2100 - Renal Flashcards
Signalling mechanism of steroids.
Intra and extra cellular receptors. Intra (classical genomic signalling): hormone binds to receptor in cytoplasm > nucleus, acts as nuclear transcription factor/genomic receptor, binds to DNA at hormone response elements > gene expression
Examples of steroids and associated organ.
Gonads - androgens - sex hormones (progesterone, testosterone and estradiol).
Adrenal cortex - corticosteroids, mineralocorticoids and androgens
Skin - vit D
Steroid production.
Enzymatically derived from cholesterol in smooth ER of cells - Steroidogenic pathway
Somatostatin is also…
GHIH
Somatotropin is also…
Growth hormone
Primary endocrine organs (9)
Hypothalamus, pituitary, pineal, thyroid/parathyroid, adrenal glands, pancreas, ovaries, testes, placenta
Secondary endocrine organs (7)
Kidney, uterus, liver, stomach, sml intestine, thymus, heart
Pineal gland releases (1)
Melatonin
Thyroid/parathyroid release (4)
T3, T4, Calcitonin, PTH
Adrenal gland releases (4?)
mineralocorticoids (aldosterone), sex hormones (androgens and estrogens), corticosteroids (glucocorticoids-cortisol), catecholamines
Pancreas releases (3)
insulin, glucagon, somatostatin (GHIH)
Ovaries release (2)
Estrogen, progesterone
Testes release (2)
Androgens, estradiol
Placenta releases (1)
hCG
Kidney releases (3)
Calcitriol (vit D), renin, erythropoietin
Uterus releases (2)
Prolactin, relaxin
Liver releases (2)
Thrombopoietin, IGF-1
Stomach releases (5)
Gastrin, ghrelin, histamine, somatostatin (GHIH), neuropeptide Y
Sml intestine releases (3)
CCK, secretin, somatostatin (GHIH)
Thymus produces (1)
Thymopoietin
Heart (1)
Atrial natriuretic peptide
Steroid transport in blood
Bound to globulins (long half life)
Globulins are made in the
liver
Hormones are inactive when
bound
Steroid properties
non-polar - lipophilic, hydrophobic
Peptide hormone production
rER and GA (chains of aa, cleaved from pro-hormone to hormone)
Peptide hormone release
Vesicles - exocytosis (Ca dependent)
Peptide hormone transport
Unbound (active)
Peptide hormone receptors
Extracellular: ligand-gated ion channel, enzyme-linked receptor, GPCR
Peptide hormone properties
Polar, hydrophilic
Peptide hormone example
Insulin (pancreas)
Amine hormone synthesis
Derived from amino acids.
Tyrosine > (nor)epinephrine, T3/4
Tryptophan > melatonin, serotonin
Which amine hormones are steroid-like
T3, T4
Which amine hormones are peptide-like
(nor)epinephrine, melatonin, serotonin
T3/4 transport in blood
Bound to plasma proteins
Amine hormone receptors
T3/4 - intracellular
(nor)epinephrine, melatonin, serotonin - GPCR
Enzyme-linked receptor examples
Receptor tyrosine kinase receptor (RTK) - phosphorylation activates relay proteins. (insulin)
Cytokine type 1 receptor - JAK activates STAT (prolactin)
GPCR subunits
Gaq - phospholipase C > DAG > PKC
Gaq - phospholipase C > IP3 > Ca channel
Gas - AC > cAMP
Gai - inhibits AC > decrease cAMP. Increase phosphodiesterase (breaks down cAMP)
Melatonin production
Retina receives light > SCN > pineal gland > inhibit melatonin release
Eicosanoids
Hormone-like lipids derived from arachidonic acid. Involved in inflammation, immunity, ovulation, blood flow, uterine contractions
What is humoral stimuli
Non-hormone components in blood - Ca, glucose
Humoral stimulus endocrine reflex example
PTH: low Ca stimulates PTH release, stimulates Ca release from bone, kidney and GI Ca reabsorption
What hormones have only tropic effects and what does this mean?
FHS, LH, TSH, ACTH. Stimulate hormone production from another endocrine organ
What hormones have only non-tropic effects and what does this mean
Prolactin, MSH. Stimulate target organ directly
What hormone has both tropic and non-tropic effects
GH
What is ACTH and function. Stimulated by?
Adrenocorticotropic hormone - stimulates adrenal cortex to secrete cortisol and androgens. Stimulated by CRH
Production of oxytocin and vasopressin (ADH) in hypothalamus and transport to pituitary
Cell bodies of large neurons in hypothalamic nuclei - paraventricular nucleus (PVN) and supraoptic nucleus (SON) - produce the peptide neurohormones oxytocin and ADH. Transported in vesicles down axon (hypothalamic-hypophyseal tract) to post pituitary
Releasing and inhibiting hormone production in hypothalamus and transport to pituitary
Small neuron cell bodies in arcuate nucleus and paraventricular nucleus (PVN) produce releasing and inhibiting hormones. Released to median eminence, through hypothalamic-hypophyseal portal system to ant pituitary.
a) ADH function
b) Oxytocin function
a) Water retention
b) Bonding, lactation, uterine contractions
Anterior pituitary gland cell (hormone released)
Gonadotropes (gonadotropins - FSH, LH)
Somatotropes (somatotropin (GH))
Thyrotropes (TSH)
Corticotropes (ACTH)
Lactotropes (prolactin)
Another word for pituitary gland - ant, post
hypophysis - adenohypophysis, neurohypophysis
Embryological development of pituitary
Cells from roof of developing mouth (stomodeum - surface ectoderm) form ant. pituitary. Cells from base of brain (diencephalon - neuroectoderm) form post pituitary. Where lobes meet is Rathke’s pouch.
