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Sexual Precocity in a 16-Month-Old5 `9 `* P) B! w8 c
Boy Induced by Indirect Topical' g; v# r3 g" W9 c7 N5 H, o% t
Exposure to Testosterone
# {) M2 ?- A |) E3 iSamar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
$ o0 J- M" z3 ^4 f5 pand Kenneth R. Rettig, MD1
" P, B Z0 |$ b, D' VClinical Pediatrics8 w& j2 J8 w* @
Volume 46 Number 6
9 p+ A* @$ [; y6 h sJuly 2007 540-543
& E! O+ {6 @) d6 @) v. j( p3 l8 [© 2007 Sage Publications
# h2 j% O5 M$ T3 u9 p0 t10.1177/0009922806296651
4 _1 I, r% ^8 P* e B9 Ihttp://clp.sagepub.com
# O: z1 Y5 J4 U* k% _hosted at: n: `0 \2 L9 b/ Y0 I$ P1 y+ g
http://online.sagepub.com2 j8 T8 |/ W2 S9 g2 \+ b1 N# H% l
Precocious puberty in boys, central or peripheral,
6 ~7 e' }. U& I3 N% e) h4 zis a significant concern for physicians. Central
# \& j: T4 N2 d6 l7 s6 \precocious puberty (CPP), which is mediated
5 ~ {+ ]7 u% A. othrough the hypothalamic pituitary gonadal axis, has( y# t+ B# l/ ~( E# Y0 r
a higher incidence of organic central nervous system. \! D+ g# r$ }1 i- E5 o
lesions in boys.1,2 Virilization in boys, as manifested
& Q; t1 V& p6 q; [by enlargement of the penis, development of pubic9 G* c8 M) M& \: I4 [* ?7 a
hair, and facial acne without enlargement of testi-
- I4 w8 T9 \3 Y% {8 q; S! Mcles, suggests peripheral or pseudopuberty.1-3 We8 C2 U& `1 X; A2 Y
report a 16-month-old boy who presented with the# Q! }& G# o& k
enlargement of the phallus and pubic hair develop-
2 s/ H6 }$ n6 `! x5 S0 O( Ament without testicular enlargement, which was due. x& B$ H5 Z/ _6 M* [) J3 V& F
to the unintentional exposure to androgen gel used by
7 Z2 e( f. M" r" j+ h% u5 ]% Zthe father. The family initially concealed this infor-; z( Y7 z- R' G _. A
mation, resulting in an extensive work-up for this
- R B, j6 [7 K) O3 g3 Qchild. Given the widespread and easy availability of
8 A; r8 m7 i$ f" ^testosterone gel and cream, we believe this is proba-* c4 \4 i% \* @& r) i5 Q/ a
bly more common than the rare case report in the3 y; `8 _4 q! ~5 S$ H
literature.4; f! ?# w. P5 o
Patient Report
, ]& K8 W# L: P, r5 J0 ^A 16-month-old white child was referred to the
) q0 x7 q; |, f% W( T9 xendocrine clinic by his pediatrician with the concern$ u$ p$ U, @8 S1 D9 E
