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Sexual Precocity in a 16-Month-Old
~8 q) ]! c0 o3 v/ ?Boy Induced by Indirect Topical
@1 m! ^3 O6 C% mExposure to Testosterone
/ s) A% E/ Z8 N; O, P G7 ]Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,28 Q7 i' z8 @- W9 m9 q! t
and Kenneth R. Rettig, MD1
# b$ y" h+ y9 g* H' OClinical Pediatrics# x1 ?% ~' |! w( G- z% |
Volume 46 Number 6 C) Y, B2 `7 i( @
July 2007 540-5433 ~5 s6 e6 r; A) s% e; {* T/ a
© 2007 Sage Publications& k5 C0 n% T2 ?# I$ @- G6 b! E
10.1177/0009922806296651
( f/ R8 O4 v" B3 Bhttp://clp.sagepub.com F! d$ v7 T3 [' z
hosted at, y8 e/ M. n! ]& a& {/ c
http://online.sagepub.com# }* M5 ?1 k; U% V8 s
Precocious puberty in boys, central or peripheral,
$ K5 K6 s8 x. E6 Yis a significant concern for physicians. Central
3 s) \7 h. j, [+ _precocious puberty (CPP), which is mediated
" n9 X/ O- W" `6 jthrough the hypothalamic pituitary gonadal axis, has
3 W: m- A* r' n! O1 }a higher incidence of organic central nervous system H. h9 c1 B( n; n7 N# S
lesions in boys.1,2 Virilization in boys, as manifested( W- ]( a( B, Z W* J$ ~: C3 ~
by enlargement of the penis, development of pubic" f* D. d9 ]" _! y( H
hair, and facial acne without enlargement of testi-0 i3 X- k1 U) c/ F4 N
cles, suggests peripheral or pseudopuberty.1-3 We; H5 D; P. C3 }, p! I. A+ o
report a 16-month-old boy who presented with the) A3 H' b( R' }, ?
enlargement of the phallus and pubic hair develop-
" a6 e, D( k- ?- y! d; }3 ^ment without testicular enlargement, which was due; S4 _3 C& U$ c ]( q+ P
to the unintentional exposure to androgen gel used by/ J; e. j4 @$ P8 c4 }: r4 Y
the father. The family initially concealed this infor-
6 }( C+ H6 U% S: X1 pmation, resulting in an extensive work-up for this0 o0 x3 a" c/ o
child. Given the widespread and easy availability of
9 E. B. k+ S+ H# `* xtestosterone gel and cream, we believe this is proba-" o( K: n) F! `- X
bly more common than the rare case report in the* K1 O1 `0 L U
literature.4+ [" T T6 q" i0 q7 a
Patient Report
; G9 z2 ^) Q! B8 CA 16-month-old white child was referred to the3 [( ~3 p: y$ {/ T; r" n$ [
endocrine clinic by his pediatrician with the concern; G0 z5 N5 t. c: |5 n0 Q
of early sexual development. His mother noticed: i& N1 v4 \" D- |
light colored pubic hair development when he was
% M/ o$ {( r$ R; |" \! SFrom the 1Division of Pediatric Endocrinology, 2University of
& T9 b4 `: p V y" qSouth Alabama Medical Center, Mobile, Alabama.
! u/ [2 T+ `$ B: n# y9 l' [Address correspondence to: Samar K. Bhowmick, MD, FACE,- g7 e- F. o" S" m
Professor of Pediatrics, University of South Alabama, College of
" q! h" c; q; d( r1 q3 Q0 K& a7 kMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297; K2 `- J: ?$ j& V1 P7 `6 y/ ?- s
e-mail: [email protected]. i; p# ~8 U8 u, U2 l- S
about 6 to 7 months old, which progressively became, i$ |8 d9 M5 ?/ r
darker. She was also concerned about the enlarge-' R& T* V8 w5 A+ q) ?1 f( h
ment of his penis and frequent erections. The child
8 T2 P# w$ F' \$ R# V8 `) O* Bwas the product of a full-term normal delivery, with/ I( d* G; j6 m; p4 V
a birth weight of 7 lb 14 oz, and birth length of
; Y4 D& H; m# `. K; u- u6 e20 inches. He was breast-fed throughout the first year: H" w6 r* ?: g
of life and was still receiving breast milk along with
1 P! m7 N9 N, H0 Xsolid food. He had no hospitalizations or surgery," ?$ P0 H$ t) f& o$ M/ T
and his psychosocial and psychomotor development
$ w. O+ ?$ ~( J- c& [( I$ Kwas age appropriate.
