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Sexual Precocity in a 16-Month-Old
; E: q; P7 x9 h" q2 Y7 PBoy Induced by Indirect Topical
: U- p5 y4 f: n4 k; N9 tExposure to Testosterone4 ~. B: Z9 ]7 T! g
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2( E5 k# }- n9 W+ a. i l! \
and Kenneth R. Rettig, MD1* A `9 K9 a$ j N/ V
Clinical Pediatrics" Q/ x; M" I: P; n& }" J0 ~& K5 n
Volume 46 Number 6
} Q8 V, t- t% p: N5 f; h; N* OJuly 2007 540-543: U# w m" V3 j% |+ c* N- Y+ X2 w. n7 R
© 2007 Sage Publications6 V( R/ n! j" j
10.1177/00099228062966519 }' }& [& f/ v! Y+ V! z$ A
http://clp.sagepub.com
4 l; _2 k9 {& s3 t( e6 Y, U5 @hosted at( q" m9 h B8 G8 `
http://online.sagepub.com" T8 f* m* z% a6 k+ {) C8 h
Precocious puberty in boys, central or peripheral,
6 }. Z' T& B- Qis a significant concern for physicians. Central
1 L% s( a$ _; C2 z+ G/ x* Cprecocious puberty (CPP), which is mediated
7 z' c2 z5 U3 V" |. l, w4 E( Kthrough the hypothalamic pituitary gonadal axis, has+ b" Z$ h/ r( x
a higher incidence of organic central nervous system
' U& ]# S* p, O' Glesions in boys.1,2 Virilization in boys, as manifested
: t; z% n1 Y5 v; P, x* X1 E- [& Pby enlargement of the penis, development of pubic# L; ?, k, v# S& d
hair, and facial acne without enlargement of testi-
~8 h# }$ U" G1 lcles, suggests peripheral or pseudopuberty.1-3 We d( p* S1 L2 U) J" Q
report a 16-month-old boy who presented with the7 z" M$ e& A1 C& ?6 r
enlargement of the phallus and pubic hair develop-
. z" ]7 n- L; X' u" D1 c) ~2 g. Jment without testicular enlargement, which was due0 A* u5 l$ k, P/ H9 F+ g) W
to the unintentional exposure to androgen gel used by; i6 v F( H( ^* ]9 O
the father. The family initially concealed this infor-
u' _' H9 y: T' B: Fmation, resulting in an extensive work-up for this3 E8 y4 P7 S/ J$ @$ P7 U
child. Given the widespread and easy availability of
. W/ A" T# I3 @7 Vtestosterone gel and cream, we believe this is proba-
8 D9 Z* h( \+ L$ I% L6 obly more common than the rare case report in the# n M/ C9 e5 a6 _0 o7 I
literature.4
2 {; r1 P( o$ B7 ]: |8 D7 TPatient Report% y' H* i, }1 P- e6 I" g5 I% \
A 16-month-old white child was referred to the* l& P* y! _! N9 v
endocrine clinic by his pediatrician with the concern
: I. C3 N9 Z( m+ y% c4 Mof early sexual development. His mother noticed! |+ `8 K/ U ~* n d3 M" O }
light colored pubic hair development when he was. G) ]1 E( O, Z. [
From the 1Division of Pediatric Endocrinology, 2University of
, y. ^; Y7 d1 w0 zSouth Alabama Medical Center, Mobile, Alabama.
, P4 R3 }3 A3 }Address correspondence to: Samar K. Bhowmick, MD, FACE,
( v6 P0 X* G" w4 n, fProfessor of Pediatrics, University of South Alabama, College of
$ t# ^& J1 t8 L2 @2 G DMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
" [$ \' F, g- f" |e-mail: [email protected].
