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is a significant concern for physicians. Central4 p" S' ~$ E& c" L- X; U; ^/ I% W
precocious puberty (CPP), which is mediated/ n0 c: M. y* a+ n
through the hypothalamic pituitary gonadal axis, has
8 q# }4 Y8 G2 w$ Fa higher incidence of organic central nervous system0 e1 ^" V6 }3 g) u! g
lesions in boys.1,2 Virilization in boys, as manifested
4 M' U$ i, z; p: R) D/ r' v1 H1 Z, Zby enlargement of the penis, development of pubic+ q% u/ k5 D) J1 V
hair, and facial acne without enlargement of testi-
; `! {2 d. R5 r. Hcles, suggests peripheral or pseudopuberty.1-3 We" T. y6 c6 V# D! C0 @
report a 16-month-old boy who presented with the
; t/ ^; f% \5 s2 A8 _5 o2 Denlargement of the phallus and pubic hair develop-
8 `4 c' @0 d) _' Fment without testicular enlargement, which was due
! [9 L% M5 w5 X5 q" e. X$ \to the unintentional exposure to androgen gel used by5 C( w; ]: ?9 N# W* k9 u
the father. The family initially concealed this infor-
5 `. U9 ]( L( a3 `6 f! lmation, resulting in an extensive work-up for this7 Q5 ^( k! i9 G. }
child. Given the widespread and easy availability of1 o' g1 @; O$ @# P0 e
testosterone gel and cream, we believe this is proba-
2 l4 X% f4 G1 V% U# Pbly more common than the rare case report in the
; b/ ^( u+ s* wliterature.4" o+ O: l% y! \( A" j; S! Q; G. j8 ?
Patient Report
4 z9 C7 h2 a- x8 C( pA 16-month-old white child was referred to the4 A3 f Z+ @) h! C# E% s
endocrine clinic by his pediatrician with the concern
9 N9 R+ T+ d& J0 u: C5 Y) T+ ^of early sexual development. His mother noticed/ B' t! n6 V" [
light colored pubic hair development when he was
+ b( O' |* u; [2 Z6 f% ~8 SFrom the 1Division of Pediatric Endocrinology, 2University of
! G9 b8 @9 j1 u- D; GSouth Alabama Medical Center, Mobile, Alabama.; r$ j7 G8 B/ y1 n& |- C2 b
Address correspondence to: Samar K. Bhowmick, MD, FACE,. J/ j( V% g3 o% f
Professor of Pediatrics, University of South Alabama, College of) A- J. V: H& d: @% c! @
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;6 q0 R/ M7 S* ^( M8 K# M
e-mail: [email protected].
" i: F/ {( U! R7 g+ T* o' T) [about 6 to 7 months old, which progressively became
; g4 I1 I) V5 M* V3 Rdarker. She was also concerned about the enlarge-
9 Q N* `3 U) ] q4 @/ Tment of his penis and frequent erections. The child+ U) ]9 Z" N! i1 @/ Q
was the product of a full-term normal delivery, with
# ?) x" p+ Y. |+ t) g6 ra birth weight of 7 lb 14 oz, and birth length of
! d o5 R! M" J5 H: v: U% f20 inches. He was breast-fed throughout the first year
' ~5 w9 q0 e% @0 ~* sof life and was still receiving breast milk along with7 |5 m# p$ ?* s( I1 C/ z
solid food. He had no hospitalizations or surgery,9 P. B/ u& T5 t/ k) m% W
and his psychosocial and psychomotor development
$ w6 B, V* x2 n: P3 B4 m9 Swas age appropriate.
- N8 y; Y9 O3 L( f# {The family history was remarkable for the father,
8 D+ q" o1 a4 R! |+ twho was diagnosed with hypothyroidism at age 16,2 O+ f9 @. D8 A
which was treated with thyroxine. The father’s
7 J4 E2 j% F# R$ |height was 6 feet, and he went through a somewhat' o" b! s" k( ~# y, z
early puberty and had stopped growing by age 14.
; C$ k1 T3 n5 r& \. s' EThe father denied taking any other medication. The
; W1 o. _3 h- u% Z Z& ]child’s mother was in good health. Her menarche: Z' R6 U1 C1 ]8 S% z1 }- i
was at 11 years of age, and her height was at 5 feet, w$ n. k8 d8 ^) {" E5 ~. U
5 inches. There was no other family history of pre-
: h2 X1 A" ?6 Ncocious sexual development in the first-degree rela-
: q1 u1 H* U6 s* s* Htives. There were no siblings.
