Endocrinology Medicine final MBBS theory and common MCQ

2. HYPOTHALAMO–PITUITARY–
ADRENAL AXIS
• The human adrenals weight 8–10 g
• Comprise an outer cortex and inner medulla.
• The cortex has three zones:
 Zona glomerulosa, which secretes aldosterone under the control of the renin–
angiotensin system
 Zona fasciculate and Zona reticularis, which produce glucocorticoids, cortisol, and sex
steroids and androgens under feedback control of the hypothalamic–pituitary–adrenal
(HPA) axis.
• The inner medulla synthesizes, stores and secretes catecholamines

4. The adrenal cortex
• The steroids produced by the adrenal cortex are grouped into three
classes, based on their predominant physiological effects:
Glucocorticoids,
Mineralocorticoids
Androgens.

6. Glucocorticoids
• These are named after
their effects on
carbohydrate
metabolism.
• They act on intracellular
corticosteroid receptors
and combine with
coactivating proteins to
bind the ‘glucocorticoid
response element’ (GRE)
in specific regions of DNA
to cause gene
transcription.

7. Mineralocorticoids
• The predominant effect of mineralocorticoids is on the extracellular
balance of sodium and potassium in the distal tubule of the kidney.
• Aldosterone, produced solely in the zona glomerulosa, is the
predominant mineralocorticoid in humans (about 50%);
corticosterone makes a small contribution to overall
mineralocorticoid activity.
• Mineralocorticoids act on type 1 corticosteroid receptors, while
glucocorticoids act on type 2 receptors, both having a very similar
structure.

8. Androgen
• Although secreted in considerable quantities, most androgens have
relatively weak intrinsic androgenic activity until metabolized
peripherally to testosterone or dihydrotestosterone.
• Dihydrotestosterone is metabolized from testosterone by 5α-
reductase and is a potent androgen receptor agonist.
• The androgen receptor has been well characterized and mutations
within this gene may cause androgen insensitivity syndromes.

9. Control of the hypothalamic–pituitary–adrenal
axis.
Pituitary adrenocorticotrophic hormone (ACTH) is
secreted in response to hypothalamic
corticotrophin-releasing hormone (CRH), triggered
by circadian rhythm, stress and other factors, and
stimulates secretion of cortisol from the adrenal.
Cortisol has multiple actions in peripheral tissues
and exerts negative feedback on the pituitary and
hypothalamus.

10. • Glucocorticoid production by the adrenal is under hypothalamic pituitary
control.
• Corticotrophin-releasing hormone (CRH) is secreted in the hypothalamus in
response to circadian rhythm, stress and other stimuli.
• CRH travels down the portal system to stimulate adrenocorticotrophin
(ACTH) release from the anterior pituitary.
• Hypothalamic vasopressin (antidiuretic hormone, ADH) also stimulates
ACTH secretion and acts synergistically.
• ACTH is derived from the prohormone pro-opiomelanocortin (POMC),
which undergoes processing within the pituitary to produce ACTH and a
number of other peptides, including beta-lipotrophin and beta-endorphin.
• Many of these peptides, including ACTH, contain melanocyte-stimulating
hormone (MSH)-like sequences, which cause pigmentation when levels of
ACTH are markedly raised as in Addison’s disease.

11. • Circulating ACTH stimulates cortisol production in the adrenal.
• The secreted cortisol (or any other synthetic corticosteroid
administered to the patient) causes negative feedback on the
hypothalamus and pituitary to inhibit further CRH/ACTH release.
• The set-point of this system varies through the day according to the
circadianrhythm, and is usually overridden by severe stress.
• Unlike cortisol, mineralocorticoids and sex steroids do not cause
negative feedback on the CRH/ACTH axis.
• Following adrenalectomy or other adrenal damage (e.g. Addison’s
disease), cortisol secretion is absent or reduced; ACTH levels will
therefore rise.
• Mineralocorticoid secretion is mainly controlled by the renin–
angiotensin system

12. Investigation of glucocorticoid abnormalities
• Basal levels
Cortisol has a circadian rhythm and increases in response to stress.
When taking a blood sample, remember:
Sampling time should be recorded.
Basal cortisol levels should be taken between 8am and 10am, near
the peak of the circadian variation, if investigating for deficiency
Stress should be minimized
Appropriate reference ranges (for time and assay method) should be
used.

