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Sexual Precocity in a 16-Month-Old
0 y. @7 J# @/ SBoy Induced by Indirect Topical; x" K- y c; x, ^
Exposure to Testosterone) G/ N _% W9 D/ I% a( `+ y: c
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
/ V0 |+ S2 Y- l* r2 land Kenneth R. Rettig, MD1
4 H# \& n- ]5 d, |Clinical Pediatrics
" c4 ^0 p) q/ Q/ R4 m0 H7 M# DVolume 46 Number 6) m) C0 |4 C) H: H: w. L# g
July 2007 540-543
! f7 Q/ @- ? b! P© 2007 Sage Publications
' `* X/ q$ W2 M: \2 g10.1177/0009922806296651
% v2 X, \) l' @& Q% }+ O( y% ]- p) }; `http://clp.sagepub.com
, O8 }5 B& y, {2 k. w0 N) jhosted at2 k# K# i# L) B0 [6 I
http://online.sagepub.com
1 w' C, F. d' o2 L) q5 fPrecocious puberty in boys, central or peripheral,
- R5 |* { e x2 d* V% ]2 xis a significant concern for physicians. Central% ? I3 b8 }' r% \/ \! J% c
precocious puberty (CPP), which is mediated( [8 E6 l5 B1 k O, ?; M& F- ]3 r
through the hypothalamic pituitary gonadal axis, has
]1 z$ ~ ]- G8 E8 A: y: m- Sa higher incidence of organic central nervous system
! [% n+ ]% C* U) O6 L* B. J/ \lesions in boys.1,2 Virilization in boys, as manifested6 c7 y2 B! z" Y
by enlargement of the penis, development of pubic: p" V `" I. `# D _/ @0 d
hair, and facial acne without enlargement of testi-' g# }3 W8 T$ `1 i5 B
cles, suggests peripheral or pseudopuberty.1-3 We
2 R% f0 h1 o8 o# \2 _2 |report a 16-month-old boy who presented with the+ Z! r8 v* C+ [( ^5 {' x( _& ]& Z
enlargement of the phallus and pubic hair develop-
. k$ q( ]: I& d3 q1 W, Tment without testicular enlargement, which was due! w% v6 H! Y2 z: X* A# l& W+ ?
to the unintentional exposure to androgen gel used by
6 S, l6 I' O2 [3 Xthe father. The family initially concealed this infor-
: g0 [. R5 e/ v- g- A- Fmation, resulting in an extensive work-up for this
( ~% I c+ w3 N1 a r/ p9 V0 |child. Given the widespread and easy availability of( l& @1 ]- }' C3 ~) U, ?! g6 o) F& m
testosterone gel and cream, we believe this is proba-' r! e2 }& m6 k
bly more common than the rare case report in the: X6 K& v" b* @4 x+ x9 ^9 j
literature.4/ d4 a( F8 j, u9 p9 x
Patient Report7 z4 a" H X# m/ z U
A 16-month-old white child was referred to the
5 C% W; n5 F1 C( O Bendocrine clinic by his pediatrician with the concern
4 C3 b: l. J; w+ y7 V4 F3 [2 {of early sexual development. His mother noticed
! X% `$ u \4 ^! Ylight colored pubic hair development when he was
) w# Z, z& E% jFrom the 1Division of Pediatric Endocrinology, 2University of$ \! k. I* K8 r9 @* G2 \
South Alabama Medical Center, Mobile, Alabama.
' F2 t% H9 l, \* VAddress correspondence to: Samar K. Bhowmick, MD, FACE,
- y, O: r4 o4 `8 r) DProfessor of Pediatrics, University of South Alabama, College of5 M+ F7 e/ X* {! y- g3 }) O+ ?
