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Sexual Precocity in a 16-Month-Old
6 h; G, T* e w8 x: kBoy Induced by Indirect Topical+ a, O, I8 i; H/ J& J8 |/ c( a
Exposure to Testosterone! a* ^3 I: C3 b6 z& {
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
2 t: W8 o; V6 `9 T4 C, L3 iand Kenneth R. Rettig, MD1" Q' P2 [* t/ h C
Clinical Pediatrics" U7 a# h9 a) x+ q0 c5 T
Volume 46 Number 6" I8 m7 m6 e4 q5 C' I1 N. A- ?
July 2007 540-543
3 [5 F! L: f2 I© 2007 Sage Publications
& A! J9 y, i* S2 N. i2 g10.1177/0009922806296651
q6 L, \; ^+ ^) x2 fhttp://clp.sagepub.com
& N/ r) o5 y, Y3 c7 \7 K% |# Phosted at
8 B H4 }8 K3 Jhttp://online.sagepub.com* @6 ^. |7 B# e4 L, b
Precocious puberty in boys, central or peripheral,
2 I; E" J, l" Yis a significant concern for physicians. Central
) W5 y& T$ {( K$ eprecocious puberty (CPP), which is mediated
. D# n( j% v1 X* `through the hypothalamic pituitary gonadal axis, has. Q3 f+ c! o0 F' R( `8 k3 @8 _
a higher incidence of organic central nervous system# \# V- m4 P1 g S* D
lesions in boys.1,2 Virilization in boys, as manifested
. j. o( @1 H- ?" p; g8 P; m7 cby enlargement of the penis, development of pubic
, q" P- n* [" i' L: s! _; Qhair, and facial acne without enlargement of testi-
0 \; w- E" |& L4 W5 q6 S( P+ mcles, suggests peripheral or pseudopuberty.1-3 We( e/ q9 N5 c- V( c
report a 16-month-old boy who presented with the
+ T8 W9 _4 q8 Wenlargement of the phallus and pubic hair develop-2 N- L) C" a. ~( h% r7 ?8 Y
ment without testicular enlargement, which was due
* i; ]3 ~' H2 x& Lto the unintentional exposure to androgen gel used by( t M) \5 l& v) k8 V6 w5 L: r
the father. The family initially concealed this infor- b! z# l9 q/ n b
mation, resulting in an extensive work-up for this
; `! Z$ I( H, h' i/ ]! echild. Given the widespread and easy availability of k5 g1 Z# I- q$ z4 j
testosterone gel and cream, we believe this is proba-+ M3 ~( F+ M. M
bly more common than the rare case report in the, [: t0 ?6 P/ I% [
literature.4
% ]) |, G" o) y YPatient Report
( z7 v, B. N. j" s* xA 16-month-old white child was referred to the
3 s# u/ r& M+ h! l8 E/ o$ I4 I$ Dendocrine clinic by his pediatrician with the concern
: r" ? _' \9 r1 nof early sexual development. His mother noticed8 f; M& [# _! H1 m. f* N" F
light colored pubic hair development when he was/ y9 i3 G) I" V2 X5 Z2 L
From the 1Division of Pediatric Endocrinology, 2University of
2 z) q3 l: T( o" [4 T* bSouth Alabama Medical Center, Mobile, Alabama., }1 ]; D( Q& V
Address correspondence to: Samar K. Bhowmick, MD, FACE,
3 }+ S2 ^2 \6 }7 M, uProfessor of Pediatrics, University of South Alabama, College of
& @! ?+ o9 i! u0 o. D0 f& hMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;$ Y! {6 T% U" H2 q
e-mail: [email protected].9 o5 R' ^8 [7 O3 y) K$ ?
