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Sexual Precocity in a 16-Month-Old2 l7 |5 S+ r+ H7 k4 ^2 H( @
Boy Induced by Indirect Topical
# @9 Z& y; M2 i: Y0 C' v. f) dExposure to Testosterone
( U3 @+ g4 k+ ]0 a9 _Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
! y0 r. K! `3 I E/ Fand Kenneth R. Rettig, MD1( L( K5 s$ D: t4 l, ]
Clinical Pediatrics
/ o3 e6 [. V$ a4 y5 FVolume 46 Number 60 @# C4 R) ~2 ]& I6 l, Q
July 2007 540-543
* _2 a7 t4 [/ ~8 `© 2007 Sage Publications
& K( l& k0 t, W6 y10.1177/00099228062966515 V, e3 U/ W. w8 T( e; Y# _; d$ X! I
http://clp.sagepub.com4 ~. ^1 Q' A5 Y5 ~" {# h3 A$ Y
hosted at
N+ [$ @/ i& i6 V" Yhttp://online.sagepub.com
) t+ t8 j D' f+ _% ? F" g, OPrecocious puberty in boys, central or peripheral,* Q% k ]6 j% a
is a significant concern for physicians. Central% I. L; Z J; O7 _! {9 w
precocious puberty (CPP), which is mediated
1 P) N1 ~# l$ c9 [0 w/ f9 ~through the hypothalamic pituitary gonadal axis, has
9 Y5 `- K& S: v) ^, @ ja higher incidence of organic central nervous system/ r* E; t* C, s1 j* v: i8 s, T" M1 O4 C
lesions in boys.1,2 Virilization in boys, as manifested) N$ J, y" N7 e& k5 ?, |
by enlargement of the penis, development of pubic. H# x% G6 y. d' d* ~" c
hair, and facial acne without enlargement of testi-1 @: ~& E5 u T2 G& ]* Z
cles, suggests peripheral or pseudopuberty.1-3 We
/ ~, g6 P6 X1 m1 \report a 16-month-old boy who presented with the
' W' A. ~) O9 ]) |0 ]; venlargement of the phallus and pubic hair develop-
+ _9 b3 ?1 V$ s: ament without testicular enlargement, which was due5 D. {7 i/ D L. O- h
to the unintentional exposure to androgen gel used by
3 ?& F" @+ [5 H" @3 `2 \$ ?) ]the father. The family initially concealed this infor-
7 I. [. Z$ ^. o6 p7 P2 mmation, resulting in an extensive work-up for this6 x) a, {" C3 z5 F: i$ ?/ b
child. Given the widespread and easy availability of- I: q1 [) |# d W; t4 D( Q( u6 h9 Z
testosterone gel and cream, we believe this is proba-
3 q3 P' Q( @; d6 O8 N. Sbly more common than the rare case report in the
* `/ F$ x. y9 B( a: s9 iliterature.4
2 l/ o, p5 X# a9 WPatient Report
" f) X X3 e: j+ |% iA 16-month-old white child was referred to the
8 b- [2 `( W# T/ Yendocrine clinic by his pediatrician with the concern, b, u6 J* Q$ q4 w% l( C
of early sexual development. His mother noticed) T# M( ]6 j3 l( p$ W
light colored pubic hair development when he was6 _" W. R z! D3 v4 p4 @
From the 1Division of Pediatric Endocrinology, 2University of
1 T/ N5 r$ ~( b/ [4 O8 zSouth Alabama Medical Center, Mobile, Alabama.
$ ~& f, _! u% ~3 S$ u2 eAddress correspondence to: Samar K. Bhowmick, MD, FACE,+ y% u6 q( L. v2 Z& F
Professor of Pediatrics, University of South Alabama, College of
/ @. g1 D! @+ R8 y. BMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;1 k3 b* g+ }/ i0 K- D. _
e-mail: [email protected].
