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Sexual Precocity in a 16-Month-Old# N9 {- ^* Y( K6 Q
Boy Induced by Indirect Topical
]/ p) T x: y/ k/ E9 J8 K0 m( ~) IExposure to Testosterone
/ }+ B9 G: b, M, `& y' f! ]Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
/ i; k7 Y5 ^. M5 yand Kenneth R. Rettig, MD1
) s& @+ f- S' F+ p6 O* AClinical Pediatrics
/ p* l5 r" G. b$ MVolume 46 Number 65 {4 w$ {2 z$ l/ E5 O
July 2007 540-543' h5 @, M/ ~" `
© 2007 Sage Publications
: Z# V$ x* M/ f/ M) c9 p* o10.1177/0009922806296651
4 S4 \/ k- |0 L E# l! yhttp://clp.sagepub.com1 G+ k) N: f( l2 r2 Q
hosted at6 c9 Y7 {" ]7 y, Y% L# w
http://online.sagepub.com
2 u% s- t% U ~ a. UPrecocious puberty in boys, central or peripheral,4 P# G1 y2 @% g& O
is a significant concern for physicians. Central" l2 \9 \$ W L$ z: Y& p: _- S
precocious puberty (CPP), which is mediated& ~) m# ^/ i9 Q9 P( m3 E* T
through the hypothalamic pituitary gonadal axis, has/ d2 }! T* i5 t: v: ^# U
a higher incidence of organic central nervous system
5 C# A ?0 Q& e' C4 r' U* Wlesions in boys.1,2 Virilization in boys, as manifested
8 R ^- \% I6 |$ Z. Q: E3 R! x" gby enlargement of the penis, development of pubic
( ^0 d8 r6 a! O% b' x5 n; dhair, and facial acne without enlargement of testi-
6 d+ p8 V5 c- pcles, suggests peripheral or pseudopuberty.1-3 We
! c5 S) e2 Z$ T2 p" n9 m- breport a 16-month-old boy who presented with the
: j2 V% V; p9 e( t- B. q+ s7 Oenlargement of the phallus and pubic hair develop-
" b; U; b0 U8 i* v5 Fment without testicular enlargement, which was due0 `2 Q, F# w+ N1 t9 x5 l
to the unintentional exposure to androgen gel used by
7 T' b# q6 E4 [. ~( \5 vthe father. The family initially concealed this infor-
1 a. z5 E- u6 v3 M- ]mation, resulting in an extensive work-up for this
" y0 o U3 |$ K3 u" F+ Uchild. Given the widespread and easy availability of
8 x. y( j; I1 ytestosterone gel and cream, we believe this is proba-
. E# J" z, G& X1 f$ D$ @- T0 @bly more common than the rare case report in the+ h& u' i( c6 i, ]: t {
literature.4/ N# g5 \; E, ?. s! b: o' o( L
Patient Report" o$ a5 k- \# l7 R
A 16-month-old white child was referred to the
* }. T0 A3 c& {* Xendocrine clinic by his pediatrician with the concern
& l8 C+ A: m; g3 A2 ^. Mof early sexual development. His mother noticed1 ~0 @" w+ _4 f+ G& z; L
light colored pubic hair development when he was
# g A6 `" Y. Y9 \ _From the 1Division of Pediatric Endocrinology, 2University of3 o+ C# x v5 |3 h
South Alabama Medical Center, Mobile, Alabama.( y: U8 p4 ]5 i z# P, n
Address correspondence to: Samar K. Bhowmick, MD, FACE,/ c) k" s% _7 ^2 E8 k$ Z4 `
Professor of Pediatrics, University of South Alabama, College of0 A5 s- [/ ?6 Z. e8 ^
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;# s* S$ S0 W0 h& P& N
e-mail: [email protected].
