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is a significant concern for physicians. Central
7 R7 ?. [5 z% t; r( fprecocious puberty (CPP), which is mediated6 ~$ W- E4 p5 _8 p
through the hypothalamic pituitary gonadal axis, has- B6 z8 P1 ~- U$ I
a higher incidence of organic central nervous system# R/ P2 m' l6 A* N$ ~
lesions in boys.1,2 Virilization in boys, as manifested4 t: Z; f2 C: s9 l" d
by enlargement of the penis, development of pubic
6 d6 \3 ?0 Z' X( qhair, and facial acne without enlargement of testi-
& m2 Z. H. F1 I7 q# O" E' hcles, suggests peripheral or pseudopuberty.1-3 We
) {9 R; }( ?7 Jreport a 16-month-old boy who presented with the. r% F3 S5 o) K9 M) B% U5 e
enlargement of the phallus and pubic hair develop-* Q& C. `7 C* F, S- k# H* z
ment without testicular enlargement, which was due
% o0 ]# ~. {/ p/ J, _. qto the unintentional exposure to androgen gel used by
2 w/ M6 ?; V* ?# ]4 `4 J/ X3 Ythe father. The family initially concealed this infor-6 x* H/ X$ y9 c/ Z! W4 l
mation, resulting in an extensive work-up for this
6 M8 U) Q" O- W! a1 Y% F4 l0 S; U6 ?5 Fchild. Given the widespread and easy availability of: d* K$ C& b4 m- V) @4 W
testosterone gel and cream, we believe this is proba-% u" v0 p4 I- J; j7 G: M
bly more common than the rare case report in the
, @- r9 G5 e$ ^0 p5 L* `literature.46 |% h- H& |7 f4 r2 ^) y: N' K
Patient Report
1 J- Z. k% @$ ^7 W- t5 NA 16-month-old white child was referred to the
/ `0 i" t* k" }( ?6 ^9 h! N& I: Mendocrine clinic by his pediatrician with the concern
8 z( ]$ ^( e( U8 D; _% N+ qof early sexual development. His mother noticed% X+ R1 _1 P+ f/ \' @) R3 J
light colored pubic hair development when he was
0 a0 R/ }. r. ~6 aFrom the 1Division of Pediatric Endocrinology, 2University of
# S# a, z" {) I8 c4 R2 ASouth Alabama Medical Center, Mobile, Alabama.. E) ~: {; h+ ~
Address correspondence to: Samar K. Bhowmick, MD, FACE,
7 `6 g0 r. i& f: P9 M3 \7 [Professor of Pediatrics, University of South Alabama, College of ]+ R; a _ K2 \! Y4 T6 n, z1 u
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
- r- f; h9 v) {$ P m/ B- ^ Ye-mail: [email protected].: F; Z1 E) a- ?3 k7 Q
about 6 to 7 months old, which progressively became8 _! T/ i6 \7 y2 h+ o
darker. She was also concerned about the enlarge-1 ]: C' i0 B6 {- G: M9 R
ment of his penis and frequent erections. The child
( h3 e% f. @# o+ `+ j1 Kwas the product of a full-term normal delivery, with
6 S7 R R: b' b) L P# p" ua birth weight of 7 lb 14 oz, and birth length of& r1 v! |2 j/ K O+ J
20 inches. He was breast-fed throughout the first year# C; e4 O: ]" K. ]0 Z6 {7 \5 \3 n
of life and was still receiving breast milk along with
9 {/ E9 e1 r" Q. G* g/ }solid food. He had no hospitalizations or surgery,9 \3 H: j1 a+ \; u: S. L% H
and his psychosocial and psychomotor development
! _$ N4 W5 O8 p: U: twas age appropriate.
( X3 v. Q5 a/ k7 U9 qThe family history was remarkable for the father,$ {' Z9 }# K: I; V$ [
who was diagnosed with hypothyroidism at age 16,9 B# `* ~4 G# e# I
which was treated with thyroxine. The father’s5 X" H2 u& _$ c+ ^ r L
height was 6 feet, and he went through a somewhat
' O7 W+ G+ w* b& bearly puberty and had stopped growing by age 14.
