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Sexual Precocity in a 16-Month-Old
) c' W' P% n X6 h/ S) YBoy Induced by Indirect Topical
' I& X, n4 o' e/ j3 p5 Z$ uExposure to Testosterone5 `0 l+ Z) i! N( N: X
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
' x1 p8 }! n9 O: ?& S0 xand Kenneth R. Rettig, MD14 F3 P: k# W. Z S* L) z* r; `
Clinical Pediatrics, m# J( k u, W+ w9 n% N
Volume 46 Number 6; }2 E1 q$ @' H$ _8 u" H* M, U$ W
July 2007 540-543+ v8 H7 A! w, o& x/ O6 A
© 2007 Sage Publications
/ p5 Z# b- F/ q/ A0 q10.1177/0009922806296651) i- Z6 t4 c# F, w/ X& z2 h
http://clp.sagepub.com
4 _3 i ?. ?" Y9 xhosted at
$ k: ~- n8 O Ihttp://online.sagepub.com
2 W6 H8 K0 v) w# {; U: k0 nPrecocious puberty in boys, central or peripheral,
( w D8 D4 G# [# O2 ois a significant concern for physicians. Central& I* S3 C1 R0 L6 Q2 F+ c
precocious puberty (CPP), which is mediated$ p4 d) \! O1 R. O
through the hypothalamic pituitary gonadal axis, has# W$ J! P. i3 S" |( Y% O
a higher incidence of organic central nervous system: t0 U- s* d( K# j7 N
lesions in boys.1,2 Virilization in boys, as manifested4 V" `) j3 Y- A- p, K5 I' m
by enlargement of the penis, development of pubic
7 `, [8 i. M0 p$ ghair, and facial acne without enlargement of testi-7 `' a# M, Z4 p) k, c& ?1 e1 n
cles, suggests peripheral or pseudopuberty.1-3 We- @* }& o% j7 {& q5 j7 x( J/ L
report a 16-month-old boy who presented with the9 }+ k! i8 B5 o: O! i
enlargement of the phallus and pubic hair develop-
& r0 I% O! A8 `' ?5 L2 ]ment without testicular enlargement, which was due* P4 q0 ~. w; n5 y) G) T7 X
to the unintentional exposure to androgen gel used by3 S, e$ O! J4 e: Q9 \; U+ M8 h
the father. The family initially concealed this infor-
: }- |4 Q! M7 E8 \7 r! F) L. nmation, resulting in an extensive work-up for this
6 a8 R& U- W- T5 k% mchild. Given the widespread and easy availability of6 C& X- y& E4 _* M: c! O
testosterone gel and cream, we believe this is proba-
2 C3 D1 k; P0 ably more common than the rare case report in the
& Y: j: i/ u7 }/ x( N+ s0 O" H* Cliterature.4
: y; l# }$ M J; X( [Patient Report+ W7 t, Z& P3 q2 N5 b$ X6 @
A 16-month-old white child was referred to the: H/ A5 I1 Y$ O3 Z: }% T
endocrine clinic by his pediatrician with the concern6 i3 `: M8 ^' f0 S
of early sexual development. His mother noticed
" x/ [3 ~6 Z% q( Blight colored pubic hair development when he was: U2 V" s1 _2 s9 ~
From the 1Division of Pediatric Endocrinology, 2University of" \- Q# G# o! P8 w* ]+ g" @1 h& [
South Alabama Medical Center, Mobile, Alabama.6 D4 W0 c7 h& h6 T
Address correspondence to: Samar K. Bhowmick, MD, FACE,1 @* u r; F. z. c F7 G6 }
Professor of Pediatrics, University of South Alabama, College of1 J6 r2 L/ ]1 [+ w" _8 ?( M
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
P. L. c m' X. O5 re-mail: [email protected].( r! W' R2 z; m/ \! A
about 6 to 7 months old, which progressively became& D9 O6 y- S0 W0 Z$ E3 m
darker. She was also concerned about the enlarge-) G" k7 v6 j, ?( m S6 B. ^' Y* Y8 ~
ment of his penis and frequent erections. The child% K& |8 L: @' U& g
was the product of a full-term normal delivery, with
F$ ^$ @% F8 s- z: Za birth weight of 7 lb 14 oz, and birth length of' @* x$ i$ G7 o$ d1 l
20 inches. He was breast-fed throughout the first year
8 w2 R; G+ B: B3 T. y" `of life and was still receiving breast milk along with
' } a. |/ ?0 s4 \solid food. He had no hospitalizations or surgery,+ t5 o) x/ C; A6 y# c& z
and his psychosocial and psychomotor development" N7 k1 j5 g. R. N* x: H
was age appropriate.% n* s( ?( v6 d5 A; p
The family history was remarkable for the father,
/ I7 T% K% h4 `0 L" Iwho was diagnosed with hypothyroidism at age 16,
( ?9 w( r' H# t" D; Y6 N- Rwhich was treated with thyroxine. The father’s+ _+ D' G$ r9 [1 L7 {
