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The symptoms and signs described are suggestive of Cushing's syndrome. Although a 24 hour urinary free cortisol can be used as an intial investigation to confirm cushing's syndrome, cortisol can be raised by  high fluid intake, stress and medications. There are also difficulties with collecting 24 hour urine so an overnight dexamethasone suppression test is preferred these days. 
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24 hour urinary free cortisol
QuestionChoice
9 am cortisol levels are the initial screening test for primary adrenal insufficiency. Given that serum cortisol levels match the circadian rhythm, a serum 9 am cortisol has no use as a screening test for Cushing's syndrome
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9 am cortisol
QuestionChoice
Cushing's syndrome can be caused by an adrenal lesion such as an adenoma or carcinoma, and imaging may help confirm this diagnosis. However, this would usually be done once a diagnosis of Cushing's syndrome has been confirmed biochemically
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CT adrenal glands
QuestionChoice
Cushing's disease is Cushing's syndrome caused by a pituitary adenoma. An MRI would be indicated to confirm the diagnosis of a pituitary adenoma; however, this would usually be done once a diagnosis of Cushing's syndrome has been confirmed biochemically
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MRI pituitary gland
QuestionChoice
The symptoms and signs described are suggestive of Cushing's syndrome. The ovrnight dexamthasone suppression test is preferred these days to 24 hour urinary free cortisol given it's practicality. 
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Overnight dexamethasone suppression test
QuestionComment
Although correct, a low-dose dexamethasone test is now used more often in place of the 24h urinary free cortisol.
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Spend more time at GP because you cannot do low dose dex test at GP that is usually done by endocrine specialist 
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Elwyn D.
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oh we love a quesmed'er who is serious enough to have their actual name and leave a beautiful comment like this!
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Witzelsucht
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Defibrillator WBC
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why not 9 am cortisol? 
22611
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in cushings cortisol will be elevated. at 9 am is when your cortisol is naturally highest due to its diurnal variation. so if a 9 am cortisol comes back elevated, it doesn't really tell you if someone has cushings. 
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Botox Stasis
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Raphael de la Ghetto
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The two most commonly used tests are:
overnight dexamethasone suppression test
this is the most sensitive test and is now used first-line to test for Cushing's syndrome
patients with Cushing's syndrome do not have their morning cortisol spike suppressed
24 hr urinary free cortisol
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Intravenous Prone
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# Summary

Cushing's syndrome is an endocrine disorder characterised by excess glucocorticoids, which can have ACTH-dependent or independent origins. Clinically, patients may present with symptoms such as proximal myopathy, obesity, hypertension, and various dermatological changes. Diagnosis is made through investigations such as a 24-hour urinary free cortisol test and low-dose dexamethasone suppression test, alongside imaging for localisation. Management includes medical therapy to reduce cortisol levels, surgery, radiotherapy, and the need for post-operative steroid replacement in successful cases.

# Definition

Cushing's syndrome is an endocrine disorder characterised by excess glucocorticoids, often resulting in distinctive clinical symptoms and signs. It is important to distinguish Cushing's syndrome from **Cushing's disease,** which specifically refers to glucocorticoid excess caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary tumour.

# Epidemiology

Cushing's syndrome is a relatively rare condition, estimated to affect 2 to 3 per million people each year. It is more common in adults, particularly women, with a peak incidence between 25-40 years.

# Aetiology

The causes of Cushing's syndrome can be divided into ACTH-dependent and ACTH-independent:

- **ACTH-dependent disease:** This is caused by excessive production of ACTH, most often due to a pituitary tumour (Cushing's disease) or ectopic ACTH-producing tumours (e.g. lung carcinoids, thymic carcinoids, and others).
- **ACTH-independent:** This arises from primary adrenal diseases, such as adrenal adenomas or adrenal carcinomas, which produce excess cortisol independently of ACTH stimulation. Exogenous steroids can also cause ACTH-independent Cushing's.

