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Sexual Precocity in a 16-Month-Old
9 G. v0 b6 ~) U6 U G: A! MBoy Induced by Indirect Topical
, x5 j! y2 f+ ^6 vExposure to Testosterone
6 a: U. G5 k* `Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,24 T; u" C- q9 l% k: F7 L. d
and Kenneth R. Rettig, MD1
) ^& V0 c' n3 u- g. y8 {. y% Z7 |Clinical Pediatrics5 w# K5 `2 P& S/ D, W$ D$ l6 ]
Volume 46 Number 6
& Y1 [6 I7 }3 gJuly 2007 540-543( g8 y6 w% x7 I+ ?
© 2007 Sage Publications! p1 Z* s5 C$ X( _
10.1177/0009922806296651
: P5 T% D6 o: }0 K W3 ~http://clp.sagepub.com
- {, k7 o) P, r: E u" ahosted at
/ h" W+ f8 B3 z; |7 C$ v$ q) o6 g; jhttp://online.sagepub.com! ]* O0 Z4 Z) @" H
Precocious puberty in boys, central or peripheral,1 A7 ~+ k+ o! B/ d
is a significant concern for physicians. Central
. {4 a: f9 Y. [/ [precocious puberty (CPP), which is mediated9 F- e: v% ?" w9 ?' l% Y9 h
through the hypothalamic pituitary gonadal axis, has2 O8 a2 U; Z# A
a higher incidence of organic central nervous system
! e% L3 T$ r5 N/ I1 Olesions in boys.1,2 Virilization in boys, as manifested8 V6 [8 Q5 D, D) h) l! I
by enlargement of the penis, development of pubic
" K* w4 {6 |7 R2 ]4 Whair, and facial acne without enlargement of testi-
* c( |6 O0 ?$ k& T' K. \. J' pcles, suggests peripheral or pseudopuberty.1-3 We
! Y9 {0 h4 O+ w/ n% |report a 16-month-old boy who presented with the0 v3 C4 ]$ H7 V- i: F9 [
enlargement of the phallus and pubic hair develop-" V' A# w E/ {9 v
ment without testicular enlargement, which was due
6 Z$ _$ C0 v: l* z1 d% ]5 H# _to the unintentional exposure to androgen gel used by4 K. ~% F: J/ A X* S
the father. The family initially concealed this infor-
5 \% F c. x$ [. Mmation, resulting in an extensive work-up for this
1 {; Q7 N% O9 ~: v% [( pchild. Given the widespread and easy availability of
+ G: k; c, B$ P5 ^, ]' ctestosterone gel and cream, we believe this is proba-
5 U9 d3 e# n& K# @# Wbly more common than the rare case report in the
& |* @) w$ G& y6 b- {$ {literature.4/ i3 _* C. j0 B" j/ I; I
Patient Report
6 ]# [9 N! M3 {* {. a$ p2 m, `8 \A 16-month-old white child was referred to the, b* i7 W" o+ r; Z
endocrine clinic by his pediatrician with the concern5 g& d# }" B+ Q
of early sexual development. His mother noticed# A2 t* W+ C$ A, c7 U
light colored pubic hair development when he was. f5 q. u C& ~& G
From the 1Division of Pediatric Endocrinology, 2University of
+ r+ {, W. q5 ~- [/ e$ }( uSouth Alabama Medical Center, Mobile, Alabama.
9 W2 A; u% t5 m8 K1 e2 L3 x L1 IAddress correspondence to: Samar K. Bhowmick, MD, FACE,. v7 d+ |. k7 |' X2 l A
Professor of Pediatrics, University of South Alabama, College of
. k( Q* O- _) Q7 i% ?Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;+ q$ a5 \; [, L& v
e-mail: [email protected].
m& c& r( C, ^4 Sabout 6 to 7 months old, which progressively became
b- q1 E' H& d. G i, \2 d, ddarker. She was also concerned about the enlarge-
. C2 V7 M$ x% j+ R! L& D, U9 v4 w2 Xment of his penis and frequent erections. The child
% X9 q r2 f) a. Q9 zwas the product of a full-term normal delivery, with9 K5 X- M/ C1 z! N, M5 @) _% B+ ^
a birth weight of 7 lb 14 oz, and birth length of" M; u* a& f/ M# o7 b0 e
20 inches. He was breast-fed throughout the first year5 @; B! e' F+ k8 o
of life and was still receiving breast milk along with
+ i) V) I3 q, r& N5 \solid food. He had no hospitalizations or surgery,
% S/ k5 O5 F6 X4 _/ Hand his psychosocial and psychomotor development2 N. U7 {6 F8 w$ l; ]- u9 U
was age appropriate.
