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is a significant concern for physicians. Central: L3 v" u% }1 s
precocious puberty (CPP), which is mediated
- l9 V* q4 B" K7 u$ t" {0 \through the hypothalamic pituitary gonadal axis, has. H# h+ [( U0 f+ x( M
a higher incidence of organic central nervous system
+ `! S6 I2 v' K) O" ~lesions in boys.1,2 Virilization in boys, as manifested, Z2 n! f$ {. \! x/ O# G
by enlargement of the penis, development of pubic# Y* K2 [2 p, ?% _: F$ _+ B8 n) S2 ?
hair, and facial acne without enlargement of testi- @6 @3 G1 R4 x, E7 ~1 o5 R4 Y3 m9 `
cles, suggests peripheral or pseudopuberty.1-3 We
. c8 m& r' i/ c4 z$ |- _report a 16-month-old boy who presented with the1 e% p( P" ^+ n) i4 z6 s3 e- C+ T
enlargement of the phallus and pubic hair develop-. E4 |) |( Q) n9 } _2 i. e2 ^8 Z( a
ment without testicular enlargement, which was due
+ j7 {$ F* q6 n0 n% k( Cto the unintentional exposure to androgen gel used by
5 g. q$ V) V* u/ E: a: a+ Dthe father. The family initially concealed this infor-0 {2 `0 E+ E9 o$ N6 ]6 B
mation, resulting in an extensive work-up for this2 c( i* ?6 O Y% n( \
child. Given the widespread and easy availability of7 [ ?# r2 W |3 M
testosterone gel and cream, we believe this is proba-
4 X, t0 x! o8 p1 ?! zbly more common than the rare case report in the
, v0 Y0 i8 L: b" eliterature.4
) F/ B* x, d5 g+ _Patient Report4 ~8 K- E+ P2 f" S0 U" B
A 16-month-old white child was referred to the
9 |! q* N, W/ a: {* J: d, f, Zendocrine clinic by his pediatrician with the concern+ T$ n0 U4 e4 t8 z9 [# l
of early sexual development. His mother noticed
! X |: Z2 J+ S, p" mlight colored pubic hair development when he was" k/ J% r7 N4 I: T4 W1 B5 k
From the 1Division of Pediatric Endocrinology, 2University of" }: I+ j& Z4 w* {2 n9 r! ~+ [& \9 x
South Alabama Medical Center, Mobile, Alabama.
" M+ t9 V, l2 Q0 j& M7 ]% n0 R7 c. XAddress correspondence to: Samar K. Bhowmick, MD, FACE,
\& T, M: t9 b pProfessor of Pediatrics, University of South Alabama, College of$ d# R4 q! F0 J( A% { j
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;* J+ g* q k6 X1 `6 z: _. f
e-mail: [email protected].
2 }% [/ c# I2 X, [% t+ a6 eabout 6 to 7 months old, which progressively became8 B; g( B9 K' a( k6 R, _* ]
darker. She was also concerned about the enlarge-
6 @& t4 R8 H( _+ i, R' C; vment of his penis and frequent erections. The child& g) }& M6 m3 U6 u2 E2 H8 |2 Z4 @) T" E
was the product of a full-term normal delivery, with) f! B+ C" ]1 H% r
a birth weight of 7 lb 14 oz, and birth length of. _; X* T) N0 F8 {* m. r
20 inches. He was breast-fed throughout the first year% L' V' D5 {' J$ _2 H) P- W
of life and was still receiving breast milk along with
) X1 O3 I/ Z$ N. M) lsolid food. He had no hospitalizations or surgery,
! Q8 l' A$ o5 a5 h, B6 C2 k8 Kand his psychosocial and psychomotor development
) Y6 p) c: Z8 B! N0 B# ~was age appropriate.7 s" J8 K& A1 N( R' G
The family history was remarkable for the father,6 R3 E5 X) A8 c/ L+ R8 ~
who was diagnosed with hypothyroidism at age 16,9 q' z6 V" R, K: R/ ^" v
which was treated with thyroxine. The father’s2 R/ G# a( D6 \- ^
height was 6 feet, and he went through a somewhat: j# i% m# G7 v% P. }( {* s
early puberty and had stopped growing by age 14." h7 H1 x; J Y$ T! c* R
The father denied taking any other medication. The( M" |) j1 s3 p- e% ^" i
child’s mother was in good health. Her menarche
2 L7 a5 S- V: mwas at 11 years of age, and her height was at 5 feet
1 A4 U% y( z( S# N0 L, X5 inches. There was no other family history of pre-; T" d6 U( h8 @# ~ [8 y% W8 \
cocious sexual development in the first-degree rela-
) [. ]/ V! o9 q4 d. b, V3 _, wtives. There were no siblings.
