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is a significant concern for physicians. Central
6 { g v5 g. B) x' i& jprecocious puberty (CPP), which is mediated6 A( ^+ [/ b* v5 }- O
through the hypothalamic pituitary gonadal axis, has* _+ J" O! E; q! `- J
a higher incidence of organic central nervous system
/ q7 v) ?( M) \( ~; Q% I6 h4 Vlesions in boys.1,2 Virilization in boys, as manifested
. \& ]( O( \6 l$ R3 T2 @by enlargement of the penis, development of pubic
3 u9 q+ c# S$ z) M9 P5 [# ehair, and facial acne without enlargement of testi-
) e; R1 y+ c3 E( y5 u& t8 tcles, suggests peripheral or pseudopuberty.1-3 We8 p( Q4 A' p/ M% x$ e1 }
report a 16-month-old boy who presented with the' \' P- @; c4 C$ i# @8 E' {! g
enlargement of the phallus and pubic hair develop-8 j) V$ V4 O4 [$ `" U9 {
ment without testicular enlargement, which was due
+ }. o1 r4 v) |to the unintentional exposure to androgen gel used by
2 ^! H1 _3 ~( z: q8 b# Xthe father. The family initially concealed this infor-3 ~2 E# {% u) _9 d" ^( X* }+ Q/ i
mation, resulting in an extensive work-up for this) N- @2 w1 S; H/ g g- x. E& M
child. Given the widespread and easy availability of
# @$ o! v9 m, r- y* }testosterone gel and cream, we believe this is proba-" @0 O2 w: r* m0 q' O$ w! C) a
bly more common than the rare case report in the& _% ~" z1 f: d' l; j6 q- W$ B9 c
literature.4* G# Q1 y2 \% m
Patient Report
- N" o! I. A! E3 m- i# SA 16-month-old white child was referred to the
+ J9 N! f$ n" O1 Uendocrine clinic by his pediatrician with the concern! ]6 S- a6 K+ w9 p
of early sexual development. His mother noticed
8 B8 G7 W6 h( clight colored pubic hair development when he was
, l1 U, @, V! G+ g" c, QFrom the 1Division of Pediatric Endocrinology, 2University of. R% |) M% ]5 c Z% o" o8 v( o
South Alabama Medical Center, Mobile, Alabama.8 t: @/ L7 j. Q: [ c$ z( s
Address correspondence to: Samar K. Bhowmick, MD, FACE,
; ^ `+ H8 D5 c- b# o2 M& H3 u4 HProfessor of Pediatrics, University of South Alabama, College of
" @# w T" a: l2 Z2 OMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
( @4 u3 F% g) V3 A. M3 {e-mail: [email protected].
5 O3 _5 v# S }5 N' q$ Uabout 6 to 7 months old, which progressively became$ B" ]! S5 ~/ a1 B
darker. She was also concerned about the enlarge-
$ R0 p" n7 e" ?) P% G( A" \7 Hment of his penis and frequent erections. The child+ R$ t9 R: U3 C$ G! S) n5 a' t, m$ ]
was the product of a full-term normal delivery, with4 y) ]9 c# O' ^0 c4 }2 d+ f
a birth weight of 7 lb 14 oz, and birth length of
/ A0 j1 @% n K6 z( X20 inches. He was breast-fed throughout the first year
8 ]4 l5 I: |/ ~: Z6 n o9 zof life and was still receiving breast milk along with
5 T8 {. n3 ~6 \( j, o: D# A% a( S& _) ysolid food. He had no hospitalizations or surgery,
5 g1 K8 T( h2 G" K4 L2 M) Eand his psychosocial and psychomotor development9 u* W7 p" O: p: U8 t
was age appropriate.
- z4 ?$ m" B! X" [ U) c- Z0 @The family history was remarkable for the father,
5 A+ R3 Z9 a" W6 I1 @, ]who was diagnosed with hypothyroidism at age 16,( ?8 t" _7 c$ A' I8 @/ Z
which was treated with thyroxine. The father’s
4 Q: L4 K( X, ]6 V o* Q5 {* @height was 6 feet, and he went through a somewhat
% ^5 f& m/ i# i% G) \* w+ S/ uearly puberty and had stopped growing by age 14.! i5 g' b8 w& [' M* d2 |3 A1 j
The father denied taking any other medication. The
" D, d+ p5 M; y' N% c9 Qchild’s mother was in good health. Her menarche
! C3 A5 x2 O& ^9 k# zwas at 11 years of age, and her height was at 5 feet0 y( B; H6 R/ B& j; X) x
5 inches. There was no other family history of pre-" l, ]5 C( d- E& g
cocious sexual development in the first-degree rela-# G; U4 D7 S: z- I3 u: T
tives. There were no siblings.
