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kaifka · 發表於前天 03:25

Sexual Precocity in a 16-Month-Old
Boy Induced by Indirect Topical
Exposure to Testosterone
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
and Kenneth R. Rettig, MD1
Clinical Pediatrics
Volume 46 Number 6
July 2007 540-543
© 2007 Sage Publications
10.1177/0009922806296651
http://clp.sagepub.com
hosted at
http://online.sagepub.com
Precocious puberty in boys, central or peripheral,
is a significant concern for physicians. Central
precocious puberty (CPP), which is mediated
through the hypothalamic pituitary gonadal axis, has
a higher incidence of organic central nervous system
lesions in boys.1,2 Virilization in boys, as manifested
by enlargement of the penis, development of pubic
hair, and facial acne without enlargement of testi-
cles, suggests peripheral or pseudopuberty.1-3 We
report a 16-month-old boy who presented with the
enlargement of the phallus and pubic hair develop-
ment without testicular enlargement, which was due
to the unintentional exposure to androgen gel used by
the father. The family initially concealed this infor-
mation, resulting in an extensive work-up for this
child. Given the widespread and easy availability of
testosterone gel and cream, we believe this is proba-
bly more common than the rare case report in the
literature.4
Patient Report
A 16-month-old white child was referred to the
endocrine clinic by his pediatrician with the concern
of early sexual development. His mother noticed
light colored pubic hair development when he was
From the 1Division of Pediatric Endocrinology, 2University of
South Alabama Medical Center, Mobile, Alabama.
Address correspondence to: Samar K. Bhowmick, MD, FACE,
Professor of Pediatrics, University of South Alabama, College of
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
e-mail: [email protected].
about 6 to 7 months old, which progressively became
darker. She was also concerned about the enlarge-
ment of his penis and frequent erections. The child
was the product of a full-term normal delivery, with
a birth weight of 7 lb 14 oz, and birth length of
20 inches. He was breast-fed throughout the first year
of life and was still receiving breast milk along with
solid food. He had no hospitalizations or surgery,
and his psychosocial and psychomotor development
was age appropriate.
The family history was remarkable for the father,
who was diagnosed with hypothyroidism at age 16,
which was treated with thyroxine. The father’s
height was 6 feet, and he went through a somewhat
early puberty and had stopped growing by age 14.
The father denied taking any other medication. The
child’s mother was in good health. Her menarche
was at 11 years of age, and her height was at 5 feet
5 inches. There was no other family history of pre-
cocious sexual development in the first-degree rela-
tives. There were no siblings.
Physical Examination
The physical examination revealed a very active,
playful, and healthy boy. The vital signs documented
a blood pressure of 85/50 mm Hg, his length was
90 cm (>97th percentile), and his weight was 14.4 kg
(also >97th percentile). The observed yearly growth
velocity was 30 cm (12 inches). The examination of
the neck revealed no thyroid enlargement.
The genitourinary examination was remarkable for
enlargement of the penis, with a stretched length of
8 cm and a width of 2 cm. The glans penis was very well
developed. The pubic hair was Tanner II, mostly around
540
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
the base of the phallus and was dark and curled. The
testicular volume was prepubertal at 2 mL each.
The skin was moist and smooth and somewhat
oily. No axillary hair was noted. There were no
abnormal skin pigmentations or café-au-lait spots.
Neurologic evaluation showed deep tendon reflex 2+
bilateral and symmetrical. There was no suggestion
of papilledema.
Laboratory Evaluation
The bone age was consistent with 28 months by
using the standard of Greulich and Pyle at a chrono-
logic age of 16 months (advanced).5 Chromosomal
karyotype was 46XY. The thyroid function test
showed a free T4 of 1.69 ng/dL, and thyroid stimu-
lating hormone level was 1.3 µIU/mL (both normal).
The concentrations of serum electrolytes, blood
urea nitrogen, creatinine, and calcium all were
within normal range for his age. The concentration
of serum 17-hydroxyprogesterone was 16 ng/dL
(normal, 3 to 90 ng/dL), androstenedione was 20
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
terone was 38 ng/dL (normal, 50 to 760 ng/dL),
desoxycorticosterone was 4.3 ng/dL (normal, 7 to
49ng/dL), 11-desoxycortisol (specific compound S)
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
and β-human chorionic gonadotropin was less than
5 mIU/mL (normal <5 mIU/mL). Serum follicular
stimulating hormone and leuteinizing hormone
concentrations were less than 0.05 mIU/mL
(prepubertal).
