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Sexual Precocity in a 16-Month-Old
4 i& ~% D8 ?1 w/ D" s @# QBoy Induced by Indirect Topical! H l7 W( V# u6 D
Exposure to Testosterone* F( p3 v, } [1 B8 }
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
9 W4 N/ Y1 v+ ], Q8 H8 y" M# Tand Kenneth R. Rettig, MD1" t+ d# |+ `* `# |: d, d
Clinical Pediatrics
! N$ x# @7 ^3 A) MVolume 46 Number 6/ k: L& Z: z4 n- N: ^0 [
July 2007 540-543
$ D, E" R$ H" R7 I \© 2007 Sage Publications
+ U* o$ f% c6 e10.1177/0009922806296651
" K0 V P: S& Ahttp://clp.sagepub.com
! ~ p. j$ ~. z9 p2 D S# g* zhosted at; f: |$ p# v) k: c, f
http://online.sagepub.com
2 k% F' Z, N* i: W$ ^8 b/ D& `Precocious puberty in boys, central or peripheral,# l4 q3 q% L' J/ i) F
is a significant concern for physicians. Central
+ |4 Q# `/ I$ [, I: S& Rprecocious puberty (CPP), which is mediated& N% n% `: f d
through the hypothalamic pituitary gonadal axis, has. C9 I5 P- e" a: b1 h, W2 c0 B
a higher incidence of organic central nervous system7 Q6 _ `$ X& _' d
lesions in boys.1,2 Virilization in boys, as manifested" b9 E( I) u- w6 \* N3 T
by enlargement of the penis, development of pubic
- f. n; b; e: O* e. [ Ehair, and facial acne without enlargement of testi-! k8 Q& n! [8 c7 \- U" y
cles, suggests peripheral or pseudopuberty.1-3 We' H3 H' H9 N% w) f# k; o/ \, f$ b
report a 16-month-old boy who presented with the
. ~5 p6 R3 {$ [9 j* Henlargement of the phallus and pubic hair develop-
" W: X$ o8 M ~* [( } Jment without testicular enlargement, which was due
1 e' g) [8 \1 ^to the unintentional exposure to androgen gel used by
2 o* q1 r" A G+ Cthe father. The family initially concealed this infor-! b u- @1 L7 |' l
mation, resulting in an extensive work-up for this
) s; \, J+ W, Pchild. Given the widespread and easy availability of: n' P$ C4 ^$ S* Y+ o; v3 q
testosterone gel and cream, we believe this is proba-
; c: x, v' q# ubly more common than the rare case report in the
3 R! }7 M- R- v6 s* {literature.4
; M `& X; ]7 @+ t2 jPatient Report
3 J7 q# R3 {4 x% I, sA 16-month-old white child was referred to the; U0 u8 _* L/ v& m/ F0 B
endocrine clinic by his pediatrician with the concern
0 ^+ S; P) S' w4 S* S( Sof early sexual development. His mother noticed c h( r! D( A2 H* B- y1 [" y; u: [( }
light colored pubic hair development when he was5 H6 U" m; q- X( A; q' H
From the 1Division of Pediatric Endocrinology, 2University of0 d( n8 X! {2 M9 w' Z
South Alabama Medical Center, Mobile, Alabama.
+ Y( V: z5 {: g7 |6 b5 eAddress correspondence to: Samar K. Bhowmick, MD, FACE,
' {1 O a# q* s7 \Professor of Pediatrics, University of South Alabama, College of
" @3 P. `2 N9 h/ f: U6 }( {( L" d3 {* zMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;- \* F; }2 A, c" p# [6 T8 j2 o
e-mail: [email protected].
3 H. b, S) u9 `* W* x% T2 |about 6 to 7 months old, which progressively became/ `( A5 X5 S3 m
darker. She was also concerned about the enlarge-# d7 X5 s2 ?7 z: u# C) G
ment of his penis and frequent erections. The child. ~ L5 ]% ]: O1 X$ R( b% a
was the product of a full-term normal delivery, with
4 |* @& @; {3 R; f c; I$ ba birth weight of 7 lb 14 oz, and birth length of) D, s4 l, ?. F
20 inches. He was breast-fed throughout the first year0 N# L4 {5 I- X& J9 z% T
of life and was still receiving breast milk along with* i2 ]+ Z( `0 c
solid food. He had no hospitalizations or surgery,
: l' w- H7 P! |0 [and his psychosocial and psychomotor development0 G1 G, m% y7 o. d& L
was age appropriate.
