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is a significant concern for physicians. Central2 [! ]! ~4 R9 H- S$ u+ c
precocious puberty (CPP), which is mediated* ]2 S6 R9 x6 c. r; Y v
through the hypothalamic pituitary gonadal axis, has
! C4 H2 I+ L' N" _7 _a higher incidence of organic central nervous system
6 U: H' B6 c! e4 Rlesions in boys.1,2 Virilization in boys, as manifested
1 k% j$ {* L2 p4 K' Tby enlargement of the penis, development of pubic
) h/ z: O) V2 v6 V9 B$ V8 ~hair, and facial acne without enlargement of testi-" d+ ^: m: a( K$ g3 B
cles, suggests peripheral or pseudopuberty.1-3 We9 D. J0 ~( ?! G: R8 B4 [. T
report a 16-month-old boy who presented with the
! }1 A" t- P6 i. ^' henlargement of the phallus and pubic hair develop-) h8 Z2 z8 ?, U3 L. W$ T
ment without testicular enlargement, which was due2 s/ X. O( g: G7 _! E
to the unintentional exposure to androgen gel used by
$ C+ V6 c6 H: q6 ^the father. The family initially concealed this infor-. D; \+ P5 v7 `1 T+ I ]. ?
mation, resulting in an extensive work-up for this
% D. v! O: l m/ echild. Given the widespread and easy availability of
9 M. c' Z9 J7 [& E% {5 i1 dtestosterone gel and cream, we believe this is proba-2 a$ ^5 v1 m/ `8 V& L7 s
bly more common than the rare case report in the
% @( D; X6 d; v4 G' e, ^literature.4: e9 S9 ?) a1 K8 A9 o8 n: Q) I
Patient Report' h1 z( T# r- W( O; R
A 16-month-old white child was referred to the$ N& R7 y7 o, p0 c- Y- ? V/ ?, @
endocrine clinic by his pediatrician with the concern) M8 ~* p, G# f# }% k5 h' ^
of early sexual development. His mother noticed
+ S1 Y+ d( E8 ?4 G, S/ o4 Xlight colored pubic hair development when he was
: u, W# [% V( @2 T% v eFrom the 1Division of Pediatric Endocrinology, 2University of
) f$ ~7 k9 p# l7 tSouth Alabama Medical Center, Mobile, Alabama.
8 a% @+ H" W0 H p+ D& tAddress correspondence to: Samar K. Bhowmick, MD, FACE,
! n+ U5 ]) O3 A( s6 R& X- ?# @9 {Professor of Pediatrics, University of South Alabama, College of
$ I: o3 j9 `& O6 ? XMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
& \- Y1 L* e* P/ j$ }3 ne-mail: [email protected].. ?1 c5 x, v( _% |3 Y8 T
about 6 to 7 months old, which progressively became' `4 i4 N# ^$ j7 G. W
darker. She was also concerned about the enlarge-, D! H6 [* T/ X$ l: l$ V9 _
ment of his penis and frequent erections. The child
" V0 w6 R! h7 ~0 W# bwas the product of a full-term normal delivery, with
; J9 j) v" D2 l' W1 {a birth weight of 7 lb 14 oz, and birth length of
9 N! A" V2 |+ q& _20 inches. He was breast-fed throughout the first year0 t3 r s6 K7 x
of life and was still receiving breast milk along with1 F- ^# h. d& ?8 P4 w4 W
solid food. He had no hospitalizations or surgery,
8 m$ q) d0 h3 d, q1 w' S3 Oand his psychosocial and psychomotor development
9 F9 F: ^6 ?1 J) rwas age appropriate.; |: U& e) G/ V0 u/ E) t
The family history was remarkable for the father,* r# b& U( h. b- b$ \( L
who was diagnosed with hypothyroidism at age 16,
. |' Q+ p" j" f) Z/ c9 mwhich was treated with thyroxine. The father’s1 R/ r9 P1 U& D6 ]! o% k, S( B
height was 6 feet, and he went through a somewhat
' Q" R9 Z5 l* \8 p& B% s/ ~$ Z2 V" Bearly puberty and had stopped growing by age 14.
