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Sexual Precocity in a 16-Month-Old1 t( C2 v* P% ^$ W9 {
Boy Induced by Indirect Topical
- @$ X9 I8 C" K. SExposure to Testosterone
% }. l0 S8 \9 Q+ V- A/ @$ CSamar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
9 Y( i* c* y: G% f2 p( H. ?6 Eand Kenneth R. Rettig, MD1
* n; |- e- o1 \# X1 cClinical Pediatrics }7 j1 g5 V! J+ b0 @
Volume 46 Number 6
7 `" r1 q) U$ b! \& M f. N6 ZJuly 2007 540-543
$ e& M# W/ V, U5 X8 y2 R8 t© 2007 Sage Publications
( f+ O$ c, m7 ^" J3 X' E10.1177/0009922806296651& n( o- h$ b$ {
http://clp.sagepub.com" c& y: E' u" u+ p4 E
hosted at
: _) y- t4 [' z" ghttp://online.sagepub.com$ w+ L( u* g8 e1 u
Precocious puberty in boys, central or peripheral,
' U" O! Q' h Q; T: V2 Q$ f5 `5 _is a significant concern for physicians. Central
) Q2 u" m7 q/ H: z, Rprecocious puberty (CPP), which is mediated
# v7 F3 m! j! h7 Gthrough the hypothalamic pituitary gonadal axis, has }# B1 `' E0 G& T6 r; c
a higher incidence of organic central nervous system F1 @; H$ S2 I. ?
lesions in boys.1,2 Virilization in boys, as manifested
: m0 u8 e0 M7 \) a% W0 O/ _" uby enlargement of the penis, development of pubic
% @# H- Q0 ~0 ?7 Ohair, and facial acne without enlargement of testi-
" r" [. J4 U# ^3 M0 Z' Z ocles, suggests peripheral or pseudopuberty.1-3 We
* n& k0 O/ D! ^report a 16-month-old boy who presented with the
1 b; g9 m# i& x1 x4 u5 a, B3 penlargement of the phallus and pubic hair develop-7 B ?" K5 X, D' w
ment without testicular enlargement, which was due
/ r) q" E( w; Zto the unintentional exposure to androgen gel used by* X, d2 y( \* |2 }7 a+ i
the father. The family initially concealed this infor-
, ], H! O' J$ B$ vmation, resulting in an extensive work-up for this
2 z6 i# B* z- n9 achild. Given the widespread and easy availability of
* N; b* J/ n* s) I3 d; j8 w" Ntestosterone gel and cream, we believe this is proba-
7 k9 {! D) V: N y# ^; ]9 Xbly more common than the rare case report in the
4 G9 S' B4 ]& W- Q- ~, Zliterature.4$ I2 L" N$ l# M; E' d, D+ L+ ?
Patient Report/ L0 V/ {+ E) C9 V
A 16-month-old white child was referred to the
: X9 E4 ?" E$ \% A9 f* Iendocrine clinic by his pediatrician with the concern2 ]! M* r6 u( F6 g& N
of early sexual development. His mother noticed
; O4 L) h, n8 c0 }; f8 Ulight colored pubic hair development when he was5 A1 }: H5 X5 |0 N) F1 t
From the 1Division of Pediatric Endocrinology, 2University of
, x7 p, X" E+ `6 T' C5 kSouth Alabama Medical Center, Mobile, Alabama./ C2 M. m+ p* T: w; e
Address correspondence to: Samar K. Bhowmick, MD, FACE,4 O5 G# L. P* U A0 A' Z, k; N
Professor of Pediatrics, University of South Alabama, College of* J% J4 k; f2 I! L
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
7 J% d& R! B3 v: K3 h- ~! Ie-mail: [email protected].* [0 e0 T( h0 V/ v( v0 S
about 6 to 7 months old, which progressively became. V2 r- s7 _2 S# Y. j) D: F
darker. She was also concerned about the enlarge-
% y$ q- y& _4 Q% s$ V1 J9 dment of his penis and frequent erections. The child
]; r5 m* X( zwas the product of a full-term normal delivery, with% Z! E j: k, M0 }# ?$ Q: N
a birth weight of 7 lb 14 oz, and birth length of
3 e2 P& E& ]( F6 J& Y20 inches. He was breast-fed throughout the first year* }7 S& s( v% f5 x* p$ [ }
of life and was still receiving breast milk along with C$ R1 p: v2 z ]6 z* e+ |
solid food. He had no hospitalizations or surgery,
/ j- X7 R( A0 B, f' ^. Land his psychosocial and psychomotor development* c/ G, u3 D+ D8 W
was age appropriate.! S0 ], R; B9 o5 O: }" f& ]2 `5 h$ M
The family history was remarkable for the father,
2 ]0 ~. e2 U: B% Wwho was diagnosed with hypothyroidism at age 16,
6 Y8 L2 Z* s; E% X/ vwhich was treated with thyroxine. The father’s
( U% @% a4 i: P6 h6 T jheight was 6 feet, and he went through a somewhat
Z) Z% o0 S) A, ?- e! E) f6 N& _( oearly puberty and had stopped growing by age 14.
