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Sexual Precocity in a 16-Month-Old l4 } Q0 k# n1 l8 }; }% X; z
Boy Induced by Indirect Topical4 [3 S4 B; @6 L7 y- T- c& v
Exposure to Testosterone
( V( n1 J+ y/ u" H& x6 S, qSamar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,22 \5 o( V$ |' B- C2 n
and Kenneth R. Rettig, MD1. C2 P: @# u6 s( m& `
Clinical Pediatrics
J1 }4 f, ~ K. h2 @! p0 rVolume 46 Number 6
( j" c V# C. bJuly 2007 540-543( W$ J$ u5 l% c$ e2 _
© 2007 Sage Publications
6 w, k& Q% T8 w10.1177/0009922806296651
$ e! m5 f; I* S8 s# }6 B6 z, }8 Phttp://clp.sagepub.com
# ?8 u, N/ k f* Xhosted at) o2 o% q: s9 b3 j. X
http://online.sagepub.com" O: s: D7 S- W& Z, {
Precocious puberty in boys, central or peripheral,
+ k3 I! V) Z& \is a significant concern for physicians. Central6 C. L+ ]- _# z" g. G, x
precocious puberty (CPP), which is mediated2 ?6 O3 }) ?2 `7 @9 T' D4 Z
through the hypothalamic pituitary gonadal axis, has/ {$ f9 x' ]* l) I
a higher incidence of organic central nervous system
: ^/ h6 h- j1 A9 P( @lesions in boys.1,2 Virilization in boys, as manifested( l! M3 R" ^% V W+ a" n
by enlargement of the penis, development of pubic8 W& Y" t% L- q( S3 Z
hair, and facial acne without enlargement of testi-/ x' M: T2 ?, h3 v) C
cles, suggests peripheral or pseudopuberty.1-3 We
* b* b# e2 x" S0 {9 o0 b5 treport a 16-month-old boy who presented with the8 x% f: T* ]% F* U2 R
enlargement of the phallus and pubic hair develop-
4 f. p, |! a0 n' a; d0 C4 _ment without testicular enlargement, which was due
+ H3 d1 n6 D& d# uto the unintentional exposure to androgen gel used by* D/ i3 ^, Y6 v0 J1 @ H* j& L
the father. The family initially concealed this infor-/ W2 e* Y2 P0 w' |
mation, resulting in an extensive work-up for this
" ~3 B F1 o* K. h/ Rchild. Given the widespread and easy availability of4 A9 ]4 B* y; r: o# J5 k. w' R
testosterone gel and cream, we believe this is proba-6 C2 O1 @0 x0 n5 M& ~1 F- D" d
bly more common than the rare case report in the/ E2 N9 @$ `+ a6 t. w4 o& J
literature.4
, b) _$ x% Z7 m; ZPatient Report" G9 x7 ~/ s% c
A 16-month-old white child was referred to the) `& b9 F/ p1 H' a& v" s" z+ |
endocrine clinic by his pediatrician with the concern
& }: e* h$ C; j- B$ d4 L2 g+ Jof early sexual development. His mother noticed: R$ T0 P: @5 S, }- k0 H ~* a- ?
light colored pubic hair development when he was/ [# `* ~: v }! H3 L2 I
From the 1Division of Pediatric Endocrinology, 2University of
. e! Z+ [% s5 T7 A8 L; ASouth Alabama Medical Center, Mobile, Alabama.
