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Sexual Precocity in a 16-Month-Old# v, D: U, D9 Y9 [
Boy Induced by Indirect Topical
: t* O3 u2 I9 J' j! f) C3 ]) TExposure to Testosterone# b7 O j: Y- r+ i$ F# S( V
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,24 F0 A7 g1 K# V( V E
and Kenneth R. Rettig, MD1
; X8 V5 j' T4 mClinical Pediatrics& O# {7 y* ]; U! y( ^/ r3 t+ Z
Volume 46 Number 6
* F% E4 s4 j/ E$ k: \/ |July 2007 540-543$ U$ f& u8 i% n& k# n. i A+ P
© 2007 Sage Publications/ H3 [3 \3 ^9 v, @4 n
10.1177/0009922806296651( ~9 c+ L$ \2 g9 i4 ]$ q+ X
http://clp.sagepub.com. ]0 `: A/ Z) C$ j& x5 l; k
hosted at
/ A/ k& c6 T7 T. C% [, mhttp://online.sagepub.com
! l9 G7 W4 y; J# S* }: JPrecocious puberty in boys, central or peripheral,, n, r q" o5 K, M( [
is a significant concern for physicians. Central4 n n4 v% {, P
precocious puberty (CPP), which is mediated- ?) O+ w2 ~) ]- e
through the hypothalamic pituitary gonadal axis, has, r8 X( l' j; u- m l
a higher incidence of organic central nervous system
1 x, U" u0 U5 U; Z4 q8 hlesions in boys.1,2 Virilization in boys, as manifested, e& F! }+ }& w" a$ @& P/ _
by enlargement of the penis, development of pubic {3 a% M% t) `& o- A, E( a ?" k! C
hair, and facial acne without enlargement of testi-
3 w0 [2 S5 T3 ?, }8 i6 b: Dcles, suggests peripheral or pseudopuberty.1-3 We
! J5 J g5 a6 R0 I" w+ Ereport a 16-month-old boy who presented with the& u1 b% K; v/ s6 I& g
enlargement of the phallus and pubic hair develop-+ a1 K; R# u+ A
ment without testicular enlargement, which was due
6 o8 d- \: n4 `" a3 P2 I3 B: R. ?to the unintentional exposure to androgen gel used by0 @# `# ^+ U3 ?5 z" o
the father. The family initially concealed this infor-
. `! M* P D6 B/ m$ a* J( f6 v1 dmation, resulting in an extensive work-up for this
2 F- M6 J' Y. I& achild. Given the widespread and easy availability of! X0 T& G; i: x5 K& D1 K
testosterone gel and cream, we believe this is proba-
1 ~# k' m8 j, ^3 _: `bly more common than the rare case report in the
5 h; N. x4 r! I; i/ yliterature.4* a8 F6 h/ a6 ^1 J1 t: k
Patient Report/ E& k0 g5 { }; u! g0 O
A 16-month-old white child was referred to the: |/ C( n1 \; t w* N
endocrine clinic by his pediatrician with the concern6 z4 O( @ F, {; x9 [. {
of early sexual development. His mother noticed
6 h2 x% }) p6 i# ~* Clight colored pubic hair development when he was
; }; ^# G3 u, YFrom the 1Division of Pediatric Endocrinology, 2University of- W/ D$ g6 D6 R% _2 X0 L# a* R
South Alabama Medical Center, Mobile, Alabama.! Q) j' r; f( w9 j+ n
Address correspondence to: Samar K. Bhowmick, MD, FACE,
% I# ?: P5 \! MProfessor of Pediatrics, University of South Alabama, College of
. ]( K4 x+ ~9 t* r4 `Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
2 o/ S/ b. U; B& _1 Ve-mail: [email protected].; g I3 X1 I6 r% B1 L$ |- _
about 6 to 7 months old, which progressively became% s4 \( W, o+ G! O0 r( y& S
darker. She was also concerned about the enlarge-
