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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-Old3 }# U7 P6 ?/ e  B+ k4 P! r4 ]; ]& y' F
Boy Induced by Indirect Topical4 `8 A, J: t' T
Exposure to Testosterone2 V, D. N. c9 l7 f) O8 g9 o
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
1 g2 z) w8 |' g! V/ H+ Yand Kenneth R. Rettig, MD1
* P$ Z$ s/ u! o( v; SClinical Pediatrics
8 ^+ G* r+ o0 u. _3 BVolume 46 Number 63 Z- K8 ]7 |& G; m1 s$ f. H
July 2007 540-543
% Y$ r4 T1 O% I( J7 q$ m! f© 2007 Sage Publications
$ _, J) z! |$ o% L; c2 E10.1177/0009922806296651: {( D* m- T! v* q/ D
http://clp.sagepub.com4 ?2 ^% E9 e6 D/ j
hosted at
: I- l0 k; S8 |1 d* C' ^http://online.sagepub.com
0 F5 R0 y' a3 L) [( P4 LPrecocious puberty in boys, central or peripheral,! G; ~4 U- q) q
is a significant concern for physicians. Central
- [8 N" X, P3 [" bprecocious puberty (CPP), which is mediated! M7 u+ R! \" q1 w4 r
through the hypothalamic pituitary gonadal axis, has( @) L  C6 F0 w
a higher incidence of organic central nervous system! a6 M+ _5 e" \
lesions in boys.1,2 Virilization in boys, as manifested
: d* B; ?7 o8 `9 a* J! pby enlargement of the penis, development of pubic
: w8 L5 R( m9 D4 O; Qhair, and facial acne without enlargement of testi-& c3 C7 K& x" n- e* i
cles, suggests peripheral or pseudopuberty.1-3 We
. Q# p7 s4 @7 V! t& R% \- W  f# n3 Wreport a 16-month-old boy who presented with the
7 X* g4 j0 o, f% M% Nenlargement of the phallus and pubic hair develop-7 [9 Z' b) H; |, a+ w
ment without testicular enlargement, which was due0 ~/ _% f4 ^, f+ r6 y
to the unintentional exposure to androgen gel used by3 K! ^; H7 ~) l  m# s$ A
the father. The family initially concealed this infor-
8 I# i; n# w0 z9 gmation, resulting in an extensive work-up for this  a2 i! o% T3 Y( S6 w; e2 F1 ^
child. Given the widespread and easy availability of& v% M0 I; `' j7 }/ F1 ]8 a
testosterone gel and cream, we believe this is proba-
8 B. H9 R% d4 |8 h' ]7 {+ fbly more common than the rare case report in the5 ~9 C4 H8 T8 \/ F* K  F3 A6 t
literature.4
0 Z8 G+ B! A& C* sPatient Report
' ^2 r/ y4 B$ [5 s; XA 16-month-old white child was referred to the& A$ F. {" i- x5 Q
endocrine clinic by his pediatrician with the concern
4 l+ _) Q/ ]1 m1 J) `of early sexual development. His mother noticed! M3 ^2 b9 ^) \  [3 b
light colored pubic hair development when he was
. e3 Q' b- R4 v  f/ O9 eFrom the 1Division of Pediatric Endocrinology, 2University of
( f1 N3 ~  l9 z2 n' e) w5 pSouth Alabama Medical Center, Mobile, Alabama.1 l) a3 z! L3 e! u5 S- m
Address correspondence to: Samar K. Bhowmick, MD, FACE,
" P- @! Q! b2 j) S1 `1 n, vProfessor of Pediatrics, University of South Alabama, College of" d/ q3 r7 T! z4 _  @
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
6 W, H. t6 e* ]e-mail: [email protected].! d/ N4 T- K* G6 f9 X) Z: V
about 6 to 7 months old, which progressively became+ ~1 N2 t. w" D! ]' a. ?; r6 O
darker. She was also concerned about the enlarge-
: W' b+ s/ p$ H) A/ _9 g- |; vment of his penis and frequent erections. The child) p$ U8 c! x; u9 g
was the product of a full-term normal delivery, with( Z0 I* K- \$ k; B' b9 n! P1 D7 A8 T
a birth weight of 7 lb 14 oz, and birth length of
' @5 j9 v7 y$ r9 o# g" b20 inches. He was breast-fed throughout the first year
' j/ L3 Y& E0 Pof life and was still receiving breast milk along with
8 a, Z3 Z0 k) E: l) P2 z/ gsolid food. He had no hospitalizations or surgery,
8 F9 t" k5 k0 u: [4 R0 l' Sand his psychosocial and psychomotor development
5 X$ g0 s/ o5 k8 J6 Gwas age appropriate.# g1 P5 a+ k' Y$ e, b
The family history was remarkable for the father,
+ d8 m1 R2 I1 P6 C) l( F0 ewho was diagnosed with hypothyroidism at age 16,
6 s+ w/ o5 `$ Z& uwhich was treated with thyroxine. The father’s
0 a' ]2 R, e1 P1 t9 I, Dheight was 6 feet, and he went through a somewhat
' F3 J$ S. W1 q7 ^2 _' cearly puberty and had stopped growing by age 14.
( n4 M: K* H# z) @+ T% L0 CThe father denied taking any other medication. The
" w6 j5 ^3 }6 E4 Uchild’s mother was in good health. Her menarche* E4 |+ c) n$ I; u
was at 11 years of age, and her height was at 5 feet
3 S1 X3 a# c( \7 B7 F5 inches. There was no other family history of pre-  y) V  ]/ m' c. u
cocious sexual development in the first-degree rela-
- l# l1 L3 W# L' z' L' X* [tives. There were no siblings.
