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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
& f  ~0 v: H" b2 F" p/ h+ b& hBoy Induced by Indirect Topical
4 g0 R* Q1 u: JExposure to Testosterone
- z8 q7 D6 h* W9 R& {) sSamar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,28 D1 Z  V3 R2 r8 ^: k
and Kenneth R. Rettig, MD1
$ K+ W0 f( u3 H4 }7 ]Clinical Pediatrics/ [: r% w( I2 q9 b. z# l
Volume 46 Number 6# n, P) |, D" q: k
July 2007 540-543
/ D. l$ ^# r4 S; H) u9 e© 2007 Sage Publications. @) Y& C$ D* }/ ?9 g5 `$ W
10.1177/0009922806296651' [2 f) D3 G" T: c# c
http://clp.sagepub.com7 O) ~# q1 ]* I6 H5 U" U6 O
hosted at7 m0 I' D" f4 l) ]2 t9 [+ F- ?
http://online.sagepub.com- X0 O# R2 t7 t  o0 t# n" t' j  _
Precocious puberty in boys, central or peripheral,6 k0 i3 T6 f. I
is a significant concern for physicians. Central4 u$ I. O* R7 j3 _+ i
precocious puberty (CPP), which is mediated/ |6 s* j, m& R6 m  g% ]
through the hypothalamic pituitary gonadal axis, has6 e  j( _  P- Q* L
a higher incidence of organic central nervous system0 F1 R8 Z% U8 I; V% Q! `
lesions in boys.1,2 Virilization in boys, as manifested9 U: g, t( U. y9 j' x4 P1 C, |
by enlargement of the penis, development of pubic
2 n: z7 h* ^: m0 V! fhair, and facial acne without enlargement of testi-
2 E7 U$ C5 e, R4 Y# ]cles, suggests peripheral or pseudopuberty.1-3 We
& s9 g5 z# T% ?* F, Areport a 16-month-old boy who presented with the
! e- T' c0 d* Z" P9 p+ z& t8 qenlargement of the phallus and pubic hair develop-; X4 D0 G& ?! y% h1 R5 R  |
ment without testicular enlargement, which was due
# M. g9 v- j! T' \to the unintentional exposure to androgen gel used by
& D9 [3 Y1 B: N+ wthe father. The family initially concealed this infor-
; @: ~) b$ @9 e  k/ {! ymation, resulting in an extensive work-up for this
' }4 H* S# f' Uchild. Given the widespread and easy availability of
6 [  Q0 C: z0 I% V+ w: Btestosterone gel and cream, we believe this is proba-
* w2 f; j$ `* ?& tbly more common than the rare case report in the
" |/ D2 i$ M4 s& {* L/ O3 Rliterature.4- w( L( |* n0 d) u
Patient Report
: P# ]8 j4 ^% @0 G$ q" tA 16-month-old white child was referred to the4 a/ k; A; a5 y' K0 N" {, [
endocrine clinic by his pediatrician with the concern
. W4 s! f9 v& a% Tof early sexual development. His mother noticed
# }' K0 V2 w! R8 Q9 r( Z8 ]light colored pubic hair development when he was: b/ a" Q8 D: j- {4 l- m/ m( t! V/ j/ {
From the 1Division of Pediatric Endocrinology, 2University of
9 N: F2 c& }. V" c0 t9 T6 gSouth Alabama Medical Center, Mobile, Alabama.
/ Z& D, o/ u+ P# DAddress correspondence to: Samar K. Bhowmick, MD, FACE,5 h' Z6 R1 P$ Q# r
Professor of Pediatrics, University of South Alabama, College of
% g; D- _: X& h7 u+ P* J8 HMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
/ l7 {6 B5 k1 ve-mail: [email protected].
5 \0 W) R4 k* g0 ]about 6 to 7 months old, which progressively became5 f2 u8 O0 K5 @- Q; n
darker. She was also concerned about the enlarge-
0 X: M: o+ @0 x% ament of his penis and frequent erections. The child6 Z  U  V( n2 N: W
was the product of a full-term normal delivery, with
- i" S) M* E  F, c) sa birth weight of 7 lb 14 oz, and birth length of, N4 ]6 q! `' i7 Y2 r
20 inches. He was breast-fed throughout the first year+ F, }6 n; X+ J
of life and was still receiving breast milk along with# N. m) ^7 N) |( g+ i* V& n
solid food. He had no hospitalizations or surgery,  N' h7 T0 Z3 T' D9 z
and his psychosocial and psychomotor development7 P5 g2 ]' s. n& K
was age appropriate.; U% x; q  R' j: X8 k8 Y
The family history was remarkable for the father,
& a' E7 m; F5 q( b8 ]; i3 Nwho was diagnosed with hypothyroidism at age 16,
) N. G" w, Z# y" i; |3 b! P( Swhich was treated with thyroxine. The father’s
7 w9 H2 y1 H& [height was 6 feet, and he went through a somewhat
. [/ F- N# l$ Qearly puberty and had stopped growing by age 14.# S( c; v% u- i+ C
The father denied taking any other medication. The
9 H$ s) \& o. Z) [* J# Tchild’s mother was in good health. Her menarche
/ X7 Y8 u3 r$ g7 m3 xwas at 11 years of age, and her height was at 5 feet
8 O$ e4 n0 {0 D- H' x+ l/ u5 inches. There was no other family history of pre-
" k' c) x9 r6 n& h! C  o: t7 l* mcocious sexual development in the first-degree rela-
+ d. d6 H! j3 l) q2 U7 d& Y2 W6 ztives. There were no siblings.# z' \5 D: [: B+ A; z5 @  {
Physical Examination3 m: ]' d! U+ W" v+ @
The physical examination revealed a very active,
# R) Y& ^) y4 x+ M5 I' ?8 O3 s" Dplayful, and healthy boy. The vital signs documented$ f" j# c* ~# W/ Y" G
a blood pressure of 85/50 mm Hg, his length was( t" H  `! G1 B) {, W$ |* |
90 cm (>97th percentile), and his weight was 14.4 kg4 J1 I4 @2 u% T8 A0 Z) I& p5 x
(also >97th percentile). The observed yearly growth
$ e) v; z0 |# t3 w" G- Qvelocity was 30 cm (12 inches). The examination of
. g6 h% H+ Z  l1 q* Y% ^( F  qthe neck revealed no thyroid enlargement.