Primary vs secondary endocrine disorders
Primary affects target organ. Secondary affects hypothalamus or pituitary. In a pituitary disorder, damage of pituitary gland is primary disorder, damage of hypothalamic stalk is secondary disorder.
Hypopituitarism causes
Acquired - tumours (non-functioning micro/macroadenomas on pituitary, craniopharyngioma on stalk) and associated treatment
- Head injury
Congenital - genetic
Hyperpituitarism cause- effect
Caused by tumours:
Prolactinomas – excess prolactin secretion (most common)
GH-secreting adenomas – excess GH
TSHoma – excess TSH
Cushing’s disease – excess ACTH
GH/IGF-1 (somatotropin) axis.
a) Hypothalamus (GHIH/GHRH) > ant pituitary (GH) > liver and other somatic cells (IGF-1).
GH hyperfunction disorders (hyperpituitarism)
Gigantism from GH secreting tumour in pre-adolescent. Associated with hyperglycaemia. (bone elongation)
Acromegaly in post-adolescent. Associated with type 2 diabetes symptoms. (bone thickening). Diabetogenic effect - increased glucose stimulates insulin > insulin resistance and beta cell degeneration
IGF-1/GH deficiency (hypopituitarism) disorders
Dwarfism (pre adolescence):
African pygmies have inability to produce IGF-1
Laron dwarfism - GH receptor mutation - no IGF-1
(post adolescence): increase fat, insulin resistance, lethargy, adrenal insufficiency, infertility, diabetes associated, muscle weakness
Function of GH
GH stimulates bone elongation (before epiphyseal fusion) and bone thickening (after fusion). Increases muscle mass and protein synthesis. regulates BGL, stimulates lipolysis, decrease glucose uptake by muscle, increase glucose production (liver/kidneys)
Function of IGF-1
IGF-1 binds to insulin receptors and IGF receptors. Antagonist effect - increase lipolysis, FA uptake by muscle. Insulin-like effect - opposes GH: decrease gluconeogenesis (kidney), increase glucose uptake muscle
GH in fasting and fed states
Fasting (pre-prandial): GH increased, insulin low, glycogenolysis and gluconeogenesis, lipolysis
Fed (post-prandial): GH suppressed, insulin increases, increase glucose uptake in skeletal muscle, glycogenesis, adipogenesis/lipogenesis.
Tests to measure hormone levels
Static - of direct hormone or surrogate marker. e.g C peptide is marker of insulin. IGFBP of IGF.
Dynamic - suppression test (glucose test diagnoses acromegaly). Stimulation test (ACTH injection determines primary/secondary disorder)
Treatment for hypofunction disorders
Replacement of peripheral hormone, drugs that reduce resistance.
Treatment for hyperfunction disorders
Radiation therapy, surgery, suppression drugs, receptor antagonists
Where are parathyroid glands located
On posterior of thymus
Blood supply to thyroid/parathyroid. Venous drainage
superior and inferior thyroid arteries. superior, middle and inferior thyroid veins + thyroid plexus
Thyroid follicle composition and function
Follicular cells and colloid cavity - produce T3 and T4 (and thyroglobulin)
Parafollicular (C) cells produce
Calcitonin
What cell is found in parathyroid gland and what does it produce
Chief cells produce parathyroid hormone
What are oxyphil cells? function?
Derived from chief cells, lower PTH
What weeks of gestation does thyroid develop in
3-7
Initial proliferation of thyroid cells occur at the _ and then descends via _ to the trachea
foramen cecum, thyroglossal duct
Abnormalities with thyroid descent (3)
Persistent thyroglossal duct, pyramidal lobe of thyroid, ectopic thyroid tissue
What develops from the 3rd pharyngeal pouch
thymus and inferior parathyroid glands.
What develops from 4th pharyngeal pouch
dorsal - superior parathyroid glands, ventral - parafollicular cells
Abnormalities with parathyroid glands (2)
ectopic - inferior glands remain with thymus
supernumerary - glands may split causing an additional gland in neck
Thyroid hormone production
thyroglobulin (has tyrosine residues) produced by follicular cell is exocytosed to colloid. Iodide from blood is transported through follicular cell to colloid then oxidised to iodine by thyroid peroxidase (TPO). thyroglobulin + iodine (organification). thyroglobulin now has iodinated tyrosine residues. Conjugation, endocytosis into follicular cell, + lysosome > protein degradation > T3 (triiodothyronine) /T4 (thyroxine) transported into blood. All of T4 produced in thyroid. 80% T3 produced by peripheral conversion
How is T4 converted to T3 or rT3
Via tissue-based deiodinases.
