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Sexual Precocity in a 16-Month-Old$ }2 ?: ^( _" U1 z7 A
Boy Induced by Indirect Topical+ ?0 X! C/ n9 U P+ F' [) x- Q. R
Exposure to Testosterone
# C$ C3 m$ b: p0 ^, e; bSamar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
7 O& ]8 `9 M' Q5 l9 B, q8 land Kenneth R. Rettig, MD1
- k( x2 o: U: ZClinical Pediatrics7 P2 q+ I" f0 s
Volume 46 Number 6
3 N5 Q' j9 l+ q1 h. n$ ]: CJuly 2007 540-543
X- a+ e* ]7 f" _; R© 2007 Sage Publications
9 o; A5 U* \. Z; c10.1177/00099228062966519 U s, e: n- q% l; M/ ]* }$ r8 y
http://clp.sagepub.com& K4 x. {2 V2 u- U' Z% I. j" R' d
hosted at3 S, {4 K2 i3 v( e W! |
http://online.sagepub.com/ h2 y7 i( n" j+ j& J, q5 f6 X; O3 ]7 _
Precocious puberty in boys, central or peripheral," i, P; L9 ~6 V, W9 P
is a significant concern for physicians. Central! x# n' `* C* c& T8 \& D- U g
precocious puberty (CPP), which is mediated. m& d7 r9 f" h7 h# v
through the hypothalamic pituitary gonadal axis, has3 W5 c6 ~1 j# Z# I% U; l" N) A
a higher incidence of organic central nervous system
1 q. n0 D" K8 Qlesions in boys.1,2 Virilization in boys, as manifested$ l6 n1 L X1 b }5 c, L( j
by enlargement of the penis, development of pubic* K+ A. q' ^5 z# t) P' b
hair, and facial acne without enlargement of testi-3 R' I/ h/ D" _9 g% L8 u
cles, suggests peripheral or pseudopuberty.1-3 We
& ?0 T7 E: q) ]$ w8 |# _# Ereport a 16-month-old boy who presented with the
, ^& j8 C' p4 c1 genlargement of the phallus and pubic hair develop-
& _! o* z8 ]6 ~3 e: |! S* \+ B/ tment without testicular enlargement, which was due
) g/ G3 w! y* N6 f( ~6 ~% ^9 ?6 wto the unintentional exposure to androgen gel used by- A3 g9 N% d9 ~6 O5 i
the father. The family initially concealed this infor-5 E8 t c2 e7 v: |
mation, resulting in an extensive work-up for this
; x5 a; \4 @; b0 i" L* c/ R! }) Bchild. Given the widespread and easy availability of+ X, P2 q- T9 S
testosterone gel and cream, we believe this is proba-6 G+ S6 E4 l) [- l" ]2 Y$ ^
bly more common than the rare case report in the( ~! V9 `1 C. B5 {: w$ h) F
literature.4% R e4 b6 U) h& g
Patient Report
. R5 l2 J; }2 n3 ^2 H) v: Q6 UA 16-month-old white child was referred to the( n: H9 a7 K8 K5 f$ g6 v
endocrine clinic by his pediatrician with the concern
+ n2 P4 H# ~ Uof early sexual development. His mother noticed8 w: h3 _0 x" V! R
light colored pubic hair development when he was
3 z% Y2 y( {6 N0 j: y# o% L% t( CFrom the 1Division of Pediatric Endocrinology, 2University of# q. ~! y. r2 a7 O2 F
South Alabama Medical Center, Mobile, Alabama.
* q7 [# d( c; U* x: tAddress correspondence to: Samar K. Bhowmick, MD, FACE,7 `6 W1 |6 }& v
Professor of Pediatrics, University of South Alabama, College of. h! M2 c: S# s3 Y, r
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297; g4 h. }9 U: e) J. P
e-mail: [email protected].
