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Sexual Precocity in a 16-Month-Old+ d7 N% _: w: u! `' O  h0 z& Y
Boy Induced by Indirect Topical
+ {0 \; e$ B) z: X! P# x8 SExposure to Testosterone2 S3 E  d& q! f5 i9 S1 {3 D# l
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2  |# s% t- f+ Z  ^# L" R
and Kenneth R. Rettig, MD1
# C$ t; r& K1 V. o. XClinical Pediatrics' r, _- d& D/ `  O' v& b+ y5 `, u2 s
Volume 46 Number 6
/ ^9 |2 d" s* J! @8 ?July 2007 540-543
0 f2 k6 A$ H- d© 2007 Sage Publications
7 W/ }7 _5 C* O  B10.1177/0009922806296651
% ?7 e& [; T  d* P% C5 U# m: Dhttp://clp.sagepub.com; j  T9 ]. b) H% e# L0 _8 Z
hosted at
, o; c" c7 u/ }  o9 ?! ihttp://online.sagepub.com
# M% W5 w' `4 a6 rPrecocious puberty in boys, central or peripheral,
- ^5 T( s# U' \' j2 O. fis a significant concern for physicians. Central! O$ W# T# z, V* Y* [; m+ Q
precocious puberty (CPP), which is mediated* g9 t( j6 \( `) w6 _5 M2 @
through the hypothalamic pituitary gonadal axis, has
- Y# F* j0 G4 u* q/ i, R% Ca higher incidence of organic central nervous system
7 K0 D, \" l* L, \" b8 Z5 ]5 \0 `& {lesions in boys.1,2 Virilization in boys, as manifested
& P7 F% x6 l* ]3 k6 Z5 S* ?by enlargement of the penis, development of pubic
7 \7 o% ]) k9 L+ t+ P( dhair, and facial acne without enlargement of testi-
2 W+ D! \; X" J# xcles, suggests peripheral or pseudopuberty.1-3 We
* N' V1 F8 v) P1 Z! `- t" s2 vreport a 16-month-old boy who presented with the
. v$ ?* @( J" g; m# Menlargement of the phallus and pubic hair develop-
5 Z" ~6 R6 `% z1 a2 Rment without testicular enlargement, which was due
) n) {: }0 L4 V$ l* ^( x- Lto the unintentional exposure to androgen gel used by1 W: M4 I( y) ^- g5 i
the father. The family initially concealed this infor-
5 G% L2 `, x5 ?. m; e1 amation, resulting in an extensive work-up for this* H3 G: E/ P5 j) |4 p* t
child. Given the widespread and easy availability of
, g! o# V3 ~% @4 W  L) etestosterone gel and cream, we believe this is proba-
9 m0 y( M) d% ?% w/ Ebly more common than the rare case report in the, N3 P0 Y, h/ t1 N3 p# c! V
literature.4
& \( b8 I! [. o5 e' {6 I" VPatient Report
2 P/ Y1 y* l/ D, tA 16-month-old white child was referred to the, i8 y6 [4 W5 P4 c. F
endocrine clinic by his pediatrician with the concern5 j, D" D4 I. _1 W
of early sexual development. His mother noticed, O5 J, z- G3 k* K$ }9 W; N
light colored pubic hair development when he was6 j! M9 j% B) h% I9 X0 w
From the 1Division of Pediatric Endocrinology, 2University of
4 X& ?5 b: g: VSouth Alabama Medical Center, Mobile, Alabama.
& b/ R; X0 k: pAddress correspondence to: Samar K. Bhowmick, MD, FACE,
, g! x7 _1 W. t; V2 g) s" I7 HProfessor of Pediatrics, University of South Alabama, College of3 x1 I) g  S) P, k" ]
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
7 A+ g' [- \0 X: `e-mail: [email protected].
5 t  f) W) _  E0 I/ n" F/ u5 N, zabout 6 to 7 months old, which progressively became" r: q4 c; r. L
darker. She was also concerned about the enlarge-
3 h/ ]. D, ^/ j8 N3 Q' Lment of his penis and frequent erections. The child
( n$ f+ g% ]2 f- E5 hwas the product of a full-term normal delivery, with1 M7 m! H* R8 {5 N+ H
a birth weight of 7 lb 14 oz, and birth length of/ Y+ G, g1 D! }# u7 ]
20 inches. He was breast-fed throughout the first year
8 P, P) K. |) X% x. O4 Jof life and was still receiving breast milk along with/ ~' y* s% ^6 ^& S
solid food. He had no hospitalizations or surgery,, k3 O, x' ]: B7 [4 A- I
and his psychosocial and psychomotor development4 S1 Z2 z- G* U0 K
was age appropriate.; M" _- ]! I6 U' P5 n! i
The family history was remarkable for the father,* j1 ]9 Q* l  s8 z, q& _; O
who was diagnosed with hypothyroidism at age 16,
% R1 c- _& P" j5 A  v5 i( Zwhich was treated with thyroxine. The father’s. r- M# q% b# t6 K( W* ~0 i
height was 6 feet, and he went through a somewhat
! y( e5 M' l) M8 mearly puberty and had stopped growing by age 14.
