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is a significant concern for physicians. Central
& F9 O- { _/ k, e/ E# i1 Z: |precocious puberty (CPP), which is mediated
; B+ r! f) m/ W/ ?& Nthrough the hypothalamic pituitary gonadal axis, has: ?( L3 J6 [- U( t& L
a higher incidence of organic central nervous system0 a& a! k" k3 n! C+ l/ M1 ~
lesions in boys.1,2 Virilization in boys, as manifested) q) j8 o: ~+ z8 J. D& Z: q" n2 |
by enlargement of the penis, development of pubic! A, O) P+ J$ f* c
hair, and facial acne without enlargement of testi-) o# x% |) z$ Y+ F! X
cles, suggests peripheral or pseudopuberty.1-3 We: F+ x0 A: t& Z& f) Y! d$ K
report a 16-month-old boy who presented with the
2 f* V: j- C- v) A$ z1 ^" penlargement of the phallus and pubic hair develop-3 O9 M( W" {# R3 u- R& d" j
ment without testicular enlargement, which was due0 V7 i6 b! p. I G. l. D
to the unintentional exposure to androgen gel used by; V% b& F) S3 C
the father. The family initially concealed this infor-% k- d# g/ }1 Q% @6 ^- V
mation, resulting in an extensive work-up for this7 R% Q) z1 J1 K* @) N- w- j! w4 d
child. Given the widespread and easy availability of
. V: J8 s( s. c1 q. utestosterone gel and cream, we believe this is proba-
9 S% M( O9 }$ _# m. N" x9 @( }bly more common than the rare case report in the/ m( j9 w- w; ~! w) x* {
literature.4
4 \1 P* L: N0 f) Y% U5 KPatient Report; W0 H% M0 t) N, G8 g9 r9 H
A 16-month-old white child was referred to the
4 I( C, ^( z+ i5 Hendocrine clinic by his pediatrician with the concern
( c. \4 C# ^( u$ B; H4 Qof early sexual development. His mother noticed, K% F$ Z# Y9 f4 U
light colored pubic hair development when he was
- a0 v3 { t/ a/ l8 m# qFrom the 1Division of Pediatric Endocrinology, 2University of% K! ]4 H, ~: S$ d
South Alabama Medical Center, Mobile, Alabama.1 K# Q$ X3 d1 w' j& U5 f% M9 q
Address correspondence to: Samar K. Bhowmick, MD, FACE,# p3 h6 G$ i3 W* S& m9 k* ^
Professor of Pediatrics, University of South Alabama, College of4 }6 K- Y2 z. ` N7 E0 c' Q2 e
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
" n& P& h `5 j, M# ]e-mail: [email protected].
4 j; d4 r( D/ {6 x+ \* X8 S5 _about 6 to 7 months old, which progressively became
. ?2 V# Z4 L1 a0 E' A# ndarker. She was also concerned about the enlarge-
4 [1 ]8 g7 v0 U6 ement of his penis and frequent erections. The child5 i1 y2 M9 @" L
was the product of a full-term normal delivery, with0 [- B% B6 {1 y3 R E: E
a birth weight of 7 lb 14 oz, and birth length of/ d) s! C( t+ U* ^/ P+ ^- L- p
20 inches. He was breast-fed throughout the first year
' w/ {$ ?# y" m2 F |, M8 wof life and was still receiving breast milk along with
6 m2 @% z. \* S/ Qsolid food. He had no hospitalizations or surgery,& r# x0 L W% p$ e. Z1 Z
