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Sexual Precocity in a 16-Month-Old
q: b& o. I: N; q! B" H4 E3 P8 eBoy Induced by Indirect Topical: f0 z" U$ M3 Q1 w2 O3 c
Exposure to Testosterone
" U( f9 G7 @% G& J4 c3 [Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
9 i" ]" Q4 o/ T4 Hand Kenneth R. Rettig, MD1( @! i4 T( O" r8 y: D- ?- e3 H% |
Clinical Pediatrics
4 M/ f5 P# V( c0 Q" { nVolume 46 Number 6' Q0 D# w7 ~5 K" Z' R
July 2007 540-543( |( V( v/ `6 ?6 @2 \, x! n9 B; `
© 2007 Sage Publications
' N) `$ g' K: W1 i; F& c10.1177/0009922806296651
& Q% Q0 b/ N" F) c- _http://clp.sagepub.com+ D1 e( e0 g& |3 T" ~
hosted at4 v) S- C8 {3 p1 l; r7 m
http://online.sagepub.com
) ^* Y+ U" V. {* L/ mPrecocious puberty in boys, central or peripheral, U! B: I; t k; O% M: [8 c
is a significant concern for physicians. Central% ~) _3 G9 b$ G) K' ?1 a: I5 k8 |
precocious puberty (CPP), which is mediated; Y3 e+ h# U" B
through the hypothalamic pituitary gonadal axis, has
% W( m; B: y: @1 \" V9 z0 La higher incidence of organic central nervous system9 K# I2 [ D( o4 l9 h
lesions in boys.1,2 Virilization in boys, as manifested
; b) O3 G1 Q2 Aby enlargement of the penis, development of pubic
5 g# _* N2 g z8 qhair, and facial acne without enlargement of testi-7 v; g6 \ d0 i8 p7 X" C& F% {
cles, suggests peripheral or pseudopuberty.1-3 We/ W5 ~9 \- C X( `$ \; E) P( v
report a 16-month-old boy who presented with the0 e9 c6 B! z7 O
enlargement of the phallus and pubic hair develop-
( `* @1 P# p( n" rment without testicular enlargement, which was due* Q" R/ M0 {7 O4 w6 t0 H
to the unintentional exposure to androgen gel used by
* y' a) ^1 I0 hthe father. The family initially concealed this infor-
9 U! X6 _& l+ E4 ^0 e6 dmation, resulting in an extensive work-up for this
3 m* s" R3 h2 h' ^child. Given the widespread and easy availability of
; y2 U% }3 N" ]5 ^+ atestosterone gel and cream, we believe this is proba-& Z" R* \% b( t, I$ Z9 B
bly more common than the rare case report in the+ p# w1 l6 i! [
literature.4
. U* }/ } Z) R, o6 q& m) XPatient Report! u6 P+ Y4 g }) @# Z2 c
A 16-month-old white child was referred to the7 O% I f3 ~+ B/ I/ ]- k- e, v
endocrine clinic by his pediatrician with the concern. H. M& l6 `& n2 k6 k5 k) u
of early sexual development. His mother noticed0 I0 v% Q p3 p1 a* m8 n
light colored pubic hair development when he was
5 N: t0 k5 g2 ?" ^% o7 | H3 WFrom the 1Division of Pediatric Endocrinology, 2University of; L1 E0 Q0 f' d a: W
South Alabama Medical Center, Mobile, Alabama.
