Old Endocrinology Flashcards
What is endocrinology?
The study of hormones, receptors and the intracellular signalling pathways and their associated diseases
Give the differences between water and fat soluble hormones:
Transport
Cell interaction
Half life
Clearance
Transport: Water - unbound Fat - Protein bound
Cell interaction: Water - Bind to surface receptor Fat - diffuse into cell
Half life: Water - short Fat - long
Clearance: Water - Fast Fat - Long
What classes of hormones are water soluble hormones?
Peptide hormones
Monoamines
What classes of hormones are fat soluble hormones?
Thyroid hormones
Steroid Hormones
Where are water soluble hormones stored?
In vesicles
Where are fat soluble hormones stored?
Typically not stored
They are synthesised on demand
Define Endocrine secretion?
Secretions go directly into the bloodstream/lymph to act at distant sites
Define exocrine secretions?
Glandular secretions poured into a duct to the site of action
Typically will act locally
Define paracrine secretions?
Cellular secretions/signals that act on adjacent cells
Define autocrine secretions?
Cellular secretions/signals that feedback on the same cell that secreted the hormone.
What is a negative feedback arch?
- Initial stimulus causes response
- Response feedback to stimulus to reduce
- Response loop shuts off
What is a positive feedback arch?
- Initial stimulus causes response
- Response causes stimulus to increase
- Response continues to increase
- Outside factor required to shut off feedback cycle
Give some basic details about peptide hormones?
- Hydrophilic and water soluble
- Usually stored in secretory granules; released in bursts or as part of a rhythmic cycle
Give an example of a peptide hormone?
Insulin
Explain how insulin exerts its effect at the receptor?
The binding of insulin to it’s receptor causes phosphorylation of the intracellular tyrosine residues associated with the receptor. This offsets the tyrosine kinase signal transduction pathway inside the cell, leading to decreased plasma glucose level.
How does insulin act to reduce blood glucose?
- Translocation of Glut-4 transporter to the plasma membrane and influx of glucose
- Glycogen synthesis (liver)
- Glycolysis
- Fatty acid synthesis (live and adipose tissue)
What are the classes of amine hormones?
Tryptophan derived amines
Tyrosine Derived amines
Give an example of a Tryptophan derived amine hormone?
Melatonin
Give an example of a Tyrosine Derived amine hormone?
Catecholamines - Dopamine, noradrenaline, adrenaline
Thyroid Hormones - T3 and T4
Where are the catecholamines secreted from?
Adrenaline and noradrenaline from the adrenal medulla
Dopamine from the hypothalamus
How does the effect of adrenaline and noradrenaline differ?
Both play a role in the body’s sympathetic nervous system;
- Adrenaline has slightly more of an effect on the heart
- Noradrenaline has slightly more of an effect on blood vessels
Are iodothyronines hydrophobic or Hydrophilic?
Hydrophobic
What are the iodothyronines?
Triiodothyronine (T3)
Thyroxine (T4)
Where are T3 and T4 produced?
T4 produced by the thyroid gland - more abundant
T3 is produced by the conversion of T4 to T3 in the periphery - more active
Explain the synthesis of T3 and T4?
- Thyroglobulin (T4 precursor) is synthesised in cells of thyroid gland and discharged into follicle lumen
- Iodide is actively transported inside the follicular cell
- Iodide is oxidised to iodine.
- Iodine is attached to tyrosine in colloid, forming Diiodotyrosine (DIT) and Monoiodotyrosine (MIT).
- DIT and MIT join together to form T3 and T4;
- MIT + DIT = T3
- DIT + DIT = T4 - T3 and T4 are stored in follicular cell
- lysosomal enzymes cleave T4 and T3 from thyroglobulin and hormones diffuse into bloodstream
What enzyme converts T4 into T3 in the peripheral circulation?
Iodothyronine deiodinase
What are the 2 classes of steroid hormones?
Corticosteroids (Adrenocorticoids)
sex steroids (Gonadal)
Why are the steroid hormones split into 2 classes?
It is based upon the receptor that they bind to!
What class do glucocorticoid and mineralocorticoid fit into?
Corticosteroids
What class do androgens, oestrogens and progestogens fit into?
Sex steroids
What are steroid hormones synthesised from?
Cholesterol
What is the pathway of synthesis of the steroid hormones?
- Cholesterol is converted to Pregnenolone
- Pregnenolone converted to Progesterone
- In adrenal glands, progesterone changed to Cortisol
- In ovaries or testes, progesterone converted to Androstenedione which is converted to Testosterone
- Testosterone converted to Estradiol in the ovaries
Are steroid hormones water or lipid soluble?
Lipid soluble
How are steroid hormones transported around the body?
Vitamin D binding protein
How do steroid hormones bind to receptors and exert their effects?
- 1️⃣ Diffuses through plasma membrane and binds to receptor (lipid soluble)
- 2️⃣ Binds to receptor in cytoplasm producing receptor-hormone complex
- 3️⃣ Receptor-hormone complex moves into nucleus
- 4️⃣ Binding inside the nucleus initiates transcription of gene to mRNA
- 5️⃣ mRNA directs protein synthesis.
How is steroid hormone secretion controlled?
Basal secretion that can be continuous or pulsatile
What are some factors that stimulate the release of steroid hormones?
- Humoral stimulus; released as result of change in environment (e.g. low calcium causes release of PTH)
- Neural stimulus; sympathetic nervous system stimulates adrenal gland to release adrenaline
- Hormone stimulus; hypothalamus releases hormone which stimulates pituitary gland which releases further hormones to stimulate other glands.
How are hormone secretions controlled?
Basal secretion - Continuous or Pulsatile
Superadded Rhythms - Day night cycle
Release inhibiting factors
Release releasing factors
How are hormone actions controlled?
Hormone metabolism
Hormone receptor induction
Hormone receptor down regulation
Synergism
Antagonism
What are the major endocrine organs?
Pituitary gland
Thyroid Gland
Parathyroid Gland
Adrenal Gland
Pancreas
Gonads - Ovary / Testes
What are the different sections of the Adrenal glands and what do they secrete?
