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Sexual Precocity in a 16-Month-Old" a& O$ B& L q/ \
Boy Induced by Indirect Topical* \) h% A( C5 N u: E2 w' ~$ z5 o
Exposure to Testosterone" Z! b e# g; v/ o8 g$ h
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,24 O0 m- t0 ^, i3 h8 ^
and Kenneth R. Rettig, MD1
. m- X+ Q! K, a5 q- h. JClinical Pediatrics
2 b/ D3 s5 X, X1 qVolume 46 Number 6
1 U! w* X# I4 T, ^0 j- s3 sJuly 2007 540-5434 u* }8 T, e( I/ N+ Q0 |
© 2007 Sage Publications
9 z; Y2 `$ Q1 f+ a/ K10.1177/0009922806296651
0 N7 y0 M! d+ e' @0 `1 _http://clp.sagepub.com
0 O: g- B; ], E. _7 F0 ^1 ~hosted at
% K' c+ b }1 M5 {5 C. W* q6 Ohttp://online.sagepub.com) Z% |, x! U) ~" e, K9 K4 H/ c
Precocious puberty in boys, central or peripheral,
5 k# \0 n" _5 N4 H1 J: P9 vis a significant concern for physicians. Central8 w, m2 |; j5 X3 p' J$ v8 C# v7 c u
precocious puberty (CPP), which is mediated% X/ t H; K& z B: v" V
through the hypothalamic pituitary gonadal axis, has
5 {( ?7 m+ |2 m3 Ua higher incidence of organic central nervous system
( J/ V: n0 ~1 C1 q, a+ _lesions in boys.1,2 Virilization in boys, as manifested
{9 @" B1 o; o6 Y+ e1 t: iby enlargement of the penis, development of pubic$ A1 n7 N5 [$ }
hair, and facial acne without enlargement of testi-' h1 q7 w; J1 M% D* R7 g
cles, suggests peripheral or pseudopuberty.1-3 We1 N( y0 k+ M( \
report a 16-month-old boy who presented with the& U# Q: l V/ N: M0 r9 b4 ^9 V
enlargement of the phallus and pubic hair develop-' H1 B9 s; R% X9 g
ment without testicular enlargement, which was due
! D9 h( T: o# u, H2 l# Zto the unintentional exposure to androgen gel used by
0 V/ ]; K1 ?1 E5 R. n7 qthe father. The family initially concealed this infor-
9 |* s6 m8 z! L: B, U; c2 ~5 k; J( w6 Kmation, resulting in an extensive work-up for this1 @- ` e% {2 O8 U! X
child. Given the widespread and easy availability of
( N3 D7 f4 A- G) A+ [" T }$ Ntestosterone gel and cream, we believe this is proba-) R. K9 t8 u# v9 L. v2 h
bly more common than the rare case report in the( E* } R9 F& H3 ~) n
literature.4
2 f2 r2 y) @; [+ f& C! a# bPatient Report: x! h7 L7 V- n
A 16-month-old white child was referred to the
3 a& |& ~1 v' M- d3 ~( q- Cendocrine clinic by his pediatrician with the concern
Y2 p' I1 J6 N3 Pof early sexual development. His mother noticed: p1 H7 y2 b" V9 x3 A) i
light colored pubic hair development when he was
0 g* |2 t0 Q+ Z0 uFrom the 1Division of Pediatric Endocrinology, 2University of
2 W x' X: [: QSouth Alabama Medical Center, Mobile, Alabama." W7 T! B6 @3 @1 i
Address correspondence to: Samar K. Bhowmick, MD, FACE,; M( P% G* n% u! v' u/ q! K
Professor of Pediatrics, University of South Alabama, College of3 c, I3 f: U, `
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;. x. ?: m( p$ y# m
e-mail: [email protected].
