Adrenocortical Function

Question 1

Basic physiology

Answer 1

Hypothalamic-pituitary-adrenal axis active during foetal development

• adrenal foetal zone (FZ) –> DHEAS synthesis which increases as foetus grows
• stimulated by foetal pituitary ACTH
• FZ regresses after birth

Zona glomerulosa, fasciculata, reticularis stimulated by RAAS and ACTH are also active

Question 2

Enzymatic reactions in the adrenal cortex

Answer 2

Cortisol and androgen synthesis (ACTH)
- hydroxylation at C17, C21 and C11

Aldosterone synthesis (RAAS)

• hydroxylation of C21, C11 and C18
• lack of C17 hydroxylation produces a molecule that retains salt

(1a) C17 by 17 alpha-hydroxylase and (1b) Desmolase/17,20-lyase
(2) 3 beta-HSD needed for all molecules
(3) C21 by 21 (alpha-)hydroxylase
(4) C11 by 11 beta-hydroxylase
(5) C18 by aldosterone synthase

Aldosterone:

• pregnenolone –> progesterone (2)
• –> 11-deoxycorticosterone (3)
• –> corticosterone (4)
• –> aldosterone (5)

Cortisol:

• pregnenolone –> 17 alpha hydroxypregnenolone (1)
• –> 17 alpha hydroxyprogesterone (2) [or directly from progesterone by (1)]
• –> 11-deoxycortisol (3)
• –> cortisol (4)

Androgens:
- 17 alpha hydroxypregnenolone –> dehydroepiandrosterone (DHEA) (1b)
- –> androstenedione (2)
- –> estrone (aromatase) –> estradiol (17 beta-HSD)
OR
- –> testosterone (17 beta-HSD) –> estradiol (aromatase)

Question 3

Congenital Adrenal Hyperplasia pathogenesis

Answer 3

AR disorders

Disrupted adrenocorticol function due to deficiency of enzymes involved in synthesis of cortisol, aldosterone or both

==> excessive trophic hormones due to less negative feedback inhibition = hyperplasia and build up of steroid intermediates which may be converted to other steroids that have biological actions

Question 4

Types of CAH and their effects on mineralocorticoids/androgens, clinical features

Answer 4

21 hydroxylase CAH

• most common, 95%
• conversion of 17-OH progesterone or progesterone to 11-deoxycorstiol or 11-deoxycorticosterone (DOC)
• Dx: RAISED 17-OH PROGESTERONE 2 days after birth
• HIGH ANDROGENS (steroid intermediates diversion), **Mineralocorticoids depend on severity
• Tx: replace missing steroids

11 beta-hydroxylase CAH

• second most common (5%)
• 11-deoxycorstiol or DOC into cortisol or corticosterone
• HIGH MINERALOCORTICOIDS (DOC has mineralocorticoid activity) and HIGH ANDROGENS
• HT due to DOC activity, female virilisation

17 alpha-hydroxylase CAH

• rare
• for glucocorticoid and androgen production
• TESTICULAR FEMINISATION syndrome due to LOW ANDROGEN

Question 5

Signs and symptoms of CAH

Answer 5

Excess androgens

• ambiguous genitalia in females
• early pubic hair and rapid growth in childhood
• precocious puberty or failure of puberty (sexual infantilism - delayed or absent puberty)
• hirsutism, virilisation and/or menstrual irregularity in adolescence
• infertility due to annovulation
• clitromegaly and shallow vagina

Insufficient androgens and oestrogen’s

• undervirilisation in XY males –> apparently female external genitalia
• hypogonadism in females –> sexual infantilism or abnormal pubertal development, infertility and other reproductive system abnormalities

Inadequate mineralocorticoids
- vomiting due to salt wasting leading to dehydration and death

Question 6

Classification of 21 hydroxylase CAH: severity, clinical features, aldosterone and cortisol levels, treatment

Answer 6

Salt-wasting

• severe deficiency
• MC cause of AMBIGUOUS GENITALIA in XX female INFANTS (prenatal virilisation)
• aldosterone and cortisol both reduced – LIFE THREATENING VOMITING and dehydration within 1st few wks; hypotension and addisonian crisis
• Tx: hydrocortisone, fludrocortisone, NaCl

Simple virilising

• moderate deficiency
• VIRILISATION in prepubertal CHILDREN (postnatal) – hirsutism, precocious puberty, acne, rapid growth in both boys and girls
• cortisol reduced but aldosterone normal
• Tx: hydrocortisone

