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鄉下的妹子太便宜,一次四個都要了[12P]

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Sexual Precocity in a 16-Month-Old% K, n" W+ n9 t9 a$ `
Boy Induced by Indirect Topical5 \5 l. o, u" T' H* v# u. \7 o
Exposure to Testosterone. B/ |" g6 Y% g7 ~. D
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2+ R/ T7 S$ G, d) n7 Z; _
and Kenneth R. Rettig, MD1
0 {. Y2 P8 S& v4 B! o- fClinical Pediatrics
$ @4 W2 v/ W5 w8 a/ W6 t4 fVolume 46 Number 60 S$ P3 a  r* G- M! N9 @
July 2007 540-543
2 p- \! ]% w2 z- U. r7 e! S© 2007 Sage Publications" f4 y9 _3 F# p& E$ u, B% x
10.1177/0009922806296651
& H9 B0 R" H1 g" _, X6 n2 z$ Ehttp://clp.sagepub.com
' _  K- ]2 I; O2 U7 n, ]) m5 P, [4 @hosted at
: H$ D6 g0 Z; R) P/ O! ^3 X; Zhttp://online.sagepub.com1 U8 ^  U. P9 \% t
Precocious puberty in boys, central or peripheral,0 {' o! i/ t& h. B4 L
is a significant concern for physicians. Central/ P0 f% ~8 E  @$ W) ], _
precocious puberty (CPP), which is mediated6 U7 A* A& n+ i- P; o2 `5 _
through the hypothalamic pituitary gonadal axis, has
) j, V& n8 Y# i& g( J" f9 t. v9 Na higher incidence of organic central nervous system
3 X8 F# j4 R& \lesions in boys.1,2 Virilization in boys, as manifested
) q' O4 N0 }+ l' qby enlargement of the penis, development of pubic
6 ~4 _9 t: O" t+ K. m# E# ?hair, and facial acne without enlargement of testi-
& Q! s- W& E+ S. E$ X! Hcles, suggests peripheral or pseudopuberty.1-3 We# [1 e5 M5 X$ f6 a2 I
report a 16-month-old boy who presented with the% ]5 F- S0 Y, {' V2 m. W
enlargement of the phallus and pubic hair develop-
. a. j1 X5 e7 ~ment without testicular enlargement, which was due
( a+ k  i7 R0 I# A; R2 ito the unintentional exposure to androgen gel used by
# ~* F9 I; S$ xthe father. The family initially concealed this infor-. h9 V9 ~" [2 @. L. O) n5 x! a
mation, resulting in an extensive work-up for this& U0 L' w: s/ Y4 _  g! N" b
child. Given the widespread and easy availability of- R' i; @! a" P& O5 x( U9 M
testosterone gel and cream, we believe this is proba-
1 J- ?' C/ a" a8 Tbly more common than the rare case report in the$ B3 }6 a3 T. ~3 f, V
literature.42 f/ y) W3 D& N
Patient Report( g2 f( L/ l7 G5 X2 Y
A 16-month-old white child was referred to the" U& g# t% s5 J, R
endocrine clinic by his pediatrician with the concern
  x+ D2 V, i. a9 x# Q' W3 x3 nof early sexual development. His mother noticed& \" l; E2 J- J3 X6 `
light colored pubic hair development when he was+ F# y) \# E; K2 I. f  g( s
From the 1Division of Pediatric Endocrinology, 2University of1 j# C' v: Z; d' o
South Alabama Medical Center, Mobile, Alabama.  i$ B( Y) N) q" P! S' c
Address correspondence to: Samar K. Bhowmick, MD, FACE,- T! {4 h! X" @1 j' I0 N
Professor of Pediatrics, University of South Alabama, College of! M3 ^5 ?/ R. I, ~! x! u
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
4 q, Q4 M. ^) T; F) Qe-mail: [email protected].0 c' N( _4 k$ ^3 o: V
about 6 to 7 months old, which progressively became5 |' M" g# j) _
darker. She was also concerned about the enlarge-4 D0 k4 R( r" X2 Q
ment of his penis and frequent erections. The child
2 m0 L9 h( r6 m* l% W2 cwas the product of a full-term normal delivery, with; ~" P- B9 Q4 X. q" [8 v
a birth weight of 7 lb 14 oz, and birth length of1 T7 Q2 o3 a7 T7 T2 R3 v" L
20 inches. He was breast-fed throughout the first year
5 D$ [- N* w( _1 \( D& _of life and was still receiving breast milk along with- ]  n! j9 {0 H9 X
solid food. He had no hospitalizations or surgery,
$ S: q# E' _) {5 t# @and his psychosocial and psychomotor development
0 g- O/ A7 i, D" m5 u+ bwas age appropriate.* @. ~4 H/ p, r
The family history was remarkable for the father,* X$ t  a1 X( c4 ^" x
who was diagnosed with hypothyroidism at age 16,. d. D) F% w; @
which was treated with thyroxine. The father’s
; N' q2 F) i- |height was 6 feet, and he went through a somewhat
( S6 f; {' G, Z- j  W- i2 Tearly puberty and had stopped growing by age 14.
8 a; p+ E$ q: q: P3 K3 LThe father denied taking any other medication. The
* l7 U: n8 @  P: a) b* x- t  bchild’s mother was in good health. Her menarche( N( N0 G+ `+ I" l# m2 S: f! ?
was at 11 years of age, and her height was at 5 feet4 ?( {4 M0 v  k7 v
5 inches. There was no other family history of pre-9 t% T- `% L$ U4 X4 C
cocious sexual development in the first-degree rela-
1 \" X+ t! A  X- ?2 p5 d0 m% S; m& O" Dtives. There were no siblings.
. L8 D' r& O2 M! j% b& z' PPhysical Examination, z; m" Z6 S7 k9 Q2 M* S' ^$ C
The physical examination revealed a very active,6 L: N+ z1 g" L0 ^& A9 C" L" l3 `5 _0 S5 U
playful, and healthy boy. The vital signs documented
# z3 Y# Q0 C) La blood pressure of 85/50 mm Hg, his length was: Y3 b; K5 P6 d, d" q) Y6 M, j
90 cm (>97th percentile), and his weight was 14.4 kg
, J& b/ d. a1 C9 o2 Z* Y(also >97th percentile). The observed yearly growth3 r/ W8 u- M7 X7 U7 {$ Z
velocity was 30 cm (12 inches). The examination of
; r4 W) {/ |4 V6 Nthe neck revealed no thyroid enlargement.
