1
Q
What is considered the conceptual framework for the study/understanding of physiology?
A
Homeostasis
2
Q
Who suggested the concept of homeostasis?
A
- Claude Bernard
- ‘The Father of modern physiology’
3
Q
What did Claude Bernard state?
A
- Our internal environment remains remarkably consistent despite changes in the external milieu
- Provides stable conditions for body cells to perform functions
4
Q
How did Walter Cannon contribute to the study of physiology?
A
- Coined the term ‘homeostasis’ to describe the relative stability of the internal environment
5
Q
Describe the homeostatic mechanism.
A
Sensory -> Integrating Center -> Effector
- Can be many or one of each
- Negative feedback response
6
Q
Describe negative feedback loops.
A
- Forever changing/dynamic
- Constant by staying within normal range
7
Q
Describe the home furnace system homeostatic mechanism if house temperature falls.
A
House temperature falls -> Sensory system (thermostat) -> Response system (furnace) switched on -> Heat is produced -> House temperature rises -> Thermostat -> Furnace switched off
8
Q
Describe the blood pressure negative feedback loop when standing up.
A
Lying down -> standing up
- Blood pressure falls (stimulus)
- Blood pressure receptors respond (sensor)
- > integrating centre - Heart rate increases (effector)
- Rise in blood pressure (negative feedback)
9
Q
Homeostatic control relies on ____?
A
Sensor - constant monitoring
Integrating centre - coordinates b/n sensor and effector
Effector - adjustment
10
Q
Which two systems maintain homeostasis in large part?
A
Nervous and Endocrine systems
11
Q
Which factors must be regulated in order to maintain homeostasis? (5)
A
- Water and electrolytes
- pH
- Oxygen and carbon dioxide
- Temperature
- Energy sources
12
Q
Which two things does homeostasis allow for?
A
- Maintenance of ‘normal’ metabolic function
- Reproductive potential
13
Q
Why do we care about the endocrine system?
A
- Many people are affected by endocrine disorders/diseases (ex. Type 2 diabetes)
- Understanding how homeostasis in the endocrine system works helps us to understand/treat them
- Diabetes Mellitus is the 6th leading cause of death in Canada
- Thyroid disorders affect about 5% of population
- Endocrine ovarian disorders affect about 6% of female population and are most common cause for infertility
14
Q
How has the prevalence of diagnosed diabetes changed over time?
A
- Increased
- Not a stand alone disease
15
Q
What does hyper-function mean?
A
- Too much hormone
16
Q
What does hypo-function mean?
A
- Too little hormone
17
Q
What does resistance mean?
A
- Too little effect
- Body doesn’t respond to it
18
Q
What is endocrinology?
A
- The study of hormones and the actions of hormones
- The study of how endocrine glands regulate the physiology and behaviour of animals
19
Q
Where does the term ‘hormone’ come from?
A
- Greek
- ‘to excite or arouse’
20
Q
What is the definition of an endocrine gland?
A
A tissue which releases/secretes a substance into the bloodstream; this substance then travels via the blood to influence a target cell
- Ex. Pancreas secretes insulin to travel to liver, muscle, and adipose tissue
21
Q
What is the classic Minkowski experiment?
A
Discovery of insulin
- Surgically remove pancreas - dog develops symptoms of diabetes (wasn’t able to clear glucose from blood)
- Implant pieces of pancreas under skin - prevents symptoms of diabetes
22
Q
What is the Banting and Best experiment?
A
Discover of insulin
- Identified anti-diabetic substance in pancreatic extracts
- Injected extract prevents symptoms of diabetes (elevated blood glucose)
23
Q
What is insulin? What does it do?
A
- Peptide hormone produced by beta cell of pancreas
- Promotes absorption of glucose from blood to skeletal muscle and fat tissue
24
Q
What does the inactive form of insulin look like?
A
- Stored form
- Hexamer
- Zinc ion and histidine residues holding subunits together
25
What are the chemical classifications of hormones (3)?
- Amines: derived from tyrosine and tryptophan
- Proteins/polypeptides (including glycoproteins)
- Steroids: derived from cholesterol
26
What are the three levels of effect for hormones?
```
Autocrine
- SC = TC
Paracrine
- SC affects TC of same tissue
Endocrine
- SC sends hormone through blood stream to TC
```
27
Describe protein/peptide hormones.
```
Synthesis: in advance
Storage: secretory vesicles
Release: exocytosis
Transport: dissolved in plasma
Half life: short
Ex. insulin
```
28
Describe steroid hormones.
```
Synthesis: on demand
Release: diffusion
Transport: bound to carrier proteins
Half life: long
Ex. estrogen/androgen
```
29
Describe catecholamine hormones.