3 F; }0 h* A8 y! d9 k" `+ IPhysical Examination/ y7 A) w* W6 G9 _0 H) ]- w) t
The physical examination revealed a very active,
. E, D6 ^/ ?4 \( l3 e" e1 Eplayful, and healthy boy. The vital signs documented
: ^5 k$ B, [1 j# z8 n3 ^a blood pressure of 85/50 mm Hg, his length was) D0 i# G ?$ Y: t/ U$ Q
90 cm (>97th percentile), and his weight was 14.4 kg
' {' ]5 \+ X9 g$ O(also >97th percentile). The observed yearly growth
+ C7 x9 |1 m( ?! \4 evelocity was 30 cm (12 inches). The examination of" U; s( V% r; {3 r; ]
the neck revealed no thyroid enlargement.
) }1 E, D2 L) V$ ~! ^- S$ \' ^& @8 b' TThe genitourinary examination was remarkable for
3 P8 ]* O7 h* R& j X3 P. K3 Yenlargement of the penis, with a stretched length of
3 o7 Q; J) W5 ?6 p5 H) v8 cm and a width of 2 cm. The glans penis was very well, C- }/ P6 I+ f! O- u' U
developed. The pubic hair was Tanner II, mostly around
* Y. S2 s% P3 U. d540* X0 u4 A8 c& w+ f1 C
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from& |+ F ^6 C3 ?0 O: O2 d+ d
the base of the phallus and was dark and curled. The
+ t$ }7 K9 I2 {7 Rtesticular volume was prepubertal at 2 mL each.
3 y9 |, @+ z$ D4 |The skin was moist and smooth and somewhat# F& b: P* `7 T& F3 l. a4 x
oily. No axillary hair was noted. There were no, x4 P i! o P1 q' M4 g7 I
abnormal skin pigmentations or café-au-lait spots.6 ?* l/ G$ P& q5 m7 t" P
Neurologic evaluation showed deep tendon reflex 2+7 F/ s( ]) s: X
bilateral and symmetrical. There was no suggestion/ {& @3 a; M. A$ k
of papilledema.$ [9 w) Q9 |* i) p$ C4 S3 a
Laboratory Evaluation w# }+ [' Y0 I# O
The bone age was consistent with 28 months by
: B2 V2 h$ B; H. pusing the standard of Greulich and Pyle at a chrono-4 @, ]# b% [! `: q1 t! ]1 {1 l
logic age of 16 months (advanced).5 Chromosomal
+ ^% x: ^5 G0 A+ zkaryotype was 46XY. The thyroid function test
/ d9 |- E K( L. Y% a% A* `0 i8 }) Jshowed a free T4 of 1.69 ng/dL, and thyroid stimu-( d9 y8 U7 ~0 y, m. n0 Q/ z4 n
lating hormone level was 1.3 µIU/mL (both normal).
+ b: P9 Z6 ]& O% z! s4 e4 ^8 KThe concentrations of serum electrolytes, blood
1 [7 V" a: t! |urea nitrogen, creatinine, and calcium all were/ a: V4 N% [0 B3 S6 u
within normal range for his age. The concentration1 R% D2 s3 K- |) Y6 t% l) o! x
of serum 17-hydroxyprogesterone was 16 ng/dL
% `$ s1 L$ C) k- W(normal, 3 to 90 ng/dL), androstenedione was 20
! s6 c/ c) A1 S) a; g- b4 w/ O/ Fng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
. x, W5 N3 h3 F3 T7 M5 c8 e4 gterone was 38 ng/dL (normal, 50 to 760 ng/dL),
% O& T. R; o2 L6 Wdesoxycorticosterone was 4.3 ng/dL (normal, 7 to
5 W8 {, k: U% {9 k0 Y+ J6 w49ng/dL), 11-desoxycortisol (specific compound S)
0 B4 F$ S, Z! ` b( }7 lwas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
/ X% U, }3 @/ T, Otisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
- M4 M( [& y* J" p& Q# y% rtestosterone was 60 ng/dL (normal <3 to 10 ng/dL),
( I" h0 B# k1 B/ _/ f nand β-human chorionic gonadotropin was less than
, H. {% C2 E& W& @1 r' b/ n5 mIU/mL (normal <5 mIU/mL). Serum follicular
! }! ~, V- @! K, e% e# }stimulating hormone and leuteinizing hormone3 o2 E& t. m# r5 N
concentrations were less than 0.05 mIU/mL" F+ I# ]( f$ J3 g- }; a; a
(prepubertal).