% H4 L; d5 q" t: Y0 ZThe genitourinary examination was remarkable for. X1 d. M+ N: g; E: X
enlargement of the penis, with a stretched length of' d2 q  j! w$ a! h, w) J& D7 a  |8 U
8 cm and a width of 2 cm. The glans penis was very well
3 C7 g5 D1 H. |( ideveloped. The pubic hair was Tanner II, mostly around; [. M. P& J3 `
5408 O7 I, W1 ]3 O' x# d& \# F; j
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
% o' I. ?( [4 ?" @5 t( t) `# pthe base of the phallus and was dark and curled. The
" z2 G* m0 I: [9 L& s5 }; jtesticular volume was prepubertal at 2 mL each.; p2 |8 G; I2 S1 e1 w. G" b
The skin was moist and smooth and somewhat$ C6 o( d& G' P1 x
oily. No axillary hair was noted. There were no
* `8 E6 w2 Z7 K8 c' ?1 Eabnormal skin pigmentations or café-au-lait spots.
" g( ]! f9 r: g% M8 GNeurologic evaluation showed deep tendon reflex 2+  [6 o, C) ^/ R2 k  d4 S% h! q
bilateral and symmetrical. There was no suggestion
( f+ O1 ?/ Z6 a2 f( Dof papilledema.. J  w& e9 l* B" _' o* i6 v. W
Laboratory Evaluation
* v1 _+ g' V' ]) f  f$ ^The bone age was consistent with 28 months by
2 S! ?$ w9 V6 H0 |; u7 uusing the standard of Greulich and Pyle at a chrono-
( _2 }$ R6 K2 n4 L) n5 X' K% Glogic age of 16 months (advanced).5 Chromosomal
5 n5 ^4 h* @. x8 d( ?, Lkaryotype was 46XY. The thyroid function test
3 W- U2 p2 ?% Q0 Gshowed a free T4 of 1.69 ng/dL, and thyroid stimu-: i+ \: Z) l( Y  t% I; i+ ^# V+ U
lating hormone level was 1.3 µIU/mL (both normal).
2 C$ j0 Y0 r' m( _- |% IThe concentrations of serum electrolytes, blood) @  H$ f* `( w  \
urea nitrogen, creatinine, and calcium all were$ ~4 c4 g, a( [' n2 o, i' w
within normal range for his age. The concentration
4 A# D( P; m" P% J3 I' pof serum 17-hydroxyprogesterone was 16 ng/dL, f& N9 J! l2 n1 Z% P
(normal, 3 to 90 ng/dL), androstenedione was 20
# b- S$ |4 X+ Sng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
3 Y% `# z& A9 ?' o- C/ |/ T) V( K. ~terone was 38 ng/dL (normal, 50 to 760 ng/dL),
; D5 }. i# _2 D! q$ _desoxycorticosterone was 4.3 ng/dL (normal, 7 to) l7 R7 q- D5 |5 a
49ng/dL), 11-desoxycortisol (specific compound S)
6 s* J% K0 m' c% V2 Bwas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-3 u5 y$ v) l2 R4 `$ }
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
" f0 a7 q! k; X) J  d# Otestosterone was 60 ng/dL (normal <3 to 10 ng/dL),' q: r7 v0 N+ K2 J# Q* s( L
and β-human chorionic gonadotropin was less than. F( i: G5 R* E' o" {- d. O, Y- M9 g' K
5 mIU/mL (normal <5 mIU/mL). Serum follicular
# |% H, Q* F6 b/ N1 tstimulating hormone and leuteinizing hormone
# B( v' H3 \5 Jconcentrations were less than 0.05 mIU/mL
2 P7 w, m$ S) g1 q(prepubertal).! k. c) I6 a3 r7 {3 M
The parents were notified about the laboratory$ s) f' U' I! @# u( j
results and were informed that all of the tests were
- ~) o1 X, o' T) B6 xnormal except the testosterone level was high. The+ [* u  U# |+ {
follow-up visit was arranged within a few weeks to( t8 S' [- c3 t, M4 s' q* c
obtain testicular and abdominal sonograms; how-
8 ?4 k) M8 B( Q# q1 p! p- N/ ~ever, the family did not return for 4 months.
8 B) U$ d  \5 n& U. w( kPhysical examination at this time revealed that the1 d# ?- b: `; ~+ n6 U; Y0 ~/ c, I
child had grown 2.5 cm in 4 months and had gained/ g1 d' z1 y. b  _  M' T
2 kg of weight. Physical examination remained6 ^; n" U& i: l) l
unchanged. Surprisingly, the pubic hair almost com-1 Z9 B3 L: K2 v( h% g
pletely disappeared except for a few vellous hairs at
. u9 A0 `5 O1 L8 Kthe base of the phallus. Testicular volume was still 2
/ Z1 e( k9 O5 y* d  ]mL, and the size of the penis remained unchanged.* I; Z" F' t( B! C7 B- f
The mother also said that the boy was no longer hav-
9 r& M2 w. A  {! ]0 f- Ting frequent erections.
* f: a! Z$ m- ?- hBoth parents were again questioned about use of; x) M/ u0 @; @# T- K9 [9 q) b
any ointment/creams that they may have applied to; t0 y9 T' V" D, [4 Y
the child’s skin. This time the father admitted the
0 D: D! C9 I; Z. FTopical Testosterone Exposure / Bhowmick et al 541
0 R0 @8 C1 S: }8 Guse of testosterone gel twice daily that he was apply-
. g) ~% N& A; A" O% ^ing over his own shoulders, chest, and back area for  ]; a1 I# H1 h8 c2 {
a year. The father also revealed he was embarrassed8 }; B! i8 D) V8 Y2 I! }! |  O9 ^) f" g
to disclose that he was using a testosterone gel pre-
1 |* W" Z0 M& [6 |scribed by his family physician for decreased libido
! a! ^9 P7 f$ b( K# T% gsecondary to depression.
' w6 t- j" L$ ^: m2 d& P- i2 _The child slept in the same bed with parents.; p# h6 j% Q" h
The father would hug the baby and hold him on his6 O  A# ?4 ~7 ?6 p5 d
chest for a considerable period of time, causing sig-
) G, F6 d- D8 c/ i/ L4 z! Snificant bare skin contact between baby and father.
