Systems endocrinology Flashcards
What is the basic structure of cholesterol?
Has a polar head group (1), a steroid body (2) and a hydrophobic side chain (3)
Is cholesterol a hormone?
NO
What part of cholesterol makes it relatively insoluble?
Fatty tail/ hydrophobic side chain
What are the 3 main types of adrenal steriords and what is their function?
Mineralocorticoids (salt and water retention)
Glucocorticoids (glucose synthesis, protein and lipid metabolism and inflammation)
Adrenal androgens (foetal steroids and growth)
What are the 3 types of sex steroids?
Androgens
Oestrogen
Progesterones
What vitamin is also a steroid hormone?
Vit D
What do all adrenal and gonadal steroids have in common with structure?
4 rings of carbon
What is the specific modification that makes cortisol different to other steroids?
11 beta hydroxyl group
What is the specific modification that makes cortisol different to other steroids?
11 beta hydroxyl group
What is the specific difference that makes aldosterone different to other steroids
Group on 17th carbon
How do steroid hormones work and what is their time of action?
- Classic receptors in the cytoplasm get activated by steroid binding- translocate to nucleus. This causes mRNA to be made, which leaves nucleus and promotes protein synthesis at the cytoplasm
- Is a slow action- > 30 mins- 48 hours
- There is another mechanism- non genomic mechanism, steroid hormones act directly on receptors e.g. ion channels in the plasma membrane.
- This is rapid signalling, < 1 min
What makes steroid hormones more soluble than cholesterol?
A hydrophobic 6 carbon chain is removed whilst making the steroid
At what area do most steroids have a varied substituent?
C-17
What enzymes are involved in steroid synthesis?
Cytochrome P450’s
Steroid dehydrogenases or reductases
What is the function of steroid dehydrogenases and reductases?
To convert inactive forms of steroid into active forms
How is cortisol changed from its active form to inactive form?
Cortisol= active
Cortisone= inactive
What happens to cortisol levels in disease state?
Free cortisol will rise
When does synthesis of cortisol occur?
In the adrenal gland, after it has been stimulated by ACTH
Where is most cortisol converted to cortisone in the body?
The liver
What percentage of cortisol binds to proteins in the circulation?
90%
What vertebrae are the adrenal glands located at?
12th thoracic vertebrae
Where is the location and other name for the adrenal glands?
Positioned bilaterally and anteriorly on the superior poles of the kidney- triangular in shape
Also called suprarenal glands
What are the two areas of the adrenal glands and what do they produce?
Cortex= 80-90% of gland. Makes steroid hormones
Medulla= makes catecholamines
What are the two areas of the adrenal glands and what do they produce?
Cortex= 80-90% of gland. Makes steroid hormones
Medulla= makes catecholamines
What is the blood supply in the adrenal gland (and drainage)?
Cortex= receives blood from 30-50 short arteries penetrating the capsule which go on to form a subcapsular plexus of arterioles
- Adrenal medulla receives long cortical arteries and capillaries from the cortex
- They both drain via the central medullary vein
What are the 3 zones of the adrenal cortex?
Zona glomerulosa
Zona fasciculata
Zona reticularis
What occurs in the zone glomerulosa?
Produces aldosterone
Is under control of the RAS- regulates salt and water retention in the kidney distal tube
What occurs in the zone fasciulata?
Production of cortisol
Under control of HPA axis and regulated by ACTH
What occurs in the zone reticularis?
Production of C19 adrenal androgens, under the control of HPA axis
What are the functions of adrenal androgens?
Inactive hormones that are responsible for secondary sexual pattern such as hair pattern
Converted to active form in peripheral tissues to testosterone and oestradiol
What is the summary of the adrenal gland layers and what stimulates them/what they release?
What determines the steroids synthesised in each layer of the adrenal gland?
Zone-specific P450 gene regulation
What is the function of cortisol?
Two actions; anabolic in liver to promote glycogenesis and catabolic in peripheral muscle and fat to promote protein and lipid breakdown
What does anabolic and catabolic mean?
anabolic – this type of pathway requires energy and is used to build up large molecules from smaller ones (biosynthesis). catabolic – this type of pathway releases energy and is used to break down large molecules into smaller ones (degradation)
What are symptoms of too much cortisol?
-Secondary diabetes mellitus (due to elevated plasma glucose)
Muscle wasting/weakness
Poor wound healing
Uncontrolled appetite
Na+ and fluid retention and hypertension (due to excess mineralocorticoid action)
What are the causes of hyper-cortisol?
Cushing’s syndrome (a pituitary, ectopic or adrenal tumour)
What is the regulation of corticotrophin releasing hormone controlled by?
