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Sexual Precocity in a 16-Month-Old& }; N5 e- t# P& j/ p
Boy Induced by Indirect Topical
. g1 C4 f1 E4 |" a9 IExposure to Testosterone
: O0 G- j _0 _) M8 ]Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2% B0 @+ z8 V3 u0 _1 l" h* u
and Kenneth R. Rettig, MD1, I! `' z* j$ u) D# K' m
Clinical Pediatrics
1 m( f% D3 @: A2 ^# u1 d2 mVolume 46 Number 6: \8 `/ y* V6 n
July 2007 540-5431 Q! I# ?3 F5 Y" w! [2 L( @. g
© 2007 Sage Publications# z, ?3 ^' P/ ]1 n
10.1177/0009922806296651
7 @( p; Y2 _5 k5 D) M2 rhttp://clp.sagepub.com% ~; ^* j, j5 A2 h
hosted at9 n" L! I# N8 }, o
http://online.sagepub.com; L& u; E( V$ \6 k; w: @' M
Precocious puberty in boys, central or peripheral,0 j2 X! ~6 Q. T1 `& h
is a significant concern for physicians. Central2 }$ A+ p- g+ y% a, n$ d
precocious puberty (CPP), which is mediated
" Z& S5 J* \- H3 A& N* ~$ ythrough the hypothalamic pituitary gonadal axis, has
( j$ ] n" p; S" K6 Ya higher incidence of organic central nervous system' Q5 D8 t3 S$ E j" E8 k1 P
lesions in boys.1,2 Virilization in boys, as manifested/ o1 B G, I* M# o
by enlargement of the penis, development of pubic
5 g; E) ?4 M8 @/ Vhair, and facial acne without enlargement of testi-7 K4 |" y( K F+ k& j
cles, suggests peripheral or pseudopuberty.1-3 We' G0 y# S# I8 z$ d T4 X, c
report a 16-month-old boy who presented with the
7 q3 q. c5 \( O& b- M- i: d% Penlargement of the phallus and pubic hair develop-
* a% f" O0 L% j$ z- e! hment without testicular enlargement, which was due
* o3 `3 ?; @7 v! s1 l) G) J: h1 g6 |to the unintentional exposure to androgen gel used by/ m7 ^3 \; H( Y% `$ t
the father. The family initially concealed this infor-
; }, Y% e1 ~8 ~9 jmation, resulting in an extensive work-up for this
) L/ q7 L. {& X7 Zchild. Given the widespread and easy availability of) I2 U. d9 F7 x0 M7 |
testosterone gel and cream, we believe this is proba-7 D7 W& T, z' `" \7 ^
bly more common than the rare case report in the; V$ u/ l8 G$ g$ V5 s$ Y
literature.4/ r. G2 _8 I1 q% F+ `. R/ Q
Patient Report
4 s1 u) L9 f. i+ ~A 16-month-old white child was referred to the2 {" D! X0 E7 |
endocrine clinic by his pediatrician with the concern: b! n6 H, A& k# p9 R
of early sexual development. His mother noticed$ {# y: L% J7 J* m% p+ `2 C
light colored pubic hair development when he was+ K$ t/ `+ K2 l
From the 1Division of Pediatric Endocrinology, 2University of
' E: ]$ t5 ^* Z8 XSouth Alabama Medical Center, Mobile, Alabama.
4 y8 A( p& w; D, P% C& m5 KAddress correspondence to: Samar K. Bhowmick, MD, FACE,+ q& a L# J- b7 ^
Professor of Pediatrics, University of South Alabama, College of
! b5 p3 x. |. w0 f! r1 w, r" kMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;/ S G5 F8 E3 J( D
e-mail: [email protected].