2 Q- w. J- t7 }2 tAddress correspondence to: Samar K. Bhowmick, MD, FACE, J2 C \! h- c
Professor of Pediatrics, University of South Alabama, College of# ^* I4 D4 n8 X
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
+ ?7 H- `" Q! C+ oe-mail: [email protected].2 d- T0 K" x3 {' ~5 s% {! n
about 6 to 7 months old, which progressively became& A" z% m6 {/ e/ l6 |: o% _
darker. She was also concerned about the enlarge-
5 v$ x: y9 t0 _5 Hment of his penis and frequent erections. The child
0 ^0 I: p+ k3 e; |( Q, F7 h" @was the product of a full-term normal delivery, with
5 p X* b2 B) `a birth weight of 7 lb 14 oz, and birth length of/ N- K$ ~; v! S! W8 ]: V# K
20 inches. He was breast-fed throughout the first year
. t& G9 x6 N' R5 Jof life and was still receiving breast milk along with
* i- g" J4 Y6 [solid food. He had no hospitalizations or surgery,( T6 L0 H W5 w4 S2 k5 q
and his psychosocial and psychomotor development
1 Y. t- U: S) i) t5 B8 o5 \was age appropriate.+ i- P! e2 [: d D+ `% ~; d1 m7 z
The family history was remarkable for the father,) F$ w4 `8 d- I7 M$ l/ Y
who was diagnosed with hypothyroidism at age 16,6 }1 w7 A j" t# `5 [3 Y4 M# w3 }* v. |( d
which was treated with thyroxine. The father’s5 R$ e% o, ]1 j' C" I' d6 c' Q; H
height was 6 feet, and he went through a somewhat
8 u. m7 O$ H+ f8 q! [% ^early puberty and had stopped growing by age 14.9 i+ o \6 C# \8 z$ w
The father denied taking any other medication. The
2 `& e8 l: t- D) Q: n* @child’s mother was in good health. Her menarche
: j9 v9 w7 Q- ?! Z* `was at 11 years of age, and her height was at 5 feet: w+ F1 @/ h6 C
5 inches. There was no other family history of pre-
7 o; g4 Z- L9 ?; F# o/ k: rcocious sexual development in the first-degree rela-
3 Z0 X. m, S; O \( l7 ttives. There were no siblings.. p5 H/ m- v) j: w d: C9 Q: j
Physical Examination
4 ?5 c( _' w0 B3 s6 d M: nThe physical examination revealed a very active,
$ f F+ o; c4 z# f, K- Zplayful, and healthy boy. The vital signs documented- O9 g( Q* C$ W- w+ g
a blood pressure of 85/50 mm Hg, his length was
7 ]+ W9 m+ Q$ ]1 q90 cm (>97th percentile), and his weight was 14.4 kg
2 B: _% M& {8 o9 X# W1 ^" ](also >97th percentile). The observed yearly growth7 D D2 S1 g9 x/ M3 }- s( B
velocity was 30 cm (12 inches). The examination of
4 O3 ~; s/ C. \0 y9 n- c' |the neck revealed no thyroid enlargement.
3 o9 P. i" }! ?The genitourinary examination was remarkable for6 A: f9 B9 S1 R- B3 k9 w9 L) d- T
enlargement of the penis, with a stretched length of
3 B1 R3 _8 j0 ?: n* x3 r8 cm and a width of 2 cm. The glans penis was very well) A ?' u0 Y( G
developed. The pubic hair was Tanner II, mostly around
# D) y( a! w5 v! b540
3 K% ^% G! @8 C+ g; I% g) I) nat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
! a' b6 g3 a, H/ G7 d, H* fthe base of the phallus and was dark and curled. The
6 ^% r6 `8 s" Utesticular volume was prepubertal at 2 mL each.
# E+ J) o; ^6 Q1 HThe skin was moist and smooth and somewhat
- H- K- I1 @$ @oily. No axillary hair was noted. There were no4 m! _+ B( o) y0 J
abnormal skin pigmentations or café-au-lait spots.
% T: K+ |9 i3 bNeurologic evaluation showed deep tendon reflex 2+
$ ^8 f, K% ^$ l$ h k* ~$ Hbilateral and symmetrical. There was no suggestion
; v5 }, D: _) }4 B8 A# y% Bof papilledema.
