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Sexual Precocity in a 16-Month-Old1 Z/ ?2 o' m h& A7 N+ J9 [5 m
Boy Induced by Indirect Topical% L* D- v6 ]. A2 I9 L4 n! z r/ C
Exposure to Testosterone: B- A- q& p* \6 \% R2 F0 t
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,24 W# _5 G# Z* n# Y9 e0 u$ I. [
and Kenneth R. Rettig, MD1
! s- J- w9 u$ \: eClinical Pediatrics
8 Z8 |: s3 T2 _5 \Volume 46 Number 6% F% x$ O I+ b7 K' W, f$ u
July 2007 540-5435 g1 n4 I7 c+ n5 A
© 2007 Sage Publications0 k4 H8 r+ {; q- D/ t! I e
10.1177/0009922806296651
! i) M! I# \! ~http://clp.sagepub.com
: H: m h$ q# ?hosted at
* J2 @4 |/ t% G6 N2 H; l. S: nhttp://online.sagepub.com' E. Y: g% T: H" p
Precocious puberty in boys, central or peripheral,: }% h6 a5 H# {$ B; [
is a significant concern for physicians. Central% [: y3 ?9 u) d6 t
precocious puberty (CPP), which is mediated
* `' p4 O7 j, V# R% s. }* U8 |through the hypothalamic pituitary gonadal axis, has
$ w1 i( v( t% p4 B6 U7 Ca higher incidence of organic central nervous system- W# K- ~% C9 v2 k
lesions in boys.1,2 Virilization in boys, as manifested
- Y' p( o. S& ]by enlargement of the penis, development of pubic
$ x }- P4 h, Z' I# l; S( Ohair, and facial acne without enlargement of testi-. H/ c3 y6 L7 r c* R1 z# w
cles, suggests peripheral or pseudopuberty.1-3 We% n% N C& k5 R5 q' e
report a 16-month-old boy who presented with the
: i1 O: b3 @$ aenlargement of the phallus and pubic hair develop-
+ }( O( \2 s% V8 G4 ?6 h5 O$ s# Oment without testicular enlargement, which was due1 O. G( n2 H: o5 l
to the unintentional exposure to androgen gel used by
2 _4 ]& X# ?6 S7 {( jthe father. The family initially concealed this infor-! j0 L, o: K2 W! i
mation, resulting in an extensive work-up for this
4 y6 I" g7 r% a1 `6 W; Vchild. Given the widespread and easy availability of
: H A: L" s$ B+ U6 Xtestosterone gel and cream, we believe this is proba-% [ q: U ]0 z' e
bly more common than the rare case report in the
4 `2 l7 N- C! K) Z/ Y$ k- w0 mliterature.4
. Y9 n/ L; H4 g% {Patient Report
( r- O, B" C' Q7 Q+ e$ JA 16-month-old white child was referred to the. K3 }- t( {) T7 V: ]1 `0 T
endocrine clinic by his pediatrician with the concern
" u3 P7 \; k7 f& | V8 Q6 L+ Eof early sexual development. His mother noticed- I7 u7 m3 E. }6 k8 P
light colored pubic hair development when he was/ x$ L( H# i) h5 L& V: a. k& \
From the 1Division of Pediatric Endocrinology, 2University of
% I) v, e' e1 {( Z: u2 vSouth Alabama Medical Center, Mobile, Alabama.0 y' a$ Z+ b8 X+ ~
Address correspondence to: Samar K. Bhowmick, MD, FACE,
( p$ ]/ k2 k+ b- `6 T7 E" ?Professor of Pediatrics, University of South Alabama, College of/ j- G7 Y/ w, }& {9 y
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
! ?* P6 t( ]" x5 o3 n2 de-mail: [email protected].9 m' \6 \" L+ A
about 6 to 7 months old, which progressively became
% m! o8 J1 H/ @% A- Zdarker. She was also concerned about the enlarge- k A# t' D) H' Y& n$ ^) Y2 Y7 G
ment of his penis and frequent erections. The child% e% U0 Q4 U* A0 ~! i- y3 a; q; z& i
was the product of a full-term normal delivery, with