0 v$ r# s' k2 C, l* l, N8 ~) P( vabout 6 to 7 months old, which progressively became
. j" d# ?6 x" ^, H; Hdarker. She was also concerned about the enlarge-
# F, O( m$ u0 Y3 }, S6 b6 s9 [ment of his penis and frequent erections. The child
; h4 V$ m/ z7 P" Y& Q' m5 Ywas the product of a full-term normal delivery, with
8 c; Z% _ m3 D" F" ia birth weight of 7 lb 14 oz, and birth length of5 Q' I/ I' d6 |: {
20 inches. He was breast-fed throughout the first year( l4 `* T/ p7 {# X! N2 P2 h4 }
of life and was still receiving breast milk along with
' V3 J8 v$ g# p/ W; {4 A* psolid food. He had no hospitalizations or surgery,% z" h& D, N' C j5 V
and his psychosocial and psychomotor development
/ r- y2 c, @* `( \, v; h4 _9 cwas age appropriate.0 {* f0 \1 J, a$ @- i
The family history was remarkable for the father,
4 a4 K' ]. F1 e) w7 ]5 {( Pwho was diagnosed with hypothyroidism at age 16,
+ ^; D) V% z0 ?; Uwhich was treated with thyroxine. The father’s% r+ L0 j: u1 }6 i+ n9 p2 L2 B- \
height was 6 feet, and he went through a somewhat* K9 C' A. z2 d5 y
early puberty and had stopped growing by age 14.
" O7 U7 u7 b" {5 P0 n* FThe father denied taking any other medication. The6 V" X. F, @. g" K' s
child’s mother was in good health. Her menarche' e3 z2 x5 J8 d( Z! C4 b. G, Z2 b
was at 11 years of age, and her height was at 5 feet1 N/ r J, X3 \
5 inches. There was no other family history of pre-
/ {$ w) r' F; [0 Scocious sexual development in the first-degree rela-
5 N( s1 C" I, _1 Z7 u+ dtives. There were no siblings., z6 y5 B9 y$ r" E( K3 o
Physical Examination
8 N1 W5 `% O+ p1 C# Z( m$ zThe physical examination revealed a very active,
6 T# _; p; ]) _playful, and healthy boy. The vital signs documented, K4 v% F3 n6 Q; ~' j. N" `- L
a blood pressure of 85/50 mm Hg, his length was
[" k9 B4 I& i2 A$ X90 cm (>97th percentile), and his weight was 14.4 kg
3 x7 Q" U* o" n3 o7 }(also >97th percentile). The observed yearly growth8 t& {; }2 k- b R6 p$ l
velocity was 30 cm (12 inches). The examination of# H1 e: M! \, A# S
the neck revealed no thyroid enlargement.. `! E% i8 d7 ~3 x
The genitourinary examination was remarkable for
, ]) Z s W/ Y* venlargement of the penis, with a stretched length of
/ c# t/ X0 I2 \9 c0 i8 cm and a width of 2 cm. The glans penis was very well7 X c/ X0 o3 S: l" C; ^4 Z
developed. The pubic hair was Tanner II, mostly around
# _, }) d: q. D6 E" n5407 w, d' p3 K {5 F/ d
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from7 a8 p4 Y' v; H1 Q: ?# J$ V/ t
the base of the phallus and was dark and curled. The
, q8 m, A$ c4 X7 x6 {! [4 Btesticular volume was prepubertal at 2 mL each.
7 k! C! U9 w% H+ d+ J+ n- Y* iThe skin was moist and smooth and somewhat
8 z' b, P7 e/ S, J+ }/ {0 U: ^/ doily. No axillary hair was noted. There were no
q6 f+ @/ B' n$ [7 uabnormal skin pigmentations or café-au-lait spots.4 Q' \7 w- V0 |6 P; V
Neurologic evaluation showed deep tendon reflex 2+
\3 Q5 u. B8 n, X) a$ {bilateral and symmetrical. There was no suggestion
3 G4 r, x7 s3 W) wof papilledema.
2 h- s8 q, |$ T9 ^8 V4 q# ?Laboratory Evaluation7 J$ _+ q. R/ N' D7 h6 ?7 s
The bone age was consistent with 28 months by
; F% O }/ G3 d& t' {using the standard of Greulich and Pyle at a chrono-
/ j/ v3 w" S! d5 R8 _1 x$ qlogic age of 16 months (advanced).5 Chromosomal9 `1 R1 @2 R" Z! U
karyotype was 46XY. The thyroid function test7 {% k: t3 u8 M5 |, ]4 L2 l" [
showed a free T4 of 1.69 ng/dL, and thyroid stimu-' s( S+ y6 S X
lating hormone level was 1.3 µIU/mL (both normal).