6 m/ v- }$ ?: p, }; @The family history was remarkable for the father,
& G+ v. i3 @3 [, q5 d7 g: x5 Wwho was diagnosed with hypothyroidism at age 16,0 N- C" O2 ^. _/ c1 C Q
which was treated with thyroxine. The father’s8 b/ Z& J) T9 ?/ _! |" b. W9 N7 O
height was 6 feet, and he went through a somewhat9 B4 z* Q- s" P( H
early puberty and had stopped growing by age 14.
5 ?# I9 M+ R7 x$ x9 DThe father denied taking any other medication. The7 q" |7 o {) [8 |
child’s mother was in good health. Her menarche2 O8 e% g$ Q# e6 T7 N$ Y& Z5 h
was at 11 years of age, and her height was at 5 feet
/ Q- P% ~' }2 D! P( C5 inches. There was no other family history of pre-
5 e5 R+ X0 w" L U ?cocious sexual development in the first-degree rela-
0 F$ A8 r% r1 R' M9 etives. There were no siblings.
8 d) E8 e' }" m9 U( cPhysical Examination/ Z4 S3 q& E! G& u! m P
The physical examination revealed a very active,
2 F. I' t0 h: M+ ]/ Tplayful, and healthy boy. The vital signs documented
' S5 {* F, b! }: z. y0 z% ~a blood pressure of 85/50 mm Hg, his length was- w1 z6 N5 b8 |! i! C x8 r
90 cm (>97th percentile), and his weight was 14.4 kg. C( X: _$ s1 R7 I$ H$ V( K
(also >97th percentile). The observed yearly growth
, V7 E, G6 W/ B" R, \* |velocity was 30 cm (12 inches). The examination of5 v6 H `8 r8 n
the neck revealed no thyroid enlargement.
( t. W; n% i# yThe genitourinary examination was remarkable for
# i8 A( t. b; Renlargement of the penis, with a stretched length of; S& h$ u/ ?) g: I' {
8 cm and a width of 2 cm. The glans penis was very well
/ W' x* M& `! N. V% ]3 Q. B z7 ^* H) zdeveloped. The pubic hair was Tanner II, mostly around+ J5 [1 _$ x) S4 x$ B& r) X( |
540# _$ K0 f/ R, [! g6 E$ S& n1 M
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
6 ?. V3 j# n2 K3 F0 O' [# xthe base of the phallus and was dark and curled. The
0 W5 i5 b4 F9 R8 d+ D+ qtesticular volume was prepubertal at 2 mL each.
3 b5 L+ K5 F' n+ [1 W# F" V* B# c4 q" IThe skin was moist and smooth and somewhat
* W) U9 y3 I1 p) poily. No axillary hair was noted. There were no
& l# ^, N, J$ x+ gabnormal skin pigmentations or café-au-lait spots.4 b9 G/ M `; Y2 }1 p- A6 ~( D x# l
Neurologic evaluation showed deep tendon reflex 2+( y0 F$ C, y$ |+ i% m4 P
bilateral and symmetrical. There was no suggestion4 E8 @4 V B( I% d- t, h5 j$ h
of papilledema.
$ e0 k+ ?! E, C8 ?Laboratory Evaluation# w2 p' o/ K: |
The bone age was consistent with 28 months by) w. f3 E( s8 I! `: x
using the standard of Greulich and Pyle at a chrono-
- T. d4 Z2 F* i% Ilogic age of 16 months (advanced).5 Chromosomal2 W: u5 M% g8 b: e1 A# S
karyotype was 46XY. The thyroid function test
* ^ G8 T( O) ^) y! I8 Bshowed a free T4 of 1.69 ng/dL, and thyroid stimu-" u+ N& K8 {/ t- O8 `! j
lating hormone level was 1.3 µIU/mL (both normal).
