesis of larger macromolecules either for function or energy storage
b. Catabolism – energy releasing; breakdown of macromolecules
- hydrolysis: glycogen →glucose
- oxidation: glucose →ATP (cellular respiration)
Balance between anabolism and catabolism
a. Not always completely balanced
i. Growth periods
ii. Short and long term “gaps” in food intake
• We’ve evolved to deal with food shortages
iii. Absorptive (fed) and post-absorptive (fasted) states
• Fluctuations in hormones due to presence of food or lack of food in the body
Increasing and decreasing glucose
- not hormones - body functions
balancing energy demands of the body
To increase blood glucose
- absorption from GI tract
- hepatic glucose productions
a. glycogenolysis – glycogen into glucose
b. gluconeogenesis – carbs and fats into carbs then glucose
decrease blood glucose
1. transport into cells
a. energy production – cellular work
b. energy storage – storage as glycogen
2. excrete excess
a. glucose is osmotically active – high concentration will cause movement of water into urine to balance
• key symptom of diabetes – high urine flow rate due to concentration of glucose
Insulin
- synthesis
- release
Synthesis
- proinsulin – a chain and b chain connected by c peptide
a. this is packaged in secretory vesicles in beta cells prior to release
b. proinsulin can be released into circulation – not as common - more often released as mature peptide into blood
a. c peptide is cleaved – releases mature peptide
b. 3 disulfide bonds between a and b chain – cystine residues
Release
- High glucose and amino acid concentrations -> insulin secretion (positive relationship)
- Feed forward regulation by glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP)
a. Signaling rom gut -> pancreas to promote insulin secretion to prepare for influx of glucose into blood stream
b. Peptides studied by Bayliss and Starling – determining anticipatory response in dogs
Effects of insulin
a. carbs
- skeletal muscle and adipose tissue
- effects of exercise on diabetes II patients
- liver
- brain
- gluconeogenesis
b. fats
c. proteins
Carbohydrate transport
- Facilitates movement of glucose through GLUT or SGLT (sodium glucose) transporters
a. Many types of GLUT – 1, 2, 3, 4 - Within skeletal muscle and adipose tissue
a. GLUT 4 -> transports most of the circulating glucose during the absorptive state into skeletal muscle and adipose tissue
i. housed in intracellular vesicles in the absence of insulin
- inserted into the cell membrane in response to insulin concentration increase
ii. Insulin binds to receptors -> signal transduction -> exocytosis and insertion of GLUT 4 into membrane
b. Diabetes type II – arises through lifestyle & more prevalent in older people
i. Exercise can alleviate symptoms – 2 reasons
- Insulin independent pathway – may increase GLUT 4 insertion into cell membrane
- Insulin dependent pathway – may increase insulin receptors; this increases insulin sensitivity at target sites – not as much insulin is required to obtain the same effects - Within liver
a. GLUT 2 transports glucose in and out of hepatocytes; always present in membrane
i. Post absorptive state (low blood glucose) -> glucose is transported out
ii. Absorptive state (high blood glucose) glucose is transported into hepatocytes
b. Insulin also facilitates conversion of glucose into glucose 6-phosphate to keep intracellular concentrations low during absorptive state
i. Maintains sufficient gradient to keep movement passive
ii. Enzyme hexokinase transforms glucose glucose 6-phosphate
c. Inhibits glycogenolysis – breakdown of glycogen to glucose - Within brain
a. Glucose uptake in the brain is by GLUT-1 & 3 largely independent of insulin
i. Glucose is the main fuel for neurons – does not need hormone to control energy transfer
- The body regulates energy balance within ECF of neurons to ensure glucose is always present - Inhibits gluconeogenesis – transformation of other substances to glucose
a. Reduces circulating amino acids & maintains AA concentrations intracellularly
Actions on fat – removal of fatty acids and glucose from the blood and storage in adipose tissue
a. Inhibits lipolysis
b. Stimulates fatty acid uptake in adipose tissue – promotes storage of energy
c. Stimulates glucose uptake and conversion to triglycerides
Actions on protein
a. Promotes amino acid uptake
b. Stimulates protein synthesis
c. Inhibits protein degradation
Types of diabetes
- early diagnosis
- urine output
Diabetes mellitus – likely the most common endocrine disorder in the western world
1. “honey running through” – comes from initial identification when physicians would taste urine
a. Diabetes - urine running through
b. Mellitus - sweet/”honey”
2. Urine output
a. Non diabetic – almost 100% of glucose is reabsorbed in kidney
b. Diabetic – high concentration of excess glucose in urine saturates transporters in renal tubules; transport maximum for glucose
• Osmotically active – pulls water into primary urine & increases urine flow rate
Other types of diabetes 1. Diabetes insipidus a. Dysfunction of AVP/ADH b. Reduction in capacity to synthesize ADH from post pit – a lot of water lost by kidney • Cannot reabsorb water in renal tubes c. Not sweet because of lack of glucose 2. Adrenal diabetes a. Dysfunction of cortisol
Types of Diabetes Mellitus
Type I or insulin-dependent diabetes -> lack of insulin secretion
a. Normally seen in children and represents a small proportion of diabetics – usually genetically based
- Insulin medication required for their whole life
Type II or non-insulin-dependent diabetes -> lack of insulin sensitivity
a. The most common form and invariably seen alongside obesity (80-90%)
b. Lacks ability to insert GLUT transporters into membrane – glucose stays in circulation
- High glucose levels following a meal due to inability of cells to absorb
Effects of insulin deficiency
- carbs
- lipids
- proteins
Primarily from perspective of type I diabetes (insulin deficient); some aspects are also applicable to type II
- Starvation in the midst of plenty – there is lots of glucose available but it’s unable to be taken up by cells
Carbohydrates – purple
- Increase in hepatic glucose output
a. GLUT 2 move glucose out of liver when insulin is not present