& l1 b1 k" n5 {# Qabout 6 to 7 months old, which progressively became
3 j% U1 ` ^' _( a# V$ k7 n' qdarker. She was also concerned about the enlarge-2 t$ h8 C$ Q4 ^ U+ ` p* `/ O
ment of his penis and frequent erections. The child
2 |6 o/ f3 d ?( ^( `! n* ?was the product of a full-term normal delivery, with
% m' K/ H0 l, ?7 F+ D1 w! f* J; ^a birth weight of 7 lb 14 oz, and birth length of
4 H, y; H/ g: J, S) q20 inches. He was breast-fed throughout the first year
$ C/ b% p% o. ^5 q" l% fof life and was still receiving breast milk along with
; h8 C4 L0 C3 R( Y; osolid food. He had no hospitalizations or surgery,
9 G$ ?0 B- o0 Y6 i9 c8 `" w9 q8 Hand his psychosocial and psychomotor development1 f5 A+ {8 y5 ~' @: q
was age appropriate./ d3 u& E6 K% P8 W; K7 |
The family history was remarkable for the father,; I/ d5 c; _' w/ u7 z1 e
who was diagnosed with hypothyroidism at age 16,( Z! b3 J* L. d5 i, q' ~2 \
which was treated with thyroxine. The father’s0 q4 N' H1 S$ ?3 F) _- b7 x
height was 6 feet, and he went through a somewhat$ Q2 }9 p d4 T/ l3 t0 C1 D
early puberty and had stopped growing by age 14.
% I( V- l) P4 k$ Q( Q$ v) iThe father denied taking any other medication. The
9 `# y. r. K$ Q; b7 Vchild’s mother was in good health. Her menarche
, z- V. t- K1 M" C3 ewas at 11 years of age, and her height was at 5 feet
% X" r% d: J, T4 K$ e" D5 inches. There was no other family history of pre-
/ g( e9 L, O# K q$ qcocious sexual development in the first-degree rela-
5 Z9 ]" P2 ^1 q, l N% U8 Ytives. There were no siblings.; w; l4 w; p' X: Q6 S
Physical Examination
' S4 _, g1 y/ o0 k8 M$ OThe physical examination revealed a very active,
3 c8 W% d6 ~$ b. I: C! s0 @/ Iplayful, and healthy boy. The vital signs documented
5 S0 p8 U3 E. Ga blood pressure of 85/50 mm Hg, his length was
$ W+ p' J, z% y; V5 y90 cm (>97th percentile), and his weight was 14.4 kg/ h; n7 h9 D( C6 o ~
(also >97th percentile). The observed yearly growth/ W8 |( }7 ?4 F
velocity was 30 cm (12 inches). The examination of4 y" y2 N4 {9 x7 |5 d$ ~
the neck revealed no thyroid enlargement.
/ j, m+ g. G1 UThe genitourinary examination was remarkable for5 ]* v" e6 E v* x7 T9 F+ R
enlargement of the penis, with a stretched length of
( E3 C- N6 ]" Y- E5 Q0 _4 |8 cm and a width of 2 cm. The glans penis was very well M$ n2 _ i+ A8 A6 C0 u* T
developed. The pubic hair was Tanner II, mostly around. L9 ?, k4 t& {2 x4 e3 E' h
540' U- W! l4 F+ x0 u+ e3 n7 u- @/ d
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
3 D" y( `1 \$ W+ J2 J2 Gthe base of the phallus and was dark and curled. The
1 m; ~) K' R& U4 Jtesticular volume was prepubertal at 2 mL each.* p4 z: O, m# |/ u9 P
The skin was moist and smooth and somewhat
- Y' L/ Z+ G8 c5 w& p. ]oily. No axillary hair was noted. There were no
- R( c1 d3 ~4 q) ?3 N' h6 zabnormal skin pigmentations or café-au-lait spots.8 o& `0 ^9 o$ d: c
Neurologic evaluation showed deep tendon reflex 2+! ~' \* ?$ ?- n4 d+ t
bilateral and symmetrical. There was no suggestion8 O7 ?. s$ K" w
of papilledema.
! G3 a( k" C9 ?& f: {Laboratory Evaluation5 n* N, n0 f+ M' ?! ^3 F1 V6 Q
The bone age was consistent with 28 months by( O! m( l% R: ?/ l
using the standard of Greulich and Pyle at a chrono-) H/ ]3 X o7 e+ ]1 K; e( ~
logic age of 16 months (advanced).5 Chromosomal v6 K- s4 ?) J# E! y! f0 Q
karyotype was 46XY. The thyroid function test
# M( Q% A; V; O) e1 dshowed a free T4 of 1.69 ng/dL, and thyroid stimu-. y+ W6 g* \8 s2 N
lating hormone level was 1.3 µIU/mL (both normal).
