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is a significant concern for physicians. Central
, k/ y: l: |, z/ e+ qprecocious puberty (CPP), which is mediated
4 T7 ^+ J4 ?; o- rthrough the hypothalamic pituitary gonadal axis, has8 x) N( w( A/ `( L5 ? b2 D) H$ A: t
a higher incidence of organic central nervous system$ Y9 w0 G% i A9 ^8 l
lesions in boys.1,2 Virilization in boys, as manifested
, E8 f3 @0 g% sby enlargement of the penis, development of pubic! ?3 I4 z0 c9 b8 _# _2 G
hair, and facial acne without enlargement of testi-* k/ F, d2 I; V! C* S
cles, suggests peripheral or pseudopuberty.1-3 We/ v8 H" t4 k o0 b7 B, d
report a 16-month-old boy who presented with the" x) G) E/ ?7 z3 K; ]/ T( D
enlargement of the phallus and pubic hair develop-" p" g/ M) ]! f$ W( t3 U
ment without testicular enlargement, which was due% ~+ K6 \' ]- F% x& N% b
to the unintentional exposure to androgen gel used by
8 g9 |8 w6 A" ^/ W Vthe father. The family initially concealed this infor- s$ o$ n2 K2 i. b( I
mation, resulting in an extensive work-up for this
! `3 s0 e( v! j) D5 P1 Qchild. Given the widespread and easy availability of
5 U+ s, S# {- z0 T) rtestosterone gel and cream, we believe this is proba-' X3 {- O# m$ |7 \6 S
bly more common than the rare case report in the8 a9 m* z2 Z+ X W' n; h
literature.4) p3 ], m7 `! j" p4 Z
Patient Report
5 t5 z) U) P, e, B, K1 a0 {A 16-month-old white child was referred to the% ^0 X! o( _- [+ D
endocrine clinic by his pediatrician with the concern9 \* X; I) N$ x* l$ {
of early sexual development. His mother noticed
4 ~! O9 R/ C# Plight colored pubic hair development when he was7 ~" c# e7 ?- F
From the 1Division of Pediatric Endocrinology, 2University of
/ E9 o7 L) S v& n4 Y0 B# fSouth Alabama Medical Center, Mobile, Alabama.
' ~: l: Y5 D. ]5 W0 Y4 KAddress correspondence to: Samar K. Bhowmick, MD, FACE,: r8 }" U% [" @% K0 x, n) B
Professor of Pediatrics, University of South Alabama, College of. V- f! T) d& E4 b5 e' W3 g
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;! T! B2 }7 V' m% _3 \4 M8 O- n
e-mail: [email protected].
; E* l0 ]3 w9 c: |: @0 z0 X4 F0 l# Habout 6 to 7 months old, which progressively became8 ] @% {, L& i
darker. She was also concerned about the enlarge-
) z5 |7 k% |1 w5 a4 @ment of his penis and frequent erections. The child( o. A% g$ v+ V1 d Q$ p1 S. T
was the product of a full-term normal delivery, with
2 F W1 Q, B$ W2 Aa birth weight of 7 lb 14 oz, and birth length of
4 b$ [5 \, O+ d+ Q. b$ M20 inches. He was breast-fed throughout the first year- H' A' s, }( Q0 ?/ t; l: H
of life and was still receiving breast milk along with7 U, @+ B9 ]2 }( o
solid food. He had no hospitalizations or surgery,
6 ?) R, U3 C7 Fand his psychosocial and psychomotor development
m* Q- M" ?7 c: r) v fwas age appropriate.
