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is a significant concern for physicians. Central2 T0 X6 m% C" M5 y2 n: T
precocious puberty (CPP), which is mediated! }! J3 j$ e+ [8 c
through the hypothalamic pituitary gonadal axis, has
5 w0 t. l4 u q ~a higher incidence of organic central nervous system
# o# q3 t9 L) L d$ {4 n+ j% I5 f0 xlesions in boys.1,2 Virilization in boys, as manifested
, v( G$ h3 b4 u& `by enlargement of the penis, development of pubic, j5 k4 @4 e" k
hair, and facial acne without enlargement of testi-! N: I( a/ L2 V i# m& P+ A: Y: V
cles, suggests peripheral or pseudopuberty.1-3 We! x7 C& D* ?& e) s# z( V
report a 16-month-old boy who presented with the
( N" R) u- x4 h2 D' l1 q6 x ?enlargement of the phallus and pubic hair develop-# S- h& J+ @3 o( w& E* U* a
ment without testicular enlargement, which was due E- M' g& B/ o. _+ f& {
to the unintentional exposure to androgen gel used by
3 z7 F1 Z( v& k! ^2 u& hthe father. The family initially concealed this infor-, G0 M/ ^0 g: E/ [( z1 H0 N
mation, resulting in an extensive work-up for this
2 ^9 t# b" c) bchild. Given the widespread and easy availability of3 R. M* E8 ^1 A" }
testosterone gel and cream, we believe this is proba-
$ D' J6 l# [4 t2 n( [% s. Ibly more common than the rare case report in the
F5 Y. B9 C; p- s. b! m+ b/ Jliterature.4
9 y9 Y3 ^8 x& H' g. Q. LPatient Report
" Z' b; e# C4 o1 h# c) ]A 16-month-old white child was referred to the7 Q. B+ e7 V: A5 ^# N8 i- @
endocrine clinic by his pediatrician with the concern
8 P6 ?. O1 J$ u2 ~% O7 gof early sexual development. His mother noticed4 ~1 h& s" U6 _: Q$ d5 }
light colored pubic hair development when he was, Y5 J/ O( y) M1 d! d
From the 1Division of Pediatric Endocrinology, 2University of0 W7 o# z; f' ~ X; F
South Alabama Medical Center, Mobile, Alabama.
, z% H4 F$ [: v1 g# ?" ]( LAddress correspondence to: Samar K. Bhowmick, MD, FACE,
) d6 R' q9 Q7 ^7 w. o0 m# E" X/ IProfessor of Pediatrics, University of South Alabama, College of! l. t1 G) t6 `! l
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
! \9 c, S4 i' a, z# j2 C' T( K0 x7 v( ie-mail: [email protected].5 U1 o$ u J+ F Z7 B
about 6 to 7 months old, which progressively became
/ p3 f9 G% q5 [" D: |6 k8 u" {darker. She was also concerned about the enlarge-7 P4 o$ y/ C% l4 t$ \' |0 ?( B
ment of his penis and frequent erections. The child
9 T: r$ ]" F0 ^1 Z8 M# r0 rwas the product of a full-term normal delivery, with
* A! |- X9 G7 T6 Ka birth weight of 7 lb 14 oz, and birth length of* ]+ G% F3 d& x r' [ R- E& U
20 inches. He was breast-fed throughout the first year
- l& b! h1 N0 V( J2 W. Hof life and was still receiving breast milk along with' D' ^* j0 v. Y
solid food. He had no hospitalizations or surgery,% v* p) N8 d! ^5 \) s' N7 @
and his psychosocial and psychomotor development
! B3 y" z9 ~ vwas age appropriate.2 X4 D! L9 v, q; G$ [
The family history was remarkable for the father,( B; s$ ?5 A$ I; p" R
who was diagnosed with hypothyroidism at age 16,
3 ^$ T9 s, L1 B4 z$ h8 Ewhich was treated with thyroxine. The father’s" d4 d* [% k. n
height was 6 feet, and he went through a somewhat2 Q; {* j, {( P6 I: I/ s- ~1 r6 q* U3 w& n
early puberty and had stopped growing by age 14.
