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Sexual Precocity in a 16-Month-Old* d# q2 i( W* `8 s7 o: T( ]6 a
Boy Induced by Indirect Topical# O, }4 S' y( p; _7 X# T
Exposure to Testosterone( ?8 a8 C0 i. d4 k+ Y
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
' i' e; k9 e2 Q# j* `0 sand Kenneth R. Rettig, MD1+ s+ E( f  [: ?, |1 P
Clinical Pediatrics" I1 z- u+ I& d: I2 ?) G
Volume 46 Number 6
+ d5 S" Y; j( t# m0 ~2 \July 2007 540-543+ \5 h5 d6 A% s3 ~
© 2007 Sage Publications
3 M) G" |0 u" o0 L10.1177/0009922806296651/ K# B7 u4 j; P- z
http://clp.sagepub.com
" w, L4 c/ K$ a4 Hhosted at
; g; g( ?9 i2 e6 q+ whttp://online.sagepub.com5 n! l6 j* Y& m- T5 }) u4 ^! q, X
Precocious puberty in boys, central or peripheral,
5 K- ]; I: v( e2 B6 K$ ]) o7 Dis a significant concern for physicians. Central
# J' T8 k' M  u& A! k' e. L0 X3 aprecocious puberty (CPP), which is mediated
1 U  B$ L3 W7 m" q8 X/ \+ G8 jthrough the hypothalamic pituitary gonadal axis, has; L8 @8 b3 m+ e) U' x
a higher incidence of organic central nervous system
3 U) j3 F4 a3 I# y: olesions in boys.1,2 Virilization in boys, as manifested5 t! G$ s* q& W) Q1 o  a
by enlargement of the penis, development of pubic$ R- V% @) E6 }1 r
hair, and facial acne without enlargement of testi-
0 B. S3 @' P6 `0 _/ b$ qcles, suggests peripheral or pseudopuberty.1-3 We
* e! v7 v# Z3 U0 T' Zreport a 16-month-old boy who presented with the
9 E) `4 s! B/ f: K, ~enlargement of the phallus and pubic hair develop-. `5 w% |7 Y2 \/ H: y7 \, K
ment without testicular enlargement, which was due
2 Q$ C+ U! c0 \/ ?9 r( U' Kto the unintentional exposure to androgen gel used by
8 l( R% U' b  c4 z9 i5 d5 s! d% ythe father. The family initially concealed this infor-9 ]4 b  K3 R  g: l& w: w: B* }4 i
mation, resulting in an extensive work-up for this: d% e8 F1 p- [; n& o% d' y  Z7 M
child. Given the widespread and easy availability of
" {! D# Y! V' o8 L7 g4 ~4 Stestosterone gel and cream, we believe this is proba-% ~( ]* G/ t  s' M" W
bly more common than the rare case report in the
( o4 _9 k0 @# Q+ N" L/ D: uliterature.4  P9 Y; V6 V* B7 n) B" T
Patient Report7 T, ]( ?" a# i! p+ ^
A 16-month-old white child was referred to the3 B5 j6 ~3 c& O
endocrine clinic by his pediatrician with the concern1 b0 u; U4 y' |5 c3 _
of early sexual development. His mother noticed  h7 t! M& F7 O1 p  U) l
light colored pubic hair development when he was
+ P8 u+ b: ~6 bFrom the 1Division of Pediatric Endocrinology, 2University of" l1 Q/ P) p! B2 ^7 \8 T6 I- Z( }
South Alabama Medical Center, Mobile, Alabama.
7 U1 ~& c: O0 p6 I! G. M7 q; _Address correspondence to: Samar K. Bhowmick, MD, FACE,* f' }" f; [1 H" C$ x- v1 M. A
Professor of Pediatrics, University of South Alabama, College of6 e- Q4 Y& T* l
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
( W8 Y6 f( ^3 d% J$ le-mail: [email protected].
2 Z* g4 O* K. pabout 6 to 7 months old, which progressively became
4 g# X+ ?6 l7 p: y! `) Mdarker. She was also concerned about the enlarge-
+ u; {6 A0 I, g4 h- gment of his penis and frequent erections. The child" `6 L# I5 w6 k1 R) g) b4 Q
was the product of a full-term normal delivery, with* z8 O7 E; H0 N' v# }8 e5 t
a birth weight of 7 lb 14 oz, and birth length of7 ~, V8 V6 V% m, W' ?' ^* T  n
20 inches. He was breast-fed throughout the first year
. R) N9 U: K& V9 i! l) l, Dof life and was still receiving breast milk along with( |7 W5 d% ~) a; \/ j0 D