3 H4 ~3 L0 D( B3 ]; \" L: B- tThe family history was remarkable for the father,
1 X' z+ G1 y# A) T* Vwho was diagnosed with hypothyroidism at age 16,
3 J8 h) j: b. Y" _- M% ~9 u7 xwhich was treated with thyroxine. The father’s
: ~& L. T6 c1 g. _) xheight was 6 feet, and he went through a somewhat
+ t, }4 _7 }! d5 e* rearly puberty and had stopped growing by age 14.
; q0 F( a7 g9 k; l) dThe father denied taking any other medication. The6 H0 Y* x2 Z0 h
child’s mother was in good health. Her menarche
, K+ g# }6 U7 q% l- wwas at 11 years of age, and her height was at 5 feet( D4 \0 Z% `1 ^1 }
5 inches. There was no other family history of pre-
# G- M" a. _4 q5 s. p# [cocious sexual development in the first-degree rela-
8 g2 l* `# [# B. T& v, I$ @' R! X) jtives. There were no siblings.
, A# Z0 v4 A+ t7 F. sPhysical Examination
! B8 P7 R/ z& I- I& sThe physical examination revealed a very active,
! p7 f( z! z) w3 C' c7 d( iplayful, and healthy boy. The vital signs documented ?8 w( ]5 ?7 Z
a blood pressure of 85/50 mm Hg, his length was8 l& z- E8 r: t, [8 v3 {
90 cm (>97th percentile), and his weight was 14.4 kg5 o# G. c, t+ q& {% k' R8 i
(also >97th percentile). The observed yearly growth5 ^5 k- v- u6 Q4 ~
velocity was 30 cm (12 inches). The examination of
/ K, y0 U8 }" L. B( Bthe neck revealed no thyroid enlargement.. ]6 r& o b$ ?5 X, y0 g
The genitourinary examination was remarkable for$ n: b/ p; l/ ]7 S+ }/ p( R# n/ L
enlargement of the penis, with a stretched length of
4 i6 X. G8 ?! |& |- p8 cm and a width of 2 cm. The glans penis was very well
8 n8 I& h" p' J4 Tdeveloped. The pubic hair was Tanner II, mostly around+ X' {% S5 c! M2 b3 k7 `9 t
540
0 T+ N2 R7 |0 T; Q) Vat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
4 f) F, s. J. x+ m$ vthe base of the phallus and was dark and curled. The
" f# o$ c R& L4 \6 [# h% X1 ttesticular volume was prepubertal at 2 mL each.
. A5 g: w* @# |The skin was moist and smooth and somewhat
( U% e* F! X/ v8 k1 koily. No axillary hair was noted. There were no
% x+ p& H7 @+ v m! b( Habnormal skin pigmentations or café-au-lait spots.
" P" ` y/ r. k* ANeurologic evaluation showed deep tendon reflex 2+! Z+ r7 w' d- _& d
bilateral and symmetrical. There was no suggestion# K' ~8 |( I9 \ w) B5 X, D" u
of papilledema.