. j# M- H0 S7 i. G. @ment of his penis and frequent erections. The child- j$ ~ r; T2 }" B' V" @
was the product of a full-term normal delivery, with8 |& s/ R6 `3 w4 Q& f6 H
a birth weight of 7 lb 14 oz, and birth length of% D2 w" B9 l- K4 K: ?# r
20 inches. He was breast-fed throughout the first year8 w# {. O1 a, `) y
of life and was still receiving breast milk along with7 {% R8 O2 h" m8 j/ S) x# j
solid food. He had no hospitalizations or surgery,
( ]. Z$ A# y3 K. c: s$ ? Fand his psychosocial and psychomotor development
7 f p, n; D4 i' W* T6 L+ Twas age appropriate.7 ^: T: A3 u) s$ U
The family history was remarkable for the father,; S- D- I( t5 t4 x
who was diagnosed with hypothyroidism at age 16,
/ Q* m0 {1 W$ Nwhich was treated with thyroxine. The father’s
# A G1 E8 O$ r9 }height was 6 feet, and he went through a somewhat" D7 \6 Y ]+ Y1 x3 R0 U
early puberty and had stopped growing by age 14.& c7 w; ~; Y1 V+ p
The father denied taking any other medication. The7 F y& J$ l) _! u
child’s mother was in good health. Her menarche
$ O, n: c$ i: F( q% h3 k+ A4 jwas at 11 years of age, and her height was at 5 feet
$ H) [0 O; X1 P2 y7 y7 e) c) @5 inches. There was no other family history of pre-7 n/ b5 Q6 F A3 X$ J8 {$ s
cocious sexual development in the first-degree rela-/ e# s1 Y9 A; C4 j( I# J2 ?
tives. There were no siblings.
; t6 v. x! J6 y, ~& l+ XPhysical Examination& N. `5 ?4 o' I: l
The physical examination revealed a very active,
9 _ i: k- {' ]; @; i1 hplayful, and healthy boy. The vital signs documented$ y& g4 h; [7 W+ h, Z
a blood pressure of 85/50 mm Hg, his length was" w$ c1 R. }5 ?$ e0 j) o+ @: x
90 cm (>97th percentile), and his weight was 14.4 kg
0 }: W4 q8 M2 @" Y! u# [ o9 B(also >97th percentile). The observed yearly growth
7 f' E4 ?5 w" K; Fvelocity was 30 cm (12 inches). The examination of! g- i0 d u7 Z
the neck revealed no thyroid enlargement.8 t. H; l: F8 i/ F3 c
The genitourinary examination was remarkable for
4 Q! d6 N0 G; t' c3 _; `. N: Genlargement of the penis, with a stretched length of$ E3 }& S K' e2 t/ h2 `5 A
8 cm and a width of 2 cm. The glans penis was very well
$ V6 B( o, ] j6 Q sdeveloped. The pubic hair was Tanner II, mostly around! \5 F1 \- \( @0 z
540
" r3 P' f+ Z6 m. ]. p2 l9 lat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from8 Q3 w& P9 M- I+ n T
the base of the phallus and was dark and curled. The8 q( J* f: J W6 h8 {5 T# O
testicular volume was prepubertal at 2 mL each.' `+ q8 s' y: e6 M5 p) l, H8 C
The skin was moist and smooth and somewhat
. g) A' I% c4 Loily. No axillary hair was noted. There were no
3 W* Q* B1 s0 ?% p" F! G4 Tabnormal skin pigmentations or café-au-lait spots.
% K# K6 L' ~$ Q4 K3 G4 p& j# U3 }Neurologic evaluation showed deep tendon reflex 2+
0 v+ z% e$ B* j! ]: Tbilateral and symmetrical. There was no suggestion- Q8 q8 W4 x& t) C! R: h% V
of papilledema.4 V2 x6 {" C+ y9 h: E: q
Laboratory Evaluation
. ^; |2 O6 e" C* m3 l9 ~, U& IThe bone age was consistent with 28 months by+ J( O2 i$ A1 v8 O& g2 s" ?