Which thyroid hormone is more active (4x)
T3
What is reverse T3 *clue: hibernating bears
An inactive isoform of T3, binds to thyroid receptors - is an antagonist and competitive inhibitor for T4-T3 conversion. Thus reducing T3, causing hypothyroidism and slowing metabolism
Thyroid hormone receptor activation + function
They have intracellular receptors. Pass membrane by monocarboxylate transporters (MCT), bind at hormone response element to regulate gene expression of Na/K ATPase pump. Use of ATP stimulates mechanisms to increase ATP such as increasing basal metabolic rate - increase glucose uptake, glycolysis/KREBS > by-product is heat, insulin production to balance
Hypothalamus/pituitary/thyroid (HPT) axis
Stimuli: needs increase in metabolism e.g. exercise
H: thyrotropin-releasing hormone (TRH)
P: thyroid-stimulating hormone (TSH)
T: T4/T3
How does TSH stimulate thyroid hormone production (5)
Increases activity of iodide pump, increases secretion of thyroglobulin into colloid, increases TPO activity, increases lysosomal protein degradation to release T3 and T4, increases size and total number of thyroid cells
What is Grave’s disease
Excess stimulation of TSH receptors from antibodies
How is a goitre formed
Excess function of thyroid causes enlargement/hypertrophy
Thyroid hormone effect on liver
Increases gluconeogenesis, glycogenolysis, LDL receptors (to increase cholesterol/triglyceride uptake)
> increase glucose uptake, ATP use and decrease FA/cholesterol
Thyroid hormone effect on adipose
Increases hormone-sensitive lipase activity and lipolysis
> decrease fat stores and glucose available (from glycerol)
Thyroid hormone effect on muscles
Stimulate type II fibers to increase strength. Excess and low thyroid cause muscle atrophy
Thyroid hormone effect on heart
Increase receptors for catecholamines. Increases B1 adrenergic receptors increase sensitivity of contractile cells in AV node
> increases HR, CO, SV and contractility
Thyroid hormone effect on vasculature
Increase B1 adrenergic receptors and decrease ANGII receptors
> increases vasodilation
Thyroid hormone effect on nervous system
Increases number of dendrites, myelination, and number of synapses
> NS excitation
excess can cause tremor and loss of sleep
low thyroid - NS depression
Thyroid hormone effect on GI tract
Increase insulin from pancreas, glucose absorption, contractility of gut, exocrine secretions
> gut motility and absorption
What is cretinism
Caused by chronic lack of thyroid hormones in development results in short statue, mental disability and thick facial features
Thyroid hormone effect on bone
Increases bone growth in children along with GH
Symptoms of hyperthyroidism
Weight loss, heat intolerance, erythema (red face), tremor, anxiety, diarrhoea, exophthalmos (protruding eyes), goitre tachycardia, muscle atrophy
Symptoms of hypothyroidism
Weight gain, cold intolerance, slow movement, bradycardia, constipation, myxoedema, maybe goitre, short (pre-puberty), muscle atrophy, hypercholesterolaemia, atherosclerosis and CV disease
Degrees of disorder (primary, secondary..)
Primary: thyroid problem
Secondary: pituitary problem
Tertiary: hypothalamus
Quaternary: tissue insensitivity
What is thyrotoxicosis
The effect of excess thyroid
Grave’s disease
Autoimmune disease - antibodies stimulate TSH receptors on follicular cells > high thyroid hormone levels. TSH and THRH are low from negative feedback. Antibodies to thyroglobulin and to the thyroid hormones may also be produced. Swelling of eyes as the thyroid gland and the extraocular muscles share a common antigen that is recognised by the antibodies - binding causes swelling of eyes. Orange skin is from antibodies under the skin causing an inflammatory reaction and subsequent fibrous plaques.
Hashimoto’s disease
mild/no symptoms at first, swelling of thyroid and difficulty swallowing. Autoimmune disease - antibodies destroy thyroid gland
what cells release parathyroid hormone
Chief cells in parathyroid gland
Tests to determine if hypo- or hyper thyroidism
Blood, iodine uptake, stimulation test (only hypo)
PTH is released in response to
low blood Ca activation of CaSR (GPCR) and high phosphate levels
Calcitriol is also called
Active Vit D
What releases calcitonin
parafollicular (c) cells in thyroid
Function of PTH
Increase blood Ca, reduce PO4: Increases bone resorption (releases Ca and PO4), increase Ca reabsorption from distal tubule kidney, decrease PO4 reabsorption
Function of calcitonin
Decrease blood Ca: decrease bone resorption (deposition of Ca and PO4 into bone), decrease Ca absorption from GI, decrease Ca and PO4 reabsorption from kidney,
Function of calcitriol (Vit D)
Increase blood Ca: increase Ca and PO4 absorption from GI (by binding to Vit D receptors to increase membrane Ca transporters and intracellular Ca binding protein, calbindin) and reabsorption from kidney, increase osteoclast activity (bone breakdown - release Ca and PO4)
Ca absorption from GI
Passive (paracellular) and active (calcitriol + VDR > Ca transporters + calbindin)
Hypercalcaemia causes and symptoms
hyperparathyroidism, dehydration, vit D excess.
Thirsty, frequent urination, nausea, vomiting, constipation, bone pain, depressed NS, heart palpitations, fainting
Hypocalcaemia causes and symptoms
hypoparathyroidism, autoimmune disease, low Mg, vitamins, kidney dysfunction.
weak nails, bone fractures, numbness in hands, feet and face, cramps, excitable NS, depression, hallucinations, memory loss
Hyperphosphataemia causes and symptoms
hypoparathyroidism - chronic kidney disease, metabolic/respiratory acidosis.
