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Sexual Precocity in a 16-Month-Old% w+ v9 l/ m b$ z; c6 d
Boy Induced by Indirect Topical
- E" _* ?% N6 P0 }0 C* K( EExposure to Testosterone2 [0 G; `$ h* ?0 i6 R' y
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
2 ]* g! c) h# d7 j B% d5 c0 Nand Kenneth R. Rettig, MD1/ z. z$ f$ l6 E' v9 L; T- S8 d
Clinical Pediatrics
8 Y4 U6 Q5 |5 kVolume 46 Number 6
' [ o" I% G( o8 P: m: F2 VJuly 2007 540-543
+ F1 y( k4 `% @© 2007 Sage Publications l- L9 [5 a' H2 l
10.1177/0009922806296651
1 l2 G- f: N$ }; ?; l- shttp://clp.sagepub.com3 N" r$ ^% }9 D
hosted at' F- x6 A4 t# e7 S* \/ H" p
http://online.sagepub.com1 o/ a% {2 V! j9 J( a' C$ m! C8 ?* p3 ]
Precocious puberty in boys, central or peripheral,
; T: e' ?- H5 y& } lis a significant concern for physicians. Central
* Z% V% N# @$ t, j) x! Eprecocious puberty (CPP), which is mediated7 n9 e, \5 @' F" `5 e, Q
through the hypothalamic pituitary gonadal axis, has
9 l4 b: _) D' }a higher incidence of organic central nervous system0 i$ l* c2 V c: u7 B4 m
lesions in boys.1,2 Virilization in boys, as manifested
' d5 L$ o& s3 _9 V. Y3 Hby enlargement of the penis, development of pubic
( y2 c7 p0 R# g4 c+ ?hair, and facial acne without enlargement of testi-4 Y. g- z5 W! s* y9 K
cles, suggests peripheral or pseudopuberty.1-3 We
) r+ Q7 J& m8 I1 Freport a 16-month-old boy who presented with the
1 k' u! L, a2 Lenlargement of the phallus and pubic hair develop-
6 b5 A% x9 \ `! Yment without testicular enlargement, which was due
6 X( [. R4 q% G V& J4 xto the unintentional exposure to androgen gel used by z( z9 ]0 |/ C. I$ C& d
the father. The family initially concealed this infor-8 ` j0 M ]9 X1 f4 l
mation, resulting in an extensive work-up for this
% U4 F) ?+ E! `( W- O* q% achild. Given the widespread and easy availability of" b$ p( y3 X4 |
testosterone gel and cream, we believe this is proba-5 v( R6 @# f1 v
bly more common than the rare case report in the! Q! n3 F5 b) Z. W. B
literature.49 p: a; M% J6 i& ]4 a7 M
Patient Report
" B! w3 o7 Y0 T* o" e ]A 16-month-old white child was referred to the1 d" }" W- J7 c
endocrine clinic by his pediatrician with the concern
F" e$ y8 X5 R: L2 Bof early sexual development. His mother noticed
1 d: Y4 ?, ^- Z3 g2 t6 wlight colored pubic hair development when he was
9 M* x. z" X* I2 P" a u& g/ _3 ?From the 1Division of Pediatric Endocrinology, 2University of
& N/ o) Z6 f6 }- h1 h2 iSouth Alabama Medical Center, Mobile, Alabama.
/ g: @8 Z( e8 ?+ a- J, QAddress correspondence to: Samar K. Bhowmick, MD, FACE,
& Z7 E/ o* ^: V4 t. ~Professor of Pediatrics, University of South Alabama, College of- H& }( H9 v) P) @) g- j
