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Sexual Precocity in a 16-Month-Old2 T7 Z6 l- r1 o* P
Boy Induced by Indirect Topical
6 [: G! S; |! \$ U# y/ i: DExposure to Testosterone
. |& p( h# C( h1 _* w/ lSamar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
, }3 z1 G5 z% ?- E Dand Kenneth R. Rettig, MD17 I% F, d7 @( j8 t0 M* ]2 ^
Clinical Pediatrics! |! Z6 o, u8 \& q$ ]1 ~
Volume 46 Number 6
! F& @$ u: }4 ?July 2007 540-543
; b; Q0 I# X' e2 Y© 2007 Sage Publications' K% g. N0 I% n8 ]
10.1177/0009922806296651) Y. q1 O3 |$ y
http://clp.sagepub.com$ \5 H7 Q1 o3 T! K2 L: J& {
hosted at+ ~8 c- S0 F. @4 k6 B9 T
http://online.sagepub.com+ h' e/ V* }$ c
Precocious puberty in boys, central or peripheral,2 j3 r; R4 e- H
is a significant concern for physicians. Central8 `) C7 @% \1 o7 t5 P+ G
precocious puberty (CPP), which is mediated' ~. z7 {2 a# ?+ x' L: E8 Y9 D
through the hypothalamic pituitary gonadal axis, has% m* A) B% H3 f
a higher incidence of organic central nervous system
3 B3 y& k" L9 T2 \" ]: olesions in boys.1,2 Virilization in boys, as manifested
; w7 {4 F$ L2 Z) cby enlargement of the penis, development of pubic8 w" K9 l) M o- G$ e9 i
hair, and facial acne without enlargement of testi-: r$ A: i4 D) n" G
cles, suggests peripheral or pseudopuberty.1-3 We7 J4 {/ u- \2 P+ [% u/ s
report a 16-month-old boy who presented with the* l3 C) l8 k, {& z: h
enlargement of the phallus and pubic hair develop-# N+ U: Z7 |5 U3 \, ?$ i' L: N, Z
ment without testicular enlargement, which was due
' u& `& ]) w3 \- o! n; D/ nto the unintentional exposure to androgen gel used by) v% x: d( C5 `. h
the father. The family initially concealed this infor-
% j% Q0 g) x4 ?! N4 [mation, resulting in an extensive work-up for this
- p! w9 G8 N8 ^' Q/ F' v+ }child. Given the widespread and easy availability of h' e7 L: h. V1 f+ m) w
testosterone gel and cream, we believe this is proba-
8 H) A6 }* r! Zbly more common than the rare case report in the; X9 B" x, E# d) J1 ^
literature.4
3 Q! m, ^) M6 R# U6 yPatient Report" |$ y5 P8 J( ~; | ~
A 16-month-old white child was referred to the
7 }0 u3 h% L: X, M# j: B% G& I8 s& Kendocrine clinic by his pediatrician with the concern
7 B- P2 ]7 [+ A' d6 _of early sexual development. His mother noticed
( L7 ]+ x7 N4 q: U* N* o. @light colored pubic hair development when he was
8 E; O( X" S/ a; ^: _8 zFrom the 1Division of Pediatric Endocrinology, 2University of ^4 q4 ~" \! k; L. W# I; Q7 E/ ~
South Alabama Medical Center, Mobile, Alabama.! K' A3 s6 ?/ e; e, i% s/ W
Address correspondence to: Samar K. Bhowmick, MD, FACE,
& h4 W! u# a5 m% ~4 mProfessor of Pediatrics, University of South Alabama, College of; O& e7 Q z. b( R" H a
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;" C! ~; Q, N: `( Z) |2 }
e-mail: [email protected].
\ R/ v0 Q: F8 f ?6 X9 Habout 6 to 7 months old, which progressively became
7 f8 r# b, u4 h3 cdarker. She was also concerned about the enlarge-' [. l) n* m5 P/ O8 {- C+ D$ M
ment of his penis and frequent erections. The child1 N- B, g, D2 e+ ]8 J
was the product of a full-term normal delivery, with
5 `6 t/ b1 X9 Ia birth weight of 7 lb 14 oz, and birth length of
3 u5 |$ k$ _3 Y, }; [- p20 inches. He was breast-fed throughout the first year
' h( k5 S! {& Z' w$ Y: m3 t# fof life and was still receiving breast milk along with2 ~& U$ u7 n8 l* K
solid food. He had no hospitalizations or surgery,
0 w( r2 X% } F9 ?% \and his psychosocial and psychomotor development/ C( ^- d% F7 {
was age appropriate.