Pulls Ca from bones to try and balance - hypocalcemia, numbness, bone pain, itchy rash
Blood supply to suprarenal arteries
Superior, middle and inferior suprarenal arteries
Adrenal glands are also called
suprarenal glands
Blood drainage of adrenal glands
Single adrenal vein: R into IVC, L into left renal vein
What are the three zones of the cortex from ext to int
Zona glomerulosa, zona fasciculata and zona reticularis
What steroid hormones are produced from the zona glomerulosa (example)
mineralocorticoids (aldosterone)
What steroid hormones are produced from the zona fasciculata (example)
glucocorticoids (cortisol)
what steroid hormones are produced in the zona reticularis (example)
androgens (androstenedione and DHEA)
What cells are in the adrenal medulla and what do they produce
Chromaffin cells - catecholamines (derived from tyrosine)
Adrenal cortex is derived from intermediate ___
mesoderm
Adrenal medulla is derived from ___ (neural __ cells)
Ectoderm, crest
Function of aldosterone
Increase blood Na, decrease blood K and H:
In collecting duct of kidney tubule - increases Na+ (and water) reabsorption and increases K+/H+ secretion/excretion
Aldosterone effect on transporters at kidney lumen
Aldosterone binds to receptor (MR) in cell > nucleus > increases transcription of:
(apical surface): Na channels (ENaC), K channels (ROMK), H+ ATPase pump
(basolateral surface): Na/K ATPase pump
Loss of aldosterone results in (3)
Loss of Na - dehydration, low BP hyperkalaemia (K+) - heart problems acidosis (H+) - low blood pH, low cardiac output
> death
Excess of aldosterone results in
Na retention - high BP
hypokalaemia - fatigue, muscle weakness, slow digestion, headache, heart failure
Metabolic alkalosis - high blood pH, confusion, nausea
RAAS system: Angiotensinogen from the __ is converted into angiotensin I via __ from the __ converted to angiotensin II via __ from the __. Ang II stimulates __ and __ activity
liver, renin, kidneys, ACE, lungs. vasoconstriction and aldosterone synthase
> aldosterone
how does atrial natriuretic peptide (ANP) effect aldosterone
It opposes it; aldosterone increase BP, detected by stretch receptors in atrium, ANP released. ANP inhibits aldosterone synthase, opposes ANGII, inhibits release of ADH from pituitary
How is ACTH permissible for aldosterone production (but not regulatory)
ACTH produces cortisol, aldosterone can be derived from cortisol precursor.
Function of cortisol (4)
Fight or flight; (1) glucose mobilisation (gluconeogenesis, lipolysis, decrease aa uptake) (2) maintain blood pressure (increased in chronic) (3) decrease inflammation (4) decrease non-essential processes (digestion..)
Where is cortisol de-activated
At the tissues where MC receptors are abundant e.g kidney (we want mineralocorticoids not glucocorticoids acting here) - oxidation via 11-b-HSD2 to cortisone
Where is cortisol re-activated
liver, lung, muscle, brain, adipose - where GC receptors are - reduction via 11-b-HSD1 from cortisone to cortisol
How does chronic stress (cortisol) increase BP
cortisol acts on nuclear receptors to increase transcription of ADH and adrenergic receptors in vasculature (constriction), cortisol also acts on MC receptors in kidney to increase Na (and water) reabsorption
Effects of chronic stress (4-5)
Increases BP, insulin resistance and insulinaemia (cortisol opposes insulin - increasing blood glucose), hyperglycaemia, tissue breakdown
What is natriuresis
Excretion of Na
What is diuresis
Loss of water
How is cortisol anti-inflammatory and immunosuppresent (4)
Cortisol decreases expression of adhesion molecules to reduce inflammatory cell migration into tissue
Stabilises lysosome cell membrane to prevent release of inflammatory molecules from damaged cells.
Reduces cytokine IL-1 release (the cause of fever)
Suppress T lymphocytes
Effects of cortisol that differ in acute vs chronic
Acute: appetite repressed, increase memory formation
Chronic: appetite stimulated, infertility via hypothalamic suppression, decrease memory retrieval
How is cortisol regulated
Circadian rhythm and stress (psychological and physical)
HPA axis for cortisol
H: CRH release from paraventricular nucleus (PVN)
P: ACTH from corticotropes
A: Cortisol via proliferation of cortical cells and production of steroidogenic enzymes
Are androgens steroid hormones?
yes
What do adrenal androgens do
Stimulate male characteristics
Why do adrenal androgens have a greater role in females?
Because the male androgen testosterone is produced in the testes
When are adrenal androgens produced
During adrenarche (maturation of adrenal cortex) which is pre-puberty (age 6-10) when zona reticularis develops. Peaks at age 20 and declines afterwards.
What stimulates adrenal androgen production
ACTH
Role of adrenal androgens in males
Normal early pubertal changes, if there is an excess leads to early (precocious) puberty. Little affect in males due to testes
Role of adrenal androgens in females
Development of hair, acne and libido in puberty. Excess causes masculinisation and virilisation. In adult contributes to libido, muscle and bone mass, energy and strength. In post-menopause produces oestrogen (ovaries are now gone)
Adrenal androgens are converted to __ in tissues
Testosterone and oestrogen
Addison’s disease
primary adrenal insufficiency - reduction in all adrenal hormones
Secondary and tertiary adrenal insufficiency effect on adrenal hormones
Decreased ACTH causes a decrease in cortisol and androgens with unchanged aldosterone (not controlled by HPA axis)
Signs and symptoms of Addisons disease
Same as low aldosterone and cortisol. Loss of Na - dehydration, low BP; hyperkalaemia (K+) - heart problems; acidosis (H+) - low blood pH, low cardiac output; fatigue, weight loss, nausea, fainting, joint pain, hyperpigmentation.
Why does Addisons disease have hyperpigmentation
ACTH is produced from pro-opiomelanocortin gene (PMOC gene). Gene produces both ACTH and MSH. Addisons is primary so high ACTH = high MSH
What is Addisonian crisis
Occurs in people with low cortisol/aldosterone when a moment of stress occurs such as infection, dehydration, withdrawal of exogenous steroids. Cannot support blood pressure, glucose needs etc.. Causes fainting, hypoglycaemia (coma), confusion, cardiac arrest
Conn’s syndrome
Primary hyperaldosteronism - excess aldosterone. Associated with low renin (-ve feedback via RAAS)
Secondary hyper-aldosteronism
high aldosterone and high renin.
