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Sexual Precocity in a 16-Month-Old* _' G: ?% W0 l
Boy Induced by Indirect Topical
) J O6 H9 Q! K8 ^( `Exposure to Testosterone/ V9 e! `5 d4 T; T* z
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
3 u6 q. U! i: ?' [8 fand Kenneth R. Rettig, MD1
: ?/ } m) S3 x3 R FClinical Pediatrics$ C9 G2 j3 s0 M: Z! T2 W
Volume 46 Number 6+ ~0 i% z/ ^; ~& l
July 2007 540-543
: Z, k+ S0 O2 H© 2007 Sage Publications3 l5 J# j( K* q" J3 y+ n
10.1177/0009922806296651
4 _3 s; E5 D: K) F, `( C7 Qhttp://clp.sagepub.com
: x7 B& n6 d7 @( j; }hosted at# s3 \* ~ j$ z1 q U9 }% }
http://online.sagepub.com
. Y1 R3 k9 _# N1 d# uPrecocious puberty in boys, central or peripheral,
0 `0 E$ Y( h Y8 `4 S: X( E2 P4 Pis a significant concern for physicians. Central
2 u% c% y1 w. l$ W( Wprecocious puberty (CPP), which is mediated
5 B/ e. @- Q2 O" x* ^* Gthrough the hypothalamic pituitary gonadal axis, has1 `8 g. M6 M5 f7 [9 a% C
a higher incidence of organic central nervous system
7 B ~9 j: [" U/ Zlesions in boys.1,2 Virilization in boys, as manifested
/ |$ V4 U( ]( F4 v6 X3 |8 Eby enlargement of the penis, development of pubic
; b2 h2 v7 I' K6 K1 n4 ?! Yhair, and facial acne without enlargement of testi-; x6 y. k d5 {4 \* i
cles, suggests peripheral or pseudopuberty.1-3 We
) {$ x) g' d7 C& |report a 16-month-old boy who presented with the3 t" K* S8 D* [: _8 A
enlargement of the phallus and pubic hair develop-
3 i+ ?& \; @/ A Y- G! U, }ment without testicular enlargement, which was due, Q1 G' d- o2 k4 D( @
to the unintentional exposure to androgen gel used by
5 I8 m1 h3 Z6 Vthe father. The family initially concealed this infor-# H8 h7 Q$ l, s
mation, resulting in an extensive work-up for this: d. P, d% Y; A* S: P7 k
child. Given the widespread and easy availability of
" }' F0 z3 b% \' O3 H: A2 _, ftestosterone gel and cream, we believe this is proba-. Z3 b( \! }! r8 ^+ |
bly more common than the rare case report in the
2 R9 _) G9 g4 p/ g# } j% f& vliterature.4+ M! p+ o# e$ N. H
Patient Report5 b) F4 I ^; ~' c
A 16-month-old white child was referred to the
- S7 X/ c5 D0 [" {+ c; _endocrine clinic by his pediatrician with the concern3 ], J. K4 b% k$ [! a
of early sexual development. His mother noticed4 o$ h+ T4 b O- M, B
light colored pubic hair development when he was- ^8 s# E: r+ B& p. k# q
From the 1Division of Pediatric Endocrinology, 2University of
9 B. V& j8 j" YSouth Alabama Medical Center, Mobile, Alabama.% m2 o$ A' C2 f' P
Address correspondence to: Samar K. Bhowmick, MD, FACE,
( ^% |% P+ ?. @Professor of Pediatrics, University of South Alabama, College of
7 n( e" z# R, A; I* @1 E5 ]* ]Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
% n% ^, p; p0 @7 l" t& g! ^e-mail: [email protected].
+ X! @, r+ n' T. _$ r& L) aabout 6 to 7 months old, which progressively became
7 }, F, m: }( Z0 `( Odarker. She was also concerned about the enlarge-: A8 U' h3 Q8 l; V) c
ment of his penis and frequent erections. The child: s' h4 x0 ?& e: M9 }" ^* ]2 M2 X& k
was the product of a full-term normal delivery, with6 x0 B7 W" h; e# Y8 c5 R
a birth weight of 7 lb 14 oz, and birth length of
3 k0 Y/ U* c3 o% t% s2 D' M: p% P20 inches. He was breast-fed throughout the first year7 q( A$ |2 W! O4 _& ?. t" B3 P8 E
of life and was still receiving breast milk along with5 m6 p. r U) w& b; }# a
solid food. He had no hospitalizations or surgery,
' L7 C0 d0 @, S Mand his psychosocial and psychomotor development) N0 R" p5 [8 r1 R2 E+ ^! b! \0 p
was age appropriate.
