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Sexual Precocity in a 16-Month-Old
( O% G; q! y+ nBoy Induced by Indirect Topical
) f7 X: V! k/ j% H# pExposure to Testosterone* S8 w2 g- k p8 S0 l
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,26 Q3 u& _, X/ g0 A, c, d/ _
and Kenneth R. Rettig, MD1
8 W# {8 t* ]& ?! v) T$ _4 v$ a# VClinical Pediatrics3 w# P; x4 t- l
Volume 46 Number 6) a& c. s7 D" g0 t4 h
July 2007 540-543
3 A- Y- I* Q* d/ n# X/ E© 2007 Sage Publications; {+ v8 e: u# p+ s7 ~, g- S" j
10.1177/0009922806296651
% H% ?( `& X* @" f& Q: N* F" N2 Shttp://clp.sagepub.com2 w, u, h) f0 o
hosted at
0 Q$ R+ x P. N( E" p: M' thttp://online.sagepub.com: t. P% ~' B7 d' k" R1 i& \5 M! d0 t
Precocious puberty in boys, central or peripheral,% r- e) D! e# F$ E. K% P
is a significant concern for physicians. Central
( i' g- ^0 D* lprecocious puberty (CPP), which is mediated/ y! l) Y% `) K( U- P: r* a/ Z
through the hypothalamic pituitary gonadal axis, has
3 `& [* u4 M9 ~a higher incidence of organic central nervous system
6 ?$ Y& H3 o- R, {, alesions in boys.1,2 Virilization in boys, as manifested/ e: C. T. h3 p% k
by enlargement of the penis, development of pubic0 K7 q w+ ^! H2 M3 J* ?6 Y
hair, and facial acne without enlargement of testi-, F+ f( m/ W8 [3 r2 C+ S
cles, suggests peripheral or pseudopuberty.1-3 We! j& I2 T/ }1 F$ i: I. f
report a 16-month-old boy who presented with the
T- A# C% R2 Z$ |4 |: A. B' penlargement of the phallus and pubic hair develop-
4 }& g! F. m: @" E: t6 I7 `6 b4 Lment without testicular enlargement, which was due
: L, ~ X' n. ~: d& A* H0 `6 s3 _4 ]to the unintentional exposure to androgen gel used by& G7 [# D2 n5 U, A* o
the father. The family initially concealed this infor-
$ X* D% V1 _5 v+ [, ]mation, resulting in an extensive work-up for this) d4 U; @/ f9 `
child. Given the widespread and easy availability of
/ u" H E7 Y2 X! Y2 xtestosterone gel and cream, we believe this is proba-
3 h) x( Z" V( T6 z. j/ t6 Kbly more common than the rare case report in the
/ s3 C) G2 n% pliterature.4
% ?; d- G$ W2 ?- B4 f+ ?Patient Report. J0 p- {% ?+ u6 ?. ]
A 16-month-old white child was referred to the2 k& \, ]3 s L0 ^- F
endocrine clinic by his pediatrician with the concern* x" k6 a, [- B; B9 v
of early sexual development. His mother noticed$ V+ l- b6 \# `" E( z
light colored pubic hair development when he was8 { Z, q! E" m S
From the 1Division of Pediatric Endocrinology, 2University of
; T+ ]+ A' y# a% q' oSouth Alabama Medical Center, Mobile, Alabama.