6 j. K* r& ?" I- E) ]* y% k' j bPhysical Examination# v! E% w3 x. Z% G
The physical examination revealed a very active,9 e8 Y- t/ I& k& r' S; x' n) \0 b. D
playful, and healthy boy. The vital signs documented9 q/ y* P( B3 K7 F: z7 y; @. B& a6 H( {
a blood pressure of 85/50 mm Hg, his length was; V; }- D1 t b
90 cm (>97th percentile), and his weight was 14.4 kg
4 v/ t9 x& O. Y+ x(also >97th percentile). The observed yearly growth
3 W8 k) w8 G" Z# M6 Tvelocity was 30 cm (12 inches). The examination of4 S( Z1 [% ]$ m# ~
the neck revealed no thyroid enlargement.' \6 R: e/ f3 G
The genitourinary examination was remarkable for
/ x" k( Z9 l/ Qenlargement of the penis, with a stretched length of7 r- m- v. E$ r/ A" E2 b
8 cm and a width of 2 cm. The glans penis was very well9 G* |9 I, r2 O" G
developed. The pubic hair was Tanner II, mostly around
" x* }: [* R/ e+ s3 z! o" g9 U540
6 Y. [/ v) ]6 S% r9 Eat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
3 S0 M# q# f( ?/ P1 Rthe base of the phallus and was dark and curled. The
7 k& D& ^2 T# V% ~( wtesticular volume was prepubertal at 2 mL each.. p) L" R" o7 F
The skin was moist and smooth and somewhat6 F/ B0 M3 T) B+ e
oily. No axillary hair was noted. There were no
- y# {9 Y# V7 Y7 Qabnormal skin pigmentations or café-au-lait spots.7 S. i) y0 c& H' @9 H4 W
Neurologic evaluation showed deep tendon reflex 2+8 j8 [+ _2 f, L$ d
bilateral and symmetrical. There was no suggestion
x! ~! V1 m7 t/ g! Zof papilledema.) P: ?1 d. Y0 p$ z* H
Laboratory Evaluation
8 h* O% C+ n- v( P. mThe bone age was consistent with 28 months by
. x& w; t0 f5 r: T6 Iusing the standard of Greulich and Pyle at a chrono-6 w7 C/ }- C" T n% I% [5 D8 [
logic age of 16 months (advanced).5 Chromosomal1 e, V- @: k) i% C
karyotype was 46XY. The thyroid function test
6 p m1 i) _; H; B- K: [showed a free T4 of 1.69 ng/dL, and thyroid stimu-
; v& r6 E# E9 y9 X% vlating hormone level was 1.3 µIU/mL (both normal).