Neurostimulatory factors that can be excitatory (AhC, serotonin) or inhibitory (GABA, cortisol negative feedback, alpha-adrenergic agonists)
Also secretion from PVN of hypothalamus is linked to the circadian rhythm
What is the rate limiting step in the production of steroid hormones?
StAR protein
It chaperones cholesterol across the mitochondrial membrane
How do levels of cortisol change throughout the day?
High on waking, lower later in the day (with stress activity spikes) and lowest in the middle of the night
What enzyme causes cholesterol to transform into aldosterone?
Aldosterone Synthase
(Through intermediate steps)
What enzymes are involved in the route distinction of aldosterone and and cortisol/adrenal androgens?
17α-Hydroxylase
What enzyme ensures cortisol is produced in the ZF?
11β-Hydroxylase
What are the 3 main physiological factors that regulate blood pressure?
- Cardiac output
- Vascular tone (stiffness or resistance of the blood vessels)
- Extracellular fluid volume (interstitial fluid in tissues and intravascular fluid in the plasma)
How is cardiac output calculated?
Stroke volume x heart rate
How do hormones effect cardiac output?
Increased by catecholamines and cortisol potentiation
How is vascular tone increased by hormones?
Increased by angiotensin II, aldosterone, catecholamines and cortisol potentiation
How is extracellular fluid volume increased by hormones?
Increased by aldosterone and cortisol (increased by kidney water resorption)
What is the mechanism of the renin-angiotensin system?
Where is renin released from?
The juxtaglomerular cells in the kidney
What triggers the release of renin?
Released in response to reduced blood pressure detected by the juxtaglomerular cell barreceptors
Also released when the macula densa cells detect decreased Na concentration in the distal tubual - activates a sympathetic loop that innervates JG and causes release of renin
Also released in response to carotid arch baroreceptors (low systemic arterial pressure). Also activates sympathetic innervation of JG.
What are the longer term effects of aldosterone?
VASCULATURE= increase in cell hypertrophy and hyperplasia
CNS= increased thirst, salt appetite and ADH hormone release
ADRENAL= increased aldosterone increase and glomerulosa cell proliferation
What is the main action of aldosterone?
Binds to a mineralcarticoid receptor which causes a messenger to migrate from cytoplasm to nucleus and cause a change in gene expression/transcription factors
This causes more epithelial sodium channels to be created so more Na+ reabsorbed, as well as increased basolateral Na+/K+ exchange
What are the quick actions of aldosterone?
VASCULATURE- increased vasoconstriction
ADRENAL- increased aldosterone and catecholamine synthesis
KIDNEY- Na+ and water reabsorption
What is primary and secondary hypertension?
High blood pressure that doesn’t have a known cause is called essential or primary hypertension. In contrast, secondary hypertension has a known cause
What are more common causes of secondary hypertension?
Neoplasia (uncontrolled, abnormal growth of cells or tissues in the body- can be benign or malignant)
Vascular causes
Endocrine causes
What percentage of hypertension is primary hypertension?
85-90%
10-15% is secondary
What are some examples of causes for primary hyperaldosteronism?
Conn’s syndrome (unilateral aldosterone producing tumour in the adrenal gland)
Bilateral adrenal hyperplasia
What is the phenotype of someone with primary hyperaldosteronism?
High aldosterone
High sodium, low K+, ECF expansion
Hypertension and low renin
What is the genetic cause of primary hyperaldosteronism?
Glucocorticoid-remediable aldosteronism
Arises from a disorder on chromosome 8
A rare form of primary aldosteronism in which aldosterone secretion is solely under the control of Adrenocorticotropic hormone (ACTH)
What are some causes of secondary hyperaldosteronism?
- A renin secreting juxtamoglomerular tumour
- Renal arterial stenosis
What is the phenotype of patients with secondary hyperaldosteronism?
High plasma renin, high aldosterone
High Na+, low K+
ECF expansion and hypertension
What are causes of cortisol over production?
Adrenal tumour (Cushing’s syndrome) or pituitary tumour (Cushing’s disease)
What is the presentation of cortisol over production?
Weight gain, stretch marks, easy brushing, proximal muscle weakness, diabetes mellitus, menstrual irregularities and depression
What is the phenotype of someone with cortisol overproduction?
High cortisol, high Na+, low K+, low renin and low aldosterone
Hypertension too
How can you tell the difference between cortisol secreting adrenal tumour and a ACTH secreting pituitary tumour?
How does elevated plasma cortisol cause hypertension?
