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Sexual Precocity in a 16-Month-Old
. D, ~& P9 N( b9 \Boy Induced by Indirect Topical
& @4 B& F7 P* B" |* pExposure to Testosterone
; u2 B3 \6 m: }- K7 P2 b/ U* ~Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
" _, \/ Q) R1 u [5 n" A+ }2 f# k% }and Kenneth R. Rettig, MD1
" d$ N- g3 L3 m. a( L7 cClinical Pediatrics
6 W8 d4 L% @) K- i- a* CVolume 46 Number 6
& C+ P2 _* v* Y# d# ^" zJuly 2007 540-543( N/ S2 C% n6 Y, j
© 2007 Sage Publications
$ _6 S X+ d4 F8 Y9 N" z* S10.1177/0009922806296651
3 _2 I% F) x; l* G8 L+ j7 G% whttp://clp.sagepub.com+ y' m) Y; X2 m1 j/ d O; m$ @
hosted at+ Q9 X: @# g5 ?- ?9 m( O
http://online.sagepub.com
4 [+ T6 z* G- ]5 |4 f' p' YPrecocious puberty in boys, central or peripheral,! _% v( G4 Y6 t) ~4 q# c5 @
is a significant concern for physicians. Central3 C$ m, d! B3 T* T" f! {
precocious puberty (CPP), which is mediated
; C5 F V* T; {through the hypothalamic pituitary gonadal axis, has
; |9 e3 J$ u) Q5 Ca higher incidence of organic central nervous system
) p( ^- ] w' K1 g1 Q/ C' clesions in boys.1,2 Virilization in boys, as manifested0 Q7 p$ w* O) f3 e. _
by enlargement of the penis, development of pubic, W. q! f- `, X! I
hair, and facial acne without enlargement of testi-3 Q$ ?. t- r* g2 K
cles, suggests peripheral or pseudopuberty.1-3 We
5 t; c% |! L9 v' j* Areport a 16-month-old boy who presented with the) q( J% ?. q0 {: q
enlargement of the phallus and pubic hair develop-+ m. \% t: l% |/ T8 t5 }3 x$ x
ment without testicular enlargement, which was due0 Y$ U' S- j' r! C' u8 I0 B" i5 B
to the unintentional exposure to androgen gel used by
& ^: T$ R0 ^" {the father. The family initially concealed this infor-3 W Z- e0 V- ^# ~/ d# |( m
mation, resulting in an extensive work-up for this. O% F4 K; |; A) Y( i0 P
child. Given the widespread and easy availability of9 K) D. T' o* [# s. B2 I) m6 A
testosterone gel and cream, we believe this is proba-
2 e, g! v! `4 |0 d, H3 Vbly more common than the rare case report in the* S0 D- _ K, u; I. k
literature.4* ?& _: R# m( a: }7 d+ T$ Y" |
Patient Report
2 ?& I) y0 M5 ~5 k1 ?8 V0 uA 16-month-old white child was referred to the
3 ~) ~6 X3 w/ J) V' qendocrine clinic by his pediatrician with the concern
/ x- I/ {: X# R# ^/ lof early sexual development. His mother noticed
. t7 ^4 d( L: `light colored pubic hair development when he was4 b# k- \7 ]( ]9 F7 v& J$ Z
From the 1Division of Pediatric Endocrinology, 2University of
( S5 N7 y8 s. r/ Y, P$ wSouth Alabama Medical Center, Mobile, Alabama.3 a5 P; i0 e! H8 _1 m' `# M! b
Address correspondence to: Samar K. Bhowmick, MD, FACE,: {' T; D& G: V. T' _) W7 w
Professor of Pediatrics, University of South Alabama, College of0 E- j8 H M2 i' E1 b4 m" `
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
4 ?1 s5 |7 Z2 {+ ie-mail: [email protected].
+ M, |' w- U9 I6 Oabout 6 to 7 months old, which progressively became% m3 r# D3 n' b: M5 C
darker. She was also concerned about the enlarge-6 W5 c: [2 W" E" N' N! O7 A
ment of his penis and frequent erections. The child0 d% M. ` @2 V4 \. g3 l
was the product of a full-term normal delivery, with
1 o$ B5 y+ p j6 J. ~9 U; Da birth weight of 7 lb 14 oz, and birth length of' D4 P5 [3 S; r0 C$ [
20 inches. He was breast-fed throughout the first year, ?6 H+ R/ X8 d
of life and was still receiving breast milk along with% m6 g, a5 |3 ^+ M- _. S8 d- v6 Q
solid food. He had no hospitalizations or surgery,* G! s3 c Q* ^. t
and his psychosocial and psychomotor development3 [9 A; a2 P/ ]( R2 _4 e
was age appropriate.
