ADRENAL INSUFFICIENCY
Dr Helena Vreede
Chemical Pathology
2023
Learning Objectives
• Understand the hypothalamic-pituitary-adrenal axis
• Understand adrenal steroidogenesis, and the biochemistry
and investigation of congenital adrenal hyperplasia (CAH)
• Understand the biochemistry and investigation of adrenal
insufficiency
HYPOTHALAMIC-PITUITARY-ADRENAL AXIS
Hypothalamus and Pituitary
DA
SS
Hypothalamic and pituitary hormones
Hypothalamic regulatory hormone
Pituitary hormone
Anterior Pituitary:
GnRH
Gonadotropin-releasing hormone
FSH
LH
Follicle stimulating hormone
Luteinizing hormone
CRH
Corticotropin releasing hormone
ACTH
Adrenocorticotropic hormone
TRH
Thyrotropin-releasing hormone
TSH
Thyroid stimulating hormone
DA
Dopamine (-)
PRL
Prolactin
GHRH
SS
Growth hormone releasing hormone
Somatostatin (-)
GH
Growth hormone
Posterior Pituitary:
ADH
Antidiuretic hormone
OT
Oxytocin
Regulation of pituitary function
a)
b)
c)
d)
Stress can alter pituitary hormone secretion and be used to test for
abnormality, e.g., insulin induces hypoglycaemia, and hypoglycaemic stress
stimulates hypothalamic hormones such as CRH and GHRH, which in turn
stimulate the production of pituitary hormones ACTH and GH
Feed-back by products of end-organ endocrine glands (eg. steroids) or tissues
(eg. IGF-l) act back, usually inhibiting, or in rare cases, enhancing, pituitary
response to hypothalamic factors. Feed-back is thus negative or positive, and
either long-loop (to hypothalamus) or short-loop (to pituitary).
Cyclic fluctuations in pituitary hormone secretion (e.g. GH and ACTH) is
mediated via CNS regulation of hypothalamic releasing factors; and may be
altered in disease.
Development. The endocrine system remains in equilibrium (constancy) via
negative feed-back mechanisms. However, the degree of negative feedback is
not constant. For example, sensitivity to negative feed-back by gonadal steroid
on gonadotropin secretion diminishes during puberty, Thus the major changes
of puberty only occur because these controlling mechanisms are no longer
restraining.
NB. Testing of pituitary dysfunction employs all of the above concepts.
Hypothalamic – Pituitary – Adrenal axis
Corticotropin releasing hormone (CRH) is a
41-amino acid peptide which stimulates
adrenocorticotropic hormone (ACTH) secretion.
Adrenocorticotropic hormone (ACTH) is a 39amino acid polypeptide that stimulates adrenal
glucocorticoid (but not minerallocorticoid)
secretion.
ACTH secretion exhibits diurnal variation,
highest at 08h00, lowest at midnight. Secretion
is greatly increased by stress, and inhibited by
cortisol in a classic negative feedback manner.
Excessive secretion of ACTH occurs with some
pituitary tumours (Cushing’s disease) and in
primary adrenal failure (Addison's disease). It is
also occasionally produced ectopically by nonpituitary tumours (eg. small cell lung CA).
Decreased ACTH leading to secondary adrenal
failure is usually part of generalised pituitary
insufficiency, though it can occur in isolation.
