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Sexual Precocity in a 16-Month-Old5 H! X* d' m0 X. v' [7 p1 Z
Boy Induced by Indirect Topical) ^% I$ _, i+ Z; a5 v C( I6 q
Exposure to Testosterone& Q* ~3 I8 p6 a& I5 _& R
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,25 o( \* G: c4 [1 W! M" v) y
and Kenneth R. Rettig, MD19 h# {+ c5 s ~' @
Clinical Pediatrics' P: A7 }' h/ O4 P4 n
Volume 46 Number 6& d. ^/ H+ o# M5 _
July 2007 540-543
7 X" o1 v( w' C6 W! t" D% U© 2007 Sage Publications
4 _& e1 j) U, h10.1177/0009922806296651 p4 A! R9 E+ M) z! P
http://clp.sagepub.com
/ c9 x9 i8 m" mhosted at+ e" V ]# i; `/ c& P3 L
http://online.sagepub.com% x7 z1 b8 I+ R& f" L( y" E
Precocious puberty in boys, central or peripheral,
' P5 a2 Z2 C6 sis a significant concern for physicians. Central3 T- N- j) v0 X2 D3 H' ^7 w
precocious puberty (CPP), which is mediated2 r2 F* {& |& u4 |" t y
through the hypothalamic pituitary gonadal axis, has- q! G$ O" u0 `/ Z4 t& \1 K
a higher incidence of organic central nervous system; M! q P1 @, ? E
lesions in boys.1,2 Virilization in boys, as manifested
( b0 u) T$ l( l5 x( h1 K2 v4 Lby enlargement of the penis, development of pubic
: Q- W0 d6 o+ b7 r; s/ ihair, and facial acne without enlargement of testi-
3 u3 m, `* r& w1 @! h* M% P+ Dcles, suggests peripheral or pseudopuberty.1-3 We
3 A7 @, d" J5 k5 b5 A+ S0 Yreport a 16-month-old boy who presented with the% E. r* j+ P6 N& v) ^
enlargement of the phallus and pubic hair develop-4 f$ ]5 h# ^6 u+ w; I& c
ment without testicular enlargement, which was due' z& o# ^; A2 V
to the unintentional exposure to androgen gel used by0 h( l3 x8 R3 z" K+ B( v
the father. The family initially concealed this infor-
* ~+ f3 F: c2 o/ I' s0 c( h kmation, resulting in an extensive work-up for this
0 B+ a5 T7 U/ C0 O* R# lchild. Given the widespread and easy availability of
5 W3 a# Z# K2 f$ s, atestosterone gel and cream, we believe this is proba-8 s/ j J& q3 G7 w+ L3 V0 _
bly more common than the rare case report in the
7 L; o! O, y3 d$ @+ lliterature.4
9 s! E3 u% X- s% q4 w4 }3 CPatient Report) u/ q6 T- c1 B7 @5 R
A 16-month-old white child was referred to the" R, ?$ ^) I+ w; Y& O
endocrine clinic by his pediatrician with the concern
w/ M. f: A( v9 p/ \+ l$ }! Jof early sexual development. His mother noticed
+ I% ?( f5 p3 }% B% rlight colored pubic hair development when he was2 d) L! O, i$ _5 ~6 \7 j