* u5 ?8 r8 s3 j1 \* w) [about 6 to 7 months old, which progressively became- p& z" h' S$ g2 N$ ~, b, \4 Z' u
darker. She was also concerned about the enlarge-
& V8 B3 x% @, j( `- `" j5 ^4 D" @ment of his penis and frequent erections. The child
) t7 v2 o* g, [; t! W1 T( Twas the product of a full-term normal delivery, with$ ?; p. }2 d3 e& b9 G, {+ T
a birth weight of 7 lb 14 oz, and birth length of' }5 v7 L. z0 w. l' o5 _: H
20 inches. He was breast-fed throughout the first year: c7 z m U4 q7 y4 x5 M
of life and was still receiving breast milk along with6 Y5 o+ k$ `5 h8 I& p
solid food. He had no hospitalizations or surgery,6 R$ M" ?# |1 e; V7 F: c
and his psychosocial and psychomotor development% t7 n" P* v( w* ~! Q
was age appropriate.
w' B, Y* B$ u0 t- [- QThe family history was remarkable for the father,' E5 E2 J9 V$ n8 c+ {) q7 p
who was diagnosed with hypothyroidism at age 16,' f9 V& R1 L* S0 F0 S# f) a
which was treated with thyroxine. The father’s
+ Z8 K+ X5 \$ `5 @8 `( V/ v: [height was 6 feet, and he went through a somewhat& J# q, ]7 [3 I$ N# Z' b0 Q0 T, M
early puberty and had stopped growing by age 14.' S j0 l; D8 t2 G. T4 u- n
The father denied taking any other medication. The
" P; s& K4 i0 \6 Achild’s mother was in good health. Her menarche. m$ |; O3 [9 T
was at 11 years of age, and her height was at 5 feet
6 ~. \: h0 y% C* J5 O+ |5 inches. There was no other family history of pre-8 T4 v* D1 G; K, V! `( f F) T( H
cocious sexual development in the first-degree rela-/ e3 z7 j/ v% ~
tives. There were no siblings.0 e" i; W8 b, P9 Y$ Z" ~, e
Physical Examination
9 c5 M+ |9 \. t M- KThe physical examination revealed a very active,2 v$ u; ]/ B: d: A2 N
playful, and healthy boy. The vital signs documented' ^- D5 O ?/ v1 d. t) _
a blood pressure of 85/50 mm Hg, his length was) v8 Z. Y8 b5 Y- G, N5 k
90 cm (>97th percentile), and his weight was 14.4 kg
' L, D- }1 Z' h% V: F9 {. X(also >97th percentile). The observed yearly growth5 v' f7 b' W5 l, N( J1 F9 V* `( }
velocity was 30 cm (12 inches). The examination of$ L2 g* J3 v. }( ?- C7 r7 U
the neck revealed no thyroid enlargement.5 F% x9 i& e$ q
The genitourinary examination was remarkable for
3 R5 `* H+ {9 d) _7 Kenlargement of the penis, with a stretched length of
$ M# t/ ]5 r9 K2 { ?8 cm and a width of 2 cm. The glans penis was very well
2 q c6 l" _& t& J5 b* Pdeveloped. The pubic hair was Tanner II, mostly around; X# z3 ^9 o! o' I6 x5 e9 ]" Z: R
540
4 {9 K) s- {8 sat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
- G+ e# C. a8 X3 R4 ?' c Z" Ythe base of the phallus and was dark and curled. The
9 g# g; j3 }% Mtesticular volume was prepubertal at 2 mL each.
& g9 V F6 H/ ~$ @7 |/ }The skin was moist and smooth and somewhat
$ y6 S4 ]2 t+ k& A! Qoily. No axillary hair was noted. There were no
" f4 L0 E$ Q: S, R+ m; N- Babnormal skin pigmentations or café-au-lait spots.* Y' X( o: b, j; L% f7 V. J4 U
Neurologic evaluation showed deep tendon reflex 2+
3 |. L# X4 t. n. d+ Ybilateral and symmetrical. There was no suggestion
! O8 `, c6 g4 R+ nof papilledema.
