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Sexual Precocity in a 16-Month-Old
( Z* d9 n9 ]2 F. g6 ~Boy Induced by Indirect Topical. K" l! _: ? o. n8 @. Y
Exposure to Testosterone
) @( ]6 d1 M2 o6 r0 rSamar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2# x3 m! ~, w9 K1 q
and Kenneth R. Rettig, MD15 F2 ^5 k: ?; u% Y
Clinical Pediatrics$ l5 m/ X8 N, y0 d$ e: Q0 x# u
Volume 46 Number 6
3 Q6 U& H" k @$ O3 C6 X( e; |July 2007 540-543
' b# C4 L# _0 D: q4 `© 2007 Sage Publications
; y$ Y& z' [8 L6 W+ R8 C8 n- Y5 R10.1177/0009922806296651- l% y7 u |6 D$ X4 C4 m9 \6 J
http://clp.sagepub.com
+ x: L( s0 Y4 w) o4 \$ w/ ahosted at7 }1 u, W$ H8 W
http://online.sagepub.com
7 d7 i& m ~3 O3 u3 LPrecocious puberty in boys, central or peripheral,
V& @0 \& x3 }( ?9 V8 Nis a significant concern for physicians. Central) V7 q, O* c1 z( W
precocious puberty (CPP), which is mediated
, d9 ?* n7 S6 A% I: d) mthrough the hypothalamic pituitary gonadal axis, has
- h* K+ J) q) ~5 I# R, Oa higher incidence of organic central nervous system# @; Z* v8 }: b0 ~$ L
lesions in boys.1,2 Virilization in boys, as manifested
~ o+ \% q' A& Sby enlargement of the penis, development of pubic
, A8 x1 a( S3 N) i* Q: j# x* rhair, and facial acne without enlargement of testi-
% {2 x5 ~0 y: U6 dcles, suggests peripheral or pseudopuberty.1-3 We
9 I, h8 x# \& s( Greport a 16-month-old boy who presented with the
! m% v; _0 x: {0 I; K4 venlargement of the phallus and pubic hair develop-
8 \! A0 y8 B9 s1 hment without testicular enlargement, which was due
3 C* d+ R6 z7 D- S0 w) A3 Hto the unintentional exposure to androgen gel used by
( t2 N( }+ l; u0 V4 l1 L4 a1 {the father. The family initially concealed this infor-
. X5 ]& e6 W# F0 |8 N# E6 g) Emation, resulting in an extensive work-up for this0 h& d3 x2 i0 r* |+ F' T
child. Given the widespread and easy availability of
" T( W) T, o ~; wtestosterone gel and cream, we believe this is proba-
) J( i: u3 N& l3 R! Y. K" T( _5 Zbly more common than the rare case report in the! N+ f; O% l/ \: c+ H
literature.4
9 F. [+ }+ b0 Z* D8 O* \9 J+ FPatient Report
) W! P, k. c3 C; e4 qA 16-month-old white child was referred to the
7 _ U" I' @" ]* z3 aendocrine clinic by his pediatrician with the concern
) @3 J" K* z9 i0 Z }of early sexual development. His mother noticed6 ]6 D6 S, q. c) G- U- ^5 X
light colored pubic hair development when he was9 R7 ^- |0 n8 f V$ ^- L# y
From the 1Division of Pediatric Endocrinology, 2University of
4 k7 p( B! g4 a, v2 F- ^2 C+ TSouth Alabama Medical Center, Mobile, Alabama.
% n$ W+ Z1 W3 \/ I) WAddress correspondence to: Samar K. Bhowmick, MD, FACE,
7 D5 T7 j) ]! EProfessor of Pediatrics, University of South Alabama, College of
5 j D3 R0 x6 l. zMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
$ J; n/ W, d- k9 Q% P2 {e-mail: [email protected].
& D' m- w% {% _! H6 g2 ]0 a! L% Z7 Vabout 6 to 7 months old, which progressively became: h" I; ^' B* Y4 o. h6 Q
darker. She was also concerned about the enlarge-
$ O4 X/ W4 k- Z" Y. b5 ument of his penis and frequent erections. The child% B$ b" l0 i4 g7 d
was the product of a full-term normal delivery, with1 J6 V# N+ ?$ k3 [, t8 u/ x: z
a birth weight of 7 lb 14 oz, and birth length of
7 ]# B5 _$ C3 `2 n8 d) x20 inches. He was breast-fed throughout the first year
7 ~8 u a, s, @6 _" A6 U5 s& H3 k/ Vof life and was still receiving breast milk along with" E" R- L G0 o9 r/ n
solid food. He had no hospitalizations or surgery,1 v& O) i1 `/ K+ D' S
and his psychosocial and psychomotor development h6 u3 A4 z, F
was age appropriate.