of early sexual development. His mother noticed7 J* C! {% u/ |* S" Z( G( \& l5 X
light colored pubic hair development when he was9 z0 X( F E% k8 X
From the 1Division of Pediatric Endocrinology, 2University of
3 P- |* X& x: `" T- Z2 ~South Alabama Medical Center, Mobile, Alabama.
, @# q: K& N; C* Z4 G" ~) eAddress correspondence to: Samar K. Bhowmick, MD, FACE,( C( I8 a0 k1 T6 G
Professor of Pediatrics, University of South Alabama, College of# C; ]9 o9 t( a4 a* {' p
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
/ K1 ~: v. [5 E* Ge-mail: [email protected].! k6 u2 \ P0 C7 q W+ i) l; c
about 6 to 7 months old, which progressively became% B, N8 T) w, r' r6 f- J
darker. She was also concerned about the enlarge-9 V# C2 {& J+ v- \
ment of his penis and frequent erections. The child; {1 |. f( A8 D; g1 ?" M
was the product of a full-term normal delivery, with
4 A& @' a6 p; ca birth weight of 7 lb 14 oz, and birth length of2 U7 K- v, |* B \/ N: ~
20 inches. He was breast-fed throughout the first year+ \) ~) a" f& f4 G) p
of life and was still receiving breast milk along with
) U$ s- v; [5 I( n1 E4 ]solid food. He had no hospitalizations or surgery,
! E/ }" |3 }! ]% A) O3 qand his psychosocial and psychomotor development
5 s3 \( @' h" r- y1 H1 y" K% i+ P wwas age appropriate.* l# z* }; L1 A( J( ~1 n8 N. f: E! O; K* u
The family history was remarkable for the father,
) z; {8 Y; |, Z6 @who was diagnosed with hypothyroidism at age 16,5 j4 l4 v1 R% }& U6 C
which was treated with thyroxine. The father’s
2 v# f* W7 P8 _ P& gheight was 6 feet, and he went through a somewhat% m) X% x1 W( ^2 }9 Q5 @
early puberty and had stopped growing by age 14.2 V; x6 J, e1 h8 j. S# E
The father denied taking any other medication. The
# t# ]( k$ ?; ?% echild’s mother was in good health. Her menarche% \5 ~5 ~3 ]+ P8 V0 l
was at 11 years of age, and her height was at 5 feet- F( _: g4 Y' Z+ q% R' J/ T& r9 K
5 inches. There was no other family history of pre-
) p# y* u8 }: q$ ~; W! ~cocious sexual development in the first-degree rela-
% j% P1 ]* h% ~8 W5 {3 U. _2 Ftives. There were no siblings.5 ?% r' ~( k9 d! e
Physical Examination
! Z% Q* C: Q6 O% k; V; ~0 v# R, qThe physical examination revealed a very active,% c2 @/ N$ _# F6 T
playful, and healthy boy. The vital signs documented
9 p, x. b+ c$ `* L: J- t6 Ja blood pressure of 85/50 mm Hg, his length was, E5 B2 `3 \- q9 n& ^) K9 ]
90 cm (>97th percentile), and his weight was 14.4 kg
9 ~, k- q8 V9 n& d2 {# s* N+ b% K- \(also >97th percentile). The observed yearly growth3 g5 h6 R+ e% `0 ?
velocity was 30 cm (12 inches). The examination of# |, M9 N/ F- r( |4 p- J
the neck revealed no thyroid enlargement.0 t' f4 D1 ]5 Q' a! p0 l. \
The genitourinary examination was remarkable for
* o1 f6 ?5 m7 {2 z/ @enlargement of the penis, with a stretched length of
! v) [. e( f. u3 t8 cm and a width of 2 cm. The glans penis was very well
% _: d# c3 Q5 e5 adeveloped. The pubic hair was Tanner II, mostly around% N) ^$ v2 j$ Y+ [8 @! r4 J! `( P
540
6 d" F' M9 L) `: B4 M/ z' M: uat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
8 ?0 K7 ~7 ]: C$ I L/ g: Jthe base of the phallus and was dark and curled. The
+ w" ~& I4 k! P% u2 Ltesticular volume was prepubertal at 2 mL each.
2 C9 F7 c+ N5 X v; K5 j# |The skin was moist and smooth and somewhat4 }4 ?& K4 a1 m9 k5 n( v: G' C
oily. No axillary hair was noted. There were no
5 G, ~1 l) E& z5 I: W! qabnormal skin pigmentations or café-au-lait spots.' s, C. K) X- u! I3 H9 p" d! y
Neurologic evaluation showed deep tendon reflex 2+7 `0 H+ y6 X7 G% M# A- k