i. Other cells are requiring glucose
ii. it’s not being converted to glucose 6 phosphate - Decreased uptake by cells
a. Through GLUT 2 in liver and GLUT 4 in skeletal muscle
b. Intracellular glucose deficiency
i. Polyphagia – excessive hunger due to inability of cells to take up glucose; cells still won’t be able to take it up - Hyperglycemia – too much glucose
a. Increased urine production due to high concentrations of glucose in urine
i. Polyuria – osmotic flow and increase in urine flow rate
b. Dehydration
i. Polydipsia – excessive drinking (person is always thirsty)
ii. Cellular shrinkage – moving from ICF to ECF due to decreased volume in ECF
- NS malfunction -> death
iii. Decrease in blood volume – decrease in BP
- Peripheral circulatory failure -> renal failure -> death
Lipids – yellow
- Lessened ability to store energy
a. Decrease triglyceride synthesis
b. Increase lipolysis – to create glucose to feed cells
i. Causes Increase in blood FA - Ketosis – alternative energy source utilization; body burns fat and forms ketones
a. Ketoacidosis/metabolic acidosis
i. Causes increased ventilation
- Heavy breathing with sweet smelling breath due to burning of fats -> produces acetate that gives sweet smell
ii. Diabetic coma -> death
- Can also result from overdose - Insulin shock can occur in type I – too much insulin causes glucose levels to plummet in ECF & forces cells to use alternate energy sources
a. Ketosis – utilized by cells in emergency when glucose is lacking (ex. neurons)
i. Increased ventilation
ii. Diabetic coma and dealth
b. More common early on in trying to learn levels of medication required
Proteins – pink
1. Decrease in AA uptake by cells and increase in protein degradation
a. Muscle wasting and weight loss (in muscle mass)
b. Increase in blood AA
i. Increase in gluconeogenesis – utilizing AA for glucose
Hyperglycemia – same effects as what occurs in purple carb box
Glucagon
- secretion
- effects on carbs, fats, proteins
- what enzymes do insulin and glucagon act though
antagonistic to insulin
Secretion
- Negative relationship between blood glucose levels and glucagon – increase in blood glucose causes decrease in glucagon
Effects – glucose liberation; large effects in liver
1. Carbohydrates
a. Stimulates hepatic glycogenolysis and gluconeogenesis – largely through phosphorylase
i. Glucagon – activates phosphorylase
o Glycogen -> glucose (glycogenolysis)
ii. Insulin – activates glycogen synthetase
o Glucose -> glycogen
- Fats
a. Increases lipolysis – release of triglycerides, diglycerides, monoglycerides from fats
b. Inhibits hepatic ketogenesis – conversion of free fatty acids (FFA) to ketone bodies.
• Working to liberate glucose - Proteins
a. Promotes hepatic protein catabolism – breakdown
Insulin and glucagon postprandial
- sugars and fats
- AA
Pancreatic α and β cells response
Sugars and fats – a and B cells work in opposite directions to regulate levels
- Production of ATP
a. inhibits K+ ATP gated pumps in b cells – stimulates release of insulin
b. stimulates K+ ATP gated pumps in a cells – inhibits release of glucagon
increase in AA – works in the same direction
1. stimulates b and a cells to secrete both insulin and glucagon
a. increase in glucagon – hyperglycemic
• increases hepatic glucose output
b. increase in inulin – hypoglycemic
• increased uptake of AA and protein synthesis
• increased uptake of glucose
• decreased hepatic glucose output
2. balances blood glucose
Males vs females
- gonads
- gametes
- reproductive tract
- accessory gland
- gonads – paired organs
a. males – testes
b. females – ovaries - gametes – formed via gametogenesis & have endocrine role
a. males – sperm
i. androgens
b. females – ova
i. estrogens and progesterone - reproductive tracts
a. males – vas deferens
b. females – fallopian tubes - accessory glands
a. Male
i. Seminal vesicles – major site of seminal fluid - Capacitation – sperm are not fully viable until they hit female tract
ii. Prostate – produces fluids that aid in survival of gametes and movement of sperm
iii. Bulbourethral (Cowper’s) glands – same function as prostate
b. Female
i. Bartholin’s glands – assist in sexual act
ii. Clitoris
iii. Breasts
Anatomy of males
- testes - anatomy and development
- cryptorchidism
- substances in lumen of seminiferous tubules
- how long can male produce gametes
- epididymis - what is produced here
- accessory glands
- within penis
- what hormone
Testes – leads into penis for ejaculation via vas deferens
a. Seminiferous tubules – production of gametes
Cell types
- Leydig cells – outside of blood testes barrier in interstitial area; important in communicating gamete development in cells
- Sertoli cells – within seminiferous tubule; support and aid in development
a. Tight junctions between cells separate developing gametes
b. Basal lamina – creates blood testes barrier (similar to BBB)
- Prevents immune system from attacking gamete
c. Myoid cells – found within basal lamina
- Critical for communicating between Leydig and Sertoli cells
- Assist in movement of fluid across cell layer
Gametes develop as they move through the seminiferous tubule into the lumen
- Gamete ECF has high K+ and steroids (testosterone) in lumen
a. Androgens binding proteins – released into lumen to bind to testosterone (lipid soluble) to keep concentration high (makes water soluble)
b. Higher K+ slows metabolism to save energy for when they’re released into female – lowers motility
Theoretically – males can continue testosterone and sperm production throughout life
- Process slows with age due to blood vessel degradation – results in androgen deficiency in aging males (ADAM)
a. Degradation in blood vessels supplying testes – results in poor communication between Leydig and Sertoli cells
b. Lower fertility
Testicular development – develop from gonadal ridge
- Descend through the inguinal canal – usually complete before 7 months of gestation within mother
a. Cryptorchidism occurs in 1-3% of newborn males – testes have failed to descend and are trapped within the body
i. Trapped testes – male tends to be infertile - Testes lie external to reduce temp – 3° lower than core body temp
a. Important for development and increased mitochondria (for energy) for sperm
i. Increased energy increases ability to fertilize egg
