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Sexual Precocity in a 16-Month-Old
9 E$ Y9 v& J. i# g! R$ ~Boy Induced by Indirect Topical
1 u/ c+ K3 G7 B2 D% V+ O* y4 L0 LExposure to Testosterone
7 |3 X4 s' x, H4 [& ?/ QSamar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,28 D' @' @, x' i1 ], ]# R
and Kenneth R. Rettig, MD1
) d) q. b. ?8 B: Y N; ~Clinical Pediatrics; T7 F# d0 `: O6 x# u( G( Z
Volume 46 Number 6
; r* i. F4 Y' \4 |& j( bJuly 2007 540-543
) g& f+ c8 p( K© 2007 Sage Publications, n9 }5 M- S. D( A6 P3 w. n
10.1177/0009922806296651
6 l z4 Y/ V! w# |* [http://clp.sagepub.com
# g& Z0 V8 z. o8 o' R, h& {hosted at9 ?) N+ \' B2 \
http://online.sagepub.com
( m% o5 n/ p7 L* X0 w' r) `0 tPrecocious puberty in boys, central or peripheral,
/ n) I# f# K, ?, q8 F* }" i; H* o% Cis a significant concern for physicians. Central; _6 y2 g c6 ^% x
precocious puberty (CPP), which is mediated
/ W3 c. X3 ~6 Gthrough the hypothalamic pituitary gonadal axis, has( w% j4 Q* v# \" Z0 Z
a higher incidence of organic central nervous system3 h& c3 R8 D3 e4 U: M8 U
lesions in boys.1,2 Virilization in boys, as manifested
& U/ n: T/ n+ R) l2 u8 k, lby enlargement of the penis, development of pubic
' Z7 y3 J+ \( O+ F1 K; X8 U& thair, and facial acne without enlargement of testi-; B8 z" l. s' Y! n. B2 b* }
cles, suggests peripheral or pseudopuberty.1-3 We8 H& z5 t: q+ p1 p% {
report a 16-month-old boy who presented with the
& ~+ T. i/ H* d3 g% L% i( Menlargement of the phallus and pubic hair develop-
! ?* p7 p" B# p7 J$ @9 r! Q! ^ment without testicular enlargement, which was due
: m7 z+ Y5 }( S0 n0 \1 `0 ]to the unintentional exposure to androgen gel used by
+ i& K G. w7 ?% l: ethe father. The family initially concealed this infor-# ^9 l- |2 p) g" ? `3 L; l
mation, resulting in an extensive work-up for this' s [- F$ J' T5 y8 P. D6 q
child. Given the widespread and easy availability of
* f/ H5 |0 s8 s, ytestosterone gel and cream, we believe this is proba-
. C: P! w0 \4 j7 ^# p" sbly more common than the rare case report in the8 I G3 I& f" i. x
literature.40 K' R- R3 Z9 a7 b! Y6 M6 G* g
Patient Report" r6 p$ J4 b k; h
A 16-month-old white child was referred to the) F' p9 \. R2 d b3 o o
endocrine clinic by his pediatrician with the concern0 B8 u: h9 \, T1 P6 L
of early sexual development. His mother noticed; G+ G7 }& x/ e0 i3 d/ H
light colored pubic hair development when he was3 N2 o' N0 Z7 C7 \, U2 {3 @. k
From the 1Division of Pediatric Endocrinology, 2University of, V3 Q" X* e' k+ u
South Alabama Medical Center, Mobile, Alabama.. R' h1 W1 X; f# D
Address correspondence to: Samar K. Bhowmick, MD, FACE,
& t: q4 h5 d1 uProfessor of Pediatrics, University of South Alabama, College of
3 h8 ?9 H, f: P+ CMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;( k2 O. f5 h" Z8 d, @
e-mail: [email protected].% V/ u* @" L* A b0 D
about 6 to 7 months old, which progressively became
% s' I0 \* b( D5 }" Xdarker. She was also concerned about the enlarge-
" a, Q, @! C( @8 H4 [1 [; D& q' N2 Lment of his penis and frequent erections. The child
, o V+ j. ]" \1 W2 u0 {+ jwas the product of a full-term normal delivery, with8 f- u6 K- ^2 o# Y* M! u7 U& p
a birth weight of 7 lb 14 oz, and birth length of+ S, ~& O B2 l L# `2 c( `
20 inches. He was breast-fed throughout the first year
& o" W. Y7 j. F# \of life and was still receiving breast milk along with
6 h. @8 ^6 q) z0 ]2 Osolid food. He had no hospitalizations or surgery,7 e0 C W$ F3 A6 P7 T9 }. t
and his psychosocial and psychomotor development+ i& ~4 P* m& Y9 l: J9 _* l' i
was age appropriate.! m) e* w+ t" j, F; h' A# R N* M$ d
The family history was remarkable for the father,
. G& }! {) p/ e* ywho was diagnosed with hypothyroidism at age 16,- ]; N; F* l- _( P) Q
which was treated with thyroxine. The father’s+ T- Y% g" V: ]" j8 K
height was 6 feet, and he went through a somewhat/ V8 H8 x% I# [. i. i
early puberty and had stopped growing by age 14.