0 ?0 V4 g6 v) U3 F: J8 }8 e& }Physical Examination: _& T# G! L3 @3 Z
The physical examination revealed a very active, N/ U* C4 ?7 x8 B/ l
playful, and healthy boy. The vital signs documented2 f1 Q. r7 [8 G, x! ?% |7 e+ a
a blood pressure of 85/50 mm Hg, his length was
) Q: k+ M0 \2 c; i% Y# \90 cm (>97th percentile), and his weight was 14.4 kg1 ]7 }2 L) q ]& l
(also >97th percentile). The observed yearly growth/ ?0 _ ~- B9 i2 R- c
velocity was 30 cm (12 inches). The examination of
% G7 ^# ?6 z# P ^the neck revealed no thyroid enlargement.: {9 Z0 V, X% P1 N; [* ~- r& Y
The genitourinary examination was remarkable for6 t1 L" G4 V$ [8 E
enlargement of the penis, with a stretched length of
1 A, O. o" Y, N: e8 cm and a width of 2 cm. The glans penis was very well+ X$ t, n4 {" b, o# Q
developed. The pubic hair was Tanner II, mostly around# d9 \ l* W. u3 S. R+ Q- H
5405 A7 [ `% h6 y4 ?% S" |
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from* M& E1 X& ]! G* p, v) @0 g8 i
the base of the phallus and was dark and curled. The
; T' k5 l; m# j; e6 ^- V* ?testicular volume was prepubertal at 2 mL each." I5 d! J3 ]# ^
The skin was moist and smooth and somewhat- |& u% m+ Z: W7 e0 Z
oily. No axillary hair was noted. There were no3 l& @2 d+ p, U
abnormal skin pigmentations or café-au-lait spots.
5 k4 p5 p$ `) v3 h0 ?4 V3 QNeurologic evaluation showed deep tendon reflex 2+
- Q5 ~$ ]; z* j0 L- d* G& c6 Vbilateral and symmetrical. There was no suggestion
. d, E5 T2 ^+ z: x3 {$ T9 Cof papilledema.
0 e7 g* t; q M, N8 m* t3 p# E9 iLaboratory Evaluation: J% E* @0 K0 x" G0 Q5 V4 O
The bone age was consistent with 28 months by
- I% ?! d; C! w Q2 Musing the standard of Greulich and Pyle at a chrono-5 v& c4 j& ?1 W& F5 {
logic age of 16 months (advanced).5 Chromosomal
# N2 L* Z- S& e0 X% lkaryotype was 46XY. The thyroid function test5 T( e" v% }, I5 y
showed a free T4 of 1.69 ng/dL, and thyroid stimu-: l+ T5 K1 Q. N- ]" [# h" F
lating hormone level was 1.3 µIU/mL (both normal).; L) A) A: n4 E" `2 x$ W
The concentrations of serum electrolytes, blood
) D+ q$ v: q6 d4 e0 m/ wurea nitrogen, creatinine, and calcium all were
, b1 z2 P9 Z* N/ Z( O' X. S( Owithin normal range for his age. The concentration* @. D2 u+ |2 l' z* V" B9 O8 @+ b. A
of serum 17-hydroxyprogesterone was 16 ng/dL
- C! T1 w. |6 b* v; i: |2 M' v(normal, 3 to 90 ng/dL), androstenedione was 201 Y( W- J2 b0 v1 H3 X
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-/ b; x- c. R: F- U/ i* `( t
terone was 38 ng/dL (normal, 50 to 760 ng/dL),
0 _2 l, o6 M& c$ j& {8 tdesoxycorticosterone was 4.3 ng/dL (normal, 7 to* Y3 \2 `2 F8 k; J$ T% J4 e ]
49ng/dL), 11-desoxycortisol (specific compound S)- x; P: t* y# F; M* ?( {
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
* l$ a' Q3 _/ o0 itisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
3 @' e* b2 V6 n+ k, Otestosterone was 60 ng/dL (normal <3 to 10 ng/dL),
0 [. d6 k1 u" o- V4 v9 n! @and β-human chorionic gonadotropin was less than
* w8 O) S, \& T3 d- P5 mIU/mL (normal <5 mIU/mL). Serum follicular# {) F7 C$ P: J, c. {
stimulating hormone and leuteinizing hormone# s, Q6 b1 @5 x/ y3 @5 t4 z N
concentrations were less than 0.05 mIU/mL
( V# C) ^+ O3 r* u(prepubertal).