0 H  g" u3 \# x6 n5 xThe genitourinary examination was remarkable for& m# x( F, w/ n+ f
enlargement of the penis, with a stretched length of+ \) ^! N. u, i; Y* f$ ~  o$ x
8 cm and a width of 2 cm. The glans penis was very well
. u; X; S. w$ m: ideveloped. The pubic hair was Tanner II, mostly around
6 O7 H% K1 Z- t3 H1 a) q540
4 J; {% u- k: U! Fat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
% X5 w. A1 S. C) u) vthe base of the phallus and was dark and curled. The1 T" X* J9 O' @: h, T7 A
testicular volume was prepubertal at 2 mL each.) U( f" j/ [$ Z2 w& p' I1 k0 N
The skin was moist and smooth and somewhat
, e; ^5 q5 R" _3 coily. No axillary hair was noted. There were no0 g' @9 P; j4 z5 `' j
abnormal skin pigmentations or café-au-lait spots.2 N% [4 F* v  s
Neurologic evaluation showed deep tendon reflex 2+% G  z7 o& X: U1 |6 S2 K
bilateral and symmetrical. There was no suggestion
" E7 n' S0 P3 }! }: l( \of papilledema.
5 k/ J- B+ W& ~/ `6 }% _Laboratory Evaluation
3 Y* L: p; _$ J3 S0 j' v$ [. e# LThe bone age was consistent with 28 months by6 L' Z9 K7 F# h: [- p0 J" b
using the standard of Greulich and Pyle at a chrono-
' y6 U* p$ x% W/ S3 C3 Rlogic age of 16 months (advanced).5 Chromosomal
7 E) Z' }. S6 B3 K5 Rkaryotype was 46XY. The thyroid function test
! Z' F. `( y4 Jshowed a free T4 of 1.69 ng/dL, and thyroid stimu-
/ I/ P5 m* r, k8 B1 K- Ulating hormone level was 1.3 µIU/mL (both normal)." u2 r) x- N0 h1 I2 `3 R7 h
The concentrations of serum electrolytes, blood
( A" h2 U# m% _) x0 s) c& n* jurea nitrogen, creatinine, and calcium all were
" Y2 F8 S% x5 C8 @- E2 L( O" t2 Jwithin normal range for his age. The concentration
% R/ C! y. w6 K; T" k- B5 uof serum 17-hydroxyprogesterone was 16 ng/dL
# `% G8 n3 A, p. t0 R(normal, 3 to 90 ng/dL), androstenedione was 20" L  j# D" B! p
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-0 s; |+ R' N! \- B% ^
terone was 38 ng/dL (normal, 50 to 760 ng/dL),* x1 b0 J! Y$ s8 s$ r
desoxycorticosterone was 4.3 ng/dL (normal, 7 to$ N+ r" T+ ?  E
49ng/dL), 11-desoxycortisol (specific compound S)
) K" Q6 E6 z6 K6 D) d/ i* owas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-/ ~0 Y8 c. f& O+ F, c* m& k
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
- ?2 J' |  M8 H5 d) d9 jtestosterone was 60 ng/dL (normal <3 to 10 ng/dL),
+ j4 V% ]$ i; r' L: f0 K9 S) aand β-human chorionic gonadotropin was less than4 b+ i! D0 O9 U( B3 h* s* n
5 mIU/mL (normal <5 mIU/mL). Serum follicular
& z5 w9 ]6 X2 A# k! R- x' Ostimulating hormone and leuteinizing hormone$ i" V+ t2 v% v! B
concentrations were less than 0.05 mIU/mL
# V% {2 \6 ~* H" v5 C(prepubertal)./ p  h. C- Q: N4 {4 K
The parents were notified about the laboratory# }9 L* p3 _* o* W* q1 y: S  s& ~3 _
results and were informed that all of the tests were  y3 i: l+ e% r9 I' d0 S+ g4 s
normal except the testosterone level was high. The" F/ _0 K, S- }
follow-up visit was arranged within a few weeks to2 D: c' U, E: W9 l
obtain testicular and abdominal sonograms; how-
8 _$ J- i; d0 ^- _; dever, the family did not return for 4 months.
- X1 s. B5 p4 C% D  @5 B- qPhysical examination at this time revealed that the
6 s: L% h1 Q' L6 uchild had grown 2.5 cm in 4 months and had gained
. \( a* _- ^# `4 W6 {! F8 C5 ]& L2 kg of weight. Physical examination remained( X# Z, I+ @  ]
unchanged. Surprisingly, the pubic hair almost com-
0 I0 \0 e3 e/ s$ {# S  _) Jpletely disappeared except for a few vellous hairs at4 R; A9 X9 \$ R& Y5 a' G# @3 z
the base of the phallus. Testicular volume was still 2
' C+ ?: S& S8 k( F) R8 lmL, and the size of the penis remained unchanged.+ L4 S, p# c. g3 P( o
The mother also said that the boy was no longer hav-
( g. p2 h9 u* p0 \ing frequent erections.
1 G7 n$ h9 N9 L" `& N% _Both parents were again questioned about use of4 f: b4 ^; I+ {" _. L
any ointment/creams that they may have applied to. |1 x" X* A2 {
the child’s skin. This time the father admitted the
: q. E$ T2 L: d: n6 |Topical Testosterone Exposure / Bhowmick et al 541; {. K; V& t. ^
use of testosterone gel twice daily that he was apply-
. H# z- |2 ^5 Z/ m, p0 @' |ing over his own shoulders, chest, and back area for: ?9 t$ A. {: j" L, p/ s) i; a  ~" H6 C
a year. The father also revealed he was embarrassed3 J  r4 Q" r6 ]3 k  k
to disclose that he was using a testosterone gel pre-! @/ i6 n& I, t; [9 W
scribed by his family physician for decreased libido6 D1 Z4 m- V0 o
secondary to depression.
, \9 s0 a$ N* A' d, T4 D9 DThe child slept in the same bed with parents.