k3 W3 J2 ]# S1 S4 ILaboratory Evaluation$ A+ E/ {/ ^& j
The bone age was consistent with 28 months by
1 P7 C9 o8 ?: s" [5 g5 Ausing the standard of Greulich and Pyle at a chrono-
4 `1 p/ r# Q/ |logic age of 16 months (advanced).5 Chromosomal0 Q+ X, j7 K9 {3 `4 t
karyotype was 46XY. The thyroid function test! Y, l1 Z6 b7 s: |
showed a free T4 of 1.69 ng/dL, and thyroid stimu-/ s4 v) |6 c7 p8 K7 p( z6 z
lating hormone level was 1.3 µIU/mL (both normal).) Z/ c, B. V( w* `: D& S
The concentrations of serum electrolytes, blood
8 e3 q. C; k. j1 `! Burea nitrogen, creatinine, and calcium all were
: P8 ~- `( {* J. n9 [within normal range for his age. The concentration
% |; z! a7 n S1 @of serum 17-hydroxyprogesterone was 16 ng/dL. J; Z' f" g5 G3 M
(normal, 3 to 90 ng/dL), androstenedione was 20
/ c, T! \+ L4 _; a: w* L3 ?ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-6 `" C8 @$ |- Y- y/ j' ?, A
terone was 38 ng/dL (normal, 50 to 760 ng/dL),
5 [' H# B1 Y3 ~, ]desoxycorticosterone was 4.3 ng/dL (normal, 7 to2 c/ j* {( l- j0 k3 ?& @: v |* P
49ng/dL), 11-desoxycortisol (specific compound S)) A% t) _/ w; w& s1 s u3 R
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-! f7 v1 P3 R/ M& s- r' S( D, ?" h2 R3 ^
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total% R3 I; l& @; t/ S% E- T
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),1 @. U5 k8 E0 X8 n
and β-human chorionic gonadotropin was less than
! i. g" v& d) \' \ K5 mIU/mL (normal <5 mIU/mL). Serum follicular4 m2 o0 i% m8 ], D" X
stimulating hormone and leuteinizing hormone
4 \' {0 b9 }, C( q z, @concentrations were less than 0.05 mIU/mL
3 h- y) n' G9 Z) n. K(prepubertal).- H/ j' B* l R
The parents were notified about the laboratory
/ R* n+ J3 V- u0 Sresults and were informed that all of the tests were
" a7 m9 M, h; j7 n7 h) m @normal except the testosterone level was high. The
, V L8 m$ u3 R4 `5 xfollow-up visit was arranged within a few weeks to
5 h( P- M! H, N Q( }# Bobtain testicular and abdominal sonograms; how-
/ N& ~" u% y9 z7 uever, the family did not return for 4 months.
* ~$ }. f3 L# V+ hPhysical examination at this time revealed that the
; W9 N1 q1 g6 q6 y k1 K3 Xchild had grown 2.5 cm in 4 months and had gained) G. _2 ?1 p2 q& W+ E: b
2 kg of weight. Physical examination remained0 T f3 V* k3 K
unchanged. Surprisingly, the pubic hair almost com-
: }. b8 f5 }, G- @* X7 o0 `pletely disappeared except for a few vellous hairs at
. I& G& C2 F. b3 A& Athe base of the phallus. Testicular volume was still 20 i8 H; S9 r" J( k; W7 @& d* ]
mL, and the size of the penis remained unchanged.
( z" E0 N$ D+ A1 B) U5 SThe mother also said that the boy was no longer hav-, ~% [1 F5 b6 D3 ^5 n
ing frequent erections.+ [' b) b8 v& a0 z/ E
Both parents were again questioned about use of: U0 K% V, G- ]; o, c' Z8 z, L
any ointment/creams that they may have applied to- `& T1 T) Y& d! A6 g% D) @) N
the child’s skin. This time the father admitted the
& g1 T% {5 ^; O8 |9 k0 A( C+ iTopical Testosterone Exposure / Bhowmick et al 541
6 {) O& @3 o Q' s; ]use of testosterone gel twice daily that he was apply-
' i- n5 m+ P/ K, ~8 Bing over his own shoulders, chest, and back area for2 m1 \* Q {% v
a year. The father also revealed he was embarrassed0 v, \; K# z! K1 x6 l6 {
to disclose that he was using a testosterone gel pre-; @+ E. z+ {' m9 |
scribed by his family physician for decreased libido
4 k u, V0 p% h# L* k% {secondary to depression.2 }9 a/ B. y/ @
The child slept in the same bed with parents.
2 i/ j- x, z) r' d" I. BThe father would hug the baby and hold him on his
* X7 p8 _; i9 n5 J6 g0 a; Xchest for a considerable period of time, causing sig-/ y0 ], j; e8 F! j/ V
nificant bare skin contact between baby and father.
