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Sexual Precocity in a 16-Month-Old
$ v9 ^1 L1 q" ~- {Boy Induced by Indirect Topical* B0 [: Q9 _# L' `$ y$ p. O
Exposure to Testosterone7 T$ a- L& r1 M0 m
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
4 o: ?7 L0 o  land Kenneth R. Rettig, MD1
2 d! J& ]* _  ?' D3 e& I0 ~' eClinical Pediatrics8 g" o/ P2 U1 r. P9 w
Volume 46 Number 6
. M) F: e6 L- `0 d6 JJuly 2007 540-543
" q6 ]/ [/ @/ G6 M© 2007 Sage Publications: S: ^; O( J) g4 G( Y: |  s
10.1177/0009922806296651
5 |' B1 \5 U( Xhttp://clp.sagepub.com
" R1 J  P4 U; x0 a  P& H/ o4 @hosted at
0 @+ K+ z. [: Y5 e, [) q+ F( f2 ]http://online.sagepub.com# y% b, n/ I9 d* i. K: m
Precocious puberty in boys, central or peripheral,9 L8 k) L) G( `* G
is a significant concern for physicians. Central
* o& x1 \$ ?; Z; j  J% Iprecocious puberty (CPP), which is mediated! _3 E" C3 j0 ^7 I2 e4 W
through the hypothalamic pituitary gonadal axis, has
- j% e' m, x3 b. L, ~a higher incidence of organic central nervous system
# `/ E, y; \, Z. _" \8 K! w) alesions in boys.1,2 Virilization in boys, as manifested4 }8 s  l' J! A5 N; j' b( ?
by enlargement of the penis, development of pubic
  X6 }( j4 v. {6 D' c* b$ l0 Khair, and facial acne without enlargement of testi-1 r9 [- t4 P# A  f
cles, suggests peripheral or pseudopuberty.1-3 We8 [" i' m# R6 B8 B3 n. R
report a 16-month-old boy who presented with the- o% |" ]! _0 p; o/ v! G' U
enlargement of the phallus and pubic hair develop-- p9 d. _6 L" ~- Z; q5 D% e
ment without testicular enlargement, which was due: _* d! w) g  N* f! m7 U
to the unintentional exposure to androgen gel used by; \3 e2 g" ~, R; o) s/ g
the father. The family initially concealed this infor-
# _  a( U& Z; N2 vmation, resulting in an extensive work-up for this
8 n& R) r2 O( e0 s+ v$ L! |child. Given the widespread and easy availability of
% v( B( e9 b+ _+ ftestosterone gel and cream, we believe this is proba-) C' e5 _$ ^. \( l  u
bly more common than the rare case report in the
% u8 Z/ J% z1 M; K& lliterature.4
  `/ a# D. i5 t. r7 RPatient Report- H$ e! s6 o  H5 }+ T/ ?
A 16-month-old white child was referred to the
7 G: `1 y- {3 v7 H* x' b- Wendocrine clinic by his pediatrician with the concern3 y7 s" E  ^" W/ H0 H( }* u
of early sexual development. His mother noticed
* ]8 H" |2 V: y5 `6 B6 {light colored pubic hair development when he was
1 I: t) g9 o& c7 dFrom the 1Division of Pediatric Endocrinology, 2University of# d; u/ x- o3 l( x& C  r
South Alabama Medical Center, Mobile, Alabama.
, _3 ^3 @- m5 I! [9 yAddress correspondence to: Samar K. Bhowmick, MD, FACE,
, _& {$ ]% {2 ?( s( d/ FProfessor of Pediatrics, University of South Alabama, College of
$ A# m# `# u. U) p- B+ tMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
/ l, q4 F3 g1 l6 h4 e6 we-mail: [email protected].6 A; }5 G8 x: [  Q! w5 Q1 ~
about 6 to 7 months old, which progressively became) W5 B" v! l+ K
darker. She was also concerned about the enlarge-
( P( \% M2 `4 {# U6 N, F; X% iment of his penis and frequent erections. The child
0 d, I0 m% Z* n1 x; S+ ?! o2 D: Pwas the product of a full-term normal delivery, with" b. U% o# z$ L7 }8 j5 d
a birth weight of 7 lb 14 oz, and birth length of- @5 x: g& E4 g- X* I# P) a
20 inches. He was breast-fed throughout the first year9 q9 e# u, L9 C, {
of life and was still receiving breast milk along with
$ `2 U8 |. O0 Lsolid food. He had no hospitalizations or surgery,& e! x2 x( D2 g8 |8 _9 D
and his psychosocial and psychomotor development
6 u& E& ?+ Q9 [$ Bwas age appropriate.; @  B- X& P' R7 S! D# ?
The family history was remarkable for the father,
9 t/ E5 p# M4 m) ]0 `' l3 }! {* Cwho was diagnosed with hypothyroidism at age 16,
8 i. F3 O4 g9 t4 X2 M/ W1 gwhich was treated with thyroxine. The father’s
0 y( W: S& n7 x; v% wheight was 6 feet, and he went through a somewhat
0 Q; a- J0 k7 ~) b5 C- Nearly puberty and had stopped growing by age 14.% T0 Q  c7 Y+ x2 h# {( T. d
The father denied taking any other medication. The- ]1 N* n9 F( r9 g7 T
child’s mother was in good health. Her menarche
4 O# t3 e0 u) s' ]' q! H# ]was at 11 years of age, and her height was at 5 feet
) t& E5 [) P2 L5 inches. There was no other family history of pre-( `; X, E+ \3 e
cocious sexual development in the first-degree rela-
1 W: K$ e+ m' p, A' O- ztives. There were no siblings.
! `8 G$ s  n6 r! V8 PPhysical Examination1 T3 e0 [- `) ?9 X" n$ h! I
The physical examination revealed a very active,
$ X% c, F! C& R7 G# I4 \playful, and healthy boy. The vital signs documented
, }/ [6 l: X" X0 `a blood pressure of 85/50 mm Hg, his length was0 o% F7 c$ ^  S! p% |
90 cm (>97th percentile), and his weight was 14.4 kg0 t3 c# v0 z1 ~  g
(also >97th percentile). The observed yearly growth* o6 E4 }- A& ~- E% }
velocity was 30 cm (12 inches). The examination of
' g  I( U9 r. w& Bthe neck revealed no thyroid enlargement.
