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Journal of Pediatric Endocrinology and Metabolism

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Virilization in two pre-pubertal children exposed to topical androgen

Danielle Nelson1 / 2 / Danièle Pacaud2 / David Stephure2

1Department of Pediatrics, Section of Community Pediatrics, University of Calgary, Calgary, Canada

2Department of Pediatrics, Section of Pediatric Endocrinology, University of Calgary, Calgary, Canada

Corresponding author: Josephine Ho, Faculty of Medicine, Department of Pediatrics, Section of Pediatric Endocrinology, University of Calgary, Alberta Children’s Hospital, 2888 Shaganappi Trail NW, Calgary, T3B 6A8, Canada, Phone: +1-403-955-7819, Fax: +1-403-955-5001, E-mail:

Citation Information: Journal of Pediatric Endocrinology and Metabolism. Volume 26, Issue 9-10, Pages 981–985, ISSN (Online) 2191-0251, ISSN (Print) 0334-018X, DOI: 10.1515/jpem-2013-0127, May 2013

Publication History

Received:
2013-03-28
Accepted:
2013-04-18
Published Online:
2013-05-24

Abstract

Androgen replacement therapy for male hypogonadism may be prescribed utilizing intramuscular, oral or more recently, topical formulations. With topical formulations, there is a risk of person-to-person transmission if appropriate precautions are not taken. We describe two cases of virilization in pre-pubertal children following passive transfer of paternal topical testosterone. A 21 month old male was referred with a 6 week history of pubic hair, phallic growth, and linear growth spurt. Genital examination revealed Tanner stage 2 pubic hair and Tanner stage 3 phallic development, which was discordant with the pre-pubertal testicular size (2 mL bilaterally). A 3 year 8 month old girl was referred for a 2 month history of increasing pubic hair development. Examination revealed Tanner stage 2 pubic hair and Tanner stage 1 breast development. Both of these patients had fathers who had been diagnosed with hypogonadism and were being treated with topical androgen gel therapy, which they applied to their arms and chest before bed. In addition, both patients often slept with their parents resulting in skin-to-skin contact. Investigations were consistent with gonadotropin independent virilization with both patients demonstrating elevated testosterone levels. Testosterone levels returned to normal pre-pubertal levels with no further development of secondary sexual characteristics following discontinuation of exposure to topical testosterone. Precautions must be taken to prevent person-to-person transfer of topical steroids. With the increasing popularity of topical steroids for the treatment of low testosterone, it is imperative that these therapies be prescribed and utilized judiciously to prevent harm, specifically gonadotropin-independent virilization.

Keywords: testosterone; topical; virilization

Introduction

Precocious puberty may occur via exposure to endogenous and exogenous sources of anabolic steroids. Endogenous sources include central or gonadotropin-dependent virilization, congenital adrenal hyperplasia, androgen-secreting adrenal tumors, luteinizing hormone (LH)- and beta-human chorionic gonadotropin (HCG)-secreting tumors, and constitutively active gonadotropin-receptors. Less commonly precocious puberty can occur as a consequence of exposure to exogenous sex steroids in the form of contaminated food, medications, or cosmetics (1–5). There are several recent reports of precocious puberty following exposure to topical androgens (6–14), while there is an increasing trend to use androgen-replacement for “androgen-deficiency” and other illnesses in the community (15), with topical gels and creams as a popular route of administration. Unfortunately, not all practitioners follow current recommendations for the diagnosis and treatment of the androgen-deficient state (16–18). These cases emphasize the need for physicians to educate patients about the risk of person-to-person contact when prescribing topical androgen replacement therapy.

Case reports

Case 1

A 21-month old boy was referred for a 6 week history of pubic hair development (sparse, light hair), and penile growth (both thickening and lengthening of the phallus). A growth spurt was noted in terms of height, along with an increase in the size of his hands and feet. There was no history of acne, diaphoresis, adult body odor, or change in voice. Some mood lability was noted by his parents. There was no history of exposure to cosmetics, ingestion, or exposure to meat products from one source or animal, head trauma, or radiation exposure.

The child’s past medical history was unremarkable other than some mild atopy (mild asthma, eczema, environmental allergies). He was born at term by cesarean section following an uncomplicated pregnancy. Birth weight was 2727 g. He had never been hospitalized. A circumcision in the neonatal period was well tolerated. His only current medication was pimecrolimus (Elidel®, Valeant Canada Ltd.) for eczema. The child had a speech delay and sleep associations. He slept in his parents’ bed and required rocking back to sleep multiple times per night (with direct skin-to-skin contact with his father).