bilateral and symmetrical. There was no suggestion8 X' Z H; v; I$ z5 p: w5 p
of papilledema.) f4 z3 H) _8 J/ T
Laboratory Evaluation
3 I6 J3 U4 k$ q1 T( l P0 lThe bone age was consistent with 28 months by
6 K/ Q5 ^- a/ Susing the standard of Greulich and Pyle at a chrono-
0 Y% [0 @' w9 V! t5 }1 Ulogic age of 16 months (advanced).5 Chromosomal8 L( s' S, m; M1 H* j7 E
karyotype was 46XY. The thyroid function test
% V" l& T* T( J, Q( U* k5 Fshowed a free T4 of 1.69 ng/dL, and thyroid stimu-
4 M |; {" d0 Y$ o3 _! g+ slating hormone level was 1.3 µIU/mL (both normal)./ h9 X6 t4 v9 Q1 u
The concentrations of serum electrolytes, blood8 l8 A+ X; j# O6 s5 z( k5 V2 c
urea nitrogen, creatinine, and calcium all were
! x6 S$ w b8 zwithin normal range for his age. The concentration! ~$ P0 C+ V7 z+ V/ C" e
of serum 17-hydroxyprogesterone was 16 ng/dL
3 ?% U& B# u/ q I" v(normal, 3 to 90 ng/dL), androstenedione was 20; M4 H# z2 g% |- [; ]
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-& O) D* ]# g% B1 O( C' T, z6 f
terone was 38 ng/dL (normal, 50 to 760 ng/dL),% Q1 P6 `! W2 P+ I, x' X: {- W( k
desoxycorticosterone was 4.3 ng/dL (normal, 7 to
9 I; f. c3 h+ M) K8 H* A49ng/dL), 11-desoxycortisol (specific compound S)( D8 e1 _ S# p% e* y$ W/ p' M) @
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
C ^# s, @% j; F4 ktisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
- r) q0 I2 P+ X! |- {2 g1 T. rtestosterone was 60 ng/dL (normal <3 to 10 ng/dL),! H" s1 n; m" ~( P% x( h, `
and β-human chorionic gonadotropin was less than
5 v3 R9 b* X+ U, c5 mIU/mL (normal <5 mIU/mL). Serum follicular
4 p( J' A$ h# v/ g! A3 A$ Kstimulating hormone and leuteinizing hormone
* U# ]) u4 T4 l: _( Sconcentrations were less than 0.05 mIU/mL
+ c& d3 \" ?8 M(prepubertal).
8 s4 I! X) i+ M. q6 N) }$ eThe parents were notified about the laboratory
e- S: s- M6 Q9 S7 wresults and were informed that all of the tests were F D7 \# N9 L
normal except the testosterone level was high. The! ?* t1 v( [2 f/ V
follow-up visit was arranged within a few weeks to5 G; L+ X: k& k2 v
obtain testicular and abdominal sonograms; how-+ q A" u7 I4 d' O
ever, the family did not return for 4 months." Y/ j4 j6 r* m z* D
Physical examination at this time revealed that the$ |: ~) k4 b }! [
child had grown 2.5 cm in 4 months and had gained) Q- @/ c9 r6 B1 K+ G7 h; [
2 kg of weight. Physical examination remained" s; D; L' C% p) K1 P
unchanged. Surprisingly, the pubic hair almost com-8 l& |# l$ b: ]4 @1 u
pletely disappeared except for a few vellous hairs at5 W3 |4 ~6 t! b: X3 @! v7 Q
the base of the phallus. Testicular volume was still 2
/ }+ T, u# F( {mL, and the size of the penis remained unchanged.9 b; o) D' s2 ~ F) Q4 M$ m0 N2 `$ }% {
The mother also said that the boy was no longer hav-. J% R1 N( _7 u! [0 S& H# t B4 f
ing frequent erections.
2 c& T" l4 H6 ~1 Y cBoth parents were again questioned about use of
' o7 G2 k/ _8 m7 ?- rany ointment/creams that they may have applied to
+ Z# v/ g* E6 athe child’s skin. This time the father admitted the9 A2 z0 I5 j* J
Topical Testosterone Exposure / Bhowmick et al 541
3 ~3 y8 k, q9 r; L- duse of testosterone gel twice daily that he was apply-' }& Y! Q9 |: y* a: \* V& j
ing over his own shoulders, chest, and back area for& c+ \, {% P, {5 ? ~
a year. The father also revealed he was embarrassed" |9 ~+ Z9 V- s% t
to disclose that he was using a testosterone gel pre-
2 ?6 L% V/ z* d' g$ f0 `$ T) A8 kscribed by his family physician for decreased libido) j' E( ^. r* t$ t) w4 r% G7 y; N
secondary to depression.4 o1 F9 K+ B3 s
The child slept in the same bed with parents.