. h, L7 s  |% r( {  t9 b1 Y- ^The father denied taking any other medication. The- a6 U# e7 P' j0 O
child’s mother was in good health. Her menarche+ ^9 x+ X0 t+ O  ^- x: m8 I
was at 11 years of age, and her height was at 5 feet
) j# J1 `! ^( |2 }5 t% t5 inches. There was no other family history of pre-
; }3 X+ d# J- m% ?, \$ Acocious sexual development in the first-degree rela-
3 F8 O5 E  ]0 L0 k0 o2 l1 P  o7 Xtives. There were no siblings.# u3 P8 X! Q; i  }
Physical Examination
# w* T. ^) X' h; lThe physical examination revealed a very active,
5 k8 K3 v6 B- f+ Bplayful, and healthy boy. The vital signs documented
5 v- d7 g7 ?# N" }6 F0 Da blood pressure of 85/50 mm Hg, his length was  z2 `8 i7 x9 O) k7 [
90 cm (>97th percentile), and his weight was 14.4 kg3 e' e. `1 e8 m% t1 j
(also >97th percentile). The observed yearly growth
1 A8 P$ s  V7 g, Tvelocity was 30 cm (12 inches). The examination of- K5 O! N, J- s3 y2 ~* V7 u7 K8 X
the neck revealed no thyroid enlargement.7 o; ]9 c* K- k& K" A. ?: b
The genitourinary examination was remarkable for! a# b& r. ~  d3 q
enlargement of the penis, with a stretched length of. k, P! \! M% x$ a( v4 A
8 cm and a width of 2 cm. The glans penis was very well
% t9 {$ S. t3 o9 j9 edeveloped. The pubic hair was Tanner II, mostly around
  a5 }! ]& |  b, n- |. c540
) S+ `. B/ a( @' s/ L, i# S% dat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
4 s2 D" g& j5 V- r- a6 vthe base of the phallus and was dark and curled. The
5 h+ [& k( h# y9 O6 I! g. Ztesticular volume was prepubertal at 2 mL each.  `! C- }8 Y' X8 [% c7 H
The skin was moist and smooth and somewhat
, o, F9 |7 [) ], b9 w! L6 Z& @# soily. No axillary hair was noted. There were no9 J( g5 j# h, }( g6 j- c# S
abnormal skin pigmentations or café-au-lait spots.* T/ M1 E2 d4 b# s# r; N' y
Neurologic evaluation showed deep tendon reflex 2+9 ~3 C. g6 r5 H0 t! N0 I
bilateral and symmetrical. There was no suggestion
" f2 c8 x, q) V7 e( G: lof papilledema.' t+ T' n" H3 e- n; ]
Laboratory Evaluation
, G2 \$ Q# N7 {# ]3 f2 nThe bone age was consistent with 28 months by
2 h1 O2 \- {. h4 \: P/ s1 h, T! A5 Uusing the standard of Greulich and Pyle at a chrono-
+ G5 c$ \$ i7 x2 w8 Vlogic age of 16 months (advanced).5 Chromosomal
, M9 W/ s, A8 R& b0 |karyotype was 46XY. The thyroid function test" j1 s3 B$ Y/ S! ^. ]1 V% F
showed a free T4 of 1.69 ng/dL, and thyroid stimu-6 L. k" C* `' ^. V
lating hormone level was 1.3 µIU/mL (both normal).5 ?8 L* T7 c8 R: {6 T; |
The concentrations of serum electrolytes, blood
+ u, }% M2 N* u; b5 H. o" Q: |urea nitrogen, creatinine, and calcium all were
; S+ w+ @; Q5 m4 ]within normal range for his age. The concentration( a+ S- A& [3 q0 W$ x; j. k/ ~$ H
of serum 17-hydroxyprogesterone was 16 ng/dL
. k4 A; }( Q! m9 V4 {7 T' L1 {8 U(normal, 3 to 90 ng/dL), androstenedione was 20- F6 c7 \' c: {4 I
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
: A9 j+ a2 Z. k" m0 H4 Q( uterone was 38 ng/dL (normal, 50 to 760 ng/dL),
* v4 I* g! i$ n$ j' j: ddesoxycorticosterone was 4.3 ng/dL (normal, 7 to
- k  e' ]* h4 Y8 d3 s0 m/ v1 {8 E' u49ng/dL), 11-desoxycortisol (specific compound S)
- u/ M) o- u5 f; v6 V3 j1 `was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
- X: p+ e) V; Ktisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total+ V2 m. M- ?4 Q% ?4 o
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
( @1 I5 S1 f2 X' {  yand β-human chorionic gonadotropin was less than/ r6 g  d/ M; z0 J2 e) f. ^
5 mIU/mL (normal <5 mIU/mL). Serum follicular
& X8 ~+ P) E- E' Y3 nstimulating hormone and leuteinizing hormone5 c. a5 e8 |) p
concentrations were less than 0.05 mIU/mL* |6 J, n& w  Q. Y7 {" S  U
(prepubertal).2 ^0 ?4 D% I, ^/ ]! Y
The parents were notified about the laboratory
# k2 l8 v  D3 |+ Cresults and were informed that all of the tests were% M, |9 |8 D5 ]
normal except the testosterone level was high. The
" O2 {. d% k& m. O- J  u4 ufollow-up visit was arranged within a few weeks to
3 D" S& T* ?! Y; ~+ k" f0 oobtain testicular and abdominal sonograms; how-
$ s3 k9 u; o0 P! ^6 K/ a! W2 gever, the family did not return for 4 months.0 A5 E  D- Y/ L3 p+ o
Physical examination at this time revealed that the
# B% ?2 V8 g0 w, d' P8 k+ _child had grown 2.5 cm in 4 months and had gained
- K1 U" r" A6 y" W2 kg of weight. Physical examination remained
% U& B% W" |) y$ Iunchanged. Surprisingly, the pubic hair almost com-. {' w& V& R) H4 G: u% J# S) N
pletely disappeared except for a few vellous hairs at
2 M) }; J; ~( h% qthe base of the phallus. Testicular volume was still 2& _! w9 W# W6 s# m
mL, and the size of the penis remained unchanged.  I) E5 c, I; j3 p) [$ J* o5 l
The mother also said that the boy was no longer hav-/ Y) m1 \6 u' R9 w2 B, P7 i
ing frequent erections.# k" b: U6 ^) Z8 D
Both parents were again questioned about use of
% u+ B9 N+ W. W, b5 p+ a  qany ointment/creams that they may have applied to4 N" \# F; G. N  s4 y
the child’s skin. This time the father admitted the3 Z6 U- g7 h4 Y: B; X7 f
Topical Testosterone Exposure / Bhowmick et al 541! q  O8 r+ I: A- m6 h
use of testosterone gel twice daily that he was apply-) e) C4 X+ \7 [7 w, O
ing over his own shoulders, chest, and back area for! w4 B& k2 Z- H9 V" Y4 J
a year. The father also revealed he was embarrassed
2 u* p3 d3 \; r& A8 E, B$ Fto disclose that he was using a testosterone gel pre-+ e% F1 q: A+ [+ _4 o; n/ Q9 b% h
scribed by his family physician for decreased libido
3 o+ L5 V2 i" d+ R2 Tsecondary to depression.( D  e- H) s# R5 T; }; ?; _
The child slept in the same bed with parents.* ?! v" R, S/ B
The father would hug the baby and hold him on his
; U3 O% T6 ^6 h' \6 D2 M4 Vchest for a considerable period of time, causing sig-
  e' K+ O8 X$ P. e; z' ^, {nificant bare skin contact between baby and father.