, J+ L: {/ q) p- ^2 P: Y. d" b2 O J) `The family history was remarkable for the father,$ Z$ A: Y9 |+ s& _% h0 b4 r8 K
who was diagnosed with hypothyroidism at age 16,$ V# n- L# \6 f& U! `
which was treated with thyroxine. The father’s$ j5 U. y, x6 y; [2 Y H; ]
height was 6 feet, and he went through a somewhat
8 f" D& J/ i; g# z Q0 S9 zearly puberty and had stopped growing by age 14.
% g4 r0 t( ^4 _0 w- PThe father denied taking any other medication. The. T' n# l% u& k* O7 d5 C3 n: r
child’s mother was in good health. Her menarche
! X' ~/ e. O7 M" L6 d9 F4 @" B* s8 Dwas at 11 years of age, and her height was at 5 feet
! Y" e5 i, j* ^* n5 inches. There was no other family history of pre-
9 Z" x$ n1 q" Xcocious sexual development in the first-degree rela-4 ~& ], n* `8 ]. e
tives. There were no siblings.
) k8 d8 }9 Q5 U/ o0 f( W- h" TPhysical Examination
( M+ u( I- b7 A, r0 s# k- p6 |The physical examination revealed a very active,- R" o7 E3 A- H0 `/ y j$ I
playful, and healthy boy. The vital signs documented
9 B- m6 j0 ?! ga blood pressure of 85/50 mm Hg, his length was
4 J+ B- B+ O7 A* L& ]' n90 cm (>97th percentile), and his weight was 14.4 kg
: h" x$ h0 E) \ K9 Z(also >97th percentile). The observed yearly growth
7 o- `1 h( E) {4 |5 |# w- ~& zvelocity was 30 cm (12 inches). The examination of5 u' z+ \$ u- F3 v: \
the neck revealed no thyroid enlargement.
. n+ e% s# e/ H- [7 p5 h( LThe genitourinary examination was remarkable for
N g d- A Senlargement of the penis, with a stretched length of: E1 u* Z* H7 {8 T- N
8 cm and a width of 2 cm. The glans penis was very well
9 r; ^0 R# G3 A; Ideveloped. The pubic hair was Tanner II, mostly around6 S8 X% m5 L- a/ V) r4 e
540$ m( G" u& p2 p( v* U7 V" T( _: y2 h/ ~
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
, c# j6 D1 J* h. H: Uthe base of the phallus and was dark and curled. The1 ?' e8 w3 O9 h1 {6 e! {
testicular volume was prepubertal at 2 mL each.
0 I! W( Z% {9 [3 g2 y rThe skin was moist and smooth and somewhat
' I3 I4 a/ y2 [, r. e- ^" E( ~- i) v' Xoily. No axillary hair was noted. There were no