/ W4 Q) `4 T% R  jThe father also admitted that after the phone call,
, Y7 F4 x+ t% ?$ G" e4 uwhen he learned the testosterone level in the baby, Z" z0 q+ \# ~% M
was high, he then read the product information7 C+ E& D: P& T6 O# A& \4 o. N
packet and concluded that it was most likely the rea-
4 K8 K' U4 k# e. U6 g  Z8 sson for the child’s virilization. At that time, they4 X1 H, ~$ \! h* ?' m  O
decided to put the baby in a separate bed, and the8 [- k8 E! `- c, N
father was not hugging him with bare skin and had* t1 I" u# w/ O, C) D7 r
been using protective clothing. A repeat testosterone
3 h- I! ^. e& Q! jtest was ordered, but the family did not go to the
$ M& j  j& o2 `7 ulaboratory to obtain the test.2 B# y: k, M4 t& y0 A! D
Discussion
" d! d; U% I4 d. ~' \. V- x- j3 @Precocious puberty in boys is defined as secondary
3 \9 X5 z4 J: u* a0 Osexual development before 9 years of age.1,4
$ v: Q& P5 H" X" M$ p* c- bPrecocious puberty is termed as central (true) when
) M  H  _' b* m1 h& G6 S( T! Y7 tit is caused by the premature activation of hypo-# l# W; _  s# ^5 o. V
thalamic pituitary gonadal axis. CPP is more com-; F! @0 G! L2 p  D" X
mon in girls than in boys.1,3 Most boys with CPP; W- ~0 y! P* Q8 M: }
may have a central nervous system lesion that is
! c0 Q* s8 ]9 J$ P! k# V# Gresponsible for the early activation of the hypothal-' o1 H' U0 V7 T5 I$ Q
amic pituitary gonadal axis.1-3 Thus, greater empha-' o0 [: U# `& w" e! \& h
sis has been given to neuroradiologic imaging in! N4 z! q' G" v5 G, c+ L# o2 U" y
boys with precocious puberty. In addition to viril-
' I: Z2 q' J4 `" P0 z+ x* wization, the clinical hallmark of CPP is the symmet-  Q  j+ V8 i5 |# [& y
rical testicular growth secondary to stimulation by4 l3 `  z0 T2 f9 @" |" _) @; u
gonadotropins.1,3
: n, E, E3 w" Q5 l+ F( BGonadotropin-independent peripheral preco-5 U# F* C4 [$ t+ Z' W
cious puberty in boys also results from inappropriate5 t3 k8 n. w+ Z
androgenic stimulation from either endogenous or
) P) l& m5 C" K! vexogenous sources, nonpituitary gonadotropin stim-# T# ?# Y* p# R' ]
ulation, and rare activating mutations.3 Virilizing+ S3 l1 E1 n7 j' {' M* v6 G
congenital adrenal hyperplasia producing excessive3 i8 n7 Q0 r8 u5 }
adrenal androgens is a common cause of precocious: ~; @$ O1 y9 M8 g
puberty in boys.3,4* |/ |5 s% v7 C
The most common form of congenital adrenal
, A1 O; c+ m# ~% h; t: ^hyperplasia is the 21-hydroxylase enzyme deficiency.
" \: w2 S. j) L, b& S7 l9 zThe 11-β hydroxylase deficiency may also result in; Y2 u) K1 H4 d0 X; L& T7 t
excessive adrenal androgen production, and rarely,
. M+ c8 y3 S7 a4 ?2 k, ean adrenal tumor may also cause adrenal androgen& ]9 x) k! Y1 u' N6 H" J
excess.1,3+ H* v* m8 ~; G& X
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
, v  S4 U& j  v4 u542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
6 C6 [" _, ~1 y  RA unique entity of male-limited gonadotropin-
7 R4 d( V( r6 k# Zindependent precocious puberty, which is also known
5 F+ ^2 Q* q* R  o& d8 G" D/ O2 |as testotoxicosis, may cause precocious puberty at a
" d. N  [$ L1 D1 Dvery young age. The physical findings in these boys7 a# g( w% m; X" d  o
with this disorder are full pubertal development,
; Z0 R$ `1 T4 F* ]including bilateral testicular growth, similar to boys
) O4 V0 C% X- Jwith CPP. The gonadotropin levels in this disorder! I2 G1 Y$ }8 ^' E5 R# n. }) S
are suppressed to prepubertal levels and do not show- C$ |5 x, e; Z0 v4 U
pubertal response of gonadotropin after gonadotropin-
. n2 A2 z' x' areleasing hormone stimulation. This is a sex-linked  {  G8 [  j/ P' @" j6 w- q! B
autosomal dominant disorder that affects only
: p2 T! E4 p' C8 O% e, _3 Rmales; therefore, other male members of the family
  H+ z8 G  N* V7 qmay have similar precocious puberty.3
1 Q1 h/ ^# Q6 q' G) a. tIn our patient, physical examination was incon-0 Z+ b4 v4 y% }: C* N
sistent with true precocious puberty since his testi-
  J$ |4 L5 W6 h: e5 Kcles were prepubertal in size. However, testotoxicosis0 l0 z- k: C! T$ f$ b3 ?
was in the differential diagnosis because his father
$ }% o+ L3 f' sstarted puberty somewhat early, and occasionally,, k3 V- v  h$ I3 N9 {
testicular enlargement is not that evident in the
, a* J! R* Q* u" sbeginning of this process.1 In the absence of a neg-
9 A: O6 _$ d/ C( l3 H, Yative initial history of androgen exposure, our" x* |$ T2 M' j8 }
biggest concern was virilizing adrenal hyperplasia,
  S- |1 |, ^9 w( d2 Xeither 21-hydroxylase deficiency or 11-β hydroxylase* O* R- T9 c9 u" f: H+ I1 z1 i  z' o
deficiency. Those diagnoses were excluded by find-
9 [3 R. R% c4 y+ K- ^! e, qing the normal level of adrenal steroids.
