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Sexual Precocity in a 16-Month-Old: S) E% c) K" s% e# |6 ~
Boy Induced by Indirect Topical/ N% {5 ?: H0 m( @& k1 B
Exposure to Testosterone
- T, ` p d+ i8 W9 k6 z6 xSamar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
% D: Q. {; V9 M* Q, r9 Eand Kenneth R. Rettig, MD1/ X3 o) C6 f4 j6 Y
Clinical Pediatrics! m3 A6 g M' N( r Q0 _
Volume 46 Number 61 G' F- r; S, X
July 2007 540-543
* x/ \ j3 N9 d4 G/ ^© 2007 Sage Publications! ~$ i7 S1 S8 n6 W' K# X1 S+ x
10.1177/00099228062966511 I2 ]% j9 ?: E7 l
http://clp.sagepub.com
/ O4 C2 k5 V) chosted at) M( l- Y1 D9 |
http://online.sagepub.com
* v! `: W! ~1 w! A) ]Precocious puberty in boys, central or peripheral," k- s$ @' \5 }7 D
is a significant concern for physicians. Central
0 w& I1 j" U* pprecocious puberty (CPP), which is mediated
6 x: l/ i. x0 ]( C) gthrough the hypothalamic pituitary gonadal axis, has
i* O. V: `# x8 K" j: e6 o$ Qa higher incidence of organic central nervous system
; ]0 f* A$ H; H" V) R( Y' ulesions in boys.1,2 Virilization in boys, as manifested8 F* M1 @: `2 M, |0 o: X& z& G3 o
by enlargement of the penis, development of pubic
3 L0 ]5 y$ g3 `4 y" fhair, and facial acne without enlargement of testi-$ x/ ]9 w( |' `' t
cles, suggests peripheral or pseudopuberty.1-3 We4 R4 k1 F, I$ o7 ?2 W7 D$ M
report a 16-month-old boy who presented with the
4 P3 f1 j. }3 Uenlargement of the phallus and pubic hair develop-
5 s0 G2 B* E+ L$ b& hment without testicular enlargement, which was due+ ?: w. J! k3 m P
to the unintentional exposure to androgen gel used by
# m' b6 U+ N$ M; m' H4 Vthe father. The family initially concealed this infor-% w8 U! K5 J: D
mation, resulting in an extensive work-up for this$ V7 F3 j* W% O# }
child. Given the widespread and easy availability of
* e, q) D! M/ U4 Y3 @2 f. K+ Ytestosterone gel and cream, we believe this is proba- r- D) }/ F. x9 K/ k9 t; G
bly more common than the rare case report in the
% m( @- k+ C: q* F, h# E. Z- F9 t( tliterature.4
+ L3 R8 E- G( T, k, F4 IPatient Report
+ i, \' l2 ` P! E) c5 A* EA 16-month-old white child was referred to the
3 j7 f8 k. k7 o0 Rendocrine clinic by his pediatrician with the concern
' O, s/ J: }, ?7 Y% ]of early sexual development. His mother noticed/ e$ _7 s6 N3 i7 e4 C# G7 X
light colored pubic hair development when he was
% m5 M/ ]6 s9 y0 _) f$ ]From the 1Division of Pediatric Endocrinology, 2University of
! s- n$ d$ n' }7 BSouth Alabama Medical Center, Mobile, Alabama.
7 N' R$ \( L1 n$ q7 bAddress correspondence to: Samar K. Bhowmick, MD, FACE,9 z3 y8 @- d. s$ ~; b7 j
Professor of Pediatrics, University of South Alabama, College of4 {/ w9 F+ \# o7 n8 i( W
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;( X$ S" x6 N6 d' Y& {5 @) O
e-mail: [email protected].
; ~5 [2 q* D3 y" u" X2 q) |; G3 Rabout 6 to 7 months old, which progressively became
- j& Q& w% `! q( z8 R0 Edarker. She was also concerned about the enlarge-
, _, ~5 `! X7 A6 d3 N) y0 sment of his penis and frequent erections. The child2 `+ m2 b# f. r; d" X* ?2 i8 @
was the product of a full-term normal delivery, with
: E! j' O9 P, t/ b/ W6 ]a birth weight of 7 lb 14 oz, and birth length of
5 x/ T8 k3 S3 l. q/ ]2 `( C20 inches. He was breast-fed throughout the first year
q7 t/ }8 x4 |) ^: Yof life and was still receiving breast milk along with. [: G: t) E/ r9 b
solid food. He had no hospitalizations or surgery, ]. @# h+ G- W( N& J/ U' N
and his psychosocial and psychomotor development
3 i) w% b8 h4 bwas age appropriate.