" I5 C c4 R' o! v2 [/ l pThe father denied taking any other medication. The
# H2 H! H3 v, Z0 T. `- m, Fchild’s mother was in good health. Her menarche
/ [4 K6 q) Y) O. }# qwas at 11 years of age, and her height was at 5 feet" i( [. {' Q: O4 L; z, `
5 inches. There was no other family history of pre-& V: c2 Z6 ]. N2 ^# U
cocious sexual development in the first-degree rela-
3 S T1 x9 Q+ ?" K# W4 w* ]tives. There were no siblings.2 V, f1 K0 p. Y/ j# j2 d
Physical Examination) f* `# s9 b. c: k; g" L
The physical examination revealed a very active,, r' c2 I: j% I9 u' p: J- T
playful, and healthy boy. The vital signs documented
0 A, k3 ^) \' k4 M4 n8 ?& Oa blood pressure of 85/50 mm Hg, his length was" l% A( p( \, M
90 cm (>97th percentile), and his weight was 14.4 kg0 o& V/ k$ W/ \+ { d/ Z
(also >97th percentile). The observed yearly growth4 a& J: f# \3 q5 x: m- p7 a! B0 e
velocity was 30 cm (12 inches). The examination of
# ]( ^" |; P: s+ ethe neck revealed no thyroid enlargement.
+ f; {* V Y+ Z" @The genitourinary examination was remarkable for. o( k4 d+ ~7 u5 D& c1 i
enlargement of the penis, with a stretched length of' [: A: \0 O% E* ~; d; `
8 cm and a width of 2 cm. The glans penis was very well
0 G* J' x8 t) B" jdeveloped. The pubic hair was Tanner II, mostly around
3 _1 h! F9 y3 {+ T; y540
; b {( y* {) ]at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
# m3 H5 K0 S# s' xthe base of the phallus and was dark and curled. The) r3 k& A* h4 ]! F
testicular volume was prepubertal at 2 mL each.( `8 w) m" F- B6 u6 V) s* [5 e
The skin was moist and smooth and somewhat
/ K, a& ]( \, X9 x! p7 qoily. No axillary hair was noted. There were no
6 O# _3 y3 A3 ?2 A' @abnormal skin pigmentations or café-au-lait spots.* }8 N& @7 Z; T8 q
Neurologic evaluation showed deep tendon reflex 2+
6 y/ b n ?( g% [bilateral and symmetrical. There was no suggestion
! x% d3 d% Z1 }" h/ A8 Hof papilledema.; M9 R0 ?) ^; L1 n
Laboratory Evaluation+ `8 O$ g$ t _8 g# P
The bone age was consistent with 28 months by
9 w* A4 d4 W6 D' ]3 a2 zusing the standard of Greulich and Pyle at a chrono-; Z# k/ [5 G: @1 T/ x
logic age of 16 months (advanced).5 Chromosomal. w( }2 M# |. N$ N
karyotype was 46XY. The thyroid function test
2 |% m$ W6 V& ^" [- `0 Hshowed a free T4 of 1.69 ng/dL, and thyroid stimu-
9 E" n& F. w0 ~0 W( S2 [lating hormone level was 1.3 µIU/mL (both normal).
; e ]7 \) q0 {8 k5 ~* pThe concentrations of serum electrolytes, blood
& F8 T; a6 k: [# Iurea nitrogen, creatinine, and calcium all were
- [, x* r J q6 `# K5 ?within normal range for his age. The concentration+ S' a D6 T) N4 c( S
of serum 17-hydroxyprogesterone was 16 ng/dL
$ Z" d, G) V n1 D% @: [(normal, 3 to 90 ng/dL), androstenedione was 20/ z4 w* w2 M8 v# T- o) ~* R+ j
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
3 @4 a e" q4 b3 ^0 R2 K1 |' O6 G) Eterone was 38 ng/dL (normal, 50 to 760 ng/dL),
# j* W8 B* L* ~& p8 [+ s4 Xdesoxycorticosterone was 4.3 ng/dL (normal, 7 to r! K3 N t% q6 _! N
49ng/dL), 11-desoxycortisol (specific compound S)
0 t- i" E7 C& S; E0 ?9 S( bwas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-: J- n) R/ p( R6 [2 ?
