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Sexual Precocity in a 16-Month-Old/ M0 F* c2 h! ]3 h1 H, u
Boy Induced by Indirect Topical3 M& \8 V8 _% A' l- B
Exposure to Testosterone. g1 R& @1 t+ j, V
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
5 a* }/ G* n, Rand Kenneth R. Rettig, MD1
2 U' p' l X/ M& X' j$ G2 hClinical Pediatrics
T" t& g1 f& E. q) c- Y5 F$ tVolume 46 Number 62 f+ W6 T+ g0 j: Y& X" o
July 2007 540-543' ]. A+ m) P0 s6 F
© 2007 Sage Publications. t6 B3 O- ]/ d8 h( k) m$ m8 H
10.1177/0009922806296651) g) q* i- s" m; Y9 u3 Y+ g
http://clp.sagepub.com0 k7 A4 { A0 j- v; ?3 @* w: ~
hosted at
3 g$ T8 B/ c; d5 fhttp://online.sagepub.com# E0 D- a$ O& z. {: E% }, }, A4 |
Precocious puberty in boys, central or peripheral,& ]$ E# G* M* ?8 X; r
is a significant concern for physicians. Central4 ~% @8 B7 c9 J
precocious puberty (CPP), which is mediated# G q% J% ]0 g, G! v% Y
through the hypothalamic pituitary gonadal axis, has
& c; v# E: J9 H7 c: Wa higher incidence of organic central nervous system
' \1 B- |1 T; {8 c5 G4 ~, wlesions in boys.1,2 Virilization in boys, as manifested
8 p" T: M* |/ T7 ^1 A" C: vby enlargement of the penis, development of pubic2 }( ^& H9 H+ R5 ^
hair, and facial acne without enlargement of testi-
, i! P# _# q8 P' _4 A2 Q0 A+ jcles, suggests peripheral or pseudopuberty.1-3 We8 s/ q9 r ~4 v/ W6 a
report a 16-month-old boy who presented with the2 }5 _: q; G) [0 r( U
enlargement of the phallus and pubic hair develop-
* k6 I5 f! }2 Dment without testicular enlargement, which was due
4 J0 r- d9 ~6 ^" e* ^" Cto the unintentional exposure to androgen gel used by
& p* s$ a8 t$ D0 k0 j8 ^- Tthe father. The family initially concealed this infor-8 i e* o! t' B5 T
mation, resulting in an extensive work-up for this0 F$ P% b* F s B2 U9 R2 M' j
child. Given the widespread and easy availability of
6 R( x$ n0 ~1 k, ~' |0 H7 Mtestosterone gel and cream, we believe this is proba-& R# @) f( s4 _: k& T8 W/ @
bly more common than the rare case report in the: r) a5 U! W% O H
literature.4
+ Q0 y3 A& ]* j% hPatient Report
3 T) Z" K; o& PA 16-month-old white child was referred to the
3 H' k/ i/ [0 i& C' U' J$ a& ?endocrine clinic by his pediatrician with the concern
/ i4 d* U+ k1 w3 O( g% _of early sexual development. His mother noticed
% T- _7 z+ c R" f$ D9 ]# rlight colored pubic hair development when he was5 m" D; R3 J% H
From the 1Division of Pediatric Endocrinology, 2University of
: [$ f4 y" r& V1 c3 e- D5 DSouth Alabama Medical Center, Mobile, Alabama.+ R! P0 I4 O$ r: G: K5 b1 ]$ `
Address correspondence to: Samar K. Bhowmick, MD, FACE,
# f5 [* l7 z! i- \ n" h; iProfessor of Pediatrics, University of South Alabama, College of
9 |* O w" J6 m6 I1 d! WMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;1 }) C Z4 g3 V N: o# y9 P
e-mail: [email protected].7 s$ S4 G# m4 l) H# E. V/ W
about 6 to 7 months old, which progressively became% q+ y. V* v/ C
darker. She was also concerned about the enlarge-
! s- Z7 B% K' m3 kment of his penis and frequent erections. The child
# b3 R. {$ {6 Bwas the product of a full-term normal delivery, with# w( C4 m, N D. U; h* e
a birth weight of 7 lb 14 oz, and birth length of4 x# Y4 D- M) S4 U& v5 b+ j