& o/ ?1 U: Q" k/ Y, ZAddress correspondence to: Samar K. Bhowmick, MD, FACE,
2 |9 A9 N6 E& ~- H5 `! tProfessor of Pediatrics, University of South Alabama, College of! u' S5 \& i8 ^2 j! b
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;3 v2 P7 _9 O0 B
e-mail: [email protected].1 B9 A m/ `7 n
about 6 to 7 months old, which progressively became
C9 M7 g+ n, h9 j ]1 D1 R/ ~darker. She was also concerned about the enlarge-
& F, I' H( ]& S+ Tment of his penis and frequent erections. The child
& S+ d. I( V% e; A( mwas the product of a full-term normal delivery, with, {! l. _6 ]5 v$ d9 U" | @7 @
a birth weight of 7 lb 14 oz, and birth length of
3 H& a/ |3 d6 y. a( ?20 inches. He was breast-fed throughout the first year
( X" Y. j2 }$ I" \8 A" x- aof life and was still receiving breast milk along with2 }. `% D7 J6 d4 Y- b- z
solid food. He had no hospitalizations or surgery,/ a. M% b! [# v+ S8 e3 Y- H
and his psychosocial and psychomotor development' J% U; X7 p9 o2 ?) i- K
was age appropriate.: K6 { t/ h0 d) J
The family history was remarkable for the father,
- ?2 B) b# ^. f O" q" A# d+ H0 ^; X# Cwho was diagnosed with hypothyroidism at age 16,
0 I. ?% G ]/ K, I, o+ j7 Mwhich was treated with thyroxine. The father’s4 w$ L+ N; j. t6 M2 G) P
height was 6 feet, and he went through a somewhat- N) c8 x* f; @) c% V
early puberty and had stopped growing by age 14.9 q: O( i' G0 m( L
The father denied taking any other medication. The
7 R4 z- z5 N7 e4 }; n0 bchild’s mother was in good health. Her menarche. q* N6 u4 u9 _) S3 Y; K8 z
was at 11 years of age, and her height was at 5 feet F. h, a1 t9 Q$ ?4 L
5 inches. There was no other family history of pre-5 S* X5 n8 D* G$ n. A j
cocious sexual development in the first-degree rela-
/ c$ M$ o3 V0 p2 ]3 [tives. There were no siblings.
* V. R$ l" g* ~7 Y# aPhysical Examination
9 ~8 K* h5 r9 h$ m! \2 FThe physical examination revealed a very active,
; F3 B- }* m7 p% D$ F: P7 |0 c- p8 _playful, and healthy boy. The vital signs documented
% ]) C+ E: r) pa blood pressure of 85/50 mm Hg, his length was& x2 q- W7 z9 ]# I" w7 Q
90 cm (>97th percentile), and his weight was 14.4 kg
0 G. P- S9 E) l(also >97th percentile). The observed yearly growth0 Q6 R- ^- W, d2 R l9 R9 X8 P
velocity was 30 cm (12 inches). The examination of8 Q0 X G: y8 {* e2 Z7 ~
the neck revealed no thyroid enlargement.
+ ^$ R6 O/ I, b+ ]) x$ Y1 }The genitourinary examination was remarkable for# [& Y# T. }4 k" \, U
enlargement of the penis, with a stretched length of8 w m2 c6 F+ l9 j+ k9 o
8 cm and a width of 2 cm. The glans penis was very well
2 Q. V, d) Y. n: x+ u, |0 R* gdeveloped. The pubic hair was Tanner II, mostly around/ @" g/ d. ~0 H0 ?& F( r% E
540, q6 q( ]8 v! {3 y8 p8 H5 g
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from) K Y) }" a& F4 o3 L
the base of the phallus and was dark and curled. The0 \5 X% d5 O1 d, j! p
testicular volume was prepubertal at 2 mL each.3 `. }( F" V( i8 w* ]# }! E
The skin was moist and smooth and somewhat' N# o0 I7 r- g% J5 Z7 ?3 M! `
oily. No axillary hair was noted. There were no
9 _! N( @+ M+ g vabnormal skin pigmentations or café-au-lait spots.! ]9 _) S9 T8 b9 [
Neurologic evaluation showed deep tendon reflex 2+0 m3 }5 p0 s4 V$ t+ Q4 j- M
bilateral and symmetrical. There was no suggestion
D& c9 ]# |$ l% Pof papilledema.
% I+ x( G% G5 @% `7 v- i( fLaboratory Evaluation! P; F5 ?/ {; F2 m8 z; e" o2 e
The bone age was consistent with 28 months by0 B' _% g8 y7 B `' I4 {- h
using the standard of Greulich and Pyle at a chrono-. y! U& @4 t, B0 t
logic age of 16 months (advanced).5 Chromosomal" j. K: e9 ~9 p) n
karyotype was 46XY. The thyroid function test
) o: H7 k- N. O, M2 N* L1 Yshowed a free T4 of 1.69 ng/dL, and thyroid stimu-
" P% D0 D$ |2 L. R1 S8 c$ [lating hormone level was 1.3 µIU/mL (both normal).
