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Sexual Precocity in a 16-Month-Old2 d7 b+ m* Q5 K% X+ c0 H
Boy Induced by Indirect Topical
+ C O. Y X) i8 d3 q& CExposure to Testosterone! ~$ ]' b O1 O7 ^' Z& O. q
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
3 \4 H8 P1 i0 L- R8 p5 o4 d& Iand Kenneth R. Rettig, MD1
, R( l+ j' Z7 I bClinical Pediatrics
- w/ y: L6 l( X: R* i& UVolume 46 Number 6
' C! }, Z6 R Y' RJuly 2007 540-543
- b I. T# O+ ~) N" Y© 2007 Sage Publications
- b, I+ B( y ]- j10.1177/00099228062966510 r4 Z6 k( R0 e) F/ w
http://clp.sagepub.com
4 P& z% f- {7 ^& Whosted at3 h! K0 ?6 Q* Q9 V2 J2 M
http://online.sagepub.com
i+ j. m% |5 Q. x, G5 u9 DPrecocious puberty in boys, central or peripheral,$ ^" U9 K+ |; }* f, j, Z
is a significant concern for physicians. Central
8 b6 h( H1 r9 e; @4 y A9 eprecocious puberty (CPP), which is mediated
* B# x5 g+ t fthrough the hypothalamic pituitary gonadal axis, has
( H7 z2 J" r) W- r7 K; I# Q4 K% sa higher incidence of organic central nervous system" o8 j: ~# h4 n* [2 h M
lesions in boys.1,2 Virilization in boys, as manifested8 R8 [2 l; U* k! y) n
by enlargement of the penis, development of pubic$ O0 e" a6 b0 V. b" E
hair, and facial acne without enlargement of testi-5 k, Y0 M( K# I0 r5 Y4 v8 n+ {2 V
cles, suggests peripheral or pseudopuberty.1-3 We9 H( M* g8 n) g
report a 16-month-old boy who presented with the
. o+ ]( k* D. u( l |. penlargement of the phallus and pubic hair develop-) S) ^# p) V: F$ D' K: v Z5 D$ f( D7 ]
ment without testicular enlargement, which was due, y% j% [: H: Z' Q, z
to the unintentional exposure to androgen gel used by' B5 r7 F5 K; V5 v4 |
the father. The family initially concealed this infor-
# T' @8 V0 o& C! Vmation, resulting in an extensive work-up for this
y4 N- x, L7 F; Y6 X$ H2 s2 _7 O, g! \ Achild. Given the widespread and easy availability of; @6 p1 L: y3 k8 y b
testosterone gel and cream, we believe this is proba-
4 B+ ]( H V" @0 a8 q9 ~) I% Pbly more common than the rare case report in the- H2 Q& o4 q4 {7 R5 }
literature.4
0 N5 Q& T; ^( C6 O$ oPatient Report
$ P* t6 `0 ~. b6 h& qA 16-month-old white child was referred to the9 B0 U! k2 G1 M8 J! @" `
endocrine clinic by his pediatrician with the concern3 L9 m Y; Z7 A# s- \/ ?
of early sexual development. His mother noticed- r( B4 v' {% H' \& Y0 R$ X. Y
light colored pubic hair development when he was
! ]6 l) t3 C/ T6 I( KFrom the 1Division of Pediatric Endocrinology, 2University of
}8 x7 I8 `& A) m/ LSouth Alabama Medical Center, Mobile, Alabama.
# m+ c/ W% c' E0 F. ~4 uAddress correspondence to: Samar K. Bhowmick, MD, FACE,+ u% g; v: Y7 I; c( t4 j/ O
Professor of Pediatrics, University of South Alabama, College of2 W6 @7 |3 Z; l8 R1 @5 _) @* K
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
# k2 ?- S$ {# Fe-mail: [email protected].: V- s6 q. a8 u, \, a: g
about 6 to 7 months old, which progressively became
1 @# u) s" z" ^6 R9 S% T. X: Xdarker. She was also concerned about the enlarge-
) ?, i' K7 B! e# ^. kment of his penis and frequent erections. The child& p7 p* E# }6 |" U+ m
was the product of a full-term normal delivery, with
. `- G. K- n/ b ]3 V$ |, Ga birth weight of 7 lb 14 oz, and birth length of
" ~* l/ u# r0 \0 v20 inches. He was breast-fed throughout the first year5 R7 e7 [( {& D# ]7 w4 b
of life and was still receiving breast milk along with2 B0 Q( v: T; {. G3 N
solid food. He had no hospitalizations or surgery,
, A" u+ N4 u& E! m" xand his psychosocial and psychomotor development
% R' X$ e# `3 ]# K# n) P) Qwas age appropriate.