solid food. He had no hospitalizations or surgery,
; f7 r( e  m8 ]% C( oand his psychosocial and psychomotor development
4 K% {3 e4 j0 H; E. x! [was age appropriate.
3 |$ P6 ~/ A# w- |# f8 aThe family history was remarkable for the father,
7 L* G  i: }" D9 _5 Xwho was diagnosed with hypothyroidism at age 16,
$ K1 `% V4 V8 K2 N. B1 twhich was treated with thyroxine. The father’s
$ v; ?7 b. x" `( W# Rheight was 6 feet, and he went through a somewhat1 }5 @8 f; i& q7 Q' U
early puberty and had stopped growing by age 14.3 A8 A* q. A' Z) Q/ h+ }
The father denied taking any other medication. The! U' N/ r3 B# b, K
child’s mother was in good health. Her menarche" C! `' m0 I$ n% X! G( w" e0 v: F( C
was at 11 years of age, and her height was at 5 feet
1 ]- R* s9 G9 \0 s) n. s0 I5 inches. There was no other family history of pre-
" D- i* Y+ S  u9 h  w8 s0 icocious sexual development in the first-degree rela-
% L. A, v" l7 M# ^0 Dtives. There were no siblings." V0 A% J+ X0 I: j  }
Physical Examination
  o. H, H; X8 C9 KThe physical examination revealed a very active,
9 x0 j% y" D- s3 e& N/ O6 eplayful, and healthy boy. The vital signs documented
7 ?3 i: N; {# C9 Fa blood pressure of 85/50 mm Hg, his length was
1 [7 E% x3 o9 Q" k$ A9 {90 cm (>97th percentile), and his weight was 14.4 kg
4 B0 e& w$ y( S, m6 E(also >97th percentile). The observed yearly growth
0 X& i6 h9 W9 `" W3 ?velocity was 30 cm (12 inches). The examination of( V5 _5 {/ c2 S- W
the neck revealed no thyroid enlargement.0 e! r  E% c4 A. G9 |/ D
The genitourinary examination was remarkable for  U6 n9 Z9 N+ V& O9 n& D+ d+ q
enlargement of the penis, with a stretched length of
! ]* G8 B# }* [1 e8 cm and a width of 2 cm. The glans penis was very well
# ]  _' E* I8 c3 H' x# a$ K$ f/ b. `developed. The pubic hair was Tanner II, mostly around. m* I& Z/ Z+ S( P% W* Y( K
540
4 V  V, b6 v( j/ V. |- Xat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from: _7 J! k$ ^7 M9 d6 X$ Q2 _# s
the base of the phallus and was dark and curled. The% i6 {- r) O! D* x! T3 x$ N
testicular volume was prepubertal at 2 mL each.2 |$ D6 B' T* D
The skin was moist and smooth and somewhat1 Y7 T' m$ _  r5 a# a
oily. No axillary hair was noted. There were no# K: T0 _; n! y
abnormal skin pigmentations or café-au-lait spots.7 N4 n8 }% z* P- F
Neurologic evaluation showed deep tendon reflex 2+
& r# l- r4 {. N, bbilateral and symmetrical. There was no suggestion
- C( r/ j4 h! y$ |, jof papilledema.8 {& r$ k6 e( P( O
Laboratory Evaluation% `* h) m! X$ `  _. O: M
The bone age was consistent with 28 months by
. [, u3 s& w. B: w- Z$ Eusing the standard of Greulich and Pyle at a chrono-
! `# s: k* t! n5 e) j" blogic age of 16 months (advanced).5 Chromosomal
( \( m( l$ x# L: R( R, [8 zkaryotype was 46XY. The thyroid function test) R6 n/ \1 d" Y( F/ w
showed a free T4 of 1.69 ng/dL, and thyroid stimu-
0 I9 \+ w/ d6 ulating hormone level was 1.3 µIU/mL (both normal).4 h1 R, _# m+ x; s3 t# D! ]0 s5 E) l5 Q
The concentrations of serum electrolytes, blood
) P/ M* f. n$ w/ Kurea nitrogen, creatinine, and calcium all were- a+ E1 x9 `4 j+ z
within normal range for his age. The concentration: _9 r: M& c+ |0 h& N( u
of serum 17-hydroxyprogesterone was 16 ng/dL& o# j, O" G# h6 h, _0 X$ M
(normal, 3 to 90 ng/dL), androstenedione was 20
3 n# E2 W( b5 h; P" u  X: hng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
, K! W2 a, z  F+ @4 o+ J( d8 Z' u1 ]0 Oterone was 38 ng/dL (normal, 50 to 760 ng/dL),# {7 e# ~1 L; v% W$ T
desoxycorticosterone was 4.3 ng/dL (normal, 7 to1 q. s7 X" }; `2 N' A, e; S
49ng/dL), 11-desoxycortisol (specific compound S)
0 w, z5 R9 A# A# Xwas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
( q+ C5 c- O- A1 h+ ztisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total- Z) p: Z* j$ M1 l
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),5 x5 r& ]5 o6 a# Y$ q6 S; G) ^; x2 E. E
and β-human chorionic gonadotropin was less than
# |6 |  u  |2 J5 mIU/mL (normal <5 mIU/mL). Serum follicular
& G( u6 E: Z7 w4 i7 n, v: dstimulating hormone and leuteinizing hormone
% t5 @3 Q" g1 r& P: j" o/ y! ?concentrations were less than 0.05 mIU/mL8 d$ A! f* E& {3 U
(prepubertal).- |- W2 r8 s- A* }
The parents were notified about the laboratory
6 p  f5 n! H' Q! `% Z, {* fresults and were informed that all of the tests were! u* I( i/ a3 Y* z5 v$ c
normal except the testosterone level was high. The$ [6 Q2 s7 S2 B* T
follow-up visit was arranged within a few weeks to  H) p8 z4 e8 v: s' |9 x; v
obtain testicular and abdominal sonograms; how-
5 E; a- o; E" g/ q, ~& gever, the family did not return for 4 months.
0 _5 N# ]3 t! M9 M1 t( X3 C: i: N( ~  MPhysical examination at this time revealed that the
' ?5 W0 E0 X1 b3 P/ d; {child had grown 2.5 cm in 4 months and had gained7 n8 w8 {) Z) N: V
2 kg of weight. Physical examination remained
7 Y) E; d' P; x6 `unchanged. Surprisingly, the pubic hair almost com-
$ c2 k. }4 d2 w# xpletely disappeared except for a few vellous hairs at4 d- z! V. m" p9 i
the base of the phallus. Testicular volume was still 2
: v/ K! R# \  Y' [mL, and the size of the penis remained unchanged.
$ ~  `  W- K, XThe mother also said that the boy was no longer hav-
' w5 @$ Y( j. G) w3 j% Q) Wing frequent erections.
  ^5 a3 P/ f( a# w# d" D5 XBoth parents were again questioned about use of
* {8 l6 a* g/ j. `" ?$ }  Many ointment/creams that they may have applied to
( B2 O) |1 i7 R& r1 {the child’s skin. This time the father admitted the
, W  x0 ]! i. n' [7 o2 o- A7 _Topical Testosterone Exposure / Bhowmick et al 5416 t) [! @$ j1 j: l6 ]
use of testosterone gel twice daily that he was apply-
" ?7 _7 }( w% ]( D1 M7 ling over his own shoulders, chest, and back area for: ?  H8 j: e  O* a% g) F) ~8 h
a year. The father also revealed he was embarrassed- e( w0 z1 E* }% L$ W
to disclose that he was using a testosterone gel pre-6 ~/ X8 n" z8 J# ?; \2 Z: M) z3 E' I
scribed by his family physician for decreased libido0 s1 j0 E. U, d
secondary to depression.7 h: f# u7 {' m: H
The child slept in the same bed with parents.
