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Sexual Precocity in a 16-Month-Old
; o! H" E* y1 XBoy Induced by Indirect Topical& }( U& r% B2 j! U
Exposure to Testosterone' J' \, {8 q' ?! ]/ h& L' X1 l
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,29 T# X. q s8 d$ ~) r
and Kenneth R. Rettig, MD1) a/ O G# x+ O
Clinical Pediatrics
* X3 }( p6 T/ s( P& yVolume 46 Number 6& k( E; _; I# ^ ]8 C. J2 _7 g
July 2007 540-543
3 _$ }6 G$ z; x3 e) i© 2007 Sage Publications
& C6 J$ J3 M8 ~( r! p6 ] |* e) T10.1177/0009922806296651
- s1 E$ Y2 u& _) @( K6 S' bhttp://clp.sagepub.com
- C: D& X K, l" i- Khosted at" b( r; F0 V: o( z
http://online.sagepub.com+ T* n4 Z/ t+ E: I+ ]0 {/ K* b
Precocious puberty in boys, central or peripheral,
# K, v: D3 o2 P1 n2 q+ @is a significant concern for physicians. Central3 d+ O# I5 v9 d1 _7 a- r9 b
precocious puberty (CPP), which is mediated7 J, E! ]/ B0 L1 e k" _
through the hypothalamic pituitary gonadal axis, has+ c; q; l& @$ i* o# k
a higher incidence of organic central nervous system
, V& {" M+ ?( s3 I# `lesions in boys.1,2 Virilization in boys, as manifested* o! I( z: E% Z7 k
by enlargement of the penis, development of pubic
& K+ X. n. \2 t; m( Phair, and facial acne without enlargement of testi-+ _9 ~; I1 T; W [% |) W
cles, suggests peripheral or pseudopuberty.1-3 We
' M- ]! @8 ?, o( f, qreport a 16-month-old boy who presented with the+ t& d$ a9 Y' e- Z% F' S, ^
enlargement of the phallus and pubic hair develop-
9 a+ I6 E* Y7 i- X" q. G, }ment without testicular enlargement, which was due( `# P, k; q6 [ j& a" d
to the unintentional exposure to androgen gel used by# G p2 V8 M9 o S" j' A* N
the father. The family initially concealed this infor-
! ]4 T# T$ m. e2 \( C$ Ymation, resulting in an extensive work-up for this$ \( C) b# t% I
child. Given the widespread and easy availability of% q/ ^9 P: w; o- z' }
testosterone gel and cream, we believe this is proba-$ u# F% p& I2 y- Q
bly more common than the rare case report in the
! Y4 L+ D+ h& i! l) o% w6 ? S+ _4 a' l! Jliterature.4% G7 S) g. _* b' A6 L2 w
Patient Report, I7 u: g( S. ]6 f
A 16-month-old white child was referred to the0 c, R% X! {% K( U z
endocrine clinic by his pediatrician with the concern3 m. v ~+ M7 R+ ?" S
of early sexual development. His mother noticed* B0 r r ]# N+ D* Y. _) _
light colored pubic hair development when he was+ V; B9 ~- X! J
From the 1Division of Pediatric Endocrinology, 2University of4 u% H4 ]2 F1 G [
South Alabama Medical Center, Mobile, Alabama.
+ m8 O* N* l* CAddress correspondence to: Samar K. Bhowmick, MD, FACE,& o3 W# ~* o l1 h- p$ r3 W
Professor of Pediatrics, University of South Alabama, College of0 N: }& k3 q, q/ \5 o9 F# m
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;8 P* O d8 W+ ^# E
e-mail: [email protected].
* Z" ^# [6 I: B( {! oabout 6 to 7 months old, which progressively became
. h" u- V$ u+ gdarker. She was also concerned about the enlarge-
% Q' p# Z6 G" s, Y7 H. J& e7 G- @ment of his penis and frequent erections. The child# r3 M5 N3 m/ b6 u/ a+ Q
was the product of a full-term normal delivery, with
x8 q* y9 r/ z( ea birth weight of 7 lb 14 oz, and birth length of
0 |$ C" ~0 f4 Z/ A$ k20 inches. He was breast-fed throughout the first year. t' U" L H: X0 O! K% N r
of life and was still receiving breast milk along with$ f- ]5 |7 t5 ~
solid food. He had no hospitalizations or surgery,( }$ ]% m- i3 X9 ]3 t$ W! z
and his psychosocial and psychomotor development& S5 Q9 D3 v3 U e( p* @
was age appropriate.