( c- J e: I. Y7 R' \The family history was remarkable for the father,$ d% J. n k# E
who was diagnosed with hypothyroidism at age 16,
4 u4 [# q. _) n! n: D6 Cwhich was treated with thyroxine. The father’s
, Z: I3 V6 `5 W4 j% r# l' Xheight was 6 feet, and he went through a somewhat+ U$ q5 `2 I6 Z: C
early puberty and had stopped growing by age 14.- Z0 ?( V, T2 W1 U( k# _: u0 o8 T
The father denied taking any other medication. The
m3 W2 g8 v, e9 F" vchild’s mother was in good health. Her menarche+ y/ U) v5 t/ h a& s0 ?; t
was at 11 years of age, and her height was at 5 feet
+ f; ?2 o1 a* ]) o% p& L5 inches. There was no other family history of pre-$ \# O7 w; Y9 G2 Z
cocious sexual development in the first-degree rela-
6 B7 p9 n3 J( Ktives. There were no siblings.- ^7 w$ `* V# l2 K
Physical Examination
; I0 F+ n' _- P5 V, ~$ I" `The physical examination revealed a very active,
& [: r% Y$ g, A# i. Z; M& i$ E; dplayful, and healthy boy. The vital signs documented' a& [" J! X+ X6 i w; [
a blood pressure of 85/50 mm Hg, his length was
) v5 Z% ~ A7 \5 s$ a90 cm (>97th percentile), and his weight was 14.4 kg: c1 f8 J& E/ y' G8 }
(also >97th percentile). The observed yearly growth
_& {* w5 H5 F6 e3 w( u% Y, _' bvelocity was 30 cm (12 inches). The examination of
$ ]( _4 t) L) ?: ythe neck revealed no thyroid enlargement.
; C9 V. S) ^5 N \4 s% J0 A- bThe genitourinary examination was remarkable for3 @% v) Y0 x: y* d) z
enlargement of the penis, with a stretched length of
8 {" L$ }7 d" j, z$ ^) P: S1 t2 g8 cm and a width of 2 cm. The glans penis was very well
& i- L/ \; l: o- C( ydeveloped. The pubic hair was Tanner II, mostly around; c# o# j, C4 \
540
4 G* C' B% X0 P" D I, oat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from- b/ K. x4 j4 D
the base of the phallus and was dark and curled. The
6 _- e# |# f( z J) R# o. Atesticular volume was prepubertal at 2 mL each.
1 y5 H6 J* ]# K) n0 F( vThe skin was moist and smooth and somewhat
/ s# U& H( Y% y/ L' m( Y/ D( y2 uoily. No axillary hair was noted. There were no
6 `8 s* { H. X* y: r1 ]abnormal skin pigmentations or café-au-lait spots.
+ N" u* _8 p5 N3 w0 y( rNeurologic evaluation showed deep tendon reflex 2+' W& H! M1 i2 T: w8 d
bilateral and symmetrical. There was no suggestion# A$ l2 e9 L8 _0 h; I
of papilledema.
# z( e3 k+ Y( z. K& n+ B4 }7 QLaboratory Evaluation
- e4 w, {9 K y% [8 G3 \The bone age was consistent with 28 months by
) h( K% D2 b/ [) e1 k5 k% ], Nusing the standard of Greulich and Pyle at a chrono-% B* T+ Z" Y# q8 R' X1 m6 U$ ]) c
logic age of 16 months (advanced).5 Chromosomal
. P& J" M* e; V7 j5 }, k* J& T" ukaryotype was 46XY. The thyroid function test
' O5 [2 ?" ~+ d+ u/ l& k& B( fshowed a free T4 of 1.69 ng/dL, and thyroid stimu-7 P5 [8 G w- e2 k" I. b
lating hormone level was 1.3 µIU/mL (both normal).