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total+ r. z5 L6 T4 u. q, ~' h/ s |
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
8 ? b5 f/ _2 h5 O, H! ^- `and β-human chorionic gonadotropin was less than! @5 m( M0 N/ g, k: W/ j
5 mIU/mL (normal <5 mIU/mL). Serum follicular1 } W4 a9 M$ C* R+ L4 K
stimulating hormone and leuteinizing hormone; r9 W4 e. Y" e+ K$ l" \* t# v; {# }9 f
concentrations were less than 0.05 mIU/mL
) y) m, }8 Z- w; L; P3 B(prepubertal)./ K p9 K* [$ Y) d
The parents were notified about the laboratory
% Q& |2 q7 r7 C" W2 Uresults and were informed that all of the tests were- f1 a% `1 p% B9 b
normal except the testosterone level was high. The
8 |( W4 M$ w6 dfollow-up visit was arranged within a few weeks to
, I' O A6 i# T$ p5 Y% M+ a; X1 Hobtain testicular and abdominal sonograms; how-% Y2 t* y& n# F$ `& @
ever, the family did not return for 4 months.
, ?6 n( S4 L6 D/ dPhysical examination at this time revealed that the
* G- y. k2 ]1 _child had grown 2.5 cm in 4 months and had gained' w6 o" n( C7 K% J' `7 x ~
2 kg of weight. Physical examination remained
: {; u$ y l3 Y2 _# L munchanged. Surprisingly, the pubic hair almost com-
4 K. y, D2 u$ spletely disappeared except for a few vellous hairs at, x9 N7 C5 Q B/ h3 a8 T
the base of the phallus. Testicular volume was still 2: k1 ?+ z* j/ |0 U1 m# I' [4 _
mL, and the size of the penis remained unchanged.1 `4 E" _$ X! O' H$ ^ ^, F
The mother also said that the boy was no longer hav-
7 k* m* \6 m+ L6 ~1 ning frequent erections.
3 E+ @6 O, k5 \2 k9 H4 \ YBoth parents were again questioned about use of3 A4 U" g3 m; s9 B2 O0 Q7 u
any ointment/creams that they may have applied to
& x1 X& p6 `/ r# gthe child’s skin. This time the father admitted the
% ]5 B. o+ D7 f( g/ fTopical Testosterone Exposure / Bhowmick et al 541: I& w# b5 i4 |# H' _
use of testosterone gel twice daily that he was apply-
% X2 ^/ E; ~% E/ h1 Iing over his own shoulders, chest, and back area for, f6 I; b8 B7 Y) j. V8 N" \# \. P
a year. The father also revealed he was embarrassed: P% Q4 O1 T* B! X1 d$ r2 D6 u
to disclose that he was using a testosterone gel pre-5 N: r) k) B1 d6 l) e
scribed by his family physician for decreased libido
4 Z9 N5 B6 r2 l8 {secondary to depression.
+ i2 a' w7 D! Y5 \The child slept in the same bed with parents.
; o- f% b" {$ A1 NThe father would hug the baby and hold him on his! U q& u( S. _* U& L y: f- x
chest for a considerable period of time, causing sig-/ r3 b, M5 D4 x3 F
nificant bare skin contact between baby and father.
0 a' d8 I: `, w( k: nThe father also admitted that after the phone call,+ K. \; b& w7 X5 L
when he learned the testosterone level in the baby q& i* n6 w, R4 u* v' Z
was high, he then read the product information
: h: v, ~' U" h* u cpacket and concluded that it was most likely the rea-: n! [" q# m# r1 I! y$ y& v* G& Q
son for the child’s virilization. At that time, they
! W$ E( z3 \! V" d" S. j! Hdecided to put the baby in a separate bed, and the: b# t/ l) D5 w' K0 ~2 Z/ m) i0 [: K
father was not hugging him with bare skin and had
! z5 p. q0 N5 o' }2 I @% k0 Ibeen using protective clothing. A repeat testosterone8 y4 e. R: y/ Z Z/ A
test was ordered, but the family did not go to the
; ^: ^; u2 J" `laboratory to obtain the test.
