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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
" ?4 r. ^/ n/ ~+ l, XBoy Induced by Indirect Topical1 r* `1 t6 s- D5 L
Exposure to Testosterone
& Q3 `& t! H8 L9 _  ISamar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,29 L6 K2 r1 z7 r; G& d
and Kenneth R. Rettig, MD1
7 p' H" O( }- V0 ?* m2 AClinical Pediatrics
" Y. m6 M; _' a1 z& n- r+ w2 LVolume 46 Number 6
+ `" X: w, l; H$ n1 `3 lJuly 2007 540-543
: d9 c! s  k" C5 V3 q( i5 U' M© 2007 Sage Publications
7 [' f& C: _* e. O10.1177/0009922806296651$ K) D4 @: |' r# Q+ q' I# a$ T. m
http://clp.sagepub.com
% V6 b8 n* n( G; j( B, ahosted at$ A4 d, y5 e1 \( j. ?1 T
http://online.sagepub.com
& x" `# T; b/ x& o. c) gPrecocious puberty in boys, central or peripheral,
% E% ]" \2 q4 U. e, Y( pis a significant concern for physicians. Central9 }9 @. V1 m+ G3 A$ [
precocious puberty (CPP), which is mediated
8 t! ~# D9 g8 s. ^through the hypothalamic pituitary gonadal axis, has+ y8 _$ N$ Z3 b& v
a higher incidence of organic central nervous system
3 U+ N& B1 f% u6 K, slesions in boys.1,2 Virilization in boys, as manifested
3 A1 l4 F* D4 v3 N. kby enlargement of the penis, development of pubic: p, `- ~, [7 l  @4 l
hair, and facial acne without enlargement of testi-4 y" ?' x! q8 Z2 \9 N  B1 c1 o) `
cles, suggests peripheral or pseudopuberty.1-3 We
0 d5 S" X( @9 C( A# {8 B1 I1 O8 Creport a 16-month-old boy who presented with the
- u$ _; q' j4 J/ J# _6 kenlargement of the phallus and pubic hair develop-
1 x8 o2 x+ Y4 O: [, y( @+ |ment without testicular enlargement, which was due
( V) {; V$ j' ^to the unintentional exposure to androgen gel used by
9 ?  P1 L6 q3 E- a2 N" Jthe father. The family initially concealed this infor-
) k9 ]' T; b+ M) A8 s; I1 H, imation, resulting in an extensive work-up for this9 ]9 a9 D5 @/ g, E# z* j
child. Given the widespread and easy availability of% y! X. u( _! j# P) R% F# M
testosterone gel and cream, we believe this is proba-$ v, L" }% r) F" u
bly more common than the rare case report in the
: m; s1 e2 F4 \9 ?% Z  C( Cliterature.4
6 v: H* W9 ^. F" T  o. }2 L& p1 n1 NPatient Report% m: l; _1 d6 f: Y2 }
A 16-month-old white child was referred to the
7 K0 n1 ~2 X' T" p# Zendocrine clinic by his pediatrician with the concern
# C* J$ o1 T" |% f' Eof early sexual development. His mother noticed
) d2 ?# F( {- M% vlight colored pubic hair development when he was
: X8 D/ P& }% n$ g+ ?From the 1Division of Pediatric Endocrinology, 2University of
0 q4 T. Q4 }( N8 N' qSouth Alabama Medical Center, Mobile, Alabama.1 o* j6 |5 @; o1 }, D/ F
Address correspondence to: Samar K. Bhowmick, MD, FACE,
7 A) ?8 t# x6 c: iProfessor of Pediatrics, University of South Alabama, College of
' e, |, G/ c- N* C+ H- K+ MMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;7 l$ w3 g& [; N1 w/ A! Q
e-mail: [email protected].
$ R) f" c! S  @0 Qabout 6 to 7 months old, which progressively became
( `' U9 Z# |0 ~( Odarker. She was also concerned about the enlarge-
8 L- x- ]" C* Lment of his penis and frequent erections. The child
+ o; y/ `$ K: ?6 ^$ s9 k1 R3 M* lwas the product of a full-term normal delivery, with  T0 c1 D) H2 q8 {! B0 `
a birth weight of 7 lb 14 oz, and birth length of3 ~# x+ K3 t7 I& t* I) |
20 inches. He was breast-fed throughout the first year/ b: H6 r# J: U. A2 _$ \
of life and was still receiving breast milk along with/ g6 Q+ C3 b! ?
solid food. He had no hospitalizations or surgery,. o+ I1 C8 @4 V! A% p, R& K
and his psychosocial and psychomotor development6 G6 Q0 C+ p# F% V: j
was age appropriate.
/ `! z) d9 O0 t- K- |The family history was remarkable for the father,- \) {& t5 \* Q
who was diagnosed with hypothyroidism at age 16,) Q" ?! B' w5 m, S: F% C
which was treated with thyroxine. The father’s2 @" I: c8 K. ?" n$ U
height was 6 feet, and he went through a somewhat8 r: U- t8 n. F1 N7 Q
early puberty and had stopped growing by age 14.8 K- s& m& b- i
The father denied taking any other medication. The
$ A; [7 @" |- D0 G4 Ochild’s mother was in good health. Her menarche
# R  O$ ]; @0 q+ J0 uwas at 11 years of age, and her height was at 5 feet
5 t$ D; m# X/ x5 L' L' w& {6 D5 inches. There was no other family history of pre-1 O, \6 _) r2 o. z) d+ c2 }
cocious sexual development in the first-degree rela-
5 q$ G: c& @) }5 Ptives. There were no siblings.