From the 1Division of Pediatric Endocrinology, 2University of
# T2 F3 E! `+ E. Z# M3 QSouth Alabama Medical Center, Mobile, Alabama.
0 X/ K+ H6 D3 F* w8 NAddress correspondence to: Samar K. Bhowmick, MD, FACE,
7 I0 p8 g) u8 V v1 [; HProfessor of Pediatrics, University of South Alabama, College of
7 q1 {( v S7 \, m) a0 s' dMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
% ~8 U; i/ s/ w+ L8 Y. ye-mail: [email protected].6 a0 e# H+ A8 N' J: e
about 6 to 7 months old, which progressively became5 C6 W+ B1 v) V, Y1 [
darker. She was also concerned about the enlarge-
k: P. k/ l8 T! j, h qment of his penis and frequent erections. The child
2 {. y) V5 ~1 ?4 P. Qwas the product of a full-term normal delivery, with4 ?; k) Z9 H1 {( |2 Z
a birth weight of 7 lb 14 oz, and birth length of& Z1 j" C. R6 Y" u
20 inches. He was breast-fed throughout the first year
" V/ t; D. m. ` ?. wof life and was still receiving breast milk along with
% ]; p1 N6 s* S8 Msolid food. He had no hospitalizations or surgery,
! m3 ]1 }; I( S( j% a8 u, v1 x* ]and his psychosocial and psychomotor development
9 }$ u5 K, }* A6 ~! ywas age appropriate.4 q5 T4 c/ b% [7 w
The family history was remarkable for the father,
3 D3 B( e9 `2 O$ N" ywho was diagnosed with hypothyroidism at age 16,2 [2 F) ^; {2 a' P3 s a$ q, L( z" o
which was treated with thyroxine. The father’s
% m, E1 N, I8 U( [* z4 yheight was 6 feet, and he went through a somewhat+ @# p \) Q; ^* W7 h
early puberty and had stopped growing by age 14.1 L8 F1 o; A4 P0 T# Z
The father denied taking any other medication. The
# h6 _) k! D* F' c' C9 T! dchild’s mother was in good health. Her menarche
1 t7 t6 G* l9 W) @' E1 Twas at 11 years of age, and her height was at 5 feet w4 |: `1 n/ T
5 inches. There was no other family history of pre-5 o, F3 j% c( C+ W: F+ ?# G# h
cocious sexual development in the first-degree rela-1 \5 H- t. f% k6 p8 A" W) |
tives. There were no siblings.5 x! m) N4 ~* T$ d3 f7 k
Physical Examination4 m, i) V' y: Y0 K* J; J
The physical examination revealed a very active,
5 A6 b5 D) P8 U& o+ K3 S2 v$ Dplayful, and healthy boy. The vital signs documented
. q+ P# x# J3 U% t& za blood pressure of 85/50 mm Hg, his length was/ I' D3 @; g4 h
90 cm (>97th percentile), and his weight was 14.4 kg2 e) g' J$ A, [# q7 C
(also >97th percentile). The observed yearly growth
% R! w, D8 k1 m# I4 Jvelocity was 30 cm (12 inches). The examination of
. ]( v/ N8 k3 Z% |, Jthe neck revealed no thyroid enlargement./ f' z: K4 q3 _* x, t: x5 \& g
The genitourinary examination was remarkable for
! [5 C0 z( T* L: _! k( aenlargement of the penis, with a stretched length of
: x O7 A k. s* {% ]/ v$ ?8 cm and a width of 2 cm. The glans penis was very well* h) R/ D5 X e5 v$ s
developed. The pubic hair was Tanner II, mostly around4 G+ z" S1 @4 k8 A, l6 K, d* q
540
: @) j- k' L. ?; vat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
- u$ l% s* z6 Q: n8 v( gthe base of the phallus and was dark and curled. The
% p5 J* s8 }( ?& utesticular volume was prepubertal at 2 mL each. q3 b8 U' S/ ^
The skin was moist and smooth and somewhat
0 W/ P- u R( m. Eoily. No axillary hair was noted. There were no
& Q( F( k2 p9 N! eabnormal skin pigmentations or café-au-lait spots.4 o1 V4 C* |" R4 g6 [/ ^
Neurologic evaluation showed deep tendon reflex 2+5 Y* S* V8 V2 E6 q& J
bilateral and symmetrical. There was no suggestion
' K+ D& C. m% o0 X/ v5 p- zof papilledema.9 u! A1 i* q% y/ L
Laboratory Evaluation