% ^2 C1 A8 E' @6 GAddress correspondence to: Samar K. Bhowmick, MD, FACE,' W7 c; x# ?0 k" x1 a
Professor of Pediatrics, University of South Alabama, College of
2 u" D; }" k, d: pMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
+ O9 _; j# r+ l6 ve-mail: [email protected].7 ^" K' U2 c9 B# D
about 6 to 7 months old, which progressively became
8 E [' I4 O. x1 }! N# Udarker. She was also concerned about the enlarge-
9 a% L) L& i/ F+ Bment of his penis and frequent erections. The child
, G( @9 o0 V) z' Fwas the product of a full-term normal delivery, with! w2 ?9 ?, E3 b) X: D9 D8 l
a birth weight of 7 lb 14 oz, and birth length of
- E5 R; l( M% U8 R4 i20 inches. He was breast-fed throughout the first year0 V$ z# h8 n( K# y3 G7 F( I
of life and was still receiving breast milk along with
8 k0 ?8 G( e& I: fsolid food. He had no hospitalizations or surgery,
: `3 R9 |( e ?" `. c/ @and his psychosocial and psychomotor development
& A; r8 t0 |- B* W! w: uwas age appropriate.* k, }- K, A9 p8 `% ]) s1 |
The family history was remarkable for the father,
7 m( S% Y5 k; Z4 Lwho was diagnosed with hypothyroidism at age 16,
7 D5 S! y, \1 f/ L2 _6 Ewhich was treated with thyroxine. The father’s
9 S2 R) C: I( m8 T& `height was 6 feet, and he went through a somewhat
! s3 j/ v0 I& z) d* U" |# c5 Y7 bearly puberty and had stopped growing by age 14.. T+ D+ ~- l, I& y$ D. v
The father denied taking any other medication. The3 S5 G- X! w0 n% L1 k/ c
child’s mother was in good health. Her menarche
4 F& F3 N( L9 y7 J: Z1 bwas at 11 years of age, and her height was at 5 feet0 d2 ?! V* D1 H4 H$ x
5 inches. There was no other family history of pre-1 @# A! y/ r1 d" T5 s7 v/ \+ @
cocious sexual development in the first-degree rela-9 G" j$ K) i3 h/ Q4 Q# D- |" ]
tives. There were no siblings.
4 M* ]; D; L& d4 [: C8 ~( E( sPhysical Examination
3 M' B! Z5 h2 L, T# zThe physical examination revealed a very active,& m; c" U) n6 ^! u% A9 F
playful, and healthy boy. The vital signs documented- E; k/ D$ b( E4 I( z- X: g- O9 n
a blood pressure of 85/50 mm Hg, his length was
8 l% k# K1 f3 f90 cm (>97th percentile), and his weight was 14.4 kg
3 P: L4 m! j# a" B* a) S$ \4 u+ @(also >97th percentile). The observed yearly growth( z. M0 m. [7 L) e) N
velocity was 30 cm (12 inches). The examination of
2 g) T) D3 N, {the neck revealed no thyroid enlargement.
# ~2 k7 T; t$ ], f0 t4 y/ A* X8 _! F% cThe genitourinary examination was remarkable for0 l; D7 R" G6 \4 [% ~/ G& v
enlargement of the penis, with a stretched length of
; l9 c1 s& s4 C9 m8 cm and a width of 2 cm. The glans penis was very well
& A! t7 m6 _7 v7 |+ {developed. The pubic hair was Tanner II, mostly around
- n1 B5 r( E( N540* h: _. E9 }3 E3 m* H: C0 K, }
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from5 W H% k' s* m- T4 V3 p) w
the base of the phallus and was dark and curled. The
6 k7 J h# i; b/ a6 R$ R7 `testicular volume was prepubertal at 2 mL each.
3 D8 j' K# b" |( Y- \* SThe skin was moist and smooth and somewhat
3 b' K" O L6 `$ ^3 J. J# i% [ Z8 ioily. No axillary hair was noted. There were no4 d: j8 Y0 o, p2 O! K
abnormal skin pigmentations or café-au-lait spots.