20 inches. He was breast-fed throughout the first year: c- l0 z0 G$ G! E0 g
of life and was still receiving breast milk along with
! o/ O% H/ i9 C8 W+ K) ]3 Vsolid food. He had no hospitalizations or surgery,; ^. K' n1 M6 s6 t7 U9 h
and his psychosocial and psychomotor development7 ~6 x, j! i: [- I, q
was age appropriate.1 l# |8 W; v% j0 S" `! w
The family history was remarkable for the father,1 \2 n4 ~) b, `2 f2 k+ @9 \. i: b
who was diagnosed with hypothyroidism at age 16,2 ?' Y, Q5 I& @7 C3 @+ {
which was treated with thyroxine. The father’s
- Q. v2 @ k9 u( f6 R" {height was 6 feet, and he went through a somewhat) \% [- m) A' i
early puberty and had stopped growing by age 14.( o" s3 e$ V( j: W4 r* j# _" Y; Y
The father denied taking any other medication. The4 z+ C- x/ A; k# j4 q8 S4 n
child’s mother was in good health. Her menarche3 O+ i: a" n. M8 Z8 `
was at 11 years of age, and her height was at 5 feet
# `! Q9 r8 B# B+ A# g6 L5 inches. There was no other family history of pre-0 o8 x U2 H) u% ]" ^
cocious sexual development in the first-degree rela-
( X; d; N4 V; ~# itives. There were no siblings.
- V# [# }; S% i- wPhysical Examination
! t3 m, S5 j$ }$ u: [" NThe physical examination revealed a very active,
2 ]3 S8 D& I* S# aplayful, and healthy boy. The vital signs documented
. R1 X- \- M, a) u# P9 ea blood pressure of 85/50 mm Hg, his length was6 c3 s; A2 h2 S
90 cm (>97th percentile), and his weight was 14.4 kg
, i S4 ]0 Q$ Z(also >97th percentile). The observed yearly growth9 |" }. }3 }# S' c* V4 h5 h1 n
velocity was 30 cm (12 inches). The examination of
! J8 I8 b- M8 K$ \# j n/ Xthe neck revealed no thyroid enlargement.& x( D( B4 Z$ a+ w9 P: B. c6 d
The genitourinary examination was remarkable for
. T8 J4 B1 y6 B6 X3 _& Q4 Zenlargement of the penis, with a stretched length of1 h3 w; v1 N9 C
8 cm and a width of 2 cm. The glans penis was very well
% C" G8 a- H4 Q; ^9 j4 x3 bdeveloped. The pubic hair was Tanner II, mostly around( u! K; j* J) Y& |5 b8 N9 r2 }, g' {. U
540. U; d( q5 u; ] x/ `6 |
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from' @9 h9 h/ v+ q- f
the base of the phallus and was dark and curled. The4 j* f5 F4 M" P
testicular volume was prepubertal at 2 mL each.# }6 _" P% u9 N3 N; m
The skin was moist and smooth and somewhat3 j7 ^( V% V S, O
oily. No axillary hair was noted. There were no
& c2 S% u9 `0 x1 Q0 Y1 Wabnormal skin pigmentations or café-au-lait spots.+ G. t! J0 U# C# Q( ^& L1 h
Neurologic evaluation showed deep tendon reflex 2+- z. [) P, D8 [$ e
bilateral and symmetrical. There was no suggestion" U; K. o7 ^# W& d/ }
of papilledema.. ]+ ^+ I1 W! r4 p( s- }, W
Laboratory Evaluation8 G/ c9 n: V: M$ U: w4 }
The bone age was consistent with 28 months by
7 X3 n. R, V; j/ Vusing the standard of Greulich and Pyle at a chrono-
8 U" F3 ] T. V& n, xlogic age of 16 months (advanced).5 Chromosomal% Z9 L) r6 C& k5 _
karyotype was 46XY. The thyroid function test
- G0 _ E4 v0 m0 j3 Sshowed a free T4 of 1.69 ng/dL, and thyroid stimu-$ l& N! U: O" b. {8 d
lating hormone level was 1.3 µIU/mL (both normal).