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;, u9 e! v& R! M/ b3 C! d! V! l3 N. J
e-mail: [email protected].3 r) H; }) w8 G1 a. l8 Z; t; r
about 6 to 7 months old, which progressively became
% q7 D2 o N% m* ^darker. She was also concerned about the enlarge-
2 M9 A3 p9 h4 T: h) b8 Vment of his penis and frequent erections. The child4 ~7 O9 W W) z' ~1 y
was the product of a full-term normal delivery, with
* W" n( |/ i" O/ ^1 Q# R& @a birth weight of 7 lb 14 oz, and birth length of& u$ f7 U* z7 G) G
20 inches. He was breast-fed throughout the first year
* P K: p, R: N, _+ Z0 I" u! ]8 U6 Qof life and was still receiving breast milk along with
7 o6 s) Q& e2 h, X# asolid food. He had no hospitalizations or surgery,/ h% k I) F' ^+ T6 K
and his psychosocial and psychomotor development1 W, i9 c4 U: ~4 E
was age appropriate.- g* h3 F* f( {4 q* F0 q2 m/ B
The family history was remarkable for the father,; `8 ~; ?8 T* `3 C5 g) M
who was diagnosed with hypothyroidism at age 16,
/ M" T" V4 w2 B+ \) A0 awhich was treated with thyroxine. The father’s2 t$ N8 y) ?! s3 s; W& Q
height was 6 feet, and he went through a somewhat
7 |" R; G. i, W4 ^early puberty and had stopped growing by age 14.
# v$ X/ W! y& P7 f7 O* MThe father denied taking any other medication. The% Q' k3 W& y" v' Z
child’s mother was in good health. Her menarche
0 A3 L" r5 P1 y% E& ]was at 11 years of age, and her height was at 5 feet
& P& W# R6 P4 R5 inches. There was no other family history of pre-4 S6 X! e$ V* x2 d; T
cocious sexual development in the first-degree rela-
1 u% `1 W( h5 o3 E ?/ ]3 Q" C+ atives. There were no siblings.
# _; T1 V; y; R5 |2 O* LPhysical Examination
; \! n6 _- Q2 MThe physical examination revealed a very active,
! S6 F# _ \2 y! D$ Oplayful, and healthy boy. The vital signs documented' ]9 c" |4 L6 Y% i9 f
a blood pressure of 85/50 mm Hg, his length was
" ], f- w( M. j/ ^5 v% l5 N6 d; C90 cm (>97th percentile), and his weight was 14.4 kg9 A& p* L7 }$ I, c- F
(also >97th percentile). The observed yearly growth
( j4 Y8 ?' i; I+ l8 W R/ t5 mvelocity was 30 cm (12 inches). The examination of2 `7 |6 o' @ {. W+ F+ `
the neck revealed no thyroid enlargement./ h# j! O6 V) P3 D+ B) x/ M
The genitourinary examination was remarkable for( W4 Y9 Z% S# ~! p
enlargement of the penis, with a stretched length of
3 E0 c' ?. J9 a5 q& ^$ U5 s8 cm and a width of 2 cm. The glans penis was very well
, ^; K% T" n; Y8 ideveloped. The pubic hair was Tanner II, mostly around2 g" Z1 {* H" p+ y5 X
540/ v# K0 r. n, N9 z/ y' B
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
# n, ~3 p% P/ O- m2 qthe base of the phallus and was dark and curled. The4 I$ r) Q5 j% G( `3 P
testicular volume was prepubertal at 2 mL each.
8 x( _1 [7 V8 W: C" A& o' PThe skin was moist and smooth and somewhat4 r/ w7 Q% \1 i$ I, Q% m" I
oily. No axillary hair was noted. There were no
n6 a s; G3 ]2 L3 d" R! Jabnormal skin pigmentations or café-au-lait spots.
: ]3 G4 c% L- V+ i% @& TNeurologic evaluation showed deep tendon reflex 2+2 J1 l7 ^5 `8 |/ {
bilateral and symmetrical. There was no suggestion
4 j, d5 U) s# J4 Aof papilledema.
4 K% h1 _* S7 {7 I1 }* SLaboratory Evaluation
% C* f. H/ x" {; p5 VThe bone age was consistent with 28 months by; j) n. j4 L1 a& X- e, c# x
using the standard of Greulich and Pyle at a chrono-, D) P" R- n' t' h7 b$ ?% g1 Z
logic age of 16 months (advanced).5 Chromosomal4 S5 i, f4 h0 M3 Z5 L9 f2 { k
karyotype was 46XY. The thyroid function test, |7 o" y% O7 d' M
showed a free T4 of 1.69 ng/dL, and thyroid stimu-
' R6 _3 I9 C. o! Glating hormone level was 1.3 µIU/mL (both normal).