# k: v/ {7 `# B+ A. h! dPhysical Examination! ?. ^0 K- C8 |0 }, M
The physical examination revealed a very active,5 V& V1 l! ]2 s7 `* B; y& e
playful, and healthy boy. The vital signs documented
: B( a0 @, _& g6 I3 oa blood pressure of 85/50 mm Hg, his length was
& d& y' S" |0 t9 k& [90 cm (>97th percentile), and his weight was 14.4 kg0 W: Y. c" y$ e' m
(also >97th percentile). The observed yearly growth2 ]3 J0 [1 k7 A- \' m
velocity was 30 cm (12 inches). The examination of
& d6 t& p% H/ f' Othe neck revealed no thyroid enlargement.- f# P1 t$ s+ |2 b2 v
The genitourinary examination was remarkable for
  f7 p; y) t1 f! ^enlargement of the penis, with a stretched length of
4 {/ i+ t- ]3 ^$ m$ }+ a8 cm and a width of 2 cm. The glans penis was very well
( d. c) S. S4 x8 F( Ldeveloped. The pubic hair was Tanner II, mostly around
2 t+ e. i; I% p% I1 V5 N- o540
5 g& D; e- x6 u9 G% r) k, p0 A4 R7 Nat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from4 V2 a' P7 {5 |9 |' \
the base of the phallus and was dark and curled. The
, ~7 a# X: `1 Q) N1 ztesticular volume was prepubertal at 2 mL each.2 Q' ~! ^( m  H) \
The skin was moist and smooth and somewhat, k+ n( S8 |% i1 {5 r
oily. No axillary hair was noted. There were no
7 d: n+ L' M2 T8 x% V+ ~% h+ n, ~abnormal skin pigmentations or café-au-lait spots.
2 l, D5 L  w) n0 `5 t1 }Neurologic evaluation showed deep tendon reflex 2+
: U0 a3 m0 K0 h, ?bilateral and symmetrical. There was no suggestion
. q# ]+ F# g% T0 r( Fof papilledema.* s3 u7 s: A. n' e
Laboratory Evaluation
. }, d( d, q" gThe bone age was consistent with 28 months by# O/ |; [* Z2 K( q" R$ K5 F
using the standard of Greulich and Pyle at a chrono-
' A4 m) H6 K9 }, \9 slogic age of 16 months (advanced).5 Chromosomal
. D) I% a+ x4 g1 [karyotype was 46XY. The thyroid function test; i4 N' s0 u7 Q% a6 d) W" P/ Z9 u
showed a free T4 of 1.69 ng/dL, and thyroid stimu-8 ]6 X' Z7 p( e0 M: f
lating hormone level was 1.3 µIU/mL (both normal)./ Z; F: _, e5 k# }: A9 f& x8 {
The concentrations of serum electrolytes, blood
4 g: \% @6 D4 p, H* f' Purea nitrogen, creatinine, and calcium all were
% P* ~+ c$ f, W6 d# A3 kwithin normal range for his age. The concentration
9 k: B" K' ^" Y: q* eof serum 17-hydroxyprogesterone was 16 ng/dL
, F6 O: x% j5 x* ](normal, 3 to 90 ng/dL), androstenedione was 20
8 p6 J) J  d" x- \9 bng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
2 U; `' L, z' F/ q: S( E7 l1 Gterone was 38 ng/dL (normal, 50 to 760 ng/dL),
6 e& M8 U7 q% W, \, Z' ddesoxycorticosterone was 4.3 ng/dL (normal, 7 to
% V( S4 }! @: D" h0 ~: p4 A6 l49ng/dL), 11-desoxycortisol (specific compound S)
! ~: p' g8 e2 X% g7 R+ k8 kwas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-# f/ j4 [+ }. u5 l
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total' t, z4 L7 n# ~; I0 H- B2 v
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),( P1 N/ J5 J- w1 p9 D6 _
and β-human chorionic gonadotropin was less than
! g1 r5 c/ t  w# p- `; A5 mIU/mL (normal <5 mIU/mL). Serum follicular8 c! B& J6 _& }
stimulating hormone and leuteinizing hormone+ o$ Q3 r" J& w! R4 x" x3 E
concentrations were less than 0.05 mIU/mL
8 X2 U! i7 W  l& t" J7 E5 [(prepubertal).
, l( L8 O% P- }0 FThe parents were notified about the laboratory
  ^# M" f7 D" p: gresults and were informed that all of the tests were
. b2 |4 W- M$ Nnormal except the testosterone level was high. The
; P5 ]4 _! C: k# o8 |5 Lfollow-up visit was arranged within a few weeks to2 x( `" T7 I; h' G  `' H7 v' q
obtain testicular and abdominal sonograms; how-
7 u% ]" \3 ?; P( `6 T* G/ v, yever, the family did not return for 4 months.4 k* N" q' j# l- R$ Q6 l. @
Physical examination at this time revealed that the+ e* u8 e3 m2 J$ Q8 q
child had grown 2.5 cm in 4 months and had gained
- F6 n: I5 O$ }7 z8 K, x2 kg of weight. Physical examination remained
  b( Z& [2 ?2 V: aunchanged. Surprisingly, the pubic hair almost com-
; W7 b. x3 D! Y. kpletely disappeared except for a few vellous hairs at9 A9 E1 [8 s& m+ V+ k$ }
the base of the phallus. Testicular volume was still 20 M- c8 ?; ^( `4 E
mL, and the size of the penis remained unchanged.$ G; x# W; ^; L! [6 w
The mother also said that the boy was no longer hav-+ N0 `2 F+ P; a1 \
ing frequent erections.7 V$ I; h7 i! _0 X( i  Y7 k5 k
Both parents were again questioned about use of8 K' \+ X7 C9 ^: B/ s$ x  Q
any ointment/creams that they may have applied to" L+ B1 G/ B9 {4 l
the child’s skin. This time the father admitted the
$ f& `8 [( O9 N4 r7 lTopical Testosterone Exposure / Bhowmick et al 541
' n) s( z; s9 e. c% q% ~  Ouse of testosterone gel twice daily that he was apply-- C" P6 R& e% s0 Z( P# ^% W2 w
ing over his own shoulders, chest, and back area for( x4 c7 c3 ^$ ^5 ^# c
a year. The father also revealed he was embarrassed
% I0 {, G+ |- K: W$ T5 g2 M% cto disclose that he was using a testosterone gel pre-0 V  S2 l( u/ n! ~
scribed by his family physician for decreased libido
" e. G/ l2 {% ~: T5 wsecondary to depression.