6 Z; c! Z, D, B9 Q1 r$ aThe concentrations of serum electrolytes, blood
) P+ [, k- e' {+ k2 |urea nitrogen, creatinine, and calcium all were D; L, g) [7 _$ \/ A
within normal range for his age. The concentration1 r4 O( j. I7 C) \, f4 V
of serum 17-hydroxyprogesterone was 16 ng/dL
4 ^! _! [/ P/ ]7 x(normal, 3 to 90 ng/dL), androstenedione was 20$ e* R; T& a. H0 m" m2 W+ a) j
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
7 D: |3 o) E; K$ v, ~terone was 38 ng/dL (normal, 50 to 760 ng/dL),
4 M, s, j8 A+ p0 d* r6 ^: P' o' y( |desoxycorticosterone was 4.3 ng/dL (normal, 7 to; w7 v) s3 V: ?( l
49ng/dL), 11-desoxycortisol (specific compound S)) q% A* p: {& ?& W$ U7 ]/ V
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
) ]1 [2 p) n/ f8 z( S! Ktisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total; z0 a! y+ T6 H7 B9 z& O
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),! v3 g5 {' N0 k3 l& k$ L
and β-human chorionic gonadotropin was less than
$ h; y7 D; J# K1 Q" j ~6 h5 mIU/mL (normal <5 mIU/mL). Serum follicular
, j5 V' I( d! W$ n" ~) ?6 qstimulating hormone and leuteinizing hormone
Y* C. q# g1 Q: y4 Iconcentrations were less than 0.05 mIU/mL& }& ~' T& v& l8 H& s
(prepubertal)., a& w1 T% D0 ^1 M
The parents were notified about the laboratory8 D+ d) Z* x1 a6 b5 y
results and were informed that all of the tests were
6 a+ \( Y) e Y' e+ ~normal except the testosterone level was high. The
1 ^2 x2 Z0 ~( [follow-up visit was arranged within a few weeks to9 D2 g7 N2 L3 Q ?4 T5 \
obtain testicular and abdominal sonograms; how-
* T' C1 j, H% Zever, the family did not return for 4 months./ _' d9 I8 a2 n5 K2 @
Physical examination at this time revealed that the
5 t1 C- A( }* T$ B: n0 Ichild had grown 2.5 cm in 4 months and had gained
m5 Q8 c1 W5 ?. |2 kg of weight. Physical examination remained
4 K) ?0 x6 j+ ]" ]- }& t- [9 _unchanged. Surprisingly, the pubic hair almost com-
# W1 j1 m: T) {) \9 Ypletely disappeared except for a few vellous hairs at/ i4 i. V* F& F
the base of the phallus. Testicular volume was still 2
5 _- N( d( H& E3 @# U6 pmL, and the size of the penis remained unchanged.! u( @! b2 w3 I9 I9 n0 R) h9 f
The mother also said that the boy was no longer hav-
, ~. x: R/ m, q( O# aing frequent erections.
& e% b4 F1 [/ F( k1 q9 q9 `4 nBoth parents were again questioned about use of) X! y( _: g6 b6 a
any ointment/creams that they may have applied to: x' _) F4 m2 x0 f& \: K$ P
the child’s skin. This time the father admitted the- R/ v! m' y' G* r* u; B; [
Topical Testosterone Exposure / Bhowmick et al 541
, b+ X6 X6 n8 b7 u. p( D! }. x, n8 |use of testosterone gel twice daily that he was apply-
3 n1 {2 v' T- Y" n! u5 Ding over his own shoulders, chest, and back area for
6 z) |5 d. m0 _- S$ H6 Pa year. The father also revealed he was embarrassed$ j5 G" D. x6 ?: {
to disclose that he was using a testosterone gel pre-
% M! B. _& U, k e: r* z1 iscribed by his family physician for decreased libido& Z1 s. }$ o# Z5 @. \) b* n
secondary to depression.$ W% ^# I$ e( S& O' L" [& a& W0 `
The child slept in the same bed with parents.9 X/ R6 K# }$ ]8 g, H
The father would hug the baby and hold him on his
; O- j1 e' ^ o' ]3 Y6 Z2 qchest for a considerable period of time, causing sig-
5 G+ `3 @& v" i2 L' Enificant bare skin contact between baby and father.
* M3 R- V' n- d$ ~7 ?5 IThe father also admitted that after the phone call,
$ R4 G" { M, V: ~2 cwhen he learned the testosterone level in the baby
! B& V$ ]0 [/ _2 g# z* \was high, he then read the product information
) M; ~% Y/ t1 y/ l% O: Zpacket and concluded that it was most likely the rea-! _' D, P# ^1 O. S/ R | X' @$ O: h
son for the child’s virilization. At that time, they
8 b/ {- ]- u) ]6 }) adecided to put the baby in a separate bed, and the8 J+ D- R' ?% |+ q d3 S
father was not hugging him with bare skin and had
* z8 N5 P5 ]& k# B& ^" Obeen using protective clothing. A repeat testosterone
4 R3 H$ L) A# O6 V: p" x+ utest was ordered, but the family did not go to the1 Z( C+ }5 Z, P
laboratory to obtain the test.