' N' k9 B: D3 ~, I& Z0 C7 LThe parents were notified about the laboratory5 u; {, [4 r0 w k. k0 ]
results and were informed that all of the tests were7 c4 k# f3 I! s. Y9 v: B) z
normal except the testosterone level was high. The: L( K( w, j6 X; N
follow-up visit was arranged within a few weeks to5 v7 ?6 }/ d6 o5 a Z7 u6 A
obtain testicular and abdominal sonograms; how-
3 _% |% F" R8 R4 Hever, the family did not return for 4 months./ h; P& ?/ u5 S. [3 }! Y1 p
Physical examination at this time revealed that the/ I1 i& ?! n' {/ u* g J0 I
child had grown 2.5 cm in 4 months and had gained
* u! Y. K0 ?% F+ ]3 h. F. c2 kg of weight. Physical examination remained) _- L) s. z: {. s* s
unchanged. Surprisingly, the pubic hair almost com-
3 i n9 S0 z7 c% lpletely disappeared except for a few vellous hairs at7 y, v6 a& t5 }
the base of the phallus. Testicular volume was still 2) Z! X0 f; g$ f! E5 W, @, f7 d
mL, and the size of the penis remained unchanged.
& i, {" |5 j& P' @The mother also said that the boy was no longer hav-
* q$ w& V4 n; o8 {0 ^* E3 ]: b1 sing frequent erections.# P7 g. R ?' g% k6 m/ n
Both parents were again questioned about use of
& }; |) f. a; c" O7 ?any ointment/creams that they may have applied to
5 m7 @; I! ]8 i; l0 k: A/ ]the child’s skin. This time the father admitted the; h# V8 X* v: k- m& M( ^1 M3 Z
Topical Testosterone Exposure / Bhowmick et al 541
8 D# ?' j% }# @- ?) quse of testosterone gel twice daily that he was apply-. C; d* B8 a4 N$ ~4 j
ing over his own shoulders, chest, and back area for
5 o5 v" j6 ]. ?$ r( f0 m# Ta year. The father also revealed he was embarrassed
, G: g# K9 Y$ Q0 Gto disclose that he was using a testosterone gel pre-
, V2 N- F" a% y \. D+ P% X, T6 wscribed by his family physician for decreased libido
: g$ G# Q9 l- x& S% e6 c% Dsecondary to depression.
, H5 b/ u3 R: Z% c9 _, vThe child slept in the same bed with parents.
" A5 i: H) D3 \1 PThe father would hug the baby and hold him on his1 Q; K, H7 L3 \1 Y" d5 ?
chest for a considerable period of time, causing sig-
; o8 W1 z: W8 s$ z, h' ~3 u3 t% Snificant bare skin contact between baby and father.
1 @5 ~8 r! ^0 nThe father also admitted that after the phone call,
4 L o9 e* I$ T* p% d( x) ?when he learned the testosterone level in the baby9 X! n! q" {& j: ~# l- j
was high, he then read the product information# E9 j# k* O$ c/ J3 T" ]4 [
packet and concluded that it was most likely the rea-
- E) V- Y! e$ F4 E: h# V/ lson for the child’s virilization. At that time, they
& a8 e! A& J# `# P t; S9 v! Hdecided to put the baby in a separate bed, and the
5 u4 k4 t t$ ~8 Q0 I3 t# T' wfather was not hugging him with bare skin and had
5 X; R. @' L+ c& Qbeen using protective clothing. A repeat testosterone' \8 l& ]0 ]( I; U: ~
test was ordered, but the family did not go to the3 Q7 ]: |* x' N! O% U% l# s: C
laboratory to obtain the test.