" j. ^, z) c4 B8 q2 M: g; yThe father denied taking any other medication. The
6 ^; W/ p% g4 N* y' \6 zchild’s mother was in good health. Her menarche
( |2 W3 B- Q8 L" bwas at 11 years of age, and her height was at 5 feet& M4 v" j- t) y( }6 S$ V. }+ D
5 inches. There was no other family history of pre-3 H' ^0 |. ]7 V% \* s4 J
cocious sexual development in the first-degree rela-
6 r+ C! c$ ?: H) \- O" r% atives. There were no siblings.' c% ^# B3 ]% h% ]; `1 g a
Physical Examination
; A6 s1 b6 a! D) \, S; L! UThe physical examination revealed a very active,
1 r9 z; |! B2 `+ C0 Wplayful, and healthy boy. The vital signs documented
# b$ b% [5 k: qa blood pressure of 85/50 mm Hg, his length was
5 ?( [9 [ I; j; J/ I2 z90 cm (>97th percentile), and his weight was 14.4 kg- }" L q1 E* r, E. n9 A2 B3 k; U
(also >97th percentile). The observed yearly growth
# n k. E' w6 a2 i% n) Svelocity was 30 cm (12 inches). The examination of- [$ o0 Y( k' I, f. J
the neck revealed no thyroid enlargement.1 j, Q2 B) ?+ D$ V
The genitourinary examination was remarkable for
: c8 g" L P7 l; J1 ?/ q8 tenlargement of the penis, with a stretched length of( Z& O. y! U3 u9 c6 L/ S5 ?" Y
8 cm and a width of 2 cm. The glans penis was very well4 ]5 P: ~6 r' v: P5 k+ a
developed. The pubic hair was Tanner II, mostly around
0 D4 y" t' G5 R/ e7 [( o540
. e( h2 V# \9 T. U/ Mat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from( ]% m) Z; D$ D3 \- W
the base of the phallus and was dark and curled. The+ h8 r1 F% O- u" v
testicular volume was prepubertal at 2 mL each.! ~8 q, [( H: C% L% k0 O
The skin was moist and smooth and somewhat5 Z/ d1 I- f6 |6 k0 R
oily. No axillary hair was noted. There were no: W3 f4 g1 s9 O5 E8 W+ Z- c* X& Q
abnormal skin pigmentations or café-au-lait spots.
6 a! S$ |; L ?( D" fNeurologic evaluation showed deep tendon reflex 2+' T" x7 X- L% T6 j; k4 u: _
bilateral and symmetrical. There was no suggestion
9 s, X8 G5 c! _" P, S4 qof papilledema.
3 r6 C9 A# [2 G6 BLaboratory Evaluation% w' a1 }5 z4 p m, E. r
The bone age was consistent with 28 months by8 f# m: a2 M* a0 N0 ^# t0 p1 l( J
using the standard of Greulich and Pyle at a chrono-
$ P. d4 d6 Q/ W2 blogic age of 16 months (advanced).5 Chromosomal
% m# F0 C0 n0 ^5 ] T okaryotype was 46XY. The thyroid function test
" @0 L# X; Z' k; H. r0 f$ _showed a free T4 of 1.69 ng/dL, and thyroid stimu-
) i' ^+ P5 i0 P% jlating hormone level was 1.3 µIU/mL (both normal).
