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Sexual Precocity in a 16-Month-Old" _' M( n2 E1 ^, y# D( R
Boy Induced by Indirect Topical$ f/ @1 S. n# `9 a5 |
Exposure to Testosterone% h4 y. L D* R* X2 i
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,29 ~1 \9 X4 P `. z8 l, }) z {3 q
and Kenneth R. Rettig, MD18 b$ L/ t& _2 [: Y/ ?: a1 ?
Clinical Pediatrics8 c2 m% z) `, W7 \' F' w
Volume 46 Number 68 v# F8 O& D$ F" d: g1 `
July 2007 540-543+ x& s5 m, v4 u ^) M0 b; V
© 2007 Sage Publications8 S8 C; u, i4 T% S' j9 r
10.1177/0009922806296651' c3 U+ d8 ~2 O* {1 e Z5 v1 K+ B4 B0 s) Z5 z
http://clp.sagepub.com- q% M" z# O0 k7 F+ A% F, b
hosted at7 {9 o) L2 u) O4 l" e& v
http://online.sagepub.com; {8 `# @1 R. Y
Precocious puberty in boys, central or peripheral,
- |0 L- G2 W: Q' j5 Y5 o9 c* v6 o* ris a significant concern for physicians. Central* s+ ~7 ?% x' k( m
precocious puberty (CPP), which is mediated
0 e; x0 l# E+ Q% U2 Sthrough the hypothalamic pituitary gonadal axis, has
0 c$ a3 I/ Z# | T7 d9 Ga higher incidence of organic central nervous system
& e9 t+ J0 N1 Q6 _lesions in boys.1,2 Virilization in boys, as manifested
; S# y$ z. @1 P/ yby enlargement of the penis, development of pubic
% R" w8 o& n# A& }; a8 Nhair, and facial acne without enlargement of testi-# S) Z% U$ T' e
cles, suggests peripheral or pseudopuberty.1-3 We+ s& l$ r" D3 ~' ~" o4 O4 u1 E
report a 16-month-old boy who presented with the
( h: G* V7 B1 U3 k Henlargement of the phallus and pubic hair develop-0 z( Q$ J, Z7 n, e
ment without testicular enlargement, which was due
1 n# L! O/ A3 i( \3 D [; oto the unintentional exposure to androgen gel used by
6 B8 e% W4 ]2 c8 Kthe father. The family initially concealed this infor-
4 p# p- u/ g {1 L5 A9 I8 Dmation, resulting in an extensive work-up for this8 Y o Z6 _ }$ s+ N0 G- S
child. Given the widespread and easy availability of3 J$ Q# |" j& Q" K% r( m
testosterone gel and cream, we believe this is proba-1 G1 p8 l5 C) Z0 C( x( P7 N
bly more common than the rare case report in the
) U1 c2 b% |2 c* o% Y; b/ eliterature.44 ^* z" s: e: O
Patient Report4 ~% _* t& b- y# V1 m
A 16-month-old white child was referred to the
' ?8 I S; v! Q& k" cendocrine clinic by his pediatrician with the concern
+ ~, }. a$ w6 X7 D. {' o3 Uof early sexual development. His mother noticed2 I1 a% R( D$ O# Y( ]$ E
light colored pubic hair development when he was
& }8 A/ o( g sFrom the 1Division of Pediatric Endocrinology, 2University of/ C3 u- a; l1 W& `: N3 U' ~
South Alabama Medical Center, Mobile, Alabama.9 s) F- G }4 ]* \7 R
Address correspondence to: Samar K. Bhowmick, MD, FACE,
+ v7 g2 J( Y- x. n5 N5 WProfessor of Pediatrics, University of South Alabama, College of* h1 f$ m1 {$ D
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
, D Z1 j: N: d! J* Ue-mail: [email protected].2 F; N8 b) G/ h3 y
about 6 to 7 months old, which progressively became- a B5 t3 ?( ~3 ]# a# z7 u0 D
darker. She was also concerned about the enlarge-
4 X/ a( {# B9 B% W: ument of his penis and frequent erections. The child9 D8 N r. h0 [' z! R
was the product of a full-term normal delivery, with4 R0 P4 M4 k) r! a! T B; c
a birth weight of 7 lb 14 oz, and birth length of. g% R3 q _2 l, a( x% m