9 h3 `' b8 _/ I. Q. o+ K4 ZThe father denied taking any other medication. The: g6 a8 K9 J& h% e$ W Z7 U
child’s mother was in good health. Her menarche
; {0 c0 G4 K% G/ b; ~2 J/ cwas at 11 years of age, and her height was at 5 feet7 z$ {' v" V0 j3 W2 o
5 inches. There was no other family history of pre-' z" v. R! q; K) B
cocious sexual development in the first-degree rela-
2 v( O9 c D N. ntives. There were no siblings.
* T5 b8 z B2 k; m5 ?% l, g2 ZPhysical Examination
" k+ v" k# f- L& |4 iThe physical examination revealed a very active,
& A! y6 }! G4 {playful, and healthy boy. The vital signs documented, a0 n2 v" j3 t g
a blood pressure of 85/50 mm Hg, his length was
) k8 j. X. j# q' I7 A( O+ F90 cm (>97th percentile), and his weight was 14.4 kg) M! N# z& g' E$ W5 r
(also >97th percentile). The observed yearly growth, ^# R( N, e0 x i4 w) [
velocity was 30 cm (12 inches). The examination of
/ p* F9 u; |4 Y8 m" E4 nthe neck revealed no thyroid enlargement.1 W+ u7 E3 h+ a5 D" p# y
The genitourinary examination was remarkable for
& o& E' |# G+ T7 cenlargement of the penis, with a stretched length of
5 a2 c6 V% k; p" K& ?1 e% O. n: Y8 cm and a width of 2 cm. The glans penis was very well
C* N% {+ d* F. i& }$ @developed. The pubic hair was Tanner II, mostly around
0 L' j5 n) _/ x+ c540
( V6 x. x* d) \8 a! t$ X. H8 uat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
0 l' ^( @# E tthe base of the phallus and was dark and curled. The) B3 C2 z# v h( @5 s& N* |
testicular volume was prepubertal at 2 mL each.2 d* F8 j6 U2 n" c3 Q
The skin was moist and smooth and somewhat
$ C* b6 a& g9 h# `3 F$ w5 _oily. No axillary hair was noted. There were no
G& l4 x6 D, M/ @abnormal skin pigmentations or café-au-lait spots.% E6 U5 x2 w& v8 R1 F1 }
Neurologic evaluation showed deep tendon reflex 2+8 M+ J$ A; e5 h2 U1 t G
bilateral and symmetrical. There was no suggestion
7 O) D, N) _' t8 I' \' {of papilledema.
' C9 v3 N$ y8 z/ C+ F% hLaboratory Evaluation
2 K( R- n3 Z% uThe bone age was consistent with 28 months by0 d' {* G6 E% U5 L- B
using the standard of Greulich and Pyle at a chrono-
; V0 N4 U1 V! q2 e- D+ flogic age of 16 months (advanced).5 Chromosomal' Q; k2 q9 ~7 V6 Y$ S9 Y8 [
karyotype was 46XY. The thyroid function test2 M! T; O* v0 H3 t. l! \) K- {
showed a free T4 of 1.69 ng/dL, and thyroid stimu-6 q' v: r* M; K/ b( y7 ]! X+ b0 j
lating hormone level was 1.3 µIU/mL (both normal)., F, y* `* ~2 k( q) u. D x
The concentrations of serum electrolytes, blood
. h4 ? ]/ Q5 {+ U3 \/ aurea nitrogen, creatinine, and calcium all were5 ]" W; V& V3 ?+ V0 Z# C
within normal range for his age. The concentration& ?% \: @" U6 [. p& W7 y! V
of serum 17-hydroxyprogesterone was 16 ng/dL
8 y/ ?3 p8 b$ g2 g+ b1 ^(normal, 3 to 90 ng/dL), androstenedione was 20
. N' o/ f- J* [7 U8 Ing/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
) k( G0 w4 K# H! _5 Cterone was 38 ng/dL (normal, 50 to 760 ng/dL),
}" U+ o4 i- |6 I) edesoxycorticosterone was 4.3 ng/dL (normal, 7 to
# A2 \% ~9 f" O49ng/dL), 11-desoxycortisol (specific compound S)* y# o f: I; ^9 a% x% |& l/ x' ?! E
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-1 c* {! z2 `, n4 i' ?
