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Sexual Precocity in a 16-Month-Old
4 R4 D8 ?9 a5 s3 _) x- l, y$ T7 e) @Boy Induced by Indirect Topical  [6 K  l( l7 t* a
Exposure to Testosterone" f' `$ C9 B; S) K+ Q0 z
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
& w/ Z( b% H! Z* U  Kand Kenneth R. Rettig, MD1
0 Q# W/ B9 j4 V9 y- f; {6 GClinical Pediatrics
( b' ?0 r+ D& F! ^- _Volume 46 Number 6
/ {1 D4 l- `9 l1 mJuly 2007 540-543  m! i3 q' G2 ^; d* u4 }5 f
© 2007 Sage Publications/ _+ x1 _. S' ~! A; T2 L
10.1177/0009922806296651
) c, r" P; a6 ?# m. @4 I2 {& z5 N5 `http://clp.sagepub.com
; E+ x) c9 F8 v# ^8 P) T+ v0 ohosted at
' @9 F& ]& [  e* Y/ C( _0 n0 ohttp://online.sagepub.com
' M5 l) ^4 r$ r9 QPrecocious puberty in boys, central or peripheral,
4 m- D9 U, z! uis a significant concern for physicians. Central
+ I( h: G. J8 t; Bprecocious puberty (CPP), which is mediated& \5 \* D- i5 F4 G' p1 L
through the hypothalamic pituitary gonadal axis, has3 O, K8 q' \- h& p: ~
a higher incidence of organic central nervous system
- F4 e( g6 I& Y2 i1 e" P  Ilesions in boys.1,2 Virilization in boys, as manifested
1 Q) x5 \- ]  b; K6 Qby enlargement of the penis, development of pubic
' a6 `" ]& ^5 b5 H2 ^7 Qhair, and facial acne without enlargement of testi-; l  G! [7 b" h+ o# w" N
cles, suggests peripheral or pseudopuberty.1-3 We  L% N9 m# w9 }$ }; G0 k) r
report a 16-month-old boy who presented with the9 J* R- o. X) n
enlargement of the phallus and pubic hair develop-
: k! I0 ^0 j# A# a% @/ p; v  zment without testicular enlargement, which was due$ z7 i& z! C- @
to the unintentional exposure to androgen gel used by
" q! s1 x$ f) }) b! k0 Othe father. The family initially concealed this infor-
3 u7 C4 }; R& ?) R, P$ J  Cmation, resulting in an extensive work-up for this
# r. p) `# V  I8 d2 Jchild. Given the widespread and easy availability of
+ v& ~1 P, \/ {5 Ktestosterone gel and cream, we believe this is proba-/ i; G+ N; l2 L# v2 v- o
bly more common than the rare case report in the; i9 v! C7 w# Z, `9 l* O2 E& b
literature.4  I8 A* \2 g8 \* {8 h
Patient Report
5 Q: Q" E9 _9 \6 y, kA 16-month-old white child was referred to the
* [7 K6 j' h3 g3 l; dendocrine clinic by his pediatrician with the concern- A' {! K/ ?' S% w
of early sexual development. His mother noticed' J* e- M2 i; f2 P. _( o( p/ A
light colored pubic hair development when he was
" g1 o' w+ ~! x2 eFrom the 1Division of Pediatric Endocrinology, 2University of
/ }6 x3 t0 c$ }$ x1 o6 NSouth Alabama Medical Center, Mobile, Alabama.8 B$ e$ |6 N5 }4 L  d
Address correspondence to: Samar K. Bhowmick, MD, FACE,
- J5 a9 Q: B5 |' `Professor of Pediatrics, University of South Alabama, College of
* r: O9 g. P, \% t! A! YMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
; e4 p1 K$ y( r9 W: L5 Z* `) Te-mail: [email protected]./ A0 z1 P+ u1 r
about 6 to 7 months old, which progressively became$ O9 w. \' c) H  d) W5 Z
darker. She was also concerned about the enlarge-# ]; I* D  {8 C0 h8 s
ment of his penis and frequent erections. The child
* D, B3 j+ B7 A5 Y+ Zwas the product of a full-term normal delivery, with
  N' Z+ U7 v! N6 `a birth weight of 7 lb 14 oz, and birth length of
6 l# o3 }1 F& T8 W' t4 l20 inches. He was breast-fed throughout the first year
6 f' q1 D' A& N+ f2 ^4 hof life and was still receiving breast milk along with
! e% _: }* x9 Ysolid food. He had no hospitalizations or surgery,
- q9 I" d* e, M1 vand his psychosocial and psychomotor development8 X( B% r- w/ m, R3 h
was age appropriate.% t0 U+ `7 {/ a6 R$ z. G# L/ x
The family history was remarkable for the father,
* N0 T) ]$ l4 @! lwho was diagnosed with hypothyroidism at age 16,8 `5 [; w1 s, O$ `) ]- X
which was treated with thyroxine. The father’s
. y. V( E# l4 q8 j! Jheight was 6 feet, and he went through a somewhat& ]) `! `) R/ L( `# z2 a/ k
early puberty and had stopped growing by age 14.. X! {$ Y# X5 `/ G# {0 t2 k
The father denied taking any other medication. The% s; @. `: y! I' A/ d- ~$ I: r
child’s mother was in good health. Her menarche
# }9 m9 j1 u" D4 f8 A( P, v3 X7 qwas at 11 years of age, and her height was at 5 feet
) U% [( M; a* P6 ?5 inches. There was no other family history of pre-
+ ^. B6 z0 C5 k) }% Gcocious sexual development in the first-degree rela-  Z3 ^- y+ P" Q4 }( ?, ]+ ~
tives. There were no siblings.2 X$ i3 A4 J; j' x: e1 \( F/ E$ B
Physical Examination
; _7 r! ]& Z1 OThe physical examination revealed a very active,
& c. d' n7 A7 D0 u. yplayful, and healthy boy. The vital signs documented
7 {- Y7 T- V7 V9 @: ta blood pressure of 85/50 mm Hg, his length was
! e" Q. I. a6 a( b* v) x  ]90 cm (>97th percentile), and his weight was 14.4 kg9 r: _& h; q! t! t( V
(also >97th percentile). The observed yearly growth" ^) t5 }# t1 w: U3 W7 m% ^+ }6 ^
velocity was 30 cm (12 inches). The examination of7 ~6 N! n7 X4 I, N  T; }$ ~
the neck revealed no thyroid enlargement.( c. V+ K% ]' a/ Q9 `
The genitourinary examination was remarkable for
; N1 H$ R( N" menlargement of the penis, with a stretched length of: H: }3 S( X, p- p: I, z7 h0 w
8 cm and a width of 2 cm. The glans penis was very well/ M! A5 f; u, m: o- L+ ?# R3 `4 e
developed. The pubic hair was Tanner II, mostly around; T" C- T* Q  A. S0 E
5404 \6 k) Z& K" A2 ^4 o3 C
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from) h! ?. Z+ P8 X( u& u2 U
the base of the phallus and was dark and curled. The0 G6 ?4 m7 x9 G
testicular volume was prepubertal at 2 mL each.