```
Synthesis: in advance
Storage: secretory vesicles
Release: exocytosis
Transport: dissolved in plasma
Half life: short
Ex. epinephrine/norepinephrine
```
30
Describe thyroid hormones.
```
Synthesis: in advance
Storage: secretory vesicles
Release: diffusion
Transport: bound to carrier proteins
Half life: long
Ex. thyroxine
```
31
Describe the specificity of receptors?
Receptors are highly specific for a particular hormone, but non-specific binding does occur (e.g. hormone 'overspill')
32
How is continued/future signalling allowed?
Continuous turn-over of receptor-hormone complex (hormone may be released)
33
Receptors for most hormones are found where?
In the plasma membrane of target cells (transmembrane receptors)
34
Where are receptors for steroid and thyroid hormones found?
Inside target cells
Steroid - Cytoplasm
Thyroid - Nucleus
35
Describe transmembrane receptor binding.
- Hormone binds extracellular domain of receptor and activates one or more cytoplasmic signaling pathways
- Many involve phosphorylation and enzyme activation
- Some lead to DNA/mRNA/protein response
- Others just have local effect in target cell
- Ex. adenylate cyclase pathway and phospholipase C pathways
36
What are the steps in adenylate cyclase pathways?
1 - Hormone binds receptor, G-proteins dissociate
2 - Alpha-subunit activates adenylate cyclase
3 - AC catalyzes production of cAMP from ATP
4 - cAMP removes regulatory unit from protein kinase
5 - PK activates other molecules (hormonal response)
37
What is an example of the adenylate cyclase pathway?
- Epinephrine binds to beta-adrenergic receptors (resulting in activation)
38
What did Robert Lefkowitz and Brian Kobilka focus on? Why is it important?
- G protein-coupled receptors
| - Crucial to unravelling complex network of signalling b/n cells
39
Describe the Phospholipase C - Ca2+ pathway?
1 - Hormone binds receptor
2 - G-proteins dissociate
3 - Alpha-subunit activates PLC
4 - PLC causes breakdown of membrane phospholipid to IP3
5 - IP3 binds endoplasmic reticulum
6 - Release of stored Ca2+ into the cytoplasm
7 - Ca2+ activates other molecules (hormonal response)
40
What is an example of the phospholipase C - Ca2+ pathway?
Epinephrine binds to alpha-adrenergic receptors
41
Which G alpha subunit subtypes correspond to which enzymes?
G(s)alpha => adenylate cyclase
| G(q)alpha => Phospholipase C
42
Describe the hypothalamus-anterior pituitary gland - peripheral target axes?
Hypothalamus (blood vessel) -H1-> Anterior pituitary cells (main circulation) -H2-> [Peripheral endocrine gland -H3-> main circulation -> tissue response] OR [Non-endocrine tissue -> tissue response]
43
What are 7 hypothalamic hormones involved in the control of the anterior pituitary gland?
- Prolactin-inhibiting hormone/dopamine
- Prolactin-releasing hormone
- Thyrotropin-releasing hormone
- Corticotropin-releasing hormone
- Growth hormone-inhibiting hormone/somatostatin
- Growth hormone-releasing hormone
- Gonadotropin-releasing hormone
44
Describe the hypothalamus - anterior pituitary gland - adrenal cortex axis?
(Hypothalamus) CRH -> (Anterior pituitary) ACTH -> (Adrenal cortex) Cortisol -> Many tissues
45
Describe the central stimulatory control of Corticotropin-releasing hormone?
- In hypothalamic paraventricular nucleus
- Noradrenergic
- Stimulates pre-proCRH gene and protein expression
- Processed to CRH
- Stimulates pulsatile release of CRH
46
What are inhibitory influences on CRH synthesis/release?
- Physiological levels of cortisol inhibit release of CRH
47
What are the steps of CRH synthesis/release?
1 - CRH produced by parvocellular neurosecretory cells within hypothalamic PVN
2 - CRH is released at median eminence from neurosecretory nerve terminals into blood vessels in hypothalamo-pituitary portal system
3 - CRH travels through blood vessels to anterior pituitary, where it stimulates corticotropes to secrete ACTH
48
What is ACTH derived from?
Pro-opiomelanocortin (or POMC)
49
What are convertases?
- Enzymes that cleave POMC
| - Different convertases give rise to different products
50
What type of hormones does the adrenal cortex release?
```
- Steroids
Specifically...
- Glucocorticoids
- Mineralocorticoids
- Sex steroids
```
51
Which category of hormones does the adrenal medulla release?
- Catecholamines
| - It is known as a modified sympathetic ganglia
52
What is cholesterol converted into in the zona fasciculata?
Cholesterol -> pregnenolone -> 17OH-pregnenolone -> 17OH-progesterone -> 11-deoxycortisol -> cortisol
53
What is the dominant glucocorticoid in humans? In rodents?