8 D/ G7 K3 s: N8 P! C( aThe father also admitted that after the phone call,1 p1 X$ J8 G) l% l' J: z
when he learned the testosterone level in the baby- W2 M9 c: O; u' b8 G$ j/ U  K
was high, he then read the product information
: ~* ~; i. C+ O8 a- Y7 \packet and concluded that it was most likely the rea-
( w& n( q% V! p+ s1 w$ Oson for the child’s virilization. At that time, they- U  q" ^; d' _1 z
decided to put the baby in a separate bed, and the" z! z' O/ _+ v6 `. s0 w
father was not hugging him with bare skin and had( N1 f: K) w( U* T
been using protective clothing. A repeat testosterone
1 u% B; T4 r; w. Dtest was ordered, but the family did not go to the' s8 |; N1 V: O! }1 m2 U( ~& |* l; k
laboratory to obtain the test.  X5 V  v( t6 O, {& P" \3 \+ r
Discussion+ I7 l$ ?: [( X( d; X0 u1 @
Precocious puberty in boys is defined as secondary
9 _0 q6 l6 w3 `+ ?1 b1 ksexual development before 9 years of age.1,4
3 A, W) i2 C' ^$ `, kPrecocious puberty is termed as central (true) when
6 m% M# O* G  F) n" G* k: j; Sit is caused by the premature activation of hypo-
7 d5 E- A/ z8 F" J* I# S  U- Ithalamic pituitary gonadal axis. CPP is more com-0 \5 o  ^* O7 n1 b4 t- ?$ T% |5 B
mon in girls than in boys.1,3 Most boys with CPP
: Z. m) h3 V% i. R! nmay have a central nervous system lesion that is
0 Y& |& }. W# iresponsible for the early activation of the hypothal-
- D" c: @+ O9 Bamic pituitary gonadal axis.1-3 Thus, greater empha-. U: a/ O9 U+ ]+ U4 c
sis has been given to neuroradiologic imaging in4 s/ p7 d0 }+ h5 f
boys with precocious puberty. In addition to viril-
* {4 |4 d" @# \) Bization, the clinical hallmark of CPP is the symmet-# b- y& ]2 y: E$ f( m2 q7 }
rical testicular growth secondary to stimulation by, L1 H0 |6 A( z7 ~6 g
gonadotropins.1,3, M$ p* ]+ M7 E: r( O
Gonadotropin-independent peripheral preco-
, k  y2 U) Q5 b* k! K& E# @4 {cious puberty in boys also results from inappropriate
3 I0 U! h! |. j7 Fandrogenic stimulation from either endogenous or
/ `* o. _( i5 G) yexogenous sources, nonpituitary gonadotropin stim-# S# f3 {% y/ k* C. H
ulation, and rare activating mutations.3 Virilizing
# C( u7 K" M& c) j6 Y8 E) K* Tcongenital adrenal hyperplasia producing excessive
; }  n% w) ]6 P" X/ y; n5 uadrenal androgens is a common cause of precocious, ~) X  Z$ T2 f* c
puberty in boys.3,4$ H  `5 s- T- l8 S. K% y8 I7 u" h
The most common form of congenital adrenal
3 y, ?: k6 W4 H, n/ phyperplasia is the 21-hydroxylase enzyme deficiency.
7 h" D) c% S8 K; E6 C) l' X. XThe 11-β hydroxylase deficiency may also result in/ D: \1 S- Y  U
excessive adrenal androgen production, and rarely,* L( c$ r9 B6 S7 H9 I
an adrenal tumor may also cause adrenal androgen8 Y; E' o  P; a
excess.1,3+ r1 M2 ]0 N) c- k  i- Z1 W' A
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from/ Y/ E4 d  K( A5 X; P' p% A
542 Clinical Pediatrics / Vol. 46, No. 6, July 20072 U- p$ `8 X- F5 p8 s
A unique entity of male-limited gonadotropin-
/ [& }, q( ?5 T+ a& D4 ^( X4 X2 Vindependent precocious puberty, which is also known5 k# Z9 `0 T! J
as testotoxicosis, may cause precocious puberty at a  s8 k# }/ {$ R( M& o
very young age. The physical findings in these boys& V4 I6 F# V- @8 U' r4 C( C2 d' l
with this disorder are full pubertal development,
& o+ K. j* W$ C+ Xincluding bilateral testicular growth, similar to boys% z1 B5 {2 m( }8 B# M5 _% E
with CPP. The gonadotropin levels in this disorder
/ B! b  Q7 R3 j/ D( G4 B$ M) mare suppressed to prepubertal levels and do not show
( j' e9 X2 _$ l* Kpubertal response of gonadotropin after gonadotropin-9 P$ |; ?# q4 e+ s
releasing hormone stimulation. This is a sex-linked; b& j" W: S! C& U; |
autosomal dominant disorder that affects only0 U6 ~) \9 p8 }; T' y# m
males; therefore, other male members of the family
3 l4 W/ L& M% D" Rmay have similar precocious puberty.3
. ~; s7 Z( Z- p' O3 K: AIn our patient, physical examination was incon-+ d$ O2 }2 E5 Z0 ~+ i
sistent with true precocious puberty since his testi-
# g* `" e6 [0 ~+ {2 F' Xcles were prepubertal in size. However, testotoxicosis" w( S9 b3 t8 o8 V6 Z- t
was in the differential diagnosis because his father) P' M7 C0 x; z5 f+ p& B) g" q3 A2 C
started puberty somewhat early, and occasionally,
7 J- t+ w/ j6 C% J/ |0 Ktesticular enlargement is not that evident in the* I: T) }8 l# Z  @' n
beginning of this process.1 In the absence of a neg-
8 M6 J( @9 Z& Hative initial history of androgen exposure, our
; L' k1 c6 y  e4 @0 Lbiggest concern was virilizing adrenal hyperplasia,
$ k2 l! v4 ^- A6 c/ g5 f! X) r; @either 21-hydroxylase deficiency or 11-β hydroxylase% e, ~" o+ K' g
deficiency. Those diagnoses were excluded by find-$ B# b" Z* C9 a" I6 I( a& Z* C/ Y2 j9 K
ing the normal level of adrenal steroids.! C' Z8 b2 [, l8 Z( q' H8 O
The diagnosis of exogenous androgens was strongly. F3 O: _; U/ w2 ?; X' @, M
suspected in a follow-up visit after 4 months because
5 J# \# x/ P& D3 A" Fthe physical examination revealed the complete disap-
, J" J$ e9 O! Q* O& v8 {! e! Fpearance of pubic hair, normal growth velocity, and
2 L5 `: M6 L2 R7 B/ c8 P) z% `decreased erections. The father admitted using a testos-
* I5 L/ D5 S  S1 o6 D9 cterone gel, which he concealed at first visit. He was+ n+ I0 A* h" }2 y3 n
using it rather frequently, twice a day. The Physicians’' v: K4 |1 M4 l4 \& y* u3 L/ v7 e
Desk Reference, or package insert of this product, gel or
1 ~8 M! L2 O0 ^  Scream, cautions about dermal testosterone transfer to7 O; m0 Q7 f0 F# O2 m$ M7 n+ l
unprotected females through direct skin exposure.5 |/ d; x7 a8 m; b7 n) ?
