Adrenal fatigue, adrenal insufficiency, adrenal dysfunction, or hypoadrenia is a common co-existing problem for those who’ve been hypothyroid for years. Adrenal fatigue is the term most commonly used by patients, though the medical profession does not recognize it and it has no insurance billing code. When thyroid levels are low, the adrenals (a small gland above the kidneys) step in with cortisol and adrenaline to compensate for the deficiency. This can make someone feel both tired and wired at the same time. Sleeping problems are common. In Addison’s disease, the adrenals produce little to no cortisol. Someone with this condition must supplement cortisol, or they would die. Those with Addison’s are usually quite thin. Cushing’s is the opposite state, where someone overproduces cortisol. Cushing’s patients are usually quite heavy, with a moon face and buffalo hump (hump on the backside of their neck).
Adrenal fatigue refers to a broad range of adrenal dysfunction. In the same way that thyroid dysfunction can range from myxedema coma on the hypothyroid end to thyrotoxicosis on the hyperthyroid end, so can adrenal fatigue range from Addison’s on one end (cortisol close to zero) to high or dysfunctional daily cortisol rhythms on the other end. If someone has Addison’s, then there is no question that they must be on hydrocortisone for life. Or if saliva cortisol labs show a flat-lined pattern at the bottom of the range all day, then that person may need to supplement with hydrocortisone too. But for most others, supporting the adrenals with adaptogens and slowly raising thyroid levels can also work. This is because thyroid and corticosteroid binding globulin (CBG) have an inverse relationship. As thyroid levels come up, CBG goes down, leaving more cortisol free. Cortisol is also released from CBG as body temperature rises, and body temperature correlates positively with thyroid levels. So raising thyroid can naturally raise cortisol levels. [1,13] But any increases must be done slowly–weekly thyroid increases are too much too soon and do not give the body time to adjust. Some people are so sensitive that they can only raise 1/4 grain of desiccated thyroid or 12.5 mcg of T4 every 12 weeks. If someone has poor T4 to T3 conversion, then taking smaller amounts of T3 throughout the day (including bedtime), instead of once a day, will also give all organs, including the adrenals, a more steady supply of energy to perform their function.
Low cortisol can have a primary cause; that is, the adrenals simply do not produce cortisol. But it can also have a secondary cause–the pituitary does not send out an adequate ACTH (AdrenoCorticoTropic Hormone) signal, which tells the adrenals to produce the cortisol. If the hypothalamus does not send out enough corticotropic-releasing hormone (CRH), which sends the signal to the pituitary to produce ACTH, that is considered a tertiary cause. If a damaged pituitary or hypothalamus and low ACTH are the cause of the low cortisol, then cortisol must be taken for life to replace the essential missing hormone. A medical alert bracelet/necklace/card should be carried at all times by someone on cortisol replacement, because the normal ACTH feedback loop does not work if someone is manually dosing their cortisol. If a stressful situation arises but the person can’t produce enough cortisol (cortisol approaches zero), it becomes a life-threatening medical condition called an adrenal crisis. An adrenal crisis can be fatal.
Adrenal fatigue seems common in those with thyroid problems. Are the adrenals somehow connected to the thyroid? Apparently they are, because without adequate thyroid levels, the adrenals themselves atrophy. Rats were given anti-thyroid drugs like carbimazole or methimazole; these drugs are used to lower thyroid levels in Graves’ patients.  Their adrenals atrophied when hypothyroid, and the adrenal cortex actually shrank in size, especially the zona fasciculata, which is where cortisol is produced. As expected, blood cortisol levels were lower in the hypothyroid rats. Interestingly, Brewer’s yeast, which is high in B vitamins and selenium, appeared to have a protective effect on the adrenal gland, somewhat offsetting the methimazole-induced atrophy.  Thyroidectomized dogs exhibited the same effect–their cortisol levels dropped significantly only seven days post-thyroidectomy. Their adrenocortical function was restored after they were given levothyroxine. 
Hydrocortisone supplementation to treat adrenal fatigue has side effects, but many are not even aware of them. They should know what these are, so they can make an informed decision if they choose to follow this protocol. People using hydrocortisone on thyroid internet forums have reported the following side effects:
- osteoporosis 
- glaucoma, which can lead to blindness 
- weight gain and “buddha belly” 
- immune suppression that can lead to fungal infections and resistance to some cancer treatments [5,6]
- cardiovascular disease / hypertension 
- diabetes 
- inability to tolerate any stress, which can lead to a fatal adrenal crisis .