Epididymis – gathering of seminiferous tubules
- Storage area for gametes
a. Not yet fertile – must be capacitated
i. Low pH due to production of H+ by infertile sperm
b. Produce defensins – protects sperm & helps to become motile
i. Partial capacitation – completed in the female reproductive tract
c. Unejaculated sperm is reabsorbed via phagocytosis
d. 80% of ** - Enters into ductus/vas deferens penis during ejaculation
a. Semi motile sperm are stored here for a few days
Accessory glands – empty into ejaculatory duct
- Prostate
a. Releases alkaline fluid, prostaglandins, clotting enzymes and fibrinolysin
b. Cancer of prostate is common - Seminal vesicle
a. Fluid contains – fructose, prostaglandins (PG’s), fibrinogen
i. ~ 50% of the seminal fluid is produced by seminal vesicles
b. Deposition into females
i. Fibrinogen – clotting enzymes promote clotting & aids in retention of sperm within females
ii. Fibrinolysin – works on fibrinogen to break clot and release sperm within female - Bulbourethral gland
a. mucus like substance – aids in sexual act as lubricant
Within penis
a. Dorsal vein and dorsal artery – deep arteries within
i. Well vascularized to allow for erection to occur – imbalance of blood flow (more in than out)
b. Corpora cavernosa – spongy tissue
Prostaglandins – hormones
a. Production
i. First identified in prostate gland
ii. Seminal vesicles produce as much if not more into sperm and fluid around sperm
b. Aid in reproductive act – promote ejaculation and contractile forces within the female tract to promote mvmt of sperm
HPG axis in males
- effects on cells
- Hypothalamus – produces GnRH -> positively stimulates ant pit
- Ant pit – FSH and LH
a. 2 main target sites – they can both act on both but have a dominant pathway
LH – targets Leydig cells for testosterone production
- 2 avenues for testosterone
a. Goes into blood and circulates
b. Negatively feedback to inhibit LH and GnRH
i. Indirect inhibition of FSH through GnRH
FSH – targets Sertoli cells and increases actions
- Effects
a. Gamete development
b. Production of androgen binding protein
c. Production of inhibin negatively feedbacks on FSH - Testosterone is key for function of Sertoli and viability of sperm
a. There are no androgen receptors on male gametes – must be converted to estrogens (sperm have receptors for estrogen)
i. Issues that society has in developing male contraception’s
Testosterone
- production
- effects - pre and post pubertal
- vasectiomy
Linked to HPG axis
o Hypothalamus secretes GnRH -> pit secretes LH -> Leydig cells produce testosterone
Functions of testosterone
a. Before birth – Influence the reproductive system
i. Development of accessory glands
- Wolffian duct differentiation and growth – sex determination
ii. External genitalia
- Growth and differentiation of scrotum and penis during fetal development
b. Pubertal – surge in testosterone
i. Development of libido – is not essential for maintenance of libido
- Vasectomy – many males are hesitant because they believe it will decrease sex drive; it won’t
ii. Development of secondary sex characteristics
- Skeleton & muscle – masculine physique, epiphyseal closure
- Vocal cords – voice deepening
- Skin – facial hair growth and/or cranial hair loss
iii. Reproductive development
- Testis – sertoli cell maturation and androgen binding protein synthesis
- External genitalia – penile and scrotal growth
- Accessory sex glands – prostate, seminal vescile and bulbourethral growth
iv. Non-reproductive actions
- Bone growth
- Males don’t produce many estrogens – have aromatase to assist in bone growth
- Aggression – increased testosterone has increased aggressive phenotype
v. Increase in testosterone – negatively feedbacks & inhibits LH in HPG axis
- Development of negative feedback regulation
Sertoli cell function
- Protect sperm cells – as they mature and move through tubules into lumen
- Feed sperm cells
a. Sperm are stored in epididymis prior to release - Remove unwanted material
a. Dead cells from meiotic division – resorbed and processed - Secrete seminiferous tubule fluid
a. Aid in supporting cell viability and life
b. Creates positive pressure – buildup of fluid pushes sperm down tubule into epididymis
i. They are otherwise non motile due to concentration of K+ - ABP secretion
a. Androgen binding protein – binds to testosterone and allows high concentration within lumen of seminiferous tubule
i. May assist in concentration gradient as well - Endocrine feedback regulation
a. Inhibin is synthesized – selectively inhibits FSH
spermatogonia
- 3 stages
- length of process and how many are available on a daily basis
- HOW MANY ARE ACC PRODUCED
- temp
- structure of sperm
3 stages
a. Mitotic proliferation
i. Spermatogonium – undifferentiated germ cells; diploid
- Undergo mitosis – produce more spermatogonia
- Undergo meiosis
b. Meiosis
i. Primary spermatocyte – undergo first meiotic division; diploid
- Crossover occurs to produce genetic variation
ii. Secondary spermatocyte – undergo second meiotic division; haploid
iii. Spermatids – underdeveloped sperm
- Each will have either X or Y chromosome
2. Y chromosome contains SRY gene – critical for sex determination
c. Development
i. Spermatids – move through seminiferous tubules into lumen
- Daughter cells stay connected until this point – there are genes on the X chromosome that are needed for development
ii. Spermatozoa – fully differentiated sperm cells; haploid
- Head – contains nucleus
- Acrosome – tip of the head & Contains enzymes for breaking through egg and fertilizing
- Mid piece – between head and tail
- Lower temp of testes promotes generation of mitochondria and allows swimming of sperm
- Tail – flagella
Approx. 64 days
a. Ongoing and constant within seminiferous tubules
i. Produced throughout lifetime
ii. 200 million sperm available on a daily basis
- Massive production and energy required
b. 16 sperms from singe spermatocyte in theory
i. Not often the case – 40-60% die in the process of development
- Sertoli cells – clean up cells that have divided and gone wrong
The male sexual act
- erection reflex
- ejaculation - volume and sperm count
- Excitement – arousal and erection
a. This is largely due to imbalance between blood inflow and outflow
