27th May 2025

Secondary adrenal failure

Background

In secondary adrenal insufficiency (SAI), the lack of steroid hormone production by the adrenal glands is secondary to inadequate pituitary or hypothalamic stimulation, resulting in reduced ACTH and corticotropin-releasing hormone (CRH) production respectively and thus reduced endogenous cortisol production.

Epidemiology

SAI is more common than primary adrenal insufficiency, with a prevalence of 150-280 per million, with a preponderance towards the female sex and commonly presenting between the 5th to 6th decades of life.

Aetiology

The most common cause is suppression of the HPA by exogenous steroid use, which may present clinically if steroids are rapidly weaned. Other causes of adrenal suppression include antipsychotics e.g. chlorpromazine and paraneoplastic steroid secretion.

Causes of SAI include:

• Congenital e.g. aplasia.
• Tumours e.g. adenomas, meningiomas, gliomas, craniopharyngiomas.
• Panhypopituitarism e.g. postpartum pituitary necrosis (aka Sheehan’s syndrome where hypovolaemic shock occurring in post-partum haemorrhage can cause pituitary infarction), pituitary apoplexy.
• Infection e.g. TB, meningitis, encephalitis, syphilis.
• Infiltration e.g. sarcoidosis, haemochromatosis, hypophysitis.
• Radiotherapy e.g. high-dose pituitary or whole-brain radiation.
• Surgery e.g. hypophysectomy.
• Trauma e.g. skull base fractures.
• Isolated ACTH deficiency.
• Corticotropin-releasing hormone (CRH) deficiency.

Diagnosis

The history is key to diagnosis of SAI, particularly regarding exogenous steroid exposure. Risk factors include systemic glucocorticoids, high doses and prolonged treatment (>3 weeks). Systemic glucocorticoid exposure can result in suppression of the HPA after 4-5 days, whereas intra-articular glucocorticoids can result in suppression in 1-4 weeks depending on dose and frequency. Adrenal crisis can occur when glucocorticoids are rapidly weaned, abruptly ceased or not increased in intercurrent illness. 

Symptoms may be similar to PAI, but signs on examination can suggest SAI. For example, in SAI, there may be Cushingoid features from long-term exogenous glucocorticoids such as moon facies, abdominal striae, dorsocervical fat pads and proximal muscle wasting. Another differentiating factor is the absence of hyperpigmentation, which is seen in PAI due to α-melanocyte-stimulating-hormone produced as a byproduct of ACTH. 

First-line investigations are as above for PAI, including FBC, U&Es, bone profile, LFTs, glucose, morning cortisol, ACTH and ACTH stimulation (synacthen) testing. The insulin tolerance test (ITT) can be impractical but can assess for partial adrenal suppression, where a normal ACTH stimulation test may be obtained (as the adrenal glands respond to ACTH stimulation) but ITT will reveal an inability of the adrenals to respond to the stress of hypoglycaemia induced in the ITT. Here 0.1 to 0.15 units/kg short-acting insulin IV is given, and plasma glucose and cortisol levels are measured at 0, 30 and 60 minutes. In partial adrenal suppression, despite symptomatic hypoglycaemia (<2.2 mmol/L) an insufficient cortisol response (<497 nmol/L) is mounted. An alternative to this test is the overnight metyrapone test.

Management

Management of SAI is the same as PAI with respect to acute crisis and in the context of intercurrent illness. There are also recommendations for tapering of glucocorticoids based on the length of treatment. The consensus is that if the duration is <1 week, glucocorticoids can be stopped without need to taper. For a duration of 1 to 3 weeks, tapering should be considered if the dose exceeds 7.5 mg prednisolone per day (or equivalent). For long-term regimens exceeding 3 weeks, it is recommended to taper by 2.5 mg prednisolone every 3 to 4 days until a physiological dose is reached. Once a dose of 2.5 mg prednisolone is reached, morning cortisol levels can be checked, and if normal, glucocorticoids can be stopped.

Complications

Complications are related to exogenous glucocorticoids as described above for PAI.