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Sexual Precocity in a 16-Month-Old
" U+ }1 h& q9 |3 {9 A4 ~Boy Induced by Indirect Topical4 @' ^8 Q% B* \( w- [
Exposure to Testosterone |5 z' \! Y# r8 s' |
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
9 Z# X. }7 Z1 m& ~and Kenneth R. Rettig, MD1
; m1 T& Y( _- P1 V; mClinical Pediatrics" _' P- a& s/ S1 I
Volume 46 Number 6 J3 e. x8 u( o8 ~, u+ b
July 2007 540-543
* N9 F( q) b* F4 t& A* r( f" [© 2007 Sage Publications
; F/ n: P/ T5 J# y: L" S10.1177/0009922806296651' {7 M5 L! b/ t0 Z
http://clp.sagepub.com
& E# J6 J# {. H+ {; s1 nhosted at
3 T/ j9 H: \$ V" L v/ a, \http://online.sagepub.com
$ q1 D2 u/ H8 E6 t* wPrecocious puberty in boys, central or peripheral,4 p" T4 j4 T. Q% l. K; r
is a significant concern for physicians. Central
. F# [9 W7 S' v2 nprecocious puberty (CPP), which is mediated# }( R/ \' P7 D1 v& C
through the hypothalamic pituitary gonadal axis, has
/ u4 ?" l8 Y) R' n, p& Q* Ca higher incidence of organic central nervous system
+ ?+ D. A# ^# Y1 K: l7 Mlesions in boys.1,2 Virilization in boys, as manifested
/ Y% p4 `; D0 ~1 ?" a4 Oby enlargement of the penis, development of pubic
/ I2 Q' m0 v- R& Q' w jhair, and facial acne without enlargement of testi-$ r5 e2 r6 o# J- ^( N
cles, suggests peripheral or pseudopuberty.1-3 We
- {/ V+ W9 S$ V R4 Hreport a 16-month-old boy who presented with the
8 G7 ^, I/ P, r9 F. S8 b, Tenlargement of the phallus and pubic hair develop-, n3 [; l: s# }" L/ o
ment without testicular enlargement, which was due1 a# v. a, \# }3 V9 _
to the unintentional exposure to androgen gel used by
) c% ~3 @, \8 E/ ?the father. The family initially concealed this infor-
' Z7 M3 w$ J: C5 r5 z% ^mation, resulting in an extensive work-up for this
/ p/ U) X/ `- Z, nchild. Given the widespread and easy availability of* A/ R) S& V% r' C% o5 @+ N
testosterone gel and cream, we believe this is proba-! m0 p0 }9 B6 n' I& j
bly more common than the rare case report in the6 H7 ~' q8 w' P& h' G
literature.4
. `$ ]9 q m3 T7 K# d% r9 Z# J$ ~2 mPatient Report1 p( H5 d4 F5 D1 v
A 16-month-old white child was referred to the& D2 }4 e/ H0 A( U' S
endocrine clinic by his pediatrician with the concern6 O% b; C2 K1 l
of early sexual development. His mother noticed
" W. u. e: p3 a9 F2 f4 Dlight colored pubic hair development when he was
/ K5 _+ y3 S* L- w' a) C) ZFrom the 1Division of Pediatric Endocrinology, 2University of
) z, Z0 H# L+ x- q6 r) ESouth Alabama Medical Center, Mobile, Alabama.2 r- f% C3 S9 g5 J: Q1 \* Q. T
Address correspondence to: Samar K. Bhowmick, MD, FACE,
2 v# l/ N2 f Y( x( @& [7 xProfessor of Pediatrics, University of South Alabama, College of+ n6 n" s! F6 t3 e2 x
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;3 ?) e* \4 [7 ~4 c" t0 A
