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Sexual Precocity in a 16-Month-Old
8 D* M: x% w6 g g* mBoy Induced by Indirect Topical {' H8 V) M5 |: X
Exposure to Testosterone
. i# @5 Z% B, ~5 H: }Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2! i( u/ J1 ~8 b2 q4 ?
and Kenneth R. Rettig, MD1 Z" C) s: U1 x; d; y4 }- @
Clinical Pediatrics0 `1 N% {' O- ~" i
Volume 46 Number 6
3 v" _# m5 M' G; Z, _ kJuly 2007 540-5433 o4 G8 |9 p4 A9 W9 |- O& ^. H* \
© 2007 Sage Publications
p& ?& ~9 B- R, n4 K10.1177/0009922806296651
2 j, P. e/ z6 R+ Uhttp://clp.sagepub.com
' w6 S) t% H) g9 ], J) H+ Khosted at
3 f8 r* G% ~2 r8 v2 s7 n3 V8 q7 dhttp://online.sagepub.com
9 }, v$ B! l8 j/ }1 @Precocious puberty in boys, central or peripheral,
' @$ f* W$ g9 g+ dis a significant concern for physicians. Central* A6 y4 e! |- G
precocious puberty (CPP), which is mediated
6 }9 e( P. r8 ]) i& H9 I: dthrough the hypothalamic pituitary gonadal axis, has5 z# O% }3 W1 d! d6 i
a higher incidence of organic central nervous system
2 S# k2 x+ {; u) C, F7 L8 glesions in boys.1,2 Virilization in boys, as manifested
?4 ^' w% W6 _% R" jby enlargement of the penis, development of pubic0 Z5 O( z' |1 `# A
hair, and facial acne without enlargement of testi-2 m8 l( V& u* F5 x# k/ m* _: i
cles, suggests peripheral or pseudopuberty.1-3 We
: ~% \4 D" n6 \7 g0 freport a 16-month-old boy who presented with the$ y2 B- C/ i3 S5 @9 ]4 ?
enlargement of the phallus and pubic hair develop-# _2 H) {0 X9 q( P1 [5 {
ment without testicular enlargement, which was due
, t# q6 H+ s2 G% ato the unintentional exposure to androgen gel used by
' D- `+ D& G( l7 ~& D" y/ o; t8 I3 x' Athe father. The family initially concealed this infor-# w+ U a; X# b8 v0 ]
mation, resulting in an extensive work-up for this. [' t ?. U4 S- N4 d
child. Given the widespread and easy availability of
1 T1 Z3 m% O4 Htestosterone gel and cream, we believe this is proba-- q8 w& r! p# |* U# w
bly more common than the rare case report in the
9 q& F3 m& ~: n" e6 j, Y% _# J& ]literature.4# S' K4 k( O& I M; P4 }
Patient Report$ q) s V" t2 l9 J& Q9 H
A 16-month-old white child was referred to the6 [3 a( `9 K3 o( e
endocrine clinic by his pediatrician with the concern% ~" i* u5 ]* n0 ^ @
of early sexual development. His mother noticed
; H0 Y% [ g4 O- Klight colored pubic hair development when he was
' u( I! m3 g! p$ E; QFrom the 1Division of Pediatric Endocrinology, 2University of
9 G1 n: X* C% `+ cSouth Alabama Medical Center, Mobile, Alabama.
5 h O, J* K2 p3 \- O, U8 RAddress correspondence to: Samar K. Bhowmick, MD, FACE,
% a8 e. X% s/ [! Z1 ~Professor of Pediatrics, University of South Alabama, College of: _ j! i$ g" s5 L
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;" i( e6 p! d8 d$ r
e-mail: [email protected].5 K4 w; k" S, V$ }6 O5 S& ]
about 6 to 7 months old, which progressively became% `# j' l' r' g$ H8 @
darker. She was also concerned about the enlarge-
4 \) a! R, [, @4 U/ d; r, wment of his penis and frequent erections. The child+ Q! _6 y/ S: r4 Y9 N
was the product of a full-term normal delivery, with' D' [9 I' X+ E! S& ?; W: q
a birth weight of 7 lb 14 oz, and birth length of
+ L2 ~$ |& l; S6 u) b- \6 ~20 inches. He was breast-fed throughout the first year+ r3 H- t: R! T2 z
of life and was still receiving breast milk along with
+ W" t4 d/ h; y- Isolid food. He had no hospitalizations or surgery,+ V# T/ p6 L/ [
and his psychosocial and psychomotor development! ?1 Z9 C h; E) i
was age appropriate.