8 `9 q( S) E  j/ y. w* ^% t% e; FThe diagnosis of exogenous androgens was strongly- H& U! \3 z1 X- l1 w
suspected in a follow-up visit after 4 months because# Y8 B+ j7 n* u( ]% F! D
the physical examination revealed the complete disap-
! F% d" G( T3 {/ _pearance of pubic hair, normal growth velocity, and& U; {* x( n' b' [4 o7 p
decreased erections. The father admitted using a testos-0 Q% o& e3 v; e" P& U
terone gel, which he concealed at first visit. He was
6 p) U# _# D' {( ~0 E4 husing it rather frequently, twice a day. The Physicians’/ w. o7 r) e0 ~5 g
Desk Reference, or package insert of this product, gel or' f- q1 g5 D( v/ |
cream, cautions about dermal testosterone transfer to# h4 a5 p6 F- Z: N
unprotected females through direct skin exposure.0 ^) [% Z( m  p( b
Serum testosterone level was found to be 2 times the
, }; U- _: T& y! L5 W) ~3 Rbaseline value in those females who were exposed to
* F7 }8 z$ |! D! C9 m& d, H3 seven 15 minutes of direct skin contact with their male
4 S. n$ \! K3 Y& a4 I0 ypartners.6 However, when a shirt covered the applica-
; ~: K# m- O( c9 C2 ltion site, this testosterone transfer was prevented.
9 F) H, W- ?1 _; d9 jOur patient’s testosterone level was 60 ng/mL,
  ]  ?3 c* \/ Awhich was clearly high. Some studies suggest that0 D2 U+ J- y- k" w4 ?9 H; b
dermal conversion of testosterone to dihydrotestos-% l1 p5 s+ t5 x# t* Y, ~" o$ W  I6 p
terone, which is a more potent metabolite, is more
& V. y! h* L+ P/ R' d) x- i; nactive in young children exposed to testosterone
9 m$ I" `; V8 fexogenously7; however, we did not measure a dihy-$ X, C$ ]% B, y( Q2 {/ s# T3 D
drotestosterone level in our patient. In addition to
4 u! N+ Z& ~% E/ I: U0 [4 uvirilization, exposure to exogenous testosterone in
" U+ o( e' O' u- Y8 k1 Z7 N; `children results in an increase in growth velocity and. u% ]2 h. z. K$ F
advanced bone age, as seen in our patient.
* [1 s5 A5 G4 P$ O8 a8 {6 LThe long-term effect of androgen exposure during; h8 R2 @. ]9 j1 ~# T$ \
early childhood on pubertal development and final
3 }4 c8 R9 C3 ^1 i% Tadult height are not fully known and always remain
4 Q5 [& r0 e/ S$ }a concern. Children treated with short-term testos-9 }# S' |2 H) O" p/ f8 Z
terone injection or topical androgen may exhibit some
+ s0 A, H$ \) V2 C9 N8 qacceleration of the skeletal maturation; however, after
, c$ H$ m2 _0 bcessation of treatment, the rate of bone maturation3 D; }; J7 s, [- z/ I$ l
decelerates and gradually returns to normal.8,9
4 z! X# I/ u3 h  A3 {. LThere are conflicting reports and controversy* J7 }8 J  p$ r1 `- `
over the effect of early androgen exposure on adult' Z: v8 ]0 E) Y1 _
penile length.10,11 Some reports suggest subnormal: a- T* x4 H, z6 B+ N; l
adult penile length, apparently because of downreg-
' D% {& a, @/ ]2 ]8 c) Aulation of androgen receptor number.10,12 However,% }) Z) N9 [; ~5 i. k8 S# [; I
Sutherland et al13 did not find a correlation between
3 k3 `, j* d# Kchildhood testosterone exposure and reduced adult
9 I% n8 O7 h0 X; }penile length in clinical studies.- B6 ~- S( Q7 M. h; G) D
Nonetheless, we do not believe our patient is2 Z+ W1 v# H2 I- i. b
going to experience any of the untoward effects from8 c. W* t* ]- _8 B! v
testosterone exposure as mentioned earlier because
4 n7 B; b6 V, T$ a1 ~the exposure was not for a prolonged period of time.
2 c; z5 R, r. q$ c2 H: b% {0 lAlthough the bone age was advanced at the time of
3 |. L- v  D  v& `1 odiagnosis, the child had a normal growth velocity at
, [/ w, v0 r6 P% [. i9 D$ tthe follow-up visit. It is hoped that his final adult
# ]" [; j. N4 T" p( N( Q$ T# E9 C- lheight will not be affected.
" R! v8 Z8 Z. g' V, yAlthough rarely reported, the widespread avail-' m* [3 k3 F' a1 [7 [9 s
ability of androgen products in our society may1 D! D4 O: H1 }; U1 l  ]
indeed cause more virilization in male or female
/ E& ]( X' }5 Tchildren than one would realize. Exposure to andro-+ z% ]$ `4 m! V
gen products must be considered and specific ques-
" M/ h+ j4 o5 N& Ztioning about the use of a testosterone product or* n# ~! G' W3 r
gel should be asked of the family members during
# C, ~0 w; x3 _' S/ P8 jthe evaluation of any children who present with vir-1 E  U: [: g2 H8 b  n3 Q8 a
ilization or peripheral precocious puberty. The diag-# Z  E# k" _4 b6 ?# N: u
nosis can be established by just a few tests and by
# Z; m8 d9 s8 K3 X& {4 @! gappropriate history. The inability to obtain such a( W" l! n6 r. y5 |7 ?0 h5 Z9 y
history, or failure to ask the specific questions, may
* i, m' E( h1 ?/ R# ?8 C1 j, \result in extensive, unnecessary, and expensive7 {  P- A% P4 E- ^8 h
investigation. The primary care physician should be$ O1 b: n& R0 z* \9 g
aware of this fact, because most of these children  Q( }: U& q. G
may initially present in their practice. The Physicians’( \1 @" \8 m! X5 Z
Desk Reference and package insert should also put a$ N! o# K$ W) s6 r  x: Z& k$ {
warning about the virilizing effect on a male or
4 w7 n; ]6 C$ y1 Wfemale child who might come in contact with some-
0 \0 ~7 o" I4 l2 Done using any of these products.