! D; t+ P0 _! N5 \1 H) ?1 j$ zabout 6 to 7 months old, which progressively became
B5 Z: I, q" ]- Udarker. She was also concerned about the enlarge-5 G# {7 h( A) ^
ment of his penis and frequent erections. The child4 s1 x: P( {* R& W* H* C
was the product of a full-term normal delivery, with' B j) n, n2 R% w9 u
a birth weight of 7 lb 14 oz, and birth length of
5 S2 R" E% i/ W, |7 J E$ r! H+ S20 inches. He was breast-fed throughout the first year& c' i. q5 @# k; K- D" S
of life and was still receiving breast milk along with
& j, I5 Z( F7 U$ E6 K, xsolid food. He had no hospitalizations or surgery,
" M" X% O) T+ @( ?* Iand his psychosocial and psychomotor development! N! B' P6 j" j/ }, F" O1 K0 M
was age appropriate. Y' Y v+ H+ L+ R+ x9 f
The family history was remarkable for the father,
$ h3 ~, f- ?) t% w# S8 [1 p- wwho was diagnosed with hypothyroidism at age 16,, \' N' n6 T5 L' Q3 p. w( i* E& ^
which was treated with thyroxine. The father’s/ E. e, P7 m8 n4 m6 e
height was 6 feet, and he went through a somewhat
; V$ A+ l. ~8 h- t2 K0 qearly puberty and had stopped growing by age 14.( S% P& \/ b) \7 a
The father denied taking any other medication. The4 X/ R/ k$ ~9 g% Q; D3 a' W
child’s mother was in good health. Her menarche
8 w7 V/ ^5 W; G3 twas at 11 years of age, and her height was at 5 feet+ J) K* D* x' Y+ u
5 inches. There was no other family history of pre-" b- E; e8 g& @9 g
cocious sexual development in the first-degree rela-3 `) A. k" w, l* k. V
tives. There were no siblings.; ^, i0 \" M+ K6 V( G/ [1 y
Physical Examination
! R" l- ~4 u4 [( q( nThe physical examination revealed a very active,' i, o# e$ N) ?7 }5 _$ v
playful, and healthy boy. The vital signs documented! g$ T9 q s% ], ?
a blood pressure of 85/50 mm Hg, his length was% Y9 x( E( N$ I! I% O. u
90 cm (>97th percentile), and his weight was 14.4 kg
% [6 I* g9 i$ n( Z( Q9 h" h(also >97th percentile). The observed yearly growth! k. k" A% ^+ ^- f, ?) X8 r
velocity was 30 cm (12 inches). The examination of, \" `8 U0 T; E" O9 |
the neck revealed no thyroid enlargement.
( M$ m" `# [2 V3 G$ W; yThe genitourinary examination was remarkable for/ H7 y* x4 X( Z9 c% ^% G3 d
enlargement of the penis, with a stretched length of
) v* D E$ J+ V4 K0 R; U8 cm and a width of 2 cm. The glans penis was very well* b, w2 s. ?( t# ?. \
developed. The pubic hair was Tanner II, mostly around
# [( P8 k' B, W0 |' i! S# ?, c( {+ U540
1 c6 {% G0 e8 u7 Iat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
6 K5 ` r$ V/ I5 d5 qthe base of the phallus and was dark and curled. The+ ~" [* G/ b' r" U( h
testicular volume was prepubertal at 2 mL each.8 [: d' z$ c) J7 Y x
The skin was moist and smooth and somewhat& r5 f& I; i2 a: n% B, | B2 u+ B
oily. No axillary hair was noted. There were no* O" v2 F% R; [( |0 P6 M
abnormal skin pigmentations or café-au-lait spots.
, [5 J' [9 y$ n! RNeurologic evaluation showed deep tendon reflex 2+" W# m9 X* H3 o& p
bilateral and symmetrical. There was no suggestion5 P) G5 K! M0 }+ W
of papilledema.