& t& E' C$ n! d9 x. ZThe genitourinary examination was remarkable for
% @3 G- z9 j/ _& ienlargement of the penis, with a stretched length of4 w: V# l" w5 w* J
8 cm and a width of 2 cm. The glans penis was very well% C% N) a( ?5 h9 y1 P
developed. The pubic hair was Tanner II, mostly around
/ B% M' q- A- B3 v" O7 [) i0 j2 d540' }* P6 Z; A& H# s2 e5 l& G
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
2 H( f% s* H& q0 b8 @the base of the phallus and was dark and curled. The+ O0 ]+ I6 |- B# S: W# R+ c* _
testicular volume was prepubertal at 2 mL each.! d: K( D3 S2 I
The skin was moist and smooth and somewhat
2 b) u# k4 ?/ e& F* p9 K/ Qoily. No axillary hair was noted. There were no; z0 ]5 X6 S3 ?9 r! J1 d6 d0 @
abnormal skin pigmentations or café-au-lait spots.
3 E8 G9 o, J  @( e! \Neurologic evaluation showed deep tendon reflex 2+8 p8 `  N+ T1 b5 v
bilateral and symmetrical. There was no suggestion2 c1 ~- o* t* a) e: q% ]
of papilledema.
1 P  j- o0 o. l4 X( i' L! }Laboratory Evaluation
, J, M. q% r9 OThe bone age was consistent with 28 months by
' A1 b0 q  e$ H9 Z4 husing the standard of Greulich and Pyle at a chrono-' \$ b- E8 o1 {' J3 }- o
logic age of 16 months (advanced).5 Chromosomal
1 H1 `' S. n, i1 b9 `! pkaryotype was 46XY. The thyroid function test
  q7 s; A; o6 j5 xshowed a free T4 of 1.69 ng/dL, and thyroid stimu-
) Q9 }  K# y; F+ Tlating hormone level was 1.3 µIU/mL (both normal).2 g. r* m; p% {1 c. L0 U, n
The concentrations of serum electrolytes, blood1 \! U% L. x3 `% Z7 ~! W
urea nitrogen, creatinine, and calcium all were
6 j5 \* p4 N$ K- J) ^6 V$ Hwithin normal range for his age. The concentration3 }- i$ d+ @4 _. K5 r
of serum 17-hydroxyprogesterone was 16 ng/dL
$ Y3 u6 F8 e& x/ l(normal, 3 to 90 ng/dL), androstenedione was 20
2 A7 g" p' ]" K4 R! `  gng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
- S8 V# Z# M3 n! B4 ]terone was 38 ng/dL (normal, 50 to 760 ng/dL),
9 b# O0 {& s2 d, ^7 c3 Cdesoxycorticosterone was 4.3 ng/dL (normal, 7 to+ r2 [: r# L9 b6 H# O  K/ O  P
49ng/dL), 11-desoxycortisol (specific compound S)3 \/ }! ?+ D6 o; ?  T) Z; }
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
$ l) R+ t7 `; E: qtisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total' U' P$ |9 ~! C7 X/ S
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),. `. H: D/ j: X% G: |# v- N/ L
and β-human chorionic gonadotropin was less than
; A  K7 a; w# I$ W' |: a5 mIU/mL (normal <5 mIU/mL). Serum follicular
. j$ F9 d, a# @/ X) o+ z; |stimulating hormone and leuteinizing hormone
) `2 |- [( s5 l% N( @' n# _concentrations were less than 0.05 mIU/mL4 k6 ]- i1 {/ d! \- G4 {9 T1 G
(prepubertal).9 m7 j+ K' X% u, e$ \  }9 O/ ^  z
The parents were notified about the laboratory1 g2 a/ t$ N+ L. `8 b5 G5 e
results and were informed that all of the tests were
! B; R; v( w8 j( V7 ynormal except the testosterone level was high. The
8 l$ v" `, K% Z, g0 i4 tfollow-up visit was arranged within a few weeks to
: g# E. Z+ e6 ~" N! U$ e& e! Oobtain testicular and abdominal sonograms; how-2 O! o( j: r. ?8 [( l" V
ever, the family did not return for 4 months.* `' R. ]! g, w' C1 i' g/ k4 l
Physical examination at this time revealed that the& c4 V0 v, I+ j6 G" J
child had grown 2.5 cm in 4 months and had gained
0 l0 E9 b6 q' ~2 kg of weight. Physical examination remained# j4 e- Q6 d! w, S/ Z& K
unchanged. Surprisingly, the pubic hair almost com-
5 T5 i; O% l) \. \, i/ a) Kpletely disappeared except for a few vellous hairs at
! o7 _* z$ m) ]( Z) B* |the base of the phallus. Testicular volume was still 2' B% `- c% a7 T, v% b
mL, and the size of the penis remained unchanged.
  R% g3 ^" f6 S4 T1 PThe mother also said that the boy was no longer hav-- t5 w+ [: _+ b$ `# R1 [9 F  i
ing frequent erections.
! D) M$ D! B* \. F" {$ \Both parents were again questioned about use of
1 _2 U; ]; x& C+ n  N6 T" m- [any ointment/creams that they may have applied to
  [# q& U& J- Y& e- sthe child’s skin. This time the father admitted the: X7 K! h- p4 q" n
Topical Testosterone Exposure / Bhowmick et al 541* D" {) z% e3 j6 p8 Q
use of testosterone gel twice daily that he was apply-
- y7 T0 D, B, ]ing over his own shoulders, chest, and back area for% o; m: r; z4 P+ }. i% s
a year. The father also revealed he was embarrassed
: a/ f( W5 f5 K8 {; ]+ n* Fto disclose that he was using a testosterone gel pre-: `% J& f3 j8 ^; I  D8 T$ Y) G
scribed by his family physician for decreased libido
  z: _& D1 Q0 Z3 I! qsecondary to depression.9 a* G# V3 c" M% [7 n: T
The child slept in the same bed with parents.6 }$ ?4 ]% f2 p
The father would hug the baby and hold him on his& g2 P, J- x+ P. ]
chest for a considerable period of time, causing sig-4 p+ @5 m1 \  i1 v# y; a% ^
nificant bare skin contact between baby and father.