, T/ }5 q$ d' G1 W: r% JThe family history was remarkable for the father,# a6 V7 J. w6 u. _4 v
who was diagnosed with hypothyroidism at age 16,7 p& b" X, Z- Y- S! f% c& E* _. c# h
which was treated with thyroxine. The father’s
, m% ]$ O+ F; rheight was 6 feet, and he went through a somewhat+ \* x3 }) x6 a: b
early puberty and had stopped growing by age 14.( B4 J9 R g& @
The father denied taking any other medication. The: O3 q0 v5 g4 F7 G+ K
child’s mother was in good health. Her menarche# ~" j3 b0 _: z# g2 M
was at 11 years of age, and her height was at 5 feet" Y, H; E3 \6 Y0 T o( t
5 inches. There was no other family history of pre-6 J0 b- U; V# ^, z6 N+ [
cocious sexual development in the first-degree rela-+ p8 L, x9 ~! v' ]3 a
tives. There were no siblings.
$ w$ z* Y+ f- o3 `" g# HPhysical Examination
# K' Y7 h" w1 s1 c! E$ o4 rThe physical examination revealed a very active," U% D8 t, s& ]7 U6 z6 |
playful, and healthy boy. The vital signs documented
& |' d# f1 g, fa blood pressure of 85/50 mm Hg, his length was
3 [- F! L6 O( c, z90 cm (>97th percentile), and his weight was 14.4 kg/ u U, B- S+ D
(also >97th percentile). The observed yearly growth
2 M* D+ }8 k. n) i* F Bvelocity was 30 cm (12 inches). The examination of
1 ^5 r) U. a8 U0 Nthe neck revealed no thyroid enlargement.
2 M d' s/ _+ \* dThe genitourinary examination was remarkable for
_2 z, Z/ |" x, A7 Y6 |+ D; Penlargement of the penis, with a stretched length of0 u: E, {/ J8 Y
8 cm and a width of 2 cm. The glans penis was very well
+ |- }: s' O8 q) k. P X/ e$ ]/ ldeveloped. The pubic hair was Tanner II, mostly around$ N0 @6 H3 f5 v+ N6 o c: c
540
! s& `% \/ }4 f" C& tat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
7 m2 T; ?4 v; F' B$ h; y: f2 zthe base of the phallus and was dark and curled. The
3 g0 p( f+ ?0 e1 y7 r8 N# u9 Itesticular volume was prepubertal at 2 mL each.8 X- j: M9 r+ C' C6 D7 F
The skin was moist and smooth and somewhat
6 t) y; w& z6 U5 H+ [oily. No axillary hair was noted. There were no
6 h1 D+ t/ F8 x6 [ yabnormal skin pigmentations or café-au-lait spots.3 [! x" v& T; i, F7 S; E# J" _
Neurologic evaluation showed deep tendon reflex 2+
( r7 M0 E5 m6 A, y* A3 sbilateral and symmetrical. There was no suggestion1 B1 J1 B# [+ z4 T4 b
of papilledema.
( C& b. Q5 h8 Q& H9 _: h$ mLaboratory Evaluation
6 ^9 j/ [+ O- k" J& x# L% zThe bone age was consistent with 28 months by
# e. V" O( ~- tusing the standard of Greulich and Pyle at a chrono-
8 a o9 {3 x* a# Ulogic age of 16 months (advanced).5 Chromosomal) D- `) t8 t3 Y& [# V# q' S
karyotype was 46XY. The thyroid function test
# s+ v$ Z6 Q! u' ?" Z/ Ishowed a free T4 of 1.69 ng/dL, and thyroid stimu-3 X7 s3 t5 r7 D6 q/ m
lating hormone level was 1.3 µIU/mL (both normal).