" }/ X5 H* G9 c( V) O) yThe child slept in the same bed with parents.7 ^4 b( ]. T- R( c2 X
The father would hug the baby and hold him on his
7 Z% @) q3 G9 Z/ [chest for a considerable period of time, causing sig-
' k2 X$ d* |8 Q! {4 @3 x' Snificant bare skin contact between baby and father.! R) @7 ]! t4 ~* K
The father also admitted that after the phone call,
2 {% W( t' Q& O1 @# d7 Xwhen he learned the testosterone level in the baby3 i) z9 n  c" ^2 p' h' {
was high, he then read the product information
# U& `" \; g$ _packet and concluded that it was most likely the rea-# G' m% K- o; [* R9 K
son for the child’s virilization. At that time, they5 i0 ]& o7 P8 B
decided to put the baby in a separate bed, and the4 F% A3 m9 D7 l/ S" Y0 L! j+ w6 I
father was not hugging him with bare skin and had
+ L7 S& G2 W- }& g4 g3 wbeen using protective clothing. A repeat testosterone& f: p$ e+ ^7 v6 H/ v9 p! s
test was ordered, but the family did not go to the  P4 N0 P( e* s
laboratory to obtain the test.
& D8 a6 o1 G- ]$ i2 Z0 v- u# cDiscussion- Q( q, g0 ^) L( G" L
Precocious puberty in boys is defined as secondary# z1 O! d! v" E/ }7 I
sexual development before 9 years of age.1,4
, Q1 q: k  k: X4 wPrecocious puberty is termed as central (true) when% S/ H3 P/ F* C) Q1 x" ~
it is caused by the premature activation of hypo-5 ?( P/ M$ g) D1 f) F
thalamic pituitary gonadal axis. CPP is more com-
; O* m4 x% ^9 Y+ `: omon in girls than in boys.1,3 Most boys with CPP" Q$ r- V7 O2 r: H
may have a central nervous system lesion that is
2 `- s, l9 E. o* n5 G$ yresponsible for the early activation of the hypothal-' X/ R& U9 s. r5 o' {% B( U
amic pituitary gonadal axis.1-3 Thus, greater empha-# p2 }. f; H7 S8 ^7 I! T' b1 l
sis has been given to neuroradiologic imaging in) w7 ]! S0 f! G7 K
boys with precocious puberty. In addition to viril-
8 e' L" H0 x1 H' jization, the clinical hallmark of CPP is the symmet-
9 u2 M5 P& F+ Drical testicular growth secondary to stimulation by
& d1 y0 I, d# V9 igonadotropins.1,3
- j. l1 ^$ O+ Y( {Gonadotropin-independent peripheral preco-5 M: a1 f4 z2 p7 z. t
cious puberty in boys also results from inappropriate
/ I% l0 n0 F, h  v# h% l2 eandrogenic stimulation from either endogenous or! W9 B" t9 @+ q
exogenous sources, nonpituitary gonadotropin stim-8 E  J/ u) F1 ]3 H1 j+ J5 }
ulation, and rare activating mutations.3 Virilizing" ^6 s! s( [9 c4 m! \
congenital adrenal hyperplasia producing excessive! N+ }4 X  R/ M, c
adrenal androgens is a common cause of precocious
( j8 z8 R+ K% ?& U, H- f6 n2 Npuberty in boys.3,4" `! c7 e. w4 C
The most common form of congenital adrenal) }5 L! A  {* E- r3 y2 Z
hyperplasia is the 21-hydroxylase enzyme deficiency.3 ?; o/ v- X) U/ \* o7 T4 u7 W
The 11-β hydroxylase deficiency may also result in, u% _- p% A  a$ E# \
excessive adrenal androgen production, and rarely,- g. M3 K% ]& M" S- e6 b
an adrenal tumor may also cause adrenal androgen: w% p7 p" f, H& J6 \% a! X
excess.1,3. Q$ L7 O$ S& x  r
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from1 n( ~# w: w; B; {# o) i' u
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
1 d: Q4 [; E5 z2 G% S0 e- G+ @A unique entity of male-limited gonadotropin-
! }. z0 c* r6 L( N" a" e, G# iindependent precocious puberty, which is also known& L6 x$ c) U& E. ]# p. |# y
as testotoxicosis, may cause precocious puberty at a
1 T. F  v$ d6 _) t# pvery young age. The physical findings in these boys+ }+ u" o9 D# G% p1 \3 ]/ h0 M
with this disorder are full pubertal development,! F5 U, R6 f  g. @  I" A6 S. |
including bilateral testicular growth, similar to boys/ Q8 k8 V: B& X
with CPP. The gonadotropin levels in this disorder6 O0 B" |0 U2 }5 K$ `
are suppressed to prepubertal levels and do not show
8 ]3 Z) V. O' b* apubertal response of gonadotropin after gonadotropin-
9 i# o- U  P; v" o2 ~6 k, D9 ]releasing hormone stimulation. This is a sex-linked
& B9 [; I) d  E3 E  l6 e9 \autosomal dominant disorder that affects only
% _% c( b6 H5 f; @9 ~2 F4 \3 e% N! lmales; therefore, other male members of the family
* K* k+ N8 g7 \: ^4 z- r+ Lmay have similar precocious puberty.3
0 _1 z3 A1 g- b% FIn our patient, physical examination was incon-
# o# k7 B8 H& T/ Y' w$ wsistent with true precocious puberty since his testi-
# B! O+ f8 X- M% j" ~  G9 |cles were prepubertal in size. However, testotoxicosis
, A, O; |1 k( u0 @was in the differential diagnosis because his father
& E2 V+ Z$ S. u3 m5 ~! \" E- O0 K! lstarted puberty somewhat early, and occasionally,
: t! f% l2 C' g4 P( z0 ptesticular enlargement is not that evident in the
, j+ R4 n0 y9 T* [7 w! Z- a- g- f4 l/ Bbeginning of this process.1 In the absence of a neg-: `& C4 e# y  S7 W  Z. X1 E
ative initial history of androgen exposure, our
9 G1 F* y3 ?& B2 mbiggest concern was virilizing adrenal hyperplasia,, @$ r* b9 g# A& ]6 {8 V
either 21-hydroxylase deficiency or 11-β hydroxylase
4 Z2 r" u4 Y7 m. Pdeficiency. Those diagnoses were excluded by find-' p1 d) l; {: S3 l3 A" G# Y
ing the normal level of adrenal steroids.