Someone on the hydrocortisone protocol must learn how to “stress dose,” or manually provide the hydrocortisone needed for any stress, since the body becomes completely dependent on external dosing. If they cannot provide the required increased hydrocortisone for the stress, it can be fatal. More than one person has ended up in the ER while on this protocol. In the same way that T3-type medications suppress TSH, taking hydrocortisone suppresses the ACTH feedback loop, which would normally stimulate natural cortisol production. One can have low cortisol symptoms in conjunction with physical signs of high cortisol because manual dosing creates high cortisol levels shortly after a dose, but low cortisol levels just before the next dose. It is extremely difficult to replicate natural cortisol production, or to mimic an automatic ACTH feedback loop. One should be aware of the risks before embarking on this protocol.
Hydrocortisone treatment doesn’t cause these side effects at physiological doses, only at excessive pharmaceutical doses, say the proponents of this protocol. But how does one define physiological? Maybe what is physiological for one person is an overdose for another. In one study of primary or secondary adrenal insufficient patients, those on hydrocortisone doses greater than 30 mg/day had a lower Quality of Life score than those on lower daily doses.  In another study of primary or secondary adrenal insufficient patients, the dosing schedule that brought the highest proportion of simulated patients within physiological cortisol targets was 10 + 5 + 5 mg at 0730, 1200 and 1630 h, respectively. However, even with this regimen, about 54%, 44% and 32% of patients would remain over- or under-treated when compared to the physiological ranges at 0800, 1600 and 2400 h, respectively.  These high percentages of being over or underdosed on what is considered a physiological dose confirm what many patients on hydrocortisone report–that it is extremely difficult to manually dose hydrocortisone. This may explain the side effects many report.
In a study of 12 Addison’s and 20 hypopituitary patients on replacement glucocorticoid therapy, 75% of the patients were found to be taking excessive doses when serum cortisol levels were correlated with 24-hour urine free cortisol excretion. Their mean daily dose of hydrocortisone was reduced from 29.5 to 20.8 mg. This caused median osteocalcin (a protein involved with bone formation) to increase (which is good) from 16.7 to 19.9 micrograms/l. Another 56% had their dosing regimen or drug changed.  Osteoporosis is a serious side effect of any glucocorticoid therapy, so it is imperative that patients are not overmedicated. 
Hydrocortisone is used to suppress the HPA (hypothalamus-pituitary-adrenal) axis through transrepression (which it does very well), but side effects like glaucoma and diabetes are from a different mechanism called transactivation. Other side effects like osteoporosis seem to involve both transrepression and transactivation. So while someone may get the intended HPA effect of suppression, they may also unknowingly be putting themselves at risk for serious side effects. 
Hydrocortisone supplementation does not seem to work as it should when someone is on other pharmaceutical drugs like benzodiazepines, or any medication that treats anxiety and depression. These drugs probably work at some level on the HPA axis and cortisol levels, creating unintended, conflicting reactions.
Also, if Lyme disease or some other underlying medical condition is present, taking hydrocortisone can exacerbate the condition because of its suppressive effect on the immune system. Hydrocortisone treatment should not be entered into lightly. Some have ended up worse than before they started any treatment.
Thoughts on thyroid internet groups.
Read patient experiences with hydrocortisone use.
