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Sexual Precocity in a 16-Month-Old
" n! e$ b; s- D$ Q9 F) b5 UBoy Induced by Indirect Topical4 h+ H$ C) t: K4 \* K5 j
Exposure to Testosterone8 L8 Y O$ k3 {3 {& i/ f& W, S
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,26 l2 |8 O- h" E- H, q3 O2 u$ I# b
and Kenneth R. Rettig, MD1
0 S( H* P4 A* a. S! bClinical Pediatrics: R1 W' B# y0 H9 z
Volume 46 Number 6
; w( `) B V5 D/ ]July 2007 540-5435 p0 H' x9 M" l. @
© 2007 Sage Publications, @4 E) D0 }* P3 w) s& D, y
10.1177/0009922806296651
: q! v3 q3 R ^& n4 L8 O! b" a2 U' m+ Phttp://clp.sagepub.com
\, ?- G7 j6 p' thosted at- O: x, s. p1 G; t C4 z! u
http://online.sagepub.com
* r. d$ q# y+ _5 \% d9 P, ^Precocious puberty in boys, central or peripheral,
( F( m8 x6 Y3 Y) }0 C" |3 zis a significant concern for physicians. Central" u) r) |" M9 ]9 j9 F- v
precocious puberty (CPP), which is mediated
1 A9 e5 B3 a. t5 Y) v3 ?& ithrough the hypothalamic pituitary gonadal axis, has
& k5 G8 P. v, u' g, P0 p" n% Wa higher incidence of organic central nervous system
9 e t3 g. X2 d; ]lesions in boys.1,2 Virilization in boys, as manifested
0 ]7 S' _3 E+ q( Q1 h2 m r% vby enlargement of the penis, development of pubic
" s! D! Q9 Z, {5 R$ V7 g5 r7 Ehair, and facial acne without enlargement of testi-
- Y6 L8 e6 P% t# w) i$ V" C7 {cles, suggests peripheral or pseudopuberty.1-3 We
* W0 g; X7 N( U" N0 d$ qreport a 16-month-old boy who presented with the' a: ~; S7 b3 @
enlargement of the phallus and pubic hair develop-4 L9 v1 k3 p: R( `- U
ment without testicular enlargement, which was due4 j7 W6 H) X) Q# o. ]/ M2 C
to the unintentional exposure to androgen gel used by7 R* ?; X+ K; ?
the father. The family initially concealed this infor-
, ~4 Z" \9 r8 bmation, resulting in an extensive work-up for this
9 I3 R$ J: b- N- j% c uchild. Given the widespread and easy availability of
% @, \6 {) j- J o; \. A Q6 Wtestosterone gel and cream, we believe this is proba-
8 \8 P+ _4 p0 [& l( vbly more common than the rare case report in the
) g( a/ F1 P; k5 M) Y& |+ eliterature.4
( u( i+ ?2 t5 @& \% yPatient Report
( R0 u/ E6 B3 V8 ]$ _5 K. e6 IA 16-month-old white child was referred to the3 M' w( ^$ i% D
endocrine clinic by his pediatrician with the concern0 @" {; H% v& ~8 |$ S
of early sexual development. His mother noticed
& s3 k+ p$ D2 t) p7 }8 H: Blight colored pubic hair development when he was
# \7 n) W" k6 @$ @2 w) V" zFrom the 1Division of Pediatric Endocrinology, 2University of# z, q5 p0 R% u0 y
South Alabama Medical Center, Mobile, Alabama.
; t0 \1 h- s5 mAddress correspondence to: Samar K. Bhowmick, MD, FACE,
. d% S# U; x8 `+ @* V0 |Professor of Pediatrics, University of South Alabama, College of% C! B) o+ N7 |0 d1 r
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;# A1 z6 C% x* M
e-mail: [email protected].- _1 M! W; T9 u
about 6 to 7 months old, which progressively became3 [5 V' a& e1 T0 B
darker. She was also concerned about the enlarge-
7 c7 s1 N/ V% Lment of his penis and frequent erections. The child
( h2 M1 N" O, z4 l: Q! {was the product of a full-term normal delivery, with* Z/ U9 e: C6 M; o
a birth weight of 7 lb 14 oz, and birth length of
4 Y* f- v8 ? b7 o1 r20 inches. He was breast-fed throughout the first year
1 [& s1 D) w2 _/ q; kof life and was still receiving breast milk along with
+ z5 u+ h+ g) O6 v% ksolid food. He had no hospitalizations or surgery,
- h$ M' R5 e; l, E8 n6 _" Gand his psychosocial and psychomotor development
+ O$ V9 g" o8 d0 J8 \# c Zwas age appropriate.