, q( x& W( L. _The bone age was consistent with 28 months by
% P) S% E) f5 U1 v, pusing the standard of Greulich and Pyle at a chrono-: W0 Z. s6 j$ }# Q! P6 I, C4 H
logic age of 16 months (advanced).5 Chromosomal
: F' C6 Z, s5 @karyotype was 46XY. The thyroid function test
; Y) K- o" S7 S$ `& G8 Qshowed a free T4 of 1.69 ng/dL, and thyroid stimu-" G7 M* I6 K H* r+ I. ]: R% Z$ |9 m
lating hormone level was 1.3 µIU/mL (both normal).! f' v! w; Q! O/ H' k7 K
The concentrations of serum electrolytes, blood
6 S0 }+ S- D9 H7 Curea nitrogen, creatinine, and calcium all were# |6 h+ a. H# E' ~6 K/ K1 f
within normal range for his age. The concentration# \4 C# i8 o) ^" _( ^
of serum 17-hydroxyprogesterone was 16 ng/dL
5 c. p1 n# V( r4 y2 Y: y(normal, 3 to 90 ng/dL), androstenedione was 20
3 h H, j' ^$ u q5 ], n2 w9 [ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-0 b) I! v3 ]9 {. _
terone was 38 ng/dL (normal, 50 to 760 ng/dL),
3 ^4 H2 f# s2 |- y4 i# y. M7 h* zdesoxycorticosterone was 4.3 ng/dL (normal, 7 to
& M: C+ _7 U# O+ g. d+ l2 K, N! O49ng/dL), 11-desoxycortisol (specific compound S)) g# q5 T% X2 o
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
3 ]! e/ L4 y, Y7 K8 @# N) ttisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total. h/ c8 y% |8 i2 Z0 l
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
6 ?: o+ | q1 k5 R0 c1 cand β-human chorionic gonadotropin was less than; ~6 J: P& j5 K- W% |
5 mIU/mL (normal <5 mIU/mL). Serum follicular
0 [( _. |1 v! `1 Pstimulating hormone and leuteinizing hormone
; p1 o2 i5 B+ W; M/ yconcentrations were less than 0.05 mIU/mL
e4 m$ q' {/ ]) {(prepubertal).
5 \; T9 N& T TThe parents were notified about the laboratory' D5 J/ Y1 X4 R5 Y, {
results and were informed that all of the tests were
5 P0 m* E& I0 f7 ]1 X% T/ Cnormal except the testosterone level was high. The
: ]5 A V* j! M# e; Nfollow-up visit was arranged within a few weeks to- W( o w" s! P6 Y3 H3 D- o, y
obtain testicular and abdominal sonograms; how-
: [3 g1 [4 S6 a5 ~6 S) O+ \ever, the family did not return for 4 months.' V% |0 U% p, ^6 e3 i3 D1 S3 s
Physical examination at this time revealed that the
% M$ }0 `/ t$ L+ P' j! M6 u* @child had grown 2.5 cm in 4 months and had gained2 ]9 }% h; c2 }# c" n; ^: Q7 G, Q
2 kg of weight. Physical examination remained
" H2 S$ L7 w8 Lunchanged. Surprisingly, the pubic hair almost com-( q. Z, K5 |3 y& g+ p' O: {
pletely disappeared except for a few vellous hairs at
" D8 P( G7 e {" `the base of the phallus. Testicular volume was still 23 ~% Q! b6 y, u! A) ?. ~% i7 U& Y
mL, and the size of the penis remained unchanged.4 g6 y; Z9 Y! `
The mother also said that the boy was no longer hav-
& L7 W, n1 |/ o2 P+ d; D6 w# l5 ling frequent erections.
2 [4 \, R0 R$ N4 o0 bBoth parents were again questioned about use of0 l! @/ o5 x& ~# ?) X2 |: \5 ^
any ointment/creams that they may have applied to7 n- _2 n3 I, f
the child’s skin. This time the father admitted the
% S6 U1 ?( T% l4 x" ]Topical Testosterone Exposure / Bhowmick et al 5410 ~/ D( x+ m7 Q2 S2 N9 E1 W
use of testosterone gel twice daily that he was apply-
- W/ c. [& r9 s3 k, m, f. h4 Ging over his own shoulders, chest, and back area for
: j9 [7 j* v8 r% k$ Aa year. The father also revealed he was embarrassed
# {6 Z5 {, Z% f8 B" F) {- hto disclose that he was using a testosterone gel pre-
2 S2 r, O' ^: z9 c7 E# ascribed by his family physician for decreased libido
V2 [: s0 G: P# P2 ~# u3 ssecondary to depression.
