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Sexual Precocity in a 16-Month-Old
" X. W$ R+ o7 `/ R2 {( S# rBoy Induced by Indirect Topical
( E: E+ c7 ^* d, c# |Exposure to Testosterone
. u9 d7 Y9 x. m- \5 C9 D* USamar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2* N! K9 _; g8 h: l! I: D/ c
and Kenneth R. Rettig, MD1# Z1 G2 g- `0 T4 D9 i I! l+ t
Clinical Pediatrics
& u3 |, D- X3 ]Volume 46 Number 6
; P6 r! b" t( j' H0 {8 B: CJuly 2007 540-5438 Q* F3 J( w7 C
© 2007 Sage Publications7 ?- y w! V7 y4 R7 f& I4 ^8 ]6 h
10.1177/0009922806296651# C1 p( w7 e, C: S. g9 X. j N! y3 B2 ?
http://clp.sagepub.com& B' C& j9 ]. b
hosted at
' r% G% d I! Vhttp://online.sagepub.com/ J9 Q1 G' D8 J7 y+ _/ p
Precocious puberty in boys, central or peripheral,
3 `) s- T7 d7 h. wis a significant concern for physicians. Central9 I1 H# G: ^- |3 M! X- l
precocious puberty (CPP), which is mediated1 y7 X% R4 {4 x1 [) h, e
through the hypothalamic pituitary gonadal axis, has) h9 t1 t: ^2 m4 {9 Z- O7 w! A
a higher incidence of organic central nervous system
1 q9 d2 \* }" C1 z, Wlesions in boys.1,2 Virilization in boys, as manifested
. L2 S# I& y8 {" T7 f# K5 t+ Yby enlargement of the penis, development of pubic
8 t1 U* A2 s( u7 F# W/ \. M, khair, and facial acne without enlargement of testi-
2 a1 n" U! E5 r9 t# S* s3 `; Dcles, suggests peripheral or pseudopuberty.1-3 We# n* L+ ~3 }/ p9 N+ x
report a 16-month-old boy who presented with the
* }1 L1 `7 a4 Q: Senlargement of the phallus and pubic hair develop-7 \. a9 x Q. C9 Y9 M% }
ment without testicular enlargement, which was due e2 ?# M: M* j; h3 F0 G
to the unintentional exposure to androgen gel used by
7 c& \; e1 r. }3 w6 L* [: c, _the father. The family initially concealed this infor-
( Y6 B, n4 j4 @* }2 B" ?9 [: Lmation, resulting in an extensive work-up for this4 c5 g4 f1 X8 U! P1 z
child. Given the widespread and easy availability of
C+ u( e g& Y a$ t* q' Wtestosterone gel and cream, we believe this is proba-
$ T( d# s6 P. q* D: k7 xbly more common than the rare case report in the
+ \3 b0 {! T9 \( Y& a% i0 J7 |literature.42 {' H6 A. k" P) S' P9 `" z/ B# A# X) j
Patient Report
1 D7 G" O4 m' w2 CA 16-month-old white child was referred to the, S# T' O/ ?4 M/ v6 r
endocrine clinic by his pediatrician with the concern" [/ Y2 ]9 ?: G+ K5 Y* |! q) m% Y$ y
of early sexual development. His mother noticed
7 q2 K! L: f4 c9 h8 H, jlight colored pubic hair development when he was
' _- o% e) ?; N6 `4 \; HFrom the 1Division of Pediatric Endocrinology, 2University of& Q- L$ z0 y: \1 V5 P" U+ C4 d
South Alabama Medical Center, Mobile, Alabama.$ }! {- b" {% S* Y! U5 s: F
Address correspondence to: Samar K. Bhowmick, MD, FACE,% `' V1 Z ^" J- x# u1 j4 q' K- B) |' G
Professor of Pediatrics, University of South Alabama, College of1 H% Y/ m3 q1 a& i5 [9 b* X
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
3 @7 W) d k6 \/ @2 J1 ae-mail: [email protected].* L2 p" O( P$ V1 `0 i9 \- B
about 6 to 7 months old, which progressively became* D4 z7 p3 h2 H: t
darker. She was also concerned about the enlarge-5 T5 D* N, k# |2 ~! l% Q6 y% U
ment of his penis and frequent erections. The child6 q) D& q' N9 N( o% |
was the product of a full-term normal delivery, with
- c5 a6 u' z1 |0 n5 ca birth weight of 7 lb 14 oz, and birth length of
A5 ^+ U6 i+ P. C( L20 inches. He was breast-fed throughout the first year% n+ S- M0 P# B/ C2 F, b0 @
of life and was still receiving breast milk along with2 x; S) k6 n+ y; y) D8 v
solid food. He had no hospitalizations or surgery,
# H; R# ~/ M+ c1 x, Aand his psychosocial and psychomotor development5 i5 g z- A2 w- f1 v
was age appropriate.