8 b+ j" [' S# V: Z, i. nThe concentrations of serum electrolytes, blood
; L; R' i t7 N- Xurea nitrogen, creatinine, and calcium all were
; I" q) Q# e8 |+ }within normal range for his age. The concentration7 Z" D9 H! G' k7 p
of serum 17-hydroxyprogesterone was 16 ng/dL! S6 t/ E+ E& r
(normal, 3 to 90 ng/dL), androstenedione was 20
8 g: i9 z4 E; gng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-- P, i/ u4 `! b9 v9 S$ h+ W
terone was 38 ng/dL (normal, 50 to 760 ng/dL),
$ E4 S4 J' { l: Adesoxycorticosterone was 4.3 ng/dL (normal, 7 to8 t' J: A# L" h8 L1 j2 u3 @1 e
49ng/dL), 11-desoxycortisol (specific compound S)
8 _0 g; L, r3 T7 N- Iwas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
* }" R" E6 j6 V, z3 i0 [tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total9 l# [% [' ]2 r- U
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
) u2 k' K% A6 \) U5 c/ Zand β-human chorionic gonadotropin was less than
& m* L- M( p9 _# y5 mIU/mL (normal <5 mIU/mL). Serum follicular
2 g. t0 W: C+ W, ]6 b: P! gstimulating hormone and leuteinizing hormone
* N1 |& S, n, w& y8 A5 ?concentrations were less than 0.05 mIU/mL
% s; b% c) ?4 w; k- R! L0 ~& o(prepubertal).
0 N: R+ E' x& q: P TThe parents were notified about the laboratory0 a2 ?1 l) c+ J! ^1 {( E
results and were informed that all of the tests were* `" C% f+ C9 ^2 I% P( ?+ v9 T
normal except the testosterone level was high. The
" |3 c6 m2 V- n. D) `follow-up visit was arranged within a few weeks to
8 }! [$ l0 X6 S$ fobtain testicular and abdominal sonograms; how-
0 I2 K" E! B" _+ O) Qever, the family did not return for 4 months.
0 b- H% d& D- m& dPhysical examination at this time revealed that the4 y) z4 {' }0 w8 ^
child had grown 2.5 cm in 4 months and had gained5 q* w- g7 S+ G0 }4 n! v
2 kg of weight. Physical examination remained) q$ _: d" Z( N! ^
unchanged. Surprisingly, the pubic hair almost com-
; V2 r* ]9 ]7 P4 {2 apletely disappeared except for a few vellous hairs at
% r% w" s) `4 O9 Uthe base of the phallus. Testicular volume was still 2: H6 z# f( v8 c
mL, and the size of the penis remained unchanged.2 j% X O3 E) f( P+ a$ u
The mother also said that the boy was no longer hav-$ v: R5 K: s4 T
ing frequent erections.
6 C7 ]3 \1 w) K1 F, d+ C6 [Both parents were again questioned about use of% s1 c h0 a2 H! l& S& O/ @
any ointment/creams that they may have applied to, E' ~, K8 |* U' d: c
the child’s skin. This time the father admitted the2 K {1 q/ o- h2 X' f
Topical Testosterone Exposure / Bhowmick et al 541
. W& G8 `$ ~ E) nuse of testosterone gel twice daily that he was apply-
" t0 |3 {& p# G7 J. E! Ving over his own shoulders, chest, and back area for: l' n# |* T. ~) \: }4 S+ x
a year. The father also revealed he was embarrassed
$ O4 l/ x; u# mto disclose that he was using a testosterone gel pre-
8 J5 x6 ?* X9 @3 J1 ?; [ Vscribed by his family physician for decreased libido, c! J" {1 M2 {' A6 V8 m$ k
secondary to depression.
$ _5 Q: k7 }# sThe child slept in the same bed with parents.
