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Sexual Precocity in a 16-Month-Old E$ L3 z$ z( x; l9 c' X' V
Boy Induced by Indirect Topical
6 n6 q% `2 {7 A/ k4 B7 fExposure to Testosterone& l, \1 U( a; W2 V1 e
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
1 m: }. `2 ~3 \* i, N* xand Kenneth R. Rettig, MD1
6 W0 _' ]7 ?& } b( T. q9 ?) n5 |Clinical Pediatrics0 y+ {" ~. z, p( `, a6 R& h3 ^" B
Volume 46 Number 6
0 C5 D8 h+ w2 I" kJuly 2007 540-5433 |5 k# z. u( a8 L# s4 Y/ W
© 2007 Sage Publications7 [' P9 u1 h9 R* C$ X6 G
10.1177/0009922806296651# |3 b3 h$ ]+ L$ a8 w. ?
http://clp.sagepub.com3 G% _$ P* G& \. f1 \7 T$ e3 N
hosted at5 w6 b: X J/ F8 o5 }
http://online.sagepub.com E/ {: q1 \) q; q# l
Precocious puberty in boys, central or peripheral,
8 m- ^ Z$ e0 O2 r& o6 k9 f" l ^is a significant concern for physicians. Central) u7 l1 y, s4 a7 I4 _" I8 G7 ~+ ~4 J2 J
precocious puberty (CPP), which is mediated
( }7 N N+ D' p) K: y1 \through the hypothalamic pituitary gonadal axis, has
4 W7 S7 `* C4 S! J: v1 x( f6 Aa higher incidence of organic central nervous system
9 [5 E+ n+ J3 t! Llesions in boys.1,2 Virilization in boys, as manifested
/ S4 B' d1 y' U7 `# z% K0 H; Vby enlargement of the penis, development of pubic
0 w/ E8 ?9 M6 D( e) Phair, and facial acne without enlargement of testi-
/ C1 d- m( h, f: i9 u; {6 @cles, suggests peripheral or pseudopuberty.1-3 We3 _* p- ^7 d h6 l+ r& g) L
report a 16-month-old boy who presented with the
3 g8 ?* _: N1 A7 Senlargement of the phallus and pubic hair develop-
5 c; [) M) c; O6 D/ ument without testicular enlargement, which was due
# m3 Y5 T% `" W& Z1 m) Rto the unintentional exposure to androgen gel used by
+ m% q! L e c, ?- x+ N0 A, k3 x" Hthe father. The family initially concealed this infor-& A$ Y, n( b* g( Z/ @1 |
mation, resulting in an extensive work-up for this
# u1 l- K; L5 Y# s. U& V; qchild. Given the widespread and easy availability of
0 Q( V4 L/ t+ J3 C* `! Dtestosterone gel and cream, we believe this is proba-4 U2 I, J/ d* X4 O
bly more common than the rare case report in the
! O/ a o/ l* k( w% rliterature.4
5 W# i. i4 l% R E i* q) O) u$ cPatient Report: P+ }( j% M5 F- k; n8 f
A 16-month-old white child was referred to the
- z( s- w# e# Y1 D" A! Cendocrine clinic by his pediatrician with the concern
' m' U/ a$ K, Xof early sexual development. His mother noticed
3 @: D3 `4 P. r1 jlight colored pubic hair development when he was
4 f8 t; n8 C! T6 }+ L1 f8 {! S8 HFrom the 1Division of Pediatric Endocrinology, 2University of
4 J& d* p% ~- P! FSouth Alabama Medical Center, Mobile, Alabama.* ?5 N6 D) |( O; u X6 ^1 z5 D
Address correspondence to: Samar K. Bhowmick, MD, FACE,. R) g5 \% u: w( M( L
Professor of Pediatrics, University of South Alabama, College of' v; s8 d" U2 m
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
% _0 Q& W- n+ Q4 ^% H$ e2 ge-mail: [email protected].. q# X& I$ d5 z8 {4 S
about 6 to 7 months old, which progressively became
' v+ R0 |4 P2 Z1 jdarker. She was also concerned about the enlarge-
; Q% L! }9 e3 U$ u2 N2 A4 V) E) v& mment of his penis and frequent erections. The child4 K' j9 d x9 G/ s1 X
was the product of a full-term normal delivery, with
8 F$ k O# o! Q" O w7 wa birth weight of 7 lb 14 oz, and birth length of
9 Z& M7 p% H+ c) }: c8 L/ T. r8 c20 inches. He was breast-fed throughout the first year; D! R( y* J0 q5 M0 f
of life and was still receiving breast milk along with9 F: K2 a/ ^6 t: {
solid food. He had no hospitalizations or surgery,
2 J+ W' `6 h3 F3 Rand his psychosocial and psychomotor development3 [- n8 R# k- T5 ]) L0 _. N
was age appropriate.
