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Sexual Precocity in a 16-Month-Old
' [6 r( W* [$ O/ Y# mBoy Induced by Indirect Topical
# g5 w& I5 j& u. I$ d4 n5 hExposure to Testosterone
3 j$ |/ r; P% R; _/ \Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
5 J: o) b' t/ `7 Z' U0 L# C$ n2 eand Kenneth R. Rettig, MD1' Y3 e5 B5 ^" I% T
Clinical Pediatrics/ P. r" Y3 n% e/ X% ^" W# x
Volume 46 Number 6- R: y9 ?) w8 f4 X$ [
July 2007 540-5436 Z8 O) K+ c; i% ?
© 2007 Sage Publications
% i4 I$ z: m8 o; K" Q9 Q! W2 Q$ k10.1177/0009922806296651$ O! ]! f% t" }, e
http://clp.sagepub.com) p2 }- c0 J2 Q& o
hosted at% {7 Z: b) V/ w+ Z2 ~* J5 \0 U
http://online.sagepub.com
4 \8 s8 E' t8 p7 A1 i/ T& PPrecocious puberty in boys, central or peripheral,$ W7 {7 R, x/ t4 V$ W% {6 Y
is a significant concern for physicians. Central
' r7 T% ^# P2 P6 [0 a* q3 Oprecocious puberty (CPP), which is mediated
/ k! Q! \' {- l2 ?4 ythrough the hypothalamic pituitary gonadal axis, has
" k( Z; W* v% M, y- P+ C+ ea higher incidence of organic central nervous system
) N: q+ j3 X+ Rlesions in boys.1,2 Virilization in boys, as manifested9 d! K1 u6 ?+ x8 S
by enlargement of the penis, development of pubic
+ L% x, c; r/ @1 M- T! thair, and facial acne without enlargement of testi-
& [8 D$ [. R* D) Lcles, suggests peripheral or pseudopuberty.1-3 We: F( B( X N5 a- W K5 z, [
report a 16-month-old boy who presented with the8 l$ ]9 S1 ?* y" m+ [" l% n
enlargement of the phallus and pubic hair develop-5 T' Y! X: U9 Q7 d) d
ment without testicular enlargement, which was due
5 x. R/ F9 F/ Y- G( s$ W4 Tto the unintentional exposure to androgen gel used by$ w S) B* y* \4 {& T9 e
the father. The family initially concealed this infor-1 y w# ~; X$ @1 Y! x q( y
mation, resulting in an extensive work-up for this
6 y! e0 F ~6 O f; z1 r0 vchild. Given the widespread and easy availability of
5 j+ S" [9 r& Z0 Otestosterone gel and cream, we believe this is proba-3 T5 v5 E T1 I" a$ s
bly more common than the rare case report in the" M* ?7 O" h5 }: j% S7 @: \8 [
literature.40 ^% B' z; v/ e, p
Patient Report
, k5 v- q6 E5 O) DA 16-month-old white child was referred to the
1 {4 s9 c, ~" x( G4 \endocrine clinic by his pediatrician with the concern9 L# H$ P8 I7 V" r* s3 `! j
of early sexual development. His mother noticed# ?* ]5 L$ r) w' B
light colored pubic hair development when he was& ^; J& u2 P6 j, V( r0 A
From the 1Division of Pediatric Endocrinology, 2University of
5 g% A7 u! |1 s; y9 JSouth Alabama Medical Center, Mobile, Alabama.