Adrenal Cortex:
Zona Glomerulosa - Mineralocorticoids - Aldosterone
Zona Fasciculata - Glucocorticoids - Cortisol/cortisone
Zona Reticularis - Androgens - Oestrogen / Testosterone
Adrenal Medulla:
Catecholamines - Adrenaline, Noradrenaline
Define Appetite?
The desire to eat food
Define Satiety?
The feeling of fullness
Disappearance of appetite after a meal
Define Anorexia?
Lack of Appetite
Define Hunger?
The need to eat
How do you work out BMI?
Weight (kg) / Height (m^2)
What are the categories of BMI?
<18.5 underweight
18.5-24.9 normal
25-29.9 overweight
30-39.9 obese
> 40 morbidly obese
What are the 2 drives of the satiety cascade?
Internal Physiological drive - a feeling that prompts the thought of food and motivates food consumption
External Psychological drive - Explains why we eat in the absence of hunger (eg. at a buffet)
What parts of the brain have key roles in appetite regulation?
The Hypothalamus
Lateral Hypothalamus - Hunger centre
Ventromedial Hypothalamic Nucleus - Satiety centre
Where is the hunger centre in the brain?
Lateral Hypothalamus
Where is the satiety centre in the brain?
Ventromedial Hypothalamic Nucleus
What factors will increase your appetite?
NPY - Neuropeptide Y
MCH - Melanin concentrating Hormone
AgRP - Agouti related peptide
Orexin
Endocannabinoid
What factors will decrease your appetite?
- α-MSH: alpha melanocyte stimulating hormone from POMC
- CART: cocaine and amphetamine regulated transcript
- GLP-1: glucagon like peptide 1
- Serotonin
- Peptide YY (PYY)
- CCK
What appetite factors are released by the brain?
NPY
POMC - α-MSH
What is POMC?
Proopiomelanocortins
Precursor polypeptides that are cleaved into 3 main hormones
ATCH
MSH
Endorphins
What is the role of α-MSH
Induces satiety by binding to the MCR3 and MCR4 receptors in the brain
What is the role of Leptin?
Expressed in adipose tissue
Switches off appetite and is immunostimulatory
Leptin is sensed by the arcuate nucleus of the hypothalamus where it stimulates the release of anti-appetie factors (POMC; CART) and inhibits the release of pro-apeptite factors (NPY; AgRP).
Where is leptin expressed?
In adipose tissue
How can decreased leptin levels lead to obesity?
Through leptin gene deficiency
Through Leptin receptor mutation
What is the role of Leptin?
Expressed in adipose tissue
Switches off appetite and is immunostimulatory
Leptin is sensed by the arcuate nucleus of the hypothalamus where it stimulates the release of anti-appetite factors (POMC; CART) and inhibits the release of pro-appetite factors (NPY; AgRP).
What appetite factors are released by the gut?
Ghrelin
PYY
GLP-1
CCK
What is the role of Ghrelin?
Stimulates GH release
Stimulates appetite (orexigenic)
Where is ghrelin secreted from?
The stomach
What is PYY?
Peptide YY
Structurally similar to NPY - binds to NPY receptors
What is the role of PYY?
Inhibits gastric motility
Reduces appetite
Where is PYY secreted from?
Neuroendocrine cells in the ileum, pancreas, colon in response to food
What is the role of CCK in appetite?
Cholecystokinin
Delays gastric emptying time
gallbladder contraction
Insulin release
Acts on the vagus nerve to stimulate satiety
What appetite factors are released by adipose tissue?
Leptin
What appetite factors are released by the pancreas?
Insulin
How does insulin act in appetite regulation?
In a similar way to Leptin
It inhibits NPY/AgRP release
It stimulates POMC/CART release
Acts to decrease appetite
Give an overview of Appetite control
Leptin and Insulin:
Stimulate POMC/CART neurones - increase CART and alpha-MSH levels
Inhibit NPY/AgRP neurones - Decrease NYP/AgRP
Overall will increase satiety and decrease appetite.
Ghrelin:
Stimulates NPY/AgRP neurone - their levels increase
Increase appetite
PYY:
Binds to an inhibitory receptor on NPY/AgRP neurones - decrease their levels
Decrease appetite
Give a summary for peripheral appetite regulation
Olfactory, visual gustatory stimuli stimulate appetite
Oral receptors monitor food intake and begin to suppress feeding
Food in stomach stimulates Ghrelin initially to increase appetite
Stretch receptors in stomach begin to release satiety factors
Release of CCK, GLP, Insulin and PYY all increase satiety to stop feeding
In the fasting state where does glucose come from?
Liver - breakdown of glycogen
-gluconeogenesis
In the fasting state, what are the levels of insulin?
Low - there is less glucose in the blood so insulin is low because it does not need to stimulate glucose storage
What do muscles use for fuel in the fasting state?
Free fatty acids
In the post prandial state what does the increase of glucose from a meal lead to?
Inhibition of glucagon secretion
Stimulation of insulin
Glucose is taken up by the liver (40%) and peripheral tissues (60%)
What does a high level of insulin and glucose promote?
Inhibition of lipolysis
reduced levels of free fatty acids
What is the site of insulin and glucagon secretion?
Islets of langerhans of the pancrease
Alpha cells - glucagon
Beta cells - Insulin
What is the paracrine function of insulin?
What is the effect of DM on this?
The release of insulin from beta cells acts on the alpha cells of the pancreas to inhibit further glucagon release.
In diabetes the insulin is lost and therefore you lose the alpha cell inhibition mechanism leading to excess glucagon and increased levels of glucose and free fatty acids in the blood.
Explain the process of insulin secretion?
Glucose is taken into the pancreas via GLUT2 transporters
Once in the pancreas glucose is metabolised by glucokinase which forms ATP
ATP then acts on the SUR1 potassium channels to close the K+ channels
This leads to depolarisation of the cell membrane and thus the opening of Ca channels
Calcium influx stimulates exocytosis of insulin secretory granules
Insulin is released
What is the action of insulin on the fat and muscle cells?
Stimulates the metabolism of GLUT4 channels to the cell membrane
Allows for the entry of glucose into the cell
What is the action of insulin?
Suppresses hepatic glucose output - Decrease glycogenolysis, Decrease gluconeogenesis.
Increase glucose uptake into insulin sensitive tissues - fat and muscle.
