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Sexual Precocity in a 16-Month-Old7 J2 F/ t! |) r1 G; d
Boy Induced by Indirect Topical# v+ c, p8 V! }( y6 m; w$ c! O
Exposure to Testosterone
! ^3 j8 @7 @, C1 D/ KSamar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
% @& Z9 F+ c. B5 i" aand Kenneth R. Rettig, MD1
) g( }# q7 b: V+ D' G2 v& NClinical Pediatrics# l) B' n, I4 N. x% B  B
Volume 46 Number 6- ~4 G1 I# `  V6 q4 k
July 2007 540-5431 n' \: r% R! e/ r8 o3 x, H' a* m
© 2007 Sage Publications
. Y# j9 x# y1 v10.1177/0009922806296651
+ x: _8 H" t' t, ehttp://clp.sagepub.com
! b9 x. _/ E+ H! Mhosted at4 }( t# {# U+ d
http://online.sagepub.com
  i/ w- ^# I1 U: R; u) r' M$ ePrecocious puberty in boys, central or peripheral,' n2 A3 I' [: `- Y- l( I  j) K0 J
is a significant concern for physicians. Central
7 y  g- C7 q" Fprecocious puberty (CPP), which is mediated
1 J% B1 f" P+ x4 {5 [6 Uthrough the hypothalamic pituitary gonadal axis, has3 Q  }# Q2 w" L8 q. w
a higher incidence of organic central nervous system
) m# o/ Y+ o) ~6 J7 `3 o7 ^$ O# Vlesions in boys.1,2 Virilization in boys, as manifested4 {) F! ^' j; t9 F+ \
by enlargement of the penis, development of pubic
4 k0 _% T$ E# u/ _hair, and facial acne without enlargement of testi-
7 |. \$ O  |1 ~/ @cles, suggests peripheral or pseudopuberty.1-3 We3 u4 N, s: |- H4 X" x
report a 16-month-old boy who presented with the
: `& W* U1 d- k  Genlargement of the phallus and pubic hair develop-( ^6 _: L3 j6 a( I9 P7 T: N
ment without testicular enlargement, which was due
- {. B4 D" }( T, b$ b+ oto the unintentional exposure to androgen gel used by
; X. c3 Q2 o$ ?, R9 C9 s3 Rthe father. The family initially concealed this infor-
" W! F$ t+ l, M- n( Nmation, resulting in an extensive work-up for this
) c. I% R2 D2 o+ v3 ^1 Xchild. Given the widespread and easy availability of
+ w4 Z$ }# a5 I1 v5 a: etestosterone gel and cream, we believe this is proba-
  i" c$ k( Y' ]" t9 B) `bly more common than the rare case report in the. }2 f% p8 v; m) G0 `- y# B
literature.4
% |, K6 X2 w7 m% _* [# QPatient Report
4 b  C; F- S# B* sA 16-month-old white child was referred to the
2 A9 ]! D! q0 Mendocrine clinic by his pediatrician with the concern
- X) I- d- g' ]0 c- gof early sexual development. His mother noticed6 Q  v/ J" E5 S* a/ K, V5 Y
light colored pubic hair development when he was
7 |) Q+ S; d  e" [/ S3 \7 zFrom the 1Division of Pediatric Endocrinology, 2University of: W8 {4 o: E2 W/ e0 |; T
South Alabama Medical Center, Mobile, Alabama.
: _" T- X# v) j, |. j$ MAddress correspondence to: Samar K. Bhowmick, MD, FACE,
4 p" e9 F/ u4 O  L1 f/ Q, y2 Y: _3 wProfessor of Pediatrics, University of South Alabama, College of
9 |4 l! f$ ?4 o' H( D9 Z  ?5 W& ]Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
, W" W) a% T6 x/ b1 He-mail: [email protected].8 e) Q; M  Z$ a8 [+ m, @6 \! A% T
about 6 to 7 months old, which progressively became
2 P/ ^6 E3 z) [7 \darker. She was also concerned about the enlarge-2 y2 N; H3 G8 w3 [
ment of his penis and frequent erections. The child
. Z$ |  I& F) R  I' rwas the product of a full-term normal delivery, with. h% {( l$ B# I
a birth weight of 7 lb 14 oz, and birth length of
7 i7 Q( r. J! j& i3 l* P20 inches. He was breast-fed throughout the first year2 r" X5 }5 I3 S! K, U
of life and was still receiving breast milk along with
- f( E1 L& [2 q  Lsolid food. He had no hospitalizations or surgery,, r+ |8 a- H: n
and his psychosocial and psychomotor development
# x2 W! D+ s8 |was age appropriate.
$ `7 \- Y/ S. C3 D# cThe family history was remarkable for the father,
! Z6 _8 m: w' }' o4 n2 o' Mwho was diagnosed with hypothyroidism at age 16,
2 y; ~% F+ ^5 `7 r% r. jwhich was treated with thyroxine. The father’s
- B3 u% \) m$ r4 {& @height was 6 feet, and he went through a somewhat2 B- D  d/ N1 M0 C# {$ d& }+ c
early puberty and had stopped growing by age 14.4 N/ c( w. |0 s
The father denied taking any other medication. The
0 J, Y& x; H) w9 S& V( }4 O% ~child’s mother was in good health. Her menarche
2 i. K7 e  _' ?, l! q5 k0 qwas at 11 years of age, and her height was at 5 feet2 l+ B& W# F* ]6 N
5 inches. There was no other family history of pre-2 D; i6 v6 U* e& t+ R
cocious sexual development in the first-degree rela-* C* B6 z" }9 C% O# A
tives. There were no siblings.
