Anna Crown; Stafford Lightman
Clinical Endocrinology. 2005;63(5):483-492.
The above review can be accessed through MedScape. You need a free account to access it. Below you will find my review of the review from an Addisonian's realistic perspective. My comments will be in light pink. All quotes taken directly from the review will be in quotation marks.
The article is summarized by saying that doctors need to try to treat primary and secondary hypoadrenal patients by giving them hydrocortisone in as physiological way as possible. Quality of life for Addison's patients is better when doses are split up and the lowest possible hydrocortisone dose is achieved. Adverse effects of overreplacement such as effects on bone, blood sugar and heart function can be avoided with optimal dosing of hydrocortisone.
Normal Physiology: The article has an interesting discussion about glucocorticoid production by normal males in early and late puberty. The authors claim that cortisol production by these males is lower than previously thought. 90% of cortisol is bound to Cortisol Binding Globulin. Cortisone is converted to cortisol in fat tissue, liver, brain and bone. The mechanism by which it is converted is very complex.
The Normal Pattern of Glucocorticoid Secretion: Diurnal and Ultradian Rhythmicity: Cortisol is released by the human body in the greatest amount prior to awakening and the amount released decreases through out the day. The article suggests that prolonged, nonphysiological, continuous exposure could decrease the the number of glucocorticoid receptors. To me, this is a good argument for the short acting steroid of hydrocortisone vs. prednisone, medrol, dexamethasone. I also think this backs up the theory of taking 50 % of the hydrocortisone dose BEFORE GETTING OUT OF BED, 25% midday and 25% in the afternoon. Don't take my word for it, check out the journal abstracts in the sidebar!
Pregnancy: Nothing noteworthy
Implications for Our Understanding of the Normal Physiology for Glucocorticoid Replacement Therapy:
- Because conversion of cortisone to cortisol in the liver is innefficient, "...very little orally administered cortisone reaches the systemic circulation. [6, 27, 28]
- "Hydrocortisone probably remains the most physiological drug of choice."
- "It is important to consider the metabolism of other synthetic glucocorticoids when considering their use as replacement therapy in adrenal insufficiency."
- We must try to "avoid unphysiologically high glucocorticoid levels" through out the day "recommending that patients take their last dose of hydrocortisone in the afternoon rather than the evening....If patients take most of their hydrocortisone in the morning and their last dose of hydrocortisone early, there will at least be a period of low receptor occupancy overnight."
- Methods of measurement of hydrocortisone (day curve and urinary free cortisol) are discussed.
- Lowest possible dose to make the patient feel well is recommended.
- ACTH measurement is not a reliable way to test glucorticoid replacement. 
Bone: "Overall, there is some evidence of a lower bone mineral density in hypoadrenal patients on glucocorticoid replacement therapy, perhaps particularly in postmenopausal women, although less evidence of a negative correlation between glucocorticoid dose and bone mineral density. Serum osteocalcin (a marker of osteoblast activity) does seem to correlate inversely with the glucocorticoid dose, although no trends are seen in other markers of bone formation or resorption: this may reflect a pharmacological effect of glucocorticoids on osteocalcin secretion per se, which is recognized to be very sensitive to glucocorticoid excess.[23,48]".
Glucose Metabolism and Cardiovascular Function: "Thus there is some evidence that untreated hypoadrenal patients may start with relatively favourable cardiovascular risk profiles, such as lower insulin concentrations and lower blood pressures than controls. There is evidence that glucocorticoid replacement therapy increases postprandial glucose and insulin concentrations in hypoadrenal patients."
Quality of Life: "Thus, the available evidence suggests that patients may complain of an impaired quality of life even on relatively high doses of steroids. Although one study showed a correlation between plasma cortisol concentrations and well-being, a more rigorous study showed no correlation between hydrocortisone dose (and urinary free cortisol excretion) and quality of life. There is some evidence that the quality of life of hypoadrenal patients is better on a twice daily replacement regimen than a once daily regimen, and may be better on a thrice daily regimen (although as discussed this data is not strong). "
Mortality: No statistical difference between us and "normals".
Interactions With Other Hormone Replacement Therapy and Medication: "Hyperthyroidism increases the metabolism and clearance of cortisol.[5,7] Rifampicin and phenytoin also increase cortisol clearance: adrenal crises have been reported in patients receiving corticosteroid replacement therapy for primary adrenal failure who were treated with rifampicin.."
'Sick day Rules', 'Well Day Recommendations' and Pregnancy:
- Double your dose if you have a fever.
- Most patients, although they might consider themselves well informed, don't know how to treat themselves when sick.
- The authors dropped the ball here: 'Well Day Recommendations'. They consider a test to be the same stress as running a marathon. They do not consider that running a marathon requires months of consistent training and stress on the body (10 - 15 hours a week). A marathon is not a one time event. NO ONE goes out and just runs 26.2 miles off the couch, even healthy people. The authors recommend that hydrocortisone NOT be increased for training based on a small study of teenage boys with CAH who were asked to fast and exercise to maximal capacity one day and then for 90 minutes the next . A one time 2 hour burst of exercise by teenage boys can not be compared to a 40 year old woman running 40 - 50 miles a week. A ridiculous oversight in my opinion.
- Pregnancy recommendations with respect to steroids are made. I won't go into the details.
- Evidence exists that women have an improved quality of life when on DHEA .