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Sexual Precocity in a 16-Month-Old. y4 O3 U/ D/ g# S. k; z" @8 |
Boy Induced by Indirect Topical: w# `6 @3 x$ _/ z& X
Exposure to Testosterone6 [3 Z- B' O# x. ]
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
/ X" y5 ~! X7 Y& cand Kenneth R. Rettig, MD11 m+ Y' i& ` ?0 E/ z O
Clinical Pediatrics1 y# ?2 i7 s8 I$ j8 q2 Y( S
Volume 46 Number 6$ ~- e2 p2 v9 {8 P6 B8 H. R! t
July 2007 540-543
' O% A% o+ q% ?% D3 P0 g© 2007 Sage Publications
- ~: \: _* v+ t `2 C8 o2 \+ Y10.1177/0009922806296651
. o$ S3 T/ h) p' G7 Xhttp://clp.sagepub.com
5 S( ?6 l$ n( }7 e" Hhosted at
& B& H b( K. h: Nhttp://online.sagepub.com
2 T1 [6 H& q1 y1 \" S' y: t* ]3 GPrecocious puberty in boys, central or peripheral,& f6 K0 k* g$ }, e8 t
is a significant concern for physicians. Central
$ O# J9 o0 g1 G+ ?; Nprecocious puberty (CPP), which is mediated
( z, |6 y( b; F4 S6 g; \( Wthrough the hypothalamic pituitary gonadal axis, has+ _7 C9 }( C" k. Z/ v% Z% M/ N. h( ^
a higher incidence of organic central nervous system
: F) P4 S6 [6 q% _1 llesions in boys.1,2 Virilization in boys, as manifested2 \& j7 g+ t( }' G& r, M' W3 F# @
by enlargement of the penis, development of pubic
. k+ f, A% f, y) |& Y/ S# @hair, and facial acne without enlargement of testi-5 C; {7 \; J, f, m8 P: B& p" f& V% Q) f' p
cles, suggests peripheral or pseudopuberty.1-3 We
5 T! ^; t0 n- e4 Qreport a 16-month-old boy who presented with the0 t+ l( ?8 v. Q* q- G0 {! ^+ t
enlargement of the phallus and pubic hair develop-
" P3 F" a9 {* V% ement without testicular enlargement, which was due) {; m5 [+ }* A& J% w# @. ]
to the unintentional exposure to androgen gel used by0 J/ W8 I7 J* A! _5 i# Q8 P& k
the father. The family initially concealed this infor-
+ n3 s8 j k9 `8 l* w- [mation, resulting in an extensive work-up for this% v8 e% C. ?% L; X E9 j G
child. Given the widespread and easy availability of4 V+ Y* [1 T- `2 @- P' ^
testosterone gel and cream, we believe this is proba-- t, Q6 d5 o( s* `/ }
bly more common than the rare case report in the
# M: H0 ]" K- O9 a5 gliterature.4
" q3 j0 \) u7 }0 xPatient Report5 ^ y3 y2 u" m" d
A 16-month-old white child was referred to the
+ A% s" Z( `" K; A3 J! c sendocrine clinic by his pediatrician with the concern
: h" k2 J" j& T1 R3 E/ Zof early sexual development. His mother noticed1 j& x4 X! B4 K' c7 i% U
light colored pubic hair development when he was9 I2 w# B" x( }, a/ J2 w
From the 1Division of Pediatric Endocrinology, 2University of
# ? a) v1 Y3 v5 v, KSouth Alabama Medical Center, Mobile, Alabama.8 K! |, H; p" e$ m2 s* w
Address correspondence to: Samar K. Bhowmick, MD, FACE,# \ _/ g; z% T" w
Professor of Pediatrics, University of South Alabama, College of b1 b3 j7 M! c Y, V( r( c" h" e3 l0 x+ x
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;9 K0 D' k! C6 y; p
e-mail: [email protected].