and his psychosocial and psychomotor development
3 M! S+ O% M% ?5 ]9 |was age appropriate.
5 Q5 r) ~0 Q9 Y5 T# c9 fThe family history was remarkable for the father,
3 J, S, Z+ q) a6 h2 \7 K8 Iwho was diagnosed with hypothyroidism at age 16," o* }1 k6 d% W" H* n" j" W* V* o" r
which was treated with thyroxine. The father’s0 J7 g. C" g5 \% o
height was 6 feet, and he went through a somewhat
# e& ~6 \( i" d' g% U) W5 Y! [early puberty and had stopped growing by age 14.5 r6 \6 |" x4 K+ _7 m0 F# {
The father denied taking any other medication. The1 q- h; m6 H; U6 s2 [* s
child’s mother was in good health. Her menarche& G8 b# O# l7 R" ?2 y
was at 11 years of age, and her height was at 5 feet! ]4 i' i0 I1 n
5 inches. There was no other family history of pre-
' O* M& P, u/ t/ Vcocious sexual development in the first-degree rela-! q; [5 D. z2 k8 c8 p8 ^* \$ ~& q4 L
tives. There were no siblings.4 S. H# k/ }% v, k5 q8 ~9 `
Physical Examination
& a( Q8 j8 q) N) Q# u( }- ZThe physical examination revealed a very active,
# D& z& W' V+ l4 Q) U) U7 m6 C6 cplayful, and healthy boy. The vital signs documented
7 q( w9 W) Y ta blood pressure of 85/50 mm Hg, his length was! L c: _! n6 H; W# N4 `/ d3 H1 S' P
90 cm (>97th percentile), and his weight was 14.4 kg0 l$ ^- i- C# N5 y# f( f0 F
(also >97th percentile). The observed yearly growth: F4 H( I' \, j4 F: {) O5 D
velocity was 30 cm (12 inches). The examination of
1 Y+ {9 |. e6 A% t" W, pthe neck revealed no thyroid enlargement.- C8 Y: N5 ^" W- Q' V
The genitourinary examination was remarkable for: m0 M4 m3 q; j! r
enlargement of the penis, with a stretched length of
' E x1 ~8 U3 m$ N, V$ z+ Z8 cm and a width of 2 cm. The glans penis was very well
1 @* P5 D- i& Fdeveloped. The pubic hair was Tanner II, mostly around) B2 s) U5 M7 v! w9 }- A
5404 C& v6 H, h: H
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from$ _3 J$ X( _, K) j3 w1 I
the base of the phallus and was dark and curled. The4 F) _8 V' v% v4 n: T5 I
testicular volume was prepubertal at 2 mL each.0 Z" ]% k. v! X$ z
The skin was moist and smooth and somewhat" l. E' M z5 G/ @2 P
oily. No axillary hair was noted. There were no
b: G1 e" d6 ~abnormal skin pigmentations or café-au-lait spots.: H% H: H. D& q' s S% ?/ Q
Neurologic evaluation showed deep tendon reflex 2+- }9 N" o9 f: o j+ R- p% m1 t
bilateral and symmetrical. There was no suggestion: u {" U% [/ R" v
of papilledema.
. v/ x% \1 N' A. Q7 Q8 RLaboratory Evaluation. [# k9 n3 t- M+ U
The bone age was consistent with 28 months by7 ^; t- _9 K% H+ r' `" [8 J
using the standard of Greulich and Pyle at a chrono-
3 \& i2 h( v, ^0 R/ \logic age of 16 months (advanced).5 Chromosomal
# X9 ?: u/ r; \# ~7 H$ T' R* `- [karyotype was 46XY. The thyroid function test
' B* m0 _* w* s z& O. V+ xshowed a free T4 of 1.69 ng/dL, and thyroid stimu-
" F E% T* C" b& rlating hormone level was 1.3 µIU/mL (both normal).