4 w: l U a. s! }. \, ]The family history was remarkable for the father,3 ^* t. C! @8 l# K- g. G
who was diagnosed with hypothyroidism at age 16,
' X6 M9 I, c8 J, \which was treated with thyroxine. The father’s
. Z2 Y9 ?4 b4 j2 @, [height was 6 feet, and he went through a somewhat
. q7 ]! N; R/ K& d/ Pearly puberty and had stopped growing by age 14.
& I' v2 M6 M: hThe father denied taking any other medication. The9 F# k* C! m4 _# n: ?
child’s mother was in good health. Her menarche
5 Z& M; K, a/ Jwas at 11 years of age, and her height was at 5 feet
" `% B) _& d- }5 inches. There was no other family history of pre- \' A. }: m6 n( d( [
cocious sexual development in the first-degree rela-
5 s" z; |, c _; ~- R' T# ^tives. There were no siblings.5 p% s7 H8 d- p$ S- `4 y
Physical Examination) l( b% ~" i! i. N
The physical examination revealed a very active,
7 J1 P- X1 s" I/ ` uplayful, and healthy boy. The vital signs documented+ y& C. ]$ w* \9 b9 U# e
a blood pressure of 85/50 mm Hg, his length was( `+ e# m5 H) c! Q
90 cm (>97th percentile), and his weight was 14.4 kg
: Y/ f, r* A( u' k$ E' \5 B: `(also >97th percentile). The observed yearly growth- v4 T- h9 u3 i& d
velocity was 30 cm (12 inches). The examination of9 f0 @" [, h( u& y- f5 i; `3 p( _7 s
the neck revealed no thyroid enlargement.
$ z1 y. `+ V$ D' Q) ^The genitourinary examination was remarkable for
- c) |" k" D/ T' m; d2 aenlargement of the penis, with a stretched length of4 F7 ?1 X" H6 x* d
8 cm and a width of 2 cm. The glans penis was very well2 @# p' v1 T0 i6 I1 S$ g2 X+ R
developed. The pubic hair was Tanner II, mostly around+ M7 C" B( M4 {* G) _1 n
540, K3 B$ t) M. S3 G/ ~
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from& h" ?4 j: E: o: L. t9 S4 ~: w$ K9 z9 w
the base of the phallus and was dark and curled. The+ U3 T4 u# a, i0 J
testicular volume was prepubertal at 2 mL each.6 T' R: w3 a. R
The skin was moist and smooth and somewhat
% Q. l! o2 c+ L1 D+ B! loily. No axillary hair was noted. There were no
' Y6 w5 D4 ^# R+ J6 pabnormal skin pigmentations or café-au-lait spots.4 O/ X7 a( `+ z6 r
Neurologic evaluation showed deep tendon reflex 2+
$ i, S$ M- [) j# \bilateral and symmetrical. There was no suggestion6 n/ f7 @+ n& ]! l- K% O% i
of papilledema.0 }: F; k2 n q" M7 r
Laboratory Evaluation
/ }* u- ]$ G' N. ?9 ~' { g# P( SThe bone age was consistent with 28 months by2 o% u2 U" a- r8 T8 ]
using the standard of Greulich and Pyle at a chrono-* G. ^: ?6 I$ u
logic age of 16 months (advanced).5 Chromosomal
* _6 W2 r2 s" Z' [karyotype was 46XY. The thyroid function test
: m" p w. a+ l- Wshowed a free T4 of 1.69 ng/dL, and thyroid stimu-
2 n/ v0 \! z C) r5 h; X H+ Ilating hormone level was 1.3 µIU/mL (both normal).