Reduces nitric oxide synthase mediated vasodilation
Also potentiates catecholamine action in the heart and vasculature
Can also inappropriately activate the kidney mineralocorticoid receptors and cause water retention
What happens when cortisol reduces eNOS mediated vasodilation?
Nitric oxide syntheses usually causes nitric oxide to be formed which is a vasodilator
Elevated cortisol levels inhibits Nitric oxide synthase
How do glucocorticoids increase blood pressure via the sympathetic nervous system?
Elevated plasma cortisol increases adrenaline activation, which causes an increased cardiac output, and peripheral resistance, both leading to increased blood pressure
Why is cortisol not constantly bound to kidney mineralocorticoid receptors?
Although has a moderate affinity and much higher concentrations than aldosterone, most of cortisol is converted in the liver to cortisone, to stop inappropriate binding
What is apparent mineralocorticoid excess?
Genetic condition where there is a mutation in the 11-beta-HSD2 so it is less active and there is a decrease in the conversion to cortisol
What is the phenotype of apparent mineralocorticoid excess?
High kidney cortisol, low RAD, high Na+ and low K+
What is an example of a 11beta-HSD2 inhibitor?
Liquorice
What is pheochromocytoma?
A catecholamine secreting tumour of the adrenal medulla- causes increased HR, vasoconstriction, increased glucagon secretion and glycogen and lipid breakdown
What are the symptoms of pheochromocytoma?
Palpitations, headache and episodic sweating
What is ADH?
Anti-diuretic hormone, same as vasopressin
What percentage of the anterior pituitary do somatotrophs make up?
35-45%
What is a disorder of excess growth hormone production?
Acromegaly
What is the growth hormone pathway?
Growth hormone releasing hormone is released from the hypothalamus, and acts on the pituitary which releases GH, which mainly acts on the liver to stimulate the release of IGF-1
What is the inhibitory factor released from the hypothalamus that acts to stop GH?
SRIF (somatotropin release inhibiting hormone)
What is GHRH enhanced by?
Estradiol, grehlin, glucocorticoids and starvation
What is GHRH blunted by?
Somatostatin, obesity, insulin, glucose and increase in age
What does the graph look like GH levels with GHRH and ghrelin?
How does ghrelin enhance growth hormone production?
It is a natural ligand of the growth hormone secretagogue receptor
What is somatostatin and what is its function?
Peptide hormone
Has a supressive effect on multiple pituitary hormones such as growth hormone and thyroid stimulating hormone, as well as insulin
Where are the majority of growth hormone receptors expressed?
In the liver
What is the predominant action of growth hormone in the liver?
Stimulation of hepatic IGF-1 synthesis and secretion
What is IGF-1?
A small peptide that is responsible for most of the linear growth promoting activities of GH
What can inherited IGF-1 variation contribute to?
Final height of an individual
Where is somatostatin released from?
Released from PVN (paraventricular hypothalamic nucleus)
What are some physiologic, hormonal and pathologic factors that stimulate GH release?
Physiological= exercise, stress, fasting, deep sleep
Hormonal= Ghrelin
Pathological factors= acromegaly,
What are some physiological, hormonal and pathological factors that inhibit growth hormone?
Elevated free fatty acids
Elevated GH levels
REM sleep
Somatostatin
Obesity
What age does GH levels peak?
Puberty, then falls with ageing (~50% every 7 years)
When is the majority of growth hormone secreted?
2/3 secreted at night with onset at slow wave sleep
What are the actions of growth hormone?
- Acts directly and indirectly (via IGF-1) to stimulate linear growth- actions on epiphyseal growth plates
- Stimulates protein synthesis
- Antagonism of insulin action (stops glucose becoming glycogen)
- Phosphate, water and sodium retention
- Increases lipolysis (breakdown of fat)
What are the actions of IGF-1?
- Decrease blood glucose/ improve insulin sensitivity
- Stimulate whole body protein synthesis and inhibit proteolysis
- Anabolic effect on bone (↑markers of bone formation)
- Negative feedback– ↓GH release
What is Laron syndrome?
Severe postnatal growth failure (short limbs)
Normal or high GH, low GH-binding protein and low IGF-1
What GH disorder gives a reduced cancer susceptibility?
Laron syndrome
What is the treatment for children with GH deficiency?
Recombinant human growth hormone recommended where epiphyses open (injection pen)
What are some of the reasons an adult would be treated for growth hormone deficiency?
Increase in muscle mass, decrease in body fat, increase in exercise capacity
What is the condition called where there is excessive secretion of growth hormone?
Acromegaly
What is the main cause of acromegaly?
75% of the time is somatotropin macroadenomas
What are symptoms of acromegaly?
