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Sexual Precocity in a 16-Month-Old% L6 r9 _ t- q6 d! q/ l
Boy Induced by Indirect Topical7 x8 o. S) u$ ~9 t- U
Exposure to Testosterone3 w. H3 W- C, X8 v) A
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2! R8 r& m3 R. B) I: J; O
and Kenneth R. Rettig, MD12 D, _; _/ K" e6 B8 f# k
Clinical Pediatrics1 s- ~1 j3 B T8 Q# e
Volume 46 Number 6
g3 x, z6 N$ C* [' hJuly 2007 540-543% I' `- F+ E$ y8 z) y% ^. i+ ?9 V, V
© 2007 Sage Publications
* c6 q6 P2 @, ?, V/ k. M10.1177/00099228062966517 m% g+ J0 F3 d9 m4 H( B2 j; p
http://clp.sagepub.com% v' v1 q4 s! O5 j! u
hosted at* n2 l7 ?+ r7 l% M
http://online.sagepub.com
( R) F5 g, S* XPrecocious puberty in boys, central or peripheral,
% b8 B, R: X6 Y1 c. m: c* x2 mis a significant concern for physicians. Central+ c1 p- R% B \0 W. d
precocious puberty (CPP), which is mediated
& p1 q2 _. q* N. r7 J- h: Kthrough the hypothalamic pituitary gonadal axis, has
* L; D4 a3 x. w# }' d* A- O7 `& Qa higher incidence of organic central nervous system
. j7 u) d. t: N2 u. P7 f H' qlesions in boys.1,2 Virilization in boys, as manifested
3 ~5 \8 a9 N8 w2 {' y# l% R6 mby enlargement of the penis, development of pubic
6 R9 \. @. Y. V' t6 `, G9 f/ Hhair, and facial acne without enlargement of testi-
$ x, h0 c" l; ncles, suggests peripheral or pseudopuberty.1-3 We
) T$ I" A+ ^1 b' J3 Ereport a 16-month-old boy who presented with the6 A0 v! p8 H& g3 p: m, W
enlargement of the phallus and pubic hair develop-6 `" V: y, e: [% M) [
ment without testicular enlargement, which was due
- x8 K2 z% f2 j' vto the unintentional exposure to androgen gel used by
( o8 |: w" @) S7 ?% ithe father. The family initially concealed this infor-
" Q/ |. A% D; o7 S2 `6 x: K3 `8 dmation, resulting in an extensive work-up for this4 d# C. [4 W% q; `( V+ Z* t( w4 L5 m
child. Given the widespread and easy availability of
- ]" X: x0 x6 s. g# k O% Y Ftestosterone gel and cream, we believe this is proba-
9 e7 \( C* W" E* ^1 j5 \2 Jbly more common than the rare case report in the
" |; ]3 P) e; i8 a& O" u5 Z' vliterature.4; ~ R% C# u3 G% F! x% f
Patient Report) | ?0 s6 u1 C" T! h1 K, P% B
A 16-month-old white child was referred to the
4 Q8 k- }& ~' z9 [2 X) t, i, pendocrine clinic by his pediatrician with the concern, f$ y* S8 f) G1 W4 T9 }
of early sexual development. His mother noticed6 N7 F' a' b% {( Z% s$ r
light colored pubic hair development when he was
3 p6 v# T' a1 [+ E4 C4 o. A$ TFrom the 1Division of Pediatric Endocrinology, 2University of3 `- N, l+ O: b$ ~* U
South Alabama Medical Center, Mobile, Alabama.
( o; X; k$ F6 j4 B5 dAddress correspondence to: Samar K. Bhowmick, MD, FACE,$ k& n/ b$ L/ g1 F* R