about 6 to 7 months old, which progressively became4 Q; c: `6 v# \% m" ]
darker. She was also concerned about the enlarge-! q0 V, }6 F. E" q
ment of his penis and frequent erections. The child
4 P6 o* T: b; {% w2 _was the product of a full-term normal delivery, with
4 e- l. F: w" A! u: v9 k0 t3 Sa birth weight of 7 lb 14 oz, and birth length of
2 H3 l7 I1 k9 s Q0 y& P* V4 U20 inches. He was breast-fed throughout the first year; x0 w8 a4 R7 J4 S0 S% y" |
of life and was still receiving breast milk along with/ S2 O! k0 J* I2 L }
solid food. He had no hospitalizations or surgery,
) y% l. V" W6 f( R1 f g6 M1 ?; @and his psychosocial and psychomotor development
+ E! U, ^4 K- X6 \/ e6 j9 uwas age appropriate.2 }0 o9 w- H; o) P' J
The family history was remarkable for the father,
0 P& b* x) E) l7 awho was diagnosed with hypothyroidism at age 16,4 Y: b% Y# `# i2 N4 [$ l) h
which was treated with thyroxine. The father’s
( R- f5 b2 M1 M3 }, ]4 E% Uheight was 6 feet, and he went through a somewhat
: N3 Y" c. |: i( N9 ?9 \( c E* Mearly puberty and had stopped growing by age 14.
! _" |! P& f h% H$ v$ TThe father denied taking any other medication. The% d8 Y1 x! b3 S# {
child’s mother was in good health. Her menarche
' v$ R& E( S8 L3 h) Mwas at 11 years of age, and her height was at 5 feet# ^* C. c8 P! ^& f5 }$ O
5 inches. There was no other family history of pre-
+ _! t, h% s2 r! f* C* acocious sexual development in the first-degree rela-5 ?4 J+ R8 L! y+ r
tives. There were no siblings.
* I0 J; p. r! r+ L" p3 MPhysical Examination
8 I. @* g7 P6 y; Z( M8 k5 lThe physical examination revealed a very active,* ~# P. S$ w9 A8 l6 C' P
playful, and healthy boy. The vital signs documented/ q+ U% M9 T& Y$ N9 Z9 E! l
a blood pressure of 85/50 mm Hg, his length was \' n. k7 z) r% U
90 cm (>97th percentile), and his weight was 14.4 kg! {, X$ ~' a4 ~- w# x5 O) |+ C
(also >97th percentile). The observed yearly growth- c# U' {: I* z% X) \
velocity was 30 cm (12 inches). The examination of
5 ?! D3 v! K! @) {& m9 Qthe neck revealed no thyroid enlargement.) R5 @' m; c G
The genitourinary examination was remarkable for+ X, {9 w; c! h+ d/ o( }+ S
enlargement of the penis, with a stretched length of
3 X% Q8 H8 h$ S& i Y. h% ]8 cm and a width of 2 cm. The glans penis was very well
$ P `, g% Y" N# [5 Mdeveloped. The pubic hair was Tanner II, mostly around+ d: ^2 v/ U$ c* V* r. D& N
540
2 H' u }9 U: o7 _; cat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from- b# J8 k" c1 v, L8 U, w
the base of the phallus and was dark and curled. The
3 k3 R. q6 W! wtesticular volume was prepubertal at 2 mL each.- p& y$ z% I$ q4 a0 @' C
The skin was moist and smooth and somewhat
7 T* A3 k6 ?, m6 uoily. No axillary hair was noted. There were no
3 ^) I$ z5 e3 w+ B+ Cabnormal skin pigmentations or café-au-lait spots.
. u& E! W, c( L: ^' [& ENeurologic evaluation showed deep tendon reflex 2+! a) c0 P# m" \& t. U
bilateral and symmetrical. There was no suggestion9 P- G% }* q- K. m1 m- C' r
of papilledema.8 s. p( S; Y# u5 G/ e. L/ o
Laboratory Evaluation
9 N$ ^) y0 u; `: oThe bone age was consistent with 28 months by
+ f: l/ I3 y8 X- w2 Gusing the standard of Greulich and Pyle at a chrono-
7 O$ \# C$ u M+ p6 t9 I9 }6 Nlogic age of 16 months (advanced).5 Chromosomal
& c5 U/ R4 ?4 K" w! u6 B$ Akaryotype was 46XY. The thyroid function test, V+ ^, i d" D8 E8 _/ _4 k
showed a free T4 of 1.69 ng/dL, and thyroid stimu-
6 `$ {0 l8 F$ }& blating hormone level was 1.3 µIU/mL (both normal).