, ?5 U4 M8 i) a4 R9 }- NDiscussion
$ e: ~; Z- Z4 I, E QPrecocious puberty in boys is defined as secondary
" K, f% O8 _ o9 B& Esexual development before 9 years of age.1,4
9 N7 I8 p: E6 C# p$ \Precocious puberty is termed as central (true) when# y) B7 j* y; Y. M$ M3 z: N
it is caused by the premature activation of hypo-2 I& P% K9 j9 W( f. T4 w. C$ i
thalamic pituitary gonadal axis. CPP is more com-7 w& }9 @6 s& A+ G7 ?
mon in girls than in boys.1,3 Most boys with CPP
# G6 i B, H& y" Omay have a central nervous system lesion that is
8 m! V$ C4 O. K+ aresponsible for the early activation of the hypothal-
- d. C* p+ G' S, I% M6 Hamic pituitary gonadal axis.1-3 Thus, greater empha-8 F1 c8 C& A* K' P; e
sis has been given to neuroradiologic imaging in
# u2 q; z' f! x- w- p1 J% u. oboys with precocious puberty. In addition to viril-* H$ W0 s# {. R. r
ization, the clinical hallmark of CPP is the symmet-
1 p; Y9 g4 Z, q& z- Mrical testicular growth secondary to stimulation by
+ }: b ]* L- ^5 i. X$ g9 @' Cgonadotropins.1,37 M' V3 Q/ {/ B
Gonadotropin-independent peripheral preco-$ W: w0 p/ B- P, ^ [& Y9 }
cious puberty in boys also results from inappropriate
' k; i* B' D% X: Y: h0 eandrogenic stimulation from either endogenous or& ]8 L2 ^5 v, P2 y; x' \: s: k
exogenous sources, nonpituitary gonadotropin stim-: g i# v5 ?. P b( X0 W+ \
ulation, and rare activating mutations.3 Virilizing5 Z/ L4 Y4 X: u2 Q r
congenital adrenal hyperplasia producing excessive: N) [) B2 f; }# @% v7 l
adrenal androgens is a common cause of precocious7 N. H- O5 L1 g
puberty in boys.3,4
" V! S9 S- O9 X& a4 V, x- GThe most common form of congenital adrenal
' m5 _3 X4 V) {hyperplasia is the 21-hydroxylase enzyme deficiency.
" `, J1 p+ K9 E+ |The 11-β hydroxylase deficiency may also result in& X, u- ]. e/ Y6 J9 B
excessive adrenal androgen production, and rarely,( ^, e: z) c- K$ N$ w. r5 W
an adrenal tumor may also cause adrenal androgen
+ I7 H# F0 _/ r3 ]' v! G4 m; {9 kexcess.1,3
( i! g% Z6 E4 O* Pat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
4 I# R7 a1 L' S; c) T3 Q542 Clinical Pediatrics / Vol. 46, No. 6, July 20078 E6 U( T( _# ?, h. \
A unique entity of male-limited gonadotropin-
2 V8 N& r* [& r! Mindependent precocious puberty, which is also known) j! T" T, }( n# p$ B' B; ?
as testotoxicosis, may cause precocious puberty at a0 K6 _. [( I4 j
very young age. The physical findings in these boys
) z- Q( Q& i9 G: X" E( Fwith this disorder are full pubertal development,% B( Z# J. V( b5 n
including bilateral testicular growth, similar to boys
: y( ^; V, ~& {/ ~; Qwith CPP. The gonadotropin levels in this disorder# g! ]4 e+ _1 T6 Z! z# ?5 \ Q
are suppressed to prepubertal levels and do not show; t0 b* y* m, r
pubertal response of gonadotropin after gonadotropin-
/ `' h- I0 c( Y P* W7 _. w# @5 Dreleasing hormone stimulation. This is a sex-linked1 o0 [- S/ J! R+ u
autosomal dominant disorder that affects only
- k" L D! m3 D# C% bmales; therefore, other male members of the family) ]" L* y+ D8 \& p9 @1 \9 P" y8 B) J
may have similar precocious puberty.3. l( q3 Q5 Z$ T
In our patient, physical examination was incon-
; F% `5 u& `3 \4 d# r6 a7 U* fsistent with true precocious puberty since his testi-6 j! m1 V- g) W! ~: O
cles were prepubertal in size. However, testotoxicosis: }; P% G5 k: n! g- _
was in the differential diagnosis because his father
- Z c$ Z2 [! a6 @6 gstarted puberty somewhat early, and occasionally,
, Z8 y. _8 O# { X. h- mtesticular enlargement is not that evident in the/ Q/ A, o- Y* A% Q3 K3 ~
beginning of this process.1 In the absence of a neg-
, B1 u9 A( {* s6 Y2 W& t4 f8 Lative initial history of androgen exposure, our2 W' g: G+ H+ ^* ^$ [
biggest concern was virilizing adrenal hyperplasia,
2 o1 ^3 \$ P* Ieither 21-hydroxylase deficiency or 11-β hydroxylase6 j* ]( }; q1 o- M5 Y4 ~2 ]3 z