3 D* A3 j) h$ z/ p+ @3 mThe diagnosis of exogenous androgens was strongly
: {" E# k) c2 k  G% n  Lsuspected in a follow-up visit after 4 months because
) J. j: A2 c4 }# othe physical examination revealed the complete disap-/ F: @) S+ n7 J) K6 G* f! N+ j
pearance of pubic hair, normal growth velocity, and" X1 P+ Q! ?: M0 K1 q0 y3 d7 |+ X; [; u
decreased erections. The father admitted using a testos-8 P) [4 W; y, @
terone gel, which he concealed at first visit. He was
- z& [2 D( n/ }$ Zusing it rather frequently, twice a day. The Physicians’) w: H" S* E6 N2 O5 M- r' I" ~! w
Desk Reference, or package insert of this product, gel or7 k# t2 n6 W0 J5 g. W! A. j
cream, cautions about dermal testosterone transfer to! `) i+ X4 m4 y4 T
unprotected females through direct skin exposure.
- F2 U3 U+ v5 BSerum testosterone level was found to be 2 times the
1 m! _% M3 ~! K0 K/ ~baseline value in those females who were exposed to1 r& @. c" u! n" q8 R
even 15 minutes of direct skin contact with their male
% \" A& s! g4 Apartners.6 However, when a shirt covered the applica-1 T$ W4 w7 r3 ?6 g* \
tion site, this testosterone transfer was prevented.
7 h: z$ C0 F$ I0 a; zOur patient’s testosterone level was 60 ng/mL,0 u# ^) s9 A) B
which was clearly high. Some studies suggest that$ a; D3 }0 h* R& t  ^, L( Q& n
dermal conversion of testosterone to dihydrotestos-
+ p/ U5 e1 ]4 K& h& r+ fterone, which is a more potent metabolite, is more
# s7 O5 S& v/ Z5 v1 \active in young children exposed to testosterone
( R1 o! H; d$ c; w( aexogenously7; however, we did not measure a dihy-
2 ^" _1 F6 D4 D) M) ldrotestosterone level in our patient. In addition to
! t" C7 p( g$ n$ K, vvirilization, exposure to exogenous testosterone in
6 {- g3 Z0 Z/ hchildren results in an increase in growth velocity and/ Y* E* c$ d/ S. a) n0 q( I+ ^
advanced bone age, as seen in our patient.
2 P8 b3 b& |1 V" y; \7 O' zThe long-term effect of androgen exposure during
; \% V. Y- C+ @" @1 w1 \7 Cearly childhood on pubertal development and final& f! \. s- E+ y8 V8 F0 f; q5 ~
adult height are not fully known and always remain
1 x. \. B- h5 G* Pa concern. Children treated with short-term testos-
7 W. g& W+ E1 }' Q0 k7 |terone injection or topical androgen may exhibit some
+ K! N4 u5 S( D" m* Gacceleration of the skeletal maturation; however, after
* M& x7 }1 I8 x& ~: E+ qcessation of treatment, the rate of bone maturation
: H" @' e7 B: u9 u. a* |decelerates and gradually returns to normal.8,9. \- C* N+ N$ i8 t- h# L
There are conflicting reports and controversy
( l4 |* B/ X. L6 x! Aover the effect of early androgen exposure on adult
8 t. T6 ?+ C: L) m& |penile length.10,11 Some reports suggest subnormal& z( h9 Q  A5 u. P, Q: s! \; _
adult penile length, apparently because of downreg-: h! b7 g7 C# E! M
ulation of androgen receptor number.10,12 However,
. g2 _8 b9 F! I* O! cSutherland et al13 did not find a correlation between
5 O( F0 V+ ~5 Q: c5 @: |9 ^childhood testosterone exposure and reduced adult/ \% {7 q2 {# u
penile length in clinical studies." P- H( J$ P- T! R% M: e7 Y
Nonetheless, we do not believe our patient is+ Q6 n3 H. Y; O5 P/ h; v# Q
going to experience any of the untoward effects from
" d' }4 k8 f6 Mtestosterone exposure as mentioned earlier because& g2 @1 @$ j1 e  d5 ^
the exposure was not for a prolonged period of time.
% [/ |1 E8 Q$ V5 x3 H/ KAlthough the bone age was advanced at the time of0 L4 [7 D& D& d6 b: k9 G
diagnosis, the child had a normal growth velocity at
2 |7 j2 z7 z$ ?8 m' n$ tthe follow-up visit. It is hoped that his final adult# F! C& M  a9 a7 Y- G. G
height will not be affected.
& @, l1 u. _4 aAlthough rarely reported, the widespread avail-
4 N! _' {7 z- r; g2 x( S- Rability of androgen products in our society may" r' o0 ~% C; U: }9 W
indeed cause more virilization in male or female
. h) p, `- m; j* |% t' Ochildren than one would realize. Exposure to andro-
, p) w8 {( T. Y# M; T1 B3 n* wgen products must be considered and specific ques-4 d- q% c/ E3 K
tioning about the use of a testosterone product or
1 H+ _& t: ]6 Q! ^gel should be asked of the family members during
* `. u3 Y- E/ V& R, }the evaluation of any children who present with vir-
. W8 B& `$ Z8 `2 c  Dilization or peripheral precocious puberty. The diag-
4 L: o) g1 o( N1 Y+ y0 E8 a' z3 Znosis can be established by just a few tests and by
. H+ v' k+ s) Xappropriate history. The inability to obtain such a
5 x  [, G, d# Zhistory, or failure to ask the specific questions, may
. ?+ |$ q5 h. @8 C* T/ Z4 lresult in extensive, unnecessary, and expensive3 I1 S' K* I( @
investigation. The primary care physician should be. i) X! G! n( Y8 ^
aware of this fact, because most of these children
: L- b8 v/ l& s+ |may initially present in their practice. The Physicians’* [2 V& r$ `# y% Z
Desk Reference and package insert should also put a
2 ^8 r8 @3 G9 f* |warning about the virilizing effect on a male or
4 j4 {" j1 ^# Z" \female child who might come in contact with some-
( l  i4 z3 \0 @7 I0 W# a5 X# p* w3 Lone using any of these products.0 ]; B& Q# l, w$ g5 i
References
* _+ v$ L  J( N$ R/ S/ F% m1. Styne DM. The testes: disorder of sexual differentiation' T8 S) P7 w2 c7 ?6 B
and puberty in the male. In: Sperling MA, ed. Pediatric9 @5 l0 I7 \, h( S# j$ D
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;- U0 A1 E, k6 f& y% h
2002: 565-628.
