Expert Opinion
1. Introduction
2. Glucocorticoid production in normal humans
3. Glucocorticoid replacement therapy in patients with Addison’s disease: knowledge and experience
4. Expert opinion
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Glucocorticoid replacement therapy in patients with Addison’s disease
Venetsana Kyriazopoulou University Hospital, Division of Endocrinology and Metabolism, Department of Internal Medicine, Patras, 26500 Patras, Greece
One hundred and fifty years ago, Thomas Addison published his classic paper on the ‘Constitutional and Local Effects of Disease of the Supra-renal Capsules’, in which he described 11 patients with the disorder that would come to bear his name. Adrenal insufficiency is a rare disease, but its prevalence is increasing. The most frequent causes of adrenal insufficiency in western countries are autoimmune adrenalitis, but other causes include, tuberculosis systemic fungal infections, AIDS, metastatic carcinoma and isolated glucocorticoid deficiency. It is clear that autoimmunity precedes overt Addison’s disease by years, as in many autoimmune endocrine disorders [1,2,3]. Adrenocortical function is lost over a period of years as it progresses to overt Addison’s disease. This editorial discusses the controversial glucocorticoid replacement therapy in patients with Addison’s disease, and aims to provide a good review of literature and suggested guidelines for appropriate treatment of this disease.
Keywords: Addison’s disease, glucocorticoid replacement therapy
Expert Opin. Pharmacother. (2007) 8(6):725-729
1. Introduction
Although Addison’s disease is well known, and despite many papers having been published regarding disease management, the replacement dose of glucocorticoids in hypoadrenal patients remains controversial. This is because it is very difficult to mimic the normal physiological state of glucocorticoid production. Therefore, the aim is to find a treatment that mirrors endogenous glucocorticoids as much as possible. All endocrinologists would like the reassurance of a method of monitoring such treatment, to confirm that they are achieving this aim. It is known that glucocorticoid secretion includes both a diurnal and a pulsative ultradian rhythm, and that 11-B-hydroxysteroid dehydrogenase enzymes interconvert active cortisol and inactive cortisone. There is no evidence of an improvement of the quality of life of hypoadrenal patients with higher doses of steroids (in fact, this has sometimes caused adverse effects). However, there is no method to confirm the appropriate replacement dose of steroids. These complexities make the target of finding an ideal replacement therapy difficult. This editorial is an overview of the recent data about the author’s understanding of normal, endogenous glucocorticoid production, and an effort to apply the present knowledge available on gucocorticoid replacement therapy. The paper discusses the treatment of patients with Addison’s disease under every-day stress, as well as in the case of pregnancy. Finally, this paper also reports on interactions of glucocorticoids with other medications. Figure 1 describes the natural history of autoimmune adrenalitis with potential subclinical and clinical hypoadrenalism.
Genetic predisposition Adrenal cortex autoantibodies Normal
Asyptomatic
Syptomatic under stress ACTH = N
Clinical overt
ACTH = N
Hypotension
CORTISOL = N
CORTISOL =
Adrenocortical function
Hyperpigmentation ACTH =
CORTISOL =
RISK FOR ADRENAL CRISIS
1
Precipitating events: stress, infection, pregnancy
ACTH: Corticotropine hormone; N: Normal.
1: Increase; V: Decrease.
2. Glucocorticoid production in normal humans
The cortisol production rate in normal individuals is lower than previously believed [4]. The authors estimated in their study that the cortisol production rate is ~ 9.9mg/day. This result is in accordance with other studies [5,6], and the levels of cortisol are markedly lower than previously believed (12 - 15mg/day). Cortisol in humans is ~ 90% plasma protein-bound. Free cortisol has a diurnal variation. Cortisone is an inactive steroid without diurnal variation. The enzymes, 11-ß-dehydrogenase type 1 (11-ß-HSD-1) and type 2 (11-B-HSD-2), interconvert cortisol and cortisone. This cortisol/cortisone ratio is to be taken into account when considering optimal replacement therapy [7].