% c* O; h* P! m% t9 U- R/ WThe concentrations of serum electrolytes, blood& j# A5 Z! f$ M" r( p% i
urea nitrogen, creatinine, and calcium all were( `( ?4 A5 P7 I: F) Z' L7 U& ?
within normal range for his age. The concentration
, Z2 L: q9 K" y5 v- U- o, @. Xof serum 17-hydroxyprogesterone was 16 ng/dL
. G) [$ H5 v% d(normal, 3 to 90 ng/dL), androstenedione was 20
" m* G3 D" K7 {: p: `7 u; Yng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-, y% N) q/ L$ N$ P, K3 e4 Q
terone was 38 ng/dL (normal, 50 to 760 ng/dL),
X* F' X, n8 V4 Kdesoxycorticosterone was 4.3 ng/dL (normal, 7 to. \" P F. u( p9 x8 n- K. Z$ H
49ng/dL), 11-desoxycortisol (specific compound S)
/ u4 b3 O$ \9 f Mwas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
; f# E$ v$ W1 p1 Otisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
# T2 @& Y6 g0 Utestosterone was 60 ng/dL (normal <3 to 10 ng/dL),
7 I5 G! `4 P1 pand β-human chorionic gonadotropin was less than: n4 l9 Q$ W' x8 G2 E1 c; P
5 mIU/mL (normal <5 mIU/mL). Serum follicular
' ~8 ^% Y4 U: a! Ostimulating hormone and leuteinizing hormone
) c5 f/ {, B" n( `concentrations were less than 0.05 mIU/mL2 [2 E8 T. f' W* B- H
(prepubertal). l* P1 i! l# W6 }
The parents were notified about the laboratory
) x# P0 Y( B: J/ ]2 x5 K" bresults and were informed that all of the tests were
( c1 E, X H& X2 N. Znormal except the testosterone level was high. The2 z) l) o+ G# G; C1 C% D
follow-up visit was arranged within a few weeks to5 R) X, B0 I9 g7 w+ t: T* O) L
obtain testicular and abdominal sonograms; how-
+ j% b( E0 H( Iever, the family did not return for 4 months.+ V% a: M9 o5 S$ ?2 Q: m
Physical examination at this time revealed that the
+ m/ s2 _) Z# B6 lchild had grown 2.5 cm in 4 months and had gained* U9 j2 U! q6 k8 ?7 Z6 L8 s) W' l: n
2 kg of weight. Physical examination remained7 v+ N2 R+ R1 z$ f. }
unchanged. Surprisingly, the pubic hair almost com-, ]) j# p$ ^1 \
pletely disappeared except for a few vellous hairs at
0 t1 s" y) D3 z# Nthe base of the phallus. Testicular volume was still 2
0 @4 i( \. T8 P2 vmL, and the size of the penis remained unchanged.
+ X: ` A' X5 i( ^The mother also said that the boy was no longer hav-: \+ R' @, Z J0 N/ J( \# g
ing frequent erections.4 X. P8 T, M1 I% | R/ b* h
Both parents were again questioned about use of) x& t9 K4 k$ `/ D; N3 N& ~
any ointment/creams that they may have applied to; U/ X" `7 G5 k# ^3 Y! k9 `) h% H Y6 x
the child’s skin. This time the father admitted the
) D. e! o) `2 n u4 HTopical Testosterone Exposure / Bhowmick et al 5416 L, | p5 F/ d# `
use of testosterone gel twice daily that he was apply-
, `5 |2 Z# P- E( V. `5 t) z4 L% iing over his own shoulders, chest, and back area for
% s A+ m, w a7 J" Z- M5 A# ca year. The father also revealed he was embarrassed( _. X2 m _: ~( F0 y6 W4 {5 m- O
to disclose that he was using a testosterone gel pre-
+ P3 j& h& f8 O. `/ f8 rscribed by his family physician for decreased libido% G8 S- h: a) ]' }) y
secondary to depression.
' S4 n: y, ^1 {2 c% L: @, XThe child slept in the same bed with parents.
, Q; k( k3 B+ J$ P$ {The father would hug the baby and hold him on his% ~- w/ S( J! I9 A' ~! l( y
chest for a considerable period of time, causing sig-' }, X1 ^; u# r/ [2 O& m$ F
nificant bare skin contact between baby and father.
