Today's Treatment

Treatment alternatives

Treatment of adrenal insufficiency involves replacing the hormones that the adrenal glands are not producing. The most commonly reported replacement regimen consists of 20-35 mg hydrocortisone administered in two or three divided oral doses per day1.  Hydrocortisone is currently only available in conventional oral dosage forms.

The available treatment alternatives differ in different countries but overall the following therapies are available:

  • Hydrocortisone  
  • Cortisone Acetate
  • Prednisone/ Prednisolone
  • Dexamethasone

In some cases, clinicians also use synthetic glucocorticoids to replace cortisol, rather than hydrocortisone. These mediciations, such as dexamethasone and prednisolone, were developed as anti-inflammatory drugs. They are much more potent with longer terminal half-lives and the risk of over-treatment and adverse effects is greater2. Cortisone acetate is similar to hydrocortisone.

It is notable that none of the currently available therapies has been the subject of specific clinical trials aimed at regulatory approval for adrenal insufficiency in the way that modern medicines are tested before approval.

The complex glucocorticoid system is difficult to mimic during oral replacement therapy and the lack of a serum marker of the biological activity of cortisol makes the dose titration and monitoring of replacement therapy difficult.

Balancing the optimal maintenance dose

The treatment of AI aims to achieve a physiological glucocorticoid systemic exposure-time profile, both during stable conditions and during stress when extra glucocorticoids are needed to be able to cope and survive.

The strategy often used is to give the lowest possible hydrocortisone maintenance dose to keep a balance between lack of symptoms associated with AI and the risk of developing adrenal crisis. Signs of suboptimal treatment such as fatigue and gastrointestinal symptoms are easy to observe and disappear immediately when the dose is increased. Overly high doses increase the risk of side-effects such as abdominal obesity, hypertension and glucose intolerance, which may to some degree explain the increased cardiovascular mortality rate observed in patients with primary AI3  and the development of osteoporosis4. These side-effects are not easily detected in the short-term dose titration perspective. The risk of overly high doses on an individual basis is therefore larger than chronic under-replacement.

Multiple daily dosing

Twice daily oral administration of hydrocortisone (morning and afternoon) results in very low serum levels of cortisol in between doses and in the early morning period as a consequence of a short elimination half-life of approximately 1.5 hours for cortisol5. This may explain some of the afternoon malaise in patients treated with glucocorticoid replacement and may be partly prevented by administration of hydrocortisone thrice daily6.

After administration of two-thirds of the daily dose in the morning and the remainder in the afternoon (i.e., at b.i.d. treatment), peak serum cortisol reaches levels above those in healthy subjects7. Similar data have been reported in children and adolescents with secondary AI using hydrocortisone administered at 08.00 and 18.00 hours8. The difficulties in matching a normal plasma/serum physiological cortisol profile was also demonstrated in the recent report by Simon et al 9 where the profile of an immediate release product was compared to a normal physiological cortisol profile. The regimen with the highest proportion of simulated patients within the physiological targets was 10 + 5 + 5 mg at 07.30, 12.00 and 16.30 h, respectively. However, even with this regimen, about 54%, 44% and 32% of patients would remain over- or under-treated at 08.00, 16.00 and 24.00 h, respectively. If the regimen is changed from t.i.d to b.i.d, a larger % of patients may meet the target in the late afternoon but this regimen causes a less advantageous therapy due to too high concentrations earlier and later in the day and low trough values in-between dosing, which is of particular importance during the day.

Results of lowering the dose of  hydrocortisone replacement therapy

Studies on short-term clinical response have been performed in which both the dose and the pattern of delivery have been adjusted. The estimated daily cortisol production rate in healthy subjects varies between 9 and 11 mg/m2, as reported in the literature (corresponding to approximately 15.5-19 mg per day in an adult subject)10. This is much lower than the most common replacement dose of hydrocortisone11. Studies have therefore been performed with the objective to study the metabolic effects of reducing the daily dose of hydrocortisone but still delivered as b.i.d. (twice daily) or t.i.d. (three times daily).

One study showed, on the basis of 24-hour sampling of serum cortisol and 24-h urinary free cortisol excretion, that 88% of the patients with primary AI required a change of treatment12. The patients’ daily dose was reduced by 30% on average (from 29.5 mg to 20.8 mg) and 56% of the patients changed dosing regimen from b.i.d. to t.i.d.. After 2 to 7 months, an increase in the serum concentration of osteocalcin, a bone formation marker, was demonstrated and indicated less glucocorticoid exposure, but without any other reported clinical changes.

Another trial studied the effects on cardiovascular function of a dose reduction from 30 mg to 15 mg of daily hydrocortisone in patients with secondary AI13. No attempt was made to change the dosing interval. After 3 months there was no change in body weight or any of the cardiovascular functional variables studied.

Another study reduced the dose of hydrocortisone on average by 50% in 11 patients with secondary AI14. At 6-12 months follow-up, a decrease in the mean body weight of 7.1 kg was observed. Fasting glucose and insulin levels were unaffected by this large dose reduction.

The results from these studies suggest that a mere dose reduction of hydrocortisone may affect bone metabolism and body weight (only shown in secondary AI), but not blood pressure or glucose metabolism to a significant extent. Conventional hydrocortisone tablets given b.i.d or t.i.d do not provide a normal physiological cortisol response.

Changing pattern of delivery of dose during the day

In an early attempt to reduce fluctuations in serum-cortisol concentrations and improve the well-being of patients with AI, the frequency of oral administration of hydrocortisone was increased from twice to thrice daily - with the same daily dose - in a small group of patients. This change was shown to improve their well-being, particularly during midday and afternoon15.

Using a subcutaneous infusion pump to re-establish the physiological circadian rhythm of cortisol, patients were able to reduce their total daily doses while experiencing improved levels of subjective health and well-being16. Changing the pattern of delivery using conventional immediate release formulations of hydrocortisone has, however, not been demonstrated to affect bone or glucose metabolism17.

In summary, it is demonstrated that the pattern of hydrocortisone delivery and the total plasma/serum cortisol exposure-time profile are critical for metabolic and neuropsychiatric effects of glucocorticoid replacement therapy.

When extra doses are needed

The total daily maintenance dose of hydrocortisone in AI is insufficient during a stressful event. The current concept has been to instruct patients with AI to double their daily dose of hydrocortisone during a minor illness18.

During a major illness or when oral administration of hydrocortisone is less likely to be helpful such as during vomiting and/or diarrhoea, treatment in an emergency unit is advocated with administration of saline infusion and parenteral hydrocortisone. The above concept has been considered safe, but recent data suggest that there may be an increase in the mortality rate from infectious diseases among patients with primary AI 19 and that current recommendations may be inadequate.



  1. Reynolds et al 2006
  2. McConnell et al 2002; Filipsson et al 2006
  3. Bergthorsdottir et al 2006
  4. Zelissen et al 1994
  5. Kehlet et al 1976; Scott et al 1978; Feek et al 1981
  6. Groves et al 1988
  7. Kehlet et al 1976; Scott et al 1978; Blomgren et al 2004
  8. DeVile et al 1997
  9. Simon et al 2010
  10. Esteban et al 1991; Kraan et al 1998
  11. Filipsson et al 2006; Reynolds et al 2006; Hahner et al 2007
  12. Peacey et al 1997
  13. Dunne et al 1995
  14. Danilowicz et al 2008
  15. Groves et al 1988
  16. Løvås et al 2007
  17. McConnell et al 2002; Suliman et al 2003
  18. Burke 1985; Arlt et al 2003
  19. Bergthorsdottir et al 2006