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is a significant concern for physicians. Central
& ?9 n* n! R2 ~- w% sprecocious puberty (CPP), which is mediated
! C! [' l5 }2 S$ A( c Wthrough the hypothalamic pituitary gonadal axis, has9 H, D: G( ^6 C5 [! `6 D
a higher incidence of organic central nervous system
8 M: W9 _+ e( t: k7 R5 H" Ylesions in boys.1,2 Virilization in boys, as manifested. b1 h( N# \* A2 |8 R, M2 P. @$ E
by enlargement of the penis, development of pubic
~( k! v, g% s: E# T/ I$ a" rhair, and facial acne without enlargement of testi-
i4 T3 |( J5 N/ F4 lcles, suggests peripheral or pseudopuberty.1-3 We
; b# G/ D5 U0 X' r8 `; Y7 Wreport a 16-month-old boy who presented with the- B* L3 W. y0 K
enlargement of the phallus and pubic hair develop-, L" {7 a( `/ x: }
ment without testicular enlargement, which was due
, V! j& L) u& D+ l- @: Zto the unintentional exposure to androgen gel used by2 }' h2 b8 k4 N- |$ s$ a8 k1 `8 R
the father. The family initially concealed this infor-
7 O4 V; p) d; x0 y! Smation, resulting in an extensive work-up for this K! U6 R, A& q7 X; l% f
child. Given the widespread and easy availability of
6 V+ _5 _- i( \$ C5 A/ `# Mtestosterone gel and cream, we believe this is proba-
( @' }& P' K! [0 U1 ]bly more common than the rare case report in the% W0 A$ @* ^6 {# `
literature.4( X- S) W2 q% E
Patient Report7 |3 z l4 P; |! }9 J% ~
A 16-month-old white child was referred to the
$ U9 r3 _% T; I3 Y1 i) l6 p! Iendocrine clinic by his pediatrician with the concern
+ z7 B7 L+ e$ Q9 b2 nof early sexual development. His mother noticed
9 ]* x* m8 W8 o8 @7 }light colored pubic hair development when he was; ^3 ?% A$ Q4 g+ z2 [
From the 1Division of Pediatric Endocrinology, 2University of( f0 o* M* j3 k# R5 H
South Alabama Medical Center, Mobile, Alabama.
8 z4 v& ], I, N5 y9 K/ kAddress correspondence to: Samar K. Bhowmick, MD, FACE,
, v6 G) Q3 s: Y b( Y5 lProfessor of Pediatrics, University of South Alabama, College of* C3 Y0 O9 n' C: `% s
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
! M. j5 G4 G3 W+ U( u `e-mail: [email protected].% a. X( N, c: ~( N$ M
about 6 to 7 months old, which progressively became
, C+ s$ }# B7 O# ~' a% M7 Ydarker. She was also concerned about the enlarge-- p* W) `$ n4 Z) e
ment of his penis and frequent erections. The child; K' e! k3 Q2 a5 X3 X
was the product of a full-term normal delivery, with
+ m L$ w6 o/ \" @, ka birth weight of 7 lb 14 oz, and birth length of: G' E( z3 h: p% t+ V: G
20 inches. He was breast-fed throughout the first year4 v: m2 S, L. Q( H7 r9 L
of life and was still receiving breast milk along with" _0 x) ^7 d+ m& Q% p2 |
solid food. He had no hospitalizations or surgery,
o( Q2 j3 L$ P" ^8 N4 Aand his psychosocial and psychomotor development
$ P' W' |& [' S' ~6 t& n0 Jwas age appropriate.
1 b% X- e' k& U( KThe family history was remarkable for the father,
3 F+ o8 ~- E/ _who was diagnosed with hypothyroidism at age 16,
# F4 ~* Q* o {4 o8 N1 ~/ J2 n* ywhich was treated with thyroxine. The father’s
% H) Z d7 G- x! Hheight was 6 feet, and he went through a somewhat1 ~4 R6 @: T5 G( @0 Y9 p# u
early puberty and had stopped growing by age 14.1 _. D9 R% m b* b. ^8 o
The father denied taking any other medication. The
, }& h# [+ |: ^' M. @( A/ ^) f- }7 Jchild’s mother was in good health. Her menarche
@4 M: y) L F' s! n K8 b9 Ywas at 11 years of age, and her height was at 5 feet" _7 T4 o1 g2 q
