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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
; d0 H9 q+ _' i8 w" J% hBoy Induced by Indirect Topical! P; A4 K- _, l  v9 P$ K
Exposure to Testosterone: E8 i! J" N9 j% q; W6 l
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2* _7 ?1 {7 ^) y+ J" A8 x: s
and Kenneth R. Rettig, MD1
/ @) s) Z, T4 {4 _; pClinical Pediatrics
6 i/ L7 V4 o" vVolume 46 Number 6
& y) q7 f+ w- w2 i- J+ E6 tJuly 2007 540-543% j$ y! _0 k6 U  V; f- f0 ^
© 2007 Sage Publications9 ^' F* I! G8 ^, c
10.1177/0009922806296651
0 R. w( }. a# U1 n( xhttp://clp.sagepub.com
1 A8 _% b- N' y) n* O, q/ D4 Ihosted at4 n6 O! o3 y7 D4 v
http://online.sagepub.com  H' ~9 s" k( Q( @' j3 @3 ]  E
Precocious puberty in boys, central or peripheral,0 e* b! c0 ~. q
is a significant concern for physicians. Central
% h$ g- T+ P$ x. N9 Kprecocious puberty (CPP), which is mediated4 ?3 b. w" S7 j7 U  ^- A
through the hypothalamic pituitary gonadal axis, has
* s- m  |0 u. g4 d% m% ?7 E. {- Y% Ia higher incidence of organic central nervous system% |7 |. K4 S! V* m0 V2 }' Q
lesions in boys.1,2 Virilization in boys, as manifested
# d( O, X! p- k  ~; N  b% K& Eby enlargement of the penis, development of pubic# K) S  N. y) L+ E
hair, and facial acne without enlargement of testi-7 V+ S" S$ L6 K" \
cles, suggests peripheral or pseudopuberty.1-3 We5 [" ^+ b( s8 K$ ?* y
report a 16-month-old boy who presented with the! P6 Q; g1 I3 B
enlargement of the phallus and pubic hair develop-
$ g6 p# t! r3 c8 E5 \$ C& Dment without testicular enlargement, which was due8 c( c$ b2 {, H1 u
to the unintentional exposure to androgen gel used by0 ]& F5 A) o, ]! f
the father. The family initially concealed this infor-
+ x7 ?) O4 g" t: \3 dmation, resulting in an extensive work-up for this3 X) `0 H3 @+ Y1 N, {+ N# e! ^
child. Given the widespread and easy availability of
5 K1 G7 n1 _" g6 K% vtestosterone gel and cream, we believe this is proba-
' p" b( Z! T5 t3 |5 G8 e7 ]bly more common than the rare case report in the
. k2 d# Q. ]! u/ I6 w" E" Pliterature.40 w# \- m2 i$ l4 l
Patient Report
# |2 x! a, z9 ]4 |% Z# _# R0 p' B, C9 t4 zA 16-month-old white child was referred to the) j: ^0 e, p* j# W7 T) t
endocrine clinic by his pediatrician with the concern! M: }4 J* ~, X8 k, z' ~
of early sexual development. His mother noticed
! b4 f) K2 s0 klight colored pubic hair development when he was
1 x# `+ E, r% N. G$ [From the 1Division of Pediatric Endocrinology, 2University of  I" `2 P( p5 `8 ?
South Alabama Medical Center, Mobile, Alabama.
* K8 l- J1 Z4 _Address correspondence to: Samar K. Bhowmick, MD, FACE,7 p4 t8 F# [4 k6 w
Professor of Pediatrics, University of South Alabama, College of5 {0 O% Y8 l; e' b' g
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;  g* @9 J7 j( B6 i
e-mail: [email protected].
; x0 ^8 }% ?: m) F5 ]about 6 to 7 months old, which progressively became
: Z: N- e6 `& @$ Ndarker. She was also concerned about the enlarge-9 ^) a+ s6 M9 @$ B% M( O. z' M
ment of his penis and frequent erections. The child
6 N+ o! \, M  `. t: N, k8 Ewas the product of a full-term normal delivery, with
/ l- A. H+ g$ Y, Ka birth weight of 7 lb 14 oz, and birth length of
7 f9 |5 e* V8 ]& k20 inches. He was breast-fed throughout the first year0 U& n! k4 D) p6 Z, C5 m% K
of life and was still receiving breast milk along with
9 A7 B" L, @5 l! n: isolid food. He had no hospitalizations or surgery,
+ K9 u; R3 @: z5 Cand his psychosocial and psychomotor development
8 j* }7 [! [8 o$ vwas age appropriate.
% ]5 y* ~+ ]2 _& IThe family history was remarkable for the father,
7 m6 u  ~$ n5 Lwho was diagnosed with hypothyroidism at age 16,
& l* V% D" m) ^! _$ c  P0 }2 vwhich was treated with thyroxine. The father’s: }# x1 k7 \1 k& b9 H1 n
height was 6 feet, and he went through a somewhat( N0 x! D' O" O8 |6 [! b0 i
early puberty and had stopped growing by age 14.