5 I" I, U& q7 R! j9 P# C/ U m$ mabnormal skin pigmentations or café-au-lait spots.
% z6 K, i% {/ e: zNeurologic evaluation showed deep tendon reflex 2+3 u O$ }$ X# M/ V: Y- \
bilateral and symmetrical. There was no suggestion
8 A, b, Z7 t9 L! a1 t' ^: F, t* Dof papilledema.3 v, r( Z4 D# q0 R# {
Laboratory Evaluation
9 U( G0 A0 w+ e* eThe bone age was consistent with 28 months by
) Z% @' ?8 E* b# _3 Susing the standard of Greulich and Pyle at a chrono-' P" ] k h: T) |4 L* u& W2 u
logic age of 16 months (advanced).5 Chromosomal y: m0 P5 s1 X& w- _8 ]# B0 ~% d
karyotype was 46XY. The thyroid function test0 H7 u" W0 x. P9 ]( K/ M) K, ~
showed a free T4 of 1.69 ng/dL, and thyroid stimu-0 U$ _) v, O% E( s( n! u
lating hormone level was 1.3 µIU/mL (both normal).' I; D1 _8 S" l
The concentrations of serum electrolytes, blood
' E( b w: Y4 B/ E+ |3 |1 eurea nitrogen, creatinine, and calcium all were+ F) N7 J+ o/ k0 u; h( K' l
within normal range for his age. The concentration) Y. s2 a. a: j) S1 W0 [' h
of serum 17-hydroxyprogesterone was 16 ng/dL5 e1 L5 y% x9 G. I! U
(normal, 3 to 90 ng/dL), androstenedione was 20: n& `0 d( d' U) Q/ O# W
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
1 L0 F3 t/ \+ @$ c' iterone was 38 ng/dL (normal, 50 to 760 ng/dL),$ [0 U# B. i" [3 R0 L5 _( M
desoxycorticosterone was 4.3 ng/dL (normal, 7 to7 z4 o' O+ z* D/ X3 Q* l( Q4 O
49ng/dL), 11-desoxycortisol (specific compound S)
) ~. l8 O, G) a9 n& [9 d# Nwas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-* U- A: `, l& G7 f9 F8 j
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total; K% b( Q2 R; \7 ~" R
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
M* K3 t8 D! e5 t; g; I) Band β-human chorionic gonadotropin was less than
' ^; D$ l r& z, D& M9 @3 q5 G# C5 mIU/mL (normal <5 mIU/mL). Serum follicular
) U1 _ {# ^. wstimulating hormone and leuteinizing hormone$ j( ] A8 y+ B% v
concentrations were less than 0.05 mIU/mL% R6 j# G) U% U2 b- f
(prepubertal).
" n t5 e$ B6 t w1 c% EThe parents were notified about the laboratory$ {/ y+ Q) l. U
results and were informed that all of the tests were* @$ n# U' \# B* I1 h
normal except the testosterone level was high. The
, x4 e& q$ U" x! {follow-up visit was arranged within a few weeks to0 e4 Q$ L8 o# W6 `' E' i2 a ]+ f
obtain testicular and abdominal sonograms; how-
3 v: s/ h9 P* j( Tever, the family did not return for 4 months.: O8 N8 n% r9 |1 C5 A
Physical examination at this time revealed that the9 r! H$ T% e8 r2 h) R7 D
child had grown 2.5 cm in 4 months and had gained# c. ?# z* Y) u5 ^% P# A9 D, {4 w
2 kg of weight. Physical examination remained
* y( I/ V: h; Tunchanged. Surprisingly, the pubic hair almost com-
1 [: B" c7 ]7 c1 C, U) Zpletely disappeared except for a few vellous hairs at% H: I8 H: E* i2 M0 E
the base of the phallus. Testicular volume was still 2
2 T% s( ?/ w/ b8 _mL, and the size of the penis remained unchanged.
, |. ^! y* N% t" r( N: G$ w, vThe mother also said that the boy was no longer hav-7 {$ w' G+ U. o' ?
ing frequent erections.& J: I' {8 J/ E" I9 l7 ~# Q
Both parents were again questioned about use of
1 X. I+ R( B7 _5 x3 yany ointment/creams that they may have applied to) \9 B- {) q( ^1 M) }+ {& B9 D
the child’s skin. This time the father admitted the
! H2 }: w0 ?2 n' Q" _( HTopical Testosterone Exposure / Bhowmick et al 541
0 C5 t! r7 Q* a# D' ?use of testosterone gel twice daily that he was apply-
9 k2 n- ]+ P0 ]" G: ging over his own shoulders, chest, and back area for
6 B4 T1 T; I8 r+ l' r; Ta year. The father also revealed he was embarrassed% r" J* M3 j" K' j9 X& M- }' S
to disclose that he was using a testosterone gel pre-* V6 [$ s6 V5 X3 T# U- g
scribed by his family physician for decreased libido
c3 w2 d$ E: }9 J8 b! F0 [secondary to depression.
; A9 `+ P0 h/ _/ Q# j5 @The child slept in the same bed with parents.2 f. A4 w9 P6 ]) ?
The father would hug the baby and hold him on his9 [, d* Z' r8 o: ?# R4 L
chest for a considerable period of time, causing sig-
, W, R0 f8 q$ m* l( knificant bare skin contact between baby and father.