+ D( ?# E7 B2 Yabout 6 to 7 months old, which progressively became
4 |3 p' X1 |: Wdarker. She was also concerned about the enlarge-* J4 ?& R1 K4 }/ J2 k
ment of his penis and frequent erections. The child
! n; m) D! @: _$ R( P. Swas the product of a full-term normal delivery, with( B, G6 I' ^9 ?2 @4 h
a birth weight of 7 lb 14 oz, and birth length of' u6 S3 [5 n9 \7 N
20 inches. He was breast-fed throughout the first year# R8 u R! m$ r w3 }3 m0 M
of life and was still receiving breast milk along with
! Y/ K4 B$ m1 Q& h. J) t# _6 u: L" qsolid food. He had no hospitalizations or surgery,1 d- f6 D# K. t9 y
and his psychosocial and psychomotor development
9 M$ w0 K+ R3 L# r/ M& zwas age appropriate.5 D) |2 e# X' [; B) ?0 @9 o, j8 f9 ]- X
The family history was remarkable for the father,* U* X5 G" m! w* ]5 V- E8 R+ u" T0 R. w
who was diagnosed with hypothyroidism at age 16,
/ B' c! _1 s0 J8 q; S' J4 p Uwhich was treated with thyroxine. The father’s
) |4 m2 z; z5 p& c1 m. E9 Zheight was 6 feet, and he went through a somewhat
~) k, ]6 f l" _) J# pearly puberty and had stopped growing by age 14.. X: k2 C0 q; K4 H$ x/ v- W
The father denied taking any other medication. The
, M3 V- |) a1 Y( ?! X9 ~child’s mother was in good health. Her menarche
9 k' r9 [/ q& C! @6 g- r3 Qwas at 11 years of age, and her height was at 5 feet' m+ u z# J4 j# W6 j! c* N
5 inches. There was no other family history of pre-
4 c# M! i. [; N8 l+ zcocious sexual development in the first-degree rela-
- s7 G0 Z2 u6 n# b* otives. There were no siblings.
1 _; q. w0 E; w9 d6 fPhysical Examination
) F8 }% ] b3 ^# e; [, `The physical examination revealed a very active,% J1 t w- ^: ^- H% t
playful, and healthy boy. The vital signs documented, t7 y/ h+ |$ W, W) S
a blood pressure of 85/50 mm Hg, his length was
: F. t A' x G* `* k& k; }, D90 cm (>97th percentile), and his weight was 14.4 kg
8 P1 y6 H- o `7 k(also >97th percentile). The observed yearly growth9 @2 a5 a( h: `0 U
velocity was 30 cm (12 inches). The examination of$ [- O" e" w/ d! K3 W* r% X
the neck revealed no thyroid enlargement.' U; g1 M4 Y, `. c7 s8 A/ w; P
The genitourinary examination was remarkable for
% t! P* J- l6 Henlargement of the penis, with a stretched length of( ~- d2 u" l4 x0 ~5 F# h' E
8 cm and a width of 2 cm. The glans penis was very well6 z" q5 ?8 o. F v
developed. The pubic hair was Tanner II, mostly around
/ ?8 m" B- p4 d540
, ^8 {* C% P2 m! Y' x% Dat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
0 G; N8 o0 ~6 g7 X! Rthe base of the phallus and was dark and curled. The' |) x; ]% u( `
testicular volume was prepubertal at 2 mL each.
' h. N7 s; U4 `5 U' p9 CThe skin was moist and smooth and somewhat4 z# d- _$ o: t+ l
oily. No axillary hair was noted. There were no
2 t. ~9 k/ n) I# {1 {# Mabnormal skin pigmentations or café-au-lait spots.( q0 |: U+ h/ v% n: T/ n, Y- e
Neurologic evaluation showed deep tendon reflex 2+
+ }* O" b q3 ? n- G3 w0 ibilateral and symmetrical. There was no suggestion: r" D, p2 ] M! a
of papilledema.2 w A1 l; f _: u' C% |/ g+ Q
Laboratory Evaluation8 x$ w* |: E/ r6 F
The bone age was consistent with 28 months by
+ ^. ]2 s' x2 q4 ^( E3 z$ [. rusing the standard of Greulich and Pyle at a chrono-4 }# Y, J/ w9 A, Q9 ?$ K* m e