Causes: renin-secreting adenoma or renal hypoperfusion (reduction in blood flow)
pseudo hyper-aldosteronism
increase in aldosterone effects + activation of MRs. Causes: inactivating mutation in 11B-HSD2 (cortisol inactivating enzyme), cross reactivity of other compounds (e.g liquorice on MR), Cushing’s syndrome (ectopic ACTH production), Liddles syndrome (ENaC activating mutation)
Cushing’s syndrome
hypercorticolism - excess cortisol production. Primary (e.g adenoma) or secondary (pituitary - Cushing’s Disease or ectopic production)
Cushings disease
Secondary hypercorticolism caused by pituitary problems. Excess ACTH
Congenital Adrenal Hyperplasia
Hyperandrogenism - excess adrenal androgens. Mutation in steroidogenic enzymes (21 alpha hydroxylase) inhibits ACTH from producing cortisol or aldosterone and shunts pathway to produces androgens.
Effect of hypercorticolism
Diabetogenic effect (excess glucose, insulin resistance), protein breakdown - muscle and bone wastage, Na retention + K loss (cortisol acts on MR at high levels), cardiac hypertrophy and obesity (chronic stress)
Effects of hyperandrogenism
Aldosterone loss - salt loss, cortisol loss - adrenal failure, excess androgens - virilisation (in females), early puberty (in males)
Adrenal pheochromocytoma
Tumour in adrenal medulla, excess catecholamines, 5Ps: pressure, palpitations, perspiration, pain, pallor
Cells in pancreatic islets function; α, β, δ
α - glucagon, β - Insulin and amylin,
δ - somatostatin (inhibits glucagon and insulin to make nutrients available in blood for longer)
Mechanism behind glucose stimulating insulin release
Glucose enters β cell via GLUT 2 transporter.
Undergoes oxidation to produce ATP closing of ATP/K channel - K is trapped inside > depolarisation.
Opening of Ca channels, Ca into beta cell, insulin exocytosed.
Proinsulin >
insulin + C-peptide
How does insulin decrease blood glucose
Insulin binds to membrane receptor > insulin receptor substrates (IRS) are
phosphorylated (P) > Downstream pathways create new proteins or change existing ones - moves GLUT onto membrane > Glucose uptake is increased (excl CNS). Insulin also inactivates enzyme that turns glycogen to glucose and opposes lipolysis
Where are GLUT 2 and GLUT 4 found?
GLUT2 in liver and pancreas, GLUT4 in skeletal muscle and fat
Amylin functions (4)
opposes glucagon, promotes satiety, not involved in glucose uptake, delays gastric emptying
Neural control of BGL - Parasympathetic and sympathetic control of glycaemia
Para: stimulated by GI distension, β cells have ACh receptors that activated cause insulin release, decrease BGL
Symp: stress or exercise, noradrenaline increases glucagon activity, increase BGL
Hormonal control of BGL (glycaemia)
GH, cortisol, adrenaline: in response to stress, increase BGL
Incretin (GLP1, GIP): released from GIT in
response to luminal nutrients, decrease BGL
Type 1 diabetes vs Type 2 diabetes
Type 1: autoimmune destruction of β cells - hyperglycaemia, hypoinsulinaemia
Type 2: insulin resistance - hyperglycaemia, hyperinsulinaemia
adv type 2 β cells exhausted and die
Why is blood test for glucose-bound Hb more accurate than RBC
Hb has a longer half life
How does an oral glucose tolerance test/uptake test work
overnight fast, consume glucose, if glucose doesnt decrease after 2 hours = Diabetes
Treatments for Type 1 diabetes (3)
exogenous insulin (bolus injection before food, basal injections for the day), insulin pump (automated infusion), fluid replacement (hyperglycaemia leads to glucosuria leads to polyuria)
Treatments for type 2 diabetes (5)
sulfonylurea drugs increase insulin, metformin suppresses gluconeogenesis,
SGLT - sodium glucose transporter inhibitors - inhibit glucose reabsorption
fluid replacement for polyuria
Exercise decreases visceral fat insulin signalling
Effect of too little insulin (increased glucose) (4)
Circulatory shock: hyperglycaemia and glucosuria - decreased water reabsorption > hypotension > sympathetic response)
Ketonaemia: Diabetic ketoacidosis (lipolysis > fatty acids converted to ketones > decreased blood pH (metabolic acidosis)
and compensatory hyperventilation (Kussmaul breathing))
Macrovascular complications: lipolysis > glycerol > arteriosclerosis + excess LDL > artherosclerosis»_space; hypertension and ischaemia - foot ulcers and poor wound healing
Microvasular complications: certain tissues dont have cells that rely on insulin
Effect of too much insulin (1)
Hypoglycaemia: Neuroglycopaenia (reduced ATP in neurons > reduced Na-K-ATPase activity > reduced APs > impaired cognition or consciousness)
Hormonal risk factors for Type 2 diabetes
Cushings - excess cortisol and acromegaly - excess GH
Kidney blood supply
renal arteries from aorta
renal veins > IVC
the medulla and cortex of the suprarenal glands are derived from
medulla: neural crest – ectoderm
cortex: mesoderm
blood supply to suprarenal glands
renal artery, aorta, inferior phrenic arteries
what is vesicoureteral reflux
Detrusor muscle forms physiological sphincter, weakness of this muscle allows for back flow known as vesicoureteral reflux
where is kidney referred pain to
lumbar back, inguinal region, lower abdomen, flank, groin
Functions of kidneys (7)