: z+ Z; I5 E1 A' y1 H Y0 b8 t5 tLaboratory Evaluation
2 n) t0 f3 @4 B0 Z2 p! B) i) u3 n* [The bone age was consistent with 28 months by$ R! [; j/ [3 x9 @: D8 A
using the standard of Greulich and Pyle at a chrono-! E* K& t3 S% ^- x" c5 A" ]
logic age of 16 months (advanced).5 Chromosomal% i( ?' {# m4 E
karyotype was 46XY. The thyroid function test
' U* g6 w% b) c4 w/ Lshowed a free T4 of 1.69 ng/dL, and thyroid stimu-
0 f6 B9 ~3 u, ]7 J( Z4 f8 H+ [lating hormone level was 1.3 µIU/mL (both normal).- E$ T& H; n) Q- _8 s( [" E7 |
The concentrations of serum electrolytes, blood
0 @2 y7 d8 m, T3 g) O X4 A9 rurea nitrogen, creatinine, and calcium all were
+ r9 y0 Z% Q, B9 i R5 [: Nwithin normal range for his age. The concentration
; _1 N6 N7 M" |* Tof serum 17-hydroxyprogesterone was 16 ng/dL/ K* s) E( X! j* d: v
(normal, 3 to 90 ng/dL), androstenedione was 20/ |9 a/ V. F: y
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-) @4 h* {1 J5 X
terone was 38 ng/dL (normal, 50 to 760 ng/dL),
; A+ S1 s7 b9 X$ Tdesoxycorticosterone was 4.3 ng/dL (normal, 7 to
% |3 r% V4 C* q- i( g- p& |0 n49ng/dL), 11-desoxycortisol (specific compound S), P% P, z4 u* r* R7 x
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
/ Y5 T% d# G& M# E3 _8 Rtisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
! S+ g2 g& e" }testosterone was 60 ng/dL (normal <3 to 10 ng/dL),, ~+ {0 ?8 v* p1 w& u8 M( q
and β-human chorionic gonadotropin was less than
+ Q3 | D! P# Z4 S) R* r5 mIU/mL (normal <5 mIU/mL). Serum follicular
( e W% ^; J) jstimulating hormone and leuteinizing hormone
$ }7 q! \! m4 Pconcentrations were less than 0.05 mIU/mL; X; u+ P( m- O) m6 r+ k
(prepubertal).6 O5 }3 F- { p& P$ h
The parents were notified about the laboratory
6 x0 `) J# l, ^* Q5 i% {results and were informed that all of the tests were
6 R, T% ? k* x9 T a) `normal except the testosterone level was high. The' H8 O( W/ [& A: G" b
follow-up visit was arranged within a few weeks to3 p5 P/ s! Y, F, p* U
obtain testicular and abdominal sonograms; how-$ i3 ]8 |$ P/ ]9 @
ever, the family did not return for 4 months., a' g0 a2 u2 d
Physical examination at this time revealed that the
z3 B* A( g5 ochild had grown 2.5 cm in 4 months and had gained
# j N. _3 \6 T6 a4 H2 kg of weight. Physical examination remained9 k7 f6 |+ D+ c: l! I9 P; ]) T
unchanged. Surprisingly, the pubic hair almost com-! u! Q/ `0 f0 Q/ ^ ?/ Y, H) J
pletely disappeared except for a few vellous hairs at/ |) q, P+ h: P c
the base of the phallus. Testicular volume was still 20 \, `/ g+ ^0 g- K
mL, and the size of the penis remained unchanged.2 W; X& }- `& c7 j, Y
The mother also said that the boy was no longer hav-
" q7 r4 I B% ]- \* `ing frequent erections.
* T2 Q0 c2 ~+ U, v7 S8 F7 H: B9 CBoth parents were again questioned about use of
x8 Q) ?) @ A. l/ Nany ointment/creams that they may have applied to7 q F# D2 z$ `) V) M( U/ S
the child’s skin. This time the father admitted the
2 M. C, f) c# S9 R" _Topical Testosterone Exposure / Bhowmick et al 541- P" h2 z3 Z& b w: k: o/ Q
use of testosterone gel twice daily that he was apply-8 ? `9 J: Y$ L9 @
ing over his own shoulders, chest, and back area for/ O- r, u2 E; O3 C( J+ ?
a year. The father also revealed he was embarrassed5 P4 J4 Q( l) o7 }% a4 y
to disclose that he was using a testosterone gel pre-( l9 y$ u: D/ L, o6 V
scribed by his family physician for decreased libido: R& a$ \& e0 G: H9 O- p2 t
secondary to depression.7 N/ a- M* H" [5 B- W! U
The child slept in the same bed with parents." X( ]* i% m6 j5 ~: G7 h5 p
The father would hug the baby and hold him on his; @2 ^/ D: h: |* o
chest for a considerable period of time, causing sig-
! j* ]9 ~6 p% \nificant bare skin contact between baby and father.