Serum testosterone level was found to be 2 times the9 r2 g) i: ^# o; o( m: N2 r
baseline value in those females who were exposed to# Q8 K4 N$ `# Y! d7 N
even 15 minutes of direct skin contact with their male3 R' I2 ~% f1 Q5 u$ F
partners.6 However, when a shirt covered the applica-& T8 d1 O0 B, q' T
tion site, this testosterone transfer was prevented.8 |# |( l  C  j0 Z
Our patient’s testosterone level was 60 ng/mL,
) n" H8 ?1 c- ?which was clearly high. Some studies suggest that4 _% }  P( \: |& \$ g
dermal conversion of testosterone to dihydrotestos-
! t( l2 L: M3 ~0 ]4 X( gterone, which is a more potent metabolite, is more
0 M4 G% w% V7 A# R: Z, d6 R; uactive in young children exposed to testosterone
/ M: C% w3 G. @4 z& Q( }exogenously7; however, we did not measure a dihy-, s) G( D& M5 X, d! O9 h; E# a
drotestosterone level in our patient. In addition to
8 i* L5 l- p/ _9 U$ Wvirilization, exposure to exogenous testosterone in
: Z2 S6 Y' ?3 `' ichildren results in an increase in growth velocity and
4 h8 x2 D0 c* \5 Ladvanced bone age, as seen in our patient.
( Y& C! Y4 x1 b4 Y3 L6 PThe long-term effect of androgen exposure during3 d! C; C5 S* B
early childhood on pubertal development and final
/ q! i1 a: h+ i1 K3 N4 r- \adult height are not fully known and always remain
$ {  ~! c9 z) L9 T" a- q8 M- m. Da concern. Children treated with short-term testos-
  c9 _) ^2 p$ I" P$ k" f+ Xterone injection or topical androgen may exhibit some1 l9 h: i. Y4 C* C
acceleration of the skeletal maturation; however, after7 \) P: Q( g( n2 D
cessation of treatment, the rate of bone maturation
) z7 u* z' F, j+ xdecelerates and gradually returns to normal.8,9$ G8 A0 J5 ?! I5 X% l* e/ ^
There are conflicting reports and controversy
! B9 G8 M8 F- g4 Sover the effect of early androgen exposure on adult
2 b* u1 }  r/ ^( V! e, \0 j+ tpenile length.10,11 Some reports suggest subnormal
9 f4 Q7 x- P4 Z7 ^8 }: Sadult penile length, apparently because of downreg-" b2 h' B/ M, K8 K/ Q
ulation of androgen receptor number.10,12 However,
" F1 k! O1 T; u/ U4 ]9 lSutherland et al13 did not find a correlation between
' y; s. P4 ]5 X. F. k. Echildhood testosterone exposure and reduced adult) z1 j6 A. y3 ^% y
penile length in clinical studies.
1 m3 N* {, ~* l2 z1 o/ d4 D+ ONonetheless, we do not believe our patient is
, K8 y, _, a) l' u& b  Fgoing to experience any of the untoward effects from
6 f) J: N  M* q2 M# \4 p( o) s4 otestosterone exposure as mentioned earlier because
8 o7 n/ U9 A& @the exposure was not for a prolonged period of time.: @: ?. I/ h- Q( h
Although the bone age was advanced at the time of# G  m; ]3 F! g* M
diagnosis, the child had a normal growth velocity at
3 ]! W" X% s$ T5 |% ^the follow-up visit. It is hoped that his final adult
  F, L8 o# M( L- o0 B( o4 Jheight will not be affected.+ H2 k  F/ V( d$ _& [. a1 f
Although rarely reported, the widespread avail-
, T0 z) q/ N) Q( k0 oability of androgen products in our society may
+ o: w8 q* Y$ S8 p$ v. s' ~+ E! {indeed cause more virilization in male or female
  M: V# ~- }) achildren than one would realize. Exposure to andro-6 i/ {& p0 ?4 y+ e8 x  N+ j- e
gen products must be considered and specific ques-
2 F+ `1 \* R* }7 m0 T# x- I( Ctioning about the use of a testosterone product or, k; t7 a3 E2 m& \5 e
gel should be asked of the family members during" \9 e2 I( V) ~4 ?$ \) s$ l8 T8 l
the evaluation of any children who present with vir-
: J- T  w- R; Y- f( [ilization or peripheral precocious puberty. The diag-
- S1 H1 c/ I" q% [nosis can be established by just a few tests and by
' T! ^, F1 z6 N4 L4 q; a1 Uappropriate history. The inability to obtain such a: D" Q$ Z' W+ x( p
history, or failure to ask the specific questions, may; x  c# P, u) d
result in extensive, unnecessary, and expensive$ O0 R, U# p, V4 l
investigation. The primary care physician should be
" j2 I, H2 }& E7 V. waware of this fact, because most of these children
. b" A3 L. p* T$ wmay initially present in their practice. The Physicians’
0 L" L8 L7 G: ?: V1 a: t9 YDesk Reference and package insert should also put a! v* S4 C! N. q/ ]
warning about the virilizing effect on a male or
2 Y* l( y9 u: {7 u1 _female child who might come in contact with some-5 Y% @- N" u# \* p* [# d
one using any of these products.6 r( b" N* d& h4 T. e, I& G9 P
References
( |/ R! @/ n! ?9 A- q7 q1. Styne DM. The testes: disorder of sexual differentiation& ]5 }& N2 b) {# q, X; j
and puberty in the male. In: Sperling MA, ed. Pediatric
$ Z* _% L6 w$ z% `Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;0 e: X3 h5 i0 D6 m! j7 o) l
2002: 565-628.