; E2 | O8 e: A& WThe father would hug the baby and hold him on his
0 |0 g' Z( v) V# \# Y5 b' Fchest for a considerable period of time, causing sig-
# h9 f w( l* x& Y9 w0 H( }nificant bare skin contact between baby and father.
8 c0 ]1 t: n5 TThe father also admitted that after the phone call,
5 d0 |: Q! _+ T7 H; C2 H {when he learned the testosterone level in the baby4 H6 r: R- J2 W3 _: d8 t1 M. b
was high, he then read the product information
5 u- b3 ?7 w1 ~1 c! ~" p1 {3 @, L( opacket and concluded that it was most likely the rea-
& R, t! u0 c5 nson for the child’s virilization. At that time, they
* i6 J3 a6 A/ tdecided to put the baby in a separate bed, and the& ?% ?# L- H! {% Q# X) c
father was not hugging him with bare skin and had/ o0 _( f7 o: |
been using protective clothing. A repeat testosterone2 l; w& N' F0 V& M. O
test was ordered, but the family did not go to the" b6 S0 L8 C# \" \
laboratory to obtain the test.
; A2 v1 u$ R( D0 h) t% uDiscussion- |6 m7 C( w" V
Precocious puberty in boys is defined as secondary
: s- T/ M: a" [; \1 K* h& F: Isexual development before 9 years of age.1,43 A7 h" q& h' x3 K2 [7 J1 x- B
Precocious puberty is termed as central (true) when
% [; t" h1 ^* ~2 B2 o1 ait is caused by the premature activation of hypo-9 I; W! d8 l0 ?5 n) s& T
thalamic pituitary gonadal axis. CPP is more com-- q y& Z0 m8 k# J1 A, {5 g
mon in girls than in boys.1,3 Most boys with CPP
) L1 [5 }! H. B& a5 _may have a central nervous system lesion that is8 K$ n/ j/ Y! F8 ~: p
responsible for the early activation of the hypothal-6 G0 U- D, e* h( K1 U' T2 v
amic pituitary gonadal axis.1-3 Thus, greater empha-% q% }6 ?6 X$ E8 q
sis has been given to neuroradiologic imaging in
8 p( ?! K) }/ H+ nboys with precocious puberty. In addition to viril-
2 Y* R5 g. @* Z3 yization, the clinical hallmark of CPP is the symmet-
: Z, L5 K" Z5 ^! _0 ]8 n5 ^rical testicular growth secondary to stimulation by
5 Z+ p# _- |! B. n6 ?8 c$ Sgonadotropins.1,3
S$ l5 w- V) {2 xGonadotropin-independent peripheral preco-: q4 i ^2 g n: p+ T' i' S
cious puberty in boys also results from inappropriate
: D- ^- u7 k3 i* u1 w, Vandrogenic stimulation from either endogenous or
( U/ E8 A+ c: N" r O" yexogenous sources, nonpituitary gonadotropin stim-
2 z4 R8 W# Q) i1 j2 \. _) Zulation, and rare activating mutations.3 Virilizing
+ c. l9 R7 W2 r0 Z3 `congenital adrenal hyperplasia producing excessive
! T) M8 C6 l7 O* J1 Dadrenal androgens is a common cause of precocious* Y. ~$ o5 Q: _ D, Y& P% q& b" m% F
puberty in boys.3,48 n3 t7 A- L- F& N$ p
The most common form of congenital adrenal/ ~: {% F% z" a w( }
hyperplasia is the 21-hydroxylase enzyme deficiency.. I! ^* E, n; ~, O& W1 O
The 11-β hydroxylase deficiency may also result in
8 W1 Z4 P9 s* i1 Y2 V8 oexcessive adrenal androgen production, and rarely,9 u' |0 ~" G( v- w
an adrenal tumor may also cause adrenal androgen
6 r0 Y- s- y' R& L* [* Wexcess.1,3% i# [" \/ [1 B0 {" P- i* i6 t. y
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from; g7 _9 F' l3 v! a
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
+ v8 p* B4 `9 Y2 S; B- L/ gA unique entity of male-limited gonadotropin-
% y: j q0 j% tindependent precocious puberty, which is also known. L6 G- s5 i& \3 c. K& Z4 R
as testotoxicosis, may cause precocious puberty at a
4 ?) B* K/ a- |) H& s' C: L( jvery young age. The physical findings in these boys0 N; V0 C& s8 S2 ?
