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Sexual Precocity in a 16-Month-Old4 q0 V5 P3 V: _& e8 H' U
Boy Induced by Indirect Topical* Y7 H# h0 n4 u) q3 { o( R( i8 J
Exposure to Testosterone3 q. q Q) @, t3 I9 \+ B
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,26 E8 b6 T( j0 h5 R% y7 B* S
and Kenneth R. Rettig, MD18 ]# G1 e, \( i
Clinical Pediatrics
d) t6 c4 @4 @6 L, o6 KVolume 46 Number 6
5 ?) M7 P% L5 O6 E) _July 2007 540-5434 _) b" r0 m, x {) b! E3 K
© 2007 Sage Publications$ l* m; }1 i& g. ~( Q% T
10.1177/00099228062966510 m9 K4 G J+ z8 c' o! V% {3 M
http://clp.sagepub.com
! K6 F+ a( T- D, ohosted at" g6 E, H1 Q$ T: l' I2 @
http://online.sagepub.com
9 I- Q3 j' R# b. T0 q% x( yPrecocious puberty in boys, central or peripheral,
: T" u% g1 `3 _, L* yis a significant concern for physicians. Central
: c# k, E# W9 o, G5 Dprecocious puberty (CPP), which is mediated* x6 V0 F& W' m' X: _
through the hypothalamic pituitary gonadal axis, has
; ?8 V0 @9 b2 |$ ^7 pa higher incidence of organic central nervous system, f) X" B- B5 b1 B Z9 p6 F
lesions in boys.1,2 Virilization in boys, as manifested
8 A* H$ Q. l" v4 xby enlargement of the penis, development of pubic
/ R8 l5 T5 ?# h4 z6 o# Qhair, and facial acne without enlargement of testi-
: y% ?$ v6 i4 v- [: X% tcles, suggests peripheral or pseudopuberty.1-3 We
$ U, Y$ ~9 g+ ^report a 16-month-old boy who presented with the
/ W* J9 n7 c4 Z+ C. lenlargement of the phallus and pubic hair develop-( `6 M' n! u3 z3 B# R/ z, t- e+ v* A
ment without testicular enlargement, which was due, O7 u9 M7 f- F B+ Z+ C
to the unintentional exposure to androgen gel used by' ?1 M8 J- M) K
the father. The family initially concealed this infor-
* b5 G0 m, {" ?' u; [9 \. nmation, resulting in an extensive work-up for this0 t( A$ w$ u- Y3 O M/ [1 R
child. Given the widespread and easy availability of
) e! m' k* R$ @, [" p6 ^ ktestosterone gel and cream, we believe this is proba-9 e% a* u* v% @5 C1 a# j7 O
bly more common than the rare case report in the" N; c# }2 N m4 r+ `8 D
literature.4, x$ J7 k: N2 o2 c) n
Patient Report
( {1 e& c& ` b; H) C" d4 r' DA 16-month-old white child was referred to the9 w# @: @( E% e) U" ]
endocrine clinic by his pediatrician with the concern7 q w: Z1 j! F; e3 C
of early sexual development. His mother noticed
+ T$ l8 h+ D1 T/ z U ^light colored pubic hair development when he was
A2 Z: e/ `0 n& r6 H, rFrom the 1Division of Pediatric Endocrinology, 2University of
- O( u- A. s2 X2 JSouth Alabama Medical Center, Mobile, Alabama.# i" @- k" A4 U
Address correspondence to: Samar K. Bhowmick, MD, FACE,
+ P1 H( t9 G* vProfessor of Pediatrics, University of South Alabama, College of5 g' [; W; A1 G% r7 ^6 \5 D
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;7 t9 T0 N# t$ M
e-mail: [email protected].