# Signs and Symptoms

Clinical features of Cushing's syndrome may include:

- Proximal myopathy
- Striae and easy bruising
- Osteoporosis and fractures
- Glucose intolerance or diabetes mellitus
- Obesity, particularly truncal or "centripetal" obesity
- Hypertension
- Hypokalaemia
- Facial changes, such as moon face and acne
- Hirsutism in women
- Fat redistribution leading to interscapular and supraclavicular fat pads
- Thin extremities due to muscle wasting
- Thin, fragile skin
- Erectile dysfunction in men
- Psychological issues, such as depression or cognitive dysfunction
- Osteopenia or osteoporosis

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# Differential Diagnosis

Key differentials include conditions that may cause similar clinical features, such as:

- Metabolic syndrome
- Polycystic ovary syndrome
- Adrenal insufficiency
- Alcohol excess
- Depression. 

Distinguishing these conditions often relies on biochemical and imaging investigations.

# Investigations

To confirm the diagnosis and identify the cause:

Biochemical evidence of cortisol excess:

- 24-hour urinary free cortisol test
- Low-dose Dexamethasone suppression test:
  - Not suppressed by low dose - Cushing’s syndrome (e.g. exogenous steroid use)
  - Not suppressed by low dose but suppressed by high dose - Cushing’s disease (pituitary source)
  - Not suppressed by low dose or by high dose dexamethasone – ectopic ACTH (not under axis control, likely ACTH-producing tumour)

Localisation of the source:

- Plasma ACTH levels to distinguish between ACTH-dependent and independent causes
- High-dose dexamethasone suppression test for suspected Cushing's disease
- Inferior petrosal sinus sampling for suspected pituitary cause
- MRI of the pituitary and/or CT of chest and abdomen for tumour localisation


# Management

Management of Cushing's syndrome varies according to the underlying cause and may involve a combination of medical, surgical, and radiotherapy options:

- **Medical Management:** Initial therapy often involves medications to decrease cortisol levels. These include Metyrapone, an inhibitor of cortisol synthesis; Ketoconazole, an adrenolytic agent; Mifepristone, a glucocorticoid receptor antagonist; and Pasireotide, a somatostatin analog.

- **Surgical Management:** Resection of the pituitary tumour is the treatment of choice for Cushing's disease, often after initial control of hypercortisolaemia with medical therapy to improve surgical outcomes.
  - NB: Old treatment for Cushing's disease used to be bilateral adrenalectomy, which has risk of developing into Nelson syndrome - enlarging of an adrenocorticotropic hormone-producing tumour in the pituitary gland.

- **Radiotherapy:** May be considered for cases where hypercortisolaemia persists post-surgery, or in cases where surgery is not possible or declined.

Successful treatment of Cushing's disease leads to cortisol deficiency and subsequently, steroid replacement post-operatively is essential. Patients need to carry a steroid card and ideally wear a medic alert bracelet in case of acute illness or emergency situations.

Patients unfit for surgery or with unresectable lesions are managed with medical therapy alone.

# References

[BNF - Cushing's syndrome](https://bnf.nice.org.uk/treatment-summaries/cushings-syndrome/#:~:text=Cushing's%20syndrome%20results%20from%20chronic,%2C%20ectopic%20ACTH%2Dsecreting%20tumours.)
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A typical appearnce of hirsutism in a woman with a cushingoid face.
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Abdominal striae  and central adiposity seen in a  gentleman with cushings.
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The diagnosis of Cushing's syndrome can be confirmed using a 24-hour urinary free cortisol test, which measures the amount of cortisol excreted in urine over a 24-hour period. Elevated levels of urinary free cortisol are indicative of hypercortisolism, supporting the diagnosis of Cushing's syndrome.
A 45-year-old woman presents to her General Practitioner (GP) with weakness in her shoulders and hips. She also reports an unintentional weight gain of 5kg over the last three months and associated easy bruising.

On examination, she is hypertensive, with central adiposity and violaceous striae are present on her abdomen.

She is subsequently referred to an endocrinologist.

Which of the following is the best initial investigation given the likely underlying diagnosis?
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