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Sexual Precocity in a 16-Month-Old3 e1 l6 O' \5 R0 l
Boy Induced by Indirect Topical
+ `2 k( @( {) s# S5 c* uExposure to Testosterone; @# R/ b+ q: R6 b$ Y4 _) i2 i+ Z, k9 o
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
7 c0 ?1 I, H' S z1 H8 iand Kenneth R. Rettig, MD1
* B; ^( ^6 c7 y# E% ~$ O6 GClinical Pediatrics
4 b1 ?; P$ d4 R2 r) b; G- H5 SVolume 46 Number 6
; |% r/ X$ \4 d5 LJuly 2007 540-543
) g5 L# Z! I4 H% a© 2007 Sage Publications
6 m0 s4 `1 D- X+ H10.1177/00099228062966518 B, z' e+ S8 k/ t
http://clp.sagepub.com
6 m4 M$ ^3 E3 d0 y9 }hosted at5 E# [, T6 X6 e% i3 _
http://online.sagepub.com
* T% H7 f @: j1 d- g. c& F) d+ pPrecocious puberty in boys, central or peripheral,
7 C8 e; u6 O$ uis a significant concern for physicians. Central7 G2 P3 I1 L/ Z$ D: _$ T7 l
precocious puberty (CPP), which is mediated
$ ]# A: J) R2 @. w% M5 \through the hypothalamic pituitary gonadal axis, has1 a# O2 H S8 I- V7 B, q9 [1 |
a higher incidence of organic central nervous system
4 o9 H- R4 p* e, ilesions in boys.1,2 Virilization in boys, as manifested
! H9 H8 {9 I aby enlargement of the penis, development of pubic
2 M2 \& z5 C& S6 Xhair, and facial acne without enlargement of testi-# n+ i" u1 g* X8 ~
cles, suggests peripheral or pseudopuberty.1-3 We
* L0 a8 B4 E- k9 {report a 16-month-old boy who presented with the
6 n% g; _/ Y% genlargement of the phallus and pubic hair develop-" g4 G" b0 k4 X
ment without testicular enlargement, which was due( q( F4 O7 q+ J3 j* X7 |* @
to the unintentional exposure to androgen gel used by, a7 S) i% `1 I+ W$ s+ A
the father. The family initially concealed this infor-
4 f' q9 c5 D3 g# Zmation, resulting in an extensive work-up for this
) q0 P: _- V. ?. b! [; }child. Given the widespread and easy availability of1 }, R" k/ b- c& T1 d* L
testosterone gel and cream, we believe this is proba-. n% `* M8 O/ N9 T9 b9 G
bly more common than the rare case report in the4 a! G. s! x- R) n0 ~
literature.4
9 v: e4 L" W5 jPatient Report
5 E9 M2 [" ?2 H; i# c* UA 16-month-old white child was referred to the. i' |$ v+ f# W3 n# r1 g
endocrine clinic by his pediatrician with the concern% p4 Z. C: S* {5 T* B" \1 B
of early sexual development. His mother noticed6 ^( W% y) V0 O% i9 s+ A
light colored pubic hair development when he was) _8 G6 n6 {* s
From the 1Division of Pediatric Endocrinology, 2University of
8 {8 O& f7 P9 Z. u4 E% ISouth Alabama Medical Center, Mobile, Alabama.
- A n4 O8 t/ x7 PAddress correspondence to: Samar K. Bhowmick, MD, FACE,( p) t$ t7 P3 L2 v2 o; l# W2 `
Professor of Pediatrics, University of South Alabama, College of1 ]4 v, e2 u. l: S w5 z0 m; l! w
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
1 n% w" ~. D4 P8 Re-mail: [email protected].1 x" d D0 a9 \
about 6 to 7 months old, which progressively became
" ^0 }; G+ b2 k( m2 O( Sdarker. She was also concerned about the enlarge-
0 ? q: I' m- O2 U @ment of his penis and frequent erections. The child
& w- D4 E2 a! _* y4 ]; B& Owas the product of a full-term normal delivery, with
" D- f2 T4 p+ Y) s- d! O5 `2 [4 \a birth weight of 7 lb 14 oz, and birth length of8 w2 q, p/ ]3 N& {+ N6 u/ o
20 inches. He was breast-fed throughout the first year
. Q* r4 B. a# Z, z! G! B \of life and was still receiving breast milk along with
2 O7 @% h- m$ `+ b. ?* Usolid food. He had no hospitalizations or surgery,
/ A; W( P2 C& f: l, K+ z6 ]and his psychosocial and psychomotor development
/ x6 p0 u) u0 ]- ?was age appropriate.
