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Sexual Precocity in a 16-Month-Old& Y2 I1 T) d$ P7 i* a  f
Boy Induced by Indirect Topical! _: @: b9 K6 W# c
Exposure to Testosterone3 e6 J1 v# f! a+ a6 G- e
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,23 Q1 p8 C  ]8 w7 x! B
and Kenneth R. Rettig, MD1
% @, D* @3 t9 f+ uClinical Pediatrics6 b5 B. s0 j! [
Volume 46 Number 61 n0 y2 n- G( F9 t' s1 n1 _" _! i/ Y
July 2007 540-543/ ]% Y! p% A# |
© 2007 Sage Publications
' |" v: H7 i! b10.1177/0009922806296651
  C) A, q% f' ?) w1 ^" Ihttp://clp.sagepub.com
4 o) V7 {1 h- u* `8 F3 |1 _hosted at
. {$ z" W3 W) Nhttp://online.sagepub.com" J0 J1 z. k0 q
Precocious puberty in boys, central or peripheral,
  l$ v6 S: K. x0 O- t. Ais a significant concern for physicians. Central
) N$ {! G; D3 e: d% P  a5 Jprecocious puberty (CPP), which is mediated7 {% S4 F) x& R( A, K
through the hypothalamic pituitary gonadal axis, has
& r+ W9 x8 q0 \a higher incidence of organic central nervous system
. {' s3 Q: e- _4 `9 `) Alesions in boys.1,2 Virilization in boys, as manifested1 p3 f8 ~/ X- h
by enlargement of the penis, development of pubic6 F: p! {0 H0 N) V+ j. z4 b: ?  H
hair, and facial acne without enlargement of testi-
8 h- m0 R, q( K4 P: u! Acles, suggests peripheral or pseudopuberty.1-3 We
3 H/ t1 l  K  Dreport a 16-month-old boy who presented with the- X3 i  r5 ^; ~: M7 z+ J
enlargement of the phallus and pubic hair develop-
& m2 R* p, O+ r: s) ^% Iment without testicular enlargement, which was due
* J- j: K" D' T6 }3 R" Q, uto the unintentional exposure to androgen gel used by! d3 `) b; }0 _! @) b2 j
the father. The family initially concealed this infor-* Y1 p) Z$ B: I: w
mation, resulting in an extensive work-up for this/ p9 |$ ^; z3 A) L! |5 p
child. Given the widespread and easy availability of8 ^1 V9 I' r, t
testosterone gel and cream, we believe this is proba-
% L' ]. @' W$ u5 b- E3 m- Xbly more common than the rare case report in the
( b% A$ M7 K4 K1 Q1 [literature.4
; M0 F* L/ T( i/ UPatient Report. v$ q4 u$ W. s4 {
A 16-month-old white child was referred to the) P1 K1 F2 X6 f3 z
endocrine clinic by his pediatrician with the concern
" w3 ~# g; p( O! aof early sexual development. His mother noticed1 l+ a, t% V% G, ~
light colored pubic hair development when he was
7 ?- x3 X  i9 J3 oFrom the 1Division of Pediatric Endocrinology, 2University of
! ]' i1 }$ U2 b% }& iSouth Alabama Medical Center, Mobile, Alabama.
6 a: ?8 ?8 o8 @( M4 u7 }Address correspondence to: Samar K. Bhowmick, MD, FACE,
6 o" u0 X' d( c9 H+ k' B; U& BProfessor of Pediatrics, University of South Alabama, College of
6 x/ |/ E, ^, t. G* YMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
( l, [% p3 \4 w8 T2 h8 le-mail: [email protected].3 x3 z. |& h% M, }
about 6 to 7 months old, which progressively became; y6 m5 j6 B; a# i
darker. She was also concerned about the enlarge-
& z# _' C/ ]  @9 jment of his penis and frequent erections. The child0 Q0 {/ H7 j1 S% C
was the product of a full-term normal delivery, with
4 \$ g# V/ S& E) i" R( @0 Wa birth weight of 7 lb 14 oz, and birth length of
& S& f, O% [" u# P5 U% H20 inches. He was breast-fed throughout the first year
& X: o( M7 t2 ^, a1 z+ Zof life and was still receiving breast milk along with
: ?) z  }! x9 p4 X3 \. ~8 Usolid food. He had no hospitalizations or surgery,
1 K: B  H6 a! H" Jand his psychosocial and psychomotor development
9 X( f7 e* s& e6 Iwas age appropriate.
& l/ C3 D6 z& T3 p6 F( {, t) TThe family history was remarkable for the father,( W2 t3 t3 U* N9 ~
who was diagnosed with hypothyroidism at age 16,
: w$ z( E4 t5 P" cwhich was treated with thyroxine. The father’s
3 f" [2 l, ~" O0 R7 f1 Sheight was 6 feet, and he went through a somewhat; g! |+ d# k, u$ P7 h
early puberty and had stopped growing by age 14.
& ~# Z$ ?( o5 _The father denied taking any other medication. The
/ Q% M8 q. B% ~" F+ }# J! Xchild’s mother was in good health. Her menarche* J7 \6 Y% I# c7 \
was at 11 years of age, and her height was at 5 feet' h4 C# f, W3 M% U2 L. }3 @0 C
5 inches. There was no other family history of pre-& y  \7 w2 h+ Y8 B6 o
cocious sexual development in the first-degree rela-
) O* _* D* M$ j5 L2 x+ I! Otives. There were no siblings.
$ t; I& c, f9 H) B/ {4 L" sPhysical Examination
! Z5 k) s: j% Q9 ~6 YThe physical examination revealed a very active,
0 _3 n/ R; P# i$ ?4 ]( L! |playful, and healthy boy. The vital signs documented: \3 y5 N0 o+ t+ b; s$ w/ D8 p8 e
a blood pressure of 85/50 mm Hg, his length was; h8 }" a+ R* E7 }3 z6 l
90 cm (>97th percentile), and his weight was 14.4 kg/ u5 g' k* Z: Y# V# N, \6 ^1 Z* _
(also >97th percentile). The observed yearly growth4 Q( c+ p- K% L& G
velocity was 30 cm (12 inches). The examination of
/ F* O) u" E- wthe neck revealed no thyroid enlargement.4 w& M" }$ s# b( r- ]
The genitourinary examination was remarkable for
0 c# N, t5 D3 }6 p# qenlargement of the penis, with a stretched length of
% {) T8 p  |9 U4 F+ ?8 ?8 cm and a width of 2 cm. The glans penis was very well% b+ c' H$ |$ G- \# e$ G
developed. The pubic hair was Tanner II, mostly around
( I. G2 p# s" ?$ o540
3 v* N/ _! a/ u& X  C4 M% s0 Nat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
$ S* e# ?, f( r' v" X: mthe base of the phallus and was dark and curled. The; P4 E1 C9 p" d$ X
testicular volume was prepubertal at 2 mL each.0 m( N/ `8 @% O8 R( p
The skin was moist and smooth and somewhat
" G; u8 e# i5 T; u% d! Z" ooily. No axillary hair was noted. There were no
  v; b1 B8 N+ ]2 oabnormal skin pigmentations or café-au-lait spots.
