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Sexual Precocity in a 16-Month-Old7 B( C6 m& e$ r9 z' e2 I
Boy Induced by Indirect Topical) X& v, `. i' b( e. W
Exposure to Testosterone
! J3 L: u( Z) T0 k3 x; s KSamar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2. w( R8 n% h2 t$ O9 q
and Kenneth R. Rettig, MD1$ W0 |4 ~% v: S7 p# G& S. J& F
Clinical Pediatrics
6 e: k9 h2 s8 i1 k: iVolume 46 Number 64 Y3 }/ g8 D- n9 C+ F8 ~# H
July 2007 540-543
+ l" T& y+ f* Q/ M© 2007 Sage Publications+ @* G, x7 q }
10.1177/0009922806296651
+ ?2 ]9 P! B Rhttp://clp.sagepub.com2 d8 N; O+ ]7 ~2 m0 i+ {7 K( j
hosted at9 W2 i: D: P1 p1 d
http://online.sagepub.com3 ^9 k: E* T/ {
Precocious puberty in boys, central or peripheral,( y& q. ]" w$ p9 G& q m
is a significant concern for physicians. Central
! }6 v4 I! v3 _, c/ Cprecocious puberty (CPP), which is mediated, p) z6 w! D) w5 a/ N! Y& T
through the hypothalamic pituitary gonadal axis, has
/ z+ ?! o9 T/ V( y7 z* La higher incidence of organic central nervous system
0 Y0 g, F) g/ P' x" Wlesions in boys.1,2 Virilization in boys, as manifested$ @( N5 x9 Y6 O c* a
by enlargement of the penis, development of pubic
I/ _- V! r4 b6 ?hair, and facial acne without enlargement of testi-, D- B a' x4 @5 y
cles, suggests peripheral or pseudopuberty.1-3 We
! Z4 Y. r! Y8 a/ ^! }7 s+ \report a 16-month-old boy who presented with the
' E( w$ M( s' ~ K' J& \enlargement of the phallus and pubic hair develop-
# Z8 O5 R6 q5 \/ [- Ement without testicular enlargement, which was due' T! L6 N% J' _; |
to the unintentional exposure to androgen gel used by
`2 P5 e7 C" Pthe father. The family initially concealed this infor-
0 ?" n1 S0 y: U4 Ymation, resulting in an extensive work-up for this
# Y& K0 ^0 Y8 S0 A8 {( U$ nchild. Given the widespread and easy availability of
; B4 G; ?/ ~+ @. I; u3 y2 B) g- ]testosterone gel and cream, we believe this is proba-0 I; |% C7 j/ u9 z4 W' R
bly more common than the rare case report in the
8 u( w2 }' i$ g8 K' X% ?literature.4" n. `! u; w7 N4 l3 Z
Patient Report! I8 i& J# r6 y2 L' k+ \0 G2 A' o8 ~
A 16-month-old white child was referred to the
4 P! E5 ]1 T0 ?) G- ^endocrine clinic by his pediatrician with the concern
1 k9 T# q! E( E$ vof early sexual development. His mother noticed
5 \$ K/ x* ]. d, D0 k$ elight colored pubic hair development when he was7 q! T# I- b8 c% A7 Y" B Q- O
From the 1Division of Pediatric Endocrinology, 2University of2 w( r$ q, [6 P3 ^
South Alabama Medical Center, Mobile, Alabama.