( j* ~+ _, y3 k7 t; I* Z4 R7 SThe skin was moist and smooth and somewhat
* E& w5 z0 M( p; u! M. m% Woily. No axillary hair was noted. There were no
0 X3 e( X/ F6 |) Q1 q7 U; Gabnormal skin pigmentations or café-au-lait spots.
" o1 {/ C: e+ {/ pNeurologic evaluation showed deep tendon reflex 2+
+ c& d1 ]5 V) G- dbilateral and symmetrical. There was no suggestion
$ e3 E7 \. i) Gof papilledema.
% i* I* D1 i7 s. I$ \Laboratory Evaluation, P2 |# g! A, K( t2 B7 W' L3 b
The bone age was consistent with 28 months by
7 X0 Y7 n: \) }; _( i( d& D  pusing the standard of Greulich and Pyle at a chrono-5 ?3 m5 ]2 w  a8 G; ^
logic age of 16 months (advanced).5 Chromosomal) b5 m$ q9 ]5 |! X- z" G7 C& }
karyotype was 46XY. The thyroid function test
9 s8 f- {! L/ M4 r9 A. q( qshowed a free T4 of 1.69 ng/dL, and thyroid stimu-
; g, W' F" M, v7 qlating hormone level was 1.3 µIU/mL (both normal).
9 T0 N: q; e; S: J2 qThe concentrations of serum electrolytes, blood
7 s' t+ F) \% ]1 k6 Y6 p! ^" f( Furea nitrogen, creatinine, and calcium all were7 x# V" R% b) S- _
within normal range for his age. The concentration
6 r8 x4 }; T" n" oof serum 17-hydroxyprogesterone was 16 ng/dL2 o* A* R# r2 J$ \4 Y
(normal, 3 to 90 ng/dL), androstenedione was 201 G3 T/ ]) S/ q7 F4 y" b# d: \
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-. c8 Q0 N& V( n
terone was 38 ng/dL (normal, 50 to 760 ng/dL),
% M# {$ n6 V- p5 ?0 Q6 {desoxycorticosterone was 4.3 ng/dL (normal, 7 to# P) U+ p5 m4 p
49ng/dL), 11-desoxycortisol (specific compound S)
% Y2 n$ \% L9 |. N+ F# b) y) owas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
( ]7 K  `! I4 qtisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total9 L3 ?6 j7 M9 k, x1 H. x0 q; L1 C
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
' A( u/ F$ t* S  ]+ w) j1 o# U) G( ]and β-human chorionic gonadotropin was less than
  r1 H; {6 ]- E$ O$ }, i  _2 A3 s5 mIU/mL (normal <5 mIU/mL). Serum follicular
) h0 G9 Q# t# N8 l1 o6 \+ n$ O1 Cstimulating hormone and leuteinizing hormone9 z$ o1 \6 c# J
concentrations were less than 0.05 mIU/mL
) ]  u6 D% Y9 H/ s5 A4 g; g(prepubertal).4 ~, |2 |: c" w
The parents were notified about the laboratory) |% a7 _( b) v' V: \2 t
results and were informed that all of the tests were9 l: k) n. w/ S8 \5 |- e
normal except the testosterone level was high. The2 K" l" F( k- {( q5 ?
follow-up visit was arranged within a few weeks to
- X# @0 ~. r& f5 @6 d6 Cobtain testicular and abdominal sonograms; how-
6 W. }: P6 W6 `* g6 `* Cever, the family did not return for 4 months.
' i- {4 Q0 O* i' Z) w8 I% sPhysical examination at this time revealed that the& Z: Y3 P* e9 a3 r$ ~
child had grown 2.5 cm in 4 months and had gained
" x' M0 C# b  ?- u( [9 z$ C2 kg of weight. Physical examination remained$ [$ o# F" s) G4 F: a; Z! L
unchanged. Surprisingly, the pubic hair almost com-! ~% X. Y9 q1 Q6 ~
pletely disappeared except for a few vellous hairs at
* p- J# b/ X7 f- a0 I8 F4 p3 P! bthe base of the phallus. Testicular volume was still 2
- c6 _. n/ R6 B* V4 v9 H' LmL, and the size of the penis remained unchanged.1 h( D/ F4 z8 f* V' C
The mother also said that the boy was no longer hav-
1 I% M' |# f" b% M( r. k, h7 ving frequent erections.
% C3 h; i" u% H  x# IBoth parents were again questioned about use of& S8 m6 I! o7 ]5 a/ n
any ointment/creams that they may have applied to$ `  n) F# M. ^- Z1 n5 L9 E3 S
the child’s skin. This time the father admitted the/ I0 n1 I) i; o$ A, m0 v
Topical Testosterone Exposure / Bhowmick et al 541, v# m8 W4 ?; R9 L$ Z" f8 k
use of testosterone gel twice daily that he was apply-
; W9 \+ Y0 p2 |" Ging over his own shoulders, chest, and back area for
7 Y# I; I9 [7 ca year. The father also revealed he was embarrassed
( ~4 z* Y, d* L0 i4 r% @! }to disclose that he was using a testosterone gel pre-
& B- Y7 S7 K4 M+ |scribed by his family physician for decreased libido# B8 X' g, h% J( h: t
secondary to depression.+ z8 m! P/ Z: l" g
The child slept in the same bed with parents.