8 K# y& S; y1 C. WNeurologic evaluation showed deep tendon reflex 2+. X5 M2 J) |$ e; s3 d/ O0 K  B- X
bilateral and symmetrical. There was no suggestion
0 w$ `# r, |) t, kof papilledema.
4 J/ E& c+ D5 q, xLaboratory Evaluation
; B4 h8 Q; J4 e8 l. N. xThe bone age was consistent with 28 months by1 P7 M0 f9 c* J
using the standard of Greulich and Pyle at a chrono-
/ K0 n; x( H1 m. `! c  clogic age of 16 months (advanced).5 Chromosomal
1 \% M0 r5 v) Y, Skaryotype was 46XY. The thyroid function test" m+ a7 M9 Y2 r" ]! W& ]' o
showed a free T4 of 1.69 ng/dL, and thyroid stimu-
5 j7 |. Z2 V* M5 f8 g# Glating hormone level was 1.3 µIU/mL (both normal).
8 X" R8 E: j0 E5 yThe concentrations of serum electrolytes, blood
  Z2 h! U, I# l5 q; nurea nitrogen, creatinine, and calcium all were5 g: c2 n2 C! F
within normal range for his age. The concentration2 J& q0 S/ ^; v4 j1 o/ o- ]( P! T
of serum 17-hydroxyprogesterone was 16 ng/dL  D8 l# Q# Z. U8 E
(normal, 3 to 90 ng/dL), androstenedione was 20$ G- j5 u4 Z1 H- s" A
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
, Y( U, Y  O) U6 r+ V6 Mterone was 38 ng/dL (normal, 50 to 760 ng/dL),; t! r( O( B7 E& M, T: z8 L
desoxycorticosterone was 4.3 ng/dL (normal, 7 to
" K( p" ~8 Q& r! T49ng/dL), 11-desoxycortisol (specific compound S)
+ q: T6 p, M7 dwas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
5 g: E8 \8 x3 H3 Utisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
8 U' d% `9 P' I* [9 K% dtestosterone was 60 ng/dL (normal <3 to 10 ng/dL),; i+ b" {3 r! j3 A
and β-human chorionic gonadotropin was less than
% p& J% i; `$ X8 F! I3 c, b8 E  n5 mIU/mL (normal <5 mIU/mL). Serum follicular. m8 [! M7 _4 c0 v% X
stimulating hormone and leuteinizing hormone4 P; V& n; m% H7 ~. @6 @8 E$ c0 f
concentrations were less than 0.05 mIU/mL% `7 j6 ?/ u0 I% P0 t
(prepubertal).' w# m; }/ [2 M# m# R" i
The parents were notified about the laboratory
# l  B, m# @7 c. [results and were informed that all of the tests were* C, K* d; d2 L  ?
normal except the testosterone level was high. The
" T, g$ i( D8 bfollow-up visit was arranged within a few weeks to
: {1 Z$ L# Y, F- aobtain testicular and abdominal sonograms; how-
+ ~) C7 W1 j4 gever, the family did not return for 4 months., c! [( B4 N, n9 b9 ^: c
Physical examination at this time revealed that the* @/ R* k8 r5 P: R! ]% `
child had grown 2.5 cm in 4 months and had gained
$ U  [- i4 H* g2 kg of weight. Physical examination remained4 n* j# P5 g4 s; P
unchanged. Surprisingly, the pubic hair almost com-
# L4 m7 N5 V- K( O" T1 N0 xpletely disappeared except for a few vellous hairs at( v: h) X# m& y! @! F' o+ U) Y
the base of the phallus. Testicular volume was still 2/ R1 N+ g) k1 I6 S
mL, and the size of the penis remained unchanged.
  \  ]1 x8 T' d/ C0 HThe mother also said that the boy was no longer hav-4 ?! f2 s+ t8 F
ing frequent erections.5 d+ t1 i/ g2 s" X! v9 z
Both parents were again questioned about use of3 R" ]9 Z* R2 {
any ointment/creams that they may have applied to" _7 H& \1 k- K: Z/ k
the child’s skin. This time the father admitted the7 {+ |  Y. e% W/ q
Topical Testosterone Exposure / Bhowmick et al 541- k0 u! D$ O: Q: V: L; z$ l
use of testosterone gel twice daily that he was apply-4 r1 ~: o  [% ~# S. x
ing over his own shoulders, chest, and back area for) u( V, m# t+ O! y- P% ?
a year. The father also revealed he was embarrassed
; |! _1 A4 u- z0 o# vto disclose that he was using a testosterone gel pre-
9 q, Z( j. v# `1 }scribed by his family physician for decreased libido
9 V% T5 F% S5 D  j$ o0 Lsecondary to depression.+ T; h* `1 T4 v4 n2 r7 q
The child slept in the same bed with parents.9 w2 x2 ]  `( t4 H/ o4 t
The father would hug the baby and hold him on his
  |  `3 ^, N/ ^. Y& Cchest for a considerable period of time, causing sig-
2 ?8 s# X; q" v0 A# Onificant bare skin contact between baby and father.
( G6 E6 m) i4 s! hThe father also admitted that after the phone call,
) b. g/ @& ^, m. U8 wwhen he learned the testosterone level in the baby
* o- x8 V" o  E( |8 g% ywas high, he then read the product information
: T( _8 G  p# X3 @' L8 Wpacket and concluded that it was most likely the rea-
/ v4 R3 F& _* x  n% |, o3 tson for the child’s virilization. At that time, they# e! ]; t$ i; d! k& Z
decided to put the baby in a separate bed, and the) R  F) D( ?* W% h4 O) W4 t5 f+ q
father was not hugging him with bare skin and had% F) y0 p5 P4 F, N8 }
been using protective clothing. A repeat testosterone/ L* V& C8 u. r9 R7 T1 ~
test was ordered, but the family did not go to the' \- |8 k. A# g* T$ g- O- Y
laboratory to obtain the test.