ADRENAL STEROIDOGENESIS
Anatomy of the adrenal gland
Hormones of the adrenal: overview
Control:
Adrenal gland:
Renin-angiotensin-aldosterone system: Adrenal cortex:
Zona glomerulosa
Hormones:
Aldosterone
Hypothalamic-pituitary-adrenal axis:
CRH → ACTH → Cortisol
Adrenal cortex:
Zona fasciculate
Zona reticularis
Cortisol
Androgens
Sympathetic nervous system
Adrenal medulla
Catecholamines
Enzymes of adrenal steroidogenesis
Short name
Full name
Adrenal cortex site
P450scc
Cholesterol side-chain cleavage enzyme
and desmolase
All zones
3βHSD
3-beta-hydroxysteroid dehydrogenase
All zones
17OH
17-alpha-hydroxylase
ZF + ZR
17,20-lyase
17,20-lyase
ZR
21OH
21-hydroxylase
ZF + ZG
11OH
11-beta-hydroxylase
ZF + ZG
18OH + 18DH 18-hydroxlase + 18-dehydrogenase =
= AS
Aldosterone synthase
ZG
Summary pathway of steroid hormone production:
Cholesterol
Pregnenolone
17OH
1 17-OH-Pregnenolone
3βHSD
1
Progesterone
17OH
Deoxycorticosterone
11OH
3
Corticosterone
2 17-OH-Progesterone
DHEA
3βHSD
3βHSD
21OH
2
1
2
Androstenedione
21OH
3 11-Deoxycortisol
11OH
4 Cortisol
18OH
4
18-OH-Corticosterone
18DH
5
Aldosterone
Mineralocorticoid pathway
Glucocorticoid pathway
Androgen pathway
Adrenal corticosteroids: types → effect
Androgen precursors
Mineralocorticoids
Glucocorticoids
CMO I = 18-Hydroxylase
CMO II = 18-Dehydrogenase
CMO I plus CMO II =
Aldosterone Synthase
ADRENAL HORMONES
Adrenal hormone (1): Cortisol
Cortisol is a 'glucocorticoid' (a cortical hormone that increases blood glucose levels):
- In liver: increases gluconeogenesis and glycogen synthesis.
- In muscle: decreases glucose uptake and consumption; increases glycogenolysis and
protein catabolism; decreases protein synthesis.
- In adipose tissue: increases lipolysis.
Other:
- Acts on the pancreas to decrease insulin and increase glucagon. (Cortisol and
glucagon both “counter-regulatory hormones”)
- Decreases peripheral tissue sensitivity to insulin
- Increases appetite and food intake and may increase fat mass
Other effects:
• Cardiovascular: Sensitizes arterioles to effect of noradrenaline → maintains BP
• Bone and calcium metabolism: Inhibits bone formation and increase bone resorption
• Immunological: Inhibits prostaglandin, various interleukins, TNF. Is anti-inflammatory
and immunosuppressive.
• Effects on CNS: improves memory
Adrenal hormone (2): Aldosterone
CONGENITAL ADRENAL HYPERPLASIA
Disorders of the Adrenal Gland
• Hypoadrenalism:
• Congenital adrenal hyperplasia
• Primary adrenal insufficiency (Addison’s disease)
• Hyperadrenalism:
• Primary hyperaldosteronism (Conn’s) - semester 5
• Primary hypercortisolism (Cushing’s) - semester 5
• Disorders of the adrenal medulla:
• Phaeochromocytoma - semester 5
Congenital Adrenal Hyperplasia
3βHSD deficiency:
21-OH deficiency:
Rare
>90%
11-OH deficiency:
17-OH deficiency:
5-10%
<5%
CAH: 21-Hydroxylase deficiency
Commonest. >90% CAH. AR.
Pathophysiology:
Decreased GC: ↓ negative feedback ↑ ACTH → adrenal hyperplasia
Decreased MC: Salt wasting
Increased Androgens: Over-virilisation of newborn females
(ambiguous genitalia)
Diagnostic precursor: ↑ 17OH-Progesterone
Female with 21-OH deficiency
CAH: 21-Hydroxylase deficiency
• Severe salt-losing form:
• severe enzyme defect
• potential adrenal crisis due to inadequate aldosterone
• hypotension, shock, hyperkalaemia
• boys at risk clinically
• Simple virilising form:
• mild enzyme defect
• adequate cortisol and aldosterone production
• accumulation of 17-OHP and excessive androgens
• over-virilisation of newborn females (ambiguous genitalia)
• virilised male (often un-noticed)
• Non-classical form:
• very mild enzyme defect (1:1000)
• no neonatal masculinisation
• young women present with menstrual irregularity, infertility, hirsutism
• mimics PCOS
• Treatment:
• Cortisol and fludrocortisone
• Monitor by measuring 17-OHP (keep slightly elevated but avoid over-treatment due
to risk of iatrogenic Cushing’s) and androgens (testosterone, DHEAS)
CAH: 3β hydroxysteroid dehydrogenase defn
Rare. AR.