' @+ A% P' A: W+ OThe family history was remarkable for the father,/ `4 W. T/ X4 m, Z& [4 s. n
who was diagnosed with hypothyroidism at age 16,4 }* ?- x% f9 b& x* {7 ~6 p1 Y
which was treated with thyroxine. The father’s
" @! o6 U+ u& \; [height was 6 feet, and he went through a somewhat
" @6 `7 |) s! @* m+ G9 \9 Cearly puberty and had stopped growing by age 14.
& p* x0 O' }; ~3 t+ uThe father denied taking any other medication. The/ J6 p) L& j* C Q( H
child’s mother was in good health. Her menarche6 o5 P, V4 Y9 U6 }2 t
was at 11 years of age, and her height was at 5 feet$ q3 b: @* z& ^; x1 ?
5 inches. There was no other family history of pre-. T) w+ e& d5 A$ L2 z
cocious sexual development in the first-degree rela-/ E h0 p/ A- E
tives. There were no siblings.
K+ v+ g0 f: Q6 O* @Physical Examination) i" E% t9 C! K% v# p
The physical examination revealed a very active,
, y- c* C8 R8 {8 \, Qplayful, and healthy boy. The vital signs documented9 x$ G' H0 D5 v$ @2 |+ F
a blood pressure of 85/50 mm Hg, his length was
1 R, l! N0 e4 n3 z. h S90 cm (>97th percentile), and his weight was 14.4 kg
' X! S3 Q; \0 t8 X( N/ l/ G8 S3 _9 Y(also >97th percentile). The observed yearly growth9 x7 L% L$ q2 P+ k
velocity was 30 cm (12 inches). The examination of
8 U2 L. U6 S) h8 h2 H K# dthe neck revealed no thyroid enlargement.1 x7 B* o( E& h) c& M. i
The genitourinary examination was remarkable for
0 x8 _% F, g+ Q6 Genlargement of the penis, with a stretched length of8 [5 y+ O9 I) p3 H
8 cm and a width of 2 cm. The glans penis was very well
- X1 b' {% O J3 t. k4 Tdeveloped. The pubic hair was Tanner II, mostly around
j' C9 T, B' ]. Q, C% G; `540, f/ f3 Q T3 }' [3 S- @; ?" B
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from5 @) x3 G- ], q+ ] `" p# W% C$ e$ u
the base of the phallus and was dark and curled. The
7 U( Q$ Y# N. Z) T4 H3 y E# Ktesticular volume was prepubertal at 2 mL each.
. g5 x5 Q- O0 Q" g) C1 ]The skin was moist and smooth and somewhat/ z8 e" \2 m5 S
oily. No axillary hair was noted. There were no
8 e6 B2 Y& l L+ R7 E+ P& A1 gabnormal skin pigmentations or café-au-lait spots.6 V# t; x u7 t2 ?
Neurologic evaluation showed deep tendon reflex 2+! t+ A7 d9 j% {3 K
bilateral and symmetrical. There was no suggestion
9 a5 R* U C$ \- H8 ^1 dof papilledema.
. y; \0 s1 j1 x" C1 NLaboratory Evaluation
5 \6 z1 l. \- N7 n8 LThe bone age was consistent with 28 months by/ H: @& i; Q% @- |2 J/ ?4 v
