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Sexual Precocity in a 16-Month-Old7 R# L/ p, c8 |2 q$ e1 N `# w
Boy Induced by Indirect Topical# f( ^& U2 ^4 z" r+ w3 e, F1 l( d
Exposure to Testosterone5 X1 p# k5 A% q8 s' F/ U
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
: u; b2 p; _7 ~and Kenneth R. Rettig, MD1
- _7 R; `# ]% b2 P5 a7 H7 nClinical Pediatrics
/ f( j0 X' p: R3 OVolume 46 Number 6
5 j, Y! |; g) v0 @July 2007 540-543, a& I, p! U- Y, v8 F+ \9 ~
© 2007 Sage Publications0 n% I1 [* u! h; r7 i
10.1177/0009922806296651
8 P2 O; ^8 t$ P/ n; K8 fhttp://clp.sagepub.com
: x; D: j$ O6 ]7 j! j% Zhosted at
. y' ?9 `5 X; {" Khttp://online.sagepub.com# w3 L5 s7 E. J5 j" R
Precocious puberty in boys, central or peripheral,
+ I9 x. d! |: X& ~is a significant concern for physicians. Central6 j7 y; B' H" N0 _' i4 n# F0 y
precocious puberty (CPP), which is mediated
. Z6 x6 f: Z' v- _& Uthrough the hypothalamic pituitary gonadal axis, has
& t" _: r0 V$ Y1 Ia higher incidence of organic central nervous system
# c: X) L+ ?9 |& D* wlesions in boys.1,2 Virilization in boys, as manifested
, ^! A' S4 @$ h6 U& c7 sby enlargement of the penis, development of pubic
$ c' O! `2 E3 m' G4 Z# V" e' fhair, and facial acne without enlargement of testi-6 [9 s8 d4 G* [
cles, suggests peripheral or pseudopuberty.1-3 We( F* D: i+ D) z/ A! m8 Q
report a 16-month-old boy who presented with the
. z- {5 j9 o/ `' g8 Xenlargement of the phallus and pubic hair develop-
+ O/ p6 t# J7 c7 a; Ement without testicular enlargement, which was due6 K+ c7 r- }. \* c9 N$ x9 i
to the unintentional exposure to androgen gel used by4 k& ^2 J( q' c5 h. G
the father. The family initially concealed this infor-( P5 B) m) t+ t+ I
mation, resulting in an extensive work-up for this# w: [* M' e9 L! O3 V5 M: q
child. Given the widespread and easy availability of+ I \. c& G- \! h- q. A4 h. x$ z
testosterone gel and cream, we believe this is proba-5 g E: @1 m7 g+ p) l
bly more common than the rare case report in the
! z9 ]( A ?- W" P7 `& l8 _literature.4; T& n! c7 G& {
Patient Report
& b* m) u/ s$ ], ?A 16-month-old white child was referred to the
$ x! z! w5 n* o; `( Pendocrine clinic by his pediatrician with the concern
( m1 m" R% k' `" t3 x+ D, u4 g. [; X" tof early sexual development. His mother noticed
; {: {, d" x% C! Plight colored pubic hair development when he was
9 E6 {6 U: M6 w1 @From the 1Division of Pediatric Endocrinology, 2University of8 l0 O# I+ }2 n
South Alabama Medical Center, Mobile, Alabama.
+ }, `; y* W2 ]Address correspondence to: Samar K. Bhowmick, MD, FACE,
* x; z2 T+ X( I5 w- d% ZProfessor of Pediatrics, University of South Alabama, College of
' ^6 }0 {# q* p3 eMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;9 M% L' ^! W- `- d, |0 D
e-mail: [email protected].