- Sonia C Dumoulin, Bertrand P Perret, Antoine P Bennet and Philippe J Caron. Opposite effects of thyroid hormones on binding proteins for steroid hormones (sex hormone-binding globulin and corticosteroid-binding globulin) in humans. European Journal of Endocrinology, Vol 132, Issue 5, 594-598,1995.http://www.eje-online.org/cgi/content/abstract/132/5/594
- R S Weinstein, R L Jilka, A M Parfitt, and S C Manolagas. Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone. J Clin Invest.1998 July 15;102(2): 274–282. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC508885/
- Tripathi R.C., Parapuram S.K., Tripathi B.J., Zhong Y., Chalam K.V. Corticosteroids and Glaucoma Risk. Drugs & Aging, Volume 15, Number 6, December 1999 , pp. 439-450(12). http://www.ncbi.nlm.nih.gov/pubmed/10641955
- Meikle, A. Wayne. A Diagnostic Approach to Cushing’s Syndrome. Endocrinologist. 3(5):311-320, September 1993. http://tinyurl.com/69hbbt5
- M. Lionakis, D. Kontoyiannis. Glucocorticoids and invasive fungal infections. The Lancet, Volume 362, Issue 9398, Pages 1828-1838, November 2003. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2803%2914904-5/abstract
- I. Herr, J. Pfitzenmaier. Glucocorticoid use in prostate cancer and other solid tumours: implications for effectiveness of cytotoxic treatment and metastases. The Lancet Oncology, Volume 7, Issue 5, Pages 425-43, May 2006. http://www.ncbi.nlm.nih.gov/pubmed/16648047
- Li Wei, Thomas M. MacDonald, and Brian R. Walker. Taking Glucocorticoids by Prescription Is Associated with Subsequent Cardiovascular Disease. Annals of Internal Medicine. November 16, 2004,vol. 141no. 10764-770. http://www.annals.org/content/141/10/764.full.pdf+html
- Heike Schäcke, Wolf-Dietrich Döcke and Khusru Asadullah. Mechanisms involved in the side effects of glucocorticoids. Pharmacology & Therapeutics Volume 96, Issue 1, October 2002, Pages 23-43. http://www.ncbi.nlm.nih.gov/pubmed/12441176
- Yoram Shenker And James B. Skatrud. Adrenal Insufficiency in Critically Ill Patients. American Journal of Respiratory & Critical Care Medicine, Volume 163, Number 7, June 2001, 1520-1523. http://ajrccm.atsjournals.org/cgi/content/short/163/7/1520
- Benjamin Bleicken, Stefanie Hahner, Melanie Loeffler, Manfred Ventz, Oliver Decker, Bruno Allolio, Marcus Quinkler. Influence of hydrocortisone dosage scheme on health-related quality of life in patients with adrenal insufficiency. Clinical Endocrinology. Volume 72, Issue 3, pages 297–304, March 2010. http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2265.2009.03596.x/abstract
- Simon, Nicolas; Castinetti, Frederic; Ouliac, Floriane; Lesavre, Nathalie; Brue, Thierry; Oliver, Charles. Pharmacokinetic Evidence for Suboptimal Treatment of Adrenal Insufficiency with Currently Available Hydrocortisone Tablets. Clinical Pharmacokinetics, Volume 49, Number 7, 1 July 2010, pp. 455-463(9) http://www.ncbi.nlm.nih.gov/pubmed/20528006
- Peacey, S.R., Guo, C.Y., Robinson, A.M., Price, A., Giles, M.A., Eastell, R. and Weetman, A. P. (1997), Glucocorticoid replacement therapy: are patients over treated and does it matter?. Clinical Endocrinology, 46: 255–261. http://www.ncbi.nlm.nih.gov/pubmed/9156031
- Henley DE, Lightman SL. New insights into corticosteroid-binding globulin and glucocorticoid delivery. Neuroscience. 2011 Apr 28;180:1-8. http://www.ncbi.nlm.nih.gov/pubmed/21371536
- Sarwar G, Parveen S. Carbimazole-induced hypothyroidism causes theadrenal atrophy in 10 days’ prenatally treated albino rats. J Coll Physicians Surg Pak. 2005 Jul;15(7):383-6. http://www.ncbi.nlm.nih.gov/pubmed/16197863
- Eik-Nes, K., & Brizzee, K. R. (1956). Adrenocortical activity and metabolism of 17-hydroxycorticosteroids in thyroidectomized dogs. American Journal of Physiology — Legacy Content, 184(2), 371-375.http://ajplegacy.physiology.org/content/184/2/371.short
- Dehghani F, Zabolizadeh J, Noorafshan A, Panjehshahin MR, Karbalay-Doust S. Protective effect of Brewer’s yeast on methimazole-induced-adrenal atrophy (a stereological study). Tokai J Exp Clin Med. 2010 Apr 20;35(1):34-9. http://www.ncbi.nlm.nih.gov/pubmed/21319024