' Y' c2 {& J) e! @5 A, LThe family history was remarkable for the father,7 N- O2 s+ j) f9 d# U2 u
who was diagnosed with hypothyroidism at age 16,3 b% b9 G2 H7 i6 y5 Q$ a
which was treated with thyroxine. The father’s
+ P. z' n7 j# A* m! B# y% Dheight was 6 feet, and he went through a somewhat
1 a9 ~6 `* Y; J6 J+ i4 `1 G. zearly puberty and had stopped growing by age 14.* ^0 _+ K3 J1 U. m5 X# X
The father denied taking any other medication. The
# O$ P8 e4 {, n* C6 P+ `child’s mother was in good health. Her menarche
7 X% e% C0 V: T9 Xwas at 11 years of age, and her height was at 5 feet
2 o: J8 p) L% g8 d5 inches. There was no other family history of pre-
" U( i( m. O1 Q! i0 C; zcocious sexual development in the first-degree rela-7 p7 V; Q; y4 p1 K2 I5 f7 d" g# C, ?
tives. There were no siblings.# i4 }3 z$ R$ S K
Physical Examination! u. N! d: b9 A; t$ i! u4 B0 @
The physical examination revealed a very active,
% B) `% K" c( r3 B/ {playful, and healthy boy. The vital signs documented
7 f3 ~. I# B' ^5 Q: l; ^$ qa blood pressure of 85/50 mm Hg, his length was
; a5 ~! M) B/ D+ J! S7 H! B! w5 i90 cm (>97th percentile), and his weight was 14.4 kg8 W# K; p5 [/ {6 w
(also >97th percentile). The observed yearly growth
, r7 \+ D2 v% g) V( Avelocity was 30 cm (12 inches). The examination of$ p( X* e6 @9 Q& e
the neck revealed no thyroid enlargement.: w1 C% Q, [3 U& F
The genitourinary examination was remarkable for$ P+ ~& y% _# U, P" Y
enlargement of the penis, with a stretched length of: i: H3 i. {2 h. K' A4 s6 \
8 cm and a width of 2 cm. The glans penis was very well; U9 i' {# p- w& B
developed. The pubic hair was Tanner II, mostly around
, d3 Z3 N/ N, {8 C% ?- Y540
/ A8 P' c' t/ x8 `% [1 Vat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from! h& M' @9 ~( v. ^9 E& B
the base of the phallus and was dark and curled. The) a7 l7 d& C; |" n$ w) C! Z8 u
testicular volume was prepubertal at 2 mL each.
8 `5 y$ g2 G( ?6 f) x" XThe skin was moist and smooth and somewhat1 d: M+ C2 W7 ~/ J5 w& D$ |
oily. No axillary hair was noted. There were no
, ~7 A4 K5 x% { c0 p1 Wabnormal skin pigmentations or café-au-lait spots.