/ m: C4 m# K; |) aThe family history was remarkable for the father,! w9 a. [8 Z5 ^, B3 I6 Z' _
who was diagnosed with hypothyroidism at age 16,
- m1 Y9 Y, [0 @which was treated with thyroxine. The father’s
! ~3 W0 J, h1 G) U9 o- |$ Nheight was 6 feet, and he went through a somewhat
$ d2 j4 d3 L- nearly puberty and had stopped growing by age 14.
$ o0 {4 d0 L* T$ T0 Q1 b k% n8 MThe father denied taking any other medication. The* p, m0 Q) S7 g3 ?' _7 d* G/ C, R9 ?7 m
child’s mother was in good health. Her menarche
|, |; K2 N- E1 dwas at 11 years of age, and her height was at 5 feet
4 z7 s, i6 J6 d# r) m5 inches. There was no other family history of pre-6 \8 T7 C4 }- Y1 r
cocious sexual development in the first-degree rela-. k" h( L& e2 R; }
tives. There were no siblings.) x+ E+ |- i8 [- ^ ~
Physical Examination
r8 d o* l! W% WThe physical examination revealed a very active,. _0 f3 ~8 l& M/ |
playful, and healthy boy. The vital signs documented* a; b$ l; S( t- r9 n% d, R
a blood pressure of 85/50 mm Hg, his length was2 F8 v* M# G% V) L7 v* s
90 cm (>97th percentile), and his weight was 14.4 kg/ j8 }, X% \* _) \% Q2 t9 Q
(also >97th percentile). The observed yearly growth! c2 m4 Y: {0 a. K( _
velocity was 30 cm (12 inches). The examination of- x* s; X# z r' K8 h6 j" s
the neck revealed no thyroid enlargement.
& N% H3 Y% d3 N! Z+ Z. s9 fThe genitourinary examination was remarkable for! \( D9 P1 d1 a$ [
enlargement of the penis, with a stretched length of
- B- n2 ~9 D, a* s8 cm and a width of 2 cm. The glans penis was very well
* C& F" ]* B1 E6 `, |* Vdeveloped. The pubic hair was Tanner II, mostly around8 {% ^0 X; G7 d, n8 l
540
7 w/ w+ [3 `: l5 Oat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
$ J8 S1 o/ z& [7 W/ cthe base of the phallus and was dark and curled. The, W' A1 w4 @) ~) ~, o' b
testicular volume was prepubertal at 2 mL each.1 x' K% t4 o( A: T* ~
The skin was moist and smooth and somewhat5 K: |- h0 c- c
oily. No axillary hair was noted. There were no
9 \+ }1 [/ w4 E. j4 Mabnormal skin pigmentations or café-au-lait spots.
9 J& Z) N( X* qNeurologic evaluation showed deep tendon reflex 2+: r E$ f8 C% _6 ^
bilateral and symmetrical. There was no suggestion
" J0 {- E4 c: B$ i, D0 H, `6 A, Dof papilledema.$ _% y% a& X7 x# v" b" g! J8 \" f
Laboratory Evaluation4 D- b/ V$ a8 [) B D% L, U
The bone age was consistent with 28 months by
$ K& Z0 [, P- xusing the standard of Greulich and Pyle at a chrono-
; p! J, ?. `, w! zlogic age of 16 months (advanced).5 Chromosomal! j+ R$ ]( a1 b7 ~3 b4 e
karyotype was 46XY. The thyroid function test
* z" O" w: v) `* b% \showed a free T4 of 1.69 ng/dL, and thyroid stimu-
) C0 c- B8 U: T2 Z+ |, U: glating hormone level was 1.3 µIU/mL (both normal).8 u9 y# q' C4 N* ?. }
The concentrations of serum electrolytes, blood
; I/ F* K& U2 G# g" }. e7 Curea nitrogen, creatinine, and calcium all were6 E X+ p0 {4 C
within normal range for his age. The concentration
5 m6 ^/ k8 `: Y, Z* \; Qof serum 17-hydroxyprogesterone was 16 ng/dL3 Q1 ]4 _) S' r
(normal, 3 to 90 ng/dL), androstenedione was 20
5 t; r8 T: w5 g/ J! n# i2 e, l( O) |ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
, U4 {; ]! D: E! E, wterone was 38 ng/dL (normal, 50 to 760 ng/dL),. ]8 x V" r" o1 L( Y
desoxycorticosterone was 4.3 ng/dL (normal, 7 to: K7 R$ H1 p3 h# c6 b) g6 }
49ng/dL), 11-desoxycortisol (specific compound S)
, G# z* N% C- i: z% {, a/ ?was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-! `2 f3 O) L) w3 \& c8 T9 W
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total4 I) I* F8 g9 m
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
/ B1 e7 j7 j T( e& |% w% B$ ~and β-human chorionic gonadotropin was less than
/ u7 Y* b l! E( |6 k1 y: H- [5 mIU/mL (normal <5 mIU/mL). Serum follicular7 V y0 N/ F$ G
stimulating hormone and leuteinizing hormone% \& x8 H2 o+ Y& {% u
concentrations were less than 0.05 mIU/mL/ a- s9 ^7 Z* B; L- H/ U$ D: p
(prepubertal).