5 inches. There was no other family history of pre-, W: C# R4 Z" M+ V% q: P
cocious sexual development in the first-degree rela-
0 J% k" {4 p7 T! d4 stives. There were no siblings.
1 q/ e, t3 ?6 F% xPhysical Examination
4 b) i) p0 e/ a7 qThe physical examination revealed a very active,
- j+ {# X; \- S! W( ]( ?playful, and healthy boy. The vital signs documented8 Q `% I+ j. F F2 ~ {7 B( o( K4 f
a blood pressure of 85/50 mm Hg, his length was o; T$ l& |) J8 Q
90 cm (>97th percentile), and his weight was 14.4 kg
6 c# h: o1 Y. [9 @. G1 T' G" ? E% E(also >97th percentile). The observed yearly growth
6 y Q9 E9 ^% V1 svelocity was 30 cm (12 inches). The examination of( W p, h$ | c$ V( {: D8 P
the neck revealed no thyroid enlargement.
& e. G9 e1 |: C$ Z' P* CThe genitourinary examination was remarkable for6 G' x1 a3 |8 r" j* f! Y
enlargement of the penis, with a stretched length of ^ `" l# D1 o) z! R4 k
8 cm and a width of 2 cm. The glans penis was very well
" o) u1 q1 k$ `( Q* Adeveloped. The pubic hair was Tanner II, mostly around
& o# g E9 Q' w! ]; Y$ n* G! f& C( ?540
9 B9 B7 b1 x& G. Y8 C* X# kat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
; p# K/ x A T: G, Y" dthe base of the phallus and was dark and curled. The
! V3 }4 U& q) J! }& x& z7 A/ }7 `) Xtesticular volume was prepubertal at 2 mL each.
5 _' B6 K: O0 p4 e4 r& m" ^. xThe skin was moist and smooth and somewhat' ~% i" f! k$ D( A
oily. No axillary hair was noted. There were no
9 S: R5 s; Q$ X: {" l5 M" N* Habnormal skin pigmentations or café-au-lait spots.1 G4 }) `' R4 G9 j* E4 q
Neurologic evaluation showed deep tendon reflex 2+' W1 E% M: y' J* Y
bilateral and symmetrical. There was no suggestion, j( I! ?6 \4 k2 L: d
of papilledema.
. r [( M2 T, H! WLaboratory Evaluation
9 Y# F5 u j# x- ~* ?' `7 xThe bone age was consistent with 28 months by/ o3 ^6 K8 K0 ]: h
using the standard of Greulich and Pyle at a chrono-1 m9 U7 Y9 D0 g t: i1 D8 x
logic age of 16 months (advanced).5 Chromosomal! G4 L5 L8 S& R. T6 ^
karyotype was 46XY. The thyroid function test
# ?7 E% z4 t0 Y; oshowed a free T4 of 1.69 ng/dL, and thyroid stimu-
0 I8 O+ U8 z! w; k4 Wlating hormone level was 1.3 µIU/mL (both normal).
0 M7 G$ C) E* g q' rThe concentrations of serum electrolytes, blood
* |) b, f& O5 a# f3 v5 a) m3 j. Surea nitrogen, creatinine, and calcium all were
; |5 I. l& ?# y9 p& R7 n" O& twithin normal range for his age. The concentration' W% F, b' f- m' f, ?+ C( n5 T
of serum 17-hydroxyprogesterone was 16 ng/dL+ s% }6 B2 v9 w) h N
(normal, 3 to 90 ng/dL), androstenedione was 20) ]; q( ~6 B x' L( w
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-/ Q1 R# B+ q" a; N
terone was 38 ng/dL (normal, 50 to 760 ng/dL),# @ R$ `% D" N) D$ t- `
desoxycorticosterone was 4.3 ng/dL (normal, 7 to( ~# u7 Y, n; B) j) `$ v
49ng/dL), 11-desoxycortisol (specific compound S)7 U) U$ I/ O, ?, T. l+ M2 m7 v% S1 K
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
! D9 r. t+ z/ L- T, ytisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total) m! i$ Z& i7 f) I, w
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
5 r; ]* A. c+ X% Eand β-human chorionic gonadotropin was less than& Y1 E6 K# b2 f: l2 \
5 mIU/mL (normal <5 mIU/mL). Serum follicular
, M+ b6 C6 q4 u5 Pstimulating hormone and leuteinizing hormone% c) E) {% i1 m" Y$ q' ]
concentrations were less than 0.05 mIU/mL% h, j" Y! R! D9 ]* l3 s
(prepubertal).
