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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  C: Z, \% N( e2 A7 K7 c4 I" \
Boy Induced by Indirect Topical
9 g/ F/ }. f" }8 c2 ^; ?7 nExposure to Testosterone) f8 F  A( u8 I+ V3 ~
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2; ?: W# E$ E. |! N4 h0 F3 V7 Q* r
and Kenneth R. Rettig, MD1% w$ b2 J( V) T$ j) Q  O
Clinical Pediatrics
' }# Z5 d" [, [' i* FVolume 46 Number 6
- c) b3 u, h- @/ |: e/ ?July 2007 540-543
3 u# w' _9 L9 T© 2007 Sage Publications- B% N  Y2 J6 d; a
10.1177/0009922806296651' m$ h8 ?, g& r. H
http://clp.sagepub.com% K3 T9 b# H1 d
hosted at3 J4 j/ d  l& I9 \2 ?) C% o) I
http://online.sagepub.com
% E' r2 I6 c& G3 [1 _  B# ~Precocious puberty in boys, central or peripheral,6 P: v7 s2 Z( ^2 Y% o! E" G
is a significant concern for physicians. Central
  k. t4 v+ ~5 u5 W, Z  v; Dprecocious puberty (CPP), which is mediated
+ q1 ]: u5 d/ `% a0 q0 Wthrough the hypothalamic pituitary gonadal axis, has
& ^/ M% E; q, S, m4 ja higher incidence of organic central nervous system  j9 P6 u( V  k, G& g: O4 a5 |
lesions in boys.1,2 Virilization in boys, as manifested2 f% t4 |* F3 R9 Q. V. G, A
by enlargement of the penis, development of pubic; X$ S4 w2 Q* K
hair, and facial acne without enlargement of testi-3 M5 H6 l4 \. M' U% y3 \
cles, suggests peripheral or pseudopuberty.1-3 We
' p( L% n  H  r' greport a 16-month-old boy who presented with the7 ~& E6 Y" e4 ?5 N5 }# X$ |8 L
enlargement of the phallus and pubic hair develop-; `! H' [% r/ s' n7 b( v" E
ment without testicular enlargement, which was due
# ~0 \9 C" Y' ?2 rto the unintentional exposure to androgen gel used by
8 J% l3 V1 w) W/ @. i) Gthe father. The family initially concealed this infor-: t0 ]" X7 a; O8 y% ~" T
mation, resulting in an extensive work-up for this
' K! z8 \4 O7 M, r6 [) uchild. Given the widespread and easy availability of
/ w+ F8 T" i- e3 l0 Wtestosterone gel and cream, we believe this is proba-
1 r* m7 N3 ?, L$ }bly more common than the rare case report in the/ v; v6 k( H2 A7 L+ S9 }3 ?
literature.4
  Z7 W$ y( u3 f$ ^/ K; e0 ~Patient Report" S3 ^: [+ \6 q9 o" k0 G4 W' M& o
A 16-month-old white child was referred to the( t5 U2 ]. c; c( ?& i8 ?
endocrine clinic by his pediatrician with the concern+ `! H# d1 L& O  g, P8 o0 X
of early sexual development. His mother noticed
+ y1 o% ~* B# j! \light colored pubic hair development when he was
1 h/ Y0 }8 Q6 L7 q- Z4 pFrom the 1Division of Pediatric Endocrinology, 2University of
8 G3 y  v; f6 v3 }* pSouth Alabama Medical Center, Mobile, Alabama.
/ [8 L. n, P: V# \# M) ^9 \Address correspondence to: Samar K. Bhowmick, MD, FACE,1 A  C. R3 p3 l& S2 e$ Z2 Y& y- D
Professor of Pediatrics, University of South Alabama, College of8 l0 E' ]3 Q! h* W& N
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;3 C' r" z: _' s
e-mail: [email protected].
# C* C, s; l* N2 Q- P  Aabout 6 to 7 months old, which progressively became
1 M2 g; @. }# V- ?/ g; W- Ddarker. She was also concerned about the enlarge-
# u' ]8 f) v; `! ]3 |3 {ment of his penis and frequent erections. The child
7 m2 x% ?. l8 P; Rwas the product of a full-term normal delivery, with3 B% Q. k1 m+ \! l1 p
a birth weight of 7 lb 14 oz, and birth length of% R  C" t8 Q9 Y- r  N
20 inches. He was breast-fed throughout the first year8 c7 E/ S6 B9 f2 K! N  F
of life and was still receiving breast milk along with& N. _9 }: R# I; X8 {/ ^  m9 Z
solid food. He had no hospitalizations or surgery,
2 G$ z3 ?: K0 M  Z5 N- `8 o; h+ Rand his psychosocial and psychomotor development( i. a+ {( x7 K9 B' G4 h, J) u/ q& @
was age appropriate.
. {! C/ t. b) [/ [The family history was remarkable for the father,
/ V: e# q! \' _who was diagnosed with hypothyroidism at age 16,2 S  b# Q* p2 k0 u4 D0 }3 G
which was treated with thyroxine. The father’s
; L$ }( A7 M9 W' p5 ?" ~6 }5 Jheight was 6 feet, and he went through a somewhat
. L$ K! R7 c' b( iearly puberty and had stopped growing by age 14.
) u& g$ w' O, G# f9 o. G- iThe father denied taking any other medication. The/ c6 u' {, l9 S1 I1 m1 J
child’s mother was in good health. Her menarche) P3 _' m6 y" ?9 A
was at 11 years of age, and her height was at 5 feet
1 K( O& _/ K$ i% Y5 @5 inches. There was no other family history of pre-
" {6 F" c# o2 l; l+ ]cocious sexual development in the first-degree rela-. J5 C) L8 m2 u1 E7 \
tives. There were no siblings.
$ |2 _: I8 h/ b1 f; E7 P7 T" APhysical Examination
  W  o% q6 D0 v- }( U: D# WThe physical examination revealed a very active,
  \* Y& ?- C" J" P$ _playful, and healthy boy. The vital signs documented% V2 c: L3 Y* m% s
a blood pressure of 85/50 mm Hg, his length was- ~* n6 H+ @  d8 J: Y6 S" j; S# ?2 P" T
90 cm (>97th percentile), and his weight was 14.4 kg* ^% R- M" M% R* I
(also >97th percentile). The observed yearly growth
" _9 l. U  j& s4 Gvelocity was 30 cm (12 inches). The examination of
2 j) y: @2 z& k9 I$ H% q* S8 f. J: Cthe neck revealed no thyroid enlargement.