' D/ e5 U% l1 }6 a3 P5 Q' Gabout 6 to 7 months old, which progressively became
" }2 ~, p' ]9 g: h0 ?darker. She was also concerned about the enlarge-
0 I- w! V) j/ w$ kment of his penis and frequent erections. The child
9 g) `- u$ [/ C5 C, |; j7 o# xwas the product of a full-term normal delivery, with$ `; o; H7 I) R
a birth weight of 7 lb 14 oz, and birth length of: x' i7 s' D; N1 ^1 J
20 inches. He was breast-fed throughout the first year; B" w8 u: O8 a y
of life and was still receiving breast milk along with& ^/ ~8 D! K7 \6 I: m$ m! H5 {
solid food. He had no hospitalizations or surgery,
* Z7 ?$ o( w7 n9 J3 x1 T) ~7 N1 b' T' yand his psychosocial and psychomotor development
: j! o# O* S1 V# }& v% {- `' }was age appropriate.8 F( x( [& c( s8 u3 d' C5 N
The family history was remarkable for the father,* Z* g) Q6 K- t7 T5 Q3 |# E( I
who was diagnosed with hypothyroidism at age 16,
7 ?# d0 ? H& Gwhich was treated with thyroxine. The father’s, X7 i: \! t) q& [) t- x7 z+ G
height was 6 feet, and he went through a somewhat
/ ]; ?/ w& S, b6 ]6 Y' R7 Bearly puberty and had stopped growing by age 14.2 A8 T6 _" g( D, p
The father denied taking any other medication. The3 W0 V+ W( ^" m5 S% R6 N e
child’s mother was in good health. Her menarche" q. O( Q( ~1 d- x8 j5 {# j& {
was at 11 years of age, and her height was at 5 feet' [0 V2 r- I/ H. v
5 inches. There was no other family history of pre-9 Y/ Q! q( H/ I! t! X2 _4 g4 p, ?
cocious sexual development in the first-degree rela-/ R1 j4 ?* W! L; D! Q* c" u+ l
tives. There were no siblings.% `1 z6 u. `7 p2 T$ a7 x# U3 b+ k
Physical Examination2 Y* @! ~" x# l
The physical examination revealed a very active,
0 _9 s ^- r j$ R: c$ t, }# |playful, and healthy boy. The vital signs documented
9 T( }/ K4 W6 J6 J7 ya blood pressure of 85/50 mm Hg, his length was% Z$ y. X: z, s* {6 O! E
90 cm (>97th percentile), and his weight was 14.4 kg8 B( m7 ~# Y4 H$ |# u# S
(also >97th percentile). The observed yearly growth. D% I$ @0 U# b1 y. l: K: Q2 [
velocity was 30 cm (12 inches). The examination of* A) n, f% d$ w v, H
the neck revealed no thyroid enlargement.' A( T3 F6 r1 y/ Z' N4 o a8 k
The genitourinary examination was remarkable for
/ @, i, I P7 k+ s# q& Y( U t* Nenlargement of the penis, with a stretched length of7 D! T D I3 K+ V! R
8 cm and a width of 2 cm. The glans penis was very well. [$ O6 H" o- D7 J! l1 K4 r
developed. The pubic hair was Tanner II, mostly around6 _/ W$ O- A4 `3 h- w
540+ ]8 s7 x* ?. w+ u
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from) t: Z1 d+ L7 O. f0 E
the base of the phallus and was dark and curled. The" O, F9 n& f D' {6 u3 S( U Z
testicular volume was prepubertal at 2 mL each.
" Z3 G H, e) HThe skin was moist and smooth and somewhat
9 k+ j7 m* Q# c5 f' ^; J& h6 Qoily. No axillary hair was noted. There were no( T: ?! H0 H) v6 X
abnormal skin pigmentations or café-au-lait spots.
" Q4 K3 }* s( U! w) U" jNeurologic evaluation showed deep tendon reflex 2+4 `/ i w/ n; [
bilateral and symmetrical. There was no suggestion7 B! \& f6 e4 b- P& ^* J3 [( ?
