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Sexual Precocity in a 16-Month-Old- W$ w1 T6 I$ ]: f
Boy Induced by Indirect Topical
! b6 M3 Q* u/ L( C. w: cExposure to Testosterone
$ \1 M3 l0 b) T3 ]Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
& L" z8 T) W" D% Z) E& oand Kenneth R. Rettig, MD1$ R+ O) R2 g9 e+ o
Clinical Pediatrics
( R( F. l5 Y# JVolume 46 Number 6
1 q) X! Y* N# t4 F2 h; xJuly 2007 540-543
, ~' t b! Y8 J" R2 x: d N$ m© 2007 Sage Publications0 d( t4 D) g8 q! [: L% ~& S
10.1177/0009922806296651' t( T! ^) i1 [
http://clp.sagepub.com# Q6 j' Z( R6 l$ k5 a: p1 O6 W, h
hosted at6 [2 e$ [2 }0 p# [7 ?6 K1 Q' A
http://online.sagepub.com
: H S! ]! D+ |0 k) q4 h4 B( iPrecocious puberty in boys, central or peripheral,
; Z1 \( p/ ?8 Y9 r( C. Iis a significant concern for physicians. Central
4 E' \! i7 M. [7 E" y$ J9 \4 Mprecocious puberty (CPP), which is mediated" `% [& `# J B
through the hypothalamic pituitary gonadal axis, has
% G9 X* ?0 k3 Qa higher incidence of organic central nervous system) t# A" J: v0 G# B7 k, Q& P' i
lesions in boys.1,2 Virilization in boys, as manifested
7 v5 E5 J" s" ^. ^& r5 L4 h& iby enlargement of the penis, development of pubic% t2 h5 b% C' K/ U2 ?
hair, and facial acne without enlargement of testi-
! P0 V8 u& d- ?9 Vcles, suggests peripheral or pseudopuberty.1-3 We: G" v3 k a( a9 t4 N
report a 16-month-old boy who presented with the$ A2 V* ?% u* p2 f9 N
enlargement of the phallus and pubic hair develop-
# S/ l2 h4 N' f4 M3 o1 Q5 M! P$ Rment without testicular enlargement, which was due0 T/ e% z$ F6 J) O( `- {/ [+ E* f
to the unintentional exposure to androgen gel used by
! y% H( ?& i( e! z kthe father. The family initially concealed this infor-
6 h) {+ m( y H4 Smation, resulting in an extensive work-up for this2 @# v9 f3 H+ C% ]' i7 Q. k
child. Given the widespread and easy availability of- d; ^" o1 Q. p: W* n" e6 a, v! h
testosterone gel and cream, we believe this is proba-1 l6 W6 A: \7 e3 n
bly more common than the rare case report in the4 V" f' P+ O& L' f4 L- P; ]
literature.40 o. }# K p+ C/ a' Y
Patient Report
7 ^, c% T- W" g& F: ]% w# ZA 16-month-old white child was referred to the
+ o/ f) D* b: w& v4 s/ {! uendocrine clinic by his pediatrician with the concern
. z8 R# H E8 c& i! i& K$ E9 n9 Gof early sexual development. His mother noticed
1 i, L1 Z% }/ P# P- t$ _light colored pubic hair development when he was% K9 L# [+ S; E M! M, @
From the 1Division of Pediatric Endocrinology, 2University of
: h* U$ m, i9 y8 f6 dSouth Alabama Medical Center, Mobile, Alabama.$ ?- e. Q% P* N% m( p8 r: @1 H
Address correspondence to: Samar K. Bhowmick, MD, FACE,* e9 ~* p o4 g5 k
Professor of Pediatrics, University of South Alabama, College of
6 c( P" W& S4 |( X( Q. Y& ZMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;# S6 {9 d* [0 z& f4 P- s7 M3 A$ g" d
e-mail: [email protected].4 T, D+ [9 c P4 z! t1 m; f# F2 [
about 6 to 7 months old, which progressively became( [ }- f& @( @0 G, q1 s" G- L
darker. She was also concerned about the enlarge-- [" X) c3 p ]/ B7 {7 f* B/ `3 S
ment of his penis and frequent erections. The child1 w0 b6 A' t3 R8 F; p
was the product of a full-term normal delivery, with4 }# ~9 ^ Q0 {" @/ R' i
a birth weight of 7 lb 14 oz, and birth length of6 L* H- ~. E& ^9 v6 Q1 b! r
20 inches. He was breast-fed throughout the first year
2 ^" |0 ^ Z# V4 E# ]of life and was still receiving breast milk along with/ T4 b& ]7 N. q( O( r/ |* k
solid food. He had no hospitalizations or surgery,9 H, L5 y# w `# ]7 b
and his psychosocial and psychomotor development
. k' n* F) N3 S5 D! ~, j" {was age appropriate.