deficiency. Those diagnoses were excluded by find-
7 K8 M. a W3 z$ e* x% iing the normal level of adrenal steroids.
6 F5 }- a2 ^: z8 h& kThe diagnosis of exogenous androgens was strongly& W6 O( S7 O7 r; F3 U8 d9 g
suspected in a follow-up visit after 4 months because
2 S: x! ?+ B( T# V3 sthe physical examination revealed the complete disap-
, j& y8 f# ]! ~; ~pearance of pubic hair, normal growth velocity, and9 X v I/ `" i, j( o
decreased erections. The father admitted using a testos-2 V- I( f* t" [3 R
terone gel, which he concealed at first visit. He was
. s$ B1 D+ u# M1 R$ Zusing it rather frequently, twice a day. The Physicians’
2 ?4 y8 _4 ]$ n' {& s# uDesk Reference, or package insert of this product, gel or
3 V2 s' r4 E' ?0 O M Hcream, cautions about dermal testosterone transfer to9 t5 k9 y5 X) w+ H
unprotected females through direct skin exposure.& j0 o4 n' o# `: i
Serum testosterone level was found to be 2 times the
# m# t. m2 M1 u5 K+ Y6 Y8 O; cbaseline value in those females who were exposed to
+ u: g! {7 y5 r$ beven 15 minutes of direct skin contact with their male
0 T/ K9 i: S6 C- x* [partners.6 However, when a shirt covered the applica-
- S/ A1 I- V1 @& _* ktion site, this testosterone transfer was prevented.
% D1 ?' T+ o% Y( P j) Q0 fOur patient’s testosterone level was 60 ng/mL,
* X' |3 V$ _" i" E1 ewhich was clearly high. Some studies suggest that6 m+ A+ Z7 J8 s$ E2 A7 S2 O
dermal conversion of testosterone to dihydrotestos-7 d3 W8 e7 U; X0 Z" i# H1 x
terone, which is a more potent metabolite, is more7 X% `- A. `4 J4 n
active in young children exposed to testosterone
7 R' z! ?9 o2 u% f( eexogenously7; however, we did not measure a dihy-) J% m# l9 q- a# R) c! H: z
drotestosterone level in our patient. In addition to% t2 P) c; Q3 j0 Z: X; A' V6 S6 O
virilization, exposure to exogenous testosterone in
* n% E r, z- x- }6 C& _children results in an increase in growth velocity and
" B5 a1 ^2 _* b, g& {5 r: wadvanced bone age, as seen in our patient.
" X, {! P; w$ }5 }( OThe long-term effect of androgen exposure during2 g$ D3 r6 p$ p! `: O
early childhood on pubertal development and final( [6 ~- f) X+ A- P. I E0 Z
adult height are not fully known and always remain! Y. t I- w" D+ H1 g/ |/ {
a concern. Children treated with short-term testos-# _; @) {/ t- A3 p: {! |2 q
terone injection or topical androgen may exhibit some0 o6 L8 d' x2 H% {
acceleration of the skeletal maturation; however, after
! }8 @3 _) D% |+ y& H, Scessation of treatment, the rate of bone maturation
3 c0 [* u4 i1 R& _$ A% C* Adecelerates and gradually returns to normal.8,92 B* r/ P1 p: ~( g2 `
There are conflicting reports and controversy3 h; G6 l5 n- l" G7 p
over the effect of early androgen exposure on adult
: _2 c) Y: y% @" ?, Bpenile length.10,11 Some reports suggest subnormal* k/ r( r! \ O/ H; D+ v* c1 Y! {
adult penile length, apparently because of downreg-/ l4 e2 \2 y% m
ulation of androgen receptor number.10,12 However,
! b, q( w2 \& u& e0 ]5 _$ SSutherland et al13 did not find a correlation between
3 g+ J" B7 j- n( `# I; R ]: wchildhood testosterone exposure and reduced adult
7 W9 I- }/ e' A3 Jpenile length in clinical studies.. b: C$ _- M) l* s
Nonetheless, we do not believe our patient is' b+ y# U9 E, e$ Q. S, ~& n! W
going to experience any of the untoward effects from
/ q' U& D8 L. Z" o% c$ j7 Ctestosterone exposure as mentioned earlier because
5 R8 x4 G, t' _ `2 p \the exposure was not for a prolonged period of time.
6 `8 Q. ?# s! T c& `- M# Q% bAlthough the bone age was advanced at the time of, J+ s6 ~5 ~# |
diagnosis, the child had a normal growth velocity at
- H3 y. }8 ^( i. K2 mthe follow-up visit. It is hoped that his final adult
+ u1 f$ i ?& g- w1 r) ]9 A3 {1 eheight will not be affected.
