Summary. Three spontaneous reports of patients in whom a relationship between hypertrichosis and inhaled corticosteroids (ICS) was suspected, were reported to Lareb, The Netherlands Pharmacovigilance Center. We sought evidence for and against a causal relationship between hypertrichosis and ICS in children. The relationship between hypertrichosis and ICS was studied mathematically by assessing the Reporting Odds Ratio (ROR) and by determining the Naranjo Score (NS). We also studied the reports sent to the Pharmacovigilance Database of the Uppsala Monitoring Centre (UMC) of the WHO and reviewed the literature. In the Dutch children, the ROR between hypertrichosis and ICS was 14.6 (95%CI 3.6-59.5), the NS was 4. In the database of the UMC 20 more reports on hypertrichosis and ICS were found, contributing to the results of the Dutch database. Taken together, 11 boys and 12 girls were involved with a mean age of 7 years (range 1-17). The time between the start of ICS and the occurrence of hypertrichosis varied between 1 month and 3 years. Besides the hypertrichosis, growth retardation was found in 5 children and adrenal suppression in 12. In 12 children the outcome after cessation was reported: in 6 children the hypertrichosis improved, whilst in 6 it did not. We found sufficient evidence to support the suspicion that hypertrichosis might be a true adverse effect of ICS. We found no simple dose-effect relationship but obviously there is an individual susceptibility. After cessation of ICS the exaggerated hair growth will not disappear in all children. Hypertrichosis may be a useful clinical pointer to exogenous steroid excess. Pediat

