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Sexual Precocity in a 16-Month-Old
' |# Z: \1 K/ Z! ?, c: K# }; T, DBoy Induced by Indirect Topical
) |! p8 E. L6 X2 Q0 ~2 QExposure to Testosterone% m$ b4 w$ \9 T5 M$ t
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2$ h8 v! B1 I+ O5 v. B( ?- q4 ?
and Kenneth R. Rettig, MD1! |6 i* n: @' o; I. _8 f# ^0 u3 N
Clinical Pediatrics# V- M) `- T- q
Volume 46 Number 6) a' a) ?* ~. n0 L6 I
July 2007 540-543
$ l: l' O! D% C) x© 2007 Sage Publications, K d6 Y) E, Z( _2 n; Q% I
10.1177/0009922806296651
. c9 r( u7 V* {: Ghttp://clp.sagepub.com
" g% C( ?/ _7 m% b: p$ G7 qhosted at0 N, m' s; @; Y& `* J
http://online.sagepub.com0 z. ?6 d# q4 i
Precocious puberty in boys, central or peripheral,
. L6 l7 H) r7 Q, v! A- E2 {) Sis a significant concern for physicians. Central6 h5 M7 i5 l. o7 s3 g
precocious puberty (CPP), which is mediated
2 I- I/ ?9 `! ], \' u4 a' [through the hypothalamic pituitary gonadal axis, has
+ z8 H) _% `1 k% v( w, y2 ?6 h2 ~a higher incidence of organic central nervous system
. |! c2 {* W& v# b! R) ylesions in boys.1,2 Virilization in boys, as manifested, s I+ ^! G. r; f. r
by enlargement of the penis, development of pubic* V2 n8 G W, M
hair, and facial acne without enlargement of testi-4 H$ N; y0 ^; c6 Y
cles, suggests peripheral or pseudopuberty.1-3 We/ x/ i8 }' ~2 e5 h# s; ?
report a 16-month-old boy who presented with the8 s! ^7 ~ ^% V6 b
enlargement of the phallus and pubic hair develop-" Y# Z+ ^/ P9 ]8 g% Z, y1 I
ment without testicular enlargement, which was due
' b1 k6 [$ f- r; K% b f+ eto the unintentional exposure to androgen gel used by
9 |8 P/ L$ c4 M- L' n1 xthe father. The family initially concealed this infor-$ L" m) t1 U/ s7 |3 x9 }' Z( [
mation, resulting in an extensive work-up for this$ v( }$ J, _( @; ?4 A
child. Given the widespread and easy availability of
, S2 U/ q+ L# P: r4 u h+ @testosterone gel and cream, we believe this is proba-
4 N _" Q4 Q- ?3 s) wbly more common than the rare case report in the3 `' g) S7 t$ V [; o7 u* A
literature.4
+ h4 R! `; Z/ f6 }& C% K K4 RPatient Report
, X; |. ?( @) [/ a# ^A 16-month-old white child was referred to the
9 f) X" g: q, x% D0 i0 ?endocrine clinic by his pediatrician with the concern; H8 h6 f/ D& z1 T0 R' t7 m! v
of early sexual development. His mother noticed7 Y& d4 h+ R$ v+ t
light colored pubic hair development when he was8 [* O) w3 q9 t5 V
From the 1Division of Pediatric Endocrinology, 2University of
7 G; @8 G/ I; s8 bSouth Alabama Medical Center, Mobile, Alabama.% U- P: ~$ A1 t! F* D
Address correspondence to: Samar K. Bhowmick, MD, FACE,+ P z" z7 M7 I i
Professor of Pediatrics, University of South Alabama, College of
Y, W X0 {4 ~Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;9 ?: e$ f9 }% w) `1 R0 k
e-mail: [email protected].1 e) {0 N" I/ M% S+ M! ?0 A0 _$ x
about 6 to 7 months old, which progressively became. R7 s$ C" t& q4 |; g5 Y
darker. She was also concerned about the enlarge-( s# |+ V. _3 ?- v) M% H5 w
ment of his penis and frequent erections. The child0 O# g, v, J0 l; I# Q, o! I
was the product of a full-term normal delivery, with
, _) d7 Z5 ]4 G3 Wa birth weight of 7 lb 14 oz, and birth length of, Y- p+ E5 Y2 a. e1 ` m$ T
20 inches. He was breast-fed throughout the first year
. A8 ~9 _ ]1 ~5 Qof life and was still receiving breast milk along with4 Q# } j; k/ h/ h
solid food. He had no hospitalizations or surgery,, T6 @. V$ O, D& V; I
and his psychosocial and psychomotor development
" a- z" |6 D$ L4 M. iwas age appropriate.
