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Sexual Precocity in a 16-Month-Old, l( b$ @& V/ T" N6 ^1 I. p; m
Boy Induced by Indirect Topical0 F J {% }4 J& s6 _8 G
Exposure to Testosterone. X: s) P y. R* J, d }8 U
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
. y, Y2 N4 n5 d6 y7 l qand Kenneth R. Rettig, MD1- c1 H, F+ D; W
Clinical Pediatrics
: B. N" c" @7 w5 g. SVolume 46 Number 6: U; y7 ]! P3 {
July 2007 540-543' F% a% C/ t; R3 c/ L% R
© 2007 Sage Publications
/ J8 c3 Q( R/ h8 ]& W: u4 u10.1177/0009922806296651
+ v, J4 k. i+ X" i5 ghttp://clp.sagepub.com
7 S7 A7 J" s; |% w: X5 jhosted at x4 Z" l% {8 t# U
http://online.sagepub.com# q4 L( p4 J, V% |7 r
Precocious puberty in boys, central or peripheral,
, O$ L) N/ w/ x5 w h, g2 k* `is a significant concern for physicians. Central0 ?% x& U& J! B4 F
precocious puberty (CPP), which is mediated
& \+ L2 {6 P, cthrough the hypothalamic pituitary gonadal axis, has7 m& B F; p" O/ Y0 p4 K
a higher incidence of organic central nervous system
: s j5 l; U6 rlesions in boys.1,2 Virilization in boys, as manifested! P% w3 L% ~+ l( z7 K6 W
by enlargement of the penis, development of pubic
2 a1 I0 ^+ j- X3 d3 t/ Lhair, and facial acne without enlargement of testi-
! P9 T# s% ]% z- U9 ], m0 Gcles, suggests peripheral or pseudopuberty.1-3 We
# G Z; |/ ]0 p' W @: E" {" nreport a 16-month-old boy who presented with the- O2 w! b4 u* p9 M0 [) z. Z+ n8 n7 I
enlargement of the phallus and pubic hair develop-; E+ x3 p3 b' V$ \ H" ~% r
ment without testicular enlargement, which was due
- A/ N# w- h3 K- sto the unintentional exposure to androgen gel used by+ F4 C. y% _) p# n3 t! E
the father. The family initially concealed this infor-
1 k$ z5 o2 J4 W3 L2 s9 u/ [$ S' `5 ]mation, resulting in an extensive work-up for this% S* Z+ \( L" l( x- h3 x6 s# L
child. Given the widespread and easy availability of
9 }% N% f9 j4 p5 Ntestosterone gel and cream, we believe this is proba- Q; V7 O9 G1 Y* F
bly more common than the rare case report in the
7 ^6 @, d" v& D3 H+ d1 ^9 qliterature.41 c8 l2 T# n7 C9 I, W! Q
Patient Report
( ` h) T1 G% z; ~8 ^% R% VA 16-month-old white child was referred to the' y0 X& I! Z4 I0 J: _9 c
endocrine clinic by his pediatrician with the concern% B! r3 b% s6 h- c, u
of early sexual development. His mother noticed
. w5 S7 M' s. B& r% q1 k0 Q8 nlight colored pubic hair development when he was
4 y) \/ i1 M$ c, lFrom the 1Division of Pediatric Endocrinology, 2University of
2 f$ @" {9 ^6 k2 U, jSouth Alabama Medical Center, Mobile, Alabama.* S3 _0 h: T* q" G
Address correspondence to: Samar K. Bhowmick, MD, FACE,
' o' L* k: a7 M- DProfessor of Pediatrics, University of South Alabama, College of
}% W4 `5 a; H; ]0 rMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
; Z% ?( e; {/ u4 ?0 p7 W5 xe-mail: [email protected]., O" f$ E3 A w H9 x3 k7 F
about 6 to 7 months old, which progressively became) `3 t* y. P% V2 s. N# ?8 V
darker. She was also concerned about the enlarge-/ Q7 U& m. Q M0 [) ^
ment of his penis and frequent erections. The child% G, s& d; A+ S% C0 u2 K c+ A$ D
was the product of a full-term normal delivery, with
1 @! a& \" c/ s/ Y, A& ha birth weight of 7 lb 14 oz, and birth length of- R4 m% v$ W3 J3 l
20 inches. He was breast-fed throughout the first year/ _3 m! U' ^! d6 x/ q9 V. s8 b- w- M/ b4 f' z