1 Regulation of water and electrolytes
2 Excretion of waste (urea, creatinine, bilirubin, toxins)
3 Regulation of pH
4 Regulation of BP via renin
5 EPO production > erythropoiesis (RBC production). Stimulated by hypoxia.
6 Production of active vit D
7 Regulation of glucose metabolism. Make glucose from glutamine in cortex (ammonia by product)
order of urine flow from kidney
minor calyx > major calyx > renal pelvis > ureter
medulla consists of renal ___
pyramids
renal corpuscle consists of
glomerulus (capillaries) and Bowman’s capsule. contains mesangial cells for support + can contract to change diameter of capillary > changes GFR
what type of cells in PCT
cuboidal with microvilli
Cortical vs medulla nephrons
location of renal corpuscle, cortical have short LOH
what blood vessel is around the LOH
peritubular capillaries
what ions mainly inside cell
K, PO4
what ions mainly outside cell
Na, Cl, HCO3
True or false: water n solute reabsorption can be regulated separately
true
How is water reabsorbed in nephron
paracellular by osmosis or transcellular via aquaporins (channels) in both membranes of cell (apical and basolateral)
> both in PCT, mainly transcellular in distal nephron
triple whammy for kidney injury
one diuretic, one ACEi/ARB, one NSAID
why are ACEi not good for kidney failure
ACEi > no ANG II > no aldosterone actions > no K excretion > hyperkalaemia
renal impairment may affect drug excretion
ACEi suffix
-pril
ARB suffix
-sartan
Adverse effects of ACEi
non-productive cough, hyperkalaemia, hypotension
Clinical indications for ACEi (reasons to take)
hypertension, chronic heart failure
adverse effects of ARB
hyperkalaemia, dizziness, headache
clinical indications of ARB
heart failure, hypertension
contraindication for ARB and ACEi
renal failure
What is acute kidney injury
sudden decline in kidney function with decreased GFR and accumulation of waste products
What are the three types of AKI
pre renal, intra renal and post renal
Causes of pre renal AKI
Hypovolemia, shock, interruption of blood flow to kidneys
Four subtypes of intra renal AKI
Glomerular disease, vascular disease, tubular disease, interstitial disease
Chronic kidney disease defined as
GFR <60ml/min for 3 months or longer
Common causes of chronic kidney disease
systemic diseases - hypertension, diabetes
kidney disease - AKI, stones
vascular disorders -
Chronic kidney disease effects
Brain function (nitrogenous waste)
anorexia and vomiting (nitrogenous waste)
hypertension
anaemia (low EPO)
bone abnormalities (altered Ca)
oedema
change in circulating volume and electrolytes
peritubular myoid cell function
contractile for sperm ejection
Spermatogenesis
In seminiferous tubules:
Puberty: 1 spermatogonium undergoes mitosis to form 2 primary spermatocyte which undergoes meiosis 1 > 2 secondary spermatocyte > meiosis 2 > 4 spermatid > spermiogenesis in epididymis > 4 spermatozoa
requires T and ABP
Sertoli cell function
form blood testis barrier
stimulate meiosis via testicular fluid
secrete ABP
secrete inhibin B
secrete anti-mullerian hormone to stop female characteristics developing
Leydig cell function
Produce 95% T and DHT
What is amplification pathway
Conversion of T to DHT via enzyme 5-alpha reductase
DHT function
- External genitalia (scrotum, penis, testes), - Testes descent (with T)
- Prostate enlargement
- Secondary male characteristics: facial hair, baldness, acne
What is aromatisation/diversification pathway
Conversion of T to estradiol/estrogen via aromatase enzyme in testis and peripherally
what type of hormone/receptor are T and DHT
steroid hormones with androgen receptors
estradiol function in males
testes - spermatazoa motility
prostate - water reabsorption
bone - closure of epiphyseal plate
brain - good mood
What causes prenatal androgen surge
hCG from maternal placenta stimulates Leydig cells to produce T
Testosterone functions
- Wolffian duct stimulation > internal genitalia (SEED - seminal vesicle, ejaculatory duct, epididymis, ductus/vas deferens
- Spermatogenesis
- Testes descent (with DHT)
- Secondary sex characteristics
- Increase BMR
what causes puberty/pubertal surge of T in males
KNDy neurons in hypothalamus > KISS1 > GnRH neurons > GnRH
pulsatile release of KISS 1 and GnRH
Stimuli that suppress KISS1 release
Energy imbalance, excess prolactin,
hyper/hypo thyroid hormones, cortisol
what is imprinting in male development
Expression of XY genes
SRY gene > TDF protein
How does tumour in pineal gland lead to hypergonadism
Pineal gland > melatonin > prolactin > inhibits KISS1
Reduced melatonin = more KISS1 = more GnRH = more T/DHT
Features of hypergonadism in males
early/exacerbated puberty - lower voice, high libido, hair loss, reduced fertility from
-ve feedback
Features of hypogonadism in males
loss of secondary sex characteristics
infertility
Where does gametogenesis occur in males/females
males - semineferous tubules
females - ovaries
Oogenesis
Foetus: Primordial germ cell > oogonium > mitosis > million primary oocytes held in prophase of meiosis I > birth
Puberty, each month: completion of meiosis I > secondary oocyte held in metaphase of meiosis II + first polar body
Fertilisation: complete meiosis II > ovum/ova > gamete + second polar body
What is ovulated each month
secondary oocyte in metaphse II
Where does secondary oocyte form
in ovarian follicles
Ovarian cycle:
Follicular phase: primary oocyte in follicle (theca and granulosa cells) >
FSH - granulosa cells - estrogen , LH - theca cells - androgen precursors > follicle grows from primordial to Graafian follicle, antrum forms, secondary oocyte forms in the Graafian follicle
Peak of estradiol to stimulate proliferation
Ovulatory phase: theca cells contract and release enzymes to break through capsule, granulosa cells release prostaglandins > Graafian follicle ruptures releasing one secondary oocyte (ovulation)
Peak in LH/FSH, inhibin B reduces FSH after peak
Luteal phase: follicle become corpus luteum (luteal cells) produce progesterone (and oestrogen) to prepare endometrium, and inhibin A to reduce FSH/LH
LH stimulates progesterone from luteal cells
Pregnancy maintains corpus luteum by placenta hormone hCG - keep high progesterone. Placenta also produces inhibin A. After wk 12 placenta takes over from corpus luteum to produce progesterone.