: R# L9 ~9 B, A3 v4 v- J3 l$ h9 PThe family history was remarkable for the father,
* I* M0 p2 D3 i9 Swho was diagnosed with hypothyroidism at age 16,1 J; T7 N9 J) u. |$ i7 T, w
which was treated with thyroxine. The father’s
* w2 N( G% x/ ^* A/ ?! Wheight was 6 feet, and he went through a somewhat
?" ^: L$ B6 J, u8 v; Q: \early puberty and had stopped growing by age 14.9 ?, E+ K# \: Y2 z' p2 G) r6 u7 g
The father denied taking any other medication. The
; a2 r: m# K9 R, ychild’s mother was in good health. Her menarche
! o5 x7 h9 h( p5 l- _was at 11 years of age, and her height was at 5 feet
& M a( f! `$ i4 V; ^' p9 t5 inches. There was no other family history of pre-
X0 J& }' ?% P& I. P" e9 w5 Scocious sexual development in the first-degree rela-/ ?1 k ]; S& s* F. K
tives. There were no siblings.& Q, t" @8 h( l: w H2 R
Physical Examination
6 T: |- `1 h- @5 G/ L0 ]The physical examination revealed a very active,; i( S6 ?: L8 K+ f
playful, and healthy boy. The vital signs documented [, E, z+ l( ]9 T. Z- [ ^
a blood pressure of 85/50 mm Hg, his length was$ f" B# a% [8 t4 h0 w7 z- X1 U
90 cm (>97th percentile), and his weight was 14.4 kg
1 ?- b1 O! H$ p(also >97th percentile). The observed yearly growth
' H: [* B! d* R' H* ]9 |% Vvelocity was 30 cm (12 inches). The examination of
$ M; x! F+ J, O# p \the neck revealed no thyroid enlargement.2 c* q5 b$ S1 W: Z0 m9 f8 d
The genitourinary examination was remarkable for
$ }8 x6 |* i1 R1 Q' ~enlargement of the penis, with a stretched length of
' ?2 }1 @6 m; X( `! b8 cm and a width of 2 cm. The glans penis was very well
# e, j7 j& D ideveloped. The pubic hair was Tanner II, mostly around+ s5 C7 |! ]. b
540
, a1 ]: _: ~4 v5 X0 B1 @! }% Qat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
; N, L* |! t5 S) rthe base of the phallus and was dark and curled. The$ q$ M" } ^6 i( r% h
testicular volume was prepubertal at 2 mL each.
$ A: v+ ^ A) z% U8 e0 s5 t% uThe skin was moist and smooth and somewhat
# J0 G# w! |( c% Voily. No axillary hair was noted. There were no2 `0 ^( V$ M/ }1 J
abnormal skin pigmentations or café-au-lait spots.% D4 a) R) R, h+ R8 p2 C* q& L
Neurologic evaluation showed deep tendon reflex 2+
0 r+ w. H C0 } @bilateral and symmetrical. There was no suggestion Q. M9 _ Y0 z! {( p+ D; U& ?