: r- x2 { L# s8 yNeurologic evaluation showed deep tendon reflex 2+: u7 t( r. Z+ z# E
bilateral and symmetrical. There was no suggestion
$ ^/ `9 `8 W2 |8 F* N/ Z( F5 g4 Kof papilledema.! @/ i0 P; Q$ `, [
Laboratory Evaluation6 b/ d( P. K0 d
The bone age was consistent with 28 months by
% r" u( U9 F! [% H. d* Iusing the standard of Greulich and Pyle at a chrono-
# I) D* Z. B i0 }, Q4 Tlogic age of 16 months (advanced).5 Chromosomal
# x2 _$ W! S( [% Hkaryotype was 46XY. The thyroid function test/ d9 O1 Q8 e- L5 F
showed a free T4 of 1.69 ng/dL, and thyroid stimu-1 P' O1 Y; j- h, r. J0 `
lating hormone level was 1.3 µIU/mL (both normal).8 Q, _9 t+ _9 Q
The concentrations of serum electrolytes, blood/ c) u; Y9 R1 |3 m, r
urea nitrogen, creatinine, and calcium all were& Z: c6 w- B1 \" }
within normal range for his age. The concentration
$ F* I1 t! I1 [* p" x4 |& g5 Gof serum 17-hydroxyprogesterone was 16 ng/dL
6 a. F. B/ E1 N% ](normal, 3 to 90 ng/dL), androstenedione was 20
" v2 }% Q, e4 ]9 X+ u8 _ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
' z. C# X, M. z% A+ bterone was 38 ng/dL (normal, 50 to 760 ng/dL), X1 E! h0 s, i2 m' r* {
desoxycorticosterone was 4.3 ng/dL (normal, 7 to
" L5 ^/ I% S. G+ [6 u/ y49ng/dL), 11-desoxycortisol (specific compound S)
/ o9 J. E# Z1 p7 j% awas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
9 ?6 |. E, Q# K n. h/ ttisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total& ~) u/ @+ X C, m
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),) n- X' L2 I& b% S+ z2 m3 h
and β-human chorionic gonadotropin was less than* y k! H8 ]3 n6 N+ _
5 mIU/mL (normal <5 mIU/mL). Serum follicular
9 X- l+ Z2 a2 s$ Kstimulating hormone and leuteinizing hormone' L: T2 z3 ]' L1 u j
concentrations were less than 0.05 mIU/mL
& W6 w" D! k. l( ?2 H(prepubertal).
3 `5 r8 j4 r& zThe parents were notified about the laboratory4 I9 E. j: p% ~6 [+ s
results and were informed that all of the tests were6 `' p1 L/ U! G1 V
normal except the testosterone level was high. The
7 D0 I; a1 D# F& M& kfollow-up visit was arranged within a few weeks to
7 _' |) i+ b& B( h, V8 C1 t& n1 ~obtain testicular and abdominal sonograms; how-
, S- ]" o' b0 L1 Vever, the family did not return for 4 months.
; s' N u4 Q' a" L0 _1 m4 G# oPhysical examination at this time revealed that the/ m8 W0 D3 _% _
child had grown 2.5 cm in 4 months and had gained
8 F- T0 h# ?# v* [& z9 y7 k9 a2 kg of weight. Physical examination remained
7 b: D. R% N6 ^/ h' Q1 Y9 Qunchanged. Surprisingly, the pubic hair almost com-
7 @# @* y& j* p6 v7 npletely disappeared except for a few vellous hairs at/ {' |& k* }) j
the base of the phallus. Testicular volume was still 2, Q( z3 o) l5 B, t7 c
mL, and the size of the penis remained unchanged.
$ A0 E& ^7 F; r4 PThe mother also said that the boy was no longer hav-
0 B' x- c6 `5 t; r3 ving frequent erections.
- ^' |) z& m+ A5 xBoth parents were again questioned about use of
* S5 V5 o( Z3 E# N1 t5 q, Many ointment/creams that they may have applied to
* |+ L% v3 n8 d. F7 Lthe child’s skin. This time the father admitted the5 R: j* t9 b3 v! Y( E; d
Topical Testosterone Exposure / Bhowmick et al 541
+ ^, l. M' k+ p7 ~& S Zuse of testosterone gel twice daily that he was apply-
7 w+ E- m/ p! ^+ `/ U8 u' cing over his own shoulders, chest, and back area for
* O; b* a& }1 |, Ha year. The father also revealed he was embarrassed9 T3 a9 D# S; [3 k( s
to disclose that he was using a testosterone gel pre-
! {! J* C X& r! S3 fscribed by his family physician for decreased libido0 N/ W/ H7 H4 o, K( _
secondary to depression.