- k! D( s* h. C  G3 |! a' SThe father would hug the baby and hold him on his
- K3 Y/ V- v3 k  I* v5 i& ^chest for a considerable period of time, causing sig-
* ~; o4 O, J6 w3 c) v7 _nificant bare skin contact between baby and father.; W: ^  `% H$ A5 b2 r
The father also admitted that after the phone call,5 x6 C  D7 v8 c
when he learned the testosterone level in the baby
& t1 m. o+ Q# n( z! zwas high, he then read the product information
1 N5 H. O9 Z9 _packet and concluded that it was most likely the rea-
; G# d9 I" N& h7 G" j" {' x# p& Tson for the child’s virilization. At that time, they
' l% v$ o" @1 q7 O4 o3 Sdecided to put the baby in a separate bed, and the
9 {6 m* v8 n  x, a$ ufather was not hugging him with bare skin and had+ D* D9 x/ a/ v. I( H
been using protective clothing. A repeat testosterone, W, e3 F% _+ f/ e/ i
test was ordered, but the family did not go to the' I5 P+ H' Z" t  f  E$ R
laboratory to obtain the test.6 V2 g; R. Z# L! A4 d! o* F8 U
Discussion
. k( [$ j; V5 a# }! |Precocious puberty in boys is defined as secondary% S& m# L: u$ D" n2 ?. p1 S5 Z
sexual development before 9 years of age.1,4
5 }; l6 C8 ^0 lPrecocious puberty is termed as central (true) when
. s- N2 l, P% U5 Q9 ^it is caused by the premature activation of hypo-- c/ ], h9 v$ E
thalamic pituitary gonadal axis. CPP is more com-
5 d- J7 u6 T# O& t1 n% }* Y/ w7 bmon in girls than in boys.1,3 Most boys with CPP" l8 ^; @! T+ Z
may have a central nervous system lesion that is
4 r2 r- B3 d# ^# J' s4 m& P1 \responsible for the early activation of the hypothal-0 k& g# O; o' |. u4 ]0 r" ?
amic pituitary gonadal axis.1-3 Thus, greater empha-# C3 z$ a! b) j% e# N0 f' ?3 M
sis has been given to neuroradiologic imaging in0 T! o+ r" [5 s4 L
boys with precocious puberty. In addition to viril-
% J6 T2 J$ T, V3 Mization, the clinical hallmark of CPP is the symmet-5 h  M$ c1 Y- Z0 |# Z4 a6 C8 `+ u
rical testicular growth secondary to stimulation by
8 J( u! A+ e1 b1 X: C, D/ b$ ygonadotropins.1,38 H0 G/ F+ [- a, Z
Gonadotropin-independent peripheral preco-0 h8 E8 m& N- Q1 ?' q# k
cious puberty in boys also results from inappropriate
. T* ~" L; U  H. A! C- }- _androgenic stimulation from either endogenous or
$ i" \5 i" w$ c, uexogenous sources, nonpituitary gonadotropin stim-
2 S0 Y# G4 N9 uulation, and rare activating mutations.3 Virilizing9 Z' B# N7 @0 r; f0 \$ W
congenital adrenal hyperplasia producing excessive
2 ?2 y) i/ y! wadrenal androgens is a common cause of precocious$ C! d! e/ F! W9 f2 e6 F
puberty in boys.3,4
: h% v$ X" u& P9 l' j; V/ k3 sThe most common form of congenital adrenal" |/ e4 Q; Z& M- T' [, l' _
hyperplasia is the 21-hydroxylase enzyme deficiency.& p" l, \9 R% v' _8 Q
The 11-β hydroxylase deficiency may also result in2 j; \, \0 U/ R' Z' \4 n; {
excessive adrenal androgen production, and rarely,
5 Y7 ]0 Z+ E( F) Z" v' u$ s) jan adrenal tumor may also cause adrenal androgen9 v8 x1 I# H. D5 o' t' m
excess.1,39 s- B( i% i, Y/ u, G
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
9 V6 y+ Y/ U* ]% y2 y7 p542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
; a6 b, Y+ d& E7 @- LA unique entity of male-limited gonadotropin-
0 D. B7 n, S2 ~$ s1 V$ ]5 Lindependent precocious puberty, which is also known: y# F8 ^+ z: o! f' o
as testotoxicosis, may cause precocious puberty at a+ ]2 \. x! H+ K1 ?
very young age. The physical findings in these boys9 I% B) j' [( s- ?0 i. e, Q! |, l
with this disorder are full pubertal development,
1 c% v0 [) S/ o# Q1 g# l/ q- U' V* [including bilateral testicular growth, similar to boys
- @; F- v" H) j: b, S7 ?with CPP. The gonadotropin levels in this disorder
5 }4 K* L# T# hare suppressed to prepubertal levels and do not show
) c; H- Q+ M1 ~* L6 Ypubertal response of gonadotropin after gonadotropin-
4 b; D- J* ~% }releasing hormone stimulation. This is a sex-linked
+ ?7 f3 n' X5 Y' Aautosomal dominant disorder that affects only/ I% ]* H6 ]/ p. ?- I& x4 B: W
males; therefore, other male members of the family1 T! k  V- O& j) u" c7 A2 @% t' p) Z
may have similar precocious puberty.3
$ T. ^& `0 \" m# BIn our patient, physical examination was incon-
6 x% R* M: O" H5 u# p0 z. F& T/ Vsistent with true precocious puberty since his testi-: [% I+ F0 w0 E: b9 I" @
cles were prepubertal in size. However, testotoxicosis
# [: ^0 r5 L  o7 F- L* `7 jwas in the differential diagnosis because his father9 G$ B2 L" M9 \& {9 c% w9 `9 F' m
started puberty somewhat early, and occasionally,1 S* ?7 T! c: P7 C' _
testicular enlargement is not that evident in the' h  v* s3 m% h4 m) o7 Q( @
beginning of this process.1 In the absence of a neg-
+ w. {# n$ t, c- Native initial history of androgen exposure, our
( I/ W9 |5 d/ d% l7 v$ a) pbiggest concern was virilizing adrenal hyperplasia,$ Q2 T' S1 J* m# X( F8 [* e6 Q
either 21-hydroxylase deficiency or 11-β hydroxylase
! ?% J+ x/ Z) r; xdeficiency. Those diagnoses were excluded by find-) {7 C% n2 `0 o
ing the normal level of adrenal steroids.
