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is a significant concern for physicians. Central! a3 m- W' w( p
precocious puberty (CPP), which is mediated
# B! g- H: Z% R. E" Lthrough the hypothalamic pituitary gonadal axis, has
- s- ^% P* g! [4 g* ?) y9 n7 U+ Q. va higher incidence of organic central nervous system
" e/ {1 g& x# b. H; j( [! l$ xlesions in boys.1,2 Virilization in boys, as manifested$ m0 }! E+ y! }% j- A# V* y
by enlargement of the penis, development of pubic- T, H) O9 ~4 q* S
hair, and facial acne without enlargement of testi-
2 Z/ q, { _, t5 tcles, suggests peripheral or pseudopuberty.1-3 We
+ w* N; n+ Y' q+ o& H5 ^report a 16-month-old boy who presented with the6 T& Q! u# l# S# c1 S
enlargement of the phallus and pubic hair develop-2 R' Z4 u: u- H8 n4 l5 l- a
ment without testicular enlargement, which was due/ u5 D! s1 C- V/ J2 ^% ~9 {2 f
to the unintentional exposure to androgen gel used by
; ^! C3 o/ |7 z I' Mthe father. The family initially concealed this infor-+ F. S# n/ d- @6 H* _3 l5 T1 k1 ]) G
mation, resulting in an extensive work-up for this
+ s M; w4 x! ?' \, Vchild. Given the widespread and easy availability of
( ?& Y8 \+ ?- J# m- ?testosterone gel and cream, we believe this is proba-; ~0 } M- r3 g
bly more common than the rare case report in the6 Y, N+ U5 O$ h9 C% `4 P
literature.4
; E# _/ X$ g% [* V& y! h, [Patient Report' ]4 A: |- h2 a; k6 r
A 16-month-old white child was referred to the. V1 A2 f0 M. j, O+ U8 w$ A
endocrine clinic by his pediatrician with the concern4 |4 P: D9 i# g& b( F. q$ X
of early sexual development. His mother noticed7 J) q& ~, D7 g
light colored pubic hair development when he was+ r- L% m4 @0 Q! J3 W1 C
From the 1Division of Pediatric Endocrinology, 2University of+ n: l. U0 W* d5 K
South Alabama Medical Center, Mobile, Alabama.8 F* ?3 y0 T2 m9 r& W% u+ b
Address correspondence to: Samar K. Bhowmick, MD, FACE,
; s# X9 w- C8 E: _' `/ ]' {Professor of Pediatrics, University of South Alabama, College of
( y h. |0 [6 DMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
r( N# L9 u" i1 B! v7 J8 a0 ae-mail: [email protected].+ X. ~0 U' n; Y
about 6 to 7 months old, which progressively became
/ W% u1 p! M* }3 Q) sdarker. She was also concerned about the enlarge-/ s2 x$ s1 S7 `% s. f& k
ment of his penis and frequent erections. The child
+ A( Y2 G' b; m9 `) z( S0 C$ f; Hwas the product of a full-term normal delivery, with7 p, @+ x- Z" F. J! Z" O- Y8 e
a birth weight of 7 lb 14 oz, and birth length of2 i4 M' E0 J, x$ m
20 inches. He was breast-fed throughout the first year
' o: ^5 s! R' i+ j: Rof life and was still receiving breast milk along with8 L- w( i3 \8 X: |
solid food. He had no hospitalizations or surgery,0 E% y9 Y8 o( k8 c. e- z# I) N; Q
and his psychosocial and psychomotor development# p: O; [) J. U* z
was age appropriate.% H1 k3 Z. i6 }" e
The family history was remarkable for the father,/ E& Q# P) I2 Z0 `& P$ s& b
who was diagnosed with hypothyroidism at age 16,
8 F2 F2 U4 s5 S( t, Y! O8 N& Dwhich was treated with thyroxine. The father’s! r! i% q, a/ u5 F- f- S
height was 6 feet, and he went through a somewhat( |1 @( j* g9 R3 t" n
early puberty and had stopped growing by age 14.& B, ?* {" q4 c, G3 R4 Y; D4 o& ?; i
The father denied taking any other medication. The1 _/ |1 y" h, n3 @
child’s mother was in good health. Her menarche X0 m0 Q$ T2 Q; _. g
was at 11 years of age, and her height was at 5 feet
~8 x: Z5 g: r' b+ F5 inches. There was no other family history of pre-
; j/ m. k0 u! y* d: r$ ^! xcocious sexual development in the first-degree rela-
8 m5 m! Q5 I2 U' }! ?tives. There were no siblings.