+ [8 _$ @3 l/ @7 K0 k8 w |; QThe child slept in the same bed with parents., t0 F4 a5 @% b5 ?9 N; G7 a; Y/ j* ]
The father would hug the baby and hold him on his
/ R1 `3 r+ R/ |) g3 E$ c8 ?chest for a considerable period of time, causing sig-
+ J: J0 X G( r: z H5 Onificant bare skin contact between baby and father.7 w4 r' z; k& x, g5 }1 M
The father also admitted that after the phone call,, h% y0 G8 K7 Q r
when he learned the testosterone level in the baby
: P% ~+ w0 M$ A- M0 Vwas high, he then read the product information
0 o' k& G- `6 h. |: ppacket and concluded that it was most likely the rea-
7 q& P, t. r( f8 g, A9 Nson for the child’s virilization. At that time, they t- w. Y- I* b5 M# J
decided to put the baby in a separate bed, and the$ S' R+ P8 ?% Z9 @- W. ~+ K, h) b
father was not hugging him with bare skin and had& F/ v/ T" r% i; `, I) |& f9 L8 h
been using protective clothing. A repeat testosterone
. b1 r7 e$ Y6 j. V8 \test was ordered, but the family did not go to the5 D f7 s. D! y8 h: ]# B
laboratory to obtain the test.3 F! j0 c; J: }( d3 b% J9 `
Discussion
9 v! i% U0 c! k6 d7 A2 NPrecocious puberty in boys is defined as secondary
! r: P( k# C. Z% d g* g( l3 n5 P- _sexual development before 9 years of age.1,4( m8 Y" N1 e+ h! R; b8 U
Precocious puberty is termed as central (true) when
& C/ Y0 E0 r8 [% Pit is caused by the premature activation of hypo-. A3 a I2 e+ H6 e$ J
thalamic pituitary gonadal axis. CPP is more com-* j% K/ R* M7 s& q* H5 Z: a, s& i3 h
mon in girls than in boys.1,3 Most boys with CPP6 O$ i1 B4 v) h+ M6 p
may have a central nervous system lesion that is3 \2 Y5 A. @+ b; f6 F
responsible for the early activation of the hypothal-9 }9 D: b. j8 I: p& u0 P0 J
amic pituitary gonadal axis.1-3 Thus, greater empha-7 a6 U# c3 @, S" X: j7 m. e
sis has been given to neuroradiologic imaging in
/ p H% P4 c: ], ^- e$ oboys with precocious puberty. In addition to viril-
5 L, O7 _( p# z5 vization, the clinical hallmark of CPP is the symmet-
' F8 [+ j. F1 k) m& Q# ]rical testicular growth secondary to stimulation by- ]+ G! p8 h0 `9 P, i0 e) J
gonadotropins.1,3: t' u8 ~/ s& Z& J
Gonadotropin-independent peripheral preco-
G- }& W; L0 O9 fcious puberty in boys also results from inappropriate
" k! B- c ^+ d/ s# Y- N& ], ~androgenic stimulation from either endogenous or; B: F/ X( _& [5 ?5 Q
exogenous sources, nonpituitary gonadotropin stim-; N* h, n% S6 Z1 g" V$ \
ulation, and rare activating mutations.3 Virilizing0 c. p; F D3 W6 l+ }
congenital adrenal hyperplasia producing excessive* o0 s- A3 w; g
adrenal androgens is a common cause of precocious
8 D% S% t% o9 ?- hpuberty in boys.3,4
6 w, `, S' R0 W* pThe most common form of congenital adrenal# m, e: U) p6 j K+ @
hyperplasia is the 21-hydroxylase enzyme deficiency.4 ]* m4 P0 d) M# ^0 ?4 A d. p+ g
The 11-β hydroxylase deficiency may also result in
8 |1 o7 A9 t# r! dexcessive adrenal androgen production, and rarely,
& l& R/ L# k, uan adrenal tumor may also cause adrenal androgen: ~, T% r% |0 N1 g' d
excess.1,38 V* ]5 {) D" ]3 p) b& Q
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from* _7 z" D& z5 J, j
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007! L8 r5 r: k6 \: q5 ]
A unique entity of male-limited gonadotropin-! ?) z3 Y* Q9 Q/ {& X! E6 r
independent precocious puberty, which is also known- @" p4 ]7 D6 E; q
as testotoxicosis, may cause precocious puberty at a
, L( }& N/ Z0 |* c% }& Bvery young age. The physical findings in these boys
: J' l7 S' q; Y. qwith this disorder are full pubertal development,# X$ x0 S% H5 ~" F