; z% S6 x) T2 ~9 Q6 Q/ ba birth weight of 7 lb 14 oz, and birth length of
- m& U9 r: T% f20 inches. He was breast-fed throughout the first year
& b8 a* b$ F- A8 m8 uof life and was still receiving breast milk along with! `1 V: U( S1 u8 q
solid food. He had no hospitalizations or surgery,+ f$ [0 N: `5 y) h$ L, Z' b! ?5 ~
and his psychosocial and psychomotor development
( k0 Y0 e( w& f% E- Z) lwas age appropriate.6 ]/ H' N; _+ y1 ~
The family history was remarkable for the father,
8 i w. y* `6 U/ s9 @who was diagnosed with hypothyroidism at age 16,% Y4 U1 H) Y+ F: s7 K/ u
which was treated with thyroxine. The father’s: F. w: w Z: r4 e) q
height was 6 feet, and he went through a somewhat) b/ ?- g, d3 ^2 n5 f& N
early puberty and had stopped growing by age 14.1 S5 J" l7 Y6 n/ j7 q% {; y0 y) r
The father denied taking any other medication. The
2 Q3 O. [+ J+ l, o. {+ U) Mchild’s mother was in good health. Her menarche
, l9 f( N# Z0 M1 H2 q. awas at 11 years of age, and her height was at 5 feet
' ?( i* e9 w% }5 inches. There was no other family history of pre-
7 r! L9 U; }4 x- ^cocious sexual development in the first-degree rela-
. L7 m' J1 q, A% Wtives. There were no siblings.
1 t' F% j8 B _8 t: I; s9 k4 zPhysical Examination
+ {& |8 V0 V0 S! [0 P' W) @+ RThe physical examination revealed a very active,
4 i* K# X7 i Qplayful, and healthy boy. The vital signs documented
1 m4 [ T' m" ^( w; ia blood pressure of 85/50 mm Hg, his length was, E U5 e6 y, e( l; F
90 cm (>97th percentile), and his weight was 14.4 kg0 R; V& O x3 f! u2 S6 w
(also >97th percentile). The observed yearly growth" }, A0 j4 U6 ]7 F$ i
velocity was 30 cm (12 inches). The examination of
: b7 `9 n( T) S' jthe neck revealed no thyroid enlargement.! {4 S! b4 X4 p& G5 v9 Y4 h! w
The genitourinary examination was remarkable for3 v* n6 l% }/ n7 E6 m7 L' X
enlargement of the penis, with a stretched length of
2 l0 w" R2 V6 Z7 p+ t" i9 H0 i( Q8 cm and a width of 2 cm. The glans penis was very well j) Y) T9 L9 K1 }4 M+ U
developed. The pubic hair was Tanner II, mostly around9 d; \" R5 k/ e& ^
540
4 K- J9 J: N+ a7 |; Rat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
7 D3 U; Y4 w% I* mthe base of the phallus and was dark and curled. The
$ C( o' M" ]. H! @& S% R: }testicular volume was prepubertal at 2 mL each.! [2 s+ I8 ~0 { F& S' o) f4 M
The skin was moist and smooth and somewhat
; S( z2 ]# R' ?$ v: q* e! foily. No axillary hair was noted. There were no* S1 _! c8 I t1 B0 j
abnormal skin pigmentations or café-au-lait spots.
9 E2 V! \/ Q) f2 I* I# C1 NNeurologic evaluation showed deep tendon reflex 2+1 ?6 _8 I% n+ W7 }4 B% b
bilateral and symmetrical. There was no suggestion7 H# [9 M- e: k/ W
of papilledema.( @2 ]2 l9 R; X
Laboratory Evaluation+ h7 D: R2 E$ v# j: v F! }
The bone age was consistent with 28 months by ]2 c0 M$ [8 l v2 k v3 `8 {
using the standard of Greulich and Pyle at a chrono-
3 B( u p( r* Qlogic age of 16 months (advanced).5 Chromosomal
' R* r* b! n% B2 b; W. H2 ~karyotype was 46XY. The thyroid function test1 } j" M$ h5 x5 A/ U
showed a free T4 of 1.69 ng/dL, and thyroid stimu-" \0 X; J5 ~! W1 G
lating hormone level was 1.3 µIU/mL (both normal).
