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is a significant concern for physicians. Central
3 h+ ^5 _/ _* I8 F+ [) g$ T7 Y) Aprecocious puberty (CPP), which is mediated
) ^; j& a1 L8 B1 w' Z( y+ ^through the hypothalamic pituitary gonadal axis, has
4 ]6 @+ X. T, Q3 U+ ba higher incidence of organic central nervous system
" v2 S" I8 N. e( Y6 ]lesions in boys.1,2 Virilization in boys, as manifested
% K+ i* B0 |, bby enlargement of the penis, development of pubic
0 e8 \$ U! a% e. ^' q- R9 ]hair, and facial acne without enlargement of testi-
$ _+ \! l! _) Z! q; P6 r( S# N6 V! ccles, suggests peripheral or pseudopuberty.1-3 We
3 e7 B4 a( L3 s$ w4 qreport a 16-month-old boy who presented with the( U0 h- @1 |- s S/ e
enlargement of the phallus and pubic hair develop-' n4 j$ p% z7 J" `4 J7 t
ment without testicular enlargement, which was due1 @2 W5 q7 g' b7 u; K1 ^
to the unintentional exposure to androgen gel used by
, C; T6 Y; z. G4 E2 athe father. The family initially concealed this infor-' I+ f- H; I: [/ B
mation, resulting in an extensive work-up for this8 [% x4 i2 G, ?9 P" X
child. Given the widespread and easy availability of+ {4 ?. R6 [( V% T. L) Z: @* _
testosterone gel and cream, we believe this is proba-' a- M5 s! }( K" T. J8 F8 |
bly more common than the rare case report in the
/ p" X: Q! ~9 r- Bliterature.4
) N( W9 c6 I0 R, c! d, V. w# VPatient Report6 ?' v r, r d
A 16-month-old white child was referred to the
' B/ T% p1 v3 X4 e5 l. pendocrine clinic by his pediatrician with the concern
# g' p1 A6 m4 e9 a$ ]% Xof early sexual development. His mother noticed! N( o0 W! j1 H- ]. ]# h' A$ g
light colored pubic hair development when he was/ L" [3 r3 _) k: l! Q4 c
From the 1Division of Pediatric Endocrinology, 2University of4 O% V+ H. F% s+ ]! s& U
South Alabama Medical Center, Mobile, Alabama., D* ]8 q# D" {- u6 D% H3 i+ \/ S
Address correspondence to: Samar K. Bhowmick, MD, FACE,6 d9 b. _2 V; Q. E5 x
Professor of Pediatrics, University of South Alabama, College of9 r" z7 f- x: e! V. ] a" D
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
4 X$ F& n5 @5 C* a! O9 F, Me-mail: [email protected].
$ {7 ~; E% t7 k" x- z" y! Uabout 6 to 7 months old, which progressively became
3 C! ^, N, h5 N! h, n8 A! _. bdarker. She was also concerned about the enlarge-7 D! e% w; y9 b# C$ h$ |
ment of his penis and frequent erections. The child$ B# V+ u V; S( t& t
was the product of a full-term normal delivery, with
# C2 f' X+ K% n# o1 M$ \% Aa birth weight of 7 lb 14 oz, and birth length of
" ]9 ~" e4 ~* ~3 c' j/ E' s. `9 I20 inches. He was breast-fed throughout the first year
" Q4 U% e/ t* n) [1 r8 @ ^- n% kof life and was still receiving breast milk along with
# l A# P. T0 {# G5 M1 S- a* asolid food. He had no hospitalizations or surgery,
) [ E# o& w5 a* E xand his psychosocial and psychomotor development
3 J0 [5 Y! e" K6 mwas age appropriate.
$ \ \0 P z2 [. m* z9 J4 y5 bThe family history was remarkable for the father,! n7 Y( j# }) T+ @5 a7 l
who was diagnosed with hypothyroidism at age 16,
y5 f4 X- z+ s; [6 ?! ^) _which was treated with thyroxine. The father’s9 o( B- C. d" D# s
height was 6 feet, and he went through a somewhat1 C2 n1 h$ g. ^
early puberty and had stopped growing by age 14.
