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Danger: transdermal testosterone and virilization of kids


guijr
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When using transdermal Testosterone be double careful when giving a hug to your kids.

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Kunz GJ, Klein KO, Clemons RD, Gottschalk ME, and Kenneth Lee Jones. Virilization of Young Children After Topical Androgen Use by Their Parents. Pediatrics. 2004;114(1):282-284.

ABSTRACT

Children were virilized by contact with adults using cutaneous steroid preparations. Parents were unaware of the dangers of passive transfer. Laboratory data were consistent with exogenous androgen exposure. Each child had opportunity for passive exposure, and discontinuation of contact resulted in a decrease of androgen levels or regression of symptoms.

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).

CASE REPORTS

Each child was referred for evaluation of physical findings of virilization or concern about precocious puberty. No patient had a family history of sexual precocity. Each patient’s past medical history and review of systems were otherwise unremarkable (Table 1: tables were not included).

Case Report 1

Patient 1 was an 18-month-old female referred for evaluation of pubic hair growth and clitoromegaly. Birth records and well-child visits through 6.5 months of age were normal. Laboratory studies included a normal 17-hydroxyprogesterone level (17-OHP) and a serum testosterone level of 390 µg/dL (13 523 pmol/L) (prepubertal children: <10 µg/dL [<347 pmol/L]). Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were both <1.0 mIU/mL (<1.0 IU/L). Bone age, determined by the standards of Gruelich and Pyle,3 was 3 years at the chronological age of 18 months.
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).

The decrease in testosterone was paralleled by an increase in 17-OHP, dehydroepiandrosterone-sulfate (DHEA-S), androstenedione, and 11-desoxycortisol. This unexpected finding prompted a corticotropin-stimulation test to evaluate for an underlying adrenal disorder. This was the only case in which a stimulation test was performed. Since normal initial baseline and corticotropin-stimulated adrenal hormone levels were documented, no adrenal disorder was present. The interval elevation of adrenal hormone levels most likely reflected the response to stressful procedures (phlebotomy).
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).

Discussion

The differential diagnosis of virilization in childhood includes both endogenous and exogenous causes. Endogenous causes include central gonadotropin secretion (precocious puberty) and LH- and ß-human chorionic gonadotropin-secreting tumors in males. The virilizing forms of congenital hyperplasia and androgen-secreting tumors of the gonad or adrenal cortex may result in virilization of both sexes. Constitutively activating mutations of the gonadotropin receptor result in virilization of patients with familial male precocious puberty (testotoxicosis) and males with McCune-Albright syndrome. Our patients had normal physical examinations apart from virilization, no laboratory evidence of adrenal enzyme deficiency or tumor markers, and no progression of clinical findings after cessation of androgen exposure.

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

REFERENCES

1. Yu YM, Punyasavatsu N, Elder D, D’Ercole AJ. Sexual development in a two-year-old boy by topical exposure to testosterone. Pediatrics. 1999:104(2). Available at: www.pediatrics.org/cgi/content/full/104/2/e23..

2. Franklin SL, Geffner ME. Precocious puberty secondary to topical testosterone exposure. J Pediatr Endocrinol Metab. 2003;16:107–110.

3. Greulich WW, Pyle SI. Radiographic Atlas of Skeletal Development of the Hand and Wrist. Stanford, CA: Stanford University Press; 1959.

4. Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child. 1969;44:291–303.

5. Marshall WA, Tanner JM. Variations in pattern of pubertal changes in boys. Arch Dis Child. 1970;45:13–23.

6. Zimmerman PA, Francis GL, Poth M. Hormone-containing cosmetics may cause signs of early sexual development. Mil Med. 1995;160:628–630.

7. Tiwary CM. Premature sexual development in children following the use of estrogen- or placenta-containing hair products. Clin Pediatr (Phila). 1998;37:733–739.

8. Beas F, Vargas L, Spada RP, Merchak N. Pseudoprecocious puberty in infants caused by a dermal ointment containing estrogens. J Pediatr. 1969;75:127–130.

9. Weber WW, Grossman M, Thom JV, Sax J, Chan JJ, Duffy MP. Drug contamination with diethylstilbestrol. Outbreak of precocious puberty due to contaminated acid hydrazide (INH). N Engl J Med. 1963;268:411–415.

10. Saenz de Rodriguez CA, Bongiovanni AM, Conde de Borrego L. An epidemic of precocious development in Puerto Rican children. J Pediatr. 1985;107:393–396.

11. Basaria S, Wahlstrom JT, Dobs AS. Clinical review 138: anabolicandrogenic steroid therapy in the treatment of chronic diseases. J Clin Endocrinol Metab. 2001;86:5108–5117.

12. Rolf C, Knie U, Lemmnitz G, Nieschlag E. Interpersonal testosterone transfer after topical application of newly developed testosterone gel preparation. Clin Endocrinol (Oxf). 2002;56:637–641.

FOOTNOTES

Received for publication Mar 17, 2003; Accepted Feb 2, 2004.

Address correspondence to Gregory J. Kunz, MD, Children’s Hospital, MC 5103, 3020 Children’s Way, San Diego, CA 92123-4282. E-mail: [email protected]

"The medals don't mean anything and the glory doesn't last. It's all about your happiness. The rewards are going to come, but my happiness is just loving the sport and having fun performing" ~ Jackie Joyner Kersee.


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