, T: d" X8 O$ A( X& mThe concentrations of serum electrolytes, blood9 ]0 A8 O+ z( `# f8 O3 `
urea nitrogen, creatinine, and calcium all were
! T7 R% _$ X7 a! ]7 W7 i# `within normal range for his age. The concentration( @% c1 r7 s3 j" T, ^+ c
of serum 17-hydroxyprogesterone was 16 ng/dL5 e. N" ?% ^3 b1 ^/ f% \3 v/ S
(normal, 3 to 90 ng/dL), androstenedione was 208 m3 K% V- T* {' G+ w, V0 V: b0 T
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
, g5 L7 x" S4 R9 |1 J7 v {terone was 38 ng/dL (normal, 50 to 760 ng/dL),
J7 b. Y6 w X {( a3 wdesoxycorticosterone was 4.3 ng/dL (normal, 7 to" f; E5 [: G! B: m
49ng/dL), 11-desoxycortisol (specific compound S)
- [5 a' S- ~8 q4 S0 L6 Xwas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-0 l7 F1 I$ K" m" p6 ^* A. W
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
& n# @8 w' k0 g6 W4 R' Q0 F; Jtestosterone was 60 ng/dL (normal <3 to 10 ng/dL),
6 i3 h, V: w& {! [# A" oand β-human chorionic gonadotropin was less than
6 s" c/ P3 M8 a. f: K, p8 @5 mIU/mL (normal <5 mIU/mL). Serum follicular
& j# f/ v3 J2 P9 {8 y3 Astimulating hormone and leuteinizing hormone
" `, B9 W. c( s# X$ z# a! i5 lconcentrations were less than 0.05 mIU/mL
+ P' q. c( \$ q! Z4 w2 n2 K(prepubertal).; t" ]9 j# B5 H+ y8 q' ]5 T% [+ l: E+ P
The parents were notified about the laboratory k+ Q) T% o7 v$ Y- Y# Q( `
results and were informed that all of the tests were+ J$ b3 d4 u% |; K. E0 \
normal except the testosterone level was high. The
* H! z3 L8 m* q0 {follow-up visit was arranged within a few weeks to }9 B; Q4 e. d+ ]# q0 j& h4 `( D4 I
obtain testicular and abdominal sonograms; how-
: z3 a2 F) I: n* k" f) mever, the family did not return for 4 months.1 n h+ O" Z0 Z
Physical examination at this time revealed that the
8 }# `& Y3 X- ^' R0 y& o& bchild had grown 2.5 cm in 4 months and had gained7 U o& _" @7 e4 l
2 kg of weight. Physical examination remained
# ]% l7 H" u- \- b7 b9 {unchanged. Surprisingly, the pubic hair almost com-
A' j, R) c5 ?- @, ?9 o, F4 C* xpletely disappeared except for a few vellous hairs at
6 H: _1 F, n" e( c/ z+ ~the base of the phallus. Testicular volume was still 2
& ]5 i4 }% p% \- X0 d6 A# NmL, and the size of the penis remained unchanged.
: Y2 a( u& d p( ]The mother also said that the boy was no longer hav-4 f @, L w$ q& M0 F6 D
ing frequent erections.. o$ Z/ A6 r |4 ]4 I
Both parents were again questioned about use of! g9 z7 M; D3 F, o8 f8 G/ m
any ointment/creams that they may have applied to
' X3 A7 o) M9 N% cthe child’s skin. This time the father admitted the, p( M3 R3 z# w) V
Topical Testosterone Exposure / Bhowmick et al 541
& y# E0 L1 g- s( kuse of testosterone gel twice daily that he was apply-
1 [. E/ S' _6 Q- {& ming over his own shoulders, chest, and back area for5 o3 Z, m+ s7 m' c0 k# j4 V" G! @% ?
a year. The father also revealed he was embarrassed9 g" U1 c* ?$ o' N2 b( S
to disclose that he was using a testosterone gel pre-
# d8 W3 B1 G, x" gscribed by his family physician for decreased libido
6 e& D* m$ i1 R+ o+ Fsecondary to depression.3 Q1 J, x; ^6 B9 p, ]' U8 p
The child slept in the same bed with parents.