  W7 ^9 H. S; G+ V5 S- }; Y1 LThe father also admitted that after the phone call,$ S) H# w) E( f# t1 M. Z
when he learned the testosterone level in the baby( A0 F6 E9 U* v( R" |7 K
was high, he then read the product information4 T( I/ y4 Y) D. t' v% i
packet and concluded that it was most likely the rea-
" B' Z; P  Q( W! y; z$ json for the child’s virilization. At that time, they
9 l( ?* m5 S( s. i1 ?6 Q. a4 Kdecided to put the baby in a separate bed, and the
- [. R8 q; T7 V( a+ hfather was not hugging him with bare skin and had
" U7 j* p* h- B) B5 v" tbeen using protective clothing. A repeat testosterone
- T$ x9 [, o& v: v% Htest was ordered, but the family did not go to the
) f& l/ ?6 K& k: `6 u" a' R" L1 plaboratory to obtain the test.
2 x5 W& J/ a$ PDiscussion- Y' X; [7 h% g  H5 k
Precocious puberty in boys is defined as secondary
2 f" L7 X8 ^/ w7 lsexual development before 9 years of age.1,4
: m5 U/ `. T9 r4 U7 yPrecocious puberty is termed as central (true) when
, k1 M5 z7 ~' U: K$ P: Eit is caused by the premature activation of hypo-7 g9 ^  B/ Y/ ^+ A
thalamic pituitary gonadal axis. CPP is more com-
( Q8 T* F# ?, W) }mon in girls than in boys.1,3 Most boys with CPP
# z( K& ]2 E0 M& v1 N1 Bmay have a central nervous system lesion that is
& X4 @1 z. v5 jresponsible for the early activation of the hypothal-
/ h+ J7 G% N2 h" Q+ jamic pituitary gonadal axis.1-3 Thus, greater empha-
6 Z0 a5 x# h" s4 J& xsis has been given to neuroradiologic imaging in
! @3 j. i; e5 a0 b- Fboys with precocious puberty. In addition to viril-
( g$ C) k2 D9 |* W7 qization, the clinical hallmark of CPP is the symmet-
4 j; y7 [  Z+ F3 n$ @rical testicular growth secondary to stimulation by( j- K4 M# ?- M/ v, _
gonadotropins.1,3
& W4 f6 d4 Z, A7 JGonadotropin-independent peripheral preco-4 M0 z6 g9 J: O" x7 `' Z5 z
cious puberty in boys also results from inappropriate
4 B! t  T, I+ W. _androgenic stimulation from either endogenous or
2 n$ g% v! E3 W9 hexogenous sources, nonpituitary gonadotropin stim-: X3 G8 H! ]9 o/ `4 P" A! s& u, k
ulation, and rare activating mutations.3 Virilizing
5 I% g0 f6 C5 h' c6 jcongenital adrenal hyperplasia producing excessive9 O# ~( r& t4 e5 C3 B" n$ ~0 @3 k
adrenal androgens is a common cause of precocious+ ^" C# n3 K9 o. X3 k9 f* M  o
puberty in boys.3,4
& d( S0 N: i4 {1 a3 {. `" _The most common form of congenital adrenal+ Q- D8 Z7 p* i2 \, X; c% M" m
hyperplasia is the 21-hydroxylase enzyme deficiency." H6 y* V* ]+ _8 k
The 11-β hydroxylase deficiency may also result in* b) |: l; r; t$ V
excessive adrenal androgen production, and rarely,
! p" t( _7 ^( f" ~4 U: \an adrenal tumor may also cause adrenal androgen4 `" p/ L2 v  N& k2 \
excess.1,3
" i  K3 ~/ ?& ~at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
2 e0 }( T5 l# ~7 d  e( O" c& v" ]542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
5 I% b) q3 P/ rA unique entity of male-limited gonadotropin-( }. z' ^) s. E
independent precocious puberty, which is also known5 V  \2 @2 q+ t1 u$ I, O
as testotoxicosis, may cause precocious puberty at a
( ?- Q* \3 z( e' H7 rvery young age. The physical findings in these boys! E5 _5 e+ g4 _: @/ @5 U
with this disorder are full pubertal development,
# J2 T/ ]- e& A: J3 Z2 j5 Yincluding bilateral testicular growth, similar to boys
. e. F( p  R3 v9 |' y; }with CPP. The gonadotropin levels in this disorder
$ \9 Z- f; d1 u4 k9 oare suppressed to prepubertal levels and do not show
8 J: c3 K$ n; X4 l' Qpubertal response of gonadotropin after gonadotropin-+ x! o- N' V! _/ M/ {# B9 b
releasing hormone stimulation. This is a sex-linked: i1 V( c4 |5 }
autosomal dominant disorder that affects only
: k0 n2 A, L) C# j, f! Q5 r+ Zmales; therefore, other male members of the family8 v% w; h5 e  x1 n
may have similar precocious puberty.3
8 [- q0 t: N) d$ Y1 P+ \0 @  EIn our patient, physical examination was incon-( V, D+ R( O( \  s& p1 Y) F
sistent with true precocious puberty since his testi-
" F* m7 [! r, i- ~8 V1 K# Bcles were prepubertal in size. However, testotoxicosis
1 n# @4 l" h6 iwas in the differential diagnosis because his father
/ k9 `4 y% g, |3 P& Z5 Lstarted puberty somewhat early, and occasionally,8 N) K, \( E! e7 }+ p* A( \
testicular enlargement is not that evident in the* d8 N. w7 y& u+ v! N* }" B; |
beginning of this process.1 In the absence of a neg-: R0 p" |) ~" {( ?: W$ z7 @% k* Z
ative initial history of androgen exposure, our
4 h/ Z/ n1 W% y  b/ Tbiggest concern was virilizing adrenal hyperplasia,- P$ L/ ]7 `. Z/ C9 t# w& Q2 J& P7 E
either 21-hydroxylase deficiency or 11-β hydroxylase7 H% m; ]& n. f4 K2 R8 E1 k
deficiency. Those diagnoses were excluded by find-
1 W; c. r: _/ G( q4 a+ \2 p( c" a4 King the normal level of adrenal steroids.
8 w6 J- m& A' B6 ]The diagnosis of exogenous androgens was strongly
* \! c# N' |( k1 ?% C4 P5 n8 ^3 t! asuspected in a follow-up visit after 4 months because3 m$ ^) X: d9 j0 A9 \$ r7 l
the physical examination revealed the complete disap-
2 L- M2 O$ f' c: a; r% Tpearance of pubic hair, normal growth velocity, and
9 N4 C3 y, O& L0 [  p3 w, d" ?decreased erections. The father admitted using a testos-* b" u) G. z' P. t
terone gel, which he concealed at first visit. He was
3 Y+ |" ?: F- Rusing it rather frequently, twice a day. The Physicians’1 R; L2 {8 s  R$ a+ a
Desk Reference, or package insert of this product, gel or
' H1 a2 h, ^' B3 y9 Z  S; q7 W# Ucream, cautions about dermal testosterone transfer to) f+ S0 `9 j2 s4 `2 [& ?