6 _5 i2 t/ W1 ?( SThe family history was remarkable for the father,
$ y+ ?6 r& t6 P: V) L2 c" b! Swho was diagnosed with hypothyroidism at age 16,
, a, U) a0 c7 Vwhich was treated with thyroxine. The father’s0 t- W' o- d9 R/ H& D
height was 6 feet, and he went through a somewhat
( z5 H- h, F" ]early puberty and had stopped growing by age 14.3 V( e' V: `( [) C6 j
The father denied taking any other medication. The
0 a d/ b1 l7 f5 M2 Fchild’s mother was in good health. Her menarche* Y7 {( p- W' p$ Z
was at 11 years of age, and her height was at 5 feet8 ~; D+ ~1 m/ V9 _$ [
5 inches. There was no other family history of pre-/ y+ z- S) ]! A V, c n
cocious sexual development in the first-degree rela-
) A# V8 Q4 J M' ?7 ?6 m% ytives. There were no siblings.
" L0 V* b3 i% N. zPhysical Examination8 n, D+ o& o/ V6 m( O
The physical examination revealed a very active,
# I# B7 ~1 o2 Z( Dplayful, and healthy boy. The vital signs documented
; f0 t2 @+ Z9 V" F2 z* u; {a blood pressure of 85/50 mm Hg, his length was
2 \$ k, A) T$ ] G; x90 cm (>97th percentile), and his weight was 14.4 kg
8 O. Q3 W9 X R6 `' d/ W i' l6 |(also >97th percentile). The observed yearly growth
7 |+ S5 d) e+ }" Z% @( m3 k# G0 {velocity was 30 cm (12 inches). The examination of# W. c1 Y! k) E
the neck revealed no thyroid enlargement./ x& _8 k( n/ z, w
The genitourinary examination was remarkable for
; p! X' Y1 L: h6 k: F. lenlargement of the penis, with a stretched length of1 \3 ~* Z/ L$ j; k9 Q$ v6 C
8 cm and a width of 2 cm. The glans penis was very well0 c5 i4 ] [$ E4 U& R* [# e0 U
developed. The pubic hair was Tanner II, mostly around" N' X$ [- X6 f0 ~
540
- U$ T3 S3 o0 U- m1 ^at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
' F( K* {! L7 v1 cthe base of the phallus and was dark and curled. The
/ J5 A Q6 G/ p6 ftesticular volume was prepubertal at 2 mL each./ [) L0 r9 @& u. L
The skin was moist and smooth and somewhat
- H+ G) v" s+ [; |1 M* koily. No axillary hair was noted. There were no" L/ N$ d" H8 s/ h, ~3 ~
abnormal skin pigmentations or café-au-lait spots.
& i0 p; U" U) l- Z, H: k7 V1 P+ UNeurologic evaluation showed deep tendon reflex 2+! ^% w' {2 d- F, f
bilateral and symmetrical. There was no suggestion- @, r" m/ s2 C3 [ [
of papilledema.; U2 M. o/ }" u7 |; g
Laboratory Evaluation% b+ G6 `6 f" a
The bone age was consistent with 28 months by
4 Z2 ?0 [ B. p! {using the standard of Greulich and Pyle at a chrono-
' w; {) N+ f. s1 ?1 j3 N# slogic age of 16 months (advanced).5 Chromosomal2 k6 A- H: G. c* F1 @. l- z# G
karyotype was 46XY. The thyroid function test) K8 n5 C* U+ V. `- B8 r
showed a free T4 of 1.69 ng/dL, and thyroid stimu-
" U% k+ @$ H E& h* Y; wlating hormone level was 1.3 µIU/mL (both normal).0 d/ g; D: r$ d" g# V/ A
The concentrations of serum electrolytes, blood% X N) o ~- @6 `" H
urea nitrogen, creatinine, and calcium all were O% e) {" q g+ \7 V2 T
within normal range for his age. The concentration1 F5 }* n7 f6 Q
of serum 17-hydroxyprogesterone was 16 ng/dL
5 t+ V* I& b) q( A, [8 a$ Z(normal, 3 to 90 ng/dL), androstenedione was 20
2 x6 c- P! n1 O4 d& o6 `ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-$ F4 I9 q* u' p
terone was 38 ng/dL (normal, 50 to 760 ng/dL),
" X" P6 w/ e& X8 I( adesoxycorticosterone was 4.3 ng/dL (normal, 7 to
; ^. V5 m; b a) L1 o49ng/dL), 11-desoxycortisol (specific compound S)6 C) C1 B$ y: p0 |6 o+ N$ a% b
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
" U4 h$ V# @8 E. P+ Rtisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total& x2 W, O* r% W m* x! i8 B, m
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
% R9 u6 f6 {/ y+ ~3 g2 eand β-human chorionic gonadotropin was less than
+ v6 D- i5 ^9 G( H5 mIU/mL (normal <5 mIU/mL). Serum follicular
% g/ [# V) d8 X2 S/ Wstimulating hormone and leuteinizing hormone
5 h5 ~8 ~" @( Z8 Q4 y# Cconcentrations were less than 0.05 mIU/mL* x& f" t( w3 G
(prepubertal).