1 J$ Q& l7 a& e4 F9 BThe concentrations of serum electrolytes, blood
B6 Q! x+ ^+ F' [/ surea nitrogen, creatinine, and calcium all were4 t5 v" A! f; I4 f( \
within normal range for his age. The concentration3 q# F& r' j/ x% [% W
of serum 17-hydroxyprogesterone was 16 ng/dL. G2 ~( l% E2 I+ ~ D/ R
(normal, 3 to 90 ng/dL), androstenedione was 20) y7 z! k. s' N+ T
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
# i; f- {7 W% C2 E9 U. \( Nterone was 38 ng/dL (normal, 50 to 760 ng/dL),# f( a; B3 L6 j! D2 X g8 \
desoxycorticosterone was 4.3 ng/dL (normal, 7 to1 L8 \% S( d' s5 z+ [- h! C/ t
49ng/dL), 11-desoxycortisol (specific compound S)
9 W3 X; I3 M6 [; o3 V/ {was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-3 c* g0 j2 k9 E/ r
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
9 y p4 y& ?: F0 ktestosterone was 60 ng/dL (normal <3 to 10 ng/dL),: E! v4 l6 [# Z' Y f
and β-human chorionic gonadotropin was less than
1 r% L) K8 v& @+ F/ w5 mIU/mL (normal <5 mIU/mL). Serum follicular9 |% R2 v$ {" M9 \4 X* ^
stimulating hormone and leuteinizing hormone
( {% o( d- L7 `6 H; z% J8 ]+ Econcentrations were less than 0.05 mIU/mL5 V, Q( h* [7 b9 l
(prepubertal).* ^' {- N, w1 b( y4 N
The parents were notified about the laboratory- a) c+ I F6 v" j
results and were informed that all of the tests were9 Z% T! P& @% Z6 ~8 ]% l
normal except the testosterone level was high. The! u# L* s2 @; ^, B- T9 k
follow-up visit was arranged within a few weeks to
1 H4 l& k( W! x, k7 D7 d! eobtain testicular and abdominal sonograms; how-
2 N5 Y# I( n0 O, W7 oever, the family did not return for 4 months.
& g! [; S# p' P W$ k! DPhysical examination at this time revealed that the
6 }$ B# u8 \% X$ }/ t% a1 l2 }& Xchild had grown 2.5 cm in 4 months and had gained6 ^7 c" H- P+ y
2 kg of weight. Physical examination remained
3 }0 t5 H C. [" v$ [9 G" r0 F4 Iunchanged. Surprisingly, the pubic hair almost com-
* t5 R; }: x( g/ ipletely disappeared except for a few vellous hairs at. \2 q+ o s r- P( p5 ^
the base of the phallus. Testicular volume was still 2
: q4 W8 c' J$ c) N ^) tmL, and the size of the penis remained unchanged., ]$ l6 e) z- I) v6 M
The mother also said that the boy was no longer hav-' G3 l O9 |- [; i
ing frequent erections. X9 u( q% d* a' `" [
Both parents were again questioned about use of; }* v0 O' Z/ R# h4 n
any ointment/creams that they may have applied to
! k4 F) ]# [6 l8 N. B; p* d6 Jthe child’s skin. This time the father admitted the
1 u4 |' @; c3 z9 o/ `0 Q6 T( jTopical Testosterone Exposure / Bhowmick et al 541
! d# T3 c. Q- g/ huse of testosterone gel twice daily that he was apply-
/ F+ A/ \- I2 o t c( X6 [ing over his own shoulders, chest, and back area for
2 e( T7 J6 ?6 w( ]# Y) ?a year. The father also revealed he was embarrassed
! O9 `9 o9 Y0 l% Jto disclose that he was using a testosterone gel pre-# l% L0 z0 q! |7 X- c# B, c* p0 c
scribed by his family physician for decreased libido* V+ e9 K9 p# ]4 ^% I% e8 {* U9 [
secondary to depression.. x5 K7 `! D7 H- e7 F: _! M
The child slept in the same bed with parents.
- {8 x% I$ E5 c4 h+ \ x/ jThe father would hug the baby and hold him on his& s- f6 E9 r2 {
chest for a considerable period of time, causing sig-
; `! H: L7 C# e" T& b2 Vnificant bare skin contact between baby and father.0 g/ j' L' ^2 K3 H, {' u
The father also admitted that after the phone call, \9 X2 v" [& ^. y5 C
when he learned the testosterone level in the baby
1 [4 Z: x: e( A* a$ n0 Wwas high, he then read the product information
/ L, O# @2 x/ A# G2 K' L$ |packet and concluded that it was most likely the rea-
+ v4 R. q+ E% L- X) ~( Ison for the child’s virilization. At that time, they
5 T( k- O9 _# e; s) Rdecided to put the baby in a separate bed, and the0 p( K2 E3 X& R& `+ s! m7 Z. L
father was not hugging him with bare skin and had
7 v. l' Y0 N. A3 R- hbeen using protective clothing. A repeat testosterone) T. ~7 }: L0 ?! U
test was ordered, but the family did not go to the3 E- e& f' v* L6 G/ F. g
laboratory to obtain the test.; y$ P/ i/ L% _& ?