7 f- e: J0 ~# v8 NThe father would hug the baby and hold him on his
$ z5 X, |8 M8 d1 _8 ^  bchest for a considerable period of time, causing sig-
0 O0 K3 U2 i( T( ?nificant bare skin contact between baby and father.
9 d1 t/ v! ?% WThe father also admitted that after the phone call,; K+ @) P8 u0 x' S6 \, Y! h; C/ ?
when he learned the testosterone level in the baby
5 s# V3 T1 \7 X% u5 kwas high, he then read the product information' ~! F0 t* s! {& I5 ~
packet and concluded that it was most likely the rea-/ |; l& v, X2 K4 ^0 f
son for the child’s virilization. At that time, they
, J: v% j! w2 a3 q* E8 p, d# k& Xdecided to put the baby in a separate bed, and the
7 G3 u$ C- y  B$ g3 {4 t/ Mfather was not hugging him with bare skin and had+ E) _! C* ]; }0 d1 y& y+ c
been using protective clothing. A repeat testosterone
; q. ~$ M( w+ ]& W9 Z9 E% ~: {& Stest was ordered, but the family did not go to the3 Y6 V9 _, H8 a2 O) h" Z2 k
laboratory to obtain the test.3 I* L" v: W# K; T# c
Discussion' e# b: e) O1 l- F, t( ^' e- _& `
Precocious puberty in boys is defined as secondary$ ]" Y) e1 b1 x0 J
sexual development before 9 years of age.1,4
% B3 M, X* \: p+ a9 GPrecocious puberty is termed as central (true) when
- F4 s; q2 k! M2 e! J4 I' Hit is caused by the premature activation of hypo-
) K7 P3 q7 [/ V! v4 q  U+ Y  Gthalamic pituitary gonadal axis. CPP is more com-' B0 [' T+ x. f# t$ q0 B6 O0 w: ~
mon in girls than in boys.1,3 Most boys with CPP
& d/ }6 L# i# Nmay have a central nervous system lesion that is8 s/ y% `7 t4 j# |, v5 y
responsible for the early activation of the hypothal-
. N5 \. h- t' S( _' }% eamic pituitary gonadal axis.1-3 Thus, greater empha-# c( P- U& J) M" {( H5 f8 x
sis has been given to neuroradiologic imaging in* b3 R+ W, c5 l7 w. N% P9 A
boys with precocious puberty. In addition to viril-
3 w" A+ H2 E, W9 ~% ?ization, the clinical hallmark of CPP is the symmet-+ ]  q% b$ \6 w3 V0 n: e
rical testicular growth secondary to stimulation by
6 V4 k8 U9 J% h7 r' L" Egonadotropins.1,3# X) \, [3 K' e4 l9 \
Gonadotropin-independent peripheral preco-0 N! ], _4 W0 i! O3 V' G
cious puberty in boys also results from inappropriate
0 W( Z0 A) S8 u7 e3 Q* B* C0 ]" Xandrogenic stimulation from either endogenous or! x/ A2 {7 u- r
exogenous sources, nonpituitary gonadotropin stim-
7 ]( _% a; Y( Q& `ulation, and rare activating mutations.3 Virilizing
9 |7 [" z: u1 J7 Ucongenital adrenal hyperplasia producing excessive
% V4 }6 d  t& O$ |+ ~7 I/ Wadrenal androgens is a common cause of precocious/ V) n$ M: g# z( G3 c. C5 P
puberty in boys.3,4( |3 C& x/ ^; z' R
The most common form of congenital adrenal' F. ~% L1 x* z$ l6 D7 U& Z7 F
hyperplasia is the 21-hydroxylase enzyme deficiency.
6 O1 u9 S7 ^0 o8 D- U- x% \8 cThe 11-β hydroxylase deficiency may also result in
* t& e! S+ _- p- \% Oexcessive adrenal androgen production, and rarely,6 F' i  n! T+ U) n$ f# h' x  ?! L
an adrenal tumor may also cause adrenal androgen6 T4 t: h' ]' V
excess.1,3
4 l- r  V" [$ o) n9 X$ Dat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from5 ^9 a5 q1 r, g0 D
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007: e# Q2 V( J% ], n. O% }
A unique entity of male-limited gonadotropin-8 q" s* |' L' m0 m( t0 p
independent precocious puberty, which is also known
4 W" k- f- N2 f6 Ras testotoxicosis, may cause precocious puberty at a8 ]9 m. {5 F: @& o( {
very young age. The physical findings in these boys8 G. B5 `3 C: \6 X* T
with this disorder are full pubertal development,
$ \" s1 H& [( w( a7 r0 _" ?7 t, wincluding bilateral testicular growth, similar to boys/ [% r- ~, ?; |4 C
with CPP. The gonadotropin levels in this disorder
2 f& ^2 j; M$ aare suppressed to prepubertal levels and do not show% D. a- n" u/ |: \
pubertal response of gonadotropin after gonadotropin-
7 y( A% G+ j3 H# Z6 Z5 Yreleasing hormone stimulation. This is a sex-linked3 A2 ^; h5 D0 S2 J% x7 ]$ y$ O. {
autosomal dominant disorder that affects only
% V- `5 t% f1 y* S  W' n. k8 Gmales; therefore, other male members of the family
& e  p7 ^4 [" F; h% P- Dmay have similar precocious puberty.3, m2 \% y5 A2 B# G( |& _' v
In our patient, physical examination was incon-
' i0 G: j! {( fsistent with true precocious puberty since his testi-. [& o# D- o- u$ [" v5 h( M. M
cles were prepubertal in size. However, testotoxicosis
$ q% ^' b: l0 `. W7 Jwas in the differential diagnosis because his father
2 m; y/ \  n2 ~started puberty somewhat early, and occasionally,
5 N; ^+ ?$ ~; i' N) d8 jtesticular enlargement is not that evident in the
! k. u" D* g  Y2 bbeginning of this process.1 In the absence of a neg-
$ P, b% J2 n6 V, R% _* ?4 ^ative initial history of androgen exposure, our
9 o8 H& S' C+ s; Rbiggest concern was virilizing adrenal hyperplasia,% S7 W: H& I5 g; W2 L3 ~3 n
either 21-hydroxylase deficiency or 11-β hydroxylase
3 F# a9 B+ z5 F" J# Z6 q5 m8 Ndeficiency. Those diagnoses were excluded by find-/ c6 `) _+ n: r$ }, o
ing the normal level of adrenal steroids.