& o, P# h- e0 g' P0 r3 e  Q* Q2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious- M0 j' J' a4 W
puberty in children with tumours of the suprasellar pineal
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Sexual Precocity in a 16-Month-Old
* X! \0 R, o- C% T- CBoy Induced by Indirect Topical* |6 V' S  W. M) U+ x
Exposure to Testosterone
" x1 c$ A6 G1 y& h! ^1 WSamar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
, [9 S5 t  j# I3 l% Q* }# Jand Kenneth R. Rettig, MD18 D/ r$ [& x: L9 r
Clinical Pediatrics' \$ W9 @# q  n8 \6 I! g2 m) E
Volume 46 Number 6, V* d' S: P, K* c$ U, w
July 2007 540-543: E1 H# F+ ^( L: ~0 o7 ]4 u% Y
© 2007 Sage Publications0 B/ t$ u% T4 w+ m. W; M
10.1177/0009922806296651
2 G- [, m9 t  V$ hhttp://clp.sagepub.com
+ K: c, _2 P5 x3 o0 U2 X& Chosted at8 N6 X  l0 }! P
http://online.sagepub.com7 l4 w7 j$ a, j% k4 b$ q
Precocious puberty in boys, central or peripheral,
0 O3 K( X  O7 H, @- s& E4 gis a significant concern for physicians. Central
% U8 {3 p. R$ `3 ^8 R; |, `precocious puberty (CPP), which is mediated
( z1 ^6 K% R( M% C7 Q2 z0 L% zthrough the hypothalamic pituitary gonadal axis, has6 C% i/ U& I" q/ @# R' y2 A: B
a higher incidence of organic central nervous system+ d+ T/ E9 d- _) y! R) O1 _% m
lesions in boys.1,2 Virilization in boys, as manifested( S- |, y9 l$ {2 B# B# `: J+ J
by enlargement of the penis, development of pubic; `- y9 M6 t% X+ s5 S4 W; J
hair, and facial acne without enlargement of testi-
; N% z! O  K0 J- Zcles, suggests peripheral or pseudopuberty.1-3 We7 D" g0 e, ^. Y! e
report a 16-month-old boy who presented with the7 P. c3 z7 n- V  X; }6 u
enlargement of the phallus and pubic hair develop-1 I" Y6 N& W! R9 c
ment without testicular enlargement, which was due7 o; [( ^, G4 `5 j
to the unintentional exposure to androgen gel used by
* M5 P! `( u0 t. i+ k2 D. Othe father. The family initially concealed this infor-3 o, Q, B% h7 n! |5 H/ ]
mation, resulting in an extensive work-up for this& D: u% J8 X, V# [# B
child. Given the widespread and easy availability of, ~# c6 ]! g: t$ F  }" H( F! q
testosterone gel and cream, we believe this is proba-1 ~$ y" D, W1 f% L7 b
bly more common than the rare case report in the  l1 d0 ?  u  f# R
literature.4( h* o' y0 u' r
Patient Report
" Y( G% O7 \/ uA 16-month-old white child was referred to the
1 B- v2 `# S' T5 \& j( a$ ]endocrine clinic by his pediatrician with the concern
7 x- n* I/ h! Q3 }- A! Z/ Z. ?3 ?of early sexual development. His mother noticed. l3 R6 K9 q' {( s# R! w/ m" h
light colored pubic hair development when he was( s8 p: t4 P  ]  t1 I
From the 1Division of Pediatric Endocrinology, 2University of4 L3 @: K9 F! o: [
South Alabama Medical Center, Mobile, Alabama.7 d: Z/ V& U& e' p# N4 B5 U
Address correspondence to: Samar K. Bhowmick, MD, FACE,
8 O4 B) k9 y1 r$ Z1 \Professor of Pediatrics, University of South Alabama, College of. ~8 k3 n  [! v7 p$ K
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
) m! U0 I3 y5 q5 G0 ke-mail: [email protected].
6 W0 w9 s/ f/ Wabout 6 to 7 months old, which progressively became
/ x( h5 e  K9 W4 s* l/ f/ ^, h# R! }# pdarker. She was also concerned about the enlarge-( w  N6 p4 Z3 q
ment of his penis and frequent erections. The child
- ]/ X0 r5 P- C& lwas the product of a full-term normal delivery, with
- v, g+ i4 F/ v* i) N7 wa birth weight of 7 lb 14 oz, and birth length of
* {! f3 X' W; E0 @0 F, W: v/ O20 inches. He was breast-fed throughout the first year- f$ _3 S+ O+ S( E
of life and was still receiving breast milk along with. ~" g, ~' D( l3 I
solid food. He had no hospitalizations or surgery,
! q  N! v8 y2 V( land his psychosocial and psychomotor development
/ _# v6 \" h: p0 P* Fwas age appropriate.
$ i+ V' Z9 u' S" ^The family history was remarkable for the father,
9 d0 q5 [8 n. x0 X. t5 `5 ^who was diagnosed with hypothyroidism at age 16,- l% L3 I5 f1 V/ a
which was treated with thyroxine. The father’s  |# O1 {/ C# _. j
height was 6 feet, and he went through a somewhat
* `% G% ]" Q3 ?) jearly puberty and had stopped growing by age 14.( `6 D" P+ R: z! W8 u
The father denied taking any other medication. The1 F9 ]& c! D" I- S. \; m) r
child’s mother was in good health. Her menarche
' X5 y) L' T; k5 \was at 11 years of age, and her height was at 5 feet! c% m' h. c* N* V  I
5 inches. There was no other family history of pre-, L  _# U! h5 ~/ `( r$ X8 u
cocious sexual development in the first-degree rela-
& _2 ?& C) D( V3 p0 gtives. There were no siblings.