4 w' L4 p' l* d$ V) u$ BThe concentrations of serum electrolytes, blood, I% |) W6 |( v5 X- y" x
urea nitrogen, creatinine, and calcium all were
! _8 ~( j9 {4 Mwithin normal range for his age. The concentration& E# A0 X4 L4 u5 E9 k/ k% f7 T
of serum 17-hydroxyprogesterone was 16 ng/dL( j& V0 G8 O' ^$ ]( c
(normal, 3 to 90 ng/dL), androstenedione was 20
" [9 R- |( Q: t! a+ @ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
0 Z$ x* j/ ~4 Z; [$ p, Aterone was 38 ng/dL (normal, 50 to 760 ng/dL),
8 S& f9 m$ b+ Wdesoxycorticosterone was 4.3 ng/dL (normal, 7 to' {3 r, u( Z, }# L
49ng/dL), 11-desoxycortisol (specific compound S)
. g- s5 g/ y% ~was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-/ w5 v, q. Z9 i8 D6 R$ M
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total) B9 }, O& @! ^
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),3 {% W% o5 q& l0 |; u! z6 N
and β-human chorionic gonadotropin was less than
- Z1 ^7 o2 B s( P9 A# w6 U6 B5 mIU/mL (normal <5 mIU/mL). Serum follicular
. S+ i2 O; J1 a+ ]. ustimulating hormone and leuteinizing hormone
* m9 D9 Q t& C/ d: Zconcentrations were less than 0.05 mIU/mL( T5 W2 ~) {* z. H! ]
(prepubertal).' G ~: m M' I! p: u" i9 _- ]
The parents were notified about the laboratory
2 N$ x! \6 v4 J( presults and were informed that all of the tests were3 {. m c1 y3 c
normal except the testosterone level was high. The
* v! a+ O E/ E1 W6 xfollow-up visit was arranged within a few weeks to
5 t1 q( x3 }, n7 o- pobtain testicular and abdominal sonograms; how-
: }& H, Y7 [* H9 vever, the family did not return for 4 months.5 J2 s: J9 C! {
Physical examination at this time revealed that the( u% c. z# U1 u2 o/ c: E0 Q
child had grown 2.5 cm in 4 months and had gained
r% `6 `1 i4 J' k2 kg of weight. Physical examination remained% P' D! ]4 V! D* F# J
unchanged. Surprisingly, the pubic hair almost com-$ b+ H% z8 B I) y+ y" H2 e
pletely disappeared except for a few vellous hairs at
. C8 f3 K( w7 t! Pthe base of the phallus. Testicular volume was still 2* `3 g& e# I, g% Y8 @. y, I
mL, and the size of the penis remained unchanged." N0 R7 z* c. Y
The mother also said that the boy was no longer hav-/ R8 q, M" C G& T
ing frequent erections.( v% m2 v( N% L5 p% B' ]
Both parents were again questioned about use of
8 x8 V6 z% h& @, s( `8 vany ointment/creams that they may have applied to
s U4 T% V$ j& l4 \the child’s skin. This time the father admitted the: V5 T) l. E" t
Topical Testosterone Exposure / Bhowmick et al 5410 |5 y6 V3 m( k8 R) L; \7 O" P# L
use of testosterone gel twice daily that he was apply-
9 n5 Y6 T3 |& H3 king over his own shoulders, chest, and back area for
* t! |( { L% z) [) Z$ sa year. The father also revealed he was embarrassed
( H, {/ J0 t6 }+ X6 S! m: p/ nto disclose that he was using a testosterone gel pre-# e+ r9 v" j0 f- b6 t) D3 t q/ t
scribed by his family physician for decreased libido
) y$ \5 r; O$ csecondary to depression.
$ H& D8 U$ B6 _# }' zThe child slept in the same bed with parents.
( f) I, T- f' g$ K5 jThe father would hug the baby and hold him on his$ P) W. C; q3 s: K" J q
chest for a considerable period of time, causing sig-
+ C8 u5 ], \6 R2 d; H2 \0 E) S) }nificant bare skin contact between baby and father.