Discussion8 V& l% X @6 ?% d2 H( H
Precocious puberty in boys is defined as secondary0 e. p+ ]- B Y# C+ F+ p* d
sexual development before 9 years of age.1,49 u( R2 T0 r+ O j9 c
Precocious puberty is termed as central (true) when
: ^% U0 h3 B6 ]# @it is caused by the premature activation of hypo-
3 b: T2 k0 e1 }, t" S3 Uthalamic pituitary gonadal axis. CPP is more com-% H) {9 ?% m, l: p. z
mon in girls than in boys.1,3 Most boys with CPP' I8 x, S. c& K2 |0 f( I
may have a central nervous system lesion that is# ^8 L+ z5 |& S( N) d& g+ J5 p
responsible for the early activation of the hypothal-! b# s! p: `5 P$ a4 m1 ^1 D
amic pituitary gonadal axis.1-3 Thus, greater empha- d+ V. ~1 Q6 A2 f/ N/ k
sis has been given to neuroradiologic imaging in
# o% ~# R- u/ [+ S: Oboys with precocious puberty. In addition to viril-
3 C$ _7 J: F1 Q# t. @7 mization, the clinical hallmark of CPP is the symmet-4 J' f. Q" q( r8 H+ ?% }# y, Q+ x% b
rical testicular growth secondary to stimulation by
( h- L) D' ~. Y, w2 D1 @gonadotropins.1,3
3 ^! k1 I% L# E) s1 p9 D0 {Gonadotropin-independent peripheral preco-( D+ T) Y% d$ p6 x4 W
cious puberty in boys also results from inappropriate
4 q% k& I! {3 jandrogenic stimulation from either endogenous or9 ` |5 I& t0 ^3 U0 Q3 u
exogenous sources, nonpituitary gonadotropin stim-% U k3 _9 q$ `- V$ e1 z
ulation, and rare activating mutations.3 Virilizing
/ C- L9 T' ?5 R0 b; w; @; S2 ^congenital adrenal hyperplasia producing excessive6 q% K- [2 i8 F+ U; p2 R
adrenal androgens is a common cause of precocious
3 f# V! H# U, u0 D9 Lpuberty in boys.3,4
) _$ k, |. h9 [1 e. f1 M% KThe most common form of congenital adrenal
6 E1 A' Y( R6 C2 p6 Q' g4 c1 r. Vhyperplasia is the 21-hydroxylase enzyme deficiency.
+ T1 c8 k" i0 X4 |6 Y) Q6 R9 FThe 11-β hydroxylase deficiency may also result in
c- d3 c# U% l8 \( v" F nexcessive adrenal androgen production, and rarely,4 A/ i& A* k h. z( n
an adrenal tumor may also cause adrenal androgen
* o4 D8 p) v3 Z Z+ Rexcess.1,3
( ~: @/ N. w9 r( {( B2 i" `at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from+ Z1 {1 ~' z/ w7 ]% S
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007# c* d1 |/ C& d2 u; P. \
A unique entity of male-limited gonadotropin-* I: a+ k3 U6 l: z% u2 {
independent precocious puberty, which is also known$ t5 R4 A: J1 t7 a) R' n
as testotoxicosis, may cause precocious puberty at a) p! L& Q8 D. A
very young age. The physical findings in these boys
: P8 K0 ~3 W9 t8 S4 [! ?2 p9 gwith this disorder are full pubertal development, H% {; Z. A2 P
including bilateral testicular growth, similar to boys
8 @' z+ T+ w5 {/ U. Nwith CPP. The gonadotropin levels in this disorder
8 K9 s" V, n$ h P# b# }4 fare suppressed to prepubertal levels and do not show
8 P' L1 o. ?- _ M# Jpubertal response of gonadotropin after gonadotropin-9 A/ N2 v$ O; d. w, m, c4 d
releasing hormone stimulation. This is a sex-linked/ p9 z- M; h0 {$ U, Z/ S" J4 a
autosomal dominant disorder that affects only9 \2 ~ v/ C2 j$ j) Z7 Q3 x
males; therefore, other male members of the family
2 ]" \& t$ F$ ]2 Q9 e1 k& Vmay have similar precocious puberty.3
) J) P- D# a) e/ [" YIn our patient, physical examination was incon-