/ ?9 ^9 p( r7 v) B2 A0 i2 \about 6 to 7 months old, which progressively became
& L$ j0 w, I: v2 o/ m+ Bdarker. She was also concerned about the enlarge-
! t# H0 Z" S: Y& a9 S; v& }5 O& Yment of his penis and frequent erections. The child' _) ^3 @& T9 ~% L7 I% |3 m
was the product of a full-term normal delivery, with% H% R# S# M9 n1 v5 t. E
a birth weight of 7 lb 14 oz, and birth length of- n, A* A! i2 U
20 inches. He was breast-fed throughout the first year# D/ F. {1 k$ P; d/ w9 z
of life and was still receiving breast milk along with
, C9 q3 o' N1 R9 a) M9 ssolid food. He had no hospitalizations or surgery,- q2 F6 J4 W1 w* [2 z- U9 b3 Q
and his psychosocial and psychomotor development
. o+ Y$ q0 ~: W9 @# o6 l( ^was age appropriate.( I) N2 U3 q' ?
The family history was remarkable for the father,
( n1 }+ u- E1 o ^& kwho was diagnosed with hypothyroidism at age 16,
5 c G1 {8 q% o5 h( l% Mwhich was treated with thyroxine. The father’s
# w& C8 P0 S& O; u. sheight was 6 feet, and he went through a somewhat9 B$ R# |: `5 _
early puberty and had stopped growing by age 14.
6 E6 g- g5 d# EThe father denied taking any other medication. The8 x% I7 x* g @/ L+ }+ p
child’s mother was in good health. Her menarche: v( t1 O3 |1 T% q9 r6 M, ?
was at 11 years of age, and her height was at 5 feet
5 p# N; d! D( U, ]4 k5 inches. There was no other family history of pre-+ p" G- |- m. \" I9 j/ p
cocious sexual development in the first-degree rela-
8 U7 o) ]' b) q! [7 B0 p$ G" p. btives. There were no siblings.0 D+ Q5 W) z- w( ^% P/ g( p6 L
Physical Examination
a0 b _) Z9 f# CThe physical examination revealed a very active,
( c* H2 u6 H1 b7 ^6 P/ zplayful, and healthy boy. The vital signs documented
6 R) n! I+ z) \. fa blood pressure of 85/50 mm Hg, his length was
* x* v7 X+ U7 W6 Q: J5 v90 cm (>97th percentile), and his weight was 14.4 kg1 P* }* P8 X4 m* S. L0 }; C
(also >97th percentile). The observed yearly growth
* W7 u* I/ h' p! Q* c# S/ Qvelocity was 30 cm (12 inches). The examination of* }4 x; [' h2 r r
the neck revealed no thyroid enlargement.9 x8 c# S+ c! ~+ Z- F2 [
The genitourinary examination was remarkable for
0 c" r4 r, [* ? T/ Z" Yenlargement of the penis, with a stretched length of
" r( y) D/ R D# N9 b& u8 cm and a width of 2 cm. The glans penis was very well
5 n6 r9 x0 ?( z8 Ideveloped. The pubic hair was Tanner II, mostly around
( J; C: C) B1 K2 K- o+ U- q. r5400 f' O |% @0 k, G' w' K
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
0 }8 v& G7 o! |0 i+ G& O% n% Dthe base of the phallus and was dark and curled. The
4 v0 ^5 Z/ O2 P" R: ]testicular volume was prepubertal at 2 mL each.
' K4 @" w- `) |1 u+ lThe skin was moist and smooth and somewhat& b( _4 i" K! k0 g
oily. No axillary hair was noted. There were no
" A$ d! z% `' j/ \# pabnormal skin pigmentations or café-au-lait spots.
7 U$ O6 V8 X9 N0 f5 }Neurologic evaluation showed deep tendon reflex 2+
2 Q, @- Z, A* K Q$ m2 m# a, dbilateral and symmetrical. There was no suggestion8 x T3 _! Q* W! ?* p: o& w9 c
of papilledema.
6 H1 \9 r0 I! b3 D- i" K) I( g2 b$ oLaboratory Evaluation) h+ c# N; c' \+ A
The bone age was consistent with 28 months by
* \3 a( n# d% {; Eusing the standard of Greulich and Pyle at a chrono-5 b9 X* X( u2 ]: Z& J
logic age of 16 months (advanced).5 Chromosomal
% B5 ?0 \" c! f H5 ?. vkaryotype was 46XY. The thyroid function test& |8 s8 n+ Y/ z7 \6 F7 Y9 w" H
showed a free T4 of 1.69 ng/dL, and thyroid stimu-: j9 [3 |: X" x
lating hormone level was 1.3 µIU/mL (both normal).
