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Sexual Precocity in a 16-Month-Old
' O* E* u( k2 ]4 [# `; E7 l' MBoy Induced by Indirect Topical: O3 c# c3 Z( v
Exposure to Testosterone# j' a3 G5 Q) W, W$ @, O: G: u, |
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2& E% `6 h A3 Y" U5 a7 P
and Kenneth R. Rettig, MD1
9 n5 P5 X ~( ]9 g; \9 Z4 A# L8 W; VClinical Pediatrics! T% [, s" e6 @7 F5 m, i
Volume 46 Number 6( s$ b% Z6 i) O I
July 2007 540-5431 P) K' U5 _# t/ R$ \) z/ q0 Z- ~2 G: @
© 2007 Sage Publications' }: N8 @/ x0 C6 M8 c* r T
10.1177/00099228062966511 C9 w6 S% T5 D' W2 E8 g; w
http://clp.sagepub.com- s2 }; U/ W6 U4 R. k
hosted at& B. w- c' I, g, A+ J* g% S) o/ o
http://online.sagepub.com
( {/ n( [5 X, ~9 e8 TPrecocious puberty in boys, central or peripheral,. q/ ?# h& B! h" K O
is a significant concern for physicians. Central
1 C2 E7 Q3 Y" W6 ^precocious puberty (CPP), which is mediated
! @% j; N2 Q. c9 L" d# V ]through the hypothalamic pituitary gonadal axis, has2 d9 s- b: [( I. \1 ]3 M
a higher incidence of organic central nervous system
+ V C# L" c- ?& glesions in boys.1,2 Virilization in boys, as manifested
" f3 f2 D2 P, T b" [/ C: Oby enlargement of the penis, development of pubic5 N: M+ f2 a* z/ G/ e3 D) m F( M5 i
hair, and facial acne without enlargement of testi-2 E5 q2 {* r8 Y9 o& z; W
cles, suggests peripheral or pseudopuberty.1-3 We
5 ~& f, K% _" Treport a 16-month-old boy who presented with the
& d }& h1 D/ p4 t9 ~& B& U; senlargement of the phallus and pubic hair develop-
6 J$ T% j# H. W' dment without testicular enlargement, which was due J: x6 N7 ~. T. x6 \& c
to the unintentional exposure to androgen gel used by" r! N$ r- z2 F' G
the father. The family initially concealed this infor-& b. H. Q4 i& j2 z$ W
mation, resulting in an extensive work-up for this% G9 J( A% P4 c+ O- ^% M
child. Given the widespread and easy availability of
# p, t8 s9 V/ p) I; x# s& N' _% ctestosterone gel and cream, we believe this is proba-7 H# ~. R! u$ z
bly more common than the rare case report in the. B' v) t* y: B8 ~6 J
literature.42 ]. \/ m. E/ C
Patient Report6 X# X' I9 q2 b. ] g
A 16-month-old white child was referred to the
! ^* @* j0 ] I# V0 Tendocrine clinic by his pediatrician with the concern
' o$ }! d) `2 o. ?2 iof early sexual development. His mother noticed
k3 ?: o1 c6 T5 W& u$ Qlight colored pubic hair development when he was
# {! o8 Q6 q5 a- {2 v2 R3 EFrom the 1Division of Pediatric Endocrinology, 2University of
' T/ @; L2 L& `( o5 z- ^8 OSouth Alabama Medical Center, Mobile, Alabama.
' V. ^9 p2 U4 F& YAddress correspondence to: Samar K. Bhowmick, MD, FACE,
1 _, K' E+ r3 m# W: _Professor of Pediatrics, University of South Alabama, College of5 N, X! t6 l1 O. a" e- c
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;$ r. k d7 p2 M8 s
e-mail: [email protected].
) w& A" [9 A) i% b; z) D3 Qabout 6 to 7 months old, which progressively became7 p7 `5 _5 _+ ~) h- H
darker. She was also concerned about the enlarge-
& Y2 D3 o# I0 p, [: u, }. r. M+ g8 kment of his penis and frequent erections. The child
x: v# i& i. j: N7 j! X/ R% owas the product of a full-term normal delivery, with k) N9 m$ ^- j% O. r
a birth weight of 7 lb 14 oz, and birth length of
}* a# V+ W- w2 u8 F& k20 inches. He was breast-fed throughout the first year
( U8 O. {7 s3 B8 v7 a/ Cof life and was still receiving breast milk along with2 |5 p1 \/ p/ S' L
solid food. He had no hospitalizations or surgery,, O- q7 Q0 |. L' G8 v ^& d% n
and his psychosocial and psychomotor development w2 z6 R! o# W9 R
was age appropriate.