e-mail: [email protected].. S( x0 t% l& g' n
about 6 to 7 months old, which progressively became
, i( k* x2 j( x% X2 vdarker. She was also concerned about the enlarge-- C3 ?5 D6 `: l2 |
ment of his penis and frequent erections. The child+ i* y v, | a6 w8 K" j1 u/ Q
was the product of a full-term normal delivery, with& A- v+ t: s+ H
a birth weight of 7 lb 14 oz, and birth length of
9 i8 o8 j1 c2 T. M2 o20 inches. He was breast-fed throughout the first year3 d; @- J& @2 |& X; l; p! }% x
of life and was still receiving breast milk along with
- x' C/ \/ Q. k( A3 l" usolid food. He had no hospitalizations or surgery,
0 g) V/ b8 y6 Y/ |4 }- gand his psychosocial and psychomotor development% ` E6 u) |0 ?0 K* Z; h6 P e' `- H
was age appropriate.+ [* a+ L3 ~* I
The family history was remarkable for the father,, l$ o! v3 F' e' D
who was diagnosed with hypothyroidism at age 16,3 w" ~4 Y0 E$ I; R- c
which was treated with thyroxine. The father’s
# u# X* [- U U' g9 ]' pheight was 6 feet, and he went through a somewhat5 d r. Q; ~/ P) J% s
early puberty and had stopped growing by age 14.& t8 x, _% ~/ J1 I* B: j) c2 l
The father denied taking any other medication. The; x/ O* a- q* B( \# {
child’s mother was in good health. Her menarche/ O6 [3 ?6 B* Y, m7 b
was at 11 years of age, and her height was at 5 feet* B& v, u6 v/ C0 N
5 inches. There was no other family history of pre-1 L. v( i8 ? n) o2 l) y
cocious sexual development in the first-degree rela-
1 Q* H) m; T9 T% Z. Etives. There were no siblings.
0 U4 p, m+ T6 C% ePhysical Examination% W0 c2 g* ~ G
The physical examination revealed a very active,
$ S- ~2 t4 q1 C* wplayful, and healthy boy. The vital signs documented
3 Q. L0 ]* f( B4 Va blood pressure of 85/50 mm Hg, his length was
1 P( E/ ?/ |$ Y6 \8 b90 cm (>97th percentile), and his weight was 14.4 kg. m3 ^) N5 T% j4 h$ f
(also >97th percentile). The observed yearly growth
1 y* P6 A) r/ E/ Z* ^7 ovelocity was 30 cm (12 inches). The examination of
. @, {2 k: \9 e1 wthe neck revealed no thyroid enlargement./ n/ q. U$ E5 M! D
The genitourinary examination was remarkable for
/ _8 P) ?/ C! i7 k& _enlargement of the penis, with a stretched length of
* u" u: @7 ^0 b& D- }8 cm and a width of 2 cm. The glans penis was very well" n$ U1 a# j9 p. |" D5 W
developed. The pubic hair was Tanner II, mostly around
$ A/ P* L" ]5 A8 A540' Q$ L$ _& `7 V9 K' e: @+ l4 Y
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from7 Q4 F6 B/ c# H0 ~5 ]+ f
the base of the phallus and was dark and curled. The* B+ a& `+ E5 ?. C, R
testicular volume was prepubertal at 2 mL each.
c, L n+ J T+ r QThe skin was moist and smooth and somewhat8 z) | D. ?6 ~ s6 l
oily. No axillary hair was noted. There were no
; D; R6 z" U, e( x2 b& pabnormal skin pigmentations or café-au-lait spots.