; C0 j9 v' F  g$ mThe father denied taking any other medication. The
5 q& T; q$ l7 Q; I3 \! Ochild’s mother was in good health. Her menarche4 o" z" e$ Y5 k: Q
was at 11 years of age, and her height was at 5 feet: @" E" k( I0 z; s+ s
5 inches. There was no other family history of pre-
; P' D$ y5 H5 l2 ncocious sexual development in the first-degree rela-
* u1 P/ a3 P  V1 J- ctives. There were no siblings.: a* i- p- e, v0 o7 n* U
Physical Examination/ |2 }% [7 s! J  G! W
The physical examination revealed a very active,
, S5 Z/ m4 f7 r$ d8 r2 o! [) Oplayful, and healthy boy. The vital signs documented7 B9 {( j3 @. n% l% x% {/ Y
a blood pressure of 85/50 mm Hg, his length was" h; @8 O) b: p
90 cm (>97th percentile), and his weight was 14.4 kg
0 j/ Y: Z/ r* u" v6 \(also >97th percentile). The observed yearly growth
0 t6 }" z6 v. ^. {& }1 ~, y( i* Nvelocity was 30 cm (12 inches). The examination of
5 y8 o. E1 n5 Y1 ~: y+ ?" t/ uthe neck revealed no thyroid enlargement.6 L# ^: h: `/ }: K* {
The genitourinary examination was remarkable for
+ g% L+ t3 ?. ?$ senlargement of the penis, with a stretched length of) ]9 i2 U1 R2 D( b
8 cm and a width of 2 cm. The glans penis was very well) G1 P: X: k  j
developed. The pubic hair was Tanner II, mostly around% o% j! o" N6 A  M! {
540
# \  b2 R' E8 c% @at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
+ r, F! F7 h5 m7 B+ W& T6 `+ y4 |* {the base of the phallus and was dark and curled. The
6 ?: V0 y7 H0 o- }6 C( Z+ C" O. o- f/ [testicular volume was prepubertal at 2 mL each.1 P1 T( \7 n# q
The skin was moist and smooth and somewhat2 U0 Q3 u  V7 j; H
oily. No axillary hair was noted. There were no
3 T$ X, t% M: z1 Wabnormal skin pigmentations or café-au-lait spots., _+ W- }$ l1 v! b" a5 `4 F
Neurologic evaluation showed deep tendon reflex 2+
: L% ~! N' b& R. o) L) Z$ zbilateral and symmetrical. There was no suggestion( z# e* \' s7 l
of papilledema.7 {( ]" F' _: }- F+ Z5 H
Laboratory Evaluation
8 F$ t/ {; j: k) xThe bone age was consistent with 28 months by
3 f7 z! y0 C( ^- `using the standard of Greulich and Pyle at a chrono-
' A. w6 B( Z1 l; Llogic age of 16 months (advanced).5 Chromosomal4 `; x7 D- S" K) X
karyotype was 46XY. The thyroid function test
; n5 N3 V8 |1 p; J% Bshowed a free T4 of 1.69 ng/dL, and thyroid stimu-9 y1 V# h9 a0 B5 ]
lating hormone level was 1.3 µIU/mL (both normal).  |5 ]" K7 O) V4 d3 N
The concentrations of serum electrolytes, blood8 r8 W7 ?8 F8 b7 c/ q
urea nitrogen, creatinine, and calcium all were
) ^2 \7 b3 m$ @; gwithin normal range for his age. The concentration5 w( E8 \- x) q3 ^# S
of serum 17-hydroxyprogesterone was 16 ng/dL
( P4 J! X3 l. U  u2 M(normal, 3 to 90 ng/dL), androstenedione was 20
4 |8 {5 j& \' `ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
! _! U0 l3 K! n+ A1 k! m$ vterone was 38 ng/dL (normal, 50 to 760 ng/dL),2 |* a- _* B5 l; l4 ?& W, _/ s
desoxycorticosterone was 4.3 ng/dL (normal, 7 to
3 X, }  l4 U- Z3 y) w49ng/dL), 11-desoxycortisol (specific compound S)
- u, Q2 j; d/ b8 ]# A; w+ twas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
7 [$ x; R/ [- N5 v: Htisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
- v1 {5 a0 j1 F- otestosterone was 60 ng/dL (normal <3 to 10 ng/dL),
. r. Q# {) ?1 j0 M3 `% Mand β-human chorionic gonadotropin was less than
, i. J7 R; m4 C4 n5 mIU/mL (normal <5 mIU/mL). Serum follicular; V# {  q0 ?* ?$ _
stimulating hormone and leuteinizing hormone
/ [) g1 A9 b/ J) v$ g4 Pconcentrations were less than 0.05 mIU/mL
2 x* t5 c1 f/ Y6 W, j/ d* Q9 ](prepubertal).
7 N" I- f' q+ v) B3 G( ]7 mThe parents were notified about the laboratory' Z, [3 n- W8 H8 T( }
results and were informed that all of the tests were" W/ G6 `* W& {/ Y# }: N& O
normal except the testosterone level was high. The
/ i) {: e8 _5 ~2 ]; tfollow-up visit was arranged within a few weeks to
8 o" i  |. U5 h( O/ e1 m7 W( H  }9 {obtain testicular and abdominal sonograms; how-
1 E: |2 I8 X5 O( M9 Mever, the family did not return for 4 months.( f9 f) c3 e: E) ]: [! n7 ~
Physical examination at this time revealed that the) j: [& u) }# v8 J
child had grown 2.5 cm in 4 months and had gained
+ s- h  |1 Z! \# m9 n0 x* C; N3 @2 kg of weight. Physical examination remained
9 \. @: d% t9 J5 R0 Bunchanged. Surprisingly, the pubic hair almost com-
; ?4 Y) w+ U, v  ipletely disappeared except for a few vellous hairs at: d2 _/ U! J1 |' t* w$ {
the base of the phallus. Testicular volume was still 22 H( V& l, d  s9 n. d3 a/ G0 H
mL, and the size of the penis remained unchanged.
, N; ~& ^) n3 {# |' AThe mother also said that the boy was no longer hav-
: I, C5 {& \3 o, ~0 V# K+ ^ing frequent erections.
1 Y2 k2 E4 a" F& F) i; vBoth parents were again questioned about use of
. l8 c; [7 x: G3 P8 ~any ointment/creams that they may have applied to) d, a3 S% Q& e0 A. m3 g: t! M* [
the child’s skin. This time the father admitted the
; w  L! }2 d# U7 t) yTopical Testosterone Exposure / Bhowmick et al 541
3 [- H# {  x* ]/ y& _7 Huse of testosterone gel twice daily that he was apply-
4 o6 j# [- T) a, E- |3 v5 a# S: Ring over his own shoulders, chest, and back area for8 S" x1 g. I0 h4 K- \. t
a year. The father also revealed he was embarrassed
5 J( B1 A) I7 w% Jto disclose that he was using a testosterone gel pre-4 x" o, t9 I+ e  z  g: ]( D2 v
scribed by his family physician for decreased libido1 d& N" [& ^* }- E  A
secondary to depression.5 _" F( y" b+ j2 E. x. J
The child slept in the same bed with parents.+ R) Z  d' E' Q' P. A. _
The father would hug the baby and hold him on his  t- _0 X5 a% q; V- b) y
chest for a considerable period of time, causing sig-: E) _" u* w, T( R
nificant bare skin contact between baby and father.