/ h6 w; R! R9 T: F/ }Physical Examination
4 b% ?& V- q8 J z+ I$ [9 IThe physical examination revealed a very active,
; \9 L' y0 j1 k! l9 @$ b u6 f2 rplayful, and healthy boy. The vital signs documented+ K3 [ B- @1 P
a blood pressure of 85/50 mm Hg, his length was
" ^- A4 j; o* K6 n3 Z. a) a" d90 cm (>97th percentile), and his weight was 14.4 kg
& l, r% W: o4 i) R! P, v(also >97th percentile). The observed yearly growth3 c! l- c# {" X% U6 R
velocity was 30 cm (12 inches). The examination of
& F, n6 X P5 q2 ythe neck revealed no thyroid enlargement.
% y+ e, `% f% X, W7 _The genitourinary examination was remarkable for& U3 O7 s# u, Y+ C0 ^* Z
enlargement of the penis, with a stretched length of) g+ l0 c, ~8 @4 a! K
8 cm and a width of 2 cm. The glans penis was very well5 y0 ^8 g& b8 S
developed. The pubic hair was Tanner II, mostly around
; d2 i3 J6 A( P& U. R/ Y# k540
+ H; v: U8 Q" [# d" q' t8 N: }at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from, b& W) c2 G6 r1 I) @
the base of the phallus and was dark and curled. The
1 c5 p6 Y/ D ~4 ztesticular volume was prepubertal at 2 mL each.4 [ t3 l. b5 m/ }, B- s/ i
The skin was moist and smooth and somewhat
# W8 s% a! q Joily. No axillary hair was noted. There were no1 L3 U; R7 R! p1 j* v; i. ^0 Y# F
abnormal skin pigmentations or café-au-lait spots.9 p5 b8 r& }0 d2 y' H- ]/ S, h+ z6 X
Neurologic evaluation showed deep tendon reflex 2+
+ ]* ^& z- Y. K( @bilateral and symmetrical. There was no suggestion
- ~% d' z( c. R7 v- C! hof papilledema.
0 }6 w* u9 w- pLaboratory Evaluation, l, r- T/ K2 n2 c% }, q
The bone age was consistent with 28 months by) p( S1 U% z3 J8 `) F' s- H! @" m! J8 s
using the standard of Greulich and Pyle at a chrono-! r, e! P) O$ O0 E5 v& J$ G
logic age of 16 months (advanced).5 Chromosomal) f3 m) t! G. [7 U4 U
karyotype was 46XY. The thyroid function test, p, R" \( ~& \) G: F+ P! l" P
showed a free T4 of 1.69 ng/dL, and thyroid stimu-2 F! W; A" }4 q' C2 o6 f5 j
lating hormone level was 1.3 µIU/mL (both normal).; T* o$ d W1 F3 U% R
The concentrations of serum electrolytes, blood
: [5 i0 H% j3 l9 o. d! e4 wurea nitrogen, creatinine, and calcium all were
4 U' G c& I* g, Bwithin normal range for his age. The concentration P K. ?; L+ I8 V0 p& U
of serum 17-hydroxyprogesterone was 16 ng/dL
+ b3 ^' l) ~( B( c3 k(normal, 3 to 90 ng/dL), androstenedione was 20: W' x8 v0 d4 Z6 n
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
4 Y' w3 Y8 r. O& l# m0 P% ?terone was 38 ng/dL (normal, 50 to 760 ng/dL),) Z9 u% W- \* B! ^' {5 S1 F+ c% [
desoxycorticosterone was 4.3 ng/dL (normal, 7 to
0 r2 G, ] P; U; x# Q8 j49ng/dL), 11-desoxycortisol (specific compound S); }# R% e" A: ~
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-. L. F- O5 x& N! b2 Y% a" A
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
" [/ P z5 B# k$ l5 f( K$ Stestosterone was 60 ng/dL (normal <3 to 10 ng/dL),/ u; n5 ?# q5 N) {3 v) w5 y- `
and β-human chorionic gonadotropin was less than& c4 m- @; Y% E
5 mIU/mL (normal <5 mIU/mL). Serum follicular! Y4 h: j% T* o5 q$ l& H" k
stimulating hormone and leuteinizing hormone
& i: U0 q6 q3 U0 I" econcentrations were less than 0.05 mIU/mL3 L, E; u1 S! E+ A' G2 t
(prepubertal).