5 r0 k5 w9 L2 NThe father also admitted that after the phone call,* o1 P& i( Z$ H+ x7 y
when he learned the testosterone level in the baby5 q# y# A6 b# v* X7 l/ Q9 _
was high, he then read the product information
* }$ l V2 B5 @1 @packet and concluded that it was most likely the rea-- C( M8 T- H" z
son for the child’s virilization. At that time, they
! b; H i& A$ k8 ~decided to put the baby in a separate bed, and the! `. t$ `* |4 Z
father was not hugging him with bare skin and had
& g: E. F7 T* _# B' Ibeen using protective clothing. A repeat testosterone
- {0 t% l0 B. A: xtest was ordered, but the family did not go to the! p( |( P. I& Z+ | t, L; R
laboratory to obtain the test.
9 n% O/ C3 ^/ LDiscussion
) t: a6 @. |+ N- u) _" B3 mPrecocious puberty in boys is defined as secondary
8 o% l0 ?: u# nsexual development before 9 years of age.1,4
3 |& A* R ~+ ]/ ?Precocious puberty is termed as central (true) when# x" o3 b, K, ^' |* f
it is caused by the premature activation of hypo-& C/ n5 a- c8 t" t
thalamic pituitary gonadal axis. CPP is more com-
! H4 C' X- K2 [" Y9 d9 O- Qmon in girls than in boys.1,3 Most boys with CPP: h3 |& U- a$ F9 r% a- O* f
may have a central nervous system lesion that is/ P4 l2 m7 [# ] K
responsible for the early activation of the hypothal-
2 N6 v9 s& I. l" |7 D( Gamic pituitary gonadal axis.1-3 Thus, greater empha-
( u" L6 X- N9 k; E- Y5 o" J6 ysis has been given to neuroradiologic imaging in
/ Q4 j& Y% c: B1 b5 qboys with precocious puberty. In addition to viril-
' A' a* J! ]: P) w% jization, the clinical hallmark of CPP is the symmet-
* s5 k/ F% I, o* S4 Frical testicular growth secondary to stimulation by1 H' e3 }8 Q% d' } e; V
gonadotropins.1,32 H/ L$ U. L3 N
Gonadotropin-independent peripheral preco-
! H1 Q+ e! L% D1 E7 V, Ecious puberty in boys also results from inappropriate4 r" ^7 y: `$ l9 W; G
androgenic stimulation from either endogenous or( m3 b" r- {" Y, F7 \5 S$ B$ _9 o4 _
exogenous sources, nonpituitary gonadotropin stim-
/ E" C$ B" C, r5 B0 gulation, and rare activating mutations.3 Virilizing
4 w3 Z+ O! y# Z. ~( n& ~congenital adrenal hyperplasia producing excessive/ L. t( j6 o' Y2 S. E, I
adrenal androgens is a common cause of precocious
1 m8 O8 Q" \/ F! i& A7 [( \puberty in boys.3,4& V$ }9 ~3 h) C
The most common form of congenital adrenal2 U/ L! |, V0 ]* ^
hyperplasia is the 21-hydroxylase enzyme deficiency.