# U% c# t0 H, b3 H" C6 a0 lAddress correspondence to: Samar K. Bhowmick, MD, FACE,
8 b. Y% l- n! B6 K$ EProfessor of Pediatrics, University of South Alabama, College of
7 l3 k% R/ N( E! G- p: QMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
" u, m! |; \/ |9 a# f6 u6 oe-mail: [email protected].* i0 m" `5 X4 C& e, M4 Z
about 6 to 7 months old, which progressively became/ A1 r4 ~& M4 W' F7 u$ X
darker. She was also concerned about the enlarge- b! C$ b/ n2 u- c$ k
ment of his penis and frequent erections. The child: c$ K- W' L8 Z7 a) y- P; e
was the product of a full-term normal delivery, with Y/ X- l1 S# `' y% ~
a birth weight of 7 lb 14 oz, and birth length of
% }5 _0 ~- W. K. R6 \- D8 p0 C20 inches. He was breast-fed throughout the first year( E7 g( r. @- U
of life and was still receiving breast milk along with/ c) i& u1 `0 Q& g& D( q5 p% Z2 v
solid food. He had no hospitalizations or surgery,
: Z$ [. ~8 r1 band his psychosocial and psychomotor development5 T' i, ]' U0 y4 {8 v' S$ v% z1 b9 S- Q
was age appropriate.2 b0 P% }7 Z" U! m: H. k4 j' V
The family history was remarkable for the father,( O3 Z) {1 ~# H6 G9 p8 f1 U! V
who was diagnosed with hypothyroidism at age 16,/ E8 d1 M1 J$ p3 Z- {1 k1 F5 |
which was treated with thyroxine. The father’s: L, E$ c. Z w
height was 6 feet, and he went through a somewhat
( L' B6 j, L: o4 Kearly puberty and had stopped growing by age 14.
' U) ?# V" X; l2 j1 Y% T( F9 ?The father denied taking any other medication. The
" c& A* P9 X0 U0 ~, A6 {! Ochild’s mother was in good health. Her menarche
, j9 {. d2 j9 }* ]$ v3 E3 R7 Cwas at 11 years of age, and her height was at 5 feet t8 T' T" E7 j% ~+ z4 E$ V8 v: e
5 inches. There was no other family history of pre-
/ h( t1 c6 A5 g# M- e& C# scocious sexual development in the first-degree rela-" @7 |: `" Y W3 ~. ?, n- K$ A
tives. There were no siblings.- I: }8 Y9 r3 ?
Physical Examination/ ?1 E* w8 M5 V e- U2 w8 g
The physical examination revealed a very active,5 Z: r. q6 \& j. h
playful, and healthy boy. The vital signs documented
* Z: j- x4 e* S7 t5 J' H% ea blood pressure of 85/50 mm Hg, his length was
1 ? m% A' M( U, }' U( g90 cm (>97th percentile), and his weight was 14.4 kg
7 A0 l* r( p5 o(also >97th percentile). The observed yearly growth
; c; M% X7 ]* {# }& z K: dvelocity was 30 cm (12 inches). The examination of
# Q5 Q6 ~8 E/ p3 r* @3 z# g9 Othe neck revealed no thyroid enlargement.5 \( j( U0 P1 f# {8 n
The genitourinary examination was remarkable for
6 M9 o. L& D# U2 H& a; Kenlargement of the penis, with a stretched length of+ R c! L" D1 t4 p X) x$ b4 L
8 cm and a width of 2 cm. The glans penis was very well J" @3 ~6 s: ^# P3 a+ v, T
developed. The pubic hair was Tanner II, mostly around
: n |/ B6 }# n( K; `540
9 o8 G# i+ s; B! s6 Bat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
1 ]! r& _6 h; Q, R! @5 Bthe base of the phallus and was dark and curled. The
$ p( @4 G, [: c* ?2 {' q" Gtesticular volume was prepubertal at 2 mL each.# V6 ?( o ]: w0 @
The skin was moist and smooth and somewhat7 v. m1 s8 l& U) e
oily. No axillary hair was noted. There were no
9 \! _( V1 |% a2 D3 y$ i6 wabnormal skin pigmentations or café-au-lait spots.
9 g& G8 Z( z2 E1 T) SNeurologic evaluation showed deep tendon reflex 2+ {5 q! Q' `/ x8 Y# F4 F ]2 B, T
bilateral and symmetrical. There was no suggestion" c1 T1 U3 `( `7 q( a4 h& x
of papilledema.
& b7 ?) j+ D. y+ {3 U! v: e, CLaboratory Evaluation6 H) {$ O) ~& J; W; i
The bone age was consistent with 28 months by
/ q* X9 P5 y5 U0 r, w+ g* eusing the standard of Greulich and Pyle at a chrono-
" J A* |8 @/ |8 }logic age of 16 months (advanced).5 Chromosomal
" u0 Y1 s/ e1 U8 O/ S- ikaryotype was 46XY. The thyroid function test
0 q- T* T# a$ a8 X5 o1 Vshowed a free T4 of 1.69 ng/dL, and thyroid stimu-
: d: I2 L3 `- C- R8 [lating hormone level was 1.3 µIU/mL (both normal).