MD T W De Vries

MPharmSc J J De Langen-Wouterse

PhD E J Duiverman

PhD L T W De Jong-Van Den Berg

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Pediatric Pulmonology 42:370–373 (2007)
Hypertrichosis as a Side Effect of Inhaled
Steroids in Children
T.W. de Vries, MD,1* J.J. de Langen-Wouterse, MPharmSc,2 L.T.W. de Jong-Van den Berg, PhD,3
and E.J. Duiverman, PhD4
Summary. Three spontaneous reports of patients in whom a relationship between
hypertrichosis and inhaled corticosteroids (ICS) was suspected, were reported to Lareb, The
Netherlands Pharmacovigilance Center. We sought evidence for and against a causal
relationship between hypertrichosis and ICS in children. The relationship between hypertrichosis
and ICS was studied mathematically by assessing the Reporting Odds Ratio (ROR) and by
determining the Naranjo Score (NS). We also studied the reports sent to the Pharmacovigilance
Database of the Uppsala Monitoring Centre (UMC) of the WHO and reviewed the literature. In the
Dutch children, the ROR between hypertrichosis and ICS was 14.6 (95%CI 3.6–59.5), the NS
was 4. In the database of the UMC 20 more reports on hypertrichosis and ICS were found,
contributing to the results of the Dutch database. Taken together, 11 boys and 12 girls were
involved with a mean age of 7 years (range 1–17). The time between the start of ICS and the
occurrence of hypertrichosis varied between 1 month and 3 years. Besides the hypertrichosis,
growth retardation was found in 5 children and adrenal suppression in 12. In 12 children the
outcome after cessation was reported: in 6 children the hypertrichosis improved, whilst in 6 it did
not. We found sufficient evidence to support the suspicion that hypertrichosis might be a true
adverse effect of ICS. We found no simple dose-effect relationship but obviously there is an
individual susceptibility. After cessation of ICS the exaggerated hair growth will not disappear in all
children. Hypertrichosis may be a useful clinical pointer to exogenous steroid excess. Pediatr
Pulmonol. 2007; 42:370–373.  2007 Wiley-Liss, Inc.
Key words: asthma; inhaled corticosteroids; side effects; hypertrichosis; hair; individual
susceptibility.
INTRODUCTION
Inhaled corticosteroids (ICS) are the cornerstones in
the maintenance treatment of asthma.1–3 Well-known
adverse drug reactions of ICS include growth retardation,
hoarseness, oral candidiasis, laryngeal irritation, and
adrenal suppression.4
Recently we screened the reports of suspected adverse
drug reactions (sADRs) in children associated with the use
of ICS and found three reports on hypertrichosis.5 In the
present article we describe these patients in more detail.
Also we describe the reports of the Pharmacovigilance
Database of the Uppsala Monitoring Centre (UMC) of
the World Health Organization (WHO) and discuss the
plausibility of the relationship between ICS and hyper-
trichosis. In this article, hypertrichosis is defined as
excessive hair growth, without a specific localization,
whereas hirsutism is excessive hair growth in the mascu-
line pattern.
REPORTS OF CASES IN THE DUTCH DATABASE
The first report concerns a 6-year-old girl who used
400 mg budesonide daily via a pressurized metered dose
inhaler (pMDI) with a spacer. She had terbutaline as a
reliever for acute dyspnoea. After the use of budesonide
growth of hair on her back, arms and legs was noted.
The second report concerns a girl of 10 years who daily
inhaled 500 mg fluticasone and budesonide 400 mg
1Department of Pediatrics, Medical Centre Leeuwarden, Leeuwarden, The
Netherlands.
2Netherlands Pharmacovigilance Centre Lareb, ‘s-Hertogenbosch, The
Netherlands.
3Department of Social Pharmacy, Pharmacoepidemiology and Pharma-
cotherapy, Groningen University Institute for Drug Exploration,
Groningen, The Netherlands.
4Department of Pediatrics, Division of Pediatric Pulmonology, Beatrix
Children’s Hospital, Groningen, The Netherlands.
*Correspondence to: T.W. de Vries, MD, Department of Pediatrics,
Medical Centre Leeuwarden, P.O. Box 888, 8901 BR Leeuwarden, The
Netherlands. E-mail: tjalling.de.vries@znb.nl
Received 13 November 2006; Revised 19 December 2006; Accepted 28
December 2006.
DOI 10.1002/ppul.20589
Published online 9 March 2007 in Wiley InterScience
(www.interscience.wiley.com).
 2007 Wiley-Liss, Inc.
concurrently as well as 50 mg beclomethasone nasal spray.
After 3 years hair growth on the back, arms and legs was
noted. She also experienced non-fatal adrenal suppression
and growth retardation, these were preceded by the
hypertrichosis. From the reporting physician we learned
that, after dose reduction of the ICS, the pattern of the hair
growth normalized.
The third patient is a 3-year-old boy who inhaled
fluticasone 250 mg daily for 3 months. He also had
triamcinolone ointment for his skin. Growth of hair on his
legs, arms and face was noted. We tried to contact the
reporting physicians and pharmacists, only in the second
case additional information was retrieved.
PHARMACOVIGILANCE DATA
Lareb, The Netherlands Pharmacovigilance Center,
received 89 sADRs on ICS in children in the years 1984–
2005, 3 of these concerned hypertrichosis (3.3%). The
relationship between ICS and reported sADRs can be
evaluated mathematically by computing the Reporting
Odds Ratio (ROR). The ROR compares the frequency of
the reported sADR for a certain drug with the frequency of
reports of that adverse effect for all other drugs in the
database. A lower limit of the 95% confidence interval of
above 1.0 suggests a possible relationship between
the reported sADR and the suspect drug.5 The ROR
for hypertrichosis and ICS in the Dutch database is
14.6 (95%CI 3.6–59.5).
The Naranjo Score (NS) evaluates the causality of
drugs on an individual basis. The NS includes relations
between drugs and side effects in time, improvement after
cessation of the drug, reappearance after reintroduction,
exclusion of other causes of the adverse effect, and dose
response relations.6
The mean NS of the three reports in the Dutch database
for hypertrichosis and ICS is 4. Both the elevated ROR and
NS are indicative of a possible causal relation between ICS
and hypertrichosis.
We studied the database of UMC of the WHO for
reports that might confirm the findings from the Dutch
database. The database of the WHO comprised
3,230 reports on ICS and 105 of these subjects (3.2%)
concerned hypertrichosis, which is nearly the same
proportion as in the Dutch database. Twenty of these
concerned individuals younger than the age of 19 years.
Table 1 summarizes the reports of hypertrichosis in the
23 children of the UMC and the Dutch database.
Eleven boys and 12 girls were involved; their mean age
was 7 years (range 1–17); 19 of them were younger
than the age of 10. The drugs suspected include
beclomethasone (three cases), betametasone (3), budeso-
nide (10), fluticasone (6), and flunisolide (1). In two of the
six children on fluticasone was the daily dose given. One