, V& g: f1 ]& X v; s) ZLaboratory Evaluation! `/ \! z- V' v! y w; w
The bone age was consistent with 28 months by
# J/ \, s" ?& U: Eusing the standard of Greulich and Pyle at a chrono-
! y! n/ m6 k* S: C4 |+ F; Nlogic age of 16 months (advanced).5 Chromosomal
( L9 k2 C& h( y: Xkaryotype was 46XY. The thyroid function test: k; G& t5 R c' O
showed a free T4 of 1.69 ng/dL, and thyroid stimu-
- z0 A8 k) }5 D/ |& i$ Nlating hormone level was 1.3 µIU/mL (both normal).. b& y8 n! Q$ a3 L7 |
The concentrations of serum electrolytes, blood: m- \1 ^5 i$ v& c6 s, L" Q
urea nitrogen, creatinine, and calcium all were5 O, a: Z7 e& m! B4 G) J" ]2 j
within normal range for his age. The concentration
% H$ y% X; M/ f# M8 wof serum 17-hydroxyprogesterone was 16 ng/dL1 i4 U2 B- f D, i% G5 G
(normal, 3 to 90 ng/dL), androstenedione was 20- A8 V" P' P6 {* Q" F) ]* c
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-0 J" U0 Z h: G
terone was 38 ng/dL (normal, 50 to 760 ng/dL),
3 Z" } z: a3 R* R2 ~desoxycorticosterone was 4.3 ng/dL (normal, 7 to5 R$ \; i1 L2 g/ O$ a: X
49ng/dL), 11-desoxycortisol (specific compound S)1 Z @) _0 x- f3 k
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
" A& y% C m$ o9 @tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
) Q2 c, v( G5 R* f3 p: gtestosterone was 60 ng/dL (normal <3 to 10 ng/dL),
' W$ T0 c4 T; jand β-human chorionic gonadotropin was less than
5 _8 o- M8 m$ e5 mIU/mL (normal <5 mIU/mL). Serum follicular- R# Y7 N' f* R* X+ ^. k
stimulating hormone and leuteinizing hormone0 `6 ]9 I9 I+ \3 S6 I
concentrations were less than 0.05 mIU/mL5 H$ L1 A5 M9 C7 E: t% Y
(prepubertal).( u) D7 y! R4 ]# q" X( e
The parents were notified about the laboratory
0 L- j: l1 w4 Wresults and were informed that all of the tests were
( W& y, m! y9 X5 Fnormal except the testosterone level was high. The
3 ]( o' t6 P% [( qfollow-up visit was arranged within a few weeks to
6 y; O" S8 Q3 @" f3 e) Q1 Wobtain testicular and abdominal sonograms; how-$ d j9 K% ~# K$ B |, G' g% k
ever, the family did not return for 4 months.
' L2 B5 V8 X8 |6 t, VPhysical examination at this time revealed that the
4 e( M5 u- X# T$ A* n; ochild had grown 2.5 cm in 4 months and had gained
) u" C6 I% E+ W5 {3 c4 x2 kg of weight. Physical examination remained
( h K: t- r) nunchanged. Surprisingly, the pubic hair almost com-% I7 T' ]% n4 y
pletely disappeared except for a few vellous hairs at# d: \) J# E+ f7 j* z3 H4 T5 t
the base of the phallus. Testicular volume was still 29 ]. P S( ~5 v7 Y1 H, G% {7 g0 L
mL, and the size of the penis remained unchanged.. c$ \/ a5 U5 A( h% ?- S$ I
The mother also said that the boy was no longer hav-2 e; X+ |7 L, R3 p/ R) o6 h, `+ `9 V
ing frequent erections.1 `. o$ u2 p s" d$ r3 w, l
Both parents were again questioned about use of0 u- m6 p4 ]/ e6 l( U! Y: w8 _6 o
any ointment/creams that they may have applied to
( S1 M' G+ Y4 j% s; d2 othe child’s skin. This time the father admitted the) X& k& `4 A/ |
Topical Testosterone Exposure / Bhowmick et al 541! L3 }8 @! E1 ]/ A- q4 T1 f0 g! i
use of testosterone gel twice daily that he was apply-4 [, Y" e* C( p' I
ing over his own shoulders, chest, and back area for
. ?" E# M1 \& o0 C, x9 e6 q' Ua year. The father also revealed he was embarrassed
A' q6 g# W% g! D+ Kto disclose that he was using a testosterone gel pre-% ~$ d! j: E) B& |6 e+ {
scribed by his family physician for decreased libido4 n# `: b" {+ S6 c
secondary to depression.) @2 n9 \3 G. [. e
The child slept in the same bed with parents.
) x$ w! `8 i) \3 m: A% @& ^The father would hug the baby and hold him on his/ g0 g$ w9 `3 v! ^( w
chest for a considerable period of time, causing sig-% `; v) R$ _) P5 p
nificant bare skin contact between baby and father.