# W" _/ I: w( }The concentrations of serum electrolytes, blood, j( }$ b/ X9 d* G' R6 j1 u6 |
urea nitrogen, creatinine, and calcium all were
3 E, G0 w) C% T1 }: k2 Iwithin normal range for his age. The concentration
! t, Y, H! K9 T: w, S- Mof serum 17-hydroxyprogesterone was 16 ng/dL! B j9 j) R9 I1 [) A
(normal, 3 to 90 ng/dL), androstenedione was 20
9 a9 r2 _: |, ang/dL (normal, 18 to 80 ng/dL), dehydroepiandros-& |( |: O5 p3 U0 Q! O( i
terone was 38 ng/dL (normal, 50 to 760 ng/dL),
x7 U) U& e" g; ?desoxycorticosterone was 4.3 ng/dL (normal, 7 to
. p. f8 i( L! [, p; o49ng/dL), 11-desoxycortisol (specific compound S): J4 J7 p0 b: P6 N
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-5 Y, H4 |0 w; { y: G8 [
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total$ x! b( D2 C1 g- q
testosterone was 60 ng/dL (normal <3 to 10 ng/dL)," @8 j# b. ?3 w
and β-human chorionic gonadotropin was less than( E* g# j8 s, Z9 g, ?6 u
5 mIU/mL (normal <5 mIU/mL). Serum follicular
8 I1 Z8 m+ R H- X5 r4 N# astimulating hormone and leuteinizing hormone
* W" m& Z& H; Econcentrations were less than 0.05 mIU/mL
, d( m. o$ {3 |! |8 \(prepubertal).
1 g9 Q3 t" L4 C$ {4 s1 g }The parents were notified about the laboratory
- x) N. _& b6 F) dresults and were informed that all of the tests were5 n0 [( e! d/ z. u- H
normal except the testosterone level was high. The g. ?/ C# x, R% l) W) I- I$ E
follow-up visit was arranged within a few weeks to
. b- {: ]! T# t5 J: T8 P8 _7 }, gobtain testicular and abdominal sonograms; how-: V( k0 f. N2 i
ever, the family did not return for 4 months.' c! M' I7 ?& m" k8 e( d
Physical examination at this time revealed that the) x% X! J4 \+ `8 W+ a
child had grown 2.5 cm in 4 months and had gained/ U' b5 E% t: H: E5 B
2 kg of weight. Physical examination remained
2 I9 e$ A6 o( zunchanged. Surprisingly, the pubic hair almost com-
0 S- Y/ d. I* `4 y- ?pletely disappeared except for a few vellous hairs at
: o" q9 e, G `& w7 U% dthe base of the phallus. Testicular volume was still 2( @" a6 _$ k. ?, u
mL, and the size of the penis remained unchanged.) y M/ m4 f6 u Z- ? B
The mother also said that the boy was no longer hav-
' o2 ?" ^8 w5 h! i& S! ?ing frequent erections.
: S1 I& c- }' p6 LBoth parents were again questioned about use of
- y1 ~9 M8 N0 x1 T# qany ointment/creams that they may have applied to3 c3 n7 }, H4 m4 R' a( y2 m
the child’s skin. This time the father admitted the
6 |' d9 I+ c o S' KTopical Testosterone Exposure / Bhowmick et al 541
% y: x, o; ]7 ?# O8 E8 s8 R+ Huse of testosterone gel twice daily that he was apply-
' x( W- y* p% sing over his own shoulders, chest, and back area for# s$ Y; t. B$ W5 p$ ~) O7 d8 z
a year. The father also revealed he was embarrassed
+ j& ` \5 c9 b; t1 _7 ?% ^to disclose that he was using a testosterone gel pre-1 f1 Z% f, p) k
scribed by his family physician for decreased libido
7 i L; c6 U& `. b' L* {# P( `0 k2 nsecondary to depression.