/ B* s$ Y4 @1 }7 @' {7 M, JThe father denied taking any other medication. The$ t) t+ T. }3 Q) T' V" }( T
child’s mother was in good health. Her menarche0 N, M S: @& p- b+ H2 d
was at 11 years of age, and her height was at 5 feet
6 ^0 u: b& O ]5 inches. There was no other family history of pre-
. q( c4 M7 t3 O0 [cocious sexual development in the first-degree rela-4 Z9 _5 U& o' ~, S* _3 G6 v9 N9 [
tives. There were no siblings.; f4 U6 a- E' |/ K4 k! P. ] K
Physical Examination
% b3 s2 P8 t) iThe physical examination revealed a very active,9 }) z: W+ t \
playful, and healthy boy. The vital signs documented$ V, G, z7 K. w7 P
a blood pressure of 85/50 mm Hg, his length was. Q" G M4 Z+ d7 _3 u& C
90 cm (>97th percentile), and his weight was 14.4 kg4 u; X" T9 z2 Y$ f/ \7 o7 f( v
(also >97th percentile). The observed yearly growth
' F; z+ H" B# X8 Z% r1 Bvelocity was 30 cm (12 inches). The examination of
4 e3 ~: J/ T7 P' J w! gthe neck revealed no thyroid enlargement.
. `; u7 J* o9 r! {4 x- e" M- D* AThe genitourinary examination was remarkable for
( J- @3 |1 c; Jenlargement of the penis, with a stretched length of, e; r3 U) b$ S9 ]3 h0 @- P
8 cm and a width of 2 cm. The glans penis was very well6 `% ~1 y7 w# M5 @; w8 }
developed. The pubic hair was Tanner II, mostly around, q0 t7 ]# {) ^: [
540$ [1 B5 P8 ~! ^2 `8 ]/ D
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
! E9 ~) H# g, T( xthe base of the phallus and was dark and curled. The* o' M( \3 k% E' S
testicular volume was prepubertal at 2 mL each.
4 d; E/ y2 N5 j5 f$ r6 @The skin was moist and smooth and somewhat% p! O% u) H1 x3 A5 t
oily. No axillary hair was noted. There were no# G" @3 ]9 c8 @3 X. g
abnormal skin pigmentations or café-au-lait spots.- _7 T' k) a# k- d( i6 X
Neurologic evaluation showed deep tendon reflex 2+
+ Y7 n& y. C' ~bilateral and symmetrical. There was no suggestion
/ L/ J2 z& X7 R& A' \1 Rof papilledema.8 ~& T- w; o, F3 Z7 S1 W* @+ i+ y
Laboratory Evaluation# Z5 C) |) [" k2 q+ Z
The bone age was consistent with 28 months by: t" X6 E, R$ @* q' B, O
using the standard of Greulich and Pyle at a chrono-
1 @ x& [/ _/ d* Z2 e) m/ rlogic age of 16 months (advanced).5 Chromosomal
. T7 `4 D2 g; }; X1 Fkaryotype was 46XY. The thyroid function test2 m. V8 g5 k" }' v, I7 ~
showed a free T4 of 1.69 ng/dL, and thyroid stimu-% `$ U" R# T! `2 q4 `
lating hormone level was 1.3 µIU/mL (both normal).8 X7 }- O0 X* }& W
The concentrations of serum electrolytes, blood1 Q: ~* |& Y6 z5 y5 W
urea nitrogen, creatinine, and calcium all were: a" a; M' T. |5 O1 Z; J
within normal range for his age. The concentration8 ~2 B, z% }) g( a
of serum 17-hydroxyprogesterone was 16 ng/dL