Non-classical CAH

• even milder deficiency
• androgen effects and INFERTILITY in adolescent and ADULT women
• neither aldosterone nor cortisol reduced

Question 7

Adrenal insufficiency causes

Answer 7

Primary: adrenal glands

• 80% due to autoimmune disease (Addison’s disease)
• Idiopathic or unknown cause (possible infection, tumour deposits, CAH)
• both glucocorticoid and mineralocorticoid low

Secondary: pituitary gland or hypothalamus

• pituitary adenoma (suppress ACTH production leading to adrenal atrophy; if reached this stage then LH/FSH, GH and TSH also likely abnormal)
• Sheehan’s syndrome
• low glucocorticoid, normal mineralocorticoid

Tertiary: hypothalamic (decease CRH)

• brain tumours
• sudden withdrawal of exogenous steroids (MC cause of insufficiency overall)
• low glucocorticoid

Question 8

Signs and symptoms of adrenal insufficiency

Answer 8

Hypoglycaemia (+ hypoNa, hyperK if primary), dehydration, weight loss, disorientation
Weakness, fatigue, low BP (loss of vascular reactivity to vasoconstrictors by glucocorticoids, failure to conserve Na by mineralocorticoids), CVS collapse, nausea, vomiting, muscle aches

Addison’s disease –> tanning of skin due to increased POMC (proopiomelanocortin, MSH component); classically at buccal mucosa and skin creases

Question 9

Tests for adrenal reserves in insufficiency, limitations

Answer 9

Short Synacthen test
- synthetic ACTH (24 aa), 0.25 mg

Normal = cortisol rise of 200nM at 30 minutes and exceeds 550nM

Low cortisol/no response = Addison’s or other causes of adrenal insufficency

Once confirmed hypo function:
ACTH to delineate causes
- high ACTH = primary
- low ACTH = secondary or tertiary
–> long synacthen test (3 successive doses of 1mg; measure 5 and 8 hrs after)
–> stepwise increase in cortisol = secondary/tertiary (gland become responsive)
–> can also test reserves in patients after withdrawal of steroid therapy

Limitations:

• invalidate if severe emotional stress, treatment with glucocorticoids within 12 hrs prior and OCP (oestrogen)
• if treating for suspected Addison’s, use dexamethasone as it doesn’t cross react with cortisol
• long synacthen test not valid if hypothyroid

Question 10

Cushing’s syndrome symptoms and causes

Answer 10

Hypercortisolism

Symptoms:

• weight gain, moon face, buffalo hump, central obesity
• glucose intolerance
• muscle: weakness
• skin: thinning, striae, hirsutism (excessive hair), acne
• psycho: anxiety, irritability, decreased libido
• vascular: high bp
• bone: increased risk of fractures
• reproductive: irregular menstruation, erectile dysfunction

Causes:
ACTH dependent
- Pituitary ACTH secreting adenoma (Cushing’s disease) – 70%
- ectopic ACTH secretion e.g. SCLC (may have hypoK alkalosis due to mineralocorticoid activity of very high cortisol)

ACTH independent

• adrenal adenoma or carcinoma secreting cortisol
• exogenous glucocorticoid therapy (long term)

Question 11

Dynamic tests for hypercortisolism

Answer 11

Dexamethasone suppression test

Synthetic glucocorticoid with 25x cortisol potency –> suppress ACTH and lowers cortisol

1. Overnight Dex (low dose: 2mg)
   - normal: suppresses cortisol (<50 nmol/L)
   - Cushing’s: no suppression

Once Cushing’s syndrome established,

2. High dose Dex (2mg Q6H 2/7)
   - 50% reduction of cortisol = Cushing’s disease (pituitary ACTH secreting tumour)
   - no suppression
   - -> low ACTH = adrenal tumour (autonomous cortisol; ACTH independent)
   - -> high ACTH = ectopic ACTH (e.g. SCLC)

Caution:
- drugs e.g. phenytoin, phenobarbitone may increase dexamethasone metabolism by inducing hepatic microsomal enzymes

(CRH test: measure ACTH and cortisol prior and 2hr after CRH –> little/no response = ectopic ACTH or adrenal; exaggerated response >600 = Cushing’s disease)

Question 12

Approach to Cushing’s syndrome

Answer 12

1. 24hr urine free cortisol or O/N LDDST
   - -> UFC 3-4x URL or no suppression –> confirmed Cushing’s – proceed to (2)
   - -> equivocal UFC –> CRH test
2. • rule out depression/alcohol causing pseudocushing’s (insulin tolerance test – true Cushing = no response to hypoglycaemia)