7 {$ {+ D2 ]4 ~The child slept in the same bed with parents.9 b g3 M2 L0 z5 n
The father would hug the baby and hold him on his
3 ?) ~( O) a$ I% N( hchest for a considerable period of time, causing sig-
# p; D& p0 z% \5 ~+ \: inificant bare skin contact between baby and father.
3 r( f0 E1 Q2 B8 e( HThe father also admitted that after the phone call,. x4 e) L! r% }: `/ W* w
when he learned the testosterone level in the baby
u! ?% [2 ^. N+ d o! @7 f, bwas high, he then read the product information9 K# n& X( v0 z7 [( f$ X8 A
packet and concluded that it was most likely the rea-$ Y' W% O9 T' @
son for the child’s virilization. At that time, they8 k/ @3 E) s4 c7 S
decided to put the baby in a separate bed, and the
+ A6 I3 J& u5 Qfather was not hugging him with bare skin and had% W* o& X5 \- r6 _8 d/ C+ D# R' O
been using protective clothing. A repeat testosterone' P8 `; Z3 m! O6 O
test was ordered, but the family did not go to the8 x8 m( T0 j$ H+ h8 o3 i
laboratory to obtain the test.! o- r d( W- p, y# u
Discussion. I8 v, \% j2 v1 d
Precocious puberty in boys is defined as secondary
1 I3 E6 L, _* M0 h: E! y" |& D+ @) wsexual development before 9 years of age.1,4
7 U! P0 u9 {1 ~% ]- lPrecocious puberty is termed as central (true) when
3 x; @( H* r# Y! ^! {/ n! l- H uit is caused by the premature activation of hypo-
6 D( `: i$ j/ G" B, ?: |! _thalamic pituitary gonadal axis. CPP is more com-
9 j' D/ R' ?( Dmon in girls than in boys.1,3 Most boys with CPP q* x7 l9 D1 I* z# C& T( _
may have a central nervous system lesion that is
0 n2 P" X" Z) ^# E9 Nresponsible for the early activation of the hypothal-
3 H4 V* i6 d& J% B& ], t7 Pamic pituitary gonadal axis.1-3 Thus, greater empha-6 b7 J# J& C" e! Z
sis has been given to neuroradiologic imaging in0 W5 F8 X2 o) M0 y0 o
boys with precocious puberty. In addition to viril-: J! ]- n* R% E+ ]* e
ization, the clinical hallmark of CPP is the symmet-
' s" C8 M+ Q% O$ qrical testicular growth secondary to stimulation by
$ [( E. \. C" U8 D! r; m( U) jgonadotropins.1,37 Q& q5 H0 V# o: M( I% Y
Gonadotropin-independent peripheral preco-
& M/ D# @2 P' m: g) c* B$ Y9 xcious puberty in boys also results from inappropriate
G8 R% {0 T0 e* H9 Kandrogenic stimulation from either endogenous or) R( D% v1 {& N. S& D4 @
exogenous sources, nonpituitary gonadotropin stim-% ?- W' H: X1 K0 d N( g
ulation, and rare activating mutations.3 Virilizing; T2 ]3 o7 C; P, K$ H
congenital adrenal hyperplasia producing excessive
4 ~. i5 @, F+ ]- k, X7 h" \adrenal androgens is a common cause of precocious
+ z: L0 E" n$ i( Hpuberty in boys.3,4
. O9 c7 k1 Y" {$ Y3 Z0 z9 XThe most common form of congenital adrenal
, C, v2 n: Q4 G2 c# S. yhyperplasia is the 21-hydroxylase enzyme deficiency.
