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Sexual Precocity in a 16-Month-Old; Q8 E% y( J% @0 Z) t+ p
Boy Induced by Indirect Topical
4 M( r( D6 r9 X' N+ KExposure to Testosterone9 C- h7 E% }, ]3 U' }! Y" X; U
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
! i# i. i" k5 Tand Kenneth R. Rettig, MD1 ~0 F) m' P4 @7 N! @$ V# r/ a
Clinical Pediatrics2 ~( M- q+ {( T* ?3 M
Volume 46 Number 68 ?: Y7 a6 d# n: L" `6 R! s
July 2007 540-543
2 i+ l6 l& l7 t# J+ _ O" e# T© 2007 Sage Publications, H' ]! G; b9 x5 e# E' d: d
10.1177/00099228062966514 N% |1 u4 X& c% [
http://clp.sagepub.com
8 p1 ~/ C- W7 k9 p3 W) l3 K6 Zhosted at
- r# a( }: J- c$ ~http://online.sagepub.com& U H5 y& O. g1 i7 F' m( x) X
Precocious puberty in boys, central or peripheral, P: Z( ^3 A, C, q, m
is a significant concern for physicians. Central
& l3 X9 S$ @4 ?6 z% F; p7 vprecocious puberty (CPP), which is mediated
& U8 |* }! z7 y. m" \3 Y% r7 Ethrough the hypothalamic pituitary gonadal axis, has
, i' F9 Y& B9 p( F, S ?a higher incidence of organic central nervous system
- i) L" Y& o" o k. `- F, z0 nlesions in boys.1,2 Virilization in boys, as manifested
: Y( i4 B3 B* ]. e5 Nby enlargement of the penis, development of pubic
5 p# R7 N9 b( yhair, and facial acne without enlargement of testi-
' E0 O1 `8 J8 T7 V. |0 kcles, suggests peripheral or pseudopuberty.1-3 We
+ A- h* c- T+ x4 c+ Zreport a 16-month-old boy who presented with the
+ w" X S* l0 J1 l# henlargement of the phallus and pubic hair develop-
0 ~$ m/ G$ r dment without testicular enlargement, which was due
8 M0 ]( @# ]+ n- j* oto the unintentional exposure to androgen gel used by
! J7 \( c8 q# k' R$ b# c. nthe father. The family initially concealed this infor-7 ^7 ~) g4 b5 w
mation, resulting in an extensive work-up for this# O) r! w! Q9 @* Q. k- `. G2 } a o
child. Given the widespread and easy availability of
' _& C' r4 l' {testosterone gel and cream, we believe this is proba-
2 _4 @5 D9 v7 E/ D- l" l& y% Bbly more common than the rare case report in the
( H/ t0 Z, p7 g4 L& J" |5 ?literature.4% w7 |8 [0 b: B' R
Patient Report
, H3 v/ E M4 Z& R6 dA 16-month-old white child was referred to the! _' X& _) ]; [
endocrine clinic by his pediatrician with the concern7 J7 ~ L8 j0 i/ [
of early sexual development. His mother noticed
Z, t2 Y: O T% F: {' Tlight colored pubic hair development when he was- S( U' Z2 g# @
From the 1Division of Pediatric Endocrinology, 2University of
( p- q0 ^$ J& b9 kSouth Alabama Medical Center, Mobile, Alabama.$ S" U0 M3 j0 ^$ t$ r6 v
Address correspondence to: Samar K. Bhowmick, MD, FACE,) }0 h& y& t- ^5 z
Professor of Pediatrics, University of South Alabama, College of% h5 f7 `0 q+ H. {
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
! Z5 F8 n; C! w% J. Be-mail: [email protected]., Y7 t& t" ?* u9 f% {
about 6 to 7 months old, which progressively became) i. H+ T# N; b, c
darker. She was also concerned about the enlarge-
9 p" L2 ~- t# \( v9 Q: x! b* Dment of his penis and frequent erections. The child ?. J. A9 [0 `/ H+ L2 [/ K* l
was the product of a full-term normal delivery, with
. d# x* p5 |- K* }% A1 L" [a birth weight of 7 lb 14 oz, and birth length of
+ M& ]3 Z1 b, l' Y1 K( D7 P20 inches. He was breast-fed throughout the first year1 q, P' I% M- V! ^) S1 E" d
of life and was still receiving breast milk along with. h! j" l& h/ P" f; M
solid food. He had no hospitalizations or surgery,
' m! K0 L8 o7 s1 @- S. K( aand his psychosocial and psychomotor development# a/ O' o9 J) ?