5 @0 y* V9 v9 }about 6 to 7 months old, which progressively became/ P' \: W' x5 f7 R
darker. She was also concerned about the enlarge- A" [/ T5 C8 e5 |) B
ment of his penis and frequent erections. The child& t9 o. Y& O% r
was the product of a full-term normal delivery, with* W1 q, \2 v- [8 N5 L
a birth weight of 7 lb 14 oz, and birth length of6 [4 e0 |: o& B0 d5 f. i0 p: D6 j; T
20 inches. He was breast-fed throughout the first year. S! i8 c, r( K4 S* y( `* b5 {
of life and was still receiving breast milk along with3 \# C& J. W/ \) \
solid food. He had no hospitalizations or surgery,
5 p# }; z+ s0 Eand his psychosocial and psychomotor development
! q# U# a3 Q9 y5 y" x& twas age appropriate.* w( L/ Y* e- U }4 \* q+ p3 S
The family history was remarkable for the father,! V- }; k8 r5 {! T# y8 o
who was diagnosed with hypothyroidism at age 16,
! _2 t1 s. l( J: J2 {3 g8 ywhich was treated with thyroxine. The father’s5 R1 j) P5 s# G; ~3 j" S7 p
height was 6 feet, and he went through a somewhat
# y. p1 P6 u# G* kearly puberty and had stopped growing by age 14.( O- e5 E# v( ~/ c+ g
The father denied taking any other medication. The
0 A y, t y9 _+ j# ^. ^5 b: n9 Lchild’s mother was in good health. Her menarche
2 W7 T5 x7 H) Iwas at 11 years of age, and her height was at 5 feet
$ y+ B) a$ b* L" V. u/ C% [5 inches. There was no other family history of pre-6 a7 Z" c0 }; B- x
cocious sexual development in the first-degree rela-9 Z" W+ n7 s% _7 t$ t2 J
tives. There were no siblings.
7 H7 M4 F. p8 x; G' O9 n. E# E$ OPhysical Examination% d: c! d$ R1 ~1 H! A2 b
The physical examination revealed a very active,$ C% Z0 ]5 S- I. ~! ]0 c
playful, and healthy boy. The vital signs documented! n) z: P1 ]. [ |
a blood pressure of 85/50 mm Hg, his length was& d5 h3 ?# z w2 Z9 B
90 cm (>97th percentile), and his weight was 14.4 kg
2 X% H; x" k- L% X* j% G# [(also >97th percentile). The observed yearly growth
C+ w$ |, n! Vvelocity was 30 cm (12 inches). The examination of
0 [8 r, S* t# `the neck revealed no thyroid enlargement.+ `6 ]! [, c( m: E! K
The genitourinary examination was remarkable for
- D) O5 @& Z0 f; l9 Uenlargement of the penis, with a stretched length of( r0 E/ F" o* _" }" e8 w* O3 q
8 cm and a width of 2 cm. The glans penis was very well
$ t6 C! {" T# | _5 ldeveloped. The pubic hair was Tanner II, mostly around2 Y8 V7 y1 Y' s* X0 a, R
5407 w& _3 K# E2 ]9 m6 D4 m }, `& F( {
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from% c( \7 }, q" |. a& c% X* @; x7 {
the base of the phallus and was dark and curled. The
8 P0 I: C i0 Vtesticular volume was prepubertal at 2 mL each.
^' z; m9 D9 N9 SThe skin was moist and smooth and somewhat
+ g5 B9 E. X0 s# X2 Roily. No axillary hair was noted. There were no. C) y5 e8 f5 ]: A* E, l0 K
abnormal skin pigmentations or café-au-lait spots.
* P6 B/ f5 [5 w5 L- q& eNeurologic evaluation showed deep tendon reflex 2+9 p! e) z+ G# j
bilateral and symmetrical. There was no suggestion! y1 P6 z. c3 U; x4 f }! S6 Z7 m
of papilledema.