8 F" b: T" I: r- C) w0 x/ sAddress correspondence to: Samar K. Bhowmick, MD, FACE,9 g4 a6 p, V4 y9 W1 L6 N
Professor of Pediatrics, University of South Alabama, College of5 c7 b# i. }. w
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;/ t7 s! D3 ~+ R) F- |9 e% j, T
e-mail: [email protected].2 A1 a1 b$ u6 a8 B
about 6 to 7 months old, which progressively became& o' ]3 o9 }; B* E4 E+ a4 J- C
darker. She was also concerned about the enlarge-% c* Y( f: I1 T
ment of his penis and frequent erections. The child
3 X8 t+ J# O+ q9 k5 Pwas the product of a full-term normal delivery, with. _2 ]& M0 [3 ?7 k' A
a birth weight of 7 lb 14 oz, and birth length of
. V- f3 A. h- F- l$ G20 inches. He was breast-fed throughout the first year
( V, c$ e' |' L3 i3 _) a( X0 Hof life and was still receiving breast milk along with
v6 G6 P" g0 _$ Ysolid food. He had no hospitalizations or surgery,
" W: P" M: K/ G, B+ ^1 Fand his psychosocial and psychomotor development
|. m2 O$ }& r6 L% S3 Fwas age appropriate.1 A! ]# o s9 c* }7 n. i/ B
The family history was remarkable for the father,; W2 C& S( g1 \4 a( r: h/ H
who was diagnosed with hypothyroidism at age 16,
- P3 b) t6 [8 y1 E. h+ L! M! ]$ w Owhich was treated with thyroxine. The father’s4 B* p/ T) Z. `3 U, q' r- B! J4 u
height was 6 feet, and he went through a somewhat
; p, w% M$ D3 u9 d( eearly puberty and had stopped growing by age 14.9 B! ?% E' o2 F2 v
The father denied taking any other medication. The3 |+ v; k9 Q; E$ b/ u( v1 d
child’s mother was in good health. Her menarche
5 f, A& }! }. f+ w2 E6 {was at 11 years of age, and her height was at 5 feet$ m z: U7 r" R) m0 x
5 inches. There was no other family history of pre-
5 i4 X3 O) N; t# p7 d0 scocious sexual development in the first-degree rela-
$ |9 ~0 P; ~, qtives. There were no siblings.
! z- W7 v7 e3 MPhysical Examination" z+ @" w! `% J/ U2 Q6 n
The physical examination revealed a very active,3 \6 e: f# O c/ n$ s
playful, and healthy boy. The vital signs documented7 D! m4 W9 M; A/ Q* h: A1 O
a blood pressure of 85/50 mm Hg, his length was
/ E: D; }, Z. n90 cm (>97th percentile), and his weight was 14.4 kg
* U6 r* E+ P1 I$ |* N4 h( _(also >97th percentile). The observed yearly growth
, r+ @, h( I; Y6 C8 Tvelocity was 30 cm (12 inches). The examination of5 q- M9 Y2 B3 u8 O2 \' \# X4 Q
the neck revealed no thyroid enlargement.9 Q* N* d$ E$ ^
The genitourinary examination was remarkable for! L! Z9 X2 ^8 s* t1 M
enlargement of the penis, with a stretched length of- Y1 |9 a9 v' s
8 cm and a width of 2 cm. The glans penis was very well' M1 C/ r2 n$ U ?5 m4 S
developed. The pubic hair was Tanner II, mostly around; G) d5 _- i: a' u% j
540
7 p/ t# r" d4 p+ H3 G5 T& p3 iat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
& |3 c$ v: L6 B0 F; O/ J) D0 Tthe base of the phallus and was dark and curled. The) e$ Z% x0 f+ U; K0 p
testicular volume was prepubertal at 2 mL each.