7 O2 Q6 u6 Y5 ?) v3 m4 p+ [. h9 uThe concentrations of serum electrolytes, blood0 ]: b: _5 x, p+ a" Z0 n
urea nitrogen, creatinine, and calcium all were
9 g4 H2 D# ^' {5 f$ M" s, Dwithin normal range for his age. The concentration
0 m, ]9 `7 Z5 i- \3 Iof serum 17-hydroxyprogesterone was 16 ng/dL0 J( z: J( Q) i5 o
(normal, 3 to 90 ng/dL), androstenedione was 20
( `! W2 E4 @! C H! Cng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
+ {- J" i. F7 }3 B% b8 y/ }terone was 38 ng/dL (normal, 50 to 760 ng/dL),
0 W! K* m0 n* M% @+ B0 D. |desoxycorticosterone was 4.3 ng/dL (normal, 7 to: X' U5 N$ s$ |* W6 E2 \* V: |
49ng/dL), 11-desoxycortisol (specific compound S)
* y# U1 a7 J) v6 L+ x1 Nwas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
* l+ h( j5 ?( g' f) M A; e- r; a. ltisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total2 [% U. X% T6 q* t, v; X" n( @
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),1 ~6 n! F+ `5 ^$ j1 n8 t& N2 Y. \
and β-human chorionic gonadotropin was less than* ?1 z2 B; B8 S& ^/ j( T" J
5 mIU/mL (normal <5 mIU/mL). Serum follicular: g) y7 y- i# J6 H. b
stimulating hormone and leuteinizing hormone
; V! }' r$ T" I. Z5 iconcentrations were less than 0.05 mIU/mL9 _8 J; r8 w& ^5 g+ b
(prepubertal).
% j( S |9 o e7 K: F& G3 @! e' |The parents were notified about the laboratory
) N! m% j/ \" y ?results and were informed that all of the tests were
) N" i# l" Q# _, Y, Y M0 {normal except the testosterone level was high. The
% o, l9 D. u8 j2 _$ @follow-up visit was arranged within a few weeks to6 t$ T0 d" A' M: w5 D1 v! o0 Q$ k
obtain testicular and abdominal sonograms; how-$ P; a. t/ n5 `5 {% D( H
ever, the family did not return for 4 months.! x( e/ ~1 o9 d# f
Physical examination at this time revealed that the
4 n9 K! A3 z6 g( F! z8 \child had grown 2.5 cm in 4 months and had gained
$ \8 G" Q! ?$ x4 o! e2 kg of weight. Physical examination remained5 t) u& Z! `- p! c/ k
unchanged. Surprisingly, the pubic hair almost com-
. O! Y7 d e8 Bpletely disappeared except for a few vellous hairs at
' q; }! y2 i5 B7 a: O/ b/ R: zthe base of the phallus. Testicular volume was still 2: k3 `7 c/ r) P2 X& M1 _* Z" [
mL, and the size of the penis remained unchanged.
. v0 R" o( ~2 N+ ?$ z6 \" NThe mother also said that the boy was no longer hav-* }: E% E, l4 c8 K& d
ing frequent erections.
+ S# Z. }" R& A2 D6 V) n2 N7 `( `9 OBoth parents were again questioned about use of
% T6 |% T. y5 z: vany ointment/creams that they may have applied to6 E% Y- l$ ]0 ^2 c
the child’s skin. This time the father admitted the
* w) u( g, u. F# a N! R2 bTopical Testosterone Exposure / Bhowmick et al 541
0 @- g; ~, @$ c& j1 Fuse of testosterone gel twice daily that he was apply-
- n- E7 U5 F8 Wing over his own shoulders, chest, and back area for8 {& G+ W3 v3 z) y
a year. The father also revealed he was embarrassed
) t/ X2 C' q% `( O4 N9 u" w' \, Tto disclose that he was using a testosterone gel pre-# g& |- M. H7 {/ ]
scribed by his family physician for decreased libido- v* X0 e! e2 q: o8 u; k3 V4 M$ i
secondary to depression.: @" O; H0 S3 ?/ d7 K; B* d
The child slept in the same bed with parents.8 [4 P8 o/ ^% F0 U% s
The father would hug the baby and hold him on his( a( ^& ~# i9 A3 ?, H) {
chest for a considerable period of time, causing sig-! _ | _( ?- F" y# s5 c9 {
nificant bare skin contact between baby and father.