& L+ r7 X: k1 U+ k6 _3 fReferences
& j% A" S( p& p0 j  Z, L: B1. Styne DM. The testes: disorder of sexual differentiation
. {" O, V8 S( M$ I) Xand puberty in the male. In: Sperling MA, ed. Pediatric$ I/ L7 k. ?: L
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;' n$ i% X/ }! Z( m- X2 l
2002: 565-628.+ `* O0 l* Y$ M2 }: T
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious- g8 y4 r2 w0 L' b6 t0 \
puberty in children with tumours of the suprasellar pineal
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Sexual Precocity in a 16-Month-Old2 e1 R$ C+ W8 a6 I
Boy Induced by Indirect Topical9 C* {: W- z  B% F
Exposure to Testosterone
( M" P. \; a( U+ J! fSamar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
+ f" Z3 O/ ?5 ?9 Uand Kenneth R. Rettig, MD1( V* Z* h: \* Y
Clinical Pediatrics$ P+ L7 O1 `' U
Volume 46 Number 6+ b% u! B7 h* \9 o+ ~# D$ j- ~; @( h
July 2007 540-543
+ e* j# q' n1 g0 K( x+ j# R© 2007 Sage Publications
) Y2 e; S$ u; b) y10.1177/0009922806296651
" ^, G: ?1 ?) c+ m. S1 Q+ `1 Dhttp://clp.sagepub.com
5 g/ k( \9 y7 U, r8 Q+ Lhosted at
2 ?5 W1 V  G; x) _http://online.sagepub.com
6 ^3 \+ g5 c/ E( A# h( `, cPrecocious puberty in boys, central or peripheral,) \% ^- R$ j' N# V( n0 d
is a significant concern for physicians. Central' A4 v7 D& D9 V8 b' x
precocious puberty (CPP), which is mediated0 s3 E: d' ?$ Y, p/ }
through the hypothalamic pituitary gonadal axis, has. G: Q. O2 |2 |3 U! C
a higher incidence of organic central nervous system
/ b8 z( E! m5 \+ c2 L5 D3 g: m5 V! U- Ulesions in boys.1,2 Virilization in boys, as manifested' s( @2 b9 P% `) ~- O8 S' |0 w
by enlargement of the penis, development of pubic2 T4 Q2 A2 y( A+ y- C9 @2 R
hair, and facial acne without enlargement of testi-
5 E3 C. Y  V" j/ {cles, suggests peripheral or pseudopuberty.1-3 We7 f" s8 G" s0 c3 ~: @6 o5 M. v1 E
report a 16-month-old boy who presented with the
0 n  l) o) d, D2 `# p5 Menlargement of the phallus and pubic hair develop-
" d. d! I" R3 F' I5 Lment without testicular enlargement, which was due* `5 C$ u1 _+ q( Y9 H0 o
to the unintentional exposure to androgen gel used by* z( k! e6 D+ v6 \
the father. The family initially concealed this infor-, j; _' p# [3 n) V$ b* P
mation, resulting in an extensive work-up for this! T2 t, U! g( x
child. Given the widespread and easy availability of
; ]- g+ N: N. \) ptestosterone gel and cream, we believe this is proba-# c% o" B# E: [+ U' C
bly more common than the rare case report in the
5 q: N6 [, j) S! H( s* I: Kliterature.4
$ V" b! t4 d+ s9 t- o" L# `Patient Report
  ~) D( b6 E+ H/ _7 eA 16-month-old white child was referred to the/ i, I9 W+ s* i, W1 \% n' I
endocrine clinic by his pediatrician with the concern
9 M" h  r# Z4 q$ j) wof early sexual development. His mother noticed' j0 B+ W( B* h2 }  Z0 L7 c  \  \
light colored pubic hair development when he was
/ ~4 H1 K3 J5 o- @8 m& u9 s' A3 v! bFrom the 1Division of Pediatric Endocrinology, 2University of$ t$ Q+ z0 B9 Y. `, h. X( v
South Alabama Medical Center, Mobile, Alabama.) K% ]( e) r7 F0 E, k: [
Address correspondence to: Samar K. Bhowmick, MD, FACE,
3 A3 A$ I2 }* s$ D( q3 _Professor of Pediatrics, University of South Alabama, College of3 ~6 }6 {+ o0 {6 w( ~" ^3 q, S. H
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;/ p% M5 E3 D1 `' t* [7 |
e-mail: [email protected].! ?/ c8 X8 ?- t5 R. B
about 6 to 7 months old, which progressively became
* L8 _; j2 }$ @3 edarker. She was also concerned about the enlarge-! V& [0 t; `; X+ L* e( S* w
ment of his penis and frequent erections. The child
3 l' U% O3 F% Z( dwas the product of a full-term normal delivery, with
0 H0 e" [. a6 _1 Y3 pa birth weight of 7 lb 14 oz, and birth length of
( f8 e/ y8 a" V4 Y. A  l: }20 inches. He was breast-fed throughout the first year
* A. H/ z5 Z- ~7 }& |" K  U- uof life and was still receiving breast milk along with3 k/ U9 A. X- u& F0 E- M
solid food. He had no hospitalizations or surgery,. p3 X) w6 {, b" B% U
and his psychosocial and psychomotor development
4 r" c! G0 a1 x2 R0 a8 vwas age appropriate.
7 ~/ x# L0 q2 z9 x4 G$ X! p" _The family history was remarkable for the father,
% F/ @3 b+ c% `  |who was diagnosed with hypothyroidism at age 16,! M4 s2 k, p6 F" q) t; B
which was treated with thyroxine. The father’s( i9 P7 \1 H, B2 b8 l
height was 6 feet, and he went through a somewhat0 t5 {! T' |; n1 w
early puberty and had stopped growing by age 14.
+ U, j0 |  X# Y$ b( }' j' l7 rThe father denied taking any other medication. The5 z) R3 L  P$ X: r
child’s mother was in good health. Her menarche
: [2 M1 \7 v5 O# a1 V) twas at 11 years of age, and her height was at 5 feet" E: U" A+ U9 v* i) l' S2 e) m
5 inches. There was no other family history of pre-
! h  P& m' A8 @4 bcocious sexual development in the first-degree rela-
  x; j; `( P  T% Z4 Utives. There were no siblings.
5 w1 L" B4 _. aPhysical Examination
# d2 Q: ^6 C' x. c3 GThe physical examination revealed a very active,
6 q/ G7 @3 P( X) Aplayful, and healthy boy. The vital signs documented
5 ^# Z$ Q8 ]# S1 i# ^7 _/ Da blood pressure of 85/50 mm Hg, his length was  P6 a8 }! x  f3 q7 {: `  m" u1 T: V
90 cm (>97th percentile), and his weight was 14.4 kg
& G( Z. d- B; t/ n+ G9 E' `(also >97th percentile). The observed yearly growth. C0 ~& \4 F  M: H" v
velocity was 30 cm (12 inches). The examination of, |* L" h# t1 x7 I# j7 e1 K1 ?
the neck revealed no thyroid enlargement.