9 n! u& ^- C( `8 B4 y6 pThe father would hug the baby and hold him on his7 L* Z: i( p! B
chest for a considerable period of time, causing sig-$ {( ?* R5 ^6 _+ x; m/ W
nificant bare skin contact between baby and father.& A" I% `+ Y1 [3 t" S6 U( I
The father also admitted that after the phone call,
$ \% g p% `% fwhen he learned the testosterone level in the baby! ]( P( l7 k: z4 m6 S6 q# Q
was high, he then read the product information
3 L8 W* i+ r" b: H, fpacket and concluded that it was most likely the rea-
' Q; z8 v j. c8 o9 uson for the child’s virilization. At that time, they* R6 R8 X* L$ Y# U3 f- v
decided to put the baby in a separate bed, and the
8 q- f" V" }, ^+ }$ l! qfather was not hugging him with bare skin and had0 s& t$ X4 L& F2 n2 ]
been using protective clothing. A repeat testosterone! r% v$ M& R8 K9 f) m; L0 b' d
test was ordered, but the family did not go to the
( o9 q' o1 z6 Slaboratory to obtain the test.
/ S" g" A u. ^+ HDiscussion+ k: I. c" D) g- `5 H6 E
Precocious puberty in boys is defined as secondary
% n3 v, U4 D% \) i: usexual development before 9 years of age.1,40 V7 ?1 \$ [4 O; y
Precocious puberty is termed as central (true) when
. c" r% x( m7 Y5 S, dit is caused by the premature activation of hypo-
2 M2 @7 X/ {# i8 I' u( \thalamic pituitary gonadal axis. CPP is more com- x6 n6 n: i. H: }; w
mon in girls than in boys.1,3 Most boys with CPP, A! B2 C. K; A5 g3 `
may have a central nervous system lesion that is
4 M; g! A e3 S: B3 j4 Q6 J% `& lresponsible for the early activation of the hypothal-
: x6 k+ D. t, ramic pituitary gonadal axis.1-3 Thus, greater empha-+ l/ |. e, v) E, V3 i
sis has been given to neuroradiologic imaging in6 y+ Y/ O% d9 |: c8 w
boys with precocious puberty. In addition to viril-
" H) E8 d5 i7 v( Aization, the clinical hallmark of CPP is the symmet-
0 ?* a( a5 x$ D9 B x: c# Y2 Jrical testicular growth secondary to stimulation by
2 h% C! l- q$ I& E. ~% _gonadotropins.1,35 ?% M) Y1 W! p/ f
Gonadotropin-independent peripheral preco-
" B; g$ p* V& I+ v: w7 q4 Xcious puberty in boys also results from inappropriate) m3 ]1 t3 b! P# R# A
androgenic stimulation from either endogenous or
$ w- }2 L0 A; P9 s0 ]. u) yexogenous sources, nonpituitary gonadotropin stim-
/ H6 r" n: C9 q( R H7 q6 Zulation, and rare activating mutations.3 Virilizing8 i' R; a# [- L% B2 f$ v+ D; g
congenital adrenal hyperplasia producing excessive
1 v- a" F2 r2 |; Q9 {. ~3 kadrenal androgens is a common cause of precocious$ s: j, `4 K! D% a
puberty in boys.3,43 x6 Q, Q. |9 {: C! K: e
The most common form of congenital adrenal
D0 r5 o$ d& B0 Rhyperplasia is the 21-hydroxylase enzyme deficiency.& w% ~' n; C9 h1 T
The 11-β hydroxylase deficiency may also result in6 F. L# A0 k7 s3 R1 l* s/ T, N
excessive adrenal androgen production, and rarely,# k( f X- @/ N n ^3 T; n! L
an adrenal tumor may also cause adrenal androgen
7 p1 ~) u+ R' W# lexcess.1,3- `7 m% m) l- ]3 D H& N0 k- U
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
8 f6 Q K5 k: T% t B) i4 S542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
, @5 T. M% e# O0 H$ ^8 @A unique entity of male-limited gonadotropin-8 N" l) y- J/ o; U& ~
independent precocious puberty, which is also known6 U8 J( w* j5 L# M0 [0 m' V
as testotoxicosis, may cause precocious puberty at a
: K# d: N; _. i: L8 g, Svery young age. The physical findings in these boys
& M6 H2 s$ W9 X$ ~: N4 m" q4 hwith this disorder are full pubertal development,
$ P/ a8 D3 t/ e# F% [0 cincluding bilateral testicular growth, similar to boys! o, u6 Z9 [0 y! F
with CPP. The gonadotropin levels in this disorder' n' o9 W, t4 l