Suppresses lipolysis and muscle breakdown
What is the action of glucagon?
Increases hepatic glucose output - increase glycogenolysis, increased gluconeogenesis
Reduces peripheral glucose uptake
stimulates peripheral release of gluconeogenic precursors - glycerol and amino acids, lipolysis, muscle glycogenolysis and breakdown.
What is diabetes mellitus (DM)?
A disorder of carbohydrate metabolism characterised by hyperglycaemia
How does DM cause morbidity and mortality?
Acute hyperglycaemia if untreated leads to diabetic ketoacidosis (DKA) and hyperosmolar hyperglycaemic states (HHS)
Chronic hyperglycaemia leads to tissue complications (macro and microvascular)
Side effects of treatment - hypoglycaemia
What are the major consequences of Diabetes?
Diabetic retinopathy
Diabetic neuropathy
Stroke
Cardiovascular disease
Diabetic Nephropathy
What are the different types of diabetes Mellitus?
Type 1 DM - Insulin dependent
Type 2 DM - Insulin Independent - Maybe be gestational or medication induced)
MODY
Pancreatic diabetes
Endocrine diabetes - Acromegaly, Cushing’s
Malnutrition related diabetes
What is MODY?
Maturity onset diabetes of youth
How is diabetes defined?
Symptoms and random plasma glucose of >11mmol/L
Fasting plasma glucose > 7mmol/L
HbA1c of 48mmol/L (6.5%)
What is the pathogenesis of T1DM?
Autoimmune destruction of pancreatic Beta cells leading to an absolute insulin deficiency.
T4 Hypersensitivity reaction.
What mechanism of autoimmunity is responsible for T1DM?
Beta cells express HLA antigens ( HLA DR3 and HLA DR4) on MHC in response to an environmental event
Activates chronic cell mediated immune response leading to chronic insulitis
What happens to insulin metabolism in T1DM and what is the consequence of this?
Loss of beta cells - Loss of insulin secretion
Leads to:
Continued glycogenolysis in the liver
Unrestricted lipolysis and skeletal muscle breakdown for gluconeogenesis
Inappropriate increase in hepatic glucose output and suppression of peripheral glucose uptake.
Glucose concentration rises lead to excretion of glucose in urine as renal reuptake routes are saturated (glycosuria)
What happens if T1DM is not treated with insulin?
Increased circulating glucagon - loss of paracrine function of beta cells - leads to increased glucose
Perceived stress increases cortisol and adrenaline secretion
Increases catabolic state and increases ketone production
Explain why fat metabolism is significant in T1DM?
Reduced insulin leads to increase lipolysis and the formation of glycerol and FFAs
FFAs are transported to the liver and oxidised to ketone bodies
Ketogenesis is highly sensitive to insulin
Poor control of diabetes leads to DKA by uncontrolled ketone formation.
What are the consequences of ketoacidosis?
Glucose and ketones are excreted in the urine
Causes osmotic diuresis
Lower blood circulating volume
Ketones cause anorexia and vomiting
Vicious circle of dehydration, hyperglycaemia and increased acidosis leads to circulatory collapse and death
What happens to glucose metabolism in T2DM?
- Insulin resistance and impaired insulin release (though insulin is always detectable)
- This leads to:
- Reduced muscle and fat uptakes after eating
- Failure to suppress lipolysis and high circulating free fatty acids
- Abnormally high glucose output after a meal
- Low levels of insulin enough to prevent muscle catabolism and ketogenesis so muscle breakdown and ketone production rarely excessive
What is the role of basal insulin in T1DM therapy?
Control glucose between meals and at night.
Adjusted to maintain fasting blood glucose between 5-7mmol/L
What is the betst treatment for T1DM?
Intesive basal bolus of insulin
What is the best treatment for T1DM?
Intensive basal bolus of insulin
What is hte role of a bolus of insulin?
Manage glucose according to carbohydrate intake and pre meal glucose
Why should we introduce insulin to those with T2DM?
Progressive damage to pancreatic beta cells and or poor glucose control warrant insulin therapy
What type of insulin is initiated first in T2DM?
Basal insulin
Which insulin analogues are associated with lower risk of symptomatic overall and overnight hypoglycaemia?
Long acting basal insulin analogues
Why are prandial insulins fit for purpose?
Their faster action means they can be adapted to the meal that is eaten
What are the different approaches to insulin therapy in T2DM?
Once daily - basal insulin
Twice daily - Mix insulin
Basal Bolus therapy
What are the advantages of basal insulin in Type 2 diabetes?
- Simple for patient - adjust insulin themselves based on fasting glucose
- Less risk of hypoglycaemia overnight
- Carries on with oral therapy
What are the disadvantages of basal insulin in Type 2 diabetes?
- Doesn’t cover meals
- Best used with long-acting insulin analogues - expensive
What are the advantages of pre-mixed insulin?
- Both basal and prandial components in a single preparation per day
- Can cover insulin requirements for the day
What are the disadvantages of pre mixed insulin?
- Not physiological
- Requires consistent meal and exercise pattern
- Cannot separately titrate individual insulin components
- Higher risk of nocturnal hypoglycaemia
- Higher risk of hyperglycaemia is basal component not high enough
- HbA1c is kept at a higher level
What is hypoglycaemia?
Low plasma glucose causing impaired brain function
What are the clinical definitions of hypoglycaemia?
Mild - self treated episodes
Severe - Requires help from someone to recover
What is the glucose value for neutropenia?
3mm/L
What is the glucose value for hypoglycaemia?
3.9 mmol/L
What are the different classifications of hypoglycaemia?
Level 1
- Alert value
- Plasma glucose of under 3.9 mmol/l (70mg/dl) and no symptoms
Level 2
- Serious biochemical
- Plasma glucose of under 3.0 mmol/l (55mg/dl)
Non-severe symptomatic
- Mild hypoglycaemia
Severe symptomatic
- Level 3
- Severe hypoglycaemia
What are the common symptoms for hypoglycaemia?
- Autonomic
- Trembling
- Palpitations
- Sweating
- Anxiety
- Hunger
- Neuroglycopenic
- Difficulty concentrating
- Confusion
- Weakness
- Drowsiness/Dizziness
- Vision changes
- Difficulty speaking
- Non-specific
- Nausea
- Headache
What is significant about the relationship between HbA1c levels and hypoglycaemic episodes?
