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EXPERIENCE AND REASON |
* Department of Pediatrics, Division of Pediatric Endocrinology, University of California, San Diego, California, and Children’s Hospital and Health Care Center, San Diego, California
Kaiser Permanente, Pediatric Endocrinology, San Diego, California
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ABSTRACT |
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 TOP ABSTRACT CASE REPORTSDISCUSSIONREFERENCES |
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Key Words: precocious puberty • pubic hair • adrenarche • anabolic steroids
Abbreviations: 17-OHP, 17-hydroxyprogesterone • LH, luteinizing hormone • FSH, follicle-stimulating hormone • DHEA-S, dehydroepiandrosterone-sulfate
Virilization in young children is uncommon and is produced by androgens, which may be from endogenous or exogenous sources. Virilization resulting from exogenous exposure is rare, with 1 previous case report from 19991 and a more recent report from 2003.2 Recently, the increased availability and use of commercial androgen products for cutaneous application has increased the risk of virilization in children through skin contact and passive absorption. We report our experience with 4 children who were virilized by contact with adults using topical androgen preparations.
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CASE REPORTS |
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TOPABSTRACTCASE REPORTSDISCUSSIONREFERENCES |
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The patient’s stepfather, the primary caretaker, was wheel-chair-confined. He had testicular dysfunction and was using testosterone cream (pharmacy compounded; actual content unknown). He applied the cream to his thighs, usually wore shorts, and did not wash his hands after application. The infant often sat on his lap during the time he cared for her.
On examination, the patient was a proportional, white/African American female who was 85.8 cm (94th percentile) tall and weighed 13.7 kg (97th percentile). Her physical examination was normal with the exception of the genital examination, which revealed Tanner stage III pubic hair4 and an enlarged clitoris measuring 3 x 1.2 cm. She had no posterior labial fusion, the labia minora were infantile, and her vaginal orifice and hymen appeared normal for age. She had no axillary hair or acne.
After the endocrinology evaluation, her mother began applying the cream to the stepfather’s back using rubber gloves. Ten days after initiating these precautions, the serum testosterone was <10 µg/dL (<347 pmol/L).
Case Report 2
Patient 2 was a 27-month-old female referred for evaluation of 3 to 4 months of pubic hair growth. Her parents reported that there had been no recent progression in the amount of pubic hair, and they noticed no growth spurt, acne, or apocrine odor. Growth records revealed that her height had been paralleling the 95th percentile since she was 12 months old.
Her father reported using a commercial product containing 4-androstenediol (50 mg/mL) advertised as a "sports skin tonic" (Androsol, BIOTEST Laboratories, LLC, Colorado Springs, CO). He applied the product daily during the time the child was 23 and 25 months of age and had been holding the child in a manner allowing skin-to-skin contact. At the time of referral, the father had not used this product for >2 months.
Laboratory studies included a normal serum 17-OHP level, a serum testosterone level of <10 ng/dL (<347pmol/L), and both LH and FSH levels <1.0 mIU/mL (<1.0 IU/L).
On physical examination she was 94.4 cm (93rd percentile) tall and weighed 18.9 kg (99th percentile). She had no palpable breast tissue, but she had Tanner stage II pubic hair. Her clitoris was prominent and protruded between the labia majora. She had no posterior labial fusion, axillary hair, or acne.
Case Report 3
Patient 3, a 5-year, 2-month-old female, was referred for pubic hair growth and acne for 9 months. Her height had increased from the 10th to the 50th percentile during this time.
Physical examination revealed thickened, dark hair on her lower extremities. She had Tanner stage III pubic hair. She had no facial or axillary hair, and no palpable breast tissue. Clitoral length was 1.2 cm, and the anogenital ratio was normal at 1.5:4.
Her father reported that he was using Androsol spray (active ingredient: 4-androstenediol, 50 mg/mL) twice a day for bodybuilding, alternating 2 months on and 2 months off. The child often slept in the parents’ bed with them, and the father slept without a shirt. His use of the spray coincided with the development and advancement of the child’s physical changes. When the father ceased use of the product, the child’s virilization regressed.
Case Report 4
Patient 4 was a 5-year, 4-month-old male referred to endocrinology for evaluation of a growth spurt and pubic hair growth. His height had paralleled the 75th percentile until 4-years, 4-months and then increased to the 95th percentile 1 year later.
His mother was using topical testosterone cream (pharmacy compounded; specific contents unknown) for female testosterone deficiency. Additional history revealed that both parents were using the cream to achieve desired effects including libido. There was opportunity for exposure in a common family bed.
On physical examination he was a muscular-appearing male weighing 25.4 kg (96th percentile) and 120.6 cm (97th percentile) tall. He had apocrine odor but no acne or axillary hair. The phallus was 8 cm in stretched length. He had normal prepubertal testes 2 cm in length and sparse Tanner stage III pubic hair.5
His serum testosterone level was 62 ng/dL (2150 pmol/L) (normal: <10 ng/dL [<347 pmol/L]). His LH and FSH levels were both <1.0 mIU/mL (<1.0 IU/L), and his bone age was 9 years.