8 g+ A$ V) v+ ^6 R' d/ } A J5 k3 SThe concentrations of serum electrolytes, blood# y, R4 |) ]* c# x9 L6 T1 c* r
urea nitrogen, creatinine, and calcium all were
9 U, T6 b, M4 m0 Lwithin normal range for his age. The concentration y n, O* _3 f* `2 e( e
of serum 17-hydroxyprogesterone was 16 ng/dL \$ M( v n2 n- I$ M3 W
(normal, 3 to 90 ng/dL), androstenedione was 20' S7 U3 t# {5 I! z( X! l& H
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-% c( B0 e" k7 E+ X: a; k
terone was 38 ng/dL (normal, 50 to 760 ng/dL),
b0 Z) d( q5 m$ f4 ~desoxycorticosterone was 4.3 ng/dL (normal, 7 to. C/ N; B$ q( z' ]. K
49ng/dL), 11-desoxycortisol (specific compound S)* M* L6 G! x( o1 ~6 B/ G
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
) {9 z& j" S# S% I# t7 ktisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total6 x9 A3 K! v% `4 R" ~- `5 k& E9 R8 ~
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),4 i1 g! P3 @! t% ]
and β-human chorionic gonadotropin was less than
, V3 J0 E0 [# v! ~1 t5 mIU/mL (normal <5 mIU/mL). Serum follicular* K! r% ~! h3 a1 p
stimulating hormone and leuteinizing hormone
8 y+ Y# \" `. R3 H8 `concentrations were less than 0.05 mIU/mL
9 R3 d: `8 P/ M# s F! G7 \(prepubertal).
2 W9 f$ P$ i; D( U/ \- M- C. R, AThe parents were notified about the laboratory
$ O* Q/ N; c( xresults and were informed that all of the tests were
% Z7 @1 a3 Q5 O7 w* T; f8 anormal except the testosterone level was high. The
- _" t+ v# u3 N! X6 sfollow-up visit was arranged within a few weeks to
+ E, h v i* a& Kobtain testicular and abdominal sonograms; how-$ O4 }4 f# Z8 y
ever, the family did not return for 4 months.
4 y4 h' y/ H$ u0 fPhysical examination at this time revealed that the9 G5 F" l; G3 I& I- l5 q
child had grown 2.5 cm in 4 months and had gained
7 X* f7 L) _4 X& D& X+ v) }2 kg of weight. Physical examination remained
6 ^) R* r. u' J& V: Zunchanged. Surprisingly, the pubic hair almost com-* Z6 S& Z# R" e2 ?7 H, `; e, Q
pletely disappeared except for a few vellous hairs at# F* i) K, z4 W9 {
the base of the phallus. Testicular volume was still 2* L/ W. U) W/ r' j6 c6 i
mL, and the size of the penis remained unchanged.: {0 h& a( g7 k7 [' i9 m
The mother also said that the boy was no longer hav-( t1 V0 L1 s& X& m: x
ing frequent erections.& q" I/ m9 ?0 g7 U, |( R
Both parents were again questioned about use of
+ m+ U5 U" h* W: A; Yany ointment/creams that they may have applied to
( G! L. A3 P# C" C3 V% S( V, othe child’s skin. This time the father admitted the- J Y- D+ M/ [2 @% k
Topical Testosterone Exposure / Bhowmick et al 5419 _+ n' Y2 R3 O, |* @ F
use of testosterone gel twice daily that he was apply-9 I. R$ I/ W' A# F% j$ g
ing over his own shoulders, chest, and back area for. A+ ]4 k. w9 B# o' k1 p
a year. The father also revealed he was embarrassed( e7 A- e: |6 F" T4 Z' f( u
to disclose that he was using a testosterone gel pre-! v2 h# _$ G) O8 ~# \+ C
scribed by his family physician for decreased libido# c5 Y1 f+ [: \2 t0 ~' a: E
secondary to depression.! Z" C% V4 J' ~8 J
The child slept in the same bed with parents.: _9 m. T# ]" _* c! K
The father would hug the baby and hold him on his% t5 C0 t1 b/ k, _
chest for a considerable period of time, causing sig-, |/ |( |/ N' ^- [5 X
nificant bare skin contact between baby and father.% f4 Y' E9 J: k6 W9 V2 [1 T
The father also admitted that after the phone call,
6 D% Z6 ?; f C9 y) Jwhen he learned the testosterone level in the baby
. ]3 n# ^8 K, L% {was high, he then read the product information% }) Q& v9 A% j/ @1 Y
packet and concluded that it was most likely the rea-, m7 o4 N: s6 W; M* L
son for the child’s virilization. At that time, they
; @ g$ k9 k; M/ Idecided to put the baby in a separate bed, and the6 u2 o* a9 {5 y5 a% [9 H, O
father was not hugging him with bare skin and had
! j! {9 b2 d! J ubeen using protective clothing. A repeat testosterone+ q+ k$ y6 g. `9 c
test was ordered, but the family did not go to the
3 m- }5 I( @4 G' _' F, o7 wlaboratory to obtain the test.