( M! A" W- W) pLaboratory Evaluation
4 K8 }+ T0 _0 d) X" YThe bone age was consistent with 28 months by
. [; M8 u8 V+ _$ T& u d, C# H. Susing the standard of Greulich and Pyle at a chrono-; ^2 X2 V4 W2 g5 p- A. m
logic age of 16 months (advanced).5 Chromosomal( d0 Z1 I: _& l4 T, @/ D
karyotype was 46XY. The thyroid function test$ ]1 ]1 h/ O% D/ b M
showed a free T4 of 1.69 ng/dL, and thyroid stimu-
, u1 Z0 H O4 C# S( Ilating hormone level was 1.3 µIU/mL (both normal).) ?; h- I1 g4 c; i6 v8 U& |
The concentrations of serum electrolytes, blood h. U- [& b- h8 E; w. m0 P
urea nitrogen, creatinine, and calcium all were
! m9 d0 R8 ^- F a* [! ~2 t; Twithin normal range for his age. The concentration9 l! t' l) W4 ?# n; o P9 w% H# D
of serum 17-hydroxyprogesterone was 16 ng/dL0 L$ ?5 ?* G3 |) w
(normal, 3 to 90 ng/dL), androstenedione was 20
O7 j: H% y( `! u2 Png/dL (normal, 18 to 80 ng/dL), dehydroepiandros-9 ^! O5 F* Y- q
terone was 38 ng/dL (normal, 50 to 760 ng/dL),
1 C5 l. ]9 |1 i5 E4 mdesoxycorticosterone was 4.3 ng/dL (normal, 7 to# s/ y0 x8 C) ~% m5 J5 t
49ng/dL), 11-desoxycortisol (specific compound S)
) a4 w" z! w3 X6 h+ w& {6 jwas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-: f0 F4 y' a% R
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
# {& a2 s s9 B: d5 C2 Z1 ctestosterone was 60 ng/dL (normal <3 to 10 ng/dL),
! V$ p. ?% K1 [& q; p; J6 Q8 _and β-human chorionic gonadotropin was less than
( a. T* A2 j9 b* [5 mIU/mL (normal <5 mIU/mL). Serum follicular
" n( ~. B) W5 O3 ustimulating hormone and leuteinizing hormone
1 G- B4 {$ F% V; yconcentrations were less than 0.05 mIU/mL" X" w# r! l0 \
(prepubertal).
4 s- m, X2 M' I3 L+ x- C3 wThe parents were notified about the laboratory9 m3 v h. R5 l- K7 C C5 F0 |
results and were informed that all of the tests were$ w" ]. A/ X& X$ u
normal except the testosterone level was high. The
6 x% |) }1 ?% a- Q# K2 y$ kfollow-up visit was arranged within a few weeks to$ R4 }& K3 x: |8 c
obtain testicular and abdominal sonograms; how-5 b1 B+ W7 C0 ]& i
ever, the family did not return for 4 months.
1 q* m. ?4 z6 Y- i SPhysical examination at this time revealed that the# Y1 }' `$ \. ~( N. x+ I# B
child had grown 2.5 cm in 4 months and had gained
! P. h+ L$ n$ e0 ]3 h6 h" Z2 kg of weight. Physical examination remained/ R8 E. L( Z$ A* e! S5 y' w9 A
unchanged. Surprisingly, the pubic hair almost com-
4 Q1 C5 B% S8 q6 Q0 p4 \pletely disappeared except for a few vellous hairs at3 [$ U7 u+ K/ {5 P. p/ [
the base of the phallus. Testicular volume was still 2
S! B2 V, C2 N4 B: hmL, and the size of the penis remained unchanged.
8 a. P- H2 _! V& D; D" _The mother also said that the boy was no longer hav-8 r6 f5 n! {& j& b
ing frequent erections.6 K* J* F! K' @) Q) F# W
Both parents were again questioned about use of
) v, Z s0 i y7 P* N! Eany ointment/creams that they may have applied to
! s: i1 m8 M, b8 C/ Lthe child’s skin. This time the father admitted the' Y4 I; V) N2 w6 m! n, `
Topical Testosterone Exposure / Bhowmick et al 541
( n* V7 u5 }3 P2 Nuse of testosterone gel twice daily that he was apply-2 o, s' y8 U; ^0 _- P" O
ing over his own shoulders, chest, and back area for
, H/ ?" f& M0 R7 c$ Ga year. The father also revealed he was embarrassed
9 m- y0 E5 K/ D% A& D2 [* Z/ Z( kto disclose that he was using a testosterone gel pre-
1 K& `5 t4 u4 Kscribed by his family physician for decreased libido4 [4 y- S/ W( |
secondary to depression.
' c2 ~' V- |; g3 l3 f. dThe child slept in the same bed with parents.