3 W9 p, {" X" D6 X5 ZThe father also admitted that after the phone call,% @4 m" W/ v0 [" n) _
when he learned the testosterone level in the baby) q% x' v( s( e: F- |! [' @
was high, he then read the product information7 m l, {: R% j$ I5 X3 _, }
packet and concluded that it was most likely the rea-: A7 p: c+ t9 `0 m/ D) \6 N
son for the child’s virilization. At that time, they% ]) ~8 P1 K Q+ M: N9 q4 i
decided to put the baby in a separate bed, and the& A6 v4 t- m% n0 m% o4 t7 I
father was not hugging him with bare skin and had
. O, h! G0 ^5 h. F9 Z$ g9 fbeen using protective clothing. A repeat testosterone
5 a3 g$ w2 u1 i; a* qtest was ordered, but the family did not go to the* X) Z$ p0 _8 X3 k( G2 w% t" z( {
laboratory to obtain the test.. z Q# k# @* A( m9 h: v' G0 U% ]
Discussion
' z8 r3 P, @! n$ y; m! z+ s% fPrecocious puberty in boys is defined as secondary) P: `$ B8 |3 Y# C3 U7 b
sexual development before 9 years of age.1,4: H4 Y& r7 ~9 M7 m2 F0 a( I# Y
Precocious puberty is termed as central (true) when6 I8 i8 M1 Z5 \6 g$ }. j/ H _
it is caused by the premature activation of hypo-, c U8 ^6 |# e( _& t7 A
thalamic pituitary gonadal axis. CPP is more com-" v2 W# ^( i: _: u# }
mon in girls than in boys.1,3 Most boys with CPP, b6 _0 \# O9 N# u
may have a central nervous system lesion that is
4 @6 ?7 g* E. T$ a% I, rresponsible for the early activation of the hypothal-* p" _# J9 O! z6 s( ]0 Y& P& W& f; c
amic pituitary gonadal axis.1-3 Thus, greater empha-& B* ]4 o( f+ s/ W9 ]
sis has been given to neuroradiologic imaging in& b% n, c& D' m# G1 B& G
boys with precocious puberty. In addition to viril-
* I1 l- W7 C$ D; }; hization, the clinical hallmark of CPP is the symmet-
" Q. t4 I) k* A" M9 E, \3 s5 I+ Hrical testicular growth secondary to stimulation by
+ O0 v* g _! C2 H# Z7 C, {+ Sgonadotropins.1,3
; g/ N9 K) [/ wGonadotropin-independent peripheral preco-
% x, m X2 J8 x* S/ a) f' N2 y Y) w0 Jcious puberty in boys also results from inappropriate5 j; c2 Q7 g2 R( @) n. j. I
androgenic stimulation from either endogenous or3 Z, u& y% Y! q' ~( J
exogenous sources, nonpituitary gonadotropin stim-
. `9 N- Z* w6 u+ [, Fulation, and rare activating mutations.3 Virilizing
) T+ R4 d$ a$ p1 V+ R6 Rcongenital adrenal hyperplasia producing excessive
9 d9 T7 a. C$ ~' |6 j! R! w' oadrenal androgens is a common cause of precocious7 ^" ]# Q: o. y$ r/ h
puberty in boys.3,48 I, H8 h- p3 L9 P& g4 W
The most common form of congenital adrenal9 Z4 u! {4 n' R* o/ e! H5 U' N3 y0 q
hyperplasia is the 21-hydroxylase enzyme deficiency.