( }+ h! x- x$ W, X& DThe parents were notified about the laboratory
3 t! u, ~+ i! \/ q0 X" Cresults and were informed that all of the tests were E( M+ q7 m$ `$ h. S5 e6 r
normal except the testosterone level was high. The
% G% q# s/ t" C, d+ o- `$ afollow-up visit was arranged within a few weeks to- h; y& m/ h8 l6 a1 Y
obtain testicular and abdominal sonograms; how-
1 w9 \5 _$ c8 R% zever, the family did not return for 4 months.9 B0 l0 n/ m0 t1 V* H+ }
Physical examination at this time revealed that the
' v: r1 b+ {3 V+ j) z4 m' @: Hchild had grown 2.5 cm in 4 months and had gained. `, R& b1 O( N8 y4 H+ E
2 kg of weight. Physical examination remained3 M4 k d* b: j# `* T2 d% W6 t$ h
unchanged. Surprisingly, the pubic hair almost com-) E% I" b# S% @3 f H, i
pletely disappeared except for a few vellous hairs at( i' z" {) j( O" F; p
the base of the phallus. Testicular volume was still 2
& D3 h0 z' g. m; O& F/ nmL, and the size of the penis remained unchanged.
) J" n( i4 D' p# HThe mother also said that the boy was no longer hav-
m& v2 Z$ ? H: [1 ring frequent erections.
" _" U: h* l7 z' ~Both parents were again questioned about use of% U+ _$ h" P) I0 w+ y
any ointment/creams that they may have applied to; G5 x" T9 s- ^
the child’s skin. This time the father admitted the- ~; r1 ^7 K1 N; m. D7 e$ w
Topical Testosterone Exposure / Bhowmick et al 541* ^( o# R: M0 {1 e6 D
use of testosterone gel twice daily that he was apply-
+ q9 n+ C9 H0 d6 @. ning over his own shoulders, chest, and back area for
& Y$ ~' { m: x4 N4 Ca year. The father also revealed he was embarrassed4 d7 z, M' T6 f ^5 q" W1 ~0 o6 ^
to disclose that he was using a testosterone gel pre-
2 l5 C2 ]) \0 F* H2 t" Fscribed by his family physician for decreased libido
+ A V/ C" I6 ]. l- g, U; G) @secondary to depression.# A2 T7 W% x9 }
The child slept in the same bed with parents. {. G- y* ~' P$ w4 V
The father would hug the baby and hold him on his) H2 s& z) R/ f
chest for a considerable period of time, causing sig-
! A# U B) h* `7 v5 c% x: ]) rnificant bare skin contact between baby and father.' U' S: G. A/ f7 X
The father also admitted that after the phone call,1 y$ u' k W! ^( C& b2 v2 a- v
when he learned the testosterone level in the baby
% B4 d3 T, }$ i+ ^3 iwas high, he then read the product information
1 ], m- g$ D2 n+ B/ v1 Rpacket and concluded that it was most likely the rea-/ P$ t& y- g9 [* l( H. S9 m4 l
son for the child’s virilization. At that time, they/ e( w3 L+ D$ [ I0 M+ h6 p9 z
decided to put the baby in a separate bed, and the
6 W' @/ Q3 _) c% Rfather was not hugging him with bare skin and had# B `2 T I7 h
been using protective clothing. A repeat testosterone
, L3 U/ Q9 ~$ Z3 |) R, Ntest was ordered, but the family did not go to the( t/ X% X1 _6 W; y [8 d
laboratory to obtain the test.