The parents were notified about the laboratory
results and were informed that all of the tests were
normal except the testosterone level was high. The
follow-up visit was arranged within a few weeks to
obtain testicular and abdominal sonograms; how-
ever, the family did not return for 4 months.
Physical examination at this time revealed that the
child had grown 2.5 cm in 4 months and had gained
2 kg of weight. Physical examination remained
unchanged. Surprisingly, the pubic hair almost com-
pletely disappeared except for a few vellous hairs at
the base of the phallus. Testicular volume was still 2
mL, and the size of the penis remained unchanged.
The mother also said that the boy was no longer hav-
ing frequent erections.
Both parents were again questioned about use of
any ointment/creams that they may have applied to
the child’s skin. This time the father admitted the
Topical Testosterone Exposure / Bhowmick et al 541
use of testosterone gel twice daily that he was apply-
ing over his own shoulders, chest, and back area for
a year. The father also revealed he was embarrassed
to disclose that he was using a testosterone gel pre-
scribed by his family physician for decreased libido
secondary to depression.
The child slept in the same bed with parents.
The father would hug the baby and hold him on his
chest for a considerable period of time, causing sig-
nificant bare skin contact between baby and father.
The father also admitted that after the phone call,
when he learned the testosterone level in the baby
was high, he then read the product information
packet and concluded that it was most likely the rea-
son for the child’s virilization. At that time, they
decided to put the baby in a separate bed, and the
father was not hugging him with bare skin and had
been using protective clothing. A repeat testosterone
test was ordered, but the family did not go to the
laboratory to obtain the test.
Discussion
Precocious puberty in boys is defined as secondary
sexual development before 9 years of age.1,4
Precocious puberty is termed as central (true) when
it is caused by the premature activation of hypo-
thalamic pituitary gonadal axis. CPP is more com-
mon in girls than in boys.1,3 Most boys with CPP
may have a central nervous system lesion that is
responsible for the early activation of the hypothal-
amic pituitary gonadal axis.1-3 Thus, greater empha-
sis has been given to neuroradiologic imaging in
boys with precocious puberty. In addition to viril-
ization, the clinical hallmark of CPP is the symmet-
rical testicular growth secondary to stimulation by
gonadotropins.1,3
Gonadotropin-independent peripheral preco-
cious puberty in boys also results from inappropriate
androgenic stimulation from either endogenous or
exogenous sources, nonpituitary gonadotropin stim-
ulation, and rare activating mutations.3 Virilizing
congenital adrenal hyperplasia producing excessive
adrenal androgens is a common cause of precocious
puberty in boys.3,4
The most common form of congenital adrenal
hyperplasia is the 21-hydroxylase enzyme deficiency.
The 11-β hydroxylase deficiency may also result in
excessive adrenal androgen production, and rarely,
an adrenal tumor may also cause adrenal androgen
excess.1,3
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
A unique entity of male-limited gonadotropin-
independent precocious puberty, which is also known
as testotoxicosis, may cause precocious puberty at a
very young age. The physical findings in these boys
with this disorder are full pubertal development,
including bilateral testicular growth, similar to boys
with CPP. The gonadotropin levels in this disorder
are suppressed to prepubertal levels and do not show
pubertal response of gonadotropin after gonadotropin-
releasing hormone stimulation. This is a sex-linked
autosomal dominant disorder that affects only
males; therefore, other male members of the family
may have similar precocious puberty.3
In our patient, physical examination was incon-
sistent with true precocious puberty since his testi-
cles were prepubertal in size. However, testotoxicosis
was in the differential diagnosis because his father
started puberty somewhat early, and occasionally,
testicular enlargement is not that evident in the
beginning of this process.1 In the absence of a neg-
ative initial history of androgen exposure, our
biggest concern was virilizing adrenal hyperplasia,
either 21-hydroxylase deficiency or 11-β hydroxylase
deficiency. Those diagnoses were excluded by find-
ing the normal level of adrenal steroids.
The diagnosis of exogenous androgens was strongly
suspected in a follow-up visit after 4 months because
the physical examination revealed the complete disap-
pearance of pubic hair, normal growth velocity, and
decreased erections. The father admitted using a testos-
terone gel, which he concealed at first visit. He was
using it rather frequently, twice a day. The Physicians’
Desk Reference, or package insert of this product, gel or
cream, cautions about dermal testosterone transfer to
unprotected females through direct skin exposure.
Serum testosterone level was found to be 2 times the
baseline value in those females who were exposed to
even 15 minutes of direct skin contact with their male
partners.6 However, when a shirt covered the applica-
tion site, this testosterone transfer was prevented.