4 k, S; X- \5 a2 u( ^about 6 to 7 months old, which progressively became
. r6 x- u! H4 b" n( w0 Rdarker. She was also concerned about the enlarge-9 E% z! X) @5 Q4 ]
ment of his penis and frequent erections. The child
$ g- [9 [9 L; Kwas the product of a full-term normal delivery, with
; x$ f4 P7 R. o" }5 x1 ]a birth weight of 7 lb 14 oz, and birth length of
+ ?( u1 A# c, X2 }2 n- e20 inches. He was breast-fed throughout the first year* ~ U+ l" h& X( c( R8 }
of life and was still receiving breast milk along with5 ~7 _+ Z* D9 i$ \
solid food. He had no hospitalizations or surgery,
$ o* N( B' s" j& x, ?% Jand his psychosocial and psychomotor development$ s& ^$ `- K6 w$ P C5 r# l
was age appropriate." p' h# S$ S6 I& Y0 d
The family history was remarkable for the father,# O) c& a: X$ F1 C! G+ M8 _- q
who was diagnosed with hypothyroidism at age 16,
" v3 F/ T3 K5 f# A$ qwhich was treated with thyroxine. The father’s
- q6 P9 k; |! P/ Bheight was 6 feet, and he went through a somewhat
, n. Q7 o+ Y4 a3 Vearly puberty and had stopped growing by age 14.: `$ ^" J- o6 Z- c1 t. z
The father denied taking any other medication. The9 F3 n7 S6 Q4 w+ T, T; P
child’s mother was in good health. Her menarche
$ }7 I0 I1 O# f. @was at 11 years of age, and her height was at 5 feet
o3 \) m: z& r* {* l5 inches. There was no other family history of pre-
) H1 L/ M4 e4 N" r/ ncocious sexual development in the first-degree rela-
" T4 H, r! ~( X1 m5 d3 stives. There were no siblings.
' C4 j: k& g! z0 i+ _$ ], IPhysical Examination
7 E3 J( n1 r2 {2 g. _2 v* v9 cThe physical examination revealed a very active,
+ }) R8 U' z: W1 `, i$ i+ v4 @playful, and healthy boy. The vital signs documented( t; O1 D1 v2 U& C8 c! e
a blood pressure of 85/50 mm Hg, his length was
/ d+ V" \8 h6 U) B4 A: G90 cm (>97th percentile), and his weight was 14.4 kg* e. e" U' p! B
(also >97th percentile). The observed yearly growth
& x4 v; v+ K- n0 C. {- o& nvelocity was 30 cm (12 inches). The examination of
( q' l/ d5 ^( H( b: e8 x; Athe neck revealed no thyroid enlargement.
) N C' r3 H" p( g5 ^3 E" wThe genitourinary examination was remarkable for. R* S' ~# J- ~ D" S* z5 [
enlargement of the penis, with a stretched length of
( p+ a: J+ ]$ B7 z1 T0 y0 @8 cm and a width of 2 cm. The glans penis was very well
" ~( }8 @6 \6 S0 j, T9 Q, Wdeveloped. The pubic hair was Tanner II, mostly around) i1 z6 @6 X R
540, R2 p: a3 `! h7 ^
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from8 ^$ }. `' z3 S* W$ d8 J, U: z
the base of the phallus and was dark and curled. The
1 j0 b4 q# b, @/ @/ v: j4 rtesticular volume was prepubertal at 2 mL each.) n# `$ M" u8 J0 D3 J5 P" q