: |' M$ k4 W: Q& ]5 e0 ~* Z/ EDiscussion8 U6 o: X1 V8 f+ s
Precocious puberty in boys is defined as secondary8 a" r; j3 k7 ^) R8 ]1 U
sexual development before 9 years of age.1,4* N& X. `/ v- v% a; | `! h' S
Precocious puberty is termed as central (true) when
8 P [) V0 m1 n+ M1 Y) t7 R+ |it is caused by the premature activation of hypo-. X2 h/ _- O% \) u
thalamic pituitary gonadal axis. CPP is more com-
; w% y& k o* M! }- hmon in girls than in boys.1,3 Most boys with CPP( o: g z9 w: z
may have a central nervous system lesion that is
. L0 |/ ?9 X+ ~1 b/ C' lresponsible for the early activation of the hypothal-
2 o. `- I1 t* S# a3 F; n( `( famic pituitary gonadal axis.1-3 Thus, greater empha-. h, n! d+ B( X5 `" Y2 m# s6 f) K
sis has been given to neuroradiologic imaging in
Q3 | e ?% W( m7 p" _' U8 r6 w2 _boys with precocious puberty. In addition to viril-
6 k8 }' N" N0 |! X+ d* O8 gization, the clinical hallmark of CPP is the symmet-+ V2 O: L( j3 B+ x: K
rical testicular growth secondary to stimulation by6 p u; e+ Z! g, ] U+ V8 q
gonadotropins.1,3) O" c0 D2 P: @! p7 l1 J ^. Y
Gonadotropin-independent peripheral preco-
) U3 d$ Q1 G, g0 ecious puberty in boys also results from inappropriate t) a- R1 [( g9 f- M
androgenic stimulation from either endogenous or# T$ d: n4 u: N3 d
exogenous sources, nonpituitary gonadotropin stim-) z5 s/ {& @1 Y# N2 m
ulation, and rare activating mutations.3 Virilizing% V1 D$ M+ |+ {. A. W0 a
congenital adrenal hyperplasia producing excessive
3 D A4 y- d# g9 }" G- [$ \adrenal androgens is a common cause of precocious( G3 b; H' O4 a3 [; C! f, g
puberty in boys.3,4, M2 p) o5 P6 U O/ f, d
The most common form of congenital adrenal
6 @( {/ z9 X4 E& khyperplasia is the 21-hydroxylase enzyme deficiency.
: Y' V- ], v s7 b2 t- rThe 11-β hydroxylase deficiency may also result in
* @: y% ]7 ~ f: a0 B' Z7 mexcessive adrenal androgen production, and rarely,
% O1 k7 f1 P/ _2 f# Ian adrenal tumor may also cause adrenal androgen
6 t4 e5 h r& A/ ]. F. Z, P+ H8 _excess.1,3
9 C4 K3 F0 |7 U2 s1 c y+ {at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
8 K9 n5 ?% @! j/ I- x9 r4 l1 L. Y542 Clinical Pediatrics / Vol. 46, No. 6, July 20076 Q" q7 r( Z w/ E7 `
A unique entity of male-limited gonadotropin-# Q5 _& L0 U$ s9 a" ]
independent precocious puberty, which is also known+ p/ E3 [/ @. {4 L1 b7 s
as testotoxicosis, may cause precocious puberty at a; o& l! ~: T% X8 M6 x/ ~* q
very young age. The physical findings in these boys
! u' A) F1 m9 D Q, V$ |with this disorder are full pubertal development,
% w, J# T0 X8 m+ F3 ~4 lincluding bilateral testicular growth, similar to boys" d& g8 U2 f+ e5 }
with CPP. The gonadotropin levels in this disorder, r; R; j4 {0 ?% a
are suppressed to prepubertal levels and do not show
- Z) A" o9 L ~+ L! c9 N/ m5 L! Epubertal response of gonadotropin after gonadotropin-
; y: T/ R, p1 g2 ^7 {: y7 Hreleasing hormone stimulation. This is a sex-linked5 w8 U9 X) t: A& Y" k7 H. U
autosomal dominant disorder that affects only) X2 l' j- v8 H- E S& i8 o/ L
males; therefore, other male members of the family6 V' D* h3 W Y; S, _
may have similar precocious puberty.3. J7 o, I8 S+ _1 K) C
In our patient, physical examination was incon-- I- s) S) W f1 z* s8 J# {
sistent with true precocious puberty since his testi-
+ q- _( g- t. O# e) \' y) i' q+ Kcles were prepubertal in size. However, testotoxicosis
! U& T2 w% B4 H0 Swas in the differential diagnosis because his father& C( n4 X/ Y- w- ]8 E
started puberty somewhat early, and occasionally,; w- j+ h, E' i0 m F: \+ A
testicular enlargement is not that evident in the# g5 W+ V; b' y/ O0 `
beginning of this process.1 In the absence of a neg-- J+ p# Q, `* r+ F1 y& w% T3 C) l
ative initial history of androgen exposure, our
$ ?& Y8 c7 O% b( D8 k" ubiggest concern was virilizing adrenal hyperplasia,+ S+ ?9 o4 a1 y4 _% S* i; m
either 21-hydroxylase deficiency or 11-β hydroxylase0 v2 A/ O; S3 n q- b: z
deficiency. Those diagnoses were excluded by find-8 }9 W3 E8 {, r, ?