; v, ]+ g5 D6 s; c; ZThe concentrations of serum electrolytes, blood
" V7 T: h* R. i7 v) o5 X! y* |urea nitrogen, creatinine, and calcium all were
# o1 }+ M5 ]# S- U& kwithin normal range for his age. The concentration
; s6 @4 ~5 ~2 ?4 [! B$ I, Sof serum 17-hydroxyprogesterone was 16 ng/dL3 I' r8 ~ ?. {0 W( L
(normal, 3 to 90 ng/dL), androstenedione was 20
$ Y1 \, ]8 |# E1 K% gng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-4 ~* C" b6 n' b! j U3 J
terone was 38 ng/dL (normal, 50 to 760 ng/dL),: E+ f) l9 R$ s; [7 C
desoxycorticosterone was 4.3 ng/dL (normal, 7 to
4 F7 C5 O+ e9 T3 C# V9 `49ng/dL), 11-desoxycortisol (specific compound S)$ I7 W* f5 t6 j+ m ~- z+ g" }4 V
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-- A# [; L4 Z1 d; C) f
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
3 d5 a: }' \% \" w% H- ftestosterone was 60 ng/dL (normal <3 to 10 ng/dL),
1 c. B( l# M& z' a9 z. ~' ?* U% tand β-human chorionic gonadotropin was less than8 c4 p, x- y" n6 ?$ t {& ^6 O
5 mIU/mL (normal <5 mIU/mL). Serum follicular' E% C, n0 s* X, {! v* v, C1 Z
stimulating hormone and leuteinizing hormone
/ p) D- m8 V; M& d5 oconcentrations were less than 0.05 mIU/mL
/ Y! s3 b( b) T) C+ n% V(prepubertal).
- L8 k3 L; c5 y5 kThe parents were notified about the laboratory
, `) I7 d8 ]* tresults and were informed that all of the tests were
; y5 [3 r: a* A% W- k- J* d, q3 tnormal except the testosterone level was high. The
: L- z$ m0 y" afollow-up visit was arranged within a few weeks to. Z2 c3 N2 Z$ p* }" e; l+ Y$ O
obtain testicular and abdominal sonograms; how-2 @. C4 s- \ C3 y$ d( \
ever, the family did not return for 4 months.
/ V5 E0 D: L, y ~$ T6 y% mPhysical examination at this time revealed that the
( h! W0 Q. A$ Q, V( |" Q: schild had grown 2.5 cm in 4 months and had gained& P( _0 V1 F% }' H; M$ s* c; [
2 kg of weight. Physical examination remained: A5 V9 }& g! m) P4 S. [
unchanged. Surprisingly, the pubic hair almost com-+ U5 W1 |. V5 i) w( X, u
pletely disappeared except for a few vellous hairs at. b& j) C+ L# m. ~5 k
the base of the phallus. Testicular volume was still 2/ M+ ^+ z5 K6 H. N7 F2 n
mL, and the size of the penis remained unchanged.& w% Y5 ^2 A# O6 t! ?6 j- r; j
The mother also said that the boy was no longer hav-& Y, r: b8 E! W$ W- T' y1 k
ing frequent erections.
. R) c: K) s$ e- ?6 R0 r* } QBoth parents were again questioned about use of( l6 u5 {5 \5 W7 _- Z
any ointment/creams that they may have applied to2 E5 b* P/ M' I% w
the child’s skin. This time the father admitted the$ ~! b' [, s u
Topical Testosterone Exposure / Bhowmick et al 541
' v' `' T/ @! l; G ause of testosterone gel twice daily that he was apply-
# `$ ?- x- D2 h# ~- x0 ]# [5 ging over his own shoulders, chest, and back area for# {' E/ Y8 R r9 z: c: D6 d( m
a year. The father also revealed he was embarrassed I3 k) B) c/ S# X" p. `* ?
to disclose that he was using a testosterone gel pre-1 ^/ Q& S! U- ?: I+ G) X+ M$ ^+ I
scribed by his family physician for decreased libido
' S3 u8 { H& Zsecondary to depression.; L# w0 C9 D# m
The child slept in the same bed with parents.
7 D! T6 }% k) t9 W# K. s. ^- ?The father would hug the baby and hold him on his3 `# Q1 B5 h9 _
chest for a considerable period of time, causing sig-9 C& a$ D6 b! F7 M/ E% M
nificant bare skin contact between baby and father.