4 u* n! v3 V9 zThe father would hug the baby and hold him on his5 M- C9 c U; C3 B+ o% v' E
chest for a considerable period of time, causing sig- Q/ j: q4 w( P4 c
nificant bare skin contact between baby and father.4 E. i* k( U8 P$ s) a) U) w% Y
The father also admitted that after the phone call,6 Z4 j$ I8 i; J" T3 q9 e$ q
when he learned the testosterone level in the baby
5 K2 r/ Q% o) t* H( }was high, he then read the product information
3 t; |4 m' }# n5 Wpacket and concluded that it was most likely the rea- E( t( y; u: g+ }0 S) I9 J+ {
son for the child’s virilization. At that time, they
3 t2 x" L2 Q, `5 H; L3 D6 Ddecided to put the baby in a separate bed, and the
8 P, E. B8 o6 p4 ~father was not hugging him with bare skin and had
- T8 v; A; [0 vbeen using protective clothing. A repeat testosterone
6 Q4 p3 B3 `% m/ P9 i, o; ] b6 @test was ordered, but the family did not go to the
' v3 l& t. r4 Y. Q6 tlaboratory to obtain the test.
8 p" o1 `$ b) {3 w' N, YDiscussion
M0 N1 B1 ]1 F! z) L+ ]) ~Precocious puberty in boys is defined as secondary# A g1 a l' o/ P9 J; t. |- C
sexual development before 9 years of age.1,4% t( s5 _: R3 e0 H6 v
Precocious puberty is termed as central (true) when/ f, z% d3 v- m6 w2 \
it is caused by the premature activation of hypo-
, s2 Q/ N5 X- x6 ^) vthalamic pituitary gonadal axis. CPP is more com-
2 G l, s" r& U9 S Jmon in girls than in boys.1,3 Most boys with CPP1 J# i6 l T6 w& F5 [1 d3 u& Z" K
may have a central nervous system lesion that is: f/ |6 w+ i* g5 F, ]& i
responsible for the early activation of the hypothal-
, w+ A* a6 f7 I: A! }: mamic pituitary gonadal axis.1-3 Thus, greater empha-. ?* N$ J1 l$ D# M8 g& c6 C `& Z' Z5 o
sis has been given to neuroradiologic imaging in/ p. N5 o/ w) a+ ~! R, N8 D9 J* a
boys with precocious puberty. In addition to viril-
1 `2 L) q" C* W8 S( V4 Y1 Tization, the clinical hallmark of CPP is the symmet-
3 K5 W$ C; V R8 Mrical testicular growth secondary to stimulation by
' [& M1 Y5 G+ h2 Egonadotropins.1,3) v, V; n5 i2 M2 ^
Gonadotropin-independent peripheral preco-
, Y- S( `" ~" Ucious puberty in boys also results from inappropriate
. ~% s+ R4 p: p/ b( F( a& {; @' a7 Handrogenic stimulation from either endogenous or
0 z: O! s2 _! A. C1 I8 \- r7 sexogenous sources, nonpituitary gonadotropin stim-* ^# X H2 m& z7 l# T# w7 W! n
ulation, and rare activating mutations.3 Virilizing" y( Q( Y+ G+ R& l) H% Y: N/ }
congenital adrenal hyperplasia producing excessive- w) p" F m: @1 z5 C" I) n
adrenal androgens is a common cause of precocious
' L- y+ A& X ~. ~# h" j9 npuberty in boys.3,45 P) O3 R4 E! Q. W9 m9 a4 Z
The most common form of congenital adrenal
4 n- X# e! `6 ^+ `hyperplasia is the 21-hydroxylase enzyme deficiency. J) e0 j$ T/ u* r/ ?0 s. A1 u
The 11-β hydroxylase deficiency may also result in. b1 | `2 b- e& i. |0 [8 x% F
excessive adrenal androgen production, and rarely,
2 {8 c$ s! p0 l( lan adrenal tumor may also cause adrenal androgen! Y! l7 k1 |8 {8 Z. C( S' b
excess.1,3
& K7 b1 N6 B! o3 m; aat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from* c/ d2 H* e% _0 T3 x% B
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
: @/ Y1 q/ `& sA unique entity of male-limited gonadotropin-
( G0 _5 M4 H) i# D' ^, y4 d* ?independent precocious puberty, which is also known
R. R8 y! ~" S' D2 O) Fas testotoxicosis, may cause precocious puberty at a
! e3 g' e2 {0 n( K- dvery young age. The physical findings in these boys
: q! N: t+ @8 I2 l1 r1 V" vwith this disorder are full pubertal development,# k, F8 G( J* H$ G
including bilateral testicular growth, similar to boys
% J2 _8 o6 N! m p# K$ n. |4 o( swith CPP. The gonadotropin levels in this disorder
- ~7 ?; C3 j& y+ ?6 n" w6 Ware suppressed to prepubertal levels and do not show! c' M9 |/ ]9 w/ [
pubertal response of gonadotropin after gonadotropin-5 k" W/ \" `& Y9 P' |( A* y, W
releasing hormone stimulation. This is a sex-linked1 D3 ?% e- z& k% V- y9 f T4 ?