& `: D+ x: v% S0 Q& bThe father also admitted that after the phone call,
7 \2 @4 H& F# p! a- hwhen he learned the testosterone level in the baby" V Y6 M0 J* Y0 d [. ]
was high, he then read the product information
0 _0 a' W4 |0 F/ ^packet and concluded that it was most likely the rea-
, K& `: @" j M1 W$ _' oson for the child’s virilization. At that time, they# m. O7 l) j$ S9 N6 D+ l& ~1 |2 `$ _
decided to put the baby in a separate bed, and the3 q5 ?8 X& o7 v, n) l8 G
father was not hugging him with bare skin and had$ J; K3 C6 S( p4 K, r3 C0 f
been using protective clothing. A repeat testosterone
9 T7 B- ^1 F+ ]# h& D( @test was ordered, but the family did not go to the
! I9 @& |9 m- V8 ]laboratory to obtain the test.5 G$ \) O8 Q1 R0 p. |
Discussion
% Q7 M" @& j0 i. k/ S" s% w! `( j( HPrecocious puberty in boys is defined as secondary7 v) X' d! o: j2 B& x4 f2 [
sexual development before 9 years of age.1,4
1 _$ g/ @! v( W' G3 dPrecocious puberty is termed as central (true) when0 A. p4 E3 `* w
it is caused by the premature activation of hypo-
# s( V; J5 Z1 u0 C8 ]thalamic pituitary gonadal axis. CPP is more com-4 T z( X4 U3 C; d+ R
mon in girls than in boys.1,3 Most boys with CPP$ c, m) I9 ]1 h, L
may have a central nervous system lesion that is t' u" d( v8 m8 U# G2 S1 v r
responsible for the early activation of the hypothal-/ T# @1 b! q) k* |
amic pituitary gonadal axis.1-3 Thus, greater empha-6 e% B9 E7 q$ p( L9 S( q
sis has been given to neuroradiologic imaging in
4 @) O; j8 L! D$ fboys with precocious puberty. In addition to viril-3 C3 c6 L* D$ n5 N* {0 S
ization, the clinical hallmark of CPP is the symmet-
7 ]4 \& o% K K% `8 H. ?rical testicular growth secondary to stimulation by
6 ^/ y R7 H/ g5 |gonadotropins.1,3+ m7 W+ x3 F6 G5 b% i" e1 X
Gonadotropin-independent peripheral preco-; E7 X* b, J9 b3 i0 M3 Q4 s
cious puberty in boys also results from inappropriate# ~6 v: B9 j6 h' Z; s" g. m/ D
androgenic stimulation from either endogenous or' ~ o! x7 M. l6 G4 O1 k
exogenous sources, nonpituitary gonadotropin stim-
: ~1 a s* K _ulation, and rare activating mutations.3 Virilizing' p7 Y0 w: j1 g. X9 R! Q
congenital adrenal hyperplasia producing excessive
) T0 [& L. d$ N, \: Sadrenal androgens is a common cause of precocious
9 F7 s$ C! j: @$ X" R2 A( tpuberty in boys.3,4& R: z0 E% k( O) h3 O
The most common form of congenital adrenal) a7 q4 G/ n& m- d7 H9 ~& |9 H
hyperplasia is the 21-hydroxylase enzyme deficiency.