# Z/ q, t  X6 Y: WDiscussion
1 ~4 w! ^# a% Y, t/ }, tPrecocious puberty in boys is defined as secondary
5 ?+ i7 R' m( s  d  Isexual development before 9 years of age.1,45 o0 T: Q0 J) |0 e' S+ Q+ E
Precocious puberty is termed as central (true) when
; a. n. H3 D" q8 m# iit is caused by the premature activation of hypo-
1 R0 G0 J; ]0 ?; Z5 _/ a0 ?1 Wthalamic pituitary gonadal axis. CPP is more com-
# y# x9 z9 }" W, Wmon in girls than in boys.1,3 Most boys with CPP* }! q! q; @2 i8 Y4 J5 U. g9 C& f
may have a central nervous system lesion that is9 n7 g# B3 z8 J
responsible for the early activation of the hypothal-: z' x$ [1 K' e5 i" T
amic pituitary gonadal axis.1-3 Thus, greater empha-
. q9 e6 i$ V9 Csis has been given to neuroradiologic imaging in, @9 H. S+ T% e& ]- N
boys with precocious puberty. In addition to viril-
8 c5 K8 S  Y6 P+ z0 R! V  C+ hization, the clinical hallmark of CPP is the symmet-
6 \1 S. x9 e  Y0 N/ y4 e* d; brical testicular growth secondary to stimulation by
; E0 ?* o) c& {gonadotropins.1,3
: W5 m" R+ x" kGonadotropin-independent peripheral preco-
5 e% U( t4 F: d9 u7 I/ H0 K+ H) hcious puberty in boys also results from inappropriate' }5 d! s  T0 H/ ^& \! F! A6 E
androgenic stimulation from either endogenous or
5 y  E" T( ], x* W9 Y$ jexogenous sources, nonpituitary gonadotropin stim-
9 Y% k& j$ Q5 ~0 h1 {. Y" M# ?ulation, and rare activating mutations.3 Virilizing
' h0 y# }' W7 ]. W+ ~0 `. Vcongenital adrenal hyperplasia producing excessive  X0 }# J3 Y& x$ a  g0 N' R
adrenal androgens is a common cause of precocious
/ _. X  Y) O+ i; G5 qpuberty in boys.3,4
$ T/ L# l9 x- R% N$ \( W* m! H! H" lThe most common form of congenital adrenal
. S, n8 Z0 P4 t) p* a5 Nhyperplasia is the 21-hydroxylase enzyme deficiency.
; u! T2 e: d/ @1 W2 |! pThe 11-β hydroxylase deficiency may also result in
) C! r/ X, c1 zexcessive adrenal androgen production, and rarely,; t& _1 d' ^% `! e3 i" O
an adrenal tumor may also cause adrenal androgen2 Y) n" g: {; e5 ~* [+ _) O) o
excess.1,3
8 I# |' `! H# l* m& q* Xat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
, T! U9 d; J* }* S8 L. a0 b542 Clinical Pediatrics / Vol. 46, No. 6, July 2007  B( ?, X4 I/ b% C$ E: _" b0 ]
A unique entity of male-limited gonadotropin-; j' J1 `8 D- g% A- s. Y) n5 g
independent precocious puberty, which is also known
/ V5 O7 q3 L! G* b0 K/ ?" p1 Pas testotoxicosis, may cause precocious puberty at a
. c& k% H' d5 v* s. O/ [very young age. The physical findings in these boys# N' [* V- @9 @% j+ \  r, h" G" E
with this disorder are full pubertal development,% x" }8 i6 z4 _7 f# b
including bilateral testicular growth, similar to boys
* b1 g; v$ U  X  l) d1 ]. }2 |9 ewith CPP. The gonadotropin levels in this disorder
" M( \) b0 P1 q1 E$ e) zare suppressed to prepubertal levels and do not show  w# Y1 z- v& o9 t3 I7 F
pubertal response of gonadotropin after gonadotropin-  J$ w% h8 |# c
releasing hormone stimulation. This is a sex-linked% y5 k+ _, F$ F# K6 c8 r
autosomal dominant disorder that affects only
# q; T# I5 s3 i* hmales; therefore, other male members of the family# w2 `+ s+ I7 d: X. _* X$ o' \
may have similar precocious puberty.3
& G4 g9 i* R, JIn our patient, physical examination was incon-6 T1 G! B0 p& t' n9 v1 A4 H
sistent with true precocious puberty since his testi-
1 p* D) ~# V! y$ [0 Bcles were prepubertal in size. However, testotoxicosis
# V+ {( R; Z4 Hwas in the differential diagnosis because his father
) g# v2 J' h0 A& estarted puberty somewhat early, and occasionally,
+ Y+ a- U$ |1 z% y, u/ ]/ M' y$ D3 ktesticular enlargement is not that evident in the
: r. d0 b0 M5 n, _6 tbeginning of this process.1 In the absence of a neg-
  w4 E; F# t) D! g. wative initial history of androgen exposure, our
  a' x1 \& p! J  r# Tbiggest concern was virilizing adrenal hyperplasia,0 W- {8 u2 S% _( R. E  K
either 21-hydroxylase deficiency or 11-β hydroxylase9 z, C. z, `+ ^5 c5 r
deficiency. Those diagnoses were excluded by find-  ?* b, e% n$ X. l
ing the normal level of adrenal steroids.
% V' J, @1 T6 n1 g2 V! bThe diagnosis of exogenous androgens was strongly- Z+ q1 j2 j, u1 E! H. G/ D7 m* @
suspected in a follow-up visit after 4 months because
) X- Q& N! n. @8 c4 ~) k% ethe physical examination revealed the complete disap-+ ]) r2 p& H$ n" x, {! O
pearance of pubic hair, normal growth velocity, and
1 z" N$ ?; `3 `; f% _6 g! ~decreased erections. The father admitted using a testos-1 D' p- d" {: V$ y0 F$ N/ H! N+ ]* T: \' g
terone gel, which he concealed at first visit. He was
5 N, t5 J3 E/ W, A0 ]using it rather frequently, twice a day. The Physicians’8 {8 m" ~6 O, T. |) a3 J, u7 Y
Desk Reference, or package insert of this product, gel or3 p6 n7 j7 `  b9 _
cream, cautions about dermal testosterone transfer to' ]0 ]& C/ s4 M5 I4 g3 z
unprotected females through direct skin exposure.