$ @" D" T. r, c8 U* j$ R2 a3 ~ }The concentrations of serum electrolytes, blood
5 _% n6 t' ` P3 c3 ?urea nitrogen, creatinine, and calcium all were
- p( }: I2 E+ t% l8 twithin normal range for his age. The concentration7 y4 v8 o6 ~! {
of serum 17-hydroxyprogesterone was 16 ng/dL
4 i& m" B! U: R- D4 _(normal, 3 to 90 ng/dL), androstenedione was 207 b/ c, Q! k6 j& K( ?
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-) @4 q7 d( W' Y; a% G+ n6 z
terone was 38 ng/dL (normal, 50 to 760 ng/dL)," G4 i9 B+ B2 L0 g8 M
desoxycorticosterone was 4.3 ng/dL (normal, 7 to1 c# e& [( o& M$ k: [& |
49ng/dL), 11-desoxycortisol (specific compound S)$ V/ q+ {. x* v% O1 P
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
6 j5 a0 H I+ S, m1 X9 ttisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total) ^$ E. y; x+ p9 U: C* _6 k
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
. { x# ~% ^+ M; R4 @and β-human chorionic gonadotropin was less than0 H6 d# V( e' X" s7 [7 x
5 mIU/mL (normal <5 mIU/mL). Serum follicular
9 \$ z% T. u; ^7 Istimulating hormone and leuteinizing hormone4 r6 G8 f# F8 B8 J2 u/ L0 ]% ^
concentrations were less than 0.05 mIU/mL& x0 v }# f5 `2 ?* P/ ]! v1 `
(prepubertal).8 b# y" v& x- D: M3 }% R, r2 H
The parents were notified about the laboratory
& F- _- v d5 _9 m) R8 `results and were informed that all of the tests were
" G7 j: u9 x4 D0 `/ {4 gnormal except the testosterone level was high. The/ v) A* `0 B) ^3 D6 z
follow-up visit was arranged within a few weeks to
) W% I0 m/ v+ A. r2 u: Jobtain testicular and abdominal sonograms; how-7 F+ X9 D3 I7 Y" d7 j
ever, the family did not return for 4 months.
! l- _- q. [6 X( r0 ~Physical examination at this time revealed that the
) H% V# x% P0 J# V/ V* Dchild had grown 2.5 cm in 4 months and had gained
% V' Q' `" t9 J6 s( E2 kg of weight. Physical examination remained3 i: R3 Y8 }2 h$ I
unchanged. Surprisingly, the pubic hair almost com-+ O: r; b6 T b& s% ^7 ^9 Z
pletely disappeared except for a few vellous hairs at
( p; p8 z& m6 ]% ]2 i5 ~6 b% D/ jthe base of the phallus. Testicular volume was still 2( n9 J; H2 r+ `$ O+ k9 Z
mL, and the size of the penis remained unchanged.
1 _0 }3 W! S, p* i. P$ vThe mother also said that the boy was no longer hav-
& {6 |- o1 |! \/ iing frequent erections.
5 M4 r" U& X) p9 G. M8 kBoth parents were again questioned about use of6 G( f$ p2 H9 N+ N4 q" m
any ointment/creams that they may have applied to
; h' G* X) y( B* `. R- v& i' ]- O4 Zthe child’s skin. This time the father admitted the
9 {+ _$ U& i. S' X, @Topical Testosterone Exposure / Bhowmick et al 541
- M M: h0 M4 }- ~& ?2 `use of testosterone gel twice daily that he was apply-0 @* \* n: I1 [# F
ing over his own shoulders, chest, and back area for& d4 x- e7 F5 U- m
a year. The father also revealed he was embarrassed
, f# V) m, [8 R% T: P4 n1 W: ]to disclose that he was using a testosterone gel pre-
* G4 d/ e0 k& t/ r. lscribed by his family physician for decreased libido! A t- K- C( m0 c+ {' F
secondary to depression.+ H' ^. v3 ? @! F8 K
The child slept in the same bed with parents. D! @( P0 q% I# I: c
The father would hug the baby and hold him on his G# E; V3 i% z! @0 r
chest for a considerable period of time, causing sig-& J4 d- G( I/ |0 b3 m2 P; K
nificant bare skin contact between baby and father.