3 T8 g; _' B! XThe family history was remarkable for the father,: T' U% ?& f& c# l
who was diagnosed with hypothyroidism at age 16,5 D/ x2 `- u! c; O
which was treated with thyroxine. The father’s
T; `! |% }6 Iheight was 6 feet, and he went through a somewhat) z( c. o" W4 _0 E$ N' N5 D2 @
early puberty and had stopped growing by age 14.2 q! @; ?* ]8 t8 \ u
The father denied taking any other medication. The" d) j" Y, X% \+ N& n2 Q! T
child’s mother was in good health. Her menarche$ t8 s1 u! Y! z/ O: r3 ^. {7 o
was at 11 years of age, and her height was at 5 feet
9 j" p: j/ b6 Q$ b( N. [+ t5 inches. There was no other family history of pre-
* A* {/ J- C, t3 S# B& T! ~2 u0 |cocious sexual development in the first-degree rela-
9 d x+ @+ w) e- O% x) S4 Atives. There were no siblings.
9 W! {( G& S1 ~9 U9 w' dPhysical Examination
3 F' |: x# E/ _The physical examination revealed a very active, z8 m3 F: y* ]) j
playful, and healthy boy. The vital signs documented5 n; R$ C* Z" A& j9 l7 k* P5 L8 |) W
a blood pressure of 85/50 mm Hg, his length was
; c* g0 j9 L/ R90 cm (>97th percentile), and his weight was 14.4 kg
3 b/ V- T! Z7 p3 |: m& i; K(also >97th percentile). The observed yearly growth. D; _2 a8 |" G1 f) k8 n
velocity was 30 cm (12 inches). The examination of/ ~7 T' h; E6 B: f
the neck revealed no thyroid enlargement.2 S9 w4 S( g) @
The genitourinary examination was remarkable for+ \9 q9 Q5 q4 M0 ~ L6 Z9 \
enlargement of the penis, with a stretched length of
' r/ y" g. E) H' \, G8 cm and a width of 2 cm. The glans penis was very well! C" u& V* e) Q/ X r
developed. The pubic hair was Tanner II, mostly around
( I9 E2 s$ e+ u7 Y5400 c1 ^8 X" Q5 t( P% u: }) e
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
# {) z- x. g( V/ c8 tthe base of the phallus and was dark and curled. The
1 B6 m% W- {! C9 p( a0 {testicular volume was prepubertal at 2 mL each.
+ l+ s$ `% d/ W7 Q1 oThe skin was moist and smooth and somewhat7 |7 O" e6 y8 [. G( L1 C: n
oily. No axillary hair was noted. There were no( Y0 b6 M2 p& L, {" P6 n5 h; n& s0 L
abnormal skin pigmentations or café-au-lait spots. H# T; B0 _( k: N% s( Z0 P1 E
Neurologic evaluation showed deep tendon reflex 2+; k" r A k) `6 V$ o$ J0 ]. S
bilateral and symmetrical. There was no suggestion
/ P: B$ T3 R0 E/ i& vof papilledema.
, V. |* B+ T5 X' m; nLaboratory Evaluation
6 O: _! G& E1 H1 J9 V1 l5 WThe bone age was consistent with 28 months by$ ]7 B1 W! f5 C+ ?/ m/ ]
using the standard of Greulich and Pyle at a chrono-- ~# N( J4 `3 x( n+ ^# _1 f9 l
logic age of 16 months (advanced).5 Chromosomal9 w+ Y' c. Z: s1 U( G. \( |
karyotype was 46XY. The thyroid function test
1 E: l t L Z& k; K0 h8 r! s sshowed a free T4 of 1.69 ng/dL, and thyroid stimu-9 x8 _* {5 L# M; f. D! h/ j# R% Q$ C
lating hormone level was 1.3 µIU/mL (both normal).