ing the normal level of adrenal steroids.- @# n1 v# K3 w' F+ R" t
The diagnosis of exogenous androgens was strongly; H/ B+ o$ g6 [
suspected in a follow-up visit after 4 months because
( ^* A$ J! N( I) u, ]the physical examination revealed the complete disap-
0 b* R5 B+ G0 D1 \; B. a9 W; Kpearance of pubic hair, normal growth velocity, and- A0 ~+ k: W0 q$ Q: Z* c
decreased erections. The father admitted using a testos-* R _, J+ j; U9 t2 z
terone gel, which he concealed at first visit. He was, h3 |7 S- D5 q% o- |) I% U# t
using it rather frequently, twice a day. The Physicians’- o. v( I2 ]7 H
Desk Reference, or package insert of this product, gel or
1 j5 L( x ~$ I/ b& M9 t$ ^% N! s' Acream, cautions about dermal testosterone transfer to
% a# ?( `6 y1 m7 n+ Junprotected females through direct skin exposure.
8 S% b6 a2 G( r: TSerum testosterone level was found to be 2 times the! v6 Q+ Q, Q( [$ r% h _
baseline value in those females who were exposed to
. b0 ?! \' T7 p/ O3 Zeven 15 minutes of direct skin contact with their male
' T6 T: `& R1 J4 }. C* opartners.6 However, when a shirt covered the applica-
3 ]1 r2 }9 A7 I6 T% Dtion site, this testosterone transfer was prevented.
# q" \1 C ?5 F' eOur patient’s testosterone level was 60 ng/mL,2 J$ x6 Y) [$ l& _! F1 W
which was clearly high. Some studies suggest that% N- v* T0 S7 l% Z* Q. r! |
dermal conversion of testosterone to dihydrotestos-4 h5 q; ?3 n6 m2 w, g7 \
terone, which is a more potent metabolite, is more
: n( L) x. @! r$ T! Tactive in young children exposed to testosterone
+ u( w& H% m7 W. O) b: ]exogenously7; however, we did not measure a dihy-: P# I0 j% u- }' A
drotestosterone level in our patient. In addition to
) \& H- f f: Y2 a8 Mvirilization, exposure to exogenous testosterone in' W) w: n: D( c2 f+ M2 |! E
children results in an increase in growth velocity and: E; {1 p7 T% ~4 i
advanced bone age, as seen in our patient.
' d6 F- S( {2 F2 N. fThe long-term effect of androgen exposure during$ C# h9 k0 f% a3 T6 l+ |
early childhood on pubertal development and final. t+ N! c% \: g% r* \! X
adult height are not fully known and always remain- D; S4 j4 ]# v- P" I7 f
a concern. Children treated with short-term testos-! h d+ _% E* w2 k$ a
terone injection or topical androgen may exhibit some
+ O; v! x# b' M( ]acceleration of the skeletal maturation; however, after
& e. L8 ^5 P: }' w% S0 l3 gcessation of treatment, the rate of bone maturation
# w7 d+ E ?9 ~9 Ddecelerates and gradually returns to normal.8,9, S- [) K" e5 L i8 z- i0 G U
There are conflicting reports and controversy" V& E6 H; ~' I
over the effect of early androgen exposure on adult
: G6 d4 k1 G/ k6 wpenile length.10,11 Some reports suggest subnormal! d& w+ m, T$ V& }9 Q( A
adult penile length, apparently because of downreg-
5 B a$ q& |# culation of androgen receptor number.10,12 However,
y- m8 k# ]0 G- sSutherland et al13 did not find a correlation between
2 I5 g- ?& R5 x w. fchildhood testosterone exposure and reduced adult
2 w7 X6 ]. L. W+ b ~6 j6 Ypenile length in clinical studies.
% I) q+ m: |0 n: S" MNonetheless, we do not believe our patient is8 ?# q6 P, ]. o0 X
going to experience any of the untoward effects from
; u( P1 o1 c0 Y* W& ^4 a+ ttestosterone exposure as mentioned earlier because
2 g% W" X, ~( A+ s7 Uthe exposure was not for a prolonged period of time.