using the standard of Greulich and Pyle at a chrono-# I2 Z. e2 Z V1 `0 y
logic age of 16 months (advanced).5 Chromosomal
# @. P$ D. Y* G, vkaryotype was 46XY. The thyroid function test% R6 @& E& S6 m) |: P& T: W! ?
showed a free T4 of 1.69 ng/dL, and thyroid stimu-
5 L9 [4 l- m$ v4 O% Xlating hormone level was 1.3 µIU/mL (both normal).
9 ~, S5 h5 T6 LThe concentrations of serum electrolytes, blood
h! @1 o# B+ `+ [urea nitrogen, creatinine, and calcium all were
# x: a% l* B3 Kwithin normal range for his age. The concentration
) d1 I- g4 e' t+ _of serum 17-hydroxyprogesterone was 16 ng/dL: x6 t) V% s( n5 Z
(normal, 3 to 90 ng/dL), androstenedione was 202 A4 t1 S9 \5 | L4 ^
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
$ D& X5 e5 [; B9 l* ~4 ?2 h1 Cterone was 38 ng/dL (normal, 50 to 760 ng/dL),
( f% {* u, I7 u" kdesoxycorticosterone was 4.3 ng/dL (normal, 7 to
$ r9 R3 w1 e' F! n, j( q! ] [49ng/dL), 11-desoxycortisol (specific compound S)) A& J S. k, H0 I' ?
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
* g' E4 g& s( d7 X& l. z. O1 Ntisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
}6 ~& |( W9 u5 Ntestosterone was 60 ng/dL (normal <3 to 10 ng/dL),
' _- f @" Q* t6 E$ m0 J0 ?and β-human chorionic gonadotropin was less than+ s! W( d2 L* V# A
5 mIU/mL (normal <5 mIU/mL). Serum follicular+ B- a) ]) r( B5 a& d# C
stimulating hormone and leuteinizing hormone* \/ ^, V* T1 j2 _
concentrations were less than 0.05 mIU/mL9 J% U& d+ h0 y4 g; q/ s8 p& W4 g
(prepubertal).; n8 B z; S* }+ R) W6 T
The parents were notified about the laboratory
4 r" c, N9 I) P6 |results and were informed that all of the tests were1 Z% ^2 j1 a% K1 y
normal except the testosterone level was high. The
z7 ?8 [1 ]: pfollow-up visit was arranged within a few weeks to
" C% |# @8 D* Uobtain testicular and abdominal sonograms; how-- i% L% A. c8 L6 |0 p7 Y& u6 j* W
ever, the family did not return for 4 months.
) b6 f3 x) ]! I7 `1 NPhysical examination at this time revealed that the
: [ k8 T$ [9 m+ [$ G7 Wchild had grown 2.5 cm in 4 months and had gained4 `1 o, i5 B- p* B, ~* W) a
2 kg of weight. Physical examination remained: i3 B+ N5 m. g9 Z, I# M
unchanged. Surprisingly, the pubic hair almost com-! t8 @% E( a8 D$ Q$ b
pletely disappeared except for a few vellous hairs at, I+ k4 W( A6 S! l( p5 a
the base of the phallus. Testicular volume was still 2
* b6 ]" Y9 j: Z: ZmL, and the size of the penis remained unchanged.' a B- ?3 o) G) t" @3 N
The mother also said that the boy was no longer hav-
0 L! j( j$ ^' z& U! `$ D! B( z# i. wing frequent erections.
% c! p5 i( ~% T+ b- G; BBoth parents were again questioned about use of( P- T6 t {2 F
any ointment/creams that they may have applied to
' o' m: B) i9 t" _$ g$ othe child’s skin. This time the father admitted the
) ^5 T$ K: B% B/ y* U# qTopical Testosterone Exposure / Bhowmick et al 541
2 q# b$ i9 H o& } huse of testosterone gel twice daily that he was apply-0 Y- I+ [+ F# m; b2 X# H5 j
ing over his own shoulders, chest, and back area for0 N4 g6 V' e( z3 M" R- A
a year. The father also revealed he was embarrassed+ w* L7 t4 w: l$ I3 f3 J
to disclose that he was using a testosterone gel pre-7 c$ |2 F6 c# U! n2 F+ P0 X2 N I
scribed by his family physician for decreased libido
+ ?; Z. N! A6 U; t, e" J. zsecondary to depression.
5 y# f6 D- `- v* s: xThe child slept in the same bed with parents.& H1 G6 o S# W2 p% ]
The father would hug the baby and hold him on his
& l" F! p% a2 ?chest for a considerable period of time, causing sig-: J) I. c0 W" z1 v8 S8 _! a# d2 N
nificant bare skin contact between baby and father.