d" r) B* F6 f9 Q4 ^The parents were notified about the laboratory
" Y2 o& `5 S" cresults and were informed that all of the tests were# R M2 j& h! r# _- D! d
normal except the testosterone level was high. The
5 s0 }% j) N6 Y8 v; |0 S( e y, Hfollow-up visit was arranged within a few weeks to
, G U( z2 O% H! q8 Eobtain testicular and abdominal sonograms; how-
0 v0 p: }3 s+ J5 `8 f+ yever, the family did not return for 4 months.) u( w p, i! c: H" h( l
Physical examination at this time revealed that the D% ]! e4 ?! T
child had grown 2.5 cm in 4 months and had gained
" Y9 J& D& w; F5 v2 kg of weight. Physical examination remained% T5 x8 N. v2 m# j: A( v
unchanged. Surprisingly, the pubic hair almost com-$ }1 ?; k* e2 P2 g8 k/ L$ |
pletely disappeared except for a few vellous hairs at
1 I( `/ q( ]/ }' X ]/ K2 ?the base of the phallus. Testicular volume was still 2
8 j, }8 F# t% R) n% W4 L. fmL, and the size of the penis remained unchanged.* F0 F% ^: }& g6 B
The mother also said that the boy was no longer hav-1 Z3 y3 Q$ z, Z6 @0 _3 i1 _: ?
ing frequent erections.7 Q* U: a0 Z5 @5 x# l7 U
Both parents were again questioned about use of+ z6 M7 A3 I- f6 k
any ointment/creams that they may have applied to
1 H D, J; Z: K% {the child’s skin. This time the father admitted the
, _, I% N' S+ m! d' c7 P3 }0 }Topical Testosterone Exposure / Bhowmick et al 541
6 n' H3 l" X6 Y- T% C; C/ v9 R. Iuse of testosterone gel twice daily that he was apply-
, Y3 g0 \, W6 j5 |4 Sing over his own shoulders, chest, and back area for m; V( v; P; B6 \$ e; ]' r, o
a year. The father also revealed he was embarrassed
' `/ e- }0 F U9 E( x! b, y, `to disclose that he was using a testosterone gel pre-4 O+ t. H2 W; d- \; y+ e
scribed by his family physician for decreased libido1 X* H8 }. L. ]; }4 p4 P$ Y
secondary to depression.2 O0 ~2 S# g& G7 u- F
The child slept in the same bed with parents.& b: [. C. X4 b: h
The father would hug the baby and hold him on his: |) b, V6 I$ g0 C# r& R4 x
chest for a considerable period of time, causing sig-; e. E7 v: `6 `* H; d
nificant bare skin contact between baby and father.+ W: Z6 Q7 r R4 c2 f
The father also admitted that after the phone call,# n9 I. P8 Z9 f: Q8 s
when he learned the testosterone level in the baby
. x% n8 G* H! b8 Iwas high, he then read the product information
# J+ o8 G U) X% g Jpacket and concluded that it was most likely the rea-
, S2 f- ]4 c) u) S) zson for the child’s virilization. At that time, they+ W, W- O# C% m' ~/ Z U0 I
decided to put the baby in a separate bed, and the7 }6 v" g: J# U) i
father was not hugging him with bare skin and had% h; e) S3 M* i- Y7 Y
been using protective clothing. A repeat testosterone
W7 e2 g4 ]. E8 k) u2 Stest was ordered, but the family did not go to the. c. d% ^# Q, K9 W5 G) J* W5 j
laboratory to obtain the test.$ d& J% w2 r: g+ A1 N0 U
Discussion" r/ Z2 Y X, ^8 _' X- N
Precocious puberty in boys is defined as secondary
r8 b& L9 l; f6 ?+ Esexual development before 9 years of age.1,4/ x' [) N1 z2 C0 m* i$ R4 ?- L0 T' x
Precocious puberty is termed as central (true) when
5 w( i! N, L6 [8 F; r4 dit is caused by the premature activation of hypo-