( W: F) }8 Y5 j3 I9 w% P8 iThe family history was remarkable for the father,
; {. L8 m! r& ~! z" M* U2 twho was diagnosed with hypothyroidism at age 16,5 L$ R9 R0 B" A$ Q. b
which was treated with thyroxine. The father’s: |' c k0 q$ P& @
height was 6 feet, and he went through a somewhat
! u) x8 P4 s( q0 h6 Searly puberty and had stopped growing by age 14.
, R5 q5 o" W- {+ J+ zThe father denied taking any other medication. The3 u0 H# K6 `1 x( p6 D4 f
child’s mother was in good health. Her menarche5 ^1 D+ V6 y6 {# }5 |
was at 11 years of age, and her height was at 5 feet
! s/ A" N4 d b9 c7 G5 inches. There was no other family history of pre-) Z8 J! `4 z H1 m1 c1 o7 m
cocious sexual development in the first-degree rela-
& ^" E3 A @8 m) k w) t5 Q2 ?: U/ Rtives. There were no siblings.; _2 X& m4 T8 I0 J2 g( ?
Physical Examination
, C# _1 W& W: F" h) kThe physical examination revealed a very active,- r/ U( Y9 c3 w
playful, and healthy boy. The vital signs documented3 P; y3 A7 y, P, R4 G A
a blood pressure of 85/50 mm Hg, his length was1 _# O7 A1 Z8 ]- u" v2 ]
90 cm (>97th percentile), and his weight was 14.4 kg1 _9 H: w) O9 C2 F
(also >97th percentile). The observed yearly growth: {+ i: b2 D/ d
velocity was 30 cm (12 inches). The examination of. o7 v- p4 Z) `% x! ~; W3 N
the neck revealed no thyroid enlargement.# w* c3 K8 b5 i) R# y
The genitourinary examination was remarkable for
8 _" i4 B, {, t/ v4 M1 _enlargement of the penis, with a stretched length of
1 g2 o# }' q+ e8 d/ y8 cm and a width of 2 cm. The glans penis was very well& e4 J! Q0 ^& @5 t4 ^
developed. The pubic hair was Tanner II, mostly around
" T, V, r4 w- p2 k* q4 a1 n* P' ]540
/ E7 \4 }& k, vat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
1 g! O3 v% }# H, }the base of the phallus and was dark and curled. The- V+ n1 Q* o- G; s: r
testicular volume was prepubertal at 2 mL each.+ y! k M% {! k5 x- a
The skin was moist and smooth and somewhat
8 I! [7 g! j& j/ P4 w( H/ t, F7 ? ?oily. No axillary hair was noted. There were no* G) y. @# I' d
abnormal skin pigmentations or café-au-lait spots., q5 O' q. d7 I* b2 C
Neurologic evaluation showed deep tendon reflex 2+
* @- |+ j+ X' K: ibilateral and symmetrical. There was no suggestion
/ r3 |3 Q+ T' Iof papilledema.
* } b; N2 p0 H, N4 KLaboratory Evaluation
1 C# x7 }! y& u5 Q& \% DThe bone age was consistent with 28 months by
+ B6 ]' i# ^0 T- Vusing the standard of Greulich and Pyle at a chrono-$ S" C* ~$ Z3 v e" n
logic age of 16 months (advanced).5 Chromosomal' [& x$ P# D5 o4 v# V
karyotype was 46XY. The thyroid function test
8 n% E: P4 X1 R, zshowed a free T4 of 1.69 ng/dL, and thyroid stimu-0 Y# B0 Z: l: @; K9 v
lating hormone level was 1.3 µIU/mL (both normal).