! }8 v8 G- J4 O% ]. y& s+ n. N: E7 PThe concentrations of serum electrolytes, blood
2 H# ^1 q# c/ k* n, A( ?2 Ourea nitrogen, creatinine, and calcium all were9 \. F, i7 F5 X% K
within normal range for his age. The concentration
, m& ], X: i2 k( A+ ^of serum 17-hydroxyprogesterone was 16 ng/dL; Q* Z& A0 U! s" [6 n" @7 b
(normal, 3 to 90 ng/dL), androstenedione was 205 P7 I/ R+ w' F9 |" `5 ]; I
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-: U+ C: e0 d. S& H4 y- [" \, }& [
terone was 38 ng/dL (normal, 50 to 760 ng/dL),
T( p5 i! j$ m' A; `0 Adesoxycorticosterone was 4.3 ng/dL (normal, 7 to8 X% h- x5 ?0 F8 e' k% u0 L3 Y
49ng/dL), 11-desoxycortisol (specific compound S)
/ a4 Q% v+ g J* E" Awas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-/ u% w- H+ m- ~( v, o/ G
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
" s) I/ B$ P* H+ M3 i! F( n, W0 rtestosterone was 60 ng/dL (normal <3 to 10 ng/dL),( g! c3 \* Z2 d" N+ g) C4 p
and β-human chorionic gonadotropin was less than2 Q3 ]5 w0 q2 P8 p9 s
5 mIU/mL (normal <5 mIU/mL). Serum follicular- a0 e6 b, W- Z% ` n0 s1 W6 p
stimulating hormone and leuteinizing hormone
% u0 h3 I R: L2 E5 P- \& E+ c4 Qconcentrations were less than 0.05 mIU/mL$ \: p1 R3 i* Z. q4 ]
(prepubertal).
; \/ a( j9 A0 f P& _8 g/ l! ^2 Y1 gThe parents were notified about the laboratory
2 p1 u& [. H5 f( ?" M' G" lresults and were informed that all of the tests were
; d/ \( {/ c f4 Y1 H0 k, pnormal except the testosterone level was high. The
; a" k* _; S; K( C- y& M, _ c8 Ufollow-up visit was arranged within a few weeks to& i4 Z, P5 [) n# [6 r* I* p3 t
obtain testicular and abdominal sonograms; how-# ^6 }5 u$ N9 d; A
ever, the family did not return for 4 months.
& K! ?8 _3 ]: k5 G- ~, F' e( r) YPhysical examination at this time revealed that the
5 L9 u8 q* D! i [( Q* T4 q; K dchild had grown 2.5 cm in 4 months and had gained
# y' o, V; k) [6 [0 P! Y2 kg of weight. Physical examination remained
& g) J0 c, f* Y, s& e' j: xunchanged. Surprisingly, the pubic hair almost com-6 m8 g( x. L9 w9 S5 S% h' s
pletely disappeared except for a few vellous hairs at
8 [+ m* ` g8 ?+ @# Pthe base of the phallus. Testicular volume was still 2( y/ c. y0 x; |8 `
mL, and the size of the penis remained unchanged.0 T7 [. U' o" v) t3 K6 t
The mother also said that the boy was no longer hav-) y0 v7 V% Y! A/ L. v' b+ {: g
ing frequent erections.
6 ?1 F( n8 d1 F7 H T$ P8 a* mBoth parents were again questioned about use of
: N* U0 j+ @7 f) s+ S7 fany ointment/creams that they may have applied to1 t7 d- I! a( v+ D6 q
the child’s skin. This time the father admitted the
/ P/ X3 X+ c( k: `% FTopical Testosterone Exposure / Bhowmick et al 5418 x$ O* `# F% g7 @
use of testosterone gel twice daily that he was apply-, [4 g7 O# `5 K5 k
ing over his own shoulders, chest, and back area for
/ X) g3 t7 L8 A1 Za year. The father also revealed he was embarrassed
% I4 E8 v0 L: A/ N; T% yto disclose that he was using a testosterone gel pre-
5 H, s6 |) e) {' p5 C' qscribed by his family physician for decreased libido. o. d% s, P% F! t9 _2 E! E' j' n" d \
secondary to depression.
