Flashcards in Physiology Deck (209):
Where is the thyroid gland located?
Anterolateral to larynx and trachea
Where are the parathyroid glands located?
Posterior aspect of each thyroid lobe
What do thyroid follicles surround and what does it contain?
- Tyrosine-containing thyroglobulin filled sphere
What is the process by which T3 and T4 are made and stored?
1. Iodine taken up by follicle cells
2. Iodine attaches to tyrosine residues on thyroglobulin:
-Forms two units
> Monoiodotyrosin unit (MIT)
> Diiodotyrosine unit (DIT)
3. Coupling of MIT and DIT:
- MIT + DIT -> T3
- DIT + DIT -> T4
4. Stored in colloid thyroglobulin until required
What thyroid hormone is secreted in larger amounts?
T4 (90% of secreted hormone)
Which thyroid hormone is more potent?
T3 (~4 times more potent than T4)
Where is T4 converted to T3?
What thyroid hormone is the major biologically active hormone?
Why do T3 and T4 bind to plasma proteins?
They are lipophilic
What plasma proteins do thyroid hormones bind to?
Thyroxine-Binding Globulin -> ~70%
Thyroxin-Binding Prealbumin -> ~20%
Albumin -> ~5%
What is the other name for thyroxine-binding prealbumin?
What are the features of T3 binding? What does this allow?
Bound 10-20 times less avidly by TBG
Not bound significantly by TTR
This allows more rapid onset and offset of action
What does the metabolic state correlate closer to; level of free hormone of level of total plasma concentration?
Level of free hormone
How does Ninewells asses thyroid hormones?
Measure fT3 and fT4
What can cause increased levels of thyroxine-binding globulin?
Oral contraceptive (Increased oestrogen)
What can cause decreased levels of thyroxine-binding globulin?
Severe systemic illness
Chronic liver disease
How do carbimazole and propylthiouracil work?
- Enzyme needed to produce MIT and DIT
What does increased TBG cause?
Increased total T4
What does decreased TBG cause?
Reduced total T4
How do T3 and T4 increase the basal metabolic rate?
Increase the number and size of mitochondria
Increase oxygen use and ATP hydrolysis
Increase synthesis of respiratory chain enzymes
How much of thermogenesis do T3 and T4 contribute to?
What effects do T3 and T4 have on carbohydrate metabolism?
Increase blood glucose:
- Stimulate glyogenolysis + gluconeogenesis
Increase insulin-dependent glucose uptake
What effects do T3 and T4 have on lipid metabolism?
Mobilise fats from adipose
Increase fatty acid oxidation
What effects do T3 and T4 have on protein metabolism?
Increase protein synthesis
What effects do T3 and T4 have on growth?
GHRH production and secretion requires T3 and T4
- Glucocorticoid-induced GHRH release
- Allows GH and somatomedin activity
What effects do T3 and T4 have on the foetal and neonatal brain?
How do changes in T3 and T4 concentrations affect the CNS?
- Slow intellectual functions
- Emotional lability
What affect does T3 and T4 have on the SNS?
Increases responsiveness to adrenaline and NA:
- By increasing the number of receptors
Also increases force and rate of heart contractions
What happens to TRH in cold temperatures (in kids)?
TRH is released:
-> TSH released -> T3 and T4 release
What effect does stress have on thyroid hormone regulation?
Inhibits TRH and TSH release
When are thyroid hormones highest and lowest?
Highest at night
Lowest in the morning
What family of 3 enzymes help activate and deactivate T3 and T4?
How do the deiodinase enzymes work?
Add/Remove an idoine atom in the outer ring of T3 and T4
What enzyme activates T4 to T3 in tissues?
Where is D1 found?
Where is D2 found?
Heart and skeletal muscle
Thyroid and pituitary
Where is D3 found?
Foetal tissue and placenta
Brain -> Except pituitary
Weight gain, bradycardia, fatigue, cold intolerance, myxoedema (adults) and cretinism (kids) are signs of what?
How does cretinism present?
Reduced mental functioning
Why does thyroid-stimulating Ig cause Grave's (hyperthyroidism)?
Acts like TSH:
- Unchecked by T3 and T4
- No negative feedback
What causes exophthalmos in Grave's?
Water-retaining carbohydrates build up behind eyes
What can a pituitary adenoma compress?
Optic chiasm -> Bitemporal hemianopia
CNs iii, iv and vi:
- iii -> Eye down and out
- iv -> Superior oblique paralysis -> Vertical diplopia
- vi -> Lateral rectus paralysis -> Horizontal diplopia
What else can a pituitary adenoma result in?