# d3 K# P b% f8 C% qThe father also admitted that after the phone call,1 r* f. }2 `! Z% g% E& j
when he learned the testosterone level in the baby
- V! I& l" O$ P, j) [6 T8 ~was high, he then read the product information, F- D0 m+ L3 J
packet and concluded that it was most likely the rea-' F: _+ H$ w) h Y0 Q
son for the child’s virilization. At that time, they
! F! H7 T+ O [* B3 |6 V+ C/ Y7 Mdecided to put the baby in a separate bed, and the. Z6 v0 w: Z' l1 H
father was not hugging him with bare skin and had
* |5 s0 ]1 A, w; }( d( P) qbeen using protective clothing. A repeat testosterone
- Q8 K$ v$ r1 g! _$ D+ }, Wtest was ordered, but the family did not go to the
) `2 ~1 \3 U0 L7 Wlaboratory to obtain the test.* R. L5 c( y0 z% Q/ ?8 [2 W
Discussion
3 E% i) e, c. I; B. W$ ]) k4 aPrecocious puberty in boys is defined as secondary! t' X. O/ c. L# ~( G
sexual development before 9 years of age.1,4+ Z, h- m- M" Z8 p2 K! ?) v
Precocious puberty is termed as central (true) when
9 P7 P+ ^7 c. H: n5 k! q7 d, V" Ait is caused by the premature activation of hypo-$ u7 r8 ]6 {* W- Y# e& t' I! r, \2 [
thalamic pituitary gonadal axis. CPP is more com-: Q' a: `2 s) P" b9 ?
mon in girls than in boys.1,3 Most boys with CPP
# v6 `7 [/ `2 w; ^4 R, mmay have a central nervous system lesion that is& R( U- w; r) h3 ?2 }8 t
responsible for the early activation of the hypothal-
. f( p) \" V: k) K8 T; k, v; Famic pituitary gonadal axis.1-3 Thus, greater empha-
F" r4 ?) ]; s7 |/ [1 o2 L8 m/ zsis has been given to neuroradiologic imaging in
+ z2 z6 h: }3 \9 e" \) Dboys with precocious puberty. In addition to viril-
( M( B6 n! x$ T1 I: ?ization, the clinical hallmark of CPP is the symmet-
- z* C5 z- C5 Z+ E. p3 i% hrical testicular growth secondary to stimulation by
( \- F9 A% Z% g; K9 Q4 V$ ^gonadotropins.1,3
3 P% Z* z- A- z5 t$ x& pGonadotropin-independent peripheral preco-
' v8 Y" N9 C8 p/ _; Jcious puberty in boys also results from inappropriate
1 I6 M, x3 v2 x eandrogenic stimulation from either endogenous or5 ?* l& ~) B; p& T
exogenous sources, nonpituitary gonadotropin stim-% }" F# s/ B1 e; l
ulation, and rare activating mutations.3 Virilizing7 r: V5 T4 q. b! m3 o
congenital adrenal hyperplasia producing excessive
! D9 @8 s% `" p: Gadrenal androgens is a common cause of precocious x) J1 f$ |' k, ~5 x R
puberty in boys.3,4
% H+ h& D$ O$ ]9 {- AThe most common form of congenital adrenal
$ [( B) @* J T, e* rhyperplasia is the 21-hydroxylase enzyme deficiency.8 f" B2 k% C5 w G& m5 l# J" U9 O
The 11-β hydroxylase deficiency may also result in! O: Z, t o# N% s* U
excessive adrenal androgen production, and rarely,
2 F& V: A) f) C% C5 fan adrenal tumor may also cause adrenal androgen
/ d. Q5 H3 b: K# ^* f! lexcess.1,3
0 l& J6 \$ N) ]# u; f7 Pat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
+ U2 S' y& [7 V& {4 Q3 ]" R, t( _9 V542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
. j8 P! S2 B w4 v& B0 @A unique entity of male-limited gonadotropin-( H$ W; d1 i. \
independent precocious puberty, which is also known2 @9 D. Y$ g" }
as testotoxicosis, may cause precocious puberty at a
' i0 d4 D; @- | Z/ ivery young age. The physical findings in these boys1 J! ^$ l& B- _) R! @1 j5 c1 ~/ h
with this disorder are full pubertal development,. s" D6 H- w& H1 n* K& n8 Y
including bilateral testicular growth, similar to boys0 S, e' B; P6 v6 z# S4 n