* F9 N* u" {. v. S: U" iThe family history was remarkable for the father,% f4 e" s4 @* S9 P
who was diagnosed with hypothyroidism at age 16,
2 E/ F' e# }4 |which was treated with thyroxine. The father’s* V% b) R' c+ I) \
height was 6 feet, and he went through a somewhat
) a# \- p. t# Z5 L2 }early puberty and had stopped growing by age 14.8 ]$ A+ v% U# n1 Y- g
The father denied taking any other medication. The
8 Z9 ^2 P( ^7 j; P) @child’s mother was in good health. Her menarche, e0 {4 s) k7 X. w9 i# x1 i
was at 11 years of age, and her height was at 5 feet0 Q x5 N }) I3 x/ e
5 inches. There was no other family history of pre-
* y9 U, y5 z; y7 V# f" ^5 ^* gcocious sexual development in the first-degree rela-, ^- U8 E: ?" Z3 f7 \8 G
tives. There were no siblings.
r4 T7 y. K; b) E. h( CPhysical Examination6 \4 j* a& R( G2 `: U
The physical examination revealed a very active,2 f' n4 Z' D# h* h% F0 M
playful, and healthy boy. The vital signs documented# W* m4 M3 U1 p$ q) B$ x' g
a blood pressure of 85/50 mm Hg, his length was
- i. I2 Q' z( C/ t90 cm (>97th percentile), and his weight was 14.4 kg0 |- }9 j# ~8 f! l
(also >97th percentile). The observed yearly growth
{3 \9 D9 P; fvelocity was 30 cm (12 inches). The examination of
% |! t& i. F+ n" [- P7 {% t' a% e( J ~2 vthe neck revealed no thyroid enlargement.0 z7 M; k2 f3 z5 P
The genitourinary examination was remarkable for
; y7 F7 q+ U menlargement of the penis, with a stretched length of; F6 k, A' S! ~3 n7 C
8 cm and a width of 2 cm. The glans penis was very well
6 Y8 t. u5 M$ @: h. y! P. E8 \ [6 }developed. The pubic hair was Tanner II, mostly around8 [( I2 F& Y: C) B8 l' O8 V# `5 _' K
540
. j6 ^+ A2 \% Z6 ]' T" r& xat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
! K, n' v2 ?% O1 m/ `+ C, ]3 t. ]( d' k- Kthe base of the phallus and was dark and curled. The8 s' ~/ d) d' ^* p$ K
testicular volume was prepubertal at 2 mL each./ n5 y" h8 _2 s6 d0 W$ e5 O+ t: [) w
The skin was moist and smooth and somewhat: i7 w0 @) d) K0 q, p2 g
oily. No axillary hair was noted. There were no
. [" ]7 z4 K# m1 u+ Eabnormal skin pigmentations or café-au-lait spots.4 C8 ?" {: M; F' }) m
Neurologic evaluation showed deep tendon reflex 2+
( K5 b( x, A; bbilateral and symmetrical. There was no suggestion
6 v5 P+ W6 s5 ?8 q: t3 oof papilledema.8 q/ Q) p3 }" b" m
Laboratory Evaluation
# A4 j) M1 f: cThe bone age was consistent with 28 months by
( M) S) n( A; H4 w t& Uusing the standard of Greulich and Pyle at a chrono-
& K& Z9 l: y, T- d2 b- c4 {" S8 \logic age of 16 months (advanced).5 Chromosomal
! ?6 U: H2 s8 g$ T# Nkaryotype was 46XY. The thyroid function test
6 e D6 T8 [$ V3 @/ y# Ishowed a free T4 of 1.69 ng/dL, and thyroid stimu-! y7 d" a c2 z- |/ m" [
lating hormone level was 1.3 µIU/mL (both normal).