, V# G3 c  [2 z- v1 J2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
5 N. O: a5 b/ F: G; Qpuberty in children with tumours of the suprasellar pineal
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Sexual Precocity in a 16-Month-Old% a. `0 J3 }& i7 Q- V$ Z
Boy Induced by Indirect Topical4 A/ s, c# J; u$ H' k+ m' u
Exposure to Testosterone1 S5 c' x* R; o; {( ^! H& O6 U
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
: ]0 G( v7 Q$ Oand Kenneth R. Rettig, MD1
9 m5 X2 C$ Y+ S; h$ S$ EClinical Pediatrics
* `; E) G  u5 b- r, NVolume 46 Number 6/ t/ F, d7 ]# L' [7 P6 x
July 2007 540-543
! k; i0 P$ G, `% V1 P© 2007 Sage Publications( Q/ w5 P) S9 B: t: S" M
10.1177/0009922806296651; P7 u# |2 p- S% J
http://clp.sagepub.com/ W$ U0 b$ o9 ?8 {, l- D" p
hosted at
; E& V+ R: h7 J8 \% o' O/ q- u3 Mhttp://online.sagepub.com
0 m$ f$ w7 l8 L% TPrecocious puberty in boys, central or peripheral,) L0 K1 e# c8 {$ b3 d
is a significant concern for physicians. Central
8 ~) v3 T/ x+ V. W. yprecocious puberty (CPP), which is mediated; A0 P! [8 D, c& U! ?) V
through the hypothalamic pituitary gonadal axis, has
( ^" Z3 `% a  I- e' B4 Na higher incidence of organic central nervous system2 B% Q! d  p0 d9 y4 F
lesions in boys.1,2 Virilization in boys, as manifested
  }, i, D' j. B6 v( ]4 Dby enlargement of the penis, development of pubic8 i  I1 s" I7 z
hair, and facial acne without enlargement of testi-' G$ G7 R( a! U6 o
cles, suggests peripheral or pseudopuberty.1-3 We
# J! f9 h4 I; }9 `! k& E" A+ R; Y0 lreport a 16-month-old boy who presented with the
$ |1 v& Q3 y3 \, N1 ~& ^6 benlargement of the phallus and pubic hair develop-
# D7 g) l9 F. w! [9 Dment without testicular enlargement, which was due
. o( B8 o% Y  \, o) c2 F; sto the unintentional exposure to androgen gel used by
0 _1 a1 Q* p6 [. }1 ~6 Fthe father. The family initially concealed this infor-
  }6 w0 ?/ A6 d2 Q; k0 Zmation, resulting in an extensive work-up for this
/ S1 ~% ~- X; T% e% Q2 Xchild. Given the widespread and easy availability of
* x6 U: l4 f; u9 ?7 _' ^testosterone gel and cream, we believe this is proba-+ {8 ?! A7 t$ I5 X8 A) e
bly more common than the rare case report in the
* T$ _: {. \* J$ l8 iliterature.41 R0 Y" J9 e+ B0 O
Patient Report
8 i3 P7 X& p: NA 16-month-old white child was referred to the0 R; c2 `0 v4 c. n- v; t2 S" W
endocrine clinic by his pediatrician with the concern( ]' x5 c( Z% }4 ]* l
of early sexual development. His mother noticed
: J9 b9 Q! L/ X6 l0 P0 g. blight colored pubic hair development when he was; C( ~7 a% Q7 }
From the 1Division of Pediatric Endocrinology, 2University of
( o1 N' k0 F  L9 o. KSouth Alabama Medical Center, Mobile, Alabama.
7 A: a) ]# j# Z) t+ c5 A4 ?4 YAddress correspondence to: Samar K. Bhowmick, MD, FACE,
% s" o9 i0 a* n! o1 n; M$ ?Professor of Pediatrics, University of South Alabama, College of
. b) [, s( s+ B6 AMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;5 T& x2 o8 H8 J2 q3 x6 v
e-mail: [email protected].) x% ?( L0 J4 r$ V, Q4 v# F  X( F
about 6 to 7 months old, which progressively became
+ J/ x( T' M4 X9 n+ pdarker. She was also concerned about the enlarge-5 m. G7 R% m3 H8 j3 L  x- S' B
ment of his penis and frequent erections. The child
1 R6 }0 ?7 ]6 R9 g! Pwas the product of a full-term normal delivery, with
3 \  b: g- j; W( S, H3 Ta birth weight of 7 lb 14 oz, and birth length of8 |# K0 p# @0 I: Z0 ~1 k, R
20 inches. He was breast-fed throughout the first year/ N( Z1 S: c3 ~3 P
of life and was still receiving breast milk along with  G" A2 b( W% h8 d! O2 c9 a$ m$ P
solid food. He had no hospitalizations or surgery,
" `. v. @; {+ A/ gand his psychosocial and psychomotor development
! C9 A( _( H  Nwas age appropriate.2 I2 x. T  N2 e
The family history was remarkable for the father,- j! K5 I! ?2 I, O1 y& ~) W' x- x
who was diagnosed with hypothyroidism at age 16,
2 r* ?& Y& h) ]2 q# a. n( Bwhich was treated with thyroxine. The father’s- R# T0 F8 t  p# t/ u! ?
height was 6 feet, and he went through a somewhat( _# B; Z# B# B& Q# u3 d
early puberty and had stopped growing by age 14.+ t' E. S+ s3 D4 |" s; s: `
The father denied taking any other medication. The
: e  H9 Y. J! k% i2 y) e( n) Pchild’s mother was in good health. Her menarche: t: \# O) l/ T# g
was at 11 years of age, and her height was at 5 feet
4 p! x# ^3 m% U5 _5 inches. There was no other family history of pre-
5 t! J# s, ^, T" W; V2 dcocious sexual development in the first-degree rela-
, D: @" [; X: N2 ltives. There were no siblings.
" t+ Z( K( K( E% |5 E* C6 l3 iPhysical Examination
$ I# T4 d" z# z7 I- _The physical examination revealed a very active,
  I0 U2 B& |2 C& H& yplayful, and healthy boy. The vital signs documented
/ j3 {; h# D0 m6 Y  Oa blood pressure of 85/50 mm Hg, his length was+ ~" @# a! G5 j! o( J) Y
90 cm (>97th percentile), and his weight was 14.4 kg3 l) z, i+ Y% i$ w& K( [
(also >97th percentile). The observed yearly growth" K# j: L9 s7 n) s/ |% N
velocity was 30 cm (12 inches). The examination of. q* [, ^; m) x9 g
the neck revealed no thyroid enlargement.6 l3 |6 M/ g0 S/ J9 D; t3 Q
The genitourinary examination was remarkable for
7 @5 _. i8 `5 E# w- eenlargement of the penis, with a stretched length of  c: J: j9 B# n/ ?! T% P, r8 @
8 cm and a width of 2 cm. The glans penis was very well
7 M3 }3 r0 T% H1 U& h2 X, [* M: Udeveloped. The pubic hair was Tanner II, mostly around( Z+ j) _+ `5 B& @8 L
540, x$ q7 L) R: R5 g8 I
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
  U4 }; b0 @  V4 kthe base of the phallus and was dark and curled. The" d+ k9 A$ p& E1 z7 f3 _* ?
testicular volume was prepubertal at 2 mL each.