( I0 l( a2 c. G' w" Z% RThe father would hug the baby and hold him on his2 h$ a+ e _' Z
chest for a considerable period of time, causing sig-7 N8 q# s& {. c4 e
nificant bare skin contact between baby and father.# P W4 r9 o+ O# h8 t
The father also admitted that after the phone call, Z6 |' n2 w* b0 y9 u
when he learned the testosterone level in the baby; @. A6 J) }" X) u
was high, he then read the product information
, V% v$ b$ t1 W, I3 opacket and concluded that it was most likely the rea-
1 l* v5 o2 n7 G0 ]: Zson for the child’s virilization. At that time, they
" @% u" t3 e) f* `* ^decided to put the baby in a separate bed, and the& v6 L, g8 I0 D% c2 L
father was not hugging him with bare skin and had
/ g3 V0 p7 Y5 Z4 ^7 _been using protective clothing. A repeat testosterone
d, m( c: z, J* J/ c" ltest was ordered, but the family did not go to the M; {% U1 t) q+ T' j* `
laboratory to obtain the test.
* K, [7 ` x: L0 I/ _- V) vDiscussion
: e& U, B ^& p: k# H. qPrecocious puberty in boys is defined as secondary
0 k2 v! m1 u( z% G% q& ?sexual development before 9 years of age.1,4- `2 c* S: x. } B+ C7 |
Precocious puberty is termed as central (true) when% A1 ~" g# q; e; x/ N0 Q0 W
it is caused by the premature activation of hypo-( `- B2 m' A4 ~3 }7 j( S5 W
thalamic pituitary gonadal axis. CPP is more com-
3 @0 r1 D9 R) g3 v* `mon in girls than in boys.1,3 Most boys with CPP
1 z. b5 Q* `" R# }- p' u b) q: ^may have a central nervous system lesion that is
! [1 P' E1 Z0 z L' E, m' Dresponsible for the early activation of the hypothal-
+ ~0 t0 O# _ @7 b9 o/ ?" [amic pituitary gonadal axis.1-3 Thus, greater empha-
' g- }) U& J% Z( }6 Wsis has been given to neuroradiologic imaging in G+ M4 R% {; @# e' [
boys with precocious puberty. In addition to viril-
! z) M7 T' X9 S. mization, the clinical hallmark of CPP is the symmet-7 \6 O: S8 r7 k& }8 ^
rical testicular growth secondary to stimulation by0 b# D9 W: X2 I8 q: Z [8 E, C
gonadotropins.1,3
1 H" I$ D% z8 l- G1 H5 u9 GGonadotropin-independent peripheral preco-3 h) H% C" Y4 R6 O+ ?5 `: w
cious puberty in boys also results from inappropriate
+ ^4 `+ m9 |3 r6 Uandrogenic stimulation from either endogenous or
+ v( R$ e. f# ]9 Qexogenous sources, nonpituitary gonadotropin stim-
( m* R, Y( A6 x2 tulation, and rare activating mutations.3 Virilizing* [5 ~" U: m7 y! ?7 `' r% W- X1 d& a
congenital adrenal hyperplasia producing excessive
4 r' t+ A) {4 L# w- Qadrenal androgens is a common cause of precocious
6 g: x# r" E# U( ] X0 d1 B7 fpuberty in boys.3,49 X- T8 V$ \1 }
The most common form of congenital adrenal
. P8 k& u2 _# A& n( Qhyperplasia is the 21-hydroxylase enzyme deficiency.2 {, O' Z% y, L: x% ?: l [- w2 I
The 11-β hydroxylase deficiency may also result in
1 W- p2 e" O+ K' b6 w2 X: s% @excessive adrenal androgen production, and rarely,! p% T8 g, e$ a$ Q
an adrenal tumor may also cause adrenal androgen
8 H( m, a% m) [5 Jexcess.1,3; Z8 L' j0 `7 ]% E
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