! k9 Q) _/ j4 W7 ZNeurologic evaluation showed deep tendon reflex 2+& ^ d8 W1 s+ S. ]+ T1 e; Y2 c3 V$ F
bilateral and symmetrical. There was no suggestion, S/ M3 O- d/ x+ Y
of papilledema.: \7 j* |. ]" }
Laboratory Evaluation
2 O5 ]% C7 u5 _9 v2 z, SThe bone age was consistent with 28 months by9 {2 I' @1 _ W5 e" l
using the standard of Greulich and Pyle at a chrono-
! [) @3 i/ ?9 |logic age of 16 months (advanced).5 Chromosomal0 v5 S* @, \' h- q
karyotype was 46XY. The thyroid function test& R8 J3 F' B: r+ r- z
showed a free T4 of 1.69 ng/dL, and thyroid stimu-
b, S/ f! s" Z1 }' H" V; E) clating hormone level was 1.3 µIU/mL (both normal).8 w" C1 ]4 G3 Z
The concentrations of serum electrolytes, blood$ \0 j6 ~0 q" j* R/ `
urea nitrogen, creatinine, and calcium all were
( E( P' U$ ~6 r1 {& a$ Zwithin normal range for his age. The concentration( h) i8 M% i, c l$ A* x5 _
of serum 17-hydroxyprogesterone was 16 ng/dL
+ |% R0 D5 ?- q( Y: h(normal, 3 to 90 ng/dL), androstenedione was 20) G1 q0 S& j1 @, i# W! F
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
3 \. A8 d8 p% t; c, |terone was 38 ng/dL (normal, 50 to 760 ng/dL),; D: U# x! ~0 z. E( w& G3 j
desoxycorticosterone was 4.3 ng/dL (normal, 7 to
( x& D. L$ {/ V! {- Y- U49ng/dL), 11-desoxycortisol (specific compound S)$ C W1 k1 t1 L# N, b5 B, Q+ H q
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-: g4 ^; \ M6 p
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
9 {3 N; G% S' L# b6 h, \& O" U4 `testosterone was 60 ng/dL (normal <3 to 10 ng/dL),$ G; M0 O" F3 {' T
and β-human chorionic gonadotropin was less than$ Y- `; t0 V4 M5 G' Y
5 mIU/mL (normal <5 mIU/mL). Serum follicular; O! } q2 b* W6 N% j# S2 i4 b
stimulating hormone and leuteinizing hormone
2 s p1 O$ E+ O8 wconcentrations were less than 0.05 mIU/mL
( d) G; `' m) N& R* H* ?(prepubertal).% Y7 @7 I7 b& W: w8 d$ J2 _+ J
The parents were notified about the laboratory
+ }2 _5 J( ?: N1 h1 Q' ?results and were informed that all of the tests were( @, c9 l6 K) U5 h' ^4 I( F
normal except the testosterone level was high. The# [$ s* R) [0 L4 K' B4 ^ [
follow-up visit was arranged within a few weeks to
8 d; x% k3 `! I; N, S' w. bobtain testicular and abdominal sonograms; how-
$ q9 h9 C& O/ q5 p' Bever, the family did not return for 4 months.
; {6 ~& W+ ]5 A7 e: q8 dPhysical examination at this time revealed that the
6 \6 Q# K8 m1 l/ G1 Cchild had grown 2.5 cm in 4 months and had gained
C8 l) T6 H: X, d$ n% l* E& O& ]( ~2 kg of weight. Physical examination remained) y% G Q) I) _- Y% F4 X- i. E* S
unchanged. Surprisingly, the pubic hair almost com-
6 G7 {9 e) S8 e9 S& t2 G2 @1 upletely disappeared except for a few vellous hairs at
# x& b& G: m5 P( v5 U4 z c7 @" vthe base of the phallus. Testicular volume was still 2
/ r; V2 |" Q$ ~$ ^# ?7 K/ ?4 m% pmL, and the size of the penis remained unchanged.9 X a' N' T* z/ Q) x
The mother also said that the boy was no longer hav-8 i, N# x9 s; t c& z
ing frequent erections.
5 M5 Z2 S9 s" G0 [2 J5 mBoth parents were again questioned about use of& U& [# B. q" T* z8 g/ ^6 e
any ointment/creams that they may have applied to9 ]2 d' a# B0 S* S& j' i
the child’s skin. This time the father admitted the5 V$ X1 \% }! {) p. @
Topical Testosterone Exposure / Bhowmick et al 541
7 z, q9 d2 O. T% i' w9 N. l; Iuse of testosterone gel twice daily that he was apply-0 g/ C0 C- |% I+ P( C4 }
ing over his own shoulders, chest, and back area for
, i9 {9 Z$ u# ra year. The father also revealed he was embarrassed2 `- q% X" g0 j
to disclose that he was using a testosterone gel pre-
( C" e1 j. S; t# Z, B) {0 C( L! W6 uscribed by his family physician for decreased libido
5 @& n% H, f' Dsecondary to depression.
8 p4 T& z, n" S( j) `The child slept in the same bed with parents.
# c4 j) Q, v. O- M0 W; P8 P1 \The father would hug the baby and hold him on his
0 X. G% s+ X4 M8 G# f; Vchest for a considerable period of time, causing sig-/ V8 n! v4 w" ]2 d6 b, `
nificant bare skin contact between baby and father.