What are physiological causes of raised PRL?
What drugs can cause a raised PRL?
Dopamine antagonists (Metoclopramide)
Antidepressants (TCSa and SSRIs)
Others (Oestrogens and Cocaine)
What are pathological causes of a raised PRL?
How do women present with a raised PRL?
How do men present with a raised PRL?
Abnormal visual field
Anterior pituitary dysfunction
In a patient with a raise PRL, what might we see in a pituitary MRI?
Pituitary stalk lesion
Optic chiasm compression
How is a prolactinoma treated?
- Bromocripton -> PO tds
- Quinagolide -> PO od
- Cabergoline -> PO twice weekly
> Least side effects (most commonly used)
What causes acromegaly?
What soft tissue features of acromegaly are there?
What cardiac features are present in acromegaly?
What are some other features of acromegaly?
- Visual fields
Colonic polyps and cancer
How do we diagnose acromegaly?
- Age and sex matched
Glucose tolerance test:
- 75g PO suppression test
- Check GH at 0, 30, 60, 90 and 120 minutes
- Normal -> GH suppressed to
What will the result of a glucose tolerance test be in a patient with acromegaly?
GH remains >1μg/L
Why does glucose suppress GH?
GH stimulates an increase in blood glucose levels
So if glucose is raised, negative feedback will cause GH levels to drop
What is the first line treatment for acromegaly?
Followed by external radiotherapy to pituitary fossa
What is the second line treatment and when is it commenced?
- Octreotide (Somatostatin analogue)
If on GTT retest, GH is still >1μg/L
At what GH level is a patient clinical safe from further progression of acromegaly?
What effects do somatostatin analogues have in acromegaly?
Reduce GH in most
Shrink the tumour by 30-50%:
- 6-12 months for effect
- Recurs 6 weeks if stopped
Relieves headaches 1 hours post-op
Improve surgical outcomes
What are some side effects of somatostatin analogues?
- Abdominal pain
- Gastritis (
How does pegvisomat work?
- Binds to GH receptor competitively
How is pegvisomat administered?
What effects does pegvisomat have?
No decrease in tumour size
May increase serum GH
Why is pegvisomat the last line therapy?
20mg does costs £36000/year
What cancers must be screened for after acromegaly has been treated?
What CVS risk factors need monitored after acromegaly treatment?
What regulates aldosterone?
What encourages the hypothalamus to increase CRH production and, hence, increase cortisol production?
Time of day (Peak at 9am)
When is the RAAS activated?
When blood pressure falls
How does angiotensin ii correct BP?
Directly by vasoconstriction
Indirectly via aldosterone:
- Increases Na+ reabsorption in kidney
- Hence water reabsorption increases
What are the 6 classes of steroid receptors?
What effect does cortisol have on the CVS?
Increases cardiac output
Increases renal blood flow -> Increases GFR
What effect does cortisol have on the CNS?
What effect does cortisol have on bone and connective tissue?
Increased rate of osteoporosis
Reduces serum calcium
Reduces collagen formation
Reduces wound healing
What effect does cortisol have on metabolism?
Increases blood glucose
What effect does cortisol have on the immune system?
Reduced capillary dilation
Reduced leucocyte migration
Reduced macrophage activity
Reduced cytokine production
What are the three main principles of using corticosteroids for clinical treatments?
Reduce inflammation -> Supraphysiological dose
Immunosuppression -> Supraphysiological dose
Replacement therapy -> Physiological dose
Which administration route is better for corticosteroids; IM or IV?
What are corticosteroids used to treat (mainly)?
What effects does aldosterone have?
- Increases Na+ reabsorption
- Increases K+/H+ secretion (and hence excretion)
Increases blood pressure:
- Water follows Na+ -> Increased water reabsorption
In which of these locations are mineralocorticoid receptors not found:
- Salivary glands
- Sweat glands
Where does primary adrenal insufficiency arise?
What can cause primary adrenal insufficiency?
What can cause secondary adrenal insufficiency?
Lack of ACTH
What causes Addison's Disease?
Autoimmune destruction of adrenal cortex
True or false; Addison's is the most common cause of adrenal insufficiency?
It is only the most common cause of primary adrenal insufficiency
Exogenous steroids are the most common cause overall
What is Addison's disease associated with?
Thyroid disease (Grave's)
What are the clinical features of Addison's disease?
