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Fluticasone propionate, a frequently prescribed potent inhaled corticosteroid, is an effective and generally safe treatment for chronic asthma. However, rare cases of dose related systemic absorption of inhaled corticosteroids leading to suppression of the hypothalamic-pituitary-adrenal (HPA) axis have been reported, particularly in children.1,2 Using the insulin tolerance test (ITT), we report two cases of symptomatic adrenocortical suppression in asthmatic adults taking inhaled fluticasone. The two patients reported here were selected from a review of 59 patients undergoing ITTs for investigation of suspected HPA dysfunction.3
Patient 1, a 38 year old woman (weight 49.9 kg) with a history of chronic asthma and allergic rhinitis, was referred for investigation of a 2 year history of fatigue, presyncope, and reduced libido. She denied symptoms of neuroglycopenia, thyroid dysfunction, headaches, arthralgia, myalgia, weight change, constipation, and diarrhoea. Past history included depression (in remission, on no current treatment) and bulimia nervosa. Menses were regular. There was no history of postpartum haemorrhage. Medications included fluticasone propionate/salmeterol xinafoate (Seretide) 250/25 µg one inhalation twice daily and mometasone furoate monohydrate (Nasonex) nasal spray 50 µg each nostril twice daily. However, adherence and dosing were variable. Of note, the patient reported that her presenting symptoms improved significantly whenever she had received oral steroids for asthma exacerbations in the past. Initial blood results are shown in table 1. Given low early morning cortisol levels in the absence of increased levels of adrenocorticotropin hormone (ACTH), an ITT was performed which revealed HPA axis suppression (table 1). Magnetic resonance imaging (MRI) demonstrated loss of upper concavity of the pituitary gland. Prednisone 2.5 mg/day was commenced and the dose of fluticasone propionate/salmeterol xinafoate was reduced to 125/25 µg one inhalation twice daily, with good symptomatic response. The patient was concurrently diagnosed with celiac disease following small bowel biopsy.
Patient 2, a 61 year old woman (weight 55 kg) with chronic asthma, treatment resistant osteoporosis, Hashimoto’s hypothyroidism and celiac disease, reported fatigue, presyncope, neuroglycopenia, adrenergic symptoms of hypoglycaemia, anorexia and weight loss. Menopause was premature at age 45 years. There was no history of significant haemorrhage. Medications included inhaled fluticasone propionate (Flixotide) 250 µg and salmeterol xinafoate (Serevent) 50 µg one inhalation of each twice daily (for 12 months prior to presentation). As morning cortisol levels were low and the ACTH level was normal, an ITT was undertaken which demonstrated suppression of the HPA and growth hormone axes (table 1). Pituitary MRI scan was unremarkable. Prednisone 2 mg/day was commenced with symptomatic improvement. The dose of prednisone was reduced to 1 mg after 4 months without recurrence of presenting symptoms.
Using the ITT, we detected HPA suppression in two adult asthmatic patients taking inhaled/intranasal corticosteroids. The variable and unpredictable absorption of inhaled corticosteroids, low body weight, and intermittent adherence and dosing in patient 1 may have contributed to the patients’ symptoms of adrenal insufficiency. The high lipophilicity of fluticasone, which results in an increased volume of distribution and prolonged elimination half life, is thought to account for the greater frequency of adrenal insufficiency in patients taking fluticasone compared with other inhaled corticosteroids.2
Adrenal suppression in asthmatic adults taking inhaled fluticasone is thought to occur less frequently than in children, particularly in patients taking <800 µg/day,4 due to a lower effective steroid dose per unit body surface area.2 However, previous studies have used relatively insensitive discriminators of HPA dysfunction such as early morning serum and salivary cortisol levels, 24 hour urinary free cortisol, and the 250 µg cosyntropin stimulation test to examine the integrity of the HPA axis in adult asthma patients taking inhaled corticosteroids.4,5 We are aware of no previous study that has used the ITT, the current “gold standard” test of HPA function,1 in this patient group. Although potentially dangerous in patients with seizure disorders and ischaemic heart disease, the ITT is a safe test when performed in experienced centres.3 Indeed, a review of >6500 ITTs reported that only seven patients (0.1%) experienced an adverse event, all of which reversed following intravenous glucose.6 To our knowledge, only two studies have used the ITT to investigate the HPA axis in asthmatic children treated with inhaled fluticasone. The first reported an inadequate response to insulin-induced hypoglycaemia in three children taking 1000–2250 µg/day.7 In the second study, nine of 18 subjects treated with 250–750 µg/day for up to 16 weeks exhibited evidence of adrenal suppression which recovered following cessation of treatment.1
Finally, as hypopituitarism of probable autoimmune aetiology has been reported in patients with celiac disease,8 the possibility that autoimmune hypophysitis contributed to the patients’ symptoms and pituitary deficiency cannot be definitively excluded.
In summary, this report suggests that inhaled (together with intranasal) fluticasone may suppress the HPA axis in adults and that symptomatic adrenal insufficiency may develop, particularly if dosing is variable and intermittent. These cases illustrate that clinical symptoms may alert the physician to the possibility of adrenal suppression which can then be confirmed using basal and/or stimulated tests of HPA function in selected patients. Further investigation to determine the prevalence of these effects in adult patients is warranted.
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