; |% }* j; E/ C: d  a5 D! SPhysical Examination" p# \  Y0 Z$ ^5 [7 j1 M" ?. |* B
The physical examination revealed a very active,
+ I/ m/ R0 H; }7 a8 q, A' g  H- V1 j8 Lplayful, and healthy boy. The vital signs documented
6 h) c" l, L' da blood pressure of 85/50 mm Hg, his length was
2 p/ G% V, V/ h. \7 i90 cm (>97th percentile), and his weight was 14.4 kg
7 Z0 N. `* W$ o$ k9 e1 e(also >97th percentile). The observed yearly growth
8 b! g  H( _5 Vvelocity was 30 cm (12 inches). The examination of" t6 ~8 i& ^% r( r$ K
the neck revealed no thyroid enlargement.# ]$ F' P* t4 u( B8 _
The genitourinary examination was remarkable for7 l+ \( J* z0 m4 H9 ^4 g! W
enlargement of the penis, with a stretched length of' h* ?; _3 R3 X9 O, f  w* H
8 cm and a width of 2 cm. The glans penis was very well
/ _0 V+ g" Q3 `' X* Gdeveloped. The pubic hair was Tanner II, mostly around
% F# O: _  Y9 W3 ]6 d; a  m540) n4 j# k/ ~  D4 D0 U5 W
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
" [( S; A+ N) D& othe base of the phallus and was dark and curled. The
/ R8 ^1 k' ~: ]( a, C9 jtesticular volume was prepubertal at 2 mL each.' y: B- k: _% g9 T8 V8 J
The skin was moist and smooth and somewhat5 d, D8 J- ]5 b1 _$ u: D
oily. No axillary hair was noted. There were no
. n' T* V$ C4 u3 h) D! v' V) xabnormal skin pigmentations or café-au-lait spots.' w3 m( `( S2 {" X* M7 e
Neurologic evaluation showed deep tendon reflex 2+& d" n3 O3 s- n- N5 {
bilateral and symmetrical. There was no suggestion& L, O+ K; {$ T* l
of papilledema.
' z- Y  C/ G4 GLaboratory Evaluation# r6 e# N" }8 ?3 F) T8 V& F  f, l* Y
The bone age was consistent with 28 months by8 F& M5 n# q3 K+ g5 S5 \) }
using the standard of Greulich and Pyle at a chrono-$ a) {. C+ `1 W
logic age of 16 months (advanced).5 Chromosomal
! U  f1 u. N! _! R* K: R5 {2 kkaryotype was 46XY. The thyroid function test. p* O: R: o4 Q4 i5 V
showed a free T4 of 1.69 ng/dL, and thyroid stimu-+ p  G# o- u& ~
lating hormone level was 1.3 µIU/mL (both normal).
3 h! J7 h- S/ CThe concentrations of serum electrolytes, blood* u2 P" t, L; L+ Q2 r. P+ l  G+ f
urea nitrogen, creatinine, and calcium all were
2 V0 x- }) @7 b/ O& qwithin normal range for his age. The concentration  j# O3 t. c$ l4 p) d! |- V, i
of serum 17-hydroxyprogesterone was 16 ng/dL4 o" e( B8 v  N+ @4 `
(normal, 3 to 90 ng/dL), androstenedione was 20
. h0 o9 ?8 U9 |  lng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
: }2 [8 e& s" qterone was 38 ng/dL (normal, 50 to 760 ng/dL),
+ \# ?; R, s- Wdesoxycorticosterone was 4.3 ng/dL (normal, 7 to3 b& s9 i/ q$ }% ?, p1 A" ]
49ng/dL), 11-desoxycortisol (specific compound S)
9 H( E" \6 N0 C6 S: qwas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-$ M9 u9 j/ g9 y+ @: s& Z& P
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
* T. b+ a! U# N7 i6 Ytestosterone was 60 ng/dL (normal <3 to 10 ng/dL),& [9 y! K& T. R+ ]
and β-human chorionic gonadotropin was less than: B. A0 @/ {5 J9 X; `, h8 z
5 mIU/mL (normal <5 mIU/mL). Serum follicular
9 Z# ]5 U* |& N5 }9 `. Jstimulating hormone and leuteinizing hormone2 |- ]% }; c8 w" m$ V5 P. E
concentrations were less than 0.05 mIU/mL
7 Y* u$ j' S1 t0 |* }) `, L(prepubertal).
6 G( n4 p0 N  _% ~9 _The parents were notified about the laboratory6 f6 ?. q. ]4 D. S& A) r7 w- U  u
results and were informed that all of the tests were
3 E. J( @  L5 Hnormal except the testosterone level was high. The: ^  k! o# v$ H" R/ |+ g3 v
follow-up visit was arranged within a few weeks to* D% Z: C- c2 n; c- A, \
obtain testicular and abdominal sonograms; how-
2 J* y* M, J6 @# q1 h* d4 Aever, the family did not return for 4 months.
& i( Z/ d% ~3 J7 T  ^9 @  `Physical examination at this time revealed that the
; V$ \; s1 v0 E- v, nchild had grown 2.5 cm in 4 months and had gained/ N" e6 v5 Q7 y& z, S
2 kg of weight. Physical examination remained, d3 u3 M: H( e
unchanged. Surprisingly, the pubic hair almost com-
2 U% Q; l$ j3 k2 z# N2 z, Dpletely disappeared except for a few vellous hairs at4 R. \, u, |& _3 B
the base of the phallus. Testicular volume was still 2
" q- J( o8 U5 Q" K8 P+ fmL, and the size of the penis remained unchanged.
# d5 \1 G7 X7 P; x; q  qThe mother also said that the boy was no longer hav-8 D- M- \7 |4 R: V( m" w2 K* D
ing frequent erections./ B5 n2 O- p( T) r% k
Both parents were again questioned about use of0 u; T' y. o# c
any ointment/creams that they may have applied to2 _+ w6 m( [; m4 u
the child’s skin. This time the father admitted the& j0 |# Y+ i" m7 D( Q1 j+ n
Topical Testosterone Exposure / Bhowmick et al 541
7 u- s# [4 _  {. V' \/ J  tuse of testosterone gel twice daily that he was apply-% ^9 `. _+ Z8 g( T# t; s. f3 o; }& h
ing over his own shoulders, chest, and back area for$ P* O5 h* }" S
a year. The father also revealed he was embarrassed
8 f. X5 I4 \2 E. Y+ H1 Bto disclose that he was using a testosterone gel pre-
$ q/ U& ~/ F& `scribed by his family physician for decreased libido
+ j: o6 J2 i4 w8 X; v5 Dsecondary to depression.6 u7 G) S& c( O
The child slept in the same bed with parents.
; u* l# ]/ p, g" L  ^The father would hug the baby and hold him on his
( t+ ]9 ?' P6 Y$ n# ~" Dchest for a considerable period of time, causing sig-  S9 R$ T' Q1 A% h8 I' ]  Y* j
nificant bare skin contact between baby and father.* Q2 ?) o6 ]. ]% c0 o% F; s
The father also admitted that after the phone call,
& O8 L& k1 @8 `: Rwhen he learned the testosterone level in the baby/ x5 z- x; ~, s1 B! p) L0 P# @
was high, he then read the product information
2 m; i. t2 f: L# G4 s6 ^! Vpacket and concluded that it was most likely the rea-
* A: V1 S* Z0 W* a' Q6 F- E7 Uson for the child’s virilization. At that time, they
* O, n$ l6 ]: T4 W+ Bdecided to put the baby in a separate bed, and the
. C6 x* y* s) q5 x4 ?. `3 v5 s8 j3 _$ |father was not hugging him with bare skin and had7 B* D% N" }( G
been using protective clothing. A repeat testosterone
% ^) Y5 |: `0 K! Vtest was ordered, but the family did not go to the/ K8 f/ [/ r( I
laboratory to obtain the test.