0 c- K8 }( V% O- c) ?7 jThe genitourinary examination was remarkable for
' r! t: v- s+ Tenlargement of the penis, with a stretched length of! d) s; z* x, k4 N8 b. i# a
8 cm and a width of 2 cm. The glans penis was very well1 a1 c. m0 m0 b4 y
developed. The pubic hair was Tanner II, mostly around
7 J( T4 q/ B+ u5408 T* G: b7 L  A' ^8 U, V
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
2 n! a6 L2 n+ `the base of the phallus and was dark and curled. The
2 Z- P) ^- o9 L5 n1 S5 n" o$ ?testicular volume was prepubertal at 2 mL each., a* l9 ?( V! d! Q2 a7 `
The skin was moist and smooth and somewhat' v8 E7 D5 k- {/ H" E# O
oily. No axillary hair was noted. There were no+ v/ h/ }: n( U1 y* t
abnormal skin pigmentations or café-au-lait spots.- H) D, k# V/ x8 C" @7 [' C
Neurologic evaluation showed deep tendon reflex 2+
+ L: U& A. f4 D5 D) _) a* {bilateral and symmetrical. There was no suggestion
2 G3 T) m# [2 |" \# {% s2 Nof papilledema." a- W& [6 e: f6 U& H
Laboratory Evaluation1 @7 D3 `3 i- I% w! s5 L( k# v
The bone age was consistent with 28 months by7 r# V+ G, R5 H
using the standard of Greulich and Pyle at a chrono-
2 ^: a+ z6 W- Jlogic age of 16 months (advanced).5 Chromosomal" N& x, X. D+ k/ H
karyotype was 46XY. The thyroid function test* L2 ]+ n/ ~8 \, I: ]6 J
showed a free T4 of 1.69 ng/dL, and thyroid stimu-
0 c! L: r0 _& E) llating hormone level was 1.3 µIU/mL (both normal).
& f( n" j1 r. ~! f6 X& BThe concentrations of serum electrolytes, blood! @1 V7 ~7 O. ?, V. j* O0 j
urea nitrogen, creatinine, and calcium all were
9 C# d' s0 t1 Y$ V1 Y3 \! }within normal range for his age. The concentration
5 p8 e# f% @5 q( w5 Eof serum 17-hydroxyprogesterone was 16 ng/dL' W. J% ?, f" x/ n
(normal, 3 to 90 ng/dL), androstenedione was 205 Y; e, M! Z/ m& E
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
, X5 Z% v9 m9 e& Mterone was 38 ng/dL (normal, 50 to 760 ng/dL),
8 q3 S" v3 I& {9 T3 k) \! |desoxycorticosterone was 4.3 ng/dL (normal, 7 to1 }4 I4 i/ Q, c" \5 m
49ng/dL), 11-desoxycortisol (specific compound S)2 l; Y2 m7 ?9 {/ Q4 q* i6 z0 k
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-1 J% t; G  [" @+ }
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
1 [+ f& V$ b0 J+ Mtestosterone was 60 ng/dL (normal <3 to 10 ng/dL),; R# I+ n& N) m) w2 ?4 d' y- Q
and β-human chorionic gonadotropin was less than
( q3 G9 N! \, w) m* S% z5 mIU/mL (normal <5 mIU/mL). Serum follicular* T! d3 i2 x3 v! S7 {9 F
stimulating hormone and leuteinizing hormone
$ \/ }$ c& T/ f& dconcentrations were less than 0.05 mIU/mL' f* d3 |, @$ Y/ s  I$ ^# d) k
(prepubertal).  A" `! M4 G* N$ T, M( G
The parents were notified about the laboratory
3 ?$ x( i! p' kresults and were informed that all of the tests were1 |7 ?, c$ W3 A
normal except the testosterone level was high. The1 D6 R6 J2 b+ C$ z7 F
follow-up visit was arranged within a few weeks to2 F0 z2 W$ d3 ]( h  r* b" d7 H" R$ ?
obtain testicular and abdominal sonograms; how-
3 R+ \+ ]2 |: r8 y( ^ever, the family did not return for 4 months.
" f* u/ K# u; S( V" B$ H8 VPhysical examination at this time revealed that the5 X& p3 V  {& ~0 z
child had grown 2.5 cm in 4 months and had gained
) t: Y" A6 y! y2 kg of weight. Physical examination remained
4 p( K* p  N& I( k7 X  F# funchanged. Surprisingly, the pubic hair almost com-! b, I5 @" r* a% k; J. Q
pletely disappeared except for a few vellous hairs at0 K+ s9 y; \6 f9 I9 b9 D) B* n* n
the base of the phallus. Testicular volume was still 2
3 V) q* e! J  P4 D! u0 B- \9 ?mL, and the size of the penis remained unchanged.5 x$ I- P3 r: q/ M2 \9 M0 r
The mother also said that the boy was no longer hav-! S+ g  G, X2 z1 P7 Y
ing frequent erections.( Z4 K# b# ?# Z
Both parents were again questioned about use of" J$ |/ J* Y! u1 L3 L: x
any ointment/creams that they may have applied to; T; u" y. W/ B" t  f% u
the child’s skin. This time the father admitted the* x  @: o, G; ^' F) D
Topical Testosterone Exposure / Bhowmick et al 541, }% [$ L+ L" I! X1 j8 x& G$ _
use of testosterone gel twice daily that he was apply-' I) c* k; X1 b
ing over his own shoulders, chest, and back area for8 x3 ~5 C' F9 m, Y
a year. The father also revealed he was embarrassed5 v+ i: F) K2 w; N: l
to disclose that he was using a testosterone gel pre-
" d# o( y' u0 W: [9 P6 E+ _scribed by his family physician for decreased libido
) g4 E$ T/ @0 H. ^secondary to depression.
4 s' S7 Q2 _8 k% a- E# qThe child slept in the same bed with parents.8 d* U2 ]& I* f; o' c! @
The father would hug the baby and hold him on his$ k  R& C2 s& V$ X
chest for a considerable period of time, causing sig-
2 T- _& A% A5 n3 _nificant bare skin contact between baby and father.4 A; q5 ^0 Q8 m6 Z; g* ~$ z
The father also admitted that after the phone call,
! `0 o2 A6 k5 Rwhen he learned the testosterone level in the baby$ B  I* w; _9 Z* C% u: X3 G7 U/ F- t
was high, he then read the product information
2 n) b2 c* ^, |8 npacket and concluded that it was most likely the rea-
+ m$ Y# \3 o0 [son for the child’s virilization. At that time, they
$ y7 N* m+ ~) l6 V5 Qdecided to put the baby in a separate bed, and the
9 ]2 ]3 e+ c- r* `father was not hugging him with bare skin and had% N" n, F2 H) l: t' D  d
been using protective clothing. A repeat testosterone
3 \! h7 C& G$ e4 @3 p* y) Ztest was ordered, but the family did not go to the
7 ?! @/ V) u6 q8 Qlaboratory to obtain the test.