2 V2 ~( z& G4 [3 @ P7 fThe father denied taking any other medication. The4 v( ]$ {" k+ B& l: e0 X
child’s mother was in good health. Her menarche4 n3 M7 T, W" I i) X& I: H
was at 11 years of age, and her height was at 5 feet6 s( ~* e) K% y2 G5 w( ^3 b4 _
5 inches. There was no other family history of pre-
p" h/ Y+ v2 t3 U: {9 ?) e+ tcocious sexual development in the first-degree rela-
5 h4 y1 F. E+ j! Ztives. There were no siblings.- v5 Z- `' Z9 r% F. [5 `% r4 b
Physical Examination
5 z3 e* ^& w* q% ^% H% o4 l eThe physical examination revealed a very active,
% q, S* r+ E4 u6 {) Y- z$ tplayful, and healthy boy. The vital signs documented! U; x4 S1 e# S6 z+ W5 |% r
a blood pressure of 85/50 mm Hg, his length was
+ k8 L/ H1 y L1 u0 x90 cm (>97th percentile), and his weight was 14.4 kg
1 F9 z9 U# u4 E, O(also >97th percentile). The observed yearly growth1 q0 P& F5 c4 @7 H8 @) b
velocity was 30 cm (12 inches). The examination of, W, ` O/ x, F) n* U
the neck revealed no thyroid enlargement.6 u* ^8 l( y1 u% h7 ^
The genitourinary examination was remarkable for
- Y, J8 a, B( I% Kenlargement of the penis, with a stretched length of
5 ~7 r" [. W1 x* b2 S$ G* z1 Q* K8 cm and a width of 2 cm. The glans penis was very well
! P1 u' j( }5 a# s: Rdeveloped. The pubic hair was Tanner II, mostly around
/ Z" w, t" S* j0 n9 n" Z' r7 Y540
! ]. G: C* w. A$ p5 k' Z) W! sat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from* V6 R8 `1 R1 G2 F( _" o( g+ I( {
the base of the phallus and was dark and curled. The
+ v- q9 G* X' q1 h% Qtesticular volume was prepubertal at 2 mL each.0 c5 X% _* R& q
The skin was moist and smooth and somewhat
$ w$ T$ \8 q: V9 r, `; a; voily. No axillary hair was noted. There were no; B; E4 Z- d8 B1 K7 D
abnormal skin pigmentations or café-au-lait spots.
5 K2 h/ H# O. i8 v, M9 D; W* U- ONeurologic evaluation showed deep tendon reflex 2+8 v. E, R' @8 r3 \0 f& |2 C/ Z, g
bilateral and symmetrical. There was no suggestion5 j0 f/ c9 p4 g$ M* P3 U
of papilledema.- H% x; E1 s6 W" R$ f
Laboratory Evaluation
8 f. ^$ B. ~7 e1 @& b! rThe bone age was consistent with 28 months by
3 R' \) E7 ]9 m6 e6 j' ]% } M# |; }using the standard of Greulich and Pyle at a chrono-7 m" l) f% }) m
logic age of 16 months (advanced).5 Chromosomal8 H# `" i" f8 _; q
karyotype was 46XY. The thyroid function test7 Y* D6 k- q& \6 C
showed a free T4 of 1.69 ng/dL, and thyroid stimu-8 ? g9 w( b/ r% I- E& _/ K6 h9 A
lating hormone level was 1.3 µIU/mL (both normal).) Z" [* b% ~1 w. P5 M0 R
The concentrations of serum electrolytes, blood+ @5 C5 w& |( W1 p
urea nitrogen, creatinine, and calcium all were
6 f) h9 K, G5 swithin normal range for his age. The concentration
% s3 v+ l, i4 V3 R: Q. A( L6 sof serum 17-hydroxyprogesterone was 16 ng/dL P6 H* @) }' D8 L: X4 q