" P. {! T. A7 @1 J  J* XThe diagnosis of exogenous androgens was strongly$ N0 o8 K5 i0 m0 ?  B5 @
suspected in a follow-up visit after 4 months because
. z; W, f' U% e5 R- jthe physical examination revealed the complete disap-5 a4 o6 R. d8 z' P1 n7 |$ C/ [
pearance of pubic hair, normal growth velocity, and4 z' K9 M& P8 H* e# j6 d* i% @
decreased erections. The father admitted using a testos-+ M# `* Y$ Q' D
terone gel, which he concealed at first visit. He was
" [$ g  u2 n1 Xusing it rather frequently, twice a day. The Physicians’$ V% H: f; p" x, Q
Desk Reference, or package insert of this product, gel or
! L3 }1 A8 G9 X# Kcream, cautions about dermal testosterone transfer to
3 n0 S0 u: g9 u1 a& punprotected females through direct skin exposure.) D$ [6 P4 m! P# |: V3 }
Serum testosterone level was found to be 2 times the# N- `* ]" H. \$ M: {. y9 K* L2 d
baseline value in those females who were exposed to
0 B" v7 D6 A8 ?2 aeven 15 minutes of direct skin contact with their male! I/ @5 r% G% G8 n$ O' ]% o
partners.6 However, when a shirt covered the applica-
% U- ?# _' k- r  g, g& ltion site, this testosterone transfer was prevented.
/ {1 {1 T* Q. h# G. k: VOur patient’s testosterone level was 60 ng/mL,
& ~- v5 \3 d4 r; n9 i' Qwhich was clearly high. Some studies suggest that
  t% V" d* }, G; L1 c  m3 Wdermal conversion of testosterone to dihydrotestos-! W- Q1 ~. P9 w& H$ Z: t: m5 S& U
terone, which is a more potent metabolite, is more
; ?- C. o# r5 C2 b9 L: Iactive in young children exposed to testosterone
7 ^' s6 L; G6 y2 z6 Yexogenously7; however, we did not measure a dihy-6 O8 x* d5 f& z7 Z1 Z
drotestosterone level in our patient. In addition to3 {+ V6 [! ~$ {$ n; X7 @
virilization, exposure to exogenous testosterone in
  S9 d2 J; a  v! y4 }) cchildren results in an increase in growth velocity and
) F4 m/ R6 d" P' U7 y! Cadvanced bone age, as seen in our patient.
9 [$ K' l9 a0 t4 tThe long-term effect of androgen exposure during$ n' n& b; W( ^3 Y
early childhood on pubertal development and final
% Z: O( P' b1 Y1 Y; sadult height are not fully known and always remain! x. R$ z0 u( n( t8 h) V+ p
a concern. Children treated with short-term testos-
: O" I: z" _1 l  Q  M. Pterone injection or topical androgen may exhibit some
3 T6 z' S0 E% a7 K2 Q6 t. Qacceleration of the skeletal maturation; however, after5 C3 i/ }+ A7 g5 r8 e4 \6 p
cessation of treatment, the rate of bone maturation+ p$ g. J( t. G( g" _
decelerates and gradually returns to normal.8,9
& x* l2 Z+ x+ ~) W/ X! FThere are conflicting reports and controversy
. M2 s" g& N3 O% I9 W& x) h* N% eover the effect of early androgen exposure on adult) a( j$ G& d# x: E- i: F) u- u
penile length.10,11 Some reports suggest subnormal
, y$ L6 O1 c6 \( _$ y  Y* w0 \adult penile length, apparently because of downreg-! A" L/ [; t( `+ N9 C% e
ulation of androgen receptor number.10,12 However,
& U5 b. w1 U4 J0 E  ]5 D* c6 wSutherland et al13 did not find a correlation between
: i( p% v) `7 F6 k' p! Achildhood testosterone exposure and reduced adult
5 F; d' _' O2 z! rpenile length in clinical studies.! n) O1 Y& V+ X1 H7 V& ]8 A) h% ]
Nonetheless, we do not believe our patient is
+ s3 s% N# I3 M; `/ bgoing to experience any of the untoward effects from
' j) S# w& \7 @: gtestosterone exposure as mentioned earlier because
& b1 |/ I( K8 ~- b+ X2 y8 N: t  Ethe exposure was not for a prolonged period of time.: v! X$ _7 t" d4 }/ ~
Although the bone age was advanced at the time of! _6 y$ k/ z' s% }
diagnosis, the child had a normal growth velocity at
" J. N3 m3 x* l7 B! o0 rthe follow-up visit. It is hoped that his final adult" @7 b2 V. W$ A9 W  ^
height will not be affected.
$ d( K9 E5 i. B" b, t/ FAlthough rarely reported, the widespread avail-( f2 P8 P7 n& z; ]
ability of androgen products in our society may/ W; e: ^  ?3 ]: I% l
indeed cause more virilization in male or female; M8 e+ l' _* s* d
children than one would realize. Exposure to andro-) s; u$ a5 ~1 B3 O. z
gen products must be considered and specific ques-
0 z: b3 S! D- W9 qtioning about the use of a testosterone product or1 B+ {6 c" A( }: c/ x. g
gel should be asked of the family members during  U  l, p! \- L. ~5 a: D( f
the evaluation of any children who present with vir-# Q/ a* h" O2 d1 r* N
ilization or peripheral precocious puberty. The diag-0 x' w) l/ U/ J4 [; G, b
nosis can be established by just a few tests and by0 m1 L1 q# K" M  F' l3 I
appropriate history. The inability to obtain such a; W" `) K" s! D& P: N
history, or failure to ask the specific questions, may& ~( C/ |! [: A  \# c' t
result in extensive, unnecessary, and expensive
6 j4 i8 K. v/ i- @8 D5 a4 Winvestigation. The primary care physician should be0 P- O5 m) L) E& I4 y# y/ l3 y3 O
aware of this fact, because most of these children
( S8 j: X1 B% Y- V3 Y. X9 {may initially present in their practice. The Physicians’$ a& P/ t# D8 J
Desk Reference and package insert should also put a( I! d5 u4 B' @. z
warning about the virilizing effect on a male or
$ z3 N% j( D1 _+ f  vfemale child who might come in contact with some-
; r2 g2 l" d1 |5 E+ Q, y) tone using any of these products.6 W7 q9 j' H4 x. |; k
References
) N3 M! o) h. q+ M) y0 A6 i1. Styne DM. The testes: disorder of sexual differentiation4 R1 e2 x& ~3 r, N- _- Q/ Z( k
and puberty in the male. In: Sperling MA, ed. Pediatric! a8 ~  K7 i9 T
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
' S& k/ q+ m6 ~: G- [* W. {2002: 565-628.