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
/ ^2 c3 D8 J7 F+ f4 S/ ~4 V* ftestosterone was 60 ng/dL (normal <3 to 10 ng/dL),
& h% w2 @- N4 P. \and β-human chorionic gonadotropin was less than! N5 ?0 L# i+ n; N# \1 r
5 mIU/mL (normal <5 mIU/mL). Serum follicular$ K& Z, c9 B5 ?! c0 O7 M) }
stimulating hormone and leuteinizing hormone z+ e& b6 c$ d1 p
concentrations were less than 0.05 mIU/mL$ `4 m9 L! C; l: {: n
(prepubertal).% x* R; O+ z7 C" S
The parents were notified about the laboratory
8 H* |1 L1 T8 e, j# D" H$ S/ Wresults and were informed that all of the tests were6 M. \1 C$ A! H/ Q9 l6 e
normal except the testosterone level was high. The" D) \4 w, h* h" T
follow-up visit was arranged within a few weeks to- F) Y9 s3 T k, n
obtain testicular and abdominal sonograms; how-0 w- f! U' t5 `" N% F; n( T& W- [
ever, the family did not return for 4 months.
4 P1 J6 Y, N/ p" r3 B. F- C9 WPhysical examination at this time revealed that the( n2 s, p, H1 z& `. n0 a
child had grown 2.5 cm in 4 months and had gained
- `# x% J; `8 D$ s& o9 L, x, k/ _2 kg of weight. Physical examination remained
& W! x' X2 |; x+ A, T, Lunchanged. Surprisingly, the pubic hair almost com-" i; Z! ~9 h3 B) @. B2 J
pletely disappeared except for a few vellous hairs at
$ ~3 y4 R( R/ j& z( z4 zthe base of the phallus. Testicular volume was still 2, L/ ~3 @- y5 W+ u
mL, and the size of the penis remained unchanged.; d1 M& O9 C/ D) p1 a4 v( M
The mother also said that the boy was no longer hav-
, \7 I$ ^3 h/ \2 L4 D7 S( bing frequent erections.
3 z/ t! m Z: FBoth parents were again questioned about use of8 V F7 H( z, H5 }" y/ p% {- d
any ointment/creams that they may have applied to: ^% n5 _$ \4 }( D; L) \
the child’s skin. This time the father admitted the
5 G1 E0 ~6 S& B+ DTopical Testosterone Exposure / Bhowmick et al 5410 N5 d$ x' [2 w5 Y) o
use of testosterone gel twice daily that he was apply-9 [) a% _. A$ x% ]. g
ing over his own shoulders, chest, and back area for
( {: H' |" Y5 C, g) h; K7 ia year. The father also revealed he was embarrassed
% p% b0 _6 P9 M! s' Sto disclose that he was using a testosterone gel pre-. b+ X4 P0 _5 F* x5 c, I6 T
scribed by his family physician for decreased libido
7 L. J7 \7 A0 J+ \* z2 t! Nsecondary to depression.
. U6 E! ?; \$ t! F2 O+ x0 [The child slept in the same bed with parents.
1 @; k5 B/ |! p1 r/ o2 m( CThe father would hug the baby and hold him on his
0 r! F0 h1 M, U& P) P. ~" T' B, W$ jchest for a considerable period of time, causing sig-4 a' U+ {: ]1 t" O! e
nificant bare skin contact between baby and father.5 ~3 l" X4 o) A2 o* L) ~3 v
The father also admitted that after the phone call,* @, A7 m8 h% X4 E4 A2 [6 K
when he learned the testosterone level in the baby; {, I' f$ ]& Y( \. E. \; h2 Q
was high, he then read the product information
; E- A% m; E6 F( i* h6 L+ j+ hpacket and concluded that it was most likely the rea-1 n! j" v( q+ F" @. k
son for the child’s virilization. At that time, they
* m& D+ A# P& s$ D+ a" `0 Tdecided to put the baby in a separate bed, and the8 z# h, S7 m! F+ Q r8 @ J
father was not hugging him with bare skin and had1 \0 v" G' V" |! e5 X. d5 U0 P
been using protective clothing. A repeat testosterone
( X) e% x5 m8 L: k- c7 `: r) I' }) Ttest was ordered, but the family did not go to the
3 g" b6 ^8 a) g9 Z- Olaboratory to obtain the test.