8 N4 i' e* U* T' a3 f% S, wThe skin was moist and smooth and somewhat
+ C! _. J/ {  E1 H5 E' c. g' Qoily. No axillary hair was noted. There were no
- E  K, P8 n, Q2 Z7 L/ oabnormal skin pigmentations or café-au-lait spots.( D( i' _) {" R6 _) l" f
Neurologic evaluation showed deep tendon reflex 2+3 F8 a$ b0 u/ u+ w% X
bilateral and symmetrical. There was no suggestion
. U' q# H0 N1 j/ y* Iof papilledema.
1 q4 s) z% N, [9 d9 c, s! mLaboratory Evaluation
! e8 X1 u- c8 N( GThe bone age was consistent with 28 months by+ H& P* C* t  p. u& K7 V) F
using the standard of Greulich and Pyle at a chrono-4 `/ W# E( U$ K& F& {# X6 z  C
logic age of 16 months (advanced).5 Chromosomal: U: C* c  d6 ^# e
karyotype was 46XY. The thyroid function test
0 n7 t- i8 ^# C( B2 ?showed a free T4 of 1.69 ng/dL, and thyroid stimu-; n( `, e* z( Q0 R6 l( r$ s# c  C
lating hormone level was 1.3 µIU/mL (both normal).6 T; K& U/ R9 _- v. g
The concentrations of serum electrolytes, blood
0 r; @. t5 \: vurea nitrogen, creatinine, and calcium all were4 S& P( k: _  e* h5 z: u
within normal range for his age. The concentration& s0 G8 K. k, [5 @- j
of serum 17-hydroxyprogesterone was 16 ng/dL
2 d3 @/ M) m3 \, a(normal, 3 to 90 ng/dL), androstenedione was 208 q6 Y, c3 |( |! d( v
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-) Q& H; q0 c1 g
terone was 38 ng/dL (normal, 50 to 760 ng/dL),/ a+ ?& K1 ]. S
desoxycorticosterone was 4.3 ng/dL (normal, 7 to5 ?6 Z& h" @* z) B: j
49ng/dL), 11-desoxycortisol (specific compound S)
3 u5 b+ U$ U% ~. w" mwas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
6 Z* f, _2 a! x* ~# mtisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
) F! I$ u, L& f! G6 ltestosterone was 60 ng/dL (normal <3 to 10 ng/dL),
3 n0 G% ]" w9 L+ H: uand β-human chorionic gonadotropin was less than# G! z; n5 ^# N" @- x, @0 F9 X
5 mIU/mL (normal <5 mIU/mL). Serum follicular' ?/ `: ^, J+ q" N7 q6 W
stimulating hormone and leuteinizing hormone5 T7 d5 }/ T2 ~: ?) {
concentrations were less than 0.05 mIU/mL9 F$ C, ?: F$ M# E. R& c  i+ t
(prepubertal).% K/ i) h5 c$ ^, ~' \$ J3 v
The parents were notified about the laboratory. V9 m% g7 d0 F
results and were informed that all of the tests were
" C5 o: q" q8 u  H7 a4 o+ {( c! ynormal except the testosterone level was high. The
7 F  U. X7 Q/ h, \2 }follow-up visit was arranged within a few weeks to
0 W8 Q8 v5 i. d; e9 Zobtain testicular and abdominal sonograms; how-" P* E: A0 C. \# d' Z
ever, the family did not return for 4 months.( t) }, M) z9 @$ H- J) ^# M
Physical examination at this time revealed that the
' a+ u, J4 k! X' k$ ochild had grown 2.5 cm in 4 months and had gained
5 n- U' U% v" v( T2 kg of weight. Physical examination remained
! f$ Z: C4 c( I  V7 tunchanged. Surprisingly, the pubic hair almost com-
, B) h" M/ J0 i2 U3 P! P2 c4 ypletely disappeared except for a few vellous hairs at4 @+ s( Q( z( v/ J  ~7 {
the base of the phallus. Testicular volume was still 2
; E) V- a* H. ], J. ?mL, and the size of the penis remained unchanged.+ C5 f  w3 ^7 s1 W" v( N/ e
The mother also said that the boy was no longer hav-
, Z7 x. A" ~: y3 iing frequent erections.) U8 G0 t( m, X$ n
Both parents were again questioned about use of1 w* B. E1 s; i  g  d+ T$ f
any ointment/creams that they may have applied to9 I; ]# r* z0 e: u8 I0 Z# _
the child’s skin. This time the father admitted the6 L1 ^& G9 c* _) Z
Topical Testosterone Exposure / Bhowmick et al 541
! L8 j$ p6 y4 l$ D: [4 k" K- ^use of testosterone gel twice daily that he was apply-
. I; U# Q3 e# Ging over his own shoulders, chest, and back area for6 e' C  e0 X( H/ ^7 o* w/ }& r
a year. The father also revealed he was embarrassed& {% W. \2 H5 [* Y( Z7 J
to disclose that he was using a testosterone gel pre-( b9 J4 P+ Q+ w3 g: J2 w( h; ^
scribed by his family physician for decreased libido
& P: |  p8 U. u/ }1 Qsecondary to depression.