was age appropriate.) C3 m# o6 h6 P! g0 F
The family history was remarkable for the father,
# y+ G$ R4 J9 z/ mwho was diagnosed with hypothyroidism at age 16,
7 A' B! G9 o$ ~9 Nwhich was treated with thyroxine. The father’s
7 [, Y% X" b/ ~0 a* A" ^height was 6 feet, and he went through a somewhat3 O7 E. M6 b' E+ R
early puberty and had stopped growing by age 14.; T9 T, r$ j' e A+ E0 g( n `
The father denied taking any other medication. The4 ?, {. I4 `; u# x* K D
child’s mother was in good health. Her menarche
% h0 s' @/ S9 L/ j' Y; H7 r& qwas at 11 years of age, and her height was at 5 feet- o1 X; t' P. E3 a/ ]- `) G; V
5 inches. There was no other family history of pre-
8 `. R4 i% H: x2 mcocious sexual development in the first-degree rela-
8 n5 B( Q' Y, ^& k( M* b1 V0 _tives. There were no siblings.. L/ O9 a! e) b" k# S
Physical Examination
( x/ q. u5 |4 N+ BThe physical examination revealed a very active,# P( d; |) K+ B- p. Y+ S8 x
playful, and healthy boy. The vital signs documented
- h7 ~% s3 J; X& ?& ea blood pressure of 85/50 mm Hg, his length was
: w1 J' X0 h4 B; x90 cm (>97th percentile), and his weight was 14.4 kg8 @* c2 B4 U6 v/ A8 @) B
(also >97th percentile). The observed yearly growth
6 f a8 H! }" x7 i# svelocity was 30 cm (12 inches). The examination of3 s7 t/ v' R q' |! H
the neck revealed no thyroid enlargement.
3 ^( Q# ~2 S/ [8 ~) B, wThe genitourinary examination was remarkable for7 e3 m/ S5 U9 k2 Y; [$ A P R: F
enlargement of the penis, with a stretched length of9 q: \# Z) v, T$ [( L N
8 cm and a width of 2 cm. The glans penis was very well! U( O7 H" i0 N7 b6 K5 e
developed. The pubic hair was Tanner II, mostly around! U. k5 [+ t" q C% O3 M
540
6 ?, z5 r, a. ] n/ kat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
9 M8 X/ A0 n- d; l0 W1 S! Wthe base of the phallus and was dark and curled. The
% g1 v% n" S/ O2 @testicular volume was prepubertal at 2 mL each.8 u' f) T6 ~$ D% A! W9 H: }* Z
The skin was moist and smooth and somewhat
% x4 Y i: v* g* ], C; s; x# Eoily. No axillary hair was noted. There were no
' s1 l3 Q& B$ mabnormal skin pigmentations or café-au-lait spots.
. M8 o) k/ l) z' ^3 Z- gNeurologic evaluation showed deep tendon reflex 2+
9 ?0 @9 g9 C7 ~' t9 {: bbilateral and symmetrical. There was no suggestion
- ]/ V" X7 B$ v+ \5 Wof papilledema.