4 Y. }: O' {4 b' e$ dThe parents were notified about the laboratory
; M2 l. ^: O+ R& j# R& hresults and were informed that all of the tests were
l" _) h. @3 E: B1 ]9 [normal except the testosterone level was high. The
! c4 N% Q2 H( j6 K, Pfollow-up visit was arranged within a few weeks to* w0 m$ s7 q3 s j8 n/ A
obtain testicular and abdominal sonograms; how-
2 [% d0 {5 U, l! zever, the family did not return for 4 months.
) z: F+ o$ [ l4 }. a; Q0 z3 k+ N8 iPhysical examination at this time revealed that the# E5 H0 f. U$ `: b& G8 p+ E
child had grown 2.5 cm in 4 months and had gained
: k, l# M9 d& ^6 O# M2 kg of weight. Physical examination remained$ P; K; ?& y/ s5 ?& g
unchanged. Surprisingly, the pubic hair almost com-: P% c0 m# d5 D: d4 Y1 m4 }
pletely disappeared except for a few vellous hairs at7 D- \1 U) ~2 Q( {1 H& c/ [
the base of the phallus. Testicular volume was still 2
( F, x) x* @3 d2 }0 zmL, and the size of the penis remained unchanged.) \: _$ x/ K8 V% y. G
The mother also said that the boy was no longer hav-% l' u$ y; |* t. X
ing frequent erections.* Z( H1 ]: S8 A2 B# D) l
Both parents were again questioned about use of
. w# }& W. j1 q5 kany ointment/creams that they may have applied to( V6 U+ L D* ?3 Q# z) z
the child’s skin. This time the father admitted the0 G8 G6 c* S9 F
Topical Testosterone Exposure / Bhowmick et al 541
1 P p0 I' m& g7 v8 O, H2 ?( b) tuse of testosterone gel twice daily that he was apply-
% T" [" i8 w% U: T; Cing over his own shoulders, chest, and back area for
5 D d. r3 F: x# N$ b' ta year. The father also revealed he was embarrassed
; J6 s5 N, s+ V$ w) _! `to disclose that he was using a testosterone gel pre-+ X( d4 a0 \: g8 J {
scribed by his family physician for decreased libido! x- t9 C& _6 _( k
secondary to depression." J) }9 R7 c) M M2 a2 O- Y
The child slept in the same bed with parents.
) o5 F) N: p! b8 F' n NThe father would hug the baby and hold him on his
5 A& k& ?8 }& Q+ ~; v4 V" E: Y9 Dchest for a considerable period of time, causing sig-
% R4 D& I+ Y( U5 u/ jnificant bare skin contact between baby and father.$ N& c6 y0 i; F8 ]
The father also admitted that after the phone call,
! W2 T2 k2 C& ~. wwhen he learned the testosterone level in the baby. L0 q, h) C* s- [, ~3 O& }
was high, he then read the product information( j- F9 w# h( e, x$ [7 {9 [
packet and concluded that it was most likely the rea-8 u; F7 i1 v) l. I
son for the child’s virilization. At that time, they! i, E# k* W# T6 ~4 g
decided to put the baby in a separate bed, and the
* ?* }4 s0 x" S. b Ifather was not hugging him with bare skin and had: [: M5 O6 U8 g& x
been using protective clothing. A repeat testosterone
9 X3 J9 G7 _4 ]( Ltest was ordered, but the family did not go to the
8 l4 j3 D$ U' ]/ ^laboratory to obtain the test.