/ h& h4 n: K$ K/ i" fPhysical Examination
1 m! H- m8 I6 ~/ {( DThe physical examination revealed a very active,  y" R+ ?! Q  j& r9 N
playful, and healthy boy. The vital signs documented+ ?0 W& `" f1 E4 E1 E- A8 L
a blood pressure of 85/50 mm Hg, his length was
6 k' [4 a4 l& {% }90 cm (>97th percentile), and his weight was 14.4 kg9 c6 p: U( [/ T& J) R
(also >97th percentile). The observed yearly growth. }- n' n# A, k5 g4 }2 g
velocity was 30 cm (12 inches). The examination of
5 G# R+ X; b! P" e2 ?! s' Mthe neck revealed no thyroid enlargement.5 W% Z# G0 l9 I/ i
The genitourinary examination was remarkable for
; W( {- Z. |  ?  Lenlargement of the penis, with a stretched length of
2 i- ~" l" Y( Y0 |% ~3 D8 cm and a width of 2 cm. The glans penis was very well
7 `! W" ]$ e  s0 c3 Zdeveloped. The pubic hair was Tanner II, mostly around. B! y( \3 \* H& N: A
540
% T: W) P2 Z! o. [. `$ V9 Jat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from: l" }. \6 z+ X. ^
the base of the phallus and was dark and curled. The
: M5 C  O7 t3 C8 H8 @2 ztesticular volume was prepubertal at 2 mL each.$ ^. E4 E$ U; j0 w
The skin was moist and smooth and somewhat4 d7 Z* S+ o, Z! Z" ~
oily. No axillary hair was noted. There were no
# e4 \0 K. T  [' |& T: O  Tabnormal skin pigmentations or café-au-lait spots.$ G* }3 S" q, ^( e0 w
Neurologic evaluation showed deep tendon reflex 2+) H5 K: s& z; r# e
bilateral and symmetrical. There was no suggestion
6 f$ u* X: p: e+ v, ]6 b% Y! Oof papilledema.
6 m( T  T  R1 h# F  ?9 m% E/ qLaboratory Evaluation
/ q1 @" f2 J9 y$ sThe bone age was consistent with 28 months by
1 R  P! _. t- W6 w( Ousing the standard of Greulich and Pyle at a chrono-: M! ]) }/ \3 L7 }1 _
logic age of 16 months (advanced).5 Chromosomal
% B, f& `  g0 t  g% ukaryotype was 46XY. The thyroid function test
+ p" J; x1 \1 ?* Ashowed a free T4 of 1.69 ng/dL, and thyroid stimu-
# J: ^! H# L$ llating hormone level was 1.3 µIU/mL (both normal).
. o! z# t3 j  T4 rThe concentrations of serum electrolytes, blood
9 h  E: s! Z9 U7 Vurea nitrogen, creatinine, and calcium all were
0 u; x. a3 s: a3 }6 cwithin normal range for his age. The concentration
; c4 ?: e3 G1 N7 yof serum 17-hydroxyprogesterone was 16 ng/dL
" m0 n. U) A  T" W(normal, 3 to 90 ng/dL), androstenedione was 20
3 I$ B+ B0 g( x: Wng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-  z7 b6 ]+ {1 ?* ^1 z& R" T
terone was 38 ng/dL (normal, 50 to 760 ng/dL),
; m% b! c  W. }$ j8 a/ ^! O' ddesoxycorticosterone was 4.3 ng/dL (normal, 7 to
& |2 L5 U; m3 y' ^+ J" C49ng/dL), 11-desoxycortisol (specific compound S)
# A% {: W8 D* I+ Rwas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
& f1 p" ~1 a& k, b2 [; i; Z. g; _4 etisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total: S  ^0 A, _: F6 m4 Y. b# v% [. J
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),* J4 i) M' X, {. Z, K
and β-human chorionic gonadotropin was less than
# `' V! ^1 m9 y5 mIU/mL (normal <5 mIU/mL). Serum follicular
! R7 t% k& G6 ustimulating hormone and leuteinizing hormone5 I9 y9 ^5 ^- R8 ~) Z
concentrations were less than 0.05 mIU/mL
3 |+ i4 N3 s. T3 e1 z  h6 O(prepubertal).& l& n. e# S% {; V( e; y8 _; j( v
The parents were notified about the laboratory. n& u9 Q" r4 M# f9 A. }: r
results and were informed that all of the tests were
" m) q4 |& t- [/ Z/ u* U; e$ q: hnormal except the testosterone level was high. The4 h8 G( O+ j. |
follow-up visit was arranged within a few weeks to
. n0 B* E) F+ w& N5 c5 Lobtain testicular and abdominal sonograms; how-% _. T' ?' A/ @; L; f9 L# u5 E! K
ever, the family did not return for 4 months.
& k" D. d: W2 S) t: BPhysical examination at this time revealed that the
' W$ M3 O5 r- W% l; M( uchild had grown 2.5 cm in 4 months and had gained
2 t2 x) s- W4 b0 J2 kg of weight. Physical examination remained3 \. I# u2 f* j3 U4 L* i  Y
unchanged. Surprisingly, the pubic hair almost com-
# \& _( N. ~, u2 _, ?pletely disappeared except for a few vellous hairs at3 [/ P4 p; J- F. ^) F$ d( R: A8 T
the base of the phallus. Testicular volume was still 2
9 b4 m; ?/ [5 ~. A3 \/ z' umL, and the size of the penis remained unchanged.
. [# ~0 l! [$ \The mother also said that the boy was no longer hav-
' V* D/ K3 W1 W/ Iing frequent erections.) v0 Y/ e& g  ?$ X
Both parents were again questioned about use of
( h; ?* v: N5 f- \, tany ointment/creams that they may have applied to$ A4 E4 u# `' H' P- e) I* n3 ]3 h
the child’s skin. This time the father admitted the* g+ o5 j$ T. P' v: l/ c
Topical Testosterone Exposure / Bhowmick et al 541' B: d( Z" h, m$ R
use of testosterone gel twice daily that he was apply-
2 f, x" _% c% V. g; W9 V! eing over his own shoulders, chest, and back area for
8 S( a! s0 x$ N! Pa year. The father also revealed he was embarrassed1 V6 R0 I6 H, ^# J1 Q4 x- F
to disclose that he was using a testosterone gel pre-. `- E" ]$ s# J! f
scribed by his family physician for decreased libido
$ j# R9 F6 H" X4 R7 J0 s; Fsecondary to depression.
) G+ @6 f6 ^  E! z0 B( q$ BThe child slept in the same bed with parents.' m4 f) n" u6 x2 M
The father would hug the baby and hold him on his3 `+ A6 R* Y% V8 m# O& n# @
chest for a considerable period of time, causing sig-, t" `: R! z! L3 J( a# |
nificant bare skin contact between baby and father.