{) \2 A$ i, K* @% N( WThe parents were notified about the laboratory
* @5 a& v( b$ v2 j: W( oresults and were informed that all of the tests were3 d# T0 d# G* f, X3 [7 f' a
normal except the testosterone level was high. The7 Z: p7 ? N. z$ G7 A1 z9 E
follow-up visit was arranged within a few weeks to, Z# y! Q: N6 S8 U5 R3 h# U% ^
obtain testicular and abdominal sonograms; how-
1 a# s: Y' d) z% g! @* Hever, the family did not return for 4 months.
$ |4 c" K' J& fPhysical examination at this time revealed that the
$ Q/ {* A, d" U, D3 jchild had grown 2.5 cm in 4 months and had gained
% {. w4 V5 s) {9 x% W2 kg of weight. Physical examination remained
L8 Q f9 x1 Q# Vunchanged. Surprisingly, the pubic hair almost com-. h8 G) P+ i' x$ ~
pletely disappeared except for a few vellous hairs at2 e) O6 F, B+ \0 |' }* c
the base of the phallus. Testicular volume was still 22 U9 ~6 K& v; ~6 U
mL, and the size of the penis remained unchanged.
o m6 ^. ~2 A, h- L/ OThe mother also said that the boy was no longer hav-
% n3 S( B# A$ K" M# w, m& q+ ~ing frequent erections.
" C. d: F0 x8 d+ R' \Both parents were again questioned about use of
* X1 [: C$ K) }" u2 Vany ointment/creams that they may have applied to ^ P6 q* _: p J
the child’s skin. This time the father admitted the
: R7 [/ T& H B" L5 hTopical Testosterone Exposure / Bhowmick et al 541
0 z3 \- T$ \! M* F2 Fuse of testosterone gel twice daily that he was apply-
; {3 m. k2 V n" zing over his own shoulders, chest, and back area for
, l2 }, n* g, b9 S2 C: Q2 t8 l: H7 q* ?a year. The father also revealed he was embarrassed
% O# {$ x& N) P# d4 I4 C' Tto disclose that he was using a testosterone gel pre-
% T" Z, ]4 p2 h7 R( ?scribed by his family physician for decreased libido
^! l% D$ k, Bsecondary to depression.4 {7 o0 j% |; O' d" U q
The child slept in the same bed with parents.
# {8 b- e f( j+ SThe father would hug the baby and hold him on his# T$ L" h6 I. R. ]6 T9 K# ~7 ]
chest for a considerable period of time, causing sig-, ^! @$ I" E3 v5 [/ F
nificant bare skin contact between baby and father.