1 I3 H7 T- z: g. g( t6 XThe skin was moist and smooth and somewhat
/ @6 i0 G8 p$ V, u3 J4 _' Yoily. No axillary hair was noted. There were no
6 B9 r' {, q/ T; {! N2 Cabnormal skin pigmentations or café-au-lait spots.( k7 r: B% R% M& |
Neurologic evaluation showed deep tendon reflex 2+ Q& a2 b! ?4 k$ f8 E% `
bilateral and symmetrical. There was no suggestion
4 A; Q7 h* {$ L7 `( z3 D. tof papilledema.
) \! a4 U) i1 ? w% n9 o4 ]6 PLaboratory Evaluation l: O% k2 y0 ^+ {
The bone age was consistent with 28 months by
, m, W- v1 q2 v' Wusing the standard of Greulich and Pyle at a chrono-( l4 i1 Y( \% m1 _9 f- [* o8 A7 L0 m
logic age of 16 months (advanced).5 Chromosomal
& @- p7 X3 l) L2 Gkaryotype was 46XY. The thyroid function test
2 P4 O# b' }, ~. ~/ s5 Ushowed a free T4 of 1.69 ng/dL, and thyroid stimu-' W/ s( y# L& c: b" ^! \" d
lating hormone level was 1.3 µIU/mL (both normal).1 y% C- V: |. A5 g- ~
The concentrations of serum electrolytes, blood" ^3 k- U4 l) X9 [" s
urea nitrogen, creatinine, and calcium all were
( I: x& ?6 A( `8 D& ~within normal range for his age. The concentration' U4 z9 X) ?9 P
of serum 17-hydroxyprogesterone was 16 ng/dL' L' Y$ @# `( N6 f, k* I
(normal, 3 to 90 ng/dL), androstenedione was 205 m7 R! i! ~4 l7 \% c6 w) d
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
( ?5 @' q7 n- A, u, cterone was 38 ng/dL (normal, 50 to 760 ng/dL),
- _1 X9 @, |4 O) [$ Wdesoxycorticosterone was 4.3 ng/dL (normal, 7 to
/ p, k* B9 P" p# j49ng/dL), 11-desoxycortisol (specific compound S)
1 \ N. E) `) E. F- A6 c+ v4 l; Lwas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
! C- m9 \1 U/ T. gtisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total, g0 Z& `, R2 P, N d
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),7 r2 M# L9 Z3 f: V a
and β-human chorionic gonadotropin was less than; d& ~1 B& y+ U* d, E
5 mIU/mL (normal <5 mIU/mL). Serum follicular
, e) }8 c* ]8 a3 \3 z$ Pstimulating hormone and leuteinizing hormone
% T! N& O/ X' F: Sconcentrations were less than 0.05 mIU/mL
2 P) w" P% i' Z2 Z: c(prepubertal).6 w! V: B( _: p. y8 I2 `% p1 {
The parents were notified about the laboratory1 _% B l% p5 [6 P* H
results and were informed that all of the tests were4 F h2 [# y& C# Z- j+ o ~% Q
normal except the testosterone level was high. The: s7 i9 `* L* K$ A& s A
follow-up visit was arranged within a few weeks to
0 x! K/ g1 {/ a% B mobtain testicular and abdominal sonograms; how-
H* N B0 C% v: }! Oever, the family did not return for 4 months. y* j5 Z; G0 S
Physical examination at this time revealed that the4 I- G( `8 [0 D. [# [! ?: R. G
child had grown 2.5 cm in 4 months and had gained0 r, R# K$ x3 J9 `$ E# i
2 kg of weight. Physical examination remained
2 O/ p# }0 ]5 ^. S6 munchanged. Surprisingly, the pubic hair almost com-
& U1 _/ M. d' K+ c: V; V# Ypletely disappeared except for a few vellous hairs at7 J4 q6 I/ K' h& q
the base of the phallus. Testicular volume was still 2
, W( |% a8 M8 S2 wmL, and the size of the penis remained unchanged.
Y/ u" u7 [* ~( g) G0 wThe mother also said that the boy was no longer hav-
! U% n* V4 @5 Y0 P/ ~1 a0 _ing frequent erections.$ @( F3 o# T$ b* M0 a3 y. P
Both parents were again questioned about use of7 s( R5 d: Z# Q4 q& A6 B
any ointment/creams that they may have applied to1 F9 l! h& N0 L: n5 k6 _. D# j
the child’s skin. This time the father admitted the
: L1 u% s8 h% ]; f% kTopical Testosterone Exposure / Bhowmick et al 541
; M" i5 ^4 A+ W, ruse of testosterone gel twice daily that he was apply-+ z) w- m1 x! O1 I3 V
ing over his own shoulders, chest, and back area for/ G6 z) l$ ^+ \
a year. The father also revealed he was embarrassed
6 I1 T7 C4 E8 v) e1 o8 W( y, @to disclose that he was using a testosterone gel pre-
- k Z. X; c) C6 A' Hscribed by his family physician for decreased libido% {5 J0 c1 i. ~! d4 n& F
secondary to depression.
7 K: u! |1 j/ ^The child slept in the same bed with parents.' P2 K0 L7 h' |5 y2 z9 L
The father would hug the baby and hold him on his
n9 A$ Y4 b; w! A1 G( ochest for a considerable period of time, causing sig-
/ u5 H- P+ l2 p% Znificant bare skin contact between baby and father.