13. • ACTH Level
The measurement of ACTH levels are only really required once
an abnormality in cortisol levels has been identified.
A plasma sample is required and has to be transported on ice to the lab
immediately.
Suppression tests are used if excess cortisol is suspected, and
stimulation tests are used if cortisol deficiency is suspected.

14. • Suppression tests
Administration of a synthetic glucocorticoid (dexamethasone) to a
normal subject produces suppression of CRH and ACTH levels, and
thus of endogenous cortisol secretion (dexamethasone is not measured
by most cortisol assays).
Three forms of the test, used in the diagnosis and differential diagnosis
of Cushing’s syndrome, are available

15. • ACTH stimulation tests
Synthetic ACTH (tetracosactide, which consists of the first 24 amino
acids of human ACTH) is given to stimulate adrenal cortisol production

16. Cushing’s syndrome
• Cushing’s syndrome describes the
clinical state of increased free
circulating glucocorticoid.
• It is most often iatrogenic following
the therapeutic administration of
synthetic steroids.
• The next most common cause is
excess endogenous secretion of
ACTH from a pituitary adenoma,
when it is called Cushing’s disease

17. • Increased circulating ACTH from the pituitary (65% of cases), known as
Cushing’s disease, or from an ‘ectopic’, non-pituitary, ACTH-producing
tumour elsewhere in the body (10%) with consequent glucocorticoid
excess (‘ACTH-dependent’ Cushing’s).
• A primary excess of endogenous cortisol secretion (25%) by an adrenal
tumour or, more rarely, by bilateral primary pigmented nodular hyperplasia
(PPNH) with suppression of ACTH (‘non-ACTH- dependent’ Cushing’s).
• Rare cases are due to aberrant expression of receptors for other hormones
(e.g. glucose-dependent insulinotrophic peptide (GIP), LH or
catecholamines) in adrenal cortical cells.
• Germline changes in protein kinase A (PKA) can also result in adrenal
hyperplasia and adenomas.

19. • Pigmentation occurs only with ACTH-dependent causes (most
frequently in ectopic ACTH syndrome).
• A cushingoid appearance can also be caused by excess alcohol
consumption (pseudo-Cushing’s syndrome); the pathophysiology is
poorly understood.
• Impaired glucose tolerance or frank diabetes is common, especially
with ectopic ACTH.
• Hypokalaemia due to the mineralocorticoid activity of cortisol is
common with ectopic ACTH secretion.
• Hypertension is common in all causes of Cushing’s syndrome.

20. Investigations
• There are two phases to investigation.
Confirmation
48-h low-dose dexamethasone test
24-hour urinary free cortisol measurements.
Circadian rhythm
Other tests: insulin stress test, desmopressin stimulation test and
corticotrophin releasing hormone (CRH)
Differential diagnosis of the cause

22. Exclude Differencial
• Adrenal CT or MRI scan. Adrenal adenomas and carcinomas causing
Cushing’s syndrome are relatively large and always detectable by CT.
Carcinomas are distinguished by their large size and irregular outline, and
signs of infiltration or metastases. Bilateral adrenal hyperplasia may be
seen in ACTH-dependent causes or in ACTH-independent nodular
hyperplasia.
• If plasma ACTH levels are normal or high on two or more occasions, this is
a reliable indicator of ACTH-dependent disease and pituitary imaging
should be planned in the first instance and biochemical tests to distinguish
between pituitary and ectopic sources of ACTH.
• Pituitary MRI. A pituitary adenoma may be seen but the adenoma is often
small and not visible in a significant proportion of cases.