0 ^" u6 B/ T* p) gThe family history was remarkable for the father,1 N# r& i% X" V) u5 I
who was diagnosed with hypothyroidism at age 16,7 v8 F* R5 Z' }, F3 Z* b N' z, v
which was treated with thyroxine. The father’s
/ `* D1 [- ]8 \! d- v0 E- Y; Iheight was 6 feet, and he went through a somewhat b0 n4 @# H6 h+ A/ E6 ]9 l: b1 V
early puberty and had stopped growing by age 14.- x' h6 }8 s. k& ? S7 D5 ~
The father denied taking any other medication. The
9 K3 M% l5 ^0 ~8 A0 Cchild’s mother was in good health. Her menarche2 J; E0 b7 w9 Q( @+ I
was at 11 years of age, and her height was at 5 feet# `) z( b; S! x; @/ o( v9 R
5 inches. There was no other family history of pre-9 b8 f& q, k: J7 t* R5 N, E4 \
cocious sexual development in the first-degree rela-! L; o+ q' n' F
tives. There were no siblings.
y+ T: |6 M. S0 p% f) { ~: G) QPhysical Examination
2 S& Q, R! i' eThe physical examination revealed a very active,
- ?" I) G3 g! O4 eplayful, and healthy boy. The vital signs documented+ V- k6 J7 i) U7 ]. y, e
a blood pressure of 85/50 mm Hg, his length was
1 ~/ V0 F2 G$ m7 M90 cm (>97th percentile), and his weight was 14.4 kg( p4 K# h- X4 v+ N0 ]- r
(also >97th percentile). The observed yearly growth
( S( t/ \7 d; ?& ]3 P% Nvelocity was 30 cm (12 inches). The examination of g6 T0 s7 I/ A9 h
the neck revealed no thyroid enlargement.
* M3 D8 D. X9 e$ t* A% H. XThe genitourinary examination was remarkable for! H) L) [# X0 f( f# h( z
enlargement of the penis, with a stretched length of4 F& R* b7 d2 d V, |* {# M9 L4 ~
8 cm and a width of 2 cm. The glans penis was very well
) L( R: T; ?9 r2 B$ K# ydeveloped. The pubic hair was Tanner II, mostly around
0 O4 e/ @- T J( [* w5405 u. h5 u8 ]- |: x
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from& E% Q8 r0 h' [- y0 a# x$ `
the base of the phallus and was dark and curled. The
) s! F) ?0 r) {$ i# a0 O% G2 X1 @testicular volume was prepubertal at 2 mL each.
# A2 a; t& j5 e t0 E2 D7 ^3 eThe skin was moist and smooth and somewhat
1 P7 ?' g8 {, ^8 xoily. No axillary hair was noted. There were no
' @) _' b: z; _# _$ b. \: labnormal skin pigmentations or café-au-lait spots.
S5 g; Y4 Q- I( N2 h$ r. eNeurologic evaluation showed deep tendon reflex 2+; r- j# b4 b3 i! z+ ^
bilateral and symmetrical. There was no suggestion8 k$ f9 C8 E# z0 Z3 s! G
of papilledema.