7 V* c, {7 F2 W. k/ h, v4 |- yThe father also admitted that after the phone call,
/ A0 O2 L' p- l. \( q( lwhen he learned the testosterone level in the baby/ Q! K. [2 A$ ]; O  G
was high, he then read the product information
5 t+ ^: K1 o4 i2 k0 c* a7 p- i, ^packet and concluded that it was most likely the rea-1 p8 h7 n% [* g
son for the child’s virilization. At that time, they
9 v4 y% b- |' M. f) \9 Cdecided to put the baby in a separate bed, and the/ I& O( z& U% ~5 N( `8 ^
father was not hugging him with bare skin and had
3 p) Y3 {* W' L2 `been using protective clothing. A repeat testosterone
0 t% D' b. q$ v1 Z+ ~test was ordered, but the family did not go to the; n: L# f6 t, x$ l8 f5 K
laboratory to obtain the test.
* V( _, Z8 V7 c" ^7 CDiscussion
4 q* _7 o6 ^) c# Z! C" m1 dPrecocious puberty in boys is defined as secondary
3 Y4 y! Q# S  M1 qsexual development before 9 years of age.1,42 D/ c/ {7 Z9 A8 e1 t
Precocious puberty is termed as central (true) when# H3 [% i3 \" n) V: a, O4 _
it is caused by the premature activation of hypo-
: R) r; s  @7 Y: S8 [9 sthalamic pituitary gonadal axis. CPP is more com-
- F& x/ H+ x% R" V% Gmon in girls than in boys.1,3 Most boys with CPP) O! P0 l, E, ?1 z
may have a central nervous system lesion that is! |6 N; o7 J$ |1 |
responsible for the early activation of the hypothal-
, e  H* [8 T5 e+ g" i5 B( Z3 m5 yamic pituitary gonadal axis.1-3 Thus, greater empha-
7 v; e' u/ K  ~0 z9 psis has been given to neuroradiologic imaging in2 V& u1 q, n: [, T! D- h
boys with precocious puberty. In addition to viril-( L# v/ B- d  [9 L0 c  B: z
ization, the clinical hallmark of CPP is the symmet-+ ?9 A6 d+ a. w7 @; `' c: A
rical testicular growth secondary to stimulation by; D# h" Y8 l2 C0 \0 r% |/ K
gonadotropins.1,3
- m1 {- C  P: K' WGonadotropin-independent peripheral preco-
  F* C+ F+ K2 r% dcious puberty in boys also results from inappropriate
& s5 T5 j* t+ \# J% e7 N0 u. `$ Nandrogenic stimulation from either endogenous or5 N, q, x# Y# c% Z
exogenous sources, nonpituitary gonadotropin stim-
8 J9 Z% b: b$ o* rulation, and rare activating mutations.3 Virilizing
- h4 Y* @& M. d2 J' zcongenital adrenal hyperplasia producing excessive
& J4 R2 W! L6 f9 U; Wadrenal androgens is a common cause of precocious: n, [) [. G. {& [: W/ g, H
puberty in boys.3,4: R0 {- K; x+ p/ j, E
The most common form of congenital adrenal
7 _; P- L6 ?. t: r* Mhyperplasia is the 21-hydroxylase enzyme deficiency.4 G4 k5 c5 i& c5 r) F8 q+ x
The 11-β hydroxylase deficiency may also result in: C5 s- t, q3 m" D
excessive adrenal androgen production, and rarely,9 C, y7 X) a1 _
an adrenal tumor may also cause adrenal androgen
9 L) v& Z) h- N: f. [' Hexcess.1,3
( V9 w7 C' t. j) P# s( ^% Kat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from5 O  v: v' G2 P9 H3 z' m
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007, o, T+ e% j5 o
A unique entity of male-limited gonadotropin-& s; D1 f; ?# P" [/ J% F- W
independent precocious puberty, which is also known7 n; A3 Q1 k+ g4 o: L6 O+ e% [) Z
as testotoxicosis, may cause precocious puberty at a
! S. v7 W) N' [; hvery young age. The physical findings in these boys
5 O; R3 r+ m$ _2 U$ vwith this disorder are full pubertal development,8 O0 d+ ~+ J* W8 M+ U3 K5 r2 y0 h
including bilateral testicular growth, similar to boys
5 [- p: e) Y' a+ E/ V$ f$ @& ?with CPP. The gonadotropin levels in this disorder
; m: ^. Q% j9 D( m( L& o- D5 nare suppressed to prepubertal levels and do not show
1 c$ T; H$ J% r. Opubertal response of gonadotropin after gonadotropin-2 Z! w% t) D% O- Z( S: S
releasing hormone stimulation. This is a sex-linked2 G% a1 K$ t6 h& A5 B3 p
autosomal dominant disorder that affects only( p/ T& o+ w8 X" ]7 d  D
males; therefore, other male members of the family
( J* C. X' @3 c% Wmay have similar precocious puberty.30 [/ N5 n! G0 |2 E$ B9 V$ L3 H
In our patient, physical examination was incon-
. X( b, _" |4 g  Hsistent with true precocious puberty since his testi-4 E0 v6 n) \( e: t3 B8 U( Y, v
cles were prepubertal in size. However, testotoxicosis9 c6 N& d9 s+ c8 J- X
was in the differential diagnosis because his father
6 k- g; J9 L1 }% \) l) I4 C; V+ Sstarted puberty somewhat early, and occasionally,6 \3 b4 V9 d. X8 B. j
testicular enlargement is not that evident in the
$ E+ O: i- T( E. X, o2 @beginning of this process.1 In the absence of a neg-7 t1 \5 Q8 [# G$ J
ative initial history of androgen exposure, our
7 _& b2 T+ h) h% K/ vbiggest concern was virilizing adrenal hyperplasia,
" A# K7 p5 N. j& R) neither 21-hydroxylase deficiency or 11-β hydroxylase
& K$ A# V5 ]( ^; C* X' U% Vdeficiency. Those diagnoses were excluded by find-1 g' N2 J/ h7 |+ J6 C; K; B
ing the normal level of adrenal steroids.# F! Y4 [, k+ g* Y
The diagnosis of exogenous androgens was strongly
8 U. r" S4 j! zsuspected in a follow-up visit after 4 months because5 z9 u  O8 l1 }& u! o
the physical examination revealed the complete disap-* y' K* f) V: @" \9 c; ^- L7 s+ R
pearance of pubic hair, normal growth velocity, and6 R+ G" g5 ^5 K' T; n; P
decreased erections. The father admitted using a testos-
! Y) {- n' e; i1 P% o; }terone gel, which he concealed at first visit. He was/ T' w- L: O9 O8 J! x% ^# v
using it rather frequently, twice a day. The Physicians’
9 f& Z: L7 V9 JDesk Reference, or package insert of this product, gel or  Z6 L5 ^( ~" E' X
cream, cautions about dermal testosterone transfer to% o5 x9 a5 d8 c% h5 |% L# C
unprotected females through direct skin exposure.4 k! p4 \( \7 Q( h9 U  ?