. r0 |# U+ {* R) d( k9 a+ X5 VThe father would hug the baby and hold him on his
5 m( R* M: b( v/ i  Lchest for a considerable period of time, causing sig-
  x( P- V  D* K0 v+ G, ?nificant bare skin contact between baby and father.% Z4 G7 b2 i( O& ^1 ^
The father also admitted that after the phone call,
* E0 I7 B% M+ w  m2 I0 O) Gwhen he learned the testosterone level in the baby
! I  L5 {: W$ ^6 ~: swas high, he then read the product information
5 u& g9 S  [- y/ Wpacket and concluded that it was most likely the rea-
6 M+ ]2 j5 ^% k1 mson for the child’s virilization. At that time, they
* G. H+ N2 d! X3 X1 a+ b6 i: Sdecided to put the baby in a separate bed, and the
- C, o( t4 F% @) V( w! V: z( z  E9 zfather was not hugging him with bare skin and had
" ~. z) T* i1 a. l8 @. K- Q4 v4 obeen using protective clothing. A repeat testosterone# [7 Q+ E' F% o; |$ G
test was ordered, but the family did not go to the
) h( M9 ^* U( O6 c3 ?laboratory to obtain the test.
8 j0 {& z6 x( S6 s9 [Discussion9 O# ~: ]- I) z
Precocious puberty in boys is defined as secondary3 v) o, ^) j0 N+ y
sexual development before 9 years of age.1,4
6 u4 G. P2 T9 Y, qPrecocious puberty is termed as central (true) when
; F. ~& A) L/ Nit is caused by the premature activation of hypo-
8 v) _! b6 m7 b1 o7 C8 Rthalamic pituitary gonadal axis. CPP is more com-
$ f1 U; {) \8 @3 Gmon in girls than in boys.1,3 Most boys with CPP9 Y7 I9 s7 o, k" n: b) h
may have a central nervous system lesion that is0 G- V) H3 K8 j
responsible for the early activation of the hypothal-9 @9 R# ^3 j5 C; Y% F
amic pituitary gonadal axis.1-3 Thus, greater empha-( x* q& D" w; h, E+ _  Y
sis has been given to neuroradiologic imaging in
0 ~2 o* e- o+ [0 N8 Xboys with precocious puberty. In addition to viril-
2 ~/ p" M5 z9 V3 m. k# }1 p% fization, the clinical hallmark of CPP is the symmet-5 y8 W! I" X, Z: E
rical testicular growth secondary to stimulation by
5 E: ^8 S/ w1 b; V7 r7 r4 ngonadotropins.1,31 ~1 L2 X' w3 X
Gonadotropin-independent peripheral preco-- E! v9 q  _; q  j8 W+ P* ?+ L
cious puberty in boys also results from inappropriate
$ Y6 f2 v1 F) D0 f- w7 m1 a2 B7 Eandrogenic stimulation from either endogenous or
; K5 W: e9 m" {, bexogenous sources, nonpituitary gonadotropin stim-6 ^0 S- J) o* {+ ~( {: ]
ulation, and rare activating mutations.3 Virilizing% R$ v) T7 A: o2 l6 c
congenital adrenal hyperplasia producing excessive5 Z: w# X" ]  Q+ g4 N2 @
adrenal androgens is a common cause of precocious
+ e2 U. s3 m4 Bpuberty in boys.3,4
+ ]1 i% R, ?6 o* Q+ A; z1 r% G6 H1 VThe most common form of congenital adrenal8 _  Q6 u* R6 A
hyperplasia is the 21-hydroxylase enzyme deficiency.
* }4 U& c/ k+ N2 v) e( zThe 11-β hydroxylase deficiency may also result in1 |. n- y: [! u# y$ y
excessive adrenal androgen production, and rarely,
" ?) z0 e8 n2 nan adrenal tumor may also cause adrenal androgen
% g% h0 i4 _, c& qexcess.1,3
5 J- E9 u9 v( H" Eat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from  k& }3 C; E8 _9 E( [
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
: }3 ~9 g. k1 s1 V& s3 sA unique entity of male-limited gonadotropin-, h& q0 t- b2 t0 y( J
independent precocious puberty, which is also known
! f8 U! j$ l/ Tas testotoxicosis, may cause precocious puberty at a
1 H9 Z) _* O: G5 Fvery young age. The physical findings in these boys+ @( N: ^: V/ A  Q4 _
with this disorder are full pubertal development,
: x) i+ m; W( t1 P  h& c( Y, xincluding bilateral testicular growth, similar to boys
' _, U. G3 g$ ]0 y+ |with CPP. The gonadotropin levels in this disorder
' d9 I' p. I4 F9 l/ Nare suppressed to prepubertal levels and do not show
! {" F. {: S1 X' D1 spubertal response of gonadotropin after gonadotropin-
! C9 Y. `- H1 [- J& i; e5 Oreleasing hormone stimulation. This is a sex-linked8 t' J9 ^0 T) s
autosomal dominant disorder that affects only; B6 v/ N4 h; Y0 K4 t' L+ a% x
males; therefore, other male members of the family! o0 {/ V% c& z3 z% @. s
may have similar precocious puberty.3
' v, r( }4 }! o) M0 Q0 W. @In our patient, physical examination was incon-
8 C  P7 F9 D8 b5 qsistent with true precocious puberty since his testi-! H7 ]5 @4 m( `: p: ~6 x+ E
cles were prepubertal in size. However, testotoxicosis" n  H1 F- y9 `  S
was in the differential diagnosis because his father
2 m" D( n' v$ {$ y9 I/ _started puberty somewhat early, and occasionally,1 s7 [8 V: ]  }8 \. r( c, y
testicular enlargement is not that evident in the
# Q8 Z  F& @! ~, [  H' ^" ]beginning of this process.1 In the absence of a neg-
$ l2 {1 y6 e' ~9 n, V: v9 yative initial history of androgen exposure, our
# ^8 _; C- c$ S/ u# rbiggest concern was virilizing adrenal hyperplasia,
; f& w- H' o  X+ ?6 Keither 21-hydroxylase deficiency or 11-β hydroxylase6 e. t( y0 k; M- S
deficiency. Those diagnoses were excluded by find-
, D9 w+ f5 E+ C$ l4 wing the normal level of adrenal steroids.' ?( m- _1 t% \; `9 x
The diagnosis of exogenous androgens was strongly
. M- I# s; C% y2 @5 ^suspected in a follow-up visit after 4 months because5 |9 Z& m$ X- ]1 ^2 L
the physical examination revealed the complete disap-% O+ r3 ?6 [2 B$ y
pearance of pubic hair, normal growth velocity, and- r9 T3 `! i7 x* D# K
decreased erections. The father admitted using a testos-- @" L6 j& }/ ~
terone gel, which he concealed at first visit. He was
; x" }: N9 f- A' j. k& wusing it rather frequently, twice a day. The Physicians’
- q, O6 b1 O) Y- Z2 M, x: i* \2 IDesk Reference, or package insert of this product, gel or) Q* Q! o0 I' b: f/ Y7 a: R+ Y
cream, cautions about dermal testosterone transfer to; a; K) i. d" n/ W* c" {- P# _
unprotected females through direct skin exposure.