Our patient’s testosterone level was 60 ng/mL,
which was clearly high. Some studies suggest that
dermal conversion of testosterone to dihydrotestos-
terone, which is a more potent metabolite, is more
active in young children exposed to testosterone
exogenously7; however, we did not measure a dihy-
drotestosterone level in our patient. In addition to
virilization, exposure to exogenous testosterone in
children results in an increase in growth velocity and
advanced bone age, as seen in our patient.
The long-term effect of androgen exposure during
early childhood on pubertal development and final
adult height are not fully known and always remain
a concern. Children treated with short-term testos-
terone injection or topical androgen may exhibit some
acceleration of the skeletal maturation; however, after
cessation of treatment, the rate of bone maturation
decelerates and gradually returns to normal.8,9
There are conflicting reports and controversy
over the effect of early androgen exposure on adult
penile length.10,11 Some reports suggest subnormal
adult penile length, apparently because of downreg-
ulation of androgen receptor number.10,12 However,
Sutherland et al13 did not find a correlation between
childhood testosterone exposure and reduced adult
penile length in clinical studies.
Nonetheless, we do not believe our patient is
going to experience any of the untoward effects from
testosterone exposure as mentioned earlier because
the exposure was not for a prolonged period of time.
Although the bone age was advanced at the time of
diagnosis, the child had a normal growth velocity at
the follow-up visit. It is hoped that his final adult
height will not be affected.
Although rarely reported, the widespread avail-
ability of androgen products in our society may
indeed cause more virilization in male or female
children than one would realize. Exposure to andro-
gen products must be considered and specific ques-
tioning about the use of a testosterone product or
gel should be asked of the family members during
the evaluation of any children who present with vir-
ilization or peripheral precocious puberty. The diag-
nosis can be established by just a few tests and by
appropriate history. The inability to obtain such a
history, or failure to ask the specific questions, may
result in extensive, unnecessary, and expensive
investigation. The primary care physician should be
aware of this fact, because most of these children
may initially present in their practice. The Physicians’
Desk Reference and package insert should also put a
warning about the virilizing effect on a male or
female child who might come in contact with some-
one using any of these products.
References
1. Styne DM. The testes: disorder of sexual differentiation
and puberty in the male. In: Sperling MA, ed. Pediatric
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
2002: 565-628.
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
puberty in children with tumours of the suprasellar pineal

kaifka · 發表於前天 03:27

Sexual Precocity in a 16-Month-Old
Boy Induced by Indirect Topical
Exposure to Testosterone
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
and Kenneth R. Rettig, MD1
Clinical Pediatrics
Volume 46 Number 6
July 2007 540-543
© 2007 Sage Publications
10.1177/0009922806296651
http://clp.sagepub.com
hosted at
http://online.sagepub.com
Precocious puberty in boys, central or peripheral,
is a significant concern for physicians. Central
precocious puberty (CPP), which is mediated
through the hypothalamic pituitary gonadal axis, has
a higher incidence of organic central nervous system
lesions in boys.1,2 Virilization in boys, as manifested
by enlargement of the penis, development of pubic
hair, and facial acne without enlargement of testi-
cles, suggests peripheral or pseudopuberty.1-3 We
report a 16-month-old boy who presented with the
enlargement of the phallus and pubic hair develop-
ment without testicular enlargement, which was due
to the unintentional exposure to androgen gel used by
the father. The family initially concealed this infor-
mation, resulting in an extensive work-up for this
child. Given the widespread and easy availability of
testosterone gel and cream, we believe this is proba-
bly more common than the rare case report in the
literature.4
Patient Report
A 16-month-old white child was referred to the
endocrine clinic by his pediatrician with the concern
of early sexual development. His mother noticed
light colored pubic hair development when he was
From the 1Division of Pediatric Endocrinology, 2University of
South Alabama Medical Center, Mobile, Alabama.
Address correspondence to: Samar K. Bhowmick, MD, FACE,
Professor of Pediatrics, University of South Alabama, College of
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
e-mail: [email protected].
about 6 to 7 months old, which progressively became
darker. She was also concerned about the enlarge-
ment of his penis and frequent erections. The child
was the product of a full-term normal delivery, with
a birth weight of 7 lb 14 oz, and birth length of
20 inches. He was breast-fed throughout the first year
of life and was still receiving breast milk along with
solid food. He had no hospitalizations or surgery,
and his psychosocial and psychomotor development
was age appropriate.
The family history was remarkable for the father,
who was diagnosed with hypothyroidism at age 16,
which was treated with thyroxine. The father’s
height was 6 feet, and he went through a somewhat
early puberty and had stopped growing by age 14.