% u0 [$ ]/ J2 g4 w2 W! QPhysical Examination, f% v+ v6 I' b( d  [- Q
The physical examination revealed a very active," \) I2 i7 G# M+ W) Q
playful, and healthy boy. The vital signs documented4 ]! q  G* V: N; p- D9 ]
a blood pressure of 85/50 mm Hg, his length was6 P0 P! @/ l* x5 u7 n+ a
90 cm (>97th percentile), and his weight was 14.4 kg, g; Y0 L7 E0 L8 L8 S6 Y+ Z$ d
(also >97th percentile). The observed yearly growth
! X+ f" P! r) n3 h, |- |velocity was 30 cm (12 inches). The examination of. x5 F4 m4 j$ e4 t0 q4 M
the neck revealed no thyroid enlargement., U7 y4 P! E4 G) {2 e
The genitourinary examination was remarkable for7 Y$ ]5 u7 m" c) i$ k4 }& ~
enlargement of the penis, with a stretched length of
* C9 l% a2 f% v1 ~& `8 cm and a width of 2 cm. The glans penis was very well, f0 |2 Y- w4 U1 h" s7 X5 v+ ~$ A
developed. The pubic hair was Tanner II, mostly around5 w$ C. d9 n8 p9 r. E4 L  H
540! k8 P6 d6 B, @: @
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
5 e% p& N3 `7 w& F( _  ~the base of the phallus and was dark and curled. The+ z. v7 M4 x: g4 U( A1 K
testicular volume was prepubertal at 2 mL each.
0 W* z/ {8 j7 k9 p( O  |' x8 nThe skin was moist and smooth and somewhat4 ]% H5 C( k. K7 ?
oily. No axillary hair was noted. There were no
9 R1 B3 w$ w) B6 Q% ^' O; fabnormal skin pigmentations or café-au-lait spots.1 ~1 }, c. i( G& e: f' h
Neurologic evaluation showed deep tendon reflex 2+
8 l, J% I5 ?0 a, f' U6 K+ t* u) Fbilateral and symmetrical. There was no suggestion( T7 F) `" M' P- h! N1 J+ w* Y
of papilledema.
5 O; L1 t/ g: q% O) }Laboratory Evaluation
, e& b9 i' P0 G8 l* A* R& uThe bone age was consistent with 28 months by
, {7 z" B2 u, S) pusing the standard of Greulich and Pyle at a chrono-6 m/ P+ `* I0 f5 U( I
logic age of 16 months (advanced).5 Chromosomal
  x. f8 g" H; X  E4 tkaryotype was 46XY. The thyroid function test
4 \/ b6 ~" `. R% `& F5 p- ashowed a free T4 of 1.69 ng/dL, and thyroid stimu-- j! Y$ X7 d  h. N( _% i( y* s
lating hormone level was 1.3 µIU/mL (both normal).
8 S* P8 f2 I1 n! d5 Q  u1 C- P3 \The concentrations of serum electrolytes, blood
$ T6 N; Y5 `" d2 gurea nitrogen, creatinine, and calcium all were
+ u# o& u8 s& z1 F, J2 i# d! |within normal range for his age. The concentration# T5 E. g1 V/ H6 t* M7 P7 |) |$ t+ K
of serum 17-hydroxyprogesterone was 16 ng/dL
0 N6 D+ }6 t; m4 a(normal, 3 to 90 ng/dL), androstenedione was 20
0 u3 q; \2 Z( i% ^/ ?! kng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
% Z% U! b" x4 m6 `% W3 zterone was 38 ng/dL (normal, 50 to 760 ng/dL),/ |# y, p" D3 f3 j9 C6 p6 R
desoxycorticosterone was 4.3 ng/dL (normal, 7 to
7 L, E& o$ L' f3 `4 e/ b' C7 p49ng/dL), 11-desoxycortisol (specific compound S)1 U' v& a0 q3 ~/ a/ Q9 r
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-0 u- `) g2 w. U9 \
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
* p' X2 E  G1 y" [testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
) _; M) i! r* W; I' X0 @and β-human chorionic gonadotropin was less than+ |; A+ s- q0 s% R# V, ^
5 mIU/mL (normal <5 mIU/mL). Serum follicular$ r) {. Y! [! ?% i( ^- r8 I
stimulating hormone and leuteinizing hormone
& h' T1 s9 r/ l$ `0 K  Kconcentrations were less than 0.05 mIU/mL
7 p  G( E' W( N; {( C$ J(prepubertal).
* T# N  R0 ~4 v/ fThe parents were notified about the laboratory
5 X( d/ n9 Q% f9 J! ?! presults and were informed that all of the tests were) g! U! I' w. m1 @
normal except the testosterone level was high. The
8 C& J% h" C9 f7 q+ b0 @follow-up visit was arranged within a few weeks to# d6 S9 Y6 A* I- U, P3 \8 v8 ]
obtain testicular and abdominal sonograms; how-
( I1 Z. k8 Q5 l1 y7 |ever, the family did not return for 4 months.. _2 b# i1 X& q
Physical examination at this time revealed that the# T1 w9 z0 B" Y& O6 V6 ]7 d
child had grown 2.5 cm in 4 months and had gained
! H# V- F' b" [9 m. c' I1 q2 kg of weight. Physical examination remained
% E' w! K, r2 M8 a3 Sunchanged. Surprisingly, the pubic hair almost com-
% |. S& h* E( {. wpletely disappeared except for a few vellous hairs at
( N1 C0 m& I1 t6 @% `the base of the phallus. Testicular volume was still 2
& H, x: h) X3 `2 N; imL, and the size of the penis remained unchanged.$ O7 M$ Z& t6 X9 A5 }
The mother also said that the boy was no longer hav-$ a$ m' Q. }) |) R
ing frequent erections.# o8 n/ [9 o1 k3 X, h$ M
Both parents were again questioned about use of
/ ]4 Z: M$ i$ X3 b( L# rany ointment/creams that they may have applied to
$ T' m: n/ Z* v9 [. ?5 g' S1 Ithe child’s skin. This time the father admitted the
+ H- o5 b6 _+ a% |0 i" |5 ATopical Testosterone Exposure / Bhowmick et al 541
9 P) G% V  p+ l! f5 Q  Guse of testosterone gel twice daily that he was apply-
# [3 V' f) p/ V0 w* D& l) t, aing over his own shoulders, chest, and back area for
5 ?" m3 o: S9 _, t1 ta year. The father also revealed he was embarrassed" f% k% n- H: J8 s
to disclose that he was using a testosterone gel pre-
6 ~% ?; X  {4 J. Sscribed by his family physician for decreased libido0 M$ P' R1 y1 j3 x6 }
secondary to depression.
* O' H5 n% ^6 n& a: \The child slept in the same bed with parents.
# l3 y  r, ~; X  YThe father would hug the baby and hold him on his
  N' t% M9 L1 x" q8 }9 \7 p" Vchest for a considerable period of time, causing sig-
: k* U% U8 A) ~1 Xnificant bare skin contact between baby and father.
