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Sexual Precocity in a 16-Month-Old) u0 Q( C- x& d+ k: L: H
Boy Induced by Indirect Topical
1 E" H5 E. f3 ^- ~$ ~Exposure to Testosterone5 `/ F q% F$ L
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
( }7 E7 \5 \* v0 }and Kenneth R. Rettig, MD1: N3 j7 P- A$ u! K+ m
Clinical Pediatrics. D: M' G2 W' s5 \5 C
Volume 46 Number 6* e9 s! E) H# r# w X+ _
July 2007 540-543
* o0 a5 C; e2 N& O- b$ x# M© 2007 Sage Publications
7 H! ~- h& E# e2 |4 \10.1177/0009922806296651
8 O$ K- W6 W/ L" |: p) V" ihttp://clp.sagepub.com0 A) }$ g; g! n7 ]8 Y
hosted at I& \' b2 K4 i: R( Q" q5 i7 U
http://online.sagepub.com, e1 ~8 f/ R# a) ^5 d
Precocious puberty in boys, central or peripheral,7 v- B+ z. \* T( R5 Q% N
is a significant concern for physicians. Central
! N' h5 y: p7 S' s1 c U* ]precocious puberty (CPP), which is mediated
! d- u e% X5 T( bthrough the hypothalamic pituitary gonadal axis, has# ?* b* o) F+ q* L/ D! F
a higher incidence of organic central nervous system5 ~/ C# F' i- O. s% e3 V9 s
lesions in boys.1,2 Virilization in boys, as manifested
. R( C$ z* h1 ^1 Xby enlargement of the penis, development of pubic0 x7 V6 d+ i. B' m. d% R: k
hair, and facial acne without enlargement of testi-
. Q( u: A2 V6 Pcles, suggests peripheral or pseudopuberty.1-3 We- h, R/ h+ k6 {% v1 I, {0 E
report a 16-month-old boy who presented with the
. G5 }" v; n+ d; J2 S# L2 Z* Wenlargement of the phallus and pubic hair develop-( k8 h- x" |' {8 U! ?) ~
ment without testicular enlargement, which was due
% a- Q f5 j8 b( Z4 ^to the unintentional exposure to androgen gel used by9 e2 r) ]9 o( A6 @* U: G" h# p8 U
the father. The family initially concealed this infor-
( Q; R. t. A0 Y6 v+ D7 Ymation, resulting in an extensive work-up for this0 m# U* y1 W, b, y3 X& y
child. Given the widespread and easy availability of
9 d w5 T5 o; A7 u5 X& t; @testosterone gel and cream, we believe this is proba-
* {. I8 B6 r3 b8 m8 ably more common than the rare case report in the: S$ Y6 w$ H5 Q4 t3 [
literature.4; h9 l9 Q! H# f- h6 i
Patient Report
- \! Z* @& x+ j$ FA 16-month-old white child was referred to the8 A2 ?7 T% U/ i, W; o* V, [6 H
endocrine clinic by his pediatrician with the concern" |; M7 ^6 m) J7 o5 `) l
of early sexual development. His mother noticed+ _; ]0 m1 a# o& m
light colored pubic hair development when he was# k2 y9 f- C& |" }; J2 g1 u
From the 1Division of Pediatric Endocrinology, 2University of2 P& I6 Y8 x, D9 } u! z7 B
South Alabama Medical Center, Mobile, Alabama.
4 W; E) I# e% y4 NAddress correspondence to: Samar K. Bhowmick, MD, FACE,; y ^5 h9 Y& x- T/ C2 [
Professor of Pediatrics, University of South Alabama, College of
& i1 |+ \( c7 V6 JMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
! a: ?& v' _; ^, `& Ue-mail: [email protected].! i9 x+ } U0 [4 @6 g- t
about 6 to 7 months old, which progressively became: O) B) k* ], u5 R
darker. She was also concerned about the enlarge-9 |& N) ~5 Z' z1 b. V/ G5 v5 g! \
ment of his penis and frequent erections. The child
$ D1 i# [& ?3 h1 P+ L7 @was the product of a full-term normal delivery, with
/ A# i( @+ r; I1 M: ^a birth weight of 7 lb 14 oz, and birth length of: J5 M, d: D/ H0 Q6 ^, {8 m$ e