! B( E$ y) Z, k' x. L @% O8 f' XLaboratory Evaluation
! R2 E; ^) H2 P7 X9 e6 EThe bone age was consistent with 28 months by& b* K9 s) d$ g6 I
using the standard of Greulich and Pyle at a chrono-/ A4 o. ?# M& P2 w+ Y* b
logic age of 16 months (advanced).5 Chromosomal5 i. m+ L5 t2 o: k' b7 i- x7 r" u% w
karyotype was 46XY. The thyroid function test& ]# o$ [6 @5 p$ p- U1 B+ A
showed a free T4 of 1.69 ng/dL, and thyroid stimu-7 \* s* H* @: r; |, x, B% x# G2 ]2 h
lating hormone level was 1.3 µIU/mL (both normal).+ @6 g! u# N2 r( M2 `& y' B
The concentrations of serum electrolytes, blood
0 M2 Z$ V2 |2 curea nitrogen, creatinine, and calcium all were
$ V, |) b- R9 a2 M' nwithin normal range for his age. The concentration/ x/ {/ p, D: z0 t$ R
of serum 17-hydroxyprogesterone was 16 ng/dL0 w8 j/ d# M/ X9 D( n/ x
(normal, 3 to 90 ng/dL), androstenedione was 206 P0 v- ]( [3 U4 d
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
- H y( |2 o! w, j0 Nterone was 38 ng/dL (normal, 50 to 760 ng/dL),1 S ?+ m& C) j1 b# M
desoxycorticosterone was 4.3 ng/dL (normal, 7 to
k! `: S/ A. }7 C8 M49ng/dL), 11-desoxycortisol (specific compound S)# J2 k5 n- y) q
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
. L* ?. w( g1 }# l/ gtisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total% I( Z+ p: b b( l1 z6 h$ f: F
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),# t3 q8 o, h0 Q: P6 M
and β-human chorionic gonadotropin was less than2 b+ H, ?1 `8 R9 I! `+ a& L) V
5 mIU/mL (normal <5 mIU/mL). Serum follicular
& ?9 c7 s+ {" l1 s% Q, q. x; jstimulating hormone and leuteinizing hormone+ E( L7 u( H( L4 X# F1 |* q* R
concentrations were less than 0.05 mIU/mL# ]. J! B! P9 c: `" H
(prepubertal).- x* `6 f$ Q# Y3 n; x: J7 E6 W: d% z
The parents were notified about the laboratory
% a( q+ \: @7 {, Nresults and were informed that all of the tests were
2 H% f' f7 [& g2 z, T! rnormal except the testosterone level was high. The
' I3 |) i& K% q( T2 M, q6 ^: i* g! Lfollow-up visit was arranged within a few weeks to! f6 |2 S5 E% G# x# ?
obtain testicular and abdominal sonograms; how- L5 o( N7 |7 k9 N+ z
ever, the family did not return for 4 months.) P& A) e& v% K; ~; S
Physical examination at this time revealed that the
6 m [- e, _& x. `- n# Echild had grown 2.5 cm in 4 months and had gained
# P& c2 f6 f, Q. F2 kg of weight. Physical examination remained
& I* X2 N/ d/ R3 M" t& Dunchanged. Surprisingly, the pubic hair almost com-
4 v1 x" t8 D2 zpletely disappeared except for a few vellous hairs at5 \! Z+ n6 L) l3 h
the base of the phallus. Testicular volume was still 2* v( c, H) a# @) V
mL, and the size of the penis remained unchanged.
% q7 ^* X# i# `! vThe mother also said that the boy was no longer hav-4 x$ X# @4 G; m
ing frequent erections.
& i6 x. Y8 T2 i2 r* ~Both parents were again questioned about use of& p1 {( Z1 h; n' t- U9 R6 Q
any ointment/creams that they may have applied to. M `* u9 l j ~0 ^
the child’s skin. This time the father admitted the
6 i) O" d2 y q+ Z( I/ I, STopical Testosterone Exposure / Bhowmick et al 541
4 a h, a0 j' u. Z& s" Ause of testosterone gel twice daily that he was apply-8 y% k" z- N) \& n6 q
ing over his own shoulders, chest, and back area for
, G+ G2 v8 z# ^5 G2 |9 F0 Oa year. The father also revealed he was embarrassed2 W+ P" A0 E1 }: B+ V5 r- M! r
to disclose that he was using a testosterone gel pre-
/ { z+ |( z6 x- s: L+ sscribed by his family physician for decreased libido
& d4 h( b# i/ k8 Zsecondary to depression., v$ g; @4 _7 [- j. X$ ?& d# a7 x
The child slept in the same bed with parents.