including bilateral testicular growth, similar to boys
) j, t, D% p* |5 s% \with CPP. The gonadotropin levels in this disorder' p4 d% L% V" A# @
are suppressed to prepubertal levels and do not show" o! i& P/ d; C# f
pubertal response of gonadotropin after gonadotropin-% C6 d/ A' _$ Z+ m
releasing hormone stimulation. This is a sex-linked
2 G% o! \$ x. d: w3 ~0 Yautosomal dominant disorder that affects only+ h; P3 u; ^( M* N; p1 }: {# y0 i
males; therefore, other male members of the family
. e" \; n. M# z. tmay have similar precocious puberty.3- V3 w7 I( B. G, l2 e' V ]
In our patient, physical examination was incon-* } C2 Z, v$ G# _, q5 t: i# h
sistent with true precocious puberty since his testi-
7 F @: Q; u# M$ `& gcles were prepubertal in size. However, testotoxicosis
" H; J; O- g+ t/ ~0 {' X7 S5 Xwas in the differential diagnosis because his father7 K0 |1 F9 v4 S% }4 r9 K v7 F
started puberty somewhat early, and occasionally,
# o: V* @% b9 U0 W+ c! X3 C# F3 rtesticular enlargement is not that evident in the8 O9 R) ~' @) E5 p8 y) T
beginning of this process.1 In the absence of a neg-% Z) R2 D6 L( Q) [' h$ h$ f
ative initial history of androgen exposure, our; _; d# o& B d
biggest concern was virilizing adrenal hyperplasia,
5 v. c% z. g& P( X- \1 leither 21-hydroxylase deficiency or 11-β hydroxylase8 G, c$ [$ f5 Y5 [; g- l2 ~
deficiency. Those diagnoses were excluded by find-: c1 q* e) |0 W" s6 [
ing the normal level of adrenal steroids.
( }% T% h: y! J- ]The diagnosis of exogenous androgens was strongly' q# H# o& L* N. g
suspected in a follow-up visit after 4 months because% b R2 ?3 n7 O8 Z
the physical examination revealed the complete disap-$ p. V8 S% ?8 q) p2 l# P
pearance of pubic hair, normal growth velocity, and
7 k7 q5 P& F& F9 w" K# Gdecreased erections. The father admitted using a testos-
, b4 S& ]) q+ Q4 D$ Vterone gel, which he concealed at first visit. He was9 h, j L* l' ^" h; k' ~$ V
using it rather frequently, twice a day. The Physicians’5 S7 ~% G+ n/ B6 q
Desk Reference, or package insert of this product, gel or2 X( x; F/ I: X# E6 J
cream, cautions about dermal testosterone transfer to
% M; b8 M+ }1 t; ~3 aunprotected females through direct skin exposure. Z7 T2 f7 S7 S+ s( ]5 @8 k7 A
Serum testosterone level was found to be 2 times the
( s, K+ ]: u6 j$ l5 j1 C* m- Ubaseline value in those females who were exposed to
4 U* S1 _8 l3 s% {* g* _even 15 minutes of direct skin contact with their male4 d/ C4 ~, ]0 {/ j2 S
partners.6 However, when a shirt covered the applica-
& J: n: m/ {% U8 ^& Qtion site, this testosterone transfer was prevented., G8 ]; h8 r$ k2 [6 U5 l
Our patient’s testosterone level was 60 ng/mL,: |5 m4 X9 d% M& U: |+ |$ V' ~
which was clearly high. Some studies suggest that
$ `/ U5 f% J8 q- B$ Z jdermal conversion of testosterone to dihydrotestos-
. Y' O8 X6 f$ u: }' e/ \# Xterone, which is a more potent metabolite, is more% X+ ^, [! G0 |
active in young children exposed to testosterone. A; E* g) B2 U! O' h. H
exogenously7; however, we did not measure a dihy-
& v$ c6 r" Y$ O5 g# u) wdrotestosterone level in our patient. In addition to
2 s/ U2 Q( e( }virilization, exposure to exogenous testosterone in
6 P+ u- \. R. ]! Q0 ~children results in an increase in growth velocity and
+ v) w0 M6 w: m% }5 w ladvanced bone age, as seen in our patient./ G! \: I, k( e3 m$ X3 Y" O
The long-term effect of androgen exposure during/ d4 ^( x z5 B( n, f- h# c
early childhood on pubertal development and final