# o2 H3 e- h9 S" h" _The father also admitted that after the phone call,
; j' F. y9 U3 y. t7 _9 B0 dwhen he learned the testosterone level in the baby+ g. z1 h) w& f$ d* z
was high, he then read the product information
; w" y2 M) t# \/ D' R hpacket and concluded that it was most likely the rea-
, }# z$ I5 r5 e( \7 zson for the child’s virilization. At that time, they
2 x" H G* C7 c+ Fdecided to put the baby in a separate bed, and the4 H7 ~$ B2 r: C2 ^( U
father was not hugging him with bare skin and had
4 h) g" o& K5 P4 T4 {been using protective clothing. A repeat testosterone; i6 u$ S% G6 m# \
test was ordered, but the family did not go to the" d$ ]) ~, M" q6 l9 T' g8 T
laboratory to obtain the test.
( D4 }* P! j1 }3 s; Q6 ^! E$ n6 aDiscussion
- Z7 @' e) M0 R. IPrecocious puberty in boys is defined as secondary
/ N l$ z. k5 q, wsexual development before 9 years of age.1,44 j8 C8 A' }# E2 B6 z {' ~
Precocious puberty is termed as central (true) when
3 F$ ~6 u) _- R9 L% Bit is caused by the premature activation of hypo-
" W- ^( m/ J+ K) E0 r& sthalamic pituitary gonadal axis. CPP is more com-
' A- E: s0 k8 Ymon in girls than in boys.1,3 Most boys with CPP
& K" b+ g( B: u4 `( `may have a central nervous system lesion that is8 S" J/ r! n F7 @/ ?2 E9 I
responsible for the early activation of the hypothal-
9 l: }1 \! R; g7 J/ l, C# aamic pituitary gonadal axis.1-3 Thus, greater empha-
, \- M* s! E: p asis has been given to neuroradiologic imaging in! a" ~- H6 P, {( ~/ n4 J
boys with precocious puberty. In addition to viril-
G$ m4 A* u4 Q6 y x2 y _ization, the clinical hallmark of CPP is the symmet-
" i) j5 d% I: |2 s* A7 \) Rrical testicular growth secondary to stimulation by
; r. n8 ]- P! n* [gonadotropins.1,3: Z, N, X& C2 x1 T# u% A. C- R8 k
Gonadotropin-independent peripheral preco-
: |9 l/ I/ v' t' p, c" mcious puberty in boys also results from inappropriate: [! v' q& Q2 L3 u+ K
androgenic stimulation from either endogenous or
" P3 V2 P5 `& c* h# e0 Cexogenous sources, nonpituitary gonadotropin stim-
: @% B7 D: Q1 X0 h @/ n) Fulation, and rare activating mutations.3 Virilizing. c& u6 Y Z6 ?6 d* C* J
congenital adrenal hyperplasia producing excessive
& Y" b5 d8 F- p0 D9 t. X6 madrenal androgens is a common cause of precocious" `- J, C! X/ u; o' f3 t
puberty in boys.3,4
8 `# l& ?& W* C2 aThe most common form of congenital adrenal l0 a; ^8 @( P. G: {/ B: J# x/ J
hyperplasia is the 21-hydroxylase enzyme deficiency.