* {0 n6 a$ ]5 d) ~2 l! DSerum testosterone level was found to be 2 times the
" a3 a2 N- a' K+ ]* S6 D, fbaseline value in those females who were exposed to3 e2 @0 \2 T1 w+ w5 _, a; b
even 15 minutes of direct skin contact with their male: ~, j1 E  K7 I. Y4 l3 R+ r# i1 s
partners.6 However, when a shirt covered the applica-5 b( @( A; U9 L- ^5 P. i9 Q2 a
tion site, this testosterone transfer was prevented.
- B0 {" Z2 N, ]Our patient’s testosterone level was 60 ng/mL,: h7 R8 L( n5 B' I
which was clearly high. Some studies suggest that
" K" B' H9 V3 H5 s& j6 e6 e7 h, q5 mdermal conversion of testosterone to dihydrotestos-
& E& G- g5 V8 Q# t  ^! ^; Tterone, which is a more potent metabolite, is more
. V  L* w0 j+ C" l. y3 jactive in young children exposed to testosterone6 M$ }9 a8 _( m2 `# S) d  K6 N
exogenously7; however, we did not measure a dihy-
3 J; r3 ]& ?! b) ?3 z) jdrotestosterone level in our patient. In addition to! E5 b8 S+ t. w' b) [0 t
virilization, exposure to exogenous testosterone in. h" u$ K8 N1 @; v$ r
children results in an increase in growth velocity and
: [! G6 O  A# G% n$ X8 }6 c+ Zadvanced bone age, as seen in our patient.
6 T- f: k$ w6 p# ]: s  zThe long-term effect of androgen exposure during
2 x  Q6 }7 F: }/ {3 S9 H; vearly childhood on pubertal development and final
; w& J# D# d* X/ b$ `adult height are not fully known and always remain; a# l+ a% r7 W% t
a concern. Children treated with short-term testos-
& r3 Y1 w; c3 J1 H& v) j* bterone injection or topical androgen may exhibit some
  ]0 [1 {/ l8 sacceleration of the skeletal maturation; however, after
4 c9 v! x* H& w4 Z2 jcessation of treatment, the rate of bone maturation) ~! q  C. ~$ f$ z/ _
decelerates and gradually returns to normal.8,9
( S! G  |2 P, fThere are conflicting reports and controversy
: g# V# V; J4 m9 n6 yover the effect of early androgen exposure on adult0 t- F' Z& o$ G/ w4 j
penile length.10,11 Some reports suggest subnormal; R; {; p% o/ S$ I* Y9 M( {
adult penile length, apparently because of downreg-0 O( S! k! ?& X
ulation of androgen receptor number.10,12 However,8 ^! D2 Y5 ~9 N% Z: _+ K
Sutherland et al13 did not find a correlation between: I4 B+ O% }+ @" |  o1 A, I
childhood testosterone exposure and reduced adult; l2 h& I* M7 y3 \
penile length in clinical studies.
1 |* t" d3 z- @% v5 iNonetheless, we do not believe our patient is$ F) _2 P9 |5 {) z# H1 g# y9 z
going to experience any of the untoward effects from
8 `. D. ^: l$ ^- T' }testosterone exposure as mentioned earlier because
2 t8 n2 A& ]5 Gthe exposure was not for a prolonged period of time.
6 g- }. r* i- ~7 X4 m2 z; i  BAlthough the bone age was advanced at the time of
- {4 E  [4 ?& f" `+ qdiagnosis, the child had a normal growth velocity at
" k$ v2 U# U) l* V6 e# Q8 t5 _: `, Vthe follow-up visit. It is hoped that his final adult# ^9 _+ h" F) G6 D- F
height will not be affected.. f  d/ B' D6 I& P: d" a
Although rarely reported, the widespread avail-. ]5 [1 S2 s: f6 w$ u
ability of androgen products in our society may: `8 w& {. M$ ?0 w/ K' C) q
indeed cause more virilization in male or female( |7 f1 w! q  T" B
children than one would realize. Exposure to andro-1 ~+ H! W, ?4 p6 E7 v1 x! w
gen products must be considered and specific ques-
! y- Y1 h& }& v4 F: X: A/ |) h1 N0 Ptioning about the use of a testosterone product or
' F4 S, B" U1 P/ L6 \gel should be asked of the family members during
" p# I/ X, F3 s$ [8 g- Tthe evaluation of any children who present with vir-! y% }4 ?7 i4 `$ R9 R0 J. t
ilization or peripheral precocious puberty. The diag-
9 r( K+ \8 g! p/ Dnosis can be established by just a few tests and by+ E) U! I9 C/ j2 \( S
appropriate history. The inability to obtain such a; h3 ]) x- T" t
history, or failure to ask the specific questions, may6 H5 l0 f! _  G9 Y6 c' c
result in extensive, unnecessary, and expensive: I3 \9 X3 k0 P3 P+ ]3 a/ E
investigation. The primary care physician should be$ L3 P9 V0 l5 M
aware of this fact, because most of these children- m- x: Q5 b8 T2 X5 j, n! E
may initially present in their practice. The Physicians’
# L% x. X! P* ODesk Reference and package insert should also put a- N) q" @- P! a+ B* y
warning about the virilizing effect on a male or
! j! Q) k$ a' P/ cfemale child who might come in contact with some-
! l: p, P) d7 p9 o4 yone using any of these products.0 u1 |/ v9 J3 A5 A: q
References
; V: z( u9 B6 t; E6 m5 C1. Styne DM. The testes: disorder of sexual differentiation% `$ B$ S2 U; [, z* E6 L. \
and puberty in the male. In: Sperling MA, ed. Pediatric
/ I! R' N5 C6 C. N5 q3 yEndocrinology. 2nd ed. Philadelphia, PA: WB Saunders;" p8 T2 J# Y9 z0 W" o4 t+ P
2002: 565-628.