Pathophysiology:
Decreased GC: ↓ negative feedback ↑ ACTH → adrenal hyperplasia
Decreased MC: Salt wasting
Decreased Andostenedione → ↓Testosterone → Under-virilisation of newborn males
Increased DHEA → Over-virilisation of newborn females
Note: The only form of CAH that can present with ambiguous genitalia of both sexes
Diagnosis: ↑ Pregnenolone, 17α-hydroxypregnenolone, DHEA, and renin
CAH: 11-Hydroxylase deficiency
AR. 5-10% CAH
Pathophysiology:
Decreased GC: ↓ negative feedback ↑ ACTH → adrenal hyperplasia
Decreased Aldosterone, but increased Deoxycorticosterone = MC: Hypertension, HypoK
Increased Androgens: Over-virilisation of newborn females (ambiguous genitalia)
Diagnostic precursor: ↑ 11-Deoxycortisol (and ↑ 17OH-Progesterone)
CAH: 17-Hydroxylase deficiency
AR. <5% CAH
Pathophysiology:
Decreased GC: ↓ negative feedback ↑ ACTH → adrenal hyperplasia
Decreased cortisol, but increased Corticosterone = weak GC: prevents adrenal crisis
Increased MC precursors: Low renin hypertension in childhood with hypoK met alkalosis
Decreased Androgens: Under-virilization of newborn males (ambiguous genitalia);
Females delayed puberty
CAH: Summary of features (1)
3βHSD deficiency:
21-OH deficiency:
Rare
>90%
11-OH deficiency:
17-OH deficiency:
5-10%
<5%
CAH: Summary of features (2)
CAH
MC defn
Salt-wasting
Hypertension
Over-virilized
Females
Under-virilized
Males
3β-HSD: sw
Yes
Yes
-
Yes +
Yes +
No
-
Yes +
Yes +
Yes
-
Yes +++
-
No
-
Yes +++
-
3β-HSD: nsw
21-OH: sw
Yes
21-OH: nsw
11-OH
No
-
Yes +++
Yes +++
-
17-OH
No
-
Yes +++
-
Yes +
ADRENAL INSUFFICIENCY
Disorders of the Adrenal Gland
• Hypoadrenalism:
• Congenital adrenal hyperplasia
• Primary adrenal insufficiency (Addison’s disease)
• Hyperadrenalism:
• Primary hyperaldosteronism (Conn’s) - semester 5
• Primary hypercortisolism (Cushing’s) - semester 5
• Disorders of the adrenal medulla:
• Phaeochromocytoma - semester 5
Adrenal insufficiency
• Primary adrenal hypofunction (Addison’s disease) (1:50 000)
• Impaired capacity to secrete cortisol and aldosterone
• Main causes:
• Autoimmune (associated with Hashimoto’s thyroiditis, type I DM,
•
•
•
•
•
•
other autoimmune diseases)
Adrenal haemorrhage
Meningococcal septicaemia (Friderichsen-Waterhouse syndrome)
Infection: TB, fungal infection
Neoplastic infiltration
Haemochromatosis, amyloidosis
Adrenoleukodystrophy
• Secondary adrenal hypofunction
• Iatrogenic due to rapid withdrawal of prolonged steroid therapy
• Hypothalamic and pituitary disease
• Lack of ACTH (no hyperpigmentation)
• Cortisol deficiency
• Intact aldosterone
Addison’s disease
• Clinical features:
• orthostatic hypotension
• dehydration
• hypoglycaemia
• pigmentation (excess ACTH)
• fatigue
• muscle weakness
• weight loss
• anorexia
POMC: pro-opiomelanocortin; ACTH: adrenocorticotropic hormone; MSH:
melanocyte-stimulating hormone; LPH: Lipotrophin; β-END: β-Endorphin