1 L5 f, W% \" W6 U5 cDiscussion
" n7 c% E5 ]1 |8 p! vPrecocious puberty in boys is defined as secondary! u) J3 Q+ p( ?0 Q
sexual development before 9 years of age.1,4* L9 ?' h& R8 Q( f6 m& W) O
Precocious puberty is termed as central (true) when
9 f3 x S: O& Z2 S+ Fit is caused by the premature activation of hypo-% M/ u& u9 E3 c# j0 p. F
thalamic pituitary gonadal axis. CPP is more com-
! a8 V/ }0 C9 U. vmon in girls than in boys.1,3 Most boys with CPP
" y1 I: X& K" ~: M* Y: Fmay have a central nervous system lesion that is$ m" f5 m$ j$ ^# F
responsible for the early activation of the hypothal-
% X5 H& q9 C3 [8 ramic pituitary gonadal axis.1-3 Thus, greater empha-
% J* }4 Q3 |! E; w ]/ g. esis has been given to neuroradiologic imaging in
* j9 x, B2 P; o7 oboys with precocious puberty. In addition to viril-
6 X. s( k2 T+ iization, the clinical hallmark of CPP is the symmet-+ [, z$ ^# Y h' T$ B! o7 C; S
rical testicular growth secondary to stimulation by \* H7 J1 i1 [8 R$ f5 h
gonadotropins.1,30 u7 w( K7 d+ i: w Z
Gonadotropin-independent peripheral preco-
' _, ]7 o( n' t0 kcious puberty in boys also results from inappropriate
" ~. T7 u6 S2 Iandrogenic stimulation from either endogenous or+ g7 _; \/ a# X
exogenous sources, nonpituitary gonadotropin stim-
H; O. w A' S2 Vulation, and rare activating mutations.3 Virilizing+ ]2 Z1 s/ m: u( e
congenital adrenal hyperplasia producing excessive0 U% X i ^8 ` v6 g
adrenal androgens is a common cause of precocious
/ |3 u4 j" b) H+ j7 qpuberty in boys.3,4
3 Q! K9 m* S2 x: N+ r* E; ^$ X; pThe most common form of congenital adrenal
$ M- S8 Z) n6 ^8 lhyperplasia is the 21-hydroxylase enzyme deficiency." m F1 \* B8 D+ t
The 11-β hydroxylase deficiency may also result in
& [$ m1 ~, W0 K9 h9 I' uexcessive adrenal androgen production, and rarely,
) O5 A3 {* p! N0 ?( Can adrenal tumor may also cause adrenal androgen
5 M0 u' k; `" | h# |" ]excess.1,30 F3 [2 P! ?4 o! W" u" K: d
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
7 f! G- m/ g( i0 m8 W; i% ^542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
l* [. c# s2 A- ZA unique entity of male-limited gonadotropin-
# O# P4 J) t4 ]& d `+ f( Zindependent precocious puberty, which is also known; _1 \+ x/ }1 }9 c1 Q
as testotoxicosis, may cause precocious puberty at a4 {( ` v) f6 o! o" G" Q
very young age. The physical findings in these boys
$ M) Q& O; g6 t. Q8 p( _with this disorder are full pubertal development,
+ ~" V3 e i# s: P4 o4 mincluding bilateral testicular growth, similar to boys
0 N$ w0 L# K( p: p2 C* owith CPP. The gonadotropin levels in this disorder! h! p- q- O! `, X5 W. n
are suppressed to prepubertal levels and do not show
% w- K% Y3 G6 V( m* L/ v) Ppubertal response of gonadotropin after gonadotropin-
7 O2 ]# ~* Q" Rreleasing hormone stimulation. This is a sex-linked+ B+ v i3 B8 Z( S7 c
autosomal dominant disorder that affects only
( x& j" t1 f. X. ~% ^males; therefore, other male members of the family7 S$ u1 s4 O% |$ I* c: q. q; ]# ~
may have similar precocious puberty.3
, u) k6 a) @$ u$ I: k; D( FIn our patient, physical examination was incon-( W% L6 K |! ~" C$ V7 J