i. Penile arteriole dilation – vasocongestion
- Inhibition of vasoconstriction neurons and sympathetic neurons that synapse with endothelial cells
ii. Blood can’t flow out and erection results
b. Similar responses through
i. Tactile stimulation – sensory neurons
ii. Mental arousal
c. Erection reflex
i. Higher brain center are activated
- Stimulation of mechanoreceptors sensory pathway
- Arousing thoughts
Descending autonomic pathway
- SNS – inhibited to decrease vasoconstriction
- Plays a role in ejaculation - PSNS – stimulated
a. Penile arteriole vasodilation erection
- Erection compresses veins and decreases outflow of blood
b. Bulbourethral and urethral glands increased mucus and lubrication - Plateau phase
a. Continued arousal includes increase in
i. heart rate
ii. mean arterial blood pressure
iii. respiration rate
iv. muscle tension - Orgasmic phase – ejaculation and muscle contraction combined with intense physical pleasure
a. Ejaculation
i. Emission – preparatory phase a few seconds prior followed by expulsion of seminal fluid and sperm from the penis
ii. Average volume – 3mL (considerable range)
- Average concentration = ~66 million sperm per mL
- Clinically infertile is < 20 million sperm per mL - Resolution phase – return to pre-arousal state
Erectile dysfunction
- who is affected
- also common with
Aspect of infertility without medication – incapable of sexual act
a. About 50% between 40 and 70
Failing to produce sufficient NO
- Common with atherosclerosis and diabetes mellitus
- Nitric oxide is synthesized by NO synthase in response to PSNS stimulation
a. Causes vasodilation through enzyme linked receptor pathway – uses cGMP as a second messenger
i. cGMP activates PKG pathway – cGMP dependant protein kinase G
- results in phosphorylation of SR Ca2+ ATPase (SERCA) – activates & lowers cytoplasmic concentration of ca2+
- results in muscle relaxation – vasodilation
Viagra – cannot cause an erection but it can sustain it
- Sildenafil – active ingredient in Viagra
- Prolongs effects of nitric oxide by inhibiting phosphodiesterase-5 breaks down cGMP
Differences in male and female reproductive tracts
- 2 critical
- complexity
- mice experiment
Much more complex than male reproductive physiology – require fetal development, parturition and nurturing
o Much greater energy investment
Two critical differences in gametogenesis from males
1. The number of available gametes is set at birth (conventional view)
a. Suggestion of embryonic stem cells in mice – have not been replicated
• Ovarian stem cells – may be there; ability to form functional oocytes has not been proven
2. Reproductive potential ceases in middle age – menopause
a. Plays role in bone degradation
b. Decrease in estrogen causes decrease in reproductive potential
c. Males – can be reproductively active until they die
• ADAM – can limit in aging males; blood vessel degradation
o Lessens motile sperm production
Female anatomy
- internal vs external
- vascularization
- embryonic origins
- ectopic pregnancy
External structure
- Embryonic origins
a. Clit – same as penile head
b. Labia minora – penile shaft
c. Labia majora – scrotum - Bipotential phase – where embryonic development could go either way
a. Dependant on presence of SRY
Internal structures
1. Fallopian tubes/oviduct – connect ovaries (gonads) to the uterine cavity
a. Fimbriae – “fingers” that hold onto ovaries
• Not a very tight connection – egg can occasionally enter into body cavity instead
b. Ectopic pregnancy – egg is fertilized outside of uterus; very rare
- usually fatal to infant and dangerous to mother without medical intervention
- implantation of fertilized egg in oviduct is damaging to mother – space does not facilitate development
2. Uterus
a. Uterine artery – delivers energy and nutrients to fetus
• Venous – removes waste
b. Outer connective tissue
c. Myometrium – very interconnected smooth muscle of uterus
d. Endometrial lining – blastocyst implants during proliferation
Oogenesis
All available gametes usually produced by the fifth month of gestation
1. During embryonic development – approx. 6-7 million available gametes
a. Oogonium – only present pre birth; diploid
• Undergo mitosis (proliferation) and meiosis (form oocytes)
2. At birth – approx. 1-2 million primary oocytes survive
a. Primary oocytes – are arrested in prophase I; diploid
3. By puberty – about 300-400 thousand primary oocytes remaining
4. Menstruation – approx. 400 oocytes are ovulated in lifetime
Meiosis
1. First division occurs just before birth but is not completed – primary oocytes are arrested in prophase I
2. One primary oocytes completes meiosis every month after puberty
a. Meiosis I is completed just prior to ovulation – arrested in prophase II
• Produces – secondary oocyte & 1 polar body
b. Meiosis II is completed after fertilization
• Polar body – produces 2 daughter polar bodies
• Secondary oocyte – produces 1 egg and 1 polar body
Ovarian cycle
- anatomy
- length
- 3 phases
- what partially determines which will be ovulated
- diameter of tertiary follicle
- collagenase
- fraternal twins
lasts ~28 days
3 phases
- Follicular phase – preparation of oocyte
a. Primordial follicles – most will never develop & die from atresia (hormone regulated death)
b. Primary follicles – contain primary oocytes
i. Primary oocytes
- Surrounded by zona pellucida – single cell layer; increases in width throughout development
ii. Primary follicle – single layer of granulosa and theca cells, separated by basal lamina (basement membrane)
- No antral space
- Granulosa cells – protect follicle from atresia (degradation) and absorption
- Basal lamina – analogous to BBB & Prevent immune system from attacking oocyte
iii. Follicle that is ovulated is dependant on
- Size – larger will be ovulated
- Smaller – can aid in development of follicle that is ovulated
c. Secondary follicle
i. Proliferation of granulosa and theca cells – direct development
- Analogous to Leydig and Sertoli cells in males
- Synthesis of steroids
ii. Granulosa & theca cells – secrete estrogens
- Estrogen levels increase – all estrogens are present
a. Estrones
b. Estradiol – highest concentration
c. Estriol
- Granulosa cells secrete fluid – forms antral cavities (rich in estrogens)