; K& B$ U% z& G% ~The father also admitted that after the phone call,- x& M1 i1 f; t" B/ [& I
when he learned the testosterone level in the baby
; T4 x( W d7 u9 gwas high, he then read the product information4 J8 R& G' z, ^6 x- [
packet and concluded that it was most likely the rea-% |) M1 g/ k# D4 E+ K1 A4 i& f
son for the child’s virilization. At that time, they
l: l, l4 E+ A: w, X3 d# Q" Cdecided to put the baby in a separate bed, and the, c% j: F& s# c0 n( J0 M) R
father was not hugging him with bare skin and had
# J E0 u' U0 f bbeen using protective clothing. A repeat testosterone; s. q4 k# X/ Y/ ^+ i
test was ordered, but the family did not go to the
" x& M; _9 o" l* t( k ^& blaboratory to obtain the test.3 a* R8 w) s: Q' B& r9 ?
Discussion0 \0 h i! E! m
Precocious puberty in boys is defined as secondary
( b( n- P9 B$ C# e* _+ ksexual development before 9 years of age.1,4
' Q, {. F; v% _' G3 pPrecocious puberty is termed as central (true) when
- b% I+ \$ E- pit is caused by the premature activation of hypo-
3 K& H9 Z+ l3 }' }1 Ythalamic pituitary gonadal axis. CPP is more com-7 R2 O; {- V/ A2 }& o8 Q
mon in girls than in boys.1,3 Most boys with CPP
' R, f4 F' M, w- i+ Cmay have a central nervous system lesion that is$ b5 X4 `1 K' t. C
responsible for the early activation of the hypothal-
2 B4 l8 e# }# G& S6 l0 k2 C( c; _amic pituitary gonadal axis.1-3 Thus, greater empha-
) t& ?. w% K1 H' O) y7 E) v3 zsis has been given to neuroradiologic imaging in
4 {5 l5 H! C6 bboys with precocious puberty. In addition to viril-( z0 G. r) v" [2 I4 u% H% r7 {
ization, the clinical hallmark of CPP is the symmet-
; X: i4 _0 d- |; y: Vrical testicular growth secondary to stimulation by/ N/ J& X: d4 z5 }, [$ ]: W; q/ K2 W
gonadotropins.1,3
X/ r9 d$ @( c" F AGonadotropin-independent peripheral preco- n; }4 U2 D. k" t9 E
cious puberty in boys also results from inappropriate
; v1 K# H3 v. ]1 mandrogenic stimulation from either endogenous or
1 H1 M- ]4 \0 fexogenous sources, nonpituitary gonadotropin stim-
, V8 v/ \' c* r9 P' m4 P Oulation, and rare activating mutations.3 Virilizing
. _/ P2 p0 o3 w- Y; Tcongenital adrenal hyperplasia producing excessive. b0 e9 o, }& c; E4 \+ Y
