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Sexual Precocity in a 16-Month-Old8 h; t \9 ^% G
Boy Induced by Indirect Topical
5 _# z! I# l# M% T8 }! jExposure to Testosterone1 c) f& ~, o# n, |; N! T
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
" _0 k7 o' {0 Q2 \/ P) h) b5 e& Mand Kenneth R. Rettig, MD18 M3 p) \ _9 e- s3 J; a
Clinical Pediatrics' ^' u( C9 R0 r" Q
Volume 46 Number 6. H5 \7 l4 F, y# i0 e* {8 G
July 2007 540-543 b# `$ O: O) x: O. ?0 v- L+ O
© 2007 Sage Publications, C6 h, N9 @7 A
10.1177/0009922806296651" R$ E* e J4 `5 I: V
http://clp.sagepub.com
; D" K7 ]0 y6 L6 bhosted at
# O2 Y4 ]' E2 H$ f% qhttp://online.sagepub.com
5 B! J) u2 a9 s m; J6 b- qPrecocious puberty in boys, central or peripheral,
) a$ |$ C' Y ~) e8 [0 N$ M" sis a significant concern for physicians. Central
, z9 h5 B/ C: k2 ^1 a+ y, |precocious puberty (CPP), which is mediated) s, |& }+ L; Q) [% ~
through the hypothalamic pituitary gonadal axis, has1 Y h, w% d* j3 f- b
a higher incidence of organic central nervous system) |4 M5 h5 f) g
lesions in boys.1,2 Virilization in boys, as manifested" Q' C' `! d0 }8 L: ~/ V
by enlargement of the penis, development of pubic
3 T# P1 }' u7 I: y8 e0 yhair, and facial acne without enlargement of testi-
, ], g, a' K) L8 V, p" Scles, suggests peripheral or pseudopuberty.1-3 We- G, r- R5 x- \3 t
report a 16-month-old boy who presented with the
& p% G. d$ H4 x- O V% N7 penlargement of the phallus and pubic hair develop-
& Q+ v; ~7 N( ^7 H+ o0 Kment without testicular enlargement, which was due
& Q5 w S9 G$ |. r- Y1 l# kto the unintentional exposure to androgen gel used by
: T2 @& w6 i7 Q; w5 \8 l" fthe father. The family initially concealed this infor-
6 o0 t, w" U. A; c% E& Qmation, resulting in an extensive work-up for this
: E6 S, L9 w' t! ?, ~child. Given the widespread and easy availability of
( |( _$ L& f* m8 M2 y* A ttestosterone gel and cream, we believe this is proba-, i& r2 y- [/ e
bly more common than the rare case report in the
) p2 w: x( O' [. p& D' z. u4 z- ^6 Wliterature.4
0 K9 x2 @! Z5 f) ^( O# u1 YPatient Report; X" z! V# Z& c: o. K
A 16-month-old white child was referred to the. G, x+ e0 _ ?% r8 G1 Z
endocrine clinic by his pediatrician with the concern
+ X( c2 ?5 T4 A3 j1 b+ @* uof early sexual development. His mother noticed( V/ D. P0 \% Q; F9 X3 b
light colored pubic hair development when he was
1 O% q2 f( _9 V: h+ M9 I8 _From the 1Division of Pediatric Endocrinology, 2University of
. t! d- _1 _7 [: E k# O: _2 |) v VSouth Alabama Medical Center, Mobile, Alabama.
, H0 `6 ?: v5 e3 vAddress correspondence to: Samar K. Bhowmick, MD, FACE," a$ ~7 {3 @/ W0 Y* L
Professor of Pediatrics, University of South Alabama, College of U& N9 K( U! M& j6 L
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
+ e* Q3 j. N/ @: M5 Ye-mail: [email protected].
9 I5 z* ~ H# K+ K, E) Nabout 6 to 7 months old, which progressively became! l3 s2 p- w2 q' a- {- K' }
darker. She was also concerned about the enlarge-' u' W: z$ T4 o% `# f
ment of his penis and frequent erections. The child
6 J3 q( t/ q/ Y4 c3 i( mwas the product of a full-term normal delivery, with$ |5 m% T! {) \3 _) f; k$ j( L
a birth weight of 7 lb 14 oz, and birth length of; _3 j! }4 E& K x0 [$ ?/ |
20 inches. He was breast-fed throughout the first year; b4 z- J! h$ E2 f$ i1 |
of life and was still receiving breast milk along with( B. ?+ x" j4 N( j2 w8 g
solid food. He had no hospitalizations or surgery,
2 R1 v" z( [ Wand his psychosocial and psychomotor development# B/ {0 j# b w% i0 z5 X3 E3 j
was age appropriate.