$ ?3 M+ d* ^, T- osistent with true precocious puberty since his testi-
$ Z, _! A1 T1 @# W% h. v( jcles were prepubertal in size. However, testotoxicosis
7 B6 o8 T4 J' ~: A/ |' V8 Jwas in the differential diagnosis because his father0 P, `* N6 {8 g3 C+ |' v
started puberty somewhat early, and occasionally,
s# o5 r6 {. N& v, Ytesticular enlargement is not that evident in the% R ~% e0 Z. d7 w2 i, ~
beginning of this process.1 In the absence of a neg-
9 v! Y' G G4 s5 y% E- Bative initial history of androgen exposure, our9 O$ p$ F1 a, }# y' ^
biggest concern was virilizing adrenal hyperplasia,0 Y# w3 @; x0 T6 l# v% i- q
either 21-hydroxylase deficiency or 11-β hydroxylase R' q, H$ X6 M8 Z
deficiency. Those diagnoses were excluded by find-( ^4 G: ~4 K% r+ x; h
ing the normal level of adrenal steroids.
8 e$ G0 l6 e3 p+ p8 y$ }The diagnosis of exogenous androgens was strongly
3 P: G6 O7 b) i% Nsuspected in a follow-up visit after 4 months because
9 P0 N& a: ^- ]the physical examination revealed the complete disap-0 x5 g: j2 P4 ~5 ~
pearance of pubic hair, normal growth velocity, and2 O* l! x& P7 p- }& d
decreased erections. The father admitted using a testos-
$ E2 \, A0 X! u9 }0 H. tterone gel, which he concealed at first visit. He was
& J! y$ f8 p3 s6 s8 D' }using it rather frequently, twice a day. The Physicians’" B) t( e s$ |
Desk Reference, or package insert of this product, gel or
9 z% v# L, {$ E, kcream, cautions about dermal testosterone transfer to0 w. s l! t: A1 F, W# w4 O
unprotected females through direct skin exposure.$ V! w# F. p! w, H
Serum testosterone level was found to be 2 times the
1 ^5 D' i* Q* d) Z+ ]baseline value in those females who were exposed to
! i+ Z6 L {4 J" @: l: deven 15 minutes of direct skin contact with their male
7 J# y" E0 c5 c8 Q) g0 y @partners.6 However, when a shirt covered the applica-9 i1 U" G% E" F$ Q) y, R
tion site, this testosterone transfer was prevented. j1 R9 l3 k: N5 _
Our patient’s testosterone level was 60 ng/mL,
, p( ~* i1 G+ k& }8 Dwhich was clearly high. Some studies suggest that
* ^% X0 Z: Q& B* Z3 tdermal conversion of testosterone to dihydrotestos-5 ^; T2 N4 k- w
terone, which is a more potent metabolite, is more
7 Z( l! d' V. _) _active in young children exposed to testosterone O- [& x% k7 F) t" V
exogenously7; however, we did not measure a dihy-
2 F: l1 b/ h- e$ {2 qdrotestosterone level in our patient. In addition to
. p+ d* n1 I4 f9 P; ~5 f Cvirilization, exposure to exogenous testosterone in8 u9 {6 D- X/ E. D
children results in an increase in growth velocity and
- \7 V' ?: I: Y: u+ Hadvanced bone age, as seen in our patient.6 R/ o: c4 E# N8 J) Y" W' s& s
The long-term effect of androgen exposure during
; v: j3 x2 E5 K1 C& aearly childhood on pubertal development and final, G9 |+ B) a8 ?& }- I
adult height are not fully known and always remain- e" u8 X- C7 p
a concern. Children treated with short-term testos-
! b1 v, ~2 ?) ?* ]# I1 wterone injection or topical androgen may exhibit some
0 N2 U+ ^. B' W& s8 }2 `) nacceleration of the skeletal maturation; however, after
7 X. t, P3 k" ^! Z5 lcessation of treatment, the rate of bone maturation