$ ^, U9 s% k6 \The parents were notified about the laboratory! |( w' |4 s' _1 u( O# j
results and were informed that all of the tests were
0 j6 G# \1 U w0 e: z# T; }5 O5 t7 a6 Xnormal except the testosterone level was high. The$ Q+ g& Y4 [7 ~
follow-up visit was arranged within a few weeks to
$ B2 }: j) \, J$ j1 Qobtain testicular and abdominal sonograms; how-
$ @' t% y& y4 V- Xever, the family did not return for 4 months.- B' H3 X5 T3 h( @
Physical examination at this time revealed that the
* o! q/ u$ E" ^) _" g( j) Pchild had grown 2.5 cm in 4 months and had gained3 m! L# P0 x5 U5 k! S# f
2 kg of weight. Physical examination remained
+ Q2 h1 [0 a' b; t) ~unchanged. Surprisingly, the pubic hair almost com-3 g7 R/ X7 M' O
pletely disappeared except for a few vellous hairs at
$ {& h0 q; z# _& r) X- X* V" {the base of the phallus. Testicular volume was still 2) e- C1 T2 j6 m* H+ t) z
mL, and the size of the penis remained unchanged.
. N' s1 `+ v0 o. @The mother also said that the boy was no longer hav-
, t% ?$ _5 p }2 x; L/ a" [ c* Ging frequent erections.
1 c4 f! k' \. w% fBoth parents were again questioned about use of
! Z& {" O& y+ c, Q& Zany ointment/creams that they may have applied to8 i/ |6 S3 @5 i( k
the child’s skin. This time the father admitted the2 }# A3 c7 A5 a1 x$ e$ q
Topical Testosterone Exposure / Bhowmick et al 541
: ?; S: O# D$ d* ] `* L U" u/ i: Buse of testosterone gel twice daily that he was apply-/ }1 B) {' ]* t3 x
ing over his own shoulders, chest, and back area for
3 Z% K7 F7 u& z, r" e% z8 aa year. The father also revealed he was embarrassed
) l+ L0 [* S& |2 Wto disclose that he was using a testosterone gel pre-
4 j7 h- A4 c4 G" g/ Uscribed by his family physician for decreased libido
O2 Z/ Z9 L- T; L ksecondary to depression./ O" O, @- Y8 G% T3 {' d
The child slept in the same bed with parents.
% H" g" X6 \& R( u3 nThe father would hug the baby and hold him on his' W8 \8 V! {1 g- r5 P& `, W9 W0 N9 y
chest for a considerable period of time, causing sig-
& ^- N a1 G+ q. z9 \nificant bare skin contact between baby and father.
