For people with Addison's adrenal insufficiency, medication is used to replace the cortisol that would usually be produced by the adrenal glands. Here we explore a little more about what the medication does, and what options are available to you.

• Introducing replacement glucocorticoid medication
• What are the main options for steroid replacement medication in the UK?
• Hydrocortisone
• Prednisolone
• What is ‘normally’ prescribed in the UK and how much?
• What does the research say today?
• What is right for me?
• The Patient Voice
• Other medications in development

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Introducing replacement glucocorticoid medication

Functioning adrenal glands make cortisol in a specific daily rhythm (circadian rhythm) and so replacement medication ideally needs to aim to follow this same pattern to help you to wake normally, get up and out of bed, carry out your daily routine, feel tired at bedtime and sleep through, all without the risk of adrenal crisis.

For all people with a diagnosis of Addison's and adrenal insufficiency, regardless of medication choice, it is important to find the correct dose of glucocorticoid replacement that avoids adrenal crisis, whilst not causing the long-term effects of steroid overreplacement, which includes obesity, increased cardiovascular risks and reduced bone density. More than that though, people with adrenal insufficiency report that the dose of their replacement medication affects appetite, energy levels, mood and mental health, among other factors; so there are many reasons to try and get it right.

In the general population, it is recognised that cortisol secretion rates vary between people, based on a number of factors (age, gender, body weight, activity, physical and psychological stress), which is one of the biggest challenges when looking to effectively replace cortisol levels in people with adrenal insufficiency.

In the UK there are two main options of glucocorticoid replacement medication: Hydrocortisone and Prednisolone.

There are Pros and Cons to both and we try and explain them below. It is a complicated subject with many factors to consider, but we have tried to keep it clear and as easy to understand as we can, to help you make an informed decision with your endocrinologist.

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What are the main options for steroid replacement medication in the UK?

There are 2 main glucocorticoid medications available to Addison's and adrenal insufficiency patients in the UK.

They are similar in chemical structure, but the body treats them very differently and so they are taken at different doses, and in a different medication regimen. This means that one or the other may be more suitable for you as an individual.

Other, infrequently used options

Dexamethasone: Like prednisolone, this has a longer ‘half-life’ so lasts a long time in the body. However, the fact that Dexamethasone is very potent (i.e. has a strong effect with a very small dose), it makes it harder to control the dosage with tablets, and people can end up having too high cortisol levels (being overdosed), so it isn’t recommended in most circumstances.

Hydrocortisone vs Prednisolone Potency (strength) Comparison 

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Hydrocortisone

This is the same chemical compound as the cortisol that is produced by functioning adrenal glands (‘natural cortisol’). A suitable dose of hydrocortisone will produce sufficient cortisol levels for 4 – 6 hours in most people, under ‘normal’ circumstances. This is because the body gets rid of it quite quickly (i.e. it does not have a long ‘half-life’).

As the body breaks down hydrocortisone quickly, replacement ‘top-up’ doses are needed throughout the day to prevent cortisol levels from dropping to a level where an adrenal crisis is possible. This means people typically need to take 2, or more often, 3 doses of hydrocortisone in 24 hours. They are usually taken on waking at about midday and 5-6pm in the evening. It takes 20-30 minutes to start to absorb a single hydrocortisone tablet from your stomach.

This means that the cortisol levels in the blood of someone on hydrocortisone will rise with their first dose, then drop, rise with their 2^nd dose, then drop and rise with their third dose then drop.

The result is cortisol levels in the blood that are not similar to the ‘natural’ cortisol curve, in that they rise, drop, rise and drop, rise and drop. This can lead to fluctuating ‘low cortisol’ symptoms, potentially significantly impacting quality of life. Taking 3 doses can affect levels of patient compliance and satisfaction.

Dosage

Tablets come in 2.5mg, 5mg and 10mg doses. A ‘common’ dose will be 20mg/day, 10mg in the morning, 5mg at lunch and 5mg in the early evening.

People can need quite different doses of these tablets, and this depends on body size, age and level of activity. Your endocrinologist will have a reasonable idea of a good starting dose for you, and then your medication can be fine-tuned over a few weeks and months to get you feeling as good as possible. This might involve taking your medication at slightly different times of day, as well as changing the dose.

Most people who are prescribed hydrocortisone will take their medication in tablet form, but there is a minority who, due to difficulty absorbing the medication through the gut, will not be able to follow this route. Some centres in the UK have offered continuous subcutaneous hydrocortisone infusion, which is delivered via a pump, into the subcutaneous fat on the abdomen. Hydrocortisone is given slowly throughout a 24-hour period that matches the usual circadian rhythm.

The NHS will only fund this delivery of hydrocortisone in specific circumstances, where no other medication options are successful. There is a risk of infusion site infection which must be managed carefully by the person.

Lower fludrocortisone dose for people with Addison's: Hydrocortisone replaces missing cortisol but also has some hormonal action that overlaps that of aldosterone, another steroid hormone that is missing in people with primary adrenal insufficiency (Addison’s disease).   However, people with Addison’s disease also need to take another medication called fludrocortisone, which replaces their aldosterone, even when taking hydrocortisone, although they can take a lower dose than if they are on prednisolone.

