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Doi:10.1530/edm-13-0080Adrenal insufficiency in a woman secondaryto standard-dose inhaled fluticasonepropionate therapy 1Department of Obstetrics and Gynecology 2Division of Reproductive Endocrinology and Infertility, Maine Medical Center, 22 Bramhall Street, Portland, Maine 04102, USA A 55-year-old woman with asthma presented with adrenal insufficiency of unknown origin. She was referred to our Division of Reproductive Endocrinology to further evaluate an undetectable morning cortisol level discovered during the evaluation of a low serum DHEA-S level. She was asymptomatic other than having mild fatigue and weight gain. Her medication list included 220 mg of inhaled fluticasone propionate twice daily for asthma, which she was taking as prescribed. On presentation, the undetectable morning cortisol level was confirmed. A urinary measurement of fluticasone propionate 17b-carboxylic acid was markedly elevated. Fluticasone therapy was discontinued and salmeterol therapy initiated with supplemental hydrocortisone. Hydrocortisone therapy was discontinued after 2 months. A repeat urinary fluticasone measurement 4 months after the discontinuation of fluticasone therapy was undetectably low and morning cortisol level was normal at 18.0 mg/dl. Inhaled fluticasone is generally considered to be minimally systemically absorbed. This patient’s only clinical evidence suggesting adrenal insufficiency was fatigue accompanying a low serum DHEA-S level. This case demonstrates that adrenal insufficiency can be caused by a routine dose of inhaled fluticasone. Missing this diagnosis could potentially result in adrenal crisis upon discontinuation of fluticasone therapy.
† Standard-dose inhaled fluticasone can cause adrenal insufficiency.
† Adrenal insufficiency should be considered in patients taking, or who have recently discontinued, inhaled fluticasone therapy and present with new onset of nonspecific symptoms such as fatigue, weakness, depression, myalgia, arthralgia, unexplained weight loss, and nausea that are suggestive of adrenal insufficiency.
† Adrenal insufficiency should be considered in postoperative patients who exhibit signs of hypoadrenalism after fluticasone therapy has been withheld in the perioperative setting.
† Routine screening for hypoadrenalism in patients without clinical signs or symptoms of adrenal insufficiency after the discontinuation of inhaled fluticasone therapy is not indicated due to the apparently low incidence of adrenal insufficiency caused by fluticasone.
and adrenocorticotropic hormone (ACTH) levels belowthe assay detection limits (1.5 mg/dl for cortisol and Adrenal suppression is a well-known consequence of 5 pg/ml for ACTH) consistent with central hypoadrenal- chronic administration of pharmacologic doses of gluco- ism. Cortisol levels remained undetectably low after corticoids. Routine doses of inhaled corticosteroids (ICS) cosyntropin stimulation. Serum thyroxine (6.1 mg/dl), are generally felt to have a minimal impact on the adrenal thyroid-stimulating hormone (TSH; 2.03 mU/ml), and axis, except in certain subsets of the population such insulin-like growth factor 1 (101 ng/ml) measurements as children and patients on specific medications such as were normal as was a chemistry panel including tests for ritonavir . It has been suggested that inhaled renal and hepatic functions and fasting glucose fluticasone propionate has an improved risk:benefit ratio (79 mg/dl). Follicle-stimulating hormone (FSH) levels compared with other ICS, probably due to a very high were in the menopausal range (66.9 IU/l). Dual energy first-pass metabolism . The safety of inhaled fluticasone X-ray absorptiometry (DEXA) bone density measurements with respect to adrenal axis suppression has been demonstrated T-scores of the spine, femoral neck, and supported by one study of 500 severe asthmatics, which total hip of K2.4, K1.9, and K2.1. Spinal Z-score was showed that high-dose inhaled fluticasone (1–2 mg daily) K1.3. Spinal BMD was stable between 2009 and 2012 did not decrease morning cortisol levels outside of the (0.794 and 0.785 g/cm2). She was placed on hydrocorti- normal range However, a large meta-analysis showed sone supplementation, but she did not tolerate it due to that inhaled fluticasone exhibited a greater dose-related malaise. At this time, she presented to our clinic for further systemic bioactivity compared with other available ICS, evaluation. She reported only mild fatigue with mild weight gain and denied having nausea, increased skin Herein, we report on a 55-year-old woman with pigmentation, or postural symptoms. Symptoms of profound adrenal axis suppression caused by routine hypoadrenalism were notably absent, despite the very doses of inhaled fluticasone. Given the prevalence of low cortisol levels. She also reported no symptoms of fluticasone prescriptions, it is likely that other cases of Cushing’s syndrome other than mild weight gain and adrenal suppression with inhaled fluticasone occur. Accor- fatigue and had no symptoms suggestive of cortisol excess ding to a 2011 review of the use of medications in the USA, on physical examination. Past medical history was published by the IMS Institute for Healthcare Informatics, relevant for asthma controlled with 220 mg of inhaled medications containing fluticasone are the 16th most fluticasone twice daily (a dose of 110 twice daily initiated prescribed medications in the country. In 2011, there in May 2001 and increased to 220 mg in February 2009), were 38.4 million prescriptions dispensed containing ipratropium bromide, and levalbuterol. She denied having fluticasone. If even a small proportion of patients using any other health problems or using steroids with no fluticasone have resulting undiagnosed adrenal insuffi- history of autoimmune or pituitary disease, hepatic or ciency, there could be significant health consequences.