, _/ e" y2 u% S6 p) ^( U7 d: w9 n! Q' v2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious6 J8 r+ K! v& ?2 g. _2 e$ \
puberty in children with tumours of the suprasellar pineal
發表於 2025-1-4 03:27:02 | 顯示全部樓層
Sexual Precocity in a 16-Month-Old
! P  l4 I6 {/ v, w! E  U7 ]# a, @Boy Induced by Indirect Topical  T) Y1 S; g6 a# Q
Exposure to Testosterone! Z; {; G: n7 v
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,25 o8 w1 U. j" D) ~* ^
and Kenneth R. Rettig, MD1
7 n$ I" h' v$ I; ~Clinical Pediatrics
* r* I% W; Q5 ?Volume 46 Number 6# y$ u4 I) p* }! Q
July 2007 540-543% j* l% c2 p% x
© 2007 Sage Publications' t5 Q* o  c* T4 ^/ A
10.1177/0009922806296651
( ?# \4 S* n# J2 Hhttp://clp.sagepub.com' z0 ]& F: Z  Z' _7 s2 L
hosted at5 H& c! ]- S; ]$ j1 X
http://online.sagepub.com
; X, y' k- u9 VPrecocious puberty in boys, central or peripheral,, c, P1 t6 ?& E
is a significant concern for physicians. Central
7 A1 C% h- m  C% D3 Eprecocious puberty (CPP), which is mediated
  ^. N- E: ]3 N( `. Fthrough the hypothalamic pituitary gonadal axis, has6 O3 I+ ~) r; x+ M* ^' O
a higher incidence of organic central nervous system
0 u8 r! T$ C& e4 v" xlesions in boys.1,2 Virilization in boys, as manifested
. D" A! k* x9 Uby enlargement of the penis, development of pubic
( k$ ^7 }! p3 S" w4 vhair, and facial acne without enlargement of testi-
$ b. F3 z! l% R- q7 o+ Acles, suggests peripheral or pseudopuberty.1-3 We
  H) E- ^2 R: S% mreport a 16-month-old boy who presented with the/ ^( d3 r/ x- S% \* I/ P5 w/ o
enlargement of the phallus and pubic hair develop-/ x1 b0 z9 e( }0 C# I" U$ [1 ~
ment without testicular enlargement, which was due8 l) Y5 W/ T7 S* i) z, _7 k% O4 q
to the unintentional exposure to androgen gel used by
3 Q# l  T0 x1 A* w% ]- Ythe father. The family initially concealed this infor-; \! l+ c  i$ x! b: K" q
mation, resulting in an extensive work-up for this
1 u9 |4 M+ F2 c7 Q: |- D9 o3 P5 vchild. Given the widespread and easy availability of
/ C, e, _/ d( u2 R$ Ctestosterone gel and cream, we believe this is proba-
% g  J# p  F% n1 Lbly more common than the rare case report in the! k7 y; j8 b- C" G) Y
literature.46 O& Z8 U8 Q3 K5 x0 @
Patient Report
* G' n  g9 X8 K) B- d3 }A 16-month-old white child was referred to the5 u6 }5 `# m4 I) L- C
endocrine clinic by his pediatrician with the concern6 ?+ E2 @& O4 }; p) ^
of early sexual development. His mother noticed. S& i* O. [! x; |
light colored pubic hair development when he was
! i: D9 V4 Y' _) D% D8 {: ~From the 1Division of Pediatric Endocrinology, 2University of' [  W. h- [, ^0 E: R4 k
South Alabama Medical Center, Mobile, Alabama.
4 ^' X, h3 h5 J9 A' R: D7 ^Address correspondence to: Samar K. Bhowmick, MD, FACE,
+ R2 Z+ N7 d! N5 k8 L* \Professor of Pediatrics, University of South Alabama, College of
' u" i% T5 t  XMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
5 B1 `" v9 c+ x. b; ae-mail: [email protected].
6 T" v" k" m: Y6 t/ C' ]7 @" Cabout 6 to 7 months old, which progressively became
' m1 g7 w' f, }darker. She was also concerned about the enlarge-
9 ]0 C; V3 W5 H  ^: Gment of his penis and frequent erections. The child: ?+ o+ n( @3 M  ?2 V
was the product of a full-term normal delivery, with
2 m( u! I0 Q( e: N5 T& m& wa birth weight of 7 lb 14 oz, and birth length of
/ T! ~& {2 e+ m: h; N" p20 inches. He was breast-fed throughout the first year
: u$ Q; @  {: h! t5 w0 b- Gof life and was still receiving breast milk along with1 |! @  A/ ^5 ^, Q% T2 ?+ `
solid food. He had no hospitalizations or surgery,
; `4 z6 l: k: e! fand his psychosocial and psychomotor development
( V( S# ]5 Y+ G% j( |) lwas age appropriate., i& L; g# ?& }( B5 Q) g& }8 j
The family history was remarkable for the father,$ q7 Y& M# M; a; c/ J7 Z
who was diagnosed with hypothyroidism at age 16,% ]+ R. R  Q9 r) M# @" M; C
which was treated with thyroxine. The father’s
$ L9 H) b2 @! Q! U" ]% k. I& kheight was 6 feet, and he went through a somewhat
# |) J9 l4 F7 \' P* gearly puberty and had stopped growing by age 14.
& n! Y* ^! \9 o) l- N" o. C& y& ~The father denied taking any other medication. The
" h$ \- w1 q' g/ m) s" c: vchild’s mother was in good health. Her menarche9 s* ]! B+ L1 I3 {6 F
was at 11 years of age, and her height was at 5 feet
! T- \5 @: T" ~( D5 inches. There was no other family history of pre-# \4 \0 E5 J; F" c) w* P3 _$ S
cocious sexual development in the first-degree rela-
& t" _0 _# H' c' Y$ o8 {tives. There were no siblings.