6 U* X& @) Z' J0 c( q8 nThe father also admitted that after the phone call,
) Z, K0 R6 X( gwhen he learned the testosterone level in the baby
. b. {2 w- h6 C$ v) E) M7 b" ]$ Kwas high, he then read the product information( y- @! P: [4 c, o3 ^2 u# Q: p
packet and concluded that it was most likely the rea-
7 c6 U! N, w% V3 W" Lson for the child’s virilization. At that time, they* y6 x! a8 i2 h/ h% J$ \
decided to put the baby in a separate bed, and the
. k/ b+ w* I! ofather was not hugging him with bare skin and had
9 o7 t, r0 a2 F) [; Cbeen using protective clothing. A repeat testosterone
7 M' \8 E& W& p4 n* mtest was ordered, but the family did not go to the/ F$ ~5 P4 A3 v- u
laboratory to obtain the test.
# N3 h' L& ~* ^% ?Discussion5 e2 X. H) J7 j3 j
Precocious puberty in boys is defined as secondary( X: ^8 \5 m9 W9 e
sexual development before 9 years of age.1,4
7 T; r% q; L8 d$ L0 IPrecocious puberty is termed as central (true) when
( m9 ^* L4 P x; o- k; G4 yit is caused by the premature activation of hypo-
$ N. }+ F% n5 j wthalamic pituitary gonadal axis. CPP is more com-; y m+ M: D' v, e, i( t
mon in girls than in boys.1,3 Most boys with CPP6 i6 p5 d) A+ n0 K6 {, {" ?$ H0 w! \1 _
may have a central nervous system lesion that is
. M* w# x* X* X7 Q% s2 Wresponsible for the early activation of the hypothal-
6 O, |* l, ~# b" C4 G, y/ h zamic pituitary gonadal axis.1-3 Thus, greater empha-# O; W7 z( N5 T
sis has been given to neuroradiologic imaging in$ |- t) l, j) }9 _
boys with precocious puberty. In addition to viril-" y* |- u/ n( S3 \
ization, the clinical hallmark of CPP is the symmet-! T; n% m: F0 I8 \( G& k- V. z: M" k
rical testicular growth secondary to stimulation by
+ N) P/ M) Q5 S' u. r. V, xgonadotropins.1,3$ W4 H9 r% ]9 V5 |4 f, V X2 S
Gonadotropin-independent peripheral preco-2 V6 A% W* {8 T
cious puberty in boys also results from inappropriate
% R6 ?7 N2 ?7 L1 {androgenic stimulation from either endogenous or
) h2 O) e$ J. Z% P# \ Texogenous sources, nonpituitary gonadotropin stim-
1 p2 p' h Y" N5 u. f/ o. aulation, and rare activating mutations.3 Virilizing
) \4 u* Y; r: |# A6 T1 z econgenital adrenal hyperplasia producing excessive% V- F, W/ m- c" @" j
adrenal androgens is a common cause of precocious
' e, E4 u3 {# mpuberty in boys.3,41 x. J N! _, u
The most common form of congenital adrenal
/ @4 G( c6 q7 p( B: g* w9 ?) |hyperplasia is the 21-hydroxylase enzyme deficiency.
$ x5 u) w' o$ oThe 11-β hydroxylase deficiency may also result in
0 s- v D/ B/ f, H) G- j5 k8 a4 o5 `excessive adrenal androgen production, and rarely,, |, K4 {3 S' X8 W4 w" P2 ?