The skin was moist and smooth and somewhat6 k$ K7 _% j0 V& f0 J$ E
oily. No axillary hair was noted. There were no
0 E; b; ]! e" {8 H) qabnormal skin pigmentations or café-au-lait spots.
& i( U! o' V! M6 ~Neurologic evaluation showed deep tendon reflex 2+
5 _! b6 C' I0 B1 bbilateral and symmetrical. There was no suggestion
/ b, V2 r1 I0 zof papilledema.# ]7 ^# y7 O" x
Laboratory Evaluation
- e% F9 s9 p2 ?- F2 |: I2 \# H5 p- hThe bone age was consistent with 28 months by. Q _5 x% v& h7 l- a% v1 S
using the standard of Greulich and Pyle at a chrono-, m, u6 x% }. F* j/ g
logic age of 16 months (advanced).5 Chromosomal
' }7 j2 T r; b8 G# S5 Ekaryotype was 46XY. The thyroid function test
! t2 W3 R$ I& @* z* A0 jshowed a free T4 of 1.69 ng/dL, and thyroid stimu-* p; s" ?" k9 y2 C3 S, [# c
lating hormone level was 1.3 µIU/mL (both normal).; e7 e" p! c% p" w& W3 J: B0 ]/ c
The concentrations of serum electrolytes, blood
& V8 O9 b+ F: b E) F; P2 \9 uurea nitrogen, creatinine, and calcium all were& h, ?% ^) J; j* c) k2 D$ l
within normal range for his age. The concentration$ u- J s8 ~& y8 r, \& e
of serum 17-hydroxyprogesterone was 16 ng/dL
8 Z! q G+ M% x6 M/ _7 r8 c(normal, 3 to 90 ng/dL), androstenedione was 20
& s% u% g9 u, |1 @4 cng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-% H. V5 k% H" s
terone was 38 ng/dL (normal, 50 to 760 ng/dL),
0 L5 T* q, E4 n3 E. Z2 v% qdesoxycorticosterone was 4.3 ng/dL (normal, 7 to
* d6 B, P) o' ]# Z49ng/dL), 11-desoxycortisol (specific compound S)* V. s' Z* u' D7 I6 r
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-. Z- q, y+ |3 v; p: k4 F- f
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
6 H4 i. v2 }1 ` Y) S$ K% ytestosterone was 60 ng/dL (normal <3 to 10 ng/dL),
$ c/ [2 ?, g8 H5 O! {9 F" rand β-human chorionic gonadotropin was less than
* P7 m% P0 y. [# Y7 \5 mIU/mL (normal <5 mIU/mL). Serum follicular6 \( L1 I) n* v; Y- v9 u
stimulating hormone and leuteinizing hormone$ C% f3 e2 r# f. B, c4 N5 N2 F
concentrations were less than 0.05 mIU/mL
/ e5 ` |# x; A9 V(prepubertal).
- P9 o- {, l0 a1 I6 t6 aThe parents were notified about the laboratory
8 o% s% `- i3 b8 {- _. |results and were informed that all of the tests were5 A' z3 P0 b6 G$ B' H
normal except the testosterone level was high. The" a$ h& Y5 W) P& E( B/ r! K* I
follow-up visit was arranged within a few weeks to
1 a1 c4 A' b: w8 Y# [0 Y$ Tobtain testicular and abdominal sonograms; how-# E q3 u0 @3 C g" @/ w
ever, the family did not return for 4 months.
2 c9 l# g" f/ N6 _- c, ^% rPhysical examination at this time revealed that the
6 M4 D1 G; C8 D( _. z+ ]! ?child had grown 2.5 cm in 4 months and had gained! I3 D @4 I% M
2 kg of weight. Physical examination remained
, q' X3 ]- W# v3 @( Y/ Lunchanged. Surprisingly, the pubic hair almost com-0 z' ^( [# ?( F6 d. Q# D7 w
pletely disappeared except for a few vellous hairs at
& i; K. w8 w$ P2 w% |; y _) _! Lthe base of the phallus. Testicular volume was still 2
9 ]/ M0 B \9 q& e( ImL, and the size of the penis remained unchanged.; _6 v/ o6 Z& w& [/ B7 B; b# K( W9 `
The mother also said that the boy was no longer hav-, F% X- Z4 H: S# }, D% x3 { |
ing frequent erections.3 w) r& m! e1 r: Y) ?5 w8 Z
Both parents were again questioned about use of
* u+ \* ]0 g+ } d) T. Rany ointment/creams that they may have applied to( R2 s6 R% O0 b2 j+ O% @
the child’s skin. This time the father admitted the9 |. ?9 ~) ?" T
Topical Testosterone Exposure / Bhowmick et al 541
) J9 F, y% V Y9 K8 \3 \9 _4 z, luse of testosterone gel twice daily that he was apply-
, W) M+ r$ I$ o" P, uing over his own shoulders, chest, and back area for: p% _% X4 @/ a+ g+ [
a year. The father also revealed he was embarrassed k1 m! f" C% J6 Y4 H: D/ Y
to disclose that he was using a testosterone gel pre-
$ n: X3 Y/ H* E9 {scribed by his family physician for decreased libido
; ^: x# O4 u* P+ Esecondary to depression.) l. A- I$ j1 W4 s
The child slept in the same bed with parents.