8 u* a0 y% ]1 v& I8 i; k/ BThe 11-β hydroxylase deficiency may also result in, f B0 X" C* b" S
excessive adrenal androgen production, and rarely,
3 Y! A5 y- y4 j7 _: Z6 W/ san adrenal tumor may also cause adrenal androgen1 G8 B/ A2 {+ L' {
excess.1,3
9 ]( r/ ]9 d" ]: \! Rat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
% i8 P* H; d* @) Y542 Clinical Pediatrics / Vol. 46, No. 6, July 2007$ T: H( U& G. `: J
A unique entity of male-limited gonadotropin-5 t7 X; w5 d& t4 h
independent precocious puberty, which is also known
: e4 S% S% c) s8 l% \, E# h1 qas testotoxicosis, may cause precocious puberty at a% t" |( W* Y; U3 d
very young age. The physical findings in these boys
7 Y% `2 i7 k" `0 O q7 n/ lwith this disorder are full pubertal development,
" C& B( @# z: pincluding bilateral testicular growth, similar to boys9 d) _( q. B8 j6 S1 C. K8 V
with CPP. The gonadotropin levels in this disorder
' U4 M$ p3 _& V' Dare suppressed to prepubertal levels and do not show
9 _9 Q% n) d0 [' x- _pubertal response of gonadotropin after gonadotropin-
. l5 e f# W5 a2 d6 ~releasing hormone stimulation. This is a sex-linked
$ K& r3 `8 m( ] I5 Z- Q$ ?2 Y( w) vautosomal dominant disorder that affects only
( X c1 x4 y: O/ Kmales; therefore, other male members of the family t- R7 a! i( f& d) g0 g
may have similar precocious puberty.3
4 L- ?9 j L# [( a+ U5 l& Q) QIn our patient, physical examination was incon-
6 C" G; @: P& J1 C/ bsistent with true precocious puberty since his testi-/ S5 b2 j5 x# u. L
cles were prepubertal in size. However, testotoxicosis
% ]( i" Q8 G+ g) `* ewas in the differential diagnosis because his father; s, Y9 k- {0 B, c1 v
started puberty somewhat early, and occasionally,
, {* A* X6 Y8 r/ `" Q# ktesticular enlargement is not that evident in the
6 Z- s, [: L/ R' \( f' E/ P, H7 j1 H [beginning of this process.1 In the absence of a neg-
$ q w3 Z% s" r' {ative initial history of androgen exposure, our7 M0 a7 W( V; D2 V: N, a
biggest concern was virilizing adrenal hyperplasia,) v' C! R6 F$ i: V4 z: b
either 21-hydroxylase deficiency or 11-β hydroxylase* v' L9 Y' R) [7 r: h
deficiency. Those diagnoses were excluded by find-
& c' v7 s1 y, r1 ^ing the normal level of adrenal steroids. r# u4 H' X3 I
The diagnosis of exogenous androgens was strongly
0 p: t2 r( l4 n1 N' ?" R# L" Qsuspected in a follow-up visit after 4 months because
7 u! G% w3 b! v. \4 jthe physical examination revealed the complete disap-
; v, ]3 _9 ~' q9 e3 Gpearance of pubic hair, normal growth velocity, and
! r% l( {0 k) l, c F# x1 hdecreased erections. The father admitted using a testos-
' F0 |% O4 w8 K! ~, `( Qterone gel, which he concealed at first visit. He was
P2 D6 h/ f' E4 eusing it rather frequently, twice a day. The Physicians’: I7 k6 F9 Q# r; Y& V& L7 ~
Desk Reference, or package insert of this product, gel or
% x" F5 \ k& ~! ]' ucream, cautions about dermal testosterone transfer to) g* Z* b5 O% R" |. Y6 Y" p
unprotected females through direct skin exposure.
# M$ }; ^' C& p( H9 tSerum testosterone level was found to be 2 times the6 c3 B* ?. T, X, K j) m
baseline value in those females who were exposed to
$ v# E; T# E2 k* g* o& F0 eeven 15 minutes of direct skin contact with their male. e, |$ l+ N# N0 o
partners.6 However, when a shirt covered the applica-2 ~1 }& a3 k0 a4 l k: Y1 x1 _
tion site, this testosterone transfer was prevented.
) i2 Z& z' g \" z3 X. B QOur patient’s testosterone level was 60 ng/mL,
1 Y# ~$ A: c% Q1 awhich was clearly high. Some studies suggest that
8 q& U0 i4 b; k4 a" i' v) x" gdermal conversion of testosterone to dihydrotestos-( ~8 M, n$ U' w! y' U* P
terone, which is a more potent metabolite, is more
" U! W- Q1 N' r9 f& iactive in young children exposed to testosterone
4 B/ @5 h% y5 ]exogenously7; however, we did not measure a dihy-
8 W- l& K# p% [ [4 `drotestosterone level in our patient. In addition to
! O, ?. i4 M) n: Z0 b' N$ ivirilization, exposure to exogenous testosterone in
; ?3 X$ J2 G; ?& y! H+ Schildren results in an increase in growth velocity and
/ r7 Q d' X5 u6 V2 f5 `1 Zadvanced bone age, as seen in our patient.