It is known that a natural cortisol peak occurs in humans early in the morning, and falls progressively to low levels in the evening [2]. Cortisol production has pulsatile and circadian rhythms. The implications of these observations have recently been reviewed [8,9], and will be summarised here. There are two types of glucocorticoid receptors: glucocorticoid receptors and mineralocorticoid receptors, with different occupancies, affini- ties and activation, depending on circulating ligands. Thus, the relative balance of activation between the two receptor types may change rapidly over the course of a cortisol pulse, such that differences in receptor distribution could allow pulses to carry different information to different tissues [7,8].
3. Glucocorticoid replacement therapy in patients with Addison’s disease: knowledge and experience.
The management of glucocorticoid deficiency remains controversial in literature [7], due to the inability to mimic the normal diurnal rhythm and ultradian pulsatility of cortisol secretion and cortisol response to daily stress in humans. The stable dose of oral steroids probably have different effects on steroid responsive enzymes and the peak cortisol concentration and absorption after oral administration differs. In one study (unpublished data), 4 and 5 h after oral administration of hydrocortisone 30 mg, serum cortisol levels were 4.0 µg/dl and 5.2 µg/dl, respectively.
Many methods have been used to find the optimal dose and pattern of glucocorticoid replacement in hypoadrenal patients, and marked interindividual variation has been observed in different papers [13,16]. However, there is no valid method that ensures appropriate replacement therapy.
To determine the appropriate drug and the appropriate dose to use, hepatic first-pass must be considered for oral treatment with glucocorticoids. The enzyme 11-B-HSD-1, found in the liver, has a high reductase capacity for reactivating cortisone to cortisol. Although it seems logical to use a combination of cortisone and cortisol as replacement therapy, it is known that very little orally administrated cortisone reaches the systemic circulation [10,11,12]. The
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maximum amounts of circulating cortisone are derived from 11-B-HSD-2 conversion of cortisol in the liver [10].
Hydrocortisone remains the most ideal drug of choice for replacement therapy, as it is very similar to endogenous glucocorticoids. It is a natural substrate for 11-B-HSD-2 conversion to cortisone in the kidney and the placenta. Endogenous cortisol production rate is ~ 10mg/day, which is lower than the standard replacement dose of 20 mg /day of hydrocortisone. However, these high doses are necessary, due to the large number of factors that change oral absorption. For Addison’s disease patients, the author recommends a dose of hydrocortisone 20 - 30 mg/day that is divided in two or three doses, with the last one early in the afternoon rather than in the evening. The rationale behind this is that if patients take most of their hydrocortisone in the morning, and the last dose early in the afternoon, there will be a period of low receptor occupancy, at least overnight. It seems to be of no clinical significance if the morning dose is taken after an overnight fast or after breakfast [13].
It is important to consider the metabolism of other synthetic glucocorticoids when considering their use as replacement therapy. Inactivation of prednisolone by 11-B-HSD-2 is more effective than that of cortisol, but 11-B-HSD-2 has a lower inactivation capacity for dexamethasone. Prednisone is the cortisone equivalent to prednisolone, and relies on convertion by 11-ß-HSD-1 in the liver for bioactivity [17].
An algorithm for glucocorticoid replacement therapy in patients with Addison’s disease is proposed in Figure 2. The authors respects other differing opinions, and acknowledge the fact that there is limited evidence to support any recommendation. When considering replacement therapy, the endocrinologist must take into account the clinical history and the general well-being of the hypoadrenal patient. Although some patients feel better when treated with pharmacological doses of glucocorticoids, it is inappropriate to continue with doses higher than the recommended dose. Skin pigmentation and postural hypotension (characteristics of untreated Addison’s disease), and excessive weight gain (Cushingoid) are clinical signs of over- or under-treatment.
Patients should be monitored at every 6 - 8 week interval at the beginning of therapy, and following this, two or three times a year. Recommendations should be given about the interactions of glucocorticoid with other medications. Rifampicin increases the clearance of cortisol, and it is well documented that adrenal crisis may be precipitated in patients treated with rifampicin [18-20], who are receiving corticosteroid replacement therapy for primary adrenal failure. Phenytoin has a similar interaction [7]. Therefore, patients must be advised to take double or triple dosages of glucocorticosteroid replacement therapy when they are being treated with these medications. The major risk with patients having adrenal insufficiency is the lack of a normal, serum cortisol response to stress. Consequently, patients must be prepared to modify therapy when this is needed. They must be informed to
Patients with Addisons’s disease
1
Start with hydrocortisone 20 mg in the morning 10 mg in early evening
↓
Fludrocortison 0.1 mg in the morning
1
The patient feels well
1
Decrease the dose to 10 - 15 mg in the morning and 5 - 10 mg in the early evening
temporarily increase doses of glucocorticoids (double or triple) whenever they have any febrile illness or injury, and should be given intravenous ampoules of glucocorticoid to be used if vomiting occurs.