2 I& h/ e" o, g/ i5 TThe family history was remarkable for the father,
5 Y) p- e, S- S F: m; zwho was diagnosed with hypothyroidism at age 16,$ G- u$ f2 T; d0 A
which was treated with thyroxine. The father’s$ s* k2 I) m' O* N) x, a1 A. {
height was 6 feet, and he went through a somewhat/ [! x- @$ w: u+ n' u
early puberty and had stopped growing by age 14.
' f, p1 R1 F0 z. [The father denied taking any other medication. The
3 E* m1 f7 O; v* n4 K" schild’s mother was in good health. Her menarche, @, J7 B' F2 `5 D7 R6 P H3 d, `
was at 11 years of age, and her height was at 5 feet
/ a+ {$ [ x" o! s5 j* P- Y5 inches. There was no other family history of pre-
" k6 E# ~4 D0 t# ^& rcocious sexual development in the first-degree rela-$ K6 `( v' k u; K: @5 Q) N+ G
tives. There were no siblings.- N2 w# c8 X9 C
Physical Examination
5 e; \/ b1 d9 x5 |0 i, gThe physical examination revealed a very active,$ W, e* U2 \: E C: y+ B
playful, and healthy boy. The vital signs documented
, H/ r" \( y4 r% w+ Na blood pressure of 85/50 mm Hg, his length was
% r' i* ~. A! x/ r0 _3 J90 cm (>97th percentile), and his weight was 14.4 kg- i1 F7 b* Z o$ p, ?
(also >97th percentile). The observed yearly growth1 D2 x( f8 o) c/ t3 ^! I- D1 z$ i+ ^; C
velocity was 30 cm (12 inches). The examination of5 q8 @* E. J" Q o" E" p
the neck revealed no thyroid enlargement.
2 V9 B- f" T2 W1 g4 P) hThe genitourinary examination was remarkable for3 @% d8 t$ p! f5 q, `7 A, u# J
enlargement of the penis, with a stretched length of9 L7 x2 v1 b1 j# f6 ^
8 cm and a width of 2 cm. The glans penis was very well
, ] _; O; I) Qdeveloped. The pubic hair was Tanner II, mostly around/ \! E( u6 A1 v' ^7 z
540
2 a |8 G u, ~; ^* a+ _0 oat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
6 `2 `0 O! e; C# vthe base of the phallus and was dark and curled. The
+ ?7 g/ h' e# x, f4 X+ o- @testicular volume was prepubertal at 2 mL each.
, M$ b3 [% @* R+ VThe skin was moist and smooth and somewhat
5 y6 D4 Y! X5 c% ]/ p6 uoily. No axillary hair was noted. There were no
3 @; y, s: b6 J( }, ^abnormal skin pigmentations or café-au-lait spots. q- c2 _$ h% F4 J; O9 `% `
Neurologic evaluation showed deep tendon reflex 2+
3 T; O0 B2 F6 W- S2 F" mbilateral and symmetrical. There was no suggestion8 M9 a. k4 ]; ?7 [5 K% D
of papilledema.' e0 d2 T! X* s9 m$ |3 |
Laboratory Evaluation
" }" B5 b6 X* K+ B: |6 r. sThe bone age was consistent with 28 months by
$ Y9 P6 ^$ T5 D4 r, \using the standard of Greulich and Pyle at a chrono-
3 o. M4 K6 u, q* {! ?logic age of 16 months (advanced).5 Chromosomal
+ D9 G/ w( ^3 ^( E8 Dkaryotype was 46XY. The thyroid function test
- ^& w! g/ h' T, Gshowed a free T4 of 1.69 ng/dL, and thyroid stimu-9 J& Q% B$ Z" Z
lating hormone level was 1.3 µIU/mL (both normal).
