Endocrine Effects of Inhaled Corticosteroids
June 1, 1998
Special Feature
Endocrine Effects of Inhaled Corticosteroids
By Myron Genel, MD, FAAP
As every pediatrician knows, asthma is perhaps the most prevalent chronic pediatric disease. It is a leading cause of morbidity throughout the world, affecting 2-10% of children. Asthma accounts for an estimated 2 million pediatric visits a year. In the United States, asthma is responsible for about one-third of all school absenteeism. Asthma is the most common cause of hospitalization of children. A consistent increase in the prevalence of asthma has been documented over the past two decades throughout the western world. Although the reason or reasons for this increase have not been convincingly demonstrated, in the United States, it appears to be associated with poverty and related exposure to mite and cockroach allergens, increasing urbanization, increasing pollution, and perhaps decreasing physical exercise in these television-dominated times.
There is universal agreement that airway inflammation and airway hyperactivity are the most important factors in the pathogenesis of asthma. Inflammation of the airway is evidenced by an inflammatory infiltrate that is rich in eosinophils. Airway hypereactivity is clinically evident by brochospasm, clinical wheezing, and airway obstruction as demonstrated by a reduced peak expiratory flow rate (PEFR).
Therapy of asthma is directed at both inflammation and brochospasm, so that the mainstays of therapy usually involve administration of beta-adrenergic antagonists and anti-inflammatory medications-especially glucocorticoid steroids. Glucosteroids were initially administered orally or parenterally, but, more recently, the therapeutic emphasis has shifted to the use of potent glucocorticoids that are delivered directly to the inflamed airway by inhalation.
A recent expert panel report from the National Institutes of Health (EPR-2) promulgated national guidelines for the diagnosis and management of asthma.1 These guidelines recommended increased use of anti-inflammatory therapy in a stop-wise fashion for the long-term control of asthma. Inhaled corticosteroids (i.e., beclomethasone, budesonide, fluticasone) have been shown to be effective in suppressing airway inflammation in children with asthma, and they are being increasingly used in management of asthmatic children. This increasing use will undoubtedly be accompanied by increasing recognition and documentation of adverse reactions.
The purpose of this review is not to discuss the management of asthma, but to outline some of the endocrinological effects that may complicate therapy with inhaled glucocorticoid preparations. The first of these is steroid associated growth retardation. The pathophysiology of growth suppression by glucocorticoid steroids involves several factors.2 Glucocorticoids in excess of physiologic levels impair the release of growth hormone (GH) by altering the hypothalamic secretion of growth-hormone releasing factor (GHRF). Even at relatively low levels, exogenous glucocorticoids may impair the release of GH, primarily through diminished amplitude rather than frequency of spontaneous pulses. In children treated with glucocorticoids for a variety of conditions, spontaneous GH secretion tends to be low, but response to GHRF is often normal, suggesting that the suppressive effects of glucocorticoids is central. It should be emphasized, however, that GH levels during glucocorticoid therapy are not always reduced, and reductions are influenced by the dose and timing of therapy. Glucocorticoids directly inhibit bone formation and may also promote bone reabsorption. A suppressive effect on collagen metabolism has also been reported.
A substantial number of reports also describe decreased growth in children receiving inhaled steroids.3,4 It may not be wholly accurate to ascribe growth retardation solely to inhaled glucocorticoids, because severe, chronic asthma may impair growth. The systemic effects of inhaled glucocorticoids appear to be largely dose-dependent, and the strength of medications may vary considerably.
| Several Preparations of Inhaled Glucocorticoids* | |||
| Medication | Low-dose | Moderate Dose | High-dose |
| Beclomethasone dipropionate | < 336 mcg/d | 378-672 mcg/d | > 672 mcg/d |
| Budesonide | < 200 mcg/d | 300-400 mcg/d | > 400 mcg/d |
| Flunisolide | < 750 mcg/d | 1000-1250 mcg/d | > 1250 mcg/d |
| Fluticasone proprionate | < 176 mcg/d | 220-440 mcg/d | > 440 mcg/d |
| Triamcinolone Acetonide | < 800 mcg/d | 900-1200 mcg/d | > 1200 mcg/d |
| *Information from the Expert Panel Report 21 | |||
There is general agreement that low-dose inhaled glucocorticoid therapy is associated with a low risk of growth suppression in almost all children. Continuous moderate dose inhaled glucocorticoids can reduce the growth rate of some children by as much as 1-1.5 cm/year, especially in the peripubertal period.2 However, even with chronic, long-term use of inhaled corticosteroids, eventual height does not appear to be affected.5 As the daily dose of inhaled glucocorticoids increases toward the high range, the risk of significant growth suppression increases proportionally. Obviously, children who require continuous, high-dose inhaled glucocorticoid therapy usually have severe disease. Not only may they receive additional parenteral or oral glucocorticoids, but the severity of disease may also affect growth.
A second major endocrinological concern about the use of inhaled glucocorticoids for the treatment of asthma is their possible effect on the hypothalamic-pituitary-adrenal axis. Even low doses may have an effect on the circadian secretion of cortisol.3 However, provocative stimulation tests remain normal in patients treated with standard doses of inhaled glucocorticoids. It must be remembered that high-dose inhaled glucocortiaoid therapy, especially if combined with frequent oral or parenteral glucocorticoids, may impair the endogenous cortisol response to stress.
How should the clinician treat and monitor asthmatic children receiving inhaled glucocorticoid therapy? First, particularly in children with mild disease, non-steroidal medications should be used as recommended by the EPR-2 guidelines. In children with moderate or severe persistent symptoms, inhaled glucocorticoids are the most effective therapy currently available for control of symptoms. These should be administered with a metered-dose inhaler, and a spacer device should be used to reduce oral deposition. The clinician should keep a record of actual continuous dose being used by a given patient. If symptoms improve, the dose of inhaled glucocorticoids should be reduced to the lowest possible dose consistent with disease control. It is evident that the physician may decide that control of severe asthma is more important than relatively modest effects on growth.6,7
Children should be seen regularly, and their height and growth velocity should be measured. Routine monitoring of the hypothalamic-pituitary-adrenal-axis is not required unless the patient is receiving moderate to high doses plus frequent systemic glucocorticoids. If such children are subjected to acute severe stress (i.e., surgery, trauma), replacement corticosteroid therapy may be prudent. v
References
1. Expert panel report 2. Guidelines for the diagnosis and management of asthma. NIH publication No. 97-4051, Bethesda, April 1997.
2. Allen DB. Influence of inhaled corticosteroids on growth: A pediatric endocrinologist's perspective. Acta Paediatr 1998;87:123-129.
3. Wolthers OD, Pederson S. Controlled study of linear growth in asthmatic children during treatment with inhaled corticosteroids. Pediatrics 1992;89:839-842.
4. Allen DB, et al. A meta-analysis of the effects of oral and inhaled glucocorticoids on growth. J Allergy Clin Immunol 1994;93:967-976.
5. Agertoft L, Pederson S. Effects of long-term treatment with an inhaled corticosteroid on growth and pulmonary function in asthmatic children. Respir Med 1994;88:373-381.
6. Lemanske RF, Allen DB. Choosing a long term controller medication in childhood asthma: The proverbial two edged sword. Am J Respir Crit Care Med 1997; 156:685-687.
7. Wagener JS, Wojtezak HA. Inhaled steroids in children: Risks versus rewards. J Pediatr 1998;132: 381-383.
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