! W, U/ X1 Y- k' J x5 k1 ]4 S5 f# ~The family history was remarkable for the father,6 C' I# r9 i/ X0 a7 [ P, l7 q
who was diagnosed with hypothyroidism at age 16,# x {3 s* U$ }/ r2 m
which was treated with thyroxine. The father’s
* [, A6 O3 r4 eheight was 6 feet, and he went through a somewhat! C p! E! q6 M$ q
early puberty and had stopped growing by age 14.
# j* }9 W; a. b& h4 CThe father denied taking any other medication. The
1 ?4 F' x. M- f! nchild’s mother was in good health. Her menarche/ a! g* I' w" g! D+ Q" J; z5 N4 `
was at 11 years of age, and her height was at 5 feet
/ c2 j' l1 [! g7 | v4 n7 _5 O5 inches. There was no other family history of pre-
# @# I+ X: ?' g% t. S& |' `6 I. p. Dcocious sexual development in the first-degree rela-* s, d' M* r$ D& J, {" R
tives. There were no siblings.- J! ^1 h3 M5 `: |' c
Physical Examination" g/ K7 V" `) _' y* U1 l
The physical examination revealed a very active,
- t& I' G! V4 W+ _. Vplayful, and healthy boy. The vital signs documented
) p* z2 t. U7 k$ Ca blood pressure of 85/50 mm Hg, his length was+ u! U! ?9 }0 u- \
90 cm (>97th percentile), and his weight was 14.4 kg
& P& q' |6 `/ z) N/ d(also >97th percentile). The observed yearly growth
" X& L4 f9 o# E) evelocity was 30 cm (12 inches). The examination of
& ~6 n. \6 E: P% Qthe neck revealed no thyroid enlargement.* d, ?9 Y/ b8 n( o* I
The genitourinary examination was remarkable for
3 Q9 s3 Q d% V, f% Lenlargement of the penis, with a stretched length of& B' U+ I. Q- Z/ F
8 cm and a width of 2 cm. The glans penis was very well
& _) E& a8 U) ddeveloped. The pubic hair was Tanner II, mostly around5 ?, v6 B. R/ E, S7 `+ I# [9 U+ ?
540+ P: W3 x c( X" ^( n- b1 U
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
6 d8 l+ e. v. mthe base of the phallus and was dark and curled. The3 m+ N' Z" L0 }$ r& e$ M
testicular volume was prepubertal at 2 mL each.: L$ f. S! A# t0 J& N
The skin was moist and smooth and somewhat
- T9 x+ }6 e. Q, H5 d" {oily. No axillary hair was noted. There were no: |" C) s" F1 c9 Z$ ]7 U, I
abnormal skin pigmentations or café-au-lait spots.% Z! P1 g) P! t% c% M
Neurologic evaluation showed deep tendon reflex 2+
0 t! f! d' i! K7 X) Ibilateral and symmetrical. There was no suggestion
6 O# X8 G, l* ?9 n" h. S1 R) Uof papilledema.& `8 h0 J4 u) N8 b
Laboratory Evaluation
4 V [; J& ?+ x9 mThe bone age was consistent with 28 months by
$ O$ R; x; s$ o4 d' r# T- Pusing the standard of Greulich and Pyle at a chrono-6 f! C3 C, c4 Q- T5 O- B
logic age of 16 months (advanced).5 Chromosomal- |7 b1 S6 _' h) a1 Y! m1 O% Q
karyotype was 46XY. The thyroid function test, L* E z& ~/ N- ^* P6 A& f& g
showed a free T4 of 1.69 ng/dL, and thyroid stimu-
) u5 I& d$ V% ^lating hormone level was 1.3 µIU/mL (both normal).4 H, r9 N. B0 s0 n. ~4 y9 }- ]
The concentrations of serum electrolytes, blood! i3 C& [+ L+ O2 z" m