! s# T1 w/ C* j2 x: B7 Z6 O3 ]2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
7 O! _. S: {7 k2 V: A& }9 wpuberty in children with tumours of the suprasellar pineal
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Sexual Precocity in a 16-Month-Old, }' @+ v, H8 _7 k$ C6 q
Boy Induced by Indirect Topical9 Z3 x0 z3 [2 X+ p# ~
Exposure to Testosterone
# x# R( Q1 l& K7 pSamar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2+ X4 F7 ]1 A7 S, S; y) h/ T8 P, Y
and Kenneth R. Rettig, MD1
. o7 h) `/ z0 `) D( s2 H/ vClinical Pediatrics9 z( q4 [; R) i$ z1 _
Volume 46 Number 68 Z, `% E* {( l, c. ^1 G) t; G
July 2007 540-543) c/ H/ e* D( u+ ]/ i
© 2007 Sage Publications
  G0 m+ L# X; Y" W10.1177/0009922806296651  h, ]. S1 U$ @$ @* }
http://clp.sagepub.com; y% `- ?# h  e( }
hosted at5 g/ P6 V- h+ A7 u
http://online.sagepub.com8 K) ], b7 U& A/ g3 e$ X
Precocious puberty in boys, central or peripheral,
; f% i) S- P# R3 [8 ]7 Wis a significant concern for physicians. Central
; b2 p& R5 f: T& `3 uprecocious puberty (CPP), which is mediated* ?3 }0 O2 C# f# B/ G
through the hypothalamic pituitary gonadal axis, has4 I1 `, ?; @4 m# C; _0 l
a higher incidence of organic central nervous system) F% j( O. f( q
lesions in boys.1,2 Virilization in boys, as manifested
8 j. W& g; f. \& g9 lby enlargement of the penis, development of pubic
+ j1 m9 H+ C  R$ [( @1 C8 {3 ~' M( @hair, and facial acne without enlargement of testi-
' @! j; r/ `' D" {: R3 \: ~cles, suggests peripheral or pseudopuberty.1-3 We
5 T1 l% {. g. ?0 i6 v1 n) Creport a 16-month-old boy who presented with the; \( k& X; L* }( |2 ~5 r! t  ?
enlargement of the phallus and pubic hair develop-. i& q7 V4 c( g2 T5 S' I# o8 {
ment without testicular enlargement, which was due
& N+ y& w' `4 t  j) ito the unintentional exposure to androgen gel used by
% d1 d" ]6 X# W& T0 Z& ?  v* dthe father. The family initially concealed this infor-) ]# \# @4 |4 M* l2 P
mation, resulting in an extensive work-up for this5 I4 R7 V$ p: u2 H
child. Given the widespread and easy availability of" p: \# A/ W; B8 U* }
testosterone gel and cream, we believe this is proba-
& q3 F: c" e! v  D3 r0 ^& nbly more common than the rare case report in the6 y  z" g" W1 r- J
literature.4
9 ?  B* R0 Y5 }( S' Y2 @Patient Report
* S8 W! ?* z6 l8 F$ J+ oA 16-month-old white child was referred to the
6 O! ~/ B5 S# w% S; H1 w: qendocrine clinic by his pediatrician with the concern# [/ }! o2 B, C6 m
of early sexual development. His mother noticed
' T$ w- O5 E0 {* M8 O# mlight colored pubic hair development when he was7 u' d4 @' n, A7 Z8 d! b& ]% L1 Z6 n
From the 1Division of Pediatric Endocrinology, 2University of! y9 S: A/ z& A
South Alabama Medical Center, Mobile, Alabama.
  C' y9 z+ z- r* }2 vAddress correspondence to: Samar K. Bhowmick, MD, FACE,
! n( w, a6 y! s. K- Q" cProfessor of Pediatrics, University of South Alabama, College of7 Y$ O* s1 \. p/ \
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
, W7 h# R7 Z7 R6 T, Pe-mail: [email protected]./ M6 D) G" T7 d+ S
about 6 to 7 months old, which progressively became4 M, }: K2 q3 V) g" m" f0 J
darker. She was also concerned about the enlarge-
1 u" u7 |3 R  s% z& E0 pment of his penis and frequent erections. The child
1 O0 a+ E6 [6 v( Q! Swas the product of a full-term normal delivery, with' }) J) s3 \7 C: l  k
a birth weight of 7 lb 14 oz, and birth length of
( r! E3 k# |" f* c+ \20 inches. He was breast-fed throughout the first year3 R, T% G& D0 ]8 |9 U+ F/ K# Y) K
of life and was still receiving breast milk along with) n. _3 o, h/ I5 N8 o( F/ e
solid food. He had no hospitalizations or surgery,) ^2 O3 Z/ [" E4 i' y. A
and his psychosocial and psychomotor development
: t; F% R7 ~7 Z+ T1 Gwas age appropriate.  i$ ]$ g: B2 ]6 o: L2 l& q. q
The family history was remarkable for the father,
: f- x4 S5 i7 Z, Q" O% lwho was diagnosed with hypothyroidism at age 16,- G. E3 y! m" O' i* l- |
which was treated with thyroxine. The father’s
2 D2 o; E0 f1 J' pheight was 6 feet, and he went through a somewhat
* n+ @# P; u8 s% h, gearly puberty and had stopped growing by age 14.6 G) A4 {( J/ i$ y- b
The father denied taking any other medication. The
  q% a( [+ `, x3 x0 E+ cchild’s mother was in good health. Her menarche7 k/ I. i7 R  F6 {) F0 [) m" S2 k
was at 11 years of age, and her height was at 5 feet! f0 d; d& _9 ~% h1 Z1 l
5 inches. There was no other family history of pre-
2 Y" _; L' a. c5 Ccocious sexual development in the first-degree rela-: Z0 C3 ^9 Q8 L* q
tives. There were no siblings.