, L+ d+ U0 N( \! B3 ~, ^; }& hDiscussion
8 e2 K. e# ~* pPrecocious puberty in boys is defined as secondary
/ N6 o' L3 w9 S1 q0 \- Q* D: s1 Xsexual development before 9 years of age.1,4
( L$ A, Q" X: @2 n* }' @, j$ aPrecocious puberty is termed as central (true) when
/ f. g# }9 V! y5 _/ t2 y" l7 T* Kit is caused by the premature activation of hypo-
/ s" i" H  x; w* u7 o* `% rthalamic pituitary gonadal axis. CPP is more com-
" @" X1 {7 x" q; |mon in girls than in boys.1,3 Most boys with CPP
  L7 C) \* k) s4 q' |7 Cmay have a central nervous system lesion that is7 T3 S0 s& ]$ F: u5 K. m. G
responsible for the early activation of the hypothal-
; T1 ~  S. M' E) g$ Lamic pituitary gonadal axis.1-3 Thus, greater empha-+ c$ U1 w8 f% Z
sis has been given to neuroradiologic imaging in  U. W6 ~3 K4 T, B
boys with precocious puberty. In addition to viril-$ R3 G$ p- V) t2 H
ization, the clinical hallmark of CPP is the symmet-7 k$ H  t8 Q: f
rical testicular growth secondary to stimulation by% |5 x* a( t$ y
gonadotropins.1,3* g( c: P: A" U7 }8 r6 W
Gonadotropin-independent peripheral preco-
( u+ U3 f, ^% s4 ], k  H. Jcious puberty in boys also results from inappropriate
& C( S6 ]# B- \7 A$ u3 }" landrogenic stimulation from either endogenous or
( B6 j* l' n" N+ Q5 E; Kexogenous sources, nonpituitary gonadotropin stim-, C; V0 m4 X9 C+ t. |* I, Q! G
ulation, and rare activating mutations.3 Virilizing
3 Q5 q2 B' H* ^: t- Y- p8 ~congenital adrenal hyperplasia producing excessive
1 V; `+ ?% t" f- k0 Y$ eadrenal androgens is a common cause of precocious4 g! F& u7 D, U3 S, C
puberty in boys.3,4
0 F7 m9 k% s, x8 R, NThe most common form of congenital adrenal1 g! `' H4 i7 Z. v
hyperplasia is the 21-hydroxylase enzyme deficiency.' R! F8 _9 S  P- W: j- m
The 11-β hydroxylase deficiency may also result in: n& x( o0 t5 t5 r( g
excessive adrenal androgen production, and rarely,% J3 t/ M6 [" E) o
an adrenal tumor may also cause adrenal androgen" d8 A6 _' S, Y, o- x
excess.1,3. ~4 W6 J( V+ D: A' A
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from$ U, T7 e  s. y; c: o. x8 c
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007# e1 r/ s7 N! Y, M
A unique entity of male-limited gonadotropin-  j& F6 g  K: W( r& y! |
independent precocious puberty, which is also known& D) ~4 h4 U+ |2 N
as testotoxicosis, may cause precocious puberty at a' ^! \' @4 j  i. K7 s2 s0 P
very young age. The physical findings in these boys
$ h4 b! ~: T( h9 c5 [$ Swith this disorder are full pubertal development,
. i3 [- l1 r& S# W  wincluding bilateral testicular growth, similar to boys
1 p% m0 \5 a4 j3 q1 F2 k6 e$ Z' d0 ewith CPP. The gonadotropin levels in this disorder
" w8 s. C# R* y. d% T  kare suppressed to prepubertal levels and do not show% P& h# B* D% `% h: n% {
pubertal response of gonadotropin after gonadotropin-9 v6 m: g* c7 n: J) a' q
releasing hormone stimulation. This is a sex-linked
4 F7 u! g5 I' N  `" D  `  c6 Zautosomal dominant disorder that affects only6 N2 I7 Y) ^' n0 E3 E
males; therefore, other male members of the family
# x2 d0 E3 |5 u" m$ Dmay have similar precocious puberty.3
. M  N& u+ }6 b+ F( a5 L# J) cIn our patient, physical examination was incon-& i; f. H* e% f- ]( B: E  f# h
sistent with true precocious puberty since his testi-9 L7 }6 r& `" C# J& s0 H
cles were prepubertal in size. However, testotoxicosis6 J' q' y5 t" C. R! K: A  ?1 p
was in the differential diagnosis because his father
7 p( {! E9 m: ~+ x; W! Q- pstarted puberty somewhat early, and occasionally,
. z2 x9 x" q; N. ]' Qtesticular enlargement is not that evident in the1 V9 n5 `+ K( Z/ p) l* d
beginning of this process.1 In the absence of a neg-
" k$ ], A7 V/ Aative initial history of androgen exposure, our4 R; F9 E/ h1 ~8 Z+ i
biggest concern was virilizing adrenal hyperplasia,  P" L2 B8 \0 D6 R5 W  J
either 21-hydroxylase deficiency or 11-β hydroxylase
- V, r8 M; m" Jdeficiency. Those diagnoses were excluded by find-
! h  W: h* K( i$ K: xing the normal level of adrenal steroids.5 [1 }2 x! @+ t
The diagnosis of exogenous androgens was strongly* v; M( _% ~: s: }! L2 L
suspected in a follow-up visit after 4 months because9 ^) ?, |8 v. T9 m9 {1 F
the physical examination revealed the complete disap-
2 B0 i$ h* G9 _" R( H" bpearance of pubic hair, normal growth velocity, and) ~) B  S! ?% K8 ?5 p
decreased erections. The father admitted using a testos-" N: X/ p; o  f1 l5 r- g
terone gel, which he concealed at first visit. He was4 m6 m8 J0 w$ D) s* N$ v
using it rather frequently, twice a day. The Physicians’
# L3 G+ w  S0 c+ F$ F; Q8 ~Desk Reference, or package insert of this product, gel or
! K$ Z( T& Z( r0 I1 k6 E3 {& jcream, cautions about dermal testosterone transfer to) h0 K" X1 z4 e4 e# q
unprotected females through direct skin exposure.