* }0 V" l7 |0 eThe diagnosis of exogenous androgens was strongly
, D# q( O  e. R, r' Asuspected in a follow-up visit after 4 months because
. j  d. @0 y: s* S9 E$ b5 Y9 Pthe physical examination revealed the complete disap-
5 v4 S' U8 m+ C% dpearance of pubic hair, normal growth velocity, and
( V% b3 D* l8 I$ ^7 i! h& tdecreased erections. The father admitted using a testos-# }3 }+ f9 y" }/ ]0 F) H. M( J
terone gel, which he concealed at first visit. He was
8 t0 T# P/ E: x4 n- k. A) \using it rather frequently, twice a day. The Physicians’5 W8 D, x4 H2 P
Desk Reference, or package insert of this product, gel or
% \* u0 t/ R0 y# ycream, cautions about dermal testosterone transfer to& o& W  A" z/ ]* t. X
unprotected females through direct skin exposure.1 W1 F" A5 s, P$ d7 X1 v$ T- j
Serum testosterone level was found to be 2 times the' p0 p0 g! [5 c) o3 X: e
baseline value in those females who were exposed to5 p+ ]5 Y7 Q" m( L# C/ `- @3 r
even 15 minutes of direct skin contact with their male8 d% X4 t1 D1 i$ v9 f9 U, C
partners.6 However, when a shirt covered the applica-
/ j/ S% M# k  g8 [tion site, this testosterone transfer was prevented.
8 h! {* ^  M: d" x8 V# ?- ROur patient’s testosterone level was 60 ng/mL," p# A* `; m) P
which was clearly high. Some studies suggest that' a6 {( N! S( T# V0 y
dermal conversion of testosterone to dihydrotestos-, {2 ~( e$ G0 g& x, a
terone, which is a more potent metabolite, is more
7 }) Y( M$ ]% U. e: H' aactive in young children exposed to testosterone
( U5 c% F0 q5 H5 ^( Wexogenously7; however, we did not measure a dihy-# H" p! _" f$ j6 U4 w- Q8 u; D+ ?
drotestosterone level in our patient. In addition to$ t. j: a5 j( d/ i# p0 T3 ?
virilization, exposure to exogenous testosterone in
& `( N) ~: ^; N3 R7 uchildren results in an increase in growth velocity and
8 q: `3 Y% U, O, H& ^+ ^advanced bone age, as seen in our patient.
7 m/ @& [+ A! j/ w; g$ Q+ JThe long-term effect of androgen exposure during
7 A3 \& X9 h1 ~" H9 {early childhood on pubertal development and final
+ p+ t: L! G4 X9 f8 C' ~' yadult height are not fully known and always remain1 b3 [2 t/ a3 p' f* x3 D1 T& U
a concern. Children treated with short-term testos-
1 ~' d, ~% L; c. Hterone injection or topical androgen may exhibit some& o/ ^& b1 b2 Q  o. b8 h$ d
acceleration of the skeletal maturation; however, after# v$ M$ O5 A" G/ l, B5 a# R2 P. v( w
cessation of treatment, the rate of bone maturation
9 t$ O& x- T- E* o. @* Mdecelerates and gradually returns to normal.8,9. i; R0 J; R' I" V( B
There are conflicting reports and controversy" V) F0 ^2 {- R
over the effect of early androgen exposure on adult5 v6 l' F! m0 q9 K
penile length.10,11 Some reports suggest subnormal; V. h% ^9 [5 K! R  N+ o4 G& P
adult penile length, apparently because of downreg-
0 T6 U: ]$ c8 k- ]% o  Y. ]( Oulation of androgen receptor number.10,12 However,: W5 Q' Z# M/ ?/ t% E
Sutherland et al13 did not find a correlation between
* _' ^! f* b6 X0 j, p/ xchildhood testosterone exposure and reduced adult' J5 _+ E) z/ g& i0 J  J, f
penile length in clinical studies.4 J- V$ J9 P+ M) G' h+ e0 E: c0 L! x
Nonetheless, we do not believe our patient is) Z+ y" R" G: [5 `
going to experience any of the untoward effects from
2 e. D7 y$ ^- Z1 H2 w+ R" G( \testosterone exposure as mentioned earlier because1 w5 L3 L3 ?  z3 N- e
the exposure was not for a prolonged period of time./ c& N# Q; T( y. P0 G' c
Although the bone age was advanced at the time of
5 h7 @7 E& d% t  Zdiagnosis, the child had a normal growth velocity at
; E3 z( W' ?. ?& u5 qthe follow-up visit. It is hoped that his final adult
- K9 _  {' z& F3 Bheight will not be affected.; z8 [, Q/ w4 X0 [- t' [- z
Although rarely reported, the widespread avail-/ N* y1 A8 \. I$ N* a  g& {* B
ability of androgen products in our society may
2 P" ^3 c, W! ]indeed cause more virilization in male or female
& T# q7 ~0 `$ ^children than one would realize. Exposure to andro-! n7 M& A( A, K- _
gen products must be considered and specific ques-
* H4 {6 R" R2 htioning about the use of a testosterone product or
+ v% S( d7 F  E* k8 o. Kgel should be asked of the family members during
8 G" y. a" y. h8 cthe evaluation of any children who present with vir-
- C$ M7 y5 G1 ~; Y5 g/ q+ \ilization or peripheral precocious puberty. The diag-
% U- g) Z3 V* u5 H9 ^nosis can be established by just a few tests and by+ T0 g7 a& {( u& I" V
appropriate history. The inability to obtain such a3 j! T: n/ _2 [$ }6 ]! i/ t. K
history, or failure to ask the specific questions, may
3 f4 n8 i" u/ L" S% zresult in extensive, unnecessary, and expensive3 _% g7 |& x/ K( w0 H6 g) l
investigation. The primary care physician should be
/ E# l9 f2 [1 Z) L) L6 R% laware of this fact, because most of these children
' n9 M4 c: W) K: q' Z2 z# h. emay initially present in their practice. The Physicians’
! D/ @0 \! s( q/ C9 VDesk Reference and package insert should also put a
  P( J1 }1 T* \$ bwarning about the virilizing effect on a male or
" t8 E1 _3 \% [4 J3 ifemale child who might come in contact with some-( L: N1 D* L' S6 m, v
one using any of these products.
7 c$ F1 @! M& [; D. y$ x8 mReferences
0 d; n, o7 p1 ^1 T7 u$ @1. Styne DM. The testes: disorder of sexual differentiation0 u; {4 R2 w, |7 n
and puberty in the male. In: Sperling MA, ed. Pediatric
! t) w$ [& M7 h4 V" i. l; q% ZEndocrinology. 2nd ed. Philadelphia, PA: WB Saunders;# D3 [9 ?2 o* V& |
2002: 565-628., }" X* C8 b1 W0 C; @
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious; @" o! Q  t, B) Z* g. N" |7 x, w
puberty in children with tumours of the suprasellar pineal
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Sexual Precocity in a 16-Month-Old* D" I# C! Q% N+ `3 p- A) |9 |$ O
Boy Induced by Indirect Topical
+ O0 K# i4 p2 L1 f5 i7 jExposure to Testosterone$ c& Y4 g# B% g: j8 f$ ?