The higher the HbA1c levels, the higher the glucose levels can be when the patient experiences a hypoglycaemic episode
What are the risk factors for severe hypoglycaemia for T1DM and T2DM?
- Type 1 DM
- History of severe episodes
- HbA1c > 48 mmol/l (6.5%)
- Long duration of diabetes
- Renal impairment
- Impaired awareness of hypoglycaemia
- Extremes of age
- Type 2 DM
- Advancing age
- Cognitive impairment
- Depression
- Aggressive treatment of glycaemia
- Impaired awareness of hypoglycaemia
- Duration of multi dose insulin therapy
- Renal impairment and other comorbidities
What normally prevents hypoglycaemia?
- Counter-regulatory hormones
- Glucagon
- Adrenaline
How do the normal physiologically mechanisms that prevent hypoglycaemia fail inT1/2DM?
Threshold for secretion of counter-regulatory hormones can be altered, allowing for a lower value of glucose to be maintained and risking hypoglycaemia
What is the impact of non-severe hypoglycaemia?
- Reduced quality of life
- Fear of hypoglycaemia
- Mental illness comorbidity
What are the consequences of hypoglycaemia?
- Accidents
- Fear
- Quality of life
- Prevents desirable HbA1c targets
- Cognitive dysfunction
- Seizures/coma
What forms part of the screening for risk of severe hypoglycaemia?
- Low HbA1c (high pre-treatment HbA1c in Type 2 DM)
- Long duration of diabetes
- History of previous hypoglycaemia
- Impaired awareness of hypoglycaemia
- Recent episodes of severe hypoglycaemia
- Daily insulin dose (>0.85 U/kg/day)
- Physically active
- Impaired renal function
What is a red flag for impaired awareness of hypoglycaemia?
Onset of symptoms below 0.3 mmol/l in blood glucose monitoring
What are the glucose targets for Type 1DM?
- Lowest HbA1c not associated with frequent hypoglycaemia
- May be appropriate to relax targets in patients with advanced disease, complications or limited life expectancy
- In these patients, aim for low enough glucose levels to limit hyperglycaemia symptoms
What are the glucose targets for Type 2 DM?
- Lowest HbA1c not associated with frequent hypoglycaemia
- HbA1c < 7% (53 mmol/l) usually appropriate for recent-onset of disease
- May be appropriate to relax targets
- Severe complications
- Advanced co-morbidities
- Cognitive impairment
- Limited life expectancy
- Unacceptable hypoglycaemia from stringent control
What do patients need to be educated about for hypoglycaemia?
- If on insulin or sulphonylureas
- How to identify and treat symptoms
- Patients should report episodes of hypoglycaemia to doctor/educator
What is the treatment of hypoglycaemia?
- Recognise symptoms
- Confirm the need for treatment with plasma glucose test
- Treat with 15g fast-acting carbohydrate to relieve symptoms
- Retest in 15 minutes to ensure blood glucose > 4 mmol/l and re-treat if needed
- Eat a long-acting carb to prevent recurrence of symptoms
Where does active Ca2+ reabsorption happen in the kidney?
DCT - this is where PTH will act.
Where in the body can Calcium come from to enter the blood?
- Absorbed from the intestine. 2. Resorbed from bone. 3. Reabsorbed at the kidney.
Where in the intestine is calcium actively absorbed?
Duodenum and jejunum.
Where in the intestine is calcium passively absorbed?
Ileum and colon.
Where does the majority of Ca2+ reabsorption happen in the kidney?
At the PCT.
What stimulates the release of PTH?
Low serum Ca2+ detected by receptors in the parathyroid.
Briefly describe the action of PTH.
- It causes bone resorption: increased Ca2+ and phosphate.
- It acts on the kidneys causing increased Ca2+ reabsorption and decreased phosphate reabsorption.
- It stimulates 1-hydroxylase which increases formation of 1,25-(OH)2-vitD and so increases the absorption of Ca2+ and phosphate from the intestine.
What is the action of calcitonin?
It reduces bone resorption and so lowers Ca2. It is the antagonist to PTH.
What do parafollicular C-cells release?
Parafollicular C cells of the Thyroid release Calcitonin.
What triggers the release of calcitonin?
High Ca2+.
Give 3 regulators of phosphate.
- PTH. 2. 1,25-(OH)2-vitD. 3. FGF-23 = major regulator!
What is the action of PTH with regards to phosphate homeostasis?
It increases phosphate absorption at the intestine and decreases phosphate reabsorption at the kidney.
Where does PTH secretion occur?
Chief cells in the parathyroid gland - possess calcium sensing receptors on their cell surface
How does PTH act on bone to increase serum calcium?
Stimulates osteoclasts to release ionic Ca2+ for reabsorption
- How does PTH act on the kidneys to increase serum calcium?
- ↑ passive calcium reabsorption by the PCT - only 1% excreted
- ↓ phosphate reabsorption - 20% excreted
- ↑ 1 alpha hydroxylation of vitamin D to form 1,25-dihydroxyvitamin D - facilitates calcium absorption in the intestines
- How does PTH act on the intestines to increase serum calcium?
↑ calcium absorption via 1,25-dihydroxyvitamin D
- What hormone regulates the decrease in serum calcium?
Calcitonin!
How does Calcitonin decrease serum calcium?
- Reduces bone resorption by inhibiting osteoclast activity
- Reduce renal reabsorption
How else is serum calcium regulated
Negative feedback! Increased serum PTH leads to reduced secretion.
What are the levels of physiological and non-physiological calcium (hypocalcaemia)?
Normal level of serum calcium:
Mild-moderate Hypocalcaemia:
Severe Hypocalcaemia:
Normal level of serum calcium: 2.2 - 2.6mmol/L
Mild-moderate Hypocalcaemia: 1.9 - 2.2 mmol/L
Severe Hypocalcaemia: <1.9 mmol/L
What are the clinical features of hypocalcaemia?
- Parasthesia - abnormal skin sensation (tingling, prickling, numbness)
- Tetany - spasms of the hands, feet, larynx and premature labour
- Seizures
- Basal ganglia calcification - associated with neuropsychiatric and motor symptoms
- Cataracts
- Chvostek and Trousseau signs
What is Chvostek sign?