4 W" K$ ]0 r+ C3 j) PThe concentrations of serum electrolytes, blood
7 |' E6 R# D( @5 Hurea nitrogen, creatinine, and calcium all were
! T% E9 W6 K! E$ ?9 s4 S. h" B6 uwithin normal range for his age. The concentration7 ?" q# ^3 {4 Q7 I- l
of serum 17-hydroxyprogesterone was 16 ng/dL# ?3 y P( L; K1 X* L. t, Z( z8 a
(normal, 3 to 90 ng/dL), androstenedione was 20
6 { W* d7 I b: Ong/dL (normal, 18 to 80 ng/dL), dehydroepiandros-$ |8 {& C: l8 [9 ^! V
terone was 38 ng/dL (normal, 50 to 760 ng/dL),
8 i/ J" E- d" C+ xdesoxycorticosterone was 4.3 ng/dL (normal, 7 to
% P% a# v8 }# V: i3 R49ng/dL), 11-desoxycortisol (specific compound S)
/ Z' O( I( F9 W1 [! wwas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
) d* |2 k% t( a) X( K( Ttisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total6 d) P0 E+ {( w! H) R
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
* G; c3 Z& }' O3 Mand β-human chorionic gonadotropin was less than0 x: ^' `: p; I1 |; E O2 f
5 mIU/mL (normal <5 mIU/mL). Serum follicular/ w s1 ^1 E, D# C$ L
stimulating hormone and leuteinizing hormone
$ [( a5 }& l. J3 w4 nconcentrations were less than 0.05 mIU/mL1 r" e# k% k# R) ]: ~
(prepubertal)." x0 g# q8 F$ a: }" c0 E
The parents were notified about the laboratory
& Y6 X) F' ^2 U# }8 a* v% fresults and were informed that all of the tests were( |0 j$ @) |) o/ m0 g" i2 K$ {& l
normal except the testosterone level was high. The
4 E6 U# i* \# y Z$ n1 `follow-up visit was arranged within a few weeks to- S( E9 D% f& r* R9 j
obtain testicular and abdominal sonograms; how-6 W q. x: l9 p; q* Y8 V# o8 `
ever, the family did not return for 4 months.1 x# C/ t" d# i7 f* F5 _
Physical examination at this time revealed that the2 ?7 w9 g( r, Y6 u% V/ G. F$ g5 g$ m
child had grown 2.5 cm in 4 months and had gained
+ b- @) w; \$ b; }2 kg of weight. Physical examination remained
! H! p% R0 Z/ ^9 i; J+ Tunchanged. Surprisingly, the pubic hair almost com-
- j' z, I G0 n6 b, J+ spletely disappeared except for a few vellous hairs at- m4 C4 I, @. B/ z7 X9 ?6 U
the base of the phallus. Testicular volume was still 2
4 K, s' u* n- K/ `. \mL, and the size of the penis remained unchanged.
- [( H+ F' M5 X0 p% f4 tThe mother also said that the boy was no longer hav-
- g) A' ^- w% v* Z' n' Xing frequent erections.
* K6 |. _+ W% C# UBoth parents were again questioned about use of3 z- x! s. H' ~( m
any ointment/creams that they may have applied to
, W+ X1 M' v; B1 W1 m* H2 \the child’s skin. This time the father admitted the
% T* b/ x. p( G! {$ rTopical Testosterone Exposure / Bhowmick et al 541( R3 p5 h0 s5 ?/ |! m/ N
use of testosterone gel twice daily that he was apply-5 B4 r4 [3 x! e1 K2 i2 j
ing over his own shoulders, chest, and back area for
: t: J, p3 H9 B0 La year. The father also revealed he was embarrassed
: i& o' a# c" q+ F. Y+ T* h$ ~to disclose that he was using a testosterone gel pre-
6 ^5 L& i* B k) Yscribed by his family physician for decreased libido
: k) [! d1 D9 s$ k2 ssecondary to depression.! u' K, S7 X2 ]+ i8 `/ t
The child slept in the same bed with parents.