2 } Y4 l! B" x542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
* E- U4 @* M' b! [A unique entity of male-limited gonadotropin-6 x ?# z, t) O9 M3 q3 o4 D
independent precocious puberty, which is also known
$ M. _# W3 f0 ?& P7 `0 sas testotoxicosis, may cause precocious puberty at a
: y3 \$ w) ], V# Rvery young age. The physical findings in these boys) Z& D ^$ ^* k$ P
with this disorder are full pubertal development,: K6 v" \! n& A/ H: {9 M
including bilateral testicular growth, similar to boys
, t6 v8 L# X5 L5 V+ I2 w: zwith CPP. The gonadotropin levels in this disorder* e0 m8 m7 p$ E6 ?+ |. K
are suppressed to prepubertal levels and do not show$ P, S$ i. A+ O' T0 Q
pubertal response of gonadotropin after gonadotropin-
- D/ o( A9 L+ R' Yreleasing hormone stimulation. This is a sex-linked) e4 Z$ S1 A' r2 O* r# P
autosomal dominant disorder that affects only8 w" Q5 Q2 }. U1 ?5 G
males; therefore, other male members of the family
* W) I* [5 H; v8 q+ e; d3 Nmay have similar precocious puberty.3. b) k0 {" ]+ |, d- d+ I* @
In our patient, physical examination was incon-& [+ ~6 C R* M$ i% ]% T
sistent with true precocious puberty since his testi-
% n- H8 x% d7 A e7 Q: h) Dcles were prepubertal in size. However, testotoxicosis' ?# [+ ]0 V1 U, C5 R) S
was in the differential diagnosis because his father
; C, J/ q& Z- \ Y0 h9 @started puberty somewhat early, and occasionally,9 `/ Q# J! I5 ]
testicular enlargement is not that evident in the7 W7 ~. k/ C8 D3 y% y2 _
beginning of this process.1 In the absence of a neg-
* Z7 S( z5 h# d* F( gative initial history of androgen exposure, our6 K4 p9 Y7 z7 r- ]6 n
biggest concern was virilizing adrenal hyperplasia, C, v, D- d9 i/ O) i) |4 S
either 21-hydroxylase deficiency or 11-β hydroxylase% A a# l9 e2 y
deficiency. Those diagnoses were excluded by find-8 j) c2 G8 x0 s
ing the normal level of adrenal steroids.- i+ F( G% k8 ]% o- m9 w. o" F
The diagnosis of exogenous androgens was strongly# C7 U; w5 H( V$ G- i7 Q6 i7 Q0 E
suspected in a follow-up visit after 4 months because- b4 g$ n: z7 D& E) t
the physical examination revealed the complete disap-
1 L" G* _8 c- [6 L- @$ Rpearance of pubic hair, normal growth velocity, and
8 X! J# `, N0 @% H$ x' Vdecreased erections. The father admitted using a testos-( M/ b4 ]7 H% u2 q4 G
terone gel, which he concealed at first visit. He was4 l+ i# f, t; I( v
using it rather frequently, twice a day. The Physicians’
& o( R0 n; l* Y9 y" @9 @) ]Desk Reference, or package insert of this product, gel or0 c% V" \+ ^+ X1 [; s# J- h
cream, cautions about dermal testosterone transfer to+ W2 i3 [5 S6 M. Q4 [- T
unprotected females through direct skin exposure.
" X/ H7 Z! d0 \0 l* g0 vSerum testosterone level was found to be 2 times the9 C& U& d. w+ n t; }
baseline value in those females who were exposed to0 Q7 g# {* x8 |3 ~* p# I$ f
even 15 minutes of direct skin contact with their male
; h3 z# |2 g' p7 [4 gpartners.6 However, when a shirt covered the applica-
" K; F& I4 a+ @; l. i3 O3 Ytion site, this testosterone transfer was prevented.