, O% o7 h# K5 g! ^* y' }! d+ d9 IThe concentrations of serum electrolytes, blood+ f6 V. R6 e& v' h# p/ j3 A- m4 u
urea nitrogen, creatinine, and calcium all were
1 ]9 u f" t) N" @8 [( E0 Qwithin normal range for his age. The concentration
. H; N# X5 P3 I" ~0 {; x2 Yof serum 17-hydroxyprogesterone was 16 ng/dL
, o; b0 j* ?: `% W(normal, 3 to 90 ng/dL), androstenedione was 20
2 @# [/ H W- Ang/dL (normal, 18 to 80 ng/dL), dehydroepiandros-- x' W1 h, h: d3 x
terone was 38 ng/dL (normal, 50 to 760 ng/dL),; ?0 I% Z$ O: h, X: K
desoxycorticosterone was 4.3 ng/dL (normal, 7 to4 p4 P+ N2 C8 C \9 ]! B
49ng/dL), 11-desoxycortisol (specific compound S)( e: \) i! [! [* Q, Z# R
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-$ [, R9 R! Z7 s' ~! A! j
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total2 m9 C. v5 {6 E m
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
+ H! a* Z4 I0 n2 `1 _. E. U- @9 C5 Yand β-human chorionic gonadotropin was less than8 M: I. V9 I& K% p
5 mIU/mL (normal <5 mIU/mL). Serum follicular3 V4 b8 a3 |* {. o- _
stimulating hormone and leuteinizing hormone: ^4 t# e: G+ t. E
concentrations were less than 0.05 mIU/mL
' l3 p- s( g% v5 O' H: l, v(prepubertal).
6 p, g K9 k) S: A0 Q+ WThe parents were notified about the laboratory/ `' {! f3 ]+ [/ Z; F9 o5 W- r% M
results and were informed that all of the tests were1 h4 ]+ [3 P8 @
normal except the testosterone level was high. The
$ r% \3 B* d0 ]$ L7 i9 {" `follow-up visit was arranged within a few weeks to! A2 X t: V0 x0 F5 \3 R
obtain testicular and abdominal sonograms; how-) h( z, x4 \4 M
ever, the family did not return for 4 months.- Z. W3 V1 S; Q& d
Physical examination at this time revealed that the6 Y5 D) w& \/ o6 E
child had grown 2.5 cm in 4 months and had gained
" \1 R3 x& D5 @4 c2 R4 @2 kg of weight. Physical examination remained
+ Q6 u4 D' s8 e/ cunchanged. Surprisingly, the pubic hair almost com-
; `2 m/ ], c" o# L4 S5 a" C y- Zpletely disappeared except for a few vellous hairs at
3 H% |* ~( Z1 M& Mthe base of the phallus. Testicular volume was still 2
9 @8 j) v/ l* q# c8 r. |mL, and the size of the penis remained unchanged.; g; ]2 O+ C, U; k# C8 q
The mother also said that the boy was no longer hav-
1 J5 a+ m5 S; k6 W, n; h# Jing frequent erections.3 g6 W3 n" v0 l5 ?
Both parents were again questioned about use of
: u+ B% l+ E" Y9 M# F, j1 Gany ointment/creams that they may have applied to
0 K2 Y7 A7 h( k; b' n, F7 Bthe child’s skin. This time the father admitted the& f8 t m5 g& V" V
Topical Testosterone Exposure / Bhowmick et al 541
2 l7 d+ N9 a9 h5 v9 |+ @use of testosterone gel twice daily that he was apply-
1 F4 o1 W; N! I3 N% y3 [: P$ c! jing over his own shoulders, chest, and back area for
; J7 ]0 Q- r1 @ n, M7 ~- na year. The father also revealed he was embarrassed
* a: K8 m0 m8 {" xto disclose that he was using a testosterone gel pre-
% \ U+ [% E- r. F9 O4 h9 h4 lscribed by his family physician for decreased libido2 S1 O4 h3 a4 @' ~7 `9 V
secondary to depression.
6 a5 ^6 y8 m [1 g) ?3 s \% BThe child slept in the same bed with parents.
: q8 n+ l" e B! `9 M+ zThe father would hug the baby and hold him on his
$ ?7 G/ c* }1 { A7 Mchest for a considerable period of time, causing sig-
7 }1 |# U0 U& c7 t. D6 Pnificant bare skin contact between baby and father.