( @/ @% i/ Q: ?, Q) MThe concentrations of serum electrolytes, blood c. Y, V2 f9 }% V
urea nitrogen, creatinine, and calcium all were
: C$ E+ f; p8 n: j4 ~within normal range for his age. The concentration
* {: m+ P# v3 ?( z+ p iof serum 17-hydroxyprogesterone was 16 ng/dL/ g. B* \# a0 D7 D: U. {' _
(normal, 3 to 90 ng/dL), androstenedione was 20
1 l, I( t. Z( }' Kng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
: g5 ?% {. r- H6 c* U. D0 U& J6 Jterone was 38 ng/dL (normal, 50 to 760 ng/dL),
[0 r1 \+ {0 pdesoxycorticosterone was 4.3 ng/dL (normal, 7 to
+ H' ?& ^, O- a3 B( d5 b8 f49ng/dL), 11-desoxycortisol (specific compound S)- O3 ~9 \8 J- \8 b5 L3 m9 h
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-. v5 F* n* [; R( S
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total0 Z+ V7 U" m. I
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),/ N6 }- h) F9 p" p1 |, u
and β-human chorionic gonadotropin was less than" `5 W, j$ d- A& j
5 mIU/mL (normal <5 mIU/mL). Serum follicular
1 H7 |7 D. y# cstimulating hormone and leuteinizing hormone
; [) o: Z" l$ |" L" P) b: t0 W# Wconcentrations were less than 0.05 mIU/mL9 T1 e; ~2 c, F- v# X* `
(prepubertal).4 j. S+ \/ { ?0 p: i2 z+ X1 S
The parents were notified about the laboratory* F; K' E8 @, c/ Z9 |
results and were informed that all of the tests were
0 V7 q7 f* I4 |5 u; ~. Anormal except the testosterone level was high. The" s% @5 {4 U4 h, j. h' p
follow-up visit was arranged within a few weeks to2 }7 H- p3 s* ~5 N6 I! H
obtain testicular and abdominal sonograms; how-
, ~5 @# ~: b2 e$ x0 I% O2 x: G" o% Tever, the family did not return for 4 months.* n2 u; `6 v% P3 q* h
Physical examination at this time revealed that the+ }6 r; L8 w. [% P
child had grown 2.5 cm in 4 months and had gained# D0 ?$ @; k( Z, u4 K! r( V# d d. Z
2 kg of weight. Physical examination remained- F7 S# s" h; B" z1 A i8 A
unchanged. Surprisingly, the pubic hair almost com-
, ~; p i* K0 ]. R+ @pletely disappeared except for a few vellous hairs at4 y7 ?. b1 |9 ]9 n$ _
the base of the phallus. Testicular volume was still 28 h/ q0 v8 C" y B: _& u2 T6 L$ D
mL, and the size of the penis remained unchanged.
! q. t% Q& U" {The mother also said that the boy was no longer hav-
0 j9 S7 g( Y! l- B+ r& Q1 n8 S. ding frequent erections.$ L) Z) Z" w/ g8 @: L- @
Both parents were again questioned about use of% g$ H! `- p$ P, z
any ointment/creams that they may have applied to
7 g& D1 q7 E+ t4 Ethe child’s skin. This time the father admitted the; w; L: [) u1 \. E+ y, [
Topical Testosterone Exposure / Bhowmick et al 541
7 K9 @$ {1 K8 R; quse of testosterone gel twice daily that he was apply-
3 i0 l' {/ ?+ c fing over his own shoulders, chest, and back area for- ~0 `* F! m+ l) z2 ]6 S6 e- y
a year. The father also revealed he was embarrassed6 y3 z; T- ?& R% b0 k2 a, p3 |* @, r
to disclose that he was using a testosterone gel pre-) M' |2 v: n8 _
scribed by his family physician for decreased libido
* Y1 A7 i0 \) [1 psecondary to depression.- P/ U& ]% ]7 l% x
The child slept in the same bed with parents.
8 a% _2 n6 T0 a' ~" RThe father would hug the baby and hold him on his
7 V! W g8 J3 g: fchest for a considerable period of time, causing sig-4 B( k: o4 z+ W$ }
nificant bare skin contact between baby and father.