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
# B5 k& M1 {4 @* I' be-mail: [email protected].
% k7 O: z6 Q$ ~' {about 6 to 7 months old, which progressively became& w1 p: N+ X/ ]( L
darker. She was also concerned about the enlarge-1 b- t( n% q; \7 i2 T& H
ment of his penis and frequent erections. The child
, o% s1 a: B6 _2 L3 ~ G: U2 iwas the product of a full-term normal delivery, with
8 B2 x- p6 H: s+ F, K6 N7 L. ~9 ?9 fa birth weight of 7 lb 14 oz, and birth length of: `& O" m1 w* Z5 j# s$ ^
20 inches. He was breast-fed throughout the first year
+ s" I3 Q* |2 }- M( [2 Fof life and was still receiving breast milk along with
" l. s- n q" G$ L i" Usolid food. He had no hospitalizations or surgery,
+ j/ @9 F7 F4 z* S( U4 Y1 P" Sand his psychosocial and psychomotor development9 q3 |6 [% l0 Q$ L6 E; v
was age appropriate.6 _8 a9 }. C1 A1 v6 f) F! E
The family history was remarkable for the father,
0 D4 L& ]. B( U2 D* `* Xwho was diagnosed with hypothyroidism at age 16,
% n) r. ]5 m6 Q$ cwhich was treated with thyroxine. The father’s
$ f. a5 m' z. jheight was 6 feet, and he went through a somewhat
, o* v, `8 J& I3 C* ]" oearly puberty and had stopped growing by age 14. ]" A \* `, v4 A% D/ ? V: {
The father denied taking any other medication. The, e# ?6 t: i8 N# s7 U8 a5 H
child’s mother was in good health. Her menarche5 A6 v- z5 g' Q, i) ?9 |
was at 11 years of age, and her height was at 5 feet; I0 t3 j1 L6 b& x: j Q
5 inches. There was no other family history of pre-
" A4 ~' r7 J9 K! c( E, w+ Z% i9 Acocious sexual development in the first-degree rela-
$ X6 W6 k! s/ f! u H' Xtives. There were no siblings.* d& ]( z7 D! l, q0 }
Physical Examination) G# I- O1 q1 M5 D% `) K9 W1 }! U
The physical examination revealed a very active,, W+ o! t- d! d
playful, and healthy boy. The vital signs documented" _' _2 l% _' ~1 ]% W
a blood pressure of 85/50 mm Hg, his length was/ M" _7 M4 E! M" O
90 cm (>97th percentile), and his weight was 14.4 kg0 j( i3 S/ t) b" w* E4 T9 ^0 F, @
(also >97th percentile). The observed yearly growth( z& D: T% Q0 o
velocity was 30 cm (12 inches). The examination of: }5 k& f+ r0 t9 A9 y
the neck revealed no thyroid enlargement.
1 v/ p* k' `3 k9 mThe genitourinary examination was remarkable for% h N2 K% W" E8 c( J$ e
enlargement of the penis, with a stretched length of+ G+ d$ O, ~' O; a }5 d: C# h/ ]
8 cm and a width of 2 cm. The glans penis was very well
- A( m4 i. M% A) K0 b+ kdeveloped. The pubic hair was Tanner II, mostly around! F6 u" q* E, S' q2 c
540
9 I5 v3 k: P! i2 `at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from6 L- p, @+ `- C; G& P# p4 N( ]
the base of the phallus and was dark and curled. The/ \1 L) j/ F' g2 [( Z& W5 u6 B/ `
testicular volume was prepubertal at 2 mL each.0 j1 o0 a6 F! }8 C4 W- p
The skin was moist and smooth and somewhat
: \0 r1 q7 ? E/ m; D( E; Ooily. No axillary hair was noted. There were no
* d Z6 r7 o6 a0 k* Kabnormal skin pigmentations or café-au-lait spots.
7 W# r0 a0 i7 c9 Q# O' LNeurologic evaluation showed deep tendon reflex 2++ }6 S5 p6 A/ O% } u# \. i
bilateral and symmetrical. There was no suggestion# D( m( F% V* w) O) s8 {/ k
of papilledema.
9 D: N" s! K* O; b: {% N" Z: _Laboratory Evaluation
: [! X2 e9 |. BThe bone age was consistent with 28 months by7 ~% y; J/ D1 w) Z$ a
using the standard of Greulich and Pyle at a chrono-
0 A1 _* S. N! p- n" Ilogic age of 16 months (advanced).5 Chromosomal
+ o7 t) J+ ~2 ^% skaryotype was 46XY. The thyroid function test
% P) m1 |5 i3 n6 V( U( ^+ V) |showed a free T4 of 1.69 ng/dL, and thyroid stimu- W8 o3 ~' G( s9 [
lating hormone level was 1.3 µIU/mL (both normal).