# c2 E, u$ F; [Discussion
! V( ~8 i3 A2 H: CPrecocious puberty in boys is defined as secondary2 `8 P9 v0 A$ F. y
sexual development before 9 years of age.1,4
* a" h% S6 |5 w1 R, XPrecocious puberty is termed as central (true) when
% |3 _. \. n6 t7 y1 ]0 p& T2 {# d2 yit is caused by the premature activation of hypo-
7 h: n$ ]6 k- W+ r8 P" Jthalamic pituitary gonadal axis. CPP is more com-& t3 D+ p% F2 L1 a
mon in girls than in boys.1,3 Most boys with CPP
# F. @* J0 E# k8 t8 Gmay have a central nervous system lesion that is
% u5 g" N. I& z2 p7 t0 Y+ v( nresponsible for the early activation of the hypothal-6 U/ y$ O- E* q
amic pituitary gonadal axis.1-3 Thus, greater empha-7 w2 w. {/ k, M) @7 j3 F
sis has been given to neuroradiologic imaging in$ ~; T% ^2 w: c
boys with precocious puberty. In addition to viril-. [* J' n; J+ Y, _! R" c+ z8 u
ization, the clinical hallmark of CPP is the symmet-
# ]) h7 f/ z2 L+ _rical testicular growth secondary to stimulation by3 |( h6 Y8 J) m% R, H, M+ a4 _
gonadotropins.1,3- Q( `/ F$ H( k! J7 d5 k8 s
Gonadotropin-independent peripheral preco-# s. M5 I$ y: l6 P& K4 W
cious puberty in boys also results from inappropriate
1 l; R3 N8 s8 s' vandrogenic stimulation from either endogenous or
/ J. p0 h5 U9 C+ r3 }exogenous sources, nonpituitary gonadotropin stim-
' f6 R) Y1 ]" }0 ?7 Rulation, and rare activating mutations.3 Virilizing
% P1 L4 n; j# J* V- \( ocongenital adrenal hyperplasia producing excessive
: {1 M* g1 D# r" ]adrenal androgens is a common cause of precocious" } }5 S& ~6 b: E( u
puberty in boys.3,4
! F7 o, d8 C8 Z7 Y' q- C [: ]3 oThe most common form of congenital adrenal
$ x5 g c. c* n) b D6 Vhyperplasia is the 21-hydroxylase enzyme deficiency., M7 t6 d3 p6 m7 t( K, c
The 11-β hydroxylase deficiency may also result in( C: n- J; C, G! E6 y
excessive adrenal androgen production, and rarely,5 A5 r6 \. j2 Z2 s
an adrenal tumor may also cause adrenal androgen
" W' Q6 s6 p& r! o+ K; Wexcess.1,3
5 C1 L; W' Q$ F# R7 p' R( \at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from) b1 r5 \/ f: _! F/ b r- W
542 Clinical Pediatrics / Vol. 46, No. 6, July 20078 E! h# }7 E/ r1 |
A unique entity of male-limited gonadotropin-
7 t2 V+ y" g$ _. windependent precocious puberty, which is also known
- Y+ S. Z0 R" V6 h- ]# I. gas testotoxicosis, may cause precocious puberty at a( f" T" Q! t$ p6 ~: a
very young age. The physical findings in these boys+ w& p1 C5 C/ w J
with this disorder are full pubertal development,+ A' }4 _8 d+ ~9 Y2 Q( b- y. A* j
including bilateral testicular growth, similar to boys7 M/ |5 G8 y$ x3 J- b1 k; V
with CPP. The gonadotropin levels in this disorder
e3 V2 W0 l' y s; Lare suppressed to prepubertal levels and do not show# S! a$ B8 c, H
pubertal response of gonadotropin after gonadotropin-
4 Z* U; R; N7 |releasing hormone stimulation. This is a sex-linked
h# G' X0 ^, k% @autosomal dominant disorder that affects only. Q0 E& g0 Q {0 W0 y( o