% ]' Z3 L: b7 yThe father would hug the baby and hold him on his/ }+ \, G3 A" G! ^: c; ?7 _
chest for a considerable period of time, causing sig-1 r! ~2 D' j% H9 ~. N7 X1 }
nificant bare skin contact between baby and father./ }/ u! o$ g: \* C4 s
The father also admitted that after the phone call,+ C# r. B% u$ E$ D; v
when he learned the testosterone level in the baby8 N$ ^# \% V. e: k' M
was high, he then read the product information
* t4 i8 h. a: N' G% x/ p# Rpacket and concluded that it was most likely the rea-4 `/ }, g: d) ]3 k% Q5 ~& r
son for the child’s virilization. At that time, they9 C2 v" ~" q8 Q, R, G
decided to put the baby in a separate bed, and the
: H. e/ d5 i/ ? }father was not hugging him with bare skin and had
4 w& l" ]5 t+ v9 a& H) I1 Z2 [+ sbeen using protective clothing. A repeat testosterone( R- H& t! Y4 @. g8 |* F2 Z& N
test was ordered, but the family did not go to the
9 ~# t4 Y+ f" P6 J8 v( b, B1 qlaboratory to obtain the test.+ ^2 [) V5 D2 k) |: _
Discussion; F. @& d; E2 T; Q. ~: v
Precocious puberty in boys is defined as secondary! k0 t$ N( z- `/ d2 V
sexual development before 9 years of age.1,47 i5 ^; V2 U* f8 }+ k1 }: h% ]9 I
Precocious puberty is termed as central (true) when6 v7 n: z. R* r8 W9 @# z0 @5 u
it is caused by the premature activation of hypo-
* h% l1 R/ C) O% sthalamic pituitary gonadal axis. CPP is more com-2 q t/ i4 Z8 h, p1 U9 q
mon in girls than in boys.1,3 Most boys with CPP- T( Z8 |8 K5 Y0 `9 b) I; P& e
may have a central nervous system lesion that is8 C3 f! @) e* h; t
responsible for the early activation of the hypothal-9 x {' W6 V' C
amic pituitary gonadal axis.1-3 Thus, greater empha-/ a4 \, A2 l8 z
sis has been given to neuroradiologic imaging in
. s( p3 ~% i, U) `& |/ i" m2 sboys with precocious puberty. In addition to viril-+ o: G2 x) J4 E4 v
ization, the clinical hallmark of CPP is the symmet-
- [5 [; l% {5 u- J" hrical testicular growth secondary to stimulation by( T1 `! y( |0 h$ |0 p
gonadotropins.1,3
4 o- ^: Q4 G' \9 zGonadotropin-independent peripheral preco-
* S$ P/ W, S: }3 M+ q+ G3 dcious puberty in boys also results from inappropriate
: U1 d8 ~ V* u& R0 Bandrogenic stimulation from either endogenous or
- k3 e4 e( T! |# Z) n: G- aexogenous sources, nonpituitary gonadotropin stim-# O- @6 ]# ^" f Q2 c
ulation, and rare activating mutations.3 Virilizing6 _5 X5 z2 L8 L3 F0 V
congenital adrenal hyperplasia producing excessive
2 L. y2 i$ m; V$ [$ p# R0 q& dadrenal androgens is a common cause of precocious% s- n9 N; u* \9 y% r. F( ~. z
puberty in boys.3,40 y9 M9 V, A7 J1 m# d0 I% k
The most common form of congenital adrenal8 X. j. ?4 [* B5 p7 d& ]& ^
hyperplasia is the 21-hydroxylase enzyme deficiency.
