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Sexual Precocity in a 16-Month-Old
1 ~! S+ D, a6 v% {- Y" v, lBoy Induced by Indirect Topical
* S: G' h+ V8 |* JExposure to Testosterone
) } {4 v6 ^! j) P( nSamar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
6 W3 ^- I2 u9 z0 |3 Qand Kenneth R. Rettig, MD12 T1 L* C- R7 U3 x5 K) M0 o9 B
Clinical Pediatrics- ]/ z8 P' h) a6 d6 p) K1 {/ H/ a
Volume 46 Number 6
& a$ [5 H. `4 t; A# jJuly 2007 540-543( U, S8 m* h, a
© 2007 Sage Publications
& }, f$ R0 g3 B& x( `- b10.1177/0009922806296651, H( T3 Y7 M& O* v( W2 _
http://clp.sagepub.com
; I7 ]4 L* e* Shosted at T2 h/ y9 q" W1 f0 V/ [& _' i
http://online.sagepub.com
8 V8 j/ E9 O9 oPrecocious puberty in boys, central or peripheral,
; n5 E. ]5 |9 U1 \; d% m2 H+ y" Wis a significant concern for physicians. Central
; C0 S. q$ N2 J, o! wprecocious puberty (CPP), which is mediated$ i; T9 A& J2 s y& h& ~9 u1 q
through the hypothalamic pituitary gonadal axis, has
4 l+ m. y: e% Aa higher incidence of organic central nervous system
. F5 Z3 m2 ]5 Z, Q% e9 R2 Wlesions in boys.1,2 Virilization in boys, as manifested
) O5 Z4 C8 o- t4 Hby enlargement of the penis, development of pubic# W% K& N K" N: H
hair, and facial acne without enlargement of testi-
8 a6 @. t/ _. l3 G3 ]9 ^cles, suggests peripheral or pseudopuberty.1-3 We; L) r( K6 u j+ x
report a 16-month-old boy who presented with the
) C6 G; q8 K( \9 D8 ]9 kenlargement of the phallus and pubic hair develop-; J' i1 P0 D9 j1 U1 U6 d. }
ment without testicular enlargement, which was due4 B4 J3 t" H8 T& z
to the unintentional exposure to androgen gel used by/ ?$ @6 Y' Q8 g* M' x
the father. The family initially concealed this infor-
$ D5 l6 O3 h% W' N$ X6 k- p! q7 dmation, resulting in an extensive work-up for this# D3 p: e5 d: b6 }
child. Given the widespread and easy availability of. q6 \ k) I% {: ]+ J9 V% O
testosterone gel and cream, we believe this is proba-! x$ L# M: A2 t2 O" a% N8 s
bly more common than the rare case report in the; O% Q7 s$ {) Y' m; B6 f, t
literature.4/ @5 h* k+ l1 D8 w
Patient Report g6 S; j2 t; i& u& G. [
A 16-month-old white child was referred to the
8 Z0 r0 O% b1 ~3 Kendocrine clinic by his pediatrician with the concern
" @6 `! b" A4 uof early sexual development. His mother noticed
4 _; k1 H" |: }0 C l1 [9 G5 R/ Nlight colored pubic hair development when he was! T. z* i* r! q) K3 E
From the 1Division of Pediatric Endocrinology, 2University of, _1 a7 A) a! E% G& u
South Alabama Medical Center, Mobile, Alabama.
. j1 o) s" ~- x$ P' ^7 q NAddress correspondence to: Samar K. Bhowmick, MD, FACE,% t# E8 F" S( v3 a- _+ Y
Professor of Pediatrics, University of South Alabama, College of
8 G' J) L: f: L% T+ L: {Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297; g# d5 C- a! {8 }, f
e-mail: [email protected].( r; j! u3 @& N
about 6 to 7 months old, which progressively became, O4 f, F* t- W1 o% }
darker. She was also concerned about the enlarge-
4 A1 \) n& r- [! G2 }6 pment of his penis and frequent erections. The child1 J9 b5 V; J* h2 {5 @+ L$ }9 Y
was the product of a full-term normal delivery, with1 I) g! A7 _2 d- G+ j
a birth weight of 7 lb 14 oz, and birth length of
0 V: c$ l Z7 U" F4 y& W# q20 inches. He was breast-fed throughout the first year1 a" G. E% Y& |; v8 M/ C
of life and was still receiving breast milk along with
& v7 l+ N0 P6 lsolid food. He had no hospitalizations or surgery,# C, s9 f- Z( M8 G7 M: {
and his psychosocial and psychomotor development# g- c* a. f1 l# f$ y- X
was age appropriate.