d. Tertiary/graafian/mature follicle – increases in diameter to ~12-16mm
i. Antrum – fusion of antral cavities
ii. Ruptured follicle – is ovulated
- Only dominant mature follicle will release egg and be ovulated
- Controlled by surge in LH
- Ovulation/menstruation – release of secondary oocyte (meiosis I is completed just prior)
a. Typically very short
b. Collagenases – secreted by the follicle; allows the mature follicle to break free
i. Secondary oocyte is expelled into the abdominal cavity – quickly drawn into the oviduct
ii. Occasionally 2 secondary oocytes are expelled – fraternal twins
- 1 egg and embryo develops twice – maternal twins - Luteal/post ovulatory phase
a. Granulosa and theca cells differentiate into corpus luteum
i. Secretes hormones to prepare reproductive tract for fertilization and implantation
- Mostly progesterone – some estrogen
ii. Luteum is full of lipids
- Provide precursor molecules for steroids – progesterone and estrogen
b. Corpus luteum is fully functional within 4 days and functions for 5 days whether or not its fertilized
i. Fertilized – further development into mature corpus luteum
- Continues to make steroids to support embryo
ii. No fertilization – degradation of luteum to albicans (white)
- Atresia – facilitated degradation
Uterine cycle
- interruptions of uterine and ovarian cycles
lasts ~28 days
3 phases
1. Menstrual phase
a. Beginning of follicular phase in ovaries
2. Proliferate – additional endometrial lining being laid down
a. Latter part of follicular phase
3. Secretory – secretion of endometrial lining to prepare for blastocyte implantation
a. Post ovulation – in luteal phase
i. Prepares uterus for implantation
Interruptions
- Pregnancy
- Menopause
- Nutritional balance – training
a. Amenorrhea – lack of menstruation in women
i. Female athletes – gymnasts and ballerinas in early teen years (prepubescent); menstrual cycles were abnormal or didn’t exist
ii. Evolutionary – lack of resources for regular cycling and resources to maintain pregnancy
iii. Can be reversed – takes time to develop normally
Oestrous
- experiment
period of enhanced sexual receptivity
a. Area of study for women trying to get pregnant
b. Core body temp increases just after ovulation
o Period of most likelihood chance of pregnancy
o Males have evolved to be more attracted to females during ovulation
c. Was initially thought this didn’t occur in human females
Lap dancer study – done by Miller
1. Studied correlation between menstrual cycles and tip earning in women who were not on contraception (experimental group) and women on contraception (control group)
a. Control group
o Women on contraction have abnormal levels of estrogen and progesterone – prevents pregnancy
b. Experimental group
o More honest signalling during periods of oestrous increased tip earning
2. Suggested presence of oestrous phase in human women
Female sexual act
- role of oxytocin
- Excitement – arousal and erection increase in PSNS and decrease in SNS
a. Arousal of tissue – clit will be engorged with blood (similar to penile head) - Plateau phase
a. Continued arousal includes increased
i. heart rate
ii. mean arterial blood pressure
iii. respiration rate
iv. muscle tension
There can be an increase in circulating levels of oxytocin
- Can also occur in males
- 2 effects
1. Promotes pair bonding between couples
a. Same sex couples – unsure of whether this occurs
2. Promotes transport of sperm within female tract
a. Promotes contraction**? of vascular tissue that lines cervical canal and the uterus
b. Promotes movement of sperm up through female tract and fertilization
- Orgasmic phase – not essential for successful fertilisation (unlike males); it does aid in sperm transport
a. Females can have multiple orgasms – there may be an increase in OT and vasoactive hormones
i. Can further promote movement of sperm through tract and fertilization of egg - Resolution phase – if stimulation is sufficient arousal decreases but females do not have a period of latency as in males
conception window
Conception can only take place in a limited window
a. Sperm can reach the oocyte within 30min following intercourse
- Can survive in the female reproductive tract for up to 5 days – lengthens window
b. If egg is not fertilized it will disintegrate and be absorbed
Fertilization
- where does it occur
- sperm actions
- aid of female reproductive system
- acrosomal reaction
- cortical reaction
Usually occurs in the distal portion of the fallopian tube
a. Favourable environment – quick access to nutrients & hormones
i. Fairly close to ovaries
b. Ectopic pregnancy – occurs outside uterus
i. Can be fetal to female and child
ii. Ectopic tubule pregnancy – occurs within oviduct & gets stuck in oviduct
- Can be fatal as well for female and child
Sperm actions
a. First appear within cervical canal within 1-3 minutes after ejaculation
b. A lot is lost
i. 97% is lost in vagina and won’t enter cervix
ii. Some is also lost in uterus and won’t enter oviduct
c. Not very many actually reach egg – this is why so many sperms need to be released
Aid of female reproductive in moving sperm – cervix oviduct
a. Compete capacitation of sperm once they’re in females
i. Dead sperm may make it to egg – shows assistance of female
b. Estrogens
i. “thinning” cervical mucous – allow fluid to form channels within cervical canal
- Canals are ideal dimensions and create forward movement of sperm
- Fibres resonate at similar frequencies as the beating of flagella of sperm
- If flagella is beating irregularly – won’t be propelled though & these will be more inhibited (they may still make it)
ii. Stimulate cervical and oviduct contraction
- oxytocin is also released during sex – may assist in contraction and motility of sperm
c. chemotaxis – cells follow chemical gradient; not a lot of chemical is required
i. humans – may only apply within oviduct itself
ii. frogs eggs releases allurim – sperm follows this concentration of chemical (allures)
d. thermotaxis – sperm follow temp gradient between vagina and cervical canal and oviduct
i. may facilitate the movement of sperm towards egg
ii. low to high gradient – marginally warmer in oviduct to promote direction
Acrosomal reaction – enzymes on sperm head that allow fertilization