. b7 V$ L, g/ e2 e0 V2 _/ zThe 11-β hydroxylase deficiency may also result in
! J% A' k. l% d8 Oexcessive adrenal androgen production, and rarely,
) p" I9 [% p' U. k* V1 Xan adrenal tumor may also cause adrenal androgen
$ E/ Z/ i6 t/ d Z6 L" s' @excess.1,3
( i9 o; }! u# n, Uat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
( _. n# Q& l! M! E542 Clinical Pediatrics / Vol. 46, No. 6, July 2007 k3 n0 ?4 ?. M
A unique entity of male-limited gonadotropin-: ?- }, u% G6 {- e
independent precocious puberty, which is also known
5 N2 w! u# G' v/ a7 Kas testotoxicosis, may cause precocious puberty at a
9 S D. P: k/ E9 hvery young age. The physical findings in these boys
, N& {8 |: r7 J3 `. ?- F' Owith this disorder are full pubertal development,
5 b* C9 W3 e7 fincluding bilateral testicular growth, similar to boys: j% n0 h" E, ]4 Z7 i
with CPP. The gonadotropin levels in this disorder% _% f8 c1 V& z
are suppressed to prepubertal levels and do not show! g9 F( S2 m4 t: H
pubertal response of gonadotropin after gonadotropin-
' c) I$ j! I: D1 ~8 j+ Areleasing hormone stimulation. This is a sex-linked
; I, ]" L! A4 Pautosomal dominant disorder that affects only
b$ g) E3 ]- p$ ?- ymales; therefore, other male members of the family+ c3 }% `% F7 D
may have similar precocious puberty.3
3 {' W! }- t1 p2 i; VIn our patient, physical examination was incon-: d8 K, N# v, T9 { e
sistent with true precocious puberty since his testi-
( j# x- }5 t) xcles were prepubertal in size. However, testotoxicosis
2 I$ K6 b# q1 g7 Z4 Pwas in the differential diagnosis because his father
% A2 q7 y3 a5 y' x; G7 Q* istarted puberty somewhat early, and occasionally,
4 h7 y, P! Z# |/ J8 Qtesticular enlargement is not that evident in the. X k, Q6 s$ E4 U- D p
beginning of this process.1 In the absence of a neg-# K/ u$ k# l' \: G9 o
ative initial history of androgen exposure, our
7 z2 u" s, O6 v/ f$ h( c( }0 abiggest concern was virilizing adrenal hyperplasia,
. o+ e$ y' {" _3 w) Ieither 21-hydroxylase deficiency or 11-β hydroxylase
) O* R% `+ a$ v7 p, ddeficiency. Those diagnoses were excluded by find-# e1 m' S4 o2 w( `/ i
ing the normal level of adrenal steroids.
8 a; v8 @; M8 u( t0 VThe diagnosis of exogenous androgens was strongly
! ^# S9 `: M2 j$ Z( `, Csuspected in a follow-up visit after 4 months because
; N4 Q$ L1 y) t# qthe physical examination revealed the complete disap-! k0 z3 r( u+ V+ ]( ?% I+ h% ^
pearance of pubic hair, normal growth velocity, and% G8 P4 y4 a6 a! s
decreased erections. The father admitted using a testos-" k( q9 q7 k" A7 ]7 P
terone gel, which he concealed at first visit. He was
! p1 i+ f% Y3 W* Q/ B! a Gusing it rather frequently, twice a day. The Physicians’
; q6 _, d/ h6 G2 f3 G+ WDesk Reference, or package insert of this product, gel or
. Z5 r( M# W8 d6 E$ scream, cautions about dermal testosterone transfer to
" S; h3 L0 Y& ? r+ A4 q& N# Junprotected females through direct skin exposure.6 J% ?+ f/ Y% D# U+ _$ a, M
Serum testosterone level was found to be 2 times the
' [* _* g# w3 P, M& I" H3 Cbaseline value in those females who were exposed to
3 H" R1 r1 ^9 R, Seven 15 minutes of direct skin contact with their male
' ^# M5 f( w* O `5 c3 opartners.6 However, when a shirt covered the applica-
$ g6 D% L: s) w: k) K2 ]+ P: wtion site, this testosterone transfer was prevented.
" Z5 @1 o. z( e2 H) U+ {' iOur patient’s testosterone level was 60 ng/mL,
' l2 h6 ?0 H) ~6 lwhich was clearly high. Some studies suggest that
4 y! G% D* E* s0 q9 Qdermal conversion of testosterone to dihydrotestos-
9 a/ U% ~( z/ U6 Wterone, which is a more potent metabolite, is more$ [! o' h2 q6 c
active in young children exposed to testosterone
4 F8 f7 H5 `, g, b4 ~exogenously7; however, we did not measure a dihy-
) X6 u/ ?0 \+ j- tdrotestosterone level in our patient. In addition to
6 M/ w& v/ B3 ` S Qvirilization, exposure to exogenous testosterone in/ q' ^# P; q& H1 f7 Y) S
children results in an increase in growth velocity and
- S* g) f! l% H" Yadvanced bone age, as seen in our patient.6 u) d: P% p4 ^4 W
The long-term effect of androgen exposure during
+ I# v% s0 C* Oearly childhood on pubertal development and final
% j: x9 }5 \# M2 M7 c1 ]# I3 radult height are not fully known and always remain9 E% H8 W/ _0 S* {: O3 C4 h! N
a concern. Children treated with short-term testos-
3 v1 E' y. ~( r+ U; y- @terone injection or topical androgen may exhibit some: s6 x3 E6 n P6 W5 t
acceleration of the skeletal maturation; however, after2 l& _# T0 _( W; P4 e# V) O+ L2 E3 E
cessation of treatment, the rate of bone maturation9 w* Y% g; f+ z& W& Z/ h* v
decelerates and gradually returns to normal.8,9
% X2 [0 m. I4 N+ c- p& qThere are conflicting reports and controversy
5 [3 s% b/ i9 J! {5 mover the effect of early androgen exposure on adult' c& a6 t1 M; L7 P% ^; C
penile length.10,11 Some reports suggest subnormal
( Q* m. g) l V6 q! e, H6 ~3 n s, jadult penile length, apparently because of downreg-
- a1 r* o1 R: O8 Lulation of androgen receptor number.10,12 However,
3 O2 L0 P* g8 r6 ~5 R4 jSutherland et al13 did not find a correlation between
$ z2 ^5 m- |; B7 J9 }childhood testosterone exposure and reduced adult0 X+ ~ |7 R. K- O5 _6 }( c# i
penile length in clinical studies.