3 y& R. Z6 o% a/ PThe father also admitted that after the phone call,
, b. r. P0 b/ u6 @& Xwhen he learned the testosterone level in the baby
- @. G7 q! ~; C6 B; jwas high, he then read the product information
: ~# _+ L* ^$ q" z" h' b! i+ Tpacket and concluded that it was most likely the rea-- z2 i2 y4 H ~6 [: s- B. B- ` ?
son for the child’s virilization. At that time, they& H" `! _7 J$ r$ T3 w
decided to put the baby in a separate bed, and the/ t8 f) n" A* h' j9 v. ~; L6 E' i
father was not hugging him with bare skin and had
# ^+ u5 H7 o' V; Z7 {( hbeen using protective clothing. A repeat testosterone
" }" G' p! ]/ u; q# etest was ordered, but the family did not go to the+ \/ y2 E2 X L& D9 |+ j
laboratory to obtain the test.
# k0 K8 p' c/ ^Discussion/ W q U! U( `+ C" ?
Precocious puberty in boys is defined as secondary! T4 G( t* j6 m$ {. ?2 h
sexual development before 9 years of age.1,46 }( n2 r S, q% B, A% Y2 }; o; ?
Precocious puberty is termed as central (true) when$ I/ L- Z) |: z/ \! U
it is caused by the premature activation of hypo-$ m1 Y/ ]$ h% u) ~3 n5 w1 B
thalamic pituitary gonadal axis. CPP is more com-
3 X- N" G# o+ h8 v0 ~mon in girls than in boys.1,3 Most boys with CPP
+ n/ x6 N# _2 v3 D% q$ omay have a central nervous system lesion that is
+ G+ U! G, M$ kresponsible for the early activation of the hypothal-7 O" a% h8 Z. e& a( M
amic pituitary gonadal axis.1-3 Thus, greater empha-6 |. Z2 [5 {" w* [& J3 v. F/ N/ S
sis has been given to neuroradiologic imaging in8 t- b& W% h. J6 u
boys with precocious puberty. In addition to viril-. @4 c7 D+ J- ]9 }1 g
ization, the clinical hallmark of CPP is the symmet-
; K- N5 ^$ b" D" ]rical testicular growth secondary to stimulation by
: Z, O! k4 M F7 K) v4 Ygonadotropins.1,3
% y6 R5 J) D" }Gonadotropin-independent peripheral preco-# o, |( N# n& p& Q
cious puberty in boys also results from inappropriate4 ]8 t; |1 a6 C9 K1 U) ?, [
androgenic stimulation from either endogenous or
, j1 v* D3 F1 q8 r8 x4 sexogenous sources, nonpituitary gonadotropin stim-
& K2 u% U' F% I2 J8 n, i. Iulation, and rare activating mutations.3 Virilizing
6 j$ H$ e, \+ Y4 ncongenital adrenal hyperplasia producing excessive
. {; t H8 }) }* v$ Yadrenal androgens is a common cause of precocious
3 c; O7 j b9 W& l1 Tpuberty in boys.3,4 H) y8 \; O. A
The most common form of congenital adrenal6 Z; Z; D- h6 _/ Q" M+ ]
hyperplasia is the 21-hydroxylase enzyme deficiency.! e8 W, G5 ~) A' m: I% f! c! G
The 11-β hydroxylase deficiency may also result in
+ i; X* `1 C+ f3 e, U! S& jexcessive adrenal androgen production, and rarely,
" H: @ i, o4 K4 qan adrenal tumor may also cause adrenal androgen
( L+ j" Q x: G1 Fexcess.1,37 C8 K$ o- q- B
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
$ ~3 L9 `! q$ v! u542 Clinical Pediatrics / Vol. 46, No. 6, July 2007; J! G/ b4 y6 j0 B6 H2 ?. P9 m
A unique entity of male-limited gonadotropin-
% H; C. `- `' n0 c3 aindependent precocious puberty, which is also known
; P( @; \- t/ {as testotoxicosis, may cause precocious puberty at a& l* |" e* a* q. s3 H( d/ t" Z& c
very young age. The physical findings in these boys
( D4 `6 s- c" @3 f$ C" `2 x8 lwith this disorder are full pubertal development,. H5 J6 ~7 G0 I) H+ `
including bilateral testicular growth, similar to boys K0 F0 @& P+ T. E; `4 y, I/ q