1 ^4 j$ A- q. y5 sThe family history was remarkable for the father,
' o, F& \0 Z1 S& | ]who was diagnosed with hypothyroidism at age 16,) {3 [3 E7 U: }
which was treated with thyroxine. The father’s4 A4 Z9 N) h/ p n- }9 L; S9 W/ P$ y
height was 6 feet, and he went through a somewhat& {( V/ I1 p2 d
early puberty and had stopped growing by age 14.
& H; O. m! b8 `4 cThe father denied taking any other medication. The2 H; r2 }3 u! w3 ~7 H
child’s mother was in good health. Her menarche
/ p) z7 o9 O5 ?/ ^/ v' Rwas at 11 years of age, and her height was at 5 feet
: y; l5 w1 v5 Y4 F+ t7 J5 inches. There was no other family history of pre-
3 i; C0 i4 F2 k7 I1 ]: w# [4 [cocious sexual development in the first-degree rela-
5 ^5 q% N7 T1 t2 X7 O; ttives. There were no siblings.* D8 {) k8 K) h2 \% o% y( j
Physical Examination8 Q- U! K/ j1 M8 i: M6 `5 u% t3 p
The physical examination revealed a very active,. |! H# M1 y) h* S, z
playful, and healthy boy. The vital signs documented- E, Y. Y, M U! V- ]2 z
a blood pressure of 85/50 mm Hg, his length was' h' I/ J) E) x; V9 z
90 cm (>97th percentile), and his weight was 14.4 kg
: d! I" q1 ~9 L# g. J6 J(also >97th percentile). The observed yearly growth: P% S$ i7 R+ c! T
velocity was 30 cm (12 inches). The examination of
) r' B8 [ t+ s" Lthe neck revealed no thyroid enlargement.% ~" K: R9 Z/ N6 f4 [& S$ j8 s2 B0 t
The genitourinary examination was remarkable for9 I- q" \4 Y: j2 P* g
enlargement of the penis, with a stretched length of
7 y$ r# N5 c% @/ _* R R8 cm and a width of 2 cm. The glans penis was very well
$ g% f0 ^, f% v$ n/ edeveloped. The pubic hair was Tanner II, mostly around
% U0 H! v/ f5 j+ ^+ a+ @/ e% i3 ?5400 r$ G3 c" Z. h2 R4 {. p
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from; t, y9 i& i8 X! i: V, U
the base of the phallus and was dark and curled. The
$ ], ^3 j4 _5 f8 L3 F8 {testicular volume was prepubertal at 2 mL each.9 d2 X$ _6 M& F# b: L7 s
The skin was moist and smooth and somewhat* \ B0 [& B; n& g" D" v5 i( I# B
oily. No axillary hair was noted. There were no/ E) e( w" _ D. {# X
abnormal skin pigmentations or café-au-lait spots.
/ X' f6 S* G: j7 e- f: v- `Neurologic evaluation showed deep tendon reflex 2+
5 y9 p1 _; L/ C8 z1 f: G; s& Ubilateral and symmetrical. There was no suggestion* Y) @+ V, Q) q b, `! F
of papilledema.
5 {( @" E$ Y, b6 ~; hLaboratory Evaluation5 j0 o' I+ |9 y j
The bone age was consistent with 28 months by
+ {1 t: a1 _2 ^2 f* Wusing the standard of Greulich and Pyle at a chrono-7 V6 T6 ]* S" Z! k" R: ^8 o: Y' H8 k
logic age of 16 months (advanced).5 Chromosomal
5 F2 C9 b! u- t1 Zkaryotype was 46XY. The thyroid function test. m$ G/ Y" P" `% B% e
showed a free T4 of 1.69 ng/dL, and thyroid stimu-6 @* w$ o& l" s# _- h/ @! Z
lating hormone level was 1.3 µIU/mL (both normal).