1 ]1 ~" p$ D. O& ^8 ?2 j& sThe concentrations of serum electrolytes, blood
5 v& S% y. G8 b; W: F6 @urea nitrogen, creatinine, and calcium all were
1 b/ |) w; W6 a6 ?( t! iwithin normal range for his age. The concentration$ d' R. R- @9 u
of serum 17-hydroxyprogesterone was 16 ng/dL- y0 {! g: F2 ^# Z; L& |+ X
(normal, 3 to 90 ng/dL), androstenedione was 20
1 I+ P/ H& `* _* ?% Gng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
' P! f8 s' w# \terone was 38 ng/dL (normal, 50 to 760 ng/dL),
0 ^8 e& @' a" |( G8 @" {6 s1 ~desoxycorticosterone was 4.3 ng/dL (normal, 7 to" \/ Z; b2 q: }) [8 D, h. U
49ng/dL), 11-desoxycortisol (specific compound S)! T; [5 H! l, G; o
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
& H# L, \$ N# utisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total+ F9 w. v, } X+ j
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
- n; |: `( ~( { Vand β-human chorionic gonadotropin was less than
: M/ m. A, I: J% _& J) A$ I- c" M( V5 mIU/mL (normal <5 mIU/mL). Serum follicular
3 Q& j& q0 U1 s4 L# z& Tstimulating hormone and leuteinizing hormone/ W8 K3 j: ?/ R" S! ]
concentrations were less than 0.05 mIU/mL: U- }6 w( v0 Q8 y
(prepubertal).* c) ?' @( G: i% m
The parents were notified about the laboratory N- u. q' a5 Z# b# k
results and were informed that all of the tests were' Z" H9 x) Y" v5 C
normal except the testosterone level was high. The
. G; `9 t. s Ifollow-up visit was arranged within a few weeks to! J$ H3 _3 S6 m) ?4 g
obtain testicular and abdominal sonograms; how-
$ |6 [, I9 l* b4 r: q1 i4 aever, the family did not return for 4 months.
- N* _, M+ Y5 v9 [Physical examination at this time revealed that the- w ]/ {- M4 [; [" @; j7 V3 d0 h
child had grown 2.5 cm in 4 months and had gained9 q- t' Z) }* I0 [/ }3 K( u/ R' `
2 kg of weight. Physical examination remained
4 m3 I- r1 {6 F& P% Ounchanged. Surprisingly, the pubic hair almost com-; U/ n% ^+ R" d& y9 c9 J
pletely disappeared except for a few vellous hairs at
! ~2 ]$ r! z9 n+ n8 b/ hthe base of the phallus. Testicular volume was still 25 e- c# Q7 }7 g$ y1 E1 O$ Z; B$ P
mL, and the size of the penis remained unchanged.
$ y+ z2 r* Q" s: z/ j& k8 WThe mother also said that the boy was no longer hav-
9 H) {4 _* I% Ging frequent erections.
$ V9 |% R3 k1 D2 g+ d6 cBoth parents were again questioned about use of( x* K6 y7 |8 p7 \' N- t
any ointment/creams that they may have applied to' a5 t3 i( [7 w' N F- X
the child’s skin. This time the father admitted the
4 Q; t% v! @8 ?0 o: J; [1 R9 g2 JTopical Testosterone Exposure / Bhowmick et al 541
' [4 u8 M; W/ m7 P9 buse of testosterone gel twice daily that he was apply-4 D0 L ]3 O% ~- _/ ]( \
ing over his own shoulders, chest, and back area for, [- `, r) N. @- y4 ^% E
a year. The father also revealed he was embarrassed" c& C% y, X+ o# f7 Z3 a
to disclose that he was using a testosterone gel pre-
4 b9 v$ U& P9 h+ cscribed by his family physician for decreased libido2 _; I9 S) m) o' o$ M$ ~6 ^
secondary to depression., Z) a/ m* ?& P9 Y7 _, @
The child slept in the same bed with parents.. N) H! ?+ {* {: z! U" b
The father would hug the baby and hold him on his% l% }! m" T3 S F0 o! [
chest for a considerable period of time, causing sig-
6 x1 f2 x. {! l0 hnificant bare skin contact between baby and father., W0 @, M/ b: v* g, T: j
The father also admitted that after the phone call,; p, \' ]' z- ], q. G/ {, L' t
when he learned the testosterone level in the baby1 l( @8 h) x+ M3 C$ ?4 h2 a
was high, he then read the product information
' N Q+ @* L. Q; Vpacket and concluded that it was most likely the rea-
# H0 T6 n4 A) _- ison for the child’s virilization. At that time, they! l7 M$ q4 X4 P' }6 J9 G
decided to put the baby in a separate bed, and the
5 l" M7 u# V$ L; P5 g& {. _8 efather was not hugging him with bare skin and had
& e& b' B" s& y& l7 [been using protective clothing. A repeat testosterone
. {9 E+ t: K- wtest was ordered, but the family did not go to the
/ ?+ F- [1 o- @ T3 R/ klaboratory to obtain the test.