9 j7 H  M( z- x4 t$ ASerum testosterone level was found to be 2 times the2 ^& g* \, f' Q6 [8 W
baseline value in those females who were exposed to0 @/ W6 Y+ e8 t. n
even 15 minutes of direct skin contact with their male
- u( M9 q4 ~8 ^- ?partners.6 However, when a shirt covered the applica-
8 v" S4 M: ?# y9 ?" e4 Ltion site, this testosterone transfer was prevented.
2 R- z$ \* M$ s9 a7 mOur patient’s testosterone level was 60 ng/mL,  ?$ v) ?) o# K
which was clearly high. Some studies suggest that! F- `: v# O4 k4 N) K  B( ^) F
dermal conversion of testosterone to dihydrotestos-
3 \" b0 ^1 U: B% w3 F: qterone, which is a more potent metabolite, is more3 J! h( o, O5 o+ G
active in young children exposed to testosterone
. K3 o5 w. X5 ^4 oexogenously7; however, we did not measure a dihy-
1 E" C0 I- o* t3 S9 Y' s( M/ J- Kdrotestosterone level in our patient. In addition to
& {& V* J* E. T) D: p" T6 B6 Yvirilization, exposure to exogenous testosterone in
' u7 L  a' T. s3 jchildren results in an increase in growth velocity and. p: c% J+ _! _
advanced bone age, as seen in our patient.
0 p% d) ]7 \$ Z. Z: F% V# J3 VThe long-term effect of androgen exposure during. r$ c: ^3 a  J5 U& _
early childhood on pubertal development and final3 v  h, Y; e0 B' V
adult height are not fully known and always remain. k) k; \" S( `) J
a concern. Children treated with short-term testos-
+ ~5 P. [# w( b* p  \; R+ Rterone injection or topical androgen may exhibit some/ \6 M4 G- n2 ]
acceleration of the skeletal maturation; however, after
8 Z. z! _4 {0 v$ }6 I+ @cessation of treatment, the rate of bone maturation; X4 I- ]# p9 |
decelerates and gradually returns to normal.8,9
0 V. m' @7 v% KThere are conflicting reports and controversy
' a9 d) N3 d. k* uover the effect of early androgen exposure on adult- e9 V0 h' s+ W* |2 b
penile length.10,11 Some reports suggest subnormal
' P7 s; \, h6 E, ]adult penile length, apparently because of downreg-" O9 C& v0 {, Q3 R2 N5 J
ulation of androgen receptor number.10,12 However,
: z4 K6 `$ B% _* S3 {( ESutherland et al13 did not find a correlation between) S, ~: X# }& z, K3 D3 E/ g4 t
childhood testosterone exposure and reduced adult$ c" i. }+ U$ x- A% n8 q) w
penile length in clinical studies.1 O; D; s' K4 J  k
Nonetheless, we do not believe our patient is
- E9 c1 ~6 G! U" fgoing to experience any of the untoward effects from& \$ o7 t* b6 d$ \' b; C+ c/ f& M: c
testosterone exposure as mentioned earlier because0 w: T' Z0 r$ v; j3 a
the exposure was not for a prolonged period of time.
$ j2 m1 Y8 o  A* X' I) X- _Although the bone age was advanced at the time of2 g# ]0 B% @4 A# c
diagnosis, the child had a normal growth velocity at
% x* d. H6 w& D5 Hthe follow-up visit. It is hoped that his final adult
4 X. b& W; z* [height will not be affected.
$ V: L6 {8 m0 Y6 @Although rarely reported, the widespread avail-) c! |4 [2 d+ _
ability of androgen products in our society may" {0 g7 \$ h! E# E& u+ B/ f& J, K
indeed cause more virilization in male or female
9 i* M9 A- V! |children than one would realize. Exposure to andro-$ n' e0 B1 S. k* i- d1 t) p6 v  {
gen products must be considered and specific ques-; d) ]9 H9 m3 S3 m% B5 e
tioning about the use of a testosterone product or& r$ `! K4 y+ T: b
gel should be asked of the family members during
" ?9 w& V8 m  K% L& P) othe evaluation of any children who present with vir-; M. h- l2 c6 @( l
ilization or peripheral precocious puberty. The diag-
4 [0 j, l! [0 E0 I3 mnosis can be established by just a few tests and by
$ B3 G! _, u- x. t& nappropriate history. The inability to obtain such a
( V4 O. r& R: Thistory, or failure to ask the specific questions, may7 Y  z% Y  i2 @0 Z, I4 W) ]1 ^( x: p, T