3 L% R9 q; ]% ]0 P5 O' oLaboratory Evaluation4 t0 l6 K* @, t& r! X) r
The bone age was consistent with 28 months by' C! O: s7 m( F O
using the standard of Greulich and Pyle at a chrono-
1 y8 v' i: O1 I" {9 n3 Ilogic age of 16 months (advanced).5 Chromosomal+ \5 n0 Z, u$ d5 S
karyotype was 46XY. The thyroid function test7 Y2 K$ g. V! y4 u8 G4 Q
showed a free T4 of 1.69 ng/dL, and thyroid stimu-7 N1 b5 o/ ?! \
lating hormone level was 1.3 µIU/mL (both normal).6 x. M# ^+ e. G5 C
The concentrations of serum electrolytes, blood1 k5 o7 u$ }9 q- l/ o% \3 f
urea nitrogen, creatinine, and calcium all were) Y" h9 r) @0 y; Z& L' @
within normal range for his age. The concentration
( }( h, l2 l- x8 f5 H4 gof serum 17-hydroxyprogesterone was 16 ng/dL
5 g6 ^$ u' H) C5 L, G$ \. {(normal, 3 to 90 ng/dL), androstenedione was 20: L3 E9 W; S. ] o
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
* U% G' |6 V4 |4 |terone was 38 ng/dL (normal, 50 to 760 ng/dL),
" H# S. E$ D4 c/ r) r4 @desoxycorticosterone was 4.3 ng/dL (normal, 7 to
- ], w& o/ z0 o {! O% R49ng/dL), 11-desoxycortisol (specific compound S)
1 X3 \; R# x$ t3 Y8 vwas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
& R' N, ~, e( R1 Ytisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
+ S$ j4 ~; \6 s( Z, c" Itestosterone was 60 ng/dL (normal <3 to 10 ng/dL),
* E& _; H+ \! {& ^& W2 D/ wand β-human chorionic gonadotropin was less than: x; j& p5 |1 P j
5 mIU/mL (normal <5 mIU/mL). Serum follicular
: f/ K, u/ U, W0 @' @3 | @( Qstimulating hormone and leuteinizing hormone
* M7 \7 h; G$ S. g4 w& o. B$ R' V iconcentrations were less than 0.05 mIU/mL
2 n9 _* y; `4 N(prepubertal).
4 B7 H+ z* w9 E4 qThe parents were notified about the laboratory
; h6 v6 m: u1 G) R- {9 nresults and were informed that all of the tests were! H/ j5 g0 ^( c: Q6 |$ u6 N3 v6 {
normal except the testosterone level was high. The
' N/ p" \; m6 Y4 Sfollow-up visit was arranged within a few weeks to
$ G S2 x1 J% P$ oobtain testicular and abdominal sonograms; how-* d; Z9 m8 p) Z4 A9 t5 Q: U
ever, the family did not return for 4 months.
: w0 \! Y' ^9 h7 I* \- B% t- wPhysical examination at this time revealed that the
+ q; j/ W6 N; Zchild had grown 2.5 cm in 4 months and had gained: z5 n+ D4 o4 K
2 kg of weight. Physical examination remained4 c. j3 a6 A' M& @
unchanged. Surprisingly, the pubic hair almost com-; K5 R [; O* x Y B: r8 J+ r
pletely disappeared except for a few vellous hairs at
: r C6 v+ W: Uthe base of the phallus. Testicular volume was still 2- E# N; U9 ^, l d* p
mL, and the size of the penis remained unchanged.5 C3 q8 a1 w6 h4 o. M6 f( J
The mother also said that the boy was no longer hav-2 `& J) ?9 s' k9 m7 Q
ing frequent erections.
* r1 j4 o; d' b/ D+ aBoth parents were again questioned about use of4 r% E2 E. Y+ B6 R
any ointment/creams that they may have applied to
) C% W, {" \' _9 M3 T& ` Z7 g- ]the child’s skin. This time the father admitted the
+ [" D3 ~9 v: R) J: u7 |Topical Testosterone Exposure / Bhowmick et al 541) g' D' c" V& s- C( y& }
use of testosterone gel twice daily that he was apply-
. a+ `1 [# i$ V) ping over his own shoulders, chest, and back area for
5 ~8 |! C4 ^+ I! fa year. The father also revealed he was embarrassed
: k% C1 r& _, |* P ito disclose that he was using a testosterone gel pre-2 B- @/ c. t r9 d y4 R4 f
scribed by his family physician for decreased libido2 S8 x2 {3 }& a* ^0 A# o. \7 T
secondary to depression. A7 S' Z+ X% r* U8 m) M) e
The child slept in the same bed with parents.+ P: F# W, u) n% F* R: _0 S; I. r
The father would hug the baby and hold him on his
: m; s4 a+ ?+ o' wchest for a considerable period of time, causing sig-
1 U' l# @( E* P6 u" e* ~nificant bare skin contact between baby and father.
7 X! ?4 _8 o3 h* l. \; uThe father also admitted that after the phone call,$ {* i i$ v% K9 c' i9 T
when he learned the testosterone level in the baby
& U0 X) |! H# X, t/ lwas high, he then read the product information' j0 G% t+ `8 @& ]+ r4 i
packet and concluded that it was most likely the rea-# X; k! E1 L! p! u) M n
son for the child’s virilization. At that time, they0 e. [9 g; x- j
decided to put the baby in a separate bed, and the/ b$ D6 s9 A% h4 Y R" i b
father was not hugging him with bare skin and had) u0 n/ w/ j, O7 y
been using protective clothing. A repeat testosterone7 A2 T+ v% ]6 G0 b9 a4 f% }
test was ordered, but the family did not go to the L1 Y" I9 z5 g3 B3 D6 g
laboratory to obtain the test.