using the standard of Greulich and Pyle at a chrono-
: p# h: C0 n, F) x! D! |! N- mlogic age of 16 months (advanced).5 Chromosomal2 X+ ]! D, w0 b( k, j1 t+ J
karyotype was 46XY. The thyroid function test8 [. Q8 T8 q3 Q5 a$ B
showed a free T4 of 1.69 ng/dL, and thyroid stimu-1 W- G6 n: p: i8 v6 h
lating hormone level was 1.3 µIU/mL (both normal).* u( U$ D% [! g) g
The concentrations of serum electrolytes, blood
$ A" F# T7 j' Q J4 o6 surea nitrogen, creatinine, and calcium all were5 X) U0 M/ @! d; u( t
within normal range for his age. The concentration
- B8 V4 ]0 m4 o$ C' q2 P0 aof serum 17-hydroxyprogesterone was 16 ng/dL0 X1 ]9 \' q, R9 c" \/ _* ^
(normal, 3 to 90 ng/dL), androstenedione was 20
6 @9 \9 }! c9 y! cng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
* ?. n" l, J( R4 Kterone was 38 ng/dL (normal, 50 to 760 ng/dL),5 p) o2 t7 m- \) s* Q" N" f
desoxycorticosterone was 4.3 ng/dL (normal, 7 to
6 o k; C& X4 ^, B) j49ng/dL), 11-desoxycortisol (specific compound S)
5 n; \* W# g6 {9 ^7 P; bwas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
6 G+ o& |! h5 l" {' Ptisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total) z2 s8 G+ m7 q8 N# C
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),7 p; U! p: Z" e/ D4 M) [
and β-human chorionic gonadotropin was less than
4 f* K" r6 z+ ~: X& _5 X0 o5 n5 mIU/mL (normal <5 mIU/mL). Serum follicular
1 t% `' A# N) |& Gstimulating hormone and leuteinizing hormone* u- L# I r9 `( ^, V
concentrations were less than 0.05 mIU/mL* x# S0 `& |2 I- H; `% f% G! W j
(prepubertal).- U1 h* R D# l0 e* U. D( O; g
The parents were notified about the laboratory: z9 w. w" \& i* Z
results and were informed that all of the tests were0 U+ z6 E7 w. c; z: K' `! E
normal except the testosterone level was high. The5 P0 W' d$ p, K
follow-up visit was arranged within a few weeks to
+ B, b% h5 E- ~3 r& [4 s0 f" t! Oobtain testicular and abdominal sonograms; how-# Y6 a/ ~- l) X3 K% P0 l
ever, the family did not return for 4 months.
4 m, R5 @+ C& i, k+ ~, t# t, CPhysical examination at this time revealed that the+ O" j2 ?2 D( x& P
child had grown 2.5 cm in 4 months and had gained/ M( C \; q4 S: [& v
2 kg of weight. Physical examination remained
$ r2 H; b* Y punchanged. Surprisingly, the pubic hair almost com-
& x$ g2 I2 C) B) Ypletely disappeared except for a few vellous hairs at7 P# ~: T1 |2 U# I) {
the base of the phallus. Testicular volume was still 2
2 C/ u8 r0 T; R% x# l! `mL, and the size of the penis remained unchanged.0 r" m# h) v* Z* q
The mother also said that the boy was no longer hav-0 x7 ^: E" f" B9 _- x
ing frequent erections.
2 _$ J1 {2 t# n( zBoth parents were again questioned about use of: a( F, b, o; m) z2 A5 d- [* h
any ointment/creams that they may have applied to- p e* j" H8 k: v0 t0 m3 O
the child’s skin. This time the father admitted the
( m# z4 N+ Q% A$ N `) eTopical Testosterone Exposure / Bhowmick et al 541
0 j, ]$ {2 d7 l' G) @8 Yuse of testosterone gel twice daily that he was apply-" n0 m# r: l" q" {$ S1 v
ing over his own shoulders, chest, and back area for+ |; E: [$ I, I3 G" o8 \" W1 T9 w) p( \
a year. The father also revealed he was embarrassed4 b+ z& Q& H7 f: Y
to disclose that he was using a testosterone gel pre-
# R- T3 W( R! K& P4 o4 c! `3 Yscribed by his family physician for decreased libido0 I) y" X. P X
secondary to depression.. |4 L- k2 ~( ?+ c, i7 X0 |
The child slept in the same bed with parents.3 B1 _* p1 E* B4 ^8 q
The father would hug the baby and hold him on his
: `8 W( }; z2 f7 ?7 dchest for a considerable period of time, causing sig-
& {% x. U+ o" u+ F5 d$ Y. h- anificant bare skin contact between baby and father.. J$ A9 N; F" l* w# G/ x
The father also admitted that after the phone call,
% x1 x2 d* E* g3 g( N/ |( x9 n+ twhen he learned the testosterone level in the baby8 r! S) K+ h. [. y0 c9 q
was high, he then read the product information# R# u I4 t( V ?& u6 ^) T: O
packet and concluded that it was most likely the rea-# f: c$ W4 K4 k9 |9 a
son for the child’s virilization. At that time, they
/ y7 W& E# s( | Z5 Y" H, Kdecided to put the baby in a separate bed, and the/ C3 t+ {5 k7 W( U8 Q
father was not hugging him with bare skin and had }+ }" V$ p$ @" T: {: f
been using protective clothing. A repeat testosterone
" @, G2 k d' a( m3 G/ Etest was ordered, but the family did not go to the
4 [1 Z' h8 n( t0 llaboratory to obtain the test.