# m  q" i# H+ T, XThe father also admitted that after the phone call,0 I. p4 B5 `' H" E
when he learned the testosterone level in the baby
! Z! ~4 n; d% `- s7 wwas high, he then read the product information
  C  o# u5 w+ x* U1 B* b1 qpacket and concluded that it was most likely the rea-7 w: I& {9 U: M  P# Y+ {/ |
son for the child’s virilization. At that time, they
3 r6 y; _9 P' M, E" U1 S# Tdecided to put the baby in a separate bed, and the
5 N. |# y1 ]- N% Rfather was not hugging him with bare skin and had. ^( y4 m1 m7 U. `$ X
been using protective clothing. A repeat testosterone  E* l+ N; T& ~7 y) P6 Q
test was ordered, but the family did not go to the
4 A0 \8 R% j0 r7 s" j' V! ^laboratory to obtain the test.9 Z9 l0 u- A+ t
Discussion- s8 o$ k2 a0 I: i% i' u# e! r
Precocious puberty in boys is defined as secondary& f7 I! O  U6 S' u+ S0 ^
sexual development before 9 years of age.1,4" z+ I$ k' t8 K- p% E" u$ ~% E+ @
Precocious puberty is termed as central (true) when
! \3 t# T! N" r6 |  }( b/ `it is caused by the premature activation of hypo-
5 [0 [& z: X' u' ^9 \  V* Z1 a3 \thalamic pituitary gonadal axis. CPP is more com-
9 o. Y; a2 m7 A& R/ S) a) qmon in girls than in boys.1,3 Most boys with CPP1 b" [8 d! [/ A
may have a central nervous system lesion that is& X4 n1 a4 W) b/ E
responsible for the early activation of the hypothal-
5 d, e. y* h! e- {4 g% Pamic pituitary gonadal axis.1-3 Thus, greater empha-  m1 b1 V4 v3 k- Z
sis has been given to neuroradiologic imaging in
) C, ?& t9 }0 h% {4 l# Kboys with precocious puberty. In addition to viril-
- F) p9 {" h0 C7 }' @% ~  G( Hization, the clinical hallmark of CPP is the symmet-
, `: c  f- c' c2 Yrical testicular growth secondary to stimulation by. x+ M1 U. A/ Y; f5 W
gonadotropins.1,3! c& o7 Y0 d! e4 a8 Y$ }$ h; P
Gonadotropin-independent peripheral preco-
2 t9 L' H0 S. w0 g3 A% y2 W( N! Rcious puberty in boys also results from inappropriate* J7 N* t: X8 Z' g
androgenic stimulation from either endogenous or
. y% W- T; }# w1 r8 p8 A) D+ zexogenous sources, nonpituitary gonadotropin stim-
6 z- T, j) _3 R& wulation, and rare activating mutations.3 Virilizing4 c* V1 Z) J& M6 ^- f
congenital adrenal hyperplasia producing excessive
- Y  o# H# d! J% g- r: l5 Madrenal androgens is a common cause of precocious/ ~  B/ w0 B0 ?3 I
puberty in boys.3,4
, Y/ N: N( R4 {3 Z7 O  d: b. X* K# fThe most common form of congenital adrenal
" j5 p7 x0 M3 P6 u- q4 Rhyperplasia is the 21-hydroxylase enzyme deficiency.
. p# W4 o0 X. FThe 11-β hydroxylase deficiency may also result in
: p9 @. y3 L# D  U  R1 Oexcessive adrenal androgen production, and rarely,5 F7 U& ]0 `0 o6 R& e7 J
an adrenal tumor may also cause adrenal androgen0 _+ v: N$ u" ~
excess.1,3
2 G. M! n. C" D/ _1 J5 c! @at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
$ X( Y1 V) T8 q$ ^' D/ |542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
; V2 |8 O$ j$ U) w& W& w! UA unique entity of male-limited gonadotropin-) ?, ]. t# v( u) C- ^
independent precocious puberty, which is also known
7 `3 x8 ]+ L" q$ v  A- T9 `" Xas testotoxicosis, may cause precocious puberty at a
( k. R- s* r- p+ L" K5 k* Tvery young age. The physical findings in these boys
( Y3 q' C! I$ W' b/ [+ s* X) A- swith this disorder are full pubertal development,( v" x5 A$ {# M! l% ]3 l/ }/ W
including bilateral testicular growth, similar to boys
, o- m/ n* V# B) a. }. H! [7 Qwith CPP. The gonadotropin levels in this disorder
* j  A& ~& j) S* f5 a3 Lare suppressed to prepubertal levels and do not show9 B8 ]8 B; E  L
pubertal response of gonadotropin after gonadotropin-
* {8 ]5 r) ~! }releasing hormone stimulation. This is a sex-linked- I+ Y9 C& d# k( V6 N) m( N* a& C. U
autosomal dominant disorder that affects only' }  ~4 b: L- r: M" ^3 T
males; therefore, other male members of the family
" [5 r* P: ~4 I) A/ x( hmay have similar precocious puberty.3
8 m& D5 e. |4 U6 e+ JIn our patient, physical examination was incon-/ _6 `1 q, _2 c+ n) U, h( I; h2 `
sistent with true precocious puberty since his testi-. l$ s2 C% A) e" O
cles were prepubertal in size. However, testotoxicosis
; D4 P4 D! I2 I+ f' S4 C% \- Bwas in the differential diagnosis because his father! f# c/ D! m% u% ]# d1 U
started puberty somewhat early, and occasionally,
( R  l6 W4 D6 a) P4 \1 h& P" U+ Mtesticular enlargement is not that evident in the
: L! d9 \0 a' zbeginning of this process.1 In the absence of a neg-+ T+ H) d: b' r$ R+ A5 P
ative initial history of androgen exposure, our
+ N8 m! D8 k$ R+ H- D; f( |& nbiggest concern was virilizing adrenal hyperplasia,9 q' i* O& w  h. E  n& ~
either 21-hydroxylase deficiency or 11-β hydroxylase
) K( B' b4 d4 f- [9 N' kdeficiency. Those diagnoses were excluded by find-
1 x, ?: m" T8 u, ring the normal level of adrenal steroids.