, T! m1 [) s/ J" I& [. w& FThe father also admitted that after the phone call,
" b$ k- Q& o2 E3 t/ t2 o9 F4 Hwhen he learned the testosterone level in the baby
% P! G9 k( b- _, j1 pwas high, he then read the product information
% S9 m9 W6 N& M5 [6 V. d3 \packet and concluded that it was most likely the rea-
7 ^2 H9 N* B% j' N+ m5 hson for the child’s virilization. At that time, they/ U) D1 g" `. k
decided to put the baby in a separate bed, and the: Y" w: K/ L4 d; n1 }
father was not hugging him with bare skin and had
2 [( p' ^# L5 a7 D3 }been using protective clothing. A repeat testosterone9 A8 O. S) c2 Q# v& p8 I: ?
test was ordered, but the family did not go to the
) Q, ~" v% Y! S$ k/ X+ y$ ilaboratory to obtain the test.
% m: b% `# i, c: L! Z8 hDiscussion! O2 K( A* o' S2 N8 y
Precocious puberty in boys is defined as secondary
8 k9 j. { @6 V q, L: Fsexual development before 9 years of age.1,44 U- R' `+ z3 ]
Precocious puberty is termed as central (true) when: v" n! R5 v; e! W+ u
it is caused by the premature activation of hypo-
: e4 B6 C4 H J$ T; F H/ m x* Jthalamic pituitary gonadal axis. CPP is more com- }" r2 a# \% y! @$ f
mon in girls than in boys.1,3 Most boys with CPP
5 M) X' i; u- H2 zmay have a central nervous system lesion that is# v, l9 v, s# x n/ l4 c, b
responsible for the early activation of the hypothal-
- i/ ]( Q8 A5 X. I" xamic pituitary gonadal axis.1-3 Thus, greater empha-
0 v% b1 u* M; l: Q2 msis has been given to neuroradiologic imaging in2 |5 C: X r; ^& G8 a7 A
boys with precocious puberty. In addition to viril-: a2 T |! ?7 [. f9 j4 H
ization, the clinical hallmark of CPP is the symmet-
5 i W) a2 S9 ?/ I: Xrical testicular growth secondary to stimulation by
& j% V$ X: i( f0 r( @9 I' d) V1 ggonadotropins.1,35 u% [9 x/ V, g) J
Gonadotropin-independent peripheral preco-3 t6 ]+ q2 r2 V2 \
cious puberty in boys also results from inappropriate
! Q; n1 E) \1 v) b$ {1 Vandrogenic stimulation from either endogenous or5 @* y& F2 V) x0 M1 U
exogenous sources, nonpituitary gonadotropin stim-1 R! c: f) F* \
ulation, and rare activating mutations.3 Virilizing
* N4 U4 S# W( g8 j' xcongenital adrenal hyperplasia producing excessive( m# ] y2 i8 b* ]
adrenal androgens is a common cause of precocious
7 l. l% \4 Z# V) rpuberty in boys.3,4% k" t$ Y! R7 ?3 ]2 S5 E
The most common form of congenital adrenal) o0 |/ q. j+ ~9 h8 \& R
hyperplasia is the 21-hydroxylase enzyme deficiency.