20 inches. He was breast-fed throughout the first year7 M3 w) P8 d5 j% O. O3 I
of life and was still receiving breast milk along with
! {. L: Y9 [, M+ Vsolid food. He had no hospitalizations or surgery,
; Y7 \% `. e/ y; h- G. r8 x3 Nand his psychosocial and psychomotor development
2 K* ~' K" B1 H$ ^* w" bwas age appropriate.
& l5 M+ f; I' |. T6 EThe family history was remarkable for the father,
5 ~8 b+ ^9 C$ W4 }who was diagnosed with hypothyroidism at age 16," S3 n; Q% {$ P X
which was treated with thyroxine. The father’s( m. l. B3 E6 V% G: e; O- m3 d
height was 6 feet, and he went through a somewhat. C1 H1 o; d5 z
early puberty and had stopped growing by age 14.
/ d$ ^- D' c/ Z5 j, {9 g% pThe father denied taking any other medication. The
: L0 u0 L, _* rchild’s mother was in good health. Her menarche
j& x& Y) R5 c3 z, ~% b% r3 D( U5 ~was at 11 years of age, and her height was at 5 feet
+ P; k1 T# X5 _* U7 Y! I. T5 inches. There was no other family history of pre-- p; ?! J( N% U. T' |2 ^: \
cocious sexual development in the first-degree rela-
: T+ D+ B# P% T4 f, {tives. There were no siblings.; p j1 y/ A: Q! c/ c' R* i/ l
Physical Examination# [1 {" V9 h/ P0 V
The physical examination revealed a very active,6 f, t$ a8 W4 |" D6 m
playful, and healthy boy. The vital signs documented( I' K4 ]$ r. y k- O2 [1 s
a blood pressure of 85/50 mm Hg, his length was9 o0 G' ?' S$ K3 ]
90 cm (>97th percentile), and his weight was 14.4 kg
5 T9 D/ q" ^9 H1 Y1 `* ~8 g" H! q(also >97th percentile). The observed yearly growth
9 I6 W" M% c- T' ?" R4 B. ^% Gvelocity was 30 cm (12 inches). The examination of/ S) R. |5 ]' \) R
the neck revealed no thyroid enlargement.
& @: {, x \' e& m& F- ~$ j( IThe genitourinary examination was remarkable for
" P( Y# c# I3 x3 M% Venlargement of the penis, with a stretched length of
* {9 d- I( L& E+ o1 P2 s$ l8 cm and a width of 2 cm. The glans penis was very well
* K, |( P1 ?, d# ndeveloped. The pubic hair was Tanner II, mostly around' v& Z) |/ i& E/ _, e
540. X& |+ s+ v- E8 I! l. x
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
2 ^8 F& D4 z- w# A2 T' `* `% t/ Hthe base of the phallus and was dark and curled. The N7 _, u& s7 Q, _
testicular volume was prepubertal at 2 mL each.' p" M$ T% M* h
The skin was moist and smooth and somewhat
Q' b- g; U" yoily. No axillary hair was noted. There were no
' {, M( |6 E; s1 y, | cabnormal skin pigmentations or café-au-lait spots.4 m! f' \* t. H) P4 K1 ]8 L4 }1 B
Neurologic evaluation showed deep tendon reflex 2+) i& P! d3 l) Q Z9 D! |
bilateral and symmetrical. There was no suggestion
' C3 l" x" P0 ]1 F7 vof papilledema.* y) Y" j& r3 k( S% D) b
Laboratory Evaluation4 C: Z- K" f) O$ J) {6 c
The bone age was consistent with 28 months by" G( D( X7 F- l3 V6 i
using the standard of Greulich and Pyle at a chrono-
! H3 [5 {5 [+ d" c" |logic age of 16 months (advanced).5 Chromosomal
% _' [7 ~7 i( X! g- xkaryotype was 46XY. The thyroid function test: |* k% ?6 @* b W8 }+ U4 s
showed a free T4 of 1.69 ng/dL, and thyroid stimu-
7 p6 D$ V2 b$ X& u: D5 ~8 N) |, X7 \lating hormone level was 1.3 µIU/mL (both normal).( k1 R0 E0 W7 @& [$ y7 [
The concentrations of serum electrolytes, blood' }2 I( i, z! z- @; X0 ^$ y