$ [& _" W. [5 S7 @' H8 K1 ~The child slept in the same bed with parents.3 }9 Q5 a8 c* T- o0 S
The father would hug the baby and hold him on his
) R+ N8 w X4 v+ C0 e' Bchest for a considerable period of time, causing sig-
8 t) c8 e5 M$ K! e- j0 | \nificant bare skin contact between baby and father.: m& c' e% ~ \" T
The father also admitted that after the phone call,
4 d4 h2 S) U9 G2 r/ @, Vwhen he learned the testosterone level in the baby- m5 u* v6 F' s S X+ ^; [
was high, he then read the product information
, L" m% v8 x W4 w! Hpacket and concluded that it was most likely the rea-. u H; o# K& k+ ~) ~' W
son for the child’s virilization. At that time, they) l3 ]2 W2 }: M9 P' Z
decided to put the baby in a separate bed, and the/ j) {, O- P8 [) f5 \: T7 V
father was not hugging him with bare skin and had: x- o m- e9 A4 _
been using protective clothing. A repeat testosterone# q: u. P3 Y/ A8 h7 p
test was ordered, but the family did not go to the
' F" d" H5 \" G, m' H8 Dlaboratory to obtain the test.
7 K( V; T8 b# a: xDiscussion6 a H' k+ h" a' {# B2 m# t; l# {
Precocious puberty in boys is defined as secondary) d9 |# { E5 P, A
sexual development before 9 years of age.1,45 G5 u+ A4 a, U, Q6 V P& |
Precocious puberty is termed as central (true) when) J: a% X, V7 ?. D
it is caused by the premature activation of hypo-
! u, ^' ^( E tthalamic pituitary gonadal axis. CPP is more com-9 u( \" v- S/ X- H' i
mon in girls than in boys.1,3 Most boys with CPP
7 z E6 Z' Y0 \may have a central nervous system lesion that is
& b3 {* v8 x/ a/ `5 Hresponsible for the early activation of the hypothal-
: m- u8 ?- V1 U4 Xamic pituitary gonadal axis.1-3 Thus, greater empha-& @7 Y# R) c4 z$ Y' L
sis has been given to neuroradiologic imaging in
j' }$ B$ }5 ^6 V+ _* R$ w, ?+ Uboys with precocious puberty. In addition to viril-' m, ?. y- n$ B. M, `
ization, the clinical hallmark of CPP is the symmet-
/ P: U9 J% I# k) q, N/ {# v# F- ?& grical testicular growth secondary to stimulation by6 a @& G% A# b5 W/ r
gonadotropins.1,3! f- A, z8 O2 y, ^( | F7 z
Gonadotropin-independent peripheral preco-3 ? V3 K; O; S8 E& O6 x
cious puberty in boys also results from inappropriate
2 Y) G4 y+ O0 M2 T3 Candrogenic stimulation from either endogenous or+ _: L3 d7 e( v
exogenous sources, nonpituitary gonadotropin stim-* t7 i* f q q- k6 J4 h Q) W( S
ulation, and rare activating mutations.3 Virilizing
9 i. D5 {! f0 d8 t3 A7 A2 m) kcongenital adrenal hyperplasia producing excessive
; k6 i' W0 u1 R n3 {adrenal androgens is a common cause of precocious- X N- O: K# \, p& c
puberty in boys.3,4
& B) Y- R; ?) f, SThe most common form of congenital adrenal
" R. x, k) O* |* _* K9 G0 dhyperplasia is the 21-hydroxylase enzyme deficiency.- n6 q/ |; M4 W1 `2 ~* z( H
The 11-β hydroxylase deficiency may also result in [0 j- U: W, p" [$ `
excessive adrenal androgen production, and rarely,' [( \1 M! p2 d3 E* g6 E. \ Q: m) L9 D
an adrenal tumor may also cause adrenal androgen- s" r# D. L( ]1 W
excess.1,3
" O- [ ^9 I, I9 Y. Gat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
0 T( T# E" I( Y* I: Z542 Clinical Pediatrics / Vol. 46, No. 6, July 20073 g5 ^. R$ q& O, I5 H' e
A unique entity of male-limited gonadotropin-- l; C, {* x8 j* Q/ P+ r
independent precocious puberty, which is also known( q2 O& p8 v s t) r
as testotoxicosis, may cause precocious puberty at a
! B( x+ z( c3 e$ ~very young age. The physical findings in these boys
5 U8 u* H# ~0 ?% C, [with this disorder are full pubertal development,
& u1 G; |/ [- eincluding bilateral testicular growth, similar to boys
7 H. T( D: L9 {with CPP. The gonadotropin levels in this disorder
1 A9 T# r+ c! i$ d4 yare suppressed to prepubertal levels and do not show3 X2 a, Y! p/ B0 n5 ~$ _
pubertal response of gonadotropin after gonadotropin-. u/ C1 A. ?* o5 X1 U ?