- t2 t8 n+ N3 o6 K, o5 J$ sThe father would hug the baby and hold him on his9 s+ K3 a$ \ B% ~+ K
chest for a considerable period of time, causing sig-
, v, q$ g- G7 R& o- `nificant bare skin contact between baby and father.; i7 G1 I1 {4 |) E
The father also admitted that after the phone call,
7 u. g" V2 C: X4 `% ywhen he learned the testosterone level in the baby
3 Q; |; R- s8 a- s& fwas high, he then read the product information5 d9 b7 z8 F5 c# ]- s: Z1 v
packet and concluded that it was most likely the rea-
8 p% v d" s/ u( H7 `son for the child’s virilization. At that time, they' P- X/ @* K" [6 ?2 r
decided to put the baby in a separate bed, and the/ k0 g, q) K; U. I
father was not hugging him with bare skin and had, c+ w# [1 y+ |
been using protective clothing. A repeat testosterone
; B6 Q/ t: v9 itest was ordered, but the family did not go to the
- l: K6 R7 t* v% glaboratory to obtain the test.5 j9 u" K a0 |, ~) I
Discussion+ @# q3 b9 `$ d1 W
Precocious puberty in boys is defined as secondary
8 r8 ?# f1 X" a1 ksexual development before 9 years of age.1,4
6 n9 o. z! n6 XPrecocious puberty is termed as central (true) when: x/ U: q. S$ M( S+ V
it is caused by the premature activation of hypo-
% O: v0 W7 ]# e# g J; _- Wthalamic pituitary gonadal axis. CPP is more com-
8 Q' X( j; t5 P' kmon in girls than in boys.1,3 Most boys with CPP1 o' o6 S l$ B) ~
may have a central nervous system lesion that is5 x) l9 n' z7 J' O
responsible for the early activation of the hypothal-
$ J" I1 q' ^0 e# J( tamic pituitary gonadal axis.1-3 Thus, greater empha- Y+ R M; T+ C$ g1 v
sis has been given to neuroradiologic imaging in
8 d# j6 [0 d+ M/ s2 Lboys with precocious puberty. In addition to viril- Z. X7 N0 O+ {0 A" ?1 p, z+ }1 {/ a
ization, the clinical hallmark of CPP is the symmet-5 ^! V, f& q/ [
rical testicular growth secondary to stimulation by- B5 W% L8 z1 L- \! v0 z# ?& [
gonadotropins.1,3; U# {/ u: Q4 f. V
Gonadotropin-independent peripheral preco-
* L: {6 W- o7 Z" X: Q- Q% ycious puberty in boys also results from inappropriate. Y+ L [( w! [5 z. W
androgenic stimulation from either endogenous or9 X2 A$ y9 j p- u4 c
exogenous sources, nonpituitary gonadotropin stim-
6 ~, b" A# i2 N9 D- k# [ julation, and rare activating mutations.3 Virilizing+ h, W. }6 f% @1 N
congenital adrenal hyperplasia producing excessive
4 {: g! x: f1 n, iadrenal androgens is a common cause of precocious$ M! s3 a, j3 O9 A2 d; q! H2 ~, i2 ~
puberty in boys.3,4
3 H8 R9 j( |; o' }* B5 lThe most common form of congenital adrenal
# @+ A4 I* z" lhyperplasia is the 21-hydroxylase enzyme deficiency.* ~; J. i7 [$ n5 t5 I
The 11-β hydroxylase deficiency may also result in
+ v. P6 o9 H4 a, c) k6 O) Sexcessive adrenal androgen production, and rarely,
% P; r7 h' p' }' i, Gan adrenal tumor may also cause adrenal androgen! m' T7 U0 s2 H+ p4 Z
excess.1,32 z, g2 k) l ~* \2 k) M- j A
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from" L- \, O5 u5 M
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007" z& Y' M7 i' R; s1 z6 w
A unique entity of male-limited gonadotropin-0 f. F+ L. \8 w; ^( J X/ _
independent precocious puberty, which is also known
0 E, v4 E$ u% t' H% }: M4 Fas testotoxicosis, may cause precocious puberty at a
6 v5 C' r% h* C. Y! @/ A# R7 Svery young age. The physical findings in these boys! I' ?, `$ ]& q' ]. R