" p# p( |0 d2 _$ ^" q$ KThe father also admitted that after the phone call,, p, x# g/ f6 A$ F
when he learned the testosterone level in the baby4 H2 ?* k# u) B! h
was high, he then read the product information
) a2 k5 l v% e: Rpacket and concluded that it was most likely the rea-7 K3 h J) C7 k3 W5 K
son for the child’s virilization. At that time, they% D1 W$ l& ?3 B9 i. b
decided to put the baby in a separate bed, and the8 Q: V9 z7 O6 v( N- C# X
father was not hugging him with bare skin and had+ V6 ^* W0 a2 g1 \7 H
been using protective clothing. A repeat testosterone
. }0 M, q/ [/ m F4 etest was ordered, but the family did not go to the2 p f3 W0 h) B
laboratory to obtain the test.
|7 H. h h( x0 i! u' b4 V! [7 oDiscussion% Z% E P# i# Z$ j' V* p; g
Precocious puberty in boys is defined as secondary
! q* y3 A# J6 L n4 zsexual development before 9 years of age.1,4% Z% e! X5 j2 Q1 u
Precocious puberty is termed as central (true) when g7 A7 M) I4 O
it is caused by the premature activation of hypo-
O6 J; }: c+ O( x! Gthalamic pituitary gonadal axis. CPP is more com-0 q, A$ j/ p! k% c6 M1 |% O
mon in girls than in boys.1,3 Most boys with CPP- \$ F- k7 f+ i5 N9 T: j- [
may have a central nervous system lesion that is5 y6 @) i- Q+ D) x/ b& N
responsible for the early activation of the hypothal-$ y+ z* s/ s1 V+ V, {8 T
amic pituitary gonadal axis.1-3 Thus, greater empha-0 ~$ a, N/ A! M( ^& X
sis has been given to neuroradiologic imaging in& }3 s: \; m5 Q. c- V( ]7 Z: o
boys with precocious puberty. In addition to viril-) u- v$ n* `$ w' }* b7 p
ization, the clinical hallmark of CPP is the symmet-
, g4 r" i; ]/ f$ |; t& F- xrical testicular growth secondary to stimulation by
' J$ _/ V& e' I6 L# v lgonadotropins.1,3$ U) N+ R* y! Z1 H6 g2 Y0 v
Gonadotropin-independent peripheral preco-
* ^1 p4 |+ m" U) X0 A$ t! E# Icious puberty in boys also results from inappropriate& D2 B3 v% U1 X' U
androgenic stimulation from either endogenous or
+ f3 N; S$ \5 G$ p* R. k: r1 Fexogenous sources, nonpituitary gonadotropin stim-
& x4 q$ R3 z9 i( vulation, and rare activating mutations.3 Virilizing$ _, W3 K- I" e+ m
congenital adrenal hyperplasia producing excessive
6 ]$ ]! l6 _4 t' jadrenal androgens is a common cause of precocious, J* h! F1 @4 Q
puberty in boys.3,4: H* K) x' J% F& }
The most common form of congenital adrenal1 u* Y/ q3 c9 F/ e+ B4 s" |7 P6 [: w
hyperplasia is the 21-hydroxylase enzyme deficiency.) i; v, v8 x4 d- [5 R+ I- a, F
The 11-β hydroxylase deficiency may also result in
0 d9 v+ W/ e) sexcessive adrenal androgen production, and rarely,4 b: m1 [4 j1 @, o9 G4 f
an adrenal tumor may also cause adrenal androgen4 N4 W: n& r W
excess.1,35 B5 @" W: S; ^1 S7 L
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
) s F. I9 X- o# V542 Clinical Pediatrics / Vol. 46, No. 6, July 20071 b$ R! y( ^. ? ~6 h: u
A unique entity of male-limited gonadotropin-
0 y8 L: t5 E& r6 i7 j0 uindependent precocious puberty, which is also known
- R1 f' U. `* ?0 P+ fas testotoxicosis, may cause precocious puberty at a
7 Z" N( t0 }1 x) M' y5 L/ U+ r. qvery young age. The physical findings in these boys _3 o6 @) k2 V8 ^
with this disorder are full pubertal development,
: u. [3 V" X% k C8 d) ~including bilateral testicular growth, similar to boys! y J4 Q# p$ x Y3 [. ?2 T t