2 `+ |4 `0 B: v* R# B& p0 [$ NThe father also admitted that after the phone call,8 x% @( `- j5 `6 g) l7 a# G
when he learned the testosterone level in the baby& U" V+ c9 @* ^
was high, he then read the product information2 @& K2 T5 C/ i7 U8 k; W$ F+ O6 m
packet and concluded that it was most likely the rea-
) ^1 ^/ d3 n* N1 ]+ X& ^" n2 E. Ason for the child’s virilization. At that time, they8 H: b) W; }& `9 A( U
decided to put the baby in a separate bed, and the
4 y% z% r* R* b* r1 x \! ofather was not hugging him with bare skin and had
. ~+ k6 ^. w) T4 P; {been using protective clothing. A repeat testosterone6 a) g9 Q; |, W6 t5 h$ A, I; k
test was ordered, but the family did not go to the- Y( ~0 Q/ Z! f
laboratory to obtain the test.
5 E3 d) o% s+ w" C [. W1 b; rDiscussion
0 k, ~* \, N% O1 b% H4 ?* gPrecocious puberty in boys is defined as secondary3 ~4 {& J& ^! W, w8 u& q2 s
sexual development before 9 years of age.1,4
7 w) q1 D) \1 O; c$ ?0 |Precocious puberty is termed as central (true) when6 |4 X% V5 V e
it is caused by the premature activation of hypo-
% d! b$ f3 W( Z4 Y; y; P* z% K' Uthalamic pituitary gonadal axis. CPP is more com-. v' k( r( Q! n. j) _& B! L$ J
mon in girls than in boys.1,3 Most boys with CPP9 G8 b H& H( G' d, D8 H
may have a central nervous system lesion that is
5 t4 ]9 Z% {. J& V2 w: q3 Presponsible for the early activation of the hypothal-5 `4 n$ T7 E1 j0 D& f1 t# U
amic pituitary gonadal axis.1-3 Thus, greater empha-, }1 c% N7 `; _. d
sis has been given to neuroradiologic imaging in
, q( k7 T+ B, }2 [& p2 j: vboys with precocious puberty. In addition to viril-
4 f* l/ _7 D: Z ~ization, the clinical hallmark of CPP is the symmet-
+ U( [# z: _' `rical testicular growth secondary to stimulation by1 J. V& X6 E+ {" R* n
gonadotropins.1,3
5 E% {, b1 ? C: O' r6 U: L7 BGonadotropin-independent peripheral preco-% c$ A2 A, ^) A8 U( K( E
cious puberty in boys also results from inappropriate' N. I/ n# O7 E4 d) [' ^
androgenic stimulation from either endogenous or
. w8 _0 u9 J! G0 |9 }3 u* _exogenous sources, nonpituitary gonadotropin stim-
n# G3 V1 p' h3 N' r$ ]- Yulation, and rare activating mutations.3 Virilizing
4 B* j! P5 O. q3 Y# V% Vcongenital adrenal hyperplasia producing excessive4 Q G3 b% f& W" d, S
adrenal androgens is a common cause of precocious
E+ `' J# i" X* _. zpuberty in boys.3,4
6 q3 o* r# ]; o0 h( P( ?The most common form of congenital adrenal
1 c6 g: J2 ]3 X$ Q+ w* shyperplasia is the 21-hydroxylase enzyme deficiency.
$ J; i, V9 o8 g2 H; ZThe 11-β hydroxylase deficiency may also result in* L( o% F. o5 h- I2 k
excessive adrenal androgen production, and rarely,! z k) c$ y2 v4 W. i N8 [
an adrenal tumor may also cause adrenal androgen+ Q& E# I1 k; I' X3 ?
excess.1,3
5 ]& E* m& M- gat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from& k; m& t3 ?2 ^2 P$ }* i) V' U: S
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007! R+ @& M* Y ^3 W/ n) G. t
A unique entity of male-limited gonadotropin-
4 u/ }4 ~! L2 A1 C; P$ Lindependent precocious puberty, which is also known# c, |7 Q6 }9 d; |
as testotoxicosis, may cause precocious puberty at a
# v0 P0 v2 Y/ R( hvery young age. The physical findings in these boys. ^! o4 V4 n, k, _3 ~! Q& S
with this disorder are full pubertal development,6 V4 v1 S4 n- L6 Z, J0 f
including bilateral testicular growth, similar to boys6 i0 \. k z' q
with CPP. The gonadotropin levels in this disorder
: n8 @8 r# T* Z% T- a! e" }1 [are suppressed to prepubertal levels and do not show9 P2 b% X! U! V0 j4 S d
pubertal response of gonadotropin after gonadotropin-
! n/ J! y' d3 z) G1 Areleasing hormone stimulation. This is a sex-linked
5 b2 j3 w1 X- Vautosomal dominant disorder that affects only
: _" B; i" x8 q0 Amales; therefore, other male members of the family
2 H! v2 b# s7 k4 L: ^may have similar precocious puberty.39 `( o1 s* |1 S( `0 E9 l
In our patient, physical examination was incon-& L6 W9 P7 _4 Q: T. J( j, M: j% p
sistent with true precocious puberty since his testi-+ p0 k. r, `, }- _( E+ I) W/ E: P
cles were prepubertal in size. However, testotoxicosis
. P; h1 x- I+ f2 A) m; L" Ewas in the differential diagnosis because his father! A+ U+ Z+ h* s$ p- I* ?