a. Contact dependant – binding molecule on sperm binds to receptor on zona pellucida
i. Outer acrosomal membrane allows release of acrosome enzymes
b. Proteins involved are very species specific – prevents cross species fertilization
i. Acrosomal enzymes allow sperm to “drill” through cell layers surrounding oocyte
- Zona pellucida – protective glycoprotein
- Corona radiata – appears on egg at ovulation; loosely connected granulosa cells
Inner acrosomal membrane protein binds to receptor on egg plasma membrane
- Fertilin – binding molecules on the sperm membrane; binds to integrin on the oocyte surface
- Fusion of inner acrosomal membrane and egg plasma membrane allows deposition of:
a. Nucleus
b. And other molecules
i. Prostaglandins
ii. Nitric oxide – induces release of stored Ca2+
- Believed to initiate the final meiotic division of oocyte (arrested in prophase II up to this point)
iii. Calcium
iv. RNA – assists in early stages of developments
v. Mitochondrial DNA – debate
- Paternal mitochondrial deposition does occur – debate is whether it’s incorporated into developing oocyte
- Most suggest paternal mitochondrial DNA is not – majority is definitely maternal
- Suggested that paternal is tagged by ubiquinone and degraded
Cortical reaction – Induces change in oocyte membrane which block polyspermy; keeps more than 1 sperm from fertilizing
- Cortical granules in peripheral of cytoplasm of egg release their contents into the space just outside egg
Zygote formation and implantation
- syngamy
- twins
- morula vs blastocyst
- implantation
- prostaglandins
- Syngamy – merging of 2 haploid genomes
a. Normally occurs in oviduct – small and nutrient rich
i. Blastocyst – proliferation; usually formed within oviduct before entering uterus
b. Occasionally 1 in 80-90 result in twins
i. Dizygotic/fraternal twins – fertilisation of two oocytes
- 2 placenta develop for dizygotic
ii. Monozygotic/maternal twins – early embryo dividing in two
iii. Conjoined or Siamese twins
- First identified by siam
- Highly publicized separation - Morula to blastocyst
a. Morula – approx. 32 cells
i. Day 3 after fertilization
ii. Inner cell mass will develop into the embryo
b. Blastocyst – supports the cells dividing at the pole during intrauterine life
i. Day 4-5 after fertilization – moves to uterus
ii. Day 5-9 after fertilization – can implant
iii. Surrounded by trophoblast – protects inner cell mass
iv. Inner cell mass continues to divide and multiply into fetus
- Full of embryonic stem cells – will differentiate into other cell types
- Pluripotent cells – divide and develop into 3 primary germ cells layers of embryo - Implantation – blastocyst adheres to the endometrium
a. Trophoblast – extend and digests the surrounding endometrium
i. The only embryonic tissue that come into direct contact with mother – forms placental barrier & create favourable environment for development
ii. Cell types
- Cytotrophoblast – inner layer of trophoblast
- Syncytiotrophoblast – outer (purple) cells
> Release proteases that degrade lining of endometrium – will continue to digest until the placenta develops
> Endometrial decidua – degraded endometrial lining where the blastocyst is submerged
iii. Stimulates prostaglandin release within endometrial decidua
- Angiogenesis – creation of new blood vessels
- Oedema – collection/gathering of fluid
- Improved storage – for nutrient transport to embryo and removal of waste
Forming placenta
- what forms fetal
- what is present after 5 weeks
- maternal vs fetal
- what can pass
~12 days after fertilization
o Embryo is completely embedded
o Trophoblast is 2 cell layers thick – forming chorion
Chorion – continues to degrade endometrial decidua
1. Chorionic villi – project into endometrial space with maternal blood; provides nutrients and removes waste
a. Within 5 weeks – should be a developing heart within embryo
b. Villi contain embryonic capillaries – creates interlocking maternal (decidual) and fetal (chorionic) tissue = placenta
• Decidual derived – material
• Chorionic derived – fetus
Placenta
- During early development – acts as lungs, kidney, digestive system
a. Only later in fetal development can the fetus support its own life - Transfer of
a. Gas, nutrients
b. No blood mixing – chemicals and molecules transfer in between - Placenta can’t prevent movement of everything
a. Fetal alcohol syndrome – usually results in impaired brain development
b. HIV can also cross
Sex determination
- chromosome - number and types
- maternally derived conditions
- sex ratios
- abnormal karyotype
- genotypic sex potential
- bipotential period
46 chromosomes in cells
1. 23 pairs
a. 22 pairs of autosomes
b. 1 pair of sex chromosomes –X and Y
2. Chromosomes determine sex
a. SRY on Y chromosome – vital
b. X is bigger than Y – there are many unmatched genes from X on Y; X genes become dominant alleles
i. Often result in maternally derived conditions – X linked mutations/conditions
o Red green colour blindness
o Hemophilia
o Muscle dystrophy
ii. Many populations have operant sex ratios
• Often 1:1 males to females – can be skewed
iii. In humans
o At fertilization: 120 male:100 female
o At birth: 105 male:100 females
- Males have a greater increased potential of not reaching term
Karyotype – chromosomal type
- XXY – viable
a. Klinefelter’s syndrome – infertile adult males - XYY – viable
a. No real side effects (super males – taller) - YO – not viable
a. X chromosome is vital – will otherwise not reach term - X0 – viable
a. Turners syndrome – usually infertile females
Genotypic sex potential – sex determined by genes
- Some organisms – sex can be determined by environment
- Bipotential period – 6-7 weeks where XY embryos have the potential to develop either way
a. Sex is undetermined
b. Sex determining region on Y – expresses SRY gene in cells on the urogenital ridge
- Stimulates the production of the protein H-Y antigen – directs the development of the male gonads
- Females lack Y and therefore the SRY gene
Development of external genitalia
- when do they differentiate
- tracts
- fertilization of X vs Y
will develop from the same undifferentiated tissue of urogenital ridge
- 5-6 week period will see development of different ducts
- Reproductive tract develops from
- Mullerian ducts –females