renal disease, or pulmonary disease other than asthma.
A 55-year-old woman was referred to our Reproductive Our initial evaluation included the confirmation of Endocrinology Clinic to further evaluate an undetectable persistent suppression of ACTH and cortisol levels, morning serum cortisol level. Initial concern for adrenal evaluation of other pituitary functions with measure- insufficiency had been raised 5 years earlier during ments of FSH and TSH levels, a complete metabolic panel, evaluation for low bone density when a serum DHEA-S measurement of serum aldosterone levels, screening of level was measured and found to be ‘low’ by the patient’s serum and urine for exogenous glucocorticoids, and history. Earlier this year, the patient’s primary gynecolo- magnetic resonance imaging of the pituitary and hypo- gist observed ‘worsening’ osteopenia and referred her to an thalamus. Undetectably low morning serum cortisol and endocrinologist. Metabolic bone evaluation was normal.
ACTH levels were confirmed. All other results were within However, the patient mentioned her history of low DHEA-S normal limits, except for the urinary measurement of level, prompting an evaluation of morning cortisol level, fluticasone propionate 17b-carboxylic acid, which was which was found to be undetectably low. She sub- markedly elevated at 7060 pg/ml. While there is no sequently underwent two cosyntropin stimulation tests standard reference range for this laboratory, 10 pg/ml is and both tests revealed baseline morning serum cortisol considered average. Repeat testing confirmed the elevated urinary fluticasone metabolite measurement with a value identification of a subpopulation of patients receiving of 2500 pg/ml. The patient confirmed that she was taking fluticasone who are more likely to have adrenal axis only the prescribed dose of inhaled fluticasone at the suppression could be identified in our patient.
This case report illustrates the potential for significant adrenal insufficiency due to standard doses of inhaledfluticasone and emphasizes the need to consider this diagnosis in patients taking ICS, particularly when Fluticasone therapy was discontinued, and the patient was glucocorticoid therapy is being discontinued. The lack of started on salmeterol therapy for asthma control. Hydro- clinical symptoms of hypoadrenalism in the patient cortisone was administered at a dose of 10 mg in the despite the consistently undetectable morning cortisol levels was most probably due to the glucocorticoid effectsof the absorbed fluticasone. Recognition of the possibilityof adrenal axis suppression by standard-dose inhaled fluticasone is important in two contexts. First, in patients Repeat morning cortisol measurements 2 weeks and similar to our patient whose adrenal status is being 2 months after the discontinuation of fluticasone therapy evaluated for reasons not related to their fluticasone use were 4.0 and 4.2 mg/dl with the afternoon hydrocortisone (e.g. fatigue, weight loss or gain, and low DHEA-S levels), dose being held on the day before testing. The patient the possibility of adrenal axis suppression should be discontinued hydrocortisone treatment at that time, considered. The reportedly low DHEA-S level in our and 3 weeks later, the morning cortisol level had risen patient while taking 110 mg of fluticasone twice daily to 8.1 mg/dl. A repeat urinary fluticasone propionate appropriately prompted an evaluation of her adrenal axis, 17b-carboxylic acid measurement was undetectably low.
although the DHEA-S finding may have been incidental.
The final morning cortisol level 4 months later was Although our patient did not exhibit hyperglycemia, low Z-scores on DEXA, or suppression of TSH or FSH secretion,these factors should also prompt an investigation ofadrenal status in patients receiving fluticasone therapy.