Humans - Cortisol
| Rodents - Corticosterone
54
Describe the binding at steroid hormone receptors?
1 - Steroid hormone transported bound to plasma carrier protein
2 - Binds cell cytoplasm receptor
3 - Translocates to nucleus and binds DNA (acts as TF)
4 - Stimulates gene transcription
5 - Protein products
6 - Response
55
Why is cortisol (stress hormone) essential for life?
- Protects against hypoglycemia by promoting gluconeogenesis (promotes breakdown of skeletal muscle for glucogenic precursors)
- Natural regulator of immune system (clinical use as anti-inflammatory agents)
- Affects brain function (mood, memory, learning)
56
What is Cushing's Syndrome?
- Result of chronically high levels of glucocorticoids in the blood
- Can be caused by taking glucocorticoid drugs, or diseases that result in excess cortisol, ACTH, or CRH levels
- Primary hypercortisolism
- Could be caused by Cushing's Disease
- ACTH levels are lower than CD
- Causes changes in metabolism which give rise to puffy appearance and CNS disorders
57
What is Cushing's Disease?
- A pituitary-dependent cause of Cushing's Syndrome
- A tumour in the pituitary gland produces large amounts of ACTH, causing adrenal glands to secrete excess cortisol
- Secondary hypercortisolism
- ACTH levels are higher than CS
58
What happens if Cushing's Syndrome is not treated?
- Disease worsens
- Health deteriorates
- Especially worsening diabetes/high blood pressure
- Can lead to strokes or myocardial infarction
59
Describe the medical management/treatment for Cushing's Syndrome
- Insulin for diabetes
- Anti-hypertensives for blood pressure
- Surgery to remove pituitary or adrenal gland
60
What is Addison's Disease?
- Caused by inadequate secretion of glucocorticoids
- Primary hypocortisolism
- Result of adrenal insufficiency (caused by genetics, autoimmune, or acquired)
- High dose steroids > 1 week begins to suppress adrenal glands by suppressing CRH and ACTH
61
Describe adrenal cortisol secretion.
- Continuous
- Pulsatile (helps to regulate)
- Circadian rhythm
62
How does insomnia relate to the HPA axis?
- People with insomnia secrete more cortisol around sleep time
63
Describe pituitary pars intermedia dysfunction.
- In horses
- pars intermedia does not form properly
- Affects older horses
- Impaired pituitary gland
- Hyperplasia/hypertrophy of pars intermedia -> increased secretion of cortisol by adrenal glands -> high blood glucose and suppression of immune system
64
What are some common signs of PPID in horses?
- Hypertrichosis (excessive hair)
- Abnormal/patchy hair coat
- Muscle atrophy
- Excessive sweating
- Formation of fat pads
- Pot-bellied
65
How is PPID diagnosed in horses?
Measure fasting, resting basal blood ACTH and insulin levels
66
What is the treatment of PPID in horses?
```
Pharmacotherapy
- Pergolide
- Acts on pituitary gland to decrease circulating ACTH
Lifestyle
- Exercise
- Weight loss (if obese)
- Limit starch/sugar in horse's diet
```
67
What is melanocyte-stimulating hormone?
- Another POMC derivative
68
What are the components of the melanocortin system?
- Opioid peptide: beta-endorphin (acts on pituitary to block pain)
- 4 peptide hormones: alpha/beta/gamma-melanocyte stimulating hormone and adrenocorticotropic hormone
- 5 melanocortin system receptors (G-protein coupled)
- 2 melanocortin system antagonists (Agouti and AGRP)
- 2 melanocortin system regulators (mahogany and syndecan-3)
69
What is the key to the melanocortin system?
- Cell specificity
- Post-translational processing of POMC is cell-specific
- Different MCRs on different cell types
- Provides latitude for control/regulation of various physiological processes
70
What are the steps in which alpha-MSH affects pigmentation?
1. alpha-MSH binds MC1R
2. Activates adenylate cyclase signalling pathway
3. Activates cAMP response element-binding protein (CREB) - TF: binds CRE and promotes microphthalmia-associated TF (MITF) synthesis
4. MITF promotes synthesis of melanogenic enzymes (ex. dopachrome tautomerase [DCT])
5. Melanin produces dark pigment
71
How does a mutation in alpha-MSH or MC1R affect pigmentation?
- Prevents dark pigmentation
72
What type of mutations are POMC mutations?
- Autosomal recessive
73
What are the clinical characteristics of POMC mutations?
- Hyperphagia (lack of alpha-MSH)
- Severe, early-onset obesity
- Normal birth weight, but rapid weight gain
- Red hair and pale skin
- Adrenal insufficiency (lack of ACTH to promote cortisol secretion from adrenal cortex)
74
What is the Agouti mouse?