N' X X: R. K ]6 g1 iThe concentrations of serum electrolytes, blood# t' S- Y. R- _
urea nitrogen, creatinine, and calcium all were1 P( x4 a5 K0 `6 T/ e% c
within normal range for his age. The concentration% t* F- Q" c/ T, x4 P$ R1 J' H1 x
of serum 17-hydroxyprogesterone was 16 ng/dL* K3 n1 @. r4 A: h6 F
(normal, 3 to 90 ng/dL), androstenedione was 20
# D6 \2 V, T$ k# Wng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
, B9 v: I" K0 n" ^" M# T% \terone was 38 ng/dL (normal, 50 to 760 ng/dL),: i/ y3 W) A0 [0 {1 Z5 ?9 G4 d' x
desoxycorticosterone was 4.3 ng/dL (normal, 7 to+ F0 v* d' W+ { o, t: G9 J" h( |
49ng/dL), 11-desoxycortisol (specific compound S): p, I+ w6 f& F
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
& Q( X/ q# w$ Rtisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total/ w8 F) N- _) ?* A
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
3 u2 T5 `5 A9 ?4 e$ J$ Sand β-human chorionic gonadotropin was less than
7 D4 g; `+ Q) [* o9 q5 mIU/mL (normal <5 mIU/mL). Serum follicular
0 q# N! _) T/ ^9 fstimulating hormone and leuteinizing hormone
% `. C% k( J9 R5 Z% K- ~& @) vconcentrations were less than 0.05 mIU/mL8 V2 W2 d6 A% c( A* I" m6 {
(prepubertal).
( ?" K, j8 ?* ~/ O, pThe parents were notified about the laboratory
( x7 Q7 S$ d4 Z. g3 X) h$ p! iresults and were informed that all of the tests were
6 j: [9 T, A; K% b$ g% Jnormal except the testosterone level was high. The
6 a; _# C1 q$ q$ `: Vfollow-up visit was arranged within a few weeks to& H, I; ]" o5 `( J# n" n: S
obtain testicular and abdominal sonograms; how-
5 F+ X! }0 M y; U( dever, the family did not return for 4 months.
: k/ ~/ H9 p( [* U3 h( u6 XPhysical examination at this time revealed that the
9 w* G( ]% s3 @7 B. Rchild had grown 2.5 cm in 4 months and had gained
8 a+ }1 ?6 D# Q' O, b1 H; J2 kg of weight. Physical examination remained
( G9 t5 e, `$ C5 h* m8 B+ _unchanged. Surprisingly, the pubic hair almost com-
3 q g" T6 X0 E$ F, H5 {% C' upletely disappeared except for a few vellous hairs at
6 \( L8 B( X2 }( v+ _the base of the phallus. Testicular volume was still 2# k, n, \- p8 C# E7 b; F+ g( R
mL, and the size of the penis remained unchanged.# y( J/ O; t( n |8 ~
The mother also said that the boy was no longer hav-
% X4 ]7 v0 q- R) m/ P' \ing frequent erections.6 ^8 K1 @7 D* I. n& w6 s
Both parents were again questioned about use of. P, p$ g! X% e: ?2 t8 b
any ointment/creams that they may have applied to4 I# K9 B7 r. _
the child’s skin. This time the father admitted the; M& y. o. s7 b! K0 O7 T9 i8 V
Topical Testosterone Exposure / Bhowmick et al 541) l1 L7 q% d8 V
use of testosterone gel twice daily that he was apply-9 {# E0 r% F5 Y; `8 `
ing over his own shoulders, chest, and back area for. }! W! q/ o; y( I7 ?1 H9 N$ e
a year. The father also revealed he was embarrassed2 _; \, E9 g' K$ k# U
to disclose that he was using a testosterone gel pre-6 n- u% [4 o; y; b6 u
scribed by his family physician for decreased libido
) r) Z2 a) R3 r+ J' Zsecondary to depression.
. W6 R% z: N4 t$ L. V$ AThe child slept in the same bed with parents.