2 x! h* ^! H6 N5 A3 {+ mThe concentrations of serum electrolytes, blood
+ f$ B! c" W% T, y% aurea nitrogen, creatinine, and calcium all were
: v c% {0 s* U G' l) W( }within normal range for his age. The concentration
. Y6 `/ d( z! Q/ _of serum 17-hydroxyprogesterone was 16 ng/dL" p4 q/ T$ m0 C
(normal, 3 to 90 ng/dL), androstenedione was 201 F( H3 O! O' O/ O
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
& h/ B( Q% Y- x& k9 g2 B& oterone was 38 ng/dL (normal, 50 to 760 ng/dL),
" G/ B# {# k2 ]: _ r; E: ~: ]" cdesoxycorticosterone was 4.3 ng/dL (normal, 7 to
P8 ^% O+ [( h5 ~, A49ng/dL), 11-desoxycortisol (specific compound S)3 M, K' n8 T( P' ?
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
: w m! U7 z# V2 ]: atisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total& r/ o' s4 [* e# _# F. d) h0 e/ [ y
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
$ B. ?& t0 a, S) qand β-human chorionic gonadotropin was less than
1 l6 B' l5 E, W+ _$ t5 mIU/mL (normal <5 mIU/mL). Serum follicular
, |5 s8 }9 b6 jstimulating hormone and leuteinizing hormone) r# N- T6 o6 S% G
concentrations were less than 0.05 mIU/mL6 S2 c6 s* O5 P* b5 c
(prepubertal).
: L0 U, @9 m7 J6 ?% P7 LThe parents were notified about the laboratory
9 b; L8 w: }# F2 a* Uresults and were informed that all of the tests were+ c& a3 {. e d" P# _9 Y% ^( x
normal except the testosterone level was high. The0 h- M. E. B/ ^( R; n1 B0 B
follow-up visit was arranged within a few weeks to
# O2 t4 f" u8 Y8 y4 iobtain testicular and abdominal sonograms; how-
6 v. f8 J) K) M7 _1 w7 Mever, the family did not return for 4 months.7 ?5 `0 X. }) k% w7 s6 s t' D
Physical examination at this time revealed that the
; f$ S/ C1 O M7 l1 c, I6 Ychild had grown 2.5 cm in 4 months and had gained
e( [9 e9 m) _4 [2 kg of weight. Physical examination remained
% G: E$ x. M" yunchanged. Surprisingly, the pubic hair almost com-
; z/ J2 F) w, h3 N, Spletely disappeared except for a few vellous hairs at
g1 v) ~$ L% s$ ithe base of the phallus. Testicular volume was still 2; @7 m) G5 U" k- Q
mL, and the size of the penis remained unchanged.
/ n5 I- j Y. p. Y" MThe mother also said that the boy was no longer hav-
6 H( ]; f& Q1 @+ I& _: Q! f' C# Ming frequent erections.
( Q* `; }1 {6 H! E! RBoth parents were again questioned about use of
6 Q* q# U9 a4 j' I4 O7 _any ointment/creams that they may have applied to
0 d% ^/ R; Q5 J) rthe child’s skin. This time the father admitted the& Q# R) J* k9 Z$ q: T
Topical Testosterone Exposure / Bhowmick et al 541& Y2 S6 ~- `4 J' c
use of testosterone gel twice daily that he was apply-3 p n Z s) ]+ R3 p+ R' W
ing over his own shoulders, chest, and back area for
. {6 h1 [, j+ F {% R5 na year. The father also revealed he was embarrassed
) z0 e; t1 ]: O1 l! Hto disclose that he was using a testosterone gel pre-0 {. d' e9 d1 s& `6 x
scribed by his family physician for decreased libido, B- k: F0 F7 e8 J$ W, `' L5 L
secondary to depression.
8 D' @1 Q/ X, w+ ]$ r1 \# {The child slept in the same bed with parents.
. a9 m2 P) h5 F# ?" tThe father would hug the baby and hold him on his, R+ _4 e& ^0 s) f& N7 j
chest for a considerable period of time, causing sig-) r4 D: r% i4 y; W7 \0 T8 H; G
nificant bare skin contact between baby and father.