2 e) T' ?3 n1 a d% mThe long-term effect of androgen exposure during
8 Z1 V% a7 @$ Nearly childhood on pubertal development and final
+ J+ T ~; Z1 O4 cadult height are not fully known and always remain; p$ f' \. T$ i' T- j `5 X
a concern. Children treated with short-term testos-6 |$ ]) y2 \7 ^% ^" Y/ W
terone injection or topical androgen may exhibit some7 @: _- x/ X ^) s5 |( u
acceleration of the skeletal maturation; however, after
( {# v# L3 Q7 fcessation of treatment, the rate of bone maturation
) W3 F _$ z$ v! h2 Adecelerates and gradually returns to normal.8,9
; }. |% J v r, V* SThere are conflicting reports and controversy
C9 g- Z( e8 e8 w. O3 lover the effect of early androgen exposure on adult" K0 V' r- y: y# y+ v2 T
penile length.10,11 Some reports suggest subnormal4 b1 l' G/ t' f3 B# k
adult penile length, apparently because of downreg-
2 d+ Z; V( q; Oulation of androgen receptor number.10,12 However,) T3 I0 G; U7 N; v( B6 k/ F: \* `
Sutherland et al13 did not find a correlation between
$ S& _* K) k( K* a' c+ E- rchildhood testosterone exposure and reduced adult
0 ~# s' h/ j7 ]4 l2 {penile length in clinical studies.
1 h5 q1 G5 r8 u* l+ m/ gNonetheless, we do not believe our patient is. E; N% c" l' r& ~3 j
going to experience any of the untoward effects from0 @' S4 Z+ h2 n$ ^
testosterone exposure as mentioned earlier because' }, f% T$ v" R8 k7 m* m9 Z2 I# A& `
the exposure was not for a prolonged period of time.
- A1 L' h: x) c. f* D+ y, _* T% D/ I4 O! KAlthough the bone age was advanced at the time of% e( e8 a0 ^9 Y; v
diagnosis, the child had a normal growth velocity at
' v& m9 J, ^/ h* Mthe follow-up visit. It is hoped that his final adult% V$ G5 B( o& l% _' n2 `
height will not be affected.
; }2 q4 T. g/ K) S; [/ e' l, MAlthough rarely reported, the widespread avail-: \) V3 o ]. N( L0 x- W
ability of androgen products in our society may
; { V# a0 [, E# c E1 Findeed cause more virilization in male or female6 ~0 `0 \8 z( Y ?
children than one would realize. Exposure to andro-
- D. Y- |* e9 a! G5 q3 Rgen products must be considered and specific ques-! i2 {" |% R( T
tioning about the use of a testosterone product or: h0 h! R2 V2 [6 H% g! `! Z2 L
gel should be asked of the family members during, |: U! S3 X1 U% X" @
the evaluation of any children who present with vir-2 v: @7 \7 w* u5 x
ilization or peripheral precocious puberty. The diag-
- a, `4 C3 K, r* H, _- o& [. \nosis can be established by just a few tests and by$ V* }+ e) x. k- H0 E
appropriate history. The inability to obtain such a7 q1 w3 e* t' m9 Q* @. K; ?
history, or failure to ask the specific questions, may
; l$ \) a; g* [$ o% p Gresult in extensive, unnecessary, and expensive
3 r( G7 k& [6 `0 Minvestigation. The primary care physician should be
8 U: _! M8 x6 K) M. N. ~aware of this fact, because most of these children# C9 |! \# h6 ^8 c# E& v
may initially present in their practice. The Physicians’& d" W+ l: s4 H W0 a f
Desk Reference and package insert should also put a
' t9 R0 h! T& l0 Z2 Xwarning about the virilizing effect on a male or
b' e- f+ B! e4 L+ k% q' rfemale child who might come in contact with some-
3 K) q, o+ m3 Gone using any of these products.
' k/ S1 a/ `8 a- b- f) ~References
" c; N/ {( W* z2 x1. Styne DM. The testes: disorder of sexual differentiation
" g5 ~& C% g; X9 N5 [0 Nand puberty in the male. In: Sperling MA, ed. Pediatric
% g6 Z c5 R4 {- T/ H" REndocrinology. 2nd ed. Philadelphia, PA: WB Saunders;6 B- P' q; m$ l; s2 s2 O2 l0 j2 l
2002: 565-628.
9 W5 P8 r# m, ?' E/ W! K3 M2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious2 [5 X. Q$ R% ~3 U! _8 w% |
puberty in children with tumours of the suprasellar pineal |
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