, G2 y2 h# j; A+ vThe family history was remarkable for the father,) G0 u( L, Z0 ~* b
who was diagnosed with hypothyroidism at age 16,
& i6 O: T! p% i: Z8 _: q0 Vwhich was treated with thyroxine. The father’s
" G" |5 f L5 f* C/ i& Oheight was 6 feet, and he went through a somewhat8 j3 X( a2 Z0 e' B! ]; v
early puberty and had stopped growing by age 14.7 y) w' N* P" W" s- I' `3 a1 r
The father denied taking any other medication. The& o( D8 v- j- G9 {( s" Y, A
child’s mother was in good health. Her menarche2 k1 ?& M9 l+ d0 L9 R
was at 11 years of age, and her height was at 5 feet) \. j' a# J l9 u) ]% V
5 inches. There was no other family history of pre-
, h, }2 @, }0 h+ h, Bcocious sexual development in the first-degree rela-
) H1 e4 q& J L" ^9 L5 i2 ntives. There were no siblings.
% z3 F! Q4 f4 y( h y$ m6 ?( E3 DPhysical Examination
) m# B+ k2 I" z* B( J& ]* j, fThe physical examination revealed a very active," X+ c% O* ]4 ]) A2 c X
playful, and healthy boy. The vital signs documented
5 G/ ]# Z* E5 m2 \7 Ma blood pressure of 85/50 mm Hg, his length was3 k, r4 j* M& b# a5 p3 l
90 cm (>97th percentile), and his weight was 14.4 kg
' D- E- G% f+ Y, {' L# A, C; Q8 R(also >97th percentile). The observed yearly growth8 V+ x! f% b2 R
velocity was 30 cm (12 inches). The examination of4 `4 O2 w7 s. ^$ n$ p# {
the neck revealed no thyroid enlargement.
3 z% P, D# v! k9 _; S& wThe genitourinary examination was remarkable for! l: N: O5 [( D! _3 f# k
enlargement of the penis, with a stretched length of
" Q0 x/ f" R* [ I" O8 cm and a width of 2 cm. The glans penis was very well
5 g! p: k, A2 z! [0 Tdeveloped. The pubic hair was Tanner II, mostly around
4 {5 A, H k, H9 B6 p, g* s540: q) u3 V- a! u* A0 b
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from- l3 L" |9 A4 a9 U6 G
the base of the phallus and was dark and curled. The
! V( Z1 [0 N5 I" u8 ~- k8 {testicular volume was prepubertal at 2 mL each.7 }4 W+ l! v, c9 ?1 Q* Z$ X* R
The skin was moist and smooth and somewhat* u' Q( }. _/ N* h
oily. No axillary hair was noted. There were no/ q$ {) X/ ?; o3 S6 g* M6 W" B
abnormal skin pigmentations or café-au-lait spots.7 c. S' J, a4 ~, p) w" Z3 m
Neurologic evaluation showed deep tendon reflex 2+
Q- @- c0 y: V% W9 x0 J7 K5 J; Kbilateral and symmetrical. There was no suggestion# Q8 v" s; `( V% u
of papilledema.