2 \: I8 I ?3 H: n! nthalamic pituitary gonadal axis. CPP is more com-; r4 T3 O- W8 b! ]$ ? t5 W
mon in girls than in boys.1,3 Most boys with CPP
( O/ z5 Q9 P3 D% omay have a central nervous system lesion that is
0 M) i7 U$ v6 A+ X% a, p lresponsible for the early activation of the hypothal-8 I0 M! ]5 e5 c5 c) {+ I: l
amic pituitary gonadal axis.1-3 Thus, greater empha-
) L$ M, f6 u7 o8 e$ ]0 Zsis has been given to neuroradiologic imaging in# ~/ ]! C m' ^$ R3 E
boys with precocious puberty. In addition to viril-& b5 g0 r5 T4 P+ z
ization, the clinical hallmark of CPP is the symmet-
6 P% I! }) ^# J' ~9 u! {rical testicular growth secondary to stimulation by, l" ~3 O7 O ]* X0 {" H
gonadotropins.1,3
- L$ Q: ?# H" a) Y8 HGonadotropin-independent peripheral preco-
9 `( X' R: X; b8 h4 T) D& z \cious puberty in boys also results from inappropriate7 a$ s- H: ~7 w; |
androgenic stimulation from either endogenous or5 X" x2 ]( q; c- b) p. S1 j) Q9 e
exogenous sources, nonpituitary gonadotropin stim-( l5 Q* d& A- _
ulation, and rare activating mutations.3 Virilizing
( @4 s* u( e% y, B& Z2 Y7 Y0 ?9 M. ^congenital adrenal hyperplasia producing excessive: ~8 D0 v8 u6 L+ E6 n4 s
adrenal androgens is a common cause of precocious
# m, x2 ]# v3 ?puberty in boys.3,4
% k) Y% m& ^ t5 lThe most common form of congenital adrenal0 I( O4 D1 v% w" m
hyperplasia is the 21-hydroxylase enzyme deficiency.6 B' {4 i2 x) P& D% J
The 11-β hydroxylase deficiency may also result in
+ g3 D. H9 f F' ^" Pexcessive adrenal androgen production, and rarely,% h% [/ j3 |) ?' H0 B& m
an adrenal tumor may also cause adrenal androgen" S- X6 `2 b# r3 } h% Y; z) G+ e
excess.1,3: u+ B q) @6 m7 I5 L8 {8 z" X/ q; U
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from2 j- }) e$ J' n2 @
542 Clinical Pediatrics / Vol. 46, No. 6, July 20078 b: ]0 D' Y1 M5 m2 L9 r F
A unique entity of male-limited gonadotropin-
, p. z, I0 y2 W; Uindependent precocious puberty, which is also known7 i& \: o4 M w r$ [( B2 \) l6 @
as testotoxicosis, may cause precocious puberty at a
& l. \ Y. N8 Overy young age. The physical findings in these boys6 [6 X8 @8 N& E/ Y
with this disorder are full pubertal development,
3 {) }5 e2 m# S, ~1 ~7 ^0 l3 nincluding bilateral testicular growth, similar to boys
( w/ y3 r8 E9 n, i4 j6 Iwith CPP. The gonadotropin levels in this disorder
( S7 d9 u/ h' V/ f) Fare suppressed to prepubertal levels and do not show
8 Q: ^5 ~; Y& B' }! \pubertal response of gonadotropin after gonadotropin-
3 Y' ?* B, z2 u! Areleasing hormone stimulation. This is a sex-linked8 O- b# d9 a+ d0 N/ R6 B& {* D
autosomal dominant disorder that affects only& j. x0 Z" G( ]: I0 J7 q" B
males; therefore, other male members of the family- b0 p8 Q2 O" G" K$ o+ ~/ D' o
may have similar precocious puberty.3
, v: y) Y9 @+ XIn our patient, physical examination was incon-
% u- X! I3 v8 [; |0 @sistent with true precocious puberty since his testi-5 J% u4 w/ I# o, Z' ?) A l
cles were prepubertal in size. However, testotoxicosis! U& D7 L4 p5 n* u3 C1 ^
was in the differential diagnosis because his father. D4 D0 y' J# j. z' I, ?