) G, D' e5 n3 P$ g5 p5 t& B(normal, 3 to 90 ng/dL), androstenedione was 20
F+ G# r9 j2 b/ ?8 Mng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
# ?1 S! F7 M" z% M E" I" Mterone was 38 ng/dL (normal, 50 to 760 ng/dL),, Q% S- m8 q, [/ o" C1 N
desoxycorticosterone was 4.3 ng/dL (normal, 7 to* O; G, u. ~4 t6 L. l! s' a" g s& v
49ng/dL), 11-desoxycortisol (specific compound S)+ r9 E' A/ D v! a
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-3 _2 \) ~$ s* t6 x* u- d- r' a
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total9 V8 G- v# T# H! K. @1 C& Q2 ?: n
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),! M" q; ~8 t, a2 H( X
and β-human chorionic gonadotropin was less than
/ Q: g+ {) W- P0 G5 mIU/mL (normal <5 mIU/mL). Serum follicular! S) f" W* s0 t2 t
stimulating hormone and leuteinizing hormone
V1 \8 v2 @1 v+ f3 P( W% }concentrations were less than 0.05 mIU/mL
9 l/ F2 b( q; \(prepubertal).9 d! Y( ]7 @2 P, H; F
The parents were notified about the laboratory$ _9 x `9 _ u6 P, F, W% g
results and were informed that all of the tests were
! i; {# Q: C) ]' B; g& F1 ynormal except the testosterone level was high. The* f) v% [- G1 e! G: C+ u
follow-up visit was arranged within a few weeks to
5 s. }* t& q" hobtain testicular and abdominal sonograms; how-- m' S3 J7 a2 g) M* f% g& @
ever, the family did not return for 4 months.
1 C) h/ ]! E7 k8 RPhysical examination at this time revealed that the9 X& X' W, I- V3 e3 r8 x, f% Q
child had grown 2.5 cm in 4 months and had gained/ `1 x( L* }) m/ g0 L
2 kg of weight. Physical examination remained
- q8 V" x" h7 B) vunchanged. Surprisingly, the pubic hair almost com-
& T+ ~, G$ D4 U0 I7 F/ @pletely disappeared except for a few vellous hairs at( Q! a. X* Y3 I% p% ~1 W r
the base of the phallus. Testicular volume was still 2
* }0 H, Z" X0 B2 @' v& _8 L6 VmL, and the size of the penis remained unchanged.
5 I0 `/ E$ V; m5 n& c' xThe mother also said that the boy was no longer hav-
' d7 @* |! S! K4 c% X+ ving frequent erections.3 s! H' T5 q" |$ r
Both parents were again questioned about use of! O$ s9 c% T+ b! Q
any ointment/creams that they may have applied to
$ G5 d9 i& ]! l+ R9 T# ^% H/ Othe child’s skin. This time the father admitted the+ E( V0 W: s: z9 o. \" C q
Topical Testosterone Exposure / Bhowmick et al 541
; ?9 ~8 Y+ {! b) J/ m. Duse of testosterone gel twice daily that he was apply-
: b5 P. x2 r) U1 T1 f: King over his own shoulders, chest, and back area for
% d/ \5 _5 @; Ja year. The father also revealed he was embarrassed" [# Y$ I+ H) q' {4 j' B1 v# B T, ~
to disclose that he was using a testosterone gel pre-
8 h" I/ W1 x+ g' ^/ L* ?& m1 Hscribed by his family physician for decreased libido
! k9 f* M9 O* T# r/ x) Csecondary to depression.