: w+ H+ H) F" b& K8 _The genitourinary examination was remarkable for+ D# D  Y( G1 t! K0 Q
enlargement of the penis, with a stretched length of
& s: }9 G7 ?6 O8 cm and a width of 2 cm. The glans penis was very well) O' `1 `8 K: l; T* H
developed. The pubic hair was Tanner II, mostly around0 Y/ j9 |9 h4 O6 n  o, F
5400 @; @) F" F' V* D+ {
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the base of the phallus and was dark and curled. The6 B! w: y$ F% C
testicular volume was prepubertal at 2 mL each.& [6 f. K6 c+ z* b* m
The skin was moist and smooth and somewhat5 q- ]& }4 K9 h7 G) p
oily. No axillary hair was noted. There were no
, J/ _+ b: ^/ G; B% u' zabnormal skin pigmentations or café-au-lait spots.$ F, \' X9 L8 m0 M' t9 u$ m
Neurologic evaluation showed deep tendon reflex 2+
) @) {% t3 g! p* q0 Tbilateral and symmetrical. There was no suggestion
8 F6 h+ i2 C7 V+ b  L1 yof papilledema.) a+ U9 d& o- d0 m
Laboratory Evaluation
0 _9 B8 u8 C: o- W5 j/ F0 B4 eThe bone age was consistent with 28 months by
. p+ Z2 `1 _7 R" ], n9 l6 fusing the standard of Greulich and Pyle at a chrono-
6 j/ A7 ^. `4 S& l2 rlogic age of 16 months (advanced).5 Chromosomal
# A( r+ R' C1 p. mkaryotype was 46XY. The thyroid function test
% t- T9 F: H' F9 u  C! {% {0 Pshowed a free T4 of 1.69 ng/dL, and thyroid stimu-3 W# Z: u$ t& [  C
lating hormone level was 1.3 µIU/mL (both normal).
" Z: K% p7 J4 t  rThe concentrations of serum electrolytes, blood1 _/ ?, I3 \) `7 W1 P, B
urea nitrogen, creatinine, and calcium all were& n% T" u; `2 V: e4 l; Z
within normal range for his age. The concentration
6 H; _/ H% M; e8 ?of serum 17-hydroxyprogesterone was 16 ng/dL
# i! S* ~/ o$ y(normal, 3 to 90 ng/dL), androstenedione was 20" ~- t/ J' Y0 T  F, V
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
7 f1 V7 F- r! I* l% m( p  I* Kterone was 38 ng/dL (normal, 50 to 760 ng/dL),
- K- y0 l* t3 xdesoxycorticosterone was 4.3 ng/dL (normal, 7 to
1 X* H+ x  n/ H2 m- t49ng/dL), 11-desoxycortisol (specific compound S)7 ?% i  @) y. Y  [
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-. ~4 J" A( a- \' [( G5 m/ {
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total+ T6 ~: }- [( G9 v' c1 V
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
6 K0 N) a; c4 K4 z  B0 {and β-human chorionic gonadotropin was less than; Y* w2 X- g4 i# o& B2 V
5 mIU/mL (normal <5 mIU/mL). Serum follicular# J% b' {+ A# m/ a9 ?! a
stimulating hormone and leuteinizing hormone
! K3 E2 X. A$ Bconcentrations were less than 0.05 mIU/mL
. _) Y( ~# o+ {$ A% U6 m7 E7 U2 F" o(prepubertal).% ^4 v5 e! j  T7 l# d, R4 v
The parents were notified about the laboratory
5 a- x+ q8 ?5 eresults and were informed that all of the tests were
( J( h) m" e5 u5 u  K2 Cnormal except the testosterone level was high. The
. j3 W; C8 H3 s5 \- n- f6 Mfollow-up visit was arranged within a few weeks to
5 v9 }! J% A0 {8 g( I) T  `obtain testicular and abdominal sonograms; how-
! g6 n8 `! `# C$ p+ L! a" ^ever, the family did not return for 4 months.
- v' c+ n& ^$ A/ R) w: cPhysical examination at this time revealed that the1 h1 w2 u. b' ^- D, N
child had grown 2.5 cm in 4 months and had gained
( {& l' {; N! v+ j5 I2 kg of weight. Physical examination remained/ }- J4 Q' C2 ]' t! ^% l$ `& Z
unchanged. Surprisingly, the pubic hair almost com-
1 F% _  [4 r* Kpletely disappeared except for a few vellous hairs at$ e& i8 H7 q4 X& L
the base of the phallus. Testicular volume was still 2& [: \9 F$ b3 s  X5 a+ \
mL, and the size of the penis remained unchanged.+ L/ b6 u' v( i% J4 [+ L( f
The mother also said that the boy was no longer hav-
8 N* U% |- X/ @; A( R5 wing frequent erections.* ?, e2 y' |1 d( O- d! h& b
Both parents were again questioned about use of/ g( o( ?. f% i  [+ Y" b
any ointment/creams that they may have applied to! p* ~) i, a) f6 |/ l" X
the child’s skin. This time the father admitted the
. J! r) Q- Y+ ~$ e) z7 ITopical Testosterone Exposure / Bhowmick et al 541
0 `: A! d8 C0 N0 T0 puse of testosterone gel twice daily that he was apply-
1 V) Y8 N2 U' e- W  w7 k' P& d' x* oing over his own shoulders, chest, and back area for, L4 o. ?6 G6 s% O& X1 }! c
a year. The father also revealed he was embarrassed
) Y% V- A+ z9 q3 dto disclose that he was using a testosterone gel pre-: I& ~2 B3 F$ A( a0 x% v
scribed by his family physician for decreased libido
/ {4 c1 R) j* W. Hsecondary to depression.
" K7 n5 {' w& @1 U: B5 O1 {1 ZThe child slept in the same bed with parents.
9 l1 a4 a8 j7 N" g3 GThe father would hug the baby and hold him on his$ t6 E" }, x3 z0 O" {) i
chest for a considerable period of time, causing sig-& {& n0 ^; h* G. W' d4 a- {* {
nificant bare skin contact between baby and father.