(normal, 3 to 90 ng/dL), androstenedione was 209 X+ m5 i+ I( S; ~+ H# m
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-7 j2 e0 O% r% I4 @- s& [
terone was 38 ng/dL (normal, 50 to 760 ng/dL),; W1 Q7 D: |7 }* X8 z
desoxycorticosterone was 4.3 ng/dL (normal, 7 to
9 n1 O% D8 Q7 o- N, ?( i49ng/dL), 11-desoxycortisol (specific compound S), u; R" `2 D% k6 z. p* ]
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
6 n# z; q6 q' X3 P P8 W- Btisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
0 q$ H4 W1 ~' G6 S2 b: Ltestosterone was 60 ng/dL (normal <3 to 10 ng/dL),8 \( k& Z' h$ m# J
and β-human chorionic gonadotropin was less than
; R, X+ h6 B6 q3 d. I9 U5 mIU/mL (normal <5 mIU/mL). Serum follicular
5 y1 u; `' A' d0 v7 W: {stimulating hormone and leuteinizing hormone9 }3 U4 G* X- Y" V; [
concentrations were less than 0.05 mIU/mL, C6 \! c, }. H- @; A2 N- W
(prepubertal).. i- h4 @3 ~. c7 V9 v; S) q/ X
The parents were notified about the laboratory9 X( K+ E0 ], p9 H
results and were informed that all of the tests were
# y5 I; B: `6 u! M2 ~2 bnormal except the testosterone level was high. The
' X' N5 W# n" Afollow-up visit was arranged within a few weeks to- A# `* H0 H1 n$ m& Y/ e
obtain testicular and abdominal sonograms; how-, Q2 _' l3 p6 O) v W3 @4 t
ever, the family did not return for 4 months.4 J: v% s) I8 I" N/ r, Y
Physical examination at this time revealed that the' _- F& [4 m0 g3 S
child had grown 2.5 cm in 4 months and had gained% g6 }' ^) t$ ]1 }
2 kg of weight. Physical examination remained
9 [- j: ^$ k4 `' s' n' h3 S( dunchanged. Surprisingly, the pubic hair almost com-( y: |0 ^$ B3 m+ I- Y0 x- z
pletely disappeared except for a few vellous hairs at T* }8 C; B! u+ l. n
the base of the phallus. Testicular volume was still 2
+ L' |( d; J2 H2 z4 X6 k I4 lmL, and the size of the penis remained unchanged., d3 l, ~# V4 d
The mother also said that the boy was no longer hav-# ]! \1 D8 E, A1 b5 @
ing frequent erections.( i' W/ ^2 b/ M4 T% Z% M" S# L' D6 q" v
Both parents were again questioned about use of
: m( `, o" \3 hany ointment/creams that they may have applied to# z4 e: |) K1 f" l
the child’s skin. This time the father admitted the% u ]' y' Q1 O$ ]8 s
Topical Testosterone Exposure / Bhowmick et al 541
) {) W" o+ Y$ T+ K$ f6 p6 Ouse of testosterone gel twice daily that he was apply-1 H( k- `4 V* \( O0 q' t
ing over his own shoulders, chest, and back area for* n0 W3 E, k# A) }
a year. The father also revealed he was embarrassed; p' T( R4 H% F: D
to disclose that he was using a testosterone gel pre-
) d! {8 l. w u( M& u& wscribed by his family physician for decreased libido
' A: {' a' B& v8 h) fsecondary to depression.
( O2 Q& J# n+ t5 F1 ~4 C1 w& MThe child slept in the same bed with parents.