started puberty somewhat early, and occasionally,
1 a8 o9 k2 O' \. ?2 g3 Mtesticular enlargement is not that evident in the
9 S4 _; M2 K1 V- n# `beginning of this process.1 In the absence of a neg-0 ~% D; W( Y& r
ative initial history of androgen exposure, our6 J! ?! g% ?- |) d
biggest concern was virilizing adrenal hyperplasia,
- w+ D8 q0 R& Leither 21-hydroxylase deficiency or 11-β hydroxylase
, M7 b5 Z# f s+ Qdeficiency. Those diagnoses were excluded by find- J4 ]) @+ _( j; |( Q, ]
ing the normal level of adrenal steroids.
$ E. ~; W6 p% _: E+ zThe diagnosis of exogenous androgens was strongly
`- }5 w( o' x6 Y# x; Hsuspected in a follow-up visit after 4 months because' n7 G; j/ x/ o D: ]3 I1 T" R6 [. ?
the physical examination revealed the complete disap-' d& T' K9 G: q8 r
pearance of pubic hair, normal growth velocity, and
+ P; C1 A" [% U( N2 h0 N9 B' Zdecreased erections. The father admitted using a testos-
( [3 p9 o+ S. oterone gel, which he concealed at first visit. He was
0 n5 q+ \7 J, C+ x& S6 H; V! c8 vusing it rather frequently, twice a day. The Physicians’
* h* c7 h" Z. W4 pDesk Reference, or package insert of this product, gel or3 g6 F3 b# L) f8 p* _$ w7 n
cream, cautions about dermal testosterone transfer to
/ ` u% p1 }7 N% N3 ?' {1 U6 Lunprotected females through direct skin exposure.& ]& y& B1 F0 j+ U* o! A4 x
Serum testosterone level was found to be 2 times the
2 t5 P l: Q0 P8 F, A+ kbaseline value in those females who were exposed to
# i5 `) e9 q% S8 Qeven 15 minutes of direct skin contact with their male
$ {% I" t0 w. Bpartners.6 However, when a shirt covered the applica-
! E0 O7 _# G, Rtion site, this testosterone transfer was prevented.# x1 F* j1 H3 [9 ]
Our patient’s testosterone level was 60 ng/mL,
, r) V" \& Y" [: q; @- t. ?% J5 wwhich was clearly high. Some studies suggest that0 x8 W4 s: p/ T" ~! l& }
dermal conversion of testosterone to dihydrotestos-! o" [. m& w# W: J S" L$ z
terone, which is a more potent metabolite, is more- n0 z! `* I" H& U
active in young children exposed to testosterone
1 r: _) ^# R) z0 A; _ \% Eexogenously7; however, we did not measure a dihy-+ s" h8 _* Q" o0 a) ^) |
drotestosterone level in our patient. In addition to
2 X# B* S& t0 S% O, \1 h2 d2 e4 s! Mvirilization, exposure to exogenous testosterone in
7 t( K2 e. Y- Q: c+ d+ ochildren results in an increase in growth velocity and
8 x3 O0 J: F3 ^- Ladvanced bone age, as seen in our patient.