23. • High-dose dexamethasone suppression test . Failure of significant
plasma cortisol suppression suggests an ectopic source of ACTH (or an
adrenal tumour).
• CRH test. An exaggerated ACTH and cortisol response to exogenous
CRH suggests pituitary-dependent Cushing’s disease, as ectopic
sources rarely respond.
• Chest X-ray. A carcinoma of the bronchus or a bronchial carcinoid is
sought. Carcinoid lesions may be very small; if ectopic ACTH is
suspected, whole-lung, mediastinal and abdominal CT scanning
should be performed.

24. Management
• Untreated Cushing’s syndrome has a very poor prognosis, with death
from venous thromboembolism, hypertension, myocardial infarction,
infection and heart failure.
• Whatever the underlying cause, cortisol hypersecretion should be
controlled prior to surgery or radiotherapy.
• Considerable morbidity and mortality are otherwise associated with
operating on unprepared patients, especially when abdominal
surgery is required.

25. Drugs
The usual drug is metyrapone, an 11β-hydroxylase
blocker,
which is given in doses of 750 mg to 4 g daily in 3–4 divided doses.
Ketoconazole (200 mg three times daily) is also used and is synergistic
with metyrapone. Plasma cortisol should be monitored, aiming
to reduce the mean level during the day to 150–300 nmol/L,
equivalent to normal production rates. Aminoglutethimide, trilostane
(which reversibly inhibits 3-hydroxysteroid
dehydrogenase/
5–5,4 isomers) and etomidate infusion (in severe cases) are
occasionally used.

26. Choice of further treatment depends upon the cause.
• Trans-sphenoidal removal of the tumour is the treatment of choice.
Selective adenomectomy nearly always leaves the patient ACTH-
deficient immediately postoperatively, and this is a good prognostic
sign. Overall, pituitary surgery results in remission in 75–80% of cases,
but results vary considerably and an experienced surgeon is essential.
• External pituitary irradiation alone is slow-acting, only effective in
50–60% even after prolonged follow-up, and mainly used after failed
pituitary surgery. Children respond much better to radiotherapy, 80%
being cured. Stereotactic radiotherapy can be useful in selected cases.

27. • Medical therapy to reduce ACTH (e.g. bromocriptine, cabergoline and
cyproheptadine) is rarely effective. The somatostatin analogue
pasireotide may provide medical control of Cushing’s in some
patients, but is associated with hyperglycaemia as a common side-
effect. Aggressive corticotroph adenomas may respond to
temozolomide chemotherapy.
• Bilateral adrenalectomy is an effective last resort if other measures
fail to control the disease (see ‘Nelson’s syndrome’ later). This can be
performed laparoscopically.

29. Addison’s disease
• There is destruction of the entire adrenal cortex.
• Glucocorticoid, mineralocorticoid and sex steroid production are
therefore all reduced.
• This differs from hypothalamic–pituitary disease, in which
mineralocorticoid secretion remains largely intact, being
predominantly stimulated by angiotensin II. Adrenal sex steroid
production is also largely independent of pituitary action.
• In Addison’s disease, reduced cortisol levels lead, through feedback,
to increased CRH and ACTH production, the latter being directly
responsible for the hyperpigmentation.

31. • These symptoms may be the prelude to an addisonian crisis with
severe hypotension and dehydration precipitated by intercurrent
illness, accident or operation.
• Pigmentation (dull, slaty, grey–brown) is the predominant sign in over
90% of cases.
• Postural systolic hypotension, due to hypovolaemia and sodium loss,
is present in 80–90% of cases, even if supine blood pressure is
normal.
• Mineralocorticoid deficiency is the cause of the hypotension.

33. Investigation
• Single cortisol measurements are of little value, although a random
cortisol below 100 nmol/L during the day is highly suggestive, and a
random cortisol higher than 550 nmol/L makes the diagnosis unlikely.
• The short ACTH stimulation test (short synacthen test) should be
performed. Note that an absent or impaired cortisol response
confirms the presence of hypoadrenalism but does not differentiate
Addison’s disease from ACTH deficiency or iatrogenic suppression by
steroid medication. The long ACTH test is no longer used because of
the availability of accurate ACTH assays.