  L1 i: S! m' D1 UDiscussion4 h3 J0 A- K' I& S" H
Precocious puberty in boys is defined as secondary
$ H. Z: F; M( v8 ?/ Rsexual development before 9 years of age.1,41 y" P' Z( s1 p& C- k
Precocious puberty is termed as central (true) when
' w0 M: P) Z- J" E: I! dit is caused by the premature activation of hypo-3 E$ m3 N' t/ ?
thalamic pituitary gonadal axis. CPP is more com-
" [- v! t8 v# T1 C5 e( {mon in girls than in boys.1,3 Most boys with CPP. g- \" K/ S) K
may have a central nervous system lesion that is# ^' s* ~4 b# @3 t
responsible for the early activation of the hypothal-, l% G7 j% o' e
amic pituitary gonadal axis.1-3 Thus, greater empha-# X/ G4 M0 D+ e1 b( \9 ~- F, ]
sis has been given to neuroradiologic imaging in
1 W. j. Y+ J' S- c1 h. Jboys with precocious puberty. In addition to viril-2 v' b( _$ s1 c
ization, the clinical hallmark of CPP is the symmet-# U  T& B# E* a) \0 `
rical testicular growth secondary to stimulation by- b2 C9 r. P7 H( [
gonadotropins.1,3
; }0 K; `, e4 OGonadotropin-independent peripheral preco-# ~8 @/ d* U: m- I. }
cious puberty in boys also results from inappropriate! X' R: w# v+ P  T' m* x( {. U
androgenic stimulation from either endogenous or$ y$ I2 t9 {5 U  x
exogenous sources, nonpituitary gonadotropin stim-+ f+ X; }1 O3 N0 d! u2 W
ulation, and rare activating mutations.3 Virilizing
+ @! T/ Q6 A# ^- |, T, e- m9 icongenital adrenal hyperplasia producing excessive
, m0 s! ~7 G" Hadrenal androgens is a common cause of precocious/ ]4 J  w" ~$ y. s1 e1 C
puberty in boys.3,4
6 X3 X& r$ B2 [2 v( e; L# [9 dThe most common form of congenital adrenal" `! A( ^: q* U: i% h/ a
hyperplasia is the 21-hydroxylase enzyme deficiency.' T. _1 |: l7 Q: p; u) C
The 11-β hydroxylase deficiency may also result in
: ]7 a5 s! P7 Y/ Lexcessive adrenal androgen production, and rarely,' K0 ^! \4 c" P1 X! L
an adrenal tumor may also cause adrenal androgen- F9 T9 F5 `4 F
excess.1,3/ \6 N: T: @. S% N# R. s
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from; y; S; R2 |; G0 C; k
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007; N" }3 D$ u& O
A unique entity of male-limited gonadotropin-/ d( Q7 I: A  `( `4 H5 X1 x. ~
independent precocious puberty, which is also known8 ?2 T" {1 p' f) V7 `$ w
as testotoxicosis, may cause precocious puberty at a. n6 E1 o0 a; R/ `0 q
very young age. The physical findings in these boys
2 F+ L# T# Q6 r  v% _9 S( Jwith this disorder are full pubertal development,
6 i  u$ z' U& u0 f+ f( N+ Mincluding bilateral testicular growth, similar to boys; n/ \+ i7 n2 N" G
with CPP. The gonadotropin levels in this disorder
) \2 f3 j/ I* D' N& a6 @are suppressed to prepubertal levels and do not show
+ a/ D. D( P$ Fpubertal response of gonadotropin after gonadotropin-
& _4 B" ^; V% N5 H: Yreleasing hormone stimulation. This is a sex-linked( e1 z+ t7 K: M7 `: M' K
autosomal dominant disorder that affects only
4 {; [5 `1 w  k5 w  [9 E+ j  Gmales; therefore, other male members of the family
6 x6 y+ }6 |. y6 Umay have similar precocious puberty.3
: A% J- i4 k+ c$ {) p8 C4 d, kIn our patient, physical examination was incon-4 M, S( O7 ~) p
sistent with true precocious puberty since his testi-
" ?- n" d- I- g' b3 n; rcles were prepubertal in size. However, testotoxicosis9 f" Y! Y; ^, ?. @( b
was in the differential diagnosis because his father4 b( w2 v- f7 i9 t7 k
started puberty somewhat early, and occasionally,3 D4 Z8 Q3 M+ W2 l/ N+ n$ u
testicular enlargement is not that evident in the; J# T! Y# `0 R
beginning of this process.1 In the absence of a neg-
, Z4 s3 ]" Q, q$ j5 Cative initial history of androgen exposure, our
' J3 F  _# p0 @5 V7 Xbiggest concern was virilizing adrenal hyperplasia,
+ l6 h: i" M+ z( J: S% o& qeither 21-hydroxylase deficiency or 11-β hydroxylase3 p( m3 @; n3 ?7 ?5 ~: U1 f
deficiency. Those diagnoses were excluded by find-
& D; i; d* L! P$ Y' ~* _/ `( Ding the normal level of adrenal steroids.# p: w' `$ c+ @* z1 n5 T+ _
The diagnosis of exogenous androgens was strongly
5 B+ R% [# x, g. l3 S4 Psuspected in a follow-up visit after 4 months because: O2 p5 C* n) x" |0 n& {; h
the physical examination revealed the complete disap-
5 S7 {. o* q0 y8 U( |9 wpearance of pubic hair, normal growth velocity, and
' l3 N# h& e- t* d5 j  Z0 zdecreased erections. The father admitted using a testos-+ }* J) k# ?3 \
terone gel, which he concealed at first visit. He was
3 H' T* c& ?# `# I3 e" [& f: x& d) g% Wusing it rather frequently, twice a day. The Physicians’+ X4 z6 w7 {# Q" w: S) I; A& u
Desk Reference, or package insert of this product, gel or
1 a' A& J+ Y. X0 J& Pcream, cautions about dermal testosterone transfer to: P. p0 s6 ~1 ~9 v! k7 U
unprotected females through direct skin exposure." A* c$ |" U4 Y4 H. a2 A* J7 _: s
Serum testosterone level was found to be 2 times the
3 U( G! C/ C8 J' G$ u( @baseline value in those females who were exposed to
8 F+ s* Z2 i1 [9 g! R6 a! leven 15 minutes of direct skin contact with their male