6 F" J  g4 n( @% z6 T& x" P: C) BSerum testosterone level was found to be 2 times the
6 d5 S* `0 p* x, n& T- [+ y) j9 bbaseline value in those females who were exposed to
4 O1 @, G7 W, x0 Meven 15 minutes of direct skin contact with their male
5 g3 m& u. d& k; n* j) p( i) rpartners.6 However, when a shirt covered the applica-
( F: C# V4 F9 Z0 f# ~+ E/ Z' Vtion site, this testosterone transfer was prevented.
" _/ {3 q8 j: ^7 K2 |Our patient’s testosterone level was 60 ng/mL,
  _& E* e- G, S5 {, [" _which was clearly high. Some studies suggest that- }# n- C7 C( _; b9 b
dermal conversion of testosterone to dihydrotestos-
! s- J5 a- C8 A# o* Pterone, which is a more potent metabolite, is more- L' L2 ]) b, r1 o: J: J
active in young children exposed to testosterone
+ o# V5 d+ j5 n0 e) Texogenously7; however, we did not measure a dihy-( `$ E$ F% m% c/ U) z- v) O
drotestosterone level in our patient. In addition to
# K/ Q/ T% b) A$ H- {virilization, exposure to exogenous testosterone in$ E  U  x: M+ T) g
children results in an increase in growth velocity and7 w3 A7 I' i6 Y; U2 f9 z
advanced bone age, as seen in our patient.$ _3 H. i3 {& M/ t/ x3 \# u+ D
The long-term effect of androgen exposure during" P% Z# [" Y: |$ j
early childhood on pubertal development and final" R& X5 p4 v; K9 `" q$ j
adult height are not fully known and always remain( ^6 p4 s0 ^1 S3 D
a concern. Children treated with short-term testos-  a! x! n+ b7 I3 T9 {: Z' z! ?4 s2 g' J
terone injection or topical androgen may exhibit some
+ y# H& y) I9 u' r- Xacceleration of the skeletal maturation; however, after$ B2 H" d3 h2 F3 m2 `
cessation of treatment, the rate of bone maturation( o" R  T7 a% U0 y6 R" Z3 V
decelerates and gradually returns to normal.8,9
/ S6 o$ G% p$ {There are conflicting reports and controversy
3 p* y9 c7 ~& mover the effect of early androgen exposure on adult  `( y3 s) c5 E- m" r! U: u" \3 a8 [
penile length.10,11 Some reports suggest subnormal2 t2 }; |3 K  ^  k% u
adult penile length, apparently because of downreg-
9 |: g1 `9 j- c/ [ulation of androgen receptor number.10,12 However,
0 Y4 c8 H( t% g/ s, ~% e+ ^Sutherland et al13 did not find a correlation between+ f% ]8 c  u$ F$ [$ x1 L
childhood testosterone exposure and reduced adult
& e5 B" S. C  ppenile length in clinical studies.
( B/ `7 k3 f) L/ v' INonetheless, we do not believe our patient is
8 n4 V5 S, Y' ?going to experience any of the untoward effects from& _! P) T9 w* L$ P5 u2 p% J
testosterone exposure as mentioned earlier because
9 L. C  {% A  V+ b! ^- X& A! Pthe exposure was not for a prolonged period of time.$ Y0 K5 P/ \& Z) m" @! Q0 y
Although the bone age was advanced at the time of
7 Q: o1 W6 Q& d4 b) u- v' Cdiagnosis, the child had a normal growth velocity at7 c8 J3 x' ]) K/ ~1 E
the follow-up visit. It is hoped that his final adult7 y' Z4 o( J5 B( k" ]5 |
height will not be affected.  k; S  J. `  r+ i
Although rarely reported, the widespread avail-# \3 h6 c2 E3 S, v- k3 {: O4 r
ability of androgen products in our society may
5 ]. v, z& b% H, Y# v0 X& Q; B+ p$ e% findeed cause more virilization in male or female  p& F, T1 Q" u# s" g9 \
children than one would realize. Exposure to andro-1 y- b9 n% Z5 m1 s: ^; ]
gen products must be considered and specific ques-
; q" S2 \9 T+ d* ^tioning about the use of a testosterone product or0 z$ o. w6 F2 C
gel should be asked of the family members during. y% b) F, i' X& z' R
the evaluation of any children who present with vir-
# w; ?9 G' x/ |% T3 e+ Z: Xilization or peripheral precocious puberty. The diag-- j' |4 ~4 W! v
nosis can be established by just a few tests and by' b" c: `/ S% k
appropriate history. The inability to obtain such a0 K% e, J" P3 [" z
history, or failure to ask the specific questions, may/ D; U( @2 e. J; Q9 V, o, x. _
result in extensive, unnecessary, and expensive
' V1 N# p& _+ p2 vinvestigation. The primary care physician should be. L& B- F: I) o! Z2 F. U: h- L
aware of this fact, because most of these children
# `3 V; A: d$ M# a! Qmay initially present in their practice. The Physicians’) R8 h& F+ t. ^6 `! _1 n7 c
Desk Reference and package insert should also put a& N( l; [$ v3 g0 p6 ]2 m
warning about the virilizing effect on a male or# l! T2 G  a6 x7 L- `* _
female child who might come in contact with some-  K9 Z! x  U% q, `% i5 v* T; W
one using any of these products.
8 N2 l7 L' w: mReferences6 |1 D+ U1 z. C0 _9 d
1. Styne DM. The testes: disorder of sexual differentiation; a1 o- A; D1 Y; i
and puberty in the male. In: Sperling MA, ed. Pediatric) j7 F7 I: N* o0 |  g' ]" F
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;/ ~' M5 y& s) I) \, v5 d3 ]
2002: 565-628.