8 s; \8 l( L) L' T0 T) qThe child slept in the same bed with parents.! R4 |5 M& G* K9 D( L; Y
The father would hug the baby and hold him on his; ?( c) \( ~) Y' d! v$ K5 }
chest for a considerable period of time, causing sig-
& O5 ]" [$ t8 |1 k3 Q. cnificant bare skin contact between baby and father." t5 e" }$ w& i. ~8 o0 W
The father also admitted that after the phone call,6 z. @, ^ }( x. b- f+ j
when he learned the testosterone level in the baby9 ^# \& e8 i. Y
was high, he then read the product information
7 L& ^4 z) P6 b# L1 e% spacket and concluded that it was most likely the rea-
7 P, E: L$ |0 Y3 {son for the child’s virilization. At that time, they' V% ~: J; r( t$ D+ t' N# W3 U
decided to put the baby in a separate bed, and the
3 B! J j( f# Ifather was not hugging him with bare skin and had6 p9 u6 L; J1 y% K' J7 D! B
been using protective clothing. A repeat testosterone
T" a& Q: Z* Z) g$ K& ctest was ordered, but the family did not go to the
4 I' Z- G0 d4 a9 T( blaboratory to obtain the test.: N0 a' @, O: W2 V1 z: O' |9 m) u
Discussion
4 ~, J% Y: V. {: u+ F9 rPrecocious puberty in boys is defined as secondary+ \6 K' `* z( E, I4 {* Q2 s
sexual development before 9 years of age.1,4
* D$ q# R! d; _9 z8 k2 QPrecocious puberty is termed as central (true) when
8 q# l+ g% A& p; A7 ~8 Sit is caused by the premature activation of hypo-
]9 A$ P) k; ethalamic pituitary gonadal axis. CPP is more com-1 k4 T5 L1 I( [ T5 A4 i
mon in girls than in boys.1,3 Most boys with CPP2 i) J4 S w* ]" [8 z
may have a central nervous system lesion that is' ^7 d+ b* a- e: K+ y4 L
responsible for the early activation of the hypothal-2 j1 W- s7 T) {$ ? t; E( f* O
amic pituitary gonadal axis.1-3 Thus, greater empha-! L/ _* I$ K3 W' R1 l2 e4 [# Q0 `
sis has been given to neuroradiologic imaging in5 H( g1 m# v- I1 \
boys with precocious puberty. In addition to viril-
; P' ?2 T* v+ m$ i; r, k# Q' wization, the clinical hallmark of CPP is the symmet-* k% J7 w& z, \6 ~5 h* }& K6 \
rical testicular growth secondary to stimulation by
. G: {6 k' T: n; V8 C$ m. ~gonadotropins.1,3* ?/ H9 v% E( m
Gonadotropin-independent peripheral preco-
9 i# c2 E$ K( l C9 U' icious puberty in boys also results from inappropriate, c& ~5 H" f" ~( N6 Z: E
androgenic stimulation from either endogenous or. g1 n3 T: o1 O* t' Q
exogenous sources, nonpituitary gonadotropin stim-
$ w9 T+ W0 Z" d) fulation, and rare activating mutations.3 Virilizing2 e- U8 h! e7 f8 L' W
congenital adrenal hyperplasia producing excessive/ E5 z* S# G1 _ M$ u3 C& M
adrenal androgens is a common cause of precocious/ A& C3 L3 W9 }5 K9 ?
puberty in boys.3,4
$ F7 U- b& q1 _- C+ y( EThe most common form of congenital adrenal
6 F1 c* n* [3 k* T1 _hyperplasia is the 21-hydroxylase enzyme deficiency.# z9 ?' a( ?2 T5 E, L- D
The 11-β hydroxylase deficiency may also result in
- \9 K$ R( b8 @ R) ^excessive adrenal androgen production, and rarely,! `# s" x! R- S2 S
an adrenal tumor may also cause adrenal androgen
- a% C4 g4 N0 R( h8 m6 k7 Lexcess.1,3; Z' R, }" U, O5 D1 F
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
% U! U f4 u$ ^9 e% @; C5 y4 W542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
/ I3 A( f" A1 \* eA unique entity of male-limited gonadotropin-
0 o/ q* O5 ^. u9 }& s/ tindependent precocious puberty, which is also known
4 f3 w! j) N2 Q# R# u$ s: @' g3 bas testotoxicosis, may cause precocious puberty at a
& z$ L8 U* S$ f+ ]very young age. The physical findings in these boys, F& w n: ?5 @& G) B. j. C( _: h
with this disorder are full pubertal development,4 g C' T4 f% [! }
including bilateral testicular growth, similar to boys
2 F& U0 B+ \% c- h% Vwith CPP. The gonadotropin levels in this disorder
& ^9 t0 \ ^) |: [' u5 m; ~are suppressed to prepubertal levels and do not show& k" T! {2 y* G* m/ \
pubertal response of gonadotropin after gonadotropin-
6 l) c+ E. x6 M) f. z$ ^: }* |releasing hormone stimulation. This is a sex-linked R- v0 [+ R( L' K
autosomal dominant disorder that affects only+ d2 W W1 x0 J2 ~1 `$ V) Q/ |( c