) M' X: b- K) MThe father also admitted that after the phone call,2 ]; `) o( l+ K7 ~& s+ n
when he learned the testosterone level in the baby
6 d  H6 g  a9 G. r- b: @3 _, gwas high, he then read the product information/ h, x; Z8 g  C- ?" V' Z9 J" _+ s; Z
packet and concluded that it was most likely the rea-
4 G. L, m2 ^3 _son for the child’s virilization. At that time, they; i) b, ?% z; h8 ~5 a2 f( M
decided to put the baby in a separate bed, and the
' |) ]- }. M" v! Tfather was not hugging him with bare skin and had
9 |7 O- D/ |/ n4 e& ibeen using protective clothing. A repeat testosterone
# f$ Z6 w8 w* Z( ?3 L' k! q3 Htest was ordered, but the family did not go to the: N, {( G1 r1 d4 m5 q- T
laboratory to obtain the test.3 `1 g0 K: Y! ^# q: N. r- `3 O; o5 @
Discussion; `0 {9 r+ V" j- ^$ V% E& O
Precocious puberty in boys is defined as secondary+ {' e. W. l4 k$ X  r; o  _7 F
sexual development before 9 years of age.1,4  H! L5 @: \5 `3 v
Precocious puberty is termed as central (true) when
* O" \5 [' |+ P& O( cit is caused by the premature activation of hypo-0 [/ g3 l8 g# a4 K! p+ ^( p
thalamic pituitary gonadal axis. CPP is more com-: t! a! V9 O: h, x& E3 Q
mon in girls than in boys.1,3 Most boys with CPP
7 n  c. |3 Z; W3 F" c( bmay have a central nervous system lesion that is
1 h% c! S% ~( `8 s* h) a* u3 h! \1 Aresponsible for the early activation of the hypothal-
3 _* s) w) ]  A5 w& S+ G5 h- yamic pituitary gonadal axis.1-3 Thus, greater empha-) C8 N* R# g0 p. w8 @' u
sis has been given to neuroradiologic imaging in! d1 Z* ^. x$ i
boys with precocious puberty. In addition to viril-
0 K- A1 |) a& G* c: \' H; Wization, the clinical hallmark of CPP is the symmet-- e' [5 A6 I* C! A; S: S
rical testicular growth secondary to stimulation by/ i- A. G( D2 [6 p9 |
gonadotropins.1,3& U+ r0 y, x, p+ z
Gonadotropin-independent peripheral preco-% ~9 D% t4 i  {5 q. j/ p& L& t/ [
cious puberty in boys also results from inappropriate* {" `8 U9 N  ~# w
androgenic stimulation from either endogenous or
9 }1 h& r& M. E+ V/ uexogenous sources, nonpituitary gonadotropin stim-: q! R. J: n& l
ulation, and rare activating mutations.3 Virilizing4 |3 G1 X2 a" V; ~. [% a0 C4 J$ Z
congenital adrenal hyperplasia producing excessive
& o6 z7 j6 C, b/ f, D  Qadrenal androgens is a common cause of precocious' x( b! k& \! y) R9 S
puberty in boys.3,4
8 j& _3 p  R9 g+ @" g+ f! }) dThe most common form of congenital adrenal9 W* m" n  s, S: v% q
hyperplasia is the 21-hydroxylase enzyme deficiency.
' K5 m2 T% J2 `9 g8 J1 _: TThe 11-β hydroxylase deficiency may also result in0 l/ I" p3 Q: Z! y/ a8 B. G
excessive adrenal androgen production, and rarely,
& C- X& a: S$ ~& i. z2 q) kan adrenal tumor may also cause adrenal androgen
; L( q9 Y# ~  o* S/ Xexcess.1,3
: Y1 z! l# m" C* \# oat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from% T: Z& n: M" h& r- q- a
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
. z' J  E8 a" E- Y- M6 r& dA unique entity of male-limited gonadotropin-$ v! V/ k' X% B9 [
independent precocious puberty, which is also known
4 o# c, Z7 T4 T3 x4 p+ }( c7 Zas testotoxicosis, may cause precocious puberty at a
( O8 N9 J2 ]7 j) H$ Zvery young age. The physical findings in these boys
& s; q+ j' ?1 j: Awith this disorder are full pubertal development,) Z5 e; q3 k: H
including bilateral testicular growth, similar to boys+ Q" U; t6 t/ A7 n6 V& E4 v! E. K
with CPP. The gonadotropin levels in this disorder5 ~. x- }/ D( ^# X4 D& h& E3 E
are suppressed to prepubertal levels and do not show
7 z  ]+ u9 a- Wpubertal response of gonadotropin after gonadotropin-; f* D$ a0 H( c, }
releasing hormone stimulation. This is a sex-linked+ x* p% B; M$ P- \
autosomal dominant disorder that affects only% j5 l4 C5 Q4 T; p
males; therefore, other male members of the family
4 y4 [" c) b2 I9 l& \  v3 N" J  omay have similar precocious puberty.3" P# }, O! g. P: H0 T: n
In our patient, physical examination was incon-
; Q) s8 C* S. N/ `, t& i2 _, c$ m3 csistent with true precocious puberty since his testi-7 J5 n$ Q# h4 P3 R! u
cles were prepubertal in size. However, testotoxicosis4 g3 ?+ N3 `/ j0 l1 [1 M. Y# y5 }
was in the differential diagnosis because his father
$ q2 \! f4 L  I& U, ystarted puberty somewhat early, and occasionally,  |0 c: _- V( w. z
testicular enlargement is not that evident in the+ J6 C. l4 D+ @# c
beginning of this process.1 In the absence of a neg-
/ h, a( S& d! R; N# Sative initial history of androgen exposure, our
; `5 Z7 U- @" N7 D  C' ybiggest concern was virilizing adrenal hyperplasia,
* r( t+ G& L8 S( J1 Z. Deither 21-hydroxylase deficiency or 11-β hydroxylase  W7 f+ c" D' N0 c
deficiency. Those diagnoses were excluded by find-
4 q: q" Z3 D) uing the normal level of adrenal steroids." l# O' a- P5 ]1 ~
The diagnosis of exogenous androgens was strongly
1 ^9 j* ]; l3 J0 T# W  csuspected in a follow-up visit after 4 months because6 ^( U; ?2 E' X, y, X7 J
the physical examination revealed the complete disap-9 Y; f9 r: h' u. P( u8 X
pearance of pubic hair, normal growth velocity, and# T/ x% C6 Q. p/ S
decreased erections. The father admitted using a testos-) t6 @2 V' p# p# a2 C
terone gel, which he concealed at first visit. He was0 n4 y; A! p7 s
using it rather frequently, twice a day. The Physicians’
% ]% t. Y: r7 oDesk Reference, or package insert of this product, gel or) L: P/ H8 h5 |" |' p6 B
cream, cautions about dermal testosterone transfer to7 t1 e) P9 f$ I. V
unprotected females through direct skin exposure.& Q6 k' s( A6 n) \
Serum testosterone level was found to be 2 times the
9 a# S) ^2 q. a6 l9 d6 Nbaseline value in those females who were exposed to
5 G; I1 N% G- ~" Xeven 15 minutes of direct skin contact with their male! I* D8 J6 b* D) z$ f# p
partners.6 However, when a shirt covered the applica-
8 `) d+ i, ]* v8 ction site, this testosterone transfer was prevented.