autosomal dominant disorder that affects only
& L/ Y: |/ ~# M( L" `males; therefore, other male members of the family, a( L# W9 ?0 M! G; f
may have similar precocious puberty.3' j5 O( E6 b1 |* a4 c% {, X% v
In our patient, physical examination was incon-3 j, t. Q' E# u+ I+ o
sistent with true precocious puberty since his testi-5 h6 b. u+ W: G
cles were prepubertal in size. However, testotoxicosis
5 H' T- P8 R! A, H% l' w# a( r" Iwas in the differential diagnosis because his father
0 P9 Q& Y( i& U2 t3 astarted puberty somewhat early, and occasionally,% |3 e0 x9 D' x
testicular enlargement is not that evident in the. T4 ?; q) N5 ]
beginning of this process.1 In the absence of a neg-
/ \3 K z4 w$ Rative initial history of androgen exposure, our
/ |- e. ]& f6 ybiggest concern was virilizing adrenal hyperplasia,4 V* C9 V+ g N0 f }
either 21-hydroxylase deficiency or 11-β hydroxylase) x7 B0 _9 {# I5 @% |- Q7 S8 v( R
deficiency. Those diagnoses were excluded by find-
- I' X- }' d8 O1 q& a' l8 H8 king the normal level of adrenal steroids.6 K4 J, ]6 @0 ^+ I+ o; [
The diagnosis of exogenous androgens was strongly
! W, p$ {, `- y0 x7 asuspected in a follow-up visit after 4 months because
( w) v# t8 Q4 N" U" S* R5 Q3 K/ [the physical examination revealed the complete disap-
+ q" h" X! s/ O- ]( j5 o* N% ipearance of pubic hair, normal growth velocity, and
3 I) g' S( e2 Adecreased erections. The father admitted using a testos-
6 a1 |/ I/ M+ Sterone gel, which he concealed at first visit. He was
; i4 @2 k; ] @* y5 o" D. t6 Yusing it rather frequently, twice a day. The Physicians’
4 d u: w/ N% B8 y" Y) ?" ~Desk Reference, or package insert of this product, gel or
8 a" g, d' y4 t: K1 |7 bcream, cautions about dermal testosterone transfer to$ g; |) d; \+ B/ b' W
unprotected females through direct skin exposure.' H2 w3 N& v8 {8 y9 d9 h0 h/ l
Serum testosterone level was found to be 2 times the
8 G0 A0 E ~( Z* R- U) q9 c6 ~- ~baseline value in those females who were exposed to
& u Y2 K C. \+ D' ^+ f3 H" weven 15 minutes of direct skin contact with their male* \2 T2 s! U4 P' O2 S
partners.6 However, when a shirt covered the applica-
# [ X3 g/ _) l! P$ U1 M+ _2 P! ction site, this testosterone transfer was prevented.0 ]9 \ |" J6 h& g' j- Q5 c
Our patient’s testosterone level was 60 ng/mL,
% T0 s9 W; \( W$ U( ewhich was clearly high. Some studies suggest that
$ W% B; J( K2 V9 Ydermal conversion of testosterone to dihydrotestos-- n1 o) p: F0 X4 A* _% S3 |
terone, which is a more potent metabolite, is more1 s* j$ `/ D" P! D
active in young children exposed to testosterone( \: d1 c: y. S& S! W
exogenously7; however, we did not measure a dihy-3 T% \' ~5 T' a
drotestosterone level in our patient. In addition to
6 v* E$ f5 X& e& Y5 s# V. evirilization, exposure to exogenous testosterone in2 J) e+ m' A- m
children results in an increase in growth velocity and
9 v# X( R2 ^; u3 r! Xadvanced bone age, as seen in our patient.7 B: j/ P% v, o' O) ?8 ]9 _
The long-term effect of androgen exposure during
% `* R E. Z' L" zearly childhood on pubertal development and final/ {& X6 x [0 ]
adult height are not fully known and always remain
0 g8 M/ q$ F6 ?9 L+ w& v1 ua concern. Children treated with short-term testos-! ~: t {3 ?3 U& f
terone injection or topical androgen may exhibit some
- Y5 p. w6 ^( [& a+ _! Vacceleration of the skeletal maturation; however, after
( w; ]# c1 B s" Vcessation of treatment, the rate of bone maturation' z5 K; w/ `# ?; Z+ U- E: R
decelerates and gradually returns to normal.8,9# N9 u* X) Z- f
There are conflicting reports and controversy
! Q3 y$ o# [9 g: l6 Uover the effect of early androgen exposure on adult
8 N, u) J* h) i8 e6 j) ?1 ipenile length.10,11 Some reports suggest subnormal
! s7 ~* @7 d0 d1 z% a- `; e% @adult penile length, apparently because of downreg-) k4 Y1 @( L* U$ b* f$ C
ulation of androgen receptor number.10,12 However,
7 i- ?, j# x! ISutherland et al13 did not find a correlation between
- N) f) \% z, ]9 fchildhood testosterone exposure and reduced adult1 `; J4 t% }3 u0 }* b7 E$ x
penile length in clinical studies.
