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.
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|
|Chronologic age||1 year 8 months||3 years 8 months|
|Bone age||2 years 8 months||3 years 6 months|
|Luteinizing hormone, IU/L||<0.1||<0.1||<1||<1||0–6|
|Follicle stimulating hormone, IU/L||0.5||0.4||1||2||0–4|
|Dehydroepiandrosterone sulfate, mmol/L||<0.1||<0.4||<0.4||0.3–6.0|
|17 Hydroxyprogesterone, nmol/L||0.2||3.4||1.6||<12|
|Thyroid stimulating hormone, mU/L||1.58||1.74||0.2–6.0|
|Beta-Human chorionic gonadotropin, IU/L||<2||0–5|
|Abdominal/pelvic magnetic resonance imaging||Normal|
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).
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 report||Age at presentation, years||Gender||Clinical findings at presentation||Exposure||Total serum testosterone level at presentation (reference range)|
|Nelson et al. (current case reports)||1.8||Male||Tanner stage 2 pubic hair, enlargement of phallus||Father on testosterone cream||3.6 nmol/L (0–1 nmol/L)|
|3.7||Female||Tanner stage 2 pubic hair||Father on testosterone cream||19.6 nmol/L, (0–1 nmol/L)|
|Franklin (19)||5.25||Twin males||Twin A: Tanner stage 3 pubic hair, Tanner stage 3 breast development, rapid growth||Mother using compounded transdemal estrogen, estradiol, and testosterone creams||Twin A: 0.32 nmol/L (<0.24 nmol/L)|
|Twin B: Tanner stage 3 breast development||Twin B: N/A|
|Cavender et al. (14)||0.8||Male||Tanner stage 2 pubic hair, enlargement of phallus||Father on testosterone cream||30.3 nmol/L (<0.1–0.3 nmol/L)|
|Stephen et al. (11)||2.6||Male||Tanner stage 2 pubic hair||Father on testosterone cream||12.9 nmol/L (<0.1–0.3 nmol/L)|
|Bhowmick et al. (13)||1.3||Male||Tanner stage 2 pubic hair, enlargement of phallus||Father on testosterone gel||2.1 nmol/L (<0.1–0.3 nmol/L)|
|Brachet et al. (12)||2.5||Female||Tanner stage 2 pubic hair, clitoromegaly, rapid height gain, greasy hair, comedones||Father on testosterone gel||5.9 nmol/L (<2.1 nmol/L)|
|1.5||Female||Pubic hair, clitoromegaly||Father on testosterone gel||3.2 nmol/L (<2.1 nmol/L)|
|2.7||Male||Tanner stage 2 pubic hair, enlargement of phallus, greasy hair||Father on testosterone gel||6.2 nmol/L (<2.1 nmol/L)|
|Svoren et al. (9)||1.7||Male||Tanner stage 2 pubic hair, enlargement of phallus, growth acceleration||Hydrocortisone cream prescribed for eczema was contaminated by testosterone||17.5 nmol/L (0–0.9 nmol/L)|
|Kunz et al. (7)||1.5||Female||Tanner stage 3 pubic hair, clitoral enlargement||Stepfather using testosterone cream||13.5 nmol/L (<0.3 nmol/L)|
|2.2||Female||Tanner stage 2 pubic hair, clitoromegaly||Father 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|
|5.2||Female||Tanner stage 3 pubic hair, acne||Father using 4-androstenediol commercial “spray for body building”||0.14 nmol/L (<0.1–0.35 nmol/L)|
|5.3||Male||Tanner stage 3 pubic hair, enlargement of phallus||Mother and father using testosterone cream||2.2 nmol/L (<0.3 nmol/L)|
|2.7||Female||Pubic hair||Father using testosterone cream||1.7 nmol/L (<0.3 nmol/L)|
|Franklin et al. (8)||2.7||Male||Tanner stage 3 pubic hair, adult sized phallus||Father on testosterone cream||12.5 nmol/L (<0.3 nmol/L)|
|Yu et al. (6)||2.7||Male||Pubic hair and enlargement of phallus||Father on testosterone cream||1.7 nmol/L (0–0.9 nmol/L)|
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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