Tap over the facial nerve - look for spasm of the facial muscles
What is Trousseau sign?
Inflate blood pressure cuff to 20mmHg above systolic for 3-5 minutes - look for carpopedal spasm
What ECG abnormality suggests possible Hypocalcaemia?
Long QT interval - primarily the prolonging of the ST segment; slow ventricular repolarisation as a result of reduced calcium entering the cell through L-type channels.
What are the causes of Hypocalcaemia?
- Hypoparathyroidism
- Acute pancreatitis
- Hyperphosphataemia
- Hypomagnesaemia
- Diuretics (frusemide)
- Pseudohypoparathyroidism
- Congenital disorders
- Critical illness (e.g. sepsis)
Why does Vitamin D deficiency cause Hypocalcaemia?
Inactive Vitamin D is converted to 1,25-dihydroxyvitamin D), which facilitates Ca2+ absorption by the gut
Why does Hypoparathyroidism cause Hypocalcaemia?
Reduced secretion of PTH by Chief cells of the parathyroid. PTH acts in incidences of low serum to increase calcium absorption from bone, kidneys and intestines
What are possible causes of Hypoparathyroidism?
- Surgery - parathyroid removal
- Radiation - parathyroid damage
- Autoimune diseases (e.g. Chronic Mucocutaneous Candidiasis)
- Infiltration - caused by condition, such as Wilson’s disease and Haemochromatosis
- Magnesium deficiency - required for release of PTH
- Syndromes
- Genetic predisposition
Name examples of conditions associated with Hypoparathyroidism.
Acute pancreatitis
Di George Syndrome
Pseudohypoparathyroidism
Why is acute pancreatitis associated with hypoparathyroidism?
Precipitation of calcium stearate (carboxylated calcium) in the abdominal cavity; causes increased calcitonin release.
Why is Di george syndrome associated with hypoparathyroidism?
A developmental abnormality of third and fourth branchial pouches of the pharyngeal arches - this causes;
- Hypoparathyroidism
- Immunodeficiency - linked to thymic hypoplasia
- Cardiac defects
- Cleft palate
Why is pseudohypoparathyroidism associated with hypoparathyroidism?
- Condition associated with the resistance of the body to PTH.
- Causes Type 1 Albright hereditary osteodystrophy which presents with the following signs
- Short stature
- Obesity
- Round facies
- Mild learning difficulties
- Subcutaneous ossification
- Short fourth metacarpals
What are the levels of physiological and non-physiological calcium (hypercalcaemia)?
Normal level of serum calcium:
Mild-moderate Hypercalcaemia:
Severe Hypercalcaemia:
Normal level of serum calcium: 2.2 - 2.6 mmol/L
Mild Hypercalcaemia: 2.7 - 2.9 mmol/L
Moderate Hypercalcaemia: 3.0 - 3.4 mmol/L
Severe Hypercalcaemia: >3.4 mmol/L
What are the clinical features of Hypercalcaemia?
Bones, stones groans and moans!
BONES - osteitis fibrosa cystica, osteoporosis
Renal STONES - kidney stones
Psychic GROANS - neurological symptoms (i.e. confusion, coma)
Abdominal MOANS - constipation, nausea, acute pancreatitis
*Also, thirst as polyuria
What ECG abnormality suggests possible Hypercalcaemia?
Short QT interval - primarily the shortening of the ST segment; faster ventricular repolarisation as a result of increased calcium entering the cell through L-type channels.
What are the causes of Hypercalcaemia?
90% of the time caused;
- Malignancies
- Hyperparathyroidism - primary and teritiary
What are the malignancies associated with hypercalcaemia?
- Myeloma - causes overexpression of RANKL which activates osteoclastic bone resorption
- Bone metastases
- Lymphoma
- PTH-Related Peptide (PTHrP) - produced in excess by a tumour; causes PTH secretion above physiological range
Why does hyperparathyroidism lead to hypercalcaemia?
Increased secretion of PTH by Chief cells of the parathyroid. PTH acts to increase calcium absorption from bone, kidneys and intestines. Excessive PTH causes elevated serum calcium.
What is primary Hyperparathyroidism?
Hyperparathyroidism caused by;
- 80% - sporadic single benign adenoma
- 15-20% - parathyroid hyperplasia
- <0.5% - parathyroid carcinoma
What is Tertiary Hyperparathyroidism?
A result of chronic secondary hyperparathyroidism. High levels of PTH production over a long period of time results in parathyroid hyperplasia; this causes an extent PTH overproduction which increases serum calcium above physiological range.
What is secondary Hyperparathyroidism?
Secondary hyperparathyroidism normally occurs as a a result of long term low serum calcium (e.g. due to kidney failure)
Where are the hypothalamus and pituitary located?
Diencephalon of the brain
What are the two groups of hypothalamic hormones?
- Hormones travelling to the APG (anterior Pituitary Gland)
Travel down the median eminence, a prolongation of the hypothalamus, into the hypophyseal portal system, which carries them to the anterior pituitary where they exert their regulatory functions.
- Hormones travelling to the PPG (Posterior Pituitary Gland)
Hormones synthesised by neurones in the hypothalamus pass down the neuronal axons which travel into the posterior pituitary. Here, they are stored in the distended parts of the axon in the posterior pituitary.
What hormones are released by the hypothalamus?
- Gonadotropin Releasing Hormone (GnRH)
- Growth Hormone Releasing Hormone (GHRH)
- Somatostatin (SST); also known as - Growth Hormone Inhibiting Hormone (GHIH)
- Tryrotropin Releasing Hormone (TRH)
- Dopamine (DA) or Prolactin-Inhibiting Hormone (PIH)
- Corticotrophin Releasing Hormone (CRH)
What is the hypophyseal portal system?
- System of blood vessels in the microcirculation at the base of the brain, connecting the hypothalamus to the anterior pituitary.
- Function to rapidly transport hormones between the hypothalamus arcuate nucleus and anterior pituitary gland.
- The capillaries in the portal system are fenestrated.
How do Hypothalamic secretions travel to the APG?