20 inches. He was breast-fed throughout the first year
6 K. K6 F$ c. t3 L/ Hof life and was still receiving breast milk along with3 m c" B. W: u8 |
solid food. He had no hospitalizations or surgery,
* [7 v% ]4 @2 y6 t3 C* B2 E7 aand his psychosocial and psychomotor development; J: E$ U6 p9 U2 w b
was age appropriate.% L; @* ?% ]+ P
The family history was remarkable for the father,! F1 C4 Y/ u2 V1 t+ Z( B
who was diagnosed with hypothyroidism at age 16,! J! D# P% n: G; f& t6 \: Q) T
which was treated with thyroxine. The father’s
3 a! `* N2 d- }8 A6 bheight was 6 feet, and he went through a somewhat8 q* [0 Z& k/ K( U; {* P6 |, P/ |8 {
early puberty and had stopped growing by age 14.+ @8 c: v: d" h2 @+ @# [2 T! `: p9 U
The father denied taking any other medication. The. a% `, X3 w, D. W7 a/ I- u: c0 ]
child’s mother was in good health. Her menarche
# ^" F9 R- S4 o- ]: D& Ewas at 11 years of age, and her height was at 5 feet" e% B7 @$ a- @3 j- D3 J) W) a' _; T
5 inches. There was no other family history of pre-5 o+ y8 |0 g. R% F* P
cocious sexual development in the first-degree rela-- r/ K$ U3 N" ~7 `' _( _0 c
tives. There were no siblings.
# V; U2 q1 d6 n5 A0 S6 { [Physical Examination
$ ?) z0 k2 U0 |4 C( F. |( OThe physical examination revealed a very active,
! ^7 G; j0 K z% cplayful, and healthy boy. The vital signs documented O9 m, F) Z J: [+ X/ v
a blood pressure of 85/50 mm Hg, his length was
5 ]# K* ~4 h- Q; R" @% [2 I90 cm (>97th percentile), and his weight was 14.4 kg
$ C+ ?' K9 x* \; ]+ u6 J! W(also >97th percentile). The observed yearly growth: O, B% y& Z+ j2 M! ?5 R
velocity was 30 cm (12 inches). The examination of9 k) k: U" z4 U5 }6 f5 Z
the neck revealed no thyroid enlargement.& n5 O3 c- [' v& Y0 r- c) }) P( j
The genitourinary examination was remarkable for; x0 Q# m# y; J, Z7 Y
enlargement of the penis, with a stretched length of6 U" F4 c0 F, T* f5 T) g" V
8 cm and a width of 2 cm. The glans penis was very well1 N& n0 a% R _5 w( I* I+ h7 }
developed. The pubic hair was Tanner II, mostly around$ a+ J4 x! G. b9 A( Z+ {
5401 N7 ]& \, e1 n, d
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from/ r$ [6 |) H2 I0 n; a7 M: y
the base of the phallus and was dark and curled. The
% J! ]. t" P* k% L1 Qtesticular volume was prepubertal at 2 mL each.
, s- g9 V$ V1 B% q' N- ^' d3 k. o8 ]The skin was moist and smooth and somewhat" I8 o" p" k G) `9 i
oily. No axillary hair was noted. There were no' d' O2 q: _7 B
abnormal skin pigmentations or café-au-lait spots.
& u0 @" k7 e7 L( [, BNeurologic evaluation showed deep tendon reflex 2+! d) ?6 s' G6 c: I
bilateral and symmetrical. There was no suggestion/ T8 ]5 R/ y% q6 R9 d/ v7 _
of papilledema.: ~+ o; H9 l) f7 N9 t
Laboratory Evaluation
5 J0 `, m5 `- G/ UThe bone age was consistent with 28 months by' ?& v. S4 K. O4 l4 N& N
using the standard of Greulich and Pyle at a chrono-
; x& L" o' K0 a1 S1 |logic age of 16 months (advanced).5 Chromosomal& L, U2 J. U7 ?+ I
karyotype was 46XY. The thyroid function test
1 d- M$ e7 A) e1 J& t/ Tshowed a free T4 of 1.69 ng/dL, and thyroid stimu-
q& ^# d5 Z% x0 [+ c) R, Clating hormone level was 1.3 µIU/mL (both normal).