# w0 R5 g. E0 S/ eDiscussion
9 N+ T9 u; `/ x! u3 kPrecocious puberty in boys is defined as secondary
6 k9 H7 @+ L K+ s0 e; L' B; Wsexual development before 9 years of age.1,4
, |0 I p0 O9 [9 Y+ O3 R" y2 q# {Precocious puberty is termed as central (true) when7 C/ p2 |4 F$ o9 Q2 _
it is caused by the premature activation of hypo-
; U$ \" n2 l( W& rthalamic pituitary gonadal axis. CPP is more com-* S* d% A1 a, f+ X6 R
mon in girls than in boys.1,3 Most boys with CPP4 w X& G* t; U9 J v( u
may have a central nervous system lesion that is! x7 T8 z+ E: ]& @5 N% a2 z9 v
responsible for the early activation of the hypothal-( a5 \- C7 h+ ^& V" P9 W c7 w
amic pituitary gonadal axis.1-3 Thus, greater empha-0 w# Y# E: @- f1 B8 F
sis has been given to neuroradiologic imaging in
6 t# ?3 g4 k$ S! _* [boys with precocious puberty. In addition to viril-/ n6 N* t% F0 x% S W
ization, the clinical hallmark of CPP is the symmet-
% X4 t# H7 j% k& Grical testicular growth secondary to stimulation by+ E. y0 t4 U6 y( B$ t9 j5 G
gonadotropins.1,3
% ^7 @# o9 t+ k$ Y5 t/ f# R2 P8 SGonadotropin-independent peripheral preco-4 ~" ]! i* z1 {: ?% b
cious puberty in boys also results from inappropriate
- ~ w/ S! Y& }2 i7 X- \; ?androgenic stimulation from either endogenous or5 h- Z5 x& t$ N' Z7 @3 C; t9 G
exogenous sources, nonpituitary gonadotropin stim-
) \' {# G/ P4 N+ gulation, and rare activating mutations.3 Virilizing
, @. M, U( G, ?3 p5 acongenital adrenal hyperplasia producing excessive4 }5 }4 I9 }9 f+ D6 `
adrenal androgens is a common cause of precocious* i7 y3 s6 a* _9 _( s ~
puberty in boys.3,46 }6 r( x& L0 Y B, @! ?0 v% R
The most common form of congenital adrenal: x: m6 N9 [9 [3 M$ i
hyperplasia is the 21-hydroxylase enzyme deficiency.( N2 s {$ R; {
The 11-β hydroxylase deficiency may also result in6 ]2 r9 G, x6 v+ b( W) c Y R. F
excessive adrenal androgen production, and rarely,
. m% N: i( P N) R" K0 [+ san adrenal tumor may also cause adrenal androgen! h* U3 V' H" p$ w7 u
excess.1,39 S5 T( b% \" S I0 i- y: q
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from" f: q& z5 @9 Q% \6 i! `) X% ~& l
542 Clinical Pediatrics / Vol. 46, No. 6, July 20076 z! _& P; k: S% X0 a
A unique entity of male-limited gonadotropin-
) @, v1 d4 L0 F% ` a/ E: dindependent precocious puberty, which is also known
" [5 X, r5 V( g8 ^9 Jas testotoxicosis, may cause precocious puberty at a
( H: }- a; Z* `7 @/ }$ @very young age. The physical findings in these boys
! ]# D3 T5 P% G& ~ l4 t( nwith this disorder are full pubertal development,6 @. H/ A9 [" k5 S! Q6 u
including bilateral testicular growth, similar to boys
# y2 y) {- r5 y# P( `6 [- vwith CPP. The gonadotropin levels in this disorder
* `( d6 x, L& ^are suppressed to prepubertal levels and do not show1 a' n w6 ~* ?" Z
pubertal response of gonadotropin after gonadotropin-8 o( A% T) L4 C( D- t: r
releasing hormone stimulation. This is a sex-linked
! i" Q, O, |5 x8 c9 vautosomal dominant disorder that affects only1 L' R" u, Q- ^" [8 n) {
males; therefore, other male members of the family
3 w! ~$ Y& D# G; T9 Mmay have similar precocious puberty.35 l' m1 h- v8 T7 G9 G2 ]
In our patient, physical examination was incon-/ |5 r8 l% \% P! \% r7 s
sistent with true precocious puberty since his testi-5 i! }4 _# L M% @# v
cles were prepubertal in size. However, testotoxicosis* D6 @" U% V) G; U8 I* P8 r
was in the differential diagnosis because his father
: Q$ v6 F, P o! B) i% gstarted puberty somewhat early, and occasionally,
2 @. P8 h2 O. E* L. ^ ]testicular enlargement is not that evident in the
0 ]- B8 o6 l# x* A( B/ X. G. abeginning of this process.1 In the absence of a neg-& K6 L; E( ]1 s' l7 c$ @
ative initial history of androgen exposure, our+ ?$ o2 N$ |! o
biggest concern was virilizing adrenal hyperplasia,9 i$ `2 y- w- {% B' g
either 21-hydroxylase deficiency or 11-β hydroxylase
' H y2 P9 s7 {5 v, w; g, F, y) ?deficiency. Those diagnoses were excluded by find-5 v% Z, l: k' [. i
ing the normal level of adrenal steroids.9 G9 N3 ?1 Q4 e8 ]* |' @
The diagnosis of exogenous androgens was strongly
1 N: ]9 c8 Y1 d% z r# ysuspected in a follow-up visit after 4 months because
0 u. ^$ I# N. t$ ~" cthe physical examination revealed the complete disap-1 D3 I0 M/ Y0 m! l# k; `+ d" U- A
pearance of pubic hair, normal growth velocity, and+ K) h3 U& S- w+ J" p, ~
decreased erections. The father admitted using a testos-
r- _3 D9 p3 R7 ?( C7 G _4 s6 e' B$ Hterone gel, which he concealed at first visit. He was( ]9 s4 E% w+ _8 S- O& `' Y
using it rather frequently, twice a day. The Physicians’6 m4 O0 H4 F% |4 X. x2 g# T
Desk Reference, or package insert of this product, gel or
5 [# Z( n) W2 Vcream, cautions about dermal testosterone transfer to
& @# s1 c, m8 D8 Hunprotected females through direct skin exposure.