7 r1 Q# O: N* i4 f/ d# KThe 11-β hydroxylase deficiency may also result in: N& Y( ?' }: M: K5 O2 x s# p
excessive adrenal androgen production, and rarely,
( H1 A% X; U- @( [( Dan adrenal tumor may also cause adrenal androgen
7 \/ ^4 k" \$ z; z7 a2 hexcess.1,3- O' _% U/ r7 Q4 f* }$ C* O
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from& S3 z* Q4 f5 d
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007+ v% s8 S) ]9 ~( A9 G
A unique entity of male-limited gonadotropin-7 d6 W$ M5 M% g0 A+ h
independent precocious puberty, which is also known
+ \5 |9 K) ?3 N4 U9 S; S. ?0 Eas testotoxicosis, may cause precocious puberty at a
1 K2 {. p& B: z7 v0 N- |* cvery young age. The physical findings in these boys5 O+ ]3 P& m$ d0 w( S
with this disorder are full pubertal development,* [* }/ A p K/ m
including bilateral testicular growth, similar to boys
2 x! Z/ W8 Q. [- }# wwith CPP. The gonadotropin levels in this disorder
) Q+ p" ^8 f# ^. H+ T$ Uare suppressed to prepubertal levels and do not show4 Y/ B* z& G, ]9 \* D
pubertal response of gonadotropin after gonadotropin-: b5 s+ k: S; T6 m
releasing hormone stimulation. This is a sex-linked
! V' T0 p& E0 N, ?4 h1 Qautosomal dominant disorder that affects only
5 p0 r4 O, I$ smales; therefore, other male members of the family- q8 |5 l! _1 {6 x5 m# d! j
may have similar precocious puberty.33 q1 y( e5 p% C4 r. o$ b6 Y
In our patient, physical examination was incon-
3 s' Z1 ^0 _( Xsistent with true precocious puberty since his testi-
. C. C5 K0 B0 F& Pcles were prepubertal in size. However, testotoxicosis
1 ]' b, C8 f6 r% K. y& Nwas in the differential diagnosis because his father
7 b ~ S' W; @* i4 V/ U1 S+ Wstarted puberty somewhat early, and occasionally,3 `2 I+ ~* x( y: {" S
testicular enlargement is not that evident in the
! M' R/ o; ~, o% {+ m& Kbeginning of this process.1 In the absence of a neg-' B: t$ \' I! `/ L7 W
ative initial history of androgen exposure, our
4 W# h1 ]3 D: h. Y$ Qbiggest concern was virilizing adrenal hyperplasia,# [; J- G- |0 Y# c9 R
either 21-hydroxylase deficiency or 11-β hydroxylase
: ?+ ]. J( `* n* F# ?& s6 q: bdeficiency. Those diagnoses were excluded by find-
; c" _+ H/ J- X/ ^4 o! `ing the normal level of adrenal steroids.4 _3 h5 o* W5 R) h1 f1 J# h
The diagnosis of exogenous androgens was strongly0 F3 r: y: U" t& r. n+ d7 K3 A
suspected in a follow-up visit after 4 months because
0 M6 [. C, ~" P2 rthe physical examination revealed the complete disap-
6 R% u$ V" G2 g3 R" ]: R1 e" \2 wpearance of pubic hair, normal growth velocity, and
, g9 w/ v4 x& P5 i. R" L+ a* Zdecreased erections. The father admitted using a testos-
5 i# j1 T) C" `7 a# ^* P! Wterone gel, which he concealed at first visit. He was6 I0 V, i5 E$ Z" _
using it rather frequently, twice a day. The Physicians’
+ @6 Y! Z) O. i6 s3 MDesk Reference, or package insert of this product, gel or
7 |+ m( H" Z! vcream, cautions about dermal testosterone transfer to6 e1 z; W* k- ]# |4 O# t
unprotected females through direct skin exposure.
9 g! w* L+ V0 c2 T) o7 iSerum testosterone level was found to be 2 times the
# X) h! E$ b0 Nbaseline value in those females who were exposed to
8 ~3 E2 I& K; zeven 15 minutes of direct skin contact with their male
( `' x" ?$ J+ a `' tpartners.6 However, when a shirt covered the applica-
9 u" L6 ~7 {6 A8 ?" x w- Dtion site, this testosterone transfer was prevented.: O+ `! T! J7 E [# n
Our patient’s testosterone level was 60 ng/mL,
) g* _" X+ b; l: P; cwhich was clearly high. Some studies suggest that0 r. i* y, m. e0 Z5 l
dermal conversion of testosterone to dihydrotestos-
) Q: p8 w) y5 C. F# k3 q1 }terone, which is a more potent metabolite, is more9 Y1 H* b& u3 ` V
active in young children exposed to testosterone
2 l0 U: w3 T- A' qexogenously7; however, we did not measure a dihy-, r8 t2 G; x+ ?" h
drotestosterone level in our patient. In addition to
/ c4 Z4 W1 i; Q1 Tvirilization, exposure to exogenous testosterone in! |/ a8 G/ E, D* s; J! W+ d; S: ^
children results in an increase in growth velocity and
! v. ^( A1 T, u8 {8 J0 V8 B# M6 p. ]advanced bone age, as seen in our patient.