% h* I# b/ V' A) TThe family history was remarkable for the father,
# y6 R) ]# e+ E! }who was diagnosed with hypothyroidism at age 16,1 ]2 t) S1 |7 w+ l& r4 C
which was treated with thyroxine. The father’s
- W- A3 G, B7 `+ o( e9 F Aheight was 6 feet, and he went through a somewhat
) E, |* o4 j: U# d" j6 Dearly puberty and had stopped growing by age 14.
1 C# R$ V k, D& U) z% Y AThe father denied taking any other medication. The
# c$ n3 n- w6 y' H$ Jchild’s mother was in good health. Her menarche
6 ^- j" g9 D# K, |8 {was at 11 years of age, and her height was at 5 feet/ A8 d$ D5 x; Y
5 inches. There was no other family history of pre-
. ~5 ?0 {! u: ccocious sexual development in the first-degree rela-# b# v; n1 W4 b4 l2 i7 u" U0 p
tives. There were no siblings.
) |& m2 |( x( T7 E1 O3 U+ ZPhysical Examination
1 }9 l: ^3 m5 c" ~% [- ^0 Z- [The physical examination revealed a very active,
) `% X3 [3 J- Kplayful, and healthy boy. The vital signs documented8 v, r, W5 g. t. s! ^
a blood pressure of 85/50 mm Hg, his length was* @- Q6 l" s0 o I& d/ L
90 cm (>97th percentile), and his weight was 14.4 kg* d4 R& a2 J" J
(also >97th percentile). The observed yearly growth
% ?0 F% E) M: n- Gvelocity was 30 cm (12 inches). The examination of7 A2 a4 T4 ?4 E1 I" c2 d5 H
the neck revealed no thyroid enlargement.3 Y$ E! _! F* |$ Y' a$ x
The genitourinary examination was remarkable for
; X+ q$ N& ~% Y; }, ienlargement of the penis, with a stretched length of, m c- y4 o8 u+ M! Y
8 cm and a width of 2 cm. The glans penis was very well- A' G6 D& A' U; q3 X7 O
developed. The pubic hair was Tanner II, mostly around; w$ a, u3 d a* L" j0 q# ^
540
6 v. C3 j7 W0 r" kat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from2 O5 {# w* Y0 P2 h9 I
the base of the phallus and was dark and curled. The$ Z# V/ _7 l7 t0 Y" {! O; C9 ^
testicular volume was prepubertal at 2 mL each.
$ ]- @0 K: P4 ZThe skin was moist and smooth and somewhat3 B0 j" {$ a0 [; _6 ?) s! v