) {- Q: d) h' L8 @6 g2 o. a: tThe father also admitted that after the phone call,
5 G5 h9 W3 Q! I4 m- |9 m9 d) Wwhen he learned the testosterone level in the baby
2 ]$ Y' i/ c0 T7 K, K1 ]1 q; S# Bwas high, he then read the product information( ]' D7 ^0 u$ c: h- @0 Z
packet and concluded that it was most likely the rea-
& C' d* K1 G8 w5 ~+ B" Y/ \$ ^son for the child’s virilization. At that time, they
, K0 s% u+ L0 }+ V& x, k9 R# O) ydecided to put the baby in a separate bed, and the- x$ v& L2 K3 R% P, F9 r
father was not hugging him with bare skin and had
0 Y1 S; }" ~# z; x. _. h' m( ubeen using protective clothing. A repeat testosterone
" z8 u2 g( L" \8 Ftest was ordered, but the family did not go to the
4 G3 C2 I/ e2 }5 ?& @laboratory to obtain the test.6 i+ W0 _% S5 w6 K' t% O* ^: ]8 z
Discussion
" U$ N! m+ R. N+ J. Q: ?& U+ L* ^, JPrecocious puberty in boys is defined as secondary
& G0 [/ n/ A# R7 t5 a6 Ssexual development before 9 years of age.1,4
, M9 X j) o& P& X* \Precocious puberty is termed as central (true) when. ? p$ }& a6 Q
it is caused by the premature activation of hypo-- C$ z% g ^" q% o- d
thalamic pituitary gonadal axis. CPP is more com-
, ]4 F* L2 o- M! q3 J' |/ Dmon in girls than in boys.1,3 Most boys with CPP
9 }5 z( _' L2 w i# c* |may have a central nervous system lesion that is
( k0 v- m* I- p) ]8 E9 Cresponsible for the early activation of the hypothal-
! t9 z+ ?2 n3 G& Uamic pituitary gonadal axis.1-3 Thus, greater empha-
+ i8 \# o0 C$ Usis has been given to neuroradiologic imaging in
( s$ Q7 K U; N+ C8 ?boys with precocious puberty. In addition to viril-* A$ ` v# x; U _ s' E( ?, T
ization, the clinical hallmark of CPP is the symmet-) U$ ]( |$ T1 B1 _. k0 s
rical testicular growth secondary to stimulation by" S: {& t- Q7 O& I- M
gonadotropins.1,3- ~- B+ i3 P2 C% y
Gonadotropin-independent peripheral preco-
. j7 t0 }$ j/ f* m! Ncious puberty in boys also results from inappropriate& `; W+ R0 e t, f/ R4 H
androgenic stimulation from either endogenous or) N0 O. l: K* _1 M/ E' s% M8 ~2 x
exogenous sources, nonpituitary gonadotropin stim-7 K. |- K2 r! n |# G" x, W
ulation, and rare activating mutations.3 Virilizing0 P3 e3 d2 j4 B
congenital adrenal hyperplasia producing excessive
) k+ P' X/ ?6 g5 _. N" Padrenal androgens is a common cause of precocious
3 S z T! D* u# Lpuberty in boys.3,4: F7 |4 M( |8 I r; [/ e
The most common form of congenital adrenal5 {2 z5 u, i) ^& d
hyperplasia is the 21-hydroxylase enzyme deficiency.