* V# v' G7 [* J8 _- l- u$ WNeurologic evaluation showed deep tendon reflex 2+% X6 g1 B' ~9 G
bilateral and symmetrical. There was no suggestion3 y2 p) ?2 d6 k% i) b
of papilledema./ K k; Y: F. K0 ]) h- |
Laboratory Evaluation2 l; t% ]4 Z2 h/ N* p8 W
The bone age was consistent with 28 months by6 @0 `' t. m2 X) J, f s
using the standard of Greulich and Pyle at a chrono-6 l9 r: [9 O* [. b; F' s* W
logic age of 16 months (advanced).5 Chromosomal: x5 ]( }1 U q2 D! x9 X
karyotype was 46XY. The thyroid function test0 e$ i- M9 L/ y* e) s: Q1 E0 |' k
showed a free T4 of 1.69 ng/dL, and thyroid stimu-
4 d6 u% }& v6 z; |' ulating hormone level was 1.3 µIU/mL (both normal).2 E8 }7 b: s8 e1 K
The concentrations of serum electrolytes, blood
, R% u' Z& f* ]0 }* e/ E [urea nitrogen, creatinine, and calcium all were, D1 f. Q0 D' B; _' d9 w J3 t
within normal range for his age. The concentration' U. }( v8 x/ t0 ]9 o4 z
of serum 17-hydroxyprogesterone was 16 ng/dL
]9 N% ]% T8 f P$ \' y& _(normal, 3 to 90 ng/dL), androstenedione was 20
6 J2 @3 j3 @% i$ n2 Z: [7 }7 g7 Png/dL (normal, 18 to 80 ng/dL), dehydroepiandros-+ u0 L" d+ L2 o. [" z
terone was 38 ng/dL (normal, 50 to 760 ng/dL),
+ u6 J$ U' r! idesoxycorticosterone was 4.3 ng/dL (normal, 7 to$ M: M6 w6 h) F3 _" `. S
49ng/dL), 11-desoxycortisol (specific compound S)& z# q+ ^1 X( T$ j3 Q5 F/ y
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
7 k0 X2 c4 p Qtisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
0 y9 v/ r* M) Ztestosterone was 60 ng/dL (normal <3 to 10 ng/dL),
0 W) \8 d) {* y. E& tand β-human chorionic gonadotropin was less than
/ ~7 n. }4 V) C9 T5 `9 ~, Q0 Y5 mIU/mL (normal <5 mIU/mL). Serum follicular
- p8 P8 g/ t5 R4 o$ j- X) pstimulating hormone and leuteinizing hormone
/ b9 H7 `& [& `concentrations were less than 0.05 mIU/mL
8 _7 P: g' @- c( H(prepubertal).
% ~' g- G [9 u& r2 IThe parents were notified about the laboratory
; ?2 E* t7 [/ T/ ?( s. {results and were informed that all of the tests were" n, _8 Z" F9 ^5 {
normal except the testosterone level was high. The' Y0 }0 ?9 `9 E
follow-up visit was arranged within a few weeks to
/ y9 @) q4 p6 T6 K# t& f) D' wobtain testicular and abdominal sonograms; how-. A' K' Y7 R' V" N; x6 } I% C
ever, the family did not return for 4 months.
- u4 D. d9 E, y4 x; QPhysical examination at this time revealed that the
1 O6 V- v# L( a8 L9 h% h! kchild had grown 2.5 cm in 4 months and had gained
9 M8 U$ F/ F* m' z; I2 kg of weight. Physical examination remained
, V- v4 Z7 S$ w+ W X: D- y8 S gunchanged. Surprisingly, the pubic hair almost com-
; m7 i) T- J1 k! o; ~pletely disappeared except for a few vellous hairs at5 Q* M9 F7 I7 c i. z4 Q
the base of the phallus. Testicular volume was still 2% A4 e0 N+ s9 Y5 L
mL, and the size of the penis remained unchanged.
2 S" ?5 x4 l9 m( k$ K6 y1 ^The mother also said that the boy was no longer hav-
% o( W8 k! t( C8 }$ fing frequent erections.
6 _/ B* n# z6 F6 w5 S+ S; wBoth parents were again questioned about use of: G) H1 Z) f+ `, s W; ~& Y
any ointment/creams that they may have applied to
2 i% P$ k& z1 Lthe child’s skin. This time the father admitted the6 v6 y. J3 M% ?0 P: g
Topical Testosterone Exposure / Bhowmick et al 541
/ v* |+ @1 x& C: M, B5 p Ruse of testosterone gel twice daily that he was apply-
, q/ y [: S$ ?, p0 }0 W/ oing over his own shoulders, chest, and back area for
' Z' K" |" J- D ka year. The father also revealed he was embarrassed
0 V. o- N* s9 E$ Pto disclose that he was using a testosterone gel pre-
# w2 D- j( c- U9 Qscribed by his family physician for decreased libido
: d" W0 X! f X+ f( g5 U( _secondary to depression.
# s: k1 q9 G( f: DThe child slept in the same bed with parents.) `! i, }2 ]0 m( i# T
The father would hug the baby and hold him on his9 Z$ l7 E- ]5 |6 e
chest for a considerable period of time, causing sig-3 ^* x9 I9 B5 n; {2 I. H
nificant bare skin contact between baby and father.