of life and was still receiving breast milk along with1 F* O# `/ P* ~' U
solid food. He had no hospitalizations or surgery,& f5 } }; w2 a1 z
and his psychosocial and psychomotor development
' c/ f- ^4 C& K7 Rwas age appropriate.! v: ^6 z' o$ q
The family history was remarkable for the father,* e0 e. Y) P' {% E
who was diagnosed with hypothyroidism at age 16,9 E( ^' p4 ]8 S" e6 b! D
which was treated with thyroxine. The father’s1 H- I( _8 }' m ]' j/ v
height was 6 feet, and he went through a somewhat
! J. Z0 y. E4 ?5 ~* _8 tearly puberty and had stopped growing by age 14., E2 d7 v$ }" @* i( A" [
The father denied taking any other medication. The0 c# l; i4 C8 z% C) n" k
child’s mother was in good health. Her menarche2 p' z. z8 r5 `/ f* D. c, q
was at 11 years of age, and her height was at 5 feet$ q( p0 E5 u3 ^6 ~( B% N
5 inches. There was no other family history of pre-2 u. n1 j: H" V' G/ S
cocious sexual development in the first-degree rela-
1 m q7 ?* h) k2 `3 j! E8 utives. There were no siblings., ]( l a; v8 \, y
Physical Examination" q' y3 |! H- j9 E+ v
The physical examination revealed a very active,- C, [& z% }; U
playful, and healthy boy. The vital signs documented
$ w; F2 u2 W; s" f& Ha blood pressure of 85/50 mm Hg, his length was
5 F# z) A1 G/ I- X4 `; b* B$ n4 o90 cm (>97th percentile), and his weight was 14.4 kg
# n. |6 @# Y" G( }5 ^' G+ T(also >97th percentile). The observed yearly growth& k* N" B0 I- l( F/ i& R9 M
velocity was 30 cm (12 inches). The examination of2 {2 D6 x4 S$ Y7 w( j
the neck revealed no thyroid enlargement.3 S6 K5 ~7 e$ H/ {" [/ {+ `$ F$ ]
The genitourinary examination was remarkable for
' [3 ^0 S" p3 S2 D8 Wenlargement of the penis, with a stretched length of8 H: `5 M7 [0 F9 y3 i& b. g
8 cm and a width of 2 cm. The glans penis was very well
]! s3 H& [7 \- m$ _9 n3 ~: a+ edeveloped. The pubic hair was Tanner II, mostly around: S$ [9 ?% p8 U4 U
540% ~; D) o5 ?9 T# D/ q
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from7 a' Q: I5 d( q9 q& |6 J E
the base of the phallus and was dark and curled. The! F! P* f, Q" j+ ~! P2 I
testicular volume was prepubertal at 2 mL each., _$ U( I# X P, ?
The skin was moist and smooth and somewhat4 N: G( B" M1 R" s6 p
oily. No axillary hair was noted. There were no3 g# L% Y7 u6 T+ a: b
abnormal skin pigmentations or café-au-lait spots.# `( n1 [# |; }/ v4 p, P9 {. H
Neurologic evaluation showed deep tendon reflex 2+
0 p, u$ B+ g7 `: abilateral and symmetrical. There was no suggestion
, A8 Y7 W2 }, z7 g; A6 V. [of papilledema.
3 Y7 X7 D1 l/ T- z7 }Laboratory Evaluation% K) M* n- _" X( M2 a/ w/ i. y
The bone age was consistent with 28 months by/ g) F4 Q1 H( v
using the standard of Greulich and Pyle at a chrono-# v8 l$ s! R7 l: y" f
logic age of 16 months (advanced).5 Chromosomal
, l" c' f4 N/ ~% T1 b: S( E! t0 ikaryotype was 46XY. The thyroid function test
( |/ }0 R* w- s! bshowed a free T4 of 1.69 ng/dL, and thyroid stimu-$ N8 x8 i3 x. w, b/ B
lating hormone level was 1.3 µIU/mL (both normal).9 {6 q( y# y9 X; P0 F( T
The concentrations of serum electrolytes, blood
" Z: A: i6 f; d! Kurea nitrogen, creatinine, and calcium all were* A% X. c# q; Y* ` R* `- A
within normal range for his age. The concentration6 ~1 i& f. m4 R+ u! [ N
of serum 17-hydroxyprogesterone was 16 ng/dL5 Q1 `! B( A8 [! E8 A; G$ z
(normal, 3 to 90 ng/dL), androstenedione was 206 i7 u Y7 j8 }, ~6 ?