unprotected females through direct skin exposure.% X: R- f: L0 B7 p* A
Serum testosterone level was found to be 2 times the
5 C+ e- O2 C! H0 V# m* F0 p9 Sbaseline value in those females who were exposed to" d+ E- Q5 _. \+ V  Y
even 15 minutes of direct skin contact with their male# g- r8 J9 \9 C* R
partners.6 However, when a shirt covered the applica-0 u! m$ b: G, M% }+ a* A
tion site, this testosterone transfer was prevented.% H* k+ V7 a1 A2 e
Our patient’s testosterone level was 60 ng/mL,5 F8 e' M- V& `
which was clearly high. Some studies suggest that$ Q: G" n1 c3 L
dermal conversion of testosterone to dihydrotestos-" c7 T/ f0 B0 ?# @: _8 y$ K
terone, which is a more potent metabolite, is more
0 x% M: ]& @* d6 G! b" U2 `active in young children exposed to testosterone
# H8 M* k/ z: C) @9 S4 }2 ~exogenously7; however, we did not measure a dihy-
: z% ?' E: l( E# ~0 L8 Qdrotestosterone level in our patient. In addition to
2 A$ ?0 M8 ?8 E$ Z( [0 P  vvirilization, exposure to exogenous testosterone in
3 @) o& A# d1 L" ?% Jchildren results in an increase in growth velocity and$ B2 O9 m6 ?0 @
advanced bone age, as seen in our patient.
9 f. T( q% G6 @  i5 l' ]The long-term effect of androgen exposure during- _8 l& a4 b* q
early childhood on pubertal development and final' E' G1 ?3 X( P; t: z
adult height are not fully known and always remain/ m' J6 |7 q) w' {4 P
a concern. Children treated with short-term testos-6 ~9 p$ Q! }0 Q3 {& |8 g) f( _
terone injection or topical androgen may exhibit some, J4 X: h5 ?2 n( S8 B+ J& D/ W
acceleration of the skeletal maturation; however, after
4 m# A, J/ Y, v' |cessation of treatment, the rate of bone maturation
8 ]& f5 ]3 s- s  edecelerates and gradually returns to normal.8,9
0 n- {; S7 M5 C5 [3 [- jThere are conflicting reports and controversy$ D9 ]+ O4 ]( l+ G
over the effect of early androgen exposure on adult. T6 g% N! v3 l1 C# x, m
penile length.10,11 Some reports suggest subnormal5 j1 k) r) L. X) @0 Y0 \
adult penile length, apparently because of downreg-2 C( h1 ~! e4 C& ^# u' h: P
ulation of androgen receptor number.10,12 However,
& Z1 i! n# ^) GSutherland et al13 did not find a correlation between9 j$ B+ M# ^, ?, w# n1 m
childhood testosterone exposure and reduced adult7 O" m  j2 m1 f& w  A
penile length in clinical studies.) D# W1 f6 k; f6 K1 ?2 z, W
Nonetheless, we do not believe our patient is
3 j0 c* C% _9 |" y0 J1 egoing to experience any of the untoward effects from
9 |; y5 u& u+ z- a+ k) Atestosterone exposure as mentioned earlier because
) ?5 o5 V% K9 m% wthe exposure was not for a prolonged period of time.( a3 t  I6 b+ E; X$ q, I# x( {5 I
Although the bone age was advanced at the time of
& }+ L- k! j# G4 ydiagnosis, the child had a normal growth velocity at
. W" R- |1 ]& y" R% Xthe follow-up visit. It is hoped that his final adult
" q% r2 ^0 M! ?+ J+ Z4 {6 k, v! Oheight will not be affected.+ ~0 R8 Q& Y, {% y) y' |
Although rarely reported, the widespread avail-2 r9 P. R4 _+ b- I5 j( C, h- Z
ability of androgen products in our society may( T6 V6 z" {4 d2 J/ y
indeed cause more virilization in male or female
1 \9 o' s1 L: O& C: Uchildren than one would realize. Exposure to andro-
; V) T5 p0 h# O) }8 @6 Q7 Vgen products must be considered and specific ques-8 I# A$ W, `! H5 k! J
tioning about the use of a testosterone product or
0 I- A- }5 W2 U( Y) a3 h8 \% Ngel should be asked of the family members during( ^9 D5 S* R+ ~" u, n9 j5 q2 b
the evaluation of any children who present with vir-7 F, k) n! m- d1 O
ilization or peripheral precocious puberty. The diag-& h/ I7 K* K. u. {. U
nosis can be established by just a few tests and by
; {7 p! N* ~- L3 x0 ~2 k2 ^appropriate history. The inability to obtain such a( e. Y3 w" S' Y; B- A
history, or failure to ask the specific questions, may) m$ E2 U9 U2 m1 I- A2 P5 U- |5 @. u
result in extensive, unnecessary, and expensive
/ N+ r! r4 D- }1 ]; k; E- _investigation. The primary care physician should be
! L/ o: e+ d' e8 s3 O7 Uaware of this fact, because most of these children
" c( R" g2 i$ T  T0 L# Kmay initially present in their practice. The Physicians’  p0 l+ x& ~/ k% ?: ?
Desk Reference and package insert should also put a
. ]+ j4 N- O4 F' g7 x6 Awarning about the virilizing effect on a male or
  y  Z& e- I* o2 |' }8 [4 Ofemale child who might come in contact with some-
7 k% W4 A8 [' e5 b, Gone using any of these products.
3 A6 h, @  _8 y0 r0 s' vReferences9 _3 t8 {# E4 N8 S3 I
1. Styne DM. The testes: disorder of sexual differentiation; z# z! u0 b3 q) i, ]
and puberty in the male. In: Sperling MA, ed. Pediatric
6 h7 r$ w4 i( M( V' uEndocrinology. 2nd ed. Philadelphia, PA: WB Saunders;% c6 p! i. I4 O* b* h( g; X# F% s  ~
2002: 565-628.