" R/ l8 M$ I, M2 u$ G* O* s, TThe father denied taking any other medication. The: b) P3 l- c0 X. K, V
child’s mother was in good health. Her menarche
; f" Y' ?" {( r5 Q c( Z9 ^was at 11 years of age, and her height was at 5 feet M, f& G& x: y8 F7 c- y* G8 }
5 inches. There was no other family history of pre-
2 b0 @$ c3 k1 T% M9 Ecocious sexual development in the first-degree rela-
7 u1 W' p6 A- N+ Ctives. There were no siblings.
" B0 F, [7 b1 z6 p: z( xPhysical Examination
% r. I5 R% \$ {& [# DThe physical examination revealed a very active,3 ~* V; m# b& j' x4 H: w
playful, and healthy boy. The vital signs documented
4 B V% p% r- v9 Ia blood pressure of 85/50 mm Hg, his length was
. k6 K% A: h" [8 w5 `90 cm (>97th percentile), and his weight was 14.4 kg2 A7 H' T1 y* A" w0 w1 u; Z
(also >97th percentile). The observed yearly growth
* D' Q% k8 Q; U1 a* R/ xvelocity was 30 cm (12 inches). The examination of. i9 Z# h% x: k% H8 i! C( C: l
the neck revealed no thyroid enlargement.6 y6 j( o, H& _9 I7 _ Y
The genitourinary examination was remarkable for) F5 T, G8 @& E0 q K% J" Q0 @7 V
enlargement of the penis, with a stretched length of% l) N" Q& [0 P2 k6 T, L0 `/ ~9 M
8 cm and a width of 2 cm. The glans penis was very well! {$ D ^+ S! C
developed. The pubic hair was Tanner II, mostly around1 q6 ~1 A4 l8 @- H0 P
540
; _7 L0 N: z9 S1 m( yat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from8 q9 E/ W' |7 P! ?/ y$ k- k$ h2 Y$ O
the base of the phallus and was dark and curled. The% ~3 [) X% G) ?# p( [, G
testicular volume was prepubertal at 2 mL each.
" G. I4 E) p' { V$ `9 |- }* qThe skin was moist and smooth and somewhat
) j, l1 W8 P0 e4 n2 A/ Hoily. No axillary hair was noted. There were no3 V. Q0 g) {. P9 e4 @6 L2 ^
abnormal skin pigmentations or café-au-lait spots.
6 o7 I. e" ^% [3 |' HNeurologic evaluation showed deep tendon reflex 2+
6 S) s$ }2 }1 C8 ^4 H9 D* Abilateral and symmetrical. There was no suggestion/ ^' g" _+ H4 l9 h7 V
of papilledema.4 u6 E2 I- x; U7 X C! J% _+ i7 k
Laboratory Evaluation% @( F/ ]5 }- f# Y, J" S; ^6 L
The bone age was consistent with 28 months by
- n @6 C. c! p7 z# Pusing the standard of Greulich and Pyle at a chrono-
. s0 O5 g, @( p( G, Z/ L2 Hlogic age of 16 months (advanced).5 Chromosomal
% T: @2 h& n2 v4 o' B( S. D* _karyotype was 46XY. The thyroid function test
7 A7 ^6 S! v+ q$ Eshowed a free T4 of 1.69 ng/dL, and thyroid stimu-
" A: H1 u6 `- c1 h5 a( Alating hormone level was 1.3 µIU/mL (both normal).