- Result of spontaneous mutation wherein mice overproduce Agouti protein
- Agouti inhibits MC1R and MC4R signalling
- In skin, alpha-MSH binding to MC1R produces dark pigmentation
- In hypothalamus, alpha-MSH binding to MC3R and MC4R helps to regulate appetite and energy balance
75
What is agouti-related protein?
- Another hypothalamic protein
| - Inhibits MC4R
76
What is red hair a result of?
- 2 copies of a recessive mutation in MC1R
77
What makes jaguar black?
- Melanism
| - Dominant gene mutation in MC1R
78
Describe the hypothalamus-anterior pituitary gland-thyroid axis?
TRH -> TSH -> Thyroid gland -> Thyroid hormones -> Many tissues
79
What is the hypothalamus-anterior pituitary gland-thyroid axis (including structures and hormones)?
Hypothalamus -Thyrotropin-releasing hormone-> Anterior pituitary -Thyroid-stimulating hormone-> Thyroid -Thyroxine-> inhibits responsiveness
80
Describe the thyroid gland and its location?
- Just below larynx
- On either side of trachea
- 2 lobes
- Connected by isthmus
- Largest purely endocrine gland
- Lateral to the first 3-8 tracheal rings
81
What do follicles do?
- Follicles include follicular cells and colloid
| - Take up iodide (I-) from blood
82
What happens in the colloid?
- Colloid is the large circular cells
| - Thyroid peroxidase helps attach it to a tyrosine residue in thyroglobulin
83
Where is thyroglobulin made?
- Made by follicle cells
- It is a long peptide chain with lots of tyrosine residues
- Transported to colloid
- Side chain of tyrosine is important in T3/T4 synthesis
84
How is I- brought into cells? What happens to it?
- I- is brought from blood into follicular cells by sodium-iodide transporter, then into colloid by a transporter called pendrin
- I- is converted to an iodine radical (extremely reactive) by TPO, and added to thyroglobulin
85
How does the iodine radical attach to thyroglobulin?
- Via tyrosine residues
1 - The attachment of 1 iodine radical on a tyrosine residue produces MIT
2 - The attachment of 2 iodine radicals on a tyrosine residue produces DIT
86
What does the iodine radicals do to tyrosine residues?
- Iodine radical causes tyrosine residues to cross-link (fold in on itself)
87
What do enzymes in the colloid do to MIT/DIT?
- Modify their structures
- Make thyroid hormones via condensation:
- > T3
- > T4
88
Are T3 or T4 bioactive?
- T3 is bioactive, but T4 is not
89
What happens after T3/T4 are synthesized?
- They are still attached to thyroglobulin
- Thyroglobulin gets taken back up by follicular cells and cut up so that the T3/T4 are separated
- T3 and T4 get secreted to bloodstream
90
What is thyroid hormone in blood bound to?
- Thyroxine-binding protein
91
What type of thyroid hormone is biologically active?
- Free thyroid hormone
| - Has to dissociate from carrier protein to produce effects in target cells
92
Describe the receptor binding of thyroid hormones?
1. Thyroxine (T4) + carrier protein
2. T4 -> T3 (triiodothyroine)
3. T3 uses binding proteins to enter nucleus
4. Hormone-receptor complex binds DNA (acts as TF)
5. Stimulates gene transcription
6. Protein products
7. Response
93
What is the timing of thyroid hormone secretion?
- Circadian rhythm of thyroid hormones in humans
| - Secretion is highest b/n 10-2 to increase basal metabolic rate
94
What are the physiological actions of thyroid hormones?
- Elevates BMR (thyroid hormone production often impairs with age)
- Needed for normal embryonic/fetal development, particularly for development of CNS
- Needed for normal gonadal development and function
- Thyroid hormone deficiency or excess may therefore have serious consequences
95
What does hypothyroidism look like?
- Abnormally low BMR = weight gain
- Lethargy
- Intolerance to cold
96
What does hyperthyroidism look like?
- Increased BMR = weight loss
- Muscular weakness
- Nervousness
- Protruding eyes (exophthalmos)
97
What is cretinism?
- Congenital deficiency of thyroid hormones usually due to maternal hypothyroidism
- Reduced physical growth and severe mental deficiency
98
How do thyroid hormones affect terminal brain differentiation?
- Thyroid hormone-dependent development of brain begins in utero - completed after birth
- Dendritic and axonal growth, myelin formation and synapsis formation
- Neuronal migration
- Maternal thyroid hormones first supply needs of embryo/fetus
99
How can cretinism be treated?
- Treatment with thyroxine (T4) soon after birth (before one month) restores development of intelligence
100
What can cretinism be caused by?
- Innate maternal hypothyroidism
| - Dietary iodine deficiency
101
What are some causes of hypothyroidism?