9 O# ?% w) D( X: m7 d5 r9 ~0 vThe child slept in the same bed with parents.( n3 O0 ^7 O5 F9 H, n3 |
The father would hug the baby and hold him on his/ t) u( A& K: `" V
chest for a considerable period of time, causing sig-, k( K$ `6 C) s ^+ `
nificant bare skin contact between baby and father.- _0 ~% Y" D, {& D0 b) B
The father also admitted that after the phone call,! X" S: c+ A* n }1 A' _7 e
when he learned the testosterone level in the baby4 a4 W9 m. C- w9 m; Y
was high, he then read the product information
0 Z, P, z' _% b" V* y5 fpacket and concluded that it was most likely the rea-, x+ d: F, }2 @5 O+ c. T5 t
son for the child’s virilization. At that time, they
7 R# f1 \9 E" d3 W: ~4 ]decided to put the baby in a separate bed, and the) s8 U$ h: k$ j! ], y
father was not hugging him with bare skin and had
5 [( h! U2 J* g( |been using protective clothing. A repeat testosterone9 x. J+ k* b: R
test was ordered, but the family did not go to the! G. z! F8 z1 X0 `. r
laboratory to obtain the test.
; T3 i8 M/ p! ?) S, t! T9 \Discussion; O2 K) A# z3 i
Precocious puberty in boys is defined as secondary: b: u- Z) t2 w3 X' x
sexual development before 9 years of age.1,4& @4 _' Y+ w% u/ P: C9 ~
Precocious puberty is termed as central (true) when/ x5 A, `- U1 S4 V- ]
it is caused by the premature activation of hypo-( I# @$ Y5 j- }' k0 u/ }
thalamic pituitary gonadal axis. CPP is more com-, ?( `7 j9 P1 m/ b
mon in girls than in boys.1,3 Most boys with CPP n- I) j$ b, `$ v8 [
may have a central nervous system lesion that is. a8 K) _ Y8 I5 \! |
responsible for the early activation of the hypothal-
4 R. k3 r# V6 J( Y0 Iamic pituitary gonadal axis.1-3 Thus, greater empha-( u8 i9 p+ s8 s( `2 ?$ ^
sis has been given to neuroradiologic imaging in
8 ^5 o2 ?) Z. T0 M: D2 Kboys with precocious puberty. In addition to viril-
$ w; O( A7 ~! Q# A" }- a% kization, the clinical hallmark of CPP is the symmet-
& X8 T7 ]6 M9 _) Y6 U5 K* ]rical testicular growth secondary to stimulation by* y; |5 W( Q, m7 f1 P
gonadotropins.1,3
5 ^ x2 z3 G- _0 \* G& B8 \Gonadotropin-independent peripheral preco-
" C; ~! S2 r" Acious puberty in boys also results from inappropriate o$ h* O! p; ^6 Z' j8 a
androgenic stimulation from either endogenous or
- o* k5 L3 }% ?* U: b9 ^$ }* {6 R' [( qexogenous sources, nonpituitary gonadotropin stim-
/ e+ i) d/ \, F& Xulation, and rare activating mutations.3 Virilizing
/ A& J# _* f: ]+ T+ Gcongenital adrenal hyperplasia producing excessive! U0 O( U7 i! V$ P0 k
adrenal androgens is a common cause of precocious
- u" O; E% y9 v, B( zpuberty in boys.3,4 t+ T, ~! H0 [1 N
The most common form of congenital adrenal, w: H! |* L! @
hyperplasia is the 21-hydroxylase enzyme deficiency.3 m4 i* Q) I3 a% n" e
The 11-β hydroxylase deficiency may also result in
" x7 m/ v( Y, Y8 {4 X0 a3 xexcessive adrenal androgen production, and rarely,
: P, V& r! c+ M- ?" l- Han adrenal tumor may also cause adrenal androgen2 t' K N& [/ P1 ]
excess.1,3; v* a$ c% o; s; X6 b/ q
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
9 _3 [) w+ l# @$ W542 Clinical Pediatrics / Vol. 46, No. 6, July 2007( l0 R4 e5 ?9 v