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
' a. w/ m2 s3 r1 @8 Y2 E" Dand Kenneth R. Rettig, MD1; u, n  \4 u2 r% H  f
Clinical Pediatrics6 t% T; b  K! b- O  U- C
Volume 46 Number 6
1 F9 J7 v2 N8 ^4 ?0 pJuly 2007 540-543
0 x8 k- M- }( I  Y- l6 c+ s© 2007 Sage Publications
. u3 @, ~$ g' n9 I! u2 i10.1177/0009922806296651
7 Y% K0 R7 {% Z, D$ E2 @( z" thttp://clp.sagepub.com: J9 o' @5 ?# \: o+ f
hosted at1 d+ X" A5 V4 i  _% i8 R& S
http://online.sagepub.com
& ]0 O) T5 C5 E% K, u6 O( ?Precocious puberty in boys, central or peripheral,
' F/ J% N* F+ T( g  ~# W  K% ]4 iis a significant concern for physicians. Central
5 x; ]: ]7 N0 N& y0 u8 e) jprecocious puberty (CPP), which is mediated6 G& c( p" q4 _8 h  f
through the hypothalamic pituitary gonadal axis, has
" Y& r6 l& F% V1 da higher incidence of organic central nervous system- ]3 j, ~* @) N/ C' h  \
lesions in boys.1,2 Virilization in boys, as manifested) D$ c4 v6 f& K& \  `
by enlargement of the penis, development of pubic
1 w9 J# u" W! I. h& Dhair, and facial acne without enlargement of testi-
6 c/ J0 u- D, F% ~2 k# ]; u, Xcles, suggests peripheral or pseudopuberty.1-3 We
6 u+ U$ A5 w# P+ S) P# mreport a 16-month-old boy who presented with the
' ~  a2 s1 L* }. V# e0 ]5 G9 f5 renlargement of the phallus and pubic hair develop-
0 Z8 @& ]0 |. r, ]' s" _ment without testicular enlargement, which was due
7 z6 C+ O4 `* p, w8 kto the unintentional exposure to androgen gel used by  k4 L1 I, y" j2 ~
the father. The family initially concealed this infor-
* R6 z& B. v& h+ U3 _mation, resulting in an extensive work-up for this
% v' r, V+ Z$ I8 t8 r, Schild. Given the widespread and easy availability of
! n, u7 I. g6 _* otestosterone gel and cream, we believe this is proba-- Q+ |) e. ]2 ^( }
bly more common than the rare case report in the7 G+ S$ ?. V) V, e
literature.4" K, K7 _! x, R8 i) A/ [; t
Patient Report1 I4 y3 I+ q6 I: R, _2 }# T4 X
A 16-month-old white child was referred to the
: K# Y0 s8 {2 r% f3 a/ H! Dendocrine clinic by his pediatrician with the concern
) y/ S; L# b# Y% tof early sexual development. His mother noticed
7 P0 u6 k2 j1 ]( _0 _light colored pubic hair development when he was4 g# n% U) D+ d6 ^
From the 1Division of Pediatric Endocrinology, 2University of
# j/ e- b' s+ b3 W7 ySouth Alabama Medical Center, Mobile, Alabama.
( i; J9 h- `. f/ ^& u* W7 uAddress correspondence to: Samar K. Bhowmick, MD, FACE,
7 I# J9 h0 X* \6 @" O% U. N4 bProfessor of Pediatrics, University of South Alabama, College of
* E2 r7 o$ C5 t+ lMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
' q* H* W3 T* i+ U5 ~* d; @' X: z4 _7 Ae-mail: [email protected].1 ]+ Q  `6 W" z: e
about 6 to 7 months old, which progressively became6 r4 ]5 g9 [* j) R" |. |4 v9 s
darker. She was also concerned about the enlarge-
" @1 K- w* d' ?ment of his penis and frequent erections. The child
; r: V4 {& ]8 U+ q2 _9 @0 Z4 Twas the product of a full-term normal delivery, with
1 N/ R, i3 b) d; Ba birth weight of 7 lb 14 oz, and birth length of  r6 U" n4 i2 l! {8 t% B
20 inches. He was breast-fed throughout the first year
  p" v$ C/ q, |: @: w/ vof life and was still receiving breast milk along with
0 ]  h, E3 u) v$ S4 usolid food. He had no hospitalizations or surgery,
3 @9 ^% I1 x' I7 L' m" Wand his psychosocial and psychomotor development
. \  S! b: N- u2 s4 Jwas age appropriate.
+ N/ H! i0 i; ^8 F' _The family history was remarkable for the father,
, c6 f: f; H7 i3 Awho was diagnosed with hypothyroidism at age 16,1 J, S0 C& [1 F# f
which was treated with thyroxine. The father’s" D& }$ d$ n: v- n/ x1 A' |! G- T
height was 6 feet, and he went through a somewhat% w5 Z0 p6 N9 H
early puberty and had stopped growing by age 14.
1 }3 f) u& d* P" rThe father denied taking any other medication. The; K" C' l, o' [' N9 u/ |
child’s mother was in good health. Her menarche2 f* o& V7 u0 l/ N! t$ T
was at 11 years of age, and her height was at 5 feet
7 a$ Q5 J$ \2 ~, j: N5 inches. There was no other family history of pre-; v9 Y/ q* a! j' y  H. t& t9 ?
cocious sexual development in the first-degree rela-
6 ^! n4 ]& D7 e+ K2 @3 D" {! u# R  stives. There were no siblings.
7 R. U3 a1 s3 M; n3 F4 z/ bPhysical Examination
5 Z$ q9 e! c! w9 W( ?The physical examination revealed a very active,
+ d* d! ]7 J1 g, q2 \! Lplayful, and healthy boy. The vital signs documented3 p5 Y- T) t0 e2 d: Y) ?5 R
a blood pressure of 85/50 mm Hg, his length was
2 G; E9 w$ w8 I" N90 cm (>97th percentile), and his weight was 14.4 kg
/ W& w$ N2 e) c6 m1 M1 Y8 ?(also >97th percentile). The observed yearly growth
% E" |2 |! B: p- bvelocity was 30 cm (12 inches). The examination of  X4 Y8 o' v' W  j
the neck revealed no thyroid enlargement.