, S# |/ W7 [1 n! m3 ?$ b* rThe child slept in the same bed with parents.* P% V7 p9 k/ D% R6 v0 Q
The father would hug the baby and hold him on his5 E& e% E6 p8 @9 I
chest for a considerable period of time, causing sig-9 r8 j# `  v( _1 l0 }
nificant bare skin contact between baby and father.# E% C0 x: m1 e! K4 |
The father also admitted that after the phone call,& u* @! A- O1 a$ F8 n0 B
when he learned the testosterone level in the baby
7 z* `2 a0 Y+ w: k( t% ]was high, he then read the product information
7 p0 m6 b/ ?/ y! mpacket and concluded that it was most likely the rea-
, y. e/ W8 ^' B4 m( }: xson for the child’s virilization. At that time, they
7 X1 U$ t/ S; T6 [/ mdecided to put the baby in a separate bed, and the( Y1 y- O0 `' `4 `, B" B
father was not hugging him with bare skin and had+ ?# w9 Q- l7 ?5 m. A: A
been using protective clothing. A repeat testosterone+ c$ L  k3 O$ i' d0 ]/ T, p  j
test was ordered, but the family did not go to the
9 ~9 ^5 L1 N  U- k; L8 hlaboratory to obtain the test.# x. o4 ^! y/ R1 S3 a3 y
Discussion$ M2 l: D  G3 K4 A& O
Precocious puberty in boys is defined as secondary
/ Q, c/ N1 g: G/ f3 C) Y% Usexual development before 9 years of age.1,4& a7 W+ F; t% N0 G; |
Precocious puberty is termed as central (true) when' ?& ?- {2 j/ |. h* c3 n+ x" n! I! q
it is caused by the premature activation of hypo-" {5 L$ o0 a  t/ L, y
thalamic pituitary gonadal axis. CPP is more com-
4 r. V# g7 Z. Q8 Hmon in girls than in boys.1,3 Most boys with CPP: F# Q" ~4 T$ l$ H2 U3 k) o
may have a central nervous system lesion that is
9 k& U- x- C! j6 y& dresponsible for the early activation of the hypothal-
9 N$ G% L: G" e9 ~& Iamic pituitary gonadal axis.1-3 Thus, greater empha-
& k9 g/ P* ~) f/ e6 Zsis has been given to neuroradiologic imaging in- y& B' |, \. |' j
boys with precocious puberty. In addition to viril-  ?6 Q9 Y% R8 |  Z) v* `4 L$ L' ?
ization, the clinical hallmark of CPP is the symmet-
) S6 _$ Y( Q5 E( Nrical testicular growth secondary to stimulation by
+ b8 I" m' G$ M& z) r, [gonadotropins.1,36 O! C! d: e5 U9 j* r" T
Gonadotropin-independent peripheral preco-
0 a7 U1 ~1 E* xcious puberty in boys also results from inappropriate
9 Q7 V5 ^- E3 gandrogenic stimulation from either endogenous or( [7 O! A0 e* |
exogenous sources, nonpituitary gonadotropin stim-1 I7 n; r7 E  \4 P
ulation, and rare activating mutations.3 Virilizing2 R# \. p7 p. K% p
congenital adrenal hyperplasia producing excessive
/ I8 d$ k$ r0 x8 T# C9 \( d% }adrenal androgens is a common cause of precocious
* |' R/ s) y! X: {7 xpuberty in boys.3,4
2 j  u1 h. U" L& i( }* L1 AThe most common form of congenital adrenal
+ K' j5 M1 M# y' E% V7 d2 G/ ~& Ohyperplasia is the 21-hydroxylase enzyme deficiency.( ?8 Z8 W% I) O( b* Q8 ?9 O7 h* W
The 11-β hydroxylase deficiency may also result in
8 r: [. G3 Q$ v7 n2 J" lexcessive adrenal androgen production, and rarely,: B, H8 d4 o, K) O; _3 s1 {
an adrenal tumor may also cause adrenal androgen
1 R+ K# O; s# [1 J3 G; aexcess.1,3) @6 t" C2 D( b' f
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$ S6 p5 D: r4 d2 {8 r4 ~542 Clinical Pediatrics / Vol. 46, No. 6, July 20074 u' S" F* T$ R  c, H
A unique entity of male-limited gonadotropin-
/ w9 \% f1 A( H; n* p' D. uindependent precocious puberty, which is also known$ ^/ r- I) M0 B' q- R$ E  T
as testotoxicosis, may cause precocious puberty at a1 P9 P" ~2 ~" W  T/ V
very young age. The physical findings in these boys9 \8 B" x1 y3 \: o4 I2 v* Q, R
with this disorder are full pubertal development,
7 Q$ S" M, S" vincluding bilateral testicular growth, similar to boys
, t9 Z! B" }& m/ Z# vwith CPP. The gonadotropin levels in this disorder
: G1 ]3 c: c1 O$ G% ~6 `are suppressed to prepubertal levels and do not show" p* P. b6 r+ R/ m9 O" e  Z3 X" P
pubertal response of gonadotropin after gonadotropin-- K( {) j: _: k: U" W' {2 L1 D
releasing hormone stimulation. This is a sex-linked
" {3 i; y- Z: I; E& U! ~" mautosomal dominant disorder that affects only
! ?5 v+ t1 n; o9 Umales; therefore, other male members of the family
2 Z4 u) S3 B; b. F+ lmay have similar precocious puberty.3: k! D  G1 V9 Z# s. r5 ]3 G& o
In our patient, physical examination was incon-
% q6 f: ^/ r  m1 Msistent with true precocious puberty since his testi-" {  d/ m, D; e( @- a7 `
cles were prepubertal in size. However, testotoxicosis$ F1 F% K: P) d$ O3 i
was in the differential diagnosis because his father1 p/ W7 {9 L' h- i: ^- @+ Q
started puberty somewhat early, and occasionally,
! v( `4 F/ u/ N1 Z* x( }testicular enlargement is not that evident in the
9 x2 z$ N: N: \* y; |  _beginning of this process.1 In the absence of a neg-6 k5 @' j( M1 k2 D
ative initial history of androgen exposure, our
% N/ _  r. J  m- @% zbiggest concern was virilizing adrenal hyperplasia,
, ^4 X& l/ P+ c8 \2 Y) p2 Teither 21-hydroxylase deficiency or 11-β hydroxylase
/ S( L/ e) p3 m. z; P6 Udeficiency. Those diagnoses were excluded by find-# Z6 I9 }! ^* e6 G/ b0 s
ing the normal level of adrenal steroids.4 E9 `6 P3 |8 }- L
The diagnosis of exogenous androgens was strongly
4 H$ \# i; S: K" X/ ususpected in a follow-up visit after 4 months because
; B$ f9 Y1 T" E9 C0 \: lthe physical examination revealed the complete disap-
. M$ h. q- K, g5 p4 a. j+ H2 w1 dpearance of pubic hair, normal growth velocity, and
' x8 r$ `- j$ jdecreased erections. The father admitted using a testos-9 T7 D4 ]% r: K& g8 J
terone gel, which he concealed at first visit. He was
$ C/ h( X. n( Z  G' cusing it rather frequently, twice a day. The Physicians’
; B4 b) C4 V2 N# w1 s: p& }& ^Desk Reference, or package insert of this product, gel or3 h2 p) y+ \6 `* _
cream, cautions about dermal testosterone transfer to
7 P1 T1 @$ C( ?unprotected females through direct skin exposure.  y5 V- y' A+ H2 R7 E1 S
Serum testosterone level was found to be 2 times the! U2 @8 s) J8 N4 M3 l( Q
baseline value in those females who were exposed to5 E% B& h8 z( D1 N7 A+ P2 h- u$ K" p
even 15 minutes of direct skin contact with their male
; m4 `% ~/ v3 [6 _# M- |1 F0 S; K6 spartners.6 However, when a shirt covered the applica-
( B7 t( E% o# l* V0 Ntion site, this testosterone transfer was prevented.; M8 n- j7 C- B! Y7 l( s
Our patient’s testosterone level was 60 ng/mL,
5 A% v4 ^0 ?: n9 c9 C1 t) Lwhich was clearly high. Some studies suggest that
; D, r$ V6 |  Jdermal conversion of testosterone to dihydrotestos-, J) s. g* b8 F
terone, which is a more potent metabolite, is more
$ |- V* w0 C2 ]# J1 L' Ractive in young children exposed to testosterone, M; ~% k2 V7 P: f7 m& J
exogenously7; however, we did not measure a dihy-
/ _. |9 c) o- h% |1 _( Ydrotestosterone level in our patient. In addition to0 s& O& }6 A/ U) i
virilization, exposure to exogenous testosterone in, G) d$ b: s  s0 f
children results in an increase in growth velocity and
& K0 t. Y6 a* B4 V$ f/ U1 n# _advanced bone age, as seen in our patient.