, r' K2 D+ L" m+ oThe concentrations of serum electrolytes, blood
( ~; R6 F6 i5 J9 ]( D" G: {5 Rurea nitrogen, creatinine, and calcium all were/ B/ A7 \1 i" h! ^
within normal range for his age. The concentration8 u( _; p. O" M Y2 H
of serum 17-hydroxyprogesterone was 16 ng/dL
, t( \. j6 D: \: A8 U0 n4 q c8 U(normal, 3 to 90 ng/dL), androstenedione was 20
, s. I6 p! N9 |4 ?9 L% K ing/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
; E$ @3 p) a/ |- B: nterone was 38 ng/dL (normal, 50 to 760 ng/dL),
; _0 l' |2 ^# P: }3 y; |" e% [( }desoxycorticosterone was 4.3 ng/dL (normal, 7 to
8 B s) x3 t3 @) F1 ^& |" V% G49ng/dL), 11-desoxycortisol (specific compound S) C, I# I8 b: P3 O- y4 N
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-3 l1 U% m# K9 F' M
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total8 u* c r7 z' r( @6 x: w& H! k
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),9 @* f$ L0 K9 C& F1 q6 U
and β-human chorionic gonadotropin was less than
1 Y/ S8 f' c( e, `2 l+ f5 mIU/mL (normal <5 mIU/mL). Serum follicular
. G: X2 N4 B3 d. Zstimulating hormone and leuteinizing hormone$ Q; c- a8 w3 E" S& X
concentrations were less than 0.05 mIU/mL& I& z3 U0 F) e. A
(prepubertal).4 Y0 N9 E1 z$ l1 E# D( a2 Y$ Z t
The parents were notified about the laboratory! h, G. z, {2 w k% S
results and were informed that all of the tests were7 J# [( B) X- H y" \' V
normal except the testosterone level was high. The
8 S7 i8 F. Z. k% I x4 y/ O/ h' afollow-up visit was arranged within a few weeks to1 I4 P! w0 }8 O1 c
obtain testicular and abdominal sonograms; how-
3 C+ s& J, W# u4 V# m4 hever, the family did not return for 4 months.( \# O$ r) y# Y s4 ]
Physical examination at this time revealed that the
% O- \' J! T! B; ~, i$ x" Mchild had grown 2.5 cm in 4 months and had gained O2 x+ s+ ]& M5 S. \9 `* L
2 kg of weight. Physical examination remained' B# ~8 R" m% q6 r# a+ ~
unchanged. Surprisingly, the pubic hair almost com-8 s, j0 W1 m% @
pletely disappeared except for a few vellous hairs at$ R- r$ c' Z; i m/ d) M1 ^8 T' B: W, Y
the base of the phallus. Testicular volume was still 25 ?1 ]8 @, O; H. ~- {/ ~' ~
mL, and the size of the penis remained unchanged., y$ @* X$ q6 `# P: g e
The mother also said that the boy was no longer hav-
+ z$ F7 u8 U0 E, ?ing frequent erections.5 v2 W; F. p& c: q
Both parents were again questioned about use of9 h+ W7 i& ^- H
any ointment/creams that they may have applied to+ t P! ?( ?2 r4 i1 X+ v0 U6 V
the child’s skin. This time the father admitted the
0 c5 c6 P/ O, V$ A+ Z7 E" QTopical Testosterone Exposure / Bhowmick et al 541; |: D1 ~" I9 A- q! T
use of testosterone gel twice daily that he was apply-9 `9 Z& N, c5 @1 l3 l* ^
ing over his own shoulders, chest, and back area for
$ W7 C6 V, j" Z+ F, E9 wa year. The father also revealed he was embarrassed* a5 v5 [4 F `2 t' k. [
to disclose that he was using a testosterone gel pre-
$ b O+ ]- r. s( sscribed by his family physician for decreased libido
+ y" h$ \, j/ Usecondary to depression.: V7 z! d, d; X% H; c
The child slept in the same bed with parents.7 j: e9 _+ |- a1 [
The father would hug the baby and hold him on his
: H8 r9 y6 Z6 |: V$ v7 x$ v1 ~chest for a considerable period of time, causing sig-5 V) u( u& b+ S8 |# E0 A
nificant bare skin contact between baby and father.% ^$ ~! d- D) @/ }) h
The father also admitted that after the phone call,* L8 J1 p+ _+ T: G# y! x L: f
when he learned the testosterone level in the baby( b3 z$ N* a( J- g
was high, he then read the product information, E. z5 g4 ]. a3 V+ I, n( s8 m ^+ X. M- Q
packet and concluded that it was most likely the rea-
$ K# B0 v+ D4 V4 H8 zson for the child’s virilization. At that time, they) {& B4 L8 ]5 f3 q1 @3 u, j
decided to put the baby in a separate bed, and the
, B3 e4 b, a; p( ^father was not hugging him with bare skin and had
1 Q; b9 z( V+ ebeen using protective clothing. A repeat testosterone
& l# i6 J. M+ X; j3 m: Mtest was ordered, but the family did not go to the
" y; i6 J5 X- [- S9 Olaboratory to obtain the test.