an adrenal tumor may also cause adrenal androgen
: S3 p# t$ x2 ^% v- ~# Q2 Eexcess.1,35 ?1 t! x- O* e4 |5 ?- r, r
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
5 Q9 w9 G0 T4 A% ]& D4 u# h; ~% @542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
5 s d6 y, q9 KA unique entity of male-limited gonadotropin-, _- _( L( x- F$ O, [
independent precocious puberty, which is also known4 p9 S+ W' a* c' E' R0 ~9 C
as testotoxicosis, may cause precocious puberty at a$ N* d$ G& _& U& A9 n; ^; T
very young age. The physical findings in these boys
3 B B$ n* N2 Z2 Ywith this disorder are full pubertal development,
- [7 f+ `. `+ ~including bilateral testicular growth, similar to boys) i! z7 C' ^/ z; S4 K: ]7 d# ~
with CPP. The gonadotropin levels in this disorder- b/ K% ~3 E5 J
are suppressed to prepubertal levels and do not show b. X- Z1 ~+ _3 M4 R% G; U
pubertal response of gonadotropin after gonadotropin-
' {7 R G3 L3 j/ T) [releasing hormone stimulation. This is a sex-linked3 h9 S+ }8 b" r7 W: z
autosomal dominant disorder that affects only; B9 ?- @+ `: C+ A
males; therefore, other male members of the family( E6 n; X" C$ a {
may have similar precocious puberty.3
# f: s, K' b$ T2 F0 c$ A2 H0 K; B* BIn our patient, physical examination was incon-
; B) Q! P' d% f ]+ [6 Isistent with true precocious puberty since his testi-
" J; y f( E8 e+ [- i: n# X) Gcles were prepubertal in size. However, testotoxicosis4 C9 o G' s1 }: ^% G
was in the differential diagnosis because his father
0 q0 b- ?& T8 L9 ]started puberty somewhat early, and occasionally,3 y2 T& o6 j2 W
testicular enlargement is not that evident in the8 v1 b7 R$ f9 C* N- p
beginning of this process.1 In the absence of a neg-
. N. w/ M1 |8 A" Z; Oative initial history of androgen exposure, our
! M, ?6 H: Z! X, s) D' z( Gbiggest concern was virilizing adrenal hyperplasia,
0 r1 V' Q$ ^3 X% Jeither 21-hydroxylase deficiency or 11-β hydroxylase8 j# X' N/ c; Q5 m! E d# k
deficiency. Those diagnoses were excluded by find-: Q9 E T- N0 ^* v; r4 x5 v# B
ing the normal level of adrenal steroids.' d5 M2 D6 R' @. y- t# g
The diagnosis of exogenous androgens was strongly
7 q" y' U4 S' i( [4 Xsuspected in a follow-up visit after 4 months because
/ H, D* F8 c; J: G S- Mthe physical examination revealed the complete disap-
! [ h& j$ Z1 n- y @pearance of pubic hair, normal growth velocity, and2 v' r! K0 `1 x9 G2 J( B% l
decreased erections. The father admitted using a testos-% a S1 F4 w3 D1 k0 a& C# A# k" H1 n
terone gel, which he concealed at first visit. He was! r8 |1 W2 A# ]. h& S+ ?
using it rather frequently, twice a day. The Physicians’" d) O8 L+ ?6 P. J
Desk Reference, or package insert of this product, gel or
: G, [, A: i. ?% K6 Qcream, cautions about dermal testosterone transfer to
* v/ b7 T$ H# v; X0 f5 B2 Nunprotected females through direct skin exposure.3 G" I. I. w. u( j" v3 g8 ~, ^
Serum testosterone level was found to be 2 times the+ m' n' n# g- I7 y' X% c6 P
baseline value in those females who were exposed to
, e7 F& y3 }: r6 L1 z1 K) Keven 15 minutes of direct skin contact with their male7 A9 Y& \6 ^9 o7 K' o3 M8 q8 M
partners.6 However, when a shirt covered the applica-
6 l. @" D: G+ n& _9 h. W* I3 Z7 Dtion site, this testosterone transfer was prevented.9 f: `; }3 j) l
Our patient’s testosterone level was 60 ng/mL,
. z0 f. p4 f6 n, m* i6 f; K3 Xwhich was clearly high. Some studies suggest that
/ r" f8 X# L# Y# J2 J4 Z9 I( V, P/ idermal conversion of testosterone to dihydrotestos-
+ A) D# z$ n" gterone, which is a more potent metabolite, is more% v- V, ^( Z/ B4 _% {* I- A: c
active in young children exposed to testosterone, l1 W/ {% Z8 j& A" |
exogenously7; however, we did not measure a dihy-: }% P% Z/ f2 M
drotestosterone level in our patient. In addition to0 L h* N# v6 {1 |2 C, t% H2 P' }
virilization, exposure to exogenous testosterone in
0 y$ \! c5 E; ^8 E' ~children results in an increase in growth velocity and* V0 x3 R9 P! M8 P2 T
advanced bone age, as seen in our patient.