Questions and recommendations regarding ‘sick-day rules’ remain unanswered, despite a number of papers on the subject [17,20]. Although it is generally accepted that short-term increase of glucocorticoids is beneficial and not harmful, there is no evidence of accurate guidance.
Some authors recommend that patients on glucocorticoid replacement therapy should increase their dose of hydro- cortisone by 50% in the last trimester of pregnancy [21], or to 5 - 10 mg/day [22]. As discussed already, hydrocortisone is preferred to other steroids as a substrate for 11-ß-HSD-2. In one study in a pregnant woman with Addison’s disease, hydrocortisone was increased to 60 mg/day from the second trimester onwards until successful labour [21].
The data on dehydroepiandrosterone (DHEA) treatment in patients with adrenal insufficiency is beyond the scope of this editorial. Trials on DHEA replacement therapy in patients with adrenal insufficiency have mainly been performed in women, and have usually lasted a few months. Improvements in mood, health-related quality of life, and libido were seen in some, but not all studies, and these outcomes were only noted with a dose of 50 mg/day. No convincing effects on bone density or serum lipids were found. Long studies are necessary before recommendations can be given.
4. Expert opinion
It is impossible for any glucocorticoid replacement therapy to mimic the physiological, normal, endogenous production of
Glucocorticoid replacement therapy in patients with Addison’s disease
cortisol. Pharmacologically driven, continuous, prolonged steroid exposure has different effects to intermittent physiological pulses. Thus, it is difficult to recommend any method of assessment for glucocorticoid replacement therapy. However, we can mark the potential risks of high doses of glucocorticoids for osteoporosis and cardiovascular disease. There is no evidence that patients experience adverse effects on low doses of glucocorticoid replacement (15 - 25 mg/day) [22,23]. There is no strong evidence that quality of life of hypoadrenal patients is better on thrice rather than than twice daily replacement therapy, but it is better for patients to have their last dose early in the evening.
Recommendations about ‘sick-day rules’ depend on experience rather than evidence. We have to be very careful in order to not over-treat patients. There is no evidence for taking additional doses of glucocorticoid to cover periods of stress such as short-term exercise or examinations [24].
It is possible that manipulations of the 11-ß-HSD enzyme system might guide replacement therapy in the future, thus protecting patients from adverse effects. Ideal therapy will be that of new preparations with modified release that are able to mimic both ultradian rhythmicity and physiological responses to daily stress. Until then, we have to avoid over-treatment of patients.
Bibliography
Papers of special note have been highlighted as either of interest (·) or of considerable interest ( ·· ) to readers.
1. EISENBARTH GS, GOTTLIEB PA .: Autoimmune polyendocrine syndromes. N. Engl J Med. (2004) 351(10):2068-2079.
2. NEUFELD M, MACLAREN NK, BLIZZARD RM: Two types of autoimmune Addison’s disease associated with different polyglandular autoimmune (PGA) syndromes. Medicine (Baltimore) (1981) 60:355-362.
3. BETTERLE C, DAL PRA C, MANTERO F, ZANCHETTA R: Autoimmune adrenal insufficiency and autoimmune polyendocrine syndromes: autoantibodies, autoantigens, and their applicability in diagnosis and disease prediction. Endocr. Rev. (2002) 23:327-364. [Erratum, Endocr. Rev. (2002) 23:579.]
4. ESTEBAN N, LOUGHLIN T, YERGEY A et al .: Daily cortisol production rate in man determined by stable isotope dilution / mass spectrometry. J. Clin. Endocrinol. Metab. (1991) 71:39-45.
5. VELDHUIS J: How does one get at glandular secretion, when only hormone concentrations are measured? Clin. Endocrinol. (1997) 46:397-400.
6. VELDHUIS J, JOHNSON M: Deconvolution analysis of hormone data. Meth. Enzymol. (1992) 210:539-575.
.. A full review of controversies in glucocorticoid replacement therapy .