0 B. f* A# _0 DThe concentrations of serum electrolytes, blood e5 R R! ?* f6 r, }+ @3 r
urea nitrogen, creatinine, and calcium all were+ Z; @+ u2 J: F. j% R" H
within normal range for his age. The concentration
2 Y+ a8 n' ~1 L+ q) t+ Z) pof serum 17-hydroxyprogesterone was 16 ng/dL
/ P5 _" k* G: B* ^; Y6 y(normal, 3 to 90 ng/dL), androstenedione was 203 B: u. a3 P, M4 h- {8 u
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-0 g1 T3 p! i& ^8 |# i
terone was 38 ng/dL (normal, 50 to 760 ng/dL),. Q5 N6 c2 C9 K* O% l% `
desoxycorticosterone was 4.3 ng/dL (normal, 7 to
& G% m9 f4 {1 Z: s49ng/dL), 11-desoxycortisol (specific compound S)" K# H- S: X5 ~. h0 |/ [! ^
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-& Y4 X- Y; x: q) D. `* K
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total' [/ j% _4 z6 ^9 u4 l1 D4 K1 F
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),; r" Y) s' n+ ~8 W N
and β-human chorionic gonadotropin was less than
3 y5 z+ ? E! p; [% k5 mIU/mL (normal <5 mIU/mL). Serum follicular
7 i* b2 q" u. S, {4 F( rstimulating hormone and leuteinizing hormone% j+ T) E O; s
concentrations were less than 0.05 mIU/mL
9 @. n7 d+ t9 r4 O(prepubertal).. }8 _6 ~+ c; h7 L% p# i9 M7 B
The parents were notified about the laboratory. N4 W8 h+ L; m
results and were informed that all of the tests were
7 y/ Y) [/ T1 R7 H- f" u$ enormal except the testosterone level was high. The
1 X& B* i% [) L: a* vfollow-up visit was arranged within a few weeks to% q/ H L4 U, G+ w: E7 V- k
obtain testicular and abdominal sonograms; how-
5 Q# R7 u! y# e' uever, the family did not return for 4 months.% A& ~( t% m' H0 _1 [/ \" Z
Physical examination at this time revealed that the, B# A) ?- N2 Q& g6 w( o( o2 R: S
child had grown 2.5 cm in 4 months and had gained
: g: ?: l! ]# T v4 d# p2 kg of weight. Physical examination remained
4 ^! S! X# N$ }2 F* T& kunchanged. Surprisingly, the pubic hair almost com-$ f4 X2 K o& l% O: p8 n( g2 F
pletely disappeared except for a few vellous hairs at1 P$ ~8 p$ @0 M
the base of the phallus. Testicular volume was still 2, [0 Z1 d# i& ~" q8 T! A
mL, and the size of the penis remained unchanged.
0 R! I2 y; q: {The mother also said that the boy was no longer hav-
+ R W' {& }* }- xing frequent erections.3 v+ u" C4 T: |
Both parents were again questioned about use of
& W9 ~4 h1 L0 u# m4 ]) uany ointment/creams that they may have applied to5 l9 z- |4 u9 L+ w. ]
the child’s skin. This time the father admitted the
`3 K! I! C `* |3 c. STopical Testosterone Exposure / Bhowmick et al 541# u, Z9 K+ {( v
use of testosterone gel twice daily that he was apply-
4 t6 b2 j3 }* G6 ^ing over his own shoulders, chest, and back area for4 b Y, k& D4 I4 H
a year. The father also revealed he was embarrassed
' r: z1 |& l+ N3 P3 Pto disclose that he was using a testosterone gel pre-/ i/ X, v( t7 W- f
scribed by his family physician for decreased libido7 {9 j3 _. T5 r6 B- } g
secondary to depression.
# r" i [6 O: P; Y; n% i9 I. GThe child slept in the same bed with parents.2 w3 b+ v4 l4 i1 \7 d
The father would hug the baby and hold him on his/ u' G- M! V+ N
chest for a considerable period of time, causing sig-$ O4 S; e( p$ R0 s
nificant bare skin contact between baby and father.) z ? X# D& i! M
The father also admitted that after the phone call,
! ^( d2 Q$ y9 uwhen he learned the testosterone level in the baby% C7 h% d( c5 J+ X# d
was high, he then read the product information
" F, a2 r; z# |packet and concluded that it was most likely the rea-9 u0 e; m* c) T: X. ~
son for the child’s virilization. At that time, they! F: o- k2 u, E$ @7 }4 A; c
decided to put the baby in a separate bed, and the( E, `$ \: C. _& B3 S
father was not hugging him with bare skin and had) X2 A& P- v+ B! ?0 `/ w4 t+ J
been using protective clothing. A repeat testosterone n2 h: Y* k' c1 i2 a5 e# {2 Z
test was ordered, but the family did not go to the3 k4 d) l* X2 l0 o" Y) N
laboratory to obtain the test.