urea nitrogen, creatinine, and calcium all were+ e$ l( n5 I# S
within normal range for his age. The concentration f" F l3 {* h7 e
of serum 17-hydroxyprogesterone was 16 ng/dL3 r# K- `* J! P0 }7 U) o# x
(normal, 3 to 90 ng/dL), androstenedione was 20
7 l/ M1 l- S" s* _# [5 x7 W' zng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-; ^$ U; C- N+ b. t ~
terone was 38 ng/dL (normal, 50 to 760 ng/dL),
; e) q) P) G7 N4 K+ odesoxycorticosterone was 4.3 ng/dL (normal, 7 to
+ C; z+ I& {$ F- x; k; ^5 S- L49ng/dL), 11-desoxycortisol (specific compound S)$ `! r- I) a/ @+ Y4 h, _
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-9 S: E- x$ j. o! V
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total9 R( d/ ~- p6 O" D2 Q7 B
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
, r0 ?$ u" O& |9 h5 S0 dand β-human chorionic gonadotropin was less than. Q! R9 G$ t7 I7 d! y/ F
5 mIU/mL (normal <5 mIU/mL). Serum follicular/ Q3 s4 s6 D* n+ O
stimulating hormone and leuteinizing hormone
4 o; G- A& D1 Qconcentrations were less than 0.05 mIU/mL
5 L# T0 f2 z6 X% I$ X/ `& }(prepubertal).
. A3 J) u1 [ EThe parents were notified about the laboratory
0 ?, y( i& }! k. Z; tresults and were informed that all of the tests were
9 c- J9 F4 H+ Znormal except the testosterone level was high. The
" g3 a/ S2 |5 yfollow-up visit was arranged within a few weeks to
0 k" Z5 P8 u# n; h/ `# yobtain testicular and abdominal sonograms; how-
$ B% V: T( i5 N! dever, the family did not return for 4 months.
: k) `( W- X4 t \4 BPhysical examination at this time revealed that the2 `/ D4 Q" ~- j8 D
child had grown 2.5 cm in 4 months and had gained, N5 t1 V% f; P% v
2 kg of weight. Physical examination remained
# V1 G8 U' H! T( H& c5 Iunchanged. Surprisingly, the pubic hair almost com-- o, p S9 H: K9 `
pletely disappeared except for a few vellous hairs at% H& b& \ U: y$ R
the base of the phallus. Testicular volume was still 2
# k( }! e1 R& L' z/ t! B) NmL, and the size of the penis remained unchanged.
, G1 p/ v1 l( q5 n& ]9 H3 w# q) mThe mother also said that the boy was no longer hav-
; z, ^. o* i1 H Bing frequent erections.
9 k$ f$ A! O* P' a3 X/ ]Both parents were again questioned about use of
! w0 m$ \5 k% p# T2 I# A% ?any ointment/creams that they may have applied to
; e0 P$ S" w7 x# t% Ithe child’s skin. This time the father admitted the) l/ c. I( S7 Y( \3 M4 v
Topical Testosterone Exposure / Bhowmick et al 541+ I$ i% F0 E% ~% o6 P; f' R
use of testosterone gel twice daily that he was apply-' a: t: S2 @# h# ?
ing over his own shoulders, chest, and back area for* M) [5 I" Z7 b# I/ A" s
a year. The father also revealed he was embarrassed
, |: r! B9 i3 x, U3 eto disclose that he was using a testosterone gel pre-# n" d N. Q* { \
scribed by his family physician for decreased libido% U( z4 B- q9 b1 n% v
secondary to depression.% K0 N3 o/ O$ ~% a1 L8 k
The child slept in the same bed with parents.