; |9 K8 `/ p8 G" @# N- t8 WDiscussion
0 ?' R) ?/ ^' {& l4 ~% C( MPrecocious puberty in boys is defined as secondary
2 w, r8 f7 J, |sexual development before 9 years of age.1,4$ Z- c' y! {/ b! Q8 a
Precocious puberty is termed as central (true) when9 v* ?. K3 Q0 a' D1 ?
it is caused by the premature activation of hypo-. L. v& ]- M: y( L3 E( |3 u
thalamic pituitary gonadal axis. CPP is more com-
- n5 `! c3 {# y9 y& vmon in girls than in boys.1,3 Most boys with CPP& H1 S; s; |2 t; S
may have a central nervous system lesion that is
, e1 b3 b# l; ]& O O3 aresponsible for the early activation of the hypothal-
& X H" A4 R$ N, @# i2 |amic pituitary gonadal axis.1-3 Thus, greater empha-' C' g# R$ Q8 d8 N+ U i7 Y
sis has been given to neuroradiologic imaging in: ^+ n' E) H n4 [! Y+ G0 W
boys with precocious puberty. In addition to viril-1 j5 F; W! ]6 N' h( n* H* C+ I
ization, the clinical hallmark of CPP is the symmet-
; A! j/ N3 E9 [ U) m. D0 D) vrical testicular growth secondary to stimulation by% w* K; B+ a3 L6 z6 o5 H' {
gonadotropins.1,3" d0 u9 y; J, i' h
Gonadotropin-independent peripheral preco-! z. a# ]" p Z8 C: f
cious puberty in boys also results from inappropriate' h$ g( m% Q+ E& a) F
androgenic stimulation from either endogenous or
3 h3 q3 J& e- Q5 E- Lexogenous sources, nonpituitary gonadotropin stim-) S" N4 ?- P; B; {9 P
ulation, and rare activating mutations.3 Virilizing
' Y; a0 N: V3 @0 e# u rcongenital adrenal hyperplasia producing excessive3 h2 X2 _5 ?2 b3 r. |
adrenal androgens is a common cause of precocious
2 V0 T( e0 x% Q$ R) x. L Apuberty in boys.3,4, _% i4 k& b) r$ q5 m }
The most common form of congenital adrenal
7 W/ x! m; W6 e7 L Xhyperplasia is the 21-hydroxylase enzyme deficiency.& O( _% E" w0 |( g# \- L( k
The 11-β hydroxylase deficiency may also result in
$ m: l5 w, P0 ^! q1 Wexcessive adrenal androgen production, and rarely,) K/ @8 O3 \# ]- J' \) |+ {. n: i
an adrenal tumor may also cause adrenal androgen
% U) j% x3 q. ~5 Y3 `excess.1,3
" ^4 o# Z: k7 J4 C7 ~at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from. }- ?# o1 H U, i4 f
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
; u, a) f8 g0 U6 D d6 C pA unique entity of male-limited gonadotropin-
& \5 X K, Z$ r6 B6 oindependent precocious puberty, which is also known
( ~6 ~( Z+ {/ L: S- Kas testotoxicosis, may cause precocious puberty at a
5 s0 h2 P, o9 R' B) g6 _$ Every young age. The physical findings in these boys3 X! N W& ^/ \! P, Y% O/ |0 ?9 {
with this disorder are full pubertal development,, I; x7 n K5 \; ^
including bilateral testicular growth, similar to boys) B# s/ H! q* `4 G: H
with CPP. The gonadotropin levels in this disorder
7 W r! W- R& ?4 m) v/ ~are suppressed to prepubertal levels and do not show7 G9 }; Q* S6 R
pubertal response of gonadotropin after gonadotropin-! v. m( {0 S, E+ |! _4 O4 S* m
releasing hormone stimulation. This is a sex-linked; \9 E- |1 ^; ]
autosomal dominant disorder that affects only