4 t$ P5 e2 q7 f, ]: k! K* [- A% X4 OThe father would hug the baby and hold him on his% `/ I# Y$ u n7 d# Q, U, G! ]5 }7 e( J' t
chest for a considerable period of time, causing sig-( J3 V4 c- G# O8 I& a9 T
nificant bare skin contact between baby and father.2 ^3 q& M. W2 T& N
The father also admitted that after the phone call,
1 j0 N+ V# |( E( b) N4 L; L4 Cwhen he learned the testosterone level in the baby: L ?7 M( x* `3 q* e& [6 Y. f
was high, he then read the product information0 @# G9 ^& N2 J. u$ R7 |8 [
packet and concluded that it was most likely the rea-$ z/ p. J* J% ]! W) Q l
son for the child’s virilization. At that time, they5 Q9 j% t4 ^8 p
decided to put the baby in a separate bed, and the. i% Y8 e. B- {1 \
father was not hugging him with bare skin and had
$ e6 f: \: r" y' S9 p8 qbeen using protective clothing. A repeat testosterone5 t- H9 r+ e8 o, F4 c
test was ordered, but the family did not go to the! `: U# E8 f4 d" b) k
laboratory to obtain the test.3 g$ m A# z, `4 O3 h# w4 }* I
Discussion
) X% \1 u t, Z7 M7 G# KPrecocious puberty in boys is defined as secondary) B5 Z, F3 {! C5 n' {& @" _
sexual development before 9 years of age.1,47 Y l# Q7 {4 l" Z. ]1 V
Precocious puberty is termed as central (true) when5 n% b" Y5 H s& I' G- `# e
it is caused by the premature activation of hypo-2 M- B" `% {( L( i9 Q( u" s# ~
thalamic pituitary gonadal axis. CPP is more com-7 I3 p# W; q( C
mon in girls than in boys.1,3 Most boys with CPP
$ h- U$ u. E# I* ]" _may have a central nervous system lesion that is
4 R7 q6 z) ~8 O/ Y1 G1 y+ }responsible for the early activation of the hypothal-
2 u1 E3 ]+ E* \7 Ramic pituitary gonadal axis.1-3 Thus, greater empha-% p% A8 ]) N G, Q( K G
sis has been given to neuroradiologic imaging in
0 G {" Y% L. |* Rboys with precocious puberty. In addition to viril-: Q# B9 n _2 C% Z4 I7 p
ization, the clinical hallmark of CPP is the symmet-
+ | j& u7 O6 o6 @# a+ ]$ u9 V6 urical testicular growth secondary to stimulation by3 b* j) y/ T- t9 n9 K2 s% T" L: K: u
gonadotropins.1,3+ Z$ k( |. _' N& }& L$ y, ^
Gonadotropin-independent peripheral preco-
- c6 K9 `, E& g* X8 R$ |% ?cious puberty in boys also results from inappropriate
@ n" S: X, D% o( T( c/ h jandrogenic stimulation from either endogenous or5 Z0 R* a. G: G8 ^( m" T! ^/ [. D: m( q
exogenous sources, nonpituitary gonadotropin stim-) X3 s7 d K) p$ k9 Z
ulation, and rare activating mutations.3 Virilizing% d w0 ?3 M* |( b# j8 V
congenital adrenal hyperplasia producing excessive0 b$ K; N% n5 k ]
adrenal androgens is a common cause of precocious; w D5 R# ]) f
puberty in boys.3,4
8 x4 L# N; Z0 B jThe most common form of congenital adrenal: y1 y- M9 Z/ h+ N
hyperplasia is the 21-hydroxylase enzyme deficiency.
, j$ s9 {5 c' R7 t8 w W8 j' S( g$ LThe 11-β hydroxylase deficiency may also result in
: k4 x; ~" ]* ^# N. vexcessive adrenal androgen production, and rarely,) [, |5 \: Y$ U7 {
an adrenal tumor may also cause adrenal androgen
: P7 I9 z; \6 ]% d! ~! ]8 Vexcess.1,3
" ~0 h( C6 R/ M z+ ?at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from0 j$ _. G+ A8 j7 w b
542 Clinical Pediatrics / Vol. 46, No. 6, July 20076 v' V/ a/ @$ [2 _$ D$ m
A unique entity of male-limited gonadotropin-
3 j% b& ^" W0 ]) k; g$ H m9 G. dindependent precocious puberty, which is also known Y. Z; }2 J8 B
as testotoxicosis, may cause precocious puberty at a
7 A' K8 u# F9 r) x) M* Y Xvery young age. The physical findings in these boys- m; B) @6 |' l' B) h