4 T: V0 V9 ^ y' Z7 ]Discussion
# q. N# a+ j; ^5 ^1 vPrecocious puberty in boys is defined as secondary" ?: B+ ?0 b1 V' u8 y( u' [
sexual development before 9 years of age.1,4
6 _2 Y3 Y; r" c4 w: Q. m% I& MPrecocious puberty is termed as central (true) when
/ |' b0 V- J( f9 Bit is caused by the premature activation of hypo-9 T1 |) j- }6 r0 I! }; D; ~; @
thalamic pituitary gonadal axis. CPP is more com-3 x* y" _; W. h1 a Z$ x9 i
mon in girls than in boys.1,3 Most boys with CPP2 a W! @0 L) X' y% O
may have a central nervous system lesion that is
) V2 p* u8 V2 N2 p) K# Dresponsible for the early activation of the hypothal-
" n* ^# \# @2 {. V( \# ~amic pituitary gonadal axis.1-3 Thus, greater empha-
R$ k: U. X7 jsis has been given to neuroradiologic imaging in9 q; G$ }- D/ v) M
boys with precocious puberty. In addition to viril-! |$ b# i. B: {3 p9 B, I& x) f7 {
ization, the clinical hallmark of CPP is the symmet-
3 ~' ~) L" Q: J- K5 m% Xrical testicular growth secondary to stimulation by: m: [# I7 K% }: p
gonadotropins.1,3, E L; C9 _0 a1 `+ a; g: {
Gonadotropin-independent peripheral preco-
+ p& K) x4 D, ^. F+ q! o8 rcious puberty in boys also results from inappropriate6 h$ P# ?1 u9 O; y" f
androgenic stimulation from either endogenous or
; P% E$ Q: w: H" k- C3 u/ @6 E- yexogenous sources, nonpituitary gonadotropin stim-) X) K2 d' y* j6 [
ulation, and rare activating mutations.3 Virilizing5 l4 I3 [" Y6 n1 }/ W8 V
congenital adrenal hyperplasia producing excessive
# P' @, v2 |. o$ I4 [+ \0 Madrenal androgens is a common cause of precocious- O5 I9 W* Y3 L5 |5 [
puberty in boys.3,4. Y, N B% A6 M
The most common form of congenital adrenal# ^( u; h8 u# v5 u0 b
hyperplasia is the 21-hydroxylase enzyme deficiency.5 y1 |, g4 j# ^! t" E& _( s
The 11-β hydroxylase deficiency may also result in5 j: X2 B: I( a, }/ o g" D
excessive adrenal androgen production, and rarely,1 x$ f: k8 ^( A8 l* S; V
an adrenal tumor may also cause adrenal androgen0 i" P; ~5 w) U( h3 |
excess.1,3
, k; r6 V* i1 `% \3 b; c9 tat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
' l# v# z# f* y* R8 o542 Clinical Pediatrics / Vol. 46, No. 6, July 2007% F( Q4 @2 c/ E' j4 ^
A unique entity of male-limited gonadotropin-
; O# |& ]: r' X. E% cindependent precocious puberty, which is also known
( z5 \ n, w8 ^7 w; O* x. e1 uas testotoxicosis, may cause precocious puberty at a
3 Q1 l7 |, j% q( ^- Cvery young age. The physical findings in these boys
( H, {2 J& ` ?" C' uwith this disorder are full pubertal development,: B. O8 Y6 @3 b5 R9 S( h
including bilateral testicular growth, similar to boys- \- O2 \! a( o2 |. J" J
with CPP. The gonadotropin levels in this disorder
1 p! d* c9 u. ?1 v2 hare suppressed to prepubertal levels and do not show, V. G- W- [* a5 `3 k. I2 e$ U1 Z4 Y
pubertal response of gonadotropin after gonadotropin-. E( w/ h8 U6 t. v# N
releasing hormone stimulation. This is a sex-linked h! j% q6 j K0 J' X; L