a. Will ultimately be expressed as female - Wolffian ducts -Males
a. Will ultimately be expressed as male
Hormones are important
1. Ovum fertilized with Y XY chromosome
a. SRY stimulates production of H-Y antigen in plasma membrane of undifferentiated gonads
• H-Y antigens directs differentiation of gonads to testes
b. Testes secrete Mullerian inhibiting factor & testosterone
i. Degeneration of Mullerian ducts
ii. Testosterone
o Wolffian ducts develop into male reproductive tract
iii. 5 alpha reductase – key enzyme that converts testosterone to DHT
- DHT – promotes development of undifferentiated external genitalia
- Insufficient 5 alpha reductase – insufficient DHT; retardation in male genitalia until puberty
• Female genitalia may be expressed at birth
• Spike in testosterone at puberty may lead to the growth of male genitalia
- Ovum fertilized with X XX chromosome
a. No Y and no SRY no H-Y antigen
• Lack of H-Y antigen causes undifferentiated gonads to develop into ovaries
b. No testosterone or Mullerian inhibiting factor
i. No testosterone
o Degeneration of Wolffian ducts
o Promotes development of undifferentiated external genitalia
ii. No Mullerian inhibiting factor
o Mullerian ducts develop into female reproductive tract
Uterine position effect
- anatomy of rats
- 3 types of females
- what occurs
rats & mice have bicornate uterus – uterus is split in 2 with developing fetuses that neighbour each other
a. developing fetuses arranged sequentially in uterine horns – compartments
i. each in its own amniotic sac with its own placental connection
b. secretions of fetal endocrine glands alter the morphology, physiology & behaviour of neighbouring compartments
i. well described in rats and mice
3 types of females
a. 0M, 1M, 2M
i. 1M – neighboured by single male
ii. 2M – neighboured by 2 males
iii. 0M – neighboured by females
By day 17 in gestation – males have 3x the testosterone of females
- there can be spillover from males to female compartments
a. female fetuses are “contaminated” by testosterone from male neighbours – hormones pass via uterine blood vessels to neighbouring fetuses
i. can masculinise females – changes in behaviour
- 2M>1M>0M
- 2M exhibit more male type behaivours – more aggressive
Fraternal birth order effect
each male developing in utero increases the probability of subsequent male being gay
- A result of “contamination” effect in rat research
- Not attributable to environmental effect
a. stepbrothers in home don’t produce effect
b. biological brothers raised apart still produce effect - Potentially explained by “maternal immunization hypothesis”
a. mother carrying first son has little exposure to male proteins due to placental barrier – particularly Y-coded
i. mixing of fetal and maternal blood at birth causes female immune response to male proteins – antibodies produced against Y coded proteins
b. subsequent sons are exposed to these antibodies which attack male-specific proteins – alters development and increasing probability of male being gay
i. each previous male increases probability of next male by 1/3
- ex. 5th male – almost certain they’ll be gay
Only applies to right handed males
Hypothalamic pituitary gonadal axis
- GnRH synthesis and release
- what protein assists
- precursor molecule
- concentration effect on gonadal release
- Hypothalamus – releases GnRH
a. Arcuate nucleus of hypothalamus – releases into median eminence & move through portal blood supply
i. Kisspeptin – neuropeptide regulated by estradiol; important and promotion of GnRH release
b. master sex hormone
i. absence no LH and FSH no sex steroid production in gonads in males and females
ii. initially thought to be 2 hormones – FSHRH and LHRH
c. concentrations
i. very low blood circulation – almost undetectable
ii. very high concentration within portal blood supply
d. preproGnRH – precursor peptide
i. mature peptide is bioactive
e. Tonic pulses in both sexes every 1-3h
i. Critical to normal function and release of LH and FSH
- Tests on different invertebrates – elevated levels caused inhibition of LH and FSH
- Caused by down regulation of GnRH signalling pathway
GnRH pulse generator influences – different mechanisms have been proposed
- Threshold of release
a. Autocrine regulation – self regulating feedback control
i. Higher levels inhibit
b. Creates pulses of GnRH release - Stimulation via NE
- Local inhibition via dopamine or GABA (universal inhibitor for neural function)
- Anterior pituitary – FSH and LH
a. gonadotrophs – release and synthesize LH and FSH - Gonads – sex steroids
Concentrations are important in type of feedback regulation – especially in females - High plasma estrogen in females – positive feedback on production of GnRH
a. Increase GnRH
i. Increase in kisspeptin causes increase in GnRH
b. Increase FSH and LH
c. Targets ovary – ovulation
i. Prior to ovulation – high levels of FSH and LH cause increase in estradiol - Moderate plasma estrogen/androgen levels in males or females – negative feedback on GnRH
a. Less GnRH
i. Less kisspeptin and GnRH
b. Decrease FSH and LH
c. Gonads – decreased estrogens and androgens produced
i. in males – you never have very high levels of androgens in males (unlike estrogen in females) - Lower levels – more classic endocrine feedback
a. No feedback on GnRH – causes increase in GnRH
b. Increase in FSH and LH
Gonads – increases
Males
- HPG axis
- onset
Classic endocrine feedback – more commonly seen in males
a. You never have excessively high levels of androgens in males like you do estrogen in females
b. GnRH secretion begins slowly at the onset of puberty
- Prepubertal period – LH and FSH are not secreted
HPG axis 1. Arcuate nucleus – GnRH 2. Gonadotrophs – LH and FSH a. Sertoli cells – FSH stimulates i. Increased o Spermatogenesis – gamete synthesis o Inhibin – selectively inhibits FSH o ABP – binds testosterone to allow high concentration within seminiferous tubules > Also released into blood b. Leydig cells – LH stimulates i. Testosterone production – negative feedback on GnRH inhibits FSH and LH o Can also target anterior pituitary production – mainly targets hypothalamus
Onset of axis – many factors
a. Energy balance
b. Genetic basis in timing
c. Melatonin may play a role
- Linked to regulation of HPG axis – long day breeders ex.