logic age of 16 months (advanced).5 Chromosomal
! k. }! D) {* Wkaryotype was 46XY. The thyroid function test {4 f+ h( E( b. n
showed a free T4 of 1.69 ng/dL, and thyroid stimu-0 r( ?" Z3 F1 a' m" A
lating hormone level was 1.3 µIU/mL (both normal).' i" V" o, e( S1 v8 A* \+ u
The concentrations of serum electrolytes, blood4 h8 o# z8 W' g8 O! a! V( p
urea nitrogen, creatinine, and calcium all were
" R3 @) `. O) e0 Q" {$ Kwithin normal range for his age. The concentration5 ?" t4 n4 f. t) s3 {
of serum 17-hydroxyprogesterone was 16 ng/dL
" q+ k, a, ?+ u7 n, D(normal, 3 to 90 ng/dL), androstenedione was 20
( j# O+ E5 e# w5 q5 B2 Mng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
2 [% E% a) l* q- N9 N5 y1 O' Cterone was 38 ng/dL (normal, 50 to 760 ng/dL),2 |% [9 }2 h; o) w. X1 s+ E9 Z
desoxycorticosterone was 4.3 ng/dL (normal, 7 to
9 }4 F2 ^1 ~% ?' N" c7 U49ng/dL), 11-desoxycortisol (specific compound S)
- ~: M2 j4 ?0 h8 B6 [6 ^' b6 {7 Kwas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-* E1 u/ _. O. s m4 E$ e
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total- D; ?: {# f* l
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),7 l4 |8 D# Z* }
and β-human chorionic gonadotropin was less than
) h/ l/ H0 R8 M! ]' t* I" o; Y9 _% b5 mIU/mL (normal <5 mIU/mL). Serum follicular' g( i( l/ s+ U8 Q
stimulating hormone and leuteinizing hormone
+ n: T! m- K5 d) A! X, Xconcentrations were less than 0.05 mIU/mL1 B/ ^2 g6 f2 c
(prepubertal).
* L. K; R2 S* BThe parents were notified about the laboratory
: H9 ^9 j! B( G+ E: a. Nresults and were informed that all of the tests were
2 d* O& ^! e! y( t2 H2 t+ L1 m Jnormal except the testosterone level was high. The1 `0 H M! ^3 c z1 p6 d7 @9 V
follow-up visit was arranged within a few weeks to% L! h' e8 L5 c7 O4 I. H: Q# u
obtain testicular and abdominal sonograms; how-
$ w1 p# d* @6 f$ j' T4 F, L/ _* |ever, the family did not return for 4 months.& U2 ^; R- i. \6 \
Physical examination at this time revealed that the
1 Y9 j b$ r8 [8 vchild had grown 2.5 cm in 4 months and had gained
$ y3 O! j( O& F5 ?2 kg of weight. Physical examination remained0 E$ o; h4 o' t5 g& Y
unchanged. Surprisingly, the pubic hair almost com-8 s. c w; ] ^; m( o5 p6 |! D) y
pletely disappeared except for a few vellous hairs at$ R- A% _2 H b3 a( g0 X6 Z
the base of the phallus. Testicular volume was still 2% W* P& W& J& z! h
mL, and the size of the penis remained unchanged./ A7 M, N: H/ T) ]& y
The mother also said that the boy was no longer hav-
2 D* ^* z8 q% M5 Z" g; U$ Aing frequent erections.
8 T) T0 n, f( y/ d/ nBoth parents were again questioned about use of" q& {" G- b/ ~& N* C- c
any ointment/creams that they may have applied to
9 l, t9 l( l( j Q- I$ c' }the child’s skin. This time the father admitted the
" G- V; W1 C( s+ WTopical Testosterone Exposure / Bhowmick et al 541
* a8 L ^- C( M8 x, d; juse of testosterone gel twice daily that he was apply-
+ p. E/ a' t% ^9 ging over his own shoulders, chest, and back area for0 I8 h( I- Z7 [* i2 _& z
a year. The father also revealed he was embarrassed& O6 \& E# T" o8 X
to disclose that he was using a testosterone gel pre-5 M0 |4 V6 ?- [4 a
scribed by his family physician for decreased libido
8 o; \$ z$ Q2 s1 N' J2 {secondary to depression.