autosomal dominant disorder that affects only- S# ^; e$ y, f0 {
males; therefore, other male members of the family
9 L% J5 ?0 ?; @2 i" Q+ \may have similar precocious puberty.37 x) L" n: \- p& H j
In our patient, physical examination was incon-
/ u* g, G) L5 p. p1 Jsistent with true precocious puberty since his testi-9 D7 z6 b; z( ~' D% g: B
cles were prepubertal in size. However, testotoxicosis; V2 t8 f0 b) } x' j: d
was in the differential diagnosis because his father
4 } M" y2 A4 D: {0 xstarted puberty somewhat early, and occasionally,
1 _, v; ^9 s2 x9 M utesticular enlargement is not that evident in the
! N V1 J5 Q9 o& s: ?' W4 gbeginning of this process.1 In the absence of a neg-4 l1 l0 H% P- _! ^
ative initial history of androgen exposure, our, p' i( @7 V1 h9 K# e. ~; X8 C1 s
biggest concern was virilizing adrenal hyperplasia,8 s e C: C- ]. ^ D) L2 p* P
either 21-hydroxylase deficiency or 11-β hydroxylase x0 n/ A9 `: O; Z
deficiency. Those diagnoses were excluded by find-, M+ M- Y# b2 G+ C: i1 S3 j$ d
ing the normal level of adrenal steroids.
& i) [- j( J9 f p, EThe diagnosis of exogenous androgens was strongly: r! }1 H4 m% N; ]5 [, j% k7 M
suspected in a follow-up visit after 4 months because
5 Y0 |6 c- s$ u# J, }the physical examination revealed the complete disap-; p1 o1 g5 k7 y6 W1 Z( Q: Y
pearance of pubic hair, normal growth velocity, and6 w- b" b3 D, ^" o! l
decreased erections. The father admitted using a testos-
; `. x& m6 }4 e% J/ A& {( v. v$ rterone gel, which he concealed at first visit. He was
) d- X$ V3 N/ z# _. i+ p4 ausing it rather frequently, twice a day. The Physicians’' u, {) s- d8 ]* Y. _
Desk Reference, or package insert of this product, gel or
- H8 {3 s# d' Z: t9 w7 j7 scream, cautions about dermal testosterone transfer to. ?) U8 _/ p1 S
unprotected females through direct skin exposure.
: T+ M; z: C) n) ]; ^ CSerum testosterone level was found to be 2 times the
) e5 ^* G3 G5 G' ]9 \- t* G0 Fbaseline value in those females who were exposed to
9 }$ X* [) L i0 Beven 15 minutes of direct skin contact with their male2 T7 q% @1 U$ s6 H: `2 V% V
partners.6 However, when a shirt covered the applica-, v: j- T6 d4 z4 h4 l4 `
tion site, this testosterone transfer was prevented.
# f0 D ~5 y. |2 ]Our patient’s testosterone level was 60 ng/mL,
8 s) n s2 P7 Ewhich was clearly high. Some studies suggest that
! ?: A9 o: A/ l# ]. vdermal conversion of testosterone to dihydrotestos-
( ]0 l# |7 {1 Fterone, which is a more potent metabolite, is more
% [) y" }9 `9 }- h( |active in young children exposed to testosterone+ z0 B0 Y+ c# Q" w
exogenously7; however, we did not measure a dihy-3 f* ~; ]2 R( n) I) _5 h" v
drotestosterone level in our patient. In addition to
. D i' l5 C+ b; {, y, s' f4 ?% Rvirilization, exposure to exogenous testosterone in4 |0 A0 E+ m; u1 X
children results in an increase in growth velocity and# M9 R0 `, X' r1 _! s( ^
advanced bone age, as seen in our patient.