- Varies depending on season
Steroidogenesis in follicle
- tertiary follicle to corpus lutem
- key role of LH and FSH
- cell functions
- Key roles of LH and FSH
a. LH – promotion of androgen production in thecal cells
i. Conversion of cholesterol to pregnenolone - Initiates delta 4 & 5 pathway
ii. Increase results in increased androgen production
b. FSH – conversion of androgens to estrogens in granulosa cells
i. Primary target – aromatase activity
ii. You only need a small amount of FSH to promote aromatase activity - Theca & granulosa cells
a. Delta 5 pathway – occurs in theca cells
i. Cholesterol pregnenolone (C21) 17-hydroxygregnenolone DHEA androstenedione
b. Diffuses to granulosa cells
i. Androstenedione testosterone estradiol
- FSH – targets aromatase activity - Luteal cells
a. Delta 4 – cells undergo shift
i. Cholesterol pregnenolone (C21) progesterone 17-hydroxyprogesterone androstenedione
ii. Alternate pathways
- 17-hydroxypregnenolone 17-hydroxyprogesterone
- DHEA androstenedione
b. Products of androstenedione
i. Testosterone (reversible) (all terminal?)
- DHT
- Estradiol 17B
- Estriol
ii. Estrone estradiol 17B (reversible) - Estradiol – major product & enters bloodstream
- LH targets P450SCC enzyme cleavage of cholesterol to pregnenolone to progesterone??**
a. Does this occur only in luteal cells??
Differences and similarities to males in control of hormones
Unlike males
- Cyclical in nature – increases and decreases of sex steroids that occur in predicable and timely fashion
- FSH and LH do not specifically target gametogenesis or gonadal hormones respectively – play a role in both
- There are both positive and negative feedback controls
Similar to males - GnRH secretion begins slowly at onset of puberty - Onset determined by o Energy balance o Genetics o Melatonin
Ovarian cycle - hormone focus
- Early follicular phase – timed with menses in uterus
a. FSH – promotes follicular development in ovary
i. Typically high in first 7 days – during menstration
ii. Antral space – formation causes slow and steady increase in estrogen production from growing follicles
b. LH – drives increase in estrogen through promotion of androgen production in theca cells
i. Conversion to estrogens in granulosa cells – low levels of FSH can maintain aromatase activity
c. Estrogens exhibit negative feedback - Late follicular phase
a. Granulosa cells of dominant follicle secrete
i. Estrogens – now positive feedback on GnRH
- Kisspeptin protein increase
- Increased GnRH LH surge
ii. Inhibin – selectively inhibits FSH
- Prevents additional follicular development
- Decline in FSH leads to atresia of all but leading follicle
- Anti Mullerian hormone (AMH) – secreted by larger follicle & plays a role in determining while follicle will become dominant & may also inhibit maturation of neighbouring follicles
b. LH surge – causes ovulation
i. Granulosa cells
- Small amounts of progesterone positively stimulate GnRH during ovulation - primarily inhibitory at any other time
- Decrease in estrogens following ovulation -> Causes decrease in GnRH decreased FSH and LH
ii. Increase in prostaglandins
- Aids in rupturing follicle and release of egg
iii. Resumes meiotic division within oocyte past prophase II
iv. Promotion of differentiation from follicle to luteal cells
- Causes increase in progesterone (delta 4 pathway) - Luteal phase – follicular cells have differentiated
a. LH – increased progesterone and estrogen levels through P450SCC enzyme
i. Surge is critical for
- Hyperplasia of endometrial lining
- Hyperemia of blood vessels
b. Corpus luteum – secretes estrogen and progesterone through delta 4 pathway
i. Increased progesterone – occurs fairly quickly
- Inhibits FSH and LH
- Stimulates exocrine activity to increase embryotroph – nutrient rich fluid; uterine milk to support early development of blastocyst and embryogenesis
ii. Increased estrogens also occurs once mature corpus luteal
- Negative feedback of GnRH
iii. Increased inhibin of FSH – don’t want another follicle developing if it does get fertilized - If fertilization does not occur
a. Corpus luteum dies – decrease in estrogen and progesterone
b. Increase in GnRH increased FSH and LH
i. Causes development of new follicles
Placental hormones
used to pinpoint timing of parturition fairly accurately
- Human Chorionic gonadotropin (hCG):
a. Glycoprotein – FSH and LH family
- Beta subunit – less conserved; targeted by pregnancy test
b. Early pregnancy – produced by the blastocyst to preserve the corpus luteum
- Promotes estrogen and progesterone
- hCG declines overtime as estrogens and progesterone increase
c. At delivery – decline in all 3 hormones (estrogen, progesterone, hCG)
- Delivery determination is indicated by ratio of 3 hormones - Human Placental Lactogen (chorionic sommatomammotropin):
a. Mammary gland development – although not essential
b. Regulating maternal metabolism – linked with gestational diabetes
- Females suffer from diabetes – 90% go back to non diabetic after birth
triggering parturition
Placenta increased CRH & ACTH
Stimulates fetal adrenal cortex
1. Increase cortisol stimulates development of fetal lungs
a. Increased pulmonary surfactant fluid in amniotic fluid increased macrophages in utero Increased interleukin 1B
i. Increased uterine stretching & IL 1B increased activated NF-kB which causes (nerve factor capa beta)
- increased interleukin 8
- increased prostaglandin production
ii. Causes lung maturation & readiness for breathing air
2. Increase DHEA targets placenta converted to estrogen in placenta
a. Increase in prostaglandin production
o cervical stretching
o contraction of myometrium
b. Increased gap junction in myometrium
o coordinated contraction of muscle
c. Increased oxytocin receptors in myometrium
o uterine responsiveness to low levels of oxytocin
o oxytocin stimulates
oxytocin effects
- neuroendocrine reflex
a. increased uterine contraction pushes fetus against cervix increased oxytocin secretion - increased prostaglandin secretion
If female is under chronic stress increased cortisol
o Tend to deliver before term
o Normal levels – easy predicted
o Low levels – gestation is prolonged
Let down reflex
Stimulus – crying baby
- Inhibition of PIH – prolactin inhibiting hormone (aka. Dopamine)
- Increased milk production by PRL - Release of oxytocin
- Increase in smooth muscle contraction