7 B9 K; q: J |! C9 _! q: f: uThe child slept in the same bed with parents.. n) [2 B8 q6 c
The father would hug the baby and hold him on his* i* H( I) u: H- F o1 {# Q6 G
chest for a considerable period of time, causing sig-8 y O5 d9 J* }
nificant bare skin contact between baby and father.7 y1 ^3 s# R# ?( M. {
The father also admitted that after the phone call,
( H( U5 S* W* Nwhen he learned the testosterone level in the baby
0 b' D/ G' C9 s( Rwas high, he then read the product information
/ d+ `' \7 _4 i( m# G" ]packet and concluded that it was most likely the rea-
D H* G# R o; w0 Cson for the child’s virilization. At that time, they
3 v; B9 S2 @ Y) G7 Q* gdecided to put the baby in a separate bed, and the; H; k! t7 x {/ y6 y- X1 C8 x3 B S" H
father was not hugging him with bare skin and had* @4 k; L6 m w3 h& v
been using protective clothing. A repeat testosterone
& h" o- l& V! `0 w/ f2 n9 N6 ftest was ordered, but the family did not go to the
) L( _; R; C% [. q6 ~ Jlaboratory to obtain the test.# U1 Z$ p1 h/ {! F1 i
Discussion0 }! c* r7 k3 m. B
Precocious puberty in boys is defined as secondary
0 G7 J/ f7 f/ L6 |; dsexual development before 9 years of age.1,4
7 M$ I1 |9 g3 nPrecocious puberty is termed as central (true) when
# K2 y" r) O+ M+ A$ V5 vit is caused by the premature activation of hypo- k4 K, W9 _3 P& q- H' `0 R9 \( q5 S% Q
thalamic pituitary gonadal axis. CPP is more com-" l* z$ G! i, J) k0 R* K8 l* W
mon in girls than in boys.1,3 Most boys with CPP
% P2 n$ e9 Q1 fmay have a central nervous system lesion that is. F6 O8 B1 U5 b0 j
responsible for the early activation of the hypothal-
6 c( ^4 W6 ?# B6 mamic pituitary gonadal axis.1-3 Thus, greater empha-
t' h4 W" r; i' g: nsis has been given to neuroradiologic imaging in4 P( |2 t/ _) B9 I4 L
boys with precocious puberty. In addition to viril-+ G8 o) Q [/ p/ l. u
ization, the clinical hallmark of CPP is the symmet-
( |* n6 V- i/ orical testicular growth secondary to stimulation by
8 }" y6 O% \) |+ i& C: A7 c2 kgonadotropins.1,3
' \4 a; ?' H7 \. I0 E- q& zGonadotropin-independent peripheral preco-
/ }! E* m$ ?6 h# e' d( \5 Gcious puberty in boys also results from inappropriate# g3 b/ v& G1 K& v
androgenic stimulation from either endogenous or& F' e3 O$ ?, d5 x: Z# F- \
exogenous sources, nonpituitary gonadotropin stim-
) }4 f3 H. E5 ^$ ]9 {5 Z( \$ pulation, and rare activating mutations.3 Virilizing
4 B5 ~3 u3 C3 {: Pcongenital adrenal hyperplasia producing excessive7 {& s1 ]6 g' v6 V/ e
adrenal androgens is a common cause of precocious
3 }* s! @' B& l/ A* o4 Y0 Cpuberty in boys.3,4
( e% d" D( z% ^1 D7 P7 RThe most common form of congenital adrenal" L# P4 C/ Y# M. Z- ?8 w+ s8 w
hyperplasia is the 21-hydroxylase enzyme deficiency.