- p2 q4 H. S9 ^5 S" i1 y. xThe father also admitted that after the phone call,+ E1 k( |3 j0 m% b$ o0 P+ `
when he learned the testosterone level in the baby
+ ^( Y. C  p. B! Y& e( ~1 L/ o1 bwas high, he then read the product information
, ]$ a# p! i: E+ Dpacket and concluded that it was most likely the rea-1 `! I% g/ j' E1 \+ L
son for the child’s virilization. At that time, they* X5 _% u' d8 M6 E5 L0 d
decided to put the baby in a separate bed, and the
/ j5 D9 g+ {( ~7 ~. m4 Ufather was not hugging him with bare skin and had
0 [9 N. C# e' X- Xbeen using protective clothing. A repeat testosterone
& d) Z  q) l# I- r# ctest was ordered, but the family did not go to the! d* c) I% _0 ?1 P. p
laboratory to obtain the test.7 ~" V% B* b/ S1 C
Discussion: S4 d; E) u* [3 e% q
Precocious puberty in boys is defined as secondary
: @! j& j* m/ e# ^" G6 |sexual development before 9 years of age.1,4
' Y: q9 p) a4 gPrecocious puberty is termed as central (true) when' G' C! {: ~- X" k3 O) r- T0 k
it is caused by the premature activation of hypo-
# e8 x& D0 u" v- {3 `! K5 zthalamic pituitary gonadal axis. CPP is more com-5 X, U) A9 `4 U
mon in girls than in boys.1,3 Most boys with CPP) I# k8 w: b2 r1 n
may have a central nervous system lesion that is
" `# v' l5 X7 G4 b' Sresponsible for the early activation of the hypothal-+ L( b" J7 P' W0 T: O# L1 B
amic pituitary gonadal axis.1-3 Thus, greater empha-3 y2 m3 t8 k$ b( L5 ~2 `
sis has been given to neuroradiologic imaging in
3 G& Q# ^+ o- L0 Tboys with precocious puberty. In addition to viril-7 z. M( p& c' R, `# ^( _
ization, the clinical hallmark of CPP is the symmet-8 q$ n, m; N) Y( K* o9 u! E: @
rical testicular growth secondary to stimulation by
" z8 [( o, E2 ^% r9 igonadotropins.1,3
1 K9 z* |4 ?8 B! E) u) `Gonadotropin-independent peripheral preco-
1 i7 v$ d5 j. P0 w4 Mcious puberty in boys also results from inappropriate
$ c, B: U: u) w3 @- O9 \androgenic stimulation from either endogenous or
. S  v9 K% e7 {. l! F0 Dexogenous sources, nonpituitary gonadotropin stim-, i+ L8 E, M+ I% m
ulation, and rare activating mutations.3 Virilizing
& R+ {" o9 `7 H1 Jcongenital adrenal hyperplasia producing excessive& k: B9 F4 q9 _0 W) `. D
adrenal androgens is a common cause of precocious3 G9 t* r$ |8 y
puberty in boys.3,4
6 n. k  n. E' [$ E+ G6 g/ RThe most common form of congenital adrenal4 O9 M  b0 r) P: v
hyperplasia is the 21-hydroxylase enzyme deficiency.1 X7 J1 k0 o( l) ^
The 11-β hydroxylase deficiency may also result in. A) G4 S, P% a, e) v
excessive adrenal androgen production, and rarely,- n, O$ _% j( S+ c
an adrenal tumor may also cause adrenal androgen; F0 t, W0 d5 ?; i# w3 k  S9 Q5 ~
excess.1,35 w4 b' ]) ]  U
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from0 w, N8 V) q2 C2 L
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
! `6 F  U8 @" U$ J4 o2 `4 rA unique entity of male-limited gonadotropin-
# f! z0 |1 f- A2 B1 Nindependent precocious puberty, which is also known
) ~; ~9 I' l0 ?9 K5 z4 Das testotoxicosis, may cause precocious puberty at a
9 k, e' [$ Z, a! Q5 Cvery young age. The physical findings in these boys! g$ u4 \) V/ S
with this disorder are full pubertal development,
6 `  B% ]) F' k1 R2 S9 I* qincluding bilateral testicular growth, similar to boys
. w; E0 T3 L$ p# p1 l9 vwith CPP. The gonadotropin levels in this disorder
6 P5 h6 e- {8 G9 g* fare suppressed to prepubertal levels and do not show
( R, Q7 o! C4 C  C0 l) kpubertal response of gonadotropin after gonadotropin-
, a; _3 u' H0 Ureleasing hormone stimulation. This is a sex-linked- o3 i& `, O& A
autosomal dominant disorder that affects only
( R' M* Y- Q( }& d( _( qmales; therefore, other male members of the family
* ?  W8 w0 _9 u) K9 \3 emay have similar precocious puberty.3# T5 U, h% l! D' T
In our patient, physical examination was incon-  d! t, J/ q5 h" P% f  A, P9 z
sistent with true precocious puberty since his testi-
. w" j7 M! H3 I) \cles were prepubertal in size. However, testotoxicosis
4 f" ?4 p( e0 rwas in the differential diagnosis because his father) |& Z1 _& |8 F, ?; n0 T, }$ d
started puberty somewhat early, and occasionally,
+ v+ G0 q( j! M$ h4 X9 Vtesticular enlargement is not that evident in the
& H2 _: R/ B" I- p/ Dbeginning of this process.1 In the absence of a neg-
, Z" G8 X/ M6 dative initial history of androgen exposure, our
0 T1 {/ \$ R: Y* g# g/ Ybiggest concern was virilizing adrenal hyperplasia,! @" X- G3 W5 ~  W$ r' I
either 21-hydroxylase deficiency or 11-β hydroxylase
' d% w: C5 ]$ {- c/ G+ ideficiency. Those diagnoses were excluded by find-
1 i# \* e# _0 r6 u. G% N( u' Zing the normal level of adrenal steroids." S  l$ v/ n  p$ s4 j* k
The diagnosis of exogenous androgens was strongly$ A: R/ n% {0 [% t/ ?9 ~
suspected in a follow-up visit after 4 months because+ S$ ?0 t. S) X, C
the physical examination revealed the complete disap-
0 K4 x9 v$ {( B% _0 ppearance of pubic hair, normal growth velocity, and
. g+ m' c: N  S/ W) J- `decreased erections. The father admitted using a testos-
2 ?( x/ ^1 e% V5 x; V' Xterone gel, which he concealed at first visit. He was( D2 N$ C4 i( @  |% W0 ^
using it rather frequently, twice a day. The Physicians’) ]; g$ Q8 ~5 U8 a* f$ z
Desk Reference, or package insert of this product, gel or
8 o$ ], |9 m- c# y3 _cream, cautions about dermal testosterone transfer to
- M5 X9 u- E, F( z' Zunprotected females through direct skin exposure.1 {7 G# k0 H0 b7 ^3 j5 d, m: ]
Serum testosterone level was found to be 2 times the
+ ^$ ^7 i& m. F* ]& \8 Abaseline value in those females who were exposed to) u0 G2 i; y0 ?) ^( b. j: k7 p
even 15 minutes of direct skin contact with their male/ t$ a6 [, i1 n+ X
partners.6 However, when a shirt covered the applica-, M1 F/ B3 }$ l6 i; v; i
tion site, this testosterone transfer was prevented.