& `0 h" x8 n9 _4 S0 R: J+ ^/ wThe 11-β hydroxylase deficiency may also result in
3 u0 u! t, Y" E/ h6 }; }excessive adrenal androgen production, and rarely,
: V. ]7 _1 ]$ ] K0 [& a. `an adrenal tumor may also cause adrenal androgen7 N2 r6 N% H$ S
excess.1,3
) L* [9 b M# y1 _8 V8 aat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from6 B+ t" e# f2 I {/ a, c
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
3 d C' i$ F4 c* kA unique entity of male-limited gonadotropin-# ?' A) q+ x; ?( N
independent precocious puberty, which is also known
Q$ [/ u9 h; B( T. L* Das testotoxicosis, may cause precocious puberty at a0 I/ k6 A& r2 ]+ A) E$ y. ]# d$ _
very young age. The physical findings in these boys& h2 N# T- i6 V
with this disorder are full pubertal development,
& I% |- S2 O& V$ d9 ^# Uincluding bilateral testicular growth, similar to boys
- J4 Y7 ]8 o3 R# T- x3 d( L8 uwith CPP. The gonadotropin levels in this disorder# q. x& [3 o+ q& l C- z/ f
are suppressed to prepubertal levels and do not show
; G7 K5 ], v) j9 ]& u/ Epubertal response of gonadotropin after gonadotropin-
7 z8 Y$ u6 p, X1 s+ V- Sreleasing hormone stimulation. This is a sex-linked7 w# V" n' q9 K% o" G3 [+ q: S* k
autosomal dominant disorder that affects only0 t$ o2 y9 H: N1 w9 }7 |3 a+ |4 ~5 \0 R
males; therefore, other male members of the family
4 u& [2 O& `& U1 t/ jmay have similar precocious puberty.33 o( A" s+ l' h- K) x
In our patient, physical examination was incon-
$ d( t9 i7 R o% i$ D% m7 U$ Lsistent with true precocious puberty since his testi-
; S; G( E+ M" o8 V2 P3 lcles were prepubertal in size. However, testotoxicosis) {0 o) J' e, t& K$ P) E7 z
was in the differential diagnosis because his father6 r% ]" K3 \) z' I4 |: k g
started puberty somewhat early, and occasionally,
/ K9 r4 ^( a5 Z: ~7 Utesticular enlargement is not that evident in the4 K0 B% }- _4 m, B
beginning of this process.1 In the absence of a neg-, T* {; A9 P: t1 B& {
ative initial history of androgen exposure, our
* Q* W* ~2 X2 N3 e: D4 x! `biggest concern was virilizing adrenal hyperplasia,5 Y9 E, p$ V+ N: G. [% ]
either 21-hydroxylase deficiency or 11-β hydroxylase
% J+ T9 x0 Q1 D- t; G7 T+ ~! N. }deficiency. Those diagnoses were excluded by find-
! j" {& k0 }5 c0 _ing the normal level of adrenal steroids.1 N6 v- f9 i* Z, x) g) V5 S+ h
The diagnosis of exogenous androgens was strongly
' I9 p3 Q" R( u0 S' W, Jsuspected in a follow-up visit after 4 months because
% v1 ^# s+ N7 Pthe physical examination revealed the complete disap-
. G, n, g7 V& ]* l5 Zpearance of pubic hair, normal growth velocity, and
7 ^5 a' i8 P7 I8 T% ]" f" Mdecreased erections. The father admitted using a testos-
- A7 u w9 m! Y! e( e+ P4 kterone gel, which he concealed at first visit. He was- ^, H; e7 H; W
using it rather frequently, twice a day. The Physicians’
; Q" z5 G0 n0 q5 `$ {Desk Reference, or package insert of this product, gel or
' a3 l! h$ w3 a4 f8 lcream, cautions about dermal testosterone transfer to
9 u4 V/ \* _ a- wunprotected females through direct skin exposure.
7 X! i, B2 j: Y- T, G9 v1 T8 ^Serum testosterone level was found to be 2 times the
5 m1 D$ g. J+ E( \* j9 y5 obaseline value in those females who were exposed to
# t; M+ T4 P. T2 ~) l3 K' l* deven 15 minutes of direct skin contact with their male: N; N3 r6 [$ e
partners.6 However, when a shirt covered the applica-
4 L6 i% M& X' A6 [, R' H: ution site, this testosterone transfer was prevented.
! F( D: K; j: q5 S( ?, KOur patient’s testosterone level was 60 ng/mL,
" f! T) A& y* {1 C0 ewhich was clearly high. Some studies suggest that2 s0 z/ v& Z: n' Q7 l3 K
dermal conversion of testosterone to dihydrotestos-9 A- t' b+ M. }# ]7 V
terone, which is a more potent metabolite, is more2 ?8 ]" Q& G; x8 B# k
active in young children exposed to testosterone! {+ G. n. W' S
exogenously7; however, we did not measure a dihy-) ` i9 k1 ^, P6 Y8 W# S x$ q
drotestosterone level in our patient. In addition to0 l* ?9 d& @3 r0 H
virilization, exposure to exogenous testosterone in
7 d \4 W3 V& K, a5 Hchildren results in an increase in growth velocity and: s+ E& M$ y1 e0 V
advanced bone age, as seen in our patient.