& u' y; J# R4 nDiscussion
+ j1 T# L, b% R. ZPrecocious puberty in boys is defined as secondary
9 W2 n5 B- k; f8 g) ~sexual development before 9 years of age.1,4, s3 b6 ]; p, R( g5 f- y9 Q$ H
Precocious puberty is termed as central (true) when
( t" v7 y1 P h, [, c5 Y$ c. L; C: }it is caused by the premature activation of hypo-5 K0 k N# L: c: I" P
thalamic pituitary gonadal axis. CPP is more com- D$ h1 j/ c8 ]3 U& \# J1 t
mon in girls than in boys.1,3 Most boys with CPP1 q* B- _9 J; j2 e. L
may have a central nervous system lesion that is1 t$ i' s9 A6 e. y4 ?
responsible for the early activation of the hypothal-8 h# P" {6 R G# H
amic pituitary gonadal axis.1-3 Thus, greater empha-0 q3 I/ U. ~! ?& Y! u& }1 ]
sis has been given to neuroradiologic imaging in
" D! U% z! q2 o' k# u8 C6 U' L/ g/ Vboys with precocious puberty. In addition to viril-. M( _% d6 l6 v& t/ `
ization, the clinical hallmark of CPP is the symmet-
" T8 y. b' \1 S) Xrical testicular growth secondary to stimulation by
: q; \: p+ i0 }, F# tgonadotropins.1,3( F1 v9 K9 H I
Gonadotropin-independent peripheral preco-2 U5 |" y( v- p$ G
cious puberty in boys also results from inappropriate8 a+ @" E; {0 ?" ~
androgenic stimulation from either endogenous or# p+ R& b, e1 M: G+ T9 j
exogenous sources, nonpituitary gonadotropin stim-
; u; G) K2 S7 c0 u3 K1 Qulation, and rare activating mutations.3 Virilizing9 X1 ^. L- M8 f: K& _6 F: ]
congenital adrenal hyperplasia producing excessive
- W7 E1 S0 ]$ t- u! U$ N- l4 N9 gadrenal androgens is a common cause of precocious- L6 `0 z1 r/ [1 |' M8 z* F1 Y
puberty in boys.3,4
8 H8 U, j, v! @% ^. xThe most common form of congenital adrenal7 [! Y, n" g0 z+ n( m
hyperplasia is the 21-hydroxylase enzyme deficiency./ b8 |" Z$ E& e9 e7 z F
The 11-β hydroxylase deficiency may also result in
q( P, w; ~+ i* j/ {& Wexcessive adrenal androgen production, and rarely,
* k5 L* j1 o/ e; j" C+ `an adrenal tumor may also cause adrenal androgen
. ]% n) _( x: n4 q C5 pexcess.1,30 \9 _' P. ]- ?+ q7 O
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
. o# D" }1 j4 ~- B5 L9 A542 Clinical Pediatrics / Vol. 46, No. 6, July 20074 s: |5 U; R) X
A unique entity of male-limited gonadotropin-
7 Z4 _' V: d8 }5 j+ O, hindependent precocious puberty, which is also known
. s9 R6 }/ d7 s, F/ p* K$ Sas testotoxicosis, may cause precocious puberty at a
3 p- y3 ~" N4 C ^9 O3 Every young age. The physical findings in these boys
1 w# o N8 y. y4 T M$ Wwith this disorder are full pubertal development,
- D, X6 @% S! K; ]3 A" oincluding bilateral testicular growth, similar to boys- e! s" S/ G# E
with CPP. The gonadotropin levels in this disorder
+ [; |$ j* b; q- o- iare suppressed to prepubertal levels and do not show4 r2 ~4 ]- b; L! Z
pubertal response of gonadotropin after gonadotropin-3 E6 W7 ~' e4 \ [$ i; r& o
releasing hormone stimulation. This is a sex-linked
4 M: D. z3 x6 W+ ]autosomal dominant disorder that affects only! X0 c' ]7 s- y: b0 d2 B T* t/ W