. I, T" k3 j# y: ?/ a; j6 UOur patient’s testosterone level was 60 ng/mL,
& V3 u8 i7 n- Dwhich was clearly high. Some studies suggest that
. n: z! @* z5 g* a' x" C+ }) [9 Q1 F5 Ydermal conversion of testosterone to dihydrotestos-
7 f; X6 u+ H: Hterone, which is a more potent metabolite, is more
, D' o9 H$ o$ F; S  S* Y  Factive in young children exposed to testosterone
3 p' d, f8 S) b/ Z) M" n& P; }exogenously7; however, we did not measure a dihy-
+ T7 I0 i4 P# A& Q3 w* X) Q' V  Tdrotestosterone level in our patient. In addition to* d: c- k9 f2 ^* ]
virilization, exposure to exogenous testosterone in
" ^! Y7 G+ ^: d/ M) Achildren results in an increase in growth velocity and
% w# m! j" b3 Q9 z* Aadvanced bone age, as seen in our patient.
( I& V0 {+ L% W: L9 c' Q7 CThe long-term effect of androgen exposure during* [/ G, w* Q5 o/ d
early childhood on pubertal development and final
/ d' E, ~4 J$ k2 Gadult height are not fully known and always remain6 N9 ]) D  w2 c
a concern. Children treated with short-term testos-
7 Q1 V$ m. d/ M9 }: rterone injection or topical androgen may exhibit some
0 A+ J6 n( i- w# h  N! a# C, I7 I) Xacceleration of the skeletal maturation; however, after
5 `  d. n; v2 N; Z4 k& |. c1 Jcessation of treatment, the rate of bone maturation
: u' S6 u/ p6 ~decelerates and gradually returns to normal.8,9! j0 [$ o. P( u( _% @
There are conflicting reports and controversy# h- }* \% _- z
over the effect of early androgen exposure on adult
7 g, q8 x  j, F6 q5 c9 openile length.10,11 Some reports suggest subnormal( P6 U( a; j& h' p$ }: T' }
adult penile length, apparently because of downreg-
7 f: P! M3 O! vulation of androgen receptor number.10,12 However,
2 X5 }4 p( G1 Z  o& J5 T: ~( }Sutherland et al13 did not find a correlation between
& y' {/ E) b( L% jchildhood testosterone exposure and reduced adult: }: Q$ z9 s! J% `# _) A2 `
penile length in clinical studies.9 A& \1 {: H5 ]' G% V
Nonetheless, we do not believe our patient is" q8 ^* v3 S$ j+ r! i
going to experience any of the untoward effects from8 v0 d3 q) o2 Z9 E' n* d* I% x
testosterone exposure as mentioned earlier because
+ B0 x' f: x) H( a% U- }; Q: Kthe exposure was not for a prolonged period of time.
1 d' O4 Q' ~; o8 f  _- {- f$ pAlthough the bone age was advanced at the time of& i2 s/ q% s5 T
diagnosis, the child had a normal growth velocity at' l1 M1 N9 l2 R
the follow-up visit. It is hoped that his final adult" _7 T- m( E2 Q7 }3 s" q. K/ A
height will not be affected.
3 ]. t6 V9 G9 G, l3 B( zAlthough rarely reported, the widespread avail-. y. u  v/ T0 Q" n! y
ability of androgen products in our society may# }$ F% |& @8 {( V/ J( _1 x
indeed cause more virilization in male or female
9 _$ K: o2 h2 c3 q0 |children than one would realize. Exposure to andro-, O' k* a3 q5 F! w% N7 O
gen products must be considered and specific ques-
2 z$ ^0 b$ u9 `+ otioning about the use of a testosterone product or) w  q* ], r; q$ r2 G7 p
gel should be asked of the family members during
1 x, C& {9 Q! l8 Xthe evaluation of any children who present with vir-
8 _! k; _2 C0 W" B5 E: y( G. Nilization or peripheral precocious puberty. The diag-
, i% r' V7 h' z) o- T. S: }% [nosis can be established by just a few tests and by
# A4 f2 @5 @+ }! F5 Happropriate history. The inability to obtain such a
# N7 m! Z8 m$ n1 ehistory, or failure to ask the specific questions, may
1 l4 M# I* [! U5 r7 Vresult in extensive, unnecessary, and expensive: c& N. G% s: w) Z
investigation. The primary care physician should be
* [. z9 @* P6 s; aaware of this fact, because most of these children& x$ z. ^& x/ b# v
may initially present in their practice. The Physicians’
8 x5 v8 [& C3 TDesk Reference and package insert should also put a
3 V: V2 h& z7 q/ Pwarning about the virilizing effect on a male or
, b" ]& M# q4 Q$ z, H( G) w- ifemale child who might come in contact with some-$ j% J4 s1 g/ ~" N
one using any of these products.