of papilledema.% O' K; Z5 V" O2 {
Laboratory Evaluation
3 q. t* Q8 n# }- N) e/ F2 BThe bone age was consistent with 28 months by$ f8 R' G. Q6 \) H
using the standard of Greulich and Pyle at a chrono-
& A$ k3 d4 Y. }( Qlogic age of 16 months (advanced).5 Chromosomal
, m2 p* d* H4 J, gkaryotype was 46XY. The thyroid function test: m7 \# n7 V+ t$ ]" \2 j' A" D
showed a free T4 of 1.69 ng/dL, and thyroid stimu-
3 K& c9 a* `) Klating hormone level was 1.3 µIU/mL (both normal).8 {/ a, J. c0 _) y! T+ I H$ G0 h" A
The concentrations of serum electrolytes, blood
' v" E6 Z5 {+ u- G5 ]' U* Rurea nitrogen, creatinine, and calcium all were$ _: u3 t& z7 m, g
within normal range for his age. The concentration
9 ^& Y% @: x8 r& Z8 ~6 U, r4 bof serum 17-hydroxyprogesterone was 16 ng/dL
: l* S3 P- e2 \6 W. e6 i(normal, 3 to 90 ng/dL), androstenedione was 20
' g7 `, M7 E- e- P+ m' qng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-% @! w. [0 I+ Q6 ]3 ^
terone was 38 ng/dL (normal, 50 to 760 ng/dL),
/ L" W8 t0 T" zdesoxycorticosterone was 4.3 ng/dL (normal, 7 to
; f* t' p D. |% [ _49ng/dL), 11-desoxycortisol (specific compound S)$ y) k" n) F& \3 ^
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
$ W( g2 J. u" [; t B- C; y( ^tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total+ `; L. a+ I& H( ~9 @
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),1 ^) ?! n3 a( n
and β-human chorionic gonadotropin was less than
1 F9 {# M: a9 P5 mIU/mL (normal <5 mIU/mL). Serum follicular. D- n' @. [9 }; w! B
stimulating hormone and leuteinizing hormone" ~- N1 Z+ e* f5 J6 s$ y
concentrations were less than 0.05 mIU/mL
9 o5 e! e; y; K: `3 d3 q" S(prepubertal).' Z! C* z" N1 Z' k0 X! `
The parents were notified about the laboratory* B# k( `4 i+ e: H" G
results and were informed that all of the tests were
7 L) N' g- ^ Y* k0 ]( _normal except the testosterone level was high. The1 X2 q& G9 x1 k& g3 K. k
follow-up visit was arranged within a few weeks to p+ _ v$ p0 z F' f1 i$ J7 m! ^) g8 k
obtain testicular and abdominal sonograms; how-" F- g3 A' D" E9 ?! K/ L! P0 i8 @
ever, the family did not return for 4 months.
+ f* w: }9 `# f+ L9 @: V) I1 yPhysical examination at this time revealed that the
f6 O+ D& I( D2 q/ echild had grown 2.5 cm in 4 months and had gained
9 P: |8 G9 ]* G- s- w$ F2 kg of weight. Physical examination remained; n/ z9 O/ y/ h7 b2 c! Z! U
unchanged. Surprisingly, the pubic hair almost com-
1 N, _7 o5 J, N/ z, k+ E( N7 [pletely disappeared except for a few vellous hairs at
2 R" f# T& a& _/ v% d9 m8 dthe base of the phallus. Testicular volume was still 2
# j" |# k" `% FmL, and the size of the penis remained unchanged.: Y9 [" d0 l$ |( N
The mother also said that the boy was no longer hav-, p( n( o% e K* Y" @6 L
ing frequent erections.4 f, q& @* `1 U
Both parents were again questioned about use of
) v; s2 Q; D7 h; {( n1 V8 y. }1 oany ointment/creams that they may have applied to0 F6 y N" v& H+ a
the child’s skin. This time the father admitted the
; V6 N7 L D% @+ L/ b2 VTopical Testosterone Exposure / Bhowmick et al 541
- F+ ?2 s3 U7 E2 fuse of testosterone gel twice daily that he was apply-
0 I9 z7 X1 x8 y. _6 fing over his own shoulders, chest, and back area for
) n& ?6 l+ t' c/ g/ o* xa year. The father also revealed he was embarrassed
: ]( o) F# j9 ?' b) O2 I$ pto disclose that he was using a testosterone gel pre-1 c* o8 J3 H9 i! C/ Y+ [
scribed by his family physician for decreased libido3 a4 p5 ]4 S3 t7 s R
secondary to depression.