3 x. ^& r& F1 k" |1 I: uThe concentrations of serum electrolytes, blood4 c: R' ?- t* g( @. p: A
urea nitrogen, creatinine, and calcium all were
2 G- \0 O b: M. U' ewithin normal range for his age. The concentration
' K/ {$ N+ Y$ `/ y; K9 Tof serum 17-hydroxyprogesterone was 16 ng/dL
4 V- ~, A4 ^ R$ W' t+ u(normal, 3 to 90 ng/dL), androstenedione was 20# G$ s# O5 y5 W& ]6 ^5 E
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-9 w/ _/ N! C0 |+ Q
terone was 38 ng/dL (normal, 50 to 760 ng/dL),
% v+ [. q) _( b$ X3 @* F! w( R. Vdesoxycorticosterone was 4.3 ng/dL (normal, 7 to
: h& n6 @& w. s49ng/dL), 11-desoxycortisol (specific compound S)
; T8 A/ i8 Q8 L, N( S% Wwas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
i1 J7 E3 O, M2 ytisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total# ~2 m L7 I9 _% G
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
; H3 Q! b1 C9 r* pand β-human chorionic gonadotropin was less than1 N& W/ \- i) p: p* i$ O2 H4 h, }
5 mIU/mL (normal <5 mIU/mL). Serum follicular ?/ f, C: w. K9 M3 I
stimulating hormone and leuteinizing hormone
+ u' _ Q" E( z" L2 r; Oconcentrations were less than 0.05 mIU/mL
/ P) t. V0 `5 i; k- }4 _0 o$ _8 D(prepubertal).
, f( T& X, e, f! _7 c& RThe parents were notified about the laboratory
z9 }" x6 @4 Presults and were informed that all of the tests were
% U7 g _! P- k! W p5 k. v' Enormal except the testosterone level was high. The
" P5 D0 W( a/ q/ d Yfollow-up visit was arranged within a few weeks to# h% u% s8 k7 A& @$ D/ _0 E/ o! p x4 s
obtain testicular and abdominal sonograms; how-
1 S. ~0 ]5 ~2 Y6 e u% H1 G8 Q0 Vever, the family did not return for 4 months.: }# q& |' r4 G4 M- q& z
Physical examination at this time revealed that the, X7 ^+ A. q% a/ A
child had grown 2.5 cm in 4 months and had gained% M% W, |( s/ n
2 kg of weight. Physical examination remained
9 N0 `7 h- _# y* ?( b0 e7 T: o! |unchanged. Surprisingly, the pubic hair almost com-
4 d6 l1 i5 u' N9 m& A2 Ipletely disappeared except for a few vellous hairs at
7 Q( R2 X( E1 H* a) ?the base of the phallus. Testicular volume was still 2& x* x% D# y3 K1 L
mL, and the size of the penis remained unchanged.. {) ?# p [" c) R9 g1 m
The mother also said that the boy was no longer hav-) w! c0 R* P6 m; [ V$ k# {8 W2 y
ing frequent erections.6 E! B. x# m+ ?6 z' z( ~& _6 Q
Both parents were again questioned about use of2 e9 r1 e7 X& Y- @
any ointment/creams that they may have applied to% X( \. G; E$ Z' r2 w3 C, S
the child’s skin. This time the father admitted the
6 Q9 x3 M) y" G# gTopical Testosterone Exposure / Bhowmick et al 541/ G+ z; j/ n! z; S: C) }
use of testosterone gel twice daily that he was apply-8 N+ ^ G, n$ ~: P a+ k. L, \
ing over his own shoulders, chest, and back area for
- v( L; N) O/ h6 f2 c0 Ja year. The father also revealed he was embarrassed# u$ \9 l& n- f+ X9 S* t7 e
to disclose that he was using a testosterone gel pre-# C& h3 Y# x5 w+ K( q
scribed by his family physician for decreased libido* S% A. L7 a( `: h4 ^* B) h) e
secondary to depression.
, c7 e2 [5 w3 f8 k5 RThe child slept in the same bed with parents.
4 M) _1 ]6 R, F/ PThe father would hug the baby and hold him on his- s0 k" o; o2 j* V
chest for a considerable period of time, causing sig-
1 c7 G( {8 O p+ Y& G. L2 enificant bare skin contact between baby and father.