) f5 S" \+ n% O6 UThe concentrations of serum electrolytes, blood! \, ^1 s* i+ L$ k
urea nitrogen, creatinine, and calcium all were
" @4 p; E/ K' g& M; nwithin normal range for his age. The concentration
b& d$ N) a" q% O0 v- X) c) |" K0 ~6 wof serum 17-hydroxyprogesterone was 16 ng/dL* [7 y. J5 o( m4 I
(normal, 3 to 90 ng/dL), androstenedione was 20- E1 ?' v6 g; O
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
+ c2 |+ h8 Q, E/ Y) B3 f! N5 z+ tterone was 38 ng/dL (normal, 50 to 760 ng/dL),9 U8 c0 M0 v1 i q
desoxycorticosterone was 4.3 ng/dL (normal, 7 to, C- K: O0 ]% o; w4 G4 N0 O. r5 [
49ng/dL), 11-desoxycortisol (specific compound S)
6 k2 R7 r1 `$ A$ Awas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-* F/ | ^2 I0 \& k# ?9 x
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total+ m( l0 ]7 |7 Q: b3 L! `3 d' F* c
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
+ h8 a& K7 ~' A! d4 yand β-human chorionic gonadotropin was less than$ h) k. P& ^" G1 ^! A5 E9 Y( b6 w0 N
5 mIU/mL (normal <5 mIU/mL). Serum follicular
3 q# Z7 N |- M4 bstimulating hormone and leuteinizing hormone
4 g3 n# L9 J! i! b# T1 }, Y5 z; @concentrations were less than 0.05 mIU/mL
T: R) i" }& |: O: U+ p k(prepubertal).
) w+ r5 t5 J, }9 s% AThe parents were notified about the laboratory' u y7 s/ D5 B, N9 h
results and were informed that all of the tests were n" Z( n- [) w4 R3 ]2 c
normal except the testosterone level was high. The1 s: b( a# W& r1 _4 z( ~
follow-up visit was arranged within a few weeks to/ a$ j0 w; L0 k' E: s# J
obtain testicular and abdominal sonograms; how-
$ z, L/ i% A* m) A8 Oever, the family did not return for 4 months.% j& ]9 J- Q: A! P7 F
Physical examination at this time revealed that the! b/ x- j2 W# R7 b6 C2 d9 z
child had grown 2.5 cm in 4 months and had gained
; W0 b* S7 ?7 Q8 x% ]6 p3 A2 kg of weight. Physical examination remained
7 ^% j3 C" I! z6 K( i& {unchanged. Surprisingly, the pubic hair almost com-
7 a6 {, F, ^# k/ j* @2 R2 @pletely disappeared except for a few vellous hairs at
- G; X% [3 r- ]1 f5 r$ F5 Bthe base of the phallus. Testicular volume was still 2
% n. P% T* M( y5 ?% QmL, and the size of the penis remained unchanged.0 a4 s7 N) S( l/ H2 K* F0 }
The mother also said that the boy was no longer hav-
+ C% p6 v, k& j9 {7 aing frequent erections.0 W( r! `9 B, [" q0 m, ]8 T
Both parents were again questioned about use of+ W; D) [' v T) R5 N/ F
any ointment/creams that they may have applied to
- S8 y# [, }3 ythe child’s skin. This time the father admitted the, o3 |& r3 c: t" K" N) x+ m
Topical Testosterone Exposure / Bhowmick et al 541- t' n+ U5 M2 V. K% T1 V% B% }
use of testosterone gel twice daily that he was apply-
( P: p H+ N7 |5 M* |ing over his own shoulders, chest, and back area for$ j' i$ f. {% E- k0 U. f
a year. The father also revealed he was embarrassed
% a2 f( L1 p, i! y/ @! f! zto disclose that he was using a testosterone gel pre-
: F! n. w$ O4 `0 u2 Fscribed by his family physician for decreased libido& X. P9 e" E5 K, h( o& {
secondary to depression.; w4 Y- J* V# V
The child slept in the same bed with parents.
" E0 B+ `0 Q T8 p6 e6 J: @7 sThe father would hug the baby and hold him on his1 R/ B8 I$ f. I2 y% {1 l
chest for a considerable period of time, causing sig-1 \5 i" E. D3 j& L( q, u' [
nificant bare skin contact between baby and father.