8 ]7 P, k9 ^6 G4 P6 d# b+ {References
0 x+ W8 V3 S2 p# J1. Styne DM. The testes: disorder of sexual differentiation- m, r% q( L1 U: z2 `8 b+ g
and puberty in the male. In: Sperling MA, ed. Pediatric
1 T* ~& q, W- l6 }1 _  Y# FEndocrinology. 2nd ed. Philadelphia, PA: WB Saunders;7 }4 i& S9 ?* _0 ~
2002: 565-628.
  |4 A3 Q' _7 n$ k( \% f2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious% ^) o  E5 b+ f: q& i
puberty in children with tumours of the suprasellar pineal
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Sexual Precocity in a 16-Month-Old
; T) g7 a: u, n+ oBoy Induced by Indirect Topical
: n! E# m; _. i' r$ aExposure to Testosterone
; d, d, D1 b% @$ i- O2 Y5 G1 RSamar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
5 S6 S% S+ H- P' ^; t) V% X* D8 oand Kenneth R. Rettig, MD1
" h2 s$ t- b$ a) ?2 NClinical Pediatrics
4 V9 @4 [5 a/ kVolume 46 Number 6
- g8 t1 S0 g7 U$ S2 R* jJuly 2007 540-5436 k. B1 ^' Z9 n6 q4 f% A
© 2007 Sage Publications! I* ]- e' P: Y' E1 z- d- c
10.1177/00099228062966512 Q9 r4 n& z% V1 i# {
http://clp.sagepub.com
1 @$ s7 k, e, a/ D6 S) whosted at
4 D7 j7 r8 k3 K$ l' z  shttp://online.sagepub.com7 H9 g3 y0 ?' q" U  e
Precocious puberty in boys, central or peripheral,
8 v8 U% S5 P) Q+ S9 c1 Eis a significant concern for physicians. Central
  j: m( y- a6 n# x, gprecocious puberty (CPP), which is mediated/ f$ [& \8 ?2 t! n5 C. F+ a
through the hypothalamic pituitary gonadal axis, has3 w0 {2 g; R) G3 f1 J" [
a higher incidence of organic central nervous system# q( b+ H1 k8 g2 B4 t
lesions in boys.1,2 Virilization in boys, as manifested0 N2 y( ]: j9 S
by enlargement of the penis, development of pubic
4 {: _; P9 ?7 T: x5 b- j9 g( _$ Zhair, and facial acne without enlargement of testi-
" T1 w8 A* g- [3 ^7 F! ycles, suggests peripheral or pseudopuberty.1-3 We
. y& |0 }# ]0 a# U4 v% c' i  rreport a 16-month-old boy who presented with the) c  y4 F3 N: ^
enlargement of the phallus and pubic hair develop-) |; Y# i2 I1 s7 p, O
ment without testicular enlargement, which was due, ~8 w/ k8 F( B- n
to the unintentional exposure to androgen gel used by
$ |7 ^2 I: |8 P6 p- O; [the father. The family initially concealed this infor-3 e9 Y; d, U% G& x( S
mation, resulting in an extensive work-up for this
3 e& x' F+ O9 M) z0 \/ H, c8 rchild. Given the widespread and easy availability of9 p: U( e6 A7 z( g* h7 U5 s9 X; K) l
testosterone gel and cream, we believe this is proba-" s. b$ Y7 ]* k1 z) \) I
bly more common than the rare case report in the
5 l) f4 O0 D1 d2 j, iliterature.40 l0 e% i7 p$ k- A
Patient Report
  ?# h5 R! c1 x: |8 TA 16-month-old white child was referred to the
% Q( l, c0 O! h  c# I( M) Lendocrine clinic by his pediatrician with the concern
7 M# b  {$ ^! ?8 c7 gof early sexual development. His mother noticed
/ S/ {  [, f( E: `2 X# K  tlight colored pubic hair development when he was! W* W; H7 p& C: @
From the 1Division of Pediatric Endocrinology, 2University of
- F3 O- v8 U0 k4 g' A7 jSouth Alabama Medical Center, Mobile, Alabama.: k3 S& B" i& i6 c1 O
Address correspondence to: Samar K. Bhowmick, MD, FACE,# e' f5 z, O4 r, m
Professor of Pediatrics, University of South Alabama, College of
! W1 Y! Z# _% o1 o4 ~Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
* \, z- A! F; Be-mail: [email protected].1 D4 [9 F8 i' N% o( w9 A8 {+ o
about 6 to 7 months old, which progressively became
3 |: q- ]& ?5 Y3 `. ndarker. She was also concerned about the enlarge-' Z  Z' \1 v" b- N
ment of his penis and frequent erections. The child
9 O# Q; |  m) f1 Q' Fwas the product of a full-term normal delivery, with  P2 N/ X1 H: D
a birth weight of 7 lb 14 oz, and birth length of
4 w$ \8 `% U# F20 inches. He was breast-fed throughout the first year
  y1 i+ w$ G5 `/ b! T" gof life and was still receiving breast milk along with
/ \3 r* l/ a% V+ o/ p8 ssolid food. He had no hospitalizations or surgery,
5 T8 B+ Y* i: I2 y4 Rand his psychosocial and psychomotor development
1 S4 d4 z  ^* Y& @was age appropriate.
3 ?6 y9 [' E+ d3 R. b! o* U1 wThe family history was remarkable for the father,
2 q9 n% ^3 t& R( m% jwho was diagnosed with hypothyroidism at age 16,4 ?2 c/ e2 ~% ^! ?
which was treated with thyroxine. The father’s
$ e# M( s- ~$ W9 |) }# rheight was 6 feet, and he went through a somewhat
# R, H4 y+ S1 f2 j. aearly puberty and had stopped growing by age 14.
4 }1 r: F- P6 I9 e0 SThe father denied taking any other medication. The
' ?0 x6 q& I! }child’s mother was in good health. Her menarche
/ W: x! k0 ~0 \7 A% u& Mwas at 11 years of age, and her height was at 5 feet) P8 @0 L: y, v0 b, E2 [3 C9 J
5 inches. There was no other family history of pre-7 r# y% ^7 J0 C
cocious sexual development in the first-degree rela-
+ k0 s8 Q0 |% d: W6 F; {) n. ^( qtives. There were no siblings.
0 q" N. y2 X% j% q3 {$ a' uPhysical Examination
0 }8 T& s# ~3 _" W) ^9 }The physical examination revealed a very active,
* ?3 y, _; m9 Aplayful, and healthy boy. The vital signs documented9 G) @% b9 B, s0 V) V6 V) z, `
a blood pressure of 85/50 mm Hg, his length was
7 x& U8 I" K* W& S7 c90 cm (>97th percentile), and his weight was 14.4 kg
8 \5 c# j" N% h+ R6 N8 g8 _5 L(also >97th percentile). The observed yearly growth
; M5 Y* z! a/ Gvelocity was 30 cm (12 inches). The examination of( _6 S4 }" r6 |# V
the neck revealed no thyroid enlargement.