1 `, h* a- m1 M1 t0 g, c- T/ BThe father also admitted that after the phone call,+ M6 j5 w: ~* J; }) ^9 w4 ^
when he learned the testosterone level in the baby
0 P% V U9 i) a# `was high, he then read the product information
8 M6 X5 O, @9 S. I. c% @packet and concluded that it was most likely the rea-. J: T" c, L; c8 R; h6 |* k; l+ O
son for the child’s virilization. At that time, they
, y# t! K" m! k& `3 ?. bdecided to put the baby in a separate bed, and the
- B1 w4 L; ~+ p9 _! B( L& M; qfather was not hugging him with bare skin and had( m, ~2 }* C; B3 d& ?
been using protective clothing. A repeat testosterone8 W% z, |' f' @* Z
test was ordered, but the family did not go to the
8 L" ~) L* k8 L `( Zlaboratory to obtain the test.
* x) o1 C2 ~! ?Discussion2 L* ]5 y$ A( D
Precocious puberty in boys is defined as secondary
- S5 s. U1 F( q- H6 F. i: Q* _sexual development before 9 years of age.1,4
" U$ l* n& _ R, XPrecocious puberty is termed as central (true) when }& a9 {0 q/ e# {
it is caused by the premature activation of hypo-- H8 `/ B; e/ C
thalamic pituitary gonadal axis. CPP is more com-
9 v7 M/ M+ R9 f: nmon in girls than in boys.1,3 Most boys with CPP5 x( h0 n: ?8 p: S% C% I* |
may have a central nervous system lesion that is
: T7 h8 w# h& z! d0 Z' E& \8 A4 B4 Gresponsible for the early activation of the hypothal-
; q, Z- ?4 a; S3 V" H7 t% G3 z! Wamic pituitary gonadal axis.1-3 Thus, greater empha-' E) _6 h# C& U2 D. |" [. f% w
sis has been given to neuroradiologic imaging in& Y, d! K2 |6 e' t/ Y
boys with precocious puberty. In addition to viril-) \4 c- H Z9 A1 k8 w# J# Z7 t
ization, the clinical hallmark of CPP is the symmet-8 ~6 l! k- S# [" Q
rical testicular growth secondary to stimulation by
4 d/ O8 I$ a1 Fgonadotropins.1,3
. C5 }$ x1 @+ H* F1 q- sGonadotropin-independent peripheral preco-9 a5 t3 V$ h* B i: P
cious puberty in boys also results from inappropriate
2 ?& |) s6 r; G% Kandrogenic stimulation from either endogenous or2 |. T6 H5 W3 T5 x6 |
exogenous sources, nonpituitary gonadotropin stim-
" e4 A: z6 N) P- Culation, and rare activating mutations.3 Virilizing8 \2 a# B5 l0 \$ ~
congenital adrenal hyperplasia producing excessive# e/ W6 Q% L R' z, r( }# F" X
adrenal androgens is a common cause of precocious' F! t& i* C, g
puberty in boys.3,44 u: ~& |7 p1 L3 E5 }# q
The most common form of congenital adrenal! j7 b8 T% T. Q9 @
hyperplasia is the 21-hydroxylase enzyme deficiency.* r% \& D8 {( y, G( y: v) \' f0 ~
The 11-β hydroxylase deficiency may also result in
0 J/ z; y6 C3 w1 t% y- ~/ yexcessive adrenal androgen production, and rarely,
s$ \$ y5 Z* oan adrenal tumor may also cause adrenal androgen: v& m. R# ]+ b2 I2 ^: I" }* g
excess.1,3
9 D4 N0 v8 n5 {; U* d( Oat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
% g5 z# S7 C; S% Y! \542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
4 N7 i8 m% ]( u. C# [* R. [0 |2 YA unique entity of male-limited gonadotropin-! D, A; T& O: L' P1 R
independent precocious puberty, which is also known
! v0 G' {% u t" F7 das testotoxicosis, may cause precocious puberty at a
) L! T( D9 b: F1 r7 Bvery young age. The physical findings in these boys/ x1 G/ r$ c) A' V
with this disorder are full pubertal development,, q2 N8 L. w7 _ g6 m
including bilateral testicular growth, similar to boys. q' e! Z) m+ @1 R