Hypotension -> Dizziness
- Abdominal pain
- Skin creases
- Buccal surfaces
What biochemistry is seen in primary adrenal insufficiency:
CRH is high
ACTH is high
Cortisol is low
Aldosterone is low
Renin is high
Na+ is low
K+ is high
What is the definitive diagnosis of primary adrenal insufficiency?
Short synACTHen test:
- Measure plasma cortisol
> 30 minutes after IV/IM ACTH
- Baseline -> >250nmol/L
- Post-ACTH -> >550nmol/L
Cortisol will barely rise on the synacthen test
Should we delay treatment of adrenal insufficiency to confirm diagnosis?
How do we treat adrenal insufficiency?
Hydrocortisone (cortisol replacement):
- IV first if unwell
- 15-30mg daily -> Divided doses
- Mimic diurinal rhythm
> 10 mg in the morning
> 5mg at lunch and at night
Fludrocortisone (aldosterone replacement):
- Monitor BP and K+
What causes secondary adrenal insufficiency?
Lack of CRH and ACTH (hypothalamic disease) or ACTH (pituitary disease)
What is the commonest cause of secondary adrenal insufficiency?
- High dose prednisolone
- Inhaled corticosteroid
What are the clinical features of secondary adrenal insufficiency?
Similar to Addison's:
- Except no hyperpigmentation (since no ^ ACTH)
- And aldosterone production is intact
How is secondary adrenal insufficiency treated?
What is Cushing's syndrome?
What are the clinical features of Cushing's syndrome?
What are the ACTH-dependent causes of Cushing's syndrome?
Pituitary adenoma -> Cushing's DISEASE (68%)
- Carcinoma (SCLC)
What are ACTH-independent causes of Cushing's syndrome?
Adrenal adenoma (10%)
Adrenal carcinoma (8%)
Nodular hyperplasia (1%)
What causes primary Hypercortisolism/Primary Cushing's syndrome?
What causes secondary Cushing's syndrome?
Pituitary adenoma (Cushing's Disease)
How can Cushing's Syndrome be screened for?
Overnight dexamethasone suppression test
24hr urinary free cortisol
Late night salivary cortisol
What is the definitive diagnostic test for Cushing's Syndrome?
Low dose dexamethasone:
- 0.6mg every 6 hours for 2 days
- Repeat to confirm
What is the commonest cause of cortisol excess?
Prolonged high dose steroid therapy:
- Chronic suppression of ACTH production
> Adrenal atrophy
What is Conn's syndrome?
Primary aldosteronism due to an adrenal adenoma
What causes primary aldosteronism?
- Independent of Angiotensin ii and K+
Usually due to:
- Adrenal hyperplasia -> Bi-/Unilateral
- Adrenal adenoma -> Conn's syndrome
True or false; Primary aldosteronism is the commonest secondary cause of hypertension?
What are the clinical features of primary aldosteronism?
What effects do aldosterone exert on the CVS?
Increase cardiac collagen
Altered endothelial function:
- Increased pressure response
Increased SNS outflow
What is the net effect of all the CVS functions of aldosterone?
What is the commonest cause of primary aldosteronism?
Bilateral adrenal hyperplasia (60%)
What percentage of primary aldosteronism cases are Conn's syndrome (adrenal adenoma)?
In what conditions are K+ channel mutations seen?
Adrenal aldosterone-producing adenomas
What is the function of the KCNJ5 channel and what happens if it is mutated?
Rectifying selective channel:
- Maintains membrane hyperpolarisation
Most mutations are gain-of-function and result in Na+ entry and depolarisation
What is the first step in diagnosing primary aldosteronism?
Confirm aldosterone excess:
- Measure plasma aldosterone and renin
> Calculate aldosterone-renin ratio (ARR)
If ARR is raised:
- Saline suppression test
- Give 2L of saline
> Failure to suppress aldosterone by >50%
> Primary aldosteronism
What is the second step in diagnosing primary aldosteronism?
- Adrenal CT -> Demonstrates adenoma
- Adrenal vein sampling -> Confirms adenoma
What surgical technique can be used to treat primary aldosteronism and when is it used? What does it cure?
Unilateral laparoscopic adrenalectomy
Only if adrenal adenoma (confirmed on vein sampling)
- 30-70% of hypertension
When is medical treatment used in primary aldosteronism and what drugs are used?
In bilateral adrenal hyperplasia
What is the commonest enzyme deficiency in CAH? What is the mode of inheritance
- 1 in 120,000 live births
- Autosomal recessive
What is classical 21-hydroxylase deficiency?
What is non-classical 21-hydroxylase deficiency?
