Precocious sexual development in a male toddler caused by unrecognized transdermal exposure to testosterone: case report and review of the literature

Abstract

Objectives:

Exogenous exposure to transdermal testosterone is often overlooked as a cause of precocious sexual development in children.

Case presentation:

A 16-month-old male presented for a second opinion consultation before commencing treatment with bicalutamide and anastrozole for a presumptive diagnosis of familial gonadotropin-independent male-limited sexual precocity. Enlargement of the penis was first observed at four months of age. The initial evaluation showed isolated elevation of his plasma testosterone level; however, by 16 months, his testosterone level was prepubertal and no pathogenic variants in the LHCGR gene were identified. The history revealed that his grandfather, who had cared for him regularly in the first year of life, had used testosterone gel for treatment of hypogonadism.

Conclusions:

Despite the 2009 “black box” warning issued by the United States Food and Drug Administration (FDA) regarding potential consequences of transdermal testosterone exposure to women and children, this continues to be an important cause of sexual precocity in children. Children are often subjected to unnecessary and costly evaluation before this exposure is recognized, underscoring the importance of obtaining a thorough medical, family, and social history tailored to the differential diagnosis.

Introduction

Unintentional exposure to cutaneous androgen products leading to virilization has previously been described in children but continues to be an overlooked cause of precocious sexual development. This prompted the United States Food and Drug Administration (FDA) to issue a “black box” warning in 2009 for commonly used topical testosterone gel products advising about this potential consequence and providing recommendations for proper use to minimize exposure in women and children [1]. With increased use of these products, additional pediatric cases of virilization have been reported from around the world. In all the previously reported cases, the source of exposure was a parent. Here, we describe a male toddler who presented to the Endocrinology Clinic for a second opinion regarding precocious sexual development after undergoing an extensive evaluation at another institution that led to a presumptive diagnosis of familial gonadotropin-independent male-limited sexual precocity and a recommendation to start medical treatment. After conducting additional investigations, which yielded negative results, we discovered that the patient’s grandfather, who had been in close contact with the patient during the first 12 months of his life, had used testosterone gel for treatment of hypogonadism. This case highlights the importance of a thorough history and physical examination to formulate a differential diagnosis and guide the appropriate diagnostic evaluation. To the best of our knowledge, this is the first reported case in whom a person other than the child’s parent was the source of exposure to transdermal testosterone.

Case description

A 16-month-old boy presented for a second opinion consultation regarding sexual precocity. He was born full-term via Cesarean section due to failure to progress and had an uncomplicated postnatal course. His parents noticed enlargement of his penis at about four months of age. At his eight-month well-child check, his pediatrician also noted sparse pubic hair and a rapid increase in length and weight. His testes were not enlarged and he did not have axillary hair or acne, and the review of systems was negative for recurrent emesis, neurologic symptoms, or changes in behavior. There was no family history of precocious puberty.

The child was referred for an initial endocrinology consultation at 10 months of age. The examination showed a large penis (stretched length 8 cm and circumference 3 cm), Tanner stage II pubic hair, and 2 mL testes bilaterally. Bone age (based on the number of ossification centers in the left hemiskeleton) was 13–15 months. Scrotal ultra-sound examination showed normal prepubertal testes and no evidence of an adrenal or hepatic mass. An adrenocorticotropic hormone (ACTH) stimulation test at 12 months of age did not show evidence of a disorder of adrenal steroid biosynthesis. Both baseline and stimulated plasma total testosterone were elevated to 243 and 396 ng/dL, respectively (normal < 10 ng/dL). At 14 months of age, a leuprolide stimulation test showed peak serum luteinizing hormone (LH) of 1.41 mIU/mL (normal < 5 mIU/mL) and peak plasma total testosterone (by mass spectrometry) of 21 ng/dL (normal ≤ 5 ng/dL). Patient received a presumptive diagnosis of familial gonadotropin-independent male-limited sexual precocity and treatment with bicalutamide 50 mg daily and anastrozole 1 mg daily was prescribed. Owing to parental concern about medication side effects, they did not start treatment and sought a second opinion.