with this disorder are full pubertal development,! ~) Z+ a- a* O' Y! k* n' f
including bilateral testicular growth, similar to boys
| B- k x( B" i3 nwith CPP. The gonadotropin levels in this disorder
S2 P2 o9 h/ E' @3 m+ zare suppressed to prepubertal levels and do not show
% y$ p; B1 T( D9 Ypubertal response of gonadotropin after gonadotropin-
- E3 w% W( C4 i. {" p/ V& dreleasing hormone stimulation. This is a sex-linked( D+ p/ p2 X P6 \( x- _
autosomal dominant disorder that affects only6 u+ D& ^$ w8 o6 L2 O" }% X
males; therefore, other male members of the family
4 C7 D \. U X* g1 f$ {may have similar precocious puberty.3
* h* c& T7 V ?! [1 f }9 n& uIn our patient, physical examination was incon-, u- _7 \; R. [9 C4 X8 ^" e- F
sistent with true precocious puberty since his testi-
: i0 c) o9 J3 l p. }7 Rcles were prepubertal in size. However, testotoxicosis
( Z, o! R- {/ e' k6 @was in the differential diagnosis because his father; j, W: N7 W; {: D$ t4 Y
started puberty somewhat early, and occasionally,$ k, M7 z& j: ^* t9 @
testicular enlargement is not that evident in the
1 v" _* i; H! g7 g* X$ ibeginning of this process.1 In the absence of a neg-- N; I: Z# z+ a4 M3 y5 V
ative initial history of androgen exposure, our3 n' j+ |! x6 [0 B6 _
biggest concern was virilizing adrenal hyperplasia,# Z2 j+ \# U1 J, r
either 21-hydroxylase deficiency or 11-β hydroxylase
0 K* c: B( P. E, _deficiency. Those diagnoses were excluded by find-3 m+ c a: Q- I. L/ }6 I- V# d% c
ing the normal level of adrenal steroids.3 n3 t9 l/ S4 c# O- f
The diagnosis of exogenous androgens was strongly D: }0 ?- u* s$ u1 o. n6 o7 x
suspected in a follow-up visit after 4 months because5 E5 `2 t, U( d
the physical examination revealed the complete disap-
. Q' F- q; ~7 {2 e& N- Dpearance of pubic hair, normal growth velocity, and
6 v( c$ _# i; T: W) Ddecreased erections. The father admitted using a testos-1 M8 r4 ~9 P J& N4 E
terone gel, which he concealed at first visit. He was3 f" k+ F2 ?% U ^! D7 z8 x/ N, |
using it rather frequently, twice a day. The Physicians’1 I. b6 R- p8 D' {
Desk Reference, or package insert of this product, gel or6 o& b4 @8 I/ j, s
cream, cautions about dermal testosterone transfer to5 K% j8 m9 |# x
unprotected females through direct skin exposure.
, F8 s% z. O$ R9 s8 X/ ?! J! sSerum testosterone level was found to be 2 times the
' ~4 q, {, ]: V1 L" @+ U6 l* ^baseline value in those females who were exposed to, K& r8 s- V% q n, Z7 Z+ X u" a
even 15 minutes of direct skin contact with their male
$ {9 X5 k3 Z+ a6 z. g7 vpartners.6 However, when a shirt covered the applica-+ A( t" K+ A& l* b
tion site, this testosterone transfer was prevented.4 `. ~! E q' {( L
Our patient’s testosterone level was 60 ng/mL,9 [' y5 z& w" Z* X/ |
which was clearly high. Some studies suggest that
4 L9 K7 ?) \% }2 K4 qdermal conversion of testosterone to dihydrotestos-$ N- N0 @% n6 m7 f4 K# M
terone, which is a more potent metabolite, is more* J! F# A5 Q# I; ^1 L
active in young children exposed to testosterone% L; O* f$ I2 E; d6 [) S
exogenously7; however, we did not measure a dihy-
& n ^1 a% c0 W# Q( O) Edrotestosterone level in our patient. In addition to
' m! ]5 y- @9 u+ d4 s0 o& Tvirilization, exposure to exogenous testosterone in/ a# K) n$ Z* K& \" T8 I