# ?8 p1 ^, s% o7 W* bOur patient’s testosterone level was 60 ng/mL,9 \2 N* F* [9 J9 x" E; Q: I* w
which was clearly high. Some studies suggest that
+ b/ j- X+ W" \# S- Zdermal conversion of testosterone to dihydrotestos-
" K4 K4 ?. I+ l, @6 ?8 ^terone, which is a more potent metabolite, is more& q; Y2 U2 v* N, E1 m9 J
active in young children exposed to testosterone3 w/ G) b6 f: s9 j" {: S6 U( ?( a
exogenously7; however, we did not measure a dihy-
* n! e; \: Z! e, M6 Q/ @! idrotestosterone level in our patient. In addition to. N$ ?; {2 n! ]& L# e% q
virilization, exposure to exogenous testosterone in6 o6 Q1 {$ V4 l. i# k1 ?/ c
children results in an increase in growth velocity and* m5 R$ I/ Y" G. H. H. S
advanced bone age, as seen in our patient.
; c; j3 f& I# xThe long-term effect of androgen exposure during! }( J2 z% T, {3 @! v5 @; ~
early childhood on pubertal development and final2 \. G, q; J7 B6 |$ j4 L; Y1 U
adult height are not fully known and always remain# V/ B* i8 v& h- o. A
a concern. Children treated with short-term testos-. i# D) B& o( w1 v3 I$ Q1 Y
terone injection or topical androgen may exhibit some
" ^2 I' B5 Q2 o3 y9 ?8 Y- o+ w5 `acceleration of the skeletal maturation; however, after2 b1 y" C' S& \! P  q! v. `
cessation of treatment, the rate of bone maturation% c4 \: S" v: e, K! j
decelerates and gradually returns to normal.8,9
7 L9 P' F8 p1 _$ A7 b' MThere are conflicting reports and controversy( _2 N3 B  {7 w
over the effect of early androgen exposure on adult$ u+ x1 u; }6 r5 i9 I
penile length.10,11 Some reports suggest subnormal- j, _4 J6 l4 U8 r" B
adult penile length, apparently because of downreg-
3 N) K7 q/ U5 ~8 q, S0 Eulation of androgen receptor number.10,12 However,! ~* D5 ~4 w3 q4 ^! L( t5 `5 V' a
Sutherland et al13 did not find a correlation between
$ c5 `6 y" t1 _+ V- a& Z& Tchildhood testosterone exposure and reduced adult
. m6 l1 A4 ]; N/ R, Hpenile length in clinical studies.2 G& o0 r' S# ?! z; Z$ u3 T4 h( \! F# l
Nonetheless, we do not believe our patient is
+ A$ J2 w& f) s$ y  W$ Mgoing to experience any of the untoward effects from
: F2 N0 I8 {; p) h9 r) `/ [testosterone exposure as mentioned earlier because) {% Q/ E( X! U2 y/ Z, ?2 @1 o
the exposure was not for a prolonged period of time.8 v* ~% r: A( Y) |
Although the bone age was advanced at the time of
( D1 B; y7 D- @' Wdiagnosis, the child had a normal growth velocity at* j3 Y. j/ m9 ]+ m) T5 e/ u  X
the follow-up visit. It is hoped that his final adult. i; r7 W* S" z( n
height will not be affected., h7 @/ d' `' p. \. A
Although rarely reported, the widespread avail-( C2 d$ Y" k. o9 p
ability of androgen products in our society may
/ q4 P% U* Z2 V1 pindeed cause more virilization in male or female
5 I# ]) T8 _( g6 V" E* r( wchildren than one would realize. Exposure to andro-
2 `! K$ z. N1 z& F; e6 s* mgen products must be considered and specific ques-
3 W! c( F! F7 x' T1 C$ ~! {tioning about the use of a testosterone product or5 J8 {; ]7 V) \3 x( h+ |% {
gel should be asked of the family members during. ^; v% ]# o; E8 _9 b- s
the evaluation of any children who present with vir-: M7 `. z7 c% x
ilization or peripheral precocious puberty. The diag-
5 K1 w+ j  p' S: |nosis can be established by just a few tests and by
1 c' k# j1 ~# _! P9 @appropriate history. The inability to obtain such a
: A" H, L. ~: u6 p6 Q- Dhistory, or failure to ask the specific questions, may
9 K5 a' b" r( yresult in extensive, unnecessary, and expensive
9 [9 v* z& u( O5 s0 rinvestigation. The primary care physician should be) A- |" P# ]- M+ C0 H: ]
aware of this fact, because most of these children
+ S7 H5 i; z( a" {may initially present in their practice. The Physicians’+ \" E' n+ I9 L8 ~
Desk Reference and package insert should also put a1 y3 H: _  t5 k9 a
warning about the virilizing effect on a male or0 C! G0 q/ o3 T; f: Q
female child who might come in contact with some-( l5 I. V" ~: y
one using any of these products.# v( [, ^! }1 s0 ~' n# p
References
' K0 C2 Y% `! P  b# k% _* g1. Styne DM. The testes: disorder of sexual differentiation
  Q8 i; ^4 ~1 I/ }and puberty in the male. In: Sperling MA, ed. Pediatric3 @+ ~; F3 @9 A: Y' \
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;% s% y; {, G. ~5 `* O6 V
2002: 565-628./ G' o9 D3 N6 P) a$ K4 q! S
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious% g) A: A4 R# x  n+ V& C