# b6 m! I' L8 eAlthough rarely reported, the widespread avail-7 W/ X$ M: J7 _: o I" T+ u5 B5 X9 o
ability of androgen products in our society may8 e# {( f; w7 p& V3 ~. N8 w
indeed cause more virilization in male or female
$ a3 k% l& f; I& g3 D" Y7 vchildren than one would realize. Exposure to andro-
; R/ k R! Y4 qgen products must be considered and specific ques-
; \, h# ^) U& W& ctioning about the use of a testosterone product or
) ~/ q" L! I- N2 p- k$ o# Lgel should be asked of the family members during
3 m7 R1 e: u( N, c" Cthe evaluation of any children who present with vir-+ j4 R7 {0 Y3 c1 c8 J8 ^
ilization or peripheral precocious puberty. The diag-
3 q6 g0 P+ M5 F( j# D! [3 V1 j6 Qnosis can be established by just a few tests and by* G# O" l4 d6 N1 T6 @
appropriate history. The inability to obtain such a8 Z! j4 i" Q$ T7 I* n/ z
history, or failure to ask the specific questions, may3 L$ k3 o( n- T( m1 j
result in extensive, unnecessary, and expensive
: M' v1 a1 s) @$ _investigation. The primary care physician should be1 L4 A5 V B1 y& ?* G
aware of this fact, because most of these children) B0 r, v+ y' |% ^ p& N
may initially present in their practice. The Physicians’
( E+ O* d& E. A2 {" XDesk Reference and package insert should also put a
: L0 K2 h B' swarning about the virilizing effect on a male or( Q7 M( t3 ~+ J' l, A2 x
female child who might come in contact with some-
" a! L+ F( v) z% q: `one using any of these products.
; C4 T1 j: }. ]1 w4 O7 BReferences: l1 z6 u; m4 G4 Y& Q- N+ f- h: @
1. Styne DM. The testes: disorder of sexual differentiation) p0 h5 _% [! H# x+ r3 \1 e# S
and puberty in the male. In: Sperling MA, ed. Pediatric& b) O1 I) c5 A) S+ ?3 |4 J
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
8 I$ E9 D( _+ U# N2002: 565-628.
% }6 F/ q2 t% M, E: t2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious! t b7 w3 s' f5 ~
puberty in children with tumours of the suprasellar pineal+ ^ g [+ M" `+ `
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from6 e0 C5 _) ]7 ^
Topical Testosterone Exposure / Bhowmick et al 543
2 Q8 G: z1 I; X' fareas: organic central precocious puberty. Acta Paediatr.
4 P) _1 D6 O- u) B' ~- w2001;90:751-756.
! b; }- L4 C/ S! x4 O1 x/ n3. Lee PA. Puberty and its disorders. In: Lifshitz F, ed.0 P, i$ K8 q) r
Pediatric Endocrinology. 4th ed. New York, NY: Marcel( n5 U+ |9 A5 T; O+ x
Dekker Inc; 2003:211-238.
! R' ~( p% B* L i4. Yu YM, Punyasavatsu N, Elder D, D’Ercole AJ. Sexual2 Y9 ~6 ?! q( X% a, @* H
development in a two-year-old boy induced by topical
+ v( W! q; z; h9 i. l Eexposure to testosterone. Pediatrics. 1999;104:e23./ I3 U8 ^6 s4 d p3 V
5. Greulich WW, Pyle SI, eds. Radiographic Atlas of1 S ]( D; z$ S/ b5 h8 G& S. d9 F
Skeletal Development of the Hand and Wrist. 2nd ed., `/ Q' [1 O2 e! u: w+ [
Stanford, CA: Stanford University Press; 1959.
, W, e( a2 i* P' K$ c& B( I6. Physicians’ Desk Reference. Androgel 1% testosterone,
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