/ N& @# ?6 X6 L; \7 j" xThe concentrations of serum electrolytes, blood
) X1 q z/ @ C1 s: v; C* Xurea nitrogen, creatinine, and calcium all were' K9 O4 `. h9 I- Q
within normal range for his age. The concentration
7 U! T; b: z4 ~& \) `of serum 17-hydroxyprogesterone was 16 ng/dL* {$ ]( _7 l: F. B1 @
(normal, 3 to 90 ng/dL), androstenedione was 20) n7 W- V' I9 ]2 \
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-2 f: }6 ?3 h/ {6 H
terone was 38 ng/dL (normal, 50 to 760 ng/dL),) R% R P4 ^1 m& {2 p8 b2 ~* D
desoxycorticosterone was 4.3 ng/dL (normal, 7 to; a2 A' p, a9 k' m, I4 D( Z
49ng/dL), 11-desoxycortisol (specific compound S)
/ M2 u( E3 i" \) r$ C# Uwas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
" O- c" s3 u6 B ^8 z9 h" F( [6 qtisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total7 G! Q# G! d* R' J3 x1 i
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),9 a& |. V& l5 K3 C/ A& q& J+ l! u& \
and β-human chorionic gonadotropin was less than
/ N+ N( o/ |9 b7 e& g$ K5 mIU/mL (normal <5 mIU/mL). Serum follicular
7 [- D. D' I4 T* l# f jstimulating hormone and leuteinizing hormone" I: f; _9 ~0 |- a2 {
concentrations were less than 0.05 mIU/mL
/ j) V( ~. g1 t# N, ]7 M(prepubertal).
5 W- M o: ]3 `# [. F L& d; u# \The parents were notified about the laboratory% F0 o% K+ _; G3 O2 r& l2 o
results and were informed that all of the tests were+ f) z3 @6 \; }6 u
normal except the testosterone level was high. The
2 h2 ^ b; m3 z9 ^2 B% afollow-up visit was arranged within a few weeks to5 E4 f- K# @3 B V
obtain testicular and abdominal sonograms; how- h; }7 D: H2 ?# r+ m
ever, the family did not return for 4 months.; i, L5 m6 m2 e- o3 P& S8 m" g
Physical examination at this time revealed that the0 {2 G: S* g1 Q+ ~
child had grown 2.5 cm in 4 months and had gained
+ L# `, O4 r) y( c4 ]' {4 d2 kg of weight. Physical examination remained
: v& L k. Z# f. \3 runchanged. Surprisingly, the pubic hair almost com-
, H# i: G+ Y5 l! C' T$ B4 m2 V; Rpletely disappeared except for a few vellous hairs at- k _( I7 Y) Y
the base of the phallus. Testicular volume was still 2, x0 e2 W3 u, ]# v& M
mL, and the size of the penis remained unchanged.' l% b; E7 ~: T( ~4 r9 P: o5 r
The mother also said that the boy was no longer hav-
1 Z# F6 d' W3 N6 ]# x+ d2 xing frequent erections.
+ h! V6 F; C# Z) b& x: TBoth parents were again questioned about use of
2 Z- C: N9 f/ Q+ M# j* uany ointment/creams that they may have applied to
' `' z& w& \" o- x$ u. R- B9 `, hthe child’s skin. This time the father admitted the
1 ]( y' \' ^) g: e) v( Y8 L$ zTopical Testosterone Exposure / Bhowmick et al 541 @$ Z/ Q5 Y, n; |. Z
use of testosterone gel twice daily that he was apply-0 ~2 X8 c6 a& H7 u
ing over his own shoulders, chest, and back area for* i- H2 {" H& e" p9 g }" \3 B* z
a year. The father also revealed he was embarrassed- |; d4 ]1 C$ v8 u2 n, N
to disclose that he was using a testosterone gel pre-
2 }/ J9 @) g- o+ ascribed by his family physician for decreased libido1 B. `. [5 L" ]
secondary to depression., f# ?% `8 n; C9 p5 y
The child slept in the same bed with parents.# t% a& a! l& u9 _
The father would hug the baby and hold him on his
' b r. J' L" P4 _4 @; u" ?chest for a considerable period of time, causing sig-$ x- o2 v) Q9 o; k$ E' @ t
nificant bare skin contact between baby and father.