& @) ?. {' O. a) j* JThe 11-β hydroxylase deficiency may also result in& W& J+ v& Y: g* x
excessive adrenal androgen production, and rarely,7 ~" H; b7 S/ q+ g! H) x1 |
an adrenal tumor may also cause adrenal androgen A' d* Y* q& g7 G5 u6 U+ ~
excess.1,36 `9 n1 {! M7 w
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
# E5 U1 V# ^: V0 i; G- d0 E1 A542 Clinical Pediatrics / Vol. 46, No. 6, July 2007/ ?9 O/ X5 L2 A7 K- g* G b
A unique entity of male-limited gonadotropin-
) S* G" g( J. C" C; Eindependent precocious puberty, which is also known" P7 U: C+ _$ @/ _# C2 T. K
as testotoxicosis, may cause precocious puberty at a }# v/ Z, P) P4 q
very young age. The physical findings in these boys
6 N/ A1 U0 y4 ]2 @. D3 ~with this disorder are full pubertal development,
, h6 w) n5 C8 m- x3 E; hincluding bilateral testicular growth, similar to boys
0 ~3 i7 [) @9 ?3 nwith CPP. The gonadotropin levels in this disorder( ~# Y" j8 `/ M+ `( B
are suppressed to prepubertal levels and do not show7 D1 G# D$ \& G6 c! L* A/ W P I
pubertal response of gonadotropin after gonadotropin-
" X, J+ ?+ B0 F4 F3 F+ ereleasing hormone stimulation. This is a sex-linked
2 z% u. ^' R. _2 V) _4 u, S" E' b( |autosomal dominant disorder that affects only
) \4 g) T, g. ]: k8 q) Hmales; therefore, other male members of the family# Z: u: Z+ Y7 \; D. {: L
may have similar precocious puberty.3! C# Y, Y% c [, ^9 l
In our patient, physical examination was incon-% l+ K+ ?" l2 K5 ? \. e9 c
sistent with true precocious puberty since his testi-
) z$ t1 {+ G2 G% ncles were prepubertal in size. However, testotoxicosis/ n8 O; l0 B0 G% A4 |4 ?, a
was in the differential diagnosis because his father" G9 @$ _; Z o, z) w. x, |
started puberty somewhat early, and occasionally,
0 q) E2 s ]4 _7 Etesticular enlargement is not that evident in the
9 Q: l6 B' V% ^. P. Kbeginning of this process.1 In the absence of a neg-
4 C* ]6 `+ o1 ~; n+ o# l( z) g) wative initial history of androgen exposure, our4 O0 ]* X a6 a+ j5 {
biggest concern was virilizing adrenal hyperplasia,+ b8 u" E8 X& B( l
either 21-hydroxylase deficiency or 11-β hydroxylase
n8 G2 [: n6 l; O2 {deficiency. Those diagnoses were excluded by find-
8 s" t2 ?# ^8 I U6 I' Q4 Uing the normal level of adrenal steroids.
- n- c/ z; e( }The diagnosis of exogenous androgens was strongly/ R2 ^5 w5 S6 D+ w0 H: J' N
suspected in a follow-up visit after 4 months because
' m( M% t# R6 B9 s8 ^the physical examination revealed the complete disap-
& H- s" Q: D- M: Y- U3 [, N- @pearance of pubic hair, normal growth velocity, and
( E3 Z" P2 o! D1 z2 `9 _+ k- z5 udecreased erections. The father admitted using a testos-1 s* N) y6 P, a* h" W
terone gel, which he concealed at first visit. He was
# D8 I2 w: d, {) _ i9 e Yusing it rather frequently, twice a day. The Physicians’( C, i* _* X2 K& M
Desk Reference, or package insert of this product, gel or9 S5 `- p1 m4 Y
cream, cautions about dermal testosterone transfer to' b. o- Y, h) o1 F, A1 P
unprotected females through direct skin exposure.
8 e) r4 U1 J" r1 j2 N8 [Serum testosterone level was found to be 2 times the! ]9 l" i! @% u" b3 E1 j- O0 C
baseline value in those females who were exposed to
" R0 R% j9 i) l+ L5 W `% v/ Teven 15 minutes of direct skin contact with their male
2 E5 ^& b; J cpartners.6 However, when a shirt covered the applica-% \% M; B" ^: A; g" f
tion site, this testosterone transfer was prevented. A7 y# C G1 z: l
Our patient’s testosterone level was 60 ng/mL,
# Q3 P/ ~9 K) C5 T* e5 V& _/ ?which was clearly high. Some studies suggest that
3 n$ P4 Y: t9 h( o9 {6 g9 idermal conversion of testosterone to dihydrotestos-
4 ~+ R% M1 Y$ D4 o8 w6 T% \terone, which is a more potent metabolite, is more: G8 o b8 z8 T+ z+ ~; C
active in young children exposed to testosterone
, @! ?' f) ]. z* ~exogenously7; however, we did not measure a dihy-5 a1 w! ]( C3 A/ T' E4 k) E
drotestosterone level in our patient. In addition to
* s, u' y' i+ u5 J' Q; U5 Nvirilization, exposure to exogenous testosterone in+ T. H/ o# i& I( a1 m
children results in an increase in growth velocity and2 e/ X1 \. @( B2 \3 T. N
advanced bone age, as seen in our patient.! s9 I' e/ ~" _) f
The long-term effect of androgen exposure during+ k6 `1 _. u3 ?