& _  [$ S3 M9 dThe genitourinary examination was remarkable for" H% N/ T6 f' V' J6 l& F2 ?' L
enlargement of the penis, with a stretched length of* E2 J. e# s/ I4 f$ j
8 cm and a width of 2 cm. The glans penis was very well
) r1 w6 @8 s. Odeveloped. The pubic hair was Tanner II, mostly around1 {4 u3 w# `) ~( w4 Q7 W
540
, t& F1 [( e, i5 p( f( cat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from& Y1 Y0 }! X2 Q1 s: P# {) ?  ]
the base of the phallus and was dark and curled. The+ f3 Z' P, Q% W7 g+ F
testicular volume was prepubertal at 2 mL each.
% m  h8 [/ E) f& }, xThe skin was moist and smooth and somewhat7 Z/ b3 [; x  G5 ^; \) b$ h
oily. No axillary hair was noted. There were no: `5 G5 \. w* d
abnormal skin pigmentations or café-au-lait spots.
" `+ [* S7 R# S* I7 }Neurologic evaluation showed deep tendon reflex 2+
. u6 a8 b7 c4 {: y* Nbilateral and symmetrical. There was no suggestion
7 e. n( S! _9 oof papilledema.0 k2 G6 @* e4 C8 }
Laboratory Evaluation2 \+ p8 n) ?! V" d# X- ?) Z
The bone age was consistent with 28 months by
3 |3 D3 N' B, q9 b4 @  }. Wusing the standard of Greulich and Pyle at a chrono-* \+ Z: o( V) p1 D4 D9 ]3 E
logic age of 16 months (advanced).5 Chromosomal+ z, y$ W/ Y! A; P; D) _  z
karyotype was 46XY. The thyroid function test8 R8 x5 z0 U; I1 U: G
showed a free T4 of 1.69 ng/dL, and thyroid stimu-+ p4 U( i7 v$ v! x; _; @4 {3 o4 F
lating hormone level was 1.3 µIU/mL (both normal).. _7 j4 T1 d9 k
The concentrations of serum electrolytes, blood% ^1 k3 X7 V9 m% I+ c( E
urea nitrogen, creatinine, and calcium all were
* k* y/ n7 y, Wwithin normal range for his age. The concentration+ L0 t5 s7 A; V! L$ |( X6 g$ f
of serum 17-hydroxyprogesterone was 16 ng/dL9 O( W  F4 P. `) f" g8 i& ^5 O
(normal, 3 to 90 ng/dL), androstenedione was 204 T2 Y1 `9 J' G4 A8 ^! ^- n
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-3 u+ E' B7 s2 A3 r) L' X3 Y: d& G
terone was 38 ng/dL (normal, 50 to 760 ng/dL),
% L# J8 n4 t% j! adesoxycorticosterone was 4.3 ng/dL (normal, 7 to0 i8 S& O( c9 y8 T
49ng/dL), 11-desoxycortisol (specific compound S)/ i$ @  w: H- @: t7 ~
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
9 Z* T5 B+ Z' H  y) g# @tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
$ e  J5 r& i( b& P1 |# t. H4 O$ h" gtestosterone was 60 ng/dL (normal <3 to 10 ng/dL),
$ Z# w% y& x+ f1 [* J! ?' Jand β-human chorionic gonadotropin was less than* _) y) h2 _! Y9 p
5 mIU/mL (normal <5 mIU/mL). Serum follicular0 X, K) O2 ~, {+ g' H; u" U
stimulating hormone and leuteinizing hormone3 E. t4 ^& z+ o
concentrations were less than 0.05 mIU/mL9 |7 s8 O) q: `! h$ c: Q: x. m
(prepubertal).
0 C! C1 h8 e; ~  mThe parents were notified about the laboratory
' c% _% E! A7 Q) Q, tresults and were informed that all of the tests were
' i2 l1 ?$ O, e3 cnormal except the testosterone level was high. The. h! x1 @5 ^0 s6 j! t- U# o
follow-up visit was arranged within a few weeks to; X/ P. Q' Y7 b- e
obtain testicular and abdominal sonograms; how-$ R; I4 e) s1 Z& [0 y* r
ever, the family did not return for 4 months.
% }/ f1 _+ ], u: M% _Physical examination at this time revealed that the* _( Q" N% O1 c0 b% f: j. q) ?
child had grown 2.5 cm in 4 months and had gained
$ d0 P8 [( N# W4 F" r& ~2 kg of weight. Physical examination remained; h% a. D" w" ]+ w9 J+ ^; g
unchanged. Surprisingly, the pubic hair almost com-# d  Z* e: K2 W" d
pletely disappeared except for a few vellous hairs at; u8 X+ m. `0 ^, V* i% B' E# O
the base of the phallus. Testicular volume was still 2* R; c% w( T- {1 s  S
mL, and the size of the penis remained unchanged.
, I9 t8 {6 i- M- f4 ~% [5 T2 wThe mother also said that the boy was no longer hav-1 e9 H- W5 h$ X" w: a
ing frequent erections.' c& K, l* N0 Z# V" [
Both parents were again questioned about use of
8 D# U6 h  y1 p( N4 {any ointment/creams that they may have applied to
* `* V/ x' K5 {: x% dthe child’s skin. This time the father admitted the
1 b  O# ~5 W$ V) _6 ?2 ^  z6 V! _$ w) T2 xTopical Testosterone Exposure / Bhowmick et al 541
% j: O* N. L& ]7 nuse of testosterone gel twice daily that he was apply-
& w; q9 O' N& J$ L  E3 }ing over his own shoulders, chest, and back area for1 f6 Q: B5 s# Z2 b
a year. The father also revealed he was embarrassed" X% }3 \, t& D
to disclose that he was using a testosterone gel pre-5 n/ p6 C" l& s; C7 u- w
scribed by his family physician for decreased libido
2 L6 I; Y; _" r& Esecondary to depression.
- a" j; ^) j0 r& @1 c+ [/ h. ~/ H  dThe child slept in the same bed with parents.* j6 v) E' J) `8 [/ w8 l3 ]
The father would hug the baby and hold him on his
, p0 g5 T( r' U. N# Lchest for a considerable period of time, causing sig-
# A  l# K& ~' a% fnificant bare skin contact between baby and father.: O( @" p# Z  _0 t( q" M) v* d# N
The father also admitted that after the phone call,
% k( l6 D3 e; Q7 i4 fwhen he learned the testosterone level in the baby
. w# X) X$ w) P  Awas high, he then read the product information
2 R" F7 \! ~! U) N( d) npacket and concluded that it was most likely the rea-4 l! Y. ?5 r+ y4 F" O
son for the child’s virilization. At that time, they
1 R' t5 S3 u+ cdecided to put the baby in a separate bed, and the
* X! s+ M3 C/ F4 A' r, b4 pfather was not hugging him with bare skin and had* G: J- B9 E9 u' w: j9 q; Y/ O# [3 d
been using protective clothing. A repeat testosterone* _9 H7 W% n9 g
test was ordered, but the family did not go to the/ r& u6 p% ]- P" t' s# j0 |
laboratory to obtain the test.