' t( T) n% I+ }) z$ B% B% ]! LNonetheless, we do not believe our patient is! K1 S- V+ P0 \& \: P
going to experience any of the untoward effects from0 r) I. _9 T' s5 E! O. x
testosterone exposure as mentioned earlier because, }. }( T# K. X4 Y! M
the exposure was not for a prolonged period of time.0 ?, v; w7 M3 z+ v- l
Although the bone age was advanced at the time of
% \" Q. O+ s6 F: _8 B2 {# j# L& bdiagnosis, the child had a normal growth velocity at
! N3 b7 Z% F3 L8 }' vthe follow-up visit. It is hoped that his final adult
$ g% S; B; E& f1 R! l, U* \height will not be affected.* K6 V& F: X% E5 l% f* {
Although rarely reported, the widespread avail-6 l5 c; M6 N) f9 ^3 a4 i
ability of androgen products in our society may
* f& _ X/ F: {' o; i- Sindeed cause more virilization in male or female+ A, j; b) N+ a- Q/ a, y
children than one would realize. Exposure to andro-" Z L# `( ?: t, W8 U3 h8 p5 b
gen products must be considered and specific ques-4 {- ~0 t7 _, ^% ~1 ] s ^( y
tioning about the use of a testosterone product or
, N$ e& Z- A2 p) o- Rgel should be asked of the family members during
; |1 G6 \2 e. @ y6 e3 m( t# Y. Gthe evaluation of any children who present with vir-, U) y2 Q0 E1 l X' s
ilization or peripheral precocious puberty. The diag-
0 P6 }- ]2 c+ B# q$ I7 z+ ?; ~nosis can be established by just a few tests and by0 E$ z# L/ `, x0 o( ~1 u; V0 Q
appropriate history. The inability to obtain such a
6 B+ g* q9 I$ V- T8 O+ d, }history, or failure to ask the specific questions, may, e Q! l& \% F: o+ X5 y8 l; B
result in extensive, unnecessary, and expensive
) j+ j5 m! A" G0 W( D9 n; Xinvestigation. The primary care physician should be
9 b! B4 H) c2 Oaware of this fact, because most of these children# N( Q7 c% Q7 U. f. F
may initially present in their practice. The Physicians’
# Q% m' t$ ]; m; ~& H# L+ n% qDesk Reference and package insert should also put a) O7 k, l ]# x* N0 q
warning about the virilizing effect on a male or
% u% e N& v* Sfemale child who might come in contact with some-
( l( F# [8 v# e* tone using any of these products.
6 t! N. K2 ~6 Z g( Y& x L4 t ^References9 J9 w4 ]9 O F+ V0 Z/ h' C) X
1. Styne DM. The testes: disorder of sexual differentiation0 T$ w- J( v1 W2 U5 }1 s P
and puberty in the male. In: Sperling MA, ed. Pediatric. Y% U, t$ b. d
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;3 T s; A- h9 V9 y* B* C- ?
2002: 565-628.; F* n' i5 O+ F- r q' R8 ]
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
! q/ F$ a, G+ q( F; Hpuberty in children with tumours of the suprasellar pineal |
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