puberty in children with tumours of the suprasellar pineal
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Sexual Precocity in a 16-Month-Old
) z2 T% h- I* z  {5 JBoy Induced by Indirect Topical0 G3 L7 O' [4 W
Exposure to Testosterone
' e/ I/ [6 h  qSamar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,29 M7 D, m$ k% l; p3 G
and Kenneth R. Rettig, MD19 G" M) P9 @; M
Clinical Pediatrics. ^$ y" u2 p' c0 S
Volume 46 Number 6& E/ B, ?8 \1 E1 Q
July 2007 540-543
- x. _( W% f) a, O) M© 2007 Sage Publications
* k7 V7 t) N% B" X. ^- L10.1177/0009922806296651  D/ q4 S, a3 M1 `. w- y
http://clp.sagepub.com
' z/ r( K& O& s6 V3 v& ]# {: t/ Uhosted at
& c0 m4 B7 \% J: r7 c; m9 dhttp://online.sagepub.com8 `6 n& v7 L% a+ {' {+ t
Precocious puberty in boys, central or peripheral,: i* o  B: b5 I
is a significant concern for physicians. Central  o& D) |. v  J
precocious puberty (CPP), which is mediated  e2 N, ?! q% l( a7 Z1 c
through the hypothalamic pituitary gonadal axis, has" S- A5 z' X& I# {* y1 p
a higher incidence of organic central nervous system' V6 O0 \5 C* ]2 E( q. |
lesions in boys.1,2 Virilization in boys, as manifested+ X2 ^% l7 E5 V  x% ^, ]
by enlargement of the penis, development of pubic
' W. W) n8 t5 E5 u, V* a; X) bhair, and facial acne without enlargement of testi-
3 y; O+ }& N$ G7 Fcles, suggests peripheral or pseudopuberty.1-3 We" k8 o2 v" d- [- D" ?; S
report a 16-month-old boy who presented with the' m3 L  C* o# U* g
enlargement of the phallus and pubic hair develop-
' ^: t) @+ Z& I4 p; Q9 wment without testicular enlargement, which was due
& ?3 p; F3 y* sto the unintentional exposure to androgen gel used by
9 x+ n6 r- J1 H& H% sthe father. The family initially concealed this infor-
( j/ L3 G* k  R0 V  qmation, resulting in an extensive work-up for this
$ |7 ]: e$ H6 j* e# V- j% gchild. Given the widespread and easy availability of
! [8 x5 S2 c8 P: y( }/ ?testosterone gel and cream, we believe this is proba-9 `, t1 P4 y' x* ~3 M% ~/ K# V
bly more common than the rare case report in the. ]! x3 G% ]& H, @/ t
literature.4* R" N( ~. y0 y4 n5 u7 x
Patient Report- t* t% y0 r" K$ t
A 16-month-old white child was referred to the
. N, @$ B3 x5 I; Q) `; Rendocrine clinic by his pediatrician with the concern
7 L* y: M  Q& @" w8 R! `3 Yof early sexual development. His mother noticed
+ v, e+ s* b. z& A. C  u9 m" alight colored pubic hair development when he was- ~. z) i2 D* l( J
From the 1Division of Pediatric Endocrinology, 2University of
' a$ u) k5 D+ q! u4 L( ^South Alabama Medical Center, Mobile, Alabama.% d+ ~( _& g+ y6 i2 Y$ w; M2 {
Address correspondence to: Samar K. Bhowmick, MD, FACE,, ^9 F% @% V  w- W+ Z  V. B0 k
Professor of Pediatrics, University of South Alabama, College of
% h* T* }( J9 x# ~$ L) O& t. t2 s4 FMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;! M: s' e' q" J& A
e-mail: [email protected].
* D% C- q* _1 [about 6 to 7 months old, which progressively became: E) p* ]. e! U6 R! P3 B7 c
darker. She was also concerned about the enlarge-
; V8 W* p1 L$ H& b" Ament of his penis and frequent erections. The child( h' P' H2 q- ?6 B, @. H; C
was the product of a full-term normal delivery, with  t% l( v% D% f: ]
a birth weight of 7 lb 14 oz, and birth length of
- h9 {- ]9 k( c3 g20 inches. He was breast-fed throughout the first year
8 h+ ]0 C& G) A& g+ T* P: V+ ]2 Vof life and was still receiving breast milk along with
7 Y& r1 |8 C8 Q7 f4 c8 csolid food. He had no hospitalizations or surgery,
5 r5 e0 V0 b% T: j* }9 \' f5 Qand his psychosocial and psychomotor development8 u# c$ j, g' L' l( B
was age appropriate.0 ^& v$ o$ i1 c8 D* N
The family history was remarkable for the father,
% e% N: n: |0 \9 q0 w, i& nwho was diagnosed with hypothyroidism at age 16,, Z, ]" v( s5 @- x
which was treated with thyroxine. The father’s) P( T$ t* W) u9 d: z
height was 6 feet, and he went through a somewhat! |9 B4 u5 s4 I6 }; d% c3 G
early puberty and had stopped growing by age 14.
! Z6 x; X" k& P* i4 oThe father denied taking any other medication. The
+ x0 v1 K$ \, O4 Zchild’s mother was in good health. Her menarche
& T  F, j7 y8 z) Wwas at 11 years of age, and her height was at 5 feet4 i3 |, t% }4 O! r
5 inches. There was no other family history of pre-* i, c1 x+ [  {9 E. E* ]7 i9 n
cocious sexual development in the first-degree rela-
2 u& [' D+ b* ]- P0 wtives. There were no siblings.