males; therefore, other male members of the family$ A2 j. W: M; S
may have similar precocious puberty.3/ [" c( a8 X+ L, M8 ^9 ]
In our patient, physical examination was incon-
3 t% [! J4 j2 ]. [sistent with true precocious puberty since his testi-8 t1 o7 U0 w( D6 _
cles were prepubertal in size. However, testotoxicosis
) S9 X* M! L5 f+ |was in the differential diagnosis because his father
! @) F0 Y- ?9 E) H: q1 y: f0 Tstarted puberty somewhat early, and occasionally,4 @/ t, d9 M& b2 P% a; h+ p6 _6 Z
testicular enlargement is not that evident in the
# C! A/ G, m5 S) V+ o5 a7 cbeginning of this process.1 In the absence of a neg-
3 r5 W- p% ]& s$ c/ u# Mative initial history of androgen exposure, our
/ @9 R' t3 F6 u6 J" y* p9 y% a7 }9 wbiggest concern was virilizing adrenal hyperplasia,
0 \3 E- M, I9 |' C$ Peither 21-hydroxylase deficiency or 11-β hydroxylase
# m5 f! T3 W. U7 R. j2 K* | A& kdeficiency. Those diagnoses were excluded by find-
; h+ m( J# l3 i7 v6 Ming the normal level of adrenal steroids.% k5 c3 [. q# _- p1 H& m( O
The diagnosis of exogenous androgens was strongly* V; o9 R$ B* L
suspected in a follow-up visit after 4 months because
" A# j. Y |. b7 U( u+ |, N- Qthe physical examination revealed the complete disap-2 y5 B5 |8 D) N7 p a$ V( `
pearance of pubic hair, normal growth velocity, and
% f$ |- O* v' u/ ^! Ndecreased erections. The father admitted using a testos-
+ d$ t* W4 u- O* Q' ~- `: mterone gel, which he concealed at first visit. He was
% s9 d, o$ b6 w9 d- M4 cusing it rather frequently, twice a day. The Physicians’# @ k7 ~. a* G6 V7 y/ \1 t
Desk Reference, or package insert of this product, gel or
& D0 C# _) X9 K4 M" wcream, cautions about dermal testosterone transfer to- f0 F$ g9 d' Z; ]) [
unprotected females through direct skin exposure.0 R0 e) u+ ]. z! c
Serum testosterone level was found to be 2 times the
! C& z& |' V( d) I6 @9 p! q9 c1 Rbaseline value in those females who were exposed to
0 F+ Z( A f4 l4 e& @even 15 minutes of direct skin contact with their male
) F4 K, J3 C' |4 I7 O! @partners.6 However, when a shirt covered the applica-9 c [, H6 h: d% [ P2 a
tion site, this testosterone transfer was prevented.
& Q, t* m. ~) E. l6 z; {) |3 ROur patient’s testosterone level was 60 ng/mL,
0 W# Y! p( S* X3 J/ twhich was clearly high. Some studies suggest that
% C# g, W2 o8 Y% P! \. \2 T6 edermal conversion of testosterone to dihydrotestos-* h# O6 I& E5 i: l% a( t9 p. P
terone, which is a more potent metabolite, is more
i' G3 E" ~8 e$ Oactive in young children exposed to testosterone2 T+ i+ v7 F1 T7 O2 ?
exogenously7; however, we did not measure a dihy-
; Y; m6 i, ~$ p# c9 kdrotestosterone level in our patient. In addition to4 A" D$ B7 W' A6 u, h2 F* x
virilization, exposure to exogenous testosterone in
6 L) L) q) T6 I, D" tchildren results in an increase in growth velocity and
3 s8 r* [( j- p- J% Eadvanced bone age, as seen in our patient.