+ r' L9 w: J2 ~+ ZThe father would hug the baby and hold him on his
) W/ U/ P2 X+ O+ P4 p! D% {1 qchest for a considerable period of time, causing sig-
( O. v7 _& P W/ `4 Pnificant bare skin contact between baby and father.9 z( l( x4 D& s
The father also admitted that after the phone call,
9 i' p4 i A/ V4 G( z/ k9 Wwhen he learned the testosterone level in the baby
& ]6 Y5 F8 c' l vwas high, he then read the product information1 _# g- i, ~' Z
packet and concluded that it was most likely the rea-
7 S7 D/ W( D8 f2 P; Xson for the child’s virilization. At that time, they2 h* P+ M! O8 S/ Z! o
decided to put the baby in a separate bed, and the" `% s4 ~, w$ C3 {+ v8 C
father was not hugging him with bare skin and had
# t/ g' X" l+ p+ [1 H+ xbeen using protective clothing. A repeat testosterone+ I W* `# b- y) T5 s
test was ordered, but the family did not go to the
! K+ Q5 {8 ^1 v& r4 Rlaboratory to obtain the test.+ N& F: W8 p' W; z7 R6 X. n
Discussion
6 { G. ]1 g \. O# K; a+ q; LPrecocious puberty in boys is defined as secondary: I; I# i* u. {6 q6 W
sexual development before 9 years of age.1,4
! o; T9 V$ Z8 B1 ]7 K4 t# \% cPrecocious puberty is termed as central (true) when# _# {2 F' n& J, m0 L7 e
it is caused by the premature activation of hypo-
2 t# p" W/ p0 k7 a, vthalamic pituitary gonadal axis. CPP is more com-2 a( U# {0 o) Y+ Z
mon in girls than in boys.1,3 Most boys with CPP
$ v8 a0 Z |8 S, U# Bmay have a central nervous system lesion that is
: O7 q' G+ s- ]responsible for the early activation of the hypothal-+ e U# q5 \2 j& g) e
amic pituitary gonadal axis.1-3 Thus, greater empha-
7 c; n z1 @8 P z6 jsis has been given to neuroradiologic imaging in$ g2 g" ]" D9 ?' p" `9 Z: J
boys with precocious puberty. In addition to viril-. @% l/ p0 c& a5 N8 j4 y- S
ization, the clinical hallmark of CPP is the symmet-! Z6 T9 R; z( Z' z% {, L
rical testicular growth secondary to stimulation by, Z! e- v+ D: B
gonadotropins.1,3
' X# d! V: N BGonadotropin-independent peripheral preco-6 S6 e' O' a' ?0 [: W
cious puberty in boys also results from inappropriate# q; N. @; g& u; Y
androgenic stimulation from either endogenous or, Q9 |4 f9 r# Q+ c+ E
exogenous sources, nonpituitary gonadotropin stim-% ]5 \! o4 D |* \! J2 ~! K
ulation, and rare activating mutations.3 Virilizing+ C; c; c& \" |: b0 B( N
congenital adrenal hyperplasia producing excessive* k' R- m3 j+ q/ A# t7 p' o
adrenal androgens is a common cause of precocious
4 v; F0 K! n9 Rpuberty in boys.3,4
+ m& m: N2 k! CThe most common form of congenital adrenal
; j% [1 Q& q( O n3 A* ?hyperplasia is the 21-hydroxylase enzyme deficiency.* i* }' \2 |& A9 ~' L3 l: T
The 11-β hydroxylase deficiency may also result in
# R5 s/ f4 H+ A# W i5 U zexcessive adrenal androgen production, and rarely,
' e6 c4 V5 l6 Van adrenal tumor may also cause adrenal androgen# U' G. L7 Z- n: Q+ o' V( D
excess.1,3
5 C D: F8 u: I% b+ D/ fat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from4 f9 y) d1 U- a& T3 i
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007: Y) a2 P- ~: R, s" C. V' k
A unique entity of male-limited gonadotropin- F3 p; E9 J5 |* G
independent precocious puberty, which is also known
5 x% T$ L) p1 P; k7 Has testotoxicosis, may cause precocious puberty at a; i. [, i: X# S: j% ^
very young age. The physical findings in these boys0 [- u0 R, N( B3 a8 f- G* t6 Y
with this disorder are full pubertal development,
* ~# {+ h6 f+ k; S* t6 n3 Y4 K- O! Vincluding bilateral testicular growth, similar to boys3 M8 _. Z1 j% u/ I" B' A1 \; n2 Q2 ?1 u
with CPP. The gonadotropin levels in this disorder: w: g% s1 P2 ~. V
are suppressed to prepubertal levels and do not show
0 r2 w, C4 o. R' z/ l6 k, npubertal response of gonadotropin after gonadotropin-3 n4 x. b% G9 f$ o0 R
releasing hormone stimulation. This is a sex-linked b; a+ ~9 y u
autosomal dominant disorder that affects only
3 E& e9 k5 A" c) e& o8 wmales; therefore, other male members of the family
9 K3 I: m6 D: J, Y; J4 [8 nmay have similar precocious puberty.3
" i& s- Z% ?: `In our patient, physical examination was incon-
$ J+ ]& ?4 e2 f' u# csistent with true precocious puberty since his testi-
, D8 \& u. ^ b; |; m- \cles were prepubertal in size. However, testotoxicosis* d$ c# W0 X2 S8 ]$ M$ ~
was in the differential diagnosis because his father3 H- D/ c, v$ F% k9 T( u
started puberty somewhat early, and occasionally,9 n) I0 |# e% ~
testicular enlargement is not that evident in the& {) j$ U3 \7 b# X k& ?