releasing hormone stimulation. This is a sex-linked
5 b. B. v- ~% `9 j* Sautosomal dominant disorder that affects only
- u( B g0 p5 Z- _% rmales; therefore, other male members of the family
7 S- m" J; d" emay have similar precocious puberty.3& |) @5 _ X( z* h3 b4 Z
In our patient, physical examination was incon-/ {$ K% h! f9 [5 ]7 t2 p) I$ ~
sistent with true precocious puberty since his testi-0 c' C) O J1 I/ |6 L2 u* m
cles were prepubertal in size. However, testotoxicosis4 P6 O8 P6 X1 x' U3 g7 H9 |
was in the differential diagnosis because his father9 E; a. L. G C4 D: Z
started puberty somewhat early, and occasionally,* k- z+ ^ y' I6 H7 V0 m
testicular enlargement is not that evident in the
# |, r: @ B/ f$ x3 r$ v' s: Cbeginning of this process.1 In the absence of a neg-" R+ i; d- a7 R G% y
ative initial history of androgen exposure, our
) o4 H# f6 T" K" Dbiggest concern was virilizing adrenal hyperplasia,
2 @! h, g# H1 n t6 z+ c& qeither 21-hydroxylase deficiency or 11-β hydroxylase- z3 ?% Z6 M" h. j0 B
deficiency. Those diagnoses were excluded by find-
& r6 O z0 e7 ~6 Q; r- J; c1 @, k. Oing the normal level of adrenal steroids.
+ |0 n+ o2 V/ }) mThe diagnosis of exogenous androgens was strongly
2 b' A4 _5 X8 e. b4 @suspected in a follow-up visit after 4 months because! s' O) y' |5 ^$ R8 Q& t( Y3 R( {, r
the physical examination revealed the complete disap-
8 N; y* K+ V; t" zpearance of pubic hair, normal growth velocity, and
' ]9 M/ K" C4 ~- Vdecreased erections. The father admitted using a testos-
4 C e* p* ]( M: U2 L, bterone gel, which he concealed at first visit. He was
' A9 U3 ~" A O8 busing it rather frequently, twice a day. The Physicians’
) E+ I3 H) q# b7 F9 oDesk Reference, or package insert of this product, gel or" j* h/ \0 d: Y4 p$ }; m
cream, cautions about dermal testosterone transfer to2 d" r, P9 Y5 q
unprotected females through direct skin exposure.) d6 T, q6 u. a3 u7 i) }: R
Serum testosterone level was found to be 2 times the
6 N* S$ r( ~1 z4 X; g& s, kbaseline value in those females who were exposed to
5 A k0 D# V, \) x' k7 o- seven 15 minutes of direct skin contact with their male
4 A! g( D* D! W" ?$ T0 u/ t2 T. I! Cpartners.6 However, when a shirt covered the applica-6 d8 x" ~. W3 f) p
tion site, this testosterone transfer was prevented. e# `0 y0 q3 [, k3 v7 @
Our patient’s testosterone level was 60 ng/mL,
/ ]. Z1 g# ^. F# Q; J1 L% @8 O% Q% wwhich was clearly high. Some studies suggest that2 c! e6 o, u0 M0 `* S
dermal conversion of testosterone to dihydrotestos-
2 X3 ?5 n/ M! c0 J, [. ~9 V/ c- f& Y+ Yterone, which is a more potent metabolite, is more
7 T8 e8 K1 d2 c* [' vactive in young children exposed to testosterone
. M8 P$ F2 o8 b! P4 {4 h# G+ B! s* wexogenously7; however, we did not measure a dihy-
: v6 \- k/ H( ddrotestosterone level in our patient. In addition to& r0 X: D9 ?; j, h1 X$ N( @
virilization, exposure to exogenous testosterone in
( q/ ]7 X5 x- l. }. S* z+ Tchildren results in an increase in growth velocity and
" I% K# T' N' d& f8 w2 l5 zadvanced bone age, as seen in our patient.4 l( d+ c/ o- Y% q
The long-term effect of androgen exposure during- V6 B. Q" u- B) d2 D7 k* Y3 Q5 Y9 Y
early childhood on pubertal development and final
% n) G7 o# t. S {7 Cadult height are not fully known and always remain1 D! L0 W( H& n- f6 Z; p
a concern. Children treated with short-term testos-, }3 v1 M' S$ o# V% g3 F# A
terone injection or topical androgen may exhibit some; O* L+ Q/ B8 f% M: T/ w; D
acceleration of the skeletal maturation; however, after
4 F- w# ?! ?* S0 T# fcessation of treatment, the rate of bone maturation- z1 ~; e' Q6 l, y
decelerates and gradually returns to normal.8,9
3 K9 p7 p4 \7 s" e* S! B/ u9 @There are conflicting reports and controversy( U$ @' p0 y1 E4 B* [' T
over the effect of early androgen exposure on adult
$ s9 r7 |) E! }penile length.10,11 Some reports suggest subnormal& z: Z& s5 G9 ~" r
adult penile length, apparently because of downreg-
+ S( ~ y2 m4 k4 m. Z& pulation of androgen receptor number.10,12 However,# w1 G7 ?3 R4 i9 e% U
Sutherland et al13 did not find a correlation between# ]/ G0 X- Z8 e$ T, j2 x
childhood testosterone exposure and reduced adult0 c: {9 K* R, M- o s- g
penile length in clinical studies.