34. • A 09:00-hours plasma ACTH level is measured, a high level (>80 ng/L) with
low cortisol confirming primary adrenal insufficiency.
• Adrenal antibodies are present in approximately 90% of cases of
autoimmune adrenalitis.
• Chest and abdominal X-rays or cross-sectional imaging of the abdomen (CT
or MRI) may show evidence of tuberculosis and/or calcified adrenals.
• Plasma renin activity is high due to low serum aldosterone.
• Serum creatinine and electrolytes classically show hyponatraemia,
hyperkalaemia and a high urea, but they can be normal.
• Blood glucose may be low, with hypoglycaemia.
• Hypercalcaemia and anaemia (after rehydration) are sometimes seen.

36. Treatment
• Acute hypoadrenalism needs
• urgent treatment.

37. Adequacy of glucocorticoid dose is judged by:
• clinical wellbeing and restoration of normal, but not
excessive, weight; ideally aiming for a low dose, for
example, total dose of hydrocortisone between 15 and 25
mg split in two or three divided doses throughout the day.
• Measuring cortisol levels during the day while on
replacement hydrocortisone (cortisol levels cannot be
used for synthetic steroids) is not recommended as an
assessment of dose adequacy.
Adequacy of fludrocortisone replacement is assessed by:
• Restoration of serum electrolytes to normal
• No evidence of hypertension or postural hypotension (it
should not fall >10 mmHg systolic after 2 minutes’
standing)
• Suppression of plasma renin activity to high normal.
Replacement therapy

38. Patient advice
All patients requiring replacement steroids should:
• know how to increase steroid replacement by doubling the dose for
intercurrent illness
• carry a ‘steroid card’
• wear a MedicAlert bracelet (or similar), which gives details of their
condition so that emergency replacement therapy can be given if
found unconscious
• keep an (up-to-date) ampoule of hydrocortisone at home in case oral
therapy is impossible, for administration by self, family, ambulance or
doctor.

39. Secondary hypoadrenalism
• This may arise from:
hypothalamic–pituitary disease (inadequate ACTH production) or
long-term steroid therapy leading to ACTH suppression.
• Most people with hypothalamic–pituitary disease have panhypopituitarism
and need T4 replacement, as well as cortisol; in this case, hydrocortisone
must be started before T4.
• Long-term corticosteroid medication for non-endocrine disease is the most
common cause of secondary hypoadrenalism.
• The hypothalamic–pituitary axis and the adrenal may both be suppressed
and the patient may have vague symptoms of feeling unwell. ACTH levels
are low in secondary hypoadrenalism.
• Weaning off steroids is often a long and difficult process.

41. Primary hyperaldosteronism
• Increased mineralocorticoid secretion from the adrenal cortex, termed
primary hyperaldosteronism, accounts for 5–10% of all hypertension.
• Other endocrine causes of hypertension should also be considered if there
is clinical suspicion.
• It is impracticable to screen all hypertensive patients for secondary
endocrine causes. The highest chances of detecting such causes are in
patients:
• under 35 years, especially those without a family history of hypertension
• with accelerated (malignant) hypertension
• with hypokalaemia
• resistant to conventional antihypertensive therapy (e.g. more than three drugs) or
• with unusual symptoms (e.g. sweating attacks or weakness).

43. • Primary hyperaldosteronism
is characterized by excess aldosterone production leading to sodium
retention, potassium loss and the combination of hypokalaemia and
hypertension.
• secondary hyperaldosteronism,
which arises when there is excess renin (and hence angiotensin II)
stimulation of the zona glomerulosa. Common causes of secondary
hyperaldosteronism are accelerated hypertension and renal artery
stenosis, when the patient will also be hypertensive.
 Causes associated with normotension include congestive cardiac
failure and cirrhosis, where excess aldosterone production
contributes to sodium retention.