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
( a0 S# F' j$ c2 h0 Bterone was 38 ng/dL (normal, 50 to 760 ng/dL),
5 @. E, N( Q' F( @: Y* ~desoxycorticosterone was 4.3 ng/dL (normal, 7 to. j, w5 f1 q: c0 T; t2 K
49ng/dL), 11-desoxycortisol (specific compound S)
* }9 {1 t% G$ a6 j$ Y: l7 N7 gwas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-! ]8 o1 O2 d: } S6 h0 D: ^
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
. m! h+ p# n! h; ~testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
; J" l+ P$ _3 X$ @6 e/ T( uand β-human chorionic gonadotropin was less than1 M% ^0 J! d& d4 {( i$ p' f& J3 d
5 mIU/mL (normal <5 mIU/mL). Serum follicular
+ d7 x9 w. ?0 M+ @. _stimulating hormone and leuteinizing hormone
I6 b6 V$ z8 e* R$ g0 g M" S. }* xconcentrations were less than 0.05 mIU/mL) K7 r; Z n1 y# q3 `/ P
(prepubertal).
2 a# w, K5 v* b5 s; HThe parents were notified about the laboratory0 A# R1 o- M2 g1 `& Q
results and were informed that all of the tests were
6 ]( G' d8 n5 A% inormal except the testosterone level was high. The8 n2 C) W; j- F; \* ?* w
follow-up visit was arranged within a few weeks to {3 R$ y% [* u$ u: V- A
obtain testicular and abdominal sonograms; how-
! s+ X6 y7 S4 G" Kever, the family did not return for 4 months.& F$ m( W @/ U. C
Physical examination at this time revealed that the# _) Z$ e) I$ e6 ]5 e/ P
child had grown 2.5 cm in 4 months and had gained3 {' }, f F8 G- j" x
2 kg of weight. Physical examination remained, [' f% ]# Z7 U4 Z4 w
unchanged. Surprisingly, the pubic hair almost com-
* O4 B9 C* D# I, j' w' _pletely disappeared except for a few vellous hairs at6 c, s) i: a" U& V* t
the base of the phallus. Testicular volume was still 2! R0 d6 q# u( T
mL, and the size of the penis remained unchanged.
0 S0 U* A$ h1 ~* RThe mother also said that the boy was no longer hav-! D3 w+ g# u; K% o
ing frequent erections.0 {7 ?. g7 \" Y! B: N; V/ o& {
Both parents were again questioned about use of
g* @0 b/ B8 Eany ointment/creams that they may have applied to9 r6 e3 y: E& I7 u
the child’s skin. This time the father admitted the
z2 A! P! g- f6 @6 a6 e- g" ?Topical Testosterone Exposure / Bhowmick et al 541
' T* {. |" F0 s1 C6 V& a! {! Nuse of testosterone gel twice daily that he was apply-
6 B; D6 V- o2 m( o$ i) Ring over his own shoulders, chest, and back area for8 w# Q2 ^) k; z3 Q8 I3 I2 f9 f& ]
a year. The father also revealed he was embarrassed
n* n0 n: a. ~" mto disclose that he was using a testosterone gel pre-- I8 S }& P) n* y
scribed by his family physician for decreased libido
4 o8 N3 m4 q) u1 u4 fsecondary to depression.( y# f7 u/ ` W0 e8 z
The child slept in the same bed with parents.3 @4 q1 f4 }8 R( a) e& c/ v
The father would hug the baby and hold him on his* ?: Y7 e5 T6 M- Q: S! }' ^+ q9 Q
chest for a considerable period of time, causing sig-2 D! v$ w9 T& o! _4 e$ u
nificant bare skin contact between baby and father.; Y% M7 k) R" E8 t& F, Y4 |6 @
The father also admitted that after the phone call,
/ @9 ]# u* l D% i s; fwhen he learned the testosterone level in the baby; S& N) p! ~. `# H; A. A3 f
was high, he then read the product information" p$ |- |# Z: a" k" F& R8 l
packet and concluded that it was most likely the rea-
/ G8 c2 Q& @* f$ fson for the child’s virilization. At that time, they/ }+ R3 M) L! M& g1 I
decided to put the baby in a separate bed, and the% n1 x) { b/ A9 v e5 o
father was not hugging him with bare skin and had
- @& v, R- S! }; {) ]# n% S% u* qbeen using protective clothing. A repeat testosterone2 v" e6 _6 t0 }- i9 D, x4 Y