% e# N" O f4 s, n" e1 t9 p* K8 CThe father also admitted that after the phone call,
" R# `; C, s- z8 Nwhen he learned the testosterone level in the baby- d0 G7 u: |5 V, z m6 f/ F- }( g+ Z2 _
was high, he then read the product information
: T0 [! P2 m5 |& E- U! i/ opacket and concluded that it was most likely the rea-
o2 t/ }4 U" `8 w: j* A; C+ v6 [son for the child’s virilization. At that time, they/ F/ t0 D5 I" P" U+ `
decided to put the baby in a separate bed, and the( u, u0 U7 c, U0 e' A
father was not hugging him with bare skin and had8 c* a- C, F& r
been using protective clothing. A repeat testosterone S3 o+ [5 ?% u6 B
test was ordered, but the family did not go to the
# V; A6 O! ]- F, u9 ]3 p5 claboratory to obtain the test.
* ]: }: S7 f$ N% ?/ GDiscussion
: `# m' p, h% i/ |9 yPrecocious puberty in boys is defined as secondary
0 t1 n6 |- ~- ~3 ]sexual development before 9 years of age.1,4
5 X4 Z- W9 A9 H( DPrecocious puberty is termed as central (true) when% `. ~; a6 u6 R- _( V, p' \
it is caused by the premature activation of hypo-9 S2 ?/ I4 f1 ^2 g( X* e
thalamic pituitary gonadal axis. CPP is more com-
, x* r) d, r3 P0 x. }$ @3 M- `; omon in girls than in boys.1,3 Most boys with CPP2 T: [: W0 a% U7 X w& w9 a
may have a central nervous system lesion that is
+ F8 J8 x/ k; x8 ]& ]$ }responsible for the early activation of the hypothal-' J! J( c& S# Q# f5 f
amic pituitary gonadal axis.1-3 Thus, greater empha-6 t# k$ G- d( ?, Q ~. Y$ S- D
sis has been given to neuroradiologic imaging in; i8 R: N4 p% d& P2 r# [
boys with precocious puberty. In addition to viril-& ?; Z& L! }) u
ization, the clinical hallmark of CPP is the symmet-1 ]6 m1 F6 w2 l# Z6 W
rical testicular growth secondary to stimulation by3 e3 ^, D) t B0 Z6 o4 w/ D" |
gonadotropins.1,3
. s ]# ]$ D8 YGonadotropin-independent peripheral preco-
$ H- Q, s& U) F* Dcious puberty in boys also results from inappropriate
) k v/ j/ [; c: uandrogenic stimulation from either endogenous or, A) O9 e7 }8 C2 G2 r
exogenous sources, nonpituitary gonadotropin stim-
7 r& A9 f; I0 _0 uulation, and rare activating mutations.3 Virilizing3 _! h) h/ a# I# i4 M8 C
congenital adrenal hyperplasia producing excessive- Q1 M/ n( n* Y+ Q6 [
adrenal androgens is a common cause of precocious
4 W3 G7 l Z) j0 l; Spuberty in boys.3,4 w8 j6 q( z* I0 B# V9 G. Z
The most common form of congenital adrenal( v8 }" C4 ]# q. h- Y
hyperplasia is the 21-hydroxylase enzyme deficiency.9 y2 A- S: d; k- l" R4 z( u3 z
The 11-β hydroxylase deficiency may also result in
# h* n* t0 I4 e9 ?/ a. ^excessive adrenal androgen production, and rarely,2 u4 y6 Q0 Y) V% q7 L
an adrenal tumor may also cause adrenal androgen
4 v* X9 R9 b; F% I! c5 n9 hexcess.1,3
1 W" z9 i9 c& N- c# y# Mat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from( J6 U& ^5 g9 \' D* Z
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007# Y/ v, m2 t* `. c, X0 p4 U) P8 t
A unique entity of male-limited gonadotropin-
0 k/ l- y* w7 ^independent precocious puberty, which is also known5 x) v5 K; e2 k" u* K, A, l2 O
as testotoxicosis, may cause precocious puberty at a/ @/ h0 `/ ^! a, Q$ C) j
very young age. The physical findings in these boys
: ]! D/ i6 t: T# T+ C9 Iwith this disorder are full pubertal development,* J/ L$ ]5 }3 r; y
including bilateral testicular growth, similar to boys