A unique entity of male-limited gonadotropin-
3 K% ]" M; h# @5 K# Q) lindependent precocious puberty, which is also known2 }& i' S# e5 w; L5 h" l1 B2 W4 w+ ?
as testotoxicosis, may cause precocious puberty at a K, w5 U, n( f
very young age. The physical findings in these boys! u' @# h' z) `% h( n: H# S
with this disorder are full pubertal development,
5 l/ t% A# m0 o5 s3 l0 Mincluding bilateral testicular growth, similar to boys; } W! E7 p# Q0 u7 `6 l& C
with CPP. The gonadotropin levels in this disorder
, r! L) L" N' f1 nare suppressed to prepubertal levels and do not show: v1 | d) M1 X( Z
pubertal response of gonadotropin after gonadotropin-
6 l% o/ x, R" f% f8 jreleasing hormone stimulation. This is a sex-linked" A4 D# @& n$ V% X
autosomal dominant disorder that affects only& Q' X1 p/ B, r( U2 ^- y. Z
males; therefore, other male members of the family
' O5 S, X |' t3 jmay have similar precocious puberty.3! q4 J2 W, n1 m4 A" U
In our patient, physical examination was incon-
8 _% q) D1 ^5 X* }* w8 @3 J& esistent with true precocious puberty since his testi-
# g9 G( y6 \7 zcles were prepubertal in size. However, testotoxicosis; h9 l' Z. d: }8 t) q
was in the differential diagnosis because his father
% ? @: G% i$ w$ ystarted puberty somewhat early, and occasionally,
# o1 h u: d/ d$ Btesticular enlargement is not that evident in the
c4 k1 p: G" V, `$ Cbeginning of this process.1 In the absence of a neg-3 |7 V+ v' X6 s" z7 D
ative initial history of androgen exposure, our7 h. ^! d% P9 E
biggest concern was virilizing adrenal hyperplasia,7 R: y I* W, {, f
either 21-hydroxylase deficiency or 11-β hydroxylase1 u5 E3 j6 C) Z" B D
deficiency. Those diagnoses were excluded by find-7 x, W9 k, x- e9 x' q+ P, L- O
ing the normal level of adrenal steroids.9 x% [& _: m( `+ x# c
The diagnosis of exogenous androgens was strongly, Y9 \4 q7 {; [6 Y
suspected in a follow-up visit after 4 months because: P4 V) N: I |, d" X1 [( E
the physical examination revealed the complete disap-3 Y$ R7 y. T6 V' f, I
pearance of pubic hair, normal growth velocity, and
* g% G0 ~# ^% [" j0 [7 Vdecreased erections. The father admitted using a testos-/ ?7 a3 W9 a( m! q: v( `5 A) y1 P
terone gel, which he concealed at first visit. He was
3 _% Y- h+ o8 h1 C$ w; ]6 u9 fusing it rather frequently, twice a day. The Physicians’; J9 F$ B2 v3 u& } S* ]+ ^
Desk Reference, or package insert of this product, gel or# a: V6 K! m8 u& ~# E- g
cream, cautions about dermal testosterone transfer to
4 _0 D: k# ~ o- J- c/ F) y7 ^3 `( junprotected females through direct skin exposure.
: }) U/ Y: W8 z/ B. x3 |Serum testosterone level was found to be 2 times the
. B: x) G x" @, P9 E' u Q# F* o2 \. mbaseline value in those females who were exposed to
& ~9 @: y0 J& Q$ ceven 15 minutes of direct skin contact with their male
6 i8 h- q, V7 zpartners.6 However, when a shirt covered the applica-
; o( P) @8 X2 d* ~& t/ r! g! ]tion site, this testosterone transfer was prevented.4 S8 l7 i1 c# F; z
Our patient’s testosterone level was 60 ng/mL,3 h) M, i1 T; w% K+ T' r: }
which was clearly high. Some studies suggest that. u2 r4 g8 h" K$ G- k. N
dermal conversion of testosterone to dihydrotestos-
4 g9 N+ D) g" Qterone, which is a more potent metabolite, is more8 U9 }& B8 S% N0 ?) \$ J* D) S
active in young children exposed to testosterone+ R$ G6 c9 _( ]( i/ E* v' a
exogenously7; however, we did not measure a dihy-( T$ c }+ I t, i
drotestosterone level in our patient. In addition to, C. J1 u% E, A7 u$ e
virilization, exposure to exogenous testosterone in9 I) r6 ]9 ? _* o4 _
children results in an increase in growth velocity and6 u& \; ~& m o9 ~
advanced bone age, as seen in our patient.2 E: O; I9 k% i) s