of papilledema.# a9 S. w5 [/ W! S# c
Laboratory Evaluation e B8 w M* _) K/ r) F7 b
The bone age was consistent with 28 months by& h H2 v* f S/ q
using the standard of Greulich and Pyle at a chrono-
( x1 \* v, @0 m$ {% ylogic age of 16 months (advanced).5 Chromosomal
/ h) @, a4 Q7 |7 J$ |" j1 ykaryotype was 46XY. The thyroid function test
, o, x' Z, ~% U1 d" Fshowed a free T4 of 1.69 ng/dL, and thyroid stimu-
; V. q" I* R$ {) V0 |lating hormone level was 1.3 µIU/mL (both normal).0 r1 A; J7 y; g4 ~4 s& O4 X" Z
The concentrations of serum electrolytes, blood
" `1 V" e, u! t, Burea nitrogen, creatinine, and calcium all were( h3 h& p' J* k4 k
within normal range for his age. The concentration: `6 ~1 K) ?6 J1 j$ D O/ ~: u
of serum 17-hydroxyprogesterone was 16 ng/dL
) B5 ?2 L2 X1 { h( [(normal, 3 to 90 ng/dL), androstenedione was 20
( L/ P( V& W+ @; y2 I# J2 r- Fng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-. z/ Y' |) t. v F$ t; @
terone was 38 ng/dL (normal, 50 to 760 ng/dL),& M2 x' ?, U9 ^3 ~/ {& T( X" h
desoxycorticosterone was 4.3 ng/dL (normal, 7 to
/ e- i% ?* L, [- A/ I- j- ?/ W4 K49ng/dL), 11-desoxycortisol (specific compound S)9 _5 J$ \0 D* g/ T$ L! v
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
$ W, z4 {, d! H0 W/ Mtisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total$ i, R0 e) H2 b! t" X' |0 j# t
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
0 Z5 e# v- |$ r1 `2 ^8 ?and β-human chorionic gonadotropin was less than
, m9 _9 w: n' n: ~9 r5 mIU/mL (normal <5 mIU/mL). Serum follicular0 u, M5 |+ [1 y
stimulating hormone and leuteinizing hormone4 A0 K: h2 {) c+ ?8 i d
concentrations were less than 0.05 mIU/mL
* C: n& f- z! I9 j- I9 v2 @(prepubertal).8 A% E+ k, \) b! m! A: I
The parents were notified about the laboratory
3 h" o% q. Q/ Iresults and were informed that all of the tests were1 l: ~. |# @( R4 q+ G; m1 K
normal except the testosterone level was high. The
- S, d) \, p; z: |follow-up visit was arranged within a few weeks to
6 a" d7 i5 K: }obtain testicular and abdominal sonograms; how-
) A# v3 w m3 F+ [ever, the family did not return for 4 months.: \, y' F& \9 l' H3 Y$ W* F- ^
Physical examination at this time revealed that the! L5 Y& l3 m: q+ O4 n3 A
child had grown 2.5 cm in 4 months and had gained; X* f/ N. L/ ]3 p$ L# s3 v
2 kg of weight. Physical examination remained
% N, ~/ U% k5 ?* ~/ {. t- d( Wunchanged. Surprisingly, the pubic hair almost com-
9 {/ O6 X" {/ z7 r9 lpletely disappeared except for a few vellous hairs at
$ [' S% F' b- e2 Qthe base of the phallus. Testicular volume was still 2 P8 Z8 o# r8 u+ l A5 M" D
mL, and the size of the penis remained unchanged.
2 Q- L9 g1 Q5 ]9 Q; I' HThe mother also said that the boy was no longer hav-
# i$ X$ S. Y2 ~! E* ?2 a, e2 |ing frequent erections.% |. @7 z7 i; f2 s5 V
Both parents were again questioned about use of: D; S" S. K$ Y' o
any ointment/creams that they may have applied to
" q) O4 A& T0 z. W7 `the child’s skin. This time the father admitted the
0 b1 A, B. i9 z; o7 b9 X+ tTopical Testosterone Exposure / Bhowmick et al 541- o1 `% H2 r; f# L2 r
use of testosterone gel twice daily that he was apply-+ V" M6 [- K Z4 b& W
ing over his own shoulders, chest, and back area for# P& P; M2 m% J6 @0 u% {4 x
a year. The father also revealed he was embarrassed$ \, U9 ~# [$ J' P
to disclose that he was using a testosterone gel pre-
! i" B3 S$ D7 t3 kscribed by his family physician for decreased libido* F3 ]$ V ]' d( }( w. x
secondary to depression.
+ b0 [& S: p b0 Y4 o, K \The child slept in the same bed with parents.
; O+ `. n2 s5 ~The father would hug the baby and hold him on his/ s% W* u& a. y2 N" n$ ~
chest for a considerable period of time, causing sig-9 w9 \3 f8 r. ]; E
nificant bare skin contact between baby and father.