) ~& P  R( `8 A# `/ [The diagnosis of exogenous androgens was strongly# T% o4 U6 u+ z8 X/ C! O2 G4 A
suspected in a follow-up visit after 4 months because8 W4 J- v# {1 S+ P% z
the physical examination revealed the complete disap-( C: g% k7 j1 z3 S' N8 z1 l
pearance of pubic hair, normal growth velocity, and( z% p1 x" q$ A. y: X7 U2 g
decreased erections. The father admitted using a testos-
4 _( a& _9 A$ h. G: @terone gel, which he concealed at first visit. He was3 N; |, o5 S9 A
using it rather frequently, twice a day. The Physicians’5 U, J5 i% `3 J
Desk Reference, or package insert of this product, gel or. e# Z9 M. L' L
cream, cautions about dermal testosterone transfer to: @+ I$ A) Y* _0 ~& M
unprotected females through direct skin exposure.% z' \" s$ G3 D& Q' w, z
Serum testosterone level was found to be 2 times the, L1 \( Y/ W! r% A* b+ b
baseline value in those females who were exposed to, l. F- P' U' o# s3 K
even 15 minutes of direct skin contact with their male6 Z8 E8 D4 l9 c/ ^: @* x) k
partners.6 However, when a shirt covered the applica-
9 o- }2 F% u3 K7 W7 qtion site, this testosterone transfer was prevented.8 q$ _3 ]. {0 ~1 |  ^" X( F
Our patient’s testosterone level was 60 ng/mL,
( ~! r. s& i* ]% r+ s' Cwhich was clearly high. Some studies suggest that
8 ^3 Y  j8 o( N, ddermal conversion of testosterone to dihydrotestos-( @1 o8 t( e2 r& I& d
terone, which is a more potent metabolite, is more8 \3 ~) w8 m$ D* \4 w, P/ ~
active in young children exposed to testosterone1 @- I4 G' Y' F
exogenously7; however, we did not measure a dihy-
9 o) j" S, ]3 G0 odrotestosterone level in our patient. In addition to+ ^- G; G. P9 y6 O0 z$ R* V+ j
virilization, exposure to exogenous testosterone in+ s! O; j; c/ b5 d- l0 p$ s4 w
children results in an increase in growth velocity and! c, P, o7 L& ]: }2 A) K( v/ ?
advanced bone age, as seen in our patient.* X, M9 I! t, n+ O: ?
The long-term effect of androgen exposure during: ~* P2 L' A/ p$ W0 Y2 a
early childhood on pubertal development and final7 W1 E& D& F! N' j( `
adult height are not fully known and always remain$ l7 {+ U. C- |% m) G$ |
a concern. Children treated with short-term testos-6 W: l" ~' E* x- m+ }- h5 u* v% Z  s
terone injection or topical androgen may exhibit some& ~6 A. {2 y9 ^  d/ v
acceleration of the skeletal maturation; however, after
5 @, [  t0 h+ g+ u! M- Acessation of treatment, the rate of bone maturation
# g( R/ n3 k( P; ?8 D) z% Gdecelerates and gradually returns to normal.8,9* g5 @; J% X& M  i% l4 A5 `
There are conflicting reports and controversy% w# f, y+ n$ q, [# J! i
over the effect of early androgen exposure on adult
7 E9 P( _5 A5 T/ |8 e0 _penile length.10,11 Some reports suggest subnormal" _( w/ A# _+ ?5 p3 f, w
adult penile length, apparently because of downreg-8 \6 n, |: m# j2 ^
ulation of androgen receptor number.10,12 However,
9 @' }% S$ X; y0 x! N/ PSutherland et al13 did not find a correlation between& P, r% P- M: @! _
childhood testosterone exposure and reduced adult
4 z2 c+ M* c4 o2 R8 q* ?! M6 l3 cpenile length in clinical studies." `, @3 h' U- C3 i  l% v7 e
Nonetheless, we do not believe our patient is
% B0 Q( A. H& q/ Jgoing to experience any of the untoward effects from
$ h# i+ M" F( s" M1 Q: N  Wtestosterone exposure as mentioned earlier because
; W% O1 O6 a' v5 M) n( d; Uthe exposure was not for a prolonged period of time.' z8 Q4 r: B7 D. u0 M
Although the bone age was advanced at the time of5 N6 e- Q( I/ m4 s  z( y
diagnosis, the child had a normal growth velocity at/ X( v- C2 S+ B) h* V& @
the follow-up visit. It is hoped that his final adult3 {8 {+ `5 P# m' F2 i
height will not be affected.9 U* V4 S9 F. `- Y" v, P" B
Although rarely reported, the widespread avail-  i) B3 y0 |7 y; A- P
ability of androgen products in our society may
" b' L2 O5 K! n& k* Vindeed cause more virilization in male or female
3 ?8 u4 c1 u0 H4 P7 Ichildren than one would realize. Exposure to andro-
% @2 [6 w2 I, vgen products must be considered and specific ques-1 H9 f) Y6 ~* U% M; |
tioning about the use of a testosterone product or
$ e6 ?; S; P# b0 c" i/ ygel should be asked of the family members during
6 t9 j7 e3 S6 a6 S  qthe evaluation of any children who present with vir-& a9 V7 j: m1 `' ?! o
ilization or peripheral precocious puberty. The diag-7 g* o( v+ A% [0 ~: V5 S) h8 x
nosis can be established by just a few tests and by
5 E3 S1 ~1 a+ s) A* uappropriate history. The inability to obtain such a- m! l  `8 T9 Y* \, f2 p
history, or failure to ask the specific questions, may
  J- |/ i! G! u. @/ H6 vresult in extensive, unnecessary, and expensive: g* U3 I% z4 Y1 h
investigation. The primary care physician should be* o1 i8 D/ p: l8 D6 _9 N! Z3 i
aware of this fact, because most of these children1 v+ p: I3 w2 [) {
may initially present in their practice. The Physicians’
% D9 [1 E2 h9 [& `4 FDesk Reference and package insert should also put a: R- ?* ~+ e3 ~
warning about the virilizing effect on a male or
' r1 S* T, m: T6 M  K, o0 gfemale child who might come in contact with some-
" h( @& \# p, e  vone using any of these products.$ Y6 N: A8 R, P) T4 M
References
2 k" t7 L2 o6 G( @$ d8 l& A1. Styne DM. The testes: disorder of sexual differentiation
' M7 R' q- F: ^5 a, Iand puberty in the male. In: Sperling MA, ed. Pediatric; g& G0 j/ }, G/ X" h8 S+ T