! D! B) O8 X* A7 q- [# U1 [The 11-β hydroxylase deficiency may also result in4 R& u2 L2 H* `1 m% t" h: m0 ?+ F8 a
excessive adrenal androgen production, and rarely," q: o4 Z+ s- g% o% t3 r
an adrenal tumor may also cause adrenal androgen* ~) t* P7 y7 k
excess.1,3
$ s$ N3 @# W" G. {. y4 P4 Eat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from* u7 u" R8 e4 a3 r
542 Clinical Pediatrics / Vol. 46, No. 6, July 20077 |8 J8 m( Q9 u* U
A unique entity of male-limited gonadotropin-
8 z) ]: z* j4 M" f! b- Gindependent precocious puberty, which is also known$ M$ v, ~, A/ y9 x* ^7 `6 m
as testotoxicosis, may cause precocious puberty at a Q5 k" o2 i$ i, r
very young age. The physical findings in these boys
4 \# M4 `% n( F' W9 u, Jwith this disorder are full pubertal development,7 c$ s0 M8 n, J
including bilateral testicular growth, similar to boys
9 f1 s; i6 C5 B9 E/ V. ]9 W9 rwith CPP. The gonadotropin levels in this disorder- `( V" B, c- Z( N/ N! h- J7 R
are suppressed to prepubertal levels and do not show
7 J' X; [' e4 D. l7 Npubertal response of gonadotropin after gonadotropin-8 w$ n7 v8 Z* Y. e/ k
releasing hormone stimulation. This is a sex-linked Q/ k; s" N# V- `0 {# V2 U% b
autosomal dominant disorder that affects only/ E/ h# o0 A$ ?9 y/ }5 T
males; therefore, other male members of the family8 L$ \. G/ P% S) s
may have similar precocious puberty.3* ^, @2 r, Q: f$ E, o, z4 |
In our patient, physical examination was incon-
/ N" F2 M9 i ^4 V+ Hsistent with true precocious puberty since his testi-
; R5 i3 V8 O+ Q' n% scles were prepubertal in size. However, testotoxicosis7 y, p% S# D1 E' N+ l& A
was in the differential diagnosis because his father
' J. p: X/ I) e( @$ Bstarted puberty somewhat early, and occasionally,3 R$ \1 t, K L# l+ J3 [6 |
testicular enlargement is not that evident in the
: s) F( w7 `4 ?; @, k/ Obeginning of this process.1 In the absence of a neg-
1 j5 I& k) c# A* R7 ?, y3 Oative initial history of androgen exposure, our
: `$ ]6 D4 O- \; n# q8 _: Fbiggest concern was virilizing adrenal hyperplasia,
% I# } E5 ?# N U, W# U4 veither 21-hydroxylase deficiency or 11-β hydroxylase, s- v# Y$ |2 g/ O" s4 w, u
deficiency. Those diagnoses were excluded by find-
% n J3 K* R G, J5 R" zing the normal level of adrenal steroids.
1 U$ ~) f% y0 ~" e+ xThe diagnosis of exogenous androgens was strongly
2 y& l& z$ g3 L, ^% |suspected in a follow-up visit after 4 months because$ c+ _2 X& t0 d' [$ ?5 Z/ B4 i3 y
the physical examination revealed the complete disap-
8 {" W8 ~: v7 c# `" n& [% Jpearance of pubic hair, normal growth velocity, and2 m, _4 {) v, _8 X
decreased erections. The father admitted using a testos-* U9 D% T. L& o
terone gel, which he concealed at first visit. He was% ]' j: u" |7 l' Q
using it rather frequently, twice a day. The Physicians’
+ ~. x( G3 G3 u* Y z* C* H+ x$ dDesk Reference, or package insert of this product, gel or1 j0 R# n' a+ `
cream, cautions about dermal testosterone transfer to* d# i; n. i6 h" i0 s% [
unprotected females through direct skin exposure.- a! T% Z; N) W t' ^
Serum testosterone level was found to be 2 times the. }$ d0 S" E3 w' u2 W
baseline value in those females who were exposed to3 s4 i) o2 W% Q; J9 j
even 15 minutes of direct skin contact with their male- o3 y3 T5 M9 Q/ ~
partners.6 However, when a shirt covered the applica-, x' l; D; T9 J. P$ O, R- X: ?
tion site, this testosterone transfer was prevented." T! H8 g7 k- z' c+ M
Our patient’s testosterone level was 60 ng/mL,
1 M; u# P5 }) h4 Pwhich was clearly high. Some studies suggest that
+ I: w; k: e% J8 }+ R$ Kdermal conversion of testosterone to dihydrotestos-
! Z# k0 }6 ] A% vterone, which is a more potent metabolite, is more, Q- a* n! H- ^: U! E0 c
active in young children exposed to testosterone
5 w1 [! D2 L# _9 y3 sexogenously7; however, we did not measure a dihy-
1 B" x; @" {" }1 jdrotestosterone level in our patient. In addition to
. U! j: r/ a6 I+ o% x, ^2 Wvirilization, exposure to exogenous testosterone in
( `$ R0 i; N1 R# bchildren results in an increase in growth velocity and" b, G' G* ~& x4 c7 d8 u) y
advanced bone age, as seen in our patient.) S. N* Y% ?/ y
The long-term effect of androgen exposure during1 y, X* ^/ ]5 y
early childhood on pubertal development and final
! [9 L5 h) R G! nadult height are not fully known and always remain. J, O2 z4 K1 c1 @0 ~8 J
a concern. Children treated with short-term testos-& B# L3 m- L8 g; x u3 y
terone injection or topical androgen may exhibit some
0 R6 U( p9 M* s' L4 h! G! wacceleration of the skeletal maturation; however, after
- n6 ^% X) q0 H' ?( f/ G1 }& X! Hcessation of treatment, the rate of bone maturation% F: T/ V4 K/ T1 S2 ]
decelerates and gradually returns to normal.8,9% ?1 W# W: R/ c
There are conflicting reports and controversy8 X$ s, ]8 n; k/ M; I" y4 G2 i
over the effect of early androgen exposure on adult
( P) t3 I8 N9 h9 r) K# ^1 Bpenile length.10,11 Some reports suggest subnormal
1 H+ R2 Q2 \' s8 C2 iadult penile length, apparently because of downreg-
3 W6 {! j) x$ ]3 n9 ^8 eulation of androgen receptor number.10,12 However,
/ V! x, |( }" GSutherland et al13 did not find a correlation between
! H) B# K& |3 y0 }& Pchildhood testosterone exposure and reduced adult; A, r9 ]" U: P( K0 h
penile length in clinical studies.