with CPP. The gonadotropin levels in this disorder
" D/ |0 C0 k p( I5 P/ hare suppressed to prepubertal levels and do not show
7 Y$ m$ V) M; j+ ~: A" gpubertal response of gonadotropin after gonadotropin-' C( k" i/ q0 }) @7 [2 N. _+ q8 _& P
releasing hormone stimulation. This is a sex-linked5 D x( p- w1 e, y
autosomal dominant disorder that affects only
# m* k3 Y1 i3 d3 W0 Lmales; therefore, other male members of the family# `! S0 g+ \/ } }% R
may have similar precocious puberty.3
: E7 I( r2 X5 ?3 l$ r7 J6 p2 FIn our patient, physical examination was incon-. Z6 o9 [+ M+ o6 e+ d
sistent with true precocious puberty since his testi-$ \3 K( `$ B4 l3 j8 r
cles were prepubertal in size. However, testotoxicosis
. Y+ Z7 Z4 K# q: G; Q! |was in the differential diagnosis because his father
1 r' L) D/ F, L# R4 mstarted puberty somewhat early, and occasionally,, n( b6 _' X( p" Z& \+ i
testicular enlargement is not that evident in the. ~! ^* u/ H+ w5 D- \8 U
beginning of this process.1 In the absence of a neg-
$ k1 o5 `, N% E+ d2 Y* g' a8 @/ g; U- gative initial history of androgen exposure, our! n' q! Z# A- ?4 \5 T
biggest concern was virilizing adrenal hyperplasia,
* u5 X2 ?9 f6 ~either 21-hydroxylase deficiency or 11-β hydroxylase
9 O# A) d, l7 N% A; u' Y& Odeficiency. Those diagnoses were excluded by find-; ]0 ~. z; K# F% X' D6 M7 q
ing the normal level of adrenal steroids.
. ]4 ~+ }- C9 l" K( K' [' G' zThe diagnosis of exogenous androgens was strongly
, ]& w4 u0 E( `2 ksuspected in a follow-up visit after 4 months because
) D' P! E3 a; O7 f8 Mthe physical examination revealed the complete disap-% o8 A3 g: r3 Z, ]- C
pearance of pubic hair, normal growth velocity, and
1 }' q9 S8 R! G1 ]decreased erections. The father admitted using a testos-
) z& @ Y8 ^- Q9 P, i/ N0 C/ _5 x' v1 Jterone gel, which he concealed at first visit. He was; w! m, w* l! O- s& m! m* [
using it rather frequently, twice a day. The Physicians’
8 Y+ p# _' { c5 DDesk Reference, or package insert of this product, gel or" ^5 v1 M; V" P
cream, cautions about dermal testosterone transfer to$ T0 H2 V* T; I
unprotected females through direct skin exposure.7 h* m1 l% ~! m% o
Serum testosterone level was found to be 2 times the
7 L. b; ~# J6 z& n& pbaseline value in those females who were exposed to+ q, P0 G' z9 M& L2 N% A
even 15 minutes of direct skin contact with their male, A2 x1 t3 n* A T
partners.6 However, when a shirt covered the applica-% d7 [: ^$ W9 ~4 H+ Z
tion site, this testosterone transfer was prevented.
; [; c0 P6 a1 N1 ~9 NOur patient’s testosterone level was 60 ng/mL,# w5 e6 v6 t! y5 M" f
which was clearly high. Some studies suggest that( }8 S" n% a1 p
dermal conversion of testosterone to dihydrotestos-' ~1 N$ j& t! V) D e) C' S
terone, which is a more potent metabolite, is more
6 ^/ u; O* g: f9 @0 h$ f# K5 jactive in young children exposed to testosterone5 q+ L# O$ E3 R7 L
exogenously7; however, we did not measure a dihy-& Z9 P2 d, W, {7 k) U1 v
drotestosterone level in our patient. In addition to
7 E6 r: j" c8 r$ J" J5 i; y4 {virilization, exposure to exogenous testosterone in
' \+ f2 E, [" K. }/ Bchildren results in an increase in growth velocity and9 k: a! U+ I+ J
advanced bone age, as seen in our patient.