0 m$ b7 h/ B+ v4 w8 m* Y; jThe family history was remarkable for the father,6 Y* q8 F2 G4 x' s* ]( @
who was diagnosed with hypothyroidism at age 16,
e0 b* f1 V/ ~7 d5 j hwhich was treated with thyroxine. The father’s
9 @6 D) O0 I1 g: Z/ V4 P* eheight was 6 feet, and he went through a somewhat: L+ V- M& k. g7 f' f$ u! a; T& N
early puberty and had stopped growing by age 14.
0 a% c5 b+ S5 R) NThe father denied taking any other medication. The- x" S. F( o7 W Q, y$ S# p
child’s mother was in good health. Her menarche
- ?* d. ]7 M( u `8 Wwas at 11 years of age, and her height was at 5 feet2 C7 \1 F) h o& N' X: S
5 inches. There was no other family history of pre-6 U$ K- d+ O# g; \( h
cocious sexual development in the first-degree rela-
. ~# ?6 V$ a3 Z0 Q8 {6 V2 V* S* g$ ltives. There were no siblings.
4 ^0 j3 j0 `" D( C N# S2 r$ u$ F/ s! IPhysical Examination
; d3 O/ t7 f. w; yThe physical examination revealed a very active," q( o( J$ ~! }: E+ S( {8 C
playful, and healthy boy. The vital signs documented
8 H- O) N* y/ `. z9 L- v# W s, ma blood pressure of 85/50 mm Hg, his length was
. [ ?2 q# s, l4 U5 [" t: v7 A90 cm (>97th percentile), and his weight was 14.4 kg
# Q2 a% x3 e5 ~: k(also >97th percentile). The observed yearly growth9 L8 w$ r+ [1 |% e' H4 e+ |
velocity was 30 cm (12 inches). The examination of$ u' f4 r1 e& x; e0 w
the neck revealed no thyroid enlargement.6 K" S$ u1 r$ @$ Q
The genitourinary examination was remarkable for# P; P7 E3 ~4 H. q; C
enlargement of the penis, with a stretched length of* `6 ^4 A6 k% n$ T9 ?! H
8 cm and a width of 2 cm. The glans penis was very well5 y' C+ n3 A( l1 e7 J8 [* X
developed. The pubic hair was Tanner II, mostly around1 G9 k8 P/ F2 @
540
: }: @$ Q+ U( z* Eat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from" S9 e, j9 ]/ \
the base of the phallus and was dark and curled. The9 w' ?, ^7 Y/ ~0 I! a2 D. T/ J
testicular volume was prepubertal at 2 mL each.8 F6 X. Q* y+ n$ Y% U
The skin was moist and smooth and somewhat& F1 x% Z, d; @8 U- u
oily. No axillary hair was noted. There were no+ ?7 n0 p! @( H5 u# g4 |! W
abnormal skin pigmentations or café-au-lait spots.
- X" P0 B; I( J( k6 INeurologic evaluation showed deep tendon reflex 2+
4 B; I3 [) ]9 `bilateral and symmetrical. There was no suggestion
0 h: O G- {1 t: }6 c2 t4 hof papilledema.8 G" m/ K7 L: s- s6 w, }2 l' S
Laboratory Evaluation
( P+ O- i8 i5 A$ i2 i/ {# RThe bone age was consistent with 28 months by
; ]& V* r6 g- n# K) {* G4 t lusing the standard of Greulich and Pyle at a chrono-
7 g$ A; R& W* U# @logic age of 16 months (advanced).5 Chromosomal
) G; ]- }3 ?5 |3 C& _" }. okaryotype was 46XY. The thyroid function test/ V" y! f) U* p% L
showed a free T4 of 1.69 ng/dL, and thyroid stimu-
) F) N2 W% `" d3 flating hormone level was 1.3 µIU/mL (both normal).