4 N% K o% V5 s0 YThe 11-β hydroxylase deficiency may also result in6 ?& V" A. y% }* j) P/ q
excessive adrenal androgen production, and rarely,! v1 F: L/ [2 q+ f- ^! C2 h5 B
an adrenal tumor may also cause adrenal androgen0 r& |4 a/ c, ?; V0 N+ A
excess.1,3
a* m3 g6 C$ W0 \* h" gat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from n; z6 W# t. q, I* G
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
% G0 c% P6 g/ k8 C5 L; X! A' WA unique entity of male-limited gonadotropin-/ M# S" c0 F4 r& D+ y
independent precocious puberty, which is also known9 o4 |; s4 X6 o) p @
as testotoxicosis, may cause precocious puberty at a
" ]6 b7 f6 c8 h6 Nvery young age. The physical findings in these boys7 ], Y, ~& h" e$ k1 |
with this disorder are full pubertal development,+ x# X; @ x+ x# @: [. u1 M
including bilateral testicular growth, similar to boys) Y5 g. D1 B6 T. [
with CPP. The gonadotropin levels in this disorder4 \9 K) t; l# N7 X
are suppressed to prepubertal levels and do not show/ z# f9 ?0 n5 i) R _
pubertal response of gonadotropin after gonadotropin-! @+ W& C' q2 q( c
releasing hormone stimulation. This is a sex-linked; q, s2 @; i- U* f
autosomal dominant disorder that affects only* a( |: x% Z4 V# u" q
males; therefore, other male members of the family
! [ r0 M& M& Z6 amay have similar precocious puberty.3
( \* D5 l# q; v: K @6 J' ~In our patient, physical examination was incon-0 R3 F; ]4 o" q
sistent with true precocious puberty since his testi-8 K) H9 }. U" _* r- G: r
cles were prepubertal in size. However, testotoxicosis' N# V5 E4 K+ q, q( i T
was in the differential diagnosis because his father
5 d/ K+ _1 Y* ~- P" j6 a" I+ Dstarted puberty somewhat early, and occasionally,
3 H% W4 s) K# w7 P/ t! x( ptesticular enlargement is not that evident in the0 M9 ~, P; _& [, v4 v
beginning of this process.1 In the absence of a neg-2 D) {4 m) L7 E9 Q, K4 Y- g% ], a$ D
ative initial history of androgen exposure, our
X) m6 H1 n3 ^" mbiggest concern was virilizing adrenal hyperplasia,
7 b, Q% m4 r( F# C/ m9 Ieither 21-hydroxylase deficiency or 11-β hydroxylase+ l4 q1 u3 M. T* @
deficiency. Those diagnoses were excluded by find-' K& ?, m6 y& J, D- y7 k, E# E+ l: Z
ing the normal level of adrenal steroids.! v, n: x5 |+ i% E3 I) K
The diagnosis of exogenous androgens was strongly* Q9 L* k# B3 W- ^
suspected in a follow-up visit after 4 months because: i5 {7 w. n8 i$ c
the physical examination revealed the complete disap-1 k. t3 S% C0 r! E! x: g3 P; B
pearance of pubic hair, normal growth velocity, and
6 D% e4 J0 U3 ^# W7 n& Kdecreased erections. The father admitted using a testos-
1 M, }( r7 c, k- g. ^. lterone gel, which he concealed at first visit. He was
7 ^) E2 X- k# M3 l1 {2 p' musing it rather frequently, twice a day. The Physicians’
0 u `! G5 t( q5 p- ODesk Reference, or package insert of this product, gel or+ }8 k" \5 ~3 g4 u
cream, cautions about dermal testosterone transfer to% p$ x! x! ]: G! Z, U# {+ P
unprotected females through direct skin exposure.
9 x7 M) Z+ Y: m# r( Y. D/ c, e0 eSerum testosterone level was found to be 2 times the; R$ Q+ t. ]) ]. `; ~2 O
baseline value in those females who were exposed to i! }1 R* A5 \- m2 P* ?0 U: n/ ?
even 15 minutes of direct skin contact with their male- q) c( A$ Q% Q
partners.6 However, when a shirt covered the applica-8 T& u. {" t0 k+ x3 H: g( v, `9 E
tion site, this testosterone transfer was prevented.