2 \& D! e8 C9 A. c. oThe long-term effect of androgen exposure during
0 T. x6 H( ~7 n8 w* _* J: }early childhood on pubertal development and final0 Q0 T j7 b% D" F: ] f
adult height are not fully known and always remain; g* M7 F1 h" H
a concern. Children treated with short-term testos-
0 u6 |! u/ M4 M- E- ^+ s. f7 dterone injection or topical androgen may exhibit some
: e8 C$ x$ Z3 G) R" iacceleration of the skeletal maturation; however, after
" d0 l: L, r {% h! A, n: fcessation of treatment, the rate of bone maturation
: e& |3 c* U& q2 q. x/ t. s) s, qdecelerates and gradually returns to normal.8,92 H% _5 r: \& ~# @; }- N! m& U$ M# E
There are conflicting reports and controversy
# C' \3 R: Q9 I: I1 s& s8 Wover the effect of early androgen exposure on adult
( r* q3 U# X: C* T! j* L0 v& Jpenile length.10,11 Some reports suggest subnormal# |9 E5 A, g7 n1 Q& K0 L( g
adult penile length, apparently because of downreg-
& W8 W, M# Z/ iulation of androgen receptor number.10,12 However,, s) a$ h/ e4 ~8 ^# w
Sutherland et al13 did not find a correlation between" ]/ }) Z4 e0 E0 b, S' G
childhood testosterone exposure and reduced adult5 [/ Q. Z {# L
penile length in clinical studies.
; a/ I5 j, T0 f/ ^- J4 X$ v7 M9 sNonetheless, we do not believe our patient is
9 G) J& W( C8 Ngoing to experience any of the untoward effects from7 U3 _- P, Q4 ~; i: d- D. h
testosterone exposure as mentioned earlier because8 {3 |# d, c" E1 y* n
the exposure was not for a prolonged period of time.
, G6 U1 U+ |( O# R/ V( V8 @4 uAlthough the bone age was advanced at the time of9 x) b4 Y2 W( \! h& ]
diagnosis, the child had a normal growth velocity at1 s9 r; u& M3 o* g
the follow-up visit. It is hoped that his final adult, A% [0 \- K! `9 ~/ M
height will not be affected.
; U3 a* x3 {0 X `Although rarely reported, the widespread avail-
$ M& |- @+ g- C/ Q$ w7 u* d0 ]ability of androgen products in our society may8 ]! B) v% V( v' x7 Z
indeed cause more virilization in male or female6 a' ^* \5 M% `, J. Z1 S
children than one would realize. Exposure to andro- W- X/ P2 Q7 `, p
gen products must be considered and specific ques-
7 t+ d6 K3 F- a ~, qtioning about the use of a testosterone product or
' S$ \0 }$ c& dgel should be asked of the family members during
/ x* M# Q" j. e, O/ t% S3 D7 A7 bthe evaluation of any children who present with vir-: f" t2 J& D) I3 h
ilization or peripheral precocious puberty. The diag-
! k9 U1 x, o0 a! enosis can be established by just a few tests and by, }( w; t; o' J3 C" |: b
appropriate history. The inability to obtain such a* Q# J) e6 x' g$ K% \1 v
history, or failure to ask the specific questions, may
- X4 l" e8 ^ ?5 r q% E( [, F, {+ Vresult in extensive, unnecessary, and expensive
9 ^; k$ V3 _% X$ C9 K( _9 Pinvestigation. The primary care physician should be
! r8 {/ Y% U$ A1 ?) u0 laware of this fact, because most of these children; M) u% j6 O5 C! ]6 g+ ?
may initially present in their practice. The Physicians’
: [! t' a9 ?4 X4 X- vDesk Reference and package insert should also put a
, v5 D1 h; z; N1 T: I% ewarning about the virilizing effect on a male or
) K/ S1 a. f9 @. ^8 K9 dfemale child who might come in contact with some-3 r" G: J7 ] b. T r7 S& X2 ]! P
one using any of these products.
) c& J* n3 ?# R" Q ]: R# b4 gReferences0 V/ M/ T: z: a9 ~: `
1. Styne DM. The testes: disorder of sexual differentiation
& X+ S& _* j5 U& ^and puberty in the male. In: Sperling MA, ed. Pediatric8 r* Z3 c8 n2 B; v+ N) }% z2 l; K# B
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;- T! f; E. M% C; A* w p3 X2 f
2002: 565-628.6 Q0 B! U9 J; Q
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious# d7 E* x' |6 g0 J {
puberty in children with tumours of the suprasellar pineal |
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