8 s. G  r8 q; A, o( F3 }2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious  N7 h+ Y7 S3 I
puberty in children with tumours of the suprasellar pineal
發表於 2025-1-4 03:27:02 | 顯示全部樓層
Sexual Precocity in a 16-Month-Old8 c! [8 s) A  }5 R
Boy Induced by Indirect Topical: W. M( ^; @: e  q" n, f% w+ z
Exposure to Testosterone
  I, \" J# F  ~0 \" ^Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
; B6 U% Y( }/ O# `+ rand Kenneth R. Rettig, MD1
' v- d' K4 O+ s0 Q) q4 PClinical Pediatrics
% @& `% H; T4 ^7 j- O; l1 MVolume 46 Number 6
, o  G2 V3 o" F! n( |7 m2 P9 MJuly 2007 540-543% m& {& b* C$ g+ h
© 2007 Sage Publications
" o$ \/ x: y( d0 z( D, L10.1177/0009922806296651
, k0 @* J9 K& U8 Q1 T% E, Xhttp://clp.sagepub.com; D- h% y; m) b/ L3 t5 B2 C$ O4 l
hosted at
7 k( P; w4 c) b2 W5 R9 n4 f( Q! [! Ohttp://online.sagepub.com' X, t1 i+ @% e5 t  H6 H4 K4 G$ C) g
Precocious puberty in boys, central or peripheral,
! _8 N% Q7 k6 d* o+ O, Fis a significant concern for physicians. Central( I; l1 o' l3 l" I; n5 c
precocious puberty (CPP), which is mediated
+ r8 G' |3 A, E* ?4 p- {- u( lthrough the hypothalamic pituitary gonadal axis, has
% {) j8 I4 e: t5 Da higher incidence of organic central nervous system
8 ?+ J, z( E6 c* e; A/ ~lesions in boys.1,2 Virilization in boys, as manifested
9 v, `3 @! c! b0 ~) _, Y9 |by enlargement of the penis, development of pubic
$ W  U1 c. w5 J3 vhair, and facial acne without enlargement of testi-
) K. }" b6 m" g4 Hcles, suggests peripheral or pseudopuberty.1-3 We* g: b# L% S+ l0 k( `# y+ o
report a 16-month-old boy who presented with the  D) f: Y) C& o9 u) K
enlargement of the phallus and pubic hair develop-
8 Y" U8 j, d+ s7 z( x  |ment without testicular enlargement, which was due
/ ^9 s- o, L% n2 u- L# N' a* X$ ato the unintentional exposure to androgen gel used by
' E" n6 ]& l( m4 C: X% bthe father. The family initially concealed this infor-
/ `* [' Q8 {- Lmation, resulting in an extensive work-up for this
$ w0 @6 E3 x+ ~& n" uchild. Given the widespread and easy availability of
( q9 D  C7 E! M- K6 s$ ?" C7 Btestosterone gel and cream, we believe this is proba-
) S, c5 z' }, u- Z4 H& J# a1 Obly more common than the rare case report in the
; Z; G7 d1 E% k" x; ?literature.4
4 p4 S) H5 {& x. f- T$ b) h6 [Patient Report( |& X, f. F1 C7 J2 ]% o* W
A 16-month-old white child was referred to the1 T3 h5 X$ d) p4 \1 Y" R! p
endocrine clinic by his pediatrician with the concern" B& E8 ~0 j+ s! w& d
of early sexual development. His mother noticed
, M. `' h* q1 K: r- glight colored pubic hair development when he was
3 T! e# Y, a  u4 g* S" N' W2 P2 {From the 1Division of Pediatric Endocrinology, 2University of# A' a/ @$ K& H! B
South Alabama Medical Center, Mobile, Alabama./ K6 {4 T& P8 L; Z0 `, H
Address correspondence to: Samar K. Bhowmick, MD, FACE,
; M1 y3 }8 X4 X; {1 G; b- LProfessor of Pediatrics, University of South Alabama, College of
+ [8 d; b4 f& eMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
) i9 `6 t! U3 r  q4 ce-mail: [email protected].( A$ I. q* P* f$ h; _+ Z
about 6 to 7 months old, which progressively became" V' d. S  A8 S& @
darker. She was also concerned about the enlarge-6 O. N- r% Q4 N
ment of his penis and frequent erections. The child
8 v9 U) U( C0 b. Z. Mwas the product of a full-term normal delivery, with* h, S# C/ R' u9 ~: R; C- ~$ F2 \! Q0 u
a birth weight of 7 lb 14 oz, and birth length of
4 G: E) F) _4 m20 inches. He was breast-fed throughout the first year7 m7 c: e& P& y  Q& K1 ~  h
of life and was still receiving breast milk along with- B2 c+ i2 Q7 j
solid food. He had no hospitalizations or surgery,
8 O+ P8 T6 x$ w7 I5 fand his psychosocial and psychomotor development
, r. d+ ]: c* I$ o" n* owas age appropriate.) R) a/ Q# b5 |8 d  q; h
The family history was remarkable for the father,
1 |* M5 ]: J* |9 C6 U& Twho was diagnosed with hypothyroidism at age 16,
0 u6 X: w1 X$ @( a! \- V  Bwhich was treated with thyroxine. The father’s# r' i- F* K* I" C
height was 6 feet, and he went through a somewhat
: f8 |+ b4 ~# i: L1 Nearly puberty and had stopped growing by age 14.; e# n  U0 d( ]4 p; l# Y
The father denied taking any other medication. The0 c+ K% M0 i( }/ X( Q, a
child’s mother was in good health. Her menarche2 v3 r! v) I* s7 V
was at 11 years of age, and her height was at 5 feet# X8 y5 P* k/ A# J& V
5 inches. There was no other family history of pre-
# Y% T" c: T$ E9 J# c, rcocious sexual development in the first-degree rela-
; K6 P5 P/ \6 vtives. There were no siblings.
. `- }/ W5 l6 U" [  S- {9 XPhysical Examination, F# S- K* K9 j( y) {5 W
The physical examination revealed a very active,
4 P$ ], W1 x( q# J# j0 Q  i8 Uplayful, and healthy boy. The vital signs documented8 L' B6 n! E$ G! F
a blood pressure of 85/50 mm Hg, his length was
& y3 j" c+ d( w; |( W1 h90 cm (>97th percentile), and his weight was 14.4 kg) a. I# Y  _1 {
(also >97th percentile). The observed yearly growth
# D, D( {1 o- F  w$ Pvelocity was 30 cm (12 inches). The examination of6 ?: x: j6 F& j* f  q$ ~3 a% I" C* V
the neck revealed no thyroid enlargement.