% y7 f) T/ i1 ]2 t N! ?The concentrations of serum electrolytes, blood
% @; T8 c# C9 N+ Curea nitrogen, creatinine, and calcium all were8 s% w/ q: f. D% @
within normal range for his age. The concentration. d5 O" a, X! S5 f6 U7 v5 c
of serum 17-hydroxyprogesterone was 16 ng/dL! i( u, E9 O; D: O# M- D/ p# ~# b
(normal, 3 to 90 ng/dL), androstenedione was 20
, P) g: B: [/ X" Bng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
7 Y$ s3 E1 p! z. ~terone was 38 ng/dL (normal, 50 to 760 ng/dL),
+ c& H, Y! _$ E: a; y5 D( Ddesoxycorticosterone was 4.3 ng/dL (normal, 7 to( [& A s' \/ P5 |& T3 t
49ng/dL), 11-desoxycortisol (specific compound S)) ` G2 m6 H0 b1 i
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
9 r% ~2 M. O/ I. b6 Y2 Ktisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
3 f: o& k! B4 S0 V9 v- O* dtestosterone was 60 ng/dL (normal <3 to 10 ng/dL),
$ S( Y$ y' [3 z D# Eand β-human chorionic gonadotropin was less than
! T% ] I; j6 g4 I9 }9 S4 `) _5 mIU/mL (normal <5 mIU/mL). Serum follicular
- p0 K# B/ w: B1 l' v. \0 Zstimulating hormone and leuteinizing hormone5 h7 W5 e9 ^0 N. P
concentrations were less than 0.05 mIU/mL
+ j% s" o9 A: A0 |(prepubertal).
" N* F9 p7 G- _6 i8 t6 _The parents were notified about the laboratory
# I; P& l+ D! W# E1 d1 H( u6 \) cresults and were informed that all of the tests were9 Z5 F/ ^3 ]/ K' Z
normal except the testosterone level was high. The5 x7 g% k. O" g5 k1 z$ E: z6 M' U
follow-up visit was arranged within a few weeks to4 V' Q" |6 X( K: B5 T1 ~9 u
obtain testicular and abdominal sonograms; how-& u# j; _% l: Z, c# ^9 \
ever, the family did not return for 4 months.
! b( P) ^4 r1 v3 SPhysical examination at this time revealed that the I! @' |- V9 m9 T8 c1 z/ p
child had grown 2.5 cm in 4 months and had gained3 M) h% l3 n5 K, q3 |4 n
2 kg of weight. Physical examination remained
1 t, n( h$ {! H6 R& }unchanged. Surprisingly, the pubic hair almost com-7 n" H$ e6 u `% X4 _- g$ d
pletely disappeared except for a few vellous hairs at% `* y# I7 t6 F. k4 Y& q7 G: q
the base of the phallus. Testicular volume was still 2
7 a: g% N4 [& `* @% u3 l, t0 H, RmL, and the size of the penis remained unchanged.
: x+ ^/ Z; Z; f$ i- [* m. f& A2 CThe mother also said that the boy was no longer hav-6 y) E; Q* o2 \# s) G% ^9 ?8 C* j
ing frequent erections.
% J: ^! n) Y! I- Q9 O' X9 \Both parents were again questioned about use of( [; i) Y( M7 f3 b* ?/ O# G
any ointment/creams that they may have applied to
) q3 X! u$ r! d5 P" |the child’s skin. This time the father admitted the
5 c# ]$ r, r/ k) k: pTopical Testosterone Exposure / Bhowmick et al 541* c' q3 `, G6 d1 u
use of testosterone gel twice daily that he was apply-" J0 ^- U* f- L0 y; B% V+ m
ing over his own shoulders, chest, and back area for
6 P- i% ]# q4 c# Q( |- La year. The father also revealed he was embarrassed
4 q; I1 o: J% ^to disclose that he was using a testosterone gel pre-8 _ R6 s2 G" p! U% Z! h
scribed by his family physician for decreased libido
: h+ {) ~. |5 P5 Ysecondary to depression.
1 { K/ c A9 ~- u( k& z3 NThe child slept in the same bed with parents.
5 j- N& d4 D* I6 f1 ?( [/ ^The father would hug the baby and hold him on his
/ |/ [- x- n1 K2 K0 S7 qchest for a considerable period of time, causing sig-: }; l) n% w/ U- N7 G* u% ~
nificant bare skin contact between baby and father.