with CPP. The gonadotropin levels in this disorder1 r; P3 R4 R3 k( a6 R3 p
are suppressed to prepubertal levels and do not show
, D( b0 B k2 J% i0 A- `% Bpubertal response of gonadotropin after gonadotropin-
" @& \+ D& _" {9 kreleasing hormone stimulation. This is a sex-linked
$ A, P! i) ]- O) h* j6 jautosomal dominant disorder that affects only
- E& C+ N/ k+ D" y8 ?' r; ?4 Pmales; therefore, other male members of the family
C; p2 R, O/ U# L5 ?" h |may have similar precocious puberty.3
& A6 ^! `0 H1 v; E) n6 Q9 XIn our patient, physical examination was incon-1 |3 Z" b1 o- h; Y: P) X( M$ Q( B9 v
sistent with true precocious puberty since his testi-; v* {3 ]& Q! G$ ^- P1 J+ J# d
cles were prepubertal in size. However, testotoxicosis
9 Q# f' o- f0 L5 v4 E0 Vwas in the differential diagnosis because his father
% {: ]+ y% o$ W5 S4 J' x7 E' Dstarted puberty somewhat early, and occasionally,
# k" ^% f, j& h( E/ t. u) Wtesticular enlargement is not that evident in the( k- }2 t. `) R _: |+ R- L6 j
beginning of this process.1 In the absence of a neg-
% u! ?- p9 r8 @; _9 ^9 m7 bative initial history of androgen exposure, our
; F1 x8 E% D0 |: K! Xbiggest concern was virilizing adrenal hyperplasia,
8 C1 Z) Z6 z" R T# Beither 21-hydroxylase deficiency or 11-β hydroxylase0 J9 Z, \8 N/ b3 X
deficiency. Those diagnoses were excluded by find-
$ ~7 a+ n9 r3 O1 s! Wing the normal level of adrenal steroids.( e( F( l- A9 Y% Q" ]- w
The diagnosis of exogenous androgens was strongly
# g# M; j+ n7 }3 wsuspected in a follow-up visit after 4 months because+ a3 @7 d, d: J u9 ^
the physical examination revealed the complete disap-
, a1 K& I7 [; j$ fpearance of pubic hair, normal growth velocity, and
& y, E+ ^1 |- V) y T8 k; hdecreased erections. The father admitted using a testos-
# q% e3 b" |5 F2 M3 ~1 w% f; ^ Rterone gel, which he concealed at first visit. He was
2 }% V. v7 _1 musing it rather frequently, twice a day. The Physicians’: X3 i* |; I4 b: e; Z
Desk Reference, or package insert of this product, gel or0 S0 x& o% ] Q1 M- {% s- F9 k1 e
cream, cautions about dermal testosterone transfer to
5 T3 g$ n! k+ k2 V9 Junprotected females through direct skin exposure.
4 F- q& j3 q3 w/ P1 T+ XSerum testosterone level was found to be 2 times the
2 n7 p7 L! K/ }. f* E' E* W$ Y5 cbaseline value in those females who were exposed to; f7 Y3 D% f) X& K. W3 A
even 15 minutes of direct skin contact with their male. d: `) |( S) K4 a
partners.6 However, when a shirt covered the applica-
" f8 @3 |, t" j8 _- B D9 O# Ftion site, this testosterone transfer was prevented.
8 p& g* M, f J+ d" Q bOur patient’s testosterone level was 60 ng/mL,
: |- x3 C5 V7 D( pwhich was clearly high. Some studies suggest that# [ l( c; W4 r" G4 E6 r$ U
dermal conversion of testosterone to dihydrotestos-# O t+ i \3 K% k
terone, which is a more potent metabolite, is more) ~' G# y, L, c8 a0 S
active in young children exposed to testosterone
( C4 a O. m$ U0 W$ [. F, gexogenously7; however, we did not measure a dihy-
3 y1 r# M" w7 {: G- g: odrotestosterone level in our patient. In addition to( W; Y) \- Z1 r
virilization, exposure to exogenous testosterone in1 l: P1 z& s1 b- @6 k; {! E: |
children results in an increase in growth velocity and
/ U- r/ H4 ], ~1 j& Jadvanced bone age, as seen in our patient.