$ G; `$ |! V0 _3 e; _7 JLaboratory Evaluation& p: g. E& D2 X# |2 E* f
The bone age was consistent with 28 months by
3 P \: ~" S0 {5 ~$ |9 `# xusing the standard of Greulich and Pyle at a chrono-, x. z1 N( h/ G
logic age of 16 months (advanced).5 Chromosomal
% |0 Y% h6 A8 H" `6 t, Bkaryotype was 46XY. The thyroid function test
! ]; H! X; u0 w8 B/ c- ^5 eshowed a free T4 of 1.69 ng/dL, and thyroid stimu-
, ^3 X" ^$ i; N c# s& R( J9 zlating hormone level was 1.3 µIU/mL (both normal).- S& x0 S: K* Q* p( i
The concentrations of serum electrolytes, blood
2 o. H2 [6 o% M$ }& o) _; z5 M; _( rurea nitrogen, creatinine, and calcium all were
6 r) h, Y G- l3 Z, C2 Bwithin normal range for his age. The concentration3 O7 e6 e. M9 ~" [2 f) b% j
of serum 17-hydroxyprogesterone was 16 ng/dL, o H* L h" m( E
(normal, 3 to 90 ng/dL), androstenedione was 20/ N/ B! m! C( a# X( C# |) c: Z9 M) }" d; S
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-6 Q A2 ?( s' }1 D0 I/ U
terone was 38 ng/dL (normal, 50 to 760 ng/dL),: K& j P# e1 R) P/ q
desoxycorticosterone was 4.3 ng/dL (normal, 7 to
$ r4 {/ g" } J49ng/dL), 11-desoxycortisol (specific compound S)
- n v4 Y. d; K; Pwas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-. r/ r) F6 M p" X1 V6 ~# F4 z
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
) Q( Y }. ~5 W; f, Utestosterone was 60 ng/dL (normal <3 to 10 ng/dL),
: g* {# t6 P- d1 [and β-human chorionic gonadotropin was less than
: e2 @- v/ o( X: u$ e5 mIU/mL (normal <5 mIU/mL). Serum follicular+ C W% N1 y' E* p; k4 l1 L$ V
stimulating hormone and leuteinizing hormone0 j0 T+ y" M T7 s8 R: n$ w
concentrations were less than 0.05 mIU/mL
7 _, Z9 y( G4 R, i8 P$ n(prepubertal).
+ j/ s5 E) Y- l" N" K% qThe parents were notified about the laboratory
6 Q, G$ K3 C8 C2 }2 Dresults and were informed that all of the tests were! Z- `. ^0 D4 B( {( |2 b: _" S8 n& n
normal except the testosterone level was high. The
; I' z" D5 w. Tfollow-up visit was arranged within a few weeks to
8 M& O; B$ l& \( Oobtain testicular and abdominal sonograms; how-
9 S# |' \0 }' x: Y; w wever, the family did not return for 4 months.
- w7 q: l" I6 C S! xPhysical examination at this time revealed that the
% ^3 w" b/ t2 [* a. [/ X% ychild had grown 2.5 cm in 4 months and had gained
r7 r( z6 p2 D/ c2 kg of weight. Physical examination remained4 P7 G+ _' G2 l
unchanged. Surprisingly, the pubic hair almost com-
) H3 |4 n9 K3 V- r$ n5 Dpletely disappeared except for a few vellous hairs at9 s# ^) ^7 K1 Z
the base of the phallus. Testicular volume was still 2
( b: e% ]: A( r% A( g8 EmL, and the size of the penis remained unchanged.) r7 d; \$ F6 ^( t& ~7 _- I
The mother also said that the boy was no longer hav-( t7 ]# \! W8 v9 O; h* H5 `1 P" s- ~
ing frequent erections.
" v( [# c2 M% |. ?Both parents were again questioned about use of0 u! G. X6 `# E( C- r; i
any ointment/creams that they may have applied to @" j( H3 v& F% H, |
the child’s skin. This time the father admitted the- k! t; |2 R( P' \6 }2 o7 c$ U& [
Topical Testosterone Exposure / Bhowmick et al 5416 Y* w8 u2 [0 {3 P3 [, A/ Y* t
use of testosterone gel twice daily that he was apply-6 S8 k0 |) k8 h2 h
ing over his own shoulders, chest, and back area for
- X5 n2 ]: X" l: S6 b+ b! ia year. The father also revealed he was embarrassed+ S+ G- b/ o9 [ K T$ [
to disclose that he was using a testosterone gel pre-
& k, o- o, g1 R" y# s+ C2 N1 uscribed by his family physician for decreased libido- L: e% p* t+ k( t0 C# x# i
secondary to depression.