' ]' y1 V8 Z+ o: }! qThe long-term effect of androgen exposure during
% B2 m/ _; d5 y) `early childhood on pubertal development and final
7 k2 D9 k' s) s/ Vadult height are not fully known and always remain
3 S! ^4 t% x, h# ~, }7 Aa concern. Children treated with short-term testos-
7 p. O/ O" B5 i; r5 Kterone injection or topical androgen may exhibit some" O. _1 b6 }7 J4 n ^. b7 J4 G
acceleration of the skeletal maturation; however, after0 m1 i; f, {) a) C- q
cessation of treatment, the rate of bone maturation
% q; P% ~5 N5 C% }6 ~decelerates and gradually returns to normal.8,9
0 i2 J- f' z7 C* u& KThere are conflicting reports and controversy T5 b: k2 A% W4 `, F6 n
over the effect of early androgen exposure on adult3 d" C. r9 C6 a8 \1 ?* B
penile length.10,11 Some reports suggest subnormal O0 k% E8 [, m: i, O
adult penile length, apparently because of downreg-
& D" y+ l% p" Q$ g# eulation of androgen receptor number.10,12 However,
- K" C4 N5 x& V) T& N, {Sutherland et al13 did not find a correlation between
- r) |( ^3 |) E9 J9 O( xchildhood testosterone exposure and reduced adult: g5 P/ f$ p) u6 A
penile length in clinical studies.
6 E# {' o- M i4 z) y0 L* oNonetheless, we do not believe our patient is
# ?$ C) D! z! b: Z7 o/ {going to experience any of the untoward effects from
7 h; f7 B" G, [6 G |testosterone exposure as mentioned earlier because
& F+ D8 G i v4 x, Uthe exposure was not for a prolonged period of time.% f' z4 v. y: |- g3 c
Although the bone age was advanced at the time of
; E, ]0 l7 y% g# l c& x: idiagnosis, the child had a normal growth velocity at
9 `( M% x5 G! T, u4 mthe follow-up visit. It is hoped that his final adult
8 Q; [- A/ W/ c( j% Aheight will not be affected.( z8 l* s% v# V% @
Although rarely reported, the widespread avail-+ O: T7 A' J9 {% k9 b
ability of androgen products in our society may7 d% }5 U8 ?7 s; g& W6 P. h; d$ ?9 q8 j9 G
indeed cause more virilization in male or female
0 L# a5 |: `6 p8 _5 S1 C' Echildren than one would realize. Exposure to andro-
' j8 K+ |. [: ^9 Ygen products must be considered and specific ques-
1 B6 h0 H* [4 Y4 G3 ~$ o3 E; Ptioning about the use of a testosterone product or- A* H6 Z& P: b( O9 f
gel should be asked of the family members during
p; V, @, E1 Cthe evaluation of any children who present with vir-/ f9 G( S" a/ A; }2 h2 G
ilization or peripheral precocious puberty. The diag-$ D+ n& i) n+ }. X- @
nosis can be established by just a few tests and by
5 x3 W7 @/ k0 l9 Y7 Qappropriate history. The inability to obtain such a2 {7 k3 G) L: G' A+ T
history, or failure to ask the specific questions, may4 O' [: Z% R ?1 f3 }3 n) k
result in extensive, unnecessary, and expensive
; q, L+ u- S3 Zinvestigation. The primary care physician should be% d; ^( T. i$ R1 s; [: U
aware of this fact, because most of these children7 Y2 f. h" f8 S1 b! O% D) y& m! O
may initially present in their practice. The Physicians’- ^% \$ M, E" \
Desk Reference and package insert should also put a5 ]; E0 x( ^! b/ L! I; `$ W+ z
warning about the virilizing effect on a male or6 R, O# I$ Z8 N% @8 g
female child who might come in contact with some-7 Z! f1 H1 s9 ^( w$ G I V( [
one using any of these products.- W+ J0 A' z) C: k
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3 b% i5 s) ]' y- z. ]! C2002: 565-628.. Z9 C' f& G- }6 _4 W8 T
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0 r5 i! e- e% ?! N. ppuberty in children with tumours of the suprasellar pineal8 _: Y) }* _) i: M2 S2 F
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0 Q& G- Q5 ^! O! a: [% Kexposure to testosterone. Pediatrics. 1999;104:e23.7 f" y. M, x# a2 o+ E% B
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Stanford, CA: Stanford University Press; 1959.; Q* g& \0 v# d+ @ s( R- f6 b+ m* P
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: M/ U2 B- j5 f1 S6 `9 k6 b- pEconomics Company, Inc; 2004:3239-3241.
3 s6 v8 s/ ^0 A- k6 S) l7. Klugo RC, Cerny JC. Response of micropenis to topical
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