0 T0 Q# W7 W' O- a; y: NPhysical Examination, v( t& K6 @9 N1 x
The physical examination revealed a very active,
( d* Z7 x2 M# S, \3 n: V7 wplayful, and healthy boy. The vital signs documented
& A6 G  X  Q/ x! N# M* ha blood pressure of 85/50 mm Hg, his length was# L* [0 }$ r. U' W3 _7 v! h2 w
90 cm (>97th percentile), and his weight was 14.4 kg
0 A# N$ q% b- r) R3 K(also >97th percentile). The observed yearly growth; |: I$ C3 k  s' ?
velocity was 30 cm (12 inches). The examination of: W$ j8 n% _# ^8 ~# L1 ~% G1 N/ N
the neck revealed no thyroid enlargement.; C( y& j& R* e' _! t8 Q% v
The genitourinary examination was remarkable for; _; _# J7 {. o3 W7 x
enlargement of the penis, with a stretched length of3 L& {) O3 Z3 A6 q% p
8 cm and a width of 2 cm. The glans penis was very well
: f# s$ X  R, V; rdeveloped. The pubic hair was Tanner II, mostly around, u; t6 C) V0 U$ F7 C
540" f2 @' {! G( X; Q
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
' t  X- J5 Y7 v5 {& ythe base of the phallus and was dark and curled. The
# f8 ~1 M+ y- A3 [& r7 Xtesticular volume was prepubertal at 2 mL each.
$ j/ ]" x/ L, r' |9 L" K; ~The skin was moist and smooth and somewhat9 G% [; A" L. i' r; [& q+ O0 ^
oily. No axillary hair was noted. There were no1 |, j2 e; Z8 v- P+ [9 R* s
abnormal skin pigmentations or café-au-lait spots.
8 `# Q8 K6 ]4 l; x* E9 [' NNeurologic evaluation showed deep tendon reflex 2+
% a; Z) M4 A2 H7 I- s% xbilateral and symmetrical. There was no suggestion
7 w: Q% L0 z( w" |& [4 t' o4 Qof papilledema.
- c( X( u9 _9 Q* g# VLaboratory Evaluation1 y/ S0 ^: ]# h
The bone age was consistent with 28 months by
) N. X% T% W4 z1 ]- W2 t4 Fusing the standard of Greulich and Pyle at a chrono-9 H1 Z2 j# K* e' n7 _' F
logic age of 16 months (advanced).5 Chromosomal+ g. E  d2 I( z6 w7 Q
karyotype was 46XY. The thyroid function test: T/ w- |+ Z$ e' l6 m- D1 y
showed a free T4 of 1.69 ng/dL, and thyroid stimu-
7 K! C( ~& o+ @/ j6 x- Y2 R) Zlating hormone level was 1.3 µIU/mL (both normal).
: U) p/ e% e- i; U. j6 @The concentrations of serum electrolytes, blood
5 K* d7 r% B, J# G' Zurea nitrogen, creatinine, and calcium all were
" _/ j3 n; k" M. ?; Kwithin normal range for his age. The concentration% H' G% r/ j9 ^8 s. f0 z) E! X; c7 {
of serum 17-hydroxyprogesterone was 16 ng/dL: C/ c1 }1 G- \7 G
(normal, 3 to 90 ng/dL), androstenedione was 20# k( v5 a! N4 {6 V
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
  n; m; D1 T$ Gterone was 38 ng/dL (normal, 50 to 760 ng/dL),
0 q. n9 d3 t3 e# q" b' sdesoxycorticosterone was 4.3 ng/dL (normal, 7 to
& v/ e5 [+ O0 U: K6 S' p49ng/dL), 11-desoxycortisol (specific compound S)
! {' W# u$ Q; L+ C0 Bwas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
! y5 B6 v: v" otisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
  A, x$ z. S2 Z: stestosterone was 60 ng/dL (normal <3 to 10 ng/dL),
4 J0 m2 _0 \/ H( uand β-human chorionic gonadotropin was less than. g7 m5 g- D- t6 c
5 mIU/mL (normal <5 mIU/mL). Serum follicular3 D1 W0 s$ D  [8 |
stimulating hormone and leuteinizing hormone  M) J3 p' N3 l  \5 f2 {# Z( c
concentrations were less than 0.05 mIU/mL
: M# _4 q/ K3 L7 j! g# U3 \(prepubertal).2 Q! W3 m6 B7 j) ~
The parents were notified about the laboratory; u7 h2 `7 I: P( W/ c
results and were informed that all of the tests were" f" P5 W. o+ t$ h7 l: w
normal except the testosterone level was high. The
. ^7 R/ N! [; Wfollow-up visit was arranged within a few weeks to! m& u' n9 y! B  `& Y3 |/ H
obtain testicular and abdominal sonograms; how-$ w9 J& V8 T) L
ever, the family did not return for 4 months.% L0 d7 O- A2 p1 ~9 J% V* w. K
Physical examination at this time revealed that the
) I7 a9 p9 m- F: K' ?% v5 J( Echild had grown 2.5 cm in 4 months and had gained
+ V2 _& \6 Q* O, \/ A2 kg of weight. Physical examination remained
: e- G8 j" C" ^6 H+ m# ?unchanged. Surprisingly, the pubic hair almost com-: K2 e+ a8 y, x6 F7 x
pletely disappeared except for a few vellous hairs at
5 p. W' r" H8 G( zthe base of the phallus. Testicular volume was still 2
$ v2 p# ~3 Y4 m/ D- Z7 hmL, and the size of the penis remained unchanged.