Professor of Pediatrics, University of South Alabama, College of
' [, ?2 X% B' q$ D' B* nMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
2 O# B) d. B9 E! S" Qe-mail: [email protected].
( H7 y2 W/ v0 s1 e* X) T Gabout 6 to 7 months old, which progressively became
1 x3 k; f% P, K2 L" w% V3 Mdarker. She was also concerned about the enlarge-
/ l; W- S, W, I/ W# o% J* O5 ]& Yment of his penis and frequent erections. The child2 G% _8 V! r8 k( ~: K
was the product of a full-term normal delivery, with7 ]( D1 C" w' l+ L4 | j" I
a birth weight of 7 lb 14 oz, and birth length of
" g% v/ K" Z. r+ Q20 inches. He was breast-fed throughout the first year
7 j: E' j, ^! f+ Gof life and was still receiving breast milk along with- i! W7 F7 T4 u/ p K/ A& _5 n* ]
solid food. He had no hospitalizations or surgery,
8 p( w/ O5 K. X6 [7 Z& f3 ?and his psychosocial and psychomotor development
5 d L9 L- O& L7 C* V; Fwas age appropriate.4 c4 m6 Y. | O
The family history was remarkable for the father,
+ M4 _6 B, u9 l' {1 nwho was diagnosed with hypothyroidism at age 16,
8 z$ [7 I( s7 U+ h7 j0 z b0 B$ w mwhich was treated with thyroxine. The father’s
! i: p# }' _; K" s+ s0 [1 dheight was 6 feet, and he went through a somewhat/ F/ v. _. G0 j: }. d \
early puberty and had stopped growing by age 14.
( X# Z% N! U: v8 }' gThe father denied taking any other medication. The4 @3 Y- i% {0 C9 | c; k
child’s mother was in good health. Her menarche* d4 H3 w2 W* K, J# m
was at 11 years of age, and her height was at 5 feet
; Q9 }& } ?2 {5 inches. There was no other family history of pre-
* m% t. y+ Y5 R& t7 K1 n: |% k7 E/ Gcocious sexual development in the first-degree rela-6 W9 t+ M# i7 g
tives. There were no siblings.
* E( G* p' j2 A3 d# f5 FPhysical Examination$ S F! _ `- Z) Z- C
The physical examination revealed a very active,
4 {- D* V0 l/ y# N. o3 S+ Cplayful, and healthy boy. The vital signs documented
3 ~# X' Q1 j) {3 U( va blood pressure of 85/50 mm Hg, his length was, M M- G- ?7 Y& w2 v) i5 g
90 cm (>97th percentile), and his weight was 14.4 kg( P) X( p! ]* f$ `
(also >97th percentile). The observed yearly growth
1 r, {' T+ P- j: K) q' Z% vvelocity was 30 cm (12 inches). The examination of! _1 q) S, h, |/ R
the neck revealed no thyroid enlargement./ [/ b- i8 @ G; K" ]+ n; `
The genitourinary examination was remarkable for7 Z' A5 r1 e7 e
enlargement of the penis, with a stretched length of* Z4 K0 X) `" \: \
8 cm and a width of 2 cm. The glans penis was very well
. T! m& s c- b* r, D+ v% ?5 ]developed. The pubic hair was Tanner II, mostly around5 l* M. p+ d6 ?" c! V
540
, C3 Y( m8 G, v8 aat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
( L- s. N+ m' `6 \+ z+ Z' Zthe base of the phallus and was dark and curled. The
2 |, l0 G+ `* vtesticular volume was prepubertal at 2 mL each.; Z' G" X9 I0 o
The skin was moist and smooth and somewhat* w% D9 s: Y! v' c4 J+ D
oily. No axillary hair was noted. There were no% F' n/ d' l- d2 c) u8 k9 J
abnormal skin pigmentations or café-au-lait spots.1 ~- F7 L: K# {8 g
Neurologic evaluation showed deep tendon reflex 2+: Z6 I& f8 e x- @" r6 ^
bilateral and symmetrical. There was no suggestion" F: W! o5 i7 {
of papilledema.
+ M, ~& A: w- c( nLaboratory Evaluation
1 [. |$ Y+ Y- Q# A! ]The bone age was consistent with 28 months by: ]4 v' f( D+ [: A( d9 p7 d
using the standard of Greulich and Pyle at a chrono-
- _* m$ R, k4 V, r% hlogic age of 16 months (advanced).5 Chromosomal
& x. p5 M& @. _# V# D2 r, pkaryotype was 46XY. The thyroid function test
/ d1 m- u m; k1 h0 b9 b. ~showed a free T4 of 1.69 ng/dL, and thyroid stimu-
+ M9 ]$ q9 M: ?( Nlating hormone level was 1.3 µIU/mL (both normal).