9 o2 F0 |/ j6 x7 q* l+ wDiscussion
: T% f0 |+ F3 o$ y& zPrecocious puberty in boys is defined as secondary/ }% \$ ^: r0 H' C( v7 @9 N4 z( k
sexual development before 9 years of age.1,4
- @% n9 I, M) m/ Z9 d, OPrecocious puberty is termed as central (true) when
( V2 M b! k- c4 [it is caused by the premature activation of hypo-
' T' ]) j$ c2 {( a3 d" xthalamic pituitary gonadal axis. CPP is more com-
4 j! g! c7 m2 c. {' Q; I4 _mon in girls than in boys.1,3 Most boys with CPP5 Z) ]- d' D: K% N2 s
may have a central nervous system lesion that is& [9 s* \5 C$ b5 G$ a5 }8 E. T
responsible for the early activation of the hypothal-
8 ?6 K$ \, `, j( P( vamic pituitary gonadal axis.1-3 Thus, greater empha-! B( `2 e# B. q4 B. x$ ^
sis has been given to neuroradiologic imaging in
% o9 c3 U5 ?0 K1 w$ ~' m2 ~boys with precocious puberty. In addition to viril-
* h+ W1 n, ?0 Eization, the clinical hallmark of CPP is the symmet-+ v0 k( @' V8 m- r( o7 h
rical testicular growth secondary to stimulation by
6 o7 ?! B/ ~0 t# vgonadotropins.1,35 ^7 b- C; L) u3 P# M
Gonadotropin-independent peripheral preco-( V5 K( `: C* u4 A
cious puberty in boys also results from inappropriate
- J4 c; \1 V a8 `androgenic stimulation from either endogenous or. A4 A5 J0 t; l3 E, m
exogenous sources, nonpituitary gonadotropin stim-
( @9 h6 E" J) f" ^ulation, and rare activating mutations.3 Virilizing
; s" I, f f: e3 [congenital adrenal hyperplasia producing excessive
1 z* d3 h: \. z- e- nadrenal androgens is a common cause of precocious
( W8 L: t6 f x) Gpuberty in boys.3,4
/ ^1 b. b- M/ }( H7 @, ^ o- ?The most common form of congenital adrenal
% ?) u1 @0 I+ K2 d8 m0 ?# ?8 chyperplasia is the 21-hydroxylase enzyme deficiency.+ p w9 |# u/ _; i& s) A9 r
The 11-β hydroxylase deficiency may also result in5 t) G4 R% ~, z7 V; E
excessive adrenal androgen production, and rarely,
4 i0 c1 y7 l! San adrenal tumor may also cause adrenal androgen; S; Y2 X/ m- C6 S G
excess.1,3. Y* B8 E2 d) V9 e n; @
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from# D5 T6 d- X# [7 L. u
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007# o5 f, [+ K+ V7 a$ U
A unique entity of male-limited gonadotropin-
; t& z. p$ C7 N5 v9 L' A9 ^" kindependent precocious puberty, which is also known
- f- h2 H1 E3 N% {* l) Ias testotoxicosis, may cause precocious puberty at a
; D# }8 W0 d; A8 P# F' }very young age. The physical findings in these boys
" l2 q# B+ z, G# f) r8 f( _ {with this disorder are full pubertal development,
: U% e# R9 v/ Z1 w( Z9 c. @including bilateral testicular growth, similar to boys
" W# Y4 }2 Y* f: M3 f2 Wwith CPP. The gonadotropin levels in this disorder: y5 i B. g2 J% W( V j$ E
are suppressed to prepubertal levels and do not show6 _# N. h9 g+ R& `1 {$ }
pubertal response of gonadotropin after gonadotropin-
+ n& h) `$ b: u) H6 F8 F, x% C% zreleasing hormone stimulation. This is a sex-linked
/ v: J0 S( p8 G. m! Wautosomal dominant disorder that affects only