& |. Q. U: d8 XSerum testosterone level was found to be 2 times the
( H( Q. j, C# @: {baseline value in those females who were exposed to
7 p: F3 L% U. F" ?, N6 @even 15 minutes of direct skin contact with their male
# M, s2 @7 m! _1 C" [3 ?5 ^- Apartners.6 However, when a shirt covered the applica-
4 D0 c9 W: R" }) ^tion site, this testosterone transfer was prevented.6 R6 V3 ?4 p: s \! u2 }
Our patient’s testosterone level was 60 ng/mL,
: i4 a* c5 O( P3 a, ^which was clearly high. Some studies suggest that
; x2 e! U/ K, w3 D; x% odermal conversion of testosterone to dihydrotestos-
; C3 |2 `. j4 S' a# kterone, which is a more potent metabolite, is more
5 l: Z- w O6 L% A+ R% Wactive in young children exposed to testosterone+ _7 I9 H: A1 Z! Z) {: e5 L
exogenously7; however, we did not measure a dihy-
$ @. P; T3 C+ `" g. |( {drotestosterone level in our patient. In addition to E7 Z5 F9 M% u7 [$ b4 z
virilization, exposure to exogenous testosterone in
, @: v# ~" ]! U5 {: Qchildren results in an increase in growth velocity and
8 j9 u9 E* k/ T5 aadvanced bone age, as seen in our patient.
/ v% H5 y$ H, r5 I" h4 [$ s1 ]The long-term effect of androgen exposure during/ Z5 V* l5 g2 f; L, ]; i: x4 _
early childhood on pubertal development and final) b1 _: I0 y5 x4 ^/ Z: x
adult height are not fully known and always remain3 d4 D6 y7 m1 C0 C; T: Q* X; [) r
a concern. Children treated with short-term testos-$ G8 ]- B5 r7 O1 E) `. S
terone injection or topical androgen may exhibit some8 p: W5 p3 b/ z0 c, V
acceleration of the skeletal maturation; however, after4 E* y' l7 M& l' |% L8 F6 H5 y. S
cessation of treatment, the rate of bone maturation0 D" h$ a& r# Z. w" U$ o q
decelerates and gradually returns to normal.8,99 M9 P- @2 C' X2 |) J. R
There are conflicting reports and controversy
8 E' r8 p4 {: ^; K0 Kover the effect of early androgen exposure on adult& J) i2 |" Z& O
penile length.10,11 Some reports suggest subnormal
' ?# ?5 B7 N) B" Wadult penile length, apparently because of downreg-
! S4 K D- \$ s4 ?ulation of androgen receptor number.10,12 However,# e! }" K" {# c% w/ U' t9 i* I p: [
Sutherland et al13 did not find a correlation between; g& N* e# o, v) c
childhood testosterone exposure and reduced adult+ u% }' y/ Z9 `4 J. E
penile length in clinical studies. {6 }8 o; y6 ~
Nonetheless, we do not believe our patient is2 }, j* c; o9 B5 a$ r% L& w
going to experience any of the untoward effects from3 m/ C3 t5 w+ w; ?- \& N2 c* C
testosterone exposure as mentioned earlier because# E2 v6 {. w* z1 n
the exposure was not for a prolonged period of time.. ~1 ]- e' M# r' X5 p7 ?% J ]
Although the bone age was advanced at the time of
$ g; _5 d0 Q% U* `diagnosis, the child had a normal growth velocity at. E9 |# i8 I6 v Y
the follow-up visit. It is hoped that his final adult, u; Q- ?6 r2 i7 K
height will not be affected.