with CPP. The gonadotropin levels in this disorder6 {7 P2 G) v+ M# C
are suppressed to prepubertal levels and do not show8 D# c4 h: }: q" H0 }1 U. \
pubertal response of gonadotropin after gonadotropin-
3 T1 n# q0 ` F/ B5 Breleasing hormone stimulation. This is a sex-linked6 T& h" t6 [# E. |" G6 U- R
autosomal dominant disorder that affects only/ R+ a+ B9 D2 l6 `3 _, Y( J/ d
males; therefore, other male members of the family
: V" v1 n1 }, z/ pmay have similar precocious puberty.3
* X8 _' T# E7 Q7 x( S+ b; EIn our patient, physical examination was incon-" H3 z+ ]+ h2 h7 I4 W/ H
sistent with true precocious puberty since his testi-
, i5 {6 L9 O+ D; O0 L& H/ B/ w& T# Qcles were prepubertal in size. However, testotoxicosis/ B" [# K! I' D" E+ j
was in the differential diagnosis because his father8 R, B, y {( O
started puberty somewhat early, and occasionally,
$ t0 O3 I t0 h2 a$ B! J2 H% Ftesticular enlargement is not that evident in the3 {0 t! D" F9 u! P, S* g% M
beginning of this process.1 In the absence of a neg-
- Q3 n- i, m$ n4 I* o4 T3 Kative initial history of androgen exposure, our
, q/ D( V9 S1 Vbiggest concern was virilizing adrenal hyperplasia,4 ]- D* `3 `0 [8 p& ?2 q
either 21-hydroxylase deficiency or 11-β hydroxylase
+ i! m; q; }% _! o, Cdeficiency. Those diagnoses were excluded by find-. n: ]8 n: F2 U: h. R' N" k! `" d" S
ing the normal level of adrenal steroids.
! G8 s" ?& V6 ~" I+ S' oThe diagnosis of exogenous androgens was strongly
& [+ v0 x1 A9 y% `7 Zsuspected in a follow-up visit after 4 months because
- j7 M0 g' X# v0 _# c jthe physical examination revealed the complete disap-! i6 {* }# N' f! e; }* V
pearance of pubic hair, normal growth velocity, and
2 e1 x0 B2 s# d* n. d+ ?: q3 xdecreased erections. The father admitted using a testos-: w5 C4 f7 u* }* C3 A x: e- S+ s7 H
terone gel, which he concealed at first visit. He was" q, L Z* p1 V. a
using it rather frequently, twice a day. The Physicians’6 H* X) C# }5 Z* g" ]
Desk Reference, or package insert of this product, gel or% t% Y+ M1 P# h
cream, cautions about dermal testosterone transfer to
; S* f# t3 c6 _+ g- `5 F# h. Punprotected females through direct skin exposure.( N6 `+ c# {; p. q J0 V
Serum testosterone level was found to be 2 times the! b9 y( u' L6 a' Y3 {( M
baseline value in those females who were exposed to. I( L1 E6 b! `4 [5 t* G
even 15 minutes of direct skin contact with their male
6 u- w- Z. P* V) ^ P' y2 z0 Spartners.6 However, when a shirt covered the applica-
+ h9 N# g, V. H5 c" L2 F; Y( ution site, this testosterone transfer was prevented.
2 g" w7 |7 s% p/ f* s9 T. d8 aOur patient’s testosterone level was 60 ng/mL,$ b6 a. }, p5 n5 t+ W
which was clearly high. Some studies suggest that
' B1 t1 `# Q9 J4 [7 z) Tdermal conversion of testosterone to dihydrotestos-+ B+ H" g" w6 z+ q
terone, which is a more potent metabolite, is more
; h/ f( q1 b4 g! Q3 {active in young children exposed to testosterone
! W2 F; f# Q% ]; z, D8 Mexogenously7; however, we did not measure a dihy-: d" J/ M `- L' ~* X1 f( a
drotestosterone level in our patient. In addition to
" m& G. h7 g# pvirilization, exposure to exogenous testosterone in
4 \, Z1 A& |) Q* e8 tchildren results in an increase in growth velocity and
" J- {, p# p u" }, T) m- |" L' N, L( sadvanced bone age, as seen in our patient.