At the time of the second opinion consultation at 16 months of age, patient’s weight and length exceeded the 99th percentile for age, with evidence of prior acceleration and an estimated growth velocity of 1.61 cm/month (19.32 cm/year). His stretched penile length was 7.5 cm (mean ± standard deviation for this age: 4.82 ± 0.44 cm) and mid-shaft diameter 2 cm. The scrotum was thin and pendulous and there were a few pubic hairs at the base of the penis. His testes were 2 mL bilaterally. Ultrasound of the testes was normal. Plasma total testosterone was <10 ng/dL, serum LH <0.1 mIU/mL, and beta-human chorionic gonadotropin <0.1 mIU/mL. Owing to our own anchoring bias and despite the inconsistent findings obtained from the available history, physical examination, and biochemical evaluation, we ordered sequencing of the LHCGR gene, which did not reveal any pathogenic variants.

Following our negative evaluation, we obtained a more thorough history from the mother. She denied parental use of androgen-containing products, but then remembered that the maternal grandfather, who provided direct care to the patient in the first year of life while mother attended school, used testosterone gel daily for treatment of hypogonadism. Since the grandfather stopped caring for him after his first birthday, the child had no further progression of secondary sex characteristics, and on follow-up at 17 months of age, his examination was unchanged. He was discharged from Endocrinology Clinic after counseling regarding the risk of central precocious puberty (CPP) as a result of early exposure to androgens. His parents provided informed consent for publication of this case.

Discussion

Although uncommon, exogenous exposure to transdermal androgen-containing products continues to be an important and often unrecognized cause of peripheral sexual precocity in children despite the 2009 United States FDA “black box” warning. A review of the literature identified a publication in 2012 that included a case presentation and review of 14 previous articles (21 cases) of peripheral sexual precocity [2]. We found five additional articles (14 cases) published between 2012 and 2019 [3–7]. Table 1 summarizes the 35 previously published cases, ranging in age from 0 (prenatal exposure) to 6.8 years. The most commonly described signs included pubic hair, enlargement of the penis or clitoris, accelerated growth, and advanced bone age. All these signs were present in our patient. Although testosterone levels varied widely, in all but two cases they were in the pubertal range at the time of the initial evaluation. In most cases, testosterone levels normalized or decreased significantly after discontinuing exposure. Among the patients whose follow-up outcomes were described (n=28), only 68% had either complete or partial regression of pubertal features. It must be noted, however, that duration of follow-up was highly variable and, in some cases, may not have been long enough to detect subtle changes. In two cases, CPP commenced within months of exposure withdrawal and both children received treatment with triptorelin [3, 6].

Table 1.

Summary of clinical characteristics of children inadvertently exposed to androgen-containing products

Characteristic	N = 35a
Age	0–6.8 years
Sex	21 M, 14 F
Duration of exposure	2 months-5.2 years
Signs:
Pubic hair	100%
Increased size of penis or clitoris; scrotal changes	88.6%
Accelerated growth	88.6%
Otherb	54.3%
Advanced bone age (n = 32)	53.1%
Maximum testosterone level (ng/dL)	9.1–938c
Investigations performed (in addition to bone age and baseline biochemical evaluation)	65.7%
Follow-up (duration 10 days-4 years):
Complete/partial regression	54.3%
No regression	20%
Progression to CPP	5.7%
Unclear/unknown	20%
Normal testosterone leveld	57.1%

^a20 articles (2–7).

^bThese include muscular appearance (n = 8), change in behavior/mood (n = 5), acne (n = 4), oily skin/hair (n = 4), erections/masturbation (n = 3), body odor (n = 1), deep voice (n = 1), testicular enlargement (n = 1; prepubertal in volume), gynecomastia (n = 1 in a child exposed to a compounded estradiol, estrone, and testosterone cream), and hyperphagia (n = 1 in a boy using hydrocortisone cream contaminated with testosterone).

^cBaseline testosterone level was normal in 2 cases (in 1 case, exposure to testosterone gel was discontinued 1 month prior to evaluation; in the second case of a child exposed to a compounded estradiol, estrone, and testosterone cream, the testosterone level was obtained at midday).

^dIn 9 cases, testosterone levels decreased significantly from baseline but remained above normal (< 10 ng/dL) at follow-up; 2 cases progressed to CPP; in 2 cases, information on follow-up testosterone level was unavailable; in 2 cases, testosterone level was normal at baseline (see above).