& b$ Y# V4 C, ?( A3 p7 [The father also admitted that after the phone call,
) v; |7 q% K$ D4 Ewhen he learned the testosterone level in the baby
1 X$ w+ F0 x2 M! l: S0 Qwas high, he then read the product information: R# e# j. Q' R3 Y3 g1 p
packet and concluded that it was most likely the rea-
. v/ o- d6 m; j. J) ~9 M' S8 s2 Tson for the child’s virilization. At that time, they
: S# Z* {2 a- B, E" n4 C& c! vdecided to put the baby in a separate bed, and the5 X3 K* W( L/ H3 O5 ~# Y
father was not hugging him with bare skin and had
+ ^9 ]) `& Z+ r" N3 {6 @" o1 wbeen using protective clothing. A repeat testosterone z' W% J8 s w
test was ordered, but the family did not go to the" [; v* ~1 y" T+ [
laboratory to obtain the test., \, m' s5 A: d
Discussion- q1 O& [2 H& k3 A3 m
Precocious puberty in boys is defined as secondary
# H, a9 N' d" v8 `# {3 _sexual development before 9 years of age.1,4
0 L6 l. D9 z( ]: g5 WPrecocious puberty is termed as central (true) when
' C& y9 I6 c9 h8 w( S+ b; p) {% @it is caused by the premature activation of hypo-
5 X. U: T( j; K1 ^thalamic pituitary gonadal axis. CPP is more com-
: n( ^! g' w2 x/ `4 R4 ?# L4 Umon in girls than in boys.1,3 Most boys with CPP
$ c( J! h- q! d, r7 Dmay have a central nervous system lesion that is
) I: ?3 b b4 U" J$ Y% }" U3 @3 ]responsible for the early activation of the hypothal-
2 U4 w0 O3 i( s0 p& Iamic pituitary gonadal axis.1-3 Thus, greater empha-
2 r8 ]; H" U+ f: C4 y, j" asis has been given to neuroradiologic imaging in6 \/ R$ b; Y+ L3 W! e: v! J. `( L
boys with precocious puberty. In addition to viril-# W" X- k6 k# M( J4 ]
ization, the clinical hallmark of CPP is the symmet-
8 d9 R: N* U1 Q' K$ b" j3 X+ B4 `' rrical testicular growth secondary to stimulation by
8 N8 l4 I- w7 D" W# r% a9 }0 R" `, H4 vgonadotropins.1,3' y7 A% f* t [# d* }2 E
Gonadotropin-independent peripheral preco-2 o6 f7 b3 j- j4 `. H7 J
cious puberty in boys also results from inappropriate9 I* s, Q. C5 C6 V; \
androgenic stimulation from either endogenous or6 G0 o( s, n$ x4 S6 @+ K
exogenous sources, nonpituitary gonadotropin stim-6 t5 ?/ ^ L, w0 U; ^/ `6 \5 y9 _ X, t$ U
ulation, and rare activating mutations.3 Virilizing; P% `/ g+ Q$ Y4 r8 F. e8 H
congenital adrenal hyperplasia producing excessive
- O' ]/ d% ^9 x8 zadrenal androgens is a common cause of precocious' A% C* t T( f/ a
puberty in boys.3,4
/ q. z' r; |* K- A8 F6 AThe most common form of congenital adrenal
5 D0 S: y+ V t3 q# O+ M! a, |hyperplasia is the 21-hydroxylase enzyme deficiency.
/ n; B4 i/ r& h4 w% oThe 11-β hydroxylase deficiency may also result in
) C# l+ |5 C( @1 E3 S, `excessive adrenal androgen production, and rarely,) `4 }& w: I' B2 W" i1 J M
an adrenal tumor may also cause adrenal androgen, S( ^0 r8 [. p
excess.1,3( \, M' Q- N. j/ k: }6 q6 g4 l3 x
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
3 R4 f3 c- F% L; j. X6 U: m542 Clinical Pediatrics / Vol. 46, No. 6, July 2007$ q% U" {/ C3 H
A unique entity of male-limited gonadotropin-, O3 {; _ p d( G
independent precocious puberty, which is also known
, R! g7 ?4 j# H) ~2 [: T, h* cas testotoxicosis, may cause precocious puberty at a/ M) S& S) M1 J0 I- \1 u
very young age. The physical findings in these boys
" z: j, H+ ^* l+ s& E& xwith this disorder are full pubertal development,% f$ e, ~- W. S
including bilateral testicular growth, similar to boys
/ s/ c1 s1 v; |8 s- K# C: Swith CPP. The gonadotropin levels in this disorder
& o! g9 g' b [2 X m4 bare suppressed to prepubertal levels and do not show
- g# p" H {$ k7 |: Bpubertal response of gonadotropin after gonadotropin-
]! D# |1 P) @# q- @ o* ]5 Dreleasing hormone stimulation. This is a sex-linked
( v: D! T4 c U6 Xautosomal dominant disorder that affects only( [3 x8 W9 J# T; Z; b
males; therefore, other male members of the family
g! u5 f# N5 [- w) s8 qmay have similar precocious puberty.3: E2 A, k" p9 q. W/ x
In our patient, physical examination was incon-. r+ X/ r7 b) s