test was ordered, but the family did not go to the2 f. U% j N0 Y0 V7 ]: ^. V
laboratory to obtain the test.3 t' N2 X2 p" @8 W
Discussion3 N9 _* N0 I. h7 l& O1 t
Precocious puberty in boys is defined as secondary/ o4 z* Q: l6 b V
sexual development before 9 years of age.1,4
! E4 p( L. t" w6 y* r- K, ]Precocious puberty is termed as central (true) when
) g K# C* e# M: ]; T/ Yit is caused by the premature activation of hypo-
+ j0 w$ r, r/ @, f9 i, [thalamic pituitary gonadal axis. CPP is more com-: u* O6 z4 X6 G+ {
mon in girls than in boys.1,3 Most boys with CPP4 k7 ^& I- u7 f! Y W
may have a central nervous system lesion that is- S& R. r0 H3 }8 _& |
responsible for the early activation of the hypothal-
' t! X1 W+ t. N8 x4 _amic pituitary gonadal axis.1-3 Thus, greater empha-
# c! `0 g% a+ H6 Q# D/ Lsis has been given to neuroradiologic imaging in/ ^1 ?1 ?$ f9 S& Q/ f* E, X
boys with precocious puberty. In addition to viril-
0 M* ?1 h# @8 A* ]ization, the clinical hallmark of CPP is the symmet-
: K1 j3 S$ O3 ]3 T3 M- ]rical testicular growth secondary to stimulation by
% f2 p( S3 q+ D- Fgonadotropins.1,3
7 {+ F. [1 }7 v$ y gGonadotropin-independent peripheral preco-
, O2 C3 _+ t. j( Ycious puberty in boys also results from inappropriate
* Y- i) A" l- `# P t9 T; Yandrogenic stimulation from either endogenous or
& X, v. a4 H) v. ]exogenous sources, nonpituitary gonadotropin stim-
9 t6 @# x9 }! S9 R) I, c# P# ?ulation, and rare activating mutations.3 Virilizing
& r5 \9 [- {4 J Scongenital adrenal hyperplasia producing excessive
0 T: S* l' t# oadrenal androgens is a common cause of precocious* Z$ x8 o6 s3 \1 n+ G
puberty in boys.3,46 N' W! M/ C6 C' m3 ^
The most common form of congenital adrenal
( \ C; j, e. i/ hhyperplasia is the 21-hydroxylase enzyme deficiency.' ~! q+ K2 V. }. K( {4 f
The 11-β hydroxylase deficiency may also result in; E1 [' q( `& Z& r
excessive adrenal androgen production, and rarely,0 J) o( J; h3 B0 [/ w. R) A! w
an adrenal tumor may also cause adrenal androgen5 f( m5 A6 S; t& U1 p5 e) Z
excess.1,3
' ^% W3 U1 k5 h% Nat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
1 D- I. F& D3 L9 n! T+ g542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
7 ?6 Q7 _5 v' f8 m5 I0 sA unique entity of male-limited gonadotropin-# h7 T v8 l/ r% f+ h4 x, x
independent precocious puberty, which is also known- T7 D8 }' I, @/ H
as testotoxicosis, may cause precocious puberty at a! a4 i2 g, g0 G2 E! u& Z
very young age. The physical findings in these boys
U6 x8 W/ I0 N2 j$ K5 [with this disorder are full pubertal development,
3 O4 t, _4 c- f( Kincluding bilateral testicular growth, similar to boys3 m* U g" |8 }# s3 \
with CPP. The gonadotropin levels in this disorder _% \9 w+ ^- [3 p
are suppressed to prepubertal levels and do not show
: i0 Q- t* _* t0 L0 N# ypubertal response of gonadotropin after gonadotropin-
: V$ r, ~ a% _7 J o& Yreleasing hormone stimulation. This is a sex-linked1 o7 o. Z3 w; U5 x2 ^; K
autosomal dominant disorder that affects only
4 b! y" s( l+ Z: C. Z7 k% nmales; therefore, other male members of the family
3 a0 D' V H9 i f. V) \may have similar precocious puberty.3
6 W2 A& L& [9 W+ W5 zIn our patient, physical examination was incon-9 B* _3 O2 k# K
sistent with true precocious puberty since his testi-
0 s6 H( | z* F1 e3 X4 p7 Rcles were prepubertal in size. However, testotoxicosis
, S: o& s( ?" g9 mwas in the differential diagnosis because his father5 h/ k8 r) ?* g
started puberty somewhat early, and occasionally,0 X9 K6 j8 p" V6 h/ e
testicular enlargement is not that evident in the