% w! R2 H5 D: c( U3 `& b: S2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
2 v7 M$ g# [/ H" M/ M" _4 }' }* X  Rpuberty in children with tumours of the suprasellar pineal
發表於 2025-1-4 03:27:02 | 顯示全部樓層
Sexual Precocity in a 16-Month-Old
6 Q+ N. s5 [  p2 v; ~6 D1 jBoy Induced by Indirect Topical
( x1 K, C# r. y8 K- Z& ^7 [Exposure to Testosterone8 F$ }$ p8 g8 k# `0 \( h* V& ~
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
2 A" R6 @- e1 b% k8 V5 T& cand Kenneth R. Rettig, MD1
% y/ e- G( {1 d; `4 S* @% J9 PClinical Pediatrics
5 R" O* e. X/ N; i* |, qVolume 46 Number 6
6 v" Y4 H9 K' m$ l3 kJuly 2007 540-543
1 L: w& W0 x. c© 2007 Sage Publications- E- ~' `0 i; }, c* ]5 Y
10.1177/0009922806296651/ t* t  j$ j1 Z4 A4 B' S% ~
http://clp.sagepub.com8 Z: \8 Z. d9 G+ v4 q
hosted at
# T( J8 ?- l4 T; ]2 Ohttp://online.sagepub.com
5 a9 a  U7 Q' g, B3 H5 }Precocious puberty in boys, central or peripheral,; w- S& S1 @6 H9 C3 n1 t
is a significant concern for physicians. Central9 O2 m% r; d4 t
precocious puberty (CPP), which is mediated
, S$ B2 I! N1 E$ Fthrough the hypothalamic pituitary gonadal axis, has
$ ]8 U, t5 P9 Z& u% m) sa higher incidence of organic central nervous system
1 M# r5 e. e( Z% E- tlesions in boys.1,2 Virilization in boys, as manifested
, N7 ?, r4 Y/ M4 \2 c; u& t" X1 ?by enlargement of the penis, development of pubic
* k3 j" k$ P$ S6 A& j4 ihair, and facial acne without enlargement of testi-* A! q, q' \) Q/ O
cles, suggests peripheral or pseudopuberty.1-3 We
( h9 s3 E5 e+ ^( R: l6 Vreport a 16-month-old boy who presented with the# t" {1 D  _  H& Z" z. s
enlargement of the phallus and pubic hair develop-! e  C3 |3 {7 T8 \0 e8 f. B
ment without testicular enlargement, which was due
* v, s: z' T, _& [; rto the unintentional exposure to androgen gel used by4 s+ \- N7 Z* d8 V
the father. The family initially concealed this infor-8 Q! l! v7 E, ~% V. K
mation, resulting in an extensive work-up for this$ ~* E6 ?- q. Z) s$ m
child. Given the widespread and easy availability of
5 _% {0 a1 w5 `. J  b2 Stestosterone gel and cream, we believe this is proba-
  R! ?; `; f3 p9 p# T; O! Dbly more common than the rare case report in the( M! j3 j7 V( J- N7 y1 j$ Y
literature.4& |$ g$ |4 B# F! K- e) \
Patient Report' b8 b  X4 ?' p2 r8 ^9 Z
A 16-month-old white child was referred to the
8 {  `) y; T3 y$ `* Lendocrine clinic by his pediatrician with the concern1 W) J0 s# a1 Y, }6 a# ]4 r* q
of early sexual development. His mother noticed
  Z/ E3 w% Z# |+ k# S+ Xlight colored pubic hair development when he was1 N' ^3 P  o) ^" h9 p3 p3 i
From the 1Division of Pediatric Endocrinology, 2University of. [6 O8 p! s: \' `! r
South Alabama Medical Center, Mobile, Alabama.6 Z9 z* s7 g! O2 v  C1 ^
Address correspondence to: Samar K. Bhowmick, MD, FACE,: ]7 o3 q2 H% ]0 b; @, u7 f* S( K
Professor of Pediatrics, University of South Alabama, College of( n( x* X) {' D
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;2 `/ }  ]. K7 d4 u
e-mail: [email protected].- h' W0 F' H# q% I6 f6 [6 r
about 6 to 7 months old, which progressively became0 [+ ?; E& f" m7 g
darker. She was also concerned about the enlarge-" V" X8 x3 V& V1 a* t9 S3 c
ment of his penis and frequent erections. The child  V% b" t: N! g" H) Y/ d2 ]
was the product of a full-term normal delivery, with
2 H7 J( ?; \# B6 S- Oa birth weight of 7 lb 14 oz, and birth length of4 i% p) t6 M! Z3 t3 s  Q/ K
20 inches. He was breast-fed throughout the first year; q9 Q( I- q6 ^/ U% }
of life and was still receiving breast milk along with' G* ]; W' w0 S/ \
solid food. He had no hospitalizations or surgery,* T7 t: v+ ~' L- K3 @( ^
and his psychosocial and psychomotor development$ }  q1 _0 R: f9 f# v
was age appropriate.
6 W* o2 D- S2 K2 h! AThe family history was remarkable for the father,& H+ ^3 ^8 F# W- U1 n( R: o
who was diagnosed with hypothyroidism at age 16,* V, b2 L4 J! N! y* j- r
which was treated with thyroxine. The father’s# k( P0 H; l& g7 b# N1 K) ]
height was 6 feet, and he went through a somewhat8 V. q& E; D9 |3 @' Q
early puberty and had stopped growing by age 14.
/ [! [2 P$ q* q8 n: H3 Q. EThe father denied taking any other medication. The, {, k$ Y/ r+ a( v
child’s mother was in good health. Her menarche
1 B! c* {+ F- r: @3 w. u4 ~, ]was at 11 years of age, and her height was at 5 feet! Q# O7 o& v4 ^6 w  N
5 inches. There was no other family history of pre-, Q3 z8 [9 L- v; p: v
cocious sexual development in the first-degree rela-2 a! U" Z  w/ l3 Z0 Q  s
tives. There were no siblings.: c# u3 e- {5 i9 k  w6 H
Physical Examination9 k& d& k5 P4 Z4 e" v9 h
The physical examination revealed a very active,2 s% H4 J$ [) N% i! Y
playful, and healthy boy. The vital signs documented
% y8 f0 _' T0 |1 Q4 V3 D8 p6 v- p: @a blood pressure of 85/50 mm Hg, his length was
/ ^+ ~2 A; M) Q, ~4 C90 cm (>97th percentile), and his weight was 14.4 kg: Z' G) F3 Q1 C8 O2 T& n$ C
(also >97th percentile). The observed yearly growth0 {4 M( @# ^/ x& C6 b! V4 I
velocity was 30 cm (12 inches). The examination of; a2 p  z' N$ }4 B
the neck revealed no thyroid enlargement.6 y1 i; t2 \* Y! q% M# f
The genitourinary examination was remarkable for/ f% C: Z* B6 L& F
enlargement of the penis, with a stretched length of- d! ~1 o0 h, t; y# o2 A5 A
8 cm and a width of 2 cm. The glans penis was very well, d4 L8 a6 i5 o( {
developed. The pubic hair was Tanner II, mostly around
3 c1 L( Y+ |4 |0 ~: v5 D, [9 a540, B( G, a9 T* Q. _  f
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from/ e+ J$ Z- e) w) x% A. M
the base of the phallus and was dark and curled. The4 C3 H4 T: x1 ]) Y$ B2 H+ e3 d
testicular volume was prepubertal at 2 mL each.