The father denied taking any other medication. The
child’s mother was in good health. Her menarche
was at 11 years of age, and her height was at 5 feet
5 inches. There was no other family history of pre-
cocious sexual development in the first-degree rela-
tives. There were no siblings.
Physical Examination
The physical examination revealed a very active,
playful, and healthy boy. The vital signs documented
a blood pressure of 85/50 mm Hg, his length was
90 cm (>97th percentile), and his weight was 14.4 kg
(also >97th percentile). The observed yearly growth
velocity was 30 cm (12 inches). The examination of
the neck revealed no thyroid enlargement.
The genitourinary examination was remarkable for
enlargement of the penis, with a stretched length of
8 cm and a width of 2 cm. The glans penis was very well
developed. The pubic hair was Tanner II, mostly around
540
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
the base of the phallus and was dark and curled. The
testicular volume was prepubertal at 2 mL each.
The skin was moist and smooth and somewhat
oily. No axillary hair was noted. There were no
abnormal skin pigmentations or café-au-lait spots.
Neurologic evaluation showed deep tendon reflex 2+
bilateral and symmetrical. There was no suggestion
of papilledema.
Laboratory Evaluation
The bone age was consistent with 28 months by
using the standard of Greulich and Pyle at a chrono-
logic age of 16 months (advanced).5 Chromosomal
karyotype was 46XY. The thyroid function test
showed a free T4 of 1.69 ng/dL, and thyroid stimu-
lating hormone level was 1.3 µIU/mL (both normal).
The concentrations of serum electrolytes, blood
urea nitrogen, creatinine, and calcium all were
within normal range for his age. The concentration
of serum 17-hydroxyprogesterone was 16 ng/dL
(normal, 3 to 90 ng/dL), androstenedione was 20
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
terone was 38 ng/dL (normal, 50 to 760 ng/dL),
desoxycorticosterone was 4.3 ng/dL (normal, 7 to
49ng/dL), 11-desoxycortisol (specific compound S)
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
and β-human chorionic gonadotropin was less than
5 mIU/mL (normal <5 mIU/mL). Serum follicular
stimulating hormone and leuteinizing hormone
concentrations were less than 0.05 mIU/mL
(prepubertal).
The parents were notified about the laboratory
results and were informed that all of the tests were
normal except the testosterone level was high. The
follow-up visit was arranged within a few weeks to
obtain testicular and abdominal sonograms; how-
ever, the family did not return for 4 months.
Physical examination at this time revealed that the
child had grown 2.5 cm in 4 months and had gained
2 kg of weight. Physical examination remained
unchanged. Surprisingly, the pubic hair almost com-
pletely disappeared except for a few vellous hairs at
the base of the phallus. Testicular volume was still 2
mL, and the size of the penis remained unchanged.
The mother also said that the boy was no longer hav-
ing frequent erections.
Both parents were again questioned about use of
any ointment/creams that they may have applied to
the child’s skin. This time the father admitted the
Topical Testosterone Exposure / Bhowmick et al 541
use of testosterone gel twice daily that he was apply-
ing over his own shoulders, chest, and back area for
a year. The father also revealed he was embarrassed
to disclose that he was using a testosterone gel pre-
scribed by his family physician for decreased libido
secondary to depression.
The child slept in the same bed with parents.
The father would hug the baby and hold him on his
chest for a considerable period of time, causing sig-
nificant bare skin contact between baby and father.
The father also admitted that after the phone call,
when he learned the testosterone level in the baby
was high, he then read the product information
packet and concluded that it was most likely the rea-
son for the child’s virilization. At that time, they
decided to put the baby in a separate bed, and the
father was not hugging him with bare skin and had
been using protective clothing. A repeat testosterone
test was ordered, but the family did not go to the
laboratory to obtain the test.
Discussion
Precocious puberty in boys is defined as secondary
sexual development before 9 years of age.1,4
Precocious puberty is termed as central (true) when
it is caused by the premature activation of hypo-
thalamic pituitary gonadal axis. CPP is more com-
mon in girls than in boys.1,3 Most boys with CPP
may have a central nervous system lesion that is
responsible for the early activation of the hypothal-
amic pituitary gonadal axis.1-3 Thus, greater empha-
sis has been given to neuroradiologic imaging in
boys with precocious puberty. In addition to viril-
ization, the clinical hallmark of CPP is the symmet-
rical testicular growth secondary to stimulation by
gonadotropins.1,3
Gonadotropin-independent peripheral preco-
cious puberty in boys also results from inappropriate
androgenic stimulation from either endogenous or
exogenous sources, nonpituitary gonadotropin stim-
ulation, and rare activating mutations.3 Virilizing
congenital adrenal hyperplasia producing excessive
adrenal androgens is a common cause of precocious
puberty in boys.3,4
The most common form of congenital adrenal
hyperplasia is the 21-hydroxylase enzyme deficiency.