Headaches, large skull lips and nose, increased sweating, enlargement of feet and hands
What is the treatment for acromegaly?
Pituitary surgery to remove the adenoma
GHR antagonists and synthesised somatostatin used as well
What is the area in the brain sensitive to plasma osmolarity and plasma sodium levels and where is it located?
Osmoreceptor, located on the floor of the third ventricle
What are the connections in the brain that lead to the release of ADH?
Osmoreceptor is connected to thirst centre (controls thirst) as well as two hypothalamic nuclei; supraoptic and paraventricular that have projections down the pituitary stalk to the posterior pituitary which releases ADH
What is plasma osmolarity?
Plasma osmolality measures the body’s electrolyte–water balance.
What occurs when plasma osmolarity rises?
Thirst- when the plasma osmolarity rises, thirst increases
There is also ADH release which acts on the kidneys to retain water
How does ADH help to retain water?
Increases water permeability and apical permeability by increasing the water channel aquaporin 2
What are the actions of ADH?
Act on kidney to cause water retention
Act on blood vessels to cause constriction
What ascending pathways can affect ADH?
- Peripheral stimuli
- Low blood pressure
- Low ECF volume
- Pain
- Nausea
What are the symptoms of excess water loss?
- Excess water loss- increased urinary output, somtimes people are thirsty
- If they fail to keep drinking to keep up with loss, sodium and osmolarity can rise and BP can fall
- Eventually can lead to collapse and confusion
What are the symptoms of excess water retention?
- Excess water retention- usually little symptoms, later increased in sodium and water osmolarity
- eventually confusion, drowsiness, nausea and even fits
What is polyuria?
Passing excessive urine volumes
What are the causes of polyuria?
Diabetes insipidus, habitual/psychogenic polydipsia, osmotic diuresis and renal impairment
What is diabetes insipidus?
Diabetes insipidus is a rare condition where you pee a lot and often feel thirsty.
Diabetes insipidus is caused by problems with a hormone called vasopressin- lack of production so water is not retained
What is osmotic diuresis?
Osmotic diuresis occurs when substances of high molecular weight, such as glucose, enter the kidney tubules. The substances cause an increase in the hydrostatic pressure or osmotic pressure within the tubule, which reduces the reabsorption of water and increases urine output.
What tests can be done to check for diabetes insipidus?
Water deprivation test
Hypertonic saline test
What are the different types of diabetes insipidus?
Cranial diabetes insipidus
Nephrogenic diabetes
What is nephrogenic diabetes inspidus?
When the kidneys do not respond to ADH, will not respond to synthetic ADH treatment
What is cranial diabetes insipidus?
Diabetes with origin in hypothalamus or posterior potuitary
Can be a lesion, head injury, tumour or due to surgery
What is the replacement for vasopressin in patients with cranial diabetes insipidus?
Desmopressin spray
What do the results of the water deprivation test show?
What is hyponatraemia?
Hyponatremia means that the sodium level in the blood is below normal.
What is SIADH?
Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a condition in which the body makes too much antidiuretic hormone (ADH)
What is the diagnosis pathway for SIADH in patients that present with excess retention of water?
Is the patient dehydrated? NO
Is the patient oedematous (abnormally swollen)? NO
Is there thyroid or adrenal ACTH deficiency? NO
What are the causes of SIADH?
Intracranial lesions, infection, antipsychotics, sedatives, nicotine, pain and nausea
What is the treatment for SIADH?
Restrict fluid
vasopressin-antagonists: ‘vaptans’
Why is simple T4 replacement for secondary hypothyroidism dangerous?
T4 exacerbates cortisol deficiency by speeding up metabolism, thus making more of a demand for glucose and speeds up degradation of cortisol in the liver, reducing ability to make glucose in response to stress
Treating is this way may precipitate a Addisonian crisis (a life threatening situation that results in low blood pressure, low blood sugar)
What is secondary hypothyroidism?
Secondary hypothyroidism involves decreased activity of the thyroid caused by failure of the pituitary gland
What is the usual balance of sodium and potassium?
Usually if plasma sodium is high, potassium will be low and vice versa
What could not maintaining plasma glucose overnight be indicative of?
Not maintaining plasma glucose overnight= not producing sufficient glucose in liver= low cortisol (cortisol in charge of regulating glucose synthesis in fasting)
What are the principal hormones involved in blood pressure regulation?
Aldosterone, vasopressin, angiotensin II, catecholamines
What is Addison’s disease?
In Addison’s disease, your adrenal gland, produce too little cortisol and, often, too little aldosterone
Autoimmune disease or cane caused by TB
Symptoms= pigmented skin
