What are the effects of chronic Prednisone (corticosteroid) use on the Hypothalamic-Pituitary-Adrenal (HPA) axis?

From the Guidelines

Chronic prednisone use suppresses the hypothalamic-pituitary-adrenal (HPA) axis, which can lead to adrenal insufficiency when the medication is discontinued, and patients on prednisone for more than 3-4 weeks should undergo a gradual taper to allow the HPA axis to recover, with stress-dose steroids considered during periods of stress, as recommended by the most recent guidelines 1.

Key Points

• The risk of HPA axis suppression increases with higher doses (typically >7.5 mg prednisone daily), longer duration of therapy (generally >3 weeks), and evening dosing.
• When discontinuing prednisone after chronic use, a gradual taper is essential to allow the HPA axis to recover, with tapering schedules typically involving reducing the dose by 10-20% every 1-2 weeks, with slower reductions at lower doses (below 5-10 mg) 1.
• During periods of stress (such as surgery, trauma, or severe illness), patients with potential HPA suppression may require stress-dose steroids (typically hydrocortisone 50-100 mg IV every 8 hours) to prevent adrenal crisis, although the evidence for this practice is limited 1.
• Recovery of the HPA axis can take months to over a year after discontinuation of chronic prednisone therapy, and some patients may benefit from morning cortisol testing or ACTH stimulation testing to assess adrenal function during and after tapering 1.

Management Considerations

• Patients on chronic prednisone therapy should be informed about the risk of adrenal insufficiency and the importance of gradual tapering when discontinuing the medication.
• During periods of stress, patients with potential HPA suppression should be closely monitored for signs of adrenal crisis, and stress-dose steroids should be considered if necessary.
• The decision to administer stress-dose steroids should be based on individual patient factors, including the dose and duration of prednisone therapy, as well as the severity of the stressor event.
• Hydrocortisone is the preferred steroid for stress-dose coverage, although dexamethasone may also be considered in some cases 1.

From the FDA Drug Label

The maximal activity of the adrenal cortex is between 2 am and 8 am, and it is minimal between 4 pm and midnight. Acting primarily through the hypothalamus a fall in free cortisol stimulates the pituitary gland to produce increasing amounts of corticotropin (ACTH) while a rise in free cortisol inhibits ACTH secretion. Normally the HPA system is characterized by diurnal (circadian) rhythm Serum levels of ACTH rise from a low point about 10 pm to a peak level about 6 am. Increasing levels of ACTH stimulate adrenocortical activity resulting in a rise in plasma cortisol with maximal levels occurring between 2 am and 8 am. This rise in cortisol dampens ACTH production and in turn adrenocortical activity There is a gradual fall in plasma corticoids during the day with lowest levels occurring about midnight Corticosteroids can produce reversible hypothalamic-pituitary adrenal (HPA) axis suppression with the potential for corticosteroid insufficiency after withdrawal of treatment. Adrenocortical insufficiency may result from too rapid withdrawal of corticosteroids and may be minimized by gradual reduction of dosage This type of relative insufficiency may persist for up to 12 months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted.

Chronic Prednisone Use and the HPA Axis:

• Chronic prednisone use can lead to reversible hypothalamic-pituitary adrenal (HPA) axis suppression.
• The HPA axis is characterized by a diurnal rhythm, with maximal activity between 2 am and 8 am, and minimal activity between 4 pm and midnight.
• Corticosteroid insufficiency may occur after withdrawal of treatment, and can be minimized by gradual reduction of dosage.
• Adrenocortical insufficiency may persist for up to 12 months after discontinuation of therapy.
• In situations of stress during this period, hormone therapy should be reinstituted 2, 2.
• Alternate day therapy may help minimize HPA axis suppression by allowing for re-establishment of normal HPA activity on the off-steroid day 2.

From the Research

Chronic Prednisone Use and the HPA Axis

• Chronic prednisone use can suppress the hypothalamic-pituitary-adrenal (HPA) axis, leading to tertiary adrenal insufficiency (AI) 3
• The risk of HPA axis suppression is influenced by factors such as dose, frequency of administration, treatment duration, and prior systemic steroid therapy 4
• Low doses of prednisone (less than 5 mg daily) are likely to cause minimal or no HPA axis suppression, while high-dose prednisone use may result in significant suppression 4, 5

Recovery of the HPA Axis

• Spontaneous recovery of the HPA axis is usual for patients who are taking prednisone at daily doses of 5 mg or less 5
• The HPA axis recovery rate for patients on prednisone after interval testing was 66.5% 3
• There is no apparent advantage to recovering HPA axis function in converting to multiple-dosing hydrocortisone 3

Assessment of HPA Axis Dysfunction

• The response to adrenocorticotropic hormone (ACTH) stimulation, insulin-hypoglycemia, and metyrapone can be used to assess HPA axis dysfunction 6
• Basal cortisol levels and the response to low-dose ACTH stimulation can be used to predict an impaired function of the HPA axis 7
• Discordant responses to different testing procedures can occur in patients with suspected HPA dysfunction 6

Factors Influencing HPA Axis Suppression

• The dose of prednisone is a significant indicator of HPA axis function, with higher doses leading to greater suppression 5
• The duration of therapy and the total cumulative steroid dose do not appear to be significant indicators of HPA axis recovery 5
• Prior systemic steroid therapy can influence the risk of HPA axis suppression 4