# X1 {8 R$ |3 C+ z* @9 E* d3 w Z2 fThe long-term effect of androgen exposure during' W8 `$ [7 \$ t0 f0 a0 g
early childhood on pubertal development and final6 F, f3 j* v( p; B
adult height are not fully known and always remain0 c6 G% y1 I2 X1 u- w
a concern. Children treated with short-term testos-
& ?( d4 x5 D" l8 h0 cterone injection or topical androgen may exhibit some
2 y* X: c3 B1 \" W' a6 m& m5 Hacceleration of the skeletal maturation; however, after- j- `& r1 x$ J* H6 s9 i, S
cessation of treatment, the rate of bone maturation
% j, f/ [( q/ Q+ ^; Wdecelerates and gradually returns to normal.8,9! |# t' n3 W+ {0 X2 b
There are conflicting reports and controversy7 @/ @- V8 ^# a
over the effect of early androgen exposure on adult5 s6 h5 c+ Y( z7 ?
penile length.10,11 Some reports suggest subnormal
0 l/ [ {2 S1 b; S5 x0 cadult penile length, apparently because of downreg-
" E( B, y3 s1 B7 o' X/ o {ulation of androgen receptor number.10,12 However,& K% A/ L$ P d+ J* z! f* h
Sutherland et al13 did not find a correlation between4 p& D) A8 @* F4 W1 @. g7 X m
childhood testosterone exposure and reduced adult
6 e6 A' V+ K0 ^. lpenile length in clinical studies.
1 j5 ~6 R: T: S4 [5 RNonetheless, we do not believe our patient is
' }- V2 @& T* { |( @5 Igoing to experience any of the untoward effects from3 D' K. E+ a, `+ q
testosterone exposure as mentioned earlier because% U) a: _7 c/ ^# m
the exposure was not for a prolonged period of time.! M9 M4 f& P" e+ v( {9 `# f# v
Although the bone age was advanced at the time of
8 D# ? r$ D- r/ E1 Ddiagnosis, the child had a normal growth velocity at) L& P; x2 C1 u* y- z
the follow-up visit. It is hoped that his final adult
+ ?" l6 I6 [% |5 d+ [, a2 ?: Sheight will not be affected.
2 | d W; @, x, c+ uAlthough rarely reported, the widespread avail-
$ N- f2 D2 f3 Q# c( d& Z* X+ Mability of androgen products in our society may& F g- H* `! n* Q! s! | X, K- O, x
indeed cause more virilization in male or female2 [5 C' o: K3 @
children than one would realize. Exposure to andro-
0 c% A/ A8 L1 f- }) b8 Z; Wgen products must be considered and specific ques-
O7 P7 F, U6 \- I! w+ V2 i( Stioning about the use of a testosterone product or
+ R5 G2 D* f# j3 Cgel should be asked of the family members during/ M1 Y* p- J5 h+ [2 z, E
the evaluation of any children who present with vir-+ v7 w/ t6 H' _( e o
ilization or peripheral precocious puberty. The diag-! u: F. }# R! X5 Y. t
nosis can be established by just a few tests and by
' u% |9 D4 {' D4 \' Pappropriate history. The inability to obtain such a
: ?9 S, j3 U+ uhistory, or failure to ask the specific questions, may. ~8 S* u( ?6 \) c. ^9 W- E4 G
result in extensive, unnecessary, and expensive' {' Y# N4 x: G! W0 H1 D
investigation. The primary care physician should be
1 P2 T+ X4 |( }aware of this fact, because most of these children
v7 ^0 q( H0 W. G. Imay initially present in their practice. The Physicians’' G d$ ~2 |- ]& V3 }/ b' _. |
Desk Reference and package insert should also put a
& m7 |8 s2 w3 K0 [6 \ O* pwarning about the virilizing effect on a male or0 g" \) r) s# j5 v
female child who might come in contact with some-! c) v# M) N9 L% S
one using any of these products.
4 J/ W7 ^' i* T/ \( [/ y3 F, [References
7 s# k# Y- Z* w o/ g1. Styne DM. The testes: disorder of sexual differentiation
0 m3 B; J; C; g& w- @7 Aand puberty in the male. In: Sperling MA, ed. Pediatric7 @+ n% B8 ], q i, K5 H
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;; r6 h" e% E7 \9 y( W$ d! z" }
2002: 565-628. [- ~/ \' `* G9 r. @$ l3 V
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious& g8 r2 G6 B( ?$ @ |
puberty in children with tumours of the suprasellar pineal |
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