+ K- @4 U. U) o! O5 |The 11-β hydroxylase deficiency may also result in( h' C9 P. S6 _1 e
excessive adrenal androgen production, and rarely,
3 ?. d# m4 T8 v# D) O& Aan adrenal tumor may also cause adrenal androgen" s t; C+ b1 y. D5 H. B3 z
excess.1,32 E' t( ], ? N9 C$ }( f( j
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from2 D+ L2 \( G$ A/ c$ [
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
; R* s3 o0 n4 o7 AA unique entity of male-limited gonadotropin-
5 ?4 u R* R2 F ^independent precocious puberty, which is also known
* a0 `2 `$ _: kas testotoxicosis, may cause precocious puberty at a q7 u. r$ k% r" y; A& }
very young age. The physical findings in these boys# Y* R5 o0 M+ d) z- \
with this disorder are full pubertal development,* w" ?* n0 U3 M; d" A
including bilateral testicular growth, similar to boys
7 X7 T1 T& l4 \with CPP. The gonadotropin levels in this disorder3 ^0 w6 L: Z- _1 ^% l0 }
are suppressed to prepubertal levels and do not show
5 n1 ~( R F% }, z! Z$ i D3 cpubertal response of gonadotropin after gonadotropin-/ K5 p" r) j; t% x0 ] l. C5 u
releasing hormone stimulation. This is a sex-linked
" O* R, Q; p6 Xautosomal dominant disorder that affects only
5 l' q6 v* L( ]$ [: f, j& ]$ ?males; therefore, other male members of the family3 ^7 j) s, Q" c( u
may have similar precocious puberty.3* c# H2 i7 C* u9 ^
In our patient, physical examination was incon-
, E9 ~: ]( v5 O0 g; V# _, e. u, Psistent with true precocious puberty since his testi-
* J2 z: R+ |; T" K& f0 C: P& dcles were prepubertal in size. However, testotoxicosis
+ K2 y$ r- V5 y( mwas in the differential diagnosis because his father
0 w5 f* A5 ^1 z' Wstarted puberty somewhat early, and occasionally,: [: g R4 ?, D& w. P9 D% G
testicular enlargement is not that evident in the3 \( G. J' A* f# G
beginning of this process.1 In the absence of a neg-$ ^( T7 l* B! J4 s' E1 n
ative initial history of androgen exposure, our# [. T; \1 O% Q* g2 P
biggest concern was virilizing adrenal hyperplasia,
; H% B7 E7 ~5 i( m, N: _either 21-hydroxylase deficiency or 11-β hydroxylase
4 Q- w! e; m) }% d) B. G! w. f6 ^deficiency. Those diagnoses were excluded by find-
; ?4 v( O: b; }5 g& oing the normal level of adrenal steroids.
' ]4 O+ j" }4 ?' CThe diagnosis of exogenous androgens was strongly
7 e7 v! C' G& ~! s, m2 rsuspected in a follow-up visit after 4 months because3 N) I7 D1 D" C5 {, p4 x
the physical examination revealed the complete disap-3 e% V5 @6 k3 l; J5 s8 G. E
pearance of pubic hair, normal growth velocity, and
( u2 A1 b) w4 Bdecreased erections. The father admitted using a testos-
' [- d7 e6 p, M! ?9 f6 [terone gel, which he concealed at first visit. He was9 ]2 s1 e8 V# n
using it rather frequently, twice a day. The Physicians’5 e& t( e4 O& @& `8 g& m
Desk Reference, or package insert of this product, gel or
! p% J9 k( ~% d0 x8 o$ }- K E, r5 xcream, cautions about dermal testosterone transfer to5 l' M1 x# i4 Z
unprotected females through direct skin exposure.
- u f: Q( E/ i% O, o1 U, SSerum testosterone level was found to be 2 times the" g* n! d* Z+ [6 `) m1 z5 n
baseline value in those females who were exposed to, O: G" I9 k* y# l3 `0 t' h
even 15 minutes of direct skin contact with their male
* h% U* A: ^. [( |3 V) e! ]8 \partners.6 However, when a shirt covered the applica-
6 U/ ]) Z; T& p" P, |tion site, this testosterone transfer was prevented.
& S+ E3 X& o4 N1 q5 \Our patient’s testosterone level was 60 ng/mL,: B3 o1 l. x1 s4 G' F A" U
which was clearly high. Some studies suggest that
/ N7 o( R/ i+ O- F: K! l' t# ?dermal conversion of testosterone to dihydrotestos-
1 z- F) i' X5 z. ]& eterone, which is a more potent metabolite, is more
3 W/ g, e- T, Qactive in young children exposed to testosterone
3 N. P5 b4 Q% s$ N; D( sexogenously7; however, we did not measure a dihy-' l+ X* G, x% z& C5 q" }) A
drotestosterone level in our patient. In addition to I8 S3 D/ b# r0 F# B6 c
virilization, exposure to exogenous testosterone in
" m" Y6 Y4 S6 R1 c7 W' gchildren results in an increase in growth velocity and
7 d0 Y4 e, O' Sadvanced bone age, as seen in our patient.