1 o1 h) p. V( b, Q: o2 gThe long-term effect of androgen exposure during
: R" H/ M* T- Zearly childhood on pubertal development and final
4 O B4 b, ?$ g5 q2 W U) U! |adult height are not fully known and always remain% [* q M, C M- s8 C4 v' b
a concern. Children treated with short-term testos-2 `5 V$ v* p5 z9 X! s
terone injection or topical androgen may exhibit some
X5 L) L9 S) dacceleration of the skeletal maturation; however, after
7 W4 K O% Y, R; ]5 j4 zcessation of treatment, the rate of bone maturation
1 W8 A& M: T7 v: K0 Udecelerates and gradually returns to normal.8,9# {3 m. G0 ~3 I* M
There are conflicting reports and controversy
( t* ?, `, n, q1 [, w4 ^# M/ Iover the effect of early androgen exposure on adult% }& d5 F# E/ S; S X$ F
penile length.10,11 Some reports suggest subnormal, q' b* {% _' L
adult penile length, apparently because of downreg-
6 {, Z# i# e4 ^1 Y' Nulation of androgen receptor number.10,12 However,
" O( T: F6 v4 Y( f @: B1 L. ?Sutherland et al13 did not find a correlation between
' f8 L& o5 x" A# h, ~. ]0 Tchildhood testosterone exposure and reduced adult+ ?+ d! Y, T; j7 g" R6 C* m
penile length in clinical studies.
# L3 o1 q* R, J; C/ c' }5 NNonetheless, we do not believe our patient is; q# j2 M. Q9 y0 p
going to experience any of the untoward effects from' b+ B5 w v3 }
testosterone exposure as mentioned earlier because
) m! D0 ]7 e' X5 w5 c' N" g9 wthe exposure was not for a prolonged period of time.4 C2 h4 s; {1 `/ A
Although the bone age was advanced at the time of
# O' a6 ~+ p0 O* ~1 Ddiagnosis, the child had a normal growth velocity at
( T) u( @( o3 B5 _. e r1 t- sthe follow-up visit. It is hoped that his final adult) u4 E9 v- i3 a5 e
height will not be affected.
3 c$ D3 r4 Z* X- {( R5 e8 M8 SAlthough rarely reported, the widespread avail-
$ b9 b2 k5 j! R. c! g# @ability of androgen products in our society may! x, h# x! u, N
indeed cause more virilization in male or female
. V( j. u; F7 X, P, ~children than one would realize. Exposure to andro-
( t3 c9 P7 D: R* I- ?& egen products must be considered and specific ques-
& G+ r' `: z3 F3 ktioning about the use of a testosterone product or
- v8 G j# v! n- A) ^( B4 ~2 K# v2 Mgel should be asked of the family members during
' @3 r1 M; c3 }/ t2 i) w$ Wthe evaluation of any children who present with vir-
# @- ]0 n" U- A. d+ [0 k3 l) Cilization or peripheral precocious puberty. The diag-
2 h9 u. R6 E" K7 y& \+ @nosis can be established by just a few tests and by
( s0 |, S! K# B0 O! J; A" W+ qappropriate history. The inability to obtain such a: |8 x1 f7 A/ b
history, or failure to ask the specific questions, may
8 E4 b: G& R4 k0 l) [3 Gresult in extensive, unnecessary, and expensive
. y% h* k( a& M iinvestigation. The primary care physician should be
2 d6 M) Z! z' E' m% ~aware of this fact, because most of these children% t8 h9 q% ?' _+ X
may initially present in their practice. The Physicians’% l4 R) B3 p. ] H9 }% ?
Desk Reference and package insert should also put a* ?4 m+ v* B6 F+ b
warning about the virilizing effect on a male or0 v- w' p( _, @) w$ ]
female child who might come in contact with some-4 i2 [+ q. u$ t
one using any of these products.( L. ?* w1 w; j: u
References3 E8 g% K0 f' h/ }% h" v- [
1. Styne DM. The testes: disorder of sexual differentiation# f. l8 i& l. L0 o6 I: ~" H$ d ?8 Z
and puberty in the male. In: Sperling MA, ed. Pediatric+ X8 S, j% f3 H# M9 E
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
! y+ s. P% X( |5 ^( \( b2002: 565-628.
- i( [% P1 Z f5 ~3 F5 c9 C2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
! ?2 t& t# P6 |" npuberty in children with tumours of the suprasellar pineal |
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