No pregnancy: Corpus luteum > corpus albicans
Theca cells produce
granulosa cells produce
Theca: androgens - T,
Granulosa: convert T to estradiol, inhibin to reduce FSH
When does pre-antral phase end and antral phase begins
When from many secondary follicles, one tertiary follicle (Graafian follicle) arises
What is the corona radiata
Layer of granulosa cells that surround zona pellucida (which surrounds secondary oocyte) for protection and nutrients
What covers secondary oocyte when it is ovulated
glycoprotein layer - zona pellucida and corona radiata (granulosa cells) for protection
What movements move the secondary oocyte from infundibulum to uterus
Ciliary action and peristalsis
Uterine/menstrual cycle
Menstrual phase: ABSENCE of P and E > functional layer: spiral arteries constrict
> ischaemia of functionale, cell death, enzymes, endometrium breakdown
Basal layer: remains to provide cells for next cycle.
Myometrium at its thinnest and contracts.
Proliferative phase: ESTROGENS from follicle > zona functionalis grows: mitosis of basal stromal cells + glandular epithelial.
Followed by cell hyperplasia + increased extracellular matrix to thicken layer.
Myometrium thickens, uterine gland proliferates
Secretory phase: After ovulation, PROGESTERONE and oestrogen from corpus luteum > secretions from endometrium, vascularisation, glycogen storage in decidual cells, endometrium thickening. P prevents contractions of myometrium, stops sloughing (bleeding). Oestrogen > growth of uterus and mammary glands, uterus contractions in birth
Overlap of uterine and ovarian cycles
Proliferative phase of uterine over follicular phase of ovarian (estradiol from follicle stimulates zona functionalis growth).
Secretory = luteal
what class are estrogen and progestrone receptors
nuclear and GPCR
Source of oestrogen production
mainly ovaries but also bone, adipose, liver, skin, brain > aromatisation
FSH affect on granulosa cells
Increase proliferation
Increase aromatase enzyme (to convert androgen precursor to estrogen)
LH affect on theca cells
proliferation, enzyme for androgen precursor, produce some progesterone
Estradiol affect on granulosa cells
+ve feedback. Increase LH and FSH receptors and sensitivty > peak of FSH/LH before ovulation
Larger LH due to -ve feedback from inhibin from granulosa cells
Sex hormones in breast development
oestrogen - fat deposition, induces ductal formation
progestrone - develops lobules and alveoli
Prolactin > milk production (+stops menstruation)
Oxytocin > milk ejection
primary vs secondary amenorrhea
Primary - never menstruated
Secondary - previously present but been
>6 months
Oligomenorrhea - irregular periods
Menopause cause
Exhaustion of follicles - lose a bunch each cycle (only one goes through whole cycle)
No more E and P
remaining hormones from adrenal glands and aromatisation
What is functional hypothalamic amenorrhea
Secondary type of amenorrhea caused by energy deficit:
weight loss, stress, high exercise (Athlete), low leptin > suppress GnRH
POCS
Secondary type of amenorrhea - excess androgens from ovaries from altered GnRH pulse > higher LH than FSH
Accompanied by excess insulin
What is hormonal imprinting
First encounter between receptor and ligand - develops normal connection for life. Critical period is pre-natal
Misimprinting
high or low ligand concentration, related molecule binds. Dependant on time of misprint.
Faulty imprinting
Endocrine disrupters (found in food, contaminants) can displace endogenous hormones or have antagonist/agonist effects (stimulate or inhibit hormonal pathways)
EDC effects
Bones and growth, reproductives, metabolism, cancer
What is foetal programming model / The Barker Hypothesis
Prenatal exposures have lifelong consequences
e.g low birth weight > increased risk of chronic adult diseases due to brain sparing (other organ development is second). Followed by post-natal excess nutrition > type II diabetes
Underdeveloped:
- kidneys lead to hypertension (decreased nephron number).
- Pancreas (decreased B cells) and liver/fat/muscle (decreased IGF-1) lead to type 2 diabetes.
- altered HPA axis > increased cortisol > hypertension + obesity
Cortisol HPA axis in mum and baby
placental CRH stimulates mum and baby axis. Maternal and foetal cortisol stimulate placental CRH (+ve)
11- beta HSD enzyme in placenta breaks down cortisol into cortisone so excess maternal cortisol doesn’t affect baby. Chronic elevated maternal cortisol can overwhelm 11-beta HSD and elevate foetal cortisol > affecting foetal HPA axis
cortisol in pregnancy
Important for foetal maturation, parturition (birth)
Elevated maternal cortisol leads to shortened gestation (quicker parturition)
What is early life stress
Social and psychological stressors affect later life health e.g abuse as a child may lead to drug abuse as an adult due to neural plasticity as brain still developing post natal.