height was 6 feet, and he went through a somewhat
9 E, G; k' H7 w4 _* Oearly puberty and had stopped growing by age 14.
* k' R# i! m9 gThe father denied taking any other medication. The
# D) ?/ [; m0 h, ^$ fchild’s mother was in good health. Her menarche; \! w3 N$ Q5 c0 w( `; D( O
was at 11 years of age, and her height was at 5 feet( @( D3 O6 I1 Y; z; j9 o- M
5 inches. There was no other family history of pre-
6 H! c- X: [ h- p, A2 ?8 r' V" |cocious sexual development in the first-degree rela-
* L4 s! |, D* Ctives. There were no siblings.. T5 m2 B' R; |( E
Physical Examination
6 n& X1 b+ G+ }" P, b: |# oThe physical examination revealed a very active,
0 L( E i+ g* [/ B; qplayful, and healthy boy. The vital signs documented
7 }3 f6 n9 V& \1 q! k7 Ca blood pressure of 85/50 mm Hg, his length was
2 _! o% R1 G# ^! w5 [90 cm (>97th percentile), and his weight was 14.4 kg, ]" l9 a5 ]1 a, X( S- T k: M$ k
(also >97th percentile). The observed yearly growth6 m" Y/ _ F, F% ]/ b
velocity was 30 cm (12 inches). The examination of* ]" H0 c: ~; p3 B: T* f+ V
the neck revealed no thyroid enlargement.3 E% U; ~1 c, Q) f A+ x% Z
The genitourinary examination was remarkable for
) g% [% Z/ w$ N" ?0 U( Z! Senlargement of the penis, with a stretched length of4 |# o: ~; d+ Z
8 cm and a width of 2 cm. The glans penis was very well6 B+ _7 h5 b1 t0 a' a
developed. The pubic hair was Tanner II, mostly around8 p: L8 c) y# m: @& X, O- m# Z
540
$ Y; K1 }) Z; i: U. aat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
0 l* b, a! c8 E8 J4 B' Qthe base of the phallus and was dark and curled. The" e' H1 d* t3 T( l1 z) w, q1 L0 m
testicular volume was prepubertal at 2 mL each.9 n$ k _9 g+ m3 @
The skin was moist and smooth and somewhat, z6 d8 c6 e9 T B) }& m' m
oily. No axillary hair was noted. There were no6 Q* [# a. C- T
abnormal skin pigmentations or café-au-lait spots., Z) W, e" }1 Y" c1 ]/ P; G7 S
Neurologic evaluation showed deep tendon reflex 2+* O) B7 G/ q' i! {
bilateral and symmetrical. There was no suggestion) p5 e2 Q5 \& p
of papilledema.& u V6 j4 c% ]" m7 m
Laboratory Evaluation
0 M% Y" d& f" D r% W. iThe bone age was consistent with 28 months by
# X- k9 I0 x8 C, q6 W2 susing the standard of Greulich and Pyle at a chrono-
* E* j, Q b; N6 t Zlogic age of 16 months (advanced).5 Chromosomal
7 [" Q7 ^' ^% c; C! E7 T2 Tkaryotype was 46XY. The thyroid function test2 c8 U0 A: f4 h. s% K( D
showed a free T4 of 1.69 ng/dL, and thyroid stimu-" X$ v7 `) o u2 M0 u/ _. V$ R
lating hormone level was 1.3 µIU/mL (both normal).