7 Y( W4 z# z& Y& e, M4 GThe father would hug the baby and hold him on his, R- n9 h- i/ Y7 H; j+ N
chest for a considerable period of time, causing sig-4 B5 Z2 h9 g" d! N
nificant bare skin contact between baby and father." M( ?: T/ t' {/ i
The father also admitted that after the phone call,# `/ ~, _! y! U4 p% V
when he learned the testosterone level in the baby% \ u% v' Z0 t5 v' x3 v* B! J4 w
was high, he then read the product information
: t# `0 K4 D! L( p; H( g3 bpacket and concluded that it was most likely the rea-/ a( c( L" ?5 O5 l" o
son for the child’s virilization. At that time, they) }8 V1 U; y- i+ o( q' |
decided to put the baby in a separate bed, and the
6 x6 r" Z8 k8 F$ y! x/ ffather was not hugging him with bare skin and had5 Q; c/ X7 z( L0 f2 j$ R
been using protective clothing. A repeat testosterone) Z. d/ t4 D( X0 \, r5 G- n
test was ordered, but the family did not go to the+ L7 D* q2 K. j6 h9 _2 O2 \
laboratory to obtain the test.. Q. O4 S$ K# r0 k% z4 e
Discussion6 R7 I, W& c7 ^6 I! H2 L8 n2 V) F+ L
Precocious puberty in boys is defined as secondary5 I' t/ h1 T/ E& W1 }6 A' Y3 P G _
sexual development before 9 years of age.1,4
9 [( [* C& S- G5 ?0 h9 kPrecocious puberty is termed as central (true) when. S9 l4 w9 W$ m, Q
it is caused by the premature activation of hypo-2 \9 m+ }1 S( T+ }1 |9 D7 C
thalamic pituitary gonadal axis. CPP is more com-
" p& {2 H( a$ W' @2 y- ~5 J6 f! dmon in girls than in boys.1,3 Most boys with CPP
! V0 x& c2 u- g; \may have a central nervous system lesion that is; x3 j$ f; a R4 k
responsible for the early activation of the hypothal-% `7 s5 q! Q4 k2 S% b Z
amic pituitary gonadal axis.1-3 Thus, greater empha-
# J x7 n: i/ \" H; p+ p0 t2 ysis has been given to neuroradiologic imaging in& D6 {9 R1 X; ?7 h% f7 k2 u
boys with precocious puberty. In addition to viril-; i* u- ], j$ R d
ization, the clinical hallmark of CPP is the symmet-( u7 l2 i6 U4 a D/ q7 G- W
rical testicular growth secondary to stimulation by
5 l% i$ T; f1 V2 R8 k& V: ggonadotropins.1,3
7 h9 ]) o- \3 G. cGonadotropin-independent peripheral preco-2 R: L- h' V. m) q4 F0 k
cious puberty in boys also results from inappropriate7 E1 b8 L0 V- ?: |& Q
androgenic stimulation from either endogenous or
( O) w1 `% h2 Z7 Yexogenous sources, nonpituitary gonadotropin stim-
4 @) P+ w5 ^0 T6 I' Yulation, and rare activating mutations.3 Virilizing! E# j2 n* {$ Q8 E& k- c, @
congenital adrenal hyperplasia producing excessive( H# Y6 s8 e, `
adrenal androgens is a common cause of precocious
$ H/ G+ o$ P0 G t5 Rpuberty in boys.3,4
0 c- \8 M1 F0 M# h1 cThe most common form of congenital adrenal- p' }8 p6 a0 s/ d7 O6 o1 _$ p( h3 c
hyperplasia is the 21-hydroxylase enzyme deficiency. p; G7 u% {2 a3 w; R
The 11-β hydroxylase deficiency may also result in- h/ s: Y/ q2 z- j: u. \2 D5 O* E7 Q
excessive adrenal androgen production, and rarely,
& T y7 y7 d* D8 z3 t+ v3 `5 M# X1 Ean adrenal tumor may also cause adrenal androgen! W+ v# T; y& L) ?; l
excess.1,36 T0 G- r4 w7 [/ ]3 w8 |" p' x, d& j) |: {
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
: G7 m/ @5 \* w542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
/ x2 e7 U5 n2 n7 x4 `A unique entity of male-limited gonadotropin-
) o- T% W! c% Sindependent precocious puberty, which is also known
5 Z% F) }: y4 Yas testotoxicosis, may cause precocious puberty at a