/ {7 R2 f# L( BThe concentrations of serum electrolytes, blood
" n4 e+ q3 J4 w( @urea nitrogen, creatinine, and calcium all were/ n1 D: l% B/ K1 c
within normal range for his age. The concentration
' u% v* u' _7 g6 [9 pof serum 17-hydroxyprogesterone was 16 ng/dL# ?# f) n' o$ [. o& T
(normal, 3 to 90 ng/dL), androstenedione was 20
! [& B* W2 t3 M+ d" ^' q( Bng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
^# W$ o# E1 a8 ?. B7 I3 B( x% ?: Fterone was 38 ng/dL (normal, 50 to 760 ng/dL),) t/ P( B0 b {7 }- }, N
desoxycorticosterone was 4.3 ng/dL (normal, 7 to
0 ]; G9 u& `( [ ?; J+ e49ng/dL), 11-desoxycortisol (specific compound S)/ M, K$ p0 d- T I2 a
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-1 W" B) O' d; @$ g( w' l; g
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total, A+ b0 ~) |8 p3 u ^% Z
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),7 p* X- {! R8 R7 j9 i: T
and β-human chorionic gonadotropin was less than- ]4 `3 V( K O5 i% D5 m7 h# L
5 mIU/mL (normal <5 mIU/mL). Serum follicular
& E4 R' H" B1 C! Istimulating hormone and leuteinizing hormone
" {- L6 v5 q0 ~0 l3 K: R Y mconcentrations were less than 0.05 mIU/mL' l; H) A* b x/ O
(prepubertal).
g \1 r( s( kThe parents were notified about the laboratory! ^& F& P- S2 A" Q
results and were informed that all of the tests were, e3 p0 ]$ i V
normal except the testosterone level was high. The
3 G; Z- z3 x7 {" v/ Bfollow-up visit was arranged within a few weeks to
" l0 a8 ^7 |$ R% M* gobtain testicular and abdominal sonograms; how-
, n4 m+ v- q$ f; Never, the family did not return for 4 months.
1 i/ \ o7 \7 Q0 f* y. a* GPhysical examination at this time revealed that the( ~( O9 p' k2 X- J, K/ M
child had grown 2.5 cm in 4 months and had gained
' X0 g5 U% }; Z6 a! {' I6 x2 kg of weight. Physical examination remained4 M/ t9 ]; c- @4 _( }
unchanged. Surprisingly, the pubic hair almost com-2 r1 B. r, ]2 p. e) y8 C
pletely disappeared except for a few vellous hairs at
0 m# M, w) l/ M Othe base of the phallus. Testicular volume was still 2. x, {2 X! p4 V& S3 Y
mL, and the size of the penis remained unchanged.* B* f3 x. R* q% ~3 X2 H
The mother also said that the boy was no longer hav-! E8 j. u3 w4 W! ^" C& L3 k; B
ing frequent erections.! \* f7 l0 }% O% N3 \8 L2 h# q
Both parents were again questioned about use of
' l% N z* a8 o. `; D- p, o0 q. m2 a6 v$ hany ointment/creams that they may have applied to3 ]+ W. H* p+ b9 d# U$ H
the child’s skin. This time the father admitted the
/ v0 p! g: t4 G+ n) KTopical Testosterone Exposure / Bhowmick et al 541: [" n( i' O1 I" c$ l: @
use of testosterone gel twice daily that he was apply-
" p, I) S2 R, x1 g8 Z @, W {ing over his own shoulders, chest, and back area for
$ G# F2 ~- f) J1 y- v/ P' }& ^6 [a year. The father also revealed he was embarrassed
( E- q/ W5 w, D' Hto disclose that he was using a testosterone gel pre-9 Q8 w, s3 {7 U# R- e9 G1 @+ y# g2 X
scribed by his family physician for decreased libido
2 |' e/ G5 {, F6 @secondary to depression.: v- E( Y$ h' |; V9 c
The child slept in the same bed with parents.
$ _% G: M3 m- w0 K4 uThe father would hug the baby and hold him on his* m7 Y2 h# ~4 |( L' b
chest for a considerable period of time, causing sig-
- \! L) p8 w0 M. G6 ]" x0 T7 xnificant bare skin contact between baby and father.