1️⃣ Neurones with cell bodies in the medial hypothalamic nuclei project to the median eminence
2️⃣ Here, the neurones secrete hormones into the pituitary portal veins
3️⃣ Hypothalmic hormones influence secretion of hormones from cells in the anterior lobe of the APG into the venous drainage of the gland.
How do Hypothalamic secretions travel to the PPG?
1️⃣ Neurones with cell bodies in the supra and paraventricular nuclei of the hypothalamus have projections to the posterior pituitary
2️⃣ Neurones release their hormones directly into the venous drainage of the gland.
What hormones are released by the APG?
- ollicle Stimulating Hormone (FSH) → Gonads
- Luteinizing Hormone (LH) → Gonads
- Growth hormone (GH) → Liver (IGF-1) and other tissue (growth)
- Thyroid Stimulating Hormone (TSH) → Thyroid
- Prolactin (PL) → Breasts
- Adrenocorticotropic Hormone (ACTH) → Adrenal Cortex
What hormone are released by the PPG?
- Vasopressin/ ADH - acts to upregulate water retention in the kidneys (aquaporins)
- Oxytocin - induces contractions of the uterus during labour
What is the Pituitary-Thyroid Axis?
1️⃣ TRH from hypothalamus acts on anterior pituitary
2️⃣ Anterior pituitary produces TSH (thyrotroph cells in anterior pituitary has receptors that TRH acts on)
3️⃣ TSH acts on thyroid which produces T4 and T3; these acts as negative feedback on both hypothalamus and pituitary
4️⃣ Deiodinases act to convert T4 to T3 by removal of iodine
What is the Pituitary-Gonadal Axis?
- 1️⃣ Hypothalamus produces GnRH which acts on pituitary
- 2️⃣ Pituitary produces LH and FSH
- 3️⃣ LH travels to the gonads and causes;
- Men
- LH stimulates interstitial cells of the testes to produce testosterone
- FSH stimulates spermatogenesis - Women
FSH and LH act to activate the ovaries to produce oestrogen and inhibin; regulate the menstrual and ovarian cycle - 4️⃣ Negative feedback for hypothalamus and pituitary
- Men
- Testosterone acts on the hypothalamus to inhibit the production of GnRH
- Women
- Oestrogen acts on the hypothalamus directly to inhibit the production of GnRH
- Inhibin acts to inhibit activin, a peripherally produced hormone that positively stimulates GnRH-producing cells
- Men
What is the Hypothalamus-Pituitary-Adrenal Axis?
1️⃣ Hypothalamus produces CRH which acts on the pituitary
2️⃣ Pituitary produces ACTH
3️⃣ ACTH acts on the adrenal glands to produce cortisol
4️⃣ Cortisol acts as negative feedback for pituitary and hypothalamus
What is the Growth Hormone-Insulin Growth Factor-I Axis?
1️⃣ Hypothalamus produces GHRH and Somatostatin which acts on pituitary
2️⃣ Pituitary produces GH which acts on liver
3️⃣ Liver produces Insulin-like Growth Factor 1; this acts as negative feedback for hypothalamic secretions
There are pulsatile secretions of GH and SMS that enable growth during sleep
What is the Hypothalamus-Pituitary-Prolactin Axis?
1️⃣ Hypothalamus produces LHRH which acts on the pituitary
2️⃣ Pituitary produces Prolactin
3️⃣ Hypothalamus also produces dopamine; this acts on the pituitary gland to reduce prolactin secretion
4️⃣ Cortisol acts as negative feedback for pituitary and hypothalamus
What are some diseases of the Pituitary Gland?
- Benign pituitary adenoma
- Craniopharyngioma
- Trauma
- Apoplexy
- Sarcoid/TB
How does a pituitary adenoma cause symptoms?
(VERY KEY POINT)
- Exerts pressure on local structures (e.g. optic nerves)
- Exert pressure on the normal pituitary
- Behaves as a functioning tumour
Name examples of visual field defects associated with a pituitary adenoma?
- Bitemporal hemianopia (Loss of lateral fields of vision in both eye)
Caused by compression of the nasal retinal fibres; responsible for carrying the information along the optic nerve. Specifically, compression of the optic chiasma; the area where optic nerves from the right and left eyes cross near the pituitary gland.
- Compression of Nasal Retinal Fibres
- Inferior nasal fibres cause reduction in upper outfield
- Superior nasal fibres cause reduction in lower outfield
What causes pituitary adenoma-related headaches?
Expansive tumour causes stretching of the dura mater; layer of connective tissue associated with the meninges
What causes pituitary adenoma-related hydrocephalus?
Accumulation of CSF within the brain caused by compression of the brain
What is the primary problem caused by pressure on a normal pituitary?
Hypopituitarism - lack of pituitary function!
Symptoms relate to deficiency of specific hormone secretions
Name clinical features caused by GH deficiency.
- Central obesity
- Decreased muscle mass
- Impaired memory
Name clinical features caused by LH and FSH deficiency.
Associated with low testosterone/ oestrogen and progesterone
- Men → loss of body hair, decreased muscle mass, anaemia, loss of sexual function
- Women → infertility, oligo-/amenorrhea (infrequent/light or absent periods), loss of sexual function
- Children → delayed puberty
Name clinical features caused by ACTH deficiency.
Associated with low cortisol!
- Pallor
- Fatigue
- Weight loss
- Failure to thrive
Name clinical features caused by TSH deficiency.
Associated with hyperthyroidism!
- Tiredness
- Constipation
- Weight gain
- Hair loss
- Low BP and HR.
Name clinical features caused by PRL deficiency.
Inability to breastfeed
Name symptoms caused by ADH deficiency.
Diabetes insipidus!
- Inability to concentrate the urine, leading to polyuria
- Dehydration and, in compensation, extreme thirst (polydipsia)
- Hypernatremia (high serum sodium).
Name symptoms caused by Oxytocin deficiency.
Rare - issues arise during breastfeeding and childbirth
What is a Prolactinoma?
Tumour causing the pituitary to make too much prolactin
What are the clinical features associated with a Prolactinoma?
- Galactorrhoea - abnormal white breast discharge
- Reduced ability to breast feed
- Amenorrhoea/ infertility
- Loss of libido
- Visual field defect - see above
How are Prolactinomas treated?