! C& z+ U6 {& f9 X; V. G( a* _The father also admitted that after the phone call,
1 A4 e# P# ]+ V2 }' H# zwhen he learned the testosterone level in the baby# M+ c! W- ~. o$ W
was high, he then read the product information3 |6 L4 O; ?4 A8 g9 l* R( t
packet and concluded that it was most likely the rea-" h6 w. A; T6 G) J2 F: ~; s
son for the child’s virilization. At that time, they# X8 N& j5 x1 w
decided to put the baby in a separate bed, and the
1 l" `7 Y0 ^4 p# Z, V0 vfather was not hugging him with bare skin and had$ B1 {* D9 x8 A: i
been using protective clothing. A repeat testosterone$ K, c3 v6 j, J* ~0 x `
test was ordered, but the family did not go to the0 Q1 I: Z( W: L: Z/ H# a9 O
laboratory to obtain the test.
( |* j; d. x3 l9 g9 ADiscussion
7 r! I$ d' ~( _; Q; Z5 h) }Precocious puberty in boys is defined as secondary
$ S5 n# Y3 p2 W0 I" A2 bsexual development before 9 years of age.1,43 y o8 p/ w' W% C
Precocious puberty is termed as central (true) when
3 O6 L2 s5 J2 @! Vit is caused by the premature activation of hypo- A* k8 K# r& Y
thalamic pituitary gonadal axis. CPP is more com-3 P+ B7 j) q6 t
mon in girls than in boys.1,3 Most boys with CPP2 G" B5 M" i4 o3 f
may have a central nervous system lesion that is
0 m. ]6 K9 R6 c% `9 B9 @* ^responsible for the early activation of the hypothal-
/ ?! {" C5 |/ ]amic pituitary gonadal axis.1-3 Thus, greater empha-0 j V( R& O% P( T3 B1 n+ q
sis has been given to neuroradiologic imaging in
v: Y) ^4 y8 R$ R, q; [boys with precocious puberty. In addition to viril-! o: |) l, D6 O& x
ization, the clinical hallmark of CPP is the symmet-- J3 _& F1 a+ w
rical testicular growth secondary to stimulation by7 ~* Z& o3 t8 u& h
gonadotropins.1,3. Y O0 G2 f" Y0 E2 r& ^$ k! s1 ~: D
Gonadotropin-independent peripheral preco-
4 G! Y+ ^1 G/ c6 C* `cious puberty in boys also results from inappropriate
* T1 ]8 r5 ~! Candrogenic stimulation from either endogenous or
) j# d; z2 X4 O6 |- W- Y8 dexogenous sources, nonpituitary gonadotropin stim-3 `1 I/ @( C6 {
ulation, and rare activating mutations.3 Virilizing5 q# V" _) ~0 I0 W
congenital adrenal hyperplasia producing excessive
0 Z, j& R' ]( gadrenal androgens is a common cause of precocious: m+ L2 e6 f6 t/ Q( u
puberty in boys.3,4
* n4 P$ O2 j2 G4 L, \$ s6 H6 S O; yThe most common form of congenital adrenal/ Q! N8 W- L4 K d, s4 p
hyperplasia is the 21-hydroxylase enzyme deficiency.