$ n9 K0 @# K% a0 W1 ]The concentrations of serum electrolytes, blood9 }$ \+ C8 t* t; o* ], }
urea nitrogen, creatinine, and calcium all were0 j/ H& R7 X: Z! ]. Q- C
within normal range for his age. The concentration
: K4 v. z2 R; |! Mof serum 17-hydroxyprogesterone was 16 ng/dL3 f" A/ w7 M B* b c( ~% _, U! W$ Z$ J
(normal, 3 to 90 ng/dL), androstenedione was 20 }" |. [0 ^, w8 u
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
- s7 q* \5 m) a7 ~7 Rterone was 38 ng/dL (normal, 50 to 760 ng/dL),
1 D: k5 a: v, U! C0 m& W4 @9 @desoxycorticosterone was 4.3 ng/dL (normal, 7 to
; v( e3 d, [5 O: s' y$ U# p49ng/dL), 11-desoxycortisol (specific compound S)
1 u3 {9 ?9 q3 e0 T) @( p0 Ywas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-' `: L, O/ S+ K7 e
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
# A+ [+ f# w Y: otestosterone was 60 ng/dL (normal <3 to 10 ng/dL),1 p/ r e' f e* |, U2 \- E+ A4 R
and β-human chorionic gonadotropin was less than4 T+ }; ~: ^1 U; w0 X; `
5 mIU/mL (normal <5 mIU/mL). Serum follicular
; v6 \4 Y2 W+ O3 Qstimulating hormone and leuteinizing hormone
' g! j. X% i9 D" {concentrations were less than 0.05 mIU/mL+ g+ W* o. e& Y8 N
(prepubertal).
7 w- h1 r; {8 i3 e+ ~# N' K# H/ h5 ?The parents were notified about the laboratory3 `0 d9 }9 k4 N" n% {6 u- n& I
results and were informed that all of the tests were
* ?- I. F7 x0 {8 m, Fnormal except the testosterone level was high. The0 ]# ^4 o( l6 ^7 `
follow-up visit was arranged within a few weeks to: b! J5 K, C3 R& Q) f* A8 T5 u
obtain testicular and abdominal sonograms; how-
" n% ] v8 I0 C' r( m9 C3 Tever, the family did not return for 4 months.' e2 ]( Z" R1 w, u8 W( q
Physical examination at this time revealed that the0 x0 s& k5 {2 {: J r
child had grown 2.5 cm in 4 months and had gained5 `+ I; z# @$ s9 i5 Z7 t. B
2 kg of weight. Physical examination remained/ M$ G; |- ?& h: R
unchanged. Surprisingly, the pubic hair almost com-0 Q) h; m" ?1 g
pletely disappeared except for a few vellous hairs at; S! [" O* E8 _( K$ b. m
the base of the phallus. Testicular volume was still 2
$ y0 p2 @) Y6 }: p* tmL, and the size of the penis remained unchanged." O6 V0 W' A0 s+ _1 F$ K1 g3 t7 J2 }
The mother also said that the boy was no longer hav-
: {1 h6 B) v5 H( H% f7 \ing frequent erections.9 ~* ^" [/ t5 K0 P
Both parents were again questioned about use of4 f$ z% {2 C, ?! U1 i
any ointment/creams that they may have applied to# M0 a( i2 f* S) c
the child’s skin. This time the father admitted the
6 L& {3 l+ z: t6 s" n" e* G. ]Topical Testosterone Exposure / Bhowmick et al 541 ^% x7 O6 [( E
use of testosterone gel twice daily that he was apply-
& `3 U1 I; Z- Z0 S. P/ ]ing over his own shoulders, chest, and back area for
6 l0 D/ J/ [# r6 l4 }# w0 xa year. The father also revealed he was embarrassed k; I* t F# q A' Z" e
to disclose that he was using a testosterone gel pre-
: D5 i; U: s: |$ nscribed by his family physician for decreased libido9 j8 j* w8 J, p* |$ |, U
secondary to depression.
. K$ j5 E& `# r7 QThe child slept in the same bed with parents.