! {; I: J! o, O9 k$ g, Y3 gAlthough the bone age was advanced at the time of
$ \8 S& D( Y# F: u0 udiagnosis, the child had a normal growth velocity at
6 ~* o% o$ `/ v7 S$ Gthe follow-up visit. It is hoped that his final adult
8 P) {0 u9 F+ ?& t: g" x3 Vheight will not be affected.4 @3 i6 I l' t5 E: _$ s
Although rarely reported, the widespread avail-) ~2 S: x* k/ x$ } F8 _0 i
ability of androgen products in our society may( l+ ]1 o& K0 ~9 D" l
indeed cause more virilization in male or female7 X7 N4 V; t# {. ]
children than one would realize. Exposure to andro-4 p" W; s$ d4 }2 {, |/ {( l
gen products must be considered and specific ques-) X. x1 l) V G6 D
tioning about the use of a testosterone product or
6 x4 g* R9 ]5 i" O& F, e6 jgel should be asked of the family members during
! {7 _; e/ ^/ p5 E- Mthe evaluation of any children who present with vir-5 Y: w3 g& h/ K0 k0 y" p, A
ilization or peripheral precocious puberty. The diag-
0 r4 ~ a3 p; j, G, F. ^; cnosis can be established by just a few tests and by
* C# T2 H; E& q. x8 O6 r; b- qappropriate history. The inability to obtain such a
. k* c6 W8 p( P/ w+ C4 p9 e) X) s! Fhistory, or failure to ask the specific questions, may
! m; a( t( ]' j+ iresult in extensive, unnecessary, and expensive
P! u6 U# X0 n* E7 finvestigation. The primary care physician should be3 r! H) o- p. f' U4 b2 I% c5 S% M
aware of this fact, because most of these children% ^9 n j: U' ]
may initially present in their practice. The Physicians’
# r2 W8 k- i9 U5 D; lDesk Reference and package insert should also put a$ X5 q( S) Y* j: E
warning about the virilizing effect on a male or
* h5 ]0 K; {% s1 p0 R+ Z% efemale child who might come in contact with some-
* k1 }$ f9 V6 i' J' I5 x' qone using any of these products.
* R* [# T0 c& y' b P2 YReferences4 J: R( j6 ~8 s+ @: f7 E" g+ j: N
1. Styne DM. The testes: disorder of sexual differentiation
5 i+ Q& T+ a8 ]+ M, G2 M" Eand puberty in the male. In: Sperling MA, ed. Pediatric
* s& R. ]% o, s9 _Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
- X! ]' |+ R5 z z0 {2002: 565-628.- e" I% h& ?) e- y* w! t
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
* F# Y7 s9 ]. k7 \puberty in children with tumours of the suprasellar pineal
; a2 A3 z2 `5 T( V# Zat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from; G4 Y- G5 e9 K. s2 Z
Topical Testosterone Exposure / Bhowmick et al 543/ z' |" f/ H& P" T( M- m
areas: organic central precocious puberty. Acta Paediatr.
( B% P8 F6 n% _' ]5 Z" _5 B. D2001;90:751-756.
9 [ ?7 q& y1 H3. Lee PA. Puberty and its disorders. In: Lifshitz F, ed.
+ h8 e; N1 D6 t5 F, p2 p3 CPediatric Endocrinology. 4th ed. New York, NY: Marcel2 s, g7 u5 j+ l8 D8 o* W+ s
Dekker Inc; 2003:211-238.: E! l. x5 R: z" s$ s+ ` t
4. Yu YM, Punyasavatsu N, Elder D, D’Ercole AJ. Sexual" g3 u @9 l, Z% w# r% J
development in a two-year-old boy induced by topical
4 y" I2 C( l+ u8 h0 m( ^: aexposure to testosterone. Pediatrics. 1999;104:e23.
5 y4 Q3 ~ B: o. s, ~5. Greulich WW, Pyle SI, eds. Radiographic Atlas of6 K' j$ h6 q# K' F5 V* G+ A' X
Skeletal Development of the Hand and Wrist. 2nd ed.6 F0 ^3 p y/ r# [7 k: R. w
Stanford, CA: Stanford University Press; 1959.
/ N r# B: `% S: M8 j8 F: L6. Physicians’ Desk Reference. Androgel 1% testosterone,1 O0 g5 U. Z# ^; J( C) b2 @
Unimed Pharmaceutical Inc. Montvale, NJ: Medical$ ~7 r7 q7 u2 ?1 a1 v7 S
Economics Company, Inc; 2004:3239-3241.
' m k4 F6 W7 i/ s* {7. Klugo RC, Cerny JC. Response of micropenis to topical9 s) |, g' Q) o0 W- M% Q
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