1 p) r" o2 l5 b$ F* D+ ]5 aThe concentrations of serum electrolytes, blood, |' d8 ]' `5 `' n5 y
urea nitrogen, creatinine, and calcium all were
1 m. V# x4 d9 \- E8 pwithin normal range for his age. The concentration6 s# [" V+ R$ @: o
of serum 17-hydroxyprogesterone was 16 ng/dL
0 \$ n5 U1 ^1 j+ r" g, m(normal, 3 to 90 ng/dL), androstenedione was 204 v l$ c/ {3 I4 }5 D, a3 O
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-& C9 Q9 c9 p! y+ D, D" Z9 X
terone was 38 ng/dL (normal, 50 to 760 ng/dL),1 u! X1 g {0 D1 O$ | Z' H
desoxycorticosterone was 4.3 ng/dL (normal, 7 to9 t* b( Y. [9 g; \
49ng/dL), 11-desoxycortisol (specific compound S)( c9 L( q, \& i, `. ? l6 U
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
6 j* l( w# }" u2 U4 w8 W; L; u6 @tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
, e2 X6 q( v1 v; M/ T$ M2 b& atestosterone was 60 ng/dL (normal <3 to 10 ng/dL),' O) u9 p, F% e
and β-human chorionic gonadotropin was less than
1 m# ?; H$ u/ o( L e* ]- q/ E/ A5 mIU/mL (normal <5 mIU/mL). Serum follicular
. O+ |0 A4 i8 @# Q' x vstimulating hormone and leuteinizing hormone" {3 n3 L' H! U% ~% G0 }5 Q O
concentrations were less than 0.05 mIU/mL5 I( Z2 _+ [: Y; o) q
(prepubertal).
) k* y' _+ ?3 P- { X% Z- UThe parents were notified about the laboratory
, x; Y" d, a2 w% t8 zresults and were informed that all of the tests were( j9 _% K% W$ n/ d
normal except the testosterone level was high. The
9 n( y9 r2 T& p; F9 p# `3 dfollow-up visit was arranged within a few weeks to
' u o3 l) U& T" ?obtain testicular and abdominal sonograms; how-1 V8 j P v( o, S+ ^
ever, the family did not return for 4 months., h9 g% s. q; y& {/ S' r/ l
Physical examination at this time revealed that the( Y9 c9 ]3 a& O& t2 p0 o, |# p
child had grown 2.5 cm in 4 months and had gained8 R3 Q7 f% z# Q7 k' l2 |
2 kg of weight. Physical examination remained; d/ j' c( q" J* j" X: t$ M
unchanged. Surprisingly, the pubic hair almost com-
( m g) A8 d1 {+ q0 Q" mpletely disappeared except for a few vellous hairs at
) T: [1 ^5 V* a6 S! othe base of the phallus. Testicular volume was still 2; H! m/ @* Z4 @+ B% t2 |! t
mL, and the size of the penis remained unchanged.* A# a/ k! H; t1 B! x
The mother also said that the boy was no longer hav-
7 Z P j, @, ?! j9 E6 v" J5 ping frequent erections., w& G6 P0 `8 p$ h
Both parents were again questioned about use of0 \2 z+ ?7 m* L# O P
any ointment/creams that they may have applied to
! f {' g! i( Q" u; _4 lthe child’s skin. This time the father admitted the
/ u k2 E1 |& g( a9 m8 RTopical Testosterone Exposure / Bhowmick et al 541
! O% U6 z5 }+ U7 u" \( U/ M1 \2 `use of testosterone gel twice daily that he was apply-/ l. F+ L; O+ a6 Z. |! v9 D
ing over his own shoulders, chest, and back area for
6 A( _5 ]' v* I% c1 za year. The father also revealed he was embarrassed' j1 Z9 T' z7 e \
to disclose that he was using a testosterone gel pre-
( \- O" W& o3 A d9 pscribed by his family physician for decreased libido
$ B* P5 C5 Q: K* [3 Esecondary to depression." l7 d, z8 q5 X! F% ^7 T
The child slept in the same bed with parents.4 V2 D. A. G9 q& x/ Q6 H" |
The father would hug the baby and hold him on his8 I# j% P; i6 [# _* e+ \
chest for a considerable period of time, causing sig-3 u5 `9 g' [6 l2 H9 V' c, a
nificant bare skin contact between baby and father.