Family history was remarkable for the child’s father having been diagnosed with androgen-deficiency (serum testosterone 4.9, 5.3, 6.0, and 7.1 nmol/L, normal adult values 8–29 nmol/L). He was started on replacement therapy with testosterone in the form of Androgel® (Abbott Laboratories, Chicago, IL, USA) 5 mg packets (1–2 packets/day) that he applied to his chest and arms before bed. There was no family history of congenital adrenal hyperplasia, pituitary disorders, brain tumors, precocious puberty, or infant deaths. The child’s full sibling (6 years of age) also had a speech delay. The rest of his family history was non-contributory.

Vital signs were stable. Growth parameters were normal. The patient was non-dysmorphic other than mild macroglossia with bottom incisor discolouration. The thyroid, cardiovascular, respiratory, abdominal, and neurologic examination were normal. There were small pre-tibial eczematous patches. Genital examination revealed Tanner stage 3 genitalia, discordant with testicular stage (testicular volume 2 mL bilaterally) and Tanner stage 2 pubic hair. There was no evidence of hirsutism or axillary hair. There were no hypo- or hyperpigmented macules. His body habitus was muscular.

At the 4 month follow-up, after discontinuation of exposure to topical androgen, there was no progression in secondary sexual characteristics. Physical examination remained unchanged otherwise. Initial investigations and follow-up are outlined in Table 1.

Case 1
Case 2
Reference range
InitialFollow-upInitialFollow-up
GenderMaleFemale
Chronologic age1 year 8 months3 years 8 months
Bone age2 years 8 months3 years 6 months
Testosterone, nmol/L3.60.419.60.30–1
Estradiol, pmol/L<19<190–130
Luteinizing hormone, IU/L<0.1<0.1<1<10–6
Follicle stimulating hormone, IU/L0.50.4120–4
Androstenedione, nmol/L0.7<1<1<1
Dehydroepiandrosterone sulfate, mmol/L<0.1<0.4<0.40.3–6.0
17 Hydroxyprogesterone, nmol/L0.23.41.6<12
Thyroid stimulating hormone, mU/L1.581.740.2–6.0
Beta-Human chorionic gonadotropin, IU/L<20–5
Abdominal ultrasoundNormalNormal
Abdominal/pelvic magnetic resonance imagingNormal
Table 1

Summary of patient investigations at initial presentation and at follow-up after discontinuing exposure.

Case 2

A 3 year 8 month old girl was referred for a 2 month history of increasing pubic hair development (sparse, light hair). The mother had noted a growth spurt recently as well as a muscular appearance on the legs and calves. There was no history of acne, diaphoresis, adult body odor, change in voice, or breast development. There was no history of head trauma or radiation exposure.

Her past medical history was remarkable for a diagnosis of genetically confirmed familial Mediterranean fever for which she was being followed by pediatric rheumatology and being treated with naproxen and colchicine. Her mother had threatened pre-term labor requiring 2 months of bed rest. She required a 3 day admission to the NICU for jaundice and feeding issues but otherwise did not have any neonatal complications.

The patient has an older brother with mild cerebral palsy and an older sister with familial Mediterranean fever. Her father had been diagnosed with androgen insufficiency and had been using topical androgen gel therapy applied to his arms before bed for the past few months. The patient often slept with her parents with skin-to-skin contact. Her mother has Meniere disease but is otherwise healthy. There was no family history of congenital adrenal hyperplasia, pituitary disorders, brain tumors, precocious puberty, or unexplained infant deaths.

Vital signs were stable. Growth parameters were normal. The patient was non-dysmorphic. The thyroid, cardiovascular, respiratory, and abdominal examinations were normal. She was Tanner stage 2 for pubic hair with no evidence of clitoromegaly. There was no evidence of breast development, acne, or coarse axillary hair.

After discontinuation of exposure to the topical androgen, there was no progression in her secondary sexual characteristics and her elevated serum testosterone level returned to normal (Table 1).

Discussion

The definition of precocious puberty is the presence of secondary sexual characteristics before the age of 9 years in males, and in females before 7 years of age. Statistically, males are more likely to have a pathologic cause of precocious puberty than females. Our two patients presented with signs of virlization at 21 months of age for the boy and 3 years 8 months of age for the girl. This is similar in timing to previous case reports, and our female patient had one of the highest serum testosterone levels at presentation (Table 2). A diagnosis of gonadotropin-independent virilization was given to both our patients. Evidence against an endogenous cause of virilization in our cases included: normal imaging, normal morning serum adrenal steroids, symmetric and small “pre-pubertal” testes for the boy, and a documented exposure to topical testosterone by history with normalization of testosterone levels following discontinuation of the exposure.