+ V4 J6 x/ }& o) {* _* g: RThe father also admitted that after the phone call,5 j% L" N0 o4 Z+ X1 ]6 h
when he learned the testosterone level in the baby5 [* p# M: f: O7 S e( b/ y# K% N6 ?
was high, he then read the product information
5 p7 I% Y6 o8 ]$ L/ s( npacket and concluded that it was most likely the rea-# _0 P. p3 n7 Z+ r
son for the child’s virilization. At that time, they( V1 K' t& ]5 D% S
decided to put the baby in a separate bed, and the) J' y8 j7 U: f) m: P
father was not hugging him with bare skin and had, }; _4 T9 T% C6 n! b: Q
been using protective clothing. A repeat testosterone
- S7 x9 }7 Q1 e- a7 K$ G- Utest was ordered, but the family did not go to the
) i/ Z2 i6 z4 E8 Z8 p! Alaboratory to obtain the test.3 w d8 w1 [8 k
Discussion
3 R0 ?/ H# J! s; q3 l4 }. ^Precocious puberty in boys is defined as secondary" k% P, q7 d5 |
sexual development before 9 years of age.1,4. K- ~, P# M; X2 E S+ `0 X
Precocious puberty is termed as central (true) when5 F0 z) a' `! H
it is caused by the premature activation of hypo-
+ Q/ f7 i3 \5 G1 Z& |' mthalamic pituitary gonadal axis. CPP is more com-
4 K( `( U- D2 w- S8 }mon in girls than in boys.1,3 Most boys with CPP D. U; P+ h* ^( e0 |8 u6 h- V2 S
may have a central nervous system lesion that is
0 @& @, R* f% Y# r4 Wresponsible for the early activation of the hypothal-" `; n- J9 j1 R5 j: R3 j
amic pituitary gonadal axis.1-3 Thus, greater empha-
6 \( b+ m* ?3 X9 i% K- A" P* Lsis has been given to neuroradiologic imaging in6 M1 o2 C0 f$ H8 f
boys with precocious puberty. In addition to viril-! U8 M' v* G0 G% I
ization, the clinical hallmark of CPP is the symmet-
7 H2 Q5 h3 g7 z0 l3 Brical testicular growth secondary to stimulation by9 f3 c" N% w. r+ ^
gonadotropins.1,3( P1 @# [1 D: k& `7 O1 `( L
Gonadotropin-independent peripheral preco-
; ~' Y% Y& o- `- R' n1 O( k5 }; Icious puberty in boys also results from inappropriate( M( D, }. ^# ]- R; [% ]( h0 m
androgenic stimulation from either endogenous or
$ F( D. x. u+ M5 M5 S7 ~, Gexogenous sources, nonpituitary gonadotropin stim-
, P( V& W3 L, e/ G5 e$ zulation, and rare activating mutations.3 Virilizing
# E8 u3 A c1 Z ?congenital adrenal hyperplasia producing excessive9 l5 z3 O# e2 r7 Y- F" e& T
adrenal androgens is a common cause of precocious
/ X$ g* A4 s. Y& @puberty in boys.3,4$ C4 o0 o; E$ U9 _% s5 [
The most common form of congenital adrenal- |5 Z5 t/ Z( L& \4 h1 y
hyperplasia is the 21-hydroxylase enzyme deficiency.# Q. H3 \, d$ E& p
The 11-β hydroxylase deficiency may also result in
* P6 h2 a x, Xexcessive adrenal androgen production, and rarely,
9 j; d; n W, t8 e3 l, n$ I, ^an adrenal tumor may also cause adrenal androgen
; e; U: w; W( ]" u5 {6 Z- X4 L/ Sexcess.1,3
2 p: P3 V3 b* d- j. `at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
4 {1 _; d3 p) C542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
4 O4 e( _, h+ aA unique entity of male-limited gonadotropin-) w! u6 x4 i* G- F, q9 o; v, H0 Z
independent precocious puberty, which is also known/ A& Q( z, W# ?