' [. W$ O& l k4 D+ fNonetheless, we do not believe our patient is
: y' R; H# c3 u4 I5 H( B5 ^going to experience any of the untoward effects from
4 e+ {3 R& d' ^! D" ^, ftestosterone exposure as mentioned earlier because
( [) s; T: r! R; {) Dthe exposure was not for a prolonged period of time.) t0 m7 Y7 g1 P, r) X: q
Although the bone age was advanced at the time of9 j5 O% }0 Z: {6 Y
diagnosis, the child had a normal growth velocity at
) c# m" T$ U" m" `5 v8 Wthe follow-up visit. It is hoped that his final adult
/ f; S; J6 w0 R3 J1 \$ E0 pheight will not be affected.
# w1 s/ R1 J. O' a {6 MAlthough rarely reported, the widespread avail-
% R9 x' a$ D) B$ L/ |ability of androgen products in our society may+ D4 G! N, H; M f% K- j+ j
indeed cause more virilization in male or female
: ^- K4 a. S' m$ r* f& Q/ e1 N5 Achildren than one would realize. Exposure to andro-
* I) v3 s% s R' n# g" Lgen products must be considered and specific ques-
1 k6 G$ P( t2 E/ W, x9 Ftioning about the use of a testosterone product or
& ?2 ?( H3 C% z" ^) g8 ~. h0 L* B. igel should be asked of the family members during
, P+ U0 _2 \! o( i- g1 ^" Lthe evaluation of any children who present with vir-
0 l7 Q! t* O8 E/ i% ^3 u Jilization or peripheral precocious puberty. The diag-
, {! U- [8 Z$ g3 f" i( Bnosis can be established by just a few tests and by) k2 U" e) q. R
appropriate history. The inability to obtain such a
1 _/ a+ A) L" Ehistory, or failure to ask the specific questions, may
6 x8 S/ e; V6 p3 z' oresult in extensive, unnecessary, and expensive
( O" c5 v' l/ v& _: pinvestigation. The primary care physician should be9 y ]$ M& u- E* M$ L
aware of this fact, because most of these children
, P+ ]* M- r* ?+ Z% q1 n3 xmay initially present in their practice. The Physicians’
: B2 ?8 _+ E, H( ?. A; ~0 x& RDesk Reference and package insert should also put a% B8 ~. h3 M% E& t$ E) h
warning about the virilizing effect on a male or( u# r1 v* \' E, p" d8 N
female child who might come in contact with some-
; f- l% m# Y9 f4 zone using any of these products.$ g e/ _0 p% b9 Q
References9 h4 m! S, C" t4 p
1. Styne DM. The testes: disorder of sexual differentiation6 v k( T$ ~) r h
and puberty in the male. In: Sperling MA, ed. Pediatric1 z( z( Q/ Z4 o
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
8 V7 n4 I: \) g, f& p. J. K2002: 565-628.
! `, Y6 l$ a, B. B. c* \2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious: D9 M h0 k0 p
puberty in children with tumours of the suprasellar pineal |
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