• ACTH (measure morning and evening; can be unstable)
  –> suppressed = adrenal cause –> adrenal CT
  –> normal/elevated = pituitary or ectopic cause –> HDDST/CRH
  —–> suppression on HDDST = pituitary –> MRI/CT pituitary (if inconclusive –> IPSS to catheterise pituitary and administer CRH to see response location)
  —–> no suppression on HDDST = ectopic –> CXR, CT chest and abdomen, tumour markers
  (–> low normal –> CRH and HDDST)

Question 13

Treatment and aftercare of Cushing’s

Answer 13

Surgical removal of adenomas

If adrenal surgery not feasible –> glucocorticoid synthesis inhibitors e.g. ketoconazole or metyrapone + glucocorticoid replacement (block and replace)

After adrenal surgery or stopping steroids, replacement steroids given until HPA axis recovered

Question 14

Hyperaldosteronism causes

Answer 14

Primary

• hyporeninaemic hyperaldosteronism due to adrenal adenoma – Conn’s syndrome
• bilateral idiopathic adrenal hyperplasia causing 70% cases

Secondary

• hyperreninaemic hyperaldosteronism due to overactivity of RAAS
• RENIN-SECRETING TUMOUR
• decreased renal arterial pressure e.g. RENAL ARTERY STENOSIS (fibromuscular dysplasia for young women); reduced ECV and Na filtration e.g. CHF, cirrhosis, diuretics, Na depletion

Question 15

Signs and symptoms of hyperaldosteronism

Answer 15

Can be asymptomatic
If symptomatic:
- fatigue, headache, hyperNa (high BP), hypoK (muscle weakness, paralysis, polyuria), hypoMg, polydipsia, metabolic alkalosis

Note: normal HT with diuretic therapy may also present as high BP with hypoK so need to withdraw drugs, replenish K and measure 2 wks later

Question 16

Tests for hyperaldosteronism

Answer 16

SCREENING with aldosterone:renin ratio
- ARR high in primary (>400 pmol/L), unchanged in secondary

Further tests:

Stop anti-HT drugs and normal fluid replacement!!

1. To confirm hyperaldo: salt loading test (5 days NaCl then measure 24hr urine Na and aldosterone –> [Na] >200 mmol confirms adequate intake and [aldo] >38 nmol = hyperaldo with lack of suppression despite ECV expansion) –> determine primary or secondary based on renin/ARR
2. *Collect blood for renin and aldosterone after supine overnight and 4hrs ambulatory (not definite diagnosis, results vary)

–> Conn’s syndrome = paradoxical decrease of aldosterone when erect (no physiological response)

–> Bilateral adrenal hyperplasia = aldosterone increase when erect (normal response)

3. Imaging only useful after identifying abnormality since there is high incidence of non-functional incidentalomas

(Urine 18-hydroxycortisol may be useful to differentiate causes – conn’s syndrome has elevated 18 OHF from action of aldosterone synthase on cortisol instead corticosterone)

Question 17

Treatment of hyperaldosteronism

Answer 17

Primary

• surgical removal of adenoma (need to lateralise affected gland by sampling blood from the 2 adrenals)
• idiopathic bilateral adrenal hyperplasia treated with aldosterone antagonists e.g. spironolactone

Secondary

• surgery if possible to improve renal perfusion
• aldosterone antagonists

Question 18

Apparent mineralocorticoid excess

Answer 18

AR disorder
Mutations of 11 beta-HSD2 which normally mediates conversion of cortisol to less active cortisone

==> excess active cortisol binds to mineralocorticoid receptors and retains Na like aldosterone

==> HT, hyperNa, hypoK (low aldosterone, low renin)

Liquorice may also cause temporary AME due to inhibition of enzyme

Question 19

DDx of secondary hypertension and mineralocorticoid excess syndrome

Answer 19

Secondary hypertension
- hyperaldosteronism
- phaeochromocytoma
- Cushing's syndrome
(other associated diseases e.g. CAH, DM etc)

Mineralocorticoid excess
- HIGH RENIN –> secondary hyperaldo (renin tumour, renal artery stenosis, bartter/gittlemans)

• LOW RENIN
• -> HIGH ALDOSTERONE –> primary hyperaldo
• -> LOW ALDOSTERONE –> acquired (hypercortisolism, liquorice) OR genetic (apparent mineralocorticoid excess, Liddle’s syndrome, CAH 11beta or 17alpha)