( W$ x7 S6 {* @0 l6 sLaboratory Evaluation" G! ]2 m% R8 L) X
The bone age was consistent with 28 months by3 Q: O' ^; O: g. a
using the standard of Greulich and Pyle at a chrono-0 T) Z8 ^: c5 _: ^
logic age of 16 months (advanced).5 Chromosomal5 K: j% s, `/ l) Q7 \) F1 p
karyotype was 46XY. The thyroid function test
b2 u5 q; C& nshowed a free T4 of 1.69 ng/dL, and thyroid stimu-; g% i7 r' ]: r- H, j8 Z
lating hormone level was 1.3 µIU/mL (both normal).) D) i$ A- C; q$ Z$ b
The concentrations of serum electrolytes, blood2 s! V0 A/ Q2 E" \7 u
urea nitrogen, creatinine, and calcium all were
. e$ I; \& B" m2 Nwithin normal range for his age. The concentration5 ]1 y2 |5 t. l# G4 B
of serum 17-hydroxyprogesterone was 16 ng/dL
9 i* z8 [* j! {8 x, {4 E, d6 `(normal, 3 to 90 ng/dL), androstenedione was 20
1 F0 P" C! z; Y* |& jng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-9 f% Y8 ~+ _' Y
terone was 38 ng/dL (normal, 50 to 760 ng/dL),
" U# X$ v, t/ z Pdesoxycorticosterone was 4.3 ng/dL (normal, 7 to- y7 u) w$ W! P6 O; `! N
49ng/dL), 11-desoxycortisol (specific compound S)
_ [) x, k2 Y ?2 E Q! r/ r, \was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-1 g0 |: X9 l) h" O7 G
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total' C1 n z4 G- ~; y1 z8 i
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
" p5 @9 a6 X/ K8 C* E4 Pand β-human chorionic gonadotropin was less than
% J! p: q {3 [; U$ t1 s& q& w2 S5 mIU/mL (normal <5 mIU/mL). Serum follicular
. n! E- Y# E7 }stimulating hormone and leuteinizing hormone/ d: x# |$ ]! G% g/ @8 V' N% ~
concentrations were less than 0.05 mIU/mL2 u/ l1 l7 O% x5 y
(prepubertal).
( \) T5 P) A2 }* _8 h# vThe parents were notified about the laboratory6 ~2 U/ n0 ~' |' e- w! [
results and were informed that all of the tests were9 G/ C: N: s/ y2 d6 t1 k$ K# G
normal except the testosterone level was high. The% A# f# G+ U2 T- p( W0 l( I+ S
follow-up visit was arranged within a few weeks to
' Y) i! {# x3 O( e' jobtain testicular and abdominal sonograms; how-: N8 k7 |' Z0 w/ I, s' k
ever, the family did not return for 4 months., q% y5 a- Y9 L
Physical examination at this time revealed that the: ]% N/ q* W7 n1 J
child had grown 2.5 cm in 4 months and had gained
5 ^% D' V6 ~- G! f2 kg of weight. Physical examination remained# M2 }$ ?# B K0 l2 S
unchanged. Surprisingly, the pubic hair almost com-! R0 |" |, |/ f! V$ ]
pletely disappeared except for a few vellous hairs at. j9 n0 f" y7 q! t! @$ k
the base of the phallus. Testicular volume was still 26 b/ h& m {! E7 h6 W
mL, and the size of the penis remained unchanged.9 ~1 F8 k4 I8 B$ a6 q; c
The mother also said that the boy was no longer hav-5 V% p7 Q8 k- t$ l; B
ing frequent erections.* i- @9 e, i" v8 a- ?4 r
Both parents were again questioned about use of
6 J+ C' V, u$ h8 dany ointment/creams that they may have applied to
v: ~1 v; x6 ]) A6 J8 ^the child’s skin. This time the father admitted the' x1 Y2 S7 b1 R3 I
Topical Testosterone Exposure / Bhowmick et al 541
5 ~: e) p T' Xuse of testosterone gel twice daily that he was apply-1 @; i% l0 [9 t) |/ G
ing over his own shoulders, chest, and back area for( D9 P4 I/ s: \3 ^
a year. The father also revealed he was embarrassed
: k; {2 p# o2 n4 _ M1 x% ^to disclose that he was using a testosterone gel pre-) ~: @3 n# k8 W- Y& w8 e+ c! _ C
scribed by his family physician for decreased libido
. g4 r; r1 S: hsecondary to depression.
: a1 k0 F) z- n1 d# K! CThe child slept in the same bed with parents.
* g6 c4 G4 t& z2 m3 _1 a: W2 h# aThe father would hug the baby and hold him on his7 Y* ~ |" q1 b
chest for a considerable period of time, causing sig-6 R: f% T" Q% A4 x2 I; x7 f. K
nificant bare skin contact between baby and father.