9 b2 R- H7 s8 C* x& |- fPhysical Examination
: z( s' m& w7 ?. V' }8 _; k" `# rThe physical examination revealed a very active,& D: A. {. P0 ?5 R  t/ f5 z8 q8 `
playful, and healthy boy. The vital signs documented
0 d( A  o# ]/ L6 {  Z+ x- H5 i% Za blood pressure of 85/50 mm Hg, his length was
( Z! s5 ^! J3 X: \, f7 B# l90 cm (>97th percentile), and his weight was 14.4 kg
% `+ h$ W& c8 u4 ~(also >97th percentile). The observed yearly growth
2 A/ v, b7 D6 k: Q4 q* Kvelocity was 30 cm (12 inches). The examination of
' p8 N  b% q. g# J" r' e  wthe neck revealed no thyroid enlargement.0 k* i6 [; E! Y
The genitourinary examination was remarkable for, t! V* ]# x# Y! `
enlargement of the penis, with a stretched length of# I8 c" a; u5 B- z! l  Z
8 cm and a width of 2 cm. The glans penis was very well
- B) }/ V9 T+ cdeveloped. The pubic hair was Tanner II, mostly around5 t* f0 t' I* _
540
9 k7 i( v( ]3 J# T6 N: F$ s4 Lat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from' W6 n) Q$ j! }4 h* H3 U: K
the base of the phallus and was dark and curled. The0 o% o$ o8 e: @; v
testicular volume was prepubertal at 2 mL each.. a, `* y, ^9 q0 e1 n
The skin was moist and smooth and somewhat$ ~+ G: e6 b% \4 J% H! c
oily. No axillary hair was noted. There were no
" y1 m! q3 T* t2 `abnormal skin pigmentations or café-au-lait spots." x" v: h3 N" P" v
Neurologic evaluation showed deep tendon reflex 2+
% {# u( D: N" o8 sbilateral and symmetrical. There was no suggestion% W" b2 U  j( P1 F: j
of papilledema." H0 ^, ]. z2 @
Laboratory Evaluation, h( x8 X" }4 [' d# U
The bone age was consistent with 28 months by* E: o# P7 |" O6 V- g
using the standard of Greulich and Pyle at a chrono-. b) T3 S- Z3 u+ [+ S% X
logic age of 16 months (advanced).5 Chromosomal, `* y( w5 s' u0 @, s0 k. d1 t
karyotype was 46XY. The thyroid function test$ A" W9 M" ~( I, B& r3 X* r
showed a free T4 of 1.69 ng/dL, and thyroid stimu-8 S5 [# K2 [  ~4 _  E+ i, d$ F
lating hormone level was 1.3 µIU/mL (both normal).& n+ w$ _  u. ~. H4 e
The concentrations of serum electrolytes, blood* N+ l! c( A( Z8 H) E
urea nitrogen, creatinine, and calcium all were
3 E5 }' S' b2 o) mwithin normal range for his age. The concentration
! C8 P( @# M& _9 Q# o" ~* s  `of serum 17-hydroxyprogesterone was 16 ng/dL
; G. N" Q3 G2 S7 p/ c(normal, 3 to 90 ng/dL), androstenedione was 201 A3 G+ C' @- |
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-; j0 ]. L5 i6 P7 C) F
terone was 38 ng/dL (normal, 50 to 760 ng/dL),& V- R4 Q) _4 r; A# X
desoxycorticosterone was 4.3 ng/dL (normal, 7 to$ y" N9 z0 |8 q, `
49ng/dL), 11-desoxycortisol (specific compound S)) H0 e, O, X9 r) n; g7 O
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
4 s* c) q; S& E+ N9 |8 H% v, Etisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total: f0 G" L- C/ f. \, R4 O
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
  K  ?  i; o' I1 `" vand β-human chorionic gonadotropin was less than
/ n3 Q) M. n" @1 [7 \5 mIU/mL (normal <5 mIU/mL). Serum follicular" k0 G2 X1 Q$ c; U
stimulating hormone and leuteinizing hormone' }/ P" S8 z1 @  N
concentrations were less than 0.05 mIU/mL
5 s. U* T/ k1 y$ [% j1 E8 c4 s- W(prepubertal).. E$ N, F$ ]; ^# L( i% J5 H
The parents were notified about the laboratory
4 P2 u. j% m+ y  B' D; p* I0 iresults and were informed that all of the tests were
0 p) C, P. E7 q8 `: M# H1 @normal except the testosterone level was high. The
7 j8 Q# G" R3 ~; r8 S4 Pfollow-up visit was arranged within a few weeks to7 W% W  r1 Z4 `4 F* D! a% K6 V. b# I
obtain testicular and abdominal sonograms; how-* D$ {7 w, ~* \/ x# O
ever, the family did not return for 4 months.
8 T) ^8 o4 i5 TPhysical examination at this time revealed that the4 H! h) @0 X! t
child had grown 2.5 cm in 4 months and had gained  I6 C0 D$ w$ R# ]# j
2 kg of weight. Physical examination remained
, W/ |7 l, o" S: l- Tunchanged. Surprisingly, the pubic hair almost com-, v# q$ Y2 k- X* v4 V! h
pletely disappeared except for a few vellous hairs at, U7 t! c1 x% I, x
the base of the phallus. Testicular volume was still 2) f& w5 g" ~/ B5 J4 \$ O( R
mL, and the size of the penis remained unchanged.
; `: \; I( y8 o1 P8 fThe mother also said that the boy was no longer hav-
8 O" j; ^$ V- a3 Xing frequent erections.
$ t4 a5 z( a0 |( L3 |Both parents were again questioned about use of
$ z7 o: z7 g% B0 p# Y( Vany ointment/creams that they may have applied to
5 ?; N  u% G8 b( k! athe child’s skin. This time the father admitted the, y  A2 V# G. k# |6 k3 n
Topical Testosterone Exposure / Bhowmick et al 541
6 r. F( w) b6 w9 e, muse of testosterone gel twice daily that he was apply-
- i6 u4 L2 ]2 b6 f3 W/ ^ing over his own shoulders, chest, and back area for
$ P. L( N/ X) y$ sa year. The father also revealed he was embarrassed
  B4 _" ]5 N- M7 A. n" U: zto disclose that he was using a testosterone gel pre-
# q9 {5 L& ]0 m- N( yscribed by his family physician for decreased libido
4 @6 K  j2 J) ysecondary to depression.
& o; K4 t' B. p/ D9 VThe child slept in the same bed with parents.
- a- n# E# U" [8 L& B0 ?The father would hug the baby and hold him on his
* T$ J2 G9 P; Jchest for a considerable period of time, causing sig-. Q6 L6 `9 U( x' M, y5 k0 Q
nificant bare skin contact between baby and father.