result in extensive, unnecessary, and expensive0 h3 Z' J" B1 o
investigation. The primary care physician should be6 Y0 U4 r5 s! t( ?+ I% m
aware of this fact, because most of these children  c' [) `# N9 P$ u+ c6 U/ P
may initially present in their practice. The Physicians’  X' g* E+ D- L3 N1 Q* r
Desk Reference and package insert should also put a5 X% k, Y0 q0 ^: W
warning about the virilizing effect on a male or  ?: S0 z' `9 ^8 f8 O( N" n
female child who might come in contact with some-
6 D8 p# p; S4 j( t8 Xone using any of these products.
4 F0 Q6 _' l  E  X8 {% n4 XReferences
- N# P: g8 r  w9 I  z6 z3 f3 z: Q1. Styne DM. The testes: disorder of sexual differentiation" w0 G8 U, [+ l
and puberty in the male. In: Sperling MA, ed. Pediatric: U2 L, l2 G( n6 k
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;  l+ J& A$ r" e. l+ x
2002: 565-628.. H  d# Q; \0 Y% l! ~
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
: N4 T: [& v. Epuberty in children with tumours of the suprasellar pineal
發表於 2025-1-4 03:27:02 | 顯示全部樓層
Sexual Precocity in a 16-Month-Old0 ^8 E5 [% s' I6 G, T( o2 R4 \
Boy Induced by Indirect Topical
, G* F! G  b7 y# e( S6 d" AExposure to Testosterone
) m5 W; {/ a+ t% U' I9 MSamar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2' X* r7 `8 i4 ]3 D2 \4 `
and Kenneth R. Rettig, MD1. m& g% x2 ]$ H1 j2 r
Clinical Pediatrics4 t  y. O: L- \/ u
Volume 46 Number 63 |9 a0 v$ z  [- p( k, z
July 2007 540-543
. o6 J# _. y' }* L5 F; ?© 2007 Sage Publications" g2 C1 `* I9 l8 c$ ^7 H1 T
10.1177/0009922806296651
/ O8 ]0 u) D3 t9 O' Hhttp://clp.sagepub.com% `6 M- [" @9 y2 u* p; `  |9 t
hosted at3 d$ S! [6 ?3 I4 T' v: l0 O
http://online.sagepub.com6 r! o1 |3 ]' K! I
Precocious puberty in boys, central or peripheral,
" s) h' R3 j/ _+ mis a significant concern for physicians. Central
2 H  a* ^4 T& G4 y2 K- zprecocious puberty (CPP), which is mediated* N" d* W+ E) w. w5 n: ]5 y
through the hypothalamic pituitary gonadal axis, has
; F( V0 Q$ A: h- La higher incidence of organic central nervous system
& k& |+ D! Y2 d$ alesions in boys.1,2 Virilization in boys, as manifested" V! ~. n) K8 F: i+ M
by enlargement of the penis, development of pubic
$ Q! t& t: u  C' B! h# `3 u6 }hair, and facial acne without enlargement of testi-
" Y1 r1 u1 V5 mcles, suggests peripheral or pseudopuberty.1-3 We# {! K5 s9 b% P( |
report a 16-month-old boy who presented with the. A/ M( S6 R' f0 Z! o; q; p' W! s
enlargement of the phallus and pubic hair develop-
9 [" F7 M" B& l. o+ Rment without testicular enlargement, which was due: Q7 T8 o1 M& v9 A
to the unintentional exposure to androgen gel used by! i; U9 ]! C) j4 Z$ _& ~. u) J
the father. The family initially concealed this infor-4 o2 o' `0 N. T
mation, resulting in an extensive work-up for this' B/ X7 y0 E1 R- W' N/ m
child. Given the widespread and easy availability of% t6 K3 U  I5 z
testosterone gel and cream, we believe this is proba-9 x' h$ l! ^: v8 B
bly more common than the rare case report in the5 `/ Q+ o" J( p) S& H% H$ {
literature.4) Z* `; q1 n  H4 T% B9 z
Patient Report
  V3 S  g6 l8 P2 C( VA 16-month-old white child was referred to the
1 u0 r* r. M0 a0 ~% V# ^endocrine clinic by his pediatrician with the concern) k& N, |, {; ~/ f' D# m
of early sexual development. His mother noticed5 o# x5 }3 u: J& A9 P
light colored pubic hair development when he was
; m/ j- H5 _: s! Q/ bFrom the 1Division of Pediatric Endocrinology, 2University of8 c% N- `, ?  p8 T
South Alabama Medical Center, Mobile, Alabama.( {* p" x1 M4 b$ n2 u
Address correspondence to: Samar K. Bhowmick, MD, FACE,: `( A3 I/ K, l& G
Professor of Pediatrics, University of South Alabama, College of% Q" I8 r% w' D% ~; C0 Z% c
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
1 r7 B: Y( _! `3 A( A" ?e-mail: [email protected].
% A0 v0 Q- _! ?, M: wabout 6 to 7 months old, which progressively became
  }# ]) h9 d# l6 q0 t  ^darker. She was also concerned about the enlarge-
2 D( g9 s5 E6 e/ N) ^6 {! N+ {% P( \ment of his penis and frequent erections. The child: e) ?0 Y! h* n' b7 y: h
was the product of a full-term normal delivery, with
4 j$ \& a# J0 y& t6 Y5 ^% _* Q& Ta birth weight of 7 lb 14 oz, and birth length of
! _( r" \& l6 z/ O, h- @7 P20 inches. He was breast-fed throughout the first year" g" t+ c3 K6 ^% F. O+ a* T
of life and was still receiving breast milk along with
' Z1 t2 z# d: R7 J5 e' ~4 Asolid food. He had no hospitalizations or surgery,
. ?1 W# a) }9 C* U; N& a/ Aand his psychosocial and psychomotor development. A" `0 r( `4 l9 {4 X$ Y) w3 m2 h+ O
was age appropriate.3 W4 A  D0 ^2 L; K" d2 e9 `( y
The family history was remarkable for the father,: k1 i( `$ D. ^$ |( s6 J. k
who was diagnosed with hypothyroidism at age 16,$ z& p- h3 A6 z- Y
which was treated with thyroxine. The father’s. w8 T. d6 E$ a0 N- w
height was 6 feet, and he went through a somewhat
2 e- l6 k" w/ I% I. J; ~- z2 _4 Cearly puberty and had stopped growing by age 14.9 Y3 E( y1 q  Q* m- K4 \5 K
The father denied taking any other medication. The1 u. G9 m( g; Q# M0 N% G
child’s mother was in good health. Her menarche
  a  n  W8 ]9 Dwas at 11 years of age, and her height was at 5 feet! v8 r) c; b. T  u4 J
5 inches. There was no other family history of pre-
- b* ^. t! }7 ccocious sexual development in the first-degree rela-
6 B4 e- O8 Y: Y( Stives. There were no siblings.
8 o  q/ B! |7 U" Q  XPhysical Examination
( j) Y* g, X3 ~& Z$ @The physical examination revealed a very active,$ l/ b  k7 K  s: H
playful, and healthy boy. The vital signs documented
. s: H- N5 W7 A, p1 ma blood pressure of 85/50 mm Hg, his length was
6 h& C' F3 B. ?' C( x$ k90 cm (>97th percentile), and his weight was 14.4 kg
; A/ N0 P5 N0 N' ^. H(also >97th percentile). The observed yearly growth# t0 c' B% A' v
velocity was 30 cm (12 inches). The examination of
8 a' o# R- Y* d& P6 ~4 H* @# {the neck revealed no thyroid enlargement.