2 p: U! u0 W; D2 R0 ~ A' nThe father also admitted that after the phone call,
4 d0 D; j% X# ewhen he learned the testosterone level in the baby7 v% j6 Q, m6 J7 n
was high, he then read the product information
2 _$ Q5 u8 Z/ Bpacket and concluded that it was most likely the rea-& r. U* V! A8 [" z
son for the child’s virilization. At that time, they+ N) [& Z7 e, J! S# B
decided to put the baby in a separate bed, and the
% E; W" c+ g1 A+ G% efather was not hugging him with bare skin and had5 G* L; z+ J% ?4 `
been using protective clothing. A repeat testosterone4 {9 x: m: z6 C. U
test was ordered, but the family did not go to the
4 ]: m8 Z. u" Vlaboratory to obtain the test.
! s2 o6 j, }) j1 ZDiscussion# I1 B2 L; x0 ]6 [$ ~6 L
Precocious puberty in boys is defined as secondary
$ T6 d0 _$ y% x- wsexual development before 9 years of age.1,43 `+ Y M) C; X( b
Precocious puberty is termed as central (true) when. E2 t, T a3 }
it is caused by the premature activation of hypo-
1 j- }$ B+ @2 G8 E+ gthalamic pituitary gonadal axis. CPP is more com-( }% m1 `( B- @& M# a& A: F
mon in girls than in boys.1,3 Most boys with CPP
; `$ E- U) T6 r3 m/ m/ y. Pmay have a central nervous system lesion that is& W) V8 L( F* M, y8 ~+ t8 z$ b( M
responsible for the early activation of the hypothal-
; n' H- w; p' o K% J! {amic pituitary gonadal axis.1-3 Thus, greater empha-
- a/ h# @' u, O' I# a0 hsis has been given to neuroradiologic imaging in, ^, J2 l7 Q; M, k9 k# Z* k
boys with precocious puberty. In addition to viril-& l3 i% Y1 x* ^- W6 ~
ization, the clinical hallmark of CPP is the symmet-& H9 }# {5 n0 n7 C6 T
rical testicular growth secondary to stimulation by
3 V& k6 t. d* U' j- p; Lgonadotropins.1,39 n- j& G' m7 V. i
Gonadotropin-independent peripheral preco-
4 ~& I4 q7 J* [ l! \cious puberty in boys also results from inappropriate# U% I. N& D" n: h! }
androgenic stimulation from either endogenous or" n. d! u# h# e
exogenous sources, nonpituitary gonadotropin stim-
6 z; q/ d! y) y4 [ulation, and rare activating mutations.3 Virilizing
" y2 @# E% t ucongenital adrenal hyperplasia producing excessive" D! m. W+ w1 v* e
adrenal androgens is a common cause of precocious+ R# h+ X. x( g* U/ z5 N$ J" r
puberty in boys.3,4
+ Z& s8 B; @4 S1 Z% W; |! v7 jThe most common form of congenital adrenal( | ~3 ~8 o3 s5 G
hyperplasia is the 21-hydroxylase enzyme deficiency.
F( J+ p3 z+ J0 T+ zThe 11-β hydroxylase deficiency may also result in' r0 {( F7 h) e+ M$ ~& U
excessive adrenal androgen production, and rarely,* x. C1 }+ ?8 E2 u! r0 _: Z7 \
an adrenal tumor may also cause adrenal androgen, M+ Z3 {" p: e$ C
excess.1,3% g+ v8 w" a3 W
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
5 i" V. s- }. ^. M5 [' ~$ W542 Clinical Pediatrics / Vol. 46, No. 6, July 20079 t# l5 q( ^4 \- Q6 S3 H4 X6 }
A unique entity of male-limited gonadotropin-4 I8 E' R8 I& l" \. X& c3 W
independent precocious puberty, which is also known- K% x- l# D- N l
as testotoxicosis, may cause precocious puberty at a5 d+ k+ s( {7 y$ S, U+ j( h8 t" [
very young age. The physical findings in these boys
8 x0 x( ^' M* `9 nwith this disorder are full pubertal development,3 E1 p+ i- s( }0 H- L2 v/ T9 A: G
including bilateral testicular growth, similar to boys1 P n t! p$ |, X' X, z r