e4 y, E" j( v) X% }5 \ d% |; Swith CPP. The gonadotropin levels in this disorder
' \% r* P6 I0 m1 i4 z3 _( I+ Sare suppressed to prepubertal levels and do not show
7 D. o% Y2 _+ D% Z! ~pubertal response of gonadotropin after gonadotropin-4 m# F, J. @. H
releasing hormone stimulation. This is a sex-linked
; E. T9 `# A" b1 {! ~" k& g% ~4 yautosomal dominant disorder that affects only. `$ K) x) j x+ ]
males; therefore, other male members of the family
) L! T6 L% @. r! c# w3 J3 t! T; n& lmay have similar precocious puberty.3
$ p+ L' N& c4 I) a% {8 `' d$ h* S, fIn our patient, physical examination was incon-
~& Y! C ~, r" [0 }sistent with true precocious puberty since his testi-
9 d; v# a/ M5 f4 Z2 Gcles were prepubertal in size. However, testotoxicosis2 S2 u! ~- e. |' V, r3 U
was in the differential diagnosis because his father
* R% f9 K9 @( F% o2 f* d g+ ustarted puberty somewhat early, and occasionally,
" A% j" K) ~( B, s/ F% m ]' S7 d vtesticular enlargement is not that evident in the3 U: q0 R/ K7 L, r6 N o7 c- A9 ]
beginning of this process.1 In the absence of a neg-
& x( S1 g) ?# E! p3 v0 ~3 qative initial history of androgen exposure, our& H7 M" r& Q( d$ D
biggest concern was virilizing adrenal hyperplasia,
& q. j+ t3 o9 o4 yeither 21-hydroxylase deficiency or 11-β hydroxylase
w, u6 ]- E5 s9 l8 ^% Y3 qdeficiency. Those diagnoses were excluded by find-
3 M) \$ b; C8 U! C0 King the normal level of adrenal steroids.% i% G. ^6 E4 e+ q7 t
The diagnosis of exogenous androgens was strongly$ ^% }3 |+ ~: C! Y5 _
suspected in a follow-up visit after 4 months because% ]( I+ a6 D+ b, C3 o: w6 ?/ Y
the physical examination revealed the complete disap-9 y( @$ m) x) i- L4 w+ h
pearance of pubic hair, normal growth velocity, and
; m6 \9 d) y( E, c( p7 p6 Idecreased erections. The father admitted using a testos-6 N! W' P- r+ n: J7 y& |, ^. y7 P
terone gel, which he concealed at first visit. He was" E& p0 Y! U: r. D7 z
using it rather frequently, twice a day. The Physicians’/ T1 q% _, q T" X
Desk Reference, or package insert of this product, gel or
1 \8 E/ G$ Y3 i7 ^2 M! rcream, cautions about dermal testosterone transfer to7 U+ @ U O7 _& B1 b0 @2 @% B0 x
unprotected females through direct skin exposure.2 w- o" M7 L' l* z0 t O
Serum testosterone level was found to be 2 times the
0 @0 Y/ }& |- g3 Z, N; I' Vbaseline value in those females who were exposed to
% E( p/ P7 q7 H5 r" {even 15 minutes of direct skin contact with their male6 C+ ]3 ?. m( h9 r: r$ J# N6 D
partners.6 However, when a shirt covered the applica-
5 q$ `: T2 S- R4 E( {tion site, this testosterone transfer was prevented. J1 u$ D. Q' P/ l2 U* w4 Z
Our patient’s testosterone level was 60 ng/mL,: A8 i5 N7 h- q- u N
which was clearly high. Some studies suggest that
. O' F [/ n/ c+ j* idermal conversion of testosterone to dihydrotestos-7 P" p- l* o* \4 f4 L' p0 `" i
terone, which is a more potent metabolite, is more! v* S0 [1 x/ Z: F6 {
active in young children exposed to testosterone
, [3 m8 @: O9 j/ T% S9 Z( ?exogenously7; however, we did not measure a dihy-
; }( t; n# b% xdrotestosterone level in our patient. In addition to
1 D8 M4 j5 l1 X2 Yvirilization, exposure to exogenous testosterone in
) L: o# R" _2 G* E" wchildren results in an increase in growth velocity and% D% {0 `' l& o
advanced bone age, as seen in our patient.