3 E- q# {& l1 R9 |Discussion
" n$ o* y$ o7 z- w7 _0 u. U0 LPrecocious puberty in boys is defined as secondary- i9 j. q/ B2 u, u
sexual development before 9 years of age.1,4& E0 e, `$ F2 u7 Z$ u* h
Precocious puberty is termed as central (true) when% `/ i6 y' h8 D+ E4 I7 H2 }( w3 k3 B
it is caused by the premature activation of hypo-5 N" Z& j; t! u1 H$ M* i8 C
thalamic pituitary gonadal axis. CPP is more com-
+ n7 p: B4 s: A3 G, q$ J% B0 {* tmon in girls than in boys.1,3 Most boys with CPP d/ |% e- L* R* v( w! i
may have a central nervous system lesion that is
4 F" {) G! c g, wresponsible for the early activation of the hypothal-
( F! o( c" E* e/ H2 Mamic pituitary gonadal axis.1-3 Thus, greater empha-
0 b W& `7 k+ @0 wsis has been given to neuroradiologic imaging in. q1 k+ q) Q* y) t; i4 ^
boys with precocious puberty. In addition to viril-- i' V6 C$ h) y$ j9 ?
ization, the clinical hallmark of CPP is the symmet-$ e; B* \! C6 N; B) u
rical testicular growth secondary to stimulation by
! I) l2 N8 A' G5 w" G& |gonadotropins.1,3% H7 w2 T& }, n& F
Gonadotropin-independent peripheral preco-# b3 r' h2 Q- l7 @/ I2 y0 W
cious puberty in boys also results from inappropriate9 M# v6 I( P& @, A7 f4 T; S% g6 q
androgenic stimulation from either endogenous or3 T- C. s$ E' u' U: a
exogenous sources, nonpituitary gonadotropin stim-
! O* c8 o: s/ C. q/ D$ Eulation, and rare activating mutations.3 Virilizing
j4 r) y0 O& Icongenital adrenal hyperplasia producing excessive
/ c9 K$ i" K$ U6 t% ^* |( Vadrenal androgens is a common cause of precocious
* P3 a9 m( D& {" \puberty in boys.3,48 H" W3 ]% K, w8 M8 H
The most common form of congenital adrenal0 T9 T$ B- L: P- r- g! F
hyperplasia is the 21-hydroxylase enzyme deficiency.) S- i2 Z5 x" n0 w B0 I9 h7 w6 d
The 11-β hydroxylase deficiency may also result in: y1 |4 h9 M: j% q- k
excessive adrenal androgen production, and rarely,
5 G2 H, _9 U* O& `6 C* F) }" kan adrenal tumor may also cause adrenal androgen
" k; _% k; H3 x! V% d) n( L5 jexcess.1,3, |; i( b: u$ ?; ^( a- e/ k
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from8 {/ }- W8 O5 Y, s
542 Clinical Pediatrics / Vol. 46, No. 6, July 20074 S: ?4 Z7 w$ S- l- b
A unique entity of male-limited gonadotropin-- h& Q/ O' W+ \- S0 v4 g. F- b( K
independent precocious puberty, which is also known
2 P5 q/ ^) Y) z& T8 das testotoxicosis, may cause precocious puberty at a' O: L0 |; m7 g$ ` e' Q% I1 Z# J
very young age. The physical findings in these boys( E6 o+ m5 N: Z5 x/ N8 s. O3 Z
with this disorder are full pubertal development,
; l, ~, N7 A* Pincluding bilateral testicular growth, similar to boys
4 z1 q; D- O [9 t4 fwith CPP. The gonadotropin levels in this disorder
) E; X- c5 c7 Care suppressed to prepubertal levels and do not show
) \& Y, c" C& r6 J1 Q3 a& e- ?pubertal response of gonadotropin after gonadotropin-
& e- b! y( X# |6 yreleasing hormone stimulation. This is a sex-linked