/ o1 {8 g' Z0 JPhysical Examination/ K- s- [% W' C* {9 T
The physical examination revealed a very active,
; K' p+ [- S) ~5 O; Nplayful, and healthy boy. The vital signs documented# E- t9 b9 Y. ]4 P6 h) R8 B) z
a blood pressure of 85/50 mm Hg, his length was
1 T4 i! k- ?3 |$ q- w90 cm (>97th percentile), and his weight was 14.4 kg
7 h! w( S& q% k(also >97th percentile). The observed yearly growth1 ^8 t) x, M' y, I5 k( M, O9 Z
velocity was 30 cm (12 inches). The examination of
: U- L! o6 e8 D' Qthe neck revealed no thyroid enlargement./ K% _* W: }$ G- r$ s! x  v
The genitourinary examination was remarkable for& b4 Q0 V1 M" y( l! ?
enlargement of the penis, with a stretched length of1 A0 `5 R% H  L0 \2 b; [( m
8 cm and a width of 2 cm. The glans penis was very well
" f2 ?7 E1 R( A" S( w! h3 {: y) Adeveloped. The pubic hair was Tanner II, mostly around
! l4 Y4 `8 a9 C/ A# A' B5400 ]) O# o) V( y
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from( [* o0 h# V9 }
the base of the phallus and was dark and curled. The" L: ?4 Z4 j8 b% ]- P0 U
testicular volume was prepubertal at 2 mL each.
8 ~2 a& z7 Y) nThe skin was moist and smooth and somewhat$ D; v  z% m0 u' l
oily. No axillary hair was noted. There were no
$ s: W& e! D' Z" A  }% cabnormal skin pigmentations or café-au-lait spots.
( l: a. v( M+ c6 V1 X# [! b, XNeurologic evaluation showed deep tendon reflex 2+
9 T1 y. M1 a) a7 j! \bilateral and symmetrical. There was no suggestion
' I6 W% D+ t# e3 Wof papilledema.
0 Y/ Y) m0 {8 f( B; PLaboratory Evaluation+ h. t5 N% x0 m  }
The bone age was consistent with 28 months by
2 H, z3 m" i) m# A6 H/ Busing the standard of Greulich and Pyle at a chrono-
- n# N# ^% M: m0 p0 u. `logic age of 16 months (advanced).5 Chromosomal
) z/ t% W+ i; F) H' u# Nkaryotype was 46XY. The thyroid function test
$ w6 W6 g4 ~5 q* u7 {+ I/ |showed a free T4 of 1.69 ng/dL, and thyroid stimu-3 E' v- `5 ?' _( h% X
lating hormone level was 1.3 µIU/mL (both normal).
2 N7 P8 ?7 J! H$ XThe concentrations of serum electrolytes, blood
: d! w$ Y% |8 durea nitrogen, creatinine, and calcium all were
; y" G2 D4 H5 a3 f& Y. b0 S7 Ewithin normal range for his age. The concentration- W6 t: B  L0 n
of serum 17-hydroxyprogesterone was 16 ng/dL8 M) j: C  p2 c7 U
(normal, 3 to 90 ng/dL), androstenedione was 206 s1 x) D) m: `" g9 \; K# l0 m
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
; z8 L' t; D4 ]& ^+ Qterone was 38 ng/dL (normal, 50 to 760 ng/dL),
5 j. B# G6 r& X- m1 Sdesoxycorticosterone was 4.3 ng/dL (normal, 7 to
( v7 S: s) T5 c2 }: }- h49ng/dL), 11-desoxycortisol (specific compound S)
/ ?! ^, k! L8 s( R; P; lwas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
! T3 w' e3 p1 J: Atisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total1 N* ]- W  U; \+ _% M
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),( b9 s' k& h: F0 U% O
and β-human chorionic gonadotropin was less than
# D7 H/ w! k2 J) n' F/ n5 G$ v5 Y5 mIU/mL (normal <5 mIU/mL). Serum follicular- f! O- e1 {9 m( ~7 ?- m/ C! H2 p
stimulating hormone and leuteinizing hormone
, `% Q6 m5 R5 U& A  Oconcentrations were less than 0.05 mIU/mL5 o# g% W2 `/ `3 E& W8 A
(prepubertal).8 `& J8 x3 p# i$ U3 R( x
The parents were notified about the laboratory
% j* H& X. V/ }0 x7 Y' K& H& p# Gresults and were informed that all of the tests were
: f- z# O) N1 g3 X; ~+ u# Xnormal except the testosterone level was high. The
' r3 M0 I9 i1 C6 Jfollow-up visit was arranged within a few weeks to" T5 n2 r  G% ?/ e
obtain testicular and abdominal sonograms; how-
+ a; O2 |0 T) B5 Z, fever, the family did not return for 4 months." \( |9 W) v5 c5 p
Physical examination at this time revealed that the1 l) w' F: R! x: _/ t4 w
child had grown 2.5 cm in 4 months and had gained% p- T* f' E4 ~3 }
2 kg of weight. Physical examination remained
& w% ~$ w7 O$ g1 C6 y6 a7 Kunchanged. Surprisingly, the pubic hair almost com-
  }6 |1 g! k. I  r1 ^2 Jpletely disappeared except for a few vellous hairs at
, p: R& q: N: v$ Xthe base of the phallus. Testicular volume was still 2
- v) o/ g0 g3 q  Q# E6 u, r5 amL, and the size of the penis remained unchanged.
( b6 i8 ]: G5 l  a- V4 ?8 ]The mother also said that the boy was no longer hav-# i' k  W5 o" i
ing frequent erections.- H, T* Q' b1 E% A2 @+ Z0 \
Both parents were again questioned about use of
: ~. n  f. y. `* x# I# X/ uany ointment/creams that they may have applied to5 c; i( e( C0 u) f9 n
the child’s skin. This time the father admitted the
4 q( ]: Q4 @9 rTopical Testosterone Exposure / Bhowmick et al 541* x1 b: G1 i3 |
use of testosterone gel twice daily that he was apply-) m, f- @9 E! L; N4 D5 C
ing over his own shoulders, chest, and back area for
; C1 O  G) J, j3 W" D' M; q  Ba year. The father also revealed he was embarrassed+ h( P" M) u+ i' g, G" |
to disclose that he was using a testosterone gel pre-, T+ `3 P2 p% N4 e' E: u6 \( \
scribed by his family physician for decreased libido
7 S2 ~4 A$ Y* c- Fsecondary to depression.
+ ?( N' m% `3 GThe child slept in the same bed with parents.! j+ P: V+ G0 j1 H; H+ M" `
The father would hug the baby and hold him on his" C% K$ K5 P! d& G& B" Q9 v
chest for a considerable period of time, causing sig-
/ i. c$ W4 }1 U7 vnificant bare skin contact between baby and father.