- e* R$ L; O7 y. F f+ C/ f0 z/ E3 COur patient’s testosterone level was 60 ng/mL,: I* Y, m1 S* z# v
which was clearly high. Some studies suggest that
; c: }$ U+ b# X* B$ Hdermal conversion of testosterone to dihydrotestos-
6 ] E: m+ x1 s( D- Y* z9 C& _terone, which is a more potent metabolite, is more
- x1 ~5 \( s' R% O) j2 ~active in young children exposed to testosterone' X( J! u) {, j* u- X
exogenously7; however, we did not measure a dihy-8 g- H' k3 [3 F' P V
drotestosterone level in our patient. In addition to& H% x8 W& D( j6 N
virilization, exposure to exogenous testosterone in/ N6 }) C. i2 V: H# B( V
children results in an increase in growth velocity and* ~ s* ^. N; x0 B) N8 Q
advanced bone age, as seen in our patient.! ?& Y' \4 E @8 K
The long-term effect of androgen exposure during
! b6 n5 y( b9 t* p# L& rearly childhood on pubertal development and final7 {9 c- k1 `; r% ?& F
adult height are not fully known and always remain ?; A. p5 @& A+ c
a concern. Children treated with short-term testos-
9 E$ E% v% g3 p7 i! Pterone injection or topical androgen may exhibit some! A$ C! ~: \0 h: s; v; {) P9 Q
acceleration of the skeletal maturation; however, after4 e4 Y$ g1 K; b$ R+ g! K7 S
cessation of treatment, the rate of bone maturation+ T6 u" p. m( _# M
decelerates and gradually returns to normal.8,9
* E. `+ `6 ]0 a+ \! K2 dThere are conflicting reports and controversy6 L) [" T& L% |1 d$ E4 I
over the effect of early androgen exposure on adult8 R0 G' E( h7 X6 ]. K5 |
penile length.10,11 Some reports suggest subnormal
7 z& l7 T" t |+ d- ladult penile length, apparently because of downreg-/ ], u+ z3 C( ~- l6 {6 F' b
ulation of androgen receptor number.10,12 However,2 ], D2 W3 H9 S9 R2 f7 u$ K5 [) K
Sutherland et al13 did not find a correlation between! i1 f1 Z0 A% X2 n
childhood testosterone exposure and reduced adult8 G8 ~' a8 F+ e. X% e
penile length in clinical studies., |2 {3 K; b$ L
Nonetheless, we do not believe our patient is
$ K1 L* E+ N& p8 r8 f6 vgoing to experience any of the untoward effects from
6 b# T4 \# t ?5 E, ytestosterone exposure as mentioned earlier because' {& ~# a6 c3 A6 R; c
the exposure was not for a prolonged period of time.
+ w a& ^# h, L8 vAlthough the bone age was advanced at the time of
5 S R: |* J$ d. z1 ]diagnosis, the child had a normal growth velocity at6 `+ o2 q g m3 n) S: x
the follow-up visit. It is hoped that his final adult$ Y% e/ I0 x" M3 `$ Z' _6 L/ M
height will not be affected.( d" f7 v( c# v J+ Y
Although rarely reported, the widespread avail-4 u1 `, y0 t/ g
ability of androgen products in our society may1 Y1 a& p, U$ r
indeed cause more virilization in male or female
; m* N. j: I7 s7 Ichildren than one would realize. Exposure to andro-& B, g5 b2 D8 O3 R g5 ^
gen products must be considered and specific ques-5 R2 ?: Y, j9 }9 Q; _: t# p
tioning about the use of a testosterone product or! }5 F) k4 L Y5 h) L* i
gel should be asked of the family members during
' Q G& b$ P& j: I$ cthe evaluation of any children who present with vir-
1 M* h0 C" V9 L; u+ n9 Dilization or peripheral precocious puberty. The diag-
; z6 v- D9 ~& s" C7 Pnosis can be established by just a few tests and by
+ O4 M' \" [% @$ ?' Y: eappropriate history. The inability to obtain such a
+ U* g) u: T1 G; nhistory, or failure to ask the specific questions, may2 H: A/ ]+ j6 _& ^8 [, I
result in extensive, unnecessary, and expensive) ]- j1 [7 Y1 y- Q
investigation. The primary care physician should be
% |3 Z: f" s% R1 h9 c9 s1 h) u0 Iaware of this fact, because most of these children
3 N. T+ D' u2 C' c, k/ ?may initially present in their practice. The Physicians’
* U4 o' l7 \! h$ Y+ g8 X0 b/ gDesk Reference and package insert should also put a E* ^+ x7 c1 S0 q% r5 A1 X
warning about the virilizing effect on a male or1 z/ c5 M; o! t" k6 S
female child who might come in contact with some-
0 N% q1 D) i. B& X( Z5 eone using any of these products.( z8 ?# ?9 ?8 ~- B3 c/ R5 ]. u+ [
References
8 l" \) I, O6 b1 A" d1. Styne DM. The testes: disorder of sexual differentiation
: U$ r a9 S$ [9 Mand puberty in the male. In: Sperling MA, ed. Pediatric8 |9 A( ?+ b/ i+ w5 P
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
5 k& j( q7 d' ^+ ^, U6 r1 G2002: 565-628.. Y0 H- {1 O' j, O! _- d
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
6 g+ h- l4 i+ { a1 V5 {; gpuberty in children with tumours of the suprasellar pineal |
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