3 T; o1 r5 S+ T( |$ }; Y: a vThe child slept in the same bed with parents.. y5 I1 s; w$ n0 A. X3 e! c; @! h
The father would hug the baby and hold him on his! a+ ?- a5 Z9 X" T! H1 m; O1 I3 F* P
chest for a considerable period of time, causing sig-0 _# Z( c( `' ?4 y- U' S
nificant bare skin contact between baby and father.$ @% ^& x% | S! q9 m, v9 K
The father also admitted that after the phone call,
F$ a. m: a! h) p! {1 l1 i2 Ewhen he learned the testosterone level in the baby/ ^4 D/ \* Y0 b/ k) d6 X$ ?5 _
was high, he then read the product information- k3 ?. [4 R# {* X) M( e
packet and concluded that it was most likely the rea-7 o! I/ n; o' B8 h# \' M
son for the child’s virilization. At that time, they
: d# L T1 i8 i0 f- j* Pdecided to put the baby in a separate bed, and the
" t7 v: D" t9 ^4 G, l' ^father was not hugging him with bare skin and had6 r8 O& d r9 |9 l( F- m4 f
been using protective clothing. A repeat testosterone
4 {7 [6 |! Y4 A' Ttest was ordered, but the family did not go to the
4 A- r' Y: `# P* K8 z+ G8 x& zlaboratory to obtain the test.1 X1 F" t" x9 R a; C6 L
Discussion3 q, e+ L/ E# t% X/ |1 G- x
Precocious puberty in boys is defined as secondary& s! M& Y" L5 A0 [: E
sexual development before 9 years of age.1,4( I" o5 A4 |: P4 D0 W1 w! V; B
Precocious puberty is termed as central (true) when
f+ a0 x; k2 A' U" l2 q+ jit is caused by the premature activation of hypo-
; w- f) p9 `% l; R; {! Tthalamic pituitary gonadal axis. CPP is more com-- b. w# `9 b' H j
mon in girls than in boys.1,3 Most boys with CPP
% O1 k4 k( L1 ~% M% d2 ^may have a central nervous system lesion that is5 y3 O, Z2 i* M$ e5 Q
responsible for the early activation of the hypothal-- I. \9 l# |6 c0 C: _. |
amic pituitary gonadal axis.1-3 Thus, greater empha-5 m* B9 l( C& p" w( @9 D- G
sis has been given to neuroradiologic imaging in7 ?) M8 |6 C- F
boys with precocious puberty. In addition to viril-
/ N4 [% F$ W& e& N; s: e4 @" Vization, the clinical hallmark of CPP is the symmet-
4 i, y' Y% O. D( \0 m! U* _rical testicular growth secondary to stimulation by- ]1 Y3 z1 c& W
gonadotropins.1,3
" W& R* g) d% {Gonadotropin-independent peripheral preco-
" m6 X; R6 f1 Kcious puberty in boys also results from inappropriate
) k- h0 E* L% C; Oandrogenic stimulation from either endogenous or
* f, P6 C# `; y' }; V3 |# \& X- Fexogenous sources, nonpituitary gonadotropin stim-
% D4 y( q7 i8 k9 }$ z3 Dulation, and rare activating mutations.3 Virilizing
: a) R* V0 `1 O qcongenital adrenal hyperplasia producing excessive
; u; f6 l9 H; u' G* W9 y. hadrenal androgens is a common cause of precocious0 O+ L% c$ O* V( G' D u' l% |# P
puberty in boys.3,44 e) s2 E' {2 Q' r7 {& x( o
The most common form of congenital adrenal0 K& _" N @+ l+ x
hyperplasia is the 21-hydroxylase enzyme deficiency.