/ e6 B0 V: i' q/ h( Z  X" tThe genitourinary examination was remarkable for
# |, ^7 m8 B5 K% H& \enlargement of the penis, with a stretched length of
+ F5 X3 v) |% o  }2 Y. e8 cm and a width of 2 cm. The glans penis was very well
, B( L$ F7 {# Ndeveloped. The pubic hair was Tanner II, mostly around% \/ W+ U. U. u, _) S
540
1 F+ s) y2 r& w" `6 n0 Pat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
) f7 F( I* ~* t1 y' {) D6 _the base of the phallus and was dark and curled. The
9 m& r1 b; l, d$ A' x4 Ptesticular volume was prepubertal at 2 mL each.0 N9 U/ s' X& Z; k+ d* d4 d0 o
The skin was moist and smooth and somewhat, _8 r1 d* I5 P
oily. No axillary hair was noted. There were no/ W7 W0 k7 {1 B8 i7 C6 Q
abnormal skin pigmentations or café-au-lait spots.5 p( I6 `! ~& k! I9 a
Neurologic evaluation showed deep tendon reflex 2+7 ?# `. M' t# n) S3 Q
bilateral and symmetrical. There was no suggestion& m3 G' F0 ^" w$ f5 v
of papilledema.8 k2 w3 F# Y- e, x
Laboratory Evaluation" h, k, G- u- h5 s
The bone age was consistent with 28 months by# a& r3 C/ F8 F- F
using the standard of Greulich and Pyle at a chrono-' R& j8 {2 h) \; w" m' W
logic age of 16 months (advanced).5 Chromosomal
( n- C% p! z, s" b" B* w5 bkaryotype was 46XY. The thyroid function test
( l$ _: `6 `3 d: n7 `$ I9 M/ Nshowed a free T4 of 1.69 ng/dL, and thyroid stimu-
+ N2 b# D  B# @' j1 |lating hormone level was 1.3 µIU/mL (both normal).7 W3 b6 W+ n: E5 m" f
The concentrations of serum electrolytes, blood" v* e& i6 X; }! R( E0 \
urea nitrogen, creatinine, and calcium all were
5 W- b4 u' k% m( Owithin normal range for his age. The concentration
! S" w/ T. ^4 s* o% G1 {" ^of serum 17-hydroxyprogesterone was 16 ng/dL
3 C6 _: c4 @, ~; X" ~" A/ l(normal, 3 to 90 ng/dL), androstenedione was 20
0 E" ]7 Q& \$ ?ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-6 ]5 @7 ?% t/ E. p& u
terone was 38 ng/dL (normal, 50 to 760 ng/dL),5 N& T! [) Z* c& w. K, l
desoxycorticosterone was 4.3 ng/dL (normal, 7 to
9 Z% H7 C% d; L" ~49ng/dL), 11-desoxycortisol (specific compound S)
7 \3 f/ K1 r7 o* ~" m8 Swas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-  {6 ?% }# ?% F! k4 ]
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total$ \8 A+ d6 p& \/ N* X: d$ q
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
( j! z2 d! s1 |9 G, [5 u3 ]and β-human chorionic gonadotropin was less than
; y7 Z1 \/ G+ ^; a- l5 mIU/mL (normal <5 mIU/mL). Serum follicular9 ~# P( c% y6 s1 P" C* d' ]
stimulating hormone and leuteinizing hormone
0 r& S6 T; l) n" E& Kconcentrations were less than 0.05 mIU/mL
# U5 h6 q7 @: ]. m(prepubertal).
) r- X  W9 s0 Z8 p' W! c: e( eThe parents were notified about the laboratory" W: S6 C! C$ k: D: ]2 }
results and were informed that all of the tests were6 B' @& j' {9 Q7 f
normal except the testosterone level was high. The
8 b( `! i) m; Lfollow-up visit was arranged within a few weeks to* c3 b2 q) c3 Q+ y* F3 s
obtain testicular and abdominal sonograms; how-1 Z4 e* U2 _9 w' Q+ X# m
ever, the family did not return for 4 months.
, D1 ]( o6 O* |( }, zPhysical examination at this time revealed that the
% h. N! Q. H7 _: ^. {" O+ Uchild had grown 2.5 cm in 4 months and had gained
1 k2 q1 p4 h/ D# {0 v9 B2 kg of weight. Physical examination remained2 `. p, a% g2 `& S
unchanged. Surprisingly, the pubic hair almost com-2 Y, I  M! d* G3 \2 G; x
pletely disappeared except for a few vellous hairs at
9 ]4 ^$ o# ]+ o" B8 Pthe base of the phallus. Testicular volume was still 2
7 r( L2 i# f. t) r, W# cmL, and the size of the penis remained unchanged.3 c, A5 @& {& \& A
The mother also said that the boy was no longer hav-
9 g/ x7 Q' ~  E5 V- n0 Sing frequent erections." \& b; ?& c+ d3 P9 K
Both parents were again questioned about use of' e+ f0 j2 D. w8 B% H6 i
any ointment/creams that they may have applied to
" ?2 B' h! o% \% mthe child’s skin. This time the father admitted the  ]( t$ p* Y! q0 F0 n
Topical Testosterone Exposure / Bhowmick et al 541* j; K# I2 v( ?+ \
use of testosterone gel twice daily that he was apply-9 _* z1 z- z# d: H8 @
ing over his own shoulders, chest, and back area for8 \- ^2 `7 o! J' ]2 J, z% Z
a year. The father also revealed he was embarrassed- D! Y" w/ ?2 E* H8 {, i
to disclose that he was using a testosterone gel pre-# C" T# G) F: _6 x3 q
scribed by his family physician for decreased libido! i9 K1 `3 S2 c" P
secondary to depression.- y$ y" m8 u# A& V0 m
The child slept in the same bed with parents.5 A8 F1 _! ~1 N+ p0 @. h/ i& o, e
The father would hug the baby and hold him on his7 m  U" K9 |1 ]$ C' P1 Q- L9 k
chest for a considerable period of time, causing sig-& q: x; p: \$ M; \
nificant bare skin contact between baby and father.