Childhood abuse can lead to methylation of glucocorticoid receptor > affects cortisol
ELS > decreased oxytocin
Significance of organisational-activational hypothesis
It is not circulating adult hormones that determine sex characteristics - it is those around birth (prenatal and slightly after)
What is the organisational-activational hypothesis
Organisation: Prenatal/neonatal exposure to gonadal steroids (sex hormones) is important for permanent sexual differentiation of brain and behaviour
Activation: secondary surge of sex hormones at puberty for sex-dependant behaviours (mostly in males)
True or False: both sex and gender can affect epigenetics that affect all systems of body
True
List some factors that can influence phenotype
Fetal programming
Organisation-activation hypothesis
ELS
Hormonal imprinting:mis- and faulty
Sex/gender
Are aboriginals less likely to have type I diabetes
Yes
A reason for aboriginal health problems
Barker hypothesis, low socioeconomics affect maternal health > high stress > affects foetal HPA axis > diabetes type II
Urogenital develops from
intermediate mesoderm
Urine production starts week
9
Waste from foetal urine goes to
maternal blood to be cleared by her kidneys
what is cryptorchidism
one or both testes fail to descend into scrotum. Could become cancerous
what is testicular ectopia
in strange place - abdomen, femoral region
If sperm is not ejactulated it is
reabsorbed by macrophages in epididymis
what is hypospadias
urethra opens prematurely
what produces seminal fluid
60% by seminal vesicles, 35% prostate, bulbourethral glands
> all still produce seminal fluid after vasectomy
(vas deferens that transport sperm are cut)
testicular hydrocele
fluid accumulation in two layers of tunica vaginalis
what nerve supplies the cremaster muscle
genitofemoral
is penis in superficial or deep perineal pouch
superficial
pelvic diaphragm muscles
levator ani (puborectalis, pubococcygeus, iliococcygeus) + coccygeus
ovarian artery is a branch of
abdominal aorta
suspensory ligament contains blood and nerves for
ovaries
where does fertilisation typically occur
in the ampulla
ligaments that support uterus
pubocervical, transverse cervical and uterosacral
Uterine wall layers (3)
Perimetrium: serosa - outer layer
Myometrium: smooth muscle, blood vessels and lymphatics - stratum vasculature. This layer hypertrophy in pregnancy.
Endometrium: 2 layers:
stratum basale
stratum functionale - shed in mestruation
Blood supply in uterine wall
uterine artery > arcuate artery > radial branch > spiral artery + straight artery
Straight supplies stratum basale
Testicular and ovarian cancer inflames
para-aortic lymph nodes
Glomerular filtration barrier
Glomerular capillary fenestrated endothelium, -ve basal lamina (3 layers), foot processes of podocytes
Pressures that determine filtration rate
Hydrostatic pressure (60): pressure from blood in glomerular capillaries causing filtration (high BP = higher hydrostatic pressure = more filtration)
Colloid/oncotic osmotic pressure (32): pressure from proteins in blood opposes filtration (high protein in glomerular capillary = less filtration)
Bowman’s capsule hydrostatic pressure (18): pressure from filtrate in capsule - opposes filtration (kidney stones block outflow = build up of filtrate in capsule = less filtration)
4th force in unhealthy individuals is colloid osmotic pressure in Bowman’s capsule from proteins that pass through
What is osmolarity
Concentration of solutes - high solutes = high osmolarity
Factors that affect GFR
Either affect pressures: renal blood flow, blood pressure affected
or filtration coefficient (Kf): filtration barrier or slit surface area affected.
what is autoregulation in kidneys
Maintains GFR over range of high blood pressures. Consists of myogenic response and tubuloglomerular feedback.
What is the myogenic response
Myogenic: high BP > stretch > smooth muscle Na channels open > stored Ca released > Ca binds to actin > contraction > afferent arteriole constriction
What is tubuloglomerular feedback
Macula densa in DCT detects tubular NaCl: High GFR = high NaCl in tubule = macula densa signal afferent arteriole to constrict (via ATP release) > reduce GFR
Low GFR = low NaCl = macula densa produce prostaglandins + NO > vasodilation of afferent arteriole.
Also signal juxtaglomerular/granular cells to secrete renin > RAAS, aldosterone increases Na channels in nephron, ang II causes efferent vasoconstriction
Nephritic Syndrome
Acute inflammation - severe. Post-infectious, damage to glomerular basement membrane so severe RBCs can pass > (1) haematuria. (2) Oedema from protein loss, (3) hypertension from RAAS activation lowers GFR = (4) oliguria (less urine).
Nephrotic Syndrome
chronic inflammation. injury to podocytes, immune-complex deposition, scarring/thickening of entire capillary wall. (1) High proteinuria, liver cannot compensate - (2) low albumin. Fluid from tissues is normally attracted into capillaries from protein - drop in oncotic pressure from loss of proteins > (3) oedema. (4) hyperlipidemia
What would neutrophils in nephron indicate
Acute inflammation - damage to podocytes and endothelial cells by immune cells - affects glomerular filtration rate
Goodpasture’s
autoimmune disease - affects basement membrane of kidneys and lungs - life threatening. type II - antibody mediated
systemic lupus
circulating immune complexes - type III, deposit at sites of high filtration b/n basement membrane and endothelial cells causing inflammation
diabetic mellitus
reduced glucose reabsorption:
increased urine osmolarity
reduced water reabsorption
increased urine - diuresis and polyuria
increased plasma osmolarity - high glucose in blood > excess thirst (polydipsia)
diabetes insipidus
lack of vasopressin (ADH) production or response:
decreased water reabsorption > high Na
increased urine - polyuria
dehydrated - polydipsia - increased thirst
fatigue
constipation
nocturnal enuresis - bed wetting
Treatment: desmopressin nasal spray + hydration
syndrome of inappropriate ADH secretion (SIADH)
Oversecretion of ADH when normal BP, low [electrolyte]
water reabsorption
dilutes Na - hyponatraemia - confusion, weakness, headache, personality change, coma
Treatment: fluid restriction, hypertonic saline, V2R blockers