% t' b6 i( x" d/ v- eThe father would hug the baby and hold him on his. I3 `4 Y4 Z5 A3 G
chest for a considerable period of time, causing sig-' Q1 K! M" x* N0 M
nificant bare skin contact between baby and father./ @& u/ D4 P6 y' Y: M/ H' r
The father also admitted that after the phone call,* S/ O' s7 S# g) ?8 t
when he learned the testosterone level in the baby5 W! Q% W- v6 T# K
was high, he then read the product information8 \" n7 ^$ S4 `3 O* R% J
packet and concluded that it was most likely the rea-+ N, m2 E. \' ~4 g: g/ y- V9 G
son for the child’s virilization. At that time, they
/ A9 _8 {8 R5 ?decided to put the baby in a separate bed, and the
( y' q. q2 d2 A5 o% o7 `father was not hugging him with bare skin and had# g* E- |- M3 Z( u5 i
been using protective clothing. A repeat testosterone& }# j& G" P7 I
test was ordered, but the family did not go to the/ m4 c* I j. A
laboratory to obtain the test.
1 V X i% ~+ c0 Y. Q1 LDiscussion1 s! T/ t0 b0 E9 m0 a: f
Precocious puberty in boys is defined as secondary
3 B9 I7 H% P! G7 ~, ^* T8 K: esexual development before 9 years of age.1,4
( J, {, G% @. W! p2 [8 X; b" tPrecocious puberty is termed as central (true) when
+ x- b- h' A0 v6 w" Y- t# z) J) y# pit is caused by the premature activation of hypo-
! s% c, k6 B9 j# J9 |, Othalamic pituitary gonadal axis. CPP is more com-+ Y. d) ^! g7 n
mon in girls than in boys.1,3 Most boys with CPP
2 p6 Z) P1 O7 R! B6 l$ G( o2 Lmay have a central nervous system lesion that is4 f- i/ v! c8 l$ \/ n
responsible for the early activation of the hypothal-
0 b' b3 h0 ~$ u% oamic pituitary gonadal axis.1-3 Thus, greater empha-
* I+ E- f5 S: C% o7 Rsis has been given to neuroradiologic imaging in
* w6 s) E( y8 w# }; h1 g' rboys with precocious puberty. In addition to viril-
3 v7 m" z& [1 l1 J4 Vization, the clinical hallmark of CPP is the symmet-! w9 Q% B* I& i7 i
rical testicular growth secondary to stimulation by; l$ o: t; f* k6 W3 u
gonadotropins.1,3. v& @( ^4 k+ i4 k5 Q
Gonadotropin-independent peripheral preco-7 U4 u$ t4 M$ k, [1 S
cious puberty in boys also results from inappropriate
. Y3 P" T% k; z$ Randrogenic stimulation from either endogenous or' ^; n2 H3 K" s( {* g0 }) |$ e
exogenous sources, nonpituitary gonadotropin stim-+ }& e( T7 Y4 y5 ~+ f/ `
ulation, and rare activating mutations.3 Virilizing
) `2 e2 c9 i0 ^( Icongenital adrenal hyperplasia producing excessive8 L7 a& {- Y& e
adrenal androgens is a common cause of precocious
) I b) Q3 B& m; Ppuberty in boys.3,4 C6 Q: V5 v- d$ N: b/ ~
The most common form of congenital adrenal
+ V; c* [ v# qhyperplasia is the 21-hydroxylase enzyme deficiency.4 e$ y- A4 y! L3 u
The 11-β hydroxylase deficiency may also result in) U" l g9 q; s) t; ?8 O. U
excessive adrenal androgen production, and rarely,
! \7 A+ x$ G: p x' j, d8 {an adrenal tumor may also cause adrenal androgen7 }% f9 \* `2 ]/ W- D
excess.1,3
T/ B/ M, T. ^& N& s* Z& [at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from* Y9 |2 S1 h6 h9 [) @