urea nitrogen, creatinine, and calcium all were
- X) e2 x7 F9 e7 T7 W& i: Dwithin normal range for his age. The concentration& n" y# F7 s' A. f& _% X* Q$ ^- v
of serum 17-hydroxyprogesterone was 16 ng/dL& H2 n% l" O" j O( `. u
(normal, 3 to 90 ng/dL), androstenedione was 204 A5 R3 B$ B4 b- r
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-7 @" T: Y$ A ^3 Z" R- y5 B
terone was 38 ng/dL (normal, 50 to 760 ng/dL),& j1 h: `+ b" \6 i& y. ~! s$ A7 Q9 F
desoxycorticosterone was 4.3 ng/dL (normal, 7 to- M+ k4 x5 \3 D% F8 `6 ]3 R7 H1 q
49ng/dL), 11-desoxycortisol (specific compound S)
6 q9 c b- y& A1 n9 Lwas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
$ S# [8 j7 Z9 k3 g+ A% Ptisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
* `/ X t6 v, ], V* o2 Ktestosterone was 60 ng/dL (normal <3 to 10 ng/dL),6 v* |$ i/ I- P* q" U" D
and β-human chorionic gonadotropin was less than9 v, p* D) k* { E2 R
5 mIU/mL (normal <5 mIU/mL). Serum follicular
6 ?; W1 W. A7 }stimulating hormone and leuteinizing hormone
! G. @+ y1 B |concentrations were less than 0.05 mIU/mL
+ v+ r! \( b: v( u(prepubertal).3 ? k) Z# w3 P: `
The parents were notified about the laboratory
; J# e/ T$ _, i2 B# gresults and were informed that all of the tests were! `0 q5 `. L+ g! O+ |
normal except the testosterone level was high. The# K O6 L4 a9 f- j# H Q# J. O
follow-up visit was arranged within a few weeks to" q* @! k7 g# @
obtain testicular and abdominal sonograms; how-3 `; t s0 N' v3 e; n$ E( }4 l
ever, the family did not return for 4 months.
# h7 ?: C. }( N* ?9 xPhysical examination at this time revealed that the5 t+ _5 f$ g/ y
child had grown 2.5 cm in 4 months and had gained+ A5 c# ~6 t0 A; f2 R# u' N
2 kg of weight. Physical examination remained# u% g8 G1 _$ o" m8 N# o! T
unchanged. Surprisingly, the pubic hair almost com-
) k' X) M' [9 V" npletely disappeared except for a few vellous hairs at# O2 Y, Y+ a3 M# Y7 {& S& E
the base of the phallus. Testicular volume was still 2
7 d- _+ t6 t" Y5 k& e( `. h8 imL, and the size of the penis remained unchanged.
3 T! C) \2 ?+ g$ R1 w ^ RThe mother also said that the boy was no longer hav-& S/ ` E6 A4 d9 b
ing frequent erections.
O6 b8 R1 d9 m2 H' S9 mBoth parents were again questioned about use of5 V1 d5 `5 X. W U" D- y
any ointment/creams that they may have applied to/ k9 H. U, }2 b! \
the child’s skin. This time the father admitted the
. O& R! c1 Y& eTopical Testosterone Exposure / Bhowmick et al 5412 ~; Q- g, R$ b& ^; L2 O3 s0 F5 v
use of testosterone gel twice daily that he was apply-; K/ y, G- I7 u
ing over his own shoulders, chest, and back area for
7 `* a1 y3 U* ]7 xa year. The father also revealed he was embarrassed2 e5 `2 |% ]/ h1 x7 F
to disclose that he was using a testosterone gel pre-' g0 j6 I2 o3 z- _$ \: R
scribed by his family physician for decreased libido
' q0 G# @8 k- D6 gsecondary to depression.
, o( i. o, v% u7 H# B$ S HThe child slept in the same bed with parents.9 t0 i0 w5 _" }0 E; v, Q6 b
The father would hug the baby and hold him on his
p s+ \- T1 ]" lchest for a considerable period of time, causing sig-$ o% t# }* f- `% o
nificant bare skin contact between baby and father.