with CPP. The gonadotropin levels in this disorder
* l& A9 F% c4 V' a( Gare suppressed to prepubertal levels and do not show+ }& V" W' s/ k k! ?" t7 L; D2 j/ ^8 j
pubertal response of gonadotropin after gonadotropin-
% z( t3 _4 Y. ureleasing hormone stimulation. This is a sex-linked
2 k9 L% D" ~/ l5 N! I% lautosomal dominant disorder that affects only) C6 M: A& u* T3 J
males; therefore, other male members of the family) ?9 y2 d" \/ l* E, c& i% Z
may have similar precocious puberty.3
0 f* S6 I9 ?8 tIn our patient, physical examination was incon-
4 s. w( O) D, J4 N% }3 Xsistent with true precocious puberty since his testi-
) C, T, P# s: d1 F5 B m2 ?4 }5 Gcles were prepubertal in size. However, testotoxicosis8 ?! W3 G6 @% T' _. S" q7 ?8 K4 I* ]
was in the differential diagnosis because his father
2 c: `1 E- G$ y! V& T1 F- L' F" f _( estarted puberty somewhat early, and occasionally,
) J1 g4 v; ~0 @ A; v3 l6 ktesticular enlargement is not that evident in the
( y2 E& w1 I! R- [' {" Jbeginning of this process.1 In the absence of a neg-
# @ I1 P* m' v, Bative initial history of androgen exposure, our1 n: y; W- x/ [3 {; L6 F
biggest concern was virilizing adrenal hyperplasia,. ~& h) U( l( x, e
either 21-hydroxylase deficiency or 11-β hydroxylase. w0 t4 v! W' J4 L. T; Y2 j& `; }
deficiency. Those diagnoses were excluded by find-
5 h! `4 Z# |" z4 {1 l J( K, L2 J& Ling the normal level of adrenal steroids.
N" k5 G" {" y* W1 nThe diagnosis of exogenous androgens was strongly
* F2 S, F7 z" I7 ?suspected in a follow-up visit after 4 months because
* x- h/ T0 z F1 Q, |. _the physical examination revealed the complete disap-9 Z* n9 k& {: M5 U+ H8 ~- o
pearance of pubic hair, normal growth velocity, and* F% K3 N' H; N% R# N* `6 x
decreased erections. The father admitted using a testos-; a1 S% Q( _, h& K" ~- v
terone gel, which he concealed at first visit. He was
# Q1 C e8 S* W l9 Husing it rather frequently, twice a day. The Physicians’- D3 u9 N3 q% l0 i6 h
Desk Reference, or package insert of this product, gel or
- d$ V U, _- M. y* g3 y: Hcream, cautions about dermal testosterone transfer to) R6 J2 {, ^$ f5 Q6 y* g" A
unprotected females through direct skin exposure.
. d( b2 q+ l2 B0 O' iSerum testosterone level was found to be 2 times the
: W- D3 N. x& t' C Ubaseline value in those females who were exposed to& z3 B. C! U' b. x. K7 h% X
even 15 minutes of direct skin contact with their male6 Q) [3 z- d1 x$ M" \, `0 M
partners.6 However, when a shirt covered the applica-
$ f. L- z( N0 y& F$ ]4 R$ P7 _tion site, this testosterone transfer was prevented.
7 E% |0 w% p, ^* f( qOur patient’s testosterone level was 60 ng/mL,
6 Q/ }6 A) i5 } E- k7 ?which was clearly high. Some studies suggest that$ ]: n8 E* m+ }5 Z
dermal conversion of testosterone to dihydrotestos-
' f U: L+ j) |1 x3 vterone, which is a more potent metabolite, is more
3 c* V& C$ _1 M. A& K, }active in young children exposed to testosterone
- {& a6 T9 ~) ], H! a7 q+ ]exogenously7; however, we did not measure a dihy-4 I4 v$ z( R5 ~/ R& Q3 Z( y2 w
drotestosterone level in our patient. In addition to" g( T- w$ {- k, v% V1 `) N* d
virilization, exposure to exogenous testosterone in
9 O$ h# F% ^2 g( ^- W) y/ Cchildren results in an increase in growth velocity and% c; Z% \: ^0 x" Z5 _3 x
advanced bone age, as seen in our patient.