& j: T( }4 K/ [" |2 C0 B* I4 FThe genitourinary examination was remarkable for
5 ?, B2 Y. }. j0 T9 ^enlargement of the penis, with a stretched length of! z' k5 W7 P! q6 {
8 cm and a width of 2 cm. The glans penis was very well
) F, B& V5 V2 @; a2 j! Vdeveloped. The pubic hair was Tanner II, mostly around9 L7 ]# T* {5 X3 ?1 d9 _) m8 I
540
# x" C& T/ ~, T  K( Dat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
# K) O5 w) N9 \, G/ Pthe base of the phallus and was dark and curled. The
$ g+ @) s, G, u# f" F8 a/ v9 Dtesticular volume was prepubertal at 2 mL each.
# @( z+ g& g5 Z# l4 \6 {The skin was moist and smooth and somewhat
6 F' ]6 b, ?8 B! K7 I# {" Joily. No axillary hair was noted. There were no
# w- U: I$ V! n$ O# k! Mabnormal skin pigmentations or café-au-lait spots.
- P4 `8 N; n- ~. _% B: i) a) GNeurologic evaluation showed deep tendon reflex 2+2 @+ A: e7 q% j
bilateral and symmetrical. There was no suggestion
2 M( m1 R8 e% ~# _$ [of papilledema.
) J, D. Q. J" }# [Laboratory Evaluation, w; ]! t/ I' A) H
The bone age was consistent with 28 months by7 q& B" d& G' B* ^/ j* q& o" a
using the standard of Greulich and Pyle at a chrono-
, q) d5 I( o: k7 J4 E3 X/ plogic age of 16 months (advanced).5 Chromosomal% w9 C" g' C' N. I5 r" w2 @
karyotype was 46XY. The thyroid function test7 y5 u2 F% p1 g! u
showed a free T4 of 1.69 ng/dL, and thyroid stimu-
9 T' [0 M7 |$ a+ T% ^lating hormone level was 1.3 µIU/mL (both normal)., O% F* ~2 w7 S3 ?# \4 ~- g# p4 [* C
The concentrations of serum electrolytes, blood
6 f( i, b. A; M) r% x* Q. burea nitrogen, creatinine, and calcium all were3 X7 @& r3 Q% D
within normal range for his age. The concentration
2 R# _: T1 x, \' |" iof serum 17-hydroxyprogesterone was 16 ng/dL' `, G! Y6 w" X+ d0 Z$ i
(normal, 3 to 90 ng/dL), androstenedione was 20
2 P/ m- t6 v3 |: ]% n9 ?6 E0 F+ G: }9 ung/dL (normal, 18 to 80 ng/dL), dehydroepiandros-' g3 s; n2 @4 U4 q: I
terone was 38 ng/dL (normal, 50 to 760 ng/dL),% V& P" h; y7 c2 V0 ~
desoxycorticosterone was 4.3 ng/dL (normal, 7 to
6 s! `$ ]* p1 L& r) b49ng/dL), 11-desoxycortisol (specific compound S)+ ?6 c4 w( d" [! P
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-" X2 D9 [! {$ {( W1 q1 ?
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total# D# p7 k4 `: W$ X2 @8 q; X
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
5 a1 \/ d- J7 x; land β-human chorionic gonadotropin was less than/ c  w2 z/ B# f+ F
5 mIU/mL (normal <5 mIU/mL). Serum follicular
) p% j0 s8 s& {) y6 vstimulating hormone and leuteinizing hormone
! N: `2 Q9 M0 G% Y) K+ w' ~concentrations were less than 0.05 mIU/mL
2 z+ N4 z4 b5 P: e! A$ F* O(prepubertal).
% L2 Z' ^# O' E6 {, sThe parents were notified about the laboratory7 o3 G2 g# ]7 h' Q' N
results and were informed that all of the tests were4 W/ }8 F2 B: Y  p1 l" G
normal except the testosterone level was high. The
: s! @0 v) I  U: ofollow-up visit was arranged within a few weeks to, r4 x- G' d( T& O1 e' A
obtain testicular and abdominal sonograms; how-! k* V. {: {) w' s% m0 N
ever, the family did not return for 4 months.9 a. d/ I. ~( A' e+ P
Physical examination at this time revealed that the
# z1 G. s  k  {; U& x$ v" @# R( a4 Jchild had grown 2.5 cm in 4 months and had gained% i: `5 Q) k+ o
2 kg of weight. Physical examination remained& d. X: I1 @+ P1 b9 s: ~1 T, k
unchanged. Surprisingly, the pubic hair almost com-
: K* s" J+ ~% U' o2 n( {8 Z" ypletely disappeared except for a few vellous hairs at
7 c& k( B" q1 k0 ~- i6 Y- Hthe base of the phallus. Testicular volume was still 2
7 X9 g% w  L( O& MmL, and the size of the penis remained unchanged.- b( b- j4 C5 N# x! o, R6 N2 q
The mother also said that the boy was no longer hav-$ L, r2 a8 o" D5 r2 ~
ing frequent erections." C# O2 s  e& Y) Z
Both parents were again questioned about use of  I5 g3 n3 T+ S
any ointment/creams that they may have applied to5 q1 ?& j7 e7 J* n
the child’s skin. This time the father admitted the
4 B  U. K4 F% t, L: h+ C# z6 f. tTopical Testosterone Exposure / Bhowmick et al 541' C+ u7 Z) @* t  N1 {7 k& r
use of testosterone gel twice daily that he was apply-" I" D' S4 X3 d
ing over his own shoulders, chest, and back area for
% I; F) {# x, ?, ?& _a year. The father also revealed he was embarrassed
. [- z& y) @. \& A8 m# \to disclose that he was using a testosterone gel pre-
/ N0 y/ H( C$ W6 g, u* escribed by his family physician for decreased libido5 s* z% M" b( l
secondary to depression.
, j0 P1 x0 w8 `The child slept in the same bed with parents.