: D# _- X/ i) OThe father also admitted that after the phone call,
- T' K( }/ Y/ l t( E5 d/ Xwhen he learned the testosterone level in the baby; W# _/ ?" o& \# m6 M5 H0 B' r
was high, he then read the product information: G9 o/ C' \' \5 y. Y9 ~
packet and concluded that it was most likely the rea-
/ X: l( B# D) ~8 `2 H% z. Dson for the child’s virilization. At that time, they+ Y* l* Q5 w: k6 B' p
decided to put the baby in a separate bed, and the
I( g; X2 I: s+ a Z0 |- m6 K( x4 Ifather was not hugging him with bare skin and had
- U5 H/ C" }2 b; obeen using protective clothing. A repeat testosterone/ s! N7 F8 I" C3 u f9 q9 n4 F
test was ordered, but the family did not go to the) m- r; v, f2 ?; c
laboratory to obtain the test.
+ ?5 M, x7 Z1 w8 e$ kDiscussion$ S& K- `7 e; K. f; [3 \3 B# X; V
Precocious puberty in boys is defined as secondary
Z6 ?% \1 ]+ o* f, F; }sexual development before 9 years of age.1,4
) @+ S2 t: L% x& A z# ?' lPrecocious puberty is termed as central (true) when$ ~3 b% f( f0 a6 @4 p# Z
it is caused by the premature activation of hypo-
$ Q n2 W5 \- athalamic pituitary gonadal axis. CPP is more com-
: @" i% X, `& Jmon in girls than in boys.1,3 Most boys with CPP
9 Q, m( O- h' D" ~) b+ cmay have a central nervous system lesion that is
: i( R9 a1 S" {; iresponsible for the early activation of the hypothal-: u) `' b# Z* z
amic pituitary gonadal axis.1-3 Thus, greater empha-
9 {% `6 k Y! p( q$ Xsis has been given to neuroradiologic imaging in
- V# P9 R- r/ x- q% m. E* Q$ Fboys with precocious puberty. In addition to viril-
/ r) S+ D+ Y/ }* t3 H7 ]1 p) kization, the clinical hallmark of CPP is the symmet-9 t" N1 t" e, M
rical testicular growth secondary to stimulation by
/ s/ d! z% ^8 T4 [7 T! L% F$ {gonadotropins.1,3
/ U2 l5 }1 L7 ?' z M/ ZGonadotropin-independent peripheral preco-0 D# r$ F X3 M% H. L. g# N
cious puberty in boys also results from inappropriate9 D9 ^5 ~( h. [* P. ]" I
androgenic stimulation from either endogenous or5 E" \# O- {. r r
exogenous sources, nonpituitary gonadotropin stim-
6 d% J8 b. D/ I2 l* p, r% Rulation, and rare activating mutations.3 Virilizing8 z. J4 d. R3 K% j5 C7 }6 |5 y7 ?: J" \
congenital adrenal hyperplasia producing excessive& d+ v' ^2 X7 E @; P& P
adrenal androgens is a common cause of precocious
) R8 n- q. g3 _7 ppuberty in boys.3,4
+ z& S! u, e) r8 m: E7 M- HThe most common form of congenital adrenal
0 C \- @/ s# m3 D5 ~3 p- nhyperplasia is the 21-hydroxylase enzyme deficiency.+ |, z! T& V, P+ J3 ?
The 11-β hydroxylase deficiency may also result in
6 j0 e; x, d5 J# }" [8 r4 K( P w1 X4 `excessive adrenal androgen production, and rarely,; t7 E0 O0 l3 t
an adrenal tumor may also cause adrenal androgen
; |: @, T$ n2 Eexcess.1,3& J c6 n3 e. A+ {8 Z
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from! u+ R0 V' T H2 v6 |5 a+ `
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007$ K4 _0 n) }! i7 c- d
A unique entity of male-limited gonadotropin-$ v0 C) B' T6 i8 x1 ?% f7 b, Z
independent precocious puberty, which is also known
( `+ \0 Z' E) {+ @ r& F; Sas testotoxicosis, may cause precocious puberty at a
9 k9 X' m" b, H( C S6 Y1 Uvery young age. The physical findings in these boys- ?3 p$ Q. V! I5 a" m0 G% g
with this disorder are full pubertal development,4 \) e7 s- Y% s0 [; ?: V/ Q- W
including bilateral testicular growth, similar to boys. ~' i5 @. k! W: ?% G7 E7 K n X/ K
with CPP. The gonadotropin levels in this disorder- o9 }: e+ @( l9 Q
are suppressed to prepubertal levels and do not show
( S7 i* E$ Q& O! N: rpubertal response of gonadotropin after gonadotropin-
' f2 Y: ?4 Z3 ^1 C% _releasing hormone stimulation. This is a sex-linked) \# `4 J8 n& n) M- C. L3 j
autosomal dominant disorder that affects only
, w* w- Z, A# ` u8 Dmales; therefore, other male members of the family
+ n% |" y. Y. p8 {) {' v$ I9 }1 I wmay have similar precocious puberty.3
9 D( K5 `+ C( Q- c5 VIn our patient, physical examination was incon-
& D8 v& u0 b% z2 ^sistent with true precocious puberty since his testi-& D2 r9 j& K# u, W
cles were prepubertal in size. However, testotoxicosis
! K& d4 j9 B: \2 l* Hwas in the differential diagnosis because his father8 s+ m$ E, O! ?