5 s* L6 \( H- U. k9 s) L0 MThe father also admitted that after the phone call,
2 x; G3 `+ {0 i8 S/ ~0 _6 r% iwhen he learned the testosterone level in the baby* v# P$ f$ [1 {1 m% r: n) J
was high, he then read the product information/ L" T7 ^/ l  z7 [$ I
packet and concluded that it was most likely the rea-
5 }/ j1 r- l- p6 {5 oson for the child’s virilization. At that time, they- j7 l% ?# J5 v8 |7 Y8 X
decided to put the baby in a separate bed, and the
: {* d2 _; U, g6 n9 \$ N0 ^father was not hugging him with bare skin and had
0 D( @5 u3 R8 X/ u! {$ H0 vbeen using protective clothing. A repeat testosterone
( F2 r1 _; B; C9 ?test was ordered, but the family did not go to the' X# C. ?, r& a9 N3 R
laboratory to obtain the test.- {/ @. j& @1 I6 o& P/ J/ o8 L
Discussion0 B+ J5 k6 d4 ?2 I8 @% X- N
Precocious puberty in boys is defined as secondary& x; Q/ T+ T) P
sexual development before 9 years of age.1,4
' U/ i7 N5 A6 Q3 s9 D8 m2 CPrecocious puberty is termed as central (true) when
- F2 ]5 n9 o2 rit is caused by the premature activation of hypo-$ x: o. O, @6 |* |8 @
thalamic pituitary gonadal axis. CPP is more com-
2 U2 y0 X5 x5 |mon in girls than in boys.1,3 Most boys with CPP
: o2 J$ x9 ~* {5 G& p# Jmay have a central nervous system lesion that is) D& ]+ u3 g' E. `" i( A
responsible for the early activation of the hypothal-* m  h. l' R1 t% C6 N7 Z
amic pituitary gonadal axis.1-3 Thus, greater empha-' a% v  U0 [9 {
sis has been given to neuroradiologic imaging in# f  W0 I" j4 z5 ~. e. Q
boys with precocious puberty. In addition to viril-
2 }' g  I- r3 _' Cization, the clinical hallmark of CPP is the symmet-
/ x) j; B' {, y0 K- @3 Y* ]rical testicular growth secondary to stimulation by
6 C- r. T( A- ?" y, ?: ugonadotropins.1,37 c4 k; h3 `/ \  @% E
Gonadotropin-independent peripheral preco-( t' }6 g( L' k- J) N: R5 }1 ~0 l
cious puberty in boys also results from inappropriate" b# A" a3 `1 t2 T3 Q5 |+ w
androgenic stimulation from either endogenous or; O2 F, y7 R7 ]2 \: b: x8 ?, p
exogenous sources, nonpituitary gonadotropin stim-) M& e6 n+ v" r" V! O% ~- g
ulation, and rare activating mutations.3 Virilizing( N* v# T9 u5 D! F% X+ o2 S8 K& s1 s6 X
congenital adrenal hyperplasia producing excessive
+ ^: ]3 \1 M9 Oadrenal androgens is a common cause of precocious
. z( Q* y* g# U& o3 i2 F5 Opuberty in boys.3,45 j  |' k4 Q" L
The most common form of congenital adrenal
- g% |2 P0 O! e& }hyperplasia is the 21-hydroxylase enzyme deficiency.
7 ~: i9 [! s: ]The 11-β hydroxylase deficiency may also result in& Q  z8 {( [+ f1 [
excessive adrenal androgen production, and rarely,
7 Y4 V: H; n) ]an adrenal tumor may also cause adrenal androgen, ?& C; T3 b0 m7 ~2 Z0 j$ Z( S
excess.1,33 m0 C1 \2 v) ^% \
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
. `$ B# K/ \  P& y, G542 Clinical Pediatrics / Vol. 46, No. 6, July 20073 i' M& i7 I# b, u2 F" a
A unique entity of male-limited gonadotropin-, C- p1 l% {; H" Z
independent precocious puberty, which is also known6 p: Y; b; b& f! ~3 ^# p/ V( N' d' P
as testotoxicosis, may cause precocious puberty at a& f. `7 p$ J1 l' d) i6 q
very young age. The physical findings in these boys
4 ?! }! j( J. m, B# z- B0 owith this disorder are full pubertal development,& M+ d% o$ S5 V" ^% c/ q" J
including bilateral testicular growth, similar to boys
3 H0 {1 K$ @% R* m  L. dwith CPP. The gonadotropin levels in this disorder4 ?' m% {7 ^$ z/ g7 W" R) H
are suppressed to prepubertal levels and do not show* v# W" E  T8 O4 D" `9 {
pubertal response of gonadotropin after gonadotropin-. r% @3 R% l  n. L9 C
releasing hormone stimulation. This is a sex-linked
, k- y( D/ s; W+ O, Hautosomal dominant disorder that affects only
- U' @2 a0 u* @" Nmales; therefore, other male members of the family$ P- r. [5 ]7 u1 N: s/ @: n
may have similar precocious puberty.38 o9 n& k$ {8 }) N5 T: c/ c/ Q
In our patient, physical examination was incon-
4 w5 a$ }$ n" L8 }  usistent with true precocious puberty since his testi-
$ O2 \+ L3 P7 e2 y* icles were prepubertal in size. However, testotoxicosis
9 O. G3 ]6 U. {was in the differential diagnosis because his father
3 ~" p0 B  \8 z9 S  }" kstarted puberty somewhat early, and occasionally," m3 r0 k/ U4 d# D
testicular enlargement is not that evident in the& U1 `: g) p1 B  k6 V
beginning of this process.1 In the absence of a neg-# ?6 V( ~( c( M8 a; a; q
ative initial history of androgen exposure, our
3 ?3 `9 W6 I) z& Jbiggest concern was virilizing adrenal hyperplasia,
5 D) {; H* Z' Z, v; ^either 21-hydroxylase deficiency or 11-β hydroxylase5 j  n( l; g- X6 l9 u( j% l
deficiency. Those diagnoses were excluded by find-
, w3 y4 e, s2 ^+ @( W3 t9 B9 Bing the normal level of adrenal steroids.) N+ S# W; D% p" [. I* E0 c
The diagnosis of exogenous androgens was strongly3 X0 ?" E4 {5 Q) b$ @" v, [! M$ C
suspected in a follow-up visit after 4 months because& v0 C/ l, ~/ j* Q) C+ `# G
the physical examination revealed the complete disap-5 c4 p( z7 k8 g
pearance of pubic hair, normal growth velocity, and$ M+ A' F: a- k# J0 C6 o
decreased erections. The father admitted using a testos-5 j, x# @% |1 [- e: M* u
terone gel, which he concealed at first visit. He was* |# O/ k5 d) w7 A# G* b. \
using it rather frequently, twice a day. The Physicians’/ C5 X1 ?5 d( O, g: x6 G4 D+ F
Desk Reference, or package insert of this product, gel or$ Y7 s: T7 G& S& b$ r
cream, cautions about dermal testosterone transfer to
+ V+ {% z0 E5 ]unprotected females through direct skin exposure." Z; ^: }) y! x
Serum testosterone level was found to be 2 times the
& R8 F- k7 `1 g9 c3 P. A8 Cbaseline value in those females who were exposed to8 b( q4 N* T0 w) J+ ]! ^, [
even 15 minutes of direct skin contact with their male$ T" [1 [1 S; X: }8 M5 J- R
partners.6 However, when a shirt covered the applica-
% L- J4 G3 K6 M. Ytion site, this testosterone transfer was prevented.