# S- o: e' @5 z: h+ p3 eThe genitourinary examination was remarkable for
  }) ]: G  X: H+ Penlargement of the penis, with a stretched length of
. ]6 W8 f0 |6 A8 cm and a width of 2 cm. The glans penis was very well7 @5 H. P9 m+ A# R) j7 f# A6 X' `
developed. The pubic hair was Tanner II, mostly around6 b  [, K1 I& h2 V) r$ D1 `8 v2 q
540
: f& U" u, P/ f8 [3 \* Tat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
  m- J8 A. s. r% _0 ithe base of the phallus and was dark and curled. The
# `7 B4 N' b5 [testicular volume was prepubertal at 2 mL each.9 e* g1 v3 @3 S  @
The skin was moist and smooth and somewhat6 E5 T% L) _3 U5 `( }
oily. No axillary hair was noted. There were no
3 {# [1 T$ L  K, e" X7 w+ labnormal skin pigmentations or café-au-lait spots.4 o/ \) H2 a3 x9 n. D6 I
Neurologic evaluation showed deep tendon reflex 2+( n* @! f/ N3 v0 ~# j6 r5 `0 M
bilateral and symmetrical. There was no suggestion
9 N0 x! w6 r0 Q+ Sof papilledema.
+ j3 s4 e# N  \- ~1 P' U; ]8 ]Laboratory Evaluation
6 ]  p& r4 {) e6 HThe bone age was consistent with 28 months by5 U6 _+ |/ Y) r6 L% x: J+ O* z8 G
using the standard of Greulich and Pyle at a chrono-+ s( x% w$ M2 H9 H
logic age of 16 months (advanced).5 Chromosomal
( A7 \0 I1 }2 I4 X" Ckaryotype was 46XY. The thyroid function test
: C- @6 p" I8 F6 d7 }7 a8 dshowed a free T4 of 1.69 ng/dL, and thyroid stimu-% ]8 j1 L( I; W# r6 G
lating hormone level was 1.3 µIU/mL (both normal).' N" Q  ~- ^; ~9 s9 y# j
The concentrations of serum electrolytes, blood
2 z, A  ^5 k5 }- V2 i" Purea nitrogen, creatinine, and calcium all were/ d" l/ w6 q$ k  d: p
within normal range for his age. The concentration2 h! N" H+ R7 Y$ g+ g! n# _
of serum 17-hydroxyprogesterone was 16 ng/dL
$ s2 j. U( i+ P! x(normal, 3 to 90 ng/dL), androstenedione was 20
; Y4 L9 x2 U' |* |9 j2 xng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
' ?/ H1 _6 V2 X0 G; Jterone was 38 ng/dL (normal, 50 to 760 ng/dL),, D% T4 i3 ^6 Z. b# \
desoxycorticosterone was 4.3 ng/dL (normal, 7 to
1 N, D6 d( f. L6 s49ng/dL), 11-desoxycortisol (specific compound S)
- Z6 ?3 {& D, ]. K2 V" A; _! Ywas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-' p0 A* t" r% ~7 f8 I
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
# e' a( W1 q, g3 t  P# g( Xtestosterone was 60 ng/dL (normal <3 to 10 ng/dL),
# C. Y! C9 U5 Y2 a- K- cand β-human chorionic gonadotropin was less than# x' J  z+ L' Z. _7 C; u- t2 X
5 mIU/mL (normal <5 mIU/mL). Serum follicular
" @2 h9 O2 ~9 V: b8 |) l- Ystimulating hormone and leuteinizing hormone
% A' \* i% l1 Z& ~8 n8 a3 xconcentrations were less than 0.05 mIU/mL2 o3 Y! x6 A  {2 F! Q/ l8 G
(prepubertal).
8 G+ m4 \7 B% F9 t' `* DThe parents were notified about the laboratory0 u0 a! N# U* s7 `) O( g
results and were informed that all of the tests were6 u+ d4 |; G4 w2 @) N0 a; ~
normal except the testosterone level was high. The
: c' P5 l0 Q1 N9 `0 ofollow-up visit was arranged within a few weeks to1 Q" e% b* ]/ t1 P) E- H
obtain testicular and abdominal sonograms; how-: V6 X! O: I" R1 m/ P
ever, the family did not return for 4 months.
" e4 q; \# O- S! x# KPhysical examination at this time revealed that the1 J# p/ |7 q  W  j- n
child had grown 2.5 cm in 4 months and had gained
; h% x3 c! d" t# S1 C2 kg of weight. Physical examination remained
! D( S! P! x/ v" t; E& o2 h$ F) Punchanged. Surprisingly, the pubic hair almost com-
6 N, N9 d' z* _! C/ [pletely disappeared except for a few vellous hairs at
6 L/ C& h1 K" V9 }- gthe base of the phallus. Testicular volume was still 2# X7 g( N/ ^& B
mL, and the size of the penis remained unchanged.
9 A4 w9 I5 e9 j' Z4 ]The mother also said that the boy was no longer hav-) x% g8 K4 i. q) r# h' v6 s0 b
ing frequent erections.
- D6 ^4 j  i: Y$ p) E% P9 XBoth parents were again questioned about use of
* Z6 l: }; H7 f' w6 [4 E) R, }any ointment/creams that they may have applied to
) H  O/ s8 \% C4 b2 Z# k! @the child’s skin. This time the father admitted the0 ~( u  d4 C8 S( H
Topical Testosterone Exposure / Bhowmick et al 541" B/ k' E: V9 N5 m% N! T% b( r( }  ]
use of testosterone gel twice daily that he was apply-
* X/ M" x" J  |% j  j8 z: ^0 cing over his own shoulders, chest, and back area for8 I* ~. _2 Z$ b! u: t$ a
a year. The father also revealed he was embarrassed) D5 ~7 |# M, a+ p! N
to disclose that he was using a testosterone gel pre-
. d0 c2 `* |4 T6 K4 i# S. yscribed by his family physician for decreased libido' u6 a  l& P* g) g, L1 d" p
secondary to depression./ i$ R# u) M' J9 Z* N2 Y
The child slept in the same bed with parents.
: x9 h  [- B/ P- q2 [The father would hug the baby and hold him on his" R% R1 `# ^. N+ o. t8 X) y
chest for a considerable period of time, causing sig-
5 I! b+ F* e4 Vnificant bare skin contact between baby and father.
3 \4 w1 ~9 N: |& M1 `7 @+ o* rThe father also admitted that after the phone call,$ |$ w, C6 z; z. e# t, I: v/ e
when he learned the testosterone level in the baby7 @. c) X: ~5 ]; q8 r$ C
was high, he then read the product information: x5 b1 ?; d* g/ Q' B, b; A& q
packet and concluded that it was most likely the rea-
3 S, Y) _6 d$ [0 W# M. Kson for the child’s virilization. At that time, they
! y0 D# o: e* d% ]% p1 X$ x8 }decided to put the baby in a separate bed, and the! k. G2 M! P0 @0 x3 ]
father was not hugging him with bare skin and had
2 f$ ]- p/ H8 r; ~# ibeen using protective clothing. A repeat testosterone7 j; z8 r, G4 {% t' K! J# }9 w" S
test was ordered, but the family did not go to the4 W# ^/ T! m2 U8 s/ k; L* p
laboratory to obtain the test.