7 F  k! _" z- D0 _2 sThe father would hug the baby and hold him on his, u3 ~, M# f3 A( Y3 w! u
chest for a considerable period of time, causing sig-
# X- H$ \- |% ?! O' L/ anificant bare skin contact between baby and father.% y( w9 ?, o% M1 L/ H
The father also admitted that after the phone call,1 W: T" B+ Q& [/ }' g
when he learned the testosterone level in the baby
2 a& j  `0 m1 n+ _/ P9 C/ nwas high, he then read the product information) e* W6 I  T: C' o
packet and concluded that it was most likely the rea-8 y4 m8 j% e( J+ ?7 ^- S
son for the child’s virilization. At that time, they
( s9 p# A9 H7 v1 v: Z" fdecided to put the baby in a separate bed, and the
9 K) j5 f) }( v* Efather was not hugging him with bare skin and had
$ B! N& G# r9 d. Lbeen using protective clothing. A repeat testosterone+ K) \* n8 d9 p( v  z
test was ordered, but the family did not go to the
  K! g: z. G/ ^2 \9 @/ ]$ Mlaboratory to obtain the test.
4 a+ v! y+ N; j) V9 Y# e& CDiscussion
- q% k7 T( p4 pPrecocious puberty in boys is defined as secondary1 [" p, L- }+ H2 a2 {% [! v: J
sexual development before 9 years of age.1,4* x" X' U2 Q# ^- F/ k5 s& M
Precocious puberty is termed as central (true) when
. [+ [( P( W/ X' Q$ H2 F% d4 \; Qit is caused by the premature activation of hypo-
8 I/ r# Y9 b7 g/ T; I$ p  jthalamic pituitary gonadal axis. CPP is more com-
6 W* F+ l5 q0 W+ i4 U0 Xmon in girls than in boys.1,3 Most boys with CPP
) N1 _! J/ J2 b4 z! [% e0 umay have a central nervous system lesion that is
4 m2 |& H# U3 ~8 m9 Oresponsible for the early activation of the hypothal-
$ M6 x$ R6 ~* r) ]. Kamic pituitary gonadal axis.1-3 Thus, greater empha-- I4 i) @; V9 F9 w& V( K
sis has been given to neuroradiologic imaging in
2 b( e1 G" q9 q0 H! \3 Eboys with precocious puberty. In addition to viril-! P; U6 Q0 X$ K
ization, the clinical hallmark of CPP is the symmet-' M# O& Y1 U# r9 j! h; v  K' M
rical testicular growth secondary to stimulation by' C# Z4 r2 F6 f- @7 I$ w
gonadotropins.1,3
- s/ P9 `; m) ?2 @  xGonadotropin-independent peripheral preco-" d4 \. s0 M* ]) j- m' S
cious puberty in boys also results from inappropriate% j, i! l/ q4 i" h, S
androgenic stimulation from either endogenous or
2 h: \: Y! W  ^/ Yexogenous sources, nonpituitary gonadotropin stim-
+ |8 Q% R4 G, k4 Xulation, and rare activating mutations.3 Virilizing
& }' U" b3 b6 Z# p" T$ Icongenital adrenal hyperplasia producing excessive2 x" ~: p( a. l% o5 I, p# C* `
adrenal androgens is a common cause of precocious
8 y' @4 V9 f  h, r$ L6 V3 `) jpuberty in boys.3,4
1 o2 o) Y/ L/ k- U1 wThe most common form of congenital adrenal6 v# P. g) `2 H' D
hyperplasia is the 21-hydroxylase enzyme deficiency.
$ z8 o4 Q/ u# z( K! a" vThe 11-β hydroxylase deficiency may also result in
$ [* E) r' m8 A' |excessive adrenal androgen production, and rarely,
5 b! Q. Q* J, ]" ~an adrenal tumor may also cause adrenal androgen
! x' a- X( B% P: Iexcess.1,3. Y. D8 {+ |* I9 i; g
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
8 w" e; v' L) {6 j) B542 Clinical Pediatrics / Vol. 46, No. 6, July 20071 u9 ]( E' J; H7 Q& }
A unique entity of male-limited gonadotropin-
' g  S; L4 D* e1 _independent precocious puberty, which is also known
, x! F5 e, t. h; ]as testotoxicosis, may cause precocious puberty at a+ u. o( u$ |8 ~' j
very young age. The physical findings in these boys
" p  P( G# j. Awith this disorder are full pubertal development,
) Y! g# e0 K- P7 G! R) P) c2 bincluding bilateral testicular growth, similar to boys
& v. m( y! X8 owith CPP. The gonadotropin levels in this disorder! O9 }' I5 s+ z; [% O3 X$ g7 s
are suppressed to prepubertal levels and do not show
! Q9 S( b8 M8 c" Tpubertal response of gonadotropin after gonadotropin-( S* v1 ~, A/ U2 Y
releasing hormone stimulation. This is a sex-linked
1 x8 N5 m) Y- zautosomal dominant disorder that affects only. z/ N3 ^" J1 Y: a$ q
males; therefore, other male members of the family% X- Y: [" \! }3 U' x( ~
may have similar precocious puberty.33 E/ N& Z9 s4 U! U: {2 _, K
In our patient, physical examination was incon-
& Y" h' T& x6 A) H0 c5 \sistent with true precocious puberty since his testi-- D  f5 V; j6 Z
cles were prepubertal in size. However, testotoxicosis( |& Z+ [1 C' A
was in the differential diagnosis because his father
, w" D# w8 D5 Wstarted puberty somewhat early, and occasionally,
' V; f+ i/ a6 L/ _" ?8 l5 Wtesticular enlargement is not that evident in the
2 \/ P; D% i% j8 qbeginning of this process.1 In the absence of a neg-
2 i' V/ H  W/ }2 a; ^: L  b' Dative initial history of androgen exposure, our
) s2 I  L0 v% H& E' h- Q2 ~$ ~8 l! Ybiggest concern was virilizing adrenal hyperplasia,, C, ?' W" g! j
either 21-hydroxylase deficiency or 11-β hydroxylase; ]0 z: D: [% N8 |  Z1 K
deficiency. Those diagnoses were excluded by find-8 K. `. Y. D8 K& b( B
ing the normal level of adrenal steroids.