# s' `( Z8 E& D3 DThe child slept in the same bed with parents.
' S% @0 O3 V' F* y! b0 G$ Q: B, G0 VThe father would hug the baby and hold him on his/ [8 o8 m( s9 F7 }+ k; ?; D
chest for a considerable period of time, causing sig-% Z. b" v" C7 M1 }% N: f
nificant bare skin contact between baby and father.; A9 }, Y" ?, l
The father also admitted that after the phone call,7 I/ N7 y# Z/ i4 `8 K
when he learned the testosterone level in the baby+ V, ?3 s) h9 S5 k+ H! E
was high, he then read the product information
5 w4 C: h3 i. b3 u1 ppacket and concluded that it was most likely the rea-
1 b0 Y4 r2 T; B9 d3 {, pson for the child’s virilization. At that time, they
! G" o1 Y6 `, |9 ddecided to put the baby in a separate bed, and the* W8 {6 I- m/ }: D) e
father was not hugging him with bare skin and had i8 ]; U: M9 W$ \" e5 D" a! o
been using protective clothing. A repeat testosterone
& e8 _* e$ P5 L; B, ctest was ordered, but the family did not go to the+ a4 N# d& [% ~/ ?* y8 N$ y. @7 L( y4 `
laboratory to obtain the test.
% `/ @: t% V: o% lDiscussion
. G# [' ?% X9 v1 Z7 E4 rPrecocious puberty in boys is defined as secondary* g2 ^3 w' ]0 Q. v; T3 |& u& Z
sexual development before 9 years of age.1,4+ P; p1 }, O: N2 j1 z
Precocious puberty is termed as central (true) when9 \$ w, `1 ~/ d7 c
it is caused by the premature activation of hypo-
9 `& }; J! ~% ^( J3 r Dthalamic pituitary gonadal axis. CPP is more com-: a- }: D- G+ @, F, {; X T" T1 Y
mon in girls than in boys.1,3 Most boys with CPP
$ L4 L! x1 @/ R& Q, `6 q) n- Vmay have a central nervous system lesion that is) ]$ D% b6 C) t8 Y3 c! z
responsible for the early activation of the hypothal-
7 r: L5 I/ d2 o: U3 `1 z7 Samic pituitary gonadal axis.1-3 Thus, greater empha-- R7 V/ n5 N7 U! f' E
sis has been given to neuroradiologic imaging in1 Z) K6 x+ b+ V- b) D: s
boys with precocious puberty. In addition to viril-. a6 \0 j4 a5 A2 o# W
ization, the clinical hallmark of CPP is the symmet-" R6 n! }7 x( K, g" a7 M" s' K2 Q
rical testicular growth secondary to stimulation by& ^; q; z" d" w) ?, `( e! G
gonadotropins.1,3
* u3 z R# d: N9 CGonadotropin-independent peripheral preco-' H) _# \- J/ e7 F8 u' p4 a$ x
cious puberty in boys also results from inappropriate
/ u0 K% @9 q# I* r0 M2 K! iandrogenic stimulation from either endogenous or
0 L& G+ t$ H! ^! C% T% Cexogenous sources, nonpituitary gonadotropin stim-& o: j1 Z4 e+ q) Z2 A& Q
ulation, and rare activating mutations.3 Virilizing9 ~7 t" P+ H# O+ T2 c/ m) H
congenital adrenal hyperplasia producing excessive+ w0 v% y6 @" }% K
adrenal androgens is a common cause of precocious
3 y: [9 K, y8 }2 z% e& [& kpuberty in boys.3,4
6 v+ R* r, v: m" l7 D* XThe most common form of congenital adrenal! V0 l3 f4 j0 \1 \ u0 d
hyperplasia is the 21-hydroxylase enzyme deficiency.