started puberty somewhat early, and occasionally,
" L2 Y% B0 Q2 F/ @ [testicular enlargement is not that evident in the# f6 C8 h, \* p! ]; G
beginning of this process.1 In the absence of a neg-# Z* e" `: p; T0 x C8 d( o7 \; _
ative initial history of androgen exposure, our, h/ b2 `6 b& t' j
biggest concern was virilizing adrenal hyperplasia,
. Z0 E/ T8 C: ~# P+ Jeither 21-hydroxylase deficiency or 11-β hydroxylase0 d, o6 w! v V
deficiency. Those diagnoses were excluded by find-8 n6 q$ q' E' \2 [' e1 x
ing the normal level of adrenal steroids.
" b1 E1 S. J) l* z1 I9 ?The diagnosis of exogenous androgens was strongly
7 g& w u/ C/ Hsuspected in a follow-up visit after 4 months because9 T% y5 Y e/ v, j4 t7 X5 y
the physical examination revealed the complete disap-3 q9 u) j1 ]0 B0 P, ?! H
pearance of pubic hair, normal growth velocity, and5 ?. P n2 ]0 V+ p
decreased erections. The father admitted using a testos-
1 D, ~1 t: {4 `% {- s# ?' [1 wterone gel, which he concealed at first visit. He was
$ p9 H8 E1 Y, T$ c; M. }( `using it rather frequently, twice a day. The Physicians’
! l/ y: m& S% l5 b. }. ~1 uDesk Reference, or package insert of this product, gel or" x9 U: q! i2 ]
cream, cautions about dermal testosterone transfer to
8 j" D7 w; F! _' {; |, x( \unprotected females through direct skin exposure.
" V- k/ I/ M7 a( c1 k. z; }+ |8 WSerum testosterone level was found to be 2 times the1 N3 s! g# m7 `0 r% `
baseline value in those females who were exposed to# \/ e, `* i* p3 ?% R8 g0 j9 h$ Y
even 15 minutes of direct skin contact with their male
+ j3 x0 _1 c! ] E: [ {partners.6 However, when a shirt covered the applica-
. k/ Y* M! v. [6 F5 ytion site, this testosterone transfer was prevented.9 ~% q, ]8 e8 u- n, e8 M3 V# f
Our patient’s testosterone level was 60 ng/mL,4 z/ T2 V3 V n$ l# f& w; i
which was clearly high. Some studies suggest that
$ {1 m2 I% z$ f0 x# d9 a, {$ Udermal conversion of testosterone to dihydrotestos-! U# q9 A) u9 u8 u9 g
terone, which is a more potent metabolite, is more
! b7 ` _9 y, e' E& n: ^4 uactive in young children exposed to testosterone& ~+ E9 y1 \( N3 O& n
exogenously7; however, we did not measure a dihy-
r- C# n4 y/ d4 C5 V/ g' M) }drotestosterone level in our patient. In addition to) J/ p$ u' K" V) t- v) V$ g
virilization, exposure to exogenous testosterone in" J9 n% X. u& B# p( K& y" e$ ~1 h- t
children results in an increase in growth velocity and8 y w+ B6 y: y, [9 B
advanced bone age, as seen in our patient.7 B7 c5 s @( i" t; K# P
The long-term effect of androgen exposure during: X. d: F ^6 H! R0 N0 Q( P) _( |
early childhood on pubertal development and final( v, _+ s' H) P( v
adult height are not fully known and always remain
( Z7 n" O6 I x- z" Sa concern. Children treated with short-term testos-) l8 f- u9 a" T! u8 R9 G
terone injection or topical androgen may exhibit some$ m& t& M) @' y; D: i& I. d' L
acceleration of the skeletal maturation; however, after
& s& B& W- u( P8 W! v1 hcessation of treatment, the rate of bone maturation
' @2 h% x4 a" A+ n4 Kdecelerates and gradually returns to normal.8,9
8 e, p# w' A; K5 Q, I0 b5 vThere are conflicting reports and controversy
9 ~9 L# w# k. x2 {7 yover the effect of early androgen exposure on adult
* j4 A* c' w9 Tpenile length.10,11 Some reports suggest subnormal
' x7 o# d5 }! ~' T$ z9 X( e, G& Tadult penile length, apparently because of downreg-
% c8 y* @5 J: |8 k7 fulation of androgen receptor number.10,12 However,7 E6 ^0 ^7 e0 u- Z
Sutherland et al13 did not find a correlation between+ b7 ]* @8 I8 D4 j
childhood testosterone exposure and reduced adult
) w, y6 t$ E! @; l: a1 j; x& u$ Ypenile length in clinical studies.