/ g4 a5 c, A3 xThe long-term effect of androgen exposure during
, `5 f# _ t( a& ?early childhood on pubertal development and final+ @' w" }" [! [5 }' P7 Z4 h
adult height are not fully known and always remain
) I' `3 q( C D h; V( Ya concern. Children treated with short-term testos-
- K; C& N5 w6 G$ `terone injection or topical androgen may exhibit some9 e; Z, {: @" K2 S1 J j
acceleration of the skeletal maturation; however, after# Y8 F: a& ^) Y' f
cessation of treatment, the rate of bone maturation' K* }7 ~1 f- B0 P5 J, o$ v) @
decelerates and gradually returns to normal.8,9
& j* o. c# E8 ?There are conflicting reports and controversy
! g2 F( ~! b5 e' t9 p8 Uover the effect of early androgen exposure on adult
+ P' q1 a& h% h- F! P* _6 fpenile length.10,11 Some reports suggest subnormal/ g: c& W4 O$ \2 y1 C! u
adult penile length, apparently because of downreg-
" J3 D, o3 e3 _; H+ ~0 b# Iulation of androgen receptor number.10,12 However,' b" @/ t; k! b& l% p& K- I
Sutherland et al13 did not find a correlation between
6 y( r) L- I8 pchildhood testosterone exposure and reduced adult
8 V# j, x% y) O2 l8 f4 Gpenile length in clinical studies. a# M2 L1 C* |( H& ]
Nonetheless, we do not believe our patient is1 O* R9 {, ~8 k5 } x' x9 y8 c" i
going to experience any of the untoward effects from, W! p; G$ ]( w! W" A5 }/ A9 z/ N
testosterone exposure as mentioned earlier because
* t5 y' q" I1 j, Mthe exposure was not for a prolonged period of time.
3 N( t5 e4 L7 t* XAlthough the bone age was advanced at the time of
3 c0 |7 o7 d* r' `4 B5 O( f3 Ldiagnosis, the child had a normal growth velocity at
! Q: s3 B. D# G; h$ P* `the follow-up visit. It is hoped that his final adult
' s) P0 s& N% w" T9 S2 S! c5 gheight will not be affected.1 H. [2 Z# y* r8 j4 i
Although rarely reported, the widespread avail-
# r0 h0 p4 a+ H5 aability of androgen products in our society may
0 T3 H2 `6 [+ h7 u) qindeed cause more virilization in male or female
0 ^# }2 y% k v- \3 a- Z: Vchildren than one would realize. Exposure to andro-
( Z h: ^) k/ m$ Sgen products must be considered and specific ques-* a2 F- ^1 B. A& q+ Y1 v3 s8 J
tioning about the use of a testosterone product or
* e: t9 S: P) O: i, \0 H& ogel should be asked of the family members during6 L# L @4 q$ q8 `# d! W
the evaluation of any children who present with vir-! N: u. O6 |3 }) R9 S
ilization or peripheral precocious puberty. The diag-2 J9 I* C# q/ O7 z; B$ U' B
nosis can be established by just a few tests and by( W; [; k; b& J' j
appropriate history. The inability to obtain such a
1 N% d5 d! Q8 |history, or failure to ask the specific questions, may" S! m8 [/ S, o" e2 C
result in extensive, unnecessary, and expensive
$ U+ [6 |& {' ~% Sinvestigation. The primary care physician should be
2 u' ^' g+ ]3 H, j$ qaware of this fact, because most of these children! `" D8 B( z0 ]8 a
may initially present in their practice. The Physicians’
# D1 A# j8 V/ e7 pDesk Reference and package insert should also put a
, n5 \- s% s9 C$ T& t, `9 n" h# [' |warning about the virilizing effect on a male or
' } Z- ^% L+ n1 b: t' Kfemale child who might come in contact with some-
4 i$ u8 C2 \+ z y5 M* Lone using any of these products.' z! g8 Q7 q# Q7 J, o; {
References
4 a O4 S5 Q( ]" g1. Styne DM. The testes: disorder of sexual differentiation
% Z6 M) t O2 n* m4 Uand puberty in the male. In: Sperling MA, ed. Pediatric
) C e. a) K5 K' \0 OEndocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
& c3 h R. T8 P; M1 J; O8 V2002: 565-628.
! W3 E1 t( ^: f2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious, N+ o& v3 ]( Q9 }8 s+ c& l
puberty in children with tumours of the suprasellar pineal |
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