as testotoxicosis, may cause precocious puberty at a7 P, F1 o: G8 L" \
very young age. The physical findings in these boys; D+ Y* F: ]* p9 D d
with this disorder are full pubertal development,
( Y+ \5 P& \$ q# @- i" c2 ` y8 bincluding bilateral testicular growth, similar to boys
# g+ Q$ a7 t& Qwith CPP. The gonadotropin levels in this disorder
$ q3 p6 `5 T+ i+ Nare suppressed to prepubertal levels and do not show& N5 q) B# t" W8 u; G
pubertal response of gonadotropin after gonadotropin-$ a" N9 _% e+ k6 a# R
releasing hormone stimulation. This is a sex-linked7 E" Q2 e! G2 n" L1 p
autosomal dominant disorder that affects only5 `2 q! K2 R& X9 w/ s
males; therefore, other male members of the family
2 z* S; _ J4 F" rmay have similar precocious puberty.3
" x3 O+ W' y% d+ p# bIn our patient, physical examination was incon-# M% |+ |8 N" u) w3 Q: @
sistent with true precocious puberty since his testi-
) \. y8 K: d; a$ Z+ jcles were prepubertal in size. However, testotoxicosis
& k0 S! ~* v E/ m5 i# ewas in the differential diagnosis because his father
$ m/ |, d9 G4 m5 istarted puberty somewhat early, and occasionally,
% X* d' r: \5 S( T" ?3 Gtesticular enlargement is not that evident in the& N$ D( j' y5 @
beginning of this process.1 In the absence of a neg-6 U7 D6 B" _5 d' d* X
ative initial history of androgen exposure, our) d; V7 S3 L; f7 Y2 ^
biggest concern was virilizing adrenal hyperplasia,
1 ^9 ]; R' r) X4 J; q5 xeither 21-hydroxylase deficiency or 11-β hydroxylase
1 y. c0 R3 F! L0 ~; S) S# gdeficiency. Those diagnoses were excluded by find-4 D" t! a* U' v8 b6 }9 d2 G
ing the normal level of adrenal steroids.
' u/ W1 {8 Z. N' _8 e# t8 OThe diagnosis of exogenous androgens was strongly
M% W! E. e% ` T( Z, tsuspected in a follow-up visit after 4 months because! A0 O2 m; J, ?$ Z
the physical examination revealed the complete disap-
) `9 c# W' [7 L$ k/ A, Gpearance of pubic hair, normal growth velocity, and7 F) R% M3 g7 a2 k
decreased erections. The father admitted using a testos-7 T$ ~+ O9 S1 ]1 h( g
terone gel, which he concealed at first visit. He was6 K V' a2 u( m, y6 s
using it rather frequently, twice a day. The Physicians’: a2 T- H1 J# V* q( Q& [* a
Desk Reference, or package insert of this product, gel or/ ^; _9 X) A( N2 _
cream, cautions about dermal testosterone transfer to9 `8 e* Q4 z6 S5 |- _) d& V
unprotected females through direct skin exposure.
% a8 @0 a- ^6 USerum testosterone level was found to be 2 times the/ {4 {* B/ [+ |! [. Y' k4 \
baseline value in those females who were exposed to
) P( \3 ~0 o' d# Q" u3 _3 Xeven 15 minutes of direct skin contact with their male" W' c" K6 I( _
partners.6 However, when a shirt covered the applica-# Y6 G5 p3 A" {9 u Q
tion site, this testosterone transfer was prevented.0 _; n: ?) A2 y7 r( v
Our patient’s testosterone level was 60 ng/mL,
: d+ @9 h1 Q; j- J' Xwhich was clearly high. Some studies suggest that
( L2 m, F& A m" c0 qdermal conversion of testosterone to dihydrotestos-
6 o. g% M a' h& [ N# rterone, which is a more potent metabolite, is more
0 [/ H. d* z" l+ ~active in young children exposed to testosterone
/ ]4 n3 Y& t/ [5 u0 `exogenously7; however, we did not measure a dihy-
7 ?- }" D0 i$ W; Ddrotestosterone level in our patient. In addition to
& a# ~! z3 m# |% F2 n2 i9 bvirilization, exposure to exogenous testosterone in
: h* c8 I' c5 b; \children results in an increase in growth velocity and
% v" v- i5 Q1 p% k- {7 w. i3 h8 }7 sadvanced bone age, as seen in our patient.