& V; y& @7 x- RThe father also admitted that after the phone call,
. p- z- M. W4 e; W. {! L- A. b& R7 Twhen he learned the testosterone level in the baby
1 G) K4 f, d2 `) \' ywas high, he then read the product information5 x0 x. i$ v5 v, C8 T
packet and concluded that it was most likely the rea-
; O* m- k/ n# _4 ason for the child’s virilization. At that time, they
- u5 o" h. z' U4 y& ` e6 _decided to put the baby in a separate bed, and the
3 `8 F! s- j! j6 K* H- dfather was not hugging him with bare skin and had( R! N) p: I4 {# h: l
been using protective clothing. A repeat testosterone
7 A& ]+ h& q$ Ftest was ordered, but the family did not go to the2 D: y" A7 o+ k: |' V/ G% N8 t
laboratory to obtain the test.
6 e3 [# \, d) s; u" Y: SDiscussion
0 p; E, I1 O6 s! S/ T" d' PPrecocious puberty in boys is defined as secondary
3 r3 Q' c" r8 N4 L% r3 Usexual development before 9 years of age.1,4
6 a7 X) i! a8 `( F: i6 h. B6 T5 NPrecocious puberty is termed as central (true) when, z" z$ z, s9 @3 F+ P. C
it is caused by the premature activation of hypo-. h2 A+ Y4 @: K' y( c% C
thalamic pituitary gonadal axis. CPP is more com-5 c+ l2 P% \$ o0 q
mon in girls than in boys.1,3 Most boys with CPP
$ Z- j+ z$ Q, a# Q9 o$ }may have a central nervous system lesion that is6 R$ j' D2 [6 o9 Y; _
responsible for the early activation of the hypothal-$ z# S+ O3 Q0 b# P% z
amic pituitary gonadal axis.1-3 Thus, greater empha-: }. K& u+ d" O4 a+ E3 T1 X
sis has been given to neuroradiologic imaging in
9 f8 m/ r& E2 o( v! t6 r& p: y% Qboys with precocious puberty. In addition to viril-
* b q: t* N6 Z' kization, the clinical hallmark of CPP is the symmet-2 ^" V3 \+ G0 o' M' O
rical testicular growth secondary to stimulation by
" R0 x* I9 l+ K4 fgonadotropins.1,3; m" d) f1 O4 M6 X0 B. K+ E
Gonadotropin-independent peripheral preco-0 [ b3 G K* p6 I( W2 I1 Q
cious puberty in boys also results from inappropriate
3 j& S5 @& R/ E3 c$ Sandrogenic stimulation from either endogenous or
) j% e* R6 q( Aexogenous sources, nonpituitary gonadotropin stim-
@2 q- K1 W9 O; eulation, and rare activating mutations.3 Virilizing! @, l/ h% D B
congenital adrenal hyperplasia producing excessive
3 |0 P2 [8 s4 h2 p1 d3 kadrenal androgens is a common cause of precocious1 D4 c1 m& r1 P
puberty in boys.3,4% B* X6 M' V9 @8 |4 ?
The most common form of congenital adrenal
+ y& Z6 w) N( Ihyperplasia is the 21-hydroxylase enzyme deficiency.
/ d: P F1 h R+ IThe 11-β hydroxylase deficiency may also result in
" Q. w* X$ _4 ]. @' Z1 eexcessive adrenal androgen production, and rarely,8 f5 W" T4 \- v/ t2 ?
