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BMJ. 1999 May 15; 318(7194): 1355.
PMCID: PMC1115736

Cushing’s syndrome induced by betamethasone nose drops

In rhinological disease betamethasone should be regarded as systemic corticosteroid
Jarrod J Homer, Specialist registrar in otorhinolaryngology
St James’s University Hospital, Leeds LS9 7TF
Tasso G Gazis, Specialist registrar in endocrinology

Editor—We agree with Findlay et al that the few case reports of Cushing’s syndrome due to nasal betamethasone drops in children may represent the tip of the iceberg.1 With colleagues we have performed a prospective study in nine adults with nasal polyposis treated with betamethasone drops for six weeks; we assessed the hypothalamopituitary-adrenal axis using a low dose (1 μg) tetracosactrin stimulation test, which may detect more subtle impairment of endogenous cortisol production than the standard test (250 μg).2 We found that all patients had significantly depressed cortisol concentrations when tetracosactrin was given after betamethasone treatment (figure; P<0.0001, analysis of variance for repeated measures).3

Gallagher and Mackay have suggested that in many cases patients tend to overcomply with treatment with nasal drops owing largely to difficulties in using the droplet dispenser.4 The perceived benefit of betamethasone over other topical nasal steroids is that its intranasal distribution is superior (because it is in drop form) to that achieved with aqueous sprays.5

We endorse the view that in rhinological disease betamethasone should be regarded as a systemic corticosteroid and caution should be exercised.

Figure
Result of low dose tetracosactrin stimulation test before and after six weeks’ treatment with betamethasone nose drops

References

1. Findlay CA, MacDonald JF, Geddes N, Donaldson MDC. Childhood Cushing’s syndrome induced by betamethasone nose drops, and repeat prescriptions. BMJ. 1998;317:739–740. . (12 September.) [PMC free article] [PubMed]
2. Dickstein G, Shechner C, Nicholson WE, Rosner I, Shen-Orr Z, Adawi F, et al. Adrenocorticotropin stimulation test: effects of basal cortisol level, time of day, and suggested new sensitive low dose test. J Clin Endocrinol Metab. 1991;72:773–778. [PubMed]
3. Gazis AG, Homer JJ, Page S, Jones NS. The effect of topical nasal betamethasone drops for nasal polyposis on adrenal function. Clin Otol. 1998;23:280.
4. Gallagher G, Mackay I. Doctors and drops. BMJ. 1991;303:761. [PMC free article] [PubMed]
5. Hardy JG, Lee SW, Wilson CG. Intranasal drug delivery by spray and drops. J Pharm Pharmacol. 1985;37:294–297. [PubMed]
BMJ. 1999 May 15; 318(7194): 1355.

Children taking intranasal corticosteroids should be monitored for growth retardation

Saul Malozowski, Medical officer
MALOZOWSKIS/at/cder.fda.gov
Mary Purucker, Medical officer
Alexandra Worobec, Medical officer

Editor—Findlay et al report two paediatric cases of iatrogenic Cushing’s syndrome associated with exogenous administration of intranasal corticosteroids.1-1 These cases clearly show the potential of “locally active” corticosteroids to cause serious systemic effects. This problem is not, however, limited to betamethasone, nor is it solely the consequence of high doses or exceptionally prolonged administration of this particular corticosteroid.

Reports to the adverse event reporting system of the US Food and Drug Administration have shown that intranasal corticosteroids given by metered dose devices are associated with systemic steroid effects, including Cushing’s syndrome and growth suppression. Reports in the peer reviewed literature,1-2 as well as unpublished data,1-3 indicate that intranasal corticosteroids taken without interruption at the currently recommended doses may significantly reduce growth velocity in children. After a review of these and additional data a joint meeting of the pulmonary-allergy drug and endocrine-metabolic drug advisory committees in July 1998 voted to recommend that the precautions section of the label for all intranasal (and oral inhaled) corticosteroids be amended to reflect these products’ potential to inhibit growth in children.

All doctors should be aware of this, particularly as intranasal beclomethasone dipropionate is available without prescription in the United Kingdom. Many patients who are prescribed intranasal corticosteroids for allergic rhinitis also receive orally inhaled corticosteroids for asthma. The additive effects of these drugs1-4 and their potential impact on growth velocity are of particular concern.