How is CAH diagnosed?
Basal/Stimulated 17-OH Progesterone will be very high:
- Normal is
Which of the following is not a presenting feature in males with classical CAH:
- Presentation at 2-3 weeks old
- Poor weight gain
- Clear biochemistry
What is the main presenting feature in females with classical CAH?
Which of the following is not a feature of non-classical CAH:
- Poor growth
- Precocious puberty
How is CAH treated in children?
Achieve maximum growth
How is CAH treated in adults?
Avoid steroid over-replacement
What do the following clinical signs indicate:
- Labile hypertension
- Postural hypotension
- Paroxysmal sweating
What are some symptoms of phaeochromocytomas?
What complications can phaeochromocytomas cause?
What happens to the following in phaeochromocytomas:
- Glucose levels
When should we investigate for phaeochromocytoma?
- If younger than 50
Hypertension + Hyperglycaemia
How do we investigate phaeochromocytoma?
Confirm catecholamine excess:
- Two 24hr urinary catecholamines
- Plasma (At time of symptoms)
How can we identify the source of the catecholamine excess?
- Whole body
How do we treat phaeochromocytoma medically?
Full α and β blockade:
- α before β
> If β done first -> Unopposed α-stimulation
-> Malignant arrhythmia
- Phenoxybenzamine (α-blocker)
How do we treat phaeochromocytoma surgically?
- Total excision
- Tumour debulking
What syndromes are phaeochromocytomas associated with?
Succinate Dehydrogenase mutations
What is the mode of inheritance of MEN2?
What causes MEN2?
Activating mutations in tyrosine kinase receptor:
- RET proto-oncogene
What is MEN2 associated with?
Medullary thyroid cancer
What causes Von-Hippel-Lindau Syndrome?
VHL gene mutations -> Autosomal dominant:
- HIF protein accumulation
- Cell proliferation
What tumours does Von-Hippel-Lindau Syndrome tend to cause?
Haemangioblastomas (CNS + retina)
What succinate dehydrogenase gene mutations can cause phaeochromocytomasa?
Inactivating mutations in SDH B, C + D:
- Destabilises HIF-1α
What do SDH-D mutations cause?
Head and neck paragangliomas
What do SDH-B mutations cause?
What are catecholamines also raised in?
What sort of secretion do catecholamines usually have?
- Normal levels in plasma and urine may vary
What sort of tumours are less-efficient at catecholamine synthesis?
Malignant and extra adrenal:
- Dopamine > NA > Adrenaline
What drugs can cause hypercalcaemia?
What granulomatous diseases can cause hypercalcaemia?
What high calcium turnover diseases can result in hypercalcaemia?
What are the biochemical features of primary hyperparathyroidism?
Increased serum calcium
Increased/Inappropriately normal serum PTH
Increased urine calcium excretion
What malignant mechanisms can result in hypercalcaemia?
Metastatic bone destruction
PTHrp from solid tumours:
- Squamous cell lung cancer
- Breast cancer
Osteoclast activating factors
How can we diagnose hypercalcaemia caused by malignancy?
Increased calcium and ALP
Isotope bone scan
What is the acute treatment of hypercalcaemia?
- Rehydrate -> 0.9% saline 4-6L/24hrs
Consider loop diuretics once rehydrated
- Single does -> Reduces calcium in 2-3 days
- Max effect at one week
- Prednisolone -> 40-60mg/day for sarcoidosis
When is Cinacalcet used?
What are indications for parathyroidectomy?
End organ damage:
- Bone disease
> Osteitis Fibrosa Cystica
> Brown tumours
> Pepper pot skull (Multiple myeloma)
- Gastric ulcers
- Renal stones
What causes primary hyperparathyroidism? What biochemistry is seen?
Primary parathyroid overactivity:
- Raised PTH
- Raised calcium
- Normal renal function
What causes secondary hyperparathyroidism? What biochemistry is seen?
Physiological response to hypocalcaemia
- Raised PTH
- Reduced calcium
What causes tertiary hyperparathyroidism? What biochemistry is seen?
Autonomous parathyroid activity after secondary
- Raised PTH
- Raised calcium
- Other electrolytes skewed
What inheritance does Hypocalciuric Hypercalcaemia have?
What mutations are present in Hypocalciuric Hypercalcaemia?
Deactivating mutations in Calcium-sensing receptor
How is Hypocalciuric Hypercalcaemia diagnosed?
Reduced urinary calcium
PTH may be slightly raised
When does oogenesis begin?
When does oogenesis restart after suspension?