' c% w& y7 B; v$ T+ i& i; F$ NThe father also admitted that after the phone call," M; K5 y5 I3 ]3 x
when he learned the testosterone level in the baby
9 p8 V& W# [9 h A) Dwas high, he then read the product information! O$ z8 u9 ~9 N; G
packet and concluded that it was most likely the rea-
; _% t0 I w" H7 O: [8 vson for the child’s virilization. At that time, they
5 \) B% e3 {! T( ?+ r0 j/ ], bdecided to put the baby in a separate bed, and the3 m( F; ^/ c! _" @- p& {' P
father was not hugging him with bare skin and had6 b8 t. @+ ]+ k! L
been using protective clothing. A repeat testosterone" P3 _- C+ y2 I* X+ O
test was ordered, but the family did not go to the5 N% |+ h- V6 ]. V/ `
laboratory to obtain the test.4 t* U( P5 I$ p/ ~
Discussion) ?* j7 p. b' E7 Z9 q1 g y
Precocious puberty in boys is defined as secondary
. c; |9 z* C' b9 jsexual development before 9 years of age.1,4
$ ?3 @1 b2 @) c2 ^; LPrecocious puberty is termed as central (true) when
# _/ k* i# o3 Q) j- rit is caused by the premature activation of hypo-
) Q- i" _2 |3 O- Lthalamic pituitary gonadal axis. CPP is more com-; W) ^, F! [$ S, L1 E7 t& s
mon in girls than in boys.1,3 Most boys with CPP0 _3 N P, o. g* s9 S
may have a central nervous system lesion that is
, x/ T5 q! e, v' L% Qresponsible for the early activation of the hypothal-
) X7 B9 L% s* |' l3 g* L3 tamic pituitary gonadal axis.1-3 Thus, greater empha-
, j2 h$ F0 \+ ?( bsis has been given to neuroradiologic imaging in* m7 C. b9 a. {' O: b' q% V
boys with precocious puberty. In addition to viril-
$ u: q' c, y( N: M% |9 ?ization, the clinical hallmark of CPP is the symmet-
4 U# ?; |7 _9 A' {7 }9 Rrical testicular growth secondary to stimulation by0 b4 `2 L2 S1 w3 Z
gonadotropins.1,3
2 N" H) m, E& |Gonadotropin-independent peripheral preco-
8 x' l2 c6 W( A$ Mcious puberty in boys also results from inappropriate, F4 X' t3 m( t2 b- w1 S
androgenic stimulation from either endogenous or
) `- x/ K, B, yexogenous sources, nonpituitary gonadotropin stim-3 F* s4 A& y @; B4 H
ulation, and rare activating mutations.3 Virilizing
2 j1 q7 G! d9 S6 I% D8 pcongenital adrenal hyperplasia producing excessive
, `4 F% ~* ~ w. F+ ]4 ~/ oadrenal androgens is a common cause of precocious" f/ v" g2 }. S: ~+ ?7 R
puberty in boys.3,4
5 R2 Y: `- T- |+ N& Z& `; N1 e0 oThe most common form of congenital adrenal
M: B: Q7 }; A/ Thyperplasia is the 21-hydroxylase enzyme deficiency.