8 d, T$ U" Y. \The long-term effect of androgen exposure during( n* t( A0 n. n+ L
early childhood on pubertal development and final' |$ |# R2 l% B& c w7 s
adult height are not fully known and always remain
" A. T$ y$ o& w" \1 ca concern. Children treated with short-term testos-' a% L5 g" o1 c$ x* n4 _1 l* X( }
terone injection or topical androgen may exhibit some
4 ~0 ~3 B' h8 G+ i+ A) uacceleration of the skeletal maturation; however, after
9 }$ ~ ^6 ^9 e! ^: [. h* |; n8 ^cessation of treatment, the rate of bone maturation5 V. {& g8 S1 a! ]! _( S% j
decelerates and gradually returns to normal.8,9
& F1 s- v. ~! @3 @! q3 H; s9 q2 ~There are conflicting reports and controversy
7 n! i' p% r. T1 i( Dover the effect of early androgen exposure on adult+ e. a& V" I- ^
penile length.10,11 Some reports suggest subnormal; S$ o9 n' q+ y0 G; N' U# n6 L
adult penile length, apparently because of downreg-4 }1 K0 v3 b' R" g2 Q/ s" I) [
ulation of androgen receptor number.10,12 However,
. `" n3 g6 W9 K8 j" H$ F4 |" vSutherland et al13 did not find a correlation between4 M \9 ?- f4 [5 A- P7 z% S
childhood testosterone exposure and reduced adult7 S9 m2 l& H9 ^& b
penile length in clinical studies./ j4 u3 q- A- }) k
Nonetheless, we do not believe our patient is4 P+ z" z- ?) i# n
going to experience any of the untoward effects from
; D. e2 A% ^; Xtestosterone exposure as mentioned earlier because5 a9 O/ d! z; I& |' j; Y
the exposure was not for a prolonged period of time.# I+ z+ D7 Q# [7 k7 t
Although the bone age was advanced at the time of- o! R) o$ k' l0 T* S. T& F
diagnosis, the child had a normal growth velocity at
3 f6 v) t0 n; l, H+ fthe follow-up visit. It is hoped that his final adult/ A' b7 B. O& y! ^+ I
height will not be affected.# `# |0 G, y7 \7 C) M+ E
Although rarely reported, the widespread avail-
' K2 t; ^2 ]$ N1 W9 }- Y" s0 Eability of androgen products in our society may
9 x# {( D8 U- D! B' J* I# Y4 O8 Xindeed cause more virilization in male or female1 m$ [! v9 w% d7 f1 q% h) f
children than one would realize. Exposure to andro-2 F; b! j+ c2 F3 ]& W$ j
gen products must be considered and specific ques-
' b/ g% N4 H- f& ?! [tioning about the use of a testosterone product or$ Y" {2 l, z+ r8 e% T, @
gel should be asked of the family members during
5 k9 D- S# n& R& e6 l" Z) Z0 v9 athe evaluation of any children who present with vir-% s3 X' j; |2 L8 ?" P
ilization or peripheral precocious puberty. The diag-
! k4 m2 ^1 ^# P+ E1 Rnosis can be established by just a few tests and by7 H, u' y; ]+ l$ u% l) T$ O
appropriate history. The inability to obtain such a% [2 J: H8 J% }
history, or failure to ask the specific questions, may
. N; K ~8 Y; w$ e5 vresult in extensive, unnecessary, and expensive/ T$ N& k; i: K7 c! I) T9 F5 n
investigation. The primary care physician should be7 f$ t0 E, i7 i/ y. H
aware of this fact, because most of these children. n+ r3 Q* `& ]( I! W$ N$ T
may initially present in their practice. The Physicians’ j7 j+ u9 x5 |: l
Desk Reference and package insert should also put a& L' b! n; w1 G4 \$ I& o
warning about the virilizing effect on a male or. f Y7 T1 V1 Z' t" k
female child who might come in contact with some-1 m$ y0 E3 r9 D. D/ E
one using any of these products.4 e& j8 f! X& \' j# w/ ^- K5 c
References) J, }# `2 e$ \) z0 g
1. Styne DM. The testes: disorder of sexual differentiation
6 \2 [$ _4 n& M8 Pand puberty in the male. In: Sperling MA, ed. Pediatric% K$ w V! @' u- V* Q# U) @0 n" a
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;( N% m8 g+ O7 l. R! t
2002: 565-628.* o7 u, v! U$ ~
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
) P- ]7 u0 P& S2 R8 rpuberty in children with tumours of the suprasellar pineal |
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