# j/ m; s3 Y6 S, z. u& ebeginning of this process.1 In the absence of a neg-6 m+ s, m; ]; U9 R, J
ative initial history of androgen exposure, our
4 J9 ^8 N( d& r5 p! Y4 B) T; `biggest concern was virilizing adrenal hyperplasia,
- s! U7 }7 q# D" j6 j' r- Seither 21-hydroxylase deficiency or 11-β hydroxylase
; H' y+ ?( ~. p* z0 O8 Tdeficiency. Those diagnoses were excluded by find-
5 P/ ^% t4 P6 @: w* U/ x: _ing the normal level of adrenal steroids.( c5 ^5 l' A" z; N# `& @
The diagnosis of exogenous androgens was strongly
- [; C' Q$ T1 C( M! zsuspected in a follow-up visit after 4 months because
_+ M: _2 Q0 W* c+ k1 cthe physical examination revealed the complete disap-; R0 b6 e; K+ h' X/ U
pearance of pubic hair, normal growth velocity, and( f c. j3 F! ?/ D N) m% \
decreased erections. The father admitted using a testos- n, v/ x% {2 v6 J* n7 v
terone gel, which he concealed at first visit. He was
: n) Y1 `1 Y( t _: }' @& Iusing it rather frequently, twice a day. The Physicians’% R$ C) G, W6 H# O; h+ R
Desk Reference, or package insert of this product, gel or
8 h7 d% G6 u7 V+ M4 t, B; lcream, cautions about dermal testosterone transfer to
% V+ j U$ E; Q& T% N, cunprotected females through direct skin exposure.
$ i9 ~- Q# n/ i; u2 R) y% A! VSerum testosterone level was found to be 2 times the
0 }: `2 n' a& ?; f$ ?" I6 vbaseline value in those females who were exposed to
8 M9 b, }: L/ `( U2 `& W' H- n5 `even 15 minutes of direct skin contact with their male; D* b' e0 h% B
partners.6 However, when a shirt covered the applica-& u! j$ u% P9 q3 g% o$ j5 E
tion site, this testosterone transfer was prevented.
+ J' Y* r' u; G1 [# rOur patient’s testosterone level was 60 ng/mL,
f) G7 U4 \' d- a8 q- X1 P$ z$ \which was clearly high. Some studies suggest that
; G# t4 G: h$ x9 P* H5 Hdermal conversion of testosterone to dihydrotestos-4 [. F, h' P+ E; g; E' T
terone, which is a more potent metabolite, is more' K$ ?# Y' m5 n: X0 _! Z# C1 C
active in young children exposed to testosterone/ W- f" N' m- u7 b. Y. v {! W9 H
exogenously7; however, we did not measure a dihy-
y1 R) G \. N& ~3 ^# w$ S! E2 @drotestosterone level in our patient. In addition to
, C5 H# _. U( b' n2 ]3 [, A4 Yvirilization, exposure to exogenous testosterone in" y0 K# e9 D4 x, z1 i# V
children results in an increase in growth velocity and
4 { w! c% M/ }advanced bone age, as seen in our patient.7 h1 K+ ~4 G& d0 ^) k) D
The long-term effect of androgen exposure during
6 d" n) D- _) Y& w6 C# Bearly childhood on pubertal development and final
% O3 [' b- c1 P( M v9 Vadult height are not fully known and always remain
* }/ y+ g) J9 K# w2 B/ Ia concern. Children treated with short-term testos-
8 y/ f5 b& |1 P hterone injection or topical androgen may exhibit some2 {/ `! h0 P: {2 w$ p
acceleration of the skeletal maturation; however, after$ f% X1 [4 G7 R: b0 }7 N7 m
cessation of treatment, the rate of bone maturation
( C9 Q; s3 z+ G' g2 a% Udecelerates and gradually returns to normal.8,9
5 X1 Y1 l2 Q% K. D& c: DThere are conflicting reports and controversy
; M; c9 ]/ j8 f& qover the effect of early androgen exposure on adult" N9 `9 L1 }! ?) L
penile length.10,11 Some reports suggest subnormal
# z' H9 X/ G7 f9 p, }7 P9 i" Oadult penile length, apparently because of downreg-8 y& f; I' `4 J d a
ulation of androgen receptor number.10,12 However,
; r( i( r1 W7 rSutherland et al13 did not find a correlation between2 f& j# W) ]0 p& s2 {% O
childhood testosterone exposure and reduced adult5 }: f! I' [3 \) V/ u6 ^
penile length in clinical studies.