+ H. x$ X+ ]9 L' J+ m" }Discussion
# u* _0 e( M. `+ a6 q- sPrecocious puberty in boys is defined as secondary
6 ?, N0 I1 z7 G- P# Csexual development before 9 years of age.1,4/ k( q9 _, ~9 H# P% Z1 u
Precocious puberty is termed as central (true) when0 @4 w) ?6 M& Y5 n( b1 L
it is caused by the premature activation of hypo-/ L8 R/ I2 y% S" _
thalamic pituitary gonadal axis. CPP is more com-- z# ]. ~0 x) S5 x
mon in girls than in boys.1,3 Most boys with CPP, N5 y+ O$ t. V2 L7 p" S& k' j
may have a central nervous system lesion that is
- x$ S$ `3 z% h" l( R: o- n, kresponsible for the early activation of the hypothal-- f6 v$ N( m P1 Y: i; {
amic pituitary gonadal axis.1-3 Thus, greater empha-
* Z7 m0 ?' [2 D% W/ Tsis has been given to neuroradiologic imaging in
& c% \' ]% e8 b5 J( T& w5 Iboys with precocious puberty. In addition to viril-
# Z" h: ^. f R" R1 [+ e3 qization, the clinical hallmark of CPP is the symmet-1 W8 v( r+ n) j3 d2 K r7 f+ m
rical testicular growth secondary to stimulation by5 F$ A. O. R! B. C
gonadotropins.1,31 e+ }; U% B) j- V/ P) ~
Gonadotropin-independent peripheral preco-
8 D8 x$ V* q o! Y8 ]7 q3 Mcious puberty in boys also results from inappropriate- k( a) ~( H9 @ V" l9 ~
androgenic stimulation from either endogenous or
& r& k p9 M6 f3 r! a5 A! jexogenous sources, nonpituitary gonadotropin stim-
! z8 R7 r: m$ S1 y" b' \ulation, and rare activating mutations.3 Virilizing4 l8 T: ]9 j0 o" B4 U
congenital adrenal hyperplasia producing excessive
/ O* I5 C" N5 r3 h3 a( {adrenal androgens is a common cause of precocious/ ~4 [, I; _' @2 d
puberty in boys.3,4' H$ q' Z0 P6 I
The most common form of congenital adrenal0 X6 @& V$ }6 i* e4 ]
hyperplasia is the 21-hydroxylase enzyme deficiency.