with CPP. The gonadotropin levels in this disorder
" p) x' {8 D# v3 G4 ^2 R8 sare suppressed to prepubertal levels and do not show
* }3 N. G; V; {4 h, ^pubertal response of gonadotropin after gonadotropin-9 C9 |/ Q# e8 m! L" n
releasing hormone stimulation. This is a sex-linked
2 K. b/ J* I3 ^( p/ j( Uautosomal dominant disorder that affects only$ }; R% G' q: D+ Q& z8 u7 k
males; therefore, other male members of the family: F. x& C" t1 u3 l, t
may have similar precocious puberty.3
" T7 v1 @ P) X6 U' b/ YIn our patient, physical examination was incon-, \$ x) A ~) \: y. ]1 G( ]5 {1 V
sistent with true precocious puberty since his testi-
9 y$ z5 ]+ s b* O: S: S0 `4 scles were prepubertal in size. However, testotoxicosis
% F% ]: X$ O% R- U- wwas in the differential diagnosis because his father" i0 p/ B0 n. C, I8 l
started puberty somewhat early, and occasionally,
! G. V3 D2 r. Z/ q* v' Mtesticular enlargement is not that evident in the
( }, F6 z. m" {1 [beginning of this process.1 In the absence of a neg-2 n1 d. ^6 d% h$ o. W% u( j
ative initial history of androgen exposure, our
& ~# ^- r+ N3 \biggest concern was virilizing adrenal hyperplasia,
8 f& K3 m& D2 C7 B% P& Beither 21-hydroxylase deficiency or 11-β hydroxylase/ l4 d& F7 e4 h3 `7 N
deficiency. Those diagnoses were excluded by find-- J; k, g6 X8 H. l% [ I& |
ing the normal level of adrenal steroids.
3 o- l" Z) [$ ZThe diagnosis of exogenous androgens was strongly
# k1 j$ q6 e8 d4 p6 gsuspected in a follow-up visit after 4 months because
4 I7 Z, ]. @, W* D0 G- Z' T+ Sthe physical examination revealed the complete disap- |) F6 \3 {4 T+ J! j/ l
pearance of pubic hair, normal growth velocity, and3 _: ^; o; Q' k4 r$ L
decreased erections. The father admitted using a testos-4 @% ^+ d, E. x: H0 c1 t$ P/ p7 b
terone gel, which he concealed at first visit. He was# [& \6 X4 p. q. ?8 ^
using it rather frequently, twice a day. The Physicians’" B$ I8 B* ~: Q$ l3 D
Desk Reference, or package insert of this product, gel or/ D; y, X; V1 v. S& B. e
cream, cautions about dermal testosterone transfer to: @3 C7 }( G# e; f9 {, L
unprotected females through direct skin exposure.
" l; [5 Q( ?1 {5 `' v1 g! Z% zSerum testosterone level was found to be 2 times the' g. r* T. z x. Z
baseline value in those females who were exposed to5 _; K$ X$ L" k x7 W
even 15 minutes of direct skin contact with their male9 _! v3 Y9 W! V
partners.6 However, when a shirt covered the applica-
; g, {9 V5 Z5 m0 ltion site, this testosterone transfer was prevented.' E; L5 l: }9 w8 j9 v' k7 e
Our patient’s testosterone level was 60 ng/mL,
+ L3 a4 V1 O: C& z8 D; T, awhich was clearly high. Some studies suggest that2 o/ W- l. s% @
dermal conversion of testosterone to dihydrotestos-0 `8 A/ s6 }+ D6 \5 j( ~
terone, which is a more potent metabolite, is more
7 x' _3 S- x8 v9 ?4 H* a8 Zactive in young children exposed to testosterone- l- |8 p/ m3 C7 V& x1 r# e
exogenously7; however, we did not measure a dihy-
( t2 {0 c; N7 z2 M; ~- e3 o( x9 Odrotestosterone level in our patient. In addition to
0 i6 O* L1 }/ s- G e) c+ [virilization, exposure to exogenous testosterone in
3 n h' g0 V. K/ schildren results in an increase in growth velocity and# @! A* ^+ o+ e: o
advanced bone age, as seen in our patient.