3 K% ]4 \& A$ i0 iThe father also admitted that after the phone call,
9 T& n. B4 n. j& c4 T, ]9 [when he learned the testosterone level in the baby; i @# {. o) E7 E+ [1 B
was high, he then read the product information
# }9 x- e% `" z9 f1 W5 D- Upacket and concluded that it was most likely the rea-
( |2 p$ G2 @' i* |, tson for the child’s virilization. At that time, they
8 \$ B: t8 F1 c+ \+ r/ adecided to put the baby in a separate bed, and the
- c3 M }2 J, C; C$ z$ {* Kfather was not hugging him with bare skin and had* W1 K4 g2 t7 J0 [0 @
been using protective clothing. A repeat testosterone
6 K$ |2 j; x5 Wtest was ordered, but the family did not go to the
" D; z1 ?+ d& Q$ C0 X6 a" tlaboratory to obtain the test.
5 {, o2 i l& A: }Discussion
z" \8 n/ a5 V5 Q* s+ NPrecocious puberty in boys is defined as secondary. n( x( ]4 N* i3 I
sexual development before 9 years of age.1,47 a) Q! r7 \5 B6 L9 A+ n
Precocious puberty is termed as central (true) when$ I2 h& O0 T3 V+ D) R& Q& _1 }
it is caused by the premature activation of hypo-! T3 C% l& ^( T* n' m! R
thalamic pituitary gonadal axis. CPP is more com-
9 W+ R: k: |+ e, f. l3 W3 I7 Lmon in girls than in boys.1,3 Most boys with CPP
1 v0 l: w: ^$ W! I! o' j6 Emay have a central nervous system lesion that is: J2 G9 t# s2 M1 }! }/ A9 {
responsible for the early activation of the hypothal-! N! c. N0 J/ w
amic pituitary gonadal axis.1-3 Thus, greater empha-! u& ]3 t, {) p# c- {
sis has been given to neuroradiologic imaging in
5 a6 o1 m. M; T6 W5 k8 B \boys with precocious puberty. In addition to viril-
* x+ @1 y- {; Qization, the clinical hallmark of CPP is the symmet-( i* q& b% [( x- }% h, x2 w
rical testicular growth secondary to stimulation by0 G1 b1 {4 b1 Y0 [
gonadotropins.1,3
7 v# k$ ?- H2 z nGonadotropin-independent peripheral preco-
9 T( h1 E D2 k6 Ycious puberty in boys also results from inappropriate! z/ c1 q2 N# P6 t, q r' L9 f
androgenic stimulation from either endogenous or
9 g6 z8 N' g- }- ?- P$ r4 Fexogenous sources, nonpituitary gonadotropin stim-
3 n8 d: P& {$ C/ }ulation, and rare activating mutations.3 Virilizing$ h+ f, q* ~0 a
congenital adrenal hyperplasia producing excessive
6 j, u# F9 p# v5 Badrenal androgens is a common cause of precocious
?* h' }% K; _2 j( ^puberty in boys.3,4
7 R5 \* C" r( t5 qThe most common form of congenital adrenal
) G8 `8 H3 }5 F, {" \hyperplasia is the 21-hydroxylase enzyme deficiency., P. n! Y) Z4 H
The 11-β hydroxylase deficiency may also result in
d: }. H" X& ~4 D, H% jexcessive adrenal androgen production, and rarely,- o+ ]5 S3 Q% \1 O8 w1 \& Y* L' Y
an adrenal tumor may also cause adrenal androgen- Y7 h2 j# x3 K Q; Y3 `
excess.1,3
* T0 s' z L6 Z. z; Pat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
3 X& r! M2 Q5 T% ]1 y: G542 Clinical Pediatrics / Vol. 46, No. 6, July 20076 X4 U6 w7 M( a+ s7 o8 E; M0 K7 {
A unique entity of male-limited gonadotropin-