started puberty somewhat early, and occasionally,) M! Y: C4 j c8 y% S8 i1 G9 n- P
testicular enlargement is not that evident in the
3 K7 l" L g& j$ R& {beginning of this process.1 In the absence of a neg-3 T$ [! a. e" F* C( ^; T; k7 o9 i5 w
ative initial history of androgen exposure, our4 G' E V4 V! Y/ f
biggest concern was virilizing adrenal hyperplasia,
: C+ n: n" n! L; b. ?* ~ ceither 21-hydroxylase deficiency or 11-β hydroxylase
* c& V% `7 F' Y, d* R adeficiency. Those diagnoses were excluded by find-8 `4 ?! @# p! ^& C0 |
ing the normal level of adrenal steroids.8 y; y2 p' X6 X& P% {
The diagnosis of exogenous androgens was strongly
8 w; U& ?1 q) g4 N) }3 s( ]5 gsuspected in a follow-up visit after 4 months because
5 c; n8 Y7 s7 D) q7 Uthe physical examination revealed the complete disap-
: ?# H | Y2 w# L4 d& Xpearance of pubic hair, normal growth velocity, and$ B/ p! b" P+ h7 j! D P
decreased erections. The father admitted using a testos-
* H* r& w2 z+ A: xterone gel, which he concealed at first visit. He was
8 M/ H5 s- P8 X1 G& R Dusing it rather frequently, twice a day. The Physicians’
{. s" O) ]9 N! w1 BDesk Reference, or package insert of this product, gel or
$ E2 d$ a1 r) {* fcream, cautions about dermal testosterone transfer to
, [& n& R( t* h" i y$ Z Xunprotected females through direct skin exposure.8 D' O9 s& d: b5 k
Serum testosterone level was found to be 2 times the
$ {5 Q G1 E; Zbaseline value in those females who were exposed to
/ P9 v& f4 K4 z$ L6 teven 15 minutes of direct skin contact with their male
& c2 X2 a; ~9 O5 L& Vpartners.6 However, when a shirt covered the applica-
' w5 P9 @$ Q8 I7 D8 c8 _6 Ttion site, this testosterone transfer was prevented.
1 h1 L) E+ \5 V! X. ^( wOur patient’s testosterone level was 60 ng/mL,
j. g) f0 m/ @3 ~3 J( i- F. lwhich was clearly high. Some studies suggest that
. S9 X5 G) w5 Z/ ^0 o; zdermal conversion of testosterone to dihydrotestos-
+ F. F% Y% e1 J, B& Lterone, which is a more potent metabolite, is more: h/ M' T. m7 D! L
active in young children exposed to testosterone! y7 m9 K; b1 [
exogenously7; however, we did not measure a dihy-
* y& I# V2 E8 s. V7 j+ ~1 [drotestosterone level in our patient. In addition to
) }$ }4 S; k) e# b* Xvirilization, exposure to exogenous testosterone in" B+ r$ O- N$ x9 P
children results in an increase in growth velocity and7 D5 c" ?0 X( m$ W* A B
advanced bone age, as seen in our patient.8 V- @" \! s8 w7 a: d
The long-term effect of androgen exposure during
+ p, x, m: S" N3 E5 u9 _: T; P5 rearly childhood on pubertal development and final# a# F0 d$ d: h% n
adult height are not fully known and always remain
1 W* C V, M, I7 d& a& ta concern. Children treated with short-term testos-- r' h6 X v& B; t* h" k
terone injection or topical androgen may exhibit some' U1 O, _/ |4 M- q* K( }6 t
acceleration of the skeletal maturation; however, after
' H6 N# q; S9 g4 n3 |6 Z8 Xcessation of treatment, the rate of bone maturation k: Z% I; D) l) X3 B: t6 d
decelerates and gradually returns to normal.8,9
; k) v. C9 O9 r( E7 x: B4 j# H4 ~There are conflicting reports and controversy0 a, L; |+ y; O6 O: z+ h5 P
over the effect of early androgen exposure on adult
5 j, s4 P5 \% t4 ~& P' E0 Ipenile length.10,11 Some reports suggest subnormal; ]6 Q1 o) w9 }2 o' Q' O6 z+ Q
adult penile length, apparently because of downreg-
: w; T8 u( d( o* x' P, Mulation of androgen receptor number.10,12 However,) r! X# W6 t* L8 b# r* L& A& E
Sutherland et al13 did not find a correlation between( W- G `; D5 t2 H7 U, O
childhood testosterone exposure and reduced adult$ D3 L2 w2 Q% a! W6 G1 K) ^, A
penile length in clinical studies.