# U" _- T6 j& R; J) ~1 JThe father also admitted that after the phone call,# f9 r6 }! s5 v6 _; C% D) M/ o. M/ W }
when he learned the testosterone level in the baby8 [- ~" L/ ]0 E7 p2 P
was high, he then read the product information
: O2 U) K& K) P3 Z$ n2 Ppacket and concluded that it was most likely the rea-
% [ M$ b e9 O. [- mson for the child’s virilization. At that time, they) N, U( f! h0 e: Q
decided to put the baby in a separate bed, and the8 O( D) Z8 Q; j, J2 s
father was not hugging him with bare skin and had
2 m; y w; o6 H9 d$ C: [0 K2 zbeen using protective clothing. A repeat testosterone' U u9 s1 Q( u+ ]3 @5 h+ c
test was ordered, but the family did not go to the, F* ]1 o0 K: l9 y5 ?7 x1 d) G% A
laboratory to obtain the test.: B: @9 m; g3 m
Discussion
; ^ J* g& l' G- s. bPrecocious puberty in boys is defined as secondary0 X# C+ f6 u4 O' |
sexual development before 9 years of age.1,4
. ^" ?$ v# q7 EPrecocious puberty is termed as central (true) when( S0 l7 _% G8 _+ o
it is caused by the premature activation of hypo-% h% @( A, ~' r, T5 n$ C# k; O$ D
thalamic pituitary gonadal axis. CPP is more com-
$ R" Q. e, _7 ?% H H1 Z& H' lmon in girls than in boys.1,3 Most boys with CPP) D0 n0 U. {% ]4 F1 P: M
may have a central nervous system lesion that is o& ?/ q/ \3 n+ O" U
responsible for the early activation of the hypothal-7 G" O( J. {) w/ W2 F
amic pituitary gonadal axis.1-3 Thus, greater empha-
0 F2 G: ?1 h: I! fsis has been given to neuroradiologic imaging in
3 W: F# z) L7 q; r+ Jboys with precocious puberty. In addition to viril-7 ~& r6 q2 A" D( m( E
ization, the clinical hallmark of CPP is the symmet-
6 F, K0 e4 v& L- ^! B! K- y1 q6 c6 ~5 grical testicular growth secondary to stimulation by! f6 _5 b, g- {( f1 D; [
gonadotropins.1,3+ \/ N* E8 K. E8 b" z2 V/ D! x
Gonadotropin-independent peripheral preco-
f: l& T, _* A$ {0 l) {cious puberty in boys also results from inappropriate: G4 A8 ~5 l6 S. V$ x! U' L) a
androgenic stimulation from either endogenous or. f& u- g5 f; o% J1 Z R& [
exogenous sources, nonpituitary gonadotropin stim-
4 h: J8 K; h) t* h4 Z& `) x; rulation, and rare activating mutations.3 Virilizing* h. V4 W/ }( }: x1 h- Q! x( V
congenital adrenal hyperplasia producing excessive% u ^6 Q6 {4 g" d# e
adrenal androgens is a common cause of precocious
/ E3 }0 [- ^9 Q" N# O/ G, mpuberty in boys.3,4
3 f g$ U1 w+ z1 L/ L& H) IThe most common form of congenital adrenal
) n" s, a9 {3 b; p) k; ihyperplasia is the 21-hydroxylase enzyme deficiency.$ u9 V0 M" z' V9 ]+ O. W6 f6 ]3 W
The 11-β hydroxylase deficiency may also result in `, y; v3 K0 |- ^$ Q
excessive adrenal androgen production, and rarely,. X, i. t; ?6 _7 x# }# @6 d
an adrenal tumor may also cause adrenal androgen6 L ~9 o! J% a! u0 i
excess.1,3
" V) V$ h3 T0 h3 m8 Z, a0 ]% a5 g; ?at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from9 B- o$ H, O- m* l
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007! ]$ Q7 j- o& M6 h- l2 o