542 Clinical Pediatrics / Vol. 46, No. 6, July 20077 C+ M v' W& ?
A unique entity of male-limited gonadotropin-
( t0 U( A8 }- L q4 `' t3 |2 xindependent precocious puberty, which is also known$ p8 G4 B* e. y5 z
as testotoxicosis, may cause precocious puberty at a
* d2 O' @3 y. rvery young age. The physical findings in these boys
( v% E- L" }) K2 ^: R% awith this disorder are full pubertal development,3 r6 S! |4 r* @$ G
including bilateral testicular growth, similar to boys
1 s) M+ @$ F4 _0 Dwith CPP. The gonadotropin levels in this disorder
x4 ]/ ~, q7 V( M; ]& gare suppressed to prepubertal levels and do not show
8 f4 U& G: [7 H3 @) p# \pubertal response of gonadotropin after gonadotropin-
/ n4 k8 P' m6 y$ Creleasing hormone stimulation. This is a sex-linked" k& X! V# o$ I6 W
autosomal dominant disorder that affects only
/ F9 @3 v. T2 D S* L, U @' I: Umales; therefore, other male members of the family
; L% }% Y8 _6 [may have similar precocious puberty.3
5 H2 r% l; x9 K/ `8 c& ]6 e& }0 kIn our patient, physical examination was incon-" V% I; b+ f3 m! O }4 B
sistent with true precocious puberty since his testi-
: T$ S/ Y4 g+ W H$ n# {* kcles were prepubertal in size. However, testotoxicosis
' `+ j0 j" b. V( A- iwas in the differential diagnosis because his father
: i; [$ B% k8 n* o& gstarted puberty somewhat early, and occasionally,
" F) A- C3 F0 ^0 o9 Z5 c2 R1 ptesticular enlargement is not that evident in the
l4 n2 ]; q/ m% B$ V: abeginning of this process.1 In the absence of a neg-0 J1 R" g& z8 G. N! X) N, G
ative initial history of androgen exposure, our7 j$ |5 b! S4 ]: ?% n( u
biggest concern was virilizing adrenal hyperplasia,
5 H- }( F8 B) Peither 21-hydroxylase deficiency or 11-β hydroxylase
P9 ?: s. Z* e% P3 |deficiency. Those diagnoses were excluded by find-
3 K- m' ^" }2 r& j' O0 r) ^ing the normal level of adrenal steroids.8 t% ]- f) T$ _0 j1 }' S1 t/ ^
The diagnosis of exogenous androgens was strongly
# Y7 P ~* j; ?0 h) t1 Q: @% [, Rsuspected in a follow-up visit after 4 months because
2 s! ]- i' T, H7 G3 H7 T- S/ pthe physical examination revealed the complete disap-% k8 z) R: E1 [+ }6 I! u2 k, W
pearance of pubic hair, normal growth velocity, and
, z& Y( ^1 g: p7 p( Xdecreased erections. The father admitted using a testos-; |. s2 _3 J4 \- Y* N! w
terone gel, which he concealed at first visit. He was% ]; L6 c- h9 ]+ @0 q+ q
using it rather frequently, twice a day. The Physicians’
m5 G2 i0 Y) u- fDesk Reference, or package insert of this product, gel or: @. B, p$ m- p9 P8 b y+ G
cream, cautions about dermal testosterone transfer to; ^7 u5 A5 n! o7 ~
unprotected females through direct skin exposure.
+ r& d9 D: F2 N" ~& o ?Serum testosterone level was found to be 2 times the
; E1 v+ f6 Q$ y$ d# i- y# |* Gbaseline value in those females who were exposed to
( _2 i; ~. R! g& a) [& W' Geven 15 minutes of direct skin contact with their male
+ Q! o0 M! C( w- O9 \partners.6 However, when a shirt covered the applica-3 x$ T D) y& l: W/ L$ r# I) }
tion site, this testosterone transfer was prevented.9 t$ v' n' }* `1 l% }& p
Our patient’s testosterone level was 60 ng/mL,1 M$ Z( X1 m5 M% y5 `1 E
which was clearly high. Some studies suggest that
" @4 M6 }9 ?6 a% e, Rdermal conversion of testosterone to dihydrotestos-7 s n1 g7 {, X/ j* Y0 d- K
terone, which is a more potent metabolite, is more
* @0 @' F g0 dactive in young children exposed to testosterone
2 p: n! h# Z) D2 @, R9 `# texogenously7; however, we did not measure a dihy-
: Z. \; `2 N3 x. C# c9 J# \drotestosterone level in our patient. In addition to5 c& O0 A' T) J7 e( x+ ]
virilization, exposure to exogenous testosterone in
2 k! V: H7 C* k3 dchildren results in an increase in growth velocity and# W, ?" Q S. y! W# n2 N- I. o9 X
advanced bone age, as seen in our patient.