- `# U* U( I3 v9 B' P" S5 Fmales; therefore, other male members of the family( M8 {2 r* x) \7 |8 G" U( a
may have similar precocious puberty.3
: w# d$ O' r, I1 ~" D: w/ FIn our patient, physical examination was incon-
& ^: R% Q4 w3 n7 h) N1 k+ esistent with true precocious puberty since his testi-* B) \- ^& R& H
cles were prepubertal in size. However, testotoxicosis2 ?6 L w5 b6 A% A: W
was in the differential diagnosis because his father
# v2 N" v S( A$ u1 Jstarted puberty somewhat early, and occasionally,
. q2 s: e1 S$ @: J' Z& X! ktesticular enlargement is not that evident in the1 y: n( T6 R. v: M, }
beginning of this process.1 In the absence of a neg-
3 T: v/ P, {( L# }( }+ q+ [" Jative initial history of androgen exposure, our
6 z! \4 E# m* @" vbiggest concern was virilizing adrenal hyperplasia,
4 P% t2 J$ A, `' e) Deither 21-hydroxylase deficiency or 11-β hydroxylase
5 Q. E/ G' W! F. Z* o* o# fdeficiency. Those diagnoses were excluded by find-
6 n, Y5 L8 ^5 z) J# M0 S5 ~ing the normal level of adrenal steroids.3 ~* M' U2 z4 ~1 `7 B
The diagnosis of exogenous androgens was strongly
6 U2 y7 s/ t. o; e1 n7 ?. w( J$ Tsuspected in a follow-up visit after 4 months because1 B$ K) e8 `% s% `/ H; G- q& Z, ~
the physical examination revealed the complete disap-3 a8 k! P: v2 P* p3 L6 A8 G( T: S
pearance of pubic hair, normal growth velocity, and
4 s P/ C8 n" [" e6 p: I& ydecreased erections. The father admitted using a testos-4 M) Q8 e8 o- Y
terone gel, which he concealed at first visit. He was
~& B5 N7 o6 W" \/ B' L" Husing it rather frequently, twice a day. The Physicians’) _( N5 t4 j5 n
Desk Reference, or package insert of this product, gel or7 }! ~; ]- L! N9 S; G
cream, cautions about dermal testosterone transfer to g# `; ^4 V$ h( _ N5 X. z
unprotected females through direct skin exposure.
) x4 V4 Y8 a3 ~9 a: a! S% cSerum testosterone level was found to be 2 times the
+ @3 Q/ n) b/ Q; j" k# ?baseline value in those females who were exposed to
2 P2 R7 s# k5 u' h8 jeven 15 minutes of direct skin contact with their male4 u: l. Q, R# I6 f$ u+ {5 ?* `" t
partners.6 However, when a shirt covered the applica-
# j- z3 y5 p: l% p3 K3 o+ ~tion site, this testosterone transfer was prevented.
2 m5 L0 x: }+ X, _Our patient’s testosterone level was 60 ng/mL,
7 A9 ^: G, [% X1 Mwhich was clearly high. Some studies suggest that
! _7 b7 f# t* [( }dermal conversion of testosterone to dihydrotestos-
9 f7 k& v3 f* ^9 B4 `) P8 dterone, which is a more potent metabolite, is more
9 R$ T) {7 P4 a- V* Kactive in young children exposed to testosterone
, Z6 ?: \" f, b" T! s- [) dexogenously7; however, we did not measure a dihy-# {: H# G0 s+ }" e, }$ ~9 b
drotestosterone level in our patient. In addition to+ N9 w( ?+ b2 G4 v: D
virilization, exposure to exogenous testosterone in
' ~7 h# V" ~; {* bchildren results in an increase in growth velocity and
/ V: ~% b6 _4 L7 @* {5 [; y3 gadvanced bone age, as seen in our patient.