A unique entity of male-limited gonadotropin-
; S; M/ @1 i+ I8 ~0 M9 d. p4 P D. Bindependent precocious puberty, which is also known' ^3 G* M9 `. Y" C* I$ @
as testotoxicosis, may cause precocious puberty at a
% O7 [) e/ A! Qvery young age. The physical findings in these boys9 }+ B ?" x# w( ?$ z
with this disorder are full pubertal development,
1 J% i, ~0 Y1 E2 V0 X8 v: Jincluding bilateral testicular growth, similar to boys3 K5 y* }- @5 S. M* w
with CPP. The gonadotropin levels in this disorder
0 D! ]4 Z' `; l2 Zare suppressed to prepubertal levels and do not show
8 [! ^: {* F3 t6 G' W7 dpubertal response of gonadotropin after gonadotropin-
* M; M) U& Z/ T5 m7 m; hreleasing hormone stimulation. This is a sex-linked
: o. V7 ^" V9 b. V0 b/ Z4 y' q' Wautosomal dominant disorder that affects only* W2 i& i: Z) K; E: H: `
males; therefore, other male members of the family7 v, p) r$ T: l) U
may have similar precocious puberty.3
8 P1 z; v3 N8 j3 k/ L4 n/ YIn our patient, physical examination was incon-" W! f2 y/ j' q3 N0 U
sistent with true precocious puberty since his testi-/ J( O; B& [9 M; D, k
cles were prepubertal in size. However, testotoxicosis
7 W( q- E; }: p9 {* ^' Ywas in the differential diagnosis because his father
- Z: O0 e) [' R& z5 Sstarted puberty somewhat early, and occasionally,9 G( A9 {& K/ y( _: X1 |8 `$ y
testicular enlargement is not that evident in the2 g9 ]9 l/ `- y
beginning of this process.1 In the absence of a neg-
7 E0 e& O/ ]( g$ r' kative initial history of androgen exposure, our3 k9 b! j6 `* p* M% P' k; o3 L
biggest concern was virilizing adrenal hyperplasia,
& y7 U, V7 B; L4 A3 L. aeither 21-hydroxylase deficiency or 11-β hydroxylase
2 \: s' |2 C" H7 q3 l& x- M6 ndeficiency. Those diagnoses were excluded by find-
& U5 N$ y$ z @, P+ A. t* Oing the normal level of adrenal steroids.
# r m/ p- i+ G: Q9 u, GThe diagnosis of exogenous androgens was strongly+ b- |' t5 B7 \8 g
suspected in a follow-up visit after 4 months because
) N* ?: V: B+ E& B- K8 E/ ?2 ^the physical examination revealed the complete disap-
/ e# w: z" C" z+ Tpearance of pubic hair, normal growth velocity, and
J. w6 ~; {( ~ Z5 Zdecreased erections. The father admitted using a testos-3 E* G5 B# i0 h, B1 t
terone gel, which he concealed at first visit. He was& ^& d+ ?3 k5 M
using it rather frequently, twice a day. The Physicians’
2 @" T1 j2 O2 `: o4 f& i9 nDesk Reference, or package insert of this product, gel or2 v! q, S: k( o# _. Z+ r6 o
cream, cautions about dermal testosterone transfer to. G5 `0 ?! R% @
unprotected females through direct skin exposure.
! N7 d9 q/ o8 U5 G( V2 }Serum testosterone level was found to be 2 times the
4 E; {. O$ @" S% k: u, h; lbaseline value in those females who were exposed to
# h5 z2 l" O( q4 \* ^; Neven 15 minutes of direct skin contact with their male+ F% R2 v+ f$ N: j
partners.6 However, when a shirt covered the applica-
U* P' U, Q0 V% Ntion site, this testosterone transfer was prevented.