4 i5 Z3 y5 D) l( lmales; therefore, other male members of the family/ [2 o+ _% f( e* m
may have similar precocious puberty.3' x. n4 s# F" ^$ P. @* Y2 p
In our patient, physical examination was incon-% C( p( y' |; f! G( G
sistent with true precocious puberty since his testi-) {7 U! W+ v1 D
cles were prepubertal in size. However, testotoxicosis
5 F! }( ^( `! c$ m' ?, Cwas in the differential diagnosis because his father9 W& b2 z; V9 m' j+ F3 f# x/ v7 u0 S
started puberty somewhat early, and occasionally,
- ~/ d' W R7 p6 qtesticular enlargement is not that evident in the
2 A9 I, h& T5 Q4 l+ I2 I+ G% Sbeginning of this process.1 In the absence of a neg-
7 w4 j G" z0 a/ Oative initial history of androgen exposure, our
6 M# k! p0 d4 l; d/ X9 M. ~5 Wbiggest concern was virilizing adrenal hyperplasia, d. ^' z9 W3 i# f
either 21-hydroxylase deficiency or 11-β hydroxylase
# H/ D; S$ l& x' W1 Ydeficiency. Those diagnoses were excluded by find-8 }$ r' P( E% z# `3 ~8 m2 b
ing the normal level of adrenal steroids.; b7 _4 _4 ]& v" W( W0 @- O) F. q
The diagnosis of exogenous androgens was strongly
+ r* a6 e' n9 z7 y% L/ ^: isuspected in a follow-up visit after 4 months because
% Q$ x5 e9 D& s/ Fthe physical examination revealed the complete disap-
6 M4 u H6 W2 o/ r2 a1 Bpearance of pubic hair, normal growth velocity, and
, W. N9 g4 g J& [7 o. V! {" kdecreased erections. The father admitted using a testos- t* I* p( Y: F( P( R
terone gel, which he concealed at first visit. He was
5 ?! t3 Y. P- ^using it rather frequently, twice a day. The Physicians’
) _- i" |( f7 z' f. I6 |3 gDesk Reference, or package insert of this product, gel or1 f9 H8 v# U" {0 n2 g7 B& W
cream, cautions about dermal testosterone transfer to
9 d) L9 a+ V, @$ V! |unprotected females through direct skin exposure. X9 d4 @5 k( g2 I3 e+ R1 z
Serum testosterone level was found to be 2 times the: q" B1 e' ~; o5 S* P* v u7 x
baseline value in those females who were exposed to& |9 P9 O% z+ u! o1 _! S i4 C
even 15 minutes of direct skin contact with their male
( v) g8 A9 z! m5 B) C: Npartners.6 However, when a shirt covered the applica-
6 W% s% |, k" E) z( ~& ^4 c3 ?tion site, this testosterone transfer was prevented. F: s, ]. a- [0 m) @5 a
Our patient’s testosterone level was 60 ng/mL,
, U& z: a7 N5 Awhich was clearly high. Some studies suggest that
, ~2 O+ _6 _* o5 a- Jdermal conversion of testosterone to dihydrotestos-& i7 p+ o) W) M1 H5 m
terone, which is a more potent metabolite, is more
+ a7 S1 r) q1 w5 Cactive in young children exposed to testosterone
* l% b3 n2 W2 ~2 {4 ]3 |4 eexogenously7; however, we did not measure a dihy-
7 ]* v% F/ F6 C) \2 q8 s4 B7 {$ f) \. ~drotestosterone level in our patient. In addition to! Q# I* r, q4 y" X; e
virilization, exposure to exogenous testosterone in
$ Q' m/ K) [2 Q, b- Rchildren results in an increase in growth velocity and0 a1 c+ {+ Y7 u3 R- E
advanced bone age, as seen in our patient.