& p" z: h; A8 {, ~. bThe father also admitted that after the phone call,2 O8 A1 L7 k" j
when he learned the testosterone level in the baby
# x' [1 J, N* L( c# X; \was high, he then read the product information
5 S4 u: J+ p0 H5 gpacket and concluded that it was most likely the rea-
3 h% l( X( l  B; y: \4 ]: g) z1 Wson for the child’s virilization. At that time, they
% {2 G' e, d' S/ |; jdecided to put the baby in a separate bed, and the4 e2 G% H4 }$ ~- j7 O; m
father was not hugging him with bare skin and had
* ~& d& C- h: Ybeen using protective clothing. A repeat testosterone
* \4 k# ]2 d4 H. Rtest was ordered, but the family did not go to the
& B- x' R) [1 olaboratory to obtain the test.
4 w5 v- b, K6 oDiscussion" c5 h/ A$ `7 p. L5 s& }
Precocious puberty in boys is defined as secondary$ E/ ?  C; J) V: N# }" R! D) y
sexual development before 9 years of age.1,4: W" g! X: p+ w0 z
Precocious puberty is termed as central (true) when' u8 F1 O, s5 M* X
it is caused by the premature activation of hypo-
$ V5 C$ w1 n5 z- H  g+ _/ B* Ithalamic pituitary gonadal axis. CPP is more com-
1 m/ U+ I1 C! u" R% _7 b7 Y; \mon in girls than in boys.1,3 Most boys with CPP
, H! G6 a* M# v$ Zmay have a central nervous system lesion that is& O& d0 k4 u- P' ]
responsible for the early activation of the hypothal-
% R1 N' j+ W: M" b/ ^) M& Xamic pituitary gonadal axis.1-3 Thus, greater empha-
) ]  j1 K1 O' M" z9 vsis has been given to neuroradiologic imaging in6 y, _$ I% Q* j% h* v$ o
boys with precocious puberty. In addition to viril-
0 Y2 Q2 F5 Q2 E1 _5 M  aization, the clinical hallmark of CPP is the symmet-7 _3 Z/ K9 `' v5 ^  _7 {
rical testicular growth secondary to stimulation by
' X  Q" i) L" w- s  d8 |6 ]) Wgonadotropins.1,3
1 B+ f7 R* ~4 \! N6 z5 ]' v) U' HGonadotropin-independent peripheral preco-
% S6 b1 S& m# R" ycious puberty in boys also results from inappropriate
) D, @$ A! v8 l% B% O$ K# bandrogenic stimulation from either endogenous or
$ f0 i/ E) |$ [) ~6 ^exogenous sources, nonpituitary gonadotropin stim-/ f. i4 o5 s$ t% q1 r$ i
ulation, and rare activating mutations.3 Virilizing1 ~/ Z; d) B! ~. V! }7 o. U
congenital adrenal hyperplasia producing excessive
0 c- ~$ x/ E0 A8 K( b$ g( Q: qadrenal androgens is a common cause of precocious
+ w3 R+ _$ c4 n/ e* Epuberty in boys.3,4& n+ f; @- I$ c/ G
The most common form of congenital adrenal
+ P3 B$ f2 A8 @2 o9 m! Yhyperplasia is the 21-hydroxylase enzyme deficiency.
# `+ U- ^2 K  r# N# b8 ]# T" HThe 11-β hydroxylase deficiency may also result in
* {& F& r. f: u6 [+ Bexcessive adrenal androgen production, and rarely,
7 ~! b7 Q. y% k% ]' k; oan adrenal tumor may also cause adrenal androgen
  l( }5 t  O, fexcess.1,3- A7 c( k/ {" A) D5 W
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from: |' c. d2 \3 w. k5 d; i  w
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007* ]; Q5 ~" g8 A  a7 c9 N, \
A unique entity of male-limited gonadotropin-  Q/ Y1 c, ?: f
independent precocious puberty, which is also known
/ n0 }+ U8 D% Q5 o5 Kas testotoxicosis, may cause precocious puberty at a( ~9 F7 k. A" r
very young age. The physical findings in these boys- `, D# ]% G, {& C
with this disorder are full pubertal development,6 I/ X; d  D) B% C" j* G
including bilateral testicular growth, similar to boys
5 K" o7 |+ L& Q& p: n4 X; Jwith CPP. The gonadotropin levels in this disorder! k. q! B: p% n5 e) E. m
are suppressed to prepubertal levels and do not show
' U' J. F* v8 cpubertal response of gonadotropin after gonadotropin-
* a- j% w* d: |# d5 Z( W7 ]& T" d- lreleasing hormone stimulation. This is a sex-linked
. _3 C) c+ [: S* C9 t8 Mautosomal dominant disorder that affects only' U. h! a3 y! z* Z6 W$ m
males; therefore, other male members of the family$ L$ Q- n- U  ?6 a
may have similar precocious puberty.3
+ |4 ?- v* I1 y8 f7 A. E* hIn our patient, physical examination was incon-
0 \" p( P# n8 Y0 d) P* O" ^sistent with true precocious puberty since his testi-; ?& e; @' [5 z) |, G
cles were prepubertal in size. However, testotoxicosis+ i" p0 E8 H* M8 r& R  [6 y
was in the differential diagnosis because his father3 U; b3 p5 V  H
started puberty somewhat early, and occasionally,
7 A) i5 I7 H, T. y3 }, etesticular enlargement is not that evident in the% m* U$ x: P: k$ S( h! O" x6 Y
beginning of this process.1 In the absence of a neg-+ x7 l% \' d4 b8 y
ative initial history of androgen exposure, our
4 |" f3 O! h( abiggest concern was virilizing adrenal hyperplasia,
" W+ E! P5 B* ]& W4 c% D0 [either 21-hydroxylase deficiency or 11-β hydroxylase2 X! W5 T1 y, r% ]( p
deficiency. Those diagnoses were excluded by find-1 n# \# G: ]; l) ~3 ?( k' E6 M
ing the normal level of adrenal steroids.! K( [7 x; k/ I% o
The diagnosis of exogenous androgens was strongly, b; \6 \- D: T9 y
suspected in a follow-up visit after 4 months because
2 O6 [# r7 i5 ^& Kthe physical examination revealed the complete disap-* u7 w& Z& g3 e4 k
pearance of pubic hair, normal growth velocity, and
% W; j' S* ?6 Z2 Y, M+ f, w; Udecreased erections. The father admitted using a testos-
8 [7 F  Y6 L) Z  f+ T8 Fterone gel, which he concealed at first visit. He was
) H3 X2 p) y$ c$ r( M# Jusing it rather frequently, twice a day. The Physicians’
( Q$ h  x+ {6 Z& n! n7 a% ~6 lDesk Reference, or package insert of this product, gel or
) M$ g/ P( `. u( g2 `cream, cautions about dermal testosterone transfer to: }9 v1 L. A+ o) i
unprotected females through direct skin exposure.