Abbreviations: CPP, central precocious puberty; F, female; M, male.

Prior exposure to endogenous sex steroids has been associated with the development of CPP in McCune-Albright syndrome, congenital adrenal hyperplasia (CAH), adrenal tumors, and familial male-limited gonadotropin-independent sexual precocity. Proposed mechanisms include the priming effect of sex steroids on the hypothalamus or a response to the abrupt decrease in sex steroid levels once control of the underlying etiology of sexual precocity is achieved. Accelerated maturation of the hypothalamic-pituitary-gonadal axis appears to be synchronous with advancement of bone age [8]. It has been suggested that adult height may be compromised in individuals who have had early exposure to sex steroids [9]; however, other studies demonstrated normalization of osseous maturation following termination of sex steroid exposure (e.g., after a brief course of intramuscular testosterone administration for treatment of micropenis) [10]. It has also been hypothesized that early sex steroid exposure may compromise adult penile length; however, several studies in humans have not substantiated this notion [9, 11].

About two-thirds of previously described cases underwent additional testing beyond baseline biochemical evaluation and bone age, including abdominal imaging, gonadotropin-releasing hormone (GnRH) agonist simulation tests, and ACTH simulation tests, before a history of exogenous exposure was ascertained. In several cases, another presumptive diagnosis (such as CAH) was initially made and several children received treatment with gluco-corticoids. In our patient, the initial diagnosis was familial gonadotropin-independent male-limited precocious puberty (without genetic confirmation), and treatment with bicalutamide and anastrozole was prescribed. These issues raise concern that many children may be exposed to uncomfortable and costly procedures and may receive unnecessary medications with adverse side-effect profiles before the correct diagnosis is made. On rare occasions, exposure to androgen-containing products may mask and delay the diagnosis of another underlying condition such as adrenocortical carcinoma [12].

In all the previously published cases, the source of the androgen exposure was a biological parent or stepparent. The most common reasons for using these products included conditions associated with hypogonadism, decreased libido, and body building. Our case is particularly unusual in that a non-parental caregiver (grandfather) caused the testosterone exposure, underscoring the importance of obtaining a comprehensive family and social history when assessing a child for peripheral sexual precocity, especially when the initial diagnostic evaluation does not suggest another organic cause. Figure 1 shows a diagnostic pathway for evaluating a boy with isosexual precocity.

Figure 1:

Flow chart guiding the diagnostic evaluation of a boy with isosexual precocity.

*Severe primary hypothyroidism can rarely present with bilateral testicular enlargement, but without any other signs of sexual development. Testicular enlargement typically regresses with thyroid hormone replacement. ^†In these conditions, testicular enlargement is mild and the testes usually remain prepubertal in volume. ^‡In equivocal cases, a gonadotropin-releasing hormone agonist stimulation test may be indicated. ^§In equivocal cases, an adrenocorticotropic hormone stimulation test may be indicated. Abbreviations: 17-OHP, 17-hydroxyprogesterone; CAH, congenital adrenal hyperplasia; CNS, central nervous system; CPP, central precocious puberty; DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulfate; FSH, follicle stimulating hormone; β-hCG, beta-human chorionic gonadotropin; HPG, hypothalamic-pituitary-gonadal; LH, luteinizing hormone; MRI, magnetic resonance imaging; T, testosterone.

What is new?

• This is the first reported case in whom a person other than the parent was the source of exposure to transdermal testosterone leading to virilization in a child.

• We provide a comprehensive review of previously reported cases of virilization caused by exogenous exposure to androgen-containing products and a diagnostic pathway for evaluation of isosexual precocity in a boy.

Learning points.

• Exogenous exposure to transdermal androgens should always be included in the differential diagnosis for children presenting with evidence of peripheral sexual precocity as it can spare patients unnecessary and costly evaluation and intervention.

• Physicians should be aware of their own anchoring biases, especially when evaluating patients for a second opinion in cases with rare diagnoses.

• Adult endocrinologists should be mindful in counseling patients treated with topical testosterone preparations about the risk of cutaneous exposure in female partners and children.