& ^$ L/ P* T# j# E( V+ _Although rarely reported, the widespread avail-
! W( ^8 v# V) F0 \ability of androgen products in our society may
( o& i4 F% {+ \1 l) t6 P) Vindeed cause more virilization in male or female
) m# c' \3 ~% d5 ?" v! C- ^& Cchildren than one would realize. Exposure to andro-4 M# X# u' q2 i
gen products must be considered and specific ques-: @, ?, e1 x9 a8 |
tioning about the use of a testosterone product or
. B! }5 o Q" t; R. @0 ]9 B( @, l- o+ J* wgel should be asked of the family members during9 ~+ ^) c1 A) H- E: A
the evaluation of any children who present with vir-
- Q% R" o' h! d/ r* Cilization or peripheral precocious puberty. The diag-
; D/ \+ q$ B4 X' k8 \6 tnosis can be established by just a few tests and by0 {3 N7 f, l$ ]5 I6 U1 W1 \* b
appropriate history. The inability to obtain such a5 e0 {) _1 W6 U& l6 Q) Q
history, or failure to ask the specific questions, may1 e' w4 w' {, G2 V" g0 e
result in extensive, unnecessary, and expensive' D' e* M' e1 ~* }4 f
investigation. The primary care physician should be
/ I1 u# T0 D& @/ H8 A; N' _aware of this fact, because most of these children
6 I$ M* S7 ~" x# }/ P8 V( M- smay initially present in their practice. The Physicians’
1 G/ I* a) ]! C, A% \7 ]3 DDesk Reference and package insert should also put a! } p. }% J6 o3 V( [" a7 \" v# X
warning about the virilizing effect on a male or
% X6 q$ I: m" I; ]3 Jfemale child who might come in contact with some-
. i; c% \4 S N6 F" tone using any of these products.
9 F- H5 T) D2 B& {1 |5 wReferences
: y R, o% E: ]0 @( ]1. Styne DM. The testes: disorder of sexual differentiation
' n9 R* Q* k) e: R/ `8 Wand puberty in the male. In: Sperling MA, ed. Pediatric3 P- z: c* l9 v3 y" l6 W/ ^
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;3 O3 T+ Y0 J( M% m: p% @
2002: 565-628.& z1 R; C- v% H
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious4 O( v% c% s8 t- u
puberty in children with tumours of the suprasellar pineal
/ N Z* Q$ D, \4 {# a) C1 {' D- hat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
% k; h/ ?# ]8 ~/ v' rTopical Testosterone Exposure / Bhowmick et al 543
% n5 x3 s: ^! a# o% fareas: organic central precocious puberty. Acta Paediatr.
7 j8 G4 w7 g4 Q2001;90:751-756.
5 J. `9 w! X; _# r1 P, B( K3. Lee PA. Puberty and its disorders. In: Lifshitz F, ed.
; d/ r! T5 I- \- ] x2 }; EPediatric Endocrinology. 4th ed. New York, NY: Marcel. A( @1 Q3 _2 V! J
Dekker Inc; 2003:211-238.% L& R' ]8 b) k$ m$ t) u8 L( j$ l7 c
4. Yu YM, Punyasavatsu N, Elder D, D’Ercole AJ. Sexual
5 {% g' i7 g& `! [development in a two-year-old boy induced by topical! m7 Q w" E2 {; u
exposure to testosterone. Pediatrics. 1999;104:e23.
! o0 c$ U4 l' b: X! C5. Greulich WW, Pyle SI, eds. Radiographic Atlas of
0 }. t. u/ r) [# [8 ~8 X& zSkeletal Development of the Hand and Wrist. 2nd ed.& w3 C. T( e: h C0 Z
Stanford, CA: Stanford University Press; 1959.( ^/ R8 |+ |$ B( `
6. Physicians’ Desk Reference. Androgel 1% testosterone,
" }; [% _1 Q( w0 ]& CUnimed Pharmaceutical Inc. Montvale, NJ: Medical
1 B: e7 b4 u8 z, `Economics Company, Inc; 2004:3239-3241. `9 b6 v7 }# e2 N+ a, |
7. Klugo RC, Cerny JC. Response of micropenis to topical5 h( F9 O6 l/ u" H+ V0 ?; [3 O
testosterone and gonadotropin. J Urol. 1978;119: h0 t0 J( i9 F' W s5 d
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