+ E+ Q: y4 `: i# uThe long-term effect of androgen exposure during
: ~' z9 p% W9 F' i3 q3 ?' rearly childhood on pubertal development and final
) p* H7 C" A  ]) B- Zadult height are not fully known and always remain! t( @+ W+ F' C/ N: g* w
a concern. Children treated with short-term testos-8 v" I0 h3 J: [6 t9 m1 i
terone injection or topical androgen may exhibit some
. W& H9 T3 C% f* x% `$ xacceleration of the skeletal maturation; however, after
" y' B' P) |5 S% Acessation of treatment, the rate of bone maturation
+ A8 q  Z. {  P( P3 b: s  x6 Jdecelerates and gradually returns to normal.8,9
/ G& s* P; X! k. nThere are conflicting reports and controversy
$ P5 M; @6 h1 nover the effect of early androgen exposure on adult
* `% w; r2 e" |- H! u$ wpenile length.10,11 Some reports suggest subnormal. Y0 \/ E' D- v$ v% ]
adult penile length, apparently because of downreg-
$ G' J( x4 K& b& E% [ulation of androgen receptor number.10,12 However,
, p( z9 w  k& }4 `7 ZSutherland et al13 did not find a correlation between+ J# V/ u% _( a8 p, N1 y. }- V
childhood testosterone exposure and reduced adult' H1 x: Z  g$ \5 B7 ~7 m) H( ^
penile length in clinical studies.. b- t  @; @7 [  h2 @) z  r
Nonetheless, we do not believe our patient is
$ I) y6 X9 x  C+ U, Y" p, hgoing to experience any of the untoward effects from
" C) k% M$ p2 T& xtestosterone exposure as mentioned earlier because
; T1 Q: H8 `" a0 Xthe exposure was not for a prolonged period of time.
2 m/ f5 ~# Y$ D. k8 LAlthough the bone age was advanced at the time of
4 X0 b% K  }/ odiagnosis, the child had a normal growth velocity at
2 x& V2 E% t1 n$ ^. ?& G. zthe follow-up visit. It is hoped that his final adult! j& V5 N- \. ?7 d
height will not be affected.
, b& ^  `* e" I" f2 LAlthough rarely reported, the widespread avail-
& ?3 n( c1 c* \" W! I* Kability of androgen products in our society may1 X- Y$ i3 B/ f. L' M6 B
indeed cause more virilization in male or female6 x9 w: f$ V0 x9 k8 Y8 C$ D
children than one would realize. Exposure to andro-) ?0 m! U$ T7 N
gen products must be considered and specific ques-
# _- ?0 x8 g. c# }2 ^tioning about the use of a testosterone product or0 V. B8 _. s( ?) v9 x/ e$ [
gel should be asked of the family members during
* U! H# f/ r' T# Xthe evaluation of any children who present with vir-
+ ~; a) t5 G" W* H8 `* \8 Filization or peripheral precocious puberty. The diag-+ |( [! I* {$ ^9 r7 e
nosis can be established by just a few tests and by$ {# M+ T3 B* F8 I" g, D
appropriate history. The inability to obtain such a
0 N+ Q2 k, _! Thistory, or failure to ask the specific questions, may, ?" @1 m; l2 g/ s2 u- w" G
result in extensive, unnecessary, and expensive" {  A- F: S6 x+ M7 w, T! R
investigation. The primary care physician should be) h, f1 w# d! `- W9 C9 _& |* a
aware of this fact, because most of these children- D; [% U) N% ]
may initially present in their practice. The Physicians’4 d- S4 u% v8 H% {; H9 ]! A
Desk Reference and package insert should also put a  K% t! \$ h9 R! x. H
warning about the virilizing effect on a male or/ {$ [) h$ j+ Z  ^- y) Q
female child who might come in contact with some-
7 T2 r- `9 R+ N% A) aone using any of these products.0 w& j" b3 E4 d3 I7 e  {
References2 X. G7 u# a# o" T
1. Styne DM. The testes: disorder of sexual differentiation, J4 {* }. A% o6 o
and puberty in the male. In: Sperling MA, ed. Pediatric
( ^" [# n, [0 S8 ?1 `. _Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
* m2 P4 I1 I6 U0 G$ ^+ s3 ]  C3 t' h2002: 565-628.9 Z) J; ]! e- ^8 }
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
7 u3 K& J( m; U4 Wpuberty in children with tumours of the suprasellar pineal
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女厕偷拍辅导班主任尿尿老师的逼很嫩还有一点
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4个什么样的?
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1 Z1 l+ Z* l( g: }$ k  k精妙絕倫的精品,感謝啊!期待你更多更好的創作哦!
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么好吧v进化过程就回国参加发uft成就和;哦i回来就好v科技股份兄弟人的 路由公开vu个v库每年b
發表於 2025-4-8 11:10:25 | 顯示全部樓層
精妙絕倫的精品,感謝啊!期待你更多更好的創作哦!
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