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
3 M! @$ d& B8 f4 v  o2002: 565-628.
0 s0 h2 X. T- |# p! \' L' D2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious& r8 w' A. x& l: m- u% I& Z
puberty in children with tumours of the suprasellar pineal
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Sexual Precocity in a 16-Month-Old
$ _; C; f( @0 W! jBoy Induced by Indirect Topical2 v- Y: e* v5 f, m! J
Exposure to Testosterone
5 ]/ z& W" f% l, `3 DSamar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
) s  {+ _1 f' d- |; ]1 cand Kenneth R. Rettig, MD1; y' w$ R/ t' B, v4 c
Clinical Pediatrics
3 _1 Z; H7 H# e' p! v' j) |Volume 46 Number 6
1 H& l  @+ Y2 l" m, Y& u+ cJuly 2007 540-543
4 N: F# c2 v( s8 H8 B: w8 W© 2007 Sage Publications) D9 f  Z7 t7 q
10.1177/0009922806296651+ T0 q, B9 h9 Z* K
http://clp.sagepub.com
9 z  n6 P" f3 T4 G" Hhosted at! w! A. R; G0 `8 ?' e% `* X% l
http://online.sagepub.com* V- S0 E; R0 p' T% x& N) q
Precocious puberty in boys, central or peripheral,
4 y  i8 o/ F1 l$ O* F$ h0 ^is a significant concern for physicians. Central6 K1 }$ J3 |9 ^
precocious puberty (CPP), which is mediated
$ y2 m/ {' v) W* M* g6 |& V2 i) f2 \through the hypothalamic pituitary gonadal axis, has* {: J+ f5 d/ z6 @( t  D/ \
a higher incidence of organic central nervous system1 n, N( N  t) _+ ]; V7 j( a9 _
lesions in boys.1,2 Virilization in boys, as manifested3 J3 l* J: f1 e# }! u
by enlargement of the penis, development of pubic0 @" D2 b/ |, q# ~4 v
hair, and facial acne without enlargement of testi-1 X0 q3 f. u+ l0 o/ F
cles, suggests peripheral or pseudopuberty.1-3 We  E" ^  X$ q, j, G
report a 16-month-old boy who presented with the
3 A9 `2 B3 w. J  Menlargement of the phallus and pubic hair develop-2 I+ L& d; j! z' ~
ment without testicular enlargement, which was due' M4 S" M7 [' F$ [
to the unintentional exposure to androgen gel used by* s6 N/ r7 f' l- [. k) P
the father. The family initially concealed this infor-  i! u5 x* d2 _6 U/ g
mation, resulting in an extensive work-up for this
2 k+ r, h8 s4 ~; k0 w) T8 kchild. Given the widespread and easy availability of$ q4 R, v3 ]0 e+ p
testosterone gel and cream, we believe this is proba-
' L3 S8 W' f* a$ f# L* D/ P1 z- ^: bbly more common than the rare case report in the
6 b( H2 }/ g3 }5 Rliterature.4
6 _# U, ~' e% X! f8 y! ZPatient Report
4 a9 w9 T0 Z( w% j0 EA 16-month-old white child was referred to the
7 a6 h: h9 Z; W6 t9 z! ^" o9 Vendocrine clinic by his pediatrician with the concern: j6 m% G& D) F
of early sexual development. His mother noticed
! b$ K/ a1 S* d: l/ F! Tlight colored pubic hair development when he was
1 f- s; ^( u6 mFrom the 1Division of Pediatric Endocrinology, 2University of$ k9 W' u/ r& _% C! |
South Alabama Medical Center, Mobile, Alabama.% \( |# ~4 v- \$ ^6 N
Address correspondence to: Samar K. Bhowmick, MD, FACE,
7 y" m( }. z) J; y1 ?8 |- u: MProfessor of Pediatrics, University of South Alabama, College of
$ K+ I& q& ^+ Z  f- TMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;2 G- W$ ^, K) J3 Z1 c' _" L
e-mail: [email protected].3 G' c  E) d! C! e2 c
about 6 to 7 months old, which progressively became
# o/ E9 G0 a+ b& @% N' ^) Hdarker. She was also concerned about the enlarge-. Z) `7 s5 }" ~; L) y" [$ l9 I
ment of his penis and frequent erections. The child
% M1 N  |" A7 R& Awas the product of a full-term normal delivery, with& D  v2 l" [! v# y# N: L
a birth weight of 7 lb 14 oz, and birth length of
" u' u* y, L& Y$ e" q# F. i20 inches. He was breast-fed throughout the first year
. q9 x2 d& |# N7 S  p, |of life and was still receiving breast milk along with" x" E/ i1 F" A+ R3 }% T
solid food. He had no hospitalizations or surgery,# ^/ C9 o: d9 R8 B' X% P) V
and his psychosocial and psychomotor development8 G7 h/ F' ~! @: ~* b7 u
was age appropriate.; k9 Y' J0 u& |" x6 o
The family history was remarkable for the father,: O: G5 o$ g6 ]) o& X, M
who was diagnosed with hypothyroidism at age 16,! l# r1 E2 V' T8 t
which was treated with thyroxine. The father’s
# C7 }$ h- O: nheight was 6 feet, and he went through a somewhat
( \$ u5 t4 M/ N  Hearly puberty and had stopped growing by age 14.3 ^) E* ?; a" U6 J9 e2 ?) Q+ a
The father denied taking any other medication. The+ {  z9 H7 e. S5 D
child’s mother was in good health. Her menarche
, U& \$ e( F/ I7 E& O' \was at 11 years of age, and her height was at 5 feet$ }0 d" n  z7 S8 N
5 inches. There was no other family history of pre-
9 P& D! |4 a4 k; z  K" T  ^cocious sexual development in the first-degree rela-
' h6 e1 S, _- t( ttives. There were no siblings.
/ D' R2 e, n  N% t* R  KPhysical Examination
7 p% T; y* F" [# mThe physical examination revealed a very active,
# A( ~# u" B7 C" O' n4 p* u# @& \playful, and healthy boy. The vital signs documented
. \+ n% A/ D6 X1 Z3 U" Ia blood pressure of 85/50 mm Hg, his length was
2 z6 U: Z: w9 H5 C- }$ ~5 Q( H90 cm (>97th percentile), and his weight was 14.4 kg