; D4 K6 w+ P- x) ]/ D, `5 PThe long-term effect of androgen exposure during8 e/ C6 L& b/ K( ]* O
early childhood on pubertal development and final0 `& ]" P4 A- }: r
adult height are not fully known and always remain
* N. k+ x" T6 g+ q2 |$ L: Aa concern. Children treated with short-term testos-1 y/ A% y! t& f+ m" K$ |" O
terone injection or topical androgen may exhibit some9 [, I; ^3 U1 g9 v4 j
acceleration of the skeletal maturation; however, after
$ {9 c' I/ W. H( u6 m; n* _cessation of treatment, the rate of bone maturation+ \- F* c2 y+ _: O5 k6 z# E
decelerates and gradually returns to normal.8,9% y, P/ L. e" I3 ~: U9 m/ G
There are conflicting reports and controversy0 w$ v8 ~8 n. ]
over the effect of early androgen exposure on adult
! R7 q) c; K1 ^/ a* f, ipenile length.10,11 Some reports suggest subnormal
% a& [ i; ]1 R& t' e! Y9 k; n3 Cadult penile length, apparently because of downreg-. r9 a" s3 r; B( I s( R
ulation of androgen receptor number.10,12 However,
0 m" r1 C, E3 f9 u" FSutherland et al13 did not find a correlation between. D9 _& B+ R* X: ^) t* L W# ]
childhood testosterone exposure and reduced adult
' }* V2 D3 G) P1 s+ m! ppenile length in clinical studies.
; G% X6 P W) X& r9 k- m6 GNonetheless, we do not believe our patient is P. }6 I5 r5 M: \% w
going to experience any of the untoward effects from
! D" {3 M0 y0 P0 Xtestosterone exposure as mentioned earlier because
; I' x* y' k, @8 g; sthe exposure was not for a prolonged period of time.; R1 R8 }8 j5 p
Although the bone age was advanced at the time of
$ t0 ~8 Q$ j( Z% @: j2 }diagnosis, the child had a normal growth velocity at
9 g# |: Q+ P9 u0 z6 Ethe follow-up visit. It is hoped that his final adult2 [; w& ~3 p0 H7 |1 U
height will not be affected.
( x; K) x f$ oAlthough rarely reported, the widespread avail-
! z1 i6 W t" Z" K* R8 N$ N) F! zability of androgen products in our society may
4 U" D1 @; G$ M3 K9 c+ {2 dindeed cause more virilization in male or female
, u J" y$ |) v, I+ _2 }children than one would realize. Exposure to andro-( _ f+ S* K, `3 q9 X
gen products must be considered and specific ques-
6 j- i7 W6 y6 F. Htioning about the use of a testosterone product or
2 T" I9 J1 [2 W; k. w% Vgel should be asked of the family members during1 T6 D$ k5 A8 d2 Z8 t
the evaluation of any children who present with vir-, G4 L! n% G1 {! f
ilization or peripheral precocious puberty. The diag-" o. k% }7 R7 x9 G8 b
nosis can be established by just a few tests and by2 ^0 e% W% J/ H# r
appropriate history. The inability to obtain such a
# V; o; C- U% ^+ E2 v8 H( ]history, or failure to ask the specific questions, may4 j5 y: Z8 q6 ~) K
result in extensive, unnecessary, and expensive! \# j: A% l& S1 |! M
investigation. The primary care physician should be2 B) `) k$ L3 I1 @% ]# @1 C
aware of this fact, because most of these children2 o* k0 `2 D) Y8 }" H
may initially present in their practice. The Physicians’ ^( g8 Z7 _ D* c0 w8 j
Desk Reference and package insert should also put a/ k$ C* Q% {3 w! U3 z
warning about the virilizing effect on a male or
j! t; s1 B& j* R3 jfemale child who might come in contact with some-
& T) ~' R! D/ V$ v) Gone using any of these products.+ F6 [6 `& l" u+ s0 ` J$ v/ z- {0 H, \
References
) i3 C$ ~7 L5 c! h/ _1. Styne DM. The testes: disorder of sexual differentiation3 a" E( B9 W; z- u1 Y$ o9 G
and puberty in the male. In: Sperling MA, ed. Pediatric1 L' ?$ S+ ` H+ x% J. s
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;, D# o$ l, n; O+ z* J7 X
2002: 565-628.. n. C3 T0 N9 T' c% @ E* }; B
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
# A7 P) `- {4 N6 ^! K5 vpuberty in children with tumours of the suprasellar pineal |
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