- {4 T* T" ~' @. mThe 11-β hydroxylase deficiency may also result in
J' i# H& X( X8 I2 K& Fexcessive adrenal androgen production, and rarely,9 p6 x; F8 b1 z: y) N! n! O- N
an adrenal tumor may also cause adrenal androgen' N) X& K2 k' N _& V I3 V
excess.1,36 C' d+ ~0 Z- v, M, M5 c' E
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from& s+ p0 m: M$ E8 `
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
! q v1 m. W' I# h: z+ D7 D/ SA unique entity of male-limited gonadotropin-2 E" K/ L* x* p$ n, J, O
independent precocious puberty, which is also known
' }, c/ Q' S# \as testotoxicosis, may cause precocious puberty at a5 w7 S+ ]- W8 w. \5 ^
very young age. The physical findings in these boys
2 O2 k9 L F p- h7 A. S4 Lwith this disorder are full pubertal development,2 o$ Z1 M" h* ]/ _- J# y" _* b
including bilateral testicular growth, similar to boys) a0 V4 I/ [3 c1 S
with CPP. The gonadotropin levels in this disorder
1 O, T3 I# ]% k: Z! ?are suppressed to prepubertal levels and do not show/ m2 Q0 L3 B1 n
pubertal response of gonadotropin after gonadotropin-
+ \( T9 U8 F1 b3 u. y5 T* e" X+ R% Wreleasing hormone stimulation. This is a sex-linked q5 n2 g/ f$ n( V4 C3 d
autosomal dominant disorder that affects only
8 u m! U, ]) `6 d" Jmales; therefore, other male members of the family
, m3 w' |/ X5 w/ ?' zmay have similar precocious puberty.3
0 w9 `( X2 W9 A y7 m+ {In our patient, physical examination was incon-
- q1 ?- n# r5 R3 l, [3 @+ l$ }sistent with true precocious puberty since his testi-
K" k4 f0 L: n- L% e1 ccles were prepubertal in size. However, testotoxicosis, u y2 h8 d c. z" _! l ^+ y& U, W; G
was in the differential diagnosis because his father! u2 J# ~$ }8 j7 i- @
started puberty somewhat early, and occasionally,
) i+ c# N* z2 R3 R; J! Utesticular enlargement is not that evident in the# y, E( q" g! N
beginning of this process.1 In the absence of a neg-
4 ^8 @2 r; F" ` mative initial history of androgen exposure, our$ O- @% m3 _( e( ~$ C
biggest concern was virilizing adrenal hyperplasia,
0 ~( u, e s0 s Leither 21-hydroxylase deficiency or 11-β hydroxylase+ H; K+ C' i: N {+ s- v9 i0 C, p! q
deficiency. Those diagnoses were excluded by find-
- I0 x3 |5 M* y% z" t. Z5 Z+ Uing the normal level of adrenal steroids.
) X9 v5 F: a$ b* t }# PThe diagnosis of exogenous androgens was strongly: x5 k, w+ l. ^- V: Y0 H- y8 h
suspected in a follow-up visit after 4 months because! w; h; p6 L8 c
the physical examination revealed the complete disap-
) f3 | D2 Z1 r- l3 q, C/ w$ Jpearance of pubic hair, normal growth velocity, and
- a7 E( c0 _8 jdecreased erections. The father admitted using a testos-
4 Z4 V# x1 u' q4 k) c* Wterone gel, which he concealed at first visit. He was) x; A3 |! `# z' R$ e
using it rather frequently, twice a day. The Physicians’
1 C8 i- |; k5 Q2 ]Desk Reference, or package insert of this product, gel or' T5 @& s. \9 b6 N8 _7 j" P
cream, cautions about dermal testosterone transfer to# R- H# ?$ ?7 }( d; a# g: C
unprotected females through direct skin exposure.- P4 U- o. u1 m1 _3 V3 e$ J
Serum testosterone level was found to be 2 times the
0 p" m% {; i% d9 Lbaseline value in those females who were exposed to
% P" p4 I: X. f! `even 15 minutes of direct skin contact with their male
6 b# o- }' B! G0 J% E `( `partners.6 However, when a shirt covered the applica-
7 w8 C. j9 L3 [9 w, \4 @tion site, this testosterone transfer was prevented.4 ?8 m- z, n6 L6 F/ X8 M
Our patient’s testosterone level was 60 ng/mL,1 K: L: E# `: E8 _( I
which was clearly high. Some studies suggest that+ x: K& w2 D$ o2 N
dermal conversion of testosterone to dihydrotestos-% z% q0 V: O* E
terone, which is a more potent metabolite, is more
$ @7 q) ~+ o4 H$ c0 }2 t1 y5 Pactive in young children exposed to testosterone
7 F) D8 _9 a1 M( P! d" v0 i% C: }9 }exogenously7; however, we did not measure a dihy-& y' J4 H# L; Z1 {$ b
drotestosterone level in our patient. In addition to6 N) f4 \) D2 k! G
virilization, exposure to exogenous testosterone in* d: s# \* P7 H
children results in an increase in growth velocity and9 c8 L _. K; H8 _% m
advanced bone age, as seen in our patient.+ S* z& T5 s8 k' S$ D
The long-term effect of androgen exposure during
; v2 N# _6 G( _4 ^' {0 Y" O1 xearly childhood on pubertal development and final6 K+ n( H, t' M5 k9 w; h; V# E
adult height are not fully known and always remain
3 K; H. v( Y8 [3 ^7 `8 ?a concern. Children treated with short-term testos-6 n F4 Y3 ?. @ I' j8 P# \; D
terone injection or topical androgen may exhibit some0 l* }8 P% q d8 q
acceleration of the skeletal maturation; however, after' A9 u9 s. @3 G
cessation of treatment, the rate of bone maturation. q: p: \% Z, q& U; i( p7 G( j
decelerates and gradually returns to normal.8,9
9 w6 v) [6 Q; f8 t2 J- |! n3 TThere are conflicting reports and controversy
+ @3 _3 u* ]9 r! u7 d& Q4 q tover the effect of early androgen exposure on adult; G. }# ]6 R1 A3 Q7 E, ]2 J
penile length.10,11 Some reports suggest subnormal; U6 H+ J2 y3 I/ v" k
adult penile length, apparently because of downreg-
0 }2 v1 [: \# V8 B0 sulation of androgen receptor number.10,12 However,! J; T! f+ j! O* ~; F Q, ^
Sutherland et al13 did not find a correlation between4 Q% P& h: w2 J! q0 b! y6 [
childhood testosterone exposure and reduced adult+ r: e% v' [3 ~+ n+ t
penile length in clinical studies.