After reported removal of exposure, his serum testosterone levels decreased to 32 ng/dL after 4 weeks and to 17 ng/dL after 4 months but did not return to prepubertal values (<10 ng/dL [<347pmol/L]; Table 2). His physical examination remained unchanged, but his growth velocity remained higher than normal for age (12.3 cm/year).
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Five months after initial evaluation, the testicular examination was unchanged, but a repeat testosterone level was 138 ng/dL (4785 pmol/L). His gonadotropins remained suppressed. The parents reported that the father had returned to using topical testosterone to improve strength and libido.
Case Report 5
Patient 5, a 2-year, 9-month-old female, was referred for the development of pubic hair starting 1.5 months before her examination.
On physical examination she was 100.7 cm (98th percentile) tall and weighed 16.8 kg (95th percentile). She had sparse, straight pubic hair. Her vaginal mucosa was prepubertal, and there was no clitoral enlargement. She had no axillary hair, no acne, and no palpable breast tissue.
Her father had been prescribed a testosterone cream, compounded locally (unknown strength/composition), that he used during the previous 2 years to boost his energy level. The father stopped using the cream when the patient initially developed pubic hair. Simultaneously, the mother was evaluated for hirsutism and had been started on metformin for a presumed diagnosis of polycystic ovary syndrome.
Initial laboratory studies included normal serum 17-OHP and DHEA-S levels but a serum testosterone level of 48 ng/dL (1665 pmol/L). Six weeks later and after removal of the cream, the testosterone level had only decreased to 36 ng/dL (1248 pmol/L). With disposal of household linens and an additional 6 weeks, the testosterone level fell to 9.9 ng/dL (343 pmol/L).
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DISCUSSION |
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TOPABSTRACTCASE REPORTSDISCUSSIONREFERENCES |
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Exogenous exposure to estrogens in cosmetics6 and hygiene products7,8 and from contamination of medicines9 and foods10 has been well documented in the past. Inquiry about exogenous estrogen exposure has become an integral part of the medical history. Androgen use in the United States has increased recently11 as a result of new medical indications, new and easier methods of delivery, and increased ease of acquisition. As a consequence, the potential for exogenous exposure, accidental or nonaccidental, has increased and now must be included in the medical history of children with virilization.
All our patients developed significant virilization from contact with adults who were unaware that the use of topical androgen preparations could be associated with risk of passive transfer of hormone to their close contacts and family members. Four young girls developed pubic hair and/or clitoral enlargement, and 1 had an advanced bone age. A young boy manifested a growth spurt, pubic hair, and advanced skeletal maturation. In all cases, there was opportunity for passive absorption of an active topical androgen. A decrease in androgen levels or regression of virilization after discontinuation of contact was documented in 4 of the 5 cases and implied in case 2.
Of the 6 caretakers, 5 stated that they used these products to achieve desired physical effects including strength, libido, or advertised athletic claims. In all cases, these products were obtained through Internet sites or interstate pharmaceutical commerce, often without a prescription. Androsol (BIOTEST Laboratories, LLC) is marketed as a topical sports skin tonic with the active ingredient 4-androstenediol (50 mg/mL); the other topical "testosterone" preparations were pharmacy compounded, and their actual content and strength are unknown. In no case were the parents aware that passive transfer was possible.
The present report differs form the findings of Rolf et al,12 who speculated that topical transfer of hormone to another person was improbable. However, that study involved adult males with a single, brief exposure in whom changes in the clinical degree of virilization would not be readily noticed. In contrast, our patients were prepubertal and had prolonged or repeated exposure. Finally, an unpublished study cited in the product literature for AndroGel testosterone gel (Unimed Pharmaceuticals, Inc, Buffalo Grove IL) reported the female partners (N = 38) of males using 10 mg of AndroGel had serum testosterone concentrations >2 times baseline after daily 15-minute sessions of vigorous skin-to-skin contact.
Virilization of young children may have negative physical and psychosocial effects. Long-term exposure to androgens may accelerate skeletal maturation and lead to risk of early central puberty and decreased final adult height. Physicians evaluating prepubertal children with virilization must consider the possibility of exogenous androgen exposure. Physicians prescribing topical androgen products and adults using such products must be aware of the risk of this exposure. Topical androgen use by adults can lead to virilization of passively exposed children, creating a serious health risk.
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FOOTNOTES |
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Address correspondence to Gregory J. Kunz, MD, Children’s Hospital, MC 5103, 3020 Children’s Way, San Diego, CA 92123-4282. E-mail: gjkunz{at}cox.net
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REFERENCES |
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TOPABSTRACTCASE REPORTSDISCUSSIONREFERENCES |
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