males; therefore, other male members of the family
4 E; q0 k) T' Z* }may have similar precocious puberty.3* l& @$ o0 y( E& T5 O
In our patient, physical examination was incon-
: _. p1 B$ g4 E; c# J6 A/ E- k' Z! _sistent with true precocious puberty since his testi-
8 |# H/ z2 q! U, n, U2 k5 M: |cles were prepubertal in size. However, testotoxicosis7 O1 H7 F% `# z
was in the differential diagnosis because his father5 ]5 M. p. \1 D! X: e' Y
started puberty somewhat early, and occasionally,2 {4 V0 ]8 {/ S* {" b. u/ t9 b
testicular enlargement is not that evident in the- H, ?' i3 a3 l* t/ R/ G' \
beginning of this process.1 In the absence of a neg-
0 g- Q* l: O, \5 Tative initial history of androgen exposure, our4 i ?3 ]* t2 L0 q, Z
biggest concern was virilizing adrenal hyperplasia,
1 h" K" ^; U# j6 h- M. V. Qeither 21-hydroxylase deficiency or 11-β hydroxylase
3 E, T% t; R3 l* Q8 Y# ydeficiency. Those diagnoses were excluded by find-
3 q1 _, d5 G7 j4 Ming the normal level of adrenal steroids.
" x# e! i |& e! n: LThe diagnosis of exogenous androgens was strongly, O/ R/ l( n! A4 s' d7 |/ x
suspected in a follow-up visit after 4 months because! ~2 C& O* m3 l r
the physical examination revealed the complete disap-5 i# v* V( T" B
pearance of pubic hair, normal growth velocity, and
6 r7 k$ B' ~. Wdecreased erections. The father admitted using a testos-, r3 s8 U: Z' N6 z) Y
terone gel, which he concealed at first visit. He was- }* M# |0 m5 j+ u" [6 N
using it rather frequently, twice a day. The Physicians’) N [& e1 A+ [' N
Desk Reference, or package insert of this product, gel or
) F( M/ G W- S7 ycream, cautions about dermal testosterone transfer to* Q$ V' C+ k: s1 u. F9 v9 Y
unprotected females through direct skin exposure.; q) F& }. S& S5 }( j8 U
Serum testosterone level was found to be 2 times the
& w1 ?; K1 r; u% y5 p T9 ybaseline value in those females who were exposed to: e% T- h+ _* E5 _( R" H5 s
even 15 minutes of direct skin contact with their male
$ O% V8 E5 v' ^( Q' q$ J( ypartners.6 However, when a shirt covered the applica-
; s9 y* R7 {% E. L$ }7 vtion site, this testosterone transfer was prevented.' ^: T7 s$ ~1 K" S3 x
Our patient’s testosterone level was 60 ng/mL,% F4 |3 Z, x8 V; o9 z/ d4 l/ X
which was clearly high. Some studies suggest that/ t: X @ [! U Q
dermal conversion of testosterone to dihydrotestos-8 g) T# a( E# ?7 D
terone, which is a more potent metabolite, is more
& n+ v- F, {* _7 b3 Dactive in young children exposed to testosterone9 ]) U8 ]8 {# n' O7 b) m
exogenously7; however, we did not measure a dihy-/ D2 i, g7 [. Q v' w% F
drotestosterone level in our patient. In addition to, b& [$ \7 U/ X' q1 Z, o
virilization, exposure to exogenous testosterone in
% I* ]# R+ w* j# |! {6 C) Kchildren results in an increase in growth velocity and, x0 B, ]: o& ?9 {, ~+ Y
advanced bone age, as seen in our patient.