/ N v, U* ]- t$ _4 O' X& YThe 11-β hydroxylase deficiency may also result in8 _2 ?% ?; p: [' S
excessive adrenal androgen production, and rarely,
7 x( q! z9 w" B' L) M# Ian adrenal tumor may also cause adrenal androgen% _! o! ~: V* V' ~7 j$ I
excess.1,3( f* S; l. |; y; A) X
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from- e1 |1 q/ {8 G. z; O6 c! g' X, L8 L$ D
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
4 @; i% t. H, B1 d6 x$ l5 |5 x8 iA unique entity of male-limited gonadotropin-+ z6 W0 d0 k# U
independent precocious puberty, which is also known6 W2 q3 R2 y! X7 J1 T
as testotoxicosis, may cause precocious puberty at a
% \1 U& h5 f1 ?8 c. n( zvery young age. The physical findings in these boys
; y" v( W0 ?& T, N) J. n% w! Iwith this disorder are full pubertal development,, C2 Z( y. n" V' y1 t
including bilateral testicular growth, similar to boys
( ]" Y, e" T8 Z$ o: E- hwith CPP. The gonadotropin levels in this disorder/ G' M; e4 L4 a, ^
are suppressed to prepubertal levels and do not show
E* B2 _- ~2 M- S1 upubertal response of gonadotropin after gonadotropin-
3 E" g1 W: r( h1 b; V; Oreleasing hormone stimulation. This is a sex-linked
( L9 H, o6 M: p! k5 ?* N7 U+ m2 g6 qautosomal dominant disorder that affects only+ t' ~: d- H) m0 C7 C8 T
males; therefore, other male members of the family
t5 Z1 O3 \) kmay have similar precocious puberty.3
( a2 Z$ j) I: `0 Q! b% b! _In our patient, physical examination was incon-" g! }. O6 X/ U1 q
sistent with true precocious puberty since his testi-8 f5 o' b; o4 u- Y
cles were prepubertal in size. However, testotoxicosis
/ h& Y. |& J) }* N( pwas in the differential diagnosis because his father
+ S! e$ f9 _, \: l1 z) q4 t9 Fstarted puberty somewhat early, and occasionally,% W# d; Y3 W) D/ X7 a$ B8 y- e
testicular enlargement is not that evident in the
* u( e. D/ i% l( fbeginning of this process.1 In the absence of a neg-
. ~( Q2 n+ X0 A2 Qative initial history of androgen exposure, our' [9 s/ p/ [" ?3 t& Z7 B
biggest concern was virilizing adrenal hyperplasia,
* U3 j* {6 K- p+ Meither 21-hydroxylase deficiency or 11-β hydroxylase
4 Q1 c5 s. [6 B; o; T% W4 d, ldeficiency. Those diagnoses were excluded by find-
' ]- [7 T1 _: J* j2 J8 j7 `& W8 x2 {ing the normal level of adrenal steroids.& s; R- x |+ P4 f2 S" \/ c9 {- p
The diagnosis of exogenous androgens was strongly) h2 R) L9 A6 q- E2 a* F
suspected in a follow-up visit after 4 months because
4 A) Q* q! D' Q( O2 r. B' qthe physical examination revealed the complete disap-5 W( G1 l% F" j
pearance of pubic hair, normal growth velocity, and" h z3 ?/ F; R G) \0 S
decreased erections. The father admitted using a testos-% B% p. O( F+ `$ C' v" W I
terone gel, which he concealed at first visit. He was9 t! r! }1 b) C# X
using it rather frequently, twice a day. The Physicians’) H5 }- b# v4 e4 c) e, s2 [, I
Desk Reference, or package insert of this product, gel or3 C1 X$ ~) S2 S' T
cream, cautions about dermal testosterone transfer to
* G$ p2 a2 R; s# V0 v0 g9 }unprotected females through direct skin exposure.
" w$ H" t" w) g. t7 u0 `2 K+ }Serum testosterone level was found to be 2 times the
; c9 z9 |; r4 H/ K7 ^7 Hbaseline value in those females who were exposed to8 v8 ^: [& H% Y' D% h
even 15 minutes of direct skin contact with their male
/ O, w2 V* s, Z. Tpartners.6 However, when a shirt covered the applica-/ D* c- h$ d0 M6 M" r
tion site, this testosterone transfer was prevented.
" {5 o0 ?% r" h8 p, iOur patient’s testosterone level was 60 ng/mL,
! A5 O# r% B+ E; ?which was clearly high. Some studies suggest that0 d5 \( M% ~7 W& o$ E- ^0 I) e& N
dermal conversion of testosterone to dihydrotestos-; u) T% [# w* ?: {7 V. H
terone, which is a more potent metabolite, is more
% h2 f$ i' D e: f, \4 @) cactive in young children exposed to testosterone
: n/ H' F( }( O0 K# X# j0 o" Z8 sexogenously7; however, we did not measure a dihy-2 ~) | y% S% q! i
drotestosterone level in our patient. In addition to, @' k2 E6 n- w( ]( u& g# F
virilization, exposure to exogenous testosterone in
8 E7 o' u- \3 i2 u" {7 schildren results in an increase in growth velocity and
! B' a4 a: D4 u% X2 uadvanced bone age, as seen in our patient.