% W8 I! Q+ I! f# Y9 cindependent precocious puberty, which is also known
9 k( a" U; B- g1 cas testotoxicosis, may cause precocious puberty at a# \0 M& [8 g5 r* B' y- p2 U- B
very young age. The physical findings in these boys: V0 L( c- j _% h; s
with this disorder are full pubertal development,
, ]+ G3 p! S+ K! \3 Z7 w7 ^( Uincluding bilateral testicular growth, similar to boys$ M I( y* I% q
with CPP. The gonadotropin levels in this disorder8 }+ K7 G% s* r* w7 i
are suppressed to prepubertal levels and do not show3 u) u. l" X: ~
pubertal response of gonadotropin after gonadotropin-
; P3 A5 x2 C. \$ sreleasing hormone stimulation. This is a sex-linked# }/ G/ c3 N) x" j3 W' g
autosomal dominant disorder that affects only9 A8 @% O2 ~) C3 e- i
males; therefore, other male members of the family
( P$ y$ Y$ ]( A& I* G7 R1 `1 Dmay have similar precocious puberty.3
6 p: X' k6 E) u, Y5 YIn our patient, physical examination was incon-
( t p D9 H$ m' ksistent with true precocious puberty since his testi-
6 w* e: P+ x& ~" [- ?( kcles were prepubertal in size. However, testotoxicosis" p3 P& D# C6 ]# Y$ a9 X6 x: U- q
was in the differential diagnosis because his father4 x& Q* _& k' H* z5 I
started puberty somewhat early, and occasionally,
. n4 M6 Q( j; atesticular enlargement is not that evident in the
. P3 o2 M" r5 G8 S4 S8 A/ Wbeginning of this process.1 In the absence of a neg-
) j, b' ~' @: L+ t' ^& n3 uative initial history of androgen exposure, our4 u* q H" a* B/ `' t/ S
biggest concern was virilizing adrenal hyperplasia,8 w0 a) F1 C* e& L
either 21-hydroxylase deficiency or 11-β hydroxylase' w/ D7 I6 @ l2 K; I9 n+ v
deficiency. Those diagnoses were excluded by find-: g9 x0 Y) u6 h% j) S- l0 F' T
ing the normal level of adrenal steroids.
`: J" E' {' G9 |% DThe diagnosis of exogenous androgens was strongly
1 h) ]" T* v: c: T8 _$ ]suspected in a follow-up visit after 4 months because
1 L. Z9 E0 j. K- hthe physical examination revealed the complete disap-
6 N5 P* D" E( b E! ~ K Kpearance of pubic hair, normal growth velocity, and
2 g; J! o! X$ [9 t1 qdecreased erections. The father admitted using a testos-9 g r7 g0 d4 i# Y
terone gel, which he concealed at first visit. He was
0 `* _& a" M7 x; xusing it rather frequently, twice a day. The Physicians’. W0 x' Z2 q8 {) x7 K5 i6 W
Desk Reference, or package insert of this product, gel or* J! \% \+ k2 B
cream, cautions about dermal testosterone transfer to
" `! E& Q4 U! N8 t' Aunprotected females through direct skin exposure.
, G1 ^9 z3 c! uSerum testosterone level was found to be 2 times the# P" c$ A, o7 C9 q% S4 H
baseline value in those females who were exposed to
. ]. C' W, l( j( T* Q8 K$ Qeven 15 minutes of direct skin contact with their male7 i+ t) z( N9 }$ e3 O! t+ q
partners.6 However, when a shirt covered the applica-; y1 V+ G1 q* r k, i% W
tion site, this testosterone transfer was prevented.