& {' n( Z1 x3 W) c/ ~5 `The long-term effect of androgen exposure during
9 R. \) @3 n+ N/ p6 x2 m! fearly childhood on pubertal development and final
# D, K+ k+ c" Madult height are not fully known and always remain
( t+ H8 x. ^ @a concern. Children treated with short-term testos-
0 Q, z' ]: i# B/ [9 t- Qterone injection or topical androgen may exhibit some p7 l; O* n/ g
acceleration of the skeletal maturation; however, after
3 u4 j+ F1 j* J; W9 j/ i; E7 Ycessation of treatment, the rate of bone maturation
2 P) D( D1 _7 ~) `; ?7 ?' L/ mdecelerates and gradually returns to normal.8,93 j6 a0 k: s; K2 ?" u
There are conflicting reports and controversy
: j" x. y: ~% i' j% H. w7 [over the effect of early androgen exposure on adult
$ h- m+ N% T0 ]/ apenile length.10,11 Some reports suggest subnormal+ V+ ?$ l2 _5 }: E- M1 a* \9 E
adult penile length, apparently because of downreg-
: Y" ]5 h- U* \- p5 e0 @ulation of androgen receptor number.10,12 However,
% g, |3 a2 M4 M( ?6 iSutherland et al13 did not find a correlation between
! P' C& V" ?! ?: t- U, ]childhood testosterone exposure and reduced adult$ x1 \# Y3 ^9 c4 M
penile length in clinical studies.
% R( @+ z2 I1 S; W, D" ~Nonetheless, we do not believe our patient is* w4 `1 ]1 C6 m; L: t& J6 ^' G
going to experience any of the untoward effects from
$ h# u2 \! J4 Y0 z M: Ftestosterone exposure as mentioned earlier because6 M1 x. c* K4 ]8 S- d3 y8 V
the exposure was not for a prolonged period of time.
; u) @- b/ ~1 F. i) P6 BAlthough the bone age was advanced at the time of
% l3 R- R, t& u" L2 {diagnosis, the child had a normal growth velocity at+ C4 E ^+ q: x
the follow-up visit. It is hoped that his final adult, N: U' X+ I# C
height will not be affected.
* e, z" S' T* _4 v) V1 r9 hAlthough rarely reported, the widespread avail-
- E) ^+ T; N0 K: n% X: W) jability of androgen products in our society may) X; A" A! |/ X6 H! L
indeed cause more virilization in male or female* o+ l# q& h* {+ y1 ~
children than one would realize. Exposure to andro-# Y" _6 ^+ N, o! N
gen products must be considered and specific ques-8 k; w1 i7 f/ j1 n' Y% u
tioning about the use of a testosterone product or
' X+ `# f3 {) k; l. k" y1 Hgel should be asked of the family members during
$ k2 F6 w# Z4 S A7 ^. [8 A' E W5 Gthe evaluation of any children who present with vir-. J4 |- q3 J- G. u; m
ilization or peripheral precocious puberty. The diag-5 { w/ Q) M; J) n' ~
nosis can be established by just a few tests and by
1 O0 d. f4 O7 Q7 X' ]2 s% G/ W8 xappropriate history. The inability to obtain such a
: {9 g0 n! o- W- Y6 Chistory, or failure to ask the specific questions, may0 c; w( k3 [2 v' o; U
result in extensive, unnecessary, and expensive
* v) ^$ s1 R/ N1 q! h+ P. v% iinvestigation. The primary care physician should be7 s) v9 A/ j% t5 o0 k
aware of this fact, because most of these children
" a) ` r- `& W0 K% umay initially present in their practice. The Physicians’ H0 k7 I4 R/ Z7 g9 `
Desk Reference and package insert should also put a; z( B9 V& o) Q* [
warning about the virilizing effect on a male or
, V2 X& X. J, {( I$ \$ K% a4 Ofemale child who might come in contact with some-; {1 T, @2 b: o" L9 c
one using any of these products.; T" c6 ?* b/ _! U: x8 e
References
" _4 ]) x2 R [& h3 x1. Styne DM. The testes: disorder of sexual differentiation
8 T9 J+ `+ M" aand puberty in the male. In: Sperling MA, ed. Pediatric
8 w$ {' w; s1 T7 B" C, r' oEndocrinology. 2nd ed. Philadelphia, PA: WB Saunders;' m+ X! @& `3 c7 V D; J1 F, E0 L
2002: 565-628.$ u( }8 X8 F: ^1 Q! Q2 p! k+ B" q
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
4 g* T- J" ^. p+ a, I. F% v4 Z( M8 apuberty in children with tumours of the suprasellar pineal |
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