8 N9 Q4 X; H. [ Z/ J" \The 11-β hydroxylase deficiency may also result in7 B4 o$ P0 Z! t( ~$ n& C0 f. d8 r
excessive adrenal androgen production, and rarely, g5 C: G$ z6 M% ^
an adrenal tumor may also cause adrenal androgen" x/ s& j' j9 i2 g" }$ i6 A
excess.1,3
' m n/ h2 e2 |6 [1 v" j8 `at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from0 J8 d4 W3 T4 \, s0 i: I/ S0 _' T
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007. D3 U# i i8 H0 ]- }6 h# }
A unique entity of male-limited gonadotropin-
8 u* P+ N( X. b& vindependent precocious puberty, which is also known) y2 K4 q0 k4 ~
as testotoxicosis, may cause precocious puberty at a
! L: H; n! T8 e6 d' R; rvery young age. The physical findings in these boys+ A( |% u) R) W* M5 S1 m
with this disorder are full pubertal development,3 f1 F* v+ m8 P, d
including bilateral testicular growth, similar to boys
/ y& X4 M" {6 o h5 Lwith CPP. The gonadotropin levels in this disorder
( y+ N2 S8 D: v0 I; x0 D" ]are suppressed to prepubertal levels and do not show
2 a; e; s j X0 r# O% L, ^- Y% Ipubertal response of gonadotropin after gonadotropin-
3 D4 k* T; M% l8 jreleasing hormone stimulation. This is a sex-linked
9 k0 I0 H5 n- W* @" Lautosomal dominant disorder that affects only
( d5 j6 S$ D9 [: ^. o" r- E, Qmales; therefore, other male members of the family
+ R V9 O0 m% ]( |may have similar precocious puberty.3
5 ~# c8 L7 d Z* b5 h0 \In our patient, physical examination was incon-7 M# _7 j1 s3 O S- n5 u
sistent with true precocious puberty since his testi-' g9 C+ z" g4 d
cles were prepubertal in size. However, testotoxicosis
- e% |( f3 x$ V0 W; xwas in the differential diagnosis because his father
/ ]. I0 i+ N" m/ _9 Astarted puberty somewhat early, and occasionally,
, h" H' Q; ^ L5 E+ [testicular enlargement is not that evident in the
; v- e1 U- I( @ H7 v4 }beginning of this process.1 In the absence of a neg-
, B! V: ~& o# v4 M7 mative initial history of androgen exposure, our
, F: p$ B0 m: q& U& r, [* `9 D6 Vbiggest concern was virilizing adrenal hyperplasia,5 V* \, f; S% f. z8 a
either 21-hydroxylase deficiency or 11-β hydroxylase
& `7 q8 S: [& N. \deficiency. Those diagnoses were excluded by find-$ E. g0 B' @8 b- k3 @2 @
ing the normal level of adrenal steroids.$ n2 [ I; l9 V/ Z
The diagnosis of exogenous androgens was strongly
; D6 r1 P8 [2 osuspected in a follow-up visit after 4 months because! {) e z8 {/ [) `
the physical examination revealed the complete disap-
( ? u4 M8 F4 Q& n2 T, epearance of pubic hair, normal growth velocity, and( L7 s2 d5 g9 _3 ?+ M" R8 ]
decreased erections. The father admitted using a testos-
& `( J, p' I1 ~5 V$ W! k0 {' \9 dterone gel, which he concealed at first visit. He was
, L/ `$ h: j" N3 }using it rather frequently, twice a day. The Physicians’2 A0 T8 s9 b8 E, T4 H4 F
Desk Reference, or package insert of this product, gel or
% F6 s4 n, n% b( h; d; r; S, `' jcream, cautions about dermal testosterone transfer to
7 c8 ?. V' w. a% t: f* E2 B V0 Wunprotected females through direct skin exposure.
9 K! I" ]% ~( [3 |, VSerum testosterone level was found to be 2 times the
+ `1 f2 |0 D* U! j9 F. h# N/ v1 a Wbaseline value in those females who were exposed to
4 {) {' I2 T/ s8 {& g, n) neven 15 minutes of direct skin contact with their male
; C. _+ O* A& p9 _partners.6 However, when a shirt covered the applica-0 r: T, C: D1 _' D# e( [7 `! G% B
tion site, this testosterone transfer was prevented.. |4 R0 c% @ d, `9 d( H. z
Our patient’s testosterone level was 60 ng/mL,3 U& z4 n6 b7 A" Z( P# T5 {/ v
which was clearly high. Some studies suggest that
* }! B) P# Y- S6 |dermal conversion of testosterone to dihydrotestos-9 w* A, Q+ n. p# M, T
terone, which is a more potent metabolite, is more
5 Q- d' x! {0 n% Y. Tactive in young children exposed to testosterone
" p$ ]2 y+ Z! V/ ]2 d8 ?2 W3 ? wexogenously7; however, we did not measure a dihy-9 \4 t( A) c# Y" d4 K
drotestosterone level in our patient. In addition to
8 z. H$ o7 X+ r3 j0 X; r: rvirilization, exposure to exogenous testosterone in- f. o" p9 x/ g& W
children results in an increase in growth velocity and
. ~- @+ m `: U: A# \; I' t1 l8 |advanced bone age, as seen in our patient.