% {9 @* U3 c% f, UThe long-term effect of androgen exposure during, A* v: f/ }& d$ {: |- F
early childhood on pubertal development and final# }1 t; |4 K$ [" I
adult height are not fully known and always remain
/ Z" _ e3 {! g5 V: ba concern. Children treated with short-term testos-/ x1 }6 E: ?6 E. t* V6 @- y
terone injection or topical androgen may exhibit some% H; Z9 N; f9 R3 q3 V7 m
acceleration of the skeletal maturation; however, after
& i5 R4 z0 O9 u, t4 |, P4 scessation of treatment, the rate of bone maturation# i. `+ G) C2 J
decelerates and gradually returns to normal.8,9+ U, [4 f5 I8 U3 R2 J! H- ~
There are conflicting reports and controversy
7 O" u4 ^( Y# R) [; r& k% Vover the effect of early androgen exposure on adult4 P3 l+ |- W( M
penile length.10,11 Some reports suggest subnormal: A; q0 G7 j# O$ d, C
adult penile length, apparently because of downreg-6 I; C/ E" H- y; W# R
ulation of androgen receptor number.10,12 However,7 | D# ^0 c5 G
Sutherland et al13 did not find a correlation between; u# `5 e; w0 j
childhood testosterone exposure and reduced adult4 \$ u, E0 d( J- K4 A
penile length in clinical studies.2 v) L) Y0 z T) F5 @3 S
Nonetheless, we do not believe our patient is; e, [# U, A6 S' k( H" w4 e. C
going to experience any of the untoward effects from) V; `1 A# ]6 N, K8 x4 N
testosterone exposure as mentioned earlier because
' s" W! t: h! }the exposure was not for a prolonged period of time." ~0 a: u4 {# \0 S7 g) m+ _. D
Although the bone age was advanced at the time of; O6 [; e& l' {) x) K9 N7 }, a
diagnosis, the child had a normal growth velocity at
3 m5 Z$ ?6 t3 kthe follow-up visit. It is hoped that his final adult* }/ X! E" `+ A' d
height will not be affected.
# M1 y9 F" A6 _) [ KAlthough rarely reported, the widespread avail-
. M, @8 s ~% aability of androgen products in our society may
. p" I& B2 D" K7 e% z4 y/ w# d% q! tindeed cause more virilization in male or female' R- U2 K3 V/ z1 B/ j' u; [
children than one would realize. Exposure to andro-
/ _7 K; [. {& k9 U/ j: [7 d- |gen products must be considered and specific ques-: I: g; }4 L% V# |* n/ @
tioning about the use of a testosterone product or
5 F* h: ^ i* [( s/ `gel should be asked of the family members during
6 m; y" ~1 Z. k% Mthe evaluation of any children who present with vir-
3 R5 E: c, B3 i( v6 |ilization or peripheral precocious puberty. The diag-2 u2 b! N7 f- `7 b; e6 ~
nosis can be established by just a few tests and by
; j) T$ Y ]/ W7 a0 N" ]. ^appropriate history. The inability to obtain such a3 J$ ^" n# q" @, X! S- l
history, or failure to ask the specific questions, may
% Y6 ?9 y9 R' v( Q3 f; Vresult in extensive, unnecessary, and expensive' a; @0 G# j/ }) z( \ _
investigation. The primary care physician should be& W- Q/ l; P5 m
aware of this fact, because most of these children
- ^ u0 B) K/ P9 bmay initially present in their practice. The Physicians’
9 ?7 M$ P6 o; z. w4 s' M3 h _/ LDesk Reference and package insert should also put a, [! _* f. m, |- @/ x+ K
warning about the virilizing effect on a male or
$ G: t8 D$ v {% n- \- T" Z. zfemale child who might come in contact with some-. h: b8 p; j% K; \' `
one using any of these products.
$ H( h* ?8 w1 s7 n; x2 FReferences: u* z% U$ i/ Q: M4 Y
1. Styne DM. The testes: disorder of sexual differentiation
: @1 x$ ]! g6 p: L1 Yand puberty in the male. In: Sperling MA, ed. Pediatric+ |2 O4 h" X4 |) ^4 E8 E
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;" l+ ?* Z6 F; \1 q) W" ~
2002: 565-628.
$ y: }, T9 x( {) o' T- M1 h2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
+ u; g9 Y& D; D$ ~: fpuberty in children with tumours of the suprasellar pineal |
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