Dopamine agonist (e.g. Cabergoline or Bromocriptine) - produces prolactin-reducing feedback
Surgery possibly
Acromegaly and Gigantism are caused by the excessive production of which hormone?
Growth hormone
What is the difference between Acromegaly and Gigantism?
Acromegaly occurs in adults - after growth plates are closed
Gigantism occurs in children caused by a pituitary tumour causing increased GH release however the tumour also presses on the pituitary so you get hypopituitarism which means the other hormones do not work and therefore they don’t go through puberty as no testosterone is being produced
What is Cushing’s Syndrome?
Chronic, excessive and inappropriate elevated levels of circulating cortisol.
(not necessarily tumour related)
**Cushing’s syndrome occurring as a result of a pituitary tumour is known specifically as Cushing’s Disease.*
Cushing’s Syndrome is caused by the excessive production of which hormone secreted by the pituitary gland?
ACTH - causes the overproduction of cortisol by the adrenal cortex
What are the clinical features of Cushing’s?
- Carbohydrate metabolism - diabetes, glucose intolerance
- Electrolyte disturbance - hypertension; sodium retention and potassium loss
- Immune suppression
- Central effects - malaise, depression, psychosis
- Suppressed gonadal function - oligo/ amenorrhoea, infertility, loss of libido
What are the most common indication of Cushing’s?
- Obesity
- Muscle wasting (protein catabolism)
- Redistribution of fat around abdomen and top of back
- Hirsutism - excessive growth of coarse hair facial, chest and back hair in women
- Repeated bruising, thin skin, thin hair and stretch marks
- Acne
What is the difference between ACTH-dependent and ACTH-independent Cushing’s?
- ACTH-dependent → caused by a pituitary adenoma (or ectopic, ACTH producing tumour)
- ACTH-independent → caused directly by the adrenal glands
What tests are used to diagnose Cushing’s?
- Urinary free cortisol
- Low dose dexamethasone suppression test - synthetic steroid feedback at pituitary and hypothalamus which leads to reduced CRH and ACTH. Therefore, low levels of cortisol found in blood.
- Late night/midnight serum or salivary cortisol.
What tests are used to diagnose Cushing’s?
- Urinary free cortisol
- Low dose dexamethasone suppression test - synthetic steroid feedback at pituitary and hypothalamus which leads to reduced CRH and ACTH. Therefore, low levels of cortisol found in blood.
- Late night/midnight serum or salivary cortisol.
What is Cushing’s Disease?
Chronic, excessive and inappropriate elevated levels of circulating cortisol that is specifically caused by a pituitary tumour
What is puberty?
Describes the physiological, morphological, and behavioural changes as the gonads switch from infantile to adult forms
What are the definitive signs of puberty?
- Girls - menarche
- First menstrual bleed
- Boys - first ejaculation
- Often nocturnal
What controls the development of secondary sexual characteristics?
- Girls
- Ovarian oestrogens
- Growth of breasts and female genitalia
- Ovarian and adrenal androgens
- Control pubic and axillary hair
- Ovarian oestrogens
- Boys
- Testicular androgens
- External genitalia and pubic hair growth
- Enlargement of larynx and laryngeal muscles
- Deepening of the voice
- Testicular androgens
What are tanner stages?
Scale of physical development through puberty
What is the volume of testes that signify the commencement of puberty?
> 3ml (>2.5cm in longest diameter)
What is used to measure testicular volume in ml?
Orchidometer
What is thelarche and what initiates it?
- Breast development
- Oestrogen
How long does thelarche take to complete?
3 years
What are the effects of oestrogen on breast tissue?
- Ductal proliferation
- Site specific adipose deposition
- Enlargement of the areola and nipple
What other hormones are involved in breast development?
- Prolactin
- Glucocorticoids
- Insulin
Describe the maturation of the uterus
- Corpus:cervix ratio flips from 1:2 to 2:1
- Changes from tubular shape to pear shape
- Increases in length and volume
- Endometrium thickens
Describe the maturation of the ovaries
- Volume increases
- Change from non-functional to multicystic
What is assessed in a pelvic ultrasound and what care should be taken when reporting findings?
- Are the Mullerian structures present?
- Fallopian tubes
- Uterus
- Uterine cervix
- Superior aspects of the vagina
- Morphology of the uterus
- Morphology of the ovaries
- Requires an experienced examiner so careful when reporting absence of structures
Describe the maturation of the vagina
- Becomes a duller red
- Epithelium thickens
- Cornification of the superficial layer of stratified squamous epithelium
- pH changes from neutral to acidic
- Secretion of clear whitish discharge in the months prior to menarche
- Increase in length
Describe the maturation of the external genitalia and which hormones cause this
- Oestrogens
- Labia majora and minora increase in size and thickness
- Rugation and change in colour of labia majora
- Hymen thickens
- Clitoris enlarges
- Vestibular glands begin secretion
- Adrenal and ovarian androgens
- Growth of pubic hair
What is adrenarche?
- Maturation process of the adrenal gland
- Specialised subset of cells arises forming the androgen producing zona reticularis
When does adrenarche occur?
- Peri-puberty
- Premature or exaggerated adrenarche can occur up to 2 years prior to puberty, especially in obese children
What hormone is associated with adrenarche?
- DHEA
- DHEA-S
- Both precursors of androgens
What happens physiologically during adrenarche?
- Mild advance in bone age
- Axillary hair growth
- Mild acne
- Body odor
What is precocious puberty?
Early puberty
Which population of patients are more likely to have ‘true’ precocious puberty and what is the significance of this?
- Up to 80% female
- If male patients present with precocious puberty, differentials should be ruled out before a diagnosis of idiopathic puberty is given
- Brain tumour may be highly likely or some other significant pathology
What is precocious pseudopuberty?
Resembles puberty, but not from normal hypothalamus activation
What can cause precocious pseudopuberty?
- Adrenal sex hormones excess
- Congenital adrenal hyperplasia
- hCG Secreting Tumours
- Gonads
- Brain
- Liver
- Retroperiteneum
- Mediastinum
What is the differential test for true precocious puberty and precocious pseudopuberty?