; H* ~) J9 E; @7 NThe skin was moist and smooth and somewhat
1 ~. w3 K2 s) ]! D. ^" Z. }oily. No axillary hair was noted. There were no' n# F1 R* W% H2 U( ?- l+ K8 ^
abnormal skin pigmentations or café-au-lait spots., o: @! C- N$ n+ Q# d) C3 U. G/ J4 Z$ S
Neurologic evaluation showed deep tendon reflex 2+# `- S* k* D% U! M( v. x; L2 G
bilateral and symmetrical. There was no suggestion! Z4 w$ o' d( u6 E' R. o+ p4 \1 I3 X
of papilledema.
5 X: R! z& M0 h; L- VLaboratory Evaluation/ p  [* Z0 _" a; i) {
The bone age was consistent with 28 months by) }# @7 C6 U3 M0 g
using the standard of Greulich and Pyle at a chrono-9 I( f+ {. R: [) D/ D* r4 ?6 v
logic age of 16 months (advanced).5 Chromosomal6 O4 r: K; z( j) C0 N" v* l# x7 A
karyotype was 46XY. The thyroid function test, R& S8 Z8 ?; `$ q: H5 K
showed a free T4 of 1.69 ng/dL, and thyroid stimu-
/ s2 C8 a# V  M; ^( p7 Alating hormone level was 1.3 µIU/mL (both normal).% z) h0 g( G( q
The concentrations of serum electrolytes, blood* d) A, O! X) }9 e) U
urea nitrogen, creatinine, and calcium all were
1 a" l: t8 a: r% w) v3 Swithin normal range for his age. The concentration6 b* V) X: o% ]4 V# C) w7 M
of serum 17-hydroxyprogesterone was 16 ng/dL9 e2 r+ w, @! l+ X  a
(normal, 3 to 90 ng/dL), androstenedione was 20/ K  e' S% Q4 }( }
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
5 P; h9 |. i3 T& u* g) rterone was 38 ng/dL (normal, 50 to 760 ng/dL),
) A: O) X4 H. L/ p5 ]% \desoxycorticosterone was 4.3 ng/dL (normal, 7 to
$ z  _- m! Z1 C49ng/dL), 11-desoxycortisol (specific compound S)
  r+ f; g% G6 s; ^' g; Q5 n" rwas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
1 _5 b, }, J4 Y% k* Itisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
; h  Q" k( `9 \' H% u2 [8 Qtestosterone was 60 ng/dL (normal <3 to 10 ng/dL),
4 X% G) v$ f( a7 ^and β-human chorionic gonadotropin was less than9 q. G  G" F& H2 g
5 mIU/mL (normal <5 mIU/mL). Serum follicular
$ N1 V% ~" J) U1 z; `stimulating hormone and leuteinizing hormone
5 X& z4 ~7 d, q6 r( G! Kconcentrations were less than 0.05 mIU/mL1 \. Y6 c0 i; ~0 o
(prepubertal).* k( K; `" ^% d/ Z
The parents were notified about the laboratory6 Q- O! c0 ]8 s0 V: F9 \& w
results and were informed that all of the tests were! f: v. e6 E" Q& ^, k2 S' X
normal except the testosterone level was high. The; {6 w) e% C! m& e
follow-up visit was arranged within a few weeks to% `% m( z1 c* l  ^7 _+ w
obtain testicular and abdominal sonograms; how-! \1 _8 t6 V% j2 i1 ]- [' P1 ]1 _
ever, the family did not return for 4 months./ o  @. C  N9 Q2 e; Y
Physical examination at this time revealed that the7 k& C( k0 E/ M- P& D  \8 _0 i
child had grown 2.5 cm in 4 months and had gained# E% G' d  ^$ ]1 U
2 kg of weight. Physical examination remained
6 r3 d$ _) @/ sunchanged. Surprisingly, the pubic hair almost com-
0 D1 _3 `# _9 A9 l# N* e6 qpletely disappeared except for a few vellous hairs at$ I+ n, J4 u. t! w5 I4 V: c7 J) J
the base of the phallus. Testicular volume was still 2
# c! B1 g/ H( h( SmL, and the size of the penis remained unchanged.1 a  P$ H% a/ W* p
The mother also said that the boy was no longer hav-
8 ^# ]+ I1 l+ I0 \; ~ing frequent erections.
6 c1 j4 m( ^1 ]3 [4 C9 S' aBoth parents were again questioned about use of
' r2 S8 f+ G2 U! l1 G  Many ointment/creams that they may have applied to5 F+ H8 X) _# V7 z
the child’s skin. This time the father admitted the
" w; `% g$ R- H. H3 oTopical Testosterone Exposure / Bhowmick et al 5417 f" N2 X$ }8 U% X, s1 Q
use of testosterone gel twice daily that he was apply-& B, c! W. S' `0 t# G( ~
ing over his own shoulders, chest, and back area for
( Z8 W: g# O. J, F3 ^& \0 ca year. The father also revealed he was embarrassed; W2 p% s" B1 D. ~
to disclose that he was using a testosterone gel pre-, L% b; I& I$ `1 I9 _
scribed by his family physician for decreased libido0 |; Y9 a0 E9 E& A9 A' J& k& K
secondary to depression.$ f. R8 |$ \4 f' G; K9 }
The child slept in the same bed with parents.
1 |$ G7 g6 j. i) JThe father would hug the baby and hold him on his
2 j6 r# F' O, hchest for a considerable period of time, causing sig-0 p+ p$ E4 P8 ]# Y! l
nificant bare skin contact between baby and father." ]& |8 Y( J% ?! c7 A- y
The father also admitted that after the phone call,0 l/ c8 U9 K  i8 A. T9 b
when he learned the testosterone level in the baby
0 W' L) m; a3 ~8 \( V/ _* v: d; a; `% U  ^0 Vwas high, he then read the product information) b" i1 P: f# m& W
packet and concluded that it was most likely the rea-
- }% L0 u5 p% _2 p0 Xson for the child’s virilization. At that time, they: R( ?3 K/ |: G- Z0 g' `, e
decided to put the baby in a separate bed, and the
# D' ^; D: D& d8 kfather was not hugging him with bare skin and had
) h+ a1 k& g  z3 [: Sbeen using protective clothing. A repeat testosterone
( s7 M6 b1 z1 T) z9 V: p# c5 a3 p3 stest was ordered, but the family did not go to the
8 j6 ]: n: E; y& ~% p, X& Slaboratory to obtain the test.