* w9 o9 K  ?1 I(also >97th percentile). The observed yearly growth
- L& Y# h0 \% k# [5 \6 xvelocity was 30 cm (12 inches). The examination of
# k! c, K; O% Xthe neck revealed no thyroid enlargement.
& j6 t: l) ?; j9 z( ^7 bThe genitourinary examination was remarkable for) ~" T( }- [! c$ G, _
enlargement of the penis, with a stretched length of
+ L. [. `2 I+ v: U- V7 x8 cm and a width of 2 cm. The glans penis was very well
! @/ \9 e1 \" C' ?1 Q1 @+ h5 ?* ndeveloped. The pubic hair was Tanner II, mostly around
# g1 g8 V0 Q! U3 P' t- V) _$ _5406 Y$ v' Y! N3 W, C5 m! R, J
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from  S1 O( T6 T: m+ J: m( {" c1 q
the base of the phallus and was dark and curled. The
% n7 [& B% v2 V: ttesticular volume was prepubertal at 2 mL each.+ H% ]% s" v8 h) H% l, r
The skin was moist and smooth and somewhat( h8 `( t, T7 l% Q/ Z  k
oily. No axillary hair was noted. There were no
& I4 ?  E' ?8 N5 {4 Gabnormal skin pigmentations or café-au-lait spots.$ \3 L6 W8 W3 p$ j) e
Neurologic evaluation showed deep tendon reflex 2+# r' |; ^" W" w
bilateral and symmetrical. There was no suggestion) K0 q# f0 X7 U: Z3 j! z
of papilledema.
( i% W! w& w. K# }- A2 ^Laboratory Evaluation( s4 |$ U" t, z! p6 S0 n& N
The bone age was consistent with 28 months by
/ @& ?1 b0 `7 Q9 ^3 z! z3 Vusing the standard of Greulich and Pyle at a chrono-' _- g# U2 ~2 s) D1 w8 a& A0 x8 ~
logic age of 16 months (advanced).5 Chromosomal
$ }8 m) s$ \: K$ m- _karyotype was 46XY. The thyroid function test( m; e2 W: a0 L) K0 Q
showed a free T4 of 1.69 ng/dL, and thyroid stimu-
/ K; R7 c# l+ c3 n- L* ]lating hormone level was 1.3 µIU/mL (both normal).: T& S5 T# l; C, `  I0 Q& n0 c
The concentrations of serum electrolytes, blood
" ~9 k; \- C% I/ Vurea nitrogen, creatinine, and calcium all were
% @/ v6 |# I6 ?within normal range for his age. The concentration
- n5 I- h/ b5 ~4 ^! n, ]of serum 17-hydroxyprogesterone was 16 ng/dL) G0 J5 @! J* |, ?- k% h9 B
(normal, 3 to 90 ng/dL), androstenedione was 20
  \4 S: K" K9 n1 ong/dL (normal, 18 to 80 ng/dL), dehydroepiandros-5 ?4 ]4 V/ H5 f" N- G4 E
terone was 38 ng/dL (normal, 50 to 760 ng/dL),
7 I' S0 N6 i: H5 o  Odesoxycorticosterone was 4.3 ng/dL (normal, 7 to8 B2 u1 E: T/ u8 J: H" k5 G
49ng/dL), 11-desoxycortisol (specific compound S)1 _4 ?* [3 [) ~1 G+ B+ j
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-6 D# i2 a  @0 }! I4 _0 z9 q
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
' e& C; ]7 B( ~8 Ptestosterone was 60 ng/dL (normal <3 to 10 ng/dL),
- A7 L" y. [. Z5 _and β-human chorionic gonadotropin was less than
; \4 S; h% |3 n! J5 mIU/mL (normal <5 mIU/mL). Serum follicular; \4 f  w/ }" y* w# F5 H
stimulating hormone and leuteinizing hormone
$ U  C  [* s1 _$ o! Tconcentrations were less than 0.05 mIU/mL% @$ l/ S) t' @8 C! g
(prepubertal).
" [( V# X* E+ VThe parents were notified about the laboratory8 `$ u; p( O6 k% ~; m. Z
results and were informed that all of the tests were
( x7 s; w# {/ ?+ lnormal except the testosterone level was high. The% @( o" P$ I& z8 @  A3 m( V
follow-up visit was arranged within a few weeks to
4 R# v1 L8 h$ T& p, [obtain testicular and abdominal sonograms; how-
1 P* X6 K: W" s* @2 K$ E% Vever, the family did not return for 4 months., e, T0 E: l0 t$ s& Z
Physical examination at this time revealed that the
+ Z3 Q5 r1 v) _; n$ T4 R5 A" S/ ^9 uchild had grown 2.5 cm in 4 months and had gained
/ q; {% D' l2 D% n9 J2 kg of weight. Physical examination remained5 n7 }" q- ~3 V. _* O/ H
unchanged. Surprisingly, the pubic hair almost com-4 u  J) [) i9 k6 [( f7 x3 X
pletely disappeared except for a few vellous hairs at' B' t" V/ |+ \9 m) n
the base of the phallus. Testicular volume was still 2( N2 B# a& {: b' l% p
mL, and the size of the penis remained unchanged.- \, A$ V# f( ~
The mother also said that the boy was no longer hav-
2 r$ K7 }: |: r7 Z3 e5 L% xing frequent erections.
5 h7 E, \8 D9 O% u4 C5 _Both parents were again questioned about use of9 [! T4 @) d' T
any ointment/creams that they may have applied to/ @" V, @2 k1 u4 n6 l4 e
the child’s skin. This time the father admitted the6 T' p! l; s7 o( a1 g
Topical Testosterone Exposure / Bhowmick et al 541
2 {& G) F! P7 R! quse of testosterone gel twice daily that he was apply-
* r/ f, o  Q! ^8 h9 Q8 Ting over his own shoulders, chest, and back area for1 x9 Z8 S% e5 L4 J) K
a year. The father also revealed he was embarrassed+ a( P' j7 }+ k: w
to disclose that he was using a testosterone gel pre-" w# X( h/ I, X8 N: _- v
scribed by his family physician for decreased libido
  I6 J7 v6 s- p2 I  |% @" Psecondary to depression.: H9 S! I( U( v
The child slept in the same bed with parents.+ X5 L1 p+ x( ~" \
The father would hug the baby and hold him on his
. u' S( g" c3 M2 _chest for a considerable period of time, causing sig-, z' w9 T$ w+ \1 O% S
nificant bare skin contact between baby and father.