7 d- L4 D8 e1 D$ g7 p3 N+ ]The 11-β hydroxylase deficiency may also result in
$ n+ W9 b S6 C9 s( F) wexcessive adrenal androgen production, and rarely,
; k7 x0 t, f2 W+ Q3 Han adrenal tumor may also cause adrenal androgen* l# g: c, g& D; k ]: }
excess.1,3! ~0 p9 d3 O- ]; P U9 d* s: m& N) B
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from" v& E* b- Z6 C& G7 V' X
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
/ `& v7 N( Z* R' x, nA unique entity of male-limited gonadotropin-
$ d2 a" \6 l9 P4 Y: L1 _' a$ t3 {% |independent precocious puberty, which is also known7 C+ I* a, _- _) A, z" l
as testotoxicosis, may cause precocious puberty at a9 M* Q/ F# ~+ g. v: B+ l, Q
very young age. The physical findings in these boys
3 @+ q4 z( i( Bwith this disorder are full pubertal development," B, l0 w$ f4 p; j, W4 |- S( j
including bilateral testicular growth, similar to boys
) u- E9 s) E1 Q4 Mwith CPP. The gonadotropin levels in this disorder
% y c# _: a2 u4 Q( N7 Sare suppressed to prepubertal levels and do not show% ~3 ]2 g& _' |0 g7 O6 F
pubertal response of gonadotropin after gonadotropin-
+ \2 r& G' U. K) B5 h: preleasing hormone stimulation. This is a sex-linked
s' m% E7 f& c dautosomal dominant disorder that affects only! h) ^( A4 k' b4 s2 y
males; therefore, other male members of the family3 [2 i# {0 j2 g; x7 C: D
may have similar precocious puberty.3! ?0 x2 {+ ? }# `# s, Z
In our patient, physical examination was incon-
" @0 _# F; Z- }5 b0 s- H* bsistent with true precocious puberty since his testi-0 L+ v" e5 f z& s! S& P
cles were prepubertal in size. However, testotoxicosis
* n- B0 s# H4 N# s3 ?was in the differential diagnosis because his father c/ I. A* d- [1 A! M/ |, W8 Z
started puberty somewhat early, and occasionally,7 ]/ p: H7 p' v& l% H. Y
testicular enlargement is not that evident in the
& ` P, x) B' f. S( }% q& Rbeginning of this process.1 In the absence of a neg-
3 g$ Y( _/ g4 Hative initial history of androgen exposure, our
" m3 ] l5 m L4 {( m+ Sbiggest concern was virilizing adrenal hyperplasia,/ X% s& R+ l" q, l% |' |. a) V
either 21-hydroxylase deficiency or 11-β hydroxylase8 p `. S3 e l
deficiency. Those diagnoses were excluded by find-! q, V- w5 I3 H F- W; R+ \
ing the normal level of adrenal steroids.( K ?$ w, L9 Z, H7 P. q
The diagnosis of exogenous androgens was strongly
# L) H: ^6 T' {+ dsuspected in a follow-up visit after 4 months because
! N( z( S7 r9 L5 F4 z5 ~# rthe physical examination revealed the complete disap-
% a' T3 h' q' qpearance of pubic hair, normal growth velocity, and
. v; y5 t5 Z- j* Jdecreased erections. The father admitted using a testos-
0 I# n! m6 S& ^( G' u4 U1 \1 Z ~terone gel, which he concealed at first visit. He was
7 D# B" y$ m6 B9 Z3 }$ Gusing it rather frequently, twice a day. The Physicians’ U9 m0 U# ~# W6 _# L
Desk Reference, or package insert of this product, gel or5 o: y8 }5 v z0 a$ F
cream, cautions about dermal testosterone transfer to
0 r/ Z3 u* v, _& gunprotected females through direct skin exposure.& L% S T; e! P: p5 w8 e8 J
Serum testosterone level was found to be 2 times the
0 U1 @8 Y' k* c2 {, s# e6 m; U8 J: Vbaseline value in those females who were exposed to: K! a; W8 [9 R' _
even 15 minutes of direct skin contact with their male. n' w# t3 M! K5 x* X
partners.6 However, when a shirt covered the applica- g( t: ]; m: M, X% y- S- e* G
tion site, this testosterone transfer was prevented.