Serum testosterone level was found to be 2 times the
# b& ]* B/ L$ |+ D, kbaseline value in those females who were exposed to' s0 }2 B8 G+ i' y, I: V6 ~" m% D
even 15 minutes of direct skin contact with their male! m/ B$ S' M% o& Y# ?$ @, ]7 P
partners.6 However, when a shirt covered the applica-
  e5 D9 }9 Z3 G7 o) N. ntion site, this testosterone transfer was prevented.
9 o6 t, H  J; k2 V+ G: u2 W) QOur patient’s testosterone level was 60 ng/mL,3 f) C1 J- l( }6 W8 l' `8 z
which was clearly high. Some studies suggest that
# F  E2 p8 W! Z. E: P1 ~dermal conversion of testosterone to dihydrotestos-! v: C8 g* R( P. ]$ d2 k
terone, which is a more potent metabolite, is more6 S6 S# V8 l+ |2 ?9 y  h
active in young children exposed to testosterone1 X; F, S' d4 L2 c+ `) }, g
exogenously7; however, we did not measure a dihy-
, z: I3 L$ f* w; {7 Xdrotestosterone level in our patient. In addition to
1 Y) ~) M4 L6 k8 ]$ E# M: Svirilization, exposure to exogenous testosterone in
. F' W% T; @( Y" J1 S9 B" ochildren results in an increase in growth velocity and, P# B& `) W+ o) ]7 }
advanced bone age, as seen in our patient.; z) H, a# n& h
The long-term effect of androgen exposure during( d" c* e; @1 Q6 `6 N0 A4 ^- ^/ i% C
early childhood on pubertal development and final$ o2 v* A9 @* w2 }6 [4 D  ?, v
adult height are not fully known and always remain
% g5 a; |9 _7 k' Z, e* x, ]a concern. Children treated with short-term testos-
2 D& P5 P2 \/ |. J4 Y. Z; j! n1 Rterone injection or topical androgen may exhibit some
; Y& o9 ^7 d$ t0 C' v" Oacceleration of the skeletal maturation; however, after3 h& @$ ^( g$ c+ c  t
cessation of treatment, the rate of bone maturation" N9 l" e; j2 E6 N+ C  k& E
decelerates and gradually returns to normal.8,9
. L8 k6 T6 h$ O' @. C! E( KThere are conflicting reports and controversy
" H4 x+ o% g: H- Yover the effect of early androgen exposure on adult
6 A4 `& K8 v' @( Z9 Tpenile length.10,11 Some reports suggest subnormal
7 y4 Q! S6 R) Eadult penile length, apparently because of downreg-
6 ~7 C- y+ M. `4 K7 A* Iulation of androgen receptor number.10,12 However,
/ g. N  W7 N9 j6 CSutherland et al13 did not find a correlation between
/ N, ?$ b2 m* p/ Rchildhood testosterone exposure and reduced adult
6 K! b, m3 i, w( `$ F: d* vpenile length in clinical studies.3 F4 N4 f) f* C3 y1 r) l7 c" ?
Nonetheless, we do not believe our patient is% G# E5 i$ u) a/ d
going to experience any of the untoward effects from
, g, _5 ?& I& ~% @% _testosterone exposure as mentioned earlier because3 W- r0 U  j9 y6 {$ e, ^* n4 ]
the exposure was not for a prolonged period of time.
, r9 v1 X- ]- z: HAlthough the bone age was advanced at the time of& O# y, q* _" C3 Q8 C
diagnosis, the child had a normal growth velocity at* k! s0 r4 ^8 P8 C# }' z
the follow-up visit. It is hoped that his final adult4 G' |& b/ {1 S" d% |& ?2 x
height will not be affected.) l" e8 ?% g- c- G  J6 y: P
Although rarely reported, the widespread avail-0 x5 ^9 `4 N& G/ V; W
ability of androgen products in our society may
4 N! P! X1 o2 o' T- m3 tindeed cause more virilization in male or female
, o3 }: {2 M; g0 `! Lchildren than one would realize. Exposure to andro-" @0 a3 B( W0 A, i) f* g1 D0 T
gen products must be considered and specific ques-
5 v, f% d4 w6 o4 u8 n, Xtioning about the use of a testosterone product or
; h$ J9 ~& F7 e4 W/ igel should be asked of the family members during
1 A) |7 z/ A6 H0 ]3 S& g8 z8 {the evaluation of any children who present with vir-
  e6 f5 k6 ~. k4 {2 bilization or peripheral precocious puberty. The diag-& ^( F, C' J; ?% D) I- U
nosis can be established by just a few tests and by
+ R0 J( G8 a4 ?1 Zappropriate history. The inability to obtain such a0 G# @, _7 `( S; r* g% i4 E. U+ B
history, or failure to ask the specific questions, may& @9 A7 P3 [- x, r
result in extensive, unnecessary, and expensive
8 G6 K; G9 K6 _: tinvestigation. The primary care physician should be8 R. A4 n: E5 o
aware of this fact, because most of these children
3 y% X- o, H9 L! W* c8 J6 fmay initially present in their practice. The Physicians’
/ j- I: m  K. V$ YDesk Reference and package insert should also put a
! n' K8 n/ b8 |: ywarning about the virilizing effect on a male or/ i/ p  D8 k9 L
female child who might come in contact with some-
9 i& \& S8 w* `$ T, [one using any of these products.
0 k9 `7 t2 H/ M& }/ B* U! bReferences
0 s/ |0 I* \- E1. Styne DM. The testes: disorder of sexual differentiation, A# g0 L, k% W7 Q# `" B
and puberty in the male. In: Sperling MA, ed. Pediatric
5 s0 d* z2 j3 dEndocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
$ B, n6 Z, J' w0 t; H; h2002: 565-628.
+ _8 r0 b6 H' z8 o6 }2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
) M5 `% Z" v8 W7 G3 J; tpuberty 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?
發表於 2025-1-19 02:41:05 | 顯示全部樓層
4 p3 j4 G# e7 A" r1 v! O/ R+ c) @
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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