8 p; s c& _8 A( v% c, TThe father also admitted that after the phone call,2 E9 E8 r# U. d, l" K: C
when he learned the testosterone level in the baby
7 A5 j$ ]" p) Cwas high, he then read the product information3 _$ I# e/ b% s
packet and concluded that it was most likely the rea-$ G2 L' G2 h H ^; W* ?5 Q: }
son for the child’s virilization. At that time, they
3 U7 [ G2 g! }2 N; g4 Xdecided to put the baby in a separate bed, and the# e- g% M0 F5 i8 x3 b
father was not hugging him with bare skin and had
2 U/ y& m: Q# f) i3 d$ m& l& W9 `6 }+ Ebeen using protective clothing. A repeat testosterone# _# q' s9 ]) w* q# B* h
test was ordered, but the family did not go to the
4 `6 j& I3 m, T9 ]laboratory to obtain the test.
: n. s0 N- ]' l4 e% TDiscussion
0 D& h% {# p# x2 {' p# HPrecocious puberty in boys is defined as secondary
* ~3 g6 Y" s7 i s asexual development before 9 years of age.1,4
5 W5 ^! D" F g, }3 Z( ZPrecocious puberty is termed as central (true) when
7 C9 S6 t% ^' P$ `5 oit is caused by the premature activation of hypo-* ^9 C5 U: l8 p# X* R1 M! T
thalamic pituitary gonadal axis. CPP is more com-2 N# M+ F' }! @& v" S
mon in girls than in boys.1,3 Most boys with CPP% m, B6 V- B( @) h5 R
may have a central nervous system lesion that is
0 D4 r# s' T9 D. Gresponsible for the early activation of the hypothal-7 H6 t9 z F# U/ [. u
amic pituitary gonadal axis.1-3 Thus, greater empha-
- @( t1 Q% S' U$ Q& ]sis has been given to neuroradiologic imaging in9 O/ m/ ]8 Y9 j! j9 _2 L$ B
boys with precocious puberty. In addition to viril-
3 f3 W3 l' I% F" j f! kization, the clinical hallmark of CPP is the symmet- ~ s3 Z! b3 p5 y
rical testicular growth secondary to stimulation by( o! H+ |/ {) d% I. ]3 N
gonadotropins.1,3; `( ^2 V5 _2 B+ Y6 T# f5 f
Gonadotropin-independent peripheral preco-
" Y" [3 ?! s- n: _5 r, [4 I8 Pcious puberty in boys also results from inappropriate
/ Z; }2 T* [2 I6 K" sandrogenic stimulation from either endogenous or1 F9 a0 E) `) @' c6 C* W
exogenous sources, nonpituitary gonadotropin stim-# Y7 o! ?. i O
ulation, and rare activating mutations.3 Virilizing
/ S8 ^5 \, ]; _7 ?2 U( Dcongenital adrenal hyperplasia producing excessive
* {, U) p! ?! M( Qadrenal androgens is a common cause of precocious
% Q/ `8 O) z/ r* Ppuberty in boys.3,45 o" N3 ^, n9 D: ]
The most common form of congenital adrenal
; y7 A; l3 t8 T$ h Q- ehyperplasia is the 21-hydroxylase enzyme deficiency.