) X4 v; @# D( Z a* PThe father would hug the baby and hold him on his4 E/ \+ d; a! T4 k- L. I
chest for a considerable period of time, causing sig-
( C; B+ n7 ~7 ?7 }- Nnificant bare skin contact between baby and father.8 D2 N# x5 U9 M
The father also admitted that after the phone call,6 V% _- ~% V0 M
when he learned the testosterone level in the baby
" W2 j5 G6 _2 W# g8 swas high, he then read the product information
! x4 P# X5 D* w1 e2 `- n8 {packet and concluded that it was most likely the rea-$ T/ g5 \; Q/ ]6 j5 h Q; y
son for the child’s virilization. At that time, they) d" w6 |+ L5 r' \8 L$ l' U
decided to put the baby in a separate bed, and the( M F6 w" u8 p% R; @0 h, y
father was not hugging him with bare skin and had
7 a4 e: D% P a: g6 M9 ubeen using protective clothing. A repeat testosterone
+ K" S5 i" }/ U, P( `8 Ytest was ordered, but the family did not go to the6 A5 W; G- D. \. w1 `
laboratory to obtain the test.
: O9 v$ O) Y2 F! B7 WDiscussion
* y6 }+ Y& J' O/ |6 G6 A3 V2 f6 `Precocious puberty in boys is defined as secondary' V8 v6 J3 o5 w P) e5 `, t) f
sexual development before 9 years of age.1,4( I- i6 d( m' n% K$ U# S; @5 r
Precocious puberty is termed as central (true) when" u- j8 g0 |, E% F
it is caused by the premature activation of hypo-
s2 e. {9 t i# q, D& R: e# Ythalamic pituitary gonadal axis. CPP is more com-
2 k+ t2 H( `! |3 Amon in girls than in boys.1,3 Most boys with CPP
: |( C; q1 J6 E `0 smay have a central nervous system lesion that is
( F, |4 b3 G4 nresponsible for the early activation of the hypothal-
7 R2 {/ ^7 _) g; J6 ?8 U+ Famic pituitary gonadal axis.1-3 Thus, greater empha-
~8 o1 W7 a' I: osis has been given to neuroradiologic imaging in8 a$ d' Q. {- T; x8 C: ]8 W# w; W
boys with precocious puberty. In addition to viril-* M. g0 ^) ^" A8 }
ization, the clinical hallmark of CPP is the symmet-5 Z6 U9 B3 e+ w2 ?
rical testicular growth secondary to stimulation by. v. q1 G7 X: t z7 S
gonadotropins.1,3
* X8 j% M; T9 jGonadotropin-independent peripheral preco-
! z1 y* p: p/ u4 bcious puberty in boys also results from inappropriate5 o$ u# L9 e q& k
androgenic stimulation from either endogenous or
. A8 r) \4 {: L. K3 @* W- B- Y+ xexogenous sources, nonpituitary gonadotropin stim-0 e: V% a9 m7 O" u' p& [; q/ o% U3 s; N
ulation, and rare activating mutations.3 Virilizing
, b/ r, b& @% ?! v: R) g5 L5 kcongenital adrenal hyperplasia producing excessive
& O: ~! b2 E* o" H# M: ?: Tadrenal androgens is a common cause of precocious) ~9 |5 O3 t8 [! H( b2 Y3 t! Q
puberty in boys.3,4; Z/ v7 r8 L! Z4 T' o+ w [3 V
The most common form of congenital adrenal y$ Z; \$ r6 o% M( y( h7 D
hyperplasia is the 21-hydroxylase enzyme deficiency.7 Q* @2 f) ?. g8 ~/ Y9 B# n! \
The 11-β hydroxylase deficiency may also result in
9 u! V9 R: B. j$ D* y, Zexcessive adrenal androgen production, and rarely,, y1 J' r q X# F) s# v
an adrenal tumor may also cause adrenal androgen
; \% s1 u, ~: `# B: [excess.1,3
2 p; h3 Y& H- tat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from: C- m* {2 j! U
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007- p* S% |- [+ D7 M1 E+ g% {
A unique entity of male-limited gonadotropin-5 ]" B+ u. p+ D