Case reportAge at presentation, yearsGenderClinical findings at presentationExposureTotal serum testosterone level at presentation (reference range)
Nelson et al. (current case reports)1.8MaleTanner stage 2 pubic hair, enlargement of phallusFather on testosterone cream3.6 nmol/L (0–1 nmol/L)
3.7FemaleTanner stage 2 pubic hairFather on testosterone cream19.6 nmol/L, (0–1 nmol/L)
Franklin (19)5.25Twin malesTwin A: Tanner stage 3 pubic hair, Tanner stage 3 breast development, rapid growthMother using compounded transdemal estrogen, estradiol, and testosterone creamsTwin A: 0.32 nmol/L (<0.24 nmol/L)
Twin B: Tanner stage 3 breast developmentTwin B: N/A
Cavender et al. (14)0.8MaleTanner stage 2 pubic hair, enlargement of phallusFather on testosterone cream30.3 nmol/L (<0.1–0.3 nmol/L)
Stephen et al. (11)2.6MaleTanner stage 2 pubic hairFather on testosterone cream12.9 nmol/L (<0.1–0.3 nmol/L)
Bhowmick et al. (13)1.3MaleTanner stage 2 pubic hair, enlargement of phallusFather on testosterone gel2.1 nmol/L (<0.1–0.3 nmol/L)
Brachet et al. (12)2.5FemaleTanner stage 2 pubic hair, clitoromegaly, rapid height gain, greasy hair, comedonesFather on testosterone gel5.9 nmol/L (<2.1 nmol/L)
1.5FemalePubic hair, clitoromegalyFather on testosterone gel3.2 nmol/L (<2.1 nmol/L)
2.7MaleTanner stage 2 pubic hair, enlargement of phallus, greasy hairFather on testosterone gel6.2 nmol/L (<2.1 nmol/L)
Svoren et al. (9)1.7MaleTanner stage 2 pubic hair, enlargement of phallus, growth accelerationHydrocortisone cream prescribed for eczema was contaminated by testosterone17.5 nmol/L (0–0.9 nmol/L)
Kunz et al. (7)1.5FemaleTanner stage 3 pubic hair, clitoral enlargementStepfather using testosterone cream13.5 nmol/L (<0.3 nmol/L)
2.2FemaleTanner stage 2 pubic hair, clitoromegalyFather using a commercial “sports skin tonic” 4-androstenediol containing substance<0.35 nmol/L (<0.1–0.35 nmol/L) No exposure for more than 2 months
5.2FemaleTanner stage 3 pubic hair, acneFather using 4-androstenediol commercial “spray for body building”0.14 nmol/L (<0.1–0.35 nmol/L)
5.3MaleTanner stage 3 pubic hair, enlargement of phallusMother and father using testosterone cream2.2 nmol/L (<0.3 nmol/L)
2.7FemalePubic hairFather using testosterone cream1.7 nmol/L (<0.3 nmol/L)
Franklin et al. (8)2.7MaleTanner stage 3 pubic hair, adult sized phallusFather on testosterone cream12.5 nmol/L (<0.3 nmol/L)
Yu et al. (6)2.7MalePubic hair and enlargement of phallusFather on testosterone cream1.7 nmol/L (0–0.9 nmol/L)
Table 2

Literature review of pediatric cases of virilization secondary to exogenous androgen exposure.

Previous reports have demonstrated transdermal transfer of topical androgens from adult males to their female partners (20–22). The transdermal absorption of topical androgens is dependent on several factors including: the area of application, the concentration of androgen, the length of exposure, and the thickness of the skin (15). Previous studies have demonstrated that, although the elevation of testosterone levels in pediatric patients exposed to topical androgens is not very high, the biological response is greater than in older populations (23). This may be related to an increase in activity of 5 alpha-reductase and a higher degree of dermal conversion to dihydrotestosterone (DHT) (24, 25). This has been supported by further studies showing increased serum DHT in younger children treated with testosterone patches.

The consequences of precocious puberty may cross both social and physical domains. Potential risks include advanced bone age with resultant decrease in final adult height, poor self-esteem, and psychosocial issues including a risk for sexual abuse (26). Advanced bone age has previously been reported following topical androgen exposure (8), and our male patient also demonstrated this. Acceleration of skeletal maturation may lead to a decreased final adult height. However, bone maturation may gradually normalize following removal of the exposure (27). Depending on how far the child has progressed through puberty, they may develop central precocious puberty following withdrawal of the androgen source (28). It has also been suggested that early exposure to testosterone may affect adult penile length (29, 30). However, more recent studies have not confirmed this effect (31).

In conclusion, there is increasing availability and use of topical androgen preparations for treatment of androgen-deficient states. This puts the pediatric population at risk for passive transfer of exogenous androgens and gonadotropin-independent virilization. Therefore, it is important to consider this in the differential diagnosis of precocious puberty in the pediatric patient. It is prudent to provide careful patient education about the risks of unintentional transmission of topical androgens, and to prescribe these formulations judiciously, to protect the pediatric population from harm.

The authors would like to gratefully acknowledge the patients and their family who have agreed to share their cases for this report.

Conflict of interest statement

The authors have no conflicts of interest to declare related to this report.

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