: @' b; L2 _+ o5 G. I d- `autosomal dominant disorder that affects only# e, @3 L) f7 ^! k5 M! w
males; therefore, other male members of the family
0 ^: c/ Z* G+ o/ Hmay have similar precocious puberty.3
5 r7 u( ?3 [. z9 A' r' mIn our patient, physical examination was incon-; K; M8 Y9 o+ O1 D9 f
sistent with true precocious puberty since his testi-
: ^$ V9 y3 r" p8 ^cles were prepubertal in size. However, testotoxicosis
& d' q! y i `+ F8 Qwas in the differential diagnosis because his father
) d' C- i5 X8 Z d( gstarted puberty somewhat early, and occasionally,( v) N# K+ l; T5 y; T5 h
testicular enlargement is not that evident in the) o$ A" H5 q$ u& _- f$ m1 \2 x
beginning of this process.1 In the absence of a neg-( P2 O! V W3 p+ F4 B
ative initial history of androgen exposure, our
2 G! E( v7 p& L8 ubiggest concern was virilizing adrenal hyperplasia,
3 m0 A* O# q" I3 ^either 21-hydroxylase deficiency or 11-β hydroxylase
% K8 B; r1 Y* F" {+ @deficiency. Those diagnoses were excluded by find-
* E( s! z" r% M# E" g: d! King the normal level of adrenal steroids.3 U4 r8 [$ F: H7 Z6 a, D& f7 H8 U; e
The diagnosis of exogenous androgens was strongly
, `- { j6 s4 Tsuspected in a follow-up visit after 4 months because
7 {9 b8 A7 N" z# K$ m0 k$ Othe physical examination revealed the complete disap-5 b& j$ y, X3 ]
pearance of pubic hair, normal growth velocity, and
# X( x8 M; g6 cdecreased erections. The father admitted using a testos-
3 R! {# _9 q* Z8 T5 Z; f0 G6 Y# rterone gel, which he concealed at first visit. He was
$ M* s) a, M% @. l; Pusing it rather frequently, twice a day. The Physicians’2 D3 ]5 f' ~7 K+ \
Desk Reference, or package insert of this product, gel or
; Q8 ~' Z) p4 d6 T1 z1 Rcream, cautions about dermal testosterone transfer to
! e7 M6 o) A; B; f! {% m# v4 yunprotected females through direct skin exposure.
% o; W6 S6 E& a5 ESerum testosterone level was found to be 2 times the
& y& w% G1 G& [, jbaseline value in those females who were exposed to; H0 O( R- J- |3 u: d
even 15 minutes of direct skin contact with their male
: `( l/ j9 C5 q: Q" V$ Apartners.6 However, when a shirt covered the applica-& z% C$ z. m# P! U* m1 k
tion site, this testosterone transfer was prevented.
& S$ c! O+ g: O) yOur patient’s testosterone level was 60 ng/mL,! S4 k, V% s. t( U
which was clearly high. Some studies suggest that
% I! D+ K# L u W" Tdermal conversion of testosterone to dihydrotestos-, w* g6 d) q2 L% I1 d9 u+ t0 `
terone, which is a more potent metabolite, is more
/ }# t9 B. K9 |% _& n# N$ u: Q( Dactive in young children exposed to testosterone4 A5 ^% [4 J- \) U: }
exogenously7; however, we did not measure a dihy-, N5 h `/ z+ }. Y+ v
drotestosterone level in our patient. In addition to
0 ]$ J7 _4 H0 B/ G! }/ Nvirilization, exposure to exogenous testosterone in: c1 [+ c- w" r1 S
children results in an increase in growth velocity and8 y' ~, @: k& B' M+ g
advanced bone age, as seen in our patient.