8 |1 g% w! w% L. lDiscussion0 y; X3 a! t1 c) {$ n  Y6 c4 g9 Q
Precocious puberty in boys is defined as secondary+ E7 v8 R" Z' m' U
sexual development before 9 years of age.1,4
+ b2 F: A' b. [) r5 x) rPrecocious puberty is termed as central (true) when/ D, Z/ @8 X6 A( j& j
it is caused by the premature activation of hypo-
+ ^3 |+ l- K) y, k: ^* s, |  xthalamic pituitary gonadal axis. CPP is more com-
2 l. r+ k3 H6 ], S  t0 c" omon in girls than in boys.1,3 Most boys with CPP
$ I: ?% p7 i* ]5 d, Hmay have a central nervous system lesion that is
3 q1 n2 q0 q) p, wresponsible for the early activation of the hypothal-2 D9 k& F0 M" ^" u$ J" i
amic pituitary gonadal axis.1-3 Thus, greater empha-
" m  w: l$ h9 _# s( c' psis has been given to neuroradiologic imaging in
  C/ D* s# L+ K; t% h+ _boys with precocious puberty. In addition to viril-& t+ O: Z  y" \5 {9 e$ W& a( \
ization, the clinical hallmark of CPP is the symmet-
! F0 o& P6 E; i# M/ o+ X$ Crical testicular growth secondary to stimulation by7 s  l: A" j. K. ~% j
gonadotropins.1,3
4 \, _. j: x  {$ a- c* }Gonadotropin-independent peripheral preco-8 c" a) {" I. e' B% j) B
cious puberty in boys also results from inappropriate
. u" s" c% y  Y7 `7 qandrogenic stimulation from either endogenous or
, V( h" M! r0 \/ v4 i6 mexogenous sources, nonpituitary gonadotropin stim-  k, ]# ]7 M; ^$ E  B' d
ulation, and rare activating mutations.3 Virilizing
4 p0 Z/ U2 Q5 M1 d/ K$ N/ Vcongenital adrenal hyperplasia producing excessive# H! h5 a3 Y$ i' n% L0 L1 w" \7 k
adrenal androgens is a common cause of precocious% X5 u& o/ A4 G2 ~+ V" j
puberty in boys.3,4
9 k( I, G; a. W2 yThe most common form of congenital adrenal3 O5 q2 v/ l7 E# W
hyperplasia is the 21-hydroxylase enzyme deficiency.
2 T5 T6 |6 q% Z# e$ j' eThe 11-β hydroxylase deficiency may also result in
* L, k. {) ^" v. d1 j7 z2 Iexcessive adrenal androgen production, and rarely,
$ W. D% V, }% {, ?# m1 R% p' j8 [6 Can adrenal tumor may also cause adrenal androgen9 X" L8 _3 H) V! n
excess.1,33 _0 c- `$ D9 R$ L3 d/ g0 M) u5 U
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from9 }9 M0 u" G8 I; K. {: l4 B
542 Clinical Pediatrics / Vol. 46, No. 6, July 20071 T7 c5 s6 |, S% c
A unique entity of male-limited gonadotropin-$ ^9 I7 I1 w: d- V0 z
independent precocious puberty, which is also known6 V: R4 r7 g# \8 j
as testotoxicosis, may cause precocious puberty at a
$ s# H+ _" [  i4 K9 E  n5 C) Every young age. The physical findings in these boys
# c% L  j; H' \* m- uwith this disorder are full pubertal development,
( \+ G& C: X# |0 J& jincluding bilateral testicular growth, similar to boys2 c, L; S; c( d( b$ g
with CPP. The gonadotropin levels in this disorder  L/ y4 p# k$ z
are suppressed to prepubertal levels and do not show
# Y- x# ]$ V1 |pubertal response of gonadotropin after gonadotropin-& h3 [7 x6 m' S
releasing hormone stimulation. This is a sex-linked
9 W* p" i# @5 c( W' b2 {autosomal dominant disorder that affects only
2 \3 X$ v1 P) m; \, ]! ^males; therefore, other male members of the family8 o6 R# d, }) [0 S5 d* V9 v
may have similar precocious puberty.3  m+ P. F1 F5 O: U! ?
In our patient, physical examination was incon-! z9 G. o* o/ w- ?) n% v1 v6 h
sistent with true precocious puberty since his testi-
, L7 V, B9 Z% M9 a9 Ncles were prepubertal in size. However, testotoxicosis+ E' Q- h% i  Z
was in the differential diagnosis because his father2 s, G; U& H6 N* J9 ?
started puberty somewhat early, and occasionally,1 q" |; j6 G; U! ?2 C, |0 O
testicular enlargement is not that evident in the+ h$ ^& d4 s5 A" r
beginning of this process.1 In the absence of a neg-
9 R' x2 M( m' P/ }9 X2 E5 `7 sative initial history of androgen exposure, our
, u( s, @: i6 d4 I  K6 J" ybiggest concern was virilizing adrenal hyperplasia,
% t# u0 L) v" B4 l9 i/ |either 21-hydroxylase deficiency or 11-β hydroxylase
, P" N: O/ \- p+ Q& Vdeficiency. Those diagnoses were excluded by find-
) \. J4 F( k( e1 A4 M/ I6 Uing the normal level of adrenal steroids.0 O5 g" \. n% ]. M! q9 f
The diagnosis of exogenous androgens was strongly
2 a$ ^& Z% I! s# x# n3 zsuspected in a follow-up visit after 4 months because
9 Z! E9 H( H# [* N* ?1 Dthe physical examination revealed the complete disap-1 e: a4 t' n" o/ ]
pearance of pubic hair, normal growth velocity, and
( k5 U) d9 ~2 S6 Zdecreased erections. The father admitted using a testos-
7 X' S0 Y- H* M( Iterone gel, which he concealed at first visit. He was# U; K! K: s1 n( D
using it rather frequently, twice a day. The Physicians’: r  W$ e+ C, C3 g: u! f8 M0 W0 L
Desk Reference, or package insert of this product, gel or
) `2 J! M  X' F1 Acream, cautions about dermal testosterone transfer to
( l# G5 l2 r7 M; U; c2 I, b# {unprotected females through direct skin exposure.