( O" W5 ^6 M5 Q/ G& ipartners.6 However, when a shirt covered the applica-( L, n! h! u+ y% A( K
tion site, this testosterone transfer was prevented.1 H3 \$ u1 |  `0 a
Our patient’s testosterone level was 60 ng/mL,8 I0 M! }. ~' i5 P
which was clearly high. Some studies suggest that
/ k. Y; s- I2 W6 B; ]dermal conversion of testosterone to dihydrotestos-
& O5 r" @7 C' ], |& [' oterone, which is a more potent metabolite, is more
8 ]$ }, ~; f" ?: E" r' Jactive in young children exposed to testosterone9 J/ W5 j$ W/ j
exogenously7; however, we did not measure a dihy-
" L! h. z0 Z! ^drotestosterone level in our patient. In addition to7 k3 x0 [% k3 o3 S4 ]$ f% Z; R
virilization, exposure to exogenous testosterone in/ b# w- e# q8 J' I
children results in an increase in growth velocity and3 |0 h& \6 M$ a* b, H, }
advanced bone age, as seen in our patient.* y2 o" b% [2 C+ X1 X: w& V
The long-term effect of androgen exposure during
  o, }7 {( y. yearly childhood on pubertal development and final
5 p  e- ]- o3 n; }adult height are not fully known and always remain$ i* T2 Z1 v7 {% M- L( C8 X
a concern. Children treated with short-term testos-4 c6 B' r: g- b. _* t: _% e+ Q
terone injection or topical androgen may exhibit some) n! _' m+ z" u! x# |
acceleration of the skeletal maturation; however, after; f* K. k, o6 d* ^. S* G. r
cessation of treatment, the rate of bone maturation
0 y1 [$ l$ a5 y+ w' I5 |decelerates and gradually returns to normal.8,9
# [7 }4 }9 S' qThere are conflicting reports and controversy* ~5 H9 w0 U& u0 f4 B; c: E
over the effect of early androgen exposure on adult/ h4 e2 Z% @4 F: }$ c9 [
penile length.10,11 Some reports suggest subnormal
3 [  N: {1 D! V/ cadult penile length, apparently because of downreg-( B( n$ t/ y# [$ Q- N9 x/ O4 H
ulation of androgen receptor number.10,12 However,
1 Z6 _" f+ B: H2 x0 t& iSutherland et al13 did not find a correlation between
2 i2 B1 E. y+ k7 Qchildhood testosterone exposure and reduced adult
- ^  q( \5 B' ?/ B% I6 t1 dpenile length in clinical studies.
0 L, O% W+ |( I- e7 Y0 X4 k. h- WNonetheless, we do not believe our patient is
- q( g/ G+ `' ^. f& C5 }4 z# Qgoing to experience any of the untoward effects from# Q+ ]+ R. m4 h( r) |3 F5 s
testosterone exposure as mentioned earlier because
5 a( t) F4 b6 w$ p$ x0 mthe exposure was not for a prolonged period of time.# P9 `8 x1 \+ ?
Although the bone age was advanced at the time of# \; I) Q  M, }5 }
diagnosis, the child had a normal growth velocity at$ E; a. r! |! p8 F$ N2 O6 x: d
the follow-up visit. It is hoped that his final adult
, A9 ^( \. @* |& R3 O, b% z; P. bheight will not be affected.
9 ]# V$ V' R0 }Although rarely reported, the widespread avail-
1 B0 M, s# S2 W6 e: y/ W/ bability of androgen products in our society may: p5 R( H: [* \2 s9 D9 s
indeed cause more virilization in male or female( F0 p* D5 }! ?: ]+ J! {1 R2 [( {
children than one would realize. Exposure to andro-
! X% n9 |8 I6 |' ~gen products must be considered and specific ques-
0 I( r) v7 ^% O. Itioning about the use of a testosterone product or
, {2 h  X* @2 a, Ggel should be asked of the family members during  w/ j2 a; K9 d- l8 R, |6 G: p% L" y
the evaluation of any children who present with vir-# T3 m" U$ c) s& D2 _, B
ilization or peripheral precocious puberty. The diag-
, L4 S9 h: r& ]2 {- K1 g2 ?nosis can be established by just a few tests and by
7 L+ j& _, Z. o  S9 H, H* zappropriate history. The inability to obtain such a
6 a9 v* N' b8 m) [history, or failure to ask the specific questions, may
/ x( m2 V+ i- |6 v. u0 eresult in extensive, unnecessary, and expensive
' a# f- y1 ?( g/ W+ O, ~4 x/ Cinvestigation. The primary care physician should be
4 V' e' m9 A: `# c9 e; E, haware of this fact, because most of these children
' I; \/ `7 }# z) q0 Y" n4 Z/ amay initially present in their practice. The Physicians’
5 n% v4 w7 Z5 u1 pDesk Reference and package insert should also put a
; o# q1 R, i+ Xwarning about the virilizing effect on a male or/ T3 m! k7 R& @3 W! }9 o" z* ]' [4 w
female child who might come in contact with some-$ [. ?+ M+ G# R
one using any of these products.; @1 f  b& ~3 Y- d4 L
References* i4 T0 K" o5 Y1 |& {7 l" o* M( o5 \
1. Styne DM. The testes: disorder of sexual differentiation
2 c4 _  l  A. B( H- {* G4 Eand puberty in the male. In: Sperling MA, ed. Pediatric. G4 G1 n# P3 E" W5 \
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
0 c- C5 o3 t1 ]+ N1 C) T$ S2002: 565-628.0 n6 |3 O" f  i1 M5 [( {
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious$ X* K: \+ R8 }1 F+ A4 \2 h+ [
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
發表於 2025-1-17 16:31:39 | 顯示全部樓層
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4个什么样的?
發表於 2025-1-19 02:41:05 | 顯示全部樓層
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精妙絕倫的精品,感謝啊!期待你更多更好的創作哦!
發表於 2025-3-8 22:04:50 | 顯示全部樓層
絕對的好貼!謝謝啊!逐字逐圖地看完這個帖子以後,我的心久久不能平靜,感恩啊!
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