beginning of this process.1 In the absence of a neg-- n( D: n8 Y M E- X. I) S
ative initial history of androgen exposure, our8 ]5 L+ N* [+ ?& q! _* M+ S5 F3 a
biggest concern was virilizing adrenal hyperplasia,
: x1 h0 f) a' `' ieither 21-hydroxylase deficiency or 11-β hydroxylase
6 P% A. n7 q% ~& V; Ndeficiency. Those diagnoses were excluded by find-$ l% p# t# M$ Y
ing the normal level of adrenal steroids.1 Z" Z/ D; }) E! _8 o
The diagnosis of exogenous androgens was strongly, ~1 n) o" \2 J1 l+ u% V
suspected in a follow-up visit after 4 months because
" ~- P5 i% }$ othe physical examination revealed the complete disap-0 }, _' O. _7 l; f9 u8 e
pearance of pubic hair, normal growth velocity, and
; D9 z+ _+ M. [) r! w; udecreased erections. The father admitted using a testos-
* I* g( o8 Y, r9 a8 l: p i2 A: z, }* yterone gel, which he concealed at first visit. He was
; p$ L3 P! k6 z0 I% m6 F. Yusing it rather frequently, twice a day. The Physicians’: I* f" _7 s) M k# n$ f
Desk Reference, or package insert of this product, gel or! |/ c* n/ i: s' |. a/ j* ^
cream, cautions about dermal testosterone transfer to
% U+ n( V4 g& Q$ w& R, Yunprotected females through direct skin exposure.
% _6 l7 I4 w" G2 V! c8 }4 }2 n& FSerum testosterone level was found to be 2 times the- Y4 C" E1 F( E. {! c( {; \- G
baseline value in those females who were exposed to
# t: i- |" G! P' Xeven 15 minutes of direct skin contact with their male
* G" l3 I3 w; z$ Z8 m5 g8 X9 ?partners.6 However, when a shirt covered the applica-
4 B# A$ g9 a/ w2 G" F/ F3 stion site, this testosterone transfer was prevented.& c2 x& `5 X1 ]/ F2 D& f
Our patient’s testosterone level was 60 ng/mL,
4 m- B% d' k) U3 g$ Swhich was clearly high. Some studies suggest that s' ?. ~+ l F1 s; |4 j2 Y+ k
dermal conversion of testosterone to dihydrotestos-
- I g& j6 N2 d- lterone, which is a more potent metabolite, is more
# P$ z$ w; ] |1 ?; @ Uactive in young children exposed to testosterone
7 [& a" ` T$ a2 L" R) y/ texogenously7; however, we did not measure a dihy-+ Q4 L, X7 }; u& M4 z. h
drotestosterone level in our patient. In addition to; ]! k8 u x% z$ G* x$ d
virilization, exposure to exogenous testosterone in4 ]7 l6 [3 }" d3 A6 O
children results in an increase in growth velocity and1 u" B1 u& E) L7 M& H% ~5 K
advanced bone age, as seen in our patient.3 [5 ?, u4 j, R; P
The long-term effect of androgen exposure during0 Q( p9 L" ?% H2 {$ T0 k
early childhood on pubertal development and final( \/ K6 n; l) q1 |; \+ t$ D, J
adult height are not fully known and always remain$ }; W" j! Y5 K* Y9 X& P, k- a8 l
a concern. Children treated with short-term testos-
" i. f$ N3 b6 H5 _ m( _terone injection or topical androgen may exhibit some% q3 O" G% h6 m: \0 k
acceleration of the skeletal maturation; however, after
: v2 N+ e+ R4 J# fcessation of treatment, the rate of bone maturation& \5 A+ a2 a0 A6 Z1 S9 W1 J& O/ n8 a
decelerates and gradually returns to normal.8,9 A" x" k" g2 M E
There are conflicting reports and controversy
& Q! m+ T* E9 o& P- w# {4 qover the effect of early androgen exposure on adult: D3 I. m/ P$ E& [! ^, L, c# ~! B0 z