sistent with true precocious puberty since his testi-, ` A% {& b! [! t
cles were prepubertal in size. However, testotoxicosis
( }! ?+ m* F' U. Owas in the differential diagnosis because his father! Z8 l( @# h) g2 Y8 z8 ?3 p
started puberty somewhat early, and occasionally,$ u$ }# R' t5 L4 L' \
testicular enlargement is not that evident in the" ^* H" s6 o. `1 J$ j8 O
beginning of this process.1 In the absence of a neg-; x6 F6 s2 K& f) \: o* n) B; c
ative initial history of androgen exposure, our b* q1 g3 R8 y3 a4 R7 Z
biggest concern was virilizing adrenal hyperplasia,& X4 _" ?8 d5 y( E; a
either 21-hydroxylase deficiency or 11-β hydroxylase
' z& d4 P9 z, Gdeficiency. Those diagnoses were excluded by find-
6 q' X! \2 D7 s+ _1 W9 fing the normal level of adrenal steroids.+ P! x- X6 u3 {, [* \8 F1 M
The diagnosis of exogenous androgens was strongly# K" A, d1 U; {& O
suspected in a follow-up visit after 4 months because( n+ ?4 Y6 k6 Y- y: t
the physical examination revealed the complete disap-: [; ^5 G) f. Q! j, a8 @% }- x$ [
pearance of pubic hair, normal growth velocity, and, l2 @) ]7 j J" a$ W5 T1 {) g& y
decreased erections. The father admitted using a testos-
- g$ e: ^- q K: @0 j" ]% G- rterone gel, which he concealed at first visit. He was3 d) `, X% l7 T$ X
using it rather frequently, twice a day. The Physicians’. z! T) p& M, s$ I R U/ |
Desk Reference, or package insert of this product, gel or
/ n7 V8 g( J) O) q' A7 |) U0 w! scream, cautions about dermal testosterone transfer to
; s# f3 T1 l' o! Wunprotected females through direct skin exposure.
8 r1 d+ L7 M' v- N7 lSerum testosterone level was found to be 2 times the6 y8 g1 w; O5 W4 X" r
baseline value in those females who were exposed to$ `% q6 L; \) |7 Q0 n
even 15 minutes of direct skin contact with their male# Y7 p2 |2 ~7 z8 Y* s; I
partners.6 However, when a shirt covered the applica-. I5 w4 O/ J- H' f0 c7 D3 v# o
tion site, this testosterone transfer was prevented. c) R p, F% p: H" G* C
Our patient’s testosterone level was 60 ng/mL,
: L9 i8 o. M7 A; h& H' g: m9 Dwhich was clearly high. Some studies suggest that' f# N! J& g6 B5 K. {1 [2 y4 W3 A0 ^
dermal conversion of testosterone to dihydrotestos-
$ R6 z+ }$ j) {9 r6 n6 b- Cterone, which is a more potent metabolite, is more
: a- u$ x# I) Y' p4 pactive in young children exposed to testosterone2 x* {5 p2 i# Q* }
exogenously7; however, we did not measure a dihy-
$ l+ {) w3 F+ S- F6 Ldrotestosterone level in our patient. In addition to
) [0 R) ^/ U9 b& O: y& A2 g; Gvirilization, exposure to exogenous testosterone in
% K- N/ j* {* z! H/ X( Cchildren results in an increase in growth velocity and2 g# r c) v. _: I, O0 p
advanced bone age, as seen in our patient.9 g! \# {6 M! v, p6 {
The long-term effect of androgen exposure during
. s2 R( P6 |+ o8 u) ^. J3 d5 ?early childhood on pubertal development and final
' s: w3 O- i! {6 Jadult height are not fully known and always remain3 u) l+ z. U; Q! I
a concern. Children treated with short-term testos-
# ?7 X. L, m- B D7 k8 oterone injection or topical androgen may exhibit some" n' f; Z: m- e% s5 t
acceleration of the skeletal maturation; however, after2 [) L6 @) J7 Q" z- j2 d
cessation of treatment, the rate of bone maturation6 f4 o/ K5 x) E. P. |7 M, m
decelerates and gradually returns to normal.8,98 |% ^, B% m2 r7 j9 \
There are conflicting reports and controversy; j" H4 B. ]. o2 ^0 p _) R$ P+ ~+ J
over the effect of early androgen exposure on adult
+ T3 E0 x& s/ E2 g+ ~0 zpenile length.10,11 Some reports suggest subnormal
! I( L( s7 M$ H! N' B/ @5 A0 F4 madult penile length, apparently because of downreg-
{- C( X5 @, V* Nulation of androgen receptor number.10,12 However,5 a ~2 e9 I0 \( _. a
Sutherland et al13 did not find a correlation between
& t7 ~' w) }3 z1 t0 tchildhood testosterone exposure and reduced adult8 c. N: r" K v& s' O* @$ Z
penile length in clinical studies.