* ] u: E2 \9 q- hadult height are not fully known and always remain) D. D5 n& ~- p' K- Q, A
a concern. Children treated with short-term testos-2 c: ~( }$ l4 R( S: `
terone injection or topical androgen may exhibit some
7 k) a8 Q% {6 I8 yacceleration of the skeletal maturation; however, after
/ k, d3 o- h/ u' t( scessation of treatment, the rate of bone maturation* H. z5 {( |8 Q2 _ U# X; a
decelerates and gradually returns to normal.8,9
3 X. M. n5 {* m9 \& c1 U( x- `There are conflicting reports and controversy
4 h1 E2 r& [/ Q5 v/ ~over the effect of early androgen exposure on adult$ ~5 g/ T0 O7 Z& P1 W
penile length.10,11 Some reports suggest subnormal+ [4 w" H) S- g) b6 l) A. u- `
adult penile length, apparently because of downreg-0 P- _4 c1 q+ l6 |7 D: F
ulation of androgen receptor number.10,12 However, ?" B5 G1 ?# g5 K4 M! V
Sutherland et al13 did not find a correlation between$ b- B0 y% ?6 W
childhood testosterone exposure and reduced adult) w; v2 j G+ i, U" U8 j
penile length in clinical studies.! F+ A, T; K+ U7 C( F {
Nonetheless, we do not believe our patient is6 \7 j3 b" A. I! [" E, x+ ]
going to experience any of the untoward effects from: y" S$ V# p% x5 K+ t
testosterone exposure as mentioned earlier because
2 s! x" |% H* C1 u" M5 rthe exposure was not for a prolonged period of time.
1 b6 h" y1 ?/ O: V+ W! G) {' h" vAlthough the bone age was advanced at the time of
* C+ L! X7 Q0 B4 e8 }6 o& Ldiagnosis, the child had a normal growth velocity at! C4 K7 H% q3 C
the follow-up visit. It is hoped that his final adult0 }: e- @8 E5 k3 L, A' K% N2 d
height will not be affected.
$ \! h/ ?7 Z( W7 c* TAlthough rarely reported, the widespread avail-
; f* P) `- w8 [5 g9 Aability of androgen products in our society may
! H3 n% B. u, O' Cindeed cause more virilization in male or female% J8 S: S& N7 K$ ?: B
children than one would realize. Exposure to andro-4 R9 s2 _2 ]7 d& a% h+ s5 `* Q
gen products must be considered and specific ques-
" X( l. \' i. v$ P" H. F2 ntioning about the use of a testosterone product or$ V3 k& [0 {' ^/ v! F& C- x
gel should be asked of the family members during: w7 ? T& |* c) t+ a
the evaluation of any children who present with vir-
5 ?4 p6 q9 p9 V( y8 c& P: yilization or peripheral precocious puberty. The diag-
& D# M$ U8 o6 M. [2 cnosis can be established by just a few tests and by9 L r# b7 h. _# L
appropriate history. The inability to obtain such a7 q: a) j& @) q) J( Z
history, or failure to ask the specific questions, may- s2 `4 K; a0 K9 l: P% u
result in extensive, unnecessary, and expensive5 B" U" q& X% F
investigation. The primary care physician should be7 `2 g& P7 W: |! t
aware of this fact, because most of these children& J) ^% }4 b& Y+ a
may initially present in their practice. The Physicians’
! f- H! k$ v. Y) CDesk Reference and package insert should also put a' }/ J- A* G4 R1 b1 C; T
warning about the virilizing effect on a male or) Z& L0 _/ I% o* v& A$ I
female child who might come in contact with some-( E- N& ~ d9 O+ a
one using any of these products.) @& I0 J& B# ~, q0 q
References
: f, a/ }! ]; E1. Styne DM. The testes: disorder of sexual differentiation2 ]& H4 a' a9 j* S. S1 W, C
and puberty in the male. In: Sperling MA, ed. Pediatric
2 M8 S" b3 K. E$ I" NEndocrinology. 2nd ed. Philadelphia, PA: WB Saunders;, D( k- |* {* ^4 @% C8 ]4 v4 h; {+ I0 F
2002: 565-628.8 z1 @; ~: E* _1 ]- T: X
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
`6 }9 A7 U+ @7 fpuberty in children with tumours of the suprasellar pineal |
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