& e* ]9 H3 h0 Q) J( b. s/ K2 k# NOur patient’s testosterone level was 60 ng/mL," v! |7 e* l/ ~/ s
which was clearly high. Some studies suggest that+ R  ?; F6 ^# l" Z* K
dermal conversion of testosterone to dihydrotestos-
+ D& R, D  j2 ^5 kterone, which is a more potent metabolite, is more+ s( M- x; L2 c4 B' K7 D
active in young children exposed to testosterone
3 F( X# \; k; _5 ]7 hexogenously7; however, we did not measure a dihy-' }* ~* m( t0 i  H/ z4 `; l; W4 [
drotestosterone level in our patient. In addition to
3 G$ o3 |: f( F* bvirilization, exposure to exogenous testosterone in
$ @) R& K4 n/ t5 n  }children results in an increase in growth velocity and
7 M( ^, u% h; y  l# W' Nadvanced bone age, as seen in our patient.
" z1 T# P! T* W/ a$ B6 i* R9 P8 W1 AThe long-term effect of androgen exposure during
$ F! f( X, @6 A5 F- |: M+ Kearly childhood on pubertal development and final( c, `3 V- c! ?, P% m9 Z5 ]  K
adult height are not fully known and always remain
6 u+ N0 E- U- }0 p) a5 s0 |a concern. Children treated with short-term testos-' E2 I" ^9 U! v2 [9 k  ~: C
terone injection or topical androgen may exhibit some& J( U- K; S& y; P3 U' D
acceleration of the skeletal maturation; however, after
" c$ W  Q  \6 i2 b$ O: Z8 gcessation of treatment, the rate of bone maturation4 n5 R2 Q( z% z, b
decelerates and gradually returns to normal.8,9* y- U/ p8 A" N* g" _
There are conflicting reports and controversy: e5 k$ ?* H9 g
over the effect of early androgen exposure on adult
7 S, ]& u) t  v2 D$ _( Q) lpenile length.10,11 Some reports suggest subnormal6 |# x2 j9 ~) L! z
adult penile length, apparently because of downreg-% o. O( f$ @6 K9 Q. e
ulation of androgen receptor number.10,12 However,
( J6 i" ?9 i+ m: }, D6 K: w! lSutherland et al13 did not find a correlation between
/ b6 N8 M8 W5 }; M6 m* o! bchildhood testosterone exposure and reduced adult
$ x2 [2 R; S3 j9 s+ Cpenile length in clinical studies.
$ U7 O9 H# Q. g; o/ J" I5 wNonetheless, we do not believe our patient is
  O- y, @7 g. J& w% fgoing to experience any of the untoward effects from
1 D) C+ m& _1 l& a, Gtestosterone exposure as mentioned earlier because
' Q4 J! R6 a  z/ ]8 {the exposure was not for a prolonged period of time.
# t; F" B. }* ]; D% q% a: cAlthough the bone age was advanced at the time of
, O7 p& \, `  D- q3 ldiagnosis, the child had a normal growth velocity at
, p0 i+ E7 ?% ]! D' c/ a" R/ Nthe follow-up visit. It is hoped that his final adult" c6 l0 E0 H  o9 b4 w
height will not be affected.) U3 n9 P, i, L/ j
Although rarely reported, the widespread avail-; V$ f4 V" `4 R0 R1 @
ability of androgen products in our society may, Y0 F$ m7 a& r; q# l* [, Q0 ]$ s3 D
indeed cause more virilization in male or female
! z! z: c) S0 W# S& `1 Wchildren than one would realize. Exposure to andro-
9 c" V4 H3 J3 l$ W, q8 Igen products must be considered and specific ques-
  S  ]9 v7 j, Jtioning about the use of a testosterone product or
* a. h+ m* X: R; s8 M) [  o0 P6 E1 b7 `gel should be asked of the family members during
, |6 e: w" }0 q  S4 o4 V0 mthe evaluation of any children who present with vir-0 V; r" A2 M. e2 D% G% F
ilization or peripheral precocious puberty. The diag-
! g  t7 ]  l3 Gnosis can be established by just a few tests and by
- [* I7 \  Y' r: g1 Sappropriate history. The inability to obtain such a  W9 ?% w3 T/ V
history, or failure to ask the specific questions, may
  U8 M$ y0 n) Z6 g$ P, I2 {result in extensive, unnecessary, and expensive
5 t2 i# W" Q0 C4 U' Z) jinvestigation. The primary care physician should be$ R/ |" {+ W3 ?. m
aware of this fact, because most of these children
" ]+ C9 s" }$ `1 Hmay initially present in their practice. The Physicians’; t( |2 P2 Z" W+ S/ U& E
Desk Reference and package insert should also put a
. H/ f0 j+ F2 z+ y) ~4 ^: Lwarning about the virilizing effect on a male or% n6 J) @( q% D" B2 W+ @
female child who might come in contact with some-
; U- U2 `. z! u; C# eone using any of these products.6 Q+ X( e" K$ F3 X0 ^+ Q! _1 T; o) i
References. ~% v  \2 t: Y8 V" r; Z
1. Styne DM. The testes: disorder of sexual differentiation
3 h: @4 y* |+ c6 d# z5 X2 @and puberty in the male. In: Sperling MA, ed. Pediatric' d# l+ K; \/ z
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;' z/ @1 _+ I( O* Q% N: [
2002: 565-628.! O" E! u) O% @6 T# M/ G
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
7 P8 M8 h; K# S1 Xpuberty 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
7 |+ Y9 n! ]5 l' X0 e3 G) m& P/ 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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