: m5 G9 @4 y0 |$ m+ Z% u7 `The long-term effect of androgen exposure during K. x9 U: O( ]6 @/ ]
early childhood on pubertal development and final- L5 g6 f: }3 u5 s4 J) l
adult height are not fully known and always remain
# L7 v+ X. O% `a concern. Children treated with short-term testos-
. ]0 C8 d# ^* q8 u" H1 e- vterone injection or topical androgen may exhibit some
c1 o2 s- U9 ] g j3 a# _acceleration of the skeletal maturation; however, after
2 K+ L! K" M( p/ m$ c" G9 W, ~3 \cessation of treatment, the rate of bone maturation" K5 v, ?1 r9 K0 z$ N- M
decelerates and gradually returns to normal.8,9. y( ~+ H, B1 {/ d+ N" g
There are conflicting reports and controversy6 D' A6 Z$ y! d/ E1 I
over the effect of early androgen exposure on adult- r; }$ Y( j4 k4 h4 v% [- T9 H9 ]
penile length.10,11 Some reports suggest subnormal! x4 s( F' K+ Z2 V
adult penile length, apparently because of downreg-1 o4 Y$ ?% R, s7 L# G( N5 `' s
ulation of androgen receptor number.10,12 However,
% S! k; J. D! F% V) @4 ]4 ISutherland et al13 did not find a correlation between+ Y5 m: e. F; \7 i- C
childhood testosterone exposure and reduced adult
$ u9 J5 Q5 y; ?, n- i* v. Wpenile length in clinical studies.
8 F) n L2 l: f$ L- {" XNonetheless, we do not believe our patient is& T3 w! f( V: k+ q/ M& T
going to experience any of the untoward effects from
3 U3 m, q& y* b$ ^3 Ktestosterone exposure as mentioned earlier because9 W* [4 n( Y0 J
the exposure was not for a prolonged period of time.+ i! W3 ]8 t+ Z( W
Although the bone age was advanced at the time of$ `: c. J$ {/ r
diagnosis, the child had a normal growth velocity at
, P$ m2 ^) R$ L2 ?& cthe follow-up visit. It is hoped that his final adult
1 |, m# S" Q$ B6 g qheight will not be affected.5 g1 |$ I: d- `, Z
Although rarely reported, the widespread avail-
) ]% x& ~! z d/ x4 a, K3 d) aability of androgen products in our society may
r' i1 x, z+ p9 Xindeed cause more virilization in male or female4 a. N8 i% ?7 e+ J; p! d* v
children than one would realize. Exposure to andro-" {, V" x7 t6 Q: E& U: a, {' |
gen products must be considered and specific ques-
4 J% Q* x# V* d0 E* c/ G' K+ J' etioning about the use of a testosterone product or
4 u3 @* C; @% `% k) H% @1 ygel should be asked of the family members during
7 M' \1 R+ K% ]) q! _the evaluation of any children who present with vir-
* Q9 y3 }: N8 ?# {( Q9 \# l" v1 @ilization or peripheral precocious puberty. The diag-
8 B2 u- ^: v G$ g" _; knosis can be established by just a few tests and by! a( F! G* e8 z1 M( ?# B2 x7 x
appropriate history. The inability to obtain such a
8 f, T4 ]' F: V, v0 {& X% u0 Qhistory, or failure to ask the specific questions, may
. r" X4 @& Q) E! T0 uresult in extensive, unnecessary, and expensive7 X; O* z* t L
investigation. The primary care physician should be! I: v8 Z' q3 G1 `; S" a4 I0 e0 p9 |
aware of this fact, because most of these children9 |7 K" X! V7 y" J2 V* d
may initially present in their practice. The Physicians’7 K: p( e- y# [2 E
Desk Reference and package insert should also put a; W$ |4 \+ w9 x
warning about the virilizing effect on a male or
' i% |. W G" V8 \female child who might come in contact with some-
! f9 E' U1 K! W# W- c( `6 Wone using any of these products.: C& S) V! i1 h3 }! Y* Z- b2 A8 p! l
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6 K. k% U* i6 r( N& ~+ r1 A4 R2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
# w, z8 j- O7 {/ f: L1 Ypuberty in children with tumours of the suprasellar pineal
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exposure to testosterone. Pediatrics. 1999;104:e23.6 p: b% [' r G4 c6 X% z
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Skeletal Development of the Hand and Wrist. 2nd ed.1 L: R m" X, [8 `( c
Stanford, CA: Stanford University Press; 1959.
6 c; T6 j) p9 N; j! u- _" H6. Physicians’ Desk Reference. Androgel 1% testosterone,# P& k9 v8 c( E" l: N
Unimed Pharmaceutical Inc. Montvale, NJ: Medical
# V, I% ~1 r7 `7 `( SEconomics Company, Inc; 2004:3239-3241. C8 V, p3 P* c* _
7. Klugo RC, Cerny JC. Response of micropenis to topical
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