3 N6 k, Y$ R* D& b# A4 u" W( a* Fdecelerates and gradually returns to normal.8,94 ?) Q/ o) |8 W% B% P6 @3 H
There are conflicting reports and controversy5 V' o9 t: S5 _0 K; q% L; d
over the effect of early androgen exposure on adult: \ Q9 \2 q$ \7 ?. a' |& C; Q, o
penile length.10,11 Some reports suggest subnormal
3 W: T4 @6 X, O: A* h$ U) ^adult penile length, apparently because of downreg-3 m, v4 f% \2 z# ?8 a' B2 d
ulation of androgen receptor number.10,12 However,5 d3 b6 B: V* h- b( m! e# W
Sutherland et al13 did not find a correlation between" S* c' B/ _9 b5 Z
childhood testosterone exposure and reduced adult: y: D9 j7 Q' o6 ?, L
penile length in clinical studies.
3 M& i( N0 k9 CNonetheless, we do not believe our patient is% A c0 U( i# r0 i% a' w) \. i
going to experience any of the untoward effects from
( L3 s& I2 V' E- C! g$ ltestosterone exposure as mentioned earlier because
# o) C3 ^" ^. Z; ~the exposure was not for a prolonged period of time., J, A9 Z. X" v1 h/ F& V
Although the bone age was advanced at the time of+ X( s$ s2 J4 y! l# _ r1 k6 ?
diagnosis, the child had a normal growth velocity at
! }! N! x( H+ @; D/ F! G0 b$ Othe follow-up visit. It is hoped that his final adult
: F' h$ |2 B1 E) Hheight will not be affected.3 U7 p" b5 a( k& R& }7 S1 n `9 E
Although rarely reported, the widespread avail-5 ~- o+ _0 i& H9 C6 B
ability of androgen products in our society may3 t. h" j% E8 H* g& D7 R& s9 `
indeed cause more virilization in male or female, g# d/ q3 e6 w: @
children than one would realize. Exposure to andro-
; e& `3 ?8 E9 [; q1 i8 Z# r# R, Lgen products must be considered and specific ques- T2 l; i+ R3 F( ]/ {
tioning about the use of a testosterone product or1 o2 ^7 [8 ~1 b3 o% |( X. E
gel should be asked of the family members during
" B6 X q2 u0 P: d( |+ @" P. ~0 L' Pthe evaluation of any children who present with vir-
7 k& O% O# d) i7 Z9 Filization or peripheral precocious puberty. The diag-: e) H* Q; k# v3 W3 E
nosis can be established by just a few tests and by+ K$ K! N. x* H% M
appropriate history. The inability to obtain such a
0 w# t1 f- R& F" N9 Ghistory, or failure to ask the specific questions, may' N+ d5 ^9 L f& m
result in extensive, unnecessary, and expensive! l( m+ v! I- e
investigation. The primary care physician should be
/ X6 {( h! `, l/ Caware of this fact, because most of these children
/ d0 t2 }/ z7 ]may initially present in their practice. The Physicians’+ M+ ]9 s9 g/ ^
Desk Reference and package insert should also put a% z( J5 z6 E% r# X( V! W% G2 ?
warning about the virilizing effect on a male or W0 U! k7 p6 H2 F* i- g
female child who might come in contact with some-
8 A# Q3 c/ N2 b* j0 i' fone using any of these products.$ g& u% R7 K! b8 N- `# a
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3 m; {& v2 d* V. `' b3 \6. Physicians’ Desk Reference. Androgel 1% testosterone,
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Economics Company, Inc; 2004:3239-3241.7 R0 t" Y* y7 C5 q6 K& I+ q' [
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testosterone and gonadotropin. J Urol. 1978;119:
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