oily. No axillary hair was noted. There were no
3 E F# w7 @/ ~. G! b$ I2 ]: |abnormal skin pigmentations or café-au-lait spots.* m0 M s( { e
Neurologic evaluation showed deep tendon reflex 2+# f4 E+ L- I7 {
bilateral and symmetrical. There was no suggestion
# h* P) S3 _# d$ z2 aof papilledema.
3 y" D3 u9 E9 p M) DLaboratory Evaluation: d' M$ Y' W- G/ _" A) f# {
The bone age was consistent with 28 months by# ?, R4 |/ A/ s0 S
using the standard of Greulich and Pyle at a chrono-, D8 `* d; A8 Q9 l6 h( ]$ w/ E
logic age of 16 months (advanced).5 Chromosomal
8 J( e/ @, L% x" k2 nkaryotype was 46XY. The thyroid function test
; a& z: B; f! t! g# xshowed a free T4 of 1.69 ng/dL, and thyroid stimu-0 W0 E- T2 `. T# x
lating hormone level was 1.3 µIU/mL (both normal).2 m- D. s$ ]; T: k
The concentrations of serum electrolytes, blood6 ~4 w: ^2 I" u g& q/ i
urea nitrogen, creatinine, and calcium all were3 w5 D, H6 ~- c3 e& u. k( s
within normal range for his age. The concentration8 s8 F9 y; W+ ~8 r
of serum 17-hydroxyprogesterone was 16 ng/dL* m; x3 F$ w) a- [+ B& X
(normal, 3 to 90 ng/dL), androstenedione was 20" J( k) R3 @" b- W' O5 W3 W* F
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
. a( p+ V* L* s& D' rterone was 38 ng/dL (normal, 50 to 760 ng/dL),
' ?# n' P; E& R& ?desoxycorticosterone was 4.3 ng/dL (normal, 7 to/ A9 z* s P; p- `- R, p3 M
49ng/dL), 11-desoxycortisol (specific compound S)
2 f1 F. G- {* N8 \was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
/ t6 Z$ t% w S0 d z( a% i) @tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total/ X+ ] ?9 B+ x. Y- _
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),/ V& Z( Z. j# G0 r, Q
and β-human chorionic gonadotropin was less than2 Y, J* g- i! g, H
5 mIU/mL (normal <5 mIU/mL). Serum follicular6 U% y2 q3 q u, D5 V0 i- P
stimulating hormone and leuteinizing hormone( ~) y* M" X; C1 O
concentrations were less than 0.05 mIU/mL
" \$ L3 Y0 c4 a) n3 t(prepubertal).
% v/ K( |+ A ~/ i9 H wThe parents were notified about the laboratory3 m8 S! ~9 L: G, T. V
results and were informed that all of the tests were4 k+ Z' _0 p4 y( f! v5 g
normal except the testosterone level was high. The- [2 }1 Z( n, Q" b" s
follow-up visit was arranged within a few weeks to+ ^' z8 E2 ^* I5 N. p( l5 N* _
obtain testicular and abdominal sonograms; how-6 P; N& c7 n; P6 J
ever, the family did not return for 4 months.& ?2 c' W4 e! Q5 Q, r
Physical examination at this time revealed that the
, l1 | h# M+ m+ P0 j& k/ l6 gchild had grown 2.5 cm in 4 months and had gained5 v) Q9 v# S, G9 {' _! p9 h, }
2 kg of weight. Physical examination remained
! a$ [1 a7 I1 [5 T% Punchanged. Surprisingly, the pubic hair almost com-$ f4 Y' {3 a* B- l( z
pletely disappeared except for a few vellous hairs at
& U/ \' V2 B' q6 U. ~the base of the phallus. Testicular volume was still 24 l* E" [6 p7 Y8 v
mL, and the size of the penis remained unchanged.; q# ~4 h# Q1 B; p
The mother also said that the boy was no longer hav-
0 o) ^ X8 M0 ^ing frequent erections.2 F ]# ~4 ~7 m
Both parents were again questioned about use of
$ W' q( Y! s ^( \any ointment/creams that they may have applied to4 |2 i) J" C1 R
the child’s skin. This time the father admitted the
1 d" s# o/ j* o DTopical Testosterone Exposure / Bhowmick et al 541
3 n4 n3 A* t, [9 |' R4 quse of testosterone gel twice daily that he was apply-: }0 S& d, @6 S h) x! i
ing over his own shoulders, chest, and back area for R* a$ h' Z0 A% l+ R
a year. The father also revealed he was embarrassed! v' x" ^5 n9 B1 u3 T4 P
to disclose that he was using a testosterone gel pre-
S; p5 @; g' O. m+ E, u/ `scribed by his family physician for decreased libido6 I+ s. ?$ r' c$ A; m
secondary to depression.