- Insufficient dietary iodine
- Thyroid gland defect
- Impaired thyroid hormone pathway
- Insufficient TSH (anterior pituitary)
- Insufficient TRH (hypothalamus)
- Mutant TSH or TRH receptors (genetic)
- Mutant thyroid hormone transport proteins
- Autoimmunity
102
What are some causes of hyperthyroidism?
- Thyroid gland defect
- Impaired thyroid hormone pathway
- Overproduction of TSH (anterior pituitary)
- Overproduction of TRH (hypothalamus)
- Mutant TSH or TRH receptors (genetic)
- Mutant thyroid hormone transport proteins
- Autoimmunity
103
What is goitre?
- Hypothyroidism
- Abnormal growth of thyroid gland
Low iodine intake (thyroid can't produce enough thyroid hormones) -> Low plasma T3 and T4 -> High TRH (from hypothalamus) -> High plasma TSH (from anterior pituitary) -> Stimulates excess growth of thyroid to try to make more thyroid hormones
104
What is Grave's disease?
- Hyperthyroidism
Autoantibodies bind TSH receptor and activate thyroid gland -> High plasma T3 and T4 -> Low TRH (from hypothalamus) -> Low plasma TSH (from anterior pituitary)
105
What are some treatments of thyroid disorders?
- Pharmacotherapy
- > Synthroid: Levothyroxine (synthetic T4)
- > Stimulants: Furosemide (increased T4->T3)
- > Blockers: Thiouracil derivatives, thiocarbamides (less iodination and T4->T3)
- Radiation therapy
- Surgery
- Diet, electrolyte infusions, etc.
106
Describe the hypothalamus-anterior pituitary gland-somatotropic axis?
GHIH -| GH -> Liver -> IGFs -> Many tissues
107
What are all the aspects of the hypothalamus-anterior pituitary gland-somatotropic axis?
PVN -GHRH-> Anterior pituitary -GH-> Liver -IGF-> Many tissues
108
Describe GH
- 191 AA polypeptide
- Synthesized, stored and secreted by somatotropic cells of anterior pituitary gland
- Most abundant anterior pituitary hormone
- Short half life: 6-20 mins
- Plays important role in growth
109
What are the GH secretion patterns like?
- GH secretion occurs as several large pulses or peaks each day, 10-30 mins in duration
- The largest GH peak occurs about 1 hr after onset of sleep
- Basal levels highest early in life; greatest during pubertal growth spurt then decline
110
List 6 factors that increase GH secretion.
- Sleep
- Exercise
- Hypoglycemia
- High dietary protein
- Steroids
- Ghrelin (hunger hormone)
111
List 3 factors that decrease GH secretion.
- Hyperglycemia
- Glucocorticoids
- Endocrine disruptors
112
What are the metabolic effects of GH and IGF?
- GH stimulates synthesis and release of IGF from many tissues
- IGF-1 (from liver): polypeptide hormone with 40% homology to insulin
- GH also mobilizes fuel sources in other tissues
- IGF affects growth in cartilage/bone and muscles/other organs
113
How is bone formed?
- Bone contains calcified extracellular matrix (ECM) formed when calcium phosphate crystals precipitate and attach to lattice (collagen) support
- Most common form of calcium phosphate crystal is hydroxyapatite (Ca10(PO4)6(OH)2
114
What are the 3 bone cell types?
Osteoblasts - bone formation
Osteoclasts - bone resorption/breakdown
Osteocytes - derived from osteoblasts
115
What does the bone look like at 2 months (fetus), 2-3 months (fetus), childhood, and adolescence?
First 2 months - just collagen/cartilage
2-3 months - blood vessel and bones begin to develop (grows from cartilage growth plates)
Childhood - more cartilage turns into bone
Adolescence - bone containing osteocytes is present, cartilage growth plates at either end of bone promote growth in young adulthood
116
Describe the processes involved in linear bone growth?
- cartilage growth (epiphyseal) plates contain chondrocytes (collagen-producing cells)
- Collagen contributes to chondrification (cartilage formation)
- Osteoblasts invade and lay bone matrix (hydroxyapatite) on top of cartilage base
- Osteoblasts get stuck in matrix -> osteocytes (paracrine and endocrine function)
- Bone remodeling requires turnover (osteoblast and osteoclast activity)
117
What hormones stimulate bone growth/turnover?
- GH and IGF-1
118
What is pituitary dwarfism?
- Under production of GH in childhood/adolescence
| - 2 types: proportionate and disproportionate
119
What is pituitary gigantism?
- Over production of GH in childhood/adolescence
120
What is Laron-type dwarfism?
- Pygmies
| - Decreased responsiveness to GH (GH receptor deficiency) that begins in childhood
121
What is reduced BMD a consequence of?