7 K: t+ q1 R1 A& o( y% Z- I" \The father also admitted that after the phone call," N+ a& b6 e1 b$ P$ A W
when he learned the testosterone level in the baby
- \" Y0 g+ P. a7 @, twas high, he then read the product information
, {1 I' V% j7 y; l8 ipacket and concluded that it was most likely the rea-3 u$ w% e( m9 `& b. G% v
son for the child’s virilization. At that time, they1 j; ^, q8 N9 I6 B2 o: q
decided to put the baby in a separate bed, and the
- j& O( g0 T2 y4 s Mfather was not hugging him with bare skin and had% Y8 ~2 |9 F* @* X% k5 e' f. }
been using protective clothing. A repeat testosterone0 E5 q G C+ b7 z4 @5 v$ {
test was ordered, but the family did not go to the
) r1 b( R9 `: E" n5 Jlaboratory to obtain the test.
: n2 [) v1 |8 s9 @6 F. pDiscussion c0 o# N u z q/ F+ c* ~# Y
Precocious puberty in boys is defined as secondary0 Q- ^- Z% P* i7 I
sexual development before 9 years of age.1,4
) \" h: E& h! m6 ~4 H! D$ F" fPrecocious puberty is termed as central (true) when2 x" X8 Q8 Z+ s1 }* n
it is caused by the premature activation of hypo-) d; H [ C9 u; c! K. S/ k* ]- a
thalamic pituitary gonadal axis. CPP is more com-
1 V4 P3 ~9 \, `+ K. Dmon in girls than in boys.1,3 Most boys with CPP7 c4 L/ y" q7 f* x/ g8 v; g
may have a central nervous system lesion that is( k* A& z2 g( E- K/ q6 { ?" d
responsible for the early activation of the hypothal-2 E4 G ~1 F) L- d$ {
amic pituitary gonadal axis.1-3 Thus, greater empha-
; o! r0 [2 q' h: i/ \" Nsis has been given to neuroradiologic imaging in4 C1 i' S3 S, R$ i/ m% q
boys with precocious puberty. In addition to viril-& I8 H0 F P" f) X$ l) k
ization, the clinical hallmark of CPP is the symmet-
; p& O$ H; N5 w# frical testicular growth secondary to stimulation by4 ?- c' |) S! M! O. Y
gonadotropins.1,39 \3 Q) m$ W& N- h, x0 v
Gonadotropin-independent peripheral preco-
0 l0 Z+ d u2 J6 V% ]# ~cious puberty in boys also results from inappropriate
' Y) D8 G' Q! T* Qandrogenic stimulation from either endogenous or
6 K- B c$ d8 s6 @* R* q& Mexogenous sources, nonpituitary gonadotropin stim-
; A- u: M: A3 zulation, and rare activating mutations.3 Virilizing
* \" g8 R3 e" Q( ]& R( Y. kcongenital adrenal hyperplasia producing excessive2 I" Z) I T, I
adrenal androgens is a common cause of precocious' y$ B* d( P0 y, ^2 H: a
puberty in boys.3,4
5 z$ l1 q# q; G7 d. V; q, H' w" L+ LThe most common form of congenital adrenal
% E2 O# ?9 Q; ^6 Bhyperplasia is the 21-hydroxylase enzyme deficiency., L; i! A. ?! X# K
The 11-β hydroxylase deficiency may also result in% M" w" E" N' F' Q+ O# T
excessive adrenal androgen production, and rarely,
$ `$ H! }$ X8 y8 F/ y8 P6 e$ }an adrenal tumor may also cause adrenal androgen
3 ^. Q% w' x( uexcess.1,32 @2 `( `% a" i& {; w. R+ K
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
- D! |8 L7 `3 A542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
- d! F& ?! s# j) o- ?A unique entity of male-limited gonadotropin-" `- {: V; P. h3 r+ f7 T1 E& K
independent precocious puberty, which is also known3 g) F9 U E* S8 _& P9 I. N; |, {
as testotoxicosis, may cause precocious puberty at a
4 M. @- F' e) g; g8 V& j4 L. ]7 Fvery young age. The physical findings in these boys: p% }2 | M7 ^2 r- C; n
with this disorder are full pubertal development,- q4 r% v4 L' i7 e2 q
including bilateral testicular growth, similar to boys& l$ W! s+ f+ q2 u6 r0 }8 x* ?! [
with CPP. The gonadotropin levels in this disorder
' m. X1 K4 o# {7 L9 @- j5 `are suppressed to prepubertal levels and do not show
0 g. \! j6 `' k3 g% A: Qpubertal response of gonadotropin after gonadotropin-5 C+ @2 U, w( t1 {9 C+ n
releasing hormone stimulation. This is a sex-linked+ J: \! F z/ f- m* {
autosomal dominant disorder that affects only1 t/ e3 `8 N+ z( g3 R, z
males; therefore, other male members of the family
' D/ E5 H0 }( K: H ~" U/ m8 Pmay have similar precocious puberty.38 }3 y: j4 V/ C& U
In our patient, physical examination was incon-
/ l. ]; E5 j6 B( e- Y5 |sistent with true precocious puberty since his testi-7 f" h- C+ j$ S. ~