: k' r7 ]) R# f7 s) @9 E, MThe long-term effect of androgen exposure during- D; S% d7 a' @) F" O
early childhood on pubertal development and final
% ~0 d* n. \2 U) @. b# yadult height are not fully known and always remain
/ D% ?) X- s2 M6 {a concern. Children treated with short-term testos-
3 c' k; p1 T6 d: lterone injection or topical androgen may exhibit some
4 Q B. O1 o9 _( l! B! z2 J9 \! xacceleration of the skeletal maturation; however, after# Q. p* ^+ N7 p# f; \7 \+ h* {
cessation of treatment, the rate of bone maturation* y w. j+ t9 l# n3 _/ y8 R
decelerates and gradually returns to normal.8,9
. y3 X& Q. H$ r/ {+ HThere are conflicting reports and controversy
- j- j* |% M b- p9 l6 y; Tover the effect of early androgen exposure on adult3 f: w5 K0 T1 E4 v
penile length.10,11 Some reports suggest subnormal$ u+ L2 I& V6 K5 d# S* O7 f) {
adult penile length, apparently because of downreg-
5 O9 P, P, @6 w. Tulation of androgen receptor number.10,12 However," { E7 ^4 u4 |: c$ z' h
Sutherland et al13 did not find a correlation between, N3 r, `- K' k+ N0 g0 h
childhood testosterone exposure and reduced adult
9 T" j O _# N+ N- [1 R0 ?penile length in clinical studies.0 ]" R# i3 Z- ~# T
Nonetheless, we do not believe our patient is
: i5 V; N! z' j: \8 }7 Hgoing to experience any of the untoward effects from% i& Y% |- T# \* H+ B: _) s
testosterone exposure as mentioned earlier because
6 ]* q1 C) }# y+ ethe exposure was not for a prolonged period of time.
" C* T, j6 Z- g5 u1 e# B2 UAlthough the bone age was advanced at the time of
! b2 i2 ~8 l& v4 F, Hdiagnosis, the child had a normal growth velocity at, B8 ]/ P# w2 l v) K1 v
the follow-up visit. It is hoped that his final adult( n, {: f0 d, {( j
height will not be affected.) {; M$ A/ [, b* u; x( f6 S* d; p9 s
Although rarely reported, the widespread avail-+ A0 ] ~% X9 W$ E4 D* l1 G
ability of androgen products in our society may
+ n( [, S# _; _2 F2 H) q- Oindeed cause more virilization in male or female! x$ C) ?1 D& `( i; r) v4 D
children than one would realize. Exposure to andro-
8 o# v" ?( _0 H: M) o' X! fgen products must be considered and specific ques-5 w. l9 R' ~6 y% {# j' t5 }
tioning about the use of a testosterone product or
; p& `0 H! T6 g$ `1 |gel should be asked of the family members during
( {) U2 F$ V6 i# Tthe evaluation of any children who present with vir-
& S- G# C+ u- F" [ilization or peripheral precocious puberty. The diag-/ H4 i/ w9 h. z, g
nosis can be established by just a few tests and by
0 `* G1 m% A. nappropriate history. The inability to obtain such a# x8 k7 E f& x) e
history, or failure to ask the specific questions, may. b- ?1 x5 L; H# h( j1 d+ {9 ]
result in extensive, unnecessary, and expensive+ u* I2 e1 l& L4 L
investigation. The primary care physician should be
w- R' q; e9 p+ Vaware of this fact, because most of these children
" N3 Y, f, @3 [ F8 ]8 E! Pmay initially present in their practice. The Physicians’
4 b X/ E' J# e% c5 @$ [7 X# A# cDesk Reference and package insert should also put a5 D6 | ?; S9 N/ ~
warning about the virilizing effect on a male or w7 t; x6 T3 Y8 T
female child who might come in contact with some-
$ z1 g/ R/ l& ]7 ^# G- B1 j8 Uone using any of these products.* A8 q* A5 d7 h4 D1 E
References) {& `1 P- ~( z+ \4 ~% g
1. Styne DM. The testes: disorder of sexual differentiation5 u9 y; N$ C6 @ |
and puberty in the male. In: Sperling MA, ed. Pediatric
6 q0 W/ Z2 W5 s0 \, C8 R0 J9 x' uEndocrinology. 2nd ed. Philadelphia, PA: WB Saunders;2 g5 o k, x9 t
2002: 565-628.
3 U3 R9 b2 _1 j7 k2 `. R2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious- N x4 b- b: I) d& Z" p
puberty in children with tumours of the suprasellar pineal |
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