with this disorder are full pubertal development,1 P* F9 I) W* q* P" g
including bilateral testicular growth, similar to boys
; O e0 b$ w3 d* z$ [ k- ]2 ?with CPP. The gonadotropin levels in this disorder
1 m* }- Y3 C, A( g0 Uare suppressed to prepubertal levels and do not show0 i$ e$ b- i3 \5 n9 U% i" w
pubertal response of gonadotropin after gonadotropin-
! T5 f8 r# E1 {, I0 O" w, Qreleasing hormone stimulation. This is a sex-linked# u: t' C g( ^+ X3 G
autosomal dominant disorder that affects only1 O7 j' I2 z- t" A
males; therefore, other male members of the family
& h m; j8 g( N) K5 F* d3 Bmay have similar precocious puberty.35 b. \7 ?0 J ~8 ^6 [
In our patient, physical examination was incon-+ v, V" n8 S% B6 o$ { ~% R
sistent with true precocious puberty since his testi-
4 `$ `" O# H. Bcles were prepubertal in size. However, testotoxicosis# X0 e6 d8 U3 e
was in the differential diagnosis because his father( V# p# r6 x0 O! q
started puberty somewhat early, and occasionally,
j J. c- \6 j" n4 f6 r% L$ ctesticular enlargement is not that evident in the
3 M" q7 P' A* n8 R$ m2 y. sbeginning of this process.1 In the absence of a neg-
: d( ?+ P5 O- b$ S1 O5 r" Uative initial history of androgen exposure, our
# I6 [6 ~6 V7 E3 kbiggest concern was virilizing adrenal hyperplasia,
& l( k/ [# l1 n; jeither 21-hydroxylase deficiency or 11-β hydroxylase
: ]$ t m8 Z( Z. N2 S8 M7 ddeficiency. Those diagnoses were excluded by find-
% `' W9 p* C. T6 u+ T: m* Uing the normal level of adrenal steroids.5 F+ \' V- d7 p
The diagnosis of exogenous androgens was strongly
! K' D9 T+ c4 {$ k9 q `suspected in a follow-up visit after 4 months because" d( c9 n. j3 O% Z& N1 w5 \
the physical examination revealed the complete disap-' e- h4 }0 G9 |3 D/ p% I
pearance of pubic hair, normal growth velocity, and
- J# K, n. P: g, e# m p: Qdecreased erections. The father admitted using a testos-
( L8 X" v% {# Jterone gel, which he concealed at first visit. He was
$ D2 b9 X9 D, v. w: B* M1 c' Y5 Iusing it rather frequently, twice a day. The Physicians’
! j7 z" P2 [ A) d4 ~5 m1 z$ M: fDesk Reference, or package insert of this product, gel or
) ^1 ?1 }, m9 \3 ~# T9 Acream, cautions about dermal testosterone transfer to
0 I0 K$ _4 P" u* q% W O0 Y& z) L' Gunprotected females through direct skin exposure.; |, J/ N. B/ Y* X- v
Serum testosterone level was found to be 2 times the/ `, S4 E0 o2 p1 N! r0 q
baseline value in those females who were exposed to2 W: A. s+ ^3 W& m2 E6 Z4 p
even 15 minutes of direct skin contact with their male( v5 |6 `/ @. C( p; K: i
partners.6 However, when a shirt covered the applica-
* A4 {1 r. y( Ction site, this testosterone transfer was prevented.
' N% b4 h! J" C0 AOur patient’s testosterone level was 60 ng/mL,5 d8 ]6 p! P! _
which was clearly high. Some studies suggest that
5 |0 I, q1 P6 n0 R3 p# f' Idermal conversion of testosterone to dihydrotestos-* c8 t( P7 X. O3 E9 R/ i1 S% `
terone, which is a more potent metabolite, is more
P e( A2 n7 @. W0 Zactive in young children exposed to testosterone
5 s- T1 J+ t) r: Z9 pexogenously7; however, we did not measure a dihy-+ \7 C [; M0 w; x: q) l* V- ?" n% ]9 U
drotestosterone level in our patient. In addition to
) S7 t& i8 g) W+ y' ~. S, uvirilization, exposure to exogenous testosterone in, D7 h* G i" ]! B8 ?$ B9 n
children results in an increase in growth velocity and; F) X% Z$ I" M) D; D& G& g
advanced bone age, as seen in our patient.