9 b( }0 j; i! K3 X, M0 HThe father also admitted that after the phone call,+ c* s' ]. p( } f
when he learned the testosterone level in the baby
' ^% c: ~, z# Lwas high, he then read the product information* \1 f* u( G$ _1 p
packet and concluded that it was most likely the rea-) g4 b' R$ P) J' B2 v) {1 a5 I
son for the child’s virilization. At that time, they
8 L* A4 a+ _% fdecided to put the baby in a separate bed, and the
; d7 l3 X* _) f; V7 R( ~father was not hugging him with bare skin and had
9 G/ @4 i# K Pbeen using protective clothing. A repeat testosterone7 z3 L# l; } Q, L7 q$ |- V$ p' W
test was ordered, but the family did not go to the
7 ]8 w2 ?! n# O* F1 }- o' Rlaboratory to obtain the test.$ ]; d' @. l/ S% Y3 V
Discussion j. } \! o/ M9 V9 ]1 E! e
Precocious puberty in boys is defined as secondary
' m& K! [; z4 A! L* Rsexual development before 9 years of age.1,49 V' M& I7 o7 N3 F$ O% B8 I- ^% ^
Precocious puberty is termed as central (true) when
* ]- g% U c8 ^* Cit is caused by the premature activation of hypo-
1 F0 I) W6 \" F1 e# ?& Sthalamic pituitary gonadal axis. CPP is more com-
/ ^7 |0 e$ H. X4 kmon in girls than in boys.1,3 Most boys with CPP
1 w" a( L& v2 Wmay have a central nervous system lesion that is; @+ j* c! D* p/ ?0 q' _2 ?1 \
responsible for the early activation of the hypothal-' |3 e1 @1 K# q) i
amic pituitary gonadal axis.1-3 Thus, greater empha-$ X6 D+ a: n% D" W. L; s2 D
sis has been given to neuroradiologic imaging in- t1 n, _" q' u. G. c* Q+ m
boys with precocious puberty. In addition to viril-, B2 O" t; |( N
ization, the clinical hallmark of CPP is the symmet-- r- i0 a( @2 O0 b6 D7 t# p! Y
rical testicular growth secondary to stimulation by5 R& [! ^ |3 `1 A) l
gonadotropins.1,3
; [' }* T* M0 Y9 XGonadotropin-independent peripheral preco-: J3 S8 s1 o" {7 z/ i
cious puberty in boys also results from inappropriate
+ Z3 t2 n$ G2 U6 Tandrogenic stimulation from either endogenous or7 D/ g6 |7 e0 Z. @ d5 X; t# k, b
exogenous sources, nonpituitary gonadotropin stim-
# ?9 j8 I, ?6 ~ulation, and rare activating mutations.3 Virilizing
1 ~( c f* G6 w1 V" h9 K6 L% n) f5 dcongenital adrenal hyperplasia producing excessive) L$ z: a$ X8 t& M. J, I
adrenal androgens is a common cause of precocious
; I) z* V: u: T) ~- c% l- tpuberty in boys.3,4
- d# [5 i3 p6 QThe most common form of congenital adrenal
) r" i3 H# D0 O" L1 b/ khyperplasia is the 21-hydroxylase enzyme deficiency.& D' b. r+ \5 ~# |5 n9 f
The 11-β hydroxylase deficiency may also result in
0 U6 }; Q- G0 o5 ^' ~2 {excessive adrenal androgen production, and rarely,& Q! l$ Y# E, O# U
an adrenal tumor may also cause adrenal androgen2 h+ x: @* E K! ]5 h# R3 {9 C
excess.1,3) k- Y1 g3 P8 t3 ?