3 e x/ v- [! l9 E& H" d+ tThe father also admitted that after the phone call,8 s" q# p/ O4 R. V
when he learned the testosterone level in the baby3 y, l; l1 |- W; m6 P
was high, he then read the product information
( n- @6 a/ I+ e7 n* wpacket and concluded that it was most likely the rea-
$ A4 S6 N: V+ V! W; i4 {son for the child’s virilization. At that time, they1 t9 r2 [ D7 R% o" J0 y) t. N
decided to put the baby in a separate bed, and the
+ m: x+ s+ M: ?" `4 Afather was not hugging him with bare skin and had; B6 N$ U" ^: r8 I- h
been using protective clothing. A repeat testosterone& R- E3 R5 `0 o4 t
test was ordered, but the family did not go to the6 }! Y: R! o3 w2 f
laboratory to obtain the test.+ @# E6 G" B2 h; P
Discussion
9 A9 m w5 {6 b6 j1 }% |Precocious puberty in boys is defined as secondary
% K5 [1 R, s. F% \$ ssexual development before 9 years of age.1,41 I; v+ r4 _5 z) y C9 X
Precocious puberty is termed as central (true) when3 f2 h; @4 a2 u! u
it is caused by the premature activation of hypo-4 R+ d( B) \ S' v% A; Y4 m; ^
thalamic pituitary gonadal axis. CPP is more com-
7 g" k. z8 X0 w) kmon in girls than in boys.1,3 Most boys with CPP0 u/ z# f6 `# ?1 J0 k* Y5 @
may have a central nervous system lesion that is( w T6 J0 _5 t8 m" F$ Q+ T, [
responsible for the early activation of the hypothal-' D2 x, d% x' R1 h9 k3 b% v
amic pituitary gonadal axis.1-3 Thus, greater empha-
& U: p! d7 R5 Y ssis has been given to neuroradiologic imaging in
. d, n) H8 S$ N- S4 Y# Z l$ tboys with precocious puberty. In addition to viril-
# w% K; f8 q! _& `+ N8 oization, the clinical hallmark of CPP is the symmet-
; v8 J% x* N! Jrical testicular growth secondary to stimulation by8 d% x1 V* ?" }0 N5 g; U" J
gonadotropins.1,3
2 i& g N# T, L: B/ DGonadotropin-independent peripheral preco-" n- g3 c6 K! W
cious puberty in boys also results from inappropriate
/ s ~( q1 C4 j( ^- handrogenic stimulation from either endogenous or
. ~$ W8 G1 Q/ O p4 bexogenous sources, nonpituitary gonadotropin stim-
7 @1 l7 H) W4 Z; t3 Hulation, and rare activating mutations.3 Virilizing g p' o r5 o* N
congenital adrenal hyperplasia producing excessive$ L) y$ }" h" Q' f
adrenal androgens is a common cause of precocious8 x3 N8 K2 [2 H# U2 i
puberty in boys.3,4+ _* E! G: y- z
The most common form of congenital adrenal
! x- c" p; f6 [* jhyperplasia is the 21-hydroxylase enzyme deficiency.
2 ]4 F* ?( z2 ~& B, K/ k9 o3 PThe 11-β hydroxylase deficiency may also result in% X$ Z# q# {2 [8 x7 @
excessive adrenal androgen production, and rarely,
+ w o/ B+ P/ Can adrenal tumor may also cause adrenal androgen5 w* d }+ I5 w
excess.1,3& B, t8 y) l; j! S' ]
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
% d4 e# |5 s: A0 o542 Clinical Pediatrics / Vol. 46, No. 6, July 20077 e. C( \+ O E7 W5 `5 R+ W7 R
A unique entity of male-limited gonadotropin-0 f9 q: F$ M* A3 f: G
independent precocious puberty, which is also known5 t3 |8 ?7 W" x v3 ]; o2 V
as testotoxicosis, may cause precocious puberty at a7 P6 W& h; D& A1 }) ~+ \$ \9 ~
very young age. The physical findings in these boys
* U, U) e! I( D8 M6 t" ~- Swith this disorder are full pubertal development,
" \9 N# ?6 U' m) t: s7 z0 pincluding bilateral testicular growth, similar to boys
3 V }/ ~! V$ p2 l6 zwith CPP. The gonadotropin levels in this disorder. u, d m' P, h7 f