with this disorder are full pubertal development,& u$ o; x/ A( N0 _8 f& d! e: `
including bilateral testicular growth, similar to boys- G2 `# N8 f) @7 }/ i' A
with CPP. The gonadotropin levels in this disorder
( \8 M0 K2 u* r3 Oare suppressed to prepubertal levels and do not show
' N" }, S S+ d" P0 a1 Cpubertal response of gonadotropin after gonadotropin-4 c1 J6 I8 P$ S9 V* D6 o
releasing hormone stimulation. This is a sex-linked5 m" P0 y" S& A
autosomal dominant disorder that affects only
* }- ]. I5 o) x, {males; therefore, other male members of the family" l' @0 d: g; C' a% t' u; E" v( z
may have similar precocious puberty.3& H Z( h% |: W( O5 i( h3 f
In our patient, physical examination was incon-
1 @* n0 G; D$ h$ [; Q3 Q, Xsistent with true precocious puberty since his testi- \; J3 c+ ?' f' U0 v
cles were prepubertal in size. However, testotoxicosis& z+ w7 k$ |/ F8 [ _& ^4 I/ _
was in the differential diagnosis because his father$ V. B& S0 `: c% M7 a, @
started puberty somewhat early, and occasionally,
2 f4 c2 Z+ ~1 vtesticular enlargement is not that evident in the3 w# X/ E0 k( ]; D2 i8 m9 C! M
beginning of this process.1 In the absence of a neg-
& h8 ?7 @1 C8 Q% E$ Y; ]ative initial history of androgen exposure, our' I* ]3 Y3 H4 t/ ~) O# r' L
biggest concern was virilizing adrenal hyperplasia,
3 x6 t% J5 P4 Y0 p. ~& xeither 21-hydroxylase deficiency or 11-β hydroxylase; ]5 N0 o8 Y b# p0 Y2 |6 g
deficiency. Those diagnoses were excluded by find-
, K9 m# ^0 @. J( King the normal level of adrenal steroids.' ]$ {, r- r/ N5 H' q
The diagnosis of exogenous androgens was strongly+ _0 a4 q% M0 c( C; t ]6 a
suspected in a follow-up visit after 4 months because1 O# j, q' ]# H$ d% Y5 i
the physical examination revealed the complete disap-
" ~; k7 ~' N' \! V% S9 c5 i7 Lpearance of pubic hair, normal growth velocity, and @9 f/ C5 w+ k9 J3 [# L# z
decreased erections. The father admitted using a testos-6 `& `; z- M2 r" S+ a; m
terone gel, which he concealed at first visit. He was4 W# [7 K; r+ O
using it rather frequently, twice a day. The Physicians’' ^: _( H% Z# D w5 C$ N
Desk Reference, or package insert of this product, gel or9 j, @ [' u- y+ T
cream, cautions about dermal testosterone transfer to( S# f N$ R, L# L7 F9 q; V
unprotected females through direct skin exposure.3 p# C$ }* |: u6 n) G8 E6 M
Serum testosterone level was found to be 2 times the
: @. b3 Q0 n7 `; e# Ebaseline value in those females who were exposed to; z7 G* { q' Y p4 \7 c7 |# E
even 15 minutes of direct skin contact with their male
: Q; K" U0 X7 B2 Hpartners.6 However, when a shirt covered the applica-( }. L# y, f8 _# U$ V; i3 n
tion site, this testosterone transfer was prevented., e- B& G A; e2 e. c6 K
Our patient’s testosterone level was 60 ng/mL,
- w% h, |% G1 B, ?* @9 B+ Xwhich was clearly high. Some studies suggest that% o: |1 n3 v* X
dermal conversion of testosterone to dihydrotestos-
( W' c# r# g! S/ n8 |terone, which is a more potent metabolite, is more
( L8 V! a, m5 f5 j# }- uactive in young children exposed to testosterone
; Z; H. T' u0 V% g2 I0 mexogenously7; however, we did not measure a dihy-
+ C0 G" b' a$ L% Z0 o! [) tdrotestosterone level in our patient. In addition to" F5 V3 X& S8 a4 q- U
virilization, exposure to exogenous testosterone in0 a# M' E) j1 J |& j
children results in an increase in growth velocity and
5 a/ n. ?- A4 F# ?' Eadvanced bone age, as seen in our patient.