' h: a% e: l7 J& eNonetheless, we do not believe our patient is
7 W( n( @. ?' ]/ M& Wgoing to experience any of the untoward effects from2 D8 U1 h" m. R, J3 l3 n- j; N! g4 x
testosterone exposure as mentioned earlier because' w2 k) M$ g9 _- z& `+ Y* d
the exposure was not for a prolonged period of time.
* Z/ e) A: v% {5 ]) {! nAlthough the bone age was advanced at the time of
# F/ n. p5 y6 T; y3 R3 K# ^$ cdiagnosis, the child had a normal growth velocity at
2 Z( ?6 r$ P. j1 I$ G3 Nthe follow-up visit. It is hoped that his final adult
# f) l( o7 u3 W0 oheight will not be affected./ `0 F) O; v! Y3 {
Although rarely reported, the widespread avail-
! r2 f! q' M* N' ]+ X5 dability of androgen products in our society may6 R" V* ^ i7 z' \" H) i4 E# B
indeed cause more virilization in male or female: Q0 f, e5 [: e; Q
children than one would realize. Exposure to andro-+ b. j( \& t: L ^, V: D) J
gen products must be considered and specific ques-
# [; n! l, c- R Xtioning about the use of a testosterone product or+ \5 {5 J# Y f* H: C* K
gel should be asked of the family members during) v; x: L, ?$ `) y/ U. x3 X
the evaluation of any children who present with vir-+ V5 X1 {% J0 @3 q/ O: G
ilization or peripheral precocious puberty. The diag-# ?, j; \% `7 N2 G+ k
nosis can be established by just a few tests and by7 w: R$ \( C5 C L1 Q% v; N* r) M
appropriate history. The inability to obtain such a9 K2 _3 D- l$ }! T& I6 D2 ~4 |- s4 ^! T M
history, or failure to ask the specific questions, may0 [, B6 ]# H) B4 V3 p1 o1 @0 M
result in extensive, unnecessary, and expensive/ Z1 I0 x' N: ~" d! q
investigation. The primary care physician should be N, C l6 f9 F6 V2 T. }
aware of this fact, because most of these children& X2 b* L v) {1 H
may initially present in their practice. The Physicians’
: A1 q$ I: d7 P j( o' C9 ODesk Reference and package insert should also put a
- P2 G5 l7 i$ u; |5 y$ [4 iwarning about the virilizing effect on a male or; m) }' M/ s. C3 F
female child who might come in contact with some-1 O; T( v6 z: e8 m
one using any of these products. X4 _! ^8 U' d3 n+ ~3 |7 [+ |$ c
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% ?: v# P8 I+ g3 `1 j6. Physicians’ Desk Reference. Androgel 1% testosterone,& h. @7 G+ O! B: g/ V
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9 v) _3 a+ H6 Q5 Q& @' e. ~7. Klugo RC, Cerny JC. Response of micropenis to topical2 _8 d& c! i4 ~% F( a( y u
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