8 A7 T( ^+ ?4 z7 c; GThe child slept in the same bed with parents.
) h# t+ Y* g# Z, a: B0 CThe father would hug the baby and hold him on his# U2 X9 {7 _+ i4 v- ]
chest for a considerable period of time, causing sig-
) P" f8 m; Q0 @9 G, O$ h' N0 T `nificant bare skin contact between baby and father.$ P+ T& T3 ]6 a8 ]
The father also admitted that after the phone call,6 a' H* W$ C( Q! a+ N- ?4 x
when he learned the testosterone level in the baby
7 A" C* C! }5 e' Qwas high, he then read the product information8 o6 L3 f8 V* z( y$ r1 b
packet and concluded that it was most likely the rea-
7 P5 p; P) |9 N! pson for the child’s virilization. At that time, they
8 R& `, E2 A$ i) _( Kdecided to put the baby in a separate bed, and the
5 ]5 Q- h" E& T1 Pfather was not hugging him with bare skin and had
$ T, X9 i$ a. \" t7 tbeen using protective clothing. A repeat testosterone
( j [- l7 p1 ] D0 ]) J/ ltest was ordered, but the family did not go to the
4 b9 @( l$ e' s" Claboratory to obtain the test.* ]9 {9 c3 h3 t" w
Discussion% B Y. X8 B4 F: ~ x' I! {5 M
Precocious puberty in boys is defined as secondary1 P. B9 I2 j, B3 l) x3 p) g
sexual development before 9 years of age.1,4& |/ z1 \% s" Z! L7 {1 ~% _
Precocious puberty is termed as central (true) when! l. ?, i6 |) G
it is caused by the premature activation of hypo-3 Q8 w% t+ |# {6 O7 G" y* B
thalamic pituitary gonadal axis. CPP is more com-
. R. D7 I( q$ }3 _- q7 N5 Ymon in girls than in boys.1,3 Most boys with CPP$ V" E* R& t2 q9 Y3 D- V# ]
may have a central nervous system lesion that is' I$ j9 N) I4 f5 o. L
responsible for the early activation of the hypothal-- T+ @# b7 M; E2 u' b* F& c
amic pituitary gonadal axis.1-3 Thus, greater empha- F' K- Z4 F& D1 E3 z* R2 \- C3 Q
sis has been given to neuroradiologic imaging in+ @: q$ I p/ s8 q
boys with precocious puberty. In addition to viril-
3 }) a$ i. [! A( l0 H: Y1 Jization, the clinical hallmark of CPP is the symmet-
6 e5 T& p, [: R' u- Nrical testicular growth secondary to stimulation by0 h/ O$ t: n9 m3 w' {$ g% V
gonadotropins.1,3, }8 t. F: i2 O: f& \* u8 @; C2 q
Gonadotropin-independent peripheral preco-/ f( g; F7 t# G# w1 c
cious puberty in boys also results from inappropriate! j8 m8 o' b. L! Q5 b0 v
androgenic stimulation from either endogenous or) }) \ B6 {' \1 i# B3 I
exogenous sources, nonpituitary gonadotropin stim-
8 s$ Y- a3 Q* h; y( a; Bulation, and rare activating mutations.3 Virilizing
$ H/ d' P+ g1 L5 @5 o5 U$ Bcongenital adrenal hyperplasia producing excessive
6 F# e( K( f" F2 ^ \. t% Vadrenal androgens is a common cause of precocious: @! B' {% F8 h Q
puberty in boys.3,4. s. C, @% \/ h, U, ^+ M+ E; l
The most common form of congenital adrenal! u, h, z j0 ]; g7 c
hyperplasia is the 21-hydroxylase enzyme deficiency.0 |, t, Z" @% Z8 C
The 11-β hydroxylase deficiency may also result in
0 B, ^4 V$ G+ d2 q# P% vexcessive adrenal androgen production, and rarely,9 a& q7 {. }, i& q* P
an adrenal tumor may also cause adrenal androgen6 e/ ^* z. \0 E; U" g
excess.1,3
6 v9 N. N# y* a$ X& _. }, O1 y$ u6 h: Tat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from$ D$ j/ | ~- `( e, F! @
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007 i' u. t& h0 S! Q
A unique entity of male-limited gonadotropin-' R ?+ K0 J% u. T5 X7 d9 t" C
independent precocious puberty, which is also known
1 U3 S& u; Z5 b5 A+ R, pas testotoxicosis, may cause precocious puberty at a
. \+ J6 O }- p& |3 ~5 Jvery young age. The physical findings in these boys( R( v, B) I- @7 Q