7. CROWN A, LIGHTMAN S: Why is the management of glucocorticoid deficiency still controversial: a review of the literature. Clin. Endocrinol. (2005) 63:483-492.
8. YOUNG E, ABELSON J, LIGHTMAN S: Cortisol pulsatility and its role in stress regulation and health. Front. Neuroendocrinol. (2004) 25:69-76
·· This reveiw discusses normal ultradian and circadian rhythm of endogenous cortisol.
9. CHROUSOS G: Ultradian, circadian,and stress-related hypothalamic-pituitary-adrenal axis activity - a dynamic digital-to-analog modulation. Endocrinology (1998) 139:437-439.
10. SECKL J, WALKER B: Minireview:11-ß-hydroxysteroid dehydrogenase type 1 - a tissue-specific amplifier of glucocorticoid action. Endocrinology (2001) 142:1371-1376.
11. FEEK C, RATCLIFFE J, SETH J, GRAY C, TOFT A, IRVINE W: Patterns of plasma cortisol and ACTH concentrations in patients with Addison’s disease treated with conventional corticosteroid replacement. Clin. Endocrinol. (1981) 14:451-458.
12. BARBATO A, LANDAU R: Serum cortisol appearance-disappearance in adrenal insufficiency after oral cortisone acetate. Acta Endocrinol. (1977) 84:600-604.
13. AANDERUD S, MYKING O: Plasma cortisol concentrations after oral substitution of cortisone in the fasting and non-fasting state. Acta Med. Scand. (1981) 210:157-161.
14. HOWLETT T: An assessment of optimal hydrocortisone replacement therapy. Clin. Endocrinol. (1997) 46:263-268.
15. WONG V, YAN T, DONALD A, MCLEAN M: Saliva and bloodspot cortisol: novel sampling methods to assess hydrocortisone replacement therapy in hypoadrenal patients. Clin. Endocrinol. (2004) 61:131-137.
16. MAH P, JENKINS R, ROSTAMI-HODJEGAN A et al .: Weight-related dosing, timing and monitoring hydrocortisone replacement therapy in patients with adrenal insufficiency. Clin. Endocrinol. (2004) 61:367-375.
17. STEWART P: The adrenal cortex. In: Williams Textbook of Endocrinology. Larsen PR, Kronenberg S, Melmed K et al. (Eds) 10th edn. Saunders, Philadelphia, USA (2003):491-551.
18. KYRIAZOPOULOU V, PARPAROUSI O, VAGENAKIS A: Rifampicin-induced adrenal crisis in addisonian patients receiving corticosteroid replacement therapy. J. Clin. Endocrinol. Metab. (1984) 59:1204-1206.
19. KYRIAZOPOULOU V, VAGENAKIS A: Abnormal overnight dexamethasone suppression test in subjects receiving Rifampicin therapy. J. Clin. Endocrinol. Metab. (1991) 75:315-317.
20. VAGENAKIS AG, KYRIAZOPOULOU V: Dexamethasone for tuberculous meningitis. N. Engl. J. Med. (2005) 352(6):628-30;
21. ADONAKIS G, GEORGOPOULOS NA, MICHAIL G et al .: Successful pregnancy outcome in a patient with primary Addison’s desease. Gynecol. Endocrinol. (2005) 21(2):90-93
22. ARLT W, ALLOLIO B: Adrenal insufficiency. Lancet (2003) 361:1881-1893.
23. DUNNE F, ELLIOT P, GAMMAGE M et al .: Cardiovascular function and glucocorticoid replacement in patients with hypopituitarism. Clin. Endocrinol. (1995) 43:623-629.
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24. WEISE M, DRINKARD B, MEHLINGER S et al .: Stress dose of hydrocortisone is not beneficial in patients with classic congenital adrenal hyperplasia undergoing short-term, high-intensity exercise. J. Clin. Endocrinol. Metab. (2004) 89:3679-3684
Affiliation
Venetsana Kyriazopoulou Associate Professor of Endocrinology, University Hospital, Division of Endocrinology and Metabolism, Department of Internal Medicine, Patras, 26500 Patras, Greece Tel: 30 6937 164707 Fax: +30 2610 999696 Email: vkyriazopoulou@med.upatras.gr