0 d5 M( U* D2 A! L% }- k _Nonetheless, we do not believe our patient is
4 S% a* I* g' s3 O+ x1 Bgoing to experience any of the untoward effects from* Q- c$ l6 z' c; p$ Z' n
testosterone exposure as mentioned earlier because8 k7 t Y( z" Z1 ?* c5 p
the exposure was not for a prolonged period of time.* F) [& d2 b) Y- D% k
Although the bone age was advanced at the time of
1 N' Y/ ~' w# d. A4 h1 ^diagnosis, the child had a normal growth velocity at; N8 k# }" E3 J. ~; {
the follow-up visit. It is hoped that his final adult
- U/ a! `- E, s! p3 Qheight will not be affected.
1 f4 [9 U% R oAlthough rarely reported, the widespread avail-
: u* |+ M, [, K' G/ A2 ~ability of androgen products in our society may) k- {0 L* w: @ `
indeed cause more virilization in male or female
/ ~& C; A. \" n& R5 G6 C$ A9 G; v4 cchildren than one would realize. Exposure to andro-0 Z+ N8 M- {7 ^* x) ^; Q
gen products must be considered and specific ques-
/ j& W, o1 H- b0 f; Xtioning about the use of a testosterone product or
; f( a( j1 b5 o! J$ K* Egel should be asked of the family members during+ O, C, O1 w- B0 {) m
the evaluation of any children who present with vir-% y8 r7 R$ E, X* N/ k5 c$ @; G$ N
ilization or peripheral precocious puberty. The diag-
" u7 k1 B9 m" j8 r, }nosis can be established by just a few tests and by! f2 e8 S/ m, N/ ?6 x
appropriate history. The inability to obtain such a% B- x+ C$ P; y
history, or failure to ask the specific questions, may" J! N4 T; K0 _- H2 ?* P1 a& R+ z
result in extensive, unnecessary, and expensive7 F# p( d3 y7 I+ e* x2 Y
investigation. The primary care physician should be2 p9 A. y2 y) b5 Z- ^
aware of this fact, because most of these children
8 H; t5 a; Q0 D& p( Vmay initially present in their practice. The Physicians’7 Y' x" M! C- \1 y& c4 v
Desk Reference and package insert should also put a
' ?! I% I, y1 Swarning about the virilizing effect on a male or! `6 i# V1 `$ C, M; v- M3 @
female child who might come in contact with some-
$ c. @8 J$ _! |1 O" r) I8 eone using any of these products.
3 D" z4 _# o; j5 d6 _References
, e/ X/ b5 z- J/ B' C: d: C1. Styne DM. The testes: disorder of sexual differentiation4 S7 }& S- A7 z) H: z7 q
and puberty in the male. In: Sperling MA, ed. Pediatric
/ x1 x( I E3 }$ x! G! H+ gEndocrinology. 2nd ed. Philadelphia, PA: WB Saunders; G) z3 c/ d5 X0 R( A$ ~
2002: 565-628.
( C* N% |5 G. s: ~7 }. M0 x2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious |' R" y4 W3 E3 Q$ m& Z
puberty in children with tumours of the suprasellar pineal |
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