  T- B3 L! ^7 PSerum testosterone level was found to be 2 times the# o$ R) `; W- x; u- `$ Z
baseline value in those females who were exposed to: ^$ ]! h7 J$ i' O! f
even 15 minutes of direct skin contact with their male
3 J% H+ e1 o& r1 d( d! gpartners.6 However, when a shirt covered the applica-9 X# V( m5 n- b: f
tion site, this testosterone transfer was prevented.
) f! w. W: H% A* |3 M+ KOur patient’s testosterone level was 60 ng/mL,
& h8 c* u: ]$ a4 ~" qwhich was clearly high. Some studies suggest that/ U# G5 ^5 m& v% D
dermal conversion of testosterone to dihydrotestos-
+ h* \5 |% ~$ ^: P6 N2 Aterone, which is a more potent metabolite, is more1 y$ {1 @' {+ I" a4 s; k( e, v
active in young children exposed to testosterone
1 u1 j, u. T/ s( T# eexogenously7; however, we did not measure a dihy-- N: ?. @) T) Q9 J# `3 ?
drotestosterone level in our patient. In addition to7 Q# B4 n0 X- K& e1 e  T. E' `& A
virilization, exposure to exogenous testosterone in6 s: E5 V. [$ _6 S( O' [: S
children results in an increase in growth velocity and
% _& _# Y5 h+ w; ?+ c( N  r4 |advanced bone age, as seen in our patient.
4 ~3 M2 ]) w; }# w" Q" m% jThe long-term effect of androgen exposure during7 X$ k, d) p$ W$ N3 s5 D3 ~
early childhood on pubertal development and final
) t# `2 f4 N1 M* g1 P8 }& v5 dadult height are not fully known and always remain/ V/ e& g5 i9 e% \8 b* P
a concern. Children treated with short-term testos-( W- R5 ~" o: Y
terone injection or topical androgen may exhibit some. ^" h7 ]) k# Y$ X8 W# v9 w. _
acceleration of the skeletal maturation; however, after
% k3 b4 t8 Y+ d. N1 [+ K4 p$ \cessation of treatment, the rate of bone maturation
$ y! U! f- k/ M8 Edecelerates and gradually returns to normal.8,9. P+ ?$ w, L5 r7 E+ o1 r
There are conflicting reports and controversy
- F# d7 a& P" eover the effect of early androgen exposure on adult$ }' a* x& X+ I, E0 q3 `% N' q- g
penile length.10,11 Some reports suggest subnormal2 b. j% V$ E( B% k3 D) y
adult penile length, apparently because of downreg-
% Y- E, M+ m+ f  Lulation of androgen receptor number.10,12 However,
/ u& {( q$ i6 VSutherland et al13 did not find a correlation between
, ^5 @! v/ U! q/ g3 schildhood testosterone exposure and reduced adult/ H$ N/ W0 L, w( _& m
penile length in clinical studies.4 i& S4 K$ \& O
Nonetheless, we do not believe our patient is$ f% s; p6 w' y" M& i5 I
going to experience any of the untoward effects from
1 o8 M7 Z$ k% R/ s! Z; Ttestosterone exposure as mentioned earlier because
9 c8 r/ n+ z+ p0 \4 O. F* gthe exposure was not for a prolonged period of time.
3 [6 u; k% `2 SAlthough the bone age was advanced at the time of7 Y: L( Y' X" A
diagnosis, the child had a normal growth velocity at) b5 H: p/ v# L4 Y- A. B
the follow-up visit. It is hoped that his final adult
/ z% @1 I' [& [8 m+ H. x- J; Nheight will not be affected./ W) n- {+ d) a0 ^) y% H
Although rarely reported, the widespread avail-
( w1 K, @  X, ]' s7 ~0 O. Wability of androgen products in our society may
6 ?" t3 @+ F) I6 N: J5 h6 |indeed cause more virilization in male or female
: G1 `8 \, ^$ K* f% W& pchildren than one would realize. Exposure to andro-5 t' y/ w1 q/ \2 N
gen products must be considered and specific ques-
6 ?  j/ m* r2 _! x- m7 x) {. etioning about the use of a testosterone product or2 ?# C$ y) e6 F' G
gel should be asked of the family members during
! G9 |6 L0 f" g, |1 X% L* jthe evaluation of any children who present with vir-" t/ f0 a; a3 J3 ?4 _. W, ?0 L
ilization or peripheral precocious puberty. The diag-3 D6 o; v" u( l3 W" k* x% T
nosis can be established by just a few tests and by, s) _1 M; z8 T$ Q
appropriate history. The inability to obtain such a
2 I9 k! P4 \4 G# A$ whistory, or failure to ask the specific questions, may
5 U) t/ E/ `3 wresult in extensive, unnecessary, and expensive! ^% G" D: ^9 a$ e
investigation. The primary care physician should be
/ d# ~9 Z( x) }" }6 eaware of this fact, because most of these children
' |6 c7 y6 Z8 b/ q- _( w: i5 Vmay initially present in their practice. The Physicians’3 R9 z" I' B& {: L4 n/ N5 D& |
Desk Reference and package insert should also put a
$ `& M  r9 }- [% U# q% U$ wwarning about the virilizing effect on a male or# }- P+ J+ m, Y/ ?
female child who might come in contact with some-
: F4 {) o- ]/ D4 zone using any of these products." _( }) p6 w) m% T
References; v% V" L: }3 P+ j1 l2 B" E
1. Styne DM. The testes: disorder of sexual differentiation- a) ^/ U+ u1 M
and puberty in the male. In: Sperling MA, ed. Pediatric
6 v8 S1 j7 t* \$ N: s1 z6 aEndocrinology. 2nd ed. Philadelphia, PA: WB Saunders;8 ^' @2 E# p0 E0 U7 h4 \
2002: 565-628.
; {5 A9 Z2 E1 b: b1 ?2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious# Q9 h5 C2 b( V% j! q% ?) T
puberty in children with tumours of the suprasellar pineal
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女厕偷拍辅导班主任尿尿老师的逼很嫩还有一点
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4个什么样的?
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) h# C- Z- d. e9 f
精妙絕倫的精品,感謝啊!期待你更多更好的創作哦!
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么好吧v进化过程就回国参加发uft成就和;哦i回来就好v科技股份兄弟人的 路由公开vu个v库每年b
發表於 2025-4-8 11:10:25 | 顯示全部樓層
精妙絕倫的精品,感謝啊!期待你更多更好的創作哦!
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