males; therefore, other male members of the family' g1 `1 }, X8 i* k7 M( b. E
may have similar precocious puberty.3
) U/ l0 k: m, |+ [In our patient, physical examination was incon-
4 ~3 `2 Q; j. asistent with true precocious puberty since his testi-# G Q- Z( ?$ ? Z1 E
cles were prepubertal in size. However, testotoxicosis
$ s& U$ q2 S& g0 D* twas in the differential diagnosis because his father1 ^- g8 r% R0 ]8 u+ Z: z3 ~4 d, U
started puberty somewhat early, and occasionally,) f) j0 e7 i0 D. D h
testicular enlargement is not that evident in the
1 Q# c4 O) B/ P) F) z. |beginning of this process.1 In the absence of a neg-5 N3 j7 O; ] s+ T! u+ S
ative initial history of androgen exposure, our
) |1 j5 J( T0 n+ cbiggest concern was virilizing adrenal hyperplasia,
$ d! x' N b' {9 keither 21-hydroxylase deficiency or 11-β hydroxylase
9 V$ |+ B, D$ Q' }: {5 Jdeficiency. Those diagnoses were excluded by find-
$ Y; E6 O$ ~" M5 X: ?/ ging the normal level of adrenal steroids.
. t8 i- S+ x2 o* o' cThe diagnosis of exogenous androgens was strongly
( K0 C6 v2 b$ f: w$ V8 d n; lsuspected in a follow-up visit after 4 months because# R8 n. c# Q7 [ V
the physical examination revealed the complete disap-
" E2 s' ^& g& x- @# K0 Lpearance of pubic hair, normal growth velocity, and
9 s7 _! [( F0 @. w+ D5 o1 @decreased erections. The father admitted using a testos-7 N, \8 j" c1 l' P8 u3 V3 d' [
terone gel, which he concealed at first visit. He was; }3 k Q Y t+ v( M4 c
using it rather frequently, twice a day. The Physicians’3 P* ?/ J# D0 U
Desk Reference, or package insert of this product, gel or
' m b- T/ }# ?" jcream, cautions about dermal testosterone transfer to
/ Y; R/ Z; s, ?' d4 Gunprotected females through direct skin exposure.
$ {5 M& c' O9 B8 V' H3 ^6 @8 QSerum testosterone level was found to be 2 times the1 h2 G/ R s, {* p; U; M9 i
baseline value in those females who were exposed to
( e! Z' [+ X d4 {even 15 minutes of direct skin contact with their male
9 P( f7 D2 ?- X4 t' Q, ^partners.6 However, when a shirt covered the applica-
! F: e( T( a* r2 W" w. s6 Otion site, this testosterone transfer was prevented.0 f9 z* N4 r1 L# f% ^6 `
Our patient’s testosterone level was 60 ng/mL,4 j8 c2 c6 h( X, c! ^9 f
which was clearly high. Some studies suggest that1 k* Y, Z- i- i, j/ x
dermal conversion of testosterone to dihydrotestos-
6 a; T( l4 O) |8 y. Z) N; pterone, which is a more potent metabolite, is more
# W) d6 O& j# n( z+ kactive in young children exposed to testosterone6 U; P& f$ e1 w# s5 }1 P
exogenously7; however, we did not measure a dihy-& x% ?. Q+ K2 E+ q) f5 `2 Z: a
drotestosterone level in our patient. In addition to
1 J( M6 _8 ^* `4 vvirilization, exposure to exogenous testosterone in
1 [$ C d. d i9 _5 F( Bchildren results in an increase in growth velocity and
8 X4 w% m& |9 q! V6 hadvanced bone age, as seen in our patient.! h- ~" \" r6 R
The long-term effect of androgen exposure during
+ P5 ~( N: V( hearly childhood on pubertal development and final2 K" J( ~4 T4 e# [
adult height are not fully known and always remain" |% g) v$ H6 s4 Q/ `4 [7 W
a concern. Children treated with short-term testos-
$ B# t" j' \/ b) ~# F2 D+ vterone injection or topical androgen may exhibit some& ~5 L q( b0 E! E2 a3 |& x6 {
acceleration of the skeletal maturation; however, after
. E, r0 w/ }# o7 Fcessation of treatment, the rate of bone maturation
7 R" F) K/ Z. \1 Cdecelerates and gradually returns to normal.8,9
: G# f. m$ \7 t2 T/ y4 _% ^1 oThere are conflicting reports and controversy
6 e) ?' F( ?! e& oover the effect of early androgen exposure on adult
( q- w+ ~" k5 @8 D) ppenile length.10,11 Some reports suggest subnormal
8 \' Z+ u0 _- R, qadult penile length, apparently because of downreg-" W( b% D; L3 t# B; A- z4 P9 W5 M
ulation of androgen receptor number.10,12 However,( u. M& g. u, Y3 ~1 r4 h" F
Sutherland et al13 did not find a correlation between
$ J. @9 g7 }; tchildhood testosterone exposure and reduced adult" e- r0 |( Q, ]# g, [
penile length in clinical studies.