7 c& w% \/ U ]+ R, k8 m4 K' S3 XThe long-term effect of androgen exposure during: m% v8 `2 R3 c# f
early childhood on pubertal development and final& i n3 g) L0 z2 s. d2 p
adult height are not fully known and always remain) n* s& y# B3 z, o4 ]
a concern. Children treated with short-term testos-
2 A( u/ J0 `; \terone injection or topical androgen may exhibit some
3 D H" ~! x9 m4 M$ r* f: racceleration of the skeletal maturation; however, after# f. H7 H# Y" W: g
cessation of treatment, the rate of bone maturation
, u# ~/ h2 J! Y9 H+ [: `decelerates and gradually returns to normal.8,9
3 |& l3 N! h/ X- JThere are conflicting reports and controversy
, | G) g( K# |# f! D8 Mover the effect of early androgen exposure on adult! z' E7 K/ n+ A
penile length.10,11 Some reports suggest subnormal, _! S; c) B' i6 p2 f
adult penile length, apparently because of downreg-+ S. }1 w; K1 e' {1 z
ulation of androgen receptor number.10,12 However,5 x& i6 t# | P; @: D
Sutherland et al13 did not find a correlation between, m1 i# d! Y: {6 ~' W* i+ m; M
childhood testosterone exposure and reduced adult
. |+ l# p5 _# |" ?penile length in clinical studies.6 [9 a( h, F6 p
Nonetheless, we do not believe our patient is) n8 v2 g% }. A0 [9 L
going to experience any of the untoward effects from4 t/ O3 i/ n# i' |) H/ ~& l
testosterone exposure as mentioned earlier because% ^; j' |2 O% T9 c |
the exposure was not for a prolonged period of time.
- C; v n9 E. B& r# Y5 S+ f2 Z4 iAlthough the bone age was advanced at the time of
5 O3 e. n* r, L% ^9 v5 }4 L$ Mdiagnosis, the child had a normal growth velocity at0 L3 e/ k/ c/ f/ ]6 N: Q. t$ A
the follow-up visit. It is hoped that his final adult3 e) P& V6 J& ^, [/ S6 }! V
height will not be affected.3 R. [" }1 G# u* u
Although rarely reported, the widespread avail-
$ q( {! f% i/ f! G3 {ability of androgen products in our society may/ ^9 \4 j( E, [' N+ I4 a3 M
indeed cause more virilization in male or female
7 y6 o% J! n$ }# G1 uchildren than one would realize. Exposure to andro-
5 D( J# Z4 @7 I7 d2 C% X- }6 Zgen products must be considered and specific ques-
- B' u; B8 h3 Ctioning about the use of a testosterone product or
" X1 p8 s% O/ B, R4 @gel should be asked of the family members during
4 c# b" z* p1 ? e* ~5 R" R: wthe evaluation of any children who present with vir-8 E: [( Y, v: t3 {6 j z% h9 @& s
ilization or peripheral precocious puberty. The diag-3 \+ L7 w, m/ K6 }5 q: D
nosis can be established by just a few tests and by# u( { e3 [3 x0 j4 p1 m
appropriate history. The inability to obtain such a
y. I5 P* T7 `4 P$ Z. ~history, or failure to ask the specific questions, may
- @* o! }- G4 Z4 d4 g9 p N, wresult in extensive, unnecessary, and expensive
o; m8 q1 O* U, n5 f! Finvestigation. The primary care physician should be3 l% f0 \! |0 V( \
aware of this fact, because most of these children
" [3 `4 E4 H6 @( N1 n. ?may initially present in their practice. The Physicians’: k/ p! F6 Q' c) c# }
Desk Reference and package insert should also put a
- w, t- _0 r; |: Y; hwarning about the virilizing effect on a male or" |" \+ i; c U! u' z% \4 x( p% ~
female child who might come in contact with some-
- B+ W- I) e/ }! aone using any of these products.' ` S6 x& x9 ^! |1 S
References) G4 C, p5 @' [0 r# G6 e8 i# e! N& t
1. Styne DM. The testes: disorder of sexual differentiation
+ I9 W+ O# ?. C4 H" p1 Aand puberty in the male. In: Sperling MA, ed. Pediatric7 d. I( d! C/ ?1 B" K: N8 t
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
( Q9 @* }0 T, B; r2 L. ^2002: 565-628. K( Y8 t7 M9 I# w
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious) P$ U1 T% \$ q9 G) U. `8 n
puberty in children with tumours of the suprasellar pineal |
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