' h O8 {8 l8 P+ [% B/ S TThe 11-β hydroxylase deficiency may also result in
2 j, @4 V( _# Q9 y; H2 mexcessive adrenal androgen production, and rarely,
1 ^# s4 V. b0 m/ ^8 Ian adrenal tumor may also cause adrenal androgen
7 S' P/ v+ j' Q: J4 iexcess.1,3
) N; a3 r6 b: Eat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from/ L* g5 L N; J/ r1 c3 r" d
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
, i+ d& a- }: B# d$ b# m# [A unique entity of male-limited gonadotropin-
" \% J# T2 d* n( A1 W9 ^independent precocious puberty, which is also known9 s" J( N9 n/ C: g5 |
as testotoxicosis, may cause precocious puberty at a
4 k4 \7 {/ d; qvery young age. The physical findings in these boys
: X+ R) B. B2 m* Xwith this disorder are full pubertal development,
' X3 _9 \6 c: [including bilateral testicular growth, similar to boys2 R d& ~* t- Q) l. d' b
with CPP. The gonadotropin levels in this disorder; S v9 s4 E. P5 q
are suppressed to prepubertal levels and do not show/ K. j1 i' r0 ` D1 y( V' m
pubertal response of gonadotropin after gonadotropin-
8 V8 @! X5 [+ Xreleasing hormone stimulation. This is a sex-linked
- ?5 R0 f+ e8 Aautosomal dominant disorder that affects only
$ b ?6 l4 ?8 H% p3 d4 Kmales; therefore, other male members of the family
" M; s$ }, C. q. {; N/ zmay have similar precocious puberty.3
J6 P4 Z6 M3 x4 L- X8 SIn our patient, physical examination was incon-
" G: M* ]/ @0 M0 n v% n6 msistent with true precocious puberty since his testi-
) T- A& ]" i( X- i$ m7 ccles were prepubertal in size. However, testotoxicosis9 ^" \( g% [- \
was in the differential diagnosis because his father
& ~! D4 F( {# [- pstarted puberty somewhat early, and occasionally,
8 v4 t# q# }. o8 mtesticular enlargement is not that evident in the7 @$ b7 ~$ M% r5 t5 l6 a4 {
beginning of this process.1 In the absence of a neg-
9 P' T* i4 i& U( Rative initial history of androgen exposure, our
( H5 g5 o! e/ {biggest concern was virilizing adrenal hyperplasia,$ q2 U, h- ?9 x/ S1 O# B' U
either 21-hydroxylase deficiency or 11-β hydroxylase6 Z2 Z4 h1 O. K# a
deficiency. Those diagnoses were excluded by find-7 B% L5 s& x2 d% \1 C5 t) I
ing the normal level of adrenal steroids.
3 M$ e; Q% r; kThe diagnosis of exogenous androgens was strongly
4 C* r; y4 r' V+ s, n% Z% D gsuspected in a follow-up visit after 4 months because3 j7 q% E# ?4 t2 \5 D
the physical examination revealed the complete disap-
$ s% m" W$ C! U; \( P2 { K& Ppearance of pubic hair, normal growth velocity, and! @6 H' k5 q" p8 X' D
decreased erections. The father admitted using a testos-
! d# S) U$ N5 W" y5 h* w1 Z) u) b3 rterone gel, which he concealed at first visit. He was! R. D2 g6 _6 c
using it rather frequently, twice a day. The Physicians’
# h) o1 @2 `, T9 N6 MDesk Reference, or package insert of this product, gel or$ W7 W& C& P: W. O$ k7 C
cream, cautions about dermal testosterone transfer to
% b8 k, B" n7 K9 i" ?unprotected females through direct skin exposure.+ {3 h" C$ U" ]
Serum testosterone level was found to be 2 times the
6 S) r/ A& \9 \) H* I2 [baseline value in those females who were exposed to
) I5 N1 z* x" Jeven 15 minutes of direct skin contact with their male
/ X6 t: j# q; B4 `6 `+ [partners.6 However, when a shirt covered the applica-1 A# {4 ?+ G6 r9 o5 G% ?6 h
tion site, this testosterone transfer was prevented.; _8 T) u2 t/ f1 n5 @
Our patient’s testosterone level was 60 ng/mL,
. P N6 _0 D' |which was clearly high. Some studies suggest that
4 y* k- c; M, U, h# B7 u. fdermal conversion of testosterone to dihydrotestos-9 {$ w5 B% ^) k- _
terone, which is a more potent metabolite, is more% B' u/ ~: {4 w- ^. h4 q# F5 i }
active in young children exposed to testosterone
& H/ f7 [! m) y- W/ x& Yexogenously7; however, we did not measure a dihy-, N, b7 B' t( T* h5 c+ c
drotestosterone level in our patient. In addition to! Y* W* s s1 G+ I' q: d0 G