are suppressed to prepubertal levels and do not show* s" Z3 i! G0 M: p8 K! H
pubertal response of gonadotropin after gonadotropin- n! K1 g) x# n0 K6 t
releasing hormone stimulation. This is a sex-linked
- x1 x! p s$ v& Q3 L& aautosomal dominant disorder that affects only1 K, \7 A; C! L! d3 I
males; therefore, other male members of the family: P J5 q, u: e5 Q
may have similar precocious puberty.3& E- i0 C3 X1 [3 v
In our patient, physical examination was incon-
0 M- {6 C G8 P) l2 }7 tsistent with true precocious puberty since his testi-
, F9 Z; E' t" x' Gcles were prepubertal in size. However, testotoxicosis# a% u: R9 S) F# z8 c
was in the differential diagnosis because his father# c' |: ^+ b. I# Z" L
started puberty somewhat early, and occasionally,( Y) d$ ]5 _: ], v1 e4 \
testicular enlargement is not that evident in the
) m! ]- N) L: _3 a- L1 f: Ebeginning of this process.1 In the absence of a neg-
) i% ~9 q9 i( p) hative initial history of androgen exposure, our
' B* s* _, _: p, R ?biggest concern was virilizing adrenal hyperplasia,
0 U* p0 q* {& ^0 F5 M6 q+ f g5 |3 Teither 21-hydroxylase deficiency or 11-β hydroxylase: i+ N1 U! F, [/ i
deficiency. Those diagnoses were excluded by find-5 A( B1 k4 `) d6 @0 }8 H% }
ing the normal level of adrenal steroids.+ ^ K* T6 w4 N" D- z
The diagnosis of exogenous androgens was strongly- P, F, G; a. k3 `3 U/ [
suspected in a follow-up visit after 4 months because8 U L" s4 h+ G) _ P" o. I2 u
the physical examination revealed the complete disap-
_. [2 t r h. N" bpearance of pubic hair, normal growth velocity, and: V, {# ]# w* o; c! g q
decreased erections. The father admitted using a testos-
) y$ t7 I7 E+ T5 fterone gel, which he concealed at first visit. He was. _9 y- o6 V9 ]+ C) x
using it rather frequently, twice a day. The Physicians’2 g- a+ Q* t' u' c; d3 j' d
Desk Reference, or package insert of this product, gel or5 U0 \8 f$ N* q
cream, cautions about dermal testosterone transfer to
# g, m" o- Z- T: f7 I6 kunprotected females through direct skin exposure.
. s+ v+ i! ?( p6 t& l) U7 QSerum testosterone level was found to be 2 times the
0 }4 Z. E# J/ c3 H# w E3 G tbaseline value in those females who were exposed to
Y1 R& b, {+ Y$ Z8 ^5 R; aeven 15 minutes of direct skin contact with their male
$ o- ?6 c/ C* [* G8 U6 w/ npartners.6 However, when a shirt covered the applica-
2 l- {0 A' Y) \3 O- ktion site, this testosterone transfer was prevented.# a, G; b$ s" t7 [9 U: v) ]0 x
Our patient’s testosterone level was 60 ng/mL, q1 s' _- q* Y) `+ h% T5 c
which was clearly high. Some studies suggest that# f5 R2 F+ Y) T. F
dermal conversion of testosterone to dihydrotestos-
" Q( S8 ~0 T! v. C% e% n2 Oterone, which is a more potent metabolite, is more
5 H, ?) y; {+ F8 |1 j( V' e7 X9 sactive in young children exposed to testosterone
1 y" h- |- w- N" @0 s3 Hexogenously7; however, we did not measure a dihy-
+ c3 }; [- V7 z+ S; k3 s0 f/ ]6 x- d# U, jdrotestosterone level in our patient. In addition to
# J( M& E/ A& D" Xvirilization, exposure to exogenous testosterone in5 P' U: b* Q8 {0 t# H) V" N8 G# D
children results in an increase in growth velocity and
& g5 w+ E2 E7 m+ b% q* ~* @0 gadvanced bone age, as seen in our patient.$ n; |( J0 Z0 F* O3 [8 r' I
The long-term effect of androgen exposure during" D- o. m- M8 C( s" x- w1 X
early childhood on pubertal development and final
* {0 h& ^ q1 `1 l! z, k% Gadult height are not fully known and always remain: A0 o, y0 c% W+ n" j2 Y& r- x1 F
a concern. Children treated with short-term testos-
* j! H4 Z; n; N& H- ~terone injection or topical androgen may exhibit some; h% [5 _! \2 [2 S1 ?