- Underproduction/decreased sensitivity to GH in adults
- BMD = bone mineral density
- Increased risk of fractures
122
What is alopecia in dogs associated with?
- Under production or decreased sensitivity to GH in adults
| - Hair loss, thin skin
123
What hormone inhibits GH synthesis?
- Increased CORTISOL inhibits GH synthesis
124
What is acromegaly?
- Over production of GH in adulthood
- Thickening of bones/joints and skin
- Enlargement of internal organs (tongue, liver, spleen)
125
Who is a real-life example of gigantism and acremegaly?
Andre the giant
126
How are GH disorders treated? What side effects would there be?
- Recombinant/synthetic human GH for children with short stature
- Daily injections for about 2 years = 1ft3" increased height
- $22000/year
- Side effects = glucose intolerance, pancreatitis, psychological problems
127
What molecules/atoms provide the structural integrity of bone?
- Calcium and phosphate
| - In the form of hydroxyapatite
128
What processes are intracellular/extracellular calcium ions essential for?
- Neuromuscular excitation
- Blood coagulation
- Hormone signalling
- Enzyme activity
- Fertilization
129
How much calcium is in your body? Where is it found?
- 70kg person has about 1.2 kg Ca2+ in their body
- 99% is in bones as hydroxyapatite
- Soft tissues: 11g intracellular, and 1g extracellular
130
Describe the regulation of intracellular calcium? Extracellular calcium?
Intracellular is tightly regulated
- Associated with membranes in mitochondria, ER, and plasma membrane
Extracellular is VERY tightly regulated
- 50% ionized/free calcium
- 40% protein-bound calcium
- 10% calcium complexed with phosphate/citrate
131
What happens if intra/extracellular levels of Ca2+ drop?
- Bone Ca2+ will be sacrificed
132
How is total body calcium maintained?
```
Intake = diet
- About 1/3 absorbed in small intestine
- Absorption is hormone-regulated
- About 1000mg/day is recommended
Output = kidneys
- Lost through urine
```
133
Which 3 hormones regulate the movement of Ca2+ b/n the intestine, bone, and kidney?
- Parathyroid hormone (PTH)
- Calcitriol (activated form of 1,25-(OH)2 Vitamin D3)
- Calcitonin (acts opposite to PTH)
134
Where is PTH made?
- Made by chief cells of 4 parathyroid glands
- Located on back of thyroid gland
- Parathyroid glands are essential for life (can NOT be removed)
135
Describe PTH and its secretion.
- Peptide hormone
- Secreted by chief cells of parathyroid glands
- When plasma Ca2+ begins to fall, PTH acts to raise Ca2+ to normal levels
- Raises blood Ca2+
136
What are the 3 mechanisms by which PTH raises blood Ca2+?
- Stimulates osteoclasts to resorb (absorb into circulation) bone
- Stimulates kidneys to reabsorb Ca2+ from filtrate
- Stimulates kidneys to produce enzyme needed to activate vitamin D (to calcitriol), which in turn promotes better intestinal absorption of dietary Ca2+
137
Describe the process of PTH stimulation of osteoclasts. What is the result?
- Resorption of bone
- Decrease in blood Ca2+ is sensed by parathyroids
- PTH is secreted
- Kidneys and bones then are activated
- Kidneys induce the reabsportion of Ca2+
- Dissolution of CaPO4 crystals in bone
- Leads to increased blood Ca2+
- Negative feedback
138
What cells are responsible for bone formation? How do they do this?
- Osteoblasts
- Secrete matrix of collagen protein
- Becomes hardened by deposits of hydroxyapatite
139
What cells are responsible for bone resorption and how do they go about this?
- Osteoclasts
| - Dissolve hydroxyapatite and return bone Ca2+ to blood
140
What does PTH stimulation of the kidneys do?
- Production of enzyme (1 alpha-hydroxylase) needed to activate vitamin D to calcitriol
- Calcitriol promotes intestinal absorption of dietary Ca2+
- 7-dehydrocholesterol is converted to vit D3 by sunlight in sebaceous glands of skin
- Vitamin D3 is bound to Vit D binding protein (DBP) for transport in blood
- In liver, Vit D3 -> 25-OH-D3 by 25-hydroxylase
- 25-OH-D3 (inactive) is released to blood bound to DBP
- Low blood 25-OH-D3 is a sign of Vit D deficiency
141
How does PTH convert vitamin D to calcitriol?
- Promotes 1alpha-hydroxylase activity in kidney
- Converts inactive 25-OH-D3 to active calcitriol (1,25-(OH)2-DH3)
- Calcitriol is released to blood bound to DBP
142
Describe calcitriol and its secretion.
- Steroid hormone
- Secreted by cells of proximal tubule of nephron of kidney in response to PTH
- Raises blood Ca2+ by 3 mechanisms
143
By what 3 mechanisms does calcitriol raise blood Ca2
| +?