early childhood on pubertal development and final: \4 s( Z P9 c6 f; {+ Z8 C
adult height are not fully known and always remain+ H& H! U) C2 z% D, m( D3 u
a concern. Children treated with short-term testos-- l. f! T" c2 B- ~% b
terone injection or topical androgen may exhibit some
; G/ k: [6 L3 ?" A/ O# Xacceleration of the skeletal maturation; however, after
~3 c% ]4 }" {4 Q" s) ecessation of treatment, the rate of bone maturation
T) y8 n! p: y: @decelerates and gradually returns to normal.8,9! g/ S# |" `9 K5 D
There are conflicting reports and controversy
3 x, N% Q, y5 ]3 I6 M1 ]" Sover the effect of early androgen exposure on adult
4 V. n) s+ z ipenile length.10,11 Some reports suggest subnormal
7 |3 P& R+ M) x5 A8 Vadult penile length, apparently because of downreg-+ J! P. l, d5 ]3 |
ulation of androgen receptor number.10,12 However,# T. W. J) U8 g
Sutherland et al13 did not find a correlation between
( Y" v2 } ]6 ?" z d8 f1 jchildhood testosterone exposure and reduced adult+ K- b2 B1 @9 {/ ^
penile length in clinical studies.' [* I! o4 |% m# S+ u) b
Nonetheless, we do not believe our patient is
3 a X6 d. R$ n% z& k5 Ogoing to experience any of the untoward effects from# x- N5 z, f. D, c
testosterone exposure as mentioned earlier because+ C0 ]! v1 Q* H) p6 P$ _) I: Z$ l
the exposure was not for a prolonged period of time.. C' r# w3 a4 r( r8 }* i
Although the bone age was advanced at the time of
' z* P2 M$ d4 h/ z+ L3 Vdiagnosis, the child had a normal growth velocity at0 |" K+ H: h' b) o9 r9 k
the follow-up visit. It is hoped that his final adult
1 U) y' J( _; e/ r% i* ?2 D/ F# P1 hheight will not be affected.
: S8 N" F' g9 J/ |Although rarely reported, the widespread avail-: C' Y3 _; x* L' }6 _( U$ E
ability of androgen products in our society may/ F& _2 Y. I: e# W! o, a. y1 D
indeed cause more virilization in male or female
g, V0 M! F( zchildren than one would realize. Exposure to andro-4 P, c6 U9 V4 B$ |' K, L
gen products must be considered and specific ques-
/ {" u8 g! Z" s9 |3 @" m" z ftioning about the use of a testosterone product or
* ^4 }' ]- v" M, Vgel should be asked of the family members during0 M4 z% j8 k- h* \: V
the evaluation of any children who present with vir-9 x; n8 v9 q \: q$ c! M, O o9 q7 ^
ilization or peripheral precocious puberty. The diag-5 Z. ?) o9 X8 p. L
nosis can be established by just a few tests and by
9 [$ w$ T& s$ v* eappropriate history. The inability to obtain such a
# z4 U! B' m" H6 Whistory, or failure to ask the specific questions, may* ^: C: |6 |1 W! b% _' `! q
result in extensive, unnecessary, and expensive, w( D4 G) s3 r9 s; @5 v) Q. r
investigation. The primary care physician should be
+ O- J R% M9 {- W. I; M+ V) saware of this fact, because most of these children
( s$ c. k' t3 L& @& f: Ymay initially present in their practice. The Physicians’
. I( ~+ ^# Q- YDesk Reference and package insert should also put a
m" m, m4 r, u4 x9 m, g( n+ E1 hwarning about the virilizing effect on a male or
4 F4 x3 b- C0 Y1 g9 a) gfemale child who might come in contact with some-
- U6 d0 e- f. B" ]+ c" G1 l, d; Fone using any of these products.
7 z9 Y0 w2 u+ C& c- a/ [References0 m: }# F2 W% F5 S* J% ~4 R8 j
1. Styne DM. The testes: disorder of sexual differentiation2 p3 y8 \+ G) D3 {
and puberty in the male. In: Sperling MA, ed. Pediatric4 D( q7 W+ b8 Z1 W) n$ N+ C( G8 ^
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
& Z: H* N ?/ U4 a' w2002: 565-628.( f. { W; Q2 R% ?
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious. C" s# g5 _$ z' {0 `# K% ?
puberty in children with tumours of the suprasellar pineal |
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