44. Adrenal adenomas (Conn’s syndrome)
Originally accounted for 60% of cases of primary hyperaldosteronism
but represented a rare cause of hypertension.
The use of the aldosterone: renin ratio in the routine investigation of
hypertension now suggests that hyperaldosteronism due to bilateral
adrenal hyperplasia(idiopathic hyperaldosteronism) is much more
common than the classical Conn’s adenoma.

45. Clinical features
• The usual presentation is simply
Hypertension
hypokalaemia(<3.5 mmol/L) is frequently not present.
The few symptoms are non-specific;
• rarely, muscle weakness
• nocturia
• tetany
• Hypertension may be severe and associated with renal, cardiac and retinal
damage.
• Adenomas, often very small, are more common in young females, while bilateral
hyperplasia rarely occurs before the age of 40 years and is more common in
males.

46. investigation
• Plasma aldosterone : renin ratio (ARR) (high) is now most frequently used
as a screening test for the condition, but raised ARR alone does not confirm
the diagnosis.
• Suppressed plasma renin activity 0.9% saline infusion (2 L over 4 h) or
fludrocortisone administration. Between 30% and 50% of people with a
raised ARR on screening will suppress normally, excluding the diagnosis.
• Elevated plasma aldesteron
• Hypokalaemia is often present but a normal potassium does not exclude
the diagnosis.
• Urinary potassium loss greater than 30 mmol daily.

47. Treatment
• An adenoma can be removed surgically, usually laparoscopically;
blood pressure falls in 70% of patients.
• Those with hyperplasia should be treated with the aldosterone
antagonist, spironolactone (100–400 mg daily); frequent side-effects
include nausea, rashes and gynaecomastia.
• The pure aldosterone receptor antagonist, eplerenone, is a useful
• Amiloride and calcium-channel blockers are moderately effective in
controlling hypertension but do not correct the hyperaldosteronism.

48. The adrenal medulla
• The adrenal medulla is the innermost part of the adrenal gland,
consisting of cells that secrete the major catecholamines,
noradrenaline (norepinephrine) and adrenaline (epinephrine), which
produce the sympathetic nervous response.
• The catecholamines are interconverted in the adrenal medulla, and
an increase in levels of their metabolites in the urine is a marker of
abnormal hypersecretion.

50. Phaeochromocytoma and paraganglioma
• These are very rare tumours of the sympathetic nervous system (less than
1 in 1000 cases of hypertension)
• secrete catecholamines, noradrenaline (norepinephrine), adrenaline
(epinephrine) and their metabolites.
 90% arise in the adrenal medulla (phaeochromocytomas)
10% occur elsewhere in the sympathetic chain (paragangliomas).
• Some are associated with MEN 2 , von Hippel–Lindau’s (VHL) syndromeand
neurofibromatosis.
• Most tumours release both noradrenaline (norepinephrine) and adrenaline
(epinephrine), but large tumours and extra-adrenal tumours produce almost
entirely noradrenaline.

51. • Paragangliomas typically occur in the head and neck but are also
found in the thorax, pelvis and bladder.
• They are more closely associated with other genetic associations than
phaeochromocytoma.
• The association of paraganglioma, bilateral adrenal
phaeochromocytomas, positive family history or young age at
presentation is seen in multiple endocrine neoplasms.
• Mutations in the succinate dehydrogenase (SDHD) gene have been
shown to be strongly associated with the development of
paraganglioma.

53. Investigations
• Measurement of urinary catecholamines and metabolites. (most sensitive
and specific)
• 24 hour urine collection of catecholamines metabolites / VMA
• Resting plasma catecholamine (increased)
• CT abdomen- localized tumor
• Plasma chromogranin A (a storage vesicle protein) is raised.
• Clonidine suppression test may be appropriate but should only be
performed in specialist centres
• Genetic testing for MEN2, VHL, SDHB and SDHD mutations should be
performed in all people with confirmed phaeochromocytoma or
paraganglioma

55. Management
• Tumours should be removed if possible; 5-year survival is about 95% for
non-malignant tumours.
• Medical preoperative and perioperative treatment is vital and includes
complete alpha-and beta-blockade with phenoxybenzamine (20–80 mg
daily in divided doses), then propranolol (120–240 mg daily)
• intravenous hydration to re-expand the contracted plasma volume.
• When operation is not possible, combined alpha-and beta-blockade can be
used long term.
• Radionucleotide treatment with MIBG has been employed but has had
limited success in malignant phaeochromocytoma.