/ ]; c7 g3 b4 O% MThe father also admitted that after the phone call,- y0 X: T6 l  X' b" i
when he learned the testosterone level in the baby) |# p1 s, ~& y/ N. f/ g: q& D
was high, he then read the product information, F* I0 W* R9 Y. e6 n; ~
packet and concluded that it was most likely the rea-9 t. `5 f( k: ^8 E3 z+ }5 u
son for the child’s virilization. At that time, they
- J. g$ @5 B/ s' Rdecided to put the baby in a separate bed, and the2 j) f% }- @) H' g
father was not hugging him with bare skin and had! o2 K. ~6 T3 [1 F
been using protective clothing. A repeat testosterone# Y# U2 ^3 {) b$ |) L1 z* M
test was ordered, but the family did not go to the
8 W5 U% Q- l2 y: zlaboratory to obtain the test.
& N8 O3 q! b. @* xDiscussion/ p7 C3 a1 ?, A9 \& Y# s) z
Precocious puberty in boys is defined as secondary
4 M1 b5 z2 }  b- lsexual development before 9 years of age.1,40 d) b. R1 O' P0 d, m0 N
Precocious puberty is termed as central (true) when
# ?. ]. I$ I% ~it is caused by the premature activation of hypo-2 c4 E5 k2 F% J5 E8 {) U4 g
thalamic pituitary gonadal axis. CPP is more com-3 b+ T9 ]0 W! v( r( S2 ]/ u
mon in girls than in boys.1,3 Most boys with CPP. x7 f+ w5 K- Q; t
may have a central nervous system lesion that is
7 W9 X  q% A" t7 I9 z, s* M  zresponsible for the early activation of the hypothal-1 b% M5 b# S) p7 ?  S. r8 f! a2 F
amic pituitary gonadal axis.1-3 Thus, greater empha-1 F, D: |) q5 L1 f" I  j1 P
sis has been given to neuroradiologic imaging in! _1 i) W2 \. g1 n
boys with precocious puberty. In addition to viril-6 f9 f+ @* Q1 d+ \) A) S/ |
ization, the clinical hallmark of CPP is the symmet-+ Z3 R2 K- d5 d7 k" ]
rical testicular growth secondary to stimulation by! S8 ]+ r& |; R" @. p' c
gonadotropins.1,3* `2 x# y" ]* w/ N4 B7 ]& P
Gonadotropin-independent peripheral preco-1 b/ K; o. v0 X) o7 |; g  d
cious puberty in boys also results from inappropriate0 z# ]* f6 x5 P: f0 d0 C
androgenic stimulation from either endogenous or9 t8 a+ b. o9 z+ R1 O7 d" z% ~
exogenous sources, nonpituitary gonadotropin stim-
! S2 s5 w# Z, P; @ulation, and rare activating mutations.3 Virilizing' d, J- M9 b4 U& ~- i: ]
congenital adrenal hyperplasia producing excessive
7 a/ }) U/ u1 m, c6 {$ l% Gadrenal androgens is a common cause of precocious' }7 ?7 v& V1 p3 ]- n, S; q: e; H3 }
puberty in boys.3,4* r; i0 t+ `2 I. @/ H" |; C; D' D
The most common form of congenital adrenal( O: w, l( b* l$ n
hyperplasia is the 21-hydroxylase enzyme deficiency.
5 c$ @; g8 @* y* Q( W$ j2 CThe 11-β hydroxylase deficiency may also result in2 W+ {: g; G1 u
excessive adrenal androgen production, and rarely,7 i& T  S. ~( _, v  x& P
an adrenal tumor may also cause adrenal androgen( e' a) o# T  P$ Q4 {
excess.1,3, D1 U* `; @- j+ X6 f% b
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from; B/ H; t8 E' |( K+ F3 c0 V; x- r
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007  U/ O( f+ T) o% I
A unique entity of male-limited gonadotropin-, Z3 B  m6 b8 s$ Z! `
independent precocious puberty, which is also known
7 x/ y" [" W4 @- S0 yas testotoxicosis, may cause precocious puberty at a$ @5 x  |0 J$ L/ {" l
very young age. The physical findings in these boys" f# I$ w* @- j' [9 \2 Z1 h4 R
with this disorder are full pubertal development,& t1 L1 H* B" c: m. t
including bilateral testicular growth, similar to boys" l  T9 h# {& [9 D: }5 }; Z% [& |
with CPP. The gonadotropin levels in this disorder8 e' R% r7 a3 A* Q5 ]0 \" h; l
are suppressed to prepubertal levels and do not show5 L# _2 ^$ `4 W3 S& `: j
pubertal response of gonadotropin after gonadotropin-5 _% w- [" W/ y$ L2 t
releasing hormone stimulation. This is a sex-linked1 k3 f2 f7 _4 j$ _+ M% R/ F
autosomal dominant disorder that affects only
: ~* _7 w3 j# ^9 `males; therefore, other male members of the family
* F% h. N7 b6 n& z8 D& _# r& Vmay have similar precocious puberty.3' g9 u% }2 y4 H% G$ d- F' U! M
In our patient, physical examination was incon-+ [" L" p8 ~& l6 G
sistent with true precocious puberty since his testi-
" {* f+ [& `1 F2 t. Pcles were prepubertal in size. However, testotoxicosis
5 a* g0 n; y. E) u6 I, b/ ywas in the differential diagnosis because his father
5 q8 P2 Y' B2 {6 B" Mstarted puberty somewhat early, and occasionally,5 {( z& R; z/ t6 M
testicular enlargement is not that evident in the
: |+ \$ U( _3 u- `' ]$ n3 ~beginning of this process.1 In the absence of a neg-' n8 ]: @' r0 j3 l
ative initial history of androgen exposure, our9 P! W" _% C' n: z  p
biggest concern was virilizing adrenal hyperplasia,
1 g! R1 a) x9 Yeither 21-hydroxylase deficiency or 11-β hydroxylase
# |; ~5 O: r. Q  pdeficiency. Those diagnoses were excluded by find-
: N# c) Z) k8 i4 H& u2 B5 l' `ing the normal level of adrenal steroids.
$ D$ @2 u7 L6 X5 }& K1 J3 fThe diagnosis of exogenous androgens was strongly! Y, m6 t, @  H$ l! P3 p
suspected in a follow-up visit after 4 months because
9 I- y3 w+ A0 o* R" A2 Sthe physical examination revealed the complete disap-
& \7 B/ A; j6 g% g' ~, O# f1 Dpearance of pubic hair, normal growth velocity, and- a( f7 Y7 e+ |, b- u' B5 L1 g- j7 W* D
decreased erections. The father admitted using a testos-
; S% N% v" r* l+ f8 Iterone gel, which he concealed at first visit. He was0 C% g* {0 O$ q1 j+ @% `
using it rather frequently, twice a day. The Physicians’0 x/ B: y. E( l
Desk Reference, or package insert of this product, gel or6 b" \  b- W1 W
cream, cautions about dermal testosterone transfer to! r, R6 h" E2 g
unprotected females through direct skin exposure.