independent precocious puberty, which is also known
/ u: y7 N, @5 ?9 s5 mas testotoxicosis, may cause precocious puberty at a: e' W* b0 R% v: L) E
very young age. The physical findings in these boys
6 \- u0 {& i! u3 c4 gwith this disorder are full pubertal development,3 _4 @+ N& [& }! R; s
including bilateral testicular growth, similar to boys/ v( Y- |5 \7 G
with CPP. The gonadotropin levels in this disorder
+ A' _, P4 a$ v" i5 Y! a+ \& L+ zare suppressed to prepubertal levels and do not show+ D4 l( j9 `: v* f0 E
pubertal response of gonadotropin after gonadotropin-' S, O. p; x5 _+ D( C8 \- D! f1 |% J
releasing hormone stimulation. This is a sex-linked' C/ I7 v. c1 j6 o$ O
autosomal dominant disorder that affects only
3 w* {7 C* @* O8 umales; therefore, other male members of the family# W) h5 ~0 c2 M# s% t0 M: ]; \0 F
may have similar precocious puberty.3
8 @0 t3 n0 X0 t0 y3 C/ d1 WIn our patient, physical examination was incon-
4 ~1 s$ F1 Y9 `sistent with true precocious puberty since his testi-
/ a( T8 x" W* h6 Ccles were prepubertal in size. However, testotoxicosis m' Y5 z E% O) \( `/ ~* {3 k1 T
was in the differential diagnosis because his father
+ y' M; l: F* P0 Ustarted puberty somewhat early, and occasionally,
2 ]% ]- c* R8 f/ D/ k) Y. W5 utesticular enlargement is not that evident in the5 G+ c+ A! E# T; Y( k! ?* R; y; b
beginning of this process.1 In the absence of a neg-3 w3 p+ j( m+ i, ?/ o
ative initial history of androgen exposure, our
! X" l( C4 i# a; |4 {2 P6 kbiggest concern was virilizing adrenal hyperplasia,! F: w8 C3 t/ _5 V
either 21-hydroxylase deficiency or 11-β hydroxylase
( t% B' ?' X) G/ ^! \' Qdeficiency. Those diagnoses were excluded by find-' f6 C9 a7 z$ [) s" v; V+ Z
ing the normal level of adrenal steroids.% M- v( _) t# `: P, b4 S
The diagnosis of exogenous androgens was strongly
1 s1 F+ s9 x O+ g9 j0 z" C8 [suspected in a follow-up visit after 4 months because9 ]8 r0 ~' V# B: |( E
the physical examination revealed the complete disap-# y1 V: ~, d" t/ X3 @/ ?5 E. z
pearance of pubic hair, normal growth velocity, and
: l9 e! j% p+ h* A$ A1 ~decreased erections. The father admitted using a testos-
5 m3 k9 A- L* P& Cterone gel, which he concealed at first visit. He was3 T6 Z! X( ~8 I7 y) o
using it rather frequently, twice a day. The Physicians’3 u/ d$ P, c/ E5 j' S4 F
Desk Reference, or package insert of this product, gel or% k/ i+ o" V2 i
cream, cautions about dermal testosterone transfer to- X" B8 ?1 k2 g' Z3 ^
unprotected females through direct skin exposure.$ P# G' W: V: V0 K; {; J
Serum testosterone level was found to be 2 times the) W6 V# u8 V6 u5 D; G3 k
baseline value in those females who were exposed to- E- O, g1 M* `" B. i9 w8 n
even 15 minutes of direct skin contact with their male, o$ ]! ?7 Q! ^! b$ {6 P4 j6 c
partners.6 However, when a shirt covered the applica-
; ^& l* k& f( P) n, otion site, this testosterone transfer was prevented.
, s4 N( @9 p4 G/ X- c6 N" ]Our patient’s testosterone level was 60 ng/mL,
8 [# U& K f- l7 Rwhich was clearly high. Some studies suggest that
5 v3 t! _$ [% r$ Zdermal conversion of testosterone to dihydrotestos-3 J" \! P9 l& K: Z/ X
terone, which is a more potent metabolite, is more) i4 H! I( n6 K. i1 o& m/ B5 ?