' v% x% N. P9 |, o6 n1 t# TNonetheless, we do not believe our patient is
( Q; Z, J) A% jgoing to experience any of the untoward effects from2 t* @+ ]0 u5 P* z$ ?
testosterone exposure as mentioned earlier because8 u7 p. P( a0 F9 \
the exposure was not for a prolonged period of time.
* h/ X! ^6 T8 \6 S j& y7 qAlthough the bone age was advanced at the time of
$ Y. w* w- H' a& m3 A5 ddiagnosis, the child had a normal growth velocity at0 P' T! O4 n: J: @; \3 P1 |
the follow-up visit. It is hoped that his final adult
1 T5 s+ j& e& q/ O; A* g5 {height will not be affected.5 e( K6 z: I0 s+ `, s# u$ v; N
Although rarely reported, the widespread avail-
& @& W2 z- ~. u B. w! O" y4 A& rability of androgen products in our society may
1 @6 V( E$ |* V" j" I' i2 ~$ O# bindeed cause more virilization in male or female8 V* C J: r+ k9 ^/ Y% ]2 n- w% z
children than one would realize. Exposure to andro-
, T9 \% `5 R( g0 I4 {$ ?# U2 Ngen products must be considered and specific ques-
( ~6 ?9 H- I5 L1 W3 etioning about the use of a testosterone product or
4 b+ M+ l6 A6 ]4 [' Lgel should be asked of the family members during0 n9 r0 t* q" t2 e
the evaluation of any children who present with vir-
" [; M o+ Y3 H& q% J- ` N: z3 \ilization or peripheral precocious puberty. The diag-+ F4 @* }3 w$ L7 C& ]( m m5 M3 c
nosis can be established by just a few tests and by
0 X- I8 Y. _ Mappropriate history. The inability to obtain such a
- h( g' R8 o) x- Zhistory, or failure to ask the specific questions, may0 P' Y: v# U! f7 R6 f
result in extensive, unnecessary, and expensive
5 k# U+ O2 m' L0 V( H; h, ^investigation. The primary care physician should be; H3 R4 O/ `8 N1 _3 a H; e
aware of this fact, because most of these children" a2 ~) E! i S8 {+ p8 f' B0 B
may initially present in their practice. The Physicians’) `: b6 |5 o8 u% {
Desk Reference and package insert should also put a
2 W! _# ]" a l$ s- [, d7 C1 Fwarning about the virilizing effect on a male or# }5 _- n) U+ C% a9 G
female child who might come in contact with some-
% n" P M, h+ d; r+ \/ S4 Q5 {one using any of these products.& h3 s5 o# e' x2 Q9 S
References
8 ~" \+ t# I/ f) R [: G" [' Z1. Styne DM. The testes: disorder of sexual differentiation1 P, D+ J8 W5 {/ o. R8 o$ A3 [
and puberty in the male. In: Sperling MA, ed. Pediatric' q2 D: X! _" j5 Q0 s
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
' G% A" n* L% B2 `; i# ~, V2002: 565-628.4 q6 h8 d) O# I, ^6 { k7 d
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
, _! b8 w* ~0 B2 r$ g& T$ \$ jpuberty in children with tumours of the suprasellar pineal |
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