5 y5 Y# C5 O) C! z, K7 F: Z+ J) fThe 11-β hydroxylase deficiency may also result in
1 Y* X! b& f+ ]8 Mexcessive adrenal androgen production, and rarely,$ x% m& n+ P! A/ S, Q D
an adrenal tumor may also cause adrenal androgen
$ ^0 ^' [) Q; `) c3 @excess.1,3
. a1 i, f8 b! H7 w. Eat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
# a/ M% x# A) j7 P5 A! o8 h+ g542 Clinical Pediatrics / Vol. 46, No. 6, July 2007# M% |2 L1 A( _' M
A unique entity of male-limited gonadotropin-
0 o# ^: @8 g5 @& a; I- Qindependent precocious puberty, which is also known+ \) D. D' C* b; |! U
as testotoxicosis, may cause precocious puberty at a0 J/ j; E3 h) W1 r* a) t
very young age. The physical findings in these boys
1 Z+ e H: f# rwith this disorder are full pubertal development,
8 u1 ^# V* Q. U! b5 l+ eincluding bilateral testicular growth, similar to boys w4 O4 ]) L0 L% J
with CPP. The gonadotropin levels in this disorder b. W; N) G+ r( n& g W
are suppressed to prepubertal levels and do not show( W4 Y/ @# I1 n) y* S2 Q5 C7 s
pubertal response of gonadotropin after gonadotropin-
6 i/ r( d+ @, _releasing hormone stimulation. This is a sex-linked/ \: A- o: C9 Q+ y" z2 S( t
autosomal dominant disorder that affects only
8 B& \) {7 o+ z4 K& J2 Umales; therefore, other male members of the family
# ^6 e6 Y3 P( ~may have similar precocious puberty.3% u6 D9 I% E+ S5 T, c, P" O: y
In our patient, physical examination was incon-
# f" K% T! X) B1 r* Qsistent with true precocious puberty since his testi-2 \) B. v0 P4 t. n; b0 w& m
cles were prepubertal in size. However, testotoxicosis
+ D1 ?& a/ q- I7 M) v, awas in the differential diagnosis because his father6 P. |) v( t) C/ V5 d3 Y f9 f
started puberty somewhat early, and occasionally,) ?" k6 Y& y- S, M: l
testicular enlargement is not that evident in the0 ^9 J2 e) W" u! _# P ?* S
beginning of this process.1 In the absence of a neg-0 S! h5 Y$ S+ T: O$ E
ative initial history of androgen exposure, our, ~& @& e+ A# u1 Z) h
biggest concern was virilizing adrenal hyperplasia,# {9 T) K" j5 Q9 _1 d
either 21-hydroxylase deficiency or 11-β hydroxylase2 {# h( ~! N$ i4 V3 }- F
deficiency. Those diagnoses were excluded by find-5 L6 @$ P+ F4 k+ i! s
ing the normal level of adrenal steroids.) r' ~6 ?9 g# v7 J
The diagnosis of exogenous androgens was strongly
: ~$ A3 U# t9 s9 D3 V# rsuspected in a follow-up visit after 4 months because- z" N! X& k. \8 U7 c3 x/ P, `
the physical examination revealed the complete disap-
" e- ~: n# J: i* Y3 R4 @3 Z0 G( Wpearance of pubic hair, normal growth velocity, and
0 [& k' Z7 A8 G% [decreased erections. The father admitted using a testos-1 g _ Q9 M( V% q( k. o
terone gel, which he concealed at first visit. He was- S# ^, c4 c3 P- p" J+ k' p/ g
using it rather frequently, twice a day. The Physicians’$ U% X |# x- Q5 n' X
Desk Reference, or package insert of this product, gel or
0 ~7 A, w- _$ }0 w" y# f6 kcream, cautions about dermal testosterone transfer to. y6 k* h9 Y) H/ T
unprotected females through direct skin exposure.
, b6 W' v; H0 H1 rSerum testosterone level was found to be 2 times the
" W/ u; p3 P$ `- D3 Z9 g( E' I" s+ sbaseline value in those females who were exposed to
8 C3 g# h& F0 }6 i0 n0 H' Seven 15 minutes of direct skin contact with their male! h% L" j4 ^6 v/ `, a" n& T# ~
partners.6 However, when a shirt covered the applica-
( k; z% I# P0 v/ @: ^$ i Dtion site, this testosterone transfer was prevented.
' ?7 a" v3 E5 }; S7 EOur patient’s testosterone level was 60 ng/mL,5 T2 l- ^1 L/ K% K' d% ?