- B0 t3 F% S, p4 x" CThe long-term effect of androgen exposure during
& \9 y. f" Y( ^early childhood on pubertal development and final' o C$ d& Q# H1 d
adult height are not fully known and always remain x" l1 d6 U- l. C
a concern. Children treated with short-term testos-0 A( n# \- s( H
terone injection or topical androgen may exhibit some
+ q' k7 W5 N8 {$ T/ f1 Eacceleration of the skeletal maturation; however, after
# Y6 w) ]" d) F* I8 T" dcessation of treatment, the rate of bone maturation
$ _: z0 f7 j# }- Mdecelerates and gradually returns to normal.8,9. t3 g9 S5 a4 m+ @0 P8 _ J
There are conflicting reports and controversy3 \; t; u1 p( ~. \ m- A0 K0 c
over the effect of early androgen exposure on adult
8 W7 x4 u6 k3 ]( a! D Hpenile length.10,11 Some reports suggest subnormal
- \; t& ?3 G( W! H( `adult penile length, apparently because of downreg-
1 X6 l! N- L- `8 I6 O- p9 Y6 @# _ulation of androgen receptor number.10,12 However,
; g1 P H6 w8 Y8 Z; lSutherland et al13 did not find a correlation between
' C p' w. D1 h1 J: u/ Pchildhood testosterone exposure and reduced adult: i/ G" B4 A$ Q
penile length in clinical studies. j: q8 W4 Y' v. D- x( P5 B
Nonetheless, we do not believe our patient is
# h5 I: {- J5 a; l3 \going to experience any of the untoward effects from
5 g+ v. P) @( |& J( l+ M( ttestosterone exposure as mentioned earlier because
0 ]2 U) g* A; ]0 u) z) M4 athe exposure was not for a prolonged period of time./ ?( E) h+ ]6 ^' ]3 Z' C# Z
Although the bone age was advanced at the time of
4 o5 e) x$ W; q r @1 k0 M; Kdiagnosis, the child had a normal growth velocity at
/ n/ G" p" S. g' E9 Rthe follow-up visit. It is hoped that his final adult* t8 i( }) `7 F, o! d" O u# H- w' v; i
height will not be affected.1 U2 n0 Z _4 b0 X
Although rarely reported, the widespread avail-
' @7 |" }6 G# \- ]ability of androgen products in our society may3 {4 k- J/ m! w0 `/ v
indeed cause more virilization in male or female7 l( t" Y& A' b* F d; d
children than one would realize. Exposure to andro-
( G* I3 e! J3 |$ O2 Tgen products must be considered and specific ques-' r# Z7 `* w( P9 v+ E! r! B1 B& |
tioning about the use of a testosterone product or: P" S X) E* Z c3 n1 D& V
gel should be asked of the family members during
9 C( r F7 ]9 t% \+ _the evaluation of any children who present with vir-
* w: E+ s7 {/ }# G- l! T" \ilization or peripheral precocious puberty. The diag-
3 |7 J4 N+ X9 n, Anosis can be established by just a few tests and by W/ ]* h' ^1 d U2 L6 e8 m
appropriate history. The inability to obtain such a. ~9 `$ [9 ]' {* L! A( B6 W6 ~
history, or failure to ask the specific questions, may
+ z! Y$ h& M V6 U! v! Jresult in extensive, unnecessary, and expensive- | I7 ?9 ^" s
investigation. The primary care physician should be
2 u- b3 R7 f% q0 Raware of this fact, because most of these children
+ p6 T1 E0 b7 F) e, Z& {may initially present in their practice. The Physicians’
8 g5 V3 t1 M9 b% x k( MDesk Reference and package insert should also put a
* t2 V: k r7 |$ B/ R1 @; M4 X; fwarning about the virilizing effect on a male or; N" E1 G3 L" B+ h
female child who might come in contact with some-8 `0 |& \3 O4 H/ u' i( i" ]
one using any of these products.
; R; m- j$ e8 ~References) s' F# n& i' |3 j6 b
1. Styne DM. The testes: disorder of sexual differentiation
. m8 d- Z+ e7 R* q, Cand puberty in the male. In: Sperling MA, ed. Pediatric7 s) q- [8 a5 h; ?
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;, p( D4 K) [9 W8 [9 F, _- T
2002: 565-628.
9 O0 g1 x& m' t) o( U [2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious) F/ t% l& b6 U; K
puberty in children with tumours of the suprasellar pineal |
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