. _/ V2 }6 a! j+ l2 y4 kThe long-term effect of androgen exposure during1 y3 C& W: A& E- ]' s3 o5 y0 j
early childhood on pubertal development and final! m+ \6 H8 B% C% t4 s2 X
adult height are not fully known and always remain# N& `" [; d$ ?- P' n
a concern. Children treated with short-term testos- x! _0 o& ?2 T% j' F* g* Q# e
terone injection or topical androgen may exhibit some* {0 K# p% a1 g. \7 Y: }0 i9 Y; }
acceleration of the skeletal maturation; however, after
* f6 R* ~1 p2 J- S4 u4 w8 Zcessation of treatment, the rate of bone maturation
: X r: q- P8 P$ w+ ldecelerates and gradually returns to normal.8,94 F& q/ c5 E z: l( D( i+ u% ]
There are conflicting reports and controversy
6 j& K1 H+ s' h9 eover the effect of early androgen exposure on adult
. g( H% { s0 w( H2 Epenile length.10,11 Some reports suggest subnormal
3 ^5 C: ~# S0 f* J7 Q5 w, A/ Radult penile length, apparently because of downreg-, u4 {) G) W7 F& H$ [" ?, x) l! c
ulation of androgen receptor number.10,12 However,6 a1 C; D% |7 u$ P, r+ I; ^
Sutherland et al13 did not find a correlation between7 ^. c9 t/ ~6 w8 P) E0 J: p; C* y
childhood testosterone exposure and reduced adult4 p9 l: r: ]3 W0 Q; J( i; t
penile length in clinical studies.
. v3 ^2 K0 N4 ^& k+ j) w1 INonetheless, we do not believe our patient is
1 l4 N/ t/ @; ?1 R7 L5 Qgoing to experience any of the untoward effects from3 \0 F; T/ v% f; l
testosterone exposure as mentioned earlier because
5 `7 w. m( z* \! k. z* H* ~the exposure was not for a prolonged period of time.
8 `+ _4 t, R7 M( w: B( a4 yAlthough the bone age was advanced at the time of
% A! T# ` d R' D! Ediagnosis, the child had a normal growth velocity at
/ j/ c! z2 P, y- E- Y& Rthe follow-up visit. It is hoped that his final adult
2 ?: y1 v0 C6 Aheight will not be affected.: O. O! B; u) B$ L# _4 i
Although rarely reported, the widespread avail-
1 p$ L$ u# \+ H) ^/ N4 o: {ability of androgen products in our society may
" n* M# a6 v. L$ `# p8 G0 Q2 O$ Tindeed cause more virilization in male or female: m) V/ j! b7 F" M8 A
children than one would realize. Exposure to andro-* R. e# a8 b4 C z
gen products must be considered and specific ques-- G: f( p0 Z$ }! @) ]
tioning about the use of a testosterone product or
2 Z0 {3 ~5 V" pgel should be asked of the family members during8 A" g# b' v6 V5 i" j
the evaluation of any children who present with vir-: E& [. Z9 p$ j5 L. L; `3 q r
ilization or peripheral precocious puberty. The diag-
9 I7 h: H7 f4 Z3 d7 U. lnosis can be established by just a few tests and by
' w5 w. G! v# c0 _8 R1 p/ ^. M, rappropriate history. The inability to obtain such a
7 s4 Z( p9 J0 B M# v* P ^history, or failure to ask the specific questions, may
+ h% V& q! R' f" Vresult in extensive, unnecessary, and expensive1 i, t' _' X! t8 E* E, @/ V8 @* Q- r
investigation. The primary care physician should be' }6 T; T4 k+ `4 t$ I+ }9 [
aware of this fact, because most of these children
2 `0 H+ M( u4 E# [may initially present in their practice. The Physicians’: j$ } K! k8 i+ d9 u
Desk Reference and package insert should also put a
/ |1 S1 }5 L2 N6 I( o6 Fwarning about the virilizing effect on a male or4 z4 }- N: h/ j! j) u4 Y
female child who might come in contact with some-
8 a7 [) b; ?* Z) s9 w1 |9 s* Eone using any of these products.
* L* m0 y5 N) {9 wReferences
0 e8 z5 W3 Y* P' s9 w0 I1 \1. Styne DM. The testes: disorder of sexual differentiation5 R( m0 M" S% Y$ _6 a! J" ^
and puberty in the male. In: Sperling MA, ed. Pediatric( U- G+ x6 i, [7 T1 U; a
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
7 T( d/ Q$ _( c; D& S, E% k' w! y2002: 565-628.- v9 F- n1 @2 K5 |" I N
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
) R, ?5 i& W7 ^" upuberty in children with tumours of the suprasellar pineal |
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