# q1 o) E- H7 E- B4 QDiscussion" d, R- h/ J6 v/ C
Precocious puberty in boys is defined as secondary4 S- R. X% N/ ~
sexual development before 9 years of age.1,4
C4 Q2 n; ?( G2 b' l. i2 r. S6 qPrecocious puberty is termed as central (true) when7 }. I3 Y. {! j- s5 y
it is caused by the premature activation of hypo-0 A& p+ a0 f+ [+ K: K, g
thalamic pituitary gonadal axis. CPP is more com-7 f+ q6 m1 c6 ~2 y
mon in girls than in boys.1,3 Most boys with CPP; g1 X, P, D. U3 X
may have a central nervous system lesion that is
% h e3 m$ l/ x; `responsible for the early activation of the hypothal-
7 ?+ ~ O" Y% H( }amic pituitary gonadal axis.1-3 Thus, greater empha-
8 E/ R- ~# k; k5 T5 O, Z# Z% A$ [sis has been given to neuroradiologic imaging in
2 b" e# Q3 C: u; Xboys with precocious puberty. In addition to viril-
. U: T- S4 i L& r0 z2 W6 \ization, the clinical hallmark of CPP is the symmet-
; H* Z0 R5 ~% {rical testicular growth secondary to stimulation by* m4 E' l6 t" S$ M8 ?
gonadotropins.1,3/ |! m- P3 F3 ^* B% g
Gonadotropin-independent peripheral preco-
- U+ F' q1 D+ g7 N$ O: W5 D8 f" pcious puberty in boys also results from inappropriate
* {: d6 I: _+ J8 Landrogenic stimulation from either endogenous or
1 r4 O! h6 M7 O9 ]- x/ sexogenous sources, nonpituitary gonadotropin stim-" ]7 s, t8 H8 ? u
ulation, and rare activating mutations.3 Virilizing
% t& D ~ H; |; F$ |% I8 ~8 T4 }+ bcongenital adrenal hyperplasia producing excessive4 E; _4 Y7 B$ M" q4 O9 o: A$ ]) S
adrenal androgens is a common cause of precocious6 K2 u r d3 E% ?7 \
puberty in boys.3,4: ]8 o. a e3 n; Q& v `$ C1 N+ D
The most common form of congenital adrenal
+ B0 E4 M2 s* [2 Y V( n4 [hyperplasia is the 21-hydroxylase enzyme deficiency.
, [, y5 v0 n6 m' |* [The 11-β hydroxylase deficiency may also result in9 I! }# Z% }; T1 f
excessive adrenal androgen production, and rarely,) M2 n j; l4 F1 Z7 E
an adrenal tumor may also cause adrenal androgen
# z l. g0 ?+ z! b% z( Rexcess.1,33 K/ b4 L3 ~, n' R
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
4 u+ G& C1 z2 o6 J5 A% m542 Clinical Pediatrics / Vol. 46, No. 6, July 20073 Z5 p2 M- L! f4 |- z; k
A unique entity of male-limited gonadotropin-
3 K( [; Z! F) e! x/ t0 A0 Yindependent precocious puberty, which is also known
: u6 ~5 r( `3 Las testotoxicosis, may cause precocious puberty at a8 B7 Q& d7 j# e9 ?