* f# e* J. Q5 z+ E8 r& m" Q O- TThe long-term effect of androgen exposure during+ Y+ l( }" Y" _7 u* \" e/ @7 ~, V
early childhood on pubertal development and final
% b( Q4 `$ E* m4 E7 zadult height are not fully known and always remain" k7 W' b- S' S' x" ?7 F' E% z
a concern. Children treated with short-term testos-
Y/ Y3 l6 Z# R3 ]terone injection or topical androgen may exhibit some+ z3 f6 j! W+ J3 w$ N% v. J) y
acceleration of the skeletal maturation; however, after; L8 O+ `( B& O: }6 p4 H
cessation of treatment, the rate of bone maturation" f) Z1 B5 c, R8 A) C, K! s- a( E
decelerates and gradually returns to normal.8,9! h1 X- ~2 J" g) a, I
There are conflicting reports and controversy
. f z! w5 R# P' n9 a# I% Sover the effect of early androgen exposure on adult& E$ B6 n9 \7 F6 w
penile length.10,11 Some reports suggest subnormal. ~2 R3 [" V, ?/ O" Z, ]
adult penile length, apparently because of downreg-5 _( w% I( V v7 a7 N5 g
ulation of androgen receptor number.10,12 However,
0 X- P7 d5 n# P! j( k9 ^Sutherland et al13 did not find a correlation between: Q3 m& s3 \# n5 l
childhood testosterone exposure and reduced adult
6 W: n; H+ \& }% f. i, npenile length in clinical studies.2 G% r1 g' F) Q9 h; r: U* g
Nonetheless, we do not believe our patient is
7 ?# a( Z) q- L y+ `! Lgoing to experience any of the untoward effects from7 ?4 m3 p$ h! V+ D% X4 ~
testosterone exposure as mentioned earlier because
: G/ E& a* B6 y" ]$ [( Zthe exposure was not for a prolonged period of time.( k/ r( e6 d6 l% |( @5 s
Although the bone age was advanced at the time of3 \% F# [1 d: S8 h+ T4 n% r3 _
diagnosis, the child had a normal growth velocity at
0 q" y' B* J1 Lthe follow-up visit. It is hoped that his final adult3 F' C# k6 i Z# z" J
height will not be affected.
) M$ a* ~# P, F" U4 J. F8 RAlthough rarely reported, the widespread avail-
8 L" J" J7 u/ e9 p; sability of androgen products in our society may' O+ L8 \/ a8 p ?: t9 U3 v1 E& {1 {
indeed cause more virilization in male or female3 n7 |1 D2 @+ `, s! z
children than one would realize. Exposure to andro-
8 }: V2 R" V4 W; ?) cgen products must be considered and specific ques-
# w- D: j. ]! r& A2 l, \2 p7 I" L0 |tioning about the use of a testosterone product or
0 j! e8 y& O" F, S: d: k5 N) Sgel should be asked of the family members during
! u% v2 Z( |) {the evaluation of any children who present with vir-
' g7 U5 h+ C$ p9 g8 O8 R- k# Zilization or peripheral precocious puberty. The diag-) e& k- M3 {: n% P0 S Z: r4 w+ h' v
nosis can be established by just a few tests and by& _% N; p5 j2 J
appropriate history. The inability to obtain such a
! h( `4 ]+ g& m, f, F- d" ]history, or failure to ask the specific questions, may; t5 c# `$ A6 [) X1 Q9 N! a
result in extensive, unnecessary, and expensive* T6 y" v7 o' x
investigation. The primary care physician should be/ f- w: b/ s9 T$ l, ]% F3 q# I D
aware of this fact, because most of these children$ s+ k5 l. e' u
may initially present in their practice. The Physicians’/ {" t0 R) k" [2 }
Desk Reference and package insert should also put a, r2 d3 @4 [8 H3 D
warning about the virilizing effect on a male or
$ u% ^) q- x4 i& Gfemale child who might come in contact with some-# B/ v5 L1 M. F
one using any of these products.
# L8 U& \) \/ v5 r+ lReferences
, i/ _1 N9 G# N3 r6 R1. Styne DM. The testes: disorder of sexual differentiation1 `! S# |- F* J9 K) P* z
and puberty in the male. In: Sperling MA, ed. Pediatric
" ^, v& z, F- E' lEndocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
. ]+ \# s( w- @" T2002: 565-628.) G1 d! \ q1 Z7 ]& b0 F
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious+ |" l+ u1 r, u1 l
puberty in children with tumours of the suprasellar pineal |
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