• Addisonian crisis: hypotension, circulatory shock,
abdominal pain (MEDICAL EMERGENCY)
• Biochemical features:
• Aldosterone deficiency
• Na and water loss in urine
• hyponatraemia
• hyperkalaemia, metabolic acidosis
• Cortisol deficiency
• hypoglycaemia
Investigation of adrenal insufficiency (1)
Electrolytes (Na, K), blood gas
Cortisol, ACTH, Aldosterone
• Primary adrenal insufficiency: ↓ aldo ↓ cortisol ↑ ACTH
• Secondary adrenal insufficiency:↓ ACTH ↓ cortisol
Stimulation tests: evaluating the ability of the adrenal to
respond to stimulation by ACTH.
• Primary adrenal insufficiency: unable to respond
• Secondary adrenal insufficiency: may be unable to
respond immediately (adrenal was chronically understimulated), but may be able to respond after longer
stimulation
Investigation of adrenal insufficiency (2)
1.
“Short” ACTH stimulation (synacthen / cosyntropin) test:
• One dose of synacthen (low dose 1 ug or high dose 250 ug)
• Measure cortisol before and 30 mins after
Interpretation:
• Normal: cortisol that increases to > 550 mmol/L
• Subnormal response may be due to primary or secondary adrenal
insufficiency
2.
“Long” ACTH stimulation (synacthen / cosyntropin) test:
• Synacthen stat plus depot injection x 3 days
• Measure cortisol before, and at 1, 2, 4, 8 and 24 hrs after last dose
Interpretation:
• Normal: Rising cortisol with a peak at 4-8 hours
• Primary adrenal insufficiency: no or poorly sustained response
• Secondary adrenal insufficiency: slowly developing response with a
peak at 24 hours
Investigation of adrenal insufficiency (3)
3.
Insulin tolerance test:
• Insulin to induce hypoglycaemia with glu < 2.2 mmol/L ** Monitor
• Hypoglycaemic stress stimulates ACTH
Interpretation same as Synacthen test:
• Normal: cortisol that increases to > 550 mmol/L
• Subnormal response may be due to primary or secondary
adrenal insufficiency
4.
Metyrapone stimulation test:
• Metyrapone inhibits the adrenal enzyme 11-β-hydroxylase which
converts 11-deoxycortisol to cortisol. The reduced cortisol reduces
negative feedback on the HPA, increases ACTH, and increases
11DOC ** Risk: reduced cortisol may precipitate Addisonian crisis
Interpretation:
• Normal HPA: ACTH and 11DOC increase
• Subnormal response of 11DOC may be due to primary or
secondary adrenal insufficiency
Investigation of adrenal insufficiency (4)
• Autoantibodies
• Anti-adrenal (21-hydroxylase, 17-hydroxylase, cholesterol side-
chain cleavage enzyme)
• Anti-thyroid
• Anti-Islet cell (type 1 DM)
• Imaging
• CT adrenal
• CT or MRI of pituitary
• CXR
END
For fun: From cholesterol to cortisol
From cholesterol to cortisol:
1. Side chain cleavage
and 20,22 Lyase
-> Pregnenolone
2. 3β-hydroxysteroid
dehydrogenase
-> Progesterone
3. 17α-hydroxylase
-> 17OH Progesterone
4. 21-hydroxylase
-> 11deoxycortisol
5. 11-hydroxylase
-> Cortisol