6 L; x9 Y% k- X% YDiscussion7 r8 \4 E3 U  [$ A" I
Precocious puberty in boys is defined as secondary; N8 ~) O" {, x& F3 E
sexual development before 9 years of age.1,4
  ^! D: x" r( W6 m3 A  n) s' MPrecocious puberty is termed as central (true) when; }0 Z+ b9 r/ ^9 b
it is caused by the premature activation of hypo-. H* F; h7 J" z( O
thalamic pituitary gonadal axis. CPP is more com-- x+ Z( m% d, @' Y
mon in girls than in boys.1,3 Most boys with CPP: w. N1 P2 H; ^# T& c
may have a central nervous system lesion that is
' i+ `" @* V$ @' a  Zresponsible for the early activation of the hypothal-8 A3 c9 x+ Z  ?, V  @7 {1 K
amic pituitary gonadal axis.1-3 Thus, greater empha-* ]$ ^' e' n8 f
sis has been given to neuroradiologic imaging in
  @( r8 E' q, ^' Xboys with precocious puberty. In addition to viril-
2 [2 p: M, m! A, c3 D, Rization, the clinical hallmark of CPP is the symmet-/ P' S# n3 S( e4 v1 @0 _
rical testicular growth secondary to stimulation by
8 r! Z  o+ X$ o* h5 {( X/ v3 Hgonadotropins.1,3
1 m! d: R# i/ m" R* yGonadotropin-independent peripheral preco-1 c  K6 P# k! v# p/ `8 ]7 j
cious puberty in boys also results from inappropriate3 Y! f8 R9 H* k
androgenic stimulation from either endogenous or
( d  [. R5 p; `- q+ pexogenous sources, nonpituitary gonadotropin stim-
; k( q5 R5 @; [/ bulation, and rare activating mutations.3 Virilizing
  D% ^6 ~2 {7 A) N2 Hcongenital adrenal hyperplasia producing excessive% K  }3 P& I( D
adrenal androgens is a common cause of precocious
) q5 V- }& e- X+ B& u# Hpuberty in boys.3,4
8 V% O! I0 [  r' L  B( M7 v+ SThe most common form of congenital adrenal
' x0 i) T5 a' r( i) m  N# v* @3 p# B. khyperplasia is the 21-hydroxylase enzyme deficiency.
6 B+ N' d; n6 |+ o$ LThe 11-β hydroxylase deficiency may also result in
% W5 \" ]1 u& Hexcessive adrenal androgen production, and rarely,
4 x) p' X0 ^0 A/ S7 {6 X. T, ^# kan adrenal tumor may also cause adrenal androgen1 _* a  l( w  z, l1 z7 I; r
excess.1,3
4 f$ S4 I) L. m) M  fat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
  i% I3 u' m+ l4 |, R- f+ D542 Clinical Pediatrics / Vol. 46, No. 6, July 20070 I6 c' |0 A" u1 N/ D
A unique entity of male-limited gonadotropin-
7 K, E! s/ L+ s- w# @6 V. Oindependent precocious puberty, which is also known
6 N8 b7 O/ g) [4 c" v9 m" K& vas testotoxicosis, may cause precocious puberty at a" J9 u: b$ h( P
very young age. The physical findings in these boys' k, C% ~7 a8 h- E" z) m6 z
with this disorder are full pubertal development,, q. j' Q& ^: H
including bilateral testicular growth, similar to boys
1 x+ O: b( B: Z6 f, Lwith CPP. The gonadotropin levels in this disorder: U) s2 v1 j6 L6 w
are suppressed to prepubertal levels and do not show
- q, D8 H( p6 s! mpubertal response of gonadotropin after gonadotropin-/ Q. f) W) b( }2 h3 M/ [/ ~5 a
releasing hormone stimulation. This is a sex-linked
1 H; A, E3 m( D% l2 ]/ y! Eautosomal dominant disorder that affects only
4 Y2 f& `1 k0 Tmales; therefore, other male members of the family
  F; c  o$ c, F$ kmay have similar precocious puberty.38 ?: `1 l( X0 _
In our patient, physical examination was incon-, m/ A0 [0 ~9 R
sistent with true precocious puberty since his testi-
, x# X$ K% a$ i  n" Acles were prepubertal in size. However, testotoxicosis
$ k* R( D3 F5 y  z+ ]8 T# L) Lwas in the differential diagnosis because his father6 N; A; B1 T- A1 N
started puberty somewhat early, and occasionally,
5 }5 a' H' t2 x0 @- A& F% Xtesticular enlargement is not that evident in the
* h7 A: E2 s  H6 T% Rbeginning of this process.1 In the absence of a neg-
4 B8 s! p# \# ~( E; Y! a" hative initial history of androgen exposure, our
; k( c9 i+ a+ l% [biggest concern was virilizing adrenal hyperplasia,, d1 q( T2 m; ]' R
either 21-hydroxylase deficiency or 11-β hydroxylase" @5 ^5 ]4 }1 t5 N
deficiency. Those diagnoses were excluded by find-
3 b2 f! p# h& ~& t3 y' king the normal level of adrenal steroids.