adrenal androgens is a common cause of precocious
' K# b+ ~& \" L* K( o9 e2 Spuberty in boys.3,4
0 `0 x+ y; ~; N1 T. pThe most common form of congenital adrenal
7 W( x2 |6 J% ?1 b. Xhyperplasia is the 21-hydroxylase enzyme deficiency.
5 t" Y* X% G6 q5 U. H6 yThe 11-β hydroxylase deficiency may also result in2 }( f8 O2 C5 I0 w6 i
excessive adrenal androgen production, and rarely,7 D% K+ C+ l, B; }, W% A* Z
an adrenal tumor may also cause adrenal androgen
" u8 Q% W! x* ]: h% \excess.1,3
$ b0 Z- v. z; I1 q; Bat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
3 G1 N1 w: ]; s! k& {) g m542 Clinical Pediatrics / Vol. 46, No. 6, July 2007; i5 V3 b, F- Z
A unique entity of male-limited gonadotropin-$ `" B# `$ m6 V4 N! E1 |) q; @
independent precocious puberty, which is also known
8 `' x3 x2 _3 Y. Cas testotoxicosis, may cause precocious puberty at a
: r! J- m3 r8 [7 j4 wvery young age. The physical findings in these boys7 U* W; S* c* @
with this disorder are full pubertal development,* S+ U. g, F/ X$ q' f% M5 X( ] _! x
including bilateral testicular growth, similar to boys
7 v0 M3 Z o2 i. n' Kwith CPP. The gonadotropin levels in this disorder1 j3 a; p: P: M q
are suppressed to prepubertal levels and do not show
4 B4 R3 Y4 Y6 S5 C( l @! K" e* `8 |pubertal response of gonadotropin after gonadotropin-5 m9 J8 f: ~% z
releasing hormone stimulation. This is a sex-linked1 t3 w9 `1 G. H0 Q% R7 V2 L" t
autosomal dominant disorder that affects only
& q( `. J. r/ D9 fmales; therefore, other male members of the family8 h- F6 u/ M3 }7 Z
may have similar precocious puberty.3; V& g( }- t2 A) c% M
In our patient, physical examination was incon-: y2 Z/ X$ v* M
sistent with true precocious puberty since his testi-+ J' {/ N J1 ?4 c5 o- q
cles were prepubertal in size. However, testotoxicosis6 H- `( G/ T7 [' i
was in the differential diagnosis because his father/ g" T2 k! P# i$ I) j& d5 d
started puberty somewhat early, and occasionally,$ n* _1 \& n3 f7 ?6 s/ T u
testicular enlargement is not that evident in the
' ~ q- J& Y7 a/ z$ A8 sbeginning of this process.1 In the absence of a neg-0 V5 x: e! F) D; o1 B
ative initial history of androgen exposure, our
: Y4 Y. B% F( u& j+ f( T$ \. hbiggest concern was virilizing adrenal hyperplasia,$ h6 _2 J3 ?( x; q+ m' P
either 21-hydroxylase deficiency or 11-β hydroxylase
* q2 X4 J' ?! k* M) F9 D5 K, vdeficiency. Those diagnoses were excluded by find-% l9 X# S5 { B8 y3 S9 e
ing the normal level of adrenal steroids.2 `: d' B( v$ y7 C* U9 `% `
The diagnosis of exogenous androgens was strongly
/ F% v& v0 [3 G) y! d9 l& Asuspected in a follow-up visit after 4 months because/ ?6 K( T- d* P1 e# z! p1 t
the physical examination revealed the complete disap-' A7 T: L2 T8 V# l
pearance of pubic hair, normal growth velocity, and
& ? Y) P% J& p1 Fdecreased erections. The father admitted using a testos-# Q3 C+ @, H# b$ Y4 ^* }
terone gel, which he concealed at first visit. He was
4 t: g. Q9 R6 `using it rather frequently, twice a day. The Physicians’
' H' \1 I* c! S/ ?. Y5 G8 mDesk Reference, or package insert of this product, gel or
; }4 _3 |! J+ g% C s( ]: Gcream, cautions about dermal testosterone transfer to) ?( n2 e7 ]7 I' m
unprotected females through direct skin exposure.
$ x- t. g8 a2 n/ Y s2 J- x% CSerum testosterone level was found to be 2 times the4 X/ I6 c8 x/ W, ?
baseline value in those females who were exposed to
5 g S- p5 ~6 A$ ?3 v6 o7 teven 15 minutes of direct skin contact with their male
: j. x* [( Z z. x3 K# ~partners.6 However, when a shirt covered the applica-: P7 P B7 M8 @ k
tion site, this testosterone transfer was prevented./ g8 a4 `, @* p* D
Our patient’s testosterone level was 60 ng/mL,
; n: R3 p; v% b2 Owhich was clearly high. Some studies suggest that7 z1 u8 Z5 {+ N
dermal conversion of testosterone to dihydrotestos-2 L, r9 z0 ]' `' _( H
terone, which is a more potent metabolite, is more7 _6 R: g9 P% h6 v( \$ g; g
active in young children exposed to testosterone$ Y6 z' u4 ~- [! |: G
exogenously7; however, we did not measure a dihy-
" I+ O* I. `& p: d- c3 g. bdrotestosterone level in our patient. In addition to6 G0 J% R, j# i9 t& G! i6 J- z; k
virilization, exposure to exogenous testosterone in
# y( u+ s- Q) Q, ]children results in an increase in growth velocity and* P Z" v. Q; ~ Z; p0 }$ {
advanced bone age, as seen in our patient.