% ]& l& h" a- t8 t3 \6 Q2 WThe long-term effect of androgen exposure during
4 w) e; j/ M j4 B, v) }5 xearly childhood on pubertal development and final
. e1 R, m2 k2 K6 T- n! X6 nadult height are not fully known and always remain3 x/ G% P- w' ^. Q) v) ^
a concern. Children treated with short-term testos-. J8 Z/ B7 j4 \/ i4 _+ M' L \" ?2 L" x
terone injection or topical androgen may exhibit some" D7 l7 _4 z) |# [* \
acceleration of the skeletal maturation; however, after
+ `, R# S' d5 a4 g; m) f/ \cessation of treatment, the rate of bone maturation' l0 t3 e/ _7 }' `# t
decelerates and gradually returns to normal.8,93 C( ?7 B- x, {" j9 u; f, [
There are conflicting reports and controversy+ _- q+ c+ L3 B* ?
over the effect of early androgen exposure on adult' k: z% C. b5 ]4 x0 s
penile length.10,11 Some reports suggest subnormal
5 s3 `# K7 w' J! z3 radult penile length, apparently because of downreg-
5 T4 d; b( k4 W9 Y- G$ W! pulation of androgen receptor number.10,12 However,
7 L+ n! a4 I3 h7 x$ M. z5 i* r/ ASutherland et al13 did not find a correlation between8 {& a6 M0 x) Y) R3 T' G
childhood testosterone exposure and reduced adult
: R; G, K& h* ^% @9 npenile length in clinical studies.9 |: v6 \; R0 r8 E" k4 b+ Q
Nonetheless, we do not believe our patient is% E Z2 w( a" u! J8 }6 U
going to experience any of the untoward effects from* A% d. e0 Z$ a7 M, V, g
testosterone exposure as mentioned earlier because! r% u: U3 M2 W. D* ?2 X+ v
the exposure was not for a prolonged period of time.
3 z' Z! ^5 g5 c# }% a( p! NAlthough the bone age was advanced at the time of2 |) _4 r1 m; e x8 N( b/ w: {( z$ O
diagnosis, the child had a normal growth velocity at" q$ _# `# ?% X
the follow-up visit. It is hoped that his final adult
* h+ n z7 ^- t4 ]' x4 l# Sheight will not be affected.
& {3 M0 O$ v. w: ^/ XAlthough rarely reported, the widespread avail-
& Y8 w3 r( U8 d1 K% k V; C5 g1 Aability of androgen products in our society may9 b3 n) }) t+ O3 P" }) R. m/ ^
indeed cause more virilization in male or female
8 ?' A6 U/ R: zchildren than one would realize. Exposure to andro-- V3 I2 q0 ]+ ^3 l0 _! A3 ^
gen products must be considered and specific ques-
' w: `, u. }4 Gtioning about the use of a testosterone product or+ N9 O# L' L5 P/ E5 h9 J
gel should be asked of the family members during$ w5 @. N7 R; }1 [7 ~! V! {
the evaluation of any children who present with vir-: ?* A: }- W' m6 h0 b
ilization or peripheral precocious puberty. The diag-
* [$ C- M: G) c# |& |+ fnosis can be established by just a few tests and by, }6 h, t* D. N& ?7 h4 x6 I
appropriate history. The inability to obtain such a5 n6 T/ }8 k0 J9 q
history, or failure to ask the specific questions, may/ z+ Z# y8 o {9 ]; P* T6 ?$ g
result in extensive, unnecessary, and expensive8 U6 I( a' }0 F' X9 m$ Q: Z! R
investigation. The primary care physician should be* C0 `( }5 I* M/ n; B
aware of this fact, because most of these children& c6 r6 G" ]) d" k \+ E" e
may initially present in their practice. The Physicians’: U. y$ i" m9 b0 B* R* i
Desk Reference and package insert should also put a
& ^( p; e" t% l/ p! Q1 f6 Fwarning about the virilizing effect on a male or
9 Z* {% S7 H% n' cfemale child who might come in contact with some-! A" M& `) f8 A- d+ s1 g# f M6 Z
one using any of these products.3 ]9 W( l7 {8 g6 w( q( M5 U/ W: p
References
2 Y. Q3 H7 _+ Z2 k$ ~6 Z( n1. Styne DM. The testes: disorder of sexual differentiation
3 U1 a/ K, a. f& } h. uand puberty in the male. In: Sperling MA, ed. Pediatric
9 F: ^6 @5 \6 p. e; |: n6 rEndocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
9 g( k$ N, ~8 i4 E) X5 U2002: 565-628.6 i! G* R+ N& T8 K3 |* w+ O
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
* e, |$ J2 A+ p3 j+ `: m) h, Ypuberty in children with tumours of the suprasellar pineal |
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