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from8 R4 X0 A9 |( `9 j+ @
542 Clinical Pediatrics / Vol. 46, No. 6, July 20074 p& n: Y8 I* N; a: c1 F3 J! ?
A unique entity of male-limited gonadotropin-* Z% O R* [3 d0 `& z( H) m+ O1 a
independent precocious puberty, which is also known8 S2 o; }! V1 i' g ^" f
as testotoxicosis, may cause precocious puberty at a
# K) q" _8 j; s; Rvery young age. The physical findings in these boys: Y( e/ i4 z' x2 v) @1 r9 ]3 Z% G. z
with this disorder are full pubertal development,
& f% O( N7 J1 x' Jincluding bilateral testicular growth, similar to boys
3 u! s) C4 I7 n/ n B: Swith CPP. The gonadotropin levels in this disorder5 i" q$ `/ X7 |9 b9 @8 e3 e
are suppressed to prepubertal levels and do not show
2 B; v. O3 y! t4 R7 M7 k! z7 C5 Epubertal response of gonadotropin after gonadotropin-
# l1 \$ u8 b2 V" Freleasing hormone stimulation. This is a sex-linked% |# o' U0 c% u) C- c
autosomal dominant disorder that affects only) r' z; s$ d! W7 I& Z
males; therefore, other male members of the family- ~5 V0 T2 q" R) w; }. I7 w
may have similar precocious puberty.35 X3 d" w! ^# |% |
In our patient, physical examination was incon-
. V1 T1 N# Z6 I; t: Dsistent with true precocious puberty since his testi-
, C1 z, V( y) ?cles were prepubertal in size. However, testotoxicosis" R; u' t$ O( B+ W7 {) u
was in the differential diagnosis because his father
8 v5 }( R* h4 m0 J8 d- sstarted puberty somewhat early, and occasionally,0 T2 E( }7 x' ~* W
testicular enlargement is not that evident in the* y- ?8 y. J3 U' `: C* N( X; @( P
beginning of this process.1 In the absence of a neg-, z: m1 J* z) ^
ative initial history of androgen exposure, our& q) l! D$ ?! O0 | w1 k
biggest concern was virilizing adrenal hyperplasia,1 z/ w8 l/ e/ \5 ?( {& a
either 21-hydroxylase deficiency or 11-β hydroxylase
+ a1 f& R5 n: \8 P ~) G2 z+ Q, {deficiency. Those diagnoses were excluded by find-
% x7 }" Y$ j0 m# u8 Qing the normal level of adrenal steroids.% b' i' b; B: _. x5 T6 K: W6 K, m
The diagnosis of exogenous androgens was strongly3 a- ] k/ U- f
suspected in a follow-up visit after 4 months because
2 b, B7 s( G2 D" Rthe physical examination revealed the complete disap-2 K5 w8 X: m4 L
pearance of pubic hair, normal growth velocity, and3 @, V# J* v3 U$ V
decreased erections. The father admitted using a testos-
% o+ C r9 C- e Dterone gel, which he concealed at first visit. He was
. d- B# g8 m0 w2 |using it rather frequently, twice a day. The Physicians’4 c' P8 l7 S+ ^. x! K
Desk Reference, or package insert of this product, gel or# ?2 |2 g* Z6 l. P. G7 j
cream, cautions about dermal testosterone transfer to
6 [" n- J/ S( L \/ p3 Iunprotected females through direct skin exposure.) q6 ~% F# Y: ~# t; u
Serum testosterone level was found to be 2 times the
( l0 E: ~; c) [+ K6 J5 ?5 Sbaseline value in those females who were exposed to
6 N$ g( b0 X" \2 U9 Y0 r+ Veven 15 minutes of direct skin contact with their male
& \ j7 ?- F5 npartners.6 However, when a shirt covered the applica- \. ?: R, Y, B- z8 n
tion site, this testosterone transfer was prevented.( F8 h6 c1 G/ k% d1 W
Our patient’s testosterone level was 60 ng/mL,+ J9 y. q/ Z/ ]$ Y+ j4 z
which was clearly high. Some studies suggest that5 Q1 y* |" E# Q8 n
dermal conversion of testosterone to dihydrotestos-" N; V! c0 V8 w' L6 A2 @1 a
terone, which is a more potent metabolite, is more. Q9 M$ z! a* W- J
active in young children exposed to testosterone" d2 D, A' R1 S) X0 |( \4 Z& J4 U
exogenously7; however, we did not measure a dihy-8 i% a$ s8 A! n1 [3 s( e
drotestosterone level in our patient. In addition to
9 {, ]8 q" |& _. z! Zvirilization, exposure to exogenous testosterone in
; j& W4 P' c y; q+ Vchildren results in an increase in growth velocity and
6 Z! S) R/ R! N% h5 T) J% Radvanced bone age, as seen in our patient." C* I0 K% A$ }4 C: R$ t r; q7 E
The long-term effect of androgen exposure during
2 ?( x, L C! K8 Hearly childhood on pubertal development and final/ G" v0 T+ G2 q+ p8 d
adult height are not fully known and always remain* s$ o" z+ _( h! \1 O- ]- q4 G
a concern. Children treated with short-term testos-
9 k/ ~6 b+ b/ p( mterone injection or topical androgen may exhibit some
" I$ d# v: j5 w- ]( s% u/ ~' gacceleration of the skeletal maturation; however, after. x: j8 \5 h* i( H