57. Questions
1. Regarding Cushing syndrome
a) Pigmentation supports adrenal tumour as a cause
b) Presence of hypo K+ favours ectopic ACTH tumour
c) Lesion is usually seen on pituitary imaging
d) May have increased predisposition for fractures
e) May have proximal muscle weakness
FTFTT

58. ACTH INDEPENDENT ACTH DEPENDENT
Exogenous glucocorticoid
Adrenal adenoma
Adrenal hyperplasia
Adrenal carcinoma
Pituitary adenoma
Ectopic ACTH secretion
Lung cancer
Carcinoid tumor
Other cancer

59. 2. Features of Conn's disease;
a) Hypertension
b) Hyponatraemia
c) Hyperkalaemia
d) Facial flushing
e) Abdominal mass can be seen
TFFTF

61. 3. In Conn's syndrome
a) Peripheral oedema is usually present
b) Proximal myopathy is due to hypokalemia
c) Polyuria and polydipsia is characteristic
d) DM is often present
e) High Renin hypertension
FTTFF

65. 4. Addison's disease
a) May present with tetani due to hypo Ca2+
b) Pigmentation of palmer increases
c) May be associated with anemia
d) May be a cause of sudden death during anti TB therapy
e) May present with prominent U waves in ECG
FTTTF

66. ECG changes in Addison's disease are
primarily due to hyperkalemia
caused by aldosterone hormone
deficiency.
• Peak T waves
• Widened QRS complex

68. 5. Obese female with hirsutism, hypertension (150/100), amenorrhea
presents to the clinic. Which of the following investigations are needed to
come to a definitive diagnosis?
a) Serum T3/T4 levels
b) Urinary VMA
c) Serum cortisol
d) Dexamethasone suppression test
e) CT scan of the abdomen
TFFTT

69. 6. 28y old male with a BMI of 17 presented with tiredness & lethargy
for 8 months’ duration. Examination revealed a vitiligo, and BP
140/60mmHg, PR- 120/sec. Ix; WBC-5500, Hb- 10.5g/dl, 1MCV - 95,
serum Na-140, serum K+- 4.2, blood urea- 20, blood glucose -
150mg/dL. Most probable diagnosis is
a) Hypopituitarism
b) Thyrotoxicosis.
c) Type 1 DM
d) Pernicious anaemia.
e) Addison disease.

70. • Types
• Autoimmune polyendocrine syndrome type 1, an autosomal recessive
syndrome due to mutation of the AIRE gene resulting in
hypoparathyroidism, adrenal insufficiency, hypogonadism, vitiligo,
candidiasis and others.
• Autoimmune polyendocrine syndrome type 2, an autosomal dominant
syndrome due to multifactorial gene involvement resulting in adrenal
insufficiency plus hypothyroidism and/or type 1 diabetes.
• Immunodysregulation polyendocrinopathy enteropathy X-linked syndrome
(IPEX syndrome) is X-linked recessive due to mutation of the FOXP3 gene
on the X chromosome. Most develop diabetes and diarrhea and many die
due to autoimmune activity against many organs. Boys are affected, while
girls are carriers and might suffer mild disease

71. 7. 32 years old young female presented with dizziness & abdominal
pain. Her BP is 90/70mmHg with significant postural drop. Her Ix
results are as follows. S. Na+ -110 mmol/l (135-145 mmol/l), S. K+ -
5.1mmol/l (3.5-5mmol/l), RBS - 68mg/dl. What is the most important Ix
to arrive at a diagnosis?
a) 24hr urine collection for cortisol
b) 24hr urine collection for VMA
c) Dexamethasone suppression test
d) Short Synacthen test
e) USS abdomen