Growth retardation could serve as an early warning of the systemic effects of corticosteroids, before Cushing’s syndrome can be diagnosed. Consequently, to reduce the risk of these untoward side effects, the Food and Drug Administration is recommending that the current label be amended to advise health practitioners that height and weight should be measured regularly in children receiving these drugs. Such measurements offer a rapid, sensitive, and inexpensive screen for detecting decreases in growth velocity and thereby may prevent other systemic adverse effects; they may also help in the development of strategies to reduce dosing.

Data regarding the lowest effective dose of any intranasal or inhaled corticosteroid are scarce. Equally rare are well controlled studies comparing the relative growth effects of different corticosteroids.

It is therefore premature to consider one corticosteroid over another as a means of diminishing this potential problem. Corticosteroids are a valuable therapeutic option in both allergic rhinitis and asthma. Intranasal and oral inhaled products provide a breakthrough in minimising the systemic effects of this class of agents, but the benefits that they offer should be balanced against the complications they might induce.

References

1-1. Findlay CA, MacDonald JF, Geddes N, Donaldson MDC. Childhood Cushing’s syndrome induced by betamethasone nose drops, and repeat prescriptions. BMJ. 1998;317:739–740. . (12 September.) [PMC free article] [PubMed]
1-2. Wolthers OD, Pedersen S. Short-term growth in children with allergic rhinitis treated with oral antihistamine, depot and intranasal glucocorticosteroids. Acta Paediatr. 1993;82:635–640. [PubMed]
1-3. Rachelefsky G, Chervinsky P, Melzer EO, Morris RM, Selzer JM, Skoner DP, et al. An evaluation of beclomethasone dipropionate aqueous nasal spray on long-term growth in children. J Allergy Clin Immunol. 1998;101:S236. . (Abstract 979.)
1-4. Lipworth BJ, Seckl JR. Measures for detecting systemic bioactivity with inhaled and intranasal corticosteroids. Thorax. 1997;52:476–482. [PMC free article] [PubMed]
BMJ. 1999 May 15; 318(7194): 1355.

Learning difficulties may complicate the issue

Tim Scorrer, Specialist registrar
John Barton, Consultant

Editor—Findlay et al highlight the dangers of intranasal corticosteroids.2-1 We have also recently seen two cases of iatrogenic Cushing’s disease associated with betamethasone nasal drops. The first was in an 11 year old boy with Down’s syndrome who presented with growth arrest and excessive weight gain. Investigations showed compensated hypothyroidism and normal growth hormone secretion but a suppressed morning cortisol concentration of <28 nmol/l. The second child was a 5 year old boy with non-specific learning difficulties, who presented with voracious appetite, weight gain, and aggressive behaviour. On examination he was obese (body mass index 25.9 kg/m2) but did not have cushingoid features. A random cortisol concentration was <28 nmol/l. In both children adrenocorticotrophic hormone was suppressed and the plasma cortisol concentration failed to increase after administration of tetracosactrin.

Although prolonged treatment may increase the risks of adverse effects (the first child had been taking betamethasone for three years), the second child had been receiving treatment for less than two months. It is interesting that one of the two children reported on by Findlay et al had Down’s syndrome. Children with the syndrome are predisposed to nasal obstruction and rhinorrhoea as a result of their abnormal craniofacial anatomy2-2 and may consequently be more likely to receive intranasal steroids. Furthermore, their short stature and tendency to obesity militates against early recognition of excess glucocorticoid exposure.

Both our children had learning difficulties, which added to the difficulty of giving betamethasone drops and may have resulted in overdosage. When intranasal steroids are indicated, giving less potent steroids by metered aerosol should be considered.

References

2-1. Findlay CA, Macdonald JF, Wallace AM, Geddes N, Donaldson MDC. Childhood Cushing’s syndrome induced by betamethasone nose drops, and repeat prescriptions. BMJ. 1998;317:739–401. . (12 September.) [PMC free article] [PubMed]
2-2. Strome M. Down’s syndrome: a modern otorhinolaryngological perspective. Laryngoscope. 1981;91:1581–1593. [PubMed]

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