% h) r3 R7 N# k4 R/ PThe long-term effect of androgen exposure during
A) D2 p8 _: I6 x; ?8 Gearly childhood on pubertal development and final9 I* W* [3 G2 z( x
adult height are not fully known and always remain
/ b4 c* ]% k' w/ T9 q9 h( o& E/ ha concern. Children treated with short-term testos- @4 N6 C6 ~- K6 l1 x
terone injection or topical androgen may exhibit some
9 V/ H+ ]0 E% @: Wacceleration of the skeletal maturation; however, after# `; L. F2 Z* D: F" T& N0 O
cessation of treatment, the rate of bone maturation0 [ F3 i9 f! w/ H& u0 P: g
decelerates and gradually returns to normal.8,93 _1 |1 P, g- t$ v# `0 N
There are conflicting reports and controversy
$ Y% ~& y8 m! wover the effect of early androgen exposure on adult8 w* ^2 g5 C. ~2 `; A+ H4 w
penile length.10,11 Some reports suggest subnormal- M- x- _( w2 i. b
adult penile length, apparently because of downreg-5 O( s) @1 J! M: { h
ulation of androgen receptor number.10,12 However,
4 w6 }9 L) z7 o0 C$ [+ mSutherland et al13 did not find a correlation between5 Z e' p' J' n. q) `' j
childhood testosterone exposure and reduced adult
% B& a6 k0 m4 ]) y' P: [+ vpenile length in clinical studies.
6 v0 I( _$ V. H+ v K8 rNonetheless, we do not believe our patient is" l5 a; O5 ]4 B" q" o5 ^
going to experience any of the untoward effects from( l/ o0 t% m6 C& U6 H! w
testosterone exposure as mentioned earlier because1 G- N6 x( p C+ Z6 D' P! C; L
the exposure was not for a prolonged period of time.2 }4 }$ |! B2 h
Although the bone age was advanced at the time of0 {$ S* G2 V5 ~+ |* @2 s# \
diagnosis, the child had a normal growth velocity at
) o' a* P6 C8 y) h3 b( k$ Pthe follow-up visit. It is hoped that his final adult% N! a+ \2 p. q6 o* ~% @% ]( t
height will not be affected.8 j7 O$ b& V% W6 h8 _/ u8 @( e
Although rarely reported, the widespread avail-
6 V+ E/ V% O4 P: V; Oability of androgen products in our society may2 C6 }4 k8 I+ [: G) ?3 u& {
indeed cause more virilization in male or female7 v1 `3 B8 T% D, v
children than one would realize. Exposure to andro-) P7 L( C' Z; ^
gen products must be considered and specific ques-
- N9 m: V, u! btioning about the use of a testosterone product or
0 `0 Z$ `2 p H1 T& g0 m. Egel should be asked of the family members during
8 b2 u# h8 ^% r+ q1 Qthe evaluation of any children who present with vir-6 {% ^& t& `* u/ ]5 ~8 _
ilization or peripheral precocious puberty. The diag-& l. z) E; Q. A& O) r- V
nosis can be established by just a few tests and by
! d2 L- D0 J6 ~. M d0 rappropriate history. The inability to obtain such a% t, l) m& g; b$ [: q; I3 C; _
history, or failure to ask the specific questions, may
! _- L: [, r$ }result in extensive, unnecessary, and expensive
; u! J3 T( C3 `& H5 i. ~investigation. The primary care physician should be
$ I+ w! f$ W( @0 \; `! i/ faware of this fact, because most of these children
1 k) h+ M% t! Lmay initially present in their practice. The Physicians’
' |. g0 `& S$ i1 ADesk Reference and package insert should also put a
: Q& R: s6 U- R, xwarning about the virilizing effect on a male or/ S8 ]0 O, V ^. I5 R8 u, T8 j, l, h
female child who might come in contact with some-9 J& ?; J, U% n2 ^4 v3 Q9 F
one using any of these products.# N/ i+ z% g8 j/ A: R
References' n( B y: X4 | a& b2 \7 p! y6 Z+ J F
1. Styne DM. The testes: disorder of sexual differentiation# O2 Q( N, U) [' N# G. D% q
and puberty in the male. In: Sperling MA, ed. Pediatric
) F/ y+ ^) `# zEndocrinology. 2nd ed. Philadelphia, PA: WB Saunders;! o% U9 K. f+ G2 g. f9 q
2002: 565-628.
+ | G) G6 N; u' k6 k2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
- a$ N- y' a; D7 e$ j% n2 s0 lpuberty in children with tumours of the suprasellar pineal |
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