virilization, exposure to exogenous testosterone in ^2 P9 |! }0 |% n8 f
children results in an increase in growth velocity and
& ~+ e! t7 V. B2 r, U8 |advanced bone age, as seen in our patient./ Z% l o- v% b3 `5 ]
The long-term effect of androgen exposure during
0 @% m H: s+ y' o `* Kearly childhood on pubertal development and final
9 n+ | K3 S# d, |adult height are not fully known and always remain
! L6 g& Y1 C8 xa concern. Children treated with short-term testos-* |) e4 d9 L$ h- v8 \9 Z$ [
terone injection or topical androgen may exhibit some
# x6 o+ v# R4 p7 _6 p7 @& `* `3 |- ?acceleration of the skeletal maturation; however, after
# `% L7 u- [6 `cessation of treatment, the rate of bone maturation
% M; r$ [4 j6 ^3 Mdecelerates and gradually returns to normal.8,9! a- \, J& C! |% i# D F; O7 O
There are conflicting reports and controversy4 c7 Q+ g0 h! m. O o& e( K
over the effect of early androgen exposure on adult: {+ ~- U/ t" Z1 K9 P
penile length.10,11 Some reports suggest subnormal
' v5 i' D5 O# K8 z9 y7 hadult penile length, apparently because of downreg-# r; ]$ K1 j# `$ {% z& Z
ulation of androgen receptor number.10,12 However,; ?% y0 S2 e: }6 A+ W
Sutherland et al13 did not find a correlation between% q8 W1 t7 ?9 z6 ^. `
childhood testosterone exposure and reduced adult
% h( i* S: w) F" ^0 Apenile length in clinical studies.' u; k8 M$ V9 Y
Nonetheless, we do not believe our patient is
' H% R2 @# c+ J. f8 o, v( agoing to experience any of the untoward effects from- F$ y0 P4 V4 z1 ~ z: C! l
testosterone exposure as mentioned earlier because0 D& y' v7 {, Z4 t+ A6 v
the exposure was not for a prolonged period of time.
1 r# {% L2 p B3 H1 g2 r! _Although the bone age was advanced at the time of
- }7 N7 r S6 ]+ Cdiagnosis, the child had a normal growth velocity at
" J1 `+ J& a# ?3 H y Dthe follow-up visit. It is hoped that his final adult
9 M" ~0 h# k" ^' P! b( Vheight will not be affected.
2 b9 b5 l* z& iAlthough rarely reported, the widespread avail-& }9 M1 T* n" n4 v. i- ?& h* _
ability of androgen products in our society may. j# E4 J' X1 S4 ^: d
indeed cause more virilization in male or female
& j* E @( I5 R4 Q, M) ^$ Vchildren than one would realize. Exposure to andro-) |0 F( I: D7 @) P/ E7 o' J4 n
gen products must be considered and specific ques-
7 R$ i: _5 n( Q( ^9 n3 K5 mtioning about the use of a testosterone product or
3 o4 U2 d* j) p: h8 Sgel should be asked of the family members during0 W: V- Y; \7 s- x
the evaluation of any children who present with vir-
8 Z: P% i( p! rilization or peripheral precocious puberty. The diag-$ X; z9 x0 L/ \3 ]4 B" \
nosis can be established by just a few tests and by
$ p* p+ s" s1 R! q* T! Mappropriate history. The inability to obtain such a
' O: f8 D5 }" b) ]# ^history, or failure to ask the specific questions, may/ {1 f2 @+ P B- o F
result in extensive, unnecessary, and expensive- r- n! w! l8 f5 Y2 I, u% B$ G
investigation. The primary care physician should be& B$ M+ n! V( J
aware of this fact, because most of these children
+ _! J9 P' S4 N6 e, o3 y wmay initially present in their practice. The Physicians’
: n* E# I1 E9 Y i" QDesk Reference and package insert should also put a0 l c* _( A0 e' Y9 z e5 P% `
warning about the virilizing effect on a male or
! M! g* p1 A: f% Ffemale child who might come in contact with some-6 [$ L- P- o; w# M, V2 H& b; l
one using any of these products.
/ d. l3 t4 V2 W& hReferences. F; b* v0 k( h+ `3 `$ ~
1. Styne DM. The testes: disorder of sexual differentiation6 ?! W$ d8 Q" G5 A7 j/ } p
and puberty in the male. In: Sperling MA, ed. Pediatric
3 m( W4 \! t9 q6 v2 }Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;* T- d, f& u2 F" q
2002: 565-628.
$ I+ U7 h9 x2 k+ }% S/ [2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious% n6 C7 g& P% w( g1 d
puberty in children with tumours of the suprasellar pineal |
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