/ V9 G. ?' P$ m' ]& @Serum testosterone level was found to be 2 times the
6 c; ^. s+ y: obaseline value in those females who were exposed to: o, t1 I- d5 B9 s
even 15 minutes of direct skin contact with their male
# c, [  A9 \) x* D* @: Wpartners.6 However, when a shirt covered the applica-' M4 M, B6 ~$ ?; e
tion site, this testosterone transfer was prevented.2 s% G9 h8 ]7 |
Our patient’s testosterone level was 60 ng/mL,( E3 t' z. _% x6 R2 R
which was clearly high. Some studies suggest that# {+ v3 i7 I2 U. \) T' F
dermal conversion of testosterone to dihydrotestos-9 L) C# P/ B2 F: b
terone, which is a more potent metabolite, is more
3 N4 N) Y3 }4 F" aactive in young children exposed to testosterone
- Y3 f" `0 m3 j( K0 vexogenously7; however, we did not measure a dihy-# S& i7 Y- ?7 k' X* B2 f! ^
drotestosterone level in our patient. In addition to
& ?6 b& P8 O' I& e+ J" W8 ?7 {4 _virilization, exposure to exogenous testosterone in3 l" f4 L. ?. Q) v- E4 u' r
children results in an increase in growth velocity and. x3 e- X% o' O: {; n
advanced bone age, as seen in our patient.& |9 V3 V- F6 [( C! g: E9 v! f0 t- L
The long-term effect of androgen exposure during
/ d' n5 I! R% c" Yearly childhood on pubertal development and final
) X2 u% p, B& S3 h: h* Vadult height are not fully known and always remain9 w; e( {/ w% c7 R; M
a concern. Children treated with short-term testos-7 Y# H$ D5 b: e' S# `2 f& }
terone injection or topical androgen may exhibit some1 v8 `9 t" D3 B, L* n1 P! R
acceleration of the skeletal maturation; however, after2 Q% F- z/ N6 l; p) s
cessation of treatment, the rate of bone maturation/ f9 a7 s( c. u' s0 t* U. m' G' n
decelerates and gradually returns to normal.8,95 f1 ^- Y. D' P1 n6 W
There are conflicting reports and controversy: l' a; L, V$ B" P* q9 N
over the effect of early androgen exposure on adult6 t# P( _4 R0 P5 F# \
penile length.10,11 Some reports suggest subnormal
2 q1 t: n. H0 Yadult penile length, apparently because of downreg-1 h# @! T1 O* \* e8 b- z! C
ulation of androgen receptor number.10,12 However,
9 p3 G/ M- l6 G) d- S( F6 m" T' BSutherland et al13 did not find a correlation between6 }" w3 x% }' y% H2 ]
childhood testosterone exposure and reduced adult8 Z( R) ^# p' m! y; h' b. N
penile length in clinical studies.8 ?' s' ^$ _6 `" D2 O
Nonetheless, we do not believe our patient is" f! L: @8 k& ?4 I, f
going to experience any of the untoward effects from" r, v% Z4 [! D4 v2 s$ F
testosterone exposure as mentioned earlier because4 P0 Q: D' C, d+ a" V: t  U
the exposure was not for a prolonged period of time.
9 }* b- L" {0 b% }) X1 e/ cAlthough the bone age was advanced at the time of2 Y- A$ y9 X4 ~, U" j2 E
diagnosis, the child had a normal growth velocity at
. i) N6 p) k6 x; E+ V  gthe follow-up visit. It is hoped that his final adult( Z  ^- A. ~- Q0 k: j) @0 y
height will not be affected., k. j5 R5 R+ s% Q
Although rarely reported, the widespread avail-
7 ?+ g6 r( x: P  E* G# y2 ~! |+ bability of androgen products in our society may
5 r: u% X! E4 ^indeed cause more virilization in male or female
1 z( q. r, C: s, G  R5 b% Bchildren than one would realize. Exposure to andro-
6 L8 l! o5 r! V3 ^$ Ugen products must be considered and specific ques-
4 s  E$ w$ U3 ]! d/ Y3 Ltioning about the use of a testosterone product or
( G+ }1 e* Y( C3 mgel should be asked of the family members during
- n  E5 n6 d9 y6 e7 g3 ~6 g) Wthe evaluation of any children who present with vir-
' H+ o/ l0 g4 c1 G6 Silization or peripheral precocious puberty. The diag-
7 L$ H7 m* l, S; `nosis can be established by just a few tests and by
' b2 P: a" T+ Q5 _- f# L3 u. D2 Cappropriate history. The inability to obtain such a
$ t3 I- Q* r7 q, D* W; f: Mhistory, or failure to ask the specific questions, may
& {9 @; b! n7 A# Z7 o; k7 presult in extensive, unnecessary, and expensive
  A( i- `" E$ I- uinvestigation. The primary care physician should be
+ x, z8 s6 O! T2 O; @: l: S2 i; S% Taware of this fact, because most of these children4 `( d8 T3 B! G( ^' p+ v' z
may initially present in their practice. The Physicians’$ q- g7 h9 B6 x7 x/ Z6 n
Desk Reference and package insert should also put a
1 P" `- z* H( b9 K# I1 H2 F' Ewarning about the virilizing effect on a male or$ A" v+ ]0 w5 \. ]
female child who might come in contact with some-
% q; d$ V: D: l, J1 Hone using any of these products.! z) q: X2 e8 o' O! M1 e3 P# G2 M5 j
References/ a6 N( `7 x. d( _
1. Styne DM. The testes: disorder of sexual differentiation
" @1 [$ e5 X* D7 c, P# s% a; I# Zand puberty in the male. In: Sperling MA, ed. Pediatric
4 J8 u  J% H4 B  \7 m" n' D4 HEndocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
) S/ p2 f/ [0 W/ T( r. m2002: 565-628.
7 Y8 s5 V% n0 P% O" d9 R, O2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious; z' W2 w# h7 ?; G- \0 U/ D& O0 J
puberty 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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; G, H) ~* K8 J  E" ]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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