# r+ B3 d. F' E0 s* w, T6 [# @# q+ `The father also admitted that after the phone call,
7 ~1 R" I  n' C' C" I6 Lwhen he learned the testosterone level in the baby
9 q" l8 N2 K2 Q: D: b% jwas high, he then read the product information
3 y# Q# }# P# f, \+ Epacket and concluded that it was most likely the rea-
* M7 Z! O4 z* c% M- C' cson for the child’s virilization. At that time, they" [9 B, R5 j3 u- K! H* }* [
decided to put the baby in a separate bed, and the- D, N- C2 e  i: }
father was not hugging him with bare skin and had" K, K! q! o7 m: U
been using protective clothing. A repeat testosterone. g8 A% x: }9 E) |, L
test was ordered, but the family did not go to the
/ L7 H1 `4 S  o( P! Elaboratory to obtain the test.& j& l! B0 L0 G3 q4 O
Discussion: |0 m3 B0 q8 S$ e5 n
Precocious puberty in boys is defined as secondary' }, D1 [! M7 l! U) W
sexual development before 9 years of age.1,4# t6 F7 m5 o1 `9 f9 G( Z4 y
Precocious puberty is termed as central (true) when, o  V+ b2 k5 d' g" G
it is caused by the premature activation of hypo-
7 t9 l& `" @7 W% o: Vthalamic pituitary gonadal axis. CPP is more com-; }3 q4 X7 ]- |
mon in girls than in boys.1,3 Most boys with CPP
# t% R7 [8 f/ E" v' m7 cmay have a central nervous system lesion that is- w7 o, S7 g! ]/ n3 l8 P
responsible for the early activation of the hypothal-5 D- O, m% I% G  c
amic pituitary gonadal axis.1-3 Thus, greater empha-& q, j6 v, z0 g; c- T* s
sis has been given to neuroradiologic imaging in
6 h4 \+ c$ w) E8 wboys with precocious puberty. In addition to viril-
- b; x- L: `4 `1 @, Q) b8 Bization, the clinical hallmark of CPP is the symmet-
1 `% j% \! g! N- @* Jrical testicular growth secondary to stimulation by5 S9 p1 `8 z' f0 q" U2 K) Q6 e
gonadotropins.1,3* [+ s. J% [4 R4 U
Gonadotropin-independent peripheral preco-
# W. Z& x+ r) S: {. t3 x. a% Ecious puberty in boys also results from inappropriate
! U5 u4 [6 }# D0 iandrogenic stimulation from either endogenous or: H+ t2 W. L# s, x) B- y, A
exogenous sources, nonpituitary gonadotropin stim-
2 C# B3 Y+ B& [9 t6 yulation, and rare activating mutations.3 Virilizing
) n) y1 |6 U$ c% L" U1 lcongenital adrenal hyperplasia producing excessive
$ N+ V* Z3 s" ]# dadrenal androgens is a common cause of precocious
' z8 x% U1 c8 h0 C: l1 q' d" `puberty in boys.3,4
8 S( I0 B" n. t+ B8 x* ]. P0 GThe most common form of congenital adrenal5 W8 t/ n: ~7 W
hyperplasia is the 21-hydroxylase enzyme deficiency.) y: T  r6 e, i' L' t
The 11-β hydroxylase deficiency may also result in
' p2 s& c& @# V8 [$ X' Lexcessive adrenal androgen production, and rarely,
  a, v, W+ _. _! L' c) ean adrenal tumor may also cause adrenal androgen8 |0 _( f: J" R# C; y+ M: }' s  R
excess.1,34 ~- ?$ {9 F+ a0 p" P0 |( U0 N" a
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from% Y8 O7 c: P9 ?9 |% w4 ]3 [3 C
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007- K' M6 R: J/ O5 V) `* u- d5 o
A unique entity of male-limited gonadotropin-
2 A0 H/ c) z$ X" J0 Lindependent precocious puberty, which is also known
8 s- w( h: q4 c4 b8 I! V9 @% eas testotoxicosis, may cause precocious puberty at a
" t% e! P( d7 B( ?/ k5 N$ `0 y7 Y! Svery young age. The physical findings in these boys3 e1 S. A- }3 k3 A; @( c; w
with this disorder are full pubertal development,% C5 k' S9 Q: G7 T8 [+ }
including bilateral testicular growth, similar to boys- ~3 q. z, i+ ~4 _+ u  A8 T% ^
with CPP. The gonadotropin levels in this disorder
, i' g7 p1 _  Y# P' T# Hare suppressed to prepubertal levels and do not show; s( A1 m1 S- \# q% ]
pubertal response of gonadotropin after gonadotropin-- Q+ K2 Z7 t" h$ i* e2 n
releasing hormone stimulation. This is a sex-linked
! g9 x- U. r# O- q$ d* I+ u9 \autosomal dominant disorder that affects only, `! W, A+ U: u' v' A) s4 L
males; therefore, other male members of the family. L9 m9 l! @6 O" [
may have similar precocious puberty.36 Y0 j6 `: Y% K/ S6 Z+ D) b
In our patient, physical examination was incon-% M- o9 S* a/ M3 U% A
sistent with true precocious puberty since his testi-
4 G% Z# j* o1 ?; f' kcles were prepubertal in size. However, testotoxicosis! d* h$ [, k" n0 ?! V' c
was in the differential diagnosis because his father, R1 C; {* U; u& Z( |/ U
started puberty somewhat early, and occasionally,
3 D: n% K1 Y6 U! S% j- {6 ktesticular enlargement is not that evident in the0 z; a; V4 ^9 \! a1 p
beginning of this process.1 In the absence of a neg-
/ H! f: \7 A3 [, J4 t* k3 `ative initial history of androgen exposure, our0 m: o7 V0 _* n" O7 J
biggest concern was virilizing adrenal hyperplasia,
- r1 A# b) d3 ]either 21-hydroxylase deficiency or 11-β hydroxylase/ x; e6 ~6 V, t
deficiency. Those diagnoses were excluded by find-/ l+ ~* ~6 n) s8 e/ Y
ing the normal level of adrenal steroids.
' z! A* d9 O' S4 OThe diagnosis of exogenous androgens was strongly
& j# @- `# I9 G) n) z1 q' Rsuspected in a follow-up visit after 4 months because, l& i' v6 o7 n, i6 Y7 |
the physical examination revealed the complete disap-
: p( C7 _* F6 O( U  C6 T! Ypearance of pubic hair, normal growth velocity, and0 {4 t0 p- D3 [4 ^$ X
decreased erections. The father admitted using a testos-
/ w4 \* d+ Q$ a! vterone gel, which he concealed at first visit. He was
. X8 l8 C- x* K/ u, I( P! `+ Jusing it rather frequently, twice a day. The Physicians’! A: `( g* X( {- a8 t9 ^" A; W
Desk Reference, or package insert of this product, gel or
' \# d- h4 W; x& Ycream, cautions about dermal testosterone transfer to
: V' `  v* |, D5 {unprotected females through direct skin exposure.