very young age. The physical findings in these boys
5 F: M6 J$ R! m0 dwith this disorder are full pubertal development,2 Z! l" o" l. u' O ~1 W
including bilateral testicular growth, similar to boys* R( b. E2 O& P5 A# C2 t3 w0 X- P
with CPP. The gonadotropin levels in this disorder1 X7 V5 A! [7 y" `+ B
are suppressed to prepubertal levels and do not show7 y' U' }- ]$ p& D1 i
pubertal response of gonadotropin after gonadotropin-% t( v4 u. d, S/ X3 ^
releasing hormone stimulation. This is a sex-linked3 M k: W9 Y b. V* r a
autosomal dominant disorder that affects only
) s+ J8 U6 N7 n, vmales; therefore, other male members of the family
( N3 H: B' [$ B. Jmay have similar precocious puberty.38 k9 `' T; w/ g- o8 I( q2 j) R
In our patient, physical examination was incon-
# B$ ]7 p* L. H/ ]% y: hsistent with true precocious puberty since his testi-. Z7 r( s" V, F
cles were prepubertal in size. However, testotoxicosis
- V( \/ ~. g0 P$ R" fwas in the differential diagnosis because his father
5 V4 Y: |. v7 xstarted puberty somewhat early, and occasionally,- W2 V% C( m5 u' a6 |: l9 a& Y; d
testicular enlargement is not that evident in the
4 a. E i6 A! j4 Z' \beginning of this process.1 In the absence of a neg-
1 X7 | H4 I$ q8 fative initial history of androgen exposure, our0 s7 x& ^, ]6 Z1 ]) E- |
biggest concern was virilizing adrenal hyperplasia," x/ @ K5 W' H: H1 _" _
either 21-hydroxylase deficiency or 11-β hydroxylase
1 a/ ~- x9 Z2 Q3 kdeficiency. Those diagnoses were excluded by find-1 z9 E# x9 M' b$ G
ing the normal level of adrenal steroids.
( ~7 K( m- H H/ q/ kThe diagnosis of exogenous androgens was strongly' ]. q H" Y9 t$ I0 V/ c
suspected in a follow-up visit after 4 months because
% |' A; h4 F; u5 n+ V: Fthe physical examination revealed the complete disap-
; t$ c; W* C bpearance of pubic hair, normal growth velocity, and
2 N+ h% ]4 T( ^: W- pdecreased erections. The father admitted using a testos-& \9 c6 k l& j" i2 k8 Q
terone gel, which he concealed at first visit. He was
4 { o) Q3 _" M$ f& [ @& Z iusing it rather frequently, twice a day. The Physicians’
y( V. r# S% J% \5 `4 wDesk Reference, or package insert of this product, gel or
. ?/ x) R9 | g; D( c# p( ncream, cautions about dermal testosterone transfer to! [9 n# d" s$ ~* `3 `8 a# x
unprotected females through direct skin exposure.* w2 i% @* X- } k
Serum testosterone level was found to be 2 times the+ h9 B" V: o8 X) K2 d/ r
baseline value in those females who were exposed to. A0 N' F' O! ]" k
even 15 minutes of direct skin contact with their male) [. O2 M# _ ?" t9 Q% F2 k& k
partners.6 However, when a shirt covered the applica-
; ]1 m, o* q' x% J6 ation site, this testosterone transfer was prevented.