; [9 Z x$ Q8 |The long-term effect of androgen exposure during
5 s5 L# e j1 m1 s9 A' E( cearly childhood on pubertal development and final+ D1 D8 I2 J' p4 t1 [3 V
adult height are not fully known and always remain( Z! o% |8 F6 c m
a concern. Children treated with short-term testos-7 r, D" I2 v! D B) x* u" ^. O
terone injection or topical androgen may exhibit some
[& k* P2 F6 z: Jacceleration of the skeletal maturation; however, after! f; r8 \" H4 u* [% ^+ o" h3 a& W
cessation of treatment, the rate of bone maturation
3 m; t: b; }! `/ i. X# hdecelerates and gradually returns to normal.8,9
j8 B; @- X) Z# k8 f6 J8 [There are conflicting reports and controversy( a! w# J- C V0 [. L
over the effect of early androgen exposure on adult
2 j" i) t, \4 _6 A. F% ?6 Z# Ppenile length.10,11 Some reports suggest subnormal4 ~* i3 y3 ~2 j8 ^, U4 m
adult penile length, apparently because of downreg-
! @4 g7 j+ E/ @: oulation of androgen receptor number.10,12 However,
) }% Y; B, h" z) GSutherland et al13 did not find a correlation between/ T% E" _/ X( j: R1 M
childhood testosterone exposure and reduced adult
2 e$ m- z4 H& _$ F* `! ~/ V, H3 qpenile length in clinical studies.
# P b. d& Z" U: r: |Nonetheless, we do not believe our patient is4 h3 [# d( _" w, R: `
going to experience any of the untoward effects from1 g" E. n8 ]* Z9 E8 v( N# `$ Z
testosterone exposure as mentioned earlier because
3 G5 l( m( X; }/ g5 `the exposure was not for a prolonged period of time.9 S4 E H8 L- K: l: X/ v2 ]
Although the bone age was advanced at the time of6 q8 F" B% v/ \* V7 o) R; o
diagnosis, the child had a normal growth velocity at
M) j' Z! Q B tthe follow-up visit. It is hoped that his final adult
* p! V! V( n* C' _height will not be affected.3 o& p' @4 l9 N: w5 ]
Although rarely reported, the widespread avail-
! G/ R- w4 f% @ c: k; _ability of androgen products in our society may3 r, e$ R1 d8 d) b1 U# T: m( h
indeed cause more virilization in male or female% e2 e A' `5 ?! }& Q
children than one would realize. Exposure to andro-
/ d9 Q4 \. ~' G# \- n0 o- ^' }gen products must be considered and specific ques-
7 R& h, Y( } a2 c1 G, gtioning about the use of a testosterone product or
8 x! r7 E8 _/ G6 ~1 Pgel should be asked of the family members during
0 g0 U M4 o1 w( r4 s" ithe evaluation of any children who present with vir-$ N' D: I% o: K. |- b+ P# E% G
ilization or peripheral precocious puberty. The diag-7 i2 w: `8 ]6 Y% S" y
nosis can be established by just a few tests and by- e( n/ d. @" X3 v% o2 }
appropriate history. The inability to obtain such a
6 T8 T" F& c9 i2 [ m( Khistory, or failure to ask the specific questions, may
% X) y0 Q, Y' K2 S- @: k' a' m5 Tresult in extensive, unnecessary, and expensive
+ Y0 P3 {0 y3 `! b$ x" ~- c# Minvestigation. The primary care physician should be3 {; ^& A" S* f8 L7 l
aware of this fact, because most of these children
! O" u9 c$ `$ T! Kmay initially present in their practice. The Physicians’# H- x0 S0 U2 v& m+ X3 Q/ e
Desk Reference and package insert should also put a. m+ C; X* p+ q" M0 o9 p
warning about the virilizing effect on a male or
( h$ Y4 L1 Y! j0 J$ ?4 I' tfemale child who might come in contact with some-& k. j* H( C- o6 ?0 I( p
one using any of these products./ A9 i0 E( h7 t3 ^, @2 _9 x3 b
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Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;$ b5 j1 r0 j8 a9 c- i' m
2002: 565-628." F% f+ D9 K* { I# k# n4 u7 V" K
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
3 Y5 ^* S* V% e8 V! H( Y7 epuberty in children with tumours of the suprasellar pineal
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development in a two-year-old boy induced by topical1 r1 G. }9 }0 q7 j8 H, M0 w9 `9 U, L
exposure to testosterone. Pediatrics. 1999;104:e23.+ _" d2 ^+ k( s O! C9 }: X0 m
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1 L. L2 E9 J* N- }Skeletal Development of the Hand and Wrist. 2nd ed.
* y* u" ]4 Z& f# m+ C2 iStanford, CA: Stanford University Press; 1959.
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