8 |4 ?0 j! J [+ i bThe 11-β hydroxylase deficiency may also result in
2 d1 E9 z5 U, w2 q# [8 x$ Oexcessive adrenal androgen production, and rarely,
" ?' K$ [- F1 Pan adrenal tumor may also cause adrenal androgen5 h- k. M# Q) {% u% {5 e+ G3 G
excess.1,3
# S0 ]7 `9 i7 e* mat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
! _3 D1 n9 H0 p( R542 Clinical Pediatrics / Vol. 46, No. 6, July 2007! _' i/ V, }9 Z5 W1 v
A unique entity of male-limited gonadotropin-
4 P3 Z! n6 e3 ]. o9 u. l. Windependent precocious puberty, which is also known
2 F: m1 v5 t/ y0 b! ias testotoxicosis, may cause precocious puberty at a& Q. n9 r: o" u+ `; k, P9 I D
very young age. The physical findings in these boys4 D) q- @6 q6 m
with this disorder are full pubertal development,
+ a, \3 i% ?( \, s. L, V1 cincluding bilateral testicular growth, similar to boys0 r0 X) M; w( U# B% O& R- M# O
with CPP. The gonadotropin levels in this disorder
. r7 A/ M E) iare suppressed to prepubertal levels and do not show' q' J% \* E1 z# }3 u# A+ W/ o5 ~
pubertal response of gonadotropin after gonadotropin-! D( t* }3 L' k4 W
releasing hormone stimulation. This is a sex-linked5 }& _& x3 N; z2 }; U1 b
autosomal dominant disorder that affects only
) q/ J; n8 ~ u- Y" ^! R8 ?9 {males; therefore, other male members of the family' [" V9 x- J" e1 s
may have similar precocious puberty.3
3 ?' ^& J0 c- T; zIn our patient, physical examination was incon-* f" W" J" I1 P( C: L8 z7 e% w
sistent with true precocious puberty since his testi-4 q" y! K8 b4 J }$ A
cles were prepubertal in size. However, testotoxicosis
; ?/ v/ |5 O }0 `- z& Xwas in the differential diagnosis because his father
) |. y" e* u' `, _started puberty somewhat early, and occasionally,
+ V8 Q) D' I. e: b' \( @testicular enlargement is not that evident in the
3 T' l# Q0 P% Y Obeginning of this process.1 In the absence of a neg-( k6 d/ A7 s e& _: h
ative initial history of androgen exposure, our
m! H1 {5 R; Q& j% n. }; jbiggest concern was virilizing adrenal hyperplasia,* I5 k2 B. e/ W" u
either 21-hydroxylase deficiency or 11-β hydroxylase
2 {1 }& B; L- O" a* e+ kdeficiency. Those diagnoses were excluded by find-
2 S% g8 R. v# Q3 a. T; _3 ting the normal level of adrenal steroids.
- u$ R; B: a$ w! lThe diagnosis of exogenous androgens was strongly
4 \& g9 {) ~" U3 J- psuspected in a follow-up visit after 4 months because
2 Q+ h4 o" f+ _& J' Mthe physical examination revealed the complete disap-
2 ]( v. z5 C! J3 f1 Kpearance of pubic hair, normal growth velocity, and- T8 Q3 j0 P8 C
decreased erections. The father admitted using a testos-
T8 M& h$ c9 b: _$ D% G, k0 V6 Kterone gel, which he concealed at first visit. He was' W4 G; [, A/ E2 ~
using it rather frequently, twice a day. The Physicians’6 u7 c+ O4 C# t; X5 h! V" ?
Desk Reference, or package insert of this product, gel or
' n z& ~0 H6 t9 Z3 D: l9 Icream, cautions about dermal testosterone transfer to
5 a; [/ R4 Q4 bunprotected females through direct skin exposure.
0 o9 F3 |1 {8 X" r+ H1 L3 a3 qSerum testosterone level was found to be 2 times the
4 ^/ b. r, \3 p7 E' I+ O8 g" Mbaseline value in those females who were exposed to
h: c5 l2 I* B) j9 L. I yeven 15 minutes of direct skin contact with their male
$ I3 p$ |+ \5 Z' r0 y" Q6 N. \partners.6 However, when a shirt covered the applica-
0 C! _: O7 q" t y1 ction site, this testosterone transfer was prevented.0 N- ^5 h0 c% R
Our patient’s testosterone level was 60 ng/mL,& x# b9 \* D7 l1 C$ Q' W
which was clearly high. Some studies suggest that
- c+ V8 z; |5 N5 e; f/ Edermal conversion of testosterone to dihydrotestos-7 e/ L& ]7 f# p, I# N: Y2 F8 J
terone, which is a more potent metabolite, is more
1 A9 H% S7 d1 [4 Aactive in young children exposed to testosterone1 w% J. v0 F: m( s
exogenously7; however, we did not measure a dihy-3 s3 V8 n( v: c6 k0 k
drotestosterone level in our patient. In addition to T# `9 i" L4 s W
virilization, exposure to exogenous testosterone in
% u6 I, D5 {* w$ s* Y) lchildren results in an increase in growth velocity and* T' |3 [' E6 D" Z6 q- a3 K' f6 f7 ^
advanced bone age, as seen in our patient.