are suppressed to prepubertal levels and do not show
* s/ s# b) M+ R, _1 x0 n, o( H1 Rpubertal response of gonadotropin after gonadotropin-- |9 ^0 g: |5 T0 w& \) A
releasing hormone stimulation. This is a sex-linked9 ^) U6 o% P- o) A8 U
autosomal dominant disorder that affects only
3 X$ Y1 F. L* j$ {: P" Omales; therefore, other male members of the family
% t2 P/ R( D* V, [$ y, y4 i/ lmay have similar precocious puberty.3
5 ~' z! W4 Q9 CIn our patient, physical examination was incon-
( s5 z+ r4 ^ {( x# A. J! V4 Bsistent with true precocious puberty since his testi-
: n6 I# X8 _& V$ y9 [7 X: t+ Ecles were prepubertal in size. However, testotoxicosis+ G8 Q! J8 k* t: q) ~) \& y; U
was in the differential diagnosis because his father0 ~8 M. ^$ K3 m4 t) u3 U7 t9 E
started puberty somewhat early, and occasionally,
6 ^& B* H- L& Q# H2 P* R% Ltesticular enlargement is not that evident in the
) E- U4 N8 m& c4 Cbeginning of this process.1 In the absence of a neg-
/ `0 X0 B, q6 I3 T F5 pative initial history of androgen exposure, our
5 w- X: C& ^" X9 Q$ b. ybiggest concern was virilizing adrenal hyperplasia,
. v% o5 a% r# I$ }either 21-hydroxylase deficiency or 11-β hydroxylase( E% H: U K! L
deficiency. Those diagnoses were excluded by find-
% D8 N$ U- _8 t2 \8 V2 ]7 k3 F8 ving the normal level of adrenal steroids.
0 T l/ K/ b |* f6 P+ L, d( E- b! KThe diagnosis of exogenous androgens was strongly
& L2 \8 V8 Q& h+ t: ]" osuspected in a follow-up visit after 4 months because5 Y" c6 z, m9 D- T$ ?/ }$ w) Q
the physical examination revealed the complete disap-3 F1 u! `- r5 P/ n0 M* e
pearance of pubic hair, normal growth velocity, and
: z$ X$ |: K: d3 r6 S7 sdecreased erections. The father admitted using a testos-; P" U8 K) Y9 i) e# }1 L; d
terone gel, which he concealed at first visit. He was' R! A' n! I" j. C7 O
using it rather frequently, twice a day. The Physicians’
& o( B, r: j9 p; `* @% Y! W* IDesk Reference, or package insert of this product, gel or- _( {. Q6 ]* L0 t" u
cream, cautions about dermal testosterone transfer to
% H+ M. t' ~2 I+ T8 k# ?% Y# W- Munprotected females through direct skin exposure.6 O6 X1 T, r0 e( c# t1 S, R* _# v; M
Serum testosterone level was found to be 2 times the1 L0 W' r/ ~% K2 D; `1 C
baseline value in those females who were exposed to
( N4 D# L" H$ M( h: neven 15 minutes of direct skin contact with their male
, Y7 {6 `5 e/ y; S! N, ^partners.6 However, when a shirt covered the applica-
+ N! \0 L8 D$ ~( }+ f1 g6 |tion site, this testosterone transfer was prevented.
8 ], m7 E- s9 B' T) zOur patient’s testosterone level was 60 ng/mL,
1 `4 K/ w2 X( \' O) S7 T5 l0 Dwhich was clearly high. Some studies suggest that
3 t6 b& m; |7 y) ?dermal conversion of testosterone to dihydrotestos-4 K2 ?6 e( Q4 E/ l2 c$ d5 ~* ^
terone, which is a more potent metabolite, is more
7 J! E- a4 G* o8 p; |active in young children exposed to testosterone
: {5 N' W0 n$ U5 ]1 `4 E Pexogenously7; however, we did not measure a dihy-, @4 M: c$ }4 |8 `9 t3 q
drotestosterone level in our patient. In addition to! B3 W9 E, A4 W& L1 D
virilization, exposure to exogenous testosterone in
1 r. t% r, H! a" z, kchildren results in an increase in growth velocity and1 O4 I. S# m) o! _9 w
advanced bone age, as seen in our patient.