with this disorder are full pubertal development,
5 _& m1 a4 z8 U, k4 g' E. Zincluding bilateral testicular growth, similar to boys
5 G* Y( z. Q9 b; h" p$ M; swith CPP. The gonadotropin levels in this disorder* a$ b! x" H; ]: v3 d" g
are suppressed to prepubertal levels and do not show
) Y/ z+ L8 G$ X V. I& v" ^5 xpubertal response of gonadotropin after gonadotropin-9 e/ E) M- t. }* d" g& L) L
releasing hormone stimulation. This is a sex-linked3 l) Y/ O. `; Q9 L
autosomal dominant disorder that affects only y" _, a5 s# D1 e! `
males; therefore, other male members of the family
g, i2 B/ O0 Z" a/ D1 Z9 xmay have similar precocious puberty.3
( _7 F, _; D. E( iIn our patient, physical examination was incon-8 w! U0 N2 v- s( j; c: @! H+ q5 h
sistent with true precocious puberty since his testi-
- u6 c- g! @2 r K- o- H) R& ccles were prepubertal in size. However, testotoxicosis
2 \ e W2 D' d) O4 ]# mwas in the differential diagnosis because his father
9 h6 [# F* a0 _started puberty somewhat early, and occasionally,7 k, e9 k0 l7 C# o
testicular enlargement is not that evident in the& M$ t6 Q. a+ o3 B3 \1 h4 K* d: C
beginning of this process.1 In the absence of a neg-
' r5 d1 G: ^3 R! g1 b6 uative initial history of androgen exposure, our* j* R. X% T9 R, ?% Z; Q
biggest concern was virilizing adrenal hyperplasia,
+ N |- q3 |: N# B4 k! c% O( [; Qeither 21-hydroxylase deficiency or 11-β hydroxylase
) l7 n8 J3 g4 \; B$ f+ h' F% udeficiency. Those diagnoses were excluded by find-
9 L; ]) {* W" V- ~ing the normal level of adrenal steroids.
) U* ~4 ^. ]+ oThe diagnosis of exogenous androgens was strongly w" L% Y% S& q; D6 H. I4 D0 j3 a
suspected in a follow-up visit after 4 months because. F0 i9 u5 M& O: Y
the physical examination revealed the complete disap-8 w* {1 H9 n$ K2 V' Y) r& v
pearance of pubic hair, normal growth velocity, and
+ Y7 |- G3 j" |7 g" n4 Xdecreased erections. The father admitted using a testos-
$ O7 ?6 B" m, z5 y7 ?1 j. Z/ w; u6 Jterone gel, which he concealed at first visit. He was
6 R/ E; g/ y0 a: `using it rather frequently, twice a day. The Physicians’. @( F. j' P9 O1 R1 ]5 M
Desk Reference, or package insert of this product, gel or& b' P4 @" e8 m1 z7 v
cream, cautions about dermal testosterone transfer to
( p; Q8 J+ B) t$ y7 Ounprotected females through direct skin exposure.
3 z$ _) i7 z9 @! P4 \! Z! XSerum testosterone level was found to be 2 times the. R( E$ L: x( _* Y* r E* ~
baseline value in those females who were exposed to3 d/ @" l8 j* S
even 15 minutes of direct skin contact with their male' \6 ^; d- B! K5 d v
partners.6 However, when a shirt covered the applica-; a" D/ q% M G# B
tion site, this testosterone transfer was prevented.' V8 d! |6 H" x8 Y2 ^
Our patient’s testosterone level was 60 ng/mL,
) E2 Z4 J" ]6 ]! _' j; Rwhich was clearly high. Some studies suggest that) |' j9 ^/ B4 Y9 z+ I; b
dermal conversion of testosterone to dihydrotestos-& W1 m! X- h6 x$ o
terone, which is a more potent metabolite, is more
& d# ]1 ]# ?: L4 f9 C$ Z+ t( _6 B5 ractive in young children exposed to testosterone
5 }7 X0 n$ p2 _exogenously7; however, we did not measure a dihy-
7 I6 P! Z: ?% M7 T& V7 hdrotestosterone level in our patient. In addition to
/ Z& z1 v2 z5 W. e" @1 _2 zvirilization, exposure to exogenous testosterone in
3 A# \3 y3 I: D/ d5 v- cchildren results in an increase in growth velocity and
& _, E% k( @! N5 [/ P6 R madvanced bone age, as seen in our patient.