of them, a girl, received 500 mg, this is more than 400 mg
fluticasone which is considered the threshold for safety.4
The other, a boy, received 250 mg fluticasone daily.
The mean daily dose of the other steroids was 277 mg. The
indication for use was asthma in eight children and
allergic rhinitis in five, in the remaining cases the
indications were not mentioned. One child also used
itraconazol, a potent antifungal drug. It decreases steroid
metabolism leading to higher systemic blood levels.7
Other co-medications used were betamimetics. Twelve
children used corticosteroids with more than one route of
administration, for example, also for dermal use. Other
drugs used include short and long acting betamimetics and
oral antihistaminics.
The latency time between the start of using ICS and
hypertrichosis in the UMC varied between 1 and
36 months. The follow-up after cessation of ICS was
reported in 12 children, 6 improved and 6 did not. The
duration of the follow-up had not been reported. Other side
effects reported in these children were growth retardation
in 6 patients and adrenal suppression and/or Cushing
syndrome in 12 patients.
DISCUSSION
In The Netherlands, hypertrichosis was reported as a
possible side effect of inhaled steroids. Because the Dutch
Pharmacovigilance Center only receives reports of sADRs
we do not have extensive information of the patients. We
contacted the reporting physicians and pharmacists to get
TABLE 1—Summary of the 23 Reports of Hypertrichosis
after ICS From the Vigibase and the Dutch Database
Sex (male/female) 11/12
Age Mean 7 years (range 1–17 years)
Primary suspected drug
Beclomethasone 3
Budesonide 10
Fluticasone 6
Betamethasone 3
Flunisolide 1
Daily dose
Fluticasone Mean: 375 mg (range 250–500 mg)
Other steroids Mean: 277 mg (range 50–500 mg)
Indicationa
Asthma 8
Allergic rhinitis 5
Latency timea Mean 9 months (range 1–36 months)
Outcomea
Improved 6
Not improved 6
Other reported side effectsa
Growth retardation 5
Adrenal suppression 12
aNot mentioned in all cases.
ICS Could Cause Hypertrichosis 371
additional information, and received some more informa-
tion about the second case. The first patient had a dose of
ICS, not exceeding the advised dose. The total dose of
steroids in the second patient exceeded the maximum dose
regarded to be safe.4
The third patient is a young boy on a normal dose of ICS
but also using dermal steroids and itraconazole. The
dermal use of triamcinolone could have increased the risk.
However, in daily practice more children receive other
forms of steroids during the use of ICS for allergic asthma
often is accompanied by other conditions also treated with
steroids, such as allergic rhinitis and atopic dermatitis.
The doses of ICS in two of these children were lower
than the dose regarded to be safe, and in the reports the
UMC in only one child did the dose exceed that level.
This points more to an individual susceptibility than a
dose-response relationship.
The latency between the start of the medication and the
reported side effect in the reports varies from 1 month to
3 years. Here, however, must be kept in mind that it takes
time for hair to grow and become visible, especially in
Caucasian children. A possible relationship between the
drug and the side-effect is therefore difficult to recognize.
Apparently, hypertrichosis can occur in girls and
even in young children. The youngest child in which
hypertrichosis was reported was 1 year of age.
In the literature, we found three descriptions of
hypertrichosis in children connected to ICS. Hollman
described an 8-year-old girl in whom inhaled triamcino-
lone caused not only growth retardation and obesity but
also hypertrichosis. The hypothalamic-pituitary axis
was tested and appeared normal. After cessation of the
triamcinolone the symptoms, including the hyper-
trichosis, disappeared.8 Patel reported eight children with
adrenal insufficiency after ICS; in one of them, a 5-year-
old boy, hypertrichosis was present. He had used
budesonide 400 mg daily for 12 months. The follow-up
of the hair growth was not described.9
Perry et al.10 described nine children on intranasal
steroids with signs of exogenous steroid excess and in five
of these children also hypertrichosis was noted.
Thus, hypertrichosis was reported in combination with
growth retardation and adrenal insufficiency in the
literature as well as in the reports presented here.
Therefore, we believe that hypertrichosis is a sign of at
an exogenous steroid excess and sometimes precedes
adrenal insufficiency. After cessation of the ICS the
hypertrichosis will improve in some children, as seen in
the children of the UMC database, however, in other
children it will not disappear. This could have an important
impact on the social well-being of the children and
especially the girls.
In the literature we found no reports of hypertrichosis in
adults after ICS. Of course, hypertrichosis does not occur
in male adults. The prevalence of hirsutism in the general
adult female population is about 5%.11 In a recent review,
ICS were not mentioned as a possible explanation of
hypertrichosis in adults.12
Hypertrichosis in childhood occurs rarely and has a
wide differential diagnosis, including pubertas praecox,
21-hydroxylase deficiency, and excess of androgens in
androgen producing tumors. Drugs associated with
hypertrichosis are cyclosporine A, tacrolimus, phenytoin,
and oral steroids. In oral corticosteroids such as
dexamethasone and hydrocortisone, hypertrichosis is
recognized as an infrequent side effect and is included in
the Summary of Product Characteristics. Hypertrichosis
occurs often in patients with endogenous excess of
corticosteroids, such as Cushing’s disease.13 Although
the systemic availability of inhaled steroids is far lower
than that of oral steroids there is a wide variety in steroid
sensitivity between individuals and in tissues.4 It could be
that some children are more susceptible than others are.
In conclusion, we believe that hypertrichosis is a rare
but true adverse effect of ICS in children and that it is
biologically plausible. The risk is possibly due to
individual susceptibility and is increased after higher
doses with concomitant steroid therapy for other diseases.
Hypertrichosis may be a useful clinical pointer to
exogenous steroid excess.
ACKNOWLEDGMENTS
We thank Dr. J. Collins for reviewing the English
language. The authors are indebted to the national
pharmacovigilance centers that contributed data for this
study. The opinions and conclusions, however, are not
necessarily those of the various centers, nor of the WHO.
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ICS Could Cause Hypertrichosis 373


Hypertrichosis as a Side Effect of Inhaled Steroids in Children

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Hypertrichosis as a Side Effect of Inhaled Steroids in Children

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