cles were prepubertal in size. However, testotoxicosis6 w, C: D' F: f9 p! h
was in the differential diagnosis because his father
7 S5 s1 m' y! Y+ I( Fstarted puberty somewhat early, and occasionally,
9 S5 S3 q+ H3 ?+ f3 z) Ktesticular enlargement is not that evident in the
8 O T1 ?% z! l" s* a' H6 t4 y* ebeginning of this process.1 In the absence of a neg-% {/ `4 C" W. q: ?
ative initial history of androgen exposure, our# T7 U n% N9 e. i
biggest concern was virilizing adrenal hyperplasia,
! j: d O8 j2 Feither 21-hydroxylase deficiency or 11-β hydroxylase
, a1 w, p) @4 a$ q( S. O1 ndeficiency. Those diagnoses were excluded by find-
2 D+ G6 i$ h2 ]ing the normal level of adrenal steroids." p9 n" b% ?8 `+ K$ s' _* n
The diagnosis of exogenous androgens was strongly& Z$ c9 k" a. j; e" T$ a8 Z
suspected in a follow-up visit after 4 months because# C$ _4 H% {: H$ W0 b& k
the physical examination revealed the complete disap-
6 O+ W- v# A G2 ]$ T4 b- Npearance of pubic hair, normal growth velocity, and
4 N7 R( t! L, g+ v, Ydecreased erections. The father admitted using a testos-: @* x' \% v g- o% c( [+ M
terone gel, which he concealed at first visit. He was
/ d! }5 y+ z) f* _( O2 N% Kusing it rather frequently, twice a day. The Physicians’) }- I* o% L/ {
Desk Reference, or package insert of this product, gel or! ^5 D4 i+ m' ~
cream, cautions about dermal testosterone transfer to
. ~. T n) V4 t* _, bunprotected females through direct skin exposure.
! b ]! v" c- [' |: G0 h3 kSerum testosterone level was found to be 2 times the
( Z) H$ b; Q ~" L* g* q* J Kbaseline value in those females who were exposed to
" F6 y6 N! `! q6 Z5 deven 15 minutes of direct skin contact with their male
) L: u3 N1 e- F/ k" e+ Ipartners.6 However, when a shirt covered the applica-# @( j& S# K4 R: n8 Z
tion site, this testosterone transfer was prevented." |7 g- x& _7 A8 h( ~0 W
Our patient’s testosterone level was 60 ng/mL,
1 r0 h7 ?; F% x; i" jwhich was clearly high. Some studies suggest that. s5 M9 h0 y9 J1 k. c2 D; h1 ]2 C
dermal conversion of testosterone to dihydrotestos-, s' V* b' g2 y' ^
terone, which is a more potent metabolite, is more7 [; u0 r8 Y- ~# y% D8 r+ r
active in young children exposed to testosterone
5 T8 c& V' s# o, E. v9 w3 P; @* Oexogenously7; however, we did not measure a dihy-
+ F& l" P# l: idrotestosterone level in our patient. In addition to
* x9 a2 R! b6 s0 Mvirilization, exposure to exogenous testosterone in9 Q4 _: t) r4 k$ [6 [& G$ x
children results in an increase in growth velocity and
. n4 l# L% v# j4 o4 {advanced bone age, as seen in our patient.