an adrenal tumor may also cause adrenal androgen
# p1 h# [, Z9 Gexcess.1,38 n+ k7 p) k4 k- }
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
: o6 p5 k5 e8 ]' X$ o6 T% }542 Clinical Pediatrics / Vol. 46, No. 6, July 20070 |3 o% |. b& }: a+ g2 P8 ^0 ~
A unique entity of male-limited gonadotropin-3 m2 v4 C& V2 ]
independent precocious puberty, which is also known$ D5 E) s+ S' ^: ]" S
as testotoxicosis, may cause precocious puberty at a
% }, q" @4 A; I! f; R: p* hvery young age. The physical findings in these boys2 {' s* G4 E5 `
with this disorder are full pubertal development, X( {# [0 @- N
including bilateral testicular growth, similar to boys
* [" s( A3 Y3 D; ^with CPP. The gonadotropin levels in this disorder
4 m# T8 c! R" j' W. t% z' [9 Y5 jare suppressed to prepubertal levels and do not show
" u9 h. _& K1 b( c2 cpubertal response of gonadotropin after gonadotropin-
8 l! u8 i& E- U5 h- n; T0 `releasing hormone stimulation. This is a sex-linked7 p5 @& y5 ?' N5 l, s( X
autosomal dominant disorder that affects only+ k) I( \0 a2 k) r" g, Y# _
males; therefore, other male members of the family
9 T$ e# u7 U: r& hmay have similar precocious puberty.3
% ~/ s, i% E2 @" p1 lIn our patient, physical examination was incon-
$ x1 q: N6 a: M# Z( ]# Ssistent with true precocious puberty since his testi-
9 |% T( g: y$ y; C& T- X! P. hcles were prepubertal in size. However, testotoxicosis# x/ X5 q ` V% L0 S2 F P
was in the differential diagnosis because his father' H0 J1 `. l5 u" n. u
started puberty somewhat early, and occasionally,
. J. E* q$ t6 M( M8 \testicular enlargement is not that evident in the2 x. X& p* i" L9 m5 G- W. r1 ?% e
beginning of this process.1 In the absence of a neg-6 H; d, o3 L) H' Q
ative initial history of androgen exposure, our k, q e0 K* ^1 ]. ^ B% S- N
biggest concern was virilizing adrenal hyperplasia,
0 F$ m7 i( p% q$ {either 21-hydroxylase deficiency or 11-β hydroxylase( F1 q }- L! v7 L' p" C: n3 V
deficiency. Those diagnoses were excluded by find-: E) a$ {7 _5 f/ G/ X0 C ~5 e
ing the normal level of adrenal steroids.
- q8 L% I! M4 o5 v6 K4 UThe diagnosis of exogenous androgens was strongly
4 I* S1 J/ ?+ i N( D: hsuspected in a follow-up visit after 4 months because
1 }7 k/ ^# L4 Y; ]) q1 ythe physical examination revealed the complete disap-3 U! ~% j- I) Z- A, B
pearance of pubic hair, normal growth velocity, and
' u/ I' t+ \% W) Q2 p, _- p8 Y( Ddecreased erections. The father admitted using a testos-
0 x0 X( u% D/ Nterone gel, which he concealed at first visit. He was7 ~# V- A& ^1 E
using it rather frequently, twice a day. The Physicians’, X7 X: [& R; V6 B* y; s
Desk Reference, or package insert of this product, gel or+ Z! \9 W4 z) a. c( w _
cream, cautions about dermal testosterone transfer to3 S W4 _$ b& w; y' N5 M. z6 Q
unprotected females through direct skin exposure.
. C" U. |2 k" ^6 ?* I/ Y6 |* N$ eSerum testosterone level was found to be 2 times the, k1 j: K% x% e% O* j* J, e# F4 {
baseline value in those females who were exposed to& {8 H0 E" J p9 Q0 V
even 15 minutes of direct skin contact with their male# S# p! ]" {8 r7 K! _
partners.6 However, when a shirt covered the applica-) Q7 V1 c2 l" V* B8 O% M' T
tion site, this testosterone transfer was prevented.
: s* S: i- P! l3 R% W- u }: a6 h: oOur patient’s testosterone level was 60 ng/mL,
! f, t0 J" e6 p: r4 c2 N* Jwhich was clearly high. Some studies suggest that5 t+ ]% E/ G4 v0 K0 u
dermal conversion of testosterone to dihydrotestos-9 F3 |6 K# P: Y
terone, which is a more potent metabolite, is more
9 i5 K; ?9 @) B5 n8 gactive in young children exposed to testosterone# r: Z/ D7 R2 J0 W3 j8 p* I7 ?# ?
exogenously7; however, we did not measure a dihy-: M" I8 @ I% j, S: j! V
drotestosterone level in our patient. In addition to& I) B y5 c& S( {4 f8 p* U
virilization, exposure to exogenous testosterone in7 U3 p# s! g) X
children results in an increase in growth velocity and9 }( n, J/ t9 U
advanced bone age, as seen in our patient.