3 x# n+ V( O5 y5 }, e8 AOur patient’s testosterone level was 60 ng/mL,
( V1 o0 ^4 @( f* |. Z0 swhich was clearly high. Some studies suggest that
9 P- g: x( d- pdermal conversion of testosterone to dihydrotestos-
2 m/ t3 i( _3 m& eterone, which is a more potent metabolite, is more3 F8 M8 j: G) }4 \3 e) T0 e
active in young children exposed to testosterone
" p1 P; m5 n6 q6 f" Sexogenously7; however, we did not measure a dihy-
: h. _9 {% C. \drotestosterone level in our patient. In addition to
: H6 v0 U/ p {- `* Ovirilization, exposure to exogenous testosterone in
1 K& h) I3 k2 h3 d6 ochildren results in an increase in growth velocity and; `7 [) A7 `% D5 e* ] S% L
advanced bone age, as seen in our patient.. K/ T) R# `4 _. Z$ M4 b
The long-term effect of androgen exposure during: k4 J8 I @% j4 F; C5 M
early childhood on pubertal development and final- j" h- m' n' a Q- v/ q& v2 J
adult height are not fully known and always remain
f! c3 a# B K" b' Pa concern. Children treated with short-term testos-
) q8 N! } ~1 s0 i. Uterone injection or topical androgen may exhibit some
# b- f$ _" w+ x4 Wacceleration of the skeletal maturation; however, after
0 ^/ a+ }: ]5 z# e3 G9 }4 ycessation of treatment, the rate of bone maturation5 ]# d- x7 F% c+ @$ o& v
decelerates and gradually returns to normal.8,9
) z; n9 {/ d) U3 _9 wThere are conflicting reports and controversy4 r) K2 p' s/ z$ a9 o
over the effect of early androgen exposure on adult" F) @6 ^7 }5 e* m
penile length.10,11 Some reports suggest subnormal# W3 N4 {0 y, P* Y. f
adult penile length, apparently because of downreg-& G1 l0 x- x9 c/ |
ulation of androgen receptor number.10,12 However,
, V$ D7 Q$ W, K5 k7 }Sutherland et al13 did not find a correlation between, k' [) U( t9 P# v$ n6 o
childhood testosterone exposure and reduced adult3 P. u" h- i Z5 Z
penile length in clinical studies.
6 v+ `( y4 _0 Q1 s' k4 U6 |Nonetheless, we do not believe our patient is& T% I4 s* o& T+ J% t+ q; J6 W! n# B
going to experience any of the untoward effects from0 {: M7 e" y; B: {% f) t" M( ]0 b
testosterone exposure as mentioned earlier because
, M( S0 i1 D* n' ?5 ^7 |the exposure was not for a prolonged period of time.
& v2 D& _1 \2 b" {7 N! G: SAlthough the bone age was advanced at the time of
; o! g1 K( |7 J' T0 Jdiagnosis, the child had a normal growth velocity at
+ [2 P% ?4 S, P: r- |2 i) S; H& w- W; Gthe follow-up visit. It is hoped that his final adult. {& m) K- K- d8 ~$ U0 l
height will not be affected.
) v! k/ a- _; Z7 sAlthough rarely reported, the widespread avail-
4 ^, @% k* w# A1 y! p9 J ~ability of androgen products in our society may
5 x) _0 U3 a+ Nindeed cause more virilization in male or female
- t b) G, N, r0 E. F( C5 q. }- fchildren than one would realize. Exposure to andro-
# c! `+ M& v5 Q" c! Wgen products must be considered and specific ques-
3 O+ q8 x: l8 ]1 G+ i' qtioning about the use of a testosterone product or
! ^7 q- t; W7 M* q' ^gel should be asked of the family members during
" J. E/ J( O6 b5 lthe evaluation of any children who present with vir-
" X1 r5 c( z+ O9 Vilization or peripheral precocious puberty. The diag-
: B D: s4 j6 M1 d- Onosis can be established by just a few tests and by
7 x. y! O( u# @8 |( V* k7 W0 Y4 Xappropriate history. The inability to obtain such a: W6 p" p+ _/ ]% W
history, or failure to ask the specific questions, may
/ ^7 \, V- C" z3 s7 Z/ `8 }result in extensive, unnecessary, and expensive- a: f4 t5 `3 N" Q
investigation. The primary care physician should be
6 }$ u O. {- e5 I; kaware of this fact, because most of these children
; }# e% M5 R d+ j q2 }may initially present in their practice. The Physicians’5 _0 d) O9 n$ I% C$ ?! u0 J
Desk Reference and package insert should also put a$ `# r( M. B: h: l. O& f' T( d6 C/ U( \
warning about the virilizing effect on a male or# l( O# c' \# g
female child who might come in contact with some-5 w; j; g4 p ], I8 h7 m3 \$ C
one using any of these products. ]* \0 I1 `4 F/ Z2 Q, K
References
! ?3 `5 X$ W! F6 h8 G1. Styne DM. The testes: disorder of sexual differentiation
" C8 ^ e* V% d* U% v9 m" jand puberty in the male. In: Sperling MA, ed. Pediatric
& T- B: m3 E+ P# ?* j" zEndocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
; B4 p& A9 W" h$ \: B, E2002: 565-628.+ d ~1 o9 ~. G7 k5 x1 d4 _
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
. K9 m, Q8 H# j, B. lpuberty in children with tumours of the suprasellar pineal |
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