acceleration of the skeletal maturation; however, after$ a d0 G' ]2 w/ w0 A
cessation of treatment, the rate of bone maturation
# M4 a8 l* m9 e0 rdecelerates and gradually returns to normal.8,9
! S l; M4 e$ D3 y9 iThere are conflicting reports and controversy
- g9 i/ v; ]5 C2 `, Mover the effect of early androgen exposure on adult
- Q+ F" D) F; x5 Npenile length.10,11 Some reports suggest subnormal
], h# ]' q) b: q* R madult penile length, apparently because of downreg-) v4 ], y% A7 l( N ?
ulation of androgen receptor number.10,12 However,* ~! K7 r1 B) U+ J$ _
Sutherland et al13 did not find a correlation between& O# `4 y" L3 G) N; k U; H6 G
childhood testosterone exposure and reduced adult1 N' ~3 g8 m: k
penile length in clinical studies.
. Z) I' X8 u* v2 ~8 pNonetheless, we do not believe our patient is
- ?5 \% l4 I ?+ P* `% t2 Zgoing to experience any of the untoward effects from! ?( N- S; L7 \; U' B4 \
testosterone exposure as mentioned earlier because; j) e" P5 x. f
the exposure was not for a prolonged period of time.$ U; L' T& W9 s [3 v# T, K
Although the bone age was advanced at the time of
8 T5 u) X5 i' ~: K& pdiagnosis, the child had a normal growth velocity at; [4 a5 Z3 c0 u+ G
the follow-up visit. It is hoped that his final adult
2 I& m& X5 S; c& }6 M9 z# Yheight will not be affected.
$ k( K9 j& F, W7 K0 s* a: A3 ~Although rarely reported, the widespread avail-9 u! X4 C& s" }
ability of androgen products in our society may
$ f# _% v( X3 R* e2 {indeed cause more virilization in male or female
! S1 a9 ?, v" v6 @0 x, ~children than one would realize. Exposure to andro-* W( h; W5 d! k1 M& x m
gen products must be considered and specific ques-
1 u6 ?+ |6 E/ p, [ Etioning about the use of a testosterone product or
& |/ [/ @- H% egel should be asked of the family members during
& E P* A3 T% S ~the evaluation of any children who present with vir-4 W( Y. [; }* `: }; J6 E3 H% Q. d: Q
ilization or peripheral precocious puberty. The diag-) U( y- f& c; x z9 c, O) ^# B
nosis can be established by just a few tests and by
+ p& q+ ~' M. F6 iappropriate history. The inability to obtain such a
X8 V- [$ u1 V# y# ghistory, or failure to ask the specific questions, may2 b1 r; F1 T! \$ U1 b! l) A# {
result in extensive, unnecessary, and expensive
& Q1 q M4 e7 V$ H! m9 i, J" ainvestigation. The primary care physician should be
# X) Y# |/ z% t$ u* ]$ \$ yaware of this fact, because most of these children! t+ b. {; H) V% \# H4 ^7 J ]
may initially present in their practice. The Physicians’
( P( A7 X- N0 J, F& qDesk Reference and package insert should also put a
* M8 A2 ~1 Y/ ~warning about the virilizing effect on a male or
0 N2 ?0 f: D L6 t6 B, _female child who might come in contact with some-
0 _0 s' u7 z6 k: v) b2 U6 pone using any of these products.8 E3 d, Z1 k$ C2 } J6 G
References
2 p$ S" O/ o- U5 `* @7 J0 P1. Styne DM. The testes: disorder of sexual differentiation' ^4 F' I$ C1 Z8 x' M6 H
and puberty in the male. In: Sperling MA, ed. Pediatric
: @9 Y; ?- t. P3 l: F- IEndocrinology. 2nd ed. Philadelphia, PA: WB Saunders;8 ?& M' |* p6 X& H' h7 {
2002: 565-628.! h4 S% H, S6 f0 L- U
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
$ ]& W4 }7 j6 f5 B7 S" y8 gpuberty in children with tumours of the suprasellar pineal |
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