+ R, n [: D: `' F. ]) k7 tThe long-term effect of androgen exposure during
. S; j1 f$ u4 r# F {early childhood on pubertal development and final2 }6 O7 ]8 N* [) x
adult height are not fully known and always remain
& q8 r/ B D4 O' g! c- Ha concern. Children treated with short-term testos-
# E# b a: W6 U7 W# }' p+ Wterone injection or topical androgen may exhibit some
: |6 A' D4 T4 }. W+ m1 v4 oacceleration of the skeletal maturation; however, after4 q) j) m P8 F* x+ Z( p: e( b
cessation of treatment, the rate of bone maturation
7 b" z2 j/ \4 o* K% O2 ydecelerates and gradually returns to normal.8,9
+ b. h& s% x+ ^There are conflicting reports and controversy5 n2 Q+ B) }9 G0 q
over the effect of early androgen exposure on adult1 H9 ^- l8 ?3 m, q' b
penile length.10,11 Some reports suggest subnormal9 j2 R/ F4 e! o
adult penile length, apparently because of downreg-" R1 t% d3 R7 w( T: G. Z2 t! d. s+ `
ulation of androgen receptor number.10,12 However,0 X/ X+ h; ]1 E
Sutherland et al13 did not find a correlation between
, R$ K* c8 A( |) ^childhood testosterone exposure and reduced adult
6 c( c8 \' S/ v2 l' f C6 Q4 |penile length in clinical studies. ]6 Z+ |# T- g) Q3 I2 A8 i9 S) ?" ]
Nonetheless, we do not believe our patient is& H' g# Y/ e# I# D
going to experience any of the untoward effects from
* s. n" s( g& Mtestosterone exposure as mentioned earlier because, g9 n. }$ X; R2 Z, ?9 i
the exposure was not for a prolonged period of time.) @& H' [4 [3 Y+ {4 b5 c8 r- ]
Although the bone age was advanced at the time of
7 J1 {/ B* G$ I' z l* ydiagnosis, the child had a normal growth velocity at- ?6 z! b, q. J: E
the follow-up visit. It is hoped that his final adult
9 ~$ b$ d2 {. ` \6 s2 Nheight will not be affected.$ ^6 H: o& Y) n" [6 t7 r
Although rarely reported, the widespread avail-; S' u% u7 y, d6 O
ability of androgen products in our society may
: k$ W3 T8 B' X% H/ qindeed cause more virilization in male or female
) Z) S0 g9 g' N* cchildren than one would realize. Exposure to andro-3 e5 J% a; p0 x& D h F- i
gen products must be considered and specific ques-
" |/ ^2 J' }1 c0 ^+ qtioning about the use of a testosterone product or8 Q. Y" `7 m8 W( Y1 q3 V6 \: y3 S2 A
gel should be asked of the family members during- i% D$ a1 A: E- W
the evaluation of any children who present with vir-
9 U; S7 u" ], h c4 }ilization or peripheral precocious puberty. The diag-
9 Y* U, m% H" @nosis can be established by just a few tests and by
" T4 b. ^1 @+ uappropriate history. The inability to obtain such a3 b4 s5 k4 @$ b6 q/ s
history, or failure to ask the specific questions, may
& w4 k" R) B; L, j: nresult in extensive, unnecessary, and expensive
0 U1 ? o# X# i# G3 z0 }7 B* z! Dinvestigation. The primary care physician should be# Q4 A3 t5 H! e: c5 v, O0 s
aware of this fact, because most of these children6 d* K" N9 d8 M$ }7 x% \1 q
may initially present in their practice. The Physicians’
4 P" l. T, E' ?# d) G4 I; i$ _# oDesk Reference and package insert should also put a
8 p% d5 ]- X( i! ]! T" xwarning about the virilizing effect on a male or7 i; i3 V; ~3 r+ C
female child who might come in contact with some-
7 O7 o, x2 T4 g9 F; K7 B5 P3 oone using any of these products.
3 W5 r2 b4 e( }& E6 ~6 `' I LReferences0 i w) O5 v8 }% H, X" I. {* O/ E1 E$ ]
1. Styne DM. The testes: disorder of sexual differentiation- ]: b8 v8 o& H% w; x1 v( J
and puberty in the male. In: Sperling MA, ed. Pediatric: H7 C- v* Q8 Y- c# l% x
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;6 z* i2 k X. s5 I( c% c) c
2002: 565-628.
. i& ^* ]: X- s% l1 p( U" G% ^5 R% u2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious3 d/ l# j) c" w0 h) \$ b. r+ e
puberty in children with tumours of the suprasellar pineal |
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