sistent with true precocious puberty since his testi-0 g/ P, a5 w5 l6 \
cles were prepubertal in size. However, testotoxicosis& m4 g6 A* N* Y( ?* @; B
was in the differential diagnosis because his father: ?( ~$ F1 d( \0 B* g
started puberty somewhat early, and occasionally,
' U9 N6 @& N" z% r# {# Ktesticular enlargement is not that evident in the3 M7 R5 Z4 w, }$ F* A: W$ Q
beginning of this process.1 In the absence of a neg-
3 l- Z+ M4 |( r4 j9 qative initial history of androgen exposure, our0 T3 k+ f. h( ~2 A9 M* i1 \
biggest concern was virilizing adrenal hyperplasia,
' l2 p2 M- f( h# e# U) J1 T% t% W; |either 21-hydroxylase deficiency or 11-β hydroxylase
+ s9 X& z) U0 J4 `& t6 I1 Ideficiency. Those diagnoses were excluded by find-
2 N; i: V+ F9 {' V7 R) r1 {ing the normal level of adrenal steroids.& }# x# k; b. x) s: w5 ~& \: Q
The diagnosis of exogenous androgens was strongly7 p% f7 X( H0 q& D
suspected in a follow-up visit after 4 months because
5 I1 P7 ]1 l) [$ Y3 g$ v0 othe physical examination revealed the complete disap-
. |: | p% C% E! K% C8 ]pearance of pubic hair, normal growth velocity, and- G- G5 Y2 v% S" _, H$ G) E
decreased erections. The father admitted using a testos-
$ s+ `/ r& V2 l$ @ c! Qterone gel, which he concealed at first visit. He was5 ^! d% q1 ?/ O7 Y
using it rather frequently, twice a day. The Physicians’: o* ^' A' @! z
Desk Reference, or package insert of this product, gel or; I0 r( ?# y5 a% {
cream, cautions about dermal testosterone transfer to4 }& A* T% c( w9 U! @
unprotected females through direct skin exposure.
! \( r' _5 M0 jSerum testosterone level was found to be 2 times the3 @8 ~6 \" P1 }4 [* K( Y# {
baseline value in those females who were exposed to
# g( h" t' ~; g8 ^ \even 15 minutes of direct skin contact with their male. u9 a0 n, D& B
partners.6 However, when a shirt covered the applica-
# ]2 z/ Z7 m/ F9 k" R0 ltion site, this testosterone transfer was prevented.
8 V4 V* K o4 X0 C/ f1 e+ qOur patient’s testosterone level was 60 ng/mL,
2 W$ y7 C' M, {5 z! N+ J' swhich was clearly high. Some studies suggest that
; J3 e# e; m9 Q- Q2 k! Ydermal conversion of testosterone to dihydrotestos-
! B6 C$ h" ]/ q! j( }7 \- lterone, which is a more potent metabolite, is more
0 c& ?: K9 V8 f& k3 m, Mactive in young children exposed to testosterone
, y1 x. j4 {3 f- o5 P3 vexogenously7; however, we did not measure a dihy-
2 R/ S0 g0 a- }; B3 x( _drotestosterone level in our patient. In addition to
5 d2 j! |' s5 t; m& svirilization, exposure to exogenous testosterone in
. H$ V" P8 r: b/ [children results in an increase in growth velocity and
e8 q. p# D& o; B) [* qadvanced bone age, as seen in our patient.0 D9 A! H5 ~. ^( z. S; Q- ~
The long-term effect of androgen exposure during
* Y5 V1 L4 L3 Z- _ p- Q4 Kearly childhood on pubertal development and final
: b( r) [! Z- `! t oadult height are not fully known and always remain) ~ j* p- Q! v3 N, Y/ N
a concern. Children treated with short-term testos-
! X, U8 h3 G! \/ }terone injection or topical androgen may exhibit some% j, x: n9 S: [" |4 |; ]+ m
acceleration of the skeletal maturation; however, after- f9 T, H% d2 z