1 ~! y7 x4 D8 R! a% y+ `; yOur patient’s testosterone level was 60 ng/mL,
) h; Y/ G3 U$ p8 C x8 a3 Iwhich was clearly high. Some studies suggest that& Q3 _. \4 b. U- n! X
dermal conversion of testosterone to dihydrotestos-% I4 a- ]0 J% B5 Y2 @
terone, which is a more potent metabolite, is more
) C: X" R- \; s& s! dactive in young children exposed to testosterone7 h" v/ K S5 w; C3 D+ n
exogenously7; however, we did not measure a dihy-
1 e1 J9 f' o2 _8 o6 ]drotestosterone level in our patient. In addition to, v0 j i C' N0 j
virilization, exposure to exogenous testosterone in
- E" c' R, ^- n* W) A8 |children results in an increase in growth velocity and9 U2 u% e2 c. m% s; K( S
advanced bone age, as seen in our patient.( `$ H' Q/ U5 V9 O6 V6 }+ M! z
The long-term effect of androgen exposure during" g$ S _+ E: C% N9 {6 o& H
early childhood on pubertal development and final
: b1 a% g3 a* Oadult height are not fully known and always remain5 k) a( d, t7 w$ b
a concern. Children treated with short-term testos-. D* Q% j# d0 l# i- @+ W' V. \1 n
terone injection or topical androgen may exhibit some
( x9 C( g8 X# M( r( Gacceleration of the skeletal maturation; however, after5 `' h+ Y7 |* r
cessation of treatment, the rate of bone maturation/ F% U! Y. g6 W) s ^
decelerates and gradually returns to normal.8,9# G6 Z6 b' j* q& S
There are conflicting reports and controversy. A7 V! B" Y7 x( }1 J
over the effect of early androgen exposure on adult: I' a8 V" W( I! L E
penile length.10,11 Some reports suggest subnormal
( |$ B, s7 |8 C4 b1 badult penile length, apparently because of downreg-( Y( s; L0 d0 e( ?( j$ Q
ulation of androgen receptor number.10,12 However,
+ b& Y$ w6 \ T* t+ J7 p4 ] ^& G% C# sSutherland et al13 did not find a correlation between
7 b( B# P" f2 C! ~# c0 [8 jchildhood testosterone exposure and reduced adult
+ @3 L0 v% t" h& y* C* spenile length in clinical studies.6 T$ ^0 ?: k5 D) a/ V* W5 i5 k5 U
Nonetheless, we do not believe our patient is
- B, o5 | s! M _, \going to experience any of the untoward effects from
& o* w- |( L, \/ u/ O: Gtestosterone exposure as mentioned earlier because
! x# C2 W% N t4 _/ h6 j- @1 C7 Dthe exposure was not for a prolonged period of time.
, j/ \! x$ P/ T: ?/ C# e& CAlthough the bone age was advanced at the time of
* x3 U$ W8 _: R: C6 z% Gdiagnosis, the child had a normal growth velocity at
4 Z) e' Q0 p9 i4 s4 Z) I' s( t7 gthe follow-up visit. It is hoped that his final adult
6 H0 M- ]3 J& C, a# A" Eheight will not be affected., T; R0 l8 Q, J# m8 a: F
Although rarely reported, the widespread avail-
4 T, D2 v" J6 O( r& v7 aability of androgen products in our society may7 Z& } U' Z9 m: B( g/ \, {9 U' A
indeed cause more virilization in male or female9 X6 a |1 r0 D/ W% ~6 x
children than one would realize. Exposure to andro-) N' a4 M: C4 ~; l( p
gen products must be considered and specific ques-- X( r$ T$ r* }) s9 S
tioning about the use of a testosterone product or
' O6 d, {. d0 ?/ P$ R( D/ |gel should be asked of the family members during" o' u2 H/ T' N5 Q& y3 p
the evaluation of any children who present with vir-- r- s3 I+ G# l% W: U; q/ S7 M: f
ilization or peripheral precocious puberty. The diag-8 f- K7 P$ n3 G- z f+ ]$ r! n
nosis can be established by just a few tests and by8 T1 I7 m0 ~- ?" Q) g0 |0 m( o
appropriate history. The inability to obtain such a Z/ l1 W' z# q; B" f$ B* r. @
history, or failure to ask the specific questions, may
k: k* g: J6 k% D% @/ Bresult in extensive, unnecessary, and expensive
7 C1 S; b( W ?9 q, m$ U4 n: b5 F" D( ~investigation. The primary care physician should be
! M1 K7 a$ S2 D4 s' laware of this fact, because most of these children1 n' G H# B2 b3 K* l
may initially present in their practice. The Physicians’
( V; {0 h( {1 n) ZDesk Reference and package insert should also put a8 x9 p4 O$ c8 M0 V+ ^# n
warning about the virilizing effect on a male or @7 O- s; G! r5 r7 R, u- q! f' M
female child who might come in contact with some-
) I5 n5 l: c+ f" o8 eone using any of these products.) V" i& j5 t) R
References" { B$ x) N4 h
1. Styne DM. The testes: disorder of sexual differentiation; Z+ j W- T X& O: R) P
and puberty in the male. In: Sperling MA, ed. Pediatric7 B4 Q5 I3 a! @$ R& j
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
8 U$ l. S4 T2 O2002: 565-628.
+ L. D; b9 Q1 ?, }% P( q2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
. k1 O6 |! P) J5 c, b& u& o1 Xpuberty in children with tumours of the suprasellar pineal |
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