9 @# D( Z  L6 l8 JSerum testosterone level was found to be 2 times the
. @/ Q+ [+ ~4 D4 M( p3 x+ w' p; ibaseline value in those females who were exposed to  ^. s9 E' K1 p
even 15 minutes of direct skin contact with their male( J8 p* h3 u6 x/ T
partners.6 However, when a shirt covered the applica-0 P% V" b# C. T: J+ H
tion site, this testosterone transfer was prevented.
/ Y; u! k+ y3 x8 |$ Y& `- N- iOur patient’s testosterone level was 60 ng/mL,% F  C& ^# ^" p, W8 N; l
which was clearly high. Some studies suggest that
  t# _) R1 d4 T3 g4 Tdermal conversion of testosterone to dihydrotestos-
! m! S: K* s/ oterone, which is a more potent metabolite, is more
/ x: R- Y: z* aactive in young children exposed to testosterone! n+ E  Z3 t, j2 V# q; }  {
exogenously7; however, we did not measure a dihy-- G* k1 Z0 s* S- S9 \/ \# C
drotestosterone level in our patient. In addition to
+ P! k* D! H$ ]0 `3 Hvirilization, exposure to exogenous testosterone in
  b5 ^/ W1 |1 T( m5 l6 {8 L  vchildren results in an increase in growth velocity and" @5 a0 p4 P; I' l" q
advanced bone age, as seen in our patient.
6 @$ O+ A$ H6 R* L+ n0 }- O7 t" GThe long-term effect of androgen exposure during8 Y1 R. \) D+ i
early childhood on pubertal development and final- H1 }$ S8 A- _' ^+ k
adult height are not fully known and always remain% b) e+ z0 b( p2 M$ w* X
a concern. Children treated with short-term testos-
2 m: h) z8 T2 ?  }, rterone injection or topical androgen may exhibit some
/ X6 V; U1 B6 z3 P8 ]% Uacceleration of the skeletal maturation; however, after
- w5 c( i3 ]4 {+ ?* Q; ?cessation of treatment, the rate of bone maturation
& _" W5 W& R/ i* B" Ndecelerates and gradually returns to normal.8,9) y4 r1 z# {8 _* ]2 R3 i- f
There are conflicting reports and controversy; g, l3 G5 y) b& t5 J  I3 Q5 h8 R8 \
over the effect of early androgen exposure on adult
0 g. z0 C" [  q) y& v. n. q- Vpenile length.10,11 Some reports suggest subnormal% {/ s6 _& x5 B# [6 h
adult penile length, apparently because of downreg-+ \4 |1 H. ?, q8 w5 v- W* s
ulation of androgen receptor number.10,12 However,  S, }3 a) T! m! y! |7 S: j" z6 D
Sutherland et al13 did not find a correlation between$ T3 T& b5 h, z7 D! r% [, n3 E
childhood testosterone exposure and reduced adult& o* X6 t: S9 a$ I6 u, [
penile length in clinical studies.
& G( G" l7 j! d! N1 H. W% FNonetheless, we do not believe our patient is
2 |4 N1 A6 [7 _2 |* i4 Cgoing to experience any of the untoward effects from
( @& I- @5 ~, j0 `testosterone exposure as mentioned earlier because% X2 |7 R; y  ?0 ~5 W
the exposure was not for a prolonged period of time." q  [# R2 [8 O
Although the bone age was advanced at the time of
' @  O4 N# J$ b4 @diagnosis, the child had a normal growth velocity at
$ O( r" Z0 K! L; |1 W- _the follow-up visit. It is hoped that his final adult% Q% x, X/ |- P& @( s
height will not be affected.
  G1 |( i& o+ H& d9 {Although rarely reported, the widespread avail-- A7 b- i# H6 O9 U* k
ability of androgen products in our society may1 S/ B) v0 K2 z, Q
indeed cause more virilization in male or female
6 T# e) R3 u4 ~* Kchildren than one would realize. Exposure to andro-0 w* {. u" J# B3 j$ p
gen products must be considered and specific ques-2 K! v6 r+ B, H/ W7 M. m
tioning about the use of a testosterone product or
, z0 ^5 F8 K7 Lgel should be asked of the family members during9 t  L0 S! a/ }: n  Z0 \
the evaluation of any children who present with vir-
. q- @9 o' V& a$ z0 Dilization or peripheral precocious puberty. The diag-" a# W: h* W  b4 i
nosis can be established by just a few tests and by" J5 z+ }9 ]/ o5 W3 ]* d# z* |
appropriate history. The inability to obtain such a
/ h9 H3 J) N2 ?) e0 }history, or failure to ask the specific questions, may" W: G, j2 `: }* _4 t# S
result in extensive, unnecessary, and expensive. R* R4 b9 Y5 D* E) L
investigation. The primary care physician should be# I5 ?7 Y6 ]/ K* L
aware of this fact, because most of these children, `/ T! N* m) Y7 [# c  I. d. `- C$ y
may initially present in their practice. The Physicians’
4 O- ]7 s9 I6 o: |1 u/ xDesk Reference and package insert should also put a. V& p/ q+ w5 ~
warning about the virilizing effect on a male or  \0 j7 A7 Q, z8 D6 g) z
female child who might come in contact with some-3 R3 S  {1 O' X
one using any of these products.
; J: K1 Y( G/ u% r$ t7 O6 B% jReferences1 l* y0 X* g; q
1. Styne DM. The testes: disorder of sexual differentiation
5 A6 C, M+ {3 `! Gand puberty in the male. In: Sperling MA, ed. Pediatric
$ w% @& X; v* b1 N% L: k/ H* \Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
) f1 J2 d, p! _9 h2002: 565-628.+ ^3 U3 W5 j" ~/ e2 s& I9 ]
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
+ B( \7 G* l* A: |- Lpuberty 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
1 v/ V( a( B  |' c7 \5 d( C1 u! P9 m
精妙絕倫的精品,感謝啊!期待你更多更好的創作哦!
發表於 2025-3-8 22:04:50 | 顯示全部樓層
絕對的好貼!謝謝啊!逐字逐圖地看完這個帖子以後,我的心久久不能平靜,感恩啊!
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