Cushing's Syndrome

Table of contents
Key points ⚡
Succinct notes to superpower your revision
Cushing's syndrome\: due to prolonged exposure to elevated glucocorticoids, endogenous or exogenous.
Aetiology\: most commonly due to the use of exogenous glucocorticoids; endogenous includes ACTH-dependent (80-85%,
pituitary adenomas) and ACTH-independent (adrenal adenomas, carcinomas).
Pathophysiology\: hypothalamic-pituitary-adrenal axis, the hypothalamus secretes CRH -> ACTH is released from the
pituitary -> the adrenal cortex releases cortisol, negative feedback regulation.
Symptoms\: weakness, facial fullness, weight gain, low mood, decreased libido, polydipsia, polyuria, frequent infections.
Examination
headaches, visual
Investigations\: 24-hour urinary free cortisol (more than 3x the upper limit is suggestive of Cushing's syndrome), low-dose
dexamethasone suppression test, late-night salivary cortisol, plasma ACTH, high-dose dexamethasone suppression test,
MRI pituitary, CT chest/abdomen.
Management\: review and reduce glucocorticoid doses for exogenous causes; resection of tumour for endogenous causes;
medical management with ketoconazole, metyrapone, mitotane; surgical options include laparoscopic adrenal excision,
trans-sphenoidal surgery.
Complications\: hypertension, diabetes, obesity, metabolic syndrome, osteoporosis.
Article 🔍
A comprehensive topic overview

Introduction

Cushing's syndrome occurs because of prolonged exposure to elevated levels of either endogenous or exogenous
glucocorticoids.
The condition is associated with signi
essential.
1

Aetiology

Pathophysiology
Glucocorticoid production is regulated by the hypothalamic-pituitary-adrenal axis (Figure 1)\:
1. Corticotropin-releasing hormone (CRH) is secreted from the hypothalamus. This release is in
levels, time of day and serum cortisol levels.
2. CRH travels in the blood and binds to speci
adrenocorticotropic hormone (ACTH).
3. ACTH is released into the bloodstream and travels to the adrenal glands, where it binds to speci
adrenal cortex.
4. This binding of ACTH to the receptors stimulates the adrenal cortex to release cortisol into the bloodstream, where it has a
wide range of e
overproduction of cortisol.
Figure 1. Hypothalamic-Pituitary-Adrenal axis diagram
The functions of cortisol include\:
The synthesis of glucose from non-carbohydrate sources (known as gluconeogenesis), resulting in increased levels of
glucose in the blood.
Promoting the breakdown of proteins, which can result in muscle wasting in chronic states of cortisol elevation.
An initial surge in cortisol levels triggers lipolysis, however, chronically elevated cortisol promotes lipogenesis.
Inhibition of the production of several in
Reduction in bone formation (chronically elevated levels of cortisol can result in osteoporosis).
In high concentrations, cortisol exhibits mineralocorticoid e
increasing potassium excretion.
Causes of Cushing's syndrome
Exogenous
The most common cause of Cushing's syndrome is the use of exogenous glucocorticoids (e.g. prednisolone,
hydrocortisone).
Endogenous
independent.
Endogenous Cushing's syndrome can be further sub-categorised as either corticotropin-dependent or corticotropin-
Corticotropin-dependent Cushing's syndrome accounts for 80-85% of cases.
2
Pituitary adenomas account for 80% of corticotropin-dependent Cushing's syndrome (known as Cushing's disease).
Ectopic production of corticotropin (e.g. small cell lung cancer) accounts for around 20% of corticotropin-dependent
Cushing's syndrome.
2
The most common causes of corticotropin-independent Cushing's syndrome are adrenal adenomas and adrenal
carcinomas.
2

Clinical features

History
Typical symptoms of Cushing's syndrome include\:Weakness
Facial fullness
Weight gain
Low mood
Decreased libido
Polydipsia
Polyuria
Increased frequency of infections
Clinical examination
Typical clinical
Truncal obesity
Bu
Supraclavicular fat pads
Moon facies
Proximal muscle wasting
Hypertension
Oedema
Headaches, visual
Figure 2. Moon facies

