Cushing's syndrome is a condition caused due to an increase in the cortisol hormone levels in our body. In this article, the author explains the aetiology, clinical manifestations, biomedical confirmation and treatment of Cushing's syndrome.

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Cushing’s syndrome

Cushing’s syndrome is an endocrine disorder caused by hypersecretion of adrenocorticotropic hormone (ACTH) leading to the release of high levels of cortisol.

Exogenous Cushing's syndrome, on the other side, is caused by the increased administration of synthetic steroids that have glucocorticoid activity. The exogenous form is a common cause of Cushing's syndrome, especially in patients with chronic diseases such as asthma.

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Aetiology

The aetiology of endogenous Cushing's syndrome can be classified as - ACTH-dependent and ACTH-independent.

ACTH-dependent Cushing's Syndrome

ACTH-dependent forms are associated with excessive production of ACTH, leading to bilateral adrenocortical hyperplasia and hypertrophy of the adrenal gland. The enlarged adrenal gland may lead to micronodular or macronodular changes.

Pituitary-dependent Cushing's syndrome or Cushing's disease is the most common form, responsible for around 80% of all cases. Women between the age of 25 and 40 years are usually affected.

Other ACTH-dependent Cushing's syndrome forms include ectopic ACTH syndrome and ectopic corticotropin-releasing hormone CRH syndrome (a rare condition).

ACTH-independent Cushing's Syndrome

ACTH-independent Cushing's Syndrome is characterised by low levels of ACTH which is mainly caused by excessive secretion of adrenal glucocorticoids or the exogenous administration of glucocorticoids. Apart from glucocorticoids, in some cases, androgens and steroid precursors may be elevated.

Adrenal adenoma or carcinoma is a common cause of ACTH-independent Cushing's Syndrome. Other causes include bilateral macronodular hyperplasia, McCune-Albright syndrome, ACTH independent macronodular adrenal hyperplasia, primary pigmented nodular adrenocortical disease (PPNAD), and exogenous glucocorticoid administration.

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Clinical manifestations

The clinical manifestations of Cushing’s syndrome reflect the chronic exposure to excess glucocorticoids and are mainly determined by the extent and duration of glucocorticoid exposure.

Cushing’s syndrome shows a broad spectrum of manifestations from mild disease to florid condition. Clinical features may include:

1. Weight gain
2. Fatigue and weakness.
3. Delayed wound healing, easy bruising.
4. Loss of height, depression.
5. Loss of libido and erectile dysfunction in males.
6. Irregular menstrual cycles, amenorrhea in females, infertility.
7. Hyperhidrosis
8. Biparietal visual loss in cases with pituitary adenoma.
9. Recurrent fungal and bacterial infections.
10. Difficulty in combing hair or rising from a sitting position.
11. Cognitive dysfunction, depression.
12. Back pain, bone pain, severe osteopenia, and bone fractures.
13. History of hypertension, peptic ulcer disease, and diabetes.

Symptoms specific to endogenous Cushings:

1. Headaches, polyuria, nocturia, visual problems, or galactorrhea seen in ACTH-producing pituitary tumours.
2. Hyposomatotropism, hypothyroidism, hyperprolactinemia or hyperprolactinemia, hypogonadism due to tumour mass effect.
3. Rapid progression of symptoms of increased glucocorticoid levels along with hyperandrogenism causing virilization in women or feminization in men due to underlying adrenal carcinoma.

Physical examinations can reveal:

1. Buffalo torso
2. Moon facies
3. Thin arms and legs
4. Acne, hirsutism
5. Proximal muscle weakness of the shoulder and hip girdle muscles
6. Paper-thin skin
7. Abdominal pain and abdominal striae

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Biochemical confirmation 

Hypercortisolaemia, loss of the normal circadian rhythm of cortisol secretion, and disturbed feedback of the hypothalamic-pituitary-adrenal (HPA) axis are the main biochemical features of Cushing's syndrome. The confirmatory tests for Cushing’s syndrome are based on these principles.

Late-night serum or salivary cortisol, urinary free cortisol and low-dose dexamethasone suppression test are the major tests which help diagnose Cushing’s syndrome. Second-line tests such as midnight serum cortisol and the dexamethasone-CRH test may be required in patients with equivocal results.

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Differential diagnosis 

Once Cushing's syndrome is confirmed, the next step is differential diagnosis to differentiate between ACTH-dependent and ACTH-independent causes. Differential diagnosis is usually made by measuring plasma ACTH.

An inappropriately normal or elevated ACTH level (>20 pg/ml, 4.4 pmol/L) is suggestive of an ACTH-dependent form of Cushing’s syndrome. While ACTH levels <5 pg/mL (1.1 pmol/L) suggest ACTH-independent Cushing’s syndrome.

Modern two-site immunoradiometric assays are recommended as they are more sensitive than the older radioimmunoassays.

Further evaluation of ACTH-dependent Cushing's syndrome

Invasive testing such as bilateral inferior petrosal sinus sampling is the "gold standard" to differentiate Cushing's disease and an ectopic source of ACTH. Non-invasive tests include the high-dose dexamethasone suppression test and the corticotrophin-releasing hormone test.

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Treatment

After accurate differential diagnosis, treatment and management strategies should be structured around resolving the underlying cause of Cushing’s syndrome.

Hypercortisolism should be controlled. Transsphenoidal microadenomectomy is the treatment of choice for ACTH-producing pituitary tumours. Surgery is aimed at a permanent cure and can resolve hypercortisolism along with the clinical consequences.

However, following an individualised approach as per the patient’s condition is recommended. So, radiation or the most commonly used medication includes adrenal enzyme inhibitors, but adrenolytic agents, drugs that target the pituitary, and glucocorticoid-receptor antagonists are also used when surgery is delayed, contraindicated, or unsuccessful can be the first-line treatment in some patients depending on the aetiology, clinical state, and patient’s choice.

Pituitary irradiation is used in patients with concerns regarding fertility and in whom a tumour is not found or those not cured by transsphenoidal resection.

After treatment, the signs and symptoms of adrenal deficiency should be corrected using steroid replacement therapy. Associated medical disorders such as diabetes mellitus, osteoporosis, and hypertension should also be managed.

The goal should be to avoid permanent dependence on therapy once the primary cause of Cushing’s syndrome is resolved. In patients with severe conditions, metabolic complications such as hyperglycaemia, hypokalaemia, and infections should be treated on priority.

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Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.