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Prednisolone

This is a synthetically made cortisol but has a very similar chemical compound to natural cortisol. You can see that the chemical structure is identical, apart from where 2 of the carbon molecules have a double bond between them, rather than a single bond. This difference gives Prednisolone a longer ‘half-life’ than hydrocortisone and also increases its strength (‘potency’), i.e. less of it is needed to achieve the same effect.

Due to the longer half-life, just one dose of prednisolone is required in the morning, and it is degraded gradually during the day, producing a ‘curve’ similar to the natural cortisol curve in someone with fully functioning adrenal glands. Like hydrocortisone, it is rapidly absorbed into the gut.

The fact that prednisolone lasts for longer can be helpful for patients who continue to experience low cortisol symptoms whilst taking hydrocortisone and can also be helpful when patients are experiencing vomiting, as just one dose is required to be absorbed to maintain cortisol levels during a 24-hour period.

Dosage

As prednisolone is more potent than hydrocortisone, much less is needed. Dosage comparisons suggest that 3 to 4mg is equivalent to 20mg of hydrocortisone. 

Tablets come in 5mg and in some cases 1mg (in the UK, though not always in other countries). Availability of the 1mg tablet is key if the dosage is to be ‘fine-tuned’ to its optimum level for each individual. 

Clinical studies have shown that to be effective in its actions, prednisolone is needed at different strengths/potencies in different tissues of the body. This is a complicated factor that makes the optimum dosage harder to define. Recent evidence suggests that 5mg is excessive for most people, and explains why prednisolone has been thought of as causing too much osteoporosis. Often it is suggested that 4mg daily is a good starting dose and that many could then reduce to 3mg if they feel well.

Fludrocortisone for AD patients: Patients on prednisolone may need to take a higher dose of fludrocortisone than they would need to if they were on hydrocortisone, although this is more marked with those on dexamethasone.

Emergency injection and Sick Day Rules for people taking prednisolone

There are Sick Day Rules for people prescribed prednisolone. Some endocrinologists advise ‘up-dosing’ using prednisolone and some advise ‘up-dosing’ with hydrocortisone. You should discuss this with your endocrinologist as it will affect what prescription you require.

There is no injectable version of prednisolone, so in the management of an adrenal crisis, an emergency injection of 100mg hydrocortisone IM will always be the course of action.

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What is ‘normally’ prescribed in the UK and how much?

In the UK, hydrocortisone has been used for treating people with Addison's and adrenal insufficiency for over 75 years so there is evidence to show a low risk of long-term use complications. It is therefore significantly more often prescribed as the first course of treatment following diagnosis with adrenal insufficiency.

In 2016, 91.8% of adrenal insufficiency patients were taking hydrocortisone and 3.7% were taking prednisolone. We don't have up-to-date figures but it is likely that this will have increased slightly, but not significantly.

In 2016, the British Endocrine Society ran a debate with two eminent endocrinologists arguing for and against using prednisolone as the first treatment choice for adrenal insufficiency. Following the debate, 60% of the medical audience (over 400 people) voted against using prednisolone as the first treatment choice for adrenal insufficiency and 37% voted for it.   

As prednisolone is less often prescribed, fewer laboratories in the UK can measure prednisolone levels in a day curve test, than can measure hydrocortisone.

Children

Hydrocortisone is the first-line replacement glucocorticoid of choice in children as it has a shorter half-life and less impact on growth compared to Prednisolone. Prednisolone would only be recommended if growing had stopped. There is also concern that Prednisolone's longer half life is more likely to cause side effects in children such as weight gain and impact bone mineral density. This is in line with NICE and BSPED guidance. Occasionally, Prednisolone is used in adolescence if adherence may be an issue. 

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What does the research say today?

Hydrocortisone has been the first-line treatment for adrenal insufficiency since the 1940s. There are studies that have compared prednisolone to hydrocortisone, but the results are only relevant for the doses compared.  

However, further and more recent research suggests that the effects on mortality factors (cardiovascular risk) and morbidity factors (osteoporosis) are related to the dose of prednisolone and the ‘overreplacement’ of cortisol. 

The suggestion is that by better testing using Prednisolone Day Curves, the dosage required can be reduced to a minimum effective dose, suggested to be between 1.8mg and 4.2mg daily (Williams EL, Choudhury S, Tan T, & Meeran K. Prednisolone replacement therapy mimics the circadian rhythm more closely than other glucocorticoids. Journal of Applied Laboratory Medicine 2016 1 152–161. (https://doi.org/10.1373/jalm.2016.020206) 

There are endocrinologists who favour prednisolone and those who favour hydrocortisone, and there are good reasons for both options. Most would agree that more evidence is required regarding the dosage for both medications and also more research is needed to look at the long-term efficacy and side effects of prednisolone.

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What is right for me?

After initial diagnosis and starting on a medication regimen with hydrocortisone, it is normal and expected that it may take some time to find both the correct dose and the correct timing of when you take your medication. It is important to discuss how you feel on hydrocortisone with your endocrinologist.

The Patient Voice

Our Chair of Trustees, Dom Hargreaves, has recently recorded his medication journey and a switch from hydrocortisone to prednisolone, which you may find of interest: The Switch

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Other medications in development

Pharmaceutical companies have been looking to develop different hydrocortisone medications that are ‘slow-release', so only need to be taken once a day.