* U/ o6 ^" N) |- J( _4 e" Hvery young age. The physical findings in these boys+ D$ E1 k* Q7 ^
with this disorder are full pubertal development,# m: [. R. [3 c6 z" j0 b3 S
including bilateral testicular growth, similar to boys+ k: k+ ]4 a9 D8 z5 X- s: W
with CPP. The gonadotropin levels in this disorder+ m9 K+ l# @% F o* a9 B& s
are suppressed to prepubertal levels and do not show8 w7 r' O# i! O4 {' z/ f3 S
pubertal response of gonadotropin after gonadotropin-
, T8 _4 V! p8 u# r$ _releasing hormone stimulation. This is a sex-linked( ]" i* G. W$ a1 @' y* l
autosomal dominant disorder that affects only
" @, Q+ s: L& a' h+ o+ ]males; therefore, other male members of the family. T6 r' M" V, @/ P
may have similar precocious puberty.3
t; b: n2 z3 J2 `+ {In our patient, physical examination was incon-
: ^0 e( c2 H% Psistent with true precocious puberty since his testi-( s/ S; ^1 I. Y8 W
cles were prepubertal in size. However, testotoxicosis
{) ?! w* G4 w- }was in the differential diagnosis because his father J: F1 P. J/ v( b7 p5 }
started puberty somewhat early, and occasionally,' q+ {# b& y6 W v
testicular enlargement is not that evident in the0 e/ p0 c0 Q* [/ `8 F
beginning of this process.1 In the absence of a neg-# n$ v5 Z' y8 d3 o2 K( F
ative initial history of androgen exposure, our
* g$ }4 m9 x2 b- D/ q; Bbiggest concern was virilizing adrenal hyperplasia,/ ^$ D) m1 B' J" ?1 j. ^9 H
either 21-hydroxylase deficiency or 11-β hydroxylase; W4 `5 v3 n9 A# f x" H
deficiency. Those diagnoses were excluded by find-9 j8 r# z# v/ Q+ K* {
ing the normal level of adrenal steroids.% n0 m7 @% F, x* }; m
The diagnosis of exogenous androgens was strongly% A- w2 J/ Y' o9 w( Z9 p
suspected in a follow-up visit after 4 months because6 |( i+ _# _4 a+ }3 M
the physical examination revealed the complete disap-" R- u4 [( o+ a |) w8 L
pearance of pubic hair, normal growth velocity, and
" o! N# h# Z$ S& D$ udecreased erections. The father admitted using a testos-. Y5 `' b* J/ t0 s* n: Y
terone gel, which he concealed at first visit. He was6 j, j, M+ r4 Z. M( ~# E
using it rather frequently, twice a day. The Physicians’
1 W4 q: T3 S2 D0 XDesk Reference, or package insert of this product, gel or
9 |, X$ V9 R! J# y9 E& H- ocream, cautions about dermal testosterone transfer to N. e- B- f& n9 e G
unprotected females through direct skin exposure.
8 O1 ^7 u, P8 k- uSerum testosterone level was found to be 2 times the6 h" u$ ]1 S9 g( p
baseline value in those females who were exposed to
4 g7 w- P1 r! @: I' xeven 15 minutes of direct skin contact with their male$ E t; G/ Z+ Z
partners.6 However, when a shirt covered the applica-
0 ?& v* X7 Y- `: C5 ^9 Rtion site, this testosterone transfer was prevented.( d0 U" G5 G; M
Our patient’s testosterone level was 60 ng/mL,
) X# x. J* n# F% V& cwhich was clearly high. Some studies suggest that; r6 p# z$ g% r+ @9 B9 H A5 Z8 m3 E
dermal conversion of testosterone to dihydrotestos-
/ d2 `4 b4 [$ t3 u3 G3 qterone, which is a more potent metabolite, is more! |" c! W2 R" L" ?5 d' n
active in young children exposed to testosterone
) s& J4 N: _9 wexogenously7; however, we did not measure a dihy-
5 Y9 p8 Y3 i5 `4 gdrotestosterone level in our patient. In addition to% P- q: h$ [$ q3 G
virilization, exposure to exogenous testosterone in
& S; t& P8 X( A$ H! ?children results in an increase in growth velocity and
: J2 I1 f L- U/ b# C4 radvanced bone age, as seen in our patient.