penile length.10,11 Some reports suggest subnormal
/ d* q9 G1 j, T' c# `adult penile length, apparently because of downreg-
' ~8 P- n" g `* l% u5 Wulation of androgen receptor number.10,12 However,. A$ @( i% b$ _. u+ d4 M
Sutherland et al13 did not find a correlation between
7 _8 l# P) ~9 h, Y7 @7 U vchildhood testosterone exposure and reduced adult* K N% z8 \5 P! ~& g( V
penile length in clinical studies.5 ] I/ v- u4 p( y/ L
Nonetheless, we do not believe our patient is
* T0 A4 h: z( w% y$ ~/ B5 Kgoing to experience any of the untoward effects from( z( ]4 H6 R' A6 Z" o P
testosterone exposure as mentioned earlier because4 ^6 i0 g% e% I" T4 n- o
the exposure was not for a prolonged period of time.- s" _: H; h0 _* @. p' H/ x3 L3 I& @
Although the bone age was advanced at the time of) V0 M) x9 P8 @6 w
diagnosis, the child had a normal growth velocity at) P! g1 g5 [+ A( o5 o" M/ D: V. B, Q1 r
the follow-up visit. It is hoped that his final adult
! z! C$ W( V0 M3 iheight will not be affected.
# l/ u* O6 r" PAlthough rarely reported, the widespread avail-5 d0 I; @ N) E$ h5 {
ability of androgen products in our society may
% @9 M4 M0 E4 O9 n3 B$ x5 bindeed cause more virilization in male or female
( z4 I# u* s' {4 @ _4 u$ O3 Uchildren than one would realize. Exposure to andro-
9 s: ~8 w& s% l. n* U4 `: \gen products must be considered and specific ques-
/ g w" z3 t% j1 ]3 Q) Stioning about the use of a testosterone product or
/ e( u# R' Z7 F: agel should be asked of the family members during
: M8 Q# W4 n9 ]2 ]3 O0 ?- E3 f. Vthe evaluation of any children who present with vir-
0 d3 R! o+ w) z8 k O: z, Gilization or peripheral precocious puberty. The diag-/ E3 A$ ~) G. W1 L/ n; w1 ^
nosis can be established by just a few tests and by
; V2 I, a5 b" Y$ Zappropriate history. The inability to obtain such a
1 \# Z8 I7 _& Q5 n0 @8 U. B8 khistory, or failure to ask the specific questions, may% ]$ l- l$ M- i
result in extensive, unnecessary, and expensive$ i: M8 n) b, D6 i6 J3 m/ s, v e0 v4 b
investigation. The primary care physician should be; l7 W( c1 L& q1 Y8 ~. d
aware of this fact, because most of these children
' k# r' E; q) c" {3 L' nmay initially present in their practice. The Physicians’; V4 s: Z& b- H1 B
Desk Reference and package insert should also put a
6 ?0 z4 @0 T: dwarning about the virilizing effect on a male or% Q! {% }( \4 p- F6 W4 Q8 C
female child who might come in contact with some-- [% C8 S- s* p( }
one using any of these products.
1 A' ?3 {3 Z( SReferences
) x% m7 N3 h- m1 C9 p/ y9 c% B1. Styne DM. The testes: disorder of sexual differentiation
! h7 F& \2 r; @7 sand puberty in the male. In: Sperling MA, ed. Pediatric; v- x; r2 o$ s$ u# s6 }$ d, g7 {
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;% [9 P. Z$ F% h5 p& Y% y- o
2002: 565-628.* Y! I. t8 R5 g$ r+ y$ C
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious3 G0 F7 L) z( I: u( j7 x# [( j
puberty in children with tumours of the suprasellar pineal |
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