) F, i6 [8 `! K2 K% `. O8 WNonetheless, we do not believe our patient is
m$ `- Y$ a& a9 R3 h% O& `/ Qgoing to experience any of the untoward effects from% }% u" N4 o8 p/ I) g
testosterone exposure as mentioned earlier because9 l: Z, `0 S3 U( k9 D. g0 I: u
the exposure was not for a prolonged period of time.
' h) @% V1 o8 A( s/ x% }; @Although the bone age was advanced at the time of
. L- g9 }, t5 z% J0 x D Wdiagnosis, the child had a normal growth velocity at( g. d: A& r- P
the follow-up visit. It is hoped that his final adult
: } d: @: }/ \/ t% w0 y8 Vheight will not be affected.5 E5 t6 g. p8 q' H( h
Although rarely reported, the widespread avail-
, y: [2 A2 H: Y3 Lability of androgen products in our society may& E$ B& P# U. l) M& r
indeed cause more virilization in male or female
c; p- N0 K# h+ W* ^4 o* ~children than one would realize. Exposure to andro-! }/ L# v$ m0 ?, L8 n0 g& a
gen products must be considered and specific ques-
+ C# C+ W S% |! d: f+ t5 y& L$ Jtioning about the use of a testosterone product or
: m) Y& @# \# x7 u; Dgel should be asked of the family members during" E% u; D' P+ o9 |) o* J5 T2 B* ?- ^
the evaluation of any children who present with vir-
$ W# L) A- ?; d5 Y, b1 eilization or peripheral precocious puberty. The diag-
6 G% \% j: ^1 W _, Enosis can be established by just a few tests and by
7 F, Y4 O( ~$ w8 l8 P' F/ r% \appropriate history. The inability to obtain such a* b8 F5 H( Z+ k/ ^: M) {5 u& ?2 i
history, or failure to ask the specific questions, may
1 W; L3 Z J) Z" M# K4 [result in extensive, unnecessary, and expensive
, J) [ z1 E. Z3 u6 p. U2 R; w. ginvestigation. The primary care physician should be
* l3 Q( M4 C6 N& T3 K# b' \aware of this fact, because most of these children. [5 G1 `7 V- @8 k7 w# D& A
may initially present in their practice. The Physicians’
1 n* M$ T( ~- k# u ODesk Reference and package insert should also put a
1 i, F& P4 c: C% A+ N' n1 uwarning about the virilizing effect on a male or
% T+ f/ u* m9 A: T2 j: V/ Zfemale child who might come in contact with some-
4 L4 m8 |8 Y2 y4 y: q% D) _one using any of these products.
* n# j: a" V( A+ bReferences# P. `/ ]% ?- M* m- n5 @
1. Styne DM. The testes: disorder of sexual differentiation0 ~* q- p/ ]! \* Y) h
and puberty in the male. In: Sperling MA, ed. Pediatric) z: [& x9 t) D" T
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
3 i# }$ b& v4 `4 z |( z2002: 565-628.; h6 G) E' r5 o; X
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
( T% y/ O5 Q u3 M5 n9 q- N# zpuberty in children with tumours of the suprasellar pineal |
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