. b: t- O8 i. \" q4 |The mother also said that the boy was no longer hav-8 [, d) L; e$ r3 P; \
ing frequent erections.8 y( P, m0 ^' p- N1 q% @
Both parents were again questioned about use of
+ C) Q# A+ P( C; T1 M8 W$ Zany ointment/creams that they may have applied to
6 h6 h5 l; K* u4 {& }# athe child’s skin. This time the father admitted the
3 u/ R6 W: v+ ~3 j# a* iTopical Testosterone Exposure / Bhowmick et al 541
9 e6 A/ j/ |) |* [use of testosterone gel twice daily that he was apply-
$ S; t3 n* q- King over his own shoulders, chest, and back area for
; U: u$ r) f7 l, {2 B/ K& pa year. The father also revealed he was embarrassed
8 w( l1 g: Z# @: Gto disclose that he was using a testosterone gel pre-# _6 d: p5 d+ |% d3 }( T2 A1 O
scribed by his family physician for decreased libido
1 f' `1 F7 M( F' gsecondary to depression.- l7 t% D& K+ q+ O8 H
The child slept in the same bed with parents.8 s- e6 p0 @& X7 ?$ P
The father would hug the baby and hold him on his* Y0 u1 e5 D& v- [5 O" b; C
chest for a considerable period of time, causing sig-
" [9 B1 O" O) B, bnificant bare skin contact between baby and father.1 H  [  K3 G1 D
The father also admitted that after the phone call,2 c( J9 q# S2 R  u+ k% G4 D
when he learned the testosterone level in the baby
6 {  b& L$ E( `8 fwas high, he then read the product information& d; E# r# Y1 X1 x; A  W# F
packet and concluded that it was most likely the rea-- ?9 a) c+ E+ J  @+ F
son for the child’s virilization. At that time, they
; `- V& _' |& b% fdecided to put the baby in a separate bed, and the
/ i# u4 i! f2 p3 _; _father was not hugging him with bare skin and had7 C) @& \8 |/ p9 ^* K; I0 }
been using protective clothing. A repeat testosterone+ ^4 N8 p( Y) ?& l9 {
test was ordered, but the family did not go to the8 {5 k0 G3 I7 _7 B0 @
laboratory to obtain the test.3 i* \: Z+ ]8 h- f- V% T8 V* M' Q
Discussion
- h- g; G9 K% m. H* _% }1 |Precocious puberty in boys is defined as secondary. V/ z6 a* k, p8 \; M
sexual development before 9 years of age.1,4, P7 |# v) R( M  A6 W, q
Precocious puberty is termed as central (true) when
/ f6 h# C" c5 C- o3 V5 T5 zit is caused by the premature activation of hypo-
* n3 p+ E! \0 h! L" @0 o& _4 ythalamic pituitary gonadal axis. CPP is more com-( C. W, T  n9 P1 I0 H7 q
mon in girls than in boys.1,3 Most boys with CPP
6 W" @# R) U. n$ Emay have a central nervous system lesion that is
/ B* t# }( o; F/ q/ k  z3 iresponsible for the early activation of the hypothal-
. o" f. P0 n' {amic pituitary gonadal axis.1-3 Thus, greater empha-
9 n8 {8 n. h. K! ~4 ~; F( Rsis has been given to neuroradiologic imaging in
; m9 r( y- y$ zboys with precocious puberty. In addition to viril-
- W, V0 d/ P! kization, the clinical hallmark of CPP is the symmet-% L: f3 |. C: J
rical testicular growth secondary to stimulation by$ w( S! D; c3 ^
gonadotropins.1,3
& y7 A$ s+ ]8 O. q& KGonadotropin-independent peripheral preco-2 K$ G2 E2 i4 e- [: V
cious puberty in boys also results from inappropriate, I7 u5 K% e& _/ O, R. q5 E
androgenic stimulation from either endogenous or8 ]' V* N1 P; q0 z; t+ C1 ~
exogenous sources, nonpituitary gonadotropin stim-7 P" W' K* u; _1 Z$ n6 Y
ulation, and rare activating mutations.3 Virilizing% w% [+ f- r* f+ U1 e
congenital adrenal hyperplasia producing excessive! ?+ d* ~0 @1 f# `" q
adrenal androgens is a common cause of precocious
( r' h4 c% N0 P  g- Y8 a& [puberty in boys.3,47 M2 B% ^& F0 _" ]) n5 l
The most common form of congenital adrenal
0 H' K9 [& N7 Z( K! Jhyperplasia is the 21-hydroxylase enzyme deficiency.
+ P. v' R6 O( C+ E' v" xThe 11-β hydroxylase deficiency may also result in7 }4 I' l: v5 S: T6 g8 |
excessive adrenal androgen production, and rarely,2 y8 H+ H! I$ B( C  a
an adrenal tumor may also cause adrenal androgen
* @& B4 ~& s" f% r! J, cexcess.1,3
! z* ^, G6 c1 H7 Z/ i8 zat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from* g1 F* l' @' e! ~, E
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
' `/ c0 ?' n$ l8 x  xA unique entity of male-limited gonadotropin-
6 D, f' }5 q0 B/ [0 E. Rindependent precocious puberty, which is also known
( O9 z/ f9 b' X. cas testotoxicosis, may cause precocious puberty at a
. x2 y: f9 q2 B2 K9 A( V. ^  uvery young age. The physical findings in these boys3 e9 |  T7 {# q' F, [5 C
with this disorder are full pubertal development,
. l: X0 |$ r0 m1 nincluding bilateral testicular growth, similar to boys
& \! B; Y. ~: Bwith CPP. The gonadotropin levels in this disorder
' I4 V9 a8 K! E6 {, e' ]7 Gare suppressed to prepubertal levels and do not show
" J. l7 S. Z8 v- u$ kpubertal response of gonadotropin after gonadotropin-
2 @. }3 ]4 ~3 B$ j$ m( \- xreleasing hormone stimulation. This is a sex-linked
( |7 I8 s% j- Uautosomal dominant disorder that affects only
5 n. d  ~7 v0 R% ?/ t! c( G' o/ Lmales; therefore, other male members of the family$ W+ O' l* h( D( z) t: O% Q
may have similar precocious puberty.3
/ p8 ^& X  o8 o2 r" t" AIn our patient, physical examination was incon-7 ]8 p9 [# ^' e) _  `
sistent with true precocious puberty since his testi-+ ?6 h9 K( |- Q- K- w' ^3 X3 x
cles were prepubertal in size. However, testotoxicosis, h2 K8 S3 O: q5 \9 t
was in the differential diagnosis because his father  l; u8 _+ S( ^7 A4 z& W  ]9 s8 R0 d2 Q
started puberty somewhat early, and occasionally,
" L# ^) @  F/ m, P3 [6 ]testicular enlargement is not that evident in the
5 z9 H/ x9 U7 ?+ ?2 q5 f7 sbeginning of this process.1 In the absence of a neg-
9 |  K5 v5 ^( N( Kative initial history of androgen exposure, our4 A" |8 l& i3 ^  {- X5 r$ n
biggest concern was virilizing adrenal hyperplasia,
# H6 L. k: G( T" [4 u/ U6 qeither 21-hydroxylase deficiency or 11-β hydroxylase
1 c% D  V' e% v; X2 R% adeficiency. Those diagnoses were excluded by find-+ i9 g* [4 t! j
ing the normal level of adrenal steroids.