3 x: o2 z, i5 M6 BNonetheless, we do not believe our patient is/ b: w4 i6 r$ U6 e9 N
going to experience any of the untoward effects from, i: ~+ P8 o3 |6 _3 ~8 P, U q
testosterone exposure as mentioned earlier because
! s% ~6 ]. l6 L- G7 Z8 Wthe exposure was not for a prolonged period of time.
+ b, b% r% b/ @$ j# r1 t7 OAlthough the bone age was advanced at the time of
9 U0 H: H/ I$ g$ q# _: Ldiagnosis, the child had a normal growth velocity at3 L4 v5 M0 q& {" A: ^( v6 h
the follow-up visit. It is hoped that his final adult' X+ M/ k3 q+ O, V/ k1 n: H
height will not be affected.* Q2 G! c3 @. L6 \: C' s
Although rarely reported, the widespread avail-9 [: A. R: f" v% {: o0 R1 Q
ability of androgen products in our society may
$ Z5 B# |7 @9 P# ]- W7 _) H1 cindeed cause more virilization in male or female
2 q* ]$ j6 Q! n6 {. r6 M- fchildren than one would realize. Exposure to andro-
0 n u- ?- }# K6 p" r! [1 C+ a, l# Jgen products must be considered and specific ques-
' J( |0 Q6 X, [! u3 \8 W; otioning about the use of a testosterone product or- H% A( A! d& X, H+ U
gel should be asked of the family members during7 n% a9 \, v& `* J; n
the evaluation of any children who present with vir-; r' p+ q0 F; Z9 g# |! m; C
ilization or peripheral precocious puberty. The diag-9 b; L5 J" t1 t; K
nosis can be established by just a few tests and by, e% W! I) b* E4 A% \
appropriate history. The inability to obtain such a
6 p; e7 O" C' s* M! t' Bhistory, or failure to ask the specific questions, may
' s+ h) y- k& m" Z, ~result in extensive, unnecessary, and expensive9 W1 k5 j5 M9 Q
investigation. The primary care physician should be- z# e# ?! [, g$ |8 D1 n7 x
aware of this fact, because most of these children
, B, a* ?8 u+ v" C1 E/ ]" ^may initially present in their practice. The Physicians’
9 P8 |, B5 n4 T; nDesk Reference and package insert should also put a$ X: V" U. v' W. S+ I+ e& y
warning about the virilizing effect on a male or( r+ a4 N( ~9 d& \% ^9 Q
female child who might come in contact with some-
5 Y' }2 e$ l2 o. ]+ U1 s, kone using any of these products.
1 v5 k8 e8 W; d0 QReferences6 C) l C3 O! A8 Z
1. Styne DM. The testes: disorder of sexual differentiation6 ]* n2 A: S: L# T0 O
and puberty in the male. In: Sperling MA, ed. Pediatric
! r/ _9 |' a$ E; v! t- E, YEndocrinology. 2nd ed. Philadelphia, PA: WB Saunders;6 @4 c; s+ \- b6 w, P) m
2002: 565-628.# ~) E0 s8 M9 X9 i
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
* `5 V* N/ V3 I6 X- ?3 j) g' zpuberty in children with tumours of the suprasellar pineal |
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