children results in an increase in growth velocity and
0 I! N9 N9 y u f: I5 I2 U" Ladvanced bone age, as seen in our patient.
0 l! \3 V+ @& J: oThe long-term effect of androgen exposure during
+ g9 X" \" o: i' }3 t! Xearly childhood on pubertal development and final
; r7 ~% B; i) ?# B4 t8 gadult height are not fully known and always remain: @# y3 Z7 X: k9 s
a concern. Children treated with short-term testos-
( T5 c; Q: ~4 f0 J7 a# ?- @( }terone injection or topical androgen may exhibit some
; D3 |) o( x' N1 Y6 x) W6 }% Uacceleration of the skeletal maturation; however, after
; h, N2 K4 {8 K7 n/ A9 d/ A/ vcessation of treatment, the rate of bone maturation0 Q% V- U& M4 | k; W
decelerates and gradually returns to normal.8,9
; ^& M- z4 |" \" H) r MThere are conflicting reports and controversy* r( m4 d/ B1 n+ F$ L4 R
over the effect of early androgen exposure on adult8 t$ m( `+ s! k/ G2 i0 C% x
penile length.10,11 Some reports suggest subnormal
0 H( Y. D( l) jadult penile length, apparently because of downreg-
0 P. I' ~& V8 P; _2 S0 Nulation of androgen receptor number.10,12 However,# t- Y, {/ H4 p S
Sutherland et al13 did not find a correlation between# u, `+ G6 T, ^3 x8 o
childhood testosterone exposure and reduced adult1 D/ R& ]% z2 m' d8 F1 G7 s& T; K
penile length in clinical studies.
) |7 |7 h) W x- dNonetheless, we do not believe our patient is4 _( h& O! G% f9 {
going to experience any of the untoward effects from
- N- w1 `& @% X _testosterone exposure as mentioned earlier because7 n; e$ H- g$ D& m/ n7 @. ?
the exposure was not for a prolonged period of time.$ W, H% o: `& @2 Z/ N0 N9 ^+ ], J/ S
Although the bone age was advanced at the time of7 ^( {" e. t4 J: A) x3 ?
diagnosis, the child had a normal growth velocity at
8 }9 ^+ z2 ~3 D9 i0 \the follow-up visit. It is hoped that his final adult+ R. m6 Y& l3 ?" e0 f( [2 J
height will not be affected.
k+ [" D- N. f$ ]/ d2 uAlthough rarely reported, the widespread avail-
( V) A& k4 L) G. w& W8 fability of androgen products in our society may
/ ~+ J# H. m2 d# m+ N8 h8 m) Oindeed cause more virilization in male or female
, \5 m h- g' Y5 T& h3 e3 x: qchildren than one would realize. Exposure to andro-/ ?& R: I* e T+ z- z5 k, `6 H4 K
gen products must be considered and specific ques-7 R! s9 n6 M( c/ Z
tioning about the use of a testosterone product or! W& M/ Z8 j# j0 V
gel should be asked of the family members during. ~+ ^" E# t7 h9 A# l6 I
the evaluation of any children who present with vir-) v7 w8 V" H7 B7 k, P- Z
ilization or peripheral precocious puberty. The diag-
T! N+ Z' R" S/ S& q; F. ?nosis can be established by just a few tests and by
. A4 z/ i+ z2 q9 h" n+ Jappropriate history. The inability to obtain such a; b, w5 V3 g) z9 l; E
history, or failure to ask the specific questions, may
1 g* g4 @8 r4 Q6 q- A# V4 w2 Vresult in extensive, unnecessary, and expensive
/ A9 b3 Y3 e, |investigation. The primary care physician should be/ [2 _! c9 O' ~
aware of this fact, because most of these children9 [* h! {( g: {
may initially present in their practice. The Physicians’
( e% }0 R- g. m; ^Desk Reference and package insert should also put a
, c# C8 P7 G6 ^4 h# X7 ]/ C ewarning about the virilizing effect on a male or
% E' G, A4 E% `0 b1 U8 e/ efemale child who might come in contact with some-; w i/ C1 j2 h: w
one using any of these products.
! Z+ F0 t1 l# {2 T( }References, _+ `9 D& y2 E8 A
1. Styne DM. The testes: disorder of sexual differentiation
: g9 R+ n( \. a2 c# \and puberty in the male. In: Sperling MA, ed. Pediatric
' W4 _! b. _" p4 f/ R# REndocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
# |% U9 c: d% M. P2002: 565-628.
6 c2 w% a% F/ B4 ~$ L2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
- D4 Z8 t* C) Q6 r" r( lpuberty in children with tumours of the suprasellar pineal |
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