If central adrenal insufficiency is evident, inhaled flutica- There have been some case reports of ICS causing adrenal sone should promptly be considered as an etiology to suppression and crisis in adult patients receiving high- avoid a potentially expensive and confusing evaluation.
dose therapy without ritonavir (for fluticasone doses R1 g Second and more importantly, adrenal insufficiency should be suspected in any patient who is discontinuing she presented with complete adrenal axis suppression inhaled fluticasone therapy and developing clinical in the setting of standard-dose inhaled fluticasone therapy symptoms of hypoadrenalism such as unusual fatigue.
in the absence of ritonavir therapy or any other pre- Recognition of adrenal insufficiency may be difficult disposing factors. She was asymptomatic other than because symptoms are nonspecific and may include having fatigue and underwent an extensive evaluation weakness, myalgia, arthralgia, nausea, weight loss, and before establishing the correct diagnosis, indicating that psychiatric symptoms in addition to fatigue. Furthermore, this occurrence may currently be difficult to recognize the lack of symptoms of adrenal insufficiency in our patient despite consistently undetectable morning cortisol The mechanism of increased fluticasone absorption in levels suggests that excess circulating fluticasone may our patient is unclear. She had no evidence of pulmonary induce glucocorticoid effects that prevent the symptoms or vascular disease. She was taking no other medications of glucocorticoid deficiency. Testing for adrenal insuffi- that would enhance absorption. The mechanism of ciency should also be conducted when fluticasone therapy adrenal axis suppression by ritonavir is the impairment is withheld in the perioperative setting if a patient’s of the cytochrome p450 system, leading to the accumu- hemodynamics or other factors suggest hypoadrenalism.
lation of fluticasone in the blood. However, in our patient, Routine screening for adrenal insufficiency in patients fluticasone propionate 17b-carboxylic acid, which is the without symptoms suggestive of hypoadrenalism after inactive metabolite of fluticasone propionate, was present the discontinuation of inhaled fluticasone therapy is not at high levels consistent with intact cytochrome p450.
warranted because the incidence of adrenal suppression Thus, no specific mechanism that would enable the due to inhaled fluticasone therapy appears to be low.
2 Schwartz RH, Neacsu O, Ascher DP & Alpan O 2012 Moderate dose inhaled corticosteroid-induced symptomatic adrenal suppression: case The authors declare that there is no conflict of interest that could be report and review of the literature. Clinical Pediatrics 51 1184–1190.
perceived as prejudicing the impartiality of the research reported.
3 Fuller R, Johnson M & Bye A 1995 Fluticasone propionate – an update on preclinical and clinical experience. Respiratory Medicine 89 3–18.
( 4 Ayres JG, Bateman ED, Lundback B & Harris TA 1995 High dose This research did not receive any specific grant from any funding agency in fluticasone propionate, 1 mg daily, versus fluticasone propionate, 2 mg the public, commercial or not-for-profit sector.
daily, or budesonide, 1.6 mg daily, in patients with chronic severeasthma. International Study Group. European Respiratory Journal 8579–586. 5 Lipworth BJ 1999 Systemic adverse effects of inhaled corticosteroid therapy: a systematic review and meta-analysis. Archives of Internal Written informed consent was obtained from the patient for publication 6 Duplantier JE, Nelson RP, Jr, Morelli AR, Good RA & Kornfeld SJ 1998 Hypothalamic–pituitary–adrenal axis suppression associatedwith the use of inhaled fluticasone propionate. Journal of Allergy andClinical Immunology 102 699–700. ( Dr D I Spratt is the patient’s primary endocrinologist and contributed to the 7 Molimard M, Girodet PO, Pollet C, Fourrier-Re´glat A, Daveluy A, writing of this case report. Dr C M Hay is an obstetrics and gynecology Haramburu F, Fayon M & Tabarin A 2008 Inhaled corticosteroids and resident who also directly cared for the patient and contributed to the adrenal insufficiency: prevalence and clinical presentation. Drug Safety 8 Todd GR 2003 Adrenal crisis due to inhaled steroids is underestimated.
Archives of Disease in Childhood 88 554–555. 9 Todd GR, Acerini CL, Ross-Russell R, Zahra S, Warner JT & McCance D 2002 Survey of adrenal crisis associated with inhaled corticosteroidsin the United Kingdom. Archives of Disease in Childhood 87 457–461.
1 Foisy MM, Yakiwchuk EM, Chiu I & Singh AE 2008 Adrenal suppression and Cushing’s syndrome secondary to an interaction between ritonavir 10 Wong J & Black P 1992 Acute adrenal insufficiency associated with and fluticasone: a review of the literature. HIV Medicine 9 389–396.
high dose inhaled steroids. BMJ 304 1415. Received in final form18 December 2013Accepted 8 January 2014
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