8 n! Y. J* |6 iThe diagnosis of exogenous androgens was strongly
6 Z; {* F" j) `8 asuspected in a follow-up visit after 4 months because
& d' v/ l: f8 J1 S/ gthe physical examination revealed the complete disap-
* m  K$ o) s9 S- Z' @! r, e8 g% Hpearance of pubic hair, normal growth velocity, and) T$ [) x8 P, ]
decreased erections. The father admitted using a testos-7 d$ o4 Q- M, K$ W: U1 `
terone gel, which he concealed at first visit. He was
1 R- i9 ?0 O, Iusing it rather frequently, twice a day. The Physicians’: R# G. g! t6 ~
Desk Reference, or package insert of this product, gel or  i% _' s9 v* @! U
cream, cautions about dermal testosterone transfer to
. }& @3 v4 z. punprotected females through direct skin exposure.* y8 J9 @7 Z9 \$ Z5 p
Serum testosterone level was found to be 2 times the) R/ v0 a7 A8 L* \$ {9 L
baseline value in those females who were exposed to: _& i1 |  _4 t" y- {* |2 J9 G
even 15 minutes of direct skin contact with their male
, a% y6 G' K2 Q! @partners.6 However, when a shirt covered the applica-* [  M! h; C" l- T
tion site, this testosterone transfer was prevented." w9 o0 e- Z; B/ j1 ]
Our patient’s testosterone level was 60 ng/mL,8 S" Q; |3 ~: G) Y1 n
which was clearly high. Some studies suggest that
$ B; {% G7 x, R* u/ j# Mdermal conversion of testosterone to dihydrotestos-
& O  f  n' t" tterone, which is a more potent metabolite, is more
7 K  I% I. P  Z2 s! i3 lactive in young children exposed to testosterone
6 C5 l0 @3 D1 T% |$ P) kexogenously7; however, we did not measure a dihy-. b# j) {7 S0 j; ?* T" B5 ~0 z7 F' U
drotestosterone level in our patient. In addition to, Y9 ?5 r/ F. p: g+ B
virilization, exposure to exogenous testosterone in+ ]* `% R8 h! x# r4 c
children results in an increase in growth velocity and$ g; x% F1 e6 t) a
advanced bone age, as seen in our patient.
$ i: p8 y' z: I* S( {( ]The long-term effect of androgen exposure during
8 B$ j* M" h' G1 A, rearly childhood on pubertal development and final; s; ]# l& p1 J6 y4 g3 B
adult height are not fully known and always remain* P/ h4 o$ R- _. I# F0 q
a concern. Children treated with short-term testos-3 n/ A( H7 `. H1 o7 Z8 R; V) t
terone injection or topical androgen may exhibit some$ U& N) q; j9 O% P7 U! w6 C- j4 w( ]
acceleration of the skeletal maturation; however, after
$ i: M: Q, Z/ Rcessation of treatment, the rate of bone maturation4 U6 [& U8 I; q/ @. Z" ]: A
decelerates and gradually returns to normal.8,9
* X& e8 z  _  b4 ]: a( tThere are conflicting reports and controversy
4 N1 E! n7 B4 ]2 F, Z# nover the effect of early androgen exposure on adult3 u& J! g" A0 Y) m: x. ~* k
penile length.10,11 Some reports suggest subnormal
. `. O0 M/ H+ T* Y2 ]adult penile length, apparently because of downreg-/ a( F7 L0 A+ j3 ?+ _! ~3 q4 T
ulation of androgen receptor number.10,12 However,
8 \- J8 o! E$ T3 L* B% x, oSutherland et al13 did not find a correlation between
: Z2 e; h1 g; r' \. xchildhood testosterone exposure and reduced adult/ O# c6 f3 A7 V. D
penile length in clinical studies.& u6 u2 R. y( ?' z
Nonetheless, we do not believe our patient is
- p' P. F8 i& l6 m3 m! Pgoing to experience any of the untoward effects from
8 o/ q, B* W# l. f  v$ ]testosterone exposure as mentioned earlier because
" |: @% X9 {/ y' X% Hthe exposure was not for a prolonged period of time.. P" G& F) X% e/ Y0 D# S
Although the bone age was advanced at the time of/ U0 r. k+ \- o
diagnosis, the child had a normal growth velocity at
0 ]4 M! }8 G% H6 W* Y9 _the follow-up visit. It is hoped that his final adult( @, W  [# @' w) x
height will not be affected.( h1 S- {. }3 |' v( C" Z
Although rarely reported, the widespread avail-
* Z" E$ ~+ _" s2 o4 yability of androgen products in our society may
! q) t! e/ _5 T) @indeed cause more virilization in male or female& _# [9 w! C  s' h# m& L! G
children than one would realize. Exposure to andro-
8 t( B# E9 ]0 B$ r5 i+ Bgen products must be considered and specific ques-
' g: D. \1 b/ ^  I) B' }- Ytioning about the use of a testosterone product or/ ?: H2 D$ M* S' }: G: D8 u9 b( M
gel should be asked of the family members during
8 b4 {; K1 r8 s, \2 ethe evaluation of any children who present with vir-( W8 {9 B- G+ N; h/ c/ a
ilization or peripheral precocious puberty. The diag-
- K( c1 p. U% P6 D: Bnosis can be established by just a few tests and by
6 N8 U, d3 H6 g$ X% Mappropriate history. The inability to obtain such a
) V4 ]8 P5 I4 ]2 B$ F9 o) M  Mhistory, or failure to ask the specific questions, may2 u! f* `; j6 i/ l+ Q% I1 @% v
result in extensive, unnecessary, and expensive
7 d/ h3 @2 z3 Q& W" o4 P5 g; sinvestigation. The primary care physician should be  ?, f2 q% V# l' \
aware of this fact, because most of these children) P0 O  J% j* V% l, U1 k
may initially present in their practice. The Physicians’$ d* C' p7 r1 X% o" \# b# `* U6 \( l& E
Desk Reference and package insert should also put a
2 t# z# f% f2 g8 ?) N1 q0 b# b" Jwarning about the virilizing effect on a male or' U; U0 r9 ~# ^7 E
female child who might come in contact with some-+ B1 v) h. l$ b0 n3 R: }4 _2 ?
one using any of these products.$ Y& }( O) u0 o) z: l
References2 T& f- c+ u9 t3 q
1. Styne DM. The testes: disorder of sexual differentiation: r. S+ L, g, j, X' V* ]. ]
and puberty in the male. In: Sperling MA, ed. Pediatric
3 F  Y) h* S" U3 Q2 `! SEndocrinology. 2nd ed. Philadelphia, PA: WB Saunders;. `9 R3 ], H% U) m
2002: 565-628.
  Q7 J5 O- X8 \7 ?4 J( Y2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious# l3 A2 k6 B) A% G7 t" Y! S' D
puberty in children with tumours of the suprasellar pineal
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感謝大大的辛勞分享!我會繼續在WK關注大大的文章!
發表於 2025-1-11 22:18:01 | 顯示全部樓層
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

4 S; j' N0 U- j  a, W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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