The 11-β hydroxylase deficiency may also result in
excessive adrenal androgen production, and rarely,
an adrenal tumor may also cause adrenal androgen
excess.1,3
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
A unique entity of male-limited gonadotropin-
independent precocious puberty, which is also known
as testotoxicosis, may cause precocious puberty at a
very young age. The physical findings in these boys
with this disorder are full pubertal development,
including bilateral testicular growth, similar to boys
with CPP. The gonadotropin levels in this disorder
are suppressed to prepubertal levels and do not show
pubertal response of gonadotropin after gonadotropin-
releasing hormone stimulation. This is a sex-linked
autosomal dominant disorder that affects only
males; therefore, other male members of the family
may have similar precocious puberty.3
In our patient, physical examination was incon-
sistent with true precocious puberty since his testi-
cles were prepubertal in size. However, testotoxicosis
was in the differential diagnosis because his father
started puberty somewhat early, and occasionally,
testicular enlargement is not that evident in the
beginning of this process.1 In the absence of a neg-
ative initial history of androgen exposure, our
biggest concern was virilizing adrenal hyperplasia,
either 21-hydroxylase deficiency or 11-β hydroxylase
deficiency. Those diagnoses were excluded by find-
ing the normal level of adrenal steroids.
The diagnosis of exogenous androgens was strongly
suspected in a follow-up visit after 4 months because
the physical examination revealed the complete disap-
pearance of pubic hair, normal growth velocity, and
decreased erections. The father admitted using a testos-
terone gel, which he concealed at first visit. He was
using it rather frequently, twice a day. The Physicians’
Desk Reference, or package insert of this product, gel or
cream, cautions about dermal testosterone transfer to
unprotected females through direct skin exposure.
Serum testosterone level was found to be 2 times the
baseline value in those females who were exposed to
even 15 minutes of direct skin contact with their male
partners.6 However, when a shirt covered the applica-
tion site, this testosterone transfer was prevented.
Our patient’s testosterone level was 60 ng/mL,
which was clearly high. Some studies suggest that
dermal conversion of testosterone to dihydrotestos-
terone, which is a more potent metabolite, is more
active in young children exposed to testosterone
exogenously7; however, we did not measure a dihy-
drotestosterone level in our patient. In addition to
virilization, exposure to exogenous testosterone in
children results in an increase in growth velocity and
advanced bone age, as seen in our patient.
The long-term effect of androgen exposure during
early childhood on pubertal development and final
adult height are not fully known and always remain
a concern. Children treated with short-term testos-
terone injection or topical androgen may exhibit some
acceleration of the skeletal maturation; however, after
cessation of treatment, the rate of bone maturation
decelerates and gradually returns to normal.8,9
There are conflicting reports and controversy
over the effect of early androgen exposure on adult
penile length.10,11 Some reports suggest subnormal
adult penile length, apparently because of downreg-
ulation of androgen receptor number.10,12 However,
Sutherland et al13 did not find a correlation between
childhood testosterone exposure and reduced adult
penile length in clinical studies.
Nonetheless, we do not believe our patient is
going to experience any of the untoward effects from
testosterone exposure as mentioned earlier because
the exposure was not for a prolonged period of time.
Although the bone age was advanced at the time of
diagnosis, the child had a normal growth velocity at
the follow-up visit. It is hoped that his final adult
height will not be affected.
Although rarely reported, the widespread avail-
ability of androgen products in our society may
indeed cause more virilization in male or female
children than one would realize. Exposure to andro-
gen products must be considered and specific ques-
tioning about the use of a testosterone product or
gel should be asked of the family members during
the evaluation of any children who present with vir-
ilization or peripheral precocious puberty. The diag-
nosis can be established by just a few tests and by
appropriate history. The inability to obtain such a
history, or failure to ask the specific questions, may
result in extensive, unnecessary, and expensive
investigation. The primary care physician should be
aware of this fact, because most of these children
may initially present in their practice. The Physicians’
Desk Reference and package insert should also put a
warning about the virilizing effect on a male or
female child who might come in contact with some-
one using any of these products.
References
1. Styne DM. The testes: disorder of sexual differentiation
and puberty in the male. In: Sperling MA, ed. Pediatric
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
2002: 565-628.
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
puberty in children with tumours of the suprasellar pineal

like007 · 發表於昨天 18:27

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