* Y' ?- p/ z5 V  s! C1 c$ rSerum testosterone level was found to be 2 times the. [: H5 u. k- U* g
baseline value in those females who were exposed to8 w8 {4 r; o, n" R9 V  f
even 15 minutes of direct skin contact with their male& r( J1 W, a( K: x4 O0 x/ T
partners.6 However, when a shirt covered the applica-
# ?6 Y) \3 J+ U+ u( `6 t0 [tion site, this testosterone transfer was prevented.5 [6 r( H$ }7 S  m* v5 e
Our patient’s testosterone level was 60 ng/mL,  I0 T- O+ l* L0 O
which was clearly high. Some studies suggest that! z$ F& j7 d( q: _2 l* f) O
dermal conversion of testosterone to dihydrotestos-- [1 S. @% B. e9 o0 p
terone, which is a more potent metabolite, is more
- F1 Y/ R% q" D( Qactive in young children exposed to testosterone9 T, q. P9 f3 m+ ~. k
exogenously7; however, we did not measure a dihy-: M6 r1 ?" z; R3 J
drotestosterone level in our patient. In addition to0 @2 V: O: G# m5 E7 F/ _/ v
virilization, exposure to exogenous testosterone in& q& m) [0 J8 [+ F: O' E1 _" z
children results in an increase in growth velocity and
3 D% q' n" t* ]* Y$ [advanced bone age, as seen in our patient.+ i3 z8 ^0 i) {" V7 g( V% ?8 I
The long-term effect of androgen exposure during
  d$ K, U/ k$ w) b8 w( n* F+ zearly childhood on pubertal development and final5 X% C; n0 o5 c/ a" I8 S& n8 d+ s( k
adult height are not fully known and always remain# H9 J7 f. W2 {% D8 \0 z1 W
a concern. Children treated with short-term testos-
; y, G7 x" d8 ^" rterone injection or topical androgen may exhibit some( o, c9 P  B1 M' o' i  J5 k
acceleration of the skeletal maturation; however, after5 Y  ~6 N5 @, U: Y# k
cessation of treatment, the rate of bone maturation, r% V* Q( m" E# o6 L
decelerates and gradually returns to normal.8,92 O  X/ g  `" a5 w$ X  M3 |
There are conflicting reports and controversy
! A9 C6 W8 Q$ Z# U8 Z  l8 [over the effect of early androgen exposure on adult9 [; m* v' a  N4 \! i! f3 h
penile length.10,11 Some reports suggest subnormal4 b1 @$ n0 `9 W, J2 V; U3 g. J
adult penile length, apparently because of downreg-: ]% H/ g- X6 e, v) x9 C; M
ulation of androgen receptor number.10,12 However,
2 \0 m4 t3 |2 ISutherland et al13 did not find a correlation between
  W8 z: D* R4 C2 C1 K  }9 z+ M. K  Schildhood testosterone exposure and reduced adult# J0 E& x; B4 N' n
penile length in clinical studies.. y3 v9 S: I4 `+ ?1 @
Nonetheless, we do not believe our patient is
' A9 J: M1 U+ ?$ V1 wgoing to experience any of the untoward effects from
* [. i; C6 Q3 P: c: p0 ~testosterone exposure as mentioned earlier because3 _) b3 r$ |  x( O# ^
the exposure was not for a prolonged period of time.
. Y/ y# Z1 n9 R/ JAlthough the bone age was advanced at the time of
6 ^# A/ G  s+ t5 w/ Hdiagnosis, the child had a normal growth velocity at
" T; Q& Y# \0 s! [2 uthe follow-up visit. It is hoped that his final adult. H, A, p  n0 R/ d3 s- [/ ~
height will not be affected.
5 o- P0 q: b2 jAlthough rarely reported, the widespread avail-
5 y; ^2 ?) l  b1 sability of androgen products in our society may9 D8 J( E7 d  E. r2 c' w* O2 n
indeed cause more virilization in male or female: b! W* H5 O& i5 A7 Q: J2 N
children than one would realize. Exposure to andro-' v4 D/ m- c: f0 `/ N: e
gen products must be considered and specific ques-
: a  E- k5 N+ v, ationing about the use of a testosterone product or9 T1 S' k+ r6 O, m
gel should be asked of the family members during' b( g( x% l8 B3 o! b' V
the evaluation of any children who present with vir-9 o1 c% w. t' i2 [0 I
ilization or peripheral precocious puberty. The diag-
8 ?; J, u; s6 v0 Lnosis can be established by just a few tests and by
! H  X  N' H! vappropriate history. The inability to obtain such a0 X7 c' V8 a8 @  v  j1 l
history, or failure to ask the specific questions, may
$ J4 I. w$ Y7 t& q% \) @result in extensive, unnecessary, and expensive
- r$ \0 h  R3 Z* @5 O, D& Cinvestigation. The primary care physician should be
  S/ V$ |( t) Y! Caware of this fact, because most of these children
" A# x. j* l. U) \may initially present in their practice. The Physicians’
  p$ q6 I1 U! e# nDesk Reference and package insert should also put a
9 ^/ t) a/ D1 n) N7 `3 ^- k# Swarning about the virilizing effect on a male or- q8 ^" }9 ~. w3 A3 Q
female child who might come in contact with some-" F% W7 `: @4 G2 F9 ?
one using any of these products.: T% E. |8 g$ N  {: G/ o9 q2 {
References
& k7 @2 }; x1 z( {1. Styne DM. The testes: disorder of sexual differentiation
/ v% k2 }4 B* D0 x1 ^and puberty in the male. In: Sperling MA, ed. Pediatric
2 q2 t# q1 {4 L$ N  A! ~Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;% e. g7 e$ ]& j- f3 K
2002: 565-628.
, b% U/ i% i7 |% @4 V: A4 d$ z2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious& g2 z* h1 X# [) E
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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3 t0 F7 }4 a  U: d精妙絕倫的精品,感謝啊!期待你更多更好的創作哦!
發表於 2025-3-11 12:31:56 | 顯示全部樓層
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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