Investigations

Laboratory investigations
Relevant laboratory investigations include\:
Full blood count (white cell count may be raised due to glucocorticoid e
Urea and electrolytes (hypokalemia, hypernatraemia)
Con
Several investigations are typically required to accurately diagnose a patient with Cushing's syndrome.24-hour urinary free cortisol
Cortisol excretion of more than three times the upper limit of normal is strongly suggestive of Cushing's syndrome.
Low-dose dexamethasone suppression test
This test is particularly useful when screening patients for Cushing's syndrome, as it is less cumbersome than a 24-hour
urinary free cortisol collection.
1mg of dexamethasone is administered at 11pm and then serum cortisol is measured at 8am the following morning.
If a patient has only mild Cushing's syndrome, it may not be detected using this test alone.
Late-night salivary cortisol measurement
This simple and reliable test relies on the fact that in healthy individuals, the level of cortisol decreases in the evening
compared to the morning.
4
In the case of Cushing's syndrome, this normal diurnal variation is absent.
Identifying the underlying cause
Plasma ACTH
Levels of ACTH have a diurnal variation, with the plasma concentration being highest at 8am and lowest at midnight.
An elevated ACTH level alongside a raised serum cortisol level suggests a diagnosis of ACTH-dependent Cushing's
syndrome (see causes above).
4
An undetectable ACTH level alongside a raised serum cortisol level suggests a diagnosis of ACTH-independent Cushing's
syndrome (see causes above).
5
High-dose dexamethasone suppression test
This test is indicated if ACTH levels are detectable.
The test is useful for di
A reduction of basal urinary free cortisol of greater than 90% supports a diagnosis of a pituitary adenoma (ectopic ACTH
causes less suppression).
Inferior petrosal sinus sampling
Inferior petrosal sinus sampling (IPSS) is an invasive procedure in which ACTH levels are sampled from veins that drain the
pituitary gland.
These ACTH levels are compared with peripheral ACTH levels to determine whether a pituitary tumour is responsible for
ACTH-dependent Cushing's syndrome.
This method is used when neuroimaging along with the previous investigations has been insu
(e.g. no visible lesion on neuroimaging of the pituitary).
Imaging
Relevant imaging investigations include\:
MRI of the pituitary\: to con
CT chest and abdomen\: to identify suspected adrenal tumours or other sources of ectopic ACTH production

Management

Exogenous Cushing's syndrome
Management of exogenous Cushing's syndrome involves reviewing the patient's current glucocorticoid treatments and
reducing doses where possible (often with steroid-sparing immunosuppressive agents).
Endogenous Cushing's syndrome
De
medical therapies to reduce cortisol production are often used in the interim period to stabilise the patient prior to
de
6Medical management
Ketoconazole, metyrapone and mitotane all directly inhibit glucocorticoid synthesis and secretion in the adrenal gland.
7
As a result, these medications can be used to temporarily reduce glucocorticoid levels to help prepare the patient for
de
In some cases, these medications can be used long-term for patients who are too un
management.
Surgical management
Surgical management di
Adrenal tumours (e.g. adrenal adenoma)\: laparoscopic excision
Pituitary tumours\: trans-sphenoidal surgery (may also require adjunct radiotherapy)

Complications

Complications of Cushing's syndrome include\:
Hypertension
Diabetes
Obesity
Metabolic syndrome
Osteoporosis

References

Biller BM, Grossman AB, Stewart PM, et al; Treatment of ACTH-dependent Cushing's syndrome\: a consensus statement. J
Clin Endocrinol Metab. 2008 Apr 15. Available from\: [LINK]
Dr Roger Henderson. Patient.info. Cushing's syndrome. Edited July 2015. Available from\: [LINK]
Boscaro M, Arnaldi G; Approach to the patient with possible Cushing's syndrome. J Clin Endocrinol Metab. 2009
Sep94(9)\:3121-31. Available from\: [LINK].
Pecori Giraldi F, Invitti C, Cavagnini F; The corticotropin-releasing hormone test in the diagnosis of ACTH-dependent
Cushing's syndrome\: a reappraisal. Clin Endocrinol (Oxf). 2001 May 54(5)\:601-7. Available from\: [LINK]
Stratakis CA; Cushing syndrome caused by adrenocortical tumours and hyperplasias (corticotropin- independent Cushing
syndrome). Endocr Dev. 200813\:117-32. doi\: 10.1159/000134829. Available from\: [LINK]
Shalet S, Mukherjee A; Pharmacological treatment of hypercortisolism. Curr Opin Endocrinol Diabetes Obes. 2008
Jun15(3)\:234-8. Available from\: [LINK]
Newell-Price J, Bertagna X, Grossman AB, et al; Cushing's syndrome. Lancet. 2006 May 13367(9522)\:1605-17. Available from\:
[LINK].
Image references
Figure 1. GeekyMedics. Hypothalamic-Pituitary-Adrenal axis diagram.
Figure 2. Moon Facies. Ozlem Celik, Mutlu Niyazoglu, Hikmet Soylu and Pinar Kadioglu. License\: [CC BY]. Available from\:
[LINK]
Figure 3. Striae. Masry. License\: [CC BY-SA]. Available from\: [LINK]

Acromegaly
Addison's Disease (Primary Adrenal Insu
Growth Hormone De
Hyperparathyroidism

Cushing's Syndrome

Introduction

Aetiology

Clinical features

Investigations

Management

Complications

References

Test yourself

Contents

Cushing's Syndrome

Introduction

Aetiology

Clinical features

Investigations

Management

Complications

References

Related notes

Test yourself

Contents