2 h% Y% w$ F8 h( ~; [( g2 kDiscussion7 K9 s+ _9 U; u$ x) x$ O7 I$ N
Precocious puberty in boys is defined as secondary8 F/ X2 a9 P$ j& I
sexual development before 9 years of age.1,4
: s# Z  G2 k4 R, H5 \* v& ]Precocious puberty is termed as central (true) when) u; k4 ]& {1 s
it is caused by the premature activation of hypo-  O, {4 k' h8 A3 H' U9 l
thalamic pituitary gonadal axis. CPP is more com-
5 ?& o* Y) g: {mon in girls than in boys.1,3 Most boys with CPP
% I+ N# d! z- g* }+ tmay have a central nervous system lesion that is1 T. s/ _9 s$ O! `9 E
responsible for the early activation of the hypothal-6 Z" g1 N$ |' p3 b
amic pituitary gonadal axis.1-3 Thus, greater empha-4 A5 E% y- N# k0 c$ \) F2 p5 o
sis has been given to neuroradiologic imaging in
% w1 }" v4 V8 {; R+ y! ?! jboys with precocious puberty. In addition to viril-! z2 M2 d! y, I  P! t/ [! u
ization, the clinical hallmark of CPP is the symmet-# O, d: j0 n4 w7 Q! q+ K3 v" G
rical testicular growth secondary to stimulation by
* N5 o3 A4 N( c2 C% [  V8 t/ Y  ugonadotropins.1,3
# d, w9 R/ X$ }( `7 j9 VGonadotropin-independent peripheral preco-
; m+ t* L* k. ]8 n; p) `cious puberty in boys also results from inappropriate. P+ P6 P. f3 m
androgenic stimulation from either endogenous or
0 H3 N$ U/ h0 a, @2 bexogenous sources, nonpituitary gonadotropin stim-
$ H, w" r2 L& Tulation, and rare activating mutations.3 Virilizing
9 r9 a& b' A! Mcongenital adrenal hyperplasia producing excessive
. n) T- D7 ~/ }, V1 _4 ^* k6 padrenal androgens is a common cause of precocious
: b  q) N8 l+ ]+ c' s; H. d* g# xpuberty in boys.3,4
* r/ g4 @+ _% l5 w3 _, CThe most common form of congenital adrenal
$ R; Y# J2 S# hhyperplasia is the 21-hydroxylase enzyme deficiency.) U3 e$ j" ?, u" T0 ~; F' V8 g$ v
The 11-β hydroxylase deficiency may also result in  O/ T6 y9 Z, z+ l8 s
excessive adrenal androgen production, and rarely,
5 J$ Y6 r0 {& H4 M# v& o3 }* T: dan adrenal tumor may also cause adrenal androgen5 D* K% S' k" c' \
excess.1,31 U4 w, L1 E' {. z% V! k6 I/ v. {
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from) H' c0 C3 I, q
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007  N/ Q$ z* V" y) h3 d$ _
A unique entity of male-limited gonadotropin-
/ O8 m. l& e0 _$ T; Aindependent precocious puberty, which is also known
' g/ f! y% v% m3 q# q% Cas testotoxicosis, may cause precocious puberty at a
3 R2 F5 ]' d+ overy young age. The physical findings in these boys
& A, h: L% i( S, qwith this disorder are full pubertal development,4 H$ a, {1 \) \2 ?
including bilateral testicular growth, similar to boys
! r+ D* `0 T* H. \6 D4 |with CPP. The gonadotropin levels in this disorder
6 \" I# Z& P2 v1 gare suppressed to prepubertal levels and do not show8 ?* R0 y8 O' ^. s5 J; \8 h
pubertal response of gonadotropin after gonadotropin-, ?( V0 G7 a" n/ |
releasing hormone stimulation. This is a sex-linked. Z4 G6 e: D7 f% M4 m6 r' V
autosomal dominant disorder that affects only& d, p1 n+ w0 P& c# M/ v. I
males; therefore, other male members of the family! f- }& i7 g0 P
may have similar precocious puberty.3- w7 \3 I3 ?3 _# ]' [* D! t4 K
In our patient, physical examination was incon-0 [3 E2 e9 \8 L/ [& q
sistent with true precocious puberty since his testi-
: K) J1 _0 n/ ecles were prepubertal in size. However, testotoxicosis
1 `/ c2 ]$ ~5 \2 z6 }was in the differential diagnosis because his father
5 o1 Y% f8 c* ^/ G; F( Istarted puberty somewhat early, and occasionally,1 X8 b* R3 S' I* L8 W8 p
testicular enlargement is not that evident in the4 f4 _2 Z$ x7 s& h0 g
beginning of this process.1 In the absence of a neg-+ F. W- i9 W7 c9 I* b. Y
ative initial history of androgen exposure, our* w  m2 e1 m- J0 g% ?
biggest concern was virilizing adrenal hyperplasia,9 ~+ m+ M* Y8 @2 u4 B# c
either 21-hydroxylase deficiency or 11-β hydroxylase
, o# _1 X* t( z# Z" K! Hdeficiency. Those diagnoses were excluded by find-: }4 o: e5 {& |8 i# p
ing the normal level of adrenal steroids.
* M, Z0 P+ a$ s" mThe diagnosis of exogenous androgens was strongly
- \4 X6 ^$ s& ]- E  _suspected in a follow-up visit after 4 months because; j, y. |0 W# C$ Z0 z
the physical examination revealed the complete disap-# i7 i' f/ j5 p9 G& ~, ~' `
pearance of pubic hair, normal growth velocity, and
2 u' s" [7 R2 |* X( i  d# W4 `decreased erections. The father admitted using a testos-
( s' s, ]: F8 K3 S$ \8 |terone gel, which he concealed at first visit. He was3 l! B; N* c4 V: Q
using it rather frequently, twice a day. The Physicians’
1 K/ m0 m  a" r3 u/ e1 d, BDesk Reference, or package insert of this product, gel or0 o9 S+ G! V3 `2 h
cream, cautions about dermal testosterone transfer to
7 J0 l8 ^' D8 b' Vunprotected females through direct skin exposure.
% |& [5 }9 b* q6 ~4 l0 X' h* WSerum testosterone level was found to be 2 times the
, k$ R) {% G" |: ^& K  h7 Mbaseline value in those females who were exposed to$ L8 M" \. G$ c+ \" K& x9 c7 V
even 15 minutes of direct skin contact with their male
7 A) X' \' `& X! l6 Q% Epartners.6 However, when a shirt covered the applica-6 [* F3 ^* C% `; ~& a( i8 F! L
tion site, this testosterone transfer was prevented.