The long-term effect of androgen exposure during
. a9 t; a ?" bearly childhood on pubertal development and final$ Q7 {* W+ |# K, y9 T# }1 t6 ~
adult height are not fully known and always remain O- L# f `" G% _
a concern. Children treated with short-term testos-0 {. S; K' A _
terone injection or topical androgen may exhibit some" S: z4 @. Z! ]) c9 X
acceleration of the skeletal maturation; however, after
0 w% ?7 `3 ^" q( J* r5 rcessation of treatment, the rate of bone maturation& u4 `" d1 K/ o0 j; w0 O/ G
decelerates and gradually returns to normal.8,9
) p( d a2 \6 d1 cThere are conflicting reports and controversy7 X, D+ s; e. z/ G$ Q8 `
over the effect of early androgen exposure on adult
) ~) @; j3 T* z: V. |/ H$ Vpenile length.10,11 Some reports suggest subnormal
$ X6 K! j" X# `7 Eadult penile length, apparently because of downreg-
6 ?' A5 G' g: Aulation of androgen receptor number.10,12 However,
4 n' |6 t, x; `3 R( s# ^1 O8 mSutherland et al13 did not find a correlation between6 C" s+ {1 l) z" g: m- J7 |1 i
childhood testosterone exposure and reduced adult
& j1 W7 H# x9 i/ p: J! qpenile length in clinical studies.
' X K4 t x# ~0 x: J& q& rNonetheless, we do not believe our patient is1 X; ]3 l$ y0 J2 c
going to experience any of the untoward effects from+ N3 q* U8 K, o6 U
testosterone exposure as mentioned earlier because8 c% ]: O2 w8 [% o5 S) {! j* {
the exposure was not for a prolonged period of time.
% Y4 X' k) E- v4 K7 z2 VAlthough the bone age was advanced at the time of1 b" i) v0 g$ U, h7 r2 P- M8 b
diagnosis, the child had a normal growth velocity at( N. c9 ^- H' m, p, u; e4 v
the follow-up visit. It is hoped that his final adult# H) @* \+ c; r0 b7 r# S# W
height will not be affected.
( r; `( J: t, z0 fAlthough rarely reported, the widespread avail-
+ D9 B/ `- r4 lability of androgen products in our society may
/ [) k$ ]6 h7 Zindeed cause more virilization in male or female
4 E$ ]$ f" H: Bchildren than one would realize. Exposure to andro-
+ M" n7 O. E% f( ~& p) sgen products must be considered and specific ques-
8 @- ?2 H4 B/ M$ Ntioning about the use of a testosterone product or
+ F W' m1 Y6 z8 |gel should be asked of the family members during/ H: N1 J+ `1 m& M1 x9 v. i
the evaluation of any children who present with vir-: g: E% R+ b. N7 r, Z/ f
ilization or peripheral precocious puberty. The diag-2 e; `5 Z7 k' L
nosis can be established by just a few tests and by: v4 @$ Y7 e% W. R3 C( M4 }
appropriate history. The inability to obtain such a8 [* h3 U$ Y/ M& r: @2 T
history, or failure to ask the specific questions, may+ ?- L* e) F0 G, \- H
result in extensive, unnecessary, and expensive
; r# e) O1 A q5 L5 Tinvestigation. The primary care physician should be
" U( ~+ R2 c1 L/ ]& ^2 n/ jaware of this fact, because most of these children
' U; a: f9 S. _- U: Hmay initially present in their practice. The Physicians’
" O+ X" F6 |7 h; [Desk Reference and package insert should also put a V5 |7 D F3 a
warning about the virilizing effect on a male or
s; [. O ^/ lfemale child who might come in contact with some-
& ~* u0 g# S4 d1 Vone using any of these products.
) k/ e: u. m5 i( M2 d) ?1 SReferences: h4 R6 O3 j C0 i
1. Styne DM. The testes: disorder of sexual differentiation! r1 t% p) H# b) {
and puberty in the male. In: Sperling MA, ed. Pediatric0 a6 }6 Q+ L( y/ D
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
. k7 P1 `! \& C# b7 r7 P( e4 j# r2002: 565-628. d* S* t# ?3 U. ]) G0 T( x/ n
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious6 k* ?4 f& a2 b( h
puberty in children with tumours of the suprasellar pineal |
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