9 R4 m+ H8 g$ k1 `, NNonetheless, we do not believe our patient is- C0 F- }' x, ?) @* ~
going to experience any of the untoward effects from' f# F5 D! A$ O5 M& k, b4 v
testosterone exposure as mentioned earlier because
) ~7 n) U7 ]* ?the exposure was not for a prolonged period of time.
6 t/ A" B3 n: J/ X8 eAlthough the bone age was advanced at the time of
, u7 Z/ @9 ~; Y* c9 O0 A$ Ddiagnosis, the child had a normal growth velocity at
+ s" @% S2 _: S8 I5 v g( othe follow-up visit. It is hoped that his final adult; q; _0 b2 S) a8 q* K4 e
height will not be affected." J& N% Z5 M% o" u5 S( k0 z5 @
Although rarely reported, the widespread avail-. r$ p! O( ^3 ?
ability of androgen products in our society may9 A9 k4 X3 G0 P
indeed cause more virilization in male or female
P6 X: S1 |5 a; ochildren than one would realize. Exposure to andro-* d8 P: ^: [( x
gen products must be considered and specific ques-
: W# i$ L$ v. ~# x9 Dtioning about the use of a testosterone product or
. x1 h/ U' o# X" ]+ Q/ _0 N2 {gel should be asked of the family members during) w( f8 L7 x3 R4 Z! d6 A+ g
the evaluation of any children who present with vir-' n, A$ n; {4 U \7 Y7 D1 r$ `
ilization or peripheral precocious puberty. The diag-
?, o: E- T$ h% J/ G ~nosis can be established by just a few tests and by
+ d' S1 Y7 E! {+ Z: kappropriate history. The inability to obtain such a( ~7 M& H% O( h- H
history, or failure to ask the specific questions, may
* v+ V; O0 }- t' y) b9 g. fresult in extensive, unnecessary, and expensive
4 |+ ]) K9 f* I5 Hinvestigation. The primary care physician should be W2 M2 y$ Y8 l
aware of this fact, because most of these children
2 I5 O4 P% w0 j) ^- X1 hmay initially present in their practice. The Physicians’3 p1 o' F- p, M1 {) P: _7 \
Desk Reference and package insert should also put a
' F. G% J# N: n; `: { D4 U1 Kwarning about the virilizing effect on a male or
6 w% j1 T! ^' x8 B3 i) N: Xfemale child who might come in contact with some-. T S) e1 J0 o; `) x
one using any of these products.
' B9 {7 y4 j# `+ I8 c& t2 p1 w. JReferences
# c- y: d% y# T8 a+ \* i5 b8 \9 c6 ]1. Styne DM. The testes: disorder of sexual differentiation6 `/ v. I" ?: H: a/ I4 ?- }
and puberty in the male. In: Sperling MA, ed. Pediatric3 K" Y2 w; g. O! a) V- ~6 \. V0 l3 J
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
( q% }: b1 ^& J6 A2002: 565-628.6 E( Q$ Q* V4 M/ p5 m3 t- L
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
# [+ y6 u& G5 W) ^3 hpuberty in children with tumours of the suprasellar pineal |
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