, B. U8 n0 [& k6 C0 f d& lThe long-term effect of androgen exposure during
9 t: G S8 W: pearly childhood on pubertal development and final
" q. j6 W: F1 I/ u& q; ~& _: B6 u! Wadult height are not fully known and always remain0 `0 Y" f, ]( s3 g
a concern. Children treated with short-term testos-% R; e' Y5 v9 G" R# B
terone injection or topical androgen may exhibit some
0 P2 m h8 B# e6 L. W; ^acceleration of the skeletal maturation; however, after1 t9 `- U; b+ S
cessation of treatment, the rate of bone maturation
+ w0 M8 H$ S1 v& Z1 h2 x3 Bdecelerates and gradually returns to normal.8,9
. M B8 b7 ~" X% E V/ I# tThere are conflicting reports and controversy
: f* k' z" }5 C- Y" I: _) W- _over the effect of early androgen exposure on adult
* J B, }2 c. c2 ?6 m! Z4 fpenile length.10,11 Some reports suggest subnormal$ f) E3 H- h/ ~0 i# c# Q- k l
adult penile length, apparently because of downreg-
9 e0 C5 i! n# u6 x" y6 bulation of androgen receptor number.10,12 However,
; o0 |8 ?: K, T2 gSutherland et al13 did not find a correlation between' T" X% D9 ~ h
childhood testosterone exposure and reduced adult
. R, p( |; ] K: t! Qpenile length in clinical studies.8 ]7 C; z- c3 V6 r
Nonetheless, we do not believe our patient is# p. p8 B) ^% B( c# r9 u
going to experience any of the untoward effects from9 X. W! f4 Q, `( h
testosterone exposure as mentioned earlier because" A8 h, V. i+ ~+ {
the exposure was not for a prolonged period of time.
/ Y+ i# Q/ g6 U% Z) P( n9 }Although the bone age was advanced at the time of5 S, l$ {# f; ^ }& [# }7 {/ V- u- @" E
diagnosis, the child had a normal growth velocity at' h! r R7 J7 O& B
the follow-up visit. It is hoped that his final adult
( b, U0 y5 S" z% `$ r, Aheight will not be affected.
, I0 q" g+ R/ N* [Although rarely reported, the widespread avail-
# w2 \5 ~& {) j6 u) @" kability of androgen products in our society may
" G# ?' N: a2 W' p3 `, Hindeed cause more virilization in male or female
; Q) |, Z. R1 H" {$ U6 C6 n- lchildren than one would realize. Exposure to andro-
# D/ L7 `3 B: E& ~: Sgen products must be considered and specific ques- ]) e3 @! d6 T* z
tioning about the use of a testosterone product or
! k' m# R2 C$ y9 ]% Hgel should be asked of the family members during
! K8 V- T" W/ ~the evaluation of any children who present with vir-/ s+ w; i3 y4 C. i% E0 E9 r* L7 a# K
ilization or peripheral precocious puberty. The diag-
2 E9 [0 D. R. i' C$ G9 Bnosis can be established by just a few tests and by
\% K+ W# n+ ]/ r/ Yappropriate history. The inability to obtain such a6 V) j4 ^. U7 _, p
history, or failure to ask the specific questions, may; ^- Y) F2 [2 n1 f: h5 m' z. L
result in extensive, unnecessary, and expensive: K9 l- D) J/ O, _ T
investigation. The primary care physician should be
( F% o1 E7 R) C6 {3 Z3 M* L9 eaware of this fact, because most of these children
6 r: }" N& o4 p8 P+ |may initially present in their practice. The Physicians’
: X9 ^: o' _0 gDesk Reference and package insert should also put a/ C5 m2 @3 X/ a/ S/ [
warning about the virilizing effect on a male or
# v8 X, C& J/ n2 o# t+ d4 `2 L" E3 lfemale child who might come in contact with some-
: ^' d: Z" x: @- {% V. K8 M+ tone using any of these products.
: ]: N; x' U9 c; W2 [: h6 ~0 A: CReferences
2 n4 Z1 R" S+ e5 A F" W b% y& I1. Styne DM. The testes: disorder of sexual differentiation$ @8 J) E0 K, ?; z( i; H
and puberty in the male. In: Sperling MA, ed. Pediatric0 p- r- p% J! q5 n
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;$ c5 A+ B, i- r3 K0 P1 j# F
2002: 565-628., T) @ ^9 K' q3 W% I" K5 {/ g* W
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
* U( J1 Z' P. [1 X0 P( s4 gpuberty in children with tumours of the suprasellar pineal |
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