/ H6 f) C& _- _% r& W9 P# y$ [The diagnosis of exogenous androgens was strongly3 _& P5 t- t( l2 G6 u6 c  o3 `7 j! ]
suspected in a follow-up visit after 4 months because
7 _) v5 c4 a! y  c7 N; Kthe physical examination revealed the complete disap-6 O, M, }  `+ B+ Q1 j* ?
pearance of pubic hair, normal growth velocity, and  k- n5 `8 }- @  C% [4 `3 g  J
decreased erections. The father admitted using a testos-. t, F1 o2 x, U4 q2 F- Q$ k! U- A
terone gel, which he concealed at first visit. He was
: `, X- |- A1 Q8 E7 J) t% Rusing it rather frequently, twice a day. The Physicians’
8 K3 S/ d- A$ B0 |Desk Reference, or package insert of this product, gel or& q# [4 E9 J1 T4 ?/ N+ [
cream, cautions about dermal testosterone transfer to
1 Z3 t) q0 ~' d( eunprotected females through direct skin exposure.8 @# d" o" U  Z* J2 X1 T
Serum testosterone level was found to be 2 times the( t; W, Y; l7 _  k- w! e
baseline value in those females who were exposed to' K4 Y, d! L- {  T
even 15 minutes of direct skin contact with their male+ J* \% @! I8 h8 W9 F
partners.6 However, when a shirt covered the applica-
/ e5 y2 H& a6 o. \/ ution site, this testosterone transfer was prevented.( G5 }8 T% C! ~2 Q& l
Our patient’s testosterone level was 60 ng/mL,
: Z) J9 I$ ^. b  n  c6 }$ }/ Bwhich was clearly high. Some studies suggest that" I# p) U$ N4 \5 b* x
dermal conversion of testosterone to dihydrotestos-$ U& N2 c0 Y2 S7 P. H
terone, which is a more potent metabolite, is more
2 `5 I) S! p7 E, r- ^7 Wactive in young children exposed to testosterone+ V4 X& C; M( i
exogenously7; however, we did not measure a dihy-
; h! U6 o3 l  U. p( cdrotestosterone level in our patient. In addition to
1 B' [* V- E7 ?& ], `9 Xvirilization, exposure to exogenous testosterone in
% ]! H4 s! B: L/ A7 I$ X4 Echildren results in an increase in growth velocity and4 D' I9 O$ Q1 C4 D
advanced bone age, as seen in our patient.
0 z) f: Z! u, H3 LThe long-term effect of androgen exposure during/ ?3 ~3 |1 x; C6 e
early childhood on pubertal development and final
5 `# c* k6 o6 o" q  h2 c( I/ O4 \adult height are not fully known and always remain5 `: r! N0 F; V, Y
a concern. Children treated with short-term testos-
# a0 R! k7 P6 ^" C) Y+ vterone injection or topical androgen may exhibit some6 g* q4 j/ g; C8 z- d$ g
acceleration of the skeletal maturation; however, after# e$ ], m. W4 K/ v) O7 C: c
cessation of treatment, the rate of bone maturation8 j9 ]* q6 |& {0 d% Q3 E
decelerates and gradually returns to normal.8,90 a0 a" n# n2 d3 }! q
There are conflicting reports and controversy7 \# Z1 S+ ]- i
over the effect of early androgen exposure on adult3 {! P( y" ^' ?6 l1 c& A
penile length.10,11 Some reports suggest subnormal
) j( Z* W. t) J" J& Kadult penile length, apparently because of downreg-
8 r( V- N- h( y+ J5 _5 f+ Bulation of androgen receptor number.10,12 However,
& @3 F3 n7 ^; E" @Sutherland et al13 did not find a correlation between7 e+ U1 i( d: N4 S% j4 ^3 u2 ?  D, z
childhood testosterone exposure and reduced adult0 C  j$ D) r! A2 e; z
penile length in clinical studies.
# [" ^# w: e6 |! Y# B+ o7 MNonetheless, we do not believe our patient is
) K' E) J0 y: E6 }going to experience any of the untoward effects from9 _. l% a3 A0 g8 E
testosterone exposure as mentioned earlier because
* x; A9 t$ X% B) r& Nthe exposure was not for a prolonged period of time.
1 b- U* z1 a- dAlthough the bone age was advanced at the time of5 M: _- }$ j8 T# W
diagnosis, the child had a normal growth velocity at! J5 Q& t4 @- j7 n
the follow-up visit. It is hoped that his final adult
3 R0 T( ]: j; W& C8 Z* S9 Iheight will not be affected.
& w2 p- _$ |0 C; z) U8 [3 {Although rarely reported, the widespread avail-
7 M0 w% D9 z9 |7 X) ~% o0 Fability of androgen products in our society may( P" c/ H  m7 o# a: W9 u
indeed cause more virilization in male or female
1 H. ^- w9 p, Z6 \% Y) \9 lchildren than one would realize. Exposure to andro-6 u# R* W  b5 W. d
gen products must be considered and specific ques-8 _3 ~& Y; ?- |0 |
tioning about the use of a testosterone product or! ?- u; O/ \1 F' L7 e3 S! k8 h
gel should be asked of the family members during
$ T& s2 z& b0 S  b1 p" z8 tthe evaluation of any children who present with vir-& T) m7 s4 z2 L8 V' c
ilization or peripheral precocious puberty. The diag-# q* B) R! ?! p/ h) V
nosis can be established by just a few tests and by
* x5 H) n# ~$ pappropriate history. The inability to obtain such a9 i) \( l+ m- ^, b
history, or failure to ask the specific questions, may- M; ?- d) n8 I. O- J( n& j  q
result in extensive, unnecessary, and expensive6 d. s/ b( W+ n/ P% M9 ?
investigation. The primary care physician should be/ h/ A7 S3 V- h- o
aware of this fact, because most of these children
+ @8 s8 F3 Z. w; kmay initially present in their practice. The Physicians’0 T& e- G: r, ?+ q, C* [. L
Desk Reference and package insert should also put a( U+ z6 h0 c4 q+ T) y, T" P, y7 [7 x
warning about the virilizing effect on a male or
4 t3 M2 V7 ~- E) Nfemale child who might come in contact with some-
* t; B+ ?, {' h0 O7 yone using any of these products.
& L" G# D- }1 s4 Z8 w8 NReferences
$ C9 o7 k) u( K, r+ b% p0 i1. Styne DM. The testes: disorder of sexual differentiation
4 ]+ s/ o3 k, T$ A! q/ M1 V( [and puberty in the male. In: Sperling MA, ed. Pediatric! q" J3 E) r; T1 t$ M5 v$ Z0 [. n
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
. Z% n3 s3 T( R* Q- [; ]) V9 {5 r2002: 565-628.
/ M7 w6 [' m4 ~+ }; v2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
5 `; A5 v! K% Z4 x  a# j6 fpuberty 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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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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