cessation of treatment, the rate of bone maturation
! [) ~3 a& b' i r) g5 Fdecelerates and gradually returns to normal.8,9& t8 u5 Y& I' q2 o
There are conflicting reports and controversy$ O! f+ Y% r' E, ]4 F) L& d
over the effect of early androgen exposure on adult5 L/ ?: y# \- W N
penile length.10,11 Some reports suggest subnormal
9 \5 d7 d6 R8 I3 A$ O Oadult penile length, apparently because of downreg-
2 o0 |- R$ d! E4 dulation of androgen receptor number.10,12 However,
! }; w, D- b: t6 z/ K' \$ `" KSutherland et al13 did not find a correlation between, T! H) }$ i- l/ T, b" Q/ L
childhood testosterone exposure and reduced adult
/ g9 ]$ G' k1 p! F5 U. Ppenile length in clinical studies./ A- }' g+ s4 b2 N7 h
Nonetheless, we do not believe our patient is' R2 z r Q; e; e+ o6 ]4 R
going to experience any of the untoward effects from
9 x+ C# M; Y u7 P" Ztestosterone exposure as mentioned earlier because
7 l! |3 B2 w2 G5 a% }the exposure was not for a prolonged period of time.
, x% g# `& P. } sAlthough the bone age was advanced at the time of
$ t1 R, J# x# J( d8 ]diagnosis, the child had a normal growth velocity at
/ P+ `9 ?4 C9 m/ B1 d! Ithe follow-up visit. It is hoped that his final adult
/ w& \$ _" d5 d: e0 D2 cheight will not be affected.% N$ J I2 H5 ]
Although rarely reported, the widespread avail-
; J9 l+ r( z0 k6 G0 gability of androgen products in our society may# s/ I! v9 i5 \" c" F) Y' |) S; q
indeed cause more virilization in male or female
+ x2 v2 z; L5 ^children than one would realize. Exposure to andro-
- {& I! g' R- @# i6 m x0 Y1 [# m$ pgen products must be considered and specific ques-3 Y8 g( Z4 B- P8 z
tioning about the use of a testosterone product or4 o6 f8 X; J4 x0 U
gel should be asked of the family members during
* j \8 A; J: ethe evaluation of any children who present with vir-
; E$ R' e0 t& c( K+ [: ~. Yilization or peripheral precocious puberty. The diag-1 F3 C, m q0 W2 R
nosis can be established by just a few tests and by( Z- c1 w/ o7 i% r& `+ i2 @
appropriate history. The inability to obtain such a) Q$ k, m! y% L# z
history, or failure to ask the specific questions, may) z0 a% S; a% @1 F
result in extensive, unnecessary, and expensive
! { }. L6 `6 Ginvestigation. The primary care physician should be+ `0 d1 n7 H: r. W# l1 h8 N/ K
aware of this fact, because most of these children
; _8 ]1 ^! X8 Z$ kmay initially present in their practice. The Physicians’
* u# N5 d9 _: B! A& ^" r& `2 V) {Desk Reference and package insert should also put a
7 T2 T- R" u! A2 X" pwarning about the virilizing effect on a male or
t6 Z. @6 H! x$ F% N: Xfemale child who might come in contact with some-
! v5 x# w& e. eone using any of these products.( t$ j, C0 z3 A; R; w r
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' ]0 D" `* F, M2 ]2 y1 U7. Klugo RC, Cerny JC. Response of micropenis to topical
* \# k) K$ @: ^ Ftestosterone and gonadotropin. J Urol. 1978;119:; _. w, k0 K6 A# N- q( E" G! R
667-668.3 J3 J( l# r: g( P6 o$ B
8. Guthrie RD, Smith DW, Graham CB. Testosterone6 f( w( B6 k- R. ^( j+ B
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