active in young children exposed to testosterone' T) R: P( h, o8 Q5 Y F2 l. u
exogenously7; however, we did not measure a dihy-! H; F7 [# @! C% @, K& g% G! V
drotestosterone level in our patient. In addition to' Q2 S! G4 r( S2 i/ [
virilization, exposure to exogenous testosterone in5 z3 Z+ M$ x3 S. l4 J9 }# ~3 S' c
children results in an increase in growth velocity and
9 l5 \0 X- d# Z# J7 ?) j9 Dadvanced bone age, as seen in our patient.( ^- E4 V' P( N" C9 J* U0 S
The long-term effect of androgen exposure during5 q( t2 I3 P q& n1 s. B1 `
early childhood on pubertal development and final1 Z$ G: c" x1 R( E! Z
adult height are not fully known and always remain
- z2 d! s% Z- k( Ca concern. Children treated with short-term testos-
9 P' O) ~3 c( \: W Cterone injection or topical androgen may exhibit some
) B. u3 k$ b$ i$ Qacceleration of the skeletal maturation; however, after
|/ p m5 P9 S- zcessation of treatment, the rate of bone maturation
, g, R% D, X# o: |$ l1 {decelerates and gradually returns to normal.8,9
* w# O. V$ E* ^/ }# MThere are conflicting reports and controversy. j. h" D3 z* Q" u& T/ Z
over the effect of early androgen exposure on adult' @% N0 \) M5 d( y* X& Y& c
penile length.10,11 Some reports suggest subnormal
" o) l% @' M( Q |5 O* T- a+ w& tadult penile length, apparently because of downreg-( |8 {5 X6 ~' P
ulation of androgen receptor number.10,12 However,
& J8 O! {* q& USutherland et al13 did not find a correlation between
! p, y2 m' j- rchildhood testosterone exposure and reduced adult
# F4 c6 x+ `8 @' y$ Ipenile length in clinical studies.
9 F; d8 M3 l' f: C( O1 z# |Nonetheless, we do not believe our patient is, e$ }+ I. h0 G6 s9 H, M
going to experience any of the untoward effects from
4 `9 ?/ z6 p5 T3 ~# qtestosterone exposure as mentioned earlier because1 F9 Y; K! n+ g( `
the exposure was not for a prolonged period of time.; [) f4 _# G) |; i
Although the bone age was advanced at the time of
8 |( c/ u% `: @$ _8 R+ Pdiagnosis, the child had a normal growth velocity at8 L# n1 a, u+ P- B
the follow-up visit. It is hoped that his final adult
7 l" C7 e& H/ o. C4 _. |, Eheight will not be affected.
6 T5 `" U8 J% H1 Q) TAlthough rarely reported, the widespread avail-6 o- b) q+ Y1 D9 Q# S, B' {' H
ability of androgen products in our society may
! S4 N7 O9 h* |, G# nindeed cause more virilization in male or female, k9 _: z9 q8 @5 T& h" ?: D- @
children than one would realize. Exposure to andro-
' H" G1 m2 C( m5 ~3 {5 L B* lgen products must be considered and specific ques-
6 ]' c5 w. W" b5 H @) ytioning about the use of a testosterone product or8 F' Z% I; l B0 o3 A. W
gel should be asked of the family members during% ?* _6 e6 i: u
the evaluation of any children who present with vir-9 r5 e2 k3 a# H5 q, ?5 [3 u5 J
ilization or peripheral precocious puberty. The diag-
* y7 U! Y/ N- e7 |nosis can be established by just a few tests and by
6 p0 }0 [# v6 e: M( `appropriate history. The inability to obtain such a- B$ G t, f& |1 w" q8 o. Q
history, or failure to ask the specific questions, may& K* v9 H# p9 r/ }- Q
result in extensive, unnecessary, and expensive- ?+ m G" S" r+ [
investigation. The primary care physician should be
% a# ?% e" o8 o8 v' ?aware of this fact, because most of these children
/ p: Z* g9 N G8 ?may initially present in their practice. The Physicians’
# K$ b# n% P. ]' p& Z7 |Desk Reference and package insert should also put a
% r$ G7 ?0 \; K3 h+ g! p3 _warning about the virilizing effect on a male or3 o% p/ O `- P0 T$ @% V7 h
female child who might come in contact with some-: v; `6 R' M* s# y( K
one using any of these products.- q3 Q' D8 {; y3 L& }+ Q( i
References
! R7 U: J3 g! j/ I' X+ }' _1. Styne DM. The testes: disorder of sexual differentiation
: X$ [2 p& {% y2 Vand puberty in the male. In: Sperling MA, ed. Pediatric+ H( Y& f* Z9 V* {% T6 {
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;* M+ r/ H# {! I# ]8 O6 Y7 d
2002: 565-628.
7 o* [9 N- X0 L! K5 ~1 k: _9 `5 v2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious" A) U6 G/ l$ |5 ?7 x5 w
puberty in children with tumours of the suprasellar pineal |
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