* F/ U3 B5 z$ N' |The long-term effect of androgen exposure during
" i- N4 N; l* e# Q- J; Aearly childhood on pubertal development and final! M" L+ }6 ^2 Q* w* h
adult height are not fully known and always remain& Q+ M- n/ h3 u: d- E& G" b
a concern. Children treated with short-term testos-
) h: l( s; |$ w; b9 b1 F Qterone injection or topical androgen may exhibit some
2 _# ]9 {( S' i, O( ]& g$ |) }' v; \. u/ Hacceleration of the skeletal maturation; however, after, o* V% X: Q6 @7 Y0 G/ o
cessation of treatment, the rate of bone maturation
* R" A! @5 _1 `$ r! L- X3 v" Edecelerates and gradually returns to normal.8,95 @% U+ Y, T7 E z! X" T
There are conflicting reports and controversy0 q/ f( O) I% y6 Z. Q+ B/ {* J2 V
over the effect of early androgen exposure on adult
4 k* ?- y) a, T& o( T5 ?penile length.10,11 Some reports suggest subnormal
2 E5 f4 N5 ?' k- ?: V& y: M( }6 tadult penile length, apparently because of downreg-
# t5 o6 g( M0 O: ~' R* V: zulation of androgen receptor number.10,12 However,
5 V- B6 L) o" O1 USutherland et al13 did not find a correlation between8 e8 M+ W; n: D
childhood testosterone exposure and reduced adult. q$ K2 k1 ^2 t7 o) p) d
penile length in clinical studies.
% G- C0 u( v+ ~Nonetheless, we do not believe our patient is
5 R6 v% ?: n9 d9 X6 [2 j Egoing to experience any of the untoward effects from2 X7 K. f. i% S) W: T: u- W
testosterone exposure as mentioned earlier because: R/ W3 K$ V: Z) S% B' K; ?! ^
the exposure was not for a prolonged period of time.6 d9 p" I& k7 i' c$ T
Although the bone age was advanced at the time of9 i& p# |: s' D$ \7 g3 r8 G
diagnosis, the child had a normal growth velocity at
* `7 R, n1 e/ [8 V1 o4 jthe follow-up visit. It is hoped that his final adult& D2 e5 H$ b: B* m8 e
height will not be affected.
' J6 j" X& W( I$ L( }, [Although rarely reported, the widespread avail-
- w2 n7 X D- u p8 M0 }" S Gability of androgen products in our society may
! }% s9 o3 R6 w" E+ T" i3 e# uindeed cause more virilization in male or female
4 o h1 k8 q# Cchildren than one would realize. Exposure to andro- L1 w' ^5 p/ t( C$ s" |& `+ g0 `
gen products must be considered and specific ques-
5 t' T: x, b# e9 R1 d! W# `tioning about the use of a testosterone product or' o" }; T4 q0 Z& U& j
gel should be asked of the family members during
0 L7 j7 m; C7 w- e6 a! C. f5 |the evaluation of any children who present with vir-, X- U) {! a2 w! c, d8 A+ g: Y
ilization or peripheral precocious puberty. The diag-
D5 b8 c: S& V) E4 _& E C3 _9 anosis can be established by just a few tests and by1 d& b. y, w7 T
appropriate history. The inability to obtain such a
' B/ p9 `/ O0 t) Chistory, or failure to ask the specific questions, may
8 @' L) Z0 {5 {* g4 U2 Q/ z0 oresult in extensive, unnecessary, and expensive
8 w& ?* _3 o) f/ pinvestigation. The primary care physician should be
' t Y& s9 J6 m4 d# u' s0 Eaware of this fact, because most of these children- y7 _8 @ j2 `+ k
may initially present in their practice. The Physicians’
! ?! E- _8 P0 r' m5 V* {: z1 M( d' DDesk Reference and package insert should also put a9 J$ M) s5 _0 h" @. Y( C) n9 C. ?. W
warning about the virilizing effect on a male or/ W$ W/ d* \/ i0 @
female child who might come in contact with some-
6 o q' \1 T+ U9 }: aone using any of these products.; S% L& h+ O$ G( |
References
% \# a/ ^1 ~4 i7 e# C4 r# w3 Y1. Styne DM. The testes: disorder of sexual differentiation
- c- J# x9 u3 m# o& {6 j: zand puberty in the male. In: Sperling MA, ed. Pediatric
& X; {$ t7 u( f* c1 b6 S; K! zEndocrinology. 2nd ed. Philadelphia, PA: WB Saunders;. @3 O* G' ^; {# i% I- C$ G, j. h
2002: 565-628.
: m4 z. I8 Y& s0 p2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
6 y+ ~- v& g5 q" Cpuberty in children with tumours of the suprasellar pineal |
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