Common Medications May Cause Adrenal Insufficiency

by Mark Newman, MS

Everyone knows that taking corticosteroids like Prednisone can be suppressive to the adrenal glands - this is why they are usually dosed in a tapering manner in order to prevent a crash. However, new research published in the April 2015 online edition of The Journal of Clinical Endocrinology and Metabolism reports that even those who use common allergy or asthma steroid inhalers and nasal sprays are at risk for adrenal insufficiency.

This is a concern as they end up making less cortisol (stress hormone) and aldosterone (salt, potassium, and water balance) causing a number of side effects. For your knowledge, common medications include: prednisone, triamcinolone, betamethasone, dexamethasone, clobetasol, and fluticasone. Brand names include: Medrol, Advair, Qvar, Pulmicort, Flovent, Azmacort, Flonase, Nasonex, Veramyst, Nasacort, Omnaris, Clobex, and Kenalog.

To "know" if a patient's adrenal production of cortisol may be suppressed, you HAVE to test free cortisol AND metabolites. Take these two cases as an example. The free cortisol pattern is similarly low. Cortisol production (as approximated by measuring metabolized cortisol) is vastly different (patient #1 makes >12X more cortisol).

Patient #1 is obese and making TONS of cortisol (even though the free cortisol implies low cortisol). Patient #2 is taking Advair (Fluticasone, a glucocorticoid). It has been shown to suppress adrenal cortisol production , and it appears to be suppressing hers. We see patients on these types of medications with suppressed cortisol production and also those with normal cortisol production on the same products.

Remember that long-term glucocorticoid use is another factor that can up-regulate cortisol clearance. This can lead to cases like Patient #1 where free cortisol is low even if cortisol production is NOT suppressed. These two examples show that if you want to "KNOW" if cortisol production is suppressed, you must test free cortisol and metabolites - otherwise you are still guessing.

Keep scrolling to read about the difference in cortisol testing with the DUTCH method and for important highlights from the research article.

The benefit of DUTCH testing by Precision Analytical is that we evaluate both the metabolized cortisol and the daily free (active) cortisol pattern as well as three markers of DHEA production (DHEA-s, etiocholanolone, and androsterone). In the above case (Patient #2) all DHEA markers were low as well, which is consistent with adrenal suppression.

Why is this important?

It is necessary to differentiate between those who just have "low" active/free cortisol and those who have true adrenal suppression (such as due to the above medications) or even Addison's disease. Patient #1 has very high metabolized cortisol and low active/free cortisol as seen in the daily free cortisol pattern. This is not adrenal insufficiency or Addison's because she is producing a lot of cortisol - her metabolized cortisol is high! This patient happens to be morbidly obese (>400lbs), which is one of the risk factors causing upregulated cortisol metabolism. In her case, the high metabolized cortisol has resulted in low amounts of active/free cortisol floating around thus she appears "low" adrenal in the graph. In the lower graphical picture, this patient has both low metabolized and active/free cortisol. Her glands are not producing a lot of cortisol causing low bioavailability of her active/free cortisol. The Advair is likely resulting in adrenal insufficiency. Be sure to investigate ALL of the medications your patients are taking as you interpret results. Treating the above patient on Advair without realizing her adrenals aren't "fatigued" (they are suppressed) could lead to inappropriate treatment.

Some highlights from the recent study are as follows ( click here to see the paper on PubMed ):

• 1190 participants of the 3753 total were diagnosed with adrenal insufficiency via a ACTH stimulation test (74 articles of 136 study groups were evaluated)
• Of those 1190, 48.7% were due to oral administration, 7.8% for inhaled, 4.7% for topical, 4.2% intra-nasal, and 52.2% of those who had their corticosteroids injected.
• Using multiple forms of corticosteroids causing adrenal insufficiency resulted in a pooled percentage of 42.7%
• 11.1% of the participants were being treated specifically for asthma. Other conditions included sinusitis, psoriasis/skin conditions, rheumatic disease, renal transplants, cancer, Crohn's disease, cystic fibrosis, and nasal polyps.
• 2.4% of those who used low dose corticosteroids had adrenal insufficiency compared to 21.5% who used the highest dosage. DOSE MATTERS!
• 1.4% of those who used corticosteroids for the short term (less than 28 days) had adrenal insufficiency compared to 11.9% of medium term users (1-12 months) and 27.4% who used them for long term (1 year or more). LENGTH OF EXPOSURE MATTERS!
• Those at highest risk were those at the highest dose for the longest timeline however even those on low dose corticosteroids for longer periods of time were at risk for insufficiency.
• The studies that did 6 month retesting after stopping the corticosteroid found that the initial percentage of adrenal insufficiency at 56.4% and 6 months later were still at 25.3%
• The authors recommended those who test for adrenal insufficiency should consider physiologic doses of glucocorticoid replacement to help.

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Reference:

Broersen, L., Pereira, A., Jorgensen, J., and Dekkers, O. (2015). Adrenal insufficiency in corticosteroid use: systematic review and meta-analysis. Retrieved from http://press.endocrine.org/doi/pdf/10.1210/jc.2015-1218