which was clearly high. Some studies suggest that
# g; @, [, m6 H8 odermal conversion of testosterone to dihydrotestos-
( q+ f& i0 b" E# t+ Bterone, which is a more potent metabolite, is more) |* J; l- G+ ~% P4 t* e
active in young children exposed to testosterone
; a% T8 X9 q/ l* o* rexogenously7; however, we did not measure a dihy-
i; V1 f! ~1 e% S0 M5 Wdrotestosterone level in our patient. In addition to
2 V, s; F' ~& ?virilization, exposure to exogenous testosterone in4 I" ^" T; k7 A3 P! X9 }6 n! t% v9 m
children results in an increase in growth velocity and
* k) W) w9 q: ? }advanced bone age, as seen in our patient.* K) g9 [* u# H" r& L
The long-term effect of androgen exposure during% q9 u; s! y2 V8 j
early childhood on pubertal development and final$ j! W/ t: k% W# Z
adult height are not fully known and always remain
/ |/ V6 ?( j* m+ t; p" Da concern. Children treated with short-term testos-
( V: J* U: v2 T1 { \4 T/ S( @terone injection or topical androgen may exhibit some% o& V0 P1 L. b9 Z+ j' e' V
acceleration of the skeletal maturation; however, after
& N* ?; T+ J/ F' rcessation of treatment, the rate of bone maturation
) W' w* S8 n) M1 n3 z9 Ddecelerates and gradually returns to normal.8,9% K9 W* L6 h9 _. H) m
There are conflicting reports and controversy
% _8 v0 y. }3 `8 i/ bover the effect of early androgen exposure on adult- i9 J+ ^3 R: V _
penile length.10,11 Some reports suggest subnormal
- _4 W" s2 O6 z& jadult penile length, apparently because of downreg-
* D. f9 u6 }" ^1 iulation of androgen receptor number.10,12 However,8 }, Y( y4 m% B& ?. m. n
Sutherland et al13 did not find a correlation between* m+ Z# J& P: X
childhood testosterone exposure and reduced adult
+ S* T7 I& ^7 B/ vpenile length in clinical studies.* \9 e" U3 K U7 u" }
Nonetheless, we do not believe our patient is
" s. n8 b0 D! hgoing to experience any of the untoward effects from! O$ J. W2 p- ], D! ?
testosterone exposure as mentioned earlier because
' x2 } f6 b( _/ i* i7 C1 k' Rthe exposure was not for a prolonged period of time.8 L; J& w( t1 h
Although the bone age was advanced at the time of7 `! R1 c D, L
diagnosis, the child had a normal growth velocity at1 ]1 p* c$ g4 a7 N! q w, s
the follow-up visit. It is hoped that his final adult
$ o7 |& `" q: `! N5 p! B2 Fheight will not be affected.3 ?* K4 q, `0 y+ d' F
Although rarely reported, the widespread avail-& ^+ W3 R) L; Y9 Z3 j
ability of androgen products in our society may
7 }& {* f$ p Y/ Y1 T, t" Iindeed cause more virilization in male or female4 _& o8 M9 F( |0 S6 A2 v0 y: ~" b
children than one would realize. Exposure to andro-
% T( k5 N5 v) A& M! n, q( t4 }9 _* C4 agen products must be considered and specific ques-0 o2 Z$ b6 E9 l, R9 Z+ A( y! n
tioning about the use of a testosterone product or- q7 S) ~6 V; Y
gel should be asked of the family members during
( Y8 c0 e/ R. E- F3 m8 dthe evaluation of any children who present with vir-
& v0 L# q, T' ^* n* a, [/ vilization or peripheral precocious puberty. The diag-
; | } Z5 _. p$ _ lnosis can be established by just a few tests and by
1 F) J% G) S* p& l, ~0 \: {appropriate history. The inability to obtain such a
6 W& Z. R M" ]7 \+ K0 v& Khistory, or failure to ask the specific questions, may
, M6 x3 d6 E4 ?; uresult in extensive, unnecessary, and expensive
* U, {# ]$ j( Z9 minvestigation. The primary care physician should be0 y' B) M( Z# M% n9 j5 M6 s6 ~* @
aware of this fact, because most of these children
; \1 q9 \7 G7 `( amay initially present in their practice. The Physicians’
* {2 _9 S. a% M# [% TDesk Reference and package insert should also put a/ J: w7 C9 v6 R- U* t) \5 D
warning about the virilizing effect on a male or
1 S+ T% a5 W2 y3 i) u* m; |female child who might come in contact with some-9 i1 v" |' ~+ i, b
one using any of these products.
2 L1 }/ {6 X. D3 h. Q" UReferences; N( D* m& I+ u/ N8 X
1. Styne DM. The testes: disorder of sexual differentiation0 c. N! w4 f; }% G- o
and puberty in the male. In: Sperling MA, ed. Pediatric
' J. ?- z: y6 GEndocrinology. 2nd ed. Philadelphia, PA: WB Saunders;) G! E" y; }8 @7 u. m8 j! ~4 N1 t* g
2002: 565-628.
# l$ f. X# u4 U9 N- m# |' ~2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious+ r2 m1 P; o7 c2 y4 ?+ v' _5 n
puberty in children with tumours of the suprasellar pineal |
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