" _$ i! [+ l5 X5 s" e1 l J6 e$ ^Our patient’s testosterone level was 60 ng/mL,2 G+ r E8 f1 _) j9 E6 P: _. u
which was clearly high. Some studies suggest that( C5 E. Z- J# {& i6 h
dermal conversion of testosterone to dihydrotestos-4 Z( @- ~6 v9 R5 r
terone, which is a more potent metabolite, is more6 Q4 ?0 E3 K# I9 `2 ^
active in young children exposed to testosterone. B! I0 ]% d! c0 K% @# i; S
exogenously7; however, we did not measure a dihy-5 V" X( c& B7 `( d
drotestosterone level in our patient. In addition to
8 S- b+ y; C- uvirilization, exposure to exogenous testosterone in' f* @1 K7 e0 n" e4 J2 K& P: y
children results in an increase in growth velocity and
7 w" Q4 o8 @" D' v" j& l, gadvanced bone age, as seen in our patient." Y( H* s& E: G+ j0 _
The long-term effect of androgen exposure during
6 v! c4 u2 F: b* l9 t! hearly childhood on pubertal development and final
# D4 @/ U2 _0 H8 [& U D! @adult height are not fully known and always remain
& l3 ]) v4 O' A8 p5 _5 y6 ma concern. Children treated with short-term testos-9 S1 x7 Q+ h1 U x* B' R
terone injection or topical androgen may exhibit some
$ x( s( A+ c3 N# d, t. K0 Cacceleration of the skeletal maturation; however, after; P& R3 i: f( ~, ?" A6 I
cessation of treatment, the rate of bone maturation) F$ o0 S8 O4 e' R t' p& z
decelerates and gradually returns to normal.8,90 ]+ Y& ?0 Q3 D" p7 M7 ]7 I
There are conflicting reports and controversy
) ~% Z- t& u8 w8 N$ wover the effect of early androgen exposure on adult1 C7 d+ f- v" C' D% b7 u& K
penile length.10,11 Some reports suggest subnormal; B8 w/ x& z6 F: B( K' s* J
adult penile length, apparently because of downreg-
* A/ i4 Z/ k; x/ `0 P7 w4 J nulation of androgen receptor number.10,12 However,' J1 R5 Q O' i5 G$ J6 b
Sutherland et al13 did not find a correlation between X K8 r, U2 Y: f' w! C
childhood testosterone exposure and reduced adult
/ B' L6 E* l$ f, R" {) Ypenile length in clinical studies.! U* K, t5 O2 e, c1 Q( ^* C1 G
Nonetheless, we do not believe our patient is1 A) D0 j; `0 N# t4 Z: [' F
going to experience any of the untoward effects from" ^8 L7 k, p" q4 a/ K
testosterone exposure as mentioned earlier because
2 w& {& \, J% i! c! Vthe exposure was not for a prolonged period of time.% b0 g0 l. j8 |- ~
Although the bone age was advanced at the time of3 r6 u* S3 i9 K% V$ G+ w
diagnosis, the child had a normal growth velocity at
6 |/ q+ c. ^: Q4 o, H7 Athe follow-up visit. It is hoped that his final adult
- z; O0 K- p2 A( U' @+ zheight will not be affected.
' p* u* o" A: [; N/ a6 [' fAlthough rarely reported, the widespread avail-0 F& O4 n$ |9 K
ability of androgen products in our society may
: ~) Y/ j9 D5 T; F$ k4 ^indeed cause more virilization in male or female
: k+ t8 l- ]( P/ q# B" [children than one would realize. Exposure to andro-+ b9 n/ Q% o) R5 g, J
gen products must be considered and specific ques-9 u$ n4 y3 s0 ?( v4 Z( B
tioning about the use of a testosterone product or0 o8 `" q% R& _5 @( N
gel should be asked of the family members during
% c7 ^ w# C$ g9 Vthe evaluation of any children who present with vir-. M1 q6 r, ?7 w% |9 E
ilization or peripheral precocious puberty. The diag-7 k- ?7 `! G7 u1 V6 j+ q( }# H
nosis can be established by just a few tests and by
9 X$ i/ m+ D7 aappropriate history. The inability to obtain such a: H. y: L( |; V
history, or failure to ask the specific questions, may3 O4 B- V! o5 e' v0 `* X; V5 z" d
result in extensive, unnecessary, and expensive
7 g' s O, l, U& ~+ ~! T" Qinvestigation. The primary care physician should be- M8 [( j& A F! h
aware of this fact, because most of these children! D- R) a8 I0 y9 F K
may initially present in their practice. The Physicians’
* g2 a& r9 u7 D0 s" M' UDesk Reference and package insert should also put a* Z0 `9 G( V" l: D) U- H1 q% \
warning about the virilizing effect on a male or
+ I- r. h4 t- `+ B0 Xfemale child who might come in contact with some-
" u& v* C7 t. Y/ Oone using any of these products.
% V# u7 [2 p4 {3 PReferences
" n' ^. A; {, X/ @9 [( c* i/ a4 x8 [1. Styne DM. The testes: disorder of sexual differentiation
! a! D2 C J: t) N" j% Gand puberty in the male. In: Sperling MA, ed. Pediatric
3 H5 m. A$ j# {Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;; g; l: j ?0 o: I, O. e+ z
2002: 565-628.
5 I7 m" l. r6 O& A3 E2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
, D; U& x; \5 U+ G% q$ j: [8 D- B. Jpuberty in children with tumours of the suprasellar pineal |
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