( t0 S# ~' Z7 ]: C7 pThe long-term effect of androgen exposure during
& j' S% o5 u- N# i* Gearly childhood on pubertal development and final! e$ e+ }8 _$ g, Y# V- d
adult height are not fully known and always remain+ ?1 M( L5 O) M9 n' Q% B
a concern. Children treated with short-term testos-
! s0 Q, y- U) D3 l. V% ~& d' Vterone injection or topical androgen may exhibit some( L8 g7 F' g0 @0 c8 M8 x& q$ F
acceleration of the skeletal maturation; however, after
- q, C& U" n0 b$ R/ r7 r5 Q" m/ h- Wcessation of treatment, the rate of bone maturation
. x7 x" p: z3 | w. Zdecelerates and gradually returns to normal.8,9 N0 \8 D* b9 P5 u( ^( G) @: L) r
There are conflicting reports and controversy
# V. B: `5 p! \2 jover the effect of early androgen exposure on adult
) B9 @/ O0 W4 d0 M$ Dpenile length.10,11 Some reports suggest subnormal5 _( Q' t/ h! Z
adult penile length, apparently because of downreg-& a; @" N) d0 x4 @
ulation of androgen receptor number.10,12 However,
0 i j/ h8 D5 ?; Q0 G, c |Sutherland et al13 did not find a correlation between
V7 ?, \6 D0 Fchildhood testosterone exposure and reduced adult3 R: s$ ^! O9 J
penile length in clinical studies.
4 N1 }/ u6 M( ? t* E5 n$ ZNonetheless, we do not believe our patient is
2 ^; H7 l3 \ Jgoing to experience any of the untoward effects from( @: V" S8 k( {* m$ f
testosterone exposure as mentioned earlier because
% l9 b, }1 w9 ]the exposure was not for a prolonged period of time.
) g+ T; ^4 u6 C, T& c9 KAlthough the bone age was advanced at the time of
7 x! a8 i+ o% {8 f: }& ^2 H. t: J& T% Tdiagnosis, the child had a normal growth velocity at3 f$ M/ X- W m4 H5 i" i
the follow-up visit. It is hoped that his final adult- G- i$ h! b! w# i6 w" |# l
height will not be affected.- I! a" b( v/ l% `) f
Although rarely reported, the widespread avail-$ v; U$ O% V9 ?# G# C& g. z1 q* M
ability of androgen products in our society may( ?, e G( k S! Q
indeed cause more virilization in male or female0 Y5 p8 c5 `+ Y: P; \
children than one would realize. Exposure to andro-$ ~4 v5 L8 ~8 T1 y; @" z. k1 }
gen products must be considered and specific ques-$ H: f, t- R4 F/ }7 L8 z0 H
tioning about the use of a testosterone product or; U+ G" n/ |) W8 {- {& o' n. H% F
gel should be asked of the family members during
0 ~' t5 E: Q, r6 [the evaluation of any children who present with vir-5 @' p! i; k: @; f: G, K+ E
ilization or peripheral precocious puberty. The diag-( k$ K; ]3 O5 d9 l
nosis can be established by just a few tests and by4 x) J; {4 J9 C- R s* v
appropriate history. The inability to obtain such a2 a3 i& C7 j3 u3 N7 q
history, or failure to ask the specific questions, may
7 f) V3 ~+ T2 F( hresult in extensive, unnecessary, and expensive) b% G6 Z9 t$ U3 M# S- R5 t
investigation. The primary care physician should be
2 ^$ g: h% ~; m: i" O( taware of this fact, because most of these children3 `! N* o: n, ^% I
may initially present in their practice. The Physicians’
& [8 D4 _# D% W3 {% Q( VDesk Reference and package insert should also put a
. t0 e) J4 F+ L6 e) y" W+ pwarning about the virilizing effect on a male or- v! ?& l" l1 ~7 a6 y
female child who might come in contact with some-
/ m* o, f1 u, |8 A. S! S) bone using any of these products.
3 S+ x: N$ y" \References
7 `# n- b- Z7 n& O; W1. Styne DM. The testes: disorder of sexual differentiation
+ I6 z# _9 p4 @1 N1 ~8 Dand puberty in the male. In: Sperling MA, ed. Pediatric
5 w: G: h' J, t6 B$ Z9 ^. k7 zEndocrinology. 2nd ed. Philadelphia, PA: WB Saunders;3 f- a( k7 t; e4 T2 g' H7 v
2002: 565-628.2 q5 F. z& d3 v9 e0 e
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious! b6 y3 i! \1 Z5 n( o& ~5 w; m
puberty in children with tumours of the suprasellar pineal |
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