: d, o# D4 b7 _/ C1 U1 pOur patient’s testosterone level was 60 ng/mL,2 O) Y0 ~& N/ g( c0 o* Z
which was clearly high. Some studies suggest that9 d' F& h, {# m( S0 k
dermal conversion of testosterone to dihydrotestos-
0 c, S$ J% y% `' b/ ~terone, which is a more potent metabolite, is more( L3 l0 B5 U f( F0 c
active in young children exposed to testosterone
3 J8 z+ P: K' L1 o+ a3 j( Gexogenously7; however, we did not measure a dihy-3 C8 p1 F6 f0 `) @: s
drotestosterone level in our patient. In addition to9 x) j. N8 D) F9 x0 X- A
virilization, exposure to exogenous testosterone in8 h) {2 B% N; G+ n3 |4 P4 q' C
children results in an increase in growth velocity and. E5 n+ W# d6 `1 b `
advanced bone age, as seen in our patient.0 X. S! r4 j, W; E% V
The long-term effect of androgen exposure during8 H+ Q$ r: O7 F$ R
early childhood on pubertal development and final
! w$ ~& J; |2 s9 d4 jadult height are not fully known and always remain; r# @7 [1 X, e6 |, u
a concern. Children treated with short-term testos-0 r) x) _8 |4 P# K( c& M( R/ i; g
terone injection or topical androgen may exhibit some' w7 X6 p! a% K8 F; O, @, R3 Q
acceleration of the skeletal maturation; however, after! c& A, I9 K; ~9 ~; a7 `" j
cessation of treatment, the rate of bone maturation
$ N4 J; D: G, n$ Edecelerates and gradually returns to normal.8,9, g3 J" C U6 U) V2 B3 ~- c
There are conflicting reports and controversy
: L% ]( \% d) w2 Q" Yover the effect of early androgen exposure on adult
; |- i# t; K" K- ~% c/ ?penile length.10,11 Some reports suggest subnormal: H! B, s" o2 l0 `
adult penile length, apparently because of downreg-
. W3 K8 x/ M; L& t! _ulation of androgen receptor number.10,12 However,
$ s; a1 c% C: p- iSutherland et al13 did not find a correlation between* R, @0 H- Z0 D3 G
childhood testosterone exposure and reduced adult& p" O( g4 D6 r: [+ h) h
penile length in clinical studies.* H* q1 \& N& u/ k: A: @. V' t
Nonetheless, we do not believe our patient is
. x0 D+ d- p) G( cgoing to experience any of the untoward effects from5 _2 t" C3 p) }5 a6 g5 v. F
testosterone exposure as mentioned earlier because: ] i- w- [$ _2 J/ P
the exposure was not for a prolonged period of time.
+ ~- v- q+ z' G4 P2 PAlthough the bone age was advanced at the time of
- P; S, k: |1 {* c$ ?diagnosis, the child had a normal growth velocity at
' i( s; N7 t% g. B! ]6 r6 c/ }$ lthe follow-up visit. It is hoped that his final adult5 }: A# @9 L. N* p; S* }
height will not be affected.2 {# V* W2 {, y" x. [2 ^. J! l4 _
Although rarely reported, the widespread avail-" l# M) q! f1 Z' F: ]8 q0 u
ability of androgen products in our society may8 f- r; L5 G3 g% N5 a! ^6 P6 J) o
indeed cause more virilization in male or female
. W! I6 O& W3 }* ^children than one would realize. Exposure to andro-5 W' @: m' v( `6 V6 x
gen products must be considered and specific ques-
3 H8 N. ^& ?& Z- Y, h% Gtioning about the use of a testosterone product or! ~/ }& ]) p! g& ?* ~6 F2 s/ y
gel should be asked of the family members during& I+ ?7 A( I5 I
the evaluation of any children who present with vir-
! x% ]. V$ c) U" }& Gilization or peripheral precocious puberty. The diag-
& i4 b- d; J: D5 dnosis can be established by just a few tests and by
1 ^' e0 x- ]8 s& ^9 L9 h9 c! G% h( Sappropriate history. The inability to obtain such a
1 ~" n5 k6 j! }) Chistory, or failure to ask the specific questions, may
2 v; l0 a& f( i2 Rresult in extensive, unnecessary, and expensive+ k* [3 V1 o5 ], X, L3 s0 u* C7 p
investigation. The primary care physician should be# L+ r6 p2 Y0 V7 {
aware of this fact, because most of these children! h! P' J! i( d& T& p
may initially present in their practice. The Physicians’
* b( @& A: T% ?9 `2 {Desk Reference and package insert should also put a
2 ^$ [2 U8 B- rwarning about the virilizing effect on a male or8 {& G' y* w; h6 y% a" g# ?
female child who might come in contact with some-
5 H7 `2 o+ ^2 e) B: u/ {3 Mone using any of these products.
% g+ I n {, H2 SReferences
; @# d! W( |+ J# D$ w! K1. Styne DM. The testes: disorder of sexual differentiation; m5 Y, m. n1 D
and puberty in the male. In: Sperling MA, ed. Pediatric
3 ^" b( _9 N! e8 Z' f% \Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;5 E7 @5 R% w) w6 d
2002: 565-628.
% M: r& ?5 v, K1 e0 G0 P" Y' m9 g2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
( D' G C7 Q: [0 O! Ppuberty in children with tumours of the suprasellar pineal |
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