% _( ?3 \" Z6 W' H9 PThe long-term effect of androgen exposure during/ [$ V* J/ B" P. P: s/ P
early childhood on pubertal development and final
; K$ \( C$ u% ^( g8 Q$ Qadult height are not fully known and always remain
5 r" r/ a8 Q4 f# _ a- K; q! Pa concern. Children treated with short-term testos-) E* |1 n- T% { X' o, P/ u
terone injection or topical androgen may exhibit some& y" |& }" {5 A( }' U3 r* R( S, a
acceleration of the skeletal maturation; however, after; D+ j* _: |8 M6 ~% U" s' H
cessation of treatment, the rate of bone maturation5 P, f, J2 x2 ?4 {/ Q9 J
decelerates and gradually returns to normal.8,94 m% @( q2 H( T$ k
There are conflicting reports and controversy
; ~6 \/ a9 L0 g6 B3 ?2 Wover the effect of early androgen exposure on adult
* m; j$ n% ^0 \' Zpenile length.10,11 Some reports suggest subnormal/ N: Q: ~, l, q/ o
adult penile length, apparently because of downreg-% Y2 R4 U: x% F4 f3 e. W7 n
ulation of androgen receptor number.10,12 However,& x. ?! t& ^/ T7 s7 \
Sutherland et al13 did not find a correlation between
$ d9 z, Z# q5 i, uchildhood testosterone exposure and reduced adult0 ^1 i! h3 O$ H0 L! i: _0 E' ]
penile length in clinical studies.
1 s8 C/ r p. G* T" p! U# uNonetheless, we do not believe our patient is
+ [0 d. b* P- F/ s" w t& _going to experience any of the untoward effects from3 _4 Z1 l4 w7 j* u* l# @
testosterone exposure as mentioned earlier because3 l4 f7 W4 H; M( [6 B: M, h/ k
the exposure was not for a prolonged period of time.- @' L" ? g" d" n" H: `
Although the bone age was advanced at the time of6 l$ D( |7 {* N4 w) o4 I
diagnosis, the child had a normal growth velocity at
: Z9 c: z" y% d0 E _' d+ rthe follow-up visit. It is hoped that his final adult
2 Q% Q. i8 _0 @8 m6 ^height will not be affected.
& j F/ F$ J; Z! WAlthough rarely reported, the widespread avail-
o* {' l4 c. oability of androgen products in our society may
, A: Y) ~ F9 ]1 x8 _, \8 P0 Mindeed cause more virilization in male or female% s& J' m7 z4 _$ g3 m! \- t* Q
children than one would realize. Exposure to andro-2 [$ p! q( ~2 r& z
gen products must be considered and specific ques-
0 r" K" f$ t! V- Y) {2 T( V' stioning about the use of a testosterone product or
7 I2 O" T$ s% G$ x2 }& Q: }1 G; _gel should be asked of the family members during
: n C$ T3 g1 @7 Fthe evaluation of any children who present with vir-
: c* M0 b% g- \: uilization or peripheral precocious puberty. The diag-3 v8 K& X+ ]& t/ i- C
nosis can be established by just a few tests and by
( ~) v p U! d1 `& Uappropriate history. The inability to obtain such a
# A0 h1 O( p- Bhistory, or failure to ask the specific questions, may2 J# c# K2 Z2 _
result in extensive, unnecessary, and expensive% e) U/ d) h: q( a
investigation. The primary care physician should be1 ~0 ~' X% q; c4 {, v* p+ M
aware of this fact, because most of these children
' j- X8 _5 P3 _# ]/ Mmay initially present in their practice. The Physicians’
, T" C' P3 z/ UDesk Reference and package insert should also put a# m# w# v2 u. ? K
warning about the virilizing effect on a male or9 e: _ C/ Z4 A$ @: K' s T
female child who might come in contact with some-
# @5 E0 o0 l" a7 s! b/ O0 R% K- Qone using any of these products.. Y5 l$ C6 P* Z( j, O2 e, {/ z k
References; o) @' | @3 `# _
1. Styne DM. The testes: disorder of sexual differentiation
1 y, `' \2 G/ f5 E9 x: H+ yand puberty in the male. In: Sperling MA, ed. Pediatric
* |; D% w" g+ ~% i& M( eEndocrinology. 2nd ed. Philadelphia, PA: WB Saunders;- t. b1 w# U( f! K+ {; B+ c2 ?( z
2002: 565-628.
5 l j* A2 O( Q0 V0 b& u2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
* ^! s1 }8 \! |+ Opuberty in children with tumours of the suprasellar pineal |
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