5 |/ C# k0 \) }9 ?1 z9 dNonetheless, we do not believe our patient is8 F# J9 z7 @. P0 _: @3 g" l
going to experience any of the untoward effects from6 E5 i) r3 e( `. ^% P u
testosterone exposure as mentioned earlier because
) M0 s4 N o, S5 f" Zthe exposure was not for a prolonged period of time.% ^( l7 X* g: z) w2 Z0 b
Although the bone age was advanced at the time of
+ d! B7 j! y& t. p0 H9 q1 X1 ?3 Pdiagnosis, the child had a normal growth velocity at) [2 X& j& n% \- S
the follow-up visit. It is hoped that his final adult) ?# @( x; A: G& F( s$ |, B
height will not be affected.
/ M0 Z1 l. o% f# }) t: ZAlthough rarely reported, the widespread avail-5 C3 V! x8 e) H, t
ability of androgen products in our society may9 y+ {9 d$ v" l [7 f3 t
indeed cause more virilization in male or female
/ @3 p" D" j# X3 a2 W, `4 B6 Dchildren than one would realize. Exposure to andro-/ `% Y+ O* T: n- s q
gen products must be considered and specific ques-1 j8 @1 l/ v% s( Y) E
tioning about the use of a testosterone product or
2 f5 X5 C0 {; Z1 I. u% ~! ?# ?gel should be asked of the family members during
% b2 n- s/ M7 Bthe evaluation of any children who present with vir-: C/ R$ z' f. N* y/ j
ilization or peripheral precocious puberty. The diag-
2 M) B1 o, `' R C' j6 E" Wnosis can be established by just a few tests and by
! k0 T9 s7 t+ B& W4 H. ~appropriate history. The inability to obtain such a3 ^' ~- u' G ]. }) S' d
history, or failure to ask the specific questions, may
5 z# ]: z& w3 ]- cresult in extensive, unnecessary, and expensive
1 d ?0 ~+ S: P% {investigation. The primary care physician should be9 g; K( T5 ]; h/ R6 \/ f( c+ e
aware of this fact, because most of these children }4 D4 H. j0 `1 \/ l5 r6 M
may initially present in their practice. The Physicians’
' U. Z" G/ X/ ~' a, vDesk Reference and package insert should also put a
( C3 t& |, X) E* x3 H0 |. }, [1 _warning about the virilizing effect on a male or
5 J7 v. t, Z! h7 t) M H2 @female child who might come in contact with some-
' F! k5 k# g1 Ione using any of these products.
0 C) U% q& T8 t Z ^, XReferences
% n9 c: C( [2 }& X Y' }9 M1. Styne DM. The testes: disorder of sexual differentiation
0 B- {; H5 B2 Qand puberty in the male. In: Sperling MA, ed. Pediatric) \# k4 U+ q3 V& X+ C
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders; Z& _$ K2 g8 _0 e2 [
2002: 565-628.0 N. m% w# ^, P8 o z# D$ Y8 s
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
3 W+ a' X# V x% L& z Wpuberty in children with tumours of the suprasellar pineal |
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