4 Y. f" J. |; BThe long-term effect of androgen exposure during, B: B& C, z) T8 ]
early childhood on pubertal development and final- \# p! F3 a) Y$ K \# h4 k) Q
adult height are not fully known and always remain/ [$ }' u8 D# s: {( W) Y# z4 q
a concern. Children treated with short-term testos-
$ ?& a7 E# L% G- o, _terone injection or topical androgen may exhibit some
2 z0 g5 g2 p# g+ w( z) Cacceleration of the skeletal maturation; however, after% Q4 ]2 a9 e! U
cessation of treatment, the rate of bone maturation8 o3 L8 S9 k" E }
decelerates and gradually returns to normal.8,9
( u0 X4 ^" a* i4 iThere are conflicting reports and controversy
$ B0 g* B' a, w, mover the effect of early androgen exposure on adult# {8 ~* L$ |! T" g L: L. g
penile length.10,11 Some reports suggest subnormal5 ]7 _' O* y* X5 \
adult penile length, apparently because of downreg-- E- A7 u% Z" h+ A5 ~8 n: }
ulation of androgen receptor number.10,12 However,
7 E5 c' h R4 WSutherland et al13 did not find a correlation between# a! ^. f$ N) I5 X
childhood testosterone exposure and reduced adult& T$ H. l" W, L) s5 c9 c: f4 T0 w) B
penile length in clinical studies.
+ \; i* U) d" y% i k, g9 _Nonetheless, we do not believe our patient is
2 p; O6 Z q5 n+ _; h! agoing to experience any of the untoward effects from
( g9 M# L j6 ~ ?testosterone exposure as mentioned earlier because
2 f% d& @9 N3 |5 P% O/ Rthe exposure was not for a prolonged period of time.
( R* j7 i- D% w K( v2 sAlthough the bone age was advanced at the time of, w& Q7 j+ W) |: F
diagnosis, the child had a normal growth velocity at
o( a! z' C4 C4 S1 }' Nthe follow-up visit. It is hoped that his final adult
" Z2 R0 r6 A' m/ a! }height will not be affected.- O3 L/ x4 {' g
Although rarely reported, the widespread avail-$ }6 }( }& M4 Z: z
ability of androgen products in our society may
! O+ I+ m2 T C" o q- [! o6 E* d6 v% jindeed cause more virilization in male or female
5 f9 J+ d# h5 Z8 x/ Lchildren than one would realize. Exposure to andro-0 V# ~! F0 z0 R
gen products must be considered and specific ques-
9 @( R/ E! j3 L$ ytioning about the use of a testosterone product or
7 K/ K+ m* ?8 \5 `+ r" j# Hgel should be asked of the family members during9 v- j6 ]3 Z8 d# f$ ^$ z
the evaluation of any children who present with vir-# J2 ]/ T/ I5 h! O
ilization or peripheral precocious puberty. The diag-
4 K3 C! P* I1 J$ Znosis can be established by just a few tests and by
4 i/ r7 y2 u4 q6 F" J; Kappropriate history. The inability to obtain such a
; X/ e' v7 A; g% w: D1 a$ k @history, or failure to ask the specific questions, may
1 D, F0 h) V, m. Kresult in extensive, unnecessary, and expensive
- k4 x" G1 p% h8 pinvestigation. The primary care physician should be
Q- t8 E) q% V2 Zaware of this fact, because most of these children
: `% e4 X- S: K8 }: `7 k+ Hmay initially present in their practice. The Physicians’
! ?, g& T9 [/ ]Desk Reference and package insert should also put a1 `% Z0 Q9 U7 ~
warning about the virilizing effect on a male or
9 U) t, ]' i: k. y. p1 Nfemale child who might come in contact with some-* o. [$ K5 P7 |* _7 K! T
one using any of these products.; H7 J6 a) l/ W0 a% {; ~
References
# E4 {/ v9 C4 x6 o7 e1. Styne DM. The testes: disorder of sexual differentiation
( @$ D# O5 b! oand puberty in the male. In: Sperling MA, ed. Pediatric# L8 o2 ^. T8 D n- `
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
# R B( b3 u# V I- ]2002: 565-628.
* g$ T. a8 r# u) i! `4 S2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious4 ~' B7 K, {' M) b, m
puberty in children with tumours of the suprasellar pineal |
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