- Maximizes bone resorption by osteoclasts (promotes bone mineralization when blood Ca2+ levels are sufficient)
- Maximizes Ca2+ reabsorption in kidney
- Increases dietary Ca2+ and P absorption in small intestine (unique to calcitriol)
144
Describe calcitonin and its secretion.
- Peptide hormone
- Secreted by parafollicular cells/C-cells of thyroid gland
- When plasma Ca2+ begins to rise, calcitonin acts to reduce blood Ca2+ by 2 mechanisms
145
By what two mechanisms does calcitonin reduce blood Ca2+?
- Promotes excretion of Ca2+ in the urine
| - Inhibits bone resorption by osteoclasts
146
What is hyperparathyroidism? What does it lead to?
- Overactive parathyroid
- Too much PTH in blood
- Hypercalcaemia (too much Ca2+ in blood)
- Increased bone resorption-> poor BMD -> fractures
- Increased thirst and urination
147
What is hypoparathyroidism and what does it lead to?
- Underactive parathyroid
- Not enough PTH in blood
- Hypocalcaemia (not enough Ca2+ in blood)
- Muscular weakness
- Ataxia (lack of voluntary muscle control)
- Cardiac arrhythmias
148
How do bone diseases occur?
- Manifest from changes in ratio of mineral to collagen in bone matrix
149
What is a bone disease associated with a vitamin D deficiency in infants?
- Rickets
- Bones do not mineralize properly during development and cannot support the body's weight when learning to walk
- Permanent
- Only reversible with surgery
- Leads to bowed legs
150
What is a bone disease in adolescents/adults that is associated with vitamin D deficiency?
- Osteomalacia
- Bones become demineralized
- Bone fractures can occur more easily
- Can be reversed with supplementation
151
What is a bone disease associated with vitamin D deficiency in middle-aged to elderly?
- Abnormal loss of both mineral and organic (collagen) parts of bone
- Bone fractures occur more easily and often lead to mortality
- Difficult to reverse due to erosion of bone
152
What was found to be successful in the treatment of rickets?
- UV treatment
| - Cod oil
153
When is peak bone mass achieved?
20-30 years of age
154
Do men or women have a higher peak bone mass?
Men
155
Who is at highest risk for osteoporosis? Why?
- Women after menopause
| - Lack of estrogen (which protects bones by stimulating osteoblasts)
156
What types of pharmaceuticals can treat osteoporosis?
- Bone-forming therapies
- Anti-resorptive therapies
- Calcitonin
- Hormone replacement therapy (for post-menopausal women)
- Selective estrogen receptor modulators
157
How can osteoporosis be prevented?
- Avoid malnutrition
- Achieve dietary vitamin D and calcium needs
- Perform regular weight-bearing exercise
- Avoid smoking and excessive alcohol intake (which prevents Ca2+/Vit D absorption)
158
Describe the hypothalamus-anterior pituitary-gonadal axis?
Hypothalamus -GnRH-> Anterior pituitary -FSH/LH-> Gonads -> Inhibin/gametes/sex steroids
159
What are the 2 parts of the testes?
- Seminiferous tubules
| - Interstitial tissue
160
Describe the cells within the seminiferous tubules?
- Sertoli cells
- Express FSH receptor
- Involved in spermatogenesis in response to FSH
- Secrete inhibin (inhibits anterior pituitary production of FSH)
- Secrete MIF (role in male reproductive system development)
161
Describe the cells within the interstitial tissue?
- Leydig cells
- Express LH receptor
- Produce testosterone in response to LH
162
What happens to testosterone after it is secreted?
- Converted to 5-DHT by 5alpha-reductase in epididymis, seminal vesicles, prostate, skin, hair, liver, and brain
163
What are the actions of testosterone/5-DHT during fetal development?
- Masculinizes reproductive system and external genitalia
164
What are the actions of testosterone/5-DHT during puberty/adulthood?
- Growth, maintenance and maturation of :
- Male reproductive system
- Secondary sex characteristics
- Bone/muscle mass
- Brain
- Sex drive
165
What are the 5 steps of sperm transport?
1 - Seminiferous tubules drain sperm and other secretions into epididymis (duct on surface of testicular capsule)
2 - Becomes vas deferens, which extends to abdomen
3 - Seminal vesicles add secretions in response to testosterone
4 - Enters prostate, which adds secretions in response to testosterone (semen)
5 - Empties into urethra
166
Describe the 4 steps in the erection of the penis?
1 - NO released from parasympathetic axon in penis and acts on VSMC to activate guanylate cyclase (catalyzing GTP->cGMP)
2 - cGMP causes Ca2+ channels in VSMC membrane to close, decreasing cytoplasmic [Ca2+]
3 - VSMC relaxes, causing vasodilation of penis arterioles and enlargement of erectile tissue
4 - Phosphodiesterase degrades cGMP, stopping erection
167
How does viagra work?