) Q* @' G! T$ l. tThe long-term effect of androgen exposure during
/ S# [) m5 ^% D% D6 Z& x1 {early childhood on pubertal development and final/ |* g/ { _, q9 ?
adult height are not fully known and always remain
% Q6 ?. s( G& J5 z4 ya concern. Children treated with short-term testos-" C, C/ A4 ?$ V/ D" S
terone injection or topical androgen may exhibit some+ k" l+ o: Z) q" v: ^' \
acceleration of the skeletal maturation; however, after
2 ^+ ^. t# C. Pcessation of treatment, the rate of bone maturation1 A! H' K9 X7 J* P! g- T
decelerates and gradually returns to normal.8,9
# N: u& G) K' F6 k1 n& w6 w1 ]& ^There are conflicting reports and controversy5 Y3 [( M" _# L5 W% W
over the effect of early androgen exposure on adult
" p0 i i0 X, rpenile length.10,11 Some reports suggest subnormal
+ X+ g0 @1 c* x" j1 uadult penile length, apparently because of downreg-$ w- b- Y+ y4 O* ^' Q( Y
ulation of androgen receptor number.10,12 However,
9 G4 y$ d9 C3 m5 p& s5 t+ J5 PSutherland et al13 did not find a correlation between; E0 n: Y4 E& o
childhood testosterone exposure and reduced adult
7 e7 I+ O( {, e8 B7 Tpenile length in clinical studies.; O2 b S! W/ \
Nonetheless, we do not believe our patient is! A3 D8 r: G& G, |' z7 w4 c
going to experience any of the untoward effects from: n1 V5 z4 b6 R4 m. A
testosterone exposure as mentioned earlier because& H1 W5 w. p3 p- p6 @% q+ T
the exposure was not for a prolonged period of time.
, ]2 d# T7 r4 a) J6 A0 BAlthough the bone age was advanced at the time of
. V1 w* [+ j* I& S" T0 a; zdiagnosis, the child had a normal growth velocity at
% R1 l# h; l1 c" i; r4 B X2 sthe follow-up visit. It is hoped that his final adult. {8 b/ ]9 g' x N
height will not be affected.1 G+ I6 R1 m% \1 f6 `
Although rarely reported, the widespread avail-, _) L( [% k" r$ b
ability of androgen products in our society may* E. n) k, i s- J- K( Q
indeed cause more virilization in male or female/ D6 V, a, V5 q( |* P% S1 \$ u
children than one would realize. Exposure to andro-# j M/ e; ]- z0 q
gen products must be considered and specific ques-: E8 m3 g& K2 x
tioning about the use of a testosterone product or& S* O7 w3 |6 T
gel should be asked of the family members during
% ?# d$ N+ m( L) j8 }the evaluation of any children who present with vir-
/ w# n$ `6 V4 x) C( C1 wilization or peripheral precocious puberty. The diag-
/ P) e: q0 b( Dnosis can be established by just a few tests and by- N9 @. L; O$ e6 \$ l6 M
appropriate history. The inability to obtain such a
# J. j+ T4 T/ j5 r0 H% D4 Jhistory, or failure to ask the specific questions, may
6 T/ y0 O0 g0 z( c( Y8 P( Q" E9 ?result in extensive, unnecessary, and expensive
; V4 S# _! C5 L* x2 _investigation. The primary care physician should be$ D8 t6 R' p2 A
aware of this fact, because most of these children
0 ]" W, w6 N R$ H! f% a. V; ?may initially present in their practice. The Physicians’
5 _* y! h2 O: }, e" fDesk Reference and package insert should also put a6 ~ \5 X3 b8 W2 n
warning about the virilizing effect on a male or
, u' r1 i# t, y4 dfemale child who might come in contact with some-
+ \1 H: V1 Q- j: hone using any of these products.2 i- x6 |+ o/ v( w
References$ ^( s j9 \& Y/ X3 ^2 u, S- e
1. Styne DM. The testes: disorder of sexual differentiation
! m1 k2 Z G& ?- @' x' c0 J, w2 rand puberty in the male. In: Sperling MA, ed. Pediatric' e7 ^9 j; \6 q& j" Q3 o
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;; d6 e5 q' ^0 D- k5 p
2002: 565-628.2 f* I% m) D- ~3 ~
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious* f/ F. {0 O' J
puberty in children with tumours of the suprasellar pineal |
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