6 }2 S! ]/ O. J7 h& G6 z, FOur patient’s testosterone level was 60 ng/mL,* |0 d9 ~. X5 _( `
which was clearly high. Some studies suggest that# g/ s+ N8 |7 t2 C
dermal conversion of testosterone to dihydrotestos-
% R- {5 ]: b' tterone, which is a more potent metabolite, is more
; w" q( a& f; [* \, Oactive in young children exposed to testosterone1 m! a# ]- C4 D7 e+ |% h
exogenously7; however, we did not measure a dihy-
- J$ g) P4 |3 q+ X# vdrotestosterone level in our patient. In addition to
# f; i2 T3 E" I+ G \6 U( Z4 h; Tvirilization, exposure to exogenous testosterone in
1 i, \ n( B" J8 l& E0 z# L0 {children results in an increase in growth velocity and
( `! ~! T: z b& m7 jadvanced bone age, as seen in our patient.1 E4 C; d( F9 t% s S7 X
The long-term effect of androgen exposure during0 c$ x3 Q) r( r& ?, P4 o, M2 a8 g
early childhood on pubertal development and final
1 t; s5 M2 f1 A' H- Oadult height are not fully known and always remain
6 q* j" ?6 v# ta concern. Children treated with short-term testos-
; o& F$ Y9 ? s% X* d5 f& }terone injection or topical androgen may exhibit some- e) `; }) v+ E
acceleration of the skeletal maturation; however, after
5 I0 W. J. l- Zcessation of treatment, the rate of bone maturation) W9 b$ v( q3 v
decelerates and gradually returns to normal.8,9
" k2 D, v! E, a; ?& \There are conflicting reports and controversy
) F1 `( U/ G2 x* U5 y. _9 {8 Zover the effect of early androgen exposure on adult/ s* d9 h, k$ d+ }3 z/ {4 t- }
penile length.10,11 Some reports suggest subnormal+ a- s8 p w2 x' l5 c/ U- e
adult penile length, apparently because of downreg-
# ?7 V# n# U( U9 \# T, _; F* g, n# v/ aulation of androgen receptor number.10,12 However,
7 p, s+ o4 L% l2 uSutherland et al13 did not find a correlation between
* v6 y# a$ w* g; wchildhood testosterone exposure and reduced adult" `2 k# c; s, Z- @/ m8 M
penile length in clinical studies.
: v$ ]+ P+ C+ x+ l7 sNonetheless, we do not believe our patient is" e) j3 g4 v E4 @# F5 k8 G& U
going to experience any of the untoward effects from
! g5 i2 A: ?0 L! Dtestosterone exposure as mentioned earlier because4 ?7 `7 F: z. ?& N% k
the exposure was not for a prolonged period of time.
; Y4 T, H, h1 g6 y/ v; b9 q+ ~Although the bone age was advanced at the time of h5 ~) q6 b& M/ {5 f- e2 o& a
diagnosis, the child had a normal growth velocity at
; f2 a- r" ]9 Qthe follow-up visit. It is hoped that his final adult! V* o* \# ?% Y6 V
height will not be affected.
# t# x# s( n' B) }" FAlthough rarely reported, the widespread avail-7 ~- l7 n. B. a. L( B0 U- Z( g1 s
ability of androgen products in our society may
h2 V8 e c/ Gindeed cause more virilization in male or female) ^0 H% J8 G4 N+ A: ?
children than one would realize. Exposure to andro-
5 s1 d( D3 B# c% r+ B5 N; Lgen products must be considered and specific ques-. \( U n: Z1 G: x
tioning about the use of a testosterone product or
) J( T0 T: a, K8 ~3 |1 X. D) Egel should be asked of the family members during
1 o6 y% k4 x) @+ A& N3 }the evaluation of any children who present with vir-
# T) {) w. e8 v, @6 M* \ilization or peripheral precocious puberty. The diag-
/ b% R. Y: e( K" L8 f9 B8 Enosis can be established by just a few tests and by) G1 |6 y2 Z, W
appropriate history. The inability to obtain such a
; [# U7 v3 k8 [( z& D/ zhistory, or failure to ask the specific questions, may
1 r$ L5 Z& D: h0 Mresult in extensive, unnecessary, and expensive
( g2 o9 v8 c3 f+ f& h8 U2 uinvestigation. The primary care physician should be$ \2 E W( K/ z
aware of this fact, because most of these children. D. |( {" l! O3 K
may initially present in their practice. The Physicians’
1 Z1 ^0 O0 e- W x0 N" l7 UDesk Reference and package insert should also put a4 w! f8 H& N$ E) [. ^5 N
warning about the virilizing effect on a male or8 c. ?1 b7 N. S
female child who might come in contact with some-
2 @5 J! y s- H e8 s: n+ \one using any of these products.
/ b- ]& r7 w8 f+ g$ nReferences5 T) H) e3 j0 {! E9 a, w
1. Styne DM. The testes: disorder of sexual differentiation
( _% u- N& o, u2 F; _and puberty in the male. In: Sperling MA, ed. Pediatric
; k9 M$ I9 Q3 U; b3 X, }. HEndocrinology. 2nd ed. Philadelphia, PA: WB Saunders;' z3 h% ~" r: g, U; I9 I) X
2002: 565-628.
. \8 B6 m4 G2 q% V# [2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious$ F# C' g; R. K9 ~ r7 v# q* h3 @# j
puberty in children with tumours of the suprasellar pineal |
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