- Inhibits PDE, increasing availability of cGMP to promotes sustained erection
168
What does anabolic steroid abuse do?
- Exogenous anabolic steroids induce negative feedback on hypothalamic-pituitary axis, inhibiting FSH and LH secretion
- Leads to reduced:
- -- Sperm -> infertility
- -- Testosterone and 5-DHT -> diminished secondary sex characteristics
169
Describe the effectiveness of testosterone as male contraception given every 4 or 6 months?
4 months: No LH, FSH, or sperm escape
6 months: Sperm escape => ineffective
170
What characterizes female reproductive physiology?
- Complex cycling of endocrine hormones
| - 2 about 28 day cycles occur simultaneously (ovarian and menstrual cycles)
171
Describe the ovarian cycle?
- Anterior pituitary hormones (FSH,LH) act on the ovaries
| - Ovaries produce ova (eggs) in preparation for fertilization
172
Describe the menstrual cycle?
- Ovaries produce hormones (estrogen, progesterone) that act on the uterus
- Uterus gets ready for pregnancy, then is stripped of endometrial lining if implantation doesn't occur
173
What does the menstrual discharge consist of?
- About 80 mL of blood, fluid, cell debris from outer layer of uterine endometrium
174
What is responsible for menstrual bleeding?
- Endometrial spiral arteries
| - Animals that lack these arteries do not bleed
175
What happens in stage 0 of 4 of the menstrual/ovarian cycle?
HPG-axis
- Increased gonadotropin (FSH/LH) secretion from anterior pituitary
Ovaries
- FSH influences several ovarian follicles to begin maturation
Uterus
- Menstrual bleeding begins = day 1
176
Describe stage 1 of 4 in the menstrual/ovarian cycle?
HPG-axis
- Early: estrogen inhibits GhRH, FSH, LH (-ve feedback)
- Late: estrogen promotes GnRH and LH (+ve feedback)
Ovaries: Follicular phase
- Early: FSH decreases
- Late: Granulosa cells of follicles secrete estrogen; LH increases
Uterus: Menstruation, Proliferative phase
- Estrogen stimulates endometrial growth
177
What happens in stage 2 of 4 of the menstrual/ovarian cycle?
OVULATION
HPG-axis
- LH surge
Ovaries
- Mature follicle ruptures, releasing oocyte into fallopian tube
- Estrogen decreases
- Released oocyte is surrounded by zona pellucide (proteins) and corona radiata (granulosa cells)
- What is left forms corpus luteum
178
Describe stage 3 of 4 of the menstrual/ovarian cycle?
HPG-axis
- Progesterone/estrogen inhibit GhRH, FSH, LH (-ve feedback)
Ovaries: Early-mid luteal phase
- Early: Corpus luteum develops, produces progesterone and estrogen
Uterus: Secretory phase
- Progesterone/estrogen promote endometrial thickening in anticipation of pregnancy
179
What happens in stage 4 of 4 of the menstrual/ovarian cycle?
HPG-axis
- Negative feedback on HPG-axis removed since progesterone and estrogen decrease
Ovaries: Late luteal phase
- Corpus luteum regresses (lives about 12 days)
Uterus: Menstruation phase
- Endometrium requires progesterone or else vasculature contracts and dies, sloughs off, menstruation starts (14 days post ovulation)
180
Why do women who want to know when they ovulate check their temperature?
- Starting at 1 day after the LH surge, basal body temperature sharply rises
- Progesterone is responsible for the change
181
How does hormonal female contraception work?
- Synthetic estrogen and progesterone
- Elevation of these ovarian hormones leads to negative feedback inhibition of HPG-axis so ovulation never occurs
- Stimulates a false luteal phase
182
What happens at menopause?
- Occurs at 45-55 years
- Point when ovaries are depleted of follicles, therefore stop secreting estrogen
- Weak form of estrogen made in adipose tissue
183
How does the amount of adipose tissue in post-menopausal women affect the risk of osteoporosis?
- Post-menopausal women with increased adipose tissue have a decreased risk of osteoporosis
- However, there is other metabolic consequences
184
What is hormone replacement therapy?
- Synthetic estrogen or estrogen and progesterone
| - Research suggests that the risks of long-term HRT use outweigh the benefits for most women
185
What are the benefits of hormone replacement therapy?
- Relieve menopausal symptoms: hot flashes, mood swings, trouble sleeping
- Reduce risk of osteoporosis and colon cancer
186
What are the risks of long-term hormone replacement therapy?
- Increase risk of breast and ovarian cancer, heart disease, stroke and pulmonary embolism
BIOM 3200
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