- y) P9 Q! _7 P+ RThe diagnosis of exogenous androgens was strongly2 g. g( a3 K1 k4 m  U' g
suspected in a follow-up visit after 4 months because
0 G4 ^  `* T1 Wthe physical examination revealed the complete disap-
, [" W: M3 \# R8 Y8 U* |0 Cpearance of pubic hair, normal growth velocity, and7 P+ B3 P7 R9 h3 w9 x
decreased erections. The father admitted using a testos-
  g% o* c8 |/ E7 X( Zterone gel, which he concealed at first visit. He was1 K5 i, C$ w2 \& X
using it rather frequently, twice a day. The Physicians’4 j% X2 O9 l$ i- Q" g
Desk Reference, or package insert of this product, gel or
& P4 @/ A+ B6 Q9 Wcream, cautions about dermal testosterone transfer to
; y) F6 W7 {' x; Gunprotected females through direct skin exposure.
- o& n) @" S6 |4 gSerum testosterone level was found to be 2 times the
- A# M# U$ B- u( @8 [baseline value in those females who were exposed to
- ~2 \5 i1 f" u7 aeven 15 minutes of direct skin contact with their male
1 V5 Y% j  D7 Spartners.6 However, when a shirt covered the applica-( Y  i2 e8 x5 x
tion site, this testosterone transfer was prevented.
% W7 @5 ?6 n! ]Our patient’s testosterone level was 60 ng/mL,$ {6 {* ^# O" u: O3 O
which was clearly high. Some studies suggest that
! V8 G/ ?1 K$ k8 wdermal conversion of testosterone to dihydrotestos-) F3 W( ^9 H* \' s! s  \
terone, which is a more potent metabolite, is more% R) R# e/ G9 l% ~5 q6 g$ K
active in young children exposed to testosterone4 U# E3 Y9 Z1 a5 T( V4 ~
exogenously7; however, we did not measure a dihy-
9 v) N% _& a  Q3 ?drotestosterone level in our patient. In addition to
8 E6 m1 `6 V( }6 P1 q: jvirilization, exposure to exogenous testosterone in
8 O# g# z* L6 J0 Nchildren results in an increase in growth velocity and
& X8 O, `; F9 Z5 ?advanced bone age, as seen in our patient.
- L" N& S7 {5 L4 CThe long-term effect of androgen exposure during5 i$ X1 \2 S/ _3 \- ~. N
early childhood on pubertal development and final
+ K8 j% g: m, n9 Zadult height are not fully known and always remain% [7 K7 e! N' @; W/ {3 |: I: ?
a concern. Children treated with short-term testos-  I) h! P2 U- z1 M5 J: g
terone injection or topical androgen may exhibit some5 h3 J" x, M9 q3 G: ]
acceleration of the skeletal maturation; however, after" O- W0 A9 {6 H/ b4 |* [$ }
cessation of treatment, the rate of bone maturation' ~$ k  E# I6 @+ H) \- a& F
decelerates and gradually returns to normal.8,9' Y: p# F6 o  _/ [( H
There are conflicting reports and controversy
/ `" A) w9 W: c  Q7 ?over the effect of early androgen exposure on adult
( r; m* F3 M& G" H, _  ]penile length.10,11 Some reports suggest subnormal
2 r/ v1 r" y5 _5 _# S" A1 uadult penile length, apparently because of downreg-
* u( y: S# b4 b$ rulation of androgen receptor number.10,12 However,
4 R4 K$ Y) \5 L/ M8 F( Q- ySutherland et al13 did not find a correlation between
; P; D4 n# N1 w: H1 g+ B2 d8 lchildhood testosterone exposure and reduced adult
5 Z$ f( N4 X& W; b# e' {- V  G: i4 Lpenile length in clinical studies., w/ o6 }1 }2 x3 E" t: h
Nonetheless, we do not believe our patient is
1 F" B# Q, i  J, u; D  E6 a1 ~going to experience any of the untoward effects from
6 T: {5 w; d: H. A+ Dtestosterone exposure as mentioned earlier because
% `) J* H! j  V; x" Y1 p1 @the exposure was not for a prolonged period of time.+ Z3 J- C! e7 o+ u/ ~* ~! K8 v9 @
Although the bone age was advanced at the time of
5 s* c8 Z- t7 \* J9 Ediagnosis, the child had a normal growth velocity at
- r! [+ g7 T" R4 \. _, v8 Tthe follow-up visit. It is hoped that his final adult* R# `+ s+ q- U: v$ ^' c4 ?6 p
height will not be affected.
/ e5 W6 r4 q" {+ AAlthough rarely reported, the widespread avail-$ L! b" S7 D8 c
ability of androgen products in our society may' u' `3 x4 ]. M  ]' _
indeed cause more virilization in male or female
, x' K: o+ U* }  S5 T) P! dchildren than one would realize. Exposure to andro-; R% g, [1 K; Z/ ]
gen products must be considered and specific ques-" [: T6 ^( O9 @. f
tioning about the use of a testosterone product or
9 f( u) M6 A7 ggel should be asked of the family members during
  n! X8 k  g/ _5 t' a0 hthe evaluation of any children who present with vir-
5 j) s8 [% S2 K6 o/ Eilization or peripheral precocious puberty. The diag-
( ~2 m2 ]4 ^; `+ \0 snosis can be established by just a few tests and by9 @6 [- Y2 O( D5 x5 [
appropriate history. The inability to obtain such a
5 A' d9 w6 o0 j% ^% O+ t) \history, or failure to ask the specific questions, may
& }% j" E2 }; n- sresult in extensive, unnecessary, and expensive. u$ l; F6 V7 _  f
investigation. The primary care physician should be/ G* j( V5 ~' W& ^" L( ~/ r
aware of this fact, because most of these children
- n. T; O0 ?& I4 fmay initially present in their practice. The Physicians’, R7 ^8 b0 d+ _( w
Desk Reference and package insert should also put a# [/ E7 J$ {2 R7 _4 \$ F
warning about the virilizing effect on a male or
; Z8 \$ u7 F* r/ ~female child who might come in contact with some-3 n0 x4 G- J$ Z" h- X
one using any of these products.+ O3 r0 X1 {) `3 m
References
' j' Q9 o. }7 ^) o" r! T4 ^1. Styne DM. The testes: disorder of sexual differentiation, S0 \  k3 S; N2 f
and puberty in the male. In: Sperling MA, ed. Pediatric# w/ _; T# I8 Q9 c3 f9 `
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;$ L: C5 K; n7 R) N) |
2002: 565-628.$ [  V% \2 Z4 ?
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious' p2 d0 q4 m, w5 D+ l
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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發表於 2025-1-19 02:41:05 | 顯示全部樓層
  w) |4 _0 U% s# O6 ^  b" n
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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