$ o4 y: P: T3 k9 K7 w# E$ p3 yThe long-term effect of androgen exposure during/ Y3 C: E: i! W# L$ u B8 }- M. {) L
early childhood on pubertal development and final7 r0 ~9 O# x% B7 R4 H* x! R
adult height are not fully known and always remain6 ^, P, }8 E8 `6 K
a concern. Children treated with short-term testos-
8 F8 v7 b& |* O" Lterone injection or topical androgen may exhibit some& _ Z4 x9 w$ i0 e3 V
acceleration of the skeletal maturation; however, after
0 n: v* h) G1 W, y/ y* Z6 W4 k1 pcessation of treatment, the rate of bone maturation
5 F, H- `8 J S# A$ x5 y" C/ P% W+ Fdecelerates and gradually returns to normal.8,9
2 l; o+ p: y- U) Y- fThere are conflicting reports and controversy. [. V. @3 d% d1 a- X
over the effect of early androgen exposure on adult7 j% F. \ I& @9 r
penile length.10,11 Some reports suggest subnormal
9 Z3 ]1 t8 f2 G' B8 Hadult penile length, apparently because of downreg-8 T: r2 ]& b/ K3 u( V8 r3 l' [
ulation of androgen receptor number.10,12 However,
' c2 W4 T, }, oSutherland et al13 did not find a correlation between
# q! G( ]$ D3 j4 y3 n, wchildhood testosterone exposure and reduced adult
" n! `0 [7 n$ |" E; ]1 Qpenile length in clinical studies.
) _: Y6 @; P5 L4 x" R" G" lNonetheless, we do not believe our patient is
z7 D# }- u8 S+ m' {going to experience any of the untoward effects from
' d( a, Z% l; `& e Ytestosterone exposure as mentioned earlier because" u' U6 h4 T2 G1 T2 j* g. @) y
the exposure was not for a prolonged period of time.
- Y0 J9 i; s) M8 JAlthough the bone age was advanced at the time of# ~5 O% I2 j& J+ W6 Q3 K
diagnosis, the child had a normal growth velocity at- ~) V" Q& a9 v2 x' Q2 q. \+ m: b
the follow-up visit. It is hoped that his final adult
1 v$ j$ b% X! ^1 R" Hheight will not be affected.2 L/ l b; V7 v% @2 K7 D `$ u
Although rarely reported, the widespread avail-& I8 l7 o5 ~) B* r2 l" k
ability of androgen products in our society may
* f" f. o4 Y: D- \7 U: U9 ]indeed cause more virilization in male or female. G6 o% a: _8 w! |
children than one would realize. Exposure to andro-5 G5 ~' p( s" @: a. \, ~
gen products must be considered and specific ques-
7 F2 F1 Q/ Q* t- U- V; ~' W4 Gtioning about the use of a testosterone product or
* L' m: S! W* e$ \ _gel should be asked of the family members during
& T2 |* B" |5 m: mthe evaluation of any children who present with vir-. `0 P" W9 s5 g2 N& }
ilization or peripheral precocious puberty. The diag-
# U8 ^( A& \* Dnosis can be established by just a few tests and by
& O' `5 ^1 }+ M) O' I# happropriate history. The inability to obtain such a3 \* s4 h+ I m0 Y- i0 y: z! H
history, or failure to ask the specific questions, may5 \' A0 Z$ Z" I4 B* V0 K( f% I
result in extensive, unnecessary, and expensive
( @8 T4 F* n& Y! U# K8 K5 Dinvestigation. The primary care physician should be
( L5 e* q) H1 m j Saware of this fact, because most of these children
- Z1 o% j0 a* S$ q) @9 Emay initially present in their practice. The Physicians’ h) w+ Q* v. B" S- k5 I& `
Desk Reference and package insert should also put a
9 \2 R8 T1 b" v3 wwarning about the virilizing effect on a male or
4 X4 ]3 }8 G1 a8 V) Hfemale child who might come in contact with some-( M! J% I$ ]& I: d$ {) `8 ^
one using any of these products.3 r0 {4 R8 G' } T1 E G0 B1 X
References
' f$ m* `: t$ S: t- A- y1. Styne DM. The testes: disorder of sexual differentiation
( |& Y: Q8 ?1 @% g: Xand puberty in the male. In: Sperling MA, ed. Pediatric2 z/ x, |4 h9 _
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
/ k6 n& x# h% q g2002: 565-628., P& T( @4 ]8 w& p% E
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
: E) A! S8 J8 H; V; ]" b" Z! _+ C7 } \puberty in children with tumours of the suprasellar pineal |
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