B: f. D& o6 P: ~: LThe long-term effect of androgen exposure during
7 L6 r: c) U4 Y0 _early childhood on pubertal development and final% u+ g5 d5 L2 o+ y' n9 {
adult height are not fully known and always remain
7 p; h+ d3 f8 M$ X7 `8 V8 C' ya concern. Children treated with short-term testos-
( v7 Y& g9 c6 X7 n8 gterone injection or topical androgen may exhibit some& z# Z2 U/ R( T; J# ~
acceleration of the skeletal maturation; however, after R, `0 a: z4 e6 K/ z! r& e
cessation of treatment, the rate of bone maturation& @. c& i0 y, L6 x
decelerates and gradually returns to normal.8,9
, J+ f R {5 s6 z z4 C) S8 J! NThere are conflicting reports and controversy: t$ q2 n2 U/ h# A+ M5 y6 }5 h! |$ {
over the effect of early androgen exposure on adult
/ x. E6 A/ ]- {: spenile length.10,11 Some reports suggest subnormal
$ G% q5 J4 d( ^6 ?. i8 Eadult penile length, apparently because of downreg-. v/ j, v; h$ Y% g7 z j& P" Y
ulation of androgen receptor number.10,12 However,, q- k" i7 f X
Sutherland et al13 did not find a correlation between
9 I8 }$ v `6 m- nchildhood testosterone exposure and reduced adult
$ R& J4 Q8 T1 Jpenile length in clinical studies.
0 L4 f4 r' F. B# R8 Y9 K0 X4 GNonetheless, we do not believe our patient is: P: }0 m4 \2 c9 _
going to experience any of the untoward effects from* k. R o q; |; P
testosterone exposure as mentioned earlier because. D4 c3 T& T8 M( T& C7 h
the exposure was not for a prolonged period of time.; m- H- w' {8 p+ Q. W0 c4 Z
Although the bone age was advanced at the time of D9 n3 G+ V o2 f( U
diagnosis, the child had a normal growth velocity at" S* q& Z6 o0 a8 E
the follow-up visit. It is hoped that his final adult
, V5 F/ i$ r% O& f; q' s) Xheight will not be affected.
2 Q5 g7 a; `; L* h0 {Although rarely reported, the widespread avail-
9 T0 I H5 v3 E& j4 e! Mability of androgen products in our society may
+ _$ e; S7 k b1 d! Tindeed cause more virilization in male or female6 a) k# c! q- s
children than one would realize. Exposure to andro-
3 `# m4 Y: V) ]" Mgen products must be considered and specific ques-
7 n# y$ N% c' J; D3 L9 z/ qtioning about the use of a testosterone product or: Z) k- U# f' A5 F+ |$ \ ?
gel should be asked of the family members during8 t( k% P3 B: L5 N* q/ O( k) }
the evaluation of any children who present with vir-; U* B- [9 l7 O# g- a! O
ilization or peripheral precocious puberty. The diag-+ @% H: a9 k5 E! K- G7 u% @3 H: \
nosis can be established by just a few tests and by
5 j+ w; [7 y/ J" A/ l8 i" V9 Zappropriate history. The inability to obtain such a
6 [1 ^3 d1 T+ D0 Mhistory, or failure to ask the specific questions, may9 F; a& x( T9 K5 x
result in extensive, unnecessary, and expensive
( j0 P: w1 R/ p, jinvestigation. The primary care physician should be2 K; V7 D9 S. W
aware of this fact, because most of these children
$ y0 W# q6 e5 }6 c8 amay initially present in their practice. The Physicians’( N( M L( Y) C5 ?
Desk Reference and package insert should also put a
" \1 O3 U! g* k& S s8 J+ Iwarning about the virilizing effect on a male or
# m: b! A; X, u* ?# w5 Gfemale child who might come in contact with some-: ?3 j, y: w2 |9 e% O
one using any of these products.+ W6 }4 R) d: t) U/ a* e
References/ t4 h+ @; p, H' K% s( e \
1. Styne DM. The testes: disorder of sexual differentiation x, H1 @- {3 O
and puberty in the male. In: Sperling MA, ed. Pediatric0 }6 w: m" g2 |: y
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;; V2 \/ j) M, p* X, Y
2002: 565-628.( m/ e3 n1 V# G, H- r
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious+ y# C6 P, B1 ]7 f& V- N t
puberty in children with tumours of the suprasellar pineal |
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