When is oogenesis complete?
When does oogenesis cease?
What are the primordial germ cells and what do they do?
Earliest recognisable female germinal cell
Capable of mitosis
Migrate to genital ridge by week 6 gestation
What is oogonia?
Completion of last pre-meiotic division -> Oocytes
When oocytes enter meoisis, what happens?
1st meiotic division -> Primary oocytes
2nd meiotic division -> Secondary oocytes
What is the polar body?
First body is one of the two products in first stage of meiosis
What does the presence of two polar bodies signify?
Sperm entry and completion of second meiotic division
What happens during the follicular phase of the menstrual cycle?
Ready for oculation at midcycle
What signifies the end of the follicular phase?
What happens during the luteal phase of the menstrual cycle?
Development of corpus luteum
Induces preparation of reproductive tract for pregnancy
What is the primary follicle?
Before birth, the primary oocyte is surrounded by a single layer of granulosa cells - Primary follicle
How many primary follicles are there at birth and what is each capable of?
Each can produce a single ovum
What happens to the primary follicles until puberty?
Degenerate to scar tissue -> Atresia
What is the secondary follicle?
Oocyte grows (x1000) and follicle expands:
- Differentiates under hormonal influence
What happens to secondary follicles after puberty?
~400 are ovulated
The rest (99.98%) undergo atresia
What happens to follicular cells left behind after ovulation?
- Become the corpus luteum
What does the corpus luteum secrete and what is this important for?
- Prepares uterine lining for implantation
After ovulation, how long does the corpus luteum continue to grow?
What is the maximum length of time the corpus luteum can survive without fertilisation?
What does the corpus luteum do if fertilisation does occur?
Produces increasing amounts of progesterone (+oestrogen) until after pregnancy
Where does FSH act and what does it do?
Acts on ovaries
Stimulates follicle development
Stimulates secretion of oestradiol
Where does LH act and what does it do?
Acts on ovaries
- Follicle maturation
- Development of corpus luteum
- Oestrogen secretion
What happens during the follicular phase?
1. Hypothalamus secretes GnRH
2. Anterior pituitary secretes FSH + LH
3. Up to 15 follicles are 'rescued' and begin to mature:
- Granulosa and theca cells develop
What do the theca cells produce?
What do the granulosa cells do?
Convert androgens to oestradiol by aromatase
What does oestradiol to?
Thins cervical mucus
What does oestrogen do?
Suppresses FSH production:
- Selection of dominant follicle
What does the granulosa in the dominant follicle express?
What causes more GnRH release and when? What does this result in?
High oestrogen levels at the mid-cycle:
- Causes FSH + LH surge from anterior pituitary
Put the following steps of ovulation in order:
- Follicle wall weakens
- LH + FSH levels fall
- Cumulus oophorus loosens
- Ovulation -> Oocyte, Zona Pellucida and cumulus
- Inc in follicular fluid + number of granulosa
- COC picked up by oviduct
1. Inc in follicular fluid + number of granulosa
2. Cumulus oophorus loosens
3. Follicle wall weakens
4. Ovulation -> Oocyte, Zona Pellucida and cumulus
5. COC (cumulus-oocyte complex) picked up by oviduct
6. LH + FSH levels fall
What causes the corpus luteum to degenerate and what does it form?
At 12 days, if there is no hCG from an embryo the corpus luteum degenerates -> Corpus Albicans
What is the function of hCG?
Maintains the corpus luteum
When does the placenta take over progesterone production from the corpus luteum?
At 6 weeks gestation
(Corpus luteum -> Corpus albicans)
What is the function of progesterone during pregnancy?
What role does FSH have in spermatogenesis?
Initiates spermatogenesis (with testosterone)
Causes Sertoli cells to express:
- Androgen Binding Globulin (ABG)
What role does FSH have in spermatocytogenesis?
Leads to development of Sertoli cells:
- Act as nursing cells for spermatids
What role does LH have in spermatocytogenesis?
Promotes Leydig cell secretion of testosterone:
- Initiates spermatogenesis
When does spermatocytogenesis occur?
In males at the age of puberty (10-14 years)
What role does LH have in spermatogenesis?
Causes interstitial Leydig cells to secrete testosterone
What role does testosterone have?
Decreases release of:
Converted to dihydrotestosterone:
- Enlargement of male sex organs
- Secondary sexual characteristics
Binds to ABG made by Sertoli cells:
- Increases its concentration in luminal fluid
> Enables spermatogenesis
> Enables sperm maturation in epididymis