% X# u n/ N8 q3 SNonetheless, we do not believe our patient is
, Q6 x3 V$ d `: u# J) Jgoing to experience any of the untoward effects from
. I; E! y x3 m" B! w. X% |testosterone exposure as mentioned earlier because
1 C. W* K. Z, e, I# T0 P2 hthe exposure was not for a prolonged period of time.
* N6 `2 W- J. ?4 w/ f, sAlthough the bone age was advanced at the time of/ ^1 M" s0 u$ @- ?& {7 b3 y4 Q
diagnosis, the child had a normal growth velocity at
( }( H$ p) o( ]" e: m& S9 W, Bthe follow-up visit. It is hoped that his final adult# H, v% w/ a$ O
height will not be affected.6 x6 t& r, N/ n; K8 t$ ~
Although rarely reported, the widespread avail-0 J% D- D A( z$ n
ability of androgen products in our society may
4 O' P- Q8 [ y0 M8 p. `% Zindeed cause more virilization in male or female
7 b, p, A8 c4 O6 l1 I7 ychildren than one would realize. Exposure to andro-
" U! s8 { x6 Z$ `, zgen products must be considered and specific ques-
9 [8 B& j: H2 L" xtioning about the use of a testosterone product or+ q8 Z# o# J9 B: p7 C
gel should be asked of the family members during% y1 v, E4 Q' f" k/ @9 p8 G* e* p5 [
the evaluation of any children who present with vir-
) w }1 M: x6 j) l5 d2 lilization or peripheral precocious puberty. The diag-
@ s' G' M# y0 lnosis can be established by just a few tests and by8 N. \* J0 y4 b; {. @: M1 @
appropriate history. The inability to obtain such a
# N6 e+ _6 ~: I& i( y; h7 vhistory, or failure to ask the specific questions, may6 L# }3 Q/ l: N0 o
result in extensive, unnecessary, and expensive
" ~5 @/ [% Z' C( h L5 Jinvestigation. The primary care physician should be
" G0 S+ _, y$ N# U/ v, Paware of this fact, because most of these children
- s" {! P& A2 q) w" d: ^ a' Dmay initially present in their practice. The Physicians’
* q% K. ?6 i$ k+ k* k* qDesk Reference and package insert should also put a. Z, [, [& h% a4 F
warning about the virilizing effect on a male or( A5 b- b! z2 i6 v }+ y
female child who might come in contact with some- q7 f% r" Y' B, I7 t5 c9 P
one using any of these products.) M5 V! A9 p: R" E
References
* C* e1 K8 Z/ S# Y$ q! e( b1. Styne DM. The testes: disorder of sexual differentiation4 q, V, Q) |: x5 [9 B. ^* [
and puberty in the male. In: Sperling MA, ed. Pediatric0 [: _& o' l0 A" s; m
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;% }# l3 G: k+ @9 ]
2002: 565-628.
6 \" i0 k" w1 i9 \5 t2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
$ I' _1 G, b4 {8 qpuberty in children with tumours of the suprasellar pineal |
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