- Use of gonadotrophin releasing hormone (or luteinising hormone-releasing hormone) test
- Measure LH and FSH before and 30 and 60 minutes after injection of GnRH (or LHRH)
- If GnRH or LHRH stimulates an increase of LH and FSH, then true puberty
- If there is not a rise of LH:FSH the likely pseudopuberty
- Stimulated LH:FSH ratio > 1 to be true precocious puberty
What is the treatment for precocious puberty?
- Use of GnRH super-agonist suppresses pulsatility of normal physiology
- Stops the process
What are the causes of true precocious puberty?
(GnRH dependent)
Idiopathic precocious puberty
CNS Tumours
CNS Disorders
Secondary central precocious puberty
Psychosocial - adoption from abroad
What are the causes of precocious pseudopuberty?
(GnRH independent)
Increased androgen secretion
Gonadotrophin secreting tumours
McCune Albright syndrome
Ovarian Cyst
Oestrogen secreting neoplasm
Hypothyroidism
Iatrogenic or exogenous sex hormones
What is the main cause of delayed puberty?
- IdiopathicHypogonadotropic Or hypergonadotropic hypogonadism
What causes idiopathic delay in puberty?
Delayed activation of the hypothalamic pulse generator
Which sex is most affected by idiopathic delays in puberty?
Males
How do you diagnose idiopathic (or constitutional) delay of growth and puberty?
Diagnosis of exclusion
What is relevant in the family history for idiopathic delay in growth and puberty?
- Late menarche in mother or sister
- Delayed growth spurt in father
What are the other causes of delayed puberty?
- Hypogonadotropic hypogonadism
- Sexual infantilism related to gonadotrophin deficiency
- Hypergonadotrophic hypogonadism
- Primary gonad problems
What do delays in puberty lead to?
- Delay in acquisition of secondary sex characteristics
- Psychological problems
- Defects in reproduction
- Reduced peak bone mass
What are indications for delayed puberty investigation?
Girls:
Lack of breast development by 13yrs
More than 5yrs between breast development and menarche
Lack of pubic hair by age 14yrs
Absent menarche by 15-16yrs
Boys:
Lack of testicular enlargement by age 14yrs
Lack of pubic hair by age 15yrs
More than 5 years to complete genital enlargement
What does the onset of puberty correlate to?
Bone age
What should you consider when taking a history for delayed puberty?
Totally absent or started and then arrested
Family Hx
Review of Symptoms
Perinatal Hx
Prior Medical Illnesses
Medication
Psychosocial deprivation
Nutrition, exercise and health
Neurological symptoms
Hypoglycaemia
Cancer Hx
Testicular injury
What laboratory investigations should you consider for delayed puberty?
- FBC
- U&Es
- Renal function test
- LFTs
- Coeliac abs
- Testosterone/oestrodiol
- Thyroid function
- Prolactin
- DHEA-S
- ACTH
- Cortisol
- Karyotyping/CGH array
- Where physical examination/biochemistry suggestive of genetic syndrome
- in all girls with short stature
Why can X rays help in identifying delayed puberty?
- Bone age (skeletal maturity)
- Delayed bone age in growth hormone
- Advanced bone age in precocious puberty
What are some functional causes of delayed puberty?
Chronic Renal disease
Chronic GI disease/malnutrition
Sickle cell disease
Chronic lung disease
Anorexia nervosa
Bulimia
Psychosocial stress
Extreme exercise
Drugs
AIDs
Poorly controlled T1DM
Hypothyroidism
Cushing’s Syndrome
Hyperprolactinaemia
What is primary hypogonadism?
- Issue with the gonads
- Also known as hypergonadotropic hypogonadism
- Gonads not responding to stimulus so hypothalamus and pituitary more stimulated
- FHS/LH will both be high
- Sex hormones will be low
What is secondary hypogonadism?
Issue with the pituitary
What is tertiary hypogonadism?
Issue with the hypothalamus
Hypogonadotrophic Hypogonadism is known by what other term?
Secondary and tertiary hypogonadism
What are the causes of hypogonadotropic hypogonadism?
CNS disorders - tumours
Kallmanns’ Syndrome - Gonadotrophin deficiency
Prader willi syndrome
sickle cell
CF
AIDS
What genetic deficits can cause hypogonodatropic hypogonadism?
- Issues with:
- GnRH neurone migration
- GnRH synthesis and release
- GnRH action
- Gonadotropin synthesis
What is the diagnostic dilemma in trying to differentiate between hypogonadotropic hypogonadism and constitutional delay in growth and puberty?
- No gold-standard diagnostic test available
- Inhibin B marker of Sertoli cell number correlates with testicular volume
- In men with central hypogonadotropic hypogonadism and severe GnRH deficiency serum levels of inhibin B are typically very low
- For partial forms of central hypogonadotropic hypogonadism, inhibin B levels overlap with those in patients with constitutional delay in growth and puberty and in healthy controls
Who is mainly affected by Kallmann Syndrome?
Mainly Males
4:1 M:F
What are the symptoms associated with Kallmanns Syndrome?
Anosmia
What causes Kallmann Syndrome?
- Failure of migration of GNRH neurones from hypothalamus to pituitary
- X-linked, autosomal recessive or dominant
What are the main Conditions which fall under the hypergonadotropic hypogonadism?
Klinefelters - Males
Turners Syndrome - Females
What is Turners Syndrome?
45 XO
Loss of an X chromosome
What are signs and symptoms of Turners Syndrome?
- At birth
- Oedema of dorsa of hands and feet
- Loose skinfolds at the nape of the neck
- Webbing of neck
- Low posterior hairline
- Small mandible
- Prominent ears
- Epicanthal folds in high arched pallet
- Broad chest
- Cubitus valgus
- Hyperconvex fingernails
- Cardiovascular malformations
- Renal malformations (horseshoe kidney)
- Recurrent otitis media
- Middle ear infections
- Short stature
- Primary hypogonadism
What is Klinefelters Syndrome?
47 XXY
What are the signs and Symptoms of Klinefleters Syndrome?
- Primary hypogonadism
- Azoospermia
- Gynaecomastia
- Reduced secondary sexual hair
- Osteoporisis
- Tall stature
- Reduced IQ
What risks are associated with Kleinfelter Syndrome?
20-fold increased risk of breast cancer