E+ X7 {+ f9 ^" m, HThe long-term effect of androgen exposure during! S5 |$ t; t2 }% n: o+ ~% c
early childhood on pubertal development and final
2 X, y9 l% s. [) o4 ^6 qadult height are not fully known and always remain" e6 G* O8 c6 f
a concern. Children treated with short-term testos-
& A" q8 r0 D' W, ~3 T# C( G* f9 Kterone injection or topical androgen may exhibit some
# [, W$ w6 U+ ]: w3 T3 O' ^acceleration of the skeletal maturation; however, after( [- z1 a9 x4 F7 q5 ]9 X
cessation of treatment, the rate of bone maturation$ Z- G. n! R3 y9 k, l% m% e8 n
decelerates and gradually returns to normal.8,9
9 V; m6 \- I( t/ g" h. wThere are conflicting reports and controversy& x" R( X/ q+ h0 c$ m
over the effect of early androgen exposure on adult1 E# A' J/ a: P3 X; F
penile length.10,11 Some reports suggest subnormal4 W$ N9 i! z2 r# s
adult penile length, apparently because of downreg-
. M" R, I& w! r4 A& eulation of androgen receptor number.10,12 However,
b6 y6 H( @3 ]9 r2 K T* {Sutherland et al13 did not find a correlation between& _( H; b2 Y4 | j
childhood testosterone exposure and reduced adult, s% d% c$ w5 N
penile length in clinical studies.$ F* `$ n7 b" e- s0 E1 \6 B
Nonetheless, we do not believe our patient is
1 a2 K, E- U4 ?: e" @, p3 ugoing to experience any of the untoward effects from
) s7 n- E |7 ^2 g; Jtestosterone exposure as mentioned earlier because
; g6 A' O! B9 V5 H+ D& S1 Pthe exposure was not for a prolonged period of time.4 B/ i& z2 Z" c* J
Although the bone age was advanced at the time of
; b# {* l) b7 S& f3 B- sdiagnosis, the child had a normal growth velocity at
: O" W$ p7 l( {) Lthe follow-up visit. It is hoped that his final adult# W( B1 ~: P: r
height will not be affected.
8 u- u8 z' g2 d gAlthough rarely reported, the widespread avail-6 a: o! d: N6 }
ability of androgen products in our society may
4 W$ G" c* U' h( ], Kindeed cause more virilization in male or female
- E4 h5 }, O3 J4 o4 x, j4 pchildren than one would realize. Exposure to andro-- j" n% l# E$ U* P9 D- A2 r" }. S
gen products must be considered and specific ques-' T- p1 s& K. W
tioning about the use of a testosterone product or
0 _/ B1 H* c" Wgel should be asked of the family members during& T; X' ?+ P/ l/ Q* j% o% w" {8 Y
the evaluation of any children who present with vir-2 x' {! `. c% v# }1 P
ilization or peripheral precocious puberty. The diag-5 Y2 d# b w4 A+ u, w
nosis can be established by just a few tests and by; Y: o% f8 u. c* ?* i% a
appropriate history. The inability to obtain such a+ j/ t3 e: {6 A
history, or failure to ask the specific questions, may
) E- T0 }- K3 Nresult in extensive, unnecessary, and expensive
' Y1 `7 y% ^8 Q6 G1 F3 Zinvestigation. The primary care physician should be$ [3 I& D/ M$ s' K+ e+ u
aware of this fact, because most of these children
4 Q& X, g2 ]$ h% N( \. Hmay initially present in their practice. The Physicians’
) y! D8 s. t$ o7 i* JDesk Reference and package insert should also put a
. ?; I& ]+ @, F8 I7 wwarning about the virilizing effect on a male or) K% u J8 s% _7 W; R. K. R+ k
female child who might come in contact with some-0 o$ t1 Y- M" c6 B
one using any of these products.+ T7 x X3 w# n* {
References
) e: ~% K0 S+ I( B! `4 A& A1. Styne DM. The testes: disorder of sexual differentiation
5 o2 u: n7 J1 j" {! `7 C/ V' Cand puberty in the male. In: Sperling MA, ed. Pediatric8 t S* N* L$ R$ ?% F, a; o
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;$ i6 z, o2 M- I
2002: 565-628.
- \, l/ \" c- x( l9 [+ Z7 f2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious' j9 `1 Q) C8 Y, y+ @8 G
puberty in children with tumours of the suprasellar pineal |
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