cessation of treatment, the rate of bone maturation
1 L: G5 s0 u' b0 M3 T" n6 }decelerates and gradually returns to normal.8,96 b, }5 T* S1 t. m6 b6 l' h& ?
There are conflicting reports and controversy
3 `# y4 {7 X2 j! H! Yover the effect of early androgen exposure on adult B" ?3 h8 o1 K! B7 @
penile length.10,11 Some reports suggest subnormal* D; U {& I# B# c8 G' H5 t
adult penile length, apparently because of downreg-
! a( p" ^% P' z A' L2 R' {ulation of androgen receptor number.10,12 However,
5 P+ ]4 w+ r, B3 }5 ?" ^Sutherland et al13 did not find a correlation between- T, @7 n# Q& m3 X. |, @
childhood testosterone exposure and reduced adult
, f- J& t; [6 h8 n9 Q- H+ w8 t* ~penile length in clinical studies.
% b' a/ \- d, {! O" x9 L: D& uNonetheless, we do not believe our patient is! o# R) o' H, y
going to experience any of the untoward effects from
: n7 j7 D7 \, X, y' Wtestosterone exposure as mentioned earlier because
! z: d, N/ b* Jthe exposure was not for a prolonged period of time.
. t% G5 c! g2 g. q+ B% FAlthough the bone age was advanced at the time of2 b2 N+ d8 q6 g/ M0 r
diagnosis, the child had a normal growth velocity at
6 B+ p! a5 ^# }% n, d4 cthe follow-up visit. It is hoped that his final adult
3 }" S. K* |8 i5 A" gheight will not be affected.
8 H& l9 F8 m& w) v( W: Y# h( i2 x& OAlthough rarely reported, the widespread avail-6 c+ O# [7 t9 } z7 }( b/ |! i O B' p
ability of androgen products in our society may2 C( ]) V `" F( K/ W" i
indeed cause more virilization in male or female
- j# y1 G8 y3 h6 j5 q, pchildren than one would realize. Exposure to andro-
5 `' ?6 M6 |9 q% P; h# Q7 Tgen products must be considered and specific ques-
. N& r2 m5 C9 X$ vtioning about the use of a testosterone product or
0 T, P# g$ M* E/ A+ j. A& J8 e5 vgel should be asked of the family members during( n9 N6 @4 t9 }# k6 a
the evaluation of any children who present with vir-
$ K; t4 h& r$ `& v9 Iilization or peripheral precocious puberty. The diag-
( O; z2 ~3 ^: ^: M0 v" f; y* \ unosis can be established by just a few tests and by
) S3 r, h& I/ v9 T2 e/ e: qappropriate history. The inability to obtain such a
8 b9 k% m8 d( e% phistory, or failure to ask the specific questions, may7 c+ v; [5 t J; ^
result in extensive, unnecessary, and expensive
/ d4 S# r: F* Q2 M% Ginvestigation. The primary care physician should be
( P0 o# j) [/ z& }. |5 Maware of this fact, because most of these children
! |- U( {- `- gmay initially present in their practice. The Physicians’9 T# M# T' q& y* @
Desk Reference and package insert should also put a4 Z& P7 W. P/ A/ Z
warning about the virilizing effect on a male or( W* ^' n- C3 e! B
female child who might come in contact with some-0 r7 A- H$ p7 Z1 b( C% t7 j
one using any of these products.
9 E' J+ N3 g4 CReferences
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Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;8 o0 k d5 w' K( X* M: k+ E
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! I9 n1 p+ g$ Y) P0 I/ A8 L3 ~; E0 Q2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
+ g% W. I- V. E$ Npuberty in children with tumours of the suprasellar pineal
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3 u* {3 S: p" R- Q1 k8 j& KEconomics Company, Inc; 2004:3239-3241.; K5 V; H$ f/ u, K6 u
7. Klugo RC, Cerny JC. Response of micropenis to topical
% B6 e3 s( Y& l. Ftestosterone and gonadotropin. J Urol. 1978;119:" i* h: c+ Q# O6 H6 Y/ R/ @
667-668., E9 J7 [$ _) G
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