1 \3 Y9 ~3 R; F' ^" H" R, TThe long-term effect of androgen exposure during2 K1 f; z9 {2 {% L
early childhood on pubertal development and final
! H; O+ r) e2 ]+ }7 N5 Xadult height are not fully known and always remain
w' K+ b% A) K( Aa concern. Children treated with short-term testos-9 w- G- ]+ A! P O
terone injection or topical androgen may exhibit some
- M5 {5 ?, Z! v, |% ]* @4 R5 |$ Facceleration of the skeletal maturation; however, after9 K+ }1 _" n# T7 P
cessation of treatment, the rate of bone maturation
2 ]0 e% y6 P. ~9 b5 K U( Odecelerates and gradually returns to normal.8,9
( K5 u. P( D& V( nThere are conflicting reports and controversy8 j. I1 w. R8 E; ^
over the effect of early androgen exposure on adult0 N) F8 s9 X% f3 B
penile length.10,11 Some reports suggest subnormal
: D. n1 y5 g* Padult penile length, apparently because of downreg-, x9 |. y J0 a& M# |
ulation of androgen receptor number.10,12 However,
. Z) q& j, ], @' ]5 F( lSutherland et al13 did not find a correlation between: N! k1 k* f: ^9 q$ I( P
childhood testosterone exposure and reduced adult
, @1 ]" r( ]! t# m7 |& l$ rpenile length in clinical studies.
8 V8 E( B6 \( h1 a JNonetheless, we do not believe our patient is
+ N" O' r/ ~* i. a7 }going to experience any of the untoward effects from
1 M% y( k. v- G etestosterone exposure as mentioned earlier because- l4 J' t" Z1 z* \+ u0 k$ y d2 H" P
the exposure was not for a prolonged period of time.: i# E8 A1 t2 T7 W1 r
Although the bone age was advanced at the time of: _' \. X% E6 W; L& |. S& A
diagnosis, the child had a normal growth velocity at
, X; |% h6 ^- G, E. ~9 Hthe follow-up visit. It is hoped that his final adult" l) q% C5 D" j8 Q
height will not be affected.
+ S* ]1 D, p$ Z+ w: R1 D: |! a |, a; oAlthough rarely reported, the widespread avail-( ]* s: t6 x* e) C
ability of androgen products in our society may$ f+ Z+ q, H. |: ^6 L( g
indeed cause more virilization in male or female: D- L, a$ W% i5 b" _+ i
children than one would realize. Exposure to andro-5 q+ k! l5 g4 p- ?3 S7 {: j
gen products must be considered and specific ques-6 h0 s# \3 X$ n" ~1 |6 a
tioning about the use of a testosterone product or
a5 w/ `/ `& T, V% F Wgel should be asked of the family members during
, n1 K" V1 W' v& ?the evaluation of any children who present with vir-8 l2 L4 I) R |" N
ilization or peripheral precocious puberty. The diag-
( S$ X3 `% N7 Snosis can be established by just a few tests and by0 q6 P. r/ B+ O" O9 ^+ h
appropriate history. The inability to obtain such a
l! Z2 ?( }# whistory, or failure to ask the specific questions, may
' ^" L4 Q& S0 G; c8 W# i( n {result in extensive, unnecessary, and expensive# b% m/ m; g9 Q! {0 I f
investigation. The primary care physician should be
2 p2 `# k; Z- a0 `aware of this fact, because most of these children
. t( \' R1 S+ ]. {5 c3 hmay initially present in their practice. The Physicians’7 Y" L( ^+ M6 x4 x7 Q
Desk Reference and package insert should also put a T- `6 R$ N& m9 B
warning about the virilizing effect on a male or
, Z/ K- F: m# O6 X2 f/ s/ M8 F! hfemale child who might come in contact with some-5 j5 E6 M( p" W& P+ e; N, L# k4 x
one using any of these products.
+ u$ o% a) \; k7 mReferences
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Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
3 X% D9 D0 u+ {2002: 565-628.
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puberty in children with tumours of the suprasellar pineal
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Stanford, CA: Stanford University Press; 1959.
7 g1 q; M. f' w) Q' P6. Physicians’ Desk Reference. Androgel 1% testosterone,
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: ~/ [, X& G q$ u+ K1 k) y0 T7. Klugo RC, Cerny JC. Response of micropenis to topical7 }' v6 T3 V5 T+ E0 o% [* V
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