3 |8 V8 j, l3 p( v! h. ~The long-term effect of androgen exposure during3 e0 M% W% i) N; j, n
early childhood on pubertal development and final
& j* q9 s- {! L( }4 l7 M- Yadult height are not fully known and always remain" ^" Q2 F2 c) ~& Y
a concern. Children treated with short-term testos-$ {) a: D+ m# T/ t: G
terone injection or topical androgen may exhibit some) o# {8 f o$ v, v3 n$ }8 J! ]2 K1 d
acceleration of the skeletal maturation; however, after& I5 t5 V+ k) t
cessation of treatment, the rate of bone maturation1 P% W# r; q- p. X8 C2 e
decelerates and gradually returns to normal.8,9& Z) g; I, o L& f6 G& p
There are conflicting reports and controversy
, E2 _! f! g0 Q: ^' Wover the effect of early androgen exposure on adult9 T" D1 `- H9 }( |( W- Q
penile length.10,11 Some reports suggest subnormal: A) y- d2 W8 a. C$ \9 O* e7 C
adult penile length, apparently because of downreg-, U; S2 b1 z9 B( K& B7 e
ulation of androgen receptor number.10,12 However,4 H$ A9 q1 `9 _2 e
Sutherland et al13 did not find a correlation between
! u, `% w u' E/ t3 K3 q% qchildhood testosterone exposure and reduced adult
5 @# ]& _/ g. V5 A+ z' r0 npenile length in clinical studies.0 _5 f# ]* ~1 w: \- V
Nonetheless, we do not believe our patient is
- J( ]. p R# T# \" x# h( r! E8 igoing to experience any of the untoward effects from
- [( J* {# d& J/ y, x% utestosterone exposure as mentioned earlier because
! Z7 y) i, K" l) Kthe exposure was not for a prolonged period of time.8 C. K; c& \ i9 w
Although the bone age was advanced at the time of; Y0 | a! B: Q5 y! S
diagnosis, the child had a normal growth velocity at
$ C, V% K D* R0 E4 j2 Zthe follow-up visit. It is hoped that his final adult
+ E+ k2 q3 d5 k, h* z8 J1 Hheight will not be affected.
" m- V' d* p( Z# d' N& @1 lAlthough rarely reported, the widespread avail-% L# J" G# [6 i
ability of androgen products in our society may
7 a2 q0 T% @7 G6 a* jindeed cause more virilization in male or female
! S' I, {1 i# ?; T( R7 G+ zchildren than one would realize. Exposure to andro-8 w6 B; \3 J$ V9 e' B% y" A" H7 Z( `
gen products must be considered and specific ques- h, r9 T+ `8 B1 ]5 `6 Z3 X& e
tioning about the use of a testosterone product or
: h$ K' v- w4 s0 g0 Q' mgel should be asked of the family members during
M+ o& G- q+ z( ?3 |0 q$ Y+ A' uthe evaluation of any children who present with vir-* R& b% o1 z$ L4 K
ilization or peripheral precocious puberty. The diag-5 m: p9 i+ c: a1 W
nosis can be established by just a few tests and by M& M) I, n: b) ?* o
appropriate history. The inability to obtain such a8 ?2 ?+ ~* r5 A
history, or failure to ask the specific questions, may
* b* Y; |/ Q S2 J- @result in extensive, unnecessary, and expensive0 I& J6 ?. R' k. s8 J. z+ g
investigation. The primary care physician should be7 ]# D! i: F3 h( n
aware of this fact, because most of these children
( F8 i6 a: g+ X8 |/ Rmay initially present in their practice. The Physicians’/ d' a: s( I2 ?6 K+ p
Desk Reference and package insert should also put a. `9 d0 q8 q8 ^) w' @
warning about the virilizing effect on a male or8 B2 l2 h9 g8 A& Q
female child who might come in contact with some-. J. L) y* C6 M5 Z2 r) _; D" b8 t7 I
one using any of these products.
7 c# U4 B; d D: ?5 K( r3 YReferences
3 [4 a H! i+ b. g; m; S& K1. Styne DM. The testes: disorder of sexual differentiation$ x+ h" r5 j2 \/ `, s5 j
and puberty in the male. In: Sperling MA, ed. Pediatric. }! `7 i& F) v8 h5 }: F. c
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
- L7 K: I% t9 ~2 k" w: V) z; t2002: 565-628.3 |8 c( i ~( I' T
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious# G1 j' } R, J3 M- k/ D! ]
puberty in children with tumours of the suprasellar pineal |
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