6 H% _$ y6 [- `6 s, N  V7 ZOur patient’s testosterone level was 60 ng/mL,, {5 l( a: O, q$ m' N1 E' z
which was clearly high. Some studies suggest that
. S- I3 _0 W9 ]7 y: udermal conversion of testosterone to dihydrotestos-# U1 Z) @( `/ Q3 j+ a
terone, which is a more potent metabolite, is more
, ]/ w2 {. B/ E, zactive in young children exposed to testosterone2 f, j+ N0 O3 }0 W  g1 e4 Z7 q! O
exogenously7; however, we did not measure a dihy-
8 K7 g8 Q& H; Jdrotestosterone level in our patient. In addition to7 Y% G0 r6 Z% ~  i! M
virilization, exposure to exogenous testosterone in# V# V0 a* L7 l: ?+ y8 H9 d& I; X
children results in an increase in growth velocity and/ ]) g8 k* q: X/ [; H$ S
advanced bone age, as seen in our patient.( T& Q6 I# }- K5 ?9 H& J
The long-term effect of androgen exposure during. H7 z3 Y8 l$ e5 Q4 N
early childhood on pubertal development and final
" D. m( }4 q# Z! W. `5 J7 Y: c8 ^adult height are not fully known and always remain
- z$ Z' H# f# t1 ~8 W. `  t* Za concern. Children treated with short-term testos-, I1 }: b( f) J% S# W' N9 E
terone injection or topical androgen may exhibit some: {& L( M! A2 Y% c7 u5 a+ P2 ^0 `
acceleration of the skeletal maturation; however, after
3 W& c! d6 a9 F, A/ I. b, ^' \cessation of treatment, the rate of bone maturation/ K7 |! P3 A: M4 d) g* b; x
decelerates and gradually returns to normal.8,9' z1 _0 o- q. _( }# i
There are conflicting reports and controversy# Z& ]4 s% o/ j* l
over the effect of early androgen exposure on adult
( C  F9 Q9 Q- A2 V3 |8 y( Wpenile length.10,11 Some reports suggest subnormal; R' G0 L# k  b0 B
adult penile length, apparently because of downreg-
. i, v6 d) f' Y: A5 t6 _ulation of androgen receptor number.10,12 However," o8 [0 K" Y+ R" t5 q9 t8 |
Sutherland et al13 did not find a correlation between
, z1 e4 a1 R9 [childhood testosterone exposure and reduced adult
/ L8 d! |1 ^$ L# q2 J! [# D5 cpenile length in clinical studies.; [# n2 c; g4 p: a0 W
Nonetheless, we do not believe our patient is5 T, r, n/ `5 F  q# ~  L% y
going to experience any of the untoward effects from
, f! ?. H" R6 P$ S1 c3 P, n+ O6 k9 S% |testosterone exposure as mentioned earlier because: T: F& @+ V! Y0 d0 R! O
the exposure was not for a prolonged period of time.' M# b: ~3 L& W
Although the bone age was advanced at the time of/ u7 z6 E' `" m3 L) l. d( j
diagnosis, the child had a normal growth velocity at$ D" {' P0 i/ ]. b/ H
the follow-up visit. It is hoped that his final adult
& \* E' D! F( l" l6 I( j: Xheight will not be affected.
9 y# D+ R: |7 o( iAlthough rarely reported, the widespread avail-
. B1 [# M9 M+ v7 t$ l5 Bability of androgen products in our society may, z7 K0 C, E/ I2 n' Q# }. m! Z
indeed cause more virilization in male or female
. r9 A0 N0 S6 ychildren than one would realize. Exposure to andro-1 _/ g" ~  m" }: {
gen products must be considered and specific ques-0 e9 `% ~' E6 A
tioning about the use of a testosterone product or
  C. |5 c7 b% w2 l2 Igel should be asked of the family members during
, v( g5 P0 s! k; Dthe evaluation of any children who present with vir-
  Y+ [' c( n8 _+ }  _5 e& D' Y$ yilization or peripheral precocious puberty. The diag-3 f- S# N4 n6 X3 f
nosis can be established by just a few tests and by
3 }- q* j7 }5 \+ Z  r9 ]6 Xappropriate history. The inability to obtain such a- L# ^; ^* ^1 S. |3 ]
history, or failure to ask the specific questions, may
/ _. h2 ?7 S0 O  a( Vresult in extensive, unnecessary, and expensive& i8 M3 ~0 Q4 ?9 k6 g
investigation. The primary care physician should be1 W) N9 V/ V, _& ~* _1 x
aware of this fact, because most of these children0 M0 w; g! k+ u* i1 ?0 |0 |) r
may initially present in their practice. The Physicians’. q8 R# W  z6 Q9 g, }4 w; P% A
Desk Reference and package insert should also put a, {$ s" r0 T' h% N
warning about the virilizing effect on a male or
! Q- y9 s0 \. b1 Sfemale child who might come in contact with some-
( W5 y5 |4 M/ k- U% Xone using any of these products., x  E3 d9 e& ~8 K# B" H
References
1 P9 A7 A$ U* e" d+ |9 d1. Styne DM. The testes: disorder of sexual differentiation1 A5 K4 M8 p' H) }
and puberty in the male. In: Sperling MA, ed. Pediatric
5 P6 J% s8 [# H; rEndocrinology. 2nd ed. Philadelphia, PA: WB Saunders;6 D7 y& ?4 I. A: Q5 J+ p: ^
2002: 565-628.
. U8 P- E: c& h( J) `2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
: ?! X5 s# |& Y3 K" R/ B4 r4 w" Dpuberty in children with tumours of the suprasellar pineal
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
4个什么样的?
發表於 2025-1-19 02:41:05 | 顯示全部樓層
# h* I& J9 |' z( k# A, c# |# H0 a
精妙絕倫的精品,感謝啊!期待你更多更好的創作哦!
發表於 2025-3-11 12:31:56 | 顯示全部樓層
么好吧v进化过程就回国参加发uft成就